ContributorsGIW wrote and revised the manuscript in response to co-author comments. He finalized all the figures and tables, performed the literature search, and assisted with data interpretation. HJK critically reviewed the manuscript and made important suggestions to improve it. He assisted with data interpretation. IBA performed the data analysis, constructed the figures and tables, and made important suggestions to improve the manuscript. H-CK assisted with the data analysis and also reviewed the manuscript. GRC critically reviewed the manuscript and made important suggestions to improve it. He assisted with data interpretation. All other authors were given the opportunity to review the manuscript and make suggestions which GIW received, either revising the paper or providing explanations. All who are not deceased were involved with approval of the manuscript.

Objectives To evaluate the ability of tacrolimus to reduce the corticosteroid dose in patients with myasthenia gravis (MG) and the drug's safety in a double-blind, placebo-controlled, parallel group study. Methods Patients being treated with oral prednisolone at doses equivalent to 10e20 mg/day, and with stable symptoms, were randomised to tacrolimus or placebo in a 28-week double-blind study. The dose of corticosteroid was tapered with the procedures specified in the protocol. The primary efficacy endpoint was the mean daily prednisolone dose given in the last 12 weeks of the study.Results Eighty patients received the study drug (40 patients in each group) and were included in the full analysis set. In the full analysis set, there was no significant difference in the primary efficacy endpoint between the two groups (p¼0.078). However, some secondary analyses suggested the steroid-sparing effect of tacrolimus. Tacrolimus was well tolerated, and no safety concerns were noted. Conclusions This study suggests that tacrolimus has a potential advantage as a steroid-sparing agent in the treatment of MG patients. Clinical trial registration number NCT00309088. Name of the trial registry: FK506 Phase 3 Study: A Study for Steroid Non-Resistant MG Patients.

To investigate the usefulness of low-dose FK506 for the treatment of myasthenia gravis (MG), we treated 19 patients with generalized MG in a 16-week open clinical trial of FK506 (3-5 mg/day). At the end of the trial, total MG scores (range: 0-27 points) improved by 3 points or more in 7 of 19 patients (37%), and activities of daily living (ADL) scores (range: 0-6 points) also improved by 1 point or more in 8 of 19 patients (42%). Nine of 19 patients (47%) showed improvement in either MG or ADL scores. Significant reduction of anti-acetylcholine receptor antibody titers and interleukin 2 production were observed at the end of this study. Minor but commonly observed side effects were an increase in neutrophil count and a decrease in lymphocyte count. No serious adverse events such as renal toxicity or diabetes mellitus were observed during the 16-week treatment period. FK506 could safely serve as an adjunct to steroid therapy for MG at low dosage.

Efficacy and safety of long term use of FK506 (2-4.5 mg/ day) for a maximum of two years were evaluated in 12 patients with generalised myasthenia gravis (MG). At the end of the study, eight patients (67%) showed improvement in either MG score or Activities in Daily Living score, and prednisolone dosage could be reduced in seven patients (58%), with a mean reduction ratio of 37%. Long term use of FK506 for MG can be more effective than short term administration, with no serious side effects.

Objectives: To compare the clinical and electrophysiological features of myasthenia gravis (MG) patients with (seropositive) or without (seronegative) antibodies to acetylcholine receptor. To investigate whether antibodies to muscle specific kinase (MuSK) and ryanodine receptor (RyR) are associated with particular features. Methods: Clinical profiles and single fibre electromyography (SFEMG) in the extensor digitorum communis (EDC) were reviewed in consecutive 57 seropositive and 13 seronegative patients. Antibodies to MuSK and RyR were measured by immunoassays. Results: Of the 13 seronegative patients, four (31%) were positive for MuSK antibodies and seven (54%) were positive for RyR antibodies, including all four MuSK positive patients. Clinical features were similar at presentation for seropositive and seronegative patients, but MuSK positive patients frequently developed myasthenic crises. Despite the similar clinical severities at the time of examination, the proportion with positive jitter (93% of seropositive patients, 50% of MuSK positive patients, and 44% of MuSK negative patients) and the extent of jitter (mean consecutive difference: 76 ms in seropositive patients, 36 ms in MuSK positive patients, and 30 ms in MuSK negative patients) were less in seronegative MG patients compared with seropositive MG patients. Conclusions: Seronegative MG is heterogeneous with respect to the presence of antibodies to MuSK. Impairment of neuromuscular synaptic transmission in EDC is less marked in seronegative than seropositive MG despite the similar clinical severity. This discrepancy may partly reflect the distribution of affected muscles in seronegative patients, but it is possible that other factors, such as impaired excitationcontraction coupling resulting from RyR antibodies, contribute to the clinical phenotype.