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INTRODUCTION

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting approximately 1% of the adult population worldwide. It may present at any age, but typically affects women in their late childbearing years. In men, RA is more prone to develop in the sixth to eighth decade. The disease occurs more commonly in women (female:male, 3:1) (Table 13–1). The primary pathology is inflammation of the synovial membrane, leading to synovitis and proliferation, which often results in loss of articular cartilage and erosion of juxtarticular bone. The natural history of the disease is one of progressive joint damage and deformity. Moreover, extra-articular manifestations, which occur in a significant minority of patients, are associated with a poor outcome. Recent advances in therapeutic strategies have dramatically altered the prognosis, particularly if RA is diagnosed and treated early. Unfortunately, many patients have suboptimal responses to treatment or tolerate therapies poorly.

Table 13–1.Classic manifestations.

The causes of RA remain elusive. The genetic contribution to RA is substantial, and more than 100 loci conferring risk for RA have been identified thus far. Most genes linked to RA influence immune responses (eg, T-cell activation, cytokine signaling). The strongest known association is with alleles of HLADRB1, which encodes the β chain of HLA-DR, a major histocompatiblity class II molecule directly involved in the presentation of antigen to T cells. Allelic variants of HLADRB1 associated with risk for RA encode a similar sequence known as the “shared epitope,” comprising amino acids 70–74. Although genetics play a significant role in determining risk of RA, most patients have no family history.

Studies of genetic risk reinforce the concept that clinical RA is not a single entity. Most notably, shared-epitope-encoding HLADRB1 alleles confer risk only for RA associated with antibodies to citrullinated protein epitopes. These anticyclic citrullinated peptide antibodies (ACPAs) are present in approximately 70% of all patients with RA. Citrullination—a posttranslational modification of proteins in which arginine residues are converted to citrulline—occurs at sites of inflammation. How patients with RA lose tolerance to citrullinated protein epitopes is uncertain. It is noteworthy that epidemiologic data link both smoking (which induces inflammation and citrullinated proteins in the lung) and periodontitis (which is associated with the citrullination of proteins in the oral cavity) to the risk of developing ACPA-positive RA. The combination of shared epitope, ACPA, and smoking increased the risk of RA 40-fold.

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