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Rheumatoid arthritis (RA) is a chronic, systemic disease that primarily targets the synovium, leading to synovial inflammation and proliferation, loss of articular cartilage, and erosion of juxtarticular bone. The natural history of the disease is one of progressive joint damage and deformity and, in a sizeable minority, the development of extra-articular manifestations. Fortunately, current therapeutic strategies, particularly if the disease is diagnosed and treated early, result in substantial clinical benefit for most patients.

RA affects approximately 1% of the adult population worldwide and is more common in women (female:male, 3:1) (Table 15–1). Although RA may present at any age, the typical age of onset in women is the late childbearing years; in men, RA develops more often in the sixth to eighth decade.

Table 15–1. Classic Manifestations.

The causes of RA remain elusive. The genetic contribution to RA is substantial, and more than 30 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 (amino acids 70–74) known as the “shared epitope.”

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 (present in approximately 70% of all patients with RA). Citrullination—a post-translational 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. Interestingly, epidemiologic data links smoking (which induces inflammation and citrullinated proteins in the lung) and periodontitis (which is associated with the citrullination of proteins in periodontal tissues) to risk of developing anti-CCP-positive RA.

James R. O’Dell, MD & John B. Imboden, MD

Articular Manifestations of RA

Essentials of Diagnosis

  • Chronic symmetric polyarthritis.
  • Symptoms often start in proximal interphalangeal (PIP), metacarpophalangeal (MCP), and metatarsophalangeal (MTP) joints.
  • Serum rheumatoid factor, antibodies to cyclic citrullinated peptides (anti-CCP), or both in 70%.
  • Radiographic changes ...

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