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.

Treatment of Refractory Melasma in Asians With the Picosecond Alexandrite Laser.

BACKGROUND/OBJECTIVES: The picosecond Alexandrite laser was studied in our practice with the diffractive lens array and the flat optic to treat melasma. METHODS AND MATERIALS: Sixty patients with melasma were treated in a prospective investigation with the picosecond Alexandrite laser. Nineteen patients were treated with the flat optic and 41 patients were treated with the diffractive lens array. Treatments were performed with 1 pass at 2-week intervals for 6 treatments. The Melasma Severity Index (MSI) was used to evaluate the patients before treatment and 3 and 6 months after the final treatment session. RESULTS: At 6 months after the last treatment, there was an 18.5% difference between the groups with a 75.7% improvement in the MSI in patients with the diffractive lens array and a 57.2% improvement in the MSI score in patients with the flat optic. At 6 months, there was recurrence of melasma in 5% of the cases with no hyperpigmentation with the diffractive optic in contrast to recurrence in 16% of the cases in the flat optic group and a transient macular hyperpigmentation in 21% of the cases. CONCLUSION: This investigation highlights the utility of a picosecond Alexandrite laser with a flat and diffractive lens to successfully treat a large percentage of Asian patients in a sunny climate.

Topical Oxymetazoline Cream 1.0% for Persistent Facial Erythema Associated With Rosacea: Pooled Analysis of the Two Phase 3, 29-Day, Randomized, Controlled REVEAL Trials

Background: Rosacea is a chronic dermatologic condition with limited treatment options. Methods: Data were pooled from two identically designed phase 3 trials. Patients with moderate to severe persistent erythema of rosacea were randomized to receive oxymetazoline cream 1.0% or vehicle once daily for 29 days and were followed for 28 days posttreatment. The primary efficacy outcome was the proportion of patients with ≥2-grade improvement from baseline on both Clinician Erythema Assessment (CEA) and Subject Self-Assessment (SSA) at 3, 6, 9, and 12 hours postdose, day 29. Results: The pooled population included 885 patients (78.8% female); 85.8% and 91.2% had moderate erythema based on CEA and SSA, respectively. The primary outcome was achieved by significantly more patients in the oxymetazoline than vehicle group (P<0.001). Individual CEA and SSA scores and reduction in facial erythema (digital image analysis) favored oxymetazoline over vehicle (P<0.001). The incidence of treatment-emergent adverse events was low (oxymetazoline, 16.4%; vehicle, 11.8%). No clinically relevant erythema worsening (based on CEA and SSA) was observed during the 28-day posttreatment follow-up period (oxymetazoline, 1.7%; vehicle, 0.6%). Conclusion: Oxymetazoline effectively reduced moderate to severe persistent facial erythema of rosacea and was well tolerated. J Drugs Dermatol. 2018;17(11):1201-1208.

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.

Delivery of light to the skin through ablated conduits.

BACKGROUND AND OBJECTIVES: Non-invasive laser skin treatment modalities are generally designed to protect the epidermis by cooling and limiting the laser energy deposition in accordance with skin type. We explore a treatment modality that uses a 2,940 nm Er:YAG laser with high tissue absorption to ablate an array of channels through the epidermis and upper dermis, and then deliver laser energy from a 1,320 nm Nd:YAG laser with lower tissue absorption through the ablated channels. Treatment through ablated conduits offers a unique capability to deliver laser radiation to a deeper level in the dermis or beyond the dermis and the delivered energy to be deposited in a nearly uniform distribution. The ablated channels represent a relatively small surface and volume fraction of the epidermis and upper dermis, and heal very fast. A pilot study was performed to explore the benefits of treatments through ablated conduits for skin tightening, cellulite, and acne scarring. MATERIALS AND METHODS: A custom-built laser from Cynosure Inc. was designed to deliver to the epidermis up to 3 J/cm2 at 2,940 nm from an Er:YAG laser followed in less than 10 ms by up to 20 J/cm2 at 1,320 nm from a Nd:YAG laser. Both laser sources were delivered to the skin through a diffractive lens array. The spatial intensity modulation created by the diffractive lens array on the skin surface consisted of a low energy density background that did not damage the epidermis and a superimposed array of much higher energy density regions where the Er:YAG laser ablated the channels, and most of the 1,320 nm laser energy was delivered through the channels. Various fluence combinations of the ablative and non-ablative lasers were tested on ex vivo human skin samples to evaluate tissue effects and parameters for a clinical test. A limited clinical study was performed to evaluate tissue response and healing effects. RESULTS: Histology confirmed the presence of ablative channels through the epidermis and upper dermis as well as the absence of epidermal damage apart from the channels. Three days posttreatment there was complete skin healing with no evidence of channel ablation or coagulation in the skin biopsies. Limited clinical testing for facial treatments showed mild improvement for acne scarring and skin laxity. CONCLUSIONS: Laser skin treatment through ablated conduits can be performed safely with fast subsequent healing of the channels ablated through the skin. Further refinement of the treatment parameters and variation of the wavelength of the non-ablative laser source may bring improved treatment efficacy. Lasers Surg. Med. 49:69-77, 2017. © 2016 Wiley Periodicals, Inc.

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.

Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 5: a guide on the management of rosacea.

The last article in this 5-part series provides a final overview of consensus recommendations from the American Acne & Rosacea Society (AARS) on the management of the common presentations of cutaneous rosacea. Optimal management of rosacea requires careful assessment of the patient's clinical features with integration of therapies that adequately treat the presenting signs and symptoms. The treatment consensus recommendations from the AARS are based on 2 major common clinical presentations of rosacea: (1) centrofacial erythema with papulopustular lesions, and (2) centrofacial erythema without papulopustular lesions. The recommendations provided here serve to guide clinicians in their clinical practice.

Consensus recommendations from the American acne & rosacea society on the management of rosacea, part 4: a status report on physical modalities and devices.

The fourth article in this 5-part series reviews physical modalities and devices used to treat cutaneous rosacea based on consensus recommendations from the American Acne & Rosacea Society (AARS) on the management of the common presentations of cutaneous rosacea. The major therapeutic uses of physical modalities and devices, especially laser and light-based systems, are for treatment of telangiectases and persistent facial erythema (background erythema). Phymas, especially rhinophyma, also are treated with physical modalities such as ablative lasers or surgical devices (eg, electrosurgical loop). Appropriately selected and properly used lasers and intense pulsed light (IPL) devices can successfully address specific clinical manifestations of rosacea that exhibit limited or no response to available medical therapies, such as telangiectases and background centrofacial erythema. Rosacea-associated symptoms also may improve. In most cases, treatment will need to be repeated intermittently to sustain improvement.

Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 3: a status report on systemic therapies.

The third article in this 5-part series reviews systemic therapies used to treat cutaneous rosacea based on consensus recommendations from the American Acne & Rosacea Society (AARS) on the management of the common presentations of cutaneous rosacea. The consensus recommendations are based on current understanding of research that describes pathophysiologic mechanisms that appear to be operative in rosacea, correlation of these underlying pathophysiologic mechanisms with specific clinical manifestations of rosacea, and outcomes from clinical trials that evaluate therapies for rosacea both as monotherapy and in combination with other agents. Systemic agents used for treatment of rosacea have been administered as oral formulations (ie, tablets, capsules). The only oral agent for rosacea approved by the US Food and Drug Administration (FDA) is a modified-release doxycycline 40-mg capsule. Other non-FDA-approved oral agents also are discussed including other tetracyclines, macrolides, metronidazole, and isotretinoin.

Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 1: a status report on the disease state, general measures, and adjunctive skin care.

Rosacea is a common clinical diagnosis that encompasses a variety of presentations, predominantly involving the centrofacial skin. Reported to present most commonly in adults of Northern European heritage with fair skin, rosacea can affect males and females of all ethnicities and skin types. Pathophysiologic mechanisms that appear to correlate with the manifestation of rosacea have been the focus of multiple research studies, with outcomes providing a better understanding of why some individuals are affected and how their visible signs and symptoms develop. A better appreciation of the pathophysiologic mechanisms and inflammatory pathways of rosacea has allowed therapeutic strategies to be optimally incorporated. Part 1 of this 5-part series discusses the rosacea disease state with an emphasis on clinical correlation, reviews adjunctive skin care for cutaneous rosacea, and provides management caveats.

An evaluation of potential correlations between pathophysiologic mechanisms, clinical manifestations, and management of rosacea.

This article discusses rosacea, a common facial dermatosis of uncertain etiology and recent investigations that have begun to shed considerable light on the sequence of events leading to clinical manifestations of rosacea. The article content is based on a dedicated meeting about rosacea sanctioned by the American Acne & Rosacea Society (AARS) and represents the consensus of the authors and AARS Board of Directors.