Serum type I interferon score as a disease activity biomarker in patients with diffuse cutaneous systemic sclerosis: a retrospective cohort study

Monique Hinchcliff¹, Dinesh Khanna², Enrico De Lorenzis³, Stefano Di Donato⁴, Antonio Carriero⁴, Rebecca L Ross⁵, Suiyuan Huang⁶, Kathleen A Aren⁷, Elana J Bernstein⁸, Mary Carns⁷, Flavia V Castelino⁹, Robyn T Domsic¹⁰, Tracy M Frech¹¹, Jessica K Gordon¹², Faye N Hant¹³, Ami A Shah¹⁴, Victoria K Shanmugam¹⁵, Virginia D Steen¹⁶, Shervin Assassi¹⁷, Francesco Del Galdo¹⁸

Affiliations

¹ Department of Internal Medicine, Section of Rheumatology, Allergy, and Immunology, Yale School of Medicine, New Haven, CT, USA. Electronic address: Monique.hinchcliff@yale.edu.
² Division of Rheumatology, Scleroderma Program, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
³ Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK; NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK; Division of Rheumatology, Catholic University of the Sacred Heart, Largo Francesco Vito 1, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy.
⁴ Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK; NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
⁵ Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
⁶ Division of Rheumatology, Scleroderma Program, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁷ Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁸ Division of Rheumatology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
⁹ Division of Rheumatology, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Division of Rheumatology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
¹¹ Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Tennessee Valley Health Care System, Nashville, TN, USA.
¹² Department of Rheumatology, Hospital for Special Surgery, New York, NY, USA.
¹³ Division of Rheumatology, Medical University of South Carolina, Charleston, SC, USA.
¹⁴ Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Division of Rheumatology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
¹⁶ Division of Rheumatology, Georgetown Medical Center, Washington DC, USA.
¹⁷ Division of Rheumatology, University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁸ Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK; NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK; Leeds Institute of Rheumatic and Musculoskeletal Medicine and Biomedical Research Centre, Chapel Allerton Hospital, Leeds, UK. Electronic address: f.delgaldo@leeds.ac.uk.

PMID: 40179922
PMCID: PMC12107440 (available on 2026-06-01)
DOI: 10.1016/S2665-9913(24)00403-X

Serum type I interferon score as a disease activity biomarker in patients with diffuse cutaneous systemic sclerosis: a retrospective cohort study

Monique Hinchcliff et al. Lancet Rheumatol. 2025 Jun.

. 2025 Jun;7(6):e403-e414.

doi: 10.1016/S2665-9913(24)00403-X. Epub 2025 Mar 31.

Authors

Affiliations

¹ Department of Internal Medicine, Section of Rheumatology, Allergy, and Immunology, Yale School of Medicine, New Haven, CT, USA. Electronic address: Monique.hinchcliff@yale.edu.
² Division of Rheumatology, Scleroderma Program, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
³ Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK; NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK; Division of Rheumatology, Catholic University of the Sacred Heart, Largo Francesco Vito 1, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy.
⁴ Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK; NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
⁵ Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
⁶ Division of Rheumatology, Scleroderma Program, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁷ Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁸ Division of Rheumatology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
⁹ Division of Rheumatology, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Division of Rheumatology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
¹¹ Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Tennessee Valley Health Care System, Nashville, TN, USA.
¹² Department of Rheumatology, Hospital for Special Surgery, New York, NY, USA.
¹³ Division of Rheumatology, Medical University of South Carolina, Charleston, SC, USA.
¹⁴ Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Division of Rheumatology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
¹⁶ Division of Rheumatology, Georgetown Medical Center, Washington DC, USA.
¹⁷ Division of Rheumatology, University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁸ Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK; NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK; Leeds Institute of Rheumatic and Musculoskeletal Medicine and Biomedical Research Centre, Chapel Allerton Hospital, Leeds, UK. Electronic address: f.delgaldo@leeds.ac.uk.

PMID: 40179922
PMCID: PMC12107440 (available on 2026-06-01)
DOI: 10.1016/S2665-9913(24)00403-X

Abstract

Background: Type I interferon (IFN) pathway activation has been associated with severe systemic sclerosis. We aimed to examine the association of serum IFN scores with disease activity and outcomes in two cohorts of patients with diffuse cutaneous systemic sclerosis.

Methods: In this retrospective cohort study, we included adult (aged >18 years) patients with diffuse cutaneous systemic sclerosis enrolled in the US Prospective Registry of Early Systemic Sclerosis (PRESS; incident cohort) or in the UK observational cohort (Stratification for Risk of Progression in Scleroderma [STRIKE]; prevalent cohort) registries and healthy controls (volunteers). Sera were analysed by Myriad-Rules Based Medicine's Luminex xMAP Technology Multiplex Assay (Austin, TX, USA), and IFN scores were generated using concentrations of CCL2, CCL8, CCL19, CXCL9, CXCL10, and CXCL11. Patients were classified as IFN-high (vs IFN-low) when mean sum of the natural logarithm of the six chemokines was greater than (or within) two standard deviations of healthy controls. The main outcome measures were the baseline and the minimal clinically important differences for modified Rodnan Skin Score, forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLCO), and Health Assessment Questionnaire-Disability Index at 12 months. A person with lived experience of systemic sclerosis was involved in writing the report.

Findings: Patients with diffuse cutaneous systemic sclerosis in the PRESS incident cohort were recruited between April 1, 2012, and Jan 1, 2019, and healthy controls and patients in the STRIKE prevalent cohort were recruited between Dec 1, 2014, and Dec 1, 2018. IFN scores were generated for 110 patients in the incident cohort (mean age 50·2 years [SD 15·0], 76 [69%] women and 34 [31%] men, 87 [79%] White) and 72 patients in the prevalent cohort (mean age 51·7 years [SD 10·9], 50 [69%] women and 22 [31%] men, 64 [89%] White), and 32 healthy controls (mean age 47·0 years [SD 12·4]; 19 [59%] women and 13 [41%] men; 24 [75%] White). 50 (45%) of 110 patients in the incident cohort and 27 (38%) of 72 patients in the prevalent cohort were classified as IFN-high. In the incident cohort, patients classified as IFN-high had worse baseline disease compared with patients classified as IFN-low, as assessed by mean predicted FVC (72·0% [SD 18·9] vs 85·3% [18·5]; p=0·0028), DLCO (56·8% [SD 21·6] vs 76·6% [25·3]; p=0·0008), and median Health Assessment Questionnaire-Disability Index (1·4 [IQR 0·8-2·0] vs 0·8 [0·4-1·5]; p=0·0033). Differences in FVC and DLCO persisted at last follow-up (median 34 months [IQR 19·8- 54·0] for FVC and median 34 months [IQR 22·5- 54·0] for DLCO). In the prevalent cohort, patients classified as IFN-high had a shorter median disease duration (2·2 years [IQR 0·7-8·2] vs 5·0 years [1·9-10·0]; p=0·035) compared to those classified as IFN-low, and worse 12-month lung outcomes independent of baseline FVC or immunosuppression (5% relative worsening of FVC in nine [39%] of 23 patients with IFN-high vs seven [17%] of 41 patients with IFN-low; p=0·051). Moreover, cumulative 5-year mortality was 24·9% (95% CI 14·9-39·7) for IFN-high versus 8·6% (3·6-19·9) for IFN-low (p=0·052).

Interpretation: Serum IFN score assessment for patients with diffuse cutaneous systemic sclerosis could identify patients with high disease activity who are more likely to have worse 12-month prognosis and overall survival.

Funding: National Scleroderma Foundation, National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases Rheumatic Disease Research Core Centers, National Institute of Health Research Leeds Biomedical Research Centre, and Kennedy Trust for Rheumatology Research.

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Conflict of interest statement

Declaration of interests MH has received consultancy fees from AbbVie and has received research grant support from Boehringer Ingelheim and Kadmon for an investigator-initiated research project. She is a member of the National Scleroderma Foundation Tri-State Chapter Medical Advisory Board. DK has research grant support from the National Institutes of Health, US Department of Defense, Boehringer Ingelheim, and Merck, and has received consulting fees from AbbVie, Amgen, Argenx, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta, Certa, Merck, and Zura Bio. He has served on the data safety monitoring and advisory board for AbbVie. EDL received support from Boehringer Ingelheim to attend the 2024 Scleroderma World Congress. RLR has received research support from the National Institute for Health Research. She has received research grants from Mitsubishi Pharma, AbbVie, and Chemomab. EJB has received research grants from Boehringer Ingelheim, Kadmon, and aTyr, has received consulting fees from Boehringer Ingelheim and Gerson Lehrman Group, has received support for travel from Boehringer Ingelheim, and serves on the advisory board for Cabaletta and Boehringer Ingelheim. FVC has participated in clinical trials funded by Boehringer Ingelheim, Prometheus, and Genentech. She has received consulting fees from Boehringer Ingelheim and Mediar Therapeutics. RTD has received consulting fees from Aisa Pharmaceuticals and AstraZeneca. She is a scientific advisory board member for CSL Behring and serves on the data safety and monitoring board for Aisa Pharmaceuticals. She holds a leadership position in the Scleroderma Clinical Trials Consortium. TMF is a member of the National Scleroderma Foundation Advisory Board and serves on the board of the Scleroderma Clinical Trials Consortium. JKG has received research grants from Merck and Cumberland Pharmaceuticals. She serves on the medical advisory board for the Scleroderma Foundation and the Scientific Committee–CONQUER Group–Scleroderma Research Foundation. AAS receives grant support from National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases; US Department of Defense; and the Scleroderma Research Foundation. She received support to conduct clinical trials from Medpace, Eicos Sciences, Arena Pharmaceuticals, and Kadmon Corporation. The work described in this manuscript was completed while VKS was employed at The George Washington University Medical Faculty Associates. VDS has grant or contracts from Kadmon, Prometheus, Genentech, GSK, Sanofi, Eicos, Roche, and Biogen. She has received consulting fees from Boehringer Ingelheim, GSK, Eicos, and CSL Behring, and honoraria from Janssen. She participates on the data safety monitoring board for Boehringer Ingelheim. SA has received research grant support from the National Scleroderma Foundation. He has research grants from Janssen, Boehringer Ingelheim, and aTyr. He has received consultancy fees from Boehringer Ingelheim, AstraZeneca, aTyr, CSL Behring, TeneoFour, Merck, and AbbVie. He has received honoraria from Cleveland Review of Rheumatic Diseases and the State of Texas Association of Rheumatologists. He has membership roles (unpaid volunteer) in the National Scleroderma Foundation, the American Rheumatology Association, and the Scleroderma Clinical Trials Consortium. He has received medical writing assistance for projects with Boehringer Ingelheim and AstraZeneca. FDG has received grant support from Leeds National Institute for Health Research Biomedical Research Centre and Kennedy Trust for Rheumatology Research Program Foundation. All other authors declare no competing interests.

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Serum type I interferon score as a disease activity biomarker in patients with diffuse cutaneous systemic sclerosis: a retrospective cohort study

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Serum type I interferon score as a disease activity biomarker in patients with diffuse cutaneous systemic sclerosis: a retrospective cohort study

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