Facial and neck erythema associated with dupilumab treatment: A systematic review.

BACKGROUND: Neither dupilumab-associated facial erythema nor neck erythema was reported in phase 3 clinical trials for the treatment of atopic dermatitis, but there have been a number of reports of patients developing this adverse event in clinical practice. OBJECTIVE: To outline all cases of reported dupilumab-associated facial or neck erythema to better characterize this adverse event, and identify potential etiologies and management strategies. METHODS: A search was conducted on EMBASE and PubMed databases. Two independent reviewers identified relevant studies for inclusion and performed data extraction. RESULTS: A total of 101 patients from 16 studies were reported to have dupilumab-associated facial or neck erythema. A total of 52 of 101 patients (52%) had baseline atopic dermatitis facial or neck involvement and 45 of 101 (45%) reported different cutaneous symptoms from preexisting atopic dermatitis, possibly suggesting a different etiology. Suggested etiologies included rosacea, allergic contact dermatitis, and head and neck dermatitis. Most commonly used treatments included topical corticosteroids, topical calcineurin inhibitors, and antifungal agents. In the 57 patients with data on the course of the adverse events, improvement was observed in 29, clearance in 4, no response in 16, and worsening in 8. A total of 11 of 101 patients (11%) discontinued dupilumab owing to this adverse event. LIMITATIONS: Limited diagnostic testing, nonstandardized data collection and reporting across studies, and reliance on retrospective case reports and case series. CONCLUSION: Some patients receiving dupilumab develop facial or neck erythema that differs from their usual atopic dermatitis symptoms. Prompt identification and empiric treatment may minimize distress and potential discontinuation of dupilumab owing to this adverse event.

Radiofrequency Microneedling: A Comprehensive and Critical Review.

BACKGROUND: Many studies have evaluated radiofrequency microneedling (RFMN) in various dermatologic conditions. However, the efficacy and safety of RFMN, and how it compares with other energy-based devices in a clinician's armamentarium, remains unclear. OBJECTIVE: To review higher-quality evidence supporting RFMN and the dermatologic conditions which it can be used in. MATERIALS AND METHODS: A search was conducted in MEDLINE and EMBASE from inception to May 13, 2020, using the terms: "radiofrequency microneedling" OR "fractional radiofrequency" OR "radiofrequency needling" OR "radiofrequency percutaneous collagen induction." Only randomized, split body or blinded studies with original data on humans were included. Non-English or non-dermatology-related studies were excluded. RESULTS: Forty-two higher-quality studies were included after applying the inclusion and exclusion criteria. There were 14 studies for skin rejuvenation, 7 for acne scars, 6 for acne vulgaris, 5 each for striae and axillary hyperhidrosis, 2 for melasma, and 1 each for rosacea, cellulite, and androgenetic alopecia. CONCLUSION: Radiofrequency microneedling is an effective intervention that can be used repeatedly and safely in combination with other treatment modalities and in individuals with darker skin phototypes. Radiofrequency microneedling-induced dermal remodeling and neocollagenesis are slow and progressive but continue to improve even 6 months after treatment.

Short-Term Evaluation of the Real-World Efficacy and Safety of Dupilumab for the Treatment of Moderate-to-Severe Atopic Dermatitis: A Canadian Multicenter Retrospective Cohort Study [Formula: see text].

BACKGROUND: Systemic therapy for atopic dermatitis (AD) has been challenging with limited safe and efficacious long-term treatment options. In 2017, dupilumab was approved in the United States, Europe, and Canada as the first targeted therapy for patients with moderate-to-severe AD. Despite promising efficacy and safety results in clinical trials, our understanding of dupilumab in clinical practice remains limited with few studies outside clinical trials in literature. OBJECTIVE: The aim of this study is to evaluate the efficacy and safety of dupilumab in clinical practice and discuss any differences in results between clinical trials and real-world results. METHODS: A retrospective chart review was conducted of consecutive patients receiving dupilumab treatment at two tertiary hospitals in Toronto, Canada, between December 2017 and May 2019. The primary efficacy endpoint was measured by Investigator's Global Assessment (IGA) score of 0/1 at 16 weeks and all adverse events (AEs) experienced by patients were recorded. RESULTS: Of the 93 patients included in the study, 51 (55%) reached IGA 0/1 and 38 (41%) experienced ≥1 AE. There were no severe AEs or discontinuation prior to 16 weeks due to an AE. CONCLUSIONS: These findings suggest a higher IGA-based efficacy profile with no newly identified safety concerns in patients treated with dupilumab at two tertiary hospitals in Toronto, Canada, compared to those in randomized controlled trials.

TYK 2 inhibitors for the treatment of dermatologic conditions: the evolution of JAK inhibitors.

Increasing understanding of cytokines as major drivers of immune-mediated diseases has revolutionized targeted treatments for these conditions. As the pathogenesis of autoimmune conditions is mediated by a complex interplay of various cytokines, Janus kinase (JAK) inhibitors have been of particular interest due to their ability to target multiple cytokines simultaneously. However, due to safety concerns with first generation JAK inhibitors, most notably from JAK2 and JAK3 inhibition, interest has shifted to more selective inhibition of TYK2. Three key TYK2 inhibitors that have advanced furthest in clinical trials for treatment of dermatologic autoimmune conditions are deucravacitinib (BMS-986165), brepocitinib (PF-06700841), and PF-06826647. This review outlines the current understanding of the efficacy and safety of these three TYK2 inhibitors from completed phase I and II studies and summarizes studies currently in progress for dermatologic conditions.

Topical treatment for postinflammatory hyperpigmentation: a systematic review.

BACKGROUND: Topical measures are the mainstay treatment for postinflammatory hyperpigmentation (PIH). Numerous studies have assessed the efficacy of topical medications for the treatment of PIH, but few have evaluated the quality of evidence supporting these topical therapies. We performed a systematic review to evaluate the evidence of topical treatments for PIH. METHODS: We included English-language studies that evaluated topical medications for PIH. We searched PubMed, MEDLINE, and EMBASE from conception to March 29 2021. We used the modified Grading of Recommendations, Assessment, Development and Evaluation scale (GRADE) scale to assess quality of evidence. RESULTS: Forty-seven of 1,224 studies with 1,853 subjects were included. Topical agents with high-quality studies included retinoids, hydroxy acids, corticosteroids, thiamidol, niacinamide and plant-derived products. Sunscreens with SPF30 or greater was recommended in almost every study. Common side effects included desquamation, burning, stinging, dryness, and pruritus. CONCLUSIONS: Retinoids, hydroxy acids and broad-spectrum sunscreen were supported by the greatest number of high-quality studies. Ongoing inflammation may be subtle, especially in darker skin phenotypes. Herein, we proposed an evidence-based algorithm for PIH based on the high-quality studies. There is a need to adopt a validated outcome measure for PIH to better compare efficacy between various treatments in future studies.

Prevalence and Characteristics of Dupilumab-Induced Ocular Surface Disease in Adults With Atopic Dermatitis.

PURPOSE: Dupilumab-induced ocular surface disease (DIOSD) is a common reaction among patients treated for atopic dermatitis. This study aimed to identify the clinical characteristics, associated risk factors, treatment strategies, and long-term outcomes of DIOSD. METHODS: We conducted a multicenter retrospective cohort study of consecutive adult outpatients treated with dupilumab for moderate-to-severe atopic dermatitis from 2017 through 2021 at 2 tertiary care centers. We used stepwise multivariable logistic regression to assess the association between patient characteristics and development of DIOSD. RESULTS: Among 210 patients treated with dupilumab, 37% (n = 78) developed DIOSD over the 52-week follow-up period. Vision-threatening complications including corneal scarring and cicatricial ectropion were noted in 1% (n = 3) of patients. Clinical features were blepharoconjunctivitis (68%, n = 53), burning/stinging/dryness (14%, n = 29), epiphora (13%, n = 10), pruritus (13%, n = 10), blurred vision (3%, n = 2), and photophobia (1%, n = 1). DIOSD was associated with a history of asthma (odds ratio: 2.94, 95% confidence interval: 1.26-6.87, P = 0.01) and a family history of atopic dermatitis (odds ratio: 2.58, 95% confidence interval: 1.08-6.17, P = 0.03). Interventions were initiated for 63% of patients with DIOSD, with artificial tears (56%) and corticosteroid drops (29%) most commonly used. Dupilumab was discontinued because of DIOSD in 4% of patients. CONCLUSIONS: DIOSD is a common adverse event that is usually mild but may lead to treatment interruption and vision-threatening complications. A personal history of asthma and family history of atopic dermatitis may be associated with a higher risk of developing DIOSD.

Identification of RSK and TTK as Modulators of Blood Vessel Morphogenesis Using an Embryonic Stem Cell-Based Vascular Differentiation Assay.

Blood vessels are formed through vasculogenesis, followed by remodeling of the endothelial network through angiogenesis. Many events that occur during embryonic vascular development are recapitulated during adult neoangiogenesis, which is critical to tumor growth and metastasis. Current antiangiogenic tumor therapies, based largely on targeting the vascular endothelial growth factor pathway, show limited clinical benefits, thus necessitating the discovery of alternative targets. Here we report the development of a robust embryonic stem cell-based vascular differentiation assay amenable to small-molecule screens to identify novel modulators of angiogenesis. In this context, RSK and TTK were identified as angiogenic modulators. Inhibition of these pathways inhibited angiogenesis in embryoid bodies and human umbilical vein endothelial cells. Furthermore, inhibition of RSK and TTK reduced tumor growth, vascular density, and improved survival in an in vivo Lewis lung carcinoma mouse model. Our study suggests that RSK and TTK are potential targets for antiangiogenic therapy, and provides an assay system for further pathway screens.

Ras Signaling Is a Key Determinant for Metastatic Dissemination and Poor Survival of Luminal Breast Cancer Patients.

Breast cancer is associated with alterations in a number of growth factor and hormone-regulated signaling pathways. Mouse models of metastatic breast cancer typically feature mutated oncoproteins that activate PI3K, Stat3, and Ras signaling, but the individual and combined roles of these pathways in breast cancer progression are poorly understood. In this study, we examined the relationship between oncogenic pathway activation and breast cancer subtype by analyzing mouse mammary tumor formation in which each pathway was activated singly or pairwise. All three oncogenes showed cooperation during primary tumor formation, but efficient dissemination was only dependent on Ras. In addition, transcriptional profiling demonstrated that Ras induced adenocarcinomas with molecular characteristics related to human basal-like and HER2(+) tumors. In contrast, Ras combined with PIK3CA(H1047R), an oncogenic mutant linked to ERα(+)/luminal breast cancer in humans, induced metastatic luminal B-like tumors. Consistent with these data, elevated Ras signaling was associated with basal-like and HER2(+) subtype tumors in humans and showed a statistically significant negative association with estrogen receptor (ER) signaling across all breast cancer. Despite this, there are luminal tumors with elevated Ras signaling. Importantly, when considered as a continuous variable, Ras pathway activation was strongly linked to reduced survival of patients with ERα(+) disease independent of PI3K or Stat3 activation. Therefore, our studies suggest that Ras activation is a key determinant for dissemination and poor prognosis of ERα(+)/luminal breast cancer in humans, and hormone therapy supplemented with Ras-targeting agents may be beneficial for treating this aggressive subtype.