Dual diagnosis of Pemphigus and pemphigoid. Retrospective review of thirty cases in the literature.

BACKGROUND: Pemphigus and pemphigoid are two distinct groups of autoimmune blistering diseases. There are many reports of the simultaneous presence of clinical and serological features of both diseases in the same patient. OBJECTIVE: This study is a retrospective review of the present literature on reports of patients with features of both pemphigus and pemphigoid. We recommend that these patients be considered as having a dual diagnosis. METHODS: A review of the English language, peer-reviewed literature was conducted on patients described with features of pemphigus and pemphigoid. Available data on clinical profile, histology, immunopathology, treatment, follow-up and outcome were studied in 30 patients. They were divided into three groups: (1) bullous pemphigoid and pemphigus vulgaris, (2) mucous membrane or cicatricial pemphigoid and pemphigus vulgaris and (3) bullous pemphigoid and pemphigus foliaceus. RESULTS: In all three groups, most patients had a clinical phenotype resembling both diseases. In 17 patients with bullous pemphigoid and pemphigus vulgaris, 83% had a skin biopsy consistent with bullous pemphigoid, 70% had direct immunofluorescence studies typical of bullous pemphigoid and sera of 83% had antibodies typical of pemphigus vulgaris on indirect immunofluorescence. In 10 patients with mucous membrane or cicatricial pemphigoid and pemphigus vulgaris, a histology of mucous membrane pemphigoid was reported in 60% of the patients, direct immunofluorescence studies typical of mucous membrane pemphigoid were reported in 70% of the patients and in 80%, autoantibodies characteristic of pemphigus vulgaris were observed. In 3 patients with bullous pemphigoid and pemphigus foliaceus, the histologies were consistent with bullous pemphigoid, direct immunofluorescence was typical of pemphigus foliaceus and their sera had both autoantibodies. The majority of the 30 patients required long-term high-dose corticosteroids and immunosuppressive agents to control their disease. Three patients with bullous pemphigoid and pemphigus vulgaris (18%) died due to effects of prolonged immunosuppression. CONCLUSION: We characterize a group of patients who have clinical, histological and immunopathological features of bullous or mucous membrane or cicatricial pemphigoid with serological features of pemphigus. These patients did not achieve a prolonged clinical remission by conventional therapy. It is possible that early identification of these patients may improve their prognosis.     

Efficacy and Safety of Cyclophosphamide, Azathioprine, and Cyclosporine (Ciclosporin) as Adjuvant Drugs in Pemphigus Vulgaris

Background:Pemphigus vulgaris is a potentially life-threatening, autoimmune bullous disease of the skin and mucous membranes. Most commonly, the disease is treated with prednisone in combination with an immunosuppressant agent, frequently referred to as adjuvant drug. However, there is no consensus regarding the first-choice adjuvant drug for the treatment of pemphigus vulgaris or the recommended dosage. Objective:To evaluate the efficacy and safety of prednisone as monotherapy and in combination with the three most popular adjuvant agents — azathioprine, cyclosporine (ciclosporin), and cyclophosphamide in the treatment of pemphigus vulgaris time to immunologic remission (non-detectable circulating pemphigus vulgaris antibodies), proportion of patients who remained free of clinical relapse within 5 years after discontinuation of therapy, time from treatment discontinuation until first relapse, and incidence of adverse effects. Results:The average (± SD) time to clinical remission was 7.2 ± 13.1 months in patients who received prednisone monotherapy, 6.8 ± 10.5 months in patients receiving additional azathioprine, 8.1 ± 11.8 months in the cyclosporine group, and 4.9 ± 6.9 months (which was significantly shorter than all other treatment groups, p < 0.05) in patients receiving cyclophosphamide. The average (± SD) times to immunologic remission were 33 ± 27 months, 28 ± 24 months, 30 ± 21 months, and 23 ± 17 months for prednisone monotherapy, azathioprine, cyclosporine, and cyclophosphamide, respectively. The proportions of patients who remained free of clinical relapse within 5 years after discontinuation of therapy were 55%, 50%, 43%, and 69% for prednisone monotherapy, azathioprine, cyclosporine, and cyclophosphamide, respectively. In patents who experienced relapse, the average (± SD) time from treatment discontinuation to clinical relapse was 10.50 ± 6.86 months in patients receiving prednisone monotherapy, 16.40 ± 17.36 months in the azathioprine group, 12.44 ± 6.48 months in the cyclosporine group, and 21.16 ± 20.13 months in the cyclophosphamide group. The safety profiles of all treatment regimens were comparable. Conclusion:Oral prednisone with cyclophosphamide is the most effective treatment for pemphigus vulgaris. All therapy regimens had a similar safety profile. In our opinion, cyclophosphamide at a dose of 1.1–1.5 mg/kg/day should be the adjuvant drug of choice in the treatment of moderate-to-severe pemphigus vulgaris.     

Efficacy of Dapsone in the Treatment of Pemphigus and Pemphigoid

Dapsone is a chemotherapeutic agent primarily used in treating leprosy, Pneumocystis jiroveci(previously carinii) pneumonia, and malaria. It is also used as an adjuvant in the treatment of pemphigus and pemphigoid. To assess the role of dapsone in the treatment of pemphigus and pemphigoid, a retrospective review of reports in the English-language literature was conducted. Information on the number of patients treated, their average age, prior therapies, indications for use, protocol (dose and interval) used, concomitant therapies, reported adverse effects, and clinical outcomes were analyzed. There were 35 case reports/series published describing the use of dapsone in a total of 427 patients. Data on 55 pemphigus patients were obtained from several case reports and some case series and one randomized controlled trial. Of these, 32 patients with pemphigus vulgaris and 14 patients with pemphigus foliaceus responded to dapsone. Data from 13 case series, each including at least five patients, accounted for 372 patients with pemphigoid. The overall response rates to dapsone, when given either alone or in combination with corticosteroids or immunosuppressive agents, were 84% in mucous membrane pemphigoid, and 81% in bullous pemphigoid. Hemolysis was the most common adverse effect observed. Dapsone is a promising and useful agent in patients with autoimmune mucocutaneous blistering diseases, especially in mucous membrane pemphigoid. It can be used as a corticosteroid-sparing agent. Therefore, its combined use with oral corticosteroids may be useful in pemphigus vulgaris and bullous pemphigoid. Adverse effects of dapsone are dose dependent and usually reversible. Hemolysis and concomitant anemia secondary to hemolysis are expected in most patients. In the opinion of the authors, dapsone is underutilized in the treatment of autoimmune mucocutaneous blistering diseases.     

Treatment of pemphigus vulgaris with mycophenolate mofetil as a steroid-sparing agent

Pemphigus vulgaris is a rare autoimmune blistering disease. Estimation of the incidence in Iran is one patient per 100,000 of the population per year. Mycophenolate mofetil is an immunosuppressive drug and successful treatment of pemphigus vulgaris and bullous pemphigoid has been reported with it, in combination with high dose prednisone, or as monotherapy. The present study describes our experience of the adjuvant use of mycophenolate mofetil in the management of 31 patients with pemphigus vulgaris as an initial treatment. We evaluated the efficacy and safety of mycophenolate mofetil combined with prednisolone in this cohort. We also assessed the relationship between the demographic indices/disease severity factors, and the failure of this treatment. In this study, mycophenolate mofetil was of definite benefit in 21 cases (67.7%). Generalized forms; patients with higher sum of the clinical scores at presentation; severe involvement of the groin; chest; face and limbs and those who had nail dystrophy also appeared to have poorer responses. When we excluded patients with generalized forms, only four patients were included in the failure group and the response rate reached 83.3%. It can be concluded that, except for generalized diseases, mycophenolate mofetil can be used safely and effectively in patients with pemphigus vulgaris as a first line, steroid sparing agent.     

Therapieoptimierung bei schweren bullösen Autoimmundermatosen

Autoimmune bullous diseases are a heterogeneous group of disorders that can be subdivided according to the level of split formation in the intraepidermal blistering pemphigus diseases and subepidermal bullous disorders, latter including pemphigoid diseases, epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis. In the majority of autoimmune bullous disorders, disease activity can be sufficiently controlled by systemic corticosteroids in combination with further immunsuppressants/-modulants such as dapsone, doxycycline, azathioprine, mycophenolate mofetil, or methotrexate. In contrast, in pemphigus, mucous membrane pemphigoid, and EBA, treatment is challenging and conventional immunosuppressive therapy induces clinical remission only in a minority of patients. Until recently, only cyclosphosphamide and high-dose intravenous immunoglobulin (IVIG) were available as potent second-line therapies. Meanwhile, immunoadsorption and the monoclonal anti-CD20 antibody rituximab have been established as further therapeutic options. The present review focuses on efficacy, adverse events, treatment protocols, and mechanisms of action of IVIG, immunoadsorption, and rituximab in the treatment of severe and/or refractory patients with bullous autoimmune diseases.     

Adjuvant high-dose intravenous gammaglobulin in the treatment of pemphigus and bullous pemphigoid: experience in six patients

At present, initial high-dose prednisone is the treatment of choice for patients with pemphigus and bullous pemphigoid. To reduce the risks associated with long-term corticosteroid treatment, other immunosuppressants are often given as steroid-sparing agents. Occasionally, the dose of steroids cannot be reduced. In this study, we report six patients with pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid, in whom the daily corticosteroid dose could only be tapered to acceptable, effective, maintenance levels following treatment with high-dose intravenous gammaglobulin.     

Bullous pemphigoid in adolescence

Bullous pemphigoid (BP) is the most common autoimmune blistering disease affecting the elderly but is quite rare in childhood. The majority of pediatric cases have been reported during early childhood. Adolescence is divided into three phases: early (10‐13 years), middle (14‐17), and late (18‐21). This review aimed to identify BP cases in adolescence and demonstrate their clinical features and course. Our literature search was performed in Medline with the terms “bullous pemphigoid in childhood and adolescence,” “childhood bullous pemphigoid,” “juvenile bullous pemphigoid,” and “autoimmune blistering and autoimmune bullous diseases in childhood.” The data extraction for late adolescence was limited by the fact that this age group is included in adult BP registries. We identified nine cases in early adolescence. Mucosa were affected in 5 of 9 cases. Treatment consisted of systemic prednisone (8/9), in combination with dapsone (2/9), azathioprine (2/9), or erythromycin/nicotinamide (1/9). Relapses were reported in 3 of 9 cases. We identified five cases occuring in middle adolescence. Mucosa were not affected. Treatment consisted of systemic prednisone (5/5), in combination with dapsone (3/5), azathioprine (2/5), doxycycline/nicotinamide (1/5), or mycophenolate mofetil (1/5). Relapses were reported in two of five cases. No case of BP in the late adolescence was included in the results, as only one case met the search criteria, and overlapped with pemphigus vulgaris. With only 14 cases found in our review, BP in adolescence appears even rarer than in earlier childhood. Despite its low prevalence, BP should be included in the differential diagnosis of autoimmune blistering diseases in adolescents.     

Successful treatment of autoimmune bullous diseases with a combination therapy of ciclosporin and corticosteroid

Three patients with autoimmune bullous diseases, pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid, were treated with a combination therapy of ciclosporin and corticosteroid. These patients responded to systemic low-dose prednisolone (or dexamethasone) and low-dose ciclosporin therapy; the result was prolonged complete remission. The addition of low-dose ciclosporin may produce enhanced clinical effects of steroid therapy without increasing any significant side effects.     

A review of high-dose intravenous immunoglobulin (hdIVIg) in the treatment of the autoimmune blistering disorders

High-dose intravenous immunoglobulin (hdIVIg) is being used increasingly for dermatological indications. Its mode of action is via a number of proposed mechanisms and it is not associated with the many side-effects of steroids and other immunosuppressive agents. The evidence for using hdIVIg in the treatment of autoimmune bullous disorders is based on uncontrolled trials and case reports. However, there are now 62 reported patients and this review aims to make a critical assessment of the current data. This has been obtained from a Medline search of the English literature from 1966 to 2000 for pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, pemphigoid gestationis, cicatricial pemphigoid, epidermolysis bullosa acquisita and linear IgA disease. Taken together hdIVIg was effective in 81% of the patients with blistering disease. Patients appear to be more likely to respond when hdIVIg is used as adjunctive therapy (91% response rate) than as monotherapy (56% response rate). hdIVIg may offer a safe potential therapeutic avenue for resistant cases of the autoimmune bullous disorders but should be further assessed using double-blind placebo-controlled trials.     

Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia,Germany

Background: Only limited epidemiologic data are available on autoimmune bullous diseases. Improved diagnostic tools should have led to an increased incidence. To test this hypothesis, all patients with autoimmune bullous disorders who were treated in the Department of Dermatology at the University of Würzburg, Germany, between January 2001 and June 2002 were analysed prospectively. Patients and Methods: Epidemiologic data of patients diagnosed with an autoimmune bullous disease during this time period were registered and statistically evaluated. Diagnosis was based on the clinical picture and specific immunopathological findings. Only patients from Lower Franconia, a well‐defined administrative region of Southern Germany, were included into this study. Results: During the study period, 41 patients with an autoimmune bullous disease were diagnosed, including 27 with bullous pemphigoid, 4 with pemphigoid gestationis and mucous membrane pemphigoid, 2 with dermatitis herpetiformis and linear IgA disease, and 1 with epidermolysis bullosa acquisita and pemphigus vulgaris, respectively. The highest incidence was calculated for bullous pemphigoid (13.4 per 1 million inhabitants per year) followed by pemphigoid gestationis (2.0) and mucous membrane pemphigoid (2.0). Patients with mucous membrane pemphigoid were found to have the highest mean age at disease onset (76 years) followed by patients with bullous pemphigoid (74 years). Conclusions: This is the first prospective study on the incidence of autoimmune bullous disorders. Subepidermal blistering autoimmune diseases were shown to be more frequent than previously reported for Central Europe. This is most likely due to improved diagnostic tools for and increased awareness of these diseases.     

大疱性类天疱疮临床评估指标的研究进展

大疱性类天疱疮是一类自身免疫性疱病。针对自身免疫性大疱病,有专门的评分指标用以评估病情的严重程度和对治疗的反应。常用的评价指标有自身免疫性疱病严重程度评分,专门针对大疱性类天疱疮的大疱性类天疱疮疾病面积指数评分,以及其他的一些评分方式。自身免疫性大疱病严重程度评分已经经过了效度检验,广泛地应用在寻常型天疱疮和其他一些自身免疫性疱病的评估中。大疱性类天疱疮疾病面积指数评分尚处于检验的过程中,应用该评分的临床试验较少。上述两种评分方式均对全身的皮肤、黏膜皮损情况,主观瘙痒程度进行了评分。     

Successful immunoapheresis of bullous autoimmune diseases: pemphigus vulgaris and pemphigoid gestationis

Background: Immunoapheresis/immunoadsorption is a specific tool to remove immunoglobulins and immune complexes from the circulation. Immunoapheresis is successfully used in various autoantibody‐mediated diseases (such as autoimmune renal disease and others). In dermatology immunoapheresis is increasingly applied as an adjuvant treatment for severe autoimmune bullous diseases. Case report: We successfully employed adjuvant immunoapheresis to treat a 57‐year‐old man with life‐threatening pemphigus vulgaris and a 30‐year‐old pregnant woman with severe pemphigoid gestationis. Immunoapheresis induced a rapid improvement and almost complete clearance of clinical symptoms without notable side effects. The clinical improvement was paralleled by a decline of the pathologic circulating autoantibodies. Following stabilization of his disease with immunoapheresis, the pemphigus vulgaris patient was continued on rituximab and remained almost free of symptoms for the next 12 months. The patient with pemphigoid gestationis was subsequently treated with systemic corticosteroids until the symptoms of her self‐limited disease ceased. Conclusion: Immunoapheresis might represent an excellent therapy for certain patients with severe pemphigus vulgaris or pemphigoid gestationis, unresponsive to conventional treatment regimens. We observed rapid improvement of clinical symptoms and no notable side effects.     

New immunomodulating drugs in autoimmune blistering diseases.

The autoimmune blistering diseases are a fascinating group of diseases characterized by the presence of blisters involving the skin and mucous membranes. Understanding of the diagnosis, pathophysiology, and advances in treatment of these diseases has grown enormously in recent years. In this article, the author discusses the major clinical and immunopathologic findings in bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, linea IgA bullous disease, and pemphigus. The article focuses on the therapeutic management of patients with autoimmune blistering diseases, including the appropriate treatment of patients, with particular emphasis on the use of immunomodulating and immunosuppresive agents.     

Rituximab therapy for refractory autoimmune bullous diseases: A multicenter,open‐label,single‐arm,phase 1/2 study on 10 Japanese patients

This was a multicenter study of rituximab, a chimeric monoclonal immunoglobulin G antibody directed against CD20, for the treatment of refractory autoimmune bullous diseases (pemphigus and pemphigoid). Ten patients (three with pemphigus vulgaris, six with pemphigus foliaceus and one with bullous pemphigoid) were treated with a single cycle of rituximab (four weekly infusions at a dose of 375 mg/m² of body surface area). The primary end‐points were the number of serious adverse events and rate of complete remission at 40 weeks. Five patients (50%) achieved complete remission with minimal therapy (defined as no active lesions with lower doses of systemic corticosteroids compared to that with prednisolone 10 mg/day). Improvements in clinical scores (Pemphigus Disease Area Index) and decreases in autoantibody titers in the sera were observed in the four pemphigus patients who failed to achieve complete remission. This suggests that rituximab was effective in nine of 10 cases. Two serious adverse events (Pneumocystis carinii pneumonia and septic shock due to infectious arthritis) were observed and adequately treated with hospitalization. CD19‐positive B lymphocytes in the peripheral blood decreased on day 29 following rituximab treatment, and remained at low levels throughout the observation period (280 days). Our results confirmed the efficacy of rituximab therapy for refractory autoimmune bullous diseases in Japan.     

UV light-induced linear IgA dermatosis

Various exogenous factors (eg, drugs, dietary antigens, trauma, infections, radiographs, and UV radiation) are known to induce or aggravate skin diseases. UV radiation in particular is known to induce or aggravate the autoimmune bullous diseases of pemphigus foliaceus, pemphigus vulgaris, and bullous pemphigoid. Its role in linear IgA dermatosis, however, is not well recognized. We report the second case of linear IgA dermatosis induced by intense sun exposure in which blistering was induced by UVA radiation. Furthermore, a review of the literature on photoinduced autoimmune bullous diseases and the wavelengths responsible for the induction of blistering is presented and several proposed mechanisms of action for the blister induction, including release or unmasking of antigens, promotion of antibody fixation by UV radiation, and launching of an inflammatory process, are discussed. We conclude that linear IgA dermatosis should be added to the list of autoimmune bullous diseases induced and/or aggravated by UV radiation.     

Schleimhautbeteiligung bei blasenbildenden Autoimmunerkrankungen

Autoimmune bullous diseases are characterized by intraepidermal or subepidermal autoantibody deposition that leads to blisters and secondary erosion. Mucous membranes are frequently affected in pemphigus vulgaris and always involved in cicatricial and mucosal pemphigoid. Mucosal lesions are detected less frequently in patients with bullous pemphigoid or epidermolysis bullosa acquisita. The diagnosis of autoimmune bullous disorders is based on determination of the subtype of autoantibodies bound in the skin and the clinical picture. Treatment is based on immunosuppression related to the type of disease and severity of the mucosal symptoms. Ocular involvement in mucosal pemphigoid and pemphigus vulgaris requires systemic treatment.     

High-dose intravenous immune globulin for the treatment of autoimmune blistering diseases: an evaluation of its use in 14 cases

High-dose intravenous immune globulin (IVIG) is used to treat a wide variety of autoimmune diseases. We report our experiences of its use in a retrospective study of 14 patients with autoimmune blistering diseases, namely epidermolysis bullosa acquisita (EBA), two; bullous pemphigoid (BP), two; pemphigoid gestationis (PG), one; nodular pemphigoid, two; and pemphigus vulgaris (PV), seven. Two patients with refractory EBA improved following regular courses of IVIG given as monotherapy. IVIG had a steroid-sparing effect in 10 patients with PV, BP and PG. However, the clinical effects were transient and of variable intervals, and repeated courses of IVIG were required. The rapid actions of IVIG were of particular benefit in two patients with extensive, rapidly progressive PV and in one patient with BP in whom swift disease control was required. In such cases, when rapid disease control is paramount, we recommend IVIG used in conjunction with conventional treatments as a safer and less invasive alternative to plasmapheresis. IVIG was ineffective in two patients with nodular pemphigoid. Analysis of indirect immunofluorescence (IIF) titres before and after IVIG showed that a fall in titre occurred after 78% of treatments and was observed in all disease groups. However, like the clinical improvements, the falls in IIF titres were transient and of variable interval, and titres rose back to pretreatment levels in all but one patient. IVIG appears to be beneficial under certain circumstances for the treatment of autoimmune blistering diseases but controlled trials are required to define its therapeutic role further.     

Occult Herpes Simplex Virus Colonization of Bullous Dermatitides

Background: Acantholytic disorders, including pemphigus vulgaris, chronic benign familial pemphigus (Hailey-Hailey disease, superficial pemphigus), Darier disease, and Grover transient acantholytic dermatosis, as well as other vesiculo-bullous disorders, including bullous pemphigoid, epidermolysis bullosa, and atopic dermatitis, are prone to florid infections by herpes simplex virus (HSV)-I and -II, and, more rarely, by varicellazoster virus (VZV). As these infections are difficult to recognize clinically and histologically, their frequency remains unknown. A possible occult viral colonization has never been documented in these disorders. The manner in which the primary bullous disorders are contaminated by herpesviridae remains unclear. Objective: To retrospectively assess the possible presence of HSV and VZV in a series of biopsies of acantholytic disorders and bullous pemphigoid. Method: The typical α-herpesviridae-related cytopathic signs were searched for by conventional microscopy in skin biopsies of patients with bullous pemphigoid (n = 20), pemphigus vulgaris (n = 19), Darier disease (n = 18), chronic benign familial pemphigus (n = 3), and Grover transient acantholytic dermatosis (n = 3). Immunohistochemistry (IHC) targeted specific HSV-I, HSV-II, and VZV antigens. Polymerase chain reaction (PCR) was used for detecting HSV- and VZV-specific DNA sequences. Results: No cytopathic signs suggestive of HSV or VZV infection were detected. However, IHC revealed HSV antigens in Darier disease (1/18, HSV-I), Grover transient acantholytic dermatosis (1/3, HSV-I), pemphigus vulgaris (1/19, HSV-I), and bullous pemphigoid (2/20, HSV-I and HSV-II). In these IHC-positive cases, PCR amplified specific HSV primers in Darier disease (1/18), pemphigus vulgaris (1/19), and bullous pemphigoid (1/20). VZV antigens and nucleic acids were never identified. The HSV antigens were nearly always restricted to the upper part of the granular layer and thus differed from the usual HSV distribution during cutaneous infection. Negative and positive controls yielded consistently positive and negative results, respectively. Conclusion: This report shows for the first time that clinically and histologically occult HSV colonization may occur in Darier disease, Grover transient acantholytic disease, pemphigus vulgaris, and bullous pemphigoid. Given the frequent use of immunosuppressive treatments for primary bullous disorders, greater awareness of HSV colonization and infection is recommended in these patients.     

Rituximab in autoimmune bullous diseases: mixed responses and adverse effects

BACKGROUND: Intolerably high doses of systemic corticosteroids and additional immunosuppressants may be required to control disease activity in autoimmune bullous skin diseases. New therapeutic options are needed for such patients. OBJECTIVES: To determine the efficacy and adverse effects of adjuvant rituximab. METHODS: Seven patients with refractory autoimmune blistering diseases (pemphigus vulgaris, PV, n = 4; bullous pemphigoid, BP, n = 2; mucous membrane pemphigoid, MMP, n = 1) were treated four times with rituximab at an individual dose of 375 mg m(-2) at weekly intervals. RESULTS: All lesions cleared in three patients (two PV, one BP), while they were reduced by more than 50% in three others (two PV, one BP). The concomitant immunosuppressive medication was reduced in five patients (four PV, one BP). The patient with MMP developed bilateral blindness while nasopharyngeal lesions resolved. Three patients (two BP, one PV) experienced severe adverse events including fatal pneumonia. CONCLUSIONS: Adjuvant B-cell depletion by rituximab is effective in otherwise therapy-resistant bullous autoimmune disorders but may be associated with substantial adverse effects including fatal outcomes.