http://informahealthcare.com/jdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, 2015; 26(1): 67–72 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/09546634.2014.880395
REVIEW ARTICLE
Mycophenolate mofetil and enteric-coated mycophenolate sodium in the treatment of pemphigus vulgaris and pemphigus foliaceus Spyridoula Doukaki, Andrea Platamone, Roberta Alaimo, and Maria Rita Bongiorno
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Department of Dermatology, University of Palermo, Palermo, Sicily, Italy
Abstract
Keywords
What is known and objective: Pemphigus is a severe, potentially life-threatening autoimmune blistering disease. The use of corticosteroids has dramatically improved the prognosis and changed its course. However, current morbidity of pemphigus is largely iatrogenic, caused by side effects of the long-term, high-dose corticosteroid therapy that is necessary to sustain disease control. In order to minimize side effects, a range of corticosteroid-sparing immunosuppressive agents have been introduced, including mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). A systematic review was performed to evaluate the effectiveness of MMF and EC-MPS in the treatment of pemphigus vulgaris and pemphigus foliaceus. Methods: A retrospective literature search was conducted through multiple electronic databases (PubMed, Medline, The Cochrane database of systematic reviews) for reports on the use of mycophenolic acid (MPA) in the treatment of pemphigus vulgaris and pemphigus foliaceus. Results: Sixteen studies with a total of 239 patients have evaluated the treatment of pemphigus vulgaris and pemphigus foliac;eus with MPA. The majority of patients had refractory disease treated with corticosteroids as monotherapy or associated to adjuvant agents. Discussion: The results of this review suggest that MPA, as MMF or EC-MPS, may be a promising adjuvant or alternative therapy for the treatment of pemphigus vulgaris and pemphigus foliaceus. It appears safe, at least in the medium term and its adverse events seem to be dose dependent. What is new and conclusion: The use of mycophenolate is first-line adjuvant therapy in the treatment of pemphigus vulgaris and pemphigus foliaceus.
Enteric-coated mycophenolate sodium, mycophenolate mofetil, mycophenolic acid, pemphigus foliaceus, pemphigus vulgaris, therapy
What is known and objective Pemphigus is a severe, potentially life-threatening autoimmune blistering disease, characterized by IgG autoantibodies against the cadherin-type adhesion molecules desmoglein (Dsg)1 and Dsg3 expressed on stratified epithelial cells (1,2). In order to minimize side effects, maximize early control of the disease, and decrease mortality, systemic corticosteroid therapy is often augmented with an additional immunosuppressive agent (3). Several corticosteroid-sparing immunosuppressive agents have been introduced, including azathioprine, mycophenolate mofetil (MMF), methotrexate and cyclophosphamide, dapsone, antibiotics, protein A immunoadsorption, rituximab, and high-dose intravenous immunoglobulins (4). Of these, the purine analogue azathioprine (AZA) was most frequently listed as drug of first choice and has been established for years in the therapy of pemphigus (5). Despite the range of treatment options, a number of patients do not achieve remission, while others show an initial treatment response but remain poorly controlled (4). The development of azathioprine toxicity Correspondence: Maria Rita Bongiorno, MD, Department of Dermatology, University of Palermo, via del Vespro 131, 90127, Palermo, Italy. E-mail: [email protected]
History Received 21 November 2013 Revised 31 December 2013 Accepted 31 December 2013 Published online 12 February 2014
[severe gastrointestinal (GI) symptoms, elevated aminotransferase levels, and/or cytopenias] is a further problem (4). Mycophenolic acid (MPA) is a relatively new adjuvant drug. It is a potent, non-competitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), preferentially of the type II isoform. This isoform controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis; therefore, MPA has potent cytostatic effects on lymphocytes and also suppresses antibody formation (6). In addition, MPA inhibits the glycosylation of lymphocyte since monocyte glycoproteins are involved in intercellular adhesion and leukocyte trafficking (6,7). At present, two formulations of MPA are commercially available: MMF, an ester of mycophenolic acid, whose use in renal transplantation was approved by the Food and Drug Administration in 1995; and the recently introduced entericcoated mycophenolate sodium (EC-MPS) (8). Azathioprine and MMF were recently shown to be equally effective with regard to treatment response in pemphigus, but MMF has significantly less hepatic toxicity and other adverse effects (5,9). The aim of this literature review is to evaluate the efficacy and the safety of MMF and EC-MPS in the treatment of PV and PF.
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Methods A retrospective review of the literature was conducted on December 2010–January 2011 for reports on the use of MPA in the treatment of PV and PF, consulting multiple electronic databases (PubMed, Medline, The Cochrane database of systematic reviews). The studies included in this analysis were based on the following inclusion criteria: (i) English or French language; (ii) diagnosis based on appropriate clinical features, histopathology, and immunofluorescence studies; (iii) provision of data on efficacy, spectrum of responses and follow-up. We excluded from each study the cases of paraneoplastic pemphigus, pemphigus herpetiformis, IgA pemphigus and other blistering autoimmune disease. At the time this manuscript was written, there were sixteen published reports describing the use of MPA, as MMF or EC-MPS, in pemphigus. The data analysed from each report are presented under the following categories (Tables 1 and 2): number of patients, subtype of pemphigus, protocol used (dose of MMF or EC-MPS and concomitant therapies), clinical outcome, duration of follow-up, and reported adverse effects. There was a marked heterogeneity in the description of clinical outcome. Terms such as ‘‘control of disease activity", ‘‘complete clearing of lesions", and ‘‘partial remission’’ (without specifying whether with or without maintenance therapy) used in most of the manuscripts, denote the absence of common terms and measurement endpoints for the assessment of therapeutic response. In order to systematically analyse the available data, we used the term ‘‘clinical improvement’’ that includes absence or significant reduction in new blister formation, rapid re-epithelialization of erosions and reduction or discontinuation of systemic corticosteroid dose, to indicate all positive responses reported by individual authors. To reflect the opinions and observations of each individual investigator, their statements have been reported.
Results Sixteen studies with a total of 239 patients have evaluated the treatment of PV and PF with MPA. Because of the small number of randomized control trials (10), we included several case series and small, non-randomized trials (11,7,8,12–20) evaluating MMF in the treatment of pemphigus. Furthermore, we analysed three reports describing patients with pemphigus treated with EC-MPA (4,8,21). All reports involved small number of participants; both participants with PV and PF were included in most of them, probably because of the relative rarity of the two diseases. Patient’s age at disease’s onset, exact duration, and severity or extent of disease could not be quantified in all studies. All patients had active disease. MMF A total of 222 patients with pemphigus, including 201 patients with PV and 21 patients with PF, were treated with MMF. Among these, 220 patients received MMF at doses of 750–3.5 g daily in combination with corticosteroids. Only two patients received MMF (2 g daily) as monotherapy. Prednisone was administrated in seven reports, prednisolone in four, i.v. betamethasone in one and methylprednisolone in another one. Initial, final doses or tapering of corticosteroids were not reported in all trials. One hundred seventy-five patients (78.8%) showed clinical improvement of the disease. We observed width variability in time to achieve remission. Complete remission, defined as complete healing of all previous lesions, was achieved in a mean of 91 ± 113 d in 20 of 21 patients (25%) receiving MMF
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(2 g/d) and oral methylprednisolone who participated in an additional multicenter, randomized, clinical trial (9). Adverse effects were documented in nine reports. The most common adverse event was increased susceptibility to infections (Table 3); 50 (22.5%) and 26 (11.7%) of 222 patients experienced bacterial or viral infections and oral candidiasis, respectively. Six patients withdrew as a result of side effects. In one patient, MMF dosage was reduced with resolution of symptoms. Antibodies titres were sequentially studied in five trials. Initial antibodies levels varied from 1:160 to 1:640; the titres reduced to 0 within 6 months (7). A steroid-sparing effect was documented in three reports. Ten pemphigus patients received a cumulative methylprednisolone dose of 10 000 mg or less during the course of treatment; four patients received 10 001 to 20 000 mg of corticosteroids; two patients 20 001 to 30 000 mg and one 50 001 to 60 000 mg. One report evaluated the steroid-sparing effect of two MMF dosages, 2 g/d, 3 g/d, versus placebo. The median cumulative steroid doses were 8.7275 mg for placebo and 7.6175 mg for combined MMF, with 7.880 and 7.4425 mg as the respective median cumulative doses for the MMF 2 and 3 g/d groups. The time that patients were maintained on prednisone doses of 510 mg/d while having no new persistent lesions was longer with MMF (median 186 d for combined MMF) than with placebo (median 136.5 d). The values for individual MMF dosing groups were 185 and 187 d for the MMF 2 and 3 g/d groups, respectively. Analysis of total prednisone dose from weeks 12 to 52, which represents the period after steroid tapering, showed that patients in the combined MMF groups (with median dose of 3220 mg) received significantly less steroid than did those receiving placebo (with median 4449.5 mg dose) (10). EC-MPS Three recent reports, describing a total of 17 patients (16 PV, 1 PF), evaluated the effect of EC-MPS in pemphigus. Three patients received EC-MPS as monotherapy. In the remaining patients, it was given along with systemic corticosteroids, such as prednisone and i.v. bethamethasone. Fourteen patients (13 PV, 1 PF) (82.35%) experienced clinical improvement of disease. Bongiorno et al. published a study of 10 patients, nine patients with PV and one patient with PF, who had relapsed or had clinically significant adverse effects from previous drug therapy (prednisone and azathioprine). They found that complete remission was achieved in nine patients (8 PV, 1 PF). After 6 months, four of the eight responsive PV patients had clinically quiescent disease (i.e. no pemphigus lesions) and decreased levels of antiDsg-1 and anti-Dsg-3 antibodies. The remaining four PV patients had minor disease activity with marked reduction in levels of antiDsg-3 antibodies. The PF patient showed clinical disease resolution, but the level of anti-Dsg-1 remained high. By month 18, all 8 PV patients had clinically quiescent disease with decreased autoantibody levels. All patients tolerated EC-MPS very well and no serious adverse events were recorded. In total, three adverse events were reported by three subjects: headache (two cases; one mild and one moderate) and significant increase in fasting blood glucose (one case) which was likely dependent on systemic corticosteroid therapy. All adverse events resolved during the course of the study (4). Baskan et al. reported their experience treating six patients with active, refractory PV with EC-MPS at a dosage of 1440 mg/d. Three patients received in combination prednisolone (70–100 mg/d). The treatment period was between 9 and 19 months (average duration 13.7 months). Complete remission was achieved in two cases with combination therapy and partial remission in two cases with monotherapy. One patient with
No. of patient (diagnosis)
58 (58 PV)
18 (18 PV)
31 (31 PV)
3 (3 PV)
2 (2 PV)
21 (17 PV, 4 PF)
Reference
Beissert et al. (16)
Strowd et al. (25)
Esmaili et al. (7)
Sarma et al. (23)
Marzano et al. (13)
Beissert et al. (14)
MMF: 2 g/d plus Mpred: 2 mg/kg/d
MMF: 2 g/d Plus IVBM: 0.1 mg/kg/d
MMF: 1 g/d plus Prednisolone: 60–80 mg/d
MMF: 2 g/d Plus Prednisolone: 2 mg/kg/d
MMF: 2–3 g/d plus Pred: 1 mg/kg/d
21 patients treated with MMF: 2 g/d plus Pred: 1–2 mg/kg/d 37 patients treated with MMF: 3 g/d plus Pred: 1–2 mg/kg/d
Drug regimen
Table 1. Review of studies on MMF in the treatment of Pemphigus vulgaris and Pemphigus foliaceum.
20 CR (complete reepithelization of all previous lesions) Relapse: new blister formation during dosage reduction of Mpred or MMF.
2 CR (absence of new lesions with complete healing of the previous lesions for a minimum of 4 wks)
21: response group [initial complete or near complete remission of lesions, no severe relapses [formation of 45 blisters/day during dosage reduction of steroid (not refractory during the follow-up period), completed the study without any side effects related to MMF, and in remission had a clinical score of 52] 2: complete improvement 1: completely healed skin lesions, mild oral disease
14: complete control of disease activity (no active lesions or no development of new lesions)
Onset of healing: 2–3 wks (skin lesions) to 6 wks (mucosal lesions) 1 withdrawal after 4 mo of maintenance therapy to control extensive, persistent oral candidiasis Treatment period: 4 and 6 mo Time to CR: 3 and 4 mo Follow-up: 3 and 13 mo 1 case relapse 1 mo after MMF withdrawal Follow-up (mean duration): 438 days CR: 91 ± 113 days Disease-free interval from CR to recurrence of lesions:123 ± 103 days
Follow-up: 35.2 mo (range: 5–130 mo) Average time to 75% disease control: 4.5 mo (range: 1–18 mo) Treatment period: 12 mo
(continued )
Hyperglicemia (3), Infection (1), Hypertension (1)
HZV infection (1), Diarrhea (1)
Oral candidiasis (2), Mild nausea and abdominal discomfort (1)
Candidiasis (14), Viral infections (HPV, HSV) (6), Bacterial infection (4), Gastritis (2), Bone marrow suppression (1), Arthralgia (1)
Infection (34), Oral candidiasis (10), Headache (7), Pyrexia (7), Hypertension (6), Cough (6), Nausea (5), Arthralgia (5), Acne (4), Lymphopenia (1), Cerebrovascular accident (1) Not reported
Treatment period: 52 wks Median time to initial response: 24.1 wks Median time to sustained response: 32 wks Relapse rate at 24 wks after treatment: 21.8 %
(No.
40 (17/21, 23/37): responders (absence of new persistent oral or cutaneous lesions at wk 52 and a Pred dose 10 mg/day from wks 48–52) 3: withdrawn because of adverse events
events
Adverse patients)
Follow-up
Clinical outcome
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16 (12 PV, 4 PF)
42 (31 PV, 11 PF)
10 (10 PV)
1 (1 PF)
5 (4 PV , 1 PF)
12 (12 PV)
2 (2 PV)
1 (1 PV)
Powell et al. (22)
Mimouni et al. (21)
Chams-Davatchi et al. (24)
Kats et al. (20)
Nousari et al. (19)
Enk et al. (12)
Grundmann-Kollmann et al. (18)
Bredlich et al. (17)
1 patient treated with MMF: 2 g/d 1 patient treated with MMF: 2 g/d plus Pred: 100 mg/d MMF: 2 g/d
MMF: 2 g/d plus Prednisolone: 2 mg/Kg/d
MMF: 2–3 g/d plus Pred: 40 mg/d MMF: 2–2.5 g/d plus Pred
MMF: 2 g/d plus Prednisolone: 17.5–60 mg/d
MMF: 35–45 mg/kg/d plus Pred: 0.5–1 mg/kg/d
MMF: 750 mg–3.5 g/d plus Prednisolone: 15–60 mg /d
Drug regimen
1 CR (100%)
2 CR
4 (3 PV/1 PF): CR (complete clearing of the lesions) 1 PV: PR (few healing superficial, oral erosions) 11 CR (clinically free of disease)
1: CR
7: clinically inactive disease (no pemphigus lesions for at least 3 mo, after an average of 15 mo of treatment) 4: improved disease (after an average of 17 mo of therapy 27(22 PV/ 5 PF): CR (absence of lesions for a minimum of 4 wks, while on MMF and Pred 0.15 mg/kg /d) 5 (1 PV/4 PF): PR (presence of 1–5 cutaneous or mucous membrane lesions lasting 4 1 wk while on MMF and Pred 0.15 mg/kg/d) Failure: relapse subsequent to remission while still undergoing combination therapy CR 9: CR (complete clearance of lesions)
Clinical outcome
No new blisters and erosions after 2 wks Time to remission: 6 wks
Time to remission: 8 and 9 wks
Treatment period: 9–12 mo Time to remission: 2 mo
Median time to remission: 6,25 mo (range: 5–8 mo)
None
Mild lymphopenia (9), Mild GI symptoms (7), Transient rises in transaminases (3), Neutropenia (1) None
None
None
GI symptoms (2)
GI symptoms (8), Febrile Neutropenia (1), Musculoskeletal pain (1)
Median treatment/follow-up period: 22.mo (range: 4–49 mo) Median time to remission: 9 mo (range: 1–13 mo) 1 dosage reduction from 45 to 30 mg/kg/d and 1 withdrawal after 8 mo of treatment because of nausea. Treatment period: 6 mo Time to remission: 6–16 wks Relapse subsequent to remission: 17 days (range: 1–60 days) Treatment period: 9 mo
Lymphopenia (9), Asthenia (2), HZV (2), Atypical Mycobacterium infection (1), Myalgia (1)
(No.
Median time on MMF: 15 mo (range: 6–28 mo) 2 withdrawal because of depression
events
Adverse patients)
Follow-up
S. Doukaki et al.
CR: complete remission, PR: partial remission; PV: pemphigus vulgaris; PF: pemphigus foliaceus; MMF: mycophenolate mofetil; Mpred: Methylprednisolone; Pred: Prednisone; IVBM: i.v. betamethasone; GI: gastrointestinal; wks: weeks; mo: months.
No. of patient (diagnosis)
Reference
Table 1. Continued
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Table 2. Review of studies on EC-MPS in the treatment of Pemphigus vulgaris and Pemphigus foliaceum. Reference
No. of patient (diagnosis)
Drug regimen
No. of improved patients
Bongiorno et al. (6) Baskan et al. (26)
10 (9 PV, 1 PF)
Pred: 75 mg/d
6 (6 PV)
Marzano et al. (13)
1 (1 PV)
3 patients treated with EC-MPS: 1440 mg/d 3 patients treated with EC-MPS: 1440 mg/d plus Pred: 70–100 mg/d EC-MPS: 1440 mg/d plus IVBM: 0.1 mg/kg/d
Follow-up
Adverse events (No. patients)
9 (8PV/1PF): clinically quiescent disease (no pemphigus lesions) 2: CR (combined therapy) 2: PR (monotherapy)
18 mo 9–19 mo
Headache (2), Hyperglycemia (1) None
1: CR
Follow-up: 3 mo
Asthenia (1)
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CR: complete remission, PR: partial remission; PV: pemphigus vulgaris; PF: pemphigus foliaceus; EC-MPS: enteric-coated mycophenolate sodium; CR: complete response; PR: partial response; Pred: Prednisone; IVBM: i.v. bethamethasone; wks: weeks; mo: months.
Table 3. Incidence of adverse effects. Mycophenolate Mofetil
No. (%)
Opportunistic viral and bacterial infections Oral candidiasis Mild lymphopenia/neutropenia Mild/moderate gastrointestinal symptoms Arthromyalgia Cough Pyrexia Asthenia Headache Transitory rises in transaminases Acne Hypertension Hyperglycemia Bone narrow suppression Cerebrovascular accident Febrile neutropenia Atypical Mycobacteriosis Enteric-coated mycophenolate sodium Headache Hyperglycemia Asthenia
50 26 20 26 8 6 7 2 7 3 4 7 3 1 1 1 1
(22.5) (11.7) (9) (11.7) (3.6) (2.7) (3.2) (0.9) (3.2) (1.3) (1.8) (3.2) (1.35) (0.45) (0.45) (0.45) (0.45)
2 (0.9) 1 (0.45) 1 (0.45)
combination therapy and one patient with monotherapy did not respond. Time to remission varied between 3 and 7 months with a mean time of 4.5 months. The addition of mycophenolate sodium has permitted dose reduction in prednisolone after 1 month. EC-MPS was well tolerated and no clinical and laboratory side effects have been observed in all patients (21). Marzano et al. conducted a trial on the treatment of refractory blistering autoimmune diseases with mycophenolic acid. One patient with refractory PV received EC-MPS (1440 mg/d) in combination with intravenous betamethasone at the initial dose of 0.1 mg/kg. Remission was achieved at 3 months. All blood parameters remained within normal limits. Patient experienced transient asthenia (8).
Discussion Pemphigus is a severe chronic disorder associated with considerable risks of morbidity and mortality (22). There is no standard treatment fulfilling the criteria of evidence-based medicine and there are few controlled studies on individual therapeutic strategies. Currently, the mainstay of treatment is corticosteroids (9). Adjuvant drugs are commonly used in combination with the aim of increasing efficacy and of having a steroid-sparing
action, thereby allowing reduced maintenance corticosteroids doses (23). Among the different immunosuppressants, azathioprine has been widely used since the late 1960s to control disease in pemphigus patients (9). MMF is most frequently used as immunosuppressive drugs of second or third choice (5). The results of this review suggest that MPA, as MMF or EC-MPS, may be a promising alternative or adjuvant therapy for the treatment of PV and PF. MMF therapeutic dose used in most patients was between 2 and 3 g/d. Nousari et al. reported that patients with immunobullous disease require higher doses of MMF than those used in other inflammatory dermatoses (14). Powel et al. found in their study that doses higher than 2 g/d had no therapeutic benefit and although these doses were not associated with an increased incidence of leucocytopenia, they were associated with increased incidence of opportunistic infection (17). Sarma et al. suggest that lower doses of 1 g/d are also effective and are not associated with any significant side effect (18). Beissert et al. stated that MMF 2 g/d offers a better risk/benefit profile in terms of response and lower adverse events rate (10). We suggest that large studies should be performed to establish appropriate therapeutic dosages in pemphigus patients. A corticosteroid-sparing effect was demonstrated in several patients studied. In some patients, corticosteroids could be discontinued entirely. In the majority of patients, the dosage was significantly reduced. The data analysed from the studies reviewed suggest that gastrointestinal toxicity, certain types of haematological toxicity (particularly lymphopenia and neutropenia) and an increased incidence of some types of infection are the principal adverse effects of MMF (Table 3). Therefore, it appears that MMF in combination with corticosteroids is effective and safe, at least in the medium term, in the management of pemphigus. Its adverse events seem to be dose dependent and compare favourably with azathioprine (17). As with any immunosuppressive therapy, the potential to develop malignancy is often the most concerning adverse effect (6). In contrast to azathioprine, MMF is non-mutagenic (9). 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 counselling of the risk of malignancy are essential (6). Reassuringly, there was no evidence of increased risk of developing any malignancy in pemphigus patients treated with MMF. The sodium salt of MPA, EC-MPS, has been investigated in the management of pemphigus in three reports. Data analysed showed a similar efficacy profile between MMF and EC-MPS.
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The EC-MPS therapy was associated with a reduction in corticosteroid dosage without any relapse in pemphigus activity. This is a significant finding in terms of reduction in corticosteroid-related morbidity. Moreover, EC-MPS was well tolerated and most patients did not experience adverse effects. Indeed, reported side effects were less common in EC-MPS-treated patients. In total, three adverse events were reported by four of the 17 patients: headache (two cases; one mild and one moderate), asthenia and significant increase in fasting blood glucose which was likely dependent on systemic corticosteroid therapy (Table 3). No clinically significant infections (including herpes zoster), gastrointestinal and haematologic side effects were reported. These findings confirm those reported previously in renal transplant recipients (8). Further trials comparing MMF with mycophenolate sodium are required to make a precise conclusion (21). In summary, these preliminary studies demonstrated that EC-MPS is effective and safe as an adjuvant therapy in patients with pemphigus whose prednisone dosage could not be adequately tapered, or in whom azathioprine as a corticosteroidsparing agent had previously failed.
What is new and conclusion One major drawback of the drug is its high cost, which remains an important factor to be considered, especially when it is to be continued for an indefinitely long period (18). Nevertheless, the need for more frequent routine laboratory monitoring, thiopurine methyl transferase screening and potentially more frequent management of adverse effects in azathioprine-treated patients may warrant the use of mycophenolate as first-line adjuvant therapy (17). However, authors recognize that there are several limitations to the data available for substantial and objective analysis. The principal reasons are that both PV and PF are rare diseases and obtaining large numbers of patients to include in randomized clinical trials is practically and logistically difficult. Moreover, as the diseases are inherently potentially fatal, there is also an ethical dilemma. Since this is a retrospective study, we do not have detailed and complete information on duration, severity and extent of the disease. There is, therefore, a pressing need for evidence guided by large international, multicenter, trials that offer the best prospect for obtaining high-quality data.
Declaration of interest The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.
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8. Marzano AV, Dassoni F, Caputo R. Treatment of refractory blistering diseases with mycophenolic acid. J Dermatol Treat. 2006;17:370–6. 9. Beissert S, Werfel T, Frieling U, et al. A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus. Archiv Dermatol. 2006;142: 1447–54. 10. Beissert S, Mimouni D, Kanwar AJ, et al. Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial. J Investig Dermatol. 2010;130: 2041–8. 11. Esmaili N, Chams-Davatchi C, Valikhani M, et al. Treatment of pemphigus vulgaris with mycophenolate mofetil as a steroid-sparing agent. Eur J Dermatol. 2008;18:159–64. 12. Bredlich RO, Grundmann-Kollmann M, Behrens S, et al. Mycophenolate mofetil monotherapy for pemphigus vulgaris. Br J Dermatol. 1999 Nov;141(5):934. 13. Grundmann-Kollmann M, Korting HC, Behrens S, et al. Mycophenolate mofetil: a new therapeutic option in the treatment of blistering autoimmune diseases. J Am Acad Dermatol. 1999;40: 957–60. 14. Nousari HC, Sragovich A, Kimyai-Asadi A, et al. Mycophenolate mofetil in autoimmune and inflammatory skin disorders. J Am Acad Dermatol. 1999;40:265–8. 15. Katz KH, Marks Jr JG, Helm KF. Pemphigus foliaceus successfully treated with mycophenolate mofetil as a steroid-sparing agent. J Am Acad Dermatol. 2000;42:514–15. 16. Mimouni D, Anhalt GJ, Cummins DL, et al. Treatment of pemphigus vulgaris with mycophenolate mofetil. Archiv Dermatol. 2003;139:739–42. 17. Powell AM, Albert S, Al Fares S, et al. An evaluation of the usefulness of mycophenolate mofetil in pemphigus. Br J Dermatol. 2003;149:138–45. 18. Sarma N, Ghosh S. Mycophenolate mofetil as adjuvant in pemphigus vulgaris. Ind J Dermatol, Venereol Leprol. 2007;73:348–50. 19. Chams-Davatchi C, Nonahal Azar R, Daneshpazooh M, et al. Open trial of mycophenolate mofetil in the treatment of resistant pemphigus vulgaris. Annales de Dermatologie et de Ve´ne´re´ologie. 2002;129:23–5. 20. Strowd LC, Taylor SL, Jorizzo JL, Namazi MR. Therapeutic ladder for pemphigus vulgaris. emphasis on achieving complete remission. J Am Acad Dermatol. 2011;64:490–4. 21. Baskan EB, Yilmaz M, Tunali S, Saricaoglu H. Efficacy and safety of long-term mycophenolate sodium therapy in pemphigus vulgaris. J Euro Acad Dermatol Venereol. 2009;23:1432–4. 22. Jessop S, Khumalo NP. Pemphigus: a treatment update. Am J Clin Dermatol. 2008;9:147–54. 23. Harman KE, Albert S, Black MM. Guidelines for the management of pemphigus vulgaris. Br J Dermatol. 2003;149:926–37. 24. Chams-Davatchi C, Esmaili N, Daneshpazhooh M, et al. Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris. J Am Acad Dermatol. 2007;57: 622–8. 25. Martin LK, Werth V, Villanueva E, et al. Interventions for pemphigus vulgaris and pemphigus foliaceus. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD006263. doi: 10.1002/14651858. CD006263.pub2. 26. Yokoyama T, Amagai M. Immune dysregulation of pemphigus in humans and mice. J Dermatol. 2010;37:205–13. 27. Akhyani M, Chams-Davatchi C, Hemami MR, Fateh S. Efficacy and safety of mycophenolate mofetil vs. methotrexate for the treatment of chronic plaque psoriasis. J Euro Acad Dermatol Venereol. 2010; 24:1447–51. 28. Villarroel MC, Hidalgo M, Jimeno A. Mycophenolate mofetil: an update. Drugs Today. 2009;45:521–32. 29. Salvadori M, Holzer H, de Mattos A, et al. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transpl. 2003; 4:231–6. 30. Groves RW. Pemphigus: a brief review. Clin Med. 2009;9:371–5. 31. Yeh SW, Ahmed B, Sami N, et al. Blistering disorders: diagnosis and treatment. Dermatol Therap. 2003;16:214–3. 32. Engineer L, Bhol KC, Ahmed AR. Analysis of current data on the use of intravenous immunoglobulins in management of pemphigus vulgaris. J Am Acad Dermatol. 2000;43:1049–57.
REVIEW ARTICLE
Mycophenolate mofetil and enteric-coated mycophenolate sodium in the treatment of pemphigus vulgaris and pemphigus foliaceus Spyridoula Doukaki, Andrea Platamone, Roberta Alaimo, and Maria Rita Bongiorno
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Department of Dermatology, University of Palermo, Palermo, Sicily, Italy
Abstract
Keywords
What is known and objective: Pemphigus is a severe, potentially life-threatening autoimmune blistering disease. The use of corticosteroids has dramatically improved the prognosis and changed its course. However, current morbidity of pemphigus is largely iatrogenic, caused by side effects of the long-term, high-dose corticosteroid therapy that is necessary to sustain disease control. In order to minimize side effects, a range of corticosteroid-sparing immunosuppressive agents have been introduced, including mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). A systematic review was performed to evaluate the effectiveness of MMF and EC-MPS in the treatment of pemphigus vulgaris and pemphigus foliaceus. Methods: A retrospective literature search was conducted through multiple electronic databases (PubMed, Medline, The Cochrane database of systematic reviews) for reports on the use of mycophenolic acid (MPA) in the treatment of pemphigus vulgaris and pemphigus foliaceus. Results: Sixteen studies with a total of 239 patients have evaluated the treatment of pemphigus vulgaris and pemphigus foliac;eus with MPA. The majority of patients had refractory disease treated with corticosteroids as monotherapy or associated to adjuvant agents. Discussion: The results of this review suggest that MPA, as MMF or EC-MPS, may be a promising adjuvant or alternative therapy for the treatment of pemphigus vulgaris and pemphigus foliaceus. It appears safe, at least in the medium term and its adverse events seem to be dose dependent. What is new and conclusion: The use of mycophenolate is first-line adjuvant therapy in the treatment of pemphigus vulgaris and pemphigus foliaceus.
Enteric-coated mycophenolate sodium, mycophenolate mofetil, mycophenolic acid, pemphigus foliaceus, pemphigus vulgaris, therapy
What is known and objective Pemphigus is a severe, potentially life-threatening autoimmune blistering disease, characterized by IgG autoantibodies against the cadherin-type adhesion molecules desmoglein (Dsg)1 and Dsg3 expressed on stratified epithelial cells (1,2). In order to minimize side effects, maximize early control of the disease, and decrease mortality, systemic corticosteroid therapy is often augmented with an additional immunosuppressive agent (3). Several corticosteroid-sparing immunosuppressive agents have been introduced, including azathioprine, mycophenolate mofetil (MMF), methotrexate and cyclophosphamide, dapsone, antibiotics, protein A immunoadsorption, rituximab, and high-dose intravenous immunoglobulins (4). Of these, the purine analogue azathioprine (AZA) was most frequently listed as drug of first choice and has been established for years in the therapy of pemphigus (5). Despite the range of treatment options, a number of patients do not achieve remission, while others show an initial treatment response but remain poorly controlled (4). The development of azathioprine toxicity Correspondence: Maria Rita Bongiorno, MD, Department of Dermatology, University of Palermo, via del Vespro 131, 90127, Palermo, Italy. E-mail: [email protected]
History Received 21 November 2013 Revised 31 December 2013 Accepted 31 December 2013 Published online 12 February 2014
[severe gastrointestinal (GI) symptoms, elevated aminotransferase levels, and/or cytopenias] is a further problem (4). Mycophenolic acid (MPA) is a relatively new adjuvant drug. It is a potent, non-competitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), preferentially of the type II isoform. This isoform controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis; therefore, MPA has potent cytostatic effects on lymphocytes and also suppresses antibody formation (6). In addition, MPA inhibits the glycosylation of lymphocyte since monocyte glycoproteins are involved in intercellular adhesion and leukocyte trafficking (6,7). At present, two formulations of MPA are commercially available: MMF, an ester of mycophenolic acid, whose use in renal transplantation was approved by the Food and Drug Administration in 1995; and the recently introduced entericcoated mycophenolate sodium (EC-MPS) (8). Azathioprine and MMF were recently shown to be equally effective with regard to treatment response in pemphigus, but MMF has significantly less hepatic toxicity and other adverse effects (5,9). The aim of this literature review is to evaluate the efficacy and the safety of MMF and EC-MPS in the treatment of PV and PF.
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Methods A retrospective review of the literature was conducted on December 2010–January 2011 for reports on the use of MPA in the treatment of PV and PF, consulting multiple electronic databases (PubMed, Medline, The Cochrane database of systematic reviews). The studies included in this analysis were based on the following inclusion criteria: (i) English or French language; (ii) diagnosis based on appropriate clinical features, histopathology, and immunofluorescence studies; (iii) provision of data on efficacy, spectrum of responses and follow-up. We excluded from each study the cases of paraneoplastic pemphigus, pemphigus herpetiformis, IgA pemphigus and other blistering autoimmune disease. At the time this manuscript was written, there were sixteen published reports describing the use of MPA, as MMF or EC-MPS, in pemphigus. The data analysed from each report are presented under the following categories (Tables 1 and 2): number of patients, subtype of pemphigus, protocol used (dose of MMF or EC-MPS and concomitant therapies), clinical outcome, duration of follow-up, and reported adverse effects. There was a marked heterogeneity in the description of clinical outcome. Terms such as ‘‘control of disease activity", ‘‘complete clearing of lesions", and ‘‘partial remission’’ (without specifying whether with or without maintenance therapy) used in most of the manuscripts, denote the absence of common terms and measurement endpoints for the assessment of therapeutic response. In order to systematically analyse the available data, we used the term ‘‘clinical improvement’’ that includes absence or significant reduction in new blister formation, rapid re-epithelialization of erosions and reduction or discontinuation of systemic corticosteroid dose, to indicate all positive responses reported by individual authors. To reflect the opinions and observations of each individual investigator, their statements have been reported.
Results Sixteen studies with a total of 239 patients have evaluated the treatment of PV and PF with MPA. Because of the small number of randomized control trials (10), we included several case series and small, non-randomized trials (11,7,8,12–20) evaluating MMF in the treatment of pemphigus. Furthermore, we analysed three reports describing patients with pemphigus treated with EC-MPA (4,8,21). All reports involved small number of participants; both participants with PV and PF were included in most of them, probably because of the relative rarity of the two diseases. Patient’s age at disease’s onset, exact duration, and severity or extent of disease could not be quantified in all studies. All patients had active disease. MMF A total of 222 patients with pemphigus, including 201 patients with PV and 21 patients with PF, were treated with MMF. Among these, 220 patients received MMF at doses of 750–3.5 g daily in combination with corticosteroids. Only two patients received MMF (2 g daily) as monotherapy. Prednisone was administrated in seven reports, prednisolone in four, i.v. betamethasone in one and methylprednisolone in another one. Initial, final doses or tapering of corticosteroids were not reported in all trials. One hundred seventy-five patients (78.8%) showed clinical improvement of the disease. We observed width variability in time to achieve remission. Complete remission, defined as complete healing of all previous lesions, was achieved in a mean of 91 ± 113 d in 20 of 21 patients (25%) receiving MMF
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(2 g/d) and oral methylprednisolone who participated in an additional multicenter, randomized, clinical trial (9). Adverse effects were documented in nine reports. The most common adverse event was increased susceptibility to infections (Table 3); 50 (22.5%) and 26 (11.7%) of 222 patients experienced bacterial or viral infections and oral candidiasis, respectively. Six patients withdrew as a result of side effects. In one patient, MMF dosage was reduced with resolution of symptoms. Antibodies titres were sequentially studied in five trials. Initial antibodies levels varied from 1:160 to 1:640; the titres reduced to 0 within 6 months (7). A steroid-sparing effect was documented in three reports. Ten pemphigus patients received a cumulative methylprednisolone dose of 10 000 mg or less during the course of treatment; four patients received 10 001 to 20 000 mg of corticosteroids; two patients 20 001 to 30 000 mg and one 50 001 to 60 000 mg. One report evaluated the steroid-sparing effect of two MMF dosages, 2 g/d, 3 g/d, versus placebo. The median cumulative steroid doses were 8.7275 mg for placebo and 7.6175 mg for combined MMF, with 7.880 and 7.4425 mg as the respective median cumulative doses for the MMF 2 and 3 g/d groups. The time that patients were maintained on prednisone doses of 510 mg/d while having no new persistent lesions was longer with MMF (median 186 d for combined MMF) than with placebo (median 136.5 d). The values for individual MMF dosing groups were 185 and 187 d for the MMF 2 and 3 g/d groups, respectively. Analysis of total prednisone dose from weeks 12 to 52, which represents the period after steroid tapering, showed that patients in the combined MMF groups (with median dose of 3220 mg) received significantly less steroid than did those receiving placebo (with median 4449.5 mg dose) (10). EC-MPS Three recent reports, describing a total of 17 patients (16 PV, 1 PF), evaluated the effect of EC-MPS in pemphigus. Three patients received EC-MPS as monotherapy. In the remaining patients, it was given along with systemic corticosteroids, such as prednisone and i.v. bethamethasone. Fourteen patients (13 PV, 1 PF) (82.35%) experienced clinical improvement of disease. Bongiorno et al. published a study of 10 patients, nine patients with PV and one patient with PF, who had relapsed or had clinically significant adverse effects from previous drug therapy (prednisone and azathioprine). They found that complete remission was achieved in nine patients (8 PV, 1 PF). After 6 months, four of the eight responsive PV patients had clinically quiescent disease (i.e. no pemphigus lesions) and decreased levels of antiDsg-1 and anti-Dsg-3 antibodies. The remaining four PV patients had minor disease activity with marked reduction in levels of antiDsg-3 antibodies. The PF patient showed clinical disease resolution, but the level of anti-Dsg-1 remained high. By month 18, all 8 PV patients had clinically quiescent disease with decreased autoantibody levels. All patients tolerated EC-MPS very well and no serious adverse events were recorded. In total, three adverse events were reported by three subjects: headache (two cases; one mild and one moderate) and significant increase in fasting blood glucose (one case) which was likely dependent on systemic corticosteroid therapy. All adverse events resolved during the course of the study (4). Baskan et al. reported their experience treating six patients with active, refractory PV with EC-MPS at a dosage of 1440 mg/d. Three patients received in combination prednisolone (70–100 mg/d). The treatment period was between 9 and 19 months (average duration 13.7 months). Complete remission was achieved in two cases with combination therapy and partial remission in two cases with monotherapy. One patient with
No. of patient (diagnosis)
58 (58 PV)
18 (18 PV)
31 (31 PV)
3 (3 PV)
2 (2 PV)
21 (17 PV, 4 PF)
Reference
Beissert et al. (16)
Strowd et al. (25)
Esmaili et al. (7)
Sarma et al. (23)
Marzano et al. (13)
Beissert et al. (14)
MMF: 2 g/d plus Mpred: 2 mg/kg/d
MMF: 2 g/d Plus IVBM: 0.1 mg/kg/d
MMF: 1 g/d plus Prednisolone: 60–80 mg/d
MMF: 2 g/d Plus Prednisolone: 2 mg/kg/d
MMF: 2–3 g/d plus Pred: 1 mg/kg/d
21 patients treated with MMF: 2 g/d plus Pred: 1–2 mg/kg/d 37 patients treated with MMF: 3 g/d plus Pred: 1–2 mg/kg/d
Drug regimen
Table 1. Review of studies on MMF in the treatment of Pemphigus vulgaris and Pemphigus foliaceum.
20 CR (complete reepithelization of all previous lesions) Relapse: new blister formation during dosage reduction of Mpred or MMF.
2 CR (absence of new lesions with complete healing of the previous lesions for a minimum of 4 wks)
21: response group [initial complete or near complete remission of lesions, no severe relapses [formation of 45 blisters/day during dosage reduction of steroid (not refractory during the follow-up period), completed the study without any side effects related to MMF, and in remission had a clinical score of 52] 2: complete improvement 1: completely healed skin lesions, mild oral disease
14: complete control of disease activity (no active lesions or no development of new lesions)
Onset of healing: 2–3 wks (skin lesions) to 6 wks (mucosal lesions) 1 withdrawal after 4 mo of maintenance therapy to control extensive, persistent oral candidiasis Treatment period: 4 and 6 mo Time to CR: 3 and 4 mo Follow-up: 3 and 13 mo 1 case relapse 1 mo after MMF withdrawal Follow-up (mean duration): 438 days CR: 91 ± 113 days Disease-free interval from CR to recurrence of lesions:123 ± 103 days
Follow-up: 35.2 mo (range: 5–130 mo) Average time to 75% disease control: 4.5 mo (range: 1–18 mo) Treatment period: 12 mo
(continued )
Hyperglicemia (3), Infection (1), Hypertension (1)
HZV infection (1), Diarrhea (1)
Oral candidiasis (2), Mild nausea and abdominal discomfort (1)
Candidiasis (14), Viral infections (HPV, HSV) (6), Bacterial infection (4), Gastritis (2), Bone marrow suppression (1), Arthralgia (1)
Infection (34), Oral candidiasis (10), Headache (7), Pyrexia (7), Hypertension (6), Cough (6), Nausea (5), Arthralgia (5), Acne (4), Lymphopenia (1), Cerebrovascular accident (1) Not reported
Treatment period: 52 wks Median time to initial response: 24.1 wks Median time to sustained response: 32 wks Relapse rate at 24 wks after treatment: 21.8 %
(No.
40 (17/21, 23/37): responders (absence of new persistent oral or cutaneous lesions at wk 52 and a Pred dose 10 mg/day from wks 48–52) 3: withdrawn because of adverse events
events
Adverse patients)
Follow-up
Clinical outcome
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Pemphigus, mycophenolate mofetil, mycophenolate sodium 69
16 (12 PV, 4 PF)
42 (31 PV, 11 PF)
10 (10 PV)
1 (1 PF)
5 (4 PV , 1 PF)
12 (12 PV)
2 (2 PV)
1 (1 PV)
Powell et al. (22)
Mimouni et al. (21)
Chams-Davatchi et al. (24)
Kats et al. (20)
Nousari et al. (19)
Enk et al. (12)
Grundmann-Kollmann et al. (18)
Bredlich et al. (17)
1 patient treated with MMF: 2 g/d 1 patient treated with MMF: 2 g/d plus Pred: 100 mg/d MMF: 2 g/d
MMF: 2 g/d plus Prednisolone: 2 mg/Kg/d
MMF: 2–3 g/d plus Pred: 40 mg/d MMF: 2–2.5 g/d plus Pred
MMF: 2 g/d plus Prednisolone: 17.5–60 mg/d
MMF: 35–45 mg/kg/d plus Pred: 0.5–1 mg/kg/d
MMF: 750 mg–3.5 g/d plus Prednisolone: 15–60 mg /d
Drug regimen
1 CR (100%)
2 CR
4 (3 PV/1 PF): CR (complete clearing of the lesions) 1 PV: PR (few healing superficial, oral erosions) 11 CR (clinically free of disease)
1: CR
7: clinically inactive disease (no pemphigus lesions for at least 3 mo, after an average of 15 mo of treatment) 4: improved disease (after an average of 17 mo of therapy 27(22 PV/ 5 PF): CR (absence of lesions for a minimum of 4 wks, while on MMF and Pred 0.15 mg/kg /d) 5 (1 PV/4 PF): PR (presence of 1–5 cutaneous or mucous membrane lesions lasting 4 1 wk while on MMF and Pred 0.15 mg/kg/d) Failure: relapse subsequent to remission while still undergoing combination therapy CR 9: CR (complete clearance of lesions)
Clinical outcome
No new blisters and erosions after 2 wks Time to remission: 6 wks
Time to remission: 8 and 9 wks
Treatment period: 9–12 mo Time to remission: 2 mo
Median time to remission: 6,25 mo (range: 5–8 mo)
None
Mild lymphopenia (9), Mild GI symptoms (7), Transient rises in transaminases (3), Neutropenia (1) None
None
None
GI symptoms (2)
GI symptoms (8), Febrile Neutropenia (1), Musculoskeletal pain (1)
Median treatment/follow-up period: 22.mo (range: 4–49 mo) Median time to remission: 9 mo (range: 1–13 mo) 1 dosage reduction from 45 to 30 mg/kg/d and 1 withdrawal after 8 mo of treatment because of nausea. Treatment period: 6 mo Time to remission: 6–16 wks Relapse subsequent to remission: 17 days (range: 1–60 days) Treatment period: 9 mo
Lymphopenia (9), Asthenia (2), HZV (2), Atypical Mycobacterium infection (1), Myalgia (1)
(No.
Median time on MMF: 15 mo (range: 6–28 mo) 2 withdrawal because of depression
events
Adverse patients)
Follow-up
S. Doukaki et al.
CR: complete remission, PR: partial remission; PV: pemphigus vulgaris; PF: pemphigus foliaceus; MMF: mycophenolate mofetil; Mpred: Methylprednisolone; Pred: Prednisone; IVBM: i.v. betamethasone; GI: gastrointestinal; wks: weeks; mo: months.
No. of patient (diagnosis)
Reference
Table 1. Continued
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Table 2. Review of studies on EC-MPS in the treatment of Pemphigus vulgaris and Pemphigus foliaceum. Reference
No. of patient (diagnosis)
Drug regimen
No. of improved patients
Bongiorno et al. (6) Baskan et al. (26)
10 (9 PV, 1 PF)
Pred: 75 mg/d
6 (6 PV)
Marzano et al. (13)
1 (1 PV)
3 patients treated with EC-MPS: 1440 mg/d 3 patients treated with EC-MPS: 1440 mg/d plus Pred: 70–100 mg/d EC-MPS: 1440 mg/d plus IVBM: 0.1 mg/kg/d
Follow-up
Adverse events (No. patients)
9 (8PV/1PF): clinically quiescent disease (no pemphigus lesions) 2: CR (combined therapy) 2: PR (monotherapy)
18 mo 9–19 mo
Headache (2), Hyperglycemia (1) None
1: CR
Follow-up: 3 mo
Asthenia (1)
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CR: complete remission, PR: partial remission; PV: pemphigus vulgaris; PF: pemphigus foliaceus; EC-MPS: enteric-coated mycophenolate sodium; CR: complete response; PR: partial response; Pred: Prednisone; IVBM: i.v. bethamethasone; wks: weeks; mo: months.
Table 3. Incidence of adverse effects. Mycophenolate Mofetil
No. (%)
Opportunistic viral and bacterial infections Oral candidiasis Mild lymphopenia/neutropenia Mild/moderate gastrointestinal symptoms Arthromyalgia Cough Pyrexia Asthenia Headache Transitory rises in transaminases Acne Hypertension Hyperglycemia Bone narrow suppression Cerebrovascular accident Febrile neutropenia Atypical Mycobacteriosis Enteric-coated mycophenolate sodium Headache Hyperglycemia Asthenia
50 26 20 26 8 6 7 2 7 3 4 7 3 1 1 1 1
(22.5) (11.7) (9) (11.7) (3.6) (2.7) (3.2) (0.9) (3.2) (1.3) (1.8) (3.2) (1.35) (0.45) (0.45) (0.45) (0.45)
2 (0.9) 1 (0.45) 1 (0.45)
combination therapy and one patient with monotherapy did not respond. Time to remission varied between 3 and 7 months with a mean time of 4.5 months. The addition of mycophenolate sodium has permitted dose reduction in prednisolone after 1 month. EC-MPS was well tolerated and no clinical and laboratory side effects have been observed in all patients (21). Marzano et al. conducted a trial on the treatment of refractory blistering autoimmune diseases with mycophenolic acid. One patient with refractory PV received EC-MPS (1440 mg/d) in combination with intravenous betamethasone at the initial dose of 0.1 mg/kg. Remission was achieved at 3 months. All blood parameters remained within normal limits. Patient experienced transient asthenia (8).
Discussion Pemphigus is a severe chronic disorder associated with considerable risks of morbidity and mortality (22). There is no standard treatment fulfilling the criteria of evidence-based medicine and there are few controlled studies on individual therapeutic strategies. Currently, the mainstay of treatment is corticosteroids (9). Adjuvant drugs are commonly used in combination with the aim of increasing efficacy and of having a steroid-sparing
action, thereby allowing reduced maintenance corticosteroids doses (23). Among the different immunosuppressants, azathioprine has been widely used since the late 1960s to control disease in pemphigus patients (9). MMF is most frequently used as immunosuppressive drugs of second or third choice (5). The results of this review suggest that MPA, as MMF or EC-MPS, may be a promising alternative or adjuvant therapy for the treatment of PV and PF. MMF therapeutic dose used in most patients was between 2 and 3 g/d. Nousari et al. reported that patients with immunobullous disease require higher doses of MMF than those used in other inflammatory dermatoses (14). Powel et al. found in their study that doses higher than 2 g/d had no therapeutic benefit and although these doses were not associated with an increased incidence of leucocytopenia, they were associated with increased incidence of opportunistic infection (17). Sarma et al. suggest that lower doses of 1 g/d are also effective and are not associated with any significant side effect (18). Beissert et al. stated that MMF 2 g/d offers a better risk/benefit profile in terms of response and lower adverse events rate (10). We suggest that large studies should be performed to establish appropriate therapeutic dosages in pemphigus patients. A corticosteroid-sparing effect was demonstrated in several patients studied. In some patients, corticosteroids could be discontinued entirely. In the majority of patients, the dosage was significantly reduced. The data analysed from the studies reviewed suggest that gastrointestinal toxicity, certain types of haematological toxicity (particularly lymphopenia and neutropenia) and an increased incidence of some types of infection are the principal adverse effects of MMF (Table 3). Therefore, it appears that MMF in combination with corticosteroids is effective and safe, at least in the medium term, in the management of pemphigus. Its adverse events seem to be dose dependent and compare favourably with azathioprine (17). As with any immunosuppressive therapy, the potential to develop malignancy is often the most concerning adverse effect (6). In contrast to azathioprine, MMF is non-mutagenic (9). 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 counselling of the risk of malignancy are essential (6). Reassuringly, there was no evidence of increased risk of developing any malignancy in pemphigus patients treated with MMF. The sodium salt of MPA, EC-MPS, has been investigated in the management of pemphigus in three reports. Data analysed showed a similar efficacy profile between MMF and EC-MPS.
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The EC-MPS therapy was associated with a reduction in corticosteroid dosage without any relapse in pemphigus activity. This is a significant finding in terms of reduction in corticosteroid-related morbidity. Moreover, EC-MPS was well tolerated and most patients did not experience adverse effects. Indeed, reported side effects were less common in EC-MPS-treated patients. In total, three adverse events were reported by four of the 17 patients: headache (two cases; one mild and one moderate), asthenia and significant increase in fasting blood glucose which was likely dependent on systemic corticosteroid therapy (Table 3). No clinically significant infections (including herpes zoster), gastrointestinal and haematologic side effects were reported. These findings confirm those reported previously in renal transplant recipients (8). Further trials comparing MMF with mycophenolate sodium are required to make a precise conclusion (21). In summary, these preliminary studies demonstrated that EC-MPS is effective and safe as an adjuvant therapy in patients with pemphigus whose prednisone dosage could not be adequately tapered, or in whom azathioprine as a corticosteroidsparing agent had previously failed.
What is new and conclusion One major drawback of the drug is its high cost, which remains an important factor to be considered, especially when it is to be continued for an indefinitely long period (18). Nevertheless, the need for more frequent routine laboratory monitoring, thiopurine methyl transferase screening and potentially more frequent management of adverse effects in azathioprine-treated patients may warrant the use of mycophenolate as first-line adjuvant therapy (17). However, authors recognize that there are several limitations to the data available for substantial and objective analysis. The principal reasons are that both PV and PF are rare diseases and obtaining large numbers of patients to include in randomized clinical trials is practically and logistically difficult. Moreover, as the diseases are inherently potentially fatal, there is also an ethical dilemma. Since this is a retrospective study, we do not have detailed and complete information on duration, severity and extent of the disease. There is, therefore, a pressing need for evidence guided by large international, multicenter, trials that offer the best prospect for obtaining high-quality data.
Declaration of interest The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.
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