Anti-MuSK antibody levels may be MG severity, treatment biomarker
Reducing levels of MuSK-IgG4 linked to good response
Blood levels of specific antibodies that target the muscle-specific tyrosine kinase (MuSK) may be biomarkers of disease severity and treatment response in people with myasthenia gravis (MG) who are positive for anti-MuSK antibodies.
A study finds that high levels of MuSK-IgG4 — an anti-MuSK antibody subclass – were associated with more severe disease, while reducing it was linked to a favorable response to treatment. The study, “Serological Markers of Clinical Improvement in MuSK Myasthenia Gravis,” was published in Neurology, Neuroimmunology & Neuroinflammation.
MG is an autoimmune disorder caused primarily by autoantibodies targeting acetylcholine receptors (AChRs) and, in some rare cases, the muscle-specific kinase (MuSK). Both proteins are located at the neuromuscular junction, where nerve and muscle cells communicate to coordinate voluntary movements. Anti-MuSK antibodies are most commonly of immunoglobulin G (IgG) type.
Over the last decade, the prognosis for people with MuSK antibodies has greatly improved because of earlier diagnoses and better therapies, particularly rituximab (brand name Rituxan, among others), which has been effective at inducing prolonged remissions and decreasing serum antibody levels.
Some patients remain with detectable antibodies despite a sustained clinical response, however.
Disease severity, treatment response with anti-MuSK antibodies
Researchers in Italy sought to assess whether levels of anti-MuSK antibodies (MuSK-IgG), IgG subclasses, and their affinity for MuSK, could serve as biomarkers of disease severity and treatment response. IgG subclasses are like specialized teams within a certain antibody, each performing unique tasks.
The researchers retrospectively analyzed MG patients with anti-MuSK antibodies (MuSK-MG) at their diagnosis who were treated at their clinic between 2000 and 2021. Twenty adults, mainly women (80%) with a median age of 48 at their disease onset, who’d been diagnosed for a median of about four years were included.
The course of the patients’ disease was generally moderate to severe, with 45% having an MG crisis during it. One patient had mild disease. Nine (45%) were treated with rituximab, three were treated with rituximab and corticosteroids, and six with corticosteroids and an immunosuppressant. Those treated with rituximab had more severe disease than those on other therapies. Almost half the patients responded to treatment, meaning they had minimal disease manifestations or achieved disease remission.
MuSK-IgG levels were determined in 43 blood samples collected at different times during the disease course, and the levels, particularly of the IgG4 subclass, strongly correlated with disease severity.
MuSK-IgG4 was present in all the patients and constituted the highest proportion of MuSK-IgG antibodies across all the samples.
When the researchers analyzed data from individual patients over time, the ones who responded to treatment generally had a reduction of MuSK-IgG, particularly the IgG4 and IgG2 subclasses. Those who didn’t improve after treatment had no changes in their antibody levels. In the group of patients who received treatment with rituximab alone, those who had a positive response also showed reduced antibody levels.
This may represent a new clinical biomarker of disease severity and outcomes that could guide treatment choices, which may include reducing or suspending immunotherapy in those who show lower IgG4 levels after treatment, the researchers said.
In a case where a patient wasn’t receiving immunotherapy, antibody affinity for MuSK increased by 100 times during an MG exacerbation, even though the overall antibody levels stayed the same. This suggests that “affinity maturation was a driver of clinical worsening and … is a key step for MuSK antibody pathogenicity [disease-causing mechanisms],” wrote the researchers, who said more “multicenter prospective studies are needed” to confirm the results and “identify reliable, predictive biomarkers that can support a personalized treatment approach” in MG.
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