Neutrophil extracellular traps activate Notch-γ-secretase signaling in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is an inflammatory chronic skin disorder of unknown etiology characterized by inflamed abscess-like nodules and boils resulting in sinus tract formation, tissue scarring, and massive infiltration of neutrophils. Multiple lines of evidence have highlighted the potential association between alterations in the Notch pathway and HS pathogenesis, but the mechanisms remain incompletely characterized. OBJECTIVE: We aimed to elucidate the role of neutrophil extracellular traps in Notch-γ-secretase signaling. METHODS: Twenty-six HS lesional tissues, primary HS macrophages, and skin fibroblasts were interrogated by quantitative PCR, Western blot, and ELISA analyses. γ-Secretase and TNF-α converting enzyme activities were measured in HS skin lesions, macrophages, and skin fibroblasts. Immunofluorescence and RNAscope analyses were performed in HS and control skin. RESULTS: A prominent presence of Notch ligands, Delta-like ligand 4 (DLL4), and Jagged (JAG) 2 were detected at the protein and mRNA levels in HS skin lesion compared to control. Levels of DLL4, JAG1, citrullinated histone H3 DNA, and γ-secretase activity correlated with HS disease severity. Additionally, significantly elevated levels of Notch ligands and γ-secretase activity were found in dissected sinus tracts compared to the rest of HS tissue. Immunofluorescence microscopy of HS skin lesions revealed activation of Notch-1 signaling in macrophages and skin fibroblasts. Neutrophil extracellular traps (NETs) purified from HS patients displayed elevated levels of DLL4. HS NETs activated the Notch pathway in macrophages and dermal fibroblasts isolated from HS patients. HS skin fibroblasts displayed elevated levels of CD90 and DPP4 in association with increased migratory capacity and Notch activation. Inhibition of Notch decreased migratory capacity and profibrotic markers in HS fibroblasts. CONCLUSION: These data support a pathogenic connection between NETs, Notch-γ-secretase activation, and the release of profibrotic molecules that promote dysregulation of macrophages and skin fibroblasts in HS. Unveiling the relevance of these molecular events not only expands our understanding of HS but also opens new venues for the development of targeted therapies to address the fibrotic complications of advanced stages of HS.

New insights on hidradenitis suppurativa phenotypes and treatment response: An exploratory automated analysis of the SUNSHINE and SUNRISE trials.

BACKGROUND: Defining hidradenitis suppurativa (HS) subtypes was previously limited by small sample sizes and poor interrater reliability; no study has investigated subtype treatment responses. The objective of this analysis was to characterize HS clusters in adult patients with moderate to severe HS and evaluate secukinumab treatment responses between clusters. METHODS: Clusters were identified via an unsupervised machine learning clustering analysis using baseline data from the randomized, placebo-controlled SUNSHINE (NCT03713619) and SUNRISE (NCT03713632) phase 3 trials. To assess treatment responses, patients received secukinumab every 2 (SECQ2W) or 4 weeks (SECQ4W) or placebo, for 16 weeks, after which, placebo patients randomly switched to SECQ2W/SECQ4W, and SECQ2W/SECQ4W patients maintained their original treatment, until week 52. Baseline outcomes included patient characteristics, disease characteristics and severity, HS-associated comorbidities and previous treatment exposures. Treatment response was assessed via the HS clinical response (HiSCR), abscess and inflammatory nodule (AN) count, flares and NRS30 (skin pain). RESULTS: Based on baseline data, three clusters were identified from 1084 patients (Cluster 1: 54.1%, Cluster 2: 17.8%, Cluster 3: 28.1%). Cluster 1 was predominantly female (65.4%) and was characterized by milder HS. Cluster 2 had more patients from the Asia Pacific, Middle East and Africa region (58.5%) and was characterized by moderate HS. Cluster 3 had the highest rates of previous exposure to biologics (45.9%) and prior HS-related surgeries (47.5%) and was characterized by severe HS. SECQ2W and SECQ4W demonstrated efficacy versus placebo in all clusters at week 16; SECQ2W and SECQ4W efficacy was maintained to week 52. SECQ2W treatment showed a trend for greater efficacy versus SECQ4W in Cluster 3 through week 52. CONCLUSIONS: Three HS clusters were identified. Secukinumab demonstrated benefit over placebo in all clusters. However, patients with more severe disease may take longer to respond and more frequent secukinumab dosing may be required for these patients. TRIAL REGISTRATION: SUNSHINE (NCT03713619) and SUNRISE (NCT03713632).

Allergen content of popular chemical hair relaxers: A product analysis.

BACKGROUND: Chemical hair relaxers are widely utilized by black women, yet little research exists on the allergens present in these products. OBJECTIVE: This study aims to investigate allergen prevalence in the most popular chemical hair relaxers. METHODS: We analysed 41 products from five major retailers, identifying allergens through ingredient lists and comparing them to the 2020 American Contact Dermatitis Group Core allergen series. RESULTS: The most common contact allergens in chemical relaxers include propylene glycol, cetyl steryl alcohol, fragrance, D/L-a-tocopherol, tea tree oil and cocamidopropyl betaine. CONCLUSION: Understanding allergen exposure in products used by individuals with textured hair is needed for managing contact dermatitis in diverse populations. This analysis underscores the presence of potential allergens in hair relaxers, emphasizing the importance of dermatologists' awareness and patient scrutiny of ingredient lists.

A Pediatric Case of Transformed Mycosis Fungoides in a BRCA2 Positive Patient.

Cutaneous T-cell lymphomas are very rare in children. Although mycosis fungoides is the most common of these rare cutaneous T-cell lymphomas in children, transformation to an aggressive malignancy remains extremely uncommon, and there are no clear guidelines for clinical management in the pediatric population. In addition, the increased usage of next-generation sequencing for pediatric patients with unusual malignancies may result in the discovery of pathogenic germline mutations, though the association between these mutations and the patient's cancer is not always clear. We present here a unique pediatric case of transformed mycosis fungoides in a patient with BRCA2 mutation.

Effect of Age, Gender, and Sun Exposure on Ethnic Skin Photoaging: Evidence Gathered Using a New Photonumeric Scale.

BACKGROUND: African-Americans are less affected by photoaging than lighter skin individuals. Although scales for photoaging have been developed for Caucasians and Asians, no scale exists for African-Americans. AIM: To develop a photonumeric scale for photoaging and to determine factors that contribute to photoaging in African-Americans. METHODS: Five participants' photographs were selected as standards to create a 9-point photonumeric scale (0 = none, 8 = most severe). Three blinded dermatologists used the scale to grade the remaining participants' photographs. RESULTS: Interrater reliabilities were 0.775 (95% CI: 0.635, 0.880) for trial 1 and 0.832 (0.747, 0.883) for trial 2. Intrarater reliabilities, assessed over a 1 week interval, were 0.863 (0.727, 0.940), 0.928 (0.890, 0.954), and 0.866 (0.739, 0.935) for the three graders, indicating strong agreement. Photoaging scores were then correlated with participants' survey on lifestyle factors, which yielded age as a significant predictor (r = 0.91, p < 0.001). Furthermore, multiple regression model to predict facial photoaging (adjusted R2 = 0.849) selected age (b1 = 0.111, p < 0.001), sun exposure (b2 = 0.206, p = 0.014), and gender (b2 = -0.388, p = 0.063) as the most important variables. CONCLUSIONS: A reliable photonumeric scale for photoaging in African Americans was developed. Age, sun exposure, and male gender were found to be contributory factors to photoaging.

Chronological Aging in African-American Skin: A Reliable Photonumeric Scale Demonstrates Age and Body Mass Index as Contributing Factors.

BACKGROUND: Increased photoprotection by natural melanin allows for African-Americans to be less impacted by photoaging than Caucasians. However, less is known about chronological aging in this population. OBJECTIVE: To create a photonumeric scale for African-Americans to evaluate chronological skin aging and to explore contributing elements to intrinsic aging. METHODS: Standardized photographs of the upper inner arm were taken from 75 African-American participants. Five participants were chosen as standards to create a 9-point photonumeric scale (0 = none, 8 = most severe). The scale was utilized by three blinded dermatologists to independently rate participants' photographs. RESULTS: The interrater agreements were 0.768 (95% CI: 0.671-0.834) for trial 1 and 0.725 (0.608-0.794) for trial 2. The intrarater agreements were 0.757 (0.596-0.875), 0.850 (0.771-0.903), and 0.790 (0.686-0.855) for the three raters. Averaged chronological aging scores were correlated with participants' survey responses, which revealed age as a significant predictor (r = 0.72, p < 0.001). LIMITATION: Our study was limited by the sample size, although the number of study participants was similar on a investigation in Caucasians. CONCLUSION: This study created the first reliable photonumeric scale for chronologic skin aging in African-Americans and found increased age and greater BMI as contributors to intrinsic skin aging phenotype in this population.

Thalidomide for the treatment of chronic refractory prurigo nodularis.

Prurigo nodularis (PN) is a highly pruritic skin condition that is caused by chronic scratching. It occurs in patients with chronic itch and is characterized by multiple hyperkeratotic papules and nodules. The pathogenesis of PN is unclear, but involves a complex interplay of numerous pathways including neurogenic and inflammatory factors. As such, PN is very difficult to treat and patients are often refractory to multiple medications before finding a treatment that is effective. We present a woman with a 20-year history of exuberant prurigo nodularis who failed multiple therapies, including dapsone, azathioprine, mycophenolic acid, prednisone, topical steroids, and phototherapy. She only obtained significant relief of chronic pruritus and lesion flattening with thalidomide 100mg daily. Thalidomide is an antipruritic and anti-inflammatory agent that has shown to be very effective in treating a variety of dermatologic conditions. However, its use today is limited by concerns for its teratogenic and neuropathic side effects. With strict adherence to medication protocols, these adverse effects can be minimized. As such, thalidomide should be considered for patients with refractory dermatologic conditions.

Management of hidradenitis suppurativa in pregnancy.

Hidradenitis suppurativa is a debilitating inflammatory skin disease with a chronic course and often disappointing response to treatment. Though a minority of persons (20%) reports symptom remission during pregnancy, the vast majority experiences no relief (72%), and few experience clinical deterioration (8%). Disease flares are also observed post-partum. The pathophysiological basis for pregnancy-associated fluctuations in clinical status is currently unknown. Because most women with HS require ongoing management throughout pregnancy, it is important to evaluate the suitability and safety of current treatment options for pregnant women. The following review will outline current management strategies for HS and their compatibility with pregnancy and lactation.

Patterns of antimicrobial resistance in lesions of hidradenitis suppurativa.

BACKGROUND: Antibiotic therapy is commonly used to treat hidradenitis suppurativa (HS). Although concern for antibiotic resistance exists, data examining the association between antibiotics and antimicrobial resistance in HS lesions are limited. OBJECTIVE: We sought to determine the frequency of antimicrobial resistance in HS lesions from patients on antibiotic therapy. METHODOLOGY: A cross-sectional analysis was conducted on 239 patients with HS seen at the Johns Hopkins Medical Institutions from 2010 through 2015. RESULTS: Patients using topical clindamycin were more likely to grow clindamycin-resistant Staphylococcus aureus compared with patients using no antibiotics (63% vs 17%; P = .03). Patients taking ciprofloxacin were more likely to grow ciprofloxacin-resistant methicillin-resistant S aureus compared with patients using no antibiotics (100% vs 10%; P = .045). Patients taking trimethoprim/sulfamethoxazole were more likely to grow trimethoprim/sulfamethoxazole-resistant Proteus species compared with patients using no antibiotics (88% vs 0%; P < .001). No significant antimicrobial resistance was observed with tetracyclines or oral clindamycin. LIMITATIONS: Data on disease characteristics and antimicrobial susceptibilities for certain bacteria were limited. CONCLUSIONS: Antibiotic therapy for HS treatment may be inducing antibiotic resistance. These findings highlight the importance of stewardship in antibiotic therapy for HS and raise questions regarding the balance of antibiotic use versus potential harms associated with antibiotic resistance.

Squamous cell carcinoma complicating a chronic lesion of hidradenitis suppurativa: a case report and review of the literature.

Squamous cell carcinoma (SCC) arising from chronic hidradenitis suppurativa (HS) is rare; however, the morbidity associated with this presentation is high and management has not been standardised or optimised. We present a case of HS of the perineum and buttocks complicated by SCC, requiring multiple extensive surgical resections. Adjuvant radiotherapy was withheld initially because of concern for poor healing of the surgical wound but was eventually initiated after a second recurrence was identified. The patient ultimately expired 4 years after the initial diagnosis of SCC. We also review 80 cases of SCC complicating HS found in the English literature. Case reports and mechanistic studies suggest the possibility that human papilloma virus and smoking may be risk factors associated with SCC in HS. Despite the majority of SCC cases being well-differentiated tumours in HS, the highly aggressive nature of SCC in HS and its high likelihood for rapid progression, recurrence, metastasis and high mortality suggests the need to advocate for aggressive treatment. We recommend an aggressive approach to management at the time of SCC diagnosis in HS, which includes appropriate imaging to establish the extent of the tumour, large and deep surgical excision, sentinel lymph node evaluation, consultation with radiation oncology for potential adjuvant radiation therapy and close surveillance.

Pigmentation in African American skin decreases with skin aging.

BACKGROUND: Tristimulus colorimetry, which uses the Commission Internationale de l'Eclairage L*a*b* model to quantify color, has previously been used to analyze pigmentation and erythema in human skin; however, colorimetry of African American skin is not well characterized. OBJECTIVE: We sought to analyze skin color patterns in African Americans and compare them with those of Caucasians. METHODS: Colorimetry readings of the sun-protected buttock and sun-exposed back of forearm were taken from 40 Caucasian and 43 African American participants from March 2011 through August 2015. African American participants also completed a lifestyle questionnaire. Correlation coefficients, paired t tests, and multivariable linear regression analyses were used for statistical comparisons. RESULTS: Forearm skin was lighter in African Americans ages 65 years and older versus 18 to 30 years (P = .02) but darker in Caucasians ages 65 years or older versus 18 to 30 years (P = .03). In African Americans ages 18 to 30 years, the buttock was darker than the forearm (P < .001), whereas in Caucasians the buttock was lighter than the forearm (P < .001). A lighter forearm than buttock was correlated with supplement use, smoking (ages 18-30 years), and less recreational sun exposure (ages ≥65 years) in African Americans. LIMITATIONS: Our study was limited by the sample size and focal geographic source. CONCLUSIONS: Pigmentation patterns regarding sun-protected and sun-exposed areas in African Americans may differ from that of Caucasians, suggesting that other factors may contribute to skin pigmentation in African Americans.

Patient-provider communication, concordance, and ratings of care in dermatology: Results of a cross-sectional study.

ObjectiveTo determine the impact of race concordance on patient perception of quality of dermatologic care.Study designCross-sectional study.SettingAcademic outpatient practices in the Departments of Dermatology of Eastern Virginia Medical School and the Johns Hopkins University School of Medicine.ParticipantsThe study cohort comprised 124 participants including 6 providers and 118 established patients.Main Outcome MeasuresWe hypothesized, a priori, that patients in race-discordant dyads would report lower ratings of participatory decision-making (PDM), satisfaction, trust in the provider, and similarities with providers.ResultsPatients in race-discordant dyads reported less positive ratings on 4 out of 8 participatory decision-making questionnaire items (p values < 0.05), and were significantly more likely to perceive differences with providers in race and culture (p values < 0.05). These differences persisted to varying degrees after controlling for key confounders such as education and income level. Participants in race-concordant and race-discordant dyads did not differ in their perceptions of satisfaction or trust.ConclusionsPatient perception of participation in the decision-making process and of shared similarities with their providers is attributable in varying degrees to race concordance. Continued strengthening of cultural competency skills during medical and dermatology residency training as well as increased diversification of the dermatologic workforce could attenuate the adverse influences of race discordance and other socioeconomic factors on patient-provider communication.

Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic disease characterized by recurrent painful abscesses and chronic sinus tracts in intertriginous areas. In the United States, HS disproportionally affects adults of African-American heritage. Depending on the severity of disease, the consequences of HS can be far-reaching, significantly affecting mental health and quality of life. In recent years, concerted research efforts have been made to better understand the pathophysiology of the disease as well as identify emerging new treatment targets. Herein, we discuss the clinical presentation, diagnostic criteria, and treatment approach of HS with a focus on skin of color.