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In: Rheumatology, Oxford University Press (OUP), Vol. 63, No. 3 ( 2024-03-01), p. 639-647

Abstract: To investigate the course of interstitial lung disease (ILD) and the effects of nintedanib in patients with limited cutaneous systemic sclerosis (lcSSc). Methods In the SENSCIS trial, patients with SSc-ILD were randomized to receive nintedanib or placebo. Patients who completed the SENSCIS trial were eligible to enter SENSCIS-ON, in which all patients received open-label nintedanib. Results Among 277 patients with lcSSc treated in the SENSCIS trial, the rate (s.e.) of decline in forced vital capacity (FVC; ml/year) over 52 weeks was −74.5 (19.2) in the placebo group and −49.1 (19.8) in the nintedanib group (difference: 25.3 [95% CI −28.9, 79.6]). Among 249 patients with data at week 52, mean (s.e.) change in FVC at week 52 was −86.4 (21.1) ml in the placebo group and −39.1 (22.2) ml in the nintedanib group. Among 183 patients with lcSSc who participated in SENSCIS-ON and had data at week 52, mean (s.e.) change in FVC from baseline to week 52 of SENSCIS-ON was −41.5 (24.0) ml in patients who took placebo in the SENSCIS trial and initiated nintedanib in SENSCIS-ON and −45.1 (19.1) ml in patients who took nintedanib in the SENSCIS trial and continued it in SENSCIS-ON. Conclusion Patients with lcSSc may develop progressive fibrosing ILD. By targeting pulmonary fibrosis, nintedanib slows decline in lung function in patients with lcSSc and ILD. Trial registration ClinicalTrials.gov (https://clinicaltrials.gov), NCT02597933 and NCT03313180

Type of Medium: Online Resource

ISSN: 1462-0324 , 1462-0332

URL: Article

DOI: 10.1093/rheumatology/kead280

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2024

detail.hit.zdb_id: 1474143-X

In: Rheumatology, Oxford University Press (OUP), Vol. 51, No. suppl 2 ( 2012-02-01), p. ii23-ii24

Type of Medium: Online Resource

ISSN: 1462-0324 , 1462-0332

URL: Article

DOI: 10.1093/rheumatology/ker486

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2012

detail.hit.zdb_id: 1474143-X

In: Annals of the Rheumatic Diseases, BMJ, Vol. 80, No. Suppl 1 ( 2021-06), p. 685-686

Abstract: Tocilizumab (TCZ) showed trends for improving skin fibrosis and prevented progression of lung fibrosis in patients with systemic sclerosis (SSc) in placebo-controlled randomised clinical trials (RCTs). However, safety and effectiveness of TCZ beyond these selected and enriched clinical trial populations in SSc is still unknown. Objectives: To assess safety and effectiveness of TCZ treatment compared to standard of care in SSc patients from the large, multicentre, observational, real-life EUSTAR network/database using propensity score matching. Methods: SSc patients from the EUSTAR network/database, who fulfilled the ACR/EULAR 2013 classification criteria, with a baseline and a follow-up visit at 12±3 months, receiving TCZ or standard of care (controls), were selected. The following variables were used for the propensity score matching (1:1): age at diagnosis, gender, disease subtype, baseline modified Rodnan skin score (mRSS), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO), co-therapy with immunosuppressives, disease duration, and year of treatment. Primary endpoints were mRSS and FVC at 12±3 months follow-up compared between the groups, using paired t-tests. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months follow-up according to standard definitions (1,2). Sensitivity analyses assessed pre-processing decisions (selection of most recent vs. random observation for control patients with multiple suitable time intervals), as well as the matching method (optimal vs. exact matching). Missing values were addressed with 100-fold multiple imputation using chained equations. Safety data were analysed in all patients. The study including the statistical analysis plan was pre-registered at www.drks.de (DRKS-ID: DRKS00015537). Results: We identified 93 SSc patients treated with TCZ and 2370 SSc patients with standard of care who fulfilled the inclusion criteria. Forty nine (57.7%) of the TCZ treated patients were diffuse, eight patients were not classified, disease duration was (mean±SD) 6.35±5.40 years, their baseline mRSS was 15.05±10.85, and 76 (81.7%) received immunosuppressive therapy in addition to TCZ.Through multiple imputation and propensity score matching, 100 imputed sets of 93 pairs of TCZ/controls were generated. Comparison between groups showed consistent effects of TCZ across all pre-defined primary and secondary endpoints: mRSS was lower in the TCZ group (mean difference (95% confidence interval (CI)) -1.8 (-4.79 to 1.19), p=0.24, Figure 1A). Similarly, FVC % predicted was higher in the TCZ group mean difference (2.25, 95% CI -4.57 to 9.06), p=0.51, Figure 1B). Considering secondary endpoints, the percentage of skin progressors as well as lung progressors at follow up was lower in the TCZ group (odds ratio OR 0.67 (95% CI 0.07 to 6.41), p=0.74 and OR 0.53 (95% CI 0.16 to 1.7); p=0.2, respectively. Consistently, the percentage of regressors for skin (OR 1.6 (95% CI 0.56 to 4.54), p=0.38) and for lung (OR 1.74 (95% CI 0.66 to 4.58), p=0.26) was higher in TCZ. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles. Conclusion: In this large, observational, controlled, real-life EUSTAR study, effectiveness of TCZ did not reach statistical significance compared to standard of care treatment but showed consistent positive effects of TCZ on skin and lung fibrosis across all pre-defined primary and secondary endpoints confirming data from recent RCTs. References: [1]Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis. Ann Rheum Dis 2016:1743-8. [2]Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis 2021:219-227. Disclosure of Interests: Simon Kuster: None declared, Suzana Jordan: None declared, Muriel Daniele Elhai: None declared, Ulrike Held: None declared, Klaus Steigmiller: None declared, Cosimo Bruni: None declared, Florenzo Iannone: None declared, Serena Vettori: None declared, Elise Siegert: None declared, Simona Rednic: None declared, Veronica Codullo: None declared, Paolo Airò Consultant of: Dr. Airo’ reports personal fees (consultancies) from Bristol Myers Squibb, Bohringer Ingelheim, non-financial support from CSL Behring, SOBI, Janssen, Roche, Sanofi, Pfizer, Yolanda Braun-Moscovici: None declared, Nicolas Hunzelmann: None declared, Maria Joao Salvador: None declared, Valeria Riccieri: None declared, Ana Maria Gheorghiu: None declared, Juan Jose Alegre Sancho: None declared, Katarzyna Romanowska-Prochnicka: None declared, Ivan Castellví: None declared, Ina Koetter: None declared, Marie-Elise Truchetet Consultant of: Marie-Elise Truchetet has had consultancy relationships and/or has received research funding from Boehringer Ingelheim, Genentech/Roche, and Sanofi in the area of potential treatments of scleroderma and its complications., Grant/research support from: Marie-Elise Truchetet has had consultancy relationships and/or has received research funding from Boehringer Ingelheim, Genentech/Roche, and Sanofi in the area of potential treatments of scleroderma and its complications., Francisco J López-Longo: None declared, Pavel Novikov: None declared, Alessandro Giollo: None declared, Yuichiro Shirai: None declared, Laura Belloli: None declared, Elisabetta Zanatta: None declared, Eric Hachulla: None declared, Vanessa Smith: None declared, Christopher Denton: None declared, Ruxandra Ionescu: None declared, Tim Schmeiser: None declared, Jörg H.W. Distler: None declared, Armando Gabrielli: None declared, Anna-Maria Hoffmann-Vold Consultant of: AMHV has received research funding and/or consulting fees and/or other remuneration from Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Grant/research support from: AMHV has received research funding and/or consulting fees and/or other remuneration from Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape. Masataka Kuwana: None declared, Yannick Allanore: None declared, Oliver Distler Speakers bureau: Oliver Distler has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Consultant of: Oliver Distler has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years): Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: The study was partially supported by a grant from Roche. Roche was not involved in analysis or interpretation of the results.

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2021-eular.2392

Language: English

Publisher: BMJ

Publication Date: 2021

detail.hit.zdb_id: 1481557-6

In: La Revue de Médecine Interne, Elsevier BV, Vol. 30 ( 2009-12), p. S344-

Type of Medium: Online Resource

ISSN: 0248-8663

URL: Article

DOI: 10.1016/j.revmed.2009.10.057

Language: French

Publisher: Elsevier BV

Publication Date: 2009

detail.hit.zdb_id: 2031063-8

In: Annals of the Rheumatic Diseases, BMJ, Vol. 81, No. Suppl 1 ( 2022-06), p. 746.2-747

Abstract: Management 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). Objectives To summarize the literature on the safety and efficacy of L-ST for SSc-DUs. Methods A 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. Results Thirteen 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, (p 〈 0.0001), 12 pts in the SP group, received rescue AT injection, all of them healed after 8 wks. Three studies reported autologous adipose-derived stromal vascular fraction(SVF) grafting and the HR ranged from 32-60%, followed up to 12 months. Transient edema and paresthesia were reported in 2 studies, and amputation in 2 ulcers in 1 study, and no complications were reported in other studies. Surgical sympathectomy was reported in 3 studies, with a median healing rate of 81%. Bone marrow derived cell transplantation in a single study showed 87% healing rate over (4-24 wks). Two surgical studies (of direct microsurgical revascularization N=4, and microsurgical arteriolysis, N=6), showed 100% healing of ulcers, no complications reported. Table 1. Characteristics of the extracted studies. Studydesign Patients (n) Baseline DU (n) Background therapy (%) Follow-up OutcomeHealed ulcers(%) Adipose tissue graft Autologous fat graft p 9 .15 PG, CCB—100ETA 26PDE-5i 13 8-12 wks 66 Adipose tissue grafting RCT 25 case13- Ctr 25-case13- Ctr PG- 100CCB 100 8 wks 92-case7-Ctr Adipose tissue implant p 15 15 no therapy 7 wks 100 Adipose tissue graft p 12 9 PG,CCB-100ETA 6 month 88 adipose derived SVF p 12 15 PDE-5i, ccb, PG allowed 22m 6 Adipose derived SVF p 12 15 CCB 50ETA16 6 m 63 Adipose derived SVF p 18 19 CCB 50PG 27ETA 5IS 71 24 wks 32 Sympathectomy Sympathectomy R 6 11 CCB-100 20 m 81 Sympathectomy R 13 35 PGCCBAPA 35 Sympathectomy, vascular bypass ( + vein graft R 17 26 Ccb 35APA 47PDE-i5 58 9 m 100 Bone marrow derived cells transplantation ) p 8 8 PG-62 36 m 87 Direct microsurgical revascularization R 4 4m 100 Limited microsurgical arteriolysis R 6 17 12 m 100 SVF =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 rate Conclusion Our 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 Interests Yossra 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

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2022-eular.3442

Language: English

Publisher: BMJ

Publication Date: 2022

detail.hit.zdb_id: 1481557-6

In: Annals of the Rheumatic Diseases, BMJ, Vol. 79, No. Suppl 1 ( 2020-06), p. 25.1-25

Abstract: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Its use has been associated with hypersensitivity pneumonitis and diffuse lung disease. Whether MTX exposure increases the risk of interstitial lung disease (ILD) in patients with RA is disputed. Objectives: We aimed to evaluate the association of antecedent MTX use with development of RA-ILD. Methods: Through a case-control study design with derivation and international validation samples, we examined the association of MTX exposure with ILD in 482 patients with RA-ILD and 741 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. Results: Analysis of the derivation sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted odds ratio [OR], 0.48; 95% confidence interval [CI] , 0.25 to 0.92; P=0.028), which was confirmed in the validation samples (pooled adjusted OR, 0.39; 95% CI, 0.23 to 0.68; P 〈 0.001). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI, 0.28 to 0.65; P 〈 0.0001). MTX ever users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high resolution computed tomography pattern. In patients with RA-ILD, ILD onset was significantly delayed in MTX ever users compared to never users (11.5 ± 10.6 years and 3.7 ± 7.1 years, respectively; P 〈 0.001). Conclusion: Our results suggest that MTX is not a risk factor for RA-ILD and support a possible disease modifying effect of MTX on development of RA-ILD. Disclosure of Interests: Pierre-Antoine Juge: None declared, Joyce S. Lee Consultant of: Celgene, Genentech, Boehringer Ingelheim, Jessica Lau: None declared, Leticia Kawano: None declared, Jorge Rojas-Serrano: None declared, Marco Sebastiani: None declared, Gouri Koduri: None declared, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking, Karina Bonfiglioli Consultant of: Roche, Abbvie, Pfizer, Janssen and BMS, Marcio Sawamura: None declared, Ronaldo Kairalla: None declared, Lorenzo Cavagna: None declared, Emanuele Bozzalla Cassione: None declared, Andreina Manfredi: None declared, Mayra Mejia: None declared, Pedro Rodríguez Henríquez: None declared, Montserrat I. Gonzalez-Perez: None declared, Ramcés Falfan-Valencia: None declared, Ivette Buendia-Roldan: None declared, Glora Perez-Rubio: None declared, Esther Ebstein Consultant of: BMS, Employee of: BMS, Steven Gazal: None declared, Raphael Borie Consultant of: Roche, Boehringer Ingelheim, Sebastien Ottaviani: None declared, Caroline Kannengiesser: None declared, Benoît Wallaert Consultant of: Roche, Boehringer Ingelheim, Yurdagul Uzunhan Consultant of: Roche, Boehringer Ingelheim,, Hilario Nunes: None declared, Dominique Valeyre Consultant of: Astra Zeneca, Roche, Boehringer Ingelheim, Nathalie Saidenberg Kermanac’h: None declared, marie-Christophe Boissier: None declared, Lidwine Wemeau Stervinou Consultant of: Roche, Janssen, BMS, Boehringer Ingelheim, Rene-Marc Flipo Speakers bureau: Novartis, Janssen, Lilly, Sylvain Marchand-Adam Consultant of: Roche, Novartis, Boehringer Ingelheim, Pascal Richette: None declared, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi, Claire Dromer: None declared, Marie-Elise Truchetet: None declared, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Thierry Schaeverbeke: None declared, Huguette Lioté: None declared, Gabriel Thabut Employee of: Astra Zeneca, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, Joshua Solomon: None declared, Tracy Doyle: None declared, Jay H. Ryu: None declared, Ivan O. Rosas Consultant of: Boehringer Ingelheim, Gerentech, Three Lakes Partners, V. Michael Holers Grant/research support from: Janssen, Celgene, and BMS, Catherine Boileau: None declared, Marie-Pierre Debray: None declared, Raphaël Porcher: None declared, David A. Schwartz Consultant of: NuMedii, Robert Vassallo Shareholder of: Pfizer, BMS, SunPharma, Bruno Crestani Shareholder of: Apellis, Boehringer Inghelheim, Medillune, Roche, Consultant of: Boehringer Ingelhiem, Astra Zeneca, Roche, Sanofi, Philippe Dieudé: None declared

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2020-eular.1678

Language: English

Publisher: BMJ

Publication Date: 2020

detail.hit.zdb_id: 1481557-6

In: Annals of the Rheumatic Diseases, BMJ, Vol. 73, No. Suppl 2 ( 2014-06), p. 197.2-197

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2014-eular.5038

Language: English

Publisher: BMJ

Publication Date: 2014

detail.hit.zdb_id: 1481557-6

In: Annals of the Rheumatic Diseases, BMJ, Vol. 81, No. Suppl 1 ( 2022-06), p. 748.2-749

Abstract: Digital 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. Objectives To summarise data on efficacy and safety of systemic treatments for SSc DU. Methods A 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. Results The 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 trials Author Year Intervention n Follow up Outcome Favours intervention Hachulla 2016 Sildenafil 83 12 weeks Time to DU healing - Andrigueti 2017 Sildenafil 41 12 weeks DU healing + Shenoy 2010 Tadalafil 24 6 weeks New DU + Khanna 2016 Macitentan 554 16 weeks New DU - Matucci-Cerinic 2011 Bosentan 188 32 weeks New DU Time to healing of DU +- Korn 2004 Bosentan 122 12 weeks New DU + Kawald 2008 IV iloprost 50 12 months DU healing - Wigley 1992 IV iloprost 35 10 weeks DU healing + Wigley 1994 IV iloprost 73 9 weeks 50% reduction in DU score - Seibold 2017 Treprostinil 148 20 weeks Net DU burden - Vayssairat 1999 Beraprost 107 25 weeks % patients with new DU - Denton 2017 Selexipag 74 12 weeks Number of new DU DU healing - Lau 1993 Cicaprost 33 4 weeks Number of DU - Abou-Raya 2008 Atorvastatin 84 4 months Number of DU + Au 2010 Cyclophosphamide 158 12 months Number of patients with DU - Beckett 1984 Dipyridamole / aspirin 41 2 years Change in general SSc - Nagaraja 2019 Riociguat 17 32 weeks Net DU burden - + significantly superior to comparator - non significantly different from comparator DU: digital ulcers IV: intravenous SSc: systemic sclerosis Several 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. Conclusion Despite 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. Acknowledgements This work was supported by the World Scleroderma Foundation. Disclosure of Interests Nancy 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

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2022-eular.3592

Language: English

Publisher: BMJ

Publication Date: 2022

detail.hit.zdb_id: 1481557-6

In: Annals of the Rheumatic Diseases, BMJ, Vol. 79, No. Suppl 1 ( 2020-06), p. 26.1-26

Abstract: Interstitial lung disease (ILD) is the most common pulmonary manifestation of rheumatoid arthritis (RA). It has emerged in recent series as a key prognostic factor including survival. The big challenge for rheumatologists is now the risk-stratification of RA patients for ILD. Chest high-resolution computed tomography (HRCT) is the gold standard for RA-ILD diagnosis, but costs and ionizing radiation may limit its use in clinical practice. Thus, circulating biomarkers could aid in this risk-stratification. Objectives: to evaluate the merit of 3 circulating markers for the diagnosis and the progression of RA-ILD. Methods: We included consecutive patients with RA, 〉 18 years of age, from 3 tertiary rheumatology centers (Paris, France, Tokyo, Japan and Zurich, Switzerland) over a 36-month period. All patients had at least one chest HRCT during the inclusion period. In the subset of French patients with ILD, HRCT lung images were obtained both at baseline (time of blood sample collection) and at a follow-up visit. The ILD status of patients with RA was established by chest HRCT. The chest HRCT pattern was classified as usual interstitial pneumonia, UIP or non-specific interstitial pneumonia, NSIP, by the local radiologist. Serum levels of lung epithelial-derived surfactant protein D , SDP, CCL-18 et Krebs von den Lungen-6 glycoprotein , KL-6 were measured by ELISA. Results: 147 patients were included (age: 66+/-12 ans, 69% of women, disease duration 11+/-10 years). Among these patients, 40 (27%) had fibrosing ILD on HRCT: 21 had a UIP pattern, 17 a NSIP pattern, and 2 had NSIP associated with chronic obstructive pulmonary disease. SPD (21.91+/-2.17 vs. 15.76+/-1.34 ng/mL, p=0.017) CCL18 (102+/-13 vs. 78+/-5 ng/mL, p=0.026) and KL6 (961+/-128 vs. 376+/-26 U/mL, p 〈 0.001) concentrations (Figure 1 A-C ) were significantly higher in patients with RA-ILD vs. unaffected RA patients. KL6 values ​​were also higher in patients with UIP compared to the other HRCT patterns and in patients with lesion extension 〉 15% as compared to patients with milder disease. ROC curve analysis to assess the diagnostic abilities of the three markers for the diagnosis of RA-ILD showed a superiority of KL-6 (Area under the curve, AUC: 0.79 95% CI 0.72-0.86) compared to SPD (AUC: 0.66 95% CI 0.58-0.74) and CCL18 (AUC: 0.62, 95% CI 0.53-0.70) (Figure 1 D ). The sensitivity of KL-6 for the diagnosis of RA-ILD was 68% with a specificity of 83%. In the French subset with longitudinal data (n=15), extension of ILD was detected on 7 patients. Baseline KL6 serum levels were significantly increased in patients who experienced ILD progression (1987+/-1294 vs. 799+/-375 U/mL, p=0.027) (Figure 1 E ). The degree of ILD progression on HRCT was also proportional to baseline KL-6 concentrations (Figure 1 F ). Conclusion: KL-6 is relevant for the diagnosis and the prognosis of RA-ILD. It may be used as a circulating non-invasive first-line marker to stratify for indication of HRCT. Indeed, given the emerging lung issues in RA patients, this simple and highly reproducible marker, which is already available in routine care in some countries, could be a good prerequisite to chest HRCT in rheumatology clinics. Figure 1A-F. Concentrations of serum markers, diagnostic value and performance of KL-6 for the progression of rheumatoid arthritis-associated interstitial lung disease A-C, Concentrations of SPD (ng/mL) (A), CCL18 (ng/mL) (B) and KL-6 (U/mL) (C) in patients with with or without RA-associated ILD. D, ROC curve illustrating the diagnostic value of SPD, CCL18 and KL-6 for diagnosis of RA-ILD. E, Concentrations of KL-6 (U/mL) according to the progression on chest HRCT of RA-ILD. F, Degree of mean ILD progression on chest HRCT according to baseline KL-6 concentrations. *p 〈 0.05 and **** p 〈 0.0001 by Student’s t test Disclosure of Interests: Jérôme Avouac Grant/research support from: Pfizer, Bristol Myers Squibb, Consultant of: Sanofi, Bristol Myers Squibb, Abbvie, Boerhinger, Nordic Pharma, Speakers bureau: Sanofi, Bristol Myers Squibb Abbvie, MSD, Pfizer, Nordic Pharma, Alexia Steelandt: None declared, Anne Cauvet: None declared, Yuichiro Shirai: None declared, Masataka Kuwana Grant/research support from: Acetelion, Consultant of: Acetelion, Bayer, Chugai, Corbus Pharmaceuticals, CSL Behring and Reata Pharmaceuticals. He was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2020-eular.4136

Language: English

Publisher: BMJ

Publication Date: 2020

detail.hit.zdb_id: 1481557-6

In: Annals of the Rheumatic Diseases, BMJ, Vol. 80, No. Suppl 1 ( 2021-06), p. 694.2-695

Abstract: Digital ulcers (DUs) affect half of the patients with systemic sclerosis (SSc) and can be complicated by gangrene and amputation. The direct involvement of platelets in the development of DUs has been suggested by in vitro studies, which encouraged physicians to consider platelet inhibitors as a therapeutic option in the management of DUs. However, until now, there is no clinical study to assess the efficacy of platelet inhibitors for DUs in SSc patients. Objectives: To demonstrate a possible relationship between treatment with platelet inhibitors and the occurrence of DUs at the next follow-up visit in patients with SSc. Methods: This study used prospectively collected data from the European Scleroderma Trials and Research group (EUSTAR) registry. Patients fulfilling the 2013 ACR/EULAR SSc classification criteria with complete longitudinal data on the presence of DUs and platelet inhibitors were included in the analysis. Multiple imputation using a random forest algorithm was implemented to handle missing values. The dataset was split into a derivation and validation cohort. To investigate the response for the binary dependent variable of DUs, a generalized linear mixed model (GLMM) was developed in the derivation cohort and validated using ROC analysis and Brier scores to address discrimination and calibration, respectively. Results: Of 3,463 patients (2,961 in the derivation cohort, 722 in the validation cohort), 453 had current DUs at the baseline and 245 were exposed to platelet inhibitors (table 1). Our GLMM revealed that the exposure to platelet inhibitors is associated with a reduced risk of DUs at the next follow up visit (OR = 0.33, 95% CI = [0.13 to 0.82]). Further factors associated with absence or presence of DUs at the next follow-up visit are shown in figure 1. This confirmed the previously identified risk factors for the presence of DUs, supporting the overall robustness and the validity of our model. The performance was evaluated by ROC curve analysis and showed an AUC = 97.97% (95% CI = [96.93% to 97.67%]) for the derivation cohort and AUC = 77.3% (95% CI = [74.01% to 81.39%] ) for the validation cohort, respectively, showing an acceptable discrimination. The Brier score was 0.05 in the derivation cohort and 0.07 in the validation cohort, suggesting a good calibration of the model. Conclusion: Our model, with acceptable discrimination and good calibration, suggests a positive treatment effect of platelet inhibitors on DUs in clinical practice. Table 1. Baseline characteristics of patients before imputation Characteristics Overall Derivation set Validation set n 3,463 2,691 772 Age (median [IQR]) 56.00 [47.00, 66.00] 56.00 [47.00, 65.00] 57.00 [48.00, 67.00] Disease duration (median [IQR]) 9.00 [4.00, 16.00] 9.00 [4.00, 16.00] 8.00 [4.00, 15.00] Disease subset = Limited cutaneous SSc (%) 1562 (65.2) 1164 (64.6) 398 (66.9) DUs (%): Current 453 (13.1) 378 (14.0) 75 (9.7) DUs (%): Never 1783 (51.5) 1326 (49.3) 457 (59.2) DUs (%): Previously 1227 (35.4) 987 (36.7) 240 (31.1) mRSS (median [IQR]) 5.00 [2.00, 11.00] 6.00 [2.00, 12.00] 4.00 [1.00, 11.00] Joint Contractures = Yes (%) 881 (26.8) 770 (29.4) 111 (16.5) LVEF (median [IQR]) 62.00 [60.00, 65.00] 60.00 [60.00, 65.00] 65.00 [60.00, 67.00] Dyspnea NYHA III and IV (%) 300 (9.5) 214 (8.6) 86 (12.7) Pulmonary hypertension = Yes (%) 244 (10.7) 200 (11.3) 44 (8.4) Lung fibrosis on HRCT = Yes (%) 685 (46.6) 600 (47.7) 85 (39.7) FVC % predicted (median [IQR]) 97.00 [82.00, 111.00] 95.00 [81.00, 110.00] 101.00 [85.00, 115.00] Serum creatinine mg/dl (median [IQR]) 0.70 [0.60, 0.90] 0.70 [0.60, 0.90] 0.70 [0.70, 0.90] Anti-Scl-70 positive = Yes (%) 1147 (33.1) 958 (35.6) 189 (24.5) CRP elevation = Yes (%) 639 (21.1) 490 (20.8) 149 (22.1) Platelet inhibitors therapy = Yes (%) 245 (7.1) 206 (7.7) 39 (5.1) Oral anti-coagulants therapy = Yes (%) 53 (1.5) 50 (1.9) 3 (0.4) Disclosure of Interests: None declared

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2021-eular.3272

Language: English

Publisher: BMJ

Publication Date: 2021

detail.hit.zdb_id: 1481557-6