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].

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.

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 [31,39].

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 [60]. 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 [60]. 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 [60,61]. More research is needed to better understand the role of sex hormones in autoimmunity and in specific autoimmune diseases.

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 [62,63]. The exact mechanisms behind the influence of cigarette smoking on the pathogenesis of autoimmune diseases are uncertain [31,62].

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 [7,10,68]. 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 [7,70,71,72,73]. Diagnostic criteria have been developed to aid in the diagnosis of some autoimmune diseases.

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 [75]. 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 [76]. Celiac disease has been associated with the co-occurrence of several autoimmune diseases, most notably Sjögren syndrome and type 1 diabetes [22,77]. Autoimmune diseases of connective tissue have generally been associated with higher rates of co-occurrence of other autoimmune diseases [78]. 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 [17,25,79,80,81].

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 [82,106]. 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 [107]. 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 [95,108]. Predictors of limited health literacy are poor self-rated reading ability, low level of education, male gender, and non-White race [108,109]. A longitudinal analysis of a range of childhood factors found that poorer speech and language ability, child depression, and the presence of maternal depression also negatively impact health literacy in adulthood [110]. 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 [82,95,108,111].

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% [57,115]. 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 [116]. If not treated, overt hyperthyroidism can result in atrial fibrillation, congestive heart failure, osteoporosis, and neuropsychiatric problems.

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 [116]. This speech is the finding with the most clinical significance for diagnosis of hypothyroidism [116].

No single clinical finding, when absent, is significant for ruling out hypothyroidism [116]. 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 [116].

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 [124,129,131]. An elevated TSH level with low levels of T3 and free T4 indicates hypothyroidism [119,124]. Subclinical hypothyroidism is indicated by a repeatedly high TSH level with normal free T4 and T3 levels [119,124]. In contrast, a low TSH level with increased T3 and T4 levels indicates hyperthyroidism [57]. 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 [124]. Thyroid autoantibodies (i.e., thyroid peroxidase and thyroglobulin antibodies) may be helpful in the diagnosis; however, 10% of patients may be antibody negative [124,128,131]. Anemia is present in 30% to 40% of patients [128].

The isotope is given orally (as a capsule or in water), and there is no consensus on the optimal dose [144]. The dose is usually determined with a dose-calculation algorithm, and the typical dose range is 5–15 mCi of ¹³¹I [129,144]. 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 [145,146].

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 [129]. Monitoring should be continued at four- to six-week intervals for six months, or until the patient becomes hypothyroid and is stable on thyroid hormone replacement [129]. Hypothyroidism can occur at any time after treatment, but most commonly occurs within two to six months [57]. 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 [129].

Most patients respond to ¹³¹I therapy with a normalization of thyroid function tests and improvement of clinical symptoms within four to eight weeks [129]. The cure rate for treatment with radioactive iodine is more than 80% [147]. 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 [148,149]. 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 [144].

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 [57,129]. 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 [150,151].

Most patients respond to ¹³¹I therapy with a normalization of thyroid function tests and improvement of clinical symptoms within four to eight weeks [129]. The cure rate for treatment with radioactive iodine is more than 80% [147]. 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 [148,149]. 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 [144].

Surgery was once frequently used to treat hyperthyroidism, but it is now the least-used treatment option. It is recommended by fewer than 1% of thyroid experts for the initial management of Graves disease [158]. 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); moderate-to-severe ophthalmopathy (because of the risks associated with radioactive iodine); or an allergy or intolerance to antithyroid drugs [129,155]. Thyroidectomy also is indicated for women planning pregnancy in less than six months who wish to avoid antithyroid drugs [155]. Thyroidectomy should be avoided in the first and third trimesters of pregnancy due to teratogenic effects associated with anesthetic agents [129]. Patients with Graves disease should be rendered euthyroid with antithyroid drugs prior to the surgery, with or without beta-blockers [129].

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 [129,162]. The diagnosis of thyroid storm relies on clinical evaluation, as laboratory testing cannot distinguish thyroid storm from uncomplicated hyperthyroidism [129]. 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 [129,162].

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 [185]. Other common symptoms of rheumatoid arthritis include fatigue, weakness, generalized muscular aches, and anorexia [173]. 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 [163,164,173]. 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 [163,173]. Other frequently occurring extra-articular manifestations include pericarditis, pleuritis, vasculitis, cervical myelopathy, and neuropathy [163]. 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 [164].

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 [185]. 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 [185]. 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 [185].

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[195]. The biologic agents include five anti-TNF-αagents (adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab) and three non-TNF-αagents, including abatacept, a selective costimulation modulator; rituximab, an anti-CD20 monoclonal antibody that depletes B lymphocytes; and tocilizumab and sarilumab, IL-6 receptor antagonists[195]. The FDA also has recently approved three biosimilar agents [209,210,211].

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 [189]. 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 [222]. 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 [222].

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 [232]. 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 [224]. 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 [232]. Among the options for surgical treatment are synovectomy, carpal tunnel release, resection of the metatarsal heads, specialized hand surgery, arthrodesis, and joint replacement [232]. The preoperative functional status is an important factor in the postoperative outcome, making early referral for surgery important [224].

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 [241,242,243]. 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 [244]. An Australian study found that although mortality rate in patients with rheumatoid arthritis had decreased from 1980 to 2015, the mortality rate remained 1.59 times higher than in community counterparts [245]. The increased mortality has been linked to several factors, including extra-articular manifestations, markers of disease severity, and diminished function within the first year [242,243]. By far, cardiovascular disease has been thought to confer the greatest risk for increased mortality [242,243].

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 [272]. 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.

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 [261].

A positive ANA titer (>1.80 on Hep-2 cells or an equivalent positive test) is required as diagnostic entry criterion [276]. The ANA titer is highly sensitive for systemic lupus, with a positive result in approximately 93% to 100% of individuals with the disease[278,279]. 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[278]. 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.

Ideally, systemic lupus should be well controlled for at least four to six months prior to conception [295]. 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 [85]. 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 [85,290]. Recommendations for treatment during pregnancy include hydroxychloroquine, prednisone, and azathioprine; evidence suggests that mycophenolate mofetil, cyclophosphamide, and methotrexate should be avoided [290,295]. Systemic lupus increases the risk for fetal loss, especially in women who have antiphospholipid antibodies [85,290,295]. 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 [290]. Heparin and low-dose aspirin are usually given throughout pregnancy to reduce the risk of miscarriage and thrombotic events.

Laboratory testing every 6 to 12 months (or more frequently, in some patients) should include urinalysis, CBC, ESR, CRP, albumin, and creatinine levels [295,318]. 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 [85,318]. 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" [324]. Early treatment with a glucocorticoid may reduce the total dose needed to suppress the flare [85].

Approximately 60% of cases of Sjögren syndrome are secondary to another autoimmune rheumatic disorder, such as systemic lupus, rheumatoid arthritis, or scleroderma [76]. 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% [76].

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%) [344,345]. Occurring less frequently are cutaneous vasculitis, lymphadenopathy, and renal involvement (e.g., proteinuria, interstitial nephritis, glomerulonephritis) [344,345]. Peripheral neuropathies are often associated with Sjögren syndrome, and the reported prevalence of this complication has ranged widely, from 10% to more than 60% [283,346]. Cognitive dysfunction has been reported in about half of individuals [283].

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 [347,354]. 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 [76,354]. 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 [355]. In its guidelines for dry eye, the AAO includes topical cyclosporine as a level IA recommendation for moderate dry eye [356]. A small randomized controlled study that compared cyclosporine 0.05% eyedrops with tacrolimus 0.03% eyedrops found that both significantly improved patient symptoms, frequency of artificial tears use, and ocular surface staining compared to placebo-controlled eyes. No significant difference was observed between the two eyedrops at improving severe dry eyes at six months [357].

Autoimmune diseases are 3 to 10 times more likely in individuals with celiac disease than in the general population [375]. 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%) [22,77].

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[37,378]. 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[378]. Diagnostic testing should be done while the patient's diet includes foods that contain gluten. The preferred single test for detection of celiac disease in children younger than 2 years of age who are not IgA deficient is the IgA anti-TTGA-IgA test [378]. Testing for children younger than 2 years of age with IgA deficiency should be performed using IgG-based antibodies (IgG DGPs and IgG TTG) [378]. Serum IgA endomysial antibodies (EMA) have also been used but are not recommended in the ACG guidelines [22,37,378].

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 [378].

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 [385,386]. 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 [385,387,388].