Etiology

The bacteria associated with ReA are common causes of venereal disease and infectious dysentery. They are gram-negative organisms, with a lipopolysaccharide component within their cell wall. These bacteria and bacterial components have been identified in synovial tissue.[13][14][15][16][17][18][19][20][21] The most commonly implicated bacterial species are Chlamydia, Salmonella, Campylobacter, Shigella, and Yersinia species, although ReA has been described after many other bacterial infections.

Chlamydia species are traditionally thought to be the most common cause of ReA.[22] Both C trachomatis and C pneumoniae are known triggers; C trachomatis is, however, a more common culprit. In one study, C trachomatis was found in 50% of patients with urogenital infections who developed ReA.[23] Ribosomal RNA transcripts from both Chlamydia species have been found in synovial tissue in patients with postchlamydial arthritis, demonstrating that viable organisms are in the joints.[13][14][15][24]

Campylobacter jejuni is probably the most important cause of postdysenteric ReA in the US.[25] The attack rate of Campylobacter-induced ReA varies across studies, ranging from 1% to 7%. The HLA-B27 genotype has not been shown conclusively to increase the risk of ReA after Campylobacter infection.[10][26][27]

Salmonella enteritidis is one of the most common enteric infections in the US, and approximately 6% to 30% of all patients with acute Salmonella infections subsequently develop ReA.[11][28]Salmonella bacterial antigens have been found in synovial fluid from patients with Salmonella-induced ReA.[19]

Bacterial DNA of Shigella organisms has been identified in the synovial tissue of ReA patients.[15][17] A 2005 Finnish study showed an overall attack rate of 7%.[29]

Data from 2 outbreaks of Yersinia infection in 1998 revealed that 12% of infected individuals developed ReA; a subsequent study of 37 adults suggested the attack rate might actually be higher (22%).[30][31][32]Yersinia bacterial antigens have been identified in synovial tissue.[18] There is some evidence to suggest that synovial-based Yersinia may be metabolically active.[16]

Pathophysiology

Bacterial DNA of known infectious triggers has been discovered in the synovial tissue of patients with ReA.

Both Chlamydia trachomatis and C pneumoniae ribosomal RNA transcripts have been found in synovial tissue in patients with postchlamydial arthritis, demonstrating that viable organisms are in the joints.[13][14][15][24] In addition, DNA from enterobacteria has been found in the synovial tissue of patients with postdysentery ReA. The significance of synovial-based persistent pathogens in patients with postchlamydial and postenteric ReA is unclear.[33] In a mouse model, chlamydial infection triggered a tumor necrosis factor (TNF)-related ReA that was dependent on a live infection; severity of the ReA correlated with bacterial load along with a reduced rate of bacterial clearance.[34]

Synovial-based chlamydiae exist in a persistent metabolically active state. Although these chlamydiae are persistent, they exist in an aberrant state, which is why these intracellular organisms cannot readily be cultured.[35][36][37] During this persistent state, gene expression is altered. Expression of the outer membrane protein (omp 1) gene, used in cell division, is down-regulated in persisting Chlamydia organisms compared with bacteria in a productive state. Further findings of up-regulation of heat shock protein (HSP)-60 in C trachomatis and C pneumoniae are important to maintaining a persistent state.[24][35][38][39] Patients with ReA have decreased bactericidal activity of their monocytes when exposed to Chlamydia.[40]

Bacterial degradation products are found in the synovial tissue of patients with postenteric ReA. However, persistent viable postenteric organisms have not been detected in the synovial tissue of ReA patients, with the possible exception of Yersinia organisms.[16]

HLA-B27

The HLA-B27 class I histocompatibility antigen is associated with the development of spondyloarthropathies. HLA-B27 is present in the general population (e.g., 8% in the UK, approximately 15% in northern Scandinavia), but prevalence in ReA epidemiology studies typically ranges from 30% to 50%.[41][42][29][43][44][45][27][46][47][48]

The pathogenic role of HLA-B27 remains unclear. The arthritogenic peptide theory proposes that HLA-B27 presents arthritogenic bacterial material to T cells, eliciting an autoimmune response (whereby T cells cross-react with molecularly similar self-peptides).[49][50] Misfolding of HLA-B27 during assembly, leading to endoplasmic reticulum stress and autophagy, has also been suggested.[49][50]

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