Efficacy and Safety of Lenabasum, a Cannabinoid Type 2 Receptor Agonist, in a Phase 3 Randomized Trial in Diffuse Cutaneous Systemic Sclerosis.

OBJECTIVE: This phase 3 study was undertaken to investigate the efficacy and safety of lenabasum, a cannabinoid type 2 receptor agonist, in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: A multinational double-blind study was conducted in 365 dcSSc patients who were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg, or placebo, each twice daily and added to background treatments, including immunosuppressive therapies (IST). RESULTS: The primary end point, the American College of Rheumatology combined response index in dcSSc (CRISS) at week 52 for lenabasum 20 mg twice a day versus placebo, was not met, with CRISS score of 0.888 versus 0.887 (P = 0.4972, using mixed models repeated measures [MMRM]). The change in the modified Rodnan skin thickness score (MRSS) at week 52 for lenabasum 20 mg twice a day versus placebo was -6.7 versus -8.1 (P = 0.1183, using MMRM). Prespecified analyses showed higher CRISS scores, greater improvement in MRSS, and lower decline in forced vital capacity in patients on background mycophenolate and those who were taking IST for ≤1 year. No deaths or excess in serious or severe adverse events related to lenabasum were observed. CONCLUSION: A benefit of lenabasum in dcSSc was not demonstrated. Most patients were treated with background IST, and treatment with mycophenolate mofetil in particular was associated with better outcomes. These findings support the use of IST in the treatment of dcSSc and highlight the challenge of demonstrating a treatment effect when investigational treatment is added to standard of care IST. These findings have relevance to trial design in SSc, as well as to clinical care.

A randomised, double-blind, placebo-controlled phase 3 study of lenabasum in diffuse cutaneous systemic sclerosis: RESOLVE-1 design and rationale.

OBJECTIVES: The multi-systemic, heterogenous nature of diffuse cutaneous systemic sclerosis (dcSSc) presents challenges in designing clinical studies that can demonstrate a treatment effect on overall disease burden. We describe the design of the first Phase 3 study in dcSSc patients where the American College of Rheumatology (ACR) Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score was chosen prospectively as the primary outcome. The CRISS measures key clinical disease parameters and patient-reported outcomes (PROs). METHODS: RESOLVE-1 is a Phase 3, randomised, double-blind, placebo-controlled trial of dcSSc patients evaluating the efficacy and safety of lenabasum. Patients ≥18 years of age with dc-SSc and disease duration ≤6 years were eligible. Patients could continue stable background therapy for dcSSc, including stable immunosuppressive therapies. They were randomised to lenabasum 5 or 20 mg twice daily or placebo. The primary efficacy outcome was the mean change from baseline to 52 weeks in the ACR CRISS score. RESULTS: The study enrolled 365 patients over 1.5 years at 77 sites in 13 countries in North America, Europe, Israel, and Asia-Pacific, with the last patient first visit on May 1, 2019. CONCLUSIONS: RESOLVE-1 is the first Phase 3 interventional study to date in dcSSc to prospectively use the ACR CRISS as the primary efficacy outcome. Eligibility criteria allowed background therapy as might occur in clinical practice. This approach also facilitated timely patient enrolment. RESOLVE-1 provides a novel study design that may be used for future Phase 3 dcSSc studies to assess the holistic efficacy of therapy.

Case Series of Fractional Ablative Laser Resurfacing of Pediatric Facial Traumatic and Surgical Scars.

BACKGROUND AND OBJECTIVES: Fractional ablative 10,600-nm carbon dioxide (CO2 ) laser has well-demonstrated safety and efficacy in resurfacing treatment of scars in the adult population and in the treatment of pediatric burn scars. However, there is a paucity of literature regarding laser resurfacing of traumatic and surgical scars for cosmetic benefit in the pediatric population, and in majority of cases previously reported, this was done under general anesthesia. STUDY DESIGN/MATERIALS AND METHODS: This was a retrospective chart review of pediatric patients under the age of 18 who underwent fractional ablative CO2 laser resurfacing (FALR) of traumatic or surgical scars at a single center between 2018 and 2019, inclusive. Primary endpoints included safety and tolerance. RESULTS: A total of 31 FALR treatments were performed in 10 patients with traumatic and surgical scars located on the face (age 4-14 years, Fitzpatrick skin type [FST] I-IV, 60% female). Settings ranged from total energy per session 0.02-0.33 kJ, with a 7-mm tip and 30-50% coverage. Nine patients had two or more treatments (average 3, maximum 8) spaced at least 4 weeks apart. All resurfacing treatments were well-tolerated with local infiltration of 1% lidocaine with epinephrine (1:100,000). Six (67%) patients were treated with additional measures including pulsed dye laser, 1927-nm fractional non-ablative low-energy, low-density laser, or intralesional agents (5-fluorouracil, triamcinolone, botulinum toxin). At follow-up (of varied intervals), short-term erythema, as expected, was seen in six patients, and hyperpigmentation in one case (FST IV), both treated with aforementioned alternate devices. Although gradual, improvement in scar appearance and texture was seen with FALR treatments. No additional scarring, infection, or hypopigmentation was seen. CONCLUSIONS: Treatment with fractional ablative laser resurfacing is safe and well-tolerated in the pediatric population in an outpatient setting with local anesthesia. Traumatic scars may cause significant distress to children and parents alike. Multimodal therapy may lead to optimal cosmesis. Given the excellent tolerability, the authors recommend consideration of laser resurfacing in pediatric patients with traumatic or surgical scars when bothersome, either cosmetically or psychologically. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Dynamic Optical Coherence Tomography of Cutaneous Blood Vessels in Melasma and Vessel Response to Oral Tranexamic Acid.

BACKGROUND AND OBJECTIVES: Melasma may be related to aberrant blood vessels, but there has been no report on the utility of dynamic optical coherence tomography (D-OCT) in studying vessel characteristics in melasma. We studied the characteristics of cutaneous blood vessels in melasma and the effects of oral tranexamic acid (TXA) with D-OCT. STUDY DESIGN/MATERIALS AND METHODS: Six patients with moderate to severe melasma had a D-OCT scanning of the areas on the face affected by melasma and not affected by it. Three of them had scans within 3 months after starting oral TXA and at a follow-up visit. Blood flow at different depths of the skin and vessel diameter were compared between the melasma and normal skin. For those taking oral TXA, we compared the percent change of blood flow and diameter between the melasma and normal skin. RESULTS: Dermal blood flow and vessel diameter were greater in the melasma skin than in the normal skin. Oral TXA reduced dermal blood flow in both the melasma and normal skin, but the reduction was more dramatic in the lesional melasma skin. CONCLUSIONS: D-OCT findings that (i) dermal blood vessels in melasma are increased in size and flow and (ii) oral TXA reduced the vessel size and flow, providing evidence supporting the relationship between melasma and cutaneous blood vessels. D-OCT may be utilized in measuring response to treatments targeting melasma. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Utilization of Laser Therapy During Pregnancy: A Systematic Review of the Maternal and Fetal Effects Reported From 1960 to 2017.

BACKGROUND: Due to concerns regarding maternal and fetal safety and the absence of evidence to the contrary, laser treatment during pregnancy has traditionally been limited to situations of absolute necessity. OBJECTIVE: This review seeks to examine the available evidence to determine the safety of laser therapy during pregnancy. METHODS: Medical databases were searched for relevant reports from all specialties regarding the use of lasers during pregnancy from 1960 to 2017. A legal case review was also performed. RESULTS: Twenty-two publications in the literature reported the use of various laser wavelengths in 380 pregnant women during all trimesters. Other than 1 case of premature rupture of membranes questionably related to the laser treatment, there were no cases of maternal or fetal morbidity or mortality, premature labor, or identifiable fetal stress. CONCLUSION: The available evidence, limited to low evidence level case reports and series, indicates cutaneous laser treatment during pregnancy is safe for both mother and fetus. Furthermore, laser physics and optics dictate there should theoretically be no risk of fetal laser exposure from commonly used cutaneous lasers.

Clinical study to evaluate the performance of a noninvasive focused ultrasound device for thigh fat and circumference reduction compared to control.

BACKGROUND AND OBJECTIVES: An FDA-cleared focused ultrasound device (UltraShape, Syneron Candela® , Yokneam, Israel) for noninvasive abdominal fat reduction produces localized mechanical cellular membrane disruption in adipocytes. This study seeks to determine the safety and efficacy of this device for use on the thighs. STUDY DESIGNS/MATERIALS AND METHODS: Fourteen women aged 33-60 were selected to receive 3 biweekly treatments to one thigh with the other thigh serving as an internal control. The subjects had a BMI range of 18-30 kg/m2 and a weight range of 54-83 kg. After the third treatment, patients were followed at 4, 8, and 16 weeks. Fat thickness was measured by both caliper and ultrasound. In addition, thigh circumference and the patient's weight were measured. Pain, edema, erythema, and adverse events as well as investigator and patient overall satisfaction were recorded at all visits. RESULTS: In comparison with the control, there was a statistically significant average reduction in fat thickness measured by calipers at all time points with a 22.20% (P = .0165) improvement in 16 weeks. By ultrasound, there was a 19.23% (4.03 mm P = .0051) reduction in fat thickness at 16 weeks with statistically significant improvement at the other follow-up visits. At 16 weeks, thigh circumference improved, on average, 2.8 cm (P = .0059) at the midline. 90.0% of the subjects were satisfied with the results at 16 weeks, and the investigator was 100% satisfied. No adverse events were reported; no edema was observed in any subject. All subjects experienced mild erythema. All reported zero pain on a 0-10 scale. CONCLUSION: Focused ultrasound is safe, effective, and well tolerated to improve the circumference and fat thickness of the thighs without significant side effects. There were no significant adverse events. Investigators and subjects were highly satisfied with the results.

Clinical and Histologic Evaluation of Ingenol Mebutate 0.015% Gel for the Cosmetic Improvement of Photoaged Skin.

BACKGROUND: No studies have examined the use of topical ingenol mebutate for improvement of photoaged skin. OBJECTIVE: To evaluate clinical results of ingenol mebutate gel applied to photoaged skin and to quantify improvement at 7, 30, and 60 days after application. MATERIALS AND METHODS: Twenty-five subjects were enrolled in the study. Picato (ingenol mebutate) (LEO Pharma, Parsippany, NJ) gel was applied to an area with a known actinic keratosis daily for 3 days. Subjects self-evaluated and were investigator evaluated on 6 characteristics on Days 7, 30, and 60 using an objective scale. The scale evaluated actinic keratosis, overall skin appearance, wrinkling, dyschromia, erythema, and texture. The subjects were also evaluated using the Griffiths' Photonumeric Photoaging Scale for overall improvement. RESULTS: Twenty-two subjects completed the clinical study and demonstrated statistically significant improvement by Day 60 in actinic keratosis, overall skin appearance, wrinkling, dyschromia, erythema, and texture (p < .05). CONCLUSION: Topical ingenol mebutate 0.015% gel produces cosmetic improvement of photoaged skin within 60 days of application.

IPL vs PDL in treatment of facial erythema: A split-face study.

BACKGROUND: Lasers and noncoherent intense pulse light sources effectively treat vascular lesions. Intense pulsed light (IPL), a nonablative treatment for photorejuvenation, uses a flashlamp which emits noncoherent light between 400 and 1400 nm. The light may be filtered to target a specific chromophore. The pulsed dye laser (PDL), at 595 nm, has been the historical standard of care in the treatment of facial erythema. We sought to determine whether IPL may be used in lieu of PDL in reducing facial erythema. OBJECTIVES: To determine whether IPL may be used to treat facial erythema with equal efficacy as PDL used at nonpurpuric settings. METHODS: Prospective investigation of a cohort of 15 subjects with unwanted bilateral facial erythema. Subjects presented for two treatments with an IPL (BBL™ BroadBand Light; Sciton, Palo Alto, CA) to one half of the face and PDL (Cynergy™; Cynosure, Westford, MA) to the other half. RESULTS: Patients with facial erythema may be successfully treated with IPL or PDL. CONCLUSIONS: Intense pulsed light and pulsed dye laser with nonpurpuric settings were equally effective in reducing facial erythema.

Energy-based device treatment of melasma: An update and review of the literature.

Melasma is an acquired pigmentary disorder commonly seen in sun-exposed areas. Predominantly affecting women of childbearing age, melasma can be difficult to treat for many patients. A variety of options currently exist; however, definitive treatment remains elusive. This article provides a review of the current literature and examines in detail the various energy-based devices used to treat melasma.

Energy-Based Devices in Treatment of Acne Vulgaris.

BACKGROUND: Acne vulgaris is a chronic dermatologic complaint with a multifactorial cause. Traditionally, antibiotics and retinoids have been used to manage the condition; patient compliance has been an ongoing issue. A variety of energy-based devices have been reported to be effective in the treatment of acne vulgaris. OBJECTIVE: To review and summarize the current literature specific to treatment of acne vulgaris with energy-based devices. METHODS: A review of the current literature of energy-based devices used for the treatment of acne vulgaris. RESULTS AND CONCLUSIONS: Although limited randomized controlled trials for the treatment of acne have been performed, significant clinical improvement of acne vulgaris, especially of inflammatory lesions, has been demonstrated with a variety of energy-based devices. Newer approaches may lead to even better results.

The Photodynamic Therapy Experience of a High Volume Laser and Dermatologic Surgery Center.

BACKGROUND: Photodynamic therapy (PDT) is an FDA approved treatment for actinic keratoses (AK's) although multiple off-label indi- cations are reported. Despite frequent use for AK's, no clear consensus exists regarding protocols for overall treatment parameters. METHODS: Retrospective chart review of 1,491 subjects who underwent PDT between 2007 and 2011 at a high volume laser surgery center. Demographic information, clinical history, treatment data, and subsequent diagnosis of skin cancers were recorded. An ex- ploratory subgroup analysis was performed for patients treated for AK and/or squamous cell carcinoma (SCC) that developed SCC or remained SCC-free one year after treatment. RESULTS: The most common indications for PDT were actinic keratoses (n=1404, 94.9%) then NMSC (n=45, 3.0%) The most common treatment site was the head and neck (n=1274, 86.1%). Blue light activation (405-420nm) was used more frequently than red light and visible light. (73.8% vs. 22.8% vs. 6.8%). The most commonly used photosensitizer was aminolevulinic acid (ALA) (98.6%, n=1456). Topical application (97.7% n=1437) of photosensitizer was used more frequently than intralesional administration (2.0%, n=29). 580 patients met subgroup analysis criteria. 66 developed SCC at treatment site (11%). Factors associated with developing SCC were older age, SCC history, Fitzpatrick skin-type 1, and sixty-minute or less incubation times (P less than 0.05 for all factors). The SCC subgroup had a unique distribution of treatment sites (P less than.001). No statistically significant differences were observed for gender or wavelength. CONCLUSION: There are differences in protocols based on indication and location of lesion. Blue light is preferable for superFIcial lesions and red light for deeper lesions. Intralesional delivery is used more commonly for NMSC. Extremities require longer incubation times. PDT may be more effective with younger patients and longer than sixty-minute incubation times. PDT chemoprevention is independent of light source used. J Drugs Dermatol. 2016;15(11):1420-1426..

Male Aesthetics: A Review of Facial Anatomy and Pertinent Clinical Implications.

Aesthetics continues to be a rapidly growing field within dermatology. In 2014, Americans spent 5 billion dollars on an estimated 9 million minimally invasive cosmetic procedures. Between 1997 and 2014, the number of aesthetic procedures performed on men increased by 273%. The approach to male aesthetics differs from that of females. Men have a squarer face, a more angled and larger jaw, and equally balanced upper and lower facial proportions. Facial muscle mass, subcutaneous tissue, and blood vessel density are also increased in men relative to women. While many of the same cosmetic procedures are performed in males and females, the approach, assessment, and treatment parameters are often different. Improper technique in a male patient can result in feminizing facial features and patient dissatisfaction. With an increasing number of men seeking aesthetic procedures, it behooves dermatologists to familiarize themselves with male facial anatomy and the practice of cosmetic dermatology in this population.

Impact of intradermal abobotulinumtoxinA on facial erythema of rosacea.

BACKGROUND: Facial erythema is a frequent and often distressing complaint of patients with rosacea. Treatment of facial erythema with botulinum toxin has previously been proposed and reported. However, the current literature has mixed results. OBJECTIVE: The primary objective of this study was to evaluate the safety and efficacy of intradermal abobotulinumtoxinA on facial erythema of rosacea. MATERIALS AND METHODS: Twenty-five subjects aged 35 to 70 years with Fitzpatrick skin Types I to IV and facial erythema of erythematotelangiectatic rosacea were enrolled in the trial. Subjects received 15 to 45 units of intradermal injections of abobotulinumtoxinA to the nasal tip, nasal bridge, and nasal alae. A nontreating investigator assessed the facial erythema of rosacea using a standardized grading system (0 = absent, 1 = mild erythema, 2 = moderate erythema, and 3 = severe erythema) to evaluate digital photographs at baseline, 1, 2, and 3 months after treatment. Statistical analysis of erythema grade included one-way repeated-measures analysis of variance and pairwise comparisons using SPSS (IBM Corporation) software. RESULTS: Fifteen of the 25 enrolled subjects completed all the appropriate follow-up visits. Only the 15 subjects with complete data were included in analysis. The subjects were of Fitzpatrick skin Types I to III, a mean age of 54 years, and 80% women. The mean baseline erythema grade was 1.80 (±0.56), and the mean erythema grade at 3 months after treatment was 1.00 (±0.38). The treatment resulted in statistically significant improvement in erythema grade at 1, 2, and 3 months after treatment when compared with baseline (p < .05, p < .001, and p < .05, respectively). Pairwise comparison to baseline showed a mean erythema grade improvement of 0.80 (p < .001) at 3-month follow-up. CONCLUSION: Intradermal injection of botulinum toxin for the treatment of facial erythema of rosacea seems both effective and safe. Larger, randomized, blinded, placebo-controlled studies are warranted. Additionally, further investigation is needed to elucidate the mechanism of action by which botulinum toxin improves facial flushing of rosacea.

Collision tumor of eccrine poroma, seborrheic keratosis, and a viral wart.

A 68-year-old woman presented for evaluation of a large, red-brown plaque on her left buttock with irregular borders and prominent overlying verrucous changes. The plaque had been present since childhood but over a three-year period had been enlarging with increasing nodularity and easy bleeding with trauma. Histopathologic examination demonstrated an enlarged papillated and polypoid heterogeneous lesion. In part of the specimen, there are bulbous aggregates of small squamous cells with foci of eccrine ductal differentiation. There are other areas with horn pseudocysts, hypergranulosis, and compact orthokeratosis with parakeratosis. There are scattered enlarged heavily pigmented melanocytes, some of which have long and thick dendrites. This collision tumor consisted of an eccrine poroma, a seborrheic keratosis, and a viral wart. The clinical and histopathologic features of collision tumors and poromas are reviewed.

Nonablative 1927 nm fractional resurfacing for the treatment of facial photopigmentation.

BACKGROUND: Long-term exposure to sunlight, including ultraviolet A and B, produces signs associated with photoaging and photodamage, including laxity and discoloration of the skin. Initial laser treatment for dyspigmentation included the use of ablative lasers, followed by Q-switched lasers and more recently fractional lasers. OBJECTIVE: We investigated the safety and efficacy of a fractionated 1927nm non-ablative thulium laser for the treatment of photo-induced pigmentation. METHODS: Prospective multi-center study of subjects with clinically identifiable photopigmentation. The study protocol was approved by BioMed Institutional Review Board (San Diego, CA). Subjects received two treatments with a non-ablative 1927nm fractionated thulium laser (Fraxel Dual 1550/1927 Laser System, Solta, Hayward CA), energy level of 10mJ, coverage of 40% and 4-6 passes. Subject pain, erythema and edema were recorded immediately after treatment. Two dimensional photography was obtained before each treatment and at one and three month follow up visits. Independent blinded physician assessment was performed evaluating overall improvement in appearance as well as pigment specific improvement. RESULTS: Forty men and women, ages 30 to 80 years, Fitzpatrick skin types I-IV, with photo-induced facial pigmentation were enrolled and treated, and 39 completed the three month follow up visit. Mean pain sensation for subjects during laser treatments was reported to be 4.3 on a 10-point scale. Mean scores for erythema, edema, and skin roughness throughout all treatments indicated moderate erythema, mild edema and mild skin roughness. Assessment of overall improvement was graded as moderate to very significant in 82% of subjects at one month and in 69% of subjects at three months after the second treatment. Assessment of lentigines and ephelides demonstrated moderate to very significant improvement in approximately 68% of subjects at the one month and in 51% of subjects at three months after the second treatment. Independent blinded physician assessment of randomized photography also demonstrated a durable response at three month follow up visit. Treatment was well tolerated and no serious adverse events related to treatment were observed or reported. Study limitations included a limited number of male subjects, lack of Fitzpatrick skin types V and VI, and decrease in improvement at 3 months post-treatment. CONCLUSIONS: Two treatments with a 1927nm non-ablative fractionated thulium laser produced moderate to marked improvement in overall appearance and pigmentation with high patient satisfaction. The response to treatment was maintained at one and three months follow up.

Convergence of anatomy, technology, and therapeutics: a review of laser-assisted drug delivers.

This is a very exciting time in cutaneous laser surgery with an ever-expanding therapeutic armamentarium and an increased sophistication of available technology. These recent trends have allowed for both a rapid development of interest and exploration of laser-assisted drug delivery and its potential applications. We review the current literature on anatomy, technology, and therapeutics as it relates to laser-assisted drug delivery. The focus of our review is on two areas of interest that have received much attention to date - photodynamic therapy in the treatment of actinic keratoses and nonmelanoma skin cancers as well as the treatment of scarring. We will also discuss potential complications of existing modalities used independently and in laser-assisted drug delivery and conclude with future indications for this burgeoning therapeutic methodology.

Ablative fractional resurfacing in topical drug delivery: an update and outlook.

BACKGROUND: The effective delivery of therapeutic molecules to varied targets in the skin and elsewhere has been an area of ongoing research and development. OBJECTIVE: To review the structure of the skin with an emphasis on topical drug delivery and to present the rationale for the use of ablative and nonablative fractional resurfacing in assisted drug delivery. METHODS AND MATERIALS: Review of the currently available scientific literature on laser-assisted drug delivery. RESULTS: A number of strategies can be employed to enhance topical drug delivery. Ablative fractional resurfacing (AFR) has been demonstrated to be effective in enhancing drug delivery. Further studies are needed to assess the use of nonablative fractional resurfacing in assisted drug delivery. CONCLUSION: AFR-assisted drug delivery is a promising tool for the future of dermatology. We expect to see a number of agents to be paired with AFR for enhanced drug delivery. Further investigation is necessary to evaluate appropriate drug specific channel density and depth parameters. Factors that must be considered include the physicochemical properties of the drug, the target tissue, skin wounding, and cost when evaluating the drugs and conditions that will most benefit from this promising new drug delivery system.

Assessment of safety and efficacy of a bipolar fractionated radiofrequency device in the treatment of photodamaged skin.

BACKGROUND: A number of devices are available for skin rejuvenation and conventional devices include both ablative and non-ablative lasers. More recently, bipolar fractionated radiofrequency (RF) devices have been introduced. OBJECTIVE: To evaluate the safety and efficacy of a novel 144 pin high density tip bipolar fractionated radiofrequency (RF) device for skin rejuvenation in Fitzpatrick skin types I-IV. METHODS AND MATERIALS: This single-center, prospective, study enrolled 25 female between the ages of 35-60 years, with mild to moderate wrinkling based on the Fitzpatrick Wrinkle Scale. The subjects were of Fitzpatrick skin types I-IV. Each subject underwent 3 full-face treatments with a 144 pin fractional bipolar RF device at 30-day intervals. All subjects underwent clinical evaluations during the study period to evaluate for any adverse events. Subsequently, all subjects were evaluated for improvement in rhytides, dyschromias and skin texture based on photographic evaluation by blinded investigators at 6 months following the final RF treatment. RESULTS: A statistically significant improvement in rhytides, dyschromias and texture was noted. Adverse events were limited to mild erythema and swelling. Post-inflammatory pigmentary changes were not observed in any subjects. CONCLUSION: The novel 144 pin high density tip bipolar fractionated RF device is both safe and effective for facial skin rejuvenation in Fitzpatrick skin types I-IV.