Mycophenolate Mofetil: Attracting Attention
Mycophenolate Mofetil: Attracting Attention
Abstracts & Commentary
Sources: Chaudhry V, et al. Mycophenolate mofetil: A safe and promising immunosuppressant in neuromuscular diseases. Neurology 2001;56:94-96. Ciafaloni E, et al. Mycophenolate mofetil for myasthenia gravis: An open-label pilot study. Neurology 2001;56:97-99.
Mycophenolate mofetil (MM, Cellcept) is of demonstrable benefit for the prevention of renal allograft rejection, and for the treatment of Crohn’s disease, systemic lupus erythematosus, and rheumatoid arthritis. It now appears promising for immune mediated neuromuscular diseases as well.
Retrospective analysis was undertaken of patients with myasthenia gravis (MG, n = 32), polymyositis (PM, n = 1), inclusion body myositis (IBM, n = 2), or chronic inflammatory demyelinating polyneuropathy (CIDP, n = 3). All had received MM 1 g twice daily for 3-36 months (mean 12 months). MM was instituted as a steroid sparing agent (n = 26) or as an adjunct to steroids (n = 32), azathioprine (n = 8), cyclosporine-A (n = 4), methotrexate (n = 3), plasma exchange, or intravenous immunoglobulin (n = 10). Improvement of 1 grade or more on functional status or reduction of steroid dose by 10 mg or more every other day was defined as improvement.
Improvement was seen in 63% overall, 22 with MG and one each with polymyositis and CIDP, at a mean of five months of treatment (range, 2-12 months). MG nonresponders tended to have a longer history of MG (14 vs 7.5 years) and a shorter period of MM treatment (8 vs 13 months). Side effects were minor and included gastrointestinal discomfort (n = 3), diarrhea, and depressed mood (n = 1 each). MM appears to be a safe and effective immunosuppressant in the treatment of autoimmune neuromuscular diseases.
Prospectively, MM appears promising as well. Twelve MG patients, including seven with refractory MG and five treated with corticosteroids alone but requiring further immunosuppression, were given MM 1 g twice daily for six months. MG was diagnosed using standard criteria (Neurology 2000;55:912-913) and patients with or without thymectomy or elevated acetylcholine receptor antibodies were included. Primary end points included reduction of more than 3 points on the quantitative MG (QMG) score (Ann NY Acad Sci 1998;841:769-772) with reduction of more than two points on manual muscle testing (MMT), or reduction of steroid dose by more than 50% without worsening of QMG or MMT. Activities of daily living (ADL), assessed by questionnaire, served as a secondary end point.
Eight patients improved and one worsened. Of the remaining three, two improved only by QMG score and one by MMT and were thus considered unchanged by end point criteria. Improvement began by two weeks and was seen in all responders by two months. No significant side effects were noted and seven responders opted for continued MM on study completion. One did not, due to the high cost of MM. MM appears to be a useful, though expensive, adjunct in the treatment of MG and may be efficacious as sole therapy. Larger, double-blinded, placebo-controlled studies are warranted.
Commentary
MM, an ester of mycophenolic acid isolated originally from penicillium culture in 1896, has antineoplastic, antibacterial, antifungal, antiviral, and, most recently discovered, immunosuppressive activity (Am J Health Syst Pharm 1997;54:285-294). Approved by the FDA in 1995 for the prevention of renal allograft rejection, it is currently one of the standard immunosuppressive agents following transplantation. Small case series have also shown MM to be beneficial in lupus nephritis (J Am Soc Nephrol 1999;10:833-839), Wegener’s granulomatosis (J Am Soc Nephrol 1999;10:1965-1971), Takayasu’s arteritis (Ann Intern Med 1999;130:422-426), and glomerulonephritis (Am J Kidney Dis 1998;31:213-217), though longer follow-up in the latter demonstrated several nonresponders and additional adverse effects (Am J Kidney Dis 1998;32:898-899). Autoimmune hepatitis (J Hepatol 2000;33:371-375) and the skin manifestations of dermatomyositis (J Rheumatol 2000;27:1542-1545) also respond to MM. With wider experience comes a single case report of tuberculosis reactivation (Am J Kidney Dis 2000;35:E12) and indications that the morbidity of cytomegalovirus (CMV) infection may be increased, although the overall incidence of CMV infection is not (Clin Transplant 2000;14:136-138).
One of four new xenobiotic immunosuppressive agents, including tacrolimus (FK506), sirolimus (rapamycin), and leflunomide, MM is a prodrug that is rapidly converted to its active metabolite, mycophenolic acid (MPA), following oral or intravenous administration. MPA blocks de novo purine biosynthesis by potently, selectively, and noncompetitively inhibiting inosine monophosphate dehydrogenase (IMPDH), the rate limiting enzyme that converts inosine monophosphate (IMP) to guanosine monophosphate (GMP). Guanosine triphosphate (GTP), and consequently DNA synthesis, is impaired and, as this de novo pathway operates in T and B lymphocytes, proliferation of T and B cells are selectively inhibited. In nonlymphocytic cells, a salvage pathway allows GMP synthesis via hypoxanthine-guanine phosphoribosyltransferase (Ann NY Acad Sci 1990;696:63-87; Clin Transplant 1993;7:96-112). MM is rapidly absorbed, with 94% bioavailability following oral administration, and converted to MPA which is further metabolized to inactive MPA glucuronide and excreted in the urine (Cancer Res 1972;32:1803-1809).
MM is generally well tolerated. In large multicenter trials, adverse effects have included gastrointestinal problems (diarrhea, abdominal pain, nausea), opportunistic infections (CMV, Herpes simplex, Herpes zoster, Candida, Pneumocystis, Aspergillus, Mucor), and myelosuppression (leukopenia, anemia, thrombocytopenia) (Transplantation 1995;60:225-232). Discontinuation of MM was necessary in 12.4% (113 patients) due to side effects, and, in the longterm, malignancies occurred more frequently in MM treated patients, albeit with an overall frequency of less than 2%. Clearly promising as a new immunosuppressant, further careful study is warranted. —Michael Rubin
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