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Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor induced myositis
  1. Iago Pinal-Fernandez1,2,
  2. Angela Quintana1,3,
  3. Jose Cesar Milisenda1,4,5,
  4. Maria Casal-Dominguez1,2,
  5. Sandra Muñoz-Braceras1,
  6. Assia Derfoul1,
  7. Jiram Torres-Ruiz1,6,
  8. Katherine Pak1,
  9. Stefania Dell'Orso1,
  10. Faiza Naz1,
  11. Gustavo Gutierrez-Cruz1,
  12. Margherita Milone7,
  13. Shahar Shelly8,
  14. Yaiza Duque-Jaimez4,
  15. Ester Tobias-Baraja4,
  16. Ana Matas-Garcia4,5,
  17. Gloria Garrabou4,5,
  18. Joan Padrosa5,
  19. Javier Ros9,
  20. Ernesto Trallero-Araguás10,
  21. Brian Walitt11,
  22. Lisa Christopher-Stine2,12,
  23. Thomas E Lloyd2,
  24. Chen Zhao13,
  25. Shannon Swift13,
  26. Arun Rajan13,
  27. Josep Maria Grau-Junyent4,5,
  28. Albert Selva-O'Callaghan3,14,
  29. Teerin Liewluck7,
  30. Andrew Lee Mammen1,2,12
  1. 1 Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
  2. 2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  3. 3 Systemic Autoimmune Disease Unit, Vall d'Hebron Research Institute, Barcelona, Catalunya, Spain
  4. 4 Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Catalunya, Spain
  5. 5 CIBERER, IDIBAPS and University of Barcelona, Barcelona, Catalunya, Spain
  6. 6 Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico city, Mexico
  7. 7 Division of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
  8. 8 Department of Neurology, Rambam Health Care Campus, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel, Haifa, Israel
  9. 9 Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Catalunya, Spain
  10. 10 Rheumatology Department, Vall d'Hebron University Hospital, Barcelona, Catalunya, Spain
  11. 11 National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland, USA
  12. 12 Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  13. 13 Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  14. 14 Universitat Autonoma de Barcelona, Barcelona, Catalunya, Spain
  1. Correspondence to Dr Andrew Lee Mammen, Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA; andrew.mammen{at}; Dr Iago Pinal-Fernandez, Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA; iago.pinalfernandez{at}


Objectives Inflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis.

Methods Bulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (seven ICI-myositis, four DM, three AS, six IMNM and two IBM).

Results Unsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1 and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed coexisting myocarditis. ICI-MYO2 was composed of patients with predominant necrotising pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway.

Conclusions We identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICI-DM and ICI-MYO1 and only ICI-MYO1 patients developed myocarditis.

  • polymyositis
  • dermatomyositis
  • autoimmune diseases

Data availability statement

Data are available on reasonable request.

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Data availability statement

Data are available on reasonable request.

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  • Handling editor Josef S Smolen

  • Twitter @DrIagoPinal

  • IP-F, AQ, JCM and MC-D contributed equally.

  • TL and ALM contributed equally.

  • Correction notice This article has been corrected since it published Online First. The ORCID details have been added for Angela Quintana.

  • Contributors All authors contributed to the development of the manuscript, including interpretation of results, substantive review of drafts and approval of the final draft for submission. Dr Mammen and Dr Pinal-Fernandez accept full responsibility for the finished work and the conduct of the study, had access to the data and controlled the decision to publish.

  • Funding This study was funded, in part, by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Cancer Institute (NCI), the Center for Cancer Research of the National Institutes of Health and through a Cooperative Research and Development Agreement between the NCI and EMD Serono Research & Development Institute, Inc, Billerica, Massachusetts, USA, an affiliate of Merck KGaA (CrossRef Funder ID: 10.13039/100004755), as part of an alliance between Merck and Pfizer. This work was also supported by the Peter Buck and the Huayi and Siuling Zhang Discovery Fund.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

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

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