Randomized controlled trial of adjuvant oral dexamethasone pulse therapy in pemphigus vulgaris: PEMPULS trial

OBJECTIVE: To determine the therapeutic effect of adjuvant dexamethasone pulse therapy when given in addition to conventional treatment of pemphigus vulgaris. DESIGN: A randomized, placebo-controlled trial. SETTING: International European, multicenter outpatient and inpatient study. PATIENTS: Of the 20 enrolled patients, 11 were randomized to the dexamethasone pulse (DP) group and 9 to the placebo pulse (PP) group. INTERVENTIONS: Oral dexamethasone in 300-mg pulses or PPs 3 days per month. During the intervention, the DP and PP groups received conventional treatment with prednisolone, 80 mg/d, which was tapered across 19 weeks, and azathioprine sodium, 3 mg/kg per day, until the end of the study. Monthly pulses were continued until prednisolone treatment was tapered to 0 mg. MAIN OUTCOME MEASURES: Number of patients in remission, time to and duration of remission, cumulative prednisolone dose, and occurrence of adverse events during 1 year of follow-up. RESULTS: Eight of the 11 DP-treated patients and all 9 PP-treated patients achieved remission. Mean time to remission was 173 days with DP and 176 days with PP. The mean duration of remission within the first year was 151 days for DP and 141 days for PP. Mean cumulative prednisolone dose was 5300 mg for DP and 4882 mg for PP. Weight gain (>5% of baseline) occurred in 8 DP-treated patients compared with 1 PP-treated patient (P<.01). We found no statistically significant difference (P>.05) of an adjuvant effect of DP on remission of pemphigus vulgaris. CONCLUSION: In patients with new pemphigus vulgaris disease activity, there was no benefit of oral DP therapy given in addition to conventional treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00127764.     

Advances of pemphigus vulgaris treatment

寻常型天疱疮是一种严重的慢性自身免疫性大疱性皮肤病,目前糖皮质激素仍是该病的主要治疗药物,部分病程较长的患者还需用免疫抑制剂如硫唑嘌呤、霉酚酸酯或环磷酰胺等.部分对大剂量激素及免疫抑制剂治疗仍抵抗的患者,则会采用更积极的治疗如IVIG、利妥昔单抗等生物制剂及血浆置换.为了找到更特异有效的药物,p38 MAPK 抑制剂、Dsg3 肽段等也已进入了临床试验阶段.     

Randomized double blind trial of prednisolone and azathioprine,vs. prednisolone and placebo,in the treatment of pemphigus vulgaris

Background The classic treatment for pemphigus vulgaris is prednisolone. Immunosuppressive drugs can be used in association. Objective To compare the efficacy of Azathioprine in reducing the Disease Activity Index (DAI). Patients and methods A double blind randomized controlled study was conducted on 56 new patients, assigned to two therapeutic groups: (i) prednisolone plus placebo; (ii) prednisolone plus Azathioprine. Patients were checked regularly for 1 year. ‘Complete remission’ was defined as healing of all lesions after 12 months, and prednisolone <7.5 mg daily, (DAI ≤ 1). Analysis was done by ‘Intention To Treat’ (ITT) and ‘Treatment Completed Analysis’ (TCA). Results Both groups were similar in age, gender, disease duration, and DAI. Primary endpoint: By ITT and TCA, the mean DAI improved in both groups with no significant difference between them. The difference became significant for the last trimester (3 months; ITT: P = 0.033, TCA: P = 0.045). Secondary endpoint: The total steroid dose decreased significantly in both groups, with no significant difference between them, except for the last trimester (ITT: P = 0.011, TCA: P = 0.035). The mean daily steroid dose decreased gradually in both groups becoming statistically significant in favour of azathioprine, in the last trimester, especially at 12th months (ITT: P = 0.002, TCA: P = 0.005). Complete remission was significant at 12 months only for TCA (AZA/Control: 53.6%/39.9%, P = 0.043). Limitations Sample size was rather small to demonstrate all differences. Other limitations include the choice of primary and secondary endpoints and the unavailability to measure thiopurine methyltransferase activity. Conclusion Azathioprine helps to reduce prednisolone dose in long‐run.     

Rituximab in the adjuvant treatment of pemphigus vulgaris: a prospective open-label pilot study in five patients

BACKGROUND: Rituximab is a monoclonal antibody directed against the CD20 antigen expressed on B lymphocytes. There are reports of its efficacy in the treatment of autoimmune diseases, including pemphigus. OBJECTIVES: Prospectively to evaluate the efficacy of rituximab as adjuvant treatment for pemphigus vulgaris (PV). METHODS: Patients with PV were treated with intravenous rituximab (375 mg m(-2)) weekly for 4 weeks in this prospective open-label pilot study. Other concurrent immunosuppression was continued. RESULTS: Of five patients, one achieved complete remission and was able to cease all medication, while two achieved clearance of clinical lesions but continued on systemic therapy. Two patients had progressive disease. Time to response was 2-8 months, with a 13- to 18-month response duration. Response was associated with reduction in serum antiepithelial antibodies. Two patients had significant infectious complications (one developed community-acquired pneumonia associated with delayed-onset neutropenia and the other developed cytomegalovirus infection). CONCLUSIONS: Rituximab has shown efficacy in the treatment of PV. Patients on multiple immunosuppressives should be closely monitored for infectious complications.     

Oral cyclophosphamide for treatment of pemphigus vulgaris and foliaceus

BACKGROUND: Cyclophosphamide is an alkylating adjuvant used in refractory cases of pemphigus. OBJECTIVE: We sought to evaluate the effectiveness and safety of oral cyclophosphamide in the treatment of patients with pemphigus vulgaris (PV) and pemphigus foliaceus (PF) with refractory disease. PATIENTS: We studied 23 patients with pemphigus (20 with PV; 3 with PF) who failed to achieve clinical remissions with the use of prednisone and antimetabolites. RESULTS: Complete remission was achieved in 17 patients with PV and 2 with PF. A total of 3 patients with PV failed therapy. A partial remission was achieved in 1 patient with PF. The treatment was administered for a median duration of 17 months with a follow-up period of 27 months. The median time to complete remission was 8.5 months. A total of 9 patients who were severely affected received concomitant plasma exchange. Adverse reactions included 5 cases of hematuria, 6 nonlife-threatening infections, and the development of transitional cell carcinoma of the bladder 15 years after discontinuation of cyclophosphamide in 1 patient. No death was associated with cyclophosphamide treatment. CONCLUSION: Oral cyclophosphamide is an effective adjuvant in the treatment of severe and refractory PV and PF, but requires close monitoring.     

Dapsone in the treatment of pemphigus vulgaris

This is a report on two cases with pemphigus vulgaris effectively controlled by dapsone. In one, dapsone was added to the treatment after a failure of combined prednisone and methotrexate therapy to control the disease completely. It is suggested that dapsone may offer a means in an attempt to minimize adverse reactions met with during the long corticosteroid regimen required in pemphigus.     

Adjuvant rituximab in the treatment of pemphigus vulgaris: a phase II clinical trial

Rituximab has been tried increasingly for the treatment of pemphigus vulgaris (PV). However, there is still no consensus about its dosing regimens, efficacy, and side effects due to insufficient clinical trials. The goal of this study was to evaluate its efficacy in the treatment of PV. This is a case series of patients with PV who received rituximab, four doses of 375 mg/m² intravenously weekly, plus concomitant oral prednisolone. The primary outcomes were the rate of initial clinical improvement and marked clinical improvement; secondary outcomes included prednisolone doses (mg/d) at baseline, three months, six months and the last visit, as well as the side effects. Forty out of 45 patients completed the study. The mean follow‐up time was 12 ± 10.69 months (range of 3–46 months). Following treatment with rituximab, all the analyzed patients with PV had initial clinical improvement after a mean period of 6.35 weeks and a marked clinical improvement after a mean of 10.13 months. The mean prednisolone dose (mg/d) decreased significantly from a baseline level of 48.75 ± 25.86 to 26.50 ± 12.95 at three months, 20.70 ± 17.51 at six months, and 15.26 ± 9.98 at the last visit (P = 0.0001). The encountered side effects following rituximab were lung abscess, sepsis, pneumonia, cavernous sinus thrombosis, skin abscess, deep vein thrombosis, generalized arthralgia, and Stevens–Johnson syndrome. According to our study, rituximab may be an effective adjuvant to prednisolone for the treatment of PV; however, its safety profile remains concerning. (IRCT registration number: IRCT201111022704N2.).     

Improved protocol for treatment of pemphigus vulgaris with protein A immunoadsorption

BACKGROUND: Pemphigus vulgaris is a life-threatening autoimmune blistering skin disease, usually treated with high-dose corticosteroids in combination with other immunosuppressants. However, this regimen may prove inadequate in severe cases and can cause dangerous side-effects. We have recently reported protein A immunoadsorption (PAIA) to be an effective adjuvant treatment for induction of remission in severe pemphigus. However, in a significant number of cases, the disease rapidly recurred once PAIA and immunosuppressive medication were tapered. AIMS: The aim of the present study was to develop a PAIA-based therapeutic regimen that would result in a more prolonged remission of pemphigus. METHODS: Nine patients with pemphigus vulgaris were treated with a modified protocol characterized by a combination of PAIA with a higher initial dose of systemic methylprednisolone (2 mg/kg). In addition, azathioprine or mycophenolate mofetil was administered as a steroid-sparing agent. RESULTS: In all nine patients treated with this regimen, we observed a sharp decline of circulating autoantibody levels and dramatic improvement of cutaneous and mucosal lesions within 4 weeks of therapy. The patients remained free of clinical disease for up to 26 months after PAIA treatment was discontinued. CONCLUSION: The improved treatment protocol appears to combine highly effective induction of clinical remission in severe or treatment-resistant pemphigus with a prolonged subsequent symptom-free interval.     

The treatment of mild pemphigus vulgaris and pemphigus foliaceus with a topical corticosteroid

Seven patients with mild pemphigus vulgaris (n = 3) or pemphigus foliaceus (n = 4) were treated with a very potent topical corticosteroid alone. Clobetasol propionate 0.05% cream was applied to mucosal lesions and involved skin twice a day for at least 15 days, then progressively tapered. Pemphigus was considered to be controlled if healing of lesions was obtained, with a 75% decrease in the number of new lesions per week without addition of any systemic treatment. In all seven patients, the disease was controlled initially with healing of cutaneous lesions within 15 days, while healing of mucosal lesions took at least 1 month. In four patients, remission was maintained with topical corticosteroid alone for a mean 19-month follow-up. In three patients, relapse occurred after 2-11 months, requiring a systemic treatment.     

The role of IVIg treatment in severe pemphigus vulgaris

BACKGROUND: High-dose intravenous immunoglobulin (IVIg) has become a part of the treatment armentarium in pemphigus vulgaris (PV). Some consider IVIg as an adjuvant steroid sparing agent in PV, while others as disease modifying that can be used as monotherapy. METHODS: We report our experience with a series of 12 PV patients with severe disease treated with IVIg as an adjuvant therapy. RESULTS: Ten of 12 patients (83%) showed response to six cycles of IVIg, six (50%) having complete remission and four (33%) having a partial response. This response rate is concordant with previous reports. The therapy was well tolerated. In all 12 patients, treatment with IVIg allowed a gradual reduction of prednisone dose compared with baseline levels. CONCLUSION: IVIg treatment was beneficial as a steroid sparing agent in our series of patients with severe PV.