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Pathogenesis of rheumatoid arthritis

INTRODUCTION

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".)

OVERVIEW

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 hypomethylation of DNA, dysregulated histone marks, or expression of microRNAs, can also increase proinflammatory gene expression [4].

The most likely mechanism for the environmental component is repeated activation of innate immunity. This process can take many years, with evidence of autoimmunity increasing gradually until some unknown process tips the balance toward clinically apparent disease. One key element is the induction of the peptidyl arginine deiminase (PAD) enzymes, which convert arginine to citrulline. Increased citrullination is not specific to RA and occurs regularly with any environmental stress, including in alveolar macrophages in cigarette smokers [5]. 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).

In “pre-RA,” ACPAs and autoantibodies like rheumatoid factors (RFs) can appear more than 10 years before clinical arthritis [6]. Note that ACPAs are not truly autoantibodies, since they are actually antibodies that recognize modified proteins such as vimentin and enolase. True autoimmunity probably occurs somewhat later due to epitope spreading. The antibodies may contribute to the initiation or exacerbation of synovitis, but do not necessarily cause RA by themselves [7]. A pattern of systemic inflammation is also apparent in pre-RA patients, as determined by multiplex analysis of cytokines in the serum [8]. Like autoantibodies, levels of multiple cytokines gradually increase in the years before RA symptoms occur.

                                     

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Literature review current through: Mar 2014. | This topic last updated: Feb 25, 2014.
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