Search

DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1.Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed.The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone.Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points • The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. • More than half of the patients with recurrent DU received bosentan and/or sildenafil. • However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone.

BackgroundVascular involvement in Systemic Sclerosis (SSc) is known to start even before clinical diagnosis, to drive Digital Ulcer disease and later in the disease natural history to cause Pulmonary Artery Hypertension, among other manifestations. Despite the proven immune origin of Scleroderma, vascular involvement is not currently targeted by immune driven interventions. Similarly, little data is available on immune or inflammatory biomarkers and outcome measures of vascular disease in SSc. Digital Artery Volume Index (DAVIX) has been recently proposed as imaging surrogate outcome measure of vascular disease activity in SSc [1].ObjectivesHere we aimed to determine the value of DAVIX as overall biomarker of vascular involvement and its correlation with Type I IFN activation in patients with SSc.MethodsEighty-six patients attending our Scleroderma Program were consecutively enrolled for the evaluation of serum IFN score as previously described [2]. Clinical features including presence or history of Digital Ulcers, Presence of Pulmonary Artery Hypertension (PAH) and DLCO, were recorded. Digital Artery Vascular Index (DAVIX) of the dominant hand’s fingers was calculated using time of flight magnetic resonance images analysed through IAG proprietary algorithm, as previously described [1]. Medians were compared by Mann-Whitney-Wilcoxon test, correlation with clinical parameters was performed using Spearman’s or Pearson test, as appropriate (R).ResultsSixty-two patients fulfilled the 2013 ACR/EULAR classification criteria for SSc (diffuse cutaneous 24.6%, limited cutaneous 75.4%) whereas 23 were classified as Very Early Diagnosis of Scleroderma (Criteria score between 6 and 8). Twenty-three patients had DU disease (History of DUs in the previous 24 weeks, presence of DUs at baseline assessment, or onset of new DUs during the following 24 weeks). Eighteen patients had reduced DLCO (1.8 (suspected PAH). DAVIX showed a negative correlation with disease duration (r=-0.33 and p=.003) and with FVC/DLCO ratio (r=-0.34 and p=.009). Patients with DU disease presented lower DAVIX than patients without (p=.018).DAVIX showed a significant correlation with Serum IFN score (r=-0.24, pConclusionDAVIX correlated both with presence of Digital Ulcer disease, DLCO and disease duration. The correlation of DAVIX and Serum IFN score does support the notion of innate immune involvement in vascular disease manifestations of SSc. Prospective testing in the context of Randomised controlled trial will determine the value of DAVIX as surrogate outcome measure of vascular disease severity in SSc.References[1]Gjeloshi K, et al. Arthritis Rheumatol. 2020.[2]Hinchcliff M et al. Arthritis Rheumatol. 2021.Disclosure of InterestsStefano Di Donato: None declared, Mike Hughes: None declared, Giuseppina Abignano: None declared, Giovanni Lettieri: None declared, Rebecca Ross: None declared, Enrico De Lorenzis: None declared, Philip O’Connor: None declared, Olga Kubassova Shareholder of: IAG Image Analysis Group, CEO, Francesco Del Galdo: None declared

BackgroundLinking novel therapeutic targets for diffuse cutaneous Systemic Sclerosis (dcSSc) to markers of disease severity and clinical outcome will enable directing the right therapeutic agents to the appropriate patient populations. Such correlation will also support patient stratification in clinical trials, increasing their informative value and success rates.CCL24 is a chemokine within the Eotaxin family, that has been shown to have a dual pro-inflammatory and pro-fibrotic role in SSc. CCL24 and its receptor, CCR3, were found to be over-expressed in SSc skin and serum samples. In-vivo CCL24 blockage was associated with reduction of bleomycin induced skin and lung injury.ObjectivesWe aimed to study the role of CCL24 in dcSSc using patient cohorts, by correlating its serum levels to disease activity markers and disease progression.MethodsRetrospective and longitudinal dSSc patients’ cohorts were analyzed for CCL24 circulating levels, clinical measurement and disease related bio-markers.ResultsIn a retrospective cohort of 56 dcSSC patients, CCL24 serum levels were significantly higher in patients that had positive anti topoisomerase antibody (ATA) compared to patients with negative ATA. In addition, within the ATA positive patients, ones that had high serum CCL24 levels (≥1500 pg/ml) also presented significantly higher fibrotic activity reflected by a higher enhanced liver fibrosis (ELF) score compared to ATA positive patients with low CCL24 (In a second longitudinal cohort of 66 patient, baseline CCL24 levels positively correlated with ELF score (r=0.42, p≤0.0005). Patients with high baseline CCL24 serum levels were also more likely to experience lung disease progression, measured by reduction in forced vital capacity (FVC) during 12 months(7 out of 17 patients with CCL24 ≥ 1500 pg/ml had at least -5% reduction of FVC). Consistent with these data, patients with normal FVC at baseline (>80% predicted) which experienced worsening in the next 12 months (at least 7%) had a statistically significant higher baseline serum CCL24 (Average 2,275 pg/ml) compared to patients that had no worsening in FVC over time (average 962 pg/ml, p≤0.001). Interestingly, the same group showed an even steeper reduction in DLCO % predicted (-6.8% vs -0.2%, p≤0.05).ConclusionWe show here using two dcSSc patient cohorts, that CCL24 serum levels are correlated with disease activity and worse prognosis reflected by high fibrotic activity and deterioration of lung function over time. This reverse translational study supports the role of CCL24 as a therapeutic target for dcSSc and it has informed a phase 2 study testing CM-101, a CCL24 neutralizing antibody, in dcSSc patients to be started in 2022.Disclosure of InterestsMichal Segal Salto Employee of: Chemomab Therapeutic Ltd., Adi Mor Employee of: Chemomab Therapeutics Ltd., Francesco Del Galdo Consultant of: Chemomab Therapeutic Ltd., Grant/research support from: Chemomab Therapeutic Ltd.

BackgroundRisk-stratification is key in a heterogeneous disease like systemic sclerosis (SSc). Until now, SSc patients are stratified according to the extent of skin involvement into limited cutaneous, diffuse cutaneous and sine scleroderma subtypes. However, this classification remains inaccurate to capture disease heterogeneity. Autoantibodies are found in more than 90% of the patients and can be detected before onset of the disease. Among them, three predominant and specific antibodies are used: anti-centromere, anti-Scl70 and RNA polymerase III antibodies.ObjectivesTo compare the performances of stratification into LeRoy’s cutaneous subtypes versus autoantibody status in SSc versus combination of cutaneous subtypes and autoantibodies status.MethodsPatients from the EUSTAR database were classified either as (i) limited cutaneous, diffuse cutaneous or sine scleroderma (based on the recording made by the treating physician) or (ii) according to autoantibodies with the following subclassifications: (1) no specific autoantibodies, (2) isolated ANA, (3) anti-centromere antibodies, (4) anti-Scl70 antibodies and (5) anti-RNA polymerase III antibodies or (iii) according to combination of cutaneous subset and auto-antibodies. The respective performance of each model to predict overall survival (OS), progression-free survival (PFS), disease progression and different organ involvements was assessed and the three models were compared by the area under the receiver operating characteristic curve (AUC 95%CI) and the net reclassification improvement (NRI). Missing data were imputed through multiple imputation using chain equations.ResultsIn all, 10’711 patients were included: 84.6% females, mean age: 54.4±13.8 years, mean disease duration: 7.9±8.2 years. In the prospective analysis (n= 6’467 to 7’829 according to the outcome), after a mean follow-up of 56 months and a mean of three visits per patient, we did not identify any difference in AUC between the cutaneous-based model and the antibody-based model for prediction of OS and disease progression. However, the NRI showed a significant improvement in prediction of OS (0.57 [0.46-0.71] vs. 0.29 [0.19-0.39]) and disease progression (0.36 [0.29-0.46] vs. 0.21 [0.14-0.28]) at 4 years using the antibody-based model. Regarding prediction of each organ involvement in longitudinal analyses, the antibody-based model showed better performance than the cutaneous-one for renal crisis (AUC: 0.719 [0.696-0.742] vs. 0.664 [0.643-0.685]), with the highest association observed with anti-RNA polymerase III (OR: 7.47 [1.63-34.24], p= 0.010). Similarly, the antibody-based model was better than the cutaneous model in predicting lung fibrosis (AUC 0.719 [0.715-724] vs. 0.653 [0.647-0.659]) and restrictive lung fibrosis (AUC 0.759 [0.749-0.766] vs. 0.711 [0.701-0.721]) which were both associated with anti-Scl70 antibodies (OR: 9.29 [8.17-10.55] and 7.92 [5.37-11.69], respectively, pConclusionAuto-antibody status outperforms the common cutaneous subsetting to risk-stratify SSc patients in the EUSTAR cohort. This easily performed subclassification using autoantibodies specific status can be used by the clinicians to risk-stratify their patients and to adapt disease monitoring in routine practice.Disclosure of InterestsMuriel Elhai Speakers bureau: BMS outside of the submitted work, Marouane Boubaya: None declared, Nanthara Sritharan: None declared, Alexandra Balbir-Gurman: None declared, Elise Siegert: None declared, Eric Hachulla: None declared, Jeska de Vries-Bouwstra: None declared, Gabriela Riemekasten: None declared, Jörg H.W. Distler: None declared, Douglas Veale: None declared, Edoardo Rosato: None declared, Francesco Del Galdo: None declared, Fabian A Mendoza: None declared, Daniel Furst Consultant of: Abbvie, Novartis, Pfizer, R-Pharm, Grant/research support from: Emerald, Kadmon, PICORI, Pfizer,Prometheus, Talaris, Mitsubishi, Carlos De la Puente Bujidos: None declared, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli: None declared, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur, Grant/research support from: Kymera, Mitsubishi Tanabe, Boehringer Ingelheim, Coralie Bloch-Queyrat: None declared, Yannick Allanore Consultant of: Actelion, Bayer, BMS, Boehringer-Ingelheim, Inventiva, Roche, Sanofi-Aventis, Grant/research support from: Actelion, Bayer, BMS, Boehringer-Ingelheim, Inventiva, Roche, Sanofi-Aventis

BackgroundLeRoy’s classification defines two main subsets of Systemic Sclerosis (SSc) based on the extent of skin fibrosis: limited cutaneous SSc (lcSSc) with skin thickening sparing the trunk and distal to the elbow and knees, and diffuse cutaneous SSc (dcSSc) with proximal and distal skin thickening. These two subsets notably differ in terms of survival and frequency of visceral involvement, dcSSc being less prevalent but having a higher mortality rate with more frequent visceral manifestations. SSc sine scleroderma (ssSSc) is a third subset initially described by Rodnan et al. and characterized by the absence of skin fibrosis but with the existence of SSc-associated visceral manifestations.ObjectivesThis study aimed to characterise the main clinical features of patients with ssSSc in comparison with the lcSSc and dcSSc subsets within the international EUSTAR database.MethodsAll patients from the EUSTAR database fulfilling the ACR2013 or 1980 classification criteria for SSc assessed by the modified Rodnan Skin score (mRSS) at inclusion and with at least one follow-up visit were eligible. Sine scleroderma (ssSSc) was defined by the absence of skin thickening (mRSS=0 and no sclerodactyly) at all available visits. The clinical characteristics of these ssSSc patients were compared to those of patients with lcSSc and dcSSc with similar disease duration at last follow-up visit. Descriptive statistics were applied.ResultsAmong the 4263 patients fulfilling the inclusion criteria, 376 (8.8%) were classified as ssSSc. Among them, 40.3% had puffy fingers, 39.4% had interstitial lung disease (ILD), 1.6% had a history of scleroderma renal crisis at inclusion visit. At last available visit, in comparison with 708 lcSSc and 708 dcSSc with the same disease duration, ssSSc patients had a lower prevalence of previous or current digital ulcers (28.2% versus 53.1% in lcSSc (PConclusionThis study highlights that ssSSc patients account for almost 10% of SSc patients with milder disease severity compared to both lcSSc and dcSSc.AcknowledgementsThe authors thank all EUSTAR collaboratorsDisclosure of InterestsAlain LESCOAT: None declared, Suiyuan Huang: None declared, Patricia Carreira: None declared, Elise Siegert: None declared, Jeska de Vries-Bouwstra: None declared, Jörg H.W. Distler: None declared, Vanessa Smith: None declared, Francesco Del Galdo: None declared, Branimir Anic: None declared, Nemanja Damjanov: None declared, Simona Rednic: None declared, Camillo Ribi: None declared, DOMNIQUE FARGE: None declared, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Jansen, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli: None declared, Oliver Distler: None declared, Dinesh Khanna: None declared, Yannick Allanore: None declared

BackgroundActivation of melanocortin 1 receptor (MC1R) is known to have broad anti-inflammatory and anti-fibrotic effects. The bleomycin (BLM)-induced skin fibrosis murine model is well-established for systemic sclerosis (SSc). α-melanocyte-stimulating hormone, an endogenous ligand of MC1R, inhibits skin fibrosis and MC1R knock-out enhances skin fibrosis in this model. These pieces of evidence suggest that MC1R agonism has potential in the treatment of SSc.ObjectivesDersimelagon phosphate (MT-7117) is an investigational small molecule that is an orally administered, selective agonist for MC1R. The purpose of this study is to investigate the potential of MT-7117 as a therapeutic agent for SSc by evaluating its efficacy and mechanism of action in complementary preclinical models. The expression and distribution of MC1R in the skin of SSc patients was investigated.MethodsThe effects of MT-7117 on skin fibrosis and lung inflammation were evaluated in BLM-induced SSc murine models that were optimized for prophylactic and therapeutic evaluation. Microarray-based gene expression analysis and serum protein profiling were performed to investigate the mechanism of action of MT-7117 in the BLM-induced SSc models. The effect of MT-7117 on TGF-β-induced activation of human dermal fibroblasts was evaluated in vitro. Immunohistochemical analyses of MC1R expression in skin samples from SSc patients were performed.ResultsProphylactic treatment with MT-7117 (≥0.3 mg/kg/day p.o.) significantly inhibited the increase in collagen content of the skin, the serum level of surfactant protein D, and the weight of the lungs from BLM-induced skin fibrosis and lung inflammation model. Therapeutic treatment with MT-7117 (≥3 mg/kg/day p.o.) significantly suppressed skin thickening and the numbers of myofibroblasts in pre-established BLM-induced skin fibrosis model. Gene array analysis using the BLM-induced SSc model demonstrated changes in numerous categories related to macrophages, monocytes, and neutrophils, followed by endothelial cell-related categories after treatment with MT-7117. In the analysis that focused on biological functions, categories of inflammatory response, activation of antigen-presenting cells, angiogenesis, atherosclerosis, vasculogenesis, and vaso-occlusion were suppressed by MT-7117. In the analysis that focused on molecular signaling pathways, triggering receptor expressed on myeloid cells-1, IL-6, and oncostatin M involved in inflammation, and peroxisome proliferator-activated receptor that is related to fibrosis were all affected by MT-7117. Serum protein profiling using BLM-induced SSc model revealed that multiple SSc-related biomarkers including P-selectin, osteoprotegerin, cystatin C, growth and differentiation factor-15 and S100A9 were suppressed by MT-7117. MT-7117 inhibited the activation of human dermal fibroblasts by suppressing TGF-β-induced ACTA2 (encoding α-smooth muscle actin) mRNA elevation in vitro. Immunohistochemical analyses showed that MC1R positivity was observed in 40 of 50 diffuse cutaneous SSc patients. MC1R was expressed by monocytes/macrophages, neutrophils, blood vessels (endothelial cells), fibroblasts, and epidermis (keratinocytes) in the skin of SSc patients.ConclusionMT-7117 demonstrates disease-modifying effects in preclinical models of SSc. Investigations of its mechanism of action and target expression analyses indicate that MT-7117 exerts its positive effects by affecting the pathologies of inflammation, vascular dysfunction, and fibrosis through inflammatory cells, endothelial cells, and fibroblasts. In view of its potent beneficial impact on all these three main pathologies of SSc, MT-7117 is a potential therapeutic agent for the treatment of clinically challenging SSc, which has diverse and difficult to treat symptoms. A phase 2 clinical trial investigating the efficacy and tolerability of MT-7117 in patients with early, progressive diffuse cutaneous SSc is currently in progress.Disclosure of InterestsMasahiro Kondo Employee of: Mitsubishi Tanabe Pharma Corporation, Tsuyoshi Suzuki Employee of: Mitsubishi Tanabe Pharma Corporation, Yuko Kawano Employee of: Mitsubishi Tanabe Pharma Corporation, Shinji Kojima Employee of: Mitsubishi Tanabe Pharma Corporation, Masahiko Miyashiro Employee of: Mitsubishi Tanabe Pharma Corporation, Atsuhiro Matsumoto Employee of: Mitsubishi Tanabe Pharma Corporation, Gabriela Kania: None declared, Przemyslaw Blyszczuk: None declared, rebecca ross: None declared, Panji Mulipa: None declared, Francesco Del Galdo Grant/research support from: Prof. F. Del Galdo received fees and research support from Abbvie, AstraZeneca, Boehringer-Ingelheim, Capella, Chemomab, Kymab, Janssen and Mitsubishi-Tanabe., Yun Zhang: None declared, Jörg H.W. Distler Grant/research support from: Prof. J.H.W. Distler received consulting fees, lecture fees, and/or honoraria from Actelion, Active Biotech, Anamar, ARXX, aTyr, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, Sanofi-Aventis, RedX, RuiYi and UCB. J. H. W. Distler is stock owner of 4D Science and Scientific head of FibroCure.

BackgroundPatient Reported Outcomes (PROs) are central to measure how patients feel and function especially when determining the effect of disease modifying agents. In patients with Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD), dyspnea is the main driver of HAQ decline but the effect of reduced lung function on both generic and specific measures of functional impairment is not well defined, and there are many potential confounding biases that could distort the apparent extent and direction of this relationship. Moreover, collider biases potentially induced by selection into the cohort and in clinical trials can also play a role.ObjectivesTo define within the EUSTAR database, the correlation of Forced Vital Capacity (FVC) and functional impairment PROs and identify potential confounders to be considered in casual inference studies.MethodsA cross-sectional analysis included for each patient with SSc-ILD (by X-ray and/or HRCT) in the EUSTAR registry the last visit with at least one PRO (Health Assessment Questionnaire Disability Index [HAQ-DI], Cochin hand function scale [CHFS] and/or dyspnoea visual analogue scale [VAS]) and % predicted FVC (%pFVC), if available. Patients with LVEF≤50% or pulmonary arterial hypertension at RHC were excluded. SSc-ILD with restricted lung volume was defined as %pFVC≤70 [1]. Spearman’s correlation analysis was performed. Results of this analysis and literature review were integrated to design a directed acyclic graph (DAG) and identify the appropriate confounder adjustment set for the total causal effect of FVC on functional impairment PROs.ResultsAmong 17.338 SSc patients in the EUSTAR registry (extracted in November 2019), 727 SSc-ILD patients fulfilled the inclusion criteria (median %pFVC 90 (IQR 74-104), median %pDLCO 60 (IQR 47-52)). Patients with %pFVCTable 1.Results are reported as number/number available (%) for dichotomic variables, or as median (IQR) (n available) for continuous variables.%pFVC≥70 (n=578)%pFVC)Age at disease onset (years)60.6 (52.3-69.3) (546)52.5 (45.6-63-7) (137)Disease duration (months)134.4 (77.5-212.2) (546)110.3 (66.3-199.7) (137)Male sex84/578 (14.5)32/149 (21.5)Anti-Scl70+231/468 (40.7)81/122 (66.4)Smoker ever52/389 (13.4)17/107 (15.9)Caucasian ethnicity545/569 (95.8)131/145 (90.3)dcSSc167/559 (29.9)74/147 (50.3)Oesophageal symptoms319/571 (55.9)93/147 (63.3)Muscle weakness78/565 (13.8)37/149 (24.8)CRP elevation141/540 (26.1)53/134 (39.6)Elevated sPAP (ECHO)45/456 (9.9)21/121 (17.2)Pericardial effusion2/448 (0.4)4/110 (3.6)Diastolic function abnormality151/431 (35.0)31/102 (30.4)Conduction blocks78/480 (16.3)35/120 (29.2)%pDLCO62 (52-74) (527)42 (35-53) (118)CHFS7 (1-23) (493)16 (2-34.8) (114)HAQ-DI0.63 (0.13-1.13) (578)1.25 (0.38-2) (139)VAS dyspnoea (0-100)15 (10-45) (391)40 (20-70) (109)NYHA stage 3/447/561 (8.4)37/143 (25.9)Subsequently, we created a DAG showing the proposed causal pathway considered relevant to the relationship between FVC and HAQ (Figure 1).ConclusionLung function as measured by FVC appears to correlate with worse patient-reported function in our unadjusted analysis of the large multicentre EUSTAR dataset. However, to estimate the total causal effect we must consider a multitude of potentially confounding factors, which need to be integrated and analysed in a causal inference framework. The proposed DAG will inform the development of simulations of the potential impact of bias (confounding, collider and omitted variable) on effect estimates we could obtain from EUSTAR cohort.References[1]Goh NS, et al. Am J Respir Crit Care Med, 2008.Disclosure of InterestsMaria Grazia Lazzaroni Grant/research support from: Research grant from Boehringer-Ingelheim, Michelle Wilson Grant/research support from: Research grant from Boehringer-Ingelheim, Elizabeth Hensor: None declared, Jörg H.W. Distler: None declared, Giovanna Cuomo: None declared, Elise Siegert: None declared, Ulf Müller-Ladner: None declared, Yannick Allanore: None declared, Maria Joao Salvador: None declared, Branimir Anic: None declared, Ulrich Walker: None declared, László Czirják: None declared, Camillo Ribi: None declared, Cristina-Mihaela Tanaseanu: None declared, Armando Gabrielli: None declared, Anna-Maria Hoffmann-Vold: None declared, Oliver Distler: None declared, Francesco Del Galdo: None declared

Background:In SSc, ILD is a major cause of morbidity and mortality. High resolution computed tomography (HRCT) is the gold standard for the diagnosis. Predictors of ILD onset are eagerly awaited to improve SSc-ILD management. Pulmonary function test (PFTs) are routinely performed to measure lung function changes.Objectives:Our aim was to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) in predicting the development of SSc-ILD.Methods:The longitudinal data of DLCO, FVC and ILD on HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t0), after 12 (±4) (t1) and 24 (±4) (t2) months. Patients with negative HRCT for any sign of ILD both at t0 and t1 were included. Patients who presented or developed pulmonary hypertension during the study period were excluded. At baseline, demographic data, disease duration from Raynaud’s onset, disease subsets, autoantibodies and other laboratory and instrumental data were recorded.Results:474/17805 patients were eligible for the study (403 females, 71 males): 26.0% dcSSc, 58.3% lcSSc, 220 (48.0%) patients with positive anticentromere antibodies (ACA) and 117 (25.4%) with positive antitopoisomerase I antibodies (Topo-I abs). Among all enrolled patients, 46 (9.7%) developed HRCT signs of ILD at t2. Patients with Topo-I abs showed an association with ILD development at t2 (16.7% vs 7.8%, p=0.0031), contrarily ACA positive patients were negatively associated with ILD appearance after 2 years of follow-up (4.4% vs 14.4%, p=0.0001). Positive t2 HRCT patients had a significant lower value of DLCO and FVC at all three assessments when compared to patients with a negative HRCT at t2 (Table 1) and both t0 DLCO and FVC values negatively correlated with ILD development (Table 1). The mean t0 to t1 change (Δ) of DLCO in patients with negative t2 HRTC and positive t2 HRCT were -0.5 (±12.6) and -1.0 (±15.1), respectively. The mean t0 to t1 ΔFVC in patients with negative t2 HRTC and positive t2 HRCT were -0.2 (±10.6) and 0.1 (±11.5), respectively. None of them predicted the appearance of ILD at t2 (ΔDLCO: OR (IC) 0.997 (0.97-1.02), p=0.8024; ΔFVC OR (IC) 1.002 (0.97-1.03), p=0.8664). The data showed an association between t0 DLCO value0 FVC value0 DLCOConclusion:Our data suggest that an impaired baseline DLCO (Table 1.DLCO and FVC values at t0, t1 and t2 values in patients with positive or negative HRCT for ILD at t2 and their statistical differences.Patients without ILD at t2 (mean±SD)Patients with ILD at t2 (mean±SD)OR (95%CL)p-valueDLCO at t079.0 ± 16.669.9 ± 17.40.97 (0.95 - 0.99)0.0006DLCO at t178.4 ± 16.868.9 ± 18.60.97 (0.95 - 0.98)0.0005DLCO at t278.0 ± 17.065.1 ± 19.10.95 (0.93 - 0.97)FVC at t0102.2 ± 17.394.6 ± 16.20.97 (0.96 - 0.99)0.0052FVC at t1101.9 ± 17.994.7 ± 16.50.98 (0.96 - 0.99)0.0092FVC at t2101.6 ± 17.694.5 ± 20.00.98 (0.96 - 1)0.0126Disclosure of Interests:Gemma Lepri: None declared, Cosimo Bruni Speakers bureau: CB reports personal fees from Actelion, personal fees from Eli Lilly, Grant/research support from: CB reports personal fees from Actelion, personal fees from Eli Lilly, grants from European Scleroderma Trial and Research (EUSTAR) group, grants from New Horizon Fellowship, grants from Foundation for Research in Rheumatology (FOREUM), grants from Fondazione Italiana per la Ricerca sull’Artrite (FIRA), outside the submitted work, Lorenzo Tofani: None declared, Alberto Moggi Pignone: None declared, Martina Orlandi: None declared, Tomasetti Sara Speakers bureau: Speaker’s fees for Roche and Boehringer Ingelheim, Mike Hughes: None declared, Francesco Del Galdo: None declared, Rosaria Irace: None declared, Oliver Distler Grant/research support from: OD (last three years) 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)., Valeria Riccieri: None declared, Yannick Allanore Speakers bureau: YA received personal fees from Boehringer, Sanofi, Menarini and Medsenic and grants from Alpine with regards to the management of systemic sclerosis, Grant/research support from: YA received personal fees from Boehringer, Sanofi, Menarini and Medsenic and grants from Alpine with regards to the management of systemic sclerosis, Ana Maria Gheorghiu: None declared, Elise Siegert: None declared, Jeska de Vries-Bouwstra: None declared, Eric Hachulla: None declared, Mohammed Tikly: None declared, Nemanja Damjanov: None declared, Francois Spertini: None declared, Luc Mouthon: None declared, Anna-Maria Hoffmann-Vold Speakers bureau: AMHV: received consulting fees from Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme and Roche; and grants from Boehringer Ingelheim., Consultant of: AMHV: received consulting fees from Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme and Roche; and grants from Boehringer Ingelheim., Grant/research support from: AMHV: received consulting fees from Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme and Roche; and grants from Boehringer Ingelheim., Armando Gabrielli: None declared, Serena Guiducci: None declared, Marco Matucci-Cerinic Speakers bureau: has received consulting fees or honorarium from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche, Grant/research support from: has received consulting fees or honorarium from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche, Daniel Furst: None declared, Silvia Bellando Randone: None declared

Background:Patient Reported Outcomes (PROs) are used to capture disease impact on patients’ Health Related Quality of Life (HRQoL) and they have been increasingly used as endpoints in clinical trials for Systemic Sclerosis (SSc). The DeSScipher project within the EUSTAR group highlighted dyspnea as one of the factors more strongly related with the highest SHAQ scores (1). Nevertheless, the SENSCIS trial in SSc-ILD (2) showed the efficacy of Nintedanib in reducing the annual rate of FVC loss, as compared to placebo, without significant changes in the PROs used as secondary endpoints (St. George’s Respiratory Questionnaire and the FACIT-Dyspnoea questionnaire). Since patient’s perspective is a crucial determinant to define the overall relevance of an intervention, the performance of PROs in reflecting different lung functional stages is a relevant issue in SSc.Objectives:To analyse in a prospective SSc cohort the inference of reduced lung function as measured by FVC on median PRO scores and the correlation among distinct commonly used PROs.Methods:A cross-sectional study was performed on data exported from the STRIKE database regarding SSc patients followed in Leeds Scleroderma Programme for SSc. Data included records of periodical visits with scores of different PROs commonly used in SSc (Scleroderma-Health Assessment Questionnaire (SHAQ), Cochin Hand Function Scale (CHFS) and Borg dyspnoea scale) and FVC%-predicted (%pFVC) and DLCO%-predicted (%pDLCO). SHAQ score was calculated as the mean value of HAQ (0-3) with the average of the 7-VAS scores divided by 3.33. The 7-VAS (score 1-10) were 1: pain, 2: general function, 3: arthritis, 4: gastro-intestinal, 5: dyspnoea, 6: Raynaud Phenomena; 7: digital ulcers. The correlation of FVC with distinct PROs, and the inter-PRO correlation, were analysed through the non-parametric Spearman test.Results:Complete data were available from 182 visits of 87 SSc patients (41 with diffuse and 46 with limited cutaneous involvement). Mean %pFVC was 95.16 ±24.93 (median 95) and mean %pDLCO was 59.31±16.51 (median 59). Overall, FVC and DLCO showed a moderate correlation with SHAQ (r=-0.36, pInter PROs analysis showed that CHFS score had a stronger correlation with SHAQ than Borg dyspnoea score in the overall population (r:0.86 vs. r:0.57, both pConclusion:The analysis of a single centre prospective cohort of SSc patients, suggests a small inference of lung function in the overall SHAQ. The stronger correlation of SHAQ with CHFS, than with Borg score, suggests a higher weight of hand function on SHAQ in this population with relatively conserved lung function. In patients with %pFVC 70%, suggesting that mild reductions in FVC might not be perceived by the patients, or at least they might not modify HrQoL as measured by SHAQ.References:[1]Jaeger VK, et al. Rheumatology 2017;57(3):441-50.[2]Distler O, et al. N Engl J Med 2019; 380:2518-2528.Disclosure of Interests:Maria Grazia Lazzaroni Grant/research support from: Boehringer-Ingelheim, Giuseppina Abignano: None declared, Michelle Wilson: None declared, Vishal Kakkar: None declared, Francesco Del Galdo Consultant of: Astra-Zeneca, Boehringer-Ingelheim, Mitsubishi-Tanabe, Capella Biosciences, Kymab, Actelion, Grant/research support from: Astra-Zeneca, Boehringer-Ingelheim, Mitsubishi-Tanabe, Capella Biosciences, Kymab, Actelion

Background:Interstitial lung disease (ILD) is the leading cause of mortality in patients with Systemic Sclerosis (SSc). Forced Vital Capacity (FVC) is a major indicator of severity in SSc ILD. The ELF serum test and its constituent biomarkers (HA, PIIINP and TIMP-1) have shown to correlate with FVC in two large, independent multicentre cohorts of 457 patients, but also showed a correlation with age.Objectives:Here we aimed to investigate the relationship of the ELF biomarkers and age in a large population of healthy controls and to identify a combined clinical and biomarkers model to stratify for risk of ILD progression in a multicentre longitudinal cohort of patients with SSc.Methods:ELF score was measured in sera from 925 healthy controls in one centre and 869 longitudinal samples from 254 SSc patients from 6 centres across 4 European countries. Clinical data were recorded according to EUSTAR Minimal Essential dataset. FVC% change over time was estimated by Mixed-effects modelling. Patients were then divided in two groups: progressors, with a %FVC drop > 3%/year (according to published MCID) and a group of patients with stable or improving FVC. Lasso penalised regression was carried out with biomarkers and the available clinical and demographic variables at patient’s first visit as potential predictors. The resulting linear predictor was used to derive two thresholds, one for optimal sensitivity (rule-out) and one for optimal specificity (rule-in). Patients within thresholds were further selected according to the ratio of TIMP-1: PIIINP (Figure 1).Results:HA was the only ELF biomarker that correlated significantly with age in the healthy control cohort. Therefore, we defined by linear regression a “residual HA” which accounted for age. TIMP1, PIIINP and residual HA were then considered as distinct biomarkers in the analysis of the SSc cohort. 189 SSc patients with 785 time-points had complete datasets and were included in the analysis. Median follow up was 33 months (IQR 18-48). One-hundred and forty patients (74%) were classified as non progressors, 94 (50%) with no change or improving FVC and 46 (24%) with FVC drop Conclusion:Building on the face and content validity of the biomarkers included in the ELF score, here we identify an easy to assess combined clinical and biomarker model to stratify patients for their risk of ILD progression. Despite its derivation from a large multicentre cohort, independent validation will determine the clinical value of Scleroscore as a stratification tool for risk of progression of SSc ILD.Disclosure of Interests:Michelle Hutchinson: None declared, Giuseppina Abignano: None declared, Jelena Blagojevic: None declared, Silvia Laura Bosello: None declared, Yannick Allanore Grant/research support from: Alpine, Boehringer Ingelheim, Genentech/Roche, Medsenic, and Sanofi, Christopher Denton Consultant of: Corbus, Actelion, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Inventiva, Boehringer Ingelheim, Roche, CSL Behring, Acceleron, Horizon, Arxx Therapeutics, Grant/research support from: Corbus, Actelion, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Inventiva, Boehringer Ingelheim, Roche, CSL Behring, Acceleron, Horizon, Arxx Therapeutics, Oliver Distler Consultant of: 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, Grant/research support from: 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, Paul Emery Consultant of: Lilly, Abbvie, Roche, Grant/research support from: Lilly, Marco Matucci-Cerinic Consultant of: Chemomab, Lilly, Abbvie, Actelion, Francesco Del Galdo Speakers bureau: Astra-Zeneca, Boehringer Ingelheim, Actelion, Consultant of: Astra-Zeneca, Mitsubishi-Tanabe, Capella Biosciences, Chemomab, Actelion, Boehringer-Ingelheim, Grant/research support from: Capella Biosciences, Chemomab, Kymab, Mitsubishi-Tanabe

Background:Oxidative stress associated with vascular damage represents one the major contributor in the pathogenesis of systemic sclerosis (SSc) [1]. Indeed, different studies demonstrated that excessive free radicals production can contribute to the activation of fibrotic process in the skin and visceral organs [1]. CXCL10 and CXCL11, together with their receptor CXCR3, are involved in vascular damage and in fibrosis [2]. Furthermore, these chemokines have been proposed as biomarkers of vascular damage progression and severe SSc prognosis [3].Emerging evidences highlight the beneficial effects of the phosphodiesterase type 5 (PDE5) inhibitor, sildenafil, to protect different cell types from reactive oxygen species (ROS)-induced DNA damage, in vitro [3]. This effect has been linked to modulation of CXCL10 concentration in different pathological conditions [4,5].Objectives:Here we set out to investigate the effects of sildenafil, in modulating the CXCR3/CXCL10, -11 inflammatory axis in dermal fibroblasts exposed to oxidative stress, in vitro.Methods:Human dermal fibroblasts isolated by SSc skin biopsies were treated for 24h with 100µM of hydrogen peroxide (H2O2), in the presence or not of sildenafil (1µM). Dermal fibrobalsts from healthy skin were used as controls. CXCL10 and CXCL11 were evaluated in cell medium by luminex technology assay; expression of chemokine receptor (CXCR)3 and peroxisome proliferator-activated receptor (PPARγ) (a regulator of CXCL10,-11 mRNA) was evaluated by western blot assay.Results:As showed in figure 1, SSc fibroblasts (grey bar) showed similar basal levels of CXCL10 (A) and CXCL11 (B) to healthy controls (black bar). H2O2 induced a significant increase of both chemokines only in SSc fibroblasts (by 4.6 fold for CXCL10 and by 4.2 fold for CXCL11) (*Pvs. c; #Pvs. healthy controls). Sildenal pre-incubation reduced by approximatively 50% the effects of H2O2 on chemokines release (Figure 1A and B) (§P2O2), and reduced the expression of CXCR3 and PPARγ induced by hydrogen peroxyde exposure (data not shown).Conclusion:In vitro study on dermal fibroblasts support clinical studies to determine the efficacy of sildenafil in the preventing tissue damage and fibrosis in SSc, by reducing the pro-inflammatory activation induced by oxidative stress.References:[1]Di Luigi L, Sgrò P, Duranti G, Sabatini S, Caporossi D, Del Galdo F, Dimauro I, Antinozzi C. Sildenafil Reduces Expression and Release of IL-6 and IL-8 Induced by Reactive Oxygen Species in Systemic Sclerosis Fibroblasts. Int J Mol Sci. 2020 Apr 30;21(9):3161. doi: 10.3390/ijms21093161. PMID: 32365773; PMCID: PMC7246497.[2]Koper OM, Kamińska J, Sawicki K, Kemona H. CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration. Adv Clin Exp Med. 2018 Jun;27(6):849-856. doi: 10.17219/acem/68846. PMID: 29893515.[3]Crescioli C, Corinaldesi C, Riccieri V, Raparelli V, Vasile M, Del Galdo F, Valesini G, Lenzi A, Basili S, Antinozzi C. Association of circulating CXCL10 and CXCL11 with systemic sclerosis. Ann Rheum Dis. 2018 Dec;77(12):1845-1846. doi: 10.1136/annrheumdis-2018-213257. Epub 2018 May 14. PMID: 29760155; PMCID: PMC6241615.[4]Giannattasio S, Corinaldesi C, Colletti M, Di Luigi L, Antinozzi C, Filardi T, Scolletta S, Basili S, Lenzi A, Morano S, Crescioli C. The phosphodiesterase 5 inhibitor sildenafil decreases the proinflammatory chemokine IL-8 in diabetic cardiomyopathy: in vivo and in vitro evidence. J Endocrinol Invest. 2019 Jun;42(6):715-725. doi: 10.1007/s40618-018-0977-y. Epub 2018 Nov 10. PMID: 30415310; PMCID: PMC6531405.[5]You N, Li J, Huang X, Wu K, Tang Y, Wang L, Li H, Mi N, Zheng L. COMMD7 activates CXCL10 production by regulating NF-κB and the production of reactive oxygen species. Mol Med Rep. 2018 May;17(5):6784-6788. doi: 10.3892/mmr.2018.8706. Epub 2018 Mar 8. PMID: 29532873.Disclosure of Interests:None declared

Background:The ACR Composite Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) was developed to measure the probability of improvement in response to treatment in patients with early diffuse cutaneous SSc (dcSSc), accounting for new/worsening cardiopulmonary involvement and/or renal crisis, and changes in modified Rodnan skin score, forced vital capacity, health assessment questionnaire disability index, and patient’s and physician’s global impressions. In patients with SSc-ILD, treatment response may be reflected as slower progression, stabilisation or improvement.Objectives:Using data from patients with dcSSc and ILD in the placebo group of the SENSCIS trial, we analysed the probability of improvement using the ACR CRISS score at week 52. We also evaluated whether the CRISS numerator could provide information on the spectrum of responses in this patient population.Methods:The SENSCIS trial enrolled subjects with SSc-ILD with onset of first non-Raynaud symptom ≤7 years before screening, FVC ≥40% predicted, and fibrotic ILD ≥10% extent on an HRCT scan. Subjects on prednisone ≤10 mg/day (or equivalent) and/or stable therapy with mycophenolate or methotrexate were allowed to participate. Subjects were randomised to receive nintedanib or placebo. Subjects were not randomised by use of mycophenolate. In patients randomised to receive placebo who had dcSSc and/or mRSS >15 at baseline, we analysed the ACR CRISS and its numerator at week 52 in subgroups by use of mycophenolate at baseline. Analyses were exploratory and descriptive.Results:Of 117 analysed subjects in the placebo group who had dcSSc and/or mRSS >15 at baseline, 60 (51.3%) were taking mycophenolate at baseline. Compared with patients not taking mycophenolate at baseline, those taking mycophenolate had a lower mean age (48.4 [SD 11.8] vs 53.1 [13.4] years), lower mean FVC % predicted (68.8 [17.0] vs 73.0 [14.6]), and a greater proportion were female (76.7% vs 71.9%); median time since first onset of non-Raynaud symptom was similar (3.9 vs 4.5 years, respectively) as was mean (SD) mRSS (16.5 [7.7] vs 15.9 [8.0], respectively). One patient (taking mycophenolate at baseline) had limited cutaneous SSc. At week 52, median (Q1, Q3) ACR CRISS score was 0.036 (0.001, 0.601) in subjects taking mycophenolate and 0.002 (0.000, 0.112) in subjects not taking mycophenolate at baseline, and mean (SD) ACR CRISS score was 0.28 (0.37) in subjects taking mycophenolate and 0.16 (0.31) in subjects not taking mycophenolate at baseline (Figure 1). In these groups, respectively, 25.0% and 14.0% of subjects had CRISS score >0.6 (considered improved) at week 52. The CRISS numerator provided a broader distribution of response values, but was not informative in this patient population.Conclusion:In exploratory analyses, among subjects with dcSSc and ILD who received placebo in the SENSCIS trial, the proportion considered improved at week 52 based on ACR CRISS score was numerically greater in patients taking than not taking mycophenolate at baseline. There remains a need for composite scores that provide better interpretation of the magnitude of response in patients with SSc.Acknowledgements:The SENSCIS trial was funded by Boehringer Ingelheim. Medical writing support was provided by FleishmanHillard Fishburn, London, UK. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE).Disclosure of Interests:Francesco Del Galdo Speakers bureau: Actelion and AstraZeneca, Consultant of: Actelion, AstraZeneca, Boehringer Ingelheim, Capella BioScience, ChemomAb and Mitsubishi Tanabe Pharma, Grant/research support from: Capella BioScience, Kymab and Mitsubishi Tanabe Pharma, Oliver Distler Consultant of: AbbVie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Bayer, Blade Therapeutics, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos NV, GlaxoSmithKline, Glenmark Pharmaceuticals, Horizon (Curzion) Pharmaceuticals, Inventiva, IQVIA, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Target Bioscience, Topadur Pharma and UCB, Grant/research support from: Kymera Therapeutics and Mitsubishi Tanabe Pharma, Christopher Denton Speakers bureau: Boehringer Ingelheim, Corbus, Janssen, and Mallinckrodt Pharmaceuticals, Consultant of: Acceleron Pharma, Arxx Therapeutics, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos NV, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mallinckrodt Pharmaceuticals, Roche, Sanofi and UCB, Grant/research support from: Arxx Therapeutics, GlaxoSmithKline and Servier, Yannick Allanore Consultant of: Boehringer Ingelheim, Medsenic, Menarini and Sanofi, Grant/research support from: Alpine Pharmaceuticals, Daniel Wachtlin Employee of: Currently an employee of Boehringer Ingelheim, Margarida Alves Employee of: Currently an employee of Boehringer Ingelheim, Dinesh Khanna Shareholder of: Eicos Sciences, Inc. (less than 5%), Consultant of: Acceleron Pharma, Actelion, AbbVie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead Sciences, Galapagos NV, Genentech/Roche, GlaxoSmithKline, Horizon Therapeutics, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis and United Therapeutics, Grant/research support from: Bayer, Bristol-Myers Squibb, Horizon Therapeutics, Immune Tolerance Network, National Institutes of Health and Pfizer, Employee of: Chief Medical Officer- CiviBioPharma/Eicos Sciences, Inc.

Background:Skin fibrosis is the hallmark fibrotic manifestation of systemic sclerosis (SSc). Despite a key role of tissue fibroblasts, skin changes extend to the keratinocyte layer, which contribute to the loss of skin function. RNA seq. analysis of SSc patient forearm skin showed that palmoplantar specific Keratin 9 (CK9) was highly expressed (1). SSc affected skin shares several features with palmoplantar skin including increased keratinocyte layer thickness and lack of hair. Seminal work of last decade has shown that long noncoding RNA in the HOX loci play a crucial role in skin keratinocyte differentiation (2), with the lncRNA HOTAIR being one of the HOX lncRNA mostly expressed in the palmoplantar region.Objectives:Following recent data suggesting a role of HOTAIR in the profibrotic phenotype of dermal fibroblasts in SSc (3), here we set out to determine if HOTAIR expressed in SSc dermal fibroblasts was a contributing factor to the high levels of CK9 found in SSc patient skinMethods:Full-thickness skin biopsies were surgically obtained from the forearms of patients with SSc of recent onset. Fibroblasts were isolated and cultured in monolayers. HOX transcript antisense RNA (HOTAIR) was expressed in healthy dermal fibroblasts by lentiviral induction employing a vector containing the specific sequence. Exosomes were isolated from dermal fibroblast media using the Total exosome isolation reagent (Thermo Fisher). Enhancer of zeste 2 (EZH2) was blocked with GSK126 inhibitor. Skin equivalents were created using scramble and HOTAIR expressing fibroblasts with primary keratinocytesResults:Media from both SSc patient fibroblasts and HOTAIR expressing fibroblasts induced CK9 expression in healthy keratinocytes in vitro. In addition, HOTAIR expressing fibroblasts induces CK9 expression in keratinocytes in 3D skin equivalent models. Media fractionation studies indicated that HOTAIR was present in fibroblasts exosomes and found at a higher concentration (2.7 fold p=0.01) in exosomes from SSc fibroblasts. Importantly, transfection of Exosomal RNAs from SSc fibroblasts could reproduce the increase in CK9 in keratinocytes. Mechanistically, CK9 induction was mediated by changes to the histone methylation profile in the keratinocytes through EZH2.Conclusion:Pro-fibrotic dermal fibroblasts in systemic sclerosis contribute to the overall skin loss of function by inducing CK9 in adjacent keratinocytes through transfer of the long non-coding RNA HOTAIR. Unraveling the crosstalk of activated fibroblasts with adjacent cells may lead to identify therapeutic targets to re-establish tissue homeostasis and function during fibrosis.References:[1]Assassi S et.al Arthritis and Rheumatology 2015[2]Rinn JL et.al Cell 2007[3]Wasson CW et.al Annals of Rheumatic Disease 2020Disclosure of Interests:Chris Wasson: None declared, rebecca ross: None declared, Jessica Bryon: None declared, Francesco Del Galdo Speakers bureau: Speakers bureau: Astra-Zeneca, Boehringer Ingelheim, Actelion, Consultant of: Astra-Zeneca, Mitsubishi-Tanabe, Capella Biosciences, Chemomab, Actelion, Boehringer-Ingelheim, Grant/research support from: Grant/research support from: Capella Biosciences, Chemomab, Kymab, Mitsubishi-Tanabe

Background:Primary systemic sclerosis heart involvement (pSSc-HI) is described in the majority of SSc patients when sensitive methods such as cardiovascular magnetic resonance (CMR) are used1. The natural history of these subclinical findings are unknown.Objectives:To evaluate for interval change in subclinical pSSc-HI, the association between change in CMR abnormalities and disease phenotype and whether disease modifying antirheumatic (DMARD) and/or vasodilator treatment influence the CMR course.Methods:SSc patients, fulfilling the 2013 ACR/EULAR criteria, with no cardiovascular (CV) disease, diabetes and no more than 2 CV risk factors had two CMRs performed (V1 & V2; minimum 1 year apart). A 3T CMR with late gadolinium enhancement (LGE), T1 mapping for extracellular volume (ECV of diffuse fibrosis) quantification and stress perfusion was undertaken.Results:31 SSc patients were evaluated, with median (IQR) follow up (between the 2 CMR scans) of 33 (17, 37) months. Median (IQR) age was 52 (47,60), 32% had diffuse cutaneous SSc, 52% interstitial lung disease (ILD), 29% Scl70+.4/31 patients had a non-ischaemic LGE pattern suggesting focal fibrosis at V1, with no change in the pattern, distribution, or median (IQR) LGE scar mass between V1 and V2 [1.88 (1.01, 6.34) vs 1.70 (1.21, 4.18)]. At V2, 2 additional patients showed focal fibrosis, of which one had an episode of clinically diagnosed myocarditis. No significant change in ECV, T1 native, myocardial perfusion reserve (MPR) or left ventricle (LV) volumes and function were noted at V2 compared with V1 (p>0.01).SSc patients with either increase in pre-existing LGE scar mass (n=1) or new fibrosis were all dcSSc, with ILD, 2 Scl70+. A reduction in forced vital capacity and total lung capacity associated with a reduction in LV ejection fraction (LVEF) (rho=0.413, p=0.021; rho-0.335, p=0.07) and MPR (rho=0.543, p=0.007; rho=0.627, p=0.002).Patients receiving DMARD treatment had higher baseline LV end-diastolic volume compared to those with no DMARD treatment [mean (SD) 78 (19) vs 69 (10), p=0.167]. A decrease in LV stroke volume and an increase in T1 native at V1 vs V2 was noted for those on DMARD [mean (SD) 49 (8) vs 46 (8), p =0.023; 1208 (65) vs 1265 (56), p=0.008 respectively] (Figure 1). No significant change in CMR measures in those receiving vasodilator or angiotensin-converting-enzyme inhibitor treatment was noted (p>0.01).Figure 1.Mean (SD) of T1 native, LVSV/BSA, LVEF, and LVEDV/BSA at V1 compared to V2 in those with and without DMARD treatment. BSA, body surface area; DMARD, disease modifying antirheumatic drugs; EDV, end-diastolic volume; SV, stroke volume; LV left ventricular; EF, ejection fraction.Conclusion:This first, pilot longitudinal study of CMR-defined subclinical pSSc-HI suggests largely stable appearances with follow-up. Progression of new focal fibrosis and decline in LV function and MPR, where observed, associated with poor prognostic factors of SSc and ILD progression. Consistent with this, individuals on DMARD appeared to show interval decline. Larger longitudinal studies are warranted to confirm these findings and inform on utility of CMR monitoring of subclinical pSSc-HI in poor prognosis SSc.References:[1]Ntusi NA et al, J Cardiovasc Magn Reson. 2014Disclosure of Interests:Raluca-Bianca Dumitru: None declared, Lesley Anne Bissell: None declared, Bara Erhayiem: None declared, Graham Fent: None declared, Ananth Kidambi: None declared, Giuseppina Abignano: None declared, John Greenwood: None declared, John Biglands: None declared, Francesco Del Galdo: None declared, Sven Plein: None declared, Maya H Buch Grant/research support from: Pfizer, Roche, and UCB, Consultant of: Pfizer; AbbVie; Eli Lilly; Gilead Sciences, Inc.; Merck-Serono; Sandoz; and Sanofi

Background:Previous studies have shown that Optical Coherence Tomography (OCT) is a reliable biomarker of skin fibrosis and significantly correlates with the severity of the skin involvement in Systemic Sclerosis (SSc)1,2.Objectives:Aim of this cross-sectional study was to evaluate the performance of skin OCT to discriminate between SSc and healthy controls (HC) and to compare results with the current gold standard, the modified Rodnan skin score (mRss), in a different SSc study cohort.Methods:Dorsal forearm skin of consecutive diffuse cutaneous SSc (dcSSc) patients and matched-HC was scanned by an investigator blinded to the clinical data using Vivosight scanner (Michelson Diagnostics, Kent, UK). Minimum Optical Density (MinOD), Maximum OD (MaxOD) and OD at 300 micron-depth (OD300) were measured. Clinical involvement was assessed by a blinded operator using the mRss and results were compared with imaging data. Statistical analysis was performed using GraphPad Prism software V.7.0.Results:A total of 88 OCT images were obtained from 22 dcSSc patients [20 Female, mean age 49 (±11) years, 12 with < 5 years disease duration) and 22 HC (20 Female, mean age 50.7 (±6.7) years]. All OCT measures (MinOD, MaxOD and OD300) were significantly lower in SSc patients than in HC (p=0.011, pConclusion:These results confirm in a cohort different from those of the previous studies that skin OCT is able to reflect the severity of skin involvement in SSc. Longitudinal studies are needed to validate its potential as surrogate outcome measure of skin fibrosis in SSc patients.References:[1]Abignano G et al. Ann Rheum Dis 2013; 2. Pires NSM et al. Ann Rheum Dis 2018.Disclosure of Interests:None declared

Background:In the SENSCIS trial in patients with SSc-ILD, nintedanib reduced the rate of decline in FVC over 52 weeks vs placebo, with no difference between groups in change in mRSS.Objectives:Analyse correlation between progression of skin fibrosis and progression of SSc-ILD in the SENSCIS trial.Methods:Patients with SSc-ILD were randomised to receive nintedanib or placebo until the last patient reached week 52 but for ≤100 weeks. We calculated Spearman correlation coefficients between FVC (mL) at baseline and change from baseline in mRSS, mRSS at baseline and change from baseline in FVC (mL), and changes from baseline in mRSS and FVC at weeks 52 and 100 in all patients. We analysed the rate of decline in FVC (mL/year) in patients who did and did not have progression of skin fibrosis (relative change from baseline in mRSS >25% and absolute change from baseline >5 points) at week 52.Results:In the nintedanib (n=288) and placebo (n=288) groups, respectively, mean (SD) baseline FVC (mL) was 2459 (736) and 2541 (816) and mRSS was 11.3 (9.2) and 10.9 (8.8); 53.1% and 50.7% had dcSSc;18.4% and 16.0% had progression of mRSS at week 52. No meaningful correlations were observed in analyses between mRSS and FVC (Table). The mean (SE) annual rate of decline in FVC in the placebo group was similar in patients who did and did not have progression of mRSS (-95.2 [27.1] and -91.4 [15.7] mL/year, respectively). The effect of nintedanib vs placebo on reducing the rate of decline in FVC was numerically more pronounced in patients who did not have progression of mRSS vs those who did (difference [95% CI] 44.3 mL/year [0.6, 88.1] vs 24.6 [-53.7, 102.9]), but the interaction p-value (0.66) did not indicate heterogeneity in treatment effect between subgroups.Conclusion:In the SENSCIS trial, the proportion of patients who had progression of skin fibrosis over 52 weeks was low, without significant differences between placebo and nintedanib. No meaningful correlations were observed between skin fibrosis at baseline or progression of skin fibrosis and progression of SSc-ILD. The rate of decline in FVC was similar between patients who did and did not have progression of mRSS. These findings suggest that in the overall patient population in the SENSCIS trial, progression of skin fibrosis and progression of ILD were distinct manifestations of disease progression.Table:FVC at baseline and change from baseline in mRSSmRSS at baseline and change from baseline in FVCChanges from baseline in mRSS and FVCNCorrelation*NCorrelation*NCorrelation*Week 52Nintedanib2470.11 (-0.01, 0.23)241-0.08 (-0.20, 0.05)238-0.07 (-0.19, 0.06)Placebo2540.12 (-0.00, 0.24)257-0.15 (-0.27, -0.03)2520.03 (-0.09, 0.15)Week 100Nintedanib730.21 (-0.02, 0.42)73-0.06 (-0.29, 0.17)700.06 (-0.17, 0.30)Placebo660.28 (0.04, 0.49)730.04 (-0.19, 0.27)66-0.14 (-0.37, 0.10)*Spearman correlation coefficient (95% CI)Disclosure of Interests:Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Kristin Highland Grant/research support from: Boehringer Ingelheim - PI for SENSCIS and SENSCIS-ON trials (paid to my institution), Consultant of: Kristin Highland has acted as a consultant to Boehringer Ingelheim. She was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), Speakers bureau: Kristin Highland reports speaker fees from Boehringer Ingelheim, Anna-Maria Hoffmann-Vold Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion, Bayer, GlaxoSmithKline, Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Otylia Kowal-Bielecka Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Inventiva, MSD, Novartis, Speakers bureau: Boehringer Ingelheim, Medac, Novartis, Roche, Sandoz, Ulrich Walker Grant/research support from: Ulrich Walker has received an unrestricted research grant from Abbvie, Consultant of: Ulrich Walker has act as a consultant for Abbvie, Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, MSD, Novartis, Pfizer, Phadia, Roche, Sandoz, Sanofi, and ThermoFisher, Paid instructor for: Abbvie, Novartis, and Roche, Speakers bureau: Abbvie, Actelion, Bristol-Myers Squibb, Celgene, MSD, Novartis, Pfizer, Phadia, Roche, Sandoz, and ThermoFisher, Francesco Del Galdo: None declared, Madelon Vonk Grant/research support from: Janssen and Ferrer, Consultant of: Boehringer Ingelheim, Janssen and GSK, Speakers bureau: Boehringer Ingelheim, BMS and Roche, Laura Hummers Grant/research support from: Boehringer Ingleheim, Corbus pharmaceuticals, CSL Behring, Cumberland Pharmaceuticals, and GlaxoSmithKline, Consultant of: Boehringer Ingleheim, Corbus pharmaceuticals, and CSL Behring, Elvira Erhardt Employee of: Employee of Boehringer Ingelheim, Manuel Quaresma Employee of: Employee of Boehringer Ingelheim, Margarida Alves Employee of: Employee of Boehringer Ingelheim, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl

Background:The VEDOSS study has recently indicated that more than 80% of patients affected by Raynaud’s phenomenon (RP) with specific SSc auto-antibodies and capillaroscopy changes satisfied ACR/EULAR 2013 criteria within 5 years. These data suggest that there is a window of opportunity for early detection of SSc in these patients.Objectives:Here we aimed to determine whether sera, skin biopsies and skin fibroblasts cultured from these patients showed any biomarker sign of SSc.Methods:Fifty-nine at risk patients identified by having RP and SSc auto-antibodies or capillaroscopy pattern (or both) were enrolled in the Kennedy national inception cohort. Sera were tested for IFN inducible chemokines (CXCL-9,10 and 11 and CCL2, 8 and 19) and biomarker of extracellular matrix turnover (ELF test), all previously shown to be increased in SSc. Further, two 3mm skin biopsies were taken from the forearms from 3 ACA+ve (anti-centromere antibodies), 3 SCL70+ve patients. One biopsy was subjected to histology analysis, including haematoxylin and eosin staining and immunohistological staining for Collagen Type 1, alpha-SMA, Caveolin 1 and CD31 as endothelial marker. The other biopsy was used to explant fibroblasts cultures. mRNA and protein were isolated from primary fibroblasts and processed for RT-qPCR and western blotting analyses.Results:Sera from at risk patients showed overall higher IFN inducible chemokines and ELF test (Pcompared to healthy control fibroblasts. Furthermore, fibroblasts from ACA or SCL70+ve patients showed limited TGF-beta induced increase in collagen and SMA expression, similar to SSc fibroblasts.Conclusion:Although pilot in nature, this study suggests that patients “at risk” already show biomarker signs of SSc both in their sera, at skin biopsy and fibroblast level. Longitudinal studies on patients at this stage of pre-clinical disease may inform on the stratification strategies for imminent progression to clinical manifestations, and offer both insights on pathogenesis of clinical signs and a window of opportunity for delaying the onset clinical intervention trials.Disclosure of Interests:rebecca ross: None declared, Ioanna Georgiou: None declared, Antonio Carriero: None declared, Giuseppina Abignano: None declared, Chris Wasson: None declared, Gemma Migneco: None declared, Ariane Herrick: None declared, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Francesco Del Galdo: None declared

Background:Neointima proliferation is a key pathologic feature of Systemic Sclerosis (SSc), causing arterial vessel narrowing and being the recognised culprit pathological lesion in Digital Ulcers (DUs), pulmonary artery hypertension and renal crisis. Nevertheless, there are no validated imaging techniques to assess the severity of vascular involvement in SSc. Digital Artery Volume index (DAVIX ©) is an MRITime of flight angiographybased quantitative score of digital arteries flow, without the need to administer contrast.Objectives:To determine the value of DAVIX in predicting the onset of digital ulcers (DUs), the worsening of patient reported outcomes (PROs) and clinical parameters in SSc patients.Methods:We enrolled 91 consecutive patients affected by Raynaud’s phenomenon, 63 of which fulfilled the 2013 ACR/EULAR classification criteria for SSc and 28 had a score Results:78/91 patients were females and median disease duration was 4 years (IQR1.91-9). Complete historical and prospective follow-up data were available for 68 patients. DAVIX© correlated with mRSS (r=-0.258, p=0.017), DLCO% (r=0.338, p=0.008) and capillaroscopy pattern (r=-0.388, p=0.001). In patients with DUs, DAVIX© showed a stronger correlation with DLCO% (r=0.786, p=0.048). DAVIX© predicted the worsening of HAQ-DI (r=-0.295, p=0.029), sHAQ (r =-0.333, p=0.029) and VAS pain (r=-0.269, p=0.038) independently of the presence of DUs. In the context of DU, 7 patients had DUs at baseline (5 with a positive history for DUs). 12 patients developed DUs within 12 months, 3 of them had DUs at baseline. 38 patients did not have either previous or current DUs, neither did they develop new DUs within 12 months. DAVIX of patients with current DUs was 3-fold lower than DAVIX of patients without DUs (0.18 vs 0.63 p=0.0093). Further, DAVIX of patients with positive history of DUs was 50% lower than in patient with a negative history (median 0.34 vs 0.64, p=0.0052). In patients without current DUs, DAVIX of patients who developed new DUs within 12 months of follow-up was 3-fold lower than in patients who didn’t develop DU (0.21 vs 0.65, p=0.0156). ROC curve analysis indicated that DAVIX threshold Conclusion:Outcome measures of vascular involvement in SSc are scanty. We demonstrated that DAVIX© is a promising and feasible surrogate outcome measure of neointima proliferation in SSc and a useful imaging biomarker of vascular disease activity. The predictive value of DAVIX for the future onset of DU could be employed as a useful stratification tool in clinical trials. The value of DAVIX in predicting the worsening of PROs and clinical parameters in overall patients, may offer insights on the role of vascular disease activity in the overall progression of SSc.References:[1]Lettieri G, Abignano G, et al Digital artery volume index: the first objective, automated, non-invasive imaging diagnostic of macrovascular involvement in ssc.Annals Rheum Dis2018Disclosure of Interests:Klodian Gjeloshi: None declared, Fiammetta Danzo: None declared, Giovanni Lettieri: None declared, Giuseppina Abignano: None declared, Mark Hinton: None declared, Anne-Maree Dean: None declared, Giovanna CUOMO: None declared, Olga Kubassova Shareholder of: IAG, Image Analysis Group, Consultant of: Novartis, Takeda, Lilly, Employee of: IAG, Image Analysis Group, Francesco Del Galdo: None declared

Background:The main clinical associations of anti-PM/Scl in Systemic Sclerosis (SSc) so far reported include calcinosis, myositis and interstitial lung disease (ILD). Nevertheless, data regarding the long-term outcome of ILD in these patients are lacking. A single centre Spanish cohort reported a better functional outcome in 14 SSc-ILD patients anti-Pm/Scl+ as compared to 49 anti-Topo I after a mean follow-up of 7 years (1).Objectives:To analyze the long-term outcome of ILD in a large multicentre EUSTAR study dedicated to anti-Pm/Scl SSc patients.Methods:A case-control study within the EUSTAR cohort collected 165 anti-PM/Scl+ SSc cases and 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration, and age at onset. Data for ILD at HRCT were available for 162/165 cases and 249/257 controls. Data for pulmonary function tests (PFT) at the baseline (T0), 1 year after diagnosis (T1) and at the last visit (LV) were analyzed.Results:A significantly higher frequency of ILD was reported in anti-Pm/Scl+ cases vs anti-Pm/Scl- controls (62.3% vs 39.4%, p:In ILD cases, %pFVC tended to improve from T0 (85.1±18.3) to T1 (89.5±16.5, p:0.045) and to LV (87.9±16.9, p:0.057), while in ILD controls remained stable from T0 (90.4±18.5) to T1 (91.1±16.5, p:0.38) and significantly declined to LV (85.0±18.0, p:0.0002). %pDLCO remained stable from T0 (60.5±16.8) to T1 (60.1±17.6, p:0.87) and to LV (60.4±16.9, p:0.77) in ILD cases, while significantly declined from T0 (67.0±18.9) to T1 (62.7±18.2, p:0.0016) and to LV (59.6±18.4, pDelta %pFVC (LV-T0) was 2.85±11.3 for the anti-Pm/Scl+ group vs -5.42±13.4 in the control group (p:0.0004) with a significant smaller proportion of patients with FVC loss ≥10% from T0 to LV in the anti-PM/Scl group (12.3% vs. 39.7%, p:0.0001). Delta %pDLCO (LV-T0) was -0.13±10.8 for the anti-PM/Scl+ group vs -7.38±14.6 in the control group (p:0.0015), with a significant smaller proportion of patients with DLCO loss ≥10% from T0 to LV in the anti-PM/Scl+ group (13.6% vs. 42.3%, pConclusion:In this multicenter real-life study, the long-term pulmonary functional outcome in SSc-ILD patients with anti-Pm/Scl positivity seems to be more favorable than in patients without anti-Pm/Scl antibodies.References:[1]Guillen-Del Castillo A, Semin Arthritis Rheum 2014, 44 (3), 331-7.Disclosure of Interests: :Maria Grazia Lazzaroni: None declared, Corrado Campochiaro Speakers bureau: Novartis, Pfizer, Roche, GSK, SOBI, Emiliano Marasco: None declared, Jeska de Vries-Bouwstra: None declared, Franco Franceschini: None declared, Francesco Del Galdo: None declared, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Lorenzo Cavagna: None declared, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Yannick Allanore Grant/research support from: BMS, Inventiva, Roche, Sanofi, Consultant of: Actelion, Bayer AG, BMS, BI, Paolo Airò: None declared

Background:Peripheral myositis in systemic sclerosis (SSc) is associated with poor prognosis and myocarditis1but non-inflammatory myopathy, which also represents a significant cause of disability in SSc remains poorly understood. Cardiovascular magnetic resonance (CMR) T1 mapping studies in asymptomatic SSc patients show increased extracellular volume (ECV), suggestive of diffuse fibrosis in both the myocardium and thoracic muscle2.Objectives:To evaluate the feasibility of T1 mapping MRI and determine ECV in peripheral muscle of SSc patients with and without myopathy and explore the association between cardiac and peripheral muscle T1 mapping in SSc.Methods:This was a hypothesis-generating pilot and feasibility study. SSc patients, fulfilling the 2013 ACR/EULAR criteria, with no cardiovascular disease or myositis but either minimal muscle symptoms (non-inflammatory myopathy) or no muscle involvement and healthy volunteers (HV) underwent peripheral muscle T1 mapping-MRI for native T1 and extracellular volume (ECV) quantification of the dominant thigh. Patients also had T1 mapping CMR, and creatine-kinase (CK) measured. Non-inflammatory myopathy was defined as current/history of minimally raised CK (Results:12 SSc patients and 10 HV were recruited. SSc patients had a median (IQR) age of 52 (41,65) years, 9/12 had limited cutaneous SSc, 4/12 interstitial lung disease, 7/12 non-inflammatory myopathy. Higher skeletal muscle ECV was recorded in SSc patients compared to HV [mean (SD) 23(11)%, vs 11(4)% p=0.04]. Skeletal muscle native T1 values were comparable between the 2 groups although modestly higher in SSc patients [mean (SD) 1396ms (56) vs 1387ms (42)] (Figure 1A).Peripheral muscle ECV associated with CK (R2=0.307, rho=0.554, p=0.061) and was higher in SSc patients with evidence of myopathy compared to those with no myopathy [28 (10)% vs 15 (5)%, p=0.023] (Figure 1B). An ECV of 22% was determined to best identify myopathy with a sensitivity of 71% and a specificity of 80%.SSc patients had raised myocardial ECV and native T1 with means (SD) of 31 (3) % and 1287 (54) ms respectively (normal reference range ECV ≤29%, native T1 ≤1240ms). No clear association between myocardial and peripheral muscle ECV (rho=-0.485) or between myocardial ECV and peripheral muscle native T1 (rho=0.470) of SSc patients was observed.Conclusion:This pilot study to determine ECV-MRI of the peripheral muscle showed higher ECV in SSc patients compared to HV, suggesting the presence of diffuse fibrosis in the peripheral muscle of SSc patients. These data support further investigation to understand the pathophysiological involvement and relationship of peripheral and cardiac muscle in SSc.References:[1]Follansbee WP et al, Am Heart J. 1993[2]Barison A et al, Eur Heart J Cardiovasc Imaging. 2015Disclosure of Interests:Raluca-Bianca Dumitru: None declared, Alex Goodall: None declared, David Broadbent: None declared, Ananth Kidambi: None declared, Sven Plein: None declared, Francesco Del Galdo: None declared, Ai Lyn Tan: None declared, John Biglands: None declared, Maya H Buch Grant/research support from: Pfizer, Roche, and UCB, Consultant of: Pfizer; AbbVie; Eli Lilly; Gilead Sciences, Inc.; Merck-Serono; Sandoz; and Sanofi

Background:Lung involvement is very common is systemic sclerosis (SSc). Approximately one quarter of patients develops pulmonary problems within the first 3 years of diagnosis and still represents the leading cause of death in these patients. In a recent clinical trail, the reduction of FVC was not accompanied by a benefit with respect to health-related quality of life and patient-reported outcomes (PROs).Objectives:To assess how the change in Pulmonary Function Test (PFTs) parameters correlates with the Patient Reported Outcomes (PROs) in an observational cohort of patients with Systemic Sclerosis (SSc).Methods:We conducted a retrospective study of 330 clinic episodes from 121 unselected patients diagnosed with systemic sclerosis according to EULAR/ACR 2013 criteria, in annual follow-up (for a total of 165 patients/year) with PFTs, Health Assessment Questionnaire Disability Index (HAQ-DI), Scleroderma Health Assessment Questionnaire (sHAQ), Modified Borg Dyspnea Scale (Borg) and Cochin Hand Function Score (CHFS). We assessed the correlation between the HAQ and the Visual Analogical Scale 1-7 at baseline (VAS1 pain, VAS2 disease severity, VAS3 arthritis activity, VAS4 intestinal problems, VAS5 dyspnea, VAS6 Raynaud’s phenomenon, VAS7 digital ulcers). We evaluated the correlation of PFTs with PROs at every time period and the correlation between the change of PFTs parameters (δFVC, δDLCO) with the change of the PROs over a year of follow-up. Following analysis of distribution, Spearman or Pearson Test were used to determine correlation coefficients, as appropiate (Prism 7).Results:The median disease duration was 5 years (IQR 3-10). The median of 12 months δFVC% and δDLCO% were 0 (IQR -5.81 to 3.28) and -2.439 (IQR -8.76 to 5.98), respectively. The analysis evidenced a strong positive correlation between VAS1-7 and HAQ. We observed also significant correlation between FVC%, DLCO% and HAQ-DI (r= - 0.355 and -0.266, respectively; pConclusion:This analysis of a monocentric non-selected population evidenced that the current commonly used PROs in SSc while showing a good correlation with lung function are poorly sensitive to change or to reflect changes in lung function over 12 months. In this sense, prudent interpretation of the lack of correlation between FVC and patient-reported outcomes in studies of phase 3 is warranted.References:[1]Rahimi S., Nintedanib for systemic sclerosis-associated interstitial lung disease, Lancet Respiratory Medicine (2020)Disclosure of Interests:None declared

Background:Arthritic involvement in systemic sclerosis (SSc) is a common manifestation impacting on the quality of life. A wide range of articular involvement is recognised including from arthralgia to inflammatory joint and tendon disease.Objectives:To assess the weight of patient reported ‘’arthritis activity’’ in determining Patient Reported Outcome Measures (PROMs) in an observational cohort of SSc patients.Methods:We conducted a retrospective study of 330 clinic episodes from 121 unselected patients diagnosed with SSc according to EULAR/ACR 2013 classification criteria, in annual follow-up (for a total of 165 patients/year) with Pulmonary Function Tests (PFTs), Health Assessment Questionnaire - Disability Index (HAQ-DI), Scleroderma Health Assessment Questionnaire (sHAQ) and Cochin Hand Function Score (CHFS). Hand disability index was assessed by CHFS and global disability index was assessed by HAQ and sHAQ. Patient reported arthritis activity was assessed by Visual Analogical Scale for Arthritis Activity (VAS3). Based on the median of VAS3, patients were classified in two groups and the evaluation of global and hand disability index was performed for each group. Furthermore, we assessed the correlation between the change of VAS3 and the modification of disability scores (ΔHAQ, ΔSHAQ, ΔCHFS) over 12 months of follow-up. Following analysis of distribution, Spearman or Pearson Test were used to determine correlation coefficients, as appropriate (Prism 7).Results:The median disease duration was 5 years (IQR 3-10). The median of VAS3 was 35 (IQR 2 - 66). In patients with VAS3 Conclusion:This analysis of a monocentric non-selected population supports the key role of joint involvement in determining global patient reported functional and hand disability in SSc. Severity of musculoskeletal involvement should be carefully considered when interpreting PROs in patients with SSc.References:[1]Sandler RD, Matucci-Cerinic M, Hughes M. Musculoskeletal hand involvement in systemic sclerosis. Seminars in Arthritis and Rheumatism (2019)Disclosure of Interests:None declared

Background Subclinical SSc-cardiomyopathy is described in up to 2/3 of the patients when sensitive methods such as cardiac MRI(CMR) are used. The prognostic implications and the natural history of these findings is unknown. Objectives To evaluate in SSc patients, free of cardiovascular (CV) risk factors and CV disease (CVD) the prevalence, clinical association and natural history of CMR abnormalities over 3 years. Methods 35 SSc patients, fulfilling the ACR/EULAR criteria, with no CVD, diabetes and ≤1 CV risk factor had 2 CMRs, 3 years apart. A 3T CMR with late gadolinium enhancement (LGE), T1 mapping for extracellular volume (ECV) quantification and stress perfusion(data available later)was undertaken. Initial CMR was compared with CMR results of 30 healthy controls(HC). Results 35 pts had an initial CMR:26(74%) female, mean(SD) age 55(, 13 15 (43%) dcSSc, 11 (31%) ACA+, 12 (34%) Scl70+,15 with(43%) interstitial lung disease(ILD) and 13 (37%) with history of digital ulcers(DU). 21 (60%) received any DMARD over the 3 year period and 10 (29%) prior treatment with cyclophosphamide. The first CMR(CMR1) of SSc pts vs HC showed higher ECV% values and comparable left ventricle(LV) volumes(table 1). LGE was present in 9/22 pts vs 1/30 HC. 22/35 pts had a second CMR (CMR2) at year 3(Y3). A further 5 pts had evidence of LGE, total of 14 (40%): 7/14 had dcSSc, 6/14 males, 2 ACA positive, 6 Scl70 positive. LGE distributed in the basal and mid segments, mainly in a linear or patchy pattern. Of those with LGE at CMR1 (5/9 pts with LGE on CMR1 had CMR2) no change in the LGE pattern at CMR2 was observed. None of the initial CMR measures associated with LGE development at Y3 (p>0.05). Whilst ECV had an overall decrease, ECV incresed in patients with ILD [mean diff.(CI) 3 (-1,6),p=0.14]and in those with higher mRSS at baseline(r=0.455,p=0.04). A significant decrease over the 3 years was observed in LV end-diastolic volume (LVEDV/BSA), LV end-systolic volume(LVESV/BSA) and left ventricular stroke volume (LVSV/BSA) (table 1). A decrease in LVEDV/BSA was noticed for those with a history of DU[mean diff.(CI) −5(−12,2), p=0.1], ILD[mean diff.(CI) −6(−12,0.5),p=0.07)]and shorter disease duration(r=-0.504, p=0.02). Conclusions This longitudinal CMR study in SSc demonstrates that CMR is sensitive to change over time. More individuals developed LGE (of focal fibrosis) despite immunosuppressive treatment, and ECV% (diffuse fibrosis) appeared to worsen in a poor prognostic group. Functional changes were also observed. These data justify larger studies to inform stratification strategy for CMR in SSc, and also provide new insights for further investigation. Disclosure of Interest None declared

Background Macrovascular involvement in Systemic Sclerosis (SSc) is caused by proliferation of vascular smooth muscle cells within the intima of arteries (neointimal proliferation). The resulting decrease in arterial volume is responsible for the severity of Raynaud’s and for the onset of severe clinical manifestations such as Renal Crisis and Pulmonary Artery Hypertension. Several RCTs have demonstrated the efficacy of Endothelin Receptor Antagonists (ERAs) in targeting neointimal proliferation, which makes them to date, the only disease modifying agent available in SSc. Nevertheless, the lack of validated early diagnostics means the intention to treat with ERAs remains limited to the diagnosis of end stage clinical manifestations of neointimal proliferation, such as presence of Digital Ulcer (DU) and PAH. Objectives Here we aimed to determine the proof of concept validity of automated Digital Artery Volume Index (DAVIX) measured by non-contrast Time of Flight (TOF) MRI as an objective diagnostic tool to be used as surrogate outcome measure of neointimal proliferation in SSc. Methods 10 Healthy Volunteers (HV) and 8 SSc patients were enrolled. Six patients underwent longitudinal assessments at least 12 months apart. MRI scans were performed on a 3T Magnetom Verio (Siemens) and consisted of a VIBE 3D T1 scan and a 2D TOF sequence of 8 min. DAVIX was calculated as the percentage of the ratio of digital artery and the respective finger volumes. The vessels and fingers were manually outlined by an expert radiologist and used as a ‘gold standard’ (DAVIX-1) and compared to a 2nd independent radiologist assessment (DAVIX-2). An automated segmentation algorithm was developed using threshold based segmentation and region growing (DAVIX-A) and validated against gold standard. Intraclass correlation coefficient (ICC) and absolute agreement were calculated to estimate reliability. Bland-Altman bias and 95% limits of agreement (LoA) were calculated as well. Results SSc patients and HV had comparable age (44±8 vs 45±8) and gender (F:M=5:2 vs 4:2). 4 fingers were affected by DUs at baseline and two fingers were affected by new DU at follow up. Mean(±SD) DAVIX in HV was 1.21 (±0.39) with no significant difference among individual fingers. Mean DAVIX in SSc patients was 0.37 (±0.18) and 0.32 (±0.39) at baseline and follow-up, respectively (p Conclusions This proof of concept study demonstrated validity and sensitivity to change of DAVIX for the automated volumetric assessment of digital arteries, which reflected clinical worsening in patients with new DU. Larger, longitudinal studies are planned to assess DAVIX’ predictive value for the onset of DU and its potential use as early diagnostic of neointimal proliferation in SSc. Disclosure of Interest None declared

Background Malnutrition and severe gastrointestinal dysfunction are the cause of mortality in 4%–15% of systemic sclerosis (SSc) patients whereas overall gastrointestinal involvement is observed in 75%–90% of cases.1 Hence, a reliable tool for stratification of risk for malnutrition would be of great value in the clinical management of SSc. Objectives Here we set out to identify a combined index predictive of significant weight loss at 12 months employing Malnutrition Universal Screening Tool (MUST) and serum adiponectin to leptin ratio (A/L) already used in other conditions. Methods This was an international, multicentre, longitudinal study employing 180 SSc patients in two independent cohorts: a study cohort (110 consecutive SSc patients) enrolled from University of Messina (60) and University of Padova,50 and a validation cohort (70) at the University of Leeds. Serum A/L ratio was measured by ELISA. MUST score, which includes BMI and weight loss reported by the patient in the last 3–6 months, was calculated as described: 0=no, 1=mild,>2= moderate/severe risk of malnutrition. End point of the study was weight loss >10% of baseline weight at 12 months. Results The two cohorts showed no significant differences in demographic and clinical features. Overall, median BMI decreased over time in both study and validation cohorts (23.5 vs 22.35 and 23.44 vs 22.49, respectively; p 10% wt despite having “no” or “mild” MUST scores. Logistic regression analysis identified the combination of BMI and A/L as the best PREdictor of MAlnutrition in Systemic Sclerosis (PREMASS). The formula 12.18-(0.63*BMI)+(1.51*A/L) predicted the end point with AUC=0.91 (95% CI:0.77–0.84). A PREMASS score >0.23 showed 91.3% sensitivity (95% CI:79.79–100) and 80.46% specificity (95% CI:72.13–88.79) for >10% wt loss with an overall 55.26% positive predictive value (PPV) (95% CI:39.45–71.07) and 97.22% negative predictive value (NPV) (95% CI:93.43–100) and a relative risk (RR) of 19.90 (95% CI:4.93–80.37). In the validation cohort, PREMASS showed 76.47% sensitivity (95% CI:56.31–96.63) and 75.47% specificity (95% CI:63.89–87.06) with an overall 50% PPV (95% CI:30.78–69.22) and 90.91% NPV (95% CI:82.41–99.4) and a RR of 5.5 (95% CI: 2–15.10). Conclusions PREMASS is the first validated index for weight loss risk stratification in the following 12 months in SSc. Prediction of future weight loss in SSc could aid both in clinical management and stratification/enrichment in clinical trials. Disclosure of Interest None declared

Background Cardiac involvement and in particular conduction abnormalities represent a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). No studies assessed the value of implantable loop recorder (ILR) for early detection of arrhythmias in asymptomatic patients with SSc; or whether cardiac magnetic resonance (CMR) features associate with arrhythmias. Objectives To assess the prevalence of conduction abnormalities over a 3 year period using an ILR (REVEAL) and evaluate relationship with disease phenotype, cardiac biomarkers and CMR in SSc patients. Methods 20 patients(pts) with ACR/EULAR criteria for SSc, with no history of cardiovascular (CV) disease and ≤1 CV risk factor had 3T CMR with late gadolinium enhancement (LGE) and T1 mapping for ECV quantification. An ILR was then inserted, for 3 years follow-up. ILR data were downloaded every 3 months. Serum cardiac biomarkers were also measured at the initial visit. Results 19 pts had available ILR data; 12 (63%) females, median (SD) age 53(,12 6 (32%) diffuse SSc(dcSSc), 6 (32%) ACA+, 4 (21%) Scl70+, 8 (42%)history of interstitial lung disease (ILD) and 7 (36%) history of digital ulcers (DU). 14/19 had any ILR abnormalities, 8/14 significant arrhythmias: 1 complete heart block; 2 non-sustained ventricular tachycardia (NSVT), and 5 atrial arrhythmias (1 atrial flutter, 1 AF, 1 SVT, 1 AF and SVT and 1 AF followed by atrial flutter and SVT). Of these 8 pts, 4 had dcSSc, 2 Scl70+, 4 ACA+, 3 with ILD and 3 DU history. All 3 patients with severe arrhythmias (NSVT/CHB) were dcSSc, 2 Scl70+, 2 males. Management comprised 1 permanent pacemaker implantation, 3 antiarrhythmic treatment, 1 anticoagulation.15 pts had CMR. The 8 pts with significant arrhythmia appeared to have higher ECV, LV mass, and LVEF%(table 1). LGE was observed in 1(NSVT), of a total of 5/15 with LGE. HsTnI was considerably higher in those with significant arrhythmias[(mean diff.(95% CI)117 (-10, 245)].NTproBNP [(mean diff.(95% CI) 92 (-30, 214)] also appeared greater in those with significant arrhythmias. There was no difference in CK levels between the two groups. Conclusions This pilot study demonstrates the ability of ILR to detect life-threatening arrhythmia in asymptomatic SSc pt. The data suggest CMR ECV(but not LGE) and cardiac biomarkers, in particular hsTnI (indicating subclinical myocardial injury) may be able to identify at risk pts that would benefit from ILR screening. Future studies can inform a risk model, and provide insight into the pathogenesis of SSc associated arrhythmias. Disclosure of Interest None declared

Background Systemic sclerosis (SSc), amongst autoimmune rheumatic disorders, shows a heterogeneous and unpredictable course from stable/mild involvement to progressive/late stage, when irreversible multiorgan fibrosis occurs.1 Early SSc diagnosis remains a clinical challenge; a delay in diagnosis leads, in turn, to therapy delay and more severe patient disability.2 3 Earliest vascular immune-mediated alterations are critical in SSc, which, indeed, has been referred to as a ‘vascular’ disease.4 Recognition of biomarker(s) involved in earliest vascular derangements might represent a clinical tool potentially useful for therapeutic approach. Blood level of chemokines IFNγ-inducible protein 10 (IP-10/CXCL10) and IFN-inducible T cell alpha chemoattractant (I-TAC/CXCL11), both involved in endothelial dysfunction, has been shown to associate with worse SSc prognosis.5,6 Objectives To investigate possible modifications of circulating CXCL10/CXCL11 in the shift from very early diagnosis of SSc (VEDOSS), when vasculopathy and fibrosis are still at very low degree, to definite SSc. Associations between chemokines and capillaroscopic pattern, autoantibody positivity were evaluated. Methods Multiplatform luminex technology was used to analyse CXCL10/CXCL11 in total 62 sera, 34 from VEDOSS and 28 from SSc patients, fulfilling the new ACR/EULAR 2013 classification criteria; none of the subjects were treated for SSc. Within VEDOSS group, we selected 29 sera of subjects with follow up (40.67±5.46 months) and, for each patient of this subcohort, chemokine levels were assessed at follow up (T1) and compared with basal level (T0). Appropriate tests were used for sample distribution and statistical analysis. Results Serum CXCL10/CXCL11 were significantly lower in all VEDOSS (CXCL10: 236.00±40.09 pg/ml; CXCL11: 38.00±6.97 pg/ml) vs all SSc sera (CXCL10: 633.90±97.60 pg/ml; CXCL11: 267.70±76.10 pg/ml; p Conclusions CXCL10/CXCL11 blood level measurement in VEDOSS patients potentially represents a noninvasive biomarker associated with vascular modifications – as shown by capillaroscopic pattern – predictive of SSc. References [1] Domsic RT, et al. Ann Rheum Dis2011Jan;70(1). [2] Pattanaik D, et al. Front Immunol2015;6:272. [3] Khanna D, et al. Best Pract Res Clin Rheumatol2010Jun;24(3). [4] Matucci-Cerinic M, et al. Arthritis Rheum2013Aug;65(8). [5] Antonelli A, et al. Rheumatology (Oxford)2008Jan;47(1). [6] Liu X, et al. Arthritis Rheum2013Jan;65(1). Disclosure of Interest None declared

Contains fulltext : 181772.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets. METHODS: We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed. RESULTS: Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly). CONCLUSIONS: We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).

Background The Enhanced Liver Fibrosis (ELF) test is a serum test including the serum concentrations of amino-terminal pro-peptide of procollagen type III (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and hyaluronic acid (HA). A recent single centre study showed that ELF score and its components are markers of overall fibrosis in systemic sclerosis (SSc) mainly reflecting skin and lung involvement (1). Objectives To determine the value of ELF score and its single analytes in an independent multicentre cohort of SSc patients. Methods 254 SSc patients from 6 European Rheumatology Centres were included in this study. Clinical data were collected at time of sampling. Serum samples were collected and stored according to EUSTAR biobanking recommendations (2). Sera were analysed employing a high-throughput in vitro diagnostic (Siemens Alpha-Centaur). Statistical analysis was performed with SPSS software V.24. Results The 254 SSc patients had a mean age 55.8±13.8 years, and included 209 females and 80 patients with diffuse cutaneous SSc (dcSSc). ELF score was overall higher in males than in females (p=0.0236) as well as in dcSSc compared to limited cutaneous SSc patients (p=0.0015). ELF score and the single markers significantly correlated with the degree of skin involvement (mRSS) and inversely correlated with FVC%, TLC% and DLCO%. Concordantly all markers significantly correlated with skin and lung severity as assessed by the Medsger9s scale (Table 1). TIMP-1 and PIIINP levels were higher in patients with lung fibrosis assessed by chest HRCT scan (p=0.0126 and p=0.0308 respectively). Significant correlation (p Conclusions The value of ELF score as independent marker of skin and lung involvement is confirmed in a second independent multicentre cohort of SSc patients. A longitudinal study paired with analysis of large cohort of healthy controls is currently on going to identify a SSc specific test with the highest predictive value for skin and lung progression independently of age and gender. References Abignano G et al. Ann Rheum Dis. 2014. Beyer C et al. Ann Rheum Dis. 2011. Disclosure of Interest None declared

Background Optical Coherence Tomography (OCT) of the skin has been proposed as imaging biomarker of fibrosis in Systemic Sclerosis (SSc) (1). However, over the past few years, growing efforts have been made to enable OCT to the study of human skin microcirculation including human nailfold (2). Dynamic OCT (D-OCT) is a newly developed OCT technology that allows detection of blood flow in vivo in addition to the images of traditional OCT scans (3). Objectives Aims of this study were: 1) to evaluate face/criterion validity and feasibility of nailfold capillary D-OCT imaging as compared with nailfold video-capillaroscopy (NVC) capillary patterns in SSc patients; 2) to investigate whether D-OCT could offer a complementary value to NVC through the 3-dimensional reconstruction and quantification of nailfold capillary abnormalities in SSc patients. Methods Fifty subjects including forty SSc patients all fulfilling 2013 EULAR/ACR classification criteria (10 with normal/non-specific, 10 with early, 10 with active, 10 with late capillary pattern respectively) and ten age/gender-matched healthy volunteers (HV) were enrolled in this study. All subjects had NVC done on 8 fingers and classified according to the capillary pattern. Nailfold of the finger with the worst capillary score in SSc patients and the 4th finger (the most affected in the SSc groups) of the dominant hand in subjects with normal capillary pattern was subsequently scanned using Vivosight D-OCT (Michelson Diagnostics Ltd., Kent, UK). D-OCT images were analyzed using the proprietary software tool to extract a quantitative measure of the speckle variance (SV)-signal. Results were expressed as mean±standard error. Statistical analysis was performed using GraphPad Prism software V.7.0. Results The finger with the worst capillary score was the 4th (83%) in the SSc patients. The typical nailfold capillary features seen at NVC were visualized at D-OCT images. Representative images are shown in figure 1. Each nailfold D-OCT scan lasted 60 seconds, was well tolerated and did not require use of gel or immersion oil. OCT mean SV-signal measurements were significantly different between HV and SSc patients with any specific capillary pattern (0.16±0.02 vs 0.10±0.01, p=0.0028) and between SSc patients without and with specific capillary pattern (0.14±0.01 vs 0.10±0.01, p=0.02). The mean SV-signal was higher in HV than in SSc patients without specific capillary pattern however the difference was not statistically significant. When analyzing the three specific capillary patterns, SV-signal measurements were not significantly different. Interestingly, within the late capillary pattern, mean SV-signal was significantly lower in patients displaying capillary loss as main feature compared with those with remarkable neoangiogenesis (p=0.03). Conclusions D-OCT is a feasible technique able to reproduce the capillary changes seen at NVC in SSc patients. More importantly D-OCT could offer a complementary value to quantify peripheral blood flow at capillary level. Future longitudinal studies are needed to evaluate the sensitivity to change over time and the potential of D-OCT as quantitative outcome measure of microvasculopathy in SSc. References Abignano G et al. Ann Rheum Dis 2013. An L et al.Opt Express 2010. Ulrich M et al.Dermatology 2016. Disclosure of Interest None declared

Background Reduction in capillaries number is the defining feature of microvascular disease in Systemic Sclerosis (SSc) and it concurs to the ischemic manifestations of the disease. Digital Ulcers (DUs) are the major complication of ischemic peripheral vasculopathy. Dynamic optical coherence tomography (D-OCT) is a recently developed imaging technique that allows non-invasive in vivo study of the microvasculature of the skin. In addition to the skin architecture and vessels morphology, it offers information about flow status, allowing the functional and quantitative evaluation of the microcirculation.1 Objectives To determine the face and content validity of D-OCT as outcome measure of the skin microvascular disease, assuming the presence of current DUs, distal to the DIP joints, as gold standard for ischemic peripheral vasculopathy in SSc. Methods A total of 54 patients were enrolled in this cross-sectional study, including 18 SSc patients with current DUs (DU group); 18 SSc patients without current DUs (no DU group) and 18 patients with Raynaud9s phenomenon and SSc specific ANA, who did not fulfilled ACR/EULAR 2013 classification criteria (SRP group). For each patient, we performed a D-OCT scan on both index and middle fingers, on the dorsal aspect of the second phalanx, employing Vivosight Scanner(Michelson Diagnostics). The speckle variance signal of D-OCT images within the first mm of skin depth was extracted, quantified as area under the curve (AUC) and defined as Micro Vascular Flow (MVF). MVF comparison between the groups was done using parametric or non-parametric tests as appropriate. Statistical Analysis was performed with SPSS V.22. Results All three groups were comparable in terms of age and gender distribution (p>0.80 for both) as well as disease duration and clinical subset between the two SSc groups (p=0.839 and p=0.646, resp.). With a scan time The distribution of MVF was not significantly different among the four fingers within each group (DU group: p=0.459, no DU group: p=0.953 and SRP group: p=0.616). On the contrary, the distribution and median MVF for all fingers was significantly different among the 3 groups: DU group=0.134 (IQR 0.121–0.134), no DU group=0.153 (IQR 0.132–0.153) and SRP group=0.167 (IQR 0.148–0.167) (p Further, sub analysis of the DU group showed that 10 of the total 20 DUs were on the left index finger. Within this subgroup the MVF of patients on Sildenafil (n=6) was significantly higher than the rest of the group (0.148±0.021 vs. 0.113±0.019, p=0.03). Conclusions MVF assessed by D-OCT is a quantitative, non-invasive surrogate outcome measure of severe peripheral ischemic vasculopathy in SSc. Longitudinal studies assessing its sensitivity to change will inform whether MVF can be used as end point of skin microvascular involvement in SSc. References C. Tolosa-Vilella et al. Semin Arthritis Rheum 46(2016):200–208. Disclosure of Interest None declared

Background Th1 cell/cytokine repertoire contributes to systemic sclerosis (SSc) pathogenesis from early autoimmune/vascular stages while Th2 dominance prevails later, when (multi)organ fibrosis occurs [1]. The Th1-type chemokine IFNγ-induced 10 kDa protein (CXCL10), involved in several autoimmune diseases (thyroiditis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory myopathy) exerts detrimental effects at systemic and tissue/cell level; it is reported in association with more severe SSc prognosis [2–4]. Objectives To compare circulating CXCL10 level in SSc patients starting iloprost (I), prostacyclin analogue with or without sildenafil (S), phosphodiesterase type 5 inhibitor, both vasoactive drugs used in SSc for Raynaud9s phenomenon digital ischemic ulcers and/or secondary pulmonary arterial hypertension; SSc subjects under immunosuppressants (DMARDs) or corticosteroids (CCs) - first choice treatments at disease onset - before and after I were also evaluated. Intracellular path activation underlying Th1 cytokine-induced CXCL10 release by human skeletal muscle cells (Hfsmc), endothelial cells (Hfaec), cardiomyocytes (Hfcm) and fibroblasts (hFbs) were compared after iloprost or sildenafil. Methods Sera of 27 SSc patients satisfying ACR/EULAR 2013 classification criteria for SSc were analyzed by ELISA before (T0, baseline) and 3 months after I intake (T3) vs. 15 age/gender-matched healthy subjects. Protein extracts from different human cell types were tested by Western blot for IFNγ+TNFα-induced NFkB, Stat1, JNK activation after S or I. Results CXCL10 serum level was higher in all SSc under each drug/drug combination (range ∼300–500 pg/ml) vs. healthy subjects (∼150 pg/ml, P Conclusions Our in vivo results show that S and I combination is the more effective in targeting circulating CXCL10 in SSc patients. Our in vitro findings show a different inhibitory drug-induced effect onto paths underlying CXCL10 production, depending on cellular/intracellular targets. Thus, we suggest I and S combination as potential pharmacological tool in SSc not limited to treat vascular dysfunction but likely helpful to control different cell/tissue involvement and damage. References Pattanaik D et al., Front Immunol 2015. Eloranta ML et al., Ann Rheum Dis 2010. Corrado A, Clin Ter 2014. Liu X et al., Arthritis Rheum 2013. Disclosure of Interest None declared

Background A consensus on DU definition in SSc has been recently reached (1),while for their evaluation,classification and categorisation it is still missing. Objectives To identify in SSc a set of essential items for DU evaluation, to assess if the existing DU classification (2) was useful and feasible in clinical practice, and to investigate if the DU categorisation (3) was preferred to the simple division of DU in recurrent and not recurrent. Methods The DU Desscipher items that reached >60% of completion rate were administered to EUSTAR centres via online survey.These items were: DU distal to the proximal interphalangeal joints, recurrent DU, DU history, infection, gangrene, amputation, total number of DU, number of new DU, number of healed DU, number of DU defined as loss of tissue, number of DU due to calcinosis and number of DU due to digital pitting scars (DPS).Questions about feasibility and usefulness of the existing DU classification (DU due to DPS, to loss of tissue, derived from calcinosis and gangrene) (2) and newly proposed DU categorisation (episodic, recurrent and chronic) (3) were also administered. Results All Desscipher and 82/194 EUSTAR centres (42.3%) completed the questionnaire.Out of 27 items selected for the Desscipher study, those scored by>70% of participants as essential and feasible for DU evaluation in clinical practice were only the following: number of DU defined as a loss of tissue (level of agreement 91.1%), recurrent DU (84%) and number of new DU (74.4%).For 64.6% of the centres,the classification of DU was considered useful and feasible in clinical practice.Moreover, 80.3% of the centres preferred the categorization of DU in episodic,recurrent and chronic. Conclusions For clinical practice, EUSTAR centres identified only three essential items for DU evaluation and considered useful and feasible the proposed classification and categorisation of DU.The set of items needs to be further validated by Delphi voting in order to implement its use in clinical practice while further implementation of DU classification and categorisation is warranted. References Suliman Y et al.Preliminary musculoskeletal ultrasound (MSUS) ulcer definition does not correlate with visual observation in systemic sclerosis (SSc) patients. J. Scleroderma Relat. Disord.2017(in press). Amanzi L et al.Digital ulcers in scleroderma: staging, characteristics and sub-setting through observation of 1614 digital lesions. Rheumatology (Oxford) 2010;49:1374–82. Matucci-Cerinic M et al.Elucidating the burden of recurrent and chronic digital ulcers in systemic sclerosis: long-term results from the DUO Registry. Ann Rheum Dis. 2016;75:1770–6. Disclosure of Interest None declared

Circumscribed hypokeratosis of palms and soles is a rare dermatosis, usually affecting women. Diagnosis is mainly based on the clinical characteristics, including the clinical appearance and anatomical site of the skin lesions and on the demographic features of the affected patients, usually middle-aged to elderly women. Skin biopsy may be performed to confirm clinical diagnosis. Optical coherence tomography (OCT) is a technique that has been undergone substantial development in dermatology in recent years, and its use in clinical practice has been growing progressively. Several dermatological conditions have been studied with this tool, but to our knowledge, it has not been used to investigate this form of hypokeratosis. We report a case of circumscribed palmar hypokeratosis for which diagnosis was confirmed by OCT, which was performed as the patient was reluctant to undergo skin biopsy because of its invasiveness. We highlight the potential use of OCT in obtaining a virtual skin biopsy to confirm clinical diagnosis and identify preclinical skin lesions amenable to early treatment.

Desmoglein-2 (Dsg2) is a desmosomal cadherin that is aberrantly expressed in human skin carcinomas. In addition to its well-known role in mediating intercellular desmosomal adhesion, Dsg2 regulates mitogenic signaling that may promote cancer development and progression. However, the mechanisms by which Dsg2 activates these signaling pathways and the relative contribution of its signaling and adhesion functions in tumor progression are poorly understood. In this study we show that Dsg2 associates with caveolin-1 (Cav-1), the major protein of specialized membrane microdomains called caveolae, which functions in both membrane protein turnover and intracellular signaling. Sequence analysis revealed that Dsg2 contains a putative Cav-1-binding motif. A permeable competing peptide resembling the Cav-1 scaffolding domain bound to Dsg2, disrupted normal Dsg2 staining and interfered with the integrity of epithelial sheets in vitro. Additionally, we observed that Dsg2 is proteolytically processed; resulting in a 95-kDa ectodomain shed product and a 65-kDa membrane-spanning fragment, the latter of which localizes to lipid rafts along with full-length Dsg2. Disruption of lipid rafts shifted Dsg2 to the non-raft fractions, leading to the accumulation of these proteins. Interestingly, Dsg2 proteolytic products are elevated in vivo in skin tumors from transgenic mice overexpressing Dsg2. Collectively, these data are consistent with the possibility that accumulation of truncated Dsg2 protein interferes with desmosome assembly and/or maintenance to disrupt cell-cell adhesion. Furthermore, the association of Dsg2 with Cav-1 may provide a mechanism for regulating mitogenic signaling and modulating the cell-surface presentation of an important adhesion molecule, both of which could contribute to malignant transformation and tumor progression.

Background Bleomycin forms part of the chemotherapy regimen (“BEP”) for germ cell testicular cancer (1). The drug is known to cause Raynaud9s phenomenon (RP) in up to 25% of men who receive the BEP regime (2). RP is also a feature of systemic sclerosis (SSc), a connective tissue disease that is studied in a mouse model using bleomycin as the agent to induce pulmonary fibrosis (3,4). There have been isolated cases where patients, treated for lymphoma with bleomycin containing regimens, have developed SSc (5,6) thus evaluation of RP and SSc is warranted in testicular cancer patients. Objectives In men with germ cell testicular cancer who have received BEP in Leeds: 1) Evaluate the prevalence, nature, and onset of RP. 2) Compare the characteristics of those that developed RP with those that did not. 3) Determine whether those reporting RP have microvascular features of SSc. Methods A patient questionnaire completed retrospectively by men receiving follow up post BEP treatment was used to collect data on the prevalence, nature, and onset of RP. A subset of patients reporting RP then underwent capillaroscopy and thermography. Results 24 eligible men completed the questionnaire. RP was prevalent in 13 of the men (54% CI 0.34–0.74), usually bilaterally (92%) and accompanied by sensory disturbance (92%). Onset was most commonly reported to be following chemotherapy completion (77%). There was no association between RP and marital status, smoking status, tumour type or total bleomycin dose (p values >0.05). No evidence was found to suggest SSc in the patients who underwent capillaroscopy and thermography. Hallmark capillary changes indicative of SSc were absent at the nailbed. The mean (SD) recovery of the fingers back to baseline temperature was 93.8 (14.57)% at ten minutes post cold challenge and the mean (SD) re-warming rate of the fingers was 0.925 (0.17) °C/minute. Conclusions The prevalence of RP in this patient group was higher than expected. The absence of SSc vasculopathy was reassuring, however not all of the men reporting RP underwent Rheumatology assessment. The retrospective nature and small sample size of this study are key limitations but our findings justify further prospective evaluation of the prevalence and the basis for bleomycin-associated RP. References Horwich A, Nicol D, Huddart R. Testicular germ cell tumours. BMJ 2013; 347: f5526 doi: 10.1136/bmj.f5526. Bokemeyer C, Berger C C, Kuczyk M A, Schmoll H. Evaluation of Long-Term Toxicity After Chemotherapy for Testicular Cancer. Journal of Clinical Oncology 1996; 14: 2923–2932. Lakos G, Takagawa S, Varga J. Animal Models of Scleroderma. In: Perl A. Ed. Methods in Molecular Medicine, Vol. 102: Autoimunity: Methods and Protocols. 2004. Humana Press Inc., Totowa, NJ. 377–393. Matucci-Cerinic M, Kahaleh B, Wigley F M. Evidence That Systemic Sclerosis Is a Vascular Disease. Arthritis & Rheumatism 2013; 65(8): 1953–1962. Passiu G, Cauli A, Atzeni F, et al. Bleomycin-induced Scleroderma: Report of a Case with a Chronic Course Rather Than the Typical Acute/Subacute Self-Limiting Form. Clinical Rheumatology 1999; 18: 422–424. Kin K H, Yoon T J, Oh C W, Ko G H, Kim T H. A Case of Bleomyin-induced Scleroderma. Journal of Korean Medical Science 1996; 11(5): 454–456. Disclosure of Interest None declared

Background VEDOSS project relied on a specific set of inclusion criteria identifying patients in very early stage of systemic sclerosis (SSc) to be submitted to a tight follow up and unravel factors linked to the progression of the disease. The components of the ELF score (PIIINP, TIMP-1 and HA) have been shown to correlate with severity of skin and lung fibrosis in SSc. Objectives Our aim was to analyze the concentrations of ELF components in a subset of patients enrolled in the VEDOSS study and determine their potential diagnostic value. Methods Sera from 114 patients enrolled into the VEDOSS data base and 67 SSc controls fulfilling ACR/EULAR 2013 criteria (subsets: 33 diffuse; 34 limited) were obtained from 2 centres. Serum concentrations of ELF components were determined on Siemens Advia Centaur platform. Logistic regression analysis of the results was performed employing classification of SSc as state variable. Results Among the 114 patients enrolled from VEDOSS, 30 subjects had primary Raynaud9s phenomenon (PRP); 54 had Raynaud9s phenomenon (RP) and at least one of the following “red flags” (risk factors) for SSc: (Puffy fingers, ANA, SSc specific autoantibodies or SSc-specific capillaroscopic pattern) without fulfilling 2013 ACR/EULAR criteria (score 9) despite having no evidence of skin involvement nor interstitial lung disease at lung high resolution CT or pulmonary arterial hypertension, left ventricular systolic impairment or renal involvement. All serum biomarkers concentrations correlated with age (p Conclusions Our data indicate that the SSc score is a simple serum test based model that can be used in patients with RP to aid in the very early diagnosis of SSc. Furthermore, the identification of VEDOSS patients with a high SSc score test and already classified as SSc even in the absence of internal organ involvement can be used in intervention trials aimed to prevent further disease progression. Disclosure of Interest None declared

Background In SSc, the management of DU is a problem in clinical practice, therefore their prevention is highly warranted. Sildenafil, iloprost, calcium channel blockers (CCB), ACE inhibitors (ACEi) and bosentan, alone or in combination, are used for DU prevention without unanimous agreement. Objectives DeSScipher (“to decipher the optimal management of SSc”) is an EC-funded FP7 research project that consists of five observational trials (OT) addressing different aspects of SSc. The aim of OT1 was to evaluate the efficacy of vasoactive and vasodilating drugs or a combination therapy for the management of DU in SSc. Methods Longitudinal data were collected for up to 24 months by 28 DeSScipher centres. In SSc patients, the efficacy of sildenafil, bosentan, sildenafil+bosentan, iloprost or CCB /ACEi for the prevention of new DU was evaluated. Clinical features, ulcer type and other drugs were also recorded. Time without new DU, proportion of patients without new DU, risk of developing new DU and the mean number of new DU per patient were evaluated at 6 months follow-up. Results In OT1, 1394 patients were enrolled. The history of DU was a significant risk factor for developing new DU (OR=3.146; (95%CI:1.19–8.31), p=0.021), therefore analysis was focused on secondary prevention (prevention of new DU in patients with DU history). 473/1394 (33.9%) had a history of DU and 268/473 (56.7%) had follow up data (58.2% limited and 41.8% diffuse SSc subset). 47/268 (17.5%) were on Bosentan, 33/268 (12.3%) on Sildenafil, 40/268 (14.9%) on Iloprost, 31/268 (11.6%) on Sildenafil and Bosentan combination and 117/268 (43.7%) on CCB/ACEi alone. In patients with history of DU in the last 24 weeks, the treatment with CCB/ACEi alone was associated with 7 fold increased risk of developing new DU compared to all other treatment arms (OR =7.313; 95%CI:1.248–42.85, p=0.027). Patients on concomitant immunosuppressive treatment had a trend towards faster DU recurrence. Conclusions History of DU in the past 24 weeks should prompt a more aggressive preventive strategy other than therapy with CCB/ACEi alone due to its lower efficacy to prevent DU recurrence compared to the other treatment options. Acknowledgement The DeSScipher project was funded by the European Community9s Framework Programme 7 (FP7-HEALTH-2012.2.4.4–2 - Observational trials in rare diseases) under grant agreement N° 305495. We acknowledge the contribution of the following EUSTAR centers: Ancona (member N°34), Assiut (168), Bad Bramstedt (187), Belgrade (55), Bucharest (100), Cluj-Napoca (16), Erlangen (106), Frankfurt (124), Hamburg (64), Iasi (162), Istanbul (21), Istanbul (133), Koln (44), Monserrato (142), Moscow (78), Moscow (190), Padua (31), Rome (94), Salford/Manchester (80), Tubingen (56), Wuppertal (192). Disclosure of Interest None declared

Background While foot problems in patients with systemic sclerosis (SSc) have been described previously and the association with disability noted, the impact of such problems on the quality of life (QoL) in people living with SSc has yet to be quantified. Objectives To identify the factors, including those arising from foot pathology, that impact on QoL in SSc. Methods Structural equation modelling (SEM) was used to explore the multifactorial pathways impacting on QoL in a cross section cohort of people with SSc. Potential candidate factors were identified through: i) a literature review with expert consultation; and ii) a cross-sectional study capturing clinical features. QoL was measured using the disease-specific SScQoL questionnaire. Results One hundred and twenty one patients with SSc were recruited (106 female; median age 59, ranges 25 to 86 years) with a median disease duration of nine years (IQR:4,13) and a median modified Rodnan Skin Score of 2 (IQR:0, 5). The model that best explained the factors contributing to the SSc impact on QoL showed complex inter-relationships between 11 factors (Figure1) (c2=37.022, df=37, p=0.468, RMSEA=0.002, GFI=0.951, CFI=1.000). Combined, these factors explained 84% of the impact on QoL (R2 =0.84) in patients with SSc. General disease factors, including physical function (standardised total effect 0.64), breathing problems (standardised total effect 0.493), and depression (standardised total effect 0.428) had the greatest impact. Foot problems had a substantial but indirect effect on quality of life (foot function and foot pain standardised total effect 0.343 and 0.327). A summary of the effects of the factors included in the model is provided in the Table 1. Conclusions The impact of SSc on QoL is substantial and complex. While loss of physical function is the most influential factor on QoL, followed by breathing difficulty and depression, foot problems significantly contribute to this impact. Disclosure of Interest None declared

Background The ELF test and its components (PIIINP, TIMP-1 and HA) have been shown to correlate with skin, lung and overall fibrosis and not with any vascular manifestation of Systemic Sclerosis (SSc) 1 . On the contrary, NT-proBNP has been suggested to be useful for stratification of SSc patients, especially to identify those at risk of pulmonary hypertension 2 . Objectives Aims of this study were: a) to validate ELF score and its single analytes on an independent cohort of scleroderma patients; b) to evaluate whether NT-proBNP could provide additional value to the development of an SSc-specific algorithm. Methods 250 sera from SSc patients from a single UK centre were analysed employing a high-throughput in vitro diagnostic of a routine NHS pathology lab to measure ELF score, its analytes and NT-proBNP levels. All patients fulfilled 2013 ACR/EULAR classification criteria for SSc. Clinical, laboratory and instrumental data were collected at time of sampling. Statistical analysis was performed using SPSS. P Results Multivariate analysis of ELF score (including the variables found statistically significant in univariate analysis) identified age, mRSS and DLCO% as independently associated with ELF score (p Conclusions Our findings validate the value of ELF score in a second independent cohort of 250 SSc sera and suggest that NT-proBNP has a complementary value correlating with other aspects of the disease such as PAH and heart severity. Longitudinal multicentres studies are warranted to determine the sensitivity to change and the predictive value of these biomarkers in SSc patients and to build up a new combined scleroderma specific algorithm including markers of fibrosis and vasculopathy. References Abignano G et al. Ann Rheum Dis 2014 Avouac J et al. Arthritis Care Res 2015 Disclosure of Interest None declared