Because HLA-B27 is a class I histocompatibility antigen, it has been postulated that HLA-B27 presents arthritogenic microbial peptides to T cells stimulating an autoimmune response, so called "molecular mimicry.'' A previous study has shown a high degree of conservation in the T-cell responses obtained from the synovial fluid of patients with recent ReA irrespective of the triggering organism .
Conversely, B27 itself may serve as the autoantigen that is targeted by the immune system. It is possible that exposure to the triggering bacteria may alter tolerance to the B27 antigen. Animal data exist to support this theory. Unlike their wild-type counterparts, HLA-B27 transgenic rats are tolerant of B27 immunization using B27-positive splenocytes or plasmid DNA. If these same splenocytes are exposed to Chlamydia in vitro, however, a cytotoxic response is generated . No such response was generated with targets transfected with control B7, B14, B40, B44, or HLA-A2. Self-tolerance to B27 may be subverted by Chlamydia and possibly by the other gram-negative-triggering bacteria.
The role of HLA-B27 may, at least in part, function outside of antigen presentation. It has been suggested that HLA-B27 enhances the invasion of Salmonella into human intestinal epithelial cells . It has also been suggested that Salmonella invasion leads to significant recognizable changes in the B27-bound peptide repertoire . A similar study, however, found only minimal changes in the peptide repertoire . Invasion of Chlamydia may not be altered by HLA-B27, but intracellular replication and formation of inclusion bodies might be suppressed by the cytoplasmic tail of this antigen . If true, this could predispose the cell to chlamydial persistence. Conversely, it has been suggested that HLA-B27 has no influence on invasion or replication of Ct serovar L2 within cell lines .
Recent data suggest that HLA-B27 restricted epitopes derived from proteo-glycans, specifically human aggrecan, serve as autoantigens, and are involved in the inflammation that is characteristic of the spondyloarthropathies and
ReA . Perhaps the only clarity of HLA-B27's role in the pathophysiology of ReA is that its exact role is still undefined and it is not the sole determinant of disease predilection.
It is clear that the causative organisms of ReA are incorporated into peripheral blood mononuclear cells. These same organisms or bacterial products persist intracellularly in synovial cells (primarily macrophages). How this process of intracellular uptake occurs is less apparent. Chlamydial infection, specifically, is initiated when the elementary body binds to the target eukaryotic cell. There are some data that suggest that the elementary body of both Ct and Cpn interact with host cell surface glycosaminoglycans during cellular uptake . Following invasion, however, the Ct was confined to distinct vacuoles that did not develop into characteristic inclusion bodies. Intriguing recent evidence suggests that apolipoprotein E, which is adherent to the surface of Ct and Cpn elementary bodies, attaches to the host cell LDL receptor family carrying the elementary body with it . This could represent a truly remarkable adaptation of Chlamydia using a basic cellular function involving cell homeostasis as its pathway to host cell attachment and uptake.
The Toll-like receptors (TLRs) recognize extracellular pathogens and activate immune cell responses as part of the innate immune system. TLR-4 recognizes lipopolysaccharide, thereby potentially playing a role in the path-ophysiology of ReA. Recent mice data have shown that effective host clearance of Ct depends on appropriate TLR-4 expression by neutrophils . TLR-4-deficient mice exposed to Salmonella demonstrate dramatically increased bacterial growth and increased demise . Certain polymorphisms of TLR-4 have been associated with gram-negative infections and Crohn's disease and ulcerative colitis, two inflammatory conditions related with the spondyloarthropathies [82-84]. These same polymorphisms, however, seem not to confer risk of ReA .
Peripheral blood mononuclear cells from eight patients with Salmonella infections (four with ReA and four without) have been analyzed in both the acute and recovery phase of the infection . All patients revealed high levels of activation and adhesion molecules and increased inflammatory and anti-inflammatory cytokine levels. During the recovery phase, the patients with ReA demonstrated completed down-regulation of CD14, whereas it was similar to healthy controls in those without ReA. Interestingly, CD14 is expressed in particularly high levels on macrophages. It functions as a coreceptor with TLR-4 for the detection of bacterial lipopolysaccharide .
After an acute infection with the causative bacteria, these organisms are trafficked to the synovial tissue and other target organs. It is possible that chemokines guide this process for it is known that chemokines and chemo-kine receptors regulate leukocyte recruitment into inflamed tissues. CCR1 and CCR5 are known to play a role recruiting Thl-type T cells under inflammatory conditions . It has been demonstrated that there is increased expression of CCR1, CXCR4, and CCR5 in the synovial tissue of patients with several types of arthritis including ReA . There was no apparent unique chemokine profile related to ReA, however, compared with the other types of arthritis studied.
Th1 versus Th2/Th3 response
Although the Th1 cytokines play a role in the clinical manifestations of ReA, their importance seems to be less than that in other types of inflammatory arthritis. This might be particularly true for chronic ReA. Tumor necrosis factor (TNF)-a has been measured in the peripheral blood of patients with ReA. Compared with patients with rheumatoid arthritis, ReA patients demonstrated significantly lower levels of TNF-a . Further, patients who were HLA-B27 positive or had disease duration of greater than 6 months secreted significantly less TNF-a in their peripheral blood. Similar findings have been demonstrated in the joints of patients with ReA (ie, higher levels of interleukin-10 and lower levels of TNF-a and interferon-g, favoring a Th2 profile) [91,92].
Temporal relationships of these different Th1 and Th2 cytokines may also be important in disease manifestations and maintenance. Slight changes in the Th1-Th2 balance may explain the relapsing course that is frequently seen with ReA. Alterations in the initial Th1-Th2 balance may also predispose to disease initiation. A Chlamydia-induced arthritis rat model demonstrated that susceptible rats mounted a lesser initial TNF-a, interferon-g, and interleukin-4 response to their Chlamydia infection . Lower initial responses of these Th1 cytokines may increase the likelihood of developing ReA compared with those patients who are exposed to the causative organism but do not develop ReA.
Other data suggest a role for the Th3 response. Gammadelta-positive synovial-based T cells from patients with ReA predominantly express transforming growth factor-b2 and granulocyte-monocyte-colony stimulating factor . Compared with CD4+ and CD8+ T cells from the same patients, they expressed a more heterogeneous cytokine profile that favored that of the Th3 response.
Finally, background cytokine levels favoring a Th2 response might contribute to bacterial persistence. In vitro data have shown that low levels of TNF-a and interferon-g help to promote the persistent state of both Ct and
Cpn [95-99]. Indeed, if the levels of these cytokines are low enough this may stimulate increased metabolic activity of the organism.
Unfortunately, there is not a diagnostic test for ReA. During the acute stage, individuals often display elevated acute phase reactants, such as an elevated sedimentation rate or C-reactive protein. Conversely, patients with chronic ReA typically display normal levels. HLA-B27 is generally increased in ReA, although rates have varied from 0% to 88% [100,101]. Most of the data regarding ReA suggest an HLA-B27 prevalence of 30% to 50% [44,48,51,52,54,55,102,103]. There may be an overreliance on this HLA type for diagnostic purposes. Isolation of the triggering infection is helpful, but this is usually not possible with routine cultures after the onset of arthritis. It has been suggested that chlamydial IgG or IgA titers are useful at diagnosing patients with persistent Chlamydia infections [104-107]. Most of these data, however, apply only to Cpn in disease states other than ReA. There is also cross-reactivity between chlamydial serotypes, so their use has been questioned. PCR analysis of synovial tissue or fluid for the causative organisms or degradation products is useful but not readily available to most practitioners.
The radiographic features of ReA include sacroiliitis, periostitis, nonmar-ginal syndesmophytes, periosteal new bone formation, joint erosions, and joint space narrowing. These findings, however, are only apparent on plain radiographs with chronic disease. There may be a role for MRI or ultrasound (of the sacroiliac or other joints) to detect earlier changes, but they have not been formally studied in ReA.
Traditional therapies for ReA include nonsteroidal anti-inflammatory drugs, corticosteroids, and disease-modifying antirheumatic drugs. Nonste-roidal anti-inflammatory drugs have been used to treat the joint inflammation associated with ReA. Although they seem to improve the articular symptoms of ReA, they are not thought to have any impact on the associated extra-articular symptoms. Although a breadth of clinical experience suggests that they help with the inflammatory arthritis associated with ReA, there are no well-designed prospective trials analyzing their efficacy for this indication.
Corticosteroids have limited benefit for the axial symptoms and may be more effective for the peripheral arthritis of ReA . Local corticosteroid injections into affected joints may provide short-term relief. Corticosteroids also seem to be helpful at treating some of the extra-articular manifestations, such as iritis. Topical corticosteroids may also be useful for circinate balanitis (CB) and keratoderma blennorrhagicum (KB).
Traditional disease-modifying antirheumatic drugs have also been used for patients with chronic ReA because these patients can develop radiographic abnormalities with subsequent joint deformities if left untreated. The best studied disease-modifying antirheumatic drug in the setting of ReA is sulfasalazine. A prospective trial of 134 subjects designed to assess the efficacy of sulfasalazine in ReA . In this trial there was a trend favoring sulfasalazine compared with placebo, because improvement was documented in 62% of the participants on sulfasalazine and 47% on placebo (P = .089). There were no significant improvements in any of the clinical measures followed compared with placebo, however, including swollen and tender joint counts. Methotrexate, azathioprine, and cyclosporine have been advocated as potential treatments but never formally evaluated in a prospective trial.
The TNF-a antagonists have demonstrated great success in the treatment of other types of spondyloarthropathies. There are potential theoretical concerns, however, regarding TNF-a antagonism in ReA. Lower levels of TNF-a have been demonstrated in ReA compared with other types of inflammatory arthritis, and ReA is believed to be more of a Th2-driven disease [90-92]. Also, in vitro data suggest that persistent Ct and Cpn levels are inversely associated with TNF-a levels [95-99]. There are no randomized trials in ReA to assess accurately their efficacy in this setting. There have, however, been a small open label study and case reports suggesting clinical benefit with these drugs in the treatment of ReA [109-111]. In an open label study with etanercept, there were five patients who were PCR positive for Chlamydia at some time during the observation period. Of the five, three were PCR positive in the synovium for Ct before treatment. Of these three, two of the patients were PCR negative on therapy and one remained positive. Two patients, however, with negative PCR results at baseline became PCR positive for Cpn while on etanercept . These equivocal results do not dissuade the theoretical concerns that exist regarding the use of these drugs in ReA. Conversely, patients with ReA do exhibit higher serum levels of TNF-a levels compared with normal controls , so this might suggest that these patients would benefit from TNF-a antagonists. The use of TNF-a antagonists in the treatment of ReA is unanswered.
The exact role of antibiotics as a treatment for ReA has yet to be fully defined. A trial assessing 3 months of treatment with lymecycline showed no benefit to patients with postdysentery ReA, whereas there was improvement in patients with Chlamydia-induced ReA . A subgroup analysis of another previous trial studying ciprofloxacin as a treatment for ReA suggested benefit in postchlamydial patients with no such improvement in the other patients . Other studies assessing doxycycline, ciprofloxacin, and azithromycin in ReA failed to show benefit, but there was no effort to separate postchlamydial patients [103,114-116]. Interestingly, a follow-up of one of the aforementioned ciprofloxacin trials suggested that this antibiotic significantly improved long-term prognosis . Finally, another study suggested significant improvement in patients with postchlamydial ReA with a combination of knee synovectomy and 3 months of azithromy-cin . It seems that there may be benefit in the postchlamydial form but not ReA that is secondary to the postdysentery organisms. The observation of viable Chlamydia, and the general lack of viable postdysentery organisms, in the synovial tissue of patients with ReA support this finding.
The complexity of antibiotics as a potential treatment for Chlamydia-induced ReA runs even deeper. In vitro data have shown that intracellular chlamydiae are driven into a persistent state when exposed to chronic mono-therapy with several antibiotics including doxycycline, azithromycin, rifam-pin, and ciprofloxacin [119-122]. These data suggest that chronic monotherapy with the aforementioned antibiotics is unlikely to eradicate the persistent infection. Interesting in vitro data suggest successful synergis-tic eradication of cells infected with persistent Chlamydia with a combination rifampin and azithromycin . In this same study, monotherapy with both of these same antibiotics did not eradicate the persistent infection. A 2004 study revealed significant improvement in patients with presumed Chlamydia-induced ReA after 9 months of a combination of rifampin and doxycycline compared with doxycycline monotherapy . It is possible that a prolonged combination of antibiotics may eradicate the persistent state of Chlamydia along with its pathogenic sequelae. As is the case with TNF-a antagonists, the exact role of antibiotics in ReA is still not clear. It seems, however, that their only potential role relates to the treatment of Chlamydia-induced ReA and not to the postenteric form.
ReA is unique in that it is one of the few disease states of which there is a known trigger. This insight into disease initiation has led to great advances in the pathophysiology. Despite this detailed knowledge, the proper treatment remains elusive. In the years to come it is possible that the specific treatment will be dictated by the triggering microbe.
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