By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: In retrospective studies of patients with generalized myasthenia gravis, those who are refractory to multiple treatments have disease onset at an earlier age, are more likely to have thymic pathology, and are more likely to be double-seronegative (neither acetylcholine receptor nor muscle-specific receptor tyrosine kinase antibodies).
SOURCE: Veltsista D, Kefalopoulou Z, Tzartos J, Chroni E. Autoantibody profile in myasthenia gravis patients with a refractory phase. Muscle Nerve 2022; Feb 23. doi: 10.1002/mus.27521. [Online ahead of print].
Drug-refractory myasthenia gravis (MG), seen in 10% to 15% of patients, is defined as disease that is clinically unchanged or worse despite corticosteroid treatment and at least two additional immunosuppressive agents, used in adequate doses for an adequate time. It has been associated with female sex, younger age at onset, thymoma, and anti-muscle-specific receptor tyrosine kinase (MuSK) antibodies, and it presents more frequently with generalized disease, bulbar symptoms, and life-threatening events. Is there an antibody profile associated with refractory MG?
In this retrospective study, MG patients, followed for at least 18 months and clinically stable for three months, at the Neuromuscular Center, Department of Neurology, University Hospital of Patras, Rion, Greece, were included. Diagnosis was based on a history of fluctuating weakness and fatigue, exclusion of alternative diagnoses, and the presence of either antibodies against the nicotinic acetylcholine receptor (AChR) or MuSK, abnormal repetitive nerve stimulation (RNS) studies, or abnormal single-fiber electromyography (SF-EMG). Disease extent and severity were measured using a) the Myasthenia Gravis Foundation of America (MGFA) classification, I-V classes, and b) the quantitative myasthenia gravis (QMG) score (range, 0-39).
Refractory disease was defined as being either a) MGFA class III for at least 12 months, b) less than MGFA class III, with at least two relapses requiring intravenous immunoglobulin (IVIG) or plasmapheresis (PLEX), despite steroid and other immunosuppressant treatment in adequate dosage for at least 12 months, or c) less than MGFA class III, requiring prolonged, high-dose, potentially harmful immunosuppressive therapy. Statistical analysis comprised the Mann-Whitney U test and the Wilcox signed-rank test, with significance set at P < 0.05.
Among 113 MG patients analyzed, 15 (13.3%) were refractory, and, compared to the non-refractory patients, were younger and with an earlier age of onset, more often had thymic pathology, and more often had undergone thymectomy, but they did not differ with respect to MGFA class at diagnosis, disease duration, or time to treatment initiation. Refractory MG patients had neither MuSK nor low-density lipoprotein receptor-related protein 4 (LRP4) antibodies, and they were more likely to be double-seronegative (neither AChR nor MuSK antibodies) than the non-refractory group. Both seropositive and seronegative refractory MG patients were comparable with regard to age at diagnosis, time interval to refractory phase, refractory treatment, and thymectomy status. Refractory, double-seronegative MG patients may represent a distinct class of MG requiring individualized, targeted treatment.
COMMENTARY
Among 990 patients with MG from 15 hospitals across Spain, reviewed in an observational, cross-sectional, multicenter study based on the Spanish MG registry, 84 (8.5%) were refractory. Of these refractory patients, 68 demonstrated anti-AChR antibodies, five were positive for anti-MuSK antibodies, 10 were seronegative, and one was double-seropositive (anti-AChR and anti-MuSK antibodies). Female sex (75% were women), younger age at onset (mean age of onset, 44.4 years), and MuSK positivity (6%) were found to be significantly related to having refractory MG, as was presenting as generalized disease (77.5% at onset, 92.3% ultimately), with bulbar symptoms (47.5%), and with life-threatening events (13.8%). Among seropositive patients, rituximab and tacrolimus were the drugs that refractory patients responded to the most, but among drug-refractory seronegative patients, 80% did not respond to any drug. Over a follow-up period of 9.8 years, 100% of anti-MuSK-positive patients and 42.6% of anti-AChR-positive patients achieved remission, compared to 10% of seronegative patients, underscoring the need for new drugs to treat this group of MG patients.1
REFERENCE
- Cortes-Vicente E, Alvarez-Velasco R, Pla-Junca F, et al. Drug-refractory myasthenia gravis: Clinical characteristics, treatments, and outcome. Ann Clin Transl Neurol 2022;9:122-131.
