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Most forms of arthritis, have a distinctive topographical pattern of joint involvement. Beyond these differences among diseases, there are also differences in phenotype and response to treatment between joints of the same type of arthritis, suggesting that molecular mechanisms may differ depending on joint location. Here we show that there are joint-specific molecular and tissue changes in the synovium and in local stromal cells (synovial fibroblasts;SF). The long non-coding RNA HOTAIR, expressed only in lower extremities SF, regulates much of this site-specific gene expression in SF. Downregulation of HOTAIR after TNF stimulation regulated relevant inflammatory pathways by epigenetic and transcriptional mechanisms and modified the migratory function of SF, decreased SF-mediated osteoclastogenesis, and increased the attraction of B cells by SF. Since site-specific expression of HOTAIR was also measured in the skin, spine and gastrointestinal tract, we propose HOTAIR as important epigenetic factor that modulates site-specific phenotypes of chronic inflammation.

To analyze the safety and effectiveness of abatacept (ABA) given in routine care to patients with systemic sclerosis (SSc).Retrospective multicenter observational study that enrolled patients with SSc treated with ABA. We collected epidemiological data and clinical outcomes. First, we analyzed the frequency of adverse effects. Secondly, we compared the evolution of different organ manifestations during ABA treatment. We collected data from 6 months before start of therapy to the last follow-up the following parameters: modified Rodnan Skin Score (mRSS), joints, lung and gastrointestinal involvement, concomitant medications, and laboratory tests.Data on twenty-seven patients with SSc were collected (93% females; 67% limited SSc). Rheumatoid arthritis was the most frequent concomitant autoimmune disease. ILD was present in 15 patients. Anti-Scl 70 antibodies were present in 13 patients and rheumatoid factor and ACPA antibodies were present in eight and seven patients respectively. The main indication to use abatacept was joint involvement (59%) followed by myositis (26%). A total of 16 adverse effects were reported in 28 months of abatacept treatment including five that required hospitalization. Most of them occurred in the first 3 months after starting abatacept. After 12 months, the number of tender and swollen joints decreased compared to baseline (p0.03 and p0.02 respectively). Moreover, a beneficial effect of abatacept on HAQ-DI at 3 and 6 months (p0.05) and on morning stiffness at 6 and 12 months (p0.03) was observed. We also observed a decrease in the modified Rodnan skin score (p0.05). No changes in lung or gastrointestinal involvement were found.ABA demonstrated a good safety profile and seems to have some effectiveness on joint involvement and related disability in SSc patients treated in routine care.

Polyarticular juvenile idiopathic arthritis (pJIA) is a subset of juvenile idiopathic arthritis (JIA), divided into two subtypes according to the presence of rheumatoid factor: pJIA without rheumatoid factor (pJIA RF-) and pJIA with positive rheumatoid factor (pJIA RF+), this latter is characterised with more structural damage. Anti-citrullinated peptide antibodies (ACPA) are often associated with RF. The respective performance of ACPA versus RF in structural outcome in pJIA, and in particular in adulthood pJIA remains unknown. Therefore, the aim of this study was to determine whether ACPA could be of value to assess structural damage in pJIA persisting in adulthood.Patients with pJIA and available data for ACPA, RF and X-ray were included retrospectively. Structural damage was assessed by two independent blinded investigators using Sharp Van Der Heijde scores.56 pJIA adult patients were included: 62% (35/56) had pJIA RF+ and 38% (21/56) pJIA RF-. ACPA positivity in pJIA was significantly associated with presence of RF (96% vs 26%, P0.001). RF positivity was significantly associated with higher Sharp van Der Heijde erosion and total scores (respectively P0.01 and P0.05). There were higher Sharp Van Der Heijde erosion, joint space narrowing and total scores in the pJIA ACPA+ subgroup than in the pJIA ACPA- subgroup, although there was no statistical significance. However, when adjusted on disease duration, pJIA ACPA+ patients had significantly higher erosion and total scores than pJIA ACPA- patients (P0.05), and pJIA ACPA+ patients required more bDMARDs than pJIA ACPA- patients (P0.05). Moreover, pJIA patients with high Sharp van Der Heijde joint space narrowing and total scores had significantly higher ACPA levels (P0.01). A correlation was identified between ACPA levels and Sharp van Der Heijde total score (r=0.54, P0.05). In the pJIA RF+ subgroup the presence of ACPA was associated with additional structural damage compared to no ACPA: sharp Van Der Heijde erosion, joint space narrowing and total scores were higher in the pJIA RF+ ACPA+ subgroup than in the pJIA RF+ ACPA- subgroup although these results did not reach significance.Our results suggest that pJIA RF+ ACPA+ adult patients may have a more severe articular phenotype than pJIA RF+ ACPA- patients. ACPA could bring an additional value to RF for pJIA patients regarding structural damage. Altogether our results show that RF and ACPA are associated with structural damage measured by Sharp Van Der Heijde score in pJIA persisting in adulthood.

Background: The current subclassification of systemic sclerosis into cutaneous subtypes does not fully capture the heterogeneity of the disease. We aimed to compare the performances of stratification into LeRoy's cutaneous subtypes versus stratification by autoantibody status in systemic sclerosis. Methods: For this cohort study, we assessed people with systemic sclerosis in the multicentre international European Scleroderma Trials and Research (EUSTAR) database. Individuals positive for systemic-sclerosis autoantibodies of two specificities were excluded, and remaining individuals were classified by cutaneous subtype, according to their systemic sclerosis-specific autoantibodies, or both. We assessed the performance of each model to predict overall survival, progression-free survival, disease progression, and different organ involvement. The three models were compared by use of the area under the curve (AUC) of the receiver operating characteristic and the net reclassification improvement (NRI). Missing data were imputed. Findings: We assessed the database on July 26, 2019. Of 16 939 patients assessed for eligibility, 10 711 patients were included: 1647 (15·4%) of 10 709 were male, 9062 (84·6%) were female, mean age was 54·4 (SD 13·8) years, and mean disease duration was 7·9 (SD 8·2) years. Information regarding cutaneous subtype was available for 10 176 participants and antibody data were available for 9643 participants. In the prognostic analysis, there was no difference in AUC for overall survival (0·82, 95% CI 0·81–0·84 for cutaneous only vs 0·84, 0·82–0·85 for antibody only vs 0·84, 0·83–0·86 for combined) or for progression-free survival (0·70, 0·69–0·71 vs 0·71, 0·70–0·72 vs 0·71, 0·70–0·72). However, at 4 years the NRI showed substantial improvement for the antibody-only model compared with the cutaneous-only model in prediction of overall survival (0·57, 0·46–0·71 for antibody only vs 0·29, 0·19–0·39 for cutaneous only) and disease progression (0·36, 0·29–0·46 vs 0·21, 0·14–0·28). The antibody-only model did better than the cutaneous-only model in predicting renal crisis (AUC 0·72, 0·70–0·74 for antibody only vs 0·66, 0·64–0·69 for cutaneous only) and lung fibrosis leading to restrictive lung function (AUC 0·76, 0·75–0·77 vs 0·71, 0·70–0·72). The combined model improved the prediction of digital ulcers and elevated systolic pulmonary artery pressure, but did poorly for cardiac involvement. Interpretation: The autoantibody-only model outperforms cutaneous-only subsetting for risk stratifying people with systemic sclerosis in the EUSTAR cohort. Physicians should be aware of these findings at the time of decision making for patient management. Funding: World Scleroderma Foundation.

ObjectivesTocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database.MethodsPatients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months.ResultsNinety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference −1.0, 95% CI −3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (−6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles.ConclusionAlthough this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population.

Objective To study the profile of type-2 diabetes (T2D) in patients with RA or OA. Methods This observational, multicentre, cross-sectional study included, over a 24-month period, consecutive patients with adult-onset diabetes and RA or OA. We collected demographics, disease activity and severity indices, current treatments for RA and diabetes, history and complications of diabetes. A systematic blood test was performed, assessing inflammatory, immunological and metabolic parameters. The homoeostasis model assessment (HOMA)2-S was used to assess insulin resistance. Results We included 167 patients with T2D, 118 with RA and 49 with OA. RA and OA patients had severe T2D with suboptimal metabolic control and a biological profile of insulin resistance. Insulin resistance was significantly higher in RA than in OA patients after stratification on age, BMI and CS use [HOMA2-S: 63.5 (35.6) vs 98.4 (69.2), P Conclusion RA patients display severe T2D with inflammation-associated insulin resistance. These findings may have therapeutic implications, with the potential targeting of insulin resistance through the treatment of joint and systemic inflammation.

Interstitial lung diseases (ILDs) are complex diseases with various courses where personalized medicine is highly expected. Biomarkers are indicators of physiological, pathological processes or of pharmacological response to therapeutic interventions. They can be used for diagnosis, risk-stratification, prediction and monitoring of treatment response. To better delineate the input and pitfalls of biomarkers in ILDs, we performed a systematic review and meta-analysis of literature in MEDLINE and Embase databases from January 1960 to February 2019. We focused on circulating biomarkers as having the highest generalizability. Overall, 70 studies were included in the review and 20 studies could be included in the meta-analysis. This review highlights that ILD associated with connective tissue diseases (CTD-ILD) and idiopathic pulmonary fibrosis (IPF) share common biomarkers, suggesting common pathophysiological pathways. KL-6 and SP-D, could diagnose lung fibrosis in both IPF and CTD-ILD, with KL-6 having the strongest value (OR: 520.95[110.07-2465.58], p0.001 in IPF and OR:26.43[7.15-97.68], p0.001 in CTD-ILD), followed by SPD (OR: 33.81[3.20-357.52], p = 0.003 in IPF and 13.24 [3.84-45.71] in SSc-ILD), MMP7 appeared as interesting for IPF diagnosis (p0.001), whereas in SSc, CCL18 was associated with ILD diagnosis. Both CCL18 and KL-6 were predictive for the outcomes of ILDs, with higher predictive values for CCL18 in both IPF (OR:10.22[4.72-22.16], p0.001 and in SSc [2.62[1.71-4.03], p0.001). However, disease specific biomarkers are lacking and large longitudinal studies are needed before the translational use of the potential biomarkers in clinical practice. With the recent availability of new effective therapies in ILDs, further studies should assess response to treatment.

International audience; Objective: To determine the performance of 3 circulating markers for the diagnosis and the progression of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA).Methods: Serum concentrations of 3 circulating markers, lung epithelial-derived surfactant protein D (SPD), chemokine CCL-18 and Krebs von den Lungen-6 glycoprotein (KL-6), were measured by ELISA in consecutive patients with established RA. These patients were recruited from 3 tertiary centers and they all had been investigated by chest high-resolution computed tomography (HRCT). For a subset of French patients, a follow-up HRCT was available (mean interval between HRCT: 3±1.5 years).Results: Among the 147 included patients (age: 66 ± 12 years, 69% women, disease duration 11 ± 10 years), 40 (27%) had RA-ILD on chest HRCT. SPD, CCL18 and KL-6 concentrations were significantly higher in patients with RA-ILD. ROC curve analysis to assess the diagnostic abilities of the three markers for the diagnosis of RA-ILD showed a superiority of KL-6 (Area under the curve, AUC: 0.79 95% CI 0.72-0.86) compared to SPD (AUC: 0.66 95% CI 0.58-0.74) and CCL18 (AUC: 0.62, 95% CI 0.53-0.70). The sensitivity of KL-6 for the diagnosis of RA-ILD was 68% with a specificity of 83%. The combination of KL-6 with SPD and CCL18 improved its diagnostic ability, with increased sensitivity from 68% to 77%, specificity from 83% to 97%. Increased KL-6 levels were independently associated with the presence of RA-ILD after the adjustment on other RA-ILD risk factors. In the French subset with longitudinal data, baseline KL-6 serum levels were predictive of ILD progression and the degree of ILD progression on HRCT was proportional to baseline KL-6 concentrations.Conclusion: These results show that KL-6 is a relevant circulating marker for the diagnosis and might be an interesting marker for the progression of RA-ILD.

Objective To investigate effectiveness of systematic switching treatment from innovator infliximab to biosimilar infliximab, and its associated factors. Methods In this prospective observational study, all adult patients receiving maintenance therapy with innovator infliximab in Cochin University Hospital were systematically switched to biosimilar infliximab. Effectiveness was assessed by the retention rate of biosimilar infliximab at the time of the third infusion. Sensitivity analyses for effectiveness included changes of disease activity parameters and infliximab trough levels between baseline and the last visit as well as the occurrence of adverse events leading to drug discontinuation. Factors associated with biosimilar infliximab discontinuation at the last visit were explored. Results 260 patients fulfilled the inclusion criteria, including 31 rheumatoid arthritis (RA), 131 axial spondyloarthritis (axSpA) and 64 inflammatory bowel diseases. The retention rate was 85% (221/260 patients) at the time of the third biosimilar infusion. Between baseline and the last visit (mean follow-up of 34 weeks), 59 patients (23%) discontinued biosimilar infliximab, mainly due to experienced inefficacy (n=47, 80%). No clinical or biological factors were associated with biosimilar discontinuation. No serious adverse events occurred. No change in objective disease activity parameters or infliximab trough levels was detected. However, a significant increase of BASDAI (2.94±2.20 vs. 3.18±2.21, p=0.046, before vs. after switch, respectively) was observed in patients with axSpA. Innovator infliximab was re-established in 47/59 patients (80%). Conclusion No changes in drug trough levels or objective parameters were observed after the systematic switch to biosimilar infliximab in a real clinical practice setting. Only changes in patient-reported outcomes were observed, suggesting attribution effects rather than pharmacological differences.

ObjectivesTo integrate published single-cell RNA sequencing (scRNA-seq) data and assess the contribution of synovial fibroblast (SF) subsets to synovial pathotypes and respective clinical characteristics in treatment-naïve early arthritis.MethodsIn this in silico study, we integrated scRNA-seq data from published studies with additional unpublished in-house data. Standard Seurat, Harmony and Liger workflow was performed for integration and differential gene expression analysis. We estimated single cell type proportions in bulk RNA-seq data (deconvolution) from synovial tissue from 87 treatment-naïve early arthritis patients in the Pathobiology of Early Arthritis Cohort using MuSiC. SF proportions across synovial pathotypes (fibroid, lymphoid and myeloid) and relationship of disease activity measurements across different synovial pathotypes were assessed.ResultsWe identified four SF clusters with respective marker genes: PRG4+ SF (CD55, MMP3, PRG4, THY1neg); CXCL12+ SF (CXCL12, CCL2, ADAMTS1, THY1low); POSTN+ SF (POSTN, collagen genes, THY1); CXCL14+ SF (CXCL14, C3, CD34, ASPN, THY1) that correspond to lining (PRG4+ SF) and sublining (CXCL12+ SF, POSTN+ + and CXCL14+ SF) SF subsets. CXCL12+ SF and POSTN+ + were most prominent in the fibroid while PRG4+ SF appeared highest in the myeloid pathotype. Corresponding, lining assessed by histology (assessed by Krenn-Score) was thicker in the myeloid, but also in the lymphoid pathotype + the fibroid pathotype. PRG4+ SF correlated positively with disease severity parameters in the fibroid, POSTN+ SF in the lymphoid pathotype whereas CXCL14+ SF showed negative association with disease severity in all pathotypes.ConclusionThis study shows a so far unexplored association between distinct synovial pathologies and SF subtypes defined by scRNA-seq. The knowledge of the diverse interplay of SF with immune cells will advance opportunities for tailored targeted treatments.

Background:Tocilizumab (TCZ) showed trends for improving skin fibrosis and prevented progression of lung fibrosis in patients with systemic sclerosis (SSc) in placebo-controlled randomised clinical trials (RCTs). However, safety and effectiveness of TCZ beyond these selected and enriched clinical trial populations in SSc is still unknown.Objectives:To assess safety and effectiveness of TCZ treatment compared to standard of care in SSc patients from the large, multicentre, observational, real-life EUSTAR network/database using propensity score matching.Methods:SSc patients from the EUSTAR network/database, who fulfilled the ACR/EULAR 2013 classification criteria, with a baseline and a follow-up visit at 12±3 months, receiving TCZ or standard of care (controls), were selected. The following variables were used for the propensity score matching (1:1): age at diagnosis, gender, disease subtype, baseline modified Rodnan skin score (mRSS), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO), co-therapy with immunosuppressives, disease duration, and year of treatment. Primary endpoints were mRSS and FVC at 12±3 months follow-up compared between the groups, using paired t-tests. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months follow-up according to standard definitions (1,2). Sensitivity analyses assessed pre-processing decisions (selection of most recent vs. random observation for control patients with multiple suitable time intervals), as well as the matching method (optimal vs. exact matching). Missing values were addressed with 100-fold multiple imputation using chained equations. Safety data were analysed in all patients. The study including the statistical analysis plan was pre-registered at www.drks.de (DRKS-ID: DRKS00015537).Results:We identified 93 SSc patients treated with TCZ and 2370 SSc patients with standard of care who fulfilled the inclusion criteria. Forty nine (57.7%) of the TCZ treated patients were diffuse, eight patients were not classified, disease duration was (mean±SD) 6.35±5.40 years, their baseline mRSS was 15.05±10.85, and 76 (81.7%) received immunosuppressive therapy in addition to TCZ.Through multiple imputation and propensity score matching, 100 imputed sets of 93 pairs of TCZ/controls were generated. Comparison between groups showed consistent effects of TCZ across all pre-defined primary and secondary endpoints: mRSS was lower in the TCZ group (mean difference (95% confidence interval (CI)) -1.8 (-4.79 to 1.19), p=0.24, Figure 1A). Similarly, FVC % predicted was higher in the TCZ group mean difference (2.25, 95% CI -4.57 to 9.06), p=0.51, Figure 1B). Considering secondary endpoints, the percentage of skin progressors as well as lung progressors at follow up was lower in the TCZ group (odds ratio OR 0.67 (95% CI 0.07 to 6.41), p=0.74 and OR 0.53 (95% CI 0.16 to 1.7); p=0.2, respectively. Consistently, the percentage of regressors for skin (OR 1.6 (95% CI 0.56 to 4.54), p=0.38) and for lung (OR 1.74 (95% CI 0.66 to 4.58), p=0.26) was higher in TCZ. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles.Conclusion:In this large, observational, controlled, real-life EUSTAR study, effectiveness of TCZ did not reach statistical significance compared to standard of care treatment but showed consistent positive effects of TCZ on skin and lung fibrosis across all pre-defined primary and secondary endpoints confirming data from recent RCTs.References:[1]Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis. Ann Rheum Dis 2016:1743-8.[2]Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis 2021:219-227.Disclosure of Interests:Simon Kuster: None declared, Suzana Jordan: None declared, Muriel Daniele Elhai: None declared, Ulrike Held: None declared, Klaus Steigmiller: None declared, Cosimo Bruni: None declared, Florenzo Iannone: None declared, Serena Vettori: None declared, Elise Siegert: None declared, Simona Rednic: None declared, Veronica Codullo: None declared, Paolo Airò Consultant of: Dr. Airo’ reports personal fees (consultancies) from Bristol Myers Squibb, Bohringer Ingelheim, non-financial support from CSL Behring, SOBI, Janssen, Roche, Sanofi, Pfizer, Yolanda Braun-Moscovici: None declared, Nicolas Hunzelmann: None declared, Maria Joao Salvador: None declared, Valeria Riccieri: None declared, Ana Maria Gheorghiu: None declared, Juan Jose Alegre Sancho: None declared, Katarzyna Romanowska-Prochnicka: None declared, Ivan Castellví: None declared, Ina Koetter: None declared, Marie-Elise Truchetet Consultant of: Marie-Elise Truchetet has had consultancy relationships and/or has received research funding from Boehringer Ingelheim, Genentech/Roche, and Sanofi in the area of potential treatments of scleroderma and its complications., Grant/research support from: Marie-Elise Truchetet has had consultancy relationships and/or has received research funding from Boehringer Ingelheim, Genentech/Roche, and Sanofi in the area of potential treatments of scleroderma and its complications., Francisco J López-Longo: None declared, Pavel Novikov: None declared, Alessandro Giollo: None declared, Yuichiro Shirai: None declared, Laura Belloli: None declared, Elisabetta Zanatta: None declared, Eric Hachulla: None declared, Vanessa Smith: None declared, Christopher Denton: None declared, Ruxandra Ionescu: None declared, Tim Schmeiser: None declared, Jörg H.W. Distler: None declared, Armando Gabrielli: None declared, Anna-Maria Hoffmann-Vold Consultant of: AMHV has received research funding and/or consulting fees and/or other remuneration from Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Grant/research support from: AMHV has received research funding and/or consulting fees and/or other remuneration from Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape. Masataka Kuwana: None declared, Yannick Allanore: None declared, Oliver Distler Speakers bureau: Oliver Distler has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Consultant of: Oliver Distler has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: The study was partially supported by a grant from Roche. Roche was not involved in analysis or interpretation of the results.

Background Different forms of chronic arthritis such as rheumatoid arthritis (RA) or spondyloarthritis show a typical pattern of joint involvement. However, mechanisms involved in this patterning remain unknown. Synovial fibroblasts (SF) isolated from different joint regions, differ in their epigenetic landscape, their gene expression and their function. The long non-coding RNA HOTAIR, which is an important regulator of the epigenetic landscape, was found to be exclusively expressed in joints of the lower extremity. Objectives We aim to clarify the role of HOTAIR in SF. Methods HOTAIR was silenced in knee SF isolated from patients with osteoarthritis (OA) by HOTAIR GapmeR using Lipofectamine, and changes in gene expression were measured by next generation RNA sequencing (Illumina NovaSeq 6000) after 48h (n=3). Pathway analysis was performed using STRING protein network, and regulated genes were confirmed by real-time PCR in SF silenced for HOTAIR from OA and RA-patients (n=8) and compared with control SF transfected with Antisense LNA GapmeR negative control. The time course of targeted genes was studied with and without cycloheximide (10ug/ml 6h and 24h) (n=2). To assess the effect of HOTAIR silencing on the canonical Wnt pathway, we employed the TOP/FOP reporter system using the dual-luciferase kit (n=3). Regulation of HOTAIR and targeted genes expression was studied after stimulation with TNF-α (n=17), IL1, LPS, TLR2, TLR4 and poly I:C (n=5). The expression of HOTAIR and TNF-α were measured in synovial tissue from RA-patients (n=7) by qPCR. Results STRING analysis identified among others three significantly enriched pathways, namely FGF, BMP and Wnt, including 19 genes differentially expressed between SF silenced for HOTAIR and controls according to p-value ( 2.5 or Conclusion Our study highlights three main pathways regulated by HOTAIR and involved in joint patterning: FGFR2/FGF7, BMP2 and LRP6/LGR5/GSK3β/beta-catenin (Wnt). These pathways are known to play a role in normal joint development, but are also involved in inflammation, proliferation and apoptosis. Consistently, we observed that HOTAIR and targeted genes were selectively down-regulated by TNF-α suggesting a role of HOTAIR in the joint specific regulation of TNF-α mediated inflammatory arthritis. Disclosure of Interests Muriel ELHAI: None declared, Mojca Frank-Bertoncelj : None declared, Kerstin Klein: None declared, Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders, Caroline Ospelt: None declared

Objective Digital ulcers (DU) are a burden in systemic sclerosis (SSc). Microangiopathy is a cardinal feature of SSc that plays a critical role in the development of DU. However, whether injury of medium or large vessels also contributes to DU in SSc remains controversial. Methods To measure concomitantly in SSc patients with and without active DU: (i) the Augmentation Index of the reflected wave (Aix_75) by radial applanation tonometry, an index of small and medium arterial function; (II) the aortic pulse wave velocity (PWV), a marker of large vessel injury (aortic stiffness). Results Sixty-three consecutive SSc patients were included (49 females, aged 60 [49–65] years, disease duration of 8.5 [5–13] years), including 10 (15.9%) with active DU. Patients with active DU versus those without had increased Aix_75 (35% [28–38] versus 28% [20–34], P = 0.041) whereas no difference existed in PWV (7.0 m/s [6.7–10.1] versus 7.6 m/s [6.8–8.7], P = 0.887), in systolic, diastolic, as well as aortic pulse pressure ( P = 0.126, 0.592, and 0.161, respectively). When compared to patients in the low tertile, patients having Aix_75 in the highest tertile had 10-fold more DU (OR = 10.23; 95% CI 1.12 to 93.34, P = 0.039). Conclusion The presence of DU is associated with increased Aix_75 whereas there is no relation with PWV. These data suggest that small and medium arteries are involved in the occurrence of DU whether large vessel stiffness does not contribute. Whether Aix_75 is predictive of further DU remained to be studied.

Background:Type-2 diabetes and rheumatoid arthritis (RA) are two chronic diseases characterized by tissue inflammation and insulin resistance. To date, no data have evaluated the influence of RA-induced joint and systemic inflammation on the course of type-2 diabetes.Objectives:To study the impact of RA on type-2 diabetesMethods:Observational, multicenter, cross-sectional usual-care study, including 7 rheumatology centers. This study included over a 24-month period consecutive patients with type-2 diabetes and RA, fulfilling the 2010 ACR / EULAR criteria, and diabetic controls with osteoarthritis (OA). The following data were collected: demographics, disease activity and severity indices, current treatment for RA and diabetes, history and complications of diabetes. A systematic blood test was performed, assessing inflammatory (CRP levels) and metabolic (fasting glycemia and insulin levels, HbA1c) parameters. The HOMA2%B (insulin secretion) and HOMA2%S (tissue insulin sensitivity) indices (HOMA calculator, © Diabetes Trials Unit, University of Oxford) were used to assess insulin resistance. Ra and OA patients were compared using parametric tests after adjusting for age and BMI. A multivariate logistic regression was performed ti identify factors independently associated with insulin resistance.Results:We included 122 RA patients (74% women, mean age 64+/-11 years, mean disease duration 15+/-11 11 years, 75% with positive ACPA antibodies and 64% with erosive disease) and 54 controls with OA. 64% of RA patients were treated with oral corticosteroids The characteristics of type-2 diabetes in the 54 OA patients corresponded to severe insulin-resistant diabetes: age> 65 years, high BMI> 30 kg/m2, mean HbA1c 7.3%+/-11 1.3%, 30% of insulin requirement, high frequency of other cardiovascular risk factors, macroangiopathy found in almost half of patients and biological criteria of insulin resistance (elevation of HOMA2%B and decrease of HOMA2%S).RA patients with type-2 diabetes had a younger age (64+/-11 years vs. 68+/-12 years, p=0.031) and lower BMI (27.7+/-11 5.5 vs. 31.5+/-11 6.3, pConclusion:RA patients with type-2 diabetes displayed severe, poorly controlled diabetes, highlighting the burden of comorbidities associated with RA. The clinical-biological profile of diabetic RA patients was severe insulin-resistant diabetes, with a biological profile of insulin resistance linked to the inflammatory activity of the disease. These findings may have therapeutic implications, with the potential targeting of insulin resistance through the treatment of joint and systemic inflammation.Acknowledgments:Société Française de Rhumatologie (research grant)Bristol Myers Squibb (research grant)Disclosure of Interests:Jérôme Avouac Grant/research support from: Pfizer, Bristol Myers Squibb, Consultant of: Sanofi, Bristol Myers Squibb, Abbvie, Boerhinger, Nordic Pharma, Speakers bureau: Sanofi, Bristol Myers Squibb Abbvie, MSD, Pfizer, Nordic Pharma, Muriel ELHAI: None declared, Marine Forien: None declared, Jérémie SELLAM: None declared, Florent Eymard Consultant of: Regenlab, Anna Moltó Grant/research support from: Pfizer, UCB, Consultant of: Abbvie, BMS, MSD, Novartis, Pfizer, UCB, Laure Gossec Grant/research support from: Lilly, Mylan, Pfizer, Sandoz, Consultant of: AbbVie, Amgen, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sandoz, Sanofi-Aventis, UCB, Frédéric Banal: None declared, Joel Daminano: None declared, Philippe Dieudé: None declared, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi

Background Few small-sized observational studies have suggested that rituximab might be a promising treatment in systemic sclerosis (SSc) Objectives To evaluate the outcomes of SSc-patients receiving in routine care Rituximab Methods Retrospective longitudinal multicenter observational study which included SSc-patients treated with rituximab upon the decision of their physician within the framework of EUSTAR. We interrogated the participating centres and EUSTAR database to determine epidemiological and clinical characteristics, the indication for initiating the treatment, and the following parameters at baseline and at the last visit under treatment: modified Rodnan Skin Score (mRSS), joint, lung and gastrointestinal involvements, treatment, laboratory tests and safety events. Results 248 patients were included: 70 (28%) men, mean age: 51±13 years, mean disease duration: 7±7 years; 150 (65%) had diffuse cutaneous-SSc, 54% were positive for anti-topoisomerase and 71% had lung fibrosis. Overlap disease was noticed in 62 patients (26%) including 23 with rheumatoid arthritis. The indication for the treatment was lung involvement (56%) followed by articular (42%) and skin involvements (30%). At baseline, 175 patients were treated with steroids and 132 with DMARDs. Mean follow-up was 2.4 (±1.9) years. In the whole sample, mRSS decreased from 15±11 to 10±8 (p For SSc-patients treated for lung with baseline FVC In the whole population, 45 patients could stop steroids and mean dose decreased from 10 mg to 7 mg in the other. During the follow-up, 78 (31%) patients had side effects including 35 (14%) with severe side effects leading to discontinuation of the treatment in 10%. Six deaths were recorded (1 heart failure, 1 sepsis, 2 respiratory insufficiencies, 2 sudden deaths). 76 patients had infection, requiring hospitalisation in 20 patients. Conclusions In this study, skin, lung and joint involvement appeared to improve under rituximab. Infections and other severe adverse events were frequently reported. A comparative study including control patients from EUSTAR centres is ongoing. Disclosure of Interest M. Elhai: None declared, O. Distler Grant/research support from: Actelion, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Sanofi, Sinoxa and UCB in the area of potential treatments of scleroderma and its complications, V. Smith : None declared, M. Matucci-Cerinic: None declared, J. J. Alegre-Sancho : None declared, M.-E. Truchetet: None declared, Y. Braun-Moscovici: None declared, F. Iannone: None declared, F. Chotchaeva: None declared, A. Lescoat : None declared, E. Siegert : None declared, I. Castellvi: None declared, P. Airo : None declared, S. Vettori: None declared, E. Hachulla: None declared, A. Erler : None declared, L. Ananieva : None declared, M. Krusche: None declared, F. Lopez-Longo : None declared, J. Distler : None declared, N. Hunzelmann : None declared, A.-M. Hoffmann-Vold : None declared, V. Riccieri: None declared, V. Hsu: None declared, M. Pozzi: None declared, C. Ancuta : None declared, E. Rosato : None declared, C. Mihai: None declared, M. Kuwana: None declared, Y. Allanore Grant/research support from: Actelion, Bayer, Boehringer Ingelheim, ChemomAb, Genentech/Roche, Inventiva, Pfizer, Sanofi, Servier, in the area of potential treatments of scleroderma and its complications.

Background Neoangiogenesis is a crucial event to promote the development of the hyperplasic proliferative pathologic synovium in Rheumatoid arthritis (RA). Ultrasound (US) is sensitive for detection of power Doppler (PD) vascularisation. Objectives To explore the associations between a set of complementary circulating angiogenic markers reflecting different angiogenic processes and a comprehensive US assessment in patients with RA. Methods Serum levels of eight angiogenic markers (Vascular Endothelial Growth Factor (VEGF), Placenta Growth Factor (PlGF), Tie-2, Angiopoietin-1, soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), Interleukin-8 (IL-8, CXCL8), CYR61 (CCN1) and Angiostatin), reflecting endothelial cell activation, proliferation, survival, growth and migration, as well as vessel maturation and stabilisation, were measured by quantitative ELISAs in a total of 125 patients with RA, who were all systematically assessed in parallel by PDUS, performed on 32 joints. Results Synovitis was detected in 84 patients with RA (67.2%). Among these patients, 53 patients (42.4%) had positive Doppler signal, including 31 with moderate to marked hyperemia. Serum levels of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) (808±293 ng/mL vs. 697±240 ng/mL, p=0.022) and Tie-2 (16.2±7.5 ng/mL vs. 13.8±4.9 ng/mL, p=0.038), were more likely to be increased in patients with synovial hyperemia detected on at least one joint (Power Doppler grade ≥1). sVCAM-1, Tie-2 and Angiostatin concentrations gradually increased together with the grade of the semiquantitative PDUS scale (figure 1A-C) and concentrations of these three markers were markedly increased in patients with moderate to marked hyperemia (Power Doppler grade 2 and 3). Levels of sVCAM-1 (r=0.20, p=0.028), Tie-2 (r=0.28, p=0.001), and Angiostatin (r=0.25, p=0.006) correlated with a global arthritis sum score, defined by the sum of the semiquantitative PDUS scores for all joints examined. Among the 81 patients with a DAS28-CRP≤3.2, 22 patients had synovial hyperemia detected on at least one joint (Power Doppler grade 1 in 13 patients, grade 2 in 6 patients and grade 3 in 3 patients). Patients with synovial hyperemia on at least one joint were more likely to have significantly increased levels of PlGF (18.9±11.2 pg/mL vs. 13.1±9.5 pg/mL, p=0.022) and Tie-2 (15.7±5.8 ng/mL vs. 12.6±3.4 ng/mL, p=0.004) than patients with absence of synovial hyperemia. Conclusions Serum levels of the angiogenic markers Tie-2, sVCAM-1 and Angiostatin were strongly associated with synovial vascularisation and inflammation assessed by PDUS among patients with established RA. Moreover, Tie-2 and PlGF were associated with persistent disease activity in RA patients in mow disease activity. These findings suggest that it may possible to find surrogate serum angiogenic biomarkers of active synovitis that might replace PDUS examination, in case of further confirmation of their pertinence. Disclosure of Interest A. Leblond: None declared, S. Pezet: None declared, A. P. Trouvin: None declared, M. Elhai: None declared, V. Gonzalez: None declared, Y. Allanore Grant/research support from: Pfizer, J. Avouac: None declared

Objective Interstitial lung disease (ILD ) in systemic sclerosis (SS c) runs a highly variable course, and prediction tools are highly desired. The aim of this study was to assess the diagnostic and prognostic performance of 4 candidate serum biomarkers for SS c‐associated ILD . Methods Serum samples from a combined cohort of SS c patients (from Paris, France and Oslo, Norway; n = 427) were analyzed by enzyme‐linked immunosorbent assay for concentrations of lung epithelial–derived surfactant protein D (SP ‐D), Krebs von den Lungen 6 glycoprotein (KL ‐6), CCL 18, and OX 40 ligand (OX 40L). Lung fibrosis was measured by high‐resolution computed tomography and pulmonary function tests. Associations of these candidate biomarkers with baseline disease involvement and prediction of disease progression over time (mean ± SD follow‐up 3.2 ± 4.4 years) were investigated. Results In SS c patients at baseline, serum levels of KL ‐6 correlated with the forced vital capacity (FVC ) (r = −0.317, P < 0.001), diffusing capacity for carbon monoxide (r = −0.335, P < 0.001), and extent of lung fibrosis (r = 0.551, P < 0.001). In multivariate analyses, serum levels of KL ‐6 and SP ‐D, but not CCL 18 and OX 40L, were associated with lung fibrosis (odds ratio [OR ] 2.41, 95% confidence interval [95% CI ] 1.43–4.07 [P = 0.001] and OR 3.15, 95% CI 1.81–5.48 [P < 0.001], respectively). In SS c patients with ILD at baseline, longitudinal, multivariate analyses showed that CCL 18 serum levels were an independent predictor of a >10% decrease in the FVC (hazard ratio [HR ] 2.90, 95% CI 1.25–6.73; P = 0.014) and de novo development of extensive disease (HR 3.71, 95% CI 1.02–13.52; P = 0.048). Matrix‐based logistic regression models for the diagnosis and prognosis of SS c‐associated ILD were constructed, and these models discriminated 3 groups of risk (mild, moderate, or high) for the diagnosis or worsening of lung fibrosis according to the serum levels of SP ‐D (for diagnosis) and serum levels of CCL 18 (for progression of disease). Conclusion These results show that SP ‐D is a relevant diagnostic biomarker for SS c‐associated ILD , whereas KL ‐6 could be used to assess the severity of lung fibrosis. CCL 18 appears to be a potential predictive marker for progression of ILD in SS c.

Resume La sclerodermie systemique est une maladie orpheline faisant partie du groupe des connectivites. Elle est caracterisee par des anomalies de la microcirculation, des desordres du systeme immunologique et des depots massifs de collagene et d’autres composants de la matrice extracellulaire dans la peau et dans les organes. Un progres majeur des annees recentes reside dans la validation de nouveaux criteres de classification permettant un diagnostic et un traitement plus precoces, a un stade precedant la fibrose irreversible et les atteintes viscerales (« fenetre d’opportunite »). Le phenomene de Raynaud, qui est habituellement le premier signe de la maladie, est considere comme le principal signe d’appel pour identifier les formes tres precoces de sclerodermie systemique. La sclerodermie systemique est cliniquement heterogene et son pronostic reste imprevisible. Il depend de l’atteinte cardiopulmonaire et des etudes recentes ont tente d’identifier des facteurs biologiques ou genetiques predictifs de la severite de l’atteinte viscerale. De plus, le suivi prospectif de grandes cohortes de patients a permis et permettra encore de degager des facteurs pronostiques puissants. Si l’evolution des manifestations vasculaires a ete recemment amelioree par des traitements cibles, des donnees recentes montrent que la mortalite n’a pas ete modifiee au cours des 40 dernieres annees. Ceci traduit l’inefficacite des traitements actuels a eviter le processus de fibrose. Neanmoins, plusieurs traitements biologiques ayant une efficacite prouvee dans d’autres pathologies immunologiques sont sur le point d’etre etudies dans la sclerodermie systemique. Des resultats prometteurs ont ete rapportes dans des etudes ouvertes de faibles effectifs. Cette mise au point presente les progres recents concernant les criteres de classification, la physiopathologie, les atteintes viscerales, le pronostic et les traitements actuels et futurs de la sclerodermie systemique.

Background Neoangiogenesis is a crucial event to promote the development of the hyperplasic proliferative pathologic synovium in Rheumatoid arthritis (RA). Ultrasound (US) is sensitive for detection of power Doppler (PD) vascularization. Objective To explore the associations between a set of complementary circulating angiogenic markers and a comprehensive US assessment in patients with RA. Patients and methods Serum levels of eight angiogenic markers were measured by quantitative ELISAs in a total of 125 patients with RA, who were all systematically assessed in parallel by PDUS, performed on 32 joints. Results Serum levels of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) and Tie-2 were more likely to be increased in patients with synovial hyperemia detected on at least one joint (Power Doppler grade ≥1). sVCAM-1, Tie-2 and Angiostatin concentrations gradually increased together with the grade of the semiquantitative PDUS scale and concentrations of these three markers were markedly increased in patients with moderate to marked hyperemia (Power Doppler grade 2 and 3). Levels of sVCAM-1, Tie-2, and Angiostatin correlated with a global arthritis sum score, defined by the sum of the semiquantitative PDUS scores for all joints examined. Levels of Tie-2 and Placenta Growth Factor (PlGF) were associated with PDUS features indicating residual disease activity. Conclusion Our results support the relevance of measuring serum levels of vascular markers to evaluate the intensity and extent of synovial vascularization. Angiogenic markers, and particularly Tie-2, could be a valuable surrogate of active synovitis and their place in relation to PDUS in clinical practice deserve further investigation.

To assess the cumulative incidence of uveitis in spondyloarthritis (SpA) and its associated factors and to evaluate the effect of DMARD treatment on uveitis in a real-life setting.A cross-sectional monocentric observational study (COSPA) was conducted. Patients with definite SpA underwent a face-to-face interview. General data and specific data concerning uveitis were collected. Cumulative incidence of uveitis flares was estimated by Kaplan-Meier survival curves. Factors associated with uveitis were determined by Cox analysis. Treatment effectiveness was evaluated by comparing the number of uveitis flares before/after treatment using Wilcoxon test.In total, 301 patients were included, 186 (61.8%) were men, with mean age and disease duration of 44.8 (±13.6) and 16.8 (±11.9) years, respectively. Among them, 82 (27.2%) had at least one uveitis flare. Prevalence of uveitis at the time of SpA diagnosis was 11.5 % (±1.9%) and increased over time to reach 39.3% (±4.1%) 20 years after diagnosis. HLA B27 positivity and heel pain were independently associated with uveitis (HR [IC 95%] = 4.5 [1.3-15.2] and 1.8 [1.1-2.9], respectively). A significant reduction in the number of uveitis before/after treatment was observed in patients treated with anti TNF monoclonal antibodies (n=27), (1.83 (±4.03) vs. 0.41 (±1.22), p=0.002), whereas it was not with etanercept (n=19), (0.44 (±0.70) and 0.79 (±1.36), p=NS).Prevalence of uveitis in SpA seems to increase with disease duration and seems more likely to appear with HLA B27 positivity and heel pain. Anti-TNF monoclonal antibodies seemed to be more effective in the reduction of uveitis flares.

To elucidate the role of gene candidates involved in pulmonary hypertension (PH) associated with systemic sclerosis (SSc).Gene candidates were identified through microarray experiments performed on Affymetrix GeneChip Human Exon 1.0 ST arrays in endothelial progenitor cell (EPC)-derived endothelial cells (ECs) obtained from patients with SSc-associated PH, patients with SSc without PH, and healthy control subjects. Expression of identified gene candidates was assessed by quantitative sandwich enzyme-linked immunosorbent assay in the serum, and by immunohistochemistry in lesional lung tissue. The functional importance of the identified gene candidates was then evaluated in fos-related antigen 2-transgenic (Fra-2-Tg) mice that spontaneously develop SSc-like features associated with an intense pulmonary vascular remodeling.Microarray experiments revealed that the matrix metalloproteinase 10 (MMP-10) gene was the top up-regulated gene in SSc-associated PH EPC-derived ECs. Circulating serum proMMP10 concentrations were markedly increased in patients with SSc-associated PH compared to SSc patients without PH and healthy controls. Consistent with these observations, a strong MMP10 staining of the thickened wall of distal pulmonary arteries was found both in the lungs of patients with SSc-associated PH and in the lungs of Fra-2-Tg mice. Daily treatment of Fra-2-Tg mice with neutralizing anti-MMP10 antibodies did not significantly affect the development and severity of pulmonary fibrosis, but did reverse established PH and markedly reduced pulmonary vascular remodeling by reducing cell proliferation, cell survival, and the platelet-derived growth factor signaling axis.Gene expression profiling of EPC-derived ECs identified MMP10 as a novel candidate gene in SSc-associated PH. MMP10 is overexpressed in the serum and pulmonary arteries of patients with SSc-associated PH, and its blockade alleviates PH in the Fra-2-Tg mouse model. MMP10 appears to be a prospective treatment target for this devastating disorder.

Objectives Several epidemiological studies have revealed the co-occurrence of other autoimmune diseases (AIDs) within patients with systemic sclerosis (SSc). However, some of these studies were based on small cohorts and wide ranges of prevalence have been reported. Therefore to overcome these limitations of individual studies, we sought to perform a meta-analysis to determine the accurate prevalence of polyautoimmunity in SSc. Methods We performed a systematic review and a meta-analysis of literature in MEDLINE and Embase databases from January 1960 to March 2013. All cohort studies reporting on prevalence of other AIDs known to be associated with SSc were analyzed. Prevalence of polyautoimmunity and of each AID were then calculated. Results Ten studies reporting polyautoimmunity were identified corresponding to a total of 6102 SSc patients. Overall 1432 patients with at least one AID were identified corresponding to a weighted prevalence of polyautoimmunity equal to 25.7% CI 95% [20.1%–31.6%]. Overall 208/5139 SSc-patients had at least two additional AIDs resulting in a weighted prevalence of 3.9% [3.3%–4.4%]. The most prevalent associated AIDs were autoimmune thyroid disease (10.4%) followed by Sjogren's syndrome (7.7%) and dermatopolymyositis/polymyositis (5.6%). Conclusion Our results confirm that SSc polyautoimmunity is a frequent condition in SSc affecting a quarter of SSc-patients. The impact on the phenotype and also on the management and therapy will need to be addressed now in further works.

ObjectivesTo determine the causes of death and risk factors in systemic sclerosis (SSc).MethodsBetween 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation.ResultsWe identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile.ConclusionCombining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.

Objective.Radiographic damage was recently identified as a feature of poor prognosis in polyarticular juvenile idiopathic arthritis (pJIA). However, most radiographic studies did not differentiate pJIA from other subtypes of JIA and little is known about pJIA persisting into adulthood. We describe radiological peripheral involvement in young adults with pJIA compared to patients with rheumatoid arthritis (RA).Methods.All consecutive patients with pJIA followed in a transition program were included. Age, sex, disease duration, and medical or surgical treatment information was collected. Laboratory tests and standard radiographs of the hands and wrists, feet, and hips were analyzed by 2 independent radiologists blinded to the diagnosis. One RA control group (age < 55 yrs), matched for sex and disease duration, was recruited.Results.Forty-three patients with pJIA and 59 with RA were included. Radiographs showed hand lesions in 79% of pJIA and 86% of patients with RA, feet lesions in 74% of pJIA and 80% of patients with RA, and hip damage in 35% of pJIA and 17% of patients with RA (p = nonsignificant). Specific to the juvenile forms were lower frequency of proximal interphalangeal joint involvement (51% vs 76%; p = 0.03) and higher risk of bilateral hip damage (86% vs 25%; p < 0.01) than in adult RA.Conclusion.Structural peripheral damage is as common and as severe in young adults with pJIA as in adults with RA. The main specific feature of pJIA seems to be a high risk of bilateral hip damage. This requires a particular monitoring of pJIA patients with unilateral hip involvement to detect bilateralization.

Vasculopathy, immunological abnormalities, and fibrosis are the key features in the pathogenesis of systemic sclerosis (SSc). Expression of each of the three pathologic features varies among SSc patients leading to disease heterogeneity and variable organ manifestations. Although the etiology of SSc has not yet been fully elucidated, a growing body of evidence suggests that extracellular matrix overproduction by activated fibroblasts results from a complex interplay between endothelial cells, immune cells and fibroblasts through cell-cell and cell-matrix interactions and communications. Relevant animal models are essential tools to in-depth investigate pathogenesis of SSc. Several murine and avian models are available; however, some models display inflammation followed by fibrosis, whether some others primarily mimic autonomous fibroblast activation. In addition, typical microvascular changes of SSc are only observed in few models. Therefore, none of these animal models encompasses all features of the human disease and a critical selection is mandatory for successful in vivo studies. Hence, we will provide an overview of the most important experimental models of dermal fibrosis and SSc and discuss their respective contribution to the better understanding of SSc pathogenesis.

Resume Les atteintes vasculaires, les anomalies immunologiques et les fibroses sont les elements cles de la pathogenese de la sclerodermie generalisee (ScG). L’expression de chacun de ces trois types de pathologies varie parmi les patients atteints de ScG entrainant une heterogeneite de la maladie et des manifestations a differents organes. Meme si l’etiologie de la ScG n’a pas encore ete tres bien elucidee, un nombre croissant de preuves suggere que la surproduction de matrice extracellulaire par des fibroblastes actives est due a une combinaison complexe entre les cellules endotheliales, les cellules immunitaires et les fibroblastes grâce a des interactions et des communications de cellule a cellule et de cellule a matrice. Des modeles animaux pertinents sont des outils indispensables a la recherche approfondie de la pathogenese de la ScG. Plusieurs modeles murin, et aviaire, sont disponibles ; cependant, certains modeles montrent une inflammation suivie d’une fibrose, alors que d’autres imitent essentiellement l’activation autonome des fibroblastes. De plus, des modifications microvasculaires typiques de la ScG sont seulement observees chez quelques modeles. Par consequent, aucun de ces modeles animaux ne regroupe toutes les caracteristiques de la maladie humaine et une selection rigoureuse est obligatoire pour reussir les etudes in vivo. Ainsi, nous apporterons une vue globale des plus importants modeles experimentaux de fibrose cutanee et de ScG et discuterons leur contribution respective a une meilleure comprehension de la pathogenese de la ScG.

Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40-OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation.

Objectives Anterior chest wall pain is a common but little studied feature of spondyloarthritis. The objectives of our study were to assess the prevalence of anterior chest wall pain and to describe its clinical characteristics in a cohort of spondyloarthritis patients in a tertiary care center. Methods Study design: retrolective single center observational study in 2010 (COSPA). Consecutive patients with definite spondyloarthritis according to Amor's criteria were included. Data collection: each patient underwent direct interview by a physician. Prevalence of anterior chest wall pain, according to spondyloarthritis subtype and its date of appearance, localization and nature were collected. Results In all, 275 consecutive spondyloarthritis patients were assessed. Among them, 102 patients (37.1%) suffered from spondyloarthritis-associated anterior chest wall pain. It was the first symptom of spondyloarthritis in 3.6% of cases. The prevalence after 5 and 10 years following the diagnosis of spondyloarthritis was 26.0% and 35.5%, respectively. Pain was usually in the upper chest and acute, increased by respiratory movements and movements of the arm; pain during the night was less frequent (41.0%). A flare lasted on average 5 weeks; recurrences were frequent (75%). Non-steroidal anti-inflammatory drugs and anti-tumor necrosis factor agents were reported as effective in 49.3% and 80.0% of cases, respectively. Conclusion Anterior chest wall pain was a frequent manifestation in spondyloarthritis. It occurred early in the disease course, but the risk persisted after disease onset. Better knowledge of the clinical characteristics of this symptom may help physicians for diagnosis and follow-up.

Resume Objectifs Les douleurs de la paroi anterieure du thorax sont un symptome frequent de la spondylarthrite, mais peu etudie. Les objectifs de notre etude etaient d’estimer la prevalence de ce type de douleur et d’en decrire les caracteristiques cliniques au sein d’une cohorte de patients spondylarthritiques suivis dans un centre de soins tertiaires. Methodes Schema de l’etude : etude observationnelle retrolective monocentrique realisee en 2010 (COSPA). Des patients atteints de spondylarthrite averee selon les criteres Amor ont ete inclus de facon consecutive. Collecte des donnees : Chaque patient a ete interviewe directement par un medecin. Des donnees ont ete recueillies sur la frequence des douleurs thoraciques anterieures, en fonction du sous-type de spondylarthrite et de leur date de survenue, ainsi que sur la localisation et la nature des douleurs. Resultats Un total de 275 patients spondylarthritiques consecutifs ont ete evalues. Parmi eux, 102 patients (37,1 %) souffraient de douleurs de la paroi anterieure du thorax associees a la spondylarthrite. Il s’agissait du premier symptome de la spondylarthrite dans 3,6 % des cas. La prevalence dans les cinq et dix ans suivant le diagnostic de spondylarthrite etait respectivement de 26,0 et 35,5 %. La douleur se situait generalement au niveau du thorax superieur et elle etait aigue, augmentee par les mouvements respiratoires et les mouvements du bras ; la presence de douleurs nocturnes etait moins frequente (41,0 %). Une poussee durait en moyenne cinq semaines ; les recidives etaient frequentes (75 %). Les traitements par anti-inflammatoires non-steroidiens et anti-TNF ont ete rapportes comme etant efficaces respectivement dans 49,3 et 80,0 % des cas. Conclusion La douleur de la paroi anterieure du thorax s’est revelee etre une manifestation frequente lors de la spondylarthrite. Elle survient de facon precoce dans le cours de la maladie, mais le risque persiste apres le debut de la maladie. Une meilleure connaissance des caracteristiques cliniques de ce symptome pourrait aider les medecins dans le diagnostic et le suivi.

Objective.To evaluate the performance of the Assessment in Spondyloarthritis International Society (ASAS) criteria (axial or peripheral) against the Amor and European Spondylarthropathy Study Group criteria in established spondyloarthritis (SpA).Methods.Rheumatologist-diagnosed patients with SpA were retrospectively classified according to the different criteria sets. Clinical characteristics of patients fulfilling all 3 criteria were compared with those who did not, by nonparametric statistics.Results.ASAS classified 90% of the 231 patients, with 169 (73%) fulfilling all 3 criteria sets. Multivariate analysis showed the 62 patients not fulfilling all criteria sets were older at symptom onset (p < 0.001) and less likely to have inflammatory back pain (p < 0.001), peripheral arthritis (p < 0.001), or elevated C-reactive protein levels (p = 0.034).Conclusion.ASAS criteria can be used in established disease.

Resume Nous rapportons l’observation d’une patiente de 38 ans hospitalisee dans notre service pour le bilan de lesions osteolytiques. Elle presentait des douleurs dorsolombaires et costales apparues dans les suites du diagnostic d’une hyperthyroidie sur goitre multi-heteronodulaire toxique. Les douleurs ont persiste malgre un traitement chirurgical du goitre. L’examen clinique retrouvait des taches cutanees « cafe au lait ». Le bilan phosphocalcique a mis en evidence un diabete phosphate. Les radiographies montraient des lesions lytiques costales ainsi que des fractures vertebrales dorsales. Au scanner, presence de multiples lesions touchant le rachis, les cotes, le sternum, les ailes iliaques et le sacrum avec un aspect typique en verre depoli. Le diagnostic de syndrome de McCune-Albright a ete porte devant cette triade caracteristique. Le traitement a consiste en une supplementation en vitamine D ainsi qu’en de fortes doses de phosphore et de 1–25 OH vitamine D3 pour le diabete phosphate ; un traitement par bisphosphonates intraveineux a ete introduit pour la prise en charge des douleurs osseuses. Nous rapportons une observation inhabituelle de syndrome de McCune-Albright revele tardivement dans les suites d’une hyperthyroidie. Nous pensons que les lesions de dysplasie fibreuse sont devenues symptomatiques du fait de l’hyper remodelage osseux lie a l’hyperthyroidie.

Objective. SSc is known as the most severe connective tissue disorder, and to be associated with a high mortality risk. Some improvements in therapy for SSc have been achieved in recent years and some preliminary data have suggested an improvement in patient survival. Thus, we set out to determine whether mortality rate in SSc patients has decreased over the past 40 years through a meta-analysis of cohort studies. Methods. We performed a systematic review and a meta-analysis of literature in MEDLINE and Embase databases from January 1960 to June 2010. All cohort studies reporting on SSc mortality were analysed. We then calculated pooled standardized mortality ratios (SMRs) of SSc mortality and calculated their changes over time using meta-regression analysis. Results. Nine studies were included, corresponding to a total of 2691 SSc patients. The pooled SMR was 3.53 [95% CI 3.03, 4.11, P < 0.0001; I 2 = 93%, P(het) = 0.001]. Mid-cohort year ranged from 1977 to 1995 (before 1980: two studies; 198090: five studies; and after 1990: two studies): adjusted meta-regression analysis did not show significant change in SMR over time (P = 0.523). Among 732 deaths, heart involvement was the most frequent cause of deaths (29%) followed by lung involvement. Conclusion. Our results confirm that SSc is a devastating condition as reflected by a pooled SMR of 3.5. Additionally, SMR has not significantly changed over the past 40 years. Further studies are needed to assess the effect of the most recent available therapies on mortality in SSc.

Objective Activated T cells are the main component of the inflammatory skin infiltrates that characterise systemic sclerosis (SSc). Our aim was to investigate the efficacy of abatacept, which tempers T-cell activation, in reducing skin fibrosis in complementary mouse models of SSc. Methods The antifibrotic properties of abatacept were evaluated in the mouse models of bleomycin-induced dermal fibrosis and sclerodermatous chronic graft-versus-host disease, reflecting early and inflammatory stages of SSc. Thereafter, we studied the efficacy of abatacept in tight skin (Tsk-1) mice, an inflammation-independent mouse model of skin fibrosis. Results Abatacept efficiently prevented bleomycin-induced skin fibrosis and was also effective in the treatment of established fibrosis. In this model, abatacept decreased total and activated T-cell, B-cell and monocyte infiltration in the lesional skin. Abatacept did not protect CB17-SCID mice from the development of bleomycin-induced dermal fibrosis, which supports that T cells are necessary to drive the antifibrotic effects of abatacept. Upon bleomycin injections, skin interleukin (IL) 6 and IL-10 levels were significantly reduced upon abatacept treatment. Moreover, treatment with abatacept ameliorated fibrosis in the chronic graft-versus-host disease model, but demonstrated no efficacy in Tsk-1 mice. The tolerance of abatacept was excellent in the three mouse models. Conclusions Using complementary models, we demonstrate that inhibition of T-cell activation by abatacept can prevent and induce the regression of inflammation-driven dermal fibrosis. Translation to human disease is now required, and targeting early and inflammatory stages of SSc sounds the most appropriate for positioning abatacept in SSc.

International audience; Systemic sclerosis (SSc) is a connective tissue disorder characterised by the development of skin fibrosis. Our current understanding of the disease pathogenesis is incomplete and the study of SSc is hindered, at least partially, by a lack of animal models that fully replicate the complex state of human disease. Murine model of bleomycin-induced dermal fibrosis encapsulates important events that take place early in the disease course.METHODS:To characterise the optimum in vivo parameters required for the successful induction of dermal fibrosis we subjected three commonly used mouse strains to repeated subcutaneous bleomycin injections. We aimed to identify the effects of genetic background and gender on the severity of skin fibrosis. We used male and female Balb/C, C57BL/6, and DBA/2 strains and assessed their susceptibility to bleomycin-induced fibrosis by measuring dermal thickness, hydroxyproline/collagen content and number of resident myofibroblasts, all of which are important indicators of the severity of skin fibrosis. All data are expressed as mean values ± SEM. The Mann-Whitney U test was used for statistical analysis with GraphPad Prism 6.04 software.RESULTS:Dermal fibrosis was most severe in Balb/C mice compared to C57BL/6 and DBA/2 suggesting that Balb/C mice are more susceptible to bleomycin-induced fibrosis. Analysis of the effect of gender on the severity of fibrosis showed that male Balb/C, C57BL/6, DBA/2 mice had a tendency to develop more pronounced fibrosis phenotype than female mice. Of potential importance, male Balb/C mice developed the most severe fibrosis phenotype compared to male C57BL/6 and male DBA/2 as indicated by significantly increased number of dermal myofibroblasts.CONCLUSION:Our study highlights the importance of genetic background and gender in the induction of murine dermal fibrosis. Robust and reproducible animal models of fibrosis are important research tools used in pharmacological studies which may lead to better understanding of the pathogenesis of fibrotic diseases and assist in identification of new drugs.

To assess the prevalence of psoriasis among a cohort of patients with spondyloarthritis (SpA), to describe the clinical characteristics of psoriasis and associations with other manifestations.This is a retrospective single-centre observational study. The patients were diagnosed with definite SpA (expert opinion), either axial or peripheral. Each patient underwent a direct interview by a physician. The data regarding history of psoriasis and its clinical characteristics were collected. Univariate and multivariate analyses of patients with versus without psoriasis were carried out.In all, 275 SpA patients were assessed: mean disease duration 16.7±11.8 years, 61.4% were men, 69.1% were diagnosed as axial SpA and 17.8% as peripheral SpA. In all, 84 patients (30.5%) had present or past psoriasis. The prevalence of psoriasis was high whatever the clinical presentation. Psoriasis was present before or concomitantly to diagnosis of SpA in 59/84 patients (70.2%). The most common types of psoriasis were plaque (66.7% of patients with psoriasis) and scalp psoriasis (65.5%). Other localisations were not rare, including palmoplantar pustulosis (20.2%) or nail psoriasis (19.1%). Patients with versus without psoriasis differed only through a lower proportion of radiological sacroiliitis (57.5% vs. 81.3 %, p0.001).With a prevalence of 30.5%, i.e. ten times higher than in the general population, this study confirms that psoriasis is a frequent and early manifestation in SpA and that a systematic search for psoriasis (e.g. scalp) is relevant in SpA for clinical practice, whatever the clinical presentation of SpA.

Systemic sclerosis is an orphan connective tissue disease characterized by alterations of the microvasculature, disturbances of the immune system and massive deposition of collagen and other matrix substances in the skin and internal organs. A major achievement of the recent years has been the validation of new classification criteria, allowing earlier diagnosis and earlier treatment of systemic sclerosis, before irreversible fibrosis and organ damage appeared ("window of opportunity"). Raynaud's phenomenon is usually the first sign of the disease and is considered as the main sentinel sign for the identification of very early systemic sclerosis. Systemic sclerosis is clinically heterogeneous and disease course remains unpredictable. Its prognosis depends on cardiopulmonary involvement and recent studies aim to identify serum or genetic biomarkers predictive of severe organ involvement. Moreover, the prospective follow-up of large cohorts has provided and will offer critical material to identify strong prognostic factors. Whereas the outcomes of vascular manifestations of the disease has been recently improved due to targeted therapy, recent data have highlighted that mortality has not changed over the past 40 years. This reflects the absence of efficacy of current available drugs to counteract the fibrotic process. Nevertheless, several targeted immunity therapies, commonly with proven efficacy in other immune diseases, are about to be investigated in systemic sclerosis. Indeed, promising results in small and open studies have been reported. This article deals with recent insights into classification criteria, pathogenesis, organ involvements, outcome and current and possible future therapeutic options in systemic sclerosis.

OBJECTIVES: In agreement with other autoimmune diseases, systemic sclerosis (SSc) is associated with a strong sex bias. However, unlike lupus, the effects of sex on disease phenotype and prognosis are poorly known. Therefore, we aimed to determine sex effects on outcomes. METHOD: We performed a prospective observational study using the latest 2013 data extract from the EULAR scleroderma trials and research (EUSTAR) cohort. We looked at (i) sex influence on disease characteristics at baseline and (ii) then focused on patients with at least 2 years of follow-up to estimate the effects of sex on disease progression and survival. RESULTS: 9182 patients with SSc were available (1321 men) for the baseline analyses. In multivariate analysis, male sex was independently associated with a higher risk of diffuse cutaneous subtype (OR: 1.68, (1.45 to 1.94); p

Background Genetic studies have pointed out that CD226 variants, encoding DNAM-1, could be associated with susceptibility to rheumatoid arthritis. Therefore, we aimed to determine the influence of DNAM-1 on the development of arthritis using the collagen-induced arthritis (CIA) mouse model. Methods CIA was induced in mice on a DBA/1 background, treated in parallel with a DNAM-1 neutralizing monoclonal antibody, a control IgG and PBS, respectively. CIA was also induced in mice deficient for DNAM-1(dnam1−/−) and control dnam-1+/+ mice on a C57/BL6 background. Mice were monitored for clinical and ultrasound signs of arthritis. Histological analysis was performed to search for inflammatory infiltrates and erosions. The Mann–Whitney U test for non-related samples was used for statistical analysis. Results There was a non-significant trend for a less arthritic phenotype in mice receiving anti-DNAM-1 mAb at both clinical, ultrasound and histological assessments. But, we did not observe any difference between dnam1+/+ and dnam1−/− mice for incidence nor severity of clinical arthritis. Histological analysis revealed inflammatory scores similar in both groups, without evidence of erosion. Collagen antibodies levels were similar in all mice, confirming immunization with collagen. Conclusion Despite some clues suggesting a role of DNAM-1 in arthritis, these complementary approaches demonstrate no contribution of CD226/DNAM-1 in the arthritic phenotype. These results contrast with previous studies showing a role in vivo of DNAM-1 in some autoimmune disorders. Electronic supplementary material The online version of this article (doi:10.1186/s12950-015-0056-5) contains supplementary material, which is available to authorized users.