Safety and efficacy of fractional radiofrequency for the treatment and reduction of acne scarring: A prospective study.

OBJECTIVES: Skin rejuvenation with radiofrequency has been a widely used treatment modality for the safe and efficient remodeling of the dermis and revision of textural irregularities, achieved with minimal downtime. The efficacy of fractional radiofrequency (FRF) specifically for acne scarring has not been widely established. The objective of this clinical trial was to establish the efficacy and safety of FRF for moderate to severe acne scarring in a wide range of Fitzpatrick skin types using two different applicator tips to deliver energy to the skin (80-pin of up to 124 mJ/pin and 160-pin of up to 62 mJ/pin). METHODS: Enrolled subjects received a series of three FRF treatments to the full face, each 4 weeks apart. A visual analog scale was utilized to assess pain of the treatment. Subject satisfaction questionnaires were completed at follow-up visits at 6 and 12 weeks post final treatment. Photographs were graded for change by three blinded evaluators using the Global Aesthetic Improvement Scale (GAIS). RESULTS: Image sets of 23 enrolled subjects were assessed by blinded evaluation, showing a statistically significant improvement (p = 0.009) from the baseline visit to the 12-week follow-up on the GAIS for acne scarring. Subject satisfaction was high with subjects giving an average satisfaction score of 3.27 ("satisfied") out of 4. Pain was "mild" as treatments were rated an average of 2.15 on a 10-point visual analog scale. The GAIS score of the 80-pin tip improved patients' acne scars treated with that applicator by 1.06 points and 0.85 for the 160-pin tip. Ninety-five percent (95.5%) of subjects reported either a mild, moderate, or significant improvement to their treatment area. Ninety-one percent of subjects reported that they would recommend the treatment to a friend. CONCLUSION: FRF produced a statistically significant improvement in acne scarring when assessed by independent blinded evaluators. No serious adverse events resulted from treatment by either applicator tip. Treatment pain was low and tolerable among subjects of all Fitzpatrick skin types. Subjects had high levels of satisfaction with the results.

Assessing Skin Biopsy Rates for Histologic Findings Indicative of Nonpathological Cutaneous Disease.

BACKGROUND: Recent increase in skin biopsies has been attributed to an epidemic of skin cancer. This may be avoidable, with potential savings. OBJECTIVE: To determine whether the increase in skin biopsies is attributable to increasing frequency of biopsies associated with histology lacking pathological cutaneous disease. Pathological cutaneous disease was defined as (1) a malignancy, precancerous lesion, or lesion of uncertain behavior; or (2) disease symptomatic or associated with adverse quality of life impact. PATIENTS AND METHODS: Retrospective cohort study, 2006 to 2013 of dermatology practice serving Florida and Ohio. Data were a consecutive sample of skin biopsies for diagnosis of dermatologic disease. RESULTS: A total of 267,706 biopsies by an average of 52 providers per month from January 06 to December 13 were analyzed. Number of biopsies per visit increased 2% per year (RR: 1.02, CI: 1.00-1.04). Likelihood of biopsy associated with histology indicative of nonpathological cutaneous disease did not increase over time (OR: 0.99, CI: 0.95-1.03, p = .6302). CONCLUSION: Rates of biopsies associated with nonpathological cutaneous disease is not increasing. Overall biopsy rates per visit have gradually increased; this seems attributable to greater rates of detection of pathological dermatologic disease.

Ixekizumab treatment shows a neutral impact on cardiovascular parameters in patients with moderate-to-severe plaque psoriasis: Results from UNCOVER-1, UNCOVER-2, and UNCOVER-3.

BACKGROUND: The impact of ixekizumab treatment for psoriasis on cardiovascular-related parameters in patients is unknown. OBJECTIVE: To investigate cardiovascular-related parameters in patients with psoriasis treated with ixekizumab. METHODS: In phase 3 trials, patients with moderate-to-severe psoriasis were randomized and treated with placebo, ixekizumab, or etanercept during the induction period (weeks 0-12; UNCOVER-1, UNCOVER-2, and UNCOVER-3). At week 12, responders were rerandomized to receive placebo or ixekizumab through the maintenance period (weeks 12-60; UNCOVER-1 and UNCOVER-2). Laboratory measures (fasting lipid profiles, glucose level, or high-sensitivity C-reactive protein [hsCRP] level), weight, blood pressure, and electrocardiograms were obtained through 60 weeks. RESULTS: Baseline parameters were within normal ranges with the exception of elevated triglyceride and hsCRP levels. After maintenance dosing, no significant changes were observed versus placebo for total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, triglyceride, apolipoprotein A1, apolipoprotein B, or fasting glucose levels or for systolic/diastolic blood pressure at 60 weeks. Importantly, low-density lipoprotein-to-high-density lipoprotein ratios remained stable during the induction and maintenance periods. HsCRP concentrations were significantly reduced versus placebo at 12 weeks and remained reduced at 60 weeks, although not significantly. Although transient changes were observed for some parameters during the induction period, these changes did not persist into the maintenance period. LIMITATIONS: A lack of echocardiogram evaluations. CONCLUSIONS: Ixekizumab had a neutral impact on cardiovascular-related parameters in patients with psoriasis.

Efficacy and safety of vismodegib in advanced basal-cell carcinoma.

BACKGROUND: Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma. METHODS: In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma. RESULTS: In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted. CONCLUSIONS: Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).

Development of Uniform Protocol for Alopecia Areata Clinical Trials.

Developing a successful treatment for alopecia areata (AA), clearly has not been at the forefront of the agenda for new drug/device development among the pharmaceutical and medical device industry. The National Alopecia Areata Foundation (NAAF), a patient advocacy group, initiated a plan to facilitate and drive clinical research toward finding safe and efficacious treatments for AA. As such, Alopecia Areata Uniform Protocols for clinical trials to test new treatments for AA were developed. The design of the uniform protocol is to accomplish the development of a plug-and-play template as well as to provide a framework wherein data from studies utilizing the uniform protocol can be compared through consistency of inclusions/exclusions, safety, and outcome assessment measures. A core uniform protocol for use by pharmaceutical companies in testing proof of concept for investigational products to treat AA. The core protocol includes standardized title, informed consent, inclusion/exclusion criteria, disease outcome assessments, and safety assessments. The statistical methodology to assess successful outcomes will also be standardized. The protocol as well as the informed consent form has been approved in concept by Liberty IRB and is ready to present to pharmaceutical companies.

Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC.

BACKGROUND: Primary analysis from the pivotal ERIVANCE BCC study resulted in approval of vismodegib, a Hedgehog pathway inhibitor indicated for treatment of adults with metastatic or locally advanced basal cell carcinoma (BCC) that has recurred after surgery or for patients who are not candidates for surgery or radiation. OBJECTIVE: An efficacy and safety analysis was conducted 12 months after primary analysis. METHODS: This was a multinational, multicenter, nonrandomized, 2-cohort study in patients with measurable and histologically confirmed locally advanced or metastatic BCC taking oral vismodegib (150 mg/d). Primary outcome measure was objective response rate (complete and partial responses) assessed by independent review facility. RESULTS: After 12 months of additional follow-up, median duration of exposure to vismodegib was 12.9 months. Objective response rate increased from 30.3% to 33.3% in patients with metastatic disease, and from 42.9% to 47.6% in patients with the locally advanced form. Median duration of response in patients with locally advanced BCC increased from 7.6 to 9.5 months. No new safety signals emerged with extended treatment duration. LIMITATIONS: Limitations include low prevalence of advanced BCC and challenges of designing a study with heterogenous manifestations. CONCLUSION: The 12-month update of the study confirms the efficacy and safety of vismodegib in management of advanced BCC.

Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib.

BACKGROUND: Vismodegib, a first-in-class Hedgehog pathway inhibitor, was US Food and Drug Administration (FDA) approved for advanced basal cell carcinomas (BCCs) based on a single, nonrandomized, phase-II trial. Consequently, additional clinical data are critical to confirm the efficacy and safety of vismodegib. OBJECTIVE: We sought to assess efficacy and safety of vismodegib, while providing early drug access to patients with advanced BCC and limited treatment options. METHODS: This was an open-label, multicenter study in patients with advanced BCC inappropriate for radiotherapy or surgery. Patients received 150 mg vismodegib daily until disease progression or intolerable toxicity. Tumor response was assessed via Response Evaluation Criteria in Solid Tumors version 1.0. RESULTS: A total of 119 patients with advanced BCC took vismodegib for a median of 5.5 months. Objective responses occurred in 46.4% of locally advanced BCC and 30.8% of patients with metastatic BCC. Response was negatively associated with prior systemic therapy in patients with locally advanced BCC (P = .002). Mean follow-up for safety was 6.5 months, with muscle spasms (70.6%), dysgeusia (70.6%), alopecia (58.0%), and diarrhea (25.2%) as the most common adverse events. LIMITATIONS: Abbreviated follow-up time because of study termination upon FDA approval was a limitation. CONCLUSION: This study provides important clinical data supporting the efficacy and safety of vismodegib. Larger studies are underway to assess predictors of response and long-term outcomes.

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.

Quantifying and characterizing adverse events in dermatologic surgery.

BACKGROUND: Although office-based dermatologic procedures are generally considered safe, there is a lack of prospective data on the rate of adverse events (AEs) associated with these procedures. OBJECTIVE: To determine the frequency of AEs after dermatologic surgery and to characterize the most commonly encountered AEs. METHODS: A web-based interface was designed to track AEs with the input of four dermatologic surgeons. Patient demographic and operative data were collected at the time of the dermatologic surgery procedure. AEs occurring at any time during the data collection period were logged according to an a priori categorization scheme. RESULTS: The AE rate was 2.0% in this series of 2,418 subjects undergoing dermatologic surgery from February 1 through December 14, 2010. The most commonly reported AEs were suspicion of infection (64%), postoperative hemorrhage (20%), and wound dehiscence (8%). Suspicion of infection was slightly less frequent in subjects who received prophylactic preoperative antibiotics (0.4%) than in those who did not (1.5%, p = .07). There were no serious AEs and no deaths. CONCLUSION: AEs are uncommon after office-based dermatologic surgery procedures. Preoperative antibiotics may further decrease the infection rate after dermatologic surgery, but the risks and benefits must be weighed given the already low AE rate.

Recommendations From a Chinese-Language Survey of Knowledge and Prevention of Skin Cancer Among Chinese Populations Internationally: Cross-sectional Questionnaire Study.

BACKGROUND: There is a paucity of studies assessing awareness and prevention of skin cancer among Chinese populations. OBJECTIVE: The aim of the study is to compare attitudes and practices regarding skin cancer risks and prevention between Chinese Asian and North American Chinese populations and between Fitzpatrick scores. METHODS: A cross-sectional, internet-based, 74-question survey in Chinese was conducted focusing on Han Chinese participants internationally. The survey included Likert-type scales and multiple-choice questions. All participants were required to read Chinese and self-identify as being 18 years or older and Chinese by ethnicity, nationality, or descent. Participants were recruited on the internet over a 6-month period from July 2017 through January 2018 via advertisements in Chinese on popular social media platforms: WeChat, QQ, Weibo, Facebook, and Twitter. RESULTS: Of the 113 completed responses collected (participation rate of 65.7%), 95 (84.1%) were ethnically Han Chinese, of which 93 (96.9%) were born in China and 59 (62.1%) were female. The mean age of these 95 participants was 35.8 (SD 13.3) years; 72 (75.8%) participants were born after 1975. Few but more North American Chinese reported that Chinese Asian populations received annual skin checks (4/30, 4.2% vs 0/65, 0%; P=.009) and believed that their clinician provided adequate sun safety education (13/30, 43.3% vs 15/65, 23.1%; P=.04). Participants with higher Fitzpatrick scores less frequently received sun safety education from a clinician (4/34, 11.8% vs 22/61, 36.1%; P=.02). More participants with lower Fitzpatrick scores used sunscreen (41/61, 67.2% vs 16/34, 47.1%; P=.05), but alternative sun protection use rates are similar across groups. CONCLUSIONS: Cultural differences and Fitzpatrick scores can affect knowledge and practices with respect to sun protection and skin cancer among social media-using Chinese Asian and North American Chinese communities based on respondent demographics. Most participants in all groups understood that people of color have some risk of skin cancer, but >30% of all groups across regions and Fitzpatrick scores are unaware of current skin protection recommendations, receive insufficient sun safety education, and do not use sunscreen. Outreach efforts may begin broadly with concerted public and private efforts to train and fund dermatologists to perform annual total body skin exams and provide more patient education. They should spark community interest through mass media and empower Chinese people to perform self-examinations and recognize risks and risk mitigation methods.

Treatment of Psoriasis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: Our aim was to summarize and evaluate the current quality of evidence regarding the efficacy of therapies for cutaneous psoriasis (PsO) in patients with psoriatic arthritis (PsA). METHODS: A literature search of MEDLINE, Embase, Cochrane Library databases, and conference abstracts was conducted to identify interventional randomized controlled trials in patients with PsA between February 2013 and December 2021. Studies were included if PsO outcomes included achieving at least 75% improvement in the Psoriasis Area and Severity Index and the blinded comparison period was ≥ 10 weeks. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was employed to assess quality of the evidence to inform and update the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations. RESULTS: A total of 116 studies and 36 abstracts identified in the initial search were screened. A total of 37 studies (40 treatment arms) met the criteria for final inclusion. Phosphodiesterase 4 inhibitors, Janus kinase inhibitors, and tyrosine kinase 2 inhibitors, interleukin 17 inhibitors (IL-17i), IL-12/23i, IL-23i, and tumor necrosis factor inhibitors (TNFi) had high-quality data broadly supporting the efficacy of each class for plaque PsO over placebo. Head-to-head studies with high-quality data supported both IL-17i and IL-23i over TNFi. CONCLUSION: Several pharmacologic therapeutic classes have high-quality evidence demonstrating efficacy for cutaneous PsO in the PsA population. The findings will be integrated into the 2021 GRAPPA treatment recommendations, intended to guide selection of a therapeutic class where efficacy in 1 or more cutaneous or musculoskeletal domains is required.

A randomized, double-blind, vehicle-controlled crossover study to determine the anti-pruritic efficacy, safety and local dermal tolerability of a topical formulation (srd174 cream) of the long-acting opiod antagonist nalmefene in subjects with atopic dermatitis.

OBJECTIVE: To investigate the efficacy, safety and tolerability of topical nalmefene (SRD174), a long acting opioid antagonist for the management of pruritus associated with atopic dermatitis (AD). DESIGN: Double-blind, vehicle-controlled, randomized, cross-over trial. SETTING: Eleven dermatology outpatient clinics in the U.S. PATIENTS: Sixty-two out of 136 screened adult subjects with confirmed AD affecting is less than or equal to 20% of body surface area and with moderate-to-severe pruritus. INTERVENTIONS: SRD174 cream or matching vehicle cream applied as required during two 7-day periods separated by a wash-out period. MAIN OUTCOME MEASURE(S): The primary efficacy variable was the period mean of the sum of pruritus intensity difference (SPID) from 0 to 4 hours (SPID0-4) where pruritus was measured on a 0-100 scale Visual Analog Scale (VAS) at seven pre-specified time-points following study drug application. A range of secondary efficacy, safety and tolerance endpoints were included. RESULTS: The LS means for the SPID0-4 (± SD) for SRD174 cream and Vehicle were 210.7 (20.4) and 212.1 (20.2), respectively (Difference = -1.3 (95% CI: -25.9, 23.3). None of the secondary efficacy endpoints tested demonstrated a statistically significant or clinically important difference between the test product and the vehicle. Overall, the SRD174 cream was well tolerated although there was a higher incidence of AEs when subjects took SRD174 cream (22, 36.7 percent of subjects) compared with when they were taking vehicle (14, 23.3 percent of subjects). CONCLUSIONS: SRD174 cream did not demonstrate efficacy in the treatment of pruritus associated with atopic dermatitis raising questions on the role of peripheral opioid receptors as a target for the treatment of pruritus in this population.

Hedgehog Pathway Inhibition for the Treatment of Basal Cell Carcinoma.

Globally, basal cell carcinoma is the most commonly diagnosed cancer. While most cases are amenable to surgery, treatment options for advanced basal cell carcinoma, including locally advanced basal cell carcinoma and metastatic basal cell carcinoma, have proved more difficult. Recent advances regarding the role of hedgehog signaling in the pathogenesis of basal cell carcinoma and the identification of hedgehog pathway inhibitors have facilitated the development of treatment options with improved clinical outcomes. The hedgehog signaling pathway regulates development, cell proliferation, and tissue repair. The pathway is tightly regulated under normal physiological conditions. However, dysregulated hedgehog signaling in human cancers was first described in patients with basal cell carcinoma nevus syndrome and sporadic basal cell carcinoma, in which germline or somatic mutations in pathway components (e.g., smoothened [Smo] and patched-1) lead to constant activation. Subsequently, inhibitors blocking hedgehog signaling either at the level of Smo (i.e., vismodegib, sonidegib, patidegib, and itraconazole) or via an unknown mode of action (arsenic trioxide) were identified. The hedgehog inhibitor vismodegib is approved for the treatment of locally advanced basal cell carcinoma and metastatic basal cell carcinoma while sonidegib is approved for the treatment of locally advanced basal cell carcinoma in the USA and Europe; and for locally advanced basal cell carcinoma and metastatic basal cell carcinoma in Switzerland and Australia. The most common treatment-emergent adverse events associated with approved hedgehog inhibitors include muscle spasms, dysgeusia, and alopecia. This review addresses the challenges associated with appropriately diagnosing locally advanced basal cell carcinoma, provides an overview of hedgehog signaling in basal cell carcinoma, and discusses the pharmacology of hedgehog inhibitors and their efficacy, and adverse events associated with hedgehog inhibitor use, and their management.

Hedgehog signaling inhibitors in solid and hematological cancers.

BACKGROUND: The hedgehog signaling pathway is normally tightly regulated. Mutations in hedgehog pathway components may lead to abnormal activation. Aberrantly activated hedgehog signaling plays a major role in the development of solid and hematological cancer. In recent years, inhibitors have been developed that attenuate hedgehog signaling; 2 have been approved for use in basal cell carcinoma (BCC), while others are under development or in clinical trials. The aim of this review is to provide an overview of known hedgehog inhibitors (HHIs) and their potential for the treatment of hematological cancers and solid tumors beyond BCC. DESIGN: Published literature was searched to identify articles relating to HHIs in noncutaneous cancer. Both preclinical and clinical research articles were included. In addition, relevant clinical trial results were identified from www.clinicaltrials.gov. Information on the pharmacology of HHIs is also included. RESULTS: HHIs show activity in a variety of solid and hematological cancers. In preclinical studies, HHIs demonstrated efficacy in pancreatic cancer, rhabdomyosarcoma, breast cancer, and acute myeloid leukemia (AML). In clinical studies, HHIs showed activity in medulloblastoma, as well as prostate, pancreatic, and hematological cancers. Current clinical trials testing the efficacy of HHIs are underway for prostate, pancreatic, and breast cancers, as well as multiple myeloma and AML. CONCLUSIONS: As clinical trial results become available, it will be possible to discern which additional tumor types are suited to HHI mono- or combination therapy with other anticancer agents. The latter strategy may be useful for delaying or overcoming drug resistance.