Identification of a neutrophil-specific PIK3R1 mutation facilitates targeted treatment in a patient with Sweet syndrome.

BackgroundAcute febrile neutrophilic dermatosis (Sweet syndrome) is a potentially fatal multiorgan inflammatory disease characterized by fever, leukocytosis, and a rash with a neutrophilic infiltrate. The disease pathophysiology remains elusive, and current dogma suggests that Sweet syndrome is a process of reactivity to an unknown antigen. Corticosteroids and steroid-sparing agents remain frontline therapies, but refractory cases pose a clinical challenge.MethodsA 51-year-old woman with multiorgan Sweet syndrome developed serious corticosteroid-related side effects and was refractory to steroid-sparing agents. Blood counts, liver enzymes, and skin histopathology supported the diagnosis. Whole-genome sequencing, transcriptomic profiling, and cellular assays of the patient's skin and neutrophils were performed.ResultsWe identified elevated IL-1 signaling in lesional Sweet syndrome skin caused by a PIK3R1 gain-of-function mutation specifically found in neutrophils. This mutation increased neutrophil migration toward IL-1ß and neutrophil respiratory burst. Targeted treatment of the patient with an IL-1 receptor 1 antagonist resulted in a dramatic therapeutic response and enabled a tapering off of corticosteroids.ConclusionDysregulated PI3K/AKT signaling is the first signaling pathway linked to Sweet syndrome and suggests that this syndrome may be caused by acquired mutations that modulate neutrophil function. Moreover, integration of molecular data across multiple levels identified a distinct subtype within a heterogeneous disease that resulted in a rational and successful clinical intervention. Future patients will benefit from efforts to identify potential mutations. The ability to directly interrogate the diseased skin allows this method to be generalizable to other inflammatory diseases and demonstrates a potential personalized medicine approach for patients with clinically challenging disease.Funding SourcesBerstein Foundation, NIH, Veterans Affairs (VA) Administration, Moseley Foundation, and H.T. Leung Foundation.

The Role of Dermatologists in the Early HIV/AIDS Epidemic: A Historical Review for the 40th Anniversary of HIV/AIDS.

In 1981, the HIV/AIDS epidemic was first recognized in young gay men presenting with opportunistic infections and Kaposi sarcoma. Over the past 40 years, there has been an unparalleled and hugely successful effort on the part of physicians, scientists, public health experts, community activists, and grassroots organizations to study, treat, and prevent HIV/AIDS. Yet the role of dermatologists in the investigation of HIV/AIDS and in the treatment of infected patients has largely been neglected in the historical literature. It is important to revisit dermatologists' historic contributions and problematic biases during this epidemic and honor the legacy of the dermatologists who were instrumental in treating and advocating for patients affected by HIV/AIDS.

Children of the Sun: a historical look at how pediatric light therapy shaped attitudes and behaviors toward sunbathing.

Today, parents are warned to protect their children from the sun's ultraviolet (UV) rays, the most preventable and leading cause of skin cancer. Yet, during the first half of the 20th century, the medical community widely extolled the health benefits of daily sunbaths for babies and children. What initially had begun as evidence-based medical therapies to prevent pediatric diseases, specifically tuberculosis and rickets, soon took on a life of its own as physicians, public health experts, and the general public embraced sunbathing and tanning as a means to ensure health and wellbeing for children and families. Here, we trace how specific medical therapies entered mainstream pediatric medicine and, converging with societal and cultural forces, shaped attitudes and behaviors towards sunbathing that still exist today. Understanding our complex history with the sun may shed light on the current peak of skin cancer incidence and future disease development. Moreover, it may help improve how we educate parents and children about sun safety by taking into account the current social and cultural context of medical practice and health communication.

Update on rosacea classification and its controversies.

Rosacea is an inflammatory skin condition that, despite its prevalence, remains imperfectly understood. Without "gold standard" laboratory markers, the diagnosis depends greatly on clinical judgment and the nomenclature used. Throughout the years, the classification schemas for rosacea have changed as clinicians and researchers study the condition. Herein, we highlight the fundamental differences between the proposed classification systems for rosacea, emphasize the areas for improvement, and discuss the implications on clinical decision-making and patient care.

Approaches to limit systemic antibiotic use in acne: Systemic alternatives, emerging topical therapies, dietary modification, and laser and light-based treatments.

Acne is one of the most common diseases worldwide and affects ∼50 million individuals in the United States. Oral antibiotics are the most common systemic agent prescribed for the treatment of acne. However, their use might be associated with a variety of adverse outcomes including bacterial resistance and disruption of the microbiome. As a result, multiple treatment guidelines call for limiting the use of oral antibiotics in the treatment of acne, although actual prescribing often does not follow these guidelines. In this review, the rationale for concerns regarding the use of oral antibiotics for the management of acne is reviewed. In addition, we will discuss our approach to complying with the intent of the guidelines, with a focus on novel topical agents, dietary modification, laser and light-based modalities, and systemic medications, such as spironolactone, combined oral contraceptives, and oral isotretinoin.

Neutrophilic dermatoses: Pathogenesis, Sweet syndrome, neutrophilic eccrine hidradenitis, and Behçet disease.

Neutrophilic dermatoses are a heterogeneous group of inflammatory skin disorders that present with unique clinical features but are unified by the presence of a sterile, predominantly neutrophilic infiltrate on histopathology. The morphology of cutaneous lesions associated with these disorders is heterogeneous, which renders diagnosis challenging. Moreover, a thorough evaluation is required to exclude diseases that mimic these disorders and to diagnose potential associated infectious, inflammatory, and neoplastic processes. While some neutrophilic dermatoses may resolve spontaneously, most require treatment to achieve remission. Delays in diagnosis and treatment can lead to significant patient morbidity and even mortality. Therapeutic modalities range from systemic corticosteroids to novel biologic agents, and the treatment literature is rapidly expanding. The first article in this continuing medical education series explores the pathogenesis of neutrophilic dermatoses and reviews the epidemiology, clinical and histopathologic features, diagnosis, and management of Sweet syndrome, neutrophilic eccrine hidradenitis, and Behçet disease.

Neutrophilic dermatoses: Pyoderma gangrenosum and other bowel- and arthritis-associated neutrophilic dermatoses.

Neutrophilic dermatoses are a heterogeneous group of inflammatory skin disorders that present with unique clinical features but are unified by the presence of a sterile, predominantly neutrophilic infiltrate on histopathology. The morphology of cutaneous lesions associated with these disorders is heterogeneous, which renders diagnosis challenging. Moreover, a thorough evaluation is required to exclude diseases that mimic these disorders and to diagnose potential associated infectious, inflammatory, and neoplastic processes. While some neutrophilic dermatoses may resolve spontaneously, most require treatment to achieve remission. Delays in diagnosis and treatment can lead to significant patient morbidity and even mortality. Therapeutic modalities range from systemic corticosteroids to novel biologic agents, and the treatment literature is rapidly expanding. The second article in this continuing medical education series reviews the epidemiology, clinical characteristics, histopathologic features, diagnosis, and management of pyoderma gangrenosum as well as bowel-associated dermatosis-arthritis syndrome and the arthritis-associated neutrophilic dermatoses rheumatoid neutrophilic dermatitis and adult Still disease.

The Association of Age With Clinical Presentation and Comorbidities of Pyoderma Gangrenosum.

Importance: Pyoderma gangrenosum is an inflammatory neutrophilic dermatosis. Current knowledge of this rare disease is limited owing to a lack of validated diagnostic criteria and large population studies. Objective: To evaluate the association of age with the clinical presentation and comorbidities of pyoderma gangrenosum. Design, Setting, and Participants: This was a multicenter retrospective cohort study performed at tertiary academic referral centers in urban settings. Adults (≥18 years) who were evaluated and diagnosed as having pyoderma gangrenosum at the Brigham and Women's and Massachusetts General Hospitals from 2000 to 2015 and the University of Pennsylvania Health System from 2006 to 2016 were included. Main Outcomes and Measures: Patient demographics, clinical features, medical comorbidities, and treatment. Results: Of the 356 validated cases of pyoderma gangrenosum included in the study, 267 (75%) were women and 284 (84.8%) were white. The mean (SD) age at presentation was 51.6 (17.7) years. Pathergy was recorded in 100 patients (28.1%). A total of 238 patients (66.9%) had associated medical comorbidities: inflammatory bowel disease in 146 patients (41.0%); inflammatory arthritis in 73 patients (20.5%); solid organ malignant neoplasms in 23 patients (6.5%); hematologic malignant neoplasms in 21 patients (5.9%); and hematologic disorders, specifically monoclonal gammopathy of undetermined significance, myelodysplastic syndrome, and polycythemia vera in 17 patients (4.8%). When stratified by age, pathergy was more common in patients 65 years or older (36.3% vs 24.3%; P = .02). Inflammatory bowel disease was the only medical comorbidity that was more common in patients younger than 65 years (47.7% vs 26.6%; P < .001), while a number of medical comorbidities were more common in those 65 years or older, including rheumatoid arthritis (13.3% vs 6.2%; P = .03), ankylosing spondylitis (1.8% vs 0%; P = .04), solid organ malignant neoplasms (13.3% vs 3.3%; P < .001), hematologic malignant neoplasms (9.7% vs 4.1%; P = .04), and the aforementioned hematologic disorders (10.6% vs 2.1%; P < .001). Conclusions and Relevance: Although clinical presentation in this large cohort was similar between different age groups, disease associations varied by age. The findings of this study may allow for a more focused, age-specific evaluation of patients with pyoderma gangrenosum.

Sweet syndrome in patients with and without malignancy: A retrospective analysis of 83 patients from a tertiary academic referral center.

BACKGROUND: Sweet syndrome is a neutrophilic dermatosis that may be categorized into classic, malignancy-associated, and drug-induced subtypes. Few studies have systematically analyzed this rare disorder. OBJECTIVE: To describe the clinicopathologic characteristics and treatment of Sweet syndrome and identify characteristics associated with concurrent malignancy. METHODS: We retrospectively reviewed patients with Sweet syndrome at the University of Pennsylvania from 2005 to 2015. RESULTS: We identified 83 patients (mean age, 57 years; 51% male) with Sweet syndrome: 30% with the classic form, 44% with the malignancy-associated form, 24% with the drug-induced form in the setting of malignancy, and 2% with the drug-induced form. Acute myeloid leukemia was the most common malignancy (in 24 of 83 patients [29%]). Filgrastim was the most common medication (used in 8 of 83 patients [10%]). Leukopenia (P < .001), anemia (P = .002), thrombocytopenia (P < .001), absence of arthralgia (P < .001), and histiocytoid or subcutaneous histopathology (P = .024) were associated with malignancy (χ2 test). LIMITATIONS: This was a retrospective study that represents patients from a single tertiary academic referral center, which may limit its generalizability to other settings. CONCLUSION: When caring for patients with Sweet syndrome, dermatologists should be aware of the potential association of leukopenia, anemia, thrombocytopenia, absence of arthralgia, and histiocytoid or subcutaneous histopathology with malignancy.

BAP1: case report and insight into a novel tumor suppressor.

BACKGROUND: BRCA1-Associated-Protein 1 (BAP1) is a dynamic tumor suppressor which, when mutated, has been associated with an increased risk of uveal melanoma, cutaneous melanoma, mesothelioma, and several other cancers. Germline BAP1 mutations have been extensively studied, where they have been found to cause hereditary cancer susceptibility. However, their sporadic counterparts, tumors that display a loss of BAP1 expression due to somatically arising mutations in the BAP1 gene, remain a poorly described entity. CASE PRESENTATION: Here we present the case of a 49-year-old female who presented with an asymptomatic dome-shaped pink papule on the dorsal foot which was found on biopsy to be deficient in the BAP1 tumor suppressor. While the patient's family history did not suggest the presence of a familial cancer syndrome, germline genetic testing was performed and was negative. The patient underwent surgical excision of this sporadically appearing "BAPoma" by Mohs surgery. CONCLUSIONS: Given the relatively banal clinical appearance of these dome-shaped neoplasms, sporadic BAPomas may often be overlooked by clinicians and dermatologists. In addition to providing a representative case, here we also provide a synopsis of the current understanding of these neoplasms, both in terms of the histopathological features, as well as the molecular mechanisms underlying BAP1 function and its ability to prevent tumorigenesis.

The reliability of teledermatology to triage inpatient dermatology consultations.

IMPORTANCE: Many hospitals do not have inpatient dermatologic consultative services, and most have reduced availability of services during off-hours. Dermatologists based in outpatient settings can find it challenging to determine the urgency with which they need to evaluate inpatients when consultations are requested. Teledermatology may provide a valuable mechanism for dermatologists to triage inpatient consultations and increase efficiency, thereby expanding access to specialized care for hospitalized patients. OBJECTIVE: To evaluate whether a store-and-forward teledermatology system is reliable for the initial triage of inpatient dermatology consultations. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 50 consenting adult patients, hospitalized for any indication, for whom an inpatient dermatology consultation was requested between September 1, 2012, and April 31, 2013, at the Hospital of the University of Pennsylvania, an academic medical center. The participants were evaluated separately by both an in-person dermatologist and 2 independent teledermatologists. MAIN OUTCOMES AND MEASURES: The primary study outcomes were the initial triage and decision to biopsy concordance between in-person and teledermatology evaluations. RESULTS: Triage decisions were as follows: if the in-person dermatologist recommended the patient be seen the same day, the teledermatologist agreed in 90% of the consultations. If the in-person dermatologist recommended a biopsy, the teledermatologist agreed in 95% of cases on average. When the teledermatologist did not choose the same course of action, there was substantial diagnostic agreement between the teledermatologist and the in-person dermatologist. The Kendall τ rank correlation coefficients for initial triage concordance between the in-person dermatologist and teledermatologists were 0.41 and 0.48. The Cohen κ coefficients for decision to biopsy concordance were 0.35 and 0.61. The teledermatologists were able to triage 60% of consultations to be seen the next day or later. The teledermatologists were able to triage, on average, 10% of patients to be seen as outpatients after discharge. CONCLUSIONS AND RELEVANCE: Teledermatology is reliable for the triage of inpatient dermatology consultations and has the potential to improve efficiency.

Cutaneous metastases from visceral malignancies mimicking interstitial granulomatous processes: a report of 3 cases.

There are multiple clinical and histopathologic presentations of cutaneous metastases. We report 3 cases of visceral malignancies metastasizing to the skin and histopathologically mimicking interstitial granulomatous processes, including granuloma annulare and interstitial granulomatous dermatitis. Histopathologic examination of skin biopsy specimens, from our patients with established histories of cancer, revealed malignant carcinoma-derived cells organized in an interstitial pattern. Of note, some of the lesional cells appeared relatively bland without significant cellular atypia. When examining a skin biopsy of a new lesion from a patient with a history of internal malignancy, it is important to perform immunohistochemical staining to evaluate for metastatic disease, even if the histological pattern is suggestive of a benign interstitial granulomatous process.

AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery.

The appropriate use criteria process synthesizes evidence-based medicine, clinical practice experience, and expert judgment. The American Academy of Dermatology in collaboration with the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery has developed appropriate use criteria for 270 scenarios for which Mohs micrographic surgery (MMS) is frequently considered based on tumor and patient characteristics. This document reflects the rating of appropriateness of MMS for each of these clinical scenarios by a ratings panel in a process based on the appropriateness method developed by the RAND Corp (Santa Monica, CA)/University of California-Los Angeles (RAND/UCLA). At the conclusion of the rating process, consensus was reached for all 270 (100%) scenarios by the Ratings Panel, with 200 (74.07%) deemed as appropriate, 24 (8.89%) as uncertain, and 46 (17.04%) as inappropriate. For the 69 basal cell carcinoma scenarios, 53 were deemed appropriate, 6 uncertain, and 10 inappropriate. For the 143 squamous cell carcinoma scenarios, 102 were deemed appropriate, 7 uncertain, and 34 inappropriate. For the 12 lentigo maligna and melanoma in situ scenarios, 10 were deemed appropriate, 2 uncertain, and 0 inappropriate. For the 46 rare cutaneous malignancies scenarios, 35 were deemed appropriate, 9 uncertain, and 2 inappropriate. These appropriate use criteria have the potential to impact health care delivery, reimbursement policy, and physician decision making on patient selection for MMS, and aim to optimize the use of MMS for scenarios in which the expected clinical benefit is anticipated to be the greatest. In addition, recognition of those scenarios rated as uncertain facilitates an understanding of areas that would benefit from further research. Each clinical scenario identified in this document is crafted for the average patient and not the exception. Thus, the ultimate decision regarding the appropriateness of MMS should be determined by the expertise and clinical experience of the physician.