| Autor: |
Beecher G; From the Division of Neurology (G.B.), Department of Medicine, University of Alberta, Edmonton, Canada; Muscle Disease Section (I.P.-F., A.L.M.), National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda; Department of Neurology (I.P.-F., A.L.M.), Johns Hopkins University School of Medicine, Baltimore, MD; and Department of Neurology (T.L.), Mayo Clinic, Rochester, MN., Pinal-Fernandez I; From the Division of Neurology (G.B.), Department of Medicine, University of Alberta, Edmonton, Canada; Muscle Disease Section (I.P.-F., A.L.M.), National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda; Department of Neurology (I.P.-F., A.L.M.), Johns Hopkins University School of Medicine, Baltimore, MD; and Department of Neurology (T.L.), Mayo Clinic, Rochester, MN., Mammen AL; From the Division of Neurology (G.B.), Department of Medicine, University of Alberta, Edmonton, Canada; Muscle Disease Section (I.P.-F., A.L.M.), National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda; Department of Neurology (I.P.-F., A.L.M.), Johns Hopkins University School of Medicine, Baltimore, MD; and Department of Neurology (T.L.), Mayo Clinic, Rochester, MN., Liewluck T; From the Division of Neurology (G.B.), Department of Medicine, University of Alberta, Edmonton, Canada; Muscle Disease Section (I.P.-F., A.L.M.), National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda; Department of Neurology (I.P.-F., A.L.M.), Johns Hopkins University School of Medicine, Baltimore, MD; and Department of Neurology (T.L.), Mayo Clinic, Rochester, MN. |
| Abstrakt: |
Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of several malignancies, with improved survival. These monoclonal antibodies target immune checkpoints, including cytotoxic T-lymphocyte-associated protein 4 (ipilimumab and tremelimumab), programmed death 1 (nivolumab, pembrolizumab, cemiplimab, and dostarlimab), programmed death ligand 1 (atezolizumab, avelumab, and durvalumab), and lymphocyte activation gene 3 (relatlimab), and effectively augment the immune response against tumor cells. Releasing the brakes on the immune system has consequences, however, in the form of immune-related adverse events (irAEs), which may affect any organ. Neurologic irAEs represent 1%-3% of all irAEs, with immune-mediated myopathy (ICI myopathy) being the most common manifestation. Recent large patient series and systematic reviews have established the key features and highlighted new insights into ICI myopathy. ICI myopathy is characterized by an acute or subacute onset of oculobulbar and/or proximal limb weakness, with or without associated respiratory insufficiency and myocarditis. Creatine kinase elevation is common. Oculobulbar presentations with or without respiratory failure may be misattributed to neuromuscular junction disorders, particularly because acetylcholine receptor antibodies are present in up to 40% of patients; however, an electrodiagnostic evidence of a defect of neuromuscular transmission is often absent even in patients with severe weakness, highlighting that the myopathic process is the driving force behind these presentations. Muscle histopathology commonly demonstrates a unique signature of multifocal clusters of necrotic and regenerating fibers, differentiating ICI myopathy from other autoimmune myopathies. Transcriptomic analysis has uncovered distinct subgroups within ICI myopathy, revealing varying degrees of type 1 and type 2 interferon pathway activation alongside notable upregulation of the interleukin (IL)-6 pathway in affected muscle tissue. This discovery presents a promising avenue for intervention through the use of therapies that suppress the interferon pathway and target IL-6 or its receptor. Despite clinical improvements with immunomodulatory therapy, with corticosteroids the mainstay of treatment, mortality remains high, particularly in those with associated myocarditis or respiratory failure requiring intubation, where mortality occurs in up to 50%. ICI withdrawal can lead to cancer progression and death, highlighting a need for improved approaches to ICI rechallenge, performed in limited patients with variable success to date. |
