Rituximab May Be Effective for Refractory Myasthenia Gravis

Abstract & Commentary

By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports no financial relationships relevant to this field of study.

Synopsis: In a restrospective review, rituximab appeared beneficial for patients with medication-resistant myasthenia gravis.

Source: Nowak RJ, et al. Response of patients with refractory myasthenia gravis to rituximab: A retrospective study. Ther Adv Neurol Disord 2011:4:259-266.

What can you offer the refractory myasthenia gravis (MG) patient when plasma exchange, intravenous immunoglobulin, corticosteroids, mycophenolate mofetil, azathioprine, and cyclosporine fail to produce remission? In a retrospective review of 14 refractory, generalized, MG patients seen at the Yale Neuromuscular Clinic between 2003-2009 — six patients who were antibody-positive for acetylcholine receptor and eight patients positive for muscle specific tyrosine kinase — rituximab, a monoclonal B-cell-directed antibody, appears to have been efficacious. Refractory MG was defined either as symptomatic despite medication, as an inability to lower immunomodulatory medication without relapse, or by the presence of significant side effects due to immunomodulatory medication. Patients were examined pre- and post-rituximab administration, and response was determined by comparing symptoms and examination findings before and after treatment. Standard dosing of rituximab was administered at 375 mg/m2 weekly for 4 weeks, with 6-month intervals between treatment courses. Statistical evaluation included t-test analysis, with P < 0.05 considered significant.

Among 13 patients who were prednisone-dependant, rituximab infusion allowed eight to taper off steroid medication completely, five by the second cycle, and an additional three by the third cycle. Plasma exchange treatments were also significantly reduced in frequency, with nine and 11 patients no longer requiring them at 6 and 12 months, respectively. After one cycle of rituximab, mycophenolate mofetil could be discontinued in the single patient who was so treated, and azathioprine could similarly be discontinued in two of four such patients, after one and two cycles in each patient, respectively. Antibody titers dropped by a mean of 52.1% after two cycles of rituximab, and clinical improvement was evident in tandem with decreased medication requirements and falling antibody titers. Rituximab was safe, with only six adverse events among a total of 132 infusions, comprising chills and rigors (n = 3, all in the same patient during sequential infusions), and one each, in individual patients, of flushing and pruritis, flushing and dyspnea, and a hot sensation throughout the body in the absence of flushing. Rituximab appears to be a safe and efficacious therapeutic option in refractory myasthenia gravis.

Commentary

Tacrolimus (Prograf) often is mentioned as yet another steroid-sparing agent that may be useful in MG. However, among 80 stable myasthenic patients, on the equivalent of 10-20 mg/day of prednisolone, and randomized in a double-blind, placebo-controlled, parallel group, 28-week study, no significant difference was observed between the placebo and active treatment group (tacrolimus 3 mg po daily) with respect to the primary endpoint of mean daily prednisolone dose given in the last 12 weeks of the study. Effective steroid sparing with tacrolimus was suggested by secondary analysis, comprising mean daily prednisolone dose every 4 weeks, mean prednisolone dose in mg/kg in the last 4 weeks, and total prednisolone dose given during the trial.1 Further study is necessary before tacrolimus can be recommended as a steroid-sparing agent in MG.

Reference

1. Yoshikawa H, et al. Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry 2011;82:970-977. Erratum in J Neurol Neurosurg Psychiatry 2011;82:1180.