Four studies of five or more patients have investigated the use of ciclosporin in the treatment of pemphigus. loannides et al.24 recently published the results of a randomised controlled, but not blinded, trial of 33 patients with newly diagnosed pemphigus vulgaris (n = 29) or pemphigus foliaceus (n = 4). Patients were randomly assigned to treatment with prednisolone (n = 17) or prednisolone plus ciclosporin (n = 16). Both groups were treated with similar initial doses of prednisolone (prednisone equivalent 1 mg/kg), which were increased by 50% every 5-10 days depending on the persistence of disease activity. One group in addition received ciclosporin 5 mg/kg. The patients in each group were similar with respect to baseline clinical characteristics and disease severity. The groups did not differ significantly in any of the variables used to measure response to treatment or in total amount of corticosteroids administered. These variables included time to heal, time to achieve partial and complete remission, and total corticosteroid dose needed to control disease activity, to heal 80% of lesions or to induce partial or complete remission. Complications were more common among patients who received combination therapy. Thus this RCT demonstrated that ciclosporin is no more effective at inducing remission than corticosteroids alone, and is not effective as a corticosteroid-reducing agent.

Similar results were reported in another RCT of ciclosporin use in oral pemphigus.14 The study consisted of 28 patients with newly diagnosed and confirmed pemphigus vulgaris restricted to the oral cavity. Patients were randomly allocated to treatment with prednisone equivalent 40 mg daily (n = 10) or to the same dose of corticosteroids in combination with either cyclophosphamide 100 mg/day (n = 10), or ciclosporin 5 mg/kg/day (n = 8). All patients were followed for 5 years. The duration of treatment required to achieve remission and the relapse rate did not differ significantly between the three groups. The incidence of complications was higher with combination treatment.

Lapidoth et al.25 compared 16 patients treated with ciclosporin plus prednisone with a historical control group of 15 patients given prednisone alone. The study and control groups did not differ significantly in the time to healing of old lesions, but the authors claim that ciclosporin significantly shortened the time of new blister formation compared with the prednisone-only group. The mean total cumulative prednisone dose was significantly smaller in the ciclosporin group and the duration of hospitalisation was also shorter in that group than in the prednisone-only group. The two groups did not differ in the mean level of serum antibody titre before or after treatment. Overall more side-effects were reported in the ciclosporin treatment group and two patients treated with ciclosporin had to leave the study because of side-effects. The authors concluded that ciclosporin was more effective than prednisone alone in the treatment of pemphigus vulgaris.

Mobini et al.26 described six patients with pemphigus vulgaris who were successfully treated with ciclosporin and prednisone. After at least 3 years of previous treatment failure, therapy with ciclosporin plus prednisone led to clearing of "most lesions" by 16-20 weeks. Over the next 1-2 years, ciclosporin was gradually reduced and eventually discontinued in all patients. The duration of follow up was 3.5-5 years and there had been no relapses during that time. The authors report "no serious side-effects", but give no details. They also say that corticosteroids were discontinued during the study, but they do not mention at what point this occurred.

Barthelemy et al27 published a small case series of nine patients treated with different regimens of ciclosporin with or without prednisone. None of the four patients treated with ciclosporin alone demonstrated clinical improvement. In four patients who showed no improvement after being treated for 2 months with prednisone, the addition of ciclosporin induced clearing of lesions within 3 weeks, but three of the four patients relapsed within an unspecified period. One patient was treated initially with ciclosporin plus prednisone. She demonstrated early improvement, but the disease worsened when the dose of prednisone was tapered. In all, three of nine patients achieved partial remission that lasted at least 18 months. In the four patients in whom ciclosporin was added after 2 months of prednisone, it is not clear whether the initial observed clinical improvement was the result of ciclosporin therapy or simply the time-dependent effects of continued prednisone treatment.

Overall, it is clear that further controlled studies are necessary to adequately evaluate the effectiveness of immunosuppressive therapy. However, most clinicians favour the early use of an immunosuppressive drug, at least in patients for whom steroid doses cannot be tapered without disease flare and in patients in whom steroids are contraindicated.

It is very difficult to evaluate the effectiveness of immunosuppressive drugs when there have been so few controlled studies. To differentiate the therapeutic benefits of immunosuppressive drugs from those of concurrently administered corticosteroids requires a comparison of clinical course, side-effects and cumulative corticosteroid dose administered to a large number of patients treated with and without immunosuppressive drugs. Unfortunately, no such studies have been performed. The few controlled trials that have been conducted are described above and demonstrate little or no benefit over steroid therapy alone. However, all of the trials are quite small and the patients are often heterogeneous with respect to age, disease severity, disease location and so on. In addition, the data regarding disease outcome and side-effects are often limited. Therefore, the results of the trials may need to be weighed more equally with some of the large case series in which beneficial effects were reported in a substantial percentage of patients.

In addition, it is important to move towards a standardised approach for each study. The methodology used to define previous studies was often incomplete, with omission of critical information such as time between onset of symptoms and treatment, length of previous treatments, or disease severity. Moreover, many investigators fail to stratify patients for other known risk factors that influence prognosis, such as age (older patients die more often and sooner) or type of pemphigus (the prognosis of pemphigus foliaceus is better than for pemphigus vulgaris).8,28 Finally, a critical aspect of evaluating the effectiveness of immunosuppressive drugs is the comparison of side-effects in patients treated with combination therapy and those treated with corticosteroids alone. Unfortunately, apart from mortality data, this information is often unavailable.

Initially proposed for the treatment of acute rejection of kidney transplants, pulse corticosteroid therapy is now commonly used to treat a variety of inflammatory and immunological diseases. The treatment is based on the rationale that intravenous delivery of steroid may achieve more rapid control of disease and decrease cumulative steroid dose, thus reducing complications resulting from long-term usage.

One retrospective case-controlled trial and a few small case series are relevant. Werth29 described 15 patients with pemphigus vulgaris who did not initially respond to prednisone and who were followed for at least 500 days after initiation of treatment. Nine patients received intravenous methylprednisolone 250-1000 mg every 24 hours for 1-5 days. The six patients assigned to the control group were selected on the basis of their similarity to patients in the experimental group except that they did not receive pulse steroid therapy. All patients in both groups received adjunctive therapy. Six (67%) of the nine patients who received pulse therapy improved during the pulse therapy. Four (44%) of the nine patients experienced complete remission lasting, on average, 2 years. None of the six control patients were in remission at the time of publication. In addition, the mean prednisone dose after 1 year of therapy was significantly lower in the pulse therapy group. One patient of the ten who underwent pulse steroid treatment died of candidal sepsis during therapy. Otherwise, patients tolerated pulse steroid therapy with minimal side-effects. Thus, the study suggests that pulse steroid therapy in combination with oral steroid and an immunosuppressive drug is more effective than a similar regimen without pulse steroids at inducing remission and lowering the requirements for oral steroids.

In a small case series of eight patients with severe or recalcitrant pemphigus vulgaris, Chryssomallis et al.30 reported that all patients achieved partial remission following pulse steroid therapy. The treatment regimen consisted of 6-10 pulses of intravenous methylprednisolone 8-10mg/kg plus oral prednisone and either azathioprine or cyclophosphamide. The follow up period ranged from 8 to 86 months. All patients achieved partial remission, but none could discontinue medication. Four patients relapsed within 16 months of pulse therapy. One patient died of cardiac arrest and one developed

Does intravenous pulse corticosteroid reduce morbidity and mortality in patients with severe widespread pemphigus vulgaris that is unresponsive to oral prednisone?

thrombophlebitis. Otherwise, side-effects were minimal.

Pulse steroid therapy has also been combined with pulse cyclophosphamide therapy (for example Pasricha et a/.19,20 - see section on cyclophosphamide). Because those studies lacked controls, and because pulse steroids were combined with potent immunosuppressive therapy, it is difficult to know what effects the pulse steroid therapy had on clinical outcome.

In summary, pulse steroid therapy may provide an effective means by which severe recalcitrant disease can be rapidly controlled, but data in support of its use are few. The results vary between studies conducted by Chryssomallis et al.30 and Werth29 with respect to remission, and may reflect the small number of patients in each study. Although remission may improve with pulse therapy, the average death rate reported from these studies (11%) does not differ significantly from the average rates reported in the most recent studies (all case series) in which only oral steroid was used (8.5%).2 Therefore, pulse steroid treatment in combination with conventional therapy may increase the rate of remission, but it is important to pursue this question further in a larger prospective RCT.

The use of immunomodulatory agents is based on the hypothesis that effective therapy can be achieved through removal of autoantibodies (plasmapheresis) or by stimulation of autoantibody degradation (IVIG).

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