Mycophenolate Mofetil in Immune-mediated Neurological Diseases - A Comprehensive Review
Mycophenolate Mofetil in Immune-mediated Neurological Diseases - A Comprehensive Review
Immunomodulating and immunosuppressant medications have become commonplace in the treatment of immune-mediated neurological conditions. In the last decade, mycophenolate mofetil (MMF) (CellCept®, Roche Pharmaceuticals) has been used increasingly in the treatment of these immunemediated conditions.
Pharmacology
MMF is the 2-morpholino-ethyl ester of mycophenolic acid (MPA), a fermentation product of Penicillium stoloniferum. MPA, the pharmacologically active compound of MMF, has immunosuppressive properties due to its ability to selectively, noncompetitively, and reversibly block the nicotanimide binding site on inosine monophosphate dehydrogenase (IMPDH), an enzyme needed for purine synthesis.
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
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