The British Journal of Dermatology

Combined Treatment With Low-dose Methotrexate and Initial Short-term Superpotent Topical Steroids in Bullous Pemphigoid
An Open, Multicentre, Retrospective Study A. Du-Thanh, S. Merlet, H. Maillard, P. Bernard, P. Joly, E. Estve, M.A. Richard, C. Pauwels, S. Ingen-Housz-Oro, B. Guillot and O. Dereure

Disclosures
The British Journal of Dermatology. 2011;165(6):1337-1343.
Abstract and Introduction Abstract Background The interest of long-term superpotent topical steroids (STS) in bullous pemphigoid (BP) has been supported by randomized controlled trials. However, inadequate compliance, poor cutaneous tolerance and nursing difficulties are potential drawbacks. Open-label studies on limited series of patients suggested that low-dose methotrexate (MTX) may be useful, permitting long-term maintenance of a clinical remission obtained by initial, short-term STS. Objectives Open, clinical records-based retrospective analysis of a multicentre series of patients receiving a combined regimen of initial, short-term STS and MTX followed by long-term MTX alone. The primary objective was evaluation of the clinical efficiency of this strategy based on initial clinical remission and subsequent clinical maintenance. The secondary objective was evaluation of the tolerance (type and rating of adverse events) of this combined regimen. Methods Seventy patients with BP (mean age 827 years) were included. Treatment consisted of an initial combination of STS and MTX for a mean duration of 123 weeks followed by long-term MTX alone for a mean duration of 848 months with a mean and median MTX dosage of 10 mg per week. Results One hundred per cent of the patients showed an initial, complete clinical remission after a mean time interval of 219 days. The overall rate of long-term disease control was 76%, whereas 24% of patients experienced at least one relapse during subsequent treatment with MTX alone. Drugrelated adverse effects were mainly haematological and gastrointestinal and resulted in treatment discontinuation in 11 patients (16%). Six patients (9%) died during the follow-up period with one death (1%) most likely to be related to treatment. Conclusions Long-term low-dose MTX combined with short-term STS may result in protracted control of BP in carefully selected patients. These results should prompt randomized controlled trials comparing this treatment with the more usual regimen of long-term STS alone.

Introduction Bullous pemphigoid (BP), the most common autoimmune blistering disease in Western countries, is characterized by the presence of autoantibodies directed against components of the skin basement membrane zone and resulting in subepidermal cleavage. The mortality rate in patients with BP is high, ranging from 10% to 40% after 1 year, possibly

related to the advanced age of most patients, many of whom have multiple associated diseases and/or an already altered general condition, and to the high doses of systemic steroids often used to treat this condition.[14] Therefore, several alternative, systemic steroidsparing therapeutic lines have been proposed, either alone or in association with steroids, such as oral tetracyclines,[5] dapsone,[6] azathioprine combined with plasma exchange,[7]cyclophosphamide,[8] ciclosporin,[9] chlorambucil,[10] mycophenolate mofetil,[11,12] leflunomide,[13]intravenous immunoglobulins,[14] methotrexate (MTX)[1518] or topical tacrolimus.[19] More recently, the French Bullous Diseases Study Group conducted two randomized controlled trials which provided good-level evidence that short-term superpotent topical steroids (STS) progressively tapered over 12 or 4 months were both efficient and well tolerated in BP.[20,21] However, this therapeutic regimen may result in practical difficulties related to nursing care, and cutaneous tolerance may prove poor on already age-altered skin. Furthermore, long-term STS applications on thin and/or inflammatory skin may result in steroids-related systemic effects. To overcome these difficulties, protracted therapy with low-dose MTX alone might be an effective and simple maintenance treatment after complete clinical remission (CCR) is obtained by the initial use of a combination of short-term STS and low-dose MTX. This hypothesis has already been investigated in limited open-label series and proved efficient with an acceptable level of adverse effects.[1517,22,23] In order to provide further support for the clinical relevance of this treatment option, the clinical records of 70 patients with BP from eight French departments of dermatology were retrospectively retrieved and analysed, with a special focus on the efficacy/tolerance balance in this fragile elderly population. All patients had been treated with an initial combination of short-term STS and low-dose MTX followed by long-term MTX alone as a maintenance therapy. Patients and Methods Patients with BP treated between 1999 and 2005 in eight French referral centres (Montpellier, Le Mans, Reims, Rouen, Orlans, Marseille, Saint-Germain-en-Laye and Paris) were retrospectively selected according to the following criteria to enter this open study: (i) a definite BP diagnosis based upon the usual clinical, histological and immunological grounds;[24](ii) presence of clinical criteria of BP as defined by a previous report by the French Bullous Diseases Study Group[24] and subepidermal blistering with eosinophils; (iii) either presence of IgG and/or complement C3 deposits along the epidermal basement membrane zone on cutaneous direct immunofluorescence (DIF) or presence of circulating anti-BP230 and/or anti-BP180 autoantibodies detected by Western blot (WB) and/or enzyme-linked immunosorbent assay (ELISA) or both; and (iv) treatment with initial, shortterm STS associated with low-dose MTX followed by long-term low-dose MTX alone. Overall, 70 of 185 screened patients fulfilled the inclusion criteria for this retrospective study and were included: 30 men (43%) and 40 women (57%) (sex ratio 075) with a mean age at diagnosis of 827 years (range 5097). All patients but two displayed a typical clinical pattern,[24] but DIF and WB and/or ELISA were consistent with BP in these two cases. DIF was consistent with BP in 66 of 70 patients (94%) with IgG and/or complement component C3 deposits along the epidermal basement membrane zone, but these data were absent in four patients. WB was performed in 28 of 70 patients (40%) and revealed the presence of circulating anti-BP230 and/or anti-BP180 autoantibodies in 27 patients (96%), including the four patients with unavailable DIF who were therefore considered as genuine patients with BP and selected to enter the study. During the initial phase of treatment, 68 of 70 patients (97%) received clobetasol propionate and two of 70 (3%) betamethasone propionate, associated with low-dose MTX.

The topical steroids were initially applied twice a day over the entire skin surface except the face, for a mean duration of 219 days, with a mean daily dosage of 26 g (range 10 60). After clinical remission was obtained, steroids were progressively tapered with a mean STS treatment duration of 123 weeks (range 180). The tapering pattern was highly variable and was dependent on each patient's specific outcome. Details regarding MTX therapy are given in Table 1; the initial weekly dosage ranged from 5 to 15 mg. The following parameters were recorded from selected patients' clinical records for further analysis: (i) initial clinical severity of BP measured by the number of new blisters per day; (ii) initial dosage and subsequent changes in and duration of both STS and MTX treatment; (iii) initial clinical remission of the disease defined as fewer than three new blisters per day during the previous 3 days;[21] (iv) number of relapses, a relapse being defined as the reappearance of at least three new blisters per day for three consecutive days, during or after the end of the treatment, as reported in previous studies by the French Bullous Diseases Study Group;[20,21] and (v) type and grading of adverse effects and their possible relationship to the treatment. Biological parameters including blood cell and platelet counts, fasting glycaemia, liver function and renal function (blood urea nitrogen, creatinine rate and creatinine clearance calculated by the Cockroft formula) were checked twice a month during MTX treatment. Patients receiving other immunosuppressive agents including oral steroids and patients with a follow-up of <4 months were excluded. The primary objective of this retrospective survey was to determine whether CCR could be initially obtained with STS combined with low-dose MTX and then maintained over time with MTX alone. The relevant parameters were: (i) the percentage of patients reaching CCR and the mean time for reaching CCR; and (ii) the percentage of patients experiencing one or more clinical relapses during subsequent treatment with MTX alone after CCR was obtained with the initial combined treatment. The retrospective design of the study makes it virtually impossible to evaluate the percentage of patients reaching CCR after a predefined duration of treatment. The secondary objective was to evaluate the tolerance of this combined regimen. The relevant parameters were: (i) the percentage of patients experiencing adverse effects and their intensity according to the Common Terminology Criteria for Adverse Events, [25] and especially serious adverse effects (SAE) including death occurring during the period of treatment; and (ii) the percentage of patients who discontinued treatment because of SAE. Results Treatment Regimen The weekly dosage of MTX was modified in 23 patients (33%): increased by 25 mg weekly in 14 patients (20%) because of relapse after the end of STS application and decreased by 25 mg weekly in nine patients (13%) because of side-effects (moderate anaemia: 2, pneumonia: 1, and unknown reasons: 6). MTX had to be stopped because of SAE in 11 patients (16%), as detailed in Table 2. The mean weekly dosage of MTX was 98 mg. The mean and median durations of overall MTX treatment (initial combination with STS followed by long-term MTX alone) were 848 months (range 118) and 8 months, respectively (see Fig. 1).

(Enlarge Image) Figure 1. Treatment regimen. Clinical Response CCR was obtained in all 70 patients with BP after the initial, full-dosage STS treatment combined with MTX, allowing the progressive tapering of the topical steroids as mentioned above. This result was then maintained in 53 of 70 patients during the entire subsequent treatment period (STS tapering and MTX, followed by MTX alone), for a 76% overall rate of disease control. However, 17 patients (24%) experienced one or more BP relapse(s) after the cessation of STS application, but all of them were subsequently controlled with a 25 mg increase in the weekly MTX dosage (14 patients) or with transient STS retreatment (three patients). These relapses appeared after a mean duration of 10 weeks (range 2 weeks7 months) after the end of the initial STS applications. A relapse occurred in four of 70 patients (6%) after unintentional, nonside-effect-related discontinuation of MTX, but these recurrences were controlled in all cases by resumption of MTX and these patients experienced no further relapse. Adverse Effects During the treatment period, 17 of 70 patients (24%) experienced one or more sideeffect(s), primarily haematological and gastrointestinal, of which 10 were serious (grade 3 or 4), possibly or probably related to MTX. These side-effects resulted in cessation of treatment in 11 cases (16%) and interruption before reintroduction with a lower dosage in two cases (3%) or dosage adjustment (decrease of 25 mg weekly) in two cases (3%). The treatment was not modified in the two remaining cases. The type and grading of side-effects possibly or probably related to MTX along with resulting changes in treatment are detailed in Table 2. Gastrointestinal side-effects reached grade 4 (intestinal and/or oral ulcerations) whenever they were clinically symptomatic (four patients, 6%) whereas only 1/3 of the haematological side-effects (3% of the patients), systematically sought by regular blood cell counts, reached grade 4. Death Occurrence During Treatment Six of the 70 patients (9%) died while being treated for BP. The causes of death were myocardial infarction at 1 and 3 months of treatment (2), major alteration in general condition (2), non-MTX-related gastrointestinal bleeding (1), and respiratory tract infection in a setting of MTX-related pancytopenia (1). Only one of these deaths was unambiguously related to MTX treatment (respiratory tract infection with pancytopenia). Discussion To our knowledge, this is the largest series of patients with BP treated with low-dose MTX combined with initial STS applications, followed by long-term MTX alone. Overall, it shows that this easy-to-handle therapeutic regimen may result in protracted control of BP in carefully selected patients, with a satisfying benefit/risk balance.

Although scarce, previous open studies (detailed in Table 3) pointed out the interest of MTX in BP. In our series, STS were initially used twice a day for a mean duration of 22 days with a mean daily dosage of 26 g of steroids in association with low-dose MTX, and this combination resulted in a CCR in 100% of the patients. This high initial efficiency of STS in obtaining CCR is reminiscent of the results previously reported by Joly et al.with either a standard regimen of clobetasol propionate cream progressively tapered over 12 months or a 'milder' regimen over 4 months only.[20,21] MTX was introduced from the very beginning of STS treatment to avoid any overlap failure between the two phases of treatment and was administered orally in most cases with a median weekly dosage of 10 mg (range 515). The mean and median durations of treatment were 848 months (range 118) and 8 months, respectively. MTX dosage had to be slightly adjusted during treatment in 23 of 70 (33%) patients ( 25 mg weekly) on the basis of disease outcome or side-effects. In the series of Kjellman et al. [18] of 61 patients receiving MTX and STS, the mean age was consistent with our patients' characteristics, but clinical remission occurred after a much longer average period of treatment (11 months vs. 22 days), although an initial treatment with STS was used as well in this series. Significant differences in STS and MTX dosage between the two series might account for this surprising discrepancy. A large majority (76%) of patients did not experience any relapse after initial remission was obtained, a result that compares favourably with relapse rates obtained with systemic steroids (6080%) and similar to STS alone (relapse rate of 35% with the standard regimen of STS and 43% with the mild regimen after a median time of 1 year for the first relapse).[20,21] The remaining patients (24%) experienced moderate relapses easily controlled by a slight increase in MTX dosage and/or transient resumption of STS applications. In the series of Kjellman et al. [18] the remission rate reached 43% at 24 months, but the relapse rate was not specified with precision, which makes it difficult to compare the two studies accurately. Tolerance is a crucial point in these elderly, fragile patients with significant, often numerous comorbidities. In previous studies, side-effects were observed in 29% of patients treated with STS vs. 54% with systemic steroids.[21] In our series, 17 patients (24%) experienced one or more side-effect(s) possibly or probably related to MTX, resulting in definitive treatment discontinuation in 11 patients (16%) even though the BP was in clinical remission. Surprisingly, folic acid supplementation did not seem to protect the patients against adverse gastrointestinal events, as 26% experienced these side-effects in the supplemented group vs. 23% in the nonsupplemented group, but the number of patients was too low in the two groups to draw any definitive conclusions. Overall, the mortality rate was 9% in our series with only one death occurring during treatment and directly attributable to MTX. However, this figure was perhaps underestimated owing to the retrospective design of the study. No treatment-related death could be attributed to STS alone. These data contrast strongly with the significantly higher mortality rates reported in previous studies, [1,3,4] which were close to 40% and 30% in patients with severe forms of BP treated with, respectively, systemic steroids and STS alone.[21] Dreno et al. did not report any mortality in patients treated with systemic steroids alone, but the follow-up was limited to 10 days.[26]Although our mortality rate seems considerably lower than that of the previously reported series, some studies did show similar mortality rates, particularly the series of Guillaume et al. [7] In this study, mortality at 6 months was assessed as mortality alone [five of 31 in the prednisolone group vs. three of 31 in the plasma exchange group; relative risk (RR) 060, 95% confidence interval (CI) 016230] or as total adverse events including mortality (10 major adverse

events including five deaths vs. six major adverse events including three deaths; RR 060, 95% CI 025145). In the series of Roujeau et al. [27] no deaths occurred among the 37 patients analysed during the treatment period (41 patients initially included). However, three patients out of 25 available for subsequent follow-up died: one in the prednisolone plus plasma exchange group and two in the prednisolone group (the calculation for the worst-case scenario including the four lost participants, two in each group, did not modify the ratio between the two groups regarding the mortality rate). Two factors may account for these important discrepancies: first, these percentages cannot be easily compared due to the different designs of the studies; second, an a priori selection of patients with a fair general condition, most notably without significant alteration in renal function according to age, probably artificially downsized the death rate compared with previous reports addressing the general prognosis of patients with BP, whatever their general condition. In the series of Kjellman et al.,[18] 2-year survival according to life-table estimates was 65%, and the median survival time was 38 months. Only five patients had to disrupt MTX owing to mild adverse events (gastrointestinal tract irritation, transient alveolitis, anaemia grade 2, raised liver enzymes), but the direct relationship with MTX was questionable as some patients might have also received systemic steroids prior to or during MTX treatment. Regardless of these methodological biases, the side-effect profile in our series was overall acceptable, even in elderly patients. Overall, this series tends to confirm that protracted monotherapy with low-dose MTX after CCR is obtained with short-term STS associated with MTX is a valuable therapeutic option in BP. Nevertheless, our results cannot be extended to all patients with BP because an a priori selection had been carried out owing to the potential toxicity of the treatment, especially in patients with associated diseases or altered renal function. Accordingly, this combined treatment, although promising, is likely to be proposed only to patients without significantly altered general condition or risk factors. In such patients, it appears to be both easy to use and efficient, and its tolerance can be properly managed in most cases when contraindications are respected and risk factors are taken into account (e.g. hazard of drug intake mistakes regarding weekly regimen, uncertain compliance, drug interactions, alcohol consumption). Interestingly, and apart from the above-mentioned discrepancies, the similarities between the series of Kjellman et al. [18] and our data further support an MTXbased strategy in BP management. Moreover, MTX is likely to be a more cost-effective treatment than long-term STS applications provided by a homecare nurse. A nationwide randomized controlled trial comparing this treatment regimen with protracted STS alone is currently under way to confirm these results.
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