Box 2 Triggering microbes of reactive arthritis

Definite causes Postvenereal Chlamydia trachomatis

Postenteric

Salmonella (S enteritidis, S typhimurium, S bovismorbificans, S blockley)

Shigella (S flexneri, S dysenteriae, S sonnei, S boydii)

Campylobacter (C jejuni, C coli)

Yersinia (Y enterocolitica, Y pseudotuberculosis)

Probable causes

Chlamydophila (Chlamydia) pneumoniae

Ureaplasma urealyticum

Bacille Calmette-Guenn (intravesicular)

Possible causes Bacillus cereus Brucella abortis Clostridium difficile Escherichia coli Helicobacter pylori Hafnia alvei Lactobacillus

Neisseria meningitidis serogroup B Pseudomona

Intestinal parasites (Strongyloides stercolis, Taenia saginata, Giardia lamblia, Ascaris lumbricoides, Filariasis, and Cryptosporidium)

Other types of inflammatory arthritis in which bacteria may play a causative role Borrelia burgdorferi (Lyme disease) Propionbacterium acnes (SAPHO) Streptococcus sp (poststreptococcal ReA) Tropheryma whippelii (Whipple's disease)

enterocytes, lyse intracellular vacuoles to enter the cytoplasm, and move from cell to cell. E coli can do none of these [42]. These capabilities are likely critical to the causation of ReA. Similar to Ct and Cpn, bacterial DNA from Shigella has been demonstrated in the synovial tissue of patients with ReA. In contrast, there have been no studies to detect viable organisms, only bacterial fragments [25,29].

Salmonella

Salmonella is a rod-shaped, motile bacterium (with two nonmotile exceptions that are not thought to cause human disease: S gallinarum and S pullorum). It is widespread in animals and environmental sources, and is one of the most common enteric infections in the United States. Salmonella is the most frequently studied enteric bacteria associated with ReA. After salmonellosis, individuals of white descent may be more likely than those of Asian descent to develop ReA [45], and children may be less susceptible than adults [11]. The attack rate of Salmonella-induced ReA has ranged between 6% and 30% [13,46]. As with the other causative organisms, efforts have been made to detect Salmonella in synovial tissue or fluid. Salmonella bacterial degradation products, but not bacterial DNA, have been detected in the synovial fluid from patients with Salmonella-induced ReA [31].

There have been large outbreaks of Salmonella typhimurium and Salmonella enteritidis with rheumatologic follow-up of affected individuals. Regarding the outbreaks of S typhimurium, these occurred in three different countries and the attack rate of ReA ranged from 6% to 14.6% with the HLA-B27 prevalence ranging from 17% to 50% of these individuals [4649]. The attack rate of ReA ranged from 6.9% to 29% with four different outbreaks of S enteritidis in four different countries [13,50,51]. A HLA-B27 prevalence of 33% affected individuals was reported in one of these outbreaks [51]. There has also been one outbreak of Salmonella bovismorbi-ficans that resulted in 12% of individuals developing ReA, of whom 45% were HLA-B27 positive [52].

Campylobacter

Campylobacter jejuni infections are now the leading cause of bacterial gastroenteritis reported in the United States [53]. In 1996, 46% of laboratory-confirmed cases of bacterial gastroenteritis reported to the Centers for Disease Control and Prevention were caused by Campylobacter species. This was followed in prevalence by salmonellosis (28%) and shigellosis (17%) [53]. It is estimated that 2.1 to 2.4 million cases of human campylo-bacter infections occur in the United States each year [53].

A study in Finland in 2002 of 870 patients with Campylobacter-positive stool cultures found that 7% of these individuals developed ReA [54]. Interestingly, the development of ReA was not associated with HLA-B27 in this study. Fourteen percent of affected individuals were HLA-B27 positive. This is similar to the background prevalence in Finland. Most of the cases were associated with C jejuni, but Campylobacter coli were also a cause. Other studies suggest a lower attack rate (1%-3%) of ReA after a Campylo-bacter infection with a possible slight increased risk in HLA-B27-positive individuals [12,55].

Yersinia

There are three species in the genus Yersinia, but only Y enterocolitica and Y pseudotuberculosis cause gastroenteritis. Both Y enterocolitica and Ypseudotuberculosis have been associated with ReA. In 1998, two different outbreaks of Y pseudotuberculosis were reported [56,57]. One occurred in Finland (serotype O:3) and resulted in 12% of affected individuals developing ReA [56]. The other occurred in Canada (serotype Ib) and 12% reported "joint pain'' after their infection [57].

As with most of the other known triggering microbes, attempts have been made to localize Yersinia in the synovial tissue or fluid of affected individuals. Two studies have shown that Yersinia does indeed traffic to the joints, as is the case with the other organisms [26,30]. One of these studies suggested that these Yerisinae are metabolically active [26]. Conversely, the other only demonstrated bacterial degradation products [30].

Other possible triggering microbes

Many other organisms have been implicated as potential causes of ReA (see Box 2). Most of these reports exist in the form of case reports and the pathophysiology is not studied with these other organisms.

Intravesicular instillation of bacillus Calmette-Guerin is successfully used as a treatment for intermediate- and high-risk superficial bladder carcinoma. It has also been reported as a rare cause of ReA. A recent review found 48 papers reporting this complication of intravesicular bacillus Calmette-Guerin therapy [58]. This form of ReA generally responds to discontinuation of bacillus Calmette-Guerin therapy or nonsteroidal anti-inflammatory drugs; however, it rarely can evolve into a chronic process.

Poststreptococcal ReA, Lyme disease, and Whipple's disease are all caused by bacterial infections. Their clinical symptoms include inflammatory arthritis but they all have enough different features that are not part of traditional ReA that they should be considered separate. Poststreptococ-cal ReA includes small joint involvement, vasculitis, glomerulonephritis, and increased prevalence of HLA-DRB1*01 [59]. A migratory arthritis with central nervous system involvement is typical of Whipple's disease. Lyme disease includes a characteristic rash (erythema migrans) with central nervous system symptoms.

Pathophysiology

Triggering microbes persist

PCR technology has occasionally demonstrated the presence of chromosomal DNA from the known triggers in the synovial tissue of patients with the postdysentery form of ReA [30,31,33]. This same technology has demonstrated the routine presence of both Ct and Cpn in the synovial tissue of patients with the postchlamydial arthritis [27,28,36,37]. One important difference is that these chlamydiae exist in a persistent metaboli-cally active state, whereas the postenteric organisms do not, with the possible exception of Yersinia [26]. The causative bacteria (or bacterial fragments) of ReA have occasionally been demonstrated in the synovial tissue of patients with various types of arthritis [60-62], so the importance of this finding has been questioned. Further, bacterial DNA from various bacteria not associated with ReA has been discovered in synovial tissue [38]. Conversely, the well-documented finding of viable Chlamydia highlights an important potential difference in the pathophysiology of postvenereal versus postenteric ReA.

The pattern of gene expression associated with persistently viable Chla-mydia is significantly different than that seen during normal active infections. For example, during the persistent state expression of the major outer membrane protein (ompl) gene and several genes required for the cell division process are severely down-regulated. This is coupled with differential regulation of the three paralog genes specifying Ct heat shock proteins (HSP)-60 (Ct110, Ct604, and Ct755) [37].

It is important to remember that the findings regarding these specific HSP paralog genes apply only to Ct and not Cpn. There are differences even within the Chlamydia genus. There have also been differences in cytokine and chemokine mRNA profiles demonstrated in human synovial tissue chronically infected with Ct versus Cpn [36]. Further, a detailed gene expression profile of intracellular viable Ct and Cpn revealed different transcrip-tional response, which was no longer present when the organisms were UV-inactivated [63]. These differences suggest more than innate immunity is involved and may explain the apparent higher risk of ReA with Ct as opposed to Cpn.

Although there are differences in the HSP paralog genes between Ct and Cpn, HSPs in general are paramount to the persistent state of both Ct and Cpn. They provide many functions involved with cell survival. HSPs are conserved molecules synthesized by both prokaryotic and eukaryotic cells, and they are known to play an essential role in protein folding, assembly, and translocation. Under stressful conditions, HSPs allow cells to survive lethal assaults by preventing protein denatur-ation [64,65]. The HSP-60 molecule has many functions that seem to be important to the pathophysiology of ReA. HSP-60 has been shown to be pivotal in the inability of Chlamydia-infected cells to undergo apoptosis [66,67]. These same molecules are also thought to play a role in antibiotic resistance [64,68] and be potentially immunogenic [69]. Elimination of the HSPs is likely to be important in abrogating the pathogenic sequelae of Chlamydia-induced ReA or ReA in general. Such an act either eliminates the immunogenic nidus itself or renders the infected cell more susceptible to apoptosis or therapy.

Host response

Although the presence of viable Chlamydia or postenteric bacterial DNA in the synovium of patients with ReA has been demonstrated, many questions remain. It is clear that the entire Chlamydia organism is incorporated intracellularly. The same might also be true for Yersinia. It is also apparent that bacterial fragments of the postenteric organisms are incorporated into the cell. These intracellular bacteria or bacterial products are then trafficked to the synovium. What governs this process is not yet evident. It is also not clear if their presence in the affected organs represents a trigger for an autoimmune response, or if these organisms are the source for the inflammatory process. As this mystery unravels, it seems that this phenomenon of host tolerance is multifactorial in nature.

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