Search results for: light therapy

Intense Pulsed-light Therapy Significantly Improves Keratosis Pilaris: A Randomized, Double-blind, Sham Irradiation-controlled Trial

Background.Keratosis pilaris (KP) is a common benign follicular disorder for which various topical and laser treatments have been used, with limited efficacy.

Efficacy and Tolerability of a Combined 445nm and 630nm Over-the-counter Light Therapy Mask with and without Topical Salicylic Acid versus Topical Benzoyl Peroxide for the Treatment of Mild-to-moderate Acne Vulgaris

a,bMark S. Nestor, MD, PhD; aNicole Swenson, DO; aAngela Macri, DO; aMitchell Manway, DO; aPaige Paparone, DO aCenter for Clinical and Cosmetic Research and Center for Cosmetic Enhancement, Aventura, Florida; bDepartment of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida Disclosure: Dr. Nestor is a consultant to La Lumiere LLC, Cleveland, Ohio, and received a research grant for this study. The authors acknowledge the editorial assistance of Dr. Carl S. Hornfeldt, Apothekon, Inc., with funding provided by La Lumiere.   Abstract Objective: To evaluate the efficacy and tolerance of a combined 445nm/630nm light therapy mask for the treatment of mild-to-moderate acne vulgaris with and without topical 1% salicylic acid with retinol versus 2.5% benzoyl peroxide. Design: A 12-week evaluator-blinded, randomized study. Subjects were randomized to be treated with the 445nm/630nm light therapy mask alone, benzoyl peroxide, or 445nm/630nm light therapy mask with topical 1% salicylic acid with retinol. Participants: Healthy male and female subjects 12 to 35 years old with Fitzpatrick skin types I to VI and mild-to-moderate facial acne vulgaris. Measurements: The primary endpoint was the change in the number of inflammatory acne lesions after 12 weeks of treatment. Secondary endpoints included the change in noninflammatory acne lesions, change in total acne lesions, change in Investigator Global Acne Assessments, and overall responder rate. Results: 445nm/630nm light therapy mask-treated subjects showed a 24.4-percent improvement in inflammatory acne lesions (p<0.01) versus 17.2 percent (p<0.05) and 22.7 percent (p<0.01) in benzoyl peroxide and 445nm/630nm light therapy mask with topical 1% salicylic acid with retinol, respectively, a 19.5-percent improvement in noninflammatory lesions (p<0.001) versus 6.3 and 4.8 percent for benzoyl peroxide and 445nm/630nm light therapy mask with topical 1% salicylic acid with retinol, respectively. Subjects in the 445nm/630nm light therapy mask group also achieved a 19.0-percent improvement in the Investigator Global Acne Assessment (p<0.001) versus 4.7 percent in benzoyl peroxide and 13.9 percent in 445nm/630nm light therapy mask with topical 1% salicylic acid with retinol (p<0.01). Treatments were well-tolerated overall with trends toward less early irritation in the 445nm/630nm light therapy mask group. Conclusion: 445nm/630nm light therapy mask appears to be a safe and effective therapy for mild-to-moderate acne. (J Clin Aesthet Dermatol. 2016;9(3):25–35.)   Acne vulgaris is a chronic inflammatory disease of pilosebaceous units. The major factors involved in the pathogenesis are increased sebum production, hypercornification of the pilosebaceous duct, ductal colonization with Propionibacterium acnes, and inflammation.[1] It remains the most commonly encountered skin disease,[2] affecting an estimated 45 million people in the United States[3] and approximately 80 to 95 percent of all individuals at some time in their lives.[2],[3] Although commonly thought to primarily affect teenagers, adolescents comprised only 36.5 percent of acne patients while adults comprised 61.9 percent.[4] It is estimated that US consumers spend $1.2 billion each year for the treatment of acne[3] with mean individual costs of $689 and ranging from $361 to $869.4 Acne can have long-lasting psychosocial effects with a severe negative impact on quality of life[5],[6] across different races and ethnicities.[7] Depression has been reported in more than 10 percent of female acne patients.[4] Despite the wide variety of available topical and systemic acne treatments, treatment for acne remains far from optimal.[2] In addition, prescription acne medications, such as systemic antibiotics and retinoids, can cause adverse effects (AEs) that occasionally pose significant health risks to the patient,[8],[9] and the long-term use of systemic antibiotics can be a significant factor in bacterial resistance.[10] Common over-the-counter (OTC) products for the treatment of acne include topical benzoyl peroxide (BPO),[11],[12] salicylic acid,[13],[14] and moisturizers.[15],[16] Unfortunately, patient satisfaction with treatment outcomes can be low, especially with OTC products.[17] Light of varying wavelengths has been shown to have a therapeutic effect on a variety of skin conditions and disorders.[18–20] Blue light has been shown to have beneficial effects on acne.[21],[22] This is believed to occur due to the effects of blue light on protoporphyrins with free radical formation and subsequent destruction of the cell membrane of Propionibacterium acnes,[23],[24] which plays an important role in the etiology of acne.[25] Red light has anti-inflammatory effects[26] and has been shown to be beneficial for the treatment of inflammatory acne lesions.[27] Several devices that employ blue light-emitting diodes (LEDs) have been developed for the treatment of acne,[28–31] which have a beneficial effect on acne lesions.[32] In addition, studies have shown the use of combined red and blue light is also very effective.21,33 The results of a randomized, double-blind, sham-controlled study indicate the addition of red light results in significant improvements in both inflammatory and noninflammatory acne lesions.[34] A device has been developed to provide home acne treatment using LEDs that emit both 445nm blue and 630nm red light. Designed to be worn as a mask, it provides full-face treatment during each daily 15-minute light therapy session (illuMask® Acne Light Therapy Mask; La Lumiere, LLC, Cleveland, Ohio). The objective of this 12-week, randomized, double-blind study was to evaluate the efficacy and tolerance of the combined 445nm blue/630nm red light therapy mask (MASK) for the treatment of mild-to-moderate acne vulgaris with and without topical 1% salicylic acid with retinol (MASK-SA) versus 2.5% BPO. METHODS Study participants. Healthy male and female subjects 12 to 35 years old with Fitzpatrick Skin Types I to VI were eligible for enrollment. Subjects were required to have mild-to-moderate facial acne vulgaris, defined as 20 to 140 total lesions, with 10 to 90 noninflammatory and 10 to 50 inflammatory facial lesions, but no nodules or cysts (Investigator’s Global Assessment Score of 2, 2.5, 3, or 3.5 using the Modified Cook’s Scale).[35] Each subject expressed a willingness to comply with the requirements of the study, which included avoiding excessive sun exposure and tanning beds, artificial tanning creams, and facial spray tans. The use of hats outdoors was strongly advised. Female subjects of childbearing potential received a urine pregnancy test prior to participating in the study and agreed to use a medically acceptable form of birth control during the study. Reasons for exclusion from the study included a known

5-Aminolevulinic Acid-based Photodynamic Intense Pulsed Light Therapy Shows Better Effects in the Treatment of Skin Photoaging in Asian Skin: A Prospective, Single-blinded, Controlled Trial

Gao Yang, MD, Laser Center, Jinshan Hospital, Fudan University, Shanghai, China; Leihong Flora Xiang, MD, PhD Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China; Michael H. Gold, MD, Gold Skin Care Center, Tennessee Clinical Research Center, Nashville, Tennesee; Vanderbilt University School of Medicine, Department of Dermatology; Vanderbilt University School of Medicine, School of Nursing, Nashville, Tennesee; Huashan Hospital, Fudan University, Shanghai, China; Number One Hospital, China Medical University, Shenyang, China

Self-diagnosis of Mild-to-Moderate Acne for Self Treatment with Blue Light Therapy

Michael H. Gold, MD, Tennessee Clinical Research Center, Nashville, Tennessee; Anneke Andriessen; RBC Consultants, The Netherlands Julie Biron, Tennessee Clinical Research Center, Nashville, Tennessee; Disclosure: Dr. Gold is a consultant to, performs research for, speaks for, and receives honoraria from Pharos Life; Ms. Andriessen and Ms. Biron report no relevant conflicts of interest.

Clinical Efficacy of Self-applied Blue Light Therapy for Mild-to-Moderate Facial Acne

Michael H. Gold, MD; Tennessee Clinical Research Center, Nashville, Tennessee; Anneke Andriessen; RBC Consultants, The Netherlands; Julie Biron; Tennessee Clinical Research Center, Nashville, Tennessee; Hinke Andriessen; RBC Consultants, The Netherlands

A Systematic Review and Meta-analysis of Randomized Controlled Trials of United States Food and Drug Administration-Approved, Home-use, Low-Level Light/Laser Therapy Devices for Pattern Hair Loss: Device Design and Technology

J Clin Aesthet Dermatol. 2021;14(11):E64–E75. by Suparuj Lueangarun, MD, MSc; Poom Visutjindaporn, MD; Yardnapar Parcharoen, PhD; Pollawat Jamparuang, BSc; and Therdpong Tempark, MD Drs. Lueangarun and Visutjindaporn are with the Division of Dermatology, Chulabhorn International College of Medicine, Thammasat University, in Pathum Thani, Thailand. Dr. Parcharoen is with the Chulabhorn International College of Medicine, Thammasat University in Pathum Thani, Thailand. Dr. Jamparuang is with the Radiometry Laboratory, Light and Color Group, Thermometry and Optical Metrology Department, National Institute of Metrology, Ministry of Higher Education, Science, Research and Innovation in Pathum Thani, Thailand. Dr. Tempark is with the Department of Pediatrics, King Chulalongkorn Memorial Hospital in Bangkok, Thailand. FUNDING: No funding was provided for this article. DISCLOSURES: The author reports no conflicts of interest relevant to the content of this article. ABSTRACT: Background. Low-level light/laser therapy (LLLT) can potentially stimulate hair growth in pattern hair loss (PHL), with many available home-use LLLT devices of different designs and technology on the market. However, not all devices are cleared by the United States (US) Food and Drug Administration (FDA), with very few studies to support their efficacy. Objectives. This systematic review and meta-analysis aimed to investigate the effectiveness of FDA-approved LLLT devices for PHL treatment. Methods. We included articles related to FDA-approved home-use LLLT devices on PubMed and Medline, using the FDA 510(K) Premarket Notification database and the systematic search of articles up to January 2020. The standardized mean difference (SMD) for the changes of hair density treated by LLLT versus sham devices was analyzed. Results. Only 32 home-use LLLT devices have been approved by the FDA as of January 2020. The meta-analysis comprised seven double-blinded, randomized, controlled trials. The overall quantitative analysis yielded a significant increase in hair density in those treated by LLLT versus sham groups (SMD: 1.27, 95% confidence interval [CI]: 0.993–1.639). The subgroup analysis demonstrated the increased hair growth in male and female subjects with both comb- and helmet-type devices. There were significant LLLT sources in the LDs alone (SMD: 1.52, 95% CI: 1.16–1.88) and the LDs combination (SMD: 0.85, 95% CI: 0.55–1.16) (p=0.043). Conclusion. LLLT is potentially effective for PHL treatment. Nonetheless, the long-term follow-up study in patients with severe PHL with combined standard treatment and comparison between LLLT devices and energy sources is recommended.  Key words: Pattern hair loss, low-level laser therapy, low-level light therapy, FDA-approved LLLT devices, androgenetic alopecia, hair loss Pattern hair loss (PHL), also called androgenetic alopecia (AGA), affects half of the men aged 50 years or older and more than half of the women aged 80 years or older.1 Although PHL is not fatal, many patients lose their confidence and become stressed.2  Oral finasteride and topical minoxidil2 in various forms, including solution, foam, and shampoo, are currently approved by the United States (US) Food and Drug Administration (FDA) for PHL treatments. Despite its treatment efficacy, oral finasteride can cause some unfavorable side effects, such as erectile dysfunction, decreased libido, and increased body hair growth.3,4 Thus, other treatment options are recommended in those who respond poorly or experience undesirable side effects.5 In 1967, a pioneer research study was first conducted to assess the “photobiostimulation” or low-level light/laser therapy (LLLT) on mice by using the ruby laser.6 Results indicated increased hair growth on the shaved-off areas of animals’ backs. The efficacy of LLLT has since been investigated by many scientists, and the utilization of LLLT therapy has been adapted worldwide, especially for certain skin diseases, such as AGA. The mechanism of LLLT in hair regrowth enhances the stimulation of mitochondria located in hair bulge stem cells, with cytochrome c oxidase (CCO) in the membrane of the mitochondria as the target chromophore of red light. This then leads to mitochondrial respiration, with reactive oxygen species (ROS) and adenosine triphosphate (ATP) to activate cellular proliferation, migration, and oxygenation, which consequently promote hair growth.7 In 2007, the first cleared LLLT device was introduced for male patients with PHL by the FDA. Since then, the numerous forms of convenient LLLT technology and devices have been modified by different manufacturers in the current US market, though some of those LLLT products with very few published articles to support their efficacy have been approved by the FDA. Thus, we aimed to investigate the efficacy of the FDA-approved LLLT devices, with different designs and light/laser sources, on hair growth in male and female patients. Also, the information on decisions of both physicians and patients regarding the most appropriate LLLT devices and specific technology was reviewed.   Methods Literature search. A search using product code “OAP” from the FDA 510(k) Premarket Notification Medical Database for all home-use LLLT devices was performed.8 The devices were sconsidered safe and effective, substantially equal to legally marketed devices. OAP was categorized as “laser, comb, hair” product code to promote hair growth. The identification of all devices in the US market was reviewed and combined with information on the manufacturers’ websites.  A search of PubMed and Medline for articles related to the devices was performed through January 5, 2020. The search terms included “low-level light therapy” OR “low-level laser therapy” OR “photobiomodulation (PBM)” OR “HairMax LaserComb” AND “androgenetic alopecia” OR “female PHL” OR “male PHL” OR “PHL” OR “hair growth.”  Inclusion and exclusion criteria. Only the studies on AGA or PHL in humans and the use of FDA-approved devices, written in English, were included. The review articles, studies on animals, usage of other modalities, not commercially available in the market, and not written in English were excluded.  All search results were screened by two reviewers for relevant abstracts and titles. Full texts of potentially relevant studies were thoroughly examined for the eligibility of final inclusion. The results were independently reviewed by two authors. Any discrepancies were discussed among all authors for inclusion and exclusion criteria. We excluded three studies of nonavailable devices,9–11 one study comparing LLLT with topical minoxidil with no sham control,12 one retrospective observational study,13 and one prospective nonrandomized control trial.8 Seven studies met the inclusion criteria for our meta-analysis (Figure 1). Study quality assessment. The methodological quality of

Photodynamic Therapy for Actinic Keratoses of the Upper Extremities using 10% Aminolevulinic Acid Gel, Red Light, and Adapalene Pretreatment

J Clin Aesthet Dermatol. 2021;14(10):19–24. by Barry I. Galitzer, MD Dr. Galitzer is with the Skin Center in Fort Lauderdale, Florida. FUNDING: This study was supported by Biofrontera, Inc. DISCLOSURES: The author reports no conflicts of interest relevant to the content of this article. ABSTRACT: Background. Actinic keratoses (AKs) are sun-induced cutaneous lesions that may progress to squamous cell carcinoma (SCC). Photodynamic therapy (PDT) is an ideal treatment option for AKs because it allows for treatment of field cancerization, selective destruction of diseased tissue, good cosmetic outcomes, and limited downtime. Objectives. This study sought to determine the efficacy and safety of pretreating AKs of the dorsal hands and forearms with adapalene gel, an inexpensive and over-the-counter retinoid, prior to debridement of the target area and PDT with aminolevulinic hydrochloride acid (ALA, 10%) gel and narrowband red light. Methods. Fifteen patients with AK lesions of the right or left dorsal hands or forearms were pretreated with adapalene gel (0.1%) twice daily for one week prior to ALA-PDT. The other hand or forearm was treated with ALA-PDT (standard therapy), but not pretreated. For PDT, all treated areas were debrided with sandpaper, degreased with acetone, incubated for one hour with 10% ALA gel under occlusion, and illuminated with narrowband red light (~635 nm). All patients experienced one PDT treatment session. Results. Eight weeks after treatment, 12 subjects in the adapalene-pretreated group achieved 50% to 100% clearance compared to 10 subjects in the standard therapy group. The median lesion count reduction in the adapalene-pretreated group was -79% compared to -57% in the standard therapy group, and this difference was significant (P=0.0164). The treatment was well-tolerated and the level of patient satisfaction was high. Conclusion. Pretreatment with adapalene gel twice daily for one week may enhance efficacy in a single ALA-PDT treatment of AK lesions of the dorsal hand or forearm. Key words: Cutaneous lesions, field cancerization, photosensitizing agent, protoporphyrin, lesion count Actinic keratoses (AKs) are sun-induced cutaneous lesions that may progress to squamous cell carcinoma (SCC).1 Although the risk that a single AK lesion will progress to SCC is variable,2,3 patients often have multiple AK lesions, and the overall risk of progression increased. Therefore, the primary goal of AK treatment is to completely clear all visible and subclinical lesions.4 Lesion-directed therapies, such as cryotherapy, curettage, and lasers, although effective against visible AKs, do not address field cancerization and may lead to high recurrence rates.5 Photodynamic therapy (PDT) is an ideal treatment option for AKs because it allows for treatment of field cancerization, selective destruction of diseased tissue, good cosmetic outcomes, and limited downtime.6 In PDT, a photosensitizing agent is applied topically and activated by visible light. Aminolevulinic acid (ALA) is a precursor in the heme pathway and is converted to the photosensitizer protoporphyrin IX (PpIX) in the skin. When exposed to red or blue light, PpIX generates reactive oxygen species, which are cytotoxic and produce an inflammatory response.7  The objective of the present study was to determine the efficacy and safety of pretreating AKs of the dorsal hands or forearm with adapalene gel (0.1%) prior to broad-area PDT with ALA (10%) gel and narrowband red light. Adapalene was chosen as the retinoid to be used in this study because it is inexpensive and available over the counter. Methods Subjects. Nine men and six women (n=15 participants) aged (mean ± standard deviation) 65.4 ± 9.3 years with AK lesions on the dorsal hand or forearm were enrolled in this study. Eligible individuals had at least five AK lesions (grade 1 or 2) in an area that included the extensor surface of the hand/forearm between the elbow and the base of the fingers. Skin types were II (n=11) and III (n=4). Women were not pregnant, were surgically sterile, or were using a medically acceptable form of birth control.  Individuals were excluded if they had porphyrin abnormalities, sensitivity to trial constituents, or a skin condition that could interfere with clinical evaluations; used tanning salons or photosensitizing drugs; had undergone recent procedures or taken topical medications directed at the treatment area; were participating in other trials; or had human immunodeficiency viral infection or another condition that required immunosuppressive therapy. All subjects provided signed informed consent for treatment, and this study was approved by an institutional review board. Treatment. This was a single-center, randomized, bilateral comparison (right vs. left) study. At the first visit (Visit 1), qualified subjects were randomized so that one dorsal hand or forearm was pretreated with adapalene gel (0.1%, Differin Gel; Galderma Laboratories, LP, Fort Worth, Texas) twice daily for one week and the other dorsal hand or forearm was not pretreated. Seven days later (Visit 2), both the pretreated area and corresponding untreated area were debrided with sandpaper and scrubbed twice with acetone before the application of 10% ALA gel (Ameluz®; Biofrontera Inc., Woburn, Massachusetts) over the entire surface. Ameluz® gel, in combination with PDT using a narrowband red light (BF-RhodoLED® lamp; Biofrontera Inc.), is indicated for lesion-directed and field-directed treatment of AKs of mild-to-moderate severity on the face and scalp.  The ALA-treated areas were occluded with plastic wrap for one hour. Care was taken to avoid sunlight or high-intensity light radiation. After one hour, the occlusive dressing was removed and the treated area was cleaned with a mild cleanser, washed thoroughly with water, and patted dry. Treatment areas were then exposed to red light continuously for 10 minutes. Discomfort during light exposure was graded by the subject on a scale of 0 to 10 immediately after treatment. The emitted wavelength of the light source (~635 nm) and light dose (37 J/cm2) were fixed by the manufacturer. Discomfort (stinging/burning) during light exposure was minimized by constant air flow with an integrated fan. Immediately after light treatment, the treated areas were cleaned with a mild cleanser and water and patted dry. Sunblock (Vanicream Sport SPF 35; Pharmaceutical Specialties Inc., Rochester, Minnesota) was applied, and each subject was advised to protect the treated skin from sunlight or prolonged or intense light by wearing protective clothing and applying sunblock regularly

Photodynamic Therapy with 5-aminolevulinic Acid 10% Gel and Red Light for the Treatment of Actinic Keratosis, Non-melanoma Skin Cancers, and Acne: Current Evidence and Best Practices

J Clin Aesthet Dermatol. 2021;14(10):E53–E65.  by Nathalie C. Zeitouni, MDCM, FRCPC; Neal Bhatia, MD; Roger I. Ceilley, MD; Joel L. Cohen, MD; James Q. Del Rosso, DO; Angela Y. Moore, MD; Gilly Munavalli, MD, MHS, FACMS; David M. Pariser, MD, FACP, FAAD; Todd Schlesinger, MD; Daniel M. Siegel, MD, MS; Andrea Willey, MD; and Mitchel P. Goldman, MD Dr. Zeitouni is with Medical Dermatology Specialists, University of Arizona COM Phoenix in Phoenix, Arizona. Dr. Bhatoa is with Therapeutics Clinical Research in San Diego, California. Dr. Ceilley is with Dermatology PC in West Des Moines, Iowa. Dr. Cohen is with AboutSkin Dermatology and DermSurgery in Greenwood Village, Colorado. Dr. Del Rosso is with JDR Dermatology Research in Las Vegas, Nevada. Dr. Moore is with Arlington Research Center in Arlington, Texas, and Baylor University Medical Center in Dallas, Texas. Dr. Munavalli is with Dermatology, Laser, & Vein Specialists of the Carolinas in Charlotte, North Carolina. Dr. Pariser is with the Department of Dermatology, Eastern Virginia Medical School and Virginia Clinical Research, Inc. in Norfolk, Virginia. Dr. Schlesinger is with the Dermatology and Laser Center of Charleston and the Clinical Research Center of the Carolinas in Charleston, South Carolina, and the Department of Dermatology, SUNY Downstate Health Sciences University and the Brooklyn VA Medical Center in Brooklyn, New York. Dr. Siegel is with Long Island Skin Cancer and Dermatologic Surgery in New York, New York. Dr. Willey is with Surgical and Aesthetic Dermatology in Sacramento, California. Dr. Goldman is with Cosmetic Laser Dermatology, A West Dermatology Company in San Diego, California.  FUNDING: An expert board meeting was organized and funded by an unrestricted grant from Biofrontera. This publication, however, was initiated by the authors, who developed the recommendations and drafted, edited, and approved the final version.  DISCLOSURES: Dr. Zeitouni is an investigator, speaker, and scientific advisory board member for Biofrontera. Dr. Bhatia has affiliations with Almirall, Biofrontera, Galderma, Ortho, Pharmaderm, and SunPharma. Dr. Ceilley is a consultant to Biofrontera and SunPharma. Dr. Cohen is a on the scientific advisory board and has participated in a clinical trial for Biofrontera. Dr. Del Rosso is a consultant for Biofrontera. Dr. Moore is a consultant and investigator for and has received grants and honoraria from Biofrontera. Dr. Schlesinger is a consultant and investigator for Biofrontera; a consultant, investigator, and on the speaker bureau for Almirall; a consultant for SunPharma; and a consultant and investigator for Galderma. Dr. Siegel is a consultant to Biofrontera, SunPharma, and Almirall. Dr. Willey holds patent PCT/US 2018/042505. Dr. Goldman is a clinical investigator for Biofrontera.  ABSTRACT: Photodynamic therapy (PDT) can be an effective treatment for actinic keratosis (AK) as well as selected non-melanoma skin cancers (NMSCs), such as Bowen’s disease and superficial basal cell carcinoma. PDT has also demonstrated effectiveness in the management of acne vulgaris. Results from controlled clinical trials have shown the safety and efficacy of PDT for these conditions with the use of different photosensitizers and a wide range of light sources. PDT has been employed effectively as monotherapy and in combination with other topicals and alternate light or laser energy therapies. This article provides expert practical guidance for the use of the newest 5-aminolevulinic acid (ALA) product (ALA 10% gel) plus red light as monotherapy for AKs, NMSC, and acne. Here, information from clinical guidelines and a summary of supporting evidence is provided for each cutaneous condition. The authors also provide detailed guidance for employing ALA 10% gel, a photosensitizer precursor, for each of these applications.  Key words: Photodynamic therapy, 5-aminolevulinic acid gel, red light, actinic keratosis, acne, non-melanoma skin cancer, BF-200 ALA, Ameluz, BF-RhodoLED ________________________________________________________________________________ Photodynamic therapy (PDT) is a widely used therapeutic modality in dermatology.1–5 The procedure is most often carried out in the office and it requires three elements6: a photosensitizer, a light source, and tissue oxygen. The therapeutic effect is achieved by light activation of a photosensitizing agent, resulting in the aerobic formation of reactive oxygen species (ROS), which irreversibly oxidize essential cellular components, causing apoptosis and necrosis as well as cell death secondary to increased autophagy.6,7  Multiple photosensitizers have been used for PDT, with the most common being the photosensitizer prodrugs 5-aminolevulinic acid (ALA) and methyl-5-aminolevulinate (MAL). ALA and MAL have been used extensively for lesion- and field-directed treatment in patients with AKs,4,8–11 Bowen’s disease, superficial and nodular basal cell carcinoma (BCC), and acne vulgaris.6,12,13 There are noteworthy differences among the branded photosensitizer prodrugs for PDT, mostly regarding the active ingredient’s stability and epidermal penetration.14 ALA is prone to degradation, and particularly older ALA preparations (e.g., ALA compounded in alcohol, topical creams, or ointments) have a very limited stability. ALA methyl ester (MAL) is less susceptible to degradation, but the ester must be cleaved before ALA can enter the heme biosynthesis pathway to be metabolized to the photosensitizer protoporphyrin IX (PpIX). As a result, MAL induces less PpIX compared to ALA after the same incubation time. In common practice, ALA and MAL are referred to as photosensitizers, and thus the same descriptive term is used in this article. A more recent photosensitizer technology stabilizes ALA within a nanoscale lipid–vesicle gel formulation (BF-200 ALA nanoemulsion gel; Biofrontera Bioscience GmbH, Leverkusen, Germany).15 This BF-200 10% ALA-HCl nanoemulsion gel formulation remains stable over 24 months. Research has also shown that nanoemulsion BF-200 can enhance the penetration of ALA through the stratum corneum.14 The BF-200 formulation of ALA (referred to hereafter to ALA 10% gel) was granted marketing authorization by the European Medicines Agency in December 2011 for the treatment of mild and moderate AKs on the face and scalp; the indication was extended to include field cancerization in 2016, superficial and nodular BCC in 2017, and AK on the extremities and trunk/neck in 2020.16 ALA 10% gel was approved in combination with the BF-RhodoLED® red light lamp (~635nm) (Biofrontera Bioscience GmbH) for treatment of lesion- and field-directed PDT of AKs on the face and scalp by the United States (US) Food and Drug Administration (FDA) in 2016.17 Given the widespread use of PDT, both on-

Biophotonic Therapy with Fluorescent Light Energy Decreases Facial Erythema, Improves Signs and Symptoms of Rosacea, and Increases Patient Satisfaction: A Postmarket Study

J Clin Aesthet Dermatol. 2021;14(7):16–21 by Martin Wade, BMed Sci, MBBS, FACD; Vanessa Charest, BSc; Bruno Ballardin, B. Eng, MBA; Deirdre Edge, PhD; and Michael Canova Engelbrecht Nielsen, PhD Dr. Wade, Ms. Charest, and Mr. Ballardin are with the London Skin and Hair Clinic in London, England. Drs. Edge and Nielsen are with Guangdong Klox Biomedical Group Co., Ltd., in Guangzhou, China. FUNDING: No funding was provided for this article. DISCLOSURES: Drs. Edge and Nielsen are employees of Guangdong Klox Biomedical Group Co., Ltd. The other authors report no conflicts of interest relevant to the content of this article. ABSTRACT: Background. Rosacea is a difficult-to-manage chronic inflammatory skin condition reported to have a negative psychosocial impact on patients. Novel approaches are sought to target the many signs and symptoms of the condition while also improving the quality of life of patients. Objective. We assessed the efficacy of the Kleresca® biophotonic platform (KLOX Technologies Inc., Laval, Canada), which creates fluorescent light energy (FLE), to induce a novel form of photobiomodulation for treating rosacea. We also assessed patient satisfaction with their facial appearance and concerns about perceptions of others before and after treatment. Methods. Nine patients were treated once a week for four weeks with FLE. Patients and the treating clinician completed questionnaires throughout and after the treatment to grade the rosacea signs and symptoms and capture patients’ perceptions of the treatment and their condition. Results. FLE significantly reduced the inflammatory erythematous reaction of the face, improved flushing and erythema associated with rosacea, and had a positive impact on patients’ self-perception and emotional wellbeing. Conclusion. Our results support FLE as an effective, noninvasive treatment modality for rosacea. Keywords: Rosacea, erythema, flushing, questionnaire, biophotonics, chromophore, fluorescent light energy, inflammatory skin conditions, FLE, photobiomodulation, skin quality, patient perception, quality of life Rosacea is a chronic inflammatory skin condition affecting both men and women, with high incidence rates in those with Fitzpatrick Skin Types I and II.1 Often underdiagnosed, it is estimated to affect approximately 5.5 percent of the population worldwide.2 While the etiology of rosacea is evolving, it is understood that an aberrant immune response, altered neurovascular signalling, and colonization of the skin with microorganisms (i.e., Demodex folliculorum) all play a role.1 Common features of rosacea include flushing, nontransient erythema, papules, pustules, telangiectasia, burning or stinging, and skin sensitivity.3 Rosacea has typically been classified into four main subtypes, erythematotelangiectatic (ETR), papulopustular (PPR), phymatous, and ocular, depending on the presentation.3 However, with updates to this classification system, it has emerged that patients often present with a variety of clinical features characteristic of more than one subtype.4 Further, major fixed centrofacial erythema is a main diagnostic feature5 and common among all presentations of rosacea.6,7  Effectively targeting erythema has posed a challenge in treating rosacea.8 Since a single patient with rosacea can have a variety of clinical features, a combined treatment approach is often prescribed. Current treatment options often include topical creams, systemic treatments, and laser and light therapy to target the broad spectrum of phenotypes of the condition.9 However, results are varied, with either low adherence or limited patient satisfaction.10,11  In addition to the physical aspects of rosacea, there is a significant psychosocial burden associated with the condition. Patients report low self-esteem, embarrassment, frustration, and affected professional interactions.10,12 Furthermore, rosacea is linked to depression and has significant effects on patients’ quality of life (QoL).12,13 There is currently no cure for rosacea; therefore, treatment options that can manage the signs and symptoms, halt progression, and improve the patient’s QoL are required.  Previous reports with the Kleresca® biophotonic platform (KBP; KLOX Technologies Inc., Laval, Canada) have been promising in not only treating rosacea signs and symptoms in rosacea subtypes 1, 2, and 3, but also in improving the visible appearance of the skin.14,15 This postmarket study sought to assess the therapeutic efficacy of the KBP while also capturing the patient and clinician perceptions of the condition and the effect of the treatment.  Methods Patients with rosacea subtype 1 (ETR) and subtype 2 (PPR) were recruited by the treating clinic to receive the treatment. At the initial consultation, the treating practitioner completed a patient information and first assessment form. The treatment procedure was conducted as per the manufacturer’s instructions for use. Briefly, a 2-mm layer of the proprietary chromophore-containing gel was applied to the cleansed face and illuminated with a multi-light-emitting diode lamp for nine minutes, once per week for four consecutive weeks (note: one patient had a three-week break between the first and second treatments due to work commitments). Patients were brought back to the clinic for a follow-up visual assessment at between eight and 12 weeks from initiation of the treatment (mean±standard error of the mean time: 9.5±0.6 weeks). Patients had their photo taken (VISIA® System; Canfield Scientific, Fairfield, New Jersey) and both the patients and the treating practitioner completed a questionnaire before every treatment and at the follow-up session. Patient questions were partly adapted from research by Zeichner et al10 addressing the severity of rosacea signs and symptoms (intensity: graded as 0=absent, 1=mild, 2=moderate, or 3=severe). The skin’s appearance was graded from 0 to 10, where 0=very bad and 10=excellent. An initial assessment specifically investigating patients’ satisfaction with their facial appearance and concerns about others’ perceptions was evaluated using a five-point Likert scale (1=strongly disagree, 2=disagree, 3=neither agree nor disagree, 4=agree, 5=strongly agree) and was completed before the first treatment and repeated after the four treatments. All patients participated on a voluntary basis and provided informed consent before the initiation of the study. Clinician questions focused on grading the rosacea signs and symptoms as well as the overall appearance of the skin.  Participants. The demographics of the study participants are outlined in Table 1. Nine patients completed the four treatment sessions to the follow-up phase. The mean age was 36±3 years and, of the nine patients, 78 percent were female and 22 percent male, diagnosed 31±13 months ago. PPR was the predominant rosacea subtype, with 80 percent of patients presenting, while 20 percent had ETR. Participants had

Regarding recently published article on Safety and Efficacy of Aminolevulinic Acid 10% Topical Gel versus Aminolevulinic Acid 20% Topical Solution Followed by Blue-light Photodynamic Therapy for Treatment of Actinic Keratosis

Dear Editor: In their article, “Safety and efficacy of aminolevulinic acid 10% topical gel versus aminolevulinic acid 20% topical solution followed by blue-light photodynamic therapy for the treatment of actinic keratosis on the face and scalp: A randomized, double-blind study,” Nestor et al assessed the response of actinic keratosis (AK) lesions in two 25-cm2 areas of skin in 40 subjects. Topical 5-aminolevulinic acid (ALA) 10% gel (GEL) was applied to one area, and ALA 20% solution (SOL) was applied to the other. After a one-hour incubation period, both areas were exposed to blue light (BLU-U) without prior curettage or occlusion. The authors acknowledged that their study conditions were a departure from labeling indications. Prescribing information for SOL indicates a 14- to 18-hour incubation period after lesional application prior to blue-light exposure, although shorter incubations after broad application have been shown to be effective and well tolerated.2 For GEL, the prescribing information calls for curettage and “roughening” of lesions, as well as occlusion of treated areas for three hours prior to red-light exposure.3 Nestor et al reported that, in an attempt to mimic treatment conditions more typically used in clinical practice, they did not include those steps in their protocol. The authors concluded that, under typical clinical conditions using blue light, the efficacies of GEL and SOL were equivalent and there were significantly more local skin reactions with SOL. To ensure appropriate integration of these results into decision-making related to patient care, more study details are needed. In particular, rigorous statistical analyses were lacking. Equivalent is a statistical term that implies a rigorous comparison between groups, but here the p<0.001 value cited as a significant test result referred only to each treated area (Day 84) in comparison with its corresponding baseline (Day 0) rather than to comparisons between treatment groups. Also, a primary investigator associated with the study stated in the summary that it is impossible to determine statistically significant differences between reduction rates in each arm (95% for GEL vs. 94% for SOL) with a sample size of only 40 patients.3 To actually compare the two treatment groups, the mean change (±standard error) would be required, and, if equivalence tests had low power due to the limited sample size, a significance test, such as analysis of variance, could be used to compare the treatments adjusted by baseline. However, tables and tests with summary statistics (i.e., mean, median, standard deviation) for baseline values and changes from baseline were not provided.  Other information would have been helpful to allow for a more meaningful evaluation. For example, how much of each product was applied? Prescribing information for GEL indicates application of a 1mm-thick layer not to exceed 2g (one tube); for SOL, two applications are indicated, with adequate drying time allowed for in between applications and without specific limitations on treatment area or volume. Under real-world conditions, not all patients return for a second treatment; therefore, knowing the percent of areas of each group that achieved 100-percent clearance after one treatment (Day 28) might be helpful. It was unclear whether the endpoint of “100-percent clearance” refers only to those lesions treated at baseline (mapped and tracked) or whether it refers to any new lesions in the treated field, regardless of prior history. Finally, it would have been interesting to learn about recurrence rates and rates of new lesion occurrence in the context of both formulations. Furthermore, the majority of local skin reaction (LSR) scores in Figure 4 were based on patient self-reporting (diary entries), which raises the question of how carefully patients were trained in the identification and grading of LSRs. “Irritation” was not evaluated, although that parameter was documented as affecting 72 percent of subjects on the ALA product labeling3 when administered with the approved red-light device. Finally, evolving concepts regarding mechanisms of PDT action demand that any conclusion about efficacy should be made with caution. AK clearance appears to be mediated by local immune or inflammatory processes, which might not be linearly related to photosensitizer dose. In other words, clearance data after a single PDT treatment might be governed by a threshold effect independent of the administered dose of the active agent. In support of this idea, Nestor et al reported clearance rates of 58 percent and 52 percent after single treatments of SOL and GEL, respectively. A previous report on single administration of a blue-light PDT after short incubation showed the following clearance values: 53 percent after two hours, broad application; 57 percent after two hours, spot application; and 57 percent after three hours, broad application.2 These values are remarkably similar to those in the study by Nestor et al. Current uncertainties about mechanism even raise the possibility that assessments of small treatment areas might limit our ability to generalize GEL versus SOL outcomes to large skin treatment areas more typical of real-world practice. With regard, Edward V. Maytin, MD, PhD; Jeanett Segal, MD; and Anna Houlihan, MA Dr. Maytin is with the Department of Dermatology and the Department of Biomedical Engineering at the Lerner Research Institute Cleveland Clinic in Cleveland, Ohio and the Wellman Center for Photomedicine at Massachusetts General Hospital, Harvard Medical School in Boston, Massachusetts.Dr. Segal and Ms. Houlihan are with Medical Affairs at Sun Pharmaceutical Industries, Inc. in Princeton, New Jersey, and Wilmington, Massachusetts, respectively. Disclosures. Dr. Maytin serves on the scientific advisory board of Sun Pharmaceutical Industries Ltd. Dr. Segal and Ms. Houlihan are employees of Sun Pharmaceutical Industries Ltd. with medial affairs responsibilities related to Levulan®-BluU photodynamic therapy. References Nestor MS, Berman B, Patel J, Lawson A. Safety and efficacy of aminolevulinic acid 10% topical gel versus aminolevulinic acid 20% topical solution followed by blue-light photodynamic therapy for the treatment of actinic keratosis on the face and scalp: a randomized, double-blind study. J Clin Aesthet Dermatol. 2019;12(3):32–38. Pariser DM, Houlihan A, Ferdon MB, et al. Randomized vehicle-controlled study of short drug incubation aminolevulinic acid photodynamic therapy for actinic keratoses of the face or scalp. Dermatol Surg. 2016;42(3):296–304.  Daily Med site. Ameluz—aminolevulinic acid hydrochloride

Safety and Efficacy of Aminolevulinic Acid 10% Topical Gel versus Aminolevulinic Acid 20% Topical Solution Followed by Blue-light Photodynamic Therapy for the Treatment of Actinic Keratosis on the Face and Scalp: A Randomized, Double-blind Study

 J Clin Aesthet Dermatol. 2019;12(3):32–38 by Mark S. Nestor, MD, PhD; Brian Berman, MD, PhD; Jigesh Patel, BS; and Alec Lawson Drs. Nestor and Berman and Messrs. Patel and Lawson are with the Center for Clinical and Cosmetic Research in Aventura, Florida. Drs. Nestor and Berman are also with the Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine in Miami, Florida. FUNDING: This study was an Investigator Initiated Study with funding provided by Biofrontera (Wakefield, Massachusetts), manufacturer of the aminolevulinic acid 10% topical gel evaluated in this study. DISCLOSURES: Drs. Nestor and Berman are consultants and investigators for Biofrontera and also participated in the US Biofrontera PDT Advisory Council. The other authors have no conflicts of interest relevant to the content of this article. ABSTRACT: Objective. Photodynamic therapy (PDT) using 10% 5-aminolevulinic acid (ALA) gel (GEL) has been shown to be highly effective for treating actinic keratosis (AK) but has only been studied using red-light activation. The goal of this study was to compare GEL and a 20% ALA solution (SOL) using blue-light activation under typical clinical conditions. Design. This double-blind, split-face study randomized subjects to GEL or SOL application to contiguous 25cm2 fields containing 4 to 8 AK lesions on either side of the face or scalp (no curettage, 1-hour incubation, no occlusion) followed by blue light exposure (1,000 seconds, 417nm, 10J/cm2). Participants. Forty adult subjects were treated on either the face (n=20) or scalp (n=20). Measurements. Primary outcomes included change in baseline AK lesions. Secondary outcomes included local skin reaction (LSR) scores and visual analog scale (VAS) pain scores. Results. Lesions treated with GEL were 97.1 percent cleared at Day 84 versus 94.9 percent for lesions treated with SOL (p<0.001 vs. baseline); additionally, 86.8 percent of areas treated with GEL and 78.9 percent of areas treated with SOL showed 100-percent clearance (p<0.001 vs. baseline). Mean VAS pain scores were minimal for the SOL and the GEL (25.4 vs. 28.5 and 16.1 vs. 19.3, respectively; p=nonsignificant). At three days after the first and second treatments, more significant LSRs were noted in areas treated with SOL, including erythema, crusting, and scaling/dryness. There were no significant adverse events observed. Conclusion. GEL was equivalent to SOL for clearing AK lesions on the face and scalp with blue-light PDT; however, SOL caused significantly more local skin reactions. KEYWORDS: actinic keratosis, photodynamic therapy, 5-aminolevulinic acid, blue light Actinic keratosis (AK) is a condition frequently encountered by dermatologists. AK presents as rough, scaly, erythematous lesions on sun-damaged areas of the face, scalp, trunk, and extremities. Chronic sun exposure causes abnormal growth of atypical epidermal keratinocytes and subsequent AK development. AK is a precancerous lesion that can progress to squamous cell skin cancer (SCC).1,2 In one study, more than 40 percent of patients with a prior diagnosis of multiple AKs developed a nonmelanoma skin cancer or melanoma during 5 to 11 years of follow-up.3  Photodynamic therapy (PDT) is a highly effective means for treating precancerous skin lesions.4 It is currently considered the method of choice for treating AK5 and is being used with increasing frequency for this purpose.6  Many AK lesions are clinically detectible; however, a larger area of skin is frequently affected by subclinical lesions in the deeper layers of the epidermis.7 Consequently, PDT can be especially helpful where there are multiple or confluent lesions.8,9 PDT has also demonstrated effectiveness in treating field cancerization associated with AK lesions, which is important for preventing the occurrence of additional AK lesions and subsequent development of SCC.10,11 The most commonly used photosensitizer in the United States (US) is 5-aminolevulinic acid (ALA). When topically applied, ALA is preferentially absorbed by dysplastic AK lesions, where it is metabolized intracellularly to protoporphyrin IX, a highly potent photosensitizer.12 When exposed to the appropriate wavelength of light in the presence of oxygen, the activation of protoporphyrin IX results in the production of reactive oxygen species and cell death. Surrounding normal tissues are minimally affected.6 A new photosensitizer (10% ALA gel; GEL) is the only PDT product that is approved by the US Food and Drug Administration for both lesion- and field-directed PDT.13 The GEL was developed for use with red illumination,13 while a 20% ALA solution (SOL) was developed for use with blue illumination,14 which is the predominant light source used in the US for PDT. Consequently, a frequent question posed by dermatologists is whether GEL can be used together with a blue illuminator for the treatment of AK. The objective of this randomized, double-blind, parallel-group study was to compare the efficacy and tolerability of GEL to SOL for treating adult subjects with AK lesions on the face and scalp following blue-light illumination under typical clinical conditions. Methods Subjects. Eligible subjects (N=40) included men and women who were at least 18 years of age with 4 to 8 discrete AK lesions within a contiguous 25cm2 field on each side of the face (n=20) or scalp (n=20). Female subjects were postmenopausal, surgically sterile, or using an effective method of birth control. Women of childbearing potential were required to have a negative urine pregnancy test result at the respective screening and baseline visits. Enrolled subjects expressed their willingness to comply with all study requirements. Subjects were excluded from participation if they presented with an incompletely healed wound, hypertrophic or hyperkeratotic lesions, cutaneous horns, or lesions that had not, to date, responded to repeated cryosurgery within the planned treatment area. Those with a history of recent use of medications or treatments that could interfere with evaluating the treatment area, including but not limited to topical medications, oral retinoids, immunomodulating agents, cytotoxic drugs, ultraviolet B phototherapy, or other therapies for AK, were also excluded.  Treatment. The screening visit occurred at 1 to 14 days prior to the baseline visit. During the screening visit, demographic information and a medical history including concomitant medications were obtained, a physical examination including vital signs and urine pregnancy tests was performed, and the treatment area was identified. During the baseline visit (Day 0), vital signs and the urine pregnancy test were repeated

Efficacy and Safety Evaluation of High-density Intense Pulsed Light in the Treatment of Grades II and IV Acne Vulgaris as Monotherapy in Dark-skinned Women of Child Bearing Age

by Ajay J. Deshpande, MBBS, DVD, DNB Dr. Deshpande is with the Maharashtra Medical Foundation Joshi Hospital in Pune, India. Funding: No funding was provided for this article. Disclosures: The author has no conflicts of interest relevant to the content of this article. Abstract: Background: Acne vulgaris is a self-limiting, chronic inflammatory disorder of the pilosebaceous unit characterized by exacerbations and remissions. It is often the early manifestation of puberty, and in girls it appears relatively early. In women, acne tends to become aggravated during the menstrual period, pregnancy, and in those who are on progesterone. Acne treatment is divided into two parts: topical and systemic. For Grades 1 and 2 acne, topical treatment is sufficient, while for Grades 3 and 4 acne, systemic drugs such as tetracyclines and retinoids are required to control the symptoms. Chemical peeling with glycolic and salicylic acids, cryosurgery with liquid nitrogen or carbon dioxide, and narrowband ultraviolet light are a few of the supportive procedural treatments available for Grades 3 and 4 acne. Objective: The author sought to determine the efficacy and safety of intense pulsed light (IPL) therapy (Magma-F-SR; FormaTK Systems, Tirat Carmel, Israel) in the treatment of Grades 3 and 4 acne as monotherapy in women of child-bearing age. Materials and Methods: One-hundred female patients with Grades 3 and 4 acne were enrolled in this study. All patients were treated with IPL using a 530nm to 1,200nm filter once a week for a total duration of six weeks. Patient and physician scores were assessed at Weeks 1 and 6 after the last treatment. Clinical photographs were also reviewed to determine the degree of efficacy. Adverse effects were noted. Results: Eighty percent of the patients involved in this study reported a significant reduction in lesion count compared to baseline. The adverse events were minimal-to-mild erythema. Conclusion: IPL therapy with 530nm to 1,200nm filter is an effective and safe modality of treatment as monotherapy in managing inflammatory Grades 3 and 4 of acne vulgaris in women of child-bearing age. Keywords: Acne vulgaris, intense pulsed light therapy, monotherapy J Clin Aesthet Dermatol. 2018;11(4):43–48 Acne vulgaris is a common self-limiting disorder of the pilosebaceous unit that is seen primarily in adolescents.1 Acne is often an early manifestation of puberty. In girls, the occurrence of acne might precede their first menstrual cycle by more than one year. The greatest number of cases are seen during the mid-to-late teenage years of life.2 The key elements in the pathogenesis of acne are follicular epidermal hyperproliferation, excess sebum production, inflammation, and the presence of Propionibacterium acnes (P. acnes).3 The disease is characterized by a variety of clinical lesions, although one type of lesion might be predominant. The course of acne can be self-limiting, while the sequelae can be lifelong with pitted or hypertrophic scar formation.3 Comedones and papules form the noninflammatory component, while pustules, nodules, and cysts are the features of the inflammatory variety. Pitted or hypertrophic scarring is more common in patients with inflammatory acne lesions.3 Acne affects primarily the face, neck, upper trunk, and upper arms. Acne can have a significant impact on the quality of life and psychosocial well-being of the patient.4,5 Therefore, early and aggressive intervention is necessary, especially in the inflammatory variety of acne vulgaris.6 Systemic antibiotics7,8 and retinoids9 are the mainstay of anti-acne management, followed by topical antibiotics,10 benzoyl peroxide,11 and topical retinoids.12 However, in women of child-bearing age, there are limitations in the systemic management of Grades 3 and 4 acne. Antibiotic resistance and adverse effects of topical anti-acne medications are on the rise, so light-based devices and technologies are proving to be effective in the treatment of acne.13,14,15–17 Mohanan et al18 has employed the use of intense pulsed light (IPL) in Indian skin for acne vulgaris with favorable results.Patidar et al19 studied the efficacy of IPL in the treatment of facial acne vulgaris and compared two different fluences. In this study, we assessed the efficacy and safety of IPL therapy (Magma-F-SR; FormaTK Systems, Tirat Carmel, Israel) as a monotherapy in the treatment of Grades 3 and 4 acne in women of child bearing age. Materials and Methods One hundred female patients aged 21 to 30 years with Fitzpatrick Skin Types IV to VI were enrolled in this study. Patients who had not received any anti-acne treatment for at least one month prior to enrollment were included. Patients with a history of herpes simplex or those with associated hormonal disorders (e.g., thyroid disorder, polycystic ovary syndrome) were excluded from this study. Patients who were undergoing treatment for infertility were only included after proper consultation with their treating gynecologist. A detailed lesion count was done prior to treatment and at Weeks 3, 6, 9, and 12 of the study.  The study adhered to the Declaration of Helsinki on the ethical conduct of medical research. Written consent for participation and use of photos and photographic documentation was completed during each visit. on risk/benefit analysis. Protective eye glasses were worn during the entire period of the procedure by both the patient and the treating physician. Transparent gel was applied over the entire face. The IPL therapy was performed using a cutoff filter of 530nm to 1,200nm wavelengths in continuous mode with 7.0J/cm² fluence with three milliseconds of pulse width. Six passes were performed over the entire face followed by six passes of two subpulses (double mode) of 14.2J/cm² (7.1J/cm²+7.1J/cm²) fluence over the lesion only. Mild erythema was noted immediately after the treatment. Cooling was achieved with the application of ice packs for 15 minutes immediately after the treatment and followed by the application of topical mometasone furoate 0.01% cream and broad-spectrum sunscreen. The erythema and stinging subsided within 30 minutes. The procedure was repeated each week for a total of six weeks. Assessment. The efficacy of the IPL therapy was assessed on the scale shown in Table 1, depending upon the lesion count. Patient and physician scores were assessed at Week 1 and Week 6 after the last treatment. A blinded evaluator assessed the efficacy

Phototherapy with Light Emitting Diodes: Treating a Broad Range of Medical and Aesthetic Conditions in Dermatology

by Glynis Ablon, MD, FAAD Dr. Ablon is with the Ablon Skin Institute and Research Center in Manhattan Beach, California.  Funding: No funding was provided for this article. Disclosures: The author has no conflicts of interest to relevant to the content of this article. Abstract: Within the field of dermatology, advances in the use of light emitting diodes (LEDs) have led to their clinical application for a variety of medical and cosmetic uses. Of note, one phototherapy device has demonstrated beneficial effects over a range of clinical applications (Omnilux™; GlobalMed Technologies, Glen Ellen, California). The study included a literature review of published studies. Using LEDs with frequencies of 415nm (blue), 633nm (red), and 830nm (infrared), this device has demonstrated significant results for the treatment of medical conditions, including mild-to-moderate acne vulgaris, wound healing, psoriasis, squamous cell carcinoma in situ (Bowen’s disease), basal cell carcinoma, actinic keratosis, and cosmetic applications. Although photodynamic therapy with the photosensitizer 5-aminolevulinic acid might cause stinging and burning, phototherapy is free of adverse events. We determined that phototherapy using LEDs is beneficial for a range of medical and aesthetic conditions encountered in the dermatology practice. This treatment displays an excellent safety profile. Keywords: Light-emitting diodes, phototherapy, photodynamic therapy, skin rejuvenation, acne vulgaris, periorbital wrinkles J Clin Aesthet Dermatol. 2018;11(2):21–27 Introduction An increasing number of individuals are seeking noninvasive procedures for improving medical and aesthetic dermatologic conditions. Phototherapy refers to the use of nonthermal, noninvasive light to achieve a therapeutic outcome and can apply to a variety of light-emitting devices. Interest in recent advances in the use of  light emitting diodes (LEDs) has led to their clinical application for a variety of medical and cosmetic uses.  Depending on the target chromophore, different wavelengths of light are used.1 Three wavelengths of light that have demonstrated several therapeutic applications are blue (415nm), red (633nm), and near-infrared (830nm). Recent publications have reignited an interest in the numerous studies performed or sponsored by a leader in the field of LED phototherapy (Omnilux™; GlobalMed Technologies, Glen Ellen, California) which clearly demonstrate the significant value of phototherapy for a range of clinical applications (Figure 1). In my private practice, LED technology is the most commonly performed procedure and is used each office day to treat a wide variety of medical and aesthetic disorders. This review will describe the broad range of clinical applications and significant results achieved for acne, wound healing, actinic keratosis, precancerous tissue, psoriasis and skin rejuvenation, and post-procedural erythema. Signed photoconsent was provided by the patients pictured herein. Medical Applications Mild-to-moderate acne vulgaris. Propionibacterium acnes (P. acnes) is a gram-positive bacterium involved in the pathogenesis of acne vulgaris.2 In-vitro studies have demonstrated that blue light is effective for treating P. acnes because it produces the strongest photoactivation of endogenous porphyrins through a process known as endogenous photodynamic therapy (PDT). The result is free radical formation and destruction of the P. acnes cell membrane.3 An open-label clinical study assessed the safety and efficacy of narrowband blue light on inflammatory and noninflammatory acne lesions in patients with mild-to-moderate facial acne (N=30).4 Subjects had not used topical, oral, or systemic treatments for two weeks and had not received oral retinoids for six months. Baseline lesions were counted and recorded by lesion type. Subjects received eight 10- or 20-minute light treatments using LEDs with peak wavelengths of 409nm to 419nm (40mW/cm2) over a four-week period. Lesion counts were repeated at Weeks 5, 8, and 12. A beneficial effect on inflammatory lesions was observed at Week 5, becoming significant at Weeks 8 and 12. The mean percent reduction in lesion counts at each time point was 25 percent, 53 percent (p<0.001), and 60 percent (p<0.001), respectively; however, there was little effect on noninflammatory lesions. Adverse events included mild and transient erythema, skin dryness, and pruritis. A second open-label study assessed the effects of phototherapy using LEDs emitting blue 415nm light at 48J/cm2 to treat subjects with mild-to-moderate acne (N=45).5 Subjects received two 20-minute treatments weekly for 4 to 8 weeks, and clinical assessments were made at baseline and two, four, and eight weeks post-treatment. Therapeutic response was measured using a global improvement scoring system: 0 (no improvement), 1 (0–25% improvement), 2 (25–50% improvement), 3 (51–75% improvement), and 4 (76–100% improvement). Among the evaluable subjects (n=43), the mean improvement score was 3.14 at four weeks and 2.90 at eight weeks. Nine patients experienced complete clearing at eight weeks, and 50 percent of subjects were highly satisfied with the treatment. There were no adverse events. Since it had been demonstrated that phototherapy with combined blue and red light could achieve even greater efficacy in the treatment of acne,6 an open-label study was designed to assess the efficacy of combining 415nm blue light and 633nm red light for treating subjects with mild-to-moderate facial acne.7 Enrolled subjects (N=24) with Fitzpatrick Skin Types II to V had not received treatment with oral or topical acne agents during the six weeks preceding the trial or oral retinoid use in the previous nine months. Subjects with a history of photosensitivity disorder were excluded. Each subject received two treatments per week, three days apart, alternating between 415nm blue light (20 minutes/session, 48J/cm2) and 633nm red light (20 minutes/session, 96J/cm2) for four weeks using an LED-based therapy system. Patients received a mild microdermabrasion prior to each treatment session. The purpose of microdermabrasion is to provide a nonchemical superficial removal of the stratum corneum. This allows products or other procedures to pass more readily through the protective barrier of the epidermis. While recent studies have reported some histologic changes in the dermis on collagen density with microdermabrasion, published data demonstrate improvement of acne when microdermabrasion is used in combination therapy.8 Acne severity was assessed at baseline and at Weeks 2, 4, 8, and 12. Among the evaluable subjects (n=22), a mean reduction in lesion count was observed at each follow-up evaluation. At the four-week follow-up, the mean lesion count was reduced by 46 percent (p=0.001) and by 81 percent at the 12-week follow-up (p=0.001).

Safety and Cosmetic Effects of Photodynamic Therapy using Hexyl Aminolevulinate and Intense Pulsed Light A Pilot Study Conducted in Subjects with Mild-to-moderate Facial Photodamage

Michael H. Gold, MD; Julie A. Biron, BSc Tennessee Clinical Research Center, Nashville, Tennessee

Pathological and Immunohistochemical Assessment of Aging of the Abdominal Skin Treated with Carboxytherapy: A Randomized, Split-body Trial

J Clin Aesthet Dermatol. 2024;17(8):62–69. by Nooshin Bagherani MD, MA, PhD Candidate; Alireza Ghanadan, MD; Golshan Mirmomeni, MA; Alireza Firooz, MD; Bruce R. Smoller, MD; Reza Shojaei, MD; Haniyeh Rafipour, MD; Negin Bagherani, bS; Mansoreh Abdolhosseini, PhD Candidate; and Gholamreza Tavoosidana, PhD Dr. Bagherani is with the Department of Molecular Medicine, School of Advanced Technologies in Medicine at the Tehran University of Medical Sciences in Tehran, Iran. Dr. Ghanadan is with the Department of Dermatopathology, Razi Hospital and Department of Pathology, Cancer Institute at the Imam Khoemini Hospital Complex in Tehran, Iran. Mrs. Mirmomeni is with the Hearing Research Center at the Ahvaz Jundishapur University of Medical Sciences in Ahvaz, Iran. Dr. Firooz is with the Center for Research & Training in Skin Diseases & Leprosy, Clinical Trial Center at the Tehran University of Medical Sciences in Tehran, Iran. Dr. Smoller is with the Department of Pathology at the University of Rochester School of Medicine and Dentistry in Rochester, NY. Dr. Shojaei is with the Department of Surgery at the Arak University of Medical sciences in Arak, Markazi Province, Iran. Dr. Rafipour is with the Medical School at the Tehran University of Medical Sciences in Tehran, Iran. Dr. Bagherani is with the Department of Cellular Biology, Payam-e-Noor University of Arak in Arak, Iran. Drs Abdolhosseini and Tavoosidana are with the Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences in Tehran, Iran. FUNDING: This article was funded by the Tehran University of Medical Sciences and Health Services. DISCLOSURES: This study was supported by Tehran University of Medical Sciences in partial fulfillment of the requirement of PhD of molecular medicine. Nik Fannavaran Plasma Co., supported through renting the carboxytherapy machine and accepting machine service-related fees. ABSTRACT: Background. Skin aging as a continuous and irreversible process is mainly the result of alterations of function and structure of the dermis. Among the modalities used for treating skin aging, carboxytherapy has been introduced as a safe minimally-invasive method for rejuvenation, reparation, and reconditioning of the skin. Objective. We assessed the efficacy of carboxytherapy for the treatment of intrinsic skin aging through pathological and immunohistochemical (IHC) investigations. Methods. Our study was a split-body, randomized clinical trial on 15 female patients with intrinsic skin aging of the abdomen. Carboxytherapy was performed on one side of the abdomen, weekly for 10 sessions, while the other side was left untreated. Two weeks after the last session, skin biopsies were taken from both sides of the abdomen. Staining with hematoxylin-eosin, Masson-trichrome, and Orcein Giemsa was performed for the assessment of epidermal and dermal thickness, collagen, and elastin organization, respectively. IHC examination was performed for investigation of TGF-β1 and VEGF. Results. Pathological examination showed a significant increase in epidermal and dermal thickness and re-organization of collagens and elastic fibers with carboxytherapy. IHC examinations revealed a significantly increased expression of TGF-β1 and VEGF with carboxytherapy. Conclusion. Our study demonstrated the effectiveness of carboxytherapy in treating and reversing intrinsic aging skin through pathological and IHC studies. Keywords. carboxytherapy, skin aging, pathology, immunohistochemistry Introduction Aging as a continuous and irreversible process affecting the skin is clinically characterized by skin laxity, wrinkling, fragility, xerosis, and pruritus, increased sensitivity to temperature, impaired wound healing, and increased risk of malignancies.3 This process, which mainly is the result of alterations of function and structure of the dermis, is characterized by thinning, decreased hydration, and loss of elasticity.4 On pathological examination, the epidermis progressively becomes thinner and rete ridges become less pronounced with aging. Aging-related uneven distribution of the pigment is due to disruption of the effective transfer of melanin pigment from the melanocytes to the keratinocytes with prolonged ultraviolet (UV) exposure.5 The normal dermis, which is mainly comprised of the type I collagen in the reticular dermis and the type III collagen in the papillary dermis, is influenced by aging largely center around UV-induced damage. The type VII collagen is also reduced with aging leading to the clinical appearance of wrinkling.6 The elastic tissue fibers, as another component of the dermal connective tissue, are composed of two components including oxytalin and elaunin. In the intrinsic skin aging process, a progressive loss of these fibers is seen ultimately leading to their near absence in the skin of the elderly.7 With aging, due to diminished extravascular support and long-standing intraluminal pressure, progressive vascular ectasia, thinning and fragility of the vessel walls and hemorrhage are observed.8 The skin aging as a complex process results from intrinsic factors with genetic basis and extrinsic factors due to detrimental environmental factors, mainly UV radiation.4 The intrinsic skin aging is an inevitable physiological process which results in fine wrinkles, xerosis, and dermal atrophy, whereas the extrinsic one leads to coarse wrinkles, rough appearance, laxity, and impaired skin elasticity.9  Compared to young skin, skin of the elderly is more prone to a variety of dermatoses; 13.3 percent of skin conditions have been reported in persons over 60 years of age. Additionally, noticeable association between systemic disorders and skin problems in general population necessitates special notice to skin aging.3  The main aim of the management of aging is improvement of the life quality and prevention of age-related conditions in the elderly. Regarding skin aging, its management is particularly important because the skin shows the most clinically noticeable features of the aging mechanism and the status of one’s health.10 Many different medical and procedural approaches have been introduced for the management of skin aging. Among these modalities, carboxytherapy has been introduced as a safe minimally invasive method for rejuvenation, reparation, and reconditioning of the skin.11 It acts through vasodilatation11–14, increased permeability of the capillary walls13, stimulation of dermal fibroblasts leading to production of higher quantities and higher quality collagen and elastin15, increased collagen remodeling14, increased flexibility and decreased firmness of collagen fibers13, improved tissue drainage12, release of  local growth factors in relation to angiogenesis12,15, lipolysis, and skin regeneration15, improved trophicity of the treated body site, and  reduction of adipose tissue.12 Regarding efficacy of carboxytherapy in the treatment of skin aging, the studies

Use of the 40-gene Expression Profile (40-GEP) Test in Medicare-eligible Patients Diagnosed with Cutaneous Squamous Cell Carcinoma (cSCC) to Guide Adjuvant Radiation Therapy (ART) Decisions Leads to a Significant Reduction in Healthcare Costs

J Clin Aesthet Dermatol. 2024;17(1):41–44. by Ally-Khan Somani, MD, PhD; Sherrif F. Ibrahim, PhD, MD; Michael Tassavor, MD; Jane Yoo MD; and Aaron S. Farberg, MD   Dr. Somani is with the Department of Dermatology at Indiana’s University School of Medicine in Indianapolis, Indiana. Dr. Ibrahim is with Rochester Dermatologic Surgery in Victor, New York. Dr. Tassavor is with Medical Dermatology and Cosmetic Surgery Centers in New York, New York. Dr. Yoo is with the Icahn School of Medicine at Mount Sinai in New York, New York. Dr. Farberg is with Baylor Scott and White Health System in Dallas, Texas. FUNDING: Funding was provided by Castle Biosciences, Inc. DISCLOSURES: Dr. Farberg is an advisor for Castle Biosciences, Inc. All other authors report no conflicts of interest relevant to the article. ABSTRACT: Objective. Adjuvant radiation therapy (ART) is often recommended for high-risk cSCC patients but carries significant costs and risks. This study aims to determine if utilizing the 40-GEP test to guide ART can reduce healthcare costs in cSCC management. Methods. Medical claims data with new diagnoses of cSCC for the 12 months ending June  2022 in the Medicare (≥65 years) population (source: IQVIA claims database) were obtained and normalized to the general population for missingness. CPT codes associated with radiation  therapy within one-year post diagnosis were used to establish adjuvant RT use (defined as ‘ART’). Average weighted direct costs for four major ART modalities were calculated from published studies and (IQVIA). Sensitivity analysis was used to assess the financial impact of ART treatment using varying distributions of 40-GEP Class results.  Results. Normalized medical claims data identified 22,917 Medicare-eligible cSCC patients who received ART within the United States. The weighted average direct cost for ART, which includes the four most used CPT code-defined modalities (IGRT, IMRT, IMPT, and XRT), was $60,693 per patient, amounting to an annual projected ART cost of $1.4 billion. Using the distribution of 40-GEP results from published studies, utilization of a 40-GEP test result to avoid ART in these patients could save up to $972 million in Medicare-eligible population. Sensitivity analysis shows, depending upon the distribution of the 40-GEP results, that for every 10% of Class 2A test results omitting ART, an extra $38-66 million in annual savings is expected  Limitations. Potential limitations include a need for more comprehensive patient information and the cost of ART-related complications. Conclusion. Utilizing the 40-GEP test results to guide ART decision-making would result in material savings to Medicare. Keywords: 40-Gene Expression Profile (40-GEP), Cutaneous Squamous Cell Carcinoma (cSCC), Adjuvant radiation therapy (ART), Cost, Medicare Studies have shown that ART is effective in reducing metastasis as well as local recurrence.1–3 As such, NCCN guidelines for cSCC recommend consideration of adjuvant radiation therapy (ART) in patients with localized high or very high risk cSCC with poor prognostic features.4 However, patients categorized as high or very high risk represent a broad range of actual metastatic risk leading to over-treatment as well as under-treatment; the majority of patients who may be considered for ART are metastasis-free without any additional intervention.5 ART is reported to benefit subsets of high risk cSCC patients; however, this subset has not been well-defined by clinical and pathological features alone, resulting in broad recommendations for its usage by national societies and guidelines.3,4  ART is also associated with clinically significant complications, ranging from short-term adverse events of radiation dermatitis, hair loss, nausea, and vomiting, as well as more long term adverse events such as lymphedema and dementia.6 Furthermore, guidelines discourage subsequent radiation therapy in the prior radiation field due to the increased risk of radiation induced secondary cancers and long-term sequelae.4 Thus, there is an unmet clinical challenge to identify those who truly benefit from ART and to optimize the balance of complications, treatment outcomes, and healthcare costs for cSCC patients.  The 40-GEP test is validated to improve upon current clinicopathologic-based risk prediction staging systems, providing more precise risk stratification for metastasis (regional/nodal and distant) in patients with high-risk cSCC.7,8 The 40-GEP test categorizes patients into three distinct risk levels for metastatic potential: low risk (Class 1), moderate risk (Class 2A), or high risk (Class 2B). 40-GEP classification is objective and independent of the clinicopathologic staging systems, including NCCN, BWH, and AJCC, as well as individual clinicopathologic risk factors.7 Retrospective and prospective clinical utility studies have shown that the 40-GEP test can direct personalized patient management decisions such as follow-up care, surveillance imaging, and ART use.9–12 The 40-GEP test significantly stratified the risk of nodal or distant metastasis in an ART-eligible population, particularly between Class 1, Class 2A and Class 2B, indicating that ART could potentially be safely avoided for Class 1 patients, and should be strongly considered for Class 2B patients based on metastatic risk.13 Furthermore, a recent multi-center study showed that patients with a Class 2B result had improved outcomes if treated with ART, while a similar benefit was not observed for Class 1 or Class 2A cases. Most importantly, in the same study, other than the 40-GEP Class 2B result, no other risk factors or staging identified a subset of patients substantially benefiting from ART.14 In light of recent evidence, this study aims to determine if utilizing the 40-GEP results to guide ART can reduce costs for cSCC management among a Medicare-eligible patient population.  Methods cSCC patients in the 12-month period ending May 2022 were identified in the IQVIA database using established ICD-10 codes. Claims data included radiation therapy CPT codes within one year post-diagnosis that were used to establish adjuvant RT (defined as “ART”). Within the same cohort, four primary CPT code-defined radiation therapy modalities, namely image-guided radiation therapy (IGRT), intensity-modulated radiation therapy (IMRT), intensity modulated proton therapy (IMPT), and radiation therapy (XRT) were identified. Cost for each of these modalities were calculated from published literature, and the weighted average cost for these modalities was calculated based on the IQVIA claims database. Data were filtered for Medicare-eligible patients (>65 years old) and normalized to national cSCC incidence (1.8 million diagnoses per year).15–17 The absence of standardized patient selection criteria for ART

Treatment Satisfaction and Acceptability of 20% Aminolevulinic Acid Photodynamic Therapy for the Treatment of Actinic Keratoses of the Face, Scalp, and Upper Extremities

J Clin Aesthet Dermatol. 2023;16(12):46–51. by Daniel Piacquadio, MD; Brian Berman, MD, PhD; Daniel M. Siegel, MD; Neal Bhatia, MD; Jason Brocato, PhD; Nicholas Squittieri, MD; and David M. Pariser, MD Drs. Piacquadio and Bhatia are with Therapeutics, Inc., in San Diego, California. Dr. Berman is with Center for Clinical and Cosmetic Research in Aventura, Florida, and University of Miami Miller School of Medicine in Miami, Florida. Dr. Siegel is with The State University of New York Downstate Health Sciences University in Brooklyn, New York, and Brooklyn Campus of the VA NY Harbor Healthcare System in Brooklyn, New York. Drs. Brocato and Squittieri are with Sun Pharmaceutical Industries, Inc. in Princeton, New Jersey. Dr. Pariser is with Eastern Virginia Medical School in Norfolk, Virginia, and Virginia Clinical Research, Inc. in Norfolk, Virginia. FUNDING: The studies were supported by DUSA Pharmaceuticals, Inc. Medical writing support was funded by Sun Pharmaceutical Industries, Inc. DISCLOSURES: DP is an employee of Therapeutics, Inc. BB has received grants and consulting fees from Almirall; Biofrontera; Bristol Myers Squibb; DUSA Pharmacuticals, Inc.; Evoimmune; Mediwound; MINO Labs; Pfizer; and Sun Pharmaceutical Industries, Inc. DS has received honoraria and/or consultant fees and/or investigator grants/research funding from Avita; Biofrontera AG; Cara Therapeutics; DermaSensor, Inc.; Medforce Technologies, Inc.; MedX Health; Pulse Biosciences; Regeneron; Sanofi Genzyme; SciBASE; Sol-Gel Technologies; Strata Skin Sciences; UCB; and Verrica Pharmaceuticals, Inc.; and may own stock and/or stock options in Biofrontera AG; Greenway Therapeutix, Inc.; Logical Images; Modernizing Medicine; Novascan; Or-Genix Therapeutics; Palmm; Plasmend; RaMedical; Seaspire Skincare; SkinVision; and Tetros Group. NB is an advisor, consultant, and investigator for AbbVie; Almirall; Arcutis; Beiersdorf; Biofrontera; Bristol Myers Squibb; Boehringer Ingelheim; Cara; Dermavant; Eli Lilly; EPI Health; Ferndale; Galderma; InCyte; ISDIN; Johnson & Johnson; LaRoche-Posay; LEO Pharma; Ortho Dermatologics; Pfizer; Regeneron; Sanofi; Sun Pharmaceutical Industries, Inc.; and Verrica Pharmaceuticals, Inc. JB and NS are employees of Sun Pharmaceutical Industries, Inc. DMP has received honoraria and grants or research funding as a consultant, advisory board participant, or investigator from Bickel Biotechnology, Dermira, LEO Pharma US, Novartis, Pfizer, and Regeneron; honoraria as a consultant or data monitoring board participant from Biofrontera AG, Bristol Myers Squibb, and Sanofi; and grants or research funding as an investigator from Almirall; Amgen; AOBiome, LLC; Asana Biosciences, LLC; Celgene; Eli Lilly; Menlo Therapeutics; Novo Nordisk A/S; and Ortho Dermatologics.  ABSTRACT: Background. Actinic keratoses (AKs) are precancerous, dysplastic, epidermal lesions caused by chronic sun exposure that may progress to squamous cell carcinoma. Aminolevulinic acid 20% solution with blue light photodynamic therapy (ALA-PDT) has previously been shown to be superior to vehicle plus PDT (VEH-PDT) for treatment of AKs of the face, scalp, and upper extremities. Objective. We report detailed patient satisfaction data for ALA-PDT. Methods. Patient satisfaction for ALA-PDT versus VEH-PDT and patient-reported acceptability of ALA-PDT versus previous treatments for AKs were assessed in three randomized, vehicle-controlled studies (two Phase II and one Phase III) in adults. Patients in the Phase II studies were treated on the scalp and/or face, and those in the Phase III study were treated on the upper extremities. Results. A total of 234, 166, and 269 patients were enrolled in the two Phase II studies and one Phase III study, respectively; overall, 79.8 percent of patients were male. Overall treatment satisfaction ranged from 79 to 88 percent for ALA-PDT, compared to 35 to 56 percent for VEH-PDT. Patients generally considered ALA-PDT to be equivalent to or more acceptable than prior treatments, including cryotherapy, 5-fluorouracil, imiquimod, previous PDT, and surgery. Similar proportions of patients receiving ALA-PDT or VEH-PDT on the upper extremities considered in-office time, side effects/adverse events (AEs), and duration of side effects/AEs to be acceptable. Limitations. The majority of patients were male, and no statistical comparisons were conducted. Conclusion. Patients were generally satisfied with ALA-PDT for the treatment of AKs of the face, scalp, and upper extremities and considered ALA-PDT to be equal to or more acceptable than previous treatments. Trial registry information. ClinicalTrials.gov: NCT01475955; NCT02239679; NCT02137785. Keywords: Photodynamic therapy, treatment satisfaction, actinic keratoses, aminolevulinic acid, acceptability Actinic keratoses (AKs) are precancerous, dysplastic, epidermal lesions that can occur in individuals with chronic sun exposure, especially those with fair skin. Generally, AKs are found on sun-exposed areas (e.g., face, scalp, forearms, and backs of hands) and are recognized as scaly, rough lesions that can disappear and reappear over a period of months or years.1 In one study, the risk of progression of AKs to primary squamous cell carcinoma was 0.6 percent at one year and 2.6 percent at four years.2 Additionally, 65 percent of all primary squamous cell carcinomas identified in the study arose in lesions that were originally diagnosed as AKs.2 Aminolevulinic acid 20% solution (ALA) with blue light photodynamic therapy (PDT) is indicated for the treatment of minimally to moderately thick AKs of the face, scalp, and upper extremities.3 In multiple randomized, vehicle (VEH)-controlled Phase II and III studies, ALA-PDT was superior to VEH-PDT in the treatment of AKs.1,4,5 A Phase II study evaluating the effect of short incubation times and spot versus broad-area application of ALA-PDT in the treatment of AKs of the face or scalp (hereafter referred to as the short incubation study) found that short incubation ALA-PDT regimens were superior to VEH-PDT.1 Another Phase II study (hereafter referred to as the field cancerization study) reported that cryotherapy followed by ALA-PDT of the entire face was superior to cryotherapy with VEH-PDT for the proportion of patients with no facial AKs at study completion among patients at risk for field cancerization.4 In a Phase III study (hereafter referred to as the upper extremities study), ALA-PDT using a three-hour incubation with occlusion was superior to VEH-PDT for clearance of AKs of the upper extremities.5 The previous ALA-PDT studies also included top-level patient satisfaction and acceptability data.1,5 In the upper extremities study, 88 percent of patients treated with ALA-PDT reported being very or moderately satisfied with treatment response at their final study visit, compared with 42 percent of patients treated with VEH-PDT.5 Similarly, 79 percent of patients who received ALA-PDT in the short incubation study reported moderate

Phototherapy and DNA Damage: A Systematic Review

J Clin Aesthet Dermatol. 2023;16(6):55–58. by Aislyn Oulee, MD; Grace S. Ahn, MD; Sogol S. Javadi, BS; and Jashin J. Wu, MD Dr. Oulee is with the University of California Riverside School of Medicine in Riverside, California. Dr. Ahn is with the University of California San Diego School of Medicine in La Jolla, California. Ms. Javadi is with the David Geffen School of Medicine at the University of California in Los Angeles, California. Dr. Wu is with the Department of Dermatology at the University of Miami Miller School of Medicine in Miami, Florida. FUNDING: No funding was provided for this article. DISCLOSURES: The authors report no conflicts of interest relevant to the content of this article. ABSTRACT: Phototherapy has gained popularity in the recent decades for the treatment of various immune-mediated dermatological conditions since it is more-cost effective and less toxic compared to systemic therapies. This systematic review aims to inform dermatology providers of the risks and benefits of phototherapy, especially in patients at risk for malignancies. Ionizing energy from phototherapy results in DNA photolesions, namely of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). Without adequate repair, these mutations increase the risk for carcinogenesis. Additionally, phototherapy can also indirectly cause DNA damage through the formation of reactive oxygen species (ROS), which damage of several structural and functional proteins and DNA. When choosing a phototherapy modality, it also important to take into consideration the side effect profiles associated with each modality. For instance, a 10-fold higher dose of NB-UVB is required to produce a similar amount of CPDs compared with BB-UVB. Patients who undergo UVA with psoralen (PUVA) can be susceptible to developing skin malignancies up to 25 years after receiving their last treatment. It would behoove providers to consider optimal radiation dosage given each patients’ level of skin pigmentation and potential for photoadaptation. Additionally, there are measures have been proposed to minimize deleterious skin changes, such as a 42-degree Celsius heat treatment using a 308nm excimer laser prior to UVB phototherapy and low frequency, low intensity electromagnetic fields along with UVB. However, as performing routine skin exams, remain paramount in the prevention of phototherapy-induced neoplasia. Keywords. DNA damage, UV radiation, phototherapy, carcinogenesis, PUVA, NB-UVB, BB-UVB Phototherapy is a type of treatment that primarily utilizes ultraviolet radiation (UVR) that has been used for over a century to treat various dermatological diseases.1 Current phototherapy modalities include broadband UVB (290-320 nm), narrowband UVB (311-313 nm), 308 nm excimer laser, UVA-1 (340-400 nm), and UVA with psoralen (PUVA).2 Phototherapy has become increasingly popular, with a 5 percent annual increase in the overall volume of phototherapy services billed to Medicare from 2000 to 2015.3 Some of the most common dermatological conditions that have been effectively treated by phototherapy include immune-mediated skin diseases such as psoriasis, atopic dermatitis, and vitiligo.4,5 Although these conditions have different etiologies and clinical manifestations, immune system dysregulation plays a key role in the development of all these conditions.6–8 Phototherapy is also effective in treating rare diseases such as mycosis fungoides and scleroderma.4 Topical and systemic treatments are also available for the treatment of include immune-mediated dermatological conditions, however; both treatment modalities possess significant limitations. Systemic immunomodulators for the treatment of psoriasis are expensive, with annual costs ranging from $1,197 to $27,577.8 Systemic therapies have also been associated with severe systemic toxicity, such as hepatotoxicity, nephrotoxicity, and severe infection.9,10 Topical therapies are only indicated for individuals with localized disease, rendering them less effective than the existing systemic therapies.11 A powerful treatment option is phototherapy, which is associated with less systemic side effects and lower annual costs than immunomodulators and is more effective than topical treatments.9 Phototherapy exerts its therapeutic effects on autoimmune and autoinflammatory diseases by inducing apoptosis of proinflammatory cells and activating immunoregulatory mechanisms.12 Common side effects associated with phototherapy include sunburn, erythema, and edema.13 Chronic side effects include lentigines, photoaging, and skin cancer.4 Herein, we present a systematic review of recent literature summarizing the known consequences of phototherapy, which include DNA damage and induction of malignancies, to better understand this increasingly popular treatment modality.   Methods This systematic review was conducted according to PRISMA guidelines. A literature search was conducted using the bibliographical databases PubMed/MEDLINE in August 2021 using the following search terms: “(Phototherapy[Title/Abstract]) and (DNA damage[Title/Abstract])” according to PRISMA reporting guidelines for systematic reviews. All available studies prior to August were considered for inclusion. Given the focus of this article, the inclusion criteria were: (1) relevant studies discussing DNA/cellular damage in adults undergoing/who underwent phototherapy and (2) articles describing the mechanisms of DNA damage/skin cancer caused by phototherapy/UVR. Exclusion criteria included studies written in languages other than English with no translation available, articles not pertaining to both phototherapy and DNA damage, and articles discussing the effects of UVR in neonatal hyperbilirubinemia. Only studies including dermatological conditions as indications for phototherapy were included in this review since phototherapy is often administered for longer time periods and at higher frequencies/doses for the treatment of chronic dermatological disease compared to the treatment of neonatal hyperbilirubinemia, which is a transient condition occurring many newborns. Additionally, the main goal of this review is to bolster dermatologists’ ability to weigh the risks and benefits of phototherapy in patients who are more at risk for malignancy and/or increased comorbidities. Results A total of 75 non-duplicated article citations were reviewed; 21 articles (Figure 1) met the inclusion/exclusion criteria. Although phototherapy has been an effective tool in treating a variety of dermatological conditions, it can cause DNA damage and has been linked to increased risk of carcinogenesis. Upon UVR penetration into the skin, its ionizing energy is absorbed by different molecules, DNA being one of them.14 The absorption of this energy by DNA leads to the formation of photolesions, which mainly consist of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs).15 These mutations can lead to errors in DNA replication which can then lead to the initiation of skin carcinogenesis if not repaired.16,17 CPDs are exclusively seen with UVR-induced DNA damage and their accumulation results in immunosuppression

Methotrexate Gel Either Alone or Combined with Narrow Band Ultraviolet B or Excimer Light for the Treatment of Vitiligo

J Clin Aesthet Dermatol. 2023;16(3):32–36. by Khaled Gharib, MD; Alshimaa Ibrahim, MD; Yasmeen El Sharkawi, MBBCH; Nagia Elmegrab, MD; and Mohamed Attia, MD All authors are with the Dermatology, Venereology and Andrology Department, Faculty of Medicine at Zagazig University in Zagazig, Egypt. FUNDING: No funding was provided for this article DISCLOSURES: The authors report no conflicts on interest relevant to the content of this article. ABSTRACT: Background. Methotrexate has been used successfully in the treatment of vitiligo. It leads to decrease in the number of TNF-α secreting T cells in association with increase in the number of interleukin (IL)-10 producing T cells. Topical forms of methotrexate do not have significant hematologic or hepatotoxic side effects unlike the systemic forms of the drug. Objective. We sought to evaluate the efficacy and safety of methotrexate gel for the treatment of vitiligo, either alone or combined with narrowband (NB) ultraviolet B (UVB) or with excimer light. Methods. Forty-eight patients with vitiligo were randomized into three treatment groups. Group I was treated with methotrexate gel twice daily. Group II was treated with methotrexate gel twice daily plus NB-UVB twice weekly. Group III was treated with methotrexate gel twice daily combined with excimer light twice weekly. Treatment was continued for three months followed by a one-month follow-up period. Results. there was a statistically significant difference between groups regarding the therapeutic response. The highest response was recorded in the group treated with methotrexate gel and NB-UVB. More patients in Group II showed good or excellent response than in the other groups. Conclusion. Methotrexate gel could increase the therapeutic effect of NB-UVB and excimer laser and shorten the treatment period of vitiligo. However, it was not effective enough to induce repigmentation when used alone. Keywords: Methotrexate, vitiligo, laser Vitiligo is the most prevalent depigmenting skin disorder that causes the selective destruction of melanocytes, resulting in depigmentation of the skin, hair, and mucosa. It appears to be equally prevalent in men and women, and there are no differences in the rate of occurrence according to skin type or race.1  The basic goals of vitiligo treatment are stopping the progression of the disease, repigmentation via promoting melanocyte differentiation and proliferation, and avoiding relapses. One of the safest and most successful treatments for vitiligo is narrowband (NB) ultraviolet B (UVB) therapy. Excimer laser (EL), a targeted phototherapy device, inhibits inflammation and induces T-cell apoptosis by emitting coherent and monochromatic light at 308 nm, which is close to 311 nm NB-UVB. Additionally, it stimulates melanocyte stem cells to differentiate, which is associated with increased migration of melanocytes to induce repigmentation with no effect on nearby skin.2,3  Methotrexate (MTX) is a folic acid antagonist, antiproliferative and immunomodulating drug that leads to decrease in the number of TNF-α-producing T cells, whereas the number of IL-10 producing T cells increases. Additionally, it suppresses B cells and controls the generation of interleukin (IL)-6 and reactive oxygen species. All of these factors help in the treatment of vitiligo. Unlike oral MXT, it has been suggested that topical preparations of the drug  have no significant related hepatotoxic and hematologic adverse effects.4–7 The aim of this study was to evaluate the efficacy and safety of MTX topical gel, either alone or combined with NB-UVB or excimer light, for the treatment of vitiligo. Methods Patients. This study included 48 patients of both sexes with localized, non-segmental vitiligo. Their ages ranged from 6 to 62 years. They were recruited from the Dermatology Department of Zagazig University Hospital. Approval was obtained from the Zagazig University Institutional Review Board (IRB #5947/5-3-2020). Patients on other treatment modalities for vitiligo, patients with photosensitivity, patients with renal or hematological disorders, patients with hepatic disease, pregnant and lactating patients were excluded. Included patients were randomly divided according to computer generated random list into three groups. Group I wass treated only by topical methotrexate gel 1% twice daily. Patients were instructed to apply one finger tip unit of methotrexate gel twice daily to the treated areas. Group II was treated with topical methorexate gel 1% twice daily combined with NB-UVB (Philips TL100, Hamburg, Germany) twice weekly with a starting dose of 200 mJ/cm2 irrespective of skin type. Increment in dose was  10% to 20% per session. The dose was adjusted according to NB-UVB treatment guidelines.2 Group III was treated with topical methotrexate gel 1% twice daily combined with excimer lamp (Peninsula Excimer system; Peninsula Company, China) with starting a dose of 100 to 150mJ/cm2 for the head and neck and from 200 to 600 mJ/cm2 for other sites. The dose was increased by 50 mJ/cm2 per session, according to the protocol described by Beggs et al.8 The duration of treatment was three months, followed by one-month follow-up period. Methotrexate gel preparation. MTX gel was prepared in the Department of Pharmaceutics at Zagazig University. Sodium benzoate and methotrexate were initially dispersed in distilled water containing 15% w/w glycerin. Then the gel base (Na CMC) was added to the solution and mixed using a mechanical stirrer at 10,000 rpm until homogeneity was attained.  Assessment of improvement. Patients were photographed before and after treatment. The improvement was classified according to the percentage of repigmentation at the end of treatment: G0=No response (0%); G1=poor (<25%); G2=moderate (25 to <50%), G3=good (≥50–75%), and G4=excellent if repigmentation 75% or greater.9 Statistical analysis. All data were collected, tabulated, and statistically analyzed using IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. Quantitative data were expressed as the mean ± SD &median (range), and qualitative data were expressed as & (percentage). Kruskall Wallis test was used to compare between more than two groups of non-normally distributed variables. Percent of categorical variables were compared using Chi-square test. All tests were two sided. p<0.05 was considered statistically significant, p<0.001 was considered statistically highly significant. Results Demographic and clinical data of the studied patients. Forty-eight patients (26 female, 22 male) completed the study. Their ages ranged from 6 to 62 years. The disease duration ranged from six months to seven years. The disease severity

Spotlight Interview: Matthew T. Reynolds, MS, MPAS, PA-C

J Clin Aesthetic Dermatol 2022;15(12 Suppl 1):S13–S15 Matthew T. Reynolds, MS, MPAS, PA-C, a native of Arkansas, received his physician assistant training at the University of Arkansas for Medical Sciences (UAMS) in Little Rock. In 2015, after completing his Master of Science degree in Physician Assistant Studies, he joined Arkansas Dermatology, where he completed a one-year physician assistant fellowship in dermatology and where he continues to practice dermatology to this day. Matt enjoys treating a wide variety of general and surgical dermatologic conditions—from psoriasis and acne to atopic dermatitis and skin cancer.  In addition to his clinical practice, Matt serves as a guest lecturer for the UAMS Physician Assistant Program, as well as a national speaker and educator for nurse practitioners and physician assistants. Over the last seven years, Matt has authored several published articles on a variety of dermatological topics, including atopic dermatitis, melanoma and nonmelanoma skin cancers, and psoriasis, and has coauthored book chapters on squamous cell skin cancer.  Matt is also the cofounder of the Arkansas Research Trials Center in North Little Rock, Arkansas, where he currently serves as a subinvestigator for many ongoing clinical studies.  What inspired you to pursue a career in dermatology?  Matt: I was initially inspired to pursue a career in dermatology when I came to the realization that nearly every systemic disease has some sort of skin manifestation, whether it is heart failure, diabetes, an autoimmune disorder, or other chronic condition. This impressed me most, and as I continue to expand my own knowledge, I often find I am humbled by the ever-expanding wealth of knowledge the dermatology field gains year after year on the many diseases we treat in the specialty. I now, more than ever, am most intrigued by the number of discoveries continually being made in immune pathway research. The number of biologic compounds that have been or are being developed that can target these pathways and disrupt the pathogenesis of these skin diseases has greatly expanded our treatment options for our patients. I continue to be inspired by not only how far we’ve come in recent years in our knowledge of skin diseases, but also by where we are heading in the future. What clinical areas in dermatology interest you the most? Matt: I am passionate about preventing and managing nonmelanoma and melanoma skin cancer. In our beautiful state of Arkansas, we have a high incidence of these types of cancers, and at Arkansas Dermatology, where I practice dermatology, we prioritize these patients so they can access high-quality care as quickly as possible for optimal outcomes.  I also enjoy treating inflammatory skin disorders, such as atopic dermatitis, plaque psoriasis, and urticaria. The ever-expanding landscape of therapies for these diseases is very promising, and I am thankful to have such a wide variety of tools available to effectively treat these patients. For example, when I initially began practicing dermatology, there were only two biologics available for the treatment of plaque psoriasis— alefacept and efalizumab; now, there are numerous therapeutic options available to patients. For atopic dermatitis, I’ve seen the launch of dupilumab, and now JAK inhibitors have made their debut, creating more therapeutic options for all patient types. In 2019, my colleagues and I founded a dedicated research facility for patients with inflammatory skin conditions; we are currently investigating several agents that will eventually be on the market.  Being involved in several clinical trials, you’ve got your finger on the pulse of new and emerging therapies in dermatology. What emerging therapies or areas of research are you most excited about?  Matt: One area of research/drug discovery that I’m very excited about is the use of oral IL-17 and-23 agents as therapeutic options for plaque psoriasis. I believe if we can get a handle on the potency and safety of these agents, we could potentially move completely away from the injectables. I’m also interested in the next generation of medication delivery systems; currently, there are several companies working on highly effective, continuous drug delivery systems that go beyond the patient having to self-inject or remember to take a daily pill. I’m very excited to see what happens over the next 10 years in this area of research. Targeted therapy, or precision medicine, has definitely become an important aspect of drug develpment for the treatment of skin cancer, psoriasis, and other chronic skin conditions. What types of targeted therapy do you utilize in skin cancer management? How do you integrate these treatments into clinical practice?   Matt: One of the greatest gifts to derm practitioners is the number targeted therapies that are availble for many skin diseases. Specifically, for nonmelanoma skin cancer, I believe the Hedgehog inhibitors have been the biggest game changer. The ability to give your patients another option for treatment besides surgery or radiation is very rewarding to me as a provider. We have patients with too many lesions to treat or who have lesion recurrence following surgery or radiation that do really well on a Hedgehog inhibitor. We manage these patients with a specialized pulse dosing regimen and L-Carnitine 1500mg daily for muscle cramps, and they typically do very well. In addition to Hedgehog inhibitors, we also heavily utilize PD-1  blockers in our practice to treat patients with advanced squamous cell carcinoma. When it comes to optimal outcomes, the more advanced the disease, the more you need to have advanced tools in your armamentarium. I can’t encourage the advanced practice provider (APP) community enough to become educated and proficient in prescribing these types of therapies. How do you keep your patients engaged in and adherent to their treatment plans?   Matt: Certainly, I try to give my patients a lot of extra attention. I will follow up with them every week or two when they are first starting an injectable for their psoriasis or eczema. I will often give away more samples than I’m probably supposed to (and without my clinic manager knowing) just so my patients can start treatment sooner. I firmly believe that if