Lymphocyte alterations and elevated complement signaling are key features of refractory myasthenia gravis

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.

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.

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.

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 was received from the NorthCare Charity, Myaware, the Academy of Medical Sciences, and the Neuromuscular Study Group.