Bullous Pemphigoid-Associated Mortality Rate in a Canadian Tertiary Referral Centre.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disorder in adults. Most individuals with BP are over the age of 60. Its worldwide incidence has been increasing owing to population aging. Observational studies published over the last 2 decades highlight the non-negligible, albeit variable overall mortality of BP patients, with reported 12-month mortality rates of 10.8% to 40.8%, and 24-month mortality rates of 20.1% to 51.0%. Data in the Canadian population are lacking. OBJECTIVES: We aimed to estimate the 12- and 24-month overall mortality rate of Canadian patients diagnosed with BP, and to identify independent risk factors adversely impacting overall survival. METHODS: A retrospective cohort study of 166 patients with a diagnosis of BP between 2010 and 2020 was carried out at Centre hospitalier de l'Université de Montréal (CHUM), a tertiary referral center in Montréal, Québec, Canada. Cumulative mortality was calculated using the Kaplan-Meier estimator, and independent prognostic factors were identified using a Cox proportional hazards regression model. RESULTS: Eighty-five patients (51.2%) in our study were female. The median age was 79.1 years old, and 80 patients (48.2%) were 80 years old or older. Mortality at 12 and 24 months in our study cohort was 16.2% (CI95% = 10.5 - 21.8) and 27.6% (CI95% = 20.5 - 34.7), respectively. In a multivariate analysis, patients who were male, 80 years old or older, and/or had a diagnosis of a major neurocognitive disorder had a poorer overall survival. CONCLUSIONS: The all-cause mortality of patients with BP in our study population compared favorably with international data reported in the literature.

Intraepithelial autoimmune bullous dermatoses disease activity assessment and therapy.

Intraepithelial autoimmune blistering dermatoses are a rare group of skin disorders characterized by disruptions of inter-keratinocyte connections within the epidermis through the action of autoantibodies. The second article in this continuing medical education series presents validated disease activity scoring systems, serologic parameters of disease, treatments, and clinical trials for pemphigus and its subtypes.

Subepithelial autoimmune bullous dermatoses disease activity assessment and therapy.

Subepidermal (subepithelial) autoimmune blistering dermatoses are a group of rare skin disorders characterized by the disruption of the dermal-epidermal junction through the action of autoantibodies. The fourth article in this continuing medical education series presents the current validated disease activity scoring systems, serologic parameters, treatments, and clinical trials for bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, bullous systemic lupus erythematosus, anti-p200 pemphigoid, linear IgA bullous dermatosis, and dermatitis herpetiformis.

In vitro and in vivo models to investigate the pathomechanisms and novel treatments for pemphigoid diseases.

Pemphigoid diseases (PD) are a subgroup of rare acute or chronic autoimmune skin disorders characterized and caused by autoantibodies directed against distinct structural components of the dermal-epidermal junction. Binding of autoantibodies to their targets leads to the formation of blisters and erosions in patients. PDs comprise eight disorders for which the molecular target antigens have been identified. First, we review the available in vitro and ex vivo models for analysis of distinct aspects of the pathogenesis of PDs. This includes the binding of autoantibodies to skin sections, the analysis of blister formation capability and skin complement activation as well as investigation of neutrophil and keratinocyte activation. In addition to this, several animal models of PD have been developed during the last decades. These animal models have greatly contributed to our current understanding of the pathogenesis of PDs. We summarize spontaneously arising PD in animals and the induction of PD by transfer of (auto)antibodies, transfer of (auto)-antigen-specific lymphocytes and by immunization. In combined use, these models allow dissecting all aspects of PD pathogenesis, for example loss of tolerance, autoantibody production and inflammatory skin processes that lead to blister formation. Overall, we aimed to foster translational biomedical research, to deepen our understanding of PD pathogenesis and to develop novel treatments for patients suffering from these life-threatening and difficult-to-treat autoimmune diseases.

Epidemiological Study of Autoimmune Bullous Dermatoses in Northeastern Romania.

BACKGROUND: Autoimmune bullous diseases (ABDs) are a rare but significant group of dermatoses that pose great challenges to the treating dermatologist. ABDs are characterized by the presence of tissue-bound and circulating autoantibodies directed against disease-specific target antigens of the skin. Most epidemiological studies have focused on a single ABD. More than that, there are few data about the incidence and prevalence of autoimmune blistering diseases in Romania. METHODS: In this study, between 2015 and 2019, we retrospectively investigated a total of 225 patients with autoimmune bullous diseases from the northeastern region of Romania. The diagnosis was based on the clinical and histo- and immunohistological findings. RESULTS: Pemphigus was the most frequently encountered ABD, with an incidence of 8.16/1,000,000 inhabitants, representing 58.7% (132 cases), followed by 24% cases of bullous pemphigoid (54 cases), 15.4% of patients were diagnosed with dermatitis herpetiformis (37 cases), and 0.9% other subepidermal autoimmune bullous dermatoses. The average age of onset of pemphigus vulgaris was 59.4 years, the majority of patients being male, while the average age of patients diagnosed with bullous pemphigoid was 73.8 years, the majority being female. CONCLUSIONS: Pemphigus vulgaris is the most frequently encountered ABDs in the northeast of Romania, with a higher incidence than in Western European countries, and this may be due to specific peculiarities of the geographical area, as well as to a genetic susceptibility of the population in this region.

Concordance of Clinical, Histologic and Direct Immunofluorescence Findings in Patients with Autoimmune Bullous Dermatoses in Vietnam.

Introduction: Autoimmune bullous dermatoses (ABD) represent a heterogeneous group of blistering disorders that may be debilitating with high morbidity. Clinical, histological, and direct immunofluorescence (DIF) studies are essential in establishing an accurate diagnosis of ABD, which is essential for its clinical management. Our study objective was to perform a systematic evaluation of ABD cases in a patient population at an academic medical center in Ho Chi Minh City, Vietnam, and determine the degree of concordance of clinical, histological, and DIF findings in ABD. Methodology: A systematic retrospective cross-sectional study was performed on 92 patients diagnosed with ABD by clinical, histological, and DIF studies at the University of Medicine and Pharmacy in Ho Chi Minh City, Vietnam, between September 2019 and September 2021. The clinical histories, H and E stained tissue sections, and DIF stains were evaluated by pathologists at the University of Medicine and Pharmacy. Results: ABD was evaluated as a whole and subdivided into an intraepidermal blister subgroup and a subepidermal blister subgroup. The analysis of paired diagnostic methods (clinical, histological, and DIF) for concordance with the final diagnosis was performed and showed that there were no statistically significant differences between the paired methods (McNemar's test, p > 0.05). There was moderate concordance between the clinical, histological, and DIF diagnoses among all ABD cases (Brennan-Prediger coefficient Kappa test, κBP = 0.522, CI = 0.95). In the intraepidermal blister subgroup, the diagnostic accuracies of the histology and DIF stains were comparable to each other, and both were more accurate than a clinical diagnosis alone. In the subepidermal blister subgroup, there was no statistically significant difference in each pair of the three diagnostic methods (clinical, histological, and DIF) (McNemar's test, p > 0.05). The concordance between the clinical, histological, and DIF diagnoses was high for the intraepidermal blister subgroup (Kappa test, κBP = 0.758, CI = 0.95). However, the concordance between the clinical, histological, and DIF diagnoses was slight for the subepidermal blister subgroup (Kappa test, κBP = 0.171, CI = 0.95). Conclusion: Histological evaluation is highly accurate in the diagnosis of the intraepidermal blister subgroup, but it is not as accurate in the diagnosis of the subepidermal blister subgroup in the Vietnamese patient cohort in which clinical, histological, and DIF studies were performed. DIF stains are a crucial diagnostic tool for ABD in this patient population.

Paraneoplastic Pemphigus Mimicking Pemphigus Vulgaris Associated With Castleman Disease.

Paraneoplastic pemphigus (PNP) is a rare bullous disease with a polymorphic presentation. Diagnosis can be difficult because it can mimic other bullous diseases, while the underlying neoplasm may be completely asymptomatic. We present the case of a 19-year-old female with a four-year history of exclusively oral bullous lesions, mimicking pemphigus vulgaris, before the diagnosis of a retroperitoneal Castleman disease. While PNP is a severe and sometimes deadly condition, our patient had a mild and long evolution on minimal treatment, with complete resolution after tumor excision. Practitioners should be aware of PNP in young patients presenting with bullous disease and should conduct prompt systemic investigations in refractory or long-evolving cases, even when PNP diagnostic criteria are not fully met.

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.

Management Options for Linear Immunoglobulin A (IgA) Bullous Dermatosis: A Literature Review.

Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is an autoimmune condition with various triggers. Because of the lack of randomized controlled trials on LABD treatment, management options are mostly anecdotal. This paper provides a comprehensive review of treatment options from a literature review of reported treatments to arm clinicians with a guideline for the management of LABD in both pediatric and adult patients as well as those recalcitrant to first-line therapy (dapsone and steroids). We additionally illustrate an algorithm to use for the management of LABD to aid clinicians when faced with unique patient circumstances.

The Role of VD/VDR Signaling Pathway in Autoimmune Skin Diseases.

BACKGROUND: Immune-related cutaneous diseases are a series of disorders, such as alopecia areata, psoriasis, atopic dermatitis, systemic lupus erythematosus and autoimmune bullous dermatoses. Vitamin D is a fat-soluble vitamin, which is known for its classical pleiotropic effect. Recent studies have found that vitamin D, after catalyzed into its biologically active form [1,25(OH) 2D], correlated with its receptor, vitamin D receptor, plays a vital role in multiple pathophysiological processes, including immune-related dermatoses. This review mainly summarizes evidence on the role of vitamin D/vitamin D receptor in immune-related cutaneous diseases and the potential therapeutic targets for skin disorders. METHODS: We have carried out a comprehensive literature search in PubMed and Google Scholar databases using keywords like "vitamin D", "vitamin D receptor", "immune", "psoriasis", "atopic dermatitis", "skin", "systemic lupus erythematosus", "alopecia areata" and "autoimmune bullous dermatoses". Only articles related to the topic were included in this review. Conference, patent, graduation thesis and articles without available full text were excluded. RESULTS: Vitamin D/vitamin D receptor is critical for skin in regulating the proliferation and differentiation of keratinocytes, keeping the integrity of the skin barrier as well as maintaining the homeostasis of the "skin's immune system". Vitamin D deficiency/vitamin D receptor mutations are potential risk factors for some immune-related cutaneous diseases. CONCLUSION: Vitamin D is a pleiotropic hormone, which is important in the homeostasis of human body. Many studies have revealed vitamin D deficiency in several skin diseases. Thus, vitamin D supplementation may be a useful therapeutic option for immune-related skin diseases.

Vitamin D status in patients with autoimmune bullous dermatoses: a meta-analysis.

BACKGROUND: The association between autoimmune bullous dermatoses (AIBD) and serum vitamin D levels has been revealed by some studies, however, inconsistent. OBJECTIVES: We aimed to evaluate the difference in vitamin D status between AIBD patients and controls. METHODS: We searched the studies about the vitamin D status of AIBD patients in electronic databases published before January 2020. Mean difference (MD) and 95% confidence intervals (CI) of eligible studies were calculated in meta-analyses of 25(OH)D levels. Pooled odds ratio (OR) and 95%CI were used in analyses of the prevalence of hypovitaminosis D. Different subgroup analyses, sensitivity analyses and publication bias assessment were conducted. RESULTS: We included nine case-control studies in the meta-analysis. Vitamin D level was significantly lower in both pemphigus (MD: -7.02, 95%CI: -10.30 to -3.74) and bullous pemphigoid (BP) (MD: -6.37, 95%CI: -12.15 to -0.58) patients than that in controls. Active pemphigus patients were at higher risk of presenting hypovitaminosis D (OR: 6.95, 95%CI: 1.37-35.25). CONCLUSIONS: Abnormal vitamin D status are more common in AIBD patients than that in general population. Therefore, regular monitoring of vitamin D levels and vitamin D supplementation should be considered as part of the management strategy for AIBD.

Exacerbation of Autoimmune Bullous Diseases After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination: Is There Any Association?

Background and Aim: There have been concerns regarding the potential exacerbation of autoimmune bullous diseases (AIBDs) following vaccination against COVID-19 during the pandemic. In the current study, vaccine safety was evaluated in patients with AIBDs. Methods: In this study, patients with AIBDs were contacted via face-to-face visits or phone calls. Patient demographics, vaccine-related information, pre- and post-vaccine disease status, and complications were recorded. The exacerbation was considered either relapse in the remission/controlled phase of the disease or disease worsening in the active phase. The univariate and multivariate logistic regression tests were employed to determine the potential risk factors of disease exacerbation. Results: Of the patients contacted, 446 (74.3%) reported receiving at least one dose of vaccine injection (54.7% female). Post-vaccine exacerbation occurred in 66 (14.8%) patients. Besides, there were 5 (1.1%) patients with AIBD diagnosis after vaccination. According to the analysis, for every three patients who received vaccines during the active phase of the disease one experienced disease exacerbation. The rate of disease exacerbation increased by three percent with every passing month from the last rituximab infusion. Active disease in the past year was another risk factor with a number needed to harm of 10. Conclusion: Risk of AIBD exacerbation after the COVID-19 vaccine is not high enough to prevent vaccination. This unwanted side effect, can be reduced if the disease is controlled at the time of vaccination.

Current and Innovated Managements for Autoimmune Bullous Skin Disorders: An Overview.

Autoimmune bullous skin disorders are a group of disorders characterized by the formation of numerous blisters and erosions on the skin and/or the mucosal membrane, arising from autoantibodies against the intercellular adhesion molecules and the structural proteins. They can be classified into intraepithelial or subepithelial autoimmune bullous dermatoses based on the location of the targeted antigens. These dermatoses are extremely debilitating and fatal in certain cases, depending on the degree of cutaneous and mucosal involvement. Effective treatments should be implemented promptly. Glucocorticoids serve as the first-line approach due to their rapid onset of therapeutic effects and remission of the acute phase. Nonetheless, long-term applications may lead to major adverse effects that outweigh the benefits. Hence, other adjuvant therapies are mandatory to minimize the potential harm and ameliorate the quality of life. Herein, we summarize the current therapeutic strategies and introduce promising therapies for intractable autoimmune bullous diseases.

Spongiotic reaction patterns in autoimmune bullous dermatoses (Review).

Spongiosis or a spongiotic reaction pattern is the histological hallmark of intercellular epidermal edema, viewed as clear spaces within the epidermis. Although considered a histopathological term, spongiosis has clinical correlations, with the variable degrees of spongiotic reaction leading to different dermatological findings. This review aimed to highlight the spongiotic reactive patterns found in different autoimmune bullous dermatoses, considering the paucity of publications in this domain. The pathogenesis of spongiosis assumes the passage of extravasated edema fluid from the dermis into the epidermis, frequently accompanied by dermal inflammatory cells, and classification of the spongiotic reaction patterns, as well as their associated spongiotic dermatitis, take into consideration the type and distribution of these inflammatory cells. It is mandatory to consider different reactive processes, specific for other skin disorders, which act as simulants of different spongiotic patterns for the diagnosis. Considering the possible transient occurrence, the heterogeneity and non-specificity of the histopathological features of these diseases, the diagnosis is very complex, requiring clinicopathological correlations and additional analyses. A deep insight into spongiosis pathogeny may open the perspectives of a classification refinement of autoimmune bullous dermatoses.

Differentiating Pemphigus Foliaceus From Pemphigus Vulgaris in Clinical Practice.

Pemphigus is a skin condition that causes intraepidermal separation of keratinocytes. Multiple types of pemphigus exist, including pemphigus vulgaris and pemphigus foliaceus. These can be differentiated by histopathology, clinical presentation, appearance of lesions, and antibodies, among other factors. It is important to distinguish between the two because of differences in management and prognosis. Here we present a case of pemphigus foliaceus, as well as a discussion of the key differences between pemphigus foliaceus and vulgaris.

A Case of Severe Bullous Dermatitis With Mixed Bullous Pemphigoid and Pemphigus Vulgaris Cutaneous Manifestations.

Bullous dermatoses include the rare, chronic autoimmune diseases pemphigus vulgaris and bullous pemphigoid. These diseases are traditionally taught to be differentiated by the presence of mucosal lesions (pemphigus vulgaris) and bullae without mucosal involvement (bullous pemphigoid). In the clinical setting, however, these diseases often contain overlapping features that present challenges to care teams without access to dermatologic care and leave patients without a clear treatment pathway. The ability to differentiate these two diseases clinically is imperative as it determines treatment regimens which when applied can mitigate unnecessary morbidity and mortality. Identifying these conditions clinically for the correct treatment also allows providers to rely less on laboratory assessments which are often unavailable or may take considerable time to result. This report details the clinical course of a patient who presented with an undifferentiated bullous dermatitis with features of both pemphigus vulgaris and bullous pemphigoid and aims to highlight the features of presentation which overlap between pemphigus vulgaris and bullous pemphigoid and those which are more characteristic for one over the other.

The Role of Mast Cells in Autoimmune Bullous Dermatoses.

Skin mast cells (MCs), a resident immune cell type with broad regulatory capacity, play an important role in sensing danger signals as well as in the control of the local immune response. It is conceivable to expect that skin MCs regulate autoimmune response and are thus involved in autoimmune diseases in the skin, e.g., autoimmune bullous dermatoses (AIBD). Therefore, exploring the role of MCs in AIBD will improve our understanding of the disease pathogenesis and the search for novel therapeutic targets. Previously, in clinical studies with AIBD, particularly bullous pemphigoid, patients' samples have demonstrated that MCs are likely involved in the development of the diseases. However, using MC-deficient mice, studies with mouse models of AIBD have obtained inconclusive or even discrepant results. Therefore, it is necessary to clarify the observed discrepancies and to elucidate the role of MCs in AIBD. Here, in this review, we aim to clarify discrepant findings and finally elucidate the role of MCs in AIBD by summarizing and discussing the findings in both clinical and experimental studies.

Esophagitis dissecans superficialis and autoimmune bullous dermatoses: A review.

Esophagitis dissecans superficialis (EDS) is a rare and severe endoscopic finding characterized by sloughing of large fragments of esophageal mucosal lining. Although EDS has been reported in association with serious illnesses and certain medications, the pathophysiological association of autoimmune bullous dermatoses with EDS has gained remarkable attention. Among these dermatoses, pemphigus vulgaris and pemphigoid frequently present with various types of esophageal involvement including EDS. We review the pathophysiology and clinical features of this involvement with the presentation of our experiences. The importance of endoscopic evaluation of this entity is discussed.