Methotrexate is an effective and safe adjuvant therapy for pemphigus vulgaris

ARTICLE

ejd.2011.1611

Auteur(s) : Sharon Baum¹ baumdr@gmail.com, Shoshana Greenberger¹, Liat Samuelov², Michal Solomon¹, Anna Lyakhovitsky¹, Henri Trau¹, Aviv Barzilai¹

¹ Department of Dermatology, Sheba Medical Center, 52621 Tel-Hashomer, Israel

² Department of Dermatology, Souraski Medical Center, Tel Aviv, Israel

Reprints: S. Baum

Pemphigus vulgaris (PV) is a chronic, potentially life threatening, autoimmune blistering disease of the mucosa and skin. Systemic steroids are the first line of treatment [1]. Yet, in order to avoid their long term adverse effects, steroid sparing agents, either immunosuppressive or immunomodulating drugs, are added. The issues of which steroid sparing agent is the most effective and what is the best protocol for its use are under continuous evaluation. Despite recently published prospective controlled studies on newer drugs as adjuvant therapies in pemphigus [2], most of our knowledge and our daily practices are based on retrospective case series [3, 4].

One of the adjuvant immunosuppressant treatments which has become a part of the treatment armamentarium in autoimmune diseases is methotrexate (MTX).

However, there are only a few reports assessing its efficacy in pemphigus vulgaris, with somewhat contradictory results [5-11]. Therefore, the aim of this retrospective study was to report our experience with MTX as an adjuvant to systemic steroids in the treatment of PV.

Materials and methods

Patients

A retrospective analysis of patients’ files was performed. Out of 192 patients with PV treated at the department of dermatology, Sheba medical center, between 1984 and 2008, 39 patients received MTX for their disease. The study was approved by the hospital ethical committee (no.7172).

Patients qualified for assessment had to meet the following inclusion criteria:

• 1. Patients whose diagnosis was based on:
  • (i). appearance of mucosal and/or cutaneous involvement, clinically compatible with PV (blisters or erosions)
  • (ii). histopathology showing suprabasal acantholysis in the epidermis
  • (iii). direct immunofluoresence demonstrating IgG with or without C3 binding in the epidermis.
• 2. Patients who were treated for at least 6 consecutive months with MTX and were followed up during their MTX treatment.

Efficacy assessment

For all patients for every visit while on MTX, the daily prednisone dose, number of erosions (including mucosal erosions), and body surface area of involvement could be obtained from the files. In order to evaluate MTX efficacy in this retrospective series, the combination of these parameters defined the disease severity. In general, for each patient, points from 1 to 3 were assigned for each parameter as detailed in table 1. The points were summed up to form the disease severity index, where 3 points was considered to be a mild disease, 4-6 as a moderate disease and 7-9 as a severe disease. Disease severity was analyzed before the beginning of MTX treatment and at 6 months after the drug initiation. In addition, patients were assessed either at termination of MTX treatment or for those patients who were still on MTX treatment, data was assessed until December 2008.

Table 1 Disease parameters used to define severity index.

Disease severity definitions: < 3 points - mild disease, 4-6 - moderate disease, 7-9 - severe disease

Safety assessment

As a routine, in each visit at the outpatient clinic, patients are questioned about possible side-effects from MTX treatment including gastrointestinal complaints, fatigue or alopecia. In addition, complete blood count and liver function tests were performed.

Statistical analysis

Statistical package for the social sciences (SPSS) version 15.0 for Windows software was used for the data entry and analysis. The paired t-test was used to assess the change in the disease severity, following a normality test (Kolmogorov-Smirnov Test and the Shapiro-Wilk Test). All tests were two–tailed with a confidence level of 95% (P < 0.05). Values are expressed as mean ± standard deviation (SD).

Results

Out of the 39 patients in whom MTX was initiated, 30 patients met the inclusion criteria and were appropriate for evaluation. Nine patients were excluded from the study group; four of them discontinued MTX before six months of treatment due to mild MTX adverse effects (nausea, abdominal pain and alopecia) and five were lost to follow up.

Patients’ characteristics and responses to MTX are detailed in table 2. The study group included 23 females (77%) and 6 males (23%). Twenty nine out of the 30 patients were of Jewish origin, 80% of them were Ashkenazi Jews. The average age of patients when initiating MTX was 54 years (± 14.1). Three patients (10%) received MTX as their first adjuvant treatment and in 27 patients MTX was given after the failure of other steroid sparing agents. These adjuvant therapies included: azathioprine, dapsone, cyclosporine, cyclophosphamide, mycophenolate mofetil and IVIG. 19 patients (63%) had skin and mucosal involvement, 6 (20%) had involvement of skin only and 5 (17%) had only mucosal involvement.

Table 2 Patients’ characteristics.

S=skin, m=mucous membranes

All patients received 15 mg MTX orally once a week, PO divided into 3 doses of 5 mg given every 12 hours and followed by 5 mg folic acid on the following day. This relatively low dose of MTX was selected as it is our clinical experience that higher doses resulted with low compliance, due to the adverse effects of the drug. The range of MTX treatment period was 6-96 months (31±29 months on average). Follow-up of patients continued between 6 months and 2.5 years. Of the 30 participants, 11 patients were still continuing the MTX treatment at the termination of this study. Four patients (13.3%) discontinued the treatment because of remission in their disease.

The mean prednisone dose prior to initiation of MTX therapy was 41.8 ± 25 mg/d, ranging from 10 mg/d to 100 mg/d. Most patients had 1-10% body surface area involvement and 5-10 lesions on average on presentation.

According to the severity index when MTX was introduced, 5 patients were defined as mild disease, 11 patients as moderate disease and 14 patients as severe disease. Following 6 months of treatment, 20 patients were defined as mild disease, 7 as moderate disease and 3 as severe disease. Among the 14 patients who were defined initially as having severe disease, 11 improved, 9 of them had a mild disease at six months of follow-up. Statistical analysis (paired t-test) showed that at the six months of MTX treatment, there was a significant improvement in the severity score (p=0.00001, figure 1). While 22 patients improved on MTX treatment, three patients worsened their disease and 5 were stable. Yet, considering only the prednisone dose as the measure of efficacy, in 23 patients (76.6%) we were able to reduce its dose (range 2.5-85 mg) and in 21 patients (76.6%) the decrease was fifty percent or more (figure 2).

Patients were assessed either at termination of MTX treatment or for those patients who were still on MTX treatment, data was collected until December 2008. Four patients (13.3%) were off the drug due to remission in their disease. 13 patients (23.3%) were still on the drug. 13 patients stopped MTX, 7 (23.3%) due to lack of improvement, 4 (13.3%) due to adverse effects (gastrointestinal in three, alopecia in one) and 2 due to a pregnancy plan.

Discussion

Methotrexate (MTX) is an immunosuppressive and immunomodulator drug that has been shown to be efficacious in autoimmune and chronic inflammatory diseases, mainly rheumatoid arthritis and psoriasis, but also ulcerative colitis and atopic dermatitis [12-16]. However, studies on its effectiveness as an adjuvant to steroids in the treatment of pemphigus were rather confusing [5-11]. Although it is widely believed that MTX has a steroid-sparing effect, evidence to support this notion was present only in a few early reports. The current series of 30 patients suggests that MTX is both effective and safe as an adjuvant therapy.

The mode of action of MTX in autoimmune or inflammatory conditions has not been fully elucidated, although several mechanisms have been postulated [17]. MTX is a potent inhibitor of the enzyme dihydrofolate reductase, leading to the inhibition of purine and pyrimidine synthesis and a reduction in T-cell proliferation [18]. In addition, it is believed that the anti-inflammatory action of MTX is also mediated by the accumulation of extracellular adenosine which acts as an endogenous anti-inflammatory agent. Adenosine can occupy specific adenosine receptors and inhibit lymphocyte proliferation as well as production of the pro-inflammatory cytokines TNF-α, IL-6, and IL-8, while stimulating transcription of the IL-1 receptor antagonist and the production of IL-10 [19, 20].

In a recent meta-analysis, Gurcan and Razzaque [5] reviewed a total of 116 patients with pemphigus vulgaris treated with MTX, in six different reports [7, 9, 11, 21-23]. Of these patients, ninety-six patients (83%) showed clinical improvement. 14 patients (12%) were free of lesions at a mean of 2.6 years (range 3 months-18 years) after discontinuation of all systemic therapy. The steroid-sparing effect of MTX could be assessed in two reports [11, 22]. Mashkilleyson et al, who studied 53 pemphigus patients, found a 50% reduction in the dose of corticosteroids after MTX [11]. In another study, systemic prednisone was discontinued after 6 months of MTX therapy in six out of nine patients [22].

The results of the present study are in accordance with these previous reports. In this series, which is one of the largest reported to date, MTX was beneficial both in reducing the severity of the disease and as a corticosteroid sparing agent.

Of note, our study was unique in two aspects. First, the study population included patients in whom MTX was given as a second or third line adjuvant therapy, thus who were probably representing a more resistant disease. Second, in the current series, MTX was beneficial at a dosage of 15 mg/week, whereas higher doses (up to 25-50 mg per week) were reported [5] in previous studies. Unlike previous studies, in which serious and fatal adverse effects led to the recommendation to avoid the use of MTX in pemphigus [3, 24], these effects were not observed in our study. All adverse effects were either manageable or reversible after cessation of treatment. Nevertheless, about third of our patients (13/30) stopped MTX due to either side effects or lack of efficacy.

Our study has several potential limitations: a retrospective study describing a relatively small number of patients, and, most importantly, the lack of a placebo control group. In this context, it should be emphasized that PV is a chronic disease with a relapsing and remitting course, influenced by many factors, making it difficult to assess the efficacy of various treatments and their long-term effects.

We used a severity score that had not been previously reported or validated. Yet, this score, which is simple and is based on our practical experience, enabled us to semi- quantify the data retrieved from the files.

Despite the current results and the previous reports indicating MTX efficacy in pemphigus [5, 7, 11], its use is disputable, especially in the light of emerging newer drugs, such as mycophenolate mophetil and rituximab, which are efficacious and well tolerated [2, 25-29]. Nevertheless, MTX is a relatively cheap and accessible drug, with which dermatologists have a vast experience. Therefore it definitely has a place in the armamentarium of pemphigus treatments.

In conclusion, the results of our study, together with previous reports, demonstrate that MTX is a safe and efficacious treatment for patients with PV and should be included in the adjuvant therapy armamentarium. These findings require prolonged, placebo-controlled or multiple arm prospective clinical trials in order to further assess the role of MTX in the treatment of pemphigus.

Disclosure

The authors have no financial or conflict of interest in the study.

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