Elevated levels of sCD48 are inversely correlated with markers of disease activity in bullous pemphigoid.

sCD48 is elevated in diseases characterized by IgE and eosinophilia. Thus, serum levels sCD48 were evaluated in relation to clinical characteristics of Bullous pemphigoid (BP) patients. sCD48 levels were determined by ELISA in sera from 26 patients with classic BP and 26 healthy controls. Disease severity scores, differential blood counts, and circulating autoantibody levels were obtained. A correlation analysis was performed to establish relationships between sCD48 and clinical and laboratory markers of disease severity. Overall, circulating levels of sCD48 were significantly elevated in BP patients; however, when stratified based on disease severity, patients with mild-moderate disease had higher levels of sCD48 than those with severe disease. A Spearman's correlation analysis identified an inverse relationship between sCD48 and disease activity, serum BP180 IgE and peripheral eosinophil numbers. Further studies are needed to determine the pathologic relevance of these findings.

Rapid cytologic diagnosis of subcutaneous fat necrosis of the newborn.

Subcutaneous fat necrosis of the newborn is a rare self-limited panniculitis that classically presents within the first few weeks of life. The diagnosis is typically clinical, but some cases require skin biopsy with hematoxylin and eosin stain for confirmation. We report a previously undocumented rapid diagnostic protocol that involves collecting a small amount of exudate from a suppurative lesion, placement onto a slide without fixation, and simply viewing the material under a microscope. This novel and practical method of diagnosis reveals doubly refractile crystals diagnostic of subcutaneous fat necrosis without a biopsy, which may be helpful for rapid diagnosis or use in low resource settings.

Hamartomas and midline anomalies in association with infantile hemangiomas, PHACE, and LUMBAR syndromes.

BACKGROUND/OBJECTIVE: The pathogenesis of infantile hemangiomas (IH), PHACE, and LUMBAR syndromes remains unknown. We aim to describe histopathologic features of midline anomalies associated with IH, including patients with PHACE and LUMBAR syndromes. METHODS: A multicenter retrospective chart review was performed to identify patients with IH, PHACE, and LUMBAR syndrome with histopathologic specimens from sternal or midline anomalies. A total of 18 midline lesions from 13 patients were included. Out of 18, 14 midline lesions underwent both histopathologic and clinical review. Three hamartoma-like chin plaques and one supraumbilical raphe underwent only clinical review. RESULTS: All 13 patients had midline lesions and IH. Histopathologic diagnoses were as follows: rhabdomyomatous mesenchymal hamartoma (3), folliculosebaceous cystic hamartoma (1), fibroepithelial polyp (1), verrucous epidermal hyperplasia with vascular proliferation and fibroplasia (1), congenital midline cervical cleft (1), pericardium with fibrosis (1), fibrous components with increased collagen (1), atrophic skin/membrane (3), angiolipomatous mass with neural components (1), and lipomatous mass (1). Due to the retrospective nature of this study, it was not possible to obtain pathology slides for all midline lesions that had previously been biopsied or resected. We show clinically and histopathologically a new association between PHACE syndrome and rhabdomyomatous mesenchymal hamartoma (RMH), in addition to demonstrating the association between PHACE syndrome and chin hamartomas. We also display histopathologic findings seen in midline lesions resected from LUMBAR patients. CONCLUSION: Rhabdomyomatous mesenchymal hamartoma is thought to be related to aberrations of mesenchymal cells during development; therefore, this may provide clues to the pathogenesis of IH and related syndromes.

A cross-sectional survey and analysis of Dermatology Foundation Career Development Award recipients.

BACKGROUND: The Dermatology Foundation (DF) has a comprehensive career development award (CDA) program. OBJECTIVE: To assess the impact of this program, a cross-sectional survey of recipients receiving support between 1990 and 2012 was performed. METHODS: Award recipients completed a questionnaire concerning their career status and record of research funding. To verify the self-reported funding data, information about each awardee was extracted from the National Institutes of Health Research Portfolio Online Reporting Tools database and used to define funding acquired by CDA recipients. RESULTS: In all, 84% of CDA recipients responded to the survey. A total of 213 awardees (79%) hold full- or part-time positions in academic medicine. Approximately 70% of the award recipients in academic medicine have received federal research funding. The National Institutes of Health Research Portfolio Online Reporting Tools database and other sources indicated that the funding acquired by CDA recipients through 2015 and 2017 amounted to approximately $365.4 million and $451.8 million, respectively. Each dollar of DF CDA funding through 2015 (ie, $36.2 million) was linked to more than $10 in grant support through 2015 and $12 through 2017. LIMITATIONS: This cross-sectional survey was retrospective and (in part) self-reported. CONCLUSIONS: The DF has succeeded in supporting the career development of basic, translational, and clinical investigators and fostered the promotion and retention of these individuals in academic medicine.

Eosinophil localization to the basement membrane zone is autoantibody- and complement-dependent in a human cryosection model of bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by antibodies (IgG and IgE) targeting cell-substrate adhesion proteins. A variety of BP models suggest that autoantibody-dependent neutrophil degranulation is essential for blister formation. However, lesional biopsies reveal a predominance of eosinophils and few neutrophils. Our goal was to evaluate the role of antibodies and complement in eosinophil localization, degranulation and split formation at the dermo-epidermal junction (DEJ) utilizing a human skin cryosection model of BP paired with a human eosinophilic cell line, 15HL-60. Expression of receptors for IgG (FcγRII), IgE (FcεRI) and complement (CR1 and CR3) was confirmed on 15HL-60 cells using flow cytometry. 15HL-60 expression of granule protein [eosinophil derived neurotoxin (EDN) and eosinophil peroxidase (EPO)] mRNA and their degranulation in vitro was confirmed using RT-PCR and ELISA, respectively. For cryosection experiments, BP or control sera or IgG and IgE antibodies purified from BP sera were utilized in combination with 15HL-60 cells ± fresh complement. Both BP serum and fresh complement were required for localization of 15-HL60 cells to the DEJ. Interestingly, eosinophil localization to the DEJ was dependent on IgG, but not IgE, and complement. However, no subepidermal split was observed. Additionally, the 15HL-60 cells did not degranulate under any experimental conditions and direct application of cell lysate to cryosections did not result in a split. Our observation that eosinophil localization to the DEJ is dependent on IgG mediated complement fixation provides additional insight into the sequence of events during the development of BP lesions.

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.

Optimization of impedance spectroscopy techniques for measuring cutaneous micropore formation after microneedle treatment in an elderly population.

PURPOSE: The objective of this study was to optimize a reproducible impedance spectroscopy method in elderly subjects as a means to evaluate the effects of microneedles on aging skin. METHODS: Human volunteers were treated with microneedles at six sites on the upper arm. Repeated impedance measurements were taken pre- and post-microneedle insertion. Two electrode types were evaluated (dry vs. gel), using either light or direct pressure to maintain contact between the electrode and skin surface. Transepidermal water loss (TEWL) was measured as a complementary technique. RESULTS: Five control subjects and nine elderly subjects completed the study. Microneedle insertion produced a significant decrease in impedance from baseline in all subjects (p < 0.05, regardless of electrode type or pressure application), confirming micropore formation. This was supported by a complementary significant increase in TEWL (p < 0.05). The gel*direct condition produced the lowest variability between measurements, as demonstrated by a coefficient of variation of 3.8% and 3.5% (control and elderly subjects, respectively). This was lower than variation between TEWL measurements at the same sites: 19.8% and 21.6% (control and elderly subjects, respectively). CONCLUSIONS: Impedance spectroscopy reproducibly measures micropore formation in elderly subjects, which will be essential for future studies describing microneedle-assisted transdermal delivery in aging populations.

Omalizumab therapy for bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) responds to a variety of immunosuppressive agents and usually controls, but does not cure, the disease. Omalizumab, Food and Drug Administration-approved for asthma, selectively suppresses the activity of IgE, an important immunoglobulin in the pathogenesis of BP. OBJECTIVE: We wished to determine if systemic omalizumab would have a therapeutic effect in patients with BP. METHODS: We treated 6 patients with BP using omalizumab and followed up their disease for up to 42 months. RESULTS: Although variable, 5 of the 6 patients with BP received therapeutic benefit from systemic omalizumab (the sixth terminated treatment because of intercurrent illness) with less use of other immunosuppressants, inhibition of new bullae, less pruritus, and dramatic decreases in eosinophil counts. None of the patients had untoward side effects from omalizumab. LIMITATIONS: This was an open, uncontrolled study. CONCLUSIONS: Omalizumab neutralizes the activity of IgE in patients with BP and improves the control of their disease activity.

Missing the target: characterization of bullous pemphigoid patients who are negative using the BP180 enzyme-linked immunosorbant assay.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies specific for the 180-kd BP antigen-2 (BP180) (also termed "type XVII collagen") protein. The BP180 enzyme-linked immunosorbent assay (ELISA) is specific for the immunodominant NC16A domain of the protein. However, we and others have observed patients whose reactivity to BP180 is exclusive of the NC16A domain (referred to henceforth as non-NC16A BP). OBJECTIVE: We sought to determine the incidence of non-NC16A BP and identify regions of reactivity within the BP180 protein. METHODS: Sera from 51 patients who met the clinical and histologic criteria for BP were screened for NC16A reactivity by ELISA. Sera that were negative by ELISA were screened for IgG reactivity to an epidermal extract, recombinant BP180 protein, and subregions of BP180, by immunoblot. Demographic and clinical data were also collected on all patients. RESULTS: Four sera (7.8%) were negative using the BP180 ELISA but positive for IgG reactivity to the extracellular domain of BP180. Further mapping identified 4 regions outside of NC16A recognized by these sera: amino acid (AA) 1280 to 1315, AA 1080 to 1107, AA 1331 to 1404, and AA 1365 to 1413. One of these sera also had IgE specific for NC16A. One patient had an atypical presentation with lesions limited to the lower aspect of the legs and scarring of the nail beds. LIMITATIONS: The small total number of patients with non-NC16A BP limits the identification of demographic or clinical correlates. CONCLUSION: It is significant that 7.8% of sera from patients with new BP react to regions of BP180 exclusively outside of NC16A and, thus, would not be identified using the currently available BP180 ELISA.

FcR-independent effects of IgE and IgG autoantibodies in bullous pemphigoid.

Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by IgE and IgG class autoantibodies specific for 180-kDa BP Ag 2 (BP180), a protein involved in cell-substrate attachment. Although some direct effects of BP IgG have been observed on keratinocytes, no study to date has examined direct effects of BP IgE. In this study, we use primary cultures of human keratinocytes to demonstrate Ag-specific binding and internalization of BP IgE. Moreover, when BP IgE and BP IgG were compared, both isotypes stimulated FcR- independent production of IL-6 and IL-8, cytokines critical for BP pathology, and elicited changes in culture confluence and viability. We then used a human skin organ culture model to test the direct effects of these Abs on the skin, whereas excluding the immune inflammatory processes that are triggered by these Abs. In these experiments, physiologic concentrations of BP IgE and BP IgG exerted similar effects on human skin by stimulating IL-6 and IL-8 production and decreasing the number of hemidesmosomes localized at the basement membrane zone. We propose that the Ab-mediated loss of hemidesmosomes could weaken attachment of basal keratinocytes to the basement membrane zone of affected skin, thereby contributing to blister formation. In this article, we identify a novel role for IgE class autoantibodies in BP mediated through an interaction with BP180 on the keratinocyte surface. In addition, we provide evidence for an FcR-independent mechanism for both IgE and IgG class autoantibodies that could contribute to BP pathogenesis.

Disease Endotypes Predict the Severity of Mucous Membrane Pemphigoid.

Mucous membrane pemphigoid is an autoimmune disease with variable clinical presentation and multiple autoantigens. To determine whether disease endotypes could be identified on the basis of the pattern of serum reactivity, the clinical and diagnostic information of 70 patients with mucous membrane pemphigoid was collected, and reactivity to dermal or epidermal antigens, using indirect immunofluorescence, and specific reactivity to bullous pemphigoid (BP) autoantigens BP180 and BP230, collagen VII, and laminin 332 were evaluated. Most patients had lesions at multiple mucosae, with the most prevalent being oropharyngeal (mouth, gingiva, pharynx; 98.6%), followed by ocular (38.6%), nasal (32.9%), genital or anal (31.4%), laryngeal (20%), and esophageal (2.9%) sites and skin (45.7%). Autoantigen profiling identified BP180 (71%) as the most common autoantigen, followed by laminin 332 (21.7%), collagen VII (13%), and BP230 IgG (11.6%). Reactivity to dermal antigens predicted a more severe disease characterized by a higher number of total sites involved, especially high-risk sites, and a decreased response to rituximab. In most cases, identification of dermal indirect immunofluorescence reactivity is an accurate predictor of disease course; however, confirmation of laminin 332 reactivity is important, with dermal indirect immunofluorescence positivity because of an increased risk of solid tumors. In addition, the ocular mucosae should be monitored in patients with IgA on direct immunofluorescence.

Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.

Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies.

Erythema migrans: a spectrum of histopathologic changes.

Early cutaneous Lyme disease, erythema migrans, manifests as a gyrate erythema at the site of a tick bite. The standard histopathologic description is that of a superficial and deep perivascular lymphocytic infiltrate in which plasma cells are identified at the periphery of the lesion and eosinophils in the center. Deviation from these commonly accepted histopathologic findings may lead to an erroneous diagnosis. Herein, we describe 4 cases of erythema migrans, all biopsied at the periphery of the lesion and confirmed by serologic studies, demonstrating a variety of unconventional histopathologic patterns. These findings include eosinophils and neutrophils at the periphery of the expanding annular plaque of erythema migrans, focal interface change, spongiosis, involvement of the superficial vascular plexus alone, and an absence of plasma cells in all cases. These cases highlight the varied and nonspecific histopathologic changes that can be seen in erythema migrans, including the absence of plasma cells and the presence of focal interface change. Based on these findings, the dermatopathologist should always consider erythema migrans as a diagnostic possibility in a biopsy specimen from an expanding gyrate or annular erythema despite the presence of unusual features. In atypical clinical cases, serologic confirmation may be required for diagnosis in the presence of histopathologic findings considered unconventional for erythema migrans.

TSST-1+Staphylococcus aureus in Bullous Pemphigoid.

A potential role of Staphylococcus aureus in bullous pemphigoid was explored by examining the colonization rate in patients with new-onset disease compared with that in age- and sex-matched controls. S. aureus colonization was observed in 85% of bullous pemphigoid lesions, 3-6-fold higher than the nares or unaffected skin from the same patients (P ≤ 0.003) and 6-fold higher than the nares or skin of controls (P ≤ 0.0015). Furthermore, 96% of the lesional isolates produced the toxic shock syndrome toxin-1 superantigen, and most of these additionally exhibited homogeneous expression of the enterotoxin gene cluster toxins. Toxic shock syndrome toxin-1‒neutralizing antibodies were not protective against colonization. However, S. aureus colonization was not observed in patients who had recently received antibiotics, and the addition of antibiotics with staphylococcal coverage eliminated S. aureus and resulted in clinical improvement. This study shows that toxic shock syndrome toxin-1‒positive S. aureus is prevalent in bullous pemphigoid lesions and suggests that early implementation of antibiotics may be of benefit. Furthermore, our results suggest that S. aureus colonization could provide a source of infection in patients with bullous pemphigoid, particularly in the setting of high-dose immunosuppression.

How Do Experts Treat Patients with Bullous Pemphigoid around the World? An International Survey.

Many treatments are currently proposed for treating patients with bullous pemphigoid (BP). We assessed treatment modalities of BP depending on the different countries, BP extent, and patients' comorbidities. We surveyed worldwide experts about how they treat patients with BP. A total of 61 experts from 27 countries completed the survey. Severe and moderate BP were treated with oral prednisone (61.4 and 53.7%, respectively) or superpotent topical corticosteroids (CSs) (38.6 and 46.3%, respectively). Conventional immunosuppressants were more frequently combined with oral prednisone (74.5%) than with superpotent topical CS (37.5%) in severe BP. Topical CSs were mainly used in Europe in mild (81.1%), moderate (55.3%), and severe (54.3%) BP. In the United States of America and Asia, systemic CSs were mainly proposed for treating severe (77.8 and 100%, respectively), moderate (70 and 77.8%, respectively), and also mild (47.1 and 33.3%, respectively) BP. Most experts reduced the initial dose of oral CS in patients with diabetes mellitus (48.1%) or cardiac insufficiency (40.2%) but rarely changed BP treatment in patients with neurological disorders or neoplasia. This survey showed major differences in the way patients with BP are treated between AmeriPac countries (United State of America, Latin America, and Australia) and Asia on the one hand and Europe and the Middle East on the other hand.

Evaluation of a Case Series of Patients With Generalized Pustular Psoriasis in the United States.

IMPORTANCE: Generalized pustular psoriasis (GPP) is a chronic, orphan disease with limited epidemiological data. OBJECTIVE: To describe the clinical characteristics, treatments, longitudinal disease course, and disease-specific health care utilization among patients with GPP across the United States. DESIGN, SETTING, AND PARTICIPANTS: A retrospective longitudinal case series involving 95 adults who met the European Rare and Severe Psoriasis Expert Network consensus definition for GPP and were treated at 20 US academic dermatology practices between January 1, 2007, and December 31, 2018. MAIN OUTCOMES AND MEASURES: The primary outcome is to describe the patient characteristics, associated medical comorbidities, treatment patterns complications, and GPP-specific health care utilization. RESULTS: Sixty-seven of 95 patients (70.5%) were women (mean age, 50.3 years [SD, 16.1 years]). In the initial encounter, 35 patients (36.8%) were hospitalized and 64 (67.4%) were treated with systemic therapies. In total, more than 20 different systemic therapies were tried. During the follow-up period, 19 patients (35.8%) reported hospitalizations at a median rate of 0.5 hospitalizations per year (IQR, 0.4-1.6). Women had a decreased risk of an emergency department or hospital encounter (odds ratio, 0.19; 95% CI, 0.04-0.83). CONCLUSIONS AND RELEVANCE: Generalized pustular psoriasis is a rare, chronic disease without standard treatment and is associated with continued health care utilization over time.