Methylprednisolone pulse therapy plus adjuvant therapy for pemphigus vulgaris: an analysis of 10 years' experience on 312 patients

Steroid pulse therapy has shown satisfactory efficacy and safety in treating pemphigus vulgaris (PV). However, there is a paucity of data about the efficacy and safety of methylprednisolone, despite its frequent administration. The aim of this study is to evaluate the efficacy and safety of steroid pulse therapy in treating PV. In this 10‐year retrospective cohort study, 312 patients with PV, who had received methylprednisolone pulse therapy, were included. Data of pulse therapy sessions, adjuvant medications, dosages, remission rates, complications, and mortalities were collected from all patients. A total of 276 patients out of 312 underwent the final follow‐up at least 6 months after the last session of pulse therapy. Complete remission off therapy was achieved in 83 patients (30%), and 152 patients (55%) had complete remission on therapy. About 29 (10.5%) patients had lesions of pemphigus at the time of the study follow‐up, and 26.8% of remained patients were on the minimal therapy. Methylprednisolone pulse therapy could be considered as an option for proper control of PV in severe cases. It might lead to shorter periods of hospitalization and reduce the need to take long‐term high‐dose oral steroid therapy.     

The transition of pemphigus vulgaris into pemphigus foliaceus: a reflection of changing desmoglein 1 and 3 autoantibody levels in pemphigus vulgaris

The transition of pemphigus vulgaris (PV) into pemphigus foliaceus (PF) is rare and the immunological changes underlying this event are not well understood. We report a 44-year-old woman who presented with oral and cutaneous erosions typical of PV. Over a 9-year period, the clinical features evolved into those of PF. To examine whether quantitative changes in desmoglein (Dsg) antibodies were associated with this transition, Dsg1 and Dsg3 antibody levels were measured by enzyme-linked immunosorbent assay in 82 sequential serum samples collected over this period. At presentation, when the phenotype was PV with oral and cutaneous erosions, antibodies to both Dsg1 and Dsg3 were detected. The disappearance of oral involvement was associated with a decline in Dsg3 antibodies, which are now undetectable, while the development of more severe skin involvement was associated with rising Dsg1 antibody levels. These data strongly suggest that the change in clinical features is a reflection of qualitative and quantitative changes in antibody profile. It is not known whether the transition to PF is permanent or whether disease relapses in the future may be associated with the re-emergence of Dsg3 antibodies, oral ulceration and a PV phenotype.     

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.     

Direct immunofluorescence of the outer root sheath in anagen and telogen hair in pemphigus vulgaris and pemphigus foliaceus

Direct immunofluorescence of peri‐lesional skin is the gold standard in the diagnosis of pemphigus. A specific immunofluorescence pattern may also be demonstrated in the outer root sheath of anagen and telogen hair. We demonstrated an intercellular reticular deposition of immunoglobulin G in the outer root sheath of plucked anagen and telogen hair in all pemphigus vulgaris patients with active disease and for the first time in all patients with active pemphigus foliaceus. Moreover, we demonstrated for the first time that plucked hair samples may be kept at ?20°C for at least 2 weeks before immunofluorescent staining and analysis.     

Case of pemphigus foliaceus that shifted into pemphigus vulgaris after adrenal tumor resection

A 79-year-old Japanese woman visited our hospital on 6 May 2003, who had suffered from erythema and crusted vesicles located on the head, face and trunk. The eruptions first appeared in February 2003. Histopathological findings included blister formation spreading from just below the horny layers to the upper squamous layers, where acantholytic cells were observed. Direct immunofluorescence disclosed immunoglobulin G depositions in the epidermal intercellular spaces. Enzyme-linked immunosorbent assay showed an elevated titer of anti-desmoglein (Dsg)1 autoantibodies (154 index value), but almost normal levels of anti-Dsg3 autoantibodies (8 index value in serum). The diagnosis at first was made as pemphigus foliaceus (PF). Topical use of corticosteroids alone could control the eruptions well. Systemic examinations on admission revealed a right adrenal tumor that had caused Cushing's syndrome. Its resection was performed on 24 July 2003. Histopathological diagnosis of the removed tumor was a functional adrenal adenoma. The symptoms had worsened after the resection. Topical use of corticosteroids alone could no longer control the symptoms. Additional p.o. medications of minocycline hydrochloride and nicotinic acid amides improved the symptoms to some extent. However, oral cavity erosions appeared in December 2004, and the titer of anti-Dsg3 autoantibodies in serum elevated, suggesting a transition from PF to pemphigus vulgaris (PV). p.o. administration of corticosteroids started, which improved the symptoms significantly. To date, there have been no reports of pemphigus complicated with an adrenal tumor that caused Cushing's syndrome in Japan. The present case is particularly interesting in that the symptoms became worse after the tumor resection and that the first diagnosis of PF shifted into PV after the operation.     

Comparison of desmoglein ELISA and indirect immunofluorescence using two substrates (monkey oesophagus and normal human skin) in the diagnosis of pemphigus

A prospective study was performed to assess the usefulness of desmoglein enzyme-linked immunosorbent assay testing compared with indirect immunofluorescence in the diagnosis of new cases of pemphigus, as well as to compare the relative sensitivities of monkey oesophagus and normal human skin as substrates for indirect immunofluorescence. These tests were performed on the sera of 29 consecutive new cases of pemphigus diagnosed over a 2-year period based on clinical, histological and direct immunofluorescence findings. Desmoglein enzyme-linked immunosorbent assay was positive in all patients whereas indirect immunofluorescence was positive in only 25 of 29 patients. All four patients with negative indirect immunofluorescence had positive antinuclear antibodies or cytoplasmic fluorescence that could have masked the anti-intercellular antibodies. Desmoglein enzyme-linked immunosorbent assay appeared to reflect the disease activity better than indirect immunofluorescence in a few patients who had active disease of recent onset. Monkey oesophagus was found to be superior or equal to human skin as a substrate for indirect immunofluorescence in both pemphigus vulgaris and foliaceus.     

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.     

Herpes simplex virus 1 and cytomegalovirus are associated with pemphigus vulgaris but not with pemphigus foliaceus disease

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are blistering autoimmune diseases that depend on interaction between genetic and environmental factors. Viral infections, like herpes simplex viruses 1 and 2 (HSV1/2), cytomegalovirus (CMV), Epstein‐Barr virus and dengue virus, could trigger or exacerbate pemphigus. IgM and IgG antibodies against these viruses in serum from PV and PF, their relatives and controls were determined. HSV1/2 expression was evaluated by direct immunofluorescence (DIF) and qPCR in affected or not oral mucosa from PV patients compared with uninjured PF mucosa. IgG anti‐HSV1 was higher in the PV group compared with all groups. IgG anti‐CMV resulted higher in PV group compared with PF patients and PV relatives. HSV1 was confirmed by DIF and qPCR on oral samples from patients with PV. Lack of HSV1 expression in the oral mucosa of patients with PF corroborate that immunosuppressive therapy cannot be the main cause for HSV1 replication in PV disease.     

Mycophenolate mofetil as an adjuvant therapy for classic and endemic pemphigus foliaceus

Pemphigus foliaceus is an autoimmune cutaneous disease with subcorneal acantholysis and pathogenic IgG4 autoantibodies directed against desmoglein 1. We present our experience with mycophenolate mofetil (MMF) in the treatment of one case of endemic pemphigus foliaceus (fogo selvagem) and two cases of the classic form. All patients had severe, refractory disease and developed marked adverse effects due to long-term corticosteroid therapy. MMF proved to be an effective corticosteroid-sparing agent at doses varying from 35 to 45 mg/kg/d. It was well tolerated, and we found no significant adverse effects from this drug.     

The clinical transition between pemphigus foliaceus and pemphigus vulgaris correlates well with the changes in autoantibody profile assessed by an enzyme-linked immunosorbent assay

BACKGROUND: There are a number of reports of pemphigus with clinical shifting between pemphigus foliaceus (PF) and pemphigus vulgaris (PV). On the other hand, a novel enzyme-linked immunosorbent assay (ELISA) against recombinant baculoproteins of desmoglein 1 (Dsg1) (PF antigen) and Dsg3 (PV antigen) has been established and found to be extremely sensitive and specific. OBJECTIVES: To characterize the change in the antibody profiles in a series of pemphigus cases with mixed features of PF and PV by various methods, including the novel ELISA. Patients/methods Sera were obtained from eight cases undergoing a shift between PF and PV and three cases of coexistent PF and PV. The autoantigens were analysed by ELISA, as well as by immunofluorescence using normal human skin sections and immunoblotting using normal human epidermal extracts. RESULTS: The results of the ELISA, immunofluorescence and immunoblotting studies showed that the transition between PF and PV correlates well with the changes of autoantibodies against either Dsg1 or Dsg3. CONCLUSIONS: The clinical phenotype at each stage is defined by the anti-Dsg antibody profile in the serum of these pemphigus patients showing mixed features of PF and PV. In addition, ELISA using recombinant baculoproteins was particularly useful in distinguishing PF and PV.     

A 6‐year treatment experience for pemphigus: retrospective study of 69 Chinese patients

There is a lack of data on treatment and prognosis of pemphigus in China. The aim of this study was to evaluate long‐term follow‐up and prognosis of pemphigus. Forty‐seven inpatients with pemphigus vulgaris (PV) and 22 with pemphigus foliaceus (PF) were recruited in this retrospective study. The average age at onset was 51.6 and 54.9 years in PV and PF, respectively. High‐dose systemic steroids were administered in 47 PV and 21 PF, of which 18 PV and 8 PF with adjuvant therapies. CD4 lymphocytopenia was found in 5 PV and 2 PF patients at admission and successfully treated by intravenous thymopentin daily. During a mean follow‐up of 37.1 months, 41 PV and 19 PF reached remission, 30 PV and 9 PF relapsed, 4 PV and 2 PF died. Major causes of death were relapse of pemphigus due to discontinuation of oral steroids by the patients themselves (four cases) and severe infections (two cases, one with severe CD4 lymphocytopenia). The 1‐year mortality rate of PV and PF was 8.5% and 4.5%, respectively. Cox regression analysis indicated that age at onset of pemphigus was an independent risk factor related to the elevated mortality. Our report confirmed the high mortality rate of pemphigus in a Chinese population and stressed that patient education was urgently needed to prevent relapses and deaths.     

An 'n-of-1' placebo-controlled crossover trial of intravenous immunoglobulin as adjuvant therapy in refractory pemphigus vulgaris

Background  Pemphigus vulgaris (PV) is an organ-specific autoimmune blistering mucocutaneous disorder that is potentially fatal. High-dose intravenous immunoglobulin (IVIg) is increasingly used in the treatment of autoimmune diseases and it has been reported that it may also be effective in PV.
Objectives  To evaluate prospectively the efficacy of IVIg for PV using an 'n-of-1' placebo-controlled trial.
Methods  A randomized, placebo-controlled, crossover trial of IVIg was conducted in a single patient with severe PV, comprising two phases of six consecutive months of either IVIg or placebo infusion. Before the commencement of the trial, the patient had received 18 months of IVIg but concerns about the continuing therapeutic efficacy of IVIg led to the double-blind placebo-controlled 'n-of-1' trial of IVIg.
Results  Pemphigus autoantibody titres were significantly higher when on placebo compared with IVIg treatment (median 1 : 80 vs. 1 : 20, P  =   0·007), desmoglein 3 (126 vs. 79, P  =   0·004) and desmoglein 1 antibody levels (126 vs. 94, P  =   0·004). There was a significant improvement in subjective disease activity scores while on IVIg compared with placebo (mean overall score 11·6 vs. 20·6, P  <   0·0001).
Conclusions  The results of this study confirm a beneficial effect of IVIg in the management of refractory PV.     

The severity of cutaneous and oral pemphigus is related to desmoglein 1 and 3 antibody levels

BACKGROUND: Pemphigus vulgaris (PV) and foliaceus (PF) are characterized by antibodies to the desmosomal proteins desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1), respectively. Past studies using indirect immunofluorescence (IIF) as a measure of pemphigus antibody levels have failed to demonstrate consistently a relationship between disease severity and IIF titres. However, IIF is not able to measure separately Dsg1 and 3 antibodies, unlike enzyme-linked immunosorbent assays (ELISA), which utilize recombinant proteins. OBJECTIVES: To compare independently Dsg1 and 3 antibody levels with the severity of both cutaneous and oral involvement in PV and PF. Patients and methods Four hundred and twenty-four serum samples were analysed from 80 subjects with PV and 24 with PF. IgG antibodies to Dsg1 and 3 were measured by ELISA. For every sample analysed, the associated severity of skin and oral disease were graded from 0 to 3; quiescent, mild, moderate and severe. RESULTS: A relationship between Dsg1 antibodies and skin severity was demonstrated such that a 10-unit increase in Dsg1 ELISA value was associated with a 34% chance of having a higher severity score [95% confidence interval (CI), 25-45%, P < 0.0005]. This was observed in both PV and PF. Oral severity was associated with Dsg3 antibody levels and a 10-unit increase in the Dsg3 ELISA value was associated with a 25% chance of a higher oral severity score (CI 17-33%, P < 0.0005). We were unable to demonstrate a relationship between Dsg1 antibodies and oral severity, even after adjusting for the effect of Dsg3 antibodies. Similarly, there was no relationship between Dsg3 antibodies and skin severity. CONCLUSIONS: This study suggests that the clinical phenotype of pemphigus, in particular the balance of skin and oral disease, is determined principally by the quantities of Dsg1 and 3 autoantibodies, respectively.     

Analysis of current data on the use of methotrexate in the treatment of pemphigus and pemphigoid

Methotrexate (MTX) is primarily used in the treatment of malignancies. It has also been used as an immunosuppressive agent in the treatment of pemphigus and pemphigoid. The objective of this study was to determine the role of MTX in the treatment of pemphigus and pemphigoid based on an analysis of the available literature. A retrospective analysis of the English language literature was conducted. The studies included in this analysis were required to fulfil the following inclusion criteria: English language; diagnosis based on histology and immunopathology; minimum of five patients in each series; and data for efficacy, spectrum of responses and follow-up. A total of 136 patients with pemphigus were reported in seven studies. One hundred and eleven of the 136 patients (82%) showed clinical improvement with MTX. A total of 79 patients with pemphigoid were reported in six studies. Overall, 74 of the 79 patients (94%) showed clinical improvement. Nausea and infection were the most common side-effects. Death due to MTX resulted in seven of 215 patients (3%). There is a lack of randomized controlled trials. In many studies in this review there was insufficient information on clinical follow-up post-therapy and on serological correlations. Analysis of the data suggests that MTX may be useful and effective in patients with pemphigus vulgaris, who are corticosteroid dependent or who develop significant complications in relation to corticosteroids. MTX is likely to be more beneficial in patients with pemphigoid, particularly in bullous pemphigoid, than in patients with pemphigus. Given the limitations of the available data, it appears that when there is a need for adjuvant therapy, MTX may be considered early in the management of moderate to moderately severe disease.     

Involvement of UV-irradiation in pemphigus foliaceus

Ultraviolet (UV) light has been implicated in inducing acantholysis in the uninvolved skin of pemphigus patients. This report presents the case of a 55-year-old man with pemphigus foliaceus in whom skin lesions were induced and exacerbated by UV-irradiation.     

Iranian guideline for rituximab therapy in pemphigus patients

Pemphigus vulgaris (PV) is an autoimmune blistering disease affecting the skin and/or mucosa. Rituximab (RTX) has been approved recently by US FDA as an effective and safe treatment of PV. The high incidence of PV in Iran encouraged our team to prepare a consensus guideline for RTX administration based on literature review and a decade experience of an expert panel. RTX is recommended for the treatment of new cases of PV as well as patients not responding to conventional therapy. Contraindications include history of anaphylaxis or IgE‐mediated hypersensitivity to murine proteins of RTX, severe active infections, pregnancy, breastfeeding, severe heart failure, and arrhythmia. Prophylactic antiviral therapy is recommended in patients at risk of reactivation of HBV and isoniazid for those at risk of reactivation of tuberculosis. Concomitant use of systemic corticosteroids is recommended as a rule. Except for methotrexate, the combination with other immunosuppressive drugs is discouraged. Intravenous immunoglobulin is recommended for those at risk of infections or with extensive disease. The recommended dosage of RTX for the first cycle is 2 g either 500 mg weekly or 1 g biweekly. There is no general consensus whether the next doses of RTX be administered upon relapse or as maintenance therapy. We strongly recommend RTX sooner in the course of pemphigus.     

Genotyping for HLA-A, B and C alleles in Japanese patients with pemphigus: prevalence of Asian alleles of the HLA-B15 family

BACKGROUND: There have been only limited reports on major histocompatibility complex class I antigens in pemphigus. OBJECTIVES: To characterize HLA-A, B and C class I alleles by genotyping in Japanese patients with pemphigus, and to analyse the possible association of class I alleles with disease susceptibility within a relatively homogeneous ethnic population. METHODS: Alleles of HLA-A, B and C, and DRB1 and DQB1 loci were fully determined in 51 Japanese patients with pemphigus. RESULTS: Asian alleles of the HLA-B15 family, including the allele B*1507, which was significantly increased in comparison with normal controls, were prevalent in patients with pemphigus vulgaris (PV). The prevalence of B*15 alleles in patients with PV was not due to linkage disequilibrium with HLA-DR4 or DR14 alleles, which have been shown to confer strong susceptibility to PV across racial barriers. In contrast to the unique distribution of the HLA-B alleles, HLA-A and C alleles were unremarkable in patients with PV when compared with normal control subjects. CONCLUSIONS: These results suggest that there may be differences in the ethnic concentrations of different HLA-B alleles in patients with PV.     

Drug-related pemphigus and angiotensin converting enzyme inhibitors

A 105-year-old woman developed pemphigus foliaceus. She had been on fosinopril, an angiotensin-converting enzyme inhibitor (ACE inhibitor) for 4 years. Anti-intercellular cement substance antibodies were positive with titre > 160. She died during admission of an unrelated illness. A 57-year-old man developed pemphigus vulgaris after 11 months treatment with quinapril. At 14 months after developing pemphigus, this man continues on prednisone and azathioprine. We speculate that these are cases of ACE-inhibitor-related pemphigus and we review ACE-inhibitor-related pemphigus.     

Pemphigus in Korea: clinical manifestations and treatment protocol

Pemphigus, a rare, chronic blistering disease of the skin and mucous membranes with severe morbidity and occasional mortality, is the most common autoimmune bullous disease in Korea. The purpose of this study was to evaluate the clinical features and propose a treatment strategy for patients with pemphigus. A retrospective analysis was conducted of 51 pemphigus patients seen between 1993 and 2001. Pemphigus vulgaris (PV) was the most common type with 32 cases, followed by 19 cases of pemphigus foliaceus (PF). The male to female ratio was 1:1.3, with females predominating, particularly among PV patients (PV, 1:1.5; PF, 1:1.1). The average ages at onset of PV and PF were 44.3 and 51.0 years old, respectively. Mucosal involvement was noted in 27 cases (84.4%) of PV but in only 3 cases (15.8%) of PF. Most patients initially received relatively low to intermediate doses (0.3-1.0 mg/kg/day) of prednisolone, and 23 (71.9%) PV patients and 10 (52.6%) PF patients also received immunosuppressive agents. Oral prednisolone and azathioprine (100 mg/day) formed the mainstay of treatment for our patients (47.1%). At the time of writing, 25.5% (13/51) of patients are in complete remission, and 72.5% (37/51) are undergoing maintenance therapy. One patient died due to sepsis during the treatment. For the treatment of pemphigus, a course of the lowest possible corticosteroid dosage in combination with immunosuppressive agents appears to be effective and less toxic than a high corticosteroid dosage.