Chapter 286 RHEUMATOID ARTHRITIS

Frank C. Arnett

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease predominantly affecting diarthrodial joints and frequently a variety of other organs. TheAmericanCollegeof Rheumatology revised the classification criteria for RA to guarantee uniformity in investigative and epidemiologic studies(Table 286-1). Although these seven items include the most characteristic clinical features of RA, a variety of other disorders may mimic the disease (see Differential Diagnosis andTable 286-3).

RA occurs worldwide in all ethnic groups. Prevalence rates range from 0.3 to 1.5% in most populations, but frequencies of 3.5 to 5.3% have been found in several Native American tribes (Yakima, Chippewa, Inuit). The peak incidence of onset is between the 4th and 6th decades, but RA may begin at any time from childhood (see Juvenile Chronic Arthritis) to later life. Females are two to three times more likely to be affected than males.

ETIOLOGY.

Despite intensive research over many decades, the cause of RA remains unknown. Three areas of interrelated research are currently most promising: (1) host genetic factors, (2) immunoregulatory abnormalities and autoimmunity, and (3) a triggering or persisting microbial infection.

Genetic susceptibility to RA has been clearly demonstrated. The disease clusters in families and is more concordant in monozygotic (30%) than dizygotic (5%) twins. Certain major histocompatibility complex (MHC) class II alleles (and their encoded HLA, or human leukocyte antigens) occur with increased frequency in affected individuals. Among white people of western European origin, HLA-DR4 occurs in 60 to 70% of seropositive patients with RA as compared with 25 to 30% of normal individuals. HLA-DR1 is found in the majority of HLA-DR4-negative patients and is most strongly associated with the disease in several other ethnic groups (Israelis, Asian Indians). Several subtypes of HLA-DR4 were initially defined by mixed lymphocyte culture and more recently by DNA sequencing(Table 286-2). Only certain HLA-DR4 subtypes predispose to RA (Dw4 or DRB1*0401, Dw14 or DRB1*0404, and Dw15 or DRB1*0405), whereas others do not (Dw10 or DRB1*0402 and Dw13 or DRB1*0403). HLA-DR4 subtypes result from only a few amino acid differences in the 3rd hypervariable region of the HLA-DR beta-chain. HLA-DR1 shares this same amino acid sequence, as do several other HLA alleles that have more recently been associated with RA in some populations (seeTable 286-2). Thus a "shared epitope" among several MHC class II molecules appears to predispose to RA. Moreover, homozygosity for the amino acid sequence, especially if carried on HLA-DR4 molecules, has been shown to correlate with disease severity, including more destructive joint disease, subcutaneous nodules, and extra-articular manifestations, especially rheumatoid lung disease and Felty's syndrome. The crucial region for the shared epitope on HLA-DR molecules appears to be a combining site for the T-cell antigen receptor (TCR). Because MHC class II molecules present processed antigen to the TCR on helper (CD4+) T lymphocytes (seeChapter 270)it appears likely that an abnormal antigen-specific cellular and/or humoral immune response is inherent to the