#94454: Autoimmune Diseases

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 [1]. 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 [1]. 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 [1,34]. Since 2010, large-scale genome-wide association studies for autoimmune diseases have successfully detected hundreds of risk variants, exemplified by studies for rheumatoid arthritis and systemic lupus erythematosus, and several loci have been identified as being associated with more than one autoimmune disease [1,35,36].

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 [31,39].

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 [31,40]. Among the environmental factors that have been found to have influence are infectious agents, stress, sex hormones (estrogens and androgens), mercury, pesticides, and cigarette smoking [40]. Imbalance of the gut microbiome also has been linked to the onset of various autoimmune diseases [40,41,42].

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 [20,43]. 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 [44,45]. Bystander effect activates T cells without antigen recognition. Other antigen-specific T cells also can be bystander-activated to induce innate immune response, resulting in autoimmune disease pathogenesis along with self-antigen-specific T cells [46].

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 [20,25,47,48,49,50]. The micro-organisms most often implicated are viral, including Epstein-Barr virus, hepatitis C virus, parvovirus, and cytomegalovirus [20,49,50,51].

Stress

Several studies in animals and humans have demonstrated that physical and psychological 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 [52]. It is hypothesized that stress may play a role in the onset and exacerbation of autoimmune disease in genetically susceptible individuals [53,54,55]. Inflammatory autoimmune diseases, such as rheumatoid arthritis and systemic lupus, are considered the most likely to be influenced by stress [55]. Psychological 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 [25,54,55,56,57,58]. 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 [59]. However, most studies have been retrospective and have lacked the statistical power to determine significance [55].

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 [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

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].

Other Factors

Exposure in humans to mercury is associated with markers of inflammation and autoimmunity, generally characterized by proinflammatory cytokines, autoantibody generation, and tissue damage. Exposure to inorganic mercury leads to lupus-like syndrome, which may be genetically regulated by mercury-induced autoinflammatory responses [40,64]. Farming and pesticide use have been associated with systemic autoimmune diseases, and while certain organochlorine insecticides and other pesticides are suspected to influence risk, the role of specific pesticides in the development of systemic autoimmunity is not known [40,65].

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 [66]. 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 [66].

Autoimmune disease exhibits a definite gender bias, with women accounting for nearly 80% of cases overall[21,24,67,68]. 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) [6,60]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[67,69].

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 [1].

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.

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 [1]. 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 [1]. 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 [74].

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].

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 [82,83]. Approaches to overcoming this barrier will be discussed in detail later in this course.

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 [54,55].

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 [84]. 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 [84].

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 [85]. Unresolved symptoms lead to a high rate of complementary and/or alternative therapies used by individuals with autoimmune diseases [25,56,85,86,87]. 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 [88]. 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 [89]. Patient trust in healthcare providers has been rated higher for clinicians who seek the patient's perspective of his or her illness [90]. 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 [90,91]. 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 [92]. 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 [93,94,95].

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].

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 [57]. 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 [57]. Ultrasonography is also useful for detecting nodules and evaluating suspicious structural abnormalities; however, it is usually not necessary for diagnosing the condition in the majority of patients [57,124,128]. A fine-needle biopsy should be done to exclude malignancy when a dominant nodule is present [57,118].

The AACE states that most primary care clinicians can diagnose and treat hypothyroidism, but the organization recommends consultation with an endocrinologist for patients with [124]:

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 [124].

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 [124,129]. 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 [118,119]. The AACE notes that the mean full replacement dosage is 1.6 mcg/kg per day [124]. Clinical evaluation of the patient and TSH testing should be done every four to eight weeks after a change in dose [124].

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 [124,128]. Also, rifampin and sertraline may accelerate levothyroxine metabolism, calling for a higher replacement dose [124].

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 [137]. 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 [137].

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 [118].

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 [138,139,140,141,142]. In addition, subclinical hypothyroidism can progress to overt hypothyroidism, with a wide range in risk of progression (3% to 20%) [119,124].

Despite a recommendation to treat subclinical hypothyroidism, there is no consensus on the TSH level that should prompt treatment [124,143]. 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 [124]. 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 [119]. 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 [124]. More studies are needed before thyroxine replacement therapy can become the standard of care for subclinical hypothyroidism [119,124].

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) [124]. 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 [124]. 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 [124]. 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 [124].

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 [124]. 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 [124]:

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 [129].

Treatment with Radioactive Iodine

In the United States, treatment with ¹³¹I has been considered to be the treatment of choice for most people, but a trend in recent years is to increase use of antithyroid drugs and reduce the use of ¹³¹I [129]. Pregnancy and breastfeeding are absolute contraindications to ¹³¹I [129]. 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 [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].

Treatment with Antithyroid Drugs

Antithyroid drugs (thionamides) interfere with thyroid hormone synthesis by preventing iodine from combining with tyrosine residues in thyroglobulin [152]. This approach is usually the treatment of choice for pregnant women, children and adolescents, and individuals who have severe Graves ophthalmopathy [144,152]. The goal of treatment is to achieve remission, defined as a biochemical euthyroid state for a minimum of one year after discontinuing treatment [129,152].

The most frequently prescribed antithyroid drugs are methimazole and propylthiouracil [129,152]. 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 [153]. 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 [153]. 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 [129]. 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 [154]. The block-replace regimen, however, was associated with a higher rate of adverse effects [154].

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 [129,147]. The starting dose is tapered according to the results of thyroid function testing, which should be done initially every two to four weeks until symptoms start to resolve and then every two to three months [155]. 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 [147]. Typical maintenance doses are 5–20 mg/day of methimazole or 100–200 mg/day of propylthiouracil [144,147]. Euthyroid levels should be achieved with minimal antithyroid therapy dosage, and repeat testing should be done in two to three months or longer intervals for long-term therapy [155]. The use of potassium iodide as a beneficial adjunct to antithyroid drug therapy for Graves disease has been investigated. One randomized controlled trial found that the administration of 38 mg potassium iodide together with 15 mg of methimazole daily resulted in better control of hyperthyroidism and fewer adverse reactions compared to 30 mg of methimazole alone [156].

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) [157]. 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 [157]. 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) [157].

With regard to duration of therapy, one year of treatment has been reported to offer better rates of remission than six months of treatment [57]. 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 [57]. A systematic review indicated that the optimal duration of a titration regimen was 12 to 18 months [154]. 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 [129]. 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 [129].

Hyperthyroidism will recur after antithyroid drug therapy in approximately 30% to 60% of individuals [57,147]. Studies have suggested that recurrence after antithyroid drug therapy is associated with several factors, including [57,144,152]:

However, the association between recurrence and any of these individual factors has not been strong enough to warrant use as a risk stratification factor [144]. 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 [129]. Another course of antithyroid drug therapy, treatment with radioactive iodine, or surgery can be used to treat recurrent hyperthyroidism [129,147].

Side effects occur in approximately 5% of individuals receiving antithyroid drugs [147]. The most common side effects are rash, arthralgia, gastrointestinal problems, and changes in taste/smell [147]. The most serious side effect, occurring in about 0.1% to 0.3% of individuals, is agranulocytosis [57]. The risk of agranulocytosis increases with higher drug doses and with age and can occur at any time during the course of treatment [57,157].

Thyroidectomy

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].

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 [144,154]. In addition, surgery offers a rapid normalization of thyroid function [144]. 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% [144].

Thyroidectomy is associated with a low rate of complications and a mortality rate of nearly zero [57,129,144]. This is particularly true if the surgery is performed by a high-volume thyroid surgeon [129]. 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) [129,159].

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 [129].

Treatment During Pregnancy

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/97/8/2543/2823170 Last Accessed: July 27, 2023)

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) [129,153]. Propylthiouracil is considered more appropriate during the first trimester, even given the FDA warning regarding liver damage [153,155]. Methimazole should be used when antithyroid treatment is started after the first trimester [129,160]. 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 [129,160]. The lowest possible dose should be used to keep total T4 and T3 levels slightly above the normal range [129]. Women treated for hyperthyroidism during pregnancy should be re-evaluated at six weeks postpartum, as disease can worsen at that time [129,160]. In women who develop hyperthyroidism during their reproductive age range, the possibility and timing of future pregnancy should be discussed. Because of the risks of the hyperthyroid state on pregnancy and fetal outcome, the American Thyroid Association recommends that women should postpone pregnancy until they have become euthyroid with therapy [129].

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 [129]. 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 [161].

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 [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].

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 [186]. 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 [187]. The impetus for this change in focus was the need for earlier diagnosis in order to begin disease-modifying drugs as soon as possible [187].

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[187]. 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[187]. 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)[187]. 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.

The ACR/EULAR recommended serologic testing involves a rheumatoid factor and an anti-citrullinated protein antibody (ACPA) [187]. 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 [172,188]. 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 [172]. The false-positive rate of rheumatoid factor for rheumatoid arthritis has been reported to be 15% [188]. As a result, the sensitivity and specificity of the test are 69% and 85%, respectively [188]. 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% [188]. 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 [187]. An ANA titer has a reported sensitivity of about 40% among individuals with rheumatoid arthritis, and false-positive results are common [172]. The ANA titer is not part of either the 1988 or 2010 diagnostic criteria [186,187].

Other recommended baseline laboratory testing includes a complete blood cell count (CBC) with differential, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) [9,189]. However, the ESR and CRP results should be interpreted with caution, as the tests are normal in about 40% of people with rheumatoid arthritis [190]. 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 [189].

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 [9]. The findings on imaging studies are not part of the 2010 classification criteria for rheumatoid arthritis [187]. However, imaging studies may be helpful in the differential diagnosis and in establishing baseline images for comparison during follow-up [189]. 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 [191].

A wide range of medical conditions should be considered in the differential diagnosis of rheumatoid arthritis, including [173,185,192]:

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 [172,185]. 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 [20].

The American College of Rheumatology strongly recommends methotrexate over hydroxychloroquine or sulfasalazine for DMARD-naive patients with moderate-to-high disease activity.

(https://assets.contentstack.io/v3/assets/bltee37abb6b278ab2c/blt9e44ccb701e1918c/63360f6775c0be225b8d943a/ra-guideline-2021.pdf Last Accessed: July 27, 2023)

Level of Evidence: Moderate

Early treatment is essential to achieving optimal outcomes with disease-modifying drugs, and the ACR and EULAR guidelines recommend that treatment with disease-modifying drugs begin immediately following the diagnosis[196,198]. 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) [195,200]. 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[200,201]. 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[202,203,204,205,206]. These additional drugs are included in the updated EULAR guidelines and are expected to be included in the forthcoming update to the ACR guidelines[197,207].

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].

Methotrexate is the most commonly prescribed DMARD and is still considered the so-called anchor drug for the treatment of rheumatoid arthritis[196,198]. 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[185,212,213]. Patients for whom monotherapy with methotrexate has failed may benefit from the addition of leflunomide, either with methotrexate or other DMARDs[213].

The ACR recommends basing the decision regarding initial treatment with a DMARD on current disease activity, prior therapies used, presence of comorbidities, and degree of disease activity (moderate-to-high)[196]. Previous guidelines had also considered prognosis, but this is now considered encompassed by disease activity. However, poor prognostic factors may be possible influential factors in physicians' and patients' decision-making [196]. Additional factors to consider when choosing a drug are side effect profiles, cost, and access to care.

The treat-to-target approach for DMARD-naïve patients with moderate-to-high disease activity involves initiation of methotrexate immediately upon diagnosis with the subsequent addition of another DMARD, when required[194,196,198]. Methotrexate monotherapy is preferred over combination therapy because the higher burdens (e.g., multiple medications, higher costs) of combination therapy outweigh the evidence that suggests greater improvements in disease activity associated with combination therapy [42]. Patients with active disease are monitored closely (every one to three months), and it is recommended that treatment adjustments be made if there is not at least a 50% improvement at three months (or if the six-month target has not been reached)[196,198]. For patients with high disease activity without poor prognostic features, the EULAR recommends methotrexate plus a glucocorticoid [198].

A systematic review and meta-analysis assessed methotrexate monotherapy or in combination with other conventional DMARDS, biologic drugs, or tofacitinib in adult patients with rheumatoid arthritis [214]. Outcomes measured were the ACR50 response (major clinical improvement), radiographic progression, and withdrawals due to adverse events. In methotrexate-naïve patients, several treatments were statistically superior to oral methotrexate for ACR50 response: sulfasalazine and hydroxychloroquine ("triple therapy"), several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56% to 67%), compared with 41% with methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression, but the estimated mean change over one year with all treatments was insignificant. Triple therapy had statistically fewer withdrawals due to adverse events than methotrexate plus infliximab. After an inadequate response to methotrexate, several treatments were statistically superior to oral methotrexate for ACR50 response: triple therapy, methotrexate plus hydroxychloroquine, methotrexate plus leflunomide, methotrexate plus intramuscular gold, methotrexate plus most biologics, and methotrexate plus tofacitinib. The probability of response was 61% with triple therapy and ranged widely (27-70%) with other treatments. No treatment was statistically superior to oral methotrexate for inhibiting radiographic progression. Methotrexate plus abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments [214].

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[196]. Individuals receiving methotrexate or leflunomide should also be tested for hepatitis B infection. Recommendations for patients with hepatitis C were not included in the 2021 ACR updated guideline, because curative antiviral therapy is now widely available [196]. Immunization may be ineffective during methotrexate therapy. Immunization with live vaccines is not recommended. Methotrexate may diminish the therapeutic effect of COVID-19 vaccines. Guidelines recommend holding methotrexate for one to two weeks after vaccine administration as permitted by underlying disease [208].

In previous guidelines, acute hepatitis B or C infection was considered a contraindication for most DMARDs and biologic agents. However, in its 2021 update, the ACR recommended that patients with active hepatitis B who are receiving effective antiviral treatment may be managed the same as patients without hepatitis[196]. The 2022 EULAR guideline recommends that patients receive influenza, pneumococcal, and tetanus vaccination in accordance with recommendations for the general population. Patients at risk of rheumatoid arthritis should receive both hepatitis A and B vaccinations [198].

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 [215].

There is good evidence that nonselective NSAIDs and COX-2 inhibitors have comparable efficacy and that COX-2 inhibitors are comparable to each other [216]. 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 [216]. 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) [217].

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 [215,216]. 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 [216]. 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 [208].

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 [189,218]. 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 [9,196,198]. 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 [189].

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 [86,219,220]. Most herbal supplements used by individuals with rheumatoid arthritis are safe, but the evidence of their benefit has been weak to moderate [221,222]. Despite the wide use of complementary and alternative medicine, most individuals (63% to 72%) do not report the use to their healthcare providers [104,220]. 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 [223]. 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 [224]. 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" [225]. 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). One study that included 696 participants with rheumatoid arthritis found that a majority (87.6%) reported use of a nonvitamin, nonmineral dietary supplement for rheumatoid arthritis, with turmeric, ginger, and fish oil among the top three supplements in current use [226]. 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 [227]. 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 [227]. Though fish oil is most often studied, krill oil (from a small, shrimp-like crustacean) has also shown similarly beneficial results [228]. 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 [229]. However, blood thinning is a side effect, and patients should be advised to eat foods rich in vitamin K1 while taking these supplements.

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].

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 psychological well-being [9,230]. One study suggests that adding task-oriented training to conventional exercise programs may help facilitate activities of daily living in patients with rheumatoid arthritis [231]. Also, because emotional stress can exacerbate disease activity, stress management interventions should be encouraged [54,55]. 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) [55].

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].

The overall management of individuals with rheumatoid arthritis includes clinical assessment and follow-up for extra-articular manifestations of rheumatoid disease [164]. 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 [164].

Both the ACR and the EULAR recommend that evidence of disease activity be evaluated, through subjective and objective measures, at each follow-up visit [189,196]. The follow-up assessment may include:

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 [189,196,198]. 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 [173,185,233]. Again, achieving low disease activity with a conservative medication regimen may be a better course than seeking clinical remission with aggressive therapy [196,199].

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[234].

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[234]. Infusion site reactions are also commonly associated with anti-TNF-αagents[234]. 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[208]. 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[208].

Individuals receiving hydroxychloroquine long term are at risk for severe retinopathy, and ophthalmologic follow-up is important for early detection and minimization of toxicity[208,235]. 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[236,237]. Given the initial low risk of retinopathy, with a proper dose and in the absence of major risk factors, the American Academy of Ophthalmology (AAO) recommends that 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. Screening should begin sooner if the risk is high based on the following factors[237]:

Lesser risk factors include older age, kidney or liver disease, and genetic predisposition to hydroxychloroquine toxicity [237]. The AAO emphasizes that these are minimum recommendations that balance cost with risk, and more frequent screening may be appropriate [237].

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. As stated, individuals receiving methotrexate or leflunomide should be tested for hepatitis B infection. Recommendations for patients with hepatitis C were not included in the 2021 ACR updated guideline because curative antiviral therapy is widely available [196]. Immunization may be ineffective during methotrexate therapy. Immunization with live vaccines is not recommended. The 2022 EULAR guideline recommends that patients receive influenza, pneumococcal, and tetanus vaccination in accordance with recommendations for the general population. Patients at risk of rheumatoid arthritis should receive both hepatitis A and B vaccinations [198]. Targeted prophylaxis for individuals at high risk for infection may also be appropriate[49,234].

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 psychological effects[234]. The ACR updated their guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis in 2022[238]. The ACR recommends optimized intake of dietary and supplemental calcium and vitamin D based on age-appropriate U.S. recommended dietary allowances 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[238]. The ACR guidelines also include recommendations for the use of oral bisphosphonates for adults 40 years of age and older who are receiving long-term glucocorticoids and who are at high or very high risk for fracture, 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) [238,239]. 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[238]. 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].

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)[240]. 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[1,122,164].

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].

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) [246]. The increased risk cannot be explained by an increased incidence of traditional cardiovascular disease risk factors [247,248,249]. 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 [243,250]. To date, only methotrexate has been shown to be associated with a reduced risk of cardiovascular disease among individuals with rheumatoid arthritis [251]. Despite the growing understanding of these mechanisms and their complex interplay with conventional cardiovascular risk factors, optimal approaches of risk stratification, prevention, and treatment in the context of rheumatoid arthritis remain unknown [252]. 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 [253].

Criteria for the classification and diagnosis of systemic lupus have been established by the ACR and was updated in 2019 (Table 12)[276,277]. 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[276,277]. 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[85].

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.

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[276]. Neuropsychiatric disorders have been reported in up to 80% of adults with systemic lupus and more than 90% of children with the disease[280,281]. The disorders may be evident before, at the time of, or after the diagnosis of systemic lupus[282]. 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%)[280,283].

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[275,284]. Evidence of renal involvement may include proteinuria or red blood cell casts and leukocytes in the urine[275]. Hematologic testing may indicate anemia (in about 40%), thrombocytopenia (in about 25% to 35%), and leukopenia (in about 15% to 20%)[284]. Metabolic abnormalities (e.g., uremia, electrolyte imbalance, or ketoacidosis) may be signs of neurologic disorders; seizures or psychosis are other signs[85].

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) [285,286,287].

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 [276,288]. 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 [261]. Serum complement levels may also be useful, as decreased levels indicate active or impending exacerbation of disease [85,276,285,286,287]. The prevalence of positive anti-double-stranded DNA titers and of decreased complement levels is lower among older individuals than among younger ones [261].

The presence of antiphospholipid antibodies is determined with testing for anticardiolipin antibodies or for lupus anticoagulant [85,276]. About 20% to 30% of people with systemic lupus have antiphospholipid antibodies, which increase the risk for thromboembolism and pregnancy loss [288].

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 [285,295]. 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. Use of hydroxychloroquine reduces the risk of disease flares by 20% to 40%. The agent also can significantly reduce risk of kidney disease progression and thrombosis/cardiovascular disease and prolong survival in patients with lupus [295,296,297,298,299,300]. Despite all these advantages, hydroxychloroquine is underutilized in practice [301].

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 [85,291]. NSAIDs may also be used to provide symptomatic relief of joint manifestations [285]. The use of both glucocorticoids and NSAIDs should be carefully considered because of their associated toxicity [285]. Glucocorticoids should be given at the lowest possible dose that suppresses manifestations of disease activity and prevents flares [85,291,295].

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 [285,291]. Intermediate-dose rather than high-dose topical glucocorticoids should be used on areas where atrophy is more likely, such as the face [285,291]. Therapies for cutaneous lesions are calcineurin inhibitors, most notably tacrolimus and pimecrolimus [293]. Moderate evidence exists for benefit with topical calcineurin inhibitors, particularly as steroid sparing agents in areas at high risk of steroid complications (e.g., facial skin) [302]. The FDA has approved tacrolimus and pimecrolimus for the treatment of moderate and severe atopic dermatitis in adults and children 2 years of age and older but has not approved them for use in systemic lupus [293]. Voclosporin is a novel calcineurin inhibitor that received FDA approval in 2021 for use in adult patients with lupus nephritis in combination with mycophenolate. The recommended dosage is 23.7 mg twice daily plus mycophenolate 1 g twice daily [208,295].

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 [85]. 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 [85,292]. Azathioprine is often the drug of choice for nonarthritic manifestations that have not responded to antimalarial treatment and low-dose glucocorticoid [85]. A study that compared the efficacy and safety of leflunomide versus azathioprine as maintenance therapy for lupus nephritis found that the safety profiles were similar [303]. 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 [49].

It has been hypothesized that biologics may be the next frontier of lupus treatment [304]. In 2011, the FDA approved belimumab, the first new drug for lupus in more than 50 years [305]. Belimumab, a monoclonal antibody against B-lymphocyte stimulator, has been associated with better clinical response compared with placebo [305,306]. 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 [307]. Belimumab is approved to treat patients with active, autoantibody-positive lupus who are receiving standard therapy [208,305]. 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 [208].

Though not FDA approved for the treatment of systemic lupus erythematosus, rituximab has shown promise in the management of lupus [307,308]. 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 [307,308]. EULAR recommends considering the off-label use of rituximab in patients with severe renal or extrarenal disease refractory to multiple other agents [291]. Additional research is ongoing.

Anifrolumab is a human monoclonal antibody to type 1 interferon subunit 1 recently investigated for the treatment of moderately to severely active systemic lupus [309]. 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%) [309]. In 2021, the FDA issued approval for anifrolumab for treatment of adults with moderate-to-severe systemic lupus who are receiving standard therapy [310]. Anifrolumab blocks the biologic activity of type 1 interferon receptors that, when elevated, play a role in the pathogenesis of systemic lupus. The agent reduced inflammatory and immunological processes [208,310]. Anifrolumab is administered IV at 300 mg every four weeks [208]. The most common adverse reactions include infection and upper respiratory tract infection [208].

Systemic lupus often affects the eyes, with about one-third of patients having dry eye syndrome (keratoconjunctivitis sicca) [236]. Symptoms are usually relatively mild (e.g., irritation and redness), and artificial tear drops can be used to treat milder forms of the condition [236]. Pain in the eye or significant visual impairment at any time during the course of disease warrants immediate referral to an ophthalmologist [236].

Neuropsychiatric disorders have been shown to have a persistent negative effect on quality of life for people with systemic lupus [280,281]. 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 [282]. 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 [85].

Systemic lupus is associated with reduced exercise capacity and decreased muscle strength, which are exacerbated by disease-related fatigue and sleep disturbances [311,312,313]. To address these issues, routine exercise should be part of the overall treatment plan for people with mild-to-moderate disease [313,314]. 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 [315]. 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 [313].

Uncontrolled systemic lupus is defined as the persistence of clinical manifestations during treatment. Several manifestations indicate uncontrolled disease, including [291,295]:

The primary care provider should refer patients with uncontrolled disease to a rheumatologist[285]. Moderate doses of a glucocorticoid may be effective for moderately severe disease without major organ involvement (e.g., arthritis, dermatitis, serositis, systemic symptoms)[85]. Glucocorticoids should be tapered as tolerated until a maintenance level can be established[85].

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[285]. 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[285]. 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[285].

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.ncbi.nlm.nih.gov/pmc/articles/PMC3437757 Last Accessed: July 27, 2023)

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)[284,285]. In 2012, the ACR published a guideline for the treatment and management of lupus nephritis[285]. 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[285]. For more advanced disease, the recommended induction therapy is cyclophosphamide or mycophenolate mofetil with glucocorticosteroids for three days, which is replaced by prednisone[285]. 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[285].

Biologic agents, including anti-TNF-αfactors, 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[306]. 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[292,306].

Approximately 50% of people with systemic lupus seek symptomatic relief with complementary and alternative methods[316]. 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[316]. In addition, counseling and therapy may improve quality of life and mood[317].

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.

Pregnant patients with symptomatic lupus nephritis may be treated with hydroxychloroquine (for mild disease) or prednisone plus azathioprine (for clinical active disease) [285]. In cases of severe persistent disease, delivery after 28 weeks may be necessary [285].

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) [318,322,323]. 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 [318].

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].

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 [318]. 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 [284,318].

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 [282]. A focused history can be used to elicit information about such symptoms as seizures, paresthesias, numbness, weakness, headache, epilepsy, and depression [318]. Clinicians should also assess patients for cognitive impairment by asking questions about problems with multitasking, household tasks, or memory [318]. If cognitive impairment is suspected, the patient should be evaluated further [318].

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 [234]. Recommended testing for individuals receiving methotrexate, mycophenolate mofetil, or azathioprine is a CBC and platelet count every three months [284]. Individuals treated with methotrexate should also have liver function studies done every three months [284]. A serum glucose level should be obtained yearly for patients treated with glucocorticoids [284]. Monitoring during treatment with cyclophosphamide should be done monthly, with a CBC, platelet count, and urinalysis [284]. 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 [49,325]. 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 [48].

Viral infections occur less commonly, and parvovirus B19 and cytomegalovirus are the most common viral micro-organisms [48,326]. Symptoms related to viral infections often mimic disease flares [326]. 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 [48]. Factors associated with heightened risk for infection include [48,49]:

Protection against infections should be proactive. 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 [325,327].

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 [49,325,326].

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 psychological effects [234,238]. Of these side effects, osteoporosis is of particular concern, with a prevalence of 4% to 24% among patients with systemic lupus [318]. According to the updated 2022 ACR guidelines, the following are recommended for the prevention and treatment of glucocorticoid-induced osteoporosis [238,239]:

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 [235,236]. Still, ophthalmologic follow-up is important for early detection and minimization of this potentially serious side effect [235]. The AAO recommends a complete ophthalmologic examination within the first year after treatment [235]. 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 [9,318].

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[290]. Among patients with systemic lupus, the prevalence of hypertension or dyslipidemia has been reported to range from approximately 11% to 75%[240,318]. Racial disparities exist, with cardiovascular events occurring at a younger age in Black women and men[328,329]. 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[290,318].

Hypertension and cardiovascular problems are among the most common comorbidities in individuals with systemic lupus (Table 16)[240]. 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[240]. Follow-up care should include patient assessment and preventive strategies for these comorbidities, as well as treatment as appropriate.

The risk of cancer is slightly increased for individuals with rheumatic diseases in general and for systemic lupus specifically [330,331]. Although several types of cancer have been reported to occur more frequently, the risk is greater for hematologic cancers, especially non-Hodgkin lymphoma [330,331,332]. The underlying link between cancer and systemic lupus is unknown, but both the disease itself and medication exposure are thought to be factors [331]. 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) [333,334]. Clinicians should assess patients for signs and symptoms of cancer and should ensure that routine cancer screening is carried out [318,330,331]. Shorter intervals for gynecologic evaluation are reasonable for women with systemic lupus due to the increased risk for cervical cancers [334].

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 [333,335].

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 [74,273]. The highest risk for polyautoimmunity has been associated with female sex, articular involvement, familial autoimmunity, and positive anti-Ro titer [272].

Systemic lupus often has a substantial impact, with disease-related symptoms interfering with quality of life and ability to work [255,256,280,281,336]. 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 [336]. Healthcare professionals should ask patients about their ability to cope with the disease and should suggest support groups or counseling as appropriate.

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 [27,337]. 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 [85,243,288,337]. Ten-year and 15-year survival rates have been reported to be approximately 90% and 80%, respectively [337,338]. Improved survival is thought to be the result of earlier diagnosis, recognition of mild disease, increased use of ANA testing, and better treatment options [243]. 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 [328,329,337,338].

The EULAR Sjögren syndrome disease activity index (ESSDAI) was developed by consensus in 2009 to measure disease activity in patients with primary Sjögren syndrome [358]. The ESSDAI is considered the criterion standard to measure disease activity in clinical studies, and as a primary outcome measure in randomized clinical trials. In 2015, EULAR published a user guide for the ESSDAI that includes definitions and precisions for rating each of 12 disease domains (e.g., organ systems, peripheral nervous system, central nervous system). The guide is intended to help clinicians detect true changes in disease activity over time, improve initial assessment of patients with primary Sjögren syndrome, and facilitate the demonstration of effectiveness of treatments. The ESSDAI has been validated in a large independent cohort and has been shown to have a high content validity, to be highly reproducible, and to be able to detect change [358,359,360].