Immune checkpoint inhibitor-induced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities

Yves Allenbach; Céline Anquetil; Ali Manouchehri; Olivier Benveniste; Olivier Lambotte; Bénédicte Lebrun-Vignes; Jean-Philippe Spano; Stéphane Ederhy; David Klatzmann; Michelle Rosenzwajg; Bruno Fautrel; Jacques Cadranel; Douglas B Johnson; Javid J Moslehi; Joe-Elie Salem

doi:10.1016/j.autrev.2020.102586

Immune checkpoint inhibitor-induced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities

Autoimmun Rev. 2020 Aug;19(8):102586. doi: 10.1016/j.autrev.2020.102586. Epub 2020 Jun 11.

Authors

Affiliations

¹ Department of Internal Medicine and Clinical Immunlogy, Sorbonne Université, Pitié-Salpêtrière University Hospital, Paris, France; Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Association Institut de Myologie, Centre de Recherche en Myologie, UMRS974 Paris, France. Electronic address: yves.allenbach@aphp.fr.
² Department of Internal Medicine and Clinical Immunlogy, Sorbonne Université, Pitié-Salpêtrière University Hospital, Paris, France; Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Association Institut de Myologie, Centre de Recherche en Myologie, UMRS974 Paris, France.
³ Cardio-Oncology Program, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ Department of Internal Medicine and Clinical Immunology, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, Université Paris Sud, Inserm, CEA, UMR, 1184 Le Kremlin-Bicêtre, France.
⁵ Regional Pharmacovigilance Centre, Department of Pharmacology, Sorbonne Université, INSERM CIC Paris-Est, Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.
⁶ Oncology departement, Sorbonne Université, Pitié-Salpêtrière University Hospital, Paris, France.
⁷ Department of cardiology, Saint-Antoine Hospital, APHP. Sorbonne université, Paris, France.
⁸ Department of Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy (i2B), Sorbonne Université, Pitié-Salpêtrière University Hospital, INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (i3), Paris, France.
⁹ Department of Rheumatology, Sorbonne Université, Pitié-Salpêtrière University Hospital, Inserm UMR 1136, Pierre Louis Institute of Health and Epidémiology Paris, France.
¹⁰ Department of Pneumology, Constitutive Center on Rare Pulmonary Diseases, Sorbonne Université, Tenon University Hospital, Paris, France.
¹¹ Cardio-Oncology Program, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Regional Pharmacovigilance Centre, Department of Pharmacology, Sorbonne Université, INSERM CIC Paris-Est, Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France. Electronic address: joe-elie.salem@aphp.fr.

PMID: 32535094
DOI: 10.1016/j.autrev.2020.102586

Abstract

Background: In addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI.

Patients methods: We performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC₀₂₅ (lower end of the IC 95% credibility interval) >0 is deemed significant.

Results: We identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 [11.6-18.4], IC₀₂₅ = 3.34), sarcoidosis (n = 94; ROR = 9.6 [7.9-11.9]; IC₀₂₅ = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 [5.2-9.2]; IC₀₂₅ = 2.24), myositis (n = 465; ROR = 4.9 [4.5-5.4]; IC₀₂₅ = 2.12), arthritis (n = 606; ROR = 1.4 [1.3-1.5]; IC₀₂₅ = 0.34) and scleroderma (n = 17; ROR = 2.0 [1.2-3.2]; IC₀₂₅ = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6-2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1-4.4, p < .05). Median time to onset occurred early for myositis (31 days [19.2-57.8]) and was the most delayed for scleroderma (395 days [323.8-457.2], p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to [0-6.7%] for other RMS-irAE (p < .0001).

Conclusions: Clinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.

Keywords: Adverse drug reactions; Immune checkpoint inhibitors; Myocarditis; Myositis; Pharmacology; Rheumatology.

Publication types

Observational Study

MeSH terms

Antineoplastic Agents, Immunological* / adverse effects
Bayes Theorem
Humans
Myositis* / chemically induced
Myositis* / mortality
Myositis* / pathology
Pharmacovigilance
Retrospective Studies

Substances

Antineoplastic Agents, Immunological