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Overview of the systemic and nonarticular manifestations of rheumatoid arthritis

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


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 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].


Symptoms and findings of systemic and nonarticular manifestations may include generalized aching, stiffness, and constitutional symptoms such as fevers, weight loss, and fatigue [9-11]. These symptoms sometimes antedate the onset of articular disease by several months. Weight may decline over time, especially among older patients and among those with elevated inflammatory markers, erosive disease, and higher initial body mass index [12]. Fatigue is often multifactorial. A systematic review has reported that pain; sleep disturbances; cognitive, emotional, and physical functioning; and social factors contribute to fatigue [11]. By contrast, no consistent relationships between inflammatory variables and fatigue have been reported [11].

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Literature review current through: Nov 2017. | This topic last updated: Oct 28, 2016.
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