ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1862

Comprehensive analysis of the major histocompatibility complex in systemic sclerosis-associated interstitial lung disease identifies novel associated loci and potential progression biomarkers

Carlos de la Rosa Báez1, Carlos Rangel Peláez1, Inmaculada Rodríguez Martín1, Martin Kerick1, Alfredo guillen-del-castillo2, Carmen Pilar Simeon3, Jose Luis Callejas4, Alexandre Voskuijl5, Alexander Kreuter6, Oliver Distler7, Susanna Proudman8, Mandana Nikpour9, Nicolas Hunzelmann10, Jeska de Vries-Bouwstra11, Ariane Herrick12, Yannick Allanore13, Lorenzo Beretta14, Maureen Mayes15, Christopher Denton16, Shervin Assassi17, Javier Martin1 and Marialbert Acosta-Herrera1, 1Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain, 2Unit of Autoimmune Diseases, Department of Internal Medicine, Hospital Universitario Vall d’Hebron, Barcelona, Spain, 3Department of Internal Medicine, Hospital Universitario Vall d’Hebron, Barcelona, Spain, 4Department of Internal Medicine, Hospital San Cecilio, Granada, Spain, 5Amsterdam University Medical Center, Amsterdam, Netherlands, 6Department of Dermatology, Venereology, and Allergology, Helios St. Elisabeth Klinik Oberhausen, University Witten-Herdecke, Oberhausen, Germany, 7Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland, Zurich, Switzerland, 8Royal Adelaide Hospital and University of Adelaide, Medindie, South Australia, Australia, 9University of Sydney School of Public Health and Department of Rheumatology, Royal Prince Alfred Hospital, Sydney, Victoria, Australia, 10Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany, 11Leiden University Medical Center, Leiden, Netherlands, 12The University of Manchester, UK, Aberdeen, United Kingdom, 13Department of Rheumatology, Université Paris Cité UFR de Médecine, Paris, France, 14Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, 15UT Health Houston Division of Rheumatology, Houston, TX, 16University College London, UK, London, United Kingdom, 17Division of Rheumatology, UTHealth Houston, Houston, Texas, USA, Houston, TX

Meeting: ACR Convergence 2025

Keywords: , ,

Session Information

Date: Tuesday, October 28, 2025

Title: (1855–1876) Systemic Sclerosis & Related Disorders – Basic Science Poster II

Session Type: Poster Session C

Session Time: 10:30AM-12:30PM

Background/Purpose: The main causes of death in systemic sclerosis (SSc) are pulmonary complications such as SSc-associated interstitial lung disease (SSc-ILD). SSc-ILD is highly heterogeneous and difficult to manage. Although several studies have proven the crucial role of genetics in SSc susceptibility, especially in the major histocompatibility complex (MHC) region, genetic research focusing on SSc-ILD patients is scarce, with limited sample size and statistical power. Considering this, we aimed to conduct a comprehensive MHC genetic scan in the largest cohort of SSc-ILD to date, encompassing a total of 2,363 SSc-ILD patients, 3,526 SSc patients without ILD, and 15,026 controls from 10 international cohorts of European ancestry.

Methods: After genotypic quality controls, the MHC region was imputed using the human leukocyte antigen (HLA) imputation tool from the Michigan Imputation Server. Variants with imputation quality > 0.3 and minor allele frequency > 0.01 were considered for association analyses. Logistic regressions were performed adjusting for the first five principal components and sex, considering two comparisons: SSc-ILD vs SSc patients without ILD, and SSc-ILD vs controls. Finally, inverse variance weighted meta-analyses were performed. To identify jointly significant variants, conditional stepwise analyses were carried out separately for HLA classical alleles, polymorphic amino acid positions (AAs), and single nucleotide polymorphisms (SNPs).

Results: Results from the meta-analyses identified 2,966 significant variants associated with SSc-ILD when compared to SSc patients without ILD, and 5,610 variants when compared to controls. After conditional analysis, the most significant associations mapped in class II HLA genes, such as HLA-DQA1*01:01:01:01 (odds ratio [OR] = 0.54 and 95% confidence interval [95%CI] [0.48 – 0.61] p-value = 3.41 x 10-21) and, interestingly, we also found novel associated variants implicating class I HLA genes as HLA-B*35:02:01:01 (OR = 2.44 [1.81 – 3.29], p-value = 5.64 x 10-9), HLA-C*07:01:01:01 (OR = 1.30 [1.19 – 1.42], p-value = 1.54 x 10-9), and the serine substitution in position 24 of HLA-B (OR = 1.28 [1.18 – 1.39], p-value = 4.44 x 10-9).

Conclusion: In this study, we identify for the first time class I HLA associated with SSc-ILD. These results emphasize the potential role for CD8⁺ T cell mediated cytotoxicity in the pathogenesis of this clinical manifestation. Risk variants in class I HLA region may contribute to the unpaired immune response and tissue injury in the lungs, leading to inflammation and fibrosis. These findings could have significant clinical implications, with potential role as progression biomarkers in SSc patients with lung involvement.

Disclosures: C. de la Rosa Báez: None; C. Rangel Peláez: None; I. Rodríguez Martín: None; M. Kerick: None; A. guillen-del-castillo: None; C. Simeon: None; J. Callejas: None; A. Voskuijl: None; A. Kreuter: None; O. Distler: 4P-Pharma, 2, 6, AbbVie/Abbott, 2, 6, Acceleron, 2, 6, Acepodia Biotech, 2, 6, Aera, 2, 6, AnaMar, 2, 6, Anaveon AG, 2, 6, Argenx, 2, 6, AstraZeneca, 2, 6, BMS, 2, 5, 6, Calluna (Arxx), 2, 6, Cantargia AB, 2, 6, CITUS AG, 8, CSL Behring, 2, 6, EMD Serono, 2, 6, Galapagos, 2, 6, Galderma, 2, 6, Gossamer, 2, 6, Hemetron, 2, 5, 6, Innovaderm, 2, 5, 6, Janssen, 2, 6, Mediar, 2, 5, 6, mir-29 for the treatment of systemic sclerosis, 10, Mitsubishi Tanabe, 2, 5, 6, MSD Merck, 2, 6, Nkarta Inc., 2, 6, Novartis, 2, 6, Orion, 2, 6, Pilan, 2, 6, Prometheus, 2, 6, Quell, 2, 6, Sumitomo, 2, 5, 6, Topadur, 2, 5, 6, UCB, 2, 5, 6; S. Proudman: Boehringer-Ingelheim, 5, 6, Janssen, 5, 6, Merck/MSD, 1; M. Nikpour: AstraZeneca, 2, 6, Boehringer Ingelheim, 2, 5, 6, GSK, 2, 6, Janssen Pharmaceuticals, 2, 5, 6; N. Hunzelmann: None; J. de Vries-Bouwstra: AbbVie/Abbott, 2, 6, Boehringer-Ingelheim, 2, 6, Jannsen-Cilag, 5, Janssen, 2, 6, Roche, 5; A. Herrick: Abbvie, 2, Boehringer-Ingelheim, 2, Janssen, 2, 6, Zura Bio, 2; Y. Allanore: None; L. Beretta: None; M. Mayes: Argenx, 2, AstraZeneca, 5, atyr, 5, Boehringer-Ingelheim, 5, Bristol-Myers Squibb(BMS), 1, 5, h, 5, Novartis, 2, prometheus merck, 5; C. Denton: AbbVie/Abbott, 2, Boehringer-Ingelheim, 2, Certa Pharmaeuticals, 2, GlaxoSmithKlein(GSK), 2, Janssen, 2, Novartis, 2; S. Assassi: AbbVie, 2, AstraZeneca, 2, aTyr, 2, 5, Boehringer Ingelheim, 2, 5, 6, 12, Medical writing support provided by Fleishman Hillard, CSL Behring, 2, Janssen, 5, Merck, 2, Mitsubishi Tanabe, 2, PeerView Institute for Medical Education, 6, Scleroderma Research Foundation, 5, 6, Takeda, 2, TeneoFour, 2; J. Martin: None; M. Acosta-Herrera: None.

To cite this abstract in AMA style:

de la Rosa Báez C, Rangel Peláez C, Rodríguez Martín I, Kerick M, guillen-del-castillo A, Simeon C, Callejas J, Voskuijl A, Kreuter A, Distler O, Proudman S, Nikpour M, Hunzelmann N, de Vries-Bouwstra J, Herrick A, Allanore Y, Beretta L, Mayes M, Denton C, Assassi S, Martin J, Acosta-Herrera M. Comprehensive analysis of the major histocompatibility complex in systemic sclerosis-associated interstitial lung disease identifies novel associated loci and potential progression biomarkers [abstract]. Arthritis Rheumatol. 2025; 77 (suppl 9). https://acrabstracts.org/abstract/comprehensive-analysis-of-the-major-histocompatibility-complex-in-systemic-sclerosis-associated-interstitial-lung-disease-identifies-novel-associated-loci-and-potential-progression-biomarkers/. Accessed .

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/comprehensive-analysis-of-the-major-histocompatibility-complex-in-systemic-sclerosis-associated-interstitial-lung-disease-identifies-novel-associated-loci-and-potential-progression-biomarkers/