Journal of neurology · 2025
Complement activation profiles in patients with immune checkpoint inhibitor-associated neuromuscular immune-related adverse events.
СтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Müller-Jensen Leonie, Möhn Nora, Skripuletz Thomas, Carl Sophia, Thomas Janin, Grote-Levi Lea, Nay Sandra, Ivanyi Philipp, von Wasielewski Imke, Gutzmer Ralf, Dittmayer Carsten, Stenzel Werner, Knauss Samuel, Endres Matthias, Lünemann Jan D, Boehmerle Wolfgang, Huehnchen Petra
Аннотация
BACKGROUND: Immune-related neuropathy (irNeuropathy) and myositis (irMyositis) are the most common neurologic adverse events (irAE-n) associated with immune checkpoint inhibitors. Although case reports suggest benefits of complement inhibitors, the role of complement activation in irAE-n is understudied.
METHODS: In a retrospective multicenter study, we enrolled patients with irNeuropathy or irMyositis, cancer controls (CCs), and healthy controls (HCs). Serum levels of 11 complement components were measured using multiplex enzyme-linked immunosorbent assays. Associations with irAE-n severity and outcomes were assessed by Spearman's correlation. C5b-9-positive complement deposition was analyzed in muscle and nerve specimens from a subset of patients.
RESULTS: Thirty-one irMyositis patients, 25 irNeuropathy patients, 25 CCs, and 17 HCs were included. Complement component levels were elevated in irNeuropathy (C3a, C5a, sC5b-9, C3, Ba, C4a), irMyositis (C3a, Ba), and CCs (C3a, C5a, sC5b-9, Bb, Ba, C4a), compared to HCs. In irMyositis, higher levels of C5a and complement regulators Factor H and I correlated with lower irAE-n severity (p = 0.02, rho = -0.45; p = < 0.01, rho = -0.56; p = < 0.001, rho = -0.67, respectively), and improved outcomes (p = 0.03, rho = -0.42; p = 0.05, rho = -0.40; p = < 0.001, rho = -0.64, respectively). Subtle C5b-9 deposition was detected in all tissue samples but showed non-specific patterns.
DISCUSSION: Systemic complement activation is detectable in cancer patients regardless of irAE-n status, and tissue complement deposition is unspecific. Our findings suggest that complement activation is not a major driver of irAE-n, leaving the therapeutic potential of complement inhibitors uncertain.
METHODS: In a retrospective multicenter study, we enrolled patients with irNeuropathy or irMyositis, cancer controls (CCs), and healthy controls (HCs). Serum levels of 11 complement components were measured using multiplex enzyme-linked immunosorbent assays. Associations with irAE-n severity and outcomes were assessed by Spearman's correlation. C5b-9-positive complement deposition was analyzed in muscle and nerve specimens from a subset of patients.
RESULTS: Thirty-one irMyositis patients, 25 irNeuropathy patients, 25 CCs, and 17 HCs were included. Complement component levels were elevated in irNeuropathy (C3a, C5a, sC5b-9, C3, Ba, C4a), irMyositis (C3a, Ba), and CCs (C3a, C5a, sC5b-9, Bb, Ba, C4a), compared to HCs. In irMyositis, higher levels of C5a and complement regulators Factor H and I correlated with lower irAE-n severity (p = 0.02, rho = -0.45; p = < 0.01, rho = -0.56; p = < 0.001, rho = -0.67, respectively), and improved outcomes (p = 0.03, rho = -0.42; p = 0.05, rho = -0.40; p = < 0.001, rho = -0.64, respectively). Subtle C5b-9 deposition was detected in all tissue samples but showed non-specific patterns.
DISCUSSION: Systemic complement activation is detectable in cancer patients regardless of irAE-n status, and tissue complement deposition is unspecific. Our findings suggest that complement activation is not a major driver of irAE-n, leaving the therapeutic potential of complement inhibitors uncertain.