Mortality Rate of Bullous Pemphigoid in a US Medical Center

All patients at the Medical College of Wisconsin Affiliated Hospitals with a new diagnosis of bullous pemphigoid (BP) between May 1, 1997 and September 1, 2002 were included in this study. The age at onset, date of death or date of last follow-up visit, mode of treatment, co-morbidities, and initial and follow-up hospitalizations were noted. Thirty-eight new patients were identified and complete follow-up data were obtained on 37 of the patients. Patients were followed a minimum of 1 y or until the time of death. The mean duration of follow-up was 20 mo. Kaplan–Meier analysis of our population indicated a 1-y survival probability of 88.96% (standard error 5.21%), with a 95% confidence interval (75.6%, 94.2%). This survival rate was considerably higher than that recently reported in several studies from Europe (29%–41% first year mortality). Although the age at onset and co-morbidities of our patients were similar to those in the European studies, the rate of hospitalization of our patients was much lower than that of patients from Europe (1.5 d per patient vs 11–25 d per patient). This study suggests that differences in practice patterns may be an important factor in the reduced mortality rate in US BP patients compared with Europe

The Anti-Desmoglein 1 Autoantibodies in Pemphigus Vulgaris Sera are Pathogenic

Pemphigus vulgaris and pemphigus foliaceus are two closely related, but clinically and histologically distinct, autoimmune skin diseases. The autoantigens for pemphigus vulgaris and pemphigus foliaceus are desmoglein 3 and desmoglein 1, respectively. The anti-desmoglein 1 antibodies in pemphigus foliaceus and anti-desmoglein 3 antibodies in pemphigus vulgaris are pathogenic as determined by immunoglobulin G passive transfer animal models. More than 50% of pemphigus vulgaris sera also contain anti-desmoglein 1 autoantibodies; however, the pathogenicity of the anti-desmoglein 1 autoantibodies in pemphigus vulgaris remains unknown. In this study, we used soluble recombinant extracellular domains of desmoglein 1 and desmoglein 3 to obtain affinity-purified anti-desmoglein 1 and anti-desmoglein 3 autoantibodies from pemphigus vulgaris sera and examined the pathogenicity of each fraction separately using the passive transfer mouse model. By immunoprecipitation, the purified anti-desmoglein 1 and anti-desmoglein 3 showed no cross-reactivity. The anti-desmoglein 1 autoantibodies in pemphigus vulgaris induced typical pemphigus foliaceus lesions in neonatal mice, whereas the anti-desmoglein 3 fraction induced pemphigus vulgaris-like lesions. In addition, the pathogenic anti-desmoglein 1 and anti-desmoglein 3 autoantibodies in pemphigus vulgaris had predominant IgG4 subclass specificity. These findings suggest that the anti-desmoglein 1 antibodies in pemphigus vulgaris are pathogenic

T Lymphocytes from a Subset of Patients with Pemphigus Vulgaris Respond to Both Desmoglein-3 and Desmoglein-1

Pemphigus vulgaris and pemphigus foliaceus are cutaneous autoimmune diseases characterized by intraepithelial blisters and autoantibodies to desmosomal glycoproteins. The antigens recognized by pemphigus vulgaris and pemphigus foliaceus autoantibodies are desmoglein- 3 (Dsg3) and desmoglein-1 (Dsg1), respectively. Dsg3 and Dsg1 are members of the desmoglein subfamily of the cadherin supergene family of cell adhesion molecules. It has been well documented that a subset of pemphigus vulgaris sera have IgG reactivity to both Dsg1 and Dsg3, suggesting that Dsg1 may also participate in the autoimmune response of these patients. The cellular mechanisms of T cell autoimmunity in these patients, however, are completely unknown. In this study, we tested the proliferative responses of T lymphocytes from eight pemphigus vulgaris patients after incubation with Dsg3 and Dsg1 fusion proteins. The sera of four of these PV patients showed reactivity with both Dsg1 and Dsg3, whereas the remaining four reacted only with Dsg3. We found that T cells obtained from those patients that exhibited the combined Dsg1/Dsg3 autoantibody reactivity showed a proliferative response after exposure to either Dsg1 or Dsg3 fusion proteins. The cellular responses to both of these recombinant proteins were highly specific and restricted to the CD4-positive T cell population. T cells from pemphigus vulgaris patients with no anti-Dsg1 serum reactivity showed a proliferative response to Dsg3, but not to Dsg1. The Dsg1 fusion protein used in this study has minimal sequence homology with Dsg3. Thus, this study provides the first evidence that T cells from a subset of pemphigus vulgaris patients respond to both Dsg1 and Dsg3

Monoclonal Antibody to a 35 kD Epidermal Protein Induces Cell Detachment

A murine monoclonal antibody (ECS-1) was prepared from BALB/c mice immunized with trypsinized cultured human foreskin keratinocytes. The antibody showed a pattern suggestive of intercellular staining on the nucleated layers of normal human epidermis, adult palm, mouse lip epidermis, and cultured human keratinocytes. ECS-1 stained human fetal skin by 9 weeks estimated gestational age. ECS-1 reacted with a 35 kD protein extracted from neonatal foreskin epidermis and cultured human keratinocytes. The protein required Nonidet P-40 or sodium dodecyl sulfate and mercaptoethanol for solubilization. ECS-1 induced epidermal cell detachment which was enhanced by complement. ECS- 1 shares characteristics with human pemphigus antibodies

Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model

Bullous pemphigoid (BP) is a cutaneous autoimmune inflammatory disease associated with subepidermal blistering and autoantibodies against BP180, a transmembrane collagen and major component of the hemidesmosome. Numerous inflammatory cells infiltrate the upper dermis in BP. IgG autoantibodies in BP fix complement and target multiple BP180 epitopes that are highly clustered within a non-collagen linker domain, termed NC16A. Anti-BP180 antibodies induce BP in mice. In this study, we generated a humanized mouse strain, in which the murine BP180NC14A is replaced with the homologous human BP180NC16A epitope cluster region. We show that the humanized NC16A (NC16A+/+) mice injected with anti-BP180NC16A autoantibodies develop BP-like subepidermal blisters. The F(ab′)2 fragments of pathogenic IgG fail to activate complement cascade and are no longer pathogenic. The NC16A+/+ mice pretreated with mast cell activation blocker or depleting of complement or neutrophils become resistant to BP. These findings suggest that the humoral response in BP critically depends on innate immune system players

Perspective From the 5th International Pemphigus and Pemphigoid Foundation Scientific Conference

The 5th Scientific Conference of the International Pemphigus and Pemphigoid Foundation (IPPF), “Pemphigus and Pemphigoid: A New Era of Clinical and Translational Science” was held in Orlando, Florida, on May 15–16, 2018. Scientific sessions covered recent, ongoing, and future clinical trials in pemphigus and bullous pemphigoid, disease activity and quality of life instruments, and the IPPF Natural History Study. Furthermore, the meeting provided an opportunity to hear firsthand from patients, investigators, and industry about their experience enrolling for clinical trials

Definitions and outcome measures for mucous membrane pemphigoid: Recommendations of an international panel of experts

Mucous membrane pemphigoid encompasses a group of autoimmune bullous diseases with a similar phenotype characterized by subepithelial blisters, erosions, and scarring of mucous membranes, skin, or both. Although knowledge about autoimmune bullous disease is increasing, there is often a lack of clear definitions of disease, outcome measures, and therapeutic end points. With clearer definitions and outcome measures, it is possible to directly compare the results and data from various studies using meta-analyses. This consensus statement provides accurate and reproducible definitions for disease extent, activity, outcome measures, end points, and therapeutic response for mucous membrane pemphigoid and proposes a disease extent score, the Mucous Membrane Pemphigoid Disease Area Index