Mycophenolate mofetil

Mycophenolate mofetil in dermatology

Alissa K. Orvis, BS,a Stanton K. Wesson, MD,b Thomas S. Breza, Jr, MD,b Ann A. Church, MD,b
Christina L. Mitchell, MD,b and Shannon W. Watkins, MDb
Gainesville, Florida

Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid (MPA), a medication used to treat psoriasis in the 1970s until side effects and the concern of carcinogenesis led to its discontinuation. The prodrug, MMF, emerged decades later in the transplant field. Dermatologists have since used MMF off-label to treat various inflammatory skin conditions, with most research concentrating on its use in psoriasis, autoimmune blistering disorders, dermatitides, and connective tissue disorders. The appeal of MMF is predicated upon its lymphocyte specificity and consequent decreased toxicity profile. These attributes may make it a preferable treatment option. Its use in the field of dermatology is currently limited by a lack of randomized controlled trials, potential unknown side effects, and cost of treatment. In reviewing both current literature and our own clinic records, MMF appears to be a promising therapeutic option for the treatment of cutaneous inflammatory diseases. ( J Am Acad Dermatol 2009;60:183-99.)

Learning objective: After completing this learning activity, participants should be able to summarize the history and pharmacology of mycophenolate mofetil as an immunosuppressant; recognize its potential role in the treatment of dermatologic conditions, including general dosing guidelines, use in pregnancy and pediatrics, and potential adverse effects; and identify future considerations and developing areas of research regarding the use of mycophenolate mofetil in dermatology.

HISTORY
Mycophenolate mofetil (MMF) is a prodrug of an older drug, mycophenolic acid (MPA). MPA was isolated as a fermentation product of Penicillium stoloniferum cultures by Gosio in 1896.1 In the 1940s, antifungal and antibacterial activity of MPA were recognized.2 It was studied as a potential antibiotic until the 1970s, when its antiviral, antitumor, and immunosuppressive properties were elucidated.3,4 MPA was used as a systemic agent to treat psoriasis in the 1970s.5,6 However, its tolerability was limited by gastrointestinal (GI) upset—it caused nausea, vomiting, diarrhea, and cramps in most patients. Furthermore, concern regarding the long-term risk of carcinogenesis arose as the link between immu- nosuppression and the development of cancer was beginning to be elucidated. Despite relatively few cases of MPA-associated malignancies, the concern surrounding the carcinogenic potential combined
with poor tolerability led to discontinuation of the use of MPA in the field of dermatology.7
Subsequent investigations led to the development of a prodrug, MMF. It proved to have higher bioa- vailability, efficacy, and fewer GI side effects.8 In 1995, MMF was approved by the US Food and Drug Administration (FDA) for the prevention of both renal and cardiac allograft rejection and later for the prevention of hepatic allograft rejection. Soon there- after, MMF showed promise for several immune- mediated dermatologic conditions.

PHARMACOLOGY
Pharmacokinetics
Following oral or parenteral administration of MMF, the 2-morpholino-ethyl ester of MPA (Fig 1), it is rapidly and completely hydrolyzed to its parent compound, MPA, by plasma esterases. In healthy adults, the oral bioavailability of the active drug, MPA, is 94% when compared to intravenous infusion. The volume of distribution is 3.6 and 4.0 L/kg following parenteral and oral administration, respec-

From the Department of Medicine,b University of Florida College
of Medicine.a Funding sources: None.
Conflicts of interest: None declared.
Reprint requests: Stanton K. Wesson, MD, Department of Medicine, University of Florida College of Medicine, PO Box 100277, Gainesville, FL 32611. E-mail: [email protected]. edu.
0190-9622/$36.00
ª 2008 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2008.08.049
tively. Ninety-seven percent of MPA circulates bound to plasma albumin. Hemodialysis has not been found to significantly remove MPA from the patient.9
MPA is mainly metabolized by glucoronyl tranfer- ase in the liver to form the phenolic glucuronide of MPA (MPAG.) MPAG is an inactive metabolite that also binds plasma albumin (82%). Circulating MPAG can be converted into active MPA through enter- ohepatic recirculation.10

183

Fig 1. Comparison of the molecular structures of myco- phenolate mofetil and mycophenolic acid. Mycophenolate mofetil is the 2-morpholino-ethyl ester prodrug of the parent drug, mycophenolic acid.

Less than 1% of the administered dose of MMF is excreted as the active drug, MPA. The majority (87%) of the administered dose is excreted as MPAG in the urine. Therefore, it is not surprising that there are increased levels of MMF metabolites, both active and inactive, in patients with renal insufficiency. 9,11 The remainder of inactive metabolites can be recovered in the feces.10

Mechanism of action
MMF is a lymphocyte selective immunosuppres- sive agent that inhibits de novo purine synthesis via its active metabolite, MPA (Fig 2). Specifically, MPA depletes guanosine nucleotides by noncompeti- tively, selectively, and reversibly inhibiting inosine monophosphate dehydrogenase (IMPDH), prefer- entially the type II isoform predominantly located on lymphocytes.7 IMPDH is required for purine synthe- sis. The enzyme converts inosine monophosphate to xanthine monophosphate. Xanthine monophos- phate is an intermediate metabolite that becomes the purine nucleotide, guanosine triphosphate (GTP). GTP is needed for RNA, DNA, and protein synthesis. Therefore, MMF depletes the de novo production of guanosine nucleotides. The addition of guanosine or deoxyguanosine has been shown to reverse the cytostatic effects MMF has on lympho- cytes by providing products of the inhibited pathway.12
T and B cell proliferation is almost solely depen- dent on such de novo purine synthesis. Other cells of the body depend heavily on a salvage pathway via

hypoxanthine-guanine phosporibosyl transferase. However, T and B cells lack this salvage pathway. This explains the selective nature of MMF for lym- phocytes and antibody formation.7
While MMF has cytostatic effects on lymphocytes, it also suppresses antibody formation. In addition, MMF inhibits the recruitment of leukocytes into areas of inflammation by decreasing lymphocyte and monocyte adhesion to endothelial cells. MMF does this by blocking glycosylation of lymphocyte and monocyte glycoproteins required for adhesion to the endothelial cells.12
Many of MMF’s appealing attributes can be illus- trated through its comparison to azathioprine. MMF interferes with the same general steps as azathio- prine, but it is more selective. Azathioprine is a prodrug of 6-mercaptopurine which competitively inhibits several enzymes in purine synthesis, includ- ing xanthine oxidase and thiopurine-s-methyltrans- ferase (TPMT).13,14 This explains why azathioprine targets several cell populations and can account for more severe and extensive side effects, whereas MMF is more selective. It further explains how azathioprine, but not MMF, can be toxic to individ- uals afflicted by TPMT deficiency. One of azathio- prine’s metabolites, 6- thioguanine, incorporates into DNA and can cause chromosomal breakage, result- ing in mutagenesis. MMF, on the other hand, is potentially less mutagenic because it is not known to cause such chromosomal breaks.7

MYCOPHENOLATE MOFETIL USE IN DERMATOLOGY
Like many other immunosuppressive agents used in the transplant field, MMF has also demonstrated a therapeutic effect against inflammatory skin dis- eases. Such applications are currently available solely off-label because of a lack of large randomized clinical trials. However, evidence is growing that MMF may be useful in treating a variety of dermato- logic conditions (Table I). The appeal of MMF in dermatology is largely related to both its steroid- sparing effects and its relative lack of toxicity. MMF currently plays its biggest role in two major patient populations. First, it is a treatment option for patients who cannot tolerate other medications secondary to concomitant disease, enzymatic deficiency, or un- bearable side effects. MMF is often used as a steroid- sparing agent to avoid or decrease the unwanted side effects accompanying chronic steroid use. Second, it is an option for the treatment of severe, refractory inflammatory skin diseases that have failed to re- spond adequately to other treatment regimens. In such situations, MMF is generally used as either monotherapy or adjuvant therapy and is usually

Fig 2. Mechanism of action of mycophenolate mofetil. Two pathways exist for creating purine nucleotides: the de novo pathway and the salvage pathway. Lymphocytes rely heavily on the de novo pathway, and the salvage pathway is less active in lymphocytes. Mycophenolate mofetil is hydrolyzed into its active metabolite, mycophenolic acid, by plasma esterases. Mycophenolic acid noncompetitively and reversibly inhibits inosine monophosphate dehy- drogenase of the de novo pathway, ultimately depleting guanosine nucleotides required for DNA, RNA, and protein synthesis. Cells which use the salvage pathway more heavily than lymphocytes are affected less, explaining mycophenolate mofetil’s selective effects on lymphocytes. (Abbreviations: dGTP, deoxyguanosine triphosphate; GMP, guanosine mono- phosphate; GTP, guanosine triphosphate; HGPRT, hypoxanthine-guanine phosphoribosyl- transferase; IMP, inosine monophosphate; MMF, mycophenolate mofetil; MPA, mycophenolic acid; PRPP, 5-phosphoribosyl-1-phosphate; XMP, xanthine monophosphate.)

titrated to 1 to 2 g daily, with a maximum dose of 3 g daily. Here we explore and review the use of MMF in the field of dermatology and discuss its therapeutic possibilities and limitations.

Psoriasis
The off-label use of MMF for skin disease emerged mainly in treating psoriasis and was first published in a case report15 in 1998. An elderly male suffering from chronic recurrent relapsing psoriasis vulgaris was successfully treated, with no side effects, using 1 g twice-daily MMF as monotherapy. The psoriatic plaques cleared completely in 3 weeks, and no signs of new lesions were evident at a 3-month follow-up. The patient’s Psoriasis Area and Severity Index
(PASI) score decreased from 22.0 to 11.4 over 5 weeks.15 Numerous reports since have described the utility of MMF in treating psoriasis as either monothe- rapy or adjuvant therapy with promising results16-20 (Table II). Two of these studies reported a 75% reduction in PASI in at least 50% of subjects.16,19 Although such reduction is the current benchmark of primary endpoints for most studies involving psori- asis, it is debated that a 50% reduction may alone be clinically important.21 All except one study re- ported reaching this less stringent cut-off in the majority of subjects.17 This study evaluated the ability to switch from cyclosporin to MMF (after a 2-4 week washoutperiod)inpatientsexperiencingcyclosporin- induced nephrotoxicity. Although PASI actually

Table I. Dermatologic conditions that have been treated with mycophenolate mofetil
Psoriasis
Autoimmune blistering diseases Bullous pemphigoid Cicatricial pemphigoid Epidermolysis bullosa acuisita Paraneoplastic pemphigus Pemphigus foliaceus Pemphigus vulgaris
Dermatitis
Actinic dermatitis Atopic dermatitis Dyshidrotic dermatitis
Connective tissue disorders
Dermatomyositis Lupus eythematosus Scleroderma Vasculitides
ChurgeStrauss syndrome Hypocomplementaemic urticarial vasculitis Microscopic polyangitis
Wegner granulomatosis Graft-versus-host disease
Acute graft-versus-host disease Chronic graft-versus-host disease
Other
Cutaneous Crohn disease Erythema multiforme Erythema nodosum Leprosy
Lichen planus
Relapsing idiopathic nodular panniculitis Sarcoidosis

increased in each patient, renal function was sig- nificantly improved. Therefore, although disease control was compromised in these cases, MMF served as an important alternative therapeutic option for patients experiencing cyclosporin-induced neph- rotoxicity. With overall promising results, a baseline and follow-up monitoring and dosage protocol for the use of MMF in treating psoriasis has been devel- oped.22 Furthermore, the possibility of applying a topical formulation of MMF to psoriatic lesions is also being investigated, with encouraging results thus
23
far.

Autoimmune blistering disorders
Several studies report advantages in treating au- toimmune blistering disorders with MMF as either adjuvant or monotherapy.24-37 Diseases include pemphigus vulgaris, bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita, pem- phigus foliaceus, and paraneoplastic pemphigus.

Nearly all of these studies conclude that MMF is a well tolerated and effective corticosteroid-sparing agent in bullous disease, and several suggest that complete remission is achieved more frequently with the use of MMF over azathioprine, with less hepato- toxicity. Most recently, two multicenter, randomized, nonblinded clinical trials using patients with pem- phigus vulgaris, pemphigus foliaceus, or bullous pemphigoid compared MMF and azathioprine as adjunct therapy to oral methylprednisone. MMF had impressive rates of complete remission (72% and 100%), with no significant differences among treatment arms regarding cumulative corticosteroid doses. Severe or life-threatening adverse effects were significantly fewer—and hepatic toxicity was signif-
34,35
icantly lower—in the MMF treatment group. Another study also noted that average length of hospital stay was reduced, which helped offset the cost of MMF. This study also investigated the possible benefit of increasing MMF dose beyond the typical
1to 2 g per day. However, doses of greater than 2 g per day did not improve disease severity and were associated with higher incidences of opportunistic infections, which parallels dose recommendations in the transplant field.9,32

Dermatitides
MMF has been used off-label to treat various types of dermatitides. These conditions act pathophysio- logically via a variety of cytokine-mediated inflam- matory pathways, causing lymphocyte proliferation and infiltration. Therefore, the application of an immunosuppressant specific to lymphocytes, such as MMF, is logical and appealing. Of the numerous dermatitides, much research has focused on the use
38-43
of MMF in treating atopic dermatitis (AD). Results generally support the use of MMF in moder- ate to severe cases, most typically as monotherapy or in addition to topical steroids. Two reports use the Scoring of Atopic Dermatitis (SCORAD) scale, a clinical tool for scoring the severity of AD.39,40 Both studies found a quick and significant decrease in SCORAD (67.7% decrease at week 12 and 55.5% decrease at week 4). In general, MMF was well tolerated, with only one case report citing a major complication (Staphylococcus aureus septicemia and endocarditis).44 Recently, MMF has been used in treating childhood AD, when symptoms usually first develop, lesions are often most active, and treatment would be quite beneficial.43
MMF has also been used in actinic dermatitis.45,46 MMF as monotherapy has shown to induce signifi- cant improvement within only 6 weeks and eventual complete clearance on a maintenance dose of MMF.45 MMF may also allow a reduced dosage of

Table II. PASI reduction after mycophenolate mofetil adjuvant or monotherapy for psoriasis
Study N Length of study Average PASI reduction Subjects reaching PASI 50* Subjects reaching PASI 75*
Zhou et al19 23 3 mos 47.0% 61.0% 22.0%
Dauden et al20 6 7 mos 82.7% 100% 67.0%
Pedraz et al18 8 4 mos 60.5% 62.5% 50.0%
Geilen et al16 11 6 wks 47.2% N/Ay 0%
Davidson et al17 8 Varied 60.0% 0% 0%

PASI, Psoriasis Area and Severity Index.
*PASI 50 and PASI 75 are defined by a 50% and 75% reduction in PASI achieved by the end of the study.
yThis study reported a 40% to 70% reduction in PASI in 63.3% of patients and a 25% to 39% reduction in PASI in 27.3% of patients after 3 weeks of mycophenolate mofetil treatment.

prednisone required during psoralen plus ultraviolet A light phototherapy (PUVA) desensitization.46 However, this use is controversial, because MMF has been associated with a reported detectable increased risk in lymphoproliferative disease and other malignant neoplasms and may potentiate the photocarcinogenic risk in conjunction with PUVA.46
Lastly, MMF may be an option for the treatment of dyshidrotic eczema. When no underlying trigger mechanism can be detected and only symptomatic therapy can be offered, patients with dyshidrotic eczema are often left with recurrent, relapsing dis- ease. The literature provides one case of a patient with a 4-year history of recurrent, severe dyshidrotic eczema refractory to conventional treatments in- cluding cyclosporine. Within 4 weeks of treatment with MMF, the lesions were completely cleared and the subject remained lesion-free with no adverse effects for 12 months of follow-up on maintenance doses of MMF.47 Interestingly, one case of MMF- induced dyshidrotic eczema is reported in a hepatic transplant patient receiving MMF for rejection pre- vention. Lesions arose within 72 hours after therapy initiation, were confirmed by biopsy and skin test- ing, and resolved with discontinuation of the drug.48 This is intriguing, but it may be a solitary and unique case in which a treatment coincidentally became the culprit.

Connective tissue disorders
Of the connective tissue disorders, lupus eryth- ematosus (LE) and dermatomyositis (DM) have re- ceived the most attention regarding off-label treatment with MMF. This is likely because both diseases can require high doses of corticosteroids and other immunosuppressive agents, with which comes a plethora of toxicities and side effects. Furthermore, both conditions tend to be refractory to conventional treatment and have severe systemic effects. Because of this, novel, efficacious, and less toxic immunosuppressant regimens are sought.
Lupus erythematosus. Most studies inves- tigating the use of MMF in LE patients focus on systemic effects that are nondermatologic. Fewer publications evaluate MMF’s ability to treat skin manifestations.49-57 One retrospective study re- ported overall poor results and even worsening of skin flares in one subject.52 Otherwise, the majority of reported cases are encouraging often with quick response, long-term disease control, or even com- plete remission. Treatment with MMF significantly improved two severe cases of resistant palmoplantar discoid LE.49 Both subacute cutaneous LE and chil- blain lupus have been treated successfully with MMF, carrying implications for a potential role in scar prevention.50,56 One large study using MMF to treat refractory systemic LE found that Systemic Lupus Erythematosus Activity Index (SLEDAI) scores de- creased by 71%.54 However, no other studies used the SLEDAI or any other index, and most evidence relies on less objective, less reliable outcomes that can be difficult to compare. Perhaps if a validated skin-specific measure is consistently used, such as the emerging Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), clearer- cut recommendations could be developed.58,59 This limitation is emphasized by Dooley,57 who states that MMF’s use to treat systemic LE manifestations other than lupus nephritis has been ‘‘evaluated only in anecdotal case reports or series, with few well designed trials’’ having limitations including ‘‘appro- priate use and interpretation of activity and damage indices.’’
Dermatomyositis. Unfortunately, the same lim- itations are encountered when evaluating MMF’s role in DM. Though a fair amount of literature is available, most focus on muscle disease as opposed to skin manifestations, and outcomes are often reported in serum creatinine kinase (CK) levels or Manual Muscle Testing (MMT) scores. These reports offer impressive data regarding such endpoints; however, they are not as relevant to the dermatologist.60 Several case reports briefly mention broad and

general statements regarding cutaneous improve- ments.61-63 However, only one specifically high- lighted dermatologic manifestations of DM, citing MMF’s success in controlling cutaneous disease activity as a steroid-sparing agent.64 With more en- couraging results, MMF may become an important treatmentoptionforpatientswithDM,especiallythose afflicted withthe amyopathictype,whoare likely to be encountered by the dermatologist. The use of a validated tool, such as the Dermatomyositis Skin Severity Index65 or the Cutaneous Dermatomyositis Disease Area and Severity Index66 could facilitate such research.
Cutaneous vasculitides. MMF has also created a niche in the treatment of certain cutaneous vasculit- ides.67 Successful treatment of skin lesions in hypo- complementaemic urticarial vasculitis, ChurgeStrauss syndrome, microscopic polyangitis, and Wegner granulomatosis are all reported with overall good tolerability and successful response rates.68-74 In light of the latter three named vasculitides, it is not surprising that interest has developed regarding the use of MMF for antineutrophil cytoplasm antibodiese associated vasculitides with the proposal that MMF may actually aid in the removal of these pathogenic antibodies.69 Although effective in several vasculiti- des, an attempt at treating Behc¸et disease has proven nonbeneficial.75
Scleroderma. When evaluating MMF’s role in scleroderma, most studies concentrate on its thera- peutic effect as maintenance therapy for associated interstitial lung disease.76-80 Some also mention im- provements in skin disease, albeit without the use of formal scoring systems. Two studies with the specific objective of evaluating cutaneous involvement use the same (although modified) standard scoring sys- tem with agreeing and promising results.81-83 MMF may also be useful in treating morphea; MMF in combination with PUVA considerably improved the condition of a patient suffering from this localized form of scleroderma.84

Graft-versus-host disease
This severe and potentially fatal disease often presents first with cutaneous manifestations. The ability to recognize and treat the disease is therefore quite pertinent to the dermatologist. MMF has been used in both the treatment and prophylaxis of acute and chronic graft-versus-host disease (GVHD), albeit with mixed results.85-93 The idea is appealing because MMF bears a relative lack of toxicity that is quite desirable in the treatment of ill and immunosup- pressed patients. However, such immunosuppres- sion also brings light to the risk of opportunistic infection. While most studies reported similar rates

of infection when comparing current standard treatment regimens to those including MMF, some authors emphasize a high risk of MMF-induced infectious complications, most notably cytomegalo- virus (CMV).85,87 A closer look at the pharmacoki- netics of MMF in stem cell transplant patients suggests that clearance of the active metabolite, MPA, is increased in these patients and that stem cell trans- plant patients may benefit from higher or more frequent dosing.94 However, this hypothesis and its effect on infectious complications has yet to be investigated. The balance between risk and benefit is still unclear, and it is with caution that MMF might be used in treating GVHD.

Further uses of mycophenolate mofetil in dermatology
Other possible applications of MMF in the field of dermatology are expanding rapidly. After the first case report of MMF-treated lichen planus emerged in 1999,95 several similar reports have been published, including the successful treatment of lichen plano- pilaris and bullous, erosive-ulcerative, oral, and genital subtypes of lichen planus.96-98 However, its effect on atrophic scarring is not yet substantiated.96 MMF has also been studied in cutaneous sarcoidosis. Reported are several cases of severe, refractory mu- cocutaneous disease responding dramatically to MMF as a corticosteroid-sparing drug.99 These results are not surprising, because MMF has also shown to be efficacious in the treatment of other aspects of sarcoidosis.100-102 MMF has also been used success- fully to treat both erythema multiforme and erythema nodosum.103,104 Furthermore, MMF has been found to treat various cutaneous manifestations of Crohn disease, including Crohn-associated pyoderma gan- grenosum.105-107 Numerous other cases of pyoderma
108-110
gangrenosum have also responded well to MMF. Lastly, evidence suggests that MMF may even be used in the treatment of leprosy reactions111 and relapsing idiopathic nodular panniculitis.112
It is clear that MMF has numerous therapeutic possibilities in the field of dermatology. Unfortunately, a scarcity of reliable and validated evidence has limited its current use. Until more about its clinical application and associated risks are understood, cau- tion should be taken when using MMF for cutaneous disorders. It is our hope that the future will bring more concrete answers, perhaps opening the door to a new and promising treatment option for many patients.

ADVERSE EFFECTS
Common side effects
MMF is generally a well tolerated immunosup- pressive agent with a preferred side effect profile

compared to other immunosuppressives, because MMF has less nephrotoxic, hepatotoxic, and neuro- toxic effects. The most commonly reported side effects are GI and are dose-dependent, occurring in up to 20% of patients at doses of 2 g daily. Patients mostly complain of diarrhea, nausea, vomiting, ab- dominal pain, anal tenderness, soft stools, frequent stools, and constipation that are usually mild and rarely severe enough to result in discontinuation of therapy.29,50,113 It is postulated that diarrhea, one of the most common GI complaints, is caused by the mitotic inhibition of intestinal epithelium and possi- bly induction of villous atrophy, especially in those who develop diarrhea several months after initiation of MMF.114 Other side effects are hematologic, oc- curring in less than 5% of patients. These are most commonly anemia, leucopenia, and thrombocyto- penia that are usually mild, dose-related, and re- versible with discontinuation of therapy or dose

especially when exceeding doses of 2 g daily.109,129 Research focuses on transplant patients, although complex therapeutic regimens and severe immune suppression makes drawing conclusions difficult. In patients receiving 2 to 3 g of MMF daily in controlled studies for the prevention of renal, cardiac, or trans- plant rejection, infectious complications occurred in approximately 2% of renal and cardiac patients and in 5% of hepatic patients.9 Most research focuses on CMV infection. In renal transplant patients, MMF has been suggested to increase the severity but not incidence of CMV tissueeinvasive disease.130,131 A retrospective study using multivariate analysis found MMF to be an independent risk factor for CMV infection in patients who were seropositive before allogenic stem cell tranplantation.87 Several other infectious complications of MMF in transplant pa- tients are reported, including herpes simplex virus, herpes zoster, human herpes virus type 6, and

reduction.50,108 However, at doses of 3 g daily, papillomavirus infections, aspergillosis, encephalitis

leukopenia may occur in up to 34.5% of patients.9
In addition, genitourinary symptoms may occur more frequently in MMF patients within the first year of therapy, including dysuria, urgency, frequency, burning on urination, and sterile pyuria, as well as hematuria and urinary tract infection. Adverse effects reported in greater than 20% of patients treated with
2to 3 g of MMF daily for the prevention of allograft rejection include: fever, chest pain, back pain, tremor, dizziness, acne, rash, dyspepsia, peripheral edema, hypercholesterolemia, hypophosphatemia, hypokalemia, hyperkalemia, hyperglycemia, dysp- nea, cough, pharyngitis, bronchitis, pneumonia, and renal function abnormalities.9

Uncommon side effects
In reviewing many case reports, several uncom- mon side effects have been identified. While tolera- ble GI upset is relatively common, rare GI side effects include oral ulcerations, GI hemorrhage, esophagitis, gastritis, duodentitis, villous atrophy, and ischemic colitis.115-118 Uncommon cutaneous side effects in- clude generalized urticaria, dishydrotic eczema, blis- tering hand dermatitis, and onycholysis.48,119,120 Although MMF is generally accepted as having a low risk of hepatotoxicity, there are published cases of MMF-induced elevated hepatic transaminases and hyperbilirubinemia.121,122 Other uncommon side ef- fects include reversible erythroid aplasia, lymphope- nia, respiratory failure, pulmonary fibrosis, acute inflammatory syndrome, and myalgia.123-128

Infectious side effects
An elevated incidence of opportunistic infections has been reported in patients treated with MMF,
with features of WernickeeKorsakoff syndrome, streptococcus B septic shock, recurrent Escherichia coli epididymitis, intestinal microsporidosis, and pediatric disseminated varicella.85,125,132
Infectious side effects are also reported outside of the transplant field. In AD patients treated with MMF, there has been an increased incidence of herpes zoster, case reports of herpes retinitis, and one report of staphylococcus septicemia with subsequent en- docarditis.41,44,133 Staphylococcal septicemia has also been reported in a patient with MMF-treated pyo- derma gangrenosum.108 In DM patients treated with MMF, complications included Mycobacterium xenopi abscess, bronchopulmonary legionella, and pulmo- nary blastomycosis.60 Other fungal infections that have been associated with MMF include cryptococ- cosis, candidiasis, mucormycosis, and Pneumocystis jirovecii.7
There has been increasing concern regarding cases of progressive multifocal leukoencephalopa- thy, caused by the reactivation of latent John Cunningham polyomavirus, in patients receiving MMF therapy. Ten confirmed and seven possible cases, some fatal, have currently been reported. In June 2008, Roche Pharmaceuticals issued a letter to health care professionals alerting physicians of these cases and encouraging the consideration of pro- gressive multifocal leukoencephalopathy in any immunosuppressed patient with neurologic symp- toms, especially hemiparesis, apathy, confusion, cognitive deficiencies, or ataxia.134
In light of the above, it is interesting to note that MMF actually possesses antibacterial, antifungal, and antiviral properties in vitro.2,3 Furthermore, MMF has been found to potentiate the effects of several

antiviral medications.135 However, the immunosup- pressive effects of both MMF and other coadminis- tered medications likely outweigh these potentially protective properties of MMF, with an overall pre- disposition towards increased infections.

Malignancy potential
As with any immunosuppressive therapy, the potential to develop malignancy is often the most concerning adverse effect. MMF has not shown to be carcinogenic in animal studies.9 However, in human studies of MMF, the risk of malignancy is felt to be related to duration and intensity of immunosuppres- sion. Often, this may be the cumulative immunosup- pressive effect rather than a MMF-specific effect.
Most studies on malignancy potential in MMF use have been in transplant patient populations. One study showed that a small percentage of transplant patients developed lymphoproliferative disease or lymphoma while on combination immunosuppres- sive therapy including MMF.133 Another study showed that the incidence of lymphoma or lympho- proliferative diseases in cardiac, renal, and liver transplant patients receiving combination immuno- suppressive therapy, including MMF, ranged from 0.4% to 1% of these transplant patients. In addition, this study also showed the incidence of nonmela- noma skin cancer in cardiac, renal, and liver trans- plant patients on combination immunosuppressive therapy, including MMF, to range from 1.6% to 4.2%.7 Postheart transplant malignancy has been reported at 12.5% for MMF-treated patients, in comparison to

internal malignancy are increased. However, this is felt to be more of a cumulative immunosuppressive effect rather than the effect of the specific agent being used. Because of the more pronounced im- munosuppression in transplant patients, most of the reported malignancies associated with MMF have been in this patient population. In dermatologic uses of MMF, the level of immunosuppression is most often not to the degree of that seen in transplant patients; however, careful monitoring and patient counseling of the risk of malignancy are essential.

DRUG INTERACTIONS
Drug interactions with MMF can be broken down into those that reduce levels of MMF, those that increase levels of MMF, and those in which myco- phenolate reduces drug levels (Table III).
Reports have shown several medications that may result in decreased levels of MMF when administered concomitantly. Studies have shown a decrease in bioavailability of MMF with long-term coadministra- tion with rifampin.142 Fluoroquinolones and metro- nidazole have also been shown to decrease the bioavailability of MMF, which may result in lower levels of immunosuppression.7 To date, there have been no interactions shown between MMF and trimethoprim/sulfamethoxazole, b-lactam antibi- otics, glycopeptides, aminoglycosides, macrolides, tetracyclines, azole antifungals, or other antifun- gals.143 Concomitant administration with other im- munosuppressives, such as glucocorticoids or cyclosporine, may also interfere with MMF bioavail-

15.6% in azathioprine-treated patients.136 Other ma- ability, resulting in lower drug levels.144,145 Other

lignancies that have been reported include breast carcinoma, recurrent carcinoma of the scalp, and squamous cell carcinoma of the epiglottis.137
In the dermatology literature, there have been few reports of malignancy associated with MMF use. In the treatment of lupus and myasthenia gravis there
medications that may result in reduced concentra- tions of MMF with coadministration include chole- styramine (and similar medications interfering with enterohepatic circulation), antacids, iron, sevel- amer, and calcium polycarbophil (found in over the counter Fibercon [Wyeth Pharmaceuticals,

have been reports of developing primary central Richmond, VA).9,146-148 However, the interaction

nervous system lymphoma after a prolonged course of MMF.138,139 There have also been two reports of EpsteineBarr virus (EBV)erelated B cell lymphoma of the central nervous system in DM patients treated with combination therapy of methotrexate and MMF with or without prednisone.61 One case of self-resolving EBV-associated B cell lymphoma of the brain occurred in a DM patient treated with methotrexate, MMF, and prednisone, which resolved with discontinuation of methotrexate and MMF.140 In addition, there has been a report of Kaposi sarcoma in a patient with pemphigus vulgaris on combined immunosuppression with prednisone and MMF.141
With prolonged high-dose immunosuppression, the risk of both nonmelanoma skin cancer and
between iron and MMF is debatable.149
MMF concentrations may become elevated if co- administeredwithother medications.Medicationsthat upon concomitant administration result in elevated concentrations of MMF include salicylates and pro- benecid. Increased risk with a higher level of immu- nosuppression therefore could be avoided with dose reduction of MMF.7,9
When taken in combination with MMF, other medications may exhibit decreased concentrations. Of particular concern is the possibility of reduced concentration of nevirapine when coadministered with MMF. This results in a decreased antiretroviral activity that may have significant consequences in HIV patients. To date, no effects have been shown

with coadministration of other antiretroviral drugs.150 Also of particular interest is the risk of

Table III. Drug interactions with mycophenolate mofetil

decreased concentrations of levonorgestrel with concomitant administration of MMF. Oral contracep- tives containing desogestrel, gestodene, or ethiny- lestradiol have shown no reduction in bioavailability
Drugs which may reduce MMF serum levels
Rifampin
Drugs which may increase MMF serum levels
Salicylates
Drugs which may have increased serum levels
if given with MMF
Nevirapine

with coadministration with MMF. However, cautious coadministration of MMF with oral contraceptives is recommended.9
Several studies on the interaction between MMF and systemic antiherpetic agents have been pub- lished. It has been shown that the antiherpes activity of acyclovir, ganciclovir, and penciclovir is potenti- ated by the coadministration of MMF.135 Acyclovir and ganciclovir may also compete for renal tubular secretion in patients with renal impairment, and cautious coadministration of MMF is advised because
Fluoroquinolones Furosemide
Metronidazole Probenacide
Glucocorticoids Acyclovir*
Cyclosporin Gancyclovir* Cholestryamine
Antacids Sevelamer Calcium
polycarbophil Iron

MMF, Mycophenolate mofetil.
Levonorgestrel Acyclovir* Gancyclovir*

of increased concentrations of both drugs.9 In addi- tion, there may be an increased risk of neutropenia with coadministration of valacyclovir and MMF, as demonstrated in one case report.151
MMF is contraindicated in patients who have experienced allergic reactions to MMF, MMA, or Polysorbate 80 (TWEEN 80; ICI Americas, Inc, Bridgewater, NJ). It is also recommended that MMF not be taken with azathioprine because both have the potential to cause bone marrow suppression, and clinical studies are not yet available regarding this combination.9

DOSING AND MONITORING
MMF is marketed by Roche Pharmaceuticals (Nutley, NJ) and is available in 250 mg capsules, 500 mg tablets, 200 mg/mL oral suspension, and 500 mg vials for intravenous injection. The cost of a month’s supply of MMF is approximately $850, which is likely one of the greatest limitations to its use.
The dosing recommendations of MMF published in the Roche Pharmaceuticals package insert are given in regard to its use in renal, cardiac, and hepatic transplant patients, because these are the only approved indications at this time. The recom- mended dose in transplant patients varies from 1 to 1.5 g twice daily, depending on the organ trans- planted. Because the use of MMF for various dermatologic diseases is off-label, there are no published dosing recommendations. However, in review the published literature on the use MMF for dermatologic disease, effective dermatologic doses are similar to those recommended in transplant patients. The starting dose typically depends on the disease being treated. Typical starting doses range from 1 to 2 g per day, usually in twice-daily dosing. If there is no improvement after 1 month of
*Both acyclovir and gancyclovir may compete with MMF metabolites for rental tubular secretion. Caution should be taken with coadministration, especially in patients with renal impairment.

therapy, doses are typically increased in 500-mg increments up to doses of 3 g per day. The package insert also recommends dosage adjustment for pa- tients with chronic renal insufficiency such that doses no higher than 1 g twice daily should be used for patients with a glomerular filtration rate less than 25 mL/min.9 It also suggests a pediatric daily dose of 600 mg/m2 based on data from renal transplant patients; however, a study with pediatric patients using MMF to treat autoimmune disease suggests a slightly higher 900 mg/m2.152
Laboratory monitoring during MMF treatment reflects the adverse effect profile discussed previ- ously. The current literature recommends a base- line complete blood cell count (CBC) with differential and platelet count, chemistry profile, and liver function tests, with only CBC with differ- ential continued weekly for the first month, bi- weekly for the second and third month, and then monthly through the first year of treatment.153 The package insert by Roche Pharmaceuticals recom- mends only CBC with differential and platelet count but following the same schedule suggested by the literature.9 With no absolute guidelines developed, it can be argued that laboratory mon- itoring schedules may be considered on an indi- vidualized basis. Obtaining a baseline chemistry and liver function profile may be considered in certain patients where chronic renal or hepatic impairment may exist. Such baseline laboratory values may help to adjust a proper MMF dose and help predict patients that may be at increased risk for serious adverse effects.

PREGNANCY AND PEDIATRIC USE
Pregnancy
For reasons of safety, there have not been any well controlled studies of MMF in pregnant women. However, in animal studies, MMF has proven to be teratogenic, causing fetal resorptions and malforma- tions.154 There have been several case reports illus- trating fetal malformations resulting from women taking MMF for transplant suppression while preg- nant. One study reported defects in four of 15 live born infants with exposure to MMF. These malfor- mations included hypoplastic nails with shortened fifth finger, cleft lip and palate, microtia, and con- genital heart defects.155 Two other reports demon- strated both facial dysmorphology with agenesis of the corpus callosum and related ear malformation

authors were able to taper off the patient’s steroid dose until she was able to be maintained on dapsone and MMF alone.36 Another case has been reported of childhood mucous membrane pemphigoid which was treated with MMF as monotherapy after tapering off the prednisone dose.160 The only case series published using MMF in childhood dermatoses was of 14 patients treated for severe AD in a retrospective analysis over 3 years. In this series, four patients achieved complete clearance, four had greater than 90% improvement, five had 60% to 90% improvement, and only one failed to respond. All were treated with MMF as systemic monotherapy.43 Further studies of safety and efficacy are warranted for use of MMF as a therapeutic alternative to other immunosuppressive agents with less favorable side effect profiles. Because

with hydrops fetalis.156,157 Unfortunately, because of the concern for risk of malignancy with long-term

many of these transplant recipients are on multidrug regimens, it is difficult to assess whether these malformations are caused by a single medication or the combination of several medications. A 2005 report by the National Transplantation Pregnancy Registry reiterated this point and encouraged more participation in the registry to gather enough data to analyze these complex questions.158 As a result of available data, MMF is currently classified as FDA pregnancy category D, meaning that there is ‘‘evi- dence of human fetal risk, though the drug’s poten- tial benefits in pregnant women may outweigh that risk.’’131
The current manufacturer’s recommendations are to only use MMF in pregnant women if the potential benefit outweighs the potential risk to the fetus. It is recommended to have a negative serum pregnancy test within 1 week before initiating therapy, and two forms of effective contraception must be used be- fore, during, and at least 6 weeks after stopping therapy. If pregnancy does occur, the patient and physician should discuss the desirability of continu- ing the pregnancy and if so, consider discontinuing therapy. The package further suggests that nursing mothers either discontinue nursing or the medica- tion. MMF metabolites have been found in the milk of rats given MMF, although human data are not yet available.9

Pediatric use
MMF has been successfully used in the pediatric population for the prevention of renal transplant rejec- tion.159 In dermatology, there have been reports of its use, with much lower frequency than that in the adult population. It was reported to be successful in a case of childhood immunoglobulin A (IgA)emediated epider- molysis bullosa acquisita. Combined with dapsone, the
immunosuppression, therapy should be attempted to be tapered until discontinued after remission has been obtained.

DISCUSSION AND OUR EXPERIENCE
A retrospective chart review of our records at the University of Florida Dermatology Clinic yielded 34 patients who had been prescribed MMF off-label for the treatment of various dermatologic diseases (Table IV). Our clinical experience with MMF is presented and discussed in this section. The relia- bility and validity of our study would be enhanced if standard scoring measures had been used. However, we feel that sharing our experience will help generate more interest and research in an area that has lacked attention and provide information that would facilitate a physician’s consideration of MMF therapy.
Our experience with the use of MMF to treat bullous pemphigoid has been good overall. Patients experienced moderate to significant responses, sat- isfactory control of disease, and minimal side effects or adverse effects. In patients with AD, MMF gener- ally provided moderate disease control and was usually used as a substitute for cyclosporine when clinically necessary. Therefore, we consider MMF to be a good rotational, temporizing drug in treating AD. In patients with LE, our general experience with MMF was mixed, with some success but many cases of suboptimal control of cutaneous disease. The use of MMF resulted in limited response, and we are unconvinced that MMF is a good second- or third- line choice for treating cutaneous manifestations of LE, although it is worthy of consideration on a case- by-case basis. In treating cicatricial pemphigoid, MMF was less than optimal, with minimal responses usually requiring further changes in treatment (most frequently replacing MMF with methotrexate) in

Table IV. Summary of our retrospective chart review (University of Florida Dermatology Clinic)
Subject no. Dx Age (y)/sex Disease severity MMF dose (g) Length of tx Response Side effects/adverse effects
1 LE 25/F Md/S 2 1 y, 5 mos Excellent None
2 LE 57/M Md/S 2 1 y Good None
3 LE 45/F S 1 4 mos None None
4 LE 45/F S 1 1 y, 1 mo Minimal Leukopenia
5 LE 26/F S Unknown Unknown None Hives and itching
6 LE 25/F Ml/Md 3 5 mos Minimal None
7 BP 38/F S 0.5-1 6 mos None None
8 BP 72/F S 1-1.5 3 y, 2 mos Good None
9 BP 86/M Md 1.5 1 y, 4 mos Excellent None
10 BP 79/F S 1 6 y, 6 mos Excellent None
11 BP 63/F S 1-2 1 y Good Gastrointestinal
disturbances 12 BP 62/M Md 1-3.5 4 y, 11 mos Good None
13 BP 33/F S 1.5 2 mos None Fatigue and dry/red eyes
14 BP 80/F Md 1.5 3 y Excellent None
15 BP 71/F Md/S 1.5 2 mos None Difficulty swallowing pills
16 PV 78/M Md 1-3 4 y, 8 mos Good None
17 PV 44/F Md/S 1 3 y, 1 mo Excellent Headache and dizziness, thrush, and furunculosis
18 PV 15/F Md/S 2 Unknown Unknown Lost to follow-up
19 PV 36/M Md/S 2 4 mos Minimal None
20 CP 19/F S 2-2.5 2 mos None None
21 CP 84/M S 2.5 6 mos Excellent None
22 CP 64/F S Unknown Unknown Minimal None
23 AD 60/F S 1-2 3 y, 9 mos Good Gastrointestinal
disturbances 24 AD 51/F Ml/Md 1.5 1 y, 4 mos Excellent None
25 AD 55/M Md 1 3 mos None None
26 AD 54/M Ml/Md 2 4 mos Good None
27 AD 68/F Md/S 0.5-1.5 1 y, 11 mos Min Onychomycosis
28 PG 48/F S 1 1 mo None None
29 PG 41/M S 1.5 2 y, 3 mos Minimal None
30 PG 39/M S 2 3 mos None None
31 PS 15/M S 3 4 mos None None
32 PS 52/F S 3 6 mos None None
33 CD 64/F S 1.5 2 y, 7 mos Excellent None
34 DM 67/F Md 1.5 3 y Excellent None

AD, Atopic dermatitis; BP, bullous pemphigoid; CD, contact dermatitis; CP, cicatricial pemphigoid; DM, dermatomyositis; Dx, diagnosis; F, female; LE, lupus erythematosus; M, male; mos, months; Md, moderate; Ml, mild; MMF, mycophenolate mofetil; PG, pyoderma gangrenosum; PS, psoriasis; PV, pemphigus vulgaris; S, severe; Tx, treatment; y, year.

order to obtain adequate disease control. In pem- phigus vulgaris, our experience was often less than optimal disease control, requiring replacement of MMF with azathioprine or cyclophosphamide to adequately control disease. MMF was generally un- successful in treating pyoderma gangrenosum. Although many literature sources cite the utility of MMF in the treatment of psoriasis, our experience has been limited to only two patients who both failed to respond to MMF. Of note, both patients had chronic, severe disease and had previously failed multiple modalities of treatment. It is possible that
MMF may play a greater role as a potential second- line agent in treating cases of psoriasis in which phototherapy, biologics, or other systemic agents are indicated but are not used for a variety of mitigating reasons. We have had substantial success using MMF to treat a single case of severe allergic contact dermatitis to formaldehyde. Lastly, we treated one case of amyopathic DM using MMF with complete resolution of cutaneous disease.
Generally, MMF was well tolerated with relatively few adverse effects. We invite readers to view Table IV for further details. A few specific cases are

noteworthy and warrant further discussion. Before visiting our clinic, one patient previously underwent a trial of MMF elsewhere and experienced hives and itching shortly after initiating treatment. Although she was not under our care at the time, we consider that she may have experienced an allergic reaction to the medication and respected her wishes to avoid a retrial of the medication. Another patient experi- enced a right gluteal cellulitis and adductor magnus myositis with significant leukopenia (white blood cell counts ranging from 2100-3000 cells/mm3) 2 months after initiating MMF, prompting discontinu- ation of the drug. Considering that she was taking several other medications at the time (including plaquenil and high-dose systemic steroids) and frequently self-adjusted her medication regimens, it is difficult to ascertain causality. However, it is possible that these adverse effects were MMF-re- lated. Regarding malignancies, one patient devel- oped a single squamous cell carcinoma after taking MMF for several years. Conversely, another patient who had previously developed multiple squamous cell carcinomas while taking cyclosporine experi- enced cessation of lesion development after switch- ing to MMF.
We recognize that treatment with MMF does not come without burdens. Laboratory monitoring is relatively stringent at first, with intervals between laboratory draws increasing over time. Our current practice is to obtain a basic metabolic panel, liver function tests, and CBC at baseline. We repeat these labs every 2 weeks for the first month, monthly for

FUTURE CONSIDERATIONS
MMF is available currently for enteral and paren- teral intravenous forms. The systemic reach of MMF is beneficial in the transplant field in order for MMF to prevent rejection. In several dermatologic condi- tions, such as those associated with DM, SLE, and other more extensive autoimmune disease, the sys- temic effects are also desired. However, in conditions limited to the skin, an effective topical form of MMF avoiding systemic side effects would be beneficial. Studies are currently investigating this possibility, which could expand MMF’s role in dermatology.23,161
An enteric-coated form of MMF’s active metabolite MPA is currently being used, and is FDA approved, in transplant patients with hopes to decrease the severity
162-164
of GI side effects and increasing tolerability. Althoughpharmacokineticsoftheenteric-coatedform differ slightly, it appears to be a promising improve- ment while maintaining equivalent MPA exposure and may become a more popular choice in the future.
One of the major limitations to the use of MMF is its relatively expensive cost. A generic form of MMF has been developed by Recalcine Pharmaceutical Corporation with good clinical results and may be available in the future as a more economical option
165,166
for patients.
Aside from its immunosuppressive effects, other advantages of MMF are being elucidated. Studies are investigating the potential benefits of MMF’s antitu- mor effects. There is evidence that MMF may help prevent tumor growth via angiogenesis inhibition and increased apoptosis; however, clinical benefits

the next 2 to 3 months, and every 2 to 3 months are not yet clear.167,168 Furthermore, interest in

thereafter, with more frequent monitoring if individ- ually clinically indicated. We explain to patients the importance of laboratory monitoring and the general risks and benefits of treatment with MMF. Furthermore, we always carefully weigh cost con- siderations and try to ensure that expense will not be burdensome.
At our clinic, we will continue to consider MMF in our therapeutic options for many of the cutaneous inflammatory diseases that we encounter. Our ex- pectation is that we will often use MMF to treat cases of bullous pemphigoid, AD, and selected cases of LE. We will still include MMF as a treatment option for pemphigus vulgaris, cicatricial pemphigoid, and py- oderma gangrenosum, although it will be ranked lower on our therapeutic option list than other current options and will likely be used in the event that our preferred treatment is ineffective or subop- timal. We will keep an open mind regarding the use of MMF to treat psoriasis and will continue to consider MMF for other various inflammatory dis- eases of the skin encountered.
MMF’s antihypertensive and antiatherosclerotic ef- fects have also emerged. It is possible that such properties may be of benefit particularly to patients at risk for cardiovascular events.169-171 Lastly, MMF has been hypothesized to directly affect fibroblast extracellular matrix remodeling, which may contrib- ute to MMF’s therapeutic effects when treating fibrotic lesions found in patients with systemic scle- rosis or GVHD. Other implications of this property, including its effect on wound healing, may be unveiled with future studies.172

REFERENCES
1.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 1913;270:1-47.
2.Florey HW, Gilliver K, Jennings MA, Sanders AC. Mycophe- nolic acid—an antibiotic from Penicillium brevicompactum. Lancet 1946;1:46-9.
3.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 1969;18:14-20.

4.Mitsui A, Suzuki S. Immunosuppressive effect of mycophe- nolic acid. J Antibiot (Tokyo) 1969;22:358-63.
5.Marinari R, Fleischmajer R, Schragger AH, Rosenthal AL. Mycophenolic acid in the treatment of psoriasis: long-term administration. Arch Dermatol 1977;113:930-2.
6.Jones EL, Epinette WW, Hackney VC, Menedez L, Frost P. Treatment of psoriasis with oral mycophenolic acid. J Invest Dermatol 1975;65:537-42.
7.Mydlarski PR. Mycophenolate mofetil: a dermatologic per- spective. Skin Therapy Lett 2005;10:1-6.
8.Lee WA, Gu L, Miksztal AR, Chu N, Leung K, Nelson PH. Bioavailability improvement of mycophenolic acid through amino ester derivatization. Pharm Res 1990;7:161-6.
9.PDRElectronicLibrary.Mycophenolatemofetil(CellCept)product information [CD-ROM]. Nutley, NJ: Roche Laboratories; 1995.
10.Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacoki- netics of mycophenolate mofetil. Clin Pharmacokinet 1998; 34:429-55.
11.Srinivas TR, Herwig-Ulf MK, Kaplan B. Pharmacokinetic prin- ciples of immunosuppressive drugs. Am J Transplant 2005;5: 207-17.
12.Allison AC, Eugui EM. Purine metabolism and immunosup- pressive effects of mycophenolate mofetil (MMF). Clin Trans- plant 1996;10(1 Pt 2):77-84.
13.Allison AC, Eugui EM. Immunosuppressive and other effects of MPA and an esther prodrug, mycophenolate mofetil. Immunol Rev 1993;136:5-28.
14.Patel AP, Swerlick RA, McCall CO. Azathioprine in dermatol- ogy: the past, the present, and the future. J Am Acad Dermatol 2006;5:390-1.
15.Haufs MG, Beissert S, Grabbe S, Schutte B, Luger TA. Psoriasis vulgaris treated successfully with mycophenolate mofetil. Br J Dermatol 1998;138:179-81.
16.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.
17.Davidson SC, Morris-Jones R, Powles AV, Fry L. Change of treatment from cyclosporin to mycophenolate mofetil in severe psoriasis. Br J Dermatol 2000;143:405-7.
18.Pedraz J, Dauden E, Delgado-Jimenez Y, Garcia-Rio I, Garcia- Diez A. Sequential study on the treatment of moderate-to- severe chronic plaque psoriasis with mycophenolate mofetil and cyclosporin. J Eur Acad Dermatol Venereol 2006;20: 702-6.
19.Zhou Y, Rosenthal D, Dutz F, Ho V. Mycophenolate mofetil (CellCept) for psoriasis: a two-center prospective open-label clinical trial. J Cutan Med Surg 2003;7:193-7.
20.Dauden E, Sanchez-Peinado C, Ruiz-Genao D, Garcia-F-Villalta M, Onate MJ, Garcia-Diez A. Plasma trough levels of mycophenolic acid do not correlate with efficacy and safety of mycophenolate mofetil in psoriasis. Br J Dermatol 2004; 150:132-5.
21.Carlin CS, Feldman SR, Krueger JG, Krueger GG, Menter A. A 50% reduction in the Psoriasis Area and Severity Index (PASI 50) is a clinically significant endoint in the assessment of psoriasis. J Am Acad Dermatol 2004;50:859-66.
22.Grundmann-Kollmann M, Mooser G, Schrader P, Zollner T, Kaskel P, Ochsendorf F, et al. Treatment of chronic plaque- stage psoriasis and psoriatic arthritis with mycophenolate mofetil. J Am Acad Dermatol 2000;42(5 Pt 1):835-7.
23.Wohlrab J, Jahn K, Plaetzer M, Neubert R, Marsch WC. Topical application of mycophenolate mofetil in plaque-type psori- asis. Br J Dermatol 2001;144:1263-4.
24.Bickle KM, Roark TR, Hsu S. Autoimmune bullous dermatoses: a review. Am Fam Physician 2002;65:1861-70.

25.Grundmann-Kollmann M, Korting HC, Behrens S, Kaskel P, Leiter U, Krahn G, et al. Mycophenolate mofetil: a new therapeutic option in the treatment of blistering autoim- mune diseases. J Am Acad Dermatol 1999;40:957-60.
26.Kirtschig G, Nonhlanhla PK. Management of bullous pem- phigoid: recommendations for immunomodulatory treat- ments. Am J Clin Dermatol 2004;5:319-26.
27.Esmaili N, Chams-Davatchi C, Valikhani M, Farshidfar F, Parvaneh N, Tamizifar B. Treatment of pemphigus vulgaris with mycophenolate mofetil as a steroid-sparing agent. Eur J Dermatol 2008;18:159-64.
28.Bohm M, Beissert S, Schwarz T, Metze D, Luger T. Bullous pemphigoid treated with mycophenolate mofetil. Lancet 1997;349:541.
29.Nousari HC, Sragovich A, Kimyai-Asadi A, Orlinsky D. Myco- phenolate mofetil in autoimmune and inflammatory skin disorders. J Am Acad Dermatol 1999;40:265-8.
30.Grundmann-Kollmann M, Kaskel P, Leiter U, Krahn G, Behrens S, Peter RU, et al. Treatment of pemphigus vulgaris and bullouos pemphigoid with mycophenolate mofetil mono- therapy. Arch Dermatol 1999;135:724-5.
31.Megahed M, Schmiedeberg S, Becker J, Ruzicka T. Treatment of cicatricial pemphigoid with mycophenolate mofetil as a steroid-sparing agent. J Am Acad Dermatol 2001;45:256-9.
32.Powell AM, Albert S, Al Fares S, Harman KE, Setterfield J, Bhogal B, et al. An evaluation of the usefulness of mycophe- nolate mofetil in pemphigus. Br J Dermatol 2003;149:138-45.
33.Sarma N, Ghosh S. Mycophenolate mofetil as adjuvant in pemphigus vulgaris. Indian J Dermatol Venereol Leprol 2007; 73:348-50.
34.Beissert S, Werfel T, Frieling U, Bo¨hm M, Sticherling M, Stadler R, et al. A comparison of oral methylprednisone plus azathi- oprine or mycophenolate mofetil for the treatment of pemphigus. Arch Dermatol 2006;142:1447-54.
35.Beissert S, Werfel T, Frieling U, Bo¨hm M, Sticherling M, Stadler R, et al. A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid. Arch Dermatol 2007;143:1536-42.
36.Tran MM, Anhalt GJ, Barrett T, Cohen BA. Childhood IgA- mediated epidermolysis bullosa acquisita responding to mycophenolate mofetil as a corticosteroid-sparing agent. J Am Acad Dermatol 2002;47:919-25.
37.Kawashita MY, Tsai K, Aoki V, Santi CG, Maruta CW, Rivitti E. Mycophenolate mofetil as an adjuvant therapy for classic and endemic pemphigus foliaceus. J Dermatol 2005;32:574-80.
38.Benez A, Fierlbeck G. Successful long-term treatment of severe atopic dermatitis with mycophenolate mofetil. Br J Dermatol 2001;144:638-9.
39.Grundmann-Kollmann M, Podda M, Ochsendorf F, Boehncke WH, Kaufmann R, Zollner TM. Mycophenolate mofetil is effective in the treatment of atopic dermatitis. Arch Dermatol 2001;137:870-3.
40.Neuber K, Schwartz I, Itschert G, Dieck AT. Treatment of atopic eczema with oral mycophenolate mofetil. Br J Dermatol 2000;143:385-91.
41.Murray ML, Cohen JB. Mycophenolate mofetil therapy for moderate to severe atopic dermatitis. Clin Exp Dermatol 2007;32:23-7.
42.Akhavan A, Rudikoff D. The treatment of atopic dermatitis with systemic immunosuppressive agents. Clin Dermatol 2003;21:225-40.
43.Heller M, Shin HT, Orlow SJ, Schaffer JV. Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol 2007;157:127-32.

44.Satchell AC, Barnetson R. Staphylococcal septicaemia com- plicating treatment of atopic dermatitis with mycophenolate. Br J Dermatol 2000;143:202-3.
45.Thomson MA, Stewart DG, Lewis HM. Chronic actinic derma- titis treated with mycophenolate mofetil. Br J Dermatol 2005; 152:784-6.
46.Nousari HC, Anhalt GJ. Mycophenolate in psoralen-UV-A desensitization therapy for chronic actinic dermatitis. Arch Dermatol 1999;135:1128-9.
47.Pickenacker A, Luger TA, Schwarz T. Dyshidrotic eczema treated with mycophenolate mofetil. Arch Dermatol 1998; 134:378-9.
48.Semhoun-Ducloux S, Ducloux D, Miguet JP. Mycophenolate mofetil-induced dyshidrotic eczema. Ann Intern Med 2000; 132:417.
49.Goyal S, Nousari HC. Treatment of resistant discoid lupus erythematosus of the palms and soles with mycophenolate mofetil. J Am Acad Dermatol 2001;45:142-4.
50.Schanz S, Ulmer A, Rassner G, Fierlbeck G. Successful treat- ment of subacute cutaneous lupus erythematosus with mycophenolate mofetil. Br J Dermatol 2002;147:174-8.
51.Hanjani NM, Nousari CH. Mycophenolate mofetil for the treatment of cutaneous lupus erythematosus with smolder- ing systemic involvement. Arch Dermatol 2006;138:1616-8.
52.Pisoni CN, Obermoser G, Cuadrado MJ, Sanchez FJ, Karim Y, Sepp NT, et al. Skin manifestations of systemic lupus erythematosus refractory to multiple treatment modalities: poor results with mycophenolate mofetil. Clin Exp Rheuma- tol 2005;23:393-6.
53.Pisoni CN, Karim Y, Cuadrado MJ. Mycophenolate mofetil and systemic lupus erythematosus: an overview. Lupus 2005; 14(Suppl 1):S9-11.
54.Karim MY, Alba P, Cuadrado MJ, Abbs C, Cruz DPD, Khamashta MA, et al. Mycophenolate mofetil for systemic lupus erythematosus refractory to other immunosuppressive agents. Rheumatology 2002;41:876-82.
55.Mok CC. Mycophenolate mofetil for non-renal manifestations of systemic lupus erythematosus: a systematic review. Scand J Rheumatol 2007;36:329-37.
56.Boehm I, Bieber T. Chilblain lupus erythematosus Hutchin- son: successful treatment with mycophenolate mofetil. Arch Dermatol 2001;137:235-6.
57.Dooley MA. Mycophenolate mofetil: what role in the treat- ment of lupus? Lupus 2006;15:179-82.
58.Albrecht J, Taylor L, Berlin JA, Dulay S, Ang G, Fakharzadeh S, et al. The CLASI (CutaneousLupus Erythematosus Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus. J Invest Dermatol 2005;125:889-94.
59.Albrecht J, Werth VP. Development of the CLASI as an outcome instrument for cutaneous lupus erythematosus. Dermatol Ther 2007;20:93-101.
60.Rowin J, Amato AA, Deisher N, Curiso J, Meriggioli MN. Mycophenolate mofetil in dermatomyositis: is it safe? Neu- rology 2006;66:1245-7.
61.Callen JP, Edge JC, Outland JD, Dempsey JR. Mycophenolate mofetil as an effective corticosteroid-sparing therapy for recalcitrant dermatomyositis. Arch Dermatol 2006;142:65-9.
62.Majithia V, Harisdangkul V. Mycophenolate mofetil (CellCept): an alternative therapy for autoimmune inflammatory myop- athy. Rheumatology (Oxford) 2005;44:386-9.
63.Tausche AK, Meurer M. Mycophenolate mofetil for dermat- omyositis. Dermatology 2001;202:341-3.
64.Gelber AC, Nousari HC, Wigley FM. Mycophenolate mofetil in the treatment of severe skin manifestations of dermatomy- ositis: a series of 4 cases. J Rheumatol 2000;27:1542-5.

65.Carroll CL, Lang W, Snively B, Feldman SR, Callen J, Jorizzo JL. Development and validation of the Dermatomyositis Skin Severity Index. Br J Dermatol 2008;158:345-50.
66.Gaines E, Werth VP. Development of outcome measures for autoimmune dermatoses. Arch Dermatol Res 2008;300:3-9.
67.Russell JP, Gibson LE. Primary cutaneous small vessel vascu- litis: approach to diagnosis and treatment. Int J Dermatol 2006;45:3-13.
68.Le Hello C, Bonte I, Mora J, Verneuil L, Guillevin L. Pyoderma gangrenosum associated with Wegner’s granulomatosis: partial response to mycophenolate mofetil. Rheumatology 2002;41:236-7.
69.Assaf C, Mewis G, Orfanos CE, Geilen CC. Churg-Strauss syndrome: successful treatment with mycophenolate mofetil. Br J Dermatol 2004;150:598.
70.Thorne JE, Hernandez MI, Rencic A, Nousari CH. Severe scleritis and urticarial lesions. Am J Ophthalmol 2002;134: 932-4.
71.Worm M, Kolde SG. Mycophenolate mofetil is effective for maintenance therapy of hypocomplementaemic urticarial vasculitis. Br J Dermatol 2000;143:1324.
72.Langford CA, Talar-Williams C, Sneller MC. Mycophenolate mofetil for remission maintenance in the treatment of Wegner’s granulomatosis. Arthritis Rheum 2004;51:278-83.
73.Taverna JA, Radfar A, Pentland A, Poggioli G, Demierre MF. Case reports: nodular vasculitis responsive to mycophenolate mofetil. J Drugs Dermatol 2006;5:992-3.
74.Koukoulaki M, Jayne DRW. Mycophenolate mofetil in anti- neutrophil cytoplasm antibodies-associated systemic vascu- litis. Nephron Clinical Practice 2006;102:100-7.
75.Adler YD, Mansmann U, Zouboulis CC. Mycophenolate mofetil is ineffective in the treatment of mucocutaneous Adaman- tiades-Behc¸et’s disease. Dermatology 2001;203:322-4.
76.Plastira SC, Vlachoyiannopoulos PG, Tzelepis GE. Mycophe- nolate mofetil for interstitial lung disease in scleroderma. Rheumatology 2006;45:1572.
77.Liossis SN, Bounas A, Andonopoulos AP. Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology 2006;45: 1005-8.
78.Swigris JJ, Olson AL, Fischer A, Lynch DA, Cosgrove GP, Frankel SK, et al. Mycophenolate mofetil is safe, well toler- ated, and preserves lung function in patients with connective tissue disease-related interstitial lung disease. Chest 2006; 130:30-6.
79.Gerbino AJ, Goss CH, Molitor JA. Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. Chest 2008;133:455-60.
80.Zamora AC, Wolters PJ, Collard HR, Connolly MK, Elicker BM, Webb WR, et al. Use of mycophenolate mofetil to treat scleroderma-associated interstitial lung disease. Respir Med 2008;102:150-5.
81.Nihtyanova SI, Brough GM, Black CM, Denton CP. Mycophe- nolate mofetil in diffuse cutaneous systemic sclerosis—a retrospective analysis. Rheumatology (Oxford) 2007;46:442-5.
82.Stratton RJ, Wilson H, Black CM. Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. Rheumatology (Oxford) 2001;40:1192.
83.Clements PJ, Lachenbruch PA, Ng SC, Simmons M, Sterz M, Furst DE. Skin score. A semiquantitative measure of cutane- ous involvement that improves prediction of prognosis in systemic sclerosis. Arthritis Rheum 1990;33:1256-63.
84.Rose RF, Goodfield MJD. Combining PUVA therapy with systemic immunosuppression to treat progressive diffuse morphoea. Clin Exp Dermatol 2005;30:226-8.

85.Baudard M, Vincent A, Moreau P, Kergueris MF, Harousseau JL, Milpied N. Mycophenolate mofetil for the treatment of acute and chronic GVHD is effective and well tolerated but induces a high risk of infectious complications: a series of 21 BM or PBSC transplant patients. Bone Marrow Transplant 2002;30:287-95.
86.Takami A, Mochizuki K, Okumura H, Ito S, Suga Y, Yamazaki H, et al. Mycophenolate mofetil is effective and well tolerated in the treatment of refractory acute and chronic graft-versus- host disease. Int J Hematol 2006;83:80-5.
87.Hambach L, Stadler M, Dammann E, Ganser A, Hertenstein B. Increased risk of complicated CMV infection with the use of mycophenolate mofetil in allogenic stem cell transplantation. Bone Marrow Transplant 2002;29:903-6.
88.Busca A, Locatelli F, Marmont F, Audisio E, Falda M. Response to mycophenolate mofetil therapy for refractory chronic graft-versus-host disease. Haematologica 2003;88:837-9.
89.Baron F,Sandmaier BM,StorerBE,MarisMB, LangstonAA, Lange T, et al. Extended mycophenolate mofetil and shortened cyclo- sporine failed to reduce graft-versus-host disease after unre- lated hematopoietic cell transplantation withnonmyeloablative conditioning. Biol Blood Marrow Transplant 2007;13:1041-8.
90.Nash RA, Johnston L, Parker P, McCune JS, Storer B, Slattery JT, et al. A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft- versus-host disease after myeloablative conditioning and allogenic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2005;11:495-505.
91.Voglesang GB, Arai S. Mycophenolate mofetil for the pre- vention and treatment of graft-versus-host disease following stem cell transplantation: preliminary findings. Bone Marrow Transplant 2001;27:1255-62.
92.Dorak CC, Callard E, Agarwal R. Use of intravenous myco- phenolate mofetil for graft-versus-host disease prophylaxis in an allogenic hematopoietic stem cell transplant recipient with an allergic reaction to cyclosporine and tacrolimus. Bone Marrow Transplant 2006;38:253-4.
93.Mori M, Muroi K, Matsuyama T, Oka S, Ono Y, Yamamoto C, et al. Benefits of mycophenolate mofetil for refractory graft- versus-host disease. Rinsho Ketsueki 2007;48:624-31.
94.van Hest RM, Doorduijn JK, de Winter BC, Cornelissen JJ, Vulto AG, Oellerich M, et al. Pharmacokinetics of mycophe- nolate mofetil in hematopoietic stem cell transplant recipi- ents. Ther Drug Monit 2007;29:385-90.
95.Nousari HC, Goyal S, Anhalt GJ. Successful treatment of resistant hypertrophic and bullous lichen planus with myco- phenolate mofetil. Arch Dermatol 1999;135:1420-1.
96.Frieling U, Bonsmann G, Schwarz T, Luger TA, Beissert S. Treatment of severe lichen planus with mycophenolate mofetil. J Am Acad Dermatol 2003;49:1063-6.
97.Tursen U, Api H, Kaya T, Ikizoglu G. Treatment of lichen planopilaris with mycophenolate mofetil. Dermatol Online J 2004;10:24.
98.Dalmau J, Puig L, Roe´ E, Peramiquel L, Campos M, Alomar A. Successful treatment of oral erosive lichen planus with mycophenolate mofetil. J Eur Acad Dermatol Venereol 2007;21:259-60.
99.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.
100.Kilmartin DJ, Forrester JV, Dick AD. Rescue therapy with mycophenolate mofetil in refractory uveitis. Lancet 1998;352: 35-6.
101.Chaussenot A, Bourg V, Chanalet S, Fornari JM, Lebrun C. Neurosarcoidosis treated with mycophenolate mofetil: two cases [in French]. Rev Neurol (Paris) 2007;163:471-5.

102.Moudgil A, Przygodzki RM, Kher KK. Successful steroid- sparing treatment of renal limited sarcoidosis with myco- phenolate mofetil. Pediatr Nephrol 2006;21:281-5.
103.Davis MDP, Rogers RS, Pittelkow MR. Recurrent erythema multiforme/Stevens-Johnson syndrome: response to myco- phenolate mofetil. Arch Dermatol 2002;138:1547-50.
104.Boyd AS. Use of mycophenolate mofetil in erythema nodosum. J Am Acad Dermatol 2002;47:968-9.
105.Miehsler W, Reinisch W, Moser G, Gangl A, Vogelsang H. Is mycophenolate mofetil an effective alternative in azathio- prine-intolerant patients with chronic active Crohn’s disease? Am J Gastroenterol 2001;96:782-7.
106.Ford AC, Towler RJ, Moayyedi P, Chalmers DM, Axon ATR. Mycophenolate mofetil in refractory inflammatory bowel disease. Aliment Pharmacol Ther 2003;17:1365-9.
107.Hohenleutner U, Mohr VD, Michel S, Landthaler M. Myco- phenolate mofetil and cyclosporine treatment for recalcitrant pyoderma gangrenosum. Lancet 1997;350:1748.
108.Lee MR, Cooper AJ. Mycophenolate mofetil in pyoderma gangrenosum. J Dermatolog Treat 2004;15:303-7.
109.Nousari H, Petri D. The effectiveness of mycophenolate mofetil in refractory pyoderma gangrenosum. Arch Dermatol 1998;134:1509-11.
110.Daniels NH, Callen JP. Mycophenolate mofetil is an effective treatment for peristomal pyoderma gangrenosum. Arch Dermatol 2004;140:1427-9.
111.Burdick AE, Ramirez CC. The role of mycophenolate mofetil in the treatment of leprosy reactions. Int J Lepr Other Mycobact Dis 2005;73:127-8.
112.Assman T, Ruzicka T. New immunosuppressive drugs in der- matology (mycophenolate mofetil, tacrolimus): unapproved uses, dosages, or indications. Clin Dermatol 2002;20:505-14.
113.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 2002;20: 505-14.
114.Ducloux D, Ottignon Y, Semhoun-Ducloux S, Labbe S, Saint- Hillier Y. Mycophenolate mofetil-induced villous atrophy. Transplantation 1998;66:1115-6.
115.Garrigue V, Canet S, Dereure O, Panabieres O, Augias D. Oral ulcerations in renal transplant recipient: a mycophenolate mofetil-inducedcomplication?Transplantation 2001;72:968-9.
116.Apostolou T, Tsagalis G. Mycophenolate mofetil and oral ulcerations. Transplantation 2003;77:1911-2.
117.Hebert MF, Ascher NL, Lake JR, Emond J, Nilolai B. Four-year follow-up of mycophenolate mofetil for graft rescue in liver allograft recipients. Transplantation 1999;67:707-12.
118.Kim HC, Park SB. Mycophenolate mofetil-induced ischemic colitis. Transplantation Proc 2000;32:1896-7.
119.Szyper-Kravitz M, Sheinberg P, Sidi Y, Schiffenbauer Y, Trubniykov E. Hypersensitivity to mycophenolate mofetil in systemic lupus erythematosus: diagnostic measures and successful desensitization. Int Arch Allergy Immunol 2005; 138:334-6.
120.Rault R. Mycophenolate-associated onycholysis. Ann Intern Med 2000;133:921-2.
121.Hantash B, Fiorentino D. Liver enzyme abnormalities in patients with atopic dermatitis treated with mycophenolate mofetil. Arch Dermatol 2006;142:109-10.
122.Chueh SC, Huang CY, Lai MK. Mycophenolate mofetil-in- duced hyperbilirubinemia in renal transplant recipients. Transplant Proc 2000;32:1901-2.
123.Arbeiter K, Greenbaum L, Balzar E, Muller T, Hofmeister F. Reproducible erythroid aplasia caused by mycophenolate mofetil. Pediatr Nephrol 2000;14:195-7.

124.Gross DC, Sasaki TM, Buick MK, Light JA. Acute respira- tory failure and pulmonary fibrosis secondary to admin- istration of mycophenolate mofetil. Transplantation 1997; 64:1607-9.
125.Shrestha NK, Mossad SB, Braun W. Pneumonitis associated with the use of mycophenolate mofetil. Transplantation 2003;75:1762.
126.Piccoli GB, Rossetti M, Guarena C, Consiglio V, Mezza E. Myalgia: an uncommon or underestimated side effect of mycophenolate mofetil after transplantation? Nephrol Dial Transplant 2004;19:1940-2.
127.Powell AM, Albert S, Fares SA, Harman KE, Setterfield J. An evaluation of the usefulness of mycophenolate mofetil in pemphigus. Br J Dermatol 2003;149:138-45.
128.Maes B, Oellerich M, Ceuppens JL, Armstrong VW, Evenepoel P. A new acute inflammatory syndrome related to the introduction of mycophenolate mofetil in patients with Wegener’s granulomatosis. Nephrol Dial Transplant 2002; 17:923-6.
129.Frieling U, Luger TA. Mycophenolate mofetil and lefluno- mide: promising compounds for the treatment of skin diseases. Clin Exp Dermatol 2002;27:562-70.
130.Sarmiento JM, Dockrell DH, Schwab TR, Munn SR, Paya CV. Mycophenolate mofetil increases cytomegalovirus invasive organ disease in renal transplant patients. Clin Transplant 2000;14:136-8.
131.Birgerson LE. Change in CellCept label for pregnancy out- comes—dear healthcare professional letter. Nutley, NJ: Roche Pharmaceuticals. Available at: http://www.rocheusa. com/products/cellcept. Accessed June 6, 2008.
132.Rothwell WS, Gloor JM, Morgenstern BZ, Milliner DS. Dis- seminated varicella infection in pediatric transplant recipi- ents treated with mycophenolate mofetil. Transplantation 1999;68:158-61.
133.Arash A, Rudikoff D. The treatment of atopic dermatitis with systemic immunosuppressive agents. Clin Dermatol 2003;21: 225-40.
134.Birgerson LE. Change in CellCept label for progressive multifocal leukoencephalopathy—dear healthcare profes- sional letter. Nutley, NJ: Roche Pharmaceuticals. Available at: http://www.rocheusa.com/products/cellcept. Accessed June 6, 2008.
135.Neyts J, Andrei G, DeClerq E. The novel immunosuppressive agent mycophenolate mofetil markedly potentiates the antiherpesvirus activities of acyclovir, ganciclovir, and penci- clovir in vitro and in vivo. Antimicrob Agents Chemother 1998;42:216-22.
136.O’Neill JO, Edwards LB, Taylor DO. Mycophenolate mofetil and risk of developing malignancy after orthotopic heart transplantation: analysis of the transplant registry of the international society for heart and lung transplantation. J Heart Lung Transplant 2006;25:1186-91.
137.Lynch WS, Roenigk HH. Mycophenolic acid for psoriasis. Arch Dermatol 1977;113:1203-8.
138.Vernino S, Salomao DR, Habermann TM, O’Neill BP. Primary CNS lymphoma complicating treatment of myasthenia gravis with mycophenolate mofetil. Neurology 2005;65:639-41.
139.Finelli PF, Naik K, DiGiuseppe JA, Prasad A. Primary lym- phoma of CNS, mycophenolate mofetil and lupus. Lupus 2006;15:886-8.
140.Waldman MA, Callen JP. Self-resolution of Epstein-Barr virus- associated B-cell lymphoma in a patient with dermatomyo- sitis following withdrawal of mycophenolate mofetil and methotrexate. J Am Acad Dermatol 2004;51(2 Suppl 1): S124-30.

141.Avalos-Peralta P, Herrera A, Rios-Martin JJ, Perez-Bernal AM, Moreno-Ramirez D. Localized Kaposi’s sarcoma in a patient with pemphigus vulgaris. J Eur Acad Dermatol Venereol 2006;20:79-83.
142.Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate glucuronosyltrans- ferase. Clin Pharmacol Ther 2005;78:81-8.
143.Husain S, Singh N. The impact of novel immunosuppressive agents on infections in organ transplant recipients and the interactions of these agents with antimicrobials. Clin Infect Dis 2002;35:53-61.
144.Cattaneo D, Perico N, Gaspari F, Gotti E, Remuzzi G. Gluco- corticoids interfere with mycophenolate mofetil bioavailabil- ity in kidney transplantation. Kidney Int 2002;62:1060-7.
145.Cattaneo D, Merlini S, Zenoni S, Baldelli S, Gotti E. Influence of co-medication with sirolimus or cyclosproine on myco- phenolic acid pharmacokinetics in kidney transplantation. Am J Transplant 2005;5:2937-44.
146.Pieper AK, Buhle F, Bauer S, Mai I, Budde K. The effect of sevelamer on the pharmacokinetics of cyclosporine A and mycophenolate mofetil after renal transplantation. Nephrol Dial Transplant 2004;19:2630-3.
147.Morii M, Ueno K, Ogawa A, Kato R, Yoshimura H. Impairment of mycophenolate mofetil absorption by iron ion. Clin Pharmacol Ther 2000;68:613-6.
148.Kato R, Ooi K, Ikura-Mori M, Tsuchishita Y, Hashimoto H. Impairment of mycophenolate mofetil absorption by calcium polycarbophil. J Clin Pharmacol 2002;42:1275-80.
149.Gelone DK, Park JM, Lake KD. Lack of an effect of oral iron administrationonmycophenolicacidpharmacokineticsinstable renal transplant recipients. Pharmacotherapy 2007;27:1272-8.
150.Sankatsing SU, Hoggard PG, Huitema AD, Sparidans RW, Kewn S. Effect of mycophenolate mofetil on the pharmaco- kinetics of antiretroviral drugs and on intracellular nucleoside triphosphate pools. Clin Pharmacokinet 2004;43:823-32.
151.Royer B, Zanetta G, Berard M, Davani S, Tanter Y. A neutro- penia suggesting an interaction between valacyclovir and mycophenolate mofetil. Clin Transplant 2003;17:158-61.
152.Filler G, Hansen M, LeBlanc C, Lepage N, Franke D, Mai I, et al. Pharmacokinetics of mycophenolate mofetil for autoimmune disease in children. Pediatr Nephrol 2004;19:962-5.
153.Wolverton SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders; 2001. pp. 193-5.
154.Tendron A, Gouyon JB, Decramer S. In utero exposure to immunosuppressive drugs: experimental and clinical studies. Pediatr Nephrol 2002;17:121-30.
155.Sifontis NM, Coscia LA, Constantinescu S, Lavelanet AF, Moritz MJ, Armenti VT. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mo- fetil or sirolimus. Transplantation 2006;82:1698-702.
156.Le Ray C, Coulomb A, Elefant E, Frydman R, Audibert F. Mycophenolate mofetil in pregnancy after renal transplan- tation: a case of major fetal malformations. Obstet Gynecol 2004;103(5 Pt 2):1091-4.
157.Tjeertes IF, Bastiaans DE, van Ganzewinkel CJ, Zegers SH. Neonatal anemia and hydrops fetalis after maternal myco- phenolate mofetil use. J Perinatol 2007;27:62-4.
158.Armenti VT, Radomski JS, Moritz MJ, Gaughan WJ, Gulati R, McGrory CH, et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 2005;69-83.
159.Ettenger R, Sarwal MM. Mycophenolate mofetil in pediatric renal transplantation. Transplantation 2005;80(Suppl 2): S201-10.

160.Alkali AS, Bharati A, Yesudian PD, Parslew RAG, Field A. Oral 10, childhood mucous membrane pemphigoid: successful control with mycophenolate mofetil monotherapy. Br J Dermatol 2007;156:1406.
161.Konstanze J, Fischer A, Neubert RHH, Wohlrab J. Investiga- tion of the penetration behaviour of mycophenolate mofetil from a semisolid formulation into human skin ex-vivo. J Pharm Pharmacol 2001;53:1581-7.
162.Johnston A, He X, Holt DW. Bioequivalence of enteric-coated mycophenolate sodium and mycophenolate mofetil: a meta- analysis of three studies in stable renal transplant recipients. Transplantation 2006;82:1413-8.
163.Budde K, Tedescop-Silva H, Pestana JM, Glander P, Neumayer HH, Felipe CR, et al. Enteric-coated mycophe- nolate sodium provides higher mycophenolic acid predose levels compared with mycophenolate mofetil: implications for therapeutic drug monitoring. Ther Drug Monit 2007; 29:381-4.
164.Masri MA, Rizk S, Attia ML, Barbouch H, Rost M. Bioavailability of a new generic formulation of mycophenolate mofetil MMF 500 versus CellCept in healthy adult volunteers. Transplant Proc 2007;39:1233-6.
165.Calvo N, Sanchez-Fructuoso AI, Conesa J, Moreno A, Barrientos A. Renal transplant patients with gastrointestinal intolerability to mycophenolate mofetil: conversion to en- teric-coated mycophenolate sodium. Transplant Proc 2006; 38:2396-7.

166.Videla C, Godoy C. Converting to a generic formulation of mycophenolate mofetil in stable kidney transplant recipients: 1 year of drug surveillence and outcome. Transplant Proc 2007;39:602-5.
167.Koehl GE, Wagner F, Stoeltzing O, Lang SA, Steinbauer M, Schlitt HJ, et al. Mycophenolate mofetil inhibits tumor growth and angiogenesis in vitro but has variable antitumor effects in vivo, possibly related to bioavailability. Transplan- tation 2007;83:607-14.
168.Vedgso G, Sebestyen A, Paku S, Bama G, Hajdu M, Toth M, et al. Antiproliferative and apoptotic effects of mycophenolic acid in human B-cell non-Hodgkin lymphomas. Leuk Res 2007;31:1003-8.
169.Gibson WT, Hayden MR. Mycophenolate mofetil and ather- osclerosis: results of animal and human studies. Ann N Y Acad Sci 2007;1110:209-21.
170.Herrera J, Ferrebuz A, MacGregor EG, Rodriguez-Iturbe B. Mycophenolate mofetil treatment improves hypertension in patients with psoriasis and rheumatoid arthritis. J Am Soc Nephrol 2006;17(12 Suppl 3):S218-25.
171.van Leuven SI, Kastelein JJ, Allison AC, Hayden MR, Stroes ES. Mycophenolate mofetil (MMF): firing at the atherosclerotic plaque from different angles? Cardiovasc Res 2006;69:341-7.
172.Roos N, Poulalhon N, Farge D, Madelaine I, Mauviel A, Verrecchia F. In vitro evidence for a direct antifibrotic role of the immunosuppressive drug mycophenolate mofetil. J Pharmacol Exp Ther 2007;321:583-9.