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Although case reports suggest benefits of complement inhibitors, the role of complement activation in irAE-n is understudied.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats: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\u2019s correlation. C5b-9-positive complement deposition was analyzed in muscle and nerve specimens from a subset of patients.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats: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 (<jats:italic>p<\/jats:italic>\u2009=\u20090.02, rho\u2009=\u2009\u22120.45; <jats:italic>p<\/jats:italic>\u2009= &lt;\u20090.01, rho\u2009=\u2009\u22120.56; <jats:italic>p<\/jats:italic>\u2009= &lt;\u20090.001, rho\u2009=\u2009\u22120.67, respectively), and improved outcomes (<jats:italic>p<\/jats:italic>\u2009=\u20090.03, rho\u2009=\u2009\u22120.42; <jats:italic>p<\/jats:italic>\u2009=\u20090.05, rho\u2009=\u2009\u22120.40; <jats:italic>p<\/jats:italic>\u2009= &lt;\u20090.001, rho\u2009=\u2009\u22120.64, respectively). Subtle C5b-9 deposition was detected in all tissue samples but showed non-specific patterns.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Discussion<\/jats:title>\n            <jats: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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00415-025-13181-2","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T11:28:44Z","timestamp":1749727724000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Complement activation profiles in patients with immune checkpoint inhibitor-associated neuromuscular immune-related adverse events"],"prefix":"10.1007","volume":"272","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6388-9375","authenticated-orcid":false,"given":"Leonie","family":"M\u00fcller-Jensen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"M\u00f6hn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Skripuletz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Carl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janin","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Grote-Levi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Nay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Ivanyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imke","family":"von Wasielewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Gutzmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Dittmayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Stenzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Knauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Endres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan D.","family":"L\u00fcnemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Boehmerle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Huehnchen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"key":"13181_CR1","doi-asserted-by":"publisher","first-page":"3044","DOI":"10.3390\/curroncol29050247","volume":"29","author":"Y Shiravand","year":"2022","unstructured":"Shiravand Y, Khodadadi F, Kashani SMA et al (2022) Immune Checkpoint Inhibitors in Cancer Therapy. 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M\u00fcller-Jensen, S. Carl, J. Thomas, L. Grote-Levi, S. Nay, P. Ivanyi, I. von Wassielewski, C. Dittmayer., W. Stenzel, S. Knauss and M. Endres declare that they have no conflict of interest. N. M\u00f6hn received speaker\u2019s honoraria from Biogen, Merck, and Novartis as well as travel grants from Biogen, Merck, and Novartis, all of which were not related to the submitted work. T. Skripuletz has received grants from the German Ministry for Education and Research (BMBF: CurePML01EN2302), the Bristol Myers Squibb Foundation for Immuno-Oncology (FA 19\u2013010), the Claudia von Schilling Foundation for Breast Cancer Research, the Else Kr\u00f6ner Fresenius Foundation, the Erwin-R\u00f6ver-Stiftung, Hannover Biomedical Research School (HBRS) and the VHV Foundation. He also received consulting fees and\/or speaker\u2019s honoraria by Alexion, Alnylam Pharmaceuticals, argenx, Bayer Vital, Biogen, Bristol Myers Squibb, Centogene, CSL Behring, Euroimmun, Grifols, Hexal AG, Horizon, Janssen-Cilag, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Siemens, Swedish Orphan Biovitrum, Teva, and Viatris, all outside the scope of the submitted work. R. Gutzmer has received grants from Amgen, Sanofi-Regeneron, Merck Serono, Kyowa Kirin, Almirall, SUN Pharma, and Recordati. He has also received consulting fees and serves as a medical advisor for Bristol Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Pierre Fabre, Merck Serono, SUN, Sanofi, Immunocore, Delcath, and Kyowa Kirin. Additionally, he has received speaker\u2019s honoraria and\/or equipment from Bristol Myers Squibb, Novartis, MSD, Almirall-Hermal, Amgen, Merck Serono, SUN Pharma, Pierre Fabre, and Sanofi-Regeneron, as well as travel support from SUN Pharma and Pierre Fabre, all not related to the current work. J.D. L\u00fcnemann has received speaker fees, research support and travel support from and\/or served on advisory boards for AbbVie, Alexion, Adivo, Amgen, Argenx, Biogen, CSL Behring, Janssen-Cilag, Merck, Moderna, Novartis, Roche, Sanofi, Takeda, and UCB Pharma. W. Boehmerle has received consulting fees and\/or speaker\u2019s honoraria from Osmol Therapeutics, the Charit\u00e9 Research Organization, Alexion, Sanofi, Bristol Myers Squibb and NOGGO e.V., all not related to the submitted work. P. Huehnchen has received grants from the German Ministry for Education and Research (BMBF) and the German Research Foundation (DFG) and was granted speaker\u2019s honoraria by the Nord-Ostdeutsche Gesellschaft f\u00fcr Gyn\u00e4kologische Onkologie e.V., all not related to the submitted work.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"The study protocol received approval from the Hannover Medical School Ethics Committee (No. 8685_BO_K2019) and the institutional review board of Charit\u00e9 Universit\u00e4tsmedizin Berlin (EA1\/099\/17 and EA4\/219\/21). The study adhered to the principles outlined in the Declaration of Helsinki. All patients provided written informed consent to participate and publish.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and patient consent"}}],"article-number":"459"}}