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Pathogenesis of rheumatoid arthritis

Gary S Firestein, MD
Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Deputy Editor
Paul L Romain, MD


Rheumatoid arthritis (RA) is the most common inflammatory arthritis and affects about one percent of the population [1]. It results from a complex interaction between genes and environment, leading to a breakdown of immune tolerance and synovial inflammation in a characteristic symmetric pattern. Distinct mechanisms regulate inflammation and matrix destruction, including damage to bone and cartilage [2]. Given the heterogeneous response to therapy, it is clear that RA in not just a single disease; instead, many pathways can lead to autoreactivity with similar clinical presentations.

The pathogenesis of RA is reviewed here. The etiology of this disorder, including putative genetic and environmental factors, is discussed separately. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis".)


The initiation of rheumatoid arthritis (RA) is a combination of pre-determined (genetic) and stochastic (random) events. Susceptibility to RA is clearly defined by a pattern of inherited genes, with the human leukocyte antigen (HLA) major histocompatability (MHC) genes as the most important. However, scores of minor genes that include cytokine promoters, T cell-signaling genes, and many others, contribute to susceptibility and severity. It is equally clear that genes are not the sole influence, since the concordance rate for identical twins is only 12 to 15 percent. Of the environmental stimuli that contribute, the best defined is smoking, which can interact with genes to increase susceptibility up to 20- to 40-fold [3]. Epigenetic influences, such as abnormal DNA, dysregulated histone marks, or expression of microRNAs, can also increase proinflammatory gene expression [4].

A likely mechanism for the environmental component is repeated activation of innate immunity, especially at mucosal surfaces. This process can take many years, with evidence of autoimmunity increasing gradually until some unknown process tips the balance toward clinically apparent disease. For example, cigarette smoking is strongly associated with RA and induces peptidyl arginine deiminase (PAD) expression in alveolar macrophages [5]. These enzymes then convert arginine to citrulline in the airway, thereby creating neoantigens that can be recognized by the adaptive immune system. Increased citrullination is not specific to RA and occurs regularly with any environmental stress. What is unique to RA is the propensity for immune reactivity to the neoepitopes created by protein citrullination with the production of anti-citrullinated protein antibodies (ACPAs).

Other mucosal surfaces can also potentially contribute. The oral mucosa harbors Porphyromonas gingivalis in periodontal disease, which is also associated with RA [6]. These bacteria express PADs, which can citrullinate peptides in the mouth. The gut microbiome is also altered in early RA, with a preponderance of Prevotella species [7]. The influence of the bacterial environment of the gut is not well defined, but clearly affects arthritis susceptibility and severity in many pre-clinical models [8].

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Literature review current through: Nov 2017. | This topic last updated: Aug 30, 2017.
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