APRN22 • Advanced Practice Nurses 2022 (Includes 22 Pharmacology Hours)

Table of Contents

APRN22 • Advanced Practice Nurses 2022 (Includes 22 Pharmacology Hours)

How to Receive Credit

NetCE 10 Hour Course #90213 • Diagnosing and Managing Headaches

90213 • Diagnosing and Managing Headaches

1. INTRODUCTION

2. EPIDEMIOLOGY

3. BASIC PATHOPHYSIOLOGY

4. WORK-UP OF HEADACHES

5. PRIMARY HEADACHES

6. SECONDARY HEADACHES

7. ACUTE VERSUS CHRONIC

8. REFERRAL

9. MEDICO-LEGAL ISSUES

10. CONCLUSION

11. ADDITIONAL SOURCES OF INFORMATION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #94453 • Autoimmune Diseases

94453 • Autoimmune Diseases

1. INTRODUCTION

2. OVERVIEW OF AUTOIMMUNE DISEASES

3. THYROIDITIS

4. RHEUMATOID ARTHRITIS

5. SYSTEMIC LUPUS ERYTHEMATOSUS

6. SJÖGREN SYNDROME

7. CELIAC DISEASE

8. CASE STUDY

9. ONLINE PATIENT EDUCATION RESOURCES

10. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 5 Hour Course #98720 • Bacterial Sexually Transmitted Infections

98720 • Bacterial Sexually Transmitted Infections

1. INTRODUCTION

2. EPIDEMIOLOGY

3. GENERAL STI ASSESSMENT AND PREVENTION COUNSELING

4. BARRIER AND NONBARRIER APPROACHES TO PREVENT OR REDUCE STI TRANSMISSION AND INFECTION

5. SCREENING

6. DIAGNOSTIC TESTING

7. PARTNER SERVICES

8. GENERAL TREATMENT CONSIDERATIONS

9. CHLAMYDIA

10. GONORRHEA

11. SYPHILIS

12. LYMPHOGRANULOMA VENEREUM

13. BACTERIAL VAGINOSIS

14. EPIDIDYMITIS

15. RARE AND EMERGING BACTERIAL STIS

16. GENERAL MANAGEMENT ISSUES

17. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

APRN22 • Advanced Practice Nurses 2022 (Includes 22 Pharmacology Hours)

John J. Whyte, MD, MPH

Lori L. Alexander, MTPW, ELS, MWC

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

APRN22 • Advanced Practice Nurses 2022 (Includes 22 Pharmacology Hours)

Expiration Date: 01/31/2023

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

90213 • Diagnosing and Managing Headaches

John J. Whyte, MD, MPH

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Headaches are considered one of the most common types of pain and one of the most frequent causes of presentation to physician offices and clinics. Millions of adults seek treatment from physicians each year related to headache pain. As a result, headaches represet a significant cause of morbidity. It has been estimated that headaches result in billions of dollars in expenses, job absenteeism, and decreased annual productivity. They also result in decreased quality of life. Coping with a chronic headache disorder may predispose the individual to other illnesses. For example, depression is three times more common in people with migraine or severe headache than in healthy individuals. A clear understanding of the types and causes of headache pain is essential for physicians and other healthcare providers to adequately address and manage the patient with headaches.

Table of Contents

90213 • Diagnosing and Managing Headaches

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. EPIDEMIOLOGY

ECONOMICS

3. BASIC PATHOPHYSIOLOGY

TYPES OF HEADACHES

4. WORK-UP OF HEADACHES

ASSESSING HEADACHES IN PATIENTS WITH THE ASSISTANCE OF AN INTERPRETER

HISTORY

PHYSICAL EXAM

WARNING SIGNS OF SIGNIFICANT DISEASE

LAB STUDIES

ELECTROENCEPHALOGRAM

LUMBAR PUNCTURE

IMAGING

5. PRIMARY HEADACHES

MIGRAINE HEADACHES

CLUSTER HEADACHES

TENSION HEADACHES

OTHER PRIMARY HEADACHES

6. SECONDARY HEADACHES

TRAUMATIC CAUSES OF HEADACHES

VASCULAR HEADACHES

NEOPLASTIC CAUSES OF HEADACHES

INFECTIOUS CAUSES OF HEADACHES

PRESSURE HEADACHES

METABOLIC/TOXIC CAUSES OF HEADACHES

OTHER CAUSES OF SECONDARY HEADACHES

7. ACUTE VERSUS CHRONIC

8. REFERRAL

9. MEDICO-LEGAL ISSUES

10. CONCLUSION

11. ADDITIONAL SOURCES OF INFORMATION

Works Cited

Evidence-Based Practice Recommendations Citations

90213 • Diagnosing and Managing Headaches

Education Category. Medical / Surgical

Release Date. 09/01/2019

Review Date. 04/01/2022

Expiration Date. 08/31/2023

Course Overview

Headaches are considered one of the most common types of pain and one of the most frequent causes of presentation to physician offices and clinics. Millions of adults seek treatment from physicians each year related to headache pain. As a result, headaches represet a significant cause of morbidity. It has been estimated that headaches result in billions of dollars in expenses, job absenteeism, and decreased annual productivity. They also result in decreased quality of life. Coping with a chronic headache disorder may predispose the individual to other illnesses. For example, depression is three times more common in people with migraine or severe headache than in healthy individuals. A clear understanding of the types and causes of headache pain is essential for physicians and other healthcare providers to adequately address and manage the patient with headaches.

Audience

This course is designed for physicians and will be of interest to nurses, pharmacists, and other medical personnel who may encounter patients who complain of headaches.

Course Objective

Given the common and difficult diagnoses associated with headaches, the purpose of this course is to educate the healthcare professional about the epidemiology and treatment of the various types of headaches so they may make early and accurate diagnoses, begin effective treatment, and/or refer patients to a specialist when necessary.

Learning Objectives

Upon completion of this course, you should be able to:

1. Illustrate the epidemiology and economic impact of headaches.

2. Demonstrate the pathophysiology of headaches.

3. Recognize the signs and symptoms of headaches, focusing on history and physical exam, and discuss the role of an interpreter in assessing non-English-proficient patients.

4. Identify the appropriate imaging modalities for headaches and their specific indications.

5. Describe the epidemiology, diagnosis, and treatment of migraine headaches.

6. Differentiate the signs and treatments for cluster and tension headaches.

7. Identify the secondary causes of headaches.

8. Compare and contrast the differences between acute and chronic headaches.

9. Recognize indications for specialist referral.

10. Analyze medico-legal issues surrounding headache diagnosis and management.

Faculty

John J. Whyte, MD, MPH, is currently the Chief Medical Officer at WebMD. In this role, he leads efforts to develop and expand strategic partnerships that create meaningful change around important and timely public health issues. Previously, Dr. Whyte was the Director of Professional Affairs and Stakeholder Engagement at the FDA’s Center for Drug Evaluation and Research and the Chief Medical Expert and Vice President, Health and Medical Education at Discovery Channel, part of the media conglomerate Discovery Communications.
Prior to this, Dr. Whyte was in the Immediate Office of the Director at the Agency for Healthcare Research Quality. He served as Medical Advisor/Director of the Council on Private Sector Initiatives to Improve the Safety, Security, and Quality of Healthcare. Prior to this assignment, Dr. Whyte was the Acting Director, Division of Medical Items and Devices in the Coverage and Analysis Group in the Centers for Medicare & Medicaid Services (CMS). CMS is the federal agency responsible for administering the Medicare and Medicaid programs. In his role at CMS, Dr.Whyte made recommendations as to whether or not the Medicare program should pay for certain procedures, equipment, or services. His division was responsible for durable medical equipment, orthotics/prosthetics, drugs/biologics/therapeutics, medical items, laboratory tests, and non-implantable devices. As Division Director as well as Medical Officer/Senior Advisor, Dr. Whyte was responsible for more national coverage decisions than any other CMS staff.
Dr. Whyte is a board-certified internist. He completed an internal medicine residency at Duke University Medical Center as well as earned a Master’s of Public Health (MPH) in Health Policy and Management at Harvard University School of Public Health. Prior to arriving in Washington, Dr. Whyte was a health services research fellow at Stanford and attending physician in the Department of Medicine. He has written extensively in the medical and lay press on health policy issues.

Faculty Disclosure

Contributing faculty, John J. Whyte, MD, MPH, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Abimbola Farinde, PharmD, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Headaches are considered one of the most common types of pain and one of the most frequent causes of presentation to physician offices and clinics. Nearly 50 million adults seek treatment from physicians each year related to headache pain [1,2]. As a result, headaches represent a significant cause of morbidity. It has been estimated that headaches result in billions of dollars in expenses, job absenteeism, and decreased annual productivity. They also result in decreased quality of life. Coping with a chronic headache disorder may predispose the individual to other illnesses. For example, depression is three times more common in people with migraine or severe headache than in healthy individuals [3]. A clear understanding of the types and causes of headache pain is essential for physicians and other healthcare providers to adequately address and manage the patient with headaches.

Headaches may be categorized as either primary or secondary. Most headaches are primary in origin—this includes migraine, cluster, and tension headaches. Secondary headaches, which are secondary to another cause (e.g., trauma, infections) are fewer in number; however, because most of the secondary causes have been well studied, secondary headaches generally can be effectively treated. Before assuming a diagnosis of primary headache, it is necessary to rule out headaches secondary to an underlying cause. It is important to keep in mind that malignancy is fairly unusual, even though anecdotal reports of individuals who have been diagnosed with a brain tumor following a headache abound. Many imaging technologies have become available to help in the diagnosis of headaches. These include computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and nuclear medicine studies. It is important that physicians understand the indications and limitations of each test so that patients are not put through unnecessary and/or costly procedures.

Several therapies exist to treat headaches. These include pharmacologic medications and nonpharmacologic interventions (e.g., alternative medicines and therapies). There are also new approaches to preventing headaches for those patients who are experiencing chronic headaches. Physicians and other clinicians should familiarize themselves with the latest evidence regarding diagnosis and management of headaches. International Headache Society (IHS) diagnostic criteria have been used throughout this course; however, it should be noted that changes to these specific criteria may be made in the future.

The following case study will be referenced throughout the text to illustrate the challenges of treating a patient who presents with a headache.

Mrs. T is an African American woman, 68 years of age, with a past medical history significant for type 2 diabetes, hypertension, hyperlipidemia, osteoarthritis, and coronary artery disease. She presents to the clinic with a chief complaint of "headache." Mrs. T describes the headache as a dull pain that has been intermittent over the past several weeks. It is not localized to any particular area, but rather seems to be more diffuse. It does not radiate to the neck, back, or any other parts of the body. It first started about a month ago.

She has taken ibuprofen and aspirin sporadically with some relief. As the headache has been persistent over the past few weeks, she thought it was important to come in and be evaluated. She states that she has been looking up information on headaches on various health websites and she now thinks she needs a "brain scan." She has no prior history or family history of migraines; she does report a history of what she considers to be some tension-type headaches in the past few years. She believes these are due to stress at work, as they usually resolve within a day with relaxation, rest, and ibuprofen. She has never been evaluated for these episodes. The patient also remarks that over the past several days she has occasionally felt a little dizzy and light-headed, but those symptoms have largely resolved. She denies any confusion or loss of consciousness, but her daughter, who accompanies her to the clinic, states that Mrs. T had an episode about a week ago where she seemed disoriented in the morning for approximately an hour. According to the daughter, "Lately, Mom sometimes seems in a fog."

2. EPIDEMIOLOGY

Almost everyone experiences a headache at some point in their life. In fact, approximately three-fourths of all adults in the United States experience some type of headache each year. The prevalence of headache varies by gender, with women having a greater incidence of headaches than men. It has been estimated that nearly nine out of ten women, and seven out of ten men, have a headache at least once during her/his lifetime [4]. In developed countries, tension-type headache is more common in women, usually by a factor of about two to one [3].

In the overwhelming majority of cases, headaches are transient and benign. People simply treat the headache with either rest and/or relaxation, or they utilize various over-the-counter analgesics. In fact, the public spends more than $2 billion annually on over-the-counter medications to treat headaches [5]. Less than 5% of adults with headaches actually seek medical attention. Even with this small percentage, however, headaches are one of the most common complaints addressed by primary care physicians and clinicians and represent the reason for nearly 3% of all visits to the emergency department [1].

People typically seek medical care when they have increased headache frequency, an unusually intense headache, or persistent symptoms. Headaches can be one of the most difficult and challenging disorders to accurately diagnose and treat, so it is important for physicians and other clinicians to become familiar with the latest evidence on headache diagnosis and management.

ECONOMICS

Headaches are a costly condition. It has been estimated that headaches are responsible for nearly 30 million days of lost productivity, both in terms of lost days at work, as well as decreased effectiveness while at work. Headaches cost an estimated $18 billion in both direct and indirect expenditures yearly. Most costs are indirect as the majority of headache sufferers do not seek medical attention [2,7,8,9].

Although migraine is more disabling than tension-type headache, tension-type headache is more common. Each year, more than 70% of the global population has episodic tension-type headache and 1% to 3% has chronic tension-type headache (i.e., headache occurring at least 15 days per month). The World Health Organization (WHO) has confirmed that the problem of lost productivity in the workplace is worldwide, with headache disorders being the third most common cause of years lost to disability and migraine alone being the sixth most common cause [2,3,6,10].

Headaches also represent a significant socioeconomic burden. Along with lost and reduced work, headaches also affect other activities, such as one's ability to perform effectively in school or enjoy time with family and friends. In essence, headaches reduce the quality of life.

3. BASIC PATHOPHYSIOLOGY

The pathophysiology of headaches is multifactorial and complex. When lesions of the brain cause headache (e.g., mass, fluid, hemorrhage), they do so by involving pain-sensitive structures inside the skull, such as arteries at the base of the brain, the dura area blood vessels, and certain cranial nerves (e.g., CN V, VII, IX, X) that carry pain fibers. In addition, the external structures of the head are all pain-sensitive and give rise to a variety of headaches.

TYPES OF HEADACHES

As noted, headaches may be categorized as either primary or secondary in nature. Primary headaches are pure headache syndromes, meaning they are self-originating and not triggered or produced by other disorders. Primary headaches include migraine, cluster, and tension-type headaches [11]. Nearly 90% of all headaches are primary in nature [12]. Although migraine headaches receive a great deal of press in medical and lay literature, of the primary headaches, tension-type is the most common, followed by migraines, and then cluster [13]. It is important to note that primary headaches are diagnosed only when other underlying disease processes have been eliminated.

Secondary headaches, as the name indicates, occur secondary to another cause (i.e., they are a symptom of other diseases). These may include vascular, traumatic, neoplastic, infectious, pressure, and metabolic disorders [11]. Secondary headaches account for only 10% of headaches. Although some causes of secondary headache are common, others are important to recognize because they are dangerous and may require specific treatment [12]. For example, patients with chronic tension headaches may present with an epidural hematoma, and patients with migraine may actually have a brain tumor. Primary and secondary headaches should not be considered mutually exclusive when evaluating a patient with headache. It is helpful to consider secondary headaches in terms of etiologic categories. Some of the more common causes of secondary headaches are as follows [13]:

Traumatic

- Epidural hematoma

- Subdural hematoma

Vascular

- Subarachnoid hemorrhage

- Giant cell arteritis

- Arterial dissection

- Stroke

Neoplastic

- Primary brain tumor

- Metastatic brain tumor

Infectious

- Meningitis

- Encephalitis

- Sinusitis

- Abscess

Pressure

- Hypertension

- Idiopathic intracranial hypertension

Metabolic

- Toxic ingestions (e.g., carbon monoxide, lead poisoning)

Other

- Syringomyelia

- Dental and myofascial

- Cervicogenic

- Medication overuse

- Herbal medications

4. WORK-UP OF HEADACHES

The work-up of headaches includes the patient's history and a thorough physical examination and may also include laboratory studies, imaging procedures, and a lumbar puncture.

ASSESSING HEADACHES IN PATIENTS WITH THE ASSISTANCE OF AN INTERPRETER

As a result of the evolving demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient history is such a vital aspect of the assessment of headaches, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Many view interpreters merely as neutral individuals who communicate information back and forth. However, another perspective is that the interpreter is an active agent, negotiating between two cultures, and assisting in promoting culturally competent communication and practice [15]. Interpreters who are professionally trained have covered aspects of ethics, impartiality, accuracy, and completeness [16]. They are also well-versed in interpreting both the overt and the latent content of information without changing any meanings and without interjecting their own biases and opinions [16]. Furthermore, knowledge about cross-cultural communication and all the subtle nuances of the dynamics of communicating in a mental health or general health setting is vital [17].

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. In any case in which information regarding diagnostic procedures, treatment options, and medication/treatment measures is being provided, the use of an interpreter should be considered.

HISTORY

As with any disease, history-taking is critical in determining the correct diagnosis. The goals of history taking are to classify the headache type(s) and screen for secondary headache. An inadequate history is the probable cause of most misdiagnoses of the headache type [11,18,19].

It is important to focus on the following characteristics when interviewing a patient who presents with a headache [13,20]:

Position/Location

- Where on the head does the pain occur?

- Is the headache unilateral or bilateral?

- Does the pain radiate anywhere (e.g., neck, back, jaw)?

- Is the face involved?

Quality/Character

- What does the headache feel like? Is it pounding, throbbing, aching, piercing, squeezing, etc.?

- How intense is the headache on a scale of 1 to 10? Is it mild, moderate, severe, or incapacitating? Is it the worst headache one has ever had?

Frequency/Duration

- How often do the headaches occur?

- How long do they last?

- What time of day do the headaches occur?

- What time of year do the headaches occur?

- If the headaches are recurrent, what is the interval between headaches?

- What is the minimum, maximum, and usual duration?

- How long has this particular type of headache been affecting the patient?

Associated Factors

- Is there a fever?

- Any nausea, vomiting, congestion, flushing, arthralgia, depression, weight loss, etc.?

- Is there photophobia?

- Any neck stiffness?

- Any dental problems?

Aggravating Factors

- What makes the headache worse?

- Does head or body position make the headache better?

- Does coughing, sneezing, or bending affect the headache?

- Is the headache associated with menses?

Alleviating Factors

- What makes the headache better?

- Does ice or compression minimize the headache?

- Does a dark, cool room make it better?

- How does movement affect the headache?

- What types of medications have been tried? Have they been effective?

Environmental Exposures

- How does the environment affect the headache? For example, does exposure to bright light, loud noises, odors, cigarette smoke, temperature, foods, or alcohol affect the headache?

- Does the patient work around any metals or an industrial plant?

Associated Neurologic Symptoms

- Any visual, sensory, or motor abnormalities?

- Any dizziness or confusion?

- Any loss of consciousness?

- Is there any weakness?

- Does the patient exhibit ataxia?

Current and Past Medical History

- At what age did headaches first occur?

- What other medical conditions does one currently have (e.g., coronary artery disease, hypertension, depression, psychiatric disorder)?

- What are the current medications, including over-the-counter medications as well as supplements and herbal medicines? Is caffeine ingested on a regular basis?

- What medications have been recently terminated?

- Any recent trauma?

- Any recent falls?

Family History

- Does anyone else in the family have these types of headaches?

- Do any diseases or other medical conditions (e.g., cancer, stroke, diabetes, hypertension) run in the family?

Social History

- How are matters at home and at work?

- Is there any significant current stress?

- Are any illicit drugs used?

- Does the patient engage in unprotected sexual intercourse? In the past?

The above sample list of questions may seem daunting, especially in the context of a brief office visit. However, it is critical that a detailed history be obtained. It may be more efficient to have a questionnaire available for patients to fill out while they are waiting, or even prior to the office visit.

Upon further questioning, Mrs. T denies any fever, nausea, or vomiting. She denies depression or weight loss. She has not had visual disturbances. She does not recall any environmental exposures. Her current medications include metformin, lisinopril, simvastatin, and celecoxib. She remarks that her job is going quite well, and she does not feel particularly stressed from work. She works as a senior account manager at a consulting firm.

She has not had any change in medications and does not use any herbs or supplements. She drinks two cups of coffee a day, and there has been no recent change in her coffee consumption. There is neither family history of headaches nor family history of cancer. Both parents died of heart disease. She does note that she recently tripped and fell outside (almost a month ago) while playing with her grandson, but denies any serious consequences from the fall other than a sore left wrist. She denies any residual weakness. She notes that she does not feel "quite 100%" but does not feel confused or "in a fog."

PHYSICAL EXAM

A thorough physical exam is necessary for all patients who present to either the physician's office or the emergency department with a headache. The goal of the history and physical evaluation is to rule out findings that may suggest a headache of secondary pathology [13,18,19,20,21,22]. All parts of the physical exam are important, but consider paying particular attention to the following:

- Vital signs: Carefully check blood pressure, respirations, heart rate, and temperature. Determine whether the patient is orthostatic.

- Skin: Observe color and texture, and carefully inspect for any rashes, petechiae, bruising, or lesions.

- Head, eyes, ears, nose, and throat (HEENT): Note the size, symmetry, and shape of the head. Inspect for bruises, masses, and/or nodules while palpating the head and neck. Palpate the temporal arteries. Be sure to auscultate for bruits over the scalp, eyes, and carotids. Assess the temporomandibular joint for clicking. Check for nuchal rigidity. Palpate the thyroid gland. Determine any decreased arterial pulsations. Check for sinus tenderness, especially frontal and maxillary areas.

- Eyes: Check visual function and extra-ocular movements, specifically looking for ptosis or miosis. Perform funduscopy to evaluate disc margins, papilledema, and any evidence of retinal hemorrhages.

- Oral cavity: Check for decay, abscesses, loose teeth, etc.

- Cardiac: Listen carefully for murmurs or abnormal heart sounds.

- Extremities: Assess thoroughly range of motion.

- Neurologic: Assess all cranial nerves, muscle strength, reflexes, and cerebellar function. Consider performing the Mini-Mental Status Exam.

WARNING SIGNS OF SIGNIFICANT DISEASE

Although most headaches are benign, clinicians should be aware of the following "red flags" or warning signs that should prompt an immediate and exhaustive work-up and possible referral to an appropriate specialist for further assessment [5,13,20,21,23]:

- Onset in or after middle age (>50 years of age)

- Sudden onset, rapid time to peak headache intensity (i.e., seconds to five minutes)

- First or worst sudden, severe headache

- Accelerating pattern, progressively worsening

- Fever

- Seizure

- Change in level of consciousness

- Abnormal neurologic, physical, or systemic findings

- New headache in patients with cancer, immunosuppression, or pregnancy

On physical exam, Mrs. T's blood pressure is 135/82 mm Hg, heart rate is 78 BPM, respirations are 18/minute, temperature is 98 degrees, height is 5'5", and weight is 135 lbs. The physical exam is largely unremarkable. There are no masses appreciated, no petechiae noted, no sinus pain or tenderness, no scalp tenderness, and no neck stiffness. There are no visual defects and no focal neurologic deficits with the exception of minimal decrease in muscle strength in lower extremities bilaterally. She scored a 26 (maximum score: 30) on the Mini-Mental Status Exam, with some difficulty remembering three objects as well as performing serial 7s.

Given the patient's age and the fact that the headache has been persistent, a clinician should order a more extensive work-up. The patient seems to be dismissive of the minor fall, but this should be explored further. Although it would be easy to attribute this headache complaint to a tension-type headache, secondary causes should be excluded.

LAB STUDIES

In general, most headache diagnoses will be made based upon the history and physical exam [13,20]. However, laboratory studies may aid in the diagnosis. For example, clinicians may want to measure basic serum chemistries, complete blood count with differential, liver function tests, and thyroid function tests. These tests will provide a general overview of the patient's health and help guide diagnosis and treatment choices.

A resting electrocardiogram (EKG) should be considered if the history or cardiac exam is abnormal or if the patient has signs of an arrhythmia. Some headaches may have a cardiac etiology, and some treatments for headaches may have an impact on cardiac function.

Mrs. T's laboratory tests are as follows:

Na 138; Cl 100; K 4.0; CO_2 26; BUN 15; Creatinine 0.9; Glucose 125; Hgb 12.5; Hct 38; WBCs 5,000; Platelets 200,000; TSH 0.9; T3 120; ALT 30; AST 32; Alk phos 70; Total bili 1.0; LDH 120; GGT 22; ESR 35

EKG: normal sinus rhythm at 78 BPM; left axis deviation; evidence of old anterior infarct. No acute changes.

ELECTROENCEPHALOGRAM

Electroencephalogram (EEG) is not frequently used and not recommended in the routine work-up of headaches. It has minimal value in determining any structural causes of headaches. It may be useful, however, when patients present with encephalopathy, focal neurologic deficits, atypical aura symptoms, or altered consciousness [21,22,24].

LUMBAR PUNCTURE

In general, lumbar puncture is indicated when there is clinical suspicion of central nervous system (CNS) infection, cancer, hemorrhage, or conditions that result in a change in cerebrospinal fluid (CSF) pressure; it is not recommended in the routine evaluation of headaches [13,21,23]. Examples of indications include meningitis, encephalitis, idiopathic intracranial hypertension, meningeal carcinomatosis, or subarachnoid hemorrhage [5,25]. If an intracranial mass lesion is suspected, or if the patient has papilledema on funduscopic exam, lumbar puncture should be deferred until after CT evaluation to reduce the possibility of cerebellar herniation [23,25,26].

When lumbar puncture is performed, it is helpful to measure the opening pressure and perform a complete analysis of CSF, including glucose, protein, and differential blood count. In addition, opening pressure, supernatant color, and latex agglutination are sometimes useful. CSF examination is helpful in diagnosing subarachnoid bleeding, infection, and high and low CSF pressure syndromes [27]. It is important to avoid a traumatic tap. Such a tap, which leads to bleeding, could make it more difficult in establishing the diagnosis of subarachnoid hemorrhage [5]. In addition, the procedure itself may actually cause a headache [28,29]. This usually occurs 48 to 72 hours following the procedure if too much fluid has been removed [30].

IMAGING

In general, routine neuroimaging, such as CT, MRI, MRA, or positron emission tomography (PET), of people with headaches and normal physical examinations has a very low yield and is not considered to be cost-effective. However, it is important to remain cognizant of the strengths and weaknesses of each imaging modality when considering and ordering such studies [31,32]. MRI may be more sensitive than CT for identifying clinically insignificant abnormalities. However, MRI may not be more sensitive for identifying clinically significant pathology that is relevant to the cause of headache [22].

CT scans may be performed either with or without contrast. Unless there is a contraindication to the use of contrast agents, most scans are performed with contrast in the diagnostic work-up of headaches. A contrast-enhancing CT scan can be an effective test for identifying several serious lesions that may be causing headaches [33,34].

Evidence Based Practice Recommendation

According to the American College of Radiology, the imaging mode of choice for patients who present with sudden onset of severe headache ("worst headache of one's life" or "thunderclap headache") is CT without contrast.

https://acsearch.acr.org/docs/69482/Narrative

Last Accessed: April 5, 2022

Level of Evidence: Expert Opinion/Consensus Statement

CT is usually obtained in the setting of trauma or the abrupt onset of headache [27]. Primary indications include acute head trauma, suspected acute intracranial hemorrhage, mental status changes, headache, acute neurologic deficits, suspected intracranial infection or hydrocephalus, brain herniation, and suspected mass tumor. It may also be used in cases in which MRI is primarily indicated but unavailable, contraindicated, or delayed [34].

In general, CT scans are widely available, quickly performed, and well-tolerated by patients. The technology has been around for quite some time, and most patients are familiar with it [34]. In addition, there are "open" CT scanners that help minimize the feeling of claustrophobia some patients experience. This scan detects most space-occupying lesions such as brain tumors, subdural hematomas, and CNS abscesses. It can also show fluid from hydrocephalus and cerebral edema, and it can reveal bleeding and structural abnormalities such as some arteriovenous malformations. However, CT scanning can miss aneurysms, and it also does not provide adequate views of the sphenoid sinus. Adding "bone windows" on CT provides much better detection of skull fractures, especially as compared to plain films.

MRI is the diagnostic test of choice for most patients [27]. However, it is not as readily available as CT [34]. MRI is more sensitive for detecting lesions within the posterior fossa (specifically because of bony artifacts that limit CT's visualization), pituitary area, paranasal sinuses, and leptomeninges [34,35]. It has also proven effective in identifying some otherwise occult tumors and infarcts. MRI is also more sensitive for detecting vascular abnormalities, although it is not as sensitive as CT in revealing early subarachnoid bleeding. In addition, special MRI images can evaluate problems with the orbit or optic nerve areas. When abnormalities of the cervical spine are suspected, MRI is the preferred imaging technique, especially compared to plain films. "Open" MRI scanners may be used to help diminish claustrophobia or to accommodate obese patients [34].

MRA is essentially an MRI of the blood vessels. MRA can be useful when suspecting circulatory causes of headache. For example, it provides increased sensitivity for unruptured aneurysms, as well as arterial stenosis. It is rarely useful, however, as a first-line study but rather helps to determine who may ultimately require an angiogram. This technology is not universally available. Many institutions also lack the appropriate staff for this procedure [32].

Plain films are rarely useful for diagnosing the etiology of headache unless CT and MRI are unavailable [34]. These films can demonstrate bony defects, such as fractures or other skeletal abnormalities, but usually there are others sources to obtain this data. In addition, the use of plain films for most cases of sinusitis is not usually cost effective in the work-up of headaches. In some institutions, nuclear medicine brain scans, or PET imaging scans, have been used with success as an ancillary procedure.

The choice of a specific imaging study depends on numerous factors, including clinical suspicion, availability of a given test, time necessary to perform the test, and the amount of time available to make a treatment decision. A patient should not undergo a test simply because it is available, but rather the information obtained from an imaging study should impact decision making. Ideally, one wishes to avoid additive tests, such as a situation in which an MRI is a better study (e.g., for posterior fossa infarcts), but a CT is ordered because it is more rapidly available.

The U.S. Headache Consortium has issued guidelines relating to neuroimaging in patients with nonacute headache. The guidelines include three consensus-based general principles of management [22]:

- Testing should be avoided if the test results will not lead to a change in management.

- Testing is not recommended if the individual is not significantly more likely than anyone else in the general population to have a significant abnormality.

- Testing that normally may not be recommended as a population policy may make sense at the individual level, resources notwithstanding. For example, exceptions might be made for patients who are disabled by their fear of serious pathology.

The Consortium additionally has issued the following specific recommendations regarding neuroimaging [22]:

- Neuroimaging should be considered in patients with nonacute headache and an unexplained abnormal finding on the neurologic exam.

- Neuroimaging is not usually warranted for patients with migraine and normal neurologic examination. For patients with atypical headache features or patients who do not fulfill the strict definition of migraine, or have some additional risk factor(s), a lower threshold for neuroimaging may be applied.

Relating to CT and MRI, the panel did find that MRI appears to be more sensitive in finding white matter lesions and developmental and/or venous anomalies than CT. However, it noted that this difference had little clinical relevance, and thus did not make any recommendations on preferred testing methods in the evaluation of headaches [22].

5. PRIMARY HEADACHES

As noted earlier, there are three types of primary headaches: migraine, cluster, and tension-type (Table 1).

Table 1: CHARACTERISTICS OF PRIMARY HEADACHES

Characteristics

Migraine

Cluster

Tension

Position

Unilateral

Unilateral

Bilateral

Quality

Throbbing, pulsating, pounding; moderate to severe

Burning, piercing, sharp; severe

Tightness, aching, pressure; mild to moderate

Radiation

None

None

None

Duration

4 to 72 hours

15 to 180 minutes

30 minutes to seven days

Triggers

Foods, oversleeping, stress, depression, decreased barometric pressure, hormonal variations, caffeine withdrawal

Alcohol, change in temperature, breezes on the face, a change in physical, mental, or emotional activity

Stress

Associated symptoms

Nausea, vomiting, photophobia

No nausea, vomiting, or photophobia

No nausea/vomiting; occasional photophobia or phonophobia

Therapies

Lifestyle modification, biofeedback, acupuncture, medications, exercise, consistent sleep schedule

100% oxygen, medications

Hot/cold packs, ultrasound, exercise, consistent sleep schedule, medications

Source: Compiled by Author

MIGRAINE HEADACHES

A migraine is a type of neurovascular headache that is initiated by a neurologic event that causes vasodilation, which in turn is interpreted by the brain as pain. It is important to realize that the event that initiates this cascade is not dilation of the blood vessels in the brain but rather a primary neural event. The exact neural event that is occurring is not completely understood, but it seems to involve the dysfunction of an ion channel in the brain stem that normally controls sensory input and exerts influences on cranial vessels [36]. Migraine is believed to have a genetic basis [3].

Adults with migraine headache describe episodic attacks with pain of moderate-to-severe intensity that are often throbbing in quality, unilateral in position, and aggravated by physical exertion. Migraines are usually associated with nausea, vomiting, and sensitivity to light and sound. Nausea is the most common characteristic. The duration of these attacks, when not treated, may last anywhere from 4 to 72 hours [3].

The prevalence of migraine headache in developed countries is in the range of 16% to 25%, with women approximately two to three times more likely to have migraines than men [3,6,37]. In children, however, prevalence is equal between males and females. It is during adolescence that a female predominance occurs. The incidence of migraine is highest among individuals 35 to 45 years of age, but it may affect much younger people, including children [3,38]. The prevalence of migraine in children has increased in the past 20 to 30 years. Environmental factors may precipitate migraine attacks in persons with a predisposition to migraine [38].

Data from the American Migraine Study II showed that the overall prevalence of migraine was higher in whites than in blacks, highest in middle life, and inversely related to household income. The frequency of severe headache was similar for males and females, with 62% reporting one or more severe headaches per month, and 36.8% reporting one to three severe headaches per month. The results of this and other studies have also indicated that the burden of migraine in the United States remains substantial (more than $13 billion per year) due to misdiagnosis, underdiagnosis, and improper treatment [37,38,39,40,41].

A study published in 2003 has suggested the use of the following three screening questions to identify migraine sufferers. A "yes" response to two of the questions can effectively identify patients who have true migraines [42]:

- Has a headache limited your activities for a day or more in the last three months?

- Are you nauseated or sick to your stomach when you have a headache?

- Does light bother you when you have a headache?

Although this set of questions has been validated, more studies are still necessary to determine its general applicability. It may be helpful, however, in identifying complicated cases. Additionally, the IHS has incorporated the criteria into their guidelines.

Migraine headaches are essentially a syndrome with a range of neurologic and non-neurologic characteristics. They are classified into two major categories (Table 2 and Table 3):

- Migraine without aura

- Migraine with aura

These were formerly referred to as "common" and "classic" migraines [43].

Table 2: CRITERIA FOR DIAGNOSIS OF MIGRAINE WITHOUT AURA

At least five attacks with the following characteristics:

1. Episodic attacks of headache lasting 4 to 72 hours

2. At least two of the following headache characteristics:

- Unilateral location

- Throbbing or pulsating quality

- Pain of moderate or severe intensity

- Aggravated by or causing avoidance of routine physical activity

3. At least one of the following symptoms during headache:

- Nausea

- Vomiting

- Photophobia

- Phonophobia

4. Not better accounted for by another diagnosis

Source: [43]

Table 3: CRITERIA FOR DIAGNOSIS OF MIGRAINE WITH AURA

At least two attacks not better accounted for by another diagnosis (particularly transient ischemic attack) fulfilling two criteria:

1. One or more of the following fully reversible aura symptoms:

- Visual

- Sensory

- Speech and/or language

- Motor

- Brainstem

- Retinal

2. At least two of the following four characteristics:

- At least one aura symptom spreads gradually over five or more minutes and/or two or more symptoms occur in succession.

- Each individual aura symptom lasts 5 to 60 minutes.

- At least one aura symptom is unilateral.

- The aura is accompanied, or followed within 60 minutes, by headache.

Source: [43]

Migraines without aura are migraine headaches without an associated neurologic disturbance. Typical characteristics include headache of unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea and/or photophobia and phonophobia. These are the most common type of migraine, accounting for nearly 80% of migraines. They have a higher average attack frequency and are usually more disabling than migraine with aura [43].

Migraines with aura, seen in approximately 15% to 20% of patients with migraine, are preceded or accompanied by transient focal neurologic symptoms that usually develop gradually over 5 to 20 minutes and last for less than 60 minutes [43]. Aura symptoms may be sensory, motor, or visual but most commonly present as visual symptoms. The visual symptoms tend to manifest as scintillating scotomata, such as flashing lights, zigzags of light, and small blind spots [13]. On average, they last 20 to 30 minutes.

Premonitory symptoms occur hours to a day or two before a migraine attack (with or without aura). They include various combinations of fatigue, difficulty in concentrating, irritability, neck stiffness, sensitivity to light or sound, nausea, blurred vision, yawning, and pallor. The IHS has recommended that the terms "prodrome" and "warning symptoms" be avoided because they are often mistakenly used to include aura [43]. Migraines with aura have been additionally subdivided into typical migraine, migraine with brainstem aura, hemiplegic migraine, and retinal migraine [43]. Additional types of migraines include episodic syndromes that may be associated with migraine, chronic migraine, complications of migraine, and probable migraine [43].

Familial hemiplegic migraine (FHM) is a type of hemiplegic migraine that is often earlier in onset than typical migraine, frequently beginning in the first or second decade. These attacks are characterized by visual disturbance, dysphasia, and severe unilateral weakness and may also be accompanied by unilateral numbness of the face, arms, and legs. The attacks tend to be prolonged and may last for hours or days [43,44]. The diagnosis of FHM requires at least one affected first-degree or second-degree relative, and most individuals diagnosed with FHM have an affected parent [44]. Three subtypes of FHM have been identified: FHM1, FHM2, and FHM3 [44]. In approximately 50% of FHM1 families, chronic progressive cerebellar ataxia occurs independently of the migraine attacks. FHM is often mistaken for epilepsy and (unsuccessfully) treated as such [43]. Molecular genetic testing is available for the three genes known to be associated with FHM [44]. In many cases, FHM1 additionally has brainstem symptoms [43].

Sporadic hemiplegic migraine is migraine with aura including motor weakness but no affected first- or second-degree relative. Sporadic cases occur with approximately the same prevalence as familial cases and have similar clinical characteristics. Sporadic cases require neuroimaging and other tests to rule out other cause. A lumbar puncture is also necessary to rule out pseudomigraine with temporary neurologic symptoms. This condition is more prevalent in males and is often associated with transient hemiparesis and aphasia [43].

Migraines with brainstem aura (previously referred to as basilar migraines) occur in adolescence and young adulthood. The origin of the neural event is in the brain stem; as a result, the basilar artery dilates and causes a variety of bilateral aura symptoms. The aura of these migraines includes two or more of the following symptoms: diplopia, vertigo, tinnitus, hypoacusis, ataxia, and decreased level of consciousness [43]. These migraines are associated with a slightly increased risk of migrainous infarction when compared to other migraine types.

Retinal migraine is a type of migraine with aura associated with repeated attacks of monocular visual disturbance, including scintillations, scotomata or blindness [43]. Diagnosis is confirmed with a clinical visual field examination and/or the patient's drawing (made after clear instruction) of a monocular field defect.

Approximately 3% to 5% of patients with migraine experience an aura without headache. This presentation, formerly known as a "migraine equivalent," tends to occur in older individuals who have had a history of migraines with aura in their earlier years [45]. They predominantly occur in men of advanced age.

The symptoms of a migraine do not always end with resolution of the headache. Following a migraine, individuals tend to have continued symptoms. These symptoms are quite varied in scope and may manifest as impaired concentration, fatigue, irritability, listlessness, muscle weakness, anorexia, food cravings, and euphoria. Keep in mind that migraine headaches are quite heterogeneous and vary widely in scope. Not only do they vary from patient to patient, they even vary in the same individual [46].

Triggers

Many different factors work to trigger migraines. These factors vary greatly from one individual to another and often no precipitating events can be clearly identified. Trigger factors increase the probability of a migraine attack in the short term (i.e., usually in less than 48 hours) in a person with migraine. Some of the more common triggers include stress, sleep disturbances, depression, low barometric pressure, food, hormonal variations, and caffeine withdrawal. Some trigger factors have been reasonably well studied epidemiologically (e.g., menstruation) or in clinical trials (e.g., chocolate, aspartame); however, causal attribution in individual patients may be difficult [43].

For individuals who are not certain of what triggers their headaches, it may be helpful to recommend keeping a headache diary. This diary allows individuals to chronicle their headaches and document details, such as warning signs, time duration of headache, location of pain, intensity of pain, and treatment attempts/effects, along with details of their diet, sleep patterns, medications, stress, and menstrual cycle (if applicable). This is a useful tool in elucidating the relationship between events, environment, and migraines. The headache diary has been shown to improve diagnostic accuracy and allow a more precise judgment of medication consumption. It may also help in judging the quantity of two or more different headache types or subtypes, and it teaches the patient how to distinguish between different headaches.

Evidence Based Practice Recommendation

The Institute for Clinical Systems Improvement asserts that migraines occurring in association with menses and not responsive to standard cyclic prophylaxis may respond to hormonal prophylaxis with use of estradiol patches, creams, or estrogen-containing contraceptives.

https://www.icsi.org/wp-content/uploads/2019/01/HeadacheRR.pdf

Last Accessed: April 5, 2022

Level of Evidence: Expert Opinion/Consensus Statement

Migraine headaches in premenopausal women often correlate with menses, when estrogen and progesterone levels precipitously drop. These same women, when on birth control pills, develop a similar headache pattern with initiation of their placebo pills, when estrogen and progesterone levels are low. It has been suggested that altering the schedule of birth control pills may significantly reduce the number and severity of the headaches; however, women who experience migraine with aura should not use a combined oral contraceptive pill [11,47]. Despite the increased prevalence of headache and migraine in premenopausal women, migraine is underdiagnosed in this population [48].

Approximately two-thirds of women with migraines experience headache improvement during the course of a pregnancy [49]. Usually, symptoms during the first trimester determine whether pregnant patients will experience relief—if symptoms resolve during the first trimester, patients usually remain headache-free throughout the pregnancy; if symptoms persist during first the trimester, they usually remain throughout the pregnancy [13]. Keep in mind that although most headaches during pregnancy are typically migraine or tension, secondary causes should be ruled out.

People who are prone to migraines also find that caffeine, which can acutely help with headaches, may work to precipitate headaches if it is withdrawn after a period of continuous daily use. Many different foods contain chemicals that may act to initiate the headache cascade (Table 4).

Table 4: COMMON FOOD TRIGGERS

Trigger

Causal Factor

Food

Chemical trigger

Cheese

Tyramine

Chocolate

Theobromine

Citrus fruits

Phenolic amines

Hot dogs, ham, cured meat

Nitrites, nitric oxide

Dairy products, yogurt

Allergenic proteins (casein)

Chinese food

Monosodium glutamate

Coffee, tea, cola

Caffeine

Artificial sweeteners

Aspartame

Wine, beer

Histamine, tyramine, sulfites

Source: Compiled by Author

In addition to determining what may trigger a headache, it is important to have an understanding of the impact of a headache on an individual's quality of life and productivity. One way to get a fast yet effective understanding is with the use of the validated questionnaire called the Migraine Disability Assessment Scale (MIDAS) (Table 5) [50]. The MIDAS was developed to measure headache-related disability and improve communication between patient and physician about the functional consequences of migraine. Scores on the MIDAS have been highly correlated with physician judgments about the severity of illness and need for treatment. It may play a role in improving the care of patients with migraine and other types of headache [51].

Table 5: MIGRAINE DISABILITY ASSESSMENT SCALE (MIDAS)

- On how many days in the last three months did you miss work or school because of your headaches?

- How many days in the last three months was your productivity at work or school reduced by half or more because of your headaches?

- On how many days in the last three months did you not do household work because of your headaches?

- How many days in the last three months was your productivity in household work reduced by half or more because of your headaches?

- On how many days in the last three months did you miss family, social, or leisure activities because of your headaches?

- On how many days in the last three months did you have a headache?

- On a scale of 0–10, on average how painful were these headaches?

Source: [50]

Treatment Goals

The goals of both pharmacologic and nonpharmacologic long-term migraine treatment are to [52,53]:

- Reduce attack frequency, severity, and disability

- Reduce reliance on poorly tolerated, ineffective, or unwanted acute pharmacotherapies

- Improve quality of life

- Avoid acute headache medication escalation

- Educate and enable patients to manage their disease to enhance personal control of their migraine

- Reduce headache-related distress and psychologic symptoms

Behavioral and physical interventions are used for preventing migraine episodes rather than for alleviating symptoms after an attack has begun. Although these modalities may be effective as monotherapy, they are more commonly used in conjunction with pharmacologic management [52].

Nonpharmacologic Treatment for Migraines

The cornerstone of nonpharmacologic therapy for treating migraine headaches involves empowering patients with knowledge. Educating patients about their diagnosis allows them to have a better understanding of what is occurring and what factors may be contributing to their headaches. Patients should be involved in formulating a management plan. Regular re-evaluation of therapy is also important [54,55].

Migraine is a chronic neurologic disorder that may require patients to undergo some level of lifestyle change. Lifestyle modification is one of the most important aspects of nonpharmacologic therapy. Lifestyle modification includes dietary changes, stress management techniques, establishment of regular sleeping and eating habits, and moderate exercise. These may help ease both the severity and frequency of migraine headaches. After the early signs of headaches are identified, additional attempts may be made to further reduce symptoms.

As noted, patients' headaches are often precipitated by food triggers. Patient education includes teaching patients to recognize these triggers and then avoid them, which may help patients to become headache-free. A headache diary, as discussed previously, may help patients to identify these food triggers [20,55]. Consultation with a nutritionist may help patients find alternative foods. In addition, patients should be counseled to maintain a regular diet and avoid skipping meals. Moreover, they should consume at least eight 8-ounce glasses of water daily [56].

It has been estimated that more than 85% of headache patients use complementary and alternative medicine (CAM) therapies. Some CAM techniques have been shown to be beneficial and effective in preventing migraine. Behavioral interventions (e.g., biofeedback, stress management, psychotherapy) should be part of the standard of care for a difficult migraine patient, especially when stress is a major trigger or when analgesics are being overused [13,55]. Stress management techniques, including biofeedback and acupuncture, have been successful for some patients and have been recommended to help patients reduce the frequency and severity of migraine headache [11,23]. These techniques are most successful with a motivated patient, especially one who is trying to avoid pharmacologic therapy. It should be considered, particularly for pregnant patients and those not easily treated with pharmacologic agents. However, it is time-consuming and requires a commitment on the part of the patient [20].

Acupuncture is another therapy with which some patients have found success. It may be used as preventive management in patients with migraine and tension headache but should be used with caution in patients with severe bleeding disorders, who are pregnant, or who wear a cardiac pacemaker [11,23]. Available studies have suggested that acupuncture is at least as effective as, or possibly more effective than, prophylactic drug treatment, with fewer adverse effects [57]. It can be a valuable nonpharmacologic tool and should be considered a treatment option for patients willing to undergo this treatment [58,59,60].

Sleep disturbances are a well-known cause of headaches [61]. Insomnia has been identified as a risk factor for tension-type headache, and sleep problems have been reported as a trigger of headaches [62]. Therefore, it is important for patients to maintain regular sleep habits. This involves going to sleep and awaking at about the same time every day. It also includes avoiding stimulants around bedtime and trying to receive at least six to eight hours of sleep daily [13,56]. Patients should avoid sleep fragmentation, if possible. Interestingly, patients with a family history of hypersomnia may also experience headache [63].

Moderate exercise has also been found to be helpful in decreasing headache frequency and intensity for some migraine patients [56,64]. Exercise that decreases stress and concurrently improves cardiovascular fitness seems to be the most effective. Simply walking 30 minutes per day during a lunch hour or after work can make quite a difference in terms of decreasing headache frequency. Other migraine patients have found some relief with regular yoga classes, especially those that focus on breathing and relaxation. At a minimum, patients should be encouraged to engage in an exercise program, especially because exercise improves overall health. Ideally, patients should exercise 30 to 60 minutes, at moderate intensity, at least three times per week.

All patients who smoke should be encouraged to quit smoking. Nicotine is a well-known vasoconstrictor, and carbon monoxide is a vasodilator. Combined they can trigger the migraine process. Therefore, current smokers should be counseled to quit.

Often, a multidisciplinary approach can be effective for some patients and may lead to a decrease in migraine pain, frequency, and intensity; improved overall health status and quality of life; and improved functional status [65]. Treatment choices should be based on the severity and frequency of the headache as well as on associated symptoms and comorbidities [24].

Pharmacologic Treatment for Migraines

Unfortunately, even if a patient has some success with nonpharmacologic options, many will still need medications. Some data have suggested an enhanced effect with a combination of treatments [66].

The pharmacologic options for migraine headache fall into two main categories: acute attack treatment (also known as abortive treatment) and preventive therapies.

Acute Attack Treatments

The U.S. Headache Consortium has identified goals for the successful treatment of acute attacks of migraine [53]:

- Treat attacks rapidly and consistently without recurrence.

- Restore the patient's ability to function.

- Minimize the use of back-up and rescue medications.

- Optimize self-care and reduce subsequent use of resources.

- Be cost-effective for overall management.

- Have minimal or no adverse events.

To meet these goals, the Consortium has recommended that clinicians [52,53,54]:

- Educate migraine sufferers about their condition and its treatment; encourage patients to participate in their own management.

- Use migraine-specific agents (i.e., triptans, dihydroergotamine [DHE]) in patients with moderate or severe migraine or whose mild-to-moderate headaches respond poorly to nonsteroidal anti-inflammatory drugs (NSAIDs) or combinations such as aspirin plus acetaminophen plus caffeine. Note: The American Academy of Family Physicians/American College of Physicians-American Society of Internal Medicine has recommended the use of migraine-specific agents only when a first-line therapy of NSAIDs (e.g., aspirin, ibuprofen, naproxen sodium, acetaminophen-aspirin-caffeine combination) has failed.

- Select a non-oral route of administration for patients with migraine associated with severe nausea or vomiting.

- Consider a self-administered rescue medication for patients with severe migraine who do not respond to (or fail) other treatments.

- Guard against medication-overuse headache.

The goal of acute attack treatment should be for the patient to be pain-free within two to four hours. The patient should be able to return to full function after this time. In addition, the headache should not return within 24 hours of being pain-free. A stepwise approach is typically recommended [38]. This approach suggests that patients are to be treated with the safest, least expensive medication during the first migraine attack, and subsequently progress to more expensive medications for subsequent attacks, if the initial ones are not effective [53,67]. As a general rule, medications used to alleviate the pain of a migraine attack should be taken early after onset, when the headache is still mild, if possible.

In 2015, the American Headache Society (AHS), in cooperation with the American Academy of Neurology (AAN), provided an updated assessment of the evidence for individual pharmacotherapies for acute attack treatment (Table 6). This assessment will form the basis of new treatment guidelines [173]. The assessment was based on a systematic review of clinical trials published from 1998 to 2013 that compared the efficacy of various acute attack treatments versus placebo. It did not compare the efficacy of individual therapies [173]. Where no new studies for a particular drug were found, classifications were based on previous AAN guidelines.

Table 6: AHS EVIDENCE ASSESSMENT OF ACUTE MIGRAINE PHARMACOTHERAPIES)

Drug Class

Specific Agents and Doses

Level A (Effective)

Analgesics

Acetaminophen 1,000 mg (for non-incapacitating headache)

Ergots

DHE nasal spray 2 mga

NSAIDs

Aspirin 500 mga

Diclofenac 50 mg, 100 mg

Ibuprofen 200 mg, 200 mg

Naproxen 500 mg, 550 mga

Opioids

Butorphanol nasal spray 1 mga

Triptans

Almotriptan 12.5 mg

Eletriptan 20, 40, 80 mg

Frovatriptan 2.5 mg

Naratriptan 1, 2.5 mga

Rizatriptan 5, 10 mga

Sumatriptan (oral 25 mg, 50 mg, 100 mga; nasal spray 10 mg, 20 mg; subcutaneous 4 mg, 6 mg)

Zolmitriptan (nasal spray 2.5 mg, 5 mg; oral 2.5 mg, 5 mga)

Combinations

Acetaminophen/aspirin/caffeine 500 mg/500 mg/130 mga

Sumatriptan/naproxen 85 mg/500 mg

Level B (Probably Effective)

Antiemetics

Chlorpromazine 12.5 mg IVa

Droperidol 2.75 mg IV

Metoclopramide 10 mg IVa

Prochlorperazine 10 mg IV/IMa

Ergots

DHE 1 mg IV, IM, SCa

Ergotamine/caffeine 1 mg/100 mga

NSAIDs

Flurbiprofen 100 mga

Ketoprofen 100 mg

Ketorolac 30–60 mg IV/IM

Other

Magnesium sulfate 1–2 g IV (for migraine with aura)

Isometheptene 65 mga

Combinations

Codeine/acetaminophen 25 mg/400 mga

Tramadol/acetaminophen 75 mg/650 mg

Level C (Possibly Effective)

Antiepileptics

Valproate 400–1,000 mg IV

Ergots

Ergotamine 1–2 mga

NSAIDs

Phenazone 1,000 mg

Opioids

Butorphanol 2 mg IMa

Codeine 30 mg POa

Meperidine 75 mg IMa

Methadone 10 mg IMa

Tramadol 100 mg IVa

Steroids

Dexamethasone 4–16 mg IV

Other

Butalbital 50 mga

Lidocaine intranasala

Combinations

Butalbital/acetaminophen/caffeine/codeine 50 mg/325 mg/40 mg/30 mga

Butalbital/acetaminophen/caffeine 50 mg/325 mg/40 mga

Level U (Conflicting or Inadequate Evidence)

NSAIDs

Celecoxib 400 mg

Other

Lidocaine IVa

Hydrocortisone 50 mg IVa

For an agent to be classified as Level A, it must be supported by at least two Class I studies (randomized controlled trials in the representative population). Level B requires one Class I study or two Class II studies (randomized controlled trials not meeting the standards of Class I), and Level C required one Class II study or two Class III studies (nonrandomized controlled studies). An agent was classified Level U when evidence to support its use was either conflicting or inadequate.

aBased on 2000 American Academy of Neurology evidence review.

Source: [173]

Acute attack pharmacologic options are used at the onset of the attack. They can be divided into nonspecific and specific drugs. The nonspecific therapies are single or combination analgesics. Routes of administration include oral, nasal, parenteral, and rectal. Appropriate situations for use, including potential side/adverse effects, drug-drug interactions, and patient-specific contraindications, should be addressed. Opioids are generally avoided, if possible, due to concerns about tolerance and dependence [54,173].

The more common analgesics used include acetaminophen, NSAIDs (e.g., aspirin, ibuprofen, naproxen sodium), and narcotics (e.g., oxycodone, morphine sulfate) [38]. Acetaminophen-aspirin-caffeine combination may also be used to treat migraines. The evidence for efficacy is most consistent for aspirin, ibuprofen, naproxen sodium, and the acetaminophen-aspirin-caffeine combination. Acetaminophen alone has been found to be ineffective [53,66,173].

In the 2000 AAN guidelines, the NSAID diclofenac was considered "probably effective" for the acute treatment of migraine. Class I studies conducted since that time resulted in the agent being reassessed by the AHS as "effective" (Level A) [14,176,177].

The nonspecific therapeutic drugs may be used to relieve the pain through many different mechanisms, although most typically work by dulling pain receptors. These are usually considered first-line therapeutic options for many individuals who find these adequate in obliterating headaches [54]. In order to increase the likelihood of efficacy it is important that these are taken as early as possible in the headache cycle [38]. In addition, a large single dose tends to be more effective than repeated smaller doses. When any of these medications are used, many clinicians add an antiemetic or pro-motility agent to increase the chance of absorption, especially during an attack when nausea is a major component [53].

Over-the-counter analgesics are often effective in treating migraine. In an observational study of the impact of over-the-counter analgesics for migraines on a patient's quality of life, nearly 100 patients who used over-the-counter medications, such as acetaminophen-aspirin-caffeine combination, and who also received educational migraine materials over a four-month period completed a general health status questionnaire. At the end of the study, patients reported significant improvements in several quality-of-life measures and increased frequency of relief [69].

Ergotamines

The specific therapies include ergotamines and triptans. The ergotamines and triptans both work as vasoconstrictors. Ergotamine derivatives, although less expensive, are more nonspecific and tend to increase the likelihood of rebound headaches after their use [53,67].

The U.S. Headache Consortium reviewed the results from 23 controlled trials of ergotamine tartrate, ergotamine-containing compounds, and ergostine-containing compounds and has recommended the following regarding the use of ergot alkaloids and derivatives, all of which are supported by the recent AHS evidence assessment of migraine pharmacotherapies [53,173]:

- In the treatment of selected patients with moderate-to-severe migraine, ergot derivatives may be considered.

- Because of their inability to tolerate or take oral medication, patients with nausea and vomiting may be given DHE subcutaneous, IV, or intramuscular (IM). Initial treatment with DHE subcutaneous or IM is a reasonable choice when the headache is moderate-to-severe or an adequate trial of NSAIDs or other nonopiate analgesics has failed to provide adequate relief in the past. The use of DHE IM or subcutaneous may be considered in patients with moderate- to-severe migraine.

- DHE IV plus antiemetics is an appropriate treatment choice for patients with severe migraine.

- The use of DHE nasal spray is an appropriate treatment choice and should be considered for use in patients with moderate-to-severe migraine. Because of their inability to tolerate or take oral medications, patients with nausea and vomiting may be given intranasal DHE. Initial treatment with DHE nasal spray is a reasonable choice when the headache is moderate-to-severe or an adequate trial of NSAIDs or other nonopiate analgesics has failed to provide adequate relief in the past.

Triptans

The triptans are serotonin 5-HT1B/1D receptor agonists and act through three possible mechanisms: vasoconstriction of intracranial vessels, inhibition of neuropeptide release from the trigeminal nerve, and inhibition of central pain transmitters. The newer triptans have fewer side effects and are much less likely to cause rebound headaches as compared to their predecessors.

Although many of the serotonin 5-HT1B/1D receptors are located in the brain, some 5-HT1B receptors are located in the heart, as determined by anatomical studies using selective antibodies [70]. Triptans have been shown to constrict coronary arteries and prevent the release of pro-inflammatory neuropeptides [71]. In rarer circumstances, they may actually cause myocardial infarction [72]. Because of this, it is contraindicated to use these drugs in the setting of ischemic heart disease, uncontrolled hypertension, pregnancy, and cerebrovascular disease, such as ischemic stroke [36,38,53,73]. They should also be avoided in the treatment of FHM and basilar migraine. Triptans should not be prescribed to patients who are also taking monoamine oxidase inhibitors (MAOIs), nor should they be given within 24 hours of use of ergotamines [73]. No evidence has supported the use of triptans during the aura phase of a migraine attack [53].

Several triptan drugs are available. The drugs may be taken orally as tablets or capsules, sublingually as quick-dissolving wafers, or intranasally as a spray. Sumatriptan is also available in subcutaneous injection form [71,74].

The U.S. Headache Consortium has found that triptans are effective and relatively safe for the acute treatment of migraine headaches. They are an appropriate initial treatment choice in patients with moderate-to-severe migraine who have no contraindications for their use [52]. Patient-reported satisfaction with triptans is modest [75]. It is advisable to switch from one oral triptan to another if three migraine attacks have been treated without success [192].

Almotriptan: Almotriptan is available in oral form. It has the highest oral bioavailability of the triptans, with approximately 70% of the dose absorbed within the first hour [73,76]. A meta-analysis of 53 randomized controlled trials demonstrated almotriptan 12.5 mg to be of comparable efficacy to sumatriptan 50 mg or 100 mg [77]. Side effects include dizziness, dry mouth, paresthesia, nausea, and somnolence [53,73].

Eletriptan: Eletriptan is available in oral form. It has been suggested as one possible therapy for those patients who have a poor response to NSAIDs. In an open-label treatment study, 113 patients who suffered from migraines and did not experience a satisfactory response to NSAIDs were given eletriptan 40 mg for one migraine attack [78]. Headache, pain-free response, absence of associated symptoms, and functional response were assessed at 1, 2, 4, and 24 hours after receiving the medication. By four hours post-dose, the pain-free response rate was greater than 40% and relief of baseline symptoms was 82%. By 24 hours post-dose, only 24% of patients had headache recurrence. In a randomized double-blind study comparing eletriptan 40 mg to naratriptan 2.5 mg and placebo, 548 patients with migraines were evaluated [79]. At four hours post-dose, 67% of patients taking naratriptan experienced headache relief versus 80% for patients taking eletriptan and 44% for placebo. Patients taking eletriptan also used fewer rescue medications. Side effects include asthenia, dizziness, dysphagia, abdominal pain/discomfort, and chest tightness [53,73]. Diagnosis should be re-evaluated if the first dose is ineffective.

Frovatriptan: Frovatriptan, available in oral form, appears to have the highest potency of the triptans and may be cerebro-selective [76]. It has one of the lowest rates of headache recurrence after use. In a review of three randomized placebo-controlled trials involving almost 2,700 patients, patients using frovatriptan 2.5 mg experienced greater headache relief than placebo [80]. Side effects include fatigue, dizziness, flushing, dyspepsia, skeletal pain, and chest tightness [73].

Naratriptan: Naratriptan has the longest half-life of all the triptans. As a result, it may be particularly effective in reducing recurrence headaches in some patients. The use of naratriptan 2.5 mg was compared to naproxen 500 mg in a small, double-blind crossover study [81]. At six hours post-dose, naratriptan was more effective in relieving headache, nausea, and vomiting and did so more quickly than naproxen. Side effects include dizziness, drowsiness, malaise, paresthesias, and throat tightness [73].

Rizatriptan: Rizatriptan is one of the quickest acting oral preparations, typically reaching peak concentration in 1 to 1.5 hours. It is also available as an orally-disintegrating wafer [73,76]. In a study comparing rizatriptan 10 mg versus zolmitriptan 2.5 mg versus placebo, both drugs showed improvement in headache relief compared to placebo but there was no significant difference in symptom relief between the two drugs [82]. When taken orally, rizatriptan 10 mg is superior to sumatriptan 100 mg and naratriptan 2.5 mg on some, but not all, efficacy outcomes [71,74]. Compared to sumatriptan 100 mg and naratriptan 2.5 mg, greater proportions of patients taking rizatriptan 10 mg have measurable pain relief one hour after taking medication and/or are completely pain-free after two hours. There is insufficient evidence to determine whether rizatriptan (or any triptan) is superior overall [71,74]. Side effects include asthenia, dry mouth, nausea, paresthesia, dizziness, and chest discomfort. The wafer preparation contains phenylalanine [53,73].

Sumatriptan: Sumatriptan is available in oral, subcutaneous, and intranasal preparations and in combination with naproxen [73]. It was the first triptan on the market and thus has been the most studied. Oral sumatriptan has been found to be significantly more effective than placebo at relieving migraine headache pain within two hours [83]. A systematic review of 61 studies involving 37,250 participants found that oral sumatriptan (100 mg) significantly improved headache relief compared to placebo [83].

Side effects include tingling/flushing, dizziness, fatigue, muscle pain or weakness, and chest discomfort [73]. There may be taste disturbance with the use of the nasal spray [53,73]. Although sumatriptan is the most commonly prescribed treatment for migraine, current formulations may be associated with limitations (e.g., difficulty taking oral medication) that can result in patients' delaying or avoiding treatment. Transdermal patches have proved effective for the delivery of sumatriptan. In 2013, the U.S. Food and Drug Administration (FDA) approved Zecuity, a sumatriptan iontophoretic transdermal system [84,85]. In 2016, the manufacturer of Zecuity suspended sale of the drug pending an FDA evaluation of reports of burns and scars associated with the patch [86]. Additional novel formulations include needle-free injectable sumatriptan [75].

Zolmitriptan: Zolmitriptan is available in oral form, nasal spray, and orally disintegrating wafers [73]. In a randomized controlled trial of nearly 1,200 patients comparing oral zolmitriptan to placebo, zolmitriptan 2.5 mg was found to significantly decrease headache symptoms, resulting in headache relief in the majority of patients [87]. Of note, a dose response effect was observed, with lower doses resulting in fewer adverse events. In a randomized controlled trial comparing the use of zolmitriptan to sumatriptan of nearly 1,500 patients with migraines, there was no significant difference in headache relief [87]. Side effects include asthenia, nausea, paresthesia, dizziness, and chest discomfort. The use of the nasal spray can cause taste disturbances. The wafer preparation contains phenylalanine [53,73].

The triptans are all closely related although they differ slightly in terms of half-life, oral bioavailability, and metabolism. Side effects vary but in general they are mild and include tingling, flushing, dizziness, somnolence, and the sensation of pressure in the head; their safety profiles are all quite similar [36]. Because sumatriptan was the first on the market and the most commonly prescribed, it is often used as a comparison in studies with newer triptans [53].

A comparative review of the safety and efficacy of the triptans has indicated that [71,73,74]:

- Indirect comparisons from placebo-controlled trials of oral triptans suggest that sumatriptan 100 mg, almotriptan 12.5 mg, eletriptan 40 mg, and zolmitriptan 5 mg all have similar efficacy, whereas frovatriptan 2.5 mg is probably inferior.

- Evidence remains inconclusive as to how the orally disintegrating wafer, nasal, and injectable forms of triptans compare in efficacy to the more conventional oral capsule or tablet forms.

- For the oral forms of eletriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan, there are no differences in adverse effects (e.g., chest tightness, CNS symptoms); data are lacking for almotriptan and frovatriptan.

- For all the triptans, the safety of treating an average of more than four headaches in a 30-day period has not yet been established.

Note that, like NSAIDs, failure with one triptan does not imply that the patient will not find relief with another triptan. At least two medications in a class should be tried before the class of medications is considered unsuccessful in headache treatment. Ultimately, individuals will need to try the different triptans and determine what works best for them. One might also consider adding an NSAID to a triptan to potentially enhance effectiveness. The first combination product of a triptan and an NSAID (Treximet) was approved by the FDA in 2008. Treximet contains sumatriptan (85 mg) and naproxen sodium (500 mg) and has found to be more effective than placebo or either sumatriptan or naproxen sodium alone [38,74].

Treating pregnant patients with migraines can be particularly challenging. In general, most medications should be avoided, and patients should be treated with behavioral intervention and nonpharmacologic measures. The triptans are considered FDA Pregnancy Risk Category C, which means risk to humans has not been ruled out [73].

Management of Acute Attack in the Emergency Department

Acute migraine attack results in 1.2 million visits to emergency departments in the United States each year [174]. While more than 20 different parenteral medications and combinations of medications are used to treatment acute migraine in U.S. emergency departments, fewer than 25% of patients experience sustained freedom from headache after treatment [175]. The ideal parenteral treatment should offer rapid, sustained freedom from headache, no short- or long-term sequelae, a rapid return to normal activities, and no adverse effects; however, no such treatment exists. This led the AHS to develop a guideline on the management of acute migraine in the emergency department, with the goal of determining which injectable medications should be considered first-line treatment for acute migraine in the emergency setting, and whether parenteral corticosteroids can prevent recurrence of migraine in adults discharged from the emergency department (Table 7) [175].

Table 7: AHS RECOMMENDATIONS FOR MANAGEMENT OF ACUTE MIGRAINE IN THE ED

Medication, Dose, Route of Administration

Pharmacologic Category

Efficacy

Recommendation

First-Line Treatment

Acetaminophen, 1 g, IV

Analgesic

Possibly effective

May offer

Acetylsalicylic acid, 0.5–1.8 g, IV

NSAID

Likely effective

May offer

Chlorpromazine, 0.1–25 mg, IV

Antimanic, antipsychotic

Possibly effective

May offer

Diclofenac, 75 mg, IM

NSAID

Possibly effective

May offer

Droperidol, 2.5–8.25 mg, IM

Antiemetic

Likely effective

May offer

Haloperidol, 5 mg, IV

Antipsychotic

Likely effective

May offer

Ketorolac, 30–60 mg, IM/IV

NSAID

Likely effective

May offer

Metoclopramide, 10–20 mg, IV

Antiemetic

Highly likely to be effective

Should offer

Prochlorperazine, 10 mg, IV

Antiemetic

Highly likely to be effective

Should offer

Sumatriptan, 6 mg, SC

Triptan

Highly likely to be effective

Should offer

Valproic acid, 500–1,000 mg, IV

Anticonvulsant; antimanic

Possibly effective

May offer

Migraine Recurrence Prevention

Dexamethasone, 8–24 mg, IV

Corticosteroid; antiemetic

Highly likely to be effective

Should offer

Source: [175]

Other Medications

Although the triptans provide effective relief from migraine for many patients, a substantial number will be unresponsive. Calcitonin gene-related peptide (CGRP) is believed to contribute to pain transmission and inflammation and, for these reasons, to the mechanisms of migraine. CGRP receptor antagonists have been shown to terminate migraine with efficacy similar to triptans by inhibiting neurogenic vasodilatation and inflammation. Four CGRP receptor antagonists (erenumab, fremanezumab, galcanezumab, and ubrogepant) have been tested in clinical trials and have shown clinical benefit and excellent tolerability [88,89,90,91].

Selective serotonin reuptake inhibitors (SSRIs) block the passage of serotonin, a neurotransmitter, in brain cells and are typically used to treat depression. In view of research suggesting that serotonin may play a role in the genesis of headache pain, SSRIs have been tested for their potential benefit in preventing headaches. Results suggest, however, that SSRIs are no better than placebo for preventing migraine or tension-type headaches [92]. Additionally, the FDA has issued a public health advisory regarding the combined use of 5-hydroxytryptamine receptor agonists (triptans), SSRIs, or selective serotonin/norepinephrine reuptake inhibitors (SNRIs). A life-threatening condition called "serotonin syndrome" may occur when triptans are used together with an SSRI or an SNRI (Table 8). Symptoms may include restlessness, hallucinations, loss of coordination, tachycardia, rapid changes in blood pressure, increased body temperature, overactive reflexes, nausea, vomiting, and diarrhea. Serotonin syndrome may be more likely to occur when starting or increasing the dose of a triptan, SSRI, or SNRI. The FDA has requested that all manufacturers of triptans, SSRIs, and SNRIs update their prescribing information to warn of the possibility of serotonin syndrome when triptans and SSRIs or SNRIs are taken together [93].

Table 8: MEDICATIONS IMPLICATED IN SEROTONIN SYNDROME

SSRIs

Citalopram

Fluvoxamine

Escitalopram

Paroxetine

Fluoxetine

Olanzapine/fluoxetine

Sertraline

SNRIs

Duloxetine

Venlafaxine

Sibutraminea

Triptans

Naratriptan

Almotriptan

Frovatriptan

Sumatriptan

Rizatriptan

Eletriptan

Zolmitriptan

Ditans

Lasmiditan

aSibutramine, a drug approved for weight loss but not depression, is an SNRI and should therefore be used with caution with triptans and other serotonergic drugs.

Source: [93]

In 2019, lasmiditan, a ditan, was approved for the treatment of migraine [73]. Lasmiditan is similar to a triptan but is a high-affinity, highly selective 5-HT1F receptor agonist. The selective targeting of the 5-HT1F receptor is hypothesized to decrease stimulation of the trigeminal system and treat migraine pain without causing vasoconstriction. In a phase 3 study, patients reporting being free of headache after two hours with lasmiditan 200 mg (32.2%) or 100 mg (28.2%) compared with placebo (15.3%). Patients who received lasmiditan were also significantly more likely to report alleviation of their most bothersome symptom compared with placebo [193]. Adverse events were mostly mild or moderate in intensity.

Botulinum Toxin

Botulinum toxin type A (Botox) injections were discovered as a treatment for migraines after individuals who had injections for cosmetic purposes found that it lessened or obliterated their migraine headaches. These observations subsequently led to a series of clinical research studies designed to assess the value of botulinum toxin type A therapy for headache prevention; however, the results from these studies have been mixed [68,94,95,96,97].

For example, a review of botulinum toxin studies was performed by the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. The Subcommittee examined evidence of the toxin's effectiveness for a variety of conditions, including migraine. According to the Subcommittee's report, the evidence indicated that botulinum toxin may be useful in the treatment of lower back pain but that it is probably not effective against episodic migraine and chronic tension-type headache. The report also stated that the available evidence was not strong or consistent enough to determine botulinum toxin's usefulness in the treatment of chronic daily headache (primarily, transformed migraine) [95,96].

In a double-blind, randomized, placebo-controlled study, researchers compared the number of headache-free days experienced by patients four weeks prior to injections of botulinum toxin type A with the number of such days occurring four to eight weeks after treatment. The number of headache-free days increased for the study's placebo and nonplacebo groups, but the difference in increase between the two groups was not significant. The researchers did find, however, that when compared with the placebo group, the patients who received botulinum toxin type A injections experienced a significant reduction in the duration of their headaches [95]. Additionally, pooled results from two large trials indicated that treatment with up to five cycles of botulinum toxin type A at 12-week intervals was effective in reducing headache symptoms, decreasing headache-related disability, and improving health-related quality of life in patients with chronic migraine [97].

Evidence Based Practice Recommendation

The American Academy of Neurology has stated that botulinum toxin type A injections should be offered as a treatment option to patients with chronic migraine (but not episodic migraine) to increase the number of headache-free days and reduce headache impact on health-related quality of life.

http://n.neurology.org/content/86/19/1818.full

Last Accessed: April 5, 2022

Strength of Recommendation: A (Established as effective for the given condition in the specified population)

It is generally recommended that use of botulinum toxin type A be restricted to patients who fail to respond to conventional preventative therapy or experience intolerable side effects from such therapy. It is important to note that botulinum toxin type A is not FDA-approved for migraine treatment [73,94]. Because its effects on a developing fetus are unknown, women who are pregnant should not receive botulinum toxin type A [73,94].

The mechanism of action of botulinum toxin type A is thought to be secondary to relieving pressure on certain nerves, such as branches of the trigeminal nerve, and thus reducing the release of neuropeptides. The actual process involves 20 to 30 injections in the forehead, temple, and neck. Side effects may include pain and bleeding at the site, exacerbation of the headache, and ptosis (eyelid droop) [73]. In those patients for whom it works, the effect typically lasts three to six months, at which time the headaches often return. This necessitates repeat injections every three to six months. This treatment is still considered to be experimental. Much more research is needed before this therapy can be considered effective.

Neuromodulation Devices

In recent years, there has been more research and development of neuromodulation devices for the treatment and prevention of headache disorders. Benefits of this type of device include proven efficacy, non-invasive nature, and very limited side effects. Due to the limited amount of time these devices have been available, ongoing research is needed to determine long-term safety and efficacy for headache disorders.

Cerena

In 2013, the Cerena transcranial magnetic stimulation (TMS) device was approved to treat migraine with aura. Patients use both hands to hold the device against the back of the head, then press a button to release a pulse of magnetic energy to stimulate the occipital cortex in the brain, which may stop or lessen the pain associated with migraine headaches. The maximum recommended dosage is one treatment in 24 hours [191].

Approval for Cerena was based on a study in which 39% of users were pain-free two hours post-treatment, compared with 22% of the control group. At 24 hours post-treatment, 34% of patients were pain-free, compared with 10% in the control group. However, studies and research on Cerena are limited [191].

Cefaly

In 2014, the first neuromodulation device received approval from the FDA for prevention of episodic migraines and received approval for acute treatment in 2017 [182,183]. The Cefaly is a prescription external trigeminal nerve stimulation (e-TNS) device that is placed on the forehead. A self-adhesive electrode transmits electrical impulses to specific areas of the trigeminal nerve, generating an analgesic effect. The Cefaly device is used 20 minutes daily at a frequency of 60 Hz to prevent migraine or can be used for acute treatment during migraine with or without aura at a frequency of 100 Hz [183].

Results of a trial published in 2019 showed that patients using Cefaly as a preventive treatment for three months experienced a 16.21% reduction in headache days and a 30.81% decrease in acute medication intake compared with a group assigned to a sham device. Minor adverse events included skin irritation under the electrode and headache worsening with vertigo [184]. Another study published in 2019 examined the efficacy in acute treatment of migraine with or without aura. One hour after beginning the Cefaly treatment, 79% of patients achieved significant pain relief and 29% reported being pain free [185]. According to results of these and other studies, the Cefaly device is considered safe and effective for both prevention and acute treatment of migraine. In 2020, Cefaly was made available over-the-counter without the need for a prescription [194].

gammaCore

In 2017, the gammaCore device was cleared by the FDA for the acute treatment of migraine and cluster headache, and as a preventive treatment for cluster headache. This device is a handheld, non-invasive vagus nerve stimulator (nVNS) that produces mild electrical stimulation to the vagus nerve through the neck, thereby reducing and preventing pain [186]. Stimulation is controlled by the user, and treatment sessions consist of 2 to 3 two-minute stimulations. Patients that have a metallic device (e.g., a stent, bone plate, or bone screw) implanted at or near their neck should not use gammaCore.

A four-week study published in 2018 examined the effects of nVNS using the gammaCore device on episodic migraine headache with or without aura. Researchers found 12.7% of patients were pain free after 30 minutes of initiation of treatment (vs. 4.2% in the sham group) and 21% after 60 minutes (vs. 10%). The only adverse event was vertigo, seen in 1% of patients. Researchers indicate that nVNS is a safe treatment that may possibly decrease the risk of medication overuse in some patients [187].

Another study published in 2018 examined the effects of nVNS on episodic and chronic cluster headache over the course of two weeks. Compared with the sham group, 16.7% of patients with episodic cluster headaches achieved pain-free status at 15 minutes for greater than 50% of their attacks (vs. 6.8%), and 64.3% of patients reported significant improvement (vs. 15.4%). Comparison of patients with chronic cluster headaches were insignificant, with patients reporting free of pain at 8.8% (vs. 6.5% in the sham group) and patients with significant improvement at 29.4% (vs. 12.9%) [188].

Clinical trials for prophylactic treatment of cluster headaches using nVNS showed that there was a significantly greater reduction in the number of cluster attacks per week versus the control (5.9 vs 2.1, respectively). Forty percent of patients reported pain relief of 50% or greater, compared with 8.3% of the control group. nVNS also led to a reduction in the use of abortive medications. There was no change in cluster headache duration or severity of acute attacks reported in this trial [186].

Nerivio Migra

Nerivio Migra received FDA de novo clearance in 2019 for acute treatment of migraine with or without aura. It is a prescription trunk and limb electrical stimulator that is used on the upper arm. Electrical pulses are controlled through a smartphone for 30 to 45 minutes. This device is expected to be available in the United States in late 2019 [189].

A study of the efficacy of Nerivio Migra was published in 2019 and included patients who experience two to eight migraines per month. Two hours post-treatment with active stimulation, Nerivio Migra provided complete pain relief to 37.4% of patients (vs. 18.4% of sham participants), significant pain relief in 66.7% of patients (vs. 38.8%), and relief of most bothersome symptoms in 46.3% of patients (vs. 22.2%). For many, pain relief was sustained 48 hours post-therapy [190].

Relivion

In 2021, the FDA cleared Relivion, a transcutaneous electrical nerve stimulator that can be self-applied at home [195]. This device consists of a headset controlled by a smartphone app and delivers stimualtion to to six branches of the occipital and trigeminal nerves. It is is indicated for the treatment of migraine with or without aura in patients 12 years of age or older.

Preventive Therapies

The initiation of a preventive agent is a decision that can be made only when a variety of factors have been considered. For example, if an individual is using abortive medications more than two times per week with only moderate success, if there are more than two seriously disabling attacks per month, if there is failure of or contraindication to abortive treatments, if there is occurrence of uncommon features, or if there is a pattern being established of medication overuse, physicians should consider the initiation of a preventive medication [38,113]. Additional factors that should be considered include the patient's preference, adverse events associated with treatments for acute migraine attacks, and how much treatment costs for acute attacks and migraine prevention [54]. Most treatment is effective within the first month.

Although the precise mechanism of action is unknown, it is believed that preventive therapies act on the CNS by raising the threshold of a migraine headache, producing "resistance" for the system to develop headaches. They also work by inhibiting the propagation of the migraine process early on.

When considering preventive agents, keep in mind the following points [98,113]:

- Start with the lowest possible dose.

- Give the medication an adequate trial, which typically is two to three months.

- Increase the dose slowly until either benefits or unacceptable adverse reactions are observed.

- Try to use long-acting formulations; these may help improve patient compliance.

- Choose an agent that may treat co- existing conditions, such as depression or hypertension.

- Encourage the patient to use a headache diary for better evaluation of effectiveness.

The proven and/or well-accepted drugs used for prevention of migraines include beta blockers (e.g., propranolol, metoprolol), tricyclic antidepressants, triptans, and antiepileptics (Table 9) [98,113]. When antiepileptic drugs are used to treat or prevent migraine, the dose is typically much lower than the dose used to treat seizures. Also, divalproex sodium and topiramate are the only antiepileptic drugs approved by the FDA for migraine prevention [73]. Antiepileptic drugs have been shown to be effective in reducing the frequency of migraine attacks by 38% to 50% or more with antiepileptics than with an inactive placebo [99,100,101]. It should be noted that, although the drug may be beneficial, the FDA has issued a warning regarding the risk of metabolic acidosis in patients receiving topiramate as well as a warning of increased risk of development of oral clefts in infants born to women treated with the drug during pregnancy [76,102].

Table 9: MEDICATIONS AND STANDARD DOSES FOR MIGRAINE PREVENTION

Medication/Therapy

Standard Dose

Beta Blockers

Propranolola

160–240 mg daily

Timolola

10–30 mg daily

Metoprolol

25–100 mg daily

Tricyclic Antidepressants

Amitriptyline

10–150 mg daily

Antiepileptics

Divalproex sodiuma

250–1,000 mg daily

Topiramatea

25–100 mg daily

CGRP Antagonists

Erenumab-aooea

70 mg monthly

Fremanezumab-vfrma

225 mg monthly

Galcanezumab-gnlma

120 mg monthly

Neuromodulation Devices

Cefalya

100 Hz, for 20 minutes daily

gammaCorea

50–60 Hz, for 4 to 6 minutes daily

aFDA-approved for migraine prevention

Source: [73,98,178,179,180,113]

Gabapentin has demonstrated some effectiveness in the prevention of migraine; however, more research is needed to determine long-term effectiveness [98,101,103,104]. The preventive treatments are often helpful but will not eradicate headaches altogether. Preventive therapy may reduce the frequency of migraines by 38% or more; such improvement is considered successful [36,99,100,101,105].

In 2018, the FDA approved three once-monthly medications for migraine prevention—erenumab-aooe, fremanezumab-vfrm, and galcanezumab-gnlm [178,179,180]. These CGRP antagonists are self-administered once per month with an autoinjector.

Physicians and other clinicians should also be cognizant that migraine sufferers often must try as many as five different medications (both acute and preventive) before they find one that is effective for their symptoms. It is important to be patient and not become frustrated during these trial periods.

CLUSTER HEADACHES

Cluster headaches are one of several types of trigeminal autonomic cephalalgias, primary headaches characterized by unilateral pain in the trigeminal nerve region. As defined by the IHS, cluster headaches are attacks of severe unilateral pain in the orbit and/or the surrounding region of the eye that last 15 to 180 minutes [43,53]. The term "cluster" refers to the headache attacks occurring in daily episodes. The patient is headache-free in between the clusters.

The attacks may occur anywhere from every other day to eight times per day and are accompanied by one or more of the following symptoms: ipsilateral conjunctival injection and/or lacrimation, nasal congestion and/or rhinorrhea, ptosis and/or miosis, eyelid edema, forehead/facial sweating, forehead/facial flushing, or sensation of fullness in the ear (Table 10). Attacks occur in series lasting for weeks or months separated by remissions lasting for months to years [43].

Table 10: DIAGNOSTIC CRITERIA FOR CLUSTER HEADACHES

At least five attacks with the following characteristics:

1. Severe or very severe unilateral pain in the orbit, surrounding area, or both, lasting 15 to 180 minutes untreated

2. Either or both of the following:

- At least one of the following signs on the side of the pain

- Conjunctival injection and/or lacrimation

- Sensation of fullness in the ear

- Nasal congestion and/or rhinorrhea

- Facial and forehead sweating

- Miosis and/or ptosis

- Facial and forehead flushing

- Eyelid edema

- A sense of restlessness or agitation

3. Frequency of attacks from every other day to eight times a day

4. Not better accounted for by another diagnosis

Source: [43]

Cluster headaches are divided into two subclasses: episodic and chronic [43]. The episodic cluster occurs at a rate six times higher than chronic cluster [106]. Episodic cluster headache attacks occur in periods lasting seven days to one year, separated by pain-free periods lasting one month or longer [43]. The chronic cluster headache occurs for more than one year without remission or with remissions lasting less than one month. Chronic cluster headache may arise de novo or evolve from the episodic subtype. Some patients may switch from chronic to episodic cluster headache [43].

Cluster headaches are typically described as an excruciating burning or piercing pain. The pain comes on quickly and reaches its peak quickly. The location is typically retro-orbital and unilateral. Although people do not experience an aura, per se, some individuals report brief warning signs prior to the headache such as a "fuzzy" feeling in the head, spasm of the neck muscles, or a general feeling of discomfort. Interestingly, when a patient is in the throes of a headache, rather than resting and remaining still (as is the characteristic "migraine" behavior) the individual will likely be seen rocking, pacing, or even banging his or her head against a wall in an attempt to somehow divert the pain. The pain is often so excruciating that it has been called the "suicide headache." Each episode lasts from 15 minutes to three hours. Nausea and vomiting are rarely present [43,107].

Prevalence varies by gender. Men are more likely to get this type of headache than women with an approximate 3:1 ratio [43]. Cluster headaches tend to start in individuals 20 to 40 years of age and often remit by 55 years of age. They may be inherited in about 5% of cases [43]. Attacks often begin during sleep, implicating a disorder of circadian rhythm. An increased incidence of sleep apnea in patients with cluster headache suggests that periods of reduced oxygenation of key tissues may trigger an attack [106].

Although the symptoms for cluster headache are quite dramatic and for the most part pathognomonic, tumors in the vicinity of the internal carotid artery may induce symptoms that mimic those seen in cluster headaches. For this reason, some clinicians advocate a CT scan or MRI for patients who are initially presenting with this type of headache [108].

Cluster headaches are quite rare, affecting only 0.1% of adults [107]. Interestingly, there are some associated risk factors. Most individuals with cluster headaches are smokers, yet smoking cessation rarely, if ever, brings relief. A history of head trauma also seems to convey an increased risk of developing cluster headaches. Headache triggers include smoking, alcohol consumption, changes in temperature, breezes on the face, and changes in physical, emotional, or mental activity [43,107].

PET scanning and functional MRI are helping to clarify the poorly understood etiology of cluster headaches. It is thought to be multifactorial and likely involves alterations in the hypothalamus [107]. It is generally believed that the trigeminal system is involved in these headaches [107].

Treatment of cluster headache involves a dual strategy of abortion (during the acute stage) and concurrent prophylaxis, which is initiated to suppress the expected recurrent headaches [109]. Patients with chronic cluster headache require long-term prophylaxis (Table 11). Patients with intractable headaches may require more aggressive intervention, including combination therapy or surgery [107,110].

Table 11: TREATMENT OF CHRONIC CLUSTER HEADACHE

Therapy

Dosage and Route

Comments

Verapamil

120 mg PO three times/day

—

Lithium

Start at 300 mg PO three times/day; use blood levels to achieve therapeutic dose

Need close monitoring of lithium levels; test 12 hours after last dose. Side effects include tremor and dysuria. Check thyroid and renal function before and during treatment.

Microvascular decompression

NA

Only used for intractable cases

Source: [73,107,109,181]

Evidence Based Practice Recommendation

According to the Institute for Clinical Systems Improvement, oxygen inhalation is a highly effective treatment for cluster headaches when delivered at the beginning of an attack with a non-rebreathing facial mask (7–15 L/min). Most patients will obtain relief within 15 minutes.

https://www.icsi.org/wp-content/uploads/2019/01/HeadacheRR.pdf

Last Accessed: April 5, 2022

Level of Evidence: Expert Opinion/Consensus Statement

The treatments of choice for acute cluster headache are oxygen, a triptan, or a combination of the two (Table 12). There has been some data suggesting the use of melatonin in patients who suffer from cluster headaches, especially those who have concomitant sleep disorders; however, the effectiveness of melatonin remains unclear because of conflicting studies [107,108].

Table 12: TREATMENT OF ACUTE CLUSTER HEADACHE

Therapy/Drug

Dosage and Route

Reported Adverse Effects

Oxygen

100% oxygen at least 7 L/min over 15 minutes

None

gammaCore (non-invasive vagus nerve stimulator)

Stimulation level between 1–40 using device on side of neck over vagus nerve at maximum level tolerable for a treatment consisting of 3 two-minute stimulations applied consecutively at the onset symptoms; additional treatment may be administered if symptoms are not aborted; use for up to four attacks (or eight separate treatments) per day (for a total of up to 24 stimulations per day).

Local skin reactions, muscle contractions, dizziness

Triptans

Sumatriptan

Up to 6 mg subcutaneously; may repeat in 24 hours OR 25–100 mg PO; repeat after two hours if significant relief not attained

Maximum: 200 mg/day

Local skin reactions, fatigue, nausea, vomiting, dizziness, burning sensations, paresthesias

20 mg nasal spray

None

Zolmitriptan

2.5 mg PO at onset (includes orally disintegrating wafer)

Maximum: 10 mg/day

Chest pain, palpitation, dizziness, somnolence, vertigo, nausea, paresthesia, warm/cold sensation

One nasal spray (5 mg) at onset

None reported

Intranasal dihydroergotamine

0.5 mg nasal spray bilaterally

Abuse potential; contraindicated in patients with cardiovascular disease

Intranasal lidocaine

1 mL of 4% lidocaine placed with a cotton swab bilaterally for 5 minutes

Unpleasant taste

Source: [73,76,107,108,111,112,188]

Preventive therapies are usually initiated when the cluster headache series begins. Preventive medications include antidepressants, antiepileptics, ergotamine, and calcium channel blockers (Table 13).

Table 13: PROPHYLAXIS OF EPISODIC CLUSTER HEADACHE

Drug/Therapy

Dosage and Route

Reported Adverse Effects

Comments

gammaCore (non-invasive vagus nerve stimulator)

Stimulation level between 1–40 using device on side of neck over vagus nerve at maximum level tolerable for a prophylaxis treatment consisting of 2 two-minute stimulations; first daily treatment should be applied within 1 hour of waking; second treatment should be applied at least 7 to 10 hours later; additional treatment may be administered if symptoms are not aborted; use for up to four attacks (or eight separate treatments) per day (for a total of up to 24 stimulations per day).

Local skin reactions, muscle contractions, dizziness

Intended to be used as an adjunctive therapy; first FDA-cleared device

Galcanezumab-gnlm

Loading dose of 240 mg subcutaneous (SQ) injection, followed by 120 mg SQ monthly

Antibody development, injection site reaction

Given by patient self-injection, FDA-approved

Verapamil

120–160 mg PO three times/day

Hypotension, bradycardia, atrioventricular block, dizziness, fatigue, nausea, constipation

In doses of 360–480 mg/ day, has been found to be effective in reducing attack frequency

Prednisone

100 mg PO/day, up to 500 mg IV (methylprednisolone or equivalent corticosteroid) titrated over five days

Increased appetite, insomnia, nervousness, hyperglycemia, dizziness, headache

Recurrences frequent toward the end of the taper; take concurrently with another prophylactic medication

Divalproex sodium

600–2,000 mg/day

Nausea, somnolence, dizziness, insomnia, anorexia, weakness, thrombocytopenia, alopecia, weight gain

Small studies indicate efficacy; use with caution in patients with renal or hepatic insufficiency; contraindicated in pregnant women

Topiramate

25 mg PO/day for seven days, then increase by 25 mg/day every week to maximum dosage of 200 mg/day

Paresthesias, cognitive effects, drowsiness, dizziness

Small studies indicate efficacy

Ergotamine

2–4 mg/day in divided doses

Vertigo, pruritus, nausea, paresthesias, weakness, cardiac valvular fibrosis, retroperitoneal or pleuropulmonary fibrosis, angina, myocardial infarction

Best for nocturnal attacks; should not be taken concurrently with sumatriptan

May cause withdrawal symptoms if suddenly discontinued

Melatonin

10 mg PO at bedtime

None reported

May be useful in some patients; drug of third choice

Source: [107,111,186]

TENSION HEADACHES

Tension headaches are among the most common headache type seen in practice today; however, it is the least studied of the primary headache disorders, despite the fact that it has the highest socioeconomic impact. The lifetime prevalence ranges from 30% to 78%, with a rate of 63% seen in men and 86% in women [21,43].

The etiology of tension headaches is multifactorial. Although once thought to be simply secondary to muscle spasm, it is now felt that other factors play important roles. In fact, although tension headaches may arise from sustained contraction of pericranial muscles, no correlation exists between muscle contraction and the presence of a tension headache. It seems that, just as in migraine headaches, tension headaches arise in part from centrally mediated neural dysfunction. This abnormality may in part be due to central sensitization in the trigeminal area [43,67].

The IHS has categorized tension headaches into two categories: episodic and chronic (Table 14). Episodic tension-type headache is further divided into infrequent (i.e., episodes that occur less than once per month) and frequent subtypes. The infrequent subtype has little impact on the individual. Frequent sufferers, however, may encounter considerable disability that requires the use of expensive drugs and prophylactic medications. The chronic subtype is always associated with disability and high personal and socioeconomic costs [43].

Table 14: DIAGNOSTIC CRITERIA FOR TENSION HEADACHE

A. Infrequent Episodic Tension Headache

1. At least 10 episodes occurring less than 1 day per month on average or less than 12 days per year

2. Duration from 30 minutes to seven days

3. At least two of the following pain characteristics:

- Pressing or tightening (non-pulsating) sensation around the head

- Mild-to-moderate severity

- Bilateral location

- No aggravation by walking, climbing stairs, or similar physical activity

4. No nausea/vomiting and no more than one photophobia or phonophobia

5. Not better accounted for by another diagnosis

B. Frequent Episodic Tension Headache

1. At least 10 episodes of headache occurring on 1 to 14 days per month on average for more than three months (≥12 and <180 days per year)

2. Duration from 30 minutes to seven days

3. At least two of the following pain characteristics:

- Bilateral location

- Pressing or tightening (non-pulsating) quality

- Mild-to-moderate severity

- No aggravation by routine physical activity such as walking or climbing stairs

4. No nausea/vomiting and no more than one of photophobia or phonophobia

5. Not better accounted for by another diagnosis

C. Chronic Tension Headache

1. More than 180 days of headache in a given year or at least 15 headaches per month for an average of greater than three months

2. Duration may be from hours or it may be continuous

3. At least two of the following pain characteristics:

- Pressing or tightening sensation around the head

- Mild-to-moderate severity

- Bilateral location

- No aggravation by walking stairs or similar physical activity

- May include one of the following: nausea, photophobia, or phonophobia

4. No evidence of organic disease

Source: [43]

Episodic tension headaches are usually associated with a stressful event. They are of moderate intensity, typically are self-limited, and usually respond well to over-the-counter headache treatments. They are usually described as soreness, tightness, or a band-like pressure around the entire head. They are often accompanied by stiffness in the neck and shoulders [114].

IHS diagnostic criteria for infrequent episodic tension-type headache include at least ten episodes occurring on less than 1 day per month on average (i.e., less than 12 days per year), lasting from 30 minutes to 7 days, with at least two of the following characteristics: a pressing or tightening (non-pulsating) sensation around the head, mild-to-moderate severity, bilateral location, and no aggravation by walking stairs or similar routine physical activity. There is no nausea, but either photophobia or phonophobia may be present [43].

Chronic tension headaches generally have the same pain characteristics as episodic tension headaches, including phonophobia or photophobia. They occur more frequently, with an incidence of at least 15 headaches per month on average for greater than three months, or greater than 180 days in a given year. The headache may last hours, or it may be continuous [43,53].

As with migraines, there are both nonpharmacologic and pharmacologic treatments. Nonpharmacologic measures tend to be more effective for tension headaches than for migraines or clusters. These measures include the use of hot or cold packs, ultrasound, electrical stimulation, improvement of posture, trigger point injections, regular exercise, and consistent sleep schedules [114]. Forward head posture and neck mobility have been associated with tension-type headache [115].

Tension headaches also tend to respond well to medications. Some commonly used medications that are effective include aspirin, acetaminophen, and NSAIDs in the standard prescribed doses [114]. Combination treatments with the above medications and caffeine, butalbital, and muscle relaxants are also effective. However, overuse of these medications, especially those containing caffeine, may lead to rebound headaches. The use of butalbital also may result in dependency, and for this reason, it is not recommended for prolonged use [53,73]. In general, narcotics should be avoided because tension headaches are typically mild-to-moderate in pain intensity. Botulinum has also been suggested for the treatment of tension headaches; however, not all researchers agree that it should be used for chronic tension-type headache [11,116]. As discussed, however, more study regarding efficacy and safety is required.

Some chronic tension headaches may not respond as well to the above modalities and may require preventive medication. Before preventive medication is initiated, it is important, as in the case with migraine headaches, to have the individual keep a headache diary to determine what factors, if any, are triggering the headache [114]. Use of nonpharmacologic measures may also be initiated. Some clinicians may try a drug-free holiday, whereby all headache drugs are stopped for at least two weeks. If none of these modalities prove effective, preventive medications may be helpful. The same preventive medications used for migraine are used for chronic tension headache. These tend to be helpful especially if the patient experiences both migraine and tension headaches.

OTHER PRIMARY HEADACHES

Primary Exercise Headache

As the name implies, primary exercise headache (formerly referred to as a primary exertional headache) is a headache that occurs with exertion, is benign in nature, and is unassociated with any structural lesions. On first occurrence of this headache type, it is mandatory to exclude subarachnoid hemorrhage (SAH) and arterial dissection [43,117].

The headache is typically described as a diffuse, bilateral pain, throbbing in quality and acute in onset. It is precipitated by strenuous physical exercise. The headache lasts from five minutes to 48 hours and occurs particularly in hot weather or at high altitude [43,117].

Primary exercise headache is believed to be vascular in origin. Strenuous physical activity increases intracranial venous sinus pressure, which leads to an increase in intracranial pressure and decreases blood flow. This results in the occurrence of the headache. Effective treatment includes ergotamines and NSAIDs. Indomethacin has been found effective in the majority of cases [43,117].

Hypnic Headache

Hypnic headaches are relatively brief in duration (15 to 240 minutes), mild-to-moderate (severe pain is reported in 20% of patients), usually dull in quality, and bilateral in about two-thirds of cases. Hypnic headaches occur during sleep and are related to the REM stage. The headaches typically awaken patients from sleep, but there are few other associated symptoms [43]. They usually occur almost every night and may last for months until patients ultimately present for evaluation. These types of headaches primarily affect the elderly [118].

The etiology is considered idiopathic, and thus, the diagnosis is primarily one of exclusion. Other causes of headache associated with sleep, such as sleep apnea and drug withdrawal, should be excluded.

One of the most effective treatments for hypnic headaches includes the use of lithium; however, it is often limited by side effects and interactions and requires monitoring of plasma concentrations to avoid toxicity. Indomethacin, atenolol, prednisone, and caffeine have also been shown to be useful [43,118].

Headache Associated with Sexual Activity

These headaches have been previously referred to as benign sex headaches, coital cephalalgias, benign vascular sexual headaches, or benign orgasmic headaches. They may be provoked by activities besides coitus and not necessarily with orgasm. Headache associated with sexual activity affects men more than women [119,120].

Two subforms (preorgasmic headache and orgasmic headache) were previously described, but further research was unable to clearly delineate the two separate entities [43]. Therefore, headache associated with sexual activity is now a single diagnosis with variable presentation. The condition is characterized by at least two episodes of pain in the head and/or neck brought on by and occurring only during sexual activity [43]. The pain becomes more severe with increasing sexual excitement and/or may be experienced as abrupt explosive intensity just before or with orgasm. The duration of severe pain is from 1 minute to 24 hours; more mild presentations may last up to 72 hours [43].

Diagnosis cannot be made until secondary causes (e.g., SAH or arterial dissection) have been excluded. For most patients, these are self-limited disorders. Patients often can lessen the severity of an impending attack by ceasing the sexual activity. Frequent, recurrent episodes may require preventive strategies, such as propranolol or indomethacin [119].

6. SECONDARY HEADACHES

As noted, it is helpful to think of secondary headaches in terms of etiologic categories, such as vascular, traumatic, neoplastic, infectious, pressure, metabolic/toxic ingestions, and medication overuse. A secondary headache may be diagnosed when another disorder known to cause headache has been demonstrated; headache occurs in close temporal relation to the other disorder and/or there is other evidence of a causal relationship; and headache is greatly reduced or resolves within three months (this may be shorter for some disorders) after successful treatment or spontaneous remission of the causative disorder. The IHS has divided secondary headaches into subtypes attributed to specific causes [43]. Table 15 shows a summary of several causes of secondary headache.

Table 15: CHARACTERISTICS OF SECONDARY HEADACHES

Type of Headache

Position

Quality

Radiation

Duration

Therapy

Subarachnoid hemorrhage

Diffuse

Sharp

Neck, back

Several days

Surgery, hypertension management, volume expansion

Giant cell arteritis

Temporal area, unilateral or bilateral

Soreness/ burning

No

Days to weeks

High-dose steroids

Arterial dissection

One-sided, nonthrobbing pain in the eye

Pounding

Neck

Days

Anticoagulants, stenting, surgery

Stroke

Diffuse

Dull

No

Hours

Supportive

Epidural hematoma

Diffuse

Severe

No

Hours to days

Surgery

Dental

Occipital, temporal

Squeezing

No

Varies

Dental referral for care

Subdural hematoma

Diffuse

Mild

No

—

Diuretics, anticonvulsants, surgical evacuation

Brain tumor

Diffuse or unilateral

Mild ache

No

—

Surgery, radiation, chemotherapy

Meningitis

Diffuse

Mild to moderate

Neck

—

Rest, fluids, electrolyte balance, antibiotics

Encephalitis

Diffuse

Dull

No

—

Rest, fluids, electrolyte balance, antiretrovirals

Sinusitis

Sinus area

Heavy fullness

No

Duration of illness

Antibiotics

Abscess

Hemicrania

Moderate to severe

Neck

—

Evacuation, antibiotics

Source: [43]

TRAUMATIC CAUSES OF HEADACHES

Epidural Hematoma

Epidural hematomas occur between the dura and skull, and thus separate the dura from the skull. In the majority of cases, there is an associated skull fracture. Typically, there is a history of head trauma, although an epidural hematoma occurs in less than 2% of all serious head injuries. Epidural hematomas are not a frequent occurrence in the elderly, partly because as one ages, the dura becomes more firmly attached to the inner part of the skull [121].

Classically, there is a brief period of unconsciousness and then a return to a normal mental status. This is known as the "lucid interval." Roughly 10% to 33% of patients demonstrate the classic presentation of a lucid interval, and alterations in the level of consciousness may have a variable presentation. After a period of hours, the hematoma expands and pushes the dura inward. Signs of rising intracranial pressure manifest as a severe, diffuse, constant headache, which develops within minutes to 24 hours after development of the hematoma [121]. Other symptoms may include papillary dilatation, hemiplegia, and eventually obtundation. Often there is weakness on the side of the body opposite the hematoma [121].

Hemorrhages usually occur in the temporal fossa from middle meningeal artery tears; they may also occur in the posterior fossa as a result of a transverse sinus tear. Posterior fossa epidural hematoma may exhibit a rapid and delayed progression from minimal symptoms to even death within minutes. Overall mortality has been estimated to be as high as 50%, so prompt evaluation and treatment is critical [43].

With respect to diagnosis through neuroimaging, in the acute setting, unenhanced CT scan is more useful than MRI imaging. Epidural hematomas have a characteristic white lenticular shape adjacent to the bone, while focal hypodense or isodense areas on CT indicate active bleeding. Because the temporal fossa is often involved, one must be careful that bony artifacts do not obscure a hemorrhage [121].

Subdural Hematoma

As the name implies, subdural hematomas occur between the surface of the brain and the dura. The source of bleeding is the venous system (i.e., bridging veins) as opposed to the arterial system. Because the subdural space is continuous, these types of hemorrhage may have significant mass effect. Subdural hematomas are more common than epidural hematomas. They tend to evolve more slowly based on the slower rate of venous bleeding compared to arterial hemorrhage. As a result, there may be a progression of symptoms over two to four weeks; the rate of progression depends upon the severity of the injury [122].

Patients often present with a mild persistent headache. There may be drowsiness and confusion, although focal neurologic signs are often absent. Symptoms may be followed by a brief lucid interval with subsequent deterioration. Subdural hematomas are seen in approximately 15% of all head traumas. Automobile accidents are a typical cause of subdural hematomas [122].

Different types of subdural hematomas should be differentiated according to their temporal profile. In acute and subacute hematomas, which usually occur after obvious head trauma, headache is frequent (11% to 53% of cases) but commonly overshadowed by focal signs and disorders of consciousness. In chronic subdural hematomas, headache is more frequent still (up to 90%) and, though moderate, may be the leading symptom [122]. The diagnosis can be difficult because the causative head trauma is often trivial and may have been forgotten by the patient [43].

Subdural hematomas are more common in the elderly than epidural hematomas, and patients on anticoagulants are at increased risk of developing a subdural hematoma. Chronic subdural hematoma should always be considered in an elderly patient with a progressive headache, particularly if there is some cognitive impairment and/or mild focal signs [43,122,123].

Patients with suspected subdural hematoma should undergo CT scanning. CT scan findings depend on the age of the hemorrhage but typically demonstrate an abnormality in the entire hemisphere, causing a shift of the midline structures. Early on, there are hyperdense areas demonstrated on CT, followed by isodense areas after a week and hypodense areas after a month [122,123].

Prompt treatment is critical because mortality can reach 60%. Treatment may include diuretics to reduce swelling. Because there is a high frequency of seizures, antiepileptics are frequently used to either control or prevent seizures. For more serious hematomas, surgical evacuation may be necessary. The long-term prognosis is actually worse than that for epidural hematomas [122,123,124].

Upon further history taking, it becomes clear that Mrs. T did experience a significant fall a few weeks ago, even though she minimized it when mentioning it. Sequelae are present. Therefore, a contrast-enhanced CT should be ordered.

The CT scan demonstrated hypodense areas in both hemispheres, consistent with subdural hematoma. There was no evidence of mass effect. The subdural hematoma is likely a result of the fall approximately one month earlier. Mrs. T was admitted to the hospital for observation and given diuretics and anticonvulsants. Her clinical course was good with resolution of the hematoma without the need for surgery.

VASCULAR HEADACHES

Subarachnoid Hemorrhage

Typically, headache due to an SAH is described as a sharp pain that usually involves the entire head. Patients classically describe it as the "worst headache of their life." It often radiates into the neck and even into the back. There is usually nausea and vomiting. In general, there are no focal neurologic deficits early on, but as it progresses, there may be loss of consciousness and altered mental state. Seizures during the acute phase occur in 10% to 25% of patients [125].

The course of this headache is abrupt in its onset and maximum intensity at its origin; it is typically incapacitating in its severity. It is exacerbated by neck and head movements. It usually remains severe for several days and then gradually diminishes [43]. An often overlooked aspect is that the acute headache may be preceded days to weeks earlier by a similar but less severe headache due to slow bleeding. Therefore, a high index of suspicion is necessary for accurate diagnosis [125].

The headache results most often (approximately 80% of cases) from rupture of an aneurysm, although this condition may also result from trauma, arteriovenous malformations, venous thrombosis, blood dyscrasias, cocaine use, amphetamine use, and a variety of metabolic conditions [43,125]. Types of aneurysms include berry aneurysms, fusiform aneurysms, atherosclerotic lesions, and mycotic aneurysms from septic emboli. Approximately 80% of nontraumatic SAHs are due to a ruptured berry aneurysm; rupture of arteriovenous malformations is the second most identifiable cause (10%) [126]. The initial pain is actually produced by tearing and distortion of the blood vessel and its adjacent arachnoid membrane. The incidence of headache in ruptured aneurysms is 90% [122].

The prevalence of SAH increases with age in a linear relationship. The mean age is 50 years [125,126,127]. On physical examination, the patient is typically in severe pain. The pain is sometimes referred to as a "thunderclap" headache [126]. Symptoms of meningeal irritation, such as nuchal rigidity and pain, back pain, and bilateral leg pain, occur in as many as 80% of patients with SAH but may take several hours to manifest [126]. Focal neurologic deficits, such as facial droop or weakness in a specific extremity, are present in 25% of patients. However, if the hemorrhage is associated with infarction it will likely involve the brain parenchyma, which may lead to hemiparesis, aphasia, or visual field abnormalities. Loss of consciousness is transient [43,125].

Patients with suspected SAH should undergo CT scanning without contrast or MRI (flair sequences) [43,122]. The CT typically demonstrates blood localized to the basal cisterns or extended into the ventricles [122]. Unenhanced CT detects SAH in about 90% of cases; however, sensitivity drops to 80% after three days. As a result, a normal CT does not exclude a small SAH [125].

If the CT is negative, equivocal, or technically inadequate, a lumbar puncture should be performed [43]. Most cases not detected on CT are identified on lumbar puncture by red blood cells (RBCs) that do not clear in three samples of CSF. A decrease in RBCs from the first to the last tube represents an artificially bloody tap, whereas an increase count in RBCs suggests SAH. The fluid is then centrifuged and examined for xanthochromia. Xanthochromia is often characterized as a yellow-tinged supernatant, although it may also be pink or orange. It represents enzymatically derived breakdown products, oxyhemoglobin, methemoglobin, and bilirubin, of in vivo red blood cells. It is always seen within 12 hours of SAH but is absent after a traumatic tap. Its presence may be helpful in the diagnosis [43]. Of note, blood in the CSF after a traumatic tap will also result in an artificial increase in white blood cells (WBCs). WBCs will increase by one for every 500 to 1,000 RBCs in the CSF. This assumes a normal WBC count, which is typically the case in SAH [126]. Ultimately, angiography may be necessary to determine aneurysm size and location, as well as to determine surgical or medical management. Treatment options include a surgical clip, management of hypertension, and volume expansion [124,126]. In 2013, the FDA approved a new oral nimodipine solution for the treatment of patients with SAH from ruptured intracranial berry aneurysms. The solution is administered enterally (e.g., oral, nasogastric tube, gastric tube route) within 96 hours of the SAH at a starting dose of 20 mL every four hours for 21 consecutive days [73,128].

SAH is a serious condition. Prompt diagnosis of SAH is critical because 50% of patients die following SAH, often before arriving at hospital, and 50% of survivors are left disabled [43,125].

Giant Cell Arteritis

Giant cell (temporal) arteritis is systemic large and medium-sized vessel vasculitis. Most often, it involves the external carotid arteries [43,129]. This headache typically begins as an intermittent soreness or burning discomfort and steadily escalates over several weeks or months to become a constant, well-localized pain. On rare occasions, it can be explosive. Many patients report that the pain is worse at night. Although the pain is usually unilateral, it may also be bilateral. Pain is classically confined to the temples. Between 70% to 90% of patients with giant cell (temporal) arteritis complain of headache [53,129].

The typical presentation is a new-onset headache in patients older than 50 years of age. Incidence is higher in females than males (ratio 3.7:1), as well as in persons of northern European descent. It represents the most common vasculitis in adults. Nearly 50% of patients with polymyalgia rheumatica also have giant cell arteritis [129].

On exam, the affected scalp artery is sometimes prominent. It may be tender and is often pulseless. The scalp itself is usually tender as well. Depending upon the progression, visual field defects and decreased acuity may be noted, although the patient does not usually exhibit focal neurologic deficits. Typically, the headache occurs in someone who is febrile, has malaise, and feels aches in the back and shoulders. Claudication of the jaw occurs commonly and is virtually pathognomonic for this condition when present during talking or chewing [129].

Giant cell arteritis involves not only the arteries of the scalp causing headache, but also other vessels, including those supplying the eye and occasionally the brain. Nearly half of patients with giant cell arteritis develop blindness, if untreated, due to ischemia of the optic nerve or retina. Because blindness can be prevented by immediate steroid treatment, prompt and accurate diagnosis is critical [43,129].

Laboratory studies often show patients to have an elevated erythrocyte sedimentation rate (ESR), typically >80 mm/hour. (In general, a normal rate would be less than or equal to the patient's age, divided by two.) Given the lack of sensitivity and specificity of this test, however, a normal ESR does not exclude the diagnosis [129]. Platelets may also be elevated, as well as liver function tests (especially alkaline phosphatase). These are nonspecific but may provide more information to make a clinical diagnosis [129].

Diagnosis is confirmed by biopsy of the temporal artery, which should be performed as an outpatient procedure within one week after the initiation of corticosteroid therapy [129]. The biopsy demonstrates skip lesions, which are due to the disease's segmental process. When ocular symptoms exist, emergency medical treatment is necessary. High-dose corticosteroids are an effective treatment. Headache usually resolves or greatly improves within three days of high-dose steroid treatment [43,129]. A maintenance dose of prednisone may be required to be administered for one to two years in some patients [129].

Arterial Dissection

Arterial dissection may cause headache. Dissection of the cervical carotid or vertebral artery typically causes sudden, nonthrobbing pain around the eye, piercing pain in the neck, and a "pounding" one-sided headache. Headache with or without neck pain may be the only manifestation of cervical artery dissection. It is by far the most frequent symptom (55% to 100% of cases), and it is also the most frequent inaugural symptom (33% to 86% of cases). Headache and facial and neck pain are usually unilateral, severe, and persistent, averaging four days in duration. However, it has no constant specific pattern and may sometimes be misleading [43]. The headache is often mistaken to be due to migraine or tension. However, the time, course, and associated symptoms are considerably different.

The cause of arterial dissection is multifactorial and may involve some sudden neck movement, causing hyperextension or significant pressure in the area. This may be a result of trauma; however, cases of dissection have been reported after patients cough or sneeze, undergo spinal manipulation, shave a beard, or place their necks in the sink at beauty salons. Underlying arteriopathies, alone or in combination with the mechanical forces, account for most of the pathophysiology [130]. Therefore, it is important to determine what a patient was doing when the headache occurred.

The dissection may begin when the rotation/hyperextension of the neck causes a small lesion in the lining of an artery. This causes bleeding, which then leads to the formation of a clot. Over time, the clot expands restricting blood flow to the brain [130].

Dissection is more common in patients younger than 50 years of age. It accounts for nearly a quarter of all strokes in that age range [130]. Diagnosis is confirmed by Duplex scanning, MRI, MRA, and/or helical CT and, ultimately, arteriography. Several of these investigations are commonly needed as any of them may be normal. Once detected, the majority of patients survive, and most dissections heal without surgery. Treatment includes the use of anticoagulants (heparin followed by warfarin for three to six months), stenting, and bypass surgery on rare occasion [43].

Stroke

Headache, migraine, and stroke are common and can be temporally related, but a direct causal association has not been definitively proven in clinical studies. Headache may be coincidental with stroke (also referred to as cerebrovascular accident or stroke syndrome), including both ischemic and hemorrhagic stroke, or it may be a consequence of stroke. Headache or migraine may increase the risk of stroke [131]. Results of the Women's Health Study, presented at the 2013 International Headache Congress, reported that migraine with aura is a strong risk factor for any type of stroke [132,133,134]. Headaches associated with stroke are typically reported as dull but diffuse (35%) [135]. They are not localized to a particular side. In addition, headache presentation of a stroke is more common in patients younger than 40 years of age [135]. Headache is more likely to occur in combination with other signs and symptoms of stroke [132]. Depending upon the type of stroke, there may be a focal neurologic deficit, such as aphasia or dysarthria. Young patients should be evaluated carefully to avoid misclassification of stroke as a complicated migraine [135].

Diagnostic work-up necessitates a CT scan or MRI to identify the location of the stroke. Treatment focuses on preventing further ischemia and bleeding [132,135]. For ischemic strokes, recombinant tissue plasminogen activator may be given within 3 to 4.5 hours of symptoms. Aspirin and other antiplatelet medications are also frequently used. For hemorrhagic stroke, most care is supportive, unless there is a large hematoma, in which case surgery may be necessary [124].

NEOPLASTIC CAUSES OF HEADACHES

Brain tumors are either primary or metastatic, and both types may have headaches as a symptom. Primary brain tumors arise from CNS tissue and account for approximately 50% of all cases of intracranial neoplasms; most do not metastasize. The remainder of brain neoplasms are caused by metastatic lesions. Gliomas, meningiomas, acoustic neuromas, and pituitary adenomas account for 95% of all primary brain tumors [136].

Estimates of the annual incidence rate of primary brain tumors range from 7 to 19.1 cases per 100,000 population. Metastatic tumors to the brain are more common, affecting more than 200,000 patients per year in the United States. Brain tumors are the second most common cancer in children, comprising 15% to 25% of all pediatric malignancies [136]. The most common primary tumors that metastasize to the brain are lung, breast, melanoma, and kidney [137]. Although the overall incidence remains low, it is increasing. This increase appears to be independent of improved diagnostic capabilities. However, it could be due to the aging population; approximately 60% of brain tumor patients are 50 to 70 years of age. Men are slightly more affected than women [136,137].

Headache (42%) and seizure (21%) are the two most common presenting symptoms of brain tumors [137]. The headache is generally described as a dull ache and nonpulsating. It may be localized to one area early on, but often it is generalized. It tends to be mild and intermittent, but it is recurrent. Over a period of days, weeks, or months, it becomes more persistent and more intense. This is due to the fact that most brain tumors tend to grow slowly over time and cause progressive symptoms. Headache is often a late complaint, not an isolated finding, and the worst presenting symptom in only one-half of patients. Most headaches in patients with brain tumors are nonspecific and resemble tension-type headaches. New onset of headaches in middle-aged or older patients is cause for concern as is a change in any patient's headache pattern [136].

The headache is typically associated with nausea. Depending upon the type, size, and location of the tumor, there may also be neurologic, visual, and/or hearing impairment. The location of the headache reliably indicates the side of the head affected, but it does not indicate the precise site of the tumor. The cause of the headache is a progressively enlarging mass causing displacement of, or traction on, pain-sensitive intracranial structures, producing a worsening headache [136,137].

Headaches are more common with posterior fossa tumors [136]. Colloid cysts of the third ventricle may produce explosive paroxysmal headaches that last minutes to several hours and may be brought on or alleviated by sudden changes in position. This occurs because they produce position-dependent intermittent obstruction.

Diagnosis is made by contrast-enhanced CT or MRI. MRI is most helpful for identifying tumors in the posterior fossa [136]. Scans should then be followed by histologic analysis (hence the phrase "tissue is the issue" in oncology). Depending upon several factors, including tumor type, degree of any metastasis, and comorbidities, treatment options include surgery, radiation, and/or chemotherapy.

INFECTIOUS CAUSES OF HEADACHES

In general, headaches related to infections tend to be painful, accompanied by nausea, and gradual in onset. Infections may be bacterial, viral, or fungal. The most common types of infections that cause headaches are meningitis, encephalitis, sinusitis, and brain abscess.

Meningitis

Meningitis is an inflammation of the meninges. The etiology of the meningitis may be bacterial, viral, or fungal.

Bacterial meningitis causes an abrupt diffuse headache associated with a high fever, altered consciousness (most commonly lethargy), focal neurologic deficits, and nuchal rigidity [43]. The severity of the headache and the acuteness of the infection are directly proportional. Focal neurologic deficits and papilledema are uncommon. Classically, a patient would show Kernig sign (i.e., resistance to knee extension following flexion of hips and knees) and Brudzinski sign (i.e., rapid flexion of the neck elicits involuntary flexing of the knees in a supine patient). However, a prospective study of 297 adults with suspected meningitis documented very low sensitivities for these signs (5% for Kernig sign; 5% for Brudzinski sign) indicating that their absence should not defer the performance of lumbar puncture [138]. In general, whenever the diagnosis of meningitis is strongly considered, a lumbar puncture should be promptly performed [139]. Laboratory studies reveal a CSF with more than 100 WBCs per mL and a protein level >100 mg/dL. CSF cell counts above 2,000/mL, a protein above 100 mg/dL, and a CSF-serum glucose ratio of <0.40 are all 99% specific for bacterial meningitis [139]. Treatment with antibiotics is usually empiric but may be modified by gram stain results. Typical organisms are Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae.

Viral meningitis causes a less severe headache that may develop over several days with a low-grade fever. The headache is usually frontal or retro-orbital. Other symptoms may include fever, irritability, nausea, vomiting, stiff neck, rash, or fatigue within the previous 18 to 36 hours. Meticulous history taking is essential and should include evaluation of exposure to ill contacts; mosquitoes, or ticks; outdoor activity in areas of endemic Lyme disease; travel history; history of medication use, including intravenous drug use; and risk of sexually transmitted disease [140]. Diagnosis may be made with the assistance of a CSF viral culture or the absence of a positive bacterial culture. Most cases of viral meningitis are caused by enteroviruses, such as coxsackieviruses and echoviruses. Herpes viruses and human immunodeficiency virus (HIV) may also cause viral meningitis. Therapy consists of bed rest, analgesics, fluids, and other conservative treatment [140].

Fungal meningitis gives a more chronic picture and may not be associated with fever or fever may be below normal. The headache is temporal, frontal, or retro-orbital. It becomes more frequent and severe over time and may be accompanied by irritability, nausea, vomiting, stiff neck, and hallucinations. Diagnosis is made by CSF analysis (fungal stain and culture, increased CSF pressure, elevated protein, decreased glucose [45% of blood glucose], and leukocytosis [40–400/mm^3—mostly mononuclear cells]). The most common organism is Cryptococcus neoformans [139]. Blastomyces and coccidioides may also cause fungal meningitis. The most common treatment is with amphotericin B, an intravenous therapy. Intrathecal medication is given to patients through the spinal cord who do not respond positively to IV therapy. Rarely, treatment may also consist of oral antifungal drug therapy [141].

Encephalitis

Encephalitis is an inflammation of the brain parenchyma. Encephalitis may be due to either infectious or noninfectious causes. Noninfectious causes include toxins, tumors, and connective tissue disorders.

Viral encephalitis is the most common infectious type. Examples include herpes, arboviruses, HIV, and cytomegalovirus. Typically, there is acute onset of low-grade fever, altered consciousness, vomiting, and sometimes seizures. There is often disorientation and some speech disturbances. Encephalitis may occur as a secondary complication after the administration of certain vaccines or during the course of an acute illness, such as measles. Dull, diffuse headache may also be present, although it is neither common nor prominent as a symptom. When present, the headache typically does not radiate. Headache is not as common a symptom as in meningitis [142].

Most cases of encephalitis are mild and benign in nature, with symptoms resolving over one to two weeks. When neurologic symptoms are present, it may take up to two months for symptoms to completely resolve. If associated with HIV, such infections may be life-threatening.

CSF examination is critical to establish the diagnosis and reveals moderate monocytosis and erythrocytosis with a variably elevated protein level. EEG is sensitive but not specific, and contrast CT is only 60% sensitive. It may be used, however, to evaluate acute disease progression and to follow up on complications. MRI is more sensitive than CT scan [142]. MRI with gadolinium enhancement is the preferred imaging study. One should keep in mind certain seasonal and geographic issues when differentiating specific etiologic agents.

Depending upon the etiology, treatment is mostly supportive (e.g., rest, fluid, electrolyte balance). For some conditions, antiretrovirals are available [142].

Sinusitis

Although the term "sinus headache" is widely used, sinus headaches are uncommon. Headaches due to sinusitis are confined to a small percentage of patients who have acute frontal sinusitis or sphenoiditis. Sinusitis rarely causes headache, let alone facial pain, except when there is an acute bacterial infection and the sinus in question cannot drain, and it is usually unilateral due to increased pressure and inflammation caused by pus trapped within the sinus cavity.

In acute rhinosinusitis, the patient may present with purulent nasal discharge, which is frequently associated with fever and leukocytosis [43]. The pain is felt as a deep, dull, heavy fullness that sometimes may be pulsatile. Shaking or flexion of the head, coughing, and sneezing exacerbate the pain. Sinus headache is seldom associated with nausea. In addition, it does not reach the same pain intensity of cluster headache or migraine. The vast majority of patients with acute sinusitis respond to antibiotics [143]. Plain radiography is generally obsolete, but exceptions include its use in confirming air-fluid levels in acute sinusitis [144]. MRI is generally reserved for the evaluation of any complications of local sinus infections, particularly suspected intracranial extension. A CT scan is highly sensitive and is the examination of choice in the evaluation of sinusitis, particularly in cases of chronic sinus disease [144]. However, it is usually not useful in acute sinusitis, as diagnosis in these cases is primarily based on clinical findings. Coronal CT imaging is the preferred initial procedure [144].

Diagnosis may be made by Gram stain of the discharge directly from the sinuses. This is a technique that is not commonly performed in the primary care office setting. The most common organism is Streptococcus. The treatment, therefore, is appropriate antibiotics, typically for 10 to 14 days. The use of local corticosteroids may offer the allergic individual added relief when nasal symptoms are prominent [145]. Decongestants are often added.

It is important to note that more than 90% of self- or physician-diagnosed sinus headaches meet the IHS criteria for migraine or probable migraine [145,146]. In those patients with migraine, the most common reasons for misdiagnosis include headache triggers, pain location, and associated features commonly attributed to sinus headache. The clinician should be aware of these unique presentations of migraine so that a correct diagnosis can be made and effective treatment instituted [145]. Additionally, a portion of patients with self-diagnosed sinus headache suffer from a headache type that is unclassifiable by the IHS criteria. These headaches are characterized by bilateral maxillary pressure, mild-to-moderate pain intensity, cranial autonomic symptoms, and the complete absence of migraine features [145].

Abscess

Brain abscesses are quite uncommon; however, when they do occur they are life-threatening. They may originate from a contiguous site of infection (e.g., sinusitis, dental infections, otitis media), hematogenous spread, or trauma. In at least 15% of cases, the source of the infection is unknown [43,146,147]. They occur usually in the first three decades of life. They are also more prevalent in immunocompromised patients [146].

A moderate-to-severe headache, frequently hemicranial, is a common complaint (70%) [147]. The level of pain remains constant and may be aggravated by straining [43]. Often, there is nuchal rigidity. Frontal lobe abscesses tend to present with headache more often than other regions. In more than half of the cases, patients present with fever, altered mental status, nausea, and vomiting. There may also be papilledema and seizures [146,147].

The time course of an abscess is reflected in the symptoms and usually progresses over one to two weeks [147]. Diagnosis is aided by CT, MRI, and nuclear medicine studies. In general, MRI provides better brain parenchymal differentiation than CT and shows the edema from the abscess in better detail [147]. The abscess is also better demonstrated because the routine brain MRI generally is multiplanar, as opposed to the routine CT, which is usually axial. However, MRI may not be useful in an acutely ill patient [146]. MR spectroscopy and some nuclear medicine studies may also be helpful to differentiate abscess from brain tumor [146]. Diffusion weighted MR may also give early indication of an infarction because this may be part of the sequelae of the abscess. Lumbar puncture is contraindicated due to its poor diagnostic yield and possible risk of herniation of the cerebellar tonsils [146,147].

The typical treatment is evacuation/drainage and an antibiotic regimen based on cultures. The most common organisms are Staphylococcus aureus, Streptococcus, Bacteroides species, and Enterobacter. Occasionally, intracranial tuberculosis or fungal infections may present as an abscess. Therefore, cultures for acid-fast bacilli and fungi should be done in all cases [43,146].

PRESSURE HEADACHES

Hypertension

High blood pressure is an infrequent cause of headaches. In general, it does not become a cause of headaches until diastolic blood pressure exceeds 120 mm Hg [43,148]. The association between blood pressure and headache is most clearly manifested in patients with systolic blood pressure greater than 200 mm Hg [148]. Whether moderate hypertension predisposes to headache at all remains controversial, but there is some evidence that it does [43].

Headaches associated with high blood pressure usually appear in the morning. Typically, the headache eases as the patient gets up and about [43,148]. It is usually dull, although sometimes throbbing, and is either diffuse or bioccipital in location. Infrequently, it is bifrontal in location. As blood pressure increases, there is often nausea, vomiting, and visual disturbances. As elevation of blood pressure progresses further, seizures and confusion may develop.

Malignant hypertension occurs when there is evidence of end-organ damage. On funduscopy, one will see papilledema and retinal hemorrhages. A diagnosis of malignant hypertension is based on the association of severely elevated blood pressure (e.g., >130 mm Hg) with severe hypertensive retinopathy [149]. The average age at diagnosis is 40 years, although a wide range of ages has been observed. Men are affected more often than women and black individuals more often than whites [150,151]. Despite progress in the overall management of hypertension, the prevalence of malignant hypertension has remained stable over the past 30 to 40 years [149].

Routine screening consists of a chest radiograph, which is useful for assessment of cardiac enlargement, pulmonary edema, or involvement of other thoracic structures. Other tests (e.g., head CT scan, transesophageal echocardiogram, renal angiography) may be indicated if directed by the initial workup. An EKG is an essential part of the evaluation to screen for ischemia, infarct, or evidence of electrolyte abnormalities or drug overdose [151]. Treatment consists of slowly reducing pressure. Too rapid a decline may cause cerebral hypoperfusion and coronary insufficiency. Recommendations advise reduction of mean arterial pressure by 25% over the first 24 to 48 hours [151]. Nitroprusside has been the drug of choice [151].

It is important not to misdiagnose the normal reactive hypertension that follows an ischemic stroke as hypertensive encephalopathy. In addition, a sudden increase in blood pressure may be the result of illicit drugs, such as cocaine or methamphetamine; this sudden increase may cause a headache [151]. Patients using MAOIs who ingest tyramine may also exhibit a precipitous rise in blood pressure that will cause a headache.

Idiopathic Intracranial Hypertension

Idiopathic intracranial hypertension (IIH) (formerly referred to as pseudotumor cerebri or benign intracranial hypertension) is characterized by increased intracranial pressure without evidence of a tumor, obstruction, infection, or encephalopathy [43,152]. The etiology is unknown [153]. Although benign, it is not without morbidity.

A majority of patients present with papilledema (although IIH without papilledema has been observed), progressive visual loss, sixth-nerve palsies (10% to 40%), and headache [43,152]. Headache is the most common symptom and is usually pulsatile and of mild severity. It is usually chronic in duration and can either be bilateral or unilateral; the most common presentation is bifrontotemporal. Overall, the patient appears in relatively reasonable health, although there may be some gastrointestinal upset [153,154].

Incidence is greatest in young obese females. Risk factors include corticosteroid use, pregnancy, large doses of vitamin A, adrenal and parathyroid disease, and venous sinus thrombosis [43,153].

The diagnosis is one of exclusion. Brain MRI with gadolinium enhancement is the study of choice for most patients with IIH because it provides sensitive screening for hydrocephalus, intracerebral masses, meningeal infiltrative or inflammatory disease, and dural venous sinus thrombosis. MR venography may be useful for patients who are at greater risk for dural venous sinus thrombosis. Brain CT scan is less expensive than MRI and is adequate to rule out larger tumors or lesions, but it is not as sensitive as MRI for meningeal infiltration and/or dural venous sinus thrombosis. On lumbar puncture, CSF pressure is elevated with a low protein level [153].

This condition may resolve spontaneously, although it may take several months to a year to completely resolve. Analgesics typically are given for the headache. Acetazolamide, or other diuretics, may be considered as well as serial lumbar punctures to drain fluid. Corticosteroids are sometimes used if there is impending visual loss. In rare circumstances, surgery consisting of lumboperitoneal shunting may be performed when the condition is refractory [153].

METABOLIC/TOXIC CAUSES OF HEADACHES

Carbon Monoxide

Numerous toxins may cause headache as a sequela. Carbon monoxide is one of the more common causes of poisoning and represents the most frequent cause of toxin-induced death. This poisoning most commonly occurs when there is inadequate or faulty ventilation. Examples of sources include car exhausts, propane heaters, and gasoline-powered generators [153,155,156,157].

Patients typically present with headache, altered mental status (most commonly confusion), nausea, chest pain, and dizziness. Cherry-red discoloration of the skin and lips has been described but is a rare manifestation. The acuity and time of exposure determine the degree of symptoms [43]. High levels may cause loss of consciousness and death [153,155,156].

High clinical suspicion is necessary as this condition mimics other illnesses with nonspecific symptoms, including significant myocardial damage. A complete blood count and arterial blood gas analysis are helpful in aiding the diagnosis. Often, there is a metabolic acidosis with an anion gap; in addition, there may be neutrophilia. Diagnosis is made through measuring venous or arterial carboxyhemoglobin, which will be elevated (>2% nonsmokers, >9% smokers). Treatment involves 100% oxygen. Some patients may need to undergo hyperbaric treatment. In severe cases of poisoning, there may be residual brain damage [158].

Lead Poisoning

Lead poisoning is fairly uncommon in adults. In general, it takes years of exposure before symptoms become apparent. Whereas children usually become exposed due to lead-based paint in old homes, adults can develop lead poisoning through occupational exposures [159].

Symptoms include headache, which generally is diffuse and nonspecific, irritability, confusion, mood disorders, and sleep problems. As levels become toxic, patients develop ataxia and convulsions [159].

Diagnosis is based on symptoms and blood or urine tests for lead. Treatment involves chelation therapy in severe cases, as well as removal of the source of exposure [159].

OTHER CAUSES OF SECONDARY HEADACHES

Syringomyelia

Syringomyelia is an uncommon presentation of headache. It is a condition in which a cyst forms within the spinal cord, either congenitally or due to trauma, malignancy, infection, or hemorrhage. In most cases, the disorder is related to a congenital abnormality of the brain called a Chiari malformation. This malformation occurs during the development of the fetus and causes the lower part of the cerebellum to protrude from its normal location in the back of the cranium into the cervical portion of the spinal canal [160].

The cyst, or syrinx, gradually expands and elongates over time, eventually resulting in destruction of the cord's center. As a result, patients may present with a variety of symptoms, although they typically present with headache, back pain and stiffness, and numbness of the extremities [160]. Symptoms usually begin between 25 and 40 years of age; they are more common in men than women and may worsen with straining (e.g., heavy lifting) or any activity that causes CSF pressure to fluctuate [160].

Signs of the disorder tend to develop slowly, although sudden onset may occur with coughing or straining. In addition, there are often long periods of stability. The preferred imaging modality is MRI, which shows dilation of the central canal and may reveal contributing factors (e.g., a tumor). The usual treatment when significant symptoms are present is surgery, which involves drainage of the syrinx. If not treated surgically, syringomyelia may lead to progressive weakness in the arms and legs, loss of hand sensation, and chronic, severe pain [160].

In the absence of symptoms, syringomyelia is usually followed by observation over time. Patients are advised to avoid activities that involve straining [160].

Dental and Myofascial Causes

There may be times when referral to a dentist is appropriate for headache management. Disorders of the teeth usually cause toothache and/or facial pain; those causing headache are rare. Pain from the teeth may be referred, however, and cause diffuse headache. The most common cause of headache is periodontitis or pericoronitis as the result of infection or traumatic irritation around a partially-erupted lower wisdom tooth [43].

Myofascial pain dysfunction (MPD) syndrome (formerly called temporomandibular joint or TMJ syndrome) originates in the muscles that move the jaw. Symptoms include dull, aching pain in and around the ear, which may radiate to the side of the scalp, back of the head, or down into the neck. In the majority of instances, the source of pain is an overuse of the masticatory musculature through parafunction. The most common dental parafunctional habits are bruxism and clenching. The patient is often unaware of the habit, which may take place while asleep [161].

Initial therapy is directed at relief of muscle spasms and involves use of heat, massage, a soft and non-chewy diet, muscle relaxing, and pain-reducing medications. For many patients, one or two weeks of such treatment is sufficient to eliminate the symptoms. Early treatment is important to prevent shifting of the jaw and arthritic changes in the jaw joint [161].

Cervicogenic Headache

Cervicogenic headache is often a sequela of head or neck injury but may also occur in the absence of trauma [162]. With this type of headache, the pain is perceived to be in the head but is actually referred from the cervical spine. Typically, the pain may be characterized as insidious in nature and unilateral in position [163]. The parietal and occipital areas are most commonly affected. The pain is usually fairly constant and may last for days to weeks. It is aggravated by neck movements. On exam, there is usually cervical paraspinal tenderness. The source of pain is usually the cervical ligaments or intervertebral discs [162].

The mean age of patients with this condition is 43 years, and it is four times more prevalent in women than in men [162,163]. Diagnostic criteria have been established, but the presenting characteristics of cervicogenic headache are often difficult to distinguish from primary headaches disorders, such as tension-type headache [43,162]. Additionally, there are significant differences, especially with respect to quality of life. In a study comparing responses on a medical outcomes questionnaire for patients with cervicogenic headache, episodic tension-type headache, and patients with migraine without aura, domain scores for physical functioning for patients with cervicogenic headache were lower than the tension-type and migraine groups [164].

Diagnostic imaging cannot confirm the diagnosis of cervicogenic headache but may lend support to its diagnosis. Successful treatment requires a multifaceted approach, including using pharmacologic, nonpharmacologic, manipulative, anesthetic, and occasionally surgical interventions. Medications alone have proven to be ineffective or, at best, to provide only modest benefit [162,163].

Medication Overuse

Medication overuse headache, also known as rebound headache, results from misuse of drugs, most notably over-the-counter analgesics or migraine medications. It is most common in patients with frequent migraine attacks or tension-type headaches [165]. Chronic tension-type headache is less often associated with medication overuse; however, episodic tension-type headache has commonly become a chronic headache through overuse of analgesics [43]. The headache is caused by frequent use of anti-headache medications for more than 15 days per month. Evidence suggests that this occurs sooner with triptan overuse than with ergotamine overuse [43,166]. The mean period of time that elapses before this type of headache evolves ranges from one to two years for the triptans, three to five years for ergotamines, and up to 5 to 10 years for over-the-counter analgesics [167]. The pathophysiology of this syndrome remains unknown.

The diagnosis of medication-overuse headache is clinically extremely important because patients rarely respond to preventative medications while overusing acute medications [43]. Treatment is withdrawal from the medication. If tapered, this may take more than two weeks, depending on the medication. Improvement should occur within two months after cessation of overuse in order for the diagnosis to be definite [43]. This is followed by prophylactic treatment of the primary headache [165,166].

Herbal Medications

It is important to consider the use of herbal medications as a possible cause of headaches. Approximately 38% of adults in the United States use at least one herbal medicine [168]. Many patients do not admit use to physicians, either because they do not consider them to be a "medication," because they do not need a prescription to obtain them, or because they are embarrassed to admit they use a medication that most physicians do not consider scientific. Herbal medications that have been reported to cause headaches include valerian root, ginkgo biloba, and ginseng [169].

7. ACUTE VERSUS CHRONIC

Although chronic headache is a term often used by patients, as well as some clinicians, it is no longer a recognized diagnosis. Patients either have a chronic primary headache or a chronic secondary headache. Chronic daily headache occurs in approximately 4% to 5% of the population [170,171]. The overwhelming majority of chronic headaches are primary headaches, typically migraine or tension. Chronic headache is not a separate syndrome. The general time frame for chronic is when the headache occurs on more than 15 days of each month, whether or not the patient is taking any medication.

8. REFERRAL

Evidence Based Practice Recommendation

The decision to seek a specialty consultation will depend upon the practitioner's familiarity and comfort with headache and its management. The Institute for Clinical Systems Improvement recommends considering specialty consultation when:

- The diagnosis cannot be confirmed.

- Etiology cannot be diagnosed or warning signals are present.

- Headache attacks are occurring with a frequency or duration sufficient to impair the patient's quality of life despite treatment or the patient has failed to respond to acute remedies or is in status migrainosus.

https://www.icsi.org/wp-content/uploads/2019/01/HeadacheRR.pdf

Last Accessed: April 5, 2022

Level of Evidence: Expert Opinion/Consensus Statement

One of the most important decisions in managing patients with headaches, especially chronic headaches, is when to continue care and when to refer care. In general, most patients with benign headaches can be managed by primary care physicians and other clinicians. There are several factors involved when one should consider referral to a specialist. These include, but are not limited to:

- Minimal physician expertise in headache management

- Unable to determine diagnosis

- Failure of the patient to respond to appropriate treatment

- Worsening symptoms

- Development of rebound cycles

- Dependence on opioids

- Significant comorbidities

When one or more of these conditions exist, referral to a specialist should be considered. Specialists typically are neurologists, although some are internists and family practitioners who focus their clinical practice on headache management. Headaches represent the most common reason for neurology visits [172]. Therefore, physicians should not view referral as failure on their part.

9. MEDICO-LEGAL ISSUES

With rising malpractice premiums, the threat of malpractice remains high on the minds of many healthcare professionals. With respect to headaches, physicians are fearful of missing that rare brain tumor or other catastrophic cause of headache. When such a misdiagnosis occurs, a malpractice claim may ensue. Any malpractice action falls under tort law.

Tort law allows injured persons to recover damages through the civil (i.e., noncriminal) judicial system. It is important to note that injury is a necessary but not sufficient requirement for recovery and most injuries do not give rise to a legal action. In the context of medical malpractice suits, the most relevant aspect of tort law is negligence as that is the claim most plaintiffs raise. A common claim for headache management is "failure to diagnose."

Not all bad outcomes, however, support a claim for negligence. There are several necessary components to negligence, all of which must be present for a plaintiff to prevail. First, the defendant must have owed some duty to the plaintiff to adhere to a specific standard of conduct and protect the plaintiff from unreasonable risk of injury. In the context of the doctor-patient relationship, this duty is for the physician to meet the standard of care for his or her profession. Generally the standard of care is the knowledge and skill held by a member of the profession in the same community or a similar community. The standard of care for specialists is somewhat higher as it is based on the knowledge and skill held by specialists.

Second, the defendant must have breached this duty by deviating from the standard of care. Such a deviation may be either an act or an omission. Finally, this breach of duty must be the actual and proximate cause of the plaintiff's injury. This means that a physician might make a clear medical error but if that error proves harmless and does not actually cause any injury to the patient, there is no legitimate claim for negligence.

In order to minimize malpractice, physicians and other clinicians should document their actions and thought processes in the medical record. In addition, it is imperative that physicians keep up-to-date on the management of the conditions that they treat. If one has little expertise in headache management and the patient's condition is not improving, one should then consider referral.

10. CONCLUSION

Headaches represent one of the most common medical conditions and are a frequent reason for physician visits. They produce a significant socioeconomic cost in terms of lost work and decreased quality of life. In general, most headaches will be benign; however, there should be a thorough history and physical exam each time a patient presents with headaches. The majority of headaches will be primary in origin (i.e., migraine, tension, cluster), but secondary causes need to be excluded. Physicians should be aware of the warning signs that warrant an immediate and thorough work-up and realize that a patient may have more than one headache disorder. Various imaging modalities, such as CT, MRI, and PET, exist but should be used prudently, based on clinical presentation and clinical suspicion of disease.

Numerous treatment modalities exist to treat the various headache syndromes. Therapies for primary headaches include both pharmacologic and nonpharmacologic interventions. Preventive therapies also should be explored for patients with repeat headaches. Finally, primary care physicians and clinicians should know when to refer patients to a specialist.

11. ADDITIONAL SOURCES OF INFORMATION

American Migraine Foundation

https://americanmigrainefoundation.org

American Headache Society (AHS)

https://americanheadachesociety.org

Help for Headaches

http://www.headache-help.org

International Headache Society

https://ihs-headache.org

National Headache Foundation

https://headaches.org

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179. U.S. Food and Drug Administration. Highlights of Prescribing Information: Ajovy (Fremanezumab-vfrm). Available at https:// www.accessdata.fda.gov/drugsatfda_docs/label/2018/761089s000lbl.pdf. Last accessed April 5, 2022.

180. U.S. Food and Drug Administration. Highlights of Prescribing Information: Emgality (Galcanezumab-gnlm). Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761063s000lbl.pdf. Last accessed April 5, 2022.

181. U.S. Food and Drug Administration. FDA Approves First Treatment for Episodic Cluster Headache that Reduces the Frequency of Attacks. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-episodic-cluster-headache-reduces-frequency-attacks. Last accessed April 5, 2022.

182. CEFALY US. FDA-Approved Cefaly Device to Stop Migraines Now Available. Available at https://www.cefaly.us/blog/1114/fda-approved-cefaly-device-stop-migraines-now-available. Last accessed April 5, 2022.

183. U.S. Food and Drug Administration. 510(k) Summary: Cefaly. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf17/K171446.pdf. Last accessed April 5, 2022.

184. Birlea M, Penning S, Callahan K, Schoenen J. Efficacy and safety of external trigeminal neurostimulation in the prevention of chronic migraine: An open-label trial. Cephalalgia Reports. 2019;2:1-10.

185. Chou DE, Shnayderman Yugrakh M, Winegarner D, et al. Acute migraine therapy with external trigeminal neurostimulation (ACME): a randomized controlled trial. Cephalalgia. 2019;39(1):3-14.

186. U.S. Food and Drug Administration. gammaCore Sapphire: 510(k) Premarket Notification. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf18/K182369.pdf. Last accessed April 5, 2022.

187. Tasorelli C, Grazzi L, de Tommaso M, et al. Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study. Neurology. 2018;91(4):e364-e373.

188. Goadsby PJ, de Coo IF, Silver N, et al. Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study. Cephalalgia. 2018;38(5):959-969.

189. U.S. Food and Drug Administration. Device Classification Under Section 513(f)(2)(de novo). Available at https://www.accessdata.fda.gov/cdrh_docs/pdf18/DEN180059.pdf. Last accessed April 5, 2022.

190. Brooks M. FDA Okays Smartphone-Controlled Wearable for Migraine Pain. Available at https://www.medscape.com/viewarticle/913538. Last accessed April 5, 2022.

191. Chawla J. What is the Efficacy of Cerena Transcranial Magnetic Stimulator (Cerena TMS) for the Treatment of Migraine Headache? Available at https://www.medscape.com/answers/1142556-170283/what-is-the-efficacy-of-cerena-transcranial-magnetic-stimulator-cerena-tms-for-the-treatment-of-migraine-headache. Last accessed April 5, 2022.

192. Ashina M. Migraine. N Eng J Med. 2020;383:1866-1876.

193. Kuca B, Silberstein SD, Wietecha L, et al. Lasmiditan is an effective acute treatment for migraine: a phase 3 randomized study. Neurology. 2018;91(24):e2222-e2232.

194. PR Newswire. Now Over-the-Counter: FDA Clears CEFALY DUAL Migraine Treatment for Use Without a Prescription. Available at https://www.prnewswire.com/news-releases/now-over-the-counter-fda-clears-cefaly-dual-migraine-treatment-for-use-without-a-prescription-301150599.html. Last accessed April 5, 2022.

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Evidence-Based Practice Recommendations Citations

1. Douglas AC, Wippold FJ II, Broderick DF, et al. ACR Appropriateness Criteria: Headache. Reston, VA: American College of Radiology; 2013. Available at https://acsearch.acr.org/docs/69482/Narrative. Last accessed April 5, 2022.

2. Beithon J, Gallenberg M, Johnson K, et al. Diagnosis and Treatment of Headache. Bloomington, MN: Institute for Clinical Systems Improvement; 2013. Available at https://www.icsi.org/wp-content/uploads/2019/01/HeadacheRR.pdf. Last accessed April 5, 2022.

3. Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(19):1818-1826. Available at http://n.neurology.org/content/86/19/1818.full. Last accessed April 5, 2022.

94453 • Autoimmune Diseases

Lori L. Alexander, MTPW, ELS, MWC

John M. Leonard, MD

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

This course provides an overview of the current understanding of the pathogenesis of autoimmune diseases and to present evidence-based approaches to the diagnosis, treatment, and follow-up for five autoimmune diseases. The five conditions discussed here represent a range of autoimmune diseases, including autoimmune thyroiditis, the most prevalent autoimmune disease; rheumatoid arthritis, systemic lupus, and Sjögren syndrome, the leading rheumatic autoimmune diseases; and celiac disease, an autoimmune disease of the gut with an increasing prevalence. The discussion of diagnosing each of the five conditions emphasizes differentiating characteristics of each disease and the need to evaluate patients for signs of other autoimmune diseases that are frequently found concurrently. Throughout, evidence-based approaches are described, when available, and patient education is highlighted, as self-management is an essential component in the treatment of a chronic disorder.

Table of Contents

94453 • Autoimmune Diseases

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. OVERVIEW OF AUTOIMMUNE DISEASES

PATHOGENESIS

RISK FACTORS

GENERAL CHARACTERISTICS

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

3. THYROIDITIS

EPIDEMIOLOGY

POTENTIAL ENVIRONMENTAL RISK FACTORS

ASSOCIATION WITH OTHER AUTOIMMUNE DISEASES

CLINICAL MANIFESTATIONS

DIAGNOSTIC EVALUATION

SCREENING FOR THYROID DISEASE

TREATMENT OPTIONS

FOLLOW-UP AND PROGNOSIS

PATIENT EDUCATION

4. RHEUMATOID ARTHRITIS

EPIDEMIOLOGY

POTENTIAL ENVIRONMENTAL RISK FACTORS

ASSOCIATION WITH OTHER AUTOIMMUNE DISEASES

CLINICAL MANIFESTATIONS

DIAGNOSTIC EVALUATION

TREATMENT OPTIONS

FOLLOW-UP AND PROGNOSIS

PATIENT EDUCATION

5. SYSTEMIC LUPUS ERYTHEMATOSUS

EPIDEMIOLOGY

POTENTIAL ENVIRONMENTAL RISK FACTORS

ASSOCIATION WITH OTHER AUTOIMMUNE DISEASES

CLINICAL MANIFESTATIONS

DIAGNOSTIC EVALUATION

REFERRAL

TREATMENT OPTIONS

FOLLOW-UP AND PROGNOSIS

PATIENT EDUCATION

6. SJÖGREN SYNDROME

EPIDEMIOLOGY

POTENTIAL ENVIRONMENTAL RISK FACTORS

ASSOCIATION WITH OTHER AUTOIMMUNE DISEASES

CLINICAL MANIFESTATIONS

DIAGNOSTIC EVALUATION

TREATMENT OPTIONS

FOLLOW-UP AND PROGNOSIS

PATIENT EDUCATION

7. CELIAC DISEASE

EPIDEMIOLOGY

POTENTIAL ENVIRONMENTAL RISK FACTORS

ASSOCIATION WITH OTHER AUTOIMMUNE DISEASES

CLINICAL MANIFESTATIONS

DIAGNOSTIC EVALUATION

TREATMENT OPTIONS

FOLLOW-UP AND PROGNOSIS

PATIENT EDUCATION

8. CASE STUDY

9. ONLINE PATIENT EDUCATION RESOURCES

10. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

94453 • Autoimmune Diseases

Education Category. Infection Control / Internal Medicine

Release Date. 08/01/2020

Expiration Date. 07/31/2023

Course Overview

This course provides an overview of the current understanding of the pathogenesis of autoimmune diseases and to present evidence-based approaches to the diagnosis, treatment, and follow-up for five autoimmune diseases. The five conditions discussed here represent a range of autoimmune diseases, including autoimmune thyroiditis, the most prevalent autoimmune disease; rheumatoid arthritis, systemic lupus, and Sjögren syndrome, the leading rheumatic autoimmune diseases; and celiac disease, an autoimmune disease of the gut with an increasing prevalence. The discussion of diagnosing each of the five conditions emphasizes differentiating characteristics of each disease and the need to evaluate patients for signs of other autoimmune diseases that are frequently found concurrently. Throughout, evidence-based approaches are described, when available, and patient education is highlighted, as self-management is an essential component in the treatment of a chronic disorder.

Audience

This course is designed for physicians, physician assistants, nurses, and other healthcare professionals involved in the diagnosis, treatment, and care of patients with autoimmune diseases.

Course Objective

The purpose of this course is to provide healthcare professionals with the information necessary to diagnose and treat the most common autoimmune diseases according to evidence-based or guideline-endorsed recommendations in order to improve patient quality of life.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe the impact and pathogenesis of autoimmune diseases in the United States.

2. Recognize genetic and environmental risk factors for autoimmune diseases.

3. Evaluate the general characteristics of autoimmune diseases, including the difficulty in reaching a diagnosis.

4. Identify approaches to the management of autoimmune diseases, with special attention to considerations for patients with limited English proficiency and/or health literacy.

5. Analyze the epidemiology, clinical manifestations, and diagnostic criteria of autoimmune thyroiditis.

6. Select the appropriate treatment for Hashimoto disease and Graves disease in various patient populations.

7. Appropriately identify and diagnose rheumatoid arthritis according to established diagnostic criteria and clinical manifestations.

8. Outline the recommended treatment of rheumatoid arthritis using pharmacologic and nonpharmacologic interventions.

9. Discuss the importance of follow-up and patient education in the treatment of patients with rheumatoid arthritis.

10. Evaluate the impact and diagnosis of systemic lupus erythematosus (systemic lupus), including indications for appropriate referral.

11. Analyze the available treatments for systemic lupus, including considerations for follow-up and prognosis.

12. Apply the available diagnostic criteria to identify and treat Sjögren syndrome.

13. Evaluate the clinical manifestations of celiac disease

14. Describe the components necessary to diagnose and treat celiac disease.

Faculty

Lori L. Alexander, MTPW, ELS, MWC, is President of Editorial Rx, Inc., which provides medical writing and editing services on a wide variety of clinical topics and in a range of media. A medical writer and editor for more than 30 years, Ms. Alexander has written for both professional and lay audiences, with a focus on continuing education materials, medical meeting coverage, and educational resources for patients. She is the Editor Emeritus of the American Medical Writers Association (AMWA) Journal, the peer-review journal representing the largest association of medical communicators in the United States. Ms. Alexander earned a Master’s degree in technical and professional writing, with a concentration in medical writing, at Northeastern University, Boston. She has also earned certification as a life sciences editor and as a medical writer.

John M. Leonard, MD, Professor of Medicine Emeritus, Vanderbilt University School of Medicine, completed his post-graduate clinical training at the Yale and Vanderbilt University Medical Centers before joining the Vanderbilt faculty in 1974. He is a clinician-educator and for many years served as director of residency training and student educational programs for the Vanderbilt University Department of Medicine. Over a career span of 40 years, Dr. Leonard conducted an active practice of general internal medicine and an inpatient consulting practice of infectious diseases.

Faculty Disclosure

Contributing faculty, Lori L. Alexander, MTPW, ELS, MWC, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Contributing faculty, John M. Leonard, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

The autoimmune diseases are comprised of a great many disorders affecting multiple body systems/organs and sharing a common pathophysiology: immune activation directed against "self." It is difficult to determine the overall burden of autoimmune diseases, because few epidemiologic studies focus on them as a single entity and because many are uncommon and ill-defined. However, the study of individual autoimmune diseases, combined with some data on the diseases collectively, indicates that the burden is substantial in terms of the number of persons affected and the associated morbidity, mortality, and financial cost.

The National Institutes of Health (NIH) estimates that 23.5 million persons (8.5% of the population) have been diagnosed with one or more of the 29 most common and best-studied autoimmune diseases, and the prevalence is considered to be rising [4,5]. When less well-studied syndromes are taken into account, an estimated 50 million individuals in the United States suffer from autoimmune-mediated disorders, a number greater than that for heart disease (26.6 million) and cancer (14.5 million) combined [1,2,309].

Autoimmune diseases are chronic illnesses, with most having no available cure. As a result, lifelong treatment is needed for diseases that cause substantial morbidity, disability, mortality, and costs. Approximately $100 billion in annual direct healthcare costs are attributed to autoimmune diseases [1].

The diagnosis of an autoimmune disease is often difficult to come by; in early-stage disease, the symptoms and signs are often subtle, nonspecific, and confusing [310]. According to a survey conducted by the American Autoimmune Diseases Association, individuals who had been diagnosed with a serious autoimmune disease had seen an average of five physicians over a period of 4.6 years before a correct diagnosis was made [310]. In addition, more than 45% of individuals with an autoimmune disease reported that they had been labeled as a chronic complainer in the early stages of their disease because no cause for their symptoms could be determined [310].

Evidence-based guidelines for diagnosis, management, and/or follow-up are available for some autoimmune diseases, but diagnosis continues to be a challenge because symptoms are often overlapping and definitive diagnostic testing is lacking for most diseases. Problems exist even when guidelines are available; some guidelines predate the emergence of more effective treatment or lack clinical utility [6,7,8,10,11]. In addition, guidelines are associated with low rates of familiarity and adherence, especially with respect to recommendations for follow-up. For example, despite guidelines recommending routine monitoring of thyroid-stimulating hormone (TSH) levels for individuals taking medication for Hashimoto hypothyroidism, studies have shown that up to 40% of these individuals have abnormal TSH levels [12,13]. In addition, adherence to some recommendations for the treatment of systemic lupus erythematosus (systemic lupus), the monitoring of its comorbidities, and the prevention of glucocorticoid-induced osteoporosis have been found to be suboptimal [11,14,15].

This course provides an overview of the current understanding of the pathogenesis of autoimmune disease and specifically addresses the diagnosis and management of the leading autoimmune diseases in adults: thyroiditis (the most prevalent autoimmune disorder), rheumatoid arthritis, systemic lupus, Sjögren syndrome, and celiac disease (an increasingly prevalent autoimmune disease of the gut) [16,17]. Although autoimmune mechanisms may be important in the initial pathogenesis of type 1 diabetes, the natural history of this disease is determined primarily by fixed pancreatic islet cell deficiency rather than chronic immune-mediated inflammation; thus, it will not be covered by this course. Each disease section includes details on epidemiology; potential environmental risk factors; association with other autoimmune diseases; diagnosis, with a focus on established diagnostic criteria and differential diagnosis; treatment options, primarily those based on evidence in guidelines and other systematic reviews and meta-analyses; and recommendations for follow-up. Patient education is highlighted, as self-management is an essential component in the treatment of a chronic disorder [18,19].

2. OVERVIEW OF AUTOIMMUNE DISEASES

Autoimmune disease is thought to encompass an array of 80 to 100 disorders, with considerable variation in the body system/organ affected and associated morbidity [1]. Researchers have identified direct evidence (the ability to transfer autoimmune disease) for 15 autoimmune diseases, and there is indirect evidence (the ability to reproduce the autoimmune disease in animal models) and circumstantial evidence (the association of autoantibodies with disease in appropriate clinical settings) for an autoimmune component in more than 80 additional diseases [3].

The autoimmune diseases with the highest reported prevalence rates are Graves disease, rheumatoid arthritis, and Hashimoto thyroiditis; prevalence rates are lower for such diseases as celiac disease and autoimmune hepatitis [21,22,23]. Among the other more commonly occurring autoimmune diseases are systemic lupus, Sjögren syndrome, multiple sclerosis, myasthenia gravis, inflammatory bowel diseases (e.g., ulcerative colitis, Crohn disease), pernicious anemia, scleroderma, primary biliary cirrhosis, Addison disease, and thrombocytopenic purpura [24]. Estimates of the prevalence of fibromyalgia have been similar to that of common autoimmune diseases [25].

The prevalence of autoimmune diseases differs according to gender, age, and race/ethnicity. Most autoimmune diseases occur far more frequently in female individuals than in male individuals, and although these diseases do occur at any age, most develop during the middle adult years, which represents the childbearing years for women [310]. Some diseases, such as type 1 diabetes, have an onset primarily in childhood and adolescence, and others, such as rheumatoid arthritis, occur primarily among older adults [21]. Differences in the prevalence of autoimmune diseases according to race/ethnicity are only beginning to emerge, and the variations have been studied only within the context of individual diseases [21].

Many autoimmune diseases follow a progressive course, even with appropriate management, and serious or life-threatening complications may develop. Functional limitations, disability, and poor quality of life are substantial concerns. For example, arthritis and rheumatism are one of the leading causes of disability in the United States, affecting as many as 8.6 million people and causing significant declines in ability to perform activities of daily living [26].

Although no autoimmune disease has been listed among the 10 leading causes of death, the aggregate mortality rate for all autoimmune diseases ranked eighth among the leading causes of death in women younger than 65 years of age in the United States in 1995 (Table 1) [27]. Similarly, researchers found that an autoimmune disease was the sixth or seventh most frequent underlying cause of death among female individuals younger than 75 years of age in England and Wales in 2003 [28]. In both studies, rheumatic fever/heart disease, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes were among the leading underlying causes of death [27,28].

Table 1: DEATHS FOR WOMEN WITH AN AUTOIMMUNE DISEASE AS AN UNDERLYING CAUSE (UNITED STATES, 1995)

Autoimmune Disease

Death Counts by Age

25 to 44 Years

45 to 64 Years

>65 Years

All Ages

Rheumatic fever/heart disease

177

582

2,832

3,613

Rheumatoid arthritis

14

183

1,244

1,442

Multiple sclerosis

254

620

514

1,391

Systemic lupus erythematosus

338

353

356

1,118

Systemic sclerosis (scleroderma)

85

318

490

902

Glomerulonephritis

44

88

745

893

Type 1 diabetesa

269

NA

NA

330

Autoimmune hepatitis

12

51

135

201

Idiopathic thrombocytic purpura

21

29

134

188

Myasthenia gravis

9

14

150

174

Autoimmune hemolytic anemia

2

11

77

93

Pernicious anemiab

0

2

68

70

Sjögren syndromeb

1

16

43

60

Graves disease

4

3

15

24

Thyroiditis

2

2

0

6

Vitiligob

0

0

0

0

aDeaths related to type 1 diabetes were included only for individuals younger than 35 years of age.

bDiseases without specific International Classification of Diseases categories.

Source: [27]

Much is still unknown about how autoimmune diseases develop, but investigators have explored host, genetic, and environmental factors and continue to evaluate potential pathways [29].

PATHOGENESIS

The human immune system is a complex, elegant mechanism for responding in balanced (modulated) fashion to a wide range of foreign proteins and other substances (antigens) that gain access to the body, while maintaining tolerance to self. This system provides defense against harmful bacteria, viruses, and even cancer cells. In a subset of the population, on occasion and in response to particular antigenic stimulation, a balanced, modulated response is lost, and unregulated immune activation produces ongoing inflammation and loss of tolerance to "self" [30]. The resulting autoimmunity can lead to a chronic inflammatory state (autoimmune disorder), with potential to cause serious damage to cells, tissues, and organs [31]. Virtually any organ system can be affected; often the dysregulated immune response targets a specific organ, as in thyroiditis, or multiple organs, as in systemic lupus.

In organ-specific diseases, such as thyroiditis, type 1 diabetes, inflammatory bowel disease, or multiple sclerosis, a normal immune response is misdirected against a self-antigen or organ, and inflammation and production of autoantibodies are usually confined to antigens specific to the target organ [31]. Multiple organs are targets in systemic autoimmune diseases, such as systemic lupus, Sjögren syndrome, or systemic sclerosis. In these types of autoimmune diseases, autoantibodies are directed to different autoantigens, typically resulting in chronic activation of innate and adaptive immune cells and an array of clinical manifestations [31]. Some autoimmune diseases are characterized by an organ-specific immune process but are systemic because they also involve autoantibodies to autoantigens outside of a specific organ. For example, rheumatoid arthritis is primarily a joint-selective disease, but other autoantibodies can cause extra-articular manifestations [31].

Organ-specific autoimmune diseases differ according to whether disease is mediated primarily though autoantibodies, autoreactive T cells, or a combination of the two [31]. Systemic autoimmune diseases may be categorized according to the prevailing character of the autoimmune response as cell-mediated, autoantibody-mediated, or immune complex disease. T-cell or B-cell activation causes tissue damage directly by binding to cell-surface autoantigens, or indirectly by forming antibody-antigen complexes that become deposited in tissues. The autoimmune inflammatory process often becomes self-perpetuating, as tissue damage leads to the release of cytokines, activated T cells, and additional self-antigens, thereby stimulating and augmenting the immune response.

The detection of an autoantibody is not necessarily indicative of an active autoimmune disease, as some autoantibodies, such as rheumatoid factor and antinuclear antibodies, are found in individuals without evidence of a specific inflammatory disease process. In addition, autoantibodies can be detected years before a related autoimmune disease develops [33]. Some level of autoimmunity is, in fact, present in all individuals, which means that other factors must be involved in the development of an autoimmune disease [34].

RISK FACTORS

Genetic Factors

Genetics have been found to play a major role in rendering a person susceptible to an autoimmune disease. In general, autoimmune diseases occur concurrently within affected individuals and their families at higher than expected rates, but there are differences in the diseases that cluster within families [4]. The mode of inheritance of an autoimmune disease is complex, and research indicates that the genes involved in autoimmune disorders are pleiotropic (meaning they affect more than one trait) rather than disease-specific [4]. This research suggests that common alleles may have the potential for alternate clinical phenotypes under different sets of genetic and environmental factors, and data support the premise that clinically distinct autoimmune diseases may have common susceptibility genes [4,35]. Currently, at least 68 genetic risk variants have been associated with various autoimmune diseases, and several loci have been identified as being associated with more than one autoimmune disease [4,36].

Studies with monozygotic twins have been done to determine the genetic basis for many autoimmune diseases. Reported concordance rates include 12% to 30% for rheumatoid arthritis, 25% to 57% for systemic lupus, 30% for multiple sclerosis, 30% to 50% for type 1 diabetes, 70% to 75% for celiac disease, and up to 80% for Graves disease [22,30,37,38]. The concordance rate does not reach 100% for any autoimmune disease, which means that factors other than genetics must have a role in the pathogenesis [31].

Environmental Factors

The role of environmental factors on the development of autoimmune disease has been studied, but exact triggers and how their interaction with genetic predisposition bears on pathogenesis have not yet been defined [31]. Among the environmental factors that have been found to have influence are infectious agents, stress, sex hormones (estrogens and androgens), and cigarette smoking.

Infectious Agents

Animal models have provided the best evidence of infectious agents inducing an autoimmune disease by immune-mediated mechanisms. On the basis of studies with these models, researchers have theorized that the immune response is triggered by antigens of a micro-organism that closely resembles self-antigens, a mechanism that has been termed molecular mimicry [3]. Another theory is that autoimmunity is induced by a mechanism known as the bystander effect: the invading micro-organism directly damages tissue during active infection, thereby exposing self-antigens to the immune system [39,40].

The diseases most often associated with infection as an etiologic factor are multiple sclerosis, type 1 diabetes, rheumatoid arthritis, systemic lupus, myasthenia gravis, and Guillain-Barré syndrome [3,25,41,42,43,44]. The micro-organisms most often implicated are viral, including Epstein-Barr virus, hepatitis C virus, parvovirus, and cytomegalovirus [3,43,44,45].

Stress

Several studies in animals and humans have demonstrated that physical and psychologic stress affects the immune system, most probably the result of downstream neuroendocrine alterations that modulate immune function. In response to stress, catecholamines and glucocorticoids released from centers in the brain and the adrenal gland exert an effect on various cell lines in the innate and adaptive arms of the immune system, thereby altering the ambient cytokine profile. This, in turn, impacts the differentiation and number of autoreactive T-cells [294]. It is hypothesized that stress may play a role in the onset and exacerbation of autoimmune disease in genetically susceptible individuals [46,47,48]. Inflammatory autoimmune diseases, such as rheumatoid arthritis and systemic lupus, are considered the most likely to be influenced by stress [48]. Psychologic stress as a trigger for autoimmune diseases is further suggested by studies in which as many as 80% of individuals reported emotional stress or major life events before the onset of symptoms, seen primarily in cases of rheumatoid arthritis and Graves disease [25,47,48,49,50]. In a large cohort study of Iraq and Afghanistan war veterans, men and women with a history of trauma exposure and post-traumatic stress disorder (PTSD) were found to have a significantly higher relative risk for the diagnosis of one or more autoimmune diseases than were veterans having no history of trauma or psychiatric diagnoses [295]. However, most studies have been retrospective and have lacked the statistical power to determine significance [48].

Sex Hormones

Sex hormones and their metabolites and receptors are involved in immunoregulation and the development of autoreactivity through their roles in lymphocyte maturation, activation, and synthesis of antibodies and cytokines [51]. Studies have shown that sex hormones are a factor in the pathogenesis of autoimmunity and that the expression of sex hormones is altered in individuals with autoimmune diseases [51]. Evidence for sex hormones as a causative factor is strongest for systemic lupus because of its incidence trend (i.e., high after puberty and low after menopause) and observed fluctuations in disease activity according to menstrual cycle and pregnancy [51,52]. More research is needed to better understand the role of sex hormones in autoimmunity and in specific autoimmune diseases.

Cigarette Smoking

Cigarette smoking and exposure to tobacco smoke has also been found to be a potential trigger for autoimmune diseases, most notably rheumatic diseases (rheumatoid arthritis and systemic lupus) and, to a lesser degree, thyroiditis [53,54]. The exact mechanisms behind the influence of cigarette smoking on the pathogenesis of autoimmune diseases are uncertain [31,53].

Other Factors

The National Institute of Environmental Health Sciences allocated $2.4 million in grant funding in 2014 to study the role of environmental exposures/toxicants in the development of autoimmunity [314]. In addition to tobacco smoke, factors deemed relevant include exposure to crystalline silica, solvents, and ultraviolet radiation. Research topics include the consequences of environmental exposures on the development of autoimmunity, the consequences of the timing of exposure (e.g., fetal perinatal, prepubertal, pubertal, adult, and aged periods), the interplay between environmental exposures and hormonal factors, and the role of environmental factors in lymphocyte activation [314].

GENERAL CHARACTERISTICS

Although each autoimmune disease is a distinct entity with its own constellation of signs and symptoms, many autoimmune diseases share some common characteristics, including female preponderance, similar symptom profiles, difficulty in diagnosis, importance of history and physical examination in diagnosis, and similarity in the approach to disease management.

Female Preponderance

Autoimmune disease exhibits a definite gender bias, with women accounting for nearly 80% of cases overall [21,24,55,56]. The female-to-male ratio varies according to disease, from Hashimoto thyroiditis, which has a female preponderance of 95%, to vitiligo, which has a female preponderance of 52% (Table 2) [51,310] However, a few diseases have been reported to occur more often in men than women, including type 1 diabetes, ulcerative colitis, Guillain-Barré syndrome, and psoriasis [55,57].

Table 2: FEMALE PREDOMINANCE OF AUTOIMMUNE DISEASES AND FIBROMYALGIA

Disease

Approximate Female-to-Male Ratio

Hashimoto thyroiditis

10:1

Sjögren syndrome

9:1

Systemic lupus erythematosus

9:1

Antiphospholipid syndrome, secondary

9:1

Primary biliary cirrhosis

9:1

Graves disease

7:1

Scleroderma

3:1

Rheumatoid arthritis

2.5:1

Antiphospholipid syndrome, primary

2:1

Multiple sclerosis

2:1

Myasthenia gravis

2:1

Source: [51,310]

Similar Symptom Profiles

The symptom profiles associated with autoimmune diseases are another shared characteristic. Extreme fatigue is common, and other shared symptoms include low-grade fever, dizziness, and general malaise. In addition, vague, nonspecific symptoms tend to wax and wane over the long-term, causing periods of remission with intermittent disease flare-ups. Clinical presentations with overlapping symptom profiles, along with a high rate of co-occurring autoimmune diseases, make it difficult to confirm the diagnosis of an autoimmune disease [4].

Difficulty in Diagnosis

Evidence of the difficulty in diagnosing autoimmune diseases is demonstrated in the results of surveys that have shown that individuals consult an average of 4 (and as many as 13) healthcare providers, typically over two to five years, before a confident diagnosis is reached [10,49,310]. There are several reasons for the difficulty. First, the initial symptoms are often subtle, nonspecific, and intermittent until the disease enters the acute stage. Symptoms can also affect many body organs, making it difficult for specialists in one area to recognize a disease within another specialty area. In addition, because many individual autoimmune diseases are rare, a primary care clinician may be unfamiliar with the clinical manifestations of each disease. Lastly, for the most part these diseases lack a single distinguishing feature or specific laboratory diagnostic test; clinicians must rely on varying combinations of information gathered from the history, physical examination, and laboratory and imaging studies [6,60,61,62,64]. Diagnostic criteria have been developed to aid in the diagnosis of some autoimmune diseases.

Importance of History and Physical Examination in Diagnosis

A careful history and comprehensive physical examination, often with repeated clinical observations over time, are usually necessary to establish the diagnosis of an autoimmune disease. Clinicians should prompt patients about symptoms that the patient may not consider important enough to report. Clinicians should also ask about any family and personal history of autoimmune diseases.

Studies within families have shown significantly higher frequencies of autoimmune disease in general and of specific autoimmune diseases among first-degree relatives compared with controls [4]. Studies have also demonstrated that an individual with a diagnosed autoimmune disease is often at increased risk for the co-occurrence of another autoimmune disease [4]. These studies have focused primarily on individuals with an index disease of multiple sclerosis, rheumatoid arthritis, autoimmune thyroiditis (hypothyroidism), type 1 diabetes, inflammatory bowel disease, and vitiligo. Among the most significant findings are a 90-fold and 68-fold higher prevalence of Hashimoto thyroiditis and Graves disease, respectively, among individuals with systemic lupus [65].

Other studies have indicated an increased risk of type 1 diabetes and ulcerative colitis among persons with multiple sclerosis, and an increased risk of rheumatoid arthritis, multiple sclerosis, and a combined category of six other diseases (Addison disease, hemolytic anemia, primary biliary cirrhosis, immune thrombocytopenia purpura, Sjögren syndrome, and systemic sclerosis) among persons with inflammatory bowel disease [66]. In approximately 60% of individuals with Sjögren syndrome, the syndrome is secondary to another autoimmune disease, most commonly rheumatoid arthritis, systemic lupus, or systemic sclerosis [67]. Celiac disease has been associated with the co-occurrence of several autoimmune diseases, most notably Sjögren syndrome and type 1 diabetes [22,68]. Autoimmune diseases of connective tissue have generally been associated with higher rates of co-occurrence of other autoimmune diseases [69]. Higher-than-expected rates of fibromyalgia have also been found in individuals with autoimmune diseases, most notably systemic lupus, rheumatoid arthritis, thyroiditis, and Sjögren syndrome [17,25,70,71,72].

Obtaining an accurate history necessitates effective patient-physician communication, which is challenging given the high number of people of various racial/ethnic minorities or with inadequate language proficiency or health literacy [73,74]. Approaches to overcoming this barrier will be discussed in detail later in this course.

Approach to Disease Management

The specific treatment of autoimmune diseases depends on the particular systems or organs affected, but the overall goals of treatment are similar: to curtail the autoimmune process, reduce inflammation, relieve symptoms, and preserve organ function. This usually requires immunomodulatory/immunosuppressant drugs. Challenges in treatment are related to the complexity of symptoms, the need for long-term medications in order to preserve organ function, and the long-term adverse effects of immunosuppressant drugs. As with diagnostic criteria, practice guidelines for the treatment of autoimmune diseases are available but limited. The long-term management of individuals with autoimmune diseases requires a multidisciplinary approach, including referral to specialists such as rheumatologists, endocrinologists, gastroenterologists, neurologists, nutritionists, physical/occupational therapists, and counselors. This multidisciplinary care is best coordinated by the primary care provider, with clear articulation of specific roles. Because of the influence of stress on the immune system—coupled with the stress of a chronic disease—the management of autoimmune diseases should include stress reduction interventions [47,48].

There is growing scientific evidence that regular, programmed physical activity is beneficial for a variety of chronic diseases, including autoimmune disease. A 2018 review highlights the salient effects of physical activity on certain aspects of the immune system and autoimmune disease expression [296]. Physical activity leads to an elevation in T-regulatory cells, decreased immunoglobulin secretion, and a decreased production of autoreactive T-cells. In addition, physical activity promotes the release of IL-6 from muscles, and IL-6 derived from muscle has been shown to induce an anti-inflammatory response through IL-10 secretion and IL-1 beta inhibition. The beneficial role of physical activity is well-documented for patients with rheumatoid arthritis, systemic lupus, and type 1 diabetes; observed outcomes include milder disease course, decreased fatigue, improved joint mobility, enhanced quality of life, and improved cardiovascular disease profile [296].

The management of autoimmune disease is often complicated by the patient's response to the diagnosis and difficulty coping with the disease. Adherence to the treatment plan is often difficult because of denial about the diagnosis, work and life demands, and frustration with the lack of symptom response to treatment [75]. Unresolved symptoms lead to a high rate of complementary and/or alternative therapies used by individuals with autoimmune diseases [25,49,75,77,79]. The chronic nature of the conditions and the need for adherence to long-term management with frequent follow-up visits is essential for optimal outcomes but is also challenging, especially for individuals in racial/ethnic minority populations who may have different perceptions of health and the disease [80]. A strong, supportive patient-clinician relationship is integral to ensuring adherence and effective management.

Patient-Clinician Relationship in Disease Management

To enhance the patient-provider relationship, healthcare professionals are advised to gain an understanding of the patient's perspective of his or her illness or disease and to ensure that the patient's primary concerns have been addressed [81]. Patient trust in healthcare providers has been rated higher for clinicians who seek the patient's perspective of his or her illness [82]. In turn, the healthcare professional's comprehensive knowledge of the patient and higher levels of patient trust have been reported to be substantial influences on adherence to medical advice, patient satisfaction, and improved health status [82,83]. In order to manage chronic disease safely and effectively, it is essential that patients have a conceptual understanding of their disease, the prognosis, and the benefits and risks of treatment options.

Effective communication is a cornerstone of the patient-provider relationship. Some communication behaviors that have been found to be positively associated with health outcomes include empathy, reassurance and support, explanations, positive reinforcement, humor, discussion of psychosocial issues, health education and information sharing, courtesy, and summarization and clarification [84]. Other factors essential for effective communication and a successful relationship are knowledge of the patient's language preference; an understanding of and respect for the patient's personal cultural values, beliefs, and practices (referred to as cultural competency); and an awareness of the patient's health literacy level [85,86,87].

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

Language, cultural competency, and health literacy are significant issues, given the growing percentages of racial/ethnic populations. According to U.S. Census Bureau data from 2018, more than 44.7 million Americans are foreign-born, 67 million Americans (21.9% of the population) speak a language other than English at home, and more than 25.6 million (8.3% of the population) report that they speak English less than "very well" [88]. Clinicians should ask their patients what language they prefer for their medical care information, as some individuals prefer their native language even though they have said they can understand and discuss symptoms in English [89].

The national standards on Culturally and Linguistically Appropriate Services (CLAS) include four standards related to language access services that are mandated for healthcare organizations [85]. Although these standards are not mandated for individual healthcare providers, the Office of Minority Health encourages clinicians to meet the standards to make their practices more culturally and linguistically accessible [85]. These standards are [85]:

- Offering and providing language assistance services, including bilingual staff and interpreter services, at no cost to each patient/consumer with limited English proficiency at all points of contact in a timely manner during all hours of operation

- Providing patients with both verbal offers and written notices (in their preferred language) that inform them of their right to receive language assistance services

- Ensuring the competence of language assistance provided to patients with limited English proficiency by interpreters and bilingual staff and avoiding the use of the patient's family and friends as interpreters

- Making easily understood patient-related materials available and posting signage in the languages of the commonly encountered groups and/or groups represented in the practice area

Convenience and cost lead many clinicians to use "ad hoc" interpreters (e.g., family members, friends, bilingual staff members) instead of professional interpreters. However, professional interpreters are preferred for several reasons. Several states have laws about who can interpret medical information for a patient, so healthcare professionals should check with their state's health officials about the use of ad hoc interpreters [90]. Even when allowed by law, the use of a patient's family member or friend as an interpreter should be avoided, as the patient may not be as forthcoming with information and the family member or friend may not remain objective [90]. Children should especially be avoided as interpreters, as their understanding of medical language is limited and they may filter information to protect their parents or other adult family members [90]. Individuals with limited English language skills have actually indicated a preference for professional interpreters rather than family members [91].

Most important, perhaps, is the fact that clinical consequences are more likely with ad hoc interpreters than with professional interpreters [92]. A systematic review of the literature showed that the use of professional interpreters facilitates a broader understanding and leads to better clinical care than the use of ad hoc interpreters, and many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care. The use of professional interpreters improves communication (errors and comprehension), utilization, clinical outcomes, and patient satisfaction with care [93,94].

Cultural competency is essential for addressing healthcare disparities among minority groups [85]. Among the issues that clinicians should understand are the patients' belief systems regarding health, healing, and wellness; their perceptions on illness, disease, and their causes; their health behaviors and attitudes toward healthcare providers; and the role of the family in decision making [85]. Understanding these aspects is integral to a successful patient-clinician relationship as well as to optimal health outcomes. For example, healthcare professionals should raise the topic of health-related customs, such as the use of complementary and alternative medicines because such use varies substantially among racial/ethnic populations and according to geographic area; may compromise the effect of traditional therapies; and is often not disclosed by the patient [25,96,97].

Knowledge of the patient's health literacy is also important, as the patient's understanding of his or her disease and its management is essential to ensuring adherence to the treatment plan and the patient's role in self-management. Yet most individuals lack adequate health literacy. According to the National Assessment of Health Literacy, 14% of individuals in the United States have "below basic" health literacy, which means they lack the ability to understand health information and make informed health decisions [73,98]. A systematic review of more than 300 studies showed that an estimated 26% of patients had inadequate literacy and an additional 20% had marginal literacy [99]. Health literacy varies widely according to race/ethnicity, level of education, and gender, and clinicians are often unaware of the literacy level of their patients [87,100]. Predictors of limited health literacy are poor self-rated reading ability, low level of education, male gender, and nonwhite race [100,101]. Several instruments are available to test patients' literacy levels, and they vary in the amount of time needed to administer and in their reliability in identifying low literacy [73,87,100,102].

Clinicians should adapt their discussions and educational resources to a patient's identified health literacy level and degree of language proficiency. The use of plain language (free of medical jargon), asking patients to repeat pertinent information, regularly assessing recall and comprehension, providing educational resources in a variety of formats (e.g., print, oral, web-based, video), and using culturally appropriate and translated educational materials can all help ensure that patients better understand their disease and its management, ultimately leading to higher quality care.

3. THYROIDITIS

Thyroiditis is the most common autoimmune disease. Autoimmune thyroiditis encompasses both Hashimoto thyroiditis, also known as chronic lymphocytic thyroiditis, and Graves disease. Hashimoto disease and Graves disease are the leading causes of hypothyroidism and hyperthyroidism, respectively [50,103]. Hashimoto disease is more common than Graves disease [13,104].

Hashimoto disease (chronic autoimmune thyroiditis) is characterized by an intense lymphocytic (T cell and B cell) infiltration of the gland and local production of antithyroid antibodies that reach high titer in the serum. Over time, thyroid tissue is gradually destroyed or replaced, thyroid hormone levels decline, and hypothyroidism supervenes. Thus, Hashimoto disease may present as either subclinical or overt hypothyroidism; subclinical disease is the more commonly encountered of the two in the primary care setting [104]. Left untreated, hypothyroidism can cause fatigue, weight gain, mental slowing, heart failure, and elevated lipid levels.

In Graves disease, circulating thyroid antibodies target the TSH receptor, which stimulates the thyroid gland, causing enlargement of the thyroid gland and increased production of thyroid hormone. As with Hashimoto disease, thyroid dysfunction with Graves disease may be subclinical or overt. Mild ophthalmopathy is present in as many as half of individuals with Graves disease, and severe ophthalmopathy occurs in 3% to 5% [50,105]. This ophthalmopathy is the result of edema and lymphocytic infiltration of orbital fat, connective tissue, and eye muscles, and exophthalmos is the characteristic sign of Graves disease [106]. If not treated, overt hyperthyroidism can result in atrial fibrillation, congestive heart failure, osteoporosis, and neuropsychiatric problems.

EPIDEMIOLOGY

According to the results of the 2007–2012 population-based National Health and Nutrition Examination Survey III (NHANES III) , the prevalence of hypothyroidism in the United States is approximately 3.7% and the prevalence of hyperthyroidism is approximately 3.4% [13,104]. Subclinical hypo- and hyperthyroidism are far more prevalent than overt disease (3.5% compared with 0.2%, and 3.1% compared with 0.3%, respectively) [104,283].

Hashimoto thyroiditis usually begins between the ages of 30 and 50 years and is nearly 10 times more common in women than in men [51,107,108]. The prevalence of hypothyroidism (subclinical and overt) increases with age; the odds for hypothyroidism are five times greater for individuals 80 years or older than for individuals 12 to 49 years of age [13]. The rate of subclinical hypothyroidism has been reported to be as high as 15% to 20% among women 60 years of age and older [104,109,110]. Graves disease typically occurs between the ages of 40 to 60 years and is about eight to nine times more common in women than men [51].

Data on the prevalence of autoimmune thyroiditis among racial/ethnic populations are limited. The prevalence of antithyroid antibodies has been greater in the white and Mexican American populations than in the black population [104]. Among the Mexican American population, the risk for hypothyroidism has been found to be the same as that for the non-Hispanic white population, but the risk for hyperthyroidism is higher [13]. The risk for hypothyroidism is lower and the risk for hyperthyroidism is higher for the non-Hispanic black population compared with the non-Hispanic white population [13].

POTENTIAL ENVIRONMENTAL RISK FACTORS

In individuals with genetic susceptibility, iodine deficiency, infection, smoking, and stress have been identified as environmental triggers for both types of autoimmune thyroiditis [54]. Recent childbirth may be an additional trigger for Graves disease [50].

ASSOCIATION WITH OTHER AUTOIMMUNE DISEASES

A coexisting autoimmune disorder is present in approximately 14% of individuals with Hashimoto disease and nearly 10% of individuals with Graves disease [111]. In a British study involving more than 3,000 individuals with autoimmune thyroiditis, rheumatoid arthritis was the most common coexisting autoimmune disorder, appearing in approximately 4% of individuals with Hashimoto disease and 3% of those with Graves disease [111]. Among the other autoimmune disorders that have been found to be associated with Hashimoto thyroiditis are pernicious anemia, systemic lupus, Addison disease, celiac disease, Sjögren syndrome, systemic sclerosis (scleroderma), type 1 diabetes, and vitiligo [111,112,113]. The frequency and type of nonthyroidal autoimmune disease in patients with Hashimoto thyroiditis varies with age at presentation. In a study of 1,053 newly diagnosed patients (500 adults and 553 children/adolescents), the prevalence of associated autoimmune diseases was significantly higher in adults, as was the likelihood of a patient suffering from two or more nonthyroidal autoimmune disorders [297]. Furthermore, the cluster of associated diseases was distinctly different in the two cohorts. Rheumatoid arthritis and systemic lupus were encountered almost exclusively in adults (6.4% compared with 0.18% in children/adolescents) and type 1 diabetes and celiac disease in children and adolescents (14.1% compared with 2.2% in adults). The authors concluded that common age-related autoimmune mechanisms may contribute to the pathogenesis of coexisting autoimmune diseases.

Genetic studies have indicated a close relationship between type 1 diabetes and autoimmune thyroid disease, and a fourfold risk of thyroiditis has been found among individuals with type 1 diabetes [4,38]. In a small study (254 participants), nonthyroid autoimmune diseases were found in approximately 9% of individuals with Graves disease, and the specific nonthyroid diseases varied according to the presence or absence of ophthalmopathy [112]. Type 1 diabetes was the most prevalent disease among individuals who did not have ophthalmopathy (approximately 7%), and vitiligo was the most prevalent autoimmune disease among those who had ophthalmopathy (4%) [112].

CLINICAL MANIFESTATIONS

Both Hashimoto disease and Graves disease may be present with no symptoms or with subtle, nonspecific symptoms, especially with early or subclinical disease. With Hashimoto disease, approximately 20% of individuals have symptoms at the time of diagnosis, although symptoms may not develop until years after thyroid dysfunction [114]. Symptoms of Graves disease are usually present for at least two to three months before diagnosis [50].

The symptoms associated with Hashimoto disease are the same regardless of whether hypothyroidism is present. In addition to nonspecific symptoms, such as fatigue, weakness, lethargy, and muscle aches, hypothyroidism can also affect a variety of body systems (Table 3) [108,113,115].

Table 3: SIGNS AND SYMPTOMS OF AUTOIMMUNE THYROID DISEASE

Body System

Hashimoto Disease

Graves Disease

General

Fatigue

Weakness

Lethargy

Hypothyroid speech

Forgetfulness

Increased sensitivity to medications

Fatigue

Weakness

Sleep disturbances

Psychiatric

Depression

Emotional instability

Nervousness, anxiety

Metabolic

Weight gain

Cold intolerance

Weight loss

Heat intolerance

Skin

Pale, dry, cold skin (may appear jaundiced)

Coarse skin

Thick, brittle nails

Dry, coarse, brittle hair or hair loss

Warm, moist skin

Pretibial myxedema

Hair loss

Cardiovascular

Slow pulse

Bradycardia

Diastolic hypertension

Peripheral edema

Rapid pulse (≥90 beats/minute)

Tachycardia, palpitations, atrial fibrillation

Elevated systolic and diastolic blood pressure

Edema

Dyspnea on exertion

Pulmonary

Slow, shallow respirations

Shortness of breath

Increased respiratory rate and depth

Neurologic

Delayed ankle reflexes

Fine finger/hand tremor

Musculoskeletal

Sore muscles

Pain and/or stiffness in joints

Proximal muscle weakness or wasting

Back pain

History of fractures

Digestive

Constipation

Increased appetite

Diarrhea

Vomiting

Abdominal pain

Hematologic

Easy bruising

Macrocytic anemia

Normocytic normochromic anemia

Easy bruising

Renal

—

Polyuria

Polydipsia

Reproductive

Menorrhagia

Irregular periods

Decreased libido

Increased rate of miscarriage, still birth, and fetal death

Amenorrhea

Irregular periods

Decreased fertility

Increased risk for miscarriage

Ophthalmologic

—

Tearing

Gritty sensation

Eye discomfort/pain

Diplopia

Exophthalmos

Source: [50,106,108,113,115]

Fatigue and weakness are also among the most common symptoms associated with Graves disease, and as with Hashimoto disease, symptoms can be related to many body systems, with the overactivity of the thyroid having the opposite effect [50,106,113,115]. For example, hypothyroidism is typically associated with bradycardia, while hyperthyroidism is usually associated with a rapid, bounding pulse and/or palpitations.

DIAGNOSTIC EVALUATION

Because of the frequency of nonspecific symptoms and the wide array of other symptoms, healthcare professionals should elicit a detailed history, with emphasis on questions related to [115,315]:

- Appetite, recent unexplained weight loss, or weight gain

- Tightness, fullness, or pain in the neck

- Eye pain or discomfort, changes in visual acuity

- Nervousness and/or anxiety

- Emotional status

- Abdominal pain

- Constipation or diarrhea

- Exertional dyspnea

- Increased perspiration

- Heat or cold intolerance

- Regularity of menstrual cycles

- Sleep disturbances

- Hair loss

The comprehensive physical examination should begin with assessment of blood pressure, weight, pulse, and other vital signs. A slow pulse is a clinically significant finding of hypothyroidism, and a rapid pulse (i.e., 90 beats per minute or more) is a clinically significant finding of hyperthyroidism (Table 4) [106]. Among individuals with hyperthyroidism, tachycardia occurs less often among older individuals than younger ones [50].

Table 4: DIAGNOSTIC ACCURACY OF CLINICAL FINDINGS FOR THYROIDITIS

Sign/Symptom

Sensitivity

Specificity

Hypothyroidism

Hypothyroid speech

37%

93%

Cool and dry skin

16%

97%

Slow pulse rate

29% to 43%

89% to 93%

Coarse skin

29% to 61%

74% to 95%

Delayed ankle reflexes

48%

86%

Hyperthyroidism

Eyelid retraction

34%

99%

Eyelid lag

19%

99%

Fine finger tremor

69%

94%

Warm and moist skin

34%

95%

Pulse ≥90 beats/minute

80%

82%

Source: [106]

Palpation and auscultation of the thyroid should be done to determine if the gland is enlarged and if nodules are present. In individuals with hypothyroidism, the thyroid gland may not be palpable or a goiter may be present [113]. An enlarged thyroid gland is a significant sign of hyperthyroidism, occurring in 70% to more than 90% of individuals with the disorder [106]. The goiter associated with hyperthyroidism is typically diffuse and symmetric, which distinguishes Graves disease from toxic nodular goiter, in which nodes are usually felt on palpation of the goiter.

Evaluation of the skin is also important. Skin that is both cool and dry is a clinically significant finding for hypothyroidism; the skin may also feel coarse or appear pale or yellowish [106]. Skin that is both warm and moist is a significant finding for hyperthyroidism. Hair loss is common with both types of thyroiditis.

An eye examination is integral to the diagnosis of Graves disease, as exophthalmos is a hallmark characteristic and is often the first sign of this disease. Eyelid retraction is the most clinically significant finding of hyperthyroidism, followed by eyelid lag; other ophthalmologic signs of Graves disease are periorbital edema and limited eye movements [106].

Hypothyroid speech—a low-pitched, hyponasal voice (as if speaking with a cold), spoken at a slow pace—is found in about one-third of individuals with hypothyroidism [106]. This speech is the finding with the most clinical significance for diagnosis of hypothyroidism [106].

A neurologic evaluation is also useful in the diagnosis. Delayed ankle reflexes are a clinically significant finding of hypothyroidism, and fine finger tremor is a clinically significant finding of hyperthyroidism [106]. Tremor is less likely to occur in older than younger individuals with hyperthyroidism [50].

No single clinical finding, when absent, is significant for ruling out hypothyroidism [106]. The lack of thyroid enlargement, a pulse of less than 90 beats per minute, and the absence of finger tremor are findings with the most significance in ruling out hyperthyroidism [106].

Among the differential diagnoses that should be considered when evaluating an individual with suspected Hashimoto thyroiditis are chronic thyroiditis, thyroid nodules, euthyroid sick syndrome, and lymphoma of the thyroid [106]. The differential diagnosis for Graves disease includes toxic nodular goiter, subacute thyroiditis, and papillary carcinoma of the thyroid [106].

Laboratory Testing

Thyroid function tests can confirm a diagnosis of Hashimoto thyroiditis or Graves disease. The single best screening test for either disease is the sensitive TSH assay (also known as thyrotropin level), and the free thyroxine (T4) level and the total triiodothyronine (T3) level also help confirm the diagnosis [113,115,316]. An elevated TSH level with low levels of T3 and free T4 indicates hypothyroidism [108,113]. Subclinical hypothyroidism is indicated by a repeatedly high TSH level with normal free T4 and T3 levels [108,113]. In contrast, a low TSH level with increased T3 and T4 levels indicates hyperthyroidism [50]. The patient's history is important to remember when interpreting the results of laboratory testing, as a low TSH level can also be caused by glucocorticoids, dopaminergic drugs, severe illness, pregnancy, diurnal variation, or pituitary dysfunction; elevated TSH levels may be caused by adrenal insufficiency [113]. Thyroid autoantibodies (i.e., thyroid peroxidase and thyroglobulin antibodies) may be helpful in the diagnosis [113,316].

Other Testing

A radioiodine-uptake scan is not useful in diagnosing hypothyroidism, but it can help distinguish hyperthyroidism from subacute thyroiditis, which is associated with low uptake values, and from multinodular toxic goiter [50]. If a radioiodine-uptake scan is not possible, ultrasonography of the thyroid gland may be done instead, and increased blood flow by Doppler correlates with an increased uptake [50]. Ultrasonography is also useful for detecting nodules and evaluating suspicious structural abnormalities [50,113]. A fine-needle biopsy should be done to exclude malignancy when a dominant nodule is present [50,107].

SCREENING FOR THYROID DISEASE

The issue of regular thyroid function screening is controversial. In 1998, the American College of Physicians recommended screening for women older than 50 years of age who have at least one general symptom that could be caused by thyroid disease [116]. Two years later, the American Thyroid Association recommended measuring thyroid function in all adults beginning at age 35 years and every five years thereafter and noted that more frequent screening may be appropriate for high-risk or symptomatic individuals [117]. In 2011, the American Academy of Family Physicians found insufficient evidence to recommend for or against routine thyroid screening in asymptomatic adults, and the American College of Obstetricians and Gynecologists recommended that physicians be aware of the symptoms and risk factors for postpartum thyroid dysfunction and evaluate patients when indicated [118,119]. In 2004, the U.S. Preventive Services Task Force concluded that the evidence was insufficient to recommend for or against routine screening for thyroid disease in adults. The Task Force noted that while there was fair evidence that TSH testing can detect subclinical thyroid disease in asymptomatic individuals, there was poor evidence that treatment improves clinically important outcomes in adults with thyroid disease detected through screening [120].

Despite the potential for serious adverse events associated with either type of autoimmune thyroiditis, the American Association of Clinical Endocrinologists (AACE) recommends "aggressive case finding" (i.e., using symptoms, family history, and personal history of thyroid damage, autoimmune disorders, or abnormal thyroid exam) rather than universal TSH testing for women of childbearing age before or during pregnancy [113]. There is insufficient evidence to support universal screening in this group, mainly because the impact of outcomes has not been demonstrated. Additionally, the AACE warns of the potential for harm with treatment during pregnancy. If testing is performed, the AACE recommends that measurement of total T4 or a free T4 index, in addition to TSH, be done to assess thyroid status [113].

The AACE recommends hypothyroidism screening for individuals older than 60 years of age, especially women [113]. However, hypothyroidism is common in older patients and the evidence supporting benefit or cost effectiveness is insufficient.

TREATMENT OPTIONS

Both the AACE and the American Thyroid Association have developed guidelines for the treatment of hypothyroidism and hyperthyroidism [113,115]. Treatment of either thyroid dysfunction must be tailored to the individual patient, and the patient should have a clear understanding of the indications and implications of all forms of therapy, including risks, benefits, and side effects. Clinicians should also encourage the patient to be an active participant in the decision-making process regarding the type of therapy. The goal of treatment for either condition is to achieve a euthyroid state.

Hashimoto Disease

The AACE states that most primary care clinicians can diagnose and treat hypothyroidism, but the organization recommends consultation with an endocrinologist for patients with [113]:

- Age 18 years or younger

- Pregnancy (or planned pregnancy)

- Cardiac disease

- Disease that is unresponsive to treatment

- Another endocrine disease

- A goiter, nodule, or other structural change in the thyroid gland

- Unusual causes of hypothyroidism or hypothyroidism caused by medications or medical conditions

Overt hypothyroidism involves lifelong thyroid replacement medication, typically levothyroxine. Various brands of the medication are available, and the AACE recommends using a high-quality brand, with the same brand used throughout treatment in order to maintain consistency [113].

Levothyroxine is prescribed as a daily, oral dose, and treatment begins with a low dose and is gradually titrated up according to the results of TSH testing [113,115]. An initial daily dose of 25–50 mcg has been recommended; lower doses may be more appropriate for older individuals or those with cardiovascular disease [107,108]. The AACE notes that the mean full replacement dosage is 1.6 mcg/kg per day [113]. Clinical evaluation of the patient and TSH testing should be done every four to eight weeks after a change in dose [113].

When titrating the dose of levothyroxine, healthcare professionals must consider the effects of other drugs the patient takes. Many drugs, including cholestyramine, ferrous sulfate, sucralfate, calcium, and some antacids containing aluminum hydroxide, can interfere with levothyroxine absorption [113]. Also, rifampin and sertraline may accelerate levothyroxine metabolism, calling for a higher replacement dose [113].

It should be noted that a small cohort of patients will retain signs of neurocognitive dysfunction, despite normal serum TSH and free T4, perhaps because more than half of the T3 in the brain is produced locally [317]. Results of a large clinical trial demonstrated that patients carrying a polymorphism in the Dio2 gene are particularly prone to this outcome, and combination treatment with liothyronine is beneficial for patients with persistent neurocognitive symptoms in spite of normal serum concentrations of TSH and free T4 [317].

Hashimoto Disease Without Hypothyroidism

Recommendations have also been made for individuals who have Hashimoto disease without hypothyroidism (i.e., who have a goiter but normal TSH levels). Treatment is not required for individuals who are asymptomatic and have a small goiter. However, many endocrinologists prescribe levothyroxine for patients with a goiter, even if the level of TSH is normal, with a goal of decreasing the size of the goiter [107].

Subclinical Hypothyroidism

The appropriate approach to subclinical hypothyroidism has been debated. Proponents of treatment note that although subclinical hypothyroidism is usually asymptomatic, treatment has been shown to offer benefit in reducing the risks of several adverse events, including cardiovascular events, hyperlipidemia, and neuropsychiatric effects [121,122,123,124,125]. In addition, subclinical hypothyroidism can progress to overt hypothyroidism, with a wide range in risk of progression (3% to 20%) [108,113].

Despite a recommendation to treat subclinical hypothyroidism, there is no consensus on the TSH level that should prompt treatment [113,126]. The AACE recommends treatment for individuals with subclinical hypothyroidism and a TSH level greater than 10 IU/mL especially if patients have symptoms of hypothyroidism, positive anti-thyroid peroxidase antibodies (TPOAb), or evidence of atherosclerotic cardiovascular disease, heart failure, or associated risk factors for these diseases [113]. Treatment should also be considered for individuals who have a strong family history of thyroid disease, who are pregnant, who have a history of heavy tobacco use, and/or who have severe lipidemia [108]. As with the treatment of overt hypothyroidism, the dose should be adjusted according to the TSH level. The TSH target recommend by AACE guidelines for non-pregnant patients should be the normal range of a third generation TSH assay (or between 0.45 and 4.12 mIU/L, when not available), and the level should be determined every six to eight weeks until the target has been reached [113]. More studies are needed before thyroxine replacement therapy can become the standard of care for subclinical hypothyroidism [108,113].

Hypothyroidism During Pregnancy

Hypothyroidism (even if mild) during pregnancy can have serious adverse effects for both the mother (e.g., hypertension, pre-eclampsia, postpartum hemorrhage) and fetus (e.g., spontaneous abortion, fetal death or stillbirth, low birth weight, abnormal brain development) [113]. The AACE states that pregnant women who have or have had positive levels of serum TPOAb and with a TSH greater than 2.5 mIU/L should be treated with levothyroxine [113]. Additionally, treatment should be considered if they have or have had positive levels of serum TPOAb, particularly when there is a history of miscarriage or hypothyroidism [113]. Women with positive levels of serum TPOAb or with a TSH greater than 2.5 mIU/L who are not being treated with levothyroxine should be monitored every 4 weeks in the first 20 weeks of pregnancy for the development of hypothyroidism [113].

Thyroid function should be monitored every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks' gestation to ensure that the requirement for L-thyroxine has not changed; the dose of thyroxine should be adjusted accordingly [113]. Some clinicians may prefer to continue regular monitoring throughout gestation. The upper limit of the normal range should be based on trimester-specific ranges for that laboratory. If ranges are not available in the laboratory, the following upper normal TSH reference ranges are recommended [113]:

- First trimester: 2.5 mIU/L

- Second trimester: 3.0 mIU/L

- Third trimester: 3.5 mIU/L

Graves Disease

As noted, the goal of treatment of Graves disease is to make the thyroid function normally or to disable the gland completely and treat the resultant hypothyroidism. The three primary treatment options are radioactive iodine (usually 131I), antithyroid drugs, or thyroidectomy. In addition, treatment with a beta blocker is recommended to provide relief of symptoms (such as tremor, palpitations, and sweating) until a euthyroid state is reached [115].

Treatment with Radioactive Iodine

Treatment with 131I is considered to be the treatment of choice for most people; however, pregnancy and breastfeeding are absolute contraindications [115]. A pregnancy test should be obtained 48 hours before treatment with 131I for all women of childbearing age who are sexually active.

The isotope is given orally (as a capsule or in water), and there is no consensus on the optimal dose [127]. The dose is usually determined with a dose-calculation algorithm, and the typical dose range is 5–15 mCi of 131I [115,127]. Randomized trials have shown no significant differences in outcome between the use of calculated doses and fixed doses, and fixed doses are now used in many institutions [128,129].

Treatment with antithyroid drugs may be indicated for some individuals, particularly older individuals or those with cardiac disease, before administration of 131I. Antithyroid drugs should be stopped one week before treatment with radioactive iodine is begun and should not resume until approximately six weeks after treatment.

The American Thyroid Association and the AACE recommend that individuals be followed up within the first one to two months after treatment to monitor the transition to a euthyroid and/or hypothyroid state [115]. Hypothyroidism can occur at any time after treatment, but most commonly occurs within two to six months [50]. Treatment with partial replacement doses of levothyroxine can usually begin two months after treatment. The timing of thyroid-replacement treatment depends on the findings of laboratory testing and clinical evaluation [115].

The cure rate for treatment with radioactive iodine is more than 80% [130]. Retrospective studies have shown that factors associated with a lack of response to 131I are a young age, a large thyroid, severe thyrotoxicosis, previous exposure to antithyroid drugs, and a higher 131I uptake value [131,132]. When necessary, a second dose should be given at least 6 to 12 months after the initial treatment, and antithyroid drugs should be stopped before and after a second treatment [127].

Treatment with 131I is safe, with the primary side effects being acute radiation thyroiditis and hypothyroidism; there is no adverse effect on fertility or on offspring conceived after treatment [50,115]. Radioactive iodine administration is the recommended modality for women who wish to become pregnant four to six months after treatment. The findings of some studies have suggested an increased risk for some types of cancer after treatment with 131I, but the results of other studies have demonstrated conflicting data, with no increases in the incidence of cancer [133,134].

Treatment with Antithyroid Drugs

Antithyroid drugs (thionamides) interfere with thyroid hormone synthesis by preventing iodine from combining with tyrosine residues in thyroglobulin [135]. This approach is usually the treatment of choice for pregnant women, children and adolescents, and individuals who have severe Graves ophthalmopathy [127,135]. The goal of treatment is to achieve remission, defined as a biochemical euthyroid state for a minimum of one year after discontinuing treatment [115,135].

The most frequently prescribed antithyroid drugs are methimazole and propylthiouracil [135]. Methimazole has become the preferred drug in the United States, especially after a 2009 U.S. Food and Drug Administration (FDA) Safety Alert noting reports of severe liver injury and acute liver failure (some fatal) in both adults and children treated with propylthiouracil [136]. The FDA recommended that physicians should "carefully consider" the choice of drug for newly diagnosed Graves disease and that propylthiouracil should not be used in children and adolescents unless the patient is allergic to or intolerant of methimazole and no other treatment options are available [136]. The FDA now requires a boxed warning on the label of propylthiouracil to alert clinicians about the risk of liver damage.

The AACE and the American Thyroid Association recommend the use of methimazole for nearly every patient; however, propylthiouracil should be used during the first trimester of pregnancy, for treatment of thyroid storm, and in patients with minor reactions to methimazole who refuse radioactive iodine therapy or surgery [115]. Antithyroid drug therapy can be given in two ways: a titration regimen or a block-replace regimen. With a titration regimen, the initial dose is high and the dose is tapered over time. With a block-replace regimen, a high dose of an antithyroid drug is given, followed by levothyroxine once a euthyroid state has been reached. No difference in efficacy has been found between the two methods, according to a systematic review of the literature published in 2010 [138]. The block-replace regimen, however, was associated with a higher rate of adverse effects [138].

The starting dose depends on the severity of the hyperthyroidism, and the typical starting doses have been 10–40 mg/day for methimazole and 100–600 mg/day (in divided doses) for propylthiouracil [115,130]. The starting dose is tapered according to the results of thyroid function testing, which should be done once a month until symptoms start to resolve and then every two to three months [127,130]. The results of thyroid function testing are also considered when tapering the dose; testing should be done every month. Use of a block-replace regimen requires less frequent testing [130]. Typical maintenance doses are 5–20 mg/day of methimazole or 100–200 mg/day of propylthiouracil [127,130].

Two starting doses of methimazole (15 mg/day and 30 mg/day) and propylthiouracil (300 mg/day) were compared in a small randomized study in Japan (240 participants) [137]. Overall, the 30 mg/day dose of methimazole normalized the serum free T4 level in significantly more individuals than the 15 mg/day dose or propylthiouracil at 12 weeks [137]. The higher dose of methimazole was also significantly more effective in the subgroup with severe hyperthyroidism (free T4 level: 7 ng/dL or greater), but there was no difference among the three treatments in the subgroup with mild or moderate disease (free T4 level: less than 7 ng/dL) [137].

With regard to duration of therapy, one year of treatment has been reported to offer better rates of remission than six months of treatment [50]. However, there has been no significant difference in remission rates at two years between individuals treated for longer than 18 months compared with those treated for 18 months [50]. A systematic review indicated that the optimal duration of a titration regimen was 12 to 18 months [138]. The AACE and the American Thyroid Association recommend methimazole be continued for 12 to 18 months, at which point it should be tapered and discontinued if the TSH level is normal [115]. If disease is not in remission after 12 to 18 months, thyroidectomy or 131I should be considered; low-dose methimazole is recommended if these options are refused or contraindicated.

Hyperthyroidism will recur after antithyroid drug therapy in approximately 30% to 60% of individuals [50,130]. Studies have suggested that recurrence after antithyroid drug therapy is associated with several factors, including [50,127,135]:

- Severe hyperthyroidism

- Long duration of symptoms before initiation of treatment

- Age younger than 40 years

- Male gender

- Family history of autoimmune thyroid disease

- History of cigarette smoking

- Presence of clinical ophthalmopathy

- High serum T3 and T4 concentrations

- Large goiter at diagnosis and/or at end of therapy

However, the association between recurrence and any of these individual factors has not been strong enough to warrant use as a risk stratification factor [127]. Thyroid function tests should continue for 6 to 12 months (at 1- to 3-month intervals) to diagnose relapse early; patients should be vigilant about recognizing the signs of hyperthyroidism [115]. Another course of antithyroid drug therapy, treatment with radioactive iodine, or surgery can be used to treat recurrent hyperthyroidism [130].

Side effects occur in approximately 5% of individuals receiving antithyroid drugs [130]. The most common side effects are rash, arthralgia, gastrointestinal problems, and changes in taste/smell [130]. The most serious side effect, occurring in about 0.1% to 0.3% of individuals, is agranulocytosis [50]. The risk of agranulocytosis increases with higher drug doses and with age and can occur at any time during the course of treatment [50,137].

Thyroidectomy

Surgery was once frequently used to treat hyperthyroidism, but it is now the least-used treatment option. The AACE and the American Thyroid Association recommend that the specific indications for thyroidectomy are a large goiter, especially with compressive symptoms (which may be resistant to radioactive iodine treatment); severe ophthalmopathy (because of the risks associated with radioactive iodine); or an allergy or intolerance to antithyroid drugs [115]. The primary advantage of thyroidectomy is that it provides definitive treatment of hyperthyroidism with none of the hazards associated with radioactive iodine, the other option with a good cure rate [127,138]. In addition, surgery offers a rapid normalization of thyroid function [127]. Thyroidectomy usually results in hypothyroidism, occurring in 12% to 80% of individuals during the first year and at a subsequent annual rate of 1% to 3% [127].

Thyroidectomy is associated with a low rate of complications and a mortality rate of nearly zero [50,115,127]. This is particularly true if the surgery is performed by a high-volume thyroid surgeon [115]. Total thyroidectomy is recommended over subtotal thyroidectomy because it has been associated with similar complication rates but better cure rates (near 0% recurrence versus 8% recurrence at five years, respectively) [115,139].

Treatment of Subclinical Hyperthyroidism

There is no consensus on whether subclinical hyperthyroidism should be treated. Treatment is generally unnecessary in younger individuals, but the AACE and the American Thyroid Association recommend that individuals 65 years of age or older with a TSH level persistently less than 0.1 mU/L should be strongly considered for treatment or treated using the same principles as outlined for overt hyperthyroidism [115].

Treatment During Pregnancy

Evidence Based Practice Recommendation

The Endocrine Society asserts that subtotal thyroidectomy may be indicated during pregnancy as therapy for maternal Graves disease if 1) a patient has a severe adverse reaction to antithyroid drug therapy, 2) persistently high doses of antithyroid drug are required, or 3) a patient is nonadherent to antithyroid drug therapy and has uncontrolled hyperthyroidism. The optimal timing of surgery is in the second trimester.

https://academic.oup.com/jcem/article/97/8/2543/

Last Accessed: July 23, 2020

Strength of Recommendation/Level of Evidence: C (At least fair evidence that the service can improve health outcomes but the balance of benefits and harms is too close to justify a general recommendation)

As with hypothyroidism, hyperthyroidism can have serious adverse effects during pregnancy, and the goal of treatment is to maintain a euthyroid state with the lowest possible dose of an antithyroid drug. In general, propylthiouracil has been the preferred drug because it crosses the placenta less than methimazole and because methimazole has caused rare cases of embryopathy (including aplasia cutis) [115,136]. Propylthiouracil is considered more appropriate during the first trimester, even given the FDA warning regarding liver damage [136]. Methimazole should be used when antithyroid treatment is started after the first trimester [115,141]. Pregnant women with Graves disease should be followed up at intervals of three to four weeks (or more frequently, if necessary); pregnancy has an ameliorative effect on hyperthyroidism, and it may be possible to lower the dose of the antithyroid drug or to discontinue its use in the third trimester [115,141]. The lowest possible dose should be used to keep total T4 and T3 levels slightly above the normal range [115]. Women treated for hyperthyroidism during pregnancy should be re-evaluated at six weeks postpartum, as disease can worsen at that time [115,141].

Treatment of Ophthalmopathy

The primary problems caused by Graves ophthalmopathy are dryness, redness, and edema. The AACE and the American Thyroid Association recommend that the overall evaluation and management of the condition is best done in a multidisciplinary clinic combining endocrinologists and ophthalmologists with experience treating Graves ophthalmopathy [115]. Many nonpharmacologic measures for symptoms related to mild Graves ophthalmopathy, including artificial tears for lubrication, sunglasses to decrease photophobia, eye protectors during sleep, and elevation of the head of the bed to decrease periorbital edema, have been recommended Other interventions include a diuretic at bedtime, application of cool compresses to the eyes, increased fluid intake, and avoidance of secondhand smoke, ceiling fans, and contact lenses. Treatment may include glucocorticoids, retro-orbital radiation, or surgery. In 2020, the first medication was approved for the treatment of thyroid eye disease. Teprotumumab is administered as an IV infusion to adults with thyroid-associated ophthalmopathy [293].

Treatment of Thyroid Storm

A complication of Graves disease is thyroid storm, a syndrome characterized by exaggerated signs and symptoms of hyperthyroidism accompanied by fever and altered mental status. Thyroid storm is most often precipitated by a concurrent illness or injury and may also occur following discontinuation of treatment with antithyroid drugs or with radioactive iodine [115,142]. The diagnosis of thyroid storm relies on clinical evaluation, as laboratory testing cannot distinguish thyroid storm from uncomplicated hyperthyroidism [115]. Thyroid storm is a complex, life-threatening syndrome, and an endocrinologist should be involved in the care. Individuals with thyroid storm should be treated in the intensive care unit, with treatment consisting of an antithyroid drug, a drug that inhibits release of thyroid hormone from the thyroid gland, and agents that decrease the peripheral effects of thyroid hormone [115,142].

FOLLOW-UP AND PROGNOSIS

The AACE and the American Thyroid Association recommend annual follow-up visits for patients with either Hashimoto or Graves disease, after a stable TSH level has been achieved [115]. Both organizations recommend that a TSH level be determined at least annually [115]. This monitoring is important, as studies have shown that as many as 40% of individuals taking thyroid medication do not have a TSH level within the normal range [12,13]. Clinicians should also ask direct questions about compliance with drug therapy.

Routine follow-up visits provide healthcare professionals with the opportunity to evaluate patients for signs or symptoms of other autoimmune diseases, especially those that have been reported to be associated with thyroiditis, such as rheumatoid arthritis, systemic lupus, pernicious anemia, and vitiligo [111,112]. In addition, because of the strong association between thyroiditis and type 1 diabetes, the patient should be evaluated closely for signs of this disease [4,38,112].

For patients with Hashimoto disease, clinicians should carefully examine the thyroid during follow-up visits, as lymphoma of the thyroid is a serious, yet rare, complication [107]. The FDA recommends that patients taking propylthiouracil for Graves disease be closely monitored for signs and symptoms of liver injury, especially within the first six months after the start of treatment [136]. Individuals with subclinical hypothyroidism should be followed up annually to determine if there are clinical or biochemical signs of loss of thyroid function, indicating progression to overt hypothyroidism [108,113].

The prognosis for individuals with autoimmune thyroid disease is good, and associated mortality for either autoimmune thyroid disease is low [27]. Remission and mortality vary according to treatment, as discussed.

PATIENT EDUCATION

A member of the healthcare team should explain the particular type of thyroid disease to the patient, focusing on how the patient can participate in his or her own care. Patient education should emphasize the importance of adhering to drug therapy and the recognition of signs and symptoms of complications (Table 5) [108,113,138]. For example, women should understand the increased risk of birth-related events associated with autoimmune thyroid disease [113]. In addition, clinicians should highlight the need for patients to report any changes in symptoms or the occurrence of new symptoms, which may indicate the response to therapy or the development of another autoimmune disease. Clinicians may also refer patients to reliable online educational resources.

Table 5: POINTS OF EMPHASIS IN PATIENT EDUCATION FOR AUTOIMMUNE THYROID DISEASE TREATMENTS

Treatment

Education Points

Hashimoto Disease

Levothyroxine

Take drug:

At same time every day

With full glass of water

When stomach is empty

Avoid the use of antacids

Graves Disease

Radioactive iodine

Abstain from close personal contact for one week after treatment (two weeks for children and pregnant women).

Avoid pregnancy for 4 to 6 months after treatment.

Antithyroid drugs

Recognize signs and symptoms of agranulocytosis (fever, sore throat, mouth ulcers), and stop taking drug if they occur.

Source: [50,108,113]

4. RHEUMATOID ARTHRITIS

Rheumatoid arthritis is a chronic disease characterized by inflammation of synovial tissue that can lead to long-term damage of the joint, resulting in chronic pain, loss of function, and disability. A cytokine network, which includes tumor-necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6, has an integral role in the development of the inflammatory response [48]. The disease is also associated with several extra-articular manifestations and comorbidities [143,144]. The course and severity of the illness vary considerably, and the disease tends to progress over time, with the occurrence of intermittent disease flares.

Most mortality studies in patients with rheumatoid arthritis have found increased death rates compared with the general population; one-third to one-half of the premature deaths in patients with rheumatoid arthritis are due to cardiovascular conditions such as ischemic heart disease and cerebrovascular accidents [149,319]. It is unclear whether cardiovascular disease results from rheumatoid arthritis or if it precedes the onset [148].

EPIDEMIOLOGY

An estimated 1.5 million American adults are affected by rheumatoid arthritis [145]. The yearly incidence of rheumatoid arthritis is approximately 53 per 100,000 for women and about half that (27.7 per 100,000) for men [145]. The prevalence of rheumatoid arthritis increases steadily with age in both sexes, being highest in the 65 to 74 years of age group [145]. However, the incidence is much higher for women in all age groups compared with men.

In most cases, updated statistics and costs related to rheumatoid arthritis are included as part of the larger category of related arthritic or rheumatic conditions. There were 20.8 million office visits for primary rheumatic conditions in 2015, totaling nearly 2.1% of all ambulatory care visits that year (2.3% for women, 1.9% for men) [146]. An estimated 23% (54.4 million) of adults in the United States reported having doctor-diagnosed arthritis between 2013 and 2015, and 50% of adults 65 years of age or older reported an arthritis diagnosis (i.e., some form of arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia) [148]. By 2040, an estimated 78.4 million Americans 18 years of age or older are projected to have diagnosed arthritis [148].

Overall, rheumatoid arthritis and related arthritic diseases have a significant impact in the United States, causing disability and premature mortality. Although many people with rheumatoid arthritis work full-time, about 10% of those with rheumatoid arthritis become severely disabled and unable to do simple daily living tasks. Many report significant limitations in vital activities such as walking, stooping/bending/kneeling, climbing stairs, and social activities [149]. Rheumatoid arthritis can shorten a patient's life expectancy by an average of three to seven years. However, individuals with severe forms of rheumatoid arthritis may die 10 to 15 years earlier than expected [149]. It has been found that people with rheumatoid arthritis are 2.3 times as likely to die as other people of the same age [148].

There are significant costs associated with rheumatoid arthritis, and these arthritic-related disease costs continue to increase. In 2013 (the year with the most recently available data), the total cost attributed to arthritis and other rheumatic conditions in the United States was $303.5 billion, up from $128 billion in 2003 [147,150]. Medical expenditures (direct costs) for arthritis and other rheumatic conditions in 2013 were $140 billion, up from $80.8 billion in 2003 [150]. Earnings losses (indirect costs) for arthritis and other rheumatic conditions in 2013 were $164 billion, up from $47 billion in 2003 [147,160]. Individuals with rheumatoid arthritis are far more likely to change occupation, reduce work hours, lose their job, retire early, and be unable to find a job compared with people without arthritis [148].

POTENTIAL ENVIRONMENTAL RISK FACTORS

Environmental factors that have been linked to rheumatoid arthritis include infection, smoking, and stress/depression. Among the infectious micro-organisms thought to be associated with rheumatoid arthritis are Epstein-Barr virus, Mycobacterium tuberculosis, Escherichia coli, Proteus mirabilis, retroviruses, parvovirus B19, and hepatitis C virus [3]. Approximately 8% to 15% of individuals have reported the onset of rheumatoid arthritis-related symptoms within a few days after an infectious illness [151].

There is emerging evidence that the community of intestinal microbes (gut microbiota) has both beneficial and adverse effects on immune regulation and the maintenance of human health. The gut microbiota composition (microbiome) is now considered to have a role as mediator of inflammation locally and at extra-intestinal sites. Several studies have linked alterations in the gut microbiome (dysbiosis) to the pathogenesis of rheumatoid arthritis and other autoimmune diseases [298]. In a study comparing the oral, salivary, and gut microbiomes of patients with rheumatoid arthritis to that of healthy controls, patients with rheumatoid arthritis were found to have a distinct dysbiosis marked by depletion of Hemophilus spp. and an overabundance of Lactobacillus salivarius [299]. These alterations in the microbiome could be correlated with clinical measures and used to stratify patients on the basis of their response to therapy. Specifically, the degree of Hemophilus spp. depletion correlated with levels of serum autoantibodies, and the amount of Lactobacillus salivarius present correlated with the level of rheumatoid disease activity. The observed dysbiosis partially resolved after treatment of the rheumatoid arthritis. Functional alterations in the transport and metabolism of iron, sulfa, zinc, and arginine were also found in the microbiota of individuals with rheumatoid arthritis in this study.

Smoking has also been identified as a significant risk factor for the development of rheumatoid arthritis, and greater smoking intensity (number of cigarettes per day) and longer smoking history further increase the risk [152]. The risk remains increased for at least 20 years after smoking cessation [152]. Research indicates that the risk of developing rheumatoid arthritis is nearly double for current smokers compared with nonsmokers [320].

Psychologic stress has been thought to play a role in the pathogenesis of rheumatoid arthritis by triggering the inflammatory process and exacerbating disease activity [47,48]. In a prospective cohort study of female nurses, women with high PTSD symptomatology were found to have an elevated risk for rheumatoid arthritis [300]. The risk increased with increasing number of PTSD symptoms and was independent of cigarette smoking history. Rheumatoid arthritis is also strongly associated with major depression (attributable risk of 18.1%), probably through its role in creating functional limitation [318].

In addition, because evidence of rheumatoid arthritis-associated antibodies has often been found many years before the onset of clinical symptoms, early environmental factors have been thought to be a contributor to the disease [153]. High birth weight and early breastfeeding cessation are two such early factors [153].

ASSOCIATION WITH OTHER AUTOIMMUNE DISEASES

As noted, autoimmune diseases of connective tissue are more likely to be associated with other autoimmune diseases [69]. Studies have shown that the coexistence of rheumatoid arthritis, thyroiditis, and type 1 diabetes is high [4,111]. In addition, features of systemic lupus are common in individuals with rheumatoid arthritis; in one study, four or more lupus features were found in approximately 16% of individuals with rheumatoid arthritis within 25 years after diagnosis [154]. This finding is significant because the co-occurrence of systemic lupus features and rheumatoid arthritis was associated with increased overall mortality [154].

As many as 25% of individuals with rheumatoid arthritis also have Sjögren syndrome, and the risk of rheumatoid arthritis appears to be higher in individuals who have inflammatory bowel disease [4,67,144]. An inverse relationship between rheumatoid arthritis and multiple sclerosis has been reported [4]. Fibromyalgia is also commonly found in association with rheumatoid arthritis, with reported rates ranging from 17% to 57% [17,155].

CLINICAL MANIFESTATIONS

Pain and stiffness in multiple joints are the primary characteristics of rheumatoid arthritis; approximately one-third of individuals with the disease initially have pain in only one joint [156]. Other common symptoms of rheumatoid arthritis include fatigue, weakness, generalized muscular aches, and anorexia [151]. Approximately 46% of individuals with rheumatoid arthritis have extra-articular manifestations, the most common of which is rheumatoid nodules, followed by pulmonary fibrosis, dry eye syndrome, and anemia of chronic disease [143,144,151]. Rheumatoid nodules are soft, poorly delineated subcutaneous nodules, and they also occasionally affect internal organs such as the pleura, sclera, vocal cords, and vertebral bodies [143,151]. Other frequently occurring extra-articular manifestations include pericarditis, pleuritis, vasculitis, cervical myelopathy, and neuropathy [143]. No reliable predictors of extra-articular manifestations have been identified, but they have been reported to be associated with male gender, smoking, more severe joint disease, worse function, high levels of inflammatory markers, and a positive rheumatoid factor and antinuclear antibody (ANA) titer [144].

DIAGNOSTIC EVALUATION

When evaluating a patient for suspected rheumatoid arthritis, healthcare professionals should focus both the history and the physical examination on the joints. Questions about symptoms related to the joint should help determine which joints are involved, when joint pain occurs (e.g., during activity, at rest), how long pain and stiffness last, and how pain limits function.

The most commonly involved joints are the wrist joints and the proximal interphalangeal and metacarpophalangeal joints; the distal interphalangeal joints and sacroiliac joints are typically not affected [156]. Affected joints may become warm and tender after long periods of inactivity, and joint symptoms are usually bilateral. Small joints of the hands and feet are not usually painful at rest. Morning joint stiffness associated with rheumatoid arthritis usually lasts more than one hour, in contrast to osteoarthritis, in which morning stiffness usually resolves within 30 minutes after waking [157]. For most individuals, symptoms develop over a long period of time (weeks to months); symptoms develop over days to weeks in approximately 15% of patients [156].

The findings on physical examination are usually normal, except for an occasional low-grade fever. The involved joint(s) may feel warm and boggy and may be tender to the touch, but there is usually no accompanying erythema [156]. Affected joints have limitations in the range of motion, and the strength of muscles near affected joints is usually decreased. The patient may keep an affected joint in flexion to avoid pain related to extension. Lymph nodes in the epitrochlear, axillary, and cervical regions may be enlarged. Rheumatoid nodules are often found in pressure areas (e.g., the elbows and finger joints) and the extensor surface of the forearm [151].

Diagnostic Criteria

In 1988, the American Rheumatism Association (now known as the American College of Rheumatology [ACR]) published its Criteria for the Classification of Rheumatoid Arthritis, and these criteria remained the standard for several years [158]. However, the criteria were criticized for a lack of sensitivity to early disease. In 2010, the ACR and the European League Against Rheumatism (EULAR) collaborated on a new classification system that focuses on features of earlier stages of rheumatoid arthritis that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features [159]. The impetus for this change in focus was the need for earlier diagnosis in order to begin disease-modifying drugs as soon as possible [159].

The new classification criteria apply only to newly presenting individuals, and two requirements must first be met: there must be evidence of currently active clinical synovitis (i.e., swelling) in at least one joint as determined by an expert assessor, and the synovitis must not be better explained by another diagnosis [159]. The ACR/EULAR note that all joints may be assessed, except for the distal interphalangeal joints, the first metatarsophalangeal joint, and the first carpometacarpal joint, as these are most often involved in osteoarthritis [159]. Individuals who are eligible according to the first two criteria are then evaluated by four additional criteria related to joint involvement, serologic testing, acute-phase reactants, and duration of symptoms (Table 6) [159]. The classification system includes a scoring system, with a possible total of 10 points; a score of 6 or more indicates "definite" rheumatoid arthritis. Although a person with a score of less than 6 does not have definite rheumatoid arthritis, the score may increase on subsequent testing.

Table 6: 2010 ACR/EULAR CLASSIFICATION CRITERIA FOR RHEUMATOID ARTHRITISa

Category

Criteria

Score

Joint involvement

1 large joint (shoulder, elbow, hip, knee, ankle)

0

2 to 10 large joints

1

1 to 3 small joints (MCP, PIP, second to fifth MTP, thumb IP joints), with or without involvement of large joints

2

4 to 10 small joints, with or without involvement of large joints

3

>10 joints (at least 1 small joint and any combination of any other joints)

5

Serology (at least 1 test result is needed for classification)

Negative RF and ACPA

0

Low-positive RF or low-positive ACPA

2

High-positive RF or high-positive ACPA

3

Acute-phase reactants (at least 1 test result is needed for classification)

Normal CRP and normal ESR

0

Abnormal CRP or abnormal ESR

1

Duration of symptoms

<6 weeks

0

≥6 weeks

1

aSee text for initial criteria and descriptions of criteria.

ACPA = anti-citrullinated protein antibody; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; IP = interphalangeal; MCP = metacarpophalangeal; MTP = metatarsophalangeal; PIP = proximal interphalangeal; RF = rheumatoid factor.

Source: [159] Reprinted with permission, from Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69:1580-1588.

The ACR/EULAR recommended serologic testing involves a rheumatoid factor and an anti-citrullinated protein antibody (ACPA) [159]. A positive rheumatoid factor has long been known as an indicator of rheumatoid arthritis, and studies have shown that this test is positive in approximately 69% to 90% of people with the disease [160,161]. However, the test may be positive in healthy individuals as well as in individuals with other rheumatic diseases (e.g., Sjögren syndrome, systemic sclerosis, systemic lupus), with chronic infections, or with pulmonary disease [160]. The false-positive rate of rheumatoid factor for rheumatoid arthritis has been reported to be 15% [161]. As a result, the sensitivity and specificity of the test are 69% and 85%, respectively [161]. Testing for ACPA began in the late 1990s, and although the sensitivity of the test (67%) is similar to that of the rheumatoid factor, its false-positive rate is lower, yielding a specificity of 95% [161]. According to the ACR/EULAR classification scoring system, the highest score is given if the results of either the rheumatoid factor or the ACPA test is highly positive, and no points are given if both tests are negative [159]. An ANA titer has a reported sensitivity of about 40% among individuals with rheumatoid arthritis, and false-positive results are common [160]. The ANA titer is not part of either the 1988 or 2010 diagnostic criteria [158,159].

Other recommended baseline laboratory testing includes a complete blood cell count (CBC) with differential, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) [8,162]. However, the ESR and CRP results should be interpreted with caution, as the tests are normal in about 40% of people with rheumatoid arthritis [163]. Baseline renal and hepatic functioning should also be determined, not because these tests are sensitive or specific for rheumatoid arthritis but because they are important in guiding the choice of medications [162].

Radiographic evaluation has been recommended as part of the diagnostic work-up for rheumatoid arthritis, but the findings on conventional radiographs of involved joints are often normal, especially in early-stage disease [8]. The findings on imaging studies are not part of the 2010 classification criteria for rheumatoid arthritis [159]. However, imaging studies may be helpful in the differential diagnosis and in establishing baseline images for comparison during follow-up. An analysis of 11 studies of magnetic resonance imaging (MRI) as a diagnostic tool showed a wide range in sensitivity and specificity, with the authors concluding that the data are inadequate to justify widespread use of MRI in the diagnosis of rheumatoid arthritis [164].

Differential Diagnosis

A wide range of medical conditions should be considered in the differential diagnosis of rheumatoid arthritis, including [151,156,165]:

- Connective tissue diseases (e.g., systemic lupus, systemic sclerosis)

- Psoriatic arthritis, gout, and other forms of arthritis

- Fibromyalgia

- Polymyalgia rheumatica

- Thyroid disease

- Sarcoidosis

- Hemochromatosis

- Still disease

- Viral arthritis

- Paraneoplastic syndrome (when onset is after 55 years of age)

Overlapping signs and symptoms can make it challenging to distinguish rheumatoid arthritis from many of these conditions, especially connective tissue diseases and other forms of arthritis. A positive ANA titer may help distinguish systemic lupus from rheumatoid arthritis, and determination of a TSH level can aid in a diagnosis of hypothyroidism [156,160]. Early in the course of rheumatoid arthritis, self-limited viral syndromes should be considered, especially hepatitis B and C, parvovirus, rubella (infection or vaccination), and Epstein-Barr virus [3].

TREATMENT OPTIONS

The primary goal of treatment for rheumatoid arthritis was once to alleviate symptoms using a pyramid approach, but the advent of disease-modifying drugs as a standard of care has shifted the focus to early remission and/or the prevention of further joint damage using a treat-to-target approach [166,323]. This approach is a tightly controlled, aggressive strategy tailored to each patient, with modifications to the individual medication regimen to achieve a particular target (remission, or alternatively, low disease activity) in a specific period of time (usually six months) [166]. Treatment goals are to preserve the structural integrity of the joint, enhance function and quality of life, minimize pain and inflammation, and control systemic complications [9,156]. These goals are achieved through a combination of disease-modifying drugs, anti-inflammatory agents, and nonpharmacologic measures. Surgery is sometimes needed when medical treatment options fail. In addition, treatment of complications or comorbidities associated with rheumatoid arthritis is often needed.

Several guidelines for the treatment of rheumatoid arthritis exist. In 2016, the ACR published updated guidelines on the use of disease-modifying antirheumatic drugs and biologic agents and emphasizes the use of the treat-to-target approach [9]. Updated ACR guidelines are anticipated to be published in late 2020 [285]. The EULAR has developed guidelines for the management of early rheumatoid arthritis and for the use of disease-modifying drugs (updated in 2019) [162,166,284].

A 2012 meta-analysis of four studies comparing tight control with usual care found that applying a treat-to-(any)target approach approximately doubled remission rates in patients with early rheumatoid arthritis with high disease activity [323]. One small-scale study comparing early aggressive treatment (i.e., methotrexate) with usual care (i.e., using milder drugs initially, with intensification of treatment as needed) found that there was approximately 50% remission in each group at the study endpoint (two years) [326]. However, during the course of the study, 23 of 24 patients in the conventional care group had progressed to aggressive treatment (with methotrexate) and most were given intra-articular corticosteroids much more frequently than those in the tight control group. It is interesting to note that the aggressive treatment (methotrexate) is not considered aggressive by today's standards, as treatment with adalimumab was started only in patients who had poor response six months after initiation of treatment. Progression of joint damage (i.e., lack of radiographic remission) occurred among a minority of participants even in the aggressive treatment group who were considered to have clinical remission (based on assessment scores); on average, radiographic and functional scores were similar in both groups at the end of the study [326]. The authors emphasize that their results do not indicate an advantage of one treatment strategy over another; instead factors such as patient preference and risk versus benefit (e.g., weighing the severe side effects of the stronger disease-modifying antirheumatic drugs [DMARDs] against their rapid response) should guide the treatment decision [326]. In addition, the measures of remission are ill-defined, and to progress from low disease activity (which may be a satisfactory target) to clinically defined remission may require a medication regimen greater than what is safe or tolerable. Most clinicians in the study were unwilling to push for remission if their patient's disease was reduced to an acceptable level with conservative treatment.

Disease-Modifying Antirheumatic Drugs

Evidence Based Practice Recommendation

In patients with symptomatic early rheumatoid arthritis with moderate-to-severe disease activity, the American College of Rheumatology recommends the use of DMARD monotherapy over double or triple therapy.

https://www.rheumatology.org/Portals/0/Files/ACR%202015%20RA%20Guideline.pdf

Last Accessed: July 23, 2020

Level of Evidence: Moderate

Early treatment is essential to achieving optimal outcomes with disease-modifying drugs, and the EULAR guideline recommends that treatment with disease-modifying drugs begin immediately following the diagnosis [166,284]. DMARDs are antimetabolite/cytotoxic agents, and several nonbiologic and biologic disease-modifying drugs are now available, allowing clinicians and patients to select a specific drug after considering several factors. In its recommendations for the use of disease-modifying drugs, the ACR discussed the use of 13 drugs (five nonbiologic and eight biologic agents) and noted that other drugs were not included because they were used infrequently, were associated with a high incidence of adverse events, or were not recommended for other reasons (Table 7) [9,167]. For example, anakinra, an IL-1 antagonist, has been found to be less effective than the other biologic agents and so was omitted from the review of the literature informing the guidelines [167,168]. Since the publication of the guidelines, three additional nonbiologic agents in the Janus kinase (JAK) inhibitor family (tofacitinib, baricitinib, and upadacitinib) and one additional biologic agent (sarilumab) have received FDA approval for the treatment of rheumatoid arthritis [286,287,288,308,321]. These additional drugs are included in the updated EULAR guidelines and are expected to be included in the forthcoming update to the ACR guidelines [284,285].

Table 7: RECOMMENDED DISEASE-MODIFYING ANTIRHEUMATIC DRUGS APPROVED BY THE U.S. FOOD AND DRUG ADMINISTRATION FOR THE TREATMENT OF RHEUMATOID ARTHRITIS

Agent

Indicationa

Dose and Administration

Most Common Adverse Effects

Nonbiologic Agents

Methotrexate

Any disease duration, any degree of disease activity, with or without poor prognosis features

12–25 mg PO, IM, or SC weekly

Nausea, diarrhea, fatigue, mouth ulcers, rash, alopecia

Leflunomide

Any disease duration, any degree of disease activity, with or without poor prognosis features

100 mg PO daily for 3 days, then 10–20 mg PO daily

Nausea, diarrhea, rash, alopecia; highly teratogenic, even after use is discontinued

Hydroxychloroquine

Short or intermediate disease duration, low disease activity, no poor prognosis features

200–400 mg PO daily

Nausea, headache, possible retinopathy

Sulfasalazine

Any disease duration, any degree of disease activity, no poor prognosis features

2–3 g PO daily (in divided doses)

Nausea, diarrhea, headache, mouth ulcers, rash, alopecia, oligospermia (reversible)

Tofacitinibb

Moderately to severely active disease despite treatment with methotrexate or intolerance of methotrexate

5 mg daily

Infections, headache, diarrhea

Baricitinibb

Moderately to severely active disease with inadequate response to one or more anti-tumor necrosis factor-α agents.

May be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs

2 mg PO daily

Infection, upper respiratory tract infection, nausea

Upadacitinibb

Moderately to severely active disease with intolerance of methotrexate.

May be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs

15 mg PO daily

Upper respiratory tract infection, nausea

Biologic Agents

Anti-tumor necrosis factor-α agents (adalimumab, etanercept, infliximab)

In combination with methotrexate: Disease duration of less than 3 months, high disease activity, features of poor prognosis, and no previous treatment with disease-modifying drugs

Alone: Inadequate response to methotrexate monotherapy AND disease duration >3 months, moderate disease activity, and poor prognosis features OR disease duration >3 months, high disease activity, with or without poor prognosis features

Adalimumab: 40 mg SC every 2 weeks

Infusion reactions, increased risk of infection (especially fungal)

Etanercept: 25 mg SC twice weekly or 50 mg SC weekly

Infliximab: 3 mg/kg IV at weeks 0, 2, and 6, then every 8 weeks

Golimumab (anti-tumor necrosis factor-α)

In combination with methotrexate: moderate-to-severe disease

50 mg SC monthly

Serious infections, upper respiratory infection, nasopharyngitis

Abatacept

Inadequate response to methotrexate-based combination or sequential administration of other nonbiologic agents, moderate-to-high disease activity, and features of poor prognosis

500–1,000 mg (depending on body weight) IV at weeks 0, 2, and 4, then every 4 weeks

Headache, nasopharyngitis, dizziness, urinary tract infection, bronchitis

Rituximab

In combination with methotrexate: Inadequate response to methotrexate-based combination or sequential administration of other nonbiologic agents, high disease activity, and features of poor prognosis

1,000 mg IV at week. 0 and 2, then every 24 weeks

Upper respiratory infection, bronchitis, nasopharyngitis, urinary tract infection

Tocilizumab

Alone or in combination with methotrexate: Moderate-to-severe disease refractory to 1 or more anti-tumor necrosis factor-α agents

4–8 mg/kg IV monthly

Serious infection, upper respiratory infection, nasopharyngitis, headache, hypertension

Sarilumab

Moderately to severely active disease with an adequate response or intolerance to one or more DMARDs

Do not use in combination with biologic DMARDs

200 mg SC every 2 weeks

Increased serum alanine aminotransferase, increased serum aspartate aminotransferase, neutropenia, antibody development, erythema at injection site

aDisease duration defined as short (less than 6 months), intermediate (6 to 24 months), or long (more than 24 months). Degree of disease activity is defined according to scores on one of several validated disease activity instruments; presence of poor prognosis features is defined as functional limitation, extra-articular disease, positive rheumatoid factor and/or positive anti-citrullinated protein antibody test, and/or osseous erosions on radiograph.

bJAK inhibitors (tofacitinib, baricitinib, and upadacitinib) should not be used in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine.

Source: [9,20,286,287,288,308,321]

Among the recommended nonbiologic agents are methotrexate, generally considered to be the standard first-line treatment; the antimalarial drug hydroxychloroquine; the JAK inhibitors tofacitinib, baricitinib, and upadacitinib; and sulfasalazine and leflunomide, drugs developed specifically for rheumatoid arthritis [9]. The biologic agents include five anti-TNF-α agents (adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab) and three non-TNF-α agents, including abatacept, a selective costimulation modulator; rituximab, an anti-CD20 monoclonal antibody that depletes B lymphocytes; and tocilizumab and sarilumab, IL-6 receptor antagonists [9].

Methotrexate is the most commonly prescribed DMARD and is still considered the so-called anchor drug for the treatment of rheumatoid arthritis [9,166]. It can be given alone or in combination with one or two other nonbiologic agents. Leflunomide, a competitive inhibitor of an intracellular enzyme needed for de novo pyrimidine synthesis, is a newer DMARD with comparable efficacy that can be substituted for methotrexate and may be particularly useful for patients with intolerance of or contraindications to methotrexate [156,324,325]. Patients for whom monotherapy with methotrexate has failed may benefit from the addition of leflunomide, either with methotrexate or other DMARDs [325].

The ACR recommends basing the decision regarding initial treatment with a DMARD on the duration of disease (early or established) and degree of disease activity (low, moderate, or high) [9]. Previous guidelines had also considered prognosis, but this is now considered encompassed by disease activity. Additional factors to consider when choosing a drug are side effect profiles, cost, and access to care.

The treat-to-target approach for patients with early high disease activity typically involves initiation of methotrexate and/or another DMARD(s) immediately upon diagnosis [9,166,323]. Initial combination therapies with DMARDs, particularly those including a biologic anti-TNF-α agent, appear to provide earlier clinical improvement and less joint damage progression in patients with early highly active disease. These therapies can be withdrawn successfully, and fewer treatment adjustments are needed than with initial monotherapies [9,25,166,327,328]. Patients with active disease are monitored closely (every one to three months), and it is recommended that treatment adjustments be made if there is no improvement at three months (or if the six-month target has not been reached) [9,166]. For patients with low-to-moderate disease activity or high disease activity without poor prognostic features, DMARD monotherapy is usually given initially.

As discussed, comparative studies of methotrexate, leflunomide, and sulfasalazine have provided no evidence that points to the benefit of one of these drugs over the others; similarly, evidence suggests similar benefit among biologic agents [167,170,171,326]. In addition, a combination of nonbiologic drugs, methotrexate, and a biologic drug have led to better clinical response rates and functional outcomes than either methotrexate or a biologic agent alone, especially in early active disease [170,172]. However, one systematic review showed no significant advantage of a methotrexate-based combination compared with methotrexate monotherapy among patients receiving initial treatment with a disease-modifying drug [173]. That review did show significant reductions in pain and improvement in physical function for methotrexate-based combinations among patients in whom disease had not responded to methotrexate monotherapy [173].

Several precautions should be taken before beginning treatment with a disease-modifying drug. The ACR recommends determining baseline CBC, liver function studies, and creatinine level before beginning or resuming treatment with any of the drugs; these laboratory tests should also be done after any significant increase in dose [9]. Individuals receiving methotrexate or leflunomide should also be tested for hepatitis B or C infection. If an individual's vaccinations are not current, influenza vaccine should be administered before treatment with a nonbiologic agent is begun, and pneumococcal vaccine should also be given before treatment with DMARDs. Both vaccinations are recommended before treatment with a biologic agent begins [9]. Routine tuberculosis screening should also be done to identify latent tuberculosis infection in individuals who are being considered for therapy with a biologic agent or tofacitinib.

In previous guidelines, acute hepatitis B or C infection was considered a contraindication for most DMARDs and biologic agents. However, in its 2016 update, the ACR recommended that patients with active hepatitis B or C who are receiving effective antiviral treatment may be managed the same as patients without hepatitis [9]. Certain medications may be preferred for other high-risk conditions, including congestive heart failure, treated or untreated malignancy, and serious infection [9].

Anti-Inflammatory Medications

Anti-inflammatory medications are used to reduce joint pain and swelling associated with rheumatoid arthritis. Because these drugs do not change the course of disease, they must be used in conjunction with a disease-modifying drug. Treatment typically begins with a nonselective nonsteroidal anti-inflammatory drug (NSAID); a cyclooxygenase-2 (COX-2)-selective inhibitor and/or glucocorticoids may also be used. A gastroprotective agent (proton-pump inhibitor) should be prescribed with an NSAID for individuals at high risk for gastrointestinal complications [176].

There is good evidence that nonselective NSAIDs and COX-2 inhibitors have comparable efficacy and that COX-2 inhibitors are comparable to each other [177]. Although COX-2 inhibitors have better tolerability in general compared with NSAIDs, there is considerable variability across individual drugs in terms of protection against serious gastrointestinal events [177]. A large, double-blind, randomized trial involving nearly 4,500 individuals with rheumatoid arthritis or osteoarthritis demonstrated that the COX-2 inhibitor celecoxib was associated with lower risks of adverse gastrointestinal events than a nonselective NSAID plus a proton-pump inhibitor (diclofenac plus omeprazole) [178].

The adverse event profiles of both nonselective NSAIDs and COX-2 inhibitors should be considered when selecting a specific drug for an individual patient. All individuals treated with NSAIDs should be monitored for long-term complications such as gastrointestinal bleeding, nephrotoxicity, cardiovascular events (e.g., myocardial infarction, stroke), and gastric ulcers and bleeding [176,177]. The increased risk of cardiovascular events associated with some COX-2 inhibitors has been well publicized, prompting the FDA to re-evaluate the risks and benefits of the COX-2 inhibitors; special care should be taken when prescribing these drugs [177]. Although certain COX-2 inhibitors (such as celecoxib) are still available, they are labeled with strong warnings and a recommendation for prescribing the lowest possible dose for the shortest possible duration [20].

In addition to their anti-inflammatory properties, glucocorticoids may substantially reduce the rate of further joint erosion and should be considered as a temporary adjunct to treatment with disease-modifying drugs [162,179]. However, because of the substantial risk of adverse effects, glucocorticoids should be given for the shortest time and at the smallest dose possible, and treatment should be discontinued gradually—over at least one month––to avoid rebound effects [8]. Administration of a glucocorticoid as an intra-articular injection may reduce swelling and inflammation in a single joint, but the clinical benefit is short term [162].

Complementary/Alternative Medicine

Many individuals with rheumatoid arthritis turn to complementary and alternative medicine to alleviate symptoms. The use of complementary and alternative medicine among individuals with rheumatoid arthritis has ranged from 28% to 90%, and the rates of use among all individuals vary across racial/ethnic populations [77,180,181]. Most herbal supplements used by individuals with rheumatoid arthritis are safe, but the evidence of their benefit has been weak to moderate [182,183]. Despite the wide use of complementary and alternative medicine, most individuals (63% to 72%) do not report the use to their healthcare providers [96,181]. Because of this, clinicians should ask direct questions about the use of complementary and alternative medicine approaches and initiate discussions about their use.

Aside from supplementation with several specific types of oils, the only complementary therapy currently endorsed by the U.S. Department of Health and Human Services for patients with rheumatoid arthritis is to consume a nutritious, balanced diet [329]. Some argue that the typical American diet, which is based on animal proteins (many of which are now devoid of significant levels of nutrients and/or are heavily processed) and typically consisting of high levels of animal fats (e.g., cheese, butter, ice cream) and simple carbohydrates promotes inflammation [334]. However, others argue that restricting the intake of good quality food sources of nutrients, such as fish and real cheese, can lead to dietary deficiencies. A growing body of evidence supports the belief that proper nutrition from food, or more specifically, avoidance or correction of nutritional deficiencies, can prevent the development of inflammatory disorders in genetically predisposed individuals. One group of researchers writes that, "diet can affect transgenerational gene expression via 'reversible' heritable epigenetic mechanisms" [330]. It is believed that certain anti-inflammatory bioactive food components (e.g., carotenoids, organosulfurs, polyphenols, phytosterols, tocopherols, tocotrienols) can lessen the rates and negative effects of acetylation, methylation, oxidation, phosphorylation, ribosylation, SUMOylation, and ubiquitination.

One food-sourced supplement, fish oil, is a proven, powerful rheumatoid arthritis therapy and contains several bioactive components, such as the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). A 2010 meta- and mega-analysis of randomized controlled trials confirmed the efficacy of fish oil for the relief of joint pain and found a significantly reduced use of anti-inflammatory drugs in patients with long-standing rheumatoid arthritis [331]. NSAIDs can cause an increased cardiovascular risk, and reduced morbidity and mortality among participants in the research groups was also attributable to fish oil supplementation, as atherosclerosis and NSAID use are both reduced with this therapy. Past research was limited to long-standing cases of rheumatoid arthritis; it is unclear whether fish oil can prevent joint damage in recent-onset rheumatoid arthritis [331]. Though fish oil is most often studied, krill oil (from a small, shrimp-like crustacean) has also shown similarly beneficial results [332]. It should be noted that concerns over bleeding risks (e.g., hemorrhagic stroke) related to a high intake of fish oil have been shown to be unfounded [333]. However, blood thinning is a side effect, and patients should be advised to eat foods rich in vitamin K1 while taking these supplements.

Nonpharmacologic Therapy

Physical therapy and/or occupational therapy can help individuals improve their ability to carry out activities of daily living at home, at work, and socially [162]. In addition, physical therapists can provide instruction in a program of range-of-motion and strengthening exercises, in joint protection, and in ways to conserve energy. Evidence of benefit from nonpharmacologic approaches is lacking, however. An overview of systematic reviews found that there was unclear benefit (low quality of evidence) for most nonpharmacologic therapies, including balneotherapy, electrical stimulation, transcutaneous electrical nerve stimulation, assistive devices, and splints [183]. The exceptions were comprehensive occupational therapy and joint protection, which were shown to improve function (with no difference in pain) according to high-quality evidence, and low-level laser therapy, which was shown to reduce pain and improve function according to evidence of moderate quality [183].

Regular participation in activities such as walking or aerobic exercises is recommended, as they can help improve joint mobility, muscle strength, and aerobic fitness; decrease fatigue; and maintain psychologic well-being [8,184]. Also, because emotional stress can exacerbate disease activity, stress management interventions should be encouraged [47,48]. Several randomized controlled trials have indicated that significant improvements in pain management and function have resulted from cognitive-behavioral therapy that has focused on therapist-guided training in coping strategies (e.g., relaxation, goal setting, imagery, and cognitive restructuring of negative thoughts related to pain) [48].

Surgical Intervention

The goals of surgical intervention for rheumatoid arthritis are to restore function and quality of life, prevent further deterioration of the joint, relieve pain, and correct deformity [185]. Surgery is reserved for patients who have structural joint damage that causes high pain levels, loss of range of motion, or severely limited function (severe disability and/or inability to work) despite pharmacologic and nonpharmacologic therapy [334]. The challenge with surgical treatment is that many joints are often involved; priority should be given to the joint that causes the greatest disability and pain [185]. Among the options for surgical treatment are synovectomy, carpal tunnel release, resection of the metatarsal heads, specialized hand surgery, arthrodesis, and joint replacement [185]. The preoperative functional status is an important factor in the postoperative outcome, making early referral for surgery important [334].

Treatment of Extra-Articular Manifestations

The overall management of individuals with rheumatoid arthritis includes clinical assessment and follow-up for extra-articular manifestations of rheumatoid disease [144]. As indicated earlier, a variety of conditions are seen involving major organs: cardiac (e.g., pericarditis, myocarditis), pulmonary (e.g., pleuritis with effusion, interstitial pneumonitis, pulmonary fibrosis), ocular (e.g., scleritis, anterior uveitis, peripheral ulcerative keratitis), vasculitis, neuropathy, osteopenia, and osteoporosis. Because extra-articular manifestations are associated with a poor prognosis, they should be identified early and managed promptly with the assistance of subspecialty consultation. Because the underlying pathophysiology often centers on inflammation and vasculitis, treatment primarily relies on glucocorticoids [144].

FOLLOW-UP AND PROGNOSIS

Close follow-up is needed for individuals with rheumatoid arthritis to evaluate response to treatment, ensure control of symptoms, and monitor for treatment side effects and disease-related comorbidities.

Response to Treatment

Both the ACR and the EULAR recommend that evidence of disease activity be evaluated, through subjective and objective measures, at each follow-up visit [9,162]. The follow-up assessment may include:

- Self-reports of degree of joint pain, duration of morning stiffness, limitation of function, and duration of fatigue

- Tender and swollen joints on physical examination

- Evidence of disease progression on physical examination (e.g., loss of motion, instability, malalignment, and/or deformity)

- Elevated ESR or CRP level

- Progression of radiographic damage of involved joints (with use of radiographic assessment scales)

- Global assessment of disease activity (by the physician and the patient)

- Standardized questionnaires to assess functional status and/or quality of life

The recommended follow-up interval is every one to three months until remission is achieved, and adjustments to the doses and/or choices of monotherapy or combination therapy with disease-modifying drugs should be made if the response is inadequate [9,162,166]. Treatment with DMARDs can lead to some level of remission in approximately 30% to 40% of individuals, but sustained remission is less common (17% to 20%), and most individuals will have persistent disease [151,156,335]. Again, achieving low disease activity with a conservative medication regimen may be a better course than seeking clinical remission with aggressive therapy [326].

Monitoring and Treatment of Drug Side Effects

A systematic approach to long-term drug monitoring is necessary because of the potential for serious adverse events associated with the long-term use of DMARDS and glucocorticoids [186].

Among the side effects of long-term use of disease-modifying drugs are infection; bone marrow suppression; gastrointestinal, hepatic, renal/genitourinary, cardiovascular, and neurologic effects; pulmonary toxicity; and skin reaction/rash [186]. Infusion site reactions are also commonly associated with anti-TNF-α agents [186]. It is recommended that individuals treated with leflunomide, methotrexate, or sulfasalazine have a CBC, liver function studies, and a serum creatinine at baseline and then every 2 to 4 weeks for the first three months after the beginning of treatment; every 8 to 12 weeks during the three- to six-month period, and every 12 weeks subsequently [20]. Individuals taking rituximab should have a CBC and platelet count done every two to four months, and individuals treated with tocilizumab should have neutrophils, platelets, and liver enzymes, as well as CBC, platelet count, and liver function studies, as indicated, assessed every four to eight weeks [20].

Individuals receiving hydroxychloroquine are at risk for severe retinopathy, and ophthalmologic follow-up is important for early detection and minimization of toxicity [187]. The reported incidence of retinopathy associated with hydroxychloroquine is low, especially within the first five years of use at a low dose (less than 400 mg/day), but the potential severity calls for ophthalmologic follow-up [187,188]. The American Academy of Ophthalmology (AAO) recommends a complete ophthalmologic examination within the first year after treatment [187]. If the results are normal, subsequent eye examinations should be performed annually after five years of treatment in all patients considered to be at low risk for hydroxychloroquine-related toxicity based on presence of the following factors [187]:

- Duration of use: Longer than five years

- Cumulative dose: >1,000 g (total)

- Daily dose: >400 mg/day (>6.5 mg/kg ideal body weight for short individuals)

- Older age

- Kidney or liver dysfunction

- Retinal disease or maculopathy

For people at high risk for toxicity (i.e., those who are treated with higher doses of hydroxychloroquine and/or for longer than five years), the AAO recommends an annual eye examination [187]. Age older than 60 years, the presence of renal or hepatic disease, and obesity are also factors that increase the risk for hydroxychloroquine-related retinopathy [187]. The AAO emphasizes that these are minimum recommendations that balance cost with risk, and more frequent screening may be appropriate.

All drugs used to treat rheumatoid arthritis are associated with a high risk of conventional and opportunistic infections, and measures to prevent infection should be taken. The ACR recommends that in addition to receiving an influenza vaccination before beginning treatment with DMARDs, individuals should receive the vaccination annually thereafter [9]. In addition, a pneumococcal vaccination should be given every five years [9]. All vaccines should be given based on age and risk. If hepatitis and/or human papillomavirus (HPV) risk factors are present, the hepatitis B and/or HPV vaccine should be administered. Live vaccines (e.g., herpes zoster) should be avoided only in individuals already receiving a biologic disease-modifying drug [9]. Targeted prophylaxis for individuals at high risk for infection may also be appropriate [43,186].

The use of glucocorticoids, especially over the long term, is associated with a wide range of potential adverse events, including osteopenia/osteoporosis, hypertension, cataracts, glaucoma, dyspepsia, weight gain, avascular necrosis of bone, Cushingoid changes, and adverse psychologic effects [186]. The ACR updated their guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis in 2017 [189]. The ACR recommends daily calcium intake (dietary plus supplement) of 1,000–1,200 mg and supplemental vitamin D (600–800 IU) in conjunction with lifestyle modifications (e.g., maintaining a balanced diet and recommended weight, smoking cessation, regular weight-bearing or resistance training exercise, and limiting alcohol intake to one to two alcoholic beverages daily)_to prevent osteoporosis in all individuals taking glucocorticoids [189]. The ACR guidelines also include recommendations for the use of bisphosphonates according to an individual's age, risk factors, and dose and duration of the glucocorticoid , noting that risk is best assessed with a combination of the Fracture Risk Assessment (FRAX) tool (adjust and increase the 10-year risk generated with FRAX by 1.15 for major osteoporotic fracture and 1.2 for hip fracture if glucocorticoid treatment is >7.5 mg/day) and bone mineral density(Table 8) [189,190]. In addition, baseline dual x-ray absorptiometry, height, prevalent fragility fractures, and serum 25-hydroxyvitamin D level should be obtained before the start of treatment with glucocorticoids and should be monitored throughout the course of treatment [189]. Better adherence to the ACR guidelines are needed, as one study showed that a baseline bone scan was done in only 39% of patients and appropriate treatment was also prescribed for only 39% [11].

Table 8: AMERICAN COLLEGE OF RHEUMATOLOGY RECOMMENDATIONS FOR USE OF BISPHOSPHONATES DURING TREATMENT WITH GLUCOCORTICOIDS WITH A DURATION OF AT LEAST THREE MONTHS

Age/Dose

Risk Factora

Treatment Recommendation

All adults taking >2.5 mg/day prednisone

—

Optimize calcium intake (1,000–1,200 mg/day), vitamin D intake (600–800 IU/day), and lifestyle modification

Adults >40 years of age taking any dose of prednisone

Low

Optimize calcium and vitamin D intake and lifestyle modifications over treatment with bisphosphonates, teriparatide, denosumab, or raloxifene

Moderate

Treat with an oral bisphosphonate over calcium and vitamin D alone.

Treat with an oral bisphosphonate over IV bisphosphonates, teriparatide, denosumab, or raloxifene

High

Treat with an oral bisphosphonate over calcium and vitamin D alone

Treat with an oral bisphosphonate over IV bisphosphonates, teriparatide, denosumab, or raloxifene

<40 years of age

Low

Optimize calcium and vitamin D intake and lifestyle modifications over treatment with bisphosphonates, teriparatide, or denosumab

Moderate to high

Treat with an oral bisphosphonate over calcium and vitamin D alone

Treat with an oral bisphosphonate over IV bisphosphonates, teriparatide, or denosumab

aTen-year risk of a major osteoporotic fracture, as defined with use of the FRAX calculator. (adjusting by 1.15 for major osteoporotic fracture and 1.2 for hip fracture if glucocorticoid treatment is >7.5 mg/day), bone mineral density, and history of fracture.

Source: [189]

Prevention of Comorbidities

Other comorbidities are prevalent among people with rheumatoid arthritis, and hypertension, gastrointestinal problems, and psychiatric problems/depression are the most common current and lifetime comorbidities (Table 9) [191]. In addition, the association between rheumatoid arthritis and an increased risk for cardiovascular disease and events is well-documented, including its impact on mortality. Follow-up care should include patient assessment and preventive strategies for these comorbidities, as well as treatment as appropriate. Individuals with rheumatoid arthritis should also be monitored for signs and symptoms indicative of autoimmune diseases commonly found in association with rheumatoid arthritis, such as thyroiditis, type 1 diabetes, Sjögren syndrome, and inflammatory bowel disease [4,111,144].

Table 9: COMORBIDITIES ASSOCIATED WITH RHEUMATOID ARTHRITIS

Comorbidity

Prevalence

Lifetime

Current

Any gastrointestinal problem

50%

15%

Hypertension

47%

32%

Any psychiatric problem

36%

16%

Depression

34%

15%

Any endocrine problem

30%

20%

Any genitourinary problem

30%

4%

Cataract

27%

10%

Any lung problem

25%

12%

Any cardiovascular problem

22%

9%

Source: [191]

Prognosis

Of all the autoimmune diseases, rheumatoid arthritis is a leading cause of mortality, especially among women older than 65 years of age [27,28]. Studies have consistently shown higher rates of mortality for individuals with rheumatoid arthritis than for the general population [192,193,194]. Furthermore, the increasing survival rates documented for the population at large since the 1950s and 1960s have not been found for individuals with rheumatoid arthritis [195]. The increased mortality has been linked to several factors, including extra-articular manifestations, markers of disease severity, and diminished function within the first year [193,194]. By far, cardiovascular disease has been thought to confer the greatest risk for increased mortality [193,194].

A meta-analysis of observational studies demonstrated that mortality related to cardiovascular disease is increased by about 50% in individuals who have rheumatoid arthritis (compared with individuals who do not have the disease) [196]. The increased risk cannot be explained by an increased incidence of traditional cardiovascular disease risk factors [197,198,199]. The underlying inflammatory mechanism is thought to have a role, and the increased use of disease-modifying drugs is expected to help improve survival in addition to function [194,200]. To date, only methotrexate has been shown to be associated with a reduced risk of cardiovascular disease among individuals with rheumatoid arthritis [201]. The increased risk of cardiovascular disease highlights the need for clinicians to assess traditional and nontraditional cardiovascular risk factors, such as hypertension, obesity, smoking, hyperlipidemia, inflammation, insulin resistance, and family history of cardiovascular disease, and provide counseling, preventive measures, and treatment as appropriate [202].

PATIENT EDUCATION

Education and self-management are valuable components of an overall treatment plan for a chronic illness such as rheumatoid arthritis [18,162]. Studies have demonstrated that patient education improves function, patients' global assessment, adherence to the treatment plan, and psychologic status [48,183].

Clinicians should emphasize the importance of noting new symptoms that may be related to adverse effects of treatment drugs and the need for strategies to minimize these effects [186]. For example, clinicians should counsel patients treated with glucocorticoids and/or immunosuppressant agents about ways to prevent osteoporosis and reduce the risk of infection and should emphasize to all patients the importance of modifying lifestyle factors that increase the risk for cardiovascular disease (Table 10).

Table 10: POINTS OF EMPHASIS IN PATIENT EDUCATION REGARDING PREVENTION OF COMORBIDITIES ASSOCIATED WITH RHEUMATIC DISEASES AND THEIR TREATMENT

Comorbidity/Complication

Preventive Measures

Infection

Wash hands frequently.

Avoid situations that increase the risk of infection (e.g., crowded areas, public transportation, children and adults who have been recently vaccinated with live vaccines).

Take precautions against injuries.

Remain up-to-date on influenza vaccination.

Osteopenia/osteoporosis

Increase dietary intake of calcium and vitamin D.

Take calcium and vitamin D supplements as prescribed.

Engage in regular weight-bearing and muscle-strengthening activities.

Stop smoking.

Avoid excessive use of alcohol.

Cardiovascular disease

Maintain proper weight (reduce weight if necessary).

Eat a healthy diet, low in fat, salt, and sugars.

Engage in regular exercise/activities.

Take any medications as prescribed (e.g., for hypertension, hyperlipidemia, or diabetes).

Reduce stress.

Stop smoking.

Avoid excessive use of alcohol.

Source: [3,189,269]

Given the high rate of complementary and alternative medicine use, along with a substantial lack of disclosure of such use, clinicians should emphasize the importance of discussing the use of herbal and/or dietary supplements. Education should focus on the risk of disease progression if alternative approaches or supplements are used to replace conventional therapies and the potential for interactions between herbal supplements and treatment drugs.

Patient education should be tailored to address individual needs. Healthcare professionals should emphasize to patients that adhering to the management program will alleviate their symptoms, improve their function, and enhance their quality of life. Clinicians should also refer patients to reliable educational resources.

5. SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus is a chronic inflammatory autoimmune disorder of the connective tissue, primarily affecting the skin, joints, blood, and kidneys; however, other body systems/organs can also be affected. The disease process in systemic lupus is complex, with an often unpredictable course and a prognosis that varies from mild to severe to life-threatening. As with other autoimmune diseases, systemic lupus is characterized by recurring remissions and exacerbations (flares).

Improved treatment options have led to longer survival for people with systemic lupus [75]. Unfortunately, along with longer survival has come an increased risk for chronic diseases, especially cardiovascular disease. In addition, the disability caused by systemic lupus can be substantial. Studies and surveys have shown that the symptoms of fatigue, pain, and neurocognitive dysfunction cause many individuals with systemic lupus to stop working. Approximately 50% of individuals stop working within 13 years after diagnosis [203]. A large telephone survey found that the percentage of individuals with systemic lupus who were working decreased from 74% to 54% between the time of diagnosis and a follow-up interview one to two years later [204]. The number of people who stop working increases with longer time from diagnosis [204].

EPIDEMIOLOGY

The prevalence of systemic lupus has ranged from 72.8 to 143.7 per 100,000, with higher rates (127 to 280 per 100,000) among women [32,59]. The incidence of systemic lupus has nearly tripled since the 1950s [194]. Approximately 161,000 to 322,000 adults in the United States have systemic lupus, according to prevalence and population estimates [56]. A 2017 systematic review, based on epidemiologic reports in 2013 and updated in 2016, estimates that the annual incidence of systemic lupus in North America is 23.2 cases per 100,000 population and the prevalence is 241 persons per 100,000 [301].

The prevalence rates for lupus are 5 to 10 times higher among women than men, reflecting the female preponderance of the disease [32,59,63]. Most women affected by the disease are of childbearing age; the average age at the time of diagnosis of adult-onset systemic lupus is 39.3 years [59]. About 3% to 18% of cases have an onset after 50 years of age [207]. The risk of the disease is 20 to 30 times more likely for the sibling of a person who has systemic lupus [42,290].

Some researchers have evaluated prevalence according to race/ethnicity, and rates of systemic lupus are higher among black, Asian, Hispanic, and Native American populations than among the white population [32,59,63,234,322]. Studies have shown that the prevalence of systemic lupus is two to three times higher among black women than white women and about twice as common among black men compared with white men [32,59,63].

POTENTIAL ENVIRONMENTAL RISK FACTORS

Several environmental factors have been evaluated as contributors to the development of systemic lupus, and the strongest evidence has been found for infection, cigarette smoking, and hormones. These same factors have been associated not only with a higher incidence of systemic lupus but also with disease of greater severity and/or increased disease activity [31].

A strong association has been identified between systemic lupus and Epstein-Barr infection, with research demonstrating that an immune response to the Epstein-Barr virus plays an important role in the development of systemic lupus in at least some individuals with systemic lupus [3,41,42,43].

The role of gut microbiota in the pathogenesis of systemic lupus has also been investigated. One group has reported that translocation of Enterococcus gallinarum, an intestinal gram-positive bacterium, can trigger autoimmunity in mice and humans [302]. The series of experimental observations reported by this group, demonstrating a causative role for E. gallinarum in a mouse model of systemic lupus, is the subject of a recent review [303]. In the initial phase, administration of oral antibiotics directed against gram-positive bacteria was shown to improve survival, reduce serum levels of autoantibodies, and diminish the permeability of the bowel in lupus-prone mice. Increased bowel permeability, of the sort present in this mouse model, may lead to translocation of bacterial products from the gut having the potential to induce inflammation. E. gallinarum is somewhat unique in this regard, as it is known to promote the production of interferon-alpha, an immune mediator implicated in the pathogenesis of systemic lupus. The group found that live bacteria, principally E. gallinarum, escaped the mouse intestine and could be cultured from adjacent lymph nodes, mesenteric veins, and liver. When the intestines of healthy mice were colonized with E. gallinarum, the bowel became leaky and these mice produced antibodies to double-stranded DNA. Using a polymerase chain reaction assay, the group also found that DNA from E. gallinarum was present in the livers of a small group of patients with systemic lupus but not in specimens obtained from healthy controls. Finally, they showed that human hepatocytes, when co-cultured with E. gallinarum, produce interferon-alpha.

As discussed, tobacco smoking has been linked to the inflammatory response in rheumatic diseases. It is thought that smoking can trigger immune responses to anti-double-stranded DNA, antibodies that are relatively specific for systemic lupus [53,211,212,213]. A meta-analysis of nine studies demonstrated a small but statistically significant association between current smoking and development of systemic lupus [214]. No association was identified between past smoking and the development of systemic lupus [214].

The mechanisms of sex hormones as a risk factor in the development of systemic lupus are unclear. A review and meta-analysis found that levels of sex hormones are altered in the presence of systemic lupus, but strong evidence of causal relationships was lacking [215]. Sex hormones and systemic lupus are more closely related among women than among men. Levels of dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEAS), progesterone, and testosterone are lower and estradiol and prolactin are higher among women with systemic lupus, whereas an increased prolactin level is the only abnormality confirmed among men with systemic lupus [215]. The effect of exogenous hormones has been debated, with some studies showing slightly increased risk for systemic lupus among women taking oral contraceptives or hormone-replacement therapy [52,216]. Evaluation of 262 incident cases of systemic lupus in the Nurses' Health Study (total of 238,308 subjects) indicated that early age at menarche, oral contraceptive use, early age at menopause, surgical menopause, and postmenopausal use of hormones were each associated with an increased risk of systemic lupus [52]. However, the development of systemic lupus in children and in women after menopause, as well as the greater severity of disease among men, calls into the question the role of estrogen [216]. Although more research is needed to determine the exact relationships of sex hormones to the development of systemic lupus, it is agreed that the disease involves a complex interaction of multiple sex hormones, including estrogen, prolactin, DHEA, and testosterone [216].

ASSOCIATION WITH OTHER AUTOIMMUNE DISEASES

Other autoimmune diseases occur frequently in individuals with systemic lupus. In one study, 41% of subjects with systemic lupus had at least one other autoimmune disease and approximately 5% had two or more autoimmune diseases in addition to systemic lupus [217]. Among the most common autoimmune diseases in individuals with systemic lupus are thyroiditis, rheumatoid arthritis, antiphospholipid antibody syndrome, and Sjögren syndrome; in addition, fibromyalgia often co-occurs with systemic lupus.

With regard to thyroiditis and systemic lupus, the prevalence of the two diseases in a single individual has varied widely [218]. In one study, autoimmune thyroiditis was found in 18% of individuals with systemic lupus [217]. Other researchers found that the prevalence of Hashimoto thyroiditis was 90-fold higher among individuals with systemic lupus than among the general population; the prevalence of Graves disease was 68-fold higher [65]. Subclinical thyroid disease has been found more often than overt disease [218].

Researchers believe that there is a common genetic susceptibility to both systemic lupus and rheumatoid arthritis, as genetic studies have shown that several loci are associated with an increased risk for both diseases [154]. Antiphospholipid antibody syndrome and Sjögren syndrome have each been found in about 14% of individuals with systemic lupus [217].

Systemic lupus has also been found to be a significant risk factor for fibromyalgia, with fibromyalgia occurring in 22% to 65% of individuals with systemic lupus [17,70,155]. However, race/ethnicity substantially affects the co-occurrence of these two diseases, with significantly positive associations among white populations but negative associations among black and Mexican populations [71,219].

CLINICAL MANIFESTATIONS

The clinical manifestations of systemic lupus vary widely, and symptoms may develop abruptly or insidiously. The classic sign of active systemic lupus is a butterfly-shaped rash in the malar area of the face, which is present in up to 90% of cases [7]. Discoid rash may also occur elsewhere on the body, and approximately 40% of individuals have photosensitivity, with a rash resulting from sunlight exposure [220].

Joint pain occurs in approximately 90% of individuals and is usually symmetrical and typically involves the proximal joints of the fingers [220]. Other common symptoms are general and nonspecific. Nearly all individuals with systemic lupus note fatigue; nearly 80% have a low-grade, unexplained fever; and about 50% have unintentional weight loss or alopecia [220]. Other symptoms vary depending on the body systems affected (Table 11) [188,220].

Table 11: MOST COMMON SIGNS AND SYMPTOMS OF SYSTEMIC LUPUS ERYTHEMATOSUS

Organ/Body System

Symptoms

General

Fatigue

Low-grade, unexplained, episodic fever

Weight loss

Generalized adenopathy

Cutaneous

Butterfly-shaped rash on face

Photosensitivity

Alopecia

Oral mucosal sores, ulcers

Raynaud phenomenon

Musculoskeletal

Arthralgia, arthritis

Myalgia, muscle tenderness

Cardiovascular

Pericarditis

Pericardial effusion

Myocarditis

Respiratory

Pleuritic pain

Pleurisy (with coughing and dyspnea)

Renal

Glomerulitis, glomerulonephritis

Neurologic

Cognitive dysfunction

Headache

Seizures

Cranial or peripheral neuropathy

Gastrointestinal

Abdominal pain

Nausea/vomiting

Ocular

Dry eye syndrome, uveitis, scleritis

Source: [188,220]

The clinical manifestations of systemic lupus often differ among older individuals. Malar and discoid rash, photophobia, arthritis, and glomerulonephritis are less common in the older population compared with the younger population, whereas fever, serositis, dry eye syndrome, and lung disease are more common in the older population [207].

DIAGNOSTIC EVALUATION

The diagnosis of systemic lupus is challenged by the waxing and waning of symptoms over time and variations in the degree of disease severity and in the organ systems involved. Because of the lower prevalence and differences in clinical manifestations among older individuals, diagnosis is especially challenging for that population and is often delayed [207].

The malar rash associated with systemic lupus can be easily misdiagnosed as rosacea or seborrheic dermatitis, but it is usually asymptomatic, lacking symptoms such as burning, itching, and tingling, that accompany other facial rashes [75]. The differential diagnosis of systemic lupus includes several other autoimmune disorders, such as early rheumatoid arthritis, undifferentiated connective tissue disease, vasculitis, and idiopathic thrombocytopenia purpura [7].

Diagnostic Criteria

Criteria for the classification and diagnosis of systemic lupus have been established by the ACR and was updated in 2019 (Table 12) [221,222]. The updated criteria include a positive ANA at least once as obligatory entry criterion, followed by seven clinical and three immunologic manifestations, weighted from 2 to 10. A score of ≥10 is needed for a definitive diagnosis of systemic lupus [221,222]. Because the criteria are based on the presence of signs and symptoms at any time during the course of the illness, an individual with early or atypical disease may not meet the criteria for definitive diagnosis. It is not uncommon for people with systemic lupus to meet only two of the clinical criteria, with the diagnosis subsequently confirmed by laboratory testing [75].

Table 12: CLASSIFICATION CRITERIA OF THE AMERICAN COLLEGE OF RHEUMATOLOGY FOR THE DIAGNOSIS OF SYSTEMIC LUPUS ERYTHEMATOSUS

Entry Criterion

Domain

Criteria

Weight

Positive antinuclear antibody (ANA) titer

ANA titer of >1.80 on Hep-2 cells or an equivalent positive test (ever)

Must be positive to continue to additive criteria

Additive Criteria, Clinical

Constitutional

Fever

2

Hematologic

Leukopenia

Thrombocytopenia

Autoimmune hemolysis

3

4

4

Neuropsychiatric

Delirium

Psychosis

Seizure

2

3

5

Mucocuteanous

Non-scarring alopecia

Oral ulcers

Subacute cutaneous OR discoid lupus

Acute cutaneous lupus

2

2

4

6

Serosal

Pleural or pericardial effusion

Acute pericarditis

5

6

Musculoskeletal

Joint involvement

6

Renal

Proteinuria >0.5 g/24h

Renal biopsy Class II or V lupus nephritis

Renal biopsy Class III or IV lupus nephritis

4

8

10

Additive Criteria, Immunology

Antiphospholipid antibodies

Anti-cardiolipin antibodies

OR

Anti-β2GP1 antibodies

OR

Lupus anticoagulant

2

Complement proteins

Low C3 OR low C4

Low C3 AND low C4

3

4

SLE-specific antibodies

Anti-dsDNA antibody

OR

Anti-Smith antibody

6

Source: [221,222]

A positive ANA titer (>1.80 on Hep-2 cells or an equivalent positive test) is required as diagnostic entry criterion. The ANA titer is highly sensitive for systemic lupus, with a positive result in approximately 93% to 100% of individuals with the disease [230,231]. However, the specificity is low, and a positive titer will also be found in 60% to 80% of people with systemic sclerosis and 40% to 70% of people with Sjögren syndrome, as well as in a substantial number of healthy individuals [230]. After a patient has tested positive, additive criteria may be considered. A negative ANA titer (less than 1:160 on standard substrate) essentially rules out a diagnosis of systemic lupus.

Physical examination can identify some of the diagnostic criteria, including constitutional, mucocutaneous, serosal, and musculoskeletal symptoms; however, the absence of these signs may not necessarily exclude systemic lupus as a potential diagnosis because of the waxing and waning of symptoms.

Seizure, psychosis, and delirium are the three neurologic criteria for the classification of systemic lupus, but many other neuropsychiatric disorders occur in conjunction with the disease [221]. Neuropsychiatric disorders have been reported in up to 80% of adults with systemic lupus and more than 90% of children with the disease [223,224]. The disorders may be evident before, at the time of, or after the diagnosis of systemic lupus [225]. In various studies of patients with systemic lupus (mainly adults), the most common manifestations of neuropsychiatric lupus were headache (87%), cognitive impairment (66%), and mood disorders (26%) [223,226].

Laboratory testing can help to identify the remaining clinical criteria, including hematologic, renal, neuropsychiatric disorders. The work-up should include a CBC with differential, platelet count, chemistry profile (especially kidney and liver function studies), and urinalysis [220,227]. Evidence of renal involvement may include proteinuria or red blood cell casts and leukocytes in the urine [220]. Hematologic testing may indicate anemia (in about 40%), thrombocytopenia (in about 25% to 35%), and leukopenia (in about 15% to 20%) [227]. Metabolic abnormalities (e.g., uremia, electrolyte imbalance, or ketoacidosis) may be signs of neurologic disorders; seizures or psychosis are other signs [75].

Other laboratory testing includes , as well as anti-double-stranded DNA, antibody to Sm nuclear antigen (anti-Sm), antiphospholipid antibodies, anti-Ro/SSA, and anti-La/SSB antibodies (Table 13) [7,228,229].

Table 13: ANTIBODY TESTING FOR SYSTEMIC LUPUS

Diagnostic Test

Prevalencea

Comments

Antinuclear antibody titer

93% to 100%

Positive titer also found in systemic sclerosis (up to 80%) and Sjögren syndrome (up to 70%), as well as many healthy individuals

Anti-double-stranded DNA

70% to 80%

Positive test highly specific for systemic lupus

Associated with greater risk of skin disease and lupus nephritis

Anti-Ro

30% to 40%

Also associated with Sjögren syndrome (up to 70%)

Associated with greater risk of skin disease, lupus nephritis, and fetal heart problems

Antiphospholipid antibodies

20% to 30%

Associated with greater risk of thrombosis and pregnancy loss

Anti-Sm

10% to 30%

Positive test highly specific for systemic lupus

Associated with greater risk of lupus nephritis

Anti-La

15% to 20%

Associated with Sjögren syndrome (up to 50%)

Associated with fetal heart problems

aAmong people with systemic lupus.

Source: [160,230,231,232,270]

Anti-double-stranded DNA and anti-Sm tests can help confirm a diagnosis of systemic lupus, as they have greater specificity than the ANA titer; however, they are not as sensitive as the ANA titer [232]. The prevalence of positive anti-Ro/SSA and anti-LA/SSB titers is also low, and these titers are more often positive among older people [207]. Serum complement levels may also be useful, as decreased levels indicate active or impending exacerbation of disease [7,75,228,229]. The prevalence of positive anti-double-stranded DNA titers and of decreased complement levels is lower among older individuals than among younger ones [207].

The presence of antiphospholipid antibodies is determined with testing for anticardiolipin antibodies or for lupus anticoagulant [7,75]. About 20% to 30% of people with systemic lupus have antiphospholipid antibodies, which increase the risk for thromboembolism and pregnancy loss [232].

REFERRAL

The ACR recommends that primary care providers refer patients with suspected lupus to a rheumatologist to confirm the diagnosis and to evaluate the activity and severity of disease [7]. The rheumatologist will establish a treatment plan, and when the disease is mild-to-moderate, the primary care provider can monitor the clinical course of the disease and drug-related toxicities. Because of the range in systems/organs that may be affected, a variety of other specialists may be needed during the course of disease. In addition, referral to physical and occupational therapies, social workers, and psychologists may also be appropriate.

TREATMENT OPTIONS

Data from large, randomized, controlled trials in the treatment of systemic lupus are lacking, creating a weak evidence base for recommendations. The ACR published guidelines for the management of systemic lupus in 1999, before the advent of many of the drugs currently used [7]. The EULAR published guidelines in 2008, acknowledging the lack of strong evidence, and updated their guidelines for the management of systemic lupus erythematosus in 2019 [233,289]. One of the challenges of treating systemic lupus is that very few drugs have FDA approval for use, leading researchers to evaluate the efficacy and safety of drugs approved for other conditions, most notably rheumatoid arthritis [235,236]. Several drugs have been used in clinical practice, with their use depending on the severity of disease (Table 14) [7,75,186,225]. First-line treatment has not changed significantly since 1993, with most physicians relying hydroxychloroquine and prednisone as the initial approach [247].

Table 14: TREATMENT OPTIONS FOR SYSTEMIC LUPUS

Agent

Typical Dosea

Indication

Side Effects

Nonsteroidal anti-inflammatory drugs (NSAIDs)

At or near the upper limit of the dose range

Mild-to-moderate arthritis, fever, mild serositis

Gastrointestinal bleeding, renal and hepatic toxicity

Immunosuppressants/cytotoxic agents

Dose varies

Usually used in conjunction with a low-dose glucocorticoid

Infection, leukopenia, anemia, thrombocytopenia, myelosuppression, lymphoma, gastrointestinal effects, alopecia

Antimalarial Agents

Hydroxychloroquine

200 mg PO twice daily

Preferred first-line treatment; effective for arthritis and rash and for preventing disease flares

Dizziness, nausea and diarrhea (usually resolves over time), macular damage

Glucocorticoids

Prednisone (low dose)

≤10 mg PO daily

Usually used in conjunction with hydroxychloroquine

Osteopenia/osteoporosis, infection, hypertension, avascular necrosis of bone, weight gain, glaucoma, cataracts, psychologic effects

Prednisone (moderate dose)

≤20 mg PO daily

Moderate disease (without organ involvement) with inadequate response to first-line treatment

Methylprednisolone (high dose)

40–60 mg PO daily or 1 g IV daily X3

Lupus nephritis, cerebritis, thrombocytopenia

Topical

Low or intermediate dose

Facial lesions

Skin atrophy, infection, contact dermatitis

Intermediate dose

Lesions on trunk or extremities

High dose

Lesions on palms or soles

Azathioprine

25–150 mg PO daily

Nonarthritic disease refractory to antimalarial agent and/or glucocorticoids; maintenance therapy for lupus nephritis, neuropsychiatric lupus

Hepatitis, pancreatitis

Methotrexate

7.5–20 mg PO weekly

Mild-to-moderate disease refractory to first-line treatment; lupus nephritis, neurologic complications

Hepatic fibrosis, cirrhosis, pulmonary infiltrates, stomatitis, mucositis; teratogenic

Cyclophosphamide

IV, dose varies

Digital vasculitis; disease with organ involvement (lupus nephritis, cerebritis)

Irreversible ovarian or testicular failure (with long-term use); nausea, alopecia, herpes zoster; teratogenic

Mycophenolate mofetil

1.5–3 g PO daily

Mild-to-moderate lupus nephritis (induction and maintenance therapy); refractory thrombocytopenia; cutaneous manifestations; uncontrolled disease

Diarrhea, nausea; teratogenic

Leflunomide

10–20 mg PO daily

Mild-to-moderate disease refractory to first-line treatment

Diarrhea, alopecia, rash; teratogenic

Topical Calcineurin Inhibitors

Tacrolimus or pimecrolimus

0.1%

Severe cutaneous lesions resistant to other agents

Peeling and burning sensation

Monoclonal Antibody

Belimumab

10 mg/kg IV every 2 weeks for 6 weeks, then every 4 weeks

Adjunctive therapy for autoantibody-positive, mild-to-moderate systemic lupus

Nausea, fever, diarrhea, nasopharyngitis, insomnia; possibly teratogenic

Rituximab

375 mg/m^2IV once weekly for 4 doses OR 500–1,000 mg on days 1 and 15

Mild-to-moderate disease refractory to first-line treatment; lupus nephritis

Nausea, fever, fatigue, cytopenias, lymphopenia; possibly teratogenic

aFor most drugs, the typical dose may vary, as no recommended dose has been established because of the lack of FDA approval.

Source: [7,20,75,186,225,236]

The goals of treatment of systemic lupus are to reduce inflammation, alleviate symptoms, achieve and maintain remissions, and prevent organ damage, all while minimizing the risk of treatment side effects. The approach to the treatment of older individuals with newly diagnosed systemic lupus is the same as that for younger individuals, but treatment is complicated in older people because of a greater likelihood of comorbidities and an increased risk of treatment-related toxicity [207].

Mild Disease (No Organ Involvement)

The cornerstone of treatment of mild systemic lupus without major organ involvement is typically an antimalarial drug and a low-dose glucocorticoid (usually prednisone), two of only three drugs approved by the FDA for use in systemic lupus. Antimalarial agents include chloroquine and hydroxychloroquine, and the latter is preferred because of its better side effect profile [7]. Antimalarial agents offer many benefits. They can alleviate joint-related, cutaneous, constitutional, and serosal manifestations of systemic lupus; they can prevent disease flares; they are well tolerated; they have been associated with a lower risk of infection than other treatment approaches; and they have a protective effect on survival [237,238]. Despite all these advantages, hydroxychloroquine is underutilized in practice [239].

A low-dose oral glucocorticoid is typically used in conjunction with an antimalarial agent to provide further relief of symptoms. For most patients with mild disease (and no major organ involvement), prednisone at a dose of 5 mg per day is effective, although some patients may need 10 mg per day [75]. NSAIDs may also be used to provide symptomatic relief of joint manifestations [7]. The use of both glucocorticoids and NSAIDs should be carefully considered because of their associated toxicity [7]. Glucocorticoids should be given at the lowest possible dose that suppresses manifestations of disease activity and prevents flares [75].

Although antimalarial drugs usually resolve systemic lupus-related rash, the mainstay of treatment for this manifestation is a topical glucocorticoid, available as a cream, liquid, or gel [7]. Intermediate-dose rather than high-dose topical glucocorticoids should be used on areas where atrophy is more likely, such as the face [7]. Novel therapies for cutaneous lesions are calcineurin inhibitors, most notably tacrolimus and pimecrolimus [236]. The use of these immunomodulators has been shown to be effective, but studies have been small [236]. The FDA has approved tacrolimus and pimecrolimus for the treatment of moderate and severe atopic dermatitis in adults and children but has not approved them for use in systemic lupus [236].

If the disease response to antimalarial drugs and tolerable doses of glucocorticoids (i.e., daily dose of prednisone of 10 mg or less) is inadequate, treatment with an immunosuppressant should be considered as a glucocorticoid-sparing approach [75]. Methotrexate and leflunomide have been evaluated in mild-to-moderate systemic lupus, and many studies have indicated benefit, especially with regard to joint- and skin-related symptoms, but the data have been conflicting [75,235]. Azathioprine is often the drug of choice for nonarthritic manifestations that have not responded to antimalarial treatment and low-dose glucocorticoid [75]. Because of the increased risk for infection associated with immunosuppressants, screening for tuberculosis and chronic viral infections should be completed before treatment with an immunosuppressant agent begins [43].

It has been hypothesized that biologics may be the next frontier of lupus treatment. In 2011, the FDA approved belimumab, the first new drug for lupus in more than 50 years [243]. Belimumab, a monoclonal antibody against B-lymphocyte stimulator, has been associated with better clinical response compared with placebo [243,251]. More research is necessary to determine if the drug is effective in black patients and patients with severe manifestations, especially those with nephritis and neurologic disease [291]. Belimumab is approved to treat patients with active, autoantibody-positive lupus who are receiving standard therapy [243]. It is administered via an intravenous infusion at an initial dose of 10 mg/kg every two weeks for six weeks; the maintenance dose is 10 mg/kg every four weeks [20].

Though not FDA approved for the treatment of systemic lupus erythematosus, rituximab has shown promise in the management of lupus [291,292]. Like belimumab, rituximab is a monoclonal antibody that selectively depletes B cells. Many open-label studies have shown improvements in lupus symptoms with the use of rituximab, including in patients with severe and/or refractory disease, but two large randomized, double-blind studies failed to show major clinical response compared with placebo [291,292]. Additional research is ongoing.

Systemic lupus often affects the eyes, with about one-third of patients having dry eye syndrome (keratoconjunctivitis sicca) [188]. Symptoms are usually relatively mild (e.g., irritation and redness), and artificial tear drops can be used to treat milder forms of the condition [188]. Pain in the eye or significant visual impairment at any time during the course of disease warrants immediate referral to an ophthalmologist [188].

Neuropsychiatric disorders have been shown to have a persistent negative effect on quality of life for people with systemic lupus [223,224]. According to EULAR guidelines, appropriate treatment depends on the cause of the disorder: glucocorticoids and immunosuppressants are recommended for disorders that reflect an immune/inflammatory process, and antiplatelet/anticoagulation therapy is recommended for disorders thought to be related to antiphospholipid antibodies [225]. Prophylaxis with low-dose aspirin may be of benefit for people with positive results on testing for antiphospholipid antibodies, as thromboembolic events occur in approximately 50% of these patients [75].

Systemic lupus is associated with reduced exercise capacity and decreased muscle strength, which are exacerbated by disease-related fatigue and sleep disturbances [240,241,242]. To address these issues, routine exercise should be part of the overall treatment plan for people with mild-to-moderate disease [242,244]. Individuals with systemic lupus who participated in a supervised cardiovascular training program had significant improvements in exercise tolerance, aerobic capacity, quality of life, and depression [245]. Exercise programs should focus on aerobic exercises as well as strength training to improve isometric strength and should begin with a formal, supervised program, as adherence has been better for such programs than for home-based ones [242].

Uncontrolled or Moderate-to-Severe Disease

Uncontrolled systemic lupus is defined as the persistence of clinical manifestations during treatment. Several manifestations indicate uncontrolled disease, including [7]:

- Pleurisy, pericarditis, and/or arthritis not controlled by NSAIDs

- Rash not controlled by topical therapies

- Vasculitis

- Digital ulcers

- Muscle weakness and/or elevated creatine phosphokinase despite glucocorticoid therapy

- Any central nervous system manifestation

- Continuing evidence of active renal disease, cardiopulmonary disease, or hematologic manifestations despite therapy

The primary care provider should refer patients with uncontrolled disease to a rheumatologist [7]. Moderate doses of a glucocorticoid may be effective for moderately severe disease without major organ involvement (e.g., arthritis, dermatitis, serositis, systemic symptoms) [75]. Glucocorticoids should be tapered as tolerated until a maintenance level can be established [75].

As systemic lupus progresses to moderate-to-severe disease, it can affect any major organ system. However, the kidneys are most commonly involved. Lupus nephritis occurs in 50% to 60% of individuals with systemic lupus within 10 years of diagnosis and leads to end-stage renal disease in 17% to 25% of patients [169]. The prevalence of lupus nephritis is higher in the black, Hispanic, and Asian populations than in the white population and is higher in male patients than female patients [169]. The goal of treating nephritis is to reduce the risk of end-stage renal disease and death, but controlling proteinuria and preventing disease flares are also important aims [169].

Evidence Based Practice Recommendation

The American College of Rheumatology Task Force Panel recommends that all patients with clinical evidence of active lupus nephritis, previously untreated, undergo renal biopsy (unless strongly contraindicated) so glomerular disease can be classified.

https://www.rheumatology.org/Portals/0/Files/ACR%20Guidelines%20for%20Screening,%20Treatment,%20and%20Management%20of%20Lupus%20Nephritis.pdf

Last Accessed: July 23, 2020

Level of Evidence: C (Consensus opinion of experts, case studies, or standard of care)

Recommended treatment for proliferative lupus nephritis is a glucocorticoid plus another immunosuppressant agent (cyclophosphamide or mycophenolate mofetil) [169,227]. In 2012, the ACR published a guideline for the treatment and management of lupus nephritis [169]. This guideline outlines an approach to treatment focused on the stage of disease (as determined by renal biopsy) and improvement in symptoms over time. Very early disease (class I or II) generally does not require immunosuppressive therapy [169]. For more advanced disease, the recommended induction therapy is cyclophosphamide or mycophenolate mofetil with glucocorticosteroids for three days, which is replaced by prednisone [169]. After six months, response to therapy is assessed and changes in the regimen are made. Mycophenolate mofetil is preferred over cyclophosphamide for black and Hispanic patients. In addition, all patients with systemic lupus erythematosus with nephritis should be treated with a background of hydroxychloroquine, unless contraindicated [169].

Biologic agents, including anti-TNF-α factors, IL-6 inhibitors, co-stimulation blockers, and anti-CD20 agents, have also been evaluated for efficacy in systemic lupus but have not been as successful as in rheumatoid arthritis, due to a lack of efficacy and/or high rates of adverse events [251]. Rituximab had preliminary success in treating resistant lupus manifestations, including central nervous system, vasculitic, hematologic, and renal manifestations; however, as noted, the results of two large phase II/III placebo-controlled, randomized controlled trials were negative [235,251].

Anifrolumab is a human monoclonal antibody to type 1 interferon subunit 1 recently investigated for the treatment of moderately to severely active systemic lupus [304]. In a phase 3 trial, patients were randomly assigned to intravenous anifrolumab (180 subjects) or placebo (182 subjects) every 4 weeks for 48 weeks, and the end-point was a clinical response at 52 weeks. Applying a standard clinical assessment tool designed to measure reduction in baseline disease activity, 47.8% in the anifrolumab group had a favorable response compared with 31.5% in the placebo group. Although the difference favoring anifrolumab was significant, the character and quality of benefit realized was only modest. Patients who received anifrolumab were more likely to have reductions in the glucocorticoid dose and in the severity of skin disease than were patients who received placebo. However, differences with respect to counts of swollen and tender joints and the annualized rate of lupus flares were not significant. While the overall number of adverse events was the same in both groups, the frequency of herpes zoster was higher with anifrolumab (7.2%) than with placebo (1.2%) [304].

Approximately 50% of people with systemic lupus seek symptomatic relief with complementary and alternative methods [252]. However, data and evidence of efficacy are lacking on a variety of these methods, including herbal medicines, dietary supplements, and acupuncture. However, small trials involving vitamin D supplements, tumeric, and omega-3 fatty acids show some promise [252]. In addition, counseling and therapy may improve quality of life and mood [248].

Treatment During Pregnancy

Pregnancy in women with systemic lupus is associated with risks for both the mother and the fetus, and pregnant women should be managed as high-risk obstetric patients [75]. Pregnancy may cause disease flares, especially in the third trimester and postnatal period, but flares are usually mild and can be controlled without excessive risk to either the mother or the fetus [75,233]. Many treatment agents may be used during pregnancy, including hydroxychloroquine, prednisone, and azathioprine; evidence suggests that mycophenolate mofetil, cyclophosphamide, and methotrexate should be avoided [233]. Systemic lupus increases the risk for fetal loss, especially in women who have antiphospholipid antibodies [75,233]. A history of lupus nephritis, antiphospholipid antibodies, and anti-Ro and/or anti-La antibodies are associated with increased risk for pre-eclampsia, miscarriage, stillbirth, premature delivery, intrauterine growth restriction, and fetal congenital heart block [233]. Heparin and aspirin are usually given throughout pregnancy to reduce the risk of miscarriage and thrombotic events.

Pregnant patients with symptomatic lupus nephritis may be treated with hydroxychloroquine (for mild disease) or prednisone plus azathioprine (for clinical active disease) [169]. In cases of severe persistent disease, delivery after 28 weeks may be necessary [169].

FOLLOW-UP AND PROGNOSIS

Follow-up care is essential for individuals with systemic lupus not only to evaluate the response to treatment but also to monitor for drug-related adverse events and to prevent infection and common comorbidities [7,169,227,233,253]. The EULAR has established evidence-based guidelines for following up patients with systemic lupus, and an expert panel in the United States proposed several quality indicators for follow-up care (Table 15) [227]. Better adherence to the quality indicators is needed, as a survey of 200 patients in a rheumatology clinic showed low rates of adherence, especially for assessment of cardiac risk factors [15]. Having a primary care physician within the care network increased the likelihood that care met quality indicators [15].

Table 15: QUALITY INDICATORS FOR FOLLOW-UP CARE FOR PATIENTS WITH SYSTEMIC LUPUS

Patient Population

Recommendation

All

Discuss risks and benefits of any newly prescribed medication. Obtain baseline studies before beginning treatment with any new medication and monitoring for drug toxicity, as recommended. Assess cardiovascular risk factors annually.

Receiving immunosuppressant treatment

Recommend annual influenza vaccination.

Receiving prednisone at a dose of ≥10 mg/day for at least 3 months (or other glucocorticoid equivalent)

Attempt to taper dose, add a steroid-sparing agent, or escalate dose of existing steroid-sparing agent.

Proteinuria ≥300 mg/day

Begin treatment with an ACE inhibitor or an ARB.

Proteinuria ≥300 mg/day and two or more blood pressure readings (including the most recent reading) with a systolic pressure >130 mm Hg or diastolic pressure >80 mm Hg over 3 months

Begin treatment for hypertension or change current antihypertensive agent (or increase dose).

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker.

Source: [227]

The ACR recommends follow-up visits every 3 to 6 months for individuals with mild disease; the later EULAR guidelines recommend follow-up assessment every 6 to 12 months, although the guidelines note that this frequency is arbitrary [7,253]. Individuals with more severe disease and/or organ involvement may need follow-up at more frequent intervals.

Disease Activity/Response to Treatment

Disease activity should be assessed by a validated instrument, and the most widely used tools are the Systemic Lupus Activity Measure (SLAM), Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), Lupus Activity Index (LAI), British Isles Lupus Assessment Group (BILAG) index, and the European Consensus Lupus Activity Measure (ECLAM) [253,254,255]. The EULAR also recommends evaluation of quality of life through patient history and/or a patient global assessment at each visit and annual assessment of organ damage [253].

Laboratory testing every 6 to 12 months should include urinalysis, CBC, ESR, CRP, albumin, and creatinine levels [253]. Anti-double-stranded DNA titer and serum complement levels should also be obtained, as an increase in the anti-double-stranded DNA titer and decreases in the serum complement levels often signal a disease flare [75,253]. As defined by an international panel of experts, a flare is "a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment" [256]. Early treatment with a glucocorticoid may reduce the total dose needed to suppress the flare [75].

Because of the risk for lupus nephritis, patients should be followed up closely for signs of progression of disease to the kidneys. For patients who have persistently abnormal urinalysis results or elevated serum creatinine level, a urine protein/creatinine ratio (or 24-hour urine for protein), urine sediment, and ultrasound of the kidney should be done, and referral for a biopsy should be considered [253]. When evidence of renal disease is found, CBC, serum creatinine level, urinalysis with microscopic evaluation, and quantitative testing of urinary protein should be done at three-month intervals [227,253].

Approximately 50% to 60% of neuropsychiatric manifestations occur within the first year after diagnosis, and patients should be evaluated carefully for relevant signs and symptoms [225]. A focused history can be used to elicit information about such symptoms as seizures, paresthesias, numbness, weakness, headache, epilepsy, and depression [253]. Clinicians should also assess patients for cognitive impairment by asking questions about problems with multitasking, household tasks, or memory [253]. If cognitive impairment is suspected, the patient should be evaluated further [253].

Monitoring and Treatment of Drug Side Effects

Infection, osteopenia/osteoporosis, and bone marrow suppression are the major side effects of treatment for systemic lupus; gastrointestinal, hepatic, renal/genitourinary, cardiovascular, and neurologic effects may also occur [186]. Recommended testing for individuals receiving methotrexate, mycophenolate mofetil, or azathioprine is a CBC and platelet count every three months [227]. Individuals treated with methotrexate should also have liver function studies done every three months [227]. A serum glucose level should be obtained yearly for patients treated with glucocorticoids [227]. Monitoring during treatment with cyclophosphamide should be done monthly, with a CBC, platelet count, and urinalysis [227]. No laboratory testing is recommended to monitor treatment with hydroxychloroquine.

Prevention of Infection

Infection has been estimated to be responsible for 30% to 50% of morbidity and mortality among individuals with systemic lupus and is a leading cause of mortality [43,257]. Approximately 80% of infections are caused by bacterial micro-organisms, with the skin, respiratory tract, and urinary tract accounting for more than two-thirds of affected sites [42].

Viral infections occur less commonly, and parvovirus B19 and cytomegalovirus are the most common viral micro-organisms [42,258]. Symptoms related to viral infections often mimic disease flares [258]. Women with systemic lupus are at increased risk for infection with the human papillomavirus (HPV)-16 virus and thus are at risk for premalignant cervical lesions [42]. Factors associated with heightened risk for infection include [42,43]:

- Active disease

- Neutropenia/lymphopenia

- Low serum complement levels

- Involvement of major organ systems (e.g., kidney, lung, central nervous system)

- Treatment with immunosuppressive agents

Treatment with antimalarial drugs has been shown to have a significant protective effect against infection, further confirming that treatment with antimalarial agents should be the standard of care unless contraindicated [257,259].

In anticipation of the need to administer glucocorticoids and possibly other immunosuppressive drugs, clinicians should perform purified protein derivative skin testing early in the management course of a patient with lupus. A positive skin test indicates latent tuberculosis and the need for isoniazid prophylaxis whenever immunosuppressive drugs are used. Other measures to prevent infection include timely pneumococcal and influenza vaccinations for individuals with stable disease [43,257,258].

Prevention of Osteoporosis

As noted, long-term use of glucocorticoids is associated with a wide range of potential adverse events, including osteopenia/osteoporosis, hypertension, cataracts, glaucoma, dyspepsia, weight gain, avascular necrosis of bone, Cushingoid changes, and adverse psychologic effects [186,189]. Of these side effects, osteoporosis is of particular concern, with a prevalence of 4% to 24% among patients with systemic lupus [253]. According to the updated 2017 ACR guidelines, the following are recommended for the prevention and treatment of glucocorticoid-induced osteoporosis [189,190]:

- Daily calcium intake (dietary plus supplement) of 1,000–1,200 mg, supplemental vitamin D (600–800 IU), and lifestyle modifications (balanced diet, maintaining weight in the recommended range, smoking cessation, regular weight-bearing or resistance training exercise, limiting alcohol intake to one to two alcoholic beverages per day) to prevent osteoporosis in all individuals taking glucocorticoids

- Use of bisphosphonates according to an individual's risk (noting that risk is best assessed with the FRAX tool, which provides a better overall clinical risk profile than bone mineral density alone)

- Dual x-ray absorptiometry, height, prevalent fragility fractures, and serum 25-hydroxyvitamin D level at baseline (before treatment starts) and at intervals throughout the course of treatment

Prevention of Treatment-Related Eye Disease

As discussed, hydroxychloroquine increases the risk for retinopathy, although this toxicity is rare at doses of less than 6.5 mg/kg/day for fewer than five years [187,188]. Still, ophthalmologic follow-up is important for early detection and minimization of this potentially serious side effect [187]. The AAO recommends a complete ophthalmologic examination within the first year after treatment [187]. Routine examination of the eyes should be done for patients treated with glucocorticoids who are at high risk for cataracts and glaucoma, and studies indicate that adherence to this recommendation is suboptimal [8,253].

Prevention of Comorbidities

The EULAR guidelines recommend a high index of suspicion and prompt evaluation for comorbidities commonly associated with systemic lupus, such as atherosclerosis, hypertension, dyslipidemia, and non-Hodgkin lymphoma [233]. Among patients with systemic lupus, the prevalence of hypertension or dyslipidemia has been reported to range from approximately 11% to 75% [191,253]. Racial disparities exist, with cardiovascular events occurring at a younger age in black women and men [260,261]. Although the increased risk of cardiovascular disease in the systemic lupus population cannot be fully explained by traditional cardiovascular risk factors, experts agree that such risk factors should be evaluated at least annually and that modifiable risk factors should be treated according to established guidelines [233,253].

Hypertension and cardiovascular problems are among the most common comorbidities in individuals with systemic lupus (Table 16) [191]. Hypertension is the leading current comorbidity, and any gastrointestinal problem is the leading lifetime comorbidity. Psychiatric problems and depression are the second and third leading current and lifetime comorbidities [191]. Follow-up care should include patient assessment and preventive strategies for these comorbidities, as well as treatment as appropriate.

Table 16: COMORBIDITIES ASSOCIATED WITH SYSTEMIC LUPUS

Comorbidity

Prevalence

Lifetime

Current

Any gastrointestinal problem

61%

27%

Any psychiatric problem

58%

34%

Depression

57%

34%

Hypertension

56%

37%

Any lung problem

42%

21%

Any endocrine problem

38%

25%

Any genitourinary problem

37%

6%

Any cardiovascular problem

32%

13%

Source: [191]

The risk of cancer is slightly increased for individuals with rheumatic diseases in general and for systemic lupus specifically [262,263]. Although several types of cancer have been reported to occur more frequently, the risk is greater for hematologic cancers, especially non-Hodgkin lymphoma [262,263,264]. The underlying link between cancer and systemic lupus is unknown, but both the disease itself and medication exposure are thought to be factors [263]. The risk for HPV infection and cervical dysplasia are increased, making patients with lupus at a greater risk for virus-associated malignancies (e.g., cervical cancer, anal cancer) [249,265]. Clinicians should assess patients for signs and symptoms of cancer and should ensure that routine cancer screening is carried out [253,262,263]. Shorter intervals for gynecologic evaluation are reasonable for women with systemic lupus due to the increased risk for cervical cancers [265].

It is interesting to note that the risk of certain other malignancies, specifically breast, ovarian, endometrial, and prostate cancers, appears to be decreased in patients with systemic lupus erythematosus, likely due to a combination of factors, including long-term use of medications and potential exogenous hormone use [249,250].

Because of the high percentage of thyroiditis and the potential for polyautoimmunity among people with systemic lupus, clinicians should carefully consider the possibility of these diseases during follow-up, especially among those at highest risk [65,218]. The highest risk for polyautoimmunity has been associated with female sex, articular involvement, familial autoimmunity, and positive anti-Ro titer [217].

Systemic lupus often has a substantial impact, with disease-related symptoms interfering with quality of life and ability to work [203,204,223,224,266]. In a survey study, the factors significantly associated with workplace activity limitations were older age, greater disease activity, fatigue, poorer health status, lower job control, greater job strain, and working more than 40 hours per week [266]. Healthcare professionals should ask patients about their ability to cope with the disease and should suggest support groups or counseling as appropriate.

Prognosis

Systemic lupus is one of the leading causes of death among autoimmune disorders, and its associated mortality is higher than that expected for the general population [27,209]. Mortality among women is consistent across all age-groups [27]. Survival has improved substantially over the years, from a four-year survival of 50% in the 1950s to a five-year survival rate of 95% today [75,194,209,232]. Ten-year and 15-year survival rates have been reported to be approximately 90% and 80%, respectively [209,267]. Improved survival is thought to be the result of earlier diagnosis, recognition of mild disease, increased use of ANA testing, and better treatment options [194]. Lower survival rates are associated with an older age at the time of diagnosis and male gender, and mortality rates are twofold to threefold higher among the black population than among the white population [209,260,261,267].

PATIENT EDUCATION

In a study of patients with lupus (predominantly women), the majority of participants indicated that they were very interested in a patient education program. Patients expected a broad range of topics to be covered as part of the program, including pregnancy, possible outcomes of the disease, specific information related to different treatments, and the management of fatigue and pain [246]. In addition, patients should receive clear information regarding management of complications, minimizing sun exposure, and physical activity.

The risk of complications and side effects associated with systemic lupus and its treatment makes it imperative for patients with lupus to understand the measures needed to prevent complications. Education should focus on the importance of the identification and prompt reporting of signs and symptoms related to drug toxicity and to following measures to prevent infection and comorbidities, especially osteoporosis and cardiovascular disease. In addition, clinicians must emphasis the importance of routine cancer screening, especially for cervical cancer, not only because of the increased risk of cancer, but also because the rate of cancer screening has been reported to be lower among individuals with systemic lupus [253,268]. Patients should also become familiar with the signs and symptoms of disease flares, to aid in early identification and treatment.

Education about avoiding sun exposure is also essential, as ultraviolet rays can induce or exacerbate both cutaneous and systemic flares of systemic lupus [7,227]. Healthcare professionals must emphasize protective measures such as the use of a sunscreen that shields against both ultraviolet A and B rays, wearing protective clothing, and avoiding exposure to the sun during its hottest periods (typically 10 a.m. to 4 p.m.) [269]. Individuals should also be reminded that fluorescent and halogen lights may emit ultraviolet rays [269]. Education regarding sun avoidance should be documented at least once in the medical record, according to quality indicators established for the treatment of systemic lupus [227].

Healthcare professionals should also counsel patients about the many benefits of regular exercise and the need to avoid exhaustion and to rest when they sense the beginning of a flare [7]. Patient education must emphasize that, although it does not seem intuitive, regular exercise or recreational activities will help alleviate the severe fatigue often associated with systemic lupus as well as enhance overall well-being and reduce the risk of cardiovascular disease [242,244,245].

6. SJÖGREN SYNDROME

Sjögren syndrome is a systemic chronic inflammatory condition characterized primarily by decreased function of lacrimal and salivary glands, enlargement of the parotid gland, and often, extraglandular manifestations. The clinical hallmark of the disease is the triad of dry mouth and eyes, fatigue, and joint pain [305]. The syndrome is classified as primary when it develops in a previously healthy individual and as secondary when it is associated with an underlying rheumatic disease.

The pathogenesis of Sjögren syndrome primarily involves organ-specific autoantibodies-antibodies to cellular antigens of salivary ducts, the thyroid gland, the gastric mucosa, erythrocytes, the pancreas, the prostate, and nerve cells. In addition, non-organ-specific autoantibodies are found in approximately 60% of individuals with the disease [67].

EPIDEMIOLOGY

The incidence of primary Sjögren syndrome has been estimated to range from 0.5% to 1% of the total population [56,67,270,354]. On the basis of prevalence and population estimates, researchers suggest that 0.4 to 3.1 million people in the United States have primary Sjögren syndrome; but experts note that approximately half of all cases are undiagnosed [56,67,271,354].

Sjögren syndrome occurs predominantly in women, at a ratio of more than 9:1, and primarily occurs during the fourth to sixth decades of life [67,354]. The age at the time of symptom occurrence has been reported to be between 45 and 55 years of age [272]. Differences in prevalence according to race/ethnicity are unknown.

POTENTIAL ENVIRONMENTAL RISK FACTORS

Data on potential environmental risk factors for Sjögren syndrome are lacking. Viral triggers, such as Epstein-Barr virus, hepatitis C virus, and human T-cell leukemia virus-1, have been suggested, but their roles have not been definitively determined [45].

ASSOCIATION WITH OTHER AUTOIMMUNE DISEASES

Approximately 60% of cases of Sjögren syndrome are secondary to another autoimmune rheumatic disorder, such as systemic lupus, rheumatoid arthritis, or scleroderma [67]. In addition, autoimmune thyroiditis (and/or thyroid dysfunction) was found in 45% of individuals with Sjögren syndrome in one study, and fibromyalgia was found in 22% [67].

CLINICAL MANIFESTATIONS

The typical clinical features of Sjögren syndrome are dry eyes (xerophthalmia or keratoconjunctivitis sicca) and dry mouth (xerostomia), which have been reported to occur in 93% and 98% of cases, respectively [272]. In addition to dryness, symptoms related to xerophthalmia include grittiness, itchiness, and sensation of a foreign body in the eye. Symptoms related to xerostomia include difficulty eating, swallowing, and speaking and the premature and accelerated loss of teeth. As with other autoimmune diseases, nearly half of individuals report debilitating fatigue [67].

Individuals with Sjögren syndrome may also have extraglandular involvement; among the most common manifestations are joint pain and/or swelling (37% to 75%), gastrointestinal symptoms (54%), pulmonary disease (e.g., chronic cough, recurrent bronchitis, fibrosis) (29%), and Raynaud phenomenon (16% to 28%) [272,273]. Occurring less frequently are cutaneous vasculitis, lymphadenopathy, and renal involvement (e.g., proteinuria, interstitial nephritis, glomerulonephritis) [272,273]. Peripheral neuropathies are often associated with Sjögren syndrome, and the reported prevalence of this complication has ranged widely, from 10% to more than 60% [226,274]. Cognitive dysfunction has been reported in about half of individuals [226].

DIAGNOSTIC EVALUATION

Diagnosing primary Sjögren syndrome is challenged by its slow, insidious onset, its variable course, its wide range of clinical features, and its symptoms, which are nonspecific and not always concurrent [67,271]. These factors have led to delays in diagnosis, often over several years [67]. Early diagnosis is essential, however, to prevent complications and to allow for surveillance to detect serious systemic manifestations.

There is no single diagnostic characteristic of Sjögren syndrome. Although xerophthalmia and xerostomia are found in nearly all individuals with the syndrome, they may be symptoms of other conditions. As a result, the diagnosis should be based on a combination of characteristic symptoms, the history and physical examination, diagnostic testing, and the distinguishing of Sjögren syndrome from other conditions with similar signs and symptoms. Differentiating Sjögren syndrome from other autoimmune diseases with similar clinical features, such as systemic lupus, rheumatoid arthritis, and scleroderma, is important to ensure appropriate treatment [67]. Healthcare professionals should remember that if another rheumatic condition is diagnosed, Sjögren syndrome may still be present, given the high rate of secondary disease [67].

In 2016, the ACR/EULAR published classification criteria for primary Sjögren syndrome as part of a collaborative expert consensus (Table 17) [78,275]. According to these criteria, a diagnosis of Sjögren syndrome is made when a score of >4 of five weighted classification criteria is achieved. Subjective measures used in older criteria, including daily dry eyes or dry mouth, have been eliminated in the ACR classification because they were shown to have poor specificity for Sjögren syndrome [78,275]. The objective measures chosen by the panel were strongly associated with the disorder, with final validation reports showing 96% sensitivity and 95% specificity [78].

Table 17: ACR/EULAR CLASSIFICATION CRITERIA FOR SJÖGREN SYNDROMEa

Inclusion Criteria

Patients meet inclusion criteria if there is a positive response to at least one of the following ocular or oral dryness symptoms:

- Have you had daily, persistent, troublesome dry eyes for more than three months?

- Do you have a recurrent sensation of sand or gravel in the eyes?

- Do you use tear substitutes more than three times per day?

- Have you had a daily feeling of dry mouth for more than three months?

- Do you frequently drink liquids to aid in swallowing dry food?)

Exclusion Criteria

Patients with a prior diagnosis of any of the following conditions are excluded a diagnosis of Sjögren syndrome:

- History of head and neck radiation treatment

- Active hepatitis C infection (with positive PCR)

- Acquired immune deficiency syndrome (AIDS)

- Sarcoidosis

- Amyloidosis

- Graft versus host disease

- IgG4-related disease

Additional Criteria After Meeting Both Inclusion and Exclusion Criteria

Criteria

Weight

Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis with a focus score ≥1 focus/4 mm

3

Positive serum anti-SSA (Ro)

3

Ocular staining score ≥5 (or van Bijsterfeld score ≥4) on at least one eye

1

Schirmer ≤5 mm/5min on at least one eye

1

Unstimulated whole saliva flow rate ≤0.1 ml/min

1

aThe classification of Sjögren syndrome, which applies to individuals with signs/symptoms that may be suggestive of the disease, will be met in patients who have at least a score of >4 of the five weighted objective features

Source: [78,275]

The physical examination should focus on evaluation of the eye, mouth, and parotid glands. In examining the eye, the clinician should look for signs of corneal ulceration and superficial erosions of the corneal epithelium, conjunctival injection, and clouding or irregularity of the cornea [67,276]. The mucous membranes of the mouth may appear dry, with a decreased salivary pool. In more severe cases, there may be erythema, fissuring, and ulceration of the mucous membranes [277]. There may also be evidence of dental caries as a result of reduced salivary flow. The parotid glands may be swollen or tender. Objective tests to assess oral and ocular symptoms are included in the 2012 criteria, and most of these tests are performed by specialists rather than primary care providers.

The non-organ-specific autoantibodies commonly found in serologic testing include ANA, rheumatoid factor, or antibodies to the anti-SSA (Ro) and anti-SSB (La) antigens [67]. Testing for ANA has been reported to be positive in 55% to 97% and rheumatoid factor is positive in 32% to 95% [67,160]. Anti-SSA and anti-SSB antigens have been found in 16% to 70% and 7% to 50%, respectively [270,271,272,277]. The presence of anti-SSA and anti-SSB antibodies is usually associated with extraglandular manifestations [160]. The ACR classification panel strongly agreed that positive anti-SSA is the most specific serologic marker for Sjögren syndrome, but that a positive rheumatoid factor and an ANA titer of 1:320 or greater is also a strong indicator in instances when anti-SSA/B serology is negative [275].

Tests to obtain the Sjögren's International Collaborative Clinical Alliance ocular staining score (OSS) use two different vital dyes to grade different areas of the ocular surface: fluorescein to grade the cornea and lissamine green to grade the bulbar conjunctiva [275,337]. In the Corneal Fluorescein Staining Pattern test, fluorescein is instilled into the cornea, and four to eight minutes after, punctate epithelial erosions that stain with fluorescein are counted and scored using a slit lamp. Additional points are added if one or more patches of confluent staining, including linear stains, are found anywhere on the cornea, punctate epithelial erosions occur in the central 4-mm diameter portion of the cornea, or one or more filaments is seen anywhere on the cornea [337]. The punctate epithelial erosions are graded according to the form, and any additional points are added to the grade for a total of 6 points for each cornea. In the Conjunctival Lissamine Green Staining Pattern test, stained dots on the conjunctivae are counted and scored with the slit lamp at 10 times magnification immediately after lissamine green dye is applied to the eyes [337]. Temporal and nasal areas of the conjunctiva are counted separately, with a maximum grade of 3 for each area or a total maximum grade of 6 for each eye. The fluorescein score for the cornea and the lissamine green scores for the conjunctiva (nasal and temporal) are added to give the total OSS for each eye. The maximum possible score for each eye is 12. Unlike previously recommended dyes used for other ocular tests, these dyes are nontoxic and nonirritating [337]. The OSS provides a simplified, non-irritating, quantitative grading system that is easily applicable to clinical practice without the need for specialized equipment other than a slit lamp.

After the Corneal Fluorescein Staining Pattern test and before the Conjunctival Lissamine Green Staining Pattern test, an external eye exam should be performed using the slit lamp, noting the presence or absence of [337]:

- Abnormalities of the conjunctiva, cornea, and lids

- Specific diseases that might affect the OSS, such as entropion, lagophthalmos, pinguecula, and pterygium

- Clinical signs of blepharitis (e.g., ulceration around the base of the lashes, collarettes, misdirected lashes, absent lashes, poliosis, tylosis)

- Evidence of meibomitis (e.g., expression of thick material from the glands, inflammation of the meibomian glands, plugging of the orifices with inspissated secretions, lid telangiectasia)

- Signs of rosacea

Labial salivary gland (LSG) biopsy and histopathology is the third component of diagnosing Sjögren syndrome in the ACR classification [275,336]. The biopsy is recommended for establishing a diagnosis of primary Sjögren syndrome in the absence of anti-SSA antibodies [305]. LSG biopsy has demonstrated much more specificity for Sjögren syndrome than testing unstimulated salivary flow rate and/or self-reported dry mouth (or dry eyes). A biopsy sample of 4 mm^2 (preferably 10–20 mm^2) is required for histopathologic exam [336]. Samples are stained with hematoxylin and eosin, and lymphocytic aggregate and infiltrate foci are counted. A score of 12 foci/4 mm^2 is typically the highest that can be counted; above that number of foci, infiltrates appear confluent [336]. Distinguishing focal lymphocytic sialadenitis from non-specific or sclerosing chronic sialadenitis is important for accurate diagnosis. Focal lymphocytic sialadenitis with a score of 1 focus/4 mm^2 or more is strongly associated with ocular and serologic indications of Sjögren syndrome [336].

TREATMENT OPTIONS

In 2016, the first ever guidelines for the treatment of Sjögren syndrome were published by the Sjögren's Syndrome Foundation (SSF). However, it was noted that there are many unmet clinical needs in regard to treatment, and there is no cure or remittive agent for Sjögren syndrome. Treatment goals are symptom palliation, prevention of complications, and proper selection of patients for immunosuppressive therapy [58]. Treatment of dry eye involves patient education regarding the nature of the problem and aggravating factors. Artificial tears have been found effective to replace moisture, and a topical anti-inflammatory agent should be used for moderate-to-severe symptoms. Preservative-free artificial tears have been better tolerated than tear solutions with preservatives because of the irritation that can be caused by frequent use of the latter type [58,67]. Randomized controlled trials have shown that topical ocular cyclosporine (0.05%) significantly improves objective measures of dry eye, blurred vision, and use of artificial tears in patients with moderate or severe dry eye [278]. In its guidelines for dry eye, the AAO includes topical cyclosporine as a level IA recommendation for moderate dry eye [279].

If symptoms are not relieved by artificial tears or anti-inflammatory agents, a muscarinic agonist can increase tear production by stimulating muscarinic receptors. These receptors are a type of cholinergic receptor and are present on exocrine glands as well as on heart muscle and smooth muscle [276]. The two muscarinic agonists shown to be effective for dry eye are pilocarpine (a nonselective agonist) and cevimeline (a selective muscarinic agonist). According to a review of the literature, placebo-controlled trials have provided evidence of improvement with these agents. In three trials, pilocarpine was associated with subjective and objective improvement of dry eye in 42% to 53% of patients (compared with 26% for the control), and in two trials, cevimeline was associated with improvement in 39% to 72% (compared with 24% to 30% for the control) [278]. Systemic cholinergic agents, such as pilocarpine and cevimeline, are a level IA recommendation for severe dry eye in the AAO guidelines [279].

Treatment of dry mouth involves stimulating production of saliva and using saliva substitutes; muscarinic agonists can be used for severe dry mouth. Saliva production can be stimulated with the use of sugar-free chewing gum and sour lozenges [276]. Saliva substitutes are available as over-the-counter and prescription products and are manufactured as lozenges, rinses, sprays, and swabs [67]. As with dry eye, muscarinic agonists can improve subjective symptoms of dry mouth. Three placebo-controlled trials showed improvement with pilocarpine in 61% to 70% of patients (compared with 24% to 31% in the placebo group), and two placebo-controlled trials showed improvement with cevimeline in 66% to 76% (compared with 35% to 37% in the placebo group) [78,278].

A systematic review published in 2010 demonstrated a low level of evidence for most of the systemic drugs that are used to treat Sjögren syndrome [278]. Systemic immunomodulatory agents, such as glucocorticoids and hydroxychloroquine, have not offered significant benefit in terms of improvement in sicca symptoms, parotid enlargement, or fatigue, myalgia, and arthralgia [278]. Similarly, immunosuppressant therapy with azathioprine or oral cyclosporine has not provided significantly improved outcomes, and methotrexate, leflunomide, and mycophenolic mofetil have led to limited improvements in sicca symptoms only [278]. Furthermore, these systemic agents have all been associated with a high rate of adverse events [278]. The off-label use of biologic agents, such as infliximab and etanercept, has also not improved outcome [278]. Rituximab has been found to have limited benefit in improving some extraglandular features (i.e., vasculitis, neuropathy, glomerulonephritis, and arthritis), but the trials have been small and primarily uncontrolled [278]. On the basis of these findings, glucocorticoid, immunosuppressive, and biologic agents are not recommended for the treatment of Sjögren syndrome. Rituximab may be considered as a rescue therapy for individuals who have not had a response to standard treatment [278].

The SSF guidelines recommend hydroxychloroquine as first-line treatment (moderate strength of recommendation). If hydroxychloroquine is not effective, methotrexate may be used. If methotrexate is ineffective, then a combination of the two should be used (moderate strength of recommendation). The next option for treatment would be a short-term corticosteroid of less than 15 mg per day for less than one month (moderate strength of recommendation). If corticosteroids are needed for more than one month (long-term treatment), efforts should be made to find a steroid-sparing agent as soon as possible [58].

FOLLOW-UP AND PROGNOSIS

In general, the prognosis for patients with established Sjögren syndrome is good, and studies have shown no increase in the rate of all-cause mortality [264,280,281]. However, close follow-up is needed for the prevention and/or early recognition of complications [276]. Among the complications reported to be associated with Sjögren syndrome are oral infections, infection or a tumor of the parotid gland, and lymphoproliferative diseases [67].

Lymphoma, primarily non-Hodgkin lymphoma, is the most serious complication of Sjögren syndrome, with a risk that has been reported to be 40 times greater than that for the general population [276]. Among the possible indicators of lymphoma are low levels of complement protein C3 or C4 at the time that Sjögren syndrome is diagnosed, persistently enlarged parotid glands, lymphadenopathy (regional or general), splenomegaly, pulmonary infiltrates, vasculitis, and hypergammaglobulinemia [67,276]. The average time from the diagnosis of Sjögren syndrome to the development of non-Hodgkin lymphoma has been six to seven years [276].

PATIENT EDUCATION

Patient education should focus on the importance of careful eye and oral care. Oral care should include frequent dental examinations, use of fluoride, and daily rinsing with an antimicrobial solution [67,282]. Healthcare professionals should emphasize the importance of maintaining general health, reporting any changes in symptoms, following the prescribed use of medications, and keeping appointments for follow-up visits.

7. CELIAC DISEASE

Celiac disease, also known as celiac sprue, is inflammation of the small intestine caused by gluten proteins, which are found in foods containing rye, wheat, and barley. Gluten proteins are not digested well by digestive enzymes in the upper gastrointestinal tract, and in individuals with a genetic predisposition, the undigested gluten proteins cause an inflammatory reaction in the mucosa of the small intestine.

EPIDEMIOLOGY

The prevalence of celiac disease is approximately 0.5% to 0.8% [338,339]. The true prevalence is thought to be higher than has previously been reported, and the number of so-called silent cases (with few or no symptoms) of the disease has increased [340]. In addition, the incidence pattern has changed, with more cases being diagnosed in adulthood [340]. A 2009 Mayo Clinic study compared stored blood samples taken from male Air Force recruits in 1950 with samples from similarly aged men around the time of the study [312]. The modern samples showed a 4.5-fold increase in the celiac antibody, which correlates with a rate of celiac disease of approximately 1%. This study underscores the fact that the incidence is truly rising, rather than the notion that increased awareness of the disease has led to a spike in its diagnosis [311,312].

Most U.S. studies have involved predominantly white populations, leaving unclear the prevalence among racial/ethnic groups. European studies (conducted in the United Kingdom, Sweden, the Netherlands, Ireland, and Finland) have indicated that the prevalence may be slightly higher in those countries [22]. Individuals with a family history of celiac disease (first-degree relative) have a higher risk for the disease, with a prevalence of 16% [22]. Serum samples or a self-reported diagnosis from a representative U.S. cohort (7,798 individuals) as part of the National Health and Nutrition Examination Survey 2009–2010 confirmed a prevalence of 1% in the non-Hispanic white population; overall, the prevalence was 0.71%, reflecting the rarity of celiac disease in non-white individuals [313].

POTENTIAL ENVIRONMENTAL RISK FACTORS

It is not clear how gluten sensitivity begins or how sensitivity is increased by early exposure. The results of studies have suggested that first exposure to dietary gluten before the age of 3 months or after the age of 6 months is a risk factor for disease [68]. Other environmental factors may be a high number of gastrointestinal infections before 6 months of age and frequent rotavirus infections in children younger than 4 years of age [68]. Alternately, the "hygiene hypothesis" posits that an increasingly sterile environment has left the immune system of many individuals unchallenged and, therefore, unfortified by the bacteria, viruses, and parasites that their ancestors faced, causing increased susceptibility to allergic and immune disorders [311].

Some researchers believe that changes in grain itself, rather than increased levels of consumption, are at least partially responsible for the increase in celiac cases [311]. Despite increasing wheat consumption in the last several decades, consumption is still significantly less than it was 100 years ago. In that time, wheat has undergone extensive hybridization as a crop (i.e., modified wheat genetics), and drastic changes during processing, which involves oxidizers, new methods of yeasting, and other chemical processes (e.g., enzymatic modification of wheat prolamins), have occurred in the past 40 years [311,312]. The effect these changes have had on the immune system is presently unknown; however, human genetic modifications in response to environmental challenges are extremely slow [312].

ASSOCIATION WITH OTHER AUTOIMMUNE DISEASES

Autoimmune diseases are 3 to 10 times more likely in individuals with celiac disease than in the general population [341]. The strongest associations have been found between celiac disease and Sjögren syndrome (4.5% to 14.7%), type 1 diabetes (1% to 12%), Addison disease (1.2% to 8%), primary biliary cirrhosis (1.3 to 7%), autoimmune hepatitis (4% to 6%), and autoimmune thyroid disease (up to 5.8%) [22,68].

CLINICAL MANIFESTATIONS

The classic symptoms of celiac disease were once diarrhea and malabsorption, but this presentation is now rare [342]. Although diarrhea, borborygmus (intestinal rumbling), abdominal pain, weight loss, and nutritional deficiencies are the most common gastrointestinal symptoms, many other nonspecific and extraintestinal symptoms often occur [342]. Fatigue is present in nearly 80% of patients, and signs of iron-deficient anemia and osteoporosis are also common [22,37,68,342]. As many as 38% of individuals have silent celiac disease [68,339].

Dermatitis herpetiformis, a skin disease characterized by blistering lesions that are intensely itchy and often painful, is found in up to 25% of individuals with celiac disease. These lesions are typically located on the extensor surfaces of the elbows, knees, buttocks, and back [343]. Neurologic manifestations develop in about 10% to 12% of individuals with celiac disease, including cerebellar ataxia, peripheral neuropathy, seizures, and myelopathy [68].

DIAGNOSTIC EVALUATION

The American College of Gastroenterology (ACG) recommends celiac disease diagnostic testing for patients with symptoms, signs, or laboratory evidence suggestive of malabsorption (e.g., chronic diarrhea with weight loss, steatorrhea, postprandial abdominal pain and bloating). The ACG also recommends [344]:

- Patients with a first-degree family member who has a confirmed diagnosis of celiac disease should also be tested if they show possible signs/symptoms or laboratory evidence of celiac disease.

- Patients with type 1 diabetes should be tested if they have any digestive symptoms/signs/laboratory evidence suggestive of celiac disease.

- Testing for celiac disease is warranted if the patient has elevated serum aminotransferase levels when no other etiology is found.

All of these are strong recommendations with a high level of evidence [344].

The differential diagnosis of celiac disease involves the exclusion of several conditions with similar characteristics, including anorexia nervosa, bacterial overgrowth, Crohn disease, and intestinal lymphoma [340]. Irritable bowel syndrome has been diagnosed before the detection of celiac disease in as many as 36% of individuals [340].

Evidence Based Practice Recommendation

The American Gastroenterological Association recommends that all diagnostic serologic testing should be done with patients on a gluten-containing diet.

https://journals.lww.com/ajg/pages/articleviewer.aspx?year=2013&issue=

Last Accessed: July 23, 2020

Level of Evidence: High (Further research is unlikely to change our confidence in the estimate of effect)

The diagnosis of celiac disease should be made on the basis of several factors, including the findings of the history and physical examination, serologic testing, and biopsy of the small intestine [37,344]. The preferred single test for detection of celiac disease in patients older than 2 years of age is the immunoglobulin A (IgA) anti-tissue transglutaminase (TTG) antibody [344]. Diagnostic testing should be done while the patient's diet includes foods that contain gluten. Children younger than 2 years of age should be screened using the IgA TTG test combined with immunoglobulin G (IgG) based testing (e.g., IgG-deamidated gliadin peptides [DGPs]) [344]. IgG-based testing (IgG DGPs and IgG TTG) should also be used in adult patients in whom low IgA or selective IgA deficiency is identified. Serum IgA endomysial antibodies (EMA) have also been used but are not recommended in the ACG guidelines [22; 37; 344].

There is no one universally accepted diagnostic standard, and the diagnosis of celiac disease should be made on the basis of several factors, including the findings of the history and physical examination, serologic testing, and biopsy of the small intestine [37].

Although the sensitivity of IgA TTG antibodies has been good (greater than 95%), the degree depends on the extent of mucosal involvement. The risk of a false-positive result is high; false-negative results may also occur in patients who have celiac disease and IgA deficiency [37]. In general, no further diagnostic testing is needed if serologic testing is negative in a patient at low risk (and without IgA deficiency); further testing (i.e., intestinal biopsy) should be done to confirm the diagnosis when serologic testing is positive [37,344]. Intestinal biopsy should also be pursued if the suspicion of celiac disease is high, even if serologies are negative [344].

Upper endoscopy with biopsy of the small intestine has been considered the criterion standard for confirmation of diagnosis of celiac disease [344]. Evaluation of a biopsy specimen will demonstrate celiac enteropathy in almost 100% of patients who have typical symptoms in combination with high titers of IgA TTG [345]. However, there is a spectrum of characteristic histologic changes in the small intestinal mucosa; villous atrophy may vary from partial to total, and other mucosal changes may include subtle crypt lengthening or increased epithelial lymphocytes. Lymphocytic infiltration of the intestinal epithelium in the absence of villous atrophy is not specific for celiac disease, and other causes should be considered [344]. Because changes may be intermittent along the mucosa, it is recommended that at least four tissue samples be obtained for evaluation from the distal duodenum and one or two from the bulb [37,344]. Findings on biopsy are not 100% sensitive or specific, as evidence of celiac disease may be similar to that of infection, enteritis, lymphoma, or bacterial overgrowth.

Given the potential difficulty in confirming the diagnosis of celiac disease with use of serologic testing and biopsy, some authors have suggested that a diagnosis can be made when four of five criteria are present (Table 18) [346]. It should be noted that these criteria are different from the ACG clinical guidelines for the diagnosis and management of celiac disease.

Table 18: SUGGESTED CRITERIA FOR DIAGNOSIS OF CELIAC DISEASEa

Criteria

Description

Typical symptoms

Chronic diarrhea, iron-deficient anemia, weight loss (adults), deficient growth (children)

High titers of serum autoantibodies

Both IgA class tTG and EMA in IgA-sufficient patients or IgG class tTG and EMA in IgA-deficient patients

HLA-DQ2 or DQ8 genotypes

Found in almost all persons with celiac disease

Biopsy findings of celiac enteropathy

Total to partial villous atrophy and crypt lengthening with an increase in lamina propria and intraepithelial lymphocytes

Response to gluten-free diet

Positive response to restricted diet

aFour of these five criteria are needed for diagnosis.

Source: [346]

The ACG guidelines state that HLA-DQ2/DQ8 genotyping testing should not be routinely used in the initial diagnosis of celiac disease, but it is recommended to effectively rule out the disease in selected clinical situations [344]. These include, but are not limited to, patients with Down syndrome, patients on a gluten-free diet in whom no celiac disease testing was done before the diet, patients with discrepant celiac-specific serology and histology, and patients with suspicion of refractory celiac disease where the original diagnosis of celiac remains in question [344]. HLA-DQ2/DQ8 genotyping testing should be used in an attempt to rule out celiac disease in patients already on a gluten-free diet before a formal gluten challenge, but a formal gluten challenge should be considered in order to obtain an accurate diagnosis.

TREATMENT OPTIONS

Celiac disease is treated with a lifetime gluten-free diet, as avoidance of gluten proteins from wheat, barley, and rye can help mucosal lesions to heal and reverse the effects of the disease. In addition to alleviating gastrointestinal symptoms, long-term compliance with a gluten-free diet can also improve outcomes related to bone density, iron-deficiency anemia, and dermatitis herpetiformis [347,348]. For example, anemia and iron-deficiency generally improve in six months and one year, respectively [347]. Some neurologic manifestations may remain despite adherence to a gluten-free diet [349].

Evidence Based Practice Recommendation

According to the American Gastroenterological Association, people with newly diagnosed celiac disease should undergo testing and treatment for micronutrient deficiencies. Deficiencies to be considered for testing should include, but not be limited to, iron, folic acid, vitamin D, and vitamin B12.

https://journals.lww.com/ajg/pages/articleviewer.aspx?year=2013&issue=05000&article=00007&type=Fulltext

Last Accessed: July 23, 2020

Strength of Recommendation/Level of Evidence: Conditional recommendation, low level of evidence

A multidisciplinary approach to treatment is needed and may involve gastroenterologists, endocrinologists, allergists, dermatologists, hepatologists, pharmacists, and social workers. Central to the team is a registered dietician. In addition to assessing the food/nutrition-related history, the results of diagnostic testing, factors affecting quality of life, gastrointestinal symptoms, and other diseases, the dietician provides medical nutrition therapy and is responsible for educating the patient about how to adhere to a gluten-free diet [344,347]. Testing and treatment for micronutrient deficiencies (particularly folic acid, iron, vitamin D, and vitamin B12) may be warranted in newly diagnosed patients. Treatment with medication and aggressive nutritional support (including parenteral nutrition) is indicated for patients with refractory celiac disease [344].

The treatment of celiac disease also includes the management of complications. Dapsone can be used to treat dermatitis herpetiformis until the gluten-free diet has had effect; the drug typically relieves symptoms within one to three days [343]. Because of the potential for dapsone to cause hemolysis in some individuals, a baseline CBC and periodic follow-up testing are recommended [343]. Calcium and vitamin D supplements may also be necessary to ensure bone health [37]. The use of bisphosphonates for osteoporosis may be appropriate, although their use for osteoporosis related to celiac disease has not been studied extensively [37].

FOLLOW-UP AND PROGNOSIS

Follow-up for individuals with celiac disease should focus on four components [22,350]:

- Monitoring adherence to a gluten-free diet

- Treatment of nutritional deficiencies

- Assessment of bone mineral density

- Evaluation for signs of lymphoma

Healthcare professionals should ensure that patients and their families have the resources, education, motivation, and support to comply with a gluten-free diet. Serologic testing should be done to monitor compliance with a gluten-free diet; strict adherence usually leads to antibody levels becoming normal within 3 to 12 months after starting the diet [37]. A lack of response according to serologic testing may indicate continued exposure to gluten; if the patient has been adhering to the gluten-free diet, the clinician should explore other diagnoses. Among other diseases that appear similar to celiac disease are microscopic colitis, pancreatic insufficiency, inflammatory bowel disease, ulcerative jejunoileitis, collagenous sprue, and T-cell lymphoma [37].

Follow-up should also include monitoring of nutritional deficiencies to ensure adequate levels of iron, folate, and vitamin B12. Low bone mineral density usually resolves in children who adhere to a gluten-free diet, but it may not resolve in adults. Thus, bone density testing may be appropriate to determine whether treatment for osteopenia or osteoporosis is needed [37]. Children should be monitored for normal growth and development [344].

Celiac disease is associated with a risk of non-Hodgkin lymphoma that is three to six times higher than that for the general population, and the risk for lymphoma is higher for individuals in whom celiac disease is diagnosed later in adulthood [351,352]. Data have suggested that the risk of lymphoma decreases over time on a strict gluten-free diet [22]. New gastrointestinal symptoms or other signs of lymphoma should prompt further evaluation. Studies have indicated that the risk of other gastrointestinal malignancies, such as esophageal, gastric, and colorectal cancer, are not increased among individuals with celiac disease [306,351,353].

PATIENT EDUCATION

Patient education is key to the success of treatment and must focus on strict adherence to a gluten-free diet. A registered dietician should talk to patients and family members on ways to be compliant, noting the importance of addressing potential nutritional deficiencies through eating whole/enriched gluten-free grains and taking a multivitamin or mineral supplement [347]. Especially important is education about possible cross-contamination in food manufacturers and restaurants as well as at home and the careful reading of food labels to identify foods containing gluten (Table 19) [37,307,347].

Table 19: COMMERCIAL AND PROCESSED FOOD THAT MAY CONTAIN GLUTEN

Baked beans (canned)

Bouillon cubes

Candy

Canned meats

Coffee (flavored instant)

Cold cuts, hot dogs, salami, sausage

Communion wafers

French fries

Fruit pie fillings

Gravy, sauces

Herbal teas

Hot cocoa mixes

Imitation fish

Matzo

Nondairy cream substitutes

Rice mixes

Potato chips

Prepared salad dressings

Seasoned tortilla chips

Self-basting turkey

Soups (canned)

Soy sauce

Vegetables in sauce

Yogurt (flavored or frozen)

Source: [37,307]

8. CASE STUDY

Patient A is a woman, 25 years of age, who recently gave birth to her second child. She visits her primary care provider because of the gradual onset of fatigue, anxiety, and a feeling of her "heart pounding." The physician finds nothing remarkable on physical examination; a CBC indicates slight anemia. The physician tells her he believes the symptoms are related to slight anemia and the stress of giving birth in addition to caring for a toddler. The physician recommends that Patient A try to rest more, take a daily multivitamin with iron, and obtain some help caring for her two small children.

Over the next year, Patient A's symptoms wax and wane. Her family is supportive as she tries to reduce the stress in her life, but her symptoms do not resolve completely. At a routine physician office visit, she describes continued extreme fatigue as well as muscle weakness. On physical examination, her skin feels warm and moist and her pulse is slightly elevated (80 beats per minute). During the history-taking, the physician learns that Patient A's mother has Graves disease. On further physical examination, the physician notes that the thyroid gland feels normal, that her eyes and eyelids appear normal, and that she has no fine finger tremor. However, based on the family history and Patient A's desire to have another child in the near future, the physician orders thyroid function studies. The TSH level is normal, as are the T3 and T4 levels. The physician reiterates the need for lifestyle modifications, including enhanced nutrition, exercise, better sleep, and over-the-counter analgesics as needed.

Rationale and comments: Several factors indicate the possibility of Graves disease, although some do not. Patient A is younger than the typical woman in whom Graves disease first occurs (40 to 60 years). But in individuals with genetic susceptibility, stress and recent childbirth have been identified as potential environmental triggers for the disease. Her symptoms of fatigue, anxiety, and palpitations are among the common symptoms of Graves disease, as is her warm, moist skin. However, the lack of thyroid enlargement, a pulse of less than 90 beats per minute, and the absence of finger tremor are findings with the most significance in ruling out hyperthyroidism.

It seems appropriate to rule out a diagnosis of Graves disease given that Patient A wants to have another child. The American Association of Clinical Endocrinologists recommends TSH with measurement of total T4 or a free T4 index testing for women of childbearing age before or during pregnancy. Laboratory testing confirmed that she did not have Graves disease, as a low TSH level with increased T4 levels indicates hyperthyroidism.

Patient A's symptoms continue, and she becomes increasingly frustrated by the lack of symptomatic relief. Among the new symptoms that have developed are dry eyes, intermittent headaches, and pain in the finger joints of both hands, all of which she attributes to too much time working on the computer at her job. The pain in her fingers resolves with rest. She also begins to have occasional pain and stiffness in both hips, especially in the morning. She starts to take large doses of over-the-counter analgesics as well as nutritional supplements. She continues to feel fatigue so overwhelming that she must call in sick to work at least once or twice every month. She wants to have another child but does not feel as though she would be able to physically handle a pregnancy and the care of a third child. She begins to have mood swings, and she feels depressed "sometimes." She makes an appointment with her primary care provider to discuss her increasing symptoms. Based on her description of new symptoms, the physician orders a rheumatoid factor test, and the result is a low positive. He refers her to a rheumatologist for possible rheumatoid arthritis.

On examining Patient A, the rheumatologist finds normal vital signs, except for a low-grade fever. There is slight limitation in the range of motion of both hips, with some decreased muscle strength in the left leg. In taking the history, the rheumatologist learns that Patient A's joint pain has been present for about one month and that her pain/stiffness in the hip lasts for about 30 to 60 minutes each morning. The physician orders a CBC, platelet count, ACPA, ESR, and CRP; the results of all are normal, except for continued slight anemia. Radiographs of the hips show slight degeneration in the left hip. The rheumatologist tells Patient A that her pain may be related to early osteoarthritis, and he prescribes a COX-2 inhibitor for pain relief, prescribes an antidepressant, and recommends regular exercise, more rest, and counseling for stress reduction. Patient A interprets the suggestion of counseling and an antidepressant as meaning that her physical symptoms are "in her head," and she becomes even more frustrated.

Rationale and comments: Again, some of the details of Patient A's case fit with a diagnosis of rheumatoid arthritis and others do not. The proximal interphalangeal and metacarpophalangeal joints are among the most commonly involved joints, and they are not usually painful at rest. Joint symptoms are usually bilateral. As is the case for most individuals, the symptoms of rheumatoid arthritis develop over a long period of time (weeks to months). Her other symptoms–fatigue, weakness, and generalized muscular aches–are also suggestive of rheumatoid arthritis. Approximately 46% of individuals with rheumatoid arthritis have extra-articular manifestations, and among the most common are dry eye syndrome and anemia of chronic disease. Depression is also common, occurring in about one-third of individuals. In addition, the findings of a low-grade fever, limitation in the range of motion of the hip, and decreased muscle strength near an affected joint are consistent with rheumatoid arthritis.

The positive rheumatoid factor would also seem to suggest rheumatoid arthritis, as this finding has long been known as an indicator of rheumatoid arthritis, and studies have shown that it is positive in approximately 69% to 90% of people with the disease. However, the test may be positive in healthy individuals as well as in individuals with other rheumatic diseases (e.g., Sjögren syndrome, systemic sclerosis, systemic lupus), with chronic infections, or with pulmonary disease. The 2010 ACR/EULAR classification criteria for rheumatoid arthritis call for a rheumatoid factor as well as an ACPA, which has a higher specificity. The negative ACPA and normal ESR and CRP level, along with her other signs and symptoms, yield a score of 5 on the diagnostic criteria, one point lower than the 6 needed for a diagnosis of "definite" rheumatoid arthritis. The radiographic evidence of degeneration in the left hip and the morning stiffness that lasts less than one hour suggest osteoarthritis.

The rheumatologist's treatment plan is appropriate. There is good evidence that nonselective NSAIDs and COX-2 inhibitors have comparable efficacy, and a COX-2 inhibitor has been associated with lower risks of gastrointestinal adverse events than a nonselective NSAID plus a proton-pump inhibitor. The recommendations for nonpharmacologic treatment are also in line with established recommendations.

Patient A adheres to her medication treatment, and the pain in her hips is somewhat relieved. However, more new symptoms appear over the course of the next year. During the winter, she becomes intolerant to cold weather, with her hands and feet becoming painful and discolored when she is exposed to cold. When she sees her primary care provider, he tells her that she may have Raynaud phenomenon. Her other symptoms continue, and he reiterates the need for her to continue with the rheumatologist's treatment plan. The following summer, she has a strange red, raised rash on her cheeks after being out in the sun. In addition, small, raised sores begin to develop on her legs and arms. The joint pain, swelling, and fatigue continue. She returns to her primary care provider who is himself frustrated by Patient A's continuing symptoms. He suggests that she return to the rheumatologist, but she says she did not have a good experience with him and wants to see a different rheumatologist. He refers her to another local rheumatologist and notes in her chart that she has been a "chronic complainer."

At the first visit, the new rheumatologist elicits Patient A's long medical history and description of her numerous symptoms. On physical examination, the vital signs are normal, except for a low-grade fever. The physician notices small ulcers in her mouth, pain and swelling in both hips, and a slight pleural rub. He orders a CBC and platelet count, an ANA titer, an anti-double-stranded DNA titer, and antiphospholipid antibodies. He also obtains biopsy samples from the lesions on her legs. The results of the lab work show a normal white blood cell count, a low platelet count (<100,000/mm^3), and positive ANA titer, anti-double-stranded DNA titer, and antiphospholipid antibodies. The findings of the skin biopsy indicate small vessel vasculitis. The rheumatologist diagnoses systemic lupus erythematosus, explaining to Patient A that all of her symptoms over the past four years can be attributed to the disease.

Rationale and comments: Patient A's constellation of symptoms indicates systemic lupus. The classic sign of a butterfly-shaped rash in the malar area of the face is present in up to 90% of cases. Other common symptoms include the discoid rash elsewhere on the body, photosensitivity, Raynaud phenomenon, joint pain (especially in proximal joints of the fingers), fatigue, dry eye syndrome, low-grade fever, small oral ulcers, pain and swelling in both hips, and slight pleural rub. The ANA titer is highly sensitive for systemic lupus, with a positive result in approximately 93% to 100% of individuals with the disease. An anti-double-stranded DNA test can help confirm a diagnosis of systemic lupus, as it has greater specificity than the ANA titer. About 20% to 30% of people with systemic lupus have antiphospholipid antibodies, which increases the risk for thromboembolism and pregnancy loss. The clinical findings, coupled with the results of laboratory testing, fulfill nine of the 11 criteria for the diagnosis of systemic lupus; four criteria are needed for a definite diagnosis.

The rheumatologist emphasizes the need for both pharmacologic and nonpharmacologic measures. He begins treatment with hydroxychloroquine (200 mg PO) twice daily and 5 mg of prednisone daily, after obtaining baseline dual x-ray absorptiometry, measuring her height, and determining the serum 25-hydroxyvitamin D level. The rheumatologist also makes several recommendations:

- Use artificial tear drops.

- Take supplemental calcium and vitamin D.

- Engage in regular exercise.

- Schedule a comprehensive eye examination.

- Schedule routine gynecologic examinations.

- Modify lifestyle factors to reduce the risk of cardiovascular disease.

- Protect skin against exposure to ultraviolet rays.

- Maintain follow-up visits at six-month intervals.

He also warns her of the risk of pregnancy loss related to the presence of antiphospholipid antibodies and encourages her to learn all she can about the disease, providing her with educational materials, a list of reliable websites, and a list of local support groups.

Rationale and comments: The rheumatologist's treatment and follow-up plan meet all the recommendations in established guidelines. The preferred first-line treatment of systemic lupus without major organ involvement is an antimalarial drug and a low-dose glucocorticoid (usually prednisone), two of only three drugs approved by the FDA for use in systemic lupus. Antimalarial agents offer many benefits. They can alleviate joint-related, cutaneous, constitutional, and serosal manifestations of systemic lupus; they can prevent disease flares; they are well tolerated; they have been associated with a lower risk of infection than other treatment approaches; and they have a protective effect on survival. Artificial tear drops are recommended for the treatment of mild dry eye syndrome related to systemic lupus. Glucocorticoid-induced osteoporosis occurs in 4% to 24% of individuals with systemic lupus, and the ACR recommends a daily calcium intake of 1,200 to 1,500 mg and supplemental vitamin D, as well as a baseline dual x-ray absorptiometry, height, and serum 25-hydroxyvitamin D level. Hydroxychloroquine increases the risk for retinopathy, although this side effect is rare at Patient A's dose. Still, ophthalmologic follow-up is important, and the American Academy of Ophthalmology recommends a complete ophthalmologic examination within the first year after treatment. Systemic lupus is associated with an increased risk for HPV infection and cervical dysplasia, making it necessary to have regular gynecologic evaluations. In addition, the risk of cardiovascular disease is increased, and steps should be taken to reduce the risk. Lastly, systemic lupus is associated with an increased risk for other autoimmune diseases, and healthcare professionals should carefully consider the possibility of these diseases during follow-up. Providing educational resources in a variety of formats helps to ensure that patients better understand their disease and its management, which is an essential component in the treatment of a chronic disorder.

Over the next month, Patient A's rash gradually resolves, and her pain and fatigue improve. She feels well enough to comply better with an exercise program, and her symptoms further improve. Her rheumatologist sees her for follow-up every six months. One year after the initiation of treatment, she continues to feel much better than she "has in a long time" and has made several new friends in her local support group.

Rationale and comments: This case reflects the challenges in diagnosing an autoimmune disease because of vague, overlapping symptoms. The absence of characteristic features on physical examination does not necessarily rule out an autoimmune disease, because signs and symptoms tend to wax and wane. As was the situation for Patient A, most individuals consult many healthcare providers, often over the course of several years, before a diagnosis is made. In addition, the attitudes of Patient A's physicians represent a common reaction. More than 45% of individuals with an autoimmune disease have reported that they had been labeled as a chronic complainer in the early stages of their disease because no cause for their symptoms could be determined.

9. ONLINE PATIENT EDUCATION RESOURCES

American Association of Clinical Endocrinologists

https://www.aace.com

American Autoimmune Related Diseases Association, Inc.

https://www.aarda.org

American College of Rheumatology

https://www.rheumatology.org

Academy of Nutrition and Dietetics

http://www.eatright.org

American Fibromyalgia Syndrome Association, Inc.

http://www.afsafund.org

American Gastroenterological Association

https://www.gastro.org

American Thyroid Association

https://www.thyroid.org

Arthritis Foundation

https://www.arthritis.org

Celiac Disease Foundation

https://celiac.org

National Celiac Association

https://nationalceliac.org

Graves' Disease and Thyroid Foundation

https://www.gdatf.org

Lupus Foundation of America, Inc.

https://www.lupus.org

Lupus Research Alliance

https://www.lupusresearch.org

National Fibromyalgia Association

https://fmaware.net

National Institute of Arthritis and Musculoskeletal and Skin Diseases

https://www.niams.nih.gov

National Institute of Diabetes and Digestive and Kidney Diseases

https://www.niddk.nih.gov

Office on Women's Health

https://www.womenshealth.gov

Sjögren's Syndrome Foundation

https://www.sjogrens.org

10. CONCLUSION

When considered collectively, autoimmune diseases affect more individuals than heart disease and cancer combined. However, because these diseases have been studied separately, their health burden has been underappreciated. As chronic illnesses with no cure, autoimmune diseases and fibromyalgia require lifelong treatment and many are associated with substantial morbidity, disability, and mortality. Healthcare professionals, especially primary care providers, face many challenges in diagnosing and treating autoimmune diseases. First, because the prevalence of each autoimmune disease is low, a typical primary care provider will not have experience with the diagnosis and care recommended for every disease. Second, many autoimmune diseases (as well as fibromyalgia) lack objective testing to confirm the diagnosis. Third, the initial symptoms of most autoimmune diseases are vague and are common across many autoimmune diseases and/or fibromyalgia. Lastly, few guidelines are available for diagnosis and management, especially guidelines with up-to-date evidence bases. As a result, it often takes several years before a definitive diagnosis is made. Even after diagnosis, the most effective treatments are not always used. Most individuals with autoimmune diseases or fibromyalgia need close follow-up to assess response to treatment, to monitor side effects of treatment, and to prevent comorbidities. At every follow-up visit, healthcare professionals should encourage their patients to participate actively in decision making and self-management. Although a variety of specialists are often involved in the care of individuals with an autoimmune disease or fibromyalgia, the primary care team has a pivotal role in the overall management of these patients.

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317. Bianco AC, Casula S. Thyroid hormone replacement therapy: three 'simple' questions, complex answers. Eur Thyroid J. 2012;1(2): 88-98.

318. Dunlop DD, Lyons JS, Manheim LM, Song J, Chang RW. Arthritis and heart disease as risk factors for major depression: the role of functional limitation. Medical Care. 2004;42(6):502-511.

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322. Ferucci ED, Johnston JM, Gaddy JR, et al. Prevalence and incidence of systemic lupus erythematosus in a population-based registry of American Indian and Alaska Native people, 2007–2009. Arthritis Rheumatol. 2014;66(9):2494-2502.

323. Jurgens MS, Welsing PM, Jacobs JW. Overview and analysis of treat-to-target trials in rheumatoid arthritis reporting on remission. Clin Exp Rheumatol. 2012;30(4 Suppl 73):S56-S63.

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325. Singer O, Gibofsky A. Methotrexate versus leflunomide in rheumatoid arthritis: what is new in 2011? Curr Opin Rheumatol. 2011;23(3):288-292.

326. van Eijk IC, Nielen MM, van der Horst-Bruinsma I, et al. Aggressive therapy in patients with early arthritis results in similar outcome compared with conventional care: the STREAM randomized trial. Rheumatology (Oxford). 2012;51(4):686-694.

327. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2007;146(6):406-415.

328. Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl J Med. 2004;350(21):2167-2179.

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330. Szarc Vel Szic K, Ndlovu MN, Haegeman G, Vanden Berghe W. Nature or nurture: let food be your epigenetic medicine in chronic inflammatory disorders. Biochem Pharmacol. 2010;80(12):1816-1832.

331. James M, Proudman S, Cleland L. Fish oil and rheumatoid arthritis: past, present and future. Proc Nutr Soc. 2010;69(3):316-323.

332. Ierna M, Kerr A, Scales H, Berge K, Griinari M. Supplementation of diet with krill oil protects against experimental rheumatoid arthritis. BMC Musculoskelet Disord. 2010;11:136.

333. Watson PD, Joy PS, Nkonde C, Hessen SE, Karalis DG. Comparison of bleeding complications with omega-3 fatty acids + aspirin + clopidogrel versus aspirin + clopidogrel in patients with cardiovascular disease. Am J Cardiol. 2009;104(8):1052-1054.

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335. Mierau M, Schoels M, Gonda G, Fuchs J, Aletaha D, Smolen JS. Assessing remission in clinical practice. Rheumatology (Oxford). 2007;46(6):975-979.

336. Daniels TE, Cox D, Shiboski CH, et al. Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjögren's syndrome among 1,726 registry participants. Arthritis Rheum. 2011;63(7):2021-2030.

337. Whitcher JP, Shiboski CH, Shiboski SC, et al. A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjögren's Syndrome International Registry. Am J Ophthalmol. 2009;149(3):405-415.

338. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163(3):286-292.

339. Kim H, Patel KG, Orosz E, et al. Time trends in the prevalence of celiac disease and gluten-free diet in the US population: results from the National Health and Nutrition Examination Surveys 2009–2014. JAMA Intern Med. 2016;176(11):1716-1717.

340. Dewar DH, Ciclitira PJ. Clinical features and diagnosis of celiac disease. Gastroenterology. 2005;128(4 suppl 1):S19-S24.

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Evidence-Based Practice Recommendations Citations

1. The Endocrine Society. Management of Thyroid Dysfunction During Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline. Chevy Chase, MD: The Endocrine Society; 2012. Available at https://academic.oup.com/jcem/article/97/8/2543/2823170. Last accessed July 23, 2020.

2. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26. Available at https://www.rheumatology.org/Portals/0/Files/ACR%202015%20RA%20Guideline.pdf. Last accessed July 23, 2020.

3. Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 2012;64(6):797-808. Available at https://www.rheumatology.org/Portals/0/Files/ACR%20Guidelines%20for%20Screening,%20Treatment,%20and%20Management%20of%20Lupus%20Nephritis.pdf. Last accessed July 23, 2020.

4. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical guidelines: diagnosis and management of celiac disease.Am J Gastroenterol. 2013;108(5):656-676. Available at https://journals.lww.com/ajg/pages/articleviewer.aspx?year=2013&issue=05000&article=00007&type=Fulltext. Last accessed July 23, 2020.

98720 • Bacterial Sexually Transmitted Infections

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

All communities in the United States are impacted by STIs. With rising concerns regarding antibiotic resistance and the development of "super strains" of these diseases, identification and appropriate treatment of bacterial STIs is of critical importance. This course will address the most prominent bacterial STIs in the United States, the major forms of which are increasing at alarming rates. Clinicians have an opportunity to identify patients at risk for bacterial STIs and intervene early in order to limit transmission and debilitating effects of the diseases.

Table of Contents

98720 • Bacterial Sexually Transmitted Infections

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. EPIDEMIOLOGY

HISTORICAL TRENDS

CURRENT TRENDS

3. GENERAL STI ASSESSMENT AND PREVENTION COUNSELING

SEXUAL HISTORY TAKING IN PATIENT INTERVIEWS

STI BEHAVIORAL COUNSELING

4. BARRIER AND NONBARRIER APPROACHES TO PREVENT OR REDUCE STI TRANSMISSION AND INFECTION

EXTERNAL CONDOMS

INTERNAL CONDOMS

INEFFECTIVE METHODS

5. SCREENING

GENERAL SCREENING RECOMMENDATIONS

CHLAMYDIA SCREENING

GONORRHEA SCREENING

6. DIAGNOSTIC TESTING

7. PARTNER SERVICES

EXPEDITED PARTNER THERAPY

8. GENERAL TREATMENT CONSIDERATIONS

ANTIMICROBIAL SUSCEPTIBILITY TESTING

APPROACHES TO TREATMENT

FOLLOW-UP

9. CHLAMYDIA

CLINICAL FEATURES

DIAGNOSIS

TREATMENT

10. GONORRHEA

CLINICAL FEATURES

DIAGNOSIS

TREATMENT

11. SYPHILIS

CLINICAL FEATURES

DIAGNOSIS

TREATMENT

FOLLOW-UP

12. LYMPHOGRANULOMA VENEREUM

CLINICAL FEATURES

DIAGNOSIS

TREATMENT

13. BACTERIAL VAGINOSIS

CLINICAL FEATURES

DIAGNOSIS

TREATMENT

14. EPIDIDYMITIS

CLINICAL FEATURES

DIAGNOSIS

TREATMENT

FOLLOW-UP

15. RARE AND EMERGING BACTERIAL STIS

CHANCROID

GRANULOMA INGUINALE (DONOVANOSIS)

MYCOPLASMA GENITALIUM

16. GENERAL MANAGEMENT ISSUES

ANTIMICROBIAL RESISTANCE

FLUOROQUINOLONE ADVERSE EFFECTS

PENICILLIN ALLERGY

17. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

98720 • Bacterial Sexually Transmitted Infections

Education Category. Infection Control / Internal Medicine

Release Date. 05/01/2020

Expiration Date. 04/30/2023

Course Overview

All communities in the United States are impacted by STIs. With rising concerns regarding antibiotic resistance and the development of "super strains" of these diseases, identification and appropriate treatment of bacterial STIs is of critical importance. This course will address the most prominent bacterial STIs in the United States, the major forms of which are increasing at alarming rates. Clinicians have an opportunity to identify patients at risk for bacterial STIs and intervene early in order to limit transmission and debilitating effects of the diseases.

Audience

This course is designed for physicians, physician assistants, nurses, pharmacists, and allied health professionals involved in the care of patients at risk for or with bacterial sexually transmitted infections.

Course Objective

The purpose of this course is to enhance clinician knowledge regarding the most common bacterial sexually transmitted infections in order to ensure that diagnosis and treatment is initiated early, when transmission risk and sequelae can be minimized.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe the epidemiology and impact of bacterial sexually transmitted infections (STIs).

2. Discuss best practice screening guidelines for bacterial STIs.

3. Describe the approach to diagnosis, prevention, and management of chlamydia.

4. Review clinical recommendations for the diagnosis and management of gonorrhea infection.

5. Analyze the appropriate approach to syphilis diagnosis, prevention, and treatment.

6. Discuss clinical issues related to the transmission, detection, and management of other bacterial STIs, including rare and emerging infections.

7. Assess management issues that may arise when caring for patients with bacterial STIs, including issues related to antimicrobial resistance.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Abimbola Farinde, PharmD, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Sexually transmitted infections, or STIs, are clinical syndromes and infections caused by pathogens acquired and transmitted through sexual activity. This course will address the prominent bacterial STIs in the United States, the major forms of which are increasing at alarming rates.

The Centers for Disease Control and Prevention (CDC) reported that from 2016 to 2020, increases were observed in syphilis and gonorrhea [1]. More than 20 million new STI cases occurred, with people 15 to 24 years of age accounting for around 50% of new cases. The annual estimated medical cost of STIs is $16 billion [2].

Until the 2010s, gonorrhea rates were at historic lows, syphilis was close to elimination, and advances in diagnostic tests and screening had led to increased detection and treatment of chlamydial infections. This progress has reversed. The number of reported syphilis cases is climbing after being largely in decline since 1941. Gonorrhea rates are now increasing, and treatment options are limited due to antimicrobial resistance [2,3]. These increases are unlikely to be due to better screening or referral.

Mass incarceration, poverty, stigma, and homophobia are persistent barriers to access of care for STI prevention, education, and treatment. However, this resurgence in STIs is believed to be mainly a symptom of a deteriorating public health infrastructure and lack of access to health care. In 2012, 52% of state and local STI programs experienced budget cuts, and 21 local health department STI clinics closed that year alone. Fewer clinics create greater barriers to STI testing and treatment, exposing hidden, fragile populations in need that are not obtaining health care and preventive services [2,3].

STI prevention and control is based on five primary strategies, implemented according to the latest recommendations [4,35]:

- Accurate risk assessment, education and counseling of patients at risk of STI to avoid high-risk behaviors and use prevention services

- Pre-exposure vaccination for vaccine-preventable STIs

- Identification of persons with asymptomatic infection or STI symptoms

- Diagnosis, treatment, counseling, and follow-up of patients with infections

- Evaluation, treatment, and counseling for sex partners of patients with STIs

2. EPIDEMIOLOGY

HISTORICAL TRENDS

Epidemiologic statistics are obtained and reported to monitor the extent of new infections, including subgroups with particular vulnerability, and to track changes over time in new infections. The total number of persons with newly diagnosed infection (cases) is valuable for understanding the magnitude of impact at a given point in time, while comparisons over time are more accurate using new cases per 100,000 population [1].

Chlamydia

Records of new chlamydia cases began in 1984. Since then, cases gradually rose until 2018, with 251.4 per 100,000 population reported in 2000, 405.3 per 100,000 population in 2009, and a peak of 539.9 per 100,000 population in 2018 [1]. Since 2018, the rates have decreased. In 2020, the rate was 481.3 cases per 100,000 population, a decrease of 13% compared with the rate in 2019 [1].

Gonorrhea

Population rates of gonorrhea rose from 1941 levels (146.7 per 100,000 population) to peak in 1976 (460.6 per 100,000 population), declined to an all-time low in 2009 (98.1 per 100,000 population), but are rising again as of 2020 (206.5 per 100,000 population) [1].

Syphilis

Population rates of syphilis infection were the highest recorded in 1943 (447.0 per 100,000 population), slowly declining until 1978 (29.2 per 100,000 population), and then doubling by 1990 (54.3 per 100,000 population). Rates then began declining again until 2005 (11.2 per 100,000 population) before beginning another rise, with prevalence more than quadrupled by 2020 (40.6 per 100,000 population) [1].

Chancroid

Chancroid rates rose from 1941 levels (2.5 per 100,000 population) to peak in 1947 (6.7 per 100,000 population), declined until 1978 (0.2 per 100,000 population) and rose again until 1987 (2.1 per 100,000 population), but declined again to remain at historic lows in 2020 (<0.1 per 100,000 population) [1].

CURRENT TRENDS

Notifiable diseases are specified infectious and noninfectious conditions for which regular, frequent, and timely information regarding individual cases is considered necessary for prevention and control of the disease. Public health department reporting is mandated for all new cases of notifiable disease [5]. The list of notifiable diseases, including STIs, is reviewed annually for revision as needed. Notifiable STIs for 2020 include [6]:

- Human immunodeficiency virus (HIV)

- Chlamydia

- Gonorrhea

- Syphilis (all stages)

- Hepatitis A, B, and C

- Chancroid

- Zika virus

Chlamydia, gonorrhea, and syphilis are nationally notifiable STIs for which there are federally funded control programs. These STIs have the most extensive data collected. STI epidemiology publications use figures from estimates or from reported cases (Table 1). Based on these data, Black Americans had the highest rates among racial/ethnic groups, followed by American Indians and Hispanic Americans. Asian Americans had lower rates than White Americans [1].

Table 1: BACTERIAL STI STATISTICS AND TRENDS, 2020

Characteristic/Population

Chlamydia

Gonorrhea

Syphilisa

Total Cases (and Rate per 100,000 Population)

2009

1,244,180 (405.3)

301,174 (98.1)

13,997 (4.6)

2014

1,441,789 (452.2)

350,062 (109.8)

19,999 (6.3)

2020

1,579,885 (481.3)

677,769 (206.5)

41,655 (12.7)

Increase between 2009 and 2020

27.0%

125.0%

197.6%

Rate By Age (per 100,000 Population)

15 to 19 years of age

1927.3

491.1

8.5

20 to 24 years of age

2686.1

845.4

29.4

25 to 29 years of age

1302.6

620.3

36.8

Prevalence By Sexb

Male

34.8%

56.9%

80.8%

Female

65.2%

42.9%

19.0%

Rate By Race/Ethnicity (per 100,000 Population)

Black

1,086.3

662.4

34.1

American Indian/Alaska Native

612.6

339.6

26.9

Native Hawaiians/Other Pacific Islanders

567.9

192.0

22.8

Hispanic

312.0

121.0

13.9

White

178.6

74.5

6.9

Asian

87.6

31.1

4.6

Multi-race

246.0

145.5

13.9

aPrimary and secondary cases of syphilis only.

bPercentages may not total 100% due to cases with unknown sex.

Source: [1]

Syphilis is only infectious and contagious during the primary and secondary stages, making these trends especially concerning. Primary and secondary syphilis infection increased 6.8% during 2019–2020. Although they remain disproportionately affected (representing 53% of male cases), increases among MSM have slowed in recent years and during 2019–2020, the number of cases of primary and secondary syphilis among MSM decreased 2.2% [1]. Rates of primary and secondary syphilis are lower among women, but rates have increased 21% during 2019–2020 and 147% during 2016–2020, suggesting that the heterosexual syphilis epidemic continues to rapidly increase in the United States [1].

3. GENERAL STI ASSESSMENT AND PREVENTION COUNSELING

SEXUAL HISTORY TAKING IN PATIENT INTERVIEWS

The "Five Ps" approach elicits sexual history information related to five key areas of interest: partners, practices, prevention of pregnancy, protection against STIs, and past history [4].

Partners

- "Do you have sex with men, women, or both?"

- "In the past two months, how many partners have you had sex with?"

- "In the past 12 months, how many partners have you had sex with?"

- "Is it possible that any of your sex partners in the past 12 months had sex with someone else while they were still in a sexual relationship with you?"

Practices

- "To understand your risks for STIs, I need to understand the kind of sex you have had recently."

- "Have you had oral sex, meaning 'mouth on penis/vagina' sex?"

- "Have you had vaginal sex, meaning 'penis in vagina' sex?"

- "Have you had anal sex, meaning 'penis in rectum/anus' sex?"

- If yes to any of the questions above, "Do you use condoms: never, sometimes, or always?"

- If "never:" "Why don't you use condoms?"

- If "sometimes:" "In what situations (or with whom) do you use condoms?"

Prevention of Pregnancy

- "What are you doing to prevent pregnancy?"

Protection against STIs

- "What do you do to protect yourself from STIs and HIV?"

Past History of STIs

- "Have you ever had an STI?"

- "Have any of your partners had an STI?"

STI BEHAVIORAL COUNSELING

Intensive behavioral counseling interventions to prevent STIs are recommended for all sexually active adolescents and adults at increased risk for STIs.

Risk Assessment

All sexually active adolescents are considered at increased risk for STIs and should be counseled. Other at-risk groups include adults with current or past-year STIs with multiple sex partners or who use condoms inconsistently. As noted, Black Americans have the highest STI prevalence of any racial/ethnic group, and STI prevalence is higher in American Indians, Alaska Natives, and Latino/as than in white populations. Increased STI prevalence rates are also found in MSM, persons with low incomes living in urban settings, current or former inmates, military recruits, persons who exchange sex for money or drugs, persons with mental illness or a disability, current or former injecting drug users, persons with sexual abuse history, and patients of public STI clinics [7].

Behavioral Counseling Interventions

Behavioral counseling interventions can reduce the risk of acquiring an STI. Interventions ranging in intensity from 30 minutes to more than two hours of contact time are beneficial; evidence of benefit increases with intervention intensity [7]. Interventions can be delivered by primary care clinicians or through referral to trained behavioral counselors. Successful interventions provide basic information on STIs and STI transmission; assess patient risk for transmission; and provide pertinent skills training, such as condom use, communication about safe sex, problem solving, and goal setting. Many successful interventions aim to increase motivation or commitment to safe sex practices [7].

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because communication with patients and families is considered an essential aspect of care, it is each practitioner's responsibility to ensure that information regarding goals and potential outcomes are explained in such a way that allows for patient understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

4. BARRIER AND NONBARRIER APPROACHES TO PREVENT OR REDUCE STI TRANSMISSION AND INFECTION

EXTERNAL CONDOMS

When used consistently and correctly, external latex condoms (also referred to as male latex condoms) are highly effective in the prevention of chlamydia and gonorrhea and reducing risks for syphilis and chancroid when the infected area or site of potential exposure is covered [8,9,10]. By limiting lower genital tract infections, condoms may reduce the risk of later pelvic inflammatory disease (PID) in women [4,11].

As U.S. Food and Drug Administration (FDA)-regulated medical devices, condoms are subject to quality-control testing. Each latex condom manufactured in the United States is tested electronically for holes before packaging. The rate of condom breakage during sexual intercourse and withdrawal is approximately 2 per 100 condoms used, with slightly higher rates during anal intercourse [12,13]. Condom failure to protect against STI or unintended pregnancy is usually caused by inconsistent or incorrect use, instead of condom breakage [14]. Latex condoms should not be used beyond their expiration date or more than five years after the manufacturing date, and users should check the expiration or manufacture date on the packaging before use [4]. In 2022,the FDA cleared the first natural rubber latex condom designed specifically to be used in anal intercourse [148].

External condoms made of materials other than latex fall in two general categories: synthetic and natural membrane condoms. Polyurethane and other synthetic condoms provide protection against STIs and pregnancy comparable to latex condoms and are used mainly as latex condom substitutes by persons with latex allergy. These condoms are more resistant to deterioration and are compatible with oil-based or water-based lubricants. The preventive efficacy of other synthetic external condoms is not well studied, and the FDA restricts their use to persons with latex sensitivity or allergy [10,15].

Natural membrane condoms (termed "natural skin" or "lambskin") are made from lamb cecum. The pores, no greater than 1,500 nm in diameter, block passage of sperm but are more than 10 times the diameter of HIV and more than 25 times that of HBV. Therefore, sexual transmission of hepatitis B, herpes simplex, and HIV organisms can occur with natural membrane condoms; it is believed that bacterial transmission is also possible. These condoms are recommended for preventing pregnancy but not STIs/HIV [15,16,17].

Providers should communicate guidance to patients to ensure correct external condom use [4]. Consistent, correct use is essential to prevent STIs/HIV infection, and a new condom should be used with each oral, vaginal, and anal sex act. It is important to carefully handle condoms to avoid damage from fingernails, teeth, or other sharp objects. Condoms should be put on after the penis is erect and before genital, oral, or anal contact. To prevent the condom from slipping off, the condom should be held firmly against the base of the penis during withdrawal, which should occur while the penis is still erect.

Adequate lubrication during vaginal and anal sex will help prevent condom breakage. With latex condoms, patients should be advised to use only water-based lubricants such as K-Y Jelly, Astroglide, Aqua Lube, or glycerin. Oil-based lubricants (e.g., petroleum jelly, shortening, mineral oil, massage oils, body lotions, cooking oil) weaken latex and should not be used, but are compatible with synthetic condoms.

INTERNAL CONDOMS

Several condoms are available for internal use (also referred to as female condoms), including the FC2 Female Condom, Reddy condom, Cupid female condom, and Woman's condom. Internal condoms can protect from acquisition and transmission of STIs, but data are limited compared with external condoms. Internal condoms are more expensive but offer the advantage of being a female-controlled STI/HIV prevention method, and newer versions may have greater acceptability to both men and women. While internal condoms have been used during receptive anal intercourse, the efficacy is unknown [18,19].

INEFFECTIVE METHODS

Cervical Diaphragms

Uncontrolled studies found that diaphragms protected against cervical gonorrhea, chlamydia, and trichomoniasis, but controlled studies found that compared with external condoms, diaphragms plus lubricant did not reduce rates of chlamydia or gonorrhea [20]. Diaphragms should not be solely relied on for protection against HIV/STIs [21,22].

Non-Barrier Contraception

Contraceptive methods that are not mechanical barriers provide no protection against HIV or other STIs. Sexually active patients who use hormonal contraception, nonhormonal intrauterine devices, or have been surgically sterilized or undergone a hysterectomy should be advised to use condoms to reduce risks for STIs [15].

Genital Hygiene

Vaginal washing and douching after sexual exposure are ineffective and may increase the risk for bacterial vaginosis, some STIs, and HIV infection [4,23].

5. SCREENING

GENERAL SCREENING RECOMMENDATIONS

STI screening is an essential component of overall efforts to reduce STI acquisition and transmission and of individual risk assessment, but it is underutilized. STIs themselves are biologic markers of risk for additional STIs, particularly for HIV in some patients [24]. As such, all persons seeking evaluation or treatment for a suspected STI should be screened for HIV and other STIs. The CDC has established guidelines for screening for bacterial STIs in specific populations (Table 2). The decision to recommend specific STI screening is determined by community prevalence and by individual demographics and STI risk factors. Clinicians should provide patients with information regarding all STIs for which they are being tested and of tests available for common STIs (such as genital herpes and HPV) that are not being provided [24].

Table 2: BACTERIAL STI SCREENING RECOMMENDATIONS

Infection

Population Screened

Women

Pregnant Women

Men

MSM

Persons with HIV

Transgender and Gender Diverse Persons

Chlamydia

All younger than 25 years of age if sexually active

25 years of age or older if sexually active and at risk

All younger than 25 years of age

All 25 years of age or older if at risk

Retest in third trimester if younger than 25 years of age or at risk

Test-of-cure 3 to 4 weeks after treatment and retest within 3 months

Consider for young men in high-risk settings

At least yearly if sexually active, at sites of contact (urethra, rectum, pharynx)a

Every 3 to 6 months if at risk

If sexually active, screen at first HIV testing and then at least yearly

More frequent screening based on risk behaviors and local prevalence

Recommendations should be adapted based on anatomy (e.g., recommendations for women may be applied to any person with a cervix).

Consider screening at the rectal site based on risk behaviors

Gonorrhea

All younger than 25 years of age if sexually active

25 years of age or older if sexually active and at risk

Retest 3 months post-treatment

Pharyngeal and/or rectal screening based on risk behaviors

All younger than 25 years of age

All 25 years of age or older if at risk

Retest 3 months post-treatment

—

At least yearly if sexually active, at sites of sexual contacta

Every 3 to 6 months if at risk

If sexually active, screen at first HIV testing and then at least yearly

More frequent screening based on risk behaviors and local prevalence

Recommendations should be adapted based on anatomy.

Consider screening at the pharyngeal or rectal site based on risk behaviors

Syphilis

—

All women at first prenatal visit

Retest early in third trimester and at delivery if high risk

—

At least yearly if sexually active

Every 3 to 6 months if at risk

If sexually active, screen at first HIV testing and then at least yearly

More frequent screening based on risk behaviors and local prevalence

Consider screening at least annually based on risk behaviors

aRegardless of condom use

Source: [25,26]

Retesting several months after diagnosis of some STIs is required to detect recurrent or treatment-nonresponsive infection. All persons testing positive for chlamydia or gonorrhea should be rescreened three months after treatment. All persons with a syphilis diagnosis should undergo follow-up serologic syphilis testing based on current practice recommendations [25].

Risk factors also determine STI screening frequency. Sexually active MSM (regardless of HIV status) should be screened for oral gonorrhea and for rectal gonorrhea and chlamydia at least annually (depending on reported sex practices) and every three to six months when risk behaviors persist or if they or their sexual partners have multiple partners [24]. STI risk factors that help determine screening frequency for any given person include [4]:

- Presentation in high-risk settings: Adolescent or STI clinics, correctional facilities

- At-risk women: A new sex partner, more than one sex partner, a sex partner with concurrent partners or an STI

- High-risk women: Multiple sex partners, exchanges sex for money or drugs, illicit drug use, history of STI

- Gonorrhea, in women: Same as high-risk, plus inconsistent condom use and not in mutually monogamous relationships

- Chlamydia, in women: Same as high-risk, plus previous chlamydia infections even if treated and/or living in a detention facility

- Men: Multiple sex partners

- High-risk MSM: HIV infection and persistent risk behaviors, sexual partner has multiple partners

Many STIs are screened because they are often asymptomatic during initial infection and likely to be unknowingly transmitted, and their detection is essential to avoid serious complications from untreated infection.

CHLAMYDIA SCREENING

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends screening for chlamydia and gonorrhea in sexually active women 24 years of age and younger and in older women who are at increased risk for infection.

https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/chlamydia-and-gonorrhea-screening

Last Accessed: October 14, 2021

Level of Evidence: B (High certainty that the net benefit is moderate or moderate certainty that the net benefit is moderate to substantial)

Most persons infected with Chlamydia lack symptoms that would prompt their seeking of medical care. Screening is necessary to identify and treat this infection, because most persons are unaware of their Chlamydia trachomatis infection, and untreated infection can have serious consequences. Up to 30% of untreated women develop PID, associated with infertility, debilitating chronic pelvic pain, and life-threatening tubal pregnancy. Chlamydial infection during pregnancy can lead to infant conjunctivitis and pneumonia and maternal postpartum endometriosis. Rectal chlamydia infection may lead to proctocolitis. In men, urethritis is the most common illness resulting from C. trachomatis infection, which progresses to epididymitis in a subset of patients [27].

GONORRHEA SCREENING

Gonococcal infections tend to cause stronger inflammatory responses than C. trachomatis, and while urethral infections often cause discharge and pain with urination, cervical, pharyngeal, and rectal infections are frequently asymptomatic. Untreated gonococcal infection is a major cause of PID in women; disseminated gonococcal infection can result in localized septic arthritis, endocarditis, and meningitis. Furthermore, gonococcal infection increases the risk of HIV. For these reasons, screening for gonorrhea is recommended in specific populations [28].

6. DIAGNOSTIC TESTING

Nucleic acid amplification tests (NAATs) detect the DNA genetic material of many STIs in specimens obtained by endocervical, vaginal, or urethral swab, first-catch urine samples, or oropharyngeal and rectal swab [29,30]. Culture tests grow bacteria from a specimen to detect STIs; they may also be used to detect inflammatory markers in urethral or genital secretions. Examples include Gram stain and methylene blue/gentian violet stain. Direct detection of bacteria is performed by examining a scraping or exudate specimen using a dark-field microscope, or by other methods.

In 2021, the FDA expanded approval of an NAAT to include use in point-of-care settings, including physician offices, health clinics, urgent care settings, and outpatient facilities [147]. The test, which uses female vaginal swabs and male urine specimens, can detect the presence of the bacteria Chlamydia trachomatis and Neisseria gonorrhoeae and provides results in about 30 minutes, allowing for earlier initiation of therapy for confirmed infection.

7. PARTNER SERVICES

For decades, partner services programs have been a foundation of state and local public health department STI control. Standard STI partner services identify, locate, and notify sex partners of infected persons to offer referral to evaluation, treatment, and care. The objective of partner services programs is to interrupt the chain of STI transmission at a level sufficient to reduce morbidity, achieved by identifying and treating undiagnosed STIs. Partner services intervene in disease progression (including incubating disease) and prevent serious sequelae, such as congenital syphilis. Partner services also contribute to understanding STI epidemiology by collecting data [31].

The types of public health partner services, and specific STIs for which services are offered, vary by agency and geographic burden of STIs. Most health departments provide partner services to all persons diagnosed with early (primary, secondary, early latent) syphilis or newly diagnosed with HIV infection. Some provide partner services for persons who may have cephalosporin-resistant gonorrhea. Fewer U.S. health departments routinely provide partner services to persons with gonorrhea, chlamydial infection, trichomoniasis, or other STIs; responsibility for ensuring the treatment of partners of persons with STIs other than syphilis and HIV often rests with the clinician and patient [4].

EXPEDITED PARTNER THERAPY

Effective management of patients with highly infectious but treatable STIs requires treatment of their current or recent sex partner(s) to prevent reinfection and further transmission. Expedited partner therapy differs from standard patient referral of their partner(s) by delivery of a prescription or appropriately packaged medication from the patient to their partner(s). The clinician should also give the patient written materials for their partner(s) that includes general education about the STI, notification the partner(s) may have been exposed, and information about the importance of treatment. These materials also should inform partners about potential therapy-related allergies and adverse effects, and symptoms that suggest complications. Expedited partner therapy bypasses the need for sex partner(s) to arrange and travel for an office visit and clinician evaluation. Providing medication is preferred because prescriptions may not be filled. Expedited partner therapy does not replace formal diagnosis, treatment, or referral, but should be available to clinicians as an option for partner treatment. Expedited partner therapy is especially beneficial when sex partner(s) have limited resources [32].

8. GENERAL TREATMENT CONSIDERATIONS

Several of the recommended steps in the process of diagnosing and treating patients with STIs are common to all or multiple STIs. All patients should be given detailed information on the natural history, transmission, treatment, and complications relevant to their diagnosed STI. Patients should also be provided with clear, accurate written information and directed to appropriate web-based patient information. All patients seeking evaluation or treatment for an STI should be tested for HIV infection.

ANTIMICROBIAL SUSCEPTIBILITY TESTING

Culture tests are used for antimicrobial susceptibility testing. These may be ordered following an apparent treatment failure to determine if an antibiotic-resistant strain is culpable, so treatment can be initiated with an alternative agent. The CDC recommends several methods for this testing in STIs. The examples below are culture tests used in gonorrheal infection.

Disk Diffusion Test

With disk diffusion testing, antibiotic-impregnated paper disks determine antimicrobial resistance of a bacterial isolate. The disks are placed on a lawn of bacterial growth, and micro-organisms that grow closer to a disk are more resistant to the antibiotic on the disk [33].

Broth Dilution and Agar Dilution Methods

Broth dilution and agar dilution methods test a bacterial isolate against a range of antimicrobial concentrations. These are similar to disk diffusion but use plastic strips with an antibiotic gradient indicating the antibiotic concentration at different points on the strip. The minimal inhibitory concentration (MIC), the lowest concentration of drug that inhibits organism growth, is read at the point where the border of growth inhibition intersects the strip [33].

APPROACHES TO TREATMENT

To improve patient adherence and/or guarantee treatment exposure, oral treatments should be provided on-site with the first dose directly observed, regardless of whether the prescription is single-dose or multiple-dose treatment [4]. Presumptive treatment is required during the initial visit of any patient with suspected chlamydia, gonorrhea, and syphilis, even before laboratory test results are available for confirmation. This is essential because early treatment decreases transmission risk, and some patients may not be able to follow through with a second visit, and remain infected [4].

FOLLOW-UP

High recurrence rates occur several months after initial treatment of chlamydia, gonorrhea, and other STIs, even in patients who are treatment adherent. Infection after a standard treatment regimen is usually due to re-infection by an untreated or new sex partner, which elevates risks for transmission and adverse outcomes. For many STIs and especially for chlamydia, gonorrhea, and syphilis, patients should be retested three months post-treatment—regardless of whether they believe their sex partners were treated or cleared of infection. If this is not possible, patients should be retested during the next clinic visit [4,34].

In the United States, confirmed cases of chlamydial infection, gonorrhea, and syphilis must be reported to the state or local public health department.

9. CHLAMYDIA

Chlamydia is a bacterial infection caused by C. trachomatis and may result in urethritis, epididymitis, cervicitis, acute salpingitis, or other syndromes when sexually transmitted; however, the infection is often asymptomatic in women [1]. Chlamydia is highly prevalent in the general population, particularly among young women. With C. trachomatis, serotypes D–K cause urogenital infection and serovars L1–L3 cause lymphogranuloma venereum [36].

The main route of infection is through penetrative sexual intercourse, but chlamydia can be detected in the conjunctiva and oropharynx without genital infection. Chlamydia infection is highly transmittable. Up to 75% of persons become infected by sex partners with chlamydia, but with asymptomatic infection the norm in men and women, most infected persons are unaware of their status. As noted, up to 30% of untreated women develop PID and associated infertility, debilitating chronic pelvic pain, or life-threatening tubal pregnancy. Chlamydia and other inflammatory STIs can facilitate HIV transmission. Infected pregnant women can transmit Chlamydia to their infants during delivery, potentially leading to pneumonia and ophthalmia neonatorum, a cause of blindness [27,36].

CLINICAL FEATURES

Asymptomatic chlamydia is common, and one year after detection, spontaneous remission without treatment occurs in as many as 45% of asymptomatic patients [37]. Symptoms and signs vary by sex. In either men or women, chlamydia can be transferred to the eye (acute conjunctivitis). An infrequent complication, reactive arthritis, is an immunologic reaction to genital or intestinal infection that can cause skin or eye lesions and noninfectious recurrent urethritis [4].

Women

Common symptoms in women include vaginal discharge, post-coital and intermenstrual bleeding, dysuria, lower abdominal pain, and deep dyspareunia. Physical exam can reveal pelvic and/or cervical motion tenderness; cervicitis (yellow, mucopurulent exudate with/without contact bleeding); or cervical ectopy (expansion of red endocervical epithelium onto vaginal surfaces of cervix) [36,38].

Men

Symptoms in men include urethral discharge, dysuria, urethritis (acute severe onset dysuria, frequency, and copious, purulent discharge mimicking gonococcal urethritis), and possible progression to epididymitis [36,38].

DIAGNOSIS

Chlamydia requires definitive diagnosis, because signs and symptoms resemble gonorrhea, and both infections require distinct antibiotic treatment approaches. Given the symptom overlap, Neisseria gonorrhoeae and C. trachomatis are often tested together [27].

NAAT is the method of choice in chlamydia testing, because it has greater sensitivity and specificity than other chlamydia tests. Specimens should be obtained from vulvovaginal swab in patients with a vagina, first-catch urine in patients with a penis, rectal swab in MSM or those who frequently receive anal sex, and oropharyngeal swab for oropharyngeal infection [27,39].

TREATMENT

Chlamydia treatment should be promptly delivered to all persons testing positive, because delayed treatment is associated with PID and other complications [38]. Recommended treatment is summarized in Table 3.

Table 3: TREATMENT OF CHLAMYDIAL INFECTIONS

Patient Population

Treatment Regimen

Recommended

Alternative

General

Doxycycline 100 mg oral twice daily for 7 days

Any one of the following:

- Azithromycin 1 g oral single-dose

- Levofloxacin 500 mg oral daily for 7 days

Pregnant women

Azithromycin 1 g oral single-dose

Amoxicillin 500 mg oral three times per day for 7 days

Source: [4]

Azithromycin and doxycycline have comparable efficacy in urogenital chlamydial, with microbial cure rates of 97% and 98%, respectively [40]. Some data suggest azithromycin may be less effective in rectal chlamydial infection, but this is debated [41,42]. Oropharyngeal chlamydia can be sexually transmitted to genital sites and should be treated with doxycycline [4,43,44].

Test-of-cure three to four weeks post-therapy to detect treatment failure should be performed with adherence doubted, persistent symptoms, or suspected reinfection. Completing chlamydial NAAT less than three weeks post-therapy increases the risks of false-positive results and is not recommended [27,45].

Treatment During Pregnancy

Doxycycline is contraindicated in the second and third trimesters, and animal studies have raised concerns over ofloxacin and levofloxacin [46]. Azithromycin is safe and effective as an alternative drug for chlamydia in pregnancy [47,48]. All pregnant women diagnosed with chlamydia should be retested three months after treatment. Women younger than 25 years of age and those at increased risk for chlamydia should be rescreened during the third trimester [49].

Amoxicillin is the preferred alternative therapy in pregnancy with persistent chlamydial symptoms following exposure to penicillin-class antibiotics [50]. Gastrointestinal side effects from erythromycin can lead to nonadherence, and lower-dose 14-day regimens can mitigate gastrointestinal intolerance. The potential hepatotoxicity of erythromycin estolate contraindicates its use in pregnancy [4].

10. GONORRHEA

Gonorrhea results from infection by the bacterium N. gonorrhoeae and can affect the cervix, uterus, and fallopian tubes in women, and the urethra, mouth, throat, eyes, and anus of both sexes and manifest as urethritis, cervicitis, proctitis, salpingitis, or pharyngitis [1]. Over time, gonorrhea can spread to the blood and joints to become a life-threatening illness [51,52]. With an estimated 820,000 new infections annually, gonorrhea is the second most commonly reported bacterial STI in the United States [34].

N. gonorrhoeae has developed resistance to almost every antimicrobial agent used against it. This highly concerning aspect of gonorrhea control is discussed later in this course.

To effectively counter rising rates of gonorrheal infection and the probability of further antimicrobial drug resistance, a 2017 paper states that such efforts require an understanding of why gonorrhea is so common in MSM. Unlike heterosexual men and women, gonorrheal infection is most commonly found in the pharynx and rectum in MSM, is highly likely to be asymptomatic (in contrast to urethral infection), and given the persistence and lack of symptoms with infection in these sites, oral-oral contact (kissing) and oral-anal sex are believed to be driving increasing gonorrheal infection rates among MSM [53].

CLINICAL FEATURES

The most common symptoms of gonorrheal infection are vaginal or penile discharge and painful or difficult urination. As with chlamydia, the most serious complications occur in women. Untreated gonorrhea can lead to PID and increased risk of HIV infection in both sexes. Mothers who acquire gonorrhea during pregnancy can pass the infection to the fetus, possibly causing blindness or life-threatening infections [51,52].

Urethral gonorrheal symptoms can cause men to seek curative treatment in time to prevent sequelae but not transmission. Gonococcal infections are often asymptomatic in women, or recognizable symptoms may not appear until complications develop such as PID [28]. Signs and symptoms of gonorrhea include [54]:

Women

- Bleeding between menstrual periods and after sexual intercourse

- Pain in the abdomen, during intercourse or urination

- Abnormal vaginal discharge

- Frequent urination

Men

- White, yellow, or greenish discharge from penis

- Pain or burning when urinating

- Pain, tenderness, or swelling of testes

DIAGNOSIS

Testing for gonorrhea and chlamydia together is increasingly recommended [27,54]. NAAT is the preferred method because it offers greater sensitivity and specificity than other gonorrhea tests, analyzes the widest range of extragenital specimens, and eliminates the need for pelvic exam in women [27,54].

Culture using Gram stain can diagnose gonorrhea in symptomatic men, but it is inaccurate in detecting non-gonococcal infection in asymptomatic men and vaginal gonorrheal infection in women [54]. Culture testing is available for detecting rectal, oropharyngeal, and conjunctival gonococcal infection [27,55,56]. With suspected or documented treatment failure, clinicians should perform culture tests for antimicrobial susceptibility and NAAT [4].

TREATMENT

Uncomplicated Gonococcal Infections

Recommended and alternative treatment approaches for all gonorrheal infection sites and stages are summarized in Table 4. Ceftriaxone plus azithromycin is the only first-line recommendation for urogenital, endocervical, anorectal, and oropharyngeal gonorrheal infection and for gonorrheal infection in pregnant women and patients with HIV [34,58]. This arose from efforts by the CDC to prevent development of cephalosporin resistance, following evidence during 2006–2011 suggesting decreasing efficacy with cefixime against N. gonorrhoeae [34]. Prior to December 2020, the CDC recommended dual ceftriaxone/azithromycin therapy. However, it shifted to a recommendation for ceftriaxone monotherapy to help combat increasing resistance to azithromycin [63]. Cefixime was removed as a first-line treatment of gonorrhea in 2012 [57].

Table 4: TREATMENT OF GONOCOCCAL INFECTIONS

Site of Infection

Treatment Regimen

Recommended

Alternative

Uncomplicated infection

Cervix, urethra, or rectum

Single-dose ceftriaxone 500 mg IMa

Single-dose gentamicin 240 mg IM PLUS azithromycin 2 g orally OR single-dose cefixime 800 mg orally

Pharynx

—

Pregnancy

Consult infectious disease specialist

Gonococcal conjunctivitis

Single-dose ceftriaxone 1 g IM

—

Disseminated infection

Arthritis and arthritis-dermatitis syndrome

Ceftriaxone 1 g IM or IV every 24 hours

Cefotaxime 1 g IV every 8 hours OR ceftizoxime 1 g every 8 hours

Gonococcal meningitis and endocarditis

Ceftriaxone 1–2 g IV every 24 hours

—

aA dose of 1 g IM should be used for patients weighing 150 kg or more.

Source: [4,34,63]

Both dual therapy agents are single-dose, which confers greater convenience and adherence. Azithromycin is preferred to doxycycline as the second antimicrobial because of single-dose use, substantially greater gonococcal resistance to tetracycline than azithromycin, and efficacy in uncomplicated urogenital gonorrhea [34]. (Azithromycin monotherapy promotes resistance and should not be used.) Azithromycin efficacy against uncomplicated genital chlamydial infection further supports this combination, because co-infection with C. trachomatis is very common in patients with gonorrheal infection [4,59,60].

Single-injection ceftriaxone 500 mg provides sustained, high bactericidal levels in the blood. In clinical trials, ceftriaxone showed cures in 99.2% of uncomplicated urogenital and anorectal infections and 98.9% of pharyngeal infections [61,62]. Other single-dose injectable cephalosporins are available but not recommended as gonorrhea treatment. Gentamicin is solely recommended for use when ceftriaxone is unavailable.

Patients with a history of IgE-mediated beta-lactam allergy, including anaphylaxis, should be considered for penicillin skin testing, although cross-reactivity to third-generation cephalosporins (ceftriaxone) is very low [64,65,66].

Follow-Up

Dispense on-site and observe first dosing for all prescribed treatment. If medications are not available when treatment is indicated, linkage to an STI treatment facility should be provided for same-day treatment [4].

All sex partners within 60 days of diagnosis should be evaluated and presumptively treated for N. gonorrhoeae and C. trachomatis infections. If the last potential exposure was more than 60 days previous, the most recent sex partner should be treated. Patients and sex partners should abstain from condomless sexual activity for seven days after treatment and until sex partners are adequately treated [4]. If a healthcare provider cannot ensure an infected patient's partner will be promptly linked to care, expedited partner therapy with cefixime (800 mg) should be delivered to the partner by the patient, a disease investigation specialist, or a collaborating pharmacy [4]. When cephalosporin treatment failure is suspected, the treating clinician should consult an infectious disease specialist, an STI/HIV Prevention Training Center clinical expert, the local or state health department STI program, or the CDC for advice [67].

All patients should be retested within three months of initial treatment [34]. A test-of-cure using either culture or NAAT is recommended in patients with pharyngeal gonorrhea 14 days after treatment with an alternative regimen. If the NAAT is positive, confirm by culture testing before retreatment. All positive test-of-cure cultures should include antimicrobial susceptibility testing. Symptoms that persist after treatment should be evaluated by culture, with or without NAAT, and any gonococci isolated should be tested for antimicrobial susceptibility [4].

Gonococcal Conjunctivitis

Gonococcal conjunctivitis is uncommon and research data on gonococcal conjunctivitis treatment in adults are limited. Consider one-time lavage of the infected eye with saline solution and consultation with an infectious disease specialist [4].

Disseminated Gonococcal Infection

Disseminated gonococcal infection frequently appears as petechial or pustular acral skin lesions, asymmetric polyarthralgia, tenosynovitis, or oligoarticular septic arthritis. The infection can be complicated by perihepatitis and rarely by endocarditis or meningitis. Some N. gonorrhoeae strains that cause disseminated infection result in minimal genital inflammation [68]. If disseminated gonococcal infection is suspected, use NAAT or culture specimens from urogenital and extragenital sites, and specimens from disseminated infection sites such as the skin, synovial fluid, blood, and central nervous system (CNS). Test all N. gonorrhoeae isolates for antimicrobial susceptibility [4].

Hospitalization and consultation with an infectious disease specialist are initially recommended, especially when treatment adherence is doubted, diagnosis uncertain, or purulent synovial effusions or other complications are present. Examine for evidence of endocarditis and meningitis [4].

Arthritis and Arthritis-Dermatitis Syndrome

When treating the arthritis-dermatitis syndrome, switch to an oral agent according to antimicrobial susceptibility testing 24 to 48 hours after substantial clinical improvement, for total treatment of at least seven days [4].

Gonococcal Meningitis and Endocarditis

The optimal treatment and duration for disseminated gonococcal infection is poorly studied. Antimicrobial susceptibility results direct the treatment of disseminated gonococcal infection, but pending susceptibility results, treatment should be guided by the clinical presentation. Meningitis treatment should continue for 10 to 14 days. Parenteral antimicrobial therapy for endocarditis should continue for more than four weeks [4].

11. SYPHILIS

Syphilis is a multistage, multisystem STI caused by infection with Treponema pallidum, a spirochete (i.e., a treponeme) bacterium. Transmission occurs through direct contact with an infectious chancre (lesion) or through vertical transmission during pregnancy. The site of bacterial entry in heterosexual patients is typically genital. In MSM, extragenital sites (e.g., anal, rectal, oral) infected through oral-anal or genital-anal contact account for 32% to 36% of transmissions [69]. The clinical course is highly variable [1].

Syphilis infection in pregnant women increases the risk of miscarriage, stillbirth, and fetal transmission during pregnancy or delivery (congenital syphilis), which can result in skeletal deformity, abnormal speech or motor development, seizures, anemia, liver disease, or neurologic disorders [52]. Full discussion of syphilis infection in pregnant women and congenital syphilis in newborns is outside the scope of this course.

CLINICAL FEATURES

Untreated syphilis can progress through stages of primary, secondary, latent (early and late), and tertiary disease. Syphilis is infectious and transmittable during early disease (primary, secondary, early latent). Clinical manifestations of syphilis vary by stage [7,51,52,69,70].

Primary Infection

After an average incubation of 21 days (range: 9 to 90 days), a painless chancre or ulcer appears at the anogenital infection site, with regional lymphadenopathy. The ulcer resolves in three to eight weeks by local immune clearance, after the bacteria have widely disseminated through blood and lymphatic systems.

Secondary Infection

Rash, mucocutaneous lesions, and generalized lymphadenopathy, the "classical triad" reflecting multisystem involvement, develop 4 to 10 weeks after the initial chancre [71]. Roughly 1% to 2% of patients develop neurologic complications during secondary syphilis.

Latent Infection

The disease becomes asymptomatic following spontaneous resolution of secondary syphilis 3 to 12 weeks from onset. The first year is termed early latent, and afterward, late latent. Early latent syphilis is considered infectious because secondary disease recurs in 25% of patients [70].

Tertiary (Late) Infection

Tertiary (late) syphilis occurs 10 to 40 years after initial infection in 33% of untreated patients. Inflammatory lesions can develop in bone (osteitis), skin (gummatous lesions), connective tissues of the cardiovascular system (aortitis, coronary vessel disease), and less often, in the respiratory tract, reproductive organs, lymph nodes, liver, or brain/CNS. This stage is potentially fatal.

Neurosyphilis

Neurosyphilis results from CNS infection by T. pallidum and can occur at any syphilis stage. Early neurosyphilis manifests in the initial months or years of infection in cranial nerve dysfunction, meningitis, stroke, altered mental status, and auditory or ophthalmic abnormalities. Late neurosyphilis manifests 10 to 30 years after primary disease as progressive dementia or paralysis with brain and/or spinal cord involvement; optical involvement manifests as syphilitic uveitis, neuroretinitis, optic neuritis, and possibly blindness.

DIAGNOSIS

Diagnostic Testing

T. pallidum infection is diagnosed using tests that detect antibodies in serum or cerebrospinal fluid (CSF). Different tests are used for detecting treponemal-specific antibodies against T. pallidum or nontreponemal antibodies against T. pallidum and similar infection. Both must be performed to diagnose syphilis at all stages. Aside from patients with suspected neurosyphilis, other testing is not needed. Antibody tests may also be used to measure treatment response [30,72].

Patients may be negative for antibodies against T. pallidum in primary syphilis, especially in the first two weeks after symptom onset. With progression into secondary syphilis, antibodies to T. pallidum reach peak titers and may persist indefinitely regardless of disease state or prior therapy. To help differentiate active from past syphilis infection, tests are used to detect antibodies against nontreponemal antigens such as cardiolipin, a lipid antigen released by host cells damaged by T. pallidum. Nontreponemal antibodies are typically positive during current infection and negative following treatment or during late/latent syphilis [73].

Nontreponemal antibody tests are highly sensitive but low in specificity to T. pallidum, and false-positives can result from other conditions such as autoimmune disease, tuberculosis, or HIV. A positive result is confirmed by a treponemal test. Common nontreponemal antibody tests include [30,72,74]:

- Rapid plasma regain (RPR): The most widely used NNT, accurate for screening and confirming positive treponemal testing, and sensitive to treatment response

- Venereal disease research laboratory (VDRL): The only FDA-approved NNT assay for CSF specimens, but otherwise replaced by RPR

- Toluidine red unheated serum test (TRUST): A modified version of VDRL with use similar to RPR

Treponemal antibody tests are highly specific to treponemal antibodies, making them insensitive to previous resolved syphilis infection; a false positive is likely for cleared infection. Nontreponemal antibodies disappear around three years after successful treatment, and positive treponemal tests require NNT confirmation to distinguish active infection (or reinfection) from previous resolved illness. Treponemal antibody tests include [30,70,72,74]:

- Fluorescent treponemal antibody absorption (FTA-ABS): Useful three to four weeks after exposure; measures antibodies in CSF to help diagnose neurosyphilis.

- T. pallidum particle agglutination assay (TP-PA): Greater specificity and fewer false positives can make it preferred over FTA-ABS.

- Microhemagglutination assay (MHA-TP): A less common confirmatory method.

Immunoassays may also be used to diagnose syphilis. Options include enzyme, multiplex flow, chemiluminescent, and microbead immunoassays.

Historically, serologic testing for syphilis used initial NNT screens such as the RPR, with positive results followed by FTA-ABS or TP-PA for confirmation. Although accurate, this analytic process is labor intensive and requires subjective interpretation by laboratory personnel [73].

Using enzyme or multiplex flow immunoassay to detect immune antibodies produced against T. pallidum (IgG, IgM, or IgG/IgM) is more popular today. These assays are highly sensitive and specific and allow objective interpretation of results and higher throughput [73,74].

The Mayo Clinic now performs syphilis screening by first using multiplex flow immunoassay to detect T. pallidum-specific IgG antibodies. IgG antibodies to syphilis can remain elevated despite appropriate antimicrobial treatment, and a reactive result does not distinguish recent from past infection. A positive multiplex flow immunoassay is followed by NNT testing using RPR; this provides supplemental serologic data, and indicators of syphilis disease state and treatment history [73].

Latent Syphilis

Latent syphilis is seroreactive, without other evidence of disease. In all patients with latent syphilis, carefully examine all accessible mucosal surfaces (e.g., oral cavity, perianal area, perineum and vagina in women, underneath the foreskin in uncircumcised men) for mucosal lesions [69].

Tertiary Syphilis

Limited information is available concerning clinical response and follow-up of patients with tertiary syphilis. They should be managed in consultation with an infectious disease specialist [4].

Neurosyphilis

Lab tests support a neurosyphilis diagnosis, but no single test has uniform accuracy. Diagnosis is based on the combination of CSF tests (e.g., CSF cell count or protein, reactive CSF-VDRL), reactive serologic test results, and neurologic signs and symptoms [75].

Patients of any syphilis stage and HIV status should be closely observed for symptoms or signs of neurologic (e.g., cognitive dysfunction, motor or sensory deficits, meningitis, stroke, hearing loss, cranial nerve palsies) or ophthalmic (e.g., uveitis, iritis, neuroretinitis, optic neuritis) disease. Evaluate suspected patients with CSF analysis, otologic exam, and ocular slit-lamp ophthalmologic exam [70,72].

When ocular manifestations are present, perform a CSF exam even when other clinical neurologic findings are negative. Refer patients with ocular syphilis to an ophthalmologist, and treat for neurosyphilis even with normal CSF exams. With ocular syphilis and abnormal CSF parameters, use follow-up CSF exam to assess treatment response [4].

In early syphilis, CSF abnormalities are common even with negative clinical neurologic findings. In this context, CSF findings do not alter recommended treatment [70,72].

Comorbid HIV Infection

HIV infection does not change treponemal and NNT diagnostics, but patients with advanced HIV infection/immunosuppression are more likely to have clinical and CSF abnormalities consistent with neurosyphilis [69].

TREATMENT

Evidence Based Practice Recommendation

According to the Minnesota Department of Health, penicillin G administered intramuscularly or intravenously is the preferred drug for treating all stages of syphilis.

https://www.health.state.mn.us/diseases/syphilis/hcp/protocol.pdf

Last Accessed: April 23, 2020

Level of Evidence: Expert Opinion/Consensus Statement

Penicillin G, the recommended treatment for all stages of syphilis, effectively achieves clinical resolution (i.e., healing of lesions and prevention of sexual transmission) and prevention of late sequelae (Table 5). Penicillin G is also the only known effective antimicrobial for preventing maternal transmission of syphilis to the fetus and for treating fetal infection [76]. Parenteral is favored over the oral route because therapy is supervised and bioavailability is guaranteed. However, deep IM injections of benzathine and procaine penicillin are painful; 1% lidocaine can be added to the injection for pain reduction [69]. Patients should be asked about known penicillin allergy before treatment. Consult an infectious disease specialist when treating any patient with penicillin allergy. A 2010 clinical trial found azithromycin as effective as penicillin IM for curing early-stage syphilis in patients without HIV. This was an important breakthrough for settings with limited resources and patients with penicillin allergic reactions [51,52].

Table 5: TREATMENT OF SYPHILIS INFECTIONS

Infection Stage or Patient Group

Treatment Regimen

Recommended

Alternative

Primary, secondary, or early latent infection with or without HIV co-infection

Single-dose benzathine penicillin G 2.4 million units IM

—

Late/latent infection of unknown duration

Benzathine penicillin G 7.2 million units IM total, given in 3 doses of 2.4 million units at one-week intervals

—

Tertiarya

Late/latent infection with HIV co-infection

Neurosyphilis or ocular syphilis with or without HIV co-infection

For 10 to 14 days:

Aqueous crystalline penicillin G 18–24 million units IV per day, given in doses of 3–4 million units every 4 hours or continuous infusion

For 10 to 14 days:

Procaine penicillin G 2.4 million units IM once daily, plus probenecid 500 mg oral four times per day

During pregnancy

Treat according to infection stage

aIn patients not allergic to penicillin and without evidence of neurosyphilis.

Source: [4]

Penicillin effectiveness as syphilis treatment was established through clinical experience before clinical trials confirmed its efficacy. Almost all current syphilis treatments are based on laboratory considerations, biologic plausibility, expert opinion, case studies, and decades of clinical experience [69]. Clinical trial data are lacking on optimal penicillin selection and non-penicillin regimens [4].

The duration of penicillin activity at treponemicidal levels should be at least seven days to cover a sufficient number of treponeme division times (30 to 33 hours) in early syphilis. With longer treatment regimens, sub-treponemicidal intervals should not be longer than 24 to 30 hours [77,78]. Longer treatment durations are used for late syphilis, because treponemes divide more slowly in late disease. Persistence of treponemes despite apparently successful treatment of late disease indicates that some may have been "resting" or dividing very slowly [69,79].

Clinicians have inadvertently but widely prescribed combination benzathine-procaine-penicillin (Bicillin C-R) instead of the standard benzathine-penicillin product (Bicillin L-A). Benzathine, procaine, and oral penicillin combinations are inappropriate for syphilis treatment [80].

Treatment for primary, secondary, latent disease, or neurosyphilis does not differ for patients with HIV infection. For all patients, additional doses of benzathine penicillin G, amoxicillin, or other antibiotics do not enhance efficacy of early syphilis treatment, and recommended syphilis treatment is effective in preventing neurosyphilis [81]. Changes in CSF parameters can occur more slowly in patients with HIV, especially with advanced immunosuppression, but use of antiretroviral therapy may improve clinical outcomes in patients with HIV and syphilis [82,83,84,85].

Jarisch-Herxheimer reaction (JHR) is an acute febrile reaction with headache, myalgia, fever, and other symptoms that develops in the first 24 hours of starting syphilis therapy. Patients should be informed about this possible adverse reaction and its management. JHR is most frequent in persons with early syphilis, and antipyretics can be used to manage symptoms [4].

Treatment of Syphilis During Pregnancy

Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection. Pregnant women with syphilis in any stage who report penicillin allergy should be desensitized and treated with penicillin [4]. The desensitization process will be discussed in more detail later in this course.

FOLLOW-UP

Early Syphilis

Patients with primary, secondary, or latent syphilis should be clinically and serologically evaluated at 3, 6, 9, 12, and 24 months post-therapy; and with neurosyphilis, at 6, 12, 18, and 24 months post-therapy [82,83]. Treatment failure or re-infection is likely in patients with persistent or re-emerging signs or symptoms or a fourfold (or greater) increase in nontreponemal test titer for more than two weeks. Patients should be treated, HIV infection retested, and a CSF exam performed to help distinguish treatment failure from reinfection [4].

Optimal management with a less than fourfold decline in post-treatment titers is unclear. At a minimum, provide additional clinical and serologic follow-up and retest for HIV infection. Re-treat when follow-up cannot be ensured. Consider CSF exam to rule out unrecognized CNS infection. With negative CSF results, weekly injection of benzathine penicillin G 2.4 million units IM for three weeks is recommended [4].

By 6 to 12 months post-treatment, failure of nontreponemal test titers to decline fourfold can indicate treatment failure. However, at one-year post-treatment, 15% to 20% of treated primary and secondary syphilis patients will not achieve the fourfold decline in nontreponemal titer that defines response [81,86].

After 24 months, if nontreponemal titers fail to decline fourfold, CSF exam can be considered and treatment administered accordingly, although low initial titers (<1:8) might not decline [86,87,88].

When serologic titers fail to decline despite repeated courses of therapy for primary, secondary, or latent syphilis and negative CSF exams, the need for additional therapy or repeat CSF exam is unclear but is generally not recommended. Serologic response to treatment is also influenced by syphilis stage (with earlier stages more likely to decline fourfold and become negative), initial nontreponemal antibody titers (with lower titers less likely to decline fourfold than higher titers), and previous syphilis treatment (in whom nontreponemal titers decline more slowly) [86,87,88].

The appropriate course of action is also unclear for a missed weekly penicillin dose. Clinical experience suggests a 10- to 14-day interval between benzathine penicillin doses for latent syphilis may be acceptable before restarting the injection sequence. Pharmacologic considerations suggest a seven- to nine-day interval between doses, if feasible, is more optimal [77,78,79]. Missed doses are unacceptable in pregnant women treated for latent syphilis, and the full therapy course must be repeated with any missed dose [89].

Latent Syphilis

Repeat nontreponemal antibody test assays at 6, 12, and 24 months, and CSF exam if observing the following [81,90]:

- A fourfold or greater increase in titer for more than two weeks

- Initially high titer (≥1:32) failing to decline at least fourfold within 12 to 24 months of therapy

- Clinical signs or symptoms of syphilis

- If CSF parameters are abnormal, treat for neurosyphilis; if normal, re-treat for latent syphilis.

Neurosyphilis

If CSF pleocytosis was present initially, CSF exams should be repeated every six months until the cell count is normal. Leukocyte count is sensitive to treatment efficacy. If the cell count has not decreased after six months or if CSF cell counts or protein remain abnormal after two years, retreatment should be considered. For immunocompetent patients and those with HIV who are on antiretroviral therapy, limited data suggest that normalizing serum RPR titers predict normalized CSF parameters following neurosyphilis treatment [82,84]. With normal CSF exam, treat with benzathine penicillin G 2.4 million units IM, once weekly for three weeks [4].

Management of Sex Partners

Sexual transmission of T. pallidum is thought to occur when mucocutaneous syphilitic lesions are present, which this is uncommon after the first year of infection. Persons sexually exposed to a patient diagnosed with primary, secondary, or early latent syphilis should be evaluated clinically and serologically and treated [4]. Anyone exposed to a sex partner within 90 days of diagnosis should be treated presumptively for early syphilis, even when serologic testing is negative. Anyone exposed to a sex partner more than 90 days before diagnosis should be treated presumptively for early syphilis if serologic test results are not immediately available and follow-up opportunity uncertain. If serologic tests are negative, no treatment is needed. If serologic tests are positive, deliver treatment based on clinical and serologic evaluation and syphilis stage.

12. LYMPHOGRANULOMA VENEREUM

Lymphogranuloma venereum is caused by infection with L1, L2, or L3 serovars of C. trachomatis, resulting in a disease characterized by genital lesions, suppurative regional lymphadenopathy, or hemorrhagic proctitis. The infection is usually sexually transmitted [1]. The L1–L3 strains differ from chlamydial serotypes that cause trachoma, inclusion conjunctivitis, urethritis, or cervicitis in that they can invade and reproduce in regional lymph nodes. L2 is the most commonly identified serovar in modern North American lymphogranuloma venereum outbreaks [91].

Lymphogranuloma venereum is endemic in parts of Africa, India, Southeast Asia, South America, and the Caribbean but occurs sporadically in the United States. Most patients diagnosed with lymphogranuloma venereum are MSM. Lymphogranuloma venereum has been a non-reportable STI in the United States since 1994, and prevalence rates are difficult to estimate. However, lymphogranuloma venereum has been tracked since 2004 in the UK, where 99% of lymphogranuloma venereum cases occur in MSM, frequently involved in dense sexual networks associated with the sex party scene and without obvious link to known lymphogranuloma venereum-endemic countries. MSM show a strong association between HIV and lymphogranuloma venereum, and compared with MSM with rectal chlamydial infection, those with rectal lymphogranuloma venereum are more likely to have proctitis symptoms and HIV infection [91,92,93].

CLINICAL FEATURES

Lymphogranuloma venereum infection disseminates from the mucosa via underlying tissue to regional lymph nodes, an infectious process that contrasts with chlamydial infection that is limited to the mucosa [91]. The clinical course of lymphogranuloma venereum is classically divided into three stages.

Stage 1 typically begins after a three-day incubation period with a small genital ulcer or papule at the site of entry. The lesion may cause ulceration of the overlying skin but often disappears by the time patients seek care [95,96].

Stage 2 usually begins roughly two to four weeks later, with the inguinal lymph nodes on one or both sides enlarging and forming large, tender, sometimes fluctuant masses (buboes). The buboes stick to deeper tissues and cause the overlying skin to become inflamed, sometimes with fever and malaise. In women, backache or pelvic pain is common; the initial lesions may appear on the cervix or upper vagina, resulting in enlargement and inflammation of deeper perirectal and pelvic lymph nodes. Multiple draining sinus tracts may develop and discharge pus or blood [95,96].

In stage 3, lesions heal with scarring, but sinus tracts can persist or recur. Persistent inflammation from untreated infection obstructs lymphatic vessels to cause swelling and skin sores [95,96].

In MSM, hemorrhagic proctitis is the primary sign of transmission to the rectal mucosa. Patients may present with rectal pain, anorectal bleeding, mucoid and/or hemopurulent rectal discharge, tenesmus, constipation, and other symptoms of lower GI inflammation. Systemic symptoms can include fever and malaise [94,97]. Outbreaks of lymphogranuloma venereum proctocolitis have occurred in some MSM communities. If not treated early, lymphogranuloma venereum proctocolitis can lead to chronic colorectal fistula and stricture, and reactive arthropathy has been reported [98].

In heterosexuals, lymphogranuloma venereum commonly manifests as tender unilateral inguinal and/or femoral lymphadenopathy. Rectal exposure in women can lead to proctocolitis that mimics inflammatory bowel disease. Clinical findings may include mucoid and/or hemorrhagic rectal discharge, anal pain, constipation, fever, and/or tenesmus [96]. Secondary bacterial infection or co-infection with another STI may develop in patients with genital or colorectal lymphogranuloma venereum lesions [4].

DIAGNOSIS

Diagnosis is based on clinical suspicion, epidemiologic information, and exclusion of non-lymphogranuloma venereum etiologies when proctocolitis, inguinal lymphadenopathy, or rectogenital ulcers are present. Lymphogranuloma venereum is suspected in [27]:

- Individuals with genital ulcers, swollen inguinal lymph nodes, or proctitis

- Patients with buboes, which can be mistaken for abscesses caused by other bacteria

- Patients who have lived in, visited, or had sexual contact with persons from areas of endemic lymphogranuloma venereum

Diagnosis of lymphogranuloma venereum is based on isolation of C. trachomatis serotype L1, L2, or L3 in specimens from recto-genital lesions or lymph nodes. Specimens are tested for C. trachomatis by culture, direct immunofluorescence, or NAAT. Rectal specimen testing by NAAT for C. trachomatis is accurate, and MSM presenting with proctocolitis should have rectal specimens tested for chlamydia using NAAT. Diagnosis can also be made by detecting antibodies to chlamydial endotoxin (complement fixation titers >1:64 or microimmunofluorescence titers >1:256) or by genotyping using PCR-based NAAT [27].

TREATMENT

During initial contact (before chlamydia test results are available), patients with a clinical syndrome consistent with lymphogranuloma venereum, including proctocolitis or genital ulcer disease with lymphadenopathy, should receive presumptive treatment for lymphogranuloma venereum (Table 6). Cases should be reported to the health department if required by state law [4].

Table 6: TREATMENT OF LYMPHOGRANULOMA VENEREUM

Patient Population

Recommended

Alternative

General

Doxycycline 100 mg orally twice per day for 21 days

Erythromycin base 500 mg orally four times per day for 21 days OR azithromycin 1 g orally once weekly for 3 weeks

Source: [4]

Using NAAT to assess microbial cure, doxycycline (100 mg oral, twice daily for 21 days) for rectal lymphogranuloma venereum in MSM showed an average 98.5% cure rate in nine reviewed trials [91]. While doxycycline is effective for most patients, reports that abscess formation and rupture of lymphogranuloma venereum buboes have occurred during doxycycline therapy suggest that 21 days of doxycycline may be insufficient for clinical and microbial cure in more severe cases. These patients may require aspiration through intact skin or incision and drainage to prevent the formation of inguinal/femoral ulcerations [91].

Patients should be followed until signs and symptoms have resolved. All patients diagnosed with lymphogranuloma venereum should be tested for HIV, gonorrhea, and syphilis [4]. Treatment does not differ for patients with HIV, but these patients may have delayed symptom resolution and require prolonged therapy [4].

Treatment During Pregnancy

Fluoroquinolone-based treatments might be effective, but optimal treatment duration has not been evaluated. Pregnant and lactating women should be treated with erythromycin. Use of doxycycline in pregnancy might be associated with discoloration of teeth, but the risk is not well defined; doxycycline is compatible with breastfeeding. Azithromycin 1 g orally once weekly for three weeks is probably effective based on its antimicrobial activity with chlamydia, but data are lacking on its use in lymphogranuloma venereum during pregnancy [4,46].

13. BACTERIAL VAGINOSIS

Bacterial vaginosis is the most common cause of abnormal vaginal discharge in women of childbearing age. Normally, hydrogen peroxide-producing lactobacilli are the dominant vaginal bacteria and maintain vaginal pH <4.5. In bacterial vaginosis, the pH rises above 4.5, up to 6.0. Lactobacilli remain present, but flora becomes dominated by anaerobic and facultative anaerobic bacteria in concentrations up to 1,000 times greater than normal. Gardnerella vaginalis and Atopobium vagainae are critical to bacterial vaginosis etiology; other commonly found bacteria belong to Prevotella, Mobiluncus, Clostridiales, Leptotrichia, and Sneathia species and Mycoplasma hominis [99,100]. Risk factors for bacterial vaginosis include frequent vaginal douching, antibiotic use, poor hygiene, receptive oral sex, lack of condom use, multiple or a new sex partner, smoking, presence of STIs (chlamydia or herpes in particular), poorly controlled diabetes, dermatitis, and immune system disorders [101,102].

Whether bacterial vaginosis results from sexually transmitted pathogens is debated, but bacterial vaginosis places women at increased risk for complications from gynecologic surgery and pregnancy and infection with HIV, N. gonorrhoeae, C. trachomatis, and herpes simplex virus. Bacterial vaginosis increases the risk for HIV transmission to male sex partners. Bacterial vaginosis-associated bacteria can be found in the male genitalia, but treatment of male sex partners has not prevented recurrences [103,104,105].

CLINICAL FEATURES

The dominant bacterial vaginosis symptom is an unpleasant fishy smell, emitted by amines that increase vaginal pH and especially noticeable after vaginal intercourse. Examination shows a thin, white discharge coating the vaginal walls and vestibule. Bacterial vaginosis is not associated with soreness, itching, or irritation, and signs of inflammation are uncommon [101,102].

DIAGNOSIS

A bacterial vaginosis diagnosis is confirmed when at least three of Amsel clinical criteria are present [106]:

- Thin, white, homogeneous discharge smoothly coating the vaginal wall

- Clue cells (vaginal epithelial cells studded with adherent coccobacilli) on microscopy

- Vaginal fluid pH >4.5

- Release of a fishy odor from vaginal discharge by adding 10% potassium hydroxide (KOH) ("whiff test")

Gram stain determines the proportion of lactobacilli to gram-negative and gram-variable rods and cocci. The criteria are defined as follows [107]:

- Grade 1 (Normal): Lactobacillus morphotypes predominate

- Grade 2 (Intermediate): Mixed flora with lactobacilli, Gardnerella, orMobiluncus morphotypes present

- Grade 3 (Bacterial vaginosis):Gardnerella and/or Mobiluncus morphotypes predominate; few/absent lactobacilli

TREATMENT

Treatment is recommended to alleviate vaginal symptoms and signs of infection (Table 7). Treatment may also reduce risks for acquiring C. trachomatis, N. gonorrhoeae, T. vaginalis, HIV, and herpes simplex type 2 [4].

Table 7: TREATMENT OF BACTERIAL VAGINOSIS

Infection Stage

Treatment Regimen

Recommended

Alternative

Initial treatment

Any of the following:

- Metronidazole 500 mg oral twice daily for 7 days

- One full applicator (5 g) metronidazole gel 0.75% IVG daily for 5 days

- One full applicator (5 g) clindamycin cream 2% IVG at bedtime for 7 days

Any of the following:

- Tinidazole 2 g oral once daily for 2 days

- Tinidazole 1 g oral once daily for 5 days

- Clindamycin 300 mg oral twice daily for 7 days

- One clindamycin ovule 100 mg IVG at bedtime for 3 days

- Secnidazole 2 g oral granules in a single dose

First recurrence

Repeat initial treatment

—

Multiple recurrences

Either of the following:

- Metronidazole IVG gel 0.75% or 750-mg suppository twice weekly for more than 3 months

- Metronidazole or tinidazole 500 mg oral, twice per day for 7 days, followed by boric acid 600 mg IVG daily for 21 days and metronidazole gel 0.75% twice weekly for 4 to 6 months

—

Suppressive therapy

Metronidazole oral 2 g plus fluconazole 150 mg monthly

—

IVG = intravaginal.

Source: [4]

Evidence Based Practice Recommendation

The Centers for Disease Control and Prevention (CDC) recommend that patients should be advised to refrain from sexual activity or to use condoms consistently and correctly during the bacterial vaginosis treatment regimen. Douching might increase the risk for relapse, and no data support use of douching for treatment or symptom relief.

https://www.cdc.gov/std/treatment-guidelines/bv.htm

Last Accessed: October 14, 2021

Level of Evidence: Expert Opinion/Consensus Statement

Metronidazole, tinidazole, and clindamycin all show 70% to 80% cure rates at four-week follow-up. Oral metronidazole is established, well-tolerated, and inexpensive [108]. Intravaginal metronidazole gel and clindamycin cream have similar efficacy [109]. Metronidazole has a theoretical advantage of less activity against lactobacilli than clindamycin, while clindamycin is more active against most bacteria associated with bacterial vaginosis than metronidazole. Tinidazole is comparable to metronidazole in antibacterial activity and efficacy [110].

Clindamycin cream can weaken condoms and contraceptive diaphragms; do not use these products within 72 hours of treatment [102]. Advise women to refrain from sexual activity or to use condoms consistently and correctly during treatment. Douching may increase the risk for relapse and should be discouraged [4].

Intravaginal lactobacillus formulations or probiotics have not shown consistent efficacy as bacterial vaginosis treatment, and no recommendations can be made on their use. Ongoing research will determine their role in bacterial vaginosis treatment and prevention [4,102].

Persistent or Recurrent Bacterial Vaginosis

Persistent or recurrent bacterial vaginosis is common. For multiple recurrences, metronidazole gel can reduce recurrences but efficacy may be lost when discontinued [111]. A sequential approach is suggested, with daily oral metronidazole or tinidazole, followed by daily intravaginal boric acid, and then suppressive long-term metronidazole gel [112]. Suppressive therapy with monthly oral metronidazole plus oral fluconazole can reduce bacterial vaginosis incidence and promote colonization with normal vaginal flora [113]. Persons with HIV infection have greater recurrence rates of bacterial vaginosis [114].

Allergy and Intolerance

With allergy or intolerance to metronidazole or tinidazole, intravaginal clindamycin cream is preferred. Intravaginal metronidazole gel is helpful for those who lack allergy but do not tolerate oral metronidazole [4].

During Pregnancy

Treatment is recommended for all symptomatic pregnant women. Tinidazole should be avoided, but vaginal clindamycin is safe for pregnant women [115]. Treat symptomatic pregnant women with oral or vaginal metronidazole or clindamycin regimens used for nonpregnant women [116].

14. EPIDIDYMITIS

Acute epididymitis is inflammation of the epididymis with an acute onset of unilateral testicular pain and swelling, often with tenderness of the epididymis and vas deferens, and occasionally with erythema and edema of the overlying skin. Testis involvement is termed epididymo-orchitis. Sexually transmitted acute epididymitis usually is accompanied by urethritis, typically asymptomatic [117]. Clinicians should be vigilant for non-infectious testicular (spermatic cord) torsion in men who present with a sudden onset of symptoms associated with epididymitis, as this condition is a surgical emergency [117].

In sexually active men older than 35 years of age, C. trachomatis or N. gonorrhoeae infection accounts for 67% of acute epididymitis cases. Younger MSM occasionally show infection from sexually transmitted enteric organisms such as Escherichia coli. Non-sexually transmitted infectious causes of acute epididymitis are uncommon in younger patients, and management should involve urologist consultation [117].

CLINICAL FEATURES

In chronic epididymitis, symptoms of discomfort and/or pain in the scrotum, testicle, or epididymis persist for six or more weeks and are frequently associated with a granulomatous reaction. Mycobacterium tuberculosis is the most common granulomatous disease affecting the epididymis and should be suspected in men with past or recent tuberculosis exposure [118].

DIAGNOSIS

If diagnosis is questionable, consult a specialist immediately, because testicular viability may be compromised by testicular torsion [117]. Bilateral symptoms suggest non-infectious cause of testicular pain, and epididymitis should be differentiated from testicular torsion using radionuclide scanning of the scrotum. Ultrasound does not reliably distinguish partial spermatic cord torsion from epididymitis [4].

Evaluate all suspected acute epididymitis cases for objective evidence of inflammation by one of the following point-of-care tests [4]:

- Gram or methylene blue/gentian violet stain of urethral secretions

- Positive leukocyte esterase test on first-void urine

- Microscopic examination of sediment from first-void urine

Test all patients with suspected acute epididymitis for C. trachomatis and N. gonorrhoeae by NAAT [27].

TREATMENT

To prevent STI complications and transmission, presumptive therapy should be provided during the office visit before all laboratory test results are known. Presumptive treatment selection is based on risk for chlamydia, gonorrhea, and/or enteric organisms (Table 8). Treatment does not differ in men with HIV infection. Effective treatment can provide microbiologic cure, alleviate symptoms, prevent transmission of chlamydia and gonorrhea, and reduce potential chlamydial/gonorrheal epididymitis complications (e.g., infertility, chronic pain) [118,119,120].

Table 8: TREATMENT OF ACUTE EPIDIDYMITIS

Likely Cause

Recommended Treatment

Sexually transmitted chlamydia or gonorrhea

Ceftriaxone 500 mg IM in a single dose, plus doxycycline 100 mg orally twice per day for 10 days

Enteric organisms

Levofloxacin 500 mg orally daily for 10 days

Sexually transmitted chlamydia, gonorrhea, or enteric organisms in MSM

Ceftriaxone 500 mg IM in a single dose, plus levofloxacin 500 mg orally once per day for 10 days

Source: [4]

Hospitalization is required when severe pain or fever suggests torsion, testicular infarction, abscess, or necrotizing fasciitis, or when antimicrobial adherence is unlikely. High fever is uncommon and indicates a complicated infection with hospitalization needed for further evaluation [118,119,120].

Use levofloxacin or ofloxacin when infection by enteric organisms is suspected after ruling out gonorrhea, post-prostate biopsy, vasectomy, and other urinary-tract procedures. Bed rest, scrotal elevation, and NSAIDs are recommended until fever and local inflammation subside. Complete resolution of discomfort might not occur until a few weeks after completion of the antibiotic regimen [118,119,120]. Treatment of patients with a history of penicillin allergy relies on desensitization; alternative regimens have not been studied [4].

FOLLOW-UP

With acute epididymitis caused by N. gonorrhoeae or C. trachomatis, advise patients to abstain from sexual intercourse until they and their partners have been adequately treated and symptoms resolved. Instruct patients to return if swelling and tenderness fail to improve by 72 hours of treatment initiation, because re-evaluation of diagnosis and therapy is required. Alternative diagnoses include tumor, abscess, infarction, testicular cancer, tuberculosis, and fungal epididymitis [118,119,120].

Management of Sex Partners

In men diagnosed with acute sexually transmitted epididymitis from chlamydial or gonorrheal infection, all sex partners within 60 days of symptom onset should be referred for evaluation, testing, and presumptive treatment. If the last sexual contact was more than 60 days previous, the most recent sex partner should be treated. Female partners should be linked to care; arrange expedited partner therapy and enhanced referral if delay is expected [121,122].

15. RARE AND EMERGING BACTERIAL STIS

Chancroid and granuloma inguinale are bacterial STIs that are now rarely encountered in the United States. However, both could be reintroduced by an index case returning from travel to high-prevalence regions such as southeast Asia and Africa; local introduction by sex trafficking of women or men from highly prevalent regions should also be considered [123].

CHANCROID

Chancroid is an STI characterized by painful genital ulceration and inflammatory inguinal adenopathy caused by infection with Haemophilus ducreyi [1]. Chancroid has been widespread in areas of the world where STI control is inadequate, often transmitted by female sex workers with little access to care. Chancroid can only be transmitted when ulceration is present [124]. The importance of chancroid as an STI became elevated in the 1980s when its role in HIV transmission was apparent; risk of HIV transmission increases by 10- to 50-fold from sexual exposure to a person with H. ducreyi and HIV co-infection [124].

Chancroid has declined substantially in the United States, with three reported cases in 2018. The CDC states this probably reflects a decline in incidence, but considering the difficulty in culturing H. ducreyi, chancroid may also be substantially underdiagnosed [1].

Clinical Features

Following exposure, a papule develops and rapidly progresses to one or more pustular lesions, which rupture to form painful, purulent, shallow ulcers with a granulomatous base that bleeds readily. Multiple ulcers are common, particularly in women. Around 30% of patients develop painful inguinal lymphadenitis that may suppurate, become fluctuant, and spontaneously rupture. Spread beyond the genital tract is rare. Lesions tend to appear in the following sites [124]:

- Men: The prepuce, coronal sulcus, and shaft of the penis

- Women: The external genitalia, rarely in the vagina or on the cervix

Diagnosis

Diagnosis should first rule out other causes of genital ulcer disease. Definitive diagnosis of chancroid requires identification of H. ducreyi on special culture media not widely available from commercial sources. Painful genital ulcer with tender suppurative inguinal adenopathy suggests a diagnosis of chancroid [123,125]. Probable diagnosis of chancroid can be made if all four of the following criteria are met:

- One or more painful genital ulcers

- The clinical presentation

- Dark-field or serologic examination, at least seven days after ulcer onset, negative forT. pallidum or syphilis

- PCR or culture test of ulcer exudate negative for herpes simplex virus

Treatment

Successful chancroid treatment cures the infection, resolves clinical symptoms, and prevents transmission. Advanced chancroid can result in scarring despite successful therapy. Ciprofloxacin has a cure rate of more than 90%, and azithromycin or ceftriaxone have advantages as single-dose therapy (Table 9). Chancroid culture is not routinely performed, which limits the information available on the current prevalence of antimicrobial resistance in the United States [4,126,127].

Table 9: TREATMENT OF CHANCROID INFECTIONS

Any of the following:

- Azithromycin 1 g oral, single-dose

- Ceftriaxone 250 mg IM, single-dose

- Ciprofloxacin 500 mg oral, twice daily for three days

- Erythromycin base 500 mg oral, three times per day for seven days

Source: [4]

Uncircumcised men and patients with HIV are less responsive to treatment than circumcised or HIV-negative patients, and HIV testing should be performed when chancroid is diagnosed. Patients should be tested for HIV at the time chancroid is diagnosed. If the initial HIV test results were negative, the provider can consider the benefits of offering more frequent testing and HIV prophylaxis therapy to persons at increased risk for HIV infection [4].

Treatment During Pregnancy

Ciprofloxacin has low risk to the fetus during pregnancy but is potentially toxic during breastfeeding; alternate drugs should be used during pregnancy and lactation [46]. No adverse effects on pregnancy outcomes from chancroid have been reported [4].

Follow-Up

Re-examine patients three to seven days after starting therapy. Ulcer symptoms usually improve by three days and objectively by seven days after successful therapy. Without improvement, clinicians should consider differential diagnosis, patient co-infection with another STI or HIV, treatment non-adherence, or an antimicrobial-resistant strain of H. ducreyi. Time to complete healing depends on ulcer size and location; large ulcers can require more than two weeks, and healing is slower in uncircumcised men with ulcers under the foreskin [4]. Patients with fluctuant buboes will experience symptomatic relief from drainage by needle aspiration, which may need to be repeated [123].

Management of Sex Partners

Even with symptom absence, sex partners should be examined and treated if they had sexual contact with the patients with chancroid in the 10 days preceding symptom onset [4].

GRANULOMA INGUINALE (DONOVANOSIS)

Granuloma inguinale is a rare, progressive infection of genital and perineal skin caused by Klebsiella (formerly Calymmatobacterium) granulomatis, a gram-negative bacterium. The disease is rare in the United States, but endemic in some tropical and developing regions such as India, New Guinea, the Caribbean, central Australia, and southern Africa [128].

Clinical Features

Granuloma inguinale is characterized by slowly progressive, painless, red, raised, and ulcerated skin lesions. Regional lymphadenopathy is uncommon. Common sites of infection include [128,129]:

- Penis, scrotum, groin, and thighs in men

- Vulva, vagina, and perineum in women

- Anus and buttocks in patients who engage in anal-receptive intercourse

- Face in both sexes

Following a 1- to 12-week incubation, the nodule slowly enlarges, becoming a raised, beefy-red, moist, smooth, foul-smelling lesion. The lesion slowly enlarges, often ulcerates, and may spread to other skin areas. Lesions heal slowly, with scarring. Secondary infections with other bacteria are common and can cause extensive tissue destruction. Occasionally, granuloma inguinale becomes systemic and spreads to the bones, joints, or liver; without treatment, anemia, wasting, and uncommonly death may occur [129,130].

Diagnosis

Granuloma inguinale is suspected in patients with travel history from endemic areas with characteristic lesions. Diagnosis is confirmed microscopically by the presence of dark-staining Donovan bodies on tissue crush preparation of fluid from scrapings from the edge of lesions. Biopsy specimens are taken if the diagnosis is unclear or if adequate tissue fluid cannot be obtained because lesions are dry, sclerotic, or necrotic. The bacteria do not grow on ordinary culture media [128,130].

Treatment

A limited number of studies suggest several antimicrobial regimens are effective for the treatment of granuloma inguinale (Table 10) [129]. Treatment can halt the progression of lesions. Healing typically proceeds inward from the ulcer margins, and prolonged therapy is usually required to permit granulation and re-epithelialization of ulcers. Relapse can occur 6 to 18 months after an apparently curative therapy response [4]. All patients should be followed until signs and symptoms have resolved.

Table 10: TREATMENT OF GRANULOMA INGUINALEa

Recommended Regimen

Alternative Regimens

Azithromycin 1 g oral once weekly or 500 mg daily

Any of the following:

- Doxycycline 100 mg oral twice daily

- Erythromycin base 500 mg oral four times per day

- One double-strength trimethoprim-sulfamethoxazole (160 mg/800 mg) tablet oral twice daily

aAll regimens should continue for at least three weeks or until complete healing of all lesions.

Source: [4]

MYCOPLASMA GENITALIUM

First identified in the early 1980s, Mycoplasma genitalium causes nongonococcal urethritis in men. It is detected in 10% to 30% of men presenting with nonchlamydial nongonococcal urethritis and up to 40% with chronic nongonococcal urethritis [131]. The recent emergence and spread of M. genitalium is concerning, because penicillins, cephalosporins, and other beta-lactam antibiotics are ineffective against this organism; beta-lactams kill bacteria by disrupting cell-wall biosynthesis, and M. genitalium lacks a cell wall [132]. The efficacy of oral single-dose azithromycin 1 g (the common first-line treatment of urogenital M. genitalium) has decreased to approach 60% [131].

With the recency of concern over M. genitalium, little data have been accrued on the long-term clinical consequences of infection. M. genitalium presence in men is associated with a 5.5-fold increased risk of nongonococcal urethritis. In women, M. genitalium has been linked to cervicitis, endometritis, PID, infertility, HIV, and adverse birth outcomes. The prevalence of M. genitalium in the United States among women is around 1%, compared with N. gonorrhoeae (0.4%) and C. trachomatis (3%). In contrast to previous contradictory findings associating M. genitalium and female genital tract pathology, more recent studies have confirmed this association. For example, 33% to 50% of PID cases are associated with N. gonorrhoeae and/or C. trachomatis, but many cases have unidentified etiology. Advances in detecting M. genitalium by NAAT are raising concerns that M. genitalium may play an important pathogenic role in cases in which other STIs are not identified. This issue is further complicated by several studies identifying M. genitalium treatment resistance among infected women [133].

Diagnosis

Mycoplasma genitalium is a slow-growing organism. Culture can take up to six months, and few laboratories are able to recover clinical isolates. NAAT is the preferred method for M. genitalium detection. More recently available is a diagnostic test using analyte-specific reagents to target M. genitalium. Any lab that performs in-house validation of the assay can use it for M. genitalium testing [134].

Treatment

The recommended treatment is moxifloxacin 400 mg/day for 14 days, after syndromic treatment failure of urethritis, cervicitis, or PID. Doxycycline is recommended for urethritis, but is largely ineffective against M. genitalium. One-gram single-dose azithromycin is significantly more effective against M. genitalium than doxycycline, but azithromycin resistance is rapidly emerging and patients with azithromycin non-response usually do not benefit from retreatment [134].

Fluoroquinolones other than moxifloxacin are not recommended for the treatment of M. genitalium. Microbiologic treatment failure (persistent bacterial detection) ranges from 30% to 67% after levofloxacin and 66% after ofloxacin. In contrast, cure rates for moxifloxacin range from 70% to 100%. The fourth-generation quinolones gatifloxacin and sitafloxacin have somewhat better efficacy against M. genitalium than levofloxacin and ofloxacin but are not available in the United States. However, treatment failures have been reported for both the 7- and 10-day moxifloxacin regimens, with few studies evaluating longer duration of treatment [134].

16. GENERAL MANAGEMENT ISSUES

ANTIMICROBIAL RESISTANCE

Antibiotic-resistant STIs have become a highly concerning issue at both the patient and public health level. The greatest immediate concern is gonorrhea.

Gonorrhea

Over the years, gonorrhea has developed resistance to nearly every drug used to treat it, including sulfonamides, penicillin, tetracycline, and fluoroquinolones. Due to widespread resistance to these antibiotics, by 2007, only cephalosporins—including the oral antibiotic cefixime and the injectable antibiotic ceftriaxone—were left to effectively treat gonorrhea [28,58].

In 1986, the Gonococcal Isolate Surveillance Project (GISP) was initiated by the CDC to closely monitor how N. gonorrhoeae responds to antibiotics. These data are the early warning signs of resistance to recommended treatments. The marker for antibiotic response is the MIC, the lowest concentration of drug needed to stop bacterial growth and an indicator of susceptibility to treatment with a given antibiotic. An increase in MIC over time means greater antibiotic dose levels are required for effective treatment and that resistant strains have appeared and propagated [4,28,58].

The epidemiology of antimicrobial resistance has guided decisions about gonococcal treatment recommendations, which have evolved to circumvent changing antimicrobial resistance patterns [4,28,58]:

- 1930s: Introduction of sulfonamide antimicrobials to treat gonococcal infection.

- 1940s: Due to increasing resistance, sulfonamides no longer recommended for gonococcal treatment; penicillin becomes treatment of choice.

- 1980s: Due to increasing resistance, penicillin and tetracycline no longer recommended to treat gonococcal infection.

- 1990s: Fluoroquinolones become predominant treatment.

- 2007: Fluoroquinolones no longer recommended with emergence of resistantN. gonorrhoeae; cephalosporins (injectable ceftriaxone, oral cefixime) are the only remaining effective antimicrobial class for gonococcal treatment.

- 2012: During 2006–2011, the increasing MIC of cefixime suggested waning effectiveness. Treatment failures with cefixime or other oral cephalosporins were reported in several countries and regions outside the United States. Gonococcal strains with elevated MICs to cefixime were susceptible to azithromycin, and only one regimen, dual treatment with ceftriaxone IM and azithromycin, became recommended for treatment of gonorrhea in the United States.

- 2016: Ceftriaxone IM plus azithromycin remains the only recommended treatment for gonococcal infection.

In 2012, evidence of emerging cefixime resistance led the CDC to issue new guidelines recommending against the use of cefixime in gonorrhea treatment. This change helped slow the emergence of cephalosporin resistance, but the only remaining recommended treatment option for gonorrheal infection is ceftriaxone IM combined with oral azithromycin [28,58].

This regimen continues to be generally effective, but CDC data indicate that resistance to azithromycin is emerging. During 2013–2014, the percentage of gonorrhea samples with elevated MICs of azithromycin increased by more than 300% (from 0.6% to 2.5%), the largest increase since azithromycin monitoring began. Gonorrhea remains more susceptible to azithromycin than other antibiotics such as penicillin (16.2% with elevated MICs in 2014) or tetracycline (25.3% with elevated MICs in 2014). Azithromycin with ceftriaxone remains effective against gonorrhea, but the data suggest time may be running out [28,58,146].

Syphilis

Azithromycin has shown efficacy in the treatment of primary and secondary syphilis. However, T. pallidum chromosomal mutations associated with azithromycin resistance and treatment failures have been documented in multiple geographic areas in the United States. Concerns over emerging azithromycin resistance have discouraged its prescribing in STIs other than gonorrhea, except when recommended treatment options are not feasible [4].

FLUOROQUINOLONE ADVERSE EFFECTS

In 2016, the FDA approved labeling changes to systemic fluoroquinolone antibacterial drugs. These drugs became associated with disabling and potentially permanent side effects involving the tendons, muscles, joints, nerves, and CNS. The revised boxed warning—FDA's strongest warning—addresses these serious safety issues. A new warning and update for the patient medication guide was also added [135]. FDA-approved fluoroquinolones include moxifloxacin (Avelox), ciprofloxacin (Cipro), gemifloxacin (Factive), levofloxacin (Levaquin), and ofloxacin.

Fluoroquinolone labels already had a boxed warning for tendinitis, tendon rupture, and worsening of myasthenia gravis, and warnings about risks of peripheral neuropathy, CNS effects, cardiac, dermatologic, and hypersensitivity reactions. In 2013, the FDA added that peripheral neuropathy may be irreversible. Post-marketing reports were submitted to FDA of apparently healthy patients who experienced disabling and potentially permanent side effects involving two or more body systems within hours to weeks after starting the fluoroquinolone, continuing an average of 14 months to as long as nine years after stopping [135].

PENICILLIN ALLERGY

Penicillin is the foundation of antimicrobial treatment for syphilis infection, but some patients have histories of penicillin allergy. The estimated prevalence of penicillin allergy in the United States is 8% to 10%; this may be higher in hospitalized patients [136,137]. Penicillin allergy imposes a therapeutic quandary, because 10% to 15% of these patients are at risk for an IgE-mediated allergic response to penicillin, with anaphylaxis, bronchospasm, urticaria, or angioedema. Anaphylactic reactions to penicillin can be fatal, and penicillin should be avoided in these patient unless they undergo induction of drug tolerance, termed "desensitization," to temporarily eliminate IgE-mediated hypersensitivity [65,138,139,140].

Many patients with a reported history of penicillin allergy have other types of adverse drug reactions or lose their penicillin sensitivity over time, and in these cases, penicillin can be safely used. Penicillin skin testing with the major and minor determinants of penicillin reliably identifies patients at high risk for IgE-mediated reactions to penicillin [139,141]. Many tests have used the major determinants only, but without minor determinants, 1% to 10% of patients with true allergy will show false-negative results and risk serious or fatal reactions to penicillin. Patients with a history of severe non-IgE-mediated reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, hemolytic anemia) are not candidates for skin testing or challenge and should avoid penicillins indefinitely [141,142,143].

Cephalosporin cross-reactivity is another concern with penicillin allergy. Patients with IgE-mediated penicillin allergy history have a 2.5% risk of allergic reaction to first-generation cephalosporins, but negligible risk with most second-generation (cefoxitin) and all third-generation (ceftriaxone) cephalosporins [64,66].

Desensitization

Patients showing a positive skin test to one of the penicillin determinants should be desensitized to penicillin. This straightforward, relatively safe procedure is performed orally or IV, with oral desensitization safer and easier to perform. Desensitization should take place in a hospital so serious IgE-mediated allergic reactions, which may occur, are rapidly treated. After the procedure is completed, the first penicillin dose is administered. Following desensitization, penicillin should be maintained continuously for the prescribed duration of the therapy course. After the course is completed, the desensitization procedure should be repeated if penicillin is required in the future [144,145].

17. CONCLUSION

Described as hidden epidemics of substantial health and economic consequence, many Americans are reluctant to address STIs because of the biologic and social characteristics of these diseases and associated stigma. However, all communities in the United States are impacted by bacterial STIs. With rising concerns regarding antibiotic resistance and the development of "super strains" of these diseases, identification and appropriate treatment of bacterial STIs is of critical importance. Clinicians have an opportunity to identify patients at risk for bacterial STIs and intervene early in order to limit transmission and debilitating effects of the diseases.

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Evidence-Based Practice Recommendations Citations

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