Overview of the systemic and nonarticular manifestations of rheumatoid arthritis

Overview of the systemic and nonarticular manifestations of rheumatoid arthritis

Authors
Eric L Matteson, MD, MPH
John M Davis, MD, MS

Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS

Deputy Editor
Paul L Romain, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2016. &#124 This topic last updated: Aug 10, 2015.

INTRODUCTION — Although rheumatoid arthritis (RA) develops its central pathology within the synovium of diarthrodial joints, many nonarticular organs become involved, particularly in patients with severe joint disease. Despite the differences between the normal form and function of joints and, for example, the bone marrow, it is becoming clearer that the same cytokines that drive synovial pathology are also responsible for generating pathology in extraarticular tissues. (See "Pathogenesis of rheumatoid arthritis".)
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 about 40 percent of patients with RA over a lifetime of disease [1,2]. These manifestations are reviewed here. Articular manifestations are discussed in detail separately. (See "Clinical manifestations of rheumatoid arthritis".)
RISK FACTORS — Risk factors for systemic, extraarticular disease include age, presence of rheumatoid factor (RF) or antinuclear antibodies, human leukocyte antigen (HLA)-DRB1 ‘shared epitope’ alleles, early disability, and smoking [1,3,4]. 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 but without extraarticular disease [5].
Extraarticular involvement in RA is a marker of disease severity and is associated with increased overall morbidity and premature mortality [6,7]. Successful management of systemic manifestations of RA is predicated upon control of the underlying joint disease and often includes glucocorticoid and immunosuppressive treatments [8].
OSTEOPENIA — Bone loss in rheumatoid arthritis (RA) may be systemic, periarticular, or focal [9]:
●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), or the effects of glucocorticoid therapy [9]. 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. Patients with RA have a 30 percent increased risk of major osteoporotic fracture and 40 percent increased risk of hip fracture [10]. 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.
Periodontal bone loss may be associated with joint destruction at the wrist, and both have been associated with the possession of the “shared epitope” [11]. The presence of a lymphocytic infiltration of the salivary glands and the sicca syndrome were also associated with periodontal bone resorption in this study [11]. (See 'Sjögren's syndrome' below.)
●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. Histopathological studies have shown these lesions to represent “osteitis” composed of replacement of bone marrow fat with lymphoid aggregates [12]. 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 [13,14].  (See "Clinical manifestations of rheumatoid arthritis", section on 'Plain film radiography'.)
●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 [15]. (See "Clinical manifestations of rheumatoid arthritis", section on 'Plain film radiography'.)
Prevalence — Osteoporosis of the hip or lumbar spine is common in adults with RA. This was illustrated in one study of 287 Norwegian patients among whom the prevalence of osteoporosis, as indicated by a bone mineral density of more than 2.5 standard deviations below the average for healthy young people at one or both sites, was 22 percent [16].
There are conflicting data on the 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 "Pathogenesis, clinical features, and evaluation of glucocorticoid-induced osteoporosis", section on 'Effect of low-dose glucocorticoid therapy'.)
All else being equal, 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. However, it is possible that, in those patients who gain greater mobility and exercise tolerance, 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 [17]. 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 [18].
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:
●Postmenopausal state
●A previous diagnosis of osteoporosis
●Disability
●Increased age
●Inadequate physical activity
●Female sex
●Family history of osteoporosis
●Disease duration
●Impaired grip strength
●Low body mass
●Fair complexion
●Cigarette smoking
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 among patients (bone mineral density [BMD] decreased by more than one standard deviation [SD]) [19]. Multiple regression analysis found advancing age and lower body weight to be 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.
There is a high incidence of stress fracture of long bones in patients with RA, particularly in those treated with glucocorticoids [20]. Synovitis and glucocorticoid use are both risk factors for thinning of cortical bone [21]. 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 [22]. Vertebral compression deformities are also more common among those with RA than among age- and gender-matched controls [23]. The higher prevalence is not fully explained by their lower BMD or by the use of glucocorticoids.
Diagnosis — It should be assumed that every patient with RA is at risk for osteoporosis. Those patients with added risk factors outlined above should be considered for baseline determinations of BMD before the disease becomes well-entrenched and before glucocorticoid therapy is started. Dual energy x-ray absorptiometry is a widely available, precise, and reliable method for measuring bone density; quantitative computerized tomography (CT) is another option. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women".)
Management — The generalized and periarticular osteopenia that affects all patients with RA should lead to a low threshold for therapy to prevent bone loss. Interventions that are used to prevent or minimize RA and glucocorticoid-induced bone loss are presented elsewhere. Rheumatologists and primary care clinicians should have a low threshold for initiating bisphosphonate therapy in patients, particularly postmenopausal women, with RA. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis", section on 'Bone protection' and "Prevention and treatment of glucocorticoid-induced osteoporosis".)
MUSCLE WEAKNESS — Muscle weakness is a common symptom in rheumatoid arthritis (RA). It may have several, often additive, causes.
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 and preventive measures for patients with rheumatoid arthritis", section on 'Exercise'.)
Myositis — In autopsy series, focal accumulation of lymphocytes and plasma cells contiguous with foci of muscle necrosis are found in almost all patients with RA. These lesions have been called nodular myositis. They are particularly common in a small but interesting subset of patients who have mild synovitis and a disproportionately elevated erythrocyte sedimentation rate [24]. Some foci of muscle lymphocytes have been shown to synthesize immunoglobulin M (IgM) rheumatoid factor (RF) [24].
Rarely, a patient with RA develops a true polymyositis, with elevated levels of serum creatine kinase and with typical findings on electromyography and muscle biopsy. These patients should be managed as are those with polymyositis, by using prednisone in moderately high doses (60 to 80 mg/day) and by having a plan of moving quickly to methotrexate (25 mgintramuscular/week) or azathioprine (up to 2.5 mg/kg per day). (See "Initial treatment of dermatomyositis and polymyositis in adults".)
Vasculitis — Patients with RA may occasionally develop vasculitis. Risk factors include high titers of 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".)
Drug-induced myopathy — Superimposed on active RA, with or without 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. (See "Glucocorticoid-induced myopathy".)
●Glucocorticoid myopathy is unusual in patients treated with less than 10 mg/day of prednisone or its equivalent.
●The higher the dose of glucocorticoid, the greater is the likelihood of developing myopathy, and the more rapid is the onset of weakness. Daily doses in excess of 40 to 60 mg/day can induce clinically important weakness within two weeks and almost always result in some degree of muscle weakness when continued for more than one month.
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's 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 'Antimalarial drugs'.)
Lipid-lowering drugs — Recognition of the increased incidence of cardiovascular disease in patients with RA and of the increased prevalence of traditional risk factors for coronary artery and other atherosclerotic disease has led to more vigorous use of lipid-lowering agents, especially statins, in many adults with RA. 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 myopathy".)
ABNORMAL BODY COMPOSITION — Body composition is frequently abnormal in patients with rheumatoid arthritis (RA), with changes of increased body fat mass and reduced lean body mass (sarcopenia), even at normal body mass index. Abnormal 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 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 [25]. 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 [26]. Increased abdominal visceral fat and epicardial fat are predictive of increased cardiometabolic risk and metabolic syndromes [27,28].
Predictors of abnormal body composition include [25,26]:
●Increased age
●Long disease duration
●High inflammatory disease activity (eg, as measured by tender joint counts, C-reactive protein, interleukin [IL]-6)
●Positive rheumatoid factor (RF)
●Sedentary lifestyle
●Lack of treatment with disease-modifying antirheumatic drugs (DMARD)
In one study the use and cumulative dose of prednisone were not associated with abnormal body composition [25]; glucocorticoid use is known to cause type II muscle fiber atrophy and has, as expected, been associated with reduced muscle density [29].
Abnormal body composition with sarcopenia and excess fat mass are predictive of disability and adverse quality of life [26,29]. 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 [30]. 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 [31]. 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.
Rheumatoid nodules — Palpable nodules are present in up to 20 to 35 percent of patients with RA at some point during their disease course. Rheumatoid factor (RF) is almost always present in patients with nodules. Nodules are common on pressure points such as the olecranon but can form anywhere within or upon the body (eg, in the lungs) (see 'Lung disease' below). Most skin nodules need no specific treatment. For painful nodules or for those that interfere with joint motion or that impinge upon nerves, local injection with a mixture of a potent glucocorticoid and local anesthetic may cause regression. Surgical excision of skin nodules is rarely indicated. A more detailed discussion of rheumatoid nodules in the skin and subcutaneous tissues is presented separately. (See "Rheumatoid nodules", section on 'Subcutaneous rheumatoid nodules'.)
Skin ulcers — Ulcerative lesions may result from venous stasis, arterial insufficiency, neutrophilic infiltration, and/or vasculitis (picture 1) [32]. 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.)
One study found that lower-extremity ulcers were relatively common in patients with RA, occurring with a cumulative incidence of about one percent of patients yearly following the diagnosis of RA [33]. 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 manifestations 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 [34]. The Raynaud phenomenon is relatively common in patients with RA, affecting nearly one-quarter of patients in one study [35]. (See "Clinical manifestations and diagnosis of the Raynaud phenomenon", section on 'Epidemiology'.)
EYE INVOLVEMENT — Episcleritis and scleritis occur in less than 5 percent of patients. Uveitis, including iritis, may also occur in rheumatoid arthritis (RA). Scleritis and peripheral ulcerative keratitis with corneal melt can be devastating consequences of RA. This is discussed in detail elsewhere. (See "Ocular manifestations of rheumatoid arthritis".)
●In episcleritis, the eye becomes acutely red and painful without a discharge (picture 5). (See "Episcleritis".)
●In scleritis, there is a deep ocular pain. In addition, dark red discoloration can appear as metalloproteases generated by activated scleral cells degrade scleral collagen (picture 6), in rare cases down to the uveal layer (called scleromalacia perforans) (picture 7). (See "Clinical manifestations and diagnosis of scleritis".)
Keratoconjunctivitis sicca, or dry eyes, occurs in 10 to 20 percent of patients as part of the sicca complex (picture 8). (See "Clinical manifestations of Sjögren's syndrome: Exocrine gland disease".)
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 lung disease 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, anti TNF agents and gold salts) 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".)
In association with an increased risk for venous thromboembolic events, the risk of pulmonary embolus may also be increased in patients with RA [36]. (See 'Peripheral vascular disease' below.)
CARDIAC DISEASE — Clinically apparent pericarditis and myocarditis are uncommon disorders in patients with rheumatoid arthritis (RA). There is an increased risk of coronary artery disease in patients with RA, and there may be an increased risk of heart failure and of atrial fibrillation [37,38]. These issues and cardiac involvement by rheumatoid nodulosis are discussed in the following sections.
Pericarditis — During the course of disease, less than 10 percent of patients have a clinical episode of pericarditis, although up to 30 percent have echocardiographic evidence of pericardial effusions that are of no clinical significance. The prevalence of pericardial involvement at a single point in time in a group of 30 patients with RA when assessed using transesophageal echocardiography was 13 percent [39]. Other patients have asymptomatic pericardial involvement detected at autopsy. Restrictive pericarditis with tamponade physiology is uncommon and may present a diagnostic challenge.
Most patients with symptomatic pericarditis have a positive test for rheumatoid factor (RF) in sera. Pericarditis occurs most frequently in patients with active rheumatoid disease and other extraarticular manifestations. As a result, management should be linked to control of the RA.
Treatment — As in other nonbacterial causes of pericarditis, glucocorticoids are preferred if maximal doses of nonsteroidal antiinflammatory drugs (NSAIDs) are not effective. High-dose prednisone (1 mg/kg per day) may be required in patients with RA and severe, exudative pericarditis. Surgery may be necessary in some patients with severe constrictive pericarditis and with associated heart failure. (See "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 [40]. 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.
Diagnosis — Echocardiography can be used to assess left ventricular function. Right ventricular biopsy at time of cardiac catheterization may be helpful diagnostically if myocarditis or chronic constrictive pericarditis is considered as a possible cause of heart failure [41]. (See "Clinical manifestations and diagnosis of myocarditis in adults".)
Differential diagnosis — The major differential diagnostic entities to consider in a patient with RA who develops heart failure are:
●Ischemic cardiomyopathy – The risk of coronary artery disease is significantly increased among patients with RA. Previously unrecognized myocardial infarction or severe ischemia may be a cause of heart failure. Rarely, widespread myocardial dysfunction can be the result of rheumatoid vasculitis [42]. (See 'Coronary artery disease' below.)
●Drug-induced myopathy – Antimalarial drugs used to treat RA can sometimes cause myopathy. Skeletal muscle and myocardium may be affected. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Neuromuscular and cardiac toxicity'.)
●NSAID-exacerbated heart failure – Use of nonselective NSAIDs and selective cyclooxygenase (COX)-2 inhibitors may unmask subclinical heart failure due to effects on blood pressure and renal function. (See "Nonselective NSAIDs: Adverse cardiovascular effects", section on 'Patients with heart failure' and "COX-2 selective inhibitors: Adverse cardiovascular effects".)
●Rheumatoid nodules – Valvular insufficiency and heart block may be manifestations of rheumatoid nodules. (See 'Rheumatoid nodules' above.)
●Amyloidosis – Deposition of AA amyloid (secondary amyloidosis) may occur, causing an infiltrative cardiomyopathy. Patients with longstanding active RA are at increased risk for this complication. Concomitant renal involvement with proteinuria or nephrotic syndrome is often present. (See "Clinical manifestations and diagnosis of amyloid cardiomyopathy".)
Treatment — Because of the rarity of rheumatoid myocarditis, optimal treatment is uncertain. In one reported case of heart failure due to rheumatoid vasculitis with myocardial involvement that was detected by right ventricular biopsy, a favorable response to glucocorticoid therapy was noted [41]. We suggest use of high-dose methylprednisolone (pulse therapy 500 to 1000 mg/day for three days or 80 mg daily) as initial therapy.
Use of an anti-tumor necrosis factor (TNF)-alpha agent could be considered for a patient with mild heart failure or with other manifestations of myocarditis. However, high doses of anti-TNF agents have been associated with increased severity and mortality when used in patients with severe heart failure of other etiologies, and their use in patients with moderate to severe heart failure should be avoided. Immunosuppressive therapies such as azathioprine and cyclophosphamide, as used for the treatment of systemic rheumatoid vasculitis, are other options for patients who do not respond to glucocorticoids. The role of biologic therapies in the management of rheumatoid myocarditis is uncertain. (See "Heart failure and left ventricular dysfunction in rheumatoid arthritis" and "Treatment of rheumatoid vasculitis".)
Asymptomatic myocardial disease — Subclinical myocardial disease is relatively common in patients with RA [43,44], despite the rarity of clinical myocarditis and the infrequency of asymptomatic left ventricular dysfunction (see 'Myocarditis' above and "Heart failure and left ventricular dysfunction in rheumatoid arthritis", section on 'Asymptomatic LV dysfunction'). In a study of 39 patients with RA without known heart disease, who were under age 65, and 39 matched controls, 46 percent of the patients with RA but none of the controls had evidence of focal fibrosis on cardiac magnetic resonance imaging (MRI), which included T1-mapping, with T2-weighted and late gadolinium enhancement imaging [44]. Diffuse myocardial fibrosis and inflammation were also evident among the patients with RA, and the fibrotic and inflammatory changes were associated with impaired strain and RA disease activity.
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. Among patients with RA, those with systemic involvement are at a higher risk of coronary events [45]. These data and other 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".)
Cardiovascular disease is a major contributor to increased mortality among patients with RA. The effect of atherosclerotic coronary artery disease on long-term patient outcomes is discussed separately. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Mortality'.)
Heart failure — The incidence of heart failure in patients with RA is increased about twofold higher than in 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, as well as left ventricular dysfunction, is presented separately. (See "Heart failure and left ventricular dysfunction in rheumatoid arthritis".)
Atrial fibrillation — Risk factors for atrial fibrillation (AF), including heart failure, ischemic heart disease, and cigarette smoking, are increased in patients with RA, although the incidence of AF in patients with RA has received little attention. A nationwide cohort study in Denmark involving 18,247 patients with RA followed for a median of 4.8 years found a significant increase in the risk of atrial fibrillation in patients with RA, compared with age- and sex-matched controls from the general population (event rates of 8.2 versus 6 per 1000 person-years) [38]. This represented a greater than 40 percent increase in the incidence of atrial fibrillation in RA (adjusted incidence rate ratio 1.41, 95% CI 1.31-1.51).
The incidence of stroke was also increased in this cohort of patients with RA. The relative risks of both AF and stroke were increased to a greater extent in younger patients, while the absolute differences in risk were higher in older patients. (See 'Stroke' below.)
Nodules — Rheumatoid nodules may develop in the pericardium, myocardium, and valvular structures [46]. They may be noted echocardiographically [47]. 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 [48]. Stroke or other manifestations of arterial embolization, as well as valvular insufficiency, may result from nodules on a heart valve [49-51]. The histopathology of rheumatoid nodules in the heart is similar to that of nodules at other sites. (See 'Rheumatoid nodules' above.)
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, to a severe, systemic condition which may resemble polyarteritis nodosa. Both small- and medium-sized vessels can be involved. Rheumatoid vasculitis is discussed in detail separately. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
The following is a brief summary of some of the varied manifestations of rheumatoid vasculitis:
●Distal arteritis that can range from nailfold infarcts (common) to gangrene of finger tips (rare).
●Cutaneous ulceration, which can resemble pyoderma gangrenosum in severe cases.
●Neurovascular disease, which can lead to a mild distal sensory neuropathy or to a severe sensorimotor neuropathy (eg, mononeuritis multiplex). Neuropathic pain may be a major problem, but this often responds to immunosuppressive treatment in patients with vasculitis-related neuropathy. Other symptoms, such as numbness or local weakness, are more likely to persist.
●Visceral arteritis, which is identical to necrotizing polyarteritis and which can involve peripheral nerves, as well as the bowel, lungs, heart, spleen, and other organs. Intestinal involvement can begin as minor abdominal pain, with an initially normal physical examination, that can progress to severe pain with abdominal tenderness and a lack of bowel sounds on physical examination, bowel infarction, and gastrointestinal bleeding.
●Palpable purpura, which is rarely found in untreated RA and which, when present, is usually linked to antirheumatic therapy.
●Digital gangrene, the presence of intestinal involvement, cardiac involvement, and mononeuritis multiplex, which are associated with a very poor prognosis. (See 'Nervous system involvement' below.)
Peripheral vascular disease — The prevalence of atherosclerotic peripheral artery disease appears to be greater in patients with RA than in otherwise healthy individuals. This was illustrated in a study that compared 234 nonsmoking North American patients with RA with 102 healthy nonsmoking controls [52]. Peripheral arterial abnormalities (an abnormal ankle or brachial index and/or evidence of occlusion of a peripheral artery) were present in a significantly greater proportion of those with RA (19 versus 5 percent). These differences were not explained by traditional markers of cardiovascular risk such as hypertension, diabetes, and hyperlipidemia. However, markers of inflammation (eg, C-reactive protein or erythrocyte sedimentation rate) and glucocorticoid use accounted for some of the excess risk seen in those with RA.
The presence of other systemic and nonarticular manifestations of RA appears to be an independent risk factor for the development of peripheral vascular disease. This was illustrated in a retrospective study of 609 patients [53]. After adjustment for other risk factors, the incidence of peripheral vascular events was significantly greater in those with severe extraarticular features of RA than in those without these features (hazard ratio 2.29, 95% CI 1.20-4.34).
In particular, patients with RA appear to have an up to twofold higher occurrence of venous thromboembolism (VTE) [54,55]. In one population-based study in the US, the risk appeared somewhat higher in patients exposed to anti-TNF agents, although it was unknown whether this was a drug effect or whether anti-tumor necrosis factor (TNF) exposure was a surrogate for more severe disease which may itself be related to this increased risk [54]. In another population-based study, conducted in Sweden, 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 [55]. 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 US 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) [36]. (See "Overview of the causes of venous thrombosis".)
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 [56-58]. Upper and lower limbs may be affected, and cases of symmetrical swelling have been reported [57]. 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 type without rapid progression of renal dysfunction; possible membranous nephropathy; and rheumatoid vasculitis. Much more common is drug toxicity, since many of the drugs used in RA, including nonsteroidal antiinflammatory drugs (NSAIDs), gold, penicillamine, and cyclosporine, can cause renal disease. 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 [59,60]. (See "Causes and diagnosis of secondary (AA) amyloidosis and relation to rheumatic diseases", section on 'Rheumatoid arthritis' and "Treatment of secondary (AA) amyloidosis".)
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 [61].
SJÖGREN'S SYNDROME — Sjögren’s syndrome 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. The clinical manifestations, classification criteria, and diagnosis of Sjögren’s syndrome are discussed in detail separately. (See "Clinical manifestations of Sjögren's syndrome: Exocrine gland disease" and "Clinical manifestations of Sjögren's syndrome: Extraglandular disease" and "Diagnosis and classification of Sjögren's syndrome".)
NERVOUS SYSTEM INVOLVEMENT — A range of neurologic abnormalities may be associated with rheumatoid arthritis (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 instability of the cervical spine, most commonly at the articulation of C1 and C2, are at increased risk for myelopathy and require particular attention. The neurologic manifestations are discussed in detail elsewhere. (See "Neurologic manifestations of rheumatoid arthritis" and "Cervical subluxation in rheumatoid arthritis".)
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. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
HEMATOLOGIC ABNORMALITIES — Anemia is commonly present in patients with active rheumatoid arthritis (RA). Neutropenia, present in Felty’s syndrome and in the large granular lymphocyte syndrome, may require therapeutic interventions, while reactive thrombocytosis and eosinophilia generally parallel disease activity and do not themselves require treatment [62].
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/inflammation" and "Hematologic manifestations of rheumatoid arthritis", section on 'Anemia of chronic disease'.)
Felty's syndrome — Patients with Felty’s 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’s syndrome are presented separately. (See "Clinical manifestations and diagnosis of Felty's syndrome" and "Drug therapy in Felty's syndrome" and "Indications for splenectomy in Felty's syndrome".)
Large granular lymphocyte syndrome — The large granular lymphocyte (LGL) syndrome in RA, or “pseudo-Felty’s syndrome,” must be distinguished from Felty’s syndrome. Patients with LGL syndrome have many circulating LGLs, neutropenia, splenomegaly, and frequent infections. The LGL syndrome 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'.)
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 5^th to 6^th 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 10^th to 12^th 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 information: Anemia of chronic disease (The Basics)")
●Beyond the Basics topics (see "Patient information: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient information: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient information: Complementary and alternative therapies for rheumatoid arthritis (Beyond the Basics)")
SUMMARY
●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 about 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. Successful management depends upon control of the underlying joint disease and upon additional strategies. (See 'Introduction' above.)
●Bone loss in RA is common. It may be generalized, resulting from immobility, the inflammatory process, and treatment effects with 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.)
●Muscle weakness is a common symptom in rheumatoid arthritis. It may have several, often additive, causes, including synovial inflammation, myositis, vasculitis, and drug-induced myopathy (eg, from glucocorticoids, hydroxychloroquine, or statins). (See 'Muscle weakness' above.)
●Body composition is frequently abnormal in patients with RA, with changes of increased body fat mass and reduced lean body mass (sarcopenia), even at normal body mass index. Abnormal 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 'Abnormal body composition' above.)
●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.)
●Symptoms of ocular and/or oral dryness are the hallmarks of Sjögren’s syndrome, 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 syndrome: Exocrine gland disease" and "Clinical manifestations of Sjögren's syndrome: Extraglandular disease" and 'Eye involvement' above.)
●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 lung disease associated with rheumatoid arthritis".)
●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".)
●Direct effects of RA on the kidney are rare and include a focal glomerulonephritis, possible membranous nephropathy, and rheumatoid vasculitis. Drug toxicity is much more common. (See 'Kidney disease' above.)
●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 'Nervous system involvement' above and "Neurologic manifestations of rheumatoid arthritis" and "Cervical subluxation in rheumatoid arthritis" and "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
●Anemia is commonly present in patients with active RA. Neutropenia, present in Felty’s syndrome and in the large granular lymphocyte (LGL) syndrome, may require therapeutic interventions, while reactive thrombocytosis and eosinophilia generally parallel disease activity and do not themselves require treatment. (See 'Hematologic abnormalities' above.)