Myasthenia Gravis (MG) is a rare autoimmune disease in which the immune system attacks the connection between nerves and muscles. This attack causes muscle weakness that can affect vision, movement, speech, swallowing, and breathing. While many patients respond to treatment, others develop a severe, treatment-resistant form of the condition known as refractory MG. Currently, there are no reliable biomarkers to help doctors predict which patients will respond to therapy and which will not.
In a new study by University of Manchester scientists published in Med, researchers aimed to uncover why these treatments fail for some individuals. To do this, the team analysed blood samples from people living with MG and compared them to those of healthy volunteers to understand the underlying cellular differences that drive standard therapy resistance.
A Pattern of Immune Imbalance
The study revealed distinct immune system abnormalities in patients with refractory MG. These patients showed an overactive adaptive immune response, specifically involving increased numbers of memory B cells.
At the same time, the researchers found that regulatory T cells—which normally act as a ‘braking system’ to suppress excessive inflammation—were markedly reduced. This combination of an overactive attack and a weakened braking system contributes to significant immune dysregulation.
The research also identified changes in the innate immune system, including reduced dendritic cells and increased monocytes, along with heightened activity of the complement system, all pointing to ongoing immune-mediated damage at the neuromuscular junction.
Predicting Treatment Response
The team also examined a small group of refractory patients treated with rituximab, a drug designed to remove B cells. Although B cells were successfully reduced in all patients, only some showed meaningful clinical improvement.
The study found that those who did not respond appeared to have a version of the disease driven by long-lived plasma cells and particularly high complement activity. This discovery suggests that these specific patients may benefit more from therapies that target the complement pathway rather than just B cells.
“For patients whose symptoms do not improve with existing treatments, the lack of clear answers can be incredibly frustrating,” said Dr Katy Dodd, Neurology Consultant at Manchester Centre for Clinical Neuroscience. “Our findings help explain why some therapies work for certain patients but not others, and point toward more personalised approaches that could improve outcomes in the future.”
“Our study identifies a distinct immune signature associated with treatment-resistant myasthenia gravis,” said Dr Madhvi Menon, UKRI Future Leaders Fellow at the Lydia Becker Institute of Immunology and Inflammation and lead author of the paper. “Understanding these immune differences brings us closer to predicting how patients will respond to therapy and to developing more targeted, personalised treatment approaches.”
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