P. R. Mydlarski, MD, FRCPC, FAAD
Division of Dermatology, Departments of Medicine and Medical Genetics, University of Calgary, Calgary, AB, Canada
Introduced in the 1970s as a treatment for psoriasis, mycophenolic acid has since been reformulated as mycophenolate mofetil (MMF). With an improved side-effect profile and enhanced bioavailability, MMF is a promising drug for immune-mediated skin disease. Currently approved for the prevention of organ rejection, its list of “off-label” dermatologic indications continues to grow. As a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), MMF inhibits de novo purine synthesis. Its relative lack of hepatonephrotoxicity and seemingly low risk of carcinogenicity offer important therapeutic advantages. While case reports and case series dominate the dermatologic literature, preliminary results are sufficiently promising to warrant larger, randomized clinical trials with this emerging therapy.
mycophenolate mofetil, CellCept®, inflammatory skin disease, dermatology
In the past two decades, an increasing number of immunosuppressive agents have been developed to prevent allograft rejection in organ transplantation. A number of these medications have shown therapeutic efficacy in inflammatory skin disease; however, patients and physicians must be mindful of their toxicities. Originally isolated from cultures of Penicillium stoloniferum, mycophenolic acid (MPA) was first recognized as a lipid-soluble, weak organic acid.1 It was later shown to have antibacterial, antiviral, antifungal, antitumoral and immunosuppressive properties.2-6 In 1975, MPA demonstrated therapeutic efficacy in psoriasis.7 However, it soon fell into disrepute with growing concerns about its long-term risk of carcinogenicity. Moreover, tolerability of MPA was limited by gastrointestinal upset. Subsequent investigations led to the development of mycophenolate mofetil (MMF) (CellCept®, Roche Pharmaceuticals), the semi-synthetic 2-morpholinoethyl ester of MPA.8 This new formulation showed enhanced bioavailability, tolerability and efficacy.8 By 1995, MMF received US FDA approval for the prevention of acute renal allograft rejection and soon became recognized as an effective treatment option for immune-mediated skin disease.
Mechanism of Action
Mycophenolate mofetil selectively and noncompetitively inhibits inosine monophosphate dehydrogenase (IMPDH) in the de novo purine synthesis pathway. This enzyme facilitates the conversion of inosine monophosphate to xanthine monophosphate, an intermediate metabolite in the production of guanosine triphosphate. As MMF results in the depletion of guanosine nucleotides, it impairs RNA, DNA and protein synthesis.9
The purine bases, adenosine and guanosine, may be synthesized through two pathways: the de novo purine synthesis pathway, and the hypoxanthine-guanine phosphoribosyl transferase salvage pathway. As lymphocytes lack the salvage pathway, MMF selectively inhibits lymphocyte proliferation and antibody formation. Moreover, MMF preferentially blocks the type II isoform of IMPDH, predominantly located on lymphocytes; thus, it also holds potent cytostatic effects on T and B cells.9 Herein lies the selective advantage of this immunosuppressive agent.
Mycophenolate also prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in adhesion to endothelial cells. It may further inhibit the recruitment of leukocytes to sites of inflammation and impair antigen presentation.10 While it does not inhibit early events in the activation of human peripheral blood mononuclear cells (i.e., IL-1 and IL-2 production), MMF blocks the coupling of these events to DNA synthesis and proliferation.9
After ingestion, MMF is hydrolyzed to its parent compound, MPA, by plasma esterases. Predominantly bound to albumin, MPA has a bioavailability that approaches 94%.11 The peak concentration of the active metabolite is obtained within 60-90 minutes after oral administration. Upon systemic absorption, MPA undergoes hepatic conjugation to its inactive glucuronide form (MPAG).
Approximately 87% of the drug is excreted through the kidneys, 6% in the feces and the remainder undergoes enterohepatic recirculation. Beta-glucuronidase, found within the epidermis and gastrointestinal tract, can convert MPAG to the active MPA form.11
At usual doses, MMF is generally well tolerated. Compared to other immunosuppressants, such as methotrexate, azathioprine and cyclosporine, the lack of hepatonephrotoxicity with MMF offers an important therapeutic advantage. The most common side-effects are gastrointestinal (i.e., nausea, diarrhea, abdominal cramps, constipation, vomiting and anorexia) and genitourinary (i.e., urgency, frequency, dysuria, hematuria and, occasionally, sterile pyuria). These occur in up to 36% and 40% of patients, respectively. Other reported adverse events include neurologic (i.e., headache, tinnitus and insomnia), cutaneous (i.e., exanthematous eruptions, acne and pedal edema), cardiorespiratory (i.e., dyspnea, cough, chest pain, palpitations and hypertension) and metabolic (i.e., hypercholesterolemia, hyperglycemia, hypophosphatemia and hypo/hyperkalemia) reactions. Severe leukopenia has been reported to occur in less than 3% of MMF-treated patients. However, unlike treatment with azathioprine, use of MMF does not put patients with an inherited deficiency of thiopurine methyltransferase at risk.12
Infection rates with MMF therapy are difficult to quantify in the dermatologic literature. Opportunistic infections occur in up to 40% of transplant patients treated with MMF; however, the majority of these patients are also treated with other immunosuppressive agents.13 In addition to standard bacterial and viral infections, patients are at increased risk for herpes simplex, herpes zoster, cytomegalovirus, candidiasis, cryptococcosis, aspergillosis, mucormycosis and Pneumocystis carinii pneumonia.13 When compared to renal transplant patients treated with azathiprine, those treated with MMF have a higher incidence of herpes simplex and tissue invasive CMV infections.13
The long-term risk of carcinogenicity with MMF remains controversial. In the dermatologic literature, few malignancies have been reported in patients receiving MMF or its pro-drug, MPA. Lymphoproliferative disease or lymphoma developed in 0.4%-1% of patients receiving MMF with other immunosuppressive agents for renal, cardiac and hepatic transplantation.13 As part of controlled clinical trials, these patients were followed for >1 year. Non-melanoma skin cancer occurred in 1.6%-4.2% of patients, while other types of malignancy appeared in 0.7%-2.1% of patients.13 Three-year safety data in renal and cardiac transplant patients failed to reveal any changes in the incidence of malignancy.13
The risk of malignancy may be related to the intensity and duration of immunosuppression rather than the use of any specific agent. However, certain immunosuppressants are known to be mutagenic and carcinogenic. For instance, urinary, myeloproliferative, lymphoproliferative and cutaneous malignancies occur in a significant number of patients treated with cyclophosphamide.13 Moreover, the active metabolite of azathioprine, 6-thioguanine, is a purine analogue that becomes incorporated into DNA. This process may cause chromosomal breakage with resultant mutagenesis.14 As a noncompetitive inhibitor of purine synthesis, MMF fails to initiate chromosomal breaks. Potentially less mutagenic than azathioprine, MMF may have a lower risk of carcinogenicity; however, it will take several years for this advantage to be substantiated.
While there are no adequate studies on MMF in pregnant women, the drug has been shown to be teratogenic in animals. Therefore, MMF should be avoided during pregnancy unless the potential benefit justifies the potential risk to the fetus (pregnancy risk C).
Possible drug interactions with MMF are listed in Table 1.
In adults, the usual dose of MMF ranges from 2-3g/day.15 In the pediatric population, MMF should be administered as 600mg/m2 per dose every 12 hours.15 While renal insufficiency has no consistent effect on the pharmacokinetics of MPA, dose reductions should be considered in patients with severe renal impairment.15 In order to prevent a disease flare, many clinicians would consider tapering MMF slowly.
Mycophenolate mofetil is currently available as 250mg capsules, 500mg tablets, a powder for oral suspension (200mg/ml), and a lyophilized, sterile powder for intravenous administration. In many countries, an enteric-coated formulation may also be accessible. While a topical formulation may yield promising results, one has yet to be made commercially available.
The average cost for a 1-month course of MMF in Canada, administered at a dose of 1g twice daily, amounts to $560 CDN.
Approved for the prevention of organ rejection, the list of “off-label” indications for MMF continues to grow. Case reports and open-label clinical trials document its use in the dermatologic literature. Potential indications are listed in Table 2, and select dermatoses are reviewed below.
|Drug||Mechanism of Drug Interaction||Effect on MP Levels|
|Cholestyramine||Inhibit enterohepatic recirculation of MP||Decrease|
|Antacids (Al, Mg)||Decrease absorption of MP||Decrease|
|Divalent Cations (Ca, Fe)||Decrease absorption of MP||Decrease|
|Metronidazole||Decrease bioavailability of MP||Decrease|
|Fluoroquinolones||Decrease bioavailability of MP||Decrease|
|Probenecid||Inhibit tubular secretion of MP||Increase|
|Acyclovir||Inhibit tubular secretion of MP||Increase|
|Ganciclovir||Inhibit tubular secretion of MP||Increase|
|Salicylates||crease free fraction||Increase|
|Azathioprine||Not studied||Not Studied|
|Table 1: Drug interactions with mycophenolate mofetil.|
MP=mycophenolate; Al=aluminum; Mg=magnesium; Ca=calcium; and Fe=iron.
|Connective tissue disease|
|Recurrent erythema multiforme|
|Cutaneous Crohn’s disease|
|Table 2: Potential dermatologic uses of mycophenolate mofetil|
Multiple case reports suggest that MMF is an effective treatment option for psoriasis.16-20 In a study of 11 patients with stable plaque-type psoriasis, the efficacy of MMF was measured using the Psoriasis Area and Severity Index (PASI) score.21 Patients initially received MMF 1g twice daily for 3 weeks followed by 0.5g twice daily. Within 3 weeks of therapy, there was a reduction in PASI of between 40% and 70% in seven of the 11 patients. Only one patient achieved a reduction in PASI of <25% from baseline. After 6 weeks, there was further improvement in six patients. However, PASI worsened in four patients when MMF was tapered to the lower dosage.
In a two-center, prospective, open-label clinical trial, 23 patients with moderate to severe psoriasis were treated with MMF 2-3g/day for 12 weeks.22 In the 18 patients who completed the study, the PASI was reduced by 24% (p < 0.001) at 6 weeks and by 47% (p < 0.001) at 12 weeks. Moreover, MMF appeared to have a beneficial effect on patients suffering from psoriatic arthritis. The treatment was well tolerated: five patients developed nausea, one patient experienced periorbital edema and pruritus, and one patient had a transient leukopenia. Thus, MMF monotherapy appears to be an effective treatment for patients with moderate-to-severe, plaque-type psoriasis.
In a pilot study of 10 patients with severe refractory atopic dermatitis, MMF was increased to a dose of
2g/day.23 After 12 weeks of therapy, the median scores for disease severity (SCORAD index) improved by 68%. These findings were associated with a significant decrease in serum IgE and a shift in the T-helper (Th)-1 to Th2 cytokine ratio.
In another study of 10 patients with moderate-to-severe atopic dermatitis, MMF was administered at 2g/day for a month and tapered to 1g/day.24 In a 20 week follow-up period, there was a 74% reduction in the SCORAD index as compared with baseline (p < 0.01). Dyshidrotic eczema and chronic actinic dermatitis have also responded to MMF therapy.
Multiple case series have documented the efficacy of MMF as a steroid-sparing agent in the autoimmune mucocutaneous blistering diseases. In a historical, prospective study, Mimouni, et al. studied 42 consecutive patients with pemphigus who were recalcitrant to standard therapies.25 Of these patients, 31 were diagnosed with pemphigus vulgaris (PV) and 11 with pemphigus foliaceus (PF). A complete remission was obtained in 22 (71%) and 5 (45%) of PV and PF patients, respectively. The treatment was administered for an average of 22 months, and the median time to achieve remission was 9 months. In two patients, MMF was discontinued for nausea and symptomatic, reversible neutropenia. Others have demonstrated similar success with MMF in treating patients with PV, PF, paraneoplastic pemphigus, bullous pemphigoid, mucous membrane pemphigoid, linear IgA disease and epidermolysis bullosa acquisita.26-32
Connective Tissue Disease
The efficacy of MMF in systemic lupus erythematosus has been clearly validated. Moreover, the cutaneous lesions of subacute cutaneous lupus, chronic discoid lupus and lupus perniosis have shown response to MMF therapy. Clinical improvement has also been demonstrated in other connective tissue diseases such as dermatomyositis, scleroderma, urticarial vasculitis, Takayasu’s arteritis, microscopic polyangiitis, Wegener’s granulomatosis, polyarteritis nodosa and Behçet’s disease.6,15
Other Dermatologic Disease
Mycophenolate mofetil has been shown to benefit other dermatologic conditions including lichen planus, pyoderma gangrenosum, graft-versus-host disease, recurrent erythema multiforme, Steven-Johnson syndrome, sarcoidosis, and cutaneous Crohn’s disease.6,15
In a variety of inflammatory skin disorders, MMF has been successfully used both in combination with systemic steroids and as monotherapy. Early reports on efficacy and tolerability suggest that MMF offers hope to patients with immune-mediated skin disease. As gleaned from transplant data, its safety profile appears reassuring. However, randomized clinical trials with long surveillance periods are warranted to validate the efficacy and safety of MMF in the treatment of dermatologic disease.
- Alsberg CL, Black OF. Contribution to the study of maize deterioration; biochemical and toxicological investigations of Penicillium puberulum and Penicillium stoloniferum. Bull Burl Anim Ind. US Dept Agr 270:1-47 (1913).
- Abraham EP. The effect of mycophenolic acid on the growth of Staphylococcus aureus in heart broth. Biochem J 39:398-404 (1945).
- Abrams R, Bentley M. Biosynthesis of nucleic acid purines. I. Formation of guanine from adenine compounds in bone marrow extracts. Arch Biochem 56(1):184-95 (1955 May).
- Cline JC, Nelson JD, Gerzon K, Williams RH, Delong DC. In vitro antiviral activity of mycophenolic acid and its reversal by guanine-type compounds. Appl Microbiol 18(1):14-20 (1969 Jul).
- Kosugi Y, Saito Y, Mori S. Antiviral activities of mizoribine and other inosine monophosphate dehydrogenase inhibitors against several ortho- and paramyxoviruses. Antiviral Chem Chemother 5:366-71 (1994).
- Liu V, Mackool BT. Mycophenolate in dermatology. J Dermatolog Treat 14(4):203-11 (2003 Dec).
- Jones EL, Epinette WW, Hackney VC, Menendez L, Frost P. Treatment of psoriasis with oral mycophenolic acid. J Invest Dermatol 65(6):537-42 (1975 Dec).
- Lee WA, Gu L, Miksztal AR, Chu N, Leung K, Nelson PH. Bioavailability improvement of mycophenolic acid through amino ester derivatization. Pharm Res 7(2):161-6 (1990 Feb).
- Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant 10(1 Pt 2):77-84 (1996 Feb).
- Mehling A, Grabbe S, Voskort M, Schwarz T, Luger TA, Beissert S. Mycophenolate mofetil impairs the maturation and function of murine dendritic cells. J Immunol 165(5):2374-81 (2000 Sep 1).
- Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34(6):429-55 (1998 Jun).
- Sievers TM, Rossi SJ, Ghobrial RM, et al. Mycophenolate mofetil. Pharmacotherapy 17(6):1178-97 (1997 Nov-Dec).
- Repchinsky C, editor. Compendium of pharmaceuticals and specialties: the Canadian drug reference for health professionals. Ottawa: Canadian Pharmacists Association (2004).
- Kitchin JE, Pomeranz MK, Pak G, Washenik K, Shupack JL. Rediscovering mycophenolic acid: a review of its mechanism, side effects, and potential uses. J Am Acad Dermatol 37(3 Pt 1):445-9 (1997 Sep).
- Assmann T, Ruzicka T. New immunosuppressive drugs in dermatology (mycophenolate mofetil, tacrolimus): unapproved uses, dosages, or indications. Clin Dermatol 20(5):505-14 (2002 Sep-Oct).
- Nousari HC, Sragovich A, Kimyai-Asadi A, Orlinsky D, Anhalt GJ. Mycophenolate mofetil in autoimmune and inflammatory skin disorders. J Am Acad Dermatol 40(2 Pt 1):265-8 (1999 Feb).
- Geilen CC, Tebbe B, Garcia Bartels C, Krengel S, Orfanos CE. Successful treatment of erythrodermic psoriasis with mycophenolate mofetil. Br J Dermatol 138(6):1101-2 (1998 Jun).
- Haufs MG, Beissert S, Grabbe S, Schutte B, Luger TA. Psoriasis vulgaris treated successfully with mycophenolate mofetil. Br J Dermatol 138(1):179-81 (1998 Jan).
- Tong DW, Walder BK. Widespread plaque psoriasis responsive to mycophenolate mofetil. Australas J Dermatol 40(3):135-7 (1999 Aug).
- Grundmann-Kollmann M, Mooser G, Schraeder P, et al. Treatment of chronic plaque-stage psoriasis and psoriatic arthritis with mycophenolate mofetil. J Am Acad Dermatol 42(5 Pt 1):835-7 (2000 May).
- Geilen CC, Arnold M, Orfanos CE. Mycophenolate mofetil as a systemic antipsoriatic agent: positive experience in 11 patients. Br J Dermatol 144(3):583-6 (2001 Mar).
- Zhou Y, Rosenthal D, Dutz J, Ho V. Mycophenolate Mofetil (CellCept(R)) for Psoriasis: A Two-Center, Prospective, Open-Label Clinical Trial. J Cutan Med Surg 7:193-7 (2003 Apr).
- Neuber K, Schwartz I, Itschert G, Dieck AT. Treatment of atopic eczema with oral mycophenolate mofetil. Br J Dermatol 143(2):385-91 (2000 Aug).
- Grundmann-Kollmann M, Kaufmann R, Zollner TM. Treatment of atopic dermatitis with mycophenolate mofetil. Br J Dermatol 145(2):351-2 (2001 Aug).
- Mimouni D, Anhalt GJ, Cummins DL, Kouba DJ, Thorne JE, Nousary HC. Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil. Arch Dermatol 139(6):739-42 (2003 Jun).
- Enk AH, Knop J. Mycophenolate is effective in the treatment of pemphigus vulgaris. Arch Dermatol 135(1):54-6 (1999 Jan).
- Farley-Li J, Mancini AJ. Treatment of linear IgA bullous dermatosis of childhood with mycophenolate mofetil. Arch Dermatol 139(9):1121-4 (2003 Sep).
- Nousari HC, Griffin WA, Anhalt GJ. Successful therapy for bullous pemphigoid with mycophenolate mofetil. J Am Acad Dermatol 39(3):497-8 (1998 Sep).
- Katz KH, Marks JG Jr, Helm KF. Pemphigus foliaceus successfully treated with mycophenolate mofetil as a steroid-sparing agent. J Am Acad Dermatol 42(3):514-5 (2000 Mar).
- Megahed M, Schmiedeberg S, Becker J, Ruzicka T. Treatment of cicatricial pemphigoid with mycophenolate mofetil as a steroid-sparing agent. J Am Acad Dermatol 45(2):256-9 (2001 Aug).
- Williams JV, Marks JG Jr, Billingsley EM. Use of mycophenolate mofetil in the treatment of paraneoplastic pemphigus. Br J Dermatol 142(3):506-8 (2000 Mar).
- Schattenkirchner S, Eming S, Hunzelmann N, Krieg T, Smola H. Treatment of epidermolysis bullosa acquisita with mycophenolate mofetil and autologous keratinocyte grafting. Br J Dermatol 141(5):932-3 (1999 Nov).