Mycophenolate Mofetil: A Dermatologic Perspective

P. R. Mydlarski, MD, FRCPC, FAAD

Division of Dermatology, Departments of Medicine and Medical Genetics, University of Calgary, Calgary, AB, Canada

ABSTRACT

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.

Key Words:
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

Pharmacokinetics

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

Safety

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.

Dosage

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.

Clinical Uses

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.

Psoriasis

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.

Dermatitis

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.

Immunobullous Disease

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

Conclusion

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.

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