Search

BackgroundThe gastrointestinal (GI) tract is frequently affected in systemic sclerosis (SSc), leading to considerable morbidity and even mortality. While important progress has been made in the last years regarding treatment of SSc, there is no disease-modifying treatment available for SSc-related GI involvement.ObjectivesWe aimed to identify, in an observational cohort study of real-life patients with SSc, an association between immunosuppressive therapy and the severity of GI symptoms, measured by the University of California at Los Angeles / Scleroderma Clinical Trial Consortium Gastro-Intestinal Tract instrument 2.0 (UCLA GIT 2.0).MethodsWe selected patients from our EUSTAR centre who met the 2013 ACR/EULAR classification criteria for SSc and had at least two visits with completed UCLA GIT 2.0 questionnaires, with an interval of 12±3 months between visits. We defined the first visit with a completed UCLA GIT 2.0 questionnaire as baseline visit. Immunosuppressive therapy was defined as exposure for at least 6 months between the two visits to at least one of the following drugs, regardless of indication: mycophenolate mofetil (MMF), cyclophosphamide, methotrexate, azathioprine, leflunomide, glucocorticoids (>10mg/d prednisone-equivalent), rituximab, tocilizumab, and abatacept. The study outcome was the UCLA GIT 2.0 score at the follow-up visit. We performed multivariable linear regression with this outcome as dependent variable and immunosuppressive therapy during follow-up, immunosuppressive therapy before baseline, baseline UCLA GIT 2.0 score and several baseline parameters selected by clinical judgment as potentially influencing GI symptoms, as independent variables. Multiple imputation was implemented to handle missing values.ResultsWe included 209 patients. Baseline characteristics were: 82.3% female, median (IQR) age 59.0 (48.6, 68.2) years, median disease duration 6.0 (2.7, 12.5) years, 40 (19.1%) diffuse cutaneous SSc, median baseline UCLA GIT 2.0 score 0.19 (0.06, 0.43). Of these, 71 patients were exposed to immunosuppressive therapy during the observation period: 27/71 methotrexate, 1/71 cyclophosphamide, 17/71 MMF, 3/71 leflunomide, 3/71 azathioprine, 6/71 glucocorticoids >10mg/d, 16/34 rituximab, 18/34 tocilizumab. Patients on immunosuppressive therapy during the observation period had, compared to patients without such treatment, overall more severe SSc, higher prevalence of treatment with proton pump inhibitors, similar UCLA GIT 2.0 scores at baseline and at follow up and tendentially less severe GI symptoms at baseline and follow-up by medical history. In multivariable linear regression, immunosuppressive therapy, lower body mass index, longer disease duration and lower baseline UCLA GIT 2.0 score were significantly associated with lower (better) UCLA GIT 2.0 scores at follow-up (Table 1).Table 1.Predictors of UCLA GIT 2.0 score at follow-upEstimates95% CIpAge0.002-0.001 – 0.0060.136Sex [male]-0.056-0.172 – 0.0610.347Disease duration-0.005-0.009 – -0.0000.030Body mass index0.0140.002 – 0.0250.017UCLA GIT 2.0 total score baseline0.6900.571 – 0.809Immunosuppressive therapy during observation period-0.119-0.228 – -0.0100.032Immunosuppressive therapy before baseline0.080-0.032 – 0.1920.160Modified Rodnan Skin Score-0.001-0.008 – 0.0070.860Forced vital capacity-0.001-0.004 – 0.0010.302Erythrocyte sedimentation rate0.003-0.001 – 0.0060.116Proton pump inhibitors-0.034-0.120 – 0.0520.435(Intercept)-0.120-0.531 – 0.2910.566Baseline factors associated with the total UCLA GIT 2.0 score at the end of the observation period. Multiple linear regression model with imputation for missing variables. N=209 patientsConclusionImmunosuppressive treatment was associated with lower UCLA GIT 2.0 scores, which suggests potential effects of immunosuppressants on GI manifestations in patients with SSc. These results need verification in additional studies and randomised controlled clinical trials.References[1]Khanna D et al. Arthritis Rheum, 2009; 61: 1257-63.Disclosure of InterestsLea Stamm: None declared, Alexandru Garaiman: None declared, Norina Zampatti: None declared, Mike O. Becker Speakers bureau: Mepha, MSD, Novartis, GSK, Bayer and Vifor, Consultant of: Mepha, MSD, Novartis, GSK, Bayer and Vifor, Grant/research support from: Mepha, MSD, Novartis, GSK, Bayer and Vifor, Cosimo Bruni Speakers bureau: Actelion, Eli-Lilly, Boehringer-Ingelheim, Grant/research support from: Abbvie, EUSTAR, Gruppo Italiano Lotta alla Sclerodermia (GILS), SCTC, Rucsandra Dobrota Consultant of: Boehringer-Ingelheim, Grant/research support from: Iten-Kohaut Foundation, Muriel Elhai: None declared, Sherif Ismail Grant/research support from: EULAR scientific training grant for young fellows 2021, Suzana Jordan: None declared, Aurora Tatu: 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, Carina Mihai Speakers bureau: Boehringer-Ingelheim, Mepha, MED Talks Switzerland, Consultant of: Boehringer-Ingelheim, Janssen, Grant/research support from: Boehringer-Ingelheim, Janssen, Roche.

BackgroundUpper-gastrointestinal involvement (GI) is associated with more severe interstitial lung disease in patients with systemic sclerosis (SSc-ILD). However, there are many unexplored GI risk factors for the presence of SSc-ILD which could be potentially revealed by machine learning algorithms.ObjectivesThe aim of our study was to identify GI related risk factors for the presence of SSc-ILD using machine learning algorithms based on decision trees (DT).MethodsData of the last follow-up visit from consecutive patients fulfilling the 2013 ACR/EULAR SSc classification criteria recorded in our local EUSTAR registry were used for this study.The study outcome was the presence of SSc-ILD on high-resolution computed tomography.Two sets of predictors were identified based on their potential association with GI. The first set contains the following variables available in the EUSTAR registry: esophageal symptoms (dysphagia and reflux), stomach symptoms (early satiety, vomiting), intestinal symptoms (diarrhea, bloating and constipation), malabsorption syndrome, body-mass-index (BMI) and proton pump inhibitor therapy, calcium channel blocker therapy and immunosuppressive therapy. In the second set, we replaced the first three EUSTAR variables of the first set with the scales of the UCLA Gastrointestinal Tract Questionnaire 2.0 (UCLA-GIT).Of these two sets, the most important variable was selected using three different DT-based algorithms: (1) recursive partitioning and regression trees (RPART) –which uses trees to build decision rules, (2) random forest (RF) - an ensemble of DT built in parallel, and (3) gradient boosting machines (GBM) - an ensemble of DT built sequentially. The selected variables were eventually integrated with established predictors for presence of SSc-ILD (diffuse cutaneous subset, anti-Scl-70 positivity, male gender, forced vital capacity [FVC] and diffusion capacity of the lung for carbon monoxide-single breath [DLCO-SB]) into final prediction models for SSc-ILD presence using RPART, RF and GBM respectively. Their performance was evaluated by C-statistics. The importance of the newly detected predictor was assessed by variable importance plots (VIPs).ResultsWe included in our study 334 patients. The median age was 61 [IQR: 50-69] years, 59 (17.7%) were males and 266 (79.6%) had limited cutaneous SSc. Median BMI was 23 [IQR: 21-26] kg/m2, 133 (39.8%) of the patients had SSc-ILD, median FVC% 93 [IQR: 81-105], DLCO 72.5 [56-84] and. Of the UCLA-GIT scales the highest score was for the distension/bloating with a value of 0.50 [IQR: 0-1.24]. Regarding medications, 167 (50%) patients were exposed to PPI, 39 (11.7%) to CCB and 105 (31.4%) to immunosuppressive therapy.The BMI was deemed by all three algorithms as the most important predictor of SSc-ILD among both sets of GI related variables (Figure 1A-F). The final model, which included established risk factors for presence of ILD and the BMI, supported the importance of BMI in predicting the SSc-ILD. The VIPs obtained by GBM also ranked the BMI as the most important predictor.Figure 1.Tree-based algorithms revealing the importance of BMI for prediction of SSc-ILD. Panels A, B and C are variable importance plots (VIPs), which reveals the most important GI-predictor for occurrence of SSc-ILD in the EUSTAR set– the predictor with the highest relative importance is the most important predictor. Panels D, E and F are VIPs reveals the most important GI-predictor for occurrence of SSc-ILD in the UCLA-GIT set.A lower BMI was associated with presence of SSc-ILD (C-statistics for the RPART, RF and GBM models were 0.79, 0.70 and 0.76, respectively, corresponding to a fair accuracy). As expected, also a lower FVC, and DLCO-SB, and a positivity for Scl-70 ab were associated with presence of ILD.ConclusionLower BMI is a novel promising predictor for the presence of ILD, which should be confirmed in additional analyses.Disclosure of InterestsAlexandru Garaiman: None declared, Carina Mihai Speakers bureau: MEDtalks Switzerland, Mepha, Rucsandra Dobrota Consultant of: Actelion and Boehringer-Ingelheim, Grant/research support from: Articulum Fellowship, Pfizer, Actelion, Cosimo Bruni Speakers bureau: Eli-Lilly, Actelion, Boehringer-Ingelheim, Grant/research support from: Gruppo Italiano Lotta alla Sclerodermia (GILS), European,, Scleroderma Trials and Research Group (EUSTAR), Scleroderma Clinical Trials Consortium (SCTC), AbbVie, Muriel Elhai: None declared, Suzana Jordan: None declared, Lea Stamm: None declared, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Jansen, Roche, Merck Sharp & Dohme, ARXX Therapeutics, Lilly and Medscape, Consultant of: Actelion, Boehringer Ingelheim, Jansen, Roche, Merck Sharp & Dohme, ARXX Therapeutics, Lilly and Medscape, Grant/research support from: Boehringer Ingelheim, Bayer, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Medscape, Novartis, Roche, Pfizer, Roche, Sanofi, Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon, Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Prometheus Biosences, Roche, Roivant, Topadur and UBC, Lilly, Pfizer, Grant/research support from: Kymera, Mitsubishi Tanabe, Mike O. Becker Speakers bureau: Mepha, MSD, Novartis, GSK, Bayer and Vifor

BackgroundInterstitial lung disease (ILD) is the leading cause of death in systemic sclerosis (SSc). European consensus guidelines consider that some patients with mild disease might not need pharmacological treatment (1). Up to now, the disease characteristics and the disease course of non-treated SSc-ILD patients remain unknown.ObjectivesTo describe disease characteristics and the disease course of non-treated SSc patients with ILD.MethodsWe included patients from our local EUSTAR center registered since 2008, who had a diagnosis of ILD on high-resolution computed tomography (HRCT) and available data on pulmonary function tests and treatment. Longitudinal study included patients with at least one follow-up visit. Patients were classified as treated if they received a potential ILD modifying drug (immunosuppressive therapy or nintedanib). Treated and untreated patients were compared at baseline. Progression in the untreated group was defined as (i) forced vital capacity (FVC) decline from baseline of ≥10% or (ii) an FVC decline of 5-9% in association with a decline in diffusing capacity for carbon monoxide (DLCO) of ≥15%, or (iii) start of a ILD modifying treatment during follow-up. In the untreated group, patients who progressed at any time were compared with patients with stable disease during follow-up. Multivariable logistic regression was performed to identify (i) factors associated with non-prescription of a treatment in ILD patients at baseline and (ii) factors associated with progression in the untreated patients. Covariates were selected according to clinical experience and literature evidence.ResultsAmong 496 patients included in our cohort, 209 (42%) patients had ILD on baseline HRCT: 48/209 (23%) were males, median disease duration 8 [IQR: 4-12] years, 67/209 (32%) of diffuse cutaneous subset and 86/209 (41%) had anti-Scl70 antibodies.Among them, 142/209 (68%) did not receive any potentially ILD modifying treatments at baseline. Untreated patients were older (59 vs. 54 years), had a longer disease duration, were less frequently smokers, had more frequently anticentromere antibodies and lower levels of CRP. They had more frequently a limited extent (In multivariable logistic regression, older age (OR: 1.04 [1.01-1.08], p=0.021), a less extensive disease on HRCT (OR: 0.29 [0.09-0.90], p=0.037) and less frequent prescription of glucocorticoids (OR: 0.036 [0.12-0.92], p=0.037) were independently associated with absence of ILD modifying treatment prescription in our cohort.From the 142 untreated patients, 96 were followed-up for 64 [39-96] months. Of these, 56 (58%) patients showed progression of ILD, of whom 43 progressed by lung function parameters. Of these 56 patients, 31 (56%) progressed in the first 18 months. Diffuse cutaneous subtype (OR: 5.26 [1.26-27.62], p=0.031), shorter disease duration (OR: 0.95 [0.90-0.99], p=0.035) and oesophageal symptoms (reflux, dysphagia) (OR: 3.51 [1.12-12.18], p=0.036) at baseline were independent predictors of progression during follow-up in untreated patients.ConclusionA considerable number of SSc patients with ILD are not treated in clinical practice, in particular patients with limited cutaneous SSc, older age and an overall less extensive ILD. However, during a follow-up of 5 years, contrary to the common belief, about 60% of the untreated patients showed ILD-progression. The diffuse cutaneous subtype, shorter disease duration and oesophageal symptoms at baseline characterized these patients. With the development of effective and safe therapies for SSc-ILD, our results support a change in practice for selecting patients for treatment.References[1]Hoffmann-Vold A-M, et al. The Lancet Rheumatology. 2020;2(2):e71-e83.Disclosure of InterestsMoritz Scheidegger: None declared, Alexandru Garaiman: None declared, Carina Mihai Speakers bureau: Boehringer-Ingelheim, MED Talks Switzerland, Consultant of: Boehringer-Ingelheim (advisory board), Janssen (advisory board), Mike O. Becker Speakers bureau: Mepha, MSD, Novartis, GSK, Bayer and Vifor, Consultant of: Mepha, MSD, Novartis, GSK, Bayer and Vifor (advisory board fees), Rucsandra Dobrota Consultant of: Boehringer-Ingelheim (Advisory Board), Cosimo Bruni Speakers bureau: Eli-Lilly2018-2021, Actelion2019, Boehringer-Ingelheim2020-2021, Grant/research support from: AbbVie (educational grant 2021), Suzana Jordan: None declared, Håvard Fretheim Speakers bureau: Personal fees form Bayer and non-financial support from GSK and Actelion, outside the submitted work., Øyvind Midtvedt: None declared, Hilde Jenssen Bjørkekjær: None declared, Imon Barua: 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, 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, Muriel Elhai Speakers bureau: Speaker fees: BMS outside the submitted work

ObjectivesTo identify the predictive clinical characteristics and establish a prediction model for the progression of mild interstitial lung disease (ILD) in patients with systemic sclerosis (SSc).MethodsPatients with SSc from two independent prospective cohorts were included in this observational study. All patients fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria, had mild ILD at baseline diagnosed by High-Resolution Computed Tomography (HRCT), available baseline and ≥1 annual follow-up pulmonary function tests and no concomitant pulmonary hypertension or airflow obstruction. ILD progression was defined as a relative decrease in forced vital capacity (FVC)%≥15%, or FVC%≥10% combined with diffusing capacity for carbon monoxide %≥15% at 1-year follow-up. Candidate predictors for multivariate logistic regression were selected by expert opinion based on clinical significance. A prediction model for ILD progression was established in the derivation cohort and validated in the multinational validation cohort.ResultsA total of 25/98 and 25/117 patients with SSc showed ILD progression in the derivation cohort and the validation cohort, respectively. Lower SpO2 after 6 min walk test (6MWT) and arthritis ever were identified as independent predictors for ILD progression in both cohorts. The optimal cut-off value of SpO2 after 6MWT for predicting ILD progression was determined as 94% by receiver operating characteristic curve analysis. The derived SPAR model combining both predictors (SPO2 and ARthritis) increased the prediction rate from 25.5% to 91.7% with an area under the curve (95% CI) of 0.83 (0.73 to 0.93).ConclusionsThe evidence-based SPAR prediction model developed in our study might be helpful for the risk stratification of patients with mild SSc-ILD in clinical practice and cohort enrichment for future clinical trial design.

ObjectivePulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc). In this longitudinal study, we aimed to identify factors associated with an unfavourable outcome in patients with SSc with early PAH (SSc-PAH) from the DETECT cohort.MethodsPatients with SSc-PAH enrolled in DETECT were observed for up to 3 years. Associations between cross-sectional variables and disease progression (defined as the occurrence of any of the following events: WHO Functional Class worsening, combination therapy for PAH, hospitalisation or death) were analysed by univariable logistic regression.ResultsOf 57 patients with PAH (median observation time 12.6 months), 25 (43.9%) had disease progression. The following factors (OR (95% CI)) were associated with disease progression: male gender (4.1 (1.2 to 14.1)), high forced vital capacity % predicted/carbon monoxide lung diffusion capacity (DLCO)% predicted ratio (3.6 (1.2 to 10.7)), high Borg Dyspnoea Index (1.7 (1.1 to 2.6)) and low DLCO% predicted (non-linear relationship).ConclusionMore than 40% of early-diagnosed patients with SSc-PAH had disease progression during a short follow-up time, with male gender, functional capacity and pulmonary function tests at PAH diagnosis being associated with progression. This suggests that even mild PAH should be considered a high-risk complication of SSc.

Background:Patient reported outcome measures (PROM) are important for clinical practice and research. Given the unmet need for a comprehensive PROM for systemic sclerosis (SSc), the ScleroID questionnaire was developed by a joint team of patients with SSc and medical experts. This is intended as a brief, specific, patient-derived, disease impact score for research and clinical use in SSc.Objectives:Here, we present the validation and final version of the ScleroID.Methods:This EULAR-endorsed project involves 9 European expert SSc centers. Patients fulfilling the ACR/EULAR 2013 criteria were prospectively included since 05/16 in a large observational cohort study. Patients completed the ScleroID and comparators SHAQ, EQ5D, SF36. They also weighted the 10 dimensions of the ScleroID by distributing 100 points according to the perceived impact on their health. The final score calculation is based on the ranking of the weights. The validation study included a reliability arm and a longitudinal arm, looking at sensitivity to change at follow-up.Results:Of the 472 patients included at baseline, 109 patients also had a reliability visit and 113 patients a follow-up visit. 84.5% of patients were female, 29.8% had diffuse SSc, mean age was 54.6 years, and mean disease duration 9.5 years. The highest weights were assigned by the patients to Raynaud`s phenomenon, fatigue, hand function and pain, confirming our previous results. The total ScleroID score showed good Spearman correlation coefficients with the comparators (SHAQ, 0.73; EQ5D -0.48; Patient’s global assessment, VAS 0.77; HAQ-DI 0.62; SF36 physical score -0.62; each pFigure 1.Conclusion:The EULAR ScleroID is a novel PROM designed for use in clinical practice and clinical trials to reflect the disease impact of SSc, showing good performance in the validation study. Importantly, Raynaud syndrome, impaired hand function, pain and fatigue were the main patient reported drivers of disease impact.Disclosure of Interests:Mike O. Becker: None declared, Rucsandra Dobrota: None declared, Kim Fligelstone: None declared, Annelise Roennow: None declared, Yannick Allanore Grant/research support from: BMS, Inventiva, Roche, Sanofi, Consultant of: Actelion, Bayer AG, BMS, BI, Patricia Carreira Grant/research support from: Actelion, Roche, MSD, Consultant of: GlaxoSmithKline, VivaCell Biotechnology, Emerald Health Pharmaceuticals, Boehringer Ingelheim, Roche, Speakers bureau: Actelion, GlaxoSmithKline, Roche, László Czirják Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, 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, Roger Hesselstrand: None declared, Gunnel Sandqvist: None declared, Otylia Kowal-Bielecka Consultant of: Bayer, Boehringer Ingelheim, Inventiva, MSD, Medac, Novartis, Roche and Sandoz, Speakers bureau: Bayer, Boehringer Ingelheim, Inventiva, MSD, Medac, Novartis, Roche and Sandoz, Cosimo Bruni Speakers bureau: Actelion, Eli Lilly, Marco Matucci Cerinic: None declared, Carina Mihai: None declared, Ana Maria Gheorghiu: None declared, Ulf Müller-Ladner Speakers bureau: Biogen, Joe Sexton: None declared, Turid Heiberg: 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

During the current global outbreak of coronavirus disease 2019 (COVID-19), risk stratification of patients is of utmost importance. Currently, patients >65 years and those with pre-existing medical conditions such as cardiovascular disease, chronic respiratory disease or diabetes mellitus are considered at higher risk for severe disease.1 The Swiss Federal Office of Public Health, like similar authorities around the world, has additionally included patients on immunosuppressants in the high-risk group for developing severe COVID-19.2 However, at this moment we do not have enough evidence either to support or to reject this assumption. We report the case of a 57-year-old woman with systemic sclerosis (SSc) who developed COVID-19. Comorbidities were insulin-dependent type 2 diabetes mellitus and WHO grade I obesity. The anti-topoisomerase I antibody-positive patient was diagnosed with SSc in 2017. SSc-associated interstitial lung disease (SSc-ILD), with cough and exertion dyspnoea, was the leading organ manifestation, associated with symmetrical, non-erosive polyarthritis, and elevated acute phase reactants. Treatment with the anti-interleukin (IL) 6 receptor blocker tocilizumab, with 8 mg/kg body weight every 4 weeks intravenously, was started, leading to a good control of both …

Background:Digital ulcers (DUs) affect half of the patients with systemic sclerosis (SSc) and can be complicated by gangrene and amputation. The direct involvement of platelets in the development of DUs has been suggested by in vitro studies, which encouraged physicians to consider platelet inhibitors as a therapeutic option in the management of DUs. However, until now, there is no clinical study to assess the efficacy of platelet inhibitors for DUs in SSc patients.Objectives:To demonstrate a possible relationship between treatment with platelet inhibitors and the occurrence of DUs at the next follow-up visit in patients with SSc.Methods:This study used prospectively collected data from the European Scleroderma Trials and Research group (EUSTAR) registry. Patients fulfilling the 2013 ACR/EULAR SSc classification criteria with complete longitudinal data on the presence of DUs and platelet inhibitors were included in the analysis. Multiple imputation using a random forest algorithm was implemented to handle missing values.The dataset was split into a derivation and validation cohort. To investigate the response for the binary dependent variable of DUs, a generalized linear mixed model (GLMM) was developed in the derivation cohort and validated using ROC analysis and Brier scores to address discrimination and calibration, respectively.Results:Of 3,463 patients (2,961 in the derivation cohort, 722 in the validation cohort), 453 had current DUs at the baseline and 245 were exposed to platelet inhibitors (table 1).Our GLMM revealed that the exposure to platelet inhibitors is associated with a reduced risk of DUs at the next follow up visit (OR = 0.33, 95% CI = [0.13 to 0.82]). Further factors associated with absence or presence of DUs at the next follow-up visit are shown in figure 1. This confirmed the previously identified risk factors for the presence of DUs, supporting the overall robustness and the validity of our model.The performance was evaluated by ROC curve analysis and showed an AUC = 97.97% (95% CI = [96.93% to 97.67%]) for the derivation cohort and AUC = 77.3% (95% CI = [74.01% to 81.39%]) for the validation cohort, respectively, showing an acceptable discrimination. The Brier score was 0.05 in the derivation cohort and 0.07 in the validation cohort, suggesting a good calibration of the model.Conclusion:Our model, with acceptable discrimination and good calibration, suggests a positive treatment effect of platelet inhibitors on DUs in clinical practice.Table 1.Baseline characteristics of patients before imputationCharacteristicsOverallDerivation setValidation setn3,4632,691772Age (median [IQR])56.00 [47.00, 66.00]56.00 [47.00, 65.00] 57.00 [48.00, 67.00]Disease duration (median [IQR]) 9.00 [4.00, 16.00] 9.00 [4.00, 16.00] 8.00 [4.00, 15.00]Disease subset = Limited cutaneous SSc (%) 1562 (65.2) 1164 (64.6) 398 (66.9)DUs (%): Current 453 (13.1) 378 (14.0) 75 (9.7)DUs (%): Never 1783 (51.5) 1326 (49.3) 457 (59.2)DUs (%): Previously 1227 (35.4) 987 (36.7) 240 (31.1)mRSS (median [IQR]) 5.00 [2.00, 11.00] 6.00 [2.00, 12.00] 4.00 [1.00, 11.00]Joint Contractures = Yes (%) 881 (26.8) 770 (29.4) 111 (16.5)LVEF (median [IQR])62.00 [60.00, 65.00]60.00 [60.00, 65.00] 65.00 [60.00, 67.00]Dyspnea NYHA III and IV (%)300 (9.5)214 (8.6)86 (12.7)Pulmonary hypertension = Yes (%) 244 (10.7) 200 (11.3) 44 (8.4)Lung fibrosis on HRCT = Yes (%) 685 (46.6) 600 (47.7) 85 (39.7)FVC % predicted (median [IQR])97.00 [82.00, 111.00]95.00 [81.00, 110.00]101.00 [85.00, 115.00]Serum creatinine mg/dl (median [IQR]) 0.70 [0.60, 0.90] 0.70 [0.60, 0.90] 0.70 [0.70, 0.90]Anti-Scl-70 positive = Yes (%) 1147 (33.1) 958 (35.6) 189 (24.5)CRP elevation = Yes (%) 639 (21.1) 490 (20.8) 149 (22.1)Platelet inhibitors therapy = Yes (%) 245 (7.1) 206 (7.7) 39 (5.1)Oral anti-coagulants therapy = Yes (%) 53 (1.5) 50 (1.9) 3 (0.4)Disclosure of Interests:None declared

Background:Timely diagnosis of patients with very early systemic sclerosis (veSSc) is essential for their personalized and optimal management. We hypothesise that changes in serum-based extracellular matrix (ECM) turnover biomarkers are already detectable in patients with veSSc, even before occurrence of specific clinical signs.Objectives:To investigate circulating ECM turnover markers as potential biomarkers for veSSc.Methods:Patients with veSSc, n=42, defined as presence of Raynaud’s syndrome and at least one of puffy fingers, positive antinuclear antibodies or pathological nailfold capillaroscopy, who did not meet any classification criteria for SSc, were compared to healthy controls (HC, n=29). Longitudinal assessment, data and sera collection were conducted by EUSTAR standards. ECM-degradation (BGM, C3M, C4M, C6M) and ECM-formation biomarkers (PRO-C3, PRO-C4, PRO-C5) were measured in serum using ELISA assays. The statistical analyses included Mann-Whitney U, Spearman correlation and ROC analysis. Using Kaplan-Meier plots and univariable Cox regression, we explored if biomarkers can predict progression towards definite SSc (fulfillment of ACR/EULAR criteria or minimum two points increase in the criteria score) during the longitudinal follow-up.Results:Compared to HC, veSSc patients showed a deregulated turnover of type III and IV collagen, with higher degradation (higher C3M, C4M, both pMedian follow up was 4.5 years (range 0.5-7.9 years), mean age was 50±2.2 years, 88% female gender, 24% with puffy fingers, 92% were ANA positive, 64% had an abnormal capillaroscopy, none had organ involvement or skin fibrosis. 14/42 veSSc patients fulfilled the ACR/EULAR classification criteria at follow-up (time to fulfilment of criteria ranged between 0.5 and 6.8 years from inclusion) and in addition, 18/42 veSSc patients gained at least two classification criteria-points. This resulted in 14, respectively 18 progressors for the longitudinal analysis. However, in univariable Cox regression, the baseline levels of the markers did not predict progression over time.Conclusion:ECM turnover is already altered in veSSc patients compared to HC. Biomarkes of type III and IV collagen distinguished between veSSc patients and HC, which may indicate them as potential biomarkers for the detection of veSSc in addition to the established immunological and capillaroscopic criteria.Disclosure of Interests:Rucsandra Dobrota: None declared, Suzana Jordan: None declared, Pernille Juhl Employee of: Nordic Bioscience, Britta Maurer Grant/research support from: AbbVie, Protagen, Novartis, congress support from Pfizer, Roche, Actelion, and MSD, Speakers bureau: Novartis, Mike O. Becker: None declared, Carina Mihai: None declared, Anne-Christine Bay-Jensen Shareholder of: Nordic Bioscience A/S, Employee of: Full time employee at Nordic Bioscience A/S., Morten Karsdal Shareholder of: Nordic Bioscience A/S., Employee of: Full time employee at Nordic Bioscience A/S., Anne Sofie Siebuhr Employee of: Nordic Bioscience, 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

Background:The gastrointestinal (GI) tract is frequently involved in systemic sclerosis (SSc). The University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 2.0 (UCLA GIT 2.0) is validated to capture GI morbidity in patients with SSc (1). The routine clinical investigation of GI involvement in these patients is not standardized and there is no consensus about when and how frequently an esophagogastroduodenoscopy (EGD) should be performed.Objectives:The main aim of this study was to analyze the capacity of UCLA GIT 2.0 to identify patients with erosive esophagitis in an unselected, real-life SSc patients’ cohort. Secondary aim was to determine whether the UCLA GIT 2.0 could discriminate SSc patients for whom an expert rheumatologist would recommend an EGD.Methods:We selected patients fulfilling the ACR/EULAR 2013 criteria for SSc from the Zurich cohort, having completed at least once the UCLA GIT 2.0 questionnaire. We reviewed the medical charts of SSc patients from 2013 to 2019 and recorded data on EGD. We analyzed by univariable logistic regression several parameters, including UCLA GIT 2.0, considered as potentially associated with 1) the referral to EGD and 2) macroscopic esophagitis according to the Los Angeles criteria.Results:We identified 346 patients (82.7% female, median age 63 years, median disease duration 10 years, 23% with diffuse cutaneous SSc) satisfying the inclusion criteria, who filled in 940 UCLA GIT 2.0 questionnaires.From 940 visits, 31 were excluded because EGD was done within 3 months before completing the UCLA GIT 2.0. In the 909 remaining visits, EGD was recommended by the expert rheumatologists in 128 cases. In logistic regression, UCLA GIT 2.0 total score and some of its subscales, but also the modified Rodnan skin score (mRSS) and esophageal and stomach symptoms by past medical history, associated with the referral to EGD (Table 1).Table 1.Logistic regression of factors associated with referral to EGDOR (95% CI)p-valuemRSS1.04 (1.01 - 1.06)0.009Hemoglobin (Hb)1.00 (0.96 - 1.04)0.978Proton pump inhibitor (PPI)0.37 (0.12 - 1.15)0.086Esophageal symptoms3.37 (2.28 - 4.96)Stomach symptoms2.93 (2.02 - 4.26)Reflux subscale2.04 (1.52 - 2.73)Distention/bloating subscale1.53 (1.24 - 1.89)Social functioning2.20 (1.57 - 3.07)Emotional wellbeing1.42 (1.03 - 1.97)0.034Total score of UCLA GIT 2.02.27 (1.55 - 3.32)We found data on 177 EGD performed in 150 patients, meaning that 49 EGD were performed on indication by another physician. In logistic regression, mRSS and esophageal symptoms correlated with esophagitis, while neither the total ULCA GIT 2.0 score nor the reflux subscale or any of the other subscales showed an association with esophagitis (Table 2).Table 2.Logistic regression of factors associated with esophagitisOR (95% CI)p-valuemRSS1.09 (1.03 - 1.15)0.001Hb1.03 (0.99 - 1.06)0.126PPI0.52 (0.27 - 1.03)0.059Esophageal symptoms2.92 (1.29 - 6.61)0.010Stomach symptoms1.60 (0.80 - 3.21)0.183Reflux subscale1.07 (0.60 - 1.93)0.816Distention/Bloating subscale0.63 (0.39 - 1.01)0.054Social functioning0.65 (0.31 - 1.35)0.245Emotional wellbeing0.77 (0.36 - 1.61)0.483Total score of UCLA GIT 2.00.67 (0.28 - 1.60)0.367Conclusion:In a real-life setting, UCLA GIT 2.0 subscales (reflux, distention/bloating, social functioning, emotional wellbeing) and total score strongly associated with expert interpretation of gastroesophageal symptoms and consecutive referral to EGD. However, they showed no correlation with esophagitis on EGD. The main clinical association of esophagitis was the presence of esophageal symptoms.References:[1]Khanna D, et al. Reliability and validity of the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument. Arthritis Rheum. 2009;61(9):1257-63.Disclosure of Interests:Norina Zampatti: None declared, Alexandru Garaiman: None declared, Suzana Jordan: None declared, Mike O. Becker: None declared, Britta Maurer Grant/research support from: AbbVie, Protagen, Novartis, congress support from Pfizer, Roche, Actelion, and MSD, Speakers bureau: Novartis, Rucsandra Dobrota: 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, Carina Mihai: None declared

Background:In systemic sclerosis (SSc) patients with interstitial lung disease (ILD) approximately 30% show progressive ILD. It is unknown whether a progressive ILD period is followed by further lung function decline. In clinical practice, treatment is frequently initiated after observation of lung function decline over 6-12 months and lung function stabilization at follow up is often interpreted as treatment effect.Objectives:Assess the predictive ability of lung function decline over 12 months for further deterioration adjusted for known risk factors for ILD and treatment in two large and well characterized SSc cohorts.Methods:Patients with SSc-ILD by HRCT, fulfilling SSc classification criteria, from the Oslo and Zurich University Hospital were included. The first period with three consecutive annual forced vital capacity (FVC) measurements (i.e. at 0, 12 and 24 months, +/- 3 months) was used. Lung function decline was assessed by absolute changes in FVC% predicted. Moderately progressive ILD was defined as FVC decline of >5-Results:In total, 240 SSc-ILD patients met the inclusion criteria (table). Of these 69 (29%) SSc-ILD patients showed progressive ILD in the first 12 months period; 34 (14%) with moderate (5-10%) and 35 (15%) with significant FVC decline (≥10%). Independent of FVC changes in the first period, 77 (32%) showed progressive ILD in the second period; 44 (18%) moderate and 33 (14%) significant FVC decline. Only 21 (9%) SSc-ILD patients had two progressive periods, and 115 (48%) were stable in the two 12 month’s periods; all independent of treatment. In multivariable logistic regression, progressive ILD in the first period (moderate, significant or combined FVC decline) was not predictive for progression in the following period. Of all applied risk factors, only mRSS was significantly predictive for further FVC decline, also when adjusted for age, gender and treatment (OR 1.03, 95%CI 1.00-1.08, p=0.035).Conclusion:Decline of FVC in one 12 months period did not predict further ILD progression in the following 12 months independent of treatment. These results have important clinical implications. Firstly, a decline of lung function in one period seems not to be the right indicator for initiating treatment. Secondly, stabilization of lung function under treatment initiated after ILD progression cannot necessarily be interpreted as a treatment response on the individual patient level.Table:First periodBoth periodsSSc-ILD (n=240)ILD progression (n=69)ILD progression (n=21)Stable ILD (n=115)Age, years (SD)48 (14.7)49 (13.8)50 (14.3)46 (15.3)Male, n (%)57 (24)18 (26)5 (24)27 (24)Disease duration yrs, mean (SD)10.2 (11.4)9.8 (10.2)8.8 (11.0)10.8 (12.3)Disease duration 68 (28)22 (32)8 (38)29 (25)Diffuse cutaneous SSc, n (%)95 (40)30 (44)11 (52)43 (27)Anti-topoisomerase I Ab, n (%)84 (35)27 (40)9 (43)42 (37)mRSS, mean (SD)10 (9.3)11 (10.2)16 (13.0)8 (8.3)CRPml, mean (SD)3.6 (7.2)3.3 (6.2)4.4 (9.1)3.1 (5.1)GERD, n (%)148 (62)44 (64)15 (74)70 (61)FVC % predicted90 (20.3)90 (21.9)92 (21.7)89 (19.3)DLCO% predicted64 (17.9)64 (16.6)70 (11.3)65 (17.5)Lung fibrosis >20%, n (%)55 (23)16 (23)4 (19)27 (24)Mycophenolate Mofetil, n (%)47 (20)15 (22)5 (24)23 (20)Other immunosuppression, n (%)79 (33)22 (32)9 (43)42 (37)Corticosteroids, n (%)62 (26)18 (26)8 (38)28 (24)Disclosure of Interests:Anna-Maria Hoffmann-Vold Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Actelion, Bayer, GlaxoSmithKline, Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Håvard Fretheim: None declared, Britta Maurer Grant/research support from: AbbVie, Protagen, Novartis, congress support from Pfizer, Roche, Actelion, and MSD, Speakers bureau: Novartis, Mike Durheim Grant/research support from: BI, Consultant of: BI, Speakers bureau: BI, Øyvind Midtvedt: None declared, Mike O. Becker: None declared, Rucsandra Dobrota: None declared, Øyvind Molberg: None declared, Suzana Jordan: 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

Background:Depression, anxiety and distress affect the quality of life of patients with systemic sclerosis (SSc) [1]. The Hospital Anxiety and Depression Scale (HADS) and Sense of Coherence 13-item scale (SOC-13, measuring comprehensibility, manageability and meaningfulness) are screening tools used in patients with different medical conditions. However, their validity, reliability and sensitivity to change in SSc patients has not been evaluated yet.Objectives:To examine the psychometric properties of HADS and its subscales HADS-A and HADS-D (measuring anxiety and depression symptoms, respectively), and unidimensional SOC-13 in a large cohort of Swiss SSc patients.Methods:Consecutive patients fulfilling the ACR/EULAR 2013 classification criteria for SSc who completed the HADS, SOC-13, Short Form-36 Health Survey (SF-36) and Scleroderma Health Assessment Questionnaire (SHAQ) were included in a cross-sectional and longitudinal analysis. Cronbach’s α, split-half reliability and construct validity were measured. Sensitivity to change (Cohen’s d coefficient) was assessed in patients who worsened within 12±3 months, defined as occurrence of any of the following events: decline in forced vital capacity (FVC)≥10%, new diagnosis of interstitial lung disease (ILD) on high-resolution computed tomography (HRCT), progression of known ILD to >20% lung involvement on HRCT (ILD20), new-onset pulmonary hypertension (PH), increase in European Scleroderma Study Group activity index (EScSG-AI) >3 points, new active digital ulcers, increase in modified Rodnan skin score (mRSS) > 7 points.Results:Of 345 patients (aged 59.34±14.17, 82.9% female, 18.8% with diffuse cutaneous SSc, 47.6% anti-centromere Ab-positive, 23.5% anti-Scl-70 Ab-positive, 13% anti-U1RNP Ab-positive and 11.3% anti-RNA polymerase III Ab-positive) 85 participated with a second visit to the sensitivity to change analysis.Internal consistency was excellent for the HADS (Cronbach’s α=0.91; split-half reliability r=0.92), and very good for HADS-A, HADS-D and SOC-13 (Cronbach’s α=0.85-0.89; split-half reliability r=0.86-0.89).Regarding construct validity, all four scales showed a strong to very strong correlation to each other, as well as with the mental components of SF-36 (Spearman’s r=0.63-0.85). There was a moderate to strong correlation with the SHAQ (Spearman’s r=0.45-0.64).Regarding sensitivity to change: HADS-A showed a large to very large effect size (ES) for progression of ILD as assessed on HRCT and increase in EScSG-AI (Cohen’s d=1-1.63), and a very small to small ES for changes in FVC, DU and mRSS (Cohen’s d=0.02-0.45). HADS-D showed a large ES for changes in the ILD20, mRSS and EScSG-AI (Cohen’s d=0.82-1), and moderate ES for changes of FVC, ILD, PH, DU (Cohen’s d=0.1-0.49). SOC-13 showed generally a very small to small EF, except for change in mRSS (Cohen’s d=0.56).Conclusion:The HADS(A/D) and SOC-13 are valid and easy-to-use tools to detect depression, anxiety and distress in SSc. However, their sensitivity to change might be limited by the respective type of organ involvement and its impact on the patients’ psychological wellbeing.References:[1]Legendre C, Allanore Y, Ferrand I, Kahan A. Evaluation of depression and anxiety in patients with systemic sclerosis. Joint Bone Spine. 2005;72(5):408–411.Disclosure of Interests:Alexandru Garaiman: None declared, Carina Mihai: None declared, Rucsandra Dobrota: None declared, Suzana Jordan: None declared, Britta Maurer Grant/research support from: AbbVie, Protagen, Novartis, congress support from Pfizer, Roche, Actelion, and MSD, Speakers bureau: Novartis, 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, Mike-Oliver Becker: None declared

ObjectiveSystemic sclerosis (SSc) is a systemic autoimmune disease with high morbidity and significant mortality. There is a great need of predictors that would allow risk stratification of patients with SSc and ultimately initiation of treatment early enough to ensure optimal clinical results. In this study, we evaluated whether a history of digital ulcers (HDU) at presentation may be a predictor of vascular outcomes and of overall clinical worsening and death in patients with SSc.MethodsPatients from the EULAR Scleroderma Trials and Research (EUSTAR) database, satisfying at inclusion the 1980 American College of Rheumatology classification criteria for SSc, who had a follow-up of at least 3 years since baseline or who have died, were included in the analysis. HDU at presentation as a predictor of disease worsening or death was evaluated by Cox proportional hazards regression analysis.Results3196 patients matched the inclusion criteria (male sex 13.2%, 33.4% diffuse subset). At presentation, 1092/3196 patients had an HDU (34.1%). In multivariable analysis adjusting for age, gender and all parameters considered potentially significant, HDU was predictive for the presence of active digital ulcers (DUs) at prospective visits (HR (95% CI)): 2.41 (1.91 to 3.03), pConclusionsIn patients with SSc, HDU at presentation predicts the occurrence of DUs at follow-up and is associated with cardiovascular worsening and decreased survival.

Background Patient reported outcome measures (PROM) are required as key outcomes in disease modifying therapeutic trials in systemic sclerosis (SSc) and could also improve the clinical care of patients with SSc. A PROM tool for clinical trials and practice in SSc, covering the different features of this multi-organ autoimmune disease, is lacking. Objectives To develop and validate a brief, disease-specific, patient-derived, composite disease impact score for scientific and clinical use in SSc. Methods This multi-center project involves SSc patients and experts from 11 European countries. Firstly, using the nominal group technique, patients with SSc selected the health dimensions where the disease has the most significant impact. The dimensions were subsequently given numeric priority by an international group of SSc patients. The dimensions with the top 10 median ranks, as ranked by the patients, were used to construct the ScleroID questionnaire using numeric rating scales. Further, the dimensions are currently weighted by distributing 100 points among the dimensions by a larger cohort of patients from all participating countries. The calculation of the score will be based on the ranking of the weights. Results 24 SSc patients selected 17 health dimensions in the nominal group exercise. The prioritization cohort included 108 SSc patients from 11 centers (female:male 82:25, limited:diffuse SSc subset 53:54). The top 10 health dimensions which were ranked most relevant by the patients were Raynaud9s phenomenon, hand function, upper and lower gastrointestinal tract symptoms, pain, fatigue, limitation of life choices and activities, body mobility, breathlessness and digital ulcers (Figure 1). Conclusions The EULAR ScleroID score is a novel tool under development designed for use in clinical practice and clinical trials to display the disease impact of SSc. Further validation of this new instrument will be performed as soon as the weighting procedure is completed. Acknowledgement Contributing patients: Yanne Perriault, Susanne Tuppeck, Helene Kambourakis, Elisabeth Scheel, Stephan Houbertz, Anna Vegh, Beata Garay Toth, Barbara Zappitello, Grazia Tassini, Silvia Sandulescu, Ana Marcela Badea, Stefana Dumitru, Rachida Amrouch, Alicia Garcia Oliva, Begona Maria Gorricho Corta, Heleen Lever, Johanna Berglind, Mervat Gaafar, Natalie Perruchoud, Alice Martins Correia, Richard Dodds, Nicola Whitehill. Disclosure of Interest R. Dobrota: None declared, M. Becker: None declared, K. Fligelstone: None declared, J. Fransen: None declared, A. Kennedy: None declared, Y. Allanore Grant/research support from: Bristol-Myers Squibb, Roche/Genentech, Inventiva, Pfizer, Sanofi, and Servier, Consultant for: Actelion, Bayer, Roche/Genentech, Inventiva, Medac, Pfizer, Sanofi, Servier, and UCB, P. Carreira: None declared, L. Czirijak: None declared, C. Denton: None declared, R. Hesselstrand: None declared, G. Sandqvist: None declared, O. Kowal-Bielecka: None declared, M. Matucci-Cerinic: None declared, C. Mihai: None declared, A. Gheorghiu: None declared, U. Muller-Ladner: None declared, M. Frerix: None declared, T. Heiberg: None declared, O. Distler Grant/research support from: Bayer, Sanofi, Ergonex, Boehringer Ingelheim, Actelion, Pfizer, Consultant for: 4 D Science, Actelion, Active Biotec, Bayer, BiogenIdec, BMS, Boehringer Ingelheim, EpiPharm, Ergonex, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Pharmacyclics, Pfizer, Serodapharm, Sinoxa

Background Nodular regenerative hyperplasia (NRH) is a rare liver disease causing non-cirrhotic intrahepatic portal hypertension (1). The knowledge of NRH is based mainly upon case reports. Although patients with NRH may remain asymptomatic, at least 50% develop life-threatening complications. Among the autoimmune diseases, SSc has been hypothesized to be associated with NRH. In SSc, microvascular injury is considered one of the earliest pathologic events, followed by inflammation and fibrosis. Similar mechanisms are supposed to be operative in NRH. Therefore, it might be hypothesized that NRH represents a yet unidentified vascular complication of SSc. Objectives To investigate the prevalence and clinical phenotype of NRH in SSc. Methods Published cases of SSc-NRH were identified by systematic literature review. Next, we screened the Zurich SSc cohort. In accordance with international guidelines, the diagnosis of NRH had to be established by liver biopsy showing a characteristic diffuse micronodular transformation without fibrous septa (2). SSc characteristics were derived from the EUSTAR database. Information on NRH was extracted from the patients9 charts. The study was approved by the local institutional review board. For the statistical analysis, SPSS version 20 was used. Continues variables are presented as mean±SD or median+range. Categorical variables are given as absolute numbers and percentage. Results The Pubmed search review retrieved 9 cases of SSc-NRH. In the Zurich cohort, 5 out of 278 patients with established SSc were diagnosed with NRH resulting in a prevalence of 1.8%. The main characteristics of all 14 patients are provided in Fig.1. The majority of patients was female (69.2%) with an average age of 44.5±12.3 years at diagnosis of SSc. Mean disease duration of SSc was 8.2±7 years when NRH was diagnosed. NRH occurred in both diffuse and limited cutaneous SSc. ACR/EULAR criteria were fulfilled by all patients. Of note, in the majority of patients, vascular features of SSc were present at the time point of the diagnosis of NRH including digital ulcers (ever 100%, active 71.4%), an active pattern on nailfold capillaroscopy (100%), and pulmonary hypertension (50%). The most prevalent auto-antibodies were anti-centromere (40%) and anti-U1nRNP (33%), whereas no patient was positive for anti-Scl70 or anti-RNA-Polymerase III. In the majority of patients, an elevation of AP and GGT (75%, 60%) was observed, whereas transaminases were not increased. Melaena and hematemesis occurred in 66.7%, resp. 50% of patients. Ultrasound detected ascites (60%) and splenomegaly (75%), but no pathologic liver morphology, although an increased stiffness was diagnosed by fibroscan (75%). Portal hypertension was diagnosed in 85.7% with oesophageal varices (70%) and variceal haemorrhage (44.4%) as main complications. Conclusions NRH might represent a rare, yet clinically important, potentially life-threatening complication in SSc patients, especially in those with prominent vascular features and positivity for anti-centromere. Elevated levels of AP and GGT, ascites and splenomegaly by ultrasound and increased stiffness by fibroscan might alert to the presence of NRH. If suspected, the diagnosis should be confirmed by liver biopsy. References Hillaire S, et al. Gut 2002; Steiner PE. Am J Pathol 1959 Disclosure of Interest B. Maurer: None declared, L. Graf: None declared, Y. Allanore Grant/research support from: Actelion, Bayer, Biogen Idec, Bristol-Myers Squibb, Genentech/ Roche, Inventiva, Medac, Pfizer, Sanofi/Genzyme, Servier and UCB., Consultant for: Actelion, Bayer, Biogen Idec, Bristol-Myers Squibb, Genentech/ Roche, Inventiva, Medac, Pfizer, Sanofi/Genzyme, Servier and UCB., R. Dobrota: None declared, S. Jordan: None declared, O. Distler Grant/research support from: Bayer, Sanofi, Ergonex, Boehringer Ingelheim, Actelion, Pfizer, Consultant for: 4 D Science, Actelion, Active Biotec, Bayer, BiogenIdec, BMS, Boehringer Ingelheim, EpiPharm, Ergonex, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Pharmacyclics, Pfizer, Serodapharm, Sinoxa

Background Heart involvement in patients with systemic sclerosis (SSc) resembles the inflammatory dilated cardiomyopathy (iDCM) phenotype with predominance of inflammation, fibrosis, vasculopathy and heart dysfunction. Animal studies of iDCM indicated bone marrow originated cells as a major source of pathological myofibroblasts. MicroRNAs are key regulators of immune cell function and are involved in many cardiac pathological processes. However, their roles in monocyte differentiation and fibrogenesis are unclear. Objectives To determine the role of circulating monocytes and microRNAs in the onset and progression of myocardial fibrosis in SSc, we examined monocyte differentiation and their microRNAs expression profile in SSc. Methods Endomyocardial biopsies from SSc/iDCM patients and healthy controls were screened by immunohistochemistry. CD14+ monocytes isolated from peripheral blood of SSc patients and healthy donors were differentiated towards the myofibroblast phenotype by stimulation with TGF-β1, IL-4, IL-10 and IL-13. In addition, CD14+ monocytes were co-cultured with dermal fibroblasts originated from SSc patients and healthy subjects. After 7 days, myofibroblast gene expression and cytokines secretion profile were evaluated. MicroRNA candidates were selected using DIANA-TarBase v7.0 and TargetScan Release 7.0 and further analysed by qPCR. Results Myocardium of SSc/iDCM patients (n=10) revealed extensive fibrosis and accumulation of inflammatory cells including CD14+ monocytes. Moreover, fibrotic myocardium from SSc patients exhibited the presence of CD14+/Fra-2+ monocyte-derived fibroblast-like cells. Bioinformatical analysis indicated several potential microRNAs being involved in monocyte differentiation, and qPCR confirmed predicted candidates. We observed decreased basal levels of let-7i (Mann-Whitney U test, p=0.005), miR-10b (p=0.005), miR-21 (p=0.005), miR-29a (p=0.005), miR-155 (p=0.002), miR-199a (p=0.008) and miR-544a (p=0.002), and increased levels of miR-29b (p=0.03) in circulating CD14+ monocytes isolated from SSc patients (n=10) compared to healthy controls (n=4). Stimulated monocytes acquired a myofibroblast-like phenotype with increased expression of collagen I, fibronectin, α smooth muscle actin and Fra-2 in comparison to untreated cells. Similarly, CD14+ monocytes exposed to dermal fibroblasts acquired myofibroblast features. CD14+ monocytes from SSc patients were characterised by higher production of IP-10, MIP-3α, LIF and NT-3. The process of monocyte to myofibroblast differentiation employed Fra-2/TGF-β signalling. Inhibition of the canonical SMAD-dependent pathway with TGFβR1 inhibitors resulted in the abrogation of monocyte-to-myofibroblast differentiation. Conclusions Here we demonstrated the capability of peripheral blood monocytes to differentiate towards the myofibroblast phenotype, indicating these cells as one of the potential sources of pathological tissue myofibroblasts in SSc. Different miRNA expression profiles in SSc monocytes indicate a primary activation state. Further studies of miRNAs regulation pathways might lead to novel treatment strategies, particularly for heart involvement. Disclosure of Interest M. Rudnik: None declared, M. Stellato: None declared, P. Blyszczuk: None declared, E. Pachera: None declared, R. Dobrota: None declared, B. Maurer: None declared, K. Klingel: None declared, J. Henes: None declared, K. Sotlar: None declared, O. Distler Grant/research support from: Bayer, Sanofi, Ergonex, Boehringer Ingelheim, Actelion, Pfizer, Consultant for: 4 D Science, Actelion, Active Biotec, Bayer, BiogenIdec, BMS, Boehringer Ingelheim, EpiPharm, Ergonex, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Pharmacyclics, Pfizer, Serodapharm, Sinoxa, G. Kania: None declared

Background Long noncoding RNAs (lncRNAs) are an emerging class of noncoding transcripts involved in the regulation of gene expression in health and disease. We have recently identified a novel lncRNA, H19X, which is strictly regulated by TGFβ in a dose and time dependent manner. Objectives To detail the differential expression of H19X in SSc and other fibrotic diseases and to characterize its function in fibrotic diseases. Methods Skin and lung biopsies from patients with SSc, idiopathic lung fibrosis (IPF), and healthy controls (HC) were obtained from cohorts at four different expert centers. Expression of H19X was analyzed by RNA Sequencing Ilumina HiSeq2000 and real-time PCR respectively. H19X was silenced in skin fibroblasts using locked nucleic acid antisense oligonucleotides (LNA GapmeRs), followed by qPCR analyses, immunofluorescence staining, SIRCOL assay, contraction assay and Western blot. In situ hybridization of H19X on SSc dermal fibroblast was performed using Stellaris FISH probes. Results H19X expression was consistently upregulated across all four cohorts (SSc n=34, HC n=26). Notably, the upregulation was also consistent across different subsets of patients. H19X showed a similar expression profile in clinically non-involved skin compared to established fibrotic skin. Moreover, expression of H19X was also significantly increased in SSc interstitial lung disease patients versus HC (n=11 each, p Conclusions H19X is a novel lncRNA which is a key factor in mediating the pro-fibrotic effects of TGFβ in systemic sclerosis and other fibrotic diseases. Disclosure of Interest E. Pachera: None declared, S. Assassi: None declared, G. Salazar: None declared, M. Frank-Bertoncelj: None declared, R. Dobrota: None declared, M. Brock: None declared, F. Kurreeman: None declared, J. de Vries-Bouwstra: None declared, T. Messemaker: None declared, C. Feghali-Bostwick: None declared, J. Distler: None declared, G. Kania: None declared, O. Distler Grant/research support from: from Bayer, Sanofi, Ergonex, Boehringer Ingelheim, Actelion, Pfizer, Consultant for: from 4 D Science, Actelion, Active Biotec, Bayer, BiogenIdec, BMS, Boehringer Ingelheim, EpiPharm, Ergonex, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Pharmacyclics, Pfizer, Serodapharm, Sinoxa

Background In clinical trials of systemic sclerosis (SSc), there is an unmet need for better inclusion criteria to enrich for patients with progressive skin fibrosis [1,2]. Recent trials on skin fibrosis frequently used active skin disease at baseline as an enrichment parameter. However, there is little data available supporting such an approach. Objectives To investigate the relationship between active skin disease at baseline and progression of skin fibrosis after one year in patients with diffuse cutaneous SSc (dcSSc). Methods A longitudinal analysis of the EUSTAR registry was performed. The inclusion criteria were: dcSSc, fulfillment of ACR criteria, baseline mRSS≥7, available data for mRSS at 12±2 months. Skin progression was defined as increase in mRSS of >5 points AND ≥25% within 1 year [1]. Activity of skin fibrosis was assessed by patient-reported parameters (worsening of skin within the past month), by using a modified skin thickness progression rate (defined as MRSS at baseline visit/disease duration (years)) and by following patients with progression of mRSS in the recent 12 months for another 12 months. Additionally, non skin specific activity parameters such as the Valentini index, elevated serum inflammatory markers, and other patient reported activity parameters were also analyzed. The Mann-Whitney and the Chi-square tests were used. Results From the 637 patients included, 9.7% had progressive skin fibrosis after 1 year. The patient-reported worsening of skin fibrosis within the past month prior to baseline was not significantly associated with progressive skin disease after 1 year (p=0.774). Similarly, the modified skin progression rate at baseline did not differ between progressive and non-progressive patients at 1 year follow up (p=0.323). Most interestingly, patients with progression of skin fibrosis in the previous year were not significantly more likely to show progression of skin fibrosis in the following year (p=0.385, none of the initially progressive patients at one year showed further progression). In addition, other more general activity parameters at baseline including the Valentini activity index (p=0.673) and inflammatory markers (Erythrocyte sedimentation rate, p=0.287; C-reactive protein p=0.358) were also not associated with progression of skin fibrosis after one year (Figure 1). Conclusions dcSSc patients with recently active skin disease have a similar or even lower likelihood to show further progression of skin fibrosis in a 12 months trial – most likely because they have reached their peak skin score already. Recently active skin disease should not be used as an enrichment criterion in clinical trials targeting skin fibrosis. References Maurer B, Graf N, Michel BA, et al. Prediction of worsening of skin fibrosis in patients with diffuse cutaneous systemic sclerosis using the EUSTAR database. Ann Rheum Dis. 2015;74(6):1124–31. Allanore Y, Distler O. Systemic sclerosis in 2014: Advances in cohort enrichment shape future of trial design. Nature Rev Rheumatol. 2015;11(2):72–4. Disclosure of Interest R. Dobrota: None declared, B. Maurer: None declared, N. Graf: None declared, O. Kowal-Bielecka Consultant for: Abbvie, Actelion, Bayer, Biogen, Pfizer, Roche, Speakers bureau: Abbvie, Actelion, Bayer, Biogen, Pfizer, Roche, M. Matucci-Cerinic: None declared, P. Airo: None declared, P. Caramaschi: None declared, P. Carreira: None declared, G. Riemekasten: None declared, E. Rosato: None declared, Y. Allanore Grant/research support from: Bristol-Myers Squibb, Roche/Genentech, Inventiva, Pfizer, Sanofi, and Servier, Consultant for: Actelion, Bayer, Roche/Genentech, Inventiva, Medac, Pfizer, Sanofi, Servier, and UCB, O. Distler Grant/research support from: Bayer, Sanofi, Ergonex, Boehringer Ingelheim, Actelion, Pfizer, Consultant for: 4 D Science, Actelion, Active Biotec, Bayer, BiogenIdec, BMS, Boehringer Ingelheim, EpiPharm, Ergonex, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Pharmacyclics, Pfizer, Serodapharm, Sinoxa

Background Patients with anti-RNA polymerase III antibodies (anti-RNAP) have an increased risk of malignancies synchronous to the onset of Systemic Sclerosis (SSc). In a multicentre EUSTAR case-control study, however, only moderate odd ratio was observed (OR 3.85, 95%CI 1.3–10.9), except than for breast cancer (OR 20.2, 95%CI 1.4–355) (1). Defining clinical and demographic features characteristic of anti-RNAP+ SSc patients who suffer from simultaneous malignancy would be useful to individuate risk factors who can guide the clinicians in every-day practice to screen anti-RNAP+ SSc patients for cancer. Objectives To individuate risk factors for malignancies synchronous to the onset of SSc in anti-RNAP+ patients. Methods EUSTAR centers were asked to participate to this study, providing data on malignancy history of their anti-RNAP+ patients in a dedicated form. Results Among 158 anti-RNAP+ SSc patients collected from 13 EUSTAR centers, 14 cases of malignancies synchronous to the onset of SSc were identified. When compared with the other 144 anti-RNAP+ patients, patients with synchronous malignancies had an older mean age at SSc onset (65.3 yrs (SD 10.0) vs 49.3 (SD13.3); p Conclusions Anti-RNAP+ SSc patients of older age, and with diffuse cutaneous subset, are particularly at risk for malignancies synchronous to the onset of SSc. The risk of malignancies other than breast cancers is greatly increased in male patients. These risk factors may help in the screening for cancer in these patients. References M.G. Lazzaroni et al. Anti-RNA Polymerase III Antibodies in Patients with Systemic Sclerosis: A Eustar Multicenter Collaborative Study. Ann Rheum Dis 2015;74:Suppl 2 88 doi:10.1136/annrheumdis-2015-eular.1728 Disclosure of Interest None declared

Background Systemic sclerosis (ScS) is a polymorphic autoimmune disease, with increased morbidity and mortality, often diagnosed in advanced stages. The recently published 2013 American College Of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc were developed to increase the identification of early/mild SSc patients. Objectives To compare the sensitivity and specificity of the 2013 ACR/EULAR criteria with 1980 ACR criteria in a single-centre cohort of patients with SSc, diagnosed according to expert oppinion. Methods Data of SSc patients evaluated in our EUSTAR centre between 2004–2015 have been retrospectively analyzed. The control cohort included patients with Raynaud9s phenomenon of other ethiology than SSc, evaluated between 2009–2015. The sensitivity and specificity of the 2013 ACR/EULAR and 1980 ACR criteria were tested using the McNemar test for correlated proportions. Results One hundred and fifty one patients with SSc (90.1% women, mean±SD age 58.4±13.2 years) and 65 controls (87.7% women, mean±SD age 43.7±14.6 years) were included. The sensitivity of the 2013 ACR/EULAR and 1980 ACR criteria were 94.7% and 84.4%, respectively (p Conclusions The 2013 ACR/EULAR criteria have a better sensitivity and missclassify fewer patients than the 1980 ACR criteria. Their excelent performance is close to the gold standard of diagnosis in SSc (expert opinion). Acknowledgement * This abstract was realized as part of the “Development of a computer-based nailfold videocapillaroscopy (NVC) system for longitudinal evaluation of patients with systemic sclerosis” (QUANTICAP) project, financed by the UEFIS-CDI PN-II-PT-PCCA-2013–4-1589 grant. Disclosure of Interest None declared

Background Currently available clinical measures in systemic sclerosis (SSc) are depending on the organ manifestation of interest and have a low sensitivity to change, in particular over shorter observation periods. Biomarkers are more sensitive than traditional measures and have been extensively studied in SSc. However, most biomarker studies focused on cross-sectional analysis, while there is an urgent need for biomarkers that are sensitive to change. Objectives We conducted a systematic literature review to identify biomarkers which are sensitive to change over time or treatment in patients with SSc. Methods Both PubMed and Cochrane CENTRAL databases were searched to identify articles pertaining to the field of SSc and biomarkers. Studies were eligible if they were written in English and presented data from human subjects. The search was initially performed on March 18th, 2011 and renewed on March 23rd, 2013. The results were reviewed by two independent scleroderma experts, through a stepwise selection strategy starting from titles, to abstracts and manuscripts. Studies which did not present original research (e.g. reviews, case studies) were excluded. Moreover, only studies reporting changes in biomarkers and clinical endpoints between the baseline and follow-up visits were included in the final analysis. The identified biomarkers were assessed according to OMERACT criteria. Results The initial search identified 960 unique citations; 721 titles were excluded, leaving 239 abstracts for review; 170 of these did not meet the study criteria. The remaining 69 papers were analyzed full-length and subsequently 15 papers showing longitudinal analysis between biomarkers and clinical endpoints were identified. After filtering according to the OMERACT criteria, several biomarkers sensitive to change over time and/or treatment were identified. Markers of skin fibrosis included E-selectin, Thrombomodulin, Interleukin-1-beta, Interleukin-6. For lung fibrosis, E-selectin, Thrombomodulin, sICAM3, sPECAM-1, KL-6, Surfactant protein D showed sensitivity to change over time or treatment. Markers of vasculopathy were as follows: pulmonary arterial hypertension (sICAM-1, sVCAM-1, sP-selectin, NT-proBNP, MMP-9, IL-12), digital ulcers (sICAM-1, t-PA), Raynaud9s (VEGF, bFGF, sVCAM-1, E-selectin, sICAM-1, t-PA, VCAM-1) and pathologic capillaroscopy (IL-6, IL-1β). Conclusions This is the first systematic analysis in SSc for biomarkers sensitive to change over time or treatment. It provides evidence based data for candidate biomarkers to be used in clinical trials and potentially in clinical practice. Disclosure of Interest M. Toniolo: None declared, R. Dobrota Grant/research support from: Articulum Fellowship (Pfizer), Actelion, P. Moinzadeh: None declared, R. Ogawa: None declared, D. Furst: None declared, C. Denton: None declared, D. Khanna: None declared, O. Distler Grant/research support from: 4D Science, Actelion, Active Biotec, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer Ingelheim Pharma, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Pharmacyclics, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation, Consultant for: 4D Science, Actelion, Active Biotec, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer Ingelheim Pharma, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Pharmacyclics, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation