Blistering Disease Research Articles

Aberrant inflammasome activation as a driving force of human autoimmune skin disease.

Autoimmune skin diseases are understood as conditions in which the adaptive immune system with autoantigen-specific T cells and autoantibody-producing B cells reacting against self-tissues plays a crucial pathogenic role. However, there is increasing evidence that inflammasomes, which are large multiprotein complexes that were first described 20 years ago, contribute to autoimmune disease progression. The inflammasome and its contribution to the bioactivation of interleukins IL-1β and IL-18 play an essential role in combating foreign pathogens or tissue damage, but may also act as a pathogenic driver of myriad chronic inflammatory diseases when dysfunctionally regulated. Inflammasomes containing the NOD-like receptor family members NLRP1 and NLRP3 as well as the AIM2-like receptor family member AIM2 have been increasingly investigated in inflammatory skin conditions. In addition to autoinflammatory diseases, which are often associated with skin involvement, the aberrant activation of the inflammasome has also been implied in autoimmune diseases that can either affect the skin besides other organs such as systemic lupus erythematosus and systemic sclerosis or are isolated to the skin in humans. The latter include, among others, the T-cell mediated disorders vitiligo, alopecia areata, lichen planus and cutaneous lupus erythematosus as well as the autoantibody-driven blistering skin disease bullous pemphigoid. Some diseases are characterized by both autoinflammatory and autoimmune responses such as the chronic inflammatory skin disease psoriasis. Further insights into inflammasome dysregulation and associated pathways as well as their role in forming adaptive immune responses in human autoimmune skin pathology could potentially offer a new field of therapeutic options in the future.

Clinical, diagnostic, and treatment comparisons between Stevens-Johnson syndrome and toxic epidermal necrolysis: review of the literature

Stevens-Johnson syndrome is a rare but serious medical condition, which is classified within the blistering diseases of the skin and mucous membranes. It is characterized by a severe and generalized immune-mediated inflammatory reaction, predominantly affecting the skin and mucous membranes, such as the eyes, mouth and genitalia.

Efficacy of anti-desmoglein 1 and anti-desmoglein 3 levels by enzyme-linked immunosorbent assay compared to biopsy of chronic oral ulcerative diseases with positive Nikolsky's sign to diagnose oral pemphigus vulgaris with or without skin involvement: a retrospective institutional observational pilot study

We assessed the efficacy of anti-desmoglein 1 (anti-DSG1) and anti-DSG3 levels by enzyme-linked immunosorbent assay (ELISA) as a preliminary diagnostic test in the diagnosis of oral pemphigus vulgaris (OPV) with or without skin involvement compared to biopsy. We retrospectively analyzed data collected from 23 patients (mean age 45.13 years) who had presented with chronic oral ulcerations, desquamative gingivitis, and a positive Nikolsky's sign. We performed ELISA, histopathologic examination, and direct immunofluorescence (DIF) and then calculated the sensitivity and specificity of the results of ELISA, histopathology, DIF, and the presence of a positive Nikolsky's sign in diagnosis. The ELISA results showed that 18 patients had elevated anti-DSG3 levels, of whom 8 also had elevated anti-DSG1 levels. The histopathology results indicated that 18 patients had OPV, of whom 4 had oral lichen planus, and 1 had sub-epithelial blistering disease confirmed to be mucous membrane pemphigoid MMP by DIF. ELISA, histopathology, and DIF had a 100% sensitivity and specificity, and the presence of a positive Nikolsky's sign had a sensitivity and specificity of 100% and 78.26%, respectively. Measurement of anti-DSG1 and anti-DSG3 levels by ELISA warrants consideration as a first-line diagnostic test for early detection of OPV with or without skin involvement over biopsy.

Pemphigus vulgaris mimicking Steven-Johnson syndrome/toxic epidermal necrolysis: report of an unusual case.

Pemphigus vulgaris (PV) is an autoimmune blistering disease affecting the skin and mucosa. It clinically presents as painful erosions, mainly in the oral cavity, and flaccid blisters and erosions on the skin. Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe mucocutaneous drug hypersensitivity reaction characterized by painful, dusky, erythematous eruptions that often progress to blisters, erosions, and extensive epidermal detachment accompanied by systemic symptoms. Herein, we report the case of a 48-year-old man who presented with extensive skin and mucosal lesions following the ingestion of an unknown medication. The patient's symptoms clinically mimicked SJS, and accordingly, a preliminary diagnosis of SJS/TEN was made. However, clinical investigation of skin biopsy and direct immunofluorescence assay results indicated PV, and a final diagnosis of PV was established.

The Essential Role of microRNAs in Inflammatory and Autoimmune Skin Diseases-A Review.

The etiopathogenesis of autoimmune skin diseases is complex and still not fully understood. The role of epigenetic factors is emphasized in the development of such diseases. MicroRNAs (miRNAs), a group of non-coding RNAs (ncRNAs-non-coding RNAs), are one of the important post-transcriptional epigenetic factors. miRNAs have a significant role in the regulation of the immune response by participating in the process of the differentiation and activation of B and T lymphocytes, macrophages, and dendritic cells. Recent advances in research on epigenetic factors have provided new insights into the pathogenesis and potential diagnostic and therapeutic targets of many pathologies. Numerous studies revealed a change in the expression of some microRNAs in inflammatory skin disorders, and the regulation of miRNA expression is a promising therapeutic goal. This review presents the state of the art regarding changes in the expression and role of miRNAs in inflammatory and autoimmune skin diseases, including psoriasis, atopic dermatitis, vitiligo, lichen planus, hidradenitis suppurativa, and autoimmune blistering diseases.

Efficacy and safety of biological agents for pemphigoid: asystematic review and meta-analysis.

Biologic agents (also termed biologics) have become an important adjuvant-targeted treatment option in autoimmune blistering disease. We evaluated the efficacy and safety of newly licensed biologics for the management of pemphigoid using a meta-analysis. PubMed, EMBASE, Web of Science, and the Cochrane Library for studies involving pemphigoid patients treated with biological agents (rituximab, dupilumab, omalizumab, or mepolizumab) were searched. The pooled risk ratio (RR) with a 95% confidence interval (CI) was used to assess the short-term efficacy, adverse event (AE), relapse, and long-term survival. A total of seven studies involving 296 patients were identified. The pooled RRs for short-term effectiveness, AE, relapse, and long-term survival rate in patients treated with biological agents versus systemic corticosteroids were 1.37 (95% CI 0.95-1.97; I2 = 82%; P = 0.09), 0.54 (95% CI 0.39-0.73; I2 = 13%; P = 0.005), 1.36 (95% CI 0.95-1.96; I2 = 16.8%; P = 0.19), and 1.08 (95% CI 0.95-1.21; I2 = 48.1%; P = 0.53), respectively. Meta-regression and subgroup analysis revealed that the RRs of efficacy were 2.10 (95% CI 1.61-2.75; I2 = 0%; P < 0.00001) for rituximab and 2.07 (95% CI 1.61-2.67; I2 = 0%; P < 0.00001) for sample size greater than 30. Compared with conventional therapy, biologics treatment was significantly associated with fewer adverse events (P < 0.05), but no significant differences were found for efficacy and relapse (P > 0.05). The findings demonstrate that a biologics-containing regimen could minimize the occurrence of AEs and might display a comparable efficacy and recurrence to that of receiving systemic corticosteroids.

510 Outcomes for Patients with SJS/TENS with Diabetes Compared to other Comorbid Conditions

Abstract Introduction Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN Overlap Syndrome are on the same spectrum of severe blistering skin diseases that affect the skin and mucosal surfaces of the body. They have an immunological etiology and are caused by toxins, drugs, or infectious agents. The mortality rate for patients with these conditions is high, but there is limited research on the outcomes for those patients with additional comorbidities. This study investigates the association of inflammatory conditions such as diabetes mellitus, obesity, and tobacco usage have on the outcomes of patients with SJS or related disease. It was predicted that each of these comorbidities would be associated with higher rates of mortality and disease complications. Methods This study is a retrospective observational cohort study using a commercially available large database, which provides deidentified electronic medical data from health care organizations all over the world. Our database was used to perform a search and analysis for patients with SJS, SJS-TEN Overlap Syndrome, and TEN as well diabetes mellitus (DM), tobacco usage (TU), or overweight/obesity status. A fourth, control cohort of patients without any comorbidities was also included. In total, 8,962 patients were included in the study: 6,348 patients in the control group; 426 patients in the TU group; 1,186 patients in the DM group, and 1,002 patients in the Obesity group. Outcome variables measured were rate and incidence of pneumonia, sepsis, and endotracheal intubation. Outcome variables from each of the four cohorts were analyzed with a total of six unique comparisons. Results Compared to the control group, the DM group had a mortality rate 14.3% higher (CI 95%, 11.8% -16.9%), pneumonia rate 7.6% higher (CI 95%, 5.4%-9.9%), sepsis rate 4.7% higher (CI 95%, 6.9%-11.4%), and endotracheal intubation rate of 1.9% higher (CI 95%, 0.8%-3.0%). Furthermore, compared to the Obesity group, the DM group had a mortality rate 11.6% higher (CI 95%, 8.5%- 14.8%) and sepsis rate 4.7% higher (CI 95%, 1.7%-7.6%). Compared to the TU group, the DM group had a mortality rate 12.4% higher (CI 95%, 8.5%- 16.3%) and sepsis rate 8.1% higher (CI 95% 4.7%-11.6%). Besides this data on the DM group, the Obesity group showed statistically significant worse outcomes as well. Compared to the control group, the Obesity group showed a mortality rate 2.7% higher (CI 95%, 0.5%-4.9%), pneumonia rate 5% higher (CI 95%, 2.7%-7.3%), sepsis rate 4.5% higher (CI 95%, 2.3%-6.6%), and intubation rate of 2.1% higher (CI 95%, 0.8%-3.4%). Conclusions Using a large multi-institutional database, Diabetes mellitus is associated with worse outcomes for patients with SJS, SJS-TEN overlaps, or TEN compared to obesity and tobacco usage. Applicability of Research to Practice This data argues the importance of examining a patient’s past medical history when evaluating their prognosis for SJS, SJS-TEN overlaps or TEN.

757 Diabetes Mellitus Associated with Worse Outcomes in Stevens-Johnson Syndrome and Related Diseases

Abstract Introduction Stevens-Johnson Syndrome(SJS),toxic epidermal necrolysis(TEN), and SJS/TEN Overlap Syndrome are on the same spectrum of severe blistering skin diseases affecting mucosal surfaces of the body.They have an immunological etiology and are caused by toxins, drugs, or infectious agents. The mortality rate for patients with these conditions ishigh, but there is limited research on the outcomes for those patients with additional comorbidities.This study investigates the association of inflammatory conditions such as diabetes mellitus, obesity, and tobacco usage have on the outcomes of patients with SJS or related disease. It was predicted that each of these comorbidities would be associated with higher rates of mortality and disease complications. Methods This study is a retrospective observational cohort study using the TriNetX Research Network, which provides deidentified electronic medical data from health care organizations all over the world. TriNetX was used to perform a search and analysis for patients with SJS, SJS-TEN Overlap Syndrome, and TEN as well diabetes mellitus(DM), tobacco usage(TU), or overweight/obesity status.A fourth, control cohort of patients without any comorbidities was also included. In total, 8,962 patients were included in the study: 6,348patientsin the control group;426 patients in the TU group; 1,186 patients in the DMgroup, and 1,002 patients in the Obesity group. Outcomes measured were rate and incidence of pneumonia, sepsis, and endotracheal intubation. Outcome variables from each of the four cohorts were analyzed with a total of six unique comparisons. Statistical analyses used included measure of association, Kaplan-Meyer Survival Curve, and measure of incidence. Results Compared to the control group, the DM group had a mortality rate14.3% higher(CI 95%, 11.8% -16.9%), pneumonia rate7.6% higher (CI 95%, 5.4%-9.9%), sepsis rate 4.7% higher (CI 95%, 6.9%-11.4%), and endotracheal intubation rate of 1.9% higher (CI 95%, 0.8%-3.0%). Furthermore,compared to the Obesity group, the DM group had a mortality rate 11.6% higher (CI 95%, 8.5%-14.8%)and sepsis rate 4.7% higher (CI 95%, 1.7%-7.6%). Compared to the TU group, the DM group had a mortality rate 12.4%higher(CI 95%, 8.5%-16.3%)and sepsis rate 8.1% higher (CI 95% 4.7%-11.6%). Besides this data on the DM group, the Obesity group showed statistically significant worse outcomes as well. Compared to the control group, the Obesity group showed a mortality rate 2.7% higher (CI 95%, 0.5%-4.9%), pneumonia rate 5% higher (CI 95%, 2.7%-7.3%), sepsis rate 4.5% higher (CI 95%, 2.3%-6.6%), and intubation rate of 2.1% higher (CI 95%, 0.8%-3.4%). Conclusions Diabetes mellitus is associated with worse outcomes for patients with SJS, SJS-TEN overlaps, or TEN compared to obesity and tobacco usage. Applicability of Research to Practice This data argues the importance of examining a patient’s past medical history when evaluating their prognosis for SJS, SJS-TEN overlaps or TEN.

A Novel In Vivo Active Pemphigus Model Targeting Desmoglein1 and Desmoglein3: A Tool Representing All Pemphigus Variants.

Background: Pemphigus is a life-threatening blistering autoimmune disease. Several forms, characterized by the presence of autoantibodies against different autoantigens, have been described. In Pemphigus Vulgaris (PV), autoantibodies target the cadherin Desmoglein 3 (DSG3), while in Pemphigus foliaceous (PF) autoantibodies target the cadherin Desmoglein 1 (DSG1). Another variant, mucocutaneous Pemphigus, is characterized by the presence of IgG against both DSG1 and DSG3. Moreover, other forms of Pemphigus characterized by the presence of autoantibodies against other autoantigens have been described. With regard to animal models, one can distinguish between passive models, where pathological IgG are transferred into neonatal mice, and active models, where B cells deriving from animals immunized against a specific autoantigen are transferred into immunodeficient mice that develop the disease. Active models recreate PV and a form of Pemphigus characterized by the presence of IgG against the cadherin Desmocollin 3 (DSC3). Further approaches allow to collect sera or B/T cells from mice immunized against a specific antigen to evaluate the mechanisms underlying the onset of the disease. Objective: To develop and characterize a new active model of Pemphigus where mice express auto antibodies against either DSG1 alone, or DSG1 and DSG3, thereby recapitulating PF and mucocutaneous Pemphigus, respectively. In addition to the existing models, with the active models reported in this work, it will be possible to recapitulate and mimic the main forms of pemphigus in adult mice, thus allowing a better understanding of the disease in the long term, including the benefit/risk ratio of new therapies. Results: The new DSG1 and the DSG1/DSG3 mixed models were developed as proposed. Immunized animals, and subsequently, animals that received splenocytes from the immunized donors produce a high concentration of circulating antibodies against the specific antigens. The severity of the disease was assessed by evaluating the PV score, evidencing that the DSG1/DSG3 mixed model exhibits the most severe symptoms among those analyzed. Alopecia, erosions, and blistering were observed in the skin of DSG1, DSG3 and DSG1/DSG3 models, while lesions in the mucosa were observed only in DSG3 and DSG1/DSG3 animals. The effectiveness of the corticosteroid Methyl-Prednisolone was evaluated in the DSG1 and DSG1/DSG3 models, that showed only partial responsiveness.

Efficacy and safety of dupilumab in bullous pemphigoid: a retrospective multicentric study of 36 patients.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease in Europe and its treatment can be challenging. Several published cases have reported dupilumab efficiency in treatment-refractory patients. We conducted a retrospective multicentric study of 36 patients to evaluate the real-life efficiency of dupilumab in BP. Our results suggest that dupilumab, in association with high-potency topical steroids, could be rapidly effective in various clinical forms of BP and seems to be well tolerated in the elderly.

The Importance of Patient-Focused Drug Development in Pemphigus and Pemphigoid

The Importance of Patient-Focused Drug Development in Pemphigus and Pemphigoid

Bacteriological profile of skin infections in hospitalized patients with pemphigus: A retrospective study of 92 cases

Pemphigus is a rare autoimmune blistering disease affecting the skin and mucosa. Infections are the most frequent complications. One or more bacterial species can be incriminated. The aim of our study was to establish the bacteriological profile of skin infections in patients with pemphigus. This is a retrospective descriptive study spread over a period of 3 years and a half (March 2019 - September 2022) having included patients hospitalized in the dermatology department of the Hassan II University Hospital of Fez for an outbreak of pemphigus with signs of skin infection. During the study period, 92 pus samples from patients with clinically infected pemphigus were received at the microbiology laboratory of the Hassan II University Hospital of Fez. 68% of them were positive with a bacteriologically confirmed infection. The average age of the patients was 53.2 years (20 to 89 years). The sex ratio (female/male) was 1.5. The medical history revealed diabetes in 10 patients (11%). Among the patients included in the study, 16% had at least one infection during their course and 21% of the samples taken were polymicrobial. Most bacterial skin infections detected in our patients were due to Staphylococcus aureus (43% of cases). Our study allowed us to confirm the predisposition to infections in patients with pemphigus. This prompts us to insist on the importance of hygienic care, early diagnosis and treatment of any type of infection.

Mouse models of pemphigus: valuable tools to investigate pathomechanisms and novel therapeutic interventions.

Autoimmune blistering diseases (AIBD) are paradigms of autoantibody-mediated organ-specific autoimmune disorders that involve skin and/or mucous membranes. Compared to other autoimmune diseases, the pathogenicity of autoantibodies in AIBD is relatively well described. Pemphigus is a potentially lethal autoantibody driven autoimmune disorder with a strong HLA class II association. It is mainly characterized by IgG against the desmosomal adhesion molecules desmoglein 3 (Dsg3) and Dsg1. Several murine pemphigus models were developed subsequently, each allowing the analysis of a characteristic feature, such as pathogenic IgG or Dsg3-specific T or B cells. Thus, the models can be employed to preclinically evaluate potentially novel therapies. We here thoroughly summarize past and recent efforts in developing and utilizing pemphigus mouse models for pathomechanistic investigation and therapeutic interventions.

Worldwide epidemiologic factors in pemphigus vulgaris and bullous pemphigoid.

Autoimmune blistering diseases such as bullous pemphigoid (BP) and pemphigus vulgaris (PV) are complex, multifactorial, and polygenic diseases, whose exact pathogenesis is difficult to pinpoint. Research aimed at elucidating the associated epidemiologic risk factors of these two diseases has been hampered by their rare disease status. Further, a lack of centralization and standardization of available data makes the practical application of this information challenging. In order to collate and clarify the available literature we comprehensively reviewed 61 PV articles from 37 different countries and 35 BP articles from 16 different countries addressing a range of disease relevant clinical parameters including age of onset, sex, incidence, prevalence, and HLA allele association. The reported incidence of PV ranged from 0.098 to 5 patients per 100,000 people, while BP ranged from 0.21 to 7.63 patients per 100,000. Prevalence of PV ranged from 0.38 to 30 per 100,000 people and BP ranged from 1.46 to 47.99 per 100,000. The mean age of onset in patients ranged from 36.5 to 71 years for PV and 64 to 82.6 years for BP. Female-to-male ratios ranged from 0.46 to 4.4 in PV and 1.01 to 5.1 in BP. Our analysis provides support for the reported linkage disequilibrium of HLA DRB1*0402 (an allele previously shown to be associated with PV) and DQB1*0302 alleles in Europe, North America, and South America. Our data also highlight that HLA DQB1*0503 (also known to be associated with PV) appears in linkage disequilibrium with DRB1*1404 and DRB1*1401, mainly in Europe, the Middle East, and Asian countries. The HLA DRB1*0804 allele was only associated with PV in patients of Brazilian and Egyptian descent. Only two HLA alleles were reported as associated with BP more than twice in our review, DQB1*0301 and DQA1*0505. Collectively, our findings provide detailed insights into the variation of disease parameters relevant to PV and BP that can be expected to inform future work aimed at unraveling the complex pathogenesis of these conditions across the globe.

Pruritic crusted lesions in an 89‐year‐old woman

Pruritic crusted lesions in an 89‐year‐old woman

Retrospective analysis of the long-term therapeutic effectiveness and safety profile of rituximab in the treatment of mucous membrane pemphigoid in a German university center between 2008 and 2019.

The B-cell-depleting anti-CD20 antibody rituximab (RTX) is often used as an adjuvant drug for the treatment of refractory cases of mucous membrane pemphigoid (MMP). This study aims to determine the therapeutic effectiveness and the safety profile of RTX in MMP. The medical records of all cases of MMP treated with RTX between 2008 and 2019 in our university medical center located in northern Germany, which specialized in autoimmune blistering skin diseases, were retrieved and systemically analyzed for treatment responses and potential adverse events over a median period of 27 months. We identified 18 MMP patients who received at least one cycle of RTX to treat MMP. RTX was always used as an adjuvant treatment, and its application did not change concomitant treatments. Under treatment with RTX, 67% of the patients achieved an improvement in their disease activity within 6 months. This was also reflected in a statistically significant reduction in the Mucous Membrane Pemphigoid Disease Index (MMPDAI) activity score. The frequency of infections under RTX treatment increased only slightly. The use of RTX is associated with an attenuation of MMP in a large proportion of MMP patients in our study. At the same time, its application was not found to further increase the susceptibility of the most strongly immunocompromised population of MMP patients to opportunistic infections. Collectively, our results suggest that the potential benefits of RTX outweigh its risks in patients with refractory MMP.

Erosive and ulcerative stomatitis in dogs and cats: which immune-mediated diseases to consider?

Immune-mediated and autoimmune diseases of the skin often present with oral cavity involvement. Autoimmune subepidermal blistering diseases and pemphigus vulgaris are classic examples. While the primary lesions (vesicles and bullae) are relatively specific, these fragile lesions evolve rapidly into erosions and ulcers, which are lesion types that overlap with many diseases. Furthermore, some immune-mediated diseases such as severe adverse drug reactions, lupus diseases, canine uveodermatological syndrome, and vasculitis, may or may not involve the oral cavity, and often nonoral clinical manifestations are more diagnostic. In these situations, disease knowledge combined with signalment, lesion distribution, and history help to narrow the differentials. Surgical biopsy is required for confirmation in most diseases, while immunosuppressive treatments most typically involve glucocorticoids with or without nonsteroidal immunosuppressants.

ASSOCIATION BETWEEN PEMPHIGUS AND PSORIASIS: A SYSTEMATIC REVIEW

Pemphigus vulgaris, foliaceus, paraneoplastic, IgA, and herpetiformis are autoimmune bullous diseases. Epidemiologically heterogeneous symptoms characterize pemphigus. The first non-HLA genes related with PV have been found, and our knowledge of pemphigus frequency, which varies widely between populations, has increased. Pemphigus causes blisters and lesions. This polymorphism is also linked to many comorbidities, including autoimmune illnesses, hematological malignancies, and psoriasis. Psoriasis is a T cell-mediated papulosquamous skin illness that results from immune system dysregulation. It is characterized by severe inflammatory and hyperproliferative alterations in the affected areas of the skin. Psoriasis has traditionally been linked to bullous pemphigoid, which is a subepidermal autoimmune bullous illness. Pemphigus is a group of IgG-mediated blistering diseases that affect the skin and mucous membranes' squamous epithelium. Pemphigus causes painful intraepidermal blisters and erosions. Pemphigus disease is chronic and autoimmune, which has increased research into its link with other autoimmune and autoinflammatory disorders. Pemphigus and psoriasis have been reported to co-occur, however their relationship is uncertain. Yet, there are also additional biological plausible reasons for this link. The "epitope spreading phenomena" may have caused the disease. This occurs when a primary autoimmune or inflammatory response damages tissue. Hence, the immune system can now detect some protein components, triggering a subsequent autoimmune reaction. Psoriasis patients are three times more likely to develop pemphigus. Psoriasis doctors should know about this epidemiological trend.

390 Examining the risk factors for worsened glucocorticoid morbidity in a prospective, multicentre, international study of patients with autoimmune blistering diseases

390 Examining the risk factors for worsened glucocorticoid morbidity in a prospective, multicentre, international study of patients with autoimmune blistering diseases

848 Generality and heterogeneity of HLA associations in autoimmune blistering disease spectrum

848 Generality and heterogeneity of HLA associations in autoimmune blistering disease spectrum