Tacrolimus for Treatment of Myasthenia Gravis
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: A large observational study performed in Korea suggests that tacrolimus is an effective immunomodulating, steroid-sparing medication for the treatment of myasthenia gravis.
SOURCE: Ahn SW, Joo IS, Kim BJ, et al. A multicenter prospective observational study on the safety and efficacy of tacrolimus in patients with myasthenia gravis. J Neurol Sci 2016; doi:10.1016/j.jns.2017.05.060. [Epub ahead of print].
Immunomodulating agents useful in the treatment of myasthenia gravis (MG) include glucocorticoids, azathioprine, mycophenolate mofetil, and cyclosporine. Patients with generalized MG who are refractory to these agents may benefit from monthly intravenous immunoglobulin, or the administration of rituximab, methotrexate, etanercept, cyclophosphamide, or tacrolimus. Recent evidence suggests that tacrolimus may serve as an effective immunosuppressant, even as an initial therapeutic agent in patients with MG.
In this prospective, observational study involving 15 Korean medical centers, 150 consecutive patients with corticosteroid-treated MG were followed for 24 months, comprising a 12-month enrollment period followed by a 12-month observational period after the initial administration of tacrolimus, 3 mg/day orally, with follow-up adjustment of dosage based on clinical judgment. Inclusion criteria encompassed age > 19 years, diagnosis of MG based on typical clinical features with positive serum autoantibodies to AchR or MuSK, decrement on repetitive nerve stimulation studies, or improvement on administration of anticholinesterase inhibitors, and MG refractory to standard corticosteroid and anticholinesterase therapy. Primary study endpoints were tolerability and safety of tacrolimus, whereas secondary endpoints were efficacy of tacrolimus based on improvement of MG Composite Scales (MGCS) and reduction of corticosteroid dosage. Patient evaluations occurred at baseline and at three-month intervals thereafter for 12 months following tacrolimus administration. Statistical analysis used the general linear model repeated measure analysis of variance (ANOVA) and Mauchly’s test of sphericity, with P values < 0.05 considered statistically significant.
Among 150 patients enrolled at baseline, two withdrew with no explanation, allowing safety to be evaluated in 148 patients, and 14 were discontinued after initiation of tacrolimus because of an adverse event or drug reaction, permitting efficacy to be evaluated among the remaining 134 patients, including 90 women and 44 men of mean age 56.2 years. Overall, 21.6% (n = 32) experienced an adverse drug reaction, usually minor, including gastrointestinal disturbances (10%), increased liver enzymes (2.7%), hyperglycemia or upper respiratory infection (2% each), or headache (1.6%). These resolved spontaneously or with dose reduction. Serious adverse reactions affected seven patients, three each with either herpes zoster or nephrotoxicity, and one with leukopenia, all of whom were removed from the study. An additional five patients were removed after consultation with their attending physician for gastrointestinal symptoms (n = 2) or chest discomfort, alopecia, and elevated liver enzymes/hyperglycemia (n = 1 each). Among the 134 patients who completed the study, mean corticosteroid dosage decreased significantly compared to baseline, both among generalized (n = 79) and ocular (n = 55) MG patients, and regardless of prior thymectomy (n = 50). MGCS significantly improved after 12 months in the generalized MG group but not in the ocular group compared to baseline. In this study, tacrolimus was an effective immunosuppressant with an acceptable safety profile for treatment of MG.
Tacrolimus, at an oral dose of 3 mg/day, reduces steroid requirements in MG and improves clinical symptoms. What is its optimal serum concentration for MG? In a Japanese study, where it is approved for treatment of MG, trough concentrations of tacrolimus were measured using a chemiluminescent enzyme immunoassay in 51 MG patients who were receiving 3 mg/day for more than a year. Median trough concentration, which correlated with minimal manifestation of disease or better, was 5.4 ng/mL (range 2.9-7.6), and, using a receiver operating characteristic curve, a minimal concentration of 4.8 ng/mL or higher was associated with better reduction of AchR antibody titers, greater improvement of activities in daily life scores, and achievement of minimal manifestation or better status. Improved MG prognosis requires an adequate tacrolimus blood concentration.1
- Kanai T, Uzawa A, Kawaquchi N, et al. Adequate tacrolimus concentration for myasthenia gravis treatment. Eur J Neurol 2017:24:270-275.
A large observational study performed in Korea suggests that tacrolimus is an effective immunomodulating, steroid-sparing medication for the treatment of myasthenia gravis.
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