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Objectives: While important progress was made regarding the treatment of systemic sclerosis (SSc), there is still no evidence-based disease-modifying treatment available for SSc-related gastrointestinal (GI) manifestations. We aimed to identify an association between immunosuppressive therapy and the the severity of GI symptoms, measured by the University of California at Los Angeles/Scleroderma Clinical Trial Consortium Gastro-Intestinal Tract instrument 2.0 (GIT)., Methods: We selected patients with SSc who had at least two visits (further referred to as 'baseline' and 'follow-up') with completed GITs, within an interval of 12±3 months. The study outcome was the GIT score at follow-up. We used multivariable linear regression with the following covariates: immunosuppressive therapy during observation, immunosuppressive therapy before baseline, baseline GIT and several baseline parameters selected by clinical judgement as potentially influencing GI symptoms., Results: We included 209 SSc patients (82.3% female, median age 59.0 years, median disease duration 6.0 years, 40 (19.1%) diffuse cutaneous SSc, median baseline GIT 0.19). Of these, 71 were exposed to immunosuppressive therapy during the observation period, and, compared with unexposed patients, had overall more severe SSc and a higher prevalence of treatment with proton pump inhibitors. In multivariable linear regression, immunosuppressive therapy during the period of observation and lower baseline GIT scores were significantly associated with lower (better) GIT scores at follow-up., Conclusion: Immunosuppressive treatment was associated with lower GIT scores in our cohort, which suggests the potential effects of immunosuppressants on GI manifestations in patients with SSc, requiring confirmation in prospective randomised clinical trials., Competing Interests: Competing interests: MB has received consultancy fees from GSK, Amgen, Novartis and Vifor. CB has received consultancy fees from Boehringer Ingelheim, grants/research support from Gruppo Italiano Lotta alla Sclerodermia (GILS), European Scleroderma Trials and Research Group (EUSTAR), Foundation for research in Rheumatology (FOREUM), Scleroderma Clinical Trials Consortium (SCTC), Scleroderma Research Foundation (SRF), EMDO foundation. Educational grants from AbbVie and Wellcome Trust, and congress support from Boehringer Ingelheim. RD has received speaker and/or consultancy fees from Actelion, Boehringer-Ingelheim; grant/research support from: Pfizer, Actelion, Iten-Kohaut; and congress participation support from Amgen and Otsuka. She also received the Walter and Sigrid Siegenthaler Fellowship. ME has received congress support from Janssen and Astra-Zeneca and research support from Novartis outside of the submitted work. She also received the Walter and Sigrid Siegenthaler Fellowship. SI has received a EULAR scientific long-term training grant for young fellows. OD has/had 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: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Argenx, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Cantargia AB, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Nkarta Inc., Novartis, Orion, Prometheus, Redxpharma, Roivant, EMD Serono, Topadur and UCB. Patent issued 'mir-29 for the treatment of systemic sclerosis' (US8247389, EP2331143). Cofounder of CITUS AG. CM received speaker and/or consultancy fees from Janssen-Cilag AG, Boehringer Ingelheim, MED Talks Switzerland, Medbase, Mepha, Novartis and PlayToKnow AG and travel support for congress from Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Clinical observation suggests that vascular activation and autoimmunity precede remodelling of the extracellular matrix (ECM) in systemic sclerosis (SSc). We challenge this paradigm by hypothesising that ECM biomarkers are already disturbed in patients with very early SSc (veSSc) when fibrosis is not yet clinically detectable., Methods: 42 patients with veSSc, defined as the presence of Raynaud's phenomenon and at least one of puffy fingers, positive antinuclear antibodies or pathological nailfold capillaroscopy, not meeting the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for SSc, were compared with healthy controls (HCs, n=29). ECM degradation (BGM, C3M, C4M and C6M) and ECM formation biomarkers (PRO-C3, PRO-C4 and PRO-C5) were measured in serum using ELISAs. A cross-sectional analysis at baseline and a longitudinal analysis was performed., Results: Compared with HC, veSSc patients showed a strongly dysregulated turnover of type III and IV collagens (higher C3M, C4M, both p<0.0001 and PRO-C3, p=0.004, lower turnover ratios PRO-C3/C3M and PRO-C4/C4M, both p<0.0001). The biglycan degradation biomarker BGM was higher in veSSc than in HC (p=0.006), whereas the degradation biomarker for type VI collagen, C6M, was lower (p=0.002). In an ROC analysis, biomarkers of type III and IV collagen excellently distinguished between veSSc and HC: C3M, AUC=0.95, p<0.0001; C4M, AUC=0.97, p<0.0001; turnover ratios PRO-C3/C3M, AUC=0.80, p<0.0001; PRO-C4/C4M, AUC=0.97; p<0.0001., Conclusion: These findings indicate ECM remodelling as a very early phenomenon of SSc occurring in parallel with microvascular and autoimmune changes. Biomarkers of type III and IV collagens distinguished between veSSc patients and HC, indicating them as potential biomarkers for the detection of veSSc., Competing Interests: Competing interests: RD: Research support: Actelion, Pfizer (Articulum fellowship), eular training bursary, Iten-Kohaut foundation; consultancy: Boehringer-Ingelheim; speakers’ buro: Actelion; congress support: Amgen, Otsuka. SJ: None. PJ: was employed at Nordic Bioscience. BM: Research support: AbbVie, Protagen, Novartis Biomedical; lectures: Boehringer-Ingelheim, GSK, Novartis, Otsuka; consultancy: Novartis, Boehringer Ingelheim, Janssen-Cilag, GSK; congress support: Medtalk, Pfizer, Roche, Actelion, Mepha, MSD; patent mir-29 for the treatment of systemic sclerosis issued (US8247389). MB: GSK, Vifor. Bayer, Amgen, MSD outside of this work. CM: speakers bureau for Boehringer-Ingelheim, medbase Switzerland, MED Talks Switzerland, Mepha and PlayToKnow AG, advisory board for Boehringer-Ingelheim, consulting fees and/or honoraria from Boehringer Ingelheim and Janssen, and congress support from Boehringer Ingelheim and Roche. A-CB-J and MAK are full-time employees, part of senior management and shareholders at Nordic Bioscience. ASS was employed as a scientist at Nordic Bioscience at the time of conduction of the study, however is not longer working within the field. OD has/had 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: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Prometheus, Redxpharma, Roivant and Topadur. Patent issued 'mir-29 for the treatment of systemic sclerosis' (US8247389, EP2331143). OD is a member of the editorial board of RMD open., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Interstitial lung disease (ILD) is the leading cause of death in systemic sclerosis (SSc). According to expert statements, not all SSc-ILD patients require pharmacological therapy., Objectives: To describe disease characteristics and disease course in untreated SSc-ILD patients in two well characterised SSc-ILD cohorts., Methods: Patients were classified as treated if they had received a potential ILD-modifying drug. ILD progression in untreated patients was defined as (1) decline in forced vital capacity (FVC) from baseline of ≥10% or (2) decline in FVC of 5%-9% associated with a decline in diffusing capacity for carbon monoxide (DLCO)≥15% over 12±3 months or (3) start of any ILD-modifying treatment or (4) increase in the ILD extent during follow-up. Multivariable logistic regression was performed to identify factors associated with non-prescription of ILD-modifying treatment at baseline. Prognostic factors for progression in untreated patients were tested by multivariate Cox regression., Results: Of 386 SSc-ILD included patients, 287 (74%) were untreated at baseline. Anticentromere antibodies (OR: 6.75 (2.16-21.14), p=0.001), limited extent of ILD (OR: 2.39 (1.19-4.82), p=0.015), longer disease duration (OR: 1.04 (1.00-1.08), p=0.038) and a higher DLCO (OR: 1.02 (1.01-1.04), p=0.005) were independently associated with no ILD-modifying treatment at baseline. Among 234 untreated patients, the 3 year cumulative incidence of progression was 39.9% (32.9-46.2). Diffuse cutaneous SSc and extensive lung fibrosis independently predicted ILD progression in untreated patients., Conclusion: As about 40% of untreated patients show ILD progression after 3 years and effective and safe therapies for SSc-ILD are available, our results support a change in clinical practice in selecting patients for treatment., Competing Interests: Competing interests: MS, MB, AG, IB, SJ, OM: none. MB: as consultancy relationship with and/or received research funding from and/or served as speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: GSK, Amgen, Novartis and outside of this research area: Vifor. HJB: grant/research support from: Janssen. CB: speakers bureau: Eli-Lilly, consultant of: Boehringer Ingelheim, grant/research support from: Gruppo Italiano Lotta alla Sclerodermia (GILS), European Scleroderma Trials and Research Group (EUSTAR), Foundation for research in Rheumatology (FOREUM), Scleroderma Clinical Trials Consortium (SCTC), Scleroderma Research Foundation (SRF). Educational grants from AbbVie and Wellcome Trust. Congress Support from: Boehringer Ingelheim. RD: speakers bureau/consultancy: Actelion, Boehringer-Ingelheim; grant/research support from: Pfizer, Actelion, Iten-Kohaut; congress participation support: Amgen, Otsuka. HF: speakers bureau: Boehringer Ingelheim, consultant of: Bayer, grant/research support from: GSK and Actelion, CM had consultancy relationship with 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: Boehringer Ingelheim, Janssen, Roche. AMHV has received research funding and/or consulting fees and/or other remuneration from ARXX, Boehringer Ingelheim, Genentech, Janssen, Lilly, Medscape, Merck Sharp & Dohme, Roche. 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; consultancy fee: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant Siences, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Redxpharna, Roivant, Sanofi and Topadur; research grants: Kymera, Mitsubishi Tanabe. OD has/had relationships with the following companies in the area of dermatomyositis in the last three calendar years: consultancy fee: Pfizer (2021). ME: congress travel support from Janssen and Astrazeneca., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)