Comparative Study of Sporadic and Immune Checkpoint Inhibitor-Related Forms of Myasthenia Gravis-Myositis Overlap Syndrome

BACKGROUND AND OBJECTIVES: Myasthenia gravis-inflammatory myopathy (MG-IM) overlap syndrome can occur as an immune-related adverse event (irAE) after immune checkpoint inhibitor (ICI) therapy. Before the advent of ICIs, a sporadic form of MG-IM (s-MG-IM), often thymoma-associated, was already described. This study compared clinical and serologic features, treatment strategies, and outcomes of s-MG-IM and ICI-related MG-IM (ir-MG-IM). METHODS: We conducted a multicenter, retrospective cohort study across 8 Italian centers, including consecutive patients fulfilling established criteria for both MG and IM, with or without previous exposure to ICIs. Clinical features, antibody profiles, oncologic history, treatments, and outcomes were collected and compared. Available serum samples were tested for binding capacity and pathogenic properties (antigenic modulation and complement-activating capacity) against clustered adult (A) and fetal (F) AChR isoforms using a live cell-based assay (L-CBA). RESULTS: Thirty-eight patients were identified (19 with s-MG-IM and 19 with ir-MG-IM). The ir-MG-IM cohort was older (median 77 vs 59 years, p < 0.001), predominantly male (84.2% vs 47.4%), and exclusively presented with concurrent MG/IM onset, whereas s-MG-IM often manifested sequentially. Thymoma was detected in 73.7% of patients with s-MG-IM but in none of the ir-MG-IM group. CK levels were higher in the ir-MG-IM cohort (median 3,145 vs 1,000 U/L, p = 0.001). Myocarditis, orbital myositis, and severe bulbar/respiratory involvement were more frequent in the ir-MG-IM cohort (p < 0.05). Anti-AChR antibodies were found in all patients with s-MG-IM and in 68% of patients with ir-MG-IM. Exploratory in vitro assays showed antigenic modulation and complement activation in s-MG-IM serum samples (8/9), whereas no activity was detected in the ir-MG-IM samples tested (0/4). Anti-titin antibodies were identified in 85.7% of patients with s-MG-IM (all thymoma-associated) and 50% of patients with ir-MG-IM. Acute mortality occurred in 36.8% of patients with ir-MG-IM and in no patients with s-MG-IM (p < 0.01). Relapses occurred in 63.2% of patients with s-MG-IM but were absent in patients with ir-MG-IM (p < 0.001). DISCUSSION: Although they share some similarities, s-MG-IM represents a chronic, predominantly thymoma-associated overlap syndrome with classical MG and IM features, whereas ir-MG-IM is typically an aggressive, likely monophasic condition characterized by severe myositis, with frequent ocular and cardiac involvement, and lacking classical MG features. Study limitations include the retrospective design, small sample size, and limited serum availability, warranting confirmation in larger prospective cohorts.