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.     

U-serrated immunodeposition pattern differentiates type VII collagen targeting bullous diseases from other subepidermal bullous autoimmune diseases

BACKGROUND: Epidermolysis bullosa acquisita (EBA) can be differentiated from other subepidermal bullous diseases by sophisticated techniques such as immunoelectron microscopy, salt-split skin antigen mapping, fluorescence overlay antigen mapping, immunoblot and enzyme-linked immunosorbent assay. OBJECTIVES: To determine whether the diagnosis can also be made by routine direct immunofluorescence microscopy. METHODS: We studied frozen skin biopsies from 157 patients with various subepidermal immunobullous diseases. RESULTS: We found three distinct 'linear' fluorescence patterns at the basement membrane zone: true linear, n-serrated and u-serrated. The true linear pattern, often seen in conjunction with either the n- or the u-serrated pattern, was found in any subepidermal immunobullous disease with nongranular depositions. In bullous pemphigoid, mucous membrane pemphigoid, antiepiligrin cicatricial pemphigoid, p200 pemphigoid and linear IgA disease the n-serrated pattern was found, corresponding with depositions located in hemidesmosomes, lamina lucida or lamina densa. However, in EBA and bullous systemic lupus erythematosus the u-serrated staining pattern was seen, corresponding with the ultralocalization of type VII collagen in the sublamina densa zone. The diagnosis of EBA with IgG or IgA autoantibodies directed against type VII collagen was confirmed by immunoelectron microscopy, salt-split skin antigen mapping, fluorescence overlay antigen mapping or immunoblotting. CONCLUSIONS: Using this pattern recognition by direct immunofluorescence microscopy we discovered several cases of EBA which would otherwise have been erroneously diagnosed as a form of pemphigoid or linear IgA disease.     

Autoimmune bullous skin diseases. Part 1: Clinical manifestations

Autoimmune bullous skin diseases are characterized by autoantibodies against adhesion molecules of the skin. Pemphigus is a disorder with an intraepidermal loss of adhesion and is characterized by fragile blisters and erosions. Pemphigus vulgaris often shows extensive lesions of the oral mucosa, while pemphigus foliaceus is commonly restricted to cutaneous involvement with puff pastry-like scale formation. Paraneoplastic pemphigus is obligatorily associated with malignancies and often presents as hemorrhagic stomatitis with multiforme-like exanthems. IgA pemphigus typically presents with pustules and annular plaques but not with mucosal involvement. The clinical spectrum of the pemphigoids includes tense blisters, urticarial plaques, and prurigo- like eczematous lesions. Pemphigoid gestationis mostly occurs during the last trimester of pregnancy and mucous membrane pemphigoid primarily involves the oral mucosa and conjunctivae and leads to scarring. Linear IgA bullous dermatosis manifests with tense blisters in a "cluster of jewels"-like pattern in childhood and is more heterogeneous in adulthood. Classical epidermolysis bullosa acquisita shows extensive skin fragility. Dermatitis herpetiformis is associated with gluten-sensitive enteropathy and manifests clinically with severe itching and papulovesicles on the extensor surfaces of the extremities and the lumbosacral area. The intention of the review is to demonstrate the heterogeneous clinical spectrum of autoimmune bullous disorders.     

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.     

Approach to the patient with autoimmune mucocutaneous blistering diseases

Autoimmune mucocutaneous blistering diseases (AMBD) are a rare group of dermatoses that can be potentially fatal. There are many subtypes and their clinical presentation can vary from being localized to general involvement. It is crucial that a diagnosis be made as early as possible and appropriate treatments are implemented. This article will discuss the diagnosis and available treatments of the major AMBDs. There are very few case-controlled studies regarding the treatments of these diseases. Most of the treatments used for these diseases are based on anecdotal reports. Hence, a synopsis of the conventional treatments and some brief recommendations will also be discussed. A brief discussion regarding "rescue" therapies that have been used for those patients with more recalcitrant cases of AMBD will also be presented.     

Infection in autoimmune bullous diseases: A retrospective comparative study

Certain autoimmune bullous diseases (AIBD), including pemphigoid and pemphigus, confer increased infection risk. Infections have not been systematically studied in these conditions, however. Little is known about infection risk in these conditions, particularly dermatitis herpetiformis (DH). We aimed to characterize and compare infection patterns and risk factors in patients with pemphigoid, pemphigus, and DH. We retrospectively studied the medical records of Olmsted County, Minnesota, residents who had a diagnosis of AIBD between 1 January 1998 and 1 January 2011. Of 81 patients studied, 54 (67%) had pemphigoid, 11 (14%) had pemphigus and 16 (20%) had DH. Most patients studied developed at least one localized infection (72%) or one systemic infection (83%). Almost one‐third of patients (31%) developed infections requiring hospitalization or contributing to death. All patients taking systemic corticosteroids experienced a localized or systemic infection during the follow‐up period. Systemic infections were significantly less frequent in patients with DH than those with pemphigoid or pemphigus (P = 0.03), as were systemic infections requiring hospitalization or contributing to death (P = 0.002). Patients with DH were significantly less likely to require systemic corticosteroids (P < 0.001) and significantly more likely to receive dapsone (P = 0.002). The study design was retrospective and a limited number of patients met the inclusion criteria. Patients with AIBD frequently developed localized and systemic infections, a substantial portion of which contributed to hospitalization or death. Patients with DH experienced infections of lesser severity than patients with pemphigoid or pemphigus.     

Recommendations for the use of immunoapheresis in the treatment of autoimmune bullous diseases

Despite the use of high‐dose systemic corticosteroids in combination with other immunosuppressants, in some patients with autoimmune bullous diseases only insufficient improvement is achieved. In these cases and in acute severe disease, adjuvant immunoapheresis has been increasingly used. A consensus meeting was held in mid‐2005 in Hamburg, aiming at developing guidelines for the use of immunoapheresis in the treatment of autoimmune bullous diseases.This paper summarizes the experts‘ recommendations.     

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.     

免疫球蛋白在自身免疫性大疱病的研究进展

免疫球蛋白作为人体内具有活性的免疫效应分子,在自身免疫性大疱病的发病、诊断及治疗中发挥着重要的作用。人免疫球蛋白可以分为IgG、IgA、IgM、IgD、IgE5大类,除IgD外其他都在自身免疫性大疱病的发病过程中存在并发挥不同的作用。IgG可通过激活补体、活化白细胞、释放蛋白水解酶等诱发水疱形成,其不同亚型也有所区别。IgA可引起粒细胞迁移从而导致水疱脓疱的发生。IgE与荨麻疹样红斑、嗜酸性粒细胞浸润相关。IgM多见于巴西落叶型天疱疮。这些都为自身免疫性大疱病的诊断和治疗提供了新的思路。     

Therapy of autoimmune mouth bullous disease: 2020 review

Most diseases of oral mucosa are either autoimmune in nature or are the results of immunologically mediated events. The diseases with autoimmune pathogenesis are namely pemphigus and pemphigoid; the oral involvement is frequent or regularly observed in these diseases. The treatments with traditional drugs or biologic agents or combinations of these molecules are employed in clinical practice. New therapeutic targets aim to provide new treatment strategies that may go beyond nonspecific immunosuppression.     

Searching for foreign antigens as possible triggering factors of autoimmunity: Torque Teno virus DNA prevalence is elevated in sera of patients with bullous pemphigoid

Objective: The Torque Teno virus (TTV), a member of virus genus Anellovirus has been shown to be commonly present in humans, yet without detectable pathogenicity. Recent studies imply that TTV may contribute to provoke autoimmune progresses in systemic lupus erythematosus and idiopathic inflammatory myopathies. We aimed to study the presence of TTV in a group of patients with autoimmune bullous diseases with a further goal to identify long‐lasting foreign antigen, such as TTV as possible triggers of skin‐specific autoimmunity. Patients and methods: We performed in silico research to study similarities between known TTV sequences and antigens of bullous pemphigoid (BP), pemphigus vulgaris (PV) and dermatitis herpetiformis (DH). Basic Local Alignment Search Tool results showed matching regions for the major BP antigens BP180 and BP230, PV antigen desmoglein 3 and DH antigen transglutaminase 3 and disclosed overlapping, antigen‐predicted sequences only for BP180 regions. We also assessed the prevalence of TTV in these disorders and compared them with the results from two healthy blood donor groups (group 1: sex‐ and age‐matched for the general bullous group, n = 95; group 2: sex‐ and age‐matched for BP, n = 50). Furthermore, we assayed lymphocytes from four TTV DNA and BP180 NC16A blot‐positive BP patients and three controls in a standard lymphocyte transformation test with a TTV peptide from the conserved ORF(Open Reading Frame)1/N22 region. Results: We found that the detection rate of TTV was comparable with that in healthy controls in the group of PV (19/33); whereas detection rates in DH showed a slight, but not significant tendency for elevation (17/20). Contrary, the TTV prevalence in BP patients was significantly elevated (group 1: 36/40 vs group 2: 31/50, P < 0.032). Lymphocytes from all four virus‐positive BP patients heavily reacted to TTV peptide while two of the three healthy controls have shown not to recognize the viral sequences. Only the TTV carrier healthy control had a minor reaction at lowest peptide concentration. The combined in silico, polymerse chain reaction and in vitro cell assay data of the present study indicate that a TTV persistence may contribute to the pathogenesis of BP.     

Animal models for autoimmune bullous dermatoses

Abstract:  Autoimmune bullous dermatoses are a group of severe diseases, which are clinically characterized by blisters and erosions of skin and/or mucous membranes. In order to investigate the pathogenesis of these potentially life-threatening diseases and to develop more specific therapeutic approaches, animal models have been developed that aim to reproduce the clinical, histological and immunopathological findings. We here review established and novel animal models of autoimmune skin blistering diseases and discuss their applications and limitations.     

Quality of life index in autoimmune bullous dermatosis patients

BACKGROUND

Autoimmune bullous dermatoses are complex diseases triggered by autoantibodies action against epidermal antigens or the dermoepidermal junction. Blisters and vesicles that evolve with erosion areas characterize them. Although rare, they present high morbidity, affecting the quality of life of patients.

OBJECTIVES

To assess the magnitude of autoimmune bullous dermatoses on life quality of patients treated in a public university service in countryside of Brazil.

METHODS

This cross-sectional study was based on an inquiry with autoimmune bullous dermatoses patients assisted at outpatient university referral service. Elements related to quality of life were evaluated by the Dermatology Life Quality Index, as well as clinical and demographic data.

RESULTS

The study evaluated 43 patients with pemphigus foliaceus, 32 with pemphigus vulgaris, 6 with bullous pemphigoid and 3 with dermatitis herpetiformis. The average age was 48 ± 16 years and 34 (40%) were female. The median score (p25-p75) of the Dermatology Life Quality Index was 16 (9-19), classified as "severe impairment" of life quality, in which the greater impact was related to symptoms and feelings, daily and leisure activities.

CONCLUSIONS

Autoimmune bullous dermatoses inflict severe impairment of quality of life for patients followed by a public outpatient clinic in the countryside of Brazil.     

Evidence for pathogenicity of autoreactive T cells in autoimmune bullous diseases shown by animal disease models

Autoimmune bullous diseases (AIBDs) are characterized by blisters and erosions on the skin and/or mucous membranes, which are caused by autoantibodies directed to structural proteins of the epidermis and the epidermal basement membrane zone. This Viewpoint Essay discusses the contribution by autoreactive T cells to the pathogenesis of bullous pemphigoid, pemphigus and epidermolysis bullosa acquisita, with an emphasis on studies using active animal mouse models for these diseases. Previous studies have demonstrated that cytokines produced by autoreactive T cells, the interaction between antigen‐specific T cells and B cells and the function of regulatory T cells are likely related to the pathogenesis of AIBDs. In interpreting the experimental results, the limitations of those animal models should be considered. Further understanding of the pathogenicity of autoreactive CD4⁺ T cells may lead to disease‐specific treatments.     

Optical coherence tomography imaging of bullous diseases

Background Optical coherence tomography (OCT) is a non‐invasive optical imaging technique with a micrometer resolution that may potentially offer real‐time bedside imaging of sufficient detail to allow for morphological discrimination between different types of bullae. Objective To explore the potential of OCT in bullous skin disorders by looking at a set of patients with skin blisters of known origin and study the OCT images for possible hallmarks of the blistering level. Materials and methods OCT provides cross‐sectional, tomographic images of the skin. A consecutive series of patients were recruited and their lesions imaged by OCT: 3 patients with bullous pemphigoid (BP), 1 patient with extensive bullae following burns, 1 patient with pemphigus, 1 patient with subcorneal pustular dermatosis, and a patient with Dariers disease. The latter two were included due to similarity to pemphigus with respect to the level of defect cell adhesion. Results In OCT images, BP bullae are easily depicted as dark, ovoid to round well‐demarquated areas, and BP bulla morphology is clearly different from the burn blisters and the pemphigus‐like disease with respect to the blistering level. Discussion Differentiation of epidermal and subepidermal blisters is demonstrated using OCT. The variation within pemphigoid lesions and pemphigus‐like diseases is however too subtle to allow for differential diagnosis; this may be ascribed to limited resolution. Enhanced resolution of OCT may overcome this obstacle.     

自身免疫性疱病与银屑病的相关性

自身免疫性疱病（AIBD）和银屑病的发病机制有部分相似性。近年来,多项研究报道银屑病与AIBD之间具有相关性,以大疱性类天疱疮多见,还包括寻常型天疱疮、红斑型天疱疮、线状IgA大疱性皮病等,多数AIBD在银屑病发病后发生,部分患者两病同时出现或AIBD先出现。本文综述AIBD与银屑病发病的相关性及可能存在的机制。     

Childhood vulval pemphigoid: a clinical and immunopathological study of five patients

We describe five girls with vulval pemphigoid: two had bullous pemphigoid confined to the vulva and three had cicatricial pemphigoid. They demonstrate a spectrum of severity from localized disease to extensive vulval scarring necessitating long-term immunosuppressive therapy and surgical correction. The age at onset of their disease ranged between 6 and 13 years. All presented with vulval discomfort and erosions. Three had oral lesions, two perianal and one eye and cutaneous involvement. Two girls with only vulval lesions and one with vulval and oral lesions responded well to topical steroids. In two, systemic treatment with prednisolone and dapsone or azathioprine was required. The diagnosis was made on the basis of histology and immunofluorescence (IF). All had positive direct IF with IgG and C3. Indirect IF demonstrated circulating IgG binding to the basement membrane zone in four, with dermal or epidermal binding on salt-split skin substrate. Immunoblotting revealed antibodies to the BP230 and BP180 antigens. Immunoelectron microscopy in the child with dermal binding IgG and BP180 and BP230 on immunoblotting showed labelling at the lamina densa-lamina lucida interface adjacent to hemidesmosomes.     

Cutaneous autoimmune effects in the setting of therapeutic immune checkpoint inhibition for metastatic melanoma

Therapeutic immune checkpoint blockade for metastatic melanoma has been associated with vitiligo, pruritus and morbilliform eruptions. Reports of other autoimmune skin disease in this setting are rare. We sought to expand the spectrum of cutaneous immune‐mediated effects related to immune checkpoint inhibitor therapy. In this report, we describe two unusual cutaneous reactions related to checkpoint inhibitor therapy, namely bullous pemphigoid (BP) and dermatitis herpetiformis. The development of BP and dermatitis herpetiformis in the context of checkpoint inhibitor therapy is consistent with previous investigations supporting the importance of effector and regulatory T cells in the pathogenesis of these diseases.     

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.