Mycophenolate mofetil (MMF) is the 2-morpholinoethyl ester of mycophenolic acid (MPA), one of the several phenol compounds first isolated by Gosio in 1896 in cultures of Penicillium stoloniferum [1]. MPA has been found to inhibit DNA synthesis by selectively inhibiting inosine monophosphate dehydrogenase (IMPDH), an enzyme that catalyzes the rate-limiting step in the de novo biosynthesis of guanine nucleotides (reviewed in [2]). MPA targets mainly T and B lymphocytes, which unlike other cell types are dependent almost exclusively on the de novo guanine nucleotide synthesis pathway for proliferation and differentiation [3]. MPA is five times more potent as an inhibitor of the IMPDH II isoform specific to lymphocytes than of the housekeeping IMPDH I isoform, found in most cell types [4]. MMF inhibits T- and B-cell proliferation [5], induces apoptosis of T cells [6], and inhibits antibody production by B cells [7].

Besides its antiproliferative effect on lymphocytes, MMF has several other mechanisms of action. Guanosine triphosphate (GTP) depletion caused by MMF impairs fucosylation and surface expression of adhesion molecules of lymphocytes and monocytes, preventing their attachment to endothelial cells during their recruitment to inflammation sites [8, 9]. As monocytes and macrophages are major producers of proinflammatory cytokines causing fibroblast recruitment and proliferation at the inflammation site (such as TNF-alpha and IL-1), their depletion reduces the production of these cytokines, inhibiting fibroblast proliferation and tissue fibrosis [10]. MPA was shown to inhibit the surface expression of antigens responsible for maturation and efficient antigen presentation by dendritic cells, thereby suppressing immune responses [11, 12]. GTP depletion also impairs inducible nitric oxide synthase (iNOS) activity, which leads to a reduction of the oxidative stress, caused by activated monocytes, macrophages, and endothelial cells [13].

MMF has 94 % oral bioavailability [14]. Following absorption MMF is converted to its active metabolite, MPA, by plasma, liver, and kidney esterases. MPA is almost completely inactivated in the liver by glucuronyl transferase [15], and a significant portion of MPA-glucuronide (MPAG) is secreted into the bile and recycled via enterohepatic recirculation. MPAG is converted back to MPA by β-glucuronidase, found mainly in the epidermis and the gastrointestinal tract. The peak plasma level of the MPA following orally administered MMF is reached in less than 1 h in healthy subjects. The mean plasma half-life time of MPA is ~17 h, making the twice-daily MMF administration reasonable. A secondary MPA peak occurs at 8–12 h and is attributed to the enterohepatic circulation [14]. Ninety-seven percent of MPA is albumin bound. Most of the drug is excreted as MPAG in the urine [14, 16].

The most common side effects of MMF are nausea, vomiting, abdominal cramps, and diarrhea, reported in 12–36 % of patients [17]. All are dose dependent and seem to be more prevalent in transplant recipients, compared to patients with autoimmune diseases, probably owing to a higher concomitant immunosuppression of these patients [18–20]. Enteric-coated mycophenolate sodium (EC-MPS), in contrast to MMF, allows the drug to be absorbed in the small bowel [21] and has been designed to reduce the gastrointestinal side effects, attributed to MMF. EC-MPS has been shown to have similar efficacy and safety to MMF in transplant recipients [22–24], and its ability to significantly reduce the rate of gastrointestinal symptoms has been debated [22–26].

Other potentially dangerous but rare gastrointestinal side effects, such as ulceration, bleeding, and perforation, have been reported [18].

Hematologic side effects, dose dependent and reversible upon discontinuation of the drug, include leukopenia, neutropenia, anemia, and thrombocytopenia [27]. Rare cases of pure red cell aplasia, sometimes reversible upon dose reduction/drug withdrawal, have been described in patients treated with MMF [28, 29]. There are reports of genitourinary side effects of urgency, frequency, dysuria, hematuria, and sterile pyuria, which generally resolve with continued drug use [27, 30, 31]. Neurologic complaints (headache, tinnitus, and insomnia), skin rash, and cardiovascular effects (peripheral edema and hypertension) have also been described [27]. MPA/MMF treatment has been associated with both bacterial and viral infections (especially herpes zoster [32, 33] and cytomegalovirus (CMV) [34–36]). Increased incidence of CMV invasive disease but not of primary CMV infection has been reported in renal transplant recipients given MMF and concomitantly treated with other immunosuppressive agents [35, 36]. In stem cell transplant recipients with positive CMV-IgG, MMF use increased the risk for both CMV infection and complicated CMV infection, but not for CMV disease [34].

Polyoma virus-associated progressive multifocal leukoencephalopathy, a demyelinating disease of the central nervous system appearing in immunocompromised patients, has been reported in a small number of renal transplant recipients [37, 38], as well as in patients with lupus [39] treated with MMF. Accordingly, a safety report was issued by FDA, informing healthcare professionals of a potential association between MMF/EC-MPS and PML [40].

The ability of MMF to induce malignancy is controversial. MMF is expected to be less carcinogenic than azathioprine because it is not incorporated into the DNA and does not cause chromosomal breaks [41]. Some studies reported a dose-dependent increase in the risk of lymphoproliferative malignancy in MMF-treated organ transplant patients [42–44], but this finding was not supported in a comparative study of MMF based and other immunosuppressive regimens in renal transplant patients [45]. Furthermore, MMF was associated with a significantly lower risk for posttransplant malignancy, as compared with azathioprine in heart transplant recipients [46]. In dermatologic literature an early report described three cases of malignancy during MMF treatment in psoriatic patients [47]. Subsequently, Epinette et al. found no increase in the incidence of cancer in psoriatic patients treated with MMF [32].

A limited number of case reports suggested that MMF exposure during pregnancy could cause serious fetal malformations, such as microtia, cleft lip, cleft palate, and atresia of the external auditory canals, as well as increase the risk for first trimester spontaneous abortion [48–51]. Accordingly, MMF/EC-MPS is classified as pregnancy category D (there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks), and it is recommended to use two different reliable methods of birth control 4 weeks prior to starting and during MMF therapy and continue birth control for 6 weeks after MMF has been stopped. One week before MMF/EC-MPS therapy is initiated, women of childbearing potential should have a negative serum or urine pregnancy test [52].

A number of drugs are known to interact with MMF via mechanisms of absorption inhibition (antacids containing aluminum and magnesium as well as divalent cations such as calcium and iron), disruption of enterohepatic recirculation (antibiotics, cholestyramine), albumin binding (phenytoin, salicylic acid), and prevention of kidney tubular secretion of MPA (acyclovir, ganciclovir, probenecid) [53, 54]. Accordingly, calcium supplementation, which is often required in patients with autoimmune bullous diseases concomitantly treated with steroids and MMF, should not be taken at the same time of the day as MMF.

MPA was first applied in dermatology in the 1970s as an anti-inflammatory agent to treat moderate to severe psoriasis [55, 56]. However, by the end of the decade, its use was discontinued owing to the gastrointestinal side effects, increased risk of latent viral infections, and possible carcinogenicity [47]. A decade later MMF, the 2-morpholinoethyl ester of MPA, received FDA approval as an immunosuppressive agent in renal transplant patients, with studies showing that it had better oral bioavailability than MPA and caused fewer gastrointestinal side effects. Owing to its long-term safety and tolerability, it began to be applied in other fields, including dermatology.

Autoimmune bullous diseases are a group of blistering disorders that share a pathogenetic mechanism of autoantibody production against different epidermal and dermoepidermal junction proteins. High-dose steroids are the traditional first-line treatment, but their multiple and potentially severe side effects with prolonged use have prompted dermatologists to seek alternative/steroid-sparing agents. Today, immunosuppressive agents such as azathioprine, cyclophosphamide, and MMF are widely used in the treatment of these diseases.

The initial evidence of the benefit of MMF for pemphigus stems from a number of case series, reporting the efficacy of MMF as a steroid-sparing agent.

Enk et al. combined MMF (2g/day) with prednisolone (2 mg/kg/day) in 12 patients with pemphigus vulgaris, who had relapsed during azathioprine and prednisolone therapy. Eleven patients responded to this therapy with no relapses during the 9–12-month follow-up period [57]. A similar regimen was applied by Chams-Davatchi in ten patients with pemphigus vulgaris with severe resistant/recurrent disease. The lesions completely cleared in nine patients by 6–16 weeks. Five patients relapsed after MMF discontinuation at a 6-month follow-up, suggesting MMF should be administered for a longer period to sustain remission [58]. Several years later, a large historical prospective trial was conducted including 31 patients with pemphigus vulgaris and 11 patients with pemphigus foliaceus, who had relapsed on prednisone therapy or had had adverse effects from previous drug therapy [20]. Combined treatment with prednisone and MMF (35–45 mg/kg) led to complete remission in 71 % of the pemphigus vulgaris group and 45 % of the pemphigus foliaceus group. The mean time to remission was 9 months, and the remission was maintained throughout the 22 months of follow-up.

Powell et al. reported treating 16 refractory pemphigus vulgaris and pemphigus foliaceus patients with MMF (starting at 500 mg/day and increasing as tolerated up to 3.5 g/day) and prednisone. Clinically inactive disease was achieved in seven patients. The much lower doses of prednisone at the time of MMF initiation in this study are noteworthy and may explain the relatively low rate of clinical remission. MMF doses higher than 2 g/day were not associated with a better outcome, but increased the risk for opportunistic infections [59].

In a recently published retrospective study of 18 pemphigus vulgaris patients treated with 2–3 g/day MMF and prednisone (ranging from 35 to 100 mg/day) and followed up for an average of 35.2 months, 86 % of previously treated patients and 75 % of patients with no prior therapy achieved complete disease control [60]. In a prospective open-label study of MMF as a steroid-sparing agent, Esmaili et al. administered MMF (2g/day) and prednisolone (2 mg/kg/day) as an initial treatment to 31 patients with active pemphigus vulgaris with a 12-month follow-up. This regimen was beneficial for 21 patients (67.7 %), making it possible to taper prednisolone down to 7.5 mg/day in those cases [61]. Similarly to MMF, EC-MPS has also been shown to be a safe and effective adjuvant to prednisone in a series of ten patients with refractory pemphigus [62].

A more recent prospective controlled trial was conducted by Beissert et al. who randomized 96 patients with mild to moderate pemphigus vulgaris to receive MMF (2–3 g/day) plus prednisolone or placebo plus prednisolone. At the end of the 52-week follow-up, a similar treatment response rate was observed in the two groups. The patients given MMF showed faster and more durable responses, but the lack of difference in the response rate may have been attributable to the milder disease of the placebo group, which may not have needed the additional immunosuppressive therapy. Similarly to the results reported by Powell et al. [59], the 2 and 3 g/day doses of MMF displayed similar efficacy, but infectious adverse events were more frequent with the higher dose [63].

In all the aforementioned studies, the MMF therapy was well tolerated. The most common side effects were gastrointestinal complaints, lymphopenia, and bacterial and viral infections [20, 57–59, 61, 63].

MMF/mycophenolate sodium monotherapy for pemphigus vulgaris has been reported in several small case series [64, 65]. However, owing its relatively low efficacy, this treatment regimen is not generally recommended.

A number of randomized open-label trials compared the efficacy of MMF as a steroid-sparing agent to other immunosuppressive drugs in patients with pemphigus. Beissert et al. treated 40 patients with pemphigus vulgaris or pemphigus foliaceus with methylprednisolone and azathioprine or methylprednisolone and MMF. There was no difference between MMF and azathioprine in efficacy, steroid-sparing effect, or safety profile [66].

In a randomized controlled study, Chams-Davatchi et al. compared four treatment regimens in 120 patients with pemphigus vulgaris: prednisolone only, prednisolone and azathioprine, prednisolone and MMF, and prednisolone and intravenous cyclophosphamide pulse therapy. There was no difference in complete remission rate between the groups (70–80 % of patients). All immunosuppressive drugs had a steroid-sparing effect; the most efficacious was azathioprine, followed by pulse cyclophosphamide and then MMF [67].

An intention to treat analysis of data from the study reported by Beissert et al. [66] revealed MMF to be more effective in inducing disease control, as compared to azathioprine. However, combined data from the aforementioned randomized open-label trials [66, 67] showed MMF to have an inferior steroid-sparing effect compared with azathioprine [68].

A few patients with paraneoplastic pemphigus were reported to benefit from combined immunosuppressive regimens, including MMF and corticosteroids [59] or MMF, corticosteroids, and azathioprine [69].

Several case reports suggested that MMF, alone or combined with corticosteroids, is effective for the treatment of bullous pemphigoid (BP) [64, 70–72]. A large prospective randomized trial of 73 patients with bullous pemphigoid found MMF to be equally efficacious to azathioprine in inducing disease remission when combined with corticosteroids [73]. Although a trend for shorter average time to complete remission was shorter in the azathioprine-treated group, the MMF group had less liver toxicity.

EC-MPS/MMF has also been used as a steroid-sparing agent [74, 75] or in combination with dapsone [76] for the treatment of cicatricial pemphigoid (CP). Two retrospective studies addressed the role of MMF in the treatment of ocular cicatricial pemphigoid. Daniel et al. reported successful control of eye inflammation at 1 year in 70 % of 18 patients treated with MMF and prednisone [77]. Saw et al. retrospectively compared various immunosuppressive drugs in 115 patients with ocular cicatricial pemphigoid and found cyclophosphamide to be more successful (69 %) than mycophenolate (59 %) in controlling the inflammation. However, mycophenolate had the fewest side effects of all the drugs used in the study [78]. In a retrospective analysis published by Doycheva et al., ten ocular cicatricial pemphigoid patients (19 eyes) were treated with 2 g/day MMF, in some patients in combination with steroids as clinically indicated, and followed up for the mean period of 6 years [79]. Complete (58 %) or partial (42 %) control of ocular inflammation was achieved in all eyes examined; however, cicatrization progression could not be prevented in 53 % of the eyes studied.

MMF/EC-MPS has shown variable success in individual patients with epidermolysis bullosa acquisita (EBA) [75, 80–82]. Similarly, a number of case reports suggested that MMF and EC-MPS were effective for the treatment of refractory linear IgA disease [83–85] and linear IgA bullous dermatosis of childhood [86].

MMF is an immunosuppressive drug widely used today in multiple fields of medicine, including dermatology. Its advantages include its wide therapeutic index, mild side effects, and lack of major end-organ toxicity. MMF has been successfully applied for the treatment of various autoimmune blistering diseases, including pemphigus, bullous pemphigoid, and cicatricial pemphigoid, mostly as a steroid-sparing agent. According to numerous case series, MMF could be of value in treating refractory disease. The few randomized clinical trials conducted to date of patients with pemphigus and bullous pemphigoid report a similar efficacy for MMF to other immunosuppressants. Large-scale clinical trials are needed to further delineate the value of MMF in this setting.