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BackgroundIn the SENSCIS trial in subjects with SSc-ILD, nintedanib reduced the rate of decline in forced vital capacity (FVC) over 52 weeks by 44% compared with placebo.ObjectivesTo investigate the effects of nintedanib on circulating biomarkers of extracellular matrix (ECM) turnover, epithelial injury and inflammation in the SENSCIS trial.MethodsSubjects had SSc with first non-Raynaud symptom in the prior ≤7 years, extent of fibrotic ILD on high-resolution computed tomography (HRCT) ≥10% and FVC ≥40% predicted. Patients were randomised to receive nintedanib or placebo stratified by anti-topoisomerase I antibody (ATA). Blood samples were taken at baseline and at weeks 4, 24 and 52. Fold changes in adjusted mean levels of circulating biomarkers were analyzed using a linear mixed model for repeated measures. Data were log10 transformed before analysis and estimates of change from baseline were back-transformed.ResultsA total of 576 subjects received trial drug (288 nintedanib, 288 placebo). A transient increase in fold change from baseline in C-reactive protein (CRP) (a marker of inflammation) was observed in subjects who received nintedanib versus placebo at week 4. After an initial increase at week 4 in the fold change from baseline in CRP degraded by MMP-1/8 (CRPM) (a marker of ECM turnover), a trend to decreasing levels was observed in subjects who received nintedanib compared with placebo at week 52. Decreases in the fold change from baseline in collagen 3 degraded by MMP-9 (C3M) and N-terminal propeptide of type VI collagen (pro-C6) (markers of ECM turnover) were observed in subjects who received nintedanib compared with placebo from week 24 and week 4, respectively. A decrease in fold change from baseline in Krebs von den Lungen-6 (KL-6) (a marker of epithelial injury) was observed in subjects who received nintedanib versus placebo at week 52. A decrease in fold change from baseline in cancer antigen 125 (CA-125) (a marker of epithelial injury) was observed in subjects who received nintedanib versus placebo from week 4 (Figure 1).ConclusionData from the SENSCIS trial suggest that nintedanib reduced circulating levels of markers of ECM turnover and epithelial injury in subjects with SSc-ILD.AcknowledgementsThe SENSCIS trial was funded by Boehringer Ingelheim. Masataka Kuwana, Toby M Maher and Oliver Distler were members of the SENSCIS trial Steering Committe.Disclosure of InterestsShervin Assassi Speakers bureau: On speaker bureau for Integrity Continuing Education, Consultant of: Abbvie, AstraZeneca, Boehringer Ingelheim, CSL Behring, Novartis, Grant/research support from: Boehringer Ingelheim, Janssen, Masataka Kuwana Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Tanabe-Mitsubishi, Ono Pharmaceuticals, Consultant of: AstraZeneca, Boehringer Ingelheim, Corbus, MochidaKissei, Grant/research support from: Boehringer Ingelheim, MBL, Ono Pharmaceuticals, Christopher P Denton Speakers bureau: Boehringer Ingelheim, Janssen, Consultant of: Abbvie, Acceleron, Boehringer Ingelheim, Corbus, CSL Behring, GlaxoSmithKline, Roche, Grant/research support from: ARXX Therapeutics, GlaxoSmithKline, Horizon Therapeutics, Servier, Toby Maher Speakers bureau: Boehringer Ingelheim, Galapagos, Genentech, Consultant of: AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Galapagos, Galecto, GlaxoSmithKline R&D, IQVIA, Pliant, Respivant, Roche, Theravance and Veracyte, Grant/research support from: AstraZeneca, GlaxoSmithKline, Claudia Diefenbach Employee of: Claudia Diefenbach is an employee of Boehringer Ingelheim, Carina Ittrich Employee of: Carina Ittrich is an employee of Boehringer Ingelheim, Martina Gahlemann Employee of: Martina Gahlemann is an employee of Boehringer Ingelheim, Oliver Distler Speakers bureau: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years:Speaker fee: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years:Consultancy fee: 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 TopadurOD has/had relationships with the following companies in the area of potential treatments for arthritides in the last three calendar years:Consultancy fee: Abbvie, Grant/research support from: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years:Research Grants: Boehringer Ingelheim, Kymera, Mitsubishi Tanabe

BackgroundIn the SENSCIS trial conducted in a population of subjects with SSc-ILD with a mean time since first non-Raynaud symptom of 3.5 years and 52% with diffuse cutaneous SSc (dcSSc), nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 44% versus placebo. Risk factors for a rapid decline in FVC in patients with SSc include early SSc, elevated inflammatory markers, significant skin involvement, and dcSSc. Patients with SSc with these risk factors for rapid progression of ILD are typically given immunosuppressants but not nintedanib.ObjectivesTo analyse the rate of decline in FVC and the effect of nintedanib on FVC decline in subjects with risk factors for a rapid decline in FVC in the SENSCIS trial.MethodsIn post-hoc analyses of data from the SENSCIS trial, we analysed the rate of decline in FVC (mL/year) over 52 weeks in all subjects and in those with early SSc (9/L), or significant skin fibrosis using two approaches (modified Rodnan skin score [mRSS] 15-40 or mRSS >18) at baseline. We also analysed the rate of decline in FVC over 52 weeks in subjects with one of these risk factors and dcSSc.ResultsOf 575 subjects analysed, 79 (13.7%) had 18. Of 299 subjects with dcSSc, 29 (9.7%) had 18. In the placebo group, the rate of decline in FVC over 52 weeks was numerically greater in subjects with these risk factors for rapid decline in FVC compared with all subjects (Figure 1). Across the subgroups, the rate of decline in FVC was numerically lower in subjects treated with nintedanib than placebo (Figure 1).Figure 1.Rate of decline in FVC (mL/year) over 52 weeks in (A) all patients and in patients with risk factors for rapid decline in FVC at baseline and (B) all patients and in patients with dcSSc and risk factors for rapid decline in FVC at baseline in the SENSCIS trial.ConclusionThe SENSCIS trial included a broad range of subjects with a fibrotic ILD complicating SSc, including those with risk factors for a rapid decline in FVC. In the placebo group, subjects with these risk factors had a more rapid decline in FVC over 52 weeks compared with the overall trial population. By targeting fibrosis with nintedanib, the rate of decline in FVC in patients with risk factors for FVC decline was reduced in patients treated with nintedanib compared with placebo.AcknowledgementsThe SENSCIS trial was funded by Boehringer Ingelheim. Toby M Maher and Masataka Kuwana were members of the SENSCIS trial Steering Committee.Disclosure of InterestsDinesh Khanna Shareholder of: Stocks - Eicos Sciences, Inc, Consultant of: AbbVie, Acceleron, Actelion, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos NV, Genentech/Roche, Gilead, GlaxoSmithKline, Horizon Therapeutics, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Prometheus, Sanofi-Aventis, Theraly, United Therapeutics, Grant/research support from: Bayer, Bristol-Myers Squibb, Horizon Therapeutics, Immune Tolerance Network, National Institutes of Health, Pfizer, Employee of: Leadership/Equity position – Chief Medical Officer - CiviBioPharma/Eicos Sciences, Inc, Toby Maher Speakers bureau: Boehringer Ingelheim, Galapagos, Genentech, Consultant of: AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Galapagos, Galecto, GlaxoSmithKline R&D, IQVIA, Pliant, Respivant, Roche, Theravance and Veracyte, Grant/research support from: AstraZeneca, GlaxoSmithKline, Elizabeth Volkmann Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, Corbus, Forbius, Horizon, Kadmon, Yannick Allanore Consultant of: AbbVie, AstraZeneca, Bayer, Boehringer, Mylan, Janssen, Medsenic, Prometheus, Sanofi, Roche, Grant/research support from: Alpine Immunosciences, Medsenic, OSE Immunotherapeutics, Vanessa Smith Speakers bureau: Actelion Pharmaceuticals, Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, UCB Biopharma Sprl, Consultant of: Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, Grant/research support from: Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, Research Foundation - Flanders (FWO), Shervin Assassi Speakers bureau: On speaker bureau for Integrity Continuing Education, Consultant of: Abbvie, AstraZeneca, Boehringer Ingelheim, CSL Behring, Novartis, Grant/research support from: Boehringer Ingelheim, Janssen, Michael Kreuter Speakers bureau: Boehringer Ingelheim and Roche, Consultant of: Boehringer Ingelheim and Roche, Grant/research support from: Boehringer Ingelheim and Roche, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme, Roche, Paid instructor for: Boehringer Ingelheim, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Masataka Kuwana Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, Consultant of: AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida, Grant/research support from: Boehringer Ingelheim, MBL, Ono Pharmaceuticals, Christian Stock Employee of: Christian Stock is an employee of Boehringer Ingelheim, Margarida Alves Employee of: Margarida Alves is an employee of Boehringer Ingelheim, Steven Sambevski Employee of: Steven Sambevski is an employee of Boehringer Ingelheim, Christopher P Denton Speakers bureau: Boehringer Ingelheim, Janssen, Consultant of: Abbvie, Acceleron, Boehringer Ingelheim, Corbus, CSL Behring, GlaxoSmithKline, Roche, Grant/research support from: ARXX Therapeutics, GlaxoSmithKline, Horizon Therapeutics, Servier

BackgroundDigital ulcers (DU) are common in systemic sclerosis (SSc) and associated with reduced survival, high morbidity and poor quality of life. Recommendations have previously been proposed for DU management yet there remains significant unmet patient need. Therefore the World Scleroderma Foundation DU Working Group intends to develop practical evidence based recommendations for DU management.ObjectivesTo summarise data on efficacy and safety of systemic treatments for SSc DU.MethodsA systematic literature review to May 2021 was performed. PubMed, MEDLINE, Embase, Web of Science, Cochrane Library, Emcare (OVID) and Academic Search Premier databases were searched for original studies on adult patients with SSc DU treated with systemic pharmacological treatment. Based on the PICO framework, eligibility criteria were defined and references were independently screened by two reviewers. Reviewers independently assessed the full text of eligible articles. Owing to interstudy heterogeneity narrative summaries were used to present data.ResultsThe search strategy identified 1271 references of which 45 eligible articles were included. Seventeen studies were randomised placebo controlled trials (RCT) pertaining to PDE5 antagonists (PDE5i) (n=3), endothelin receptor antagonists (ERA) (n=3), prostanoids (n=7), antiplatelet agents (n=1) and other (n=3) (Table 1). No head to head RCT was retrieved. All other studies were observational studies (OBS). Studies were highly heterogeneous with application of differing definition of DU, variable study eligibility criteria, clinical endpoints and follow up periods. This limited the calculation of effect size and comparison across studies.Table 1.Characteristics of placebo controlled randomised controlled trialsAuthor YearInterventionnFollow upOutcomeFavours interventionHachulla 2016Sildenafil8312 weeksTime to DU healing-Andrigueti 2017Sildenafil4112 weeksDU healing+Shenoy 2010Tadalafil246 weeksNew DU+Khanna 2016Macitentan55416 weeksNew DU-Matucci-Cerinic 2011Bosentan18832 weeksNew DU Time to healing of DU+-Korn 2004Bosentan12212 weeksNew DU+Kawald 2008IV iloprost5012 monthsDU healing-Wigley 1992IV iloprost3510 weeksDU healing+Wigley 1994IV iloprost739 weeks50% reduction in DU score-Seibold 2017Treprostinil14820 weeksNet DU burden-Vayssairat 1999Beraprost10725 weeks% patients with new DU-Denton 2017Selexipag7412 weeksNumber of new DU DU healing-Lau 1993Cicaprost334 weeksNumber of DU-Abou-Raya 2008Atorvastatin844 monthsNumber of DU+Au 2010Cyclophosphamide15812 monthsNumber of patients with DU-Beckett 1984Dipyridamole / aspirin412 yearsChange in general SSc-Nagaraja 2019Riociguat1732 weeksNet DU burden-+ significantly superior to comparator- non significantly different from comparatorDU: digital ulcers IV: intravenous SSc: systemic sclerosisSeveral RCT found improved DU healing with treatment: two with PDE5i, one with iloprost and one showed improved DU healing and prevention with atorvastatin. Two RCT demonstrated effective prevention of new DU with bosentan. OBS studies with a total of 621 patients showed variable improvements in the healing of DU with CCB, PDE5i, ERA, statins, N-acetylcysteine, prostanoids and ketanserin and prevention of new DU with ERA.Regarding safety, all treatments were generally tolerated with few serious adverse events. Treatment was ceased in 6.25-17.5% of patients in RCT due to treatment related side effects.ConclusionDespite several studies assessing the efficacy and safety of systemic pharmacological treatment of SSc DU, it is not possible to draw solid conclusions due to study heterogeneity. Small RCT have shown treatment benefit with PDE5i, iloprost and atorvastatin. Large studies demonstrated effective prevention of new DU with bosentan. Our results highlight the urgent need for improved clinical trial design to generate more robust evidence and novel therapies to guide the management SSc DU.AcknowledgementsThis work was supported by the World Scleroderma Foundation.Disclosure of InterestsNancy Maltez: None declared, Laura Ross: None declared, Michael Hughes Speakers bureau: Actelion Pharmaceuticals, Eli Lilly and Pfizer outside of the submitted work., Jan Schoones: None declared, Murray Baron: None declared, Lorinda Chung Consultant of: Eicos, Corrado Campochiaro: None declared, Yossra A. Suliman: None declared, Dilia Giuggioli: None declared, Pia Moinzadeh Speakers bureau: Actelion Pharmaceuticals, Boehringer Ingelheim, Yannick Allanore: None declared, Christopher P Denton: None declared, Oliver Distler Speakers bureau: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur., Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur., Grant/research support from: Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143), Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur., Tracy Frech: None declared, Daniel Furst: None declared, Dinesh Khanna Consultant of: Eicos Sciences Inc, Janssen, Thomas Krieg: None declared, Masataka Kuwana Speakers bureau: Speaker fees from AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, and consultancy fees from AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida outside of the submitted work., Marco Matucci-Cerinic: None declared, Janet Pope: None declared, Alessia Alunno: None declared

BackgroundRecent studies using single cell RNA sequencing have delineated distinct subpopulations of fibroblasts in skin and other organs. To improve understanding of functional differences between fibroblast subpopulations, we have developed a novel technique to selectively isolate “migratory” fibroblasts, and non-migratory “resident” fibroblasts from heathy control (HC) and SSc skin.ObjectivesTo compare migratory and resident populations of dermal fibroblasts in systemic sclerosis by their differential gene or protein expression, and through functional assays of fibrotic potential.MethodsForearm skin punch biopsies were collected from dcSSc(n=3), and healthy control skin(n=3).Migratory fibroblasts were first isolated by standard explant culture, then the residual biopsy fragments underwent collagenase digestion to yield a population of resident fibroblasts that retained in the biopsy fragments. These populations were further expanded for use at passage 3-6.Functional characterisation included 3-D collagen gel contraction, and migratory scratch-wound assays. Expression of pro-collagen I (Col1), CTGF and αSMA was compared by western blot. Bulk RNAseq on each fibroblast population was performed. Statistical analysis was carried out using Rsoftware “tidyverse”. Criteria for significant differences in gene expression were a fold change of ≥1.5, and adjusted p-value (FDR) of ResultsCompared with HC, all SSc fibroblast populations showed a hallmark fibrotic phenotype with increased gel contraction, faster migration, and overexpression of Col1, CTGF and αSMA compared with HC. However, SSc resident fibroblasts showed attenuated contraction, migration, and reduced levels of αSMA compared to migratory SSc fibroblasts. Bulk RNAseq performed on each fibroblast population confirmed 5579 significantly differentially expressed genes between SSc resident and SSc migratory fibroblasts, whereas no genes were significantly differentially expressed between HC resident and migratory fibroblasts.SSc and HC migratory fibroblasts and resident fibroblasts were then compared, to understand disease-related differences between the two fibroblast populations. 739 genes were significantly overexpressed in the migratory fibroblast population (including ASPM, TRIP3), whereas 745 genes were significantly upregulated in the resident fibroblast population. The genes upregulated in resident fibroblasts included CCL2, CXCL8, and ICAM1.Many genes typically associated with SSc (such as SERPINE1, COMP), were not significantly different between the SSc fibroblast subpopulations, but were significantly elevated in both SSc subpopulations compared to HC fibroblast populations, suggesting that these reflect a more generic SSc phenotype.ConclusionMigratory and resident SSc fibroblast populations exhibit distinct functional and transcriptional differences that are much less apparent for HC biopsies. Further work is required to understand the precise contribution these distinct SSc fibroblast populations in pathogenesis, and how they might be targeted therapeutically. Our findings also highlight that conventional explant culture techniques may ignore important fibroblasts populations and highlight the importance of more detailed analysis such as single cell analysis to better understand pathobiology of SSc.Table 1.Table of the most significantly differentially expressed genes with highest fold change and adjusted p-value (FDR) between the migratory and resident SSc fibroblast populationSignificantly upregulated genes in SSc migratory fibroblastsSignificantly upregulated genes in SSc resident fibroblastsFold changeAdjusted p valueFold changeAdjusted p valueGPR15.990.01CCL238.66PPME14.860.011CXCL824.360.0001KIF20A4.340.015ICAM115.38CENPF4.310.018EGR115.190.0002STC24.180.01EGR212.770.0002ASPM3.880.02IFI44L11.50.002TRIB33.600.011CXCL611.43HAPLN13.360.039PDGF-D10.140.0003CCNB23.290.025OAS38.940.0009KIF143.240.027IFIT18.580.004Disclosure of InterestsKristina Clark: None declared, Alice Cole: None declared, Xu Shiwen: None declared, Voon Ong: None declared, Christopher D Buckley Employee of: founder of Mestag Therapeutics https://mestagtherapeutics.com/, Christopher P Denton: None declared.

BackgroundManagement of digital ulcers (DUs) in systemic sclerosis (SSc) is a major clinical challenge. To date, systemic therapy is generally considered as the ‘standard of care’ for significant SSc-DUs. However, there is a strong rationale to develop local approaches to DUs, to avoid side effects from systemic therapies. World Scleroderma Foundation DU Working Group intends to develop practical, evidence-based recommendations for DU management including local, Surgical Treatment (L-ST).ObjectivesTo summarize the literature on the safety and efficacy of L-ST for SSc-DUs.MethodsA systematic literature review (SLR) was conducted up to May 2021. According to the PICO framework, eligibility criteria were defined and original research articles about surgical treatment of SSc DUs in adult patients were included. References were independently screened by 2 reviewers who assessed the full text of eligible articles and extracted data.ResultsThirteen eligible articles out of 790 total publications were identified (Table 1). Due to the paucity of randomized controlled trials of surgical treatments for SSc-DU, we included retrospective studies and case series with at least 4 patients. Autologous fat (adipose tissue AT) grafting was the surgical modality mostly identified (7 studies of which 1 RCT and 6 prospective open label single arm). The healing rate (HR) with autologous fat grafting (4 studies) ranged from 66-100 %. In the RCT, two age and sex matched groups were included, adipose tissue (AT)group (n=25 pts) and sham procedure (SP) group (n=13), DU healing was reported in 23/25 in AT group versus 1/13 in the SP group in 8 wks, (pTable 1.Characteristics of the extracted studies.StudydesignPatients (n)Baseline DU (n)Background therapy (%)Follow-upOutcomeHealed ulcers(%) Adipose tissue graftAutologous fat graftp9.15PG, CCB—100ETA 26PDE-5i 138-12 wks66Adipose tissue graftingRCT25 case13- Ctr25-case13- CtrPG- 100CCB 1008 wks92-case7-CtrAdipose tissue implantp1515no therapy7 wks100Adipose tissue graftp129PG,CCB-100ETA6 month88adipose derived SVFp1215PDE-5i, ccb, PG allowed22m6Adipose derived SVFp1215CCB 50ETA166 m63 Adipose derived SVFp1819CCB 50PG 27ETA 5IS 7124 wks32SympathectomySympathectomyR611CCB-10020 m81SympathectomyR1335PGCCBAPA35Sympathectomy, vascular bypass (+vein graftR1726Ccb 35APA 47PDE-i5 589 m100Bone marrow derived cells transplantation)p88PG-6236 m87Direct microsurgical revascularizationR44m100Limited microsurgical arteriolysisR61712 m100SVF =stromal vascular fraction P = prospective. R = retrospective. RCT= double blind randomized-controlled trial. ETA = endothelin antagonist. CCB= calcium channel blockers. APA= anti-platelet agents. PG= prostaglandins. ARB= angiotensin receptor antagonist. ACEi= ACE inhibitors. PDE-5i= PDE-5 inhibitors. IS= immunosuppression. M=median. SoC= standard of care. HR= healing rateConclusionOur SLR has identified several surgical modalities for SSc-DUs. L-STseemed generally effective and safe for DU healing, thus Significant methodological issues emerged including small numbers of pts, lack of comparator, failure to report confounders such as background therapies and variable follow up. Future research is warranted to rigorously investigate surgical interventions for Dus.Disclosure of InterestsYossra A. Suliman: None declared, Corrado Campochiaro: None declared, Michael Hughes Speakers bureau: speaking fees from Actelion pharmaceuticals, Eli Lilly, and Pfizer, outside of the submitted work, Jan Schoones: None declared, Dilia Giuggioli: None declared, Nancy Maltez: None declared, Pia Moinzadeh Speakers bureau:: speaking fees from Actelion pharmaceuticals and Boehringer Ingelheim, Laura Ross: None declared, Lorinda Chung: None declared, Yannick Allanore: None declared, Murray Baron: None declared, Christopher P Denton: None declared, Oliver Distler Shareholder of: Consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Speakers bureau: Consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Consultant of: Consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: Consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Tracy Frech: None declared, Daniel Furst: None declared, Dinesh Khanna Speakers bureau: Janssen and Eicos Sciences, Inc., Paid instructor for: Janssen and Eicos Sciences, Inc., Consultant of: Janssen and Eicos Sciences, Inc., Thomas Krieg: None declared, Masataka KUWANA Speakers bureau: Speakers fees from AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, and Consultant fees from AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida, outside of the submitted work., Paid instructor for: Speakers fees from AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, and Consultant fees from AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida, outside of the submitted work., Consultant of: Speakers fees from AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, and Consultant fees from AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida, outside of the submitted work., Marco Matucci-Cerinic: None declared, Janet Pope: None declared, Alessia Alunno: None declared

BackgroundDigital ulcers(DUs) in systemic sclerosis(SSc) represent a major clinical challenge. There are no recommendations for the local management of SSc-DUs. Systemic therapy is considered the standard of care. However, there is a strong rationale for local approaches to DU by avoiding side effects from systemic therapies. The World Scleroderma Foundation DU Working Group intends to develop evidence-based recommendations for DU management including local, non-surgical treatment(ln-sT).ObjectivesTo summarise the literature on the safety and efficacy of ln-sT for SSc-DUs.MethodsA systematic literature review(SLR) of papers describing the use of ln-sT for DU in SSc was performed up to May 2021 according to the PICO framework. References were independently screened by two reviewers who independently assessed the full text of eligible articles and extracted data.ResultsAmong 790 retrieved references, 12 were included. Median(range) number of patients per study was 9(7–84), mean age ranging from 37 to 62.5 years. In 5(41%) studies a control group was included. Background systemic therapies are summarized in Table 1. The most studied treatment was botulin toxin A(BTA). It was used as hand injection in 3 studies (median dose ranging from 90 to 150 U) and as 50 U single finger injection in 1 study. Healing rate after a median time of 8-49 weeks ranged from 71% to 100%. In 2 studies a reduction in VAS pain was observed from 20% to 100%. Transient muscle weakness was the most common side effect in 10% of patients. Amniotic(Am) and hydrocolloid membranes(HyM) were used in 1 study each. They were associated with a good healing rate, statistically significant for the HyM. Tadalafil 2% cream was studied in 1 study and was associated with a reduction in the median DU number from 1.6 to 1 per patient after a median time of 4 weeks and a reduction by 1.4 point in the 10-mm VAS scale. Vitamin E gel was shown to be associated with a statistically significant reduction in the healing time compared to SoC alone in 1 RCT(13.2 ± 2.7 versus 20.9 ± 3.6 weeks, P=Table 1.Characteristics of the studies.TreatmentType of studyPatientsBaseline DUBackground therapy (%) ETA CCB APA PG ARB ACE-I PDE-5i ISFollow-up (weeks)Healing rate(%)*Pain Reduction (VAS/10)ComparatorHydrodissection and corticosteroid injectionP1202334.4Rheumatoid ArthritisTadalafil 2% Vitamin E gelRRCT15131.6(1)3.5±2.30462700130704 241(1)Reduced time to heal**1.4SoCAmHyMRP67310001002800002817033143810090**SoCBTAMedian 90 U per handHigh-concentration hand100 U non-dominant handSingle finger 50 URRPP772010314571140718558551008514201001414718 4981277717510020%100%Untreated CHLow-level light therapyP8102537025378100ESWP9493355661144441**1.31Dimethyl sulfoxideDBRCT84No change, skin toxicity with 70% formulation*Unless otherwise stated. **Statistically significant. ARB= angiotensin receptor antagonist. ACEi= ACE inhibitors. APA= anti-platelet agents. CCB= calcium channel blockers. CH= contralateral hand. DBRCT= double blind randomized-controlled trial. ETA = endothelin antagonist. IS= immunosuppression. PG= prostaglandins. PDE-5i= Phosphodiesterase type-5 inhibitors. P = prospective. R = retrospective. SoC= standard of care (as per local protocol).ConclusionOur SLR supports interest to develop ln-sTs for SSc-DUs. The number of studies is limited and mainly case reports and small single studies are present. Treatments were well tolerated and there was evidence of efficacy for BTA, vitamin E, ESW and HyM in refractory DUs. The evidence is not robust and confounding factors (vasodilators background therapies) could impact on the findings. Future research is indicated to conduct larger, well-designed studies.Disclosure of InterestsCorrado Campochiaro: None declared, Yossra A. Suliman: None declared, Michael Hughes Speakers bureau: Actelion pharmaceuticals, Eli Lilly, and Pfizer, outside of the submitted work., Jan Schoones: None declared, Dilia Giuggioli: None declared, Pia Moinzadeh Speakers bureau: speaking fees from Actelion pharmaceuticals and Boehringer Ingelheim, Nancy Maltez: None declared, Laura Ross: None declared, Murray Baron: None declared, Lorinda Chung: None declared, Yannick Allanore: None declared, Christopher P Denton: None declared, Oliver Distler Speakers bureau: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur, Tracy Frech: None declared, Daniel Furst: None declared, Dinesh Khanna Speakers bureau: Janssen and Eicos Sciences, Inc., Thomas Krieg: None declared, Masataka Kuwana Speakers bureau: Speakers fees from AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, and Consultant fees from AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida, outside of the submitted work., Marco Matucci-Cerinic: None declared, Janet Pope: None declared, Alessia Alunno: None declared

BackgroundFew data are available on the progression and management of ILD, or the management of adverse events associated with drug treatment, in patients with lcSSc. SENSCIS-ON is an open-label extension trial that is collecting data on decline in forced vital capacity (FVC) and adverse events in patients treated with nintedanib over the long term.ObjectivesTo assess decline in FVC and adverse events in patients with lcSSc and ILD treated with nintedanib in SENSCIS-ON.MethodsPatients with SSc-ILD were eligible to enter SENSCIS-ON if they completed the randomized placebo-controlled SENSCIS trial (in which patients received trial drug until the last patient reached week 52 but for ≤100 weeks) or a drug–drug interaction (DDI) study of nintedanib and oral contraceptive (in which female patients received nintedanib for ≤28 days). Among patients with lcSSc, we analysed changes from baseline in FVC and adverse events over 52 weeks of SENSCIS-ON in patients who received nintedanib in SENSCIS and continued it in SENSCIS-ON (“continued nintedanib” group) and in patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON or who received nintedanib for a short time in the DDI study (“initiated nintedanib” group). Analyses were descriptive.ResultsThere were 98 patients with lcSSc in the continued nintedanib group and 127 patients with lcSSc (114 from SENSCIS, 13 from the DDI study) in the initiated nintedanib group. In these groups, respectively, mean (SD) FVC values at inclusion in SENSCIS-ON were 2449 (662) mL and 72.7(16.7) % predicted and 2508 (771) mL and 74.1 (17.4) % predicted. Mean (SE) changes in FVC from baseline to week 52 of SENSCIS-ON were −45.1 (19.1) mL in the continued nintedanib group, −41.5 (24.0) mL in the initiated nintedanib group, and −43.3 (15.3) mL in all patients with lcSSc, similar to the change in FVC in patients with lcSSc at week 52 of the SENSCIS trial (−39.1 [22.2] mL). The adverse event profile of nintedanib in SENSCIS-ON was consistent with that reported over 52 weeks of the SENSCIS trial (Table 1). Over 52 weeks, adverse events led to discontinuation of nintedanib in 3.1% of patients with lcSSc who continued nintedanib in SENSCIS-ON and 16.5% who initiated nintedanib in SENSCIS-ON.Table 1.Adverse events (irrespective of causality) reported over 52 weeks in patients with lcSSc and ILD in SENSCIS and SENSCIS-ON.SENSCISSENSCIS-ONNintedanib(n=135)Placebo(n=142)Continued nintedanib(n=98)Initiated nintedanib(n=127)Most frequent adverse events*Diarrhoea104 (77.0)43 (30.3)70 (71.4)89 (70.1)Nausea45 (33.3)20 (14.1)19 (19.4)32 (25.2)Vomiting33 (24.4)16 (11.3)15 (15.3)31 (24.4)Nasopharyngitis21 (15.6)29 (20.4)18 (18.4)23 (18.1)Upper respiratory tract infection18 (13.3)19 (13.4)13 (13.3)18 (14.2)Skin ulcer11 (8.1)18 (12.7)11 (11.2)14 (11.0)Cough17 (12.6)25 (17.6)13 (13.3)8 (6.3)Adverse event(s) leading to permanent treatment discontinuation25 (18.5)12 (8.5)3 (3.1)21 (16.5)Adverse event(s) leading to dose reduction47 (34.8)5 (3.5)17 (17.3)62 (48.8)Serious adverse event(s)30 (22.2)26 (18.3)22 (22.4)31 (24.4)n (%) of patients with lcSSc with ≥1 such event reported over 52 weeks (or until 28 days after last drug intake if earlier in SENSCIS or until 7 days after last trial drug intake if earlier in SENSCIS-ON). *Adverse events reported in >10% of patients with lcSSc in either group in SENSCIS-ON. Adverse events were coded according to preferred terms in the Medical Dictionary for Regulatory Activities.ConclusionThe change in FVC in patients with lcSSc and ILD who received nintedanib over 52 weeks, and the safety profile of nintedanib, in SENSCIS-ON were similar to that observed in patients with lcSSc and ILD who received nintedanib in SENSCIS. These analyses support a continued effect of nintedanib on slowing decline in FVC and the ability to manage adverse events of nintedanib in patients with lcSSc and ILD over the longer term.AcknowledgementsThe SENSCIS-ON trial was funded by Boehringer Ingelheim.Disclosure of InterestsYannick Allanore Consultant of: Abbvie, AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Medsenic, Mylan, Prometheus, Roche, Sanofi, Grant/research support from: Alpine Immunosciences, Medsenic, OSE immunotherapeutics, Dinesh Khanna Shareholder of: Stocks - Eicos Sciences, Inc., Consultant of: AbbVie, Acceleron, Actelion, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos NV, Genentech/Roche, Gilead, GlaxoSmithKline, Horizon Therapeutics, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Prometheus, Sanofi-Aventis, Theraly, United Therapeutics, Grant/research support from: Bayer, Bristol-Myers Squibb, Horizon Therapeutics, Immune Tolerance Network, National Institutes of Health, Pfizer, Employee of: Leadership/Equity position – Chief Medical Officer - CiviBioPharma/Eicos Sciences, Inc, Vanessa Smith Speakers bureau: Actelion Pharmaceuticals, Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, UCB Biopharma Sprl, Consultant of: Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, Grant/research support from: Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer-Ingelheim Pharma GmbH&Co, Janssen-Cilag NV, Research Foundation - Flanders (FWO), Martin Aringer Speakers bureau: AbbVie, AstraZeneca, Boehringer Ingelheim, BristolMyersSquibb, Chugai, Galapagos, GlaxoSmithKline, Lilly, MSD, Novartis, Otsuka, Pfizer, Roche, Sanofi, UCB, Consultant of: AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Galapagos, GlaxoSmithKline, Lilly, Pfizer, Roche, Sanofi, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme, Roche, Paid instructor for: Boehringer Ingelheim, Consultant of: Actelion, ARXX, Bayer, Boehringer Ingelheim, Lilly, Medscape, Merck Sharp & Dohme, Roche, Grant/research support from: Boehringer Ingelheim, Masataka Kuwana Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, Consultant of: AstraZeneca, Boehringer Ingelheim, Corbus, MochidaKissei, Grant/research support from: Boehringer Ingelheim, MBL, Ono Pharmaceuticals, Peter A Merkel Consultant of: AbbVie, AstraZeneca, Boeringher Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Immagene, InflaRx, Jannsen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, Pfizer, Regeneron, Sparrow, Takeda, Talaris, Grant/research support from: AbbVie, AstraZeneca, Boeringher Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Eicos, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi, Takeda, Alexandra James Employee of: Alexandra James is an employee of Elderbrook solutions GmbH that is contracted by Boehringer Ingelheim, Steven Sambevski Employee of: Steven Sambevski is an employee of Boehringer Ingelheim, Margarida Alves Employee of: Margarida Alves is an employee of Boehringer Ingelheim, Christopher P Denton Speakers bureau: Boehringer Ingelheim, Janssen, Consultant of: Abbvie, Acceleron, Boehringer Ingelheim, Corbus, CSL Behring, GlaxoSmithKline, Roche, Grant/research support from: ARXX Therapeutics, GlaxoSmithKline, Horizon Therapeutics, Servier

BackgroundA highly controversial question is whether or not corticosteroids should be prescribed for patients with early diffuse cutaneous systemic sclerosis (dcSSc). Although the painful and disabling features of early dcSSc (including tight itchy skin, contractures, fatigue) have an inflammatory basis and are likely to respond to corticosteroids, corticosteroids are a risk factor for potentially life-threatening scleroderma renal crisis.ObjectivesOur aim was to examine safety and efficacy of moderate dose prednisolone in patients with early dcSSc. Specific objectives were to evaluate whether moderate dose prednisolone reduced pain and disability, and improved skin score, and whether prednisolone was safe with particular reference to renal functionMethodsPRedSS set out as a Phase II, multicentre, double-blind randomised controlled trial, converted to open-label because of the Covid-19 pandemic. Patients were randomised to receive either moderate dose prednisolone (approximately 0.3 mg/kg) or matching placebo (or no treatment during open-label) for 6 months. The co-primary endpoints were the Health Assessment Questionnaire Disability Index (HAQ-DI) and modified Rodnan skin core (mRSS) at 3 months. Over 20 secondary endpoints included patient reported outcome measures reflecting pain, itch, anxiety and depression, fatigue and helplessness. 72 participants randomised 1:1 were planned and anticipated to yield 60 evaluable, giving over 80% power for each co-primary outcome in ANCOVA analyses [assumptions; HAQ-DI (α = 0.025, δ = -0.6, σ = 0.9, ρ = 0.6), mRSS (α = 0.025, δ = -5.5, σ = 8.2, ρ = 0.6)]. Mixed Models for Repeated Measures (week 6, month 3, month 6) were fitted with covariates trial arm, baseline score, anti-Scl-70 and their interactions with time point. An unstructured covariance matrix was assumed with the primary focus being the trial arm effect at 3 months.ResultsThe study terminated early due to the Covid-19 pandemic and consequently did not meet the recruitment target of 72 patients. Thirty-five patients (Table 1) were randomised (17 to prednisolone and 18 to placebo/control, 25 during the double-blind phase), of whom 34 completed the 3 month assessment. The adjusted mean difference between treatment groups at 3 months in HAQ-DI score was -0.10 (97.5% CI -0.29 to 0.10), p=0.25, and in mRSS -3.90 (97.5% CI -8.83 to 1.03), p=0.070, both favouring prednisolone but not significantly. Patients in the prednisolone group experienced less pain, helplessness and anxiety than control patients at 3 months: mean difference in pain scores -0.49, 95%CI (-0.93 to -0.06), p=0.027, in Hospital Anxiety and Depression (HADS) anxiety scores -2.05, 95%CI (-3.73 to -0.37), p=0.018, and in helplessness scores -1.54, 95%CI (-3.01 to -0.07), p=0.040. There were no renal crises.Table 1.Baseline characteristics of patients by treatment allocationCharacteristicPrednisolone (n=17)Control (n=18)Age (years)52.7 (14.0)55.3 (12.7)Female n (%)10 (59)9 (50)Duration of skin thickening (years)1.6 (0.8)1.7 (0.8)Anti-topoisomerase-1 n (%)5 (29)6 (33)Anti-RNA polymerase III n (%)6 (35)8 (44)HAQ-DI1.6 (0.8)1.7 (0.7)mRSS18.8 (7.9)23.5 (8.6)Values are mean (standard deviation) unless stated otherwiseConclusionPRedSS exemplified the challenges of running a clinical trial of an investigational medicinal product potentially associated with increased infection risk during the Covid-19 pandemic. Because PRedSS was terminated prior to target recruitment, it was underpowered, and any conclusions have to be extremely cautious. Although PRedSS suggested some benefit from moderate dose prednisolone, the small sample indicates the need for a further randomised trial.References[1]Herrick AL et al. Clinical trial protocol: PRednisolone in early diffuse cutaneous Systemic Sclerosis. J Scleroderma Rel Disord 2021; 6: 146-153.AcknowledgementsThis work was funded by Versus ArthritisDisclosure of InterestsDeb Griffiths-Jones: None declared, Yvonne Sylvestre Garcia: None declared, David Ryder: None declared, John Pauling Speakers bureau: Janssen, Consultant of: Janssen, Boehringer Ingelheim, Permeatus Inc, Sojournix Pharma and Astra Zeneca, Frances Hall Consultant of: Sobi, Roche, Grant/research support from: Alexion, Lilly, BMS, Actelion, Sobi, Peter Lanyon Grant/research support from: Vifor pharma, Justin Mason Consultant of: Pfizer, Novartis, Janssen and Roche., Christopher P Denton Speakers bureau: Janssen, Boehringer Ingelheim, Consultant of: GSK, Boehringer Ingelheim, CSL Behring, Corbus, Roche, Gesynta, Grant/research support from: Servier, GSK, Arxx Therapeutics, Horizon, Ariane Herrick Speakers bureau: Janssen, Consultant of: Arena, Boehringer-Ingelheim, Camurus, CSL-Behring, Gesynta, Grant/research support from: Gesynta

Background Scleroderma (SSc) is an autoimmune connective tissue disease involving complex interactions between various cell types leading to organ-based tissue fibrosis. Emergence of the monocytes (Mo)/macrophages (Mφ) lineage(s) as key contributors to inflammation, vascular dysfunction and scarring in scleroderma 1,2 have led to increased scrutiny of their phenotype and function. Objectives To determine the circulating Mo subpopulations and phenotypes of Mφ in SSc. Methods PBMC were collected from healthy (HC) and SSc donors, and analysed by flow cytometry using Mo phenotypic antibodies or purified and cultured in vitro . For flow cytometry immunophenotyping, Mo were gated on CD3 - CD19 - CD56 - HLA-DR + populations, and subsets defined by CD14, CD16, CD163 and CD206 expression. For Mφ cultures, Mo were negatively selected from PBMCs, cultured for 7 days, and treated with IFN-γ(5 ng/ml) or IL-4(20 ng/ml) for 24 hours. Cytokine levels in the conditioned media were evaluated by MSD analyses and normalised to total protein levels. Results The frequency of circulating CD163 + non-classical Mo (CD14 lo CD16 hi ) was 2-fold higher in SSc patients than in HC (unpaired t-test, p=0.026). No difference was found in the frequency of CD206 + monocyte subsets between HC and SSc. In vitro , unstimulated SSc Mφ (M0) secreted higher levels of classically-activated pro-inflammatory (M1) and alternatively-activated pro-regenerative (M2) cytokines. Compared to HC cells, SSc Mφ were more readily polarised towards an M1 phenotype or an M2 phenotype, when cultured in the presence of IFN-γ or IL-4, respectively. Th17 markers and MMPs were significantly increased in SSc Mφ (table 2). Conclusions Studies exploring Mo have revealed distinct populations with selective biological functions. Our observation of an increased number of CD163 + non-classical Mo in SSc suggests that this subpopulation may play a key role in inflammatory-driven fibrosis and act as an important source of pro-fibrotic cytokines. This data is consistent with previous reports of elevated serum levels of CD163 and increased CD163 secretion by SSc PBMCs 3 . SSc Mφ showed a pronounced and enhanced dual M1 and M2 polarisation basally compared to HC, indicating cells were ‘primed’ to undergo phenotypic polarisation. Our studies support the notion that Mφ cytokine secretion generates a pro-fibrotic milieu in scleroderma tissues, playing a prominent role in dysregulated tissue repair in fibrosis. References [1] Chia JJ, Lu TT. Curr Opin Rheumatol2015Nov;27(6):530–536. [2] Christmann RB, Lafyatis R. Arthritis Res Ther. 2010;12(5):146. [3] Hassan WASE, et al. Eur J Rheumatol2016Sep;3(3):95–100. Disclosure of Interest None declared

To assess the prevalence of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) patients with interstitial lung disease (ILD) and the effect of CPFE on the pulmonary function tests used to evaluate the severity of SSc-related ILD and the likelihood of pulmonary hypertension (PH).High-resolution computed tomography (HRCT) scans were obtained in 333 patients with SSc-related ILD and were evaluated for the presence of emphysema and the extent of ILD. The effects of emphysema on the associations between pulmonary function variables and the extent of SSc-related ILD as visualized on HRCT and echocardiographic evidence of PH were quantified.Emphysema was present in 41 (12.3%) of the 333 patients with SSc-related ILD, in 26 (19.7%) of 132 smokers, and in 15 (7.5%) of 201 lifelong nonsmokers. When the extent of fibrosis was taken into account, emphysema was associated with significant additional differences from the expected values for diffusing capacity for carbon monoxide (DLco) (average reduction of 24.1%; P0.0005), and the forced vital capacity (FVC)/DLco ratio (average increase of 34.8%; P0.0005) but not FVC. These effects were identical in smokers and nonsmokers. Multivariate analysis showed that the presence of emphysema had a greater effect than echocardiographically determined PH on the FVC/DLco ratio, regardless of whether it was analyzed as a continuous variable or using a threshold value of 1.6 or 2.0.Among patients with SSc-related ILD, emphysema is sporadically present in nonsmokers and is associated with a low pack-year history in smokers. The confounding effect of CPFE on measures of gas exchange has major implications for the construction of screening algorithms for PH in patients with SSc-related ILD.

Systemic sclerosis (scleroderma, SSc) is characterized as a severe and very heterogeneous disease with a bright variation of skin and organ manifestations in individual patients. The pathogenesis is still not fully elucidated; however, it is known that this disease starts with an initial vascular damage, which then leads to an inflammatory process and finally promotes the development of an accumulation of collagen and other extracellular matrix (ECM) components. As a result of the heterogeneous characteristics of this multisystem, autoimmune disease, it is always a challenge to identify high-risk patients and to monitor the fibrotic activity also in response to therapies. This can be achieved by several physical methods including the mRSS, the durometer and ultrasound determination of skin thickness. However, this also requires the use of laboratory biomarkers, which are easily detectable and that reflect the inflammatory and/or fibrotic activity. As skin correlates well with the extent of fibrosis also in other organs, we focused in this review on biomarkers which reflect skin involvement of scleroderma patients. These include growth factors, cytokines and proteases as well as their inhibitors. Moreover, several ECM proteins, especially the collagens have been determined in skin biopsies and in blood/serum samples. Determination of proteins has been supported by mRNA levels using PCR techniques and expression analysis of gene expression patterns. This review summarizes all non-invasive physical and laboratory examinations, which permit a better understanding of the fibrotic activity of the disease, can be effectively used to assess potential therapeutic response and help to find better treatment options.

The physical disabilities associated with scleroderma are well known but the psychological impact of the condition has received less attention. Few studies have examined appearance related issues, most notably of the face. The aim of this study is to evaluate the psychological impact of facial, aesthetic and functional changes in scleroderma. One hundred seventy-one patients with a clinical diagnosis of scleroderma were recruited into the study. Digital photographs were objectively graded into groups based on severity of disfigurement as judged by an observer. Facial movement was recorded using a modified House-Brackmann Grading Scale. Psychological evaluation comprised the Derriford Appearance Scale short-form (DAS), the Noticeability and Worry score and the Hospital Anxiety and Depression Scale (HADS). Severity of disfigurement predicted decreased mouth opening, the extent to which participants judged their appearance as noticeable to others, and the level of appearance-related concern as measured by the DAS24. There was an inverse relationship with age. Facial changes were ranked as the most worrying aspect of the condition. This study shows facial disfigurement impacts on patient with scleroderma independent of functional changes related to systemic disease. The major difficulty is with the perceived noticeably of the condition to other people and the resulting self-consciousness in social encounters.

Oesophageal scintigraphy is an effective, non-invasive screening test to detect oesophageal dysmotility and reflux. Our objective was to assess the long term effect of lansoprazole therapy on gastroesophageal dysmotility in systemic sclerosis (SSc).24 SSc patients were randomised to receive either lansoprazole 30 mg or placebo for 12 months. Gastroesophageal motility was assessed by scintigraphy at baseline, after 6 months and after 12 months. Symptoms were evaluated by self-reported gastrointestinal questionnaire.Of 21 patients starting treatment, 17 (81%) completed the first 6 months and 13 (62%) completed the study. 3 patients from each group were withdrawn due to adverse events. As expected, lansoprazole appeared to decrease frequency of gastroesophageal symptoms in the first 6 months of treatment, but long term benefit was not evident. Scintigraphy showed worsening oesophageal dysmotility in SSc patients irrespective of lansoprazole treatment. In addition, early signs of dysmotility were found in asymptomatic patients. We found no correlation of scintigraphy findings with symptoms of gastroesophageal dysmotility.Although lansoprazole 30 mg daily appears to suppress SSc-related gastroesophageal symptoms in the short term, benefit was not sustained at 12 months, and there was no evidence that progression of gastroesophageal motility was prevented. Scintigraphy findings did not correlate with symptoms of dysphagia.

The aim of the study was to evaluate the validity of collagen type I metabolites as markers of disease activity in scleroderma (SSc), through a systematic review of the literature and by validating the results by measuring collagen type I metabolites in well characterized patients with scleroderma spectrum disorders and in Raynaud's phenomenon.A systematic review was performed of studies of collagen type I metabolites in scleroderma spectrum disorders published from 1980 to 2003. The collected results from the literature were compared with our own measurements of collagen type I metabolites (PINP and ICTP) in a small number of well characterized patients within the scleroderma spectrum and in patients with primary and "autoimmune" Raynaud's phenomenon. Peptide concentrations from all sources, including the present study, were compared. Reported correlations between peptide concentrations and clinical variables were also analysed.Of 19 papers identified by an extensive Medline search, 12 were eligible for systematic analysis. There was a considerable heterogeneity in the results with a wide range of metabolite concentrations. Values from disease groups and healthy controls overlapped. These findings were confirmed by our study where, similarly, there was a large range of values in all groups, but particularly in the diffuse SSc subset. When the correlation between peptide levels and clinical variables was assessed, large discordance between the studies was observed.We have not found sufficient evidence to support the use of serum markers of collagen turnover in the assessment of scleroderma activity and severity, in view of their low specificity and the heterogeneity of the results of various studies. Lack of standardized routine evaluation of SSc patients in clinical studies might have accounted for the variability of the findings. However, due to the small sizes of most published studies, demonstration of no effect should come from large-scale randomised trials. Longitudinal serial analysis of these molecules in individual patients may play a future role in the evaluation of the response to fibroblast-targeting therapeutic strategies in scleroderma patients.

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine with a role in the pathogenesis of a number of conditions including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. Etanercept (Enbrel; Immunex Corp., Seattle, WA, USA) is a recombinant soluble fusion protein of TNF-alpha type II receptor and IgG which acts by blocking the action of TNF-alpha. It is licensed for use in rheumatoid arthritis and juvenile chronic arthritis. A number of studies report the development of antinuclear and anti-double-stranded DNA antibodies in patients treated with TNF antagonists for rheumatoid arthritis. There are few reports of the development of clinical features of discoid, subacute or systemic lupus erythematosus. We present one of the first reported cases of etenercept-induced systemic lupus erythematosus and review the literature of lupus and TNF antagonists.

Reporter transgenes were introduced into the type 1 tight-skin (Tsk1/+) mouse model of scleroderma to test the hypothesis that fibroblast-specific genetic programs are activated in fibrosis.Transgenes harboring upstream fragments of the 5' flanking region of the mouse proalpha2(I) collagen gene (Col1a2), linked to a 400-bp minimal Col1a2 promoter driving an Escherichia coli beta-galactosidase (LacZ) reporter gene, were introduced into Tsk1/+ mice by breeding. Expression of these transgenes, which function as lineage-specific markers of fibroblast differentiation, was compared between the Tsk-LacZ mice and non-Tsk littermates. Responsiveness of these constructs to the profibrotic cytokine, transforming growth factor beta1 (TGFbeta1), was investigated by transient transfection of reporter constructs in tissue-culture cells.There was significant activation of reporter genes harboring the upstream enhancer in Tsk1/+ mice starting from 1 week of age. This was maximal at 6 weeks old (mean +/- SD 237 +/- 24% of non-Tsk controls; P= 0.001). Recombinant TGFbeta1 significantly activated reporter genes regulated by the upstream enhancer in transient transfection, and Tsk-LacZ fibroblasts showed elevated LacZ expression in tissue culture.These data suggest that activating signals in Tsk1/+ mice may act via fibroblast-specific regulatory elements within the murine Col1a2 gene. Although TGFbeta has been implicated in the pathogenesis of fibrosis, and reporter genes regulated by the upstream enhancer appear to be TGFbeta responsive in vitro, our results suggest that fibroblast-specific pathways may also be involved.

To compare the efficacy and tolerability of losartan, an antagonist of angiotensin II receptor type 1, with nifedipine for the treatment of primary and secondary Raynaud's phenomenon (RP) in a pilot study.In a randomized, parallel-group, controlled trial, patients with primary RP (n = 25) or RP secondary to systemic sclerosis (SSc [scleroderma]; n = 27) were allocated to receive 12 weeks' treatment with either losartan (50 mg/day) or nifedipine (40 mg/day). Primary outcome variables were the severity and frequency of RP episodes and findings on vascular measurements, including thermography and laser Doppler flowmetry. Serum levels of soluble adhesion molecules, endothelin 1, fibrinogen, von Willebrand factor, and procollagen type I N-terminal propeptide (PINP) were also measured.There was a reduction in the severity of RP episodes following treatment with losartan and with nifedipine, but this effect was greater in the losartan arm of the study (P0.05): episode frequency was reduced only in the losartan group (P0.01 versus baseline). Symptomatic improvement was associated with a significant reduction in soluble vascular cell adhesion molecule 1 and PINP (P0.01). Subgroup analysis suggested that although these biochemical changes occurred mainly in SSc patients, the clinical benefit was greater in the primary RP group.This study confirms the tolerability of short-term treatment of RP with losartan, and our data suggest its clinical benefit. Further evaluation of this drug as a long-term treatment for SSc-associated RP should be considered, since it may have additional disease-modifying potential.

We established a co-culture system to investigate endothelial cell-fibroblast interaction in scleroderma (systemic sclerosis, SSc). Such a system allows reciprocal interaction between these cells. The pattern of phenotypic modulation for normal and SSc fibroblasts in co-culture was compared.A virally transformed human umbilical vein endothelial cell (HUVEC) derived cell line (1E-7) was cultured on nitrocellulose membrane inserts above dermal fibroblast monolayers. The effect of co-culture on fibroblast number, [3H]-thymidine ([3H]-TdR) incorporation, and collagen (type I) production were compared for 10 SSc and 5 control cell lines. Co-culture with the epithelial lines A549 and A431, and nontransformed HUVEC, was also investigated.We observed a statistically significant increase in cell number and a reduction in collagen production for SSc, but not control, fibroblasts co-cultured with endothelial cells. This co-culture also promoted [3H]-TdR incorporation in both SSc and control fibroblasts. While epithelial cell lines did not influence fibroblast cell number, collagen production by SSc fibroblasts was diminished by A549.Endothelial cell derived soluble factors modulated fibroblast properties in co-culture, and the different response of SSc compared with normal fibroblasts provides further evidence for a link between endothelial and fibroblast dysfunction in this disease. However, similar effects on SSc fibroblast collagen production were also observed for some epithelial cells, suggesting that modulation of fibroblast properties is not restricted to cells of endothelial origin.

Anaphylactic reactions to platinum compounds are well recognised, but uncommon. These vary from true type I reactions to direct histamine release due to nonimmunological mechanisms. We present 6 cases to illustrate this--5 due to cisplatin and a report of this occurring with carboplatin--with a near fatal outcome in 3 of the cases.

Human sera from patients with IgM paraproteinaemia were screened for IgM binding to frozen sections of the rat cerebellum by the indirect immunoperoxidase procedure. Out of 18 patients with a benign IgM gammopathy and associated demyelinating polyneuropathy (PPN), 17 showed binding to the surface of specific neurons, i.e. those of the deep cerebellar nuclei and the intermediate cell of Lugaro. Examination of other regions of the mouse brain suggests that the reactivity is restricted to cells of certain nuclei of the sensory-motor system. The use of F(ab)2 and monoclonal anti-idiotype antibodies demonstrate that the binding involves the antigen binding sites of the paraprotein. This reactivity indicates that some neurons have on their surface an antigen having an hapten in common with human myelin-associated glycoprotein (MAG) and the pi granules of human Schwann cells and furthermore is an additional serological characteristic of this group of patients. In addition 3 sera from the PPN group stained a particulate component in the cytoplasm of all medium-sized and large neurons. A similar staining was found with 7 out of 52 other unselected IgM paraproteinaemias.

A 39-year-old woman with a 2-year history of Raynaud’s phenomenon, a previous diagnosis of systemic sclerosis sine scleroderma, and the recent onset of symmetric polyarthritis is reported. Clinical, laboratory, and imaging (radiographs, ultrasonography, and magnetic resonance) features are presented. Treatment and disease course are underlined. Systemic sclerosis articular involvement and its pathologic, clinical, laboratory, imaging, and therapeutic aspects are discussed. The peculiarities of the case are addressed.

Digital ulcers (DUs) are frequent manifestations of systemic scleroderma (SSc). This study assessed functional limitations due to DUs among patients enrolled in the Digital Ulcer Outcome (DUO) Registry, an international, multicentre, observational registry of SSc patients with DU disease.Patients completed at enrolment a DU-specific functional assessment questionnaire with a 1-month recall period, measuring impairment in work and daily activities, and hours of help needed from others. Physician-reported clinical parameters were used to describe the population. For patients who completed at least part of the questionnaire, descriptive analyses were performed for overall results, and stratified by number of DUs at enrolment.This study included 2327 patients who completed at least part of the questionnaire. For patients with 0, 1-2, and ≥3 DUs at enrolment, mean overall work impairment during the prior month among employed/self-employed patients was 28%, 42%, and 48%, respectively. Across all included patients, ability to perform daily activities was impaired on average by 35%, 54%, and 63%, respectively. Patients required a mean of 2.0, 8.7, and 8.8 hours of paid help and 17.0, 35.9, and 63.7 hours of unpaid help, respectively, due to DUs in the prior month. Patients with DUs had more complications and medication use than patients with no DUs.With increasing number of DUs, SSc patients reported more impairment in work and daily activities and required more support from others.