Efficacy of combination therapy of steroid and methotrexate for refractory pemphigus

The first line of treatment for pemphigus is systemic corticosteroids. When steroids alone do not result in remission, additional immunosuppressants are recommended. Twenty‐two patients with pemphigus vulugris were treated with steroids and other immunomodulators. However, they were refractory, and hence, methotrexate (MTX) was administered. The efficacy of MTX was assessed for 16 patients who were able to continue MTX therapy for 1 year. Steroid dose reduction was possible in 11 patients. One patient with severe infections had diabetes and was elderly. Our results suggested that MTX was useful as a steroid‐sparing agent in treating recalcitrant pemphigus, when an initial immunosuppressant treatment had failed. However, adverse effects should be closely monitored.


| INTRODUC TI ON
Methotrexate (MTX) is a folate antagonist for the treatment of malignancies 1 and is used in non-neoplastic diseases as an immunosuppressive agent. 2,3 In the guidelines for pemphigus treatment, steroids are mentioned as the first choice, and the efficacy of MTX in combination has already been reported. [4][5][6][7][8][9][10][11][12] Recently, the British guidelines have positioned MTX as the third-line treatment following the second-line treatment with azathioprine and mycophenolate mofetil. 13,14 In Japan, guidelines for pemphigus treatment indicate that MTX is effective in reducing steroid use. 15 However, reports on the efficacy of MTX in treating pemphigus in Japan are limited.
Because steroids alone do not lead to remission in many cases, the combined use of an immunosuppressant can be considered.
We have encountered patients with relapsing diseases or adverse effects even after several types of immunomodulators were administered. Therefore, we evaluated the efficacy and safety of oral MTX in 16 patients who were able to continue MTX therapy for 1 year of 22 patients with pemphigus vulgaris who were refractory to the treatment with steroid and other immunomodulators and who were added MTX.   [16][17][18] ; the scores range from 0 to 263. Two groups were compared using paired Student's t-test. Fisher's exact test was used to compare the categorical data. Results with p < 0.05 were considered statistically significant.

| C A S E S ERIE S
A total of 22 Japanese patients met the criteria for inclusion in this study ( Table 1). The mean time from diagnosis to initiation of MTX therapy was 37.7 ± 35.5 months (range: 4-154 months, median: 23.5 months). Prior to the start of MTX therapy, PSL was combined with other immunomodulators; mizoribine was the most used immunomodulator, followed by azathioprine and cyclosporine.
Efficacy was evaluated in 16 patients who were able to continue MTX therapy for 1 year (Figure 1a).
In these 16 patients in whom MTX therapy was initiated, the mean dose of PSL at the time of initiation was 0.37 ± 0. 19   The age at the start of MTX therapy in the patient who had infections was 70 years old, which was higher than the mean age of the 22 patients (53.0 years). In this study, no patients had adverse events such as interstitial pneumonia or leukopenia. Adverse effects were observed in two patients (9%) with anemia and liver dysfunction. 12 Reports from Japan on the treatment of pemphigus using MTX are limited. In this study, patients who were refractory to treatment with other immunomodulators in addition to PSL received an average of 7.6 mg/wk of MTX for 1 year, which resulted in a reduction in steroid dosage in 15 of 22 patients (68.2%). The 11 patients who did not add another treatment other than MTX were also able to reduce their steroid doses in all cases. In these cases, the PSL dose was significantly reduced 1 year after the initiation of MTX administration. Despite the fact that MTX usage in Japan was lower than that reported abroad, this study also found cases of lower steroid doses, lower antibody titers, and improved symptoms. Considering these results, it may be possible to expect an effect with MTX therapy even if initial treatment with immunosuppressants, which is the second-line in addition to steroids, failed.

| DISCUSS ION
One of the 22 patients who developed serious infections was elderly and had diabetes. It has been reported that the immunosuppressive effect of MTX therapy in rheumatoid arthritis increases the infection rate and the severity of infection, especially in patients with diabetes and those on steroids. [19][20][21] In conclusion, MTX is useful as a steroid-sparing agent in recalcitrant pemphigus after the treatment with first nonsteroidal immunosuppressant has failed. It is necessary to pay attention to the infection profile, especially, in elderly diabetic patients. Therefore, careful follow-up is required when using MTX in combination with PSL, as some patients may develop severe infections during the course of the therapy.

| DECL AR ATION S EC TION
Approval of the research protocol: The study was approved by the Institutional Review Board of Yokohama City University.

ACK N OWLED G EM ENT
We would like to express our sincere gratitude to all the staff of the Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine for their cooperation in this study. We would like to thank Editage (www.edita ge.com) for English language editing.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.