INTRODUCTION — The central pathology of rheumatoid arthritis (RA) develops within the synovium of diarthrodial joints, but nonarticular organs and tissues may also be affected, particularly in patients with severe joint disease. Despite the many differences between the joints and other tissues, many of the same cytokines that drive synovial pathology are also responsible for the changes in extraarticular sites. (See "Pathogenesis of rheumatoid arthritis".)
Successful management of systemic manifestations of RA is predicated upon control of the underlying joint disease and often includes glucocorticoid, immunosuppressive, and biologic therapies .
The systemic and extraarticular manifestations of RA are reviewed here. Articular manifestations and an overview of the treatment of RA are discussed separately. (See "Clinical manifestations of rheumatoid arthritis" and "General principles and overview of management of rheumatoid arthritis in adults".)
EPIDEMIOLOGY AND RISK FACTORS — Extraarticular involvement of some type is common in rheumatoid arthritis (RA) and is associated with more severe and typically seropositive disease.
Involvement of the musculoskeletal system other than joints (eg, bone and muscle) and of organs not considered part of the musculoskeletal system (eg, skin, eye, lung, heart, kidney, blood vessels, salivary glands, central and peripheral nervous systems, and bone marrow) occurs in approximately 40 percent of patients with RA [2-5]. There is limited evidence that some extraarticular features, such as rheumatoid nodules, Sjögren's disease, and vasculitis, may have been diminishing in frequency since the mid-1990s [3,6-8].
Risk factors for systemic, extraarticular disease include age, presence of rheumatoid factor (RF) or antinuclear antibodies, human leukocyte antigen (HLA) DRB1 "shared epitope" alleles, disease duration, early disability, and smoking [2,7,9,10]. Patients with severe extraarticular RA often have high levels of RF at presentation of systemic manifestations and are more likely to have circulating antibodies against citrullinated proteins than are patients with RA who lack extraarticular disease . A study from Sweden suggested that patients treated with tumor necrosis factor (TNF) inhibitors are at slightly higher risk of developing extraarticular disease; however, channeling bias could not be excluded .
Extraarticular involvement in RA is a marker of disease severity and is associated with increased overall morbidity and premature mortality [12,13].
CONSTITUTIONAL/SYSTEMIC SYMPTOMS — Constitutional and systemic symptoms and findings of rheumatoid arthritis (RA) may include generalized aching, stiffness, and constitutional symptoms such as fevers, weight loss, and fatigue [14,15]; these symptoms may sometimes antedate the onset of articular disease by several months. Some patients with RA also experience chronic widespread pain and may meet criteria for fibromyalgia. RA can also be associated with mood disorders such as depression.
●Fatigue – Fatigue is often multifactorial. Pain; sleep disturbances; cognitive, emotional, and physical functioning; and social factors contribute to fatigue, although no consistent relationships between specific inflammatory variables and fatigue have been reported [15,16].
●Chronic widespread pain/fibromyalgia – Chronic widespread pain and fibromyalgia are present in a substantial proportion of patients with RA and are more strongly associated with seronegative than seropositive arthritis. While estimates of prevalence vary, approximately one in five patients with RA has associated fibromyalgia [17,18]. These patients have higher levels of pain, fatigue, sleep and mood disturbances, neuropathic symptoms, and worse physical and mental health, compared with patients without fibromyalgia, yet they exhibit lower levels of systemic and joint inflammation. Chronic widespread (centralized) pain in RA is discussed in detail separately. (See "Overview of chronic widespread (centralized) pain in the rheumatic diseases", section on 'Rheumatoid arthritis'.)
●Psychiatric disease – Affective disorders, particularly depression, are common in RA. (See 'Neurologic and psychiatric disease' below.)
●Weight loss – Weight may decline over time, especially among older patients and among those with elevated inflammatory markers, erosive disease, and higher initial body mass index .
Anatomic areas affected by osteopenia — Bone loss in rheumatoid arthritis (RA) may be systemic, periarticular, or focal :
●Systemic – Generalized bone loss occurs when systemic bone resorption exceeds bone formation and is caused by immobility, systemic inflammation mediated by cytokines (eg, tumor necrosis factor [TNF] and interleukin [IL] 1), and the effects of glucocorticoid therapy . The decrease in bone density secondary to the disease itself is separate from glucocorticoid-induced osteopenia; in some patients, however, the disease and glucocorticoid treatment are additive, producing substantial morbidity. Glucocorticoid-induced osteoporosis is discussed separately. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Patients with RA have a 60 to 100 percent greater risk of osteoporotic fracture compared with persons who do not have RA . These individuals are those who are particularly prone to loss of height, symptomatic vertebral compression fractures, and stress fractures of metatarsals or long bones in the leg. Patients who develop fractures are often immobilized for significant periods; this deficiency of normal weightbearing amplifies bone loss by diminishing new bone formation while bone resorption continues at an accelerated pace.
●Periarticular – Demineralization in a periarticular distribution is characteristic of RA and results from inhibition of bone formation by the effects of cytokines on local immune cells. Magnetic resonance imaging (MRI) studies have revealed periarticular bone edema lesions identified as bright areas on T2-weighted sequences. Histopathologic studies have shown these lesions to represent "osteitis" composed of replacement of bone marrow fat with lymphoid aggregates . Decline in local hand bone density in early RA is predictive of a higher risk of radiographic erosions, although this may not have any impact on physical function or quality of life [23,24]. (See "Clinical manifestations of rheumatoid arthritis", section on 'Plain film radiography'.)
●Periodontal – Periodontal bone loss may be associated with joint destruction at the wrist, and both have been associated with the possession of the "shared epitope" . The presence of a lymphocytic infiltration of the salivary glands and the sicca syndrome were also associated with periodontal bone resorption in this study . (See 'Sjögren's disease' below.)
●Focal – A hallmark of RA is the development of bone erosions due to activation of osteoclasts and invasive synovial pannus. The presence of focal erosions also correlates with systemic bone loss and osteoporosis in the course of early disease; beyond the first few years of RA, this relationship is blurred by other confounding factors . (See "Clinical manifestations of rheumatoid arthritis", section on 'Plain film radiography'.)
Prevalence and risk factors — Osteoporosis of the hip or lumbar spine is common in adults with RA. In one study in the United Kingdom, the prevalence of osteoporosis in a cohort of patients with established RA referred for a bone mineral density (BMD) study was approximately 1.5- to 2-fold greater than age- and sex-matched comparators without RA (30 versus 17 percent) . This was similar to a prior study of Norwegian patients selected to be representative of the RA patient population, among whom the prevalence of osteoporosis was 22 percent . This risk is strongly associated with cumulative disease activity over time [29,30].
●Contribution of glucocorticoid therapy – It is likely that net bone loss in a patient with RA who is taking low-dose daily prednisone would exceed that in a patient not treated with glucocorticoids. Nevertheless, fracture incidence in newly diagnosed RA patients exposed to glucocorticoids is twice as prevalent as it is among nonexposed patients . However, it is possible in those patients who gain greater mobility and exercise tolerance that with the use of 5 to 7.5 mg of prednisone each day, the increase in bone loss from the therapy would be offset by an increase in new bone formation associated with an increase in muscle contraction and weightbearing . In a multivariable analysis of several risk factors for vertebral compression fracture in 925 women with RA, a one-point increase in disability (as measured by the health assessment questionnaire) was associated with more fracture risk than a 1-gram cumulative dose of prednisone .
There are conflicting data on the precise frequency of glucocorticoid-associated osteopenia in rheumatoid patients taking low-dose (<7.5 mg/day) prednisone. This issue and the mechanism of glucocorticoid-induced osteoporosis are discussed in detail elsewhere. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis", section on 'Epidemiology and risk factors'.)
●Risk factors other than inflammation and glucocorticoids – In addition, there may be factors other than the disease process itself and glucocorticoid therapy that are associated with an increased risk of osteoporosis. These include:
•A previous diagnosis of osteoporosis
•Inadequate physical activity
•Family history of osteoporosis
•Impaired grip strength
•Low body mass
●Low bone mass in men with rheumatoid arthritis – Although most studies of osteopenia in patients with RA have included a preponderance of women, men with the disorder also appear to have lower bone mass. In one study of 94 males with RA compared with population controls, there was a twofold increase in osteopenia (BMD decreased by more than one standard deviation below the reference population mean peak bone mass) . Multiple regression analysis found advancing age and lower body weight were associated with lower BMD at the femoral neck and total hip. However, disease-related factors, including concurrent glucocorticoid use, rheumatoid factor (RF) status, and self-reported disability, were not associated with osteopenia in the hip or spine.
●Fracture risk – There is a high incidence of stress fracture of long bones in patients with RA, particularly in those treated with glucocorticoids . Synovitis and glucocorticoid use are both risk factors for thinning of cortical bone . The fibula is the most common fracture site and, in older patients, often manifests as acute and debilitating pain in the lateral leg with no history of trauma.
Other fractures can be facilitated by geodes, the subchondral cysts that develop when high intraarticular pressures force synovial fluid through breaks in the subchondral plate in patients who have particularly aggressive, proliferative synovitis .
Vertebral compression deformities are also more common among those with RA than among age- and sex-matched controls . The higher prevalence is not fully explained by their lower BMD or by the use of glucocorticoids.
Diagnosis and management
●Diagnosis – Low bone mass and osteoporosis are diagnosed by analysis of the BMD, usually by dual-energy x-ray absorptiometry (DXA). It should be assumed that every patient with RA is at risk for osteoporosis. Those patients with added risk factors beyond the diagnosis of RA alone, specifically postmenopausal women and older men or those who screen positive for high risk using a fracture risk calculator, should undergo baseline determinations of BMD before the disease becomes well-entrenched and before glucocorticoid therapy is started (see 'Prevalence and risk factors' above). The assessment of BMD and the approach to prevention of glucocorticoid-induced osteoporosis are described separately. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women" and "Clinical features and evaluation of glucocorticoid-induced osteoporosis" and "Osteoporotic fracture risk assessment".)
●Management – Because patients with RA are at higher risk for osteoporosis and fracture, assessment of bone density is essential. Accordingly, the widely used tool for assessment of fracture risk and need for therapy, the Fracture Risk Assessment Tool (FRAX), can provide estimates that include RA and glucocorticoid use as risk factors in its calculations (see "Osteoporotic fracture risk assessment", section on 'Fracture risk assessment tool'). FRAX risk assessment incorporates RA, but may over-estimate the long-term risk of fracture, likely a function of the lower life expectancy of patients with RA . Interventions that are used to prevent or minimize RA and glucocorticoid-induced bone loss, such as calcium and vitamin D supplementation and pharmacotherapy (including bisphosphonates), are presented elsewhere. (See "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Overview of the management of osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men" and "Prevention of osteoporosis".)
MUSCLE WEAKNESS — Muscle weakness is a common symptom in rheumatoid arthritis (RA). It may have several, often additive, causes. These include synovial inflammation, drug-induced muscle disease, myositis, and vasculitis. (See 'Synovial inflammation' below and 'Drug-induced myopathy' below and 'Myositis' below and 'Vasculitis' below.)
Synovial inflammation — Synovial inflammation is usually associated with diminished motion of joints, which rapidly results in atrophy of muscle serving these joints. This effect is most obvious in the knee, in which synovitis quickly leads to quadriceps weakness. This weakness results in greater mechanical stress on the affected joints. As an example, when the quadriceps muscles weaken, more force is applied directly through the patella than when quadriceps strength is normal. Exercise can help prevent muscle weakness or can help restore muscle strength when due to synovitis. (See "Nonpharmacologic therapies for patients with rheumatoid arthritis", section on 'Physical activity'.)
Drug-induced myopathy — Superimposed upon active RA, with or without disease-related muscle involvement, a drug-induced myopathy can gradually weaken a patient and can confuse the clinician, who may assume that there is an inflammatory cause for the weakness. Glucocorticoids, antimalarial drugs, and statin drugs are among the drugs that can cause myopathy:
●Glucocorticoids – There is wide variation in the glucocorticoid dose and duration of treatment prior to the onset of muscle weakness. Some patients become weak after a low dose of glucocorticoids for a few weeks, while others never develop myopathy despite receiving large doses for months or years. Despite this variability, there is a general dose relationship for systemic glucocorticoid therapy, and it is unusual in patients treated with less than 10 mg/day of prednisone or its equivalent. Glucocorticoid-induced myopathy is discussed in detail elsewhere. (See "Glucocorticoid-induced myopathy".)
Other features of glucocorticoid excess such as moon facies, diabetes, mood alteration, skin fragility, and osteoporosis are often, but not always, present in patients with myopathy. (See "Major side effects of systemic glucocorticoids" and "Epidemiology and clinical manifestations of Cushing syndrome".)
Glucocorticoid-induced myopathy is a diagnosis of exclusion, being based upon the history and timing of glucocorticoid exposure and upon the absence of other causes of myopathy. The diagnosis should be strongly suspected if weakness develops at a time when the other signs of RA have become quiescent, and it is generally established by demonstrating improved strength within three to four weeks after appropriate dose reduction.
●Antimalarial drugs – Antimalarial drugs used to treat RA (eg, hydroxychloroquine and chloroquine) rarely cause muscle weakness as a symptom of drug-induced myopathy. Antimalarial drug-induced myopathy is discussed elsewhere. (See "Drug-induced myopathies", section on 'Chloroquine/hydroxychloroquine'.)
●Lipid-lowering drugs – Statins and other lipid-lowering drugs may cause muscle injury, typically with muscle pain. Thus, treatment with a statin or, rarely, with other lipid-lowering drugs should be considered as a cause of myalgia or weakness in a patient with RA who is being treated for dyslipidemia. (See "Statin muscle-related adverse events".)
Myositis — Although evidence of inflammatory changes of muscle may occasionally be seen on conventional light microscopy of muscle biopsy tissue, true polymyositis, with elevated levels of serum creatine kinase and typical findings on electromyography and muscle biopsy, is rare in RA .
These patients are typically managed as are those with polymyositis, often using prednisone and either methotrexate or azathioprine. The treatment of polymyositis is discussed in detail separately. (See "Initial treatment of dermatomyositis and polymyositis in adults".)
Vasculitis — Patients with RA may occasionally develop vasculitis. Risk factors include high titers of rheumatoid factor (RF) and active extraarticular disease elsewhere, such as nodulosis or scleritis. Involvement of skeletal muscle vessels can cause acute pain in muscle bundles associated with an acute flare of disease, while a vasculitic neuropathy can cause muscle weakness and a mononeuritis multiplex. With the use of aggressive and effective disease-modifying antirheumatic drug (DMARD) therapies for RA, this manifestation has become less common, occurring in less than 1 percent of patients. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
ALTERED BODY COMPOSITION — Body composition is frequently altered in patients with rheumatoid arthritis (RA), with changes of increased body fat mass and reduced lean body mass (sarcopenia), even with a normal body mass index. Altered body composition contributes to reduced physical function and cardiometabolic risk and may be attenuated by formal exercise interventions and control of the underlying inflammatory disease.
Studies using dual-energy x-ray absorptiometry (DXA) or quantitative computed tomography (CT) have shown that patients have higher fat mass and reduced lean body mass (sarcopenia) compared with controls, even among subjects with a normal body mass index . The differences in body fat mass between patients and controls are starkest among females. Similarly, muscle density at the mid-thighs is decreased in patients compared with controls . Increased abdominal visceral fat and epicardial fat are predictive of increased cardiometabolic risk and metabolic syndromes [43,44].
Predictors of altered body composition include [41,42]:
●Long disease duration
●High inflammatory disease activity (eg, as measured by tender joint counts, C-reactive protein, interleukin [IL] 6)
●Positive rheumatoid factor (RF)
●Lack of treatment with disease-modifying antirheumatic drugs (DMARD)
In one study, the use and cumulative dose of prednisone were not associated with altered body composition ; glucocorticoid use is known to cause type II muscle fiber atrophy and has, as expected, been associated with reduced muscle density .
Altered body composition with sarcopenia and excess fat mass are predictive of disability and adverse quality of life [42,45]. However, exercise may improve body composition, as illustrated by a randomized trial involving 40 patients who received either a six-month, individualized aerobic and resistance high-intensity exercise program or a control intervention of standard advice on exercise benefits and lifestyle changes . The patients in the individualized program experienced a significant reduction in body fat percentage, improvements in cardiometabolic risk factors, and a reduction in RA disease activity compared with the control group.
SKIN DISEASE — The most common of the cutaneous manifestations of rheumatoid arthritis (RA) is the rheumatoid nodule . Other cutaneous manifestations may arise when rheumatoid vasculitis is present (see 'Noncardiac vascular disease' below), or such manifestations may arise due to dermal infiltration of neutrophils. Atrophic skin over involved joints is sometime present. (See 'Rheumatoid nodules' below and 'Skin ulcers' below and 'Neutrophilic dermatoses' below and 'Medication-induced skin changes' below.)
Rheumatoid nodules — Palpable nodules are present in a minority of patients with seropositive RA at some point during their disease course, usually in the skin and subcutaneous tissues. Nodules are common on pressure points such as the olecranon but can form anywhere within or upon the body, including the lungs (see "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Rheumatoid lung nodules'). Most skin nodules need no specific treatment. Rheumatoid nodules and their management are discussed in detail separately. (See "Rheumatoid nodules".)
Skin ulcers — Ulcerative lesions may result from venous stasis, arterial insufficiency, neutrophilic infiltration, and/or vasculitis (picture 1) . Chronic ulcers in patients with RA are often multifactorial and may require aggressive immunosuppression for healing. (See 'Neutrophilic dermatoses' below and 'Noncardiac vascular disease' below and "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Cutaneous vasculitis'.)
One study found that lower-extremity ulcers were relatively common in patients with RA, occurring with a cumulative incidence of approximately 1 percent of patients yearly following the diagnosis of RA . They typically take a month to heal, but when associated with vasculitis, may result in serious complications, including a requirement for amputation, and are associated with increased risk for premature mortality.
Neutrophilic dermatoses — Dermal manifestations associated with sterile infiltration of neutrophils are uncommon; these include Sweet syndrome (picture 2), pyoderma gangrenosum (picture 3), and rheumatoid neutrophilic dermatitis (picture 4). (See "Neutrophilic dermatoses".)
Medication-induced skin changes — Medications used to treat RA can cause skin changes. These include skin atrophy and ecchymoses from glucocorticoids, as well as petechiae from medications that cause thrombocytopenia. (See "Major side effects of systemic glucocorticoids" and "Hematologic complications of rheumatoid arthritis".)
Other — Rare cutaneous manifestations include erythema elevatum diutinum, linear bands or annular lesions, urticarial eruptions, and dermal papules which may have various histologic appearances, ranging from edema, vasculitis, or palisading granulomatous inflammation . Raynaud phenomenon is relatively common in patients with RA, affecting nearly one-quarter of patients in one study . (See "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Epidemiology'.)
EYE INVOLVEMENT — Eye involvement, other than Sjögren's disease, is uncommon in patients with rheumatoid arthritis (RA), but other inflammatory ophthalmic manifestations can occur and sometimes require urgent attention by an ophthalmologist. Patients with significant change in visual acuity over a period of several days or weeks, moderate to severe ocular pain, or new-onset redness that is progressive should be referred for urgent evaluation to an ophthalmologist with expertise in the management of ocular inflammation or cornea-external diseases. (See "Ocular manifestations of rheumatoid arthritis", section on 'Indications for urgent referral to an ophthalmologist'.)
Major ocular manifestations of RA are discussed separately and include:
●Sjögren's disease – (picture 5) (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease", section on 'Dry eye'.)
●Episcleritis – (picture 6) (See "Ocular manifestations of rheumatoid arthritis", section on 'Episcleritis'.)
●Scleritis – Scleritis (picture 7) may rarely result in scleromalacia perforans (picture 8). (See "Ocular manifestations of rheumatoid arthritis", section on 'Scleritis'.)
●Other disorders – Rare ophthalmic manifestations include uveitis, including iritis; and peripheral ulcerative keratitis, which may result in corneal melt. (See "Ocular manifestations of rheumatoid arthritis".)
LUNG DISEASE — The clinical manifestations, diagnosis, and management of pleural (eg, pleuritis and pleural effusion) and parenchymal lung diseases (eg, interstitial fibrosis, pulmonary nodules, bronchiolitis obliterans, and organizing pneumonia) that are associated with rheumatoid arthritis (RA) are presented separately. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis".)
Lung disease caused by drugs or other agents used to treat RA may occur as a result of direct pulmonary toxicity (eg, rarely methotrexate, leflunomide, anti-tumor necrosis factor [TNF] agents, or other biologic agents) or as a result of infectious complications resulting from immunosuppression (eg, glucocorticoids, antimetabolites, and anticytokine therapies). (See "Drug-induced lung disease in rheumatoid arthritis" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)
CARDIAC DISEASE — There are several forms of heart disease that may affect patients with rheumatoid arthritis (RA), including conditions affecting the peri- and myocardium, coronary arteries, and the conduction system.
These conditions are discussed in detail elsewhere and include:
●Pericarditis – Clinical episodes of pericarditis are uncommon in RA, but asymptomatic disease is more often detected by echocardiography or on autopsy. Restrictive pericarditis with tamponade physiology is very uncommon. Pericarditis occurs most frequently in patients with active seropositive RA and other extraarticular manifestations. Rheumatoid pericarditis and its management is discussed separately. (See "Pericardial involvement in systemic autoimmune diseases", section on 'Rheumatoid arthritis' and "Diagnosis and treatment of pericardial effusion".)
●Myocarditis – Myocarditis, which can be either granulomatous or interstitial, is rare in RA and is usually associated with active articular disease and with other nonarticular manifestations. Granulomatous myocarditis has higher specificity for RA, while the interstitial form is much less frequent in RA than in systemic lupus erythematosus (SLE). Direct granulomatous involvement of the endocardium can produce mitral insufficiency, while involvement of the conduction system can induce atrioventricular block. Myocarditis associated with RA and its management are described in detail separately. (See "Clinical manifestations and diagnosis of myocarditis in adults" and "Overview of heart disease in rheumatoid arthritis".)
●Coronary artery disease – The risks of sudden death and myocardial infarction appear to be increased in patients with RA. Although a higher prevalence of traditional cardiac risk factors may be present in patients with RA than in the general population, epidemiologic data suggest that RA is an independent risk factor for coronary artery disease. Issues related to coronary heart disease in patients with RA are presented elsewhere. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications" and "Coronary artery disease in rheumatoid arthritis: Implications for prevention and management".)
●Heart failure – The incidence of heart failure in patients with RA is increased approximately twofold compared with people without RA. As is the case with coronary heart disease, the increased risk of heart failure is not fully explained by other, traditional risk factors. A discussion of the evidence for an association between RA and heart failure, particularly heart failure with a preserved ejection fraction (HFpEF), is presented separately. (See "Heart failure in rheumatoid arthritis".)
Other causes of heart failure in patients with RA include ischemic cardiomyopathy (see "Heart failure in rheumatoid arthritis"); drug-induced myopathy (eg, from antimalarial agents) (see "Antimalarial drugs in the treatment of rheumatic disease", section on 'Neuromuscular toxicity'); nonsteroidal antiinflammatory drug (NSAID)-exacerbated heart failure (see "NSAIDs: Adverse cardiovascular effects"); rheumatoid nodules, which may cause valvular insufficiency and heart block (see "Rheumatoid nodules", section on 'Cardiac nodules'); and AA (secondary) amyloidosis. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)
●Asymptomatic myocardial disease – Subclinical cardiovascular disease can be detected using magnetic resonance imaging (MRI) and other techniques in RA, including findings of focal and diffuse myocardial fibrosis and inflammation. These changes are associated with RA disease activity and are described in more detail separately. (See "Overview of heart disease in rheumatoid arthritis".)
●Atrial fibrillation – The risk of atrial fibrillation (AF) is increased in patients with RA, as are risk factors for AF, including heart failure, ischemic heart disease, and cigarette smoking. Stroke risk is also increased. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation" and "Overview of heart disease in rheumatoid arthritis".)
●Rheumatoid nodules – Rheumatoid nodules may develop in the pericardium, myocardium, and valvular structures, and may be noted echocardiographically. Symptoms related to the presence of nodules are rare, but syncope or death due to heart block from a lesion situated in the conduction system can occur. Stroke or other manifestations of arterial embolization, as well as valvular insufficiency, may result from nodules on a heart valve. (See "Rheumatoid nodules", section on 'Cardiac nodules'.)
The overall risk of cardiac disease among patients with RA has declined since the 1980s, possibly owing, at least in part, to improved management of the underlying systemic inflammatory disease of RA .
NONCARDIAC VASCULAR DISEASE — Vascular disease can take several forms in patients with rheumatoid arthritis (RA). Vasculitis of small to medium blood vessels can occur, and higher-than-expected rates of coronary artery, peripheral vascular, and cerebrovascular disease are also seen.
Vasculitis — The manifestations of rheumatoid vasculitis range from a relatively limited condition, with focal digital involvement alone (eg, with nailfold infarcts), to a severe, systemic condition with visceral arteritis that can involve a range of organ systems and can resemble polyarteritis nodosa. Other manifestations include cutaneous ulceration, digital gangrene, neurovascular disease resulting in peripheral neuropathy (eg, mild distal sensory neuropathy, severe sensorimotor neuropathy), and palpable purpura. Both small- and medium-sized vessels can be involved. Rheumatoid vasculitis is discussed in detail separately. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
Peripheral vascular disease — Patients with RA are at increased risk of atherosclerotic peripheral arterial disease and of venous thromboembolic disease, including pulmonary embolism:
●Atherosclerotic peripheral vascular disease – The prevalence of atherosclerotic peripheral artery disease appears to be greater in patients with RA than in otherwise healthy individuals. Risk factors include elevated inflammatory markers, the presence of extraarticular disease manifestations, and glucocorticoid use.
In one study comparing nonsmoking patients with healthy, nonsmoking controls, peripheral arterial abnormalities were present in a greater proportion of those with RA (19 versus 5 percent) . Markers of inflammation (eg, C-reactive protein or erythrocyte sedimentation rate) and glucocorticoid use accounted for some of the excess risk; however, the increase in risk was not explained by traditional markers of cardiovascular risk such as hypertension, diabetes, and hyperlipidemia.
In another study, the presence of other systemic and nonarticular manifestations of RA appeared to be an independent risk factor, with more than doubling of risk in patients with severe extraarticular disease compared with those lacking these features .
●Venous thromboembolic disease – Patients with RA appear to have an up to twofold higher occurrence of venous thromboembolism (VTE), but the factors that are responsible for this increase are uncertain, although selected drugs used to treat RA may be implicated in a subset of these patients:
•A population-based study conducted in Sweden noted that the increase in risk among patients with RA compared with the general population could be detected within the year following diagnosis and did not increase further during the first decade of disease . The risk was further increased among patients who required hospitalization, although the increase in such patients with RA was comparable with that in the general population.
•Another study, involving a United States cohort of 22,143 patients with RA and 88,572 matched controls without RA, found an elevated risk of venous thromboembolic events (a composite of deep vein thrombosis and pulmonary embolism) in patients with RA, even after adjustment for multiple risk factors for VTE (eg, cardiovascular disease, hospitalization, surgery, and medications; hazard ratio 1.4, 95% CI 1.1-1.7) .
The risk for VTE may be affected by medications used to treat RA, particularly the Janus kinase (JAK) inhibitors (eg, tofacitinib, baricitinib, upadacitinib), prompting the US Food and Drug Administration (FDA) to require a warning about this risk. Details of the evidence and regulatory guidance are presented separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'JAK inhibitor therapy'.)
Additionally, in one population-based study in the United States, the risk for VTE appeared somewhat higher in patients exposed to anti-tumor necrosis factor (TNF) agents as well as other biologics [59,60]. The occurrence of VTE in a study of inpatients with RA appeared to be related to switching, rather than initiation of, biologic therapy, suggesting that VTE in this setting may be more related to higher disease activity and poor disease control than the biologic agent .
Stroke — Patients with RA may be at increased risk for stroke, although the supporting data are not as conclusive as those reporting an increased risk of coronary artery disease. This is discussed in more detail separately. (See "Neurologic manifestations of rheumatoid arthritis", section on 'Stroke'.)
Lymphatic obstruction — Impaired lymphatic drainage leading to lymphedema is an unusual extraarticular manifestation of RA. In some cases involving unilateral extremity swelling, lymphoscintigraphy confirmed lymphatic obstruction [61-63]. Upper and lower limbs may be affected, and cases of symmetric swelling have been reported . Other causes of lymphedema should be considered before attributing lymphatic obstruction to RA. (See "Clinical features and diagnosis of peripheral lymphedema", section on 'Inflammatory disorders'.)
KIDNEY DISEASE — Direct effects of rheumatoid arthritis (RA) on the kidney are rare and include a focal glomerulonephritis, usually of the mesangioproliferative or membranous type without rapid progression of renal dysfunction, and rheumatoid vasculitis [64-66]. Drug toxicity affecting the kidney is more common because several of the drugs used in RA, including nonsteroidal antiinflammatory drugs (NSAIDs) and cyclosporine, can cause renal disease. There are rare reports of glomerulonephritis developing in patients treated with tumor necrosis factor (TNF) inhibitors .
An observational study has shown that patients with RA experience a higher incidence of reduced kidney function (persistent estimated glomerular filtration rate <60 mL/min/1.73 m2) than non-RA subjects; these changes were predicted by cardiovascular disease, dyslipidemia, elevated sedimentation rate in the first year of RA, and NSAID use .
In addition, patients with longstanding inflammatory disease may develop AA (secondary) amyloidosis, although secondary amyloidosis is now relatively rare in RA because of more effective means of controlling inflammation. Among patients who develop the disease, control of the inflammatory process with medical therapy may lead to resolution both of the proteinuria and of the tissue deposits [69,70]. (See "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases", section on 'Rheumatoid arthritis' and "Treatment of AA (secondary) amyloidosis".)
SJÖGREN'S DISEASE — Sjögren's disease has both a primary form, in which it is apparently the sole systemic disease, and a secondary form, in which it is associated with rheumatoid arthritis (RA) or another rheumatic disease. Symptoms of ocular and/or oral dryness are the hallmarks of this disorder, although other systems may also be affected. The clinical manifestations, classification criteria, and diagnosis of Sjögren's disease are discussed in detail separately. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease" and "Diagnosis and classification of Sjögren’s disease".)
NEUROLOGIC AND PSYCHIATRIC DISEASE — Patients with rheumatoid arthritis (RA) may experience a wide range of neurologic complications. The most common psychiatric disorder in RA is depression.
●Neurologic disease – A range of neurologic abnormalities may be associated with RA, which can involve the peripheral or central nervous system and which can result from local or systemic factors. Carpal tunnel syndrome is the most common neurologic manifestation, and myelopathy or radiculopathy can also occur. Patients with instability of the cervical spine, most commonly at the articulation of C1 and C2, are at increased risk for myelopathy and require particular attention.
Patients with rheumatoid vasculitis may experience subtle or more severe neurologic disease, such as mononeuritis multiplex or a symmetric polyneuropathy. Central nervous system involvement is uncommon.
The neurologic manifestations of RA and rheumatoid vasculitis are discussed in detail elsewhere. (See "Neurologic manifestations of rheumatoid arthritis" and "Cervical subluxation in rheumatoid arthritis" and "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
●Psychiatric disease – Depression is relatively common in patients with RA, and symptoms of depression are associated with increased pain, fatigue, and disability . In addition, depression is an independent risk factor for mortality .
A 2013 meta-analysis reported a 17 percent pooled prevalence of major depressive disorder and a 39 percent prevalence of depression using the Patient Health Questionnaire-9 in patients with RA . It is unclear if depression is mediated by negative cognitive perceptions, behavioral tendencies, or immune-mediated processes . A proposed disease model suggests that RA disease activity and physical and mental health are connected via central neuroendocrine pathways as well as altered dopaminergic pathways, resulting in abnormal pain processing, negative affect, and maladaptive coping strategies, contributing ultimately to physical and psychosocial distress in some patients .
Psychological factors affecting patients with RA and other chronic medical conditions and the management of these issues are described in detail separately. (See "Psychological factors affecting other medical conditions: Clinical features, assessment, and diagnosis" and "Psychological factors affecting other medical conditions: Management".)
HEMATOLOGIC ABNORMALITIES — There are several different hematologic manifestations of rheumatoid arthritis (RA), most of which are associated with disease activity or severity. The hematologic complications of RA are described in more detail separately. (See "Hematologic complications of rheumatoid arthritis".)
Anemia is commonly present in patients with active RA. Neutropenia, present in Felty syndrome and in large granular lymphocyte (LGL) leukemia (also termed LGL syndrome), may require therapeutic interventions, while reactive thrombocytosis and eosinophilia generally parallel disease activity and do not themselves require treatment. (See "Hematologic complications of rheumatoid arthritis", section on 'High WBC or eosinophil count' and "Hematologic complications of rheumatoid arthritis", section on 'High or low platelet count'.)
Hematologic abnormalities associated with RA include:
●Anemia – Most patients with RA have a mild normocytic hypochromic anemia that correlates with the erythrocyte sedimentation rate and general disease activity. The anemia is that of chronic inflammation, in which there is an inability of the marrow to incorporate stored iron into red blood cells and in which the hemoglobin concentration is rarely less than 10 g/dL. (See "Anemia of chronic disease/anemia of inflammation" and "Hematologic complications of rheumatoid arthritis", section on 'Anemia'.)
●Felty syndrome – Patients with Felty syndrome have seropositive RA and neutropenia. Many have an associated anemia or thrombocytopenia, an enlarged spleen, and, rarely, leg ulcers. More detailed discussions of the clinical manifestations, the drug treatment, and the role of splenectomy in Felty syndrome are presented separately. (See "Clinical manifestations and diagnosis of Felty syndrome" and "Drug therapy in Felty syndrome" and "Role of splenectomy for Felty syndrome".)
●Large granular lymphocyte leukemia – Also known as "pseudo-Felty syndrome" (and also termed LGL syndrome), LGL leukemia must be distinguished from Felty syndrome. Patients with LGL leukemia have many circulating LGLs, neutropenia, splenomegaly, and frequent infections. LGL leukemia is discussed in detail elsewhere. (See "Large granular lymphocyte leukemia in rheumatoid arthritis".)
●Lymphoproliferative disease – LGL proliferation may be present in some patients with RA, and, in a minority, it will progress to LGL leukemia. (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia", section on 'Autoimmune disorders'.)
In addition, the risk of lymphoma is increased in patients with RA, both in those treated with methotrexate and in those with active disease who have not been exposed to methotrexate or to other immunosuppressive agents. Longstanding, active disease is the major risk factor for lymphoma in patients with RA. (See "Major side effects of low-dose methotrexate" and "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Lymphoproliferative disorders'.)
●Drug-induced cytopenia – Neutropenia or lymphopenia may occur with use of tumor necrosis factor (TNF) inhibitors and other agents, including interleukin (IL) 6 inhibitors and Janus kinase (JAK) inhibitors. Bone marrow suppression can be seen with a variety of immunosuppressive agents. Drug-related hematologic changes are described separately. (See "Hematologic complications of rheumatoid arthritis", section on 'Neutropenia causes'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Anemia of inflammation (anemia of chronic disease) (The Basics)")
●Epidemiology and risk factors – Involvement of the musculoskeletal system other than joints (eg, bone and muscle) and of nonarticular organs (eg, skin, eye, lungs, heart, and others) occurs in approximately 40 percent of patients with rheumatoid arthritis (RA) over the course of the disease. Risk factors for systemic, extraarticular disease include the presence of rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPA), and smoking. Extraarticular involvement in RA is associated with increased severity of disease, with overall morbidity, and with premature mortality. (See 'Epidemiology and risk factors' above.)
●Constitutional symptoms – Constitutional and systemic symptoms and findings may include generalized aching, stiffness, and constitutional symptoms such as fevers, weight loss, and fatigue; these features sometimes antedate the onset of articular disease by several months. (See 'Constitutional/systemic symptoms' above.)
●Osteopenia – Bone loss in RA is common. It may be generalized, resulting from immobility, the inflammatory process, and treatment effects of glucocorticoids; periarticular, due to local inhibition of bone formation by immune cells; or focal, due to degradation of juxtaarticular bone by activated osteoclasts. In the absence of antiresorptive therapy, all patients with RA can be expected to lose bone mineral. The generalized and periarticular osteopenia that affects all patients with RA should lead to a low threshold for therapy to prevent bone loss. (See 'Osteopenia' above.)
●Sarcopenia – Muscle weakness is a common symptom in RA. It may have several, often additive, causes. These include synovial inflammation, drug-induced muscle disease, myositis, and vasculitis. (See 'Synovial inflammation' above and 'Drug-induced myopathy' above and 'Myositis' above and 'Vasculitis' above.)
●Weight gain – Body composition is frequently altered in patients with RA, with changes of increased body fat mass and reduced lean body mass (sarcopenia), even at normal body mass index. Altered body composition contributes to reduced physical function and cardiometabolic risk and may be attenuated by formal exercise interventions and control of the underlying inflammatory disease. (See 'Altered body composition' above.)
●Cutaneous manifestations – The most common of the cutaneous manifestations of RA is the rheumatoid nodule. Other cutaneous manifestations may arise when rheumatoid vasculitis is present or may be due to dermal infiltration of neutrophils. Atrophic skin over involved joints is sometimes present. (See 'Skin disease' above and "Rheumatoid nodules".)
●Ocular manifestations – Symptoms of ocular and/or oral dryness are the hallmarks of Sjögren's disease, which may occur in association with RA. Eye involvement in RA also may include episcleritis, scleritis, peripheral ulcerative keratitis, and, less frequently, uveitis. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease" and 'Eye involvement' above.)
●Pulmonary manifestations – Pulmonary involvement in RA may include pleurisy and parenchymal lung diseases (eg, interstitial fibrosis, pulmonary nodules, bronchiolitis obliterans, and organizing pneumonia), as well as lung disease caused by drugs or other agents used to treat RA or as a result of infectious complications resulting from immunosuppression. (See 'Lung disease' above and "Drug-induced lung disease in rheumatoid arthritis" and "Overview of pleuropulmonary diseases associated with rheumatoid arthritis".)
●Cardiac manifestations – Cardiac involvement, such as clinically apparent pericarditis and myocarditis, and the presence of rheumatoid nodules in the pericardium, myocardium, or valvular structures are uncommon in patients with RA, although there is an increased risk of coronary artery disease, heart failure, and atrial fibrillation (AF). Vascular disease can take several forms in patients with RA. Vasculitis of small to medium blood vessels can occur, and higher-than-expected rates of coronary artery, peripheral vascular, and cerebrovascular disease are also seen. (See 'Cardiac disease' above and 'Noncardiac vascular disease' above and "Clinical manifestations and diagnosis of rheumatoid vasculitis" and "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications" and "Heart failure in rheumatoid arthritis" and "Overview of heart disease in rheumatoid arthritis".)
●Renal manifestations - Direct effects of RA on the kidney are rare. Membranous and mesangioproliferative glomerulonephritis are the most commonly reported nephropathies. Rheumatoid vasculitis may also occur. Drug toxicity is much more common. (See 'Kidney disease' above.)
●Neurologic manifestations – A range of neurologic abnormalities may be associated with RA, which can involve the peripheral or central nervous systems and which can result from local or systemic factors. Carpal tunnel syndrome is the most common neurologic manifestation, and a compressive myelopathy or radiculopathy can also occur. Patients with rheumatoid vasculitis may experience subtle or more severe neurologic disease. (See 'Neurologic and psychiatric disease' above and "Neurologic manifestations of rheumatoid arthritis" and "Cervical subluxation in rheumatoid arthritis" and "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
●Hematologic manifestations – Anemia is commonly present in patients with active RA. Other hematologic abnormalities, including neutropenia, which is present in Felty syndrome and in large granular lymphocyte (LGL) leukemia (LGL syndrome), may require therapeutic interventions, while reactive thrombocytosis and eosinophilia generally parallel disease activity and do not themselves require treatment. Cytopenias related to the drugs used to treat RA also may be seen. (See 'Hematologic abnormalities' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Schur, MD, Carl Turesson, MD, and Eric Matteson, MD, MPH, who contributed to an earlier version of this topic review.
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