Pathogenesis of reactive arthritis

There is good evidence that bacteria persist in vivo in patients with reactive arthritis (ReA). While Chlamydia seem to hide inside the joint, other areas such as gut mucosa or lymph nodes seem to be more likely places for Salmonella and Yersinia. T-helper (Th) 1 cells secreting cytokines such as IFNg and TNFa are crucial for an effective elimination of these bacteria. An inhibited Th1-response could be demonstrated in ReA, probably contributing to bacterial persistence. While HLA-B27 is found in only approximately 50% of patients with acute ReA, HLA-B27 seems to be crucial for the development of features typical with chronic spondyloarthropathy, such as sacroiliitis. Among several hypotheses to explain the interaction of bacteria with HLA-B27, the most likely seems to be that until now unknown bacterial or selfantigens were presented by HLA-B27 to CD8+ T-cells. An important site where the immunopathology takes place seems to be at the insertion of tendons and ligaments at bone. Because antibiotics have failed so far in the treatment of ReA immunomodulatory therapies, based on a better understanding of the pathogenesis, alone or in combination with antibiotics might be an option for the future.     

Report on the Fourth International Workshop on Reactive Arthritis

There are large differences in the antigenicity and biology of the ReA-associated bacteria. For induction of arthritis, the relevance seems to be only that antigenic material reaches the joint, alive or dead. If there is a common antigen, it has to be a highly conserved one. Bacterial hsp60 seems to be an immunodominant T cell antigen in ReA, but there must be other relevant antigens shared by these different bacteria. An ineffective immune response (for example, low production of TNFalpha) seems to contribute to the manifestations and course of ReA. Although arthritis can also occur in its absence, HLA-B27 plays an important role in the pathogenesis of ReA and the other SpA. Current data suggest that B27 probably acts as an antigen-presenting molecule for a still-unknown arthritogenic molecule. Comparison of ReA with IBD-associated arthritis suggests that there might indeed be a common antigen shared by ReA-associated bacteria and bacteria of the gut flora. CD8+ T cells seem to be important in ReA and other SpA. In some parts of the world, such as in Mexico, ReA could be a major predisposing cause of the development of AS. Antibiotic treatment is not effective, probably because the triggering bacteria are already dead or in a partly latent state at the time arthritis occurs. Based on this knowledge and on new technologies, it should be possible in future years to derive answers to the questions about ReA and the other SpA and, as a consequence, to find a cure.     

Disease mechanisms in reactive arthritis

Reactive arthritis (ReA) occurs after a preceding bacterial infection of the urogenital or gastroenteral tract. The bacteria triggering ReA persist in vivo and seem to be responsible for triggering an immune response. A cytokine imbalance with a relative lack of T-helper 1 cytokines may play an important role allowing these bacteria to survive. This seems to be relevant for manifestation and chronicity of the arthritis. For the chronic cases and cases evolving into ankylosing spondylitis, the interaction between bacteria and human leukocyte antigen B27 plays an additional crucial role. Among others, the arthritogenic peptide hypothesis is one way to explain this association. Human leukocyte antigen B27-restricted peptides from Yersinia and Chlamydia, which are stimulatory for CD8+ T cells derived from patients with ReA, have been identified. The exact role of such peptides for the pathogenesis of ReA and other spondyloarthritides still has to be defined.     

Low secretion of tumor necrosis factor alpha, but no other Th1 or Th2 cytokines, by peripheral blood mononuclear cells correlates with chronicity in reactive arthritis.

OBJECTIVE: To determine Th1 and Th2 cytokine production in patients with reactive arthritis (ReA) in relation to disease outcome and in comparison with rheumatoid arthritis (RA). METHODS: Secretion of tumor necrosis factor alpha (TNFalpha), interferon-gamma, interleukin-10 (IL-10), and IL-4 by peripheral blood mononuclear cells (PBMC) from 53 patients with early ReA (disease duration <8 weeks, 64% HLA-B27 positive) and 30 patients with early, untreated RA (disease duration <6 months) was determined by enzyme-linked immunosorbent assay (ELISA) after ex vivo stimulation. Intracellular cytokine staining with quantification of positive T cells by fluorescence-activated cell sorting (FACS) was performed in 12 ReA patients and 12 RA patients. In 27 ReA patients, cytokine secretion was measured again after 3 months. Patients were followed up for 1 year, and cytokine patterns were correlated with disease duration. RESULTS: TNFalpha secreted by whole PBMC and by T cells was significantly lower, by ELISA and by FACS, in ReA patients than in RA patients, while no significant differences were detected for the other cytokines. ReA patients with a disease duration of > or =6 months showed significantly lower TNFalpha secretion than patients with a disease duration of <6 months (mean +/- SD 385 +/- 207 pg/ml versus 684 +/- 277 pg/ml; P = 0.003). Furthermore, low TNFalpha secretion after 3 months also correlated significantly with a more chronic course of disease. HLA-B27 positive patients secreted less TNFalpha than did those who were B27 negative (338 +/- 214 pg/ml versus 512 +/- 207 pg/ml; P = 0.05), and patients with a more chronic course had a higher frequency of B27 positivity (47% versus 80%; P = 0.01). Among the 27 HLA-B27 positive patients, TNFalpha secretion in those with a disease duration of > or = 6 months was lower than that in the 7 with a disease duration of <6 months (308 +/- 167 pg/ml versus 562 +/- 308 pg/ml; P = 0.04). CONCLUSION: Low TNFalpha secretion and HLA-B27 status correlate with longer disease duration in ReA patients, possibly with an additive effect. The diminished TNFalpha production might reflect a state of relative immunodeficiency contributing to bacterial persistence in ReA.     

Determinants of synoviocyte clearance of arthritogenic bacteria

OBJECTIVE: Persistence of intracellular organisms may play a critical role in the initiation and perpetuation of synovitis in reactive arthritis (ReA). We investigated factors that may influence local clearance of arthritogenic pathogens in ReA. METHODS: We studied 11 HLA-B27 positive patients with spondyloarthropathies and contrasted these patients with 6 HLA-B27 negative control patients with rheumatoid arthritis or osteoarthritis. We employed an ex vivo system in which human synoviocytes derived from patients with ReA are cocultured with arthritogenic pathogens, and intracellular clearance is measured by quantitating colony-forming units over time. RESULTS: The clearance kinetics of the organisms bore no relationship to the HLA-B27 status of the patient. Clearance of S. typhimurium over a 10 day period was accompanied by a progressive rise in nitric oxide (NO) production, but this appeared not to be rate-limiting, since (1) clearance kinetics were comparable between high versus low NO-producing synoviocytes; and (2) L-NMMA inhibition of NO production did not alter clearance kinetics of S. typhimurium. Interferon-g (IFN-g) was observed to have a small but measurable effect on bacterial clearance. In certain patients with ReA there was a paradoxical stimulatory response to IFN-g, in which the addition of IFN-g was accompanied by an increase in intracellular bacteria. This effect was found to be attributable to IFN-g mediated suppression of NO production in these cells. This pattern was not observed in B27 negative synoviocytes. CONCLUSION: Intracellular persistence of arthritogenic organisms may contribute to the cellular basis of ReA, but the molecular basis of the bacteriocidal pathways in synoviocytes has not been fully resolved. Our findings indicate that a direct effect of HLA-B27 on these events is unlikely, but that alterations in cytokine response profiles may play a contributory role. Characterizing these mechanisms holds the promise of more specific therapeutic interventions in this disease.     

Reactive arthritis: advances in diagnosis and treatment

Reactive Arthritis (ReA) is an aseptic synovitis developing after a primary infection distant from the joint, mainly localized in the gastrointestinal (Enteroarthritis) or genitourinary tract (Uroarthritis). Because of either the asymmetric joint involvement, the possibility of involvement of the spine and enthesis, and the HLA-B27 association ReA is considered one of the spondylarthropathies. Recently, bacterial components or viable bacteria were found in joints during ReA. For this reason, the limits between ReA itself and infectious arthritis are now less definite. Generally accepted diagnostic and classification criteria are still lacking but the improvement in techniques for detection of bacteria increase the possibility to identify the triggering agents. Several studies have examined the role of antimicrobial drugs in ameliorating the natural course of ReA, with some positive results for Uroarthritis only. However, more conventional treatments based on NSAIDs, sulfasalazine and steroids are effective in many cases.     

Distribution of HLA-B27 and its alleles in patients with reactive arthritis and with ankylosing spondylitis in Tunisia

The purpose of the present study is to investigate the frequency of HLA-B27 and its alleles in reactive arthritis (ReA) and in ankylosing spondylitis (AS) in Tunisia. HLA-B27 alleles were typed by PCR amplification with sequence-specific primers. We studied 17 patients with ReA associated with urethritis or with gastrointestinal infection; 42 HLA-B27-positive patients with AS and 100 healthy controls. Eleven ReA patients (67.7%) were HLA-B27 positive. There was an increased frequencies of HLA-B27 (P = 7.76 × 10⁻¹², OR = 59.30) and a moderate increase of HLA-B51 (P = 0.015; OR = 4.91) alleles in ReA patients when compared with healthy controls. Four B27 subtypes were identified: B*2702, 05, 09 and B*2712. The distribution of these alleles in the ReA patients was 37.5% for B*2702 and B*2705. Only these two subtypes were detected in 18 (42.8%) and 24 (57.1%), respectively, of the AS patients. B*2709 and B*2712 were relatively rare in ReA patients and were identified in one case each. Our results showed a restricted number of HLA-B27 subtypes associated with ReA and AS. B*2702 and 2705 were common in ReA and AS patients.     

Reactive arthritis in HIV-infected patients: immunopathogenic aspects

Reactive arthritis ReA is still an incompletely understood rheumatic disorder whose immunopathogeny involves several mechanisms. There is an association with Class-I histocompatibility antigens HLA-B27 and history of previous gastrointestinal or genitourinary infections. The molecular mimicry between bacterial and self antigens suggests the possibility of cross reactivity as a disease mechanism. The infection pandemics by the human immunodeficiency virus HIV changed the profile of the occurrence of a number of rheumatic diseases including ReA which appears to be more frequent more severe and refractory to the usual treatment for retrovirus-infected patients. The intensity of articular and extra-articular manifestations of ReA often makes the use of immunosuppressant drugs in these patients necessary. Due to the immunosuppression resulting from the retrovirosis itself the treatment becomes a dilemma for rheumatologists. HIV seems to play a role in the main ReA immunopathogenesis mechanisms either acting as direct arthritogenic agent or causing an immune dysfunction in the CD4 T lymphocytes T CD8 relationship leading to the deregulation in the production of cytokines or in advanced immunosuppression stages predisposing to infection by other arthritogenic pathogens. The use of highly active anti-retroviral therapy HAART has changed the profile of rheumatic events and the immunopathogeny of the HIV ReA association. The understanding of the basic ReA immunopathogenic mechanisms in HIV-infected patients is vital in the attempt of elucidating many still existing questions.     

Reaktive Arthritis

Reactive arthritis (ReA) was first described 100 years ago. It is defined as a sterile joint inflammation following a primary, extra-articular infection often in the form of urethritis or enteritis and less frequently respiratory infection and is characterized by the presence of bacterial antigens or non-culturable bacteria in the joint,. The prevalence is estimated to be 40/100,000 adults, while the incidence is 4-5/100,000. The classic HLA-B27-associated form with asymmetric involvement of the lower extremities and/or the spine is part of the spondyloarthritis concept. The phenomenon of persistence, which will be discussed in detail herein, plays an important role in the pathogenesis of ReA. Up to 30% of patients develop chronic symptoms posing a therapeutic challenge. Combination antibiotic treatment showing a response in up to 63% of patients has recently been proposed. Biologics could represent an alternative therapeutic option for patients showing a severe and highly active disease course.     

Reactive arthritis

ReA consists of sterile axial or peripheral articular inflammation,enthesitis, and extra-articular manifestations. Most patients are HLA-B27 positive, although determining the B27 status of an individual patient is irrelevant. Exposure to specific bacterial antigens is usually the inciting factor. Diagnosis usually can be made by clinical examination and history. The current standard therapy is NSAIDs and physiotherapy, but molecular biologic treatment may ultimately become the mainstay in recalcitrant and severe ReA.     

Infection and musculoskeletal conditions: Reactive arthritis

Reactive arthritis (ReA) has been recognized as a clinical disease entity for nearly 100 years. The prevalence is estimated to be 30-40/100,000 adults. The HLA-B27-associated form is part of the spondyloarthritis concept. According to the current hypothesis the arthritis follows a primary extra-articular infection and is characterized by the presence of bacterial antigen and/or of viable but non-culturable bacteria persisting within the joint. Pathogenesis involves the modification of host cells by pathogen-associated molecular patterns (PAMPs, e.g. lipopolysaccharide), bacterial effector proteins, the adaptive immune system, and the genetic background. Up to 30% of patients develop chronic symptoms, and therapeutic options for these patients are still limited. Data for recommendations to apply conventional disease-modifying anti-rheumatic drugs (DMARDs) are rare; however, sulfasalazine seems to be effective, and first reports on agents that block tumour necrosis factor (TNF) are promising. Combination therapy of several antibiotics might open the window to curing the disease; however, controlled clinical studies are needed.     

A proposal for the classification of patients for clinical and experimental studies on reactive arthritis.

OBJECTIVE: To propose classification criteria for patients entering clinical and basic studies on reactive arthritis (ReA). METHODS: From a MEDLINE search of articles published between 1980 and 1996, we identified reports on HLA-B27 related ReA and Reiter's syndrome as study groups and analyzed the items that constituted the diagnostic, classification, and inclusion (or entry) criteria of patients. We developed disease categories that constituted our classification proposal. RESULTS: We reviewed 175 articles containing 110 study groups of patients with ReA and 94 with Reiter's syndrome. Most articles (89.7%) relied on arthritis for diagnosis, but only 48.0% relied on infection. Only 22.5% of articles used published criteria for diagnosis. Articles including a bacterial name to further describe a group of patients with ReA relied on cultures at the site of infection, serum antibodies, or both to confirm the diagnosis. There were inter/intra-group variations and overlapping of diagnostic criteria, at least 32 different terms referring to ReA or Reiter's syndrome, and 6 patterns of disease. According to these data, we propose 3 categories of disease for patients entering clinical and basic studies on ReA: probable ReA (2 subgroups); definite ReA triggered by bacteria (2 subgroups); and bacterial-associated undifferentiated oligoarthritis or spondyloarthropathy. CONCLUSION: This proposal provides a rationale for reducing the heterogeneity found in criteria for including patients with ReA in research and to facilitate scientific communication. In contrast to diagnostic criteria, this proposal does not restrict the study population to a minority of patients, but allows the investigator to include several forms of disease and to analyze results according to different categories.     

Chlamydia pneumoniae as a triggering infection in reactive arthritis.

OBJECTIVE: To determine the role of Chlamydia pneumoniae as a triggering infection in reactive arthritis (ReA). METHODS: Sixty patients with acute arthritis were screened for the evidence of triggering infections. In all patients, bacterial stool cultures, culture of Chlamydia trachomatis in urethra/cervix, and/or bacterial serology were studied. Chlamydia pneumoniae antibodies were measured by specific microimmunofluorescence test. RESULTS: Thirty-five of 60 patients fulfilled the diagnostic criteria for ReA. Thirty-one patients had microbial/serological evidence of preceding infection due to Salmonella, Yersinia, Campylobacter or Chlamydia trachomatis, or they had enteritis or urethritis prior to arthritis. Four additional patients had high antibody titre for C. pneumoniae. Three of these four patients had preceding lower respiratory symptoms, and were positive for HLA-B27. The clinical picture of C. pneumoniae-positive ReA patients was similar to that of ReA patients with other definite aetiology. CONCLUSION: Chlamydia pneumoniae is a triggering factor in approximately 10% of patients with acute ReA.     

Neutrophils of healthy subjects with a history of reactive arthritis show enhanced responsiveness, as defined by CD11b expression in adherent and non-adherent whole blood cultures

OBJECTIVES: To study innate immune responsiveness of HLA-B27 positive subjects recovered from Yersinia-triggered reactive arthritis (B27 + ReA+). METHODS: Whole blood samples from 15 B27 + ReA+, 15 B27 + ReA- and 15 B27 - ReA- subjects were heparinized, aliquoted and (i) kept at 0 degree C to preserve constitutive cell surface marker status, or (ii) cultured with or without bacterial lipopolysaccharide (LPS) supplement, in adherent and non-adherent conditions at 37 degrees C for 4 h. Neutrophil surface expression of CD11b, CD14 and CD16 was quantified flow cytometrically, and compared between the subject groups using Jonckheere-Terpstra test. RESULTS: The B27 + ReA+ group showed significantly higher CD11b levels than the B27 - ReA- group on non-adherent neutrophils cultured with LPS as 100 pg/ml (P = 0.027), 10 ng/ml (P = 0.048) or 1 microg/ml (P = 0.024), or on adherent neutrophils without LPS supplement (P = 0.040). CD14 and CD16 expression on cultured neutrophils and constitutive expression of all three markers were comparable between the groups. CONCLUSIONS: Enhanced neutrophil reactivity observed may exacerbate innate immune inflammation in HLA-B27 positive ReA patients.     

IL10.G microsatellites mark promoter haplotypes associated with protection against the development of reactive arthritis in Finnish patients

OBJECTIVE: To investigate the association of microsatellites and single-nucleotide promoter polymorphisms (SNPs) in the gene for the cytokine interleukin-10 (IL-10) with susceptibility to and outcome of reactive arthritis (ReA). METHODS: From genomic DNA, IL-10 microsatellites G and R and IL-10 promoter polymorphisms at positions -1087 and -524 were typed by polymerase chain reaction, automated fragment length analysis, and restriction fragment digestion in 85 Finnish patients with ReA and 62 HLA-B27-positive Finnish controls. ReA patients had been followed up for 20 years. Genotypes and haplotypes of IL-10 were correlated with distinct features of the disease course, such as triggering agent, chronic arthritis, development of ankylosing spondylitis, and other chronic features. RESULTS: There was a significant decrease in the promoter alleles G12 (allele frequency 0.206 versus 0.033; corrected P < 0.001, odds ratio 0.14) and G10 (0.183 versus 0.092; P < 0.05, odds ratio 0.44) in the ReA group compared with the HLA-B27-positive controls. Chronic arthritis developed significantly more frequently in the B27-positive subjects than in the B27-negative subjects (P < 0.05) as well as in patients with [corrected] the IL10.G8 allele. No associations were observed for either SNP or for the IL10.R microsatellite polymorphism. CONCLUSION: IL10.G12 and G10 microsatellite alleles show a strong protective effect against the development of ReA in Finnish subjects. Since these polymorphic markers themselves do not have direct functional implications, they most likely mark promoter haplotypes with distinct functional properties, suggesting that differential production of IL-10 is an important susceptibility factor for the development of ReA.     

HLA-B27 modulates nuclear factor kappaB activation in human monocytic cells exposed to lipopolysaccharide

OBJECTIVE: To study whether HLA-B27 modifies some key factors controlling inflammatory responses on lipopolysaccharide (LPS) stimulation in human monocytic cells. METHODS: U937 human monocytic cells were stably transfected with either HLA-B27 genomic DNA, HLA-B27 complementary DNA, HLA-A2 genomic DNA, or with the resistant vector pSV2neo (mock) alone. The cells were stimulated with LPS. Electrophoretic mobility shift assay was performed to determine nuclear factor kappaB (NF-kappaB) and heat-shock factor 1 activities, Western blotting was performed to detect the expressions of inhibitory kappaBalpha (IkappaBalpha) and heat-shock proteins (HSPs), and enzyme-linked immunosorbent assay was performed to measure tumor necrosis factor alpha (TNFalpha) secretion. RESULTS: The expression of HLA-B27 modulated the response to LPS in U937 human monocytic cells. Stimulation with LPS led to faster degradation of IkappaBalpha regulatory proteins, accompanied by faster and prolonged activation of NF-kappaB in HLA-B27-expressing cells compared with HLA-A2 and mock transfectants. The secretion of TNFalpha upon LPS stimulation correlated well with the activation of NF-kappaB. No activation of the heat-shock response was observed. CONCLUSION: Our data indicate that HLA-B27 has effects on host responses to LPS that are unrelated to antigen presentation. Two crucial events in the development of arthritis, the activation of NF-kappaB and the secretion of TNFalpha, were found to be enhanced in HLA-B27-expressing cells upon LPS stimulation. Because LPS is known to be present in the inflamed joints of patients with reactive arthritis (ReA), the enhanced inflammatory response of HLA-B27-positive cells upon LPS stimulation offers an attractive explanation for the role of HLA-B27 in the development of ReA.     

Potential triggering infections of reactive arthritis

OBJECTIVES: The aim of the study was to investigate possible triggering infections causing reactive arthritis (ReA) of urogenital origin. METHODS: One hundred and twenty ReA patients, 85 control group patients with other arthritides (61 with rheumatoid arthritis, 13 with osteoarthritis, and 11 with microcrystal arthritis), and 52 healthy persons were tested for urogenital tract inflammation and several infectious agents. Ligase chain reaction was used for detection of Chlamydia trachomatis (CT). Genital mycoplasmas Ureaplasma urealyticum (Uu) and Mycoplasma hominis (Mh) were tested using the Mycoplasma Duo Test (MDT). Only titres greater than 10(4) CCU/mL were accepted as pathogenecity threshold levels for Uu. RESULTS: Inflammation of the urogenital tract (most frequently urethritis in men and cervicitis in women) was found in 95% of patients with acute ReA. Possible causative pathogens were identified in 58% of ReA patients. CT was found in 29%, Uu in 21%, and Mh in 8% of patients with ReA. While CT and Uu were found more often in HLA-B27-positive than in HLA-B27-negative patients, this was statistically proved only for CT. In ReA males Uu was found four times more frequently than in men with other arthritides. CONCLUSIONS: In active ReA of urogenital origin, inflammation of the urogenital tract is found in the majority of patients. Although CT is the main microorganism associated with urethritis in men and cervicitis in women, mycoplasmas, especially Uu, may be possible aetiological factors for ReA.     

Antigenic responses in reactive arthritis.

In this article, the mechanisms by which infection at a distant site could lead to ReA and whether they could explain the association of ReA with HLA-B27 have been discussed. We propose that ReA synovitis is primarily due to specific synovial T-cell proliferation to fragments of the triggering bacterial found in the joint. Nonspecific T cells amplify synovitis with antibodies playing only a secondary role. First, we have shown that the triggering bacterial antigen is present in a nonviable form in ReA synovium and that this, not cross-reactive joint autoantigen, stimulates the specific synovial immune response. Second, the studies of the humoral immune response in ReA have been reviewed. Further evidence of bacterial persistence in the joint comes from work demonstrating intrasynovial bacteria-specific antibody synthesis. Continuing maturation of the antibody response also points to persisting antigen. In enteric but not genitourinary ReA, the humoral response is mainly IgA, implying chronic stimulation of the gut mucosa. Analysis of the molecules against which the humoral response is directed has shown no difference between yersinia arthritis and yersiniosis, but in CTA, the response to the 57kD and 59kD antigens differs from CT urethritis suggesting they may be arthritogenic. Finally, the antibody response may be absent in ReA patients rendering antibody titres diagnostically less useful and confirming their secondary role in the pathogenesis of synovitis. Third, studies of cellular response in ReA have been analyzed. We show there is a specific synovial MNC proliferative response to fragments of the triggering bacteria found in the joint, which is potentially of diagnostic use. The proliferation is due to CD4+ and CD8+ T cells and restricted by MHC class I and II antigens. This antigen-specific T-cell response is accompanied by an antigen-independent recruitment of nonspecific T cells, which may contribute to the amplification of synovitis. The importance of the synovial APC in determining the synovial immune response is unarguable but the exact mechanisms are unclear. Further details on the possible role of HLA-B27 in the presentation of arthritogenic peptides and on the exact identity of the antigenic epitopes recognized in ReA must await analysis of a large panel of T-cell clones. Finally, it is hoped that advances in this field will lead to specific and effective immunologic therapies or vaccines for this currently untreatable disease.     

The role of infection in the pathogenesis of spondyloarthropathies with special reference to human leukocyte antigen-B27

Spondyloarthropathies consist of many inflammatory diseases that are closely associated with human leukocyte antigen (HLA)-B27. One of these diseases is reactive arthritis (ReA), which is a joint inflammation that occurs after infections that are caused by certain gram-negative bacteria. The importance of these infections as causative agents of ReA has been clearly established. It is not clear, however, whether these infections contribute to the development of other forms of spondyloarthropathies. The exact mechanism by which HLA-B27 influences disease susceptibility in spondyloarthropathies remains to be determined. The role of HLA-B27 as an antigen-presenting molecule is certainly important in the pathogenesis of these diseases; however, recent data indicate that this molecule may exhibit other functions unrelated to antigen presentation, which may be important in the pathogenesis of ReA. In this paper, the authors summarize the current knowledge of the role of infection in the spondyloarthropathies.