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Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer
Mehdi Touat1, Thierry Maisonobe2, Samuel Knauss2
1From Sorbonne Université (M.T., D.P.), Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, APHP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin; OncoNeuroTox Group (M.T., T.M., N.W., T.L., D.P.), Center for Patients With Neurological Complications of Oncologic Treatments, Hôpitaux Universitaires Pitié-Salpetrière-Charles Foix et Hôpital Percy, Paris, France; Department of Oncologic Pathology (M.T.), Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA; Service de Neuropathologie Raymond Escourolle (T.M., S.L.-L.), Départment de Neurophysiologie Clinique (T.M., T.L., S.L.-L.), Département de Médecine Interne et Immunologie Clinique (B.H., Y.A., O.B.), and Centre de Référence de Pathologie Neuromusculaire Paris-Est (B.H., A.B., Y.A., O.B., S.L.-L.), APHP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Paris, France; Charité-Universitatsmedizin Berlin Klinik fur Neurologie mit Experimenteller Neurologie (S.K.), Experimentelle Neurologie; Centrum fur Schlaganfallforschung Berlin (S.K.), Germany; Service de Réanimation Médicale (O.B.H.S.), Service de Médecine Interne (T.-A.S.), and Département de Dermatologie (N.K.), Hôpital Cochin, APHP, Hôpitaux Universitaires Paris Centre; Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris) (B.H.), Sorbonne Universités; Service d'Explorations Fonctionnelles (K.A.), APHP, Hôpital Ambroise Paré, Boulogne-Billancourt; Service de Pneumologie (C.L.) and Service d'Anatomie Pathologique (J.-F.B.), Centre Hospitalier Chartres-Louis-Pasteur, Le-Coudray; Service de Dermatologie (P.L.), APHP, Hôpital Saint Louis; Service de Pneumologie et Oncologie Thoracique (J.C.), Centre de Compétences pour les Maladies Pulmonaires Rares, APHP, Hôpital Tenon, Sorbonne Universités; Sorbonne Université (N.W.), Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM, Centre de Recherche Saint-Antoine, APHP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Département de Neurologie, Unité de réanimation neurologique; Inserm UMR974 (Y.A., O.B.), Centre de recherche en myologie, Université Pierre-et-Marie-Curie, Sorbonnes Universités, Paris, France; and Department of Neuropathology (W.S.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Germany. mehdi.touat@gmail.com werner.stenzel@charite.de sarah.leonard-louis@aphp.fr.
Objective:
To report the clinicopathologic features and outcome of myositis in patients treated with immune checkpoint inhibitors (ICIs) (irMyositis).
Methods:
We retrospectively analyzed patients diagnosed with irMyositis in tertiary centers in Paris, France, and Berlin, Germany, from January 2015 to July 2017. The main outcomes were clinical manifestations and muscle histology, which included major histocompatibility complex class I (MHC-I), C5b-9, CD3, CD4, CD8, CD20, CD68, programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L) 1, and programmed cell death 1 ligand 2 (PD-L2).
Results:
Ten patients with metastatic cancer were included; median age was 73 (range 56-87) years. Median follow-up duration was 48 (range 16-88) weeks. Six patients developed myositis during nivolumab therapy, 1 patient during pembrolizumab, 1 patient during durvalumab, and 2 patients during combined nivolumab and ipilimumab. Median delay between ICI initiation and myositis onset was 25 (range 5-87) days. Clinical manifestations were dominated by acute or subacute myalgia (8 patients) and limb-girdle (7), axial (7), and oculomotor (7) weakness. Four patients had evidence of myocarditis. In all patients, creatine kinase levels were elevated (median 2,668, range 1,059-16,620 U/L), while anti-acetylcholine receptor and myositis-associated antibodies were negative. Electrodiagnostic studies showed myopathic process without decrement in all patients. Muscle biopsy constantly showed multifocal necrotic myofibers, sarcolemmal MHC-I, and endomysial inflammation, consisting mainly of CD68+ cells expressing PD-L1 and CD8+ cells expressing PD-1. ICI treatment was withdrawn in all patients; 9 patients received immunosuppressive therapy, which consistently led to marked clinical improvement.
Conclusions:
irMyositis presents with remarkably homogeneous and unique clinicopathologic features, expanding the nosologic spectrum of inflammatory myopathies in patients with cancer. ICI withdrawal and treatment with corticosteroids improve outcome.
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