Risk factors and sequelae of epidermolysis bullosa acquisita: A propensity-matched global study in 1,344 patients

Identification of risk factors and sequelae of any given disease is of key importance. For common diseases, primary prevention and disease management are based on this knowledge. For orphan diseases, identification of risk factors and sequelae has been challenging. With the advent of large databases, e.g., TriNetX, this can now be addressed. We used TriNetX to identify risk factors and sequelae of epidermolysis bullosa acquisita (EBA), a severe and orphan autoimmune disease. To date, there is only enigmatic information on EBA comorbidity. We recruited 1,344 EBA patients in the Global Collaborative Network of TriNetX. Using the “explore outcomes” function we identified 55 diagnoses with a different prevalence between EBA and no-EBA patients. We next performed propensity-matched, retrospective cohort studies in which we determined the risk of EBA development following any of the identified 55 diseases. Here, 31/55 diseases were identified as risk factors for subsequent EBA. Importantly, the highest risk for EBA were other chronic inflammatory diseases (CID), especially lupus erythematosus and lichen planus. Lastly, we determined the risk to develop any of the identified diseases after EBA diagnosis. Here, 38/55 diseases were identified as sequelae. Notably, EBA patients showed an increased risk for metabolic and cardiovascular disease, and thrombosis. Furthermore, the risk for CIDs, especially lupus erythematosus and lichen planus, was elevated. These insights into risk factors and sequelae of EBA are not only of clinical relevance, e.g., optimizing cardiovascular disease risk, but in addition, point to shared pathogenetic pathways between EBA and other inflammatory diseases

The Usefulness of Indirect Immunofluorescence in Pemphigus and the Natural History of Patients With Initial False-Positive Results: A Retrospective Cohort Study

The specificity and the predictive values of indirect immunofluorescence (IIF) in real-life settings is yet to be firmly established. The natural history of patients with false-positive results has not been sufficiently elucidated. The primary aim of the current study is to evaluate the diagnostic value of IIF analysis on monkey esophagus in pemphigus, utilizing a large cohort arising from the real-life experience of a tertiary referral center. The secondary endpoint was to determine the clinical outcomes of patients with false-positive results. This was a retrospective cohort study including all patients who were tested for the presence of intercellular autoantibodies by IIF on monkey esophagus between 2000 and 2017. Overall, 770 sera from different individuals were tested by IIF microscopy. Of those, 176 patients had been diagnosed with pemphigus vulgaris (PV) and 29 patients with pemphigus foliaceus (PF). The sensitivity of this immunoassay was significantly higher for the diagnosis of PV (87.4%; 95% CI, 81.5–91.9%) as compared to PF (69.0%; 95% CI, 49.2–84.7%; P = 0.018). The specificity for the diagnosis of pemphigus was 93.5% (95% CI, 91.1–95.4%). Patients with false-positive results (n = 37) were followed for a median duration of 5.3 years contributing 280.8 person-years. Thirty patients (81.1%) were eventually diagnosed clinically and immunopathologically with subepidermal autoimmune bullous diseases, whereas the remaining patients (18.9%) were diagnosed clinically and histologically with other inflammatory dermatoses, but none of them developed pemphigus during the follow-up duration. Of note, 7.0% (n = 23) of all patients diagnosed with bullous pemphigoid (BP) in the same period (n = 328) were tested positive for IgG intercellular antibodies. Histopathological review of the biopsy specimens of these patients did not reveal acantholysis. In conclusion, the predictive value of negative test in IIF on monkey esophagus is particularly reliable to exclude a diagnosis of pemphigus. Individuals tested positive for intercellular antibodies without an initial overt pemphigus did not show an increased risk for developing pemphigus subsequently. A sizable fraction of patients with BP showed circulating intercellular autoantibodies by IIF, without a histopathological evidence for acantholysis

Poly-β-(1→6)-N-acetyl-D-glucosamine mediates surface attachment, biofilm formation, and biocide resistance in Cutibacterium acnes

BackgroundThe commensal skin bacterium Cutibacterium acnes plays a role in the pathogenesis of acne vulgaris and also causes opportunistic infections of implanted medical devices due to its ability to form biofilms on biomaterial surfaces. Poly-β-(1→6)-N-acetyl-D-glucosamine (PNAG) is an extracellular polysaccharide that mediates biofilm formation and biocide resistance in a wide range of bacterial pathogens. The objective of this study was to determine whether C. acnes produces PNAG, and whether PNAG contributes to C. acnes biofilm formation and biocide resistance in vitro.MethodsPNAG was detected on the surface of C. acnes cells by fluorescence confocal microscopy using the antigen-specific human IgG1 monoclonal antibody F598. PNAG was detected in C. acnes biofilms by measuring the ability of the PNAG-specific glycosidase dispersin B to inhibit biofilm formation and sensitize biofilms to biocide killing.ResultsMonoclonal antibody F598 bound to the surface of C. acnes cells. Dispersin B inhibited attachment of C. acnes cells to polystyrene rods, inhibited biofilm formation by C. acnes in glass and polypropylene tubes, and sensitized C. acnes biofilms to killing by benzoyl peroxide and tetracycline.ConclusionC. acnes produces PNAG, and PNAG contributes to C. acnes biofilm formation and biocide resistance in vitro. PNAG may play a role in C. acnes skin colonization, biocide resistance, and virulence in vivo

Pathogenic Activation and Therapeutic Blockage of FcαR-Expressing Polymorphonuclear Leukocytes in IgA Pemphigus

Pathomechanisms in IgA pemphigus are assumed to rely on Fc-dependent cellular activation by antigen-specific IgA autoantibodies; however, models for the disease and more detailed pathophysiologic data are lacking. In this study, we aimed to establish in vitro models of disease for IgA pemphigus, allowing us to study the effects of the interaction of anti-keratinocyte IgA with cell surface FcαRs. Employing multiple in vitro assays, such as a skin cryosection assay and a human skin organ culture model, in this study, we present mechanistic data for the pathogenesis of IgA pemphigus, mediated by anti–desmoglein 3 IgA autoantibodies. Our results reveal that this disease is dependent on FcαR-mediated activation of leukocytes in the epidermis. Importantly, this cell-dependent pathology can be dose-dependently abrogated by peptide-mediated inhibition of FcαR:IgA-Fc interaction, as confirmed in an additional model for IgA-dependent disease, that is, IgA vasculitis. These data suggest that IgA pemphigus can be modeled in vitro and that IgA pemphigus and IgA vasculitis are FcαR-dependent disease entities that can be specifically targeted in these experimental systems

S2k guidelines on the management of paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND Paraneoplastic pemphigus (PNP), also called paraneoplastic autoimmune multiorgan syndrome (PAMS), is a rare autoimmune disease with mucocutaneous and multi-organ involvement. PNP/PAMS is typically associated with lymphoproliferative or haematological malignancies, and less frequently with solid malignancies. The mortality rate of PNP/PAMS is elevated owing to the increased risk of severe infections and disease-associated complications, such as bronchiolitis obliterans. OBJECTIVES These guidelines summarize evidence-based and expert-based recommendations (S2k level) for the clinical characterization, diagnosis and management of PNP/PAMS. They have been initiated by the Task Force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology with the contribution of physicians from all relevant disciplines. The degree of consent among all task force members was included. RESULTS Chronic severe mucositis and polymorphic skin lesions are clue clinical characteristics of PNP/PAMS. A complete assessment of the patient with suspected PNP/PAMS, requiring histopathological study and immunopathological investigations, including direct and indirect immunofluorescence, ELISA and, where available, immunoblotting/immunoprecipitation, is recommended to achieve a diagnosis of PNP/PAMS. Detection of anti-envoplakin antibodies and/or circulating antibodies binding to the rat bladder epithelium at indirect immunofluorescence is the most specific tool for the diagnosis of PNP/PAMS in a patient with compatible clinical and anamnestic features. Treatment of PNP/PAMS is highly challenging. Systemic steroids up to 1.5 mg/kg/day are recommended as first-line option. Rituximab is also recommended in patients with PNP/PAMS secondary to lymphoproliferative conditions but might also be considered in cases of PNP/PAMS associated with solid tumours. A multidisciplinary approach involving pneumologists, ophthalmologists and onco-haematologists is recommended for optimal management of the patients. CONCLUSIONS These are the first European guidelines for the diagnosis and management of PNP/PAMS. Diagnostic criteria and therapeutic recommendations will require further validation by prospective studies

The Growing Incidence of Bullous Pemphigoid: Overview and Potential Explanations

Bullous pemphigoid (BP) is the most common type of subepidermal autoimmune bullous diseases. BP characteristically affects the elderly and is seen mainly in patients older than 70 years. While the annual incidence of BP has been estimated to be between 2.4 and 23 cases per million in the general population, it rises exponentially to 190–312 cases per million in individuals older than 80 years. In addition, a growing body of evidence reports a remarkable trend of increased incidence of BP, showing a 1.9- to 4.3-fold rise over the past two decades. This demonstrable increase warrants a higher awareness of the increased risk to develop BP. This review summarizes the current understanding of the epidemiological features of BP and sheds light on the putative explanations for its growing incidence

Pemphigus Vulgaris and Pemphigus Foliaceus: Differences in Epidemiology and Mortality

Little is known about differences in epidemiological features and prognosis between pemphigus vulgaris (PV) and pemphigus foliaceus (PF). The objective of this study was to compare PV and PF patients regarding ethnic variations and mortality rates. Mortality of PV and PF patients was compared with age- and sex-matched control subjects in the general population. The study cohort comprised 207 patients with PV and 30 with PF diagnosed during the period 2000 to 2015. The incidence rate of PV among Jews was 3.6-fold higher than among Arabs (p < 0.001), whereas no ethnic predisposition to PF was noted (p = 0.379). The risk of death for patients with PV was almost 3-fold higher than in the general population (standardized mortality ratio (SMR) 2.6). For patients with PF, the risk of mortality was not significantly increased relative to the general population (SMR 1.4). There is a racial predisposition to PV, whereas PF is sporadic. Mortality among patients with PV is higher compared with PF and the general population