Rosacea Core Domain Set for Clinical Trials and Practice: A Consensus Statement.

Importance: Inconsistent reporting of outcomes in clinical trials of rosacea is impeding and likely preventing accurate data pooling and meta-analyses. There is a need for standardization of outcomes assessed during intervention trials of rosacea. Objective: To develop a rosacea core outcome set (COS) based on key domains that are globally relevant and applicable to all demographic groups to be used as a minimum list of outcomes for reporting by rosacea clinical trials, and when appropriate, in clinical practice. Evidence Review: A systematic literature review of rosacea clinical trials was conducted. Discrete outcomes were extracted and augmented through discussions and focus groups with key stakeholders. The initial list of 192 outcomes was refined to identify 50 unique outcomes that were rated through the Delphi process Round 1 by 88 panelists (63 physicians from 17 countries and 25 patients with rosacea in the US) on 9-point Likert scale. Based on feedback, an additional 11 outcomes were added in Round 2. Outcomes deemed to be critical for inclusion (rated 7-9 by ≥70% of both groups) were discussed in consensus meetings. The outcomes deemed to be most important for inclusion by at least 85% of the participants were incorporated into the final core domain set. Findings: The Delphi process and consensus-building meetings identified a final core set of 8 domains for rosacea clinical trials: ocular signs and symptoms; skin signs of disease; skin symptoms; overall severity; patient satisfaction; quality of life; degree of improvement; and presence and severity of treatment-related adverse events. Recommendations were also made for application in the clinical setting. Conclusions and Relevance: This core domain set for rosacea research is now available; its adoption by researchers may improve the usefulness of future trials of rosacea therapies by enabling meta-analyses and other comparisons across studies. This core domain set may also be useful in clinical practice.

Patient perspectives on topical minoxidil for hair loss: a survey-based study from the University of Michigan Alopecia Clinic.

Topical minoxidil is a widely used therapy for alopecia. Its availability over the counter in the United States makes it easily accessible. Various factors impact whether an individual decides to pursue treatment and/or continue long-term use. Our study aimed to investigate patient awareness, opinions, and hesitations regarding topical minoxidil use for hair loss treatment. The study also aimed to identify information sources influencing these viewpoints. A survey was administered to new patients seeking evaluation for alopecia aged 18 and above at the University of Michigan Alopecia Clinic. Data collection occurred between August 2022 and August 2023. Demographics, patient-reported hair loss diagnosis, history of minoxidil use, opinions on minoxidil, influential information sources, and concerns about minoxidil were collected. A total of 47 surveys were completed, primarily by females (78.7%) ages 18-40 years (44.7%). Respondents were aware of minoxidil (97.9%), with 63.8% reporting they had heard of minoxidil, but had not used it. Medical professionals were the most influential information source (34%), followed by close contacts (17%), internet searches (10.6%), and television (10.6%). Overall, positive opinions on minoxidil were expressed by 51.1%, negative opinions by 31.9%, and neutral opinions by 17%. Most common concerns included the need for continuous use (46.8%), required regular application (31.9%), skepticism about hair regrowth (29.8%), and expense (25.5%). Addressing personalized concerns and tailoring communication based on hair loss type and information sources may lead to more informed decisions and improved adherence. Gauging the opinions of this population provides valuable insights, aiding dermatologists in patient education and counseling strategies.

Formylpeptide receptor 1 contributes to epidermal barrier dysfunction-induced skin inflammation through NOD-like receptor C4-dependent keratinocyte activation.

BACKGROUND: Skin barrier dysfunction may both initiate and aggravate skin inflammation. However, the mechanisms involved in the inflammation process remain largely unknown. OBJECTIVES: We sought to determine how skin barrier dysfunction enhances skin inflammation and molecular mechanisms. METHODS: Skin barrier defect mice were established by tape stripping or topical use of acetone on wildtype mice, or filaggrin deficiency. RNA-Seq was employed to analyse the differentially expressed genes in mice with skin barrier defects. Primary human keratinocytes were transfected with formylpeptide receptor (FPR)1 or protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) small interfering RNA to examine the effects of these gene targets. The expressions of inflammasome NOD-like receptor (NLR)C4, epidermal barrier genes and inflammatory mediators were evaluated. RESULTS: Mechanical (tape stripping), chemical (acetone) or genetic (filaggrin deficiency) barrier disruption in mice amplified the expression of proinflammatory genes, with transcriptomic profiling revealing overexpression of formylpeptide receptor (Fpr1) in the epidermis. Treatment with the FPR1 agonist fMLP in keratinocytes upregulated the expression of the NLRC4 inflammasome and increased interleukin-1ß secretion through modulation of ER stress via the PERK-eIF2α-C/EBP homologous protein pathway. The activation of the FPR1-NLRC4 axis was also observed in skin specimens from old healthy individuals with skin barrier defect or elderly mice. Conversely, topical administration with a FPR1 antagonist, or Nlrc4 silencing, led to the normalization of barrier dysfunction and alleviation of inflammatory skin responses in vivo. CONCLUSIONS: In summary, our findings show that the FPR1-NLRC4 inflammasome axis is activated upon skin barrier disruption and may explain exaggerated inflammatory responses that are observed in disease states characterized by epidermal dysfunction. Pharmacological inhibition of FPR1 or NLRC4 represents a potential therapeutic target.

Ocular side effects of systemic isotretinoin - a systematic review and summary of case reports.

Background: Isotretinoin is frequently used for treatment of severe nodulocystic and papulopustular acne, however use is limited by mucocutaneous, ocular, and systemic side effects.Objective: (1) provide a systematic meta-analysis of ocular side effects during isotretinoin use and their corresponding incidences; (2) provide a narrative summary of ocular side effects during isotretinoin use reported in case reports.Methods: A systematic database search using predefined search terms was performed in PubMed, EMBASE, and Scopus from inception to 5 March, 2021. Predetermined inclusion and exclusion criteria were used to select included studies. In total, 53 original studies qualified for meta-analysis, and 41 case reports/series qualified for narrative results.Results: The studies included in the meta-analysis reported incidences of various ocular side effects including dry eye, eye sensitivity, vision changes, and ocular inflammatory conditions. Incidences across studies did vary, leading to considerable heterogeneity. The narrative results summarize more uncommon, but equally important, ocular side effects.Conclusions: Dry eye is the most commonly reported ocular side effect. Other less common, but more serious, ocular side effects including vision changes can occur. We recommend that isotretinoin prescribers monitor for dry eye. Limitations include the heterogeneity of reported incidences of ocular side effects between studies.

The ERAS Supplemental Application: Current Status and Recommendations for Dermatology Applicants and Programs.

The 2021-2022 dermatology residency program application cycle involved an optional common supplemental application piloted by the Association of American Medical Colleges' (AAMC) Electronic Residency Application Service (ERAS). In this article we present data on the utilization and opinions of applicants and programs regarding the supplemental application, discuss changes to the supplemental application for the upcoming application cycle, and offer recommendations to applicants and programs entering year 2 of the ERAS supplemental application.

Cytokine responses in nonlesional psoriatic skin as clinical predictor to anti-TNF agents.

BACKGROUND: A major issue with the current management of psoriasis is our inability to predict treatment response. OBJECTIVE: Our aim was to evaluate the ability to use baseline molecular expression profiling to assess treatment outcome for patients with psoriasis. METHODS: We conducted a longitudinal study of 46 patients with chronic plaque psoriasis treated with anti-TNF agent etanercept, and molecular profiles were assessed in more than 200 RNA-seq samples. RESULTS: We demonstrated correlation between clinical response and molecular changes during the course of the treatment, particularly for genes responding to IL-17A/TNF in keratinocytes. Intriguingly, baseline gene expressions in nonlesional, but not lesional, skin were the best marker of treatment response at week 12. We identified USP18, a known regulator of IFN responses, as positively correlated with Psoriasis Area and Severity Index (PASI) improvement (P = 9.8 × 10-4) and demonstrate its role in regulating IFN/TNF responses in keratinocytes. Consistently, cytokine gene signatures enriched in baseline nonlesional skin expression profiles had strong correlations with PASI improvement. Using this information, we developed a statistical model for predicting PASI75 (ie, 75% of PASI improvement) at week 12, achieving area under the receiver-operating characteristic curve value of 0.75 and up to 80% accurate PASI75 prediction among the top predicted responders. CONCLUSIONS: Our results illustrate feasibility of assessing drug response in psoriasis using nonlesional skin and implicate involvement of IFN regulators in anti-TNF responses.

Noninvasive Tape-Stripping with High-Resolution RNA Profiling Effectively Captures a Preinflammatory State in Nonlesional Psoriatic Skin.

Tape stripping is a minimally invasive, nonscarring method that can be utilized to assess gene expression in the skin but is infrequently used given technical constraints. By comparing different tape stripping technologies and full-thickness skin biopsy results of lesional and nonlesional psoriatic skin from the same patients, we demonstrate that tape stripping with optimized high-resolution transcriptomic profiling can be used to effectively assess and characterize inflammatory responses in the skin. Upon comparison with single-cell RNA-sequencing data from psoriatic full-thickness skin biopsies, we illustrate that tape-stripping efficiently captures the transcriptome of the upper layers of the epidermis with sufficient resolution to assess the molecular components of the feed-forward immune amplification pathway in psoriasis. Notably, nonlesional psoriatic skin sampled by tape stripping demonstrates activated, proinflammatory changes when compared to healthy control skin, suggesting a prepsoriatic state, which is not captured on full-thickness skin biopsy transcriptome profiling. This work illustrates an approach to assess inflammatory response in the epidermis by combining noninvasive sampling with high throughput RNA-sequencing, providing a foundation for biomarker discoveries and mechanism of action studies for inflammatory skin conditions.

Effect of Costimulatory Blockade With Abatacept After Ustekinumab Withdrawal in Patients With Moderate to Severe Plaque Psoriasis: The PAUSE Randomized Clinical Trial.

IMPORTANCE: Psoriasis relapse may involve compensatory T-cell activation pathways in the presence of CD28-CD80/CD86 blockade with abatacept. OBJECTIVE: To determine whether costimulatory signaling blockade with abatacept prevents psoriasis relapse after ustekinumab withdrawal. DESIGN, SETTING, AND PARTICIPANTS: Psoriasis Treatment with Abatacept and Ustekinumab: a Study of Efficacy (PAUSE), a parallel-design, double-blind, placebo-controlled randomized clinical trial, was conducted at 10 sites in the US and Canada. Participant enrollment opened on March 19, 2014, and concluded on April 11, 2016. Participants were adults with moderate to severe plaque psoriasis and received ustekinumab in a lead-in phase. Those who responded to ustekinumab at week 12 were randomized 1:1 to either the continued with ustekinumab group (ustekinumab group) or the switched to abatacept group (abatacept group). Treatment was discontinued at week 39, and participants were followed up for psoriasis relapse until week 88. Statistical analyses were performed in the intention-to-treat (ITT) and safety samples from May 3, 2018, to July 6, 2021. INTERVENTIONS: Participants received subcutaneous ustekinumab at weeks 0 and 4 (45 mg per dose for those ≤100 kg; 90 mg per dose for those >100 kg). Participants randomized to the abatacept group at week 12 received subcutaneous abatacept, 125 mg weekly, from weeks 12 to 39 and ustekinumab placebo at weeks 16 and 28. Participants randomized to the ustekinumab group received ustekinumab at weeks 16 and 28 and abatacept placebo weekly from weeks 12 to 39. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of participants with psoriasis relapse (loss of ≥50% of the initial Psoriasis Area and Severity Index improvement) between weeks 12 and 88. Secondary end points included time to psoriasis relapse, proportion of participants with psoriasis relapse between weeks 12 and 40, and adverse events. The psoriasis transcriptome and serum cytokines were evaluated. RESULTS: A total of 108 participants (mean [SD] age, 46.1 [12.1] years; 73 [67.6%] men) were treated with open-label ustekinumab; 91 were randomized to blinded treatment. Similar proportions of participants in the abatacept group and the ustekinumab group relapsed between weeks 12 and 88 (41 of 45 [91.1%] vs 40 of 46 [87.0%]; P = .41). Median time to relapse from the last dose of ustekinumab was similar between groups as well: 36 weeks (95% CI, 36-48 weeks) in the abatacept group vs 32 weeks (95% CI, 28-40 weeks) in the ustekinumab group. Similar numbers and rates of adverse events occurred. Abatacept did not maintain suppression of the pathogenic IL-23-mediated psoriasis molecular signature in lesions after ustekinumab withdrawal, and serum IL-19 levels increased. CONCLUSIONS AND RELEVANCE: This parallel-design, double-blind randomized clinical trial found that abatacept did not prevent psoriasis relapse that occurred after ustekinumab withdrawal because it did not completely block the pathogenic psoriasis molecular pathways that led to relapse. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01999868.

The Malignancy Potential of Porokeratosis: A Single-Center Retrospective Study.

Background Porokeratosis (PK) is a rare group of keratinization disorders. While the overall prognosis of PK is favorable, malignant transformation of PK to skin cancer has been reported in 6.9% to 11.6% of the cases. Prior estimates of malignant transformation of PK have been based on reviews of published cases, which introduces possible publication bias. We aim to eliminate this potential bias and quantify the characteristics, risk factors, and malignancy potential of PK. Methodology A single-center retrospective chart review of patients with a diagnosis of PK was conducted. Results In this study, 6.4% to 16.4% of histologically confirmed PK lesions demonstrated malignant transformation. A higher proportion of disseminated superficial actinic porokeratosis (DSAP) cases (as high as 29.3%) showed malignant transformation compared to PK of Mibelli (as high as 6.0%). Out of the two cases of linear PK, both demonstrated malignant transformation. Conclusions In summary, PKs are at risk for malignant transformation, and patients with DSAP and linear PK, in particular, should receive more long-term surveillance. Limitations of this study include the inability to control for confounding factors due to the retrospective nature and the small size of our cohort.

Dermatology residency preparation curriculum: a model for initiating new residents into dermatology clinical care.

Entering dermatology residency is an immersive experience requiring new specialty-specific skills. There is no standard Accreditation Council for Graduate Medical Education (ACGME) protocol for orienting new dermatology residents. We aimed to design, develop, and evaluate a curriculum for incoming first-year dermatology residents focusing on practical introduction to dermatologic clinical care emphasizing ACGME dermatology milestones. A concentrated 8-hour residency preparation course for first-year dermatology residents was designed and developed by faculty. The course encompassed clinical competencies, procedural techniques, and professionalism and collegiality principles. Teaching methods included lectures, video demonstrations, simulated patient experiences, and one-on-one practical instruction. Surveys were distributed before, immediately after, and 6-months following the course from 2016-2018 to assess participants' skill-based confidence level and perceived usefulness of the course. A total of 24 first-year dermatology residents participated in the residency preparation course over 3 years from 2016-2018. Residents' confidence levels in performing dermatology-specific skills immediately increased following the course and continued to increase 6 months into training. The majority of first-year residents "agreed" or "strongly agreed" that the course was helpful for improving clinical competence. Our residency preparation course increased first-year residents' confidence and perceived competence in performing clinical skills related to ACGME dermatology milestones.

Development of an Illustrated Scale for Acute Radiation Dermatitis in Breast Cancer Patients.

PURPOSE: Scales for rating acute radiation dermatitis (ARD) have not been validated despite decades of clinical use, and little is known regarding the relationship between toxicity scores and patient-reported symptoms. Skin tone also complicates assessment of ARD, and as such we sought to design an illustrated scale to consistently describe ARD across several skin tone types in breast cancer patients undergoing radiation (RT). METHODS AND MATERIALS: Patients undergoing RT for breast cancer were enrolled on a prospective study with photographs obtained at 2-week intervals. Photographs were clustered according to the apparent severity of acute radiation dermatitis and a descriptive photonumeric scale was developed. Four clinically experienced raters used both the illustrated photonumeric scale and the Common Terminology Criteria for Adverse Events to independently score the collection of photographs in 2 independent sessions. RESULTS: Among 80 unique patients with 192 photographs, 47 patients (59%) completed questionnaires about their symptoms during RT. Physicians completed toxicity forms at the point-of-care for 52 patients (65%). Photonumeric ratings compared against patient reports of dry and moist desquamation demonstrated high specificity (95% and 93%, respectively) and negative predictive value (84% and 92%), indicating correct identification of patients who did not report dry or moist desquamation. The sensitivity and positive predictive value for separate measures of dry and moist desquamation were considerably lower. A combined measure of any desquamation (dry or moist) portrayed higher diagnostic accuracy, resulting in 72% sensitivity, 93% specificity, 75% positive predictive value, and 92% negative predictive value. Photonumeric ratings of dry or moist desquamation were significantly associated with patient reports of itching, burning or stinging, hurting, and swelling. CONCLUSIONS: The Michigan scale for acute radiation dermatitis is a simple grading rubric that is distinguished by characterization of its intra- and interrater reliability and diagnostic accuracy, correlation with patient-reported symptoms of bother and pain, and applicability across the spectrum of skin pigmentation.

Association of dermatology wait times with insurance coverage in Michigan.

OBJECTIVES: Although the Affordable Care Act has greatly expanded coverage, the physician workforce has not increased commensurately. Data on wait times, especially among dermatologists who accept Medicaid, are lacking. The objective of this study was to evaluate wait times in dermatology clinics by insurance coverage and chief complaint. STUDY DESIGN: A "secret shopper" survey was conducted. METHODS: Between June and July 2016, 186 dermatology clinics in Michigan were contacted to determine the earliest available appointment for a patient seeking an evaluation of a changing mole, a chronic rash, and botulinum toxin administration. RESULTS: The mean (standard error [SE]) wait time regardless of insurance or chief complaint was 28.8 (1.29) days. Clinics that accept Medicaid had longer wait times (32.9 [2.19] vs 25.4 [1.50] days; P = .024). The mean (SE) wait time for a mole or rash was longer for patients with Medicaid compared with those with private insurance (40.0 [4.08] vs 27.7 [1.54] days; P = .003). The mean (SE) wait time for Medicaid patients compared with patients with private insurance was also longer, even within the same clinic (39.1 [4.11] vs 27.5 [1.57] days; median, 23.5 vs 16.0 days). Patients with Medicaid were able to obtain appointments sooner for botulinum toxin administration (22.5 [2.10] days) compared with evaluation of a mole (40.0 [6.63] days) or rash (40.1 [4.99] days) (P = .004). CONCLUSIONS: Wait times for clinic appointments were longer for patients with Medicaid, especially when requesting an evaluation for a medical dermatologic issue compared with a cosmetic consultation. Delay in medical dermatologic care, especially among Medicaid patients, must be addressed.

Atrophic and hypertrophic photoaging: Clinical, histologic, and molecular features of 2 distinct phenotypes of photoaged skin.

BACKGROUND: Exposure to the sun causes premature skin aging, known as photoaging. Clinical features of photoaging vary widely among individuals. In one form, skin appears thin with telangiectasia, and in another form, skin appears thickened with coarse wrinkles. Etiologic, clinical, and therapeutic distinctions among different forms of photoaging remain largely unknown. OBJECTIVE: To characterize the clinical, histologic, and molecular features of hypertrophic and atrophic photoaging. METHODS: In total, 53 individuals were clinically classified as having primarily atrophic or hypertrophic photoaging or neither (controls). Participants' demographic and sun exposure-related lifestyle data were captured by questionnaire. Fifteen clinical features of participants were qualitatively or quantitively scored. Facial biopsies were analyzed for gene expression and histologic characteristics. RESULTS: Actinic and seborrheic keratosis, telangiectasia, and prior incidence of skin cancers were statistically significantly greater and photoaging scale severity, coarse wrinkles, thickness, and sallowness were significantly reduced in atrophic versus hypertrophic groups. Histology also revealed significantly less elastotic material in atrophic photoaging. Gene expression of matrix metalloproteinases and collagens did not differ between the 2 forms of photoaging. LIMITATIONS: The study was not designed to identify other possible subtypes of photoaging. CONCLUSION: Systematic, categorical, and quantitative clinical and histologic assessments distinguish atrophic and hypertrophic photoaging.