Unusual subepidermal bullous diseases with immunologic features of bullous pemphigoid.

Sixty-seven patients with histologic and immunologic features of bullous pemphigold (BP) were evaluated. Eleven patients had a localized blistering disease that was predominantly confined to one area of the body, most commonly the lower extremities. Two patients displayed a dapsone-responsive blistering disease that was characterized by a flexural distribution of ten to 20 1-cm or less, intensely pruitic, subepidermal bullae and linear IgA basement membrane zone deposition. Two patients had a chronic recalcitrant generalized scarring, hyperkeratotic, subepidermal blistering eruption that demonstrated serologic and direct immunofluorescence (IF) findings of BP. One patient displayed grouped small vesicles surmounted on an erythematous base; the clinical diagnosis was dermatitis herpetiformis, but direct IF examination of the biopsy specimen showed features of BP. One patient with epidermolysis bullosa acquisita had serologic and direct IF features suggestive of BP.     

Bullous Pemphigoid and Epidermolysis Bullosa Acquisita: Presentation,Prognosis, and Immunopathology in 11 Children

Abstract: The immunobullous diseases bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA) are very rare in childhood. Although case studies have been detailed, there are no reports of a large series of patients documenting the effectiveness of treatment and long-term prognosis. We report the clinical presentation, immunopathologic features, disease course, and long-term prognosis of BP and EBA in a series of 11 children. The initial diagnoses based on clinical features were BP (5), EBA (3), and chronic bullous disease of childhood (CBDC) (3). These were subsequently revised from BP to EBA (2), CBDC to BP (2), and CBDC to BP or EBA (1) following the results of direct and indirect immunofluorescence and immunoblotting. Analysis of IgG subclasses in eight cases showed that the predominant subclasses were lgG1 (8) and lgG4 (6). The clinical features appeared to be highly variable, and in patients presenting with inflammatory blistering, laboratory studies were required in order to differentiate between BP and EBA. All patients improved on treatment with corticosteroids and/or sulfones, although treatment regimens showed wide variation. Their diseases tended to remit within 2 years, and their long-term prognosis was good.     

Bullous pemphigoid: from the clinic to the bench

Bullous pemphigoid (BP) constitutes the most frequent autoimmune subepidermal blistering disease. It is associated with autoantibodies directed against the BP antigens 180 (BP180, BPAG2) and BP230 (BPAG1-e). The pathogenicity of anti-BP180 antibodies has been convincingly demonstrated in animal models. The clinical features of BP are extremely polymorphous. The diagnosis of BP critically relies on immunopathologic findings. The recent development of novel enzyme-linked immunosorbent assays has allowed the detection of circulating autoantibodies with relatively high sensitivity and specificity. Although potent topical steroids have emerged in the past decade as first-line treatment of BP, management of the disease may be challenging.     

Experimental models for the autoimmune and inflammatory blistering disease,Bullous pemphigoid

Bullous pemphigoid (BP) is a subepidermal skin blistering disease characterized immunohistologically by dermal-epidermal junction (DEJ) separation, an inflammatory cell infiltrate in the upper dermis, and autoantibodies targeted toward the hemidesmosomal proteins BP230 and BP180. Development of an IgG passive transfer mouse model of BP that reproduces these key features of human BP has demonstrated that subepidermal blistering is initiated by anti-BP180 antibodies and mediated by complement activation, mast cell degranulation, neutrophil infiltration, and proteinase secretion. This model is not compatible with study of human pathogenic antibodies, as the human and murine antigenic epitopes are not cross-reactive. The development of two novel humanized mouse models for the first time has enabled study of disease mechanisms caused by BP autoantibodies, and presents an ideal in vivo system to test novel therapeutic strategies for disease management.     

Bullous pemphigoid: using animal models to study the immunopathology

Bullous pemphigoid was first described by Lever in 1953 as a subepidermal blistering disease. Its immunohistological features include dermal-epidermal junction separation, an inflammatory cell infiltrate in the upper dermis, and basement membrane zone-bound autoantibodies. These autoantibodies show a linear staining at the dermal-epidermal junction, activate complement, and recognize two major hemidesmosomal antigens, BP230 (BPAG1) and BP180 (BPAG2 or type XVII collagen). An IgG passive transfer mouse model of BP was developed by administering rabbit antimurine BP180 antibodies to neonatal mice. This model recapitulates the key features of human bullous pemphigus. Using this in vivo model system, several key cellular and molecular events leading to the bullous pemphigus disease phenotype were identified, including IgG binding, complement activation, mast cell degranulation, and neutrophil infiltration and activation. Proteinases and reactive oxygen species released by neutrophils work together to damage the basement membrane zone, causing dermal-epidermal junction separation. Recent experimental data from human bullous pemphigus studies suggest that human bullous pemphigus and its mouse IgG passive transfer model counterpart may well share not only common immunohistological features but also pathological mechanisms underlying the development of this antibody-mediated disease.     

Bullous pemphigoid: end of the century overview.

Bullous pemphigoid (BP) was first described by Lever in 1953 as a subepidermal blistering disease. Immunohistological features of BP include dermal-epidermal junction separation with an inflammatory cell infiltrate in the upper dermis, and autoantibodies in patients' circulation and bound to the basement membrane zone (BMZ). These autoantibodies show a linear staining at the dermal-epidermal junction (DEJ) and recognize two major hemidesmosomal proteins, the BP230 (BPAG1) and BP180 (BPAG2). An IgG passive transfer mouse model of BP was developed, that recapitulates the key features of human BP. Using this in vivo model system, key cellular and molecular events leading to BP disease phenotype are identified, including IgG binding to its target, complement activation, mast cell degranulation, neutrophil infiltration and activation. Proteinases and reactive oxygen species released by neutrophils work together to damage BMZ, causing DEJ separation. T cells from BP patients show a specific proliferative response to recombinant BP180 NC16A. These NC16A-responding T lymphocytes express alpha/beta T cell receptors and CD4 memory T cell surface markers and exhibited a Th1/Th2 mixed cytokine profile. After almost a half-century of studies, we have learned a great deal about IgG-mediated tissue injury and begin to understand the autoimmune responses leading to pathogenic IgG production in BP.     

儿童大疱性类天疱疮

大疱性类天疱疮是一获得性自身免疫性疾病,常累及老年人,儿童少见。儿童大疱性类天疱疮的发病率无明显的人种、性别区别,年龄跨度较大,儿童期各年龄组均有报道。儿童大疱性类天疱疮的诊断主要依据临床表现、组织病理及直接免疫荧光检查。在病因及临床表现上儿童有别于成人,但在组织病理及直接免疫荧光上与成人大疱性类天疱疮相似。     

Role of BP230 autoantibodies in bullous pemphigoid

Bullous pemphigoid (BP) is an autoimmune disease associated with subepidermal blistering due to autoantibodies directed against BP180 and BP230. BP180 is currently considered as the major pathogenic autoantigen. However, previous clinical findings suggested that anti-BP230 autoantibodies alone can cause skin lesions in animal models and many BP patients. The characteristics of BP230 and the pathogenic roles of anti-BP230 antibodies have been proposed. First, at the molecular level, BP230 mediates the attachment of keratin intermediate filaments to the hemidesmosomal plaque and interacts with other constituents of hemidesmosomes. Second, the presence of BP230 autoantibodies may correlate with specific clinical features of BP. The immunoglobulin (Ig)G autoantibodies from BP patients react mainly against the C-terminus of BP230, while the IgE autoantibodies are still inconclusive. Third, in vivo, autoantibodies against BP230 involved in the disease may not only induce the inflammatory response but also impair the structural stability of hemidesmosomes. This article reviews recently published work about the role of BP230 and its antibodies, including IgG and IgE, aiming to find clues of its clinical association and lay the foundation for the research on the pathogenicity of antibodies against BP230.     

Detection of linear IgE deposits in bullous pemphigoid and mucous membrane pemphigoid: a useful clue for diagnosis

Summary Background Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease of the skin associated with IgG autoantibodies to BP180 and BP230, while mucous membrane pemphigoid (MMP) comprises a heterogeneous group of autoimmune blistering diseases characterized by a predominant mucous membrane involvement and scarring tendency associated with an autoantibody response to various autoantigens, including BP180. While the pathogenicity of IgG autoantibodies to BP180 has been demonstrated in BP, the role of IgE autoantibodies in mediating tissue damage in BP and MMP is unclear. Objectives To assess the presence of tissue‐bound IgE in patients with BP and MMP, and their correlation with distinct clinical features. Methods In this retrospective study, we assessed the presence of IgE deposits as detected by direct immunofluorescence microscopy of skin biopsy specimens obtained from 44 and 13 patients with a new diagnosis of BP and MMP, respectively. Distinct clinical features at time of diagnosis, such as itch, urticarial papules and plaques and eczematous lesions, were noted. Results In 18 of 44 (41%) patients with BP linear deposits of IgE of variable intensity were detectable along the dermoepidermal junction. In 14 (32%) of the cases, IgE deposits were found concomitantly with IgG and C3. In two (5%) patients, diagnosis of BP was based on the isolated detection of IgE together with consistent clinicopathological features. Nine of 13 (69%) patients with MMP also exhibited linear IgE deposits, including one case with isolated linear IgE deposits. Patients with BP with tissue‐bound IgE deposits had clinically significant urticarial papules and plaques when compared with patients with BP without IgE deposits. Conclusions Our findings indicate that demonstration of tissue‐bound IgE deposits provides an additional useful criterion for diagnosis of BP and MMP in some patients. Prospective studies are needed to better correlate the presence of tissue‐bound and circulating IgE autoantibodies and their specificity with distinct clinical features and course of BP and MMP.     

儿童大疱性类天疱疮

大疱性类天疱疮是一获得性自身免疫性疾病.常累及老年人,儿童少见.儿童大疱性类天疱疮的发病率无明显的人种、性别区别,年龄跨度较大,儿童期各年龄组均有报道.儿童大疱性类天疱疮的诊断主要依据临床表现、组织病理及直接免疫荧光检查.在病因及临床表现上儿童有别于成人,但在组织病理及直接免疫荧光上与成人大疱性类天疱疮相似.     

Grover disease and bullous pemphigoid: a clinicopathological study of six cases

Grover disease (GD) is an idiopathic dermatosis that typically manifests as itchy papules over the trunk in middle‐aged men. Bullous pemphigoid (BP) is an autoimmune bullous disease that affects older people. Not only are the two diseases easily distinguishable on clinical grounds, they are also characterized by differences in histopathology, pathogenesis and response to treatment Thus, the co‐occurrence of these two conditions in the same patient is usually considered coincidental. In this report, we present a multicentre retrospective analysis of six patients who developed both GD and BP over a short period of time, and in all cases but one, GD preceded BP. We discuss the clinical and histopathological features of these patients, and the suggested mechanisms of the diseases. We conclude that GD might predispose to the development of BP.     

Immunoglobulin E and bullous pemphigoid

Clinical features and histological findings in bullous pemphigoid (BP) suggest a Th2-oriented inflammatory reaction, especially in the early stages of the disease. Elevated total serum IgE levels, blood eosinophilia, and elevated serum levels of different soluble inflammatory Th2 response mediators have been described in large cohorts of patients with classic clear-cut BP manifestations. Direct immunofluorescence, indirect immunofluorescence, and anti-BP230 and anti-BP180 IgE ELISA testing show self-reactive IgE autoantibodies in a consistent number of BP patients. Both IgE autoantibodies and a Th2-oriented immune response may play a role in the initial phases of BP and atypical cases of BP, such as severe erythematous and urticarial forms of BP, as well as blister formation. Two recently reported experimental murine models employing IgE autoantibodies against BP180 have been reported and the successful treatment of bullous pemphigoid with the anti-IgE antibody, omalizumab, supports the roles played by IgE autoantibodies in BP pathogenesis.     

Immunoelectron microscopy in subepidermal autoimmune bullous diseases: a prospective study of IgG and C3 bound in vivo in 32 patients

Thirty-two patients suffering from subepidermal autoimmune bullous disease were studied prospectively by clinical examination and immunoelectron microscopy. Clinically, 1 patient had herpes gestationnis, 14 typical bullous pemphigoid (BP), 3 epidermolysis acquisita (EBA), 3 cicatricial pemphigoid (CP), and 11 patients overlapping clinical diseases. These 11 patients shared clinical features of BP, EBA, or CP and a clinical diagnosis could not be done safely. Immunoelectron microscopy revealed diaminobenzidine deposits in 20 patients on the epidermal side of dermo-epidermal junction in the lamina lucida as in BP. In 5 patients, deposits located mostly under the anchoring fibril zone, in the floor of a sublamina densa dermoepidermal separation for 2 of them, were consistent with a diagnosis of EBA. In 6 patients, deposits were located mostly in the lamina densa, in the floor of a dermoepidermal separation occurring in the lamina lucida for 3 of them. This suggests that some of these 6 patients had neither EBA or BP, but another autoimmune bullous disease again, an uncharacterized component of dermoepidermal junction located in the lamina densa. Finally, a correlation exists between the sites of IgG and/or C3 components on epidermal or dermal side of dermoepidermal junction and the presence or absence of characteristic clinical features such as scar, milia formation, or mucosal involvement.     

Dermatitis herpetiformis and bullous pemphigoid. Intermediate and mixed forms.

Nine patients had clinical and histological features suggestive of both dermatitis herpetiformis (DH) and bullous pemphigold (BP). Five patients responded to treatment with sulfapyridine or sulfones: in two the response was inconsistent, and the disease was controlled by combined treatment with prednisone; in one patient, there was no response to sulfapyridine or sulfones. Immunofluorescence studies showed IgA deposits in a linear homogeneous pattern at the basement membrane zone in all patients, and IgG was present in five. No circulating anti-basement membrane antibodies were detected by repeated immunofluorescence examinations. The authors conclude that the occasional overlapping of BP and DH should not lead to dropping the distinction between the two entities. For overlap cases that cannot be classified as BP or DH, the term "intermediate or mixed form of DH and BP" seems to be most suitable.     

Differentiating anti-lamina lucida and anti-sublamina densa anti-BMZ antibodies by indirect immunofluorescence on 1.0 M sodium chloride-separated skin

Sixty-one bullous disease sera containing IgG anti-BMZ antibodies were examined by indirect immunofluorescence on intact skin and skin separated through the lamina lucida by incubation in 1.0 M NaCl. All sera produced an indistinguishable pattern of linear immunofluorescence on intact skin at dilutions of 1:10 or higher. On separated skin, antibodies bound to either the epidermal (epidermal pattern), dermal (dermal pattern), or epidermal and dermal (combined pattern) sides of the separation. The binding patterns were consistent on separated skin from several donors and titers of anti-basement membrane zone antibodies on separated skin were comparable to those on intact skin. Sera from 3 patients with herpes gestationis (HG), 36 patients with bullous pemphigoid (BP), and 1 patient with clinical and histologic features of epidermolysis bullosa acquisita (EBA) showed an epidermal pattern. Sera from 9 patients with BP showed a combined pattern and sera from 6 patients with EBA and 6 patients with clinical and histologic features of BP showed a dermal pattern. Indirect immunoelectron microscopy of selected sera showed antibodies producing the epidermal and combined patterns were anti-lamina lucida antibodies and those producing the dermal pattern were anti-sublamina densa antibodies. These results show indirect immunofluorescence on separated skin is a dependable method for differentiating bullous disease anti-lamina lucida and anti-sublamina densa antibodies and that differentiating between the antibodies is essential for accurate diagnosis in some patients. The results also suggest BP anti-lamina lucida antibodies may have more than one antigenic specificity.     

A patient with both bullous pemphigoid and epidermolysis bullosa acquisita: an example of intermolecular epitope spreading

Bullous pemphigoid (BP) and epidermolysis bullosa acquisita are distinct autoimmune blistering disorders. BP is characterized by autoantibodies directed against the NC16A domain of collagen XVII, whereas patients with epidermolysis bullosa acquisita have autoantibodies against the NC1 domain of type VII collagen. We followed up a patient with BP for 9 years. During that time his clinical disease took on several features suggestive of epidermolysis bullosa acquisita. The objective of this study was to determine if the patient's autoantibody profile reflected the change in his clinical picture. Enzyme-linked immunosorbent assay and immunoblotting for detection and subclass determination of autoantibodies to type XVII and type VII collagen were performed on banked patient sera from the 9-year period. The patient's initial autoantibodies were exclusively IgG1 directed against collagen XVII. During the course of his illness, the subclass specificity of the patient's type XVII collagen autoantibodies shifted to the IgG4 subclass and during the same time interval the patient developed IgG2 autoantibodies directed against type VII collagen. This patient with BP exhibited both subclass shifting and development of a second autoantibody system that correlated with a change in the clinical appearance of the disease. The analysis of the patient's autoantibodies provides strong evidence for the involvement of epitope spreading in the evolution of his autoimmune disease.     

Dipeptidyl‐peptidase IV inhibitors (DPP4i)‐associated bullous pemphigoid: Estimating the clinical profile and exploring intraclass differences

Data regarding the clinical characteristics of patients with dipeptidyl‐peptidase IV inhibitors (DPP4i)‐associated BP is inconclusive. We aimed to characterize the clinical features of patients with DPP4i‐associated BP, and to assess whether there are phenotypic differences associated with different agents belonging to the DPP4i class. A retrospective prevalence study was performed, including all consecutive patients diagnosed with BP throughout the years 2000 to 2019. The study included 397 patients with BP, of whom 58 (14.6%) were DPP4i‐associated. Compared to other patients with BP, patients with DPP4i‐associated BP had a more prominent male preponderance (60.3% vs 41.0%; P = .006), presented more frequently with extensive disease (60.3% vs 46.3%; P = .049), had greater truncal (96.6% vs 85.5%; P = .019) and cephalic (51.7% vs 33.6%; P = .008) involvement, and had less frequent peripheral eosinophilia (25.9% vs 51.9%; P < .001). Compared to patients with vildagliptin‐associated BP, those with linagliptin‐associated BP were managed by higher dosage of systemic corticosteroids in order to achieve disease control (prednisone > 1 mg/kg: 68.2% vs 40.0%; P = .046). In conclusion, DPP4i‐associated BP seems to have a unique clinical profile characterized by male predominance, extensive disease, truncal and cephalic involvement, and less peripheral eosinophilia. Linagliptin may be associated with a harder course necessitating more aggressive therapy.     

Clinical presentation and diagnostic delay in bullous pemphigoid: a prospective nationwide cohort

Summary Background Prospective systematic analyses of the clinical presentation of bullous pemphigoid (BP) are lacking. Little is known about the time required for its diagnosis. Knowledge of the disease spectrum is important for diagnosis, management and inclusion of patients in therapeutic trials. Objectives The primary aims of the study were: (i) to characterize the clinical features of BP at time of diagnosis; and (ii) to assess the diagnostic delay in BP and its impact on prognosis Methods All new cases of BP diagnosed in Switzerland between 1 January 2001 and 31 December 2002 were prospectively registered by means of a standardized data collection form. Results One hundred‐seventeen patients with BP were included in the study. 97cases (82.9%) had typical features with vesicles, blisters and/or erosions at time of diagnosis, while in the remaining cases (17.1%) only excoriations, eczematous and/or urticarial infiltrated lesions were observed. Head/neck as well as palmo‐plantar involvement were found in up to 20% of patients, while mucosal lesions were present in 14.5% of the cases. Diagnosis was made after a mean of 6.1 months after the first symptoms. In patients, in whom the diagnostic delay was 4 months or more (defined as late diagnosis group), lesions were more often limited to one body area. The type of lesions did not affect the diagnostic delay. Diagnosis was made more rapidly in patients with limb involvement compared to those without. The calculated mortality rate in the early and late diagnosis group was 18.9% and 17.9%, respectively, without significant difference. Conclusion BP often presents with bullous lesions at time of diagnosis after a mean diagnostic delay of 6 months. Nevertheless, up to 20% of patients lack obvious blistering and postbullous erosions, mimicking thus a variety of inflammatory dermatoses. Localized disease is associated with an increased diagnostic delay, which has however no impact on prognosis.     

Childhood vulval lichen sclerosus: autoimmunity to the basement membrane zone protein BP180 and its relationship to autoimmunity

Lichen sclerosus (LS) is associated with autoimmune disease in female children and adults. In adult women, there are antibody and T‐cell responses to proteins in the basement membrane zone (BMZ). The aim of this study was to investigate reactivity to the BMZ in girls with LS. Nine girls with vulval LS were studied clinically and serologically. The presence of circulating BMZ autoantibodies was investigated. Autoimmunity was assessed by personal and family history of autoimmune diseases and autoantibodies. We detected circulating BMZ antibodies in four of the nine children, all with IgG responses. Three patients were positive by indirect immunofluorescence, one had a positive ELISA reaction to bullous pemphigoid antigen (BP)180, and three had a positive reaction on BP180 immunoblots. There was no association with autoimmune disease or clinical features. To our knowledge, this is the first study to find BMZ autoantibodies in children with vulval LS. The autoantibodies were directed at BP180 and were exclusively of the IgG class.     

Two cases of subepidermal blistering disease with anti-p200 or 180-kD bullous pemphigoid antigen associated with psoriasis

We describe two patients with psoriasis vulgaris who subsequently developed a subepidermal blistering disease which disclosed IgG and C3 at the basement membrane zone in direct immunofluorescence. The first case was a 75-year-old Japanese man with herpetiform lesions. Histopathology showed neutrophil infiltration. IgG antibodies bound to the dermal side of the salt-split skin. Immunoblot analysis identified a 200-kD antigen in dermal extracts. The second case was a 70-year-old Japanese man. Histopathology showed eosinophil infiltration. IgG antibodies bound to the epidermal side of salt-split skin. Immunoblot analysis identified a 180-kD bullous pemphigoid (BP) antigen in epidermal extracts. We review the clinical and pathological features of psoriatic patients who presented a subepidermal blistering disease in which antigens were detected by immunoblot analysis; i.e., anti-p200 pemphigoid (14 cases) or BP (12 cases). There were few distinct clinical differences between two diseases. However, neutrophils were predominant in anti-p200 pemphigoid, while eosinophils were predominant in BP. After blister formation, ciclosporin was used effectively in addition to systemic steroids in the treatment of anti-p200 pemphigoid. On the other hand, ciclosporin was not used in the treatment of BP with psoriasis.