Blistering Disease Research Articles

Cytoskeletal anchorage of different Dsg3 pools revealed by combination of hybrid STED/SMFS-AFM

Desmoglein 3 (Dsg3) is a desmosomal cadherin mediating cell adhesion within desmosomes and is the antigen of the autoimmune blistering skin disease pemphigus vulgaris. Therefore, understanding of the complex desmosome turnover process is of high biomedical relevance. Recently, super resolution microscopy was used to characterize desmosome composition and turnover. However, studies were limited because adhesion measurements on living cells were not possible in parallel. Before desmosomal cadherins are incorporated into nascent desmosomes, they are not bound to intermediate filaments but were suggested to be associated with the actin cytoskeleton. However, direct proof that adhesion of a pool of desmosomal cadherins is dependent on actin is missing. Here, we applied single-molecule force spectroscopy measurements with the novel single molecule hybrid-technique STED/SMFS-AFM to investigate the cytoskeletal anchorage of Dsg3 on living keratinocytes for the first time. By application of pharmacological agents we discriminated two different Dsg3 pools, only one of which is anchored to actin filaments. We applied the actin polymerization inhibitor Latrunculin B to modify the actin cytoskeleton and the PKCα activator PMA to modulate intermediate filament anchorage. On the cellular surface Dsg3 adhesion was actin-dependent. In contrast, at cell–cell contacts, Dsg3 adhesion was independent from actin but rather is regulated by PKC which is well established to control desmosome turn-over via intermediate filament anchorage. Taken together, using the novel STED/SMFS-AFM technique, we demonstrated the existence of two Dsg3 pools with different cytoskeletal anchorage mechanisms.

Nail Changes in Immuno-Bullous Disorders: A Cross-Sectional Study.

Autoimmune blistering (AIBD) disorders affect mucosae, skin, and appendages. Appendageal involvement has not been studied extensively to date. However, they are important as nail changes are commonly encountered during a flare-up of the disease. To determine the prevalence and patterns of nail changes in various Immunobullous disorders and to study the relationship between the nail changes and the disease duration and severity. A cross-sectional study was conducted at the Department of Dermatology, venerology, and leprosy at a tertiary care center in Mumbai. A cross-sectional study including a total of 74 cases of Immunobullous diseases was conducted and the prevalence of nail changes was determined. The association between the mean number of nail changes and the disease duration and severity was analyzed using ANOVA (Analysis of variance) and unpaired t-test. The Statistical Package for Social Studies (SPSS) software was used for statistical evaluation. We found that the prevalence of nail changes was 91%. There was a significant difference in the mean number of nail changes with respect to the severity grades of mucosal involvement in AIBD (P value < 0.05). There was no significant difference in the mean number of nail changes with respect to the severity grades of Pemphigus vulgaris (PV), Pemphigus foliaceous (PF), subepidermal blistering diseases, and the duration of AIBD. Nails are frequently affected in AIBD. The number of nail changes is related to the severity of mucosal disease but not to duration.

Rituximab Treatment and Improvement of Health-Related Quality of Life in Patients With Pemphigus.

Pemphigus is an autoimmune blistering disease that can negatively affect patients' lives. Assessing the impact of treatment from a patient's perspective using outcome assessment measures is important and relevant in trials of new pemphigus treatments including rituximab (RTX). We sought to evaluate the effect of RTX on health-related quality of life (HRQOL) in pemphigus patients and peruse the clinical relevance of the patient-reported outcomes. A retrospective cross-sectional study was designed with 96 pemphigus patients given RTX either 3 months earlier or in the last 2 weeks. The treatment was evaluated by patients using HRQOL assessment tools: 36-Item Short Form Survey (SF-36) and Dermatology Life Quality Index (DLQI). Another patient-reported assessment was the patient global assessment (PGA). We found that RTX administration in pemphigus patients led to rapid and notable improvement in HRQOL and patient-assessed measures.

Issues occupying our minds: Nomenclature of autoimmune blistering diseases requires updating, pemphigus vulgaris propensity to affect areas adjacent to natural body orifices unifies seemingly diverse clinical features of this disease.

In this conceptual analysis, we present our concepts on two issues regarding autoimmune bullous diseases (AIBD), namely (i) current nomenclature of AIBD requires updating by incorporating molecular data and (ii) pemphigus vulgaris (PV) "likes" areas adjacent to natural body orifices. The problem of inadequacy of the currently used nomenclature was noticed recently by Zillikens, who proposed to form a group with the task of updating it. The early efforts by Dmochowski to update this nomenclature happened to be a daunting task. Nevertheless, the ideal nomenclature should retain the bulk of clinical data, which generations of dermatologists are accustomed to, including triggers if known, and incorporate molecular data revealing targets of autoimmune response and immunoglobulin isotypes involved. The natural body orifices affected by PV were previously described in numerous publications. However, these openings are described separately in these publications. Here, Dmochowski comes up with an intellectual concept that this propensity of PV unifies seemingly diverse clinical features of this disease.

Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa

BackgroundDystrophic epidermolysis bullosa is a rare genetic blistering skin disease caused by mutations in COL7A1, which encodes type VII collagen (C7). Beremagene geperpavec (B-VEC) is a topical investigational herpes simplex virus type 1 (HSV-1)–based gene therapy designed to restore C7 protein by delivering COL7A1.MethodsWe conducted a phase 3, double-blind, intrapatient randomized, placebo-controlled trial involving patients 6 months of age or older with genetically confirmed dystrophic epidermolysis bullosa. For each patient, a primary wound pair was selected, with the wounds matched according to size, region, and appearance. The wounds within each pair were randomly assigned in a 1:1 ratio to receive weekly application of either B-VEC or placebo for 26 weeks. The primary end point was complete wound healing of treated as compared with untreated wounds at 6 months. Secondary end points included complete wound healing at 3 months and the change from baseline to weeks 22, 24, and 26 in pain severity during changes in wound dressing, assessed with the use of a visual analogue scale (scores range from 0 to 10, with higher scores indicating greater pain).ResultsPrimary wound pairs were exposed to B-VEC and placebo in 31 patients. At 6 months, complete wound healing occurred in 67% of the wounds exposed to B-VEC as compared with 22% of those exposed to placebo (difference, 46 percentage points; 95% confidence interval [CI], 24 to 68; P=0.002). Complete wound healing at 3 months occurred in 71% of the wounds exposed to B-VEC as compared with 20% of those exposed to placebo (difference, 51 percentage points; 95% CI, 29 to 73; P<0.001). The mean change from baseline to week 22 in pain severity during wound-dressing changes was −0.88 with B-VEC and −0.71 with placebo (adjusted least-squares mean difference, −0.61; 95% CI, −1.10 to −0.13); similar mean changes were observed at weeks 24 and 26. Adverse events with B-VEC and placebo included pruritus and chills.ConclusionsComplete wound healing at 3 and 6 months in patients with dystrophic epidermolysis bullosa was more likely with topical administration of B-VEC than with placebo. Pruritus and mild systemic side effects were observed in patients treated with B-VEC. Longer and larger trials are warranted to determine the durability and side effects of B-VEC for this disease. (Funded by Krystal Biotech; GEM-3 ClinicalTrials.gov number, NCT04491604.)

A Case of Pemphigus Vulgaris in a Patient with Human Immunodeficiency Virus

Pemphigus vulgaris is the most common variant of autoimmune chronic blistering skin diseases. Its appearance in patients infected with acquired immunodeficiency virus (HIV) is rare. A 40-year-old woman is reported, who presented skin lesions in 90% of the body surface, characterized by blisters of 3 to 4 cm that, when broken, left denuded areas, excoriations and pruritic meliceric crusts. A skin biopsy was performed that showed a characteristic pattern of pemphigus vulgaris. Elisa for HIV positive. She evolved with septic shock and died 72 hours later. Understanding the relationship between HIV and autoimmune blistering disorders can help guide the therapeutic and prognostic management of these patients. Proposed mechanisms include molecular mimicry, polyclonal B-cell stimulation, and highly active antiretroviral therapy possibly associated with immune restoration. Clinically, these patients may present limited mucosal symptoms or develop multiple erosions that may spread, merge, and progress to exfoliative erythroderma. Glucocorticoids serve as the first line of management; however, they can have important adverse effects such as infectious complications that pose a therapeutic challenge for the doctor and could influence mortality.

The efficacy of adding oral sodium cromoglycate to stable treatment for controlling bullous pemphigoid-related pruritus: A retrospective study.

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease which mainly affects the elderly. It manifests as severe pruritus, urticarial plaques, and tense bullae and is associated with significant mortality. Therapy options for itch in BP patients are limited, mainly because the pathogenesis of itch in BP remains unclear. Sodium cromoglycate was commonly used in the past as an inhaled drug for the management of bronchial asthma and as an oral treatment for children with urticaria pigmentosa. In this study we sought to assess its efficacy in reducing BP associated itch. Assessing the efficacy of oral sodium cromoglycate in reducing BP-related pruritus after stabilization of disease activity. We retrospectively reviewed the medical records of patients with a confirmed diagnosis of BP who were treated with sodium cromoglycate. Patient reported outcome measures (PROM) including: BPDAI pruritus, ABQOL and TABQOL, and BPDAI activity score were compared at two points in time: before commencing treatment with sodium cromoglycate or before commencing maximal dose of this treatment, and at least 4 weeks after treatment commencement. A total of 21 patients met the inclusion criteria. After at least 4 weeks of treatment with oral sodium cromoglycate BPDAI pruritus, ABQOL and TABQOL scores were statistically significantly decreased compared to the scores prior to treatment commencement, P < 0.000, P < 0.008, and P < 0.004, respectively. Oral treatment with sodium cromoglycate for the management of pruritus in BP patients may be beneficial, however, further prospective studies are required to better assess its efficacy.

Thromboembolism and bleeding in patients with autoimmune blistering disease.

The prevention and early detection of venous thromboembolism (VTE), including pulmonary embolism (PE), is essential in daily medical practice. We previously reported the risk of VTE in patients with autoimmune blistering disease (AIBD). We have also experienced multiple cases of pemphigus or pemphigoid that developed severe complications related to abnormal blood coagulation other than VTE. This study summarizes and discusses those cases. Nine patients with AIBD developed thromboembolism and/or bleeding; these included (some patients overlapped) six patients with VTE, including five patients with PE; three patients with severe bleeding; one patient with sudden critical limb ischaemia resulting in thigh amputation; and one patient with cerebral infarction. Although five patients developed PE, only one had apparent respiratory symptoms with PE, and a second developed severe bleeding during the treatment for PE. Clinicians should be aware of the systemic complications related to abnormal blood coagulation when treating patients with AIBD.

Clinical course and outcomes of pemphigus vulgaris and foliaceus: A retrospective study using a nationwide database in Japan.

Pemphigus is a life-threatening autoimmune blistering disease. Patient characteristics, treatment courses, and outcomes remain unclear owing to its rarity. To describe the background, treatment, and outcomes of pemphigus, we identified 2598 patients with pemphigus vulgaris and 1186 patients with pemphigus foliaceus from a nationwide inpatient database in Japan. Patients with pemphigus vulgaris were younger (62 vs 72 years, P< 0.001), had fewer comorbidities, and were more likely to be admitted to high-volume hospitals (38% vs 30%, P< 0.001) than those with pemphigus foliaceus. Patients with pemphigus vulgaris had undergone more aggressive treatment, including steroid pulse therapy, intravenous immunoglobulin, or plasmapheresis, compared with those with pemphigus foliaceus (48% vs 42%, P= 0.001); specifically, in patients aged <70 years, the pemphigus vulgaris group was more likely to undergo aggressive treatment than the pemphigus foliaceus group (52% vs 45%), whereas there was no significant difference in patients aged ≥70 years (40% vs 40%). Immunosuppressive agents (30% vs 26%, P= 0.015) and analgesics, including opioids (45% vs 36%, P< 0.001), were used more frequently, whereas topical corticosteroids were used less frequently (32% vs 48%, P< 0.001) in patients with pemphigus vulgaris compared with those with pemphigus foliaceus. In-hospital mortality was lower in patients with pemphigus vulgaris than in those with pemphigus foliaceus (2.2% vs 4.0%, P= 0.002); in the comparison stratified by age, the mortality was equivalent among the two groups (0.6% in patients aged <70 years and 6.1% in those aged ≥70 years). Overall, patients with pemphigus vulgaris had a 10-day longer hospitalization period and higher hospitalization costs than those with pemphigus foliaceus. Our findings provide useful information for understanding the current trends in the management of pemphigus in Japan.

What's new in the pathogeneses and triggering factors of bullous pemphigoid.

Bullous pemphigoid (BP) is a subepidermal blistering disease induced by autoantibodies to type XVII collagen (COL17, also called BP180) and BP230. Previous studies using patients' samples and animal disease models elucidated the complement-dependent and complement-independent pathways of blister formation, the pathogenic roles of immune cells (T and B cells, macrophages, mast cells, neutrophils, eosinophils), and the pathogenicity of IgE autoantibodies in BP. This review introduces the recent progress on the mechanism behind the epitope-spreading phenomenon in BP, which is considered to be important to understand the chronic and intractable disease course of BP, and the pathogenicity of anti-BP230 autoantibodies, mainly focusing on studies that used active disease models. To clarify the pathogenesis of BP, the mechanism behind the breakdown of immune tolerance to BP antigens should be investigated. Recent studies using various experimental models have revealed important roles for regulatory T cells in the maintenance of self-tolerance to COL17 and BP230 as well as in the suppression of inflammation triggered by the binding of antibodies to COL17. Notably, physical stresses such as trauma, thermal burns, bone fractures, irradiation and ultraviolet exposure, some pathologic conditions such as neurological diseases and hematological malignancies, and the use of dipeptidyl peptidase-IV inhibitors and immune checkpoint inhibitors have been reported as triggering factors for BP. These factors and certain underlying conditions such as genetic background, regulatory T-cell dysfunction or aging might synergistically affect some individuals and eventually induce BP. Further studies on the breakdown of self-tolerance and on the identification of key molecules that are relevant to blister formation and inflammation may expand our understanding of BP's etiology and may lead to the development of novel therapeutic approaches.

Childhood Pemphigus Vulgaris during COVID-19 Outbreak Successfully Treated with Prednisone and Azathioprine: A Case Report and Literature Review.

pemphigus vulgaris is a rare autoimmune blistering disease that involves the skin and mucous membranes and rarely occurs in pediatric age. we present a case of childhood pemphigus in a 9-year-old patient from Burkina Faso, which initially manifested with erosive lesions symmetrically distributed in the oral cavity. After a few months, we also observed hyperchromic lesions of the back. Histopathological examination of skin samples showed intraepidermal acantholysis, while direct immunofluorescence showed deposits of complement (C3) and immunoglobulins G (IgG) in the epidermidis; an ELISA test highlighted the presence of circulating autoantibodies against desmoglein 3. the follow-up of this patient was made difficult by the advent of the COVID-19 outbreak. However, after about one year of combined therapy with systemic steroids and azathioprine the patient reached clinical remission.

Follicular lymphoma manifests as multiple erosive and proliferative lesions of the oral mucosa: case report and brief literature review

BackgroundErosion is one of the most common and basic lesions of oral mucosal diseases. Long-term refractory oral erosions, induced by autoimmune blistering diseases, infectious diseases, malignant diseases, and some rare conditions, may substantially reduce the quality of life of patients or even constitute a life-threatening condition, resulting in a clinical dilemma regarding the accurate diagnosis and precise management of these diseases. As a special type of malignant lymphoma, most lesions of follicular lymphoma (FL) in the oral mucosa present as masses or swelling of the oral mucosa, while emerging novel presentations lead to intractable diagnoses. Hence, diagnostic algorithms for such diseases are clinically required. Case presentationA 55-year-old female patient presented to the clinic with long-lasting oral mucosal erosions and proliferative lesions. Blood tests, pathological examinations of oral lesions including haematoxylin–eosin (HE) staining, and direct immunofluorescence precluded all of the potential diagnoses described previously. Unexpectedly, positron emission tomography/computed tomography (PET/CT) and abdominal CT of the patient revealed a dense mass in the retroperitoneal area, and the final diagnosis of the retroperitoneal mass was FL. After three courses of chemotherapy conducted by the haematologist, the erosion and proliferative lesions in the patient's oral mucosa had significantly improved. HE and immunohistochemical staining results of intraoral lesions also confirmed it as oral FL. The successful diagnosis of FL in this case is of great clinical significance, as the oral and abdominal FL were treated in a timely manner to avoid unfavourable outcomes.ConclusionsTo the best of our knowledge, this is the first case of FL that exhibited widespread erosions interspersed with proliferative lesions. Clinicians should be aware of oral FL or seek systemic factors in the presence of similar refractory oral erosions when treatment is non-responsive and the diagnosis is intractable.

040 Vildagliptin administration alters mouse skin proteome

Bullous pemphigoid (BP) is a subcutaneous blistering skin disease in which IgG autoantibodies are formed against the hemidesmosomal protein BP180. Epidemiological studies have revealed a strong association between an increased risk of BP and the use of dipeptidyl peptidase 4 inhibitors (DPP4i/gliptins), especially vildagliptin. We performed a proteomic study on vildagliptin-exposed mice to reveal factors for the development of DPP4i-associated BP. We administered vildagliptin via drinking water to mice (control group, n = 5, treatment group n = 6) for three months and used minimum two-dimensional difference gel electrophoresis (2D-DIGE) to study the effects of vildagliptin on the skin proteome.

299 High efficiency and safe base editor correction of recurrent COL7A1 mutations underlying dominant dystrophic epidermolysis bullosa

Dominant dystrophic epidermolysis bullosa (DDEB) is an inherited blistering skin disease caused by heterozygous mutations in COL7A1, which encodes type VII collagen (C7), the major component of anchoring fibrils that maintain the integrity of the dermal-epidermal junction. Most COL7A1 mutations in DDEB are single nucleotide variants, resulting in glycine substitutions within the C7 triple helix. Functionally, such mutations cause impaired assembly or secretion of C7 and result in dominant-negative interference through faulty C7 assembly of wild-type and mutant chains into anchoring fibrils.

302 Availability of mRNA Obtained from Peripheral Blood Mononuclear Cells for Mutational Analysis in Dystrophic Epidermolysis Bullosa

Dystrophic epidermolysis bullosa (DEB) is an inheritable blistering disease caused by mutations in COL7A1, which encodes type VII collagen. To address the issue of genotype-phenotype correlations in DEB, analyzing the consequences of COL7A1 mutations using mRNA is indispensable. Herein we established a novel method for testing the effect of mutations in DEB using COL7A1 mRNA extracted from peripheral blood mononuclear cells (PBMCs). We investigated the consequences of four COL7A1 mutations (c.6573 + 1G > C, c.6216 + 5G > T, c.7270C > T and c.2527C > T) in three Japanese individuals with recessive DEB.

084 Clinical characteristics and treatments of pemphigus vulgaris and pemphigus foliaceus: a descriptive study of 3795 patients using a nationwide inpatient database in Japan

Pemphigus is a group of autoimmune blistering disease caused by autoantibodies against desmoglein 1 and 3. The two major subtypes of pemphigus are pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Their epidemiology is known to differ by ethnicities. Hence, using a nationwide inpatient database in Japan, we retrospectively identified 3795 patients admitted with either PV (2608 patients) or PF (1187 patients) and investigated their backgrounds, treatments, and outcomes. Overall, the median age at admission was 65 (interquartile range, 51–76) years.

016 PC111, a novel, First In Class, human anti-FasL antibody for the treatment of Pemphigus: a translational study

Pemphigus is a rare and debilitating autoimmune blistering disease due to keratinocyte cell-cell detachment (acantholysis). Treatments focus on immune suppression but are often associated with severe side effects, slow onset of action and frequent clinical relapses; therefore, innovative and non-immunosuppressive therapies are needed to provide rapid, safer and long-lasting responses. Patients’ autoantibodies (PVIgG) are fundamental for initiating the pathologic mechanisms of pemphigus. We have recently demonstrated that soluble Fas Ligand (sFasL), that is massively up-regulated and released from keratinocytes upon PVIgG binding, is essential for blister formation.

070 Treating Bullous Pemphigoid by Inhibiting FcRn: A Phase 2/3 Trial with Efgartigimod

Efgartigimod (EFG) is an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor (FcRn), thereby reducing the levels of circulating immunoglobulin G (IgG), including pathogenic IgG autoantibody, levels. EFG is clinically efficacious and generally well tolerated in phase 2 and 3 trials in multiple IgG-mediated disorders. Bullous pemphigoid (BP) is an autoimmune blistering disease, characterized by subepidermal blisters and mediated by IgG autoantibodies against BP180 (type XVII collagen) and BP230, structural proteins of the dermal-epidermal junction. Administration of an EFG analogue prior to and after that of pathogenic anti-BP180 IgG antibodies in a BP mouse model demonstrated efficacy in reducing skin disease activity. EFG will be evaluated as a therapy for BP in BALLAD, a phase 2/3 randomized, double-blinded, placebo-controlled trial (NCT05267600). BALLAD will be conducted in two parts – a proof-of-concept Part A (N=40) and a confirmatory Part B (N=120). Both parts are identical in schedule, structure, assessments, and conduct. 2000 mg EFG PH20 SC will be given on days 1 and 8, and 1000 mg EFG PH20 SC will be given weekly through week 35. Oral corticosteroids starting at 0.5 mg/kg/day of prednisone will be administered to the EFG PH20 SC and placebo PH20 SC groups and adjusted to each participant’s disease status. The primary endpoint is the proportion of participants in complete remission on minimal oral corticosteroid therapy (≤0.1 mg/kg/day) for ≥8 weeks at week 26. Key secondary endpoints include cumulative dose of oral corticosteroids from day 1 to week 36, change in the Bullous Pemphigoid Disease Area Index (BPDAI) score, incidence and severity of adverse events, and quality of life scores.

043 A novel tool to analyse the pathogenic impact of IgG binding to extracellular domain 5 of Desmoglein 3

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease characterized by autoantibodies (auto-ab) against the desmosomal adhesion molecules desmoglein3 (Dsg3) and Dsg1. Binding of Dsg specific auto-ab to target structures induces an interruption of the desmosomal integrity which ultimately results in the clinical manifestation of flaccid blisters and erosions in PV patients. Underlying mechanisms inducing blister formation upon binding of Dsg-specific auto-ab are largely unknown. Numerous studies demonstrated the pathogenicity of auto-ab specific for the amino-terminal region (extracellular domain 1, EC1) of Dsg3.

502 Analysis of checkpoint inhibitor therapy-associated pemphigoid in a series of five Bulgarian patients

Programmed cell death 1 (PD-1) inhibitors used as target anti-cancer immunotherapy have been largely reported for their cutaneous immune-related adverse events (irAEs) ranging from xeroderma or pruritus to atopic dermatitis, psoriasis, vitiligo, etc. Autoimmune blistering diseases (AIBD) from the pemphigoid spectrum, namely bullous pemphigoid (BP) and rarely lichen planus pemphigoides (LPP) have also been associated with checkpoint inhibitors (CI). There is a growing interest in investigating their causal relation, characteristics, and treatment response.