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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.

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.

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

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.

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.

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.

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.

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.

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.

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.

International audience; INTRODUCTION: Interleukin-6 (IL-6) is a pleiotropic cytokine for which preliminary data have suggested that it might contribute to systemic sclerosis (SSc). Our aims were to investigate, firstly, IL-6 expression in patients with SSc and, secondly, the efficacy of both passive and active immunization against IL-6 to reduce skin fibrosis in complementary mouse models of SSc. METHODS: Human serum levels and skin expression of IL-6 were determined by enzyme-linked immunosorbent assay and immunohistochemistry, respectively. We first evaluated the antifibrotic properties of the monoclonal anti-IL-6R antibody, MR16-1, in the bleomycin-induced dermal fibrosis mouse model, reflecting early and inflammatory stages of SSc. Then, we assessed the efficacy of MR16-1 in tight skin-1 (Tsk-1) mice, an inflammation-independent model of skin fibrosis. Additionally, we have developed an innovative strategy using an anti-IL-6 peptide-based active immunization. Infiltrating leukocytes, T cells, and B cells were quantified, and IL-6 levels were measured in the serum and lesional skin of mice after passive or active immunization. RESULTS: Serum and skin levels of IL-6 were significantly increased in patients with early SSc. Treatment with MR16-1 led in the bleomycin mouse model to a 25% (P = 0.02) and 30% (P = 0.007) reduction of dermal thickness and hydroxyproline content, respectively. MR16-1 demonstrated no efficacy in Tsk-1 mice. Thereafter, mice were immunized against a small peptide derived from murine IL-6 and this strategy led in the bleomycin model to a 20% (P = 0.02) and 25% (P = 0.005) decrease of dermal thickness and hydroxyproline content, respectively. Passive and active immunization led to decreased T-cell infiltration in the lesional skin of mice challenged with bleomycin. Upon bleomycin injections, serum and skin IL-6 levels were increased after treatment with MR16-1 and were significantly reduced after anti-IL-6 active immunization. CONCLUSIONS: Our results support the relevance of targeting IL-6 in patients with early SSc since IL-6 is overexpressed in early stages of the disease. Targeting IL-6 by both passive and active immunization strategies prevented the development of bleomycin-induced dermal fibrosis in mice. Our results highlight the therapeutic potential of active immunization against IL-6, which is a seductive alternative to passive immunization.

To characterize ultrasonographic (US) features in the hand of patients with systemic sclerosis (SSc) and to evaluate the sensitivity of US in the detection of calcinosis and acroosteolysis.The local ethics committee approved this study, and oral informed consent was obtained. A total of 44 consecutive patients with SSc (34 women; mean age, 56.1 years ± 12.1 [standard deviation]; 10 men; mean age, 45.0 years ± 14.0) and 30 healthy control subjects (20 women; mean age, 46.3 years ± 12.1; 10 men; mean age, 39.6 years ± 10.8) were included between October 2010 and December 2011. Bilateral US, including Doppler assessment of the wrists, hands, and fingers, was performed, and presence of synovitis, tenosynovitis with or without a layered appearance, calcifications, acroosteolysis, and distal vascularization was recorded. Radiography of both hands was performed to assess for acroosteolysis and calcinosis. Frequency of US features, sensitivity of US for calcinosis and acroosteolysis, and respective confidence intervals were calculated.Synovitis was found in 17 patients (39%). Tenosynovitis was found in 12 patients (27%), and it had a layered pattern in 15 (41%) of 37 cases. Calcinosis was found in 17 patients (39%) with US, with a sensitivity of 89%. Acroosteolysis was found in nine (20%) patients with US and in 10 (23%) patients with radiography, with 90% sensitivity for US. Distal vascularization was detected in 26 patients (59%) and 30 control subjects (100%) and was in contact with the acroosteolysis bed in seven (78%) of nine patients with SSc.US can be used to assess features of SSc, including synovitis, tenosynovitis, calcinosis, acroosteolysis, and distal vascularization and is sensitive for calcinosis and acroosteolysis detection. A layered pattern (similar to the appearance of an artichoke heart) of tenosynovitis was seen commonly. Online supplemental material is available for this article.

ObjectiveTo investigate the contribution of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of dermal fibrosis on gene inactivation and targeted molecular strategies.MethodsHuman skin expression of DNAM-1 was determined by immunohistochemistry. Mice deficient for DNAM-1 (dnam1−/−) and wild-type controls (dnam1+/+) were injected with bleomycin or NaCl. Infiltrating leucocytes, T cells, B cells and monocytes were quantified and inflammatory cytokines were measured in lesional skin of dnam1−/−and dnam1+/+mice. The anti-fibrotic potential of a DNAM-1 neutralising monoclonal antibody (mAb) was evaluated in the mouse model of bleomycin-induced dermal fibrosis.ResultsOverexpression of DNAM-1 was detected in the skin of patients with SSc (systemic sclerosis). Dnam1−/−mice were protected from bleomycin-induced dermal fibrosis with reduction of dermal thickening (75±5%, p=0.03), hydroxyproline content (46±8%, p=0.04) and myofibroblast counts (39±5%, p=0.01). Moreover, the number of T cells was significantly decreased in lesional skin of dnam1−/−mice (69±15%, p=0.0007). Dnam1−/−mice also displayed decreased levels of TNF-α and IL-6 in lesional skin. Consistent with the gene inactivation strategy, treatment of mice with DNAM-1 neutralising mAb prevented dermal fibrosis induced by bleomycin with reduction of dermal thickness (64±6%, p=0.002), hydroxyproline content (61±8%, p=0.004) and myofibroblast counts (83±12%, p=0.002).ConclusionsAn inactivation gene strategy showed that DNAM-1 exerts profibrotic effects by controlling T cell activation and cytokine release. A molecular targeted strategy confirmed that DNAM-1 neutralising mAb has potent antifibrotic properties, supporting the hypothesis that inhibition of DNAM-1 might be a promising new approach for the treatment of SSc and potentially other related fibrotic diseases.

Objectives. Radiological cervical spine involvement in JIA has already been assessed with a large range of prevalence (580%), but most studies were performed a long time ago, in symptomatic JIA and without differentiating subsets of JIA. We set out to describe structural cervical spine involvement in young adults with polyarticular JIA (pJIA) regardless of the cervical symptoms and to compare lesions with those observed in adult RA. Methods. All consecutive pJIAs followed in a transition programme were included. Standard radiographs of the cervical spine, hands, feet and hip were analysed by two independent radiologists blinded to the diagnosis. An RA control group (

Objective.Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype-phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk.Methods.Known SLE and SSc TNFSF4 susceptibility variants (rs2205960, rs1234317, rs12039904, rs10912580, and rs844648) were genotyped in 1031 patients with SSc and 1014 controls of French white ancestry. Genotype-phenotype association analysis and metaanalysis of available data were performed, providing a population study of 4989 patients with SSc and 4661 controls, all of European white ancestry.Results.Allelic and genotypic associations were observed for the 5 single-nucleotide polymorphisms (SNP) with the subset of patients with SSc who are positive for anticentromere antibodies (ACA) and only a trend for association with SSc and limited cutaneous SSc. Rs2205960 exhibited the strongest allelic association in ACA+ patients with SSc [p = 0.0015; OR 1.37 (1.12–1.66)], with significant intra-cohort association when compared to patients with SSc positive for ACA. Metaanalysis confirmed overall association with SSc but also raised preferential association with the ACA+ subset and strongest effect with rs2205960 [T allele p = 0.00013; OR 1.33 (1.15–1.54) and TT genotype p = 0.00046; OR 2.02 (1.36–2.98)].Conclusion.We confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype.

Objective To investigate ultrasonographic (US) hand features in systemic sclerosis (SSc) patients and their relationship with clinical, biologic, and radiographic data. Methods Fifty-two consecutive SSc patients were included in a cross-sectional observational study together with 24 rheumatoid arthritis (RA) patients enrolled as controls. All patients underwent clinical examination, including tender and swollen joint counts, measurement of disability indices, and hand/wrist radiographs. US was performed on the hand and wrist joints and was aimed at the detection of synovitis, tenosynovitis, and calcinosis. Results Synovitis and tenosynovitis were more frequently detected with US in SSc patients (46% and 27%, respectively) than with clinical examination (15% and 6%, respectively; P < 0.01 for both comparisons). Fifty-seven percent of patients had inflammatory synovitis (mostly Doppler grade 1), and tenosynovitis was either inflammatory or fibrotic. Calcifications were observed using US and radiographs in 40% and 36% of SSc patients, respectively (P = 0.8). As compared to RA, US features specific to SSc were sclerosing tenosynovitis (P < 0.01) and soft tissue calcifications (P = 0.01). Conclusion Our study confirms that articular involvement in SSc is underestimated by a single clinical examination. It is characterized by mild inflammatory changes and the specific findings include sclerotic US aspects together with calcinosis. Further prospective studies are warranted to evaluate the predictive value of these findings and determine whether they should be considered for adapting a therapeutic strategy.

Objectives. Work status is an important outcome in SpA. The objective was to assess work instability and its determinants in a cohort of patients with SpA, using the AS-work instability scale (AS-WIS). Methods. We performed a cross-sectional monocentre study. Patients were definite SpA patients with paid work. Work instability was measured by the AS-WIS. Its determinants were assessed by correlations with SpA scores (BASDAI, BASFI and patient’s global assessment) and patients with low work instability (AS-WIS score < 11) were compared with those with moderate to high instability, through backward logistic regression. Results. In all, 156 patients were assessed: mean (S.D.) age 41 (11) years, mean disease duration 15 (11) years; 71 (45.5%) were on TNF blockers. The mean AS-WIS score was 9.5 (5.5); 55 (35%) patients had moderate and 8 (5%) patients had high work instability. Correlations of the AS-WIS score with SpA scores were significant but moderate (BASDAI R = 0.42, BASFI R = 0.41, patient’s global assessment R = 0.53; P < 0.0001). In multivariate analysis, high patient’s global assessment was the only element associated with moderate to high work instability; demographic characteristics and treatments were not significant elements. Conclusion. Work instability was found to be high and its main determinant was patient’s global assessment. The predictive validity of the AS-WIS in terms of job retention should be further assessed.

Hip involvement is a classic feature of spondyloarthritis (SpA). The aim of the present paper is to study the prevalence, clinical and radiological features of hip involvement, and the association with criteria for severity, in a cohort of patients with SpA in a tertiary care centre.retrospective single centre observational study in 2010 of patients with definite SpA who underwent direct interview by a physician. Hip involvement was defined as hip pain considered related to SpA inflammation and confirmed radiographically. Other data collection: demographic data, SpA characteristics, treatments performed for hip involvement.prevalence of hip involvement was analysed according to disease duration (Kaplan-Meyer). Multivariate Cox analysis compared patients with vs. without hip involvement over time.In all, 275 SpA patients were assessed. The median age was 45 (IQR 35-55) years, the median SpA symptom duration 14 (7-25) years, 61% (169) were men, and 79% were HLA-B27 positive. Hip involvement was found in 18% (49) SpA patients, with already 13% after 5 years of disease duration and with frequent bilateral involvement (61%). Hip involvement was associated with non-Caucasian origin (p=0.05). Thirty-three percent (16/49) needed surgery (23 total joint replacements in all) with good functional results.Hip involvement is a frequent manifestation in SpA (18%), often bilateral, and associated with non-Caucasian origin. One third of the patients needed total joint replacement. Physicians should be wary of hip pain in SpA patients and implement rapid diagnostic procedures in such cases.

Heel pain is a common but poorly studied feature of spondyloarthritis (SpA). The aims of this study were to assess the prevalence and clinical features of heel pain in a cohort of patients with SpA.This was a retrolective single centre observational study in 2010. Patients with SpA as defined by Amor's criteria were recruited. The data collected were: demographic and disease characteristics, history of heel pain, age at first heel pain, localisation, nature and intensity of pain and treatments. The analyses were descriptive.A total of 275 SpA patients (mean age 44.6±13.5 yrs, mean disease duration 16.7±11.8 yrs, 61.5% men) were assessed. A history of heel pain was reported in 130 patients (47.1%), and was the first symptom of SpA in 15.7% of all patients. Heel pain was frequent in both axial (89/201, 44.3%) and peripheral disease (27/56, 48.2%). Distribution was more frequently inferior (88, 69.3%) than posterior (61, 48.0%) (p0.0001), and frequently bilateral: simultaneously (41.9%) rather than alternatively (29.1%) (p=0.03). Main clinical symptoms were: morning pain on weight bearing (83.6%), but also night pain (34.4%), and/or patient-described swelling (24.2%). Heel pain was frequently recurrent (74.2%), intense (70.3%), source of a limp (71.6%), and often resistant to non-steroidal anti-inflammatory drugs (NSAIDs) (54/108, 50%). Tumour necrosis factor blockers were efficacious on heel pain in 72/94 (76.6%) of cases.This study confirmed heel pain as a frequent symptom in both axial and peripheral SpA. It occurred early in the disease course and it was frequently recurrent and resistant to NSAIDs.

Dactylitis is a common but little studied feature of spondylarthritis (SpA). Our objective was to assess the prevalence of dactylitis among a cohort of patients with spondylarthritis in a tertiary care centre and to describe the clinical characteristics of dactylitis.This was a prospective single centre observational study carried out in 2010. The patients included had been diagnosed as having definite SpA based on Amo's criteria. Each patient was interviewed by a physician. The data collected included prevalence of dactylitis and its clinical characteristics, effectiveness of the different treatments, and association with severe manifestations of SpA, and analysed by descriptive analysis.275 consecutive SpA patients were assessed: mean age 43.2±13.5 years, mean disease duration 14.0±11.8 years, 169 (61.4%) were men. In all, 59 patients (21.5%) suffered from SpA-associated dactylitis. The localisation of dactylitis was toes in 46 patients (78.0%) and/or fingers in 25 patients (42.4%). The most frequent localisations were the second toe and the second finger. Dactylitis was the first symptom of SpA in 14 patients (5.1%), and 28.8% (n=17) of dactylitis appeared within the first 5 years of disease. Dactylitis was present in 35.1% (n=13) of patients with undifferenciated SpA and in 30.6% (n=15) of patients with psoriatic arthritis. It was significantly associated with history of peripheral arthritis or heel pain. In our population, there was no correlation between dactylitis and HLA B27 status or sex and it was not a marker of severity of disease.Dactylitis is a frequent manifestation in SpA (21.5%) particularly in peripheral disease and it may be the first manifestation of the disease with localisation being more frequent in the toes.

erosions of the odontoid process (34%) and atlanto-axial impaction (20%). Apophyseal joint ankylosis (AJA) was rare (10%) but involvement of the posterior cervical spine (AJA and apophyseal joint arthritis) was more frequent (42%). Presence of radiographic cervical lesions was correlated in univariate analysis with a more severe disease phenotype: more erosive disease (hand and feet), higher number of biotherapies per patient (respectively 1.4±1.3 vs 0.5±0.5, p=0.003), and higher frequency of surgery (p=0.03, OR 7.74[0.92-65]) but not with RF status. Multivariate analysis confirmed only the association with the higher number of biotherapies per patients (p=0.04). 50% of pJIA with radiographic abnormalities had no clinical symptoms. In pJIA sub-group with cervical symptoms (n=24), patients needed more DMARDs and biotherapies per patient. Finally, comparison between pJIA and RA for radiographic findings showed only differences for two structural features: hypotrophy of vertebrae (24% vs 7%) and AJA (10% vs 0%). Conclusion Structural cervical spine involvement is a frequent manifestation in pJIA followed at adulthood and is correlated with a more severe disease. Radiologic assessment of cervical spine should be done systematically at onset and regularly during the course of the disease regardless of clinical symptoms. Cervical symptoms may be considered as a warning signal revealing presence of AJA.