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Background <p>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.</p> Methods <p>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.</p> Results <p>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 (<i>p</i> = 0.02, rho = −0.45; <i>p</i> = &lt; 0.01, rho = −0.56; <i>p</i> = &lt; 0.001, rho = −0.67, respectively), and improved outcomes (<i>p</i> = 0.03, rho = −0.42; <i>p</i> = 0.05, rho = −0.40; <i>p</i> = &lt; 0.001, rho = −0.64, respectively). Subtle C5b-9 deposition was detected in all tissue samples but showed non-specific patterns.</p> Discussion <p>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.</p>

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Complement activation profiles in patients with immune checkpoint inhibitor-associated neuromuscular immune-related adverse events

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月12日

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  • Leonie Müller-Jensen,
  • Nora Möhn,
  • Thomas Skripuletz,
  • Sophia Carl,
  • Janin Thomas,
  • Lea Grote-Levi,
  • Sandra Nay,
  • Philipp Ivanyi,
  • Imke von Wasielewski,
  • Ralf Gutzmer,
  • Carsten Dittmayer,
  • Werner Stenzel,
  • Samuel Knauss,
  • Matthias Endres,
  • Jan D. Lünemann,
  • Wolfgang Boehmerle,
  • Petra Huehnchen

摘要

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.