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Lookup NU author(s): Dr James Miller
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Authors. Background: A significant proportion of patients with myasthenia gravis (MG) remain refractory to standard immunosuppressive therapy, and biomarkers to help guide treatment decisions are lacking. We investigated whether refractory disease is associated with a distinct circulating immune profile. Methods: We performed comprehensive immune phenotyping of peripheral blood from patients with acetylcholine-receptor-antibody-positive MG with differing treatment requirements and compared them with healthy controls. In a subset of refractory patients treated with anti-CD20 therapy, B cell reconstitution and clinical response were evaluated. Findings: Refractory MG patients displayed the highest frequency of memory B cells and increased production of interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) upon Toll-like receptor/CD40 activation in vitro. These changes were accompanied by a dramatic loss of regulatory T cells (Tregs) and dendritic cells. Refractory MG was further characterized by elevated circulating complement proteins (C3, C5, and clusterin) and increased expression of complement receptors on lymphocytes. Following anti-CD20 therapy, residual plasmablasts persisted in circulation. Notably, a low baseline B cell frequency (<3%) was associated with poor clinical response to rituximab in refractory disease, although the sample size was limited. Conclusions: Our findings define a distinct immune signature in refractory MG, identify potential biomarkers of treatment resistance, and highlight plasma cell depletion, IL-6 or complement inhibition, and Treg expansion as promising therapeutic avenues. Funding: Funding was received from the NorthCare Charity, Myaware, the Academy of Medical Sciences, and the Neuromuscular Study Group.
Author(s): Dodd KC, Baillie K, Holt JKL, Leite MI, Lin L, West PW, Miller JAL, Spillane J, Viegas S, Zelek WM, Sussman J, Menon M
Publication type: Article
Publication status: Published
Journal: Med
Year: 2026
Pages: Epub ahead of print
Online publication date: 06/02/2026
Acceptance date: 10/12/2025
Date deposited: 23/02/2026
ISSN (print): 2666-6359
ISSN (electronic): 2666-6340
Publisher: Cell Press
URL: https://doi.org/10.1016/j.medj.2025.100987
DOI: 10.1016/j.medj.2025.100987
Data Access Statement: Data will be made available upon a written proposal and data transfer agreement. This study did not generate any original computer code. Any additional information required to reanalyze the data reported in this work paper is available from the lead contact upon request.
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