Rheumatoid Arthritis

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Self-Assessment Questions

    1 . Regarding rheumatoid arthritis (RA), the incidence
    A) is higher in men.
    B) decreases with age.
    C) is equal in men and women.
    D) is approximately 53 per 100,000 for women annually, and about half that for men.

    EPIDEMIOLOGY AND COSTS

    An estimated 1.5 million American adults are affected by RA [1]. The yearly incidence of RA is approximately 53 per 100,000 for women and about half that (27.7 per 100,000) for men [1]. These figures vary significantly based on the age of the cohort. The data show that the incidence of RA increases steadily with age in both sexes, until approximately 65 to 74 years of age, when incidence peaks [1]. However, women in all age groups have a much higher incidence compared with men.

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    2 . Which of the following statements related to comorbid conditions and arthritis is TRUE?
    A) There is no correlation with increased depression rates and RA.
    B) One-fifth of the premature deaths in patients with RA are due to increased cardiovascular disease.
    C) The risk of developing RA is nearly double for current smokers compared with nonsmokers.
    D) Studies have found similar mortality rates in patients with RA as compared with the general population.

    EPIDEMIOLOGY AND COSTS

    Overall, RA and related arthritic diseases have a significant impact in the United States, causing disability and premature mortality. Although many people with RA work full-time, about 10% of those with RA 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 [4]. RA can shorten a patient's life expectancy by an average of three to seven years. However, individuals with severe forms of RA may die 10 to 15 years earlier than expected [4]. In general, people with RA have a shorter life expectancy, reduced by as much as 10 to 15 years compared with people without RA [5].

    There are significant costs associated with RA, and these arthritic-related disease costs continue to increase. In 2013 (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 [6]. Medical expenditures (direct costs) for arthritis and other rheumatic conditions in 2013 were $140 billion, up from $80.8 billion in 2003 [6]. Earnings losses (indirect costs) for arthritis and other rheumatic conditions in 2013 were $164 billion, up from $47 billion in 2003 [6]. Individuals with RA 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 [3].

    Research shows that the risk of developing RA is nearly double for current smokers compared with nonsmokers [7]. RA is strongly associated with major depression (attributable risk of 18.1%), probably through its role in creating functional limitation [8]. As discussed, most mortality studies in patients with RA have found increased mortality rates as compared with the general population, with studies showing one-third to one-half of the premature deaths in patients with RA are due to cardiovascular conditions such as ischemic heart disease and cerebrovascular accidents [4,9]. It is unclear whether cardiovascular disease results from RA or if it precedes the onset [3].

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    3 . Which of the following is TRUE about the etiology of RA?
    A) It is likely an autoimmune disease.
    B) It is believed that infectious, genetic, and hormonal factors may be contributing factors.
    C) If one monozygotic twin has RA, there is a 1 in 2 chance that the other twin will develop the same disease.
    D) Both A and B

    ETIOLOGY

    As noted, RA is defined as a chronic inflammatory disease characterized by uncontrolled proliferation of synovial tissue and a wide array of multisystem comorbidities[10]. In its most common presentation, RA affects the joints, causing inflammation of the synovium and cartilage and bone loss (Figure 1). The precise etiology of RA is presently unknown[11]. Most likely it has an autoimmune origin (whereby an individual's immune system confuses healthy synovial tissue for foreign substances, thereby attacking the synovial joint surfaces) given that autoantibodies (e.g., rheumatoid factor, anti-citrullinated protein antibody [ACPA]) are present and often precede the clinical manifestation of RA by many years [7; 12; 13].

    The course and severity of the illness can vary considerably, and infection, genetic factors, and hormones may contribute to the disease. RA appears to require the complex interaction of genetic and environmental factors with the immune system and ultimately in the synovial tissues throughout the body. Triggers for RA have long been the target of active research. Purported triggers have included bacteria (Mycobacterium, Streptococcus, Mycoplasma, Escherichia coli, Helicobacter pylori), viruses (rubella, Epstein-Barr virus, parvovirus), and superantigens [7,11,14].

    Although RA has a clear genetic component, only about 1 in 25 white individuals with the so-called shared epitope develop RA [14]. Even if one monozygotic twin has RA, there is only approximately a one in six chance that the other twin will develop the same disease. Thus, other factors in addition to genetics are active as precipitators or triggers of RA [14].

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    4 . In the classic symptomatic presentation of rheumatoid arthritis,
    A) joint pain is most often localized to one region.
    B) joint stiffness is most prominent in the evening.
    C) there is decreased muscle strength and range of motion in joints.
    D) physical exam most often shows a markedly elevated body temperature.

    SIGNS, SYMPTOMS, AND DIAGNOSIS

    The history and physical examination are the most sensitive and specific tools for RA diagnosis. Findings on general physical examination are normal except for an occasional low-grade fever (38°C) and a slightly elevated pulse rate. The characteristic patient with RA initially presents with complaints of pain and stiffness in multiple joints. There is prominent and prolonged morning stiffness (lasting more than one hour) that usually begins gradually with fatigue, loss of appetite, widespread muscle aches, and weakness [4,7,14].

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    5 . Which laboratory finding is NOT often seen in patients with RA?
    A) Thrombocytosis
    B) Normocyctic normochromic anemia
    C) C-reactive protein level <0.5 pg/mL
    D) Anti-cyclic citrullinated peptide (anti-CCP) antibody

    SIGNS, SYMPTOMS, AND DIAGNOSIS

    The 2010 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) joint working group recommends several laboratory tests for the diagnosis of RA, including rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and anti-cyclic citrullinated peptide (anti-CCP) antibody [13]. A positive rheumatoid factor is the most specific and sensitive laboratory marker of RA, as it is seen in about 70% to 80% of patients [4,10,14]. It is also present in many healthy individuals, patients with other rheumatic diseases, and individuals with chronic infections [11]. ESR is typically ≥30 mm/hour, and CRP level is typically ≥0.7 pg/mL. Both levels are associated with disease activity, and the CRP value over time correlates with radiographic progression [10,11,15]. The anti-CCP antibody test is a specific blood test available for diagnosing RA and distinguishing it from other types of arthritis [10,14]. The anti-CCP antibody test is a marker of ACPA and is positive in about 80% to 90% of patients; it can also be present in other diseases, including active tuberculosis, and is especially useful in early synovitis. While RA differs from person to person, individuals with rheumatoid factor, the anti-CCP antibody, or subcutaneous nodules tend to have more severe forms of the disease [10,11,14].

    As noted, RA is a clinical diagnosis [16]. To date, biomarkers for the initial tissue processes that cause joint damage in RA lack prognostic accuracy and are therefore inadequate as stand-alone tests, but they can help to rule out other causes of arthritis when a patient has clinical features of RA [17]. In 2010, a multi-biomarker disease activity test, Vectra DA, was introduced. This test uses a unique algorithm to derive a composite score (1 to 100) based on the results of 12 blood protein biomarkers, including vascular cell adhesion molecule-1, epidermal growth factor, vascular endothelial growth factor A, interleukin-6 (IL-6), tumor necrosis factor (TNF) receptor type 1, matrix metalloproteinase-1 or collagenase-1, matrix metalloproteinase-3 or stromelysin-1, YKL-40, leptin, resistin, serum amyloid, and CRP [18,19]. Vectra DA has been independently verified and found to correlate well to disease activity measured with RA assessment tools (e.g., Disease Activity Score in 28 joints using the CRP level). The test is validated for use in adults already diagnosed with RA but is not intended to diagnose RA [20].

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    6 . Which statement is TRUE regarding the differential diagnosis of RA?
    A) Chronic tophaceous gout rarely mimics severe nodular RA.
    B) Sarcoidosis is not a condition that should be considered in the differential diagnosis.
    C) Systemic lupus erythematosus, psoriatic arthritis, and reactive arthritis should be considered in both early and late RA.
    D) In later disease, self-limited viral syndromes such as hepatitis B and C, parvovirus, rubella, and Epstein-Barr virus should be considered.

    SIGNS, SYMPTOMS, AND DIAGNOSIS

    A number of different medical conditions may be considered in the differential diagnosis of RA (Table 1) [16,28,29,30]. These include:

    • Connective tissue diseases (e.g., lupus, scleroderma, polymyositis)

    • Fibromyalgia

    • Hemochromatosis

    • Infectious endocarditis

    • Lyme arthritis

    • Osteoarthritis

    • Polyarticular sepsis

    • Sarcoidosis

    • Thyroid disease

    • Viral arthritis

    Early in the course of RA, self-limited viral syndromes should be considered, especially hepatitis B and C, parvovirus, rubella (infection or vaccination), and Epstein-Barr virus [28,29,30]. At any time, systemic lupus erythematosus, psoriatic arthritis, and reactive arthritis may present diagnostic challenges. This requires a targeted history and examination to elucidate associated clinical symptoms, such as rashes, oral ulcers, nail changes, dactylitis, urethritis, and renal, pulmonary, gastrointestinal, or ophthalmologic complications [4,28]. Remitting rheumatoid factor-negative symmetrical synovitis with pitting edema and paraneoplastic syndromes should be considered in elderly patients with fulminant-onset RA [29]. Chronic tophaceous gout may also mimic severe nodular RA. Hypothyroidism not only causes many rheumatic manifestations but also occurs commonly in conjunction with RA and, therefore, should be kept in mind [29].

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    7 . Which of the following most correctly describes the classification of RA?
    A) Arthritis should affect at least two joints.
    B) At least one of the swollen joints should be in the large joints.
    C) A duration of symptoms of seven weeks is scored as 1 point.
    D) According to the American College of Rheumatology (ACR) scale, there are 10 criteria for classification.

    CLASSIFICATION

    2010 AMERICAN COLLEGE OF RHEUMATOLOGY/EUROPEAN LEAGUE AGAINST RHEUMATISM CLASSIFICATION CRITERIA FOR RHEUMATOID ARTHRITISa

    CriteriaScore
    Joint Involvement
    1 large jointb0
    2–10 large joints1
    1–3 small jointsc (with or without involvement of large joints)2
    4–10 small joints (with or without involvement of large joints)3
    >10 joints (at least 1 small joint)5
    Serology (at least 1 test result needed for classification)
    Negative RF and negative ACPA0
    Low-positive RF or low-positive ACPA2
    High-positive RF or high-positive ACPA3
    Acute-Phase Reactants (at least 1 test result needed for classification)
    Normal CRP and normal ESR0
    Abnormal CRP and abnormal ESR1
    Duration of Symptoms
    Less than 6 weeks0
    6 or more weeks1
    a Target population: patients who have at least 1 joint with definite clinical synovitis in whom the synovitis is not better explained by another disease.
    b Large joints include shoulders, elbows, hips, knees, and ankles.
    c Small joints refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.
    RF = rheumatoid factor; ACPA = anti-citrullinated protein antibody; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate.
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    8 . Regarding the classification of patients with RA,
    A) probable RA is clearly defined.
    B) a patient can be designated as having classic RA.
    C) a patient with Class I disease is limited in his/her ability to perform usual self-care activities.
    D) a patient is said to have RA if he/she scores at least 6 points in the established classification criteria.

    CLASSIFICATION

    For classification purposes, a patient has definite RA if they score at least 6 points in the established classification system. There is no designation as classic or probable RA [13]. The ACR has also developed the global functional status report [31,32]:

    • Class I: Completely able to perform usual activities of daily living (self-care, vocational, and avocational)

    • Class II: Able to perform usual self-care and vocational activities, but limited in avocational activities

    • Class III: Able to perform usual self-care activities, but limited in vocational and avocational activities

    • Class IV: Limited in ability to perform usual self-care, vocational, and avocational activities

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    9 . Which of the following best describes the treatment of RA?
    A) RA does not require lifelong treatment.
    B) RA is a curable disease that can be treated with a set pharmaceutical regimen.
    C) Patients with suspected RA should be referred within one month of presentation.
    D) The earlier a patient's rheumatoid arthritis disease is diagnosed, the earlier aggressive treatment for RA can be started, thereby delaying joint destruction.

    TREATMENT

    RA has no known prevention or cure. Lifelong treatment is usually required, including medication, physical therapy, exercise, and possibly surgery. In order to provide the best outcomes, patients should be educated regarding the most appropriate treatment regimens for their disease manifestations, as earlier RA diagnosis can assist in aggressive early treatment for RA (when indicated), thereby delaying joint destruction. The 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis is now a well-established diagnostic and prognostic tool; as such, guidelines (e.g., the 2016 update of the EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-Modifying Antirheumatic Drugs and the 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis) recommend that patients start treatment with a disease-modifying antirheumatic drug (DMARD) immediately following a RA diagnosis [33,197]. Therapeutic goals include preservation of function and quality of life, minimization of pain and inflammation, joint protection, and control of systemic complications, with the ultimate aim being low disease activity or remission [4,10,14,33,34,197].

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    10 . Which of the following is recommended as the modern standard for RA treatment?
    A) Treat-to-target
    B) Watch and wait
    C) Pyramid approach
    D) Symptom alleviation

    TREATMENT

    Today, the recommended standard of treatment 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) [33,36]. The "treat-to-target" approach for a patient with early high disease activity and poor prognostic features typically involves initiation of methotrexate and/or another DMARD(s) immediately upon diagnosis [33,34,36]. Initial combination therapies with DMARDs, particularly those including a biologic anti-TNF agent, appear to provide earlier clinical improvement and less joint damage progression in patients with early moderate or highly active disease; they can be withdrawn successfully, and fewer treatment adjustments are needed than with initial monotherapies [33,36,37,38,39]. 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) [33,36]. Patients with low-to-moderate disease activity or high disease activity without poor prognostic features are typically started on DMARD monotherapy.

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    11 . What factor should determine the choice of DMARD therapy?
    A) Disease severity
    B) Patient compliance
    C) Presence of various comorbidities
    D) All of the above

    TREATMENT

    DMARDs are the current standard of pharmaceutical care for RA, and their choice for a patient should be determined by several factors, including patient compliance, disease severity, physician experience, and the presence of various comorbidities. Table 3 provides a list of the most commonly used DMARDs and their most common adverse effects [37,38,39,197].

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    12 . Which of the following is NOT considered common DMARD therapy?
    A) Leflunomide
    B) Azathioprine
    C) Sulfasalazine
    D) Methotrexate

    TREATMENT

    Methotrexate is the most commonly prescribed DMARD and is still considered the "anchor drug" for the treatment of RA [33,42,197]. 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; methotrexate is still the preferred initial DMARD due to its utility as an anchor in combination regimens, its lower cost, and its greater dosing flexibility [10,33,43,44,197]. Patients who have failed monotherapy with methotrexate may benefit from the addition of leflunomide, either with methotrexate or other DMARDs [33,36,44]. Other commonly prescribed DMARD medications include hydroxychloroquine, minocycline, and sulfasalazine; the anti-TNF biologic agents adalimumab, etanercept, infliximab, certolizumab pegol, and golimumab; and the non-TNF biologic agents abatacept, anakinra, rituximab, and tocilizumab [42]. Sulfasalazine and hydroxychloroquine are anti-malarial medications that are often prescribed as first-line therapy. However, the treatment effects of the anti-malarial medications may take weeks or months in order to be effective [39,45]. In more severe cases (i.e., moderate or high disease activity and poor prognostic features), combination therapy with two or three DMARDs is used as immediate first-line treatment [33,39,45,197].

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    13 . Which of the following is TRUE about biologic DMARD therapy?
    A) Adalimumab is a surface antibody on B cells.
    B) Rituximab is given as an oral monthly medication.
    C) Tumor necrosis factor (TNF) inhibitors are generally only used if non-TNF agents fail to control disease.
    D) TNF inhibitors block a protein in the body involved in producing inflammation.

    TREATMENT

    Biologic agents (anti-TNF and non-TNF) have been used since 1998 and are now a well-established form of DMARD therapy [42]. Non-TNF agents are generally only used if TNF-alpha inhibitors fail to control disease or if they are contraindicated [33,197]. The TNF-alpha inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol, and golimumab) block the proteins responsible for the inflammation process and are given subcutaneously or intravenously, thereby lowering TNF-alpha levels, which are elevated in the synovial fluid in patients with RA [4,10,14,36]. Treatment with anti-TNF therapies also significantly improves the anemia associated with RA [39,46,47]. Etanercept is a soluble TNF-alpha-receptor fusion protein, with some studies showing comparable long-term treatment effects to methotrexate [10,48]. However, etanercept elicits more rapid symptom improvement, often within two weeks [39]. A systematic review found that etanercept plus methotrexate was more efficacious than either drug alone and that the combination slowed joint radiographic progression after up to three years of treatment [49]. Infliximab is another anti-TNF-alpha antibody that has shown greater response than placebo (52% versus 17%) in patients who had a poor response to methotrexate [50,51]. Results from one controlled trial found that infliximab plus methotrexate produced a significant reduction in MRI evidence of synovitis and erosions at one year, and at two years, functional and quality of life benefits were sustained, despite withdrawal of infliximab [52]. Adalimumab, a recombinant TNF-alpha antibody, has an additive effect when taken with methotrexate [53].

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    14 . In regards to the use of anti-inflammatory medications for RA,
    A) they are adequate therapy to use alone as they alter the disease course.
    B) symptoms will not recur when steroids are abruptly withdrawn as therapy.
    C) cyclooxygenase-2 inhibitors must be used with caution due to potential adverse effects.
    D) the maximum effective steroid dosages should be used because of the high risk of side effects, such as osteoporosis, cataracts, Cushingoid symptoms, and blood glucose level elevation.

    TREATMENT

    NSAIDs, glucocorticoids, or cyclooxygenase-2 (COX-2) inhibitors are often used concurrently to treat RA-associated joint pain and inflammation. However, they do not alter the disease course and should not be used as single therapy.

    Potential side effects are a consideration with these medications as well. Patients taking NSAIDs should be monitored for long-term NSAID-associated complications such as gastrointestinal bleeding, cardiovascular problems (e.g., myocardial infarction, stroke), and gastric ulcers and bleeding. COX-2 inhibitors block an inflammation-promoting enzyme called cyclooxygenase; this drug class was initially believed to work as well as traditional NSAIDs, but with fewer stomach problems. However, myocardial infarction and stroke reports have prompted the FDA to re-evaluate the risks and benefits of the COX-2 inhibitors. 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 [41].

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    15 . Which of the following is TRUE about nonpharmacologic treatments for RA?
    A) The most successful surgery occurs in the hands.
    B) Range of motion exercises are generally not useful.
    C) Surgeries cannot relieve joint pain, correct deformities, or improve joint function.
    D) Special devices may be used to apply deep heat or electrical stimulation to reduce pain and improve joint mobility.

    TREATMENT

    Occasionally, surgery is needed to correct severely affected joints. Surgeries serve to relieve joint pain, correct deformities, and modestly improve joint function [4,10,14]. The most successful locations of surgery are those performed on the knees and hips [4,10,14]. The first surgical treatment performed is a synovectomy, which removes part or all of the joint lining (synovium). This procedure may only provide temporary relief, but it can be effective for patients for whom pharmacologic treatment has not resulted in improvements. Surgeries performed in later-onset disease include total joint replacement with a joint prosthesis. In extreme cases, total knee or hip replacement can have enhanced importance, making the difference between a dependent or independent lifestyle for a patient.

    There are a significant number of total joint replacements performed each year in the United States, and the procedures are considered relatively safe and effective. However, some patients will experience prosthesis failure. Risk factors for failure include male gender, age younger than 55 years at the time of surgery, obesity, and the presence of comorbidities. In terms of factors related to the surgeon, greater procedure volume (both of the surgeon and the facility), prosthesis choice, and surgical technique (e.g., proper alignment of the prosthesis) all contribute to better patient outcomes [76]. It is important to note that both knee and hip replacement are associated with a high risk of deep vein thrombosis (DVT) and pulmonary embolism compared with other surgeries. Without prophylaxis, DVT will develop in most patients [77]. Therefore, prophylactic treatment, usually with either low-molecular-weight heparin or warfarin, is recommended for patients undergoing one of these procedures, unless contraindications are present. In general, total joint replacement is reserved for patients for whom other treatments have been ineffective.

    Range-of-motion exercises and individualized exercise programs prescribed by a physical therapist can also delay the loss of joint function. Joint protection techniques, heat and cold treatments, and splints or orthotic devices to support and align joints may be of assistance [4,10,14]. Some therapists will use specialized devices to apply deep heat or electrical stimulation to reduce pain and improve joint mobility [4,10,14]. Occupational therapists can construct splints for the hand and wrist and teach patients with RA how to protect and use their joints most effectively. In addition to physiotherapy, occupational therapists can also show patients with RA how to better cope with limitations that can affect their daily tasks at work and at home. For example, many clinicians have recommended frequent rest periods between activities and proper sleeping habits (e.g., 8 to 10 hours of sleep per night) [78].

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    16 . Which of the following complementary/ alternative therapies has a proven and powerful action in reducing RA symptoms?
    A) Yoga
    B) Fish oil
    C) Biofeedback
    D) Thunder god vine extract

    TREATMENT

    One food-sourced supplement, fish oil, is a proven, powerful RA 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 RA [91]. A 2015 randomized controlled trial examined the effects of high versus low doses of fish oil in early RA by employing a treat-to-target protocol of combination DMARDs [92]. DMARD-naïve patients with RA of less than 12 months' duration were randomized to either fish oil at high dose (5.5 g/day) or low dose (0.4 g/day), considered the control. All patients received methotrexate, sulfasalazine, and hydroxychloroquine, with doses adjusted to account for disease activity and toxicity. Reported results included lower failure of triple DMARD therapy and significantly greater remission in the high-dose group compared with the control group, with no differences in dose of methotrexate, health assessment results, or adverse events [92].

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    17 . Which of the following is a characteristic of RA-associated pericarditis?
    A) Diagnosis confirmed by angiogram
    B) Chest x-ray to confirm the condition
    C) At least four objective criteria to confirm the condition
    D) Peripheral edema, dyspnea/orthopnea, ascites, or dysrhythmia

    EXTRA-ARTICULAR MANIFESTATIONS

    EXTRA-ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITIS

    ConditionDiagnostic Criteria
    Pericarditis
    Clinical judgment and exudation verified by echocardiography. If not available, use following clinical criteria (at least one required):
    Typical pericardial pain, peripheral edema, dyspnea/orthopnea, ascites, dysrhythmia (heart rate 140 beats/min, atrial flutter/fibrillation, 2–3 degree atrioventricular block, ventricular tachycardia)
    Objective criteria compatible with pericarditis on physical examination, cardiac catheterization results, or histologic examination
    Other causes unlikely (e.g., tuberculosis or other infection, metastases, primary tumor, postoperative status, other trauma)
    PleuritisClinical judgment and exudation verified by chest x-ray. Other causes improbable.
    Felty syndrome
    Splenomegaly (clinically evident or by ultrasound) and neutropenia (<1.8 ×109/L) on two occasions
    Other causes improbable (e.g., drug adverse effects or infection)
    Major cutaneous and organ vasculitis
    Cutaneous vasculitis: diagnostic biopsy or dermatologic clinical judgment
    Organ vasculitis: Organ specialist diagnosis and biopsy compatible with vasculitis
    NeuropathyClinical judgment and signs of polyneuropathy/mononeuropathy at electromyography/electroneurography
    Scleritis, episcleritis, or retinal vasculitisClinical judgment by ophthalmologist
    GlomerulonephritisNephrologist diagnosis and positive biopsy
    AmyloidosisClinical judgment and positive biopsy from affected organ
    Keratoconjunctivitis siccaPositive rose-bengal staining or result of Schirmer's test <5 mm/min
    XerostomiaAbnormal sialometry, sialography, salivary scintigraphy, or salivary gland biopsy with lymphocytic infiltrate
    Secondary Sjögren syndrome
    Two of three criteria:
    Keratoconjunctivitis sicca
    Xerostomia
    Serologic evidence: rheumatoid factor, antinuclear antibody, anti-Ro (SSA), anti-La (SSB) positive, or hypergammaglobulinaemia
    Pulmonary fibrosisDecreased vital capacity or carbon dioxide transfer factor by 15%
    Bronchiolitis obliterans organizing pneumoniaPulmonologist clinical judgment
    Osteoporosis and osteopeniaSerologic evidence: elevated RANK ligand receptor, IL-1, and TNF-alpha levels
    Cervical myelopathy
    Clinical judgment
    Increased atlantoaxial movement as seen on x-ray
    Rheumatoid nodules (subcutaneous and elsewhere)Clinical judgment and positive biopsy
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    18 . Which of the following is NOT a clinical criterion for the diagnosis of secondary Sjögren syndrome associated with RA?
    A) Xerostomia
    B) Positive biopsy
    C) Keratoconjunctivitis sicca
    D) Serologic tests positive for rheumatoid factor, anti-Ro (SSA), or anti-La (SSB) antibodies

    EXTRA-ARTICULAR MANIFESTATIONS

    EXTRA-ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITIS

    ConditionDiagnostic Criteria
    Pericarditis
    Clinical judgment and exudation verified by echocardiography. If not available, use following clinical criteria (at least one required):
    Typical pericardial pain, peripheral edema, dyspnea/orthopnea, ascites, dysrhythmia (heart rate 140 beats/min, atrial flutter/fibrillation, 2–3 degree atrioventricular block, ventricular tachycardia)
    Objective criteria compatible with pericarditis on physical examination, cardiac catheterization results, or histologic examination
    Other causes unlikely (e.g., tuberculosis or other infection, metastases, primary tumor, postoperative status, other trauma)
    PleuritisClinical judgment and exudation verified by chest x-ray. Other causes improbable.
    Felty syndrome
    Splenomegaly (clinically evident or by ultrasound) and neutropenia (<1.8 ×109/L) on two occasions
    Other causes improbable (e.g., drug adverse effects or infection)
    Major cutaneous and organ vasculitis
    Cutaneous vasculitis: diagnostic biopsy or dermatologic clinical judgment
    Organ vasculitis: Organ specialist diagnosis and biopsy compatible with vasculitis
    NeuropathyClinical judgment and signs of polyneuropathy/mononeuropathy at electromyography/electroneurography
    Scleritis, episcleritis, or retinal vasculitisClinical judgment by ophthalmologist
    GlomerulonephritisNephrologist diagnosis and positive biopsy
    AmyloidosisClinical judgment and positive biopsy from affected organ
    Keratoconjunctivitis siccaPositive rose-bengal staining or result of Schirmer's test <5 mm/min
    XerostomiaAbnormal sialometry, sialography, salivary scintigraphy, or salivary gland biopsy with lymphocytic infiltrate
    Secondary Sjögren syndrome
    Two of three criteria:
    Keratoconjunctivitis sicca
    Xerostomia
    Serologic evidence: rheumatoid factor, antinuclear antibody, anti-Ro (SSA), anti-La (SSB) positive, or hypergammaglobulinaemia
    Pulmonary fibrosisDecreased vital capacity or carbon dioxide transfer factor by 15%
    Bronchiolitis obliterans organizing pneumoniaPulmonologist clinical judgment
    Osteoporosis and osteopeniaSerologic evidence: elevated RANK ligand receptor, IL-1, and TNF-alpha levels
    Cervical myelopathy
    Clinical judgment
    Increased atlantoaxial movement as seen on x-ray
    Rheumatoid nodules (subcutaneous and elsewhere)Clinical judgment and positive biopsy
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    19 . Regarding the pharmacologic management of RA,
    A) no difference has been noted between the outcomes of single and combination DMARD therapy.
    B) more than 75% of patients studied have shown remission with methotrexate and biologic therapy.
    C) severe disability and life-threatening complications have increased with current treatment modalities.
    D) None of the above

    DISEASE MANAGEMENT

    Although RA is a lifelong illness, there have been significantly improved trends in disease management. For example, DMARD combination therapy has been shown to have better treatment outcomes than individual DMARD therapy in patients with high disease activity. Combinations of methotrexate and the newer biologic DMARD agents can lead to remission in 30% to 40% of patients with RA. Sustained remission has historically been observed in only 17% to 20% of patients. Although the concept of sustained remission is becoming an achievable goal, the reported rates of sustained remission depend on the remission criteria, treatment regimen (e.g., early, intensive treatment), and RA patient population [28,31,163,164]. As treatment for RA has improved, severe disability and life-threatening complications have decreased considerably and many people not in clinical remission live relatively normal lives with low levels of disease activity.

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    20 . With optimal treatment of RA, what percentage of patients will achieve sustained remission?
    A) 17% to 20%
    B) 30% to 40%
    C) 40% to 50%
    D) 60% to 70%

    DISEASE MANAGEMENT

    Although RA is a lifelong illness, there have been significantly improved trends in disease management. For example, DMARD combination therapy has been shown to have better treatment outcomes than individual DMARD therapy in patients with high disease activity. Combinations of methotrexate and the newer biologic DMARD agents can lead to remission in 30% to 40% of patients with RA. Sustained remission has historically been observed in only 17% to 20% of patients. Although the concept of sustained remission is becoming an achievable goal, the reported rates of sustained remission depend on the remission criteria, treatment regimen (e.g., early, intensive treatment), and RA patient population [28,31,163,164]. As treatment for RA has improved, severe disability and life-threatening complications have decreased considerably and many people not in clinical remission live relatively normal lives with low levels of disease activity.

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