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. 2025 Aug 4:e252574.
doi: 10.1001/jamaneurol.2025.2574. Online ahead of print.

Early Treatment With Intravenous Immunoglobulins and Outcomes of Patients With Anti-IgLON5 Disease

Thomas Grüter  1   2 , Carles Gaig  3   4   5 , Yvette S Crijnen  6 , Maarten J Titulaer  6 , Lidia Sabater  3   7 , Anna Heidbreder  8   9   10 , Justina Dargvainiene  11 , Anja Tietz  12 , Stjepana Kovac  13 , Andre Dik  13 , María Elena Erro  14 , Jan Lewerenz  15 , Andrea Kraft  16 , Frank Seifert  17 , Romana Höftberger  18 , Franziska S Thaler  19   20 , Lucie de Azevedo  21 , Jonathan Wickel  22 , Juna M de Vries  6 , Agnita J W Boon  6 , Robin W van Steenhoven  6 , Ralf Gold  1 , Klaus-Peter Wandinger  11   12 , Gregor Kuhlenbäumer  12 , Josep O Dalmau  3   4   7   23 , Frank Leypoldt  11   12 , Francesc Graus  3 , Ilya Ayzenberg  1 ; Anti-IgLON5 Disease Study Group
Collaborators, Affiliations

Early Treatment With Intravenous Immunoglobulins and Outcomes of Patients With Anti-IgLON5 Disease

Thomas Grüter et al. JAMA Neurol. .

Abstract

Importance: Anti-IgLON5 disease is an autoimmune encephalopathy that often leads to severe disability or death. The efficacy of immunotherapy remains unknown.

Objective: To investigate whether early immunotherapy is associated with disability and death in anti-IgLON5 disease.

Design, setting, and participants: This retrospective, multicenter cohort study of patients with anti-IgLON5 disease was conducted from 2014 to 2024, with a median (IQR) follow-up of 66 (33-97) months after disease onset. Data from the German Network for Research on Autoimmune Encephalitis Registry, University Hospital Clinic of Barcelona (Spain), and Erasmus University Medical Center (the Netherlands) were analyzed. Eligibility criteria were clinical features consistent with anti-IgLON5 disease and the presence of IgLON5 antibodies in serum or cerebrospinal fluid. Data were collected by treating physicians using a structured questionnaire. Of 121 patients systematically selected from participating centers and registries, 14 patients were excluded due to insufficient clinical information or withdrawal of consent.

Intervention: Initiation of immunotherapy based on the treating physician's decision.

Main outcomes and measures: Clinical disability was assessed using the modified Rankin Scale (mRS) at the most recent follow-up visit and the proportion of patients who died.

Results: Among 107 patients with anti-IgLON5 disease (46 female [43.0%] and 61 male [57.0%]; median [IQR] age at the time of disease onset, 64 [57-70] years), 25 patients (23.4%) received immunotherapy during the first year of disease onset and 57 patients (53.3%) received it later. Among early treated patients, 9 individuals (36.0%) received intravenous immunoglobulins and 13 individuals (52.0%) received rituximab. A total of 44 patients (41.1%) died, and at least two-thirds of these deaths were related to anti-IgLON5 disease (28 patients [63.6%]). Early immunotherapy was the only modifiable independent factor associated with a lower long-term disability (odds ratio, 0.32; 95% CI, 0.13-0.83; P = .02) and survival (odds ratio, 2.70; 95% CI, 0.99-7.69; P = .047). Only intravenous immunoglobulin started within the first year of disease onset was associated with a lower median (IQR) mRS score at the most recent follow-up (2 [1-2.5] vs 3 [2-6]; P = .005; r = 0.55) and a lower proportion of deaths (0 of 9 patients vs 6 of 16 patients [37.5%]; P = .04) compared with other early immunotherapies despite a similar baseline mRS score.

Conclusions and relevance: In this study, early initiation of intravenous immunoglobulins (within the first year of onset) was associated with favorable long-term outcomes and improved survival in anti-IgLON5 disease. Larger prospective studies are needed to validate this finding.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Grüter reported receiving personal fees from CSL Behring, Sanofi, Novartis, and Teva outside the submitted work. Dr Titulaer reported serving on advisory boards for Amgen, Argenx, UCB, and Arialys; consulting for Guidepoint LLC; and receiving grants from Euroimmun, EpilepsieNL, Dioraphte, ZonMW/Dutch Research Council, ItsME, Erasmus Trust Foundation, and Erasmus MC Foundation outside the submitted work and having a patent for a KCTD16 antibody test issued to Erasmus MC and a copyright for PROSE, an encephalitis-specific PROM, issued to Erasmus MC, and receiving royalties from UpToDate Inc for providing text. Dr Heidbreder reported receiving personal fees from Idorsia, Bioprojet, and Vanda outside the submitted work. Dr Kovac reported receiving honoraria and travel support from UCB, Jazz Pharma, Angelini, and Eisai. Dr Lewerenz reported receiving grants from the Bundesministerium für Bildung und Forschung during the conduct of the study and financial compensation for clinical trials conducted as principal investigator to Ulm University from the Cure Huntington’s Disease Initiative and SOM Biotech outside the submitted work and serving as a member of the executive board of the German Society for Cerebrospinal Fluid Diagnostics and Clinical Neurochemistry. Dr Höftberger reported receiving speaker honoraria from UCB and BMS and payment to the Medical University of Vienna for antibody assays and antibody validation experiments organized by Euroimmun; Austrian research of Dr Höftberger was partially supported by a grant from the Austrian Science Fund and the Austrian Research Promotion Agency. Dr Thaler reported receiving grants from Novartis Pharma GmbH and personal fees from Alexion Pharmaceuticals outside the submitted work. Dr Wickel reported receiving personal fees from Argenx and samples for experimental research from IONIS outside the submitted work. Dr Boon reported receiving personal fees from AbbVie outside the submitted work. Dr Kuhlenbäumer reported receiving grants from the German Ministry of Research and Education during the conduct of the study. Dr Dalmau reported receiving grants from Euroimmune during the conduct of the study and having a patent for IgLON5 with royalties paid from Euroimmun. Dr Leypoldt reported receiving grants from E-Rare Joint Transnational research support and HORIZON MSCA and personal fees from Roche and Argenx during the conduct of the study and personal fees from Grifols and Biogen outside the submitted work. Dr Graus reported having a patent licensed to Euroimmun for the use of IgLON5 in an autoantibody test, for which he receives royalties, and receiving honoraria from Neurology for his role as associate editor. Dr Ayzenberg reported receiving grants from Roche, Alexion, and Amgen and personal fees from Roche, Alexion, Amgen, Sanofi, Merck, and Argenx outside the submitted work. No other disclosures were reported.

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