0283: Transcriptomic Profiles in Muscle Biopsies from Systemic Sclerosis Patients with Different Autoantibodies

Maria Casal-Dominguez¹, Jose Cesar Milisenda², Iago Pinal-Fernandez¹, Katherine Pak³, Sandra Muñoz-Braceras¹, Jose Jiram Torres-Ruiz¹, Stefania Dell´Orso⁴, Faiza Naz⁴, Gustavo Gutierrez-Cruz⁴, Shamima Islam¹, Yaiza Duque-Jaimez², Ana Matas-Garcia², Francesc J Garcia-Garcia², Mariona Guitart-Manpel², Gloria Garrabou², Ernesto Trallero-Araguas⁵, Brian Wallit⁶, Lisa Christopher-Stine⁷, Tom Lloyd⁸, Alfredo Guillen-Del-Castillo⁹, Carmen Pilar Simeon-Aznar¹⁰, Josep Maria Grau², Albert Selva-O’Callaghan⁵ and Andrew Mammen¹¹, ¹Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ²Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain, ³National Institutes of Health, Bethesda, MD, ⁴National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ⁵Systemic Autoimmune Disease Unit, Vall d’Hebron Institute of Research, Barcelona, Spain, ⁶National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD, ⁷Johns Hopkins University, Baltimore, MD, ⁸Johns Hopkins University School of Medicine, Baltimore, MD, ⁹Unit of Autoimmune Diseases, Department of Internal Medicine, Hospital Universitario Vall d'Hebron, Barcelona, Spain, ¹⁰Department of Internal Medicine, Systemic Autoimmune Diseases Unit, Hospital Universitario Vall d'Hebronh, Barcelona, Spain, ¹¹NIH, Bethesda, MD

Background/Purpose: The inflammatory myopathies (IM) include dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), inclusion body myositis (IBM), and overlap myositis (OM), in which IM exists in the context of another rheumatologic disease, such as systemic sclerosis (SSc).

The objective of this study was to define the transcriptomic profiles of muscle tissue from patients with OM-SSc and to compare these with the transcriptomic profiles of muscle tissue from patients with other types of IM as well as healthy volunteers.

Methods: Bulk RNA sequencing was performed on muscle biopsies obtained from(a) OM-SSc patients with defined SSc autoantibodies recognizing PMScl, Scl70, or centromeric autoantigens, (b) patients with DM, AS, IMNM, IBM, and (c) healthy volunteers.

Results: In muscle biopsies from patients with OM-SSc, there was upregulation of genes associated with type I interferon (IFN) signaling (ISG15, MX1), type II IFN signaling (GBP2, PSMB8, IFI30), muscle regeneration (NCAM1, MYH3, MYH8, MYOD, MYOG, PAX7), immunoglobulin production (IGH1, IGH2, IGH3, IGHM, IGHA2), and specific types of immune cells (CD3E, CD4, CD8B, CD14, CD68, CD19, and CD20). The upregulation of these genes was more pronounced in biopsies from patients with OM-SSc who had anti-PMScl autoantibodies compared to those with other SSc autoantibodies. Specifically, the upregulation of type I IFN-associated genes in biopsies from patients with anti-PmScl was intermediate, resembling that observed in biopsies from patients with AS, while type II IFN-associated upregulation was high and comparable in biopsies from patients with AS and IBM. Conversely, structural muscle genes such as MYH1, MYH2, ACTA, and TTN, were downregulated in patients with all types of autoantibody-defined OM-SSc.

Conclusion: Muscle tissue from patients with OM-SSc exhibit significant upregulation of interferon type I and II signaling, immunoglobulin production, muscle regeneration-related genes, and immune cell markers. Notably, these gene expression changes are more pronounced in muscles from patients with SSc who had anti-PMScl autoantibodies compared to those with anti-Scl70 and anti-centromere autoantibodies. These findings contribute to our understanding of the molecular mechanisms underlying SSc and provide insights into potential therapeutic targets.


M. Casal-Dominguez: None; J. Milisenda: None; I. Pinal-Fernandez: None; K. Pak: None; S. Muñoz-Braceras: None; J. Torres-Ruiz: None; S. Dell´Orso: None; F. Naz: None; G. Gutierrez-Cruz: None; S. Islam: None; Y. Duque-Jaimez: None; A. Matas-Garcia: None; F. Garcia-Garcia: None; M. Guitart-Manpel: None; G. Garrabou: None; E. Trallero-Araguas: None; B. Wallit: None; L. Christopher-Stine: None; T. Lloyd: None; A. Guillen-Del-Castillo: None; C. Simeon-Aznar: None; J. Grau: None; A. Selva-O’Callaghan: None; A. Mammen: None.