Autoantibody Profiles of Immune Checkpoint Inhibitor-Associated Myasthenia and Myositis
Tomoya Kawazoe, Toshiki Tezuka, Keisuke Ishizawa, Yoshiyuki Matsuki, Masatoshi Kawai, Akihito Hao, Takanobu Iri, Hiroshi Yaguchi, Funato Sato, Morinobu Seki, Kazushi Takahashi, Shigeaki SuzukiIntroduction
Immune checkpoint inhibitor (ICI)-associated myasthenia and myositis are rare, potentially life-threatening neuromuscular immune-related adverse events, but their serological spectrum remains incompletely characterized. This study aimed to elucidate their autoantibody profiles and explore associations with severe clinical features.
Methods
This retrospective, multicenter, serum-repository-based observational cohort study included 50 patients with ICI-associated myasthenia and myositis referred from institutions throughout Japan. Clinical data and serum samples were analyzed using conventional autoantibody assays, cytometric cell-based assays, RNA immunoprecipitation, and immunohistochemistry. Antibody–outcome associations were evaluated exploratorily using Firth logistic regression.
Results
Among 50 patients, the median age was 71.5 years, and 35 (70%) were male. Two patients had preexisting thymoma-associated myasthenia. Underlying malignancies were diverse and included thoracic, gastrointestinal, urological, and other cancers. All but one patient received programmed cell death protein-1 inhibitors. The median interval from the first ICI administration to symptom onset was 31.5 days, although 7 patients showed delayed onset beyond 62 days. Severe toxicity, defined as Common Terminology Criteria for Adverse Events (CTCAE) grade 4 or 5, occurred in 15 patients, respiratory insufficiency in 12, and myocarditis in 9. Anti-acetylcholine receptor (AChR) antibodies were detected in 9 patients (18%) and showed exploratory associations with severe toxicity and respiratory insufficiency, although anti-muscle-specific kinase antibodies were not detected. Among striational antibodies, anti-titin and anti-Kv1.4 antibodies were detected in 21 and 22 patients, respectively. Anti-Kv1.4 antibodies showed an exploratory association with myocarditis. All 7 weak myositis-specific immunodot reactivities involved RNA-associated targets and lacked corresponding RNA immunoprecipitates. Reactivity on commercial paraneoplastic neurological syndrome (PNS) immunodot assays, accompanied by supportive neuronal tissue reactivity, was observed in 5 patients without classical PNS manifestations.
Conclusion
In this retrospective referral cohort, anti-AChR and anti-Kv1.4 reactivities showed exploratory associations with selected severe clinical features. These findings require prospective external validation.