Pemphigus vulgaris: a review of treatment over a 19-year period

BACKGROUND: Pemphigus vulgaris is an autoimmune blistering disease of the skin and mucous membranes with a high mortality if left untreated. OBJECTIVE: We present a retrospective analysis of 159 patients with pemphigus vulgaris and pemphigus vegetans who were admitted to the Department of Dermatology and Venereology, Zagreb University Hospital Center (Zagreb, Croatia) from 1980 to 1998. RESULTS: Female to male ratio was approximately 2:1. The mean age was 53 years. During the war years in Croatia (1991-95) we noticed a low incidence of pemphigus vulgaris, and from 1996 to 1998 the incidence almost doubled. Diagnosis was based on histopathology [showing typical pemphigus vulgaris changes in 156 (98%) patients], indirect immunofluorescence [positive in 122 (77%) patients], direct immunofluorescence [positive in 141 (89%) patients], and blister smear cytology (Tzanck test) [positive in 115 (72%) patients]. High dosages of prednisone (100-150 mg) were given to 129 patients, which was combined with azathioprine. Patients with refractory pemphigus vulgaris were treated with intramuscular gold (14 patients) and plasmapheresis (five patients). All patients were treated with local ointments. The prolonged use of high doses of corticosteroids and immunosuppressants caused several complications, in particular, steroid diabetes (37 patients), skin infections (26 patients), arterial hypertension (23 patients), cardiorespiratory diseases (22 patients), sepsis (nine patients), etc. During the hospital treatment, 14 patients died, 10 during 1980-89 and only four during the 1990-98 period. The main causes of death were cardiorespiratory failure (six patients) and sepsis (five patients). CONCLUSIONS: Although pemphigus vulgaris is still a life-threatening disease, today it can be successfully treated with a combination of immunosuppressive agents. Early diagnosis and treatment of pemphigus vulgaris allow a better prognosis with lower mortality rates.     

Pemphigus

Pemphigus is an infrequent, organ-specific, autoimmune bullous disease, which affects the skin, mucous membranes and appendages. Histopathologically, it is characterized by acantholysis. Pemphigus has classically been divided into two major groups, pemphigus vulgaris and pemphigus foliaceus, with their respective clinical variants pemphigus vegetans and pemphigus erythematosus. In recent years, new variants of pemphigus have been described: paraneoplastic pemphigus, IgA pemphigus and pemphigus herpetiformis. This article reviews the epidemiology, etiopathogenesis, clinical symptoms, diagnosis, treatment and prognosis of pemphigus. Advances in molecular biology techniques have made it possible to more precisely identify the different antigens against which antibodies are directed, and to fine-tune ELISA diagnostic techniques. Treating pemphigus vulgaris and foliaceus with general steroids has modified their prognosis; it is estimated that mortality in recent decades is less than 10 %. Managing the clinical complications that appear during the evolution of the pemphigus has contributed to reducing morbidity and mortality.     

Pemphigus: a survey of 85 patients between 1970 and 1974.

A survey was made of 85 cases of pemphigus seen at the dermatology departments of 11 Japanese universities from 1970 to 1974. The overall mortality for all types of pemphigus was 8%. The mortality from pemphigus vulgaris and pemphigus vegetans treated with systemic corticosteroids was 11%. An analysis of the data indicated that 88% of patients with pemphigus vulgaris and pemphigus vegetans were controlled with 100mg of a prednisone equivalent or less daily, and supported the view that both mortality and incidence of therapy complications closely correlate with the maximum daily dose of steroids required to bring about remission. The suggestion is that in the treatment of pemphigus better results may be obtained with moderate rather than high doses of steroid.     

Pemphigus vulgaris in three adolescents: the course of the disease

We report three adolescents with pemphigus vulgaris whose disease started at the age of 13, 15 and 14 years, respectively. The course of the disease and the treatment approaches were reviewed. Pemphigus vulgaris during childhood and adolescence is a very rare disease in this part of Europe. Among 410 pemphigus vulgaris patients that we treated during the 20-year period, only three patients (0.73%) were under the age of 18 years. According to our experience, the course of pemphigus vulgaris in patients before the age of 18 years is comparable with the course of pemphigus vulgaris in adults.     

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.     

The use of plasmapheresis and immunosuppression in the treatment of pemphigus vulgaris

BACKGROUND: Pemphigus vulgaris is an autoimmune blistering disease for which the mainstay of treatment is systemic corticosteroids and immunosuppressants. This therapy had reduced the mortality of pemphigus; however, it is associated with significant morbidity. OBJECTIVE: The objective of this study was to assess the group's experience with plasmapheresis in the treatment of pemphigus vulgaris and report on its utility. METHODS: Seven patients with severe or resistant pemphigus vulgaris underwent a series of 5 plasma exchanges over an average of 8 days. Immunosuppressive drugs were administered immediately after plasmapheresis to prevent the "rebound" flare of disease that can occur after plasmapheresis. RESULTS: Remission was induced in 4 patients, partial remission was induced in 2 patients, and 1 patient continues to have active disease. CONCLUSION: This study suggests that plasmapheresis is a useful intervention in patients with pemphigus vulgaris who are not responding to standard therapy or who require unacceptably high doses of steroids or immunosuppressants.     

A clinico-pathological study of 70 cases of pemphigus

A clinicopalhological study of 70 cases of pemphigus observed over a span of four and a half years from January 1992 to June 1996 at the Sir J.J. Group of Hospitals and Grant Medical College, Mumbai is reported. Pemphigus vulgaris constituted the single largest group of 43 cases, followed by pemphigus foliaceus (25 cases) and pemphigus vegetans (2 cases). Majority of the cases were seen in the age group of 21-60 years, with a slight male predominance. The youngest patient was 14 years while the eldest was aged 75 years. Mucosal involvement was seen in 31 cases of pemphigus vulgaris, as opposed to only 5 cases of pemphigus foliaceus. Flaccid bullae were present in 100% cases. Pruritus was complained of in 14 cases, though it was more common in pemphigus vegetans and vulgaris. Salient histopathological features of pemphigus vulgaris observed were (I) intraepidermal suprabasal blisters (35 cases), (2) presence of acantholytic cells (40 cases), (3) "Row of tombstone appearance" (I8 cases) and (4) acantholysis involving follicular sheath (20 cases). Main histopathological features of pemphigus foliaceus were (1) subcorneal blister (15 case), (2) acantholysis (24 cases) and (3) bulla cavity containing inflammatory infiltrate (12 cases). Both cases of pemphigus vegetans showed hyperkeratosis, papillomatosis and irregular acanthosis with intra-epidermal eosinophilic abscesses besides suprabasal lacunae.     

Epidemiology of pemphigus in south-western Iran: a 10-year retrospective study (1991-2000)

BACKGROUND: Pemphigus is a disease demonstrating an uneven geographic distribution. This is the first epidemiologic study of pemphigus in Iran. METHODS: Data were collected from the files of all newly registered patients with pemphigus at the sole dermatologic referral center for south-western Iran located in the city of Shiraz, during the period 1991-2000. The data were analyzed with regard to age, sex, subtypes of pemphigus, clinical presentation, and season of onset. RESULTS :The results showed that the mean incidence of the disease for the overall population in Shiraz was 0.67/10(5)/year. The male to female ratio was 1 : 1.33. The mean age at onset of the disease was 38 years (range, 12-93 years). The disease was most common in the third to fifth decades (62.1% of the overall patients). Pemphigus vulgaris was the most commonly encountered type, followed by pemphigus foliaceus (87.7% and 9%, respectively). The first manifestations of the illness most often occurred during winter (30.8% of the patients). CONCLUSIONS: The results reveal a high incidence of pemphigus vulgaris in south-western Iran compared with that encountered in other countries. Our patients also had a relatively young age at onset and a female predominance.     

Diagnosis and clinical features of pemphigus vulgaris

Autoimmune bullous diseases are associated with autoimmunity against structural components that maintain cell-cell and cell-matrix adhesion in the skin and mucous membranes. They include those where the skin blisters at the basement membrane zone and those where the skin blisters within the epidermis (pemphigus vulgaris, pemphigus foliaceus, and other subtypes of pemphigus). The variants of pemphigus are determined according to the level of intraepidermal split formation. There are 5 main variants of pemphigus: pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, drug-induced pemphigus, and paraneoplastic pemphigus. This review focuses only on pemphigus vulgaris.     

Pemphigus vulgaris and myasthenia gravis

This paper describes the occurrence of pemphigus vulgaris in a 46-year-old female with a thymic tumour. The myasthenia gravis went into remission within a few months of thymectomy, but the patient continued to need steroids for pemphigus vulgaris for a further 5 years. The histological appearances of the thymic tumour and skin and the serological findings are described.     

Nonendemic pemphigus foliaceus presenting as fatal bullous exfoliative erythroderma

Pemphigus foliaceus is a cutaneous autoimmune blistering disease that is characterized by lower morbidity and mortality than those observed in pemphigus vulgaris or paraneoplastic pemphigus. However, erythrodermic forms of the endemic variant of pemphigus foliaceus have been associated with a higher mortality. We report a case of nonendemic pemphigus foliaceus that presented as fatal bullous exfoliative erythroderma, and thus, we will emphasize the inclusion of this entity in the differential diagnosis and the use of skin direct immunofluorescence in the evaluation of patients with erythroderma.     

Life‐threatening course of pemphigus vulgaris complicated by sepsis caused by azathioprine‐induced bone marrow suppression,successfully managed with combination therapy

Severe forms of pemphigus vulgaris (PV) that are resistant to standard treatment present a life‐threatening disease with a mortality of 5–10%. The treatment is usually individualized. The most popular procedures used today include intravenous applications of immunoglobulins and rituximab. Currently the common use of pulse corticosteroids, often in first‐line treatment, is being neglected. This particular case documented the severity of the disease and also the need for combined and comprehensive care, in which corticosteroid pulse therapy still plays an important role.     

Treatment of pemphigus vulgaris with pulse intravenous cyclophosphamide.

BACKGROUND--Although corticosteroids have dramatically altered the prognosis in pemphigus vulgaris, morbidity and mortality from systemic corticosteroid side effects remains high. While immunosuppressive agents have been successfully used in pemphigus vulgaris, there is a high incidence of side effects with these agents as well. Particularly bothersome are reports of increased risk of malignancy with long-term use of immunosuppressive agents. For these reasons, we used a protocol that includes low-dose oral cyclophosphamide coupled with pulse intravenous cyclophosphamide in two patients with recalcitrant pemphigus vulgaris. OBSERVATIONS--Both patients responded well to monthly doses of intravenous cyclophosphamide with rapid decrease in the frequency and severity of blistering, resulting in resolution of their disease after 7 and 10 months, respectively. CONCLUSIONS--Pulse doses of immunosuppressive agents appear to be successful in the treatment of pemphigus vulgaris. High-dose steroid therapy can be tapered with the use of this treatment. Because monthly intravenous doses of cyclophosphamide lead to a substantially reduced cumulative dose, when compared with standard oral regimens, the risk of developing malignancy may also be reduced. Further studies using larger groups of patients are needed to evaluate the efficacy of pulse intravenous cyclophosphamide in pemphigus vulgaris. Long-term follow up will be necessary to compare the incidence of malignancy in patients receiving pulse doses of immunosuppressive agents with that in patients receiving continuous oral treatment.     

Visken as supplementary drug in the treatment of pemphigus.

Results of combined treatment with low doses of steroids (50-10-5 mg) and Visken (7.5-15 mg) in 5 cases of pemphigus erythematosus and 5 cases of pemphigus vulgaris are presented. Treatment lasted from 30 days to 1.5 years. Some of the patients had been previously treated with steroids and immunosuppressive drugs, but had active lesions or frequent recurrences. In pemphigus erythematosus, very good results were obtained in 3 of 5 cases, and failure in 2 cases was probably related to insufficient dosage of steroids, or no treatment with steroids at all. In pemphigus vulgaris results were not satisfactory. Visken can serve as a supplementary drug in the treatment of pemphigus erythematosus. No complications were observed, and the drug may be regarded as safe.     

Pemphiguserkrankungen bei Kindern und Jugendlichen

The pemphigus diseases, which include some of the most severe bullous autoimmune skin reactions, are seen predominantly in middle-aged and elderly individuals. Only endemic pemphigus foliaceus in South America most frequently affects juveniles and children. All non-endemic pemphigus diseases, including paraneoplastic pemphigus, have been reported to occur in adolescents and even very rarely in children younger than 10 years. Pemphigus vulgaris in pregnancy represents a frequently overseen medical problem and may result in fetal growth retardation, intrauterine death, premature delivery and – in about 30% – in neonatal pemphigus vulgaris of the newborn. Contrary to pemphigus vulgaris, the transplacental crossing of autoantibodies against desmoglein1 in pregnant women with pemphigus foliaceus hardly ever leads to neonatal skin lesions in the offspring. This phenomenon can be explained by differences in the distribution and cross-compensation of the pemphigus antigens desmoglein3 and 1 in neonatal and adult skin or mucosa, respectively.     

Severe Multi-Resistant Pemphigus vulgaris: prolonged remission with a single cycle of Rituximab

Pemphigus vulgaris is an autoimmune bullous disease whose therapy is based on systemic corticosteroids, with or without immunosuppressants. Rituximab is a chimeric monoclonal antibody of the IgG class, directed at a specific CD20 B cell surface antigen, used in pemphigus vulgaris empirically since 2002, with success in 90% of the cases and long periods of remission. Male patient, 33 years old, diagnosed with pemphigus vulgaris, confirmed by histopathology and direct immunofluorescence. He was treated for seven months with numerous treatments, including immunosuppressive drugs, with an unsatisfactory response, until he had complete remission with the use of rituximab. During a 34-month follow-up period, the patient presented a slight clinical relapse, which was successfully controlled with prednisone in a daily dose of 120mg, soon reduced to 20mg.     

Childhood Pemphigus Vulgaris Treated with Dapsone: A Case Report

Abstract: A 5-year-old boy developed hemorrhagic mucocutaneous blisters on various parts of the body leading to fetor, dysphagia, dysuria, anal pruritus, pain on defecation, and weight loss. The histopathology showed the classic features of pemphigus vulgaris, and direct immunofluorescence showed intercellular deposition of IgG and C3 in the epidermis. Circulating pemphigus antibodies were also detected. He was treated with a combination of systemic prednisone and dapsone which induced a rapid remission and controlled the disease well. He has been in remission for 1 year and 7 months with no immunosuppressive therapy except for the use of topical agents for the oral lesions. An adjuvant to corticosteroids has been used only once before in children with pemphigus vulgaris under the age of 12 years. This is the third and the youngest child in the literature treated in this fashion.     

Therapy of pemphigus. Critical remarks based on 44 clinical cases

The results are evaluated of therapy administered between 1957 and 1983 to 44 patients with pemphigus (28 pemphigus vulgaris, 5 pemphigus vegetans, 11 pemphigus seborrhoicus). The mean initial steroid dosage was 87 mg prednisone equivalent per day. The 5-year survival rate was 83%. Fifteen patients who were additionally treated with azathioprine during the initial phases of the disease had a 5-year survival rate of 100%. However, after having the disease for 5 years 41% of all pemphigus patients have to be rehospitalized. This percentage is only 21% in the group requiring less than 100 mg prednisone per day initially. Mortality related to pemphigus or infection occurs significantly earlier than cardiovascular deaths. The prognosis for survival is relatively good, but the prognosis for recovery remains uncertain. Combined therapy with corticosteroids and azathioprine in the early stages of the disease resulted in a 5-year survival rate of 100%, and is therefore recommended. However, even this therapeutic modality does not change the uncertain prognosis regarding recovery.     

Pemphigus: analysis of 1209 cases

BACKGROUND: Pemphigus is a rare and chronic life-threatening disease. The clinical picture varies in reports from different regions of the world. OBJECTIVE: To define the clinical forms of pemphigus in a large cohort of patients. METHODS: Prospective analysis of 1209 patients diagnosed and followed at the Pemphigus Research Unit, Tehran University for Medical Sciences, from 1984 to 2003. RESULTS: The mean age at onset was 42 years with a female to male ratio of 1.5/1. The most frequent form was pemphigus vulgaris. In pemphigus vulgaris, patients' mucous membrane involvement alone was observed in 18%, skin involvement alone in 12%, and both in 70%. Pemphigus foliaceus was observed in 7% of the patients. Most complications were iatrogenic. CONCLUSION: In Iran, pemphigus vulgaris is the most frequent form of pemphigus. Females are more prone to the disease. The incidence of pemphigus in Tehran is approximately 1.6 per 100,000/year, and in Iran 1.0 per 100,000/year. The age of onset was lower than classically reported. Death occurred in 6.2% of the patients. In pemphigus vulgaris, the mucosal and skin form together had a worse prognosis than the other clinical forms.     

Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature

BACKGROUND: Treatment of pemphigus vulgaris can be challenging. Systemic steroids associated with other immunosuppressant agents are the mainstay of therapy and have dramatically reduced morbidity and mortality from pemphigus vulgaris. In some patients, however, these agents are not able to control the disease or have severe adverse effects. Rituximab (MabThera; Roche, Basel, Switzerland), a chimeric monoclonal anti-CD20 antibody, induces depletion of B cells in vivo and has shown efficacy in patients with refractory antibody-mediated autoimmune disorders. We report 10 cases of pemphigus vulgaris and 2 cases of pemphigus foliaceous treated with rituximab--to our knowledge the largest series of patients so far--and review the existing literature on the topic. OBSERVATION: The 12 patients were selected for treatment with the anti-CD20 antibody. Rituximab was administered intravenously at a dosage of 375 mg/m(2) once weekly for 4 weeks. The treatment was well tolerated, and all 12 patients showed a good clinical response during an 18-month follow-up period, along with a consensual decline of the serum antidesmoglein titers. No infectious complications were observed. CONCLUSIONS: Rituximab is able to induce a prolonged clinical remission in patients with both pemphigus vulgaris and pemphigus foliaceous after a single course of 4 treatments. The preliminary experiences worldwide make rituximab a promising therapeutic option for patients with autoimmune diseases. The high costs and the limited knowledge of long-term adverse effects, however, limit its use to selected patients with treatment-resistant or life-threatening disease.