Anti-NC16A IgA from Patients with Linear IgA Bullous Dermatosis Induce Neutrophil-Dependent Subepidermal Blistering in Mice.

Linear IgA bullous dermatosis (LABD) is an acquired autoimmune subepidermal blistering skin disease characterized by circulating and tissue-bound IgA autoantibodies that recognize epitopes within the hemidesmosomal protein BP180, including its NC16A domain. Histologically, LABD has long been defined by neutrophil infiltration and dermal-epidermal separation. However, the pathogenic roles of anti-NC16A IgA and neutrophils in LABD, as well as their interactions, have not been thoroughly studied. We show that passive transfer of patient-derived anti-NC16A IgA induce clinical and histologic LABD pathology in humanized NC16A mice that are reconstituted locally or systemically with human neutrophils. The lesional skin of mice exhibits significantly elevated levels of the neutrophil chemoattractants CXCL-1 and CXCL-2. Furthermore, we show significantly increased levels of the neutrophil chemoattractant IL-8 in blister fluids of patients with LABD. This study provides direct evidence that anti-NC16A IgA in patients with LABD are pathogenic and interact with neutrophils to mediate tissue injury and subepidermal blister formation. This study further corroborates the importance of neutrophil-mediated tissue injury in LABD disease physiology and establishes a clinically relevant in vivo model system that can be used to systematically dissect the immunopathogenesis of LABD.

Retrospective analysis of autoimmune bullous diseases in Middle Franconia.

Introduction: Autoimmune bullous diseases (AIBDs) are a group of rare cutaneous disorders affecting cornified skin and mucous membranes. They are characterized by tense or flaccid blistering and erosions due to autoantibodies against desmosomal and hemidesmosomal structural proteins of the skin. This group of disorders can be divided into those of pemphigoid and those of pemphigus diseases. If left untreated, these autoimmune diseases can cause serious or even life-threatening complications such as loss of fluid, superinfections or impaired food intake. Due to modern standardized serological assays, the diagnosis of AIBDs can usually be confirmed in combination with their clinical appearance. Whereas for a long time corticosteroids were the major players in the treatment of these diseases, with the approval of rituximab and other immunosuppressive agents, the therapy has increasingly improved. Methods: In this study, we aimed to investigate epidemiologic and clinical features as well as diagnostics and therapy of bullous autoimmune diseases in Middle Franconia, a governorate within the German federal state of Bavaria. Patients diagnosed or treated because of a AIBDs between 01.04.2013 and 31.03.2019 at the dermatological department of the university hospital Erlangen were included in this retrospective study (n = 242). Patients were either diagnosed for the first time (n=176) or the diagnosis has been confirmed (n=66) at the department. The respective incidence was calculated among the 176 subjects who had been diagnosed at the center in this period. Data was taken from patient records and analyzed with Microsoft® Excel. The evaluation included the diagnoses of pemphigus vulgaris (PV), pemphigus foliaceus (PF), bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), linear IgA dermatosis (LAD), epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH). Results: This study shows that the incidence of each AIBDs in Middle Franconia is low and comparable (PV, PF, LAD, EBA) or lower (BP, MMP, DH) than in other studies and regions. BP is the most common newly diagnosed AIBD in Middle Franconia. Discussion: Due to the chronic and sometimes severe course of AIBDs, repeated in-house treatments are often necessary. To date, mainly topically and systemically applied corticosteroids in combination with immunomodulators are used as first-line therapy.

IgA autoantibody may be the foremost pathogenic in three cases of linear IgA/IgG bullous dermatosis.

Linear IgA/IgG bullous dermatosis (LAGBD) is a relatively rare autoimmune bullous disease characterized by both IgA and IgG antibodies to basement membrane zone. The heterogeneity and pathogenesis of antibodies and the relationship between IgA and IgG in LAGBD have not been fully elucidated. We observed clinical, histological and immunological features of three LAGBD cases at different time points in the disease course. In our cohort, two cases showed IgA antibodies to epidermal antigens vanished when their lesions cleared after 3 months of treatment. One refractory case showed increasing antigens targeted by IgA antibodies with the progression of the disease. Collectively, the results suggest that IgA antibodies may play a major role in LAGBD. In addition, epitope spreading may be related to disease relapse and treatment refractory.

Case Report: Prurigo nodularis-like linear IgA/IgG bullous dermatosis: a case report and literature review.

Linear IgA/IgG bullous dermatosis (LAGBD) is a rare autoimmune subepidermal bullous disorder characterized by linear deposition of concurrent IgA and IgG autoantibodies along the basement membrane zone (BMZ). The clinical features of LAGBD can be diverse, including tense blisters, erosions, erythema, crusting and mucosa involvement, while papules or nodules are generally absent. In this study, we present a unique case of LAGBD, which showed prurigo nodularis-like clinical appearance on physical examination, linear deposition of IgG and C3 along the basement membrane zone (BMZ) in direct immunofluorescence (DIF), IgA autoantibodies against the 97-kDa and 120-kDa of BP180 and IgG autoantibodies against the 97-kDa of BP180 by immunoblotting (IB), while BP180 NC16a domain, BP230, and laminin 332 were negative by enzyme-linked immunosorbent assay (ELISA). After administration of minocycline, the skin lesions improved. We performed a literature review of LAGBD cases with heterogeneous autoantibodies and found clinical presentations of most cases resemble bullous pemphigoid (BP) and linear IgA bullous disease (LABD), which is consistent with previous reported findings. We aim to increase our understanding of this disorder and to enhance the importance of applying immunoblot analyses and other serological detection tools in clinic for precise diagnosis as well as accurate treatment strategy of various autoimmune bullous dermatoses.

A propósito de un caso: enfermedad IgA lineal de la infancia / Apropos of a case: Linear IgA bullous dermatosis of childhood

La enfermedad IgA lineal se trata de un trastorno autoinmune poco frecuente. En la infancia aparece sobre todo en edad preescolar, y en adultos es necesario realizar un buen diagnóstico diferencial con otras enfermedades ampollosas como la dermatitis herpetiforme o el penfigoide ampollar. Hasta un cuarto de los casos se relacionan con infecciones o con la toma de medicamentos entre los que destacan antibióticos y antiinflamatorios no esteroideos. El diagnóstico se basa en la clínica, biopsia cutánea e inmunofluorescencia. Típicamente se presenta como ampollas anulares tensas de morfología anular con imagen característica en collar de perlas. Al realizar el estudio de inmunofluorescencia directa se evidencia una banda lineal de IgA en la unión dermoepidérmica. Suele responder de forma completa a la retirada del fármaco causante y al tratamiento con Dapsona oral y glucocorticoides tópicos. (AU)

Molecular Tumor Board Case Series: Targeted Treatments For Cancer And Their Toxicities: Amivantamab-Induced Linear IgA Bullous Dermatosis.

In the era of targeted treatments based on next generation sequencing (NGS) analysis, clinicians must be diligent in aligning patients with treatments giving them the best chance of survival while weighing the risk of toxicity caused by agents targeting specific gene mutations. In this case, we describe a patient with Epidermal Growth Factor Receptor (EGFR) exon 20 insertion mutation positive recurrent lung adenocarcinoma who received amivantamab and experienced severe dermatologic toxicity.

Linear IgA bullous dermatosis in an acute myeloid leukemia patient: a rare case report.

Linear IgA bullous dermatosis (LABD) is a rare autoimmune bullous disease characterized by linear IgA deposition along the skin basal membrane. In children, LABD classically presents with a "cluster of jewels" appearance, whereas in adults the classic presentation is itchy papules with tense vesicles and bullae on an erythematous base. We report the case of a 41-year-old woman with LABD that we suspect was induced by acute myeloid leukemia presenting with multiple vesicles and bullae that coalesced, forming the typical clinical manifestation of LABD and confirmed with histopathological and direct immunofluorescence. The patient was treated with a combination of oral and topical corticosteroids with excellent results.

Eosinophil-rich linear IgA bullous dermatosis induced by mRNA COVID-19 booster vaccine.

We present a case of eosinophil-rich linear IgA bullous disease (LABD) following the administration of a messenger RNA COVID-19 booster vaccine. A 66-year-old man presented to the emergency department with a 3-week history of a pruritic blistering rash characterized by fluid-filled bullae and multiple annular and polycyclic plaques. He was initially diagnosed with bullous pemphigoid based on a biopsy showing a subepidermal blister with numerous eosinophils. However, direct immunofluorescence studies showed linear IgA and IgM deposition along the basement membrane zone with no immunoreactivity for C3 or IgG. Additionally, indirect immunofluorescence was positive for IgA basement membrane zone antibody. The patient was subsequently diagnosed with LABD and initiated on dapsone therapy with resolution of his lesions at 3-month follow-up. This case illustrates the growing number of autoimmune blistering adverse cutaneous reactions from vaccination. Dermatopathologists should be aware that features of autoimmune blistering diseases can overlap and may not be distinguishable based on these histopathological findings alone. Confirmation with direct immunofluorescence and/or serological studies may be necessary for accurate diagnosis.

Linear IgA bullous dermatosis in the setting of angioimmunoblastic T-cell lymphoma.

We report an 80-year-old male developing linear IgA bullous dermatosis (LAD) in the setting of angioimmunoblastic T-cell lymphoma (AITL). This phenomenon is rare, as only three cases have been described in the literature. The pathophysiologic process can be attributed to dysregulation in somatic hypermutation and the expression of chemokine receptor 5 in AITL, contributing to increased IgA. Immunoglobulin production resulting from clonal plasma cell expansion may be because of the B-cell promotional effect by neoplastic follicular helper T-cells. Beyond providing a pathophysiologic platform for AITL-associated LAD, we also briefly summarized prior cases. This report demonstrates the importance of considering LAD in the differential diagnosis for patients with a bullous eruption in the setting of AITL.

Linear IgA bullous dermatosis associated with immunotherapy.

Linear IgA bullous dermatosis (LABD) is a rare mucocutaneus blistering autoimmune disease caused by IgA autoantibodies. Its clinical manifestation can be indistinguishable from bullous pemphigoid (BP), a similar autoimmune bullous disease caused by IgG and IgE autoantibodies. Although BP has been reported as an adverse cutaneous effect of immunotherapy, LABD has rarely been associated with immunotherapy in the literature. We present the case of a 67-year-old woman with metastatic ovarian cancer receiving anti-PD1 and anti-CTLA4 with new onset pruritic tense bullae to the trunk, hands, elbows (in annular distribution) that occurred after immunotherapy. Skin biopsy showed subepidermal blister with abundant neutrophils on H&E histology, and linear IgA staining at the basement membrane on direct immunofluorescence consistent with the diagnosis of LABD. The condition did not improve on initial prednisone taper, but blisters rapidly resolved a few days after initiation of dapsone therapy. We favor that our patient's LABD is secondary to her immunotherapy. Our case highlights the importance of both H&E histology and direct immunofluorescence in diagnosis of blistering disorders in patients on immunotherapy to help in choosing the most effective treatment option in an attempt to avoid discontinuation of immunotherapy.