Mycophenolate Mofetil in Immune-mediated Neurological Diseases – A Comprehensive Review

This effect manifests clinically as an anti-proliferative effect on T- and B-lymphocytes, inhibition of polyclonally activated B-lymphocyte antibody formation, decreased production of the inducible form of nitric oxide (NO) (reducing tissue damage by nitrites), and the prevention of glycosylation and expression of certain adhesion molecules on lymphocytes leading to decreased lymphocytic and monocytic recruitment and penetration into sites of inflammation.^1–3 It has also been shown to inhibit the superantigen-induced production of interleukins (IL^)-1–6 and 10, tumor necrosis factor (TNF)-a, TNF-ß, and granulocyte– monocyte colony stimulating factor (GM-CSF) using in-vitro-activated human mononuclear cells.⁴

MMF was initially approved for the prophylaxis of organ rejection in adult renal, cardiac, and hepatic allograft recipients in the mid-to-late 1990s. Soon after, reports of successful treatments of such neurological diseases as myasthenia gravis (MG), multiple sclerosis (MS), dysimmune neuropathies, and inflammatory myopathies began to appear in the literature. It has also been used as an effective treatment of other autoimmune diseases, including lupus, vasculitis, rheumatoid arthritis (RA),Takayasu’s arteritis, and psoriasis.⁵

Dosing and Safety
MMF is utilized at similar doses as in the large organ transplant trials, typically up to 2–3g per day in two divided doses. It has a relatively low side effect profile limited mostly to gastrointestinal (GI) complaints— specifically diarrhea, vomiting, and/or mild abdominal pain. Mild lymphocytopenia can also occur, but both typically respond to dose reduction, thrice-daily dosing, or discontinuation in severe cases. However, due to its ability to suppress T- and B-lymphocytes, the potential for more significant lymphocytopenia without neutropenia or anemia exists. Chronic suppression of lymphocytes has been shown to lead to an increased risk of lymphoproliferative disorders, including non-Hodgkin’s lymphoma, thought to be secondary to antigenicity of transplanted tissue, inadequate cytotoxic T-cell activity, and Epstein–Barr virus (EBV)-infected lymphocytes. Vernino et al. reported a case of immunosuppressionrelated primary central nervous system lymphoma (PCNSL), in an elderly patient who had been taking MMF for MG for three years, that responded to discontinuation of MMF and a trial of four courses of rituximab therapy.6 Diminished leukocyte counts could also theoretically lead to an increased risk of infections. In a study looking at the safety and tolerability of MMF in MG, Meriggioli et al. reported a single case of West Nile virus (WNV) that occurred during MMF therapy.⁷ Current recommendations call for monthly complete blood cell counts and MMF dose reduction if the total leukocyte count is less than 1,300/µl.6 In the authors’ clinic, they usually receive bi-weekly blood counts with differentials for the first two months, followed by monthly blood counts with differentials for four to six months to monitor for downward trends.

Galindo et al.8 reported a case of toxic myopathy induced by MMF, in a patient being treated for lupus nephritis characterized by asthenia, proximal lower extremity weakness, elevated muscle enzymes, a ‘myopathic’ electromyogram (EMG), and an abnormal muscle biopsy, that improved after drug cessation.⁸ Levin et al.⁹ reported a case of a papulosquamous psoriatic skin eruption in a young man that began approximately one month after institution of MMF for MG.⁹

Review of Clinical Studies

Myasthenia Gravis
MG is an acquired autoimmune disease in which autoantibodies against acetylcholine receptors (AChRs) at the neuromuscular junction prevent adequate neuromuscular transmission, leading to fatigue and weakness of striatal muscles ranging from mild proximal limb weakness and/or diplopia to severe quadriparesis, bulbar dysfunction, and respiratory failure requiring mechanical ventilation.

Traditional therapies for MG have included surgical thymectomy, symptomatic treatment with acetylcholinesterase inhibitors such as pyridostigmine, short-term immunosuppression with plasma exchange or intravenous (IV) immunoglobulin, and long-term immunosuppression with corticosteroids, azathioprine, cyclosporine, and cyclophosphamide.

In the last decade, newer agents such as MMF have been used with increasing frequency for long-term immunosuppression. The first reported successful treatment of MG with MMF was by Hauser et al.10 In this case report, the authors describe a 14-year-old girl with severe MG refractory to previous treatments with azathioprine, prednisone, and cyclosporine who improved rapidly and eventually reached pharmacological remission after insitituting MMF at 1,500mg per day in three divided doses. Merrigioli and Rowin reported another case of a young woman with seropositive, generalized MG refractory to thymectomy, prednisone, azathioprine, and cyclosporine, who responded to MMF within three weeks of 2g daily dosing. Eventually, the patient’s pyridostigmine requirements and prednisone and cyclosporine doses were reduced and her quantitative myasthenia gravis score (QMGS) improved from 18 to ^{10. 11}

These reports led to a six-month open-label pilot study of twelve patients receiving MMF for refractory MG. Each patient received MMF 1g twice-daily for the duration of the study with goal efficacy defined as a reduction in the QMGS by three points, manual muscle testing (MMT) score by two points, or a 50% corticosteroid dose reduction. Eight patients improved, two by corticosteroid dose reduction and six by QMGS and MMT scores. In all eight patients, improvement began between two and eight weeks and continued through the duration of the trial. No serious side effects were reported.¹²

Chaudhry et al. retrospectively studied 32 refractory myasthenic patients treated with MMF 1g twice-daily either alone or in combination with corticosteroids. They reported that 69% of their patients demonstrated improvement as evidenced by reduction of steroid dose (50%) or by functional improvement in strength (59%). No serious side effects were reported.¹³

Meriggioli et al. performed a double-blind placebocontrolled pilot study of 14 MG patients with suboptimally treated, stable disease as defined by “persistent daily symptoms of fatigable weakness involving ocular, bulbar, or extremity muscles.”14 All patients receiving MMF significantly improved their QMG and MMT scores and had greater reduction in AChR antibody titers compared with placebo. Single-fiber EMG jitter decrease in treated patients was statistically significant. No serious side effects were reported.¹⁴

Merrigioli et al. also retrospectively reviewed 85 MG patients treated with MMF, looking at efficacy, safety, and tolerability utilizing the Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) scale.^7,15 Doses ranged from 1g to 3g/day. Seventy-three per cent attained a PIS rating of ‘pharmacologic remission’, ‘minimal manifestations’, or ‘improved’. Of the 62 patients receiving corticosteroids, a corticosteroid-sparing effect was seen with discontinuation in 13%. Thirty-seven per cent decreased their steroid dose by at least 50% and 23% decreased their dose by less than 50%. Of the 51 patients receiving pyridostigmine, the dose was decreased in 57%. Mean onset to objective improvement was 10.8 weeks with maximal objective improvement occurring by a mean of 26.7 weeks. One or more side effects were seen in 27%. MMF was discontinued due to side effects in five patients (6%).⁷ In summary, MMF appears to be a well-tolerated, effective therapy for the treatment of MG. There are currently two on-going large, prospective, randomized placebo-controlled studies to further evaluate the safety, efficacy, and steroid-sparing effects of MMF, and to provide support for US Food and Drug Administration (FDA) approval of MMF in MG.

Inflammator Myopathies
MMF is a potentially viable option for the idiopathic inflammatory myopathies, a group of disorders traditionally treated with steroids and other immunosuppressants that typically have more side effects. Of the three most common—polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM)—PM would appear to be the bestsuited for MMF as it is characterized by endomysial infiltrates consisting primarily of CD8-positive cells, and to a lesser degree, CD4-positive cells, macrophages,and B-cells.¹⁶ However, there have been no randomized controlled trials evaluating MMF in inflammatory myopathies to date. Mowzoon et al. reported a single case of PM secondary to limb-girdle muscular dystrophy and another of IBM that responded well to MMF therapy.17 The patient with PM went from being wheelchair bound to standing and taking a few steps within one month of MMF at 1g twice-daily. The patient with biopsy-proven IBM had reported increases in grip and tibialis anterior strength after 12 months of MMF 1,500–2,000mg/day and prednisone 30mg/day.¹⁷

Schneider et al. reported successful treatment of a patient with severe, biopsy-proven PM associated with pleuritis, ulcerative colitis, and ankylosing spondylitis refractory to intravenous immunoglobulin (IVIg), oral glucocorticoids, azathioprine, and cyclophosphamide. The patient demonstrated clinical improvement within four weeks of MMF therapy at 1.5g/day and by six months was in clinical remission, allowing for discontinuation of glucocorticoids and eventual reduction of MMF dose to 1g per day. No serious side effects were reported.¹⁶ Chaudhry et al. reported one patient with PM who responded to MMF and two patients with IBM who did not.¹³

Majithia and Harisdangkul reported a case series of MMF-responsive, biopsy-proven, refractory inflammatory myopathies in a total of seven patients—four with DM and three with PM. Six out of seven patients responded to MMF at 2g per day for 12 to 36 months’ treatment duration. Improvement was measured by increased strength, decreased serum muscle enzymes, and decreased inflammatory markers. One severely affected, refractory patient died during treatment as a result of sepsis and respiratory failure not felt to be secondary to MMF treatment. One patient experienced cytopenia while concomitantly receiving azathioprine. No other serious adverse events were reported.¹⁸

Immune-mediated Neuropathies
MMF has been used in chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and anti-myelin associated glycoproteins (MAG) neuropathy with varying degrees of success. However, there have been no randomized controlled trials evaluating MMF in the treatment of dysimmune neuropathies. In the case series by Mowzoon et al, two patients had severe, refractory CIDP of eight years’ duration with ‘maximum disability’ requiring frequent IVIg in one and plasma exchange (PE) in the other.¹⁷ Both demonstrated moderate improvement (at least two Medical Research Council (MRC) grades of improvement in one to five muscle groups or sensory areas), within three and 18 months of MMF treatment at 1g twice-daily. No side effects were reported.17 Chaudhry et al. reported improvement in one out of three patients with CIDP treated with MMF at 2g per day based on improved strength and a steroid-sparing effect.¹³ Gorson et al. reported their experience with MMF in the treatment of refractory CIDP, demyelinating neuropathy associated with osteosclerotic myeloma, and monoclonal gammopathy of unknown significance (MGUS). In their series they looked at 21 patients with demyelinating neuropathy receiving a mean dose of MMF of 2.1g per day.Twelve patients met criteria for CIDP and were treated for an average of 15 months. Four of eight patients with monoclonal protein elevations had anti-MAG antibodies, and all eight were treated for an average of 14 months. After MMF treatment, there were no significant differences found in median MRC, sensory, or Rankin scores in comparison with baseline; however, the average amount of M-protein dropped by 22% in the eight patients with elevated M-protein. Twenty per cent of their patients did exhibit a beneficial effect of decreased steroid dose and increased duration between IVIg infusions. No serious adverse events were reported. The authors suggested that the severity of disease in their patient population may be an explanation for the relatively poor response.¹⁹

Benedetti et al. treated six patients, two with CIDP and four with MMN, who were IVIg-dependent (2g/Kg every four weeks), with MMF 2g per day for an average of nine months.The IVIg dosage was reduced by half in two patients and discontinued in two. Four patients were also able to discontinue their other immunosuppressant agents. Two patients discontinued MMF secondary to anorexia, weight loss, abdominal pain, and increased serum amylase levels.²⁰

In summary, it appears that MMF can likely provide a steroid-sparing effect, decrease IVIg need, and possibly diminish the need for other potentially more toxic immunosuppressant therapies in immunemediated neuropathies. Case reports such as those by Mowzoon et al. should be taken with caution given that patients with maximal weakness for several years are unlikely to respond to immununomodulatory therapies due to axonal loss. Randomized controlled trials are necessary.¹⁷

Multiple Sclerosis
MS is an autoimmune disease mediated by activated T- and B-lymphocytes that attack myelinated axons in the CNS, and is an apparently suitable disease for MMF therapy. Although more selective immunomodulatory therapies currently exist, their overall clinical effectiveness leaves open a possible role for adjunctive therapies.MMF has already shown success in animal models of experimental allergic encephalomyelitis.^21,22 Ahrens et al. performed an open-label trial of MMF 2g per day in seven patients with refractory chronic progressive or relapsing MS.²³ They reported improvement in five patients as measured by number of relapses, improved movement, magnetic resonance imaging (MRI) lesion load, or decreased or halted progression. Side effects were minimal, except in one patient who had to decrease the dose secondary to frequent infections.²³

Frohman et al. retrospectively reviewed their experience with 79 patients with longstanding MS (mean duration 17.6 years) treated with MMF 2g per day as mostly an adjunctive therapy to either interferon (IFN)-? or glatiramer acetate.⁵ Although MMF was well-tolerated, no objective change in clinical course was observed; twelve patients, well known to the authors, exhibited subjective improvements in relapse rate, activities of daily living, daily chronic fatigue, ambulation, assistive device need, or exercise tolerance. Side effects were minimal.⁵

In summary, further randomized controlled trials will be needed to determine the efficacy of MMF as adjunctive or sole treatment of MS.There is currently an on-going prospective randomized controlled trial examining MMF in combination with IFN-?1a in early MS. Cluster Headache
Rozen recently reported a case of severe refractory cluster headache transiently responsive to MMF therapy.²⁴ In this report, the author discusses MMF’s ability to block IL-2-dependent T-cell proliferation as a possible mechanism for treating cluster headache, and MMF’s possible role as a steroid-sparing agent.24 Randomized controlled studies are warranted.

Comparison with Competitor Products
Although no head-to-head clinical trials involving MMF in the treatment of MG, inflammatory myopathies, dysimmune neuropathies, and MS currently exist, it may be possible to compare MMF with other currently used immunosuppressants based on reported efficacy rates and side effect profiles. In general, MMF is far more expensive than corticosteroids and azathioprine but cheaper than cyclosporine A (CyA), cyclophosphamide, and IVIg. One must also consider the accompanying morbidity of oral glucocorticoids and how this may affect healthcare costs for the patient on long-term steroid therapy, so that any steroid-sparing effect of MMF may actually limit the costs of chronic therapy. This also applies to the other previously mentioned agents.

Oral corticosteroids have traditionally been a mainstay of treatment in MG, inflammatory myopathies, and dysimmune neuropathies. They induce improvement in about 80% of patients with MG.²⁵ Recent reviews of retrospective studies in the treatment of PM, DM, and CIDP suggest effective clinical improvement in 60–70% of patients treated with oral steroids.^26,27 Their rapid effect and low cost make them ideal in the acute setting of MG. However, long-term use of steroids leads to weight gain, impaired glucose tolerance or diabetes, hypertension, mood alterations, bone density loss, skin changes, and cataract formation.

Azathioprine (Aza), a suppressor of B- and T-cell proliferation via modulation of the purine synthesis pathway, produces improvement in roughly 80% of patients with MG;28 however, maximal improvement may take up to 12 months. It has also been shown to decrease relapse rate and MRI lesion load in MS.²⁹ Aza appears to be effective in the treatment of inflammatory myopathies when used in combination with methotrexate (MTX).30 Side effects include nausea, vomiting, myelotoxicity, hepatotoxicity, pancreatitis, frequent infections, flu-like symptoms, and an increased risk of lymphoma.^31,32

CyA is a potent immunosuppressant that alters the production of IL-2 and suppresses T-helper lymphocytes. Recent studies of CyA in severe, refractory MG suggested improvement in 85% of patients.³³ Its use in inflammatory myopathies and dysimmune neuropathies is limited to case reports and open trials that suggest some potential use in steroid-dependent or IVIgrefractory cases.^26,27 Side effects include myelotoxicity less severe than Aza, renal toxicity, hypertension, tremor, gingival hyperplasia, hirsutism, and headaches.³²

Cyclophosphamide (CP) is an alkylating chemotherapeutic agent that blocks cell proliferation and is a strong suppressor of B-lymphocyte activation and antibody production. Owing to its toxicity, it is considered a last-line agent for the treatment of neurological immune-mediated conditions. CP has been shown to be a relatively safe and effective means of treating moderate to severe MG as an alternative to ineffective immunosuppressants or of reducing total steroid dose.^34–36 It was also recently reported as successful therapy in a refractory case of anti-musclespecific tyrosine kinase (MuSK)-associated MG.³⁷ Experience with treatment of inflammatory myopathies and CIDP is limited to case reports and small open-label trials with mixed results.^38–41 CP, given in pulse IV doses followed by oral maintenance therapy, has been shown to be an effective treatment in refractory MMN.^42–44 Many trials support the use of

CP in refractory relapsing or progressive forms of MS, with stabilization rates near 50–60%.45 Side effects include nausea, anorexia, alopecia, pulmonary fibrosis, hemorrhagic cystitis, leukopenia, and increased risk of malignancy.³²

Other newer immunosuppressants have also been appearing in the literature as potential therapies for immune-mediated neurological conditions, including tacrolimus for MG, inflammatory myopathies, and animal models of MS;46–49 rituximab for MG, MMN, anti-MAG associated neuropathy, and DM;^50–54 and etanercept for MG and CIDP.^55,56

Conclusions
MMF has shown promise as a potentially safe and effective therapy for several immune-mediated neurological conditions. It may also be an alternative to other therapies with more serious side effects, higher cost, and greater need for frequent monitoring of side effects. Additional randomized placebo-controlled studies are needed to further solidify its place in the permanent armamentarium of immune-suppressing agents utilized for neurological conditions, particularly in the realm of inflammatory myopathies, dysimmune neuropathies, and MS.