Roflumilast Cream, 0.15%, for Atopic Dermatitis in Adults and Children: INTEGUMENT-1 and INTEGUMENT-2 Randomized Clinical Trials.

Importance: Safe, effective, and well-tolerated topical treatment options available for long-term use in patients with atopic dermatitis (AD) are limited and associated with low adherence rates. Objective: To evaluate efficacy and safety of once-daily roflumilast cream, 0.15%, vs vehicle cream in patients with AD. Design, Setting, and Participants: Two phase 3, randomized, double-blind, vehicle-controlled trials (Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis 1 and 2 [INTEGUMENT-1 and INTEGUMENT-2]), included patients from sites in the US, Canada, and Poland. Participants were 6 years or older with mild to moderate AD based on Validated Global Assessment for Atopic Dermatitis (assessed on a 5-point scale ranging from 0 [clear] to 4 [severe]). Intervention: Patients were randomized 2:1 to receive roflumilast cream, 0.15%, or vehicle cream once daily for 4 weeks. Main Outcomes and Measures: The primary efficacy end point was Validated Investigator Global Assessment for Atopic Dermatitis success at week 4, defined as a score of 0 or 1 plus at least a 2-grade improvement from baseline. Secondary end points included Eczema Area and Severity Index and Worst Itch Numeric Rating Scale. Safety and local tolerability were also evaluated. Results: Among 1337 patients (654 patients in INTEGUMENT-1 and 683 patients in INTEGUMENT-2), the mean (SD) age was 27.7 (19.2) years, and 761 participants (56.9%) were female. The mean body surface area involved was 13.6% (SD = 11.6%; range, 3.0% to 88.0%). Significantly more patients treated with roflumilast than vehicle achieved the primary end point (INTEGUMENT-1: 32.0% vs 15.2%, respectively; P < .001; INTEGUMENT-2: 28.9% vs 12.0%, respectively; P < .001). At week 4, statistically significant differences favoring roflumilast also occurred for the achievement of at least 75% reduction in the Eczema Area and Severity Index (INTEGUMENT-1: 43.2% vs 22.0%, respectively; P < .001; INTEGUMENT-2: 42.0% vs 19.7%, respectively; P < .001). Roflumilast was well tolerated with low rates of treatment-emergent adverse events. At each time point, investigators noted no signs of irritation at the application site in 885 patients who were treated with roflumilast (≥95%), and 885 patients who were treated with roflumilast (90%) reported no or mild sensation at the application site. Conclusions and Relevance: In 2 phase 3 trials enrolling adults and children, once-daily roflumilast cream, 0.15%, improved AD relative to vehicle cream, based on multiple efficacy end points, with favorable safety and tolerability. Trial Registration: ClinicalTrials.gov Identifiers: NCT04773587, NCT04773600.

Resident memory T cells in dirty mice suppress innate cell activation and infiltration into the skin following stimulation with alarmins.

Trm cells are sequestered at barrier tissues as a swift first line defense against peripheral reinfections in both antigen dependent and antigen independent bystander modes. Trm cells are also capable of mediating autoimmune diseases, such as psoriasis, wherein autoreactive Trm cells are aberrantly activated. To quickly combat infections, activated Trm cells can stimulate the influx and activation of memory T cells and innate immune cells. However, there is significant heterogeneity in the inflammatory responses that Trm cell populations can induce, specifically in the activation of the innate profile. Most studies to date have utilized a reductionist approach to examine single Trm populations, specific pathogens, and defined tissues. Herein, we adopted a more holistic approach utilizing barrier-free 'dirty' mice to profile activated innate cells attracted to the skin in the presence of quiescent cutaneous Trm cells. Notably, dirty mice are a more human predictive model due to having a diverse microbial experience that leads to the development of a complete complement of Trm cells in the skin. We demonstrate that in the dirty mouse model mice have a significant reduction in cutaneous neutrophils and monocytes compared to SPF mice following local treatment with two separate innate stimuli. These findings reveal that cutaneous Trm cells have the capacity to temper the innate immune response and further substantiate the implication that Trm cells are heterogenous in their functions depending in large part on their tissue residency. However, in an autoimmune microenvironment Trm cells are capable of recruiting innate cells to the site of an exposure to a damage-associated molecular pattern. Likely due to the imbalance of IL-17 and IFN-γ.

Dermatology medications with the highest cost burden on Medicare Part D: Potential implications of the Inflation Reduction Act.

Signed into law in August 2022, the Inflation Reduction Act includes provisions requiring the federal government to negotiate prices for medications covered under Medicare Part D. Initial negotiations will target drugs with the highest total spending and price increases relative to inflation. In this study, we identify dermatology prescriptions with the highest cost burden on Medicare Part D and analyze recent trends in total spending and unit costs.

A 30-nation investigation of lay heritability beliefs.

Lay beliefs about human trait heritability are consequential for cooperation and social cohesion, yet there has been no global characterisation of these beliefs. Participants from 30 countries (N = 6128) reported heritability beliefs for intelligence, personality, body weight and criminality, and transnational factors that could influence these beliefs were explored using public nation-level data. Globally, mean lay beliefs differ from published heritability (h2) estimated by twin studies, with a worldwide majority overestimating the heritability of personality and intelligence, and underestimating body weight and criminality. Criminality was seen as substantially less attributable to genes than other traits. People from countries with high infant mortality tended to ascribe greater heritability for most traits, relative to people from low infant mortality countries. This study provides the first systematic foray into worldwide lay heritability beliefs. Future research must incorporate diverse global perspectives to further contextualise and extend upon these findings.

Long-term safety and effectiveness of roflumilast cream 0.3% in adults with chronic plaque psoriasis: A 52-week, phase 2, open-label trial.

BACKGROUND: Efficacy and/or safety profiles limit topical psoriasis treatments. OBJECTIVE: Evaluate long-term effects of once-daily roflumilast cream 0.3% in patients with psoriasis. METHODS: In this open-label phase 2 trial, adult patients (N = 332) with psoriasis who completed the phase 2b parent trial or were newly enrolled applied roflumilast once-daily for 52 weeks. Safety and effectiveness were assessed. RESULTS: Overall, 244 patients (73.5%) completed the trial; 13 patients (3.9%) discontinued due to adverse events (AEs) and 3 (0.9%) due to lack of efficacy. Twelve patients (3.6%) reported treatment-related AEs; none were serious. ≥97% of patients had no irritation. No tachyphylaxis was observed with 44.8% of the patients achieving Investigator Global Assessment (IGA) Clear or Almost Clear at Week 52. LIMITATIONS: Intertriginous-IGA and Psoriasis Area and Severity Index (PASI) were not evaluated in all patients. CONCLUSIONS: In this long-term trial, once-daily roflumilast cream was well-tolerated and efficacious up to 64 weeks in patients in the earlier trial, suggesting it is suitable for chronic treatment, including the face and intertriginous areas.

Incorporating a Prognostic Gene Expression Profile Test into the Management of Cutaneous Squamous Cell Carcinoma: An Expert Consensus Panel Report.

BACKGROUND:  Cutaneous squamous cell carcinoma (cSCC) is a growing health concern with a rapidly increasing incidence. Disease-specific mortality is typically preceded by a metastasis, but current staging systems have significant limitations in predicting this event. The 40-gene expression profile (40-GEP) test is a validated method of further stratifying patients based on the risk of regional or distant metastasis, but limited guidelines exist for incorporating this test into clinical practice. OBJECTIVE:  To review the available literature on the use of gene expression profile (GEP) testing to assess prognosis in cSCC and create consensus statements to guide dermatology clinicians on its use. METHODS:  A comprehensive literature search of PubMed, EMBASE, and Scopus was completed for English-language original research articles on the use of GEP testing to assess cSCC prognosis. A panel of 8 dermatologists with significant expertise in diagnosing and managing cSCC gathered to review the articles and create consensus statements. A modified Delphi process was used to approve each statement and a strength of recommendation was assigned using the Strength of Recommendation Taxonomy (SORT) criteria. RESULTS:  The literature search produced 157 articles that met the search criteria. A thorough screening of the studies for relevance to the research question resulted in 21 articles that were distributed to the panelists for review prior to the roundtable discussion. The panel unanimously voted to adopt 7 consensus statements and recommendations, 6 of which were given a strength of "A" and 1 of which was given a strength of "C". CONCLUSION:  The 40-GEP test provides accurate and independent prognostic information beyond standard staging systems that only incorporate pathologic data. Incorporation of GEP testing into national guidelines can help further stratify patients based on risk of metastasis and thus may improve morbidity and mortality. J Drugs Dermatol. 2023;22(12):54-60.   doi:10.36849/JDD.7691.

An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis.

BACKGROUND: The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23-receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production. METHODS: In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16. RESULTS: A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose-response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups. CONCLUSIONS: After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23-receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Research and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.).

Melanoma Detected Through Teledermatology Versus In-Person Visits.

Background: Early detection of melanoma improves survival; however, patients face long wait times to receive dermatology care. Teledermatology (TD) is a promising tool to optimize access to care and has shown promise for the identification of malignancies but has not been well studied for melanoma. We evaluated the utility of TD as a triage tool to allow high-risk lesions of concern to be seen more expeditiously. Methods: Patient sociodemographic factors and histological characteristics of 836 melanomas biopsied between March 2020 and November 2022 in the University of Pittsburgh Medical Center health system were retrospectively evaluated, stratified by initial appointment type of TD versus in-person visit. Results: Patients first seeking care through teledermatology had shorter wait times to initial evaluation (p < 0.001) and eventual biopsy (p < 0.001), and these melanomas had higher Breslow thickness (p < 0.001), were more ulcerated (p = 0.002), invasive (p = 0.001), and of a more aggressive subtype (p = 0.007) than those initially evaluated in-person. TD was also utilized by a higher proportion of younger (p = 0.001) and non-white (p = 0.03) patients who identified their own lesion (p < 0.001). Conclusions: TD may be a strategy to improve melanoma outcomes by providing an accessible avenue of expedited care for high-risk lesions associated with worse clinical prognosticators of disease.

Descriptive and Concordance Data for Asynchronous Teledermatology Consultations for Dermatitis: A Retrospective Study.

Background: Implementation of teledermatology for assessing dermatitis patients provides comparable diagnostic and management outcomes to in-person visits, but studies on consumer to physician asynchronous teledermatology (eDerm) consults submitted by patients in large dermatitis cohorts are limited. The objective of this study was to retrospectively assess associations of eDerm consults with diagnostic accuracy, management, and follow-up in a large cohort of dermatitis patients. Methods: One thousand forty-five eDerm encounters between April 1, 2020, and October 29, 2021, recorded in the University of Pittsburgh Medical Center Health System Epic electronic medical record were reviewed. Descriptive statistics and concordance were analyzed using chi-square. Results: Asynchronous teledermatology modified/changed treatment in 97.6% of cases and had the same diagnosis between teledermatology and in-person follow-up in 78.3% of cases. Patients following up in the time line requested were more likely to follow-up in person (61.2% vs. 43.8%) than those who did not. Patients with intertriginous dermatitis (p = 0.003), preexisting conditions (p = 0.002), who required follow-ups (<0.0001), and moderate-high severity scores of 4-7 (p = 0.019) were more likely to follow up in the time line requested. Limitations: Lack of similar in-person visit data did not allow us to compare descriptive and concordance data between eDerm and clinic visits. Conclusions: eDerm offers a quick accessible solution to provide comparable dermatologic care for patients with dermatitis.

Real-world effectiveness of risankizumab in patients with moderate-to-severe psoriasis using the CorEvitas Psoriasis Registry.

BACKGROUND: Psoriasis, an inflammatory skin disease, is often treated with biologic therapeutics. OBJECTIVE: To determine the real-world treatment effectiveness of risankizumab, an interleukin-23 inhibitor, in the treatment of moderate-to-severe plaque psoriasis. METHODS: A retrospective, observational study was conducted using the CorEvitas Psoriasis Registry for eligible adults with a diagnosis of moderate-to-severe psoriasis and persistent use of risankizumab at 12 (±3) months after initiation. Skin clearance measures and patient-reported outcomes were analyzed for the entire study population and by prior biologic treatment. RESULTS: Among 287 patients with persistent risankizumab use at 1 year, most achieved clear or clear/almost clear skin and reported significant reductions in Dermatology Life Quality Index scores, psoriasis symptoms (fatigue, skin pain, and overall itch), and work and activity impairment. LIMITATIONS: The CorEvitas Psoriasis Registry is not necessarily representative of all adults with psoriasis in the United States and Canada and does not measure patient adherence. CONCLUSION: Patients treated with risankizumab, regardless of prior treatment, achieved high levels of clear and clear/almost clear skin, Dermatology Life Quality Index scores of 0/1, and significant reductions in psoriasis symptoms (fatigue, skin pain, and overall itch) and work and activity impairment 1 year after initiation.

Pharmacokinetics, safety, and efficacy of cedirogant from phase I studies in healthy participants and patients with chronic plaque psoriasis.

Cedirogant is an inverse agonist of retinoic acid-related orphan receptor gamma thymus (RORγt) developed for the treatment of moderate to severe chronic plaque psoriasis. Here, we report the results from two phase I studies in which the pharmacokinetics (PK), safety, and efficacy of cedirogant in healthy participants and patients with moderate to severe chronic plaque psoriasis were evaluated. The studies consisted of single (20-750 mg) and multiple (75-375 mg once-daily [q.d.]) ascending dose designs, with effect of food and itraconazole on cedirogant exposure also evaluated. Safety and PK were evaluated for both healthy participants and psoriasis patients, and efficacy was assessed in psoriasis patients. Following single and multiple doses, cedirogant mean terminal half-life ranged from 16 to 28 h and median time to reach maximum plasma concentration ranged from 2 to 5 h across both populations. Cedirogant plasma exposures were dose-proportional after single doses and less than dose-proportional from 75 to 375 mg q.d. doses. Steady-state concentrations were achieved within 12 days. Accumulation ratios ranged from approximately 1.2 to 1.8 across tested doses. Food had minimal effect and itraconazole had limited impact on cedirogant exposure. No discontinuations or serious adverse events due to cedirogant were recorded. Psoriasis Area and Severity Index (PASI) and Self-Assessment of Psoriasis Symptoms (SAPS) assessments demonstrated numerical improvement with treatment of cedirogant 375 mg q.d. compared with placebo. The PK, safety, and efficacy profiles of cedirogant supported advancing it to phase II clinical trial in psoriasis patients.

Incorporating a Prognostic Gene Expression Profile Test into the Management of Cutaneous Squamous Cell Carcinoma: An Expert Consensus Panel Report.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is a growing health concern with a rapidly increasing incidence. Disease-specific mortality is typically preceded by a metastasis, but current staging systems have significant limitations in predicting this event. The 40-gene expression profile (40-GEP) test is a validated method of further stratifying patients based on the risk of regional or distant metastasis, but limited guidelines exist for incorporating this test into clinical practice. OBJECTIVE: To review the available literature on the use of gene expression profile (GEP) testing to assess prognosis in cSCC and create consensus statements to guide dermatology clinicians on its use. METHODS: A comprehensive literature search of PubMed, EMBASE, and Scopus was completed for English-language original research articles on the use of GEP testing to assess cSCC prognosis. A panel of 8 dermatologists with significant expertise in diagnosing and managing cSCC gathered to review the articles and create consensus statements. A modified Delphi process was used to approve each statement and a strength of recommendation was assigned using the Strength of Recommendation Taxonomy (SORT) criteria. RESULTS: The literature search produced 157 articles that met the search criteria. A thorough screening of the studies for relevance to the research question resulted in 21 articles that were distributed to the panelists for review prior to the roundtable discussion. The panel unanimously voted to adopt 7 consensus statements and recommendations, 6 of which were given a strength of "A" and 1 of which was given a strength of "C". CONCLUSION: The 40-GEP test provides accurate and independent prognostic information beyond standard staging systems that only incorporate pathologic data. Incorporation of GEP testing into national guidelines can help further stratify patients based on risk of metastasis and thus may improve morbidity and mortality. J Drugs Dermatol. 2023;22(12): doi:10.36849/JDD.7691e.

Clinical Utility of an AI-powered, Handheld Elastic Scattering Spectroscopy Device on the Diagnosis and Management of Skin Cancer by Primary Care Physicians.

BACKGROUND: Patients with lesions suspicious for skin cancer often present to primary care physicians (PCPs), who may have limited training in skin cancer diagnosis. OBJECTIVE: To measure the impact of an adjunctive handheld device for PCPs that employs elastic scattering spectroscopy (ESS) on the diagnosis and management of skin cancer. METHODS: Fifty-seven PCPs evaluated 50 clinical images of skin lesions (25 malignant and 25 benign), first without and then with knowledge of the handheld ESS device output, and in each case indicated if a lesion was likely to be benign or malignant. RESULTS: The diagnostic sensitivity of the PCPs with and without the use of the ESS device was 88% (95% CI, 84%-92%) and 67% (95% CI, 62%-72%), respectively (P < .0001). In contrast, no significant difference was observed in the diagnostic specificity. The management sensitivity of the physicians with and without the use of the ESS device was 94% (95% CI, 91%-96%) and 81% (95% CI, 77%-85%), respectively (P = .0009). Similarly, no significant difference was observed in the management specificity. CONCLUSION: The use of the ESS device may have the potential to help improve skin cancer diagnosis and confidence in management decision-making in a primary care setting.

Melanoma Detection in Alaska Native, American Indian, Asian, Black, Hispanic, and Pacific Islander Patients in a Large Skin Cancer Screening Initiative.

This cohort study investigates patterns in melanoma detection in racial and ethnic minority populations as part of a large, primary care­based screening initiative.