MEDVERSATION^®

Extra-Articular Manifestations of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic disease with articular and extensive extra-articular manifestations. While much of the focus of this disease is on the pathology and treatment of joint involvement, there are a number of challenges assessing the overall systemic impact of the disease. They include lack of uniformity in the definition or usage of the term extra-articular among studies, a lack of consistent diagnostic criteria for specific manifestations of extra-articular disease, differences in study cohorts, and duration of follow-up.

As a result, a precise determination of incidence or prevalence of extra-articular manifestation of RA is challenging. Estimates from studies of the occurrence of extra-articular manifestations range from 8% -57% of patients with RA.^{10254,  10293,  11042}  Some studies have also indicated an increased mortality associated with the occurrence of extra-articular manifestations compared with RA patients without extra-articular disease.¹⁰²⁹³ 

Extra-articular manifestations can include peripheral nodulosis (rheumatoid nodules  Rheumatoid Nodules), pulmonary disease ( Pulmonary Extra-Articular Manifestations of Rheumatoid Arthritis), cardiac disease ( Cardiac Extra-Articular Manifestations of Rheumatoid Arthritis), ocular disease ( Ocular Extra-Articular Manifestations of Rheumatoid Arthritis), vasculitis ( Vasculitis in Rheumatoid Arthritis), and nervous system disorders ( Neurologic Extra-Articular Manifestations of Rheumatoid Arthritis).

The prevalence and distribution of extra-articular manifestations of RA was reported in a retrospective analysis of 489 patients at the University Hospital in Sweden from January 1990 to June 1994, fulfilling the 1987 American College of Rheumatology criteria. Identification of extra-articular manifestations was done by examining case records and applying an established criteria described in Fig.1035, which allowed for a retrospective evaluation in a uniform manner. It is important to note that most drugs and biologic products are not approved for the treatment of the extra-articular manifestations of RA.

Baseline patient characteristics were compared between those patients who eventually developed extra-articular manifestations and an equal number of blindly selected patients who did not develop extra-articular manifestations matched for disease duration at study entry. At time of study entry, there were no statistically significant differences between the groups in terms of age, number of previous hospital admissions, and number of patients receiving treatment with disease-modifying antirheumatic drugs (DMARDs). A significantly higher proportion of patients who developed extra-articular manifestations were receiving corticosteroids at the beginning of the study compared with patients who did not develop extra-articular manifestations (51% vs. 19%; P=0.003).

Of the 489 patients followed in the study, 37 developed extra-articular manifestations over the study period, for an overall period prevalence of 7.9%. Mortality rates were also increased in the extra-articular group. In all, there were 23 deaths per 100 patient-years at risk for the extra-articular group, compared with 8.7 deaths per 100 patient-years at risk for the non–extra-articular disease group. The excess mortality associated with extra-articular disease tended to be greater among males than females. Mortality rates were also compared for each group, and the age and sex-adjusted mortality rate was found to be 2.49 (95% confidence interval [CI], 1.44-4.31). The expected survival rates for the 2 subgroups were also calculated using Swedish age-specific mortality statistics. The standardized mortality ratio was greater in the extra-articular disease group than in the non–extra-articular disease group [2.50 (95% CI, 1.02-3.98) vs. 1.82 (95% CI, 1.48-2.16)].¹⁰²⁹³ 

The resources of the Rochester Epidemiology Project were used to conduct a retrospective medical record review on a cohort of 609 cases of RA in Olmsted County, Minn. This study was undertaken to investigate the trends in the incidence of extra-articular RA over time in a community-based cohort.⁴⁷⁹⁷  Identification of extra-articular manifestations was done by examining case records and applying an established criteria described below, which allowed for a retrospective evaluation in a uniform manner.^{10254,  10514} 

Important para-articular and extra-articular findings in RA are depicted in Fig.1020.⁴⁵⁶⁶ 

Weakness is commonly out of proportion to pain on examination. Morning stiffness lasting at least 45 minutes after initiating movement is also frequently observed. Myalgia, due to referred pain, may be prominent if large joints, such as the hips and shoulders, are involved. Low-grade fever, fatigue, malaise, and other systemic complaints may also be present lists clinical features frequently observed in RA patients. Fig.1021 lists clinical features frequently observed in RA patients.

The cohort included all individuals ≥18 years of age diagnosed with RA, as defined by the 1987 criteria for RA, between 1955 and 1994.¹⁰²⁵⁴  Patients were followed up from 1955 to 2000. The amount of time before extra-articular RA was detected was compared and adjusted for the decade in which the patient was included in the cohort (1955-1964, 1965-1974, 1975-1984, and 1985-1994). To ensure comparable follow-up time in each subgroup in this analysis, patients with an RA diagnosis during the period 1955-1964 were followed up until December 31, 1970, those diagnosed in 1965-1974 were followed up until December 31, 1980, those diagnosed in 1975-1984 were followed up until December 31, 1990, and those diagnosed in 1985-1994 were followed up until December 31, 2000. Of these patients, 445 were female, and 164 were male. The median age at diagnosis was 58.2 years, and median follow-up period was 11.8 years.¹⁰²⁵⁴ 

During the follow-up period, 247 (40.6%) patients developed extra-articular manifestations, for a 30-year cumulative incidence of 46%.¹⁰²⁵⁴  The most common extra-articular manifestations were rheumatoid nodules (n=172; 30-year cumulative incidence 34.0% [standard error (SE), 3.4%]), secondary Sjögren’s syndrome (n=58; 30-year cumulative incidence 11.4% [SE, 2.6%]), and pulmonary fibrosis (n=34; 30-year cumulative incidence 6.8% [SE, 1.9%]).^{4797,  10254}  Overall, extra-articular manifestation-free survival by decade of RA diagnosis decreased significantly during the period (P=0.001) indicating that extra-articular manifestations occurred more frequently for each new decade. This increase was primarily a result of the increase in the number of patients with rheumatoid nodules. Multivariate analyses from this cohort demonstrated that development of extra-articular manifestations were predicted by rheumatoid factor positivity at diagnosis (risk ratio [RR] 1.56; [95% CI, 1.19-2.04], smoking (RR 1.52; [95% CI, 1.15-2.01]), disability at diagnosis (Steinbroker Class III-IV, (RR 1.42; [95% CI, 1.04-1.94]), and antinuclear antibody positivity at diagnosis (RR 1.58; [95% CI, 1.12-2.21]). The main predictors of severe extra-articular manifestations were smoking  Smoking Hypothesis in Rheumatoid Arthritis (RR 2.94; [95% CI, 1.68-5.13]) and early disability  Rheumatoid Arthritis-Related Disability and Other Concerns (RR 2.45, [95% CI, 1.51-4.00]).

Rheumatoid Nodules

Perhaps one of the most common manifestations of extra-articular disease is the development of rheumatoid nodules. These subcutaneous nodules occur most frequently in rheumatoid factor positive patients, and rarely occur in seronegative patients. They typically present over areas of the body exposed to mechanical pressure, particularly the elbows and extensor surfaces of the forearms, but can also occur on pressure points over tendons and bone on the fingers, feet, knees, and scalp and back.^{6621,  10083,  11477}  The early nodule consists of a perivascular infiltrate of mononuclear cells. The usual larger nodule has a center of caseating necrosis, surrounded by palisading epithelial cells and a ragged cuff of lymphocytes.^{6621,  10083}  Peripheral rheumatoid nodules are generally more of a nuisance, although, they can ulcerate and serve as a portal for bacteremia. However, nodules can also form in some organs (e.g., heart, lung, eye, etc.), where they may have a greater propensity for causing symptoms.¹⁰⁰⁸³ 

Pulmonary Extra-Articular Manifestations of Rheumatoid Arthritis

Rheumatoid arthritis can also affect the respiratory system. There are at least 6 forms of pulmonary disease associated with RA. One of the most common manifestations is pleural disease. Although clinical prevalence has been estimated to be low, postmortem evidence of pleural involvement has been found in 40% -75% of RA patients.^{10266,  10350,  10430,  10891,  11044}  Pleural effusions often occur bilaterally, although unilateral involvement can occur.^{10266,  10430}  They generally resolve spontaneously, but can persist and require therapeutic intervention with thoracentesis and/or corticosteroids.¹⁰²⁶⁶  Persistent effusions can cause pulmonary fibrosis.

Interstitial pulmonary involvement and pulmonary fibrosis have become a well-recognized pulmonary manifestation of RA. Prevalence estimates of these complications vary depending on the diagnostic criteria and detection methodology utilized. In one study of 516 patients with RA, 8 were noted to have evidence of diffuse interstitial fibrosis on radiograph, for an overall incidence of 1.6%.¹⁰³⁷⁰  Another study reported 41% of patients with RA demonstrated pulmonary function test abnormalities consistent with fibrotic changes, while yet another reported interstitial involvement in up to 80% of RA patients undergoing open lung biopsy.^{10968,  10175}  Eleven of these patients were asymptomatic, and 3 had normal chest radiographs.

Although symptomatic joint involvement precedes the development of pulmonary disease in a majority of patients, a small proportion of patients may develop symptomatic lung disease before the development of joint manifestations.^{10266,  11023}  The clinical features of pulmonary fibrosis in RA are similar to those of idiopathic pulmonary fibrosis and can include dyspnea, cough, chest pain, digital clubbing, and inspiratory crackles.^{10675,  11023}  The radiological presentation of pulmonary fibrosis in RA varies and includes early basilar alveolar opacities, a more progressive reticulonodular presentation with interstitial densities, or honeycomb pattern in the lung bases, characteristic of more end-stage disease.^{10675,  11023} 

Rheumatoid nodules can also form in the lungs of RA patients. These nodules usually occur with a greater frequency in seropositive patients than those who are rheumatoid factor negative.¹⁰⁸⁷⁷  As are the cases with other pulmonary manifestations of RA, the reported prevalence of pulmonary nodules varies depending on the study methodology and diagnostic criteria utilized. For example, in 1 clinical report of 516 RA patients, only 2 were found to have radiographic evidence of pulmonary nodules.¹⁰³⁷⁰  In a study involving 77 RA patients, 17 (22%) had nodular densities when evaluated using high-resolution computed tomography (HRCT), while another study involving 40 RA patients undergoing open-lung biopsy reported nodules in 13 (32%) of these patients.^{10649,  10910} 

Histologically, rheumatoid pulmonary nodules are very similar to those rheumatoid nodules occurring in the periphery. They are composed of a central zone of fibrinoid necrosis surrounded by palisading mononuclear cells with an outer zone consisting of chronic inflammatory cells and granulation tissue.^{10176,  10326,  10877}  ,¹⁰⁹¹⁰  Nodular disease is seen most frequently in a peripheral or subpleural distribution or associated with interlobular septa. The clinical course of pulmonary rheumatoid nodulosis varies substantially. In general, nodules are asymptomatic, however, given their proximity to the pleural surface, complications can include pleural effusion, pneumothorax, pyopneumothorax, and bronchopleural fistula.^{10430,  10877} 

Another serious potential, but less common pulmonary manifestation of RA is obliterative bronchiolitis. This condition is characterized by granulomatous infiltration of the distal bronchi and bronchial wall thickening, fibrotic obliteration of bronchial lumen, and relative sparing of the alveolar space.¹⁰⁷⁵⁴  Lung biopsy shows submucosal and peribronchiolar fibrosis and narrowing of the bronchiolar lumen with minimal inflammation.¹⁰⁸⁷⁷  Clinically, patients usually present with dyspnea and nonproductive cough. Symptoms are usually severe and rapidly progressive. A more commonly observed condition is bronchiolitis obliterans with organizing pneumonia (BOOP). This condition results from presence of granulation tissue in the lumen of the bronchioles and alveolar ducts.^{10721,  10786}  Organizing pneumonia is usually observed distal to these areas, hence its descriptive name. Conventional chest radiograph may be unremarkable, or it may show bilateral, asymmetric consolidation with patchy pneumonic foci.¹⁰⁸⁷⁷  The clinical presentation of BOOP includes dyspnea, and a productive cough as well as constitutional symptoms, such as weight loss and fever.^{10363,  10754}  Unlike with obliterative bronchiolitis, patients with BOOP generally have a better prognosis.

Additional pulmonary findings in patients with RA include bronchiectasis and arteritis with pulmonary hypertension. Radiographic findings of bronchiectasis or bronchiolectasis have been reported in 30%-50% of RA patients undergoing HRCT.^{10580,  10649}  The reasons for the development of bronchiectasis remain unclear, but may be as a result of an increased susceptibility of RA patients to airway inflammation and resulting structural abnormalities and respiratory infections. There may also be a genetic predisposition for the development of bronchiectasis.¹⁰⁸⁷⁷ 

Isolated pulmonary arteritis is a rare complication of RA, as is primary pulmonary hypertension. Secondary pulmonary hypertension is more common, and is generally observed in patients with advanced lung disease from other pulmonary parenchymal complications of RA, usually interstitial lung disease.¹⁰⁸⁷⁷ 

Cardiac Extra-Articular Manifestations of Rheumatoid Arthritis

Cardiac disease is a recognized comorbidity associated with rheumatoid arthritis (RA), and is the most common cause of morbidity and mortality in patients with RA. Wolfe, et al., examining the medical records of 11,572 patients (9,093 with RA; 2,479 with osteoarthritis [OA]) from the practices of 709 US community-based rheumatologists found a significantly increased risk of cardiovascular and/or cerebrovascular disease (CCVD) and stated that RA is associated with an increased risk of CCVD morbidity due to myocardial infarction, congestive heart failure, and probably cerebrovascular accident, and may be an independent risk factor for these events.^{6411,  11007}  Similarly, Roman, et al., in a matched cross-sectional study of 98 consecutive outpatients with RA who were followed by rheumatologists compared with 98 controls matched on age, gender, and ethnicity found that despite having a more favorable cardiovascular risk factor profile, patients with RA had a 3-fold increase in carotid atherosclerotic plaque (44% vs 15%; P≤0.001), and concluded that patients with RA have a high prevalence of preclinical atherosclerosis independent of traditional risk factors, suggesting that chronic inflammation and, possibly, disease severity are atherogenic in this population.¹⁰⁴⁶⁸ 

Pericarditis is the most common manifestation of heart disease in RA. Although rarely of clinical significance, postmortem studies of patients with RA have noted the presence of pericarditis in up to 50% of these patients.^{6815,  10969}  Pericarditis generally occurs in seropositve RA patients with rheumatoid nodules. Pericardial fluid analysis results in findings similar to pleural effusions. These findings include a variable white blood cell count, high protein concentrations, decreased complement and glucose concentrations, and the presence of rheumatoid factor and immune complexes. Symptomatic patients with mild disease generally respond to treatment with nonsteroidal anti-inflammatory medications. Corticosteroids or pericardiocentesis are occasionally required for the management of severe disease or treatment-refractory disease. Chronic or constrictive pericarditis necessitating pericardiectomy are infrequent.^{6815,  10969} 

Myocardial disease is common in RA. Matteson and Harris concluded that cardiovascular disease results from the presence of nodular granulomatous lesions or infiltration of the myocardium by mononuclear cells resulting in more diffuse fibrosing lesions. Nonspecific myocarditis is usually asymptomatic and rarely affects cardiac function.^{6815,  10969} 

Abnormalities of the myocardial conduction pathways have also been observed in patients with RA, and is probably related to direct granulomatous lesion involvement within the myocardium, which interferes with electrical conduction within the cardiac tissues.^{6815,  10969}  Pathologic evaluation may reveal proliferative lesions or healed areas with scar tissue. Complete heart block has been described in some RA patients. It generally occurs in patients with erosive, nodular disease and results from granulomas in or near the atrioventricular node or bundle of His.^{6815,  10969} 

Additionally, echocardiographic evidence has suggested that some degree of valve involvement occurs in up to 30% of patients with RA, probably as a result of vasculitis and nodule formation.^{6815,  10969}  Characteristic lesions in RA patients include posterior pericardial effusion, aortic root abnormalities, and valvular thickening. Despite valvular involvement, hemodynamic instability is uncommon.^{4561,  10969} 

Ocular Extra-Articular Manifestations of Rheumatoid Arthritis

Ocular disease is a well-recognized extra-articular manifestation of RA. The most common ophthalmological manifestation of RA is keratoconjunctivitis sicca. Most studies report a prevalence of between 15% and 25% of RA patients.¹⁰⁹⁶⁴  Keratoconjunctivitis sicca results from decreased secretion of tears from the main and accessory lacrimal glands as a consequence of atrophic and cirrhotic changes.^{10919,  10964}  Common patient complaints include dryness, sandy or gritty sensation, burning, and photophobia. The earliest ocular sign of keratoconjunctivitis sicca is a diminished corneal pre-tear film meniscus, which is also more viscous than usual.^{10919,  10964} 

Inflammation of the episclera and sclera is also observed with increased frequency in patients with RA. Episcleritis has been classified as both simple and nodular. With both, vascular engorgement, edema, and inflammatory infiltrate are found in the superficial episcleral plexus and do not involve the deep episcleral plexus or the sclera.¹⁰⁴⁶⁰  This inflammatory process results in the red hue characteristic of episcleritis. Simple episcleritis refers to a diffuse pattern of edema and infiltration, while nodular episcleritis results when single or multiple inflammatory nodules develop and are confined to the episclera.

The occurrence of scleritis in RA patients is less common than episcleritis, and typically develops in patients with more severe systemic disease, particularly vasculitis.¹⁰³⁶⁷  Scleritis can also be diffuse or nodular in its presentation, but it can also be necrotizing, either with or without inflammation (scleromalacia perforans).^{10367,  10460} 

Other unusual ocular findings in RA include uveitis, episcleral nodulosis, ulcerative keratitis, and corneal filamentary keratitis.¹⁰⁹⁶⁹ 

Vasculitis in Rheumatoid Arthritis

Vasculitis is a general term referring to a group of diseases that are characterized by the inflammation of blood vessels. Vasculitis can affect any organ in the body. The vasculitis syndromes include giant cell arteritis, Wegener’s granulomatosis, Churg-Strauss vasculitis, Takayasu arteritis, polyarteritis nodosa, isolated central nervous system vasculitis, cryoglobulinemia, and Henoch-Schönlein purpura.^{10205,  10744} 

Occasionally vasculitis can be a complicating extra-articular manifestation of RA. Although not uniformly replicated between studies, the variables commonly associated with the development of rheumatoid vasculitis include male gender, high titer of rheumatoid factor, the presence of other extra-articular manifestations (especially rheumatoid nodules), the presence of severe disease (characterized by the presence of joint destruction and high levels of inflammatory markers), and utilization of intensive therapeutic regimens including disease-modifying antirheumatic drugs and glucocorticoids.^{6602,  6622} 

Blood vessels of all sizes have the potential to be affected by vasculitis. All layers of the vessel wall are typically infiltrated by lymphocytes, but neutrophils and plasma cells may also be present.¹⁰⁵⁶⁸  Intimal proliferation and thrombosis may be apparent, especially in the digital arteries. Small vessel vasculitis commonly involves the skin and can cause nail-fold infarcts, digital gangrene, and cutaneous ulceration.^{6815,  10565,  10568,  10969}  Occasionally, rheumatoid nodules may contain a central venulitis. Distal sensory neuropathy without other clinical manifestations of vasculitis can also occur.¹⁰⁹⁶⁹  Patients may present with a necrotizing arteritis that is indistinguishable from polyarteritis nodosa. This larger vessel involvement has a poorer prognosis, and can include such manifestations as visceral infarction, cerebral vasculitis, coronary arteritis, or a widespread sensorimotor neuropathy (mononeuritis multiplex).^{6815,  10568,  10969} 

Neurologic Extra-Articular Manifestations of Rheumatoid Arthritis

Various types of neurologic impairments have been reported in association with rheumatoid arthritis (RA). The most common neurologic manifestation of RA is neuropathy, which can be classified into 3 types: 1) compression or entrapment neuropathy, 2) distal sensory neuropathy, 3) sensorimotor neuropathy. Entrapment neuropathies occur around joints where swollen tissue compresses peripheral nerves. Commonly affected nerves include the median, ulnar, posterior tibial, and posterior interosseous branch of the radial nerve.¹⁰⁰⁸⁶  Other related conditions, such as AA amyloid can also cause compressive neuropathy. Noncompressive neuropathies can also occur, typically manifesting as a distal sensory neuropathy. This usually presents as a dysesthesia or burning of the feet or hands.^{10086,  10344}  Histologically, this mild sensory neuropathy is consistent with a mild loss of predominantly large myelinated fibers in the absence of clinical vasculitis. Patients with more severe sensorimotor neuropathies demonstrate a more profound loss of large myelinated fibers and electromyographic evidence of denervation, often accompanied by clinical features of vasculitis. Occasionally these sensorimotor neuropathies can be very progressive and disabling typically in patients with more severe RA.¹⁰⁰⁸⁶ 

The cervical spine can also be involved in RA. Subaxial cervical spine involvement, including subluxation, can occur at several levels resulting in neurologic complications, such as paresthesia and muscle weakness.¹⁰⁰⁸⁶  Rarely, RA can be associated with central nervous system disease that may manifest as stroke, seizure, encephalopathy, and meningitis as a result of cerebral vasculitis, amyloidosis, or rheumatoid nodules, or both.^{10689,  10845,  10969} 

Content on this page was last reviewed on March 31, 2008.

Content on this page was last changed on March 25, 2009.

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4561

Harris ED Jr. Clinical features of rheumatoid arthritis. In: Harris ED Jr, Budd RC, Firestein GS, et al. Kelley’s Textbook of Rheumatology . Vol. II. 7th ed. Philadelphia, PA: WB Saunders; 2004:1043-1054.

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Sommer OJ, Kladosek A, Weiler V, Czembirek H, Boeck M, Stiskal M. Rheumatoid arthritis: a practical guide to state-of-the-art imaging, image interpretation, and clinical implications. Radiographics . 2005;25(2):381-398.

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Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet . 2001;358(9285):903-911.

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Turesson C, O’Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol . 2002;29(1):62-67.

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Wolfe F, Freundlich B, Straus WL. Increase in cardiovascular and cerebrovascular disease in rheumatoid arthritis. J Rheumatol. 2003 Jan;30(1):36-40.

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6602

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