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Background Spondyloarthritis (SpA) is one of the most frequent chronic inflammatory rheumatisms that affects axial skeleton, peripheral joints and may result in ankylosis of the spine and sacroiliac joints. Extra-articular features including uveitis, psoriasis and inflammatory bowel disease are frequent. Current SpA treatments are only symptomatic, relieving inflammatory symptoms. SpA aetiology is largely multifactorial with a genetic component dominated by the association with the HLA-B27 allele. This allele, however, is not sufficient for the disease to occur. Whereas dendritic cells (DCs) are believed to play a key role in SpA pathogenesis, the precise mechanisms underlying disease development and the role of HLA-B27 remain poorly understood. To shed light on the genes involved, we recently carried out a transcriptomic analysis of monocyte-derived DCs (MD-DCs) from patients and healthy controls, also accounting for HLA-B27. Material and methods Transcriptomic profiles of MD-DCs were obtained with the Affymetrix Human Gene 1.0 ST technology from SpA patients (n = 23 HLA-B27+) and from healthy controls (n = 23 HLA-B27+, n = 21 HLA-B27-). Analysis of differentially expressed (DE) genes was conducted with LIMMA accounting for both the disease and the HLA-B27 status, followed by quantitative gene set enrichment analyses (quSAGE) and functional annotation. We performed three comparisons to identify DE genes and generating three lists: A, including 800 DE genes between SpA patients and HLA-B27- controls; B, including 673 DE genes between HLA-B27+ controls and HLA-B27- controls; and C, including 466 DE genes between SpA patients and HLA-B27+ controls. Subtracting A–B left 656 genes, of which 68 are in list C. Results By combining a transcriptomic analysis and innovative comparative approaches, we identified a set of 68 genes affected by SpA overcoming the potential HLA-B27 effect. Based on functional annotation, those genes are mainly related to lipid synthesis, regulation and trafficking suggesting that MD-DCs from SpA patients exhibit major functional dysregulations. Conclusion In SpA patients, DCs present a defect in lipid intracellular regulation and signalling which may be involved in SpA physiopathology and may contribute to its development and progression. Our work may help to improve the understanding of SpA pathogenesis and open new perspectives in therapeutic approaches.

Background and aim HLA-B27/human β2m transgenic rats (B27-rats), a model of spondylarthritis (SpA) develop spontaneous colitis and arthritis. Recently, we demonstrated that altered DCs function could be critical for triggering SpA since DCs from B27 rats promote a biassed expansion of pro-inflammatory Th17 cells, which might have a pathogenic role. Furthermore, the altered interaction of DC/T cell induces a modification of regulatory T cells function, resulting in decreased IL-10 and enhanced IL-17 production by those cells. Interestingly, in vitro blockade of ICOS-ICOSL interaction demonstrated that ICOS signalling plays a key role in generation and maintenance of IL-10/IL-17 imbalance production by regulatory T cells, and biassed-Th17 cells expansion. Thus, we hypothesised that in vivo modulation of ICOS-ICOSL pathway may have therapeutic utility in this model. To investigate this hypothesis we used a genetic approach producing B27. ICOS (B27. ICOS-KO) knockout rats. Material and methods Using TALEN technology for disrupt the ICOS locus, Dr Anegon and colleagues produced the ICOS. Kcnockout rats that were backcrossed onto the B27 transgenic background. B27 and B27. ICOS-KO rats were weekly weighted, examined and scored for clinical symptoms, including colitis (intensity of diarrhoea), arthritis (severity of swelling), alopecia, orchitis and nail dystrophy Results As expected, chronic diarrhoea was the most common and persistent finding, being present in all B27 rats. Arthritis and alopecia developed only in some B27 rats. The clinical disease score progressively worsened in B27 rats. In contrast, the B27. ICOS-KO rats did not develop any symptom of disease until age of 16 weeks. Attenuated symptoms were observed in B27. ICOS-KO animals until 24 weeks compared to B27 rats. Conclusions Our preliminary clinical results suggest a protective role of Icos deletion in onset and severity of the disease in B27 rats.

Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

Objective In rats transgenic for human HLA–B27 and β2-microglobulin (B27-transgenic rats), colitis and peripheral inflammation develop spontaneously. Therefore, B27-transgenic rats provide a model of spondylarthritis. Because inflammation in these rats requires CD4+ T lymphocytes and involves intestinal pathology, we hypothesized that dendritic cells (DCs) that migrate from the intestine and control CD4+ T cell differentiation would be aberrant in B27-transgenic rats. Methods Migrating intestinal lymph DCs were collected via thoracic duct cannulation from B27-transgenic and control (HLA–B7–transgenic or nontransgenic) rats. The phenotypes of these DCs and of mesenteric lymph node DCs were assessed by flow cytometry. The ability of DCs to differentiate from bone marrow precursors in vitro was also assessed. Results Lymph DCs showed increased activation and, strikingly, lacked the specific DC population that is important for maintaining tolerance to self-antigens. This population of DCs was also depleted from the mesenteric lymph nodes of B27-transgenic rats. Furthermore, in vitro culture of DCs from bone marrow precursors revealed a defect in the ability of B27-transgenic rats to produce DCs of the migratory phenotype, although the DCs that were generated induced enhanced interleukin-17 (IL-17) production from naive CD4+ T cells. Conclusion We describe 2 different mechanisms by which HLA–B27 may contribute to inflammatory disease: increased apoptotic death of B27-transgenic DCs that normally function to maintain immunologic tolerance and enhanced IL-17 production from CD4+ T cells stimulated by the surviving B27-transgenic DCs.

Objective A robust association between polymorphisms in the non-major histocompatibility complex gene ERAP1 and ankylosing spondylitis (AS) in several populations was recently identified. The aim of the current study was to determine the level of association of ERAP1 polymorphisms with spondyloarthritis (SpA) in French/Belgian populations with particular attention to genotype–phenotype correlations. Methods We studied 734 independent SpA cases and 632 controls from two European cohorts. Five single-nucleotide polymorphisms (SNPs), rs27044, rs17482078, rs10050860, rs30187 and rs2287987 were genotyped, and case-control association analyses were carried using PLINK 1.07 software. Linkage disequilibrium and haplotypes were estimated with Haploview. Analysis was first carried out in SpA as a whole group, and then separately in AS and non-radiographic SpA (non-AS) patients. Results Consistent with previous studies conducted in AS, rs30187 was the most significantly associated SNP with SpA (p=0.008 in the French, and p=6.46×10 −4 in the Belgian cohorts). In the combined cohorts, this SNP was associated with both AS and non-AS (P combined = 3.9×10 −5 and P combined = 0.005, respectively). A similar trend was observed with other SNPs. The rs17482078/rs10050860/rs30187-CCT haplotype was significantly associated with increased risk of SpA in both cohorts (P combined = 9.08×10 −4 ), including AS and non-AS (P combined =6.16×10 −4 and P combined =0.049, respectively), whereas the -TTC haplotype was associated with reduced risk of SpA, including AS and non-AS (P combined =2.36×10 −7 , P combined = 5.69×10 −6 and P combined = 2.13×10 −4 , respectively). Conclusions This is the first study to show an association between several polymorphisms located in ERAP1 and SpA as a whole. Our findings demonstrate consistent association of the same SNPs and haplotypes with both AS and non-AS subtypes of SpA.

Joint Bone Spine - In Press.Proof corrected by the author Available online since mercredi 1 aout 2012

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 Conclusions In patients with recent IBP suggestive of spondyloarthritis, psoriasis is associated with active axial disease and frequent concomitant enthesopathy and dactylitis.

Joint Bone Spine - In Press.Proof corrected by the author Available online since lundi 30 juillet 2012

International audience; Power Doppler ultrasound (PDUS) has proved to be a highly sensitive tool for assessing enthesitis in spondyloarthritis (SpA). In patients with a suspected SpA, diagnosis could be improved by detecting enthesitis with PDUS. OBJECTIVE: To evaluate the performance of PDUS for the diagnosis of SpA alone or combined with other clinical, laboratory and imaging findings in patients consulting for a suspected SpA. METHODS: Prospective, multicenter French cohort study (Boulogne-Billancourt, Brest, Caen, Grenoble, Marseille and Nancy). Outpatients consulting for symptoms suggestive of SpA (inflammatory back pain [IBP], arthritis or inflammatory arthralgia [IA], enthesitis or dactylitis [ED], HLA-B27 positive uveitis [B27+U], familiarity for SpA [Fam]) were recruited and followed up for at least 2years. Sample size was set to 500 patients (for estimated prevalence of SpA of 30±5% after 2years). At baseline, patients were submitted to standardized physical examination, pelvic X-ray, sacroiliac joints magnetic resonance imaging (MRI), HLA-B typing, and other tests judged useful for diagnosis. For each patient, a blinded PDUS examination of 14 enthesitic sites was performed at baseline and at years 1 and 2. Patients were planned to be followed during 5years. The diagnosis of SpA ascertained by an experts' committee, blind to PDUS results, after at least 2years of follow-up, with a revaluation of doubtful patients at 5years will be used as gold standard for evaluating the diagnostic performance of PDUS and the best diagnostic procedure by combining PDUS, clinical symptoms and other tests. RESULTS: Between January 2005 and September 2007, 489 patients were included (96% of the target population). Nineteen patients (0.2%) retired their informed consensus or were lost to follow-up immediately after their inclusion. At baseline, mean age of the 470 remaining patients was 40years, mean duration of symptoms was 6.1years; 42% of them were HLA-B27+ and 63% were female. Primary inclusion criterion was IBP in 53%, IA in 27%, ED in 9%, B27+U in 8% and Fam in 4%. Follow-up is still ongoing. CONCLUSION: We have set up a unique diagnostic cohort which includes the entire spectrum of SpA manifestations. By using PDUS we expected to improve the diagnostic procedure of SpA.

Objective HLA–B27/human β2-microglobulin–transgenic (B27-transgenic) rats, a model of spondylarthritis (SpA), develop spontaneous colitis and arthritis under conventional conditions. CD4+ T cells are pivotal in the development of inflammation in B27-transgenic rats. This study was undertaken to characterize the phenotype of CD4+ T cells in this model and to determine whether dendritic cells (DCs) induce proinflammatory T cells. Methods The phenotype of CD4+ T cells from rat lymph nodes (LNs) draining the sites of inflammation was analyzed by flow cytometry. Immunostaining was used to detect interleukin-17 (IL-17)–producing cells in the rat joints. DCs from B27-transgenic or control rats (transgenic for HLA–B7 or nontransgenic) were cocultured with control CD4+ T cells and stimulated with anti–T cell receptor α/β. Results IL-17A– and tumor necrosis factor α (TNFα)–producing CD4+ T cells were expanded in mesenteric and popliteal LNs from B27-transgenic rats. The accumulation of Th17 cells correlated with disease development, in contrast to Th1 or Treg cells. IL-17–positive mononuclear cells were detected in the arthritic joints of B27-transgenic rats but not in the joints of control rats. Finally, in vitro cocultures demonstrated that Th17 cells were preferentially induced and expanded by DCs from B27-transgenic rats, by a process that may involve defective engagement of costimulatory molecules. Conclusion Our findings indicate that expanded CD4+ T cells in B27-transgenic rats exhibit a proinflammatory Th17 phenotype characterized by IL-17A and TNFα production. Furthermore, this population is preferentially induced by DCs from B27-transgenic rats. These data point toward an induction of Th17 cells as a possible pathogenic mechanism in this model of SpA. However, their pathogenic role still needs to be shown.

Early diagnosis of spondyloarthritis (SpA) is sometimes difficult owing to the lack of reliable diagnostic criteria. The objective of this study was to determine the diagnostic accuracy of detecting enthesitis by power Doppler ultrasonography (PDUS) in patients with suspected SpA.A prospective single-centre cohort study was performed in patients with symptoms suggestive of SpA (inflammatory back pain, arthritis, enthesitis or dactylitis, HLAB27+ uveitis) who underwent clinical examination, pelvic x-ray, MRI of lumbar spine/sacroiliac joints, HLA-B typing and other tests judged useful for diagnosis. Blinded PDUS examination of seven sites of enthesitis was performed at baseline. The gold standard was the diagnosis made by the referring rheumatologist according to the development of symptoms and findings, blinded to PDUS results, during routine follow-up for up to 2 years.Between November 2002 and October 2004, 118 patients were included in the study. After 2 years a definite diagnosis was retained for 99 patients (51 SpA and 48 non-SpA). PDUS detection of at least one vascularised enthesis provided good predictive value for diagnosing SpA (sensitivity 76.5%; specificity 81.3%; positive likelihood ratio 4.1; OR 14.1; p0.0001). Vascularised enthesitis detected by PDUS and Amor's criteria were the only independent contributors to a diagnosis of SpA in multivariate logistic regression (c-index=0.87). Alternatively, CART analysis resulted in a highly sensitive and specific diagnostic tree by combining PDUS with Amor's criteria.PDUS appears to be a valuable first-line diagnostic tool to confirm a diagnosis of SpA.

We have previously produced lines of rats transgenic for HLA-B27 and human beta 2-microglobulin (h beta 2m) that develop a progressive inflammatory disease sharing many clinical and histologic features with the B27-associated human spondyloarthropathies, including gut and male genital inflammation, arthritis, and psoriasiform skin lesions. Other transgenic lines that express lower levels of B27 and h beta 2m remain healthy. To investigate the cellular basis for the multisystem inflammatory disease in these rats, we transferred lymphoid cell populations from disease-prone transgenic lines to irradiated disease-resistant transgenic and nontransgenic recipients. In recipients of cells from two different disease-prone lines, successful transfer required engraftment of bone marrow cells. Transfer of disease with fetal liver cells suggested that neither mature effector cells nor active disease in the donors was necessary for induction of disease in the recipients. Remission of the spontaneous disease in irradiated transgenic rats was induced by engraftment of nontransgenic bone marrow. These results suggest that the expression of HLA-B27 in bone marrow-derived cells alone is sufficient for the development of B27-associated disease, and that disease transfer requires engraftment of a bone marrow precursor cell for which mature cells in spleen or in lymph node cannot substitute.

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.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.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.TCZ is a promising new treatment for ASD.

Objective Spondylarthritis (SpA) is characterized by spinal and peripheral joint inflammation, frequently combined with extraarticular manifestations. Despite the well-established association of SpA with the class I major histocompatibility complex (MHC) allele HLA–B27, there are still different, parallel hypotheses on the relationship between HLA–B27 and disease mechanisms. The present study was undertaken to investigate several characteristics of mature dendritic cells (DCs), which are believed to be essential for triggering disease in a model of SpA in HLA–B27–transgenic rats. Methods We combined different whole-proteome approaches (2-dimensional polyacrylamide gel electrophoresis and iTRAQ) to define the most aberrant molecular processes occurring in spleen DCs. Videomicroscopy and flow cytometry were used to confirm both cytoskeletal and class II MHC expression deficiencies. Results Our proteome studies provided evidence of up-regulation of proteins involved in class I MHC loading, and unfolded protein response, along with a striking down-regulation of several cytoskeleton-reorganizing proteins. The latter result was corroborated by findings of deficient motility, altered morphology, and decreased immunologic synapse formation. Furthermore, class II MHC surface expression was reduced in DCs from B27-transgenic rats, and this could be linked to differences in class II MHC–induced apoptotic sensitivity. Finally, we found reduced viability of the CD103+CD4− DC subpopulation, which likely exerts tolerogenic function. Conclusion Taken together, our findings have different important implications regarding the physiology of B27-transgenic rat DCs, which have a putative role in spontaneous disease in these rats. In particular, the reduced motility and viability of putatively tolerogenic CD4+ DCs could play an important role in initiating the inflammatory process, resulting in SpA.

Spondyloarthritis (SpA) is a chronic inflammatory disorder with a strong genetic predisposition dominated by the role of HLA-B27. However, the contribution of other genes to the disease susceptibility has been clearly demonstrated. We previously reported significant evidence of linkage of SpA to chromosome 9q31–34. The current study aimed to characterize this locus, named SPA2. First, we performed a fine linkage mapping of SPA2 (24 cM) with 28 microsatellite markers in 149 multiplex families, which allowed us to reduce the area of investigation to an 18 cM (13 Mb) locus delimited by the markers D9S279 and D9S112. Second, we constructed a linkage disequilibrium (LD) map of this region with 1,536 tag single-nucleotide polymorphisms (SNPs) in 136 families (263 patients). The association was assessed using a transmission disequilibrium test. One tag SNP, rs4979459, yielded a significant P-value (4.9×10−5). Third, we performed an extension association study with rs4979459 and 30 surrounding SNPs in LD with it, in 287 families (668 patients), and in a sample of 139 cases and 163 controls. Strong association was observed in both familial and case/control datasets for several SNPs. In the replication study, carried with 8 SNPs in an independent sample of 232 cases and 149 controls, one SNP, rs6478105, yielded a nominal P-value, Author Summary Spondyloarthritis (SpA) is a common variety of articular inflammatory disorder characterized by axial and/or peripheral arthritis, frequently associated with extra-articular manifestations such as psoriasis, uveitis, and inflammatory bowel diseases (ulcerative colitis or Crohn's disease (CD)). SpA is a complex disorder with high heritability. The MHC class I HLA-B27 allele is a very strong risk factor for its development, but other genetic factors located outside the MHC also play a role in disease susceptibility. By a previous whole-genome linkage investigation, we have demonstrated that a region located on the chromosome 9q31–34 was involved in SpA susceptibility. The present study aimed to further characterize this locus. Using a stepwise linkage and association approach, we identified a haplotype spanning 6 single-nucleotide polymorphisms strongly associated with SpA and located in a genomic region paralogous to the MHC, near to the TNFSF15 gene. Interestingly, polymorphisms of this gene have previously been shown to be associated with CD. This original finding offers a new research track for the understanding of SpA pathophysiology, which is still poorly understood, as well as new hope for diagnostic and therapeutic innovation.

A minority of patients with ankylosing spondylitis (AS) fail to respond to infliximab treatment. This study compared the circulating infliximab concentration and the presence of clinical symptoms in patients continuously treated with infliximab or after treatment interruption.Patients with active AS were randomly assigned at week 0 to receive infliximab either at weeks 4, 6, 10, and then every 6 weeks (continuous treatment), or at weeks 4, 6, and 10 and then upon symptom recurrence (on-demand treatment). The circulating concentration of infliximab was determined early during treatment and at weeks 46 and 52 for the continuous treatment group or upon relapse for the on-demand group. Response in the continuous treatment group was defined at week 58 using the ASsessment in AS International Working Group Criteria for 20% improvement.Among the 93 patients in the continuous treatment group, treatment failure was not associated with a low circulating concentration of infliximab, either during early treatment or at 1 year. Eleven (39.2%) of the 28 nonresponders had an infliximab concentration of10 microg/ml at week 52, whereas 9 (13.8%) of the 65 responders had an infliximab concentration of1 microg/ml. In the on-demand group, the infliximab concentration at relapse closely correlated with the time to relapse. However, 24 (36.9%) of 65 patients had a resurgence of clinical symptoms at an infliximab concentration of10 microg/ml, whereas 25 patients (38.4%) had a relapse at an infliximab concentration of0.5 microg/ml.Responsiveness to infliximab treatment is highly heterogeneous among individuals with AS, and this parameter overcomes the circulating infliximab concentration to explain treatment success or failure.

Objective To evaluate and improve the reliability of power Doppler ultrasonography (PDUS) for detecting and scoring enthesitis in patients with spondylarthitis, using a 3-step procedure. Methods In the first step, we evaluated the reliability of 5 sonographers by bilaterally scanning 5 entheses twice in 5 patients. In the second step, starting from disagreements observed during the first step, we established consensus guidelines. The sonographers' implementation was further evaluated in 2 reliability exercises: one on 60 PDUS enthesitis images and the other by scanning 5 new patients. In the third step, we performed a final reliability evaluation of 5 additional patients after 1 year. Kappa coefficients (κ) as well as variance component analysis (VCA) and generalizability theory (GT) were used to assess reliability. Results The initial intra- and interobserver reliability were poor, especially for detecting and scoring Doppler signal. VCA and GT showed that most variability was accounted for by interaction between sonographer and enthesis. Implementation of consensus guidelines was associated with a significant improvement in Doppler reliability between the first and second steps (mean interobserver κ increased from 0.13 to 0.51 for binary Doppler scoring in patients; P < 0.005), which persisted in the third step (mean interobserver κ = 0.57). The high GT coefficients reached in the last steps supported such improvement. Conclusion The 3-step procedure used in this study to standardize PDUS technique was associated with a significant improvement in interobserver reliability for detecting enthesitis in spondylarthritis patients. Such an approach can be useful to standardize PDUS assessment of musculoskeletal disorders.

Objective:To examine the recurrence of manifestations belonging to the spectrum of spondylarthropathy (SpA) in first-degree relatives of patients with SpA, and to estimate the recurrence risk ratio.Methods:Parents and siblings of consecutive SpA probands have been thoroughly investigated, including clinical data collection, pelvic x ray and human leukocyte antigen (HLA)-B27 status determination. The diagnosis of SpA was made according to European Spondylarthropathy Study Group and/or the Amor criteria. The recurrence risk ratio λ1, which gives an estimate of the weight of genetic factors, was calculated as the ratio of the recurrence risk of SpA in first-degree relatives compared with the population prevalence of SpA. The λnon-HLA was obtained by similar calculations restricted to HLA-B27+ individuals.Results:Most manifestations of SpA were more frequent among the 157 HLA-B27+ relatives of 83 probands than among their 111 HLA-B27- relatives. A diagnosis of SpA was made in 50 relatives of 31 (37%) probands. Recurrence was very similar between parents and siblings, without gender difference, resulting in overall recurrence risk of 12% in first-degree relatives and of 22.7% in HLA-B27+ relatives. The λ1 value was 40 and the λnon-HLA value was 6.5, very close to the λHLA value of 6.25 estimated from linkage study in SpA.Conclusions:A similar recurrence risk of SpA was observed between parents and siblings, consistent with a model of inheritance with no dominance variance and without sex influence. The weight of the non-HLA genetic component was equivalent to that estimated for the HLA locus, and fitted a model of multiplicative interaction between HLA and non-HLA genetic components.

Objective.Bone metabolism in spondyloarthritis (SpA) is not well elucidated. We investigated alterations in bone in the HLA-B27 transgenic rat, a model of SpA.Methods.Femur, tibia, and lumbar vertebral bodies of disease-prone HLA-B27 transgenic, healthy HLA-B7 transgenic, and nontransgenic control rats were used for bone histomorphometric and dual energy x-ray absorptiometry (DEXA) analysis. Serum levels of type I collagen C-telopeptides (CTX), N-terminal propeptide of type I procollagen (P1NP), and osteocalcin, as well as receptor activator of nuclear factor-κ B ligand (RANKL) and osteoprotegerin (OPG), were measured. RNA was isolated from the bone tissue of the femura to analyze gene expression of RANKL, OPG, and osteocalcin.Results.Histomorphometric analysis indicated a significant decrease in bone volume as well as trabecular number and thickness in the HLA-B27 rats. Trabecular separation was increased. Numbers of osteoblasts, osteoclasts, and osteoid volume were not altered significantly. The decrease in bone mineral density was confirmed using DEXA. Levels of RANKL mRNA were significantly increased in the bone tissue of HLA-B27 transgenic rats, resulting in an increased RANKL to OPG ratio. Osteocalcin mRNA expression was also significantly elevated in bone of HLA-B27 rats. Serum levels of CTX, RANKL, OPG, P1NP, and osteocalcin did not differ significantly.Conclusion.Our data indicate that, similarly to SpA in humans, HLA-B27 transgenic rats show a reduced bone mass, and suggest an involvement of the RANKL/OPG system in the mechanism of bone loss in this disease. This model may be adequate to study osteoporosis in SpA.

Objective To examine the functional capacity of dendritic cells (DCs) from a panel of HLA–B27/human β2-microglobulin (Huβ2m)–transgenic rat lines and crosses with varying susceptibilities to spondylarthritis (SpA)–like disease. Methods Mature splenic DCs were isolated from HLA–B27–transgenic, HLA–B7–transgenic, and/or Huβ2m-transgenic rats and tested for support of allogeneic proliferation, compared with nontransgenic controls (all male rats on Lewis background). Graded numbers of DCs were cultured with allogeneic lymph node CD4+ T cells (dark agouti background). Proliferation was assayed by incorporation of tritiated deoxythymidine after 2–4 days of culture. Results Allogeneic proliferation stimulated by DCs from the healthy HLA–B27/Huβ2m–transgenic line 21-3 and from the healthy Huβ2m-transgenic line 283-2 was weakly decreased (21–3) or close to normal (283–2) as compared with that observed with control nontransgenic Lewis rat DCs. In contrast, the ability of DCs from (21-3 × 283-2)F1 rats, which develop a dramatic SpA phenotype, to stimulate allogeneic proliferation was markedly defective. When DC-induced allogeneic proliferation was compared among different transgenic lines and crosses with distinct levels of susceptibility to SpA-like disease, stimulatory capacity was inversely correlated with disease susceptibility. Conclusion In HLA–B27/Huβ2m–transgenic rats, a defective functional capacity of DCs correlates with susceptibility to SpA. Since it was previously demonstrated that defective DC function is not a consequence of disease, it could well be a principal factor in the spontaneous development of SpA in these lines.

The association of spondyloarthropathy (SpA) with multiple sclerosis (MS) in the same patient is seldom reported. The aim of this study was to collect cases of association of SpA with MS, to describe their main characteristics and to study the potential influence of one disease upon the other. This retrospective study included patients fulfilling criteria for SpA according to Amor’s criteria and for MS according to McDonald’s criteria. Twenty-one cases were collected (table 1), 10 men and 11 women. The diagnosis of SpA precedes the diagnosis of MS in 14 cases. The mean age at diagnosis for SpA was …

Objective To investigate the molecular mechanism responsible for the reduced capacity of dendritic cells (DCs) from HLA–B27–transgenic rats to form conjugates with naive T cells. Methods We monitored interactions between DCs derived from HLA–B27–transgenic, HLA–B7–transgenic control, and nontransgenic rats and naive CD4+ T cells. Chemoattraction was studied in Transwell assays, and the formation of an immunologic synapse was examined by videomicroscopy and electron microscopy. Involvement of specific molecules in the defective interaction was examined in antibody-blocking assays. Results T cells migrated normally toward B27 DCs, but upon contact, the frequency of T cells undergoing a Ca2+ response was decreased, indicating impaired immunologic synapse formation. The immunologic synapse formed between B27 DCs and T cells appeared to be normal, as assessed by electron microscopy and by the Ca2+ response. Blocking lymphocyte function−associated antigen 1 on T cells or blocking activated leukocyte cell adhesion molecules on DCs inhibited an equivalent proportion of conjugates from forming between B27 or control DCs and T cells, whereas blocking CD86 on DCs and blocking CD28, CD2, or CD4 on T cells inhibited a greater number of conjugates from forming with control DCs, indicating specific involvement of costimulatory molecules in the reduced formation of conjugates with B27 DCs. Mature B27 molecules on the DC surface were responsible for this decreased formation of conjugates. Conclusion In the HLA–B27–transgenic rat model of spondylarthropathy, mature B27 molecules expressed by DCs impair the formation of an antigen-independent immunologic synapse with naive CD4+ T cells by interfering with the engagement of costimulatory molecules. This phenomenon could potentially affect the production and/or maintenance of regulatory T cells and contribute to the expansion of pathogenic CD4+ T cells.

Latent tuberculosis infection (LTBI) is detected with the tuberculin skin test (TST) before anti-TNF therapy. We aimed to investigate in vitro blood assays with TB-specific antigens (CFP-10, ESAT-6), in immune-mediated inflammatory diseases (IMID) for LTBI screening.Sixty-eight IMID patients with (n = 35) or without (n = 33) LTBI according to clinico-radiographic findings or TST results (10 mm cutoff value) underwent cell proliferation assessed by thymidine incorporation and PKH-26 dilution assays, and IFNgamma-release enzyme-linked immunosorbent spot (ELISPOT) assays with TB-specific antigens.In vitro blood assays gave higher positive results in patients with LTBI than without (p0.05), with some variations between tests. Among the 13 patients with LTBI diagnosed independently of TST results, 5 had a negative TST (38.5%) and only 2 a negative blood assays result (15.4%). The 5 LTBI patients with negative TST results all had positive blood assays results. Ten patients without LTBI but with intermediate TST results (6-10 mm) had no different result than patients with TST result/=5 mm (p0.3) and lower results than those with LTBI (p0.05) on CFP-10+ESAT-6 ELISPOT and CFP-10 proliferation assays.Anti-TB blood assays are beneficial for LTBI diagnosis in IMID. Compared with TST, they show a better sensitivity, as seen by positive results in 5 patients with certain LTBI and negative TST, and better specificity, as seen by negative results in most patients with intermediate TST as the only criteria of LTBI. In the absence of clinico-radiographic findings for LTBI, blood assays could replace TST for antibiotherapy decision before anti-TNF.

OBJECTIVE: Ankylosing spondylitis (AS) is a debilitating chronic inflammatory condition with a high degree of familiality (lambda(s) = 82) and heritability (>90%) that primarily affects spinal and sacroiliac joints. Whole genome scans for linkage to AS phenotypes have been conducted, although results have been inconsistent between studies and all have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective meta-analysis. METHODS: The International Genetics of Ankylosing Spondylitis Consortium combined data from three whole genome linkage scans for AS (n = 3744 subjects) to determine chromosomal markers that show evidence of linkage with disease. Linkage markers typed in different centres were integrated into a consensus map to facilitate effective data pooling. We performed a weighted meta-analysis to combine the linkage results, and compared them with the three individual scans and a combined pooled scan. RESULTS: In addition to the expected region surrounding the HLA-B27 gene on chromosome 6, we determined that several marker regions showed significant evidence of linkage with disease status. Regions on chromosome 10q and 16q achieved 'suggestive' evidence of linkage, and regions on chromosomes 1q, 3q, 5q, 6q, 9q, 17q and 19q showed at least nominal linkage in two or more scans and in the weighted meta-analysis. Regions previously associated with AS on chromosome 2q (the IL-1 gene cluster) and 22q (CYP2D6) exhibited nominal linkage in the meta-analysis, providing further statistical support for their involvement in susceptibility to AS. CONCLUSION: These findings provide a useful guide for future studies aiming to identify the genes involved in this highly heritable condition.

Background While there is an increasing need to better understand the epidemiology of ankylosing spondylitis (AS), such data in France are limited 1,2 or issued from cohorts, with the inherent risk of selection bias. Objectives To estimate the prevalence of severe AS in France and the frequency of chronic, severe co-morbidities, as compared with a control group based on a national representative claims database. Methods The EGB database is a national representative 1/97 sample of individuals covered by the 3 main French insurance schemes. This database lists all healthcare consumption and allows identification of beneficiaries eligible for full health insurance coverage due to severe conditions (list of conditions is defined by the French Sickness fund and called “ALD”). The studied population comprised adults (>18 yrs) with severe AS in 2012. Frequency of serious chronic co-morbidities, such as inflammatory bowel diseases (IBD), cardiovascular diseases and malignancies were identified based on ALD eligibility and compared with a control group without full coverage due to AS and matched by sex and age. Results Among 470,326 adults in the database, 827 patients with severe AS were identified, corresponding to a crude prevalence rate of 0.18% and a nationwide prevalence estimate of 88,275 patients in 2012 in France. Their M/F sex ratio was 1.2, mean (±SD) age was 50.4 (±14.3) years and the time since decision for full health insurance coverage due to AS was 9.7 (±7.8) years. IBD, high blood pressure (HBP), recurrent major depressive disorders and other co-morbidities taken as a whole were significantly more frequent in AS patients than controls (Table; 3.5 vs 0.24%, p Conclusions Analysis of a national representative claim database provides up-to-date data on the current prevalence of severe AS in France. These initial results also indicate an increase in several co-morbidities, such as IBD, HBP and depression. No differences were seen regarding malignancies or mortality rates. Further research is needed to confirm these findings. References Saraux A. Ann Rheum Dis 2005;64:1431–1435. Costantino F. Ann Rheum Dis 2013 [Epub ahead of print] Acknowledgements The authors acknowledge Costello Medical Consulting for editorial assistance which was funded by UCB Pharma. Disclosure of Interest M. Breban Consultant for: UCB Pharma, P. Claudepierre Consultant for: UCB Pharma, T. de Chalus Employee of: UCB Pharma, J. M. Joubert Employee of: UCB Pharma, C. Laurendeau Employee of: CEMKA mandated by UCB Pharma for the analysis of the database, J. Gourmelen: None declared, F. Fagnani Employee of: CEMKA mandated by UCB Pharma for the analysis of the database

International audience; OBJECTIVE: To evaluate the continuation and safety of treatment with infliximab in ankylosing spondylitis (AS) over a 2-yr period. METHODS: This study was an open, observational, 2-yr extension study of an open-label study of three induction infusions of infliximab in refractory AS. The fourth infusion was performed only in case of relapse. Thereafter, infliximab was to be administered as needed according to the rheumatologist's opinion; however, for some patients, infusions were performed systematically. RESULTS: None of the 50 recruited patients was lost to follow-up. Thirteen patients (26%) interrupted their treatment by infliximab: four for inefficacy, seven for adverse events, of which four were for allergic reactions to the infusion, and two for other reasons. For all of the 46 patients who had had three infusions judged efficacious and well tolerated, a fourth infusion was performed because of a flare of the disease, after a mean interval of 20.3+/-9.9 weeks (range 7.3-57.9). Over the 24 months, the mean interval between infusions was 11.6+/-9.0 weeks. This interval was longer when patients were treated only as needed (mean 14.3+/-12.1 weeks) than systematically (mean 9.8+/-5.7 weeks). Side-effects were similar to those noted in shorter-term studies; seven patients suffered serious adverse events. There were no deaths, no malignancies and no tuberculosis. CONCLUSION: This study confirms the long-term treatment continuation of infliximab in AS, and shows an acceptable safety profile. It appears that for some patients the disease can be controlled with long intervals between infusions; these findings warrant further studies.

This chapter reviews evidence from family and twin studies supporting the strong genetic predisposition of the spondyloarthritides (SpA), which is only partially attributable to the major histocompatibility locus. The current concept of SpA heterogeneity has been challenged by family studies which showed that all articular and extra-articular manifestations were linked together, and most likely to the same genetic factors.

Objective A disease resembling the human spondylarthropathies develops in HLA–B27–transgenic rats. This disease in rats is mediated by CD4+ T cells, but antigen-presenting cells (APCs) may also play a role. Dendritic cells (DCs) have been reported to be defective in allogeneic mixed lymphocyte culture in this model. Here, we further investigated the functional defect of APCs. Methods DCs and B cells from nontransgenic, HLA–B27 (33–3)–transgenic, and HLA–B7 (120–4)–transgenic rats were used to stimulate T cells. Surface expression of HLA–B transgene and rat molecules on APCs and the formation of conjugates between DCs and T cells were monitored by flow cytometry. Results We observed a strikingly defective stimulation of allogeneic and syngeneic T lymphocytes by APCs from HLA–B27 but not HLA–B7 rats, even if stimulation was driven in the presence of anti–T cell receptor (TCR) antibody. We found no evidence that HLA–B27 DCs were immature, lacked production of some diffusible factor, or produced an inhibitory factor for T cells. When comparing the levels of expression of class II major histocompatibility complex, CD2, intercellular adhesion molecule 1, lymphocyte function–associated antigen 1, B7, and CD40 molecules at the surface of DCs from 33-3, 120-4, and nontransgenic rats, we found little difference. However, HLA–B27–transgenic DCs formed fewer conjugates with T cells than did nontransgenic DCs. Furthermore, the proportion of conjugates formed between DCs and T cells, as well as the difference between nontransgenic and HLA–B27–transgenic DCs, were in large part reduced by blocking CD86 on DCs. Conclusion We confirmed defective stimulation of T cells by APCs in HLA–B27 rats, the mechanism of which appears to implicate APC/T cell contact, independent of TCR engagement. In addition, decreased use of the CD86 costimulatory molecule by B27 DCs was observed. Impaired costimulatory function could result in a loss of tolerance toward microbial flora in this model.

In patients with ankylosing spondylitis (AS), inflammatory processes have been detected in the ileal and colonic mucosa. The inducible isoform of nitric oxide synthase (iNOS) may be expressed early in the inflammatory process. We investigated iNOS activity and lymphocytic infiltration in the duodenum and colon in patients with AS and ulcerative colitis compared with controls.Gastroscopy with duodenal biopsies and/or colonoscopy with biopsies were conducted in 42 patients with AS treated or not treated with nonsteroidal antiinflammatory drugs (NSAID), in 15 with ulcerative colitis, and in 46 controls. Lymphocytic infiltration in the lamina propria and intraepithelial infiltration were quantified by histological score. iNOS expression was assessed by immunohistochemistry with monoclonal antibodies, and iNOS activity was determined by radiochemical assay.Endoscopic examination of the gastroduodenal or colonic mucosa did not reveal macroscopic lesions in the AS patients. In the duodenum, mucosal lymphocytic infiltration was found in 83.3% of the AS group compared to 48.6% of controls (p = 0.02), and was independent of the NSAID intake. Intraepithelial lymphocyte infiltration was increased in both duodenum and colon in AS patients compared to controls. iNOS activity in duodenum and colon and expression of iNOS protein in lamina propria inflammatory cells was increased in AS patients compared to controls.Lymphocytic infiltration and iNOS expression and activity were detected in duodenal and colonic mucosa from patients with AS. Such findings may indicate an inflammatory process in the small intestine and colon of patients with AS.

CLASSICAL DATA: Spondyloarthropathies regroup several rheumatological entities (ankylosing spondylitis, reactive arthritis, psoriatic rheumatism, entero-colopathic disease rheumatism, undifferentiated spondyloarthropathies ) with validated diagnosis criteria. Drug therapy is based upon NSAIDs (non-steroidal antiinflammatories). Refractory forms may lead to severe functional impairment, raising the need of more effective treatments. IN FAVOUR OF ANTI-TNF-ALPHA AGENTS: Several arguments (TNF-alpha serum levels, elevated levels of mRNA, TNF messengers, in sacro iliac biopsies, efficacy of anti TNF-alpha agents in Crohn's disease ) justify the use of anti-TNF-alpha agents in the treatment of spondyloarthropathies. Two biologic agents have been assessed in these circumstances: a monoclonal antibody (Infliximab) and a soluble form of the TNF receptor (Etanercept). EFFICACY AND SAFETY: Results of open and controlled studies, although on small series, demonstrated the significant efficacy of anti-TNF-alpha agents on the various clinical, biological, functional and quality of life parameters, and confirmed by imaging (MRI ). Tolerance is fair, but two cases of diffuse tuberculosis have been reported with Infliximab. THERAPEUTIC PROGRESS: Even if additional studies are required to answer some questions (long term efficacy and safety, treatment modalities), anti TNF agents appear as a therapeutic progress in refractory spondyloarthropathies, for which few validated options have existed up till now.

To determine the changes in bone mineral density (BMD) in patients with spondyloarthropathy (SpA) treated with infliximab.29 patients (six women; 23 men) aged 22-68 years, with persistently active SpA despite a high dose of non-steroidal anti-inflammatory drug and/or treatment with methotrexate or sulfasalazine, were studied. Median duration of disease was 13 years (range 3-30). Twenty five patients were treated with 5 mg/kg and four with 3 mg/kg of infliximab at weeks 0, 2, 6 and then received either no infusion (n=3), or additional infusion of infliximab every other month (n=6), and the remainder received one infusion only in the case of a relapse. Lumbar and femoral BMD was measured by dual energy x ray absorptiometry at baseline and six months later. Serum osteocalcin and urinary deoxypyridinoline were measured in 19 patients at weeks 0, 2, 24, and in 13 patients at all visits.In six months there was a significant increase in BMD at the spine (3.6%, p=0.001), total hip (2.2%, p=0.0012), and trochanter (2.3%, p=0.0012). A trend for increase (1.1%) was observed at the femoral neck. There was an increase in osteocalcin between baseline and week 6 (third infusion)-median 1.45 micro g/l (p=0.013). No change in marker of bone resorption was observed at the same time. There was no change in biochemical markers between baseline and final visits. There was a trend for a correlation between the decrease at six months in erythrocyte sedimentation rate, and lumbar spine BMD change (r(s)=-0.35, p=0.06).These data suggest that a benefit of anti-tumour necrosis factor alpha therapy on BMD in patients with SpA may be through an uncoupling effect on bone cells.

Objective To assess the prevalence and severity of peripheral enthesitis among the different subtypes of spondylarthropathy (SpA) by using ultrasonography (US) in B mode with power Doppler. Methods One hundred sixty-four consecutive patients with SpA (according to the criteria of the European Spondylarthropathy Study Group) and 64 control patients (34 with mechanical low back pain [MBP] and 30 with rheumatoid arthritis [RA]) underwent US examination of major entheses of their limbs. Particular attention was given to the detection of vascularization at the following sites: cortical bone insertion of entheses, junction between tendon and entheses, body of tendon, and bursa. Results Abnormal US findings consistent with at least one enthesitis were observed in 161 of 164 SpA patients (98%), affecting 1,131 of 2,952 entheses examined (38%). In contrast, only 132 of 1,152 entheses (11%) were found to be abnormal in 33 of 64 control patients (52%). US enthesitis was most commonly distributed in the distal portion of the lower limbs, irrespective of SpA subtype and of skeletal distribution of clinical symptoms. None of the abnormal entheses in control patients showed vascularization, compared with 916 of 1,131 abnormal entheses in SpA patients (81%), where it was always detected at the cortical bone insertion and sometimes also in the bursa. In SpA patients, the US pattern depended on the clinical presentation, with a higher prevalence of the most severe stages in those with peripheral forms. Conclusion US in B mode combined with power Doppler allowed the detection of peripheral enthesitis in a majority of SpA patients, but not in MBP or RA patients. The presence of entheseal involvement was independent of SpA subtype, but its degree of severity appeared to be greater in peripheral forms. US could be very useful for both the diagnosis and the assessment of SpA activity.

OBJECTIVE To evaluate the efficacy and safety of a loading regimen of the anti-tumour necrosis factor alpha (TNF-alpha) antibody infliximab in predominantly axial severe ankylosing spondylitis (AS). METHODS We enrolled in this study 50 patients (76% males, 87% HLA-B27(+), median age 35 yr, median disease duration 13 yr) with active AS [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) >or=30/100 and serum C-reactive protein concentration >or=15 mg/l) despite treatment with a non-steroidal anti-inflammatory drug, and without peripheral arthritis, uveitis or active inflammatory bowel disease. Other disease-modifying anti-rheumatic drugs were discontinued >or=3 months before inclusion and were not allowed during the study. Patients received three infusions of infliximab (5 mg/kg) at weeks 0, 2 and 6 and were monitored clinically and biologically until week 24. RESULTS Forty-eight patients completed the treatment. In intention-to-treat analysis, all parameters were significantly improved at week 2 and generally reached maximal improvement at week 8. The proportion of responders, defined by a reduction of >or=20% in the global assessment of pain (GAP) or by the AS Assessment Study Group (ASAS 20%) criteria, and the proportion of patients reaching partial remission were 98, 94 and 70% respectively. Relapse, defined as >or=50% loss of maximal GAP improvement, occurred in 73% of completers, with a median delay of 14 weeks after the third infusion. No serious adverse event related to the treatment was observed. CONCLUSIONS This study confirms, in a large group of severely affected AS patients, the remarkable efficacy of infliximab. Relapse usually occurred after discontinuation of the drug, but almost one-third of completers were still free of relapse 4 months after the last infusion.

The therapeutic options for patients suffering from the more severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is now accumulating evidence that anti-tumour necrosis factor (anti-TNF) therapy is highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Based on the data recently published on more than 200 AS patients, and more than 100 PsA patients, this treatment seems to be even more effective than it is in rheumatoid arthritis (RA). The two major anti-TNF-alpha agents currently available, infliximab (Remicade) and etanercept (Enbrel), are approved for the treatment of RA in Europe and in the USA. The situation in SpA is different from RA because there is an unmet medical need, especially in AS, because disease-modifying anti-rheumatic therapy is not available for severely affected patients. Thus, TNF blockers might even be considered first-line immunosuppressive treatment in patients with active AS who are not sufficiently treated with non-steroidal anti-inflammatory drugs (NSAIDs). For infliximab, a dose of 5mg/kg was required, and intervals between 6 and 12 weeks were necessary for constant suppression of disease activity - a major aim also for long-term treatment. However, it remains to be shown whether patients benefit from long-term therapy and whether radiological progression and ankylosis can be stopped. The optimal doses of infliximab might well be determined individually. Allergic reactions and increased susceptibility to tuberculosis are rare side-effects which need to be recognized early. As it stands now, the benefits of anti-TNF therapy in AS seem to outweigh these shortcomings. The efficacy of etanercept was first demonstrated in PsA. A double-blind study has now been performed in AS - with similar results. There is preliminary evidence that both agents also work in other SpA such as undifferentiated SpA. Hopefully, both agents will be approved soon for the short-term treatment of severe SpA. In parallel, studies should be performed to document the long-term efficacy and safety of this treatment.

In contrast to rheumatoid arthritis (RA), the concept of disease modification in ankylosing spondylitis (AS) remains to be clarified. Endpoint measures employed in AS trials primarily assess features related to symptomatology while endpoints considered more relevant to the concept of disease modification, such as spinal mobility, acute-phase reactants and radiological progression, either lack sensitivity to change or have not been comprehensively validated. NSAIDs alleviate symptoms of AS but most trials have been short term, precluding meaningful conclusions regarding disease modification. Among disease-modifying therapies used in RA, sulfasalazine has been studied in several controlled trials mostly in patients with longstanding disease, effect sizes being small and limited to those with peripheral synovitis. No conclusions can be drawn from the limited studies evaluating methotrexate.

To analyze ocular and extraocular manifestations in patients with HLA-B27-associated uveitis.Large, observational case series.One hundred seventy-five consecutive patients with HLA-B27-associated uveitis seen in a single center between January 1996 and March 2001.Features of uveitis were noted and patients were referred systematically to rheumatologists. The history of previous uveitis attacks and extraocular manifestations of spondyloarthropathy was recorded. Assessments of spondyloarthropathies were based on criteria established by the European Spondyloarthropathy Study.Percentage of patients with extraocular manifestations. The time between the first episode of uveitis and symptoms or diagnosis of extraocular disease was estimated. Characteristics of uveitis were analyzed.The male-to-female ratio was 1.3 to 1, and the median age at the time of the first attack of uveitis was 31 years. An HLA-B27-associated extraocular disorder was seen in 136 cases (77.7%). Of these, ankylosing spondylitis was diagnosed in 81 patients (46.3%) and presumed in 17 (9.7%). Undifferentiated spondyloarthropathy was observed in 21 patients (12%) and other HLA-B27-associated diseases in 17 patients (9.7%). The onset of extraocular symptoms occurred at a younger age (mean+/-standard deviation [SD], 26.4+/-11.1 years) than the first attack of uveitis (mean+/-SD, 34.0+/-14.1 years; P0.0001). The diagnosis of an extraocular disease was made only after the appearance of ophthalmic manifestations in 88 of 136 patients. Among 117 patients (66.9%) with more than 1 episode of uveitis, same eye attacks were observed in 48 of 117 patients (41.0%), more than the expected percentage than attacks of a random eye (P0.0001). The median +/- SD frequency of active episodes of uveitis was 0.8+/-0.6 per year and decreased as the duration of the disease lengthened (P0.0001). Patients with extraocular disease had a greater total number of attacks of uveitis (P = 0.02), but other ophthalmic findings did not differ between patients with and without an extraocular disorder.Uveitis is frequently the first indication of a previously undiagnosed HLA-B27-associated extraocular disease. The most common of these diseases are spondyloarthropathies.

During the last decade, articular ultrasonography (US) has been found effective in evaluating inflammatory, degenerative, and traumatic abnormalities of articular and periarticular tissues. In clinical practice, US used in combination with a thorough clinical evaluation can help rheumatologists to confirm or to refute diagnostic hypotheses. US is safer than computed tomography (CT), an advantage shared by magnetic resonance imaging (MRI). As compared to CT and MRI, US is less expensive; in addition, it can be performed immediately, for several joints, as often as needed. Furthermore, US allows dynamic studies. Several articles published in rheumatology journals emphasize the value of US in patients with musculoskeletal diseases. The present review article discusses the indications, efficacy, and limitations of articular US.

Background The use of propensity scores (PS) to balance covariates in the groups of treatment in order to address the indication bias in treatment effect evaluation in longitudinal studies, are more and more frequently used. However, no consensus exists regarding the selection of covariates to include in the PS. Objectives To compare two approaches for variable selection in the construction of a PS for TNF alpha blockers (TNFb) effectiveness assessment in a cohort of patients (pts) with inflammatory back pain (IBP). Methods Prospective, multi-centre cohort (DESIR). 708 pts with early IBP suggestive of ax-SpA. Data of the first 2 years of follow-up were included in this analysis. Statistical analysis: a) Exposure: receiving at least 1 TNFb during the first 2 years of follow-up. b) Outcome: ASAS40 response at the last available visit still on treatment (mean 74±30.9w). Data to assess such outcome was available in 197 pts c) Construction of 2 PS: PScomplete : logistic regression was calculated to predict exposure by including all covariates available at baseline visit (except for comorbidities) in the model. No variable selection (no univariate testing or correlation testing) was performed. PSselect : association of each covariate to the outcome was tested by univariate analysis, and only variables with a significant (p Results PScomplete included 52 variables. PSselect included only 9 variables. Variables selected in PSselect with a significant association with outcome were: gender ( p=0,0024 ), synovitis ( p=0.0297 ), uveitis ( p=0.0138 ), highest education level ( p=0.0859 ), BASGweek ( p=0.0174 ), disease activity (physician) ( p=0.0034 ), HLA-B27 ( p=0.0087 ), ESR (p ), CRP ( p=0.0002 ), Xray sacroiliitis ( p=0.0072 ) and MRI sacroiliitis ( p=0.0001 ); among these, some were highly correlated and were eliminated. The final PSselect model included 9 covariates: gender, synovitis, disease activity, highest level of education, uveitis, MRI sacroiliitis, X-ray sacroiliitis, CRP and HLAB27. Model comparison: Likelihood test p Conclusions Variable selection for construction of PS did not show any advantage compared to include all available covariates: the selective model failed to better fit data and the outcome estimation was comparable with either model. Furthermore in both cases, TNFb lead to a doubled chance of ASAS 40 response at 2 years. The effectiveness of TNFb may be sufficiently robust to “erase” methodological differences. Simulation studies should allow confirming our findings. Acknowledgements Anna Molto has been granted with a bursary from Societe Francais de Rhumatologie Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.2570

Background Radiographic sacroiliitis is an important outcome in SpA and is mandatory to establish a diagnosis of ankylosing spondylitis (AS). However, few data are available on the factors associated with radiographic sacroiliitis and even less on the predictors of progression from nonradiographic SpA to AS. Objectives To identify factors associated with radiographic sacroiliitis in a cross-sectional study and predictors of progression to AS in a longitudinal study of SpA patients with positive family history. Methods The studied cohort consisted of 1,358 patients fulfilling the ASAS criteria for SpA and having at least one first- or second-degree SpA-affected relative, who were recruited by the Groupe Francais d9Etude Genetique des Spondylarthrites (GFEGS) and followed longitudinally. Anteroposterior radiographs of the pelvis were examined blindly and independently by 2 qualified examiners (RSN, MB), using the modified New York grading system. Definite radiographic sacroiliitis corresponded to a grade ≥2 bilateral, or grade ≥3 unilateral. Association between definite radiographic sacroiliitis at inclusion and demographic and clinical variables was examined using univariate and multivariate regression analysis. Of the 448 cases without definite sacroiliitis at inclusion, 160 patients were followed-up (with new pelvic X-ray) for 2 to 15 years. Factors associated with progression to definite sacro-iliitis were only assessed by univariate regression analysis because of the smaller study sample. Results In multivariate analysis, factors positively associated with definite sacroiliitis at inclusion were male sex (p=7x10–8), younger age at disease onset (p=0.04), longer disease duration (p=0.0005), HLA-B27 positivity (p=0.02), inflammatory back pain (p=0.02) and uveitis (p=9.8x10–5). The only negatively associated factor was enthesitis (p=0.002). In longitudinal study, 38 of the 160 patients (23.75%) developed definite sacroiliitis after a mean follow-up duration of 8.8±3.0 years. The only baseline factor associated with progression to definite sacroiliitis throughout follow-up was a low grade radiographic sacroiliitis at inclusion (p=0.002). Uveitis and buttock pain occurring during the follow-up period were also associated with progression to definite sacro-iliitis (p=0.04 and p=0.05, respectively). Conclusions After an average follow-up duration of almost 9 years, 23.75% of the patients with non-radiographic SpA had developed definitive sacroiliitis (i.e. AS). Factors associated with definitive radiographic sacroiliitis were male sex, younger age at disease, longer disease duration, HLA-B27 positivity, inflammatory back pain, uveitis and lack of enthesitis in the baseline cross-sectional analysis, and low grade radiographic sacroiliitis at inclusion, uveitis and buttock pain during the follow-up in the longitudinal follow-up study. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2661

Background Local injections of corticosteroid represent a standard of care for epicondylitis, albeit it may adversely impair the healing process (1). Recently, local injections of growth factors-containing platelet-rich plasma (PRP) have been proposed as a new therapeutic technique, with the aim of boosting tendon repair (2). Ultrasound guidance of intra-tendinous injections seems to optimize the technical procedure (3). Objectives The main objective was to assess the efficacy of two local injections of PRP to treat epicondylitis of recent evolution. Methods A prospective double-blind placebo-controlled randomized trial was conducted during 2011-2012. Inclusion criteria were recent epicondylitis (pain≤3 months), confirmed by MRI and/or ultrasound and written informed consent. Exclusion criterion was previous corticosteroid infiltration. Two ultrasound-guided injections were performed at 4 weeks interval of either PRP (ACP®, Arthrex) or saline solution. Patients were monitored by an independent clinical evaluator blinded to the treatment at baseline, 1, 3, 6 and 12 months follow-up. The primary evaluation criterion was the relative improvement from baseline to 6 months in pain score (PS) on visual analog scale (0-10). Secondary criteria were the assessment of pain (yes/no) on isometric contraction of the second radial and of the extensor digitorum communis, the Roles-Maudsley score (1 to 4), the proportion of asymptomatic patients (PS ≤1) at 6 and 12 months follow-up and the proportion of patients with persistent pain (PS>2) at 12 months follow-up. Based on a sample size calculation, 21 patients in each group were needed. Results Fifty patients were included, 25 in each group, 34 men/16 women, mean age 47±9.2 years in the ACP group and 46.4±8.6 years in the control group. Six patients dropped out of the study between baseline and 6 months, 3 in each arm. At 6-month follow-up, no statistically significant difference was found between groups for mean relative improvement in pain (ACP: -63.2±22.4%, control: -69.7±25.1%, p=0.24). No statistically significant difference was found for the secondary criteria. In the two groups, the pain score decreased significantly between two consecutive visits from 6.8±0.8 (PRP) and 7±1 (control) at baseline to 2.5±1.6 (PRP) and 2.1±1.6 (control) at 6 months and 1.65±1.5 (PRP) and 1.8±2.1 (control) at 12 months. At 6-month, 34% of all patients were asymptomatic and 66% at 1-year. The proportion of patients with persistent pain at 12 months was 23.8% in both groups. No adverse-effect was observed. Conclusions The therapeutic effect of two ultrasound-guided ACP injections for epicondylitis of recent evolution (≤3 months) was not significantly superior to injections of saline, in a prospective randomized double-blind study with 12-months follow-up. The similarly favorable outcome registered in both study groups, may be linked to a stimulating role of ultrasound-guided intra-tendinous injections (“prolotherapy”) on the process of tendon repair. References Coombes BK et al., JAMA 2013 6; 309(5):461-9 Peerbooms JC et al., Am J Sports Med 2010;38(2):255-62 Chiavaras MM, Jacobson JA, Semin Musculoskelet Radiol 2013;17(1):85-90 Disclosure of Interest P. Le Goux: None declared, B. Montalvan: None declared, J. Leparc: None declared, S. Klouche: None declared, P. Hardy Grant/research support: Arthrex, M. Breban: None declared DOI 10.1136/annrheumdis-2014-eular.2480

Background and Objectives Ankylosing spondylitis (AS), a common inflammatory arthritis affecting primarily the spine and pelvis, is a highly heritable disease. In addition to HLA-B*27, 25 loci were associated with AS in populations of European ancestry in a recent international collaborative study, using the “Immunochip”. There is, however, well-known heterogeneity of allele frequencies across populations. We therefore re-examined this large dataset (10,619 patients and 15,145 controls) and focused on the Portuguese sample, asking whether alleles might be distinctly associated with AS in Portugal. Materials and Methods We extracted the data subset corresponding to 184 AS patients (according to the modified New York criteria) and 161 controls, all from mainland Portugal. Written informed consent was obtained from all subjects. Removal of outliers with Eigenstrat and quality control of genotyping data left 325 subjects (174 cases / 151 controls) genotyped with 119768 SNPs. Association analysis was performed using PLINK (v1.07). Results Apart from the MHC, there was no significant association at the genome-wide level (5 x 10 -8 ). However, 14 SNPs in 12 loci were associated with a nominal P -4 . The top-ranking SNP was in the inducible T-cell co-stimulator ligand (ICOSLG) gene (P = 7.56 x 10 -7 , OR = 5.014), previously associated in the whole consortium dataset. Other listed loci include USP34, an ubiquitin hydrolase that acts as regulator of the Wnt signalling pathway, CLEC16A, a member of the C-lectin type domain family, and several transcription factors or DNA-binding proteins. Conclusions Association of ICOSLG points to a potential alteration of the T-cell costimulation pathway in AS pathogenesis and warrants functional studies. Failure to replicate some of the loci associated in the whole consortium dataset likely results from our relatively small sample size. Conversely, new association findings will need confirmation in independent samples and may lead to population-specific genomic variants predisposing to AS.

Background Early reports have emphasised the efficacy of the anti-TNF-alpha monoclonal antibody, infliximab, to treat spondylarthropathy patients. Further studies are required to evaluate the extent of such efficacy in large subgroups of well-defined patients. Objectives To examine the effect of infliximab, in severe AS with predominant axial symptoms. Methods Patients suffering of severe AS, with evidence of systemic inflammation (modified New-York criteria; BASDAI > = 30/100; CRP > = 15 mg/l)), and without present peripheral arthritis or extraskelettal manifestation were included. Previous DMARD’s had to be discontinued for > = 3 months. Intake of NSAID had to be stable. Eligible patients received 3 infusions of infliximab (5 mg/kg, weeks 0, 2 and 6). Clinical and biological monitoring was planned for 6 months. Results We enrolled 48 parents (36 M/12 F; mean age = 36 ± 9 yr); 41/46 (89%) were HLA-B27+; 43 (90%) completed the treatment, as scheduled, whereas 5 received only 2 infusions. Interim result (wk 8) is shown, and compared to baseline in the table. Altogether, 44 patients (92%) were responders, as defined by a reduction of global pain on VAS of at least 20%, as compared to baseline level. Conclusion Our data confirm the remarkable efficacy of infliximab in AS. It indicate that most, patients suffering of inflammatory active AS promptly and dramatically respond to this treatment.

OBJECTIVE To study the concordance between abdominal scintigraphy using technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO)-labelled leucocytes (ASTLL) and ileocolonoscopy in patients with spondyloarthropathies (SpA) and without clinical evidence of inflammatory bowel disease (IBD). PATIENTS AND METHODS Fifteen patients with SpA (European Spondylarthropathy Study Group 1991 criteria) without clinical evidence of IBD were studied prospectively with ASTLL and ileocolonoscopy. RESULTS This cohort consisted of seven men and eight women aged 31.8+/-10.5 yr (18-47) [mean age +/- S.D. (range)] and with a disease duration of 6.0+/-4.4 yr (0.4-15). ASTLL showed abnormal uptake in four patients. Ileocolonoscopy was abnormal in five patients, showing acute inflammatory lesions in one patient with reactive arthritis, undifferentiated chronic inflammatory lesions in two cases, and features indistinguishable from those of Crohn's disease in two cases. ASTLL was negative in two cases in which ileocolonoscopy showed inflammatory lesions and was positive (terminal ileum) in one case with normal ileocolonoscopy. The concordance between the two examinations was statistically significant (kappa = 0.53; P = 0.008). CONCLUSION ASTLL may be an interesting tool to detect subclinical gut inflammation in patients with SpA.