Yves Allenbach1, Céline Anquetil2, Ali Manouchehri3, Olivier Benveniste2, Olivier Lambotte4, Bénédicte Lebrun-Vignes5, Jean-Philippe Spano6, Stéphane Ederhy7, David Klatzmann8, Michelle Rosenzwajg8, Bruno Fautrel9, Jacques Cadranel10, Douglas B Johnson3, Javid J Moslehi3, Joe-Elie Salem11. 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.
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.
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.
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