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Diagnosis of spondyloarthritis: when to think about it? Spondyloarthritis represents the second most frequent chronic inflammatory rheumatism, along with rheumatoid arthritis. It characteristically affects joints with axial distribution predominance. The paucity of physical examination and imaging findings during the first years of evolution frequently exposes to deleterious misdiagnosis. In order to improve its recognition and to optimize its care, it is necessary to seek for characteristic past or present clinical manifestations, the combination of which will contribute to establish the diagnostic conviction. In some instances, therapeutic test(s) using anti-inflammatory drug(s) or even biotherapies could be required to reinforce it, even if all complementary examinations are negative.Diagnostic d’une spondyloarthrite : quand y penser ? Les spondyloarthrites représentent le deuxième rhumatisme inflammatoire chronique le plus fréquent avec la polyarthrite rhumatoïde. Elles se caractérisent par une atteinte articulaire prédominant sur le squelette axial. La discrétion des signes d’examens physique et d’imagerie durant les premières années d’évolution est souvent responsable d’une errance diagnostique préjudiciable. Pour en améliorer la reconnaissance et permettre une prise en charge optimale, il faut s’appuyer sur l’interrogatoire, à la recherche des manifestations caractéristiques, présentes ou passées, dont la combinaison permet d’asseoir la conviction diagnostique. Des tests thérapeutiques par antiinflammatoires, voire biothérapie peuvent permettre de le confirmer, même quand tous les examens complémentaires sont négatifs.

Objectives Veillonella parvula is an anaerobic Gram-negative coccus rarely involved in bone and joint infections. Patients and method We report the case of a Veillonella parvula vertebral osteomyelitis (VO) in a female patient without any risk factor. Results The 35-year-old patient was immunocompetent and presented with Veillonella parvula VO. She was admitted to hospital for inflammatory lower back pain. The discovertebral sample was positive for Veillonella parvula. Literature data on Veillonella VO is scarce. Reported cases usually occurred in immunocompromised patients. Diagnosis delay can be up to four months. Patients are usually afebrile. Outcome with antimicrobial treatment alone is favorable in half of cases. Other patients must undergo surgery. Conclusions Veillonella VO may occur in immunocompetent patients and have a clinical spectrum of mechanical lower back pain.

Author(s): Deodhar, Atul; Gensler, Lianne S; Sieper, Joachim; Clark, Michael; Calderon, Cesar; Wang, Yuhua; Zhou, Yiying; Leu, Jocelyn H; Campbell, Kim; Sweet, Kristen; Harrison, Diane D; Hsia, Elizabeth C; van der Heijde, Desiree | Abstract: ObjectiveTo evaluate the efficacy and safety of ustekinumab in 3 randomized, placebo-controlled studies in patients with axial spondyloarthritis (SpA). Studies 1 and 2 included patients with radiographic axial SpA (anti-tumor necrosis factor [anti-TNF]-naive patients and patients with inadequate response or intolerance to anti-TNF, respectively); study 3 patients had nonradiographic axial SpA.MethodsIn all 3 studies, patients were randomly assigned (1:1:1) to receive subcutaneous ustekinumab at 45 mg or 90 mg or placebo up to 24 weeks, after which placebo-treated patients were rerandomized to receive ustekinumab at 45 mg or 90 mg. The primary end point in studies 1 and 2 was the proportion of patients who met the Assessment of SpondyloArthritis international Society criteria for 40% improvement in disease activity (achieved an ASAS40 response). The primary end point in study 3 was the proportion of patients who achieved an ASAS20 response. Other disease activity and safety measures were also evaluated. A week 24 analysis of study 1 was preplanned to determine continuation of studies 2 and 3.ResultsFor study 1, the primary and major secondary end points were not met, and the study was discontinued. As a result, studies 2 and 3 were prematurely discontinued before they were fully enrolled. For all 3 studies, neither ustekinumab dose group demonstrated clinically meaningful improvement over placebo on key efficacy end points. The proportion of patients experiencing adverse events in the ustekinumab groups was consistent with that in previous studies.ConclusionIn these 3 placebo-controlled trials, efficacy of ustekinumab in the treatment of axial SpA was not demonstrated. The safety profile was consistent with that of studies in other indications.

Resume La cause des maladies inflammatoires chroniques reste dans la plupart des cas meconnue. Parmi les hypotheses possibles, celle d’une infection chronique reste soulevee. L’evolution recente des techniques permet d’etudier de facon approfondie le contenu microbien – ou microbiote – de l’intestin et d’y decrire une grande variete de germes qui sont pour la plupart non cultivables. Les maladies inflammatoires de l’intestin ont ete associees a des perturbations caracteristiques du microbiote intestinal, qui persistent en dehors des periodes inflammatoires et pourraient contribuer a la pathogenie de ces maladies. Les relations entre microbiote intestinal et inflammation articulaire, mises en evidence dans des modeles murins d’arthrite, restent encore peu explorees chez les patients. Des etudes recentes revelent toutefois l’existence de perturbations significatives de ce microbiote aussi bien au cours de la polyarthrite rhumatoide que du rhumatisme psoriasique et des spondyloarthrites, avec des differences selon les pathologies et les etudes. De facon interessante, certaines des anomalies decrites (restriction de la diversite microbienne, reduction de la frequence de groupes bacteriens du phylum des Firmicutes connus pour leurs proprietes immuno-regulatrices) ressemblent a celles maintenant bien etablies au cours des maladies inflammatoires de l’intestin. Les perspectives ouvertes par ces resultats sont importantes aussi bien pour la comprehension de la maladie que pour le developpement de biomarqueurs ou d’approches therapeutiques innovantes.

ObjectiveMore than 40 loci have been associated with ankylosing spondylitis (AS), but less is known about genetic associations in spondyloarthritis (SpA) as a whole. We conducted a family-based genome-wide association study (GWAS) to identify new non-major histocompatibility complex (MHC) genetic factors associated with SpA.Methods906 subjects from 156 French multiplex families, including 438 with SpA, were genotyped using Affymetrix 250K microarrays. Association was tested with Unphased. The best-associated non-MHC single nucleotide polymorphisms (SNPs) were then genotyped in two independent familial cohorts (including 215 French and 294 North American patients with SpA, respectively) to replicate associations.Results43 non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p−4). In the extension studies, association was replicated at a nominal p value of pMAPK14, and SpA (p=3.5×10−7). Such association appeared to be independent of HLA-B27.ConclusionsWe report here for the first time a family-based GWAS study on SpA and identified an associated polymorphism near MAPK14. Further analyses are needed to better understand the functional basis of this genetic association.

Objective To determine whether disease manifestations at baseline would combine according to distinguishable ordered phenotypes in patients with early inflammatory back pain (IBP) suggestive of spondyloarthritis (SpA). Methods Baseline clinical and demographic characteristics as well as imaging features and biologic data on patients included in the French multicenter Devenir des Spondyloarthropathies Indiffererenciees Recentes cohort were analyzed by multiple correspondence analysis and cluster analysis to identify subgroups of patients based on shared characteristics. Results Cluster analysis allowed us to classify the 679 patients with no missing data into 2 major groups-one with a predominance of isolated axial manifestations and the other with associated peripheral symptoms. The application of the same analysis to selected subsets of the cohort, such as HLA-B27-positive and -negative patients and patients fulfilling the Assessment of SpondyloArthritis international Society classification criteria for axial SpA, resulted again in an optimal division of the samples into 2 recurrent clusters of patients similar to those observed in the whole cohort. Conclusion Cluster analysis of SpA manifestations among patients with early IBP highly suggestive of SpA allowed us to clearly identify at baseline 2 different clinical phenotypes-one with predominant axial manifestations and the other with predominant peripheral manifestations. Ongoing follow-up will allow us to determine whether these clusters correspond to different patterns of disease severity.

Resume Objectifs Desir est une etude de cohorte prospective, longitudinale, multicentrique, francaise de patients souffrant de rachialgie inflammatoire evocatrice de spondyloarthrite, avec un suivi de 10 ans. Le but est d’evaluer les performances des differents systemes de criteres de classification de la spondyloarthrite axiale, et de decrire la frequence et les caracteristiques des signes cliniques de spondyloarthrite axiale. Methodes Les donnees demographiques et les items permettant la classification et le calcul des indices ont ete recueillis, ainsi que les donnees biologiques et d’imagerie. Les donnees a l’inclusion furent analysees. La performance de plusieurs systemes de criteres de classification fut evaluee (LR, rapport de vraisemblance) avec le diagnostic du medecin comme « gold standard ». Concernant la presentation clinique de la spondyloarthrite axiale, une analyse descriptive a ete realisee. Resultats Parmi les patients, 708 sont inclus ; 92 % d’entre eux satisfont a au moins un systeme de criteres de classification : mNY 26 %, 79 % Amor, ESSG 78 %, ASAS 70 % ; le niveau de confiance du medecin est de 6,8 ± 2,7. Parmi les patients, 81 et 83 % remplissent les criteres modifies (y compris IRM) d’Amor ou de l’ESSG. Une atteinte axiale est presente dans 100 % des cas. Les AINS sont pris par 90 % des patients, avec un score d’AINS de 50 ± 46. Un BASDAI superieur a 40 est note dans 60 % des cas et une CRP elevee dans 30 % des cas. L’antigene HLA-B27 est present dans 58 % des cas. Suivant l’ASDAS CRP, 12,7 % des patients ont une maladie inactive, 63 % une activite de la maladie tres elevee ; le BASFI moyen etait de 30. Une atteinte peripherique est presente dans 57 % des cas, avec une arthrite dans 37 % de ceux-ci. Une enthesite est notee chez 49 % des patients, et constitue le premier symptome chez 22,5 % des cas ; la participation de la paroi thoracique anterieure est notee dans 44,6 % des cas, et une dactylite dans 13 %. Parmi les manifestations extra-articulaires supplementaires, le psoriasis est repertorie dans 16 % des cas, une uveite dans 8,5 % et une maladie inflammatoire chronique intestinale (MICI) dans 5,1 %. Le tabagisme est present dans 36,3 % des cas et une hypertension arterielle dans 5,1 % des cas. Conclusion Ces donnees representent la base de l’evaluation du suivi de cette cohorte, permettant de futures etudes specifiques.

PURPOSE. Acute anterior uveitis (AAU) is a common intraocular inflammatory disease. AAU occurs in 30% to 50% of patients with ankylosing spondylitis (AS), and both conditions are strongly associated with human leukocyte antigen (HLA)-B27, implying a shared etiology. This study aims to apply genomewide association study (GWAS) to characterize the genetic associations of AAU and their relationship to the genetics of AS. METHODS. We undertook the GWAS analyses in 2752 patients with AS with AAU (cases) and 3836 patients with AS without AAU (controls). There were 7,436,415 single-nucleotide polymorphisms (SNPs) available after SNP microarray genotyping, imputation, and quality-control filtering. RESULTS. We identified one locus associated with AAU at genomewide significance: rs9378248 (P = 2.69 × 10−8, odds ratio [OR] = 0.78), lying close to HLA-B. Suggestive association was observed at 11 additional loci, including previously reported AS loci ERAP1 (rs27529, P = 2.19 × 10−7, OR = 1.22) and NOS2 (rs2274894, P = 8.22 × 10−7, OR = 0.83). Multiple novel suggestive associations were also identified, including MERTK (rs10171979, P = 2.56 × 10−6, OR = 1.20), KIFAP3 (rs508063, P = 5.64 × 10−7, OR = 1.20), CLCN7 (rs67412457, P = 1.33 × 10−6, OR = 1.25), ACAA2 (rs9947182, P = 9.70 × 10−7, OR = 1.37), and 5 intergenic loci. The SNP-based heritability is approximately 0.5 for AS alone, and is much higher (approximately 0.7) for AS with AAU. Consistent with the high heritability, a genomewide polygenic risk score shows strong power in identifying individuals at high risk of either AS with AAU or AS alone. CONCLUSIONS. We report here the first GWAS for AAU and identify new susceptibility loci. Our findings confirm the strong overlap in etiopathogenesis of AAU with AS, and also provide new insights into the genetic basis of AAU.

Background:Objectives:To describe current management and outcome of septic arthritis on native joint in French rheumatology departments.Methods:Retrospective, nation-wide multicentric study. 127 French rheumatology departments were contacted to report 10 successive cases of septic arthritis on native joint that occurred between the 01/01/16 to 31/12/17 (excluding mycobacteria). Characteristics, diagnosis procedure, therapeutic management and outcome were recorded.Results:52 centers included 363 patients (mean age 64± 18.7 years, mean Charlson comorbidity index 4±3). 28.3% patients had a preexisting arthropathy on affected joint. Monoarthritis was observed in 89.6% patients, knee was the most frequent site (38.9%). The most frequent pathogens wereStaphylococcus sp(50.7%) andStreptococcus sp.(23.3%). Bacteremia was found in 156 (45.1%) patients and endocarditis in only 12 (3.0%). Management was heterogeneous. All patients received antibiotics for a mean duration of 46.7±22 days (including intravenous route: 17.3±15.4 d). An initial monotherapy was administered in 42.3% of patients. Surgical procedure (mostly lavage 70.6%) was performed in 171 (48.3%), joint immobilization in 128 (35.3%) (median duration of 21.7±14.1 days). 94 (29.2%) patients have had serious complications including 29 (9.5%) death. Factors associated with death are reported in the table.Conclusion:This study shows that management of septic arthritis is very heterogenous with a still high rate of morbidity and mortality. We identified age, comorbidities, bacteremia and recent antibiotherapy were associated with mortality. Of note, duration of antibiotics was not. Thus, new guidelines are needed in order to facilitate septic arthritis management.Table:FactorsSurvivor(N=276)Dead(N=29)Univariate analysispAdjusted Odds ratio (95%IC)Multivariate analysispAge65 (16-97)82 (32-98)1,07 (1,03-1,12)< 0.001Charlson’s index1 (0-12)2 (0-9)0,00011,3 (1,05-1,63)0,018Delay before antibiotic initiation8,5 (0-310)5 (0-75)0,04840,99 (0,96-1,02)0,562Corticosteroid in the previous 3 months13,9%33,3%0,01842,56 (0,75-8,74)0,133Bacteriemia42,4%71,4%0,00615,07 (1,4-18,370,013Antibiotics in the previous 3 months26,6%56,6%0,00566,7 (2,04-22,01)0,002Disclosure of Interests:Pauline Richebé: None declared, Sophie Godot: None declared, Guillaume Coiffier: None declared, Pascal GUGGENBUHL: None declared, Denis Mulleman: None declared, Marion Couderc: None declared, Emmanuelle Dernis Speakers bureau: Lilly, Novartis, Valentine Deprez: None declared, Carine Salliot: None declared, Saik Urien: None declared, Rachel Brault: None declared, Adeline Ruyssen-Witrand Grant/research support from: Abbvie, Pfizer, Consultant of: Abbvie, BMS, Lilly, Mylan, Novartis, Pfizer, Sandoz, Sanofi-Genzyme, Emmanuel Hoppe: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Christian Roux: None declared, Sebastien Ottaviani: None declared, Maxime Breban: None declared, Marie Beaufrere: None declared, Alexia Michaut: None declared, Loic Pauvele: None declared, Christelle Darrieutort: None declared, Daniel Wendling: None declared, Pascal COQUERELLE: None declared, Géraldine Bart: None declared, Elisabeth Gervais: None declared, Vincent Goeb: None declared, Marc Ardizzone: None declared, Edouard Pertuiset: None declared, Sophie Derolez: None declared, Jean Marc Ziza: None declared, René-Marc Flipo Consultant of: Johnson and Johnson, MSD France, Novartis, Sanofi, Speakers bureau: Johnson and Johnson, MSD France, Novartis, Sanofi, Raphaèle Seror Consultant of: BMS UCB Pfizer Roche

Objective Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the spine and pelvis of young adults. On the HLA-B27 genetic background, the occurrence of AS is influenced by the intestinal microbiota. The goal of our study was to test whether breast feeding, which influences microbiota, can prevent the development of AS. Methods First, 203 patients with HLA-B27-positive AS fulfilling the modified New York criteria were recruited in the Department of Rheumatology, Ste Marguerite hospital in Marseilles. A total of 293 healthy siblings were also recruited to make up a control group within the same families. Second, 280 healthy controls, and 100 patients with rheumatoid arthritis and their siblings were recruited. The data collected were age, gender, number of brothers and sisters, age at disease onset, type and duration of feeding (breast or bottle). Results Patients with AS had been breast fed less often than healthy controls. In families where children were breast fed, the patients with AS were less often breast fed than their healthy siblings (57% vs 72%), giving an OR for AS onset of 0.53 (95% CI (0.36 to 0.77), p value=0.0009). Breast feeding reduced familial prevalence of AS. The frequency of breast feeding was similar in the AS siblings and in the 280 unrelated controls. However, patients with AS were less often breast fed compared with the 280 unrelated controls (OR 0.6, 95% CI (0.42 to 0.89), p Conclusions Our study suggests a breastfeeding-induced protective effect on the occurrence of AS. To our knowledge, this is the first study of breastfeeding history in patients with AS.

Objectives The aim was to assess the efficacy of two intra-tendinous injections of platelet-rich plasma (PRP) on epicondylitis of recent evolution (≤3 months). Methods Our study was a double-blind placebo-controlled randomized trial. Two US-guided injections of either PRP (autologous conditioned plasma) or saline solution were performed with an interval of 4 weeks. The exclusion criterion was previous CS infiltration. Patients were monitored by an independent evaluator blinded to treatment at baseline and 1, 3, 6 and 12 months of follow-up. The primary evaluation criterion was the relative improvement from baseline to 6 months in pain score on visual analog scale (0-10). Secondary criteria were the Roles-Maudsley score and the assessment of pain on isometric contraction of extensor carpi radialis brevis and extensor digitorum communis. Results Twenty-five patients were randomly assigned to each group. Three patients in each arm dropped out before 6 months. In both groups, the pain score [mean (s.d.)] decreased significantly between two consecutive visits from 6.8 (0.8) (PRP) and 7 (1) (saline) at baseline to 2.5 (1.6) and 1.6 (1.5) (PRP) and to 2.1 (1.6) and 1.8 (2.1) (saline) at 6 and 12 months, respectively. At 6 months, no statistically significant difference was found between groups for relative improvement in pain score [autologous conditioned plasma: -63.2 (22.4%); saline: -69.7 (25.1%); P = 0.24]. No significant difference was found for the secondary criteria. Conclusion Two US-guided PRP injections for epicondylitis of recent evolution were not more efficacious than saline injections, until 6- and 12-months follow-up. Trial registration ClinicalTrials.gov; https://clinicaltrials.gov/; NCT02378285.

Objective To evaluate the effect of tumor necrosis factor (TNF) inhibitors on nonsteroidal antiinflammatory drug (NSAID) intake in a cohort of patients with early axial spondyloarthritis (SpA) over the first 2 years of followup. Methods The Devenir des Spondylarthropathies Indifferenciees Recentes (DESIR) cohort is a prospective, multicenter, observational study cohort of patients with early inflammatory back pain. The management and treatment of these patients were decided by their treating rheumatologists. Data regarding NSAID intake (yes/no) and the Assessment of SpondyloArthritis international Society NSAID score were collected at each visit over 2 years of followup. Patients receiving a TNF inhibitor were matched with those receiving usual care, based on a propensity score. The NSAID-sparing effect of TNF inhibitors was estimated by comparing the percentage of patients reaching several end points (e.g., a decrease in the NSAID score to 50% or to

Objective Several polymorphisms in ERAP1 are strongly associated with susceptibility to spondyloarthritis (SpA). The combination of rs17482078, rs10050860, and rs30187 results in the construction of 3 major haplotypes that are associated with SpA (the “protective” haplotype T/T/C, the “neutral” haplotype C/C/C, and the “susceptibility” haplotype C/C/T). The aim of the present study was to determine whether such haplotypes might affect endoplasmic reticulum aminopeptidase 1 (ERAP-1) messenger RNA (mRNA) expression, protein level, and/or enzymatic activity in antigen-presenting cells, a type of cell that is potentially relevant to disease pathogenesis. Methods Monocyte-derived dendritic cells (DCs) were generated in 2 cohorts (a discovery cohort and a replication cohort) comprising a total of 23 SpA patients and 44 healthy controls. Lymphoblastoid B cell lines were established from individuals who were homozygous for the risk, the neutral, or the protective ERAP1 haplotype, respectively. In those samples, we investigated the relationship between ERAP1 haplotypes and mRNA expression level. We also used Western blot analysis to measure the relative protein expression of ERAP-1 and a fluorogenic assay to measure its enzymatic activity. Results In monocyte-derived DCs, there was a strong association between ERAP1 haplotypes and the ERAP-1 mRNA expression level, with higher levels in subjects harboring the susceptibility haplotype (P = 0.001 and P = 5.6 × 10−7 in the discovery and replication cohorts, respectively). In lymphoblastoid B cell lines, we observed a significant correlation between haplotype risk score and ERAP1 transcript or protein level (P = 0.003, ρ = 0.92 for both). Enzymatic activity followed a similar trend both in monocyte-derived DCs and in lymphoblastoid B cell lines. Conclusion These data provide strong evidence that SpA-associated ERAP1 polymorphisms affect the level of gene expression in antigen-presenting cells. How increased production/activity of ERAP-1 may influence susceptibility to SpA remains to be determined.

Background After more than 40 years of research, the mechanisms underlying the association of HLA-B27 with spondyloarthritis (SpA) remain poorly understood. We hypothesised that Drosophila might be a relevant model to study HLA-B27 and particularly for deciphering the cellular cascade and the genetic pathways affected by HLA-B27 mutation. To do so, we developed HLA-B2705, HLA-B0702 (control) and human Beta-2-microglobulin (hB2m) transgenic Drosophila. Methods Gateway Technology and UAS-Gal4 system used for developing transgenic HLA-B/human hB2m Drosophila. UAS-hB2m transgene was inserted in the long arm of chromosome 3 and UAS-HLA-B2705 and UAS-HLA-B0702 were alternatively inserted at another position in the short arm of the same chromosome. For each construct, various transgenic lines were obtained and crossed with several tissue specific driver strains, to induce the expression of the sequence coding for HLA-B0702 and hB2m or HLA-B2705 and hB2m placed under the control of UAS sequences. Results HLA-B2705/hB2m transgenes were first expressed in Drosophila thanks to the vestigialGa4 driver line allowing to produce targeted proteins in the Vestigial domain (dorso-ventral frontier of the wing epithelia). We observed positive staining with HC10 antibodies (class I heavy chain) and W6/32 antibody (HLA-A, HLA-B and HLA-C conformation) for both tested HLA-B/hB2m but only HLA-B27/hB2m was labelled with ME1 (anti-HLA B/C) antibodies, suggesting a different conformation of HLA-B27 and HLA-B7 with hB2m in the wing epithelia. Furthermore, by mean of the nubbin or engrailed drivers which drive the expression in a larger part of the wing, we observed specific loss of the posterior cross-vein following HLA-B27/hB2m expression but not HLA-B7/hB2m. Conclusion Drosophila lines were established allowing tissue specific expression of different HLA-B alleles. Our data suggest that the expression of HLA-B/hB2m transgenes in epithelial cells leads to a plasma membrane localization for HLA-B2705/hB2m but not for HLA-B0702/hB2m. Furthermore, we observed that tissue specific expression of HLA-B27/hB2m but not HLA-B7/hB2m induced specific loss of cross-vein suggesting it interferes with developmental pathways involved in differentiation. This is the first time that differences in localization between HLA-B2705, a subtype associated with SpA, and HLA-B0702, which is not associated with the disease are reported. These results show that transgenic Drosophila might be a pertinent model to decipher molecular mechanisms involved in HLA-B27 trafficking and to better understand potential different behaviours of HLA-B subtypes.

Resume La spondyloarthrite (SpA) est une maladie multifactorielle complexe possedant une forte composante hereditaire, reflet d’un terrain genetique predisposant. Les etudes familiales ont permis d’estimer l’heritabilite de la maladie a plus de 90 % et d’etablir son caractere multigenique. En effet, si l’antigene HLA-B27 est le facteur majeur de susceptibilite a la maladie, expliquant a lui seul 25 a 50 % de la predisposition genetique, plus de 20 autres locus de susceptibilite a la maladie ont ete identifies ces dernieres annees grâce a de vastes etudes d’association pan-genomiques (Genome Wide Association Studies [GWAS]). Un grand nombre de polymorphismes de susceptibilite sont partages entre la SpA et d’autres maladies inflammatoires qui lui sont frequemment associees comme les maladies inflammatoires chroniques de l’intestin ou le psoriasis. Par ailleurs, des etudes genetiques s’interessant a l’ensemble des sous-types de SpA ont permis de confirmer certaines des associations deja mises en evidence dans la spondylarthrite ankylosante (SA), sous-type emblematique de la maladie. L’ensemble de ces elements est en faveur d’un terrain genetique partage entre ces differentes pathologies. Ces decouvertes ont egalement permis d’identifier ou de confirmer de nouvelles voies intervenant dans la survenue de la SpA comme la voie de differenciation lymphocytaire Th17 ou la famille des aminopeptidases. Des etudes fonctionnelles ont egalement demontre les consequences de certains polymorphismes de susceptibilite (comme le polymorphisme rs30187 dans le gene ERAP1 ou rs11209026 dans le gene IL23R ) permettant de mieux comprendre l’implication des locus dans la maladie. Cependant, le polymorphisme causal reste a identifier pour la majorite des locus de susceptibilite. Malgre les decouvertes recentes, l’ensemble des variants identifies a ce jour n’explique qu’une tres faible partie de la predisposition genetique totale et le defi actuel consiste a identifier ce qui constitue encore la part « d’heritabilite manquante ». Le developpement rapide du sequencage haut debit pourrait aider a la decouverte de variants rares, difficiles a identifier par les approches GWAS classiques.

Objective HLA–B27/human β2-microglobulin (hβ2m)–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.

Objective Mechanisms underlying the striking association of spondyloarthritis (SpA) with the class I major histocompatibility complex molecule HLA–B27 remain poorly understood. SpA-like disease develops spontaneously in B*2705-transgenic rats, in conjunction with high HLA–B27 expression levels. This study was undertaken to examine the effects of increased expression of HLA–B27 alleles that are differentially associated with SpA on oligomerization and intracellular redistribution. Methods HeLa cells were transfected with complementary DNA encoding for HLA–B proteins fused to yellow fluorescent protein and/or Renilla luciferase and harvested at an early phase and a later phase of expression. We monitored HLA–B intracellular trafficking and localization by means of microscopy and live-cell imaging. Bioluminescence resonance energy transfer (BRET) and Western blotting were used to monitor HLA–B oligomerization. Results At low expression levels, BRET signals were similarly elevated for all SpA-associated HLA–B27 alleles tested, but were lower for the nonassociated B*2706. Of note, at higher expression levels, HLA–B27 signals remained steady while signal for HLA–B7 decreased sharply, reaching the level observed for B*2706. This was due at least in part to a decreased oligomer proportion without unfolded protein response outbreak. Such differential behavior was not abrogated by proteasome inhibition. With increased expression, all HLA–B proteins accumulated to a high density in cytoplasmic vesicles with labile form and size. The extent of this phenomenon was closely correlated with the level of association with predisposition to SpA. Conclusion To our knowledge, this is the first report of a correlation between the level of predisposition to SpA conferred by HLA–B27 alleles and their biochemical behavior. These findings open new perspectives for understanding the pathogenicity of HLA–B27.

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.

ObjectiveAltered microbiota composition or dysbiosis is suspected to be implicated in the pathogenesis of chronic inflammatory diseases, such as spondyloarthritis (SpA) and rheumatoid arthritis (RA).Methods16S 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.ResultsIn 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.ConclusionOur 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.

Objective To evaluate if contrast-enhanced ultrasound (CEUS) can improve the detection and quantification of the vascularization of mild enthesitis in spondyloarthritis (SpA) and to evaluate the influence of nonsteroidal antiinflammatory drugs (NSAIDs) on such detection. Methods Fourteen patients with mildly active SpA were evaluated at 3 consecutive visits: at baseline while undergoing NSAID treatment (V1), after 1 week of stopping NSAIDs (V2), and after 1 week of resuming NSAIDs (V3). At each visit, enthesitis was evaluated clinically and by power Doppler US (PDUS). A selected enthesis with a doubtful PDUS vascularization signal was studied by CEUS in 2 steps: 1) using a dedicated technology that preserves microbubbles (Contrast Tuned Imaging technology [CEUS-CnTI]) and 2) using high PD (CEUS-PD) to destroy microbubbles. A linear mixed model statistical analysis, taking visits and contrast agent as fixed factors and the patient as a random factor, was used. Results Disease activity and PDUS findings increased between V1 and V2 and then decreased between V2 and V3. As compared with PDUS alone, CEUS-PD and CEUS-CnTI each detected 1 supplementary vascularized enthesis at V1, CEUS-PD detected 1 vascularized enthesis and CEUS-CnTI detected 3 vascularized entheses at V2, and CEUS-PD and CEUS-CnTI each detected 2 vascularized entheses at V3. The mean inflammation score was increased by the use of CEUS (P = 0.04). This score increased between V1 and V2 (P = 0.03 by CEUS-PD and P = 0.01 by CEUS-CnTI) and decreased between V2 and V3. Conclusion CEUS improved the detection of enthesitis in SpA patients by confirming all doubtful enthesitis signals and confirming the absence of enthesis vascularization. The use of NSAIDs influenced the detection of vascularization.

Objective To estimate the prevalence of spondyloarthritis (SpA) in reference to HLA-B27 in the French population. Methods In 1989, 20 625 employees of the French national gas and electricity company aged 35–50 years were enrolled in the GAZEL cohort. In 2010, 18 757 still active participants were screened by a questionnaire validated for the detection of SpA. Responders with available DNA were retained for further studies. Pelvic radiograph and HLA-B27 typing were performed in all the self-reported cases of SpA or psoriatic arthritis. Self-reported diagnosis was verified by a qualified rheumatologist. HLA-B27 determination was also performed in subjects without any SpA feature. Results The target population consisted of 6556 responders with available DNA. Their male:female ratio was 3.6 and their mean age was 65.5±3.3 years. A diagnosis of SpA was confirmed in 32 of the 72 self-reported cases, 75% of them being HLA-B27 positive. Estimated SpA prevalence adjusted for sex was 0.43% (95% CI 0.26% to 0.70%). HLA-B27 positivity rate in 2466 healthy controls was 6.9% (95% CI 5.9% to 7.9%). The relative risk of SpA in HLA-B27 positive individuals was 39 (95% CI 17 to 86). Conclusions We estimated the prevalence of SpA in the French population in 2010 to 0.43%. With an estimated prevalence of 75.0% in SpA and 6.9% in healthy controls, HLA-B27 increased the disease risk 39-fold, as compared with HLA-B27 negative subjects.

Objective.Spondyloarthritis (SpA) is a complex inflammatory disorder. We investigated the influence of environmental factors on SpA disease activity.Methods.A prospective cohort of adults with SpA was followed for 3 years. Patients logged on to a secured Website every 3 months to complete a questionnaire. They reported whether they had been exposed to environmental factors such as stressful or traumatic life events, infections, or vaccinations. Outcome variables included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), and pain and patient global assessment (PGA) on visual numerical scales (each rated 0–10). Analyses were performed using a generalized estimating equation for repeated measures, adjusted for the outcome variable collected by the previous questionnaire.Results.In total, 272 patients were included in the analysis, completing the questionnaire on 2240 occasions. The average time (mean ± SD) between 2 connections to the Website was 4.0 ± 2.0 months. Occurrence of life events was followed by an increase of 0.5 (95% CI 0.4–0.7) in the BASDAI, 0.5 (95% CI 0.3–0.6) in the BASFI, 0.7 (95% CI 0.5–0.9) in the PGA, and 0.8 (95% CI 0.6–1.0) for pain (p < 0.0001 for all variations). A moderately statistically significant link was found between vaccination and an elevation of the BASDAI of 0.3 (95% CI 0.0–0.5; p = 0.032). No influence of other factors was detected.Conclusion.This prospective study in a dedicated SpA cohort shows for the first time a link between stressful events and disease activity. Although this link was statistically highly significant, its clinical meaning remains to be determined because the average magnitude of variation of the different variables studied was rather mild.

ObjectivesTo evaluate the efficacy and safety of rituximab in patients with primary Sjögren's syndrome (pSS).MethodsThe AutoImmune and Rituximab registry has included 86 patients with pSS treated with rituximab, prospectivey followed up every 6 months for 5 years.ResultsSeventy-eight patients with pSS (11 men, 67 women), who already had at least one follow-up visit, were analysed. Median age was 59.8 years (29–83), median duration of disease was 11.9 years (3–32). Indications for treatment were systemic involvement for 74 patients and only severe glandular involvement in four patients. The median European Sjögren's Syndrome disease activity index (ESSDAI) was 11 (2–31). 17 patients were concomitantly treated with another immunosuppressant agent. Median follow-up was 34.9 months (6–81.4) (226 patient-years). Overall efficacy according to the treating physician was observed in 47 patients (60%) after the first cycle of rituximab. Median ESSDAI decreased from 11 (2–31) to 7.5 (0–26) (pConclusionsIn common practice, the use of rituximab in pSS is mostly restricted to patients with systemic involvement. This prospective study shows good efficacy and tolerance of rituximab in patients with pSS and systemic involvement.

Resume L’echographie par Power Doppler a ultrasons (PDUS) ou Doppler puissance a prouve sa sensibilite comme instrument pour evaluer les enthesites dans les spondylarthropathies (SpA). Chez les patients suspects de SpA, le diagnostic peut etre ameliore par la detection des enthesites par le PDUS. Objectifs Evaluer la performance du PDUS pour le diagnostic des SpA, seul ou combine avec les autres resultats cliniques, biologiques ou radiologiques chez les patients consultant pour une suspicion de SpA. Methodes Etude prospective, multicentrique, d’une cohorte francaise (Boulogne-Billancourt, Caen, Grenoble, Marseille et Nancy). Les patients ont ete recrutes en externe et suivis pendant au moins deux ans pour des symptomes suggerant une SpA (rachialgie inflammatoire (RI), arthrite ou arthralgie inflammatoire (AI), enthesite ou dactylite (ED), uveite B 27 positif (B27+U), antecedents familiaux de SpA (fam). La taille de l’echantillon a ete fixee a 500 patients (pour une prevalence estimee de SpA de 30 ± 5 % apres deux ans). Les patients ont ete soumis a un examen clinique standardise, radiographies du bassin, IRM. des articulations sacro-iliaques, typage HLA et tout autre examen juge utile pour le diagnostic. Pour chaque patient, un examen par PDUS en aveugle des 14 sites enthesitiques a ete effectue a l’inclusion et dans l’annee 1 et 2. Il est prevu de suivre les patients pendant cinq ans. Le diagnostic de SpA affirme par un comite d’experts ignorant les resultats du PDUS, apres au moins deux ans de suivi avec une reevaluation des patients douteux a cinq ans, sera utilise comme « gold standard » pour evaluer les performances diagnostiques du PDUS ainsi que la meilleure procedure en combinant les symptomes cliniques et les autres examens. Resultats Entre janvier 2005 et septembre 2007, 489 patients ont ete inclus (96 % de la population cible). Dix-neuf patients (0,2 %) ont retire leur consentement ou ont ete perdus de vue immediatement apres leur inclusion. A l’inclusion, la moyenne des 470 restants etait de 40 ans, la duree moyenne des symptomes de 6,1 ans ; 42 % d’entre eux etaient B27 positifs et 63 % etaient de sexe feminin. Le critere d’inclusion primaire etait une RI dans 53 %, une AI dans 27 %, une ED dans 9 %, U B27+ dans 8 % et fam dans 4 %. Le suivi est toujours en cours. Conclusion Nous avons mis en place une cohorte unique a visee diagnostique qui inclut l’eventail complet des manifestations de la SpA. En utilisant le PDUS nous nous attendons a ameliorer la procedure du diagnostic des SpA.

The role of adaptive immunity (i.e. the involvement of B and T lymphocytes) in the pathogenesis of axial spondyloarthritis has been investigated in both human disease and relevant animal models. Studies of B cell responses have not generally implicated an autoantibody in the disease, but there are abnormalities of antibody responses, particularly increased titres of antibodies to various gut bacteria. T cells are critical to the disease in animal models other than those where overexpression of a cytokine is engineered, suggesting that they are the drivers of the inflammatory response. There is convergent evidence from animal models, genetics in humans, and direct observation of human peripheral blood and joints to implicate T cells producing IL-17 under the influence of IL-23. These in turn may be responding to bacteria either in the gut or on the skin.

HLA-B27 transgenic rats and strains of HLA-B27-transgenic β2-microglobulin (β2m)-deficient mice develop a multisystem inflammatory disease affecting the joints, skin, and bowel with strong similarity to human spondyloarthritis. We show that HLA-B27 transgenic mice and rats express HC10-reactive, β2m-free HLA-B27 homodimers (B272) and multimers, both intracellularly and at the cell surface of leukocytes, including rat dendritic cells. Fluorescent-labeled tetrameric complexes of HLA-B27 homodimers (B272 tetramers) bind to populations of lymphocytes, monocytes, and dendritic cells. The murine (and probably rat) paired Ig-like receptors (PIRs) are ligands for B272. Thus, B272 tetramers stain RBL cells transfected with murine activating PIR-A4 and inhibitory PIR-B receptors. Murine PIR-A and -B can be immunoprecipitated from the RAW264.7 macrophage cell line, and murine PIR-A can be immunoprecipitated from the J774.A1 line using B272. B272 tetramer staining corresponds to the distribution of PIR expression on lymphoid and myeloid cells and on murine macrophage cell lines. B272 can induce TNF-α release from the J774.A1 macrophage cell line. The binding of B272 to PIR is inhibited by HC10, an mAb that ameliorates arthritis in HLA-B27+ β2m−/− mice. The expression and PIR recognition of B272 could explain the pathogenesis of rodent spondyloarthritis.

In most chronic inflammatory diseases, the cause remains unknown. Chronic infection is, however, among the current hypotheses. Recent technological advances have allowed in-depth studies of the gut microflora, or microbiota, which contains a vast array of organisms, most of which cannot be cultured. Inflammatory bowel disease has been associated with distinctive changes in the gut microbiota, which persist between disease flares and may play a pathogenic role. Links have been demonstrated between the gut microbiota and joint inflammation in murine models of arthritis but have received little attention in human patients. Recent work has nevertheless demonstrated substantial alterations in the gut microbiota in patients with rheumatoid arthritis, psoriatic arthritis, or spondyloarthritis, with differences across diagnoses and studies. Interestingly, some of these alterations resemble those now firmly established in inflammatory bowel disease; examples include decreased microbial diversity and lower frequencies of bacterial groups belonging to the Firmicutes phylum known to have immunoregulatory properties. These new findings open up important new horizons both for understanding disease and for developing novel biomarkers and treatment strategies.

Objective To evaluate the prevalence of joint inflammatory abnormalities and erosions detected by grey-scale and Doppler ultrasound (US) in the small joints of hands and feet in healthy subjects. Methods US of the dorsal surface of 32 joints (10 metacarpophalangeal, 10 proximal interphalangeal, 10 metatarsophalangeal (MTP) and 2 wrists) was performed in 207 healthy subjects without joint symptom. Synovial effusion (SE), synovial hypertrophy (SH) and power Doppler (PD) signal were scored using a semiquantitative grading scale (0–3) and erosion binary. Results One-hundred and eighty-two subjects had at least one US abnormality: 52% of the subjects had SE alone, 13% SH alone (5% with and 8% without PD) and 35% both SH and SE. US findings were detected in 9% of the total joints examined, mostly in the feet, and in particular in the MTP1 (33% of the positive joints). SE was the most frequently detected finding (68% of the positive joints), followed by SH (31%). Severity was mild (grade 1 in average) whatever the finding recorded (SH, SE or PD). Four erosions were detected (MTP1). Conclusions This study describes for the first time, in a large cohort of healthy subjects, the prevalence and location of US signs of joint inflammation and of structural damage in small joints of hands and feet. US abnormalities were quite common, and mostly located in the feet. Further studies are needed to define which US components may allow to discriminate between pathological and physiological findings in the joints commonly affected by inflammatory arthritis conditions.

Objective Spondyloarthritis is a group of articular disorders sharing a genetic background. Polymorphisms in the IL-1 gene cluster have previously been associated with ankylosing spondylitis (AS), a subset of spondyloarthritis. This study examined the association between several of these polymorphisms and the whole spondyloarthritis. Particular attention was devoted to genotype–phenotype correlations. Methods Seven single-nucleotide polymorphisms (SNP) and a variable number tandem repeat located in the IL-1 gene cluster were genotyped in 185 independent spondyloarthritis trios. Family-based association test (FBAT) was computed using the FBAT software. Analysis was carried in spondyloarthritis as a whole and also in AS. A case–control replication study was performed for four of the SNP, in an independent sample of 414 spondyloarthritis and 264 controls. A combined analysis of both studies was performed. Results The SNP rs2856836 in IL1A was significantly associated with spondyloarthritis (p=0.009) and AS (p=0.010) in the family study. The case–control study revealed an association between another IL1A variant (rs1894399) and AS (p=0.035), and between IL1F10.3 (rs3811058) and spondyloarthritis (p=0.041). By combining family and case–control studies an association between AS and IL1A was confirmed (rs1894399, p=0.024), whereas non-AS was more significantly associated with IL1F10.3 (p=0.0043). Family-based and case–control studies revealed significant association between the two most frequent haplotypes combining the four SNP of the replication study and both spondyloarthritis (p=0.0054 and p=0.038) and AS phenotypes (p=0.018 and 0.0036). Conclusion This study is the first to demonstrate an association between several polymorphisms located in the IL-1 gene cluster and spondyloarthritis as a whole. The IL1A locus was strongly associated with AS phenotype, whereas IL1F10 was associated with non-AS.

Revue du rhumatisme - In Press.Proof corrected by the author Available online since mercredi 11 janvier 2017

Objectives The French Society of Rheumatology has initiated a large national multicenter, longitudinal, prospective follow-up of patients presenting with early inflammatory back pain in order to set up a database to facilitate several investigations on diagnosis, prognosis, epidemiology, pathogenesis and medico-economics in the field of early inflammatory back pain and spondyloarthritis. Methods Patients were recruited if they had inflammatory back pain of more than 3 months and less than 3 years. Patients will be followed every 6 months during the first 2 years then every year during at least 5 years. Apart from information collected on a Case Report Form (demographics, disease activity, severity, co-morbidities, socio-economics, treatments, radiological and MRI evaluation of the spine and the pelvis according to the local investigators, and for some centers bone densitometry and ultrasonography of entheses), the digital X-rays and MRI of the spine and pelvis are stored using a specific software (Carestream) and the biological samples (DNA, RNA, sera, urines) are centralized at the Biological Resources Center (Bichat Hospital). Results The recruitment period of the 708 patients (mean age: 34 ± 9 years, female 54%, HLA-B27 positive: 57%) in the 25 centers was 26 months (from December 2007 to April 2010). The modified New York criteria, Amor criteria, ESSG criteria and axial ASAS criteria were fulfilled by 26%, 77%, 76% and 67% of the patients at entry, respectively. A history or current symptoms suggestive of peripheral arthritis, acute anterior uveitis and inflammatory bowel disease were observed in 21%, 9% and 4% of the patients, respectively. The disease was active (BASDAI: 45 ± 20) despite an NSAID intake in 66% of the patients. Conclusion This large cohort should facilitate the conduct of researches in different areas (clinical, medico-economics, translational) in order to improve our knowledge on the pathogenesis and natural history of axial spondyloarthritis.

Resume Objectifs La Societe francaise de rhumatologie a mis en place une importante etude prospective, nationale, multicentrique, longitudinale, de suivi d’une cohorte de patients avec rachialgie inflammatoire recente, afin de constituer une base de donnees pour faciliter la recherche sur le diagnostic, le pronostic, l’epidemiologie, la physiopathogenie et les aspects medicoeconomique des rachialgies inflammatoires recentes et des spondylarthropathies. Methodes Les patients recrutes devaient avoir une rachialgie inflammatoire evoluant depuis plus de trois mois et moins de trois ans. Ils seront suivis tous les six mois pendant les deux premieres annees, puis chaque annee pendant au moins cinq ans. En plus des informations colligees sur un questionnaire individuel (caracteristiques demographiques, activite de la maladie, severite, comorbidites, aspects socioeconomique, traitements, radiographies standard et IRM du rachis et du pelvis par les investigateurs locaux, et pour certains centres, osteodensitometrie osseuse et echographie des entheses), les radiographies numerisees et l’IRM du rachis et du pelvis sont stockees grâce a un logiciel specifique (Carestream). Les echantillons biologiques (ADN, ARN, serum, urines) sont centralises au centre de ressources biologiques (CRB) de l’hopital Bichat. Resultats La periode de recrutement des 708 patients (moyenne d’âge : 34 ± 9 ans, femmes 54 %, HLA-B27 positif : 57 %) dans les 25 centres a ete de 26 mois (de decembre 2007 a avril 2010). Les criteres de New York modifies, les criteres d’Amor, les criteres ESSG et les criteres rachidiens de l’ASAS etaient remplis par respectivement 26 %, 77 %, 76 % et 67 % des patients a l’inclusion. Des antecedents de symptomes evocateurs d’arthrite peripherique, une uveite anterieure aigue et une maladie inflammatoire chronique de l’intestin etaient presents respectivement chez 21 %, 9 % et 4 % des patients. La maladie etait active (BASDAI : 45 ± 20 mm) malgre les AINS pris par 66 % des patients. Conclusion Cette grande etude devrait faciliter la realisation de travaux de recherche dans differents domaines (clinique, medicoeconomiques, recherche translationnelle) afin d’ameliorer notre connaissance sur la physiopathologie et l’evolution naturelle des spondylarthropathies axiales.

ObjectiveTo evaluate rituximab (RTX) in primary Sjögren's syndrome (pSS) with peripheral nervous system (PNS) involvement.MethodsPatients with pSS and PNS involvement who were included in the French AIR registry were analysed.Results17 patients (age 60 years (44–78 years); 14 were female) were analysed.Neurological improvement was noted in 11 patients (65%) at 3 months. Rankin scale decreased from 3 (1–5) to 2 (1–5), 2 (1–5) and 2 (1–6) after 3, 6 and 9 months (p=0.02). European Sjögren's Syndrome Disease Activity Index decreased from 18 (10–44) to 11 (5–20), 11 (5–29) and 12 (5–30) after 3, 6 and 9 months (pRTX was effective in neurological involvement in 9/10 patients with vasculitis or cryoglobulinaemia (90%) (group 1) at 3 months and in 2/7 cases (29%) without cryoglobulinaemia and vasculitis (p=0.03). Rankin and European Sjögren's Syndrome Disease Activity Index scales decreased significantly in group 1.ConclusionRTX seems effective in cryoglobulinaemia or vasculitis-related PNS involvement in pSS.

Objective Our group previously identified a new susceptibility region linked to spondylarthritis (SpA) on chromosome 9q31–34. Fine mapping of this SPA2 locus allowed us to refine the peak of linkage to a 1.3-Mb interval. The objective of this study was to resequence most positional candidate genes lying in that region, to identify polymorphisms, and to examine their association with SpA. Methods Variants screening was performed in 30 independent patients with SpA from families with a high linkage score to the SPA2 locus and 30 control subjects. The coding regions, intron–exon boundaries, and 5′- and 3′-flanking regions of ZNF618, A1L4R1_HUMAN (AF495724), AMBP, KIF12, ORM1, ORM2, C9ORF91, ENSESTG000000230601, and TNFSF8 were resequenced to identify polymorphisms. Selected variants were genotyped in an extended French cohort (442 patients and 268 control subjects overall). Replication was performed in a combined Belgian and Portuguese cohort (433 patients and 299 control subjects). Results Variants screening allowed us to identify 98 polymorphisms, 5 of which were selected for further studies, based on statistical significance. The rare intronic single-nucleotide polymorphism (SNP) rs3181357, located in TNFSF8, was significantly associated with SpA in the French and the replication cohorts (odds ratio [OR] 2.03, P = 0.009 and OR 2.26, P = 0.0014, respectively) and in the pooled analysis (OR 2.14, P = 0.0001). Conclusion Positional candidate gene screening in the SPA2 locus allowed us to identify and replicate an association between a rare SNP located in TNFSF8 and SpA. This new finding appears to be independent of an association with a haplotype near TNFSF15, which we recently reported.

Objective There is an unmet need for the treatment of adult Still's disease (ASD), the pathogenesis of which may involve interleukin-6 (IL-6). We report the first series of patients with ASD treated with tocilizumab (TCZ), a humanized anti–IL-6 receptor antibody. Methods All ASD patients treated with TCZ in France between July 2006 and July 2009 after failure to all available therapies were included in this cohort study. The main outcome measures were the European League Against Rheumatism (EULAR) improvement criteria and resolution of systemic symptoms at the 3- and 6-month followup periods. Results Fourteen patients with refractory ASD were included. At the start of TCZ treatment, despite a mean prednisone dosage of 23.3 mg/day, based on a 28-joint count, mean tender joints were 10.5, mean swollen joints were 7.9, and the mean Disease Activity Score in 28 joints was 5.61. Recurrent systemic involvement, including fever and rash, was present in 7 patients. TCZ was administered at 5–8 mg/kg every 2 or 4 weeks (8 mg/kg/month, n = 9). Eleven patients successfully completed the 6-month study; 1 withdrew due to necrotizing angiodermatitis, another due to chest pain at each TCZ infusion, and a third due to systemic flare. A good EULAR response was observed in 64% of patients (9 of 14) at 3 months and EULAR remission was observed in 57% (8 of 14) at 6 months. Systemic symptoms were resolved in 86% of patients (6 of 7). Moreover, corticosteroid dose was reduced by 56%. No other severe adverse effects occurred. Conclusion TCZ is a promising new treatment for ASD.

Upon publication of the original article [1], it was noted that references 11 and 22 were miscited in the reference list.

Objectives We previously identified a new susceptibility region linked to SpA in 9q31-34. Tenascin-C (TNC) appears as one of the best positional and functional candidate genes lying within this SPA2 locus. The objectives of the present study were to identify TNC polymorphisms, and to examine their putative association with SpA. Methods We first performed variants screening in 20 independent SpA patients from families with high linkage score to the SPA2 locus, and three unrelated controls: TNCs coding regions (28 exons), intron-exon boundaries and 5'- and 3'-flank regions were fully re-sequenced to identify polymorphisms. Then we genotyped selected variants in 183 independent trios, and assessed their intrafamilial association with SpA by transmission disequilibrium test. Results Variants screening allowed us to identify 26 polymorphisms, 7 of which were selected for further study, in addition to an intronic polymorphism previously reported as associated with Achilles tendon injuries. In intrafamilial association test, none of the variants showed significant transmission disequilibrium. Results from analysis restricted to AS were not different from those obtained on the whole SpA group. Conclusions TNC was one of the best positional and functional candidate genes within the SPA2 locus. Nevertheless, we found no association between polymorphisms in this gene and SpA. However, we cannot exclude that variants located in intronic regions or in the vicinity of TNC, which were not tested in the present study, could be implicated in the predisposition to SpA.

The highly effective treatment of rheumatoid arthritis by B cell depletion and the presence of B cells in the peripheral and axial lesions of patients with spondylarthritis (SpA) raise the question as to whether B lymphocytes could also be an appropriate therapeutic target in the latter disease. We describe 2 male HLA-B27-positive patients who had active SpA despite absence of B cells. One patient developed SpA with sacroiliitis and asymmetric oligoarthritis after having been diagnosed as having severe Bruton agammaglobulinemia. Since extensive investigations excluded an infectious origin of the SpA, this case illustrates that functional B cells and/or gamma globulins are not strictly required for SpA pathogenesis. The second patient had severe axial and peripheral SpA that was treated successfully with etanercept. After discontinuation of etanercept treatment because of non-Hodgkin's B cell lymphoma, both axial and peripheral SpA symptoms relapsed rapidly, and this exacerbation of articular disease activity was not modulated by successful B cell depletion therapy for the lymphoma. Although case reports have obvious limitations, our clinical observations provide evidence that active SpA can occur in the absence of functional mature B cells and thus emphasize the need for systematic studies of the exact role and function of B lymphocytes in this disease.

Resume Objectif Actualiser au nom de la Societe francaise de rhumatologie les recommandations pour l'utilisation en pratique quotidienne des anti-TNF α au cours de la spondylarthrite ankylosante (SA) et du rhumatisme psoriasique (RP). Methodes La methodologie recommandee par Shekelle et al., pour la mise a jour de recommandations, a ete utilisee : determination par un groupe restreint d'experts des items a reevaluer, analyse critique de la litterature, proposition de libelles par le comite restreint, validation interne et externe des recommandations. La structure restait identique, en trois themes : indication des anti-TNF α, initiation en pratique, surveillance et adaptation therapeutique. Resultats Pour retenir l'indication d'un traitement anti-TNF α : 1) le diagnostic de SA ou de RP doit etre certain. Cette certitude s'appuiera pour la SA : sur les criteres de New York modifies ou, en leur absence, sur des atteintes caracteristiques des sacro-iliaques, du rachis ou de sites peripheriques mises en evidence sur les radiographies ou le scanner (atteinte structurale) ou l'IRM (imagerie par resonance magnetique) [atteinte inflammatoire] ; pour le RP : sur des criteres valides, tels que ceux de Moll et Wright ou CASPAR ; 2) la maladie doit etre active depuis plus d'un mois avec : a) Bath ankylosing spondylitis disease activity index (BASDAI) superieur ou egal a 4 pour les formes a predominance axiale ou superieur ou egal a trois articulations douloureuses et gonflees (NAD et NAG) ; b) jugement global de l'activite par le medecin superieur ou egal a quatre (0–10) ; 3) un echec prealable a au moins trois AINS pour les formes axiales et a un traitement de fond pour les formes peripheriques (methotrexate, salazopyrine ou leflunomide) ; 4) les contre-indications doivent etre respectees. Lors de l'initiation d'un anti-TNF α : 1) un bilan pretherapeutique doit etre realise ; 2) il n'y a pas de hierarchie des molecules anti-TNF fondee sur l'efficacite. Le choix se fera dans le cadre d'une decision partagee avec le patient, en fonction des donnees de tolerance disponibles et des caracteristiques du patient ; 3) il n'y a pas d'arguments pour recommander une association systematique d'un traitement de fond conventionnel en terme d'efficacite ; 4) le suivi des patients doit etre regulier et standardise. L'adaptation d'un anti-TNF α se fondera sur les regles suivantes : 1) l'objectif therapeutique est : pour les formes axiales : amelioration du BASDAI superieure ou egale a deux points et pour les formes peripheriques : amelioration superieure ou egale a 30 % du NAD et du NAG ; 2) en cas de non-reponse, il n'y a pas d'arguments pour recommander l'introduction d'un traitement de fond. Il est possible de modifier la frequence des perfusions ou de la posologie de l'infliximab ou de remplacer un anti-TNF par un autre ; 3) en cas d'intolerance a l'un des anti-TNF, l'utilisation d'un autre anti-TNF est possible selon la nature de l'effet indesirable observe ; 4) en cas de remission, il est recommande d'envisager une reduction, voire un arret, du traitement anti-inflammatoire associe. En cas de remission prolongee, il est possible d'envisager une reduction de la posologie de l'anti-TNF.