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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

BackgroundNintedanib slows the progression of fibrosing ILDs, with a safety profile characterised predominantly by gastrointestinal events.ObjectivesAssess the safety and tolerability of nintedanib in patients with autoimmune disease-related ILDs by sex and age.MethodsThe SENSCIS trial was conducted in patients with ILD associated with systemic sclerosis. The INBUILD trial was conducted in patients with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis. Patients were randomised to receive nintedanib 150 mg bid or placebo. Dose reductions to 100 mg bid and treatment interruptions were permitted to manage adverse events (AEs). Data from all patients in SENSCIS and patients with autoimmune disease-related ILDs in INBUILD were pooled. In subgroups based on sex and age (ResultsAmong 746 patients; 70.1% were female; 29.1% were aged ≥65 years. Mean (SD) exposure to nintedanib or placebo was 10.8 (3.2) and 11.1 (2.9) months in females and males, and 11.0 (3.0) and 10.6 (3.5) months in patients aged ConclusionIn patients with autoimmune-disease related ILDs, the AE profile of nintedanib in subgroups by sex and age was generally consistent with the known safety profile, but certain types of AE and dose reductions were more frequent in female patients, while serious AEs were more common in male patients.Table 1.Adverse events in patients with autoimmune disease-related ILDs in the SENSCIS and INBUILD trials in subgroups by sex and age at baseline.FemaleMaleAge Age ≥65 yearsNintedanib(n=268)Placebo(n=255)Nintedanib(n=102)Placebo(n=121)Nintedanib(n=267)Placebo(n=262)Nintedanib(n=103)Placebo(n=114)Most frequent adverse events*Diarrhoea198 (73.9)77 (30.2)73 (71.6)38 (31.4)197 (73.8)85 (32.4)74 (71.8)30 (26.3)Nausea92 (34.3)35 (13.7)21 (20.6)14 (11.6)86 (32.2)38 (14.5)27 (26.2)11 (9.6)Vomiting73 (27.2)22 (8.6)12 (11.8)14 (11.6)61 (22.8)27 (10.3)24 (23.3)9 (7.9)Skin ulcer42 (15.7)37 (14.5)12 (11.8)13 (10.7)42 (15.7)45 (17.2)12 (11.7)5 (4.4)Nasopharyngitis34 (12.7)41 (16.1)12 (11.8)21 (17.4)33 (12.4)43 (16.4)13 (12.6)19 (16.7)Weight decreased34 (12.7)8 (3.1)10 (9.8)6 (5.0)29 (10.9)9 (3.4)15 (14.6)5 (4.4)Decreased appetite29 (10.8)9 (3.5)13 (12.7)4 (3.3)25 (9.4)10 (3.8)17 (16.5)3 (2.6)Abdominal pain32 (11.9)18 (7.1)8 (7.8)5 (4.1)27 (10.1)19 (7.3)13 (12.6)4 (3.5)Upper respiratory tract infection30 (11.2)31 (12.2)9 (8.8)8 (6.6)31 (11.6)33 (12.6)8 (7.8)6 (5.3)Cough23 (8.6)39 (15.3)13 (12.7)19 (15.7)27 (10.1)46 (17.6)9 (8.7)12 (10.5)Liver-related investigations, signs and symptoms49 (18.3)11 (4.3)13 (12.7)6 (5.0)42 (15.7)12 (4.6)20 (19.4)5 (4.4)Adverse event(s) leading to dose reduction101 (37.7)9 (3.5)18 (17.6)3 (2.5)81 (30.3)9 (3.4)38 (36.9)3 (2.6)Adverse event(s) leading to treatment discontinuation44 (16.4)21 (8.2)17 (16.7)13 (10.7)39 (14.6)18 (6.9)22 (21.4)16 (14.0)Serious adverse event(s)57 (21.3)53 (20.8)40 (39.2)37 (30.6)63 (23.6)54 (20.6)34 (33.0)36 (31.6)n (%) of patients with ≥1 such adverse event over 52 weeks. Adverse events were coded based on preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA), except for liver-related investigations, signs and symptoms, which was based on a standardised MedDRA query. *Adverse events reported in >10% of patients with autoimmune disease-related ILDs in the nintedanib or placebo group.AcknowledgementsThe SENSCIS and INBUILD trials were funded by Boehringer Ingelheim. Oliver Distler was a member of the SENSCIS trial Steering Committee.Disclosure of InterestsAnna-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, 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, Astra-Zeneca, Bayer, Boehringer, Mylan, Janssen, Medsenic, Prometheus, Roche, Sanofi, Grant/research support from: Alpine Immunosciences, Medsenic, OSE immunotherapeutics, 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, Jeska de Vries-Bouwstra Speakers bureau: Boehringer Ingelheim, Janssen, Consultant of: Abbvie, Boehringer Ingelheim, Grant/research support from: Galapagos NV, Janssen and Roche B.V., 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), Inga Tschoepe Employee of: Inga Tschoepe is an employee of Elderbrook Solutions that is contracted by Boehringer Ingelheim., Lazaro Loaiza Employee of: Lazaro Loaiza is an employee of Boehringer Ingelheim, Madhu Kanakapura Employee of: Madhu Kanakapura 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

OBJECTIVE To investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD). METHODS Patients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL-6 levels and the course of the FVC and DLco over 1 year according to treatment arm. RESULTS Baseline KL-6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL-6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL-6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only). CONCLUSION In a rigorously conducted clinical trial for SSc-related ILD, KL-6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL-6 and CCL18 levels were more likely to experience disease progression despite treatment. KL-6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.

BackgroundIn one of our previous studies, we demonstrated that long non-coding RNA (lncRNA) H19X plays a crucial role in the development of TGFβ driven fibrosis in systemic sclerosis (SSc) and other fibrotic diseases1.ObjectivesTo define the functional relevance of H19X in endothelial cell (EC) activation as a decisive process in SSc vasculopathy.MethodsCorrelation of H19X expression and microvascular gene signature was computed on bulk RNA-Seq data derived from SSc skin biopsies of patients enrolled in the multicentre Prospective Registry of Early Systemic Sclerosis cohort (PRESS, n=48 SSc vs. n=33 healthy controls, HCs). Single cell RNA sequencing (scRNA-seq) data were collected from 27 diffuse cutaneous SSc (dcSSc) and 10 HC skin biopsies. Single cells were barcoded and encapsulated in droplets using a 10X Genomics system. After cDNA synthesis, the libraries were prepared and sequenced using Illumina NovaSeq-500 platform. Seurat package in R (v.3.0) was used to perform data analysis. EC were identified by enrichment of EC markers CLDN5, VWF and PECAM1. One thousand five hundred eighty-three and 3398 EC were identified from HC and SSc patients, respectively. Cells were analysed for the expression of H19X and EC activation markers. Additionally, differential expression and pathway enrichment analysis between H19X expressing cells and H19X negative cells was carried out. The function of H19X was investigated in human dermal microvascular EC (HDMEC) by silencing, using locked nucleic acid antisense oligonucleotides (LNA GapmeRs). Gene expression was measured by qPCR. Protein levels of endothelial adhesion molecules were analysed by Western Blot. Endothelial adhesion was evaluated by co-culture of HDMEC and fluorescently labelled peripheral blood mononuclear cells (PBMCs).ResultsH19X expression was found significantly upregulated in SSc skin biopsies of the PRESS cohort (pH19X positively correlated with the microvascular endothelial cell gene signature in all subjects (SSc and HC, R=0.43, pH19X is expressed in this cell type. To determine if H19X might be an important factor in SSc EC dysfunction scRNAseq was performed. This analysis revealed a significant upregulation of H19X in SSc EC as compared to HC EC (p=0.0095). H19X was found to be upregulated in several EC subclusters including arterial (SEMA3G, HEY1), capillary (CA4, RGCC), venous (ACKR1, VCAM1) and lymphatic (PROX1, LYVE1). H19X displayed highest expression in injured SSc EC and capillary SSc EC. Co-expression analysis of the scRNA-seq data revealed higher expression of several adhesion molecules in EC expressing H19X, including VCAM1, ICAM and JAM3. KEGG pathway analysis revealed that differentially expressed genes in H19X expressing cells were highly associated with the ‘Cell adhesion molecule’ pathway (p=2.209e-7). H19X silencing lead to a significant downregulation of mRNA levels of genes encoding adhesion molecules VCAM1 (n=7, pH19X on endothelial adhesion was confirmed by PBMCs with H19X silenced HDMEC where we were able to demonstrate a significant decrease in leucocyte-to-endothelial cell adhesion (n=5, pConclusionOur results show that lncRNA H19X could contribute to EC activation in SSc vasculopathy, acting as a regulator of expression of adhesion molecules in EC.References[1]Pachera E, et al. Long noncoding RNA H19X is a key mediator of TGF-β-driven fibrosis. J Clin Invest. 2020 Sep 1;130(9):4888-4905.Disclosure of InterestsFrancesca Tirelli: None declared, Elena Pachera: None declared, Robert Lafyatis Consultant of: Pfizer, Bristol Myers Squibb, Boehringer-Ingleheim, Formation, Sanofi, Boehringer-Mannheim, Merck and Genentech/Roche, Grant/research support from: Corbus, Formation, Moderna, Regeneron, Pfizer and Kiniksa, Menqi Huang: None declared, Shervin Assassi: None declared, Eva Camarillo: None declared, Francesco Zulian: None declared, Gabriela Kania: 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.

BackgroundClinically feasible and valid biomarkers of systemic sclerosis-interstitial lung disease (SSc-ILD) are needed. While promising candidate biomarkers are under investigation (e.g., KL-6, CCL-8), clinical assays for these proteins are not currently available. C-reactive protein (CRP) measurements are feasible, cost-effective, and have been shown to predict mortality in SSc.1 Measuring interleukin (IL)-6, a proinflammatory cytokine implicated in SSc-ILD pathogenesis, is also feasible in most clinical settings.Objectives(1) To investigate whether CRP and IL-6 levels change in response to treatment with immunosuppression in SSc-ILD; (2) To explore whether the change in CRP and IL-6 predict the future course of forced vital capacity (FVC).MethodsCRP and IL-6 levels were measured in serum at baseline and after 12 months in participants of Scleroderma Lung Study (SLS) II (patients with active SSc-ILD receiving 24 months of mycophenolate or 12 months cyclophosphamide followed by 12 months of placebo2). Measured values were log-transformed to remove skewness. The FVC%-predicted was measured every 3 months over the course of 24 months. Spearman’s correlations evaluated the relationship between baseline CRP or IL-6 measurements and other patient parameters. Paired t-tests were used to compare the change in individual CRP and IL-6 measurements from baseline to 12 months. Linear mixed effects models were used to examine the relationship between the change in CRP and IL-6 (baseline to 12 months) and the subsequent course of the FVC (12 to 24 months). All analysis were performed for the entire cohort and separately by treatment arm.ResultsOf the 142 participants of SLS II, 101 had CRP and IL-6 measurements at baseline and 12 months. Baseline CRP and IL-6 levels correlated significantly with higher modified Rodnan skin score (CRP: r=0.3, P=0.005; IL-6: r=0.2, P=0.01) and shorter disease duration (CRP: r=-0.3, P=0.005; IL-6: r=-0.2, P=0.01) and were higher in patients with diffuse SSc (CRP: P=0.007; IL-6: P=0.01). Relationships to baseline FVC and DLCO were not observed. CRP decreased significantly from baseline to 12 months in the whole group (P=0.01), but the decrease was slightly greater in patients randomized to mycophenolate versus cyclophosphamide (-0.47 vs. -0.33 ug/mL). IL-6 also decreased from baseline to 12 months in the whole group with a trend towards significance (P=0.10) (Figure 1). The mean decrease in IL-6 was again slightly greater in patients randomized to mycophenolate versus cyclophosphamide (-0.31 vs. -0.10 pg/mL). After controlling for baseline FVC and treatment arm in the mixed effects model, there was a relationship between the decrease in CRP from baseline to 12 months and an improved course of FVC 12 to 24 months (Estimate -0.64), but this did not reach significance (P=0.14). However, after controlling for baseline FVC and treatment arm, a greater decrease in IL-6 from baseline to 12 months was significantly associated with a greater improvement in FVC from 12 to 24 months (Estimate -1.28; P=0.01).Figure 1.Change in CRP (A) and IL-6 (B) from baseline to 12 months by treatment arm in SLS II. CYC=cyclophosphamide (Blue), MMF=mycophenolate (red)ConclusionPatients with active SSc-ILD receiving one year of immunosuppressive therapy in the SLS II study experienced reductions in their CRP and IL-6 levels over this interval. The magnitude of the decrease in CRP and IL-6 over the first year also correlated with the course of FVC over the ensuing 12 months. These findings suggest a dynamic relationship between CRP and IL-6 measurements and the course of SSc-ILD in patients on immunosuppressive therapy. Further investigation of these findings is warranted.References[1]Liu et al. Arthritis Care Res 2013.[2]Tashkin et al. Lancet Resp Med 2016.Disclosure of InterestsElizabeth Volkmann Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Grant/research support from: Forbius, Kadmon, Horizon, Boehringer Ingelheim, Donald Tashkin: None declared, Holly Wilhalme: None declared, Marka Lyons: None declared, Grace Kim: None declared, Jonathan Goldin: None declared, Michael Roth Grant/research support from: Genentech, Shervin Assassi Consultant of: Boehringer Ingelheim

Introduction. Understanding the genetic architecture of scleroderma (SSc) susceptibility is vital both in gene discovery and in determining the influence of previously identified susceptibility variants. It is particularly important in understanding disease mechanism in a disease with few therapies and great morbidity and mortality. Methods. We selected 557 cases from the Australian Scleroderma Cohort Study (ASCS), for genotyping with the Immunochip, a custom Illumina Infinium genotyping array containing 196 524 rare and common variants shown to be important in a wide variety of autoimmune disorders. A total of 4537 controls were taken from the 1958 British Birth cohort. Genotype data were analysed with PLINK. Samples and SNPs with low call rates were excluded, as were SNPs in Hardy-Weinberg disequilibrium or with less than two occurrences of the minor allele. Eigenstrat was used to analyse population structure. The final data set consisted of 505 cases, 4491 controls and 146 867 SNPs. Allelic association analyses were conducted using Fisher's exact test. Genotype clusters were manually examined for all associations of P < 10−5 since calling is difficult for some rare variants. Results. Significant and suggestive associations were detected at seven loci. Several of these have been previously implicated in scleroderma susceptibility (HLA-DRB1 and STAT4) and several are novel associations, including SNPs near PXK (P = 4.4 × 10−6) and CFDP1(P = 2.6 × 10−6). The strongest associations were with SNPs in the Class II region of the MHC. One of the most strongly associated SNPs [rs4639334; P = 1.6 × 10−8; odds ratio (OR) = 1.8] is in linkage disequilibrium (r2 = 0.46) with the Class II allele HLA-DRB1*11:01. This allele has been associated with SSc. Another strongly associated SNP is rs2857130 (P = 1.6 × 10−8; OR = 0.67), which lies in the promoter region of HLA-DRB1, but is not in LD with any classical MHC alleles. Outside the MHC, there were six regions of association with P < 10−5,including the confirmed SSc locus at STAT4. Several SNPs implicate a locus at PXK, which has been previously associated with SLE but not with SSc. The remaining associations are novel for both SSc and SLE and require replication. Of particular interest is a rare variant located within a non-coding RNA on chromosome 6q21 which was ∼20 times more frequent in cases than controls. We are currently dissecting the potential biological implications of this locus. Conclusions. This pilot study has confirmed previously reported SSc associations, revealed further genetic overlap between SSc and SLE, and identified putative novel SSc susceptibility loci including a rare allele with major effect size

Introduction Le syndrome de Hughes-Stovin est une maladie rare, le plus souvent de cause inconnue. Il se caracterise par la combinaison de plusieurs anevrismes des arteres pulmonaires et de thromboses veineuses profondes. Affection decrite pour la premiere fois en 1959 par deux medecins britanniques du nom de John Patterson Hughes et Peter George Ingle Stovin. Il s’agit d’une variante rare de la maladie de Behcet, mais depourvue de certaines manifestations, particulierement dermatologiques. Moins d’une soixantaine d’observations ont ete rapportees a ce jour dans la litterature. L’affection touche particulierement les jeunes de sexe masculin (20 a 40 ans). Nous rapportons 2 cas de patients d’origine infectieuse pour l’un et inconnue pour le second. Methodes L’affection touche particulierement les jeunes de sexe masculin (20 a 40 ans). Nous rapportons 2 cas de patients d’origine infectieuse pour l’un et inconnue pour le second. Resultats Le syndrome de Hughes Stoven represente une forme incomplete de la maladie de Behcet avec certains traits communs notamment angiographiques et histopathologiques. Son etiologie reste peu cernee. On incrimine souvent une cause infectieuse, mais aussi une vascularite et l’angiodysplasie. Il semble exister une predisposition de formation de thrombus affectant les veines peripheriques. La thrombose de la veine cave et de l’oreillette droite. La presence d’anevrisme associe est evocatrice de la maladie. Ceux-ci sont secondaires a une destruction de la paroi arterielle associee a une infiltration lymphomonocytaire perivasculaire des capillaires et des veinules. Le traitement repose essentiellement sur une corticotherapie suivie ou non par des immunosuppresseurs. Le recours a la chirurgie reste une option delicate. Celle-ci permet de prevenir le risque d’une eventuelle hemoptysie cataclysmique. Conclusion La presence de thrombose arterielle pulmonaire chez un sujet jeune, accompagne ou non d’une ectasie vasculaire, necessite une attention particuliere afin de poser un diagnostic precoce du syndrome de Hughes Stoven et d’eviter des hemoptysies foudroyantes par rupture anevrysmale.

Objective. We previously showed that DU significantly increased global and hand disability with a significant impact on activities of daily living (ADLs) and work disability. This study aims to evaluate the impact of digital ulcer (DU) healing on disability and daily activity limitations in SSc. Methods. From January 2008 and June 2009, we prospectively evaluated 189 SSc patients for DU history, disability, employment and occupational status during meetings of the French SSc Patient Association (n = 86, 45.5%) or during hospitalization (n = 103, 54.5%)1. Among the 60 patients with at least one active DU at baseline (M0), 40 patients were followed longitudinally over 6 (3) months. These patients were evaluated for DU history, global and hand disability, health-related quality of life (HRQoL), daily activity limitation and employment status. Results. The median (IQR) age was 57.5 (43.5-68) years and the median (IQR) disease duration was 8.3 (3-16.5) years. Twenty-two (55%) patients had diffuse SSc and 34 (85%) were females. At baseline, a mean of 2.9 (2.8) DU per patient was reported. Thirty-three (82.5%) patients had ischaemic DU, 7 (17.5%) patients had >1 DU associated with calcinosis and 13 (32.5%) patients had mechanical DU. Thirteen (32.5%) patients had >4 DU at baseline. Among the 40 patients, 16 (40%) patients showed complete ulcer healing. In these patients with DU, the presence of calcinosis was associated with a lower probability of healing (P = 0.03). Comparison between healed and no-healed DU patients showed an improvement of hand disability provided by an improvement of the Cochin Hand Function score (P = 0.05)) and a trend towards HAQ domain dressing and grooming (P = 0.06) between M0 and M6 (3) visit in healed patients but not in no-healed patients. Concerning HRQoL, there were no difference for Mental and Physical component Scores of SF-36 but significant improvement of Bodily Pain score (P = 0.04) and Physical Role score (P = 0.05) between M0 and M6 (3) visit in patients with healed DU. The absence of healing was associated with significantly decreased work productivity (P = 0.05), whereas the performance in ADL was not significantly decreased (P = 0.15). Patients who were on sick-leave and who received some help for household tasks at the time of active DU were more likely to heal. Conclusion. For the first time, we provide prospective data with evidence that DU healing is associated with an improvement in hand function. Sick leave was associated with better healing of DU

Introduction Le TDM6 s’est impose depuis plus d’une decennie pour evaluer la tolerance a l’effort ainsi que les effets du reentrainement chez le malade insuffisant respiratoire. Cependant, ce dernier se limite a evaluer la distance parcourue par le patient durant un temps de 6 minutes bien que celle-ci reste tributaire de plusieurs facteurs, notamment de l’âge, de la taille, du poids, des troubles de la marche ou d’eventuelles malformations. La podometrie apparait comme un moyen simple qui permet de repondre a cette insuffisance notre objectif est de connaitre l’interet de la podometie dans le TDM6, a travers la recherche d’une correlation entre la distance parcourue pendant les 6 minutes et le nombre de pas utilise ainsi que leur qualite personnalisee. Methodes Il s’agit d’une etude prospective, cas temoins, qui a concerne 60 sujets ayant tous subit une podometrie pendant le TDM6 avec calcul du nombre de pas, de leur ecart, de leur cadence ainsi que la distance parcourue. Notre travail s’est deroule en 2 temps. D’abord, l’evaluation de la podometrie pendant 6 minutes chez des sujets sains avec des tailles differentes. Nous avons eu recours a une triple methode de calculs podometrique, a la fois visuelle que par le biais d’un podometre et d’un logiciel « pacer » telechargeable. Nos malades sont stratifies selon leur etat fonctionnel. La meme technique est utilisee chez des sujets presentant une BPCO a l’etat stable et en exacerbation. Resultats Nous avons constate que la podometrie et la distance varient en fonction de la taille chez les sujets sains 155cm–164 cm : Moy. Nombre de pas : 614 [585–644] 165cm–174 cm : Moy. Nombre de pas : 601 [592–610] ≥ 175 cm : Moy. Nombre de pas : 600 [598–603]. Conclusion La correlation entre le TDM6 et la podometrie etait significative chez les sujets sains, les BPCO en etat stable ainsi que les BPCO en exacerbation ( p

Introduction Une exposition reguliere aux irritants inhales peut provoquer une pneumopathie interstitielle diffuse. Ces irritants comprennent l’amiante, la poussiere de silice, le talc, la poussiere de charbon, les poussieres de metaux, la poussiere de cereales de l’elevage, les proteines d’oiseaux, mais peu d’observations ont ete faites sur le gaz d’echappement. Methodes Nous rapportons ici 3 cas de pneumopathies interstitielles diffuses dues a une inhalation de gaz d’echappement de vehicules. Resultats Tous nos patients etaient des hommes, âges de 18, 22 et 22 ans, qui presentaient a l’admission des hemoptysies, de la fievre, une dyspnee et des douleurs thoraciques faisant suite a une longue histoire d’inhalation quotidienne de gaz d’echappement de voiture. Cette etrange toxicomanie etait utilisee comme une drogue, ils ont egalement l’habitude de consommer du cannabis, de l’alcool un sniff d’essence. La duree moyenne d’exposition etait de 5 ans avec inhalation quotidienne des gaz refoules directement du pot d’echappement des voitures. La tomodensitometrie a revele l’aspect de pneumopathie alveolo-interstitielle diffuses chez tous 3 les patients. Resultats biologiques montres : la recherche de mycobacterium tuberculosis dans l’expectoration etait positive chez un patient. L’endoscopie bronchique n’a montre aucune anomalie chez nos patients, cependant, le lavage broncho-alveolaire a revele l’existence d’une hemorragie alveolaire chez un patient. L’evolution etait favorable sous traitement chez tous les malades. Conclusion Cette observation permet de mettre de doigt sur les dangers de cette toxicomanie a partir de gaz brules d’echappement de voitures et les lesions engendres par celle-ci.

Introduction Le kyste hydatique est une parasitose due au developpement dans le poumon de la forme larvaire du Tenia echinococcus granulosus, parasite habituel du chien et la plupart des carnivores, l’homme peut etre accidentellement atteint. La localisation pulmonaire represente 20 a 40 % de l’ensemble des kystes hydatiques de l’organisme et 90 % des hydatidose intra-thoraciques. Notre objectif est donc d’etudier les caracteristiques cliniques et evolutives des kystes hydatiques. Methodes Il s’agit d’une etude retrospective portant sur une periode de 8 ans (2009–2017) incluant 56 dossiers de malade. Cette population est constituee de 27 sujets de sexe masculin (48,21 %) et 29 de sexe feminin (51,78 %). L’âge moyen est de 32,85 ans avec des extremes (15–77 ans). Resultats Le diagnostic a ete pose dans plusieurs stades evolutifs de la maladie : un kyste sain dans 4 cas ; kyste rompu avec plusieurs types d’image radiologiques : – image cavitaire dans 16 cas ; – image hydroaerique 11cas ; – incarceration de membrane 5 cas ; – radiographie pulmonaire normale ou subnormale 7 cas. Quant a la rupture dans la cavite pleurale on la retrouve dans 7 cas, realisant un pyopneumothorax. Polykystoses hydatiques dans 4 cas. Et un cas de kystes hydatiques pulmonaire et intracardiaque. L’hemoptysie est un symptome frequent lors des KHP non operes (17 cas, 30,35 %) elle peut aller d’une faible abondance a une hemoptysie foudroyante. Conclusion Malgre les progres et les espoirs suscites par les perspectives du traitement medical, ainsi que les mesures preventives de plus en plus rigoureuses dans les pays endemiques notamment en Algerie, l’hydatidose pulmonaire continue a engager le pronostic fonctionnel et vital des patients souvent jeunes, elle reste dans la grande majorite des cas du ressort de la chirurgie.

Introduction La silicose est une maladie pulmonaire chronique en rapport avec l’inhalation prolongee des poussieres de silice cristalline C’est la plus frequente des pneumoconioses et la plus importante des maladies professionnelles. Les malades peuvent demeurer asymptomatiques avec une radiographie du thorax longtemps normale ou presentant une symptomatologie respiratoire temoignant d’une complication. Methodes Nous avons collige 81 dossiers de patients atteints de silicose de 2005 a 2016 hospitalises au service de pneumologie CHU Batna. Resultats Tous nos patients etaient de sexe masculin dont 59 etaient tabagiques, la moyenne d’âge etait de 31 ans, tous les patients presentaient des lesions etendues a la radiographie du thorax et 19 patients ont plus d’une complication necessitant plusieurs hospitalisation Les motifs de consultations etaient nombreux allant de la toux seche chronique voir dyspnee jusqu’a la douleur thoracique dans un contexte d’alteration de l’etat general. Les complications etaient un pneumothorax chez 34 patients dont 13 cas bilateraux, une tuberculose chez 33 patients dont 27 cas de tuberculose pulmonaire et 6 cas extra pulmonaire avec 11 cas presentant une tuberculose multiresistante, 4 patients ayant un cœur pulmonaire chronique et 3 cas d’insuffisance renale ont ete decrites et une association silicose maladie systemique a ete observee chez 7 cas. Conclusion Les malades silicotiques peuvent presenter plusieurs complications qui marquent un tournant evolutif de leur maladie, de ce fait une surveillance de ces malades a long terme est necessaire afin de guetter les incidents de la maladie silicotique.

Introduction Le chylothorax ou pleuresie chyleuse est une affection rare mais aux consequences potentiellement serieuses. Ses origines sont diverses. Il est le plus souvent secondaire a une lesion ou a un blocage du canal thoracique par une neoplasique, un traumatisme, voir d’une tuberculose. Il se caracterise par la presence d’un liquide pleural lactescent riche en lymphocytes avec un taux de triglycerides superieur a 1,1 g/L. Notre objectif est donc d’etudier les caracteristiques cliniques et etiologiques, les modalites therapeutiques et l’evolution de la pleuresie chyleuse. Methodes Une etude retrospective concernant 8 patients representee par 5 femmes et 3 hommes. Resultats L’origine de la pleuresie chyleuse etait successivement : un lymphome malin dans 4 cas (hodgkinien : 3 cas, non hodgkinien : 1 cas), une tuberculose (1 cas), un traumatisme thoracique (1 cas), enfin un chylothorax familiale (2 cas) dont l’etiologie n’est pas encore connu. Le diagnostic est pose respectivement chez les 4 premiers patients a travers la biopsie ganglionnaire pour 3 patients et amygdalienne pour l’autre. La tuberculose est confirmee par la culture de BK a partir du liquide pleural chez le 5e malade. Des adenopathies mediastinales sont visibles a la T.D.M dans ces 5 situations. Conclusion Les causes de chylothorax peuvent etre principalement divisees en deux categories : traumatiques ou non traumatiques. La prise en charge therapeutique comprend principalement un drainage pleural et des mesures dietetiques adaptees, devant toujours etre associes au traitement de la pathologie sous-jacente. En cas d’echec, la prise en charge chirurgicale est indiquee.