Relevant outcomes

Relevant outcome measures include the prevention of new blister formation, the healing of old lesions and a reduction in dose, or cessation, of treatment. Because there is no single definition of remission in the literature, for the purposes of this evaluation we will define a partial remission as a given period of time during which the patient is free of all lesions, and a complete remission as being free of all lesions and receiving no systemic therapy.


Is there an optimal initial dosing strategy for oral prednisolone that effectively controls disease progression in patients newly diagnosed with moderate-to-severe pemphigus?

Corticosteroids have been used extensively for the treatment of pemphigus, and are the mainstay of therapy. Many case series were published from the 1950s through the 1970s, and the results of a single randomised controlled trial (RCT) appeared in 1990. In the only RCT to address steroid dosing regimens, Ratnam et al compared the efficacy of different prednisolone doses with respect to adequacy of disease control and side-effects.4 Twenty-two previously untreated patients with severe disease (>50% of body surface area affected) were treated with either "high-dose" (120-150 mg/day) (n = 11) or "low-dose" (30-60 mg/day) (n = 11) prednisolone. Patients also received adjuvant therapy once formation of new blisters ceased. Patients were followed for 5 years. All patients were seronegative for pemphigus autoantibodies after 3 months of treatment (initial titres ranged from 1:40 to 1:160). The groups did not differ significantly in the duration of prednisolone therapy needed before "initial control of disease was achieved" (average 20 days). In addition, there was no significant correlation between duration of disease before treatment and duration of treatment necessary to achieve remission. Two patients in the low-dose regimen and four patients in the high-dose regimen required at least a 15 mg increase in prednisolone dose to control their disease. Although virtually all patients experienced complications, the incidence of complications was similar in the two groups. No deaths were reported in the study. Therefore, this trial suggested that with respect to initial disease control, relapse rate and length of time before relapse, a "high-dose" regimen offered no advantage over a "low-dose" regimen.

Because of the wide variation in disease course among patients, it is possible that the study of Ratnam et al4 simply had too few patients to demonstrate a statistically significant difference between the two dosing regimens. In addition, it is difficult to understand why, if the low-dose regimen can control severe disease as effectively as high-dose therapy, some of the patients on the high-dose regimen required an increase in the dose of steroid. If an initial daily dose of 30-60 mg prednisolone effectively controls the condition in one experimental group, why would 120 mg be insufficient? In support of this study, others have noted that most patients' disease could be controlled with moderate doses of prednisolone. Hirone5 demonstrated that 56 of 64 patients (88%) with pemphigus, treated between 1970 and 1974, achieved control with initial daily doses of prednisone of 100 mg or less. Rates of remission in the series were not analysed, but overall mortality was only 8%. In a case series by Block et al,6 initial control of disease was achieved in 11 of 13 patients with 80-120 mg of prednisone per day. Mortality was 7-6%.

Previous studies also addressed the issue of the optimal initial dose of steroid. In response to the belief that mortality was often associated with undertreatment, Lever and White7 suggested that "beginning with a too high daily dose [of prednisone] was preferable to beginning with too low a dose". In a case series of 32 patients with pemphigus vulgaris, treated between 1950 and 1959, each patient was given 180 mg prednisone daily for 6-8 weeks.7 If a patient's condition did not improve rapidly, the dose was increased, often doubled. The mortality rate was 19%. Eight patients (25%) experienced a period of at least 2 months during which they were free of lesions and without therapy. It is not clear how long it took patients to achieve a disease-free state. Virtually all patients experienced serious side-effects from long-term use of corticosteroids.

In studies that attempted to follow the guidelines of Lever and White,7 adverse effects of corticosteroids were often the major cause of death. Ryan8 reported a mortality rate of 45% in 45 patients with pemphigus vulgaris treated between 1949 and 1969. In a large series of 107 consecutive cases of pemphigus seen between 1949 and 1970, Rosenberg et al9 found that deaths from corticosteroid complications were more frequent than deaths from uncontrolled pemphigus. Thus, Lever and Schaumburg-Lever10 modified their earlier recommendation of rigid adherence to high-dose steroids for all patients, and suggested a two-tiered approach. Those patients "in the early, stable stage", presumably patients with mild disease, were treated with prednisone 40 mg daily in combination with an immunosuppressant. Patients with moderate or severe disease were still treated with high initial doses of prednisone (180 mg or higher). Using this approach in 63 patients with pemphigus vulgaris, treated between 1961 and 1975, mortality was 9%. Thirty-five per cent of patients experienced a complete remission during the study.10 Therefore, compared with the previous study by Lever and White,7 mortality and remission improved with the stratified approach.

While investigators were determining optimal steroid dosing regimens in the early 1970s, the first studies were being conducted on adjuvant therapy for the treatment of pemphigus. The rationale for adjuvant therapy was to employ a second therapeutic agent in an attempt to reduce the overall steroid dose. In some respects, this was unfortunate in that it confounded attempts to interpret the results of a new steroid regimen because it was not clear whether observed clinical benefits were the result of improved steroid dosing or the adjuvant therapy. In addition, it is not clear how the outcome was influenced by improvements in the management of the complications of steroid treatment that had occurred since earlier studies. Yet, it is evident that the stratification of patients according to disease severity and employing lower doses of steroids for patients with milder disease reduced complications and mortality associated with prolonged high-dose steroid treatment.

In summary, the evidence indicates that most patients achieve control with a daily dose of prednisolone below 100 mg/day. Apart from the study of Ratnam et al.,4 there is no evidence that one dosing regimen is clearly indicated and effective in all patients. Moreover, there is a lack of studies attempting to identify factors that might aid in determining which patients will require higher doses. The treatment regimens used by many clinicians today originated, in large part, from observations made from the large case series, and from recommendations of the series' authors. The typical treatment regimen for a patient with moderate pemphigus consists of a dose of prednisolone of approximately 1 mg/kg/day. If there is no response in 5-7 days, the dose is increased in increments of 0-25-0-5 mg/kg/day until blistering ceases, complications arise or a dose of 2-0-2-5 mg/kg/day is reached.3,11 Again, evidence for the efficacy of this specific dosing strategy comes from historical trends in observed rates of mortality and, in later studies, rates of remission, rather than from controlled clinical trials.

Reasons for the lack of controlled clinical trials are multiple. In part, the low incidence of pemphigus makes it difficult to recruit sufficient patients to generate substantial statistical power. A second issue that has hindered the progress of therapy for pemphigus is the lack of universally accepted criteria for assessing disease severity and for defining a remission. Without clear guidelines, therapeutic success will vary dramatically from patient to patient.

Do immunosuppressive drugs (azathioprine, cyclophosphamide, methotrexate, ciclosporin) in addition to corticosteroids reduce mortality and improve the rate of remission in patients with pemphigus vulgaris?

Two RCTs and a number of case series describe the use of immunosuppressive agents in the treatment of pemphigus. We have restricted our evaluation to controlled trials and selected case series (at least five patients) that represent the best available evidence for each treatment. In most studies, there is no direct comparison of corticosteroid treatment with and without immunosuppression, but it is the best evidence to support its use.

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