Patients with refractory double seronegative myasthenia gravis (MG), ie, without detectable antibodies for nicotinic acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK) antibodies, should be treated as a distinctive group of patients, according to a new retrospective single-center study.

“Approximately 10% of MG patients will experience a refractory period during the course of the disease,” said the authors of the study published in Muscle Nerve.

However, the occurrence of such periods might be determined by their autoantibody profiles: patients with double seronegative MG seem to have a higher probability of treatment resistance than those with anti-MuSK antibodies since none of the MuSK-positive patients in this study cohort experienced refractory MG.

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The percentage of patients with double seronegative MG was higher among refractory patients than among nonrefractory patients (40% vs 16.3%, respectively). More than a quarter (27.3%) of the patients with double seronegative MG developed refractory MG. Moreover, 11.4% of AChR positive patients also developed refractory MG.

None of the refractory double seronegative patients with MG had antibodies against low-density lipoprotein receptor-related protein 4 (LRP4). This was expected by the authors as LRP4-positive patients with MG usually respond well to standard therapy in contrast to refractory patients.

Out of the 113 patients with MG enrolled in the study, 15 had a refractory phase during follow-up. “We introduced the term ‘refractory phase’ to more accurately describe a potentially reversible condition based on treatment modifications,” the authors explained.

Nearly half (46.7%) of the patients with refractory MG met refractory criterion 1, followed by criterion 2 (26.6%), criteria 1 and 3 (20%), and criterion 3 (6.7%). Patients with refractory MG showed earlier disease onset and a higher incidence of thymic pathology and thymectomy.


Veltsista D, Kefalopoulou Z, Tzartos J, Chroni E. Autoantibody profile in myasthenia gravis patients with a refractory phase. Muscle Nerve. Published online February 23, 2022. doi:10.1002/mus.27521