Putative Pathobionts in HLA-B27-Associated Spondyloarthropathy.

Spondyloarthritis (SpA) is a group of immune mediated inflammatory diseases with a strong association to the major histocompatibility (MHC) class I molecule, HLA-B27. Although the association between HLA-B27 and AS has been known for almost 50 years, the mechanisms underlying disease pathogenesis are elusive. Over the years, three hypotheses have been proposed to explain HLA-B27 and disease association: 1) HLA B27 presents arthritogenic peptides and thus creates a pathological immune response; 2) HLA-B27 misfolding causes endoplasmic reticulum (ER) stress which activates the unfolded protein response (UPR); 3) HLA-B27 dimerizes on the cell surface and acts as a target for natural killer (NK) cells. None of these hypotheses explains SpA pathogenesis completely. Evidence supports the hypothesis that HLA-B27-related diseases have a microbial pathogenesis. In animal models of various SpAs, a germ-free environment abrogates disease development and colonizing these animals with gut commensal microbes can restore disease manifestations. The depth of microbial influence on SpA development has been realized due to our ability to characterize microbial communities in the gut using next-generation sequencing approaches. In this review, we will discuss various putative pathobionts in the pathogenesis of HLA-B27-associated diseases. We pursue whether a single pathobiont or a disruption of microbial community and function is associated with HLA-B27-related diseases. Furthermore, rather than a specific pathobiont, metabolic functions of various disease-associated microbes might be key. While the use of germ-free models of SpA have facilitated understanding the role of microbes in disease development, future studies with animal models that mimic diverse microbial communities instead of mono-colonization are indispensable. We discuss the causal mechanisms underlying disease pathogenesis including the role of these pathobionts on mucin degradation, mucosal adherence, and gut epithelial barrier disruption and inflammation. Finally, we review the various uses of microbes as therapeutic modalities including pre/probiotics, diet, microbial metabolites and fecal microbiota transplant. Unravelling these complex host-microbe interactions will lead to the development of new targets/therapies for alleviation of SpA and other HLA-B27 associated diseases.

Novel Inter-omic Analysis Reveals Relationships Between Diverse Gut Microbiota and Host Immune Dysregulation in HLA-B27-Induced Experimental Spondyloarthritis.

OBJECTIVE: To define inflammation-related host-microbe interactions in experimental spondyloarthritis (SpA) using novel inter-omic approaches. METHODS: The relative frequency of gut microbes was determined by 16S ribosomal RNA (rRNA) gene sequencing, and gene expression using RNA-Seq of host tissue. HLA-B27/human ß2 -microglobulin-transgenic (HLA-B27-transgenic) and wild-type rats from dark agouti, Lewis, and Fischer backgrounds were used. Inter-omic analyses using Cytoscape were employed to identify relevant relationships. PICRUSt was used to predict microbial functions based on known metagenomic profiles. RESULTS: Inter-omic analysis revealed several gut microbes that were strongly associated with dysregulated cytokines driving inflammatory response pathways, such as interleukin-17 (IL-17), IL-23, IL-17, IL-1, interferon-γ (IFNγ), and tumor necrosis factor (TNF). Many microbes were uniquely associated with inflammation in Lewis or Fischer rats, and one was relevant on both backgrounds. Several microbes that were strongly correlated with immune dysregulation were not differentially abundant in HLA-B27-transgenic compared to wild-type controls. A multi-omic network analysis revealed non-overlapping clusters of microbes in Lewis and Fischer rats that were strongly linked to overlapping dysregulated immune/inflammatory genes. Prevotella, Clostridiales, and Blautia were important in Lewis rats, while Akkermansia muciniphila and members of the Lachnospiraceae family dominated in Fischer rats. Inflammation-associated metabolic pathway perturbation (e.g., butanoate, propanoate, lipopolysaccharide, and steroid biosynthesis) was also predicted from both backgrounds. CONCLUSION: Inter-omic and network analysis of gut microbes and the host immune response in experimental SpA provides an unprecedented view of organisms strongly linked to dysregulated IL-23, IL-17, IL-1, IFNγ, and TNF. Functional similarities between these organisms may explain why animals of different genetic backgrounds exhibit common patterns of immune dysregulation, possibly through perturbation of similar metabolic pathways. These results highlight the power of linking analyses of gut microbiota with the host immune response to gain insights into the role of dysbiotic microbes in SpA beyond taxonomic profiling.

The microbiome and HLA-B27-associated acute anterior uveitis.

Acute anterior uveitis (AAU) and the spondyloarthritis (SpA) subtypes ankylosing spondylitis, reactive arthritis and psoriatic arthritis are among the inflammatory diseases affected by the biology of the intestinal microbiome. In this Review, the relationship between AAU, SpA and the microbiome is discussed, with a focus on the major SpA risk gene HLA-B*27 and how it is associated with both intestinal tolerance and the loss of ocular immune privilege that can accompany AAU. We provide four potential mechanisms to account for how dysbiosis, barrier function and immune response contribute to the development of ocular inflammation and the pathogenesis of AAU. Finally, potential therapeutic avenues to target the microbiota for the clinical management of AAU and SpA are outlined.

Effects of HLA-B27 on Gut Microbiota in Experimental Spondyloarthritis Implicate an Ecological Model of Dysbiosis.

OBJECTIVE: To investigate whether HLA-B27-mediated experimental spondyloarthritis (SpA) is associated with a common gut microbial signature, in order to identify potential drivers of pathogenesis. METHODS: The effects of HLA-B27 on 3 genetic backgrounds, dark agouti (DA), Lewis, and Fischer, were compared, using wild-type littermates and HLA-B7-transgenic Lewis rats as controls. Cecum and colon tissue specimens or contents were collected from the rats at 2, 3-4, and 6-8 months of age, and histologic analysis was performed to assess inflammation, RNA sequencing was used to determine gene expression differences, and 16S ribosomal RNA gene sequencing was used to determine microbiota differences. RESULTS: Both HLA-B27-transgenic Lewis rats and HLA-B27-transgenic Fischer rats developed gut inflammation, while DA rats were resistant to the effects of HLA-B27, and HLA-B7-transgenic rats were not affected. Immune dysregulation was similar in affected Lewis and Fischer rats and was dominated by activation of interleukin-23 (IL-23)/IL-17, interferon, tumor necrosis factor, and IL-1 cytokines and pathways in the colon and cecum, while DA rats exhibited low-level cytokine dysregulation without inflammation. Gut microbial changes in HLA-B27-transgenic rats were strikingly divergent on the 3 different host genetic backgrounds, including different patterns of dysbiosis in HLA-B27-transgenic Lewis and HLA-B27-transgenic Fischer rat strains, with some overlap. Interestingly, DA rats lacked segmented filamentous bacteria that promote CD4+ Th17 cell development, which may explain their resistance to disease. CONCLUSION: The effects of HLA-B27 on gut microbiota and dysbiosis in SpA are highly dependent on the host genetic background and/or environment, despite convergence of dysregulated immune pathways. These results implicate an ecological model of dysbiosis, with the effects of multiple microbes contributing to the aberrant immune response, rather than a single or small number of microbes driving pathogenesis.

Faecal microbiota study reveals specific dysbiosis in spondyloarthritis.

OBJECTIVE: Altered microbiota composition or dysbiosis is suspected to be implicated in the pathogenesis of chronic inflammatory diseases, such as spondyloarthritis (SpA) and rheumatoid arthritis (RA). METHODS: 16S ribosomal RNA gene sequencing was performed on faecal DNA isolated from stool samples in two consecutive cross-sectional cohorts, each comprising three groups of adult volunteers: SpA, RA and healthy controls (HCs). In the second study, HCs comprised a majority of aged-matched siblings of patients with known HLA-B27 status. Alpha and beta diversities were assessed using QIIME, and comparisons were performed using linear discriminant analysis effect size to examine differences between groups. RESULTS: In both cohorts, dysbiosis was evidenced in SpA and RA, as compared with HCs, and was disease specific. A restriction of microbiota biodiversity was detected in both disease groups. The most striking change was a twofold to threefold increased abundance of Ruminococcus gnavus in SpA, as compared with both RA and HCs that was significant in both studies and positively correlated with disease activity in patients having a history of inflammatory bowel disease (IBD). Among HCs, significant difference in microbiota composition were also detected between HLA-B27+ and HLA-B27 negative siblings, suggesting that genetic background may influence gut microbiota composition. CONCLUSION: Our results suggest that distinctive dysbiosis characterise both SpA and RA and evidence a reproducible increase in R. gnavus that appears specific for SpA and a marker of disease activity. This observation is consistent with the known proinflammatory role of this bacteria and its association with IBD. It may provide an explanation for the link that exists between SpA and IBD.

The microbiota in pediatric rheumatic disease: epiphenomenon or therapeutic target?

PURPOSE OF REVIEW: There has been increasing interest in the contents and function of the microbiota, as it relates to pediatric inflammatory diseases. Here, we discuss the factors underlying the development of the microbiota, its role in juvenile idiopathic arthritis (JIA) and prospects for therapeutic interventions in the microbiota. RECENT FINDINGS: The human microbiota undergoes a succession of changes, until it reaches a mature form. A variety of early-life exposures, including mode of delivery and form of feeding, can affect the contents of the microbiota and possibly impact upon long-term risk of developing autoimmune diseases. The microbiota is altered in children with JIA, including elevated Bacteroides genus in JIA as a whole and decreased Faecalibacterium prausnitzii in pediatric spondyloarthritis. Although there are limited data so far indicating that microbiota-based therapies can result in therapeutic improvement of arthritis, most of the data are on adults and thus may not be applicable to children. SUMMARY: Perturbations of the microbiota during childhood may result in the development of a microbiota associated with increased risk of pediatric rheumatic illness. Whether the microbiota can be targeted is a focus of ongoing research.

The interaction between host genetics and the microbiome in the pathogenesis of spondyloarthropathies.

PURPOSE OF REVIEW: The intestinal microbiome is increasingly implicated in the pathogenesis of ankylosing spondylitis, reactive arthritis, and other diseases collectively known as the spondyloarthropathies (SpAs). In common with other complex inflammatory diseases, SpAs have both a strong genetic and environmental component. Recent genetic studies have highlighted host pathways that may intersect the host-microbiota interaction and offer novel paradigms to understand the pathophysiology of these diseases. RECENT FINDINGS: Genetic association studies have identified genes such as RUNX3, PTPEN2, and IL-33 as susceptibility loci for SpAs. Functional studies in humans have extended knowledge of established genetic risk factors for ankylosing spondylitis that include ERAP1, ERAP2, and interleukin-23R. Recent basic research has identified new mechanisms that regulate host immune responses to the microbiota that conceivably may be dysregulated in SpA. SUMMARY: Intestinal barrier function, deletional tolerance, Th17 signature response, and endoplasmic reticulum stress pathways have been recently linked to SpA. Dysregulated immune responses to the gut microbiota and an altered microbial community structure are shared features of SpA. Although the cause-effect dynamic of this relationship remains equivocal, it nonetheless has major implications for both intestinal and extra-intestinal pathology observed in SpA.

Chlamydia trachomatis elementary bodies in synovial fluid of patients with reactive arthritis and undifferentiated spondyloarthropathy in India.

OBJECTIVES: Reportedly, there is little information on the magnitude of genitourinary-induced reactive arthritis (gReA) from India. Genital infection with Chlamydia trachomatis is a major health problem in India because of its high prevalence; therefore, this study was conducted with the aim to screen ReA/undifferentiated spondyloarthropathy (uSpA) patients (n = 20) attending a major city hospital in New Delhi, for investigating the presence of intra-articular chlamydial antigen in knee joints. Patients with rheumatoid arthritis (RA) and osteoarthritis (OA) served as controls (n = 20). METHODS: Synovial fluid samples were screened for chlamydial elementary bodies (EBs) using a commercial kit (MicroTrak C. trachomatis Direct Specimen Test; Trinity Biotech, USA) for performing direct fluorescence assay (DFA). RESULTS: Chlamydia trachomatis EBs were detected in the synovial fluid cell deposits of six patients in Group I, namely, 33.3% (4/12) ReA and 25% (2/8) uSpA. All C. trachomatis positive patients exhibited an oligoarticular clinical picture with knee joint involvement. In the synovial fluid cell deposits of control patients, namely, RA/OA, no chlamydial EBs could be detected. CONCLUSIONS: This is the first study reporting the presence of C. trachomatis EBs in the synovial fluid of spondyloarthropathy patients, namely, ReA/uSpA from our country and it can be concluded that the prevalence of C. trachomatis-induced ReA is underestimated. Although our study had limitations in terms of sample size and lower sensitivity of DFA, yet this test can be used as an initial diagnostic tool for screening and patients with positive results may undergo specific tests for validation.

Gut microbes, immunity, and spondyloarthritis.

The last decade has witnessed an explosion of studies evaluating the impact of the human microbiota on a variety of disease states. The microbiota can impact diseases in multiple ways, including through abnormalities in the diversity and contents of the microbiota, as well as by acting as targets of immunologic dysregulation. Herein, evidence that the microbiota in spondyloarthritis is both altered and abnormally targeted by the immune system will be presented.

[Role of Porphyromonas gingivalis in rheumatoid arthritis and inflammatory spondyloarthropathies]. / Rola Porphyromonas gingivalis w reumatoidalnym zapaleniu stawów i spondyloartropatiach zapalnych.

The most recent studies confirm the link between rheumatoid arthritis (RA) and periodontal disease. RA patients have higher prevalence of chronic periodontitis and periodontal disease is often more severe in these patients. Both RA and PD show similar pathophysiological mechanisms and risk factors. Autoimmunity to citrullinated peptides is the primary element in the pathogenesis of RA, not found in other diseases. Porphyromonas gingivalis, the major periodontal pathogen associated with the etiology of chronic periodontitis, is the only bacterium currently known to produce the enzyme peptidylarginine deiminase (PAD) allowing protein citrullination. This bacterium likely fulfils a significant role in the pathogenesis of RA due to its capacity for citrullination of its own protein and host peptides, which may result in a loss of immune tolerance. A few epidemiological studies also indicate the potential link between spondyloarthropathies and periodontal disease.

Diagnosis of Chlamydia trachomatis in patients with reactive arthritis and undifferentiated spondyloarthropathy.

INTRODUCTION: There is a paucity of information on the frequency of Chlamydia trachomatis-induced reactive arthritis (ReA) and undifferentiated spondyloarthropathy (uSpA) in India. In this study, arthritic patients suffering from ReA, uSpA, and rheumatoid arthritis (RA) were screened to investigate the presence of C. trachomatis infection in the synovial fluid (SF) or serum by molecular and non-molecular methods. METHODOLOGY: A total of 76 arthritic patients with ReA (n = 16) and uSpA (n = 22) composed the study group while those with RA (n = 38) served as controls. The detection of C. trachomatis DNA was done by semi-nested PCR (snPCR) and nested PCR (nPCR) targeting two different genes of C. trachomatis, namely major outer membrane protein and plasmid, respectively. The presence of serum or SF immunoglobulin IgG and IgA antibodies against C. trachomatis was studied by commercial enzyme-linked immunosorbent assay kits. RESULTS: The SF from 9 of 38 (23.6%) patients (5 with ReA and 4 with uSpA) was positive for at least one C. trachomatis DNA by snPCR or nPCR in comparison to RA (1/38 [2.6%]; p value < 0.05). There was no correlation between the snPCR or nPCR and the serological results of patients with ReA or uSpA. CONCLUSIONS: As molecular diagnostic techniques established intra-articular C. trachomatis infection among this group of seronegative spondyloarthropathies in India, these findings should be viewed with concern, and snPCR or nPCR should be considered for a more reliable diagnosis.

Identification of immunogenic HLA-B*27:05 binding peptides of salmonella outer membrane protein in patients with reactive arthritis and undifferentiated spondyloarthropathy.

OBJECTIVE: Salmonella outer membrane proteins (OMP) are major immunogenic targets to synovial fluid lymphocytes of patients with reactive arthritis (ReA)/undifferentiated spondyloarthropathy (uSpA). Because these patients have genetic predisposition to HLA-B*27 and its subtype HLA-B*27:05, we sought to identify immunogenic HLA-B*27:05-binding salmonella OMP peptides in patients with ReA/uSpA. METHODS: A total of 125 HLA-B*27:05-binding salmonella OMP peptides identified using ProPred-I software were synthesized and grouped in 23 pools. The peptide pools, along with crude enteric bacterial lysates and salmonella OMP, were cultured with synovial fluid (SF) or peripheral blood mononuclear cells (PBMC) from 23 patients with ReA/uSpA, 10 with rheumatoid arthritis (RA), and 10 healthy individuals in 96-well culture plates. Proliferation was measured by tritiated thymidine uptake and interferon-γ (IFN-γ) levels in culture supernatant. Individual peptides from pools having significant responses were retested with cryopreserved cells. Immunogenic peptides thus identified were further tested in 5 additional new patients with ReA/uSpA by flow cytometry. A Basic Local Alignment Search Tool program was used to search for similar peptides from a protein bank of arthritogenic bacteria and human protein. RESULTS: Nineteen of 23 SFMC from ReA/uSpA showed a significant proliferative response to salmonella OMP, with minimal response of PBMC (1/10) from ReA/uSpA, SFMC from RA (1/10), or PBMC from controls (1/10). Nine salmonella OMP peptides, QRAEMLPTL, SRSGLNIAL, LRFLYAKSL, RLEGTWVKL, ARCIAPYAL, KLFLTTAAL, YRNSDFFGL, QRPAVRVKL, and YRVGPGDVL, were identified. Response to QRAEMLPTL was seen in 6/7 HLA-B*27:05-positive patients. All immunogenic peptides had sequence similarity with peptides from arthritogenic bacterial proteins, while 5 had similarity with peptides from human proteins. CONCLUSION: Nine novel immunogenic OMP peptides binding to HLA-B*27:05 were identified that showed sequence similarity with other arthritogenic bacteria.

The pathogenic role of Chlamydia in spondyloarthritis.

PURPOSE OF REVIEW: Topics relating to the spondyloarthropathies have been reviewed recently, but the detailed roles of Chlamydia trachomatis and C. pneumoniae in induction of spondyloarthritis have not been discussed. This review focuses on new information regarding how these pathogens elicit joint disease, with emphasis on C. trachomatis in its role in Chlamydia-induced reactive arthritis. RECENT FINDINGS: Molecular methods continue to provide insights into the molecular genetic and cell biologic basis for chlamydial pathogenesis. For chlamydiae, residence in the synovium in patients with acute or chronic Chlamydia-induced arthritis involves organisms in an unusual infection state designated persistence. The profiles of overall metabolism and gene expression characteristic of chlamydial persistence have been assessed and unusual aspects noted, including transcriptional attenuation of one hsp60 paralog and upregulation of expression for another. Strain determinations have demonstrated that genital serotypes of C. trachomatis are not present in the joint; rather, inflammation at that site is elicited by ocular serotypes of the organism. This indicates that much remains to be learned concerning the biology of chlamydial dissemination from the urogenital tract. Analyses of undifferentiated spondyloarthritis continue to suggest that chlamydiae, and perhaps other pathogens function in the etiology of the disease. Progress has been made in developing effective treatment for patients with Chlamydia-induced arthritis. SUMMARY: Molecular genetic analyses regarding the role of chlamydiae in induction of inflammatory arthritis have increased our detailed understanding of the pathogenic mechanisms utilized by these organisms in the joint. Importantly, progress has been made in developing effective therapies for treatment of Chlamydia-induced arthritis.

Helicobacter pylori: an underestimated factor in acute anterior uveitis and spondyloarthropathies?

Acute anterior uveitis (AAU) is the most common form of intraocular inflammation, but its aetiology is still unclear. Fifty percent of AAU patients are HLA-B27-positive, and half of these also have spondyloarthropathies (SpA). Numerous serological studies have shown elevated levels of serum antibodies to various Gram-negative bacteria in HLA-B27-positive AAU and SpA patients. Antigenic similarities between these bacteria and host components (HLA-B27) have already been shown. Still, the mechanism underlying these diseases has not been clarified. Among the Gram-negative bacteria, Helicobacter pylori has not been screened in AAU patients. The purpose of our study was to see if this common human pathogen somehow interferes with AAU. In addition Chlamydia trachomatis, Yersinia enterocolitica 03 and 09, Salmonella sp. and Proteus OX19 were also examined. A total of 60 patients consisting of 4 groups (15 patients with AAU, 15 with SpA, 15 with AAU+SpA and 15 healthy control persons) were examined. A high percentage of the serological results of all investigated bacteria was positive: 80% in the AAU, 93.3% in the SpA and 100% in the AAU+SpA group, while it amounted to 66.7% in the control group (p < 0.05). H. pylori showed the highest percentage of positivity in all 3 patient groups (66.7% in the AAU, 73.3% in the SpA and 80% in the AAU+SpA group). In contrast, 26.7% of the controls were anti-H.-pylori-positive, thus showing a statistically significant difference between the patients and the control group (p < 0.05). HLA-B27/B7-CREG positivity was detected in 53.3% of the AAU, 66.7% of the SpA and 93.3% of the AAU+SpA patients and in none of the controls. Our results suggest that H. pylori might be a candidate participating in the development of AAU and SpA. They also support the theory of genetic (HLA-B27) and exogenous factors (Gram-negative bacteria) as probable background of these diseases.

[Antibodies to Klebsiella O-antigens in patients with seronegative spondyloarthropaties]. / Przeciwciala przeciwko antygenom somatycznym O paleczek Gram-ujemnych z rodzaju Klebsiella u chorych na spondyloartropatie seronegatywne.

OBJECTIVES: The pathogenesis of seronegative spondyloarthropathies is still unknown. A microbial etiology has been suggested. The aim of the study was to analyze the antibodies against Klebsiella O-antigens in serum of patients with seronegative spondyloarthropathies. METHODS: 30 patients with seronegative spondyloarthropathies, 20 with rheumatoid arthritis and 20 healthy volunteers were included in the study. The serum antibodies against Klebsiella O1 and O3 antigens were analyzed by enzyme-linked immunosorbent assay (ELISA). RESULTS: In serum of patients with seronegative spondyloarthropaties the antibodies against Klebsiella antigen O1 and O3 occur less frequently (6.67%) than in serum of patients with rheumatoid arthritis (35%) and that in serum of healthy subjects (40%). CONCLUSIONS: The results do not confirm the role of LPS in the pathogenesis of seronegative spondyloarthropthies, but on the other hand we could not exclude the concept that it may play an important role.

[The role of Salmonella and Yersinia in the pathogenesis of spondyloarthropathies and rheumatoid arthritis. I. Detection of bacteria, bacterial DNA, lipopolysaccharide and ECA antigen in synovial fluid or blood]. / Udzial paleczek z rodzaju Salmonella i Yersinia w patogenezie zapalenia stawów ze szczególnym uwzglednieniem spondyloartropatii i reumatoidalnego zapalenia stawów. I. Wystepowanie paleczek z rodzaju Salmonella i Yersinia, fragmentów ich genów, lipopolisacharydów oraz antygenu ECA w plynie stawowym badz we krwi osób z zapaleniem stawów.

To investigate the role of Salmonella and Yersinia in the pathogenesis of spondyloarthropathies and rheumatoid arthritis synovial specimens from 92 patients were analysed for the presence of bacterial DNA with the use of polymerase chain reaction and for the presence of lipopolysaccharide and enterobacterial common antigen (ECA) with the use of Dot-ELISA. In addition, peripheral blood samples were available for PCR analysis from 68 patients. Salmonella and Yersinia chromosomal DNA was not found in any of the synovial specimens and blood samples from the patients. All of the synovial fluids were also culture-negative. Salmonella LPS antigens were observed in 8 (8.6%), Yersinia in 20 (21.7%) and ECA antigens in 32 (34.9%) synovial specimens. Our findings revealed the presence of bacterial degradation products, but not bacteria from the genus Salmonella and Yersinia or their DNA in the synovial fluid or blood of patients with spondyloarthropathies and rheumatoid arthritis.

Lumbosacral radiographic signs in patients with previous enteroarthritis or uroarthritis.

OBJECTIVE: To investigate if there are differences in radiological findings in lumbosacral spine radiographs between different subgroups of patients with previous reactive arthritis. METHODS: 95 patients with previous enteroarthritis (n = 53), uroarthritis (n = 37), or Reiter's syndrome, aetiology unknown (n = 5) were included in the study. Lumbosacral radiographs were taken 7 to 38 years after the initial arthritis. Three independent observers read the radiographs. Spinal changes included squaring of vertebrae, Romanus lesions, syndesmophytes, and osteophytes. Sacroiliitis was recorded according to the New York and Stoke methods. Signs of enthesitis in the iliac crest and disc space narrowing were recorded. Interobserver reliability and intraobserver reproducibility were determined. RESULTS: 23% of patients had grade 2-4 sacroiliitis (New York criteria) and 14% had syndesmophytes. There was more frequent sacroiliitis (32% v 13%) in uroarthritis than in enteroarthritis, and more syndesmophytes (mean 0.54 v 0.15 per patient; prevalence 24% v 6%, respectively). In other radiological features, no significant differences were present between the groups. In the material as a whole, patients with sacroiliitis of grade 2 or more had significantly less disc space narrowing both in patient comparisons (chi(2) test) and in numbers of spaces involved (Mann-Whitney test). Interobserver and intraobserver agreement, calculated using Cohen's kappa method, varied from 0.2 to 1. CONCLUSIONS: Syndesmophytes and sacroiliitis are more common in patients with previous uroarthritis than in those with previous enteroarthritis, but radiological findings in lumbosacral spine radiographs are characteristically similar.

Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy, with special reference to chlamydia-induced arthritis. A prospective, randomized 9-month comparison.

OBJECTIVE: Chlamydia is a known trigger of reactive arthritis (ReA). It may also be common cause of undifferentiated spondyloarthropathy (uSpA). Persistent, metabolically active, Chlamydiae have been observed in the synovial tissue of these patients years after their initial exposure. Trials with lymecycline and rifampin have shown benefit in early/acute Chlamydia-induced arthritis. In vitro data suggest that persistent Chlamydia become resistant to chronic monotherapy of tetracyclines or rifampin, whereas no such resistance is noted when rifampin is added to antimicrobials that are active against Chlamydia. Rifampin and doxycycline also show synergistic effect against Chlamydia. In addition, rifampin inhibits chlamydial production of heat shock proteins (HSP). HSP60 plays a key role in the chronic persistent state of Chlamydia. We conducted a prospective, randomized 9-month trial to evaluate the efficacy of doxycycline versus a combination of doxycycline and rifampin in the treatment of uSpA. METHODS: The study enrolled 30 patients with chronic inflammatory arthritis (average disease duration 10 yrs) who fulfilled the European Spondylarthropathy Study Group criteria, with no evidence of inflammatory bowel disease, psoriasis, ankylosing spondylitis, or preceding dysentery. Patients received doxycycline 100 mg po twice daily or a combination of doxycycline 100 mg po twice daily and rifampin 600 mg po daily. They received a 4-question self-questionnaire and a blinded joint examination at each visit. The questions include a visual analog scale (VAS) for their current amount of back pain, duration of morning stiffness, back pain at night, and peripheral joint pain. The blinded joint examination consisted of a swollen joint count (SJC) and a tender joint count (TJC). These 6 variables were assessed at baseline and at 1, 3, 6, and 9 months. Responders were defined as those who improved > or = 20% in at least 4 of the 6 variables at 9 months of therapy. RESULTS: Comparing the doxycycline + rifampin arm (D/R) versus the doxycycline arm (D) at 9 months of therapy, all 6 variables improved more in D/R versus D, 4 of which were statistically significant. The mean VAS (scale of 100) decreased 24.4 points in D/R in contrast to 3 points in D (p < 0.03). Duration of morning stiffness decreased by 1.2 h in D/R, with a slight increase of 0.1 h in D (p < 0.003). The back pain at night and peripheral joint pain both improved in D/R group versus D (not statistically significant). Finally, the SJC and TJC also improved in D/R (-2.1 and -2.5) versus D (-0.4 and -0.6; p = 0.02, p = 0.03, respectively). Eleven of 15 patients in the D/R arm were responders, whereas only 2 of 15 D group patients were considered responders (p < 0.003). CONCLUSION: The combination of doxycycline and rifampin for 9 months seemed to be effective in treatment of chronic uSpA. This is the first study to demonstrate therapeutic benefit with antimicrobials to a chronic inflammatory arthritis possibly secondary to persistent Chlamydia.