Mycophenolic acid in dermatology a century after
its discovery

Sarah J Strathie Page1 and Clare P Tait1,2
1Royal Perth Hospital, Perth, Western Australia, Australia, 2Department of Dermatology

bioavailability, efficacy and gastrointestinal side-effects

ABSTRACT
Mycophenolic acid was first discovered in 1913 and first used clinically in the 1970s as an immunosup- pressant to prevent organ transplantation rejection. It was later used in the treatment of psoriasis. However due to its side-effect profile and fears over its carci- nogenic potential it was abandoned. From the late 1990s a prodrug, mycophenolate mofetil (MMF), was developed and more recently, enteric-coated mycophenolate sodium (EC-MPS), both of which have gained increasing use in the field of dermatology for a variety of skin conditions. This review discusses the pharmacology, mechanisms of action, side-effects and current clinical applications in dermatology of MMF and EC-MPS.
Key words: dermatology, dermatomyositis, lichen planopilaris, lichen planus, mycophenolate mofetil review, mycophenolate mofetil, mycophenolic acid, pemphigoid, pemphigus, psoriasis.

INTRODUCTION
Mycophenolic acid (MPA), a weak, lipid-soluble organic acid, was first isolated from cultures of Penicillium stoloniferum by researchers in the US Department of Agri- culture in 19131,2 and was found to have antiviral, antibac- terial, anti-tumoural, antifungal and immunosuppressive properties.2–6
Mycophenolate mofetil (MMF), an ester derivative of
compared with MPA and was again trialled in the treatment of dermatological conditions.2,7 By the late 1990s MMF was released onto the Australasian market, followed several years later by enteric-coated mycophenolate sodium (EC- MPS).8 The pharmacokinetics of each preparation are described in Table 1.
MMF and EC-MPS are only licensed on the Pharmaceuti- cal Benefits Scheme (PBS) in Australia for use in acute transplant rejection and MMF is available in New Zealand on a special authority scheme.12–16 Despite this restriction, MMF in particular has grown increasingly popular in treat- ing various immunological disorders including several der- matological conditions.5,7,17 On the centenary of the isolation of mycophenolic acid, this article examines this drug and its use in dermatological disease.

MECHANISM OF ACTION
MPA is a reversible, selective and non-competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo purine syn- thesis required for lymphocyte proliferation.9
Adenosine and guanosine are purine bases that can be synthesised by two different pathways; the hypoxanthine- guanine phosphoribosyl transferase salvage pathway and de novo purine synthesis.2,18 Unlike other cell lines that can use salvage pathways, lymphocytes almost entirely rely on de novo purine synthesis; therefore blocking IMPDH inhib- its many functions of lymphocytes without significantly affecting other cells.2,9,18,19 MPA causes a cytostatic effect on

Abbreviations:

MPA, was later developed and used initially for the preven- tion of organ transplant rejection. It had improved
AZA
CSA
azathioprine cyclosporine

EC-MPS enteric-coated mycophenolate sodium
GI gastrointestinal

Correspondence: Dr Sarah J Strathie Page, Royal Perth Hospital, Wellington St, Perth, WA 6000, Australia. Email: sarah
[email protected]
Sarah J Strathie Page, MBBS. Clare P Tait, FRACD. Conflict of interest: none
Submitted 5 January 2014; accepted 26 August 2014.
IMPDH
MMF
MPA
MPAG
Mtx
PBS
inosine monophosphate dehydrogenase mycophenolate mofetil
mycophenolic acid mycophenolic acid glucuronide methotrexate
Pharmaceutical Benefits Scheme

© 2014 The Australasian College of Dermatologists

Table 1 Pharmacokinetics of mycophenolate mofetil (MMF) and enteric coated mycophenolic sodium (EC-MPS)9–11

and the use of other immunosuppressants.21 Malignancy was reported in several case reports with the early use of

MMF
EC-MPA
the now-obsolete MPA for dermatological conditions, but absolute numbers were low.2,27 Malignancy data on the cur-

Bioavailability (MPA) (%) 72 72
Peak concentrations (min) 60–90 90–120
Effect of food on bioavailability No effect Acidic conditions –
MPA not released Binding of serum proteins (%) 97 97
Elimination (MPAG) (approx. %) 93 renal 93 renal
Elimination half- life (h) 12–16 12–16
MPA, mycophenolic acid; MPAG, mycophenolic acid glucuronide.

lymphocytes and a reduction in antibody formation, migra- tion and cellular adhesion.9,18

ADVERSE EFFECTS
The active metabolite of both MMF and EC-MPS is highly selective for lymphocytes and has a favourable side-effect profile than other immunosuppressive agents including methotrexate (Mtx), cyclosporine (CSA) and azathioprine (AZA).20,21 Information on the side-effects of these two for- mulations comes predominantly from renal transplant patients, who may have a risk of an adverse reaction that is different from that of the general population.22 Transplant recipients may also be receiving MPA-based drugs as part of a combination immunosuppressive regimen and these are often administered at higher doses than are usually used in dermatological conditions.23 Common side-effects are listed in Table 2.

Common adverse effects
Gastrointestinal The most common dose-related side- effects are gastrointestinal (GI) including nausea, vomiting, diarrhoea, abdominal cramps and, infrequently, gastroin- testinal bleeding (Table 2).5 MMF has been described as having a side-effect profile similar to non-steroidal anti- inflammatory drugs.24 On 2g of MMF approximately 20% of patients experience gastrointestinal side-effects.21

Infection Due to the immunosuppressive effects of MMF, increased rates of infection are commonly seen in the geni- tourinary tract, respiratory system and wounds of patients. Infection rates of up to 40% have been reported in trans- plant patients; however, many of these patients were also receiving concomitant immunosuppressive agents.10,11 Genitourinary symptoms have been reported with MMF, including urgency, dysuria, haematuria and urinary tract infections.21

Blood dyscrasias Leukopenia, thrombocytopenia and anaemia have been reported in 5–9% of patients taking MMF.21,25,26 Most of these haematological abnormalities are dose related, reversible and mild.21

Less common adverse effects
Malignancy Malignancy risk with MPA derivatives is thought to depend on the dose and duration of treatment
rently used MPA derivates come almost entirely from trans- plant patients. Safety data comparing MMF and AZA in transplant patients showed a comparable incidence of malignancy between the groups. The overall incidence of malignancy in patients taking AZA was between 0.3–3%, compared to 0.4–4% taking MMF across three different transplant populations.10
In the dermatology literature malignancy is infrequently reported in patients using MMF.18 It is thought that the risk of malignancy in dermatology patients would be signifi- cantly less than that of a transplant population due to the lower doses and fewer combinations of immunosuppres- sants being utilised.21 Further research in the dermatology patient population is needed.

Lympho-proliferation Several industry-sponsored studies examined malignancy in renal and cardiac transplant recipients taking MMF compared to AZA or placebo over 3 years. The rates of lymphoproliferative malignancy were 0.6–1% of patients taking MMF (2–3g/day) and 0.3% taking AZA (1–3 mg/kg/day) in the same period.10

Skin cancer Non-melanoma skin cancer rates in a trans- plant study were between 4–4.2 % of patients taking MMF and 2–3% in patients taking AZA.10

PREGNANCY AND FERTILITY
MMF is classified as category D in pregnancy by the Aus- tralian Drug Evaluation Committee. Few data are available on its use in pregnant women; however, malformations have been reported in foetuses exposed to MMF. Contracep- tion is recommended 4 weeks prior to treatment with MMF and for 6 weeks after conclusion of therapy. In animal studies no major effects on fertility have been shown.10

MONITORING
The British Association of Dermatologists recommends monitoring of MMF by a weekly full blood count, urea and electrolytes and liver function tests for the first month and then less frequently.25,28 Adverse effects can be minimised with a reduction in the dose and concomitant immunosup- pressant agents.21

PRECAUTIONS
MMF and EC-MPS should be used with caution or avoided in the following groups: women of child-bearing potential, lactation and pregnancy, chronic renal impairment, elderly patients (> 65), patients with phenylketonuria and hypoxanthine-guanine phosphoribosyltransferase defi- ciency, patients using other immunosuppressant medica-

Table 2 Side-effects of enteric coated mycophenolic sodium (EC-MPS) or mycophenolate mofetil (MMF)
System Very common Common Uncommon/ unknown frequency

Gastrointestinal Diarrhoea, nausea Abdominal distension, abdominal pain, vomiting, constipation, gastritis, constipation, oral/GI moniliasis, melaena, flatulence, liver damage, jaundice, cholelithiasis, stomatitis, gingivitis, GI ulcer, dyspepsia, hepatitis, ascites, dysphagia
Pancreatitis, GI perforation, gingival hyperplasia, GI haemorrhage, eructation, hepatic failure, intestinal necrosis

Infections
Bacterial/fungal/viral infection, sepsis
Upper respiratory tract infections, pneumonia, pharyngitis, bronchitis, furunculosis, cellulitis
Wound infections, progressive multifocal leukoencephalopathy, meningitis, infective endocarditis, osteomyelitis

Cardiac
Hypertension, hypotension
Atrial fibrillation, tachycardia, angina
Myocardial infarction

Respiratory
Cough, sinusitis, dyspnoea, hypoxia, rhinitis, atelectasis, pulmonary oedema, pleural fibrosis, hypoxia
Wheezing, lung fibrosis, pulmonary embolism

Nervous system
Headache, tremor, insomnia, neuropathy, dizziness, paraesthesia, confusion, depression, convulsion, amnesia, agitation, anxiety
Cerebrovascular accident

General
Asthenia, chest pain, back pain, oedema, headache, fevers, chills, sweating, weight gain, rash, dizziness, depression, anxiety, confusion
Fatigue, pyrexia, arthralgia, bone pain, myalgia, malaise, injection site reaction, alteration of drug level, insomnia, cysts, flu-like illness, neuropathy, weight loss, dehydration, psychosis
Myopathy, photophobia

Endocrine/metabolic Hyperglycaemia, hypoglycaemia
Lactic dehydrogenase increase, hypophosphatemia, hepatic function abnormalities, hyperlipidaemia, hypothyroidism, electrolyte disturbance
Anorexia

Blood
Leukopenia, anaemia, thrombocytopenia, eccymosis
Leukocytosis
Lymphocele, lymphopenia, neutropenia, lymphadenopathy, pure red cell aplasia, lymphoproliferative disorders

Genitourinary
Urinary tract infection
Micturition disturbance, dysuria, oliguria, renal failure
Haematuria, renal tubular necrosis, BK virus associated nephropathy

Malignancy
Non-melanoma skin cancer, lymphoma, other malignancy

The very common (≥10%), common (1–10%), and unspecified frequency side-effects of these drugs are tabulated and are based on doses of 1.4g EC-MPS for renal transplant patients and 2–3g MMF taken by cardiac/renal or hepatic transplant patients for up to 12 months.10,11 GI, gastrointestinal.

tions or with impaired immunity or underlying serious GI disease and children, particularly those aged under 2 years of age.10,11

DRUG INTERACTIONS
Drugs that can impair the absorption of MMF or EC-MPS when used concurrently include iron supplements, phos- phate binders such as sevelamer and antacids. Plasma con- centrations can also be decreased by drugs that interfere with enterohepatic recycling, such as cholestyramine. Levels can be increased by drugs that impair secretion via the renal tubules including probenecid and aciclovir. Bone marrow suppression may be increased when used in con- junction with other immunosuppressant drugs including
AZA. Live attenuated vaccines are contraindicated in patients with reduced immunity.10,11

USES IN DERMATOLOGY/CLINICAL
APPLICATIONS
Psoriasis (level II evidence for MPA; level III/IV for MMF and EC-MPS)
There is evidence to support the use of MMF in recalcitrant psoriasis, especially if other systemic therapies are not tol- erated or are ineffective.5,18
In the 1970s MPA was shown to be effective in reducing the severity of resistant psoriasis. Three major trials showed promising results but with some concerning side- effects.27,29,30 Lynch and Roenigk found that three patients out

of 32 developed neoplasms while on MPA.27 In a study of 76 patients Epinette and colleagues found that 75% had severe gastrointestinal side-effects, but with fewer neoplasms.31 These studies sparked discussion and the fear of using MPA for psoriasis. It was subsequently abandoned in the treat- ment of psoriasis.
From the late 1990s with the introduction of MMF there were several case reports and uncontrolled case series that showed variable results for MMF in the treatment of psoriasis but few reports of GI side-effects and neoplasms.5 However, none of these studies were controlled and none included as many patients as the earlier trials for MPA.
Further studies looked at MMF compared to Mtx and CSA, and found the latter drugs were more effective in the treatment of psoriasis. MMF was, however, found to cause less nausea than Mtx and less renal toxicity than CSA.5,18,32–34 This supported the use of MMF as an alterna- tive for patients with psoriasis who might be unable to tolerate CSA or Mtx.
There has been one case report of topical MMF in the treatment of plaque type psoriasis. The patient had good regression of erythema, plaque and scale.35

Immunobullous disease
Bullous pemphigoid (level III evidence) A prospective non- blinded, randomised German study involving 13 centres and 73 patients was conducted in 2007.36 The study randomised patients with bullous pemphigoid into two groups and treated them with oral prednisolone in combi- nation with either MMF or AZA. Both MMF and AZA were shown to be equally effective in causing remission in bullous pemphigoid; however, because a prednisolone monotherapy arm was not included the steroid-sparing effect could not be determined.36 MMF showed less liver toxicity than AZA.18,36 In a recent review article, a daily dosage of MMF between 1–1.5g/day in monotherapy was recommended for bullous pemphigoid. For more severe disease, co-administration of 30 mg daily of prednisolone has been recommended.37

Ocular mucous membrane pemphigoid/
cicatricial pemphigoid (level III evidence)
The use of MMF to treat ocular mucous membrane pemphigoid/cicatricial pemphigoid was examined in a ret- rospective cohort study of 236 patients with inflammatory ocular disease, although only 7% (18 patients) had mucous membrane pemphigoid.38 Of these patients 70% had control of inflammation after 1 year on MMF.38 A similar observational study showed a 80% control of symptoms with MMF in combination with other immuno- suppressants.39 Another study including 115 patients with ocular pemphigoid showed that cyclophosphamide was more effective in control of inflammation than MMF (69 vs 59%); however, MMF had fewer side-effects.40 Further smaller studies showed similar results and are summa- rised in Appendix S1.

Pemphigus (level II evidence)
Martin and colleagues conducted a systematic review on randomised clinical trials on pemphigus vulgaris and pem- phigus foliaceus. They concluded that MMF was more effec- tive than AZA in disease control using an intention-to- treat protocol; however, no difference was found using per pro- tocol analysis. Although MMF, CSA and AZA were found to be effective steroid-sparing agents, MMF was less potent than AZA. The authors concluded that further randomised controlled studies were warranted to further clarify optimum treatment for pemphigus.41
Since that systematic review, an international multi- centre randomised controlled trial (industry sponsored) has been conducted in 94 patients.42 The study found that the addition of MMF demonstrated more prolonged effects and a faster response, than the placebo. All groups also received oral prednisolone. Patients in this MMF group were main- tained on lower prednisolone doses and slightly lower overall steroid exposure. It also suggested that MMF 2g/day was preferable to 3g/day; mainly because of the side-effect burden.42 Although MMF is probably beneficial, compara- tive studies with other immunosuppressants and biologics would be needed to confirm its relative efficacy. 43

Eczematous dermatitis (level III evidence)
Some small case reports, series and studies have exam- ined the use of MMF in the treatment of eczematous der- matitis, with mixed results. Several cases of atopic eczema, dyshidrotic eczema and chronic actinic dermatitis were treated successfully with MMF on its own or in com- bination with phototherapy and prednisolone.5,44 Further studies showed a reduction in the scoring atopic dermati- tis index in atopic eczema and a reduction in the severity of disease in chronic dermatitis, according to the investi- gators.45 Four of the seven patients with atopic dermatitis included in a recent Australian study achieved complete remission and a further two achieved partial remission on an average dose of MMF 2g/day. Most patients in this study were taking other systemic agents.26 A controlled study of 55 patients compared CSA with EC-MPS and found that EC-MPS was as effective in maintenance treat- ment in patients with atopic dermatitis. When EC-MPS was ceased, remission was also longer lasting than CSA.46

Lichen planus/lichen planopilaris (level IV evidence)
Five case reports and case series have described MMF as a treatment for lichen planus or lichen planopilaris over the last 10 years. The current evidence for MMF for lichen planus and lichen planopilaris has been positive, showing variable amounts of disease regression in often recalcitrant cases. In several of these, concomitant prednisolone was able to be ceased.5,47–49 The largest study in 2009 involved 16 patients. Five patients showed a complete response, five a partial response and two treatment failure in 20 weeks of

treatment on MMF 1–2 g/day.50 A recent review suggests that MMF is a good choice as a third-line or fourth-line agent in refractory cases of lichen planus and lichen planopilaris.51

Dermatomyositis (level IV evidence)
The evidence base for MMF in cutaneous dermatomyositis mainly consists of case reports and small case series. MMF has been shown to be effective for recalcitrant dermatomyositis after initial therapy of a combination of corticosteroid, Mtx and hydroxychloroquine was ineffective or not tolerated, and corticosteroid doses were often able to be reduced.5,52,53 A retrospective review of 12 patients with recalcitrant dermatomyositis found that 10 patients responded to MMF. This improvement was achieved in 4–8 weeks on 1–2g/day and was judged clinically.54
One case series, involving 50 children, has been pub- lished on cutaneous outcomes of MMF in juvenile dermatomyositis. Over the 12-month study period improve- ment was shown in both muscle and cutaneous manifesta- tions; however, there was no concurrent control group.55
It is worthwhile considering MMF in the treatment of dermatomyositis including the juvenile form, as it shows promising initial results in allowing the reduction of steroid dosages.

Systemic lupus erythematosus (level IV evidence)
There is very little evidence on the use of MMF in systemic lupus erythematosus. In 2007 a systematic review identified five case series in which 16 patients had refractory cutane- ous systemic lupus erythematosus.56 Previous failed treat- ments included anti-malarials, AZA, Mtx, dapsone and topical and systemic corticosteroids. In all, 69% of patients demonstrated a good response to treatment.56 Two more recent case series showed an improvement in most patients.57,58

Pyoderma gangrenosum (level IV evidence)
Interest in the use of MMF for pyoderma gangrenosum has been steadily increasing since it was first reported in the literature in 1997.59 Most research published involves case reports and series. Recalcitrant pyoderma gangrenosum has shown to respond well to MMF alone or in combi- nation with other agents including dapsone, CSA and prednisolone.5,26,60–62
A recent Australian retrospective case series included 26 patients with pyoderma gangrenosum using MMF and con- comitant prednisolone, of whom 85% demonstrated clinical improvement and 50% (13 participants) achieved complete regression.17,62 Another smaller Australian study showed similar results, with 46% of patients with neutrophilic der- matosis (eight with pyoderma gangrenosum) achieving complete remission on MMF.26

Cutaneous Crohn’s disease (level IV evidence)
Several case series have shown perianal and vulval cutaneous Crohn’s disease to be responsive to MMF on its own and in combination with prednisolone, mesalazine and thalidomide.5,63

DOSAGE
The British Association of Dermatologists (BAD) and the American Academy of Dermatologists have issued guidance for the dosing of immunosuppressants in the treatment of dermatological conditions. Initial doses of 250–500 mg/day of MMF with titration up to a maintenance dose of 1–1.5g/
day has been advocated in the treatment of psoriasis. The BAD recommends up to 3g/day of MMF for the treatment of pemphigus vulgaris and 2g/day in the treatment of bullous pemphigoid, although the evidence base for this is not strong.25,64,65 A recent audit of 33 patients in St Vincent’s Hospital in Melbourne, Australia found the commonest starting dose was 1g/day with a maintenance dose of 1.5g twice daily and duration of treatment from 1–160 months.17 Further research is warranted to determine dosage guide- lines for different dermatological conditions.

COST AND AVAILABILITY
The use of MMF and EC-MPS for dermatological conditions in Australia is off-label and does not attract a public subsidy. The approximate cost to the patient is $8–9 a day for 2g/day MMF or the equivalent dose of EC-MPS. For comparison, the total cost of 50 mg/day of AZA to the patient and the PBS is approximately 40 cents a day, with the patient paying only a portion of this. CSA, which is approved on the PBS for severe atopic dermatitis and psoriasis, costs approximately
$5 a day for 100–150 mg/day.13 In New Zealand MMF has been available through a special authority scheme since 2011 and costs the patient approximately $2 a day for 2g/day of MMF. Patients must be a transplant recipient or have another disease in which AZA and steroids or cyclophos- phamide have failed or are contraindicated. AZA in New Zealand costs approximately 10 cents a day for 50 mg/day and CSA costs $3.50 a day for 100–150 mg/day. EC-MPS is not available in New Zealand.14–16.

CONCLUSIONS
On the centenary of the discovery of MPA there have been many reports of the use of its derivatives in various derma- tological conditions, particularly as steroid-sparing agents. MMF and EC-MPS appear to have a better side-effect profile than MPA, but their use is not without risk. Adverse effect profiles for these drugs are, however, largely based on studies conducted in transplant recipients and this needs to be considered when looking at their use in dermatological patients.
Although it has been shown to have a marginally better gastrointestinal side-effect profile than MMF, there are few studies on the use of EC-MPS in dermatology. Further

Table 3 Levels of evidence for MMF in dermatology

20/2/45/51/new-drugs/278/mycophenolate%20mofetil/ (Ac- cessed 1 October 2014).

Condition Psoriasis
Immunobullous disease
•Bullous pemphigoid
•Pemphigus vulgaris
•Cicatricial pemphigoid Eczematous dermatitis Lichen planus
Pyoderma gangrenosum Cutaneous Crohn’s disease Systemic lupus erythematosus
Dermatomyositis/juvenile dermatomyositis
Level of evidence
IV II–III

III
IV
IV
IV
IV
IV
9.Krensky A, Vincenti F, Bennett W. Immunosuppressants, tolerogens, and immunostimulants’. In Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics, 11th edn. New York: McGraw-Hill, 2006; 1414–5.
10.Roche. CellCept capsule data sheet. Roche; 2012. Available from URL: http://www.medsafe.govt.nz/profs/Datasheet/c/
CellCeptcapsuspinf.pdf. (Accessed 20 Sep 2013.)
11.Novartis. Myfortic (mycophenolic acid) delayed-release tablets. 2011. Available from URL: http://www.fda.gov/safety/
medwatch/safetyinformation/ucm310868.htm. (Accessed 21 Nov 2013.)
12.European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined

Dermatological conditions treated by MMF and levels of evidence based on NHMRC guidelines of evidence.66

research should be conducted on EC-MPS if it is to be used in the management of dermatological conditions.
The best evidence for the use of MMF in dermatology is in the treatment of bullous pemphigoid and pemphigus. MMF can be considered as a first-line or second-line adjuvant agent in the treatment of these conditions. MMF has rea- sonable evidence supporting its use in psoriasis, but other agents have been found to be more effective, leaving MMF as a third-line agent for non-responders or for patients who do not tolerate systemic agents such as Mtx or CSA. Topical MPA derivatives may prove to be effective, but controlled trials have not been conducted (Table 3).
Evidence is mostly weak for the use of MMF in ocular mucous membrane pemphigoid, cutaneous Crohn’s disease, pyoderma gangrenosum, lichen planus, lichen planopilaris, systemic lupus erythematosus, dermato- myositis and eczematous dermatitis. Until better evidence is available, therapeutically trialling MMF in selected patients with these conditions who have failed to respond or are intolerant of standard treatments may be reasonable.

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SUPPORTING INFORMATION
Additional Supporting Information may be found in the online version of this article at the publisher’s web-site:

Appendix S1 Summary of studies conducted using MPA/RS-61443
MMF or EC-MPS in dermatology.