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Spondyloarthritis or spondyloarthropathy (SpA) is a multifactorial disease in which a disturbed interplay occurs between the immune system and environmental factors on a predisposing genetic background, which leads to inflammation and structural damage of target tissue. Many recent researches on development of SpA showed important role of innate and adaptive immunity as well as of prominent bone tissue remodeling which leads to osteoproliferation and ankylosis. It is believed that possible sites of inflammation in SpA are entheses, sinovium and gut. Current knowledge on inflammation and tissue destruction leads to conclusion that SpA is disease characterized by disorders on different levels. Disorder on the first level is disturbed pathogen recognition and immune response activation, on second level disturbed inflammatory cells migration and on third level disturbed immune response regulation. As follows, disease progress depends on range of disturbances: disease course can be short, as in reactive arthritis, or long-lasting with substantial structural damage, as in ankylosing spondylitis. Unfortunately, there are still no confident markers of disease progression, so at the mere beginning disease is often described as undifferentiated.

Since there is no evidence regarding the efficacy of conventional synthetic disease modifying anti-rheumatic drugs in the improvement of axial spondyloarthritis (SpA), anti-tumor necrosis factors (anti-TNFs) are recommended if nonsteroidal anti-inflammatory drugs fail, or in case of high disease activity. Anti-TNFs show encouraging data regarding pain reduction, improved mobility and quality of life in both ankylosing spondylitis and non-radiographic axial spondyloarthritis. However, withdrawal of anti-TNF therapy leads to relapse of disease activity in SpA. Moreover, osteoproliferation does not seem to be influenced by anti-TNFs.

Objective: To analyze the clinical relevance of the levels of TNFα blockers and anti-drug antibodies (anti-drug Ab) in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) treated with adalimumab (ADA), etanercept (ETA), or infliximab (INF) for a prolonged period of time., Methods: Clinical characteristics (disease activity, and adverse events), serum TNFα blockers, and anti-drug Ab levels were evaluated in 62 RA and 81 SpA patients treated with TNFα blockers for a median of 28 months., Results: Anti-ADA Ab were detected in 1 (4.0%) and anti-INF Ab in 14 out of 57 (24.6%) RA and SpA patients. Patient with anti-ADA Ab and 57.1% patients with anti-INF Ab were considered nonresponders to treatment. Anti-ETA Ab were not found in any of 61 ETA treated patients. Anti-ADA and anti-INF Ab levels differ between responders and nonresponders (P > 0.05). Three (5.3%) patients with high serum anti-INF Ab levels developed infusion related reactions. Patients with anti-INF Ab more often required changing to another biologic drug (OR 11.43 (95% CI 1.08-120.93)) and treatment discontinuation (OR 9.28 (95% CI 1.64-52.52))., Conclusion: Patients not responding to treatment had higher serum anti-ADA and anti-INF Ab concentrations. Anti-INF Ab formation is related to increased risk of infusion related reactions, changing to another biologic drug, and treatment discontinuation.

The clinical features of spondyloarthritides include extraarticular manifestations involving the skin, eyes, and gastrointestinal tract. At these sites, a membrane integrin can be acquired by virtue of the presence of CD4+ T cells and specific dendritic cells and correlates with a regulatory behavior of these cells. This membrane integrin conjugates the beta7 subunit and the alphaE subunit, also known as CD103. CD103 expression requires high levels of TGF-beta and retinoic acid; in addition, expression of CD103 by T cells requires antigen recognition. Whether CD103 is found in the entheses has not yet been investigated. CD103 is expressed at high levels in the skin, eyes, and bowel but it is found in only very low levels in the bloodstream. CD8+ CD103+ T cells differ markedly from other CD103+ cells in that they are resident cells with no tendency to migrate and usually exert predominantly cytotoxic functions as opposed to regulatory functions. Several bacteria, such as Salmonella, can become dormant within the mucous membranes and/or their lymph nodes, where they use CD103+ dendritic cells and CD4+ CD103+ regulatory T cells (Tregs) to evade the immune response. This phenomenon could be studied in other tissues targeted by spondyloarthritides, where dormant microorganisms can migrate by using M2 macrophages as Trojan horses, since M2 macrophages express the CD103 ligand E-cadherin. Microorganism peptide recognition by CD8+ CD103+ T cells (which are overrepresented in psoriasis and joint fluid in some forms of spondyloarthritis) induces an inflammatory response that may be sufficient to transiently reverse the regulatory function of the CD103+ dendritic cells and CD4+ CD103+ T cells during disease flares. The sensitivity of these diseases to retinoids further supports a pathogenic role for transient CD103+ cell failure., (Copyright © 2014 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objectives: Aortic disease is a known complication of HLA-B27-associated spondyloarthritis. We present the case of a 52-year-old HLA-B27-positive woman with aortitis of the abdominal aorta and spondyloarthritis., Methods: In addition to the case reported, a literature search (MEDLINE) for articles published between 1946 and September 2013 was performed using combinations of the MEDLINE subject headings keywords "spondylarthritis," "ankylosing spondylitis," "reactive arthritis," "psoriatic arthritis," "aortitis," and "abdominal aorta." Relevant references were retrieved., Case Report: Our patient presented to the ER in June 2008 with a 3-week history of worsening of severe cramping lower abdominal pain. Her history also included recurrent acute episodes of iritis, which eventually led to enucleation of her left eye despite treatment with corticosteroids. CT of the abdomen showed findings suggesting aortitis of the abdominal aorta. She responded to therapy with prednisone, and follow-up imaging showed eventual resolution of the aortitis. She later went on to be diagnosed with psoriatic arthritis with spondylitis., Review of Literature: Six previously reported cases of abdominal aortitis in spondyloarthritis were found. Four of these were reported in patients with ankylosing spondylitis, one in reactive arthritis, and one in psoriatic arthritis. The first case reported was in 1958 and the most recent in 2012., Conclusions: Rheumatologists should be aware of the possibility of abdominal aortitis occurring in their patients with SpA and should consider it as part of the differential diagnosis in a SpA patient with unexplained visceral pain or systemic features out of proportion to clinically apparent disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The intestinal microbiota is firmly implicated not only in the pathogenesis of inflammatory bowel disease (IBD) but increasingly also in the development of inflammation at extraintestinal tissue sites. Significant clinical, genetic, immunological, and microbiological overlap exists between IBD and spondyloarthritis (SpA), which indicates that pathophysiological mechanisms are shared between these diseases and may center on the intestinal microbiota. Recently, culture-independent techniques have enabled the microbiota in health and disease to be described in increasing detail. Moreover, functional studies have identified myriad host effector and regulatory pathways that shape or are shaped by this microbial community. We consider the complex relationship between SpA pathogenesis and gut microbes, with a discussion of how manipulation of the gut microbiota itself may be a promising future target for SpA therapy., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: HLA-B27/human β2 -microglobulin (hβ2 m)-transgenic (B27-transgenic) rats develop an inflammatory disorder resembling spondyloarthritis, with accumulation of proinflammatory Th17 cells. Because Treg cells and Th17 cells have opposing effects in inflammatory disorders, we sought to determine whether biased expansion of Th17 cells could result from altered Treg cell frequency and/or function in B27-transgenic rats., Methods: We characterized the phenotype and function of Treg cells from B27-transgenic rats in comparison with those from control rats, by examining their expression of cell surface markers, suppressive activity, cytokine production, and differentiation pattern., Results: In B27-transgenic rats, the preferential accumulation of CD4+ Teff cells over Treg cells was not associated with a defect in Treg cell differentiation or suppressive activity. The expression of Treg cell markers was similar between B27-transgenic and control rats, with the exception of the inducible costimulator (ICOS) molecule, which was overexpressed in B27-transgenic rats. High levels of ICOS are considered to be a hallmark of Treg cells with heightened suppressive activity and interleukin-10 (IL-10) expression. Paradoxically, the production of IL-10 by Treg cells was reduced in B27-transgenic rats, whereas the production of IL-17 was enhanced. Moreover, the addition of anti-ICOS monoclonal antibodies during Treg cell differentiation in the presence of dendritic cells from B27-transgenic rats reversed this cytokine profile, restoring the balance between IL-10 and IL-17 in Treg cells from B27-transgenic rats., Conclusion: We observed dysregulated production of IL-10 and IL-17 by Treg cells from B27-transgenic rats, which may contribute to disease development. Moreover, our data highlight a key role for ICOS signaling in the generation of imbalanced production of IL-10 and IL-17 by Treg cells in this experimental model of spondyloarthritis., (Copyright © 2014 by the American College of Rheumatology.)

Objective: To assess the efficacy of etanercept in the treatment of early active nonsteroidal antiinflammatory drug (NSAID)-refractory nonradiographic axial spondyloarthritis (SpA)., Methods: The study population consisted of patients who met the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA but not the modified New York radiographic criteria for ankylosing spondylitis (as assessed by a radiologist at the central trial site), had a symptom duration of >3 months but <5 years, had a score of ≥4 on the Bath Ankylosing Spondylitis Disease Activity Index, and had been treated unsuccessfully with ≥2 NSAIDs. Patients were randomized to receive etanercept 50 mg/week or placebo and continued background NSAID treatment for 12 weeks (double-blind study); during the subsequent open-label period, all patients received etanercept 50 mg/week. The primary study end point was meeting the ASAS criteria for 40% improvement (ASAS40) at week 12. Magnetic resonance imaging (MRI) of the sacroiliac joints and spine was performed at baseline and week 12., Results: One hundred six patients were randomized to the etanercept group and 109 to the placebo group. Of the 215 patients, the mean ± SD age at baseline was 32.0 ± 7.8 years, 154 (72%) were HLA-B27 positive, and 174 (81%) had MRI-confirmed sacroiliitis. At 12 weeks, the proportion of patients with improvement according to the ASAS40 was significantly higher in the etanercept group than in the placebo group (34 of 105 [32%] versus 17 of 108 [16%]; P = 0.006). Patients who received etanercept exhibited a greater reduction in MRI-based scores for sacroiliac joint inflammation (-46.9% versus -10.9%; P < 0.001) and spinal inflammation (-45.4% versus -33.4%; P = 0.04) compared with placebo-treated patients at week 12. Post hoc analyses suggested a possible association between higher baseline C-reactive protein levels or MRI sacroiliac joint inflammation scores and higher rates of ASAS40 response to etanercept. At week 24, patients in the placebo group who had switched to etanercept at 12 weeks exhibited improvement similar to that observed in patients who had received etanercept for 24 weeks., Conclusion: In patients with nonradiographic axial SpA, etanercept treatment was associated with rapid, significant improvement in symptomatic disease activity, function, and systemic and skeletal inflammation over 12 weeks; clinical/functional improvement was sustained over 24 weeks., (© 2014 Pfizer Inc. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Purpose of Review: Thirty years ago, the concept of microscopic gut inflammation in spondyloarthritis (SpA) was established. Over the past decade, there has been tremendous progress in the earlier diagnosis of SpA. In addition, it has been suggested that, because of improved hygiene over the past years, exposure to microorganisms has changed, leading to a shift in diseases, for example, a decreased incidence of reactive arthritis. It is therefore necessary to re-establish the role of gut inflammation in SpA., Recent Findings: The prevalence of microscopic gut inflammation could be confirmed in c. 50% of patients with early axial and/or peripheral SpA. More importantly, a predictive model could be developed linking gut inflammation with clinical factors, that is, higher disease activity, extensive sacroiliac bone marrow edema, and progressive disease. In addition, there is increasing evidence indicating that the presence or absence of gut inflammation in SpA may influence therapeutic decision-making in the future. A clear demonstration of this is the different efficacy of IL-17 blockade in Crohn's disease versus SpA., Summary: Microscopic gut inflammation is present in almost 50% of SpA patients and appears relevant for prognosis and therapeutic decision-making. SpA patients with the chronic type of gut inflammation seem to have a less favorable disease course. It is therefore conceivable that assessment of gut inflammation should be included in future models for risk stratification of SpA.

Purpose of Review: Various novel therapies for spondyloarthritis (SpA) are currently under development. In this review, we discuss the scientific rational to target the interleukin (IL)-23/IL-17 axis in SpA and give an overview of the proof-of-concept trials with drugs directed towards this axis., Recent Findings: Cumulative evidence from genetics (e.g. the strong genetic association with the IL-23 receptor gene), in-vitro models (e.g. the increased IL-23 production upon HLA-B27 misfolding), human expression studies (e.g. the expansion of IL-17 producing innate cells in SpA) and animal models (e.g. the increased IL-17 production in HLA-B27 transgenic rats) strongly supports the involvement of the IL-23/IL-17 axis in the pathogenesis of SpA. Ustekinumab (a monoclonal antibody directed against the common p40 subunit of IL-23 and IL-12), secukinumab, ixekizumab (both monoclonal antibodies directed against IL-17A), and brodalumab a monoclonal antibody against the IL-17RA receptor) have been recently used in proof-of-concept and randomized trials in the ankylosing spondylitis and/or psoriatic arthritis subforms of SpA, with overall very promising clinical efficacy., Summary: The first results for novel drugs blocking key cytokines in the IL-23/IL-17 axis are promising in SpA and more novel compounds are upcoming. This will teach us more on the role of the IL-23/IL-17 axis in the pathophysiology of SpA.

Objectives: To determine the adherence of practicing rheumatologists, before and after an educational project, to Assessment of SpondyloArthritis international Society (ASAS) classification criteria and to ASAS recommendations for the use of anti-tumor necrosis factor (TNF)-alpha agents in patients with axial spondyloarthritis (SpA)., Methods: The project involved 53 rheumatologists attending 2 educational meetings on an update of SpA. Each meeting included interactive sessions on 1) clinical cases, 2) clinimetric evaluation, including ASAS core set for daily practice and 3) imaging. Diagnostic and therapeutic approach of each participant was tested using short clinical cases, obtained from real-life rheumatology settings, at the beginning and at the end of this educational project. Each case for diagnostic (n=10) or therapeutic purpose (n=10) had 10 possible choices. Each participant gave a score from 0 (total disagreement) to 10 (total agreement) for each choice., Results: At baseline, the rheumatologists had an excellent agreement with ASAS classification criteria for axial SpA and anti-TNF-alpha treatment according to ASAS recommendations with a further significant improvement after the educational programme. In axial SpA cases with acute anterior uveitis (AU) or Crohn's disease, anti-TNF-alpha treatment was indicated mainly as monoclonal anti-TNF antibody. In presence of elevated levels of CRP, anti-TNF option has been considered useful., Conclusions: Practicing rheumatologists had a satisfying adherence to ASAS classification criteria and to ASAS recommendations for the use of anti-TNF-alpha agents for patients with axial SpA. Extra-articular manifestations and other variables might play a role in the decision-process of the management of axial SpA.

Objective: Spondyloarthritides (SpA) occur in 1% of the population and include ankylosing spondylitis (AS) and arthropathy of inflammatory bowel disease (IBD), with characteristic spondylitis, arthritis, enthesitis, and IBD. Genetic studies implicate interleukin-23 (IL-23) receptor signaling in the development of SpA and IBD, and IL-23 overexpression in mice is sufficient for enthesitis, driven by entheseal-resident T cells. However, in genetically prone individuals, it is not clear where IL-23 is produced and how it drives the SpA syndrome, including IBD or subclinical gut inflammation of AS. Moreover, it is unclear why specific tissue involvement varies between patients with SpA. We undertook this study to determine the location of IL-23 production and its role in SpA pathogenesis in BALB/c ZAP-70(W163C)-mutant (SKG) mice injected intraperitoneally with β-1,3-glucan (curdlan)., Methods: Eight weeks after curdlan injection in wild-type or IL-17A(-/-) SKG or BALB/c mice, pathology was scored in tissue sections. Mice were treated with anti-IL-23 or anti-IL-22. Cytokine production and endoplasmic reticulum (ER) stress were determined in affected organs., Results: In curdlan-treated SKG mice, arthritis, enthesitis, and ileitis were IL-23 dependent. Enthesitis was specifically dependent on IL-17A and IL-22. IL-23 was induced in the ileum, where it amplified ER stress, goblet cell dysfunction, and proinflammatory cytokine production. IL-17A was pathogenic, while IL-22 was protective against ileitis. IL-22+CD3- innate-like cells were increased in lamina propria mononuclear cells of ileitis-resistant BALB/c mice, which developed ileitis after curdlan injection and anti-IL-22., Conclusion: In response to systemic β-1,3-glucan, intestinal IL-23 provokes local mucosal dysregulation and cytokines driving the SpA syndrome, including IL-17/IL-22-dependent enthesitis. Innate IL-22 production promotes ileal tolerance., (Copyright © 2014 by the American College of Rheumatology.)

Objectives: The pathogenesis of axial spondyloarthritis (axSpA) is still unclear. There is a strong association with HLA-B27 and other genes. Recently, anti-CD74 antibodies with specificity to a class II-associated invariant chain peptide (anti-CLIP-ABs) were found in axSpA patients. We examined the prevalence, sensitivity and specificity of anti-CLIP-ABs in axSpA in comparison with controls., Methods: Sera of axSpA and non-SpA patients were analysed for IgG-antibodies against CD74 by ELISA with specificity for CLIP developed in cooperation with AESKU Diagnostics (Germany). A cut-off of ≥4 SDs of arbitrary units (AU) from mean serum levels was used to differentiate the results. The laboratory workers were completely blinded for clinical data., Results: We analysed 145 sera from 94 axSpA and 51 non-SpA patients. AxSpA patients were more often male and younger. HLA-B27 status was available in 72 patients. Anti-CLIP-ABs were detected in 85.1% in axSpA but in only 7.8% in non-SpA patients (p≤0.0001). AxSpA patients showed higher levels of anti-CLIP-ABs versus non-SpA: mean 14.5 versus 0.8 AU (p≤0.0001). The sensitivity of anti-CLIP-ABs for diagnosing axSpA was 85.1%, specificity 92.2%, likelihood ratio (LR) LR+ was 10.8 and LR- was 0.08. Anti-CLIP-ABs and HLA-B27 were positive in 87.5% patients with axSpA, but only 14.9% were anti-CLIP-negative, while 23.6% were HLA-B27-negative., Conclusions: Anti-CLIP antibodies were strongly associated with axSpA. The LR for confirming axSpA by using anti-CLIP was even higher than by using HLA-B27. More studies using this promising new method in patients with non-radiographic axial SpA or peripheral SpA are needed to establish its usefulness in clinical practice.

Objectives: Killer cell lectin-like receptor G1 (KLRG1) is an NK cell marker also expressed on T cells showing an immunosenescent phenotype. KLRG1 binding to its ligand E-cadherin inhibits functional responses. It was recently shown that soluble E-cadherin (sE-cadherin) also influences KLRG1 signalling, although its involvement in arthritis is unknown. Our goal was to evaluate the contribution of KLRG1(+) T cells to synovitis., Methods: Paired peripheral blood (PB) and synovial fluid (SF) mononuclear cells from 21 patients with spondyloarthritis (SpA) or rheumatoid arthritis (RA), eight with crystal-induced arthritis and 10 controls were obtained. T cells were characterised for KLRG1 expression directly ex vivo, while TNF-α/IFN-γ production was assessed after polyclonal stimulation. Assays of chemotaxis response towards SF were conducted. Additionally, sE-cadherin levels in our paired samples were determined. Moreover, TNF-α/IFN-γ production by antigen-specific T cells was evaluated in the presence of sE-cadherin., Results: KLRG1(+) T cells were enriched in SF as opposed to PB of SpA and RA patients, which contrasts with results obtained in crystal-induced arthritides. KLRG1(+) T cells were more functionally active as opposed to KLRG1(-) T cells and migrated preferentially towards SpA and RA SF. sE-cadherin levels were higher in SF versus plasma. The presence of sE-cadherin enhanced the number of KLRG1(+) CD4(+) T cells able to produce TNF-α but not IFN-γ., Conclusions: sE-cadherin contributes to the local proinflammatory environment in the joint by favouring TNF-α production by KLRG1(+) CD4(+) T cells. This pathway seems to be operational in both SpA and RA, but not in crystal-induced arthritis.

Background: Spondyloarthritis (SpA) is a common debilitating inflammatory disorder. Establishing the diagnosis is often difficult, since abnormalities in conventional X-ray develop with a latency of several years and only HLA-B27 is used as a laboratory marker. The goal of our study was to identify new autoantibodies as diagnostic markers of SpA., Methods: Protein array technology was used to screen for new autoantigens in ankylosing spondylitis. Then, the results were confirmed by ELISA using Class II-associated invariant chain peptide domain of CD74 as antigen. Sera for the ELISA were obtained from 216 patients with axial (n=156) and peripheral (n=60) SpA. Sera of patients with psoriatic arthritis without axial involvement as another subtype of peripheral SpA, rheumatoid arthritis, systemic lupus erythematosus, HIV infection and blood donors served as controls. All donors provided informed consent for the study which was approved by the local ethics committee (project number 4928)., Results: Using protein arrays, we detected IgG antibodies against CD74 in SpA sera. Using ELISA technology on sera that had previously been frozen for several years, IgG autoantibodies against CD74 were found in 67% of the SpA patients and were even more frequent in patients with a short disease duration. In the controls, the prevalence of the new autoantibodies was 18/40 (45%) in psoriatic arthritis without axial involvement, 9/80 (11%) in rheumatoid arthritis, 6/40 (15%) in systemic lupus erythematosus, 1/40 (2.5%) in HIV and 1/125 (0.8%) in blood donors., Conclusions: Antibodies against CD74 could provide an important additional tool for diagnosis of SpA.

The 40-year-old association of HLA-B27 with ankylosing spondylitis is one of the best examples of disease association with a hereditary marker. Genomewide association and family studies suggest that other important major histocompatibility complex (MHC) influences are operative in ankylosing spondylitis (AS) susceptibility. HLA-B27 positive hepatitis C individuals are immunologically more efficient in combating viral infections such as HIV-1, hepatitis C, and influenza and less efficient in combating against certain bacteria (and perhaps other organisms) capable of surviving intracellularly. A recent representative population survey of the frequency of HLA-B27 in the USA found a lower frequency of HLA-B27 in older US adults, perhaps reflecting this. Other HLA class I and class II alleles have been implicated in AS susceptibility, the most consistent being HLA-B*40/B60 (B*40:01) but also B14, B15, A*0201, DRB1*04:04, and certain DPA1 and DPB1 alleles. Non-HLA MHC alleles have also been implicated, although many such studies have been inconsistent, likely due to power issues related to the low number of HLA-B27-negative AS patients examined. The best evidence is for major histocompatibility complex class I chain-related gene A (MICA) whose recognition by intestinal epithelial T cells expressing different V-delta-1 gamma/delta TCR further implicates the gut in AS pathogenesis. The HLA class I and class II and other non-HLA allelic associations underscore the importance of T cells in AS pathogenesis.

Objective: In HLA-B27-transgenic rats, the development of a disorder that mimics spondyloarthritis (SpA) is highly correlated with dendritic cell (DC) dysfunction. The present study was undertaken to analyze the underlying mechanisms of this via transcriptome analysis., Methods: Transcriptome analysis of ex vivo-purified splenic CD103+CD4+ DCs from B27-transgenic rats and control rats was performed. Transcriptional changes in selected genes were confirmed by quantitative reverse transcriptase-polymerase chain reaction. A meta-analysis of our rat data and published data on gene expression in macrophages from ankylosing spondylitis (AS) patients was further performed., Results: Interferon (IFN) signaling was the most significantly affected pathway in DCs from B27-transgenic rats; the majority of genes connected to IFN were underexpressed in B27-transgenic rats as compared to controls. This pattern was already present at disease onset, persisted over time, and was conserved in 2 disease-prone B27-transgenic rat lines. In DCs from B27-transgenic rats, we further found an up-regulation of suppressor of cytokine signaling 3 (which may account for reverse IFN signaling) and a down-regulation of interleukin-27 (a cytokine that opposes Th17 differentiation and promotes Treg cells). The meta-analysis of data on conventional DCs from rats and data on monocyte-derived macrophages from humans revealed 7 IFN-regulated genes that were negatively regulated in both human and rat SpA (i.e., IRF1, STAT1, CXCL9, CXCL10, IFIT3, DDX60, and EPSTI1)., Conclusion: Our results suggest that expression of HLA-B27 leads to a defect in IFNγ signaling in antigen-presenting cells in both B27-transgenic rats and SpA patients, which may result in Th17 expansion and Treg cell alteration (as shown in B27-transgenic rats) and contribute to disease pathogenesis., (Copyright © 2014 by the American College of Rheumatology.)

Objectives: Cellular expression of non-classical forms of human leukocyte antigen (HLA)-B27 (NC-B27) may be involved in spondyloarthritis (SpA) pathogenesis. We used a novel B27-specific monoclonal antibody, HD6, to ask if B27 transgenic (TG) rat splenocytes express these NC-B27 molecules. We also investigated whether B27-binding peptides could affect the expression and functional immune recognition of HD6-reactive B27 molecules., Methods: Splenocytes from B27-TG, B7-TG and non-transgenic rats, and HLA-B27+ cell lines were stained with monoclonal antibodies recognising classical (ME-1, HLA-ABC-m1) and non-classical (HD6, HC10) B27. Cells were further cultured in the presence of HLA-B27-binding peptides, or subjected to brief low pH treatment prior to mAb staining and/or immunoprecipitation or co-culture with KIR3DL2-CD3ε-expressing Jurkat reporter cells., Results: HD6-reactive molecules were detected in the majority of adult B27-TG rat splenocyte cell subsets, increasing with age and concomitant increased B27 expression. HD6 staining was inhibited by incubation with B27-binding peptides and induced by low pH treatment. HD6 staining correlated with KIR3DL2-CD3ε-expressing Jurkat reporter cell activity. Thus, IL-2 production was decreased when B27-expressing antigen-presenting cells were preincubated with B27-binding peptides, but increased following pretreatment with low pH buffer., Conclusions: Surface expression of HD6-reactive B27 molecules on B27-TG rat splenocytes is consistent with a pathogenic role for NC-B27 in SpA. Interaction of NC-B27 with innate immune receptors could be critical in SpA pathogenesis, and we show that this may be influenced by the availability and composition of the B27-binding peptide pool.

Introduction: Spondyloarthritis (SpA) comprises a group of diseases often associated with HLA-B27 and characterized by inflammation of the entheses and joints of the axial skeleton. The inflammatory process in SpA is presumably driven by innate immune cells but is still poorly understood. Thus, new tools for monitoring and treating inflammation are needed. The family of CD18 integrins is pivotal in guiding leukocytes to sites of inflammation, and CD18 hypomorphic mice develop a disease resembling SpA. Previously, we demonstrated that altered soluble CD18 (sCD18) complexes in the blood and synovial fluid of patients with arthritis have anti-inflammatory functions. Here, we study the mechanisms for these alterations and their association with SpA disease activity., Methods: Plasma levels of sCD18 in a study population with 84 patients with SpA and matched healthy controls were analyzed with a time-resolved immunoflourometric assay (TRIFMA). Binding of sCD18 to endothelial cells and fibroblast-like synoviocytes (FLSs) was studied with confocal microscopy. Shedding of CD18 from peripheral blood mononuclear cells (PBMCs) was studied with flow cytometry and TRIFMA., Results: Plasma levels of sCD18 were decreased in patients with SpA compared with healthy volunteers (P <0.001), and the lowest levels were in the HLA-B27-positive subgroup (P <0.05). In a multiple regression model, the sCD18 levels exhibited an inverse correlation with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (P <0.05), the level of morning stiffness (P <0.05), the Bath Ankylosing Spondilitis Metrology Index (P <0.05), the physician global assessment score (P <0.01), and the sacroiliac magnetic resonance imaging activity score (P <0.05). The mechanisms for these changes could be simulated in vitro. First, sCD18 in plasma adhered to inflammation-induced intercellular adhesion molecule 1 (ICAM-1) on endothelial cells and FLS, indicating increased consumption. Second, CD18 shedding from SpA PBMCs correlated inversely with the BASDAI (P <0.05), suggesting insufficient generation. CD18 was shed primarily from intermediate CD14⁺⁺ CD16⁺ monocytes, supporting the view that alterations in innate immunity can regulate the inflammatory processes in SpA., Conclusions: Taken together, the failure of patients with SpA to maintain adequate sCD18 levels may reflect insufficient CD18 shedding from monocytes to counterbalance the capture of sCD18 complexes to inflammation-induced ICAM-1. This could increase the availability of ICAM-1 molecules on the endothelium and in the synovium, facilitating leukocyte migration to the entheses and joints and aggregating disease activity.

Objectives: Spondyloarthritides (SpA) are characterised by both peripheral and axial arthritis. The hallmarks of peripheral SpA are the development of enthesitis, most typically of the Achilles tendon and plantar fascia, and new bone formation. This study was undertaken to unravel the mechanisms leading towards enthesitis and new bone formation in preclinical models of SpA., Results: First, we demonstrated that TNF(ΔARE) mice show typical inflammatory features highly reminiscent of SpA. The first signs of inflammation were found at the entheses. Importantly, enthesitis occurred equally in the presence or absence of mature T and B cells, underscoring the importance of stromal cells. Hind limb unloading in TNF(ΔARE) mice significantly suppressed inflammation of the Achilles tendon compared with weight bearing controls. Erk1/2 signalling plays a crucial role in mechanotransduction-associated inflammation. Furthermore, new bone formation is strongly promoted at entheseal sites by biomechanical stress and correlates with the degree of inflammation., Conclusions: These findings provide a formal proof of the concept that mechanical strain drives both entheseal inflammation and new bone formation in SpA.

Spondyloarthrites (SPA) represent a group of heterogenous rheumatic diseases (ankylosing spondylitis/SA, psoriatic arthritis/PsA, reactive arthritis/ReA, spondyloarthritis in bowel inflammatory diseases/BID, undifferentiated spondyloarthritis/undif SpA) with distinct clinical features and common genetic predisposition (HLA-B27). SpA may also affect other organs, ocular involvement, represented by uveitis and conjunctivitis, being one of the most important extraskeletal manifestations. Pathogenic mechanisms of ocular involment in SpA are not entirely known; nevertheless, the inflammatory process which characterizes the main rheumatic diseases seems to be responsible for this extraskeletal manifestation. SpA treatment targeted at clinical remission has a favourable effect not only on articular but also on ocular involvement. The discovery of new pathogenic mechanisms of both rheumatic and eye disease in SpA have contributed to identification of new pathogenic therapies. The interdisciplinary team work of rheumatologists and ophtalmologists have prove essential for the management of SpA patients with ocular manifestations.

The classification criteria recently developed by the Assessment of Spondyloarthritis International Society (ASAS) highlighted a specific entity: non radiographic axial spondyloarthritis (nr-axSpA). Although more and more widely used in the literature as well as clinical trials, limits and profile of this entity is still under known or debated. Some studies have already compared those forms to classical AS, even in recent forms. They showed that, apart from the difference in the ossification process, and the greater degree and frequency of systemic and MRI inflammation in AS, those 2 forms of SpA share the same genetic background, clinical patterns, and burden of disease. TNF antagonists seemed as effective in controlling symptoms in patients with nr-axSpA. Concerning the long-term outcome of nr-ax-SpA, only long-term ongoing cohorts of patients with recent nr-axSpA will be able to determine what proportion of patients have persistent non-radiographic disease and what proportion do progress to AS.

Objective: To investigate the features of ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (nr-axSpA) in a Canadian cohort of 639 patients with AS and 73 patients with nr-axSpA., Methods: Clinical and laboratory data were compared for patients with AS and nr-axSpA enrolled in a longitudinal SpA cohort., Results: The proportion of male patients was higher in AS than in nr-axSpA (76.2% vs 47.9%; p < 0.0001). There was no difference in the presence of HLA-B27 between AS (78.9%) and nr-axSpA (72.5%) patients, nor in age at the time of diagnosis, although AS patients were younger at the time of symptom onset (23.9 yrs vs 26.4 yrs; p = 0.03). Disease duration at the time of last clinic visit was longer for AS than for nr-axSpA patients (17.7 yrs vs 12.1 yrs; p = 0.0002). Acute-phase reactants were higher in AS than in nr-axSpA (C-reactive protein 11.4 vs 5.2, p < 0.0001; erythrocyte sedimentation rate 13.7 vs 9.9, p = 0.02). The Bath Ankylosing Spondylitis Metrology Index was higher in patients with AS (2.84 vs 1.35, p < 0.0001)., Conclusion: Patients with nr-axSpA were more likely to be female and to have lower inflammatory markers than patients with AS. When restricted to female patients only, acute-phase reactants did not differ significantly between AS and nr-axSpA. The evidence provides indirect support for the concept that nr-axSpA may represent an early form of AS, but that also has features of a distinct disease entity with significant burden of symptoms.

The axial spondyloarthritis (SpA) classification criteria cover both patients with ankylosing spondylitis and non-radiographic axial SpA. After failure of NSAIDs TNF-α-inhibitors (TNF-blockers) can be given to patients with active axial SpA. Until recently, the TNF-blockers infliximab, adalimumab, etanercept and golimumab are labeled for the treatment of active ankylosing spondylitis while for active nr-axSpA only adalimumab has been approved in Europe. The TNF-blocker certolizumab pegol has recently been evaluated in the RAPID-axSpA trial which is the first placebo-controlled randomized-controlled trial in the entire group of axial SpA. An elevated C-reactive protein and/ or evidence of bone marrow edema on MRI of the sacroiliac joints were required for inclusion in RAPID-axSpA, and patients could have been preexposed to TNF-blockers. The interesting data of this important trial in the context of the emerging therapeutic field of non-radiographic axial SpA therapy is discussed in this review.

Objectives: To compare drug survival of different anti-TNF drugs (infliximab, INF, etanercept, ETA, and adalimumab, ADA) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) by analysing data collected from an Italian multicenter observational cohort study., Methods: All patients with RA or SpA registered in the MonitorNet database who started their first course of anti-TNF therapy were included. Overall drug survival was measured, along with specific reasons of discontinuation (inefficacy or adverse events). A first set of analyses using RA as reference category assessed the relationship between diagnosis and drug survival. A second set of analyses stratified by diagnosis (RA and SpA) used INF as reference drug. Adjustment for confounders was performed. The results are presented as adjusted hazard ratios (adjHR) and 95% confidence intervals (95%CI)., Results: 2640 RA patients and 1220 SpA patients with a median follow-up of 17 months (IQR 7.2-33.4) were included in the analyses. Patients with a diagnosis of SpA showed a lower risk of drug discontinuation with an adjHR (95%CI) of 0.81 (0.73, 0.90). In SpA, the subset of patients with ankylosing spondylitis (AS) showed the best survival on treatment. In RA, both ETA and ADA showed a significantly lower probability of withdrawal when compared to INF [adjHR (95%CI) 0.46 (0.38, 0.56) and 0.68 (0.57, 0.81), respectively]. Similar results were found in SpA., Conclusions: Drug survival for SpA is longer than that in RA mainly due to the AS subgroup. In both RA and SpA, ETA and ADA showed a better retention on treatment when compared to INF.

Objective: There is an unacceptable delay in the diagnosis of axial spondyloarthritis (axSpA) in its early stages among patients at high risk, in particular those with inflammatory bowel disease (IBD). Our objectives were to develop a sensible and reliable questionnaire to identify undetected axSpA among patients with IBD., Methods: Literature was reviewed for item generation in the Toronto axSpA Questionnaire on IBD (TASQ-IBD). Sensibility of the questionnaire was assessed among healthcare professionals and patients. This assessment was related to purpose and framework (clinical function, clinical justification, and clinical applicability), face validity, comprehensiveness [oligo-variability (limiting the questionnaire to important items) and transparency], replicability, content validity, and feasibility. The test-retest reliability study was administered to 77 patients with established IBD and axSpA. Kappa agreement coefficients and absolute agreement were calculated for items., Results: Three domains included IBD, inflammatory back symptoms, and extraaxial features. The entry criterion required a patient to have IBD and back pain or stiffness that ever persisted for ≥ 3 months. Iterative sensibility assessment involved 16 items and a diagram of the back. Kappa coefficients ranged from 0.81-1.00 for each item. Absolute agreement across all items ranged from 91% to 100%., Conclusion: TASQ-IBD is a newly developed, sensible, and reliable case-finding questionnaire to be administered to patients with IBD who have ever had chronic back pain or stiffness persisting for ≥ 3 months. It should facilitate identification and timely referral of patients with IBD to rheumatologists and minimize the delay in diagnosis of axSpA. Consequently, it should assess the prevalence of axSpA in IBD.

Objectives: The combination of clinical items suggestive of inflammatory back pain has proved useful for early identification of patients with axial SpA (axSpA) in primary care. However, whether HLA B27 contributes to that is unclear, and published recommendations have advised against it. In this study, we reanalysed data of that trial in relation to the HLA B27 results., Methods: Consecutive patients <45 years old (n = 950) with back pain (BP) >2 months presenting to 143 orthopaedists were referred to 36 rheumatologists who made the diagnosis. The predictive value of HLA B27 (n = 298) alone and in combination, including modelling and a two-step strategy, was calculated., Results: Among all patients (mean age 36 years, 52% female, median duration of BP 32 months), 107 had axSpA (36%). Using a simple model, HLA B27 alone performed better than all combinations of clinical items and adding it did not improve likelihood ratios (LRs). Using modelling, two-phase strategies were analysed. Additional items were only relevant in the HLA B27-negative group: improvement by movement, buttock pain and psoriasis. Combining this information revealed the presumably best strategy to predict axSpA in primary care: more than one of these items or HLA B27 need to be present (sensitivity 80.4%, specificity 75.4%, LR+ 3.27 and LR- 0.26)., Conclusion: This is the first study to show that patients with axSpA are more reliably identified in primary care by a strategy that includes HLA B27. Because of the two-step approach, the test needs to be performed in only about half of patients with chronic BP.

Spondyloarthritis (SpA) is a group of inflammatory rheumatic diseases whose main clinical feature is inflammation of the axial spine. Articular, periarticular, and extra-articular manifestations can also occur, depending on the type of spondyloarthritis. The most common clinical subsets of SpA are ankylosing spondylitis (AS) and psoriatic arthritis (PsA). SpA is a major health challenge given the propensity to affect young adults and the potential requirement for lifelong treatment. Although the precise etiology of SpA is unknown, there is mounting evidence that these diseases are a result of complex interplay of genetic, environmental, and immunological factors. In this review on SpA, we will discuss genetic variants with genome-wide significance, highlight potential clinical application of genetic variants, and discuss challenges in further elucidating the genetic basis of SpA.

Purpose of Review: The spondyloarthropathies (SpAs) are a group of interrelated inflammatory disorders with overlapping clinical features. Current SpA treatments only provide partial symptomatic and functional relief in a subgroup of patients. Consequently, there is a need to better understand the pathophysiology of SpA to develop more specific and effective treatments for these conditions., Recent Findings: Genetic and mechanistic evidence links SpA with inflammatory bowel disease (IBD) and psoriasis, and the symptoms of these diseases partially overlap. Regulatory T cells (Tregs) and dendritic cells control the adaptive immune response, and failures in their functions are likely to contribute to the establishment of chronic inflammation. The contributions of Tregs and dendritic cells to IBD and SpA have been assessed in both animal models of disease and patients., Summary: Although defects in Tregs are important in psoriasis and in animal models of IBD, there is little evidence that they are important in SpA. However, data from animal models indicate that dendritic cells drive pathogenic T-cell responses, partly through the production of interleukin-23 (IL-23). Dendritic cells from SpA patients may also contribute to disease by producing IL-23, therefore supporting the differentiation of the Th17 cells that contribute to inflammation. The driving forces in SpA pathophysiology are now becoming clear; these data may lead to the development of novel therapies to target SpA and related inflammatory disorders.

Purpose of Review: HLA-B27 is associated with low viral load and long-term nonprogression in HIV infection as well as spontaneous clearance of hepatitis C virus (HCV) infection. This review summarizes mechanisms that have been suggested to be involved in this protective effect of HLA-B27, and highlights possible lessons for the role of HLA-B27 in spondyloarthritis., Recent Findings: Recent studies linked protection by HLA-B27 in HIV and HCV infection to virological mechanisms such as a complicated pathways of viral escape from immunodominant HLA-B27-restricted virus-specific CD8+ T-cell epitopes. In addition, several immunological mechanisms have been proposed, including CD8+ T-cell polyfunctionality and functional avidity, thymic selection of CD8+ T-cell precursors, specific T-cell receptor repertoires and clonotypes, efficient antigen processing, and evasion from regulatory T-cell-mediated suppression., Summary: Multiple virological and immunological mechanisms have been suggested to contribute to HLA-B27-mediated protection in HIV and HCV infection. Some of these mechanisms may also be involved in HLA-B27-associated pathogenesis in spondyloarthritis.

Purpose of Review: Natural killer (NK) cells, gamma delta (γδ) T-cells and other innate immune cells are important lymphocyte subsets able both to produce cytokines including the pro-inflammatory cytokine IL-17 and to kill cellular targets. This review describes the features of NK cells, γδ T-cells and other innate immune cells, and outlines the evidence for their potential pathogenic roles in spondyloarthritis (SpA)., Recent Findings: NK cells and T cells both express receptors that recognize aberrantly folded human leucocyte antigen. This interaction seems to polarize towards a type 17 immunity programme which has been increasingly implicated in SpA pathology. γδ T-cells have also been shown to be polarized towards a type 17 immunity programme in SpA. Gut interactions with the microbiome can influence NK and innate lymphoid immune responses in SpA and other related diseases. A newly identified population of resident lymphoid cells at the enthesis for the first time offers an explanation for the anatomical localization of SpA., Summary: NK cells, γδ T-cells and other innate immune cells are capable of sharing expression of both transcription factors, including RORγt, and cell surface receptors, such as the killer immunoglobulin-like receptors. There is increasing genetic and functional evidence that they contribute to the RORγt-driven inflammatory type 17 immune responses, and they may link gut inflammation and joint pathology in SpA.

The seronegative spondyloarthopathies (SpA) share certain common articular and peri-articular features that differ from rheumatoid arthritis (RA) and other forms of inflammatory arthritis. These include the tendency of the SpAs to involve the axial skeleton in addition to the diarthrodial joints, and the prominent involvement of the extra-articular entheses (sites of ligamentous and tendon insertion), which are not common sites of primary pathology in RA and other inflammatory arthropathies. The differential anatomic sites of bone pathology in the SpAs in comparison to the other forms of arthritis suggest that the underlying pathogenic processes and cellular and molecular mechanisms that account for the peri-articular bone pathology involve different underlying disease mechanisms. This review will highlight the molecular and cellular processes that are involved in the pathogenesis of the skeletal pathology in the SpAs, and provide evidence that many of the factors involved in regulation of bone cell function exhibit potent immune-regulatory activity, providing support for the general concept of osteoimmunology.

Background: Psoriasis is an important clinical feature in spondyloarthritis. However, the influence of psoriasis on the clinical, functional and imaging features of patients with inflammatory back pain (IBP) related to spondyloarthritis is not known., Objectives: To determine the prevalence of psoriasis and its impact in patients with recent IBP suggestive of spondyloarthritis., Methods: The prevalence of psoriasis was determined in 692 patients (mean age 33.3±8.5 years, 53.8% female, 58.3% human leucocyte antigen B27 positive) included in the DESIR cohort. Demographic characteristics, imaging features and blood tests of patients with and without psoriasis were compared., Results: The prevalence of psoriasis was 16.6%. Patients with rather than without psoriasis more often presented with enthesitis (59.1% vs 47.5%; p=0.02) and had more active disease (BASDAI 4.8±1.8 vs 4.4±2.0; p=0.05) and poorer functional status (BASFI 3.6±2.2 vs 3.0±2.3; p=0.006; SF-36 (physical function) 61.9±24.4 vs 66.9±24.9; p=0.04). Patients with psoriasis showed higher levels of C-reactive protein (p=0.02), total cholesterol (p=0.01) and triglycerides (p=0.02). The two groups did not differ in structural changes as assessed by standard x-rays or MRI at the spinal and sacroiliac levels. However, ultrasonography of the Achilles tendon revealed psoriasis associated with bone erosions (p=0.0003) and abnormal vascularisation (p=0.04). Multivariate regression analysis revealed BASFI score (p=0.03), cholesterol level (p=0.02), dactylitis (p=0.0006) and family history of psoriasis (p<0.0001) as independent predictors of psoriasis., Conclusions: In patients with recent IBP suggestive of spondyloarthritis, psoriasis is associated with active axial disease and frequent concomitant enthesopathy and dactylitis.

Objectives: This open-label study is based on a translational approach with the aim of detecting changes in the clinical condition as well as in imaging and synovial biological markers in both synovial fluid (SF) and synovial tissue (ST) in peripheral spondyloarthritis (SpA) patients following intra-articular (IA) blockade of TNF-α by serial etanercept injections., Methods: Twenty-seven SpA patients with resistant knee synovitis underwent four biweekly IA injections of etanercept (E) (12.5 mg). The primary outcome of Thompson's Knee Index (THOMP), and secondary outcomes of Knee Joint Articular Index (KJAI), C-reactive protein (CRP), HAQ-Disability Index (HAQ-DI), maximal synovial thickness (MST) according to ultrasonography (US) and contrast-enhanced magnetic resonance (C+MR) imaging, ST-CD45+ mononuclear cells (MNC) and ST-CD31+ vessels, IL-1β, IL-1Ra and IL-6 levels in SF were assessed at baseline and at the end of the study., Results: At the study end, clinical and imaging outcomes as well as ST and SF biological markers were significantly reduced compared to baseline. There were significant correlations between clinical, imaging and biological markers (CRP with either THOMP, or KJAI, or HAQ-DI or SF-IL-1Ra; US-MST with KJAI, ST-CD45+ with either THOMP, or KJAI, or ST-CD31+, or SF-IL-1β; SF-IL-6 with either THOMP, or KJAI, or SF-IL-1β, or IL-1Ra)., Conclusions: The proof of concept study revealed early improvement either in local and systemic clinical scores, in synovial thickness measures by C+MR and US, or expression of synovial biological markers. CD45+, CD31+ in ST and IL-6 and IL-1β in SF may be considered potential biomarkers of the peripheral SpA response to IA TNF-α blocking., (Copyright © 2012 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Introduction: Only non-steroidal anti-inflammatories (NSAIDs) and TNF inhibitors (TNFi) are effective in ankylosing spondylitis (AS). However, not all patients successfully respond to these drugs and a subset may have contraindications to their use., Areas Covered: In the last decade, an earlier diagnosis of AS has been achieved due to the increasing availability of MRI. This has led to prompt treatment initiation with improved outcomes. NSAIDs and TNFi are the current treatments for AS which lead to sustained clinical responses in the long term. Recent studies have shown other potential biomarkers in AS, such as the IL-17/IL-23 axis. This has translated into the development of new drugs which interfere with these pathways, such as apremilast and secukinumab, which have shown efficacy in early clinical trials., Expert Opinion: AS carries considerable short- and long-term disabilities. Anti-TNF-α therapies reduce pain, improve function and decrease inflammation as seen by MRI. New treatment options are being developed which may prove efficacious on those patients not responding to anti-TNF. The ultimate research goal should focus on treatments to prevent and stop new bone formation.

Spondylarthritis is still viewed as a reaction to infectious agents, as opposed to an infection by persistent bacteria, for several reasons: (a) an infection is considered proven only when the organism can be cultured; (b) no studies have identified dormant bacteria in the tissues targeted by spondylarthritis; (c) the bacterial persistence hypothesis has no therapeutic implications at the time being, since antibiotics are effective neither on dormant bacteria nor on the manifestations of spondylarthritis; and (d) the high prevalence of borderline disorders combining features of spondylarthritis and of psoriatic arthritis, or even rheumatoid arthritis (RA), would indicate a role for dormant bacteria in these last two diseases. However, recent data on dormant bacteria have rekindled interest in the bacterial persistence hypothesis. Dormant bacteria cannot be cultured, because they express only a small group of genes, known as the regulon, which includes genes for transcription factors that block the expression of the usual bacterial genes. Certain forms of cell stress, such as molecule misfolding, promote the entry of bacteria into a state of dormancy, which induces the low-level release by the host cells of cytokines such as TNF. Whether HLA-B27 misfolding facilitates the persistence of dormant bacteria within spondylarthritis tissue targets remains to be determined. If it does, then treatments that reactivate dormant bacteria might make these organisms susceptible to appropriate antibiotics and might therefore serve as useful adjuncts to nonsteroidal anti-inflammatory drugs and TNFα antagonists. TNFα antagonists rarely reactivate dormant bacteria, with the exception of Mycobacterium tuberculosis, which, together with metastatic cells, is the most extensively studied latency model to date., (Copyright © 2012 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Background: The prevalence of spondyloarthritis (SpA) varies across populations. In Mexicans, the prevalence of SpA is still unknown., Objective: The objective of this study was to determine the prevalence of SpA in the community as well as that of inflammatory back pain (IBP) and ankylosing spondylitis (AS)., Methods: We identified individuals older than 18 years with nontraumatic back pain (BP) in a door-to-door nurse survey using the Community Oriented Program for the Control of Rheumatic Diseases. Then, general physicians and rheumatology fellows selected those likely to have IBP (Berlin criteria). Finally, 2 expert rheumatologists assessed IBP individuals according to clinical data and classification criteria and requested HLA-B27 and radiographic studies to determine the clinical condition of the individual and SpA (European SpA Study Group) classification., Results: The prevalence of BP among 4059 individuals was 14.6% (95% confidence interval [CI], 13.6-15.8). The prevalence of IBP and SpA was 1.3% (95% CI, 1.0-1.7) and 0.6% (95% CI, 0.4-0.9), respectively. Ankylosing spondylitis prevalence was 0.1% (95% CI, 0.02-0.2). Inflammatory back pain and SpA percentage of males and females was similar. The percentage of individuals with IBP according to the 2 experts was lower than that determined by general physicians and rheumatology fellows, but all cases with HLA-B27, radiographic sacroiliitis, SpA, and AS had previous IBP confirmation by the expert., Conclusions: The prevalence and sex distribution of patients classified with SpA in this community study--as well as that of patients diagnosed with AS--are consistent with those found in recent studies. Expert assessment of individuals with positive responses to questionnaires is relevant for the classification of IBP and SpA.

Objective: The presence of disease-specific autoantibodies in RA but not spondyloarthritis (SpA) suggests that B-cell tolerance is preserved in the latter condition despite chronic joint inflammation. Which factors control B-cell tolerance vs autoimmunity in chronic arthritis remains incompletely understood. As single nucleotide polymorphisms in the B-cell scaffold protein with ankyrin repeats (BANK1) gene have recently been associated with various autoantibody-positive autoimmune diseases including RA, we explored whether altered expression of BANK1 was associated with humoral autoimmunity in arthritis., Methods: Peripheral B-cell subsets and inflamed synovial tissue were obtained from active SpA and RA. Quantitative PCR was used to assess the expression of full-length BANK1 and delta2 BANK1, a splice variant lacking exon 2 that counteracts BANK1 function. B-cell subsets, autoantibody titres and clinical disease were monitored upon CIA induction in Bank1 knockout (KO) mice., Results: Whereas full-length BANK1 was not differentially expressed, the BANK1 delta2 splicing variant was decreased in naïve peripheral B cells as well as in synovial tissue of SpA compared with RA. However, no differences were observed in seropositive vs seronegative RA. Performing functional analysis in mice, we found no differences in B-cell subsets and anti-collagen antibodies upon CIA induction between Bank1 KO mice and littermate controls. Accordingly, the incidence and severity of clinical disease were not altered in Bank1 KO mice., Conclusion: This study did not reveal a major role for BANK1 in humoral autoimmunity in chronic arthritis. The decreased levels of BANK1 delta2 in SpA, however, warrant more detailed analysis of the functional consequences of an altered BANK1/BANK1 delta2 balance.

Spondyloarthritis (SpA) is a family of many diseases, and these diseases share some clinical, genetic, and radiologic features. The disease process in the spine at the beginning is spinal inflammation, in which TNF α is the principal cytokine involved. Therefore, the dramatic clinical and pathologic response of anti-TNF α therapy in SpA is based upon the presence of increased TNF α in synovial tissues and sacroiliac joints, which perpetuates chronic inflammation. The increased Toll-like receptors (TCR) 2 and 4 in the serum, peripheral blood mononuclear cells, or synovial tissues of ankylosing spondyloarthritis (AS) or SpA patients suggest that SpA is highly associated with innate immunity. Any drug including anti-TNF α blocker which can downregulate the TCR, infiltrated neutrophils, or CD163+ macrophages in the synovial tissue is the rationale for the management of SpA. Like rheumatoid arthritis, the increased TH22 and TH17 cells either in blood, synovial fluid, or synovial tissues were also demonstrated in SpA. Thus, TH17 and TH22 may be reasonable cellular targets for therapeutic intervention. Drugs (anti-IL6R or anti-IL6) which can reduce the binding of IL6 and IL6R to the cell surface may be beneficial in SpA. Many proteins are implicated in the new bone formation (syndesmophyte) or ankylosis in AS or SpA. The enhanced BMP and Wnt pathway will activate osteoblasts which promote the new bone formation. However, no drug including anti-TNF α can stop or prevent the syndesmophyte in AS. In summary, looking for new targeting therapies for either anti-inflammation (beyond anti-TNF) or anti-bone formation (including anti-TGF β or PDGF) is warranted in the future.

Background and Aim: To evaluate presence of sero-negative spondyloarthritis (SpA) in celiac disease (CD) patients, and whether compliance with a gluten free diet (GFD) improved arthritis manifestations in these patients., Methods: We undertook a prospective, questionnaire based, cross-sectional cohort study to evaluate the presence or absence of SpA simultaneously in both CD and non-CD cohorts., Results: 356/590 (60.3%) patients with CD participated in this study. 99% had diagnosis confirmed by a diagnostic test (79% small bowel biopsy, 19.8% blood test, 3.9% stool test). Approximately 131 (37%) cases of arthritis were reported in CD patients. Of the 6/356 CD patients with seronegative spondyloarthritides, four had sacroiliitis, two ankylosing spondylitis, and one psoriatic arthritis, compared to one ankylosing spondylitis and five psoriatic arthritis in non-CD. Osteoarthritis (89 vs 59, P = 0.93) was the most common diagnosis reported by respondents. More CD patients with diarrhea (94%) and anemia (81%) improved on GFD, compared to arthritis symptoms (30%). Autoimmune thyroiditis (10.6% vs 0.4%), insulin dependent diabetes mellitus (IDDM) (2.2% vs 1.7%), systemic Lupus erythematosus (SLE) (1.1% vs 0), and psoriasis (12.9% vs 5.5%) occurred more frequently in CD patients. The prevalence of Crohn's disease, ulcerative colitis, Sjogren's syndrome, primary biliary cirrhosis, and primary sclerosing cholangitis was around 1% each. Univariate Logistic regression analysis showed ≤ high school education (odds ratio [OR] 2.01, P < 0.003), age ≥ 60 years (OR 4.13, P < 0.001), and osteoporosis (OR 2.78, P < 0.001) to be significantly associated with report of arthritis in CD patients., Conclusion: We did not find a high rate of SpA in CD patients. In contrast, increased rates of autoimmune thyroiditis, SLE, IDDM, and psoriasis were seen in CD., (© 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Introduction: Spondyloarthritis (SpA), an interrelated group of rheumatic diseases, has been suggested to be triggered by bacterial infections prior to the development of an autoimmune response that causes inflammation of the spinal and peripheral joints. Because human heat shock protein 60 (HSP60), recently renamed HSPD1, and bacterial HSP60 are highly homologous, immunological cross-reactivity has been proposed as a mechanism of disease initiation. However, previous investigations of the humoral immune response to HSP60 in SpA patients have lacked determination of immunoglobulin G (IgG) subclasses and patient follow-up. In this study, we have focused on these parameters in a cohort of axial SpA patients with a well-established set of clinical characteristics, including MRI changes and human leukocyte antigen B27., Methods: IgG subclass antibodies (IgG1, IgG2, IgG3 and IgG4) against recombinant HSP60 of three reactive arthritis-related bacteria; human HSP60; and the microorganisms Chlamydia trachomatis and C. pneumoniae were determined by ELISA. Serum samples collected from 2004 to 2006 and in 2010 and 2011 from 39 axial SpA patients were analyzed and compared with samples from 39 healthy controls. The Mann-Whitney U test and Wilcoxon matched pairs test were used to compare the antibody levels in different and paired groups, respectively. P < 0.01 was considered significant. The Spearman nonparametric correlation was used to determine correlation between antibody levels and between antibody levels and the disease parameters., Results: Elevated levels of IgG1 and IgG3 to human HSP60 and IgG1 to HSP60 of Salmonella enterica Enteritidis were observed in SpA patients compared with healthy controls at both time points. The antibody levels were almost constant over time for IgG1, whereas high levels of IgG3 to human HSP60 tended to decrease over time. The antibody response to human HSP60 was predominantly of the IgG3 subclass, and patients with high levels of IgG3 to this antigen had low levels of IgG1, indicating an inverse association. Different IgG subclasses were produced against bacterial and human HSP60 in the same serum sample, IgG1 and IgG3, respectively, indicating that there was no cross-reaction., Conclusions: A significant association was observed between axial SpA and the presence of IgG1/IgG3 antibodies to human HSP60 and of IgG1 to S. enterica Enteritidis and C. trachomatis. Generation of antibodies to human HSP60 was independent of the presence of antibodies to bacterial HSP60. No association was observed between clinical and MRI changes with antibodies over time. Altogether, such antibodies do not reflect the disease activity in these patients. This study has been approved by the Regional Research Ethics Committee of Central Jutland, Denmark., Trial Registration Numbers: 20050046 and 20100083

Seronegative spondyloarthritis is strongly correlated to HLA-B27, and in the long term, it causes limitations to the movements of vertebral joints. In recent years, the numbers of patients diagnosed with axial spondyloarthritis have increased due to the widespread use of magnetic resonance imaging (MRI) for diagnostic imaging. We report the cases of 2 pediatric patients diagnosed with axial spondyloarthritis, and whose disease activity was successfully controlled using adalimumab. In case 1, the patient was a 15-year-old boy. The onset of the disease was marked by neck pain ; HLA-B27 was positive, and the MRI revealed sacroiliac arthritis. After being diagnosed with axial spondyloarthritis, he began receiving oral steroid therapy. Gradual recurrence was observed, and adalimumab treatment was initiated. In case 2, the patient was a 9-year-old boy. Bilateral pain was present in the shoulder joints, ankles, and knee joints. The patient was diagnosed with polyarticular juvenile idiopathic arthritis, and treatment using oral steroids, immunosuppressants and tocilizumab. The arthralgia disappeared, but at the age of 12 years, pain recurred in the sacroiliac joint and the Achilles tendon, the HLA-B27 was positive, and the MRI revealed sacroiliac arthritis. The condition was diagnosed as axial spondyloarthritis; adalimumab treatment was initiated. Adalimumab was effective in the treatment of axial spondylitis occurring in childhood.