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Complement activation was common but non-specific in immune-related neuropathy and myositis, questioning the utility of complement inhibitors.  

Researchers conducted a retrospective study published in June 2025 issue of Journal of Neurology to investigate the role of complement activation in immune-related neuropathy (irNeuropathy) and myositis (irMyositis) associated with immune checkpoint inhibitors (ICI).  

They enrolled individuals diagnosed with irNeuropathy or irMyositis, along with cancer controls (CCs) and healthy controls (HCs). Serum concentrations of 11 complement components were measured using multiplex enzyme-linked immunosorbent assays. Spearman’s correlation was used to examine the relationships between complement levels, severity, and clinical outcomes of immune-related neurologic adverse events (irAE-n). Complement deposition marked by C5b-9 was analyzed in nerve and muscle tissue samples from a subset of participants.  

The results showed that 31 individuals with irMyositis, 25 with irNeuropathy, 25 CCs, and 17 HCs were included. Complement components were elevated in irNeuropathy [C3a, C5a, soluble C5b-9 (sC5b-9), C3, Ba, C4a], irMyositis [C3a, Ba], and CCs [C3a, C5a, sC5b-9, Bb, Ba, C4a], when compared to HCs. In irMyositis, higher levels of C5a and complement regulatory proteins Factor H and Factor I correlated with lower severity of irAE-n [C5a: P= 0.02, rho = −0.45; Factor H: P< 0.01, rho = −0.56; Factor I: P< 0.001, rho = −0.67] and better outcomes [C5a: P= 0.03, rho = −0.42; Factor H: P= 0.05, rho = −0.40; Factor I: P< 0.001, rho = −0.64] and C5b-9 deposition was observed in all tissue samples, although the patterns were non-specific.  

Investigators concluded that systemic complement activation occurred irrespective of irAE-n status, and its limited tissue specificity indicated an uncertain therapeutic role for complement inhibition. 

Source: link.springer.com/article/10.1007/s00415-025-13181-2