Immune Checkpoint Inhibitor–Associated Myositis: Expanding the Spectrum of Cardiac Complications of the Immunotherapy Revolution

Abstract

◼ myositis I mmune checkpoint inhibitors (ICIs) provide frequent durable responses and improve patient overall survival in numerous cancers.Blocking immune checkpoints (Programmed cell Death 1 [PD-1]/PD-ligand 1 or Cytotoxic T Lymphocyte-Associated Protein 4 [CTLA-4]) to restore antitumor immune response may also break immune tolerance to self-antigens and induce specific immune-related adverse events (irAEs). 1 Most patients experience at least 1 irAE during therapy, but treatment-related mortality is <1% to 2%. 2 irAEs most commonly affect the skin, gastrointestinal tract, and endocrine organs, but ICI-associated myocarditis is a major cause of ICI-associated mortality.3 It is interesting to note that the initial descriptions of ICIassociated myocarditis described 25% of concomitant myositis.To date, ≈10 cases of myositis, characterized by muscle weakness, high creatine kinase levels, and muscular inflammatory infiltrates, have been reported.It is intriguing that ICI-associated myositis may present with typical muscle inflammation symptoms, and ocular symptoms, as well, that are similar to those observed in autoimmune disorders of the neuromuscular junction (myasthenia gravis).4 With the increased rate of ICI use, improvement in recognition, description, and management of muscular irAEs is required.We used VigiBase (http://www.vigiaccess.org/),the World Health Organization database of individual safety case reports maintained by the Uppsala Monitoring Center in Sweden.Through March 25, 2018, we identified 180 cases of myositis by using the High Level Term "Muscle infections and inflammations" of the Medical Dictionary for Regulatory Activities terms and then refined the search with "Myositis" as Preferred Term.We included 7 approved ICIs in the search: nivolumab, pembrolizumab, ipilimumab, tremelimumab, avelumab, durvalumab, and atezolizumab.Myocarditis was defined by selection of myocarditis at preferred term level using Medical Dictionary for Regulatory Activities in the individual safety case reports.Institutional review board approval was not required (no intervention with human subjects or access to identifiable information).Affected patients had a median age of 71 years (range, 29-90 years, data available in 134/180 reports) and had most often been treated for melanoma or lung cancer.Eighty-five percent of patients were treated with ICI monotherapy (Table ).Precise timing to myositis onset was available in 61 patients.In these patients, the median time of myositis onset was 26 days (range, 18-39 days) after the initial exposure to ICIs.Among all patients with myositis, 16.1% (n=29) also presented with myocarditis and 15.6% (n=28) presented with myasthenia gravis-like symptoms.Both myocarditis and myasthenia gravis-like symptoms occurred in 3.3% (n=6) of those with myositis.Other concurrent irAEs included hepatitis (n=14), colitis (n=3), thyroiditis (n=3), nephritis (n=3), and hypophysitis (n=2).