Autoimmune Blistering Disease Research Articles

The pathological function of neutrophils in pemphigoid diseases

Abstract Pemphigoid diseases (PDs) are a group of autoimmune blistering diseases, including bullous pemphigoid, epidermolysis bullosa acquisita, mucous membrane pemphigoid, linear immunoglobulin A disease, and other rare variants. These diseases are characterized by the presence of autoantibodies that target proteins at the dermal-epidermal junction, resulting in the formation of tense blisters and erosions on the skin and/or mucosa. The current therapeutic approaches, such as systemic corticosteroid, are associated with significant adverse effects, highlighting that safer and more effective treatment options are an urgent clinical need. To address this unmet need, a comprehensive understanding of the detailed mechanisms underlying PDs is essential. Based on their histopathological infiltration in pemphigoid lesions, neutrophils have long been implicated as major contributors to the initiation and progression of the diseases. Numerous in vivo and in vitro studies have investigated the role of neutrophils in the pemphigoid pathology, revealing various pathological mechanisms induced by these cells, including the release of neutrophil elastase and matrix metalloproteinase-9, as well as the formation of neutrophil extracellular traps. The present review provides a comprehensive summary and critical evaluation of the current understanding regarding the role of neutrophils in PDs. In addition, it discusses the potential of targeting neutrophil-associated pathways as a novel therapeutic approach for the diseases.

Remission Rate of Pemphigus Vulgaris and Pemphigus Foliaceus in the Institute of Dermatology: A 7 Years Retrospective Study

Pemphigus, an autoimmune blistering disease caused by autoantibodies targeting desmoglein 1, desmoglein 3, and desmosomal cadherins, is characterized by blister formation and can be a long-term condition with the possibility of relapse. This study aimed to evaluate the remission rates and compare them between pemphigus vulgaris (PV) and pemphigus foliaceus (PF) at the Institute of Dermatology. A retrospective analysis was conducted on 426 patients diagnosed and treated at the Institute of Dermatology in Bangkok, Thailand, between January 1, 2016, and December 31, 2022, for PV and PF. Patients were followed up for 1, 2, and 5 years to assess complete remission using Consensus statement criteria. The remission rates for PV and PF were 3.3%, 17.5%, and 48.4% at 1, 2, and 5 years, and 7.9%, 33.1%, and 61.6% at the same intervals, respectively. PF demonstrated significantly higher remission rates compared to PV at all time points (p< .001). The average time to remission was 60 months for PV and 36 months for PF. Prognostic factors associated with complete remission included age, age at onset, control of underlying disease, disease severity, primary site of involvement, and initial mucosal involvement. In conclusion, the remission rates for PV and PF at five years were 48.4% and 61.6%, respectively. PF achieved complete remission more frequently than PV. Good control of underlying disease, absence of initial mucosal involvement, and mild disease severity were associated with better prognosis for both PV and PF.

Frequency of infections during rituximab treatment of autoimmune blistering diseases.

This study investigates the frequency of infections in autoimmune blistering disease (AIBD) patients treated with rituximab and evaluates the difference in infectious complications in patients on concomitant antibiotic and/or antiviral prophylaxis. The study retrospectively reviewed 43 AIBD patients who received rituximab over a five-year interval. The patients were categorized based on prophylaxis type (antibiotic, antiviral, or both) and concomitant immunosuppression status, which we defined as treatment with an immunosuppressive medication during the time frame they were given Rituximab. Our findings suggest that concomitant immunosuppression alongside rituximab did not significantly increase the risk of developing infectious complications compared to rituximab monotherapy. Results revealed that 34.4% of patients with concomitant immunosuppression had a secondary bacterial infection, defined as bacterial complications requiring hospitalization, consistent with prior studies. Moreover, antibiotic prophylaxis did not significantly reduce infection risk in patients on rituximab, with 45.1% of these patients experiencing bacterial complications. There was an absence of pneumocystis pneumonia in the study population. Despite the small sample size and limited timeline, this study suggests that antibiotic prophylaxis may not significantly mitigate the risk of infections in AIBD patients receiving rituximab, and the risk of infection with concomitant immunosuppression with rituximab requires additional investigation for definitive causal risk.

Role of auto-antibodies in the mechanisms of dengue pathogenesis and its progression: a comprehensive review.

A complex interaction among virulence factors, host-genes and host immune system is considered to be responsible for dengue virus (DENV) infection and disease progression. Generation of auto-antibodies during DENV infection is a major phenomenon that plays a role in the pathophysiology of dengue hemorrhagic fever and dengue shock syndrome. Hemostasis, thrombocytopenia, hepatic endothelial dysfunction, and autoimmune blistering skin disease (pemphigus) are different clinical manifestations of dengue pathogenesis; produced due to the molecular mimicry of DENV proteins with self-antigens like coagulation factors, platelets and endothelial cell proteins. This review elaborately describes the current advancements in auto-antibody-mediated immunopathogenesis which inhibits coagulation cascade and promotes hyperfibrinolysis. Auto-antibodies like anti-endothelial cell antibodies-mediated hepatic inflammation during severe DENV infection have also been discussed. Overall, this comprehensive review provides insight to target auto-antibodies that may act as potential biomarkers for disease severity, and a ground for the development of therapeutic strategy against DENV.

Pemphigus Foliaceous with special reference to Visphota Kushta

Pemphigus is an autoimmune blistering disease which can be fatal if left untreated. In case of secondarily infected skin lesions, life threatening sepsis may develop. There is no specific treatment protocol for the management of pemphigus. The present study is aimed to treat a 57-year-old male patient clinically diagnosed with pemphigus foliaceus admitted in Kayachikitsa department in Govt. Ayurveda College, Thiruvananthapuram. Treatment was aimed at controlling the progression of disease, preventing infection and inducing healing of the affected area. In Ayurveda symptoms are more similar to Kaphapitha kushta especially Visphota kushta. Langhana, Snehapana and repeated Sodhana were the treatment protocols adopted. Ayurvedic approach in this single case of pemphigus is beneficial in correcting the inherent Agnimandya at Koshta and Dhatu level and thus provides significant result. PDAI score was used for assessment. Before treatment PDAI was 96, reduced to 24 after Sodhana and after treatment it was 6. There was no recurrence of symptoms after 2 weeks.

Sensitive and specific assay for the serological diagnosis of anti-p200 pemphigoid based on the recombinant laminin β4 subunit.

Anti-p200 pemphigoid is an autoimmune blistering disease that often resembles other pemphigoid disorders. This study developed a test for the detcetion of autaontibodies against laminin β4, an additional autoantigen in anti-p200 pemphigoid, to facilitate its diagnosis. The test demonstrated excellent sensitivity and specificity, making it a valuable tool for diagnosing this condition and distinguishing it from similar skin disorders.

Management of Linear IgA through Ayurveda -A Case study

Linear IgA bullous dermatosis (LABD)/ Chronic bullous disease of childhood (CBDC) is a rare autoimmune blistering disease characterized by the linear deposition of IgA at the dermoepidermal junction. The disease has an incidence of 0.2 to 2.3 per 1000000 million per year showing diverse clinical manifestations and etiologies1.In this case, a 6-year-old child presented with erythematous vesiculobullous lesions on her perianal region, groins, thighs and in both upper and lower limbs since 1 month.The symptoms were gradually progressive in nature.A biopsy was performed, which was consistent with linear immunoglobulin A bullous dermatosis and later confirmed by direct immunofluorescence studies.The child was advised to consume samana aushadhis (internal medicines)for 6 months, which led to remarkable changes in the lakshanas and the patient had no such symptoms till date.This case shows the significant role of ayurvedic intervention in the management of such diseases.

Low pH condition impairs BP-IgG binding to the basement membrane zone.

Bullous pemphigoid (BP), an autoimmune subepidermal blistering disease, shows tense blisters associated with urticarial erythema. Tissue-bound Immunoglobulin G (IgG) at the basement membrane zone (BMZ) detected by direct immunofluorescence (DIF) is strong evidence for a diagnosis of BP. The sensitivity of DIF is higher in complement component 3 (C3) than in IgG, but the reason for this different sensitivity is not fully understood. In this study, we performed several exvivo studies to investigate the possible mechanism of IgG negativity and C3 positivity at the BMZ by DIF in some BP cases. First, sera from BP patients showing IgG negativity by DIF were found to clearly react to the BMZ in their own DIF skin samples. Next, indirect immunofluorescence (IIF) was performed using sera diluted with different pH phosphate-buffered saline (PBS), pH 7.4, 6.0, and 3.0. Patients' sera diluted with pH 7.4 PBS showed linear staining at the BMZ, but sera diluted with pH 6.0 PBS and pH 3.0 PBS showed lower fluorescence intensities. Finally, sections of skin from BP patients were pre-incubated with different pH PBS (pH 3.0, 6.0, and 7.4), followed by staining with anti-human IgG and C3. The fluorescence intensities were notably lower for IgG and C3 that had been pre-incubated with pH 3.0 PBS and pH 6.0 PBS than for IgG and C3 that had been pre-incubated with pH 7.4 PBS. These results suggest that a low pH condition hinders the binding of autoantibodies to the BMZ, that is, the drop in tissue pH induced by inflammation inhibits autoantibodies from depositing at the BMZ. Furthermore, the drop in tissue pH causes tissue-bound autoantibodies to detach from the BMZ. Complement fragments are activated not only on IgG but also on the cell surface of cells close to IgG during complement activation. IgG may detach from the BMZ under low pH condition induced by inflammation, but some complement fragments remain at the BMZ. These phenomena may help to explain why C3 is more sensitive than IgG when DIF is used to diagnose BP.

TARC/CCL17 reflects the severity of pemphigus (pemphigus vulgaris and pemphigus foliaceus) at the initial presentation

AbstractBackgroundPemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune blistering diseases targeting desmoglein 3 (Dsg3) or desmoglein 1 (Dsg1). The current scoring system, pemphigus disease area index (PDAI), has limitations including inter‐ and intra‐evaluator variability, as well as a time‐consuming evaluation process.ObjectivesTo identify objective and quantitative surrogate markers for assessing disease severity in PV and PF.MethodsEleven PV and PF patients were included. PDAI scores and candidate biomarkers [anti‐Dsg3 antibody, anti‐Dsg1 antibody, thymus and activation‐regulated chemokine (TARC)/CCL17, immunoglobulin E (IgE) levels and eosinophil counts] were measured before oral corticosteroid treatment. Pearson's correlation coefficient was used for correlations between PDAI and candidate biomarkers.ResultsSerum TARC/CCL17 levels significantly correlated with PDAI scores in PV and PF (R = 0.72, p = 0.02), while anti‐Dsg3 antibody levels correlated with PDAI scores for PV (R = 0.86, p = 0.012). No significant correlations were observed for anti‐Dsg1 antibody, eosinophil counts or IgE levels.ConclusionsSerum TARC/CCL17 may be a quantitative and unbiased disease biomarker in pemphigus patients, although further studies involving larger patient cohorts are needed.

Efficacy of Omalizumab for the treatment of Bullous Pemphigoid. Spanish multicenter real-world experience.

Bullous Pemphigoid (BP) is the most common autoimmune blistering disease. Most patients are elderly and associate multiple comorbidities. Topical and systemic corticosteroids are considered as the first-line treatment for BP and immunosuppressors are used as steroid-sparing treatments but both have side effects and contraindications which are even more common in this elderly population. New treatments targeting interleukins and receptors related to BP pathogenesis have been proposed to decrease this side effects while achieving equal or better effectiveness response rates.Omalizumab is a monoclonal antibody that targets IgE that has been proposed for the treatment of BP due to the evidence that IgE autoantibodies play an essential role in BP pathogenesis. To assess the efficacy and security of Omalizumab for the treatment of BP, we carried out a multicenter, retrospective, observational study including patients diagnosed of BP who received omalizumab for at least 3 months from 15 tertiary hospitals in Spain. IgE levels prior to treatment was measured and we evaluate the possible correlation with clinical response. We excluded patients treated with Omalizumab for less than 3 months as we consider this duration is insufficient for a comprehensive assessment of its efficacy. To evaluate the effectiveness of the treatment we used the percentage of BSA improvement. We included 36 patients. The vast majority associate multiple comorbidities and all patients had used other systemic therapies apart from corticoids before Omalizumab.83% experienced some kind of treatment response and 42% of all patient treated achieved complete response.We did not find any correlation between higher levels and a better response (p=0,1791).All patients tolerated Omalizumab without reported side-effects. Omalizumab is a good therapeutic alternative for BP as it obtained clinical response in most patients and nearly half of the cases achieving complete response. It showed no side effects which is crucial in elderly patients suffering from BP.

Anti-BP230 IgE autoantibodies in bullous pemphigoid intraindividually correlate with disease activity

BackgroundBullous pemphigoid (BP), the most common subepidermal autoimmune blistering disease, is classically defined by the presence of IgG autoantibodies directed against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230 and the predominance of skin lesions. Several studies have addressed the role of anti-BP180 IgE in patients and experimental models, while data on anti-BP230 IgE are scarce. ObjectiveTo assess anti-BP230 IgE level by ELISA in BP sera and to correlate it with disease severity and clinical characteristics. MethodsBP sera underwent anti-BP230 IgE ELISA and Western blotting against human BP230 fragments. ResultsWe demonstrate that 36/154 (23%) of BP sera were positive for anti-BP230 IgE. Anti-BP230 IgE levels had no correlation with clinical phenotype or disease activity per se. Interestingly, anti-BP230 IgE was significantly associated with disease activity within individuals during the course of the disease. Additionally, anti-BP230 IgE and total IgE levels showed a significant correlation. Notably, anti-BP230 IgG correlated interindividually with disease activity. By Western blotting, the C-terminal domain of BP230 fragments (C2; amino acids 2024–2349 and C3; amino acids 2326–2649), provided the best serological assay for anti-BP230 IgE detection. ConclusionAs a complementary tool, IgE immunoblotting is recommended to obtain an optimal serological diagnosis, particularly in patients with severe disease without IgG reactivity by BP180- or BP230-specific ELISA. Although the detection of serum anti-BP230 IgE is not of major diagnostic significance, it may be relevant for therapeutic decisions, e.g., for anti-IgE-directed treatment, which has been successfully used in case series of BP.

The management of pemphigus vulgaris and mucous membrane pemphigoid in a joint oral medicine and dermatology clinic: a five-year narrative review

Pemphigus disease and mucous membrane pemphigoid are autoimmune blistering diseases (AIBDs) which may involve both oral and extra-oral tissues. The Bristol Joint Oral Medicine and Dermatology Combined Clinic was set up in 2014, with the primary aim of improving the standard of care for patients with AIBDs. This interdisciplinary approach aimed to address the medical management challenges due to the multisite nature of these AIBDs.We present a narrative report of the clinical work undertaken within this clinic, focused on the management of this patient cohort within a five-year span (2017-2022). This report outlines the multisite nature of AIBDs and the range of topical and systemic treatments that were employed to achieve adequate disease control and optimise outcomes for patients. We reflect on the experiential benefits of this multidisciplinary clinic extended beyond immediate patient benefits to areas such as specialist training, both from a dermatologist's and oral physician's perspective.

Laryngeal Manifestations of Bullous Pemphigoid: Case Report and Review of the Literature.

Bullous pemphigoid (BP) is an autoimmune blistering disease that affects primarily the skin and rarely involves the mucosa of the oral cavity, larynx, pharynx, or esophagus. Diagnosis is based on the clinical presentation, histology, and immunopathological examination. Laryngeal involvement in BP is extremely rare and patients may be asymptomatic or may present with dysphonia, dysphagia, and/or respiratory distress. The authors of this article report a rare case of BP with laryngeal involvement with a review of the literature. Early diagnosis and initiation of treatment is highly recommended to prevent any long-term complications.

Patients suffering from dystrophic epidermolysis bullosa are prone to developing autoantibodies against skin proteins: A longitudinal confirmational study.

Epidermolysis bullosa (EB) is a heritable skin blistering disease caused by variants in genes coding for proteins that secure cell-cell adhesion and attachment of the epidermis to the dermis. Interestingly, several proteins involved in inherited EB are also associated with autoimmune blistering diseases (AIBD). In this study, we present a long-term follow-up of 15 patients suffering from recessive dystrophic or junctional EB. From these patients, 62 sera were analysed for the presence of autoantibodies associated with AIBD. We show that patients suffering from recessive dystrophic EB (RDEB) are more susceptible to developing autoantibodies against skin proteins than patients suffering from junctional EB (70% vs. 20%, respectively). Interestingly, no correlation with age was observed. Most patients showed reactivity to Type XVII collagen/linear IgA bullous dermatosis autoantigen (n = 5; 33%), followed by BP230 (n = 4; 27%), Type VII collagen (n = 4; 27%) and laminin-332 (n = 1; 7%). The pathogenicity of these autoantibodies remains a subject for future experiments.

Serum interleukin 6 concentration in patients with pemphigus

Pemphigus is a rare autoimmune blistering disease that detrimentally affects the integumentary system and decreases patients’ quality of life. Recent studies have shown that interleukin 6 (IL-6) is closedly involved in the immunophathogenesis of pemphigus. Therefore, this study was performed to evaluate the role of IL-6 in the pathogenesis and severity of pemphigus disease. The case-series study was conducted in Ho Chi Minh City Hospital of Dermato-Venereology from January 2022 to August 2022, involving 26 patients with pemphigus vulgaris (PV), 4 patients with pemphigus foliaceus (PF), and 20 healthy volunteers. The serum IL-6 concentrations of patients with PV and PF were significantly higher than those of the healthy volunteers (P < 0.001). Serum IL-6 concentrations were significantly higher in patients with a positive than a negative Nikolsky sign (P < 0.001). A significant correlation was found between the serum IL-6 concentration and the pemphigus disease area index (r = 0.8, P < 0.001). Our results suggest that IL-6 may play an important role in the pathogenesis and severity of pemphigus. Therefore, new therapies targeting IL-6 may be a promising choice for treating pemphigus, especially in its severe forms.

Restoring immune tolerance in pemphigus vulgaris

Intravenous immunoglobulin (IVIg), a preparation of polyclonal serum IgG pooled from numerous blood donors, has been used for nearly three decades and is proving to be an efficient treatment for many autoimmune blistering diseases, including pemphigus vulgaris (PV). Despite its widespread use and therapeutic success, its mechanisms of action are not completely understood. Some of its anti-inflammatory and immunomodulatory actions have been studied. In this study, the authors present a twenty-year follow-up of 21 patients with clinical and immunopathological confirmed PV, treated with IVIg as monotherapy, according to an established published protocol. IVIg therapy produced long-term sustained, clinical, serological, and immunopathological remission. For 20 y, these patients received no drugs and experienced no disease. This observation suggests that there was the establishment of immune balance or restoration of immune regulation in these PV patients. Twelve (57%) patients experienced no relapse during follow-up. Six (29%) patients experienced a relapse due to acute stress or post-coronavirus infection and/or vaccination. Reinstitution of IVIg resulted in prompt sustained recovery. Three (14.2%) patients, in clinical and serological remission, died due to unrelated causes. No severe adverse effects from IVIg were documented in all 21 patients. The simultaneous or sequential anti-inflammatory and immunomodulatory effects of IVIg may have influenced the long-term clinical remission observed. This study provides a human prototype to examine the pathophysiology of autoimmunity and a model to study immune regulation and mechanisms that can facilitate restoring immune tolerance.

Overview of Clinical Trials With Efgartigimod in Autoimmune Blistering Diseases: Pemphigus Vulgaris and Pemphigus Foliaceus (ADDRESS and ADDRESS+) and Bullous Pemphigoid (BALLAD and BALLAD+)

Introduction & Objectives: Efgartigimod is an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor (FcRn), thereby reducing levels of circulating IgG including pathogenic IgG autoantibodies. Pemphigus vulgaris (PV), pemphigus foliaceus (PF), and bullous pemphigoid (BP) are autoimmune blistering diseases. Pemphigus is mediated by IgG autoantibodies targeting desmoglein (Dsg)-3 in PV, and Dsg-1 in mucocutaneous PV (in addition to Dsg-3), while PF is attributed to IgG autoantibodies against Dsg-1 only. Dsg-3 and Dsg-1 are desmosomal proteins mediating keratinocyte cell-cell adhesion. BP is mediated by IgG autoantibodies against BP180 (type XVII collagen) and BP230 structural proteins of the dermal-epidermal junction. Materials & Methods: ADDRESS is a multicenter, randomized, double-blind, placebo-controlled trial evaluating efficacy and safety of efgartigimod in patients with PV or PF (NCT04598451). Participants are undergoing randomization (2:1) to receive subcutaneous efgartigimod co-formulated with PH20 or placebo/PH20 on top of oral prednisone (or equivalent). Primary endpoint is the proportion of patients with PV or PF who achieve complete remission on minimal therapy (CRmin) within 30 weeks. BALLAD is a global, multicenter, phase 2/3, randomized, double-blind, placebo-controlled trial evaluating efficacy and safety of subcutaneously administered efgartigimod in patients with BP (NCT05267600). Part A will be a proof-of-concept study and recruit 40 participants, while the Part B confirmatory study will recruit 120 participants. Parts A and B will be identical in schedule, structure, assessments, and conduct. Primary endpoint is the proportion of participants in complete remission off oral corticosteroid therapy for ≥8 weeks at week 36. Results & Conclusions: As of February 28, 2023, 222 participants have been enrolled into ADDRESS and enrolment of BALLAD has started. It is anticipated that the recruitment of the ADDRESS full study and BALLAD part A will be completed, and a further update will be given at the time of presentation.

Development of De Novo Pemphigus Vulgaris Following COVID-19 Vaccination

The vaccines manufactured by Pfizer, Moderna, and AstraZeneca to prevent the spread of SARS-CoV-2 have been reported to cause a wide range of adverse cutaneous reactions. The most common of these include delayed large local reactions, injection site reactions, urticaria, and morbilliform eruptions. The rarest and severe cutaneous reactions include the development of autoimmune blistering diseases such as pemphigus vulgaris and bullous pemphigoid. In this case report, we present a 73-year-old female patient who developed de novo pemphigus vulgaris two weeks after receiving the Pfizer-BioNTech COVID-19 vaccine. To the best of our knowledge, ours is the first case of new-onset pemphigus vulgaris following the Pfizer COVID-19 vaccine in the United States and only the third worldwide. This report confirms a suspected association between COVID-19 vaccination and the onset of pemphigus vulgaris, although it is exceedingly rare. It also highlights the importance of considering the COVID-19 mRNA vaccines as etiologies for new-onset pemphigus vulgaris and potentially other autoimmune blistering disorders. This knowledge may be important for medical providers when considering a differential diagnosis of new-onset blistering disease to expedite accurate diagnosis and initiation of treatment.

Bullous pemphigoid and diabetes mellitus: a systematic review and meta-analysis.

We aimed to systematically review and meta-analyze the association between diabetes mellitus (DM) and bullous pemphigoid (BP). Bullous pemphigoid (BP) is a prevalent autoimmune subepidermal blistering disease. Comorbid health conditions like neurological diseases and malignancies have been associated with BP. Growing evidence suggests that type 2 diabetes mellitus (T2DM) may increase the risk of developing BP. This review aims to synthesize this evidence. A systematic literature review was performed using Medline, PubMed, and Scopus in March 2022. Studies exploring the association between BP and DM were included. Data were extracted, and quality was assessed using the Newcastle-Ottawa scale. Meta-analysis was conducted to identify the odds ratio (OR) and 95% confidence intervals (CI) of the association. Seventeen studies were included, most being case-control studies from Europe and Asia. The pooled OR was 2.06 (95% CI: 1.61-2.62), suggesting a significant association between DM and BP. However, strong heterogeneity (I2 = 88%) was observed. Evidence consolidates a significant relationship between DM and BP, potentially due to alterations in the immune system and skin properties caused by diabetes. Strengths of this review include a comprehensive search, rigorous methodology, large sample size, and heterogeneity evaluation. However, varying study quality, potential publication bias, and unaccounted confounding factors present limitations. There is a potential link between T2DM and an increased risk of BP. Further studies are required to understand this association and the underlying mechanisms.

Relationship between bullous pemphigoid and malignancy: A Mendelian randomization study.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, which primarily affects the elderly. However, the relationship between BP and malignancy remains controversial in traditional observational studies. The aim of this study, which included only European populations, was to assess the potential causative link between BP and 13 types of malignant tumors in a two-sample Mendelian randomization (MR) study. BP was not associated with an increased risk of developing 13 types of malignant tumors. This study did not find a causal relationship between BP and malignant tumors. However, further research is warranted to examine the generalizability of this conclusion in non-European populations.