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.

Oxymetazoline and Energy-Based Therapy in Patients with Rosacea: Evaluation of the Safety and Tolerability in an Open-Label, Interventional Study.

BACKGROUND AND OBJECTIVES: The objectives of this study were to evaluate the safety, tolerability, and efficacy of oxymetazoline hydrochloride cream, 1% (oxymetazoline) when used as an adjunctive treatment with energy-based therapy for patients with moderate to severe facial erythema associated with rosacea. STUDY DESIGN/MATERIALS AND METHODS: In this Phase 4, multicenter, interventional, open-label study, eligible patients received one of four energy-based therapies (potassium titanyl phosphate laser, intense pulsed light therapy, pulsed-dye laser Vbeam Perfecta, or pulsed-dye laser Cynergy) on day 1 and day 29 and once-daily application of oxymetazoline on days 3 through 27 and days 31 through 56. Improvement from baseline in Clinician Erythema Assessment (CEA) score, patient satisfaction measures, incidence of treatment-emergent adverse events (TEAEs), and worsening from baseline on dermal tolerability assessments and the Clinician Telangiectasia Assessment (CTA) were assessed. Data were summarized using descriptive statistics. RESULTS: A total of 46 patients (mean age, 51.1 years; 78.3% female) enrolled in this study. Similar numbers of patients received each of the energy-based therapies in addition to oxymetazoline. All patients demonstrated an improvement from baseline in CEA during the study with 39 of 43 evaluable patients (90.7%) demonstrating an improvement 6 hours posttreatment on day 56. Most patients were satisfied or very satisfied with treatment at the end of the study. All TEAEs were mild or moderate in severity. Some patients experienced worsening in dermal tolerability assessment symptoms (range: 4-21 patients; 8.7-45.7%). Worsening in CEA and CTA were each reported by three patients (6.5%) at any time during the study. CONCLUSIONS: Treatment with oxymetazoline as adjunctive therapy with energy-based therapy was safe, well tolerated, and reduced facial erythema in patients with moderate to severe persistent facial erythema associated with rosacea. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.

Clinically Relevant Reduction in Persistent Facial Erythema of Rosacea on the First Day of Treatment With Oxymetazoline Cream 1.0.

BACKGROUND: Persistent facial erythema is a clinically challenging feature of rosacea. OBJECTIVE: To evaluate persistent erythema reduction on the first day of treatment from pooled data from two pivotal trials of topical oxymetazoline cream 1.0% (oxymetazoline) in persistent facial erythema of rosacea. METHODS: In two identically designed, phase 3, multicenter trials, adults with moderate to severe persistent facial erythema of rosacea (Clinician Erythema Assessment [CEA] grade ≥3 and Subject Self-Assessment [SSA] grade ≥3) were randomized 1:1 to once-daily topical oxymetazoline or vehicle; the primary efficacy endpoint was ≥2-grade composite CEA and SSA improvement from baseline on day 29. This post hoc analysis evaluated the proportion of patients achieving ≥1-grade composite and individual CEA and SSA improvement at 1, 3, 6, 9, and 12 hours postdose on day 1 (N=885). RESULTS: Significantly more patients achieved ≥1-grade composite and individual CEA and SSA improvement with the first application of oxymetazoline than with vehicle (P less than 0.001) at all postdose time points, beginning with hour 1. Day 1 safety assessments were similar between treatments. LIMITATIONS: Short-term, post hoc analysis. CONCLUSIONS: A ≥1-grade improvement in persistent erythema achieved after the first dose of once-daily topical oxymetazoline demonstrated clinically meaningful improvement from the beginning of therapy. J Drugs Dermatol. 2018;17(6):621-626.

Pivotal Trial of the Efficacy and Safety of Oxymetazoline Cream 1.0% for the Treatment of Persistent Facial Erythema Associated With Rosacea: Findings from the Second REVEAL Trial.

Rosacea is a chronic dermatologic condition with limited treatment options, particularly for persistent erythema. This pivotal phase 3 study evaluated oxymetazoline, an a1A-adrenoceptor agonist, for the treatment of moderate to severe persistent erythema of rosacea. Eligible patients were randomly assigned 1:1 to receive oxymetazoline cream 1.0% or vehicle applied topically to the face once daily for 29 days. The primary efficacy outcome was ≥2-grade improvement from baseline on both Clinician Erythema Assessment (CEA) and Subject Self-Assessment for rosacea facial redness (SSA) (composite success) at 3, 6, 9, and 12 hours postdose on day 29. Digital image analysis of rosacea facial erythema was evaluated as a secondary efficacy outcome measure. Safety assessments included treatment-emergent adverse events (TEAEs) and dermal tolerability. Patients were followed for 28 days posttreatment to assess worsening of erythema (1-grade increase in severity from baseline on composite CEA/SSA in patients with moderate erythema at baseline; rebound effect). The study included 445 patients (mean age: 50.3 years; 78.7% female); most had moderate erythema at baseline (84.0% on CEA; 91.5% on SSA). The proportion of patients achieving the primary efficacy outcome was significantly greater with oxymetazoline versus vehicle (P=0.001). Similar results favoring oxymetazoline over vehicle were observed for the individual CEA and SSA scores (P less than 0.001 and P=0.011, respectively). Median reduction in rosacea facial erythema on day 29 as assessed by digital image analysis also favored oxymetazoline over vehicle (P less than 0.001). Safety results were similar between oxymetazoline and vehicle; discontinuations due to TEAEs were low (2.7% vs 0.5%). Following cessation of treatment, 2 (1.2%) patients in the oxymetazoline group and no patient in the vehicle group had rebound effect compared with their day 1 baseline score. Topical oxymetazoline applied to the face once daily for 29 days was effective, safe, and well tolerated in the treatment of moderate to severe persistent facial erythema of rosacea.

J Drugs Dermatol. 2018;17(3):290-298.

Short-pulsed laser for the treatment of tattoos, pigmented lesions, scars and rejuvenation.

This review describes the use of picosecond lasers for the treatment of tattoos, pigmented lesions, scars, and their use in rejuvenation. These devices have delivered enhanced efficacy for the treatment of tattoos and pigmented lesions when compared to the older 40-50 nanosecond devices. The fractional delivery with the picosecond devices have opened up a new method of rejuvenation for photodamaged skin and the treatment of scars. The delivery of these high-energy short pulses have created zones of injury in the skin referred to as areas of laser-induced optical breakdown. These areas of damage appear to produce cytokines and chemokines which result in epidermal and dermal repair and remodeling. The dual use of these devices with the flat and the fractional optics have made these devices useful in many ways that have been unanticipated.

The histology of skin treated with a picosecond alexandrite laser and a fractional lens array.

BACKGROUND AND OBJECTIVES: The treatment of acne scars and wrinkles with a picosecond Alexandrite laser was recently FDA cleared. In 2014 we presented our initial histologic findings with this device on in vivo and ex vivo skin. This current study expands on the 2014 pilot study with an investigation of different energy settings using histology and the confocal microscope to describe the changes observed in the skin. MATERIALS AND METHODS: We used a 755 nm picosecond Alexandrite laser with a fractional optic with three different energy settings to treat in vivo. After treatment, the patients and skin samples were also evaluated with a confocal microscope followed by biopsies which were evaluated histologically. RESULTS: Histology revealed unique intra-epidermal cavities. The number, density, and the size of these cavities were dependent on the melanin index and delivered energy when evaluated with histopathology and the confocal microscope. These localized zones of injury appear to form microscopic epidermal injury zones which are exfoliated over a 3-week period. CONCLUSIONS: These intra-epidermal cavities result from areas of laser-induced optical breakdown (LIOB). This injury is most consistent with a localized plasma formation in the epidermis initiated by the melanin absorption of the high energy picosecond light. It appears that treatments with this device and optic result in improvements in dyspigmentation and acne scars with new collagen, elastic tissue, and mucin. The production of this LIOB could directly stimulate an epidermal repair mechanism that results in these clinical findings. Lasers Surg. Med. 48:646-652, 2016. © 2016 Wiley Periodicals, Inc.

Comparison of the Cutaneous Thermal Signatures Over Twenty-Four Hours With a Picosecond Alexandrite Laser Using a Flat or Fractional Optic.

INTRODUCTION: This study explored immediate heat signatures with different passing techniques and the delayed thermal data points with the picosecond Alexandrite laser with the 6mm at and fractional optic during and after treatment. We sought to clarify the im- mediate effects of heating and understand the thermal and short term clinical difference when using these optics. RESULTS: There were no immediate differences or a signi cant temperature rise with different passing techniques using the at or the fractional optic. However, after treatments a signi cant temperature elevation over 24 hours with manageable erythema was noted with the fractional optic. Only faint redness was appreciated with the at optic. CONCLUSION: The different passing methods with these optics did not result in a significant thermal change. However, the fractional optic produces a localized area of epidermal necrosis which results in a significant clinical and a delayed thermal effect. With multiple treatments over time, collagen, elastic tissue, and mucin is produced resulting in improvement of acne scars and photo-damaged skin. This process suggests that a well-placed epidermal injury can stimulate an inflammatory cascade with dermal remodeling. J Drugs Dermatol. 2016;15(11):1347-1352..

A Controlled Comparison Study of Topical Fluourouracil 5% Cream Pre-Treatment of Aminolevulinic Acid/Photodynamic Therapy for Actinic Keratosis.

INTRODUCTION: Topical Fluorouracil 5% cream (5-FU) and 20% aminolevulinic acid (ALA)/ photodynamic therapy (PDT) are both FDA approved for the treatment of Actinic Keratosis (AK). We have studied the use of these 2 agents alone and in a sequential manner. We have also used a 5-FU re-challenge 3 months after treatment to highlight the efficacy of these treatments. METHODS: This was an investigator-blinded randomized study in which 30 patients were randomized 1:1:1 into the following groups: Group 1 patients pretreated for 6-7 days with 5-FU, ALA applied with incubation of 2 hours, ALA removed with wet gauze, illuminated treated areas with 10 J/cm(2) with Blu-U device; Group 2 patients treated with 5-FU BID for 6-7 days and no ALA/PDT; Group 3 patients received no pretreatment, ALA applied with incubation of 2 hours, ALA removed with wet gauze, illuminated treated areas with 10 J.cm2 with Blu-U device. Patients were seen at screening/baseline, treatment for ALA/PDT, 24 hours post treatment, 1 week post treatment and 3 months post treatment. All subjects were then given a re-challenge course of 5-FU for 6 days and reassessed. RESULTS: AK counts in all groups were dramatically decreased and similar at 1 and 3 months post treatment. The re-challenge brought a significant difference with many subclinical lesions in the area of activity in the ALA and 5-FU alone groups. CONCLUSIONS: All three arms appeared equal in treating visible AKs. These data strongly suggests a synergistic role of 5-FU with ALA/PDT over ALA/PDT or 5-FU alone in treating the subclinical lesions demonstrated on a 5-FU re-challenge. Treatment of these subclinical lesions should result in a longer remission. The data also suggests that a 5-FU re-challenge could be a clinical tool to judge the efficacy of treatment for AK if these subclinical lesions are proven to be an AK precursor.

A Randomized, Double-Blind Trial to Investigate the Equivalence of IncobotulinumtoxinA and OnabotulinumtoxinA for Glabellar Frown Lines.

BACKGROUND: IncobotulinumtoxinA and onabotulinumtoxinA are indicated for the temporary improvement in the appearance of glabellar frown lines (GFL). This is the first randomized direct comparator study to date, at the Food and Drug Administration-recommended dose of 20 units (U), for the treatment of GFL. OBJECTIVE: To investigate the dose equivalence of incobotulinumtoxinA (20 U) and onabotulinumtoxinA (20 U) for the treatment of moderate-to-severe GFL. MATERIALS AND METHODS: Prospective, randomized (1:1), double-blinded, parallel-group study in 250 females (18-50 years), employing a single treatment with incobotulinumtoxinA or onabotulinumtoxinA, followed by a 4-month observational period. RESULTS: At the primary efficacy endpoint (1 month after treatment), incobotulinumtoxinA was equivalent to onabotulinumtoxinA in the treatment of GFL at the 20 U dose within the prespecified ± 15% margin of equivalence. Efficacy remained similar between treatment groups through 4 months after treatment as assessed by the independent masked panel and the masked treating physicians. Patient satisfaction ratings were similar between groups and favorable (>90%) throughout. Both treatments were well tolerated. CONCLUSION: Equivalence was demonstrated at the primary endpoint between incobotulinumtoxinA and onabotulinumtoxinA in the treatment of GFL at the 20 U dose at 1 month. Similar efficacy and tolerability profiles were observed through 4 months after treatment.

Optimizing the use of topical brimonidine in rosacea management: panel recommendations.

Rosacea is a chronic inflammatory disease with a complex pathophysiology that manifests with central facial redness with or without papulopustular lesions. Often, patients with rosacea present with a constellation of signs and symptoms; for best results, the treatment plan should take into account all symptoms manifesting in the individual patient. The first available pharmacologic treatment to address the redness associated with rosacea is topical brimonidine. In the United States, brimonidine topical gel 0.33% is indicated for persistent facial erythema of rosacea; approval was based on clinically significant efficacy and good safety data from large-scale clinical trials. Use of brimonidine in routine clinical practice has yielded new insights that elaborate on the findings from clinical trials. For example, real-world use has shown that a percentage of patients (in our experience, approximately 10 to 20%) treated with brimonidine experience a worsening of erythema that has been called "rebound." Our routine use of this agent for >1 year has yielded strategies to set patient expectations, optimize treatment initiation, and minimize potential problems; this article details those strategies. Because we believe that the term "rebound" has been used to describe several physiologically distinct events, we have also proposed more specific terminology for such events.

Split-face randomized treatment of facial telangiectasia comparing pulsed dye laser and an intense pulsed light handpiece.

BACKGROUND AND OBJECTIVE: Facial telangiectasia and other vascular lesions have historically been effectively treated with the pulsed dye laser (PDL). This study compares the safety and efficacy of the PDL to an intense pulsed-light (IPL) handpiece with dual-band spectral absorption, shorter pulse widths, and constant output power. STUDY DESIGN/MATERIALS AND METHODS: Sixteen subjects were enrolled with facial telangiectasia in this single-site study. Subjects were randomized to receive up to two split-face treatments 1 month apart with PDL on one side and IPL on the other. PDL treatments were performed at 595 nm with either a 10 or 7 mm spot at a fluence range of 8.1-14.5 J/cm(2), and either 10 or 40 mseconds pulse width. Zimmer air cooling (setting of 4) and ultrasound gel were used for patient comfort. IPL treatments were performed with a spectral range of 500-670 and 870-1,200 nm, a 10 mm × 15 mm spot, fluence range of 34-70 J/cm(2), either a 10 or 100 mseconds pulse width, and 5°C contact cooling. Safety assessments were conducted by the study investigator immediately, 48-96 hours and 1-2 months post-treatment. Independent, blinded-review assessments were conducted 3 months post-treatment. Efficacy was evaluated using a seven-point Telangiectasia Grading Scale (TGS: -1 to 5). Subject self-assessment data were also collected. RESULTS: The difference in incidence rate and severity of adverse side effects between the two devices were not statistically significant (P ≥ 0.39, Fisher's exact test) at any of the three evaluation periods. Per blinded-review assessment, the mean TGS score for both devices was 3.3 (IPL 95% CI: 2.8-3.7; PDL 95% CI: 2.9-3.8). The difference in blinded-ratings for the two devices were not statistically significant (P = 0.82, ANOVA for repeated measures). CONCLUSION: The IPL studied here successfully treated facial telangiectasia, resulting in equivalent safety and efficacy outcomes as compared to the PDL.

Characterization of an optimized light source and comparison to pulsed dye laser for superficial and deep vessel clearance.

BACKGROUND AND OBJECTIVE: An arc lamp-based device providing optimized spectrum and pulse shape was characterized and compared with two pulsed dye laser (PDL) systems using a vascular phantom. Safety and effectiveness for facial telangiectasia are presented in clinical case studies. STUDY DESIGN/MATERIALS AND METHODS: An optimized pulsed light source's (OPL) spectral and power output were characterized and compared with two 595 nm PDL devices. Purpuric threshold fluences were determined for the OPL and PDLs on Fitzpatrick type II normal skin. A vascular phantom comprising blood-filled quartz capillaries beneath porcine skin was treated by the devices at their respective purpuric threshold fluences for 3 ms pulse widths, while vessel temperatures were monitored with an infrared (IR) camera. Patients with Fitzpatrick skin types II-III received a split-face treatment with the OPL and a 595 nm PDL. RESULTS: The OPL provided a dual-band output spectrum from 500 to 670 nm and 850-1,200 nm, pulse widths from 3 to 100 ms, and fluences to 80 J/cm(2). The smooth output power measured during all pulse widths provides unambiguous vessel size selectivity. Percent energy in the near infra-red increased with decreasing output power from 45% to 60% and contributed 15-26% to heating of deep vessels, respectively. At purpuric threshold fluences the ratio of OPL to PDL vessel temperature rise was 1.7-2.8. OPL treatments of facial telangiectasia were well-tolerated by patients demonstrating significant improvements comparable to PDL with no downtime. CONCLUSIONS: Intense pulsed light (IPL) and PDL output pulse and spectral profiles are important for selective treatment of vessels in vascular lesions. The OPL's margin between purpuric threshold fluence and treatment fluence for deeper, larger vessels was greater than the corresponding margin with PDLs. The results warrant further comparison studies with IPLs and other PDLs.

Complications of laser dermatologic surgery.

BACKGROUND AND OBJECTIVE: Innovations in lasers, light and radiofrequency devices have allowed for improved therapeutic efficacy and safety and the ability to treat patients with an ever-increasing number of medical and aesthetic indications. Safety remains a primary concern and the timely communication of complications and their management is vital to insure that treatments be as safe as possible. The purpose of this report on the Proceedings of the First International Laser Surgery Morbidity Meeting is to provide laser experts the opportunity to present and discuss complications that their patients have experienced and how they were successfully managed. METHODS: Laser experts were invited to present complications of laser, light, and radiofrequency treatments that their patients have experienced and to discuss the potential mechanisms leading to the complications their management and final outcomes. RESULTS: Nineteen unique cases are presented and the clinical management of each case discussed. Eighteen sets of pre- and post-operative photos are presented. CONCLUSION: This report shows that even experts, with extensive experience using light-based therapies, can and do have patients who develop complications. Sound clinical judgment, and knowing how to avoid complications and their timely post-operative management, is essential to insure optimal therapeutic outcome.

A multicenter, randomized, double-blind trial of tazarotene 0.1% cream in the treatment of photodamage.

BACKGROUND: Previous studies indicate that tazarotene is efficacious in reducing signs of photodamage. Objective We sought to confirm the efficacy and tolerability of tazarotene 0.1% cream in the treatment of facial photodamage. METHODS: A total of 568 patients with at least moderate fine wrinkling or mottled hyperpigmentation applied tazarotene 0.1% cream or vehicle cream to their face once daily for 24 weeks. RESULTS: Tazarotene cream was significantly more effective than vehicle in reducing fine wrinkles, mottled hyperpigmentation, lentigines, irregular depigmentation, apparent pore size, elastosis, tactile roughness, and an overall integrated assessment of photodamage. Significance was achieved as early as week 2 for some parameters and had not plateaued by week 24. The majority of patients reported improvements in their photodamage as early as week 4. Adverse events were predominantly mild or moderate signs or symptoms of skin irritation. CONCLUSION: Once-daily tazarotene 0.1% cream is effective in ameliorating multiple signs of facial photodamage.

Multipass treatment of photodamage using the pulse dye laser.

BACKGROUND: Pulse dye lasers (PDLs) alter structural proteins in scars and photodamaged skin, in addition to their effects on dermal vasculature. The PDL has become an option in the treatment of photodamage. Although improvements to skin texture are generally modest when compared with ablative resurfacing, PDL offers a treatment with few side effects. A number of methods have been proposed in an effort to improve treatment outcomes. These range from single, low-fluence treatment with no purpura to multiple passes and treatment sessions as well as purpuric doses. OBJECTIVE: To evaluate several of the PDL treatment methods to improve photorejuvenation outcomes while limiting the risk of side effects. METHODS: Twenty patients with photodamage were separated into two groups. Each group received a series of four single-pass treatments or four double-pass treatments at 2-week intervals. Treatments were done using a 595-nm PDL (PhotoGenica V-Star) and a 585-nm PDL (PhotoGenica V) at a pulse duration of 0.5 ms and a 10-mm handpiece. Treatment fluences were maintained below the individual's purpuric threshold, ranging from 3 to 4 J/cm2. Photos were taken before treatment and during follow-up. Efficacy of treatment was based on subjective grading of photos and by patient self-reporting. RESULTS: Multiple treatments resulted in improvements to skin tone and texture, including a reduction in the appearance of rhytids and, in particular, improved pigmentary evenness. There was no significant difference between laser or treatment methods. No side effects were noted. CONCLUSION: PDL treatments provide effective photorejuvenation with minimal risk of side effects.