Old therapy offers new hope for skin disease

Everything old is new again could be the theme of a promising new therapy for sufferers of immune-mediated skin disease - CellCept®. P. Régine Mydlarski, M.D., F.R.C.P.C., assistant professor at the University of Calgary, says the reformulation of medication that has been around for nearly a century is an up-and-coming treatment for skin conditions in the hands of the dermatologist.

Mycophenolic acid (MPA) first came on the scene in 1913 - isolated as a fermentation product of Penicillium stoloniferum. It was used as a weak organic acid that was found to be lipid soluble and fairly easily absorbed.

Studies that followed showed MPA to have antibacterial, anti-fungal, antiviral and immunosuppressive properties. It was shown to be effective in the treatment of psoriasis in 1975, but fell out of favor because of concerns about potential side effects including: immunosuppression, carcinogenicity and gastrointestinal upset.

"Efforts were focused on creating new immunosuppressive agents and led to the development of the new semi-synthetic morpholineoethylester of MPA which is called mycophenolate mofetil (MMF or CellCept)."

As a result, the U.S. Food and Drug Administration (FDA) approved the use of MMF for kidney transplant patients in1995. Shortly thereafter, its effect on dermatological conditions was recognized, and MMF's off-label uses began to grow.

As the director of immunodermatology at the university, Dr. Mydlarski has had occasion to witness the effectiveness of MMF.

She says the medication shows potential for the treatment of a variety of skin conditions such as: psoriasis, atopic dermatitis, bullous disease, lichen planus, pyoderma gangrenosum, sarcoidosis, Behçet's disease, Crohn's disease, erythema multiforme, graft-versus-host disease and connective tissue disease, such as lupus erythematosus and dermatomyositis.

Safe optionIt appears to offer a safe, generally well-tolerated treatment option for dermatological patients. The commonly prescribed dosage is 2 to 3 grams per day. Potential side effects are headache, nausea, upset stomach, vomiting, diarrhea and urinary frequency and/or urgency.

Dr. Mydlarski says, "There is no increase in nephrotoxicity, hepatotoxicity, hypertension, or neurotoxicity when MMF is used in conjunction with cyclosporin and corticosteroids. Potentially less mutagenic than azathioprine, more extensive trials are required to determine whether MMF offers a lower risk of carcinogenicity."

Because MMF has only recently re-entered the field of dermatology, reports of its effectiveness are primarily anecdotal. But Dr. Mydlarski says the preliminary results of its use are promising enough to justify larger, randomized clinical trials.

Why effect?Dr. Mydlarski explains why MMF has the effect it does on skin conditions.

"As a non-competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), MMF blocks the conversion of inosine-5-phosphate and xanthine-5-phosphate to guanosine-5-phosphate necessary for RNA and DNA synthesis.

"Purine nucleotides may be synthesized by one of two pathways: the de novo purine synthesis pathway and the hypoxanthine-guanine phosphoribosyl transferase salvage pathway." Dr. Mydlarski goes on to say, "Not only do T and B lymphocytes lack the salvage pathway, but they possess the type II IMPDH isoform to which MMF has a particular affinity. Herein lies the selective advantage for MMF in inhibiting lymphocyte proliferation and antibody formation."

In addition, compared to its earlier incarnation, MMF is metabolized to its parent compound MPA and offers better bioavailability and tolerability, says the doctor.