Experience with Mycophenolate Mofetil among Jordanian Patients with Myasthenia Gravis

Abstract

Objectives: To  investigate  the  short- term  efficacy  and safety  of  Mycophenolate  Mofetil  treatment  among Jordanian patients with refractory myasthenia  gravis.

Methods:  This study was conducted in King Hussein Medical Centre, Prince Rashed Hospital and Prince Hashem Hospital between January 2007 and January 2009. The study included 18 patients with poorly controlled generalized moderate to severe myasthenia gravis despite treatment with Prednisolone alone or with Azathioprine. All patients received Mycophenolate Mofetil 1.5-2g daily for 9 months. The primary efficacy measure was a reduction of three points in the manual muscle test score and/or a reduction of 50% in corticosteroid dose.

Results: All patients completed the study. Twelve patients improved, beginning after 3-5 months.  The maximum benefit was after 7 months of treatment. No serious adverse effects were observed.

Conclusions: Mycophenolate mofetil is a promising alternative to other currently available immunosuppressive drugs for the treatment of refractory myasthenia gravis.

Key words: Myasthenia gravis, Mycophenolate mofetil, Refractory

JRMS September 2011; 18(3): 21-26

Introduction

Myasthenia gravis (MG) is an uncommon autoimmune condition, in which antibodies against the postsynaptic acetylcholine receptors (AChR) or related structures result in failure of neuromuscular transmission. Current estimates of prevalence in the United States are about 20 per 100.000.⁽¹⁾

 Therapy for myasthenia gravis includes symptomatic treatment with cholinesterase inhibitors, thymectomy for selected patients, immunomodulation with intravenous immunoglobulin (IVIg) and plasma exchange, and immunosuppressive therapies.

Oral immunosuppressants including corticosteroids, azathioprine and cyclosporine have been commonly used in MG. However, variable efficacy, patient tolerance and adverse side effects limit their effectiveness. Thus, more favorable alternatives are needed. Mycophenolate mofetil (MMF) has been successfully used for treating patients with allogenic transplants and immune mediated diseases.⁽²⁾  The first report suggesting efficacy of MMF  in myasthenia gravis appeared in 1998.⁽³⁾ This was followed by uncontrolled case series,^(4-6) a small double-blind controlled trial⁽⁷⁾ and a Cochrane review.⁽⁸⁾ These studies reported benefit in the majority of MG patients treated with MMF, including those with refractory disease and popularized use of the drug. However, two recently concluded randomized, controlled trials- the Muscle Study Group (MSG) and the Aspreva trials - did not demonstrate additional benefit of MMF over prednisolone as initial immunosuppression in generalized MG or a steroid-sparing effect over a period   of   9   months.^(9,10)    On  the  other  hand,  a recently published retrospective analysis has provided class IV evidence that MMF begins to improve AChR-positive MG after 6 months, both with prednisolone and as monotherapy.⁽¹¹⁾

Table I.  MGFA clinical classification

Score each function as: 0 = normal; 1 = 25% weak/mild impairment; 2 = 50% weak/moderate impairment; 3 = 75% weak/severe impairment; 4 = paralyzed/unable to do

Fig. 1. Manual muscle testing Score (5)

Fig. 2. Score for activities of daily living (5)

In this study, we report local experience using MMF in 18 Jordanian patients with refractory MG, despite treatment with prednisolone with or without azathioprine.

Methods

This study investigated the short term efficacy and safety   of   mycophenolate  mofetil  (MMF)  among Jordanian patients with uncontrolled MG over nine months. The patients were enrolled for this study from Neurology clinics at King Hussein Medical Centre (KHMC), Prince Rashed Hospital, and Prince Hashem Hospital, between January 2007 and January 2009. All patients previously diagnosed with MG and having Class III-IV (moderate-severe) disease according to the Myasthenia Gravis Foundation of America (MGFA) classification (Table I) despite high-dose immunosuppressive treatment were enrolled into the study. The patients may or may not have had previous thymectomy. Patients were considered refractory if they had a baseline  manual muscle test (MMT) score of at least 5, despite treatment with prednisolone 20mg/day or more for at least 3 months with or without azathioprine (100-200 mg/day) for at least 12 months. Patients who had undergone treatment with plasmapheresis or intravenous immunoglobulin, or had a change in their immunosuppressive medication during the previous 3 months were excluded. Azathioprine was stopped if used previously, and all patients were started on MMF 500 mg twice daily for 4 weeks, and then the dose was increased as tolerated up to 1 g twice daily.

The primary efficacy measure was a reduction of at least 3 points in the MMT and/or a reduction of at least 50% in corticosteroid dose for minimum of 3 months without worsening of the MMT scores. The MMT (Fig. 1) is a recently described, physician applied, scoring system of strength in muscles that are typically affected in MG. It has been shown to have acceptable inter rater reliability and to correlate strongly with the more established quantitative myasthenia gravis (QMG) score.^(12,13) We also used the  Activities of Daily Living (ADL) profile as a secondary efficacy measure. (Fig. 2)

MMT and ADL scores for each patient were always estimated by the same author to ensure optimal reliability.

The patients were followed-up in clinic every month for the first three months, then every two months for the remaining six months. During these clinic assessments, the MMT and ADL scores were measured, possible adverse effects of MMF were noted, and blood tests for complete blood count and biochemical profile were performed.

Results

All 18 patients completed the study.  There were 10 female and eight male patients, aged from 22 to 64 years (mean 41.5 y). Eleven patients had undergone thymectomy 3-10 years earlier. The duration of MG varied from 1 to 12 years (mean 5.1 years).  The clinical and treatment details of all patients are provided in Table II.

Table III shows the treatment results.  At the end of the study, the primary efficacy measure was achieved in twelve (66.7%) patients, nine of whom had an improvement in the MMT score of 3 or more and were able to reduce their corticosteroid dose by at least 50%. The other three patients did not have an improvement in their MMT score of 3 or more, but were able to reduce their corticosteroid dose by at least 50%. Improvement in all responders started after 3-5 months and was maximal after 7 months. Improvement in the ADL score was seen in 11 patients. 

No major side effects were observed.  No diarrhea was reported. Two patients developed heartburn and three patients developed mild nausea that improved either spontaneously or with symptomatic treatment. Three patients reported hand tremors that resolved after 2-3 weeks. One patient had muscle cramps. The hemoglobin value decreased in one patient (by 1.9 g/dl), but she was found to have iron deficiency as the cause of her anemia. No significant leukopenia or thrombocytopenias were recorded. No infections occurred.

Discussion

Mycophenolate mofetil is a prodrug of mycophenolic acid (MPA), an ihibitor of inosine monophosphate dehydrogenase, a key enzyme in the de novo (but not the salvage) pathway of purine synthesis. Since lymphocytes exclusively use the de novo pathway (whereas other cells use both pathways), MPA depletes guanosine nucleotides preferentially in T and B lymphocytes and ihibits their proliferation, thereby suppressing cell mediated immune responses and anibody formation. MPA also inhibits the glycosylation and expression of adhesion molecules, and the recruitment of lymphocytes and monocytes into sites of inflammation. It is through that MMF exert its anti inflammatory activity via all these mechanisms.^(14,15)  MMF has a strong safety profile and no major organ toxicity or mutagenic effect, and  has been used safely   and  effectively  in  managing  patients  with renal transplants.⁽¹⁴⁾  Reports in western countries showed   that   MM   appeared   to   be   effective  as adjunctive therapy in the treatment of severe, refractory and steroid-dependant myasthenia gravis.^(3-6)

Table II. Clinical characteristics of study patients

AChR-Ab = acetylcholine receptor antibodies; Aza = azathioprine; Pred = prednisone; Pyr = pyridostigmine; M=male; F=female

Table III. Manual Muscle Test (MMT) scores, Activities of Daily Living (ADL) scores and doses of prednisolone (mg) at baseline and 9 months