. 2025 Nov 1;64(11):5751-5760.

doi: 10.1093/rheumatology/keaf346.

Distinct cytokine and cytokine receptor expression patterns characterize different forms of myositis

Raphael A Kirou^{1

2}, Iago Pinal-Fernandez^{1

3}, Maria Casal-Dominguez^{1

3}, Katherine Pak¹, Corinna Preusse^{4

5}, Dilbe Dari⁴, Stefania Del Orso⁶, Faiza Naz⁶, Shamima Islam⁶, Gustavo Gutierrez-Cruz⁶, Elie Naddaf⁷, Teerin Liewluck⁷, Werner Stenzel⁴, Albert Selva-O'Callaghan⁸, Jose C Milisenda⁹, Andrew L Mammen^{1

3

10}

Affiliations

¹ Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
² College of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY, USA.
³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
⁵ Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
⁶ Genomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
⁷ Division of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁸ Systemic Autoimmune Diseases Unit, Internal Medicine Department, Vall d'Hebron General Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
⁹ Muscle Research Unit, Internal Medicine Service, Hospital Clinic; Barcelona University; CIBERER and IDIBAPS; Barcelona, Spain.
¹⁰ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

PMID: 40579223
PMCID: PMC12596072
DOI: 10.1093/rheumatology/keaf346

Distinct cytokine and cytokine receptor expression patterns characterize different forms of myositis

Raphael A Kirou et al. Rheumatology (Oxford). 2025.

. 2025 Nov 1;64(11):5751-5760.

doi: 10.1093/rheumatology/keaf346.

Authors

Affiliations

¹ Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
² College of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY, USA.
³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
⁵ Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
⁶ Genomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
⁷ Division of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁸ Systemic Autoimmune Diseases Unit, Internal Medicine Department, Vall d'Hebron General Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
⁹ Muscle Research Unit, Internal Medicine Service, Hospital Clinic; Barcelona University; CIBERER and IDIBAPS; Barcelona, Spain.
¹⁰ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

PMID: 40579223
PMCID: PMC12596072
DOI: 10.1093/rheumatology/keaf346

Abstract

Objective: Myositis is a heterogeneous family of inflammatory myopathies. We sought to define the differential expression of cytokines, cytokine receptors and immune checkpoint genes in muscle biopsies from patients with different forms of myositis in order to characterize patterns of inflammation in each.

Methods: Bulk RNA-sequencing was performed on muscle biopsy samples from 669 patients, including 105 with DM, 80 with immune-mediated necrotizing myopathy (IMNM), 65 with anti-synthetase syndrome, 53 with IBM, 19 with anti-PM/Scl myositis, 310 with other inflammatory or genetic myopathies and 37 controls with normal tissue (NT). Myositis clinical groups and autoantibody subgroups were analysed separately. Expression data were analysed for 338 genes encoding cytokines, cytokine receptors and immune checkpoints. Myositis group-specific genes were identified from this list by finding genes that were specifically differentially expressed in one group compared with all samples and compared with NT (α < 0.001).

Results: IBM patients had the most differentially overexpressed genes (71) among all clinical groups, including 37 that were IBM-specific. Among the top genes were several involved in type 1 inflammation, including CCL5, CXCR3, CCR5, CXCL9 and IFNG. Anti-Jo1 and anti-PM/Scl patients exhibited differential overexpression of a similar set of genes, while DM patients exhibited differential overexpression of a different set of genes involved in type 1 inflammation. IMNM patients had the least number of differentially overexpressed genes with no predominant inflammatory pattern.

Conclusion: Each myositis clinical group and autoantibody subgroup had differentially overexpressed inflammatory mediators, including a strong type 1 inflammatory gene signature in IBM.

Keywords: DM; IBM; RNA-sequencing; cytokines; myositis.

Published by Oxford University Press on behalf of the British Society for Rheumatology 2025.

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Figures

**Figure 1.**
Correlation heatmaps for top differentially overexpressed genes by clinical group vs muscle and leucocyte markers. For all heatmaps, the x-axis displays the top 15 differentially overexpressed genes for that clinical group, or all differentially overexpressed genes if there are <15, ordered from lowest q-value vs all samples to highest. The y-axis displays mature muscle markers (*ACTA1*, *MYH1*, *MYH2*), markers of muscle regeneration (*NCAM1*, *MYOG*, *PAX7*, *MYH3*, *MYH8*), mitochondrial markers (*MT-CO1*, *MT-CO2*), B cell markers (*CD19*, *MS4A1*), T cell markers (*CD3E*, *CD4*, *CD8A*), macrophage markers (*CD14*, *CD68*), dendritic cell markers (*CD1C*, *CD1E*), type 1 markers (*TBX21*, *STAT1*), type 2 markers (*GATA3*, *STAT6*) and type 3 markers (*RORC*, *STAT3*). Heatmaps displayed are for DM (A), IMNM (B), ASyS (C), IBM (D) and PM/Scl (E)

**Figure 2.**
Correlation heatmaps for top differentially overexpressed genes by autoantibody subgroup vs muscle and leucocyte markers. For all heatmaps, the x-axis displays the top 15 differentially overexpressed genes for that autoantibody subgroup, or all differentially overexpressed genes if there are <15, ordered from lowest q-value vs all samples to highest. The y-axis displays mature muscle markers (*ACTA1*, *MYH1*, *MYH2*), markers of muscle regeneration (*NCAM1*, *MYOG*, *PAX7*, *MYH3*, *MYH8*), mitochondrial markers (*MT-CO1*, *MT-CO2*), B cell markers (*CD19*, *MS4A1*), T cell markers (*CD3E*, *CD4*, *CD8A*), macrophage markers (*CD14*, *CD68*), dendritic cell markers (*CD1C*, *CD1E*), type 1 markers (*TBX21*, *STAT1*), type 2 markers (*GATA3*, *STAT6*) and type 3 markers (*RORC*, *STAT3*). Heatmaps displayed are for Mi2 (A), MDA5 (B), NXP2 (C), TIF1 (D), HMGCR (E), SRP (F) and Jo1 (G)

**Figure 3.**
Heatmap of type 1, type 2 and type 3 gene expression by group. The heatmap displays median expression levels of type 1, type 2 and type 3 genes for each group. Groups included are all autoantibody subgroups (Mi2, MDA5, NXP2, TIF1, HMGCR, SRP, Jo1, PM/Scl), as well as IBM (no autoantibody subgroup) and NT (control)

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Update of

Distinct Cytokine and Cytokine Receptor Expression Patterns Characterize Different Forms of Myositis.
Kirou RA, Pinal-Fernandez I, Casal-Dominguez M, Pak K, Preusse C, Dari D, Del Orso S, Naz F, Islam S, Gutierrez-Cruz G, Naddaf E, Liewluck T, Stenzel W, Selva-O'Callaghan A, Milisenda JC, Mammen AL. Kirou RA, et al. medRxiv [Preprint]. 2025 Feb 21:2025.02.17.25321047. doi: 10.1101/2025.02.17.25321047. medRxiv. 2025. Update in: Rheumatology (Oxford). 2025 Nov 1;64(11):5751-5760. doi: 10.1093/rheumatology/keaf346. PMID: 40034760 Free PMC article. Updated. Preprint.

References

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1. Pinal-Fernandez I, Casal-Dominguez M, Derfoul A et al. Machine learning algorithms reveal unique gene expression profiles in muscle biopsies from patients with different types of myositis. Ann Rheum Dis 2020;79:1234–42. - PMC - PubMed
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Distinct cytokine and cytokine receptor expression patterns characterize different forms of myositis

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Distinct cytokine and cytokine receptor expression patterns characterize different forms of myositis

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