A clinical therapeutic trial of cyclosporine in myasthenia gravis. Mycophenolate mofetil for myasthenia gravis: a double-blind, placebo-controlled pilot study. A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Myasthenia Gravis Study Group. Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. Efficacy of low-dose FK506 in the treatment of Myasthenia gravis--a randomized pilot study. Use of intravenous pulsed cyclophosphamide in severe, generalized myasthenia gravis. A randomised clinical trial comparing prednisone and azathioprine in myasthenia gravis. Results of the second interim analysis. Myasthenia Gravis Clinical Study Group.
We randomly assigned 39 patients with steroid-dependent generalized myasthenia gravis to treatment with cyclosporine (5 mg/kg per body weight in divided doses) or placebo. Duration of treatment was 6 months. Patients were evaluated monthly. Primary measures of efficacy were quantified strength testing, antihuman acetylcholine receptor antibody titer, and dosage of corticosteroid medication. At the end of the study, patients in the cyclosporine group had significantly greater improvement in strength (p = 0.004) and a reduction in antireceptor antibody titer (p = 0.01). Percentage reduction of steroid medication was greater in the cyclosporine group, although the difference was not statistically significant (p = 0.12). There were no treatment failures, and there was one drug failure in the cyclosporine group. In the placebo group, there were three treatment failures. No significant nephrotoxicity was noted at this dosage during the first 6 months. During the subsequent 18 months of open-label therapy, continued reduction in steroid dosage occurred. Cumulative side effects, however, caused 35% of patients to discontinue the medication; 10% did so secondary to slowly progressive nephrotoxicity. Mycophenolate mofetil (MM) is an immunosuppressive agent developed and originally used to prevent acute rejection of solid-organ transplantation. There have been preliminary reports of its successful use in the treatment of autoimmune myasthenia gravis (MG). We conducted a double-blind, placebo-controlled pilot trial of MM in the treatment of suboptimally controlled, stable MG. Results of this pilot study are promising and suggestive of greater improvement in the patients who received MM compared to placebo. We compared prednisolone (PRED) and azathioprine (AZA) versus prednisolone alone in the treatment of MG. Prednisolone alone or combined with azathioprine is widely used in the treatment of MG, but no randomized placebo-controlled comparative trial data are available. The prednisolone dose and clinical outcome were compared in a multicenter randomized double-blind study of 34 MG patients who were followed up for 3 years. One group (PRED + AZA) received prednisolone (on alternate days) plus azathioprine (2.5 mg/kg); the other group received prednisolone on alternate days plus placebo (PRED + PLAC). Initial high-dose prednisolone (1.5 mg/kg on alternate days) was tapered at remission to the minimal dose required to maintain remission. The prednisolone dose did not differ significantly between the two groups at 1 year (median values: PRED + AZA, 37.5 mg on alternate days; PRED + PLAC, 45 mg on alternate days) but was reduced at 2 and 3 years in the PRED + AZA group (median value at 3 years: PRED + AZA, 0 mg on alternate days; PRED + PLAC, 40 mg on alternate days; p=0.02). Relapses and failures to remit over the 3 years were more frequent in the PRED + PLAC group. There was a sharp rise in the anti-acetylcholine receptor (AChR) titers in the PRED + PLAC group at 2 years. Incidence of side effects was slightly less in the PRED + AZA group. Azathioprine as an adjunct to alternate day prednisolone in the treatment of antibody-positive generalized MG reduces the maintenance dose of prednisolone and is associated with fewer treatment failures, longer remissions, and fewer side effects. We randomly assigned 20 patients with progressively worsening generalized myasthenia gravis of recent onset whose illness was not controlled by anticholinesterase therapy to treatment with either cyclosporine (6 mg per kilogram of body weight per day) or placebo. Patients who had been treated with thymectomy, steroids, or other immunosuppressive agents were excluded. The duration of treatment was 12 months. Disease activity was assessed by quantified strength testing and by measurements of antihuman acetylcholine-receptor antibody. Patients were assessed at 6 months and 12 months, or at the following early end points: drug failure (doubling of creatinine), treatment failure (respiratory or swallowing difficulty), or protocol violation (stopping medication for more than five days). At six months, patients in the cyclosporine group had had significantly more objective improvement in strength; one early end point had been reached (drug failure; no treatment failures). In the placebo group, three early end points had been reached (all treatment failures). The decline in titers of acetylcholine-receptor antibody was larger in the treated group, although the difference was not statistically significant. At the end of the study (after 12 months of treatment or arrival at an earlier end point), improvement in strength and reduction in titers of anti-receptor antibody continued to be greater in the cyclosporine group. Nephrotoxicity occurred in three patients receiving cyclosporine but was nonprogressive with a reduction in dosage and reversible with discontinuation of the drug. These results are preliminary and need confirmation, but we conclude that cyclosporine is probably an effective therapy in some patients with myasthenia gravis. To determine the efficacy of low-dose FK506 in the treatment of myasthenia gravis (MG), untreated de novo patients were randomly selected to receive treatment with (n = 18) or without (n = 16) FK506, and were evaluated for 1 year after treatment with limitation of daily dose of prednisolone. Low-dose FK506 reduced the duration of early-phase therapy in hospital (p < 0.05) and the need for combined therapy with plasmapheresis and high-dose intravenous methylprednisolone or high-dose intravenous methylprednisolone alone (p < 0.05). It also reduced the daily dose of prednisolone (p < 0.05) required to maintain minimal manifestations of MGFA postintervention status. None of the patients exhibited significant side effects up to 1 year after treatment. These findings suggest that low-dose FK506 is safe and efficacious for the treatment of de novo MG patients. Twenty-three myasthenia gravis (MG) subjects, mean (SD) age 41.6 years (14), showing poor disease control or steroid-related side effects, received treatment for 12 months with intravenous cyclophosphamide (CP; n = 12) or placebo (PL; n = 11) in a randomized, double-blind trial. Pulses were given monthly at an initial dose of 500 mg/m(2) of body surface, and titrated according to changes of peripheral muscle strength or side effects. Changes of muscle strength, steroid and pyridostigmine requirements, and development of ventilatory failure or swallowing impairment were evaluated at 0, 3, 6, and 12 months. No differences were observed between groups at baseline. Statistically significant reductions of methylprednisone doses were noted in both groups but were more pronounced in subjects receiving CP than PL at 6 months (P < 0.05) and at 12 months (P < 0.03). At 12 months, five subjects on CP had tapered off their steroids whereas no subject on PL achieved further reductions (P < 0.03). Four CP subjects were not receiving steroids 36 months after completing the study and three other CP subjects had stopped pyridostigmine. CP improved muscle strength at 3 and 6 months, and this reached statistical significance compared to PL at 12 months mainly in the bulbar and masticatory (P < 0.009) and extraocular muscles (P < 0.03). Ventilatory failure was noted in one subject on CP (due to bronchopneumonia) and two on PL (due to muscle weakness). No significant increases of CP-related side effects were observed. Thus, this study suggests that intravenous pulses of CP allow reductions of systemic steroids usage without muscle strength deterioration or CP-related side effects.
                Copyright 2002 Wiley Periodicals, Inc. From January 1983 to October 1990, 41 patients with generalised myasthenia gravis were randomly given either prednisone or azathioprine. The main goal was to record the time to the occurrence of the first episode of deterioration. During a mean follow-up of 30 months, 21 patients showed deterioration, 12 in the prednisone group and nine in the azathioprine group (p = 0.40). No difference was observed between the two groups in muscular score and functional grade, assessed at the end of each treatment year, or in tolerance. Treatment failure occurred in 17 patients, 12 in the prednisone group and five in the azathioprine group (p = 0.02); even after adjustment for imbalances in prognostic features, the failure rate remained 2.8 times higher in the prednisone group than in the azathioprine group (p = 0.5). In the patients in whom treatment failed, symptoms were initially more severe than in the others, but the combination of prednisone and azathioprine resulted in clinical improvement, consisting of remission or only minor deficits in half of the patients after two years of treatment. These findings indicate that azathioprine increases treatment response compared with prednisone, although no difference in the duration of improvement was demonstrated. Nevertheless, it appears that the most severe forms of the disease, often resistant to prednisone or azathioprine alone, could benefit from the combination of both drugs.
In generalised MG, limited evidence from small RCTs suggests that ciclosporin, as monotherapy or with corticosteroids, or cyclophosphamide with corticosteroids, significantly improve MG. Limited evidence from RCTs shows no significant benefit from azathioprine (as monotherapy or with steroids), mycophenolate mofetil (as monotherapy or with either corticosteroids or ciclosporin) or tacrolimus (with corticosteroids or plasma exchange). Bigger, better-designed, longer trials are needed.