Lymphocyte alterations and elevated complement signalling are key distinguishing 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. Here, we examined the circulating immune profile of patients with acetylcholine receptor antibody positive MG of differing treatment requirements compared to controls.

Refractory patients displayed the highest frequency of memory B cells, and increased production of IL-6 and TNF-α upon toll-like receptor/ CD40 activation in vitro , suggesting an enhanced inflammatory phenotype. This was mirrored by a dramatic loss of regulatory T cells (Tregs) and dendritic cells in refractory disease. Refractory MG was also characterised by higher circulating complement proteins C3, C5 and clusterin as well as increased expression of complement receptors on B and T cells. Following anti-CD20 therapy, residual plasmablasts were found in circulation, likely to be drivers of ongoing disease. Baseline low B cell frequency (<3%), and high complement receptor expression were associated with poor response to rituximab, suggesting that alternative treatment strategies such as complement inhibition might be more favourable in these patients.

Overall, our findings highlight an altered lymphocyte signature in patients with refractory MG and support the use of plasma cell depletion and therapies that promote Treg expansion as promising therapeutic avenues.