What is the pathophysiology of reactive arthritis (ReA)?

Updated: Dec 24, 2020
  • Author: Carlos J Lozada, MD; Chief Editor: Herbert S Diamond, MD  more...
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Answer

ReA is usually triggered by a GU or GI infection (see Etiology). Evidence indicates that a preceding Chlamydia respiratory infection may also trigger ReA. [14] The frequency of ReA after enteric infection averages 1-4% but varies greatly, even among outbreaks of the same organism. Although severely symptomatic GI infections are associated with an increased risk of ReA, [15, 16] asymptomatic venereal infections more frequently cause this disease. [15] About 10% of patients have no preceding symptomatic infection.

ReA is associated with histocompatibility leukocyte antigen B-27 (HLA-B27), a major histocompatibility complex (MHC) class I molecule involved in T-cell antigen presentation. Results for HLA-B27 are positive in 65-96% of patients (average, 75%) with ReA. [17] Patients with HLA-B27, as well as those with a strong family clustering of the disease, tend to develop more severe and long-term disease. [12]

Sun et al reported that susceptibility to ReA arthritis is affected by the levels of certain killer cell immunoglobulin-like receptors (KIRs), which correspond with specific HLA-C ligand genotypes. In individuals with high levels of activating and low levels of inhibitory KIR signals, pathogens can more easily trigger natural killer cell and T cell innate and adaptive immune responses, resulting in the overproduction of cytokines that contribute to the pathogenesis of ReA. [18]

Their study of 138 patients with ReA found that KIR2DS1, which is activating, is associated with susceptibility to ReA, when present alone or in combination with the HLA-C1C1 genotype. KIR2DL2, which is inhibitory, in combination with the HLA-C1 ligand is associated with protection against ReA. Patients with ReA had significantly lower frequencies of KIR2DL2 and KIR2DL5 than did controls. The presence of more than seven inhibitory KIR genes was protective. [18]

The mechanism by which the interaction of the inciting organism with the host leads to the development of ReA is not known. It is possible that microbial antigens cross-react with self-proteins, stimulating and perpetuating an autoimmune response mediated by type 2 T helper (Th2) cells. Chronicity and joint damage have been associated with a Th2 cytokine profile that leads to decreased bacterial clearance. [15]

Synovial fluid cultures are negative for enteric organisms or Chlamydia species. However, a systemic and intrasynovial immune response to the organisms has been found with intra-articular antibody and bacterial reactive T cells. Furthermore, bacterial antigen has been found in the joints. Thus, the elements for an immune-mediated synovitis are present.


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