Mycophenolate mofetil as second line immunosuppressant in myasthenia gravis - a long-term prospective open-label study
European Journal of Medical Research volume 14, Article number: 364 (2009)
The preferred immunosuppressive drug for long term treatment of myasthenia gravis (MG) is azathioprine (AZA). Mycophenolate mofetil (MMF) was suggested as an effective and safe second line alternative to AZA.
In a prospective open-label study, 11 patients with acetylcholine receptor antibody (AchR-ab) positive MG (n = 4 ocular MG, n = 7 generalized MG) were treated with MMF which replaced AZA. Reasons for the change of immunosuppressant therapy were side effects (n = 9) or unresponsiveness under AZA (n = 3).
Mean duration of MMF treatment was 16.9 months (6-46 months). During MMF treatment AZA side effects resolved in 8/9 patients, concomitant therapy could be discontinued in 4 patients and reduced in 5 patients, and 5 patients remitted and 3 remained in remission. One MMF-refractory patient required add-on IVIG therapy and another with ocular MG showed signs of generalization after 20 months of MG treatment. One patient was diagnosed with bronchial carcinoma after 10 months of MMF treatment.
Due to its favourable spectrum of side effects compared to AZA MMF might serve as a second-line immunosuppressant in those MG patients who have not tolerated AZA.
Steroid-sparing immunosupressants such as azathioprine (AZA) for the long-term course of myasthenia gravis (MG) are the preferred first-line treatment for generalized and severe ocular AchR-ab positive MG. However, 10-20% of MG patients treated with AZA do not respond sufficiently to AZA and side effects occur frequently (nausea, elevated liver enzymes, leuco- or thrombocytopenia).
In the present prospective open-label study we replaced AZA by MMF in eleven patients with AChR-ab positive MG and analysed the effect and safety of MMF for a mean duration of 16.9 months ± 11.1 (6-46). Four patients with pure ocular and seven patients with generalized MG were included. AChR-ab titer, QMGS, MGFA postintervention status, and concomitant drugs were assessed before the beginning and during MMF treatment (Table 1).
The reasons for the exchange from AZA to MMF were gastrointestinal (liver enzyme increase n = 4, nausea/vomiting n = 2, increase of pancreatic enzymes n = 1) and haematological adverse effects (leuco- or pancytopenia n = 3), peripheral edema (n = 1), unresponsiveness to AZA (n = 3). According to the QMGS treatment resulted in complete (pat. 8) and incomplete (pat.6, 7, 10, 11) pharmacological remission, three patients remained in complete pharmacological remission (pat. 1, 5) or with minimal manifestation (pat. 2). Clinical improvement was seen after a period of 2-9 months. In two patients clinical improvement along with decreasing AChR-ab occurred after more than six months on MMF (pat. 7, 11). Patient 3 with disabling unilateral ptosis was refractory despite a combined therapy of prednisolone, high dose pyridostigmine, and MMF. Symptoms improved during a concomitant therapy of intravenous immunoglobins. Patient 4 showed signs of generalization (head lifting weakness) after 20 months on MMF. Patient 2 with mild unilateral ptosis discontinued MMF after sixteen months due to its fear of side effects. Concomitant medication (prednisolone, pyridostigmine) could be discontinued in 4 patients (pat. 1, 2, 5, 7) and reduced in 5 patients (pat. 4, 6, 8, 10, 11). Laboratory parameters which had led to the change from AZA to MMF normalized in all patients affected (n = 8) except pat. 9. In the latter patient MMF treatment had to be discontinued due to persistent increase of pancreatic enzymes and recurrent gastrointestinal problems. One patient was diagnosed with bronchial carcinoma after 10 months of MMF treatment (pat. 5). The daily MMF dosage ranged from 0.5 to 2.5 g and had to be reduced in three patients due to gastrointestinal problems (pat. 3), and persistent leucopenia (pat. 10).
Anecdotic reports, uncontrolled open label and retro spective studies with MMF had shown clinical improvement and steroid dose reduction in patients with severe refractory MG [2, 4]. The time to improvement in that trials was highly variable and ranged from 2 weeks to 12 months [6, 7]. A small double-blind, placebo-controlled pilot trial of MMF with concomitant prednisolon and/or cyclosporine A medication in MG showed a significant improvement of MMF compared to placebo . However, two recent randomized, double blind, placebo-controlled studies with larger cohorts failed to show a benefit for MMF in generalized MG using quantiative MG scores during a treatment period of 12 and 36 weeks, respectively [5, 6]. It is unclear whether this was due to the short duration of the follow-up period, the effect of the add-on steroid therapy, or the insufficient effect of MMF in MG itself. Consistent with our study side effects of MMF are often transitory and mild, including mostly gastrointestinal symptoms as nausea and diarrhoea or headache [4, 5]. However, severe side effects as an increased risk of lymphoproliferative disorders  and severe skin reactions might also be associated with MMF therapy. It remains open whether the bronchial cancer diagnosed in one of our patients was related to MMF.
The present study shows that MMF led to the reduction of concomitant medication and of AZA induced side effects in the majority of patients.
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Hanisch, F., Wendt, M. & Zierz, S. Mycophenolate mofetil as second line immunosuppressant in myasthenia gravis - a long-term prospective open-label study. Eur J Med Res 14, 364 (2009). https://doi.org/10.1186/2047-783X-14-8-364