Mycophenolate [MMF] for progressive MS



For odd reasons, the name mycophenolate mofetil [MMF, CellCept®] yields little references in a literature search whereas the abbreviation or the commercial name offers additional.



MMF exerts its immunosuppressive effects as an inhibitor of inosine monophosphate dehydrogenase [IMPDH] required in the synthesis of guanosine nucleotides), which is necessary for de novo biosynthesis in lymphocytes. T- and B-lymphocytes are more dependent on this pathway than other cell types are. Along with azathioprine, leflunomide, methotrexate, it is classified as antimetabolites among many other immunosuppressive drugs of interest for autoimmune diseases [21]. Moreover, MMF is a fivefold more potent inhibitor of the type II isoform of IMPDH, which is expressed in activated lymphocytes, than of the type I isoform of IMPDH, which is expressed in most cell types [1]. It has been shown to inhibit superantigen-induced production of IL-1-6 & IL-10 and TNF-alpha. Moreover, MMF can induce apoptosis of activated T-lymphocytes, which may eliminate clones of cells responding to antigenic stimulation; by depleting guanosine nucleotides, MMF suppresses glycosylation and the expression of some adhesion molecules, thereby decreasing the recruitment of lymphocytes and monocytes into sites of inflammation and graft rejection; and finally, by depleting guanosine nucleotides MMF also depletes tetrahydrobiopterin, a co-factor for the inducible form of nitric oxide synthase. MMF thus suppresses tissue damage mediated by NO. In total, MMF has therefore a more potent cytostatic effect on lymphocytes than on other cell types.

         MMF is the morpholinoethyl ester of mycophenolic acid, which is its active metabolite. This can be measured and was found to reach maximum levels within 60 min after oral ingestion [2]. Neumann et al. [3] found a high interindividual alteration among pharmacokinetic data both in renal transplant patients and patients with autoimmune diseases and recommend therefore therapeutic drug monitoring. In renal transplant, MMF has been described to provide improved renal function while maintaining adequate immunosuppression [4]. The drug has a rapidly reversible activity without deposit effects.

         What disturbs with other immunosuppressives is a rather unspecific action, a high rate of adverse effects compared to the more diffuse aspects of a therapeutic one. Therefore, azathioprine can rely upon long use and mitoxantron on controlled studies instead. In contrast, MMF has only been used as a desperate alternative in comparatively few patients but therefore, it mainly affects the desired cell types, shows a good safety profile and (in striking contrast to mitoxantron) does not accumulate.


Therapeutic use in various diseases

The drug is primarily used for prevention of organ transplant rejection, where improved graft survival rates have been reported. In large multicenter trials with almost 1500 patients [ref. required], MMF has been proven highly efficacious for transplant rejection prophylaxis with the main side-effects of gastrointestinal disorders and a slightly increased incidence of viral infections. Anecdotic reports of success have been given in many autoimmune diseases:

         Filler et al. [2] used MMF in 15 children with various types of vasculitis and connective tissue disease. MMF induced remission in 4 of 9 patients with active disease. Only 1 of the 5 other patients relapsed. All 6 patients with controlled disease maintained remission. In uveitis, Zierhut et al. [5] used MMF in 10 patients, who had stopped other immunosuppressive therapy due to adverse effects. Eight patients remained free of recurrences while the success was partial in the remaining two.

         Mieshler et al. [6] compared the use of MMF in 15 patients with Crohn’s disease with 30 matched patients treated with AZA. Both drugs are effective in inducing remission. but AZA seemed to be more effective in maintaining remission. Almost 20% stopped therapy during the first year. Also Neurath [7] used it for patients with Crohn’s disease.

         Grundmann-Kollmann et al. [8] used MMF for psoriasis in a 10-week study of 11 patients, during which time only patients with moderate psoriasis and psoriatic arthritis improved with therapy, whereas patients with severe psoriasis did not respond. The same study group [9] tried MMF in the treatment of blistering autoimmune diseases (pemphigus vulgaris and bullous pemphigoid). All patients were completely free of symptoms within 8 to 11 weeks of therapy. Nousari et al. [10] employed it for 8 patients with various autoimmune skin diseases, most of whom had developed adverse effects to other immunosuppressives. MMF was effective in all these cases but the doses necessary varied from 500 to 1250 mg twice daily. Geilen et al. [11] used MMF in 11 cases of psoriasis, in 10 evaluated as successful but in one case, the drug was discontinued, suspected of causing muscle pain.

         Kouba et al. [12] reported successful use of MMF in five patients with sarcoidosis, leading to decreased use if steroids. Goldblum [13] used it against rheumatoid arthritis.

         In animal studies, Maksimovic [14] demonstrated an antidiabetic effect.


Use of Cell-Cept in MS

From a theoretical basis, MMF has been suggested as an agent against MS [15,16]. Experimentally, Tran et al. [17,18] have shown that MMF is superior to cyclosporine A in treating EAE. In clinical practice, however, only two small open studies were actually found, offering data upon a few patients with progressive MS. Ahrens et al. [19] presented data of 7 patients (ages 34-51 years, duration of MS 4-21 years, EDDS 4.0-7.0) where MMF was utilized as a rescue medication, apparently without maintaining previous therapy. In 5 of these 7, MMF led to improvement or stopped progression, but one of these five stopped therapy due to nausea and another had to reduce the dosage to 1.5 g daily because of frequent infections. Heesen et al. [20] described another 4 patients, in which the drug acted as rescue medication (stopping progress) in 3 cases while the 4th case retrospectively was classified as a benignous MS in which anything could be attributed to success. I hope the practical basis for this theoretically promising drug can be supplemented by publications offering a more broad practical basis.



Oral treatment is begun with 0.5 g twice a day, doubled within a week (3 g daily does not offer any advantages to 2 g), unless adverse effects (nausea, susceptibility to dangerous infections) make an interruption mandatory. Combination with other immunosuppressive agents (except glucocorticoids) should be avoided.


Inserted December 12, 2002

Last revision May 1, 2004

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        1     Allison AC, Eugui EM . Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000;47:85-118.

        2     Filler G, Hansen M, LeBlanc C, Lepage N, Franke D, Mai I, Feber J. Pharmacokinetics of myco­phenolate mofetil for autoimmune disease in children. Pediatr Nephrol 2003 Apr 8; [epub ahead of print]

        3     Neumann I, Haidinger M, Jager H, Grutzmacher H, Griesmacher A, Muller MM, Bayer PM, Meisl FT. Pharmacokinetics of mycophenolate mofetil in patients with autoimmune diseases compared renal transplant recipients. J Am Soc Nephrol 2003;14:721-7.

        4     de Mattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis 2000;35:333-46.

        5     Zierhut M, Stubiger N, Aboalchamat W, Landenberger H, Bialasiewicz AA, Engelmann K. Immunosuppressive therapy with mycophenolate mofetil (CellCept) in treatment of uveitis (article in German). Ophthalmologe 2001;98:647-51.

        6     Miehsler W, Reinisch W, Moser G, Gangl A, Vogelsang H. Is mycophenolate mofetil an effective alternative in azathioprine-intolerant patients with chronic active Crohn's disease? Am J Gastroenterol 2001;96:782-7.

        7     Neurath MF, Wanitschke R, Peters M, Krummenauer F, Meyer zum Buschenfelde KH, Schlaak JF. Randomized trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Chrohn’s disease. Gut 1999;44:625-8.

        8     Grundmann-Kollmann M, Mooser G, Schraeder P, Zollner T, Kaskel P, Ochsendorf F, Boehncke WH, Kerscher M, Kaufmann R, Peter RU. Treatment of chronic plaque-stage psoriasis and psoriatic arthritis with mycophenolate mofetil. J Am Acad Dermatol 2000;42:835-7.

        9     Grundmann-Kollmann M, Korting HC, Behrens S, Kaskel P, Leiter U, Krahn G, Kerscher M, Peter RU. Mycophenolate mofetil: a new therapeutic option in the treatment of blistering autoimmune diseases. J Am Acad Dermatol 1999;40:957-60.

      10     Nousari HC, Sragovich A, Kimyai-Asadi A, Orlinsky D, Anhalt GJ. Mycophenolate mofetil in autoimmune and inflammatory skin disorders. J Am Acad Dermatol 1999;40:265-8.

      11     Geilen CC, Arnold M, Orfanos CE. Mycophenolate mofetil as a systemic antipsoriatic agent: positive experience in 11 patients. Br J Dermatol 2001;144:583-6.

      12     Kouba DJ, Mimouni D, Rencic A, Nousari HC. Mycophenolate mofetil may serve as a steroid-sparing agent for sarcoidosis. Br J Dermatol 2003;148:147-8.

      13     Goldblum R. Therapy of rheumatoid arthritis with mycophenolate mofetil. Clin Exp Rheumatol 1993;11(Suppl 8):S117-9.

      14     Maksimovic D, Stojkovic MM, Stosic-Grujicic S. Antidiabetogenic effect of mycophenolate mofetil is associated with down-regulation of adhesive interactions and autoreactive cell activation. Ann N Y Acad Sci 2002;958:148-51.

      15     Confavreux C, Moreau T. Emerging treatments in multiple sclerosis: azathioprine and mofetil. Multiple Sclerosis 1996;6:379-84.

      16     Burkhardt H, Kalden JR. Xenobiotic immunosuppressive agents: therapeutic effects in animal models of autoimmune diseases. Rheumatol int 1997;17:85-90.

      17     Tran GT, Carter N, Hodgkinson SJ. Mycophenolate mofetil treatment accelerates recovery from experimental allergic encephalomyelitis. Int Immunopharmacol 2001 Sep;1(9-10):1709-23

      18     Tran GT, Carter N, He XY, Spicer TS, Plain KM, Nicolls M, Hall BM, Hodgkinson SJ. Reversal of experimental allergic encephalomyelitis with non-mitogenic, non-depleting anti-CD3 mAb therapy with a preferential effect on T(h)1 cells that is augmented by IL-4. Int Immunol 2001;13:1109-20.

      19     Ahrens N, Salama A, Haas J. Mycophenolate-mofetil in the treatment of refractory multiple sclerosis. J Neurol 2001;248;713-4.

      20     Heesen C, Engelmann K, Sturm V, Koch E, Mönch A, Feldmann H, Gbadamosi J. Mycophenolate-mofetil (MMF) for progressive MS and uveitis – experience with 4 patients. Europ. Charcot Foundat. Symp.on immunosuppressive treatments in MS, Sevilla  28-30.11.02.

      21     Kovarik JM, Burtin P. Immunosuppressants in advanced clinical development for organ transplantation and selected autoimmune diseases.Expert Opin Emerg Drugs 2003;8:47-62.