Search

Systemic sclerosis (SSc) is a debilitating autoimmune disease characterized by severe lung outcomes resulting in reduced life expectancy. Fra-2-transgenic mice offer the opportunity to decipher the relationships between the immune system and lung fibrosis. This study was undertaken to investigate whether the Fra-2-transgenic mouse lung phenotype may result from an imbalance between the effector and regulatory arms in the CD4+ T cell compartment.We first used multicolor flow cytometry to extensively characterize homeostasis and the phenotype of peripheral CD4+ T cells from Fra-2-transgenic mice and control mice. We then tested different treatments for their effectiveness in restoring CD4+ Treg cell homeostasis, including adoptive transfer of Treg cells and treatment with low-dose interleukin-2 (IL-2).Fra-2-transgenic mice demonstrated a marked decrease in the proportion and absolute number of peripheral Treg cells that preceded accumulation of activated, T helper cell type 2-polarized, CD4+ T cells. This defect in Treg cell homeostasis was derived from a combination of mechanisms including impaired generation of these cells in both the thymus and the periphery. The impaired ability of peripheral conventional CD4+ T cells to produce IL-2 may greatly contribute to Treg cell deficiency in Fra-2-transgenic mice. Notably, adoptive transfer of Treg cells, low-dose IL-2 therapy, or combination therapy changed the phenotype of Fra-2-transgenic mice, resulting in a significant reduction in pulmonary parenchymal fibrosis and vascular remodeling in the lungs.Immunotherapies for restoring Treg cell homeostasis could be relevant in SSc. An intervention based on low-dose IL-2 injections, as is already proposed in other autoimmune diseases, could be the most suitable treatment modality for restoring Treg cell homeostasis for future research.

Resume Les patients atteints de rhumatisme inflammatoire chronique peuvent presenter des risques d’infection osteoarticulaire en rapport avec leur âge, la presence de comorbidites, la realisation de gestes locaux intra-articulaires ou d’actes chirurgicaux ou par l’utilisation de certains traitements immunosuppresseurs dont les corticoides ou les traitements cibles. Les donnees relatives au risque d’infection osteoarticulaire restent pour l’instant peu nombreuses et limites aux anti-TNF-α. Bien qu’un surrisque d’infection osteoarticulaire sur articulation native ou sur prothese articulaire sous traitement biologique cible soit rapporte dans differents registres, celui-ci apparait comme modere, inferieur aux infections respiratoires, cutanees et urinaires. Ce risque d’infection osteoarticulaire est egalement stable au cours du temps, similaire a celui decrit avant l’ere des biotherapies. Par ailleurs, ce surrisque doit etre mis en balance avec celui des corticoides, souvent necessaires pour controler les poussees induites par la suspension de l’agent biologique. Le Staphylococcus aureus reste le microorganisme le plus frequemment retrouve, mais certaines especes, habituellement rarement mises en cause dans les infections articulaires peuvent etre impliquees et doivent etre evoquees chez ces patients. L’absence de signes generaux et/ou de syndrome inflammatoire biologique ne doit pas faire eliminer l’infection chez ces patients sous traitements cibles, et peuvent conduire a proposer certains examens comme une biopsie synoviale. Plusieurs questions restent pour l’instant sans reponse, notamment le poids du traitement cible dans le surrisque d’infection osteoarticulaire par rapport aux autres facteurs de risques, notamment l’âge, la maladie articulaire sous-jacente ou la corticotherapie.

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.

Introduction La prévalence des formes asymptomatiques d’infection COVID-19 en population générale est mal connue à ce jour (

• Objectives: to estimate the seroprevalence of SARS-CoV-2 infection in patients with rheumatic diseases and to specify the proportion of asymptomatic and symptomatic forms of COVID-19. • Methods: we screened for SARS-CoV-2 infection among spondyloarthritis (SpA, n=143) or rheumatoid arthritis (RA, n=140) patients in our outpatient clinic at Cochin Hospital in Paris between June and August 2020. We performed a qualitative SARS-CoV-2 serological test which detects IgG directed against the N nucleocapsid protein (anti-N) and, for some patients, against the Spike protein (anti-S). Descriptive analyses were managed. • Results: during June–August 2020, the SARS-CoV-2 seroprevalence rate in our population was 2.83% (8/283 patients) without significant difference between RA and SpA patients (2.14% and 3.5% respectively). We report 11 out of 283 patients (3.8%) with a diagnosis of SARS-CoV-2 infection. Among these 11 patients, 1 patient was asymptomatic (9%) with a confirmed diagnosis of COVID-19 by anti-S serology. Of the 283 patients, 85% were under bDMARDs, mainly on rituximab (RTX) (n=44) and infliximab (IFX) (n= 136). • Conclusions: the seroprevalence of SARS-CoV-2 in patients with rheumatic diseases, mainly under bDMARDs treatments, was 2.83%. Among infected patients, 9% were asymptomatic. Detecting SARS-CoV-2 infections could be based on the strategy using patients’ interview and anti-N serology.

We aimed to estimate the amount of scarring in the liver with the fibrosis-4 (FIB-4) index in patients with rheumatoid arthritis (RA) with special interest in methotrexate (MTX) influence.This was a cross-sectional monocentric study including successive RA patients recruited for a 12-month period. Data on liver function, disease activity, hepatotoxic and cardiovascular risk factors were systematically collected. The FIB-4 index was calculated according the following formula: (age(years)× AST(U/L)/platelet (PLT) (109/L)×√ALT(U/L)).We included 170 patients with established RA: 141 (83%) were women with a mean age of 59±12 years and mean disease duration of 15±11 years. The FIB-4 was low and not significantly different between patients receiving MTX (n=102), patients previously treated with MTX (n=39) and patients never treated with MTX (n=29). No correlation was observed between FIB-4 values and cumulative MTX dose (r=0.09, p=0.271). No relationship was observed between FIB-4 and MTX treatment duration. The FIB-4 index was found significantly increased in patients receiving leflunomide (n=24), (median (range) 1.58 (0.46-3.16) vs. 1.18 (0.54-3.40), p=0.019) and tocilizumab (n=14), (median (range) 1.82 (0.75-3.73) vs. 1.18 (0.54-3.40), p=0.005) compared to patients not receiving DMARDs (n=29). Multivariate logistic regression analyses revealed an independent association between increased FIB-4 (1.45) and male gender, low disease activity, and treatment with leflunomide and tocilizumab.RA patients with long-term maintenance MTX therapy have low FIB-4 values suggesting that MTX is not associated with an increased risk of advanced liver fibrosis. Increased FIB-4 values have been detected in leflunomide- and tocilizumab-treated patients, which will deserve dedicated further investigations.

Introduction La pandémie de COVID-19 a catalysé l’émergence rapide de la télémédecine. Cet outil a été l’unique moyen de poursuivre l’activité de consultation pendant la première vague de la pandémie. Notre objectif a été de décrire sur quels paramètres les malades atteints de polyarthrite rhumatoïde (PR) vus en téléconsultation ont été évalués, et d’identifier les éléments sur lesquels les rhumatologues se sont appuyés pour prendre leur décision. Patients et méthodes Il s’agit d’une étude rétrospective monocentrique observationnelle. Nous avons inclus l’ensemble des patients atteints de PR, définie par le rhumatologue dans le « catalogue rhumatologique » du logiciel ORBIS, vus pour leur suivi entre mars et septembre 2020 en consultation téléphonique ou en téléconsultation réalisée à partir du système ORTIF. Les paramètres ayant permis l’évaluation du patient ont été recueillis dans le dossier médical. L’intervention du rhumatologue a été définie par une intensification thérapeutique et/ou une convocation pour une visite présentielle en consultation ou hospitalisation (de jour ou conventionnelle). Résultats 143 patients atteints de PR ont été inclus (117 femmes, 82 %) avec un âge moyen de 58 ± 16 ans et une durée de la maladie de 14 ± 11 ans. Les anti-CCP étaient positifs chez 104 patients (73 %), les facteurs rhumatoïdes chez 100 patients (70 %) et 75 patients présentaient des érosions (52 %). Sur le plan thérapeutique, 96 recevaient du méthotrexate (67 %), 67 une corticothérapie (47 %) et 69 un traitement biologique ou synthétique ciblé (48 %). La téléconsultation a eu lieu par téléphone pour 106 patients (74 %) et par visioconsultation pour 37 patients (26 %). La survenue de poussées de la maladie a été recherchée pour l’ensemble des patients et a été détectée chez 43 d’entre eux (30 %). Un seul patient avec poussée avait arrêté ses traitements par crainte de la pandémie. Les indices utilisés pour évaluer la PR ont été, par ordre décroissant : la présence et/ou le nombre d’articulations douloureuses (n = 109, 76 %), la durée de la raideur matinale (n = 95, 66 %), le nombre de réveils nocturnes (n = 95, 66 %), la valeur de la CRP (n = 77, 54 %), l’EVA globale évaluée par le patient (n = 68, 48 %), la valeur de la vitesse de sédimentation (n = 51, 36 %), la présence et/ou le nombre d’articulations gonflées (n = 48, 33,5 %), le score DAS28 (VS ou CRP) (n = 37, 26 %), l’EVA douleur (n = 33, 23 %) et l’EVA Asthénie (n = 24, 17 %). La téléconsultation a conduit à une intensification thérapeutique chez 13 patients (introduction ou augmentation de la corticothérapie chez 8 patients, introduction ou majoration du méthotrexate chez 4 patients et introduction de l’hydroxychloroquine chez 1 patient) et à une demande de visite présentielle pour 7 patients. Après analyse multivariée par régression logistique, la survenue d’une ou plusieurs poussées (Odds Ratio, OR : 15,6 ; IC95 % : 3,37–68,28) et une CRP > 5 mg/L (OR : 3,32, IC95 % : 1,12–13,27) étaient les seules variables indépendamment associées à une intervention du médecin. Conclusion La survenue de poussées, le nombre d’articulations douloureuses, la durée de la raideur matinale, le nombre de réveils nocturnes et la valeur de la CRP étaient les paramètres les plus fréquemment collectés au cours de la téléconsultation. La survenue d’une ou plusieurs poussées de PR et une valeur de CRP élevée ont été les éléments principaux ayant motivé une intervention du rhumatologue en téléconsultation. La validation de ces paramètres pour une utilisation en pratique courante de télémédecine est en cours dans une étude prospective.

Background:The COVID-19 pandemic requires measures to reduce patient exposure to the risk of contamination, in particular by limiting hospital admissions and promoting lockdown. In order to respond to these healthcare measures, patients were offered to replace intravenous infusions (IV) of abatacept (ABT) and tocilizumab (TCZ) to subcutaneous injections (SC).Objectives:To assess the outcome of patients who switched from IV ABT or TCZ to SC during the COVID-19 pandemic.Methods:A survey was conducted in December 2020 in partnership with the national AFP-RIC patient association to assess the outcome and satisfaction of patients who switched from ABT or TCZ IV to SC during the first wave of COVID-19 pandemic.We also analysed the outcome of patients who switched from IV ABT or TCZ to SC in the rheumatology department of Cochin Hospital during the lockdown in April/may 2020. Articular activity parameters (swollen joint count, pain joint count, visual analogic pain scale, CRP, DAS-28 activity score) were assessed at medical visits before and 6 months after switching from IV to SC.The data collected from the AFP-RIC patient association and the rheumatology department of Cochin Hospital were then aggregated and analyzed by Chi-square and Wilcoxon tests.Results:81 patients responded to the survey carried out by AFP-RIC patient association, including 29 treated with IV ABT (n=15, 52%) or TCZ (n=14, 48%). 17/29 (59%) were offered to switch from IV to SC, 14/17 patients (82%) accepted and 7 patients were still receiving ABT or TCZ SC injections in December 2020. In the rheumatology department of Cochin hospital, 71 patients were scheduled in April/May 2020 to receive IV ABT or TCZ, and 27 (38%) switched to SC. After 6 months, 19 patients (70%) had maintained SC injections, were satisfied with this injection route of administration and their articular activity parameters were unchanged (Table 1).Table 1.Course of Disease parameters evaluated in the 19 patients who maintained abatacept or tocilizumab SC injections in the Rheumatology department of Cochin HospitalParameter, mean(SD)Inclusion visitSwitch to SC(n=19)6 month visit (n=19)P-valueDAS282.3 (1.2)2.3 (0.7)0.62Tender joint count2.5 (3.5)1.3 (1.7)0.49Swollen joint count1.3 (2.5)0.9 (0.6)0.35Patient Global Health (cm)3.2 (1.9)2.6 (1.8)0.60CRP (mg/L)3.2 (4.1)5.2 (4.9)0.56CRP: C-Reactive Protein, SD: Standard DeviationThe combined analysis of these two populations included 41 patients (33 rheumatoid arthritis, RA, 7 juvenile idiopathic arthritis, JIA and 1 polymyalgia rheumatica) who switched to SC ABT or TCZ. 26/41 (63.5%) patients maintained SC injections and IV was re-established in 15/41 (36.5%). Reasons for returning to IV were poor tolerance of SC injections (n=6, 40%), worsening symptoms (n=11, 73%), patient preference to see a rheumatologist in hospital (n=10, 67%) and the high number of SC injections (n=2, 13%). The proportion of patients returning to IV was higher in RA patients compared to patients with JIA (42% vs. 14%, p = 0.08). Age and disease duration were not significantly different between patients who maintained SC injections and those who returned to IV (respectively p=0.97 and p=0.63).Conclusion:Our study suggests that switching from IV ABT or TCZ to SC is an acceptable procedure during the COVID-19 pandemic, especially for patients with JIA.Acknowledgements:Association AFP-RIC (Angélique Hochedé, Cyrielle Beller, Sandrine Rollot) and the members of the association for their help in the conduction of the surveyDisclosure of Interests:None declared.

Background The pathogenesis of systemic sclerosis (SSc) involves a distinctive triad of autoimmune, vascular and inflammatory alterations resulting in fibrosis. Evidence suggests that peroxisome proliferator-activated receptors (PPARs) play an important role in SSc-related fibrosis and their agonists may become effective therapeutic targets. Objective To determine the expression of PPARs in human fibrotic skin and investigate the effects of IVA337, a pan PPAR agonist, in in vitro and in vivo models of fibrosis. Methods The antifibrotic effects of IVA337 were studied using a bleomycin-induced mouse model of dermal fibrosis. The in vivo effect of IVA337 on wound closure and inflammation were studied using an excisional model of wound healing. Results Low levels of PPARα and PPARγ were detected in the skin of patients with SSc compared with controls. In mice, IVA337 was associated with decreased extracellular matrix (ECM) deposition and reduced expression of phosphorylated SMAD2/3—intracellular effector of transforming growth factor (TGF)-β1. Although the antifibrotic effect of pan PPAR was similar to that of PPARγ agonist alone, a significant downregulation of several markers of inflammation was associated with IVA337. Despite its anti-inflammatory and antifibrotic properties, IVA337 did not interfere with wound closure. In vitro effects of IVA337 included attenuation of transcription of ECM genes and alteration of canonical and non-canonical TGF-β signalling pathways. Conclusions These findings indicate that simultaneous activation of all three PPAR isoforms exerts a dampening effect on inflammation and fibrosis, making IVA337 a potentially effective therapeutic candidate in the treatment of fibrotic diseases including SSc.

In recent years, accumulating evidence suggest that regulatory T cells (Tregs) are of paramount importance for the maintenance of immunological self-tolerance and immune homeostasis, even though they represent only about 5-10% of the peripheral CD4+ T cells in humans. Their key role is indeed supported by the spontaneous development of autoimmune diseases after Tregs depletion in mice. Moreover, there is also a growing literature that investigates possible contribution of Tregs numbers and activity in various autoimmune diseases. The contribution of Tregs in autoimmune disease has opened up a new therapeutic avenue based on restoring a healthy balance between Tregs and effector T-cells, such as Treg-based cellular transfer or low-dose IL-2 modulation. These therapies hold the promise of modulating the immune system without immunosuppression, while several issues regarding efficacy and safety need to be addressed. Systemic sclerosis (SSc) is an orphan connective tissue disease characterized by extensive immune abnormalities but also microvascular injury and fibrosis. Recently, data about the presence and function of Tregs in the pathogenesis of SSc have emerged although they remain scarce so far. First, there is a general agreement in the medical literature with regard to the decreased functional ability of circulating Tregs in SSc. Second the quantification of Tregs in patients have led to contradictory results; although the majority of the studies report reduced frequencies, there are conversely some indications suggesting that in case of disease activity circulating Tregs may increase. This paradoxical situation could be the result of a compensatory, but inefficient, amplification of Tregs in the context of inflammation. Nevertheless, these results must be tempered with regards to the heterogeneity of the studies for the phenotyping of the patients and of the most importance for Tregs definition and activity markers. Therefore, taking into account the appealing developments of Tregs roles in autoimmune diseases, together with preliminary data published in SSc, there is growing interest in deciphering Tregs in SSc, both in humans and mice models, to clarify whether the promises obtained in other autoimmune diseases may also apply to SSc.

Patients with systemic sclerosis (SSc) develop a broad spectrum of vascular manifestations including the almost universal Raynaud’s phenomenon, commonly digital ulceration and more rarely critical digital ischaemia. In parallel, within this very heterogeneous disease, some patients will develop vascular related organ damages leading to heart or kidney failure. In addition, SSc patients commonly exhibit telangiectasia that are visible macular, dilated superficial blood vessels. They can develop near the surface of the skin or the mucous membranes. Cutaneous telangiectasia are now included in the classification criteria and may be a marker of more aggressive vascular phenotype. Furthermore, telangiectasia can occur in the gut and promote the development of more structured damages like vascular ectasias and sometimes the very specific gastric antral vascular ectasia. All these vascular lesions induce severe and recurrent chronic iron-deficiency anaemia that can require specific local treatments to stop the bleeding. They also occur in subsets of SSc patients at risk of other SSc complications that will be highlighted in the clinical cases to be presented. Disclosure of Interest None declared

Background Recent accumulating evidences indicate a crucial role of macrophage lineage in the pathogenesis of fibrotic diseases including systemic sclerosis (SSc). CD163 is a surface marker expressed by M2 macrophages that accumulate during the healing phase of acute inflammation. It is actively released from the plasma membrane in response to certain inflammatory stimuli and enters the circulation in its soluble form (sCD163). Objectives In this study, we aimed to evaluate the performance of serum and urinary sCD163 concentrations as possible biomarker in SSc. Methods Urine and serum samples were obtained from SSc patients, fulfilling the 2013 ACR/EULAR classification criteria for SSc, and age- and sex-matched controls. Serum and urinary sCD163 concentrations were measured by commercially available ELISA kit (R and D systems) and evaluated for their significance as potential biomarkers. Statistical analysis was carried out using Mann-Whitney U test and the relationship between parameters was statistically examined by Spearman’s rank test. Results Two hundred and three SSc patients were included, 163 (80%) were female, with a mean ±standard deviation (SD) age of 59±13 years and a mean ±SD disease duration of 12±9 years. Eighty-one (41%) patients had diffuse cutaneous SSc and mean ±SD mRSS was 6.6±7.7. Lung fibrosis on imaging was observed in 33% of the patients, 7% had pulmonary arterial hypertension, 44% had history of digital ulcers and 41% were taking immunosuppressive therapy. Control group consisted of 47 age- and sex-matched patients with non-inflammatory diseases, being osteoporosis for the very large majority. Serum sCD163 levels were significantly higher in SSc patients compared with controls (mean ±SD: 529±251 vs 385.1±153 ng/ml; p Conclusions To our knowledge this is the first evaluation of both serum and urinary sCD163 levels in SSc. Our results show a significant difference for sera values that should be prioritised for further studies as compared to urinary concentrations conversely to what has been described in lupus. Our results further support that the M2 macrophages/CD163 signalling system may play a role in the pathogenesis of SSc. However, further studies are required to address the exact role of CD163 in the pathogenesis of SSc and to determine whether it could help in the risk-stratification of the patients in this heterogeneous disease. Disclosure of Interest None declared

Background Several studies have consistently showed that the extent of skin involvement has a major impact on disease prognosis in the diffuse cutaneous subtype of systemic sclerosis. The large majority of the ongoing clinical trials aim at identifying efficient drug in this subset. By contrast, little is known about the limited cutaneous subset (LcSSc) and the translation of the data coming for DcSSc to LcSSc is uncertain. Objectives Therefore, our aim was to investigate skin and lung involvement trajectories of LcSSc patients using the large EUSTAR registry. Methods We analysed the longitudinal data extracted from the EUSTAR cohort collected before February 2017. Worsening of skin fibrosis was defined by an increase in modified Rodnan skin score (mRSS) >3.5 points from baseline to 2nd visit. Interstitial lung disease (ILD) was defined by any fibrosis on imaging (X-ray/computed tomography). Worsening of ILD was defined by a decrease of FVC >10% from baseline to 2nd visit. For predicting models, predictors with p Results 8013 LcSSc were included with a mean follow-up of about 3.3±3.7 years. At baseline, mean ±SD mRSS was 6±5 and ILD was present in 28.4% of all patients. Worsening of skin fibrosis was observed in 6.4% (19/298), 7.8% (97/1248) and 9.8% (289/2957) of LcSSc patients at 6, 12 and 24 months follow-up respectively. In multivariate analysis, variables predicting skin fibrosis progression were elevated European Scleroderma Study Group activity index (EScSG-AI) (OR [95 IC]: 1.22 [1.05–1.4], p=0.007) for 12 months progression and EScSG-AI (1.24 [1.13–1.38], p Worsening of ILD was observed in 11.7% (23/196) and 19.9% (65/326) of LcSSc patients with ILD at baseline, at 12 and 24 months follow-up respectively. In multivariate analysis, variables predicting ILD progression at 24 months were EScSG-AI >3 (OR [95 IC]: 3.8 [1.51–9.56], p=0.005), FVC (1.03 [1.01–1.04], p Conclusions It appears that only few LcSSc patients progress for skin fibrosis ; this limits the use of mRSS in this subset and the potential of anti-fibrotic drugs of skin disease. However, a substantial rate of ILD progression was identified as well as relevant predictors. These results support the inclusion of LcSSc patients in SSc-ILD trials evaluating anti-fibrotic drugs. Our predictive models will be helpful to define enriched population in future clinical trials. Acknowledgements: This work was supported by an unrestricted grant from INVENTIVA Disclosure of Interest None declared

Objective. To evaluate the performance of serum and urinary sCD163 concentrations as possible biomarker in systemic sclerosis (SSc). Methods. Urine and serum samples were obtained from SSc patients and age- and sex-matched controls. Serum and urinary sCD163 concentrations were measured by commercially available ELISA kit. SSc patients were assessed following international guidelines. Cross-sectional analyses were performed. Results. Two hundred and three SSc patients were included. The control group consisted of 47 age- and sex-matched patients having noninflammatory diseases, mainly osteoporosis. Serum sCD163 levels were significantly higher in SSc patients compared with controls (mean ± SD: 529 ± 251 versus 385 ± 153 ng/mL; p<0.001). Urinary sCD163 concentrations were higher in SSc patients than controls, but this did not reach significance (236 ± 498 versus 176 ± 173 ng/mg uCr; p=0.580). The sCD163 concentrations were not associated with clinical, laboratory, and instrumental characteristics of SSc patients. Conclusion. To our knowledge, this is the first evaluation of both serum and urinary sCD163 levels in SSc. Our results show a significant difference for sera values that should be prioritized for further studies as compared to urinary measurements. Our results further support that the M2 macrophages/CD163 signaling system may play a role in the pathogenesis of SSc, although we could not identify a subset of SSc patients with higher concentrations.

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.

Joint Bone Spine - In Press.Proof corrected by the author Available online since mardi 26 avril 2016

The purpose of this study was to assess health-related quality of life (HRQoL) and disease perception in a large, international group of patients with systemic sclerosis (SSc).We placed a standardized questionnaire on a website for patient access. Socio-demographic information, disease characteristics, and self-assessment questionnaires-the Short Form 36 (SF-36) and the Revised Illness Perception Questionnaire (IPQ-R)-were collected.A total of 1902 patients from 60 countries were included. HRQoL appeared to be impaired in SSc, particularly for physical health (PCS, mean ± SD = 43.4 ± 23.4). SSc patients also had strong perceptions about the chronic nature and negative consequence of the disease, and experienced negative emotions due to SSc. Patients with diffuse cutaneous SSc had a poorer HRQoL than those with limited cutaneous SSc, for both physical (PCS, mean ± SD = 46.6 ± 23.7 vs. 39.8 ± 22.3; p0.0001) and mental components (MCS, mean ± SD = 53.8 ± 23.0 vs. 50.3 ± 23.2; p = 0.003). Late-stage SSc patients were more likely to perceive their disease chronic (p0.0001), less controllable (p = 0.03) and with more consequences (p = 0.008), but they had a better understanding of their disease and experienced fewer negative emotions. Raynaud's phenomenon and gastrointestinal complications were the organ involvements with the greatest impact on QoL, they were the two variables associated with the most negative perception of illness severity.This study, performed on the largest group ever set up for this purpose, confirms the major impact on QoL and the negative perceptions of their disease expressed by SSc patients. However, the perception of this illness tended to improve with disease duration, suggesting that patients find effective coping strategies.

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.

Background Early stages of systemic sclerosis (SSc) are characterized by inflammatory skin infiltrates mainly composed of activated T cells. Cytotoxic T-lymphocyte associated molecule-4 (CTLA-4) is a key regulator of T cell activation and preliminary data have suggested that it might contribute to SSc. Objectives Our aim was to investigate the efficacy of the CTLA-4-Ig abatacept, an inhibitor of T cell activation, in reducing skin fibrosis in complementary mouse models of SSc. Methods We first evaluated the antifibrotic properties of abatacept in the mouse model of bleomycin-induced dermal fibrosis, reflecting early and inflammatory stages of SSc. To assess whether abatacept might prevent the development of dermal fibrosis, six-week-old C57BL/6 mice received in parallel subcutaneous injections bleomycin (0.5 mg/ml) and intraperitoneal (i.p) injections of abatacept or purified human IgG1 at a dose of 100 mg every other day for three weeks. To assess whether abatacept might induce the regression of established dermal fibrosis, six-week-old C57BL/6 mice were challenged with bleomycin for 6 weeks and received i.p injections of 100 mg of abatacept or control IgG1 every other day during the last 3 weeks. Then, we investigated abatacept in the tight skin (Tsk-1) mice, an inflammation-independent mouse model of skin fibrosis. To this end, five-week-old Tsk-1 mice received i.p injections of 100 mg of abatacept or control IgG1 every other day for 5 weeks. Infiltrating leukocytes and T cells were quantified in lesional skin by immunohistochemistry. Results Treatment with abatacept prevented the induction of bleomycin-induced dermal fibrosis: dermal thickness was significantly reduced by 48±5% in mice treated with abatacept compared to mice receiving the control IgG1 (p=0.03). Consistent with decreased dermal thickness, hydroxyproline content and myofibroblast counts were reduced upon treatment with abatacept by 63±4% (p=0.02) and 41±6% (p=0.04) respectively, compared to mice receiving the control antibody. In addition, treatment with abatacept led to decreased leukocyte and T cell infiltrates in the lesional skin of mice challenged with bleomycin. Abatacept also induced the regression of established bleomycin-induced dermal fibrosis: dermal thickness, hydroxyproline content and myofibroblast counts were reduced by 15±2% (p Conclusions Using complementary mouse models of SSc, we demonstrate that abatacept can prevent and induce the regression of inflammation-driven experimental dermal fibrosis. Translation to human disease is now required, and targeting early and inflammatory stages of SSc sounds the most appropriate. This strategy is currently under investigation in a phase-3 clinical trial assessing the efficacy of abatacept to improve skin involvement in patients with early diffuse SSc. Disclosure of Interest None declared

Background Systemic sclerosis (SSc) is known as one of the most fatal rheumatic diseases, but it also promotes many detrimental effects on health-related quality of life (HRQOL). However, the data provided so far on HRQOL in SSc suffer from a weak power related to the difficulty to recruit large sample. Furthermore, previous works mostly reported the outcome of early diffuse cutaneous SSc (DcSSc) subset. Objectives To assess HRQOL and disease perception in a large and international cohort of SSc patients using validated questionnaires. Methods We conducted an international cross-sectional survey supported by EUSTAR, FESCA and Scleroderma US Foundation, from December 2013 to April 2014. We built a standardized questionnaire translated by patient associations and available on a website, including: Socio-demographic information, disease characteristics and self-assessment questionnaires namely Short Form 36 (SF-36) and Revised Illness Perception Questionnaire (IPQ-R). Results 1902 SSc patients from 60 countries were included with a mean ± standard deviation (SD) age of 54±16 years and a mean ± SD disease duration of 13±12 years. 712 (34.4%) patients had DcSSc, 853 (44.8%) limited cutaneous SSc (LcSSc) and 122 (6.4%) sine scleroderma SSc. HRQOL appeared to be strongly impaired in SSc patients; in physical health (PCS, mean ± SD 43.4±23.4; 100=best health) but also in mental health (MCS, mean ± SD 52.3±23.1; 100=best health). SSc patients also held strong perceptions of the chronicity and negative consequence of the disease, and experienced negative emotions due to SSc. Compared to LcSSc, patients with DcSSc had poorer HRQOL both in physical (PCS, mean ± SD 46.6±23.7 vs 39.8±22.3; p Patients ranked organ involvements having the most severe impact on daily life and on illness severity perception: Raynaud phenomenon (6.6 and 6.5/10), gastrointestinal complications (5.4 and 5.5/10), musculoskeletal (4.9 and 5/10) and skin lesion (4.5 and 4.6/10) were the top rated involvements. Non-European SSc patients had a greater impact on their QOL, mainly in physical health (PCS, mean ± SD 39.9±22.6 vs 46.0±23.7; p Conclusions This study provides unique information about patient perception of the disease and impact on QOL according to disease subset, disease duration and various geographical origins. The key message overall is the major impact on QOL and rather negative perception of their disease by SSc patients. Nevertheless, illness perception tends to improve with disease duration suggesting effective coping strategies. These results will have to be taken into consideration for patient management and also future trials. Disclosure of Interest None declared

Background Several studies have already focused on anti-cyclic citrullinated peptide (anti-CCP) antibodies in juvenile idiopathic arthritis (JIA). Results of these studies showed that anti-CCP were associated with polyarticular sub-type (pJIA) and more severe disease, especially for structural damages. However, these studies analysed global JIA without focusing on the polyarticular form and especially on rheumatoid factors (RF) positive pJIA. Objectives Determine the prevalence of anti-CCP and evaluate their clinical and radiographic significance in polyarticular JIA at adulthood. Methods Anti-CCP antibodies were determined in a large cohort of polyarticular form of JIA at adulthood. Following demographic and clinical data were collected: sex, age at diagnostic, medical treatments (corticosteroids, DMARDs and biotherapies), history of surgery, number of synovitis and C-reactive protein at the last medical visit. Rheumatoid factors (RF) and antinuclear antibodies (AAN) have been collected. Radiographic damages were evaluated by the Sharp Van Der Heijde score. Results 56 patients with polyarticular form of JIA, fulfilling the ILAR criteria, persisting at adulthood were included with mean age of 25±8.1 years and mean disease duration of 14.3±8.7 years. Antibodies status (anti-CCP, RF and AAN) was performed after a mean of 11.6±9 years after the diagnosis. 29/56 (52%) patients were anti-CCP positive. Anti-CCP positive pJIA had a significant association with presence of RF (97% vs 26%, p In the sub-group of RF positive pJIA (n=35), 28 were anti-CCP positive and 7 negative. No differences for sex, clinical data, medical treatments, surgery and radiographic damages have been detected. Conclusions In this large cohort of polyarticular JIA patients at adulthood, anti-CCP antibodies are associated with a higher need of biotherapies but not with a more structural radiographic severe disease. A small sub-group of patients were RF+ and anti-CCP-. Comparison of RF+ and anti-CCP+ and RF+ and anti-CCP- patients showed that anti-CCP did not seem to bring more information as RF but a larger cohort will be necessary to confirm these results. Finally, our results suggest that polyarticular JIA patients evolving at adulthood are independent of anti-CCP antibodies status at the difference of the pJIA in childhood in which anti-CCP status remains a poor prognostic factor. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5319

Objectives Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations. Methods SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses. Results The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP. AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001]. Conclusion Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality.