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  • Phenotyping by persistent inflammation in systemic sclerosis associated interstitial lung disease: a EUSTAR database analysis

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Interstitial lung disease
Original research
Phenotyping by persistent inflammation in systemic sclerosis associated interstitial lung disease: a EUSTAR database analysis
  1. Sabina Guler1,2,
  2. Adela-Cristina Sarbu3,
  3. Odile Stalder4,
  4. Yannick Allanore5,
  5. Vera Bernardino6,
  6. Joerg Distler7,
  7. Armando Gabrielli8,
  8. Anna-Maria Hoffmann-Vold9,
  9. Marco Matucci-Cerinic10,11,
  10. Ulf Müller-Ladner12,
  11. Vera Ortiz-Santamaria13,
  12. Simona Rednic14,
  13. Valeria Riccieri15,
  14. Vanessa Smith16,
  15. Susanne Ullman17,
  16. Ulrich A Walker18,
  17. Thomas K Geiser1,2,
  18. Oliver Distler19,
  19. Britta Maurer2,3,
  20. Florian Kollert3
  1. 1 Department of Pulmonary Medicine, Inselspital University Hospital Bern, Bern, Switzerland
  2. 2 Department of BioMedical Research, University of Bern, Bern, Switzerland
  3. 3 Department of Rheumatology and Immunology, Inselspital University Hospital Bern, Bern, Switzerland
  4. 4 CTU Bern, University of Bern, Bern, Switzerland
  5. 5 Department of Rheumatology, Cochin Hospital, Paris, France
  6. 6 Internal Medicine Department 7.2, Hospital Curry Cabral, Centro Hospitalar Universitário Lisboa Central, Lisboa, Portugal
  7. 7 Department of Rheumatology and Hiller Research Center, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
  8. 8 Fondazione di Medicina Molecolare e Terapia Cellulare, Università Politecnica delle Marche, Ancona, Italy
  9. 9 Rheumatology, Oslo University Hospital Ullevål, Oslo, Norway
  10. 10 Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy
  11. 11 Unit of Immunology, Rheumatology, Allergy and Rare diseases (UnIRAR), San Raffaele Hospital, Milano, Italy
  12. 12 Department of Rheumatology and Clinical Immunology, University of Giessen, Campus Kerckhoff, Bad Nauheim, Germany
  13. 13 Unidad de Enfermedades Sistémicas, Reumatología, Hospital General de Granollers, Granollers, Spain
  14. 14 Department of Rheumatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
  15. 15 Clinical Medicine and Therapy, Sapienza University of Rome, Roma, Italy
  16. 16 Rheumatology, Ghent University Hospital, Gent, Belgium
  17. 17 Department of Dermatology, Copenhagen University Hospital, Bispebjerg, Denmark
  18. 18 Department of Rheumatology, University Hospital Basel, Basel, Switzerland
  19. 19 Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Dr Sabina Guler, Department of Pulmonary Medicine, Inselspital University Hospital Bern, Bern, Bern, Switzerland; Sabina.Guler{at}insel.ch

Abstract

Background Systemic sclerosis (SSc) is a heterogeneous disease with frequently associated interstitial lung disease (SSc-ILD). We aimed to determine the prognostic potential of phenotyping patients with SSc and SSc-ILD by inflammation and to describe disease trajectories stratified by inflammation and immunosuppressive treatment.

Methods Patients from the European Scleroderma Trials and Research (EUSTAR) group cohort were allocated to persistent inflammatory, intermediate and non-inflammatory phenotypes if C-reactive protein (CRP) levels were ≥5 mg/L at ≥80%, at 20–80% and at <20% of visits, respectively. Cox regression models were used to analyse mortality risk and mixed effect models to describe trajectories of FVC and diffusing capacity for carbon monoxide (DLCO) %-predicted stratified by inflammation and immunosuppressive treatment.

Results 2971 patients with SSc and 1171 patients with SSc-ILD had at least three CRP measurements available. Patients with SSc-ILD with a persistent inflammatory phenotype had a 6.7 times higher risk of mortality within 5 years compared with those with a persistent non-inflammatory phenotype (95% CI 3 to 15). In the inflammatory phenotype, FVC %-predicted was declining without (−1.11 (95% CI −2.14 to −0.08)/year), but stable with immunosuppressive treatment (−0.00 (95% CI −0.92 to 0.92)/year). In the non-inflammatory phenotype, patients with and without immunosuppressive treatment had a significant decline in FVC %-predicted, which was more pronounced in those with immunosuppressive treatment (−1.26 (95% CI −1.87 to −0.64) and −0.84 (95% CI −1.35 to −0.33)/year, respectively).

Conclusions Phenotyping by persistent inflammation provides valuable prognostic information, independent of demographics, disease duration, cutaneous subtype, treatment and SSc-ILD severity. The findings from this study support early immunosuppressive treatment in patients with SSc-ILD with persistent inflammation.

  • Rheumatoid lung disease
  • Systemic disease and lungs
  • Interstitial Fibrosis

Data availability statement

Data are available upon reasonable request. Requests to access the data analysed in this project can be addressed to the EUSTAR board.

https://doi.org/10.1136/thorax-2023-220541

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    Data availability statement

    Data are available upon reasonable request. Requests to access the data analysed in this project can be addressed to the EUSTAR board.

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    Footnotes

    • SG and A-CS are joint first authors.

    • Twitter @SabinaAGuler

    • SG and A-CS contributed equally.

    • Contributors SG is the guarantor of the study and responsible for the overal content of the manuscript. SG, A-CS, BM and FK contributed to the conception and design of the study, and acquisition, analysis and interpretation of the data. OS contributed to analysis of the data. YA, VB, JD, AG, A-MH-V, MM-C, UM-L, VO-S, SR, VR, VS, SU, UAW, TKG and OD contributed to the acquisition and interpretation of the data. All authors revised the manuscript for important intellectual content and provided final approval of the version to be published. SG and A-CS contributed equally to this paper.

    • Funding This study was funded by Stiftung Lindenhof, Bern, Switzerland.

    • Competing interests SG reports grants, contracts, consulting or lecture fees from Roche, MSD, Boehringer Ingelheim, and support for this study from the Stiftung Lindenhof, Bern, Switzerland. YA reports grants, contracts, consulting or lecture fees from Medsenic, Alpine ImmnunoSciences, Boehringer, Astra-Zeneca, Galderma, Prometheus, Abbvie, Chugai, Benevolent. JHWD has received research funding from Anamar, ARXX, BMS, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, Galapagos, GSK, Inventiva, Kiniksa, Sanofi-Aventis, RedX, UCB. JD is stock owner of 4D Science. JD has consultancy relationships with AbbVie, Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Janssen, Novartis, Pfizer, and UCB. Scientific lead of FibroCure. AG reports grants or contracts from Janssen, Boehringer Ingelheim, Roche. A-MH-V reports grants, contracts, consulting or lecture fees from ARXX, Boehringer Ingelheim, Janssen, Medscape, Roche, Genentech, Bayer, Lilly, Merck Sharp & Dohme. MMC reports consulting or lecture fees from Sandoz, Biogen, Boehringer. SR reports grants, contracts, consulting or lecture fees from Janssen, Novartis, Boehringer Ingelheim, Abbvie, Lilly, Sandoz, Ewopharma, Pfizer, Astra Zeneca, Novartis. VR reports consulting or lecture fees from MSD, Boehringer Ingelheim. VS reports grants, contracts, consulting or lecture fees from Research Foundation Flanders, Belgian Fund for Scientific Research, Boehringer Ingelheim, Janssen-Cilag, Galapagos. TKG reports consulting or lecture fees Boehringer Ingelheim, Roche. OD reports grants, contracts, consulting or lecture fees from 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Horizon, Inventiva, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Prometheus, Redxpharma, Roivant, Sanofi and Topadur. BM reports grants contracts, consulting or lecture fees from AbbVie, Protagen, Novartis Biomedical Research, Novartis, Boehringer Ingelheim, Janssen-Cilag, GSK, Boehringer-Ingelheim, GSK, Novartis, MSD, Medtalk, Pfizer, Roche, Actelion, Mepha, MSD. FK is a shareholder of Roche, was a consultant of Actelion, BMS, Boehringer-Ingelheim, and Pfizer, had grant/research support from Gilead, Pfizer and Roche, and is employed by Roche. All other authors (A-CS, OS, VB, UM-L, VO-S, SU, UAW) declare no competing interests.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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