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JDD

RESIDENT ROUNDS NEWS, VIEWS, & REVIEWS PIPELINE PREVIEWS CLINICAL TRIAL REVIEW

ISSN: 1545 9616 November 2019 • Volume 18 • Issue 11

ANTI-AGING · AESTHETIC · MEDICAL DERMATOLOGY

CONTINUING EDUCATION: Facial Skin Tightening With Microfocused Ultrasound and Dermal Fillers

HIFEM in Dermatology

Re-pigmentation of Hypopigmentation

MFU-V for Acne Scars

Topical Treatments for Melasma

SPECIAL FOCUS:

LASERS, LIGHT SOURCES, AND DEVICES

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MinoLira Tablets bring immediate- and sustained-release minocycline together for the fi rst time ever in functionally

scored tablets (105 and 135mg) for broad dosing options and safety similar to placebo.1

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INDICATION AND USAGEMINOLIRA is indicated to treat only infl ammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older.

MINOLIRA did not demonstrate any effect on non-infl ammatory acne lesions. Safety of MINOLIRA has not been established beyond 12 weeks of use. This formulation of minocycline has not been evaluated in the treatment of infections. To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, MINOLIRA should be used only as indicated.

IMPORTANT SAFETY INFORMATION• This drug is contraindicated in persons who have shown

hypersensitivity to any of the tetracyclines.

• Minocycline, like other tetracycline-class drugs, can cause fetal harm when administered to a pregnant woman.

• The use of MINOLIRA during the second and third trimesters of pregnancy, infancy, and childhood up to

the age of 8 years may cause permanent discoloration of the teeth (yellow-gray-brown) and reversible inhibition of bone growth.

• If pseudomembranous colitis occurs, discontinue MINOLIRA.

• If renal impairment exists, MINOLIRA doses may need to be adjusted to avoid accumulations of the drug and possible liver toxicity.

• Minocycline may cause central nervous system side effects, including light-headedness, dizziness, or vertigo.

• Minocycline may cause intracranial hypertension and autoimmune disorders in adults and adolescents. Discontinue MINOLIRA if symptoms occur.

• Minocycline has been associated with anaphylaxis, serious skin reactions, erythema multiforme, and DRESS syndrome. Discontinue MINOLIRA immediately if symptoms occur.

• The most commonly observed adverse reactions are headache, fatigue, dizziness, and pruritus.

To report SUSPECTED ADVERSE REACTIONS, contact EPI Health, LLC at 1-800-499-4468 or FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

For Full Prescribing Information, please visit www.minolira.com

REFERENCE: 1. MinoLira Tablets [Package Insert]. Charleston, SC: EPI Health, LLC; 2018.

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November 2019 1069 Volume 18 • Issue 11

Copyright © 2019 EDITORIAL BOARD Journal of Drugs in Dermatology

SENIOR ASSOCIATE EDITORSKenneth Beer MD

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Copyright © 2019 TABLE OF CONTENTS Journal of Drugs in Dermatology

CONTINUING EDUCATION ARTICLE

1073 Facial Skin Tightening With Microfocused Ultrasound and Dermal Fillers: Considerations for Patient Selection and OutcomesGabriela Casabona MD and Kai Kaye PhD

GUEST EDITORIAL

1088 High Intensity Focused Electromagnetic Field (HIFEM) Devices in Dermatology Macrene Alexiades MD, PhD

ORIGINAL ARTICLES

1090 Re-pigmentation of Hypopigmentation: Fractional Lasers vs Laser-Assisted Delivery of Bimatoprost vs Novel Epidermal Melanocyte Harvesting System Jill S. Waibel MD, Ashley Rudnick BS, Kristopher L. Arheart EdD, Nicole Nagrani MD, Adrianna Gonzalez MD, Chloe Gianatasio MS

1098 Simultaneous Changes in Abdominal Adipose and Muscle Tissues Following Treatments by High-Intensity Focused Electromagnetic (HIFEM) Technology-Based Device: Computed Tomography EvaluationDavid E. Kent MD, Carolyn I. Jacob MD

1104 A Randomized, Controlled, Split-Face Study of the Efficacy of a Picosecond Laser in the Treatment of MelasmaAlexis B. Lyons MD, Ronald L. Moy MD, Jennifer L. Herrmann MD

1109 Safety and Effectiveness of Microfocused Ultrasound With Visualization for the Correction of Moderate to Severe Atrophic Acne ScarsCorey S. Maas MD, John H. Joseph MD

1116 Combined 400-600nm and 800-1200nm Intense Pulsed Phototherapy of Facial Acne VulgarisJ. Matthew Knight MD




Copyright © 2019 TABLE OF CONTENTS Journal of Drugs in Dermatology

ORIGINAL ARTICLES (CONTD)

1124 Improper Potency and Impurities in Compounded PolidocanolMargaret Mann MD, Gilly S. Munavalli MD, Lisa Amatangelo MD, and Nick Morrison MD

1128 Tretinoin 0.05% Lotion for the Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris: Impact of Gender and Race on Efficacy and SafetyEdward Lain MD, Doris Day MD, Julie Harper MD, Eric Guenin PharmD PhD MPH

1140 A Cohort Study Using a Facial Cleansing Brush With Acne Cleansing Brush Head and a Gel Cleanser in Subjects With Mild-to-Moderate Acne and Acne-Prone SkinMichael H. Gold MD FAAD, Glynis R. Ablon MD FAAD, Anneke Andriessen PhD, Vivian W. Bucay MD FAAD, David J. Goldberg MD JD, Jeremy B. Green MD FAAD, Deirdre Hooper MD FAAD, Stephen H. Mandy MD FAAD, Mark S. Nestor MD PhD, Arisa Ortiz MD FAAD FACMS

1147 Efficacy and Tolerability of a Novel Tretinoin 0.05% Lotion for the Once-Daily Treatment of Moderate or Severe Acne Vulgaris in Adult FemalesJulie C. Harper MD, Hilary Baldwin MD, Linda Stein Gold MD, Eric Guenin PhD PharmD MPH

1156 Topical Treatments for Melasma: A Systematic Review of Randomized Controlled TrialsEvan Austin BS, Julie K. Nguyen MD, Jared Jagdeo MD MS

CASE REPORTS

1174 Successful Treatment of Porokeratosis With Ablative Fractional Carbon Dioxide Laser and Vitamin C, E, and Ferulic Acid SerumJulie K. Nguyen MD, Silvia Mancebo MD, Brady Bleicher MD, and Jared Jagdeo MD MS

1180 Successful Treatment of Lower Extremity Telangiectasias Using 585-nm Pulsed-Dye Laser at Low Fluence Combined With Optical Coherence Tomography: A Case Report Ali Rajabi-Estarabadi MD, Caiwei Zheng BA, Natalie Williams BS, Samuel C. Smith MS, Keyvan Nouri MD, Robert S. Kirsner MD PhD

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Copyright © 2019 Journal of Drugs in Dermatology

Journal of Drugs in Dermatology (JDD) is indexed in MEDLINE®/PubMed® and is published monthly by the Journal of Drugs in Dermatology115 E. 23rd Street, 3rd Floor, Unit 322, New York, NY 10010telephone: 212-213-5434 | fax: 212-213-5435 | JDDonline.com

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Statement of NeedHuman facial aging is a gradual and ongoing process involving various factors including photodamage, skin laxity, volume loss of subcutaneous tissue, and bony resorption. As the aging US population is growing, minimally invasive strategies have become the primary treatment modalities for addressing mild to moderate age-related facial changes. The introduction of microfocused ultrasound (MFU) represents a method to produce a deeper wound healing response with increased collagen remodeling and more durable clinical response. MFU-V treatment protocols continue to be refined and use in combination with other minimally invasive strategies including injectable dermal fillers such as diluted calcium hydroxylapatite for skin laxity and appearance of lines in the neck and décolletage has been studied. Need exists for expanded understanding of dermatology providers on the application of microfocused ultrasound in combination with injectable dermal fillers as a treatment approach for lifting skin on the neck and face and for improving lines and wrinkles on the chest.

Educational ObjectivesThe information and educational goals for this enduring activity are to expand awareness of microfocused ultrasound as an emerging treatment strategy for the effects of normal facial aging and to demonstrate positive outcomes in facial skin tightening strategies utilizing combination treatment including microfocused ultrasound and injectable dermal fillers. Upon completion of this continuing education activity participants should be able to:

• Summarize the mechanism of action of high-resolution ultrasound imaging (MFU-V) for lifting skin on the neck and face, improving lines and wrinkles on the chest and improving collagen synthesis

• Identify patients best suited for treatment with MFU-V in combination with injectable dermal fillers

• Compare features, benefits, and safety profile MFU-V treatment in lifting skin on the neck and face and for improving lines and wrinkles on the chest

Target AudienceThis activity is intended for dermatologists, residents, and fellows in dermatology, and physician assistants, nurse practitioners, and other healthcare providers with an interest in aesthetic treatment of patients of all skin types.

Credit StatementsCategory 1: Creighton University Health Sciences Continuing Education designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

AAPA accepts AMA Category 1 credit for the PRA from organizations accredited by ACCME.

Nurse CE: Creighton University Health Sciences Continuing Education designates this activity for 1.0 contact hour for nurses. Nurses should claim only credit commensurate with the extent of their participation in the activity.

Accreditation StatementIn support of improving patient care, this activity has been planned and implemented by Creighton University Health Sciences Continuing Education (HSCE) and Physicians Continuing Education Corporation. Creighton University Health Sciences Continuing Education (HSCE) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team.

How to Obtain CE CreditYou can earn 1.0 AMA PRA Category 1 Credits™ and ANCC credit by reading the article contained in this issue and completing a Journal post-test, web-based post-test, and evaluation. Test is valid through October 31, 2020 (no credit will be given after this date).


Copyright © 2019 CONTINUING EDUCATION Journal of Drugs in Dermatology

FACIAL SKIN TIGHTENING WITH MICROFOCUSED ULTRASOUND AND DERMAL FILLERS: CONSIDERATIONS FOR PATIENT SELECTION AND OUTCOMESRelease Date: November 1, 2019

Termination Date: October 31, 2020

Estimated Time to Complete This CME Activity: 1.0 hours

Medium or Combination of Media Used: Written article

Method of Physical Participation: Journal article, Journal post-test, web-based post-test, and evaluation

Hardware/Software Requirements: High speed internet connection, any web browser



To receive credit for this activity, please go to www.JDDonline.com and click on CME Activities under “Library.” You will find instructions for taking the post-test and completing the program evaluation. You must earn a passing score of at least 70% and complete and submit the activity evaluation form in order to receive a certificate for 1.0 AMA PRA Category 1 Credit™. There is no fee for this CME activity. Once you have completed the form online, you will be able to print your certificate directly. You can also receive credit for this activity by completing the post-test and evaluation printed in this issue and faxing or mailing it to JDD, 115 East 23rd Street, Third Floor, Unit 322, New York, NY 10010 or fax to 212-213-5439.

Faculty CredentialsGabriela Casabona MD is affiliated with Clinica Vida and the Laser Department at the Universidade ABC in Sao Paulo, Brazil. Dr. Casabona is a Mohs surgeon and specializes in cosmetic and laser procedures. Since 2001, she has authored numerous articles and papers in prestigious international peer-reviewed literature and has co-authored several chapters in scientific texts. She is a regular, invited speaker and conferences at educational courses across the globe.

Peer Reviewer CredentialsPerry Robins, MD is Professor Emeritus of Dermatology at New York University Medical Center, New York, NY.

DisclosuresPolicy on Faculty and Provider Disclosure: It is the policy of Creighton University Health Sciences Continuing Education (HSCE) to ensure fair balance, independence, objectivity, and scientific rigor in all activities. All faculty participating in CME activities sponsored by Creighton University Health Sciences Continuing Education (HSCE) are required to present evidence-based data, identify and reference off-label product use, and disclose all relevant financial relationships with those supporting the activity or others whose products or services are discussed. Any real or apparent conflicts of interest have been addressed through a peer review process, as required by ACCME. The faculty/authors have disclosed the following relationships with commercial interests:

The primary author of this article, Gabriella Casabona MD, serves as a consultant to Merz Pharma. Kai Kaye MD assisted Dr. Casabona with the development of this article has no relationships to disclose.

Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US FDA. Creighton University Health Sciences Continuing Education (HSCE), the Journal of Drugs in Dermatology, and the activity supporters do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the Creighton University Health Sciences Continuing Education (HSCE), the Journal of Drugs in Dermatology, and the activity supporters. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclosure of Commercial Support: This activity is supported by an educational grant provided by Merz North America, Inc.

Contact InformationIf you need technical support or have questions about the course, please e-mail [email protected].

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CopyrightAll of the content in this educational activity is copyrighted by the Journal of Drugs in Dermatology. Creighton University Health Sciences Continuing Education (HSCE) has obtained permission from the Journal of Drugs in Dermatology to use the content in this educational activity.






Copyright © 2019 ORIGINAL ARTICLE Journal of Drugs in Dermatology

SPECIAL TOPIC

Facial Skin Tightening With Microfocused Ultrasound and Dermal Fillers:

Considerations for Patient Selection and OutcomesGabriela Casabona MD and Kai Kaye PhD

Ocean Clinic, Marbella, Spain

BACKGROUNDMicrofocused ultrasound (MFU) is a technology developed from focused ultrasound (FU) and used in high intensity mode to generate heat (high intensity focused ultrasound; HIFU). Focused ultrasound was discovered by Frank Fry in 1972 and was used to destroy brain cancer cells.1 HIFU is a modality in which the ultrasound beam is focused precisely on the target to deliver acoustic energy to part of the body in a non-invasive or minimally invasive manner. The purpose of HIFU is to heat a target tissue without affecting the tissue in the ultrasound propagation pathway. HIFU can increase the temperature of a selected area above 55ºC, which results in coagulative necrosis and immediate cell death in a specific depth through a focused ultrasound beam.

Because the ultrasound wavelength at megahertz frequencies has a millimeter-scale beam size and the ultrasound probe has a concave shape, the ultrasound beam can be focused into small, clinically relevant volumes of tissue. The energy absorp-tion raises the temperature at the focus point but increases only to non-cytotoxic levels outside the region.2,3 Almost 30 years later, noninvasive facial treatment with intense microfocused

ultrasound (MFU) started to be developed, such as Ulthera® System (Merz North America, Raleigh, NC), which also includes ultrasound visualization (DeepSee®; Merz North America, Ra-leigh, NC), followed by Doblo (Hironic®, Korea), which does not include real-time visualization in some models, and Ultrafor-mer (Cryomed®, Australia), which does not offer visualization (Table1).

During development, some HIFU parameters were adjusted to reach the goal of generating thermal coagulation zones (TCPs). The final prototype transducer had shorter pulse durations of 50–200ms, a higher frequency of 4 to 7 MHz, and a decreased energy of 0.5 to 10J.4 As a result, more precise energy delivery was achieved with the microfocused ultrasound with visual-ization (MFU-V) device during aesthetic treatments for facial tissue.

In 2004, the first preclinical trials were started with a prototype device, followed shortly thereafter by several clinical trials.5-8

White and colleagues6 reported the first aesthetic use of fo-cused ultrasonography and its ability to specifically target the

Introduction: Microfocused ultrasound (MFU) is a heat technology that is developed from focused ultrasound (FU) used in a high intense mode to generate heat (HIFU). Patient assessment is very complex and involves more than just addressing complaints. It is a challenge to evaluate, decide on options, and give treatments that guarantee the best outcomes. In order to facilitate the process, the authors divided the protocol into five steps: Assess (expectations, features); Decide (which depth to customize); Select (choose a number of lines to achieve the objective); Plan (combination, if needed); Treat (documentation, safety, and comfort). Methods: The PubMed search engine was used to search all publications from 1900–2019 that mention HIFU. The information col-lected was then grouped into the five protocol steps.Discussion: MFU is a focused ultrasound device that, at certain energy levels, produces heat over 55ºC at the focal point, which leads to thermal coagulation points (TCPs) in the target tissue. The creation of TCPs leads to a healing cascade, ending with neocollagenesis and neoelastogenesis. At different levels, this can bring about either a lifting effect or skin tightening, depending on the structure tar-geted. Therefore, the two most important tools for precision and efficacy of treatment are visualization with ultrasound and real-time evaluation of severity and structural changes (such as bone or fat loss).Conclusion: MFU-V is a well-known and, based on the evidence, an effective tool for non-invasive lifting and skin tightening. The secret to successful use of the device is to assess adequately patient needs and expectations and plan ahead for the combination of other treatment if necessary to achieve the desired outcome.

J Drugs Dermatol. 2019;18(11):1075-1082.

ABSTRACT



1076

Journal of Drugs in DermatologyNovember 2019 • Volume 18 • Issue 11

G. Casabona, K. Kaye

needed for wound healing. These represent the basis for the new connective tissue matrix, serving to close tissue gaps and to restore the mechanical strength of the wound. Subsequent-ly, the synthesis of collagen increases throughout the wound, while the proliferation of fibroblasts declines successively, ad-justing to a balance between synthesis and degradation of the ECM.17 The third phase can last from 21 days to 1 year, depend-ing on the scar tissue.

One of the most important factors is sufficient stimulation during the first phase to have enough fibroblasts to produce organized collagen and elastin. Organized collagen forma-tion (scar tissue) is the physiological endpoint of mammalian wound repair. There is some evidence that inflammation during the process of wound healing is directly linked to the extent of scar formation.15 First, fetal wound healing, which lacks the typi-cal inflammatory response, is scarless until a certain age.18,19 In addition, scar formation does occur when inflammation is induced in fetal wounds.20 Also, reproductive hormones have been shown to have an influence on inflammation and the for-mation of scars. Studies show that low estrogen levels in mice resulted in an impaired rate of healing with excessive inflam-mation and scarring.15,21,22

To summarize, a TCP induces tissue coagulation and necrosis and starts the healing cascade. To achieve the desired quantity and quality of collagen, a certain amount of inflammation is needed under certain basic conditions such as the required levels of mediators, hormones, and cell migration. The aging

superficial muscular aponeurotic system (SMAS). The current clearance by the FDA for the aesthetic use of MFU-V are brow-lift, face, and neck lift, and décolleté tightening.9-12

METHODSThe PubMed search engine was used to review all publications from 1900–2019 that mention high intensity focused ultrasound, and the information collected was collated into a step by step approach for didactic purposes.

Mechanism of ActionAs MFU is a focused ultrasound device, at certain energy lev-els, it produces heat over 55ºC at the focal point, which leads to thermal coagulation points (TCPs) in the target tissue. The creation of TCPs leads to a healing cascade, ending with neo-collagenesis and neoelastogenesis. This healing is regulated and described as an “orchestra playing” by Reinke and Song,14 which begins immediately after the first phase of the injury and lasts for 1 to 3 days. This is the most important phase for the purpose of collagen stimulation.15,16 During this very early phase, mediators such as interleukins (IL-1 and IL-6), tumoral necrosis factor (TNF-α), and other factors (FGF-2, IGF-1, TGF-β, and VEGF) lead to the production of new collagen and elastin, as well as neovascularization within the extra cellular matrix (ECM).

The second phase of proliferation lasts for 5-10 days. Under the control of regulating cytokines (IFN-α, TGF-β), fibroblasts synthesize collagen, fibronectin, and other basic substances

TABLE 1.

HIFU Devices, Transducers, and Visualization Method

Device Brand Approved Visualization Transducers

Ultherapy - MFU Merz Pharma - GermanyCanada, US, Europe, Asia, Australia,

Central and South AmericaReal Time USG

1,5mm(micro)3.0mm (micro)4,5mm (micro)

Doublo - HIFU Hironic - Korea Asia, South AmericaNot Real Time USG in some versions

1,5mm (micro)3,0mm (micro)4,5mm (micro)13mm (macro)

Ultraformer - HIFU Cryomed - AustraliaUS, Europe, South America, China,

Russia, AustraliaNo Visualization

1,5mm (micro)2,0mm (micro)3,0mm (micro)4,5mm (micro)6,0mm (macro)9,0mm (macro)13,0mm (macro)



1077



process involves more than just collagen and elastin resto-ration. We must understand that there are different needs in terms of stimulation. Therefore, patient assessment becomes a key point in understanding whether just one treatment such as MFU-V is enough to induce collagen formation, or if other procedures that up-regulate mediators and cell migration23 are also needed during the first phases of healing started by MFU. These include calcium hydroxylapatite (CaHa) or poly-L-lactic acid (PLLA), as shown in a recent study where the histology of the skin after combining both procedures on the same day resulted in larger collagen and elastin formation by increasing stimulation during the first phases of the healing cascade.24

The Devices Most HIFU devices have more than one transducer depth and size focus (Table 1). Macrofocused transducers are used for fat reduction, and are not safe for collagen stimulation because the TCPs are too large and the pulse duration is usually longer. Microfocused transducers have different frequencies. A MFU-V transducer with a frequency of 4 MHz has a depth of 4.5mm and creates a TCP of 1mm4, while a transducer with a frequency of 7 MHz has a 3mm depth and creates a TCP of 0.3mm4, and a transducer with a frequency of 10 MHz has a 1.5mm depth and creates a TCP of 0.18mm4 (Figure 1).6 All devices work with one handpiece, and the transducers are interchangeable and should be used over a thin layer of gel to guarantee good contact with the skin (See video http://jddonline.com).10

How to Achieve the Best ResultsPatient assessment is far more complex than just observing the complaints of the patients who arrive at our office. Sometimes it is hard to estimate the number of lines or which procedures should be combined to provide a natural and satisfactory result. For didactic reasons and to try to facilitate a certain procedure on why and when to use a certain number of MFU-V treatment lines and depths, as well as when to combine other treatments, the authors have divided patient assessment into five steps:

1) Assess – expectations, features 2) Decide – which depth to customize3) Select – choose a number of lines to achieve the objective4) Plan – combination, if needed5) Treat – documentation, safety, and comfort

1. AssessIn this step, there are two main goals:

A. ExpectationsIdentify patient expectations based on the MFU procedure alone. A retrospective study24 showed discordance between physician and patient regarding satisfaction with results. Some-times, even though the physician graded the result as only mild improvement, the patients were happy and satisfied, but the opposite can also occur. Sobanko et al26 showed how important psychological aspects are in improving appearance and how patient motivations for the treatment can differ. Also, patient

FIGURE 1. Schematic illustration of different frequencies present in each different transducer and the wave size and TCP sizes.



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FIGURE 3. Pre-MFU-V (A) and after 3 months (B). Difference in scale score (right side 2, left side 3) showing improvement related to differences in height of mandible and angle of mandible projection. In these cases, not only horizontal correction of the left side would be needed, but also vertical enhancement of the mandible height and angle.

satisfaction can be enhanced with a close interaction with the physician.27 B. Vectors and SeverityAssess the patient’s real needs regarding vectors and proce-dures needed to meet patient expectations. This is the moment where the physician should decide and make clear if, given the level of expectation, the patient is a candidate for a single or combination treatment. In 2005, Marten and Connell28 de-scribed ways of evaluating severity and different patient needs before facelift.

Through different facial positions, the severity of the loss in one specific vector (horizontal, vertical, or projection) needs to be identified to decide if MFU-V alone is the perfect indication as each procedure corrects a different vector (Figures 2 A–C).

One way of assessing involves using the severity scales for face, neck, and chest aging, and other areas such as knees, buttocks, and anterior and posterior thighs.28-33 According to patient self-assessment scores, the necessary treatment inten-sity or frequency, the number of treatment lines, or number of repeated treatments, or if the severity indicates that more than one procedure is indicated, can be discussed (Figures 3 A,B).

FIGURE 2. A patient after MFU-V treatment. (A) 3 months after treatment showing that the displacement occurred in the direction of the tragus area in the face and in the direction of the mandible border in the superior neck, (B) 3 months after injection of dilute CaHa in face showing a more intense displacement in same direction (horizontal) and in vertical manner in superior neck, and (C) 1 month after injection of CaHa as a filler to the zygomatic arch, lower mandible border, and angle of the mandible showing a new displacement more perpendicular to the skin layer represented by the red arrows.

(A) (B) (C)

(A) (B)



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2. DecideAt this point, the MFU-V depth to achieve the desired outcome needs to be decided. There are two possible goals with MFU-V: skin lifting or skin tightening. For a lifting effect, the SMAS or superficial fascia system (SFS) needs to be targeted. The number of TCPs required to create sufficient tightening and to deposit sufficient new collagen and elastin to achieve a lifting effect needs to be determined. Skin tightening can be achieved by making the skin thicker and, therefore, denser and firmer.

To decide the depth of the SMAS and SFS, the physician must master the ability to identify these layers through real-time ul-trasound visualization. This is important because a recent study by Casabona et al34 showed that the SMAS and SFS can change with age, gender, and body mass index (BMI), and in different areas of the face and body (Figures 4 A,B).35,37Another study38 showed that patients who received a customized transducer selection based on ultrasound visualization were far more satisfied with results after MFU-V alone (Figures 5 A–C). In con-clusion, if the MFU-V treatment lines are not directed exactly to the appropriate tissue layers, the procedure can be less effec-tive, leading to frustration with the final results.

3. SelectIn this step, the physician should check the number of lines needed based on two parameters: the transducer to use and the coverage area provided by each one, according to appear-ance, severity, and treatment goal. The amount of collagen that MFU-V can produce depends on the number of lines and therefore the linear coverage or density of lines in the same area (Figures 6 A,B). A recent study published by Sasaki et al39 showed more treatment lines produce better clinical results. It would be logical to conclude that different severities would require different density of lines or even different number of

FIGURE 4. Ultrasound image (DeepSee®, Ulthera System) showing difference in depth of the SMAS in face buccal space at 4.5mm (A)and masseteric space 3.8mm (B). Should be treating with 4/4.5mm and 7/3.0 buccals space and change to 7/3.0mm with pressure and 10/1.5mm in masseteric area.

FIGURE 5. Patient before MFU-V (A), after 3 months of non-customized MFU-V treatment (B), 3 months after second treatment, and 3 years later showing a much better improvement (C).

FIGURE 6. Skin stained with picrossirius after treatment with MFU-V coverage 32% with 4.5mm and 5% with 3.0mm (A), and coverage 60% with 4.5mm and 7% with 3.0mm (B). The stain is used to color collagen fibers and shows more concentration in (B) where the number of lines and coverage was higher.

(A)

(B)

(A)

(B)

(A) (B) (C)



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layers treated to achieve the same endpoint in same vector (horizontal or vertical depending on area). As mentioned be-fore, the recommended protocol of transducers per area needs to be adapted according to SMAS or SFS depth. Therefore, the coverage needed to be adapted to bring the same result once the TCP area of the 4mm/4.5 MHz transducer (1mm3) is much bigger than the 7mm/3.0 MHz (0.3mm3) or 10mm/1.5mm MHz (0.2mm3) transducers. The author developed a table using the ruler provided with some HIFU devices that has an area of 2.5cm x 5cm and is used to mark and distribute the determined number of lines when delivered by a transducer in a certain area of face and body (Table 2). This table might help to convert the number of lines from one transducer to the other if needed. Although, it is important to point out that we do not have data on what is the ideal conversion of one transducer to the other to keep the same clinical result. The authors recommend these corrections when changing transducers: 4/4.5 to 7/3.0–50% more lines of standard protocol, 7/3.0 to 10/1.5–30% more lines of the standard protocol (Figures 7A–C).40

4. PlanIn this step, the most important assessments are the vectors involved in the aging appearance for each patient and each area of complaint. The face, neck, and chest have different ways of aging, and the same layers of skin are disposed differently in these three areas. Also, it is very important to evaluate the patient in dynamic and resting conditions because this will provide a hint about which layer is more important to treat to effectively address the specific patient complaint.

• Face: Only MFU-V can provide correction in a horizontal manner on the face, tightening the skin and SMAS from the corner of the mouth to pre-auricular area (fixed part of the SMAS).39,41

• Neck: Only MFU-V can provide correction in a vertical manner in the neck, recreating the mandible definition by tightening the platysma and skin from its origin (mandible region) and insertion (clavicle).39

• Décolleté: Only MFU-V can provide correction in a vertical manner on the chest as shown in clinical experience.42,43

FIGURE 7. Pre-treatment with MFU-V (A) and (B) after 3 months showing conversion of coverage from one transducer to the other. (C) Scheme of coverage per region per transducer.

TABLE 2.

Ruler Area and Transducer Coverage Based on Number of Lines

Ruler Coverage

Lines Height (mm) Length (mm) Total (mm2) 4/4.5 7/4.5 7/3.0 10/1.5

240.0 50.0 25.0 1250,00 256.22% 163.98% 31.20% 21.67%

120.0 50.0 25.0 1250,00 128.11% 81.99% 15.60% 10.83%

60.0 50.0 25.0 1250,00 64.06% 41.00% 7.80% 5.42%

30.0 50.0 25.0 1250,00 32.03% 20.50% 3.90% 2.71%

40.0 50.0 25.0 1250,00 42.70% 27.33% 5.20% 3.61%

25.0 50.0 25.0 1250,00 26.69% 17.08% 3.25% 2.26%

15.0 50.0 25.0 1250,00 16.01% 10.25% 1.95% 1.35%

Other procedures such as biostimulators and fillers can enhance the strength of other vectors such as horizontal or projection on the frame of the face, neck, and chest (Figure 8).44,45 They can be boosters (enhance collagen stimulation same areas) or highlighters (enhancing visual result of MFU-V by restoring the structure of bone and fat creating a stretching effect on the tis-sue envelope from SFS to epidermis). The more vectors you treat without overtreating one or the other, the more natural results look.

(A) (B)

(C)



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Also, it is very important in this step to plan if the procedure(s) will be done the same day. Carruthers et al published a consen-sus on the combination of MFU-V and other procedures with experts recommendations regarding best timing.46 According to this consensus, it is best to treat in single procedures separated by 15 days to allow recovery from possible adverse effects; however, patients may prefer to have several treatments on the same day. Devices such as MFU-V should be used first, fol-lowed by injectables such as fillers, biostimulators, and toxins, followed by superficial treatments such as peels, micronee-dling, and creams.46,47,48 One recent publication by Yutskoskaya (2019) showed that combining MFU-V and CaHa on the same day is superior to other timings for combination treatment.49

5. TreatIn this step, it is important to ensure patient comfort, that the treatment goes as planned, and that the patient is satisfied. Photography is important to demonstrate that MFU-V was ef-fective with realistic results.50 It also serves as a quality control tool. Currently available 3D cameras that standardize light ex-posure and facial position can be used for the face, neck, and chest.

Pain control is an important part of the experience. In some publications, patients evaluated the procedure poorly despite good aesthetic improvements because of the treatment-related

pain.24,42,51 There are different protocols described for pain con-trol, and very few publications on what is most commonly used (Table 3).39,42,51 Although not mentioned in most publications, in the authors' opinion, after using the device for 7 years, the most efficient and easy methods of pain control are a topical paste containing lidocaine and tetracaine 7%/7% (Pliaglis®, Gal-derma Laboratories) applied 40 minutes prior to the procedure, oral ketorolac 10mg applied 10 minutes prior to the procedure, and good conversation and energy adjustment during the pro-cedure.

An important safety factor during treatment with MFU-V is to be sure the gel coat being used is not too thick, thus interfering with ultrasound penetration that could possibly cause a burn injury.52 The distribution of the lines needs to be correct. A cer-tain amount of overlap is acceptable, but stacking treatment lines is not acceptable because it could also cause burns.52 Be-fore every pulse, be sure the transducer is targeting the right layer to guarantee not only efficacy but also safety, and to avoid adverse events such as nerve damage.52,53

Finally, it is important to contact the patient for further evalu-tion in 3, 6, and 12 months. Published data show that due to lack of estrogen, especially in some older patients, treatment response can be slow, and it is important to be in close contact with the patient to manage expectations and results.20,24

CONCLUSIONThe aim of this article was to give an updated overview of the history and changes of this procedure as seen through an ex-perienced physician’s eye. Through this review, it has become clear that in last 7 years since use of the first MFU-V device was approved, the treatment assessment and protocols have changed. However, some retrospective studies make it very clear that patient satisfaction is related not only to the result itself but also to the whole experience of physician-patient interaction, especially regarding expectations, pain, and fol-low- up.

DISCLOSUREGabriela Casabona MD is a consultant for Merz Global. Kai Kaye PhD does not have any conflicts.

REFERENCES1. Fry FJ, Goss SA, Patrick JT. Transkull focal lesions in cat brain produced by

ultrasound. J Neurosurg. 1981;54(5):659-63.2. Haar GT, Coussios C. High intensity focused ultrasound: physical principles

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sound: a review of present knowledge. Ultrasound Med Biol. 2017;43:1085-1104.

4. Suh DH, Shin MK, Lee JS, et al. Intense focused ultrasound tightening in Asian skin: clinical and pathologic results. Dermatol Surg. 2011;37:1595–602.

5. White WM, Makin IR, Slayton MH, et al. Selective transcutaneous delivery of energy to porcine soft tissues using intense ultrasound. Lasers Surg Med. 2008;40:67–75.

6. White WM, Makin IR, Barthe PG, et al. Selective creation of thermal injury

TABLE 3.

Pain Control Measures Prior to MFU-V Treatment39,42,49

Oral

Diazepam (2.5–10mg), ibuprofen (400–1,200mg), or acetaminophen (400–1,000mg) administered 30–60 minutes before treatment Hydrocodone/acetaminophen, 7.5/500mg or 7.5mg/750mg; hydrocodone 7.5mg or 10mg plus diazepam 5mg or lorazepam 2mg

IntramuscularIntramuscular ketorolac tromethamine 60 mg was given 60 minutes prior to treatment

FIGURE 8. Scheme of each procedure and each vector per area.



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35. Frank K, Hamade H, Casabona G, et al. Influences of age, gender, and body mass index on the thickness of the abdominal fatty layers and its relevance for abdominal liposuction and abdominoplasty. Aesthet Surg J. 2019 May 6 [Epub ahead of print].

36. Frank K, Casabona G, Gotkin RH, et al. Influence of age, gender and body mass index on the thickness of the gluteal subcutaneous fat - implications for safe buttock augmentation procedures. Plast Reconstr Surg. 2019 Apr 9 [Epub ahead of print].

37. Montes J, Santos E. Patient satisfaction following treatment with microfo-cused ultrasound with visualization: results of a retrospective cross-section-al survey. J Drugs Dermatol. 2019;18(1):75-79.

38. Sasaki G, Abelev N, Papadopoulos L. A split face study to determine the sig-nificance of adding increased energy and treatment levels at the marionette folds. Aesthet Surg J. 2017;37:1-14.

39. Fabi S, Joseph J, Sevi J, Green J, Peterson J. Optimizing patient outcomes by customizing treatment with microfocused ultrasound with visualization: gold standard consensus guidelines from an expert panel. J Drugs Derma-tol. 2019;18(5):426-432.

40. Sandulescu T, Büchner H, Rauscher D, et al. Histological, SEM and three-dimensional analysis of the midfacial SMAS − new morphological insights. Ann Anat. 2019;222:70-78

41. Fabi S. Microfocused ultrasound with visualization for skin tightening and lifting: my experience and a review of the literature. Dermatol Surg. 2014;40:S164-S167

42. Gold M, Sensing W, Biron J. Use of micro-focused ultrasound with visualiza-tion to lift and tighten lax knee skin. J Cosmet Laser Ther. 2014;16:225-9.

43. Friedmann D, Fabi S, Goldman M. Combination of intense pulsed light, Sculptra, and Ultherapy for treatment of the aging face. J Cosmet Dermatol. 2014;13:109-118.

44. Hart D, Fabi S, White W, et al. Current concepts in the use of PLLA: clini-cal synergy noted with combined use of microfocused ultrasound and poly-L-lactic acid on the face, neck, and décolletage. Plast Reconstr Surg. 2015:136:180S-187S.

45. Kerscher M, Nurrisyanti A, Eiben-Nielson C, et al. Clinical and biophysical outcomes of combining microfocused ultrasound with visualization and calcium hydroxylapatite filler for facial treatment. Dermatol Ther (Heidelb). 2019;9:135-142.

46. Carruthers J, Burgess C, Day D. Consensus recommendations for combined aesthetic interventions in the face using botulinum toxin, fillers, and energy-based devices. Dermatol Surg. 2016;42:586-597.

47. Fabi S, Goldman M, Mills D, et al. Combining microfocused ultrasound with botulinum. toxin and temporary and semi-permanent dermal fillers: safety and current use. Dermatol Surg. 2016;42:S168-S176

48. Fabi SG, Burgess C, Carruthers A, et al. Consensus recommendations for combined aesthetic interventions using botulinum toxin, fillers, and micro-focused ultrasound in the neck, décolletage, hands, and other areas of the Body. Dermatol Surg. 2016;42:1199-1208.

49. Yutskovskaya Y., Sergeevab A., Koganc E. Clinical and morphological assess-ment of efficacy and portability of the combination of injectable RadiesseTR dilute with normal saline and microfocused ultrasound skin tightening proce-dure (UltherapyTR). J Drugs Dermatol. 2019 (in press).

50. Swanson E. The importance of photographic standardization in evalu-ating microfocused ultrasound facial skin treatments. Aesthet Surg J. 2017;37:NP142–NP144.

51. Hitchcock T, Dobke M. Review of the safety profile for microfocused ultra-sound with visualization. J Cosmet Dermatol. 2014;13:329-335.

52. Friedmann D, Bourgeois G, Chan H, et al. Complications from microfocused transcutaneous ultrasound: case series and review of the literature. Lasers Surg Med. 2018;50:13-19

53. Marr K., Carruthers J, Humphrey S. Transient nerve damage after microfo-cused ultrasound with visualization. Dermatol Surg. 2017;43:894-896.

zones in the superficial musculoaponeurotic system using intense ultra-sound therapy: a new target for noninvasive facial rejuvenation. Arch Facial Plast Surg. 2007;9:22–9.

7. Laubach HJ, Makin IR, Barthe PG, et al. Intense focused ultrasound: evalu-ation of a new treatment modality for precise microcoagulation within the skin. Dermatol Surg. 2008;34:727–34.

8. Gliklich RE, White WM, Slayton MH, et al. Clinical pilot study of intense ul-trasound therapy to deep dermal facial skin and subcutaneous tissues. Arch Facial Plast Surg. 2007;9:88–95.

9. Alam M, White LE, Martin NE, et al. Ultrasound tightening of facial and neck skin: a rater-blinded prospective cohort study. J Am Acad Dermatol. 2010;62:262–9.

10. Brobst R, Ferguson M., Perkins S. Ulthera: initial and six month results. Fa-cial Plast Surg Clin N Am. 2012;20:163-176.

11. US Food and Drug Administration, Center for Drug Evaluation and Research. Ulthera K072505 approval letter. 2009. Available: http://www.accessdata.fda.gov/cdrh_docs/pdf7/K072505.pdf. Accessed November 1, 2011.

12. Oni G, Hoxworth R, Teotia S, et al. Evaluation of a microfocused ultrasound system for improving skin laxity and tightening in the lower face. Aesthet Surg J. 2014;34:1099-110.

13. Fabi S, Goldman M, Dayan S, et al. A prospective multicenter pilot study of the safety and efficacy of microfocused ultrasound with visualization for im-proving lines and wrinkles of the d´ecollete. Dermatol Surg. 2015;41:327-335

14. Reined JM, Sorg H. Wound repair and regeneration. Eur Surg Res. 2012;49:35-43.

15. Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol. 2007;127:514-525.

16. Leibovich SJ, Ross R: The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975;78:71-100.

17. Madden JW, Peacock EE. Studies on the biology of collagen during wound healing. 3. Dynamic metabolism of scar collagen and remodeling of dermal wounds. Ann Surg. 1971; 174:511-520.

18. Bullard KM, Longaker MT, Lorenz HP. Fetal wound healing: current biology. World J Surg. 2003;27:54-61.

19. Redd MJ, Cooper L, Wood W, et al. Wound healing and inflammation: em-bryos reveal the way to perfect repair. Philos Trans R Soc Lond B Biol Sci. 2004;359:777-784.

20. Whitby DJ, Ferguson MW: Immunohistochemical localization of growth fac-tors in fetal wound healing. Dev Biol. 1991;147:207-215.

21. Ashcroft G, Mills S, Lei K, et al. Estrogen modulates cutaneous wound heal-ing by downregulating macrophage migration inhibitory factor. J Clin Invest. 2003;111:1309-1318.

22. Ashcroft GS, Yang X, Glick AB, et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol. 1999;1:260-266.

23. Zerbinati N, Calligaro A. Calcium hydroxylapatite treatment of human skin: evidence of collagen turnover through picrosirius red staining and circularly polarized microscopy. Clin Cosmet Investig Dermatol. 2018;11:29-35.

24. Casabona G, Michalany N. Microfocused ultrasound with visualization and fillers for increased neocollagenesis: clinical and histological evaluation.Der-matol Surg. 2014;40 Suppl 12:S194-8.

25. Fabi S, Goldman M. Retrospective evaluation of micro-focused ultrasound for lifting and tightening the face and neck. Dermatol Surg. 2014;40:569-575.

26. Sobanko JF, Taglienti AJ, Wilson AJ, et al. Motivations for seeking minimally invasive cosmetic procedures in an academic outpatient setting. Aesthet Surg J. 2015;35:1014-1020.

27. Chung KC, Hamill JB, Kim HM, et al. Predictors of patient satisfaction in an outpatient plastic surgery clinic. Ann Plast Surg. 1999;42:56-60.

28. Marten T, Feldman J, Connell B, Little W. Treatment of full obtuse neck. Aes-thetic Surgery Journal. 2005;25 (4):387-397.

29. Landau M, Geister T, Leibou L, et al. Validated assessment scales for decollet´e wrinkling and pigmentation. Dermatol Surg. 2008;34:S179–S183

30. Kaminer M, Casabona G, Peeters W, et al. Validated assessment scales for skin laxity on the posterior thighs, buttocks, in female patients. Dermatol Surg. 2019 (in press).

31. Kaminer M, Casabona G., Peeters W, et al. Validated assessment scales for skin laxity on the anterior thighs, and knees in female patients. Dermatol Surg. 2019 (in press)

32. Narins RS, Carruthers J, Flynn TC et al. Validated assessment scales for the lower face. Dermatol Surg. 2012 Feb;38(2 Spec No.):333-42

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AUTHOR CORRESPONDENCE

Gabriela Casabona MDE-mail:................……......................... [email protected]



1. What is HIFU ?

a. It is an ultrasound

b. It is a focused ultrasound

c. It is a focused ultrasound with high intensity

d. All the above

2. What adaptations are needed in FU technology to be finally used as a non-invasive procedure: adequate pulse duration, controlled energy, and depth?

a. Higher energies, higher frequencies, and better focus

b. Less focus, lower energy, and lower frequencies

c. Variable frequencies, higher energy, and higher focus

d. Variable frequencies, controlled focus, and variable energies

3. What is the main mechanism of action?

a. Stimulation of collagen through protein shock

b. Stimulation of fibrotic tissue

c. Stimulations of extra cellular matrix

d. Stimulation of collagen and elastin through 2- healing intention cascade

4. What are the 5 steps concerning assessment and treat-ment suggested in this article?

a. Assessment, decision, treatment, picture, and post-procedure care

b. Assess, decide, select, plan, treat

c. Assess, decide, select, treat, and follow up

d. Patient conversation and assessment, visualization, treatment, call back

5. Is HIFU treatment always indicated as a single procedure? Can it be combined with other procedures and when should it be combined and indicated?

a. Yes, only as a single procedure.

b. It should be combined with fillers and biostimulators when the patient evaluation shows a need for different vector correction or a boost correction in one vector due to severity and it can be done the same day or 15 days apart.

c. It should be combined with fillers but not biostimulators when the patient evaluation shows a need for different vector correction and it can be done the same day or 15 days apart.

d. It should be combined with fillers and biostimulators when the patient evaluation shows a need for different vector correction or a boost correction in one vector due to severity and it cannot be done the same day, only 15 days apart.



CME Post-Test: For fastest results, please complete this activity online by scanning the QR code below or visiting www.JDDonline.com in the Medical Education Library, where you will be able to receive your CME certificate immediately upon achieving the passing score. Successful completion of the Post-Test is required to earn 1.0 AMA PRA Category 1 CME Credits™ and ANCC Credits. You must earn a passing score of at least 70% and complete the activity evaluation form in order to complete the course and receive a certificate for 1.0 AMA PRA Category 1 CME Credits™ and ANCC Credit. You can take the test online as many times as you require to achieve the passing score. Alternatively, you may select your best answer for each of the following questions and insert them into the Answer Grid found on the Evaluation/Certificate Request Form on page 1084 and return your completed Evaluation/Certificate Request Form to JDD, 115 East 23rd Street, Third Floor, Unit 322, New York, NY 10010 or fax to 212-213-5439.



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atopic dermatitis (Trial 7). The safety profile of DUPIXENT in subjects followed through Week 52 was similar to the safety profile observed at Week 16 in Trial 6. The long-term safety profile of DUPIXENT observed in adolescents was consistent with that seen in adults with atopic dermatitis.AsthmaA total of 2888 adult and adolescent subjects with moderate-to-severe asthma (AS) were evaluated in 3 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks duration (AS Trials 1, 2, and 3). Of these, 2678 had a history of 1 or more severe exacerbations in the year prior to enrollment despite regular use of medium- to high-dose inhaled corticosteroids plus an additional controller(s) (AS Trials 1 and 2). A total of 210 subjects with oral corticosteroid-dependent asthma receiving high-dose inhaled corticosteroids plus up to two additional controllers were enrolled (AS Trial 3). The safety population (AS Trials 1 and 2) was 12-87 years of age, of which 63% were female, and 82% were white. DUPIXENT 200 mg or 300 mg was administered subcutaneously Q2W, following an initial dose of 400 mg or 600 mg, respectively.In AS Trials 1 and 2, the proportion of subjects who discontinued treatment due to adverse events was 4% of the placebo group, 3% of the DUPIXENT 200 mg Q2W group, and 6% of the DUPIXENT 300 mg Q2W group.Table 2 summarizes the adverse reactions that occurred at a rate of at least 1% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator groups in Asthma Trials 1 and 2.Table 2: Adverse Reactions Occurring in ≥1% of the DUPIXENT Groups in Asthma Trials 1 and 2 and Greater than Placebo (6-Month Safety Pool)

a Injection site reactions cluster includes erythema, edema, pruritus, pain, and inflammation.

b Eosinophilia = blood eosinophils ≥3,000 cells/mcL, or deemed by the investigator to be an adverse event. None met the criteria for serious eosinophilic conditions [see Section 5.3 Warnings and Precautions].

Injection site reactions were most common with the loading (initial) dose. The safety profile of DUPIXENT through Week 52 was generally consistent with the safety profile observed at Week 24.Chronic Rhinosinusitis with Nasal PolyposisA total of 722 adult subjects with chronic rhinosinusitis with nasal polyposis (CRSwNP) were evaluated in 2 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks duration (CSNP Trials 1 and 2). The safety pool consisted of data from the first 24 weeks of treatment from both studies.In the safety pool, the proportion of subjects who discontinued treatment due to adverse events was 5% of the placebo group and 2% of the DUPIXENT 300 mg Q2W group.Table 3 summarizes the adverse reactions that occurred at a rate of at least 1% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in CSNP Trials 1 and 2.Table 3: Adverse Reactions Occurring in ≥1% of the DUPIXENT Group in CRSwNP Trials 1 and 2 and Greater than Placebo (24 Week Safety Pool)

a Injection site reactions cluster includes injection site reaction, pain, bruising and swelling.

b Conjunctivitis cluster includes conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, giant papillary conjunctivitis, eye irritation, and eye inflammation.

The safety profile of DUPIXENT through Week 52 was generally consistent with the safety profile observed at Week 24.Specific Adverse ReactionsConjunctivitis During the 52-week treatment period of concomitant therapy atopic dermatitis trial (Trial 3), conjunctivitis was reported in 16% of the DUPIXENT 300 mg Q2W + TCS group (20 per 100 subject-years) and in 9% of the placebo + TCS group (10 per 100 subject-years). Among asthma subjects, the frequency of conjunctivitis was similar between DUPIXENT and placebo. In the 52-week CRSwNP study (CSNP Trial 2), the frequency of conjunctivitis was 3% in the DUPIXENT subjects and 1% in the placebo

subjects; all of these subjects recovered [see Warnings and Precautions (5.2)]. Eczema Herpeticum and Herpes Zoster The rate of eczema herpeticum was similar in the placebo and DUPIXENT groups in the atopic dermatitis trials. Herpes zoster was reported in <0.1% of the DUPIXENT groups (<1 per 100 subject-years) and in <1% of the placebo group (1 per 100 subject-years) in the 16-week atopic dermatitis monotherapy trials. In the 52-week DUPIXENT + TCS atopic dermatitis trial, herpes zoster was reported in 1% of the DUPIXENT + TCS group (1 per 100 subject-years) and 2% of the placebo + TCS group (2 per 100 subject-years). Among asthma subjects the frequency of herpes zoster was similar between DUPIXENT and placebo. Among CRSwNP subjects there were no reported cases of herpes zoster or eczema herpeticum.Hypersensitivity Reactions Hypersensitivity reactions were reported in <1% of DUPIXENT-treated subjects. These included serum sickness reaction, serum sickness-like reaction, generalized urticaria, rash, erythema nodosum, and anaphylaxis [see Contraindications (4), Warnings and Precautions (5.1), and Adverse Reactions (6.2)]. Eosinophils DUPIXENT-treated subjects had a greater initial increase from baseline in blood eosinophil count compared to subjects treated with placebo. In subjects with atopic dermatitis, the mean and median increases in blood eosinophils from baseline to Week 4 were 100 and 0 cells/mcL respectively. In subjects with asthma, the mean and median increases in blood eosinophils from baseline to Week 4 were 130 and 10 cells/mcL respectively. In subjects with CRSwNP, the mean and median increases in blood eosinophils from baseline to Week 16 were 150 and 50 cells/mcL, respectively. Across all indications, the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was similar in DUPIXENT and placebo groups. Treatment-emergent eosinophilia (≥5,000 cells/mcL) was reported in <2% of DUPIXENT-treated patients and <0.5% in placebo-treated patients. Blood eosinophil counts declined to near baseline levels during study treatment [see Warnings and Precautions (5.3)]. Cardiovascular (CV)In the 1-year placebo controlled trial in subjects with asthma (AS Trial 2), CV thromboembolic events (CV deaths, non-fatal myocardial infarctions [MI], and non-fatal strokes) were reported in 1 (0.2%) of the DUPIXENT 200 mg Q2W group, 4 (0.6%) of the DUPIXENT 300 mg Q2W group, and 2 (0.3%) of the placebo group.In the 1-year placebo controlled trial in subjects with atopic dermatitis (Trial 3), CV thromboembolic events (CV deaths, non-fatal MIs, and non-fatal strokes) were reported in 1 (0.9%) of the DUPIXENT + TCS 300 mg Q2W group, 0 (0.0%) of the DUPIXENT + TCS 300 mg QW group, and 1 (0.3%) of the placebo + TCS group.In the 24-week placebo controlled trial in subjects with CRSwNP (CSNP Trial 1), CV thromboembolic events (CV deaths, non-fatal myocardial infarctions, and non-fatal strokes) were reported in 1 (0.7%) of the DUPIXENT group and 0 (0.0%) of the placebo group. In the 1-year placebo controlled trial in subjects with CRSwNP (CSNP Trial 2), there were no cases of CV thromboembolic events (CV deaths, non-fatal myocardial infarctions, and non-fatal strokes) reported in any treatment arm.6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to dupilumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Approximately 5% of subjects with atopic dermatitis, asthma, or CRSwNP who received DUPIXENT 300 mg Q2W for 52 weeks developed antibodies to dupilumab; ~ 2% exhibited persistent ADA responses, and ~ 2% had neutralizing antibodies. Approximately 9% of subjects with asthma who received DUPIXENT 200 mg Q2W for 52 weeks developed antibodies to dupilumab; ~4% exhibited persistent ADA responses, and ~4% had neutralizing antibodies.Approximately 4% of subjects in the placebo groups in the 52-week studies were positive for antibodies to DUPIXENT; ~2% exhibited persistent ADA responses, and ~1% had neutralizing antibodies.Approximately 16% of adolescent subjects with atopic dermatitis who received DUPIXENT 300 mg or 200 mg Q2W for 16 weeks developed antibodies to dupilumab; ~ 3% exhibited persistent ADA responses, and ~ 5% had neutralizing antibodies.Approximately 4% of adolescent subjects with atopic dermatitis in the placebo group were positive for antibodies to DUPIXENT; ~ 1% exhibited persistent ADA responses, and ~ 1% had neutralizing antibodies.The antibody titers detected in both DUPIXENT and placebo subjects were mostly low. In subjects who received DUPIXENT, development of high titer antibodies to dupilumab was associated with lower serum dupilumab concentrations [see Clinical Pharmacology (12.3) in the full prescribing information]. Two subjects who experienced high titer antibody responses developed serum sickness or serum sickness-like reactions during DUPIXENT therapy [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS 7.1 Live Vaccines Avoid use of live vaccines in patients treated with DUPIXENT.

Adverse Reaction

CSNP Trial 1 and Trial 2

DUPIXENT 300 mg Q2W

N=440 n (%)

Placebo N=282 n (%)

Injection site reactionsa 28 (6%) 12 (4%)

Conjunctivitisb 7 (2%) 2 (1%)

Arthralgia 14 (3%) 5 (2%)

Gastritis 7 (2%) 2 (1%)

Insomnia 6 (1%) 0 (<1%)

Eosinophilia 5 (1%) 1 (<1%)

Toothache 5 (1%) 1 (<1%)

Adverse Reaction

AS Trials 1 and 2

DUPIXENT 200 mg Q2W

N=779 n (%)

DUPIXENT 300 mg Q2W

N=788 n (%)

Placebo

N=792 n (%)

Injection site reactionsa 111 (14%) 144 (18%) 50 (6%)

Oropharyngeal pain 13 (2%) 19 (2%) 7 (1%)

Eosinophiliab 17 (2%) 16 (2%) 2 (<1%)

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Sanofi - 193150Project: Approved for Patients aged 12 and older

Campaign: Sept-Oct 2019

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Manufactured by: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591 U.S. License # 1760; Marketed by sanofi-aventis U.S. LLC, (Bridgewater, NJ 08807) and Regeneron Pharmaceuticals, Inc. (Tarrytown, NY 10591). DUPIXENT® is a registered trademark of Sanofi Biotechnology/© 2019 Regeneron Pharmaceuticals, Inc./sanofi-aventis U.S. LLC. All rights reserved. Issue Date: June 2019 US-DUP-1104(2)

7.2 Non-Live Vaccines Immune responses to vaccination were assessed in a study in which subjects with atopic dermatitis were treated once weekly for 16 weeks with 300 mg of dupilumab (twice the recommended dosing frequency). After 12 weeks of DUPIXENT administration, subjects were vaccinated with a Tdap vaccine (Adacel®) and a meningococcal polysaccharide vaccine (Menomune®). Antibody responses to tetanus toxoid and serogroup C meningococcal polysaccharide were assessed 4 weeks later. Antibody responses to both tetanus vaccine and meningococcal polysaccharide vaccine were similar in dupilumab-treated and placebo-treated subjects. Immune responses to the other active components of the Adacel and Menomune vaccines were not assessed. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DUPIXENT during pregnancy.Please contact 1-877-311-8972 or go to https://mothertobaby.org/ongoing-study/dupixent/ to enroll in or to obtain information about the registry.Risk SummaryAvailable data from case reports and case series with DUPIXENT use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, DUPIXENT may be transmitted from the mother to the developing fetus. There are adverse effects on maternal and fetal outcomes associated with asthma in pregnancy (see Clinical Considerations). In an enhanced pre- and post-natal developmental study, no adverse developmental effects were observed in offspring born to pregnant monkeys after subcutaneous administration of a homologous antibody against interleukin-4-receptor alpha (IL-4Rα) during organogenesis through parturition at doses up to 10-times the maximum recommended human dose (MRHD) (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo-fetal RiskIn women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control. DataAnimal Data In an enhanced pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of homologous antibody against IL-4Rα up to 10 times the MRHD (on a mg/kg basis of 100 mg/kg/week) from the beginning of organogenesis to parturition. No treatment-related adverse effects on embryofetal toxicity or malformations, or on morphological, functional, or immunological development were observed in the infants from birth through 6 months of age. 8.2 Lactation Risk SummaryThere are no data on the presence of dupilumab in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal and limited systemic exposure to dupilumab on the breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DUPIXENT and any potential adverse effects on the breastfed child from DUPIXENT or from the underlying maternal condition.8.4 Pediatric Use Atopic DermatitisThe safety and efficacy of DUPIXENT have been established in pediatric patients 12 years of age and older with moderate-to-severe atopic dermatitis. A total of 251 adolescents ages 12 to 17 years old with moderate-to-severe atopic dermatitis were enrolled in Trial 6. The safety and efficacy were generally consistent between adolescents and adults [see Adverse Reactions (6.1) and Clinical Studies (14.2) in the full prescribing information]. Safety and efficacy in pediatric patients (<12 years of age) with atopic dermatitis have not been established.AsthmaA total of 107 adolescents aged 12 to 17 years with moderate to severe asthma were enrolled in AS Trial 2 and received either 200 mg (N=21) or 300 mg (N=18) DUPIXENT (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) Q2W. Asthma exacerbations and lung function were

assessed in both adolescents and adults. For both the 200 mg and 300 mg Q2W doses, improvements in FEV1 (LS mean change from baseline at Week 12) were observed (0.36 L and 0.27 L, respectively). For the 200 mg Q2W dose, subjects had a reduction in the rate of severe exacerbations that was consistent with adults. Safety and efficacy in pediatric patients (<12 years of age) with asthma have not been established. Dupilumab exposure was higher in adolescent patients than that in adults at the respective dose level which was mainly accounted for by difference in body weight [see Clinical Pharmacology (12.3) in the full prescribing information]. The adverse event profile in adolescents was generally similar to the adults [see Adverse Reactions (6.1)]. CRSwNP CRSwNP does not normally occur in children. Safety and efficacy in pediatric patients (<18 years of age) with CRSwNP have not been established.8.5 Geriatric Use Of the 1472 subjects with atopic dermatitis exposed to DUPIXENT in a dose-ranging study and placebo-controlled trials, 67 subjects were 65 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) in the full prescribing information].Of the 1977 subjects with asthma exposed to DUPIXENT, a total of 240 subjects were 65 years or older. Efficacy and safety in this age group was similar to the overall study population.Of the 440 subjects with CRSwNP exposed to DUPIXENT, a total of 79 subjects were 65 years or older. Efficacy and safety in this age group were similar to the overall study population. 10 OVERDOSE There is no specific treatment for DUPIXENT overdose. In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately. 17 PATIENT COUNSELING INFORMATION Advise the patients and/or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Pregnancy RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DUPIXENT during pregnancy. Encourage participation in the registry [see Use in Specific Populations (8.1)].Administration InstructionsProvide proper training to patients and/or caregivers on proper subcutaneous injection technique, including aseptic technique, and the preparation and administration of DUPIXENT prior to use. Advise patients to follow sharps disposal recommendations [see Instructions for Use].Hypersensitivity Advise patients to discontinue DUPIXENT and to seek immediate medical attention if they experience any symptoms of systemic hypersensitivity reactions [see Warnings and Precautions (5.1)]. Conjunctivitis and Keratitis Advise patients to consult their healthcare provider if new onset or worsening eye symptoms develop [see Warnings and Precautions (5.2)]. Eosinophilic ConditionsAdvise patients to notify their healthcare provider if they present with clinical features of eosinophilic pneumonia or vasculitis consistent with eosinophilic granulomatosis with polyangiitis [see Warnings and Precautions (5.3)].Not for Acute Asthma Symptoms or Deteriorating DiseaseInform patients that DUPIXENT does not treat acute asthma symptoms or acute exacerbations. Inform patients to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with DUPIXENT [see Warnings and Precautions (5.4)].Reduction in Corticosteroid DosageInform patients to not discontinue systemic or inhaled corticosteroids except under the direct supervision of a physician. Inform patients that reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy [see Warnings and Precautions (5.5)].Patients with Comorbid AsthmaAdvise patients with atopic dermatitis or CRSwNP who have comorbid asthma not to adjust or stop their asthma treatment without talking to their physicians [see Warnings and Precautions (5.6)].

HH1068880_M07_Sept19_Brief_Summary_A_Size.indd 3 7/22/19 5:19 PM

References: 1. DUPIXENT Prescribing Information. 2. Simpson EL, Bieber T, Guttman-Yassky E, et al; SOLO 1 and SOLO 2 Investigators. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348. 3. Data on file, Regeneron Pharmaceuticals, Inc. 4. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017;389(10086):2287-2303.

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JDD Podcasts present the latest journal content related to advances in drugs, devices and treatment methods in dermatology, in a new convenient audio format. From article abstracts to interviews, JDD Podcasts provide a fresh perspective of the peer reviewed content you have come to rely on from JDD (Journal of Drugs in Dermatology).

Hosted by Adam Friedman, MD and released monthly, each episode will feature an interview with, and practical pearls from, the principal investigator of a high-profile JDD manuscript in a convenient audio format. Each podcast will place the selected article into a clinically useful perspective that is easy to listen to in the office or on the go.

Listen Now at JDDonline.com/PODCAST

NEW EPISODE - CME AVAILABLEPicking up on Prescribing Patterns for Psoriasis: A Real Deal Assessment Drs. Joel Gelfand, Megan Noe and Adam Friedman

We (and our patients) are fortunate to live during a time when we have many safe and effective options to treat a chronic inflammatory skin disease such as Psoriasis. We are reminded of this, nay inundated, with warm and fuzzy headlines in the lay dermatology press that humblebrag said efficacy. However, how does this translate to the real world, when the perfect, neat lines of clinical trials are blurred by practical issues such as access, patient and practitioner perception, and long term use and efficacy? In a JDD Podcast first, we had not one but two investigators share their work and first steps to evaluate just that. Dr. Megan Noe, Instructor of Dermatology at the Brigham and Women’s Hospital and Harvard Medical School, and Dr. Joel Gelfand, Professor of Dermatology and of Epidemiology, Vice Chair for Clinical Research (Dermatology), and Director of the Psoriasis and Phototherapy Treatment Center at the University of Pennsylvania join us to discuss their study Prescribing Patterns Associated With Biologic Therapies for Psoriasis from a United States Medical Records Database from the August 2019 edition of the JDD. Hear how they formulated this big data dive. Learn which biologics did not get an encore with a refill. Discover which scenarios most often lead our colleagues to use combination therapy and with what. And most importantly, digest Dr. Noe and Gelfands’ approach to picking the right biologic for the right patient. All that and more – I (nail) pity the fool who doesn’t check it out.


https://jddonline.com/podcast



Copyright © 2018 GUEST EDITORIAL Journal of Drugs in Dermatology

Electromagnetic field devices, specifically high intensity fo-cused electro-magnetic field (HIFEM), comprise the latest class of technologies being developed for dermatologic ap-plications. The FDA clearance of these technologies includes such intended uses as “the stimulation of neuromuscular tissue for bulk muscle excita-tion in the legs or arms” and Macrene Alexiades MD PhD

High Intensity Focused Electromagnetic Field (HIFEM) Devices in Dermatology

“improvement of abdominal tone, strengthening of the abdom-inal muscles, development of firmer abdomen; strengthening, toning and firming of buttocks, thighs and calves; and improvement of muscle tone and firmness, for strengthening muscles in arms.”1,2

Electromagnetic fields are composed of both electric and magnetic fields. Electromagnetic phenomena are defined by the electromagnetic force which in turn includes electric-ity and magnetism. Electric fields are the result of electric charges, measured in volts per meter (V/m). Magnetic fields arise from the movement of electric charges as in a current and measured in tesla (T) or the gauss (G; 10.000 G= 1 T). While electric fields are shielded by wood and metal, mag-netic fields easily pass through most common materials. There are four basic principles for understanding electro-magnetic theory. First, electric charges attract or repel each other with a force that is inversely proportional to the dis-tance between them. Second, magnetic poles attract or repel each other like electric charges and exist in pairs. Third, and importantly, an electric current in a wire generates a circumferential magnetic field surrounding the wire. The di-rection of the magnetic field is perpendicular to the wire and in the direction of your fingers of your right hand curled around the wire with your thumb pointing in the direction of the current (Figure 1).

Fourth, and conversely, an electric current is induced in a loop of wire when moved towards or away from a magnetic field or a magnet is moved towards or away from it. In the current instance of HIFEM technology, a rapidly varying magnetic field induces an electric current in the target tissue (Figure 2).

In the use of HIFEM technologies for muscular sculpting, the rapidly moving magnet in the handpiece generates an electric current in tissue that depolarizes motor nerves re-sulting in muscular contractions. Magnetic field intensity delivered are up to 2.5 Tesla. Other applications are being in-vestigated, including fat apoptosis and pelvic floor stimulation. An important safety issue that needs to be addressed is the dosage of electromagnetic field being generated per treatment. The World Health Organization has estab-lished potential long-term effects of childhood leukemia from average magnetic field exposures in the 0.3 T range.3

As our laser, light, and energy-based device field evolves with new areas of research and treatments using novel applications, we should continue to emphasize the importance of rigorous research and long-term clinical trials.

Department of Dermatology, Yale University School of Medicine Dermatology and Laser Surgery Center of New York, New York, NY

Macrene Alexiades MD PhD

1. https://www.accessdata.fda.gov/cdrh_docs/pdf16/K160992.pdf

2. https://www.accessdata.fda.gov/cdrh_docs/pdf19/K190456.pdf

3. https://www.who.int/peh-emf/publications/facts/fs322/en/

FIGURE 1. Magnetic field generated surrounding a wire conveying an electric current.

FIGURE 2. A rapidly moving magnet induces an electric current.

References



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SPECIAL TOPIC

Re-pigmentation of Hypopigmentation: Fractional Lasers vs Laser-Assisted Delivery of Bimatoprost

vs Epidermal Melanocyte Harvesting System Jill S. Waibel MD,a Ashley Rudnick BS,a Kristopher L. Arheart EdD,b Nicole Nagrani MD,c

Adrianna Gonzalez MD,c Chloe Gianatasio MSa

ªMiami Dermatology and Laser Institute, Miami, FLBDepartment of Public Health Science, University of Miami Miller School of Medicine, Miami, FL

cDepartment of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL

Background: Hypopigmentation is a common cutaneous manifestation that frequently poses a therapeutic challenge for dermatolo-gists. Current treatments have varying efficacies and rarely provide patients with long-term results. However, new treatments are emerging, and head-to-head studies comparing these treatments are warranted.Methods & Materials: In this prospective, Institutional Review Board (IRB)-approved, double-blinded study, 40 subjects with moderate to severe hypopigmentation were randomized into 1 of 4 treatment arms; non-ablative fractional laser, ablative fractional laser, ablative fractional laser with laser-assisted delivered bimatoprost, and an epidermal harvesting system. Results: All patients in this study showed improvement regardless of the treatment modality. The average improvement score was calculated on a 0 to 4 scale, and Group 3 (fractional ablative laser and bimatoprost) was found to have a significantly higher average im-provement than all other treatments, with 76% of the patients exhibiting at least a grade 3 (over 50%) improvement over the treatment course. Group 1 (non-ablative fractional) also had a significantly higher average score compared with group 2 (fractional ablative laser). Conclusion: New and emerging therapies have shown promise in helping re-pigmentation of cutaneous hypopigmentation. In this head-to-head trial, it was shown that laser-assisted delivery of bimatoprost had a greater statistically significant improvement compared with 3 possible treatment modalities for stimulation of pigment in medical and cosmetic hypopigmentation.

J Drugs Dermatol. 2019;18(11):1090-1096.

ABSTRACT

INTRODUCTION

Hypopigmentation is a common cutaneous manifes-tation that frequently poses a therapeutic challenge for dermatologists. Hypopigmentation can generally

be seen after surgery, laser procedures, trauma, or as a conse-quence of various inflammatory conditions. The pathogenesis of acquired hypopigmentation has been linked to inflamma-tion, whereby various inflammatory factors cause suppression of pigmentation-related signaling, leading to decreased mela-nin production.1

Hypopigmentation can be a significant issue in patients with skin of color. In prior studies, it has been shown that many hy-popigmented skin conditions may have inactive melanocytes that may be stimulated by various modalities to produce pig-ment.2 Presumably, the target is stimulation of the human epidermal melanocyte. Melanocytes are melanin-producing neural crest-derived cells located in the stratum basale. Once these cells are stimulated, they synthesize melanin in special

organelles called melanosomes, which are transported to kera-tinocytes to induce pigmentation. The depth of the melanocyte depends on the patient skin site, but ranges from 20 microm-eters to 141 micrometers (Table 1).3

Current treatment modalities for hypopigmentation include split thickness skin grafting, excisional surgery, exogenous pigment procedures (such as tattooing), dermabrasion, chemical peels, and laser therapy. However, current treatments have varying efficacies and rarely provide patients with long term results. In the past decade, it has been shown that laser therapy may demonstrate improvement in hypopigmentation of acne and surgical scars. Fractional lasers were among the many devices studied to help improve hypopigmentation in acne and surgi-cal scars. The mechanism of action is hypothesized to be the repopulation of melanocytes in the hypopigmented areas from surrounding hair follicle stem cells and basal melanocytes.4-7



1091


J.S. Waibel, A. Rudnick, K.L. Arheart, et al

transfer of autologous epidermis that includes melanocytes to recipient site. This device is Food and Drug Administration (FDA)-approved for wound ulcers and was first used by Ander-son et al in Vietnam for children with radiation burns and vitiligo for re-pigmentation.17 This emerging technology is currently be-ing used to treat chronic ulcers. To our knowledge, there have been some proofs of concept work done, but no official derma-tology studies with this novel epidermal transplant device.

In this study, the efficacies of non-ablative and ablative fraction-al lasers for the treatment of hypopigmentation are evaluated, along with the combination of fractional ablative laser with bimatoprost, a prostaglandin agonist known to stimulate pig-mentation. The epidermal harvesting system in combination with fractional ablative laser is also assessed and all 4 treat-ment modalities are compared. Throughout the clinical trial there are a variety of conditions treated in each group (Table 2).

METHODSSubject PopulationThis prospective, randomized head-to-head comparison studies new and innovative procedures for hypopigmentation, includ-ing fractional laser monotherapy (non-ablative and ablative), laser-assisted delivery of bimatoprost, and a novel epidermal melanocyte automated transplant system. The protocol was approved by an IRB, and written informed consent from each patient was obtained. The inclusion criteria for selection of the patient population consisted of healthy individuals ages 18 to 80 years with all Fitzpatrick skin types and moderate to severe hypopigmentation on any body location. Exclusion criteria in-cluded pregnancy, breast-feeding, oral retinoids 6 months prior to treatment, active infection, or lesions suspicious for malig-nancy.

Treatment ParadigmAfter informed consent was obtained, a visual skin examination and a brief interview on relevant medical history was performed prior to taking photographs of the treatment areas. Patients were then randomly allocated by the clinical coordinator into 1 of 4 groups: Group A – 1550 nm wavelength non-ablative fractional erbium-doped fiber (n=10); Group B – 10,600 nm wavelength fractional ablative laser (n=10); Group C – 10,600 nm wavelength fractional ablative laser followed by topical applica-tion with bimatoprost immediately after laser treatment and for 14 days after (n=10); and Group D – epidermal harvesting sys-tem with fractional ablative laser to recipient site (n=10) (Figure 1). Laser parameters were kept to a penetration depth of 150 to 300 micrometers. Patients received 3 treatment sessions at 4- to 6-week intervals.

In the technique for laser-assisted delivery of the bimatoprost arm, immediately after fractional ablative laser therapy, topical bimatoprost 0.03% topical solution was applied over treatment

In 2010, ablative fractional laser (AFXL) was introduced as a new drug delivery-enhancement technique.8-13 The technique is based on fractional photothermolysis, which uses focused laser beams to create an array of very small thermal injuries in the skin.14 Available AFXL systems include the carbon dioxide (CO2, λ = 10,600 nm) and erbium-doped yttrium aluminum garnet (Er:YAG, λ = 2,940 nm) lasers. These far-infrared lasers vapor-ize tissue efficiently, creating an array of very small channels into the skin. These channels cross the skin barrier, providing direct access to viable epidermis and dermis until the channels close by local wound repair, typically within 48 hours, with-out scarring. Geometrically, the diameter, depth, and number of channels per unit skin area can be independently adjusted to regulate uptake and penetration of topical drugs to specific depths based on target.15

Bimatoprost 0.03% topical solution is a drug that was initially brought to market to treat glaucoma. This drug was then noted to have a side effect which caused periocular hyperpigmenta-tion due to increased melanogenesis. There appears to be a dose dependent relationship of bimatoprost and the mecha-nism for increased melanogenesis, and increased transfer of melanosomes with absence of melanocyte atypia. We hy-pothesize that bimatoprost may induce melanogenesis from dormant melanocytes in hypopigmented conditions.16 In this study, the concept of laser-assisted delivery of bimatoprost was used to get the drug past the stratum corneum barrier and into the basal layer of the epidermis where melanocytes reside to possibly stimulate melanogenesis.

The last modality studied is a novel epidermal harvesting technology. This device performs scar-less and painless epider-mal autologous grafting from the donor site. This enables the

TABLE 1.Depth of the Melanocyte



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TABLE 2.Conditions Treated With the Four Treatment Modalities



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The data are ordinal with a range of 1 to 4. All time 1 scores were 1; therefore, only time 2 scores were analyzed with a Friedman nonparametric test. First, the scores were ranked within each of the 3 observers. Then a general linear model was used with the ranks as the dependent variable; treatment and observer were the independent variables. Model means and standard errors were reported with P-values for planned comparisons among the 4 treatment groups. The 0.05 alpha level was used to deter-mine statistical significance. SAS 9.4 (SAS Institute, Inc.; Cary, NC) was used for all analyses.

RESULTSForty patients with hypopigmentation of various body locations were recruited for participation in this research study. Patients were assigned to 1 of the different treatment groups. All patients tolerated the intervention well with no adverse events. Re-pig-mentation was assessed by 3 blinded dermatologists who were randomly presented with 80 photographs taken at baseline and 6 months post-treatment.

All patients in this current study showed improvement in hy-popigmentation regardless of the treatment modality (Figure 2 and Table 7). The average improvement score was based on a 0 to 4 scale; and Group 3 (10,600 nm wavelength fractional ablative laser & bimatoprost) was found to have a significantly higher rank than any of the other treatments, with 76% of the patients exhibiting a grade 3 or higher (over 50%) improvement in pigmentation over the treatment course (Table 5). In Table 7, Group 3 with a mean rank score of 29.9 and standard error of 1.7 was significantly higher than Group 1 (21.0 ± 1.8; P=0.001), Group 4 (18.3 ± 1.8; P<0.001), and Group 2 (13.3 ± 1.8; P<0.001). Group 1 was also significantly higher than Group 2 (21.0 ± 1.8 vs 13.3 ± 1.8; P=0.006). Group 1 (1550 nm wavelength non-ablative fractional erbium-doped fiber) also had a significantly higher average score (Table 3) compared with group 2 (10,600 nm wavelength fractional ablative laser) (Table 4). Unfortunately, with all the treatment modalities, many had a decrease of 50% for re-pigmentation (Tables 3-6; Figures 3-8).

areas and gently massaged for approximately 30 seconds to 1 minute. Patients were instructed to apply the medication twice a day for 14 days following the laser treatment.

The epidermal harvesting system technology creates micro suc-tion blisters known as micro-domes by using a combination of vacuum and warmth. This tool allows for epidermal skin grafting in an outpatient setting. The procedure starts with washing of the donor site, which is typically the inner thigh or buttocks due to melanocyte rich areas. Then, the device is applied on the se-lected area, which raises autologous epidermal micro-blisters in the donor site for 30 minutes. After the initial 30 minutes, there is an assessment to verify that there is sufficient micro-dome formation. Next, preparation for the recipient site is completed and fractional ablative carbon dioxide laser at superficial depth is conducted. Next, the graft acquisition occurs and the ready-to-apply on Tegaderm array of autologous epidermal micro-grafts is transferred to the recipient hypopigmented sites. The donor site is covered for 24 hours post procedure. The recipient site is covered with hypo-fix for 3 to 5 days post procedure.

The primary outcome objective was photographic evalua-tion showing clinical improvements in scar appearance at 6 months post treatment, as evaluated by 3 blinded independent investigators using the Visual Analogue Scale (VAS). The pho-tographs were ordered as “before” and “after,” and randomly presented to the investigators for comparison (grade 1: <25% improvement, grade 2: 26-50% improvement, grade 3: 51-75% improvement, grade 4: > 75% improvement). For each subject, scores were averaged between the 3 independent investigators to provide a final score. The intra-class correlation coefficient (a measure of inter-rater reliability) was statistically interpreted.

Clinical AssessmentsTreatment responses were assessed by comparing pre- and post-treatment clinical photographs. Independent physician evaluators assessed each photograph at 6 months after the last treatment using a quartile grading scale (grade 1, <25% improvement, grade 2, 26-50% improvement, grade 3, 51-75% improvement, grade 4, >75% improvement).

Statistical AnalysisOrdinal logistic regression was used for comparison between baseline and follow-up evaluations.

FIGURE 1. Patients were then randomly allocated by the clinical coordinator into 1 of 4 groups.

TABLE 3.Average Improvement in Pigmentation Score With Non-Ablative Fractional Laser

TABLE 4.Average Improvement in Pigmentation Score With Fractional Ablative Laser



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TABLE 5.Improvement in Pigmentation Score With Ablative Fractional Laser + Bimatoprost

FIGURE 3. (A) Before photo of patient with hypopigmented traumatic scar due to laser complication from hair removal. (B) After photo of the patient in Group 1, 3 treatments of fractional non-ablative laser only in 4 to 6-week intervals.

FIGURE 2. All patients in this current study showed improvement in hypopigmentation regardless of the treatment modality.

Average Improvement Score

TABLE 6.Average Improvement in Pigmentation Score With Epidermal Harvesting Graft System

TABLE 7.

Comparison of Group Rank Scores

Rank Within OBS Comparison P-Values

FIGURE 4. (A) Before photo of patient with idiopathic guttate hypomelanosis. (B) After photo of the patient in Group 2, 3 treatments of fractional ablative laser only in 4- to 6-week intervals.

FIGURE 5. (A) Before photo of patient with hypopigmented traumatic scar due to face lift approximately 8 years ago. (B) After photo of the patient in Group 1, 3 treatments of fractional non-ablative laser only in 4- to 6-week intervals.

FIGURE 6. (A) Before photo of patient with hypopigmented, atrophic burn and traumatic scars due to car accident fire in 2011. (B) After photo of the patient in Group 3, 3 treatments of fractional ablative laser with laser assisted drug delivery of bimatoprost topical solution twice a day for 14 days in 4- to 6-week intervals.

It is still questionable if additional treatment, additional pigmen-tation, or additional combination therapies address different mechanisms of action for re-pigmentation. In this clinical trial, we hypothesized that skin of color responds to treatment more robustly because the Fitzpatrick skin types in Group 3 are higher on average (Table 2).

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DISCUSSIONThe mechanism by which fractional lasers are speculated to work in treating hypopigmentation is through the repopulation of melanocytes from surrounding hair follicles and basal me-lanocytes, causing an overall increase in pigmentation.6 This is accomplished through the production of microscopic thermal zones of injury, which induce a molecular cascade that stimulate rapid healing and collagen remodeling.14 The fractional lasers induce healing via hundreds of unique biological growth fac-tors, interleukins, adhesion proteins, and differentiated cells in the dermis, which are postulated to help “turn back on” the me-lanocyte to produce melanosomes.

The ablative fractional resurfacing laser differs from the non-ablative fractional laser due to its ability to disrupt the barrier function of the cornified layer of skin by ablating columns ex-tending from the epidermal layers to the deeper dermal layers at a greater depth, allowing for increased stimulation of wound-healing and prolonged effects.7,15 However, because the microscopic treatment zones include damage to the epidermis and possibly some focal loss or heating of the melanocyte, the ablative laser causes more aggressive damage with increased recovery time.

Interesting to note in this small study is that the non-ablative fractional lasers had better re-pigmentation than the abla-tive fractional laser. However, the laser-assisted delivery with stimulatory bimatoprost scored the best. This function of abla-

tive lasers has been used for delivery-enhancement purposes, whereby the vertical channels of ablation created by photo-thermolysis serve as a conduit for deeper penetration to the underlying skin and greater bioavailability of topical medi-cations.14,18,19 Laser assisted delivery has been studied using various medications with favorable outcomes; and it appears that the combination of the 2 modalities have synergistic effects for many indications.8-13

Although bimatoprost is a synthetic prostaglandin originally indicated for the treatment of glaucoma, it has been shown to have the side effect of periocular hyperpigmentation. The mechanism by which this medication causes increased me-lanogenesis is thought to be due to the induction of dormant melanocytes and through the transfer of melanosomes to basal keratinocytes without melanocyte proliferation, inflammation, or melanocyte atypia.20 It appears that prostaglandin analogs cause hyperpigmentation in a dose-dependent manner, which becomes more evident with increased contact to the skin.

Based on this principle, studies have shown promising results in the treatment of hypopigmented scars using prostaglandin analogs when combined with fractional lasers. This synergis-tic effect was first investigated by Massaki et al, who showed that combining the non-ablative fractionated laser systems with topical bimatoprost, and tretinoin or pimecrolimus, had signif-icant improvement (>50%) in more than 85% (12/14) of those in the treatment group. This concept was further explored by Siadar et al using the ablative fractional laser, with 11 out of 14 patients demonstrating over 50% improvement in hypopig-mentation when treated with the 10,600-nm fractional CO2 laser plus latanoprost 0.005%, an outcome significantly different when compared with placebo over a 6-treatment time course. However, in this study researchers instructed patients to apply topical prostaglandin analog twice a day for 6 months, whereas patients in our current study only applied bimatoprost 0.03% twice a day for 14 days following each laser treatment.

The novel device currently used to perform epidermal grafting procedures is a donor site sparing harvesting system, which enables the transfer of autologous epidermis, including live melanocytes, by creating microsuction blisters known as mi-crodomes using a combination of vacuum and heat. In this procedure, only the epidermal portion of the donor area is graft-ed, and therefore the graft acquires the characteristics of the recipient site. This has the potential to allow for improved cos-metic outcomes and color matching, without significant donor site morbidities such as scarring.20 This epidermal harvesting system technology has proven to be effective in the treatment of vitiligo and wounds, yet clinical data are lacking.21 Additional benefits of this grafting procedure are that it can be performed in the outpatient setting, it requires limited resources and clini-cal training, and it is more cost-effective when compared with skin grafting.22-24 In this study, the ablative fractional laser was

FIGURE 7. (A) Before photo of patient with hypopigmented, atrophic burn and traumatic scars due to car accident fire in 2011. (B) After photo of the patient in Group 3, 3 treatments of fractional ablative laser with laser assisted drug delivery of bimatoprost topical solution twice a day for 14 days in 4- to 6-week intervals.

FIGURE 8. (A) Before photo of the patient that has a hypopigmented, hypertrophic burn and traumatic scar due to hot water spill in September 2014. (B) After photo of the patient in Group 4, 3 treatments of Cellutome epidermal harvesting system in 4- to 6-week intervals.

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used to prepare the recipient site. This may not be the optimal approach for recipient site preparation, and other methods that may work better include medical sandpaper, microderm-abrasion, or liquid nitrogen to create bullae 24 hours prior to optimize engraftment.

CONCLUSIONAlthough lasers have proven to be effective in the treatment of hypopigmentation, comparative studies to determine the most safe and effective method for the treatment of hypopigment-ed scars are lacking. The results of this study demonstrate that all of the selected laser interventions can potentially improve hypopigmentation, but combining fractionated laser systems with topical bitmatoprost appeared to be the most efficacious treatment to accomplish re-pigmentation. In this small compari-son, most patients (52%) exhibited over 75% improvement in hypopigmentation within just 3 sessions and without adverse ef-fects. Our data are consistent with previous studies showing the superiority of combination fractional laser with a prostaglandin analog when compared with fractional laser alone. However, this study further compared hypopigmentation improvement outcomes amongst ablative and non-ablative fractional lasers, and also to the novel epidermal harvesting system technique for a more comprehensive evaluation.

In the past 5 years, new technologies are emerging which may give new hope for treatment of hypopigmentation. Among these new technologies, fractional lasers have been demonstrated in early case reports to produce improvement in hypopigmenta-tion. Laser-assisted drug delivery using fractional laser is an evolving modality that may allow for greater precise depth of penetration by existing topical medications to deliver to tar-get cells such as melanocytes. In our study, using bimatoprost solution immediately post ablative fractional laser to increase melanogenesis as well as melanosome transfer to basal kerati-nocytes increased pigmentation over laser alone.

To our knowledge, this is the first clinical trial performed to com-pare the efficacy of fractional laser(s), ablative and non-ablative, vs laser-assisted delivery of bimatoprost vs epidermal melano-cyte transplantation for the re-pigmentation of hypopigmented areas. The limitations of this study include the lack of objective evaluator assessments for the results and small sample sizes.

DISCLOSURESThis research was funded by the ASDS Cutting Edge Research Grant. The fractional ablative laser used in the study was pro-vided to Dr. Jill Waibel by Lumenis with whom she has done another clinical trial. All other authors have nothing to disclose.

REFERENCES1. Wang CQF, Akalu YT, Suarez-Farinas M, et al. IL-17 and TNF synergistically

modulate cytokine expression while suppressing melanogenesis: potential relevance to psoriasis. J Invest Dermatol. 2013;133(12):2741-2752.

2. Hachiya A, Kobayashi T, Takema Y, Imokawa G. Biochemical characterization of endothelin-converting enzyme-1alpha in cultured skin-derived cells and its postulated role in the stimulation of melanogenesis in human epidermis. J Biol Chem. 2002;15;277(7):5395-5403.

3. Sasaki G. Micro-needling depth penetration, presence of pigment particles, and fluorescein-stained platelets: clinical usage for aesthetic concerns. Aes-thet Surg J. 2016;1-13. DOI: 10.1093/asj/sjw120.

4. Glaich AS, Rahman Z, Goldberg LH, Friedman PM. Fractional resurfacing for the treatment of hypopigmented scars: a pilot study. Dermatol Surg. 2007;33(3):289-294; discussion 293-284.

5. Tierney E, Mahmoud BH, Srivastava D, Ozog D, Kouba DJ. Treatment of sur-gical scars with nonablative fractional laser versus pulsed dye laser: a ran-domized controlled trial. Dermatol Surg. 2009;35(8):1172-1180.

6. Tierney EP, Hanke CW. Review of the literature: Treatment of dyspigmenta-tion with fractionated resurfacing. Dermatol Surg. 2010;36(10):1499-1508.

7. Waibel J, Beer K. Fractional laser resurfacing for thermal burns. J Drugs Der-matol. 2008;7(1):59-61.

8. Waibel JS, Rudnick A, Shagalov DR, Nicolazzo DM. Update of ablative fractional lasers to enhance cutaneous topical drug delivery. Adv Ther. 2017;34(8):1840-1849.

9. Waibel JS, Rudnick A. Laser-assisted delivery to treat facial scars. Facial Plast Surg Clin North Am. 2017;25(1):105-117.

10. Waibel JS, Rudnick A, Noursari C, Bhanusali DG. Fractional ablative laser followed by transdermal acoustic pressure wave device to enhance the drug delivery of aminolevulinic acid: In vivo fluorescence microscopy study. J Drugs Dermatol. 2016;15(1):14-21.

11. Waibel JS, Mi QS, Ozog D, Qu L, Zhou L, Rudnick A, Al-Niaimi F, Woodward J, Campos V, Mordon S. Laser-assisted delivery of vitamin C, vitamin E, and ferulic acid formula serum decreases fractional laser postoperative recovery by increased beta fibroblast growth factor expression. Lasers Surg Med. 2016;48(3):238-244.

12. Sklar LR, Burnett CT, Waibel JS, Moy RL, Ozog DM. Laser assisted drug deliv-ery: a review of evolving technology. Lasers Surg Med. 2014;46(4):249-262.

13. Waibel JS, Wulkan AJ, Shumaker PR. Treatment of hypertrophic scars us-ing laser and laser-assisted corticosteroid delivery. Lasers Surg Med. 2013;45(3):135-140.

14. Manstein D, Herron GS, Sink RK, Tanner H, Anderson RR. Fractional photo-thermolysis: a new concept for cutaneous remodeling using microscopic patterns of thermal injury. Lasers Surg Med. 2004;34(5):426-438.

15. Hantash BM, Bedi VP, Kapadia B, et al. In vivo histological evaluation of a nov-el ablative fractional resurfacing device. Lasers Surg Med. 2007;39(2):96-107.

16. Massaki AB, Fabi SG, Fitzpatrick R. Repigmentation of hypopigmented scars using an erbium-doped 1,550-nm fractionated laser and topical bimatoprost. Dermatol Surg. 2012;38(7 Pt 1):995-1001.

17. Tam J, Wang Y, Farinelli WA, Jimenez-Lozano J, Franco W, Sakamoto FH, Cheung EJ, Purschke M, Doukas AG, Anderson RR. Fractional skin harvest-ing: autologous skin grafting without donor-site morbidity. Plast Reconstr Surg Glob Open. 2013;1(6):e47.

18. Kapur R, Osmanovic S, Toyran S, Edward DP. Bimatoprost-induced peri-ocular skin hyperpigmentation: histopathological study. Arch Ophthalmol. 2005;123(11):1541-1546.

19. Centofanti M, Oddone F, Chimenti S, Tanga L, Citarella L, Manni G. Preven-tion of dermatologic side effects of bimatoprost 0.03% topical therapy. Am J Ophthalmol. 2006;142(6):1059-1060.

20. Massaki AB, Fabi SG, Fitzpatrick R. Repigmentation of hypopigmented scars using an erbium-doped 1,550-nm fractionated laser and topical bimatoprost. Dermatol Surg. 2012;38(7 Pt 1):995-1001.

21. Osborne SN, Schmidt MA, Harper JR. An automated and minimally inva-sive tool for generating autologous viable epidermal micrografts. Adv Skin Wound Care. 2016;29(2):57-64.

22. Yamaguchi Y, Itami S, Tarutani M, Hosokawa K, Miura H, Yoshikawa K. Regulation of keratin 9 in nonpalmoplantar keratinocytes by palmoplantar fibroblasts through epithelial-mesenchymal interactions. J Invest Dermatol. 1999;112(4):483-488.

23. Smith OJ, Edmondson SJ, Bystrzonowski N, et al. The CelluTome epider-mal graft-harvesting system: a patient-reported outcome measure and cost evaluation study. Int Wound J. 2017;14(3):555-560.

24. Serena T, Francius A, Taylor C, MacDonald J. Use of a novel epidermal harvesting system in resource-poor countries. Adv Skin Wound Care. 2015;28(3):107-112.


Jill S. Waibel MD E-mail:................……............... [email protected]



Before After 2 Txs

Photos courtesy of Vic Ross, M.D.

© 2019, Cutera, Inc. All rights reserved. Results may vary. AP002998 rA


https://cutera.com/excelVplus




SPECIAL TOPIC

Simultaneous Changes in Abdominal Adipose and Muscle Tissues Following Treatments by High-Intensity Focused

Electromagnetic (HIFEM) Technology-Based Device: Computed Tomography Evaluation

David E. Kent MD,a Carolyn I. Jacob MDb

aSkin Care Physicians of Georgia, Macon, GAbChicago Cosmetic Surgery and Dermatology, Chicago IL

ABSTRACT

Objective: This study investigates the effects of high-intensity focused electromagnetic technology for induction of changes in abdomi-nal muscles and abdominal subcutaneous fat.Methods: 22 male and female subjects (aged 34 to 64, mean BMI, 23.5kg/m2) underwent 8 treatments of the abdomen (2 per week) with a high-intensity focused electromagnetic field device. Subjects were scanned by computed tomography (CT) at baseline and 1 month after the eighth treatment. Sub-umbilical and epi-umbilical slices were used to measure the thickness of subcutaneous fat and abdominal muscles and the abdominal separation. In addition, standardized photographs, weight, and circumference measurements were collected.Results: While comparing baseline to follow-up measurements, CT data showed on average 17.5% (-3.1±1.9mm) reduction in subcu-taneous fat and simultaneous 14.8% (+1.5±0.8mm) thickening of the rectus abdominis muscle. Subjects lost on average 3.9±3.1cm in the waist circumference. Most of the waist reduction effect was achieved after the fourth treatment. The width of abdominal separation decreased by 9.5% (-2.0±1.7mm). All results were highly significant (P<0.01) while weight change was insignificant (P<0.05). Digital photographs showed aesthetic improvement in most subjects. The treatments were painless and without adverse events.Conclusion: Results suggest that the investigated device is effective for abdominal body sculpting. This technology produced rectus muscle hypertrophy and a reduction in subcutaneous abdominal fat. Data suggests 4 treatments as the ideal protocol delivering 86% of the observed improvement.

J Drugs Dermatol. 2019;18(11):1098-1102.

INTRODUCTION

Long-term intensive resistance training programs are known to improve isometric strength1,2 and result in muscle hypertrophy,3,4 with accepted hypotheses that

the hypertrophic effects are primarily caused by induced mus-cular micro injury.5,6 Yet studies demonstrate that approximately 50% of people attempting to follow some kind of exercise pro-gram drop out due to lack of motivation after several months.7,8 Magnetic stimulation was investigated as an alternative to re-sistance training and results showed improvement in muscle strength.9,10

Recent studies11–14 reported that intense muscle contractions induced by application of high-intensity focused electromag-netic (HIFEM) technology increased anterior abdominal muscle mass, reduced subcutaneous fat thickness, and reduced the distance between the rectus abdominis muscles. The net result was a reduction in abdominal waist circumference and an im-provement in the overall appearance of the abdomen. HIFEM technology is based on a rapidly changing magnetic field gen-

erated with a wire coil that, as described by the Faraday’s law of electromagnetic induction, induces a secondary electric current in the underlying tissue.15 The current triggers action potentials in motor neurons which consequently lead to muscle contrac-tions in the area of application.15

Initial HIFEM studies that reported changes in both muscle and fat tissues applied four-treatments. It has been proposed that a higher number of induced muscle contractions will result in more muscle micro injury with resultant increased muscle hypertrophy and fat reduction. However, studies that have in-vestigated this hypothesis are lacking.

This study investigated an extended treatment protocol of a novel device (EMSCULPT, BTL Industries Inc., Boston, MA) uti-lizing a high-intensity focused electromagnetic (HIFEM) field. The goal of this study is to evaluate the safety and effects of adipose and muscle tissues in the abdomen using computed tomography (CT) and an extended treatment protocol.



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D.E. Kent, C.I. Jacob

rectus abdominis muscle, and the width of abdominal muscle separation. Measurements were taken at both epi-umbilical and sub-umbilical slices, and their average was recorded.

Waist circumference was measured at baseline and after each treatment by anthropometric tape. The measurements were performed at the upper edge of the umbilicus which served as a standardized point throughout the measurements. Further, standardized photographs and weight measures were taken throughout the study to monitor the subjects’ progress. All data were statistically tested for significance using two-sample paired t-test with the significance level α set to 5%.

RESULTSAll 22 subjects completed the full set of treatments and un-derwent CT imaging at baseline and 1 month after the last treatment. The weight of all subjects was maintained within 5 lbs of the baseline with an average weight change of 1.0 lb (P>0.05). Fat thickness and abdominal separation were reduced, while muscle thickness increased significantly at the 1-month mea-surements. Waist circumference was gradually decreasing over the course of the treatments. The result summary can be seen in Table 1.

Evaluation of the CT scans showed a statistically significant in-crease (P<0.001) of rectus abdominis muscle thickness by an average of 14.8% (1.5±0.8mm). All subjects demonstrated an increase in muscle thickness except subject ID15 who did not show any muscle thickening despite a 14.6% abdominal fat reduction. In 15 subjects the measured muscle thickening ex-ceeded 10%.

Analysis of the subcutaneous adipose tissue revealed a notice-able decrease (P<0.001) in the average fat thickness by 17.5% (-3.1±1.9mm). In 18 out of the 22 subjects, the measured reduc-tion in subcutaneous fat exceeded 10%, and 12 out of the 22 subjects showed fat reduction higher than 16%. Subject ID10 did not show any fat reduction while her abdominal muscle thick-ened by 8%. Subject ID8 had an extremely thin fat layer and it

MATERIALS AND METHODSStudy DesignEligible candidates for this study were men or women aged 21-65 years with no weight changes exceeding 5 lbs in the preceding month. For the duration of the study, subjects were instructed to avoid major diet and lifestyle changes. Exclusion criteria for this study ruled out candidates with pregnancy, implanted electronic devices, metal implants (in near proximity to the treatment area, such as hip replacements; shoulder replacements, and/or knee replacements were not considered as exclusion criteria), heart disorders, treatment for active malignancy, and any medical conditions contraindicating the application of an electromag-netic field.

In total, 3 male and 19 female subjects were recruited for the study. The subjects aged from 34 to 65 years (mean age, 47.3±8.5 years) and had a mean BMI of 23.5±3.5 kg/m2. Before the treatments, all subjects received informed consent about the treatment procedure and signed written consent. The treatment was applied to the abdomen using the EMSCULPT device (BTL Industries Inc., Boston, MA) based on HIFEM technology. The device consists of a control unit and a cable connecting the unit to a coil applicator, which is applied over the treatment area. The circular coil located in the applicator induces a magnetic field with intensities reaching up to 1.8 T and an active depth of approximately 7cm.

The treatment protocol consisted of 8 sessions kept 2-3 days apart. The protocol was approved by IRB and conformed to the ethical guidelines of the 1975 Declaration of Helsinki. The duration of a single treatment was 30 minutes. Subjects were positioned in a supine position, and the treatment was per-formed by placing the applicator centred over their umbilicus. The applicator was secured by a Velcro belt. During the first session, the intensity of the magnetic stimulation was initially set to low levels of around 10% of the device’s maximum out-put to allow the subjects experience the sensation felt during the treatment. The intensity was then gradually increased to in-duce challenging but not painful muscle contractions just below subjects’ tolerance threshold. All subjects reached 100% inten-sity and were able to maintain this level of stimulation during treatment sessions. During each session and follow up visit the subjects were screened for any adverse events related to the treatment.

Data CollectionComputed tomography (CT) imaging was used to evaluate the outcome of the treatments. Subjects were scanned by a General Electric VCT 64 Slice Lightspeed CT scanner (the body section defined by the T2 and S1 vertebrae) at baseline and 1 month af-ter the last treatment. The sub-umbilical and epi-umbilical slices were extracted from the acquired CT scans and analyzed and measured for the thickness of subcutaneous fat, the thickness of

TABLE 1.

Result Summary

Measurement Baseline 1 month FU Difference

Rectus abdominis thickness [mm]

11.0±2.1 12.5±2.01.5±0.8

(P<0.001)

Subcutaneous fat thickness [mm]

18.3±7.1 15.2±6.5-3.1±1.9

(P<0.001)

Abdominal separation [mm]

20.1±9.2 18.1±8.8-2.0±1.7

(P<0.001)

Waist circumference [cm]

81.1±7.9 77.2±7.4 -3.9±3.1

(P<0.001)

Weight [lb] 143.8±23.6 142.8±23.5 -1.0±2.8 (P>0.05)



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measurements, however, the main descent was observed dur-ing the first four sessions (average 3.0±2.52 cm). Additional treatments lead to further circumferential reduction (0.93±1.78 cm) but not to such extent as during the first four treatments. The course of the waist circumference throughout the proce-dure is documented in Figure 2, where a polynomial curve of a 3rd order was fitted into the data.

The subjects, who experienced muscle contractions induced by the electromagnetic field for the first time, described the initial pulses of the treatment as intense, but quickly adapted to the feeling and further on found the treatments comfortable. Most of them reported intense and strong muscle contractions but no discomfort. None of the subjects reported any pain associ-ated with the treatment. Several subjects reported soreness and muscle fatigue on the day after the treatment, which was com-parable to post-workout fatigue. Besides that, no adverse events were observed.

DISCUSSIONThe results of this study demonstrate that the HIFEM technology effectively induced a dual effect in abdominal fat and skeletal muscles. Increased muscle thickening was accompanied by re-duction of the abdominal fat layer and waist circumference in almost all patients. One subject did not show fat reduction and one subject did not show any muscle thickening yet each sub-ject showed improvement in at least 2 out of the 3 conducted measurements. There were no non-responding patients. The de-gree of fat reduction appears to be independent of the degree of muscle thickening.

The increase in muscle thickness by 14.8% correlates with a study done by Kinney et al11 who used MRI evaluations of mus-cle thickness 2 months after the protocol of 4 treatments and found an average reduction of 15.4% (Difference was statistically insignificant P<0.05). Because CT scans were obtained 1 month post-treatment, transient muscle swelling can be ruled out as a reason for the observed hypertrophy, as it typically resolves within 7 to 11 days after muscle micro injury.16 Comparison of

was not possible to measure any change in thickness. No signifi-cant correlation was found between the muscle thickening and reduced fat thickness (r=0.07, n=21, P=0.77).

The width of abdominal rectus muscle separation showed a decrease on average by 9.5% (-2.0±1.7mm) (P<0.001)). No corre-lation was found between the muscle thickening and reduction of abdominal separation of the right and left rectus muscles (r=0.35, n=20, p=0.13). Baseline and 1-month CT scans of three subjects are displayed as an example in Figure 1. Rectus ab-dominis separation was not measurable in subject ID1 who had undergone abdominoplasty some time before this study.

Waist circumference measurements showed an average de-crease 3.9±3.1 cm (P<0.001) when compared to post-treatment measurements. The decreasing trend was seen throughout all

FIGURE 1. CT scans of three subjects taken at baseline (left) and 1 month post-treatment (right). (A) Subject ID 9, reduction of subcutaneous fat by -30.3% (-5.38mm), thickening of rectus abdominis muscle by +8.4% (+1.5mm). Reduction in waist circumference by -2.0cm and abdominal separation by 3.1mm. (B) Subject ID11, reduction of subcutaneous fat by -32.4% (-6.8mm) with simultaneous thickening of rectus abdominis muscle by +28.0% (+2.5mm) and reduction in abdominal separation by 2.9mm. The subject lost 2.5 cm in waist circumference. (C) Subject ID 5, reduction of subcutaneous fat by -7.7% (-1.0mm) and thickening of rectus abdominis muscle by +21.4% (+2.4mm). Reduction in abdominal separation by 0.84mm and 9cm in waist circumference.

FIGURE 2. Chart displaying the average waist circumference after each session.

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our results with the Kinney et al data is seen in Table 2. Subjects maintained their regular diet and activity level without any modifications. In the absence of other mechanisms of fat reduction, it is likely the observed fat reduction resulted from lipolytic and/or apoptotic actions induced by the intense muscle contractions during the treatment. Intensive resistance training is known to induce lipolysis.17,18 The study by Weiss et al14 found an increased apoptotic index in the porcine model after single HIFEM treatment. They hypothesized that local supramaximal sustained muscle contractions may cause high levels of lipoly-sis which can induce stress of endoplasmic reticulum and fat cell apoptosis.

Our fat thickness measurements when compared to previous studies of Kinney et al and Katz et al13 (Table 2) had similar fat reduction. Their data demonstrated 18.6% and 19% reduction one month post four treatments, respectively. While not entire-ly certain, the slightly higher average improvement of Kinney et al might be attributed to the difference in time of the after measurements. Measures performed by Kinney et al were ob-tained 2 months post-treatment, which were twice as long as our study. Theoretically, skeletal muscles thus had more time to adapt to contractions by muscle growth, and more fat cells could be flushed out of the system when compared to our mea-surements 1 month post-treatment. The age of the subjects could also play a role. The subject group in the study by Kinney et al was approximately 8 years younger, and younger subjects could, therefore, yield more prominent changes. Similarly, for muscle thickness, the comparison indicates that protocol with more than 4 treatments may not necessarily produce any ad-ditional fat reduction.

No changes were observed in the BMI, which can be explained by the fact that the increased volume of the muscles compen-sated for the weight of the reduced fat. The waist circumference was reduced during the first 4 treatments (-3.0±2.52cm), then,

the circumference reduced in a slower pace by additional 0.93±1.78cm. This suggests that 4 treatments may be sufficient for inducing substantial changes in the abdominal skeletal mus-cle. The reduction of the waist circumference can be caused not only by the fat reduction but also by firmer abdominal muscu-lature. The waist circumference reduction observed in our study conforms to study by Jacob et al.12 who found a reduction of 3.29±1.9cm after the fourth treatment with HIFEM device and even 4.37±2.63cm reduction during 3-month follow-up.

One of the limitations of the present study is the patient popula-tion as the study included 22 subjects. A bigger patient group would provide higher reliability of the statistical analysis and would bring a broader insight on how different patient group react to the treatments and whether the same result would have been seen. Another limitation of the study is that the present study evaluated the subjects 1-month post-treatment. Future studies focusing on longer-term evaluation and follow up regard-ing the durability of results would be beneficial. Additionally, studies designed to evaluate the role of potential maintenance treatments for sustained improvement would be insightful. Functional parameters that measure isometric strength19 and dynamic endurance19 of abdominal muscles might provide in-sight into actual physical conditioning.

CONCLUSIONResults show that a HIFEM device is successful for abdominal body sculpting. CT scans documented improvement in both subcutaneous adipose tissue reduction and abdominal skeletal muscle hypertrophy. These results provided pleasing aesthetic improvement. This device also has a very low-risk profile with no thermal effects. Comparison with other studies suggests that treatment protocol including eight sessions does not nec-essarily bring a significant increment in results compared to 4 treatment protocol results.

DISCLOSURESDavid Kent MD and Carolyn I. Jacob are medical advisors for BTL.

ACKNOWLEDGMENTWe would like to thank the Radiology Associates of Macon for performing all CT scans.

REFERENCES1. Skelton DA, Young A, Greig CA, Malbut KE. Effects of Resistance training on

strength, power, and selected functional abilities of women aged 75 and old-er. J Am Geriatr Soc. 1995;43(10):1081-1087. doi:10.1111/j.1532-5415.1995.tb07004.x

2. Macaluso A, De Vito G. Muscle strength, power and adaptations to re-sistance training in older people. Eur J Appl Physiol. 2004;91(4):450-472. doi:10.1007/s00421-003-0991-3

3. Verdijk LB, Gleeson BG, Jonkers RAM, et al. Skeletal muscle hypertrophy fol-lowing resistance training is accompanied by a fiber type–specific increase in satellite cell content in elderly men. J Gerontol Ser A. 2009;64A(3):332-339. doi:10.1093/gerona/gln050

TABLE 2.

Comparison of the Present Study With Kinney et al

Study Kinney et al.* Present Study**

Evaluation MRI CT

#Subjects 22 22

Age 39.4 47.3

BMI 25.7kg/m2 23.5kg/m2

#Treatments 4 8

Waist reduction 3.8cm 3.9cm

Muscle thickening 15.4% 14.8%

Fat reduction 18.6% 17.5%

Abdominal separation 10.4% 9.7%

*Measurements 2 months post-treatments**Measurements 1 month post-treatments



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4. Ruther CL, Golden CL, Harris RT, et al. Hypertrophy, resistance training, and the nature of skeletal muscle activation. J Strength Cond Res. 1995;9(3):155.

5. Evans WJ. Effects of exercise on senescent muscle. Clin Orthop. 2002;(403 Suppl):S211-220.

6. Hill M, Goldspink G. Expression and splicing of the insulin-like growth fac-tor gene in rodent muscle is associated with muscle satellite (stem) cell activation following local tissue damage. J Physiol. 2003;549(Pt 2):409-418. doi:10.1113/jphysiol.2002.035832

7. Matsumoto H, Takenaka K. Motivational profiles and stages of exercise be-havior change. Int J Sport Health Sci. 2004;2:89-96. doi:10.5432/ijshs.2.89

8. Wilson K, Brookfield D. Effect of goal setting on motivation and adherence in a six-week exercise program. Int J Sport Exerc Psychol. 2009;7(1):89-100. doi:10.1080/1612197X.2009.9671894

9. Selkowitz DM. Improvement in Isometric strength of the quadriceps femoris muscle after training with electrical stimulation. Phys Ther. 1985;65(2):186-196. doi:10.1093/ptj/65.2.186

10. Currier DP, Mann R. Muscular Strength Development by Electrical Stimu-lation in Healthy Individuals. Phys Ther. 1983;63(6):915-921. doi:10.1093/ptj/63.6.915

11. Kinney BM, Lozanova P. High intensity focused electromagnetic therapy evaluated by magnetic resonance imaging: Safety and efficacy study of a dual tissue effect based non-invasive abdominal body shaping. Lasers Surg Med. 0(0). doi:10.1002/lsm.23024

12. Jacob CI, Paskova K. Safety and efficacy of a novel high-intensity focused electromagnetic technology device for noninvasive abdominal body shaping. J Cosmet Dermatol. September 2018. doi:10.1111/jocd.12779

13. Katz BE, Bard RL, Goldfarb R, et al. Changes in subcutaneous abdominal fat thickness following high-intensity focused electro-magnetic hifem field treatments: a multi center ultrasound study. In: Vol 50. Dallas TX, USA: La-sers in Surgery and Medicine. 2018:360-361. doi:10.1002/lsm.22814

14. Weiss R, Bernardy J. Induction of fat apoptosis by a non-thermal device: safety and mechanism of action of non-invasive HIFEM technology evalu-ated in a histological porcine model. Present Annu Meet Am Soc Lasers Surg Med. 2018.

15. Barker AT. An introduction to the basic principles of magnetic nerve stimula-tion. J Clin Neurophysiol Off Publ Am Electroencephalogr Soc. 1991;8(1):26-37.

16. Zainuddin Z, Newton M, Sacco P, et al. Effects of massage on delayed-onset muscle soreness, swelling, and recovery of muscle function. J Athl Train. 2005;40(3):174-180.

17. Ormsbee MJ, Thyfault JP, Johnson EA, et al. Fat metabolism and acute resistance exercise in trained men. J Appl Physiol Bethesda Md 1985. 2007;102(5):1767-1772. doi:10.1152/japplphysiol.00704.2006

18. Chatzinikolaou A, Fatouros I, Petridou A, et al. adipose tissue lipolysis is up-regulated in lean and obese men during acute resistance exercise. Diabetes Care. 2008;31(7):1397-1399. doi:10.2337/dc08-0072

19. Porcari JP, Miller J, Cornwell K, et al. The effects of neuromuscular electrical stimulation training on abdominal strength, endurance, and selected anthro-pometric measures. J Sports Sci Med. 2005;4(1):66-75.


David E. Kent MDE-mail:................……......................... [email protected]



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SPECIAL TOPIC

A Randomized, Controlled, Split-Face Study of the Efficacy of a Picosecond Laser in the Treatment of Melasma

Alexis B. Lyons MD,ª Ronald L. Moy MD,B Jennifer L. Herrmann MDb,c

ªDepartment of Dermatology, Henry Ford Hospital, Detroit, MIbMoy, Fincher, Chipps Facial Plastics & Dermatology, Beverly Hills, CA

cDepartment of Dermatology, Harbor UCLA, Torrance, CA

Introduction: Melasma is a common disorder where patients develop hyperpigmented macules and patches on the face and is thought to be the result of sun exposure and hormonal contributions, although the pathogenesis is not completely understood. Lasers have been used for melasma treatment with varying degrees of success.Objectives: The objective of this study was to examine the safety and efficacy of a novel picosecond laser for the treatment of me-lasma. Materials and Methods: Ten subjects received nine weekly laser treatments with a picosecond laser to a randomized half of their face. A lightening cream was applied to the entire face to serve as a control. The primary outcome measure was clinical efficacy measured by a patient-reported outcome survey, the Melasma Quality of Life (MELASQOL) questionnaire, and physician assessment with the Global Aesthetic Improvement Scale (GAIS). The secondary outcome measure was safety, which was assessed by monitoring for adverse events. Photos were taken before every treatment and at a 1-week follow-up. Results: Ninety percent of subjects rated their melasma as at least slightly better, and 90% percent of subjects would recommend this laser treatment to others with melasma. MELASQoL questionnaire scores improved by an average of 5.7 points after laser treat-ment. Assessments by two board-certified dermatologists using the GAIS revealed an overall improvement in 80% of patients on the laser treatment side versus 20% on the control side. Side effects, including erythema and discomfort, were minimal and transient post-treatment.Conclusions: This study suggests that picosecond laser treatments are a safe and efficacious way to treat melasma.

J Drugs Dermatol. 2019;18(11):1104-1107.

ABSTRACT

INTRODUCTION

Melasma is a pigmentary disorder in which patients develop symmetric, hyperpigmented macules and patches most commonly on the face. Although the

pathogenesis has not been completely elucidated, sun expo-sure and hormones are thought to contribute to the condition. It occurs most commonly in women and is more prevalent in darker skinned individuals but can occur in all skin types.1

With more than 5 million Americans affected, melasma is a common reason for dermatology appointments and can negatively impact the quality of life of patients.2,3 Despite its widespread prevalence, the treatment of melasma has proven to be difficult. The challenges of treatment are attributed to the chronicity, recurrence rate, and unclear pathogenesis. Many la-sers have been used for the treatment of melasma with varying degrees of success. The aim of this study was to investigate the efficacy and safety of a novel picosecond laser for the treatment of melasma.

MATERIALS AND METHODSThis was a randomized, controlled, split-face prospective study. A total of 10 subjects with a previous diagnosis of melasma were recruited from a dermatology office in Beverly Hills, CA. In-clusion criteria included subjects ages 18-65 with a diagnosis of melasma who were able to provide informed consent. Exclusion criteria included subjects under the age of 18 or over the age of 65, those who had used bleaching creams, chemical peels, or la-ser treatments within the past month prior to enrollment, those who were pregnant or breast feeding, and those who were on oral contraceptive pills.

Informed consent was obtained from subjects who fulfilled the eligibility criteria. Subjects were then randomized to laser treatment on one side of the face and underwent nine weekly picosecond laser treatments using the PiQo4 laser (Lumenis). Subjects were given and instructed to use a topical lightening cream containing .05% tretinoin/3% kojic acid/6% hydroqui-none/1% hydrocortisone to their entire face daily for the duration



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A.B. Lyons, R.L. Moy, J.L. Herrmann

39 (77%) Korean patients had greater than 51% improvement in relative lightness values with a combination of daily 2% HQ and 5 weekly laser treatments of dual-wavelength 1064 plus 595 nm on a 750 picosecond laser versus only 3% of subjects on 2% HQ alone.26 Similarly, Lee et al also successfully treated three Ko-rean patients with treatment resistant melasma with a 755 nm picosecond laser with two patients reporting good improvement and one with fair improvement.28 In addition, a recent study on thirty female subjects with melasma found that treatment with fractional picosecond 1064 nm laser combined with 4% HQ was superior than 4% HQ alone with a modified melasma area sever-ity index (mMASI) score significantly reduced in the laser group (3.52 ± 1.4 and 4.18 ± 2.03, respectively).27

This study emphasizes the utility of using a combination of 595 and 1064 nm on lighter skin phototypes and using 1064 on dark-er skin phototypes. These picosecond treatment settings offer patients the benefit of little to no downtime in contrast to other laser treatment options which can have significant periods of associated erythema or peeling. In addition, the 1064 nm treat-ment is safe on darker skin phototypes with no resultant PIH seen in this cohort.

Limitations include a relatively small sample size and the study being limited to female patients. Longer follow-up is needed to assess continued improvement and the durability of treatment. This study also lacked Fitzpatrick skin types V-VI; thus, further studies are needed to assess the safety and efficacy of these laser treatments in African American patients.

In conclusion, picosecond lasers are an efficacious treatment modality for patients with refractory melasma. Nine out of 10 subjects in this study reported an improvement in their melas-ma and would recommend the treatment to others. MELASQOL scores decreased 5.7 points on average indicating a decreased effect of melasma on patient quality of life. GAIS evaluation by physicians revealed an overall improvement in 80% of patients on the laser treatment side versus 20% on the control side. Side effects were minimal and transient with the laser treatment. This study suggests that picosecond laser treatments are a safe and efficacious way to treat melasma with little down time.

DISCLOSURESABL is a sub-investigator for Incyte, Bayer, Unigen Inc., Lenicura, Estee Lauder, Miragen, Biofrontera. RLM is the medical director of DNA EGF Renewal. JLH has no relevant disclosures.

REFERENCES1. Tamega Ade A, Miot LD, Bonfietti C, Gige TC, Marques ME, Miot HA. Clinical

patterns and epidemiological characteristics of facial melasma in Brazilian women. J Eur Acad Dermatol Venereol. 2013;27(2):151-156.

2. Grimes PE. Melasma. Etiologic and therapeutic considerations. Arch Derma-tol. 1995;131(12):1453-1457.

3. Balkrishnan R, McMichael AJ, Camacho FT, et al. Development and valida-tion of a health-related quality of life instrument for women with melasma.

DISCUSSIONMelasma is a clinical diagnosis and typically falls under the patterns of centrofacial, malar, and mandibular, although ex-trafacial melasma on the arms, neck, chest, or back has also been described.5,6 The centrofacial pattern is the most common presentation and occurs in 50-80% of patients.1 Melasma has a gender predilection with approximately 90% of affected patients being women. In addition to female gender, risk factors include darker skin type, pregnancy, sun exposure, oral contraceptive pills, and positive family history.7 The frequency of melasma varies between skin types and ethnicities with Fitzpatrick skin types III and IV most commonly affected.8 The prevalence of me-lasma has been studied in many subpopulations with estimates ranging between 9% in Hispanic women in the United States to 41% in India.9-12 Melasma also carries a genetic predisposition with 40% of patients having relatives with the disease.13

Patient reported outcomes for the treatment of melasma are important as this condition can have a significant negative im-pact on patient quality of life. The Melasma Quality of Life scale (MELASQOL) is a validated scale to assess the effect of melasma on patient quality of life.3 Our subjects experienced an average improvement of 5.7 points on their MELASQOL.

The first line therapy for melasma is sun protection and the use of topical lightening agents including hydroquinone and retinoids among others, while second line therapy includes chemical peels.14 These treatment modalities are often used in combination to optimize management. More recently, oral tranexamic acid has been tried for refractory melasma with promising results.15-17

Laser therapies have become more popular in recent years, es-pecially in patients with refractory disease. Laser treatments for melasma patients can be a challenge as excess heat can cause post-inflammatory hyperpigmentation (PIH) and melasma exacerbation. Q-switched lasers have been used for treating melasma, but PIH is a common pitfall.18,19 Similar resultant hy-perpigmentation have also been described post- erbium:YAG and CO2 laser treatments.20,21 Although fractional resurfacing la-sers, which minimize thermal damage to microzones within the skin may mitigate PIH, there are few studies that have shown satisfactory results with these devices.22,23 Intense pulsed light (IPL) has also been used with varying degrees of success but requires maintenance treatments and can cause exacerbation of hyperpigmentation if lower wavelengths of light are used.24

Because generation of heat is often considered the key factor in post-laser hyperpigmentation, picosecond lasers that deliver energy in exceptionally short pulse durations, minimize photo-thermal effects and are a promising strategy for treatment of melasma.25 Indeed, recent studies have supported the use of pi-cosecond lasers for melasma.26-28 Choi et al found that 30 out of



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FIGURE 1. Subject self-rating of change in melasma after picosecond laser treatment.

FIGURE 2. 45-year-old female (A) treatment side at baseline, (B)treatment side after nine picosecond laser treatments, (C) control side at baseline, (D) control side at the end of the study period.

(A) (B)

(C) (D)

of the study. Subjects were also counseled to apply an SPF 30 sunscreen daily to their entire face, which was provided to them at their first visit for consistency. Prior to each treatment, patients were asked about adverse events and side effects, pho-tographs were obtained, and the face was washed with a gentle cleanser. The settings for the first treatment were: wavelength of 1064 nm, pulse duration of 8 nm, fluence of 1 J/cm2, and spot size of 9 mm for 3-5 passes. Subsequent treatment settings were: wavelength of 1064 nm, pulse duration of 800 ps, fluence of 1.0 J/cm2 (approximately 400 mJ), and spot size of 7 mm. In addition, for patients with Fitzpatrick skin types 1-3, one pass of: wavelength 532nm, pulse duration of 800 ps, fluence 0.2 J/cm2, and spot size of 9 mm was performed at each visit. Subjects completed the Melasma Quality of Life (MELASQOL) question-naire3 at their first and last visits. Subjects were asked to rate their change in melasma on the laser treatment side as: “worse”, “no change”, “slightly better”, “better”, or “much better”. They were also asked if they would recommend the treatment to oth-ers with melasma. Photographs were evaluated by 2 physicians using the Global Aesthetic Improvement Scale (GAIS)4 (Table 1).

RESULTSThe average age of subjects enrolled was 42 (range, 26-50) with Fitzpatrick skin phototypes ranging from II-IV. None of the subjects reported a worsening of their melasma. One patient reported her melasma as unchanged, 4 reported it as slightly better, 2 reported it as better, and 3 reported it as much bet-ter (Figure 1). The average MELASQOL score improved by 5.7 points from an initial average of 31.8 to a final average of 26.1. Nine out of ten of the subjects said they would recommend this treatment to others with melasma. Assessments by two physi-cians revealed an overall improvement in 80% (n=8) of patients on the treatment side vs 20% (n=2) on the control side (Table 2, Figure 2).

Side effects included mild discomfort during the treatment and transient erythema that resolved within a couple of hours. Two patients developed petechiae after one of the treatments which resolved after 2-3 days. None of the subjects experienced hyper-pigmentation from the treatments.

TABLE 1.

Global Aesthetic Improvement Scale (GAIS)

(3) Very Much Improved Optimal cosmetic result

(2) Much ImprovedMarked improvement in appearance from the initial condition but not com-pletely optimal

(1) ImprovedObvious improvement in appearance from the initial condition, but a touch up is indicated

(0) No ChangeThe appearance is essentially the same as the original condition

TABLE 2.

Patient GAIS Scores

Treatment side % (n) Control side % (n)

3 10% (1) 0% (0)

2 30% (3) 0% (0)

1 40% (4) 20% (2)

0 20% (2) 80% (8)

-1 0% (0) 0% (0)



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Br J Dermatol. 2003;149(3):572-577.4. Kopera D, Palatin M, Bartsch R, et al. An open-label uncontrolled, mul-

ticenter study for the evaluation of the efficacy and safety of the dermal filler Princess VOLUME in the treatment of nasolabial folds. Biomed Res Int. 2015;2015:195328.

5. Sanchez NP, Pathak MA, Sato S, Fitzpatrick TB, Sanchez JL, Mihm MC, Jr. Melasma: a clinical, light microscopic, ultrastructural, and immunofluores-cence study. J Am Acad Dermatol. 1981;4(6):698-710.

6. Ritter CG, Fiss DV, Borges da Costa JA, de Carvalho RR, Bauermann G, Ce-stari TF. Extra-facial melasma: clinical, histopathological, and immunohisto-chemical case-control study. J Eur Acad Dermatol Venereol. 2013;27(9):1088-1094.

7. Sheth VM, Pandya AG. Melasma: a comprehensive update: part I. J Am Acad Dermatol. 2011;65(4):689-697.

8. Ortonne JP, Arellano I, Berneburg M, et al. A global survey of the role of ul-traviolet radiation and hormonal influences in the development of melasma. J Eur Acad Dermatol Venereol. 2009;23(11):1254-1262.

9. Werlinger KD, Guevara IL, Gonzalez CM, et al. Prevalence of self-diagnosed melasma among premenopausal Latino women in Dallas and Fort Worth, Tex. Arch Dermatol. 2007;143(3):424-425.

10. Ishiy PS, Silva LR, Penha M, Handel AC, Miot HA. Skin diseases re-ported by workers from UNESP campus at Rubião Jr. An Bras Dermatol. 2014;89(3):529-531.

11. Shenoi SD, Davis SV, Rao S, Rao G, Nair S. Dermatoses among paddy field workers--a descriptive, cross-sectional pilot study. Indian J Dermatol Vene-reol Leprol. 2005;71(4):254-258.

12. Sivayathorn A. Melasma in Orientals. Clin Drug Investig. 1995;10(2):34-40.13. Handel AC, Miot LD, Miot HA. Melasma: a clinical and epidemiological re-

view. An Bras Dermatol. 2014;89(5):771-782.14. Sheth VM, Pandya AG. Melasma: a comprehensive update: part II. J Am

Acad Dermatol. 2011;65(4):699-714.15. Wu S, Shi H, Wu H, et al. Treatment of melasma with oral administration of

tranexamic acid. Aesthetic Plast Surg. 2012;36(4):964-970.16. Karn D, Kc S, Amatya A, Razouria EA, Timalsina M. Oral tranexamic acid for

the treatment of melasma. Kathmandu Univ Med J (KUMJ). 2012;10(40):40-43.

17. Shin JU, Park J, Oh SH, Lee JH. Oral tranexamic acid enhances the efficacy of low-fluence 1064-nm quality-switched neodymium-doped yttrium alumi-num garnet laser treatment for melasma in Koreans: a randomized, prospec-tive trial. Dermatol Surg. 2013;39(3 Pt 1):435-442.

18. Taylor CR, Anderson RR. Ineffective treatment of refractory melasma and postinflammatory hyperpigmentation by Q-switched ruby laser. J Dermatol Surg Oncol. 1994;20(9):592-597.

19. Tse Y, Levine VJ, McClain SA, Ashinoff R. The removal of cutaneous pigment-ed lesions with the Q-switched ruby laser and the Q-switched neodymium: yttrium-aluminum-garnet laser. A comparative study. J Dermatol Surg Oncol. 1994;20(12):795-800.

20. Manaloto RM, Alster T. Erbium:YAG laser resurfacing for refractory melasma. Dermatol Surg. 1999;25(2):121-123.

21. Angsuwarangsee S, Polnikorn N. Combined ultrapulse CO2 laser and Q-switched alexandrite laser compared with Q-switched alexandrite laser alone for refractory melasma: split-face design. Dermatol Surg. 2003;29(1):59-64.

22. Rahman Z, Alam M, Dover JS. Fractional Laser treatment for pigmentation and texture improvement. Skin Therapy Lett. 2006;11(9):7-11.

23. Rokhsar CK, Fitzpatrick RE. The treatment of melasma with fractional photo-thermolysis: a pilot study. Dermatol Surg. 2005;31(12):1645-1650.

24. Wang CC, Hui CY, Sue YM, Wong WR, Hong HS. Intense pulsed light for the treatment of refractory melasma in Asian persons. Dermatol Surg. 2004;30(9):1196-1200.

25. Trivedi MK, Yang FC, Cho BK. A review of laser and light therapy in melasma. Int J Womens Dermatol. 2017;3(1):11-20.

26. Choi YJ, Nam JH, Kim JY, et al. Efficacy and safety of a novel picosecond laser using combination of 1 064 and 595 nm on patients with melasma: A prospective, randomized, multicenter, split-face, 2% hydroquinone cream-controlled clinical trial. Lasers Surg Med. 2017;49(10):899-907.

27. Chalermchai T, Rummaneethorn P. Effects of a fractional picosecond 1,064 nm laser for the treatment of dermal and mixed type melasma. J Cosmet Laser Ther. 2018;20(3):134-139.

28. Lee YJ, Shin HJ, Noh TK, Choi KH, Chang SE. Treatment of Melasma and Post-Inflammatory Hyperpigmentation by a Picosecond 755-nm Alexandrite Laser in Asian Patients. Ann Dermatol. 2017;29(6):779-781.


Alexis B. Lyons MDE-mail:................……......................... [email protected]

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SPECIAL TOPIC

Safety and Effectiveness of Microfocused Ultrasound With Visualization for the Correction of Moderate to

Severe Atrophic Acne Scars Corey S. Maas MD,a John H. Joseph MDb

aThe Maas Clinic, San Francisco, CAbClinical Testing of Beverly Hills, Beverly Hills, CA

Objective: To assess the effectiveness of microfocused ultrasound with visualization (MFU-V) for treating moderate to severe atrophic acne scars.Design: Healthy subjects (N=20) seeking correction of moderate to severe atrophic acne scars on the cheeks and/or temples were enrolled. Scars were predominantly rolling- and boxcar-type, affecting an area ≥5.0cm2. Eighteen subjects completed the study.Intervention: The treatment area was marked with 14mm2 and 25mm2 squares and treated with four transducers: 7 MHz (3.0mm focal depth) and 10 MHz (1.5mm focal depth), each in 14mm and 25mm widths. During each session, MFU-V treatment lines were applied 2-3mm apart, within each treatment area, with a maximum length of 25mm. Each square received 30 treatment lines at two transducer depths (60 total lines). Subjects received three total treatments, with 30 days between each session. The primary outcome measure was improvement in baseline appearance of scars at 90 and 180 days after the final treatment. Secondary outcome measures included changes in severity using an Acne Scar Improvement Scale (ASIS) and Global Aesthetic Improvement Scale (GAIS) at 60-, 90-, and 180-days post-treatment, and a satisfaction questionnaire at 90-days post-treatment. Results: Among the 90-day images available for assessments (n=11), 100% were rated as improved by blinded reviewers, and 64% of pre- and post-treatment images were correctly selected. Among 180-day images (n=15), 100% were rated as improved, and 40% of pre- and post-treatment images were correctly selected. Most subjects were determined to have 25-50% improvement in investiga-tor ASIS scores at 60-, 90-, and 180-days post-treatment. All subjects noted some improvement in severity at the 60-day assessment when measured using ASIS. Based on investigator GAIS scores, 100% of subjects were “Improved” or “Much Improved” at 60-, 90-, and 180-days post-treatment. Based on subject GAIS scores, all subjects noted improvement at the 60-day assessment, and 83% and 89% at the 90- and 180-day assessments, respectively. Overall, 17 subjects (94.4%) expressed some degree of satisfaction at 90-days post-treatment.Conclusions: The results of this study demonstrated that MFU-V therapy is beneficial and well tolerated for the treatment of rolling- and boxcar-type acne scars.

J Drugs Dermatol. 2019;18(11):1109-1114.

ABSTRACT

INTRODUCTION

Acne vulgaris is an exceedingly common skin disorder with a reported prevalence ranging from 75%1 to more than 90%2 in adolescents, and this condition often per-

sists into adulthood.3,4 Acne affects both genders equally2 and all racial groups.5,6 The negative impact of acne on patient self-esteem, psychosocial functioning, and overall quality of life is the topic of numerous publications.7-10

An unfortunate long-term consequence of severe acne is scar-ring. Acne scars have been reported to occur with a frequency as high as 11% in men and 14% in women.11 In one acne study, 1% of patients had scars, and 1 in 7 (14%) scars was considered disfiguring.4 The severity of acne scarring has been correlated with overall acne severity and the duration of untreated acne.12

A delay of up to 3 years between acne onset and adequate treatment corresponded with the final extent of scarring.12 Fa-cial scarring is associated with diminished quality of life13 and negative perceptions by society.14

While the etiology of acne scarring is not well understood, it is thought to result from skin damage during the healing pro-cess following active acne.3 Depending on changes in skin collagen, acne scars are classified as atrophic or hypertrophic. Most (80 to 90%) are atrophic scars caused by the loss of col-lagen.3 Based on morphology, atrophic scars are subclassified as ice pick (60 to 70%), boxcar (20 to 30%), or rolling scars (10 to 15%).3 Histological examination of acne-scar tissue revealed decreased dermal thickness and loss of pilosebaceous units, in-flammatory cell infiltrates, and inadequate dense collagen-fiber deposition in the whole dermis.15



1110


C.S. Maas, J.H. Joseph

be willing to use an acceptable method of birth control during the study.

Reasons for exclusion from study participation included the presence of an active systemic or local skin disease that may affect wound healing; severe solar elastosis; excessive sub-cutaneous fat or skin laxity in the planned treatment areas or significant scarring that could affect outcome assessments; severe or cystic acne on the areas to be treated, defined as >3 active inflammatory acne lesions in either the right or left treatment area; recent or current history of inflammatory skin disease, infection, cancerous/pre-cancerous lesion, or unhealed wound in the planned treatment areas; a history of systemic granulomatous diseases or connective tissue or autoimmune disease; hypertrophic acne scars, any evidence of keloid scar-ring, or predominantly (>50%) icepick scarring or sinus-tract scars; presence of a metal stent or implant in the treatment area; hypersensitivity to ibuprofen, acetaminophen, lidocaine, or tetracaine; history of chronic drug or alcohol abuse; current or recent smoker within the last 2 years; history of the follow-ing cosmetic treatments (timeframe) in the planned treatment areas: skin tightening (12 months); injectable filler includ-ing hyaluronic acid (12 months), calcium hydroxyapatite (12 months), poly-L-lactic acid (12 months), cultured fibroblasts (2 years), or permanent fillers (at any time); neurotoxin injections (3 months); microdermabrasion or prescription-level glycolic acid treatments (4 weeks); ablative resurfacing laser treatment (2 years); nonablative, rejuvenative laser or light treatment (6 months); surgical dermabrasion or deep facial peels (2 years); contour threads (at any time); prescription acne medications in-cluding isotretinoin or other systemic retinoids (6 months) or topical retinoids (2 weeks); current antiplatelet/ anticoagulants including aspirin >82 mg daily; any other concurrent therapy or illness that might jeopardize the objectives of the study; inabil-ity to understand the protocol or provide informed consent; or participation in any study involving the use of investigational devices or drugs within the past 30 days.

Treatment ProcedureEach subject was pretreated with oral ibuprofen (800mg) 1 hour prior to treatment and a topical anesthetic cream containing 7% lidocaine and 7% tetracaine (Pliaglis® Cream; Galderma Labora-tories, LP, Fort Worth, TX) was applied to the treatment area 30 minutes prior to treatment. Standardized images of each subject, using fixed camera and lighting conditions, were obtained prior to treatment (Visia®; Canfield Scientific, Inc., Parsippany, NJ).

For each subject, the area to be treated was identified and the number of squares needed to cover the cheek and temple areas affected by acne scars was determined; 25mm2 squares were used for standard transducers and 14mm2 squares for narrow transducers, as necessary, to cover the area of scarring. Ace-tate paper was placed over the area, and the fixed anatomical

Numerous treatments are available for atrophic acne scars including chemical peels, dermabrasion/microdermabrasion, radiofrequency, laser treatment, punch techniques, dermal grafting, subcision, needling, and combined therapies.3,16 While all of these techniques have demonstrated varying degrees of effectiveness, the optimal treatment for acne scars remains unknown. The results of a recent Cochrane Review concluded that high-quality evidence regarding the various interventions for treating acne scars is lacking due to poor methodology, underpowered studies, lack of standardized improvement as-sessments, and different baseline variables. The results of that review did not provide support for the first-line use of any type of intervention for treating acne scars.17

A microfocused ultrasound with visualization (MFU-V) device has been developed as a non-invasive aesthetic treatment to lift the eyebrow and lax submental and neck tissue and to improve lines and wrinkles of the décolleté (Ultherapy®; Merz North America, Raleigh, NC). The device is also capable of ultrasound imaging to avoid unwanted target areas such as bone and large blood vessels. Using transducers of varying frequencies and focal depths, the device is designed to focus ultrasound energy to produce small (<1mm3) microcoagulation zones in the mid-to-deep reticular layer of dermis and sub-dermis, while sparing overlying papillary dermal and epidermal layers of skin.18 The result is immediate contraction of denatured collagen,19 neocol-lagenesis, and tissue remodeling.20

As neocollagenesis and tissue remodeling are hypothesized to improve the appearance of acne scars,21,22 the noninvasive characteristics of this MFU-V device and its ability to produce subcutaneous tissue remodeling make it a good candidate for the treatment of atrophic acne scars. The following open-label pilot study was designed to assess the effectiveness of MFU-V to treat moderate to severe atrophic acne scars.

METHODSStudy ParticipantsHealthy male and female subjects, 18 to 70 years of age, who were seeking correction of moderate to severe atrophic acne scars on the cheeks and/or temples were enrolled. Scars were required to be predominantly rolling- and boxcar-type scars, af-fecting an area ≥5.0cm2, with few or no icepick scars present. The majority of scars were distensible with tension applied to the skin. Additional inclusion criteria were the willingness of subjects to: abstain from additional aesthetic therapies in the planned treatment areas during the study, if they were judged by the investigator to potentially affect study outcomes; comply with protocol requirements, including follow-up visits; maintain their current skin care regimen; and refrain from adding new products or drugs for acne or acne scars during the study. Wom-en of childbearing potential were required to provide a negative urine pregnancy test result at Visit 1, must not be lactating, and



1111



Primary EndpointWhen compared to images obtained at baseline, improvement in the appearance of acne scars was determined by a blinded, qualitative comparison of facial images obtained 90 and 180 days after the final MFU-V treatment. For each subject, three physicians reviewed pre- and post-treatment images in blinded, randomized order (ie, the reviewers were not aware which im-ages were pre-treatment and which were post-treatment). Each reviewer independently evaluated the images for any improve-ment in appearance of acne scars or if there was no change. Clinical improvement was recorded using the following scale: exacerbation (-1), no change (0), 1 to 25% improvement (1), 26 to 50% improvement (2), 51 to 75% improvement (3), or 76 to 99% improvement (4). If improvement was assessed, the reviewer was asked choose the correct post-treatment image.

Secondary EndpointThe principal investigator assessed changes in acne-scar sever-ity using an Acne Scar Improvement Scale (ASIS) and Global Aesthetic Improvement Scale (GAIS) at 60-, 90-, and 180-days post-treatment. Each subject assessed their own overall aes-thetic improvement using an ASIS and GAIS at 60-, 90-, and 180-days post-treatment. Subjects also completed a satisfaction questionnaire at the 90-day follow-up visit.

SafetyDuring the MFU-V treatment procedure, subjects were asked to rate the level of pain they experienced using a validated 11-point (0-10) Numerical Rating Scale (NRS), with 0 denoting no pain and 10 denoting the worst possible pain.23 Pain scores were obtained following the treatment of each area and for each transducer used. Following treatment, the investigator exam-ined each subject for the presence of any acute response, such as erythema or edema.

Statistical AnalysisAvailable data were summarized for each time point. Subjects with incomplete data were included in summaries for which data were available. Categorical variables were summarized as frequencies and percentages in each category. Continuous and ordinal variables were summarized as the number of subjects (n), means, standard deviations (SD), medians, and ranges (min, max). All programs for data output and analyses were written in SAS® version 9.2 (SAS Institute, Inc., Cary, NC).

The primary effectiveness analysis was performed using sub-jects who completed the 90-and 180-day assessments. The primary effectiveness assessment was improvement in the ap-pearance of acne scars as determined by a blinded, qualitative assessment of photographs at 90 and 180 days after the final treatment when compared to baseline. Adverse events are pre-sented as the number of subjects reporting each event.

landmarks of the tragus, lateral canthi, and mouth corner were marked. The treatment squares were drawn on the acetate pa-per, which was saved for use during subsequent treatments. Four transducers were available for the application of MFU-V: a 7 MHz transducer with a 3.0mm focal depth and a 10 MHz transducer with a 1.5 mm focal depth, each available as a 25mm or 14mm (narrow) width. After applying ultrasound gel, an ul-trasound image was obtained for each proposed treatment area to ensure ultrasound coupling between the transducer and skin (DeepSEE®, Merz North America, Raleigh, NC). Within each treat-ment area, MFU-V treatment lines were applied 2 to 3mm apart with a maximum length of 25mm. Each treatment line required approximately 3 seconds to complete. Each treatment square received 30 treatment lines per transducer depth, for a total of 60 lines per treatment square, delivered in a crosshatch pattern (Figure 1). Each subject received three MFU-V treatments ses-sions 30 days apart.

FIGURE 1. Treatment areas. The area to be treated and the number of 25 mm2 and 14 mm2 squares needed to cover areas affected by acne scars were identified. The treatment squares were drawn on acetate paper placed over the area; paper was saved for use during subsequent treatments.



1112



EthicsEach subject provided signed, informed consent and Health In-surance Portability and Accountability Act (HIPAA) authorization prior to participating in any study-related procedures, as well as written consent to be photographed during the study. This study protocol and related materials were approved by a commer-cial institutional review board (Asentral IRB, Inc., Newburyport, MA). ClinicalTrials.gov Identifier: NCT02145364.

RESULTSDemographicsMale (n=8) and female (n=12) subjects with a mean (SD) age of 44.5 (11.5) years and mean (SD) body mass index (BMI) of 24.4 (3.9) kg/m2 were enrolled. Other subject demographics and baseline characteristics are summarized in Table 1. One subject withdrew consent after the first treatment, and one subject was lost to follow-up.

Primary EndpointPre- and post-treatment images were only available for 11 of the 18 subjects completing the 90-day follow-up visit; deficient im-ages were either not obtained during the visit, had inconsistent lighting, or the subject was wearing make-up. Three of the 180-day images were excluded due to inconsistent lighting.

Among the 90-day images available for blinded assessments (n=11), all were determined to be improved (100%), and the post-treatment image was correctly selected for 64%. Among the available 180-day images (n=15), all were assessed as im-proved, and a correct post-treatment image was selected for 40%. Representative pre- and 90-day post-treatment images are shown in Figure 2.

Secondary EndpointThe 60-, 90-, and 180-day post-treatment investigator and sub-ject ASIS scores are summarized in Table 2. Most subjects were determined to have 25 to 50% improvement. One subject had 75 to 99% improvement at day 180. No subjects had exacerbation in their acne scars, and none showed any change in their skin appearance. The 60-, 90-, and 180-day post-treatment investiga-tor and subject GAIS scores are summarized in Table 3. At each time point, 100% of subjects showed improvement with most rated as Improved or Much Improved.

All subjects noted some improvement in acne-scar severity at the 60-day assessment, and one subject each indicated no change at the 90- and 180-day assessments. All subjects (100%) noted some degree of improvement at the 60-day assessment, decreasing to 83% and 89% at the 90- and 180-day assessments, respectively. The results of the 90-day subject satisfaction ques-tionnaire show that 17 subjects (94.4%) noted improvement in their acne scores and expressed some degree of satisfaction.

SafetyAs measured using an 11-point (0-10) NRS, the mean pain scores during treatment with the 7 MHz/3.0 mm transducer were 4.2, 5.2, and 5.0 for treatments 1, 2, and 3, respectively. For the 10 MHz/1.5 mm transducer, the mean pain scores were 4.9, 6.2, and 5.9 for treatments 1, 2, and 3, respectively. Scores for both transducers indicate moderate pain severity. Examination of the treatment area revealed no evidence of skin damage or other se-quelae such as scarring, burns, or hypo- or hyper-pigmentation.

FIGURE 2. Treatment results. Representative pre- (left) and 90-day post-treatment (right) changes in acne scar appearance.

TABLE 1.

Subject Demographics and Baseline Characteristics

Mean age, years (SD) 44.5 (11.5), range 24-64

Mean BMI, kg/m2 (SD) 24.4 (3.9), range 18.6-35.2

Female gender, n (%) 12 (60)

Ethnicity, n (%)

Hispanic/Latino 7 (35)

Non-Hispanic/Latino 13 (65)

Race, n (%)

Caucasian 15 (75)

Asian 4 (20)

Native American/Alaska Native 1 (5)

Fitzpatrick Skin Type, n (%)

I 2 (10)

II 3 (15)

III 9 (45)

IV 4 (20)

V 2 (10)

BMI, Body mass index.



1113



There was no exacerbation of acne scars. Adverse events were reported by two subjects: one underwent surgery for Dupuy-tren’s contracture, and one reported having the cold/flu. Both events were unrelated to the study procedure.

DISCUSSIONThe results of this study demonstrated that a three-session program of MFU-V applied 30 days apart is beneficial and well tolerated for the treatment of rolling- and boxcar-type acne scars. For most treated subjects (64%), the appearance of acne scars was determined to be improved at the 90-day assessment. It should be noted that a potential limitation of this study was

the use of blinded evaluations of two-dimensional photographic images, as these images may not accurately capture acne-scar deformities as well as live evaluations of study subjects. The reliability of live assessments in determining improvement su-persedes photographic evaluation as evidenced by GIAS and ASIS scores. Future studies will benefit from prioritizing live as-sessments over photographic evaluations in order to make more definitive statements about effectiveness of the procedure.

Importantly, the improved appearance in acne scars was long lasting based on investigator GAIS, and subject and investigator ASIS scores; the degree of improvement remained essentially unchanged between the 60- and 180-day visits. Nearly 95% of subjects showed up to 50% improvement in ASIS scores at days 60 and 90, which remained approximately 90% at 180 days. Similarly, investigator GAIS scores showed 100% of subjects demonstrated improvement at day 60, and this improvement was maintained through day 180. It is the authors’ clinical ex-perience that the level of improvement observed through 180 days tends to diminish over longer periods of time. Therefore, retreating atrophic acne scars with MFU-V after 12 to 18 months may be helpful for maintaining long-term improvement, but ad-ditional studies would be necessary to fully evaluate the benefit. Assessments of treatment efficacy were similar among subjects. Based on subject ASIS scores, 72% of subjects achieved up to 50% improvement in acne-scar appearance at day 60, and this improvement remained at 61% and 56% on days 90 and 180, re-spectively. Based on subject GAIS scores, nearly 90% continued to note improvement in acne-scar appearance at day 180, and none indicated worsening of scar appearance. Overall, 95% of subjects were satisfied with their treatment results at day 90, of which more than 60% were Satisfied or Extremely Satisfied.

The improvements in acne-scar appearance observed in this study are consistent with the known mechanism of action of MFU-V. Several in vitro and in vivo studies have demonstrated the ability of MFU-V to cause points of thermal injury within the dermis, which results in immediate tissue contraction19,24 and leads to neocollagenesis and tissue remodeling.25,26 Clinically, the net effect is lifting and tightening of lax skin in various ana-tomical areas.27-31

A wide range of other treatments have been used for treating atrophic acne scars. Similar to MFU-V, these treatments are also based on increasing collagen formation to reduce scar severity, including subcision,32 injectable poly-L-acid fillers,33 mi-croneedling and percutaneous collagen induction,21,34 chemical reconstruction,35 and energy-based devices.36-38 While demon-strating varying degrees of effectiveness, all are also associated with various drawbacks, such as the need for repeated treat-ments, adverse events, or extensive down time. Effectiveness comparisons of these alternate treatments with MFU-V are not possible at this time.

TABLE 2.

Acne Scar Improvement Scale (ASIS) Scores

InvestigatorDay 60 (N=18)n (%)

Day 90 (N=18)n (%)

Day 180 (N=18)n (%)

1% to 25% improvement 5 (27.8) 7 (38.9) 10 (55.6)

26% to 50% improvement 12 (66.7) 10 (55.6) 6 (33.3)

51% to 75% improvement 1 (5.6) 1 (5.6) 1 (5.6)

76% to 99% improvement 0 0 1 (5.6)

Acne scar exacerbation 0 0 0

No change in appearance 0 0 0

Subject

1% to 25% improvement 5 (27.8) 7 (38.9) 10 (55.6)

26% to 50% improvement 12 (66.7) 10 (55.6) 6 (33.3)

51% to 75% improvement 1 (5.6) 1 (5.6) 1 (5.6)

76% to 99% improvement 0 0 1 (5.6)

Acne scar exacerbation 0 0 0

No change in appearance 0 0 0

TABLE 3.

Global Aesthetic Improvement Scale (GAIS) Scores

InvestigatorDay 60 (N=18)n (%)

Day 90 (N=18)n (%)

Day 180 (N=18)n (%)

1 (Very much improved) 0 1 (6) 1 (6)

2 (Much improved) 2 (11) 2 (11) 2 (11)

3 (Improved) 16 (89) 15 (83) 15 (83)

4 (No change) 0 0 0

5 (Worse) 0 0 0

Any improvement 18 (100) 18 (100) 18 (100)

Subject

1 (Very much improved) 0 2 (11) 2 (11)

2 (Much improved) 7 (39) 5 (28) 7 (39)

3 (Improved) 11 (61) 8 (44) 7 (39)

4 (No change) 0 3 (17) 2 (11)

5 (Worse) 0 0 0

Any improvement 18 (100) 15 (83) 16 (89)



1114



CONCLUSIONThe results of this study demonstrated that a three-session program of MFU-V applied 30 days apart is beneficial and well tolerated for the treatment of rolling- and boxcar-type acne scars. Furthermore, investigator GAIS, and investigator and subject ASIS scores indicated that the degree of improvement was sustained at 180 days post-treatment. Based on these posi-tive results, MFU-V is a safe and beneficial means for improving the appearance of atrophic acne scars. Further research should be considered in a larger subject population and utilizing a ran-domized study design to further evaluate the clinical benefits of MFU-V. A study design that includes higher-density treatments for older acne scars, improved subject selection, more standardized study photography processes, live assessments of subjects for primary endpoints, and longer follow-up should be considered. DISCLOSURESAuthors do not report any conflicts of interests.

ACKNOWLEDGMENTThe authors satisfied the requirements for authorship accord-ing to the guidelines of the International Committee of Medical Journal Editors, as revised in 2013. The authors acknowledge the editorial assistance of Dr. Carl Hornfeldt, Apothekon, Inc., with funding provided by Merz North America. This study was sponsored by Merz North America, Raleigh, NC.

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35. Leheta T, El Tawdy A, Abdel Hay R, Farid S. Percutaneous collagen induction versus full-concentration trichloroacetic acid in the treatment of atrophic acne scars. Dermatol Surg. 2011;37:207-216.

36. El-Domyati M, Abd-El-Raheem T, Medhat W, Abdel-Wahab H, Al Anwer M. Multiple fractional erbium: yttrium-aluminum-garnet laser sessions for up-per facial rejuvenation: clinical and histological implications and expectations. J Cosmet Dermatol. 2014;13:30-37.

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John H. Joseph MDE-mail:................……......................... [email protected]



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Combined 400-600nm and 800-1200nm Intense Pulsed Phototherapy of Facial Acne Vulgaris

J. Matthew Knight MDKnight Dermatology Institute, Orlando, FL

Background and Objective: Laser and light-based therapies are relatively new treatment options for acne vulgaris patients. Intense pulsed light (IPL) is believed to exploit the photosensitivity of P. acnes residing in the pilosebaceous units at lower wavelengths and induce anti-inflammatory effects by influencing cytokine release at higher wavelengths. Our study aimed to assess the clinical safety and efficacy of a novel dual-band “notch” acne filter (400-600nm and 800-1200nm) in improving inflammatory and non-inflammatory lesions in patients presenting with mild-to-moderate acne. Materials and Methods: The study was designed as a single-site, prospective study of 10 patients with Fitzpatrick skin types II-V presenting with mild to moderate inflammatory facial acne vulgaris. A total of five whole-face light treatments were conducted at 1-2-week intervals with an IPL system (Lumenis M22 System, Lumenis Ltd.) equipped with a dual-band “notch” acne filter (400-600nm and 800-1200nm). Follow-up visits were performed at 1 and 4 weeks following the last treatment session. Acne mean change from baseline was assessed using the 4-point Investigator Global Assessment (IGA) scale. Comprehensive facial photographs were taken, and lesions were counted at screening, treatment 4, and both 1- and 4-week follow-up visits. The investigator and the patients assessed overall improvements in appearance, using the 5-point Likert scale. Subjects also completed the Cardiff Acne Disability Index (CADI) questionnaire and rated their satisfaction from treatment. Subject-reported pain, using the visual analog scale (VAS), and downtime were also recorded. Results: Treatment impact on overall lesion clearance was most substantial at 4 weeks follow-up, at which 50% of patients showed at least a 50% reduction from baseline of lesion counts (P<0.0001). IGA scores improved throughout the course of the study, and significant improvements in the overall skin condition was noted, with mean 1.63-point and 1.50-point increases from baseline in the acne improvement ratings, at 1- and 4-weeks follow-up, respectively (P=0.0074, 0.0063). Patient-assessed CADI improved through-out the treatment and follow-up visits, peaking at a 3.22-point and 4.9-point average reductions from baseline at 1-week follow-up (P=0.0001) and 1-month follow-up (P<0.0001), respectively. The majority of the patients (80%) rated their acne lesions as improved, much improved, or very much improved at 4-weeks follow-up (P=0.0004). Significant enhancements were also noted for skin texture. Eighty percent of the patients reported overall satisfaction with treatment outcomes, while 60% rated their satisfaction as “good” or “very good” at 4-weeks follow-up (P<0.0001). Treatments were well tolerated, with mean per-session VAS scores being ≤3.77, while the mean downtime was negligible (a few hours). Conclusion: The use of an IPL device equipped with a proprietary “notch” acne filter elicited a significant effect on acne vulgaris. No severe pain, erythema, edema, folliculitis, crusting or exfoliation was noted, emphasizing the safety of our technique.

J Drugs Dermatol. 2019;18(11):1116-1122.

ABSTRACT

INTRODUCTION

Acne vulgaris is estimated to affect up to 87% of the pop-ulation, predominately adolescents and young adults, and is associated with significant, and occasionally per-

manent, morbidity and psychological burden.1,2 Key pathogenic elements include hypercornification of the pilosebaceous unit and increased sebum production,2,3 which fosters the coloniza-tion of Propionibacterium acnes (P. acnes) in the pilosebaceous ducts. In turn, the hair follicles become inflamed, triggering the upregulation of pro-inflammatory mediators.4,5

The clinical manifestations of acne range from micro-comedo-nes to inflamed papules, pustules, and nodules, the latter of

which can lead to permanent atrophic or hypertrophic scarring.6 Conventional treatments, such as topical and systemic antimi-crobials, anti-inflammatories, hormones, and retinoids, have been proven to be effective in targeting the pathogenic fac-tors of acne vulgaris.7,8,9 Although these regimens are standard first-line treatment modalities, they are seldom 100% effective. Additionally, such remedies carry the risk of skin irritation, an-tibiotic resistance, hematologic abnormalities, and in some cases, teratogenicity. Moreover, obtaining the patients’ long-term compliance can be challenging, thus leading to greater difficulty in treating acne.7,10,11



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25-35 msec. Most treatments included a whole-face double pass technique. Test spots were performed and monitored for up to 72 hours. Patients showing an excessive skin reaction were ex-cluded from the study.

Study DesignA total of five whole-face IPL treatments were conducted at 1-2-week intervals. Follow-up visits were performed at 1 and 4 weeks following the last treatment session. Prior to receiving treatment, the patient’s face was gently cleansed to remove all makeup, lipstick/gloss and eyeshadow. Protective ocular safety measures were enforced throughout the treatment sessions. All subjects were instructed to gently cleanse their skin with tepid water, to hydrate with a moisturizer, and to avoid mechanical damage (friction, squeezing) to the skin between treatments. Patients were also asked to refrain from using contraindicated cosmeceuticals and prescription medications throughout the study period and were instructed to avoid sun exposure and to regularly apply sunscreen (SPF≥30).

Clinical AssessmentsComprehensive facial photographs were taken using a profes-sional digital camera system (Omnia, Canfield Imaging Systems, Inc.). Head position, angle, framing, exposure and lighting condi-tions were standardized for all photographs. Photographs were taken at screening, treatment 4, and at both follow-ups (1 and 4 weeks). Patient evaluation was conducted by counting acne lesions of all types over the entire face. Acne lesions included in the count were comprised of non-inflammatory comedones, in-flammatory lesions with surrounding halos and erythema, and deep inflammatory lesions (including nodules and cysts). Initial skin assessments were conducted by the non-blinded principal investigating dermatologist or sub-investigator.

Acne mean change from baseline was assessed using the 4-point IGA scale for acne vulgaris, with “0” indicating clear skin without inflammatory or non-inflammatory lesions and “4” indicating severe acne, with many non-inflammatory and inflammatory lesions but no more than a few nodular lesions. Lesion count and IGA grading were conducted at screening, treatment 4, and at 1- and 4-week follow-ups.

Over the course of treatment, the investigator and patient as-sessed overall improvements in appearance, using the 5-point Likert scale, with “-1” indicating “worse”, “0” indicating “no change”, “1” indicating improved, “2” indicating much im-proved, and “3” indicating “very much improved”. Subjects also completed the Cardiff Acne Disability Index (CADI) ques-tionnaire, which evaluates the impact of acne on quality of life, with a maximum score of 15 and a minimum score of 0. The CADI questionnaire was completed at treatment 4, and at the 1- and 4-week follow-ups. Overall satisfaction from treatment was scored by patients at treatment 4, and at 1 week and 4 weeks

Modern technological advancements have provided new options for patients afflicted with acne vulgaris. Laser and light-based therapies, which induce photo-thermal heating of the pilo-sebaceous units,12 are relatively new treatment alterna-tives for acne patients. Intense pulsed light (IPL) therapy emits high-intensity, polychromatic, non-coherent visible light at wavelengths ranging from 400-1200 nm, which can safely tar-get specific skin structures across a range of skin types. When used to treat acne, IPL exploits the photosensitivity of P. acnes, rooted in endogenously expressed porphyrins, which absorb best at wavelengths between 410 and 630nm. Upon photoacti-vation, highly reactive singlet oxygen is formed, which oxidizes bacterial cell walls, proteins, and lipids, culminating in bacte-rial destruction.13,14 IPL has been proven potent in the treatment of acne,15-17 with blue light showing particular effectiveness in lowering lesion counts and destroying bacteria residing in the pilosebaceous unit.18,19 On the other hand, red light (620-750nm) and near-infrared light displays anti-inflammatory effects by inducing cytokine release from macrophages, while increasing synthesis of fibroblast growth factors (FGF) from photoactivated macrophage-like cells.21 Both the anti-bacterial and anti-inflammatory mechanisms of blue and red light have been demonstrated by Papageorgiou et al17 and Goldberg and Russel20 who noted a dramatic effect of combined blue-red light phototherapy in acne vulgaris patients.

Our study aimed to assess the clinical safety and efficacy of a novel dual-band “notch” acne filter (400-600nm and 800-1200nm) in improving inflammatory and non-inflammatory acne lesions in patients presenting with mild-to-moderate acne.

MATERIALS AND METHODSPatientsHealthy patients, aged 15-45, with skin type I-V, presenting with mild to moderate inflammatory facial acne vulgaris, categorized as grade 2-3, as per the Investigator Global Assessment Scale (IGA), and with at least 15 inflammatory papules or pustules, were eligible to participate in this study. Exclusion criteria in-cluded the use of oral, topical, or systemic antibiotics within two weeks preceding enrollment, steroid use within 6 months preceding the trial, pregnancy or lactation, and/or a history of photosensitivity. All subjects were screened prior to treatment and a full medical history was recorded. All subjects provided informed written consent to participate in the trial.

Light SourceThe CE-marked and FDA-cleared M22™ system (Lumenis Ltd., Yokneam, Israel) was equipped with a dual-band “notch” fil-ter to simultaneously deliver 1-3 sub-pulses of non-coherent blue-to-yellow light (400-600nm) and near-infrared (IR) light (800-1200nm) over a 15x35 mm spot size, at fluences of 10-32 J/cm2. The fluence in the present study ranged from 11-17 J/cm2, pulse durations from 4.0-5.0 msec, and interpulse delays from



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considerable effects recorded 1 week following the full course of treatment, where 50% of patients showed >50% reduction from baseline in lesion counts (Table 2). Overall lesion clearance, which includes non-inflammatory, inflammatory, deep inflam-matory, tender and/or painful lesions and inflammatory lesions with surrounding halos or erythema lesions, was most substan-tial four weeks after completion of the treatment regimen (Table 2). In addition, the mean percentage reduction in lesion counts was found statistically significant (P<0.0001). At the last follow up visit, the average IGA scores improved significantly (2.00 ± 0.67) as compared to baseline (2.85 ± 0.69) (Table 3). Significant improvements in overall skin condition were also observed and the mean improvement increased by 1.63 (±1.06) and 1.50 (±1.35) points from baseline to four weeks following last treatment (P=0.0074, 0.0063). These findings are illustrated in the before and after photographs (Figure 1). Furthermore, patient-reported CADI improved throughout the treatment and follow-up visits, peaking at 3.22 ± 2.82-point and 4.90 ± 1.91-point average reduc-tions from baseline at 1-week follow-up (P=0.0001) and 1-month follow-up (P<0.0001), respectively (Table 4).

following the last treatment session. Additionally, patients sub-jectively rated the improvement of their acne (follow-ups vs baseline).

Subject-reported pain (10-point visual analog scale) and down-time were recorded throughout the study, and immediate (30 minutes post-treatment) and long-term responses (1-2 weeks after each treatment and at the 1 month follow up visit) were assessed and recorded by the investigative team.

Statistical MethodsAll statistical analyses and data presentations were performed using SAS® version 9.4 (SAS Institute, Cary NC) software. Study data were summarized with descriptive statistics, where continuous variables are presented as a mean (with standard deviation) and discrete variables as a count and percentage. For confidence intervals, the confidence level was 95%. Study variables were modeled using repeated measures analysis of variance (ANOVA), where each variable was modeled indi-vidually as a function of its baseline value (when relevant) and visit (as a categorical variable). LSmeans per visit and the differ-ences between visits were estimated from the models and are presented with level of significance. Statistical significance was defined as a P-value ≤ 0.05. Nominal P-values are presented.

RESULTSA total of 13 patients, of a mean age of 23.5±4.8, primarily fe-male (76.9%), and of skin types II-III (84.7%), were included in this study (Table 1). Ten patients completed the entire course of treatment and follow-up, while the remaining were lost to follow-up. All subjects underwent test-spots prior to initiation of treatment and none required anesthesia.

When assessing treatment impact on inflammatory lesions, a significant and gradual improvement in lesion counts was ob-served with subsequent treatments and duration of follow-up (p<0.0001). A significant effect was observed at 1 week and 4 weeks post-treatment, where 62.5% and 80% of patients showed over 50% improvement, respectively (Table 2). A tran-sient improvement was noted in non-inflammatory lesions, with

TABLE 1.

Patient Demographics and Baseline Characteristics

N=13

Age, mean (SD) 23.5 (4.8)

Gender, n (%)

Female 10 (76.9)

Male 3 (23.1)

Race, n (%)

Caucasian 9 (69.2)

Caucasian-Hispanic/Latino 1 (7.7)

Hispanic/Latino 3 (23.1)

Skin Type, n (%)

II 4 (30.8)

III 7 (53.9)

IV 1 (7.7)

V 1 (7.7)

TABLE 2.

Lesion Count and Treatment Success Rates With Treatment Progression

Inflammatory Lesions Non-Inflammatory Lesions Overall Lesions#

Lesion Count*Success

RateLesion Count

*Success Rate

Lesion Count*Success

Rate

Mean (SD) Range % Mean (SD) Range % Mean (SD) Range %

Baseline; n=13 19.7 (5.8) 10-30 20.5 (16.0) 6-50 41.5 (19.1) 16-75

1W FU; n=8 7.5 (4.0) 0-13 62.5 7.1 (3.3) 2-11 50 15.4 (5.2) 7-22 37.5

1M FU; n=10 5.5 (3.4) 0-10 80 10.0 (4.9) 3-20 30 15.6 (7.1) 6-30 50*Defined as reduction from baseline of ≥50% in lesion count. #Including inflammatory, non-inflammatory, deep inflammatory, tender and/or painful lesions, inflammatory lesions with surrounding halos or erythema



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The majority of patients (80%) rated their acne lesions as “improved” to “very much improved” (Figure 2A-1-month fol-low-up). Significant changes were noted for skin texture, with 60% of the patients rating their skin as “improved” to “very much improved” (Figure 2B-1-month follow-up). In both fol-low up visits, the subject’s self-improvements were statistically significant (for acne lesions: P=0.0054 and P=0.0004 at 1- and 4-weeks follow-ups, respectively; for skin texture: P=0.0017 and P=0.0002 at 1 and 4 weeks FUs, respectively). In addition, 80% of patients reported an overall skin improvement as “improved” to “very much improved” (mean score P=0.0016) at 4 weeks fol-low-up (Figure 3). Eighty percent of the patients reported some level of satisfaction with treatment outcomes (Figure 4). By the end of the study, 90% of patients viewed their acne condition as a “minor problem” (Figure 5).

Patients found the treatment regimen tolerable (VAS of 3.77±2.00), and no significant differences in pain levels were recorded across the treatment sessions. The mean social down-

FIGURE 1. Acne improvement following dual-band phototherapy of acne vulgaris. Affected areas were photographed before and after the five-session course of dual-band phototherapy. Representative photos from three patients are shown.

Sub 202

Sub 206

Sub 201

BEFORE AFTER

TABLE 3.

Improved Investigator Global Assessment (IGA) Scores Following Dual-Band Phototherapy of Acne Vulgaris.

IGA Score

Mean (SD)Mean (SD)

Change from baseline

P-value*

Baseline; n=13 2.85 (0.69) -- --

1W FU; n=8 2.50 (0.93) -0.13 (0.83) 0.3881*1M FU; n=10 2.00 (0.67) -0.70 (0.95) 0.0046

Mean IGA scores were recorded before treatment 4 (n=13), and 1 (n=8) and 4 (n=10) weeks following completion of the five-session treatment course. *Change from baseline was statistically significant (P<0.05).

TABLE 4.

Improved Cardiff Acne Disability Indexes (CADI) Following Dual-Band Phototherapy Of Acne Vulgaris.

Cardiff Acne Disability Index (CADI)

Mean (SD)Mean (SD)

Change from baseline

P-value

Baseline; n=13 8.00 (2.74) -- --

1W FU; n=9 5.00 (2.69) -3.22 (2.82) 0.0001

1M FU; n=10 3.30 (1.83) -4.90 (1.91) <0.0001

CADI scores were recorded before treatments (n=13), and 1 (n=9) and 4 (n=10) weeks following completion of the five-session treatment course. Means changes from baseline are presented. Improvement values from baseline were statistically significant (P-values: 0.0001 for 1-week follow-up and <0.0001 for 1-month follow-up respectively).

time associated with treatment was less than a single day in all treated subjects and was considered negligible. Mean redness-related downtime was 3.6 hours. Two patients reported side effects in the form of mild pruritus and mild blistering on the left chin and cheek, both of which self-resolved within one day after the treatment session without sequelae.



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FIGURE 2. Improved patient-rated acne lesion scores following dual-band phototherapy of acne vulgaris. Patient categorical ratings of acne lesion (A) and skin texture (B) improvements were recorded before treatment sessions (n=13), and 1 (n=8) and 4 (n=10) weeks following completion of the five-session treatment course. P-values for mean acne lesion scores were 0.0054 and 0.0004 for 1 week and 4 weeks follow-ups, respectively, and 0.0017 and 0.0002 for skin texture at 1 week and 4 weeks follow-ups, respectively. Data shown as % of patients (of total patients at the time of assessment).

FIGURE 3. Overall improvement rating by patients. Overall patient categorical ratings of improvement were recorded before treatment sessions (n=13), and 1 (n=8) and 4 (n=10) weeks following completion of the five-session treatment course. P-values for mean scores: 0.0025 and 0.0016 for 1 week and 4 weeks from baseline values, respectively. Data shown as % of patients (of total patients at the time of assessment).

FIGURE 4. Patients viewing of their acne condition. Subjective assessment of acne condition (CADI) was done at baseline and at 1 week and 4 weeks following last treatment session. Data shown as % of patients (of total patients at the time of assessment).

FIG 2

*

**

#

A B

Acne lesion improvement score distributions

Subject self-improvement acne lesions meanscore is statistically significant (p=0.0054 and0.0004 at 1W and 1M follow-up respectively)

Skin texture improvement score distributions

Subject self-improvement of skin texture mean score is statistically significant (p=0.0017 and 0.0002 at 1W and 1M follow-up respectively)

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Subject overall self-improvement mean score isstatistically significant (p=0.0025 and 0.0016 at1W and 1M follow-up respectively)

FIG 3

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Overall satisfaction by subjectsSubject satisfaction mean score is statisticallysignificant (p=0.0002 and <0.0001 at 1W and1M follow-up respectively)

FIG 4

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DISCUSSIONSeveral pharmaceutical treatment options for acne demonstrate well-established efficacy and are considered the mainstays of therapy. However, technological advances, coupled with in-creasing concerns over drug resistance, have led physicians to reevaluate treatment options for this chronic disease. An in-creasing body of evidence suggests that phototherapy induces marked effects on inflammatory acne lesions with minimal ad-verse effects. Earlier promising findings regarding the safety and efficacy of combined blue and near-infrared light therapy, thought to address both the inflammatory and bacterial as-pects of acne, were corroborated by our study. The results in our study demonstrated a reduction in lesion counts, reaffirmed by improved IGA and CADI scores throughout the one-month follow-up period.

In their comparative assessment of a mixed red-blue light regimen versus blue light only, cool white light, or topical 5% benzoyl peroxide treatments, Papageorgiou et al17 noted supe-rior performance following daily mixed-light treatment for 12 weeks. Goldberg and Russell20 found that biweekly treatment of mild to severe facial acne vulgaris with alternating 415nm and 633nm light yielded a mean 81% reduction in lesion counts at a 12-week follow-up visit, with a slightly greater response ob-served among patients with severe acne. Asian patients with moderate to severe acne benefitted from a five-session IPL treatment regimen, delivering both 400-700nm and 870-1200nm light. Immediate improvement was observed after a single treat-ment session, with significant decreases in lesion counts after

five sessions, without eliciting any significant side effects.16 Of note, a marked (but less potent and more transient) effect of phototherapy on non-inflammatory lesions has been observed by other groups as well.15,17

IPL delivers non-coherent, broad-bandwidth, filtered light, which can be easily adjusted to meet desired wavelength, flu-ence, pulse duration and delay. The light therapy is presumed to evoke a bactericidal effect on P. acne, by activating its endog-enous porphyrins that specifically absorb blue wavelengths.24,25

This photoexcitation elevates reactive oxygen species levels, resulting in rapid and selective elimination of bacteria.18 In con-trast, phototherapy with other mid-range wavelengths, eg, PDL, demonstrate little to no impact on P. acnes colonization.26

Light therapy with higher wavelengths is also assumed to affect the immunological aspect of acne, in that IPL-triggered photo-thermal injury induces a wound healing response mediated by an array of inflammatory factors,21 including upregulation of TGF-ß1 expression, correlating with enhanced nuclear local-ization of Smad3.27 These cytokines, reported to derive from laser-induced cellular infiltrates, drive dermal remodeling and inhibit keratinocyte proliferation, which may interfere with mi-cromedone formation.28

Taken together, use of the notch acne filter used in our study induces a robust effect, influencing both the bacterial and in-flammatory factors underlying acne vulgaris. In our study, no severe pain, erythema, edema, folliculitis, crusting or exfoliation was noted, emphasizing the safety of our technique.

As this study was an open, before-after design, additional ran-domized and controlled studies are required to support our conclusions. Comparison of the long-term efficacy of IPL treat-ment in combination with common topical anti-acne agents (ie, real world use) versus IPL treatment alone will be of particular interest. In addition, the present study involved only five treat-ment sessions, performed at 1-2-week intervals. Further studies will be required to assess whether addition of treatment ses-sions, and extension of the intersession intervals, can enhance the clinical effect and its longevity.

DISCLOSURES This study was sponsored by Lumenis Ltd. (Yokneam, Israel). Dr. Knight is a consultant, investigator, and speaker for Lumenis Ltd.

REFERENCES1. Dreno B, Poli F. Epidemiology of acne. Dermatology. 2003;206(1):7-10.2. Bhambri S, Del Rosso JQ, Bhambri A. Pathogenesis of acne vulgaris: recent

advances. J Drugs Dermatol. 2009;8(7):615-618.3. Leyden JJ. Therapy for acne vulgaris. N Engl J Med. 1997;336(16):1156-1162.4. Toyoda M, Morohashi M. Pathogenesis of acne. Med Electron Microsc.

2001;34(1):29-40.5. Burkhart CN, Gottwald L. Assessment of etiologic agents in acne pathogen-

FIGURE 5. Patients viewing of their acne condition. Subjective assessment of acne condition (CADI) was done at baseline and at 1 week and 4 weeks following last treatment session. Data shown as % of patients (of total patients at the time of assessment).

Cardiff Acne Disability Index - Please indicate how bad you think your acne is now

FIG 5

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90

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J. Matthew Knight MD E-mail:................……......................... [email protected]

esis. Skinmed. 2003;2(4):222-228.6. Purdy S, de Berker D. Acne. BMJ. 2006;333(7575):949-953.7. Katsambas AD, Stefanaki C, Cunliffe WJ. Guidelines for treating acne. Clin

Dermatol. 2004;22(5):439-444.8. Thiboutot DM, Strauss JS. Diseases of the sebaceous glands. Burns, Tony;

Breathnach, Stephen; Cox, Neil; Griffiths, Christopher. Fitzpatrickâ€™s der-matology in general medicine (6th ed.). New York: McGraw-Hill. 2003:67287.

9. Jones DH, Greenwood R, Cunliffe WJ. Dose-response relationship of se-bum suppression by 13-cis-retinoic acid in severe acne. Br J Dermatol. 1983;109(3):366-367.

10. Munavalli GS, Weiss RA. Evidence for laser- and light-based treatment of acne vulgaris. Semin Cutan Med Surg. 2008;27(3):207-211.

11. Paithankar DY, Ross EV, Saleh BA, Blair MA, Graham BS. Acne treatment with a 1,450 nm wavelength laser and cryogen spray cooling. Lasers Surg Med. 2002;31(2):106-114.

12. Ross EV. Optical treatments for acne. Dermatol Ther. 2005;18(3):253-266.13. Arakane K, Ryu A, Hayashi C, et al. Singlet oxygen (1 delta g) generation

from coproporphyrin in Propionibacterium acnes on irradiation. Biochem Bio-phys Res Commun. 1996;223(3):578-582.

14. Futsaether CM, Kjeldstad B, Johnsson A. Intracellular pH changes induced in Propionibacterium acnes by UVA radiation and blue light. J Photochem Photobiol B. 1995;31(3):125-131.

15. Elman M, Slatkine M, Harth Y. The effective treatment of acne vulgaris by a high-intensity, narrow band 405-420 nm light source. J Cosmet Laser Ther. 2003;5(2):111-117.

16. Kawana S, Tachihara R, Kato T, Omi T. Effect of smooth pulsed light at 400 to 700 and 870 to 1,200 nm for acne vulgaris in Asian skin. Dermatol Surg. 2010;36(1):52-57.

17. Papageorgiou P, Katsambas A, Chu A. Phototherapy with blue (415 nm) and red (660 nm) light in the treatment of acne vulgaris. Br J Dermatol. 2000;142(5):973-978.

18. Omi T, Munavalli GS, Kawana S, Sato S. Ultrastructural evidence for thermal injury to pilosebaceous units during the treatment of acne using photopneu-matic (PPX) therapy. J Cosmet Laser Ther. 2008;10(1):7-11.

19. Morton CA, Scholefield RD, Whitehurst C, Birch J. An open study to deter-mine the efficacy of blue light in the treatment of mild to moderate acne. J Dermatolog Treat. 2005;16(4):219-223.

20. Goldberg DJ, Russell BA. Combination blue (415 nm) and red (633 nm) LED phototherapy in the treatment of mild to severe acne vulgaris. J Cosmet Laser Ther. 2006;8(2):71-75.

21. Young S, Bolton P, Dyson M, Harvey W, Diamantopoulos C. Macrophage responsiveness to light therapy. Lasers Surg Med. 1989;9(5):497-505.

22. Sakamoto FH, Doukas AG, Farinelli WA, et al. Selective photothermolysis to target sebaceous glands: theoretical estimation of parameters and prelimi-nary results using a free electron laser. Lasers Surg Med. 2012;44(2):175-183.

23. Barikbin B, Ayatollahi A, Younespour S, Hejazi S. Evaluation of efficacy of intense pulsed light (IPL) system in the treatment of facial acne vulgaris: comparison of different pulse durations; a pilot study. J Lasers Med Sci. 2011;2(2):67.

24. Melo TB, Reisaeter G. Photodestruction of endogenous porphyrins in rela-tion to cellular inactivation of Propionibacterium acnes. Z Naturforsch C. Sep-Oct 1986;41(9-10):867-872.

25. Cunliffe WJ, Goulden V. Phototherapy and acne vulgaris. Br J Dermatol. 2000;142(5):855-856.

26. Seaton ED, Mouser PE, Charakida A, Alam S, Seldon PM, Chu AC. Inves-tigation of the mechanism of action of nonablative pulsed-dye laser ther-apy in photorejuvenation and inflammatory acne vulgaris. Br J Dermatol. 2006;155(4):748-755.

27. Ali MM, Porter RM, Gonzalez ML. Intense pulsed light enhances transform-ing growth factor beta1/Smad3 signaling in acne-prone skin. J Cosmet Der-matol. 2013;12(3):195-203.

28. Pietenpol JA, Holt JT, Stein RW, Moses HL. Transforming growth factor beta 1 suppression of c-myc gene transcription: role in inhibition of keratinocyte proliferation. Proc Natl Acad Sci USA. 1990;87(10):3758-3762.



Results and patient experience may vary. Patients shown in the B&A pictures are within +/- 5 lbs of their original weight unless specified. As with any medical procedure, ask your doctor if the Emsculpt procedure is right for you. The Emsculpt procedure is U.S. FDA cleared for improvement of abdominal tone, strengthening of the abdominal muscles, development of firmer abdomen, strengthening, toning and firming of buttocks. ©2018 BTL Group of Companies. All rights reserved. BTL® and EMSCULPT® are registered trademarks in the United States of America, the European Union and/or other countries. The products, the methods of manufacture or the use may be subject to one or more U.S. or foreign patents or pending applications.

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SPECIAL TOPIC

Improper Potency and Impurities in Compounded Polidocanol Margaret Mann MD,a Gilly S. Munavalli MD,b Lisa Amatangelo MD,c and Nick Morrison MDd

aInnova Dermatology, Hendersonville, TNbDermatology, Laser & Vein Specialists of the Carolinas, Charlotte, NC

cWeill Cornell Vein Treatment Center, New York, NYdCenter for Vein Restoration, Mesa, AZ

Polidocanol is an FDA-approved sclerosant indicated for treating uncomplicated spider veins and reticular veins in the lower extremities. Despite restrictions against compounding drugs that are essentially copies of FDA-approved or commercially available products, polido-canol is also available from compounding pharmacies and outsourcing facilites. Compounded drug products are not FDA-approved and have not undergone premarket FDA review for safety, effectiveness, and quality. Seven samples of polidocanol were obtained from three compounding pharmacies and analyzed using high pressure liquid chromatography. None of the samples contained the labeled concen-tration of polidocanol and five contained excessive levels of impurities. Since the potency and purity of compounded polidocanol injection cannot be assured, physicians who use these products should consider FDA-approved products to ensure optimal safety and efficacy.

J Drugs Dermatol. 2019;18(11):1124-1127.

ABSTRACT

INTRODUCTION

Varicose veins are enlarged superficial veins, most commonly found in the lower extremities. Risk factors include family history, advancing age, female gender,

pregnancy, obesity and sedentary lifestyle.1 Spider veins are similar, but they are smaller, more superficial and often red or blue. Some varicose veins become symptomatic and require treatment. Symptoms may include burning, throbbing, muscle cramping, itching, and edema. Depending on their size and severity, treatments for varicose veins include compression,2

energy-based radiofrequency3 and laser devices,4 a variety of surgical procedures,5 and sclerotherapy.6 Sclerotherapy involves injecting a sclerosant into the lumen of a vein, resulting in fibrosis and eventual vein ablation.7 Despite the increased popularity of new cutaneous laser devices, sclerotherapy remains the gold standard for treatment of reticular varicose and spider veins,15,16 especially since FDA-approval of sclerosant agents in 2010.19,20

Available FDA-approved liquid sclerosing agents include sodium tetradecyl sulfate and polidocanol.8 Polidocanol was first approved for use as a sclerosing agent in the United States in 2010 (Asclera® Injection, Merz North America, Raleigh NC).9 Specifically, this drug product is indicated to sclerose uncomplicated spider veins (varicose veins ≤1 mm in diameter) and uncomplicated reticular veins (varicose veins 1 to 3 mm in diameter) in the lower extremities. Polidocanol is also an approved sclerosing agent in Europe (Aethoxysklerol®, Chemische Fabrik Kreussler & Co. GmbH, Wiesbaden, Germany). The safety and efficacy of polidocanol as a sclerosant have been demonstrated in large trials.21

Polidocanol is also available from certain compounding pharmacies and outsourcing facilities, despite government restrictions on compounding drugs that are “essentially copies” of FDA-approved or commercially available products.10 Compounded drug products are not FDA-approved and have not undergone FDA premarket review for safety, effectiveness, and quality. Of note, polidocanol is manufactured according to strict FDA regulations for purity and potency throughout the entire manufacturing process. Unlike pharmaceutical companies, compounding pharmacies and outsourcing facilities are not required to report adverse events to the FDA.11 Despite FDA restrictions for compounding drugs, polidocanol remains available from compounding pharmacies and outsourcing facilities, potentially exposing patients to potentially serious health risks.

Previous investigations have demonstrated the inferiority of compounded sclerosants. Among compounded products in one study, three did not contain the labeled drug concentration: two were super-potent, one was sub-potent and all contained impurities.12 These products were believed to be made by diluting the active substance from industrial chemical sources. In another study, five of six samples obtained from three pharmacies did not contain the labeled drug concentration, exceeding it by 20% to 300%, and all six contained impurities.13

In a third study, chemical impurities were measured in eight of nine compounded samples from three pharmacies and some contained unknown particulate matter, while no impurities were detected in the original FDA-approved product.14



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M. Mann, G.S. Munavalli, L. Amatangelo, N. Morrison

DISCUSSIONSimilar to previous studies,12,13 compounded polidocanol solutions did not deliver the claimed potency in six of seven tested samples and five samples contained excessive contaminants. This inconsistency poses unacceptable risks, most importantly to the patient, but also medicolegal risks to the treating physician. In contrast, clinical trials have demonstrated FDA-approved polidocanol provides effective treatment of chronic venous insufficiency with low toxicity, minimal risk and few complications.21

Contaminants found in the tested compounded polidocanol samples in several publications included foreign fatty C-14 alcohol ethoxylate impurities, excessive formaldehyde and unknown impurities. Other reported contaminants in compounded sclerosants include carbitol,12 tetradecanol, several isomers of 7-ethyl-2-methyl-undec-3/4 ene,14 chlorobutanol (trichloro-2-methyl-2-propanol), benzaldehyde, and benzyl alcohol13 (some samples contained multiple contaminants). Together, these results indicate the lack of purity of the ingredients and/or the absence of sufficient manufacturing controls used to compound these products.

In addition to frequently not meeting the labeled ingredient specifications for potency and purity, there is no requirement for compounded product labeling to include an approved shelf life. If the compounded product is not immediately used, there is no assurance that the product will remain potent and efficacious.

As compounded polidocanol for the treatment of varicose veins continues to be available from several pharmacies and outsourcing facilities in the United States, the objective of this study was to obtain and analyze samples of compounded polidocanol for potency and purity.

METHODSSeven samples of polidocanol were purchased from three compounding pharmacies. Labeled concentrations of polidocanol ranged from 1.5% to 5%. Each sample was analyzed for potency of lauromacrogol 400 (polidocanol) and purity with reversed phase high pressure liquid chromatography (HPLC) with refractive index (RI) detection (Chemische Fabrik Kreussler & Co. GmbH, Wiesbaden, Germany). The results were compared with an FDA-approved polidocanol product (Asclera® Injection, Merz North America, Raleigh NC).

RESULTSResults of the analysis are summarized in Table 1. Among the seven samples analyzed, six were sub-potent, containing 65.8 to 91.4% of the labeled concentration, and one was super-potent, containing 108.7% of the labeled concentration. Five contained a 10-fold excess of foreign fatty alcohol ethoxylate impurities and four exceeded the limit for unknown impurities. Overall, none of the tested samples were equivalent to the commercially marketed, FDA-approved product (Asclera) with respect to potency and purity.

TABLE 1.

Analysis Results of Compounded Polidocanol for Sclerotherapy Injection

Pharmacy #1

Pharmacy #1

Pharmacy #2

Pharmacy #2

Pharmacy #2

Pharmacy #3

Pharmacy #3

FDA-Approved Product

Specificationc

FDA-Approved Product

Specificationc

Labeled PolidocanolConcentration

1.5% 5% 1.5% 3% 5% 2% 3% 0.5% 1%

Actual PolidocanolConcentration

16.3 mg/mL (108.7%)

45.7 mg/mL(91.4%)

13.1 mg/mL(87.3%)

19.8 mg/mL(66.0%)

32.9 mg/mL(65.8%)

15.3 mg/mL(76.6%)

22.8 mg/mL(75.8%)

4.75-5.25 mg/mL95.0-105.0%)

9.5-10.5 mg/mL95.0-105.0%)

1-Dodecanol 0.63% 0.66% 0.50% 0.67% 0.74% --a --a ≤1.5% ≤1.5%

foreign fatty alcohol ethoxylate impurities

0.1% 0.1% 26.3%b 27.0%b 27.2%b 22.0%b 22.0%b ≤2% ≤2%

Formaldehyde <0.2 ppm <0.2 ppm 1.3 ppm 0.3 ppm 0.5 ppm --a --a ≤1 ppm ≤1 ppm

Acetaldehyde <0.2 ppm 0.4 ppm 3.7 ppm 1.1 ppm 1.7 ppm --a --a ≤2 ppm ≤5 ppm

Unknown Impurities

0.05% 0.04% 0.67% 0.64% 0.70% 0.30% 0.40% ≤0.3% ≤0.3%

aInsufficient sample size. bPrimarily foreign fatty alcohol ethoxylate impurities. Bold font denotes nonconforming results.c Asclera® Injection, Merz North America, Raleigh NC.



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Since compounded drugs have not undergone FDA review to determine their safety and effectiveness, their potency and purity cannot be assured as demonstrated by the current analysis of several compounded polidocanol products. It has been recognized for many years that physicians who use these products may be at risk legally in the event of an adverse outcome.28 A physician involved in litigation related to the use of a compounded sclerosant should be prepared to explain why an unapproved agent was used when an FDA-approved agent is available and whether a compounded product was used to increase profit.29

CONCLUSIONCompounded drug products have not undergone FDA review to establish safety and efficacy. An analysis of seven samples of compounded polidocanol injection found all of them to be outside the labeled concentration and five had excessive contaminant levels. Physicians who use these products should consider FDA-approved products to ensure optimal treatment outcomes.29

ACKNOWLEDGMENTThe authors acknowledge the editorial assistance of Dr. Carl S. Hornfeldt, Apothekon, Inc., during the preparation of this manuscript. This work was funded by Merz North America, Raleigh, NC.

DISCLOSURESThe authors have no further disclosures to report.

REFERENCES1. National Heart Lung and Blood Institute; National Institute of Health.

Varicose Veins. Available: https://www.nhlbi.nih.gov/health-topics/varicose-veins. Accessed: July 2019.

2. Attaran RR, Ochoa Chaar CI. Compression therapy for venous disease. Phlebology. 2017;32:81-88.

3. Woźniak W, Kielar M, Mlosek RK, Ciostek P. Comparative analysis of five-year outcomes of lower extremity varicose vein therapy using monopolar and segmental radiofrequency ablation. Int Angiol. 2018;37:457-464.

4. Wallace T, El-Sheikha J, Nandhra S, et al. Long-term outcomes of endovenous laser ablation and conventional surgery for great saphenous varicose veins. Br J Surg. 2018 105:1759-1767.

5. Kemp N. A synopsis of current international guidelines and new modalities for the treatment of varicose veins. Aust Fam Physician. 2017;46:229-233.

6. Duffy DM. Sclerosants: a comparative review. Dermatol Surg. 2010;36:1010-1025.

7. Zimmet SE. Sclerotherapy treatment of telangiectasias and varicose veins. Tech Vasc Interv Radiol. 2003;6:116-120.

8. Bush R, Bush P. Evaluation of sodium tetradecyl sulfate and polidocanol as sclerosants for leg telangiectasia based on histological evaluation with clinical correlation. Phlebology. 2017;32:496-500.

9. Asclera®(polidocanol) Injection [package insert]. Raleigh, NC: Merz North America, Inc: 2010.

10. United States Food and Drug Administration. Center for Drug Evaluation and Research, 2018. Guidance for Industry. Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act.

11. Gudeman J, Jozwiakowski M, Chollet J, Randell M. Potential risks of pharmacy compounding. Drugs R D. 2013;13:1-8.

12. Goldman MP. Sodium tetradecyl sulfate for sclerotherapy treatment of veins: is compounding pharmacy solution safe? Dermatol Surg. 2004;30:1454-1456.

The Federal Food, Drug, and Cosmetic Act requires that all FDA-approved drugs must be safe and effective and manufactured according to current good manufacturing practices (GMPs) to ensure their identity, strength, quality, and purity;22 however, some pharmacies are compounding drugs that are essentially copies of approved medications and doing so outside of GMPs. According to the FDA, “Compounding is a practice in which a licensed pharmacist, a licensed physician, or in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient.” The FDA has created provisions to allow the practice of compounding for individual patient needs when a drug product is not commercially available. This is common in dermatology practice for therapies such as topical anesthetic (BLT) or an acne cream, but these provisions are not applicable for an injectable product for which the FDA-approved product is medically suitable for a patient. Compounding pharmacies are advertising for physicians to use or switch to compounding sclerosant(s) in lieu of FDA-approved polidocanol, but such promotional statements are prohibited if they are false or misleading, such as baseless statements that compounded products are superior or failing to disclose significant risks associated with unapproved uses that are promoted.

There are numerous cases of injury resulting from various improperly compounded medications.11 An outbreak of meningitis in 2012 caused by a contaminated steroid injection intended for epidural injection made in a compounding pharmacy23 affected 753 patients in 20 states with 64 deaths.24

Subsequently, the United States Congress passed the Drug Quality and Security Act in November, 2013.25 Among other requirements, the Act stipulates that pharmaceutical compounders are not allowed to essentially copy products that are already FDA-approved and commercially available, unless there is a manufacturing product shortage.25 Serious patient illness and death associated with poor quality compounded drugs continue to occur.26 This is also made clear under Section 503A of the Federal Food, Drug, and Cosmetic Act:27

“The restrictions on making drugs that are essentially copies ensure that pharmacists and physicians do not compound drug products under the exemptions for patients who could use a commercially available drug product. Such a practice would create significant public health risks because patients would be unnecessarily exposed to drug products that have not been shown to be safe and effective and that may have been prepared under substandard manufacturing conditions. FDA has investigated serious adverse events in patients who received contaminated compounded drugs when a comparable approved drug, made in a facility subject to CGMP requirements, was available.”



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13. Weiss RA, Voigts R, Howell DJ. Absence of concentration congruity in six compounded polidocanol samples obtained for leg sclerotherapy. Dermatol Surg. 2011;37:812-815.

14. Almeida JI, Raines JK. FDA-approved sodium tetradecyl sulfate (STS) versus compounded STS for venous sclerotherapy. Dermatol Surg. 2007;33:1037-1044.

15. Rabe E, Pannier F. Sclerotherapy of varicose veins with polidocanol based on the guidelines of the German Society of Phlebology. Dermatol Surg. 2010;36:968-975.

16. Weiss MA, Hsu JT, Neuhaus I, Sadick NS, Duffy DM. Consensus for sclerotherapy. Dermatol Surg. 2014;40:1309-1318.

17. Rabe E, Schliephake D, Otto J, Breu FX, Pannier F. Sclerotherapy of telangiectases and reticular veins: a double-blind, randomized, comparative clinical trial of polidocanol, sodium tetradecyl sulphate and isotonic saline (EASI study). Phlebology. 2010;25:124-131.

18. Weiss RA, Weiss MA, Goldman MP. Physicians' negative perception of sclerotherapy for venous disorders: review of a 7-year experience with modern sclerotherapy. South Med J. 1992;85:1101-1106.

19. Mann MW. Sclerotherapy: it is back and better. Clin Plast Surg. 2011;38:475-487.

20. United States Food and Drug Administration. Asclera (polidocanol) 0.5% and 1% Injection Approval Letter (NDA 021201) March 30, 2010. Available: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/021201s000ltr.pdf. Accessed: May 2019.

21. Eckmann DM. Polidocanol for endovenous microfoam sclerosant therapy. Expert Opin Investig Drugs. 2009;18:1919-1927.

22. United States Food and Drug Administration. Code of Federal Regulations Title 21: Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals. 2012. Available: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211 Accessed May 2019.

23. Cabaleiro J. New England Compounding Center indictment. Int J Pharm Compd. 2015;19:94-102.

24. Centers for Disease Control and Prevention. Multistate Outbreak of Fungal Meningitis and Other Infections – Case Count. October 29, 2015. Available: https://www.cdc.gov/hai/outbreaks/meningitis-map-large.html#casecount_table. Accessed: 17 May 2019.

25. Gabay M. The drug quality and security act. Hosp Pharm. 2014;49:615-676.26. United States Food and Drug Administration. Compounding Risk Alerts.

2018. Available: https://www.fda.gov/drugs/human-drug-compounding/compounding-risk-alerts. Accessed: May, 2019.

27. United States Food and Drug Administration. Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act. Guidance for Industry 2018. Available: https://www.fda.gov/media/98973/download Accessed: May 2019.

28. McKenna KJ. Compounding sclerosing agents. Risks and consequences. Vein Magazine. 2008;March 31.

29. McKenna KJ. Compounded sclerosing agents: risks and consequences. Vein Magazine. 2015;April 1.


Margaret Mann MDE-mail:................……......................... [email protected]

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SPECIAL TOPIC

Tretinoin 0.05% Lotion for the Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris: Impact of Gender

and Race on Efficacy and SafetyEdward Lain MD,a Doris Day MD,B Julie Harper MD,c Eric Guenin PharmD PhD MPHd

ªAustin Institute for Clinical Research, Pflugerville, TXbDay Dermatology and Aesthetics New York, NY

cUniversity of Alabama at Birmingham Dermatology and Skin Care Center of Birmingham, Birmingham, ALdOrtho Dermatologics, Bridgewater, NJ

Background: There has been an increasing interest in gender and racial differences both in the pathogenesis and treatment of acne vulgaris (acne), and postinflammatory hyperpigmentation (PIH) is a major concern in patients of color. Female acne patients report more anxiety and depression with acne improvement positively influencing Quality of Life (QoL) than their male counterparts, and there are differences in acne presentation. The first lotion formulation of tretinoin was developed using novel polymeric emulsion technology to provide an important alternative option to treat these acne patients, especially those who may be sensitive to the irritant effects of other tretinoin formulations. Objective: To determine the impact of gender and race on the efficacy and safety of tretinoin 0.05% lotion in treating moderate or severe acne.Methods: Post hoc analysis of 2 multicenter, randomized, double-blind, vehicle-controlled Phase 3 studies in moderate-to-severe acne. Subjects (aged 9 to 58 years, N=1640) were randomized (1:1) to receive tretinoin 0.05% lotion or vehicle, once-daily for 12 weeks. Ef-ficacy assessments included changes in baseline inflammatory and noninflammatory lesions and treatment success (at least 2-grade reduction in Evaluator’s Global Severity Score [EGSS] and clear/almost clear). Quality of Life was assessed using the validated Acne QoL scale. Safety, adverse events (AEs), cutaneous tolerability, and hypo-/hyper-pigmentation (using a 4-point scale where 0=none and 3=severe) were evaluated at each study visit.Results: At week 12, mean percent reduction in inflammatory lesion counts were 56.9% and 53.4% respectively in female and male patients compared with 47.1% and 39.4% with vehicle (P≤0.001), with females statistically significant to males at week 8 [P=0.026]). Mean percent reduction in noninflammatory lesion counts in females and males were 51.7% and 46.1% respectively, compared with 34.9% and 29.7% with vehicle (P<0.001), with females statistically significant to males at week 12 (P=0.035). Treatment success was achieved by 23.6% and 16.1% of female and male patients treated with tretinoin 0.05% lotion by week 12 (P≤0.001 vs vehicle) with females statistically significant compared with males (P=0.013). Significant differences in inflammatory lesion count reductions were reported in Caucasian patients from week 8, and Black African/American male patients at week 12. Only male patients reported signifi-cant differences in both races in terms of noninflammatory lesions, and only Caucasian patients reported significant differences in treat-ment success. Female patients treated with tretinoin 0.05% lotion had statistically significant improvements in each Acne QoL domain (except role-social) compared with vehicle. Improvements in QoL in male subjects were only statistically different for acne symptoms. Tretinoin 0.05% lotion was well-tolerated in both genders. There were more treatment-related AEs in the female subpopulation, with a significantly greater incidence of skin dryness (P=0.006), that was more common in the younger Caucasian females.Conclusions: Tretinoin 0.05% lotion has been shown to be effective and well tolerated in moderate-to-severe acne. Treatment was sig-nificantly more effective in females than males. Tretinoin 0.05% lotion was well tolerated by both genders, although there was a higher incidence of treatment-related AEs, especially skin dryness, in females. There were racial and gender differences in QoL and beneficial effects on PIH in those patients most at risk.

J Drugs Dermatol. 2019;18(11):1128-1138.

ABSTRACT

INTRODUCTION

Acne vulgaris (acne) is a very common skin disease, typically associated with an adolescent population but recognized to persist or be prevalent in adulthood. As

our appreciation of the disease increases, there has been a cor-

responding interest in gender and racial differences both in its pathogenesis and treatment. Although the disease presenta-tion is generally similar in adults and adolescents, its character-istics appear to vary. Acne prevalence is similar in adolescents of both genders,1 but more common in women in the adult



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E. Lain, D. Day, J. Harper, E. Guenin

Efficacy EvaluationEfficacy evaluations were performed by the investigator and comprised of inflammatory and noninflammatory lesion counts and EGSS assessment at screening, baseline, and subsequent study visits (weeks 4, 8, and 12). Efficacy endpoints included percent change from baseline to week 12 in inflammatory and noninflammatory lesion counts and percent of patients who were treatment successes (ie, those patients who achieved at least a 2-grade reduction from baseline in EGSS and were also ‘clear’ or ‘almost clear’ at the same visit).

Additional assessments included a patient satisfaction score (PSS), and a validated acne-specific quality of life (Acne-QoL) questionnaire (Merck &Co, Inc. Whitehouse NJ). Patients were asked to rate their satisfaction with prior facial acne therapy on a PSS scale of 1 to 10 (where a score of 5 or greater was con-sidered as ‘satisfied’) at baseline, and with study treatment at week 12. Acne-QoL questionnaire scores were grouped into 4 domains (self-perception, role-emotional, role-social, and acne symptoms), where lower scores represented poorer QoL.

Safety and Cutaneous Tolerability EvaluationAdverse events (AEs) were evaluated throughout and summa-rized by treatment groups, severity, and relationship to study medication. All AEs occurring during the studies were recorded and classified on the basis of medical dictionary for drug regula-tory activities terminology (MedDRA Version 18.0) for the safety population. Counts reflected numbers of patients reporting one or more AEs that mapped to MedDRA. At each level of sum-marization patients were only counted once under the greatest reported relationship. Treatment-emergent AEs were those with an onset after the first application of study drug. Treatment group comparisons were made by tabulating the frequency of patients with one or more AEs during the study.

Cutaneous safety (erythema and scaling) and tolerability (itch-ing, burning, and stinging) were evaluated using a 4-point scale, where 0 (none), 1 (mild), 2 (moderate), and 3 (severe). Erythe-ma, scaling, hyperpigmentation and hypopigmentation severity were assessed by the investigator at the time of each study visit. Itching, burning, and stinging severity were solicited from the patient as an average of their symptoms during the period since their previous visit.

RESULTSAcross the 2 studies, there was a higher proportion of females (N=909) enrolled compared with males (N=731).

Female Acne PatientsA high proportion of female patients (N=763, 83.9%) completed the studies with ‘lost to follow-up’ (N=76, 8.4%) and ‘subject re-quest’ (N=43, 4.7%) the main reasons for study discontinuation (Figure 1). Only 4 (0.9%) female patients treated with tretinoin

population.2 In addition, female acne patients are more likely to develop anxiety and depression and, because of its visibility, it is known to have both psychosocial and functional impacts resulting in poor acne-related Quality of Life (QoL).

However, data are limited on racial differences in the clini-cal characteristics of acne and its burden on adult females.3

Women with acne tend to exhibit low QoL and negative self-perceptions. Data on racial differences suggest Caucasian women have higher mean scores on each of the 4 Acne-QoL domains (ie, higher QoL) than non-Caucasian women; but dif-ferences were not statistically significant.3

Over two-thirds of Black/African American women with acne experience postinflammatory hyperpigmentation (PIH).4 As a result, strategies that minimize the risk of pigmentary ab-normalities such as avoiding irritation associated with some topical therapies and reducing inflammation are important treatment considerations.5,6 A web-based study showed that, while clearing lesions was important in White females with acne, eliminating PIH was of primary importance in non-White females;3 supporting other work highlighting the importance of considering race-related characteristics when treating acne.7

Recently, clinical efficacy and safety data on a novel tretinoin 0.05% lotion were published.8 Tretinoin 0.05% lotion was sig-nificantly more effective than vehicle in treating moderate or severe acne, with a highly favorable safety and tolerability pro-file where the incidence of erythema, dryness and skin burning were lower than previously reported with other formulations of tretinoin.9 Here we present a post hoc analysis of the 2 phase 3 studies in 1640 patients with moderate or severe acne to study the impact of gender and race on efficacy and safety.

METHODSStudy DesignA post hoc analysis of 2 vehicle-controlled, randomized multi-center, double-blind studies in 1640 patients with moderate or severe acne. Patients were randomized (1:1) to receive tretinoin 0.05% lotion or vehicle applied to the face once-daily for 12 weeks.8

Study PopulationEligible patients for the post hoc analysis included patients aged 9 to 58 years who presented with 20 to 40 inflammatory lesions (papules, pustules, and nodules), 20 to 100 noninflammatory le-sions (open and closed comedones), and 2 nodules or less; and an Evaluator Global Severity Score [EGSS] score of 3 (moder-ate) or 4 (severe).

The post hoc analysis studied the impact of gender and race on efficacy, safety, and tolerability of tretinoin 0.05% lotion.



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TABLE 1.

Demographics and Baseline Characteristics by Gender (ITT Population, Pooled Data, N=1640)

Female population (N=909) Male population (N=731)

Tretinoin 0.05%(N=433)

Vehicle(N=476)

Total(N=909)


Vehicle(N=345)

Total(N=731)

Age- Mean years (SD) 22.4 (8.10) 22.4 (8.23) 22.4 (8.16) 18.1 (5.10) 18.1 (5.27) 18.1 (5.18)

Range 9-54 9-58 9-58 9-54 11-52 9-54

Ethnicity N (%)

Hispanic 183 (42.3%) 229 (48.1%) 412 (45.3%) 188 (48.8%) 166 (48.1%) 354 (48.5%)

Non-Hispanic 250 (57.7%) 247 (51.9%) 497 (54.7%) 197 (51.2%) 179 (51.9%) 376 (51.5%)

Race N (%)

American Indian or Alaska Native 3 (0.7%) 1 (0.2%) 4 (0.4%) 1 (0.3%) 1 (0.3%) 2 (0.3%)

Asian 18 (4.2%) 24 (5.0%) 42 (4.6%) 18 (4.7%) 9 (2.6%) 27 (3.7%)

Black or African American 111 (25.6%) 98 (20.6%) 209 (23.0%) 54 (14.0%) 45 (13.0%) 99 (13.5%)

Native Hawaiian or Other Pacific Islander 3 (0.7%) 4 (0.8%) 7 (0.8%) 1 (0.3%) 4 (1.2%) 5 (0.7%)

Caucasian 286 (66.1%) 336 (70.6%) 622 (68.4%) 307 (79.5%) 283 (82.0%) 590 (80.7%)

Other 12 (2.8%) 13 (2.7%) 25 (2.8%) 5 (1.3%) 3 (0.9%) 8 (1.1%)

Evaluator’s Global Severity Score N (%)

3 – Moderate 400 (92.6%) 435 (91.4%) 835 (92.0%) 337 (87.3%) 287 (83.2%) 624 (85.4%)

4 – Severe 32 (7.4%) 41 (8.6%) 73 (8.0%) 49 (12.7%) 58 (16.8%) 107 (14.6%)

Inflammatory Lesion Count- Mean (SD) 25.7 (5.34) 25.3 (4.86) 25.5 (5.10) 27.0 (5.60) 27.4 (5.96) 27.2 (5.77)

Noninflammatory Lesion Count- Mean (SD) 39.7 (17.03) 42.4 (18.39) 41.1 (17.80) 44.7 (18.71) 45.5 (19.48) 45.1 (19.07)

One male patient treated with tretinoin did not report ethnicityOne female patient treated with tretinoin did not report severity

FIGURE 1. Patient disposition by gender [ITT population, showing percent completion and reasons for discontinuation (all randomized patients, N=1640, pooled data)].

were slightly higher in Caucasian females, with reasons for discontinuation similar to the overall study populations. Three Caucasian females treated with tretinoin 0.05% lotion discontin-ued due to AEs. At baseline, 92.0% of female patients (N=835) had moderate acne (EGSS=3) and 8.0% (N=73) severe acne (Ta-ble 1). Mean inflammatory and noninflammatory lesions counts (SD) were 25.5 (5.10) and 41.1 (17.80) respectively.

0.05% lotion discontinued due to AEs (irritant dermatitis, contact dermatitis, burning face sensation, and facial swelling, erythe-ma, and burning). Mean age (SD) was 22.4 (8.16) years (Table 1). Compared with other acne trials, there was a high proportion of Hispanics (N=412, 45.3%), and in terms of race most (91.4%) female patients were either Caucasians (N=622, 68.4%) or Black/African American (N=209, 23.0%). Completion rates (84.6%)



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Changes in inflammatory and noninflammatory lesions in fe-male patients were significant compared with vehicle from week 8 and week 4 respectively (P=0.003 and P=0.004). By week 12, the percent change from baseline (LS mean) was 56.9% (P=0.001 vs vehicle) and 51.7% (P<0.001) respectively, compared with 47.1% and 34.9%, see Figures 2 and 3. Treatment success (at least a 2-grade improvement in EGSS and ‘clear’ or ‘almost clear’) was significant compared with vehicle from week 8 (P=0.046), and by

week 12, 23.6% of patients were treatment successes (compared with 13.5% on vehicle, P<0.001), see Figure 4.

At week 12, inflammatory and noninflammatory lesion count reduction in the Caucasian females (56.3% and 52.6%), com-pared with 45.4% [P=0.001] and 34.9% [P<0.001] with vehicle, was similar to the overall population (Figures 5 and 6); and treat-ment success was achieved in 23.3% of patients (compared with

FIGURE 2. Percent change in inflammatory lesions from baseline to week 12 by gender (ITT population, LS mean).

FIGURE 3. Percent change in noninflammatory lesions from baseline to week 12 by gender (ITT population, LS mean).



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FIGURE 4. Treatment success. Percent of patients with at least a 2-grade improvement in EGSS and ‘clear’ or ‘almost clear’ at each study visit by gender (ITT population pooled data).

FIGURE 5. Percent change in inflammatory lesions from baseline to week 12 by gender and race (ITT population, LS mean).

12.6% on vehicle, P=0.001), see Figure 7. Although lesion count reduction was greater in Black/African American female patients treated with tretinoin 0.05% lotion compared with vehicle, differ-ences were not significant. There were no significant differences between Caucasian and Black/African American female patients in terms of inflammatory (56.2% vs 57.3%, P=0.879) and nonin-flammatory (52.8% vs 49.3%, P=0.236) lesion count reduction at week 12; or treatment success (23.3% vs 23.0%, P=0.946) with tretinoin 0.05% lotion.

Patient satisfaction (as assessed by PSS responses) was signifi-cantly greater with tretinoin 0.05% lotion at week 12 (7.2 vs 6.5, P<0.001). There was no significant difference between Caucasian and Black/African American females in terms for improvements in patient satisfaction (P=0.382).

Improvements (absolute change from baseline) in all 4 Acne QoL domains with tretinoin 0.05% lotion were also significant com-pared with vehicle at week 12 (Figure 8), as were improvements



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FIGURE 6. Percent change in noninflammatory lesions from baseline to week 12 by gender and race (ITT population, LS mean).

FIGURE 7. Treatment success. Percent of patients with at least a 2-grade improvement in EGSS and ‘clear’ or ‘almost clear’ at each study visit by gender and race (ITT population pooled data).



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in Caucasian females with the exception of self-perception (P=0.051) and role-social (P=0.104). There was no significant dif-ference in Acne QoL domain improvements between female Black/African American or Caucasian patients: self-perception (P=0.245), role-emotional (P=0.205), role-social (P=0.101), and acne symptoms (P=0.178).

Male Acne PatientsA high proportion of male patients completed the studies (N=618, 84.5%), with ‘lost to follow-up’ (N=58, 7.9%) and ‘subject request’ (N=33, 4.5%) the main reasons for study discontinua-tion, see Figure 1. Only 2 (0.5%) patients treated with tretinoin 0.05% lotion discontinued due to AEs. Mean age (SD) was 18.1 (5.18) years, see Table 1. Again, there was a high proportion of

Hispanics (N=354, 48.5%), and most patients (94.4%) were ei-ther Caucasian (N=590, 80.7%) or Black/African American (N=99, 13.5%). Completion rates (84.4%) were similar in the White males, with reasons for discontinuation similar to the overall study populations. Two Caucasian males treated with tretinoin 0.05% lotion discontinued due to AEs. At baseline, 85.4% of male patients (N=624) had moderate acne (EGSS=3) and 14.6% (N=107) severe acne, see Table 1. Mean inflammatory and nonin-flammatory lesions counts (SD) were 27.2 (5.77) and 45.1 (19.07) respectively.

Changes in inflammatory and noninflammatory lesions were significant compared with vehicle from week 8 and week 4 respectively (P=0.003 and P=0.001). By week 12, the percent

FIGURE 8. Improvement in acne QoL from baseline to week 12 by gender (ITT population pooled data).

FIGURE 9. Investigator assessed cutaneous safety and tolerability (scaling and erythema) from baseline to week 12 by gender (safety population, pooled data, patients treated with tretinoin 0.05% lotion).



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change from baseline (LS mean) was 53.4% (P<0.001 vs vehi-cle) and 46.1% (P<0.001) respectively compared with 39.4% and 29.7%, see Figures 2 and 3. Treatment success (at least a 2-grade improvement in EGSS and ‘clear’ or ‘almost clear’) was signifi-cant compared with vehicle from week 8 (P=0.080), and at week 12 16.1% of patients (compared with 7.6%, P=0.001) were treat-ment successes, see Figure 4.

At week 12, lesion count reduction in the Caucasian males (51.9% and 45.9% with tretinoin compared with 40.1% [P=0.001] and 31.4% [P<0.001] with vehicle) was similar to the overall study population, see Figures 5 and 6; and treatment success was achieved in 15.4% of patients (compared with 7.7% in the vehicle group, P=0.007), see Figure 7. There were no signifi-cant differences between active and vehicle in Black/African

American patients, and no significant differences between male Caucasian and Black/African American patients in terms of in-flammatory (52.1% vs 58.2%, P=0.346) and noninflammatory (45.9% vs 49.1%, P=0.522) lesion count reduction or treatment success (15.4% vs 18.0%, P=0.668) at week 12.

Patient satisfaction (as assessed by PSS responses) was signifi-cantly greater with tretinoin 0.05% lotion at week 12 (7.3 vs 6.7, P=0.003). There was no significant difference between White and Black/African American males in terms for improvements in pa-tient satisfaction (P=0.641).

Improvements (absolute change from baseline) in only one Acne QoL domain with tretinoin 0.05% lotion (acne symptoms) were sig-nificant compared with vehicle at week 12 (P=0.004), see Figure 8.

FIGURE 10. Patient reported cutaneous safety and tolerability (itching, burning, and stinging) from baseline to week 12 by gender (safety population, pooled data, patients treated with tretinoin 0.05% lotion).

FIGURE 11. Investigator assessed cutaneous safety and tolerability (hyperpigmentation) from baseline to week 12 by gender and race (safety population, pooled data).



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Improvements in White males were only significant vs vehicle for acne symptoms (P=0.035). There was no significant differ-ence in Acne QoL domain improvements between male Black/African American or White patients: self-perception (P=0.911), role-emotional (P=0.606), role-social (P=0.490), and acne symp-toms (P=0.942).

Gender DifferencesOverall compliance with tretinoin 0.05% lotion treatment across the 2 studies was slightly better in the female population than the males. Calculated compliance (a patient was considered compliant if they did not miss more than 5 consecutive days dosing and applied 80% to 120% of the expected applications) was 92.0% in males and 94.0% in females. There was a signifi-cant difference in terms of inflammatory lesion count reduction between female and male patients, favouring female patients, at week 8 only (46.0% vs 39.4%, P=0.026), and a significant dif-ference in terms of noninflammatory lesion count reduction at week 12 (51.7% vs 46.1%, P=0.035).

There was a significant difference between female and male patients in terms of treatment success at week 12 (23.6% vs 16.1%, P=0.013); and between female and male Caucasian pa-tients in terms of noninflammatory lesion count reduction (52.7% and 46.0%, P=0.016) and treatment success (23.3% vs 15.4%, P=0.024). There were no significant differences between female and male Caucasian patients in inflammatory lesion count reduction (56.1% and 52.2%, P=0.129) at week 12; and no significant differences between female and male Black/African American patients in terms of inflammatory or noninflammato-ry lesion count reduction (57.4% and 49.4% vs 58.8% and 49.3% respectively, P=0.856 and P=0.922) or treatment success (23.0% vs 18.0%, P=0.501).

Patient satisfaction with prior facial acne treatment was similar between gender and race, although the differences seen be-tween Caucasian and Black/African American patients was more marked in males (4.9 and 4.3 respectively, compared with 4.5 and 4.6 in females). Treatment satisfaction with tretinoin 0.05% lotion by week 12 (as assessed by PSS responses) was not sig-nificantly different between female and male patients treated with tretinoin 0.05% lotion by week 12 (7.2 vs 7.3, P=0.932), or between Caucasian females and males (7.2 vs 7.3, P=0.444).

At baseline, Acne-QoL domain scores tended to be higher in the male patients (ie, better QoL) who were subsequently treated with tretinoin 0.05% lotion: self-perception (17.6 vs 12.8 in fe-males), role-emotional (17.2 vs 13.0), role-social (16.2 vs 13.7), and acne symptoms (15.9 vs 13.4). All domain scores increased with treatment, although there were not significant differences between gender in terms of absolute change. In all cases do-main scores were higher in male patients at week 12. Similar results were seen in Caucasian and Black/African American pa-

tients. In female patients, improvements in Acne-QoL domains were greater in Caucasians than in Black/African Americans in all cases, whereas in males, improvements in each domain score were greater in Black/African Americans.

Safety and Cutaneous TolerabilityThere was a significant difference in treatment-related AEs be-tween female and male patients (N=43, 10.6% and N=19, 5.2% respectively, P=0.008), with a significant difference in terms of application site dryness (N=22, 5.4% and N=6, 1.7% respectively, P=0.006), see Table 2. Treatment-related AEs were most prevalent in adolescent females (13.5%), and differences between gen-der age groups was also significant (P=0.021). Application site dryness was also most common in the adolescent (<18 years) females (6.4% vs 4.9% in the adult females). There was also a significant difference in Caucasian females and males (N=29, 10.9% and N=16, 5.5% respectively, P=0.028), with a significant difference in terms of application site dryness (N=16, 6.0% and N=5, 1.7% respectively, P=0.013). Overall there were 4 reports (2.6%) of application site dryness in Black/African American pa-tients, all in females.

TABLE 2.

Comparison of Male and Female Subpopulations: Treatment-Emergent and Related Adverse Event (AE) Characteristics through Week 12 (Pooled Data – Safety Population)

Tretinoin 0.05% Lotion

Male Patients(N=363)


Female Patients(N=404)

Patients reporting any TEAE 79 (21.8%) 101 (25.0%)

Patients reporting any SAE 2 (0.6%) 5 (1.2%)

Patients who died 0 (0.0%) 0 (0.0%)

Patients who discontinued due to TEAE

2 (0.6%) 10 (2.5%)

Severity of AEs reported

Mild 47 (12.9%) 58 (14.4%)

Moderate 27 (7.4%) 40 (9.7%)

Severe 5 (1.4%) 3 (0.7%)

Relationship to study drug (% by patient)

Related 19 (5.2%) 43 (10.6%)

Unrelated 60 (16.5%) 58 (14.4%)

Treatment Related AEs reported by ≥1% patients*

Application site pain 8 (2.2%) 16 (4.0%)

Application site dryness 6 (1.7%) 22 (5.4%)

Application site erythema 4 (1.1%) 7 (1.7%)

Application site exfoliation 2 (0.6%) 5 (1.2%)

Application site pruritus 1 (0.3%) 6 (1.5%)*difference between two groups overall and for dryness was significant (P=0.008)



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The investigator assessment of scaling and erythema (Figure 9) and patient reports of itching, burning, and stinging (Figure 10) were very similar in female and male patients at baseline. Ery-thema and itching were the most common, reported in 30% to 40% of patients. Both were markedly reduced in incidence and severity by week 12. There was a slight increase in mild scaling in the male patients treated with tretinoin 0.05% lotion. Hyper-pigmentation was more prevalent in Black/African American female patients at baseline, with more reports of moderate (2) or severe (3) severity (Figure 11). Both the incidence and sever-ity of the hyperpigmentation were reduced by week 12. Mean scores reduced from 0.9 to 0.7 (females) and 0.6 to 0.4 (males), where 1=mild.

DISCUSSIONAcne is a common disease in adolescents and many adults. Fe-males are more vulnerable to acne across all age groups, with female gender and acne being two independent contributing factors in developing major depression.10,11 However, the impact of acne on different genders remains controversial, and poorly studied.

Our post hoc analysis of two large phase 3 studies in patients with moderate or severe acne studied the impact of gender and race on treatment outcomes. Studies have shown that male pa-tients typically are less compliant than females, especially with topical treatments.12 In these phase 3 studies overall adherence was high, although slightly better in the female population (94% vs 92%). Tretinoin 0.05% lotion was generally more effective in female patients; 23.6% of females were treatment successes by week 12 compared with 16.1% of males (P=0.013). There were also significant gender differences in favor of the female patients in terms of lesion count reductions; and a previous pub-lication has reported that reduction in noninflammatory lesions in adult females with tretinoin 0.05% lotion was greater than that reported in adolescents.16

Among women, acne is more common in skin of color, with a prevalence of 37% in Black, 32% Hispanic, and 30% Asian women compared with 24% in Caucasian women.13 Although racial/ethnic differences in acne presentation are reported in the literature, there are little data on how these differences might relate to QoL. Women are generally more concerned than men about their physical appearance, making then more susceptible to poorer QoL.14 A web-based survey of female adults showed White and Black subjects reported less negative impact of acne on QoL than Hispanics and Asians, although in only 2 domains (self-perception and role-social) were differences significant.15

In our post hoc analysis, QoL was worse in the female popu-lation at baseline, and while QoL improved in both genders following treatment with tretinoin 0.05% lotion, there was no significant difference in absolute change in domain scores by

week 12 between genders.

Variations in Acne-QoL were observed between race and gender. Baseline domain scores were lower in the Caucasian fe-males, and improvements by week 12 greater than those seen in Black/African American females. The reverse was noted in male patients where baseline domain scores were lowest in Black/Af-rican Americans, and improvements greater in Caucasians.

Local tolerability issues with topical therapy, such as cutaneous irritation, erythema, dryness, peeling, and scaling can lead to poor adherence.17,18 As might be expected, erythema and itching were common at baseline. All aspects of cutaneous tolerability improved with treatment, and these improvements were similar across genders. By week 12, more than 70% of patients reported no erythema or scaling, and 90% of patients reported no itching, burning, or stinging.

Treatment-related AEs were significantly more common in females, especially those under 18 years old and Caucasian fe-males, with application site dryness being the most prevalent. It is not uncommon to see adult women with acne and dry skin, perhaps a result of decreased sebum production;19 and in both groups of women their education on the use of appropriate moisturizers and gentle, non-soap cleansers with pH close to skin should be a part of the patient’s treatment plan.20

Hyperpigmentation is of greater concern in acne patients with darker skin tones than lesion clearance. In the Black/African American subpopulation hyperpigmentation was more com-mon in females at baseline. In both groups the incidence and severity decreased with tretinoin 0.05% lotion, suggesting a benefit of treatment as retinoids are well known to treat both acne and PIH.21

CONCLUSIONTretinoin 0.05% lotion has been shown to be highly effective and well tolerated in patients with moderate or severe acne. Ef-ficacy appears greatest in Caucasian females, with significantly more reports of application site dryness than in males that should be easily managed with appropriate use of moisturizers. There were racial and gender differences in QoL, and tretinoin 0.05% lotion seemed to have a beneficial effect on PIH in those patients most at risk.

DISCLOSURESDr Guenin is an employee of Bausch Health. Dr Lain and Dr Harper are advisors and/or investigators with Bausch Health. Dr Day has participated in speaker programs for Bausch Health.

REFERENCES1. Smithard A, Glazebrook C, Williams HC. Acne prevalence, knowledge about

acne and psychological morbidity in mid-adolescence: a community-based study. Br J Dermatol. 2001;145:274-279.



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2. Collier CN, Harper JC, Cafardi JA. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008;58(1):56-59.

3. Callender VD, Alexis AF, Daniels SR, et al. Racial differences in clinical char-acteristics, perceptions and behaviors, and psychosocial impact of adult fe-male acne. J Clin Aesthet Dermatol. 2014;7(7):19-31.

4. Callender VD. Acne in ethnic skin: special considerations for therapy. Derma-tol Ther. 2004;17(2):184-195.

5. Yin NC, McMichael AJ. Acne in patients with skin of color: practical manage-ment. Am J Clin Dermatol. 2014;15(1):7-16.

6. Alexis AF. Acne in patients with skin of color. J Drugs Dermatol. 2011;10:sl3–sl6.

7. Shah SK, Alexis AF. Acne in skin of color: practical approaches to treatment. J Dermatol Treat. 2010;21:206-211.

8. Tyring SK, Kircik LH, Pariser DM, et al. Novel tretinoin 0.05% lotion for the once-daily treatment of moderate-to-severe acne vulgaris: assessment of efficacy and safety in patients aged 9 years and older. J Drugs Dermatol. 2018;17(10):1084-1091.

9. Harper JC, Roberts WE, Zeichner JA, et al. Novel tretinoin 0.05% lotion for the once-daily treatment of moderate-to-severe acne vulgaris: assessment of safety and tolerability in subgroups. J Dermatolog Treat. 2019 Apr 2:1-8. [Epub ahead of print].

10. Uhlenhake E, Yentzer BA, Feldman SR. Acne vulgaris and depression: a retro-spective examination. J Cosmet Dermatol. 2010;9(1):59-63.

11. Yentzer BA, Hick J, Reese E, et al. Acne vulgaris in the United States: A descriptive epidemiology. Cutis. 2010;86(2):94-99.

12. Jones-Cabellero M, Pedrosa E, Penas PF. Self-reported adherence to treatment and quality of life in mild to moderate acne. Dermatology. 2008;217:309-314.

13. Perkins AC, Cheng CE, Hillebrand GG, et al. Comparison of the epidemiol-ogy of acne vulgaris among Caucasian, Asian, Continental Indian and African American women. J Eur Acad Dermatol Venereol. 2011;25(9),1054-1060.

14. Pliner P, Chaiken S, Flett GL. Gender differences in concern with body weight and physical appearance over the life span. Personality and Social Psychol-ogy Bulletin. 1990;16(2):263-273.

15. Gorelick J, Daniels SR, Kawata AK, et al. Acne-related quality of life among female adults of different races/ethnicities. J Dermatol Nurses Assoc. 2015;7(1):154-162.

16. Kircik LH, Baldwin H, Lain E, et al. Novel tretinoin 0.05% lotion for the once-daily treatment of moderate-to-severe acne vulgaris in an adult and adoles-cent female population. J Drugs Dermatol. 2019;18(2):178-188.

17. Akomeah FK. Topical dermatological drug delivery: Quo Vardis? Curr Drug Deliv. 2010;7(4):283–296.

18. Castro GA, Ferreira LA. Novel vesicular and particulate drug delivery system for topical treatment of acne. Expert Opin Drug Deliv. 2008;5(6):665-679.

19. Zeichner JA, Baldwin HE, Cook-Bolden FE, et al. Emerging issues in adult female acne. J Clin Aesthet Dermatol. 2017;10(1):37-46.

20. Yang JH, Weng SL, Lee CY, et al. A comparative study of cutaneous mani-festations of hyperandrogenism in obese and non-obese Taiwanese women. Arch Gynecol Obstet. 2010;282(3):327-333.

21. Orthonne JP, Passermon T. Melanin pigmentary disorders: treatment update. Dermatol Clin. 2005;23:209-226.


Edward Lain MDE-mail:................……................................. [email protected]




https://www.janmarini.com/




SPECIAL TOPIC

A Cohort Study Using a Facial Cleansing Brush With Acne Cleansing Brush Head and a Gel Cleanser in Subjects

With Mild-to-Moderate Acne and Acne-Prone SkinMichael H. Gold MD FAAD,a Glynis R. Ablon MD FAAD,b Anneke Andriessen PhD,c Vivian W. Bucay MD FAAD,d David J. Goldberg MD JD,e Jeremy B. Green MD FAAD,f

Deirdre Hooper MD FAAD,g Stephen H. Mandy MD FAAD,h Mark S. Nestor MD PhD,i Arisa Ortiz MD FAAD FACMSj

aGold Skin Care Center, Nashville, TNBAblon Skin Institute & Research Center, University of California, Los Angeles, Manhattan Beach, CA

cRadboud UMC Nijmegen, Andriessen Consultants, Malden, NLDBucay Center for Dermatology and Aesthetics, San Antonio, TX

eSkin Laser & Surgery Specialists of NY and NJ, Hackensack, NJ; Icahn School of Medicine at Mt. Sinai, New York, NYfSKIN Associates of South Florida, Miami, FL

gAudubon Dermatology, New Orleans, LAhDepartment of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami FL

IMD, PhD, Center for Clinical and Cosmetic Research, Adventura FL; Center for Cosmetical Enhancement, Adventura, FLjLaser & Cosmetic Dermatology, Department of Dermatology, UC San Diego, San Diego, CA

Introduction: Acne vulgaris is a highly prevalent skin condition that can adversely affect the quality of life. Acne-predisposed skin is in a state of subclinical inflammation leading to skin barrier dysfunction. A multi-center cohort study was designed to evaluate clinical efficacy and safety of twice daily facial cleansing using an oscillatory sonic brush, acne brush head, and cleansing gel for 4 weeks. Methods: Subjects with mild-to-moderate acne and acne-prone skin used the cleansing regime after which they applied the skin care products they routinely used. Physician-assessed skin condition comparing baseline versus week 4 using the FDA/IGA scale and sub-ject satisfaction with cleansing efficacy and handling properties of the regime were scored during the last visit. Results: Forty-six subjects completed the study. Physician-scored skin condition showed a statistically significant improvement in FDA/IGA scores and a significant reduction of inflammatory and non-inflammatory lesions comparing baseline versus 4 weeks. Thirty-five (76.0%) subjects had cleared or almost cleared. Subjects similarly assessed their skin to be improved. Conclusion: Both the physician and subject scores revealed the gentle cleansing routine using the sonic brush to be effective reducing the number of acne lesions, improving skin condition. No adverse events were reported during the study period. The cleansing regime may offer an attractive, safe option for maintenance and treatment of subjects with mild-to-moderate acne and acne-prone skin.

J Drugs Dermatol. 2019;18(11):1140-1145.

ABSTRACT

INTRODUCTION

Acne vulgaris is a highly prevalent skin condition.1 The common onset of acne is in early adolescence, about 85% of those affected have the condition between the

ages 8 and 17 years.1 Acne affects a substantial number of adults, particularly women, who are more likely to view it as a disorder that requires treatment even when the condition is mild.1-3 Compared to adolescent acne, adult acne tends to be more inflammatory3 with the involvement of the cheeks and lower half of the face.3 The presence of comedones in adult acne is uncommon.3

Acne can adversely affect the quality of life due to psychologi-cal and emotional distress, including poor self-esteem, social anxiety, depression, and suicidal ideation.4 There is an unmet

need for acne information, education, and treatments that pro-vide the best patient outcomes.4

Acne has a complex, multifactorial pathophysiology.5 Acne-pre-disposed skin is in a state of subclinical inflammation, which may be linked to changes in skin surface pH and disturbances of the stratum corneum.5 Inflammatory events trigger acne le-sions and correlate to skin barrier dysfunction.5

The impaired skin barrier in acne may benefit from a gentle cleanser used along with other therapeutic measures. Twice daily use of a gentle cleanser in patients with mild-to-moderate acne demonstrated a reduction in acne lesion counts in clinical studies6,7 without damage to the skin barrier or sebum over-compensation.



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M.H. Gold, G.R. Ablon, A. Andriessen, et al

OutcomesThe purpose of the cohort study was to evaluate clinical efficacy and safety of twice daily facial cleansing using a sonic brush, acne brush head and cleansing gel by subjects with mild-to-moderate acne as part of a daily skin care routine.

The primary objective was physician-assessed skin condition comparing baseline versus day 28 (+/- 5 days) (end) using the FDA/IGA scale (Clear (0), Almost clear/minimal (1), Mild (2), Moderate (3), Severe (4)).

An oscillatory sonic brush uses the skin’s elastic properties by applying an optimal amplitude and frequency range.8 The sonic brush has been shown to be safe and effective at cleansing the skin for various dermatologic conditions.8 Effective cleansing clears pores of debris, allowing sebum to leave the skin surface unimpeded. Cleansing and moisturizing help to manage pH levels of the skin, enabling sufficient water retention.9

METHODSCohort PopulationA multi-center cohort study evaluated the efficacy and safety of a facial cleansing regimen when used twice daily by subjects with mild-to-moderate acne and acne-prone skin as part of a daily skin care routine. Subjects were included in the cohort study with mild-to-moderate facial acne (score 2-3 on the FDA Investigator Global Acne Assessment scale (FDA/IGA), 5-10 in-flammatory acne lesions (papules, pustules) and 10 or more non-inflammatory acne lesions (open and closed comedones) (Table 1). Fifty subjects were recruited from 10 centers in the USA, each of the five participating physicians aimed to recruit five subjects.

Regional/local ethical committee approval was obtained for the study. Prior to subject inclusion, the physician informed the sub-ject about the study and obtained the subject’s written consent for participation.

Study InterventionsThe Clarisonic Mia 2 facial sonic cleansing brush with acne cleansing brush head (Clarisonic Redmond, WA) and Pore and Blemish Gel Cleanser, were used by subjects with mild-to-mod-erate acne as part of a daily skin care routine.

Depending on the severity of the condition, once/twice daily (morning and bedtime) facial cleansing using the sonic brush and gel was performed by the subject over a 4-week (+/- 5 days) period. After cleansing, subjects applied the skin care products they routinely used. The sonic brush, brush head, and cleansing gel were provided at the start of the study and were to be used according to the instructions of the manufacturer (Figure 1). Be-fore starting the cohort, the physician demonstrated the use of the sonic brush and cleansing gel to each subject.

Subjects were allowed to use acne medication (topical and sys-temic) and/or the over-the-counter products they were using at the time of inclusion in the study, except the cleanser. Subjects who have been using acne medication and/or the over-the-counter products for at least two weeks prior to the study start were instructed to continue the same acne medication and/or the over-the-counter products until the end of the study (week 4 (+/- 5 days).

FIGURE 1. Use of the sonic brush and cleansing gel. Prior to the first use, charge the facial cleansing brush handle for 24 hours. Remove the eye makeup by hand. Apply quarter-size amount of the gel cleanser directly to moistened skin or to a wet acne cleansing brush head. Push the on/off button to turn on your sonic brush. Select the desired speed. Follow T-Timer prompts while gently moving the brush head in small circular motions. It is recommended: 1) 20 seconds on forehead; 2) 20 seconds on nose and chin; 3) 10 seconds on one cheek; 4) 10 seconds on the other cheek. NOTE: Keep the brush head flush to the skin. Pressing too hard will impede the motion and reduce effectiveness.

TABLE 1.

FDA Investigator Global Acne (IGA) Assessment

Acne Grade Description of Facial Condition

0 = noneClear skin with no inflammatory or non-inflammatory lesions

1 = minimalAlmost clear; rare non-inflammatory lesions with no more than one small inflammatory lesion

2 = mild

Mild severity; greater than Grade 1; some non-inflammatory lesions with no more than a few inflammatory lesions (papules/pustules only, no nodular lesions)

3 = moderate

Moderate severity; greater than Grade 2; up to many non-inflammatory lesions and may have some inflammatory lesions, but no more than one small nodular lesion

4 = severeSevere; greater than Grade 3; up to many non-inflammatory and inflammatory lesions, but no more than a few nodular lesions



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RESULTSThe multi-center cohort study aimed to include 50 subjects with mild-to-moderate facial acne. Four subjects withdrew consent before the start of the study and forty-six subjects started with the sonic brush cleansing regime after giving informed consent. Subjects had a mean age of 27.55 ( ± SD 8.02) years, were mainly female: 42 (91.3%) with 4 (8.7%) males.

FDA/IGA acne score at baseline was mild in 28 (60.9%) of the cases, moderate in 14 (30.4%) and severe in 2 (4.3%) of the cas-es. For 2 (4.3%) cases severity class was not scored (Table 3).

Secondary objectives were subject satisfaction with cleansing efficacy and handling properties of the sonic brush, cleansing head and cleansing gel scored at day 28 (+/- 5 days) during the last visit. The subjects scored their findings on a 5-Point Likert scale: Strongly disagree (1), Disagree (2), Neutral (3), Agree (4), Strongly agree (5).

All unexpected adverse events observed by or reported to the investigators were evaluated. The intensity, duration and causal relationship to the treatment were rated for all adverse events.

Study DesignThe cohort had an evaluation duration of 28 days (+/- 5 days) during which the cleansing regime was used. Two or three (depending if screening and baseline assessments could be combined during visit 1) visits were planned during the study period (Table 2).

The sample size for the study was calculated at fifty subjects, which was deemed large enough to collect clinically meaningful data and allowed for a dropout rate of 15%. Subjects used the cleansing regime for a period of 28 days (+/- 5 days). Statisti-cal evaluation was performed using IBM SPSS (IBM Corporation Armonk, New York, NY). A paired T-test or ANOVA was applied to analyze skin condition comparing baseline (day 0) versus day 28 (+/- 5 days) (end) per subject and per group. Where appropriate tests were carried out at the 5% significance level and a confi-dence interval of 95%.

FIGURE 2. Physician-assessed skin condition at baseline and at the end of the study. Mean difference: 1.33 (SD ± 0.68). Two-tailed paired samples test: t(42) = 12.78, P< 0.05*

*FDA/IGA scale: 0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe. FDA Investigator Global Acne Assessment scale (FDA/IGA)

TABLE 2.

Visits and Activities

Visit # TimelineVisit 1:Week 0

(Baseline)*

Visit 2:Week 4

(+/- 5 days)end of study

Informed Consent X --

Medical history on facial acne X --

Demographics X --

Physician assessment of facial skin area using a clinical scale

X X

Eligibility Assessment X --

Twice-daily treatment with a sonic brush, acne brush head and cleansing gel and use of routine skin care regime

X x

Patient SatisfactionQuestionnaire

-- X

Concomitant facialmedications

X X

Assess AEs/SAEs X X

End of evaluation -- X

AE: Adverse event; SAE: Serious adverse event*Can be the same day as screening

TABLE 3.

Demographics and Physician-Assessed Skin Condition at Baseline

N = 46 (100%)

Age (years): 27.55

Mean: ( ± SD)

( ± SD 8.02)

Range 30

Gender:Male: 4 (8.7%)Female: 42 (91.3%)

Physician-scored FDA/IGA

0 = none

1 = minimal

2 = mild

3 = moderate

4 = se-

vere

Not scored

Baseline: Frequency (%)

0 028.0

(60.9%) 14.0

(30.4%)

2.0 (4.3%)

2 (4.3%)

FDA/IGA scale: 0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = severeFDA Investigator Global Acne Assessment scale (FDA/IGA), Inflammatory lesions (IL), Non-inflammatory lesions (NIL)



1143



Treatments reported at the start of the study that were continued throughout included: benzoyl peroxide and a topical retinoid ei-ther alone or in combination (with/without a topical antibiotic) for mild acne and oral antibiotics combined with topical therapy for moderate-to-severe acne. Only two subjects used a non-comedogenic moisturizer to reduce inflammation and/or side effects from treatment, such as skin irritation or dryness.

Forty-four subjects (95.7%) completed the study period and were included in the analysis. Two subjects were lost to follow-up. No adverse events were reported during the study period. At the end of the study physician-scored skin condition revealed that 35 (76.0%) subjects had cleared or almost cleared, 8 (17.4%) had mild acne and 1 (2.2%) had moderate acne (Table 4). The mean improvement in FDA/IGA comparing skin condition at baseline versus 28 days (+/- 5 days) was significant (1.33 (SD ± 0.68)); Two-tailed Paired Samples Test: t(42) = 12.78, P< 0.05 as well as the reduction in the number of physician-scored inflam-matory and non-inflammatory lesions (Figure 2).

The subject scored skin condition using a 5-Point scale (Strongly disagree (1), Disagree (2), Neutral (3), Agree (4), Strongly agree (5)) at the end of the study revealed comparable results to the physician scores on improvement of skin condition. When asked if the number of skin imperfections had reduced they scored a mean of 4.13 (SD ± 0.99) (Agree/Strongly agree). The subjects further reported that the excess of sebum was removed (4.31 (SD ± 0.82)), visible blackheads had reduced (4.07 (SD ± 1.00)) as well as redness (4.04 (SD ± 0.93)) providing a more even facial skin complexion (4.08 (SD ± 0.87)). The subjects rated the brush and gel as easy (4.89 (SD ± 0.32)), fast and effective to use (4.84 (SD ± 0.43)), and fitted their skin care regimen (4.77 (SD ± 0.57)). The subjects reported that after using the sonic brush and gel for 4 weeks they felt better about their facial skin (4.61 (SD ±

0.75)) and more confident in their personal (4.39 (SD ± 0.92)) and professional life (4.41 (SD ± 0.95)) (Table 5).

DISCUSSIONAcne affected skin is characterized by inflammation leading to disruption of normal physiological functions of the epidermis, in-cluding the stratum corneum.5,15,16 Moreover acne therapies can induce alterations in the epidermis. Enhanced trans-epidermal water loss is reported with benzoyl peroxide, tretinoin, tazaro-tene, and isotretinoin use.5 Xerosis and dermatitis commonly result from acne treatment and are very important reasons for non-compliance.4

The compromised skin barrier in acne may be improved with a gentle cleansing regime, potentially reducing acne lesion counts and enhancing antimicrobial defenses.10,16

The evaluated oscillatory sonic brush applies an optimal am-

TABLE 4.

Physician-Assessed Skin Condition at Baseline and at Week 4 Baseline N = 46 (100%); End of study N = 44 (95.7%)

Physician-scored FDA/IGA

0 = none

1 = minimal

2 = mild

3 = moderate

4 = severe

Not scored

Baseline: Frequency (%)

0 028.0

(60.9%) 14.0

(30.4%)

2.0 (4.3%)

2 (4.3%)

End of study: at 28 days (+/- 5 days): Frequency (%)

6.0 (13.0%)

29.0 (63.0%)

8.0 (17.4%)

1.0 (2.2%)

02.0

(4.3%)

Comparing baseline versus end results: Mean difference: 1.33 (SD ± 0.68); Two-tailed Paired Samples Test: t(42) = 12.78, P< 0.05 (0.00). FDA/IGA scale: 0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = severeFDA Investigator Global Acne Assessment scale (FDA/IGA), inflammatory lesions (IL), non-inflammatory lesions (NIL)

TABLE 5.

End of Study Subject Scores on Skin Condition

N = 46: Item scored Mean

( ± SD )

The number of skin imperfections is reduced 4.13 (0.99)

The pores are deeply cleaned 4.20 (0.81)

The excess of sebum is removed 4.31 (0.82)

The imperfections are dried out 3.91 (1.08)

Blackheads are visibly reduced 4.07 (1.00)

The redness from imperfections is visibly reduced

4.04 (0.93)

The marks left by spots are less visible 3.88 (1.00)

The complexion is more even 4.08 (0.87)

The skin is smoother 4.47 (0.76)

The skin is softer 4.58 (0.81)

The skin is more radiant 4.20 (0.73)

The sonic brush is easy to use 4.89 (0.32)

Cleansing with the sonic brush is fast and effective

4.84 (0.43)

Using the sonic brush fits my skin care regime 4.77 (0.57)

Using the sonic brush gives me the best clean to help fight my breakouts

4.52 (0.82)

The frequency of breakouts is reduced 4.22 (0.96)

The severity of breakouts is reduced 4.34 (0.91)

I feel better about my facial skin after using the brush

4.61 (0.75)

I feel more confident in my personal life after using the brush

4.39 (0.92)

I feel more confident in my professional life after using the brush

4.41 (0.95)

5-Point scale: Strongly disagree (1), Disagree (2), Neutral (3), Agree (4), Strongly agree (5)

Agree /Strongly Agree



1144



plitude (angular) and frequency (60–90Hz) range to efficiently remove dirt and debris.8 Moreover the cyclic mechanical stimu-lation of the sonic brush was shown to increase expression of certain dermal proteins (such as, collagen 4 and 7, procollagen, laminin 5, fibronectin, fibrillin, and decorin) ex-vivo in human skin.8 The mechanical stimulation of the tissue while using the brush may improve skin condition such as wrinkle presentation when using the brush regularly as part of an anti-aging regime.Clinical studies have shown the use of the oscillatory sonic brush is safe (compared to stand-alone use of a cleanser) and does not cause erythema or other clinical signs of irritation.10,11

Other investigations demonstrated safety and efficacy of vari-ous cleansers and skin care products for acne in combination with the sonic brush.12-14

The present study demonstrated a significant (mean difference: 1.33 (SD ± 0.68); Two-tailed Paired Samples Test: t(42) = 12.78, P< 0.05)) improvement in physician scored FDA/IGA scale and subject scored skin condition after 28 days (+/- 5 days) of sonic brush and cleansing gel use. The cleansing regime was easy, fast, and safe, as there were no reported adverse events during the study period.

Four typical cases are shown to illustrate these results (Figures 3–6).

FIGURE 4. Case 2. Female 37-year-old presented with mild acne at baseline. After 28 days of sonic brush use (A) Physician scored acne lesions had almost cleared. (B) Subject scored skin condition confirmed this result, improving all scored aspects, making her feel better and more confident about her appearance. Handling of the brush was easy and fast and no skin irritation occurred. Case and photographs courtesy of Dr. M.H. Gold

FIGURE 3. Case 1. Female 45-year-old presented with mild acne at baseline. After 28 days of sonic brush use (A) Physician-scored acne lesions had almost cleared. (B) Subject-scored skin condition confirmed this result, improving skin radiance, making her feel more confident about her appearance. Handling of the brush was easy and fast and no skin irritation occurred. Case and photographs courtesy of Dr. M.H. Gold

FIGURE 5. Case 3. Female 30-year-old presented with mild acne at baseline. After 28 days of sonic brush use (A) Physician scored acne lesions had almost cleared. (B) Subject scored skin condition confirmed this result, improving skin complexion and texture, making her feel more confident about her appearance. Handling of the brush was easy and fast and no skin irritation occurred. Case and photographs courtesy of Dr. M.H. Gold

(A)

(B)

(A)

(B)

(A)

(B)



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LIMITATIONSThis study gave a description of practice and did not have a comparator or control group; therefore, cause and effect rela-tionships cannot be inferred. It was beyond the scope of this study to draw any conclusions regarding the possible impact of the evaluated cleansing regime on the underlying disease if it was used as monotherapy; this impact will be explored in future studies. Moreover, the subjects were not on a standardized acne regimen upon entering the trial; therefore, therapeutics added shortly prior to study initiation could represent confounders.

CONCLUSIONSCleansing of the face (shown to remove dirt, excess of sebum, and other unwanted debris) may potentially improve skin in mild-to-moderate acne patients. The gentle and effective cleans-ing routine using the sonic brush reduced significantly (P< 0.05) the number of physician-scored inflammatory and non-inflammatory lesions in the treated subjects. Subjects similarly assessed their skin to be improved. No adverse events were re-ported during the study period. The cleansing regime using the sonic brush may offer an attractive, safe option for maintenance and treatment of subjects with mild-to-moderate acne and acne-prone skin.

DISCLOSURESDr. Michael Gold is a consultant and has performed research for Clarisonic. All authors contributed to the development, ex-ecution of the study, writing, or critical review of the article. The study products used were provided by Clarisonic, who sup-ported a one-day meeting for study protocol development. All authors are registered in ORCID.

REFERENCES1. Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol.

2013;168:474–85.2. Lynn DD, et al. The epidemiology of acne vulgaris in late adolescence. Ado-

lesc Health Med Ther. 2016;7:13–25.3. Perkins AC, Maglione J, Hillebrand GG, et al. Acne vulgaris in women: preva-

lence across the lifespan. J Womens Health (Larchmt). 2012;21:223–30.4. Tan JK, et al. Effect of quality of life impact and clinical severity on adherence

to topical acne treatment. J Cutan Med Surg. 2009;13(4):204–8.5. Thiboutot D, et al. Acne vulgaris and the epidermal barrier: is acne vulgaris

associated with inherent epidermal abnormalities that cause impairment of barrier functions? Do any topical acne therapies alter the structural and/or functional integrity of the epidermal barrier? J Clin Aesthet Dermatol. 2013;6(2):18–24.

6. Choi YS, et al. A study of the efficacy of cleansers for acne vulgaris. J Derma-tolog Treat. 2010;21(3):201–5.

7. Isoda K, et al. Effects of washing of the face with a mild facial cleanser for-mulated with sodium laureth carboxylate and alkyl carboxylates on acne in Japanese adult males. Skin Res Technol. 2015;21(2):247–53.

8. Caberlotto E, Ruiz L, Miller Z, Poletti M, Tadlock L. Effects of a skin-massag-ing device on the ex-vivo expression of human dermis proteins and in-vivo facial wrinkles. PLoS One. 2017;12(3):e0172624.

9. Jordan L, Baldwin HE: Stratum corneum abnormalities and disease-affected skin: strategies for successful outcomes in inflammatory acne. J Drugs Der-matol. 2016;15:1170–3.

10. Draelos Z, Akridge R. Re-examining methods of facial cleansing. Cosmet Dermatol. 2006;19:671–5.

11. Akridge R, Jackson L, Rodriguez S, Henes EM, Ortblad K. Clinical efficacy of a new sonic skin care brush for facial cleansing. J Am Acad Dermatol. 2006;54(3):AB417.

12. Henes E, Ortblad K, Kearney M, Koski N, Tadlock L. Efficacy and safety of a novel sonic brush head designed for cleansing acneic skin. J Am Acad Dermatol. 2013;68(4):AB14.

13. Tadlock L, Rapaka S, Alejandro N, Baumann L, Gold M, Kircik L, McDaniel D, Sieger D, Davis G, Peterson G, Ortblad K. A multicenter clinical trial to evalu-ate the safety and efficacy of two OTC acne regimens comparing sonic to manual cleansing in individuals with mild to moderate acne vulgaris. J Am Acad Dermatol. 2016;74(5):AB1.

14. Ortblad K, Draelos ZD, Peterson GC, Akridge R. Long-term efficacy and toler-ance of a sonic brush and salicylic acid cleanser for cleansing acneic skin. J Am Acad Dermatol. 2014;70(5):AB8.

15. Rocha MA, Costa CS, Bagatin E. Acne vulgaris: an inflammatory disease even before the onset of clinical lesions. Inflamm Allergy Drug Targets. 2014;13(3):162–7.

16. Surber C, Abels C, Maibach H (eds): pH of the skin: issues and challenges. Curr Probl Dermatol. Basel, Karger. 2018;54:115–22.

FIGURE 6. Case 4. Female 34-year-old presented with mild acne at baseline. After 28 days of sonic brush use (A) Physician-scored acne lesions had cleared. (B) Subject scored skin condition confirmed this result, improving skin condition and self-confidence significantly. Handling of the brush was easy and fast and no skin irritation occurred.Case and photographs courtesy of Dr. M.H. Gold


Anneke Andriessen PhDE-mail:................……......................... [email protected]

(A)

(B)



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SPECIAL TOPIC

Efficacy and Tolerability of a Novel Tretinoin 0.05% Lotion for the Once-Daily Treatment of Moderate or

Severe Acne Vulgaris in Adult FemalesJulie C. Harper MD,a Hilary Baldwin MD,b,c Linda Stein Gold MD,d Eric Guenin PhD PharmD MPHe

ªThe Dermatology and Skin Care Center of Birmingham, Birmingham, AL BThe Acne Treatment and Research Center, Morristown, NJ

cRutgers Robert Wood Johnson Medical Center, Newark, NJ DHenry Ford Hospital, Detroit, MI

eOrtho Dermatologics, Bridgewater, NJ

Background: A novel tretinoin 0.05% lotion formulation has been shown to be efficacious and well-tolerated, and especially effective in adult female acne patients. While it is perhaps counter-intuitive that patients with more severe disease would show clinically signifi-cant improvement with topical monotherapy, topical retinoids have been shown to offer realistic treatment options in these patients.Objective: To evaluate the safety and efficacy of once-daily tretinoin 0.05% lotion in adult females with moderate or severe acne.Methods: Post hoc analysis of two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies. Adult females (>=18 years of age) with moderate (N=551) and severe (N=55) acne were randomized (1:1) to receive tretinoin 0.05% lotion or vehicle, once-daily for 12 weeks. Efficacy assessments included changes in baseline inflammatory/noninflammatory lesions, treatment success (at least 2-grade reduction in Evaluator’s Global Severity Score [EGSS] and clear/almost clear) and quality of life (QoL) using the validated Acne-QoL questionnaire. Safety, adverse events (AEs), and cutaneous tolerability were evaluated throughout.Results: At week 12, efficacy in adult females with moderate acne (EGSS=3) treated with tretinoin 0.05% lotion was significantly greater than that reported with vehicle. Mean percent reduction in inflammatory and noninflammatory lesion counts was 58.5% and 55.5% respectively compared with 50.3% and 39.8% with vehicle (P=0.039 and P<0.001). Treatment success was achieved by 25.4% of subjects by week 12, compared with 15.4% with vehicle (P=0.006). Tretinoin 0.05% lotion was numerically more effective in adult fe-males with severe acne (EGSS=4). Mean percent reduction in inflammatory and noninflammatory lesion counts was 59.0% and 58.8% respectively (compared with 53.5% and 45.5% with vehicle), and treatment success was achieved by 17.9% of subjects (compared with 4.5% with vehicle), with 46.6% of subjects achieving at least a 2-grade improvement in EGSS by week 12. Quality of life improve-ments with tretinoin 0.05% lotion were significant compared with vehicle in adult females with moderate acne (except role-social), but not in severe acne (probably due to the group size). The majority of AEs were mild and transient; more frequently reported in the moderate acne population where application site pain (2.9%), and application site dryness (5.0%) were the most common, compared with one report (4.5%) of application site pain and dryness in the severe acne population. Local cutaneous safety and tolerability as-sessments were generally mild-to-moderate and improved by week 12. Limitations: The number of severe subjects enrolled in the studies was considerably less than the number of subjects with moderate acne, and the studies were not powered to demonstrate a difference in efficacy based on acne severity.Conclusions: Tretinoin 0.05% lotion was significantly more effective than vehicle in achieving treatment success and reducing inflam-matory and noninflammatory lesions in adult females with moderate acne, with notable improvements in treating adult females with severe acne. It was well-tolerated, and all treatment-related AEs were mild or moderate.

J Drugs Dermatol. 2019;18(11):1147-1154.

ABSTRACT

INTRODUCTION

Acne vulgaris (acne) is a common skin disease in adoles-cence and a growing concern in adult women. Howev-er, there are few good prospective studies addressing

its severity and response to treatment in this patient popula-tion. Treatment considerations include their slow response to therapy, increased likelihood of skin dryness and irritation, and high psychosocial impact.1 Tolerability is very important in this

patient group because topicals are most commonly used and local skin side effects can lead to poor adherence. Also, there are no acne clinical trials exclusively in adult females. Studies with topical therapy in severe acne are limited to combination studies with oral antibiotics,2-9 or post hoc analyses of topical fixed combinations in moderate-to-severe acne.10-13 Our knowl-edge on the effectiveness of topical therapy in adult females is also largely restricted to post hoc analyses.14-20



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J.C. Harper, H, Baldwin, L. Stein Gold, E. Guenin

Additional assessments included a patient satisfaction score (PSS) and validated acne-specific quality of life (Acne-QoL) questionnaire (Merck &Co, Inc. Whitehouse NJ). Patients were asked to rate their satisfaction with prior facial acne therapy on a PSS scale of 1-10 (where a score of 5 or greater was consid-ered as ‘satisfied’) at baseline and following study treatment at week 12.

Safety EvaluationCutaneous safety (erythema and scaling) and tolerability (itch-ing, burning, and stinging) were evaluated on a 4-point scale from 0 (none) to 3 (severe). The investigator assessed erythema and scaling at the time of the study visit. Itching, burning, and stinging were solicited from the patient as an average of their symptoms during the period since the previous visit. Hyperpig-mentation and hypopigmentation severity were assessed by the investigator at each study visit, using the same a 4-point scale.Adverse events (AEs) were evaluated throughout; summarized by treatment group, severity, and relationship to study medication.

Statistical AnalysisThe intent-to-treat (ITT) population comprised all patients ran-domized and provided with study drug and vehicle. The safety population comprised all randomized patients who were pre-sumed to have used the study medication or vehicle at least once and who provided at least one post baseline evaluation. The primary method of handling missing efficacy data in the ITT analysis set was based on estimation using the Markov Chain Monte Carlo multiple imputation method. No imputations were made for missing safety data.

Reductions in lesion counts were presented as least square means and treatment P-values from an analysis of covariance with factors of treatment and analysis center and the respective baseline lesion count as covariate, values adjusted for multiple imputations. Significance of EGSS reductions were obtained from logistic regression (using Firth’s Penalized Likelihood) with factors of treatment group and analysis center. All statisti-cal analyses were conducted using SAS® version 9.3 or later. Statistical significance was based on 2-tailed tests of the null hypothesis resulting in P-values of 0.05 or less.

All AEs occurring during the studies were recorded and classified on the basis of medical dictionary for drug regulatory activities terminology (MedDRA) for the safety population. Treatment group comparisons were made by tabulating the frequency of patients with one or more AEs during the study.

RESULTSBaseline CharacteristicsA total of 606 adult female acne patients (≥18 years old) were in-cluded in the post hoc analysis. Patients had moderate (EGSS=3, N=551) or severe (EGSS=4, N=55) disease. Overall, 494 patients

Although topical monotherapy is not recommended for the treatment of severe papulopustular, non-nodulocystic acne, a topical therapy effective enough to improve severe inflamma-tory acne would address a significant unmet need and might reduce the additional risks of systemic treatments.21

Recently, clinical efficacy and safety data on tretinoin 0.05% lotion that utilize unique polymeric emulsion technology were published.22 Tretinoin 0.05% lotion was significantly more effec-tive than vehicle in treating moderate or severe acne, with a highly favorable safety and tolerability profile where the inci-dence of erythema, dryness and skin burning were lower than previously reported with other formulations of tretinoin.23 Here we present a post hoc analysis the two phase 3 studies in 606 adult female patients with moderate or severe acne.

METHODSStudy DesignA post hoc analysis of adult female patients (≥18 years old) from 2 multicenter, randomized, double-blind, vehicle-controlled, par-allel group clinical studies in patients with moderate or severe acne was performed. Protocols received approval before patient enrollment from the appropriate institutional review board (IRB) and studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practices (GCP) and in compliance with local regulatory requirements. All patients were informed of the study details and provided written consent.

Patients were randomized (1:1) to receive tretinoin 0.05% lotion or vehicle applied to the face once-daily for 12 weeks.

Study PopulationEligible patients for the post hoc analysis included adult female patients aged 18 to 58 years who presented with 20 to 40 in-flammatory lesions (papules, pustules, and nodules), 20 to 100 noninflammatory lesions (open and closed comedones), and two nodules or less; and an Evaluator Global Severity Score [EGSS] score of 3 (moderate) or 4 (severe).

Efficacy EvaluationEfficacy evaluations were comprised of inflammatory, and non-inflammatory lesion counts and EGSS assessment at screening, baseline, and subsequent study visits (weeks 4, 8, and 12) were performed. Key efficacy endpoints included changes from base-line in inflammatory and noninflammatory lesion counts and the proportion of patients who were treatment successes (ie, achieved at least a 2-grade reduction from baseline in EGSS and were also considered ‘clear’ or ‘almost clear’ at that same vis-it). For those adult female patients with severe acne (EGSS=4), treatment success would represent at least a 3-grade reduction in EGSS (ie, from severe to almost clear), and additional data are provided on the number of patients who achieved at least a 2-grade improvement, to mild [EGSS=2]).



1149



Demographic data (Table 1) were also similar across the 2 treat-ment arms. Patients were predominantly Caucasian (N=400, 66.0%) or Black/African American (N=155, 25.6%). The Asian population was higher in those females with severe disease (10.9% vs 4.5%).

At baseline, the mean number (SD) of inflammatory and non-inflammatory lesions in the severe and moderate acne groups

(81.5%) completed the studies, including 236 patients (82.2%) on tretinoin 0.05% lotion and 258 (80.9%) on vehicle (Figure 1). Study completion was better in those adult females with moder-ate acne, and in both cases slightly worse in the vehicle groups.The most common reasons for study discontinuations were ‘lost to follow-up’ (N=60, 9.9%) or ‘subject request’ (N=37, 6.1%). Two adult females with moderate acne and treated with treti-noin 0.05% lotion discontinued due to AEs.

TABLE 1.

Demographics and Baseline Characteristics by Severity (ITT adult female [≥18 years] population, pooled data, N=606)

Moderate Disease (N=551)EGSS=3

Severe Disease (N=55) EGSS=4


Vehicle(N=290)

Total(N=551)


Vehicle(N=29)

Total(N=55)

Age- Mean years (SD) 26.4 (7.14) 26.5 (7.31) 26.5 (7.22) 25.8 (7.28) 24.1 (7.25) 24.9 (7.24)

Range 18-54 18-58 18-58 18-45 18-50 18-50

Ethnicity N (%)

Hispanic 123 (47.1%) 145 (50.0%) 268 (48.6%) 12 (46.2%) 18 (62.1%) 30 (54.5%)

Non-Hispanic 138 (52.9%) 145 (50.0%) 283 (51.4%) 14 (53.8%) 11 (37.9%) 25 (45.5%)

Race N (%)

American Indian or Alaska Native 1 (0.4%) 1 (0.3%) 2 (0.4%) 1 (3.8%) 0 (0.0%) 1 (1.8%)

Asian 9 (3.4%) 16 (5.5%) 25 (4.5%) 2 (7.7%) 4 (13.8%) 6 (10.9%)

Black or African American 82 (31.4%) 62 (21.4%) 144 (26.1%) 4 (15.4%) 7 (24.1%) 11 (20.0%)

Native Hawaiian or Other Pacific Islander 2 (0.8%) 1 (0.3%) 3 (0.5%) 1 (3.8%) 1 (3.4%) 2 (3.6%)

Caucasian 163 (62.5%) 203 (70.0%) 366 (66.4%) 17 (65.4%) 17 (58.6%) 34 (61.8%)

Other 4 (1.5%) 7 (2.4%) 11 (2.0%) 1 (3.8%) 0 (0.0%) 1 (1.8%)

Inflammatory Lesion Count- Mean (SD) 25.1 (4.84) 24.9 (4.46) 25.0 (4.64) 29.8 (6.72) 28.7 (5.97) 29.2 (6.30)

Noninflammatory Lesion Count- Mean (SD) 36.9 (14.48) 39.5(15.84) 38.3 (15.25) 45.8 (19.69) 41.4 (22.44) 43.5 (21.10)

FIGURE 1. Patient disposition by baseline disease severity [showing percent completion and reasons for discontinuation (all adult female [≥18 years] randomized patients, N=606, pooled data)].



1150



was 29.2 (6.30) and 43.5 (21.10), and 25.0 (4.64) and 38.3 (15.25), respectively.

EfficacyLesion countsIn adult females with moderate acne, tretinoin 0.05% lotion resulted in statistically significant reductions in both inflamma-tory and noninflammatory lesion counts compared with vehicle from week 12 (Figure 2) and week 4 (Figure 3) respectively. At week 12, mean percentage change (LS mean) from baseline in

inflammatory and noninflammatory lesion counts was 58.5% and 55.5% respectively compared with 50.3% (P=0.039) and 39.8% with vehicle (P<0.001). Median percent reductions in in-flammatory and noninflammatory lesion counts with tretinoin 0.05% lotion were 67.4% and 60.6%, compared with 61.6% and 51.3% with vehicle.

In adult females with severe acne, tretinoin 0.05% lotion result-ed in numerically greater reductions in both inflammatory and noninflammatory lesion counts compared with vehicle, but re-

FIGURE 2. Percent change in inflammatory lesions from baseline to week 12 by severity (ITT population, LS mean). Adult female [≥18 years] population, pooled data (N=606).

FIGURE 3. Percent change in noninflammatory lesions from baseline to week 12 by severity (ITT population, LS mean). Adult female [≥18 years] population, pooled data (N=606).



1151



sults were not significant. At week 12, mean percentage change (LS mean) from baseline in inflammatory and noninflammatory lesion counts was 59.0% and 58.8% respectively, compared with 53.5% and 45.5% with vehicle.

Treatment successTreatment success was defined as at least a 2-grade improve-ment in global severity by EGSS and ‘clear’ or ‘almost clear’. By week 12, 25.4% of adult females with moderate acne were treat-ment successes following treatment with tretinoin 0.05% lotion compared with 15.4% on vehicle (P=0.006), see Figure 4. In the adult females with severe disease, 17.9% achieved treatment success by week 12, compared with 5.4% treated with vehicle

(P=0.185). Almost half the adult female patients (46.6%) with se-vere acne treated with tretinoin 0.05% lotion achieved at least a 2-grade reduction in baseline EGSS by week 12.

Patient satisfaction and quality of lifePatient satisfaction with treatment in those adult female acne patients with moderate disease was significantly greater with tretinoin 0.05% lotion than vehicle by week 12 (P=0.002). Base-line mean scores with tretinoin increased from 4.3 (satisfaction with previous therapy) to 7.3. Patient satisfaction at baseline in the severe acne adult female population was lower (mean score 3.9) and increased greater with treatment to 7.8, although differ-ences to vehicle (mean score 6.7) were not significant, probably

FIGURE 4. Treatment success. Percent of patients with at least a 2-grade improvement in EGSS and ‘clear’ or ‘almost clear’ at each study visit by severity (ITT population pooled data). Adult female [≥18 years] population, pooled data (N=606).

FIGURE 5. Improvement in Acne QoL from baseline to week 12 by severity (ITT population pooled data). Adult female [≥18 years] population, pooled data (N=606).



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FIGURE 6. Investigator assessed cutaneous safety and tolerability (scaling and erythema) from baseline to week 12 by severity (safety population, pooled data, adult female [≥18 years] patients treated with tretinoin 0.05% lotion).

TABLE 2.

Comparison of Subpopulations by Severity: Treatment-Emergent and Related Adverse Event (AE) Characteristics through Week 12 (Pooled Data – Safety Population). Adult female [≥18 years] population


Moderate Adult Female

Patients(N=240)


Severe Adult Female Patients(N=22)

Patients reporting any TEAE 55 (22.9%) 5 (22.7%)

Patients reporting any SAE 4 (1.7%) 0 (0.0%)

Patients who died 0 (0.0%) 0 (0.0%)

Patients who discontinued due to TEAE

7 (2.9%) 0 (0.0%)

Severity of AEs reported

Mild 31 (12.9%) 4 (18.2%)

Moderate 21 (8.8%) 1 (4.5%)

Severe 3 (1.3%) 0 (0.0%)

Relationship to study drug (% by patient)

Related 22 (9.2%) 1 (4.5%)

Unrelated 33 (13.8%) 4 (18.2%)

Treatment Related AEs reported by ≥1% patients*

Application site pain 7 (2.9%) 1 (4.5%)

Application site dryness 12 (5.0%) 1 (4.5%)

Application site erythema 4 (1.7%) 0 (0.0%)

Application site exfoliation 3 (1.3%) 0 (0.0%)

Application site pruritus 4 (1.7%) 0 (0.0%)

due to the small sample size.

At baseline, mean score for each Acne-QoL domain (self-per-ception, role-emotional, role-social, and acne symptoms) in the tretinoin group were much lower in the severe acne population (8.0, 8.9, 9.6, and 9.7 respectively, compared with 11.8, 12.1, 12.9 ,and 12.6 in the moderate group). When these patients were subsequently treated with tretinoin 0.05% lotion, the QoL im-provements (in terms of absolute change from baseline) were also greater in the severe patient population (10.8, 11.5, 7.4, and 8.8 respectively, compared with 9.5, 8.8, 6.3, and 8.5 in the mod-erate group), see Figure 6. Improvements in Acne-QoL in those adult females with moderate acne were all significant compared with the vehicle group, with the exception of role-social. There were no statistically significant differences in the improvement between treatment groups based on the mean Acne-QoL as-sessments for each domain in the severe acne population.

SafetyThere were a similar proportion of treatment emergent adverse events (TEAEs) in both moderate and severe active treatment groups (Table 2). Most AEs were mild or moderate. There were only 3 (1.3%) severe AEs (in the adult females with moderate acne), with 2 being related to study drug. Seven (2.9%) adult female patients with moderate disease subsequently treated with tretinoin 0.05% lotion discontinued due to TEAEs. Four TEAEs (1.7%) were treatment-related (contact and irritant der-matitis, stinging, burning, and itching), and treatment-related AEs with tretinoin 0.05% lotion were generally uncommon. Ap-plication site dryness (5.0%) and pain (2.9%) were reported most frequently in the moderate acne group; one adult female with severe disease reported application site pain and dryness.



1153



Cutaneous Safety and Tolerability Erythema and scaling were recorded by the investigator and were more common in the severe acne subpopulation. Both im-proved over the study period, see Figure 6.

Itching, burning, and stinging severity scores were obtained from the patients. About a third of patients reported itching at baseline. Reports of burning and stinging were rare and gener-ally mild. All improved with treatment, see Figure 7.

Hyperpigmentation was generally mild at baseline, and more prevalent in the severe group (mean score=0.8, compared with 0.6 in the moderate group, where 1=mild). There were no in-creases in mean scores over the 12-week treatment period.

DISCUSSIONWhile it is perhaps counter-intuitive that patients with more severe disease would show clinically significant improvement with topical monotherapy, we were able to report good results with tretinoin 0.05% lotion in adult females with severe acne (EGSS=4). Although the results were not significant vs vehicle, probably due to the small sample size, tretinoin 0.05% lotion achieved almost a 60% reduction in both inflammatory and comedonal lesions by week 12. In addition, almost half the adult female patients (47%) with severe disease treated with tretinoin 0.05% lotion achieved at least a 2-grade reduction in baseline EGSS by week 12.

As expected, satisfaction with prior acne treatment and base-line QoL were much lower in the female patients with severe acne than those with more moderate severity. However, im-provements in patient satisfaction and Acne-QoL domain scores following treatment with tretinoin 0.05% lotion were greater, suggesting the improvements in efficacy were clinically rel-evant. Tolerability was also good in the severe acne population,

FIGURE 7. Patient reported cutaneous safety and tolerability (itching, burning and stinging) from baseline to week 12 by severity (safety population, pooled data, adult female [≥18 years] patients treated with tretinoin 0.05% lotion.

with only one patient reporting a treatment-related AE (appli-cation site dryness and pain). Efficacy and tolerability in adult females with severe acne would warrant a larger study to gain further insights in this increasingly important group of patients.

The data in adult female acne patients with moderate disease (EGSS=3) are also noteworthy, given the limited clinical data and the increased likelihood of skin irritation in adult females treated with retinoids. Previous evaluations of the efficacy and tolerability of retinoids to treat adult female acne are limited to post hoc analyses of larger studies of predominantly mild to moderate acne. A small post hoc analysis of 2 studies with adapalene 0.3% gel (N=74) reported numerical greater efficacy in reducing inflammatory and noninflammatory lesions (me-dian percent reductions 61.2% and 50.7% respectively) in adult females with moderate acne.14 While not head to head compari-sons, tolerability of adapalene 0.3% gel in the phase 3 study was similar to that reported with adapalene 0.1% gel, with a higher incidence of skin discomfort and dry skin than noted with treti-noin 0.05% lotion.

The only previous study that included tretinoin was a subgroup analysis of the efficacy and safety of clindamycin 1.2%-treti-noin 0.025% gel in adult males and females in comparison to its individual active ingredients and vehicle.13 Overall, efficacy in reducing inflammatory and noninflammatory lesions with clindamycin 1.2%-tretinoin 0.025% gel from 3 12-week stud-ies was significantly greater vs the comparators in adolescent acne and mild/moderate disease. In patients with more severe disease, clindamycin 1.2%-tretinoin 0.025% gel was not signifi-cantly more effective than either individual active ingredient. In the subsequent post hoc analysis in adult females, efficacy of tretinoin 0.025% gel was statistically inferior to the fixed combination clindamycin 1.2%-tretinoin 0.025% gel in reduc-ing inflammatory lesions (median percent reductions of 72.4%



1154



fixed-dose combination adapalene 0.3 %/benzoyl peroxide 2.5 % gel:a ran-domized, double blind, parallel-group, controlled study. Am J Clin Dermatol. 2016;17:293-303.

11. Stein Gold L. Efficacy and tolerability of a fixed combination of clindamycin phosphate (1.2%) and benzoyl peroxide (3.75%) aqueous gel in moderate and severe acne vulgaris subpopulations. J Drugs Dermatol. 2015;14(9):969-974.

12. Webster G, Rich P, Gold MH, et al. Efficacy and tolerability of a fixed combina-tion of clindamycin phosphate (1.2%) and low concentration benzoyl perox-ide (2.5%) aqueous gel in moderate or severe acne vulgaris subpopulations. J Drugs Dermatol. 2009;8(8):736-743.

13. Dréno B, Bettoli V, Ochsendorf F, et al. Efficacy and safety of clindamycin phosphate 1.2%/tretinoin 0.025% formulation for the treatment of acne vul-garis: pooled analysis of data from three randomised, double-blind, parallel-group, Phase III studies. Eur J Dermatol. 2014;24:201-209.

14. Berson D, Alexis A. Adapalene 0.3% 48. for the treatment of acne in women. J Clin Aesthet Dermatol. 2013;6(10):32-35.

15. Dreno B. Treatment of adult female acne: a new challenge. J Eur Acad Der-matol Venereol. 2015;29(Suppl 5):14-19.

16. Tanghetti E. The evolution of benzoyl peroxide therapy. Cutis. 2008;5(Sup-pl):5-11.

17. Harper JC. The efficacy and tolerability of a fixed combination clindamycin (1.2%) and benzoyl peroxide (3.75%) aqueous gel in patients with facial acne vulgaris: gender as a clinically relevant outcome variable. J Drugs Dermatol. 2015;14(4):381-384.

18. Zeichner JA. The efficacy and tolerability of a fixed combination clindamycin (1.2%) and benzoyl peroxide (3.75%) aqueous gel in adult females with facial acne vulgaris. J Clin Aesthetic Dermatol. 2015;8(4):21-25.

19. Stein Gold L, Dreno B, Kerrouche N, et al. Adapalene-benzoyl peroxide gel is efficacious and safe in adult female acne. Presented at Maui Derm; Maui, Hawaii; January 2015.

20. Tanghetti E, Harper JC, Oefelein MG. The efficacy and tolerability of dapsone 5% gel in female vs male patients with facial acne vulgaris: gender as a clini-cally relevant outcome variable. J Drugs Dermatol. 2012;11(12):1417-1421.

21. Stein Gold L, Baldwin HE, Lin T. Management of severe acne vulgaris with topical therapy. J Drugs Dermatol. 2017;16(11):1134-1138.

22. Tyring SK, Kircik LH, Pariser DM, et al. Novel tretinoin 0.05% lotion for the once-daily treatment of moderate-to-severe acne vulgaris: assessment of efficacy and safety in patients aged 9 years and older. J Drugs Dermatol. 2018;17(10):1084-1091.

23. Harper JC, Roberts WE, Zeichner JA, et al. Novel tretinoin 0.05% lotion for the once-daily treatment of moderate-to-severe acne vulgaris: assessment of safety and tolerability in subgroups. J Dermatolog Treat. 2019 Apr 2:1-8. [Epub ahead of print.]

24. Dreno B, Thiboutot D, Layton AM, et al. Large-scale international study en-hances understanding of an emerging acne population: adult females. J Eur Acad Dermatol Venereol. 2015;29(6):1096-1106.


Julie C. Harper MDE-mail:................……......................... [email protected]

and 63.3% respectively). However, there was no significant dif-ference in reductions in comedonal lesions between the fixed combination and tretinoin monotherapy (median percent re-ductions of 55.2% and 48.6% respectively).15 In a condition commonly characterized by both comedones and inflammatory papules,24 the efficacy observed with tretinoin 0.05% lotion is likely to be important in adult female acne. In addition, although there are no head to head comparisons, the lower incidence of application site reactions than those reported with other treti-noin clinical trials should help patient adherence.25

CONCLUSIONTretinoin 0.05% lotion was significantly more effective than vehicle in achieving treatment success and reducing both inflam-matory and comedonal lesions in adult females with moderate acne; with improvements in adult females with severe acne sup-ported through patient reported outcomes. The low potential to cause skin irritation should help compliance in this increasingly important population of acne sufferers.

ACKNOWLEDGMENTThe authors acknowledge Brian Bulley MSc of Konic Limited for medical writing support. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.

DISCLOSURESDrs Harper, Baldwin and Stein Gold are advisors and/or investi-gators with Ortho Dermatologics. Dr Guenin is an employee of Bausch Health.

REFERENCES1. Dreno B, Layton A, Zouboulis CC et al. Adult female acne: a new paradigm.

J Eur Acad Dermatol Venereol. 2013; 27:1063-1070. 2. Gold LS, Cruz A, Eichenfield L, et al. Effective and safe combination thera-

py for severe acne vulgaris: a randomized, vehicle-controlled, double-blind study of adapalene 0.1%-benzoyl peroxide 2.5% fixed-dose combination gel with doxycycline hyclate 100 mg. Cutis. 2010;85:94-104.

3. Thiboutot DM, Shalita AR, Yamauchi PS, et al. Combination therapy with ada-palene gel 0.1% and doxycycline for severe acne vulgaris: a multicenter, in-vestigator-blind, randomized, controlled study. Skinmed. 2005;4(3):138-146.

4. Dréno B, Kaufmann R, Talarico S, et al. Combination therapy with adapalene-benzoyl peroxide and oral lymecycline in the treatment of moderate to se-vere acne vulgaris: a multicentre, randomized, double-blind controlled study. Br J Dermatol. 2011;165:383-390.

5. Cunliffe WJ, Meynadier J, Alirezai M, et al. Is combined oral and topical ther-apy better than oral therapy alone in patients with moderate to moderately severe acne vulgaris? A comparison of the efficacy and safety of lymecycline plus adapalene gel 0.1%, vs lymecycline plus gel vehicle. J Am Acad Derma-tol. 2003;49(3 suppl):S218-26.

6. Zhou R, Jiag X. Effects of adapalene-benzoyl peroxide combination gel in the treatment or maintenance therapy of moderate or severe acne vulgaris: a meta-analysis. Ann Dermatol. 2014;26(1):43-52.

7. Shemer A, Shiri J, Mashiah J, et al. Topical minocycline foam for moderate to severe acne vulgaris: Phase 2 randomized double-blind, vehicle-controlled study results. J Am Acad Dermatol. 2016;74(6):1251-1252.

8. Hull PR, Demkiw-Bartel C. Isotretinoin use in acne: prospective evaluation of adverse events. J Cutan Med Surg. 2000;4:66-70.

9. Faghihi G, Rakhshanpour M, Adtahi-Naeini B, et al. The efficacy of 5% dap-sone gel plus oral isotretinoin vs oral isotretinoin alone in acne vulgaris: A randomized double-blind study. Adv Biomed Res. 2014;3:177-182.

10. Stein Gold L, Weiss J, Rueda MJ, et al. Moderate and severe inflamma-tory acne vulgaris effectively treated with single-agent therapy by a new



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SPECIAL TOPIC

Topical Treatments for Melasma: A Systematic Review of Randomized Controlled Trials

Evan Austin BS,ª Julie K. Nguyen MD,a,b Jared Jagdeo MD MSa,b

ªDepartment of Dermatology, State University of New York, Downstate Medical Center, Brooklyn, NY BDermatology Service, VA New York Harbor Healthcare System Brooklyn Campus, Brooklyn, NY

Background: Melasma is an acquired skin disease characterized by symmetric hyperpigmentation on sun-exposed areas, particularly on the face. Recently, there has been tremendous scientific interest in novel, safe, and effective topical agents to manage melasma.Objective: To evaluate topical treatments for melasma and provide evidence-based recommendations for clinical use and further re-search.Methods: We performed a systematic review of randomized controlled trials (RCTs) on topical agents for the treatment of melasma on March 4th, 2019 using PRISMA guidelines. Clinical recommendations were based on the American College of Physicians guidelines. Results: After screening, we identified 35 original RCTs using azelaic acid, cysteamine, epidermal growth factor, hydroquinone (lipo-somal-delivered), lignin peroxidase, mulberry extract, niacinamide, Rumex occidentalis, triple combination therapy, tranexamic acid, 4-n-butylresorcinol, glycolic acid, kojic acid, aloe vera, ascorbic acid, dioic acid, ellagic acid and arbutin, flutamide, parsley, or zinc sulfate for melasma.Conclusions: Cysteamine, triple combination therapy, and tranexamic acid received strong clinical recommendations for the treatment of melasma. Cysteamine has excellent efficacy and is reported to have anti-cancer properties, but has not been directly compared with hydroquinone. Triple combination agents and tranexamic acid are effective, but carry theoretical risks for ochronosis and thrombosis, respectively. Natural compounds are associated with low risk for adverse events, but more research is needed to determine the ef-ficacy, optimal formulation, and appropriate concentration of novel treatments.

J Drugs Dermatol. 2019;18(11):1156-1171.

ABSTRACT

INTRODUCTION

Melasma is an acquired skin disease characterized by symmetric patches of hyperpigmentation on sun-exposed areas such as the cheeks, forehead, chin,

nose, and upper lips. Histological features may include epider-mal and dermal pigmentation, solar elastosis, increased vascu-larization, and mastocytosis.1

Although the true incidence of melasma is unknown, melasma has been reported to affect 1% to 50% of the population glob-ally.2 Melasma is more prevalent in female patients of Asian, Latin American, Middle Eastern, and African descent due to multifactorial causes including increased skin pigmentation, alterations in hormone levels, family history, and sun expo-sure.3-6 Melasma has a tremendous societal and psychosocial impact as patients with melasma report dramatically lower self-esteem, depression, and social isolation.7,8

Therapy for melasma remains a clinical challenge and topical agents are the mainstay. First-line topical treatment options for melasma are hydroquinone (HQ) and triple combination (TC) therapies, which include HQ, a retinoid, and a steroid. Second-

line treatments include chemical peels and laser therapies.9

There have been concerns about the long-term safety and efficacy of HQ. Topical HQ is associated with ochronosis, a blu-ish-gray discoloration of the skin.9 In response, HQ has been banned in the European Union as a cosmetic additive, but is available as a prescription medication.9

Recently, there has been tremendous scientific and general public interest in novel, safe, and effective topical agents to im-prove melasma. To determine the safety and efficacy of newer topical agents for melasma, we performed a systematic review of randomized controlled trials (RCTs) on topical agents for the treatment of melasma and provided evidence-based recom-mendations for clinical use and further research.

METHODSAccording to the Preferred Reporting Items for Systematic Re-views and Meta-analysis (PRISMA) protocol, we performed a systematic search for novel and currently used topical treatments for melasma on March 4th, 2019 (Figure 1). Included articles were RCTs using topical treatments for melasma published within the



1157


E. Austin, J.K. Nguyen, J. Jagdeo

last 15 years (since January 1st, 2003) as this period was consid-ered clinically relevant. Clinical recommendations were based on the American College of Physicians (ACP) guidelines.10 We excluded studies using proprietary or undescribed active ingre-dients (as these studies and outcomes would not be verifiable or reproducible by third parties, if desired) and those evaluat-ing non-topical agents (ie, oral medications, bleaching agents, chemical peels, intralesionally administered drugs, laser, and light-based therapies) as stand-alone or combination ap-proaches. Patients were allowed to apply daily sunscreen in the included studies. Non-randomized original reports, literature reviews, conference abstracts, oral presentations, basic science investigations, animal studies, and non-English articles were ex-cluded. We examined the bibliographies of included published original reports and literature reviews to ensure that relevant articles were included in the systematic search.

RESULTSOur systematic search identified 9,413 articles. After screening titles, abstracts, and full text articles, we identified 35 original RCTs using azelaic acid (2), cysteamine (2), epidermal growth factor (EGF) (1), liposomal hydroquinone (1), lignin peroxidase (1), mulberry extract (1), niacinamide (1), Rumex occidentalis (1), tranexamic acid (TXA) (5), TC therapy (5), 4-n-butylresorcinol (3), glycolic acid (2), kojic acid (2), aloe vera (1), ascorbic acid (1), dioic acid (1), ellagic acid and arbutin (1), flutamide (1), parsley (1), or zinc sulfate (2) for melasma. Table 1 provides a detailed summary of the identified studies and highlights study de-signs, treatment parameters, results, and adverse events (AEs).

FIGURE 1. PRISMA Systematic search strategy. We performed a systematic search on March 4th, 2019, according to PRISMA guidelines.

TABLE 1.

Summary of Topical Treatments for Melasma

Author DesignNo. of

Patients†

Skin Type (Location)

Follow-up

Primary Outcome

Other Outcome Measures

Regimen Treatment Baseline‡ Results‡ Side Effects

Benefits outweigh risks and burden

Azelaic acid

Farshi11 OL 29Not

reported(Iran)

8 weeks

MASI NoneTwice

daily for 8 weeks

20% azelaic acid

7.6 ± 3.53.8

± 2.8#

Erythema, irritation,

and pruritus

4% HQ 7.2 ± 3.26.2

± 3.6


and pruritus

Mazurek12 OL 60I-III

(Poland)24

weeks

Colorim-etry using

Mexameter® (pigment

within lesion)

Skin hydration, elasticity, erythema

Twice daily for 24 weeks

10% azelaic acid, 10%

d-panthenol 25.0U 19.5 U* Not

reported

5% azelaic acid, 5%

pyruvic acid16.0 U 13.0 U* Not

reported

20% azelaic acid,

10% mandelic acid,

5% phytic acid,

5% 4-n-butyl resorcinol, 2%

ferulic acid

19.6 U 12.5 U* Not reported



1158



TABLE 1. CONTINUED


Author DesignNo. of

Patients†


Follow-up

Primary Outcome




Cysteamine

Mansouri14 DB, PC 50III and IV

(Iran)16

weeks

Colorim-etry using

Mexameter (relative melanin value)

MASI, IGAOnce daily

for 16 weeks

5% cysteamine

75.2 ± 3726.2 ± 16#

Erythema, dryness, itching, burning

sensation, and irrita-

tion

Placebo 68.9 ± 3160.7

± 27.3None

Farshi13 DB, PC 40III and IV

(Iran)16

weeks

Colorim-etry using

Dermacatch (difference between

pigmented and normal

skin)

MASI, IGAOnce

daily for 16 weeks

5% cysteamine

72.3 ± 27.8

23.8 ± 12.9#

Erythema, dryness, itching, burning

sensation, and irrita-

tion

Placebo52.9 ± 16.4

50 ± 18 None

Epidermal growth factor

Lyons17 DB, PC, SF

15

Not reported

(California, USA)

8 weeks

Physician GAIS

MelasQoL, PSA


EGF --

Improve-ment in 73.4% of patients

None

Placebo --

Improve-ment in 13% of

patients

None


Hydroquinone (Liposome-encapsulated)

Taghavi18 DB, SF 20III and IV

(Iran)16

weeksMASI None

Once daily for 12 weeks

4% HQ10.73 ± 4.7

6.07 ± 3.8*

Not reported

4% liposomal HQ

10.73 ± 4.7

6.25 ± 4.0*

Not reported

Lignin Peroxidase

Draelos19 SF, SB 30

I-IV (North

Carolina, USA)

12 weeks

MASI

Colo-rimetry,

dermato-spectropho-

tometer, IGA, PSA


Lignin peroxidase

Not reported

No dif-ference between groups

None

4% HQNot

reported-- None

Draelos19 SF, SB 30

I-IV (North

Carolina, USA)

12 weeks

MASI

Colo-rimetry,

dermato-spectropho-

tometer, IGA, PSA


Lignin peroxidase

Not reported

Sig-nificant

improve-ment*

None

No treatmentNot

reported-- None

Mulberry extract

Alvin20 SB, PC 50

III-V(Philip-pines)

8 weeks

MASIColo-

rimetry, MelasQoL


75% mulberry extract oil

4.076 ± 0.24#

2.884 ± 0.25*# Mild itching

Placebo3.484 ± 0.52

3.392 ± 0.53

Mild pruritus and

erythema



1159



TABLE 1. CONTINUED


Author DesignNo. of

Patients†


Follow-up

Primary Outcome



Niacinamide

Navarrete-Solis22 DB, SF 27

III-V(Mexico)

8 weeks

MASI

Chromame-ter, IGA, infrared

thermog-raphy,

histological sections

Every3 hours during

daytime for 8

weeks

4% niacinamide

3.7 (95% CI: 2.9–4.4)

1.4 (95% CI: 3.3–4.7)*

Erythema,pruritus,

and burning

4% HQ 4 (95% CI: 90.9–1.8)

1.2 (95% CI: 0.8–1.6)*

Erythema,pruritus,

and burning

Rumex occidentalis (Western Dock)

Mendoza23 DB, SF 45

Not reported(Philip-pines)

8 weeks

MASIColorim-etry, IGA,

PSA


3% R. occidentalis

cream

Not reported

0.60 ± 0.86

decrease*

Mildpeeling

4% HQNot

reported

0.55 ± 0.62

decrease*

None

PlaceboNot

reported

0.09 ± 0.12

decreaseNone

Tranexamic acid

Atefi26 DB 60Not

reported (Iran)

12 weeks

MASIPatient

satisfaction


5% TXA 4.80

± 1.062.33

± 0.71* None

2% HQ4.37

± 0.932.30

± 0.65*

Erythema and skin irritation

Banihash-emi27 SF, DB 23

III-V(Iran)

16 weeks

MASI NoneTwice

daily for 12 weeks

5% liposomal TXA

14.72 ± 2.2

6.78 ± 2.9* None

4% HQ14.60 ± 2.3

7.60 ± 2.2*

Skin irritation

Ebrahimi28 SF, DB 39Not

reported (Iran)

12 weeks

MASI IGA, PSATwice

daily for 12 weeks

3% TXA31.68

± 10.3210.76

± 9.43*

Erythema, skin

irritation, xerosis,

and scaling

3% HQ and 0.01% dexa-methasone

29.52 ± 11.72

10.48 ± 7.84*

Erythema, skin

irritation, dryness of the skin,

scaling, hy-pertrichosis, and inflam-

mation

Kanechorn Na Ayuthaya25

DB, SF, VC

21Not

reported (Thailand)

12 weeks

MASIColorim-etry, IGA,

PSA


5% TXANot

reported

Sig-nificant

improve-ment from

baseline, non-sig-nificant

difference between groups

Minor skin irritation

VehicleNot

reported--

Minor skin irritation



1160



TABLE 1. CONTINUED


Author DesignNo. of

Patients†


Follow-up

Primary Outcome



Viyoch24 DB, VC 60IV

(Thailand)8

weeks

Colorim-etry using

Mexameter® (relative melanin value)

MASI, moisture content,

pH, erythema


6.5% TXA80.6 ± 19.7

59.4 ± 17.4*#

Erythema, scaling,

burning and/or stinging

Vehicle74.4

± 17.375.4 ± 16.3

Erythema, edema,

burning and/or stinging

Triple Combination

Ferreira Cestari32

OL 119II-V

(Brazil)8

weeks

Proportion of patients

with complete clearance

IGA, PSA, tolerability


4% HQ, 0.05% RA, and

0.01% FA -- 35%#

Erythema,burning

sensation, desquama-

tion, telangi-ectasia, and headache


4% HQ -- 5.1%

Erythema,burning

sensation, desquama-

tion, telangi-ectasia, and headache

Chan33 SB 242

II-V(East and Southeast

Asia)

8 weeks

Global Severity

Score (GSS) at 8 weeks

GSS at 4 weeks,

MASI, IGA, PSA,

patient sat-isfaction


4% HQ, 0.05% RA,

and 0.01% FA

100% of patients

with GSS of moder-

ate or severe

64.2% of patients

with GSS of none or mild*#


exfoliation, and

discomfort


4% HQ

100% of patients

with GSS of

moderate or severe

39.4% of patients

with GSS of none or mild*#


exfoliation, and

discomfort

Taylor34 SB 641§

I-IV(Multi-center, USA)

8 weeks


with complete clearance


with complete or near-

complete clearance


HQ 4%, 0.05% RA,

and 0.01% FA-- 26.1%#

Erythema,desquama-tion, burn-

ing, dryness, and pruritus

0.05% RA and 4% HQ

-- 9.5%



0.05% RA and 0.01% FA

-- 1.9%



4% hydroquinone and 0.01% FA

-- 2.5%


ing, dryness, atrophy and

pruritus



1161



TABLE 1. CONTINUED


Author DesignNo. of

Patients†


Follow-up

Primary Outcome



Gong30 DB, PC 211Not

reported(China)

8 weeks

Decreased Index of

Total Target Score

(DITTS)¶

Improve-ment

rate of target skin

melanin (by spectropho-

tometer), integral

therapeutic efficacy

rate


4% HQ, 0.05% RA,

and 0.01% FA--

0.48 ± 0.21#

Erythema, stabbing

pain, peeling, tel-angiectasia, burning, dry

skin, itch-ing, sensa-tion of thin skin, and redness/swelling

Placebo --0.10

± 0.14

Burning, dry skin,

tautening, and itching

Astaneh31 DB 32III-V

(Iran)12

weeks

Investi-gator’s

subjective assessment

NoneOnce

daily for 12 weeks

4% HQ --

31.3% of patients

with good to

excellent results

Erythema and

scaling

4% HQ, 0.05% RA,and 0.05%

dexametha-sone

--

81.2% of patients

with good to

excellent results #

Erythema and

scaling#

4-n-butylresorcinol

Huh38 DB, SF, VC

20III-V

(South Korea)

8 weeks

Colorimetry using Mex-

ameter®

NoneTwice

daily for 8 weeks

0.1% 4-n-bu-tylresorcinol

206.85±31.60

196.20±28.42#

Mild erythema

and itching

Vehicle205.77±33.74

209.80±32.19

None

Huh39 DB, SF, VC

23

Not reported (South Korea)

8 weeks


ameter®

PSATwice

daily for 8 weeks

0.1% liposome-

encapsulated 4-n-butylres-

orcinol

200.68 ± 38.24

185.42 ± 38.81# None

Vehicle201.13 ± 39.78

194.43 ± 39.03

None

Khemis40 DB, SF, VC

30§III-V

(France)12

weeks

Clinical pig-mentation

score

Colo-rimetry,

tolerability, skin accept-ability, in-

vestigator’s assessment of improve-ment, PSA


0.3% 4-n-bu-tylresorcinol

7.5 ± 1.

6.2 ± 2.3#

Mild stinging, burning, pruritus,

erythema, dryness,

peeling and desquama-

tion

Vehicle7.5

± 1.96.7

± 2.1Depigmen-

tation



1162



TABLE 1. CONTINUED


Author DesignNo. of

Patients†


Follow-up

Primary Outcome



Benefits closely balanced with risks

Glycolic acid

Guevara43 VC, DB 35III-V

(Texas, USA)

12 weeks

MASI and colorimetry using Mex-

ameter®

IGA, PSATwice

daily for 12 weeks

4% HQ, 10% buffered

glycolic acid, vitamins C and E, and sunscreen

Not reported

Sig-nificant

improve-ment in

MASI and Mexam-

eter score from

baseline and

between groups

Burning, itching, redness, dryness, peeling,

edema, and scaling

Vehicle (sunscreen

only)

Not reported

--

Burning, itching, redness, dryness,

peeling, and scaling

Ibrahim44 SB, PC 100Not

reported(Egypt)

12 weeks

mMASI

IGA, PSA, digital image

analysis, dermos-

copy


4% HQ 12.410 ± 3.915

5.740 ± 5.713*

Burning, itching, redness, dryness, peeling,

edema, and scaling

4% HQ and 10%

glycolic acid

10.030 ± 2.456

6.060 ± 4.550*

Erythema, erosion,

scaling, and crusting

4% HQ and 0.01% hyaluronic

acid

11.600 ± 4.447

4.080 ± 3.041* Pruritus

4% HQ, 0.01% hyaluronic,

and 10% glycolic acid

12.570 ± 5.522

3.430 ± 3.336*

Pruritus, erythema,

scaling, and crusting

Placebo10.540 ± 2.699

10.540 ± 2.699

None

Kojic acid

Deo45 SB 80IV and V(India)

12 weeks

MASI

IGA, PSA, therapeutic response according to ∆MASI


1% kojic acid9.145 ± 7.69

3.57 ± 3.04* Burning

1% kojic acid and 2% HQ

8.38 ± 4.92

2.09 ± 1.62* Burning

1% kojic acid and 0.1% be-tamethasone

valerate

11.02 ± 7.33

7.58 ± 6.493

None

1% kojic acid, 2% HQ, and 0.1% beta-methasone

valerate

15.61 ± 9.03

7.115 ± 7.03*

Acneiform eruptions



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TABLE 1. CONTINUED


Author DesignNo. of

Patients†


Follow-up

Primary Outcome



Monteiro46 -- 60Not

reported(India)

12 weeks

MASI NoneTwice

daily for 12 weeks

0.75% kojic acid cream and 2.5% vitamin C

11.177 ± 6.4817

8.773 ± 5.6743*

Erythema

4% HQ15.613

± 9.66264.334 ±

3.5709*#

Erythema and mild burning

Risks and burden outweigh benefits

Parsley

Khosra-van47 DB 54

Not reported

(Iran)

8weeks

MASI NoneOnce

daily for 8 weeks

Parsley (brewed

2.5 g in 125 ml of water) every week

6.66 ± 4.39

4.92 ± 3.07*

Redness and

itching

4% HQ6.68

± 3.245.06

± 2.66*

Redness and

itching

Zinc Sulfate

Iraji48 SB 55Not

reported (Iran)

6 months

MASI PSATwice

daily for 6 months

10% zinc sulfate

solution

5.7 ± 3.2

5.1 ± 2.9*

Not reported

4% HQ 6.4

± 3.43.3

± 2.4*#

Not reported

Yousefi49 DB 82Not

reported (Iran)

5 months

MASI NoneOnce daily

for 2 months

10% zinc sulfate

6.3 ± 2.1

5.1 ± 2.0*

Mild post-inflammato-ry hyperpig-mentation, irritation

4% HQ6.4 ±1.6

3.9 ± 1.4*# Irritation

Insufficient evidence to determine net benefit

Aloe Vera

Ghafarza-deh50 DB 180

Not reported

(Iran)

5 weeks

MASI NoneNot

reported

Aloe vera gel extract

15.5 ± 2.4

13.9 ± 2.7

None

Liposome-encapsulated Aloe vera gel

extract

15.0 ± 1.8

10.2 ± 2.0# None

Ascorbic Acid

Espinal-Perez51 DB 180

IV and V(Mexico)

16 weeks

PSA and colorimetry using Der-maSpect®

Digital photograph and regular color slides

Once daily for

16 weeks

5% L-ascorbic acid

--Signifi-

cant sub-jective

improve-ment on HQ side, no sig-nificant

difference in colo-rimetric

measures

Irritation

4% HQ -- Irritation



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TABLE 1. CONTINUED


Author DesignNo. of

Patients†


Follow-up

Primary Outcome



Dioic Acid

Tirado-Sanchez52 OL 96

III(Mexico)

12 weeks

MASI NoneTwice

daily for 12 weeks

1% dioic acid14.52 ± 3.4

6.05 ± 1.2*

Erythema, burning,

pruri-tus, and

acneiform reaction

2% HQ15.22 ± 2.4

6.34 ± 1.3*

Erythema, burning, pruritus,

acneiform reaction

Ellagic acid and Arbutin

Ertam53 OL 29II-IV

(Turkey)6

months


ameter®

NoneTwice

daily for 6 months

1% arbutin --Z =

-2.803* None

1% synthetic ellagic acid

--Z =

-2.075* None

1% natural ellagic acid

(plant extract)--

Z = -2.803* None

Flutamide

Adalat-khah54 DB 73

Not reported

(Iran)

4 months

MASI and colorimetry using Mex-

ameter®

Patient sat-isfaction

Once daily for

4 months

1% flutamide --Sig-

nificant improve-ment in MASI from

baseline for both groups with su-

perior ef-ficacy for flutamide group; no

signifi-cant dif-

ference in colori-metric

measures between groups

Not reported

4% HQ --Not

reported

DB: double-blind, DITTS: Decreased Index of Total Target Score, EGF: epidermal growth factor, FA: fluocinolone acetonide, GAIS: Global Aesthetic Improvement Scale, GSS: Global Severity Score, HQ: hydroquinone, IGA: Investigator’s Global Assessment, MASI: Melasma Area and Severity Index, mMASI: Modified Melasma Area and Severity Index, MelasQoL: Melasma Quality of Life scale, OL: open label, PC: placebo-controlled, PSA: Patient’s Self-Assessment, RA: retinoic acid, SB: single-blind, SF: split-face, TXA: tranexamic acid, VC: vehicle-controlled. Asterisks (*) denotes significant improvement from baseline. Hash sign (#) denotes significant improvement compared to other treatment groups. †Sample size is based on per-protocol population (i.e., all patients who completed assigned treatment) unless otherwise specified. ‡Baseline values and results are based on primary outcome measure(s). §Sample size is based on intent-to-treat population (i.e., all patients who were randomized). ¶DITTS > 0.3 indicates Improvement30



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TABLE 2.

Recommendations and Quality of Evidence

Medication (# of RCTs)Strength of

RecommendationQuality of Evidence

Comparison to HQ Notes


Azelaic acid (2) Weak Moderate More effective in open-label RCT Poorly designed RCTs.

Cysteamine (2) Strong Moderate None

Reported to have anti-cancer effects. May lead to diffuse skin brightening. No long-term adverse event. May have unpleasant smell.

Epidermal growth factor (1) Weak Moderate None Small sample size.

Hydroquinone (liposomal-delivered) (1)

Weak Moderate Similar Theoretical enhanced skin penetration.

Lignin Peroxidase (1) Weak Moderate Similar efficacy and safety profile. Small sample size.

Mulberry extract (1) Weak Moderate None Mild adverse event profile.

Niacinamide (1) Weak ModerateSimilar efficacy with milder

adverse events.Evaluated in one poorly powered study.

Rumex Occidentalis (1) Weak Moderate None Mild adverse event profile

Tranexamic acid (5) Strong HighSimilar efficacy with fewer

adverse events.Theoretical risk for thrombosis.

Triple Combination (5) Strong HighBetter efficacy with similar

adverse event profile.Risk of ochronosis and theoretical risk for carcinogenesis.

4-n-butylresorcinol (3) Weak High None Mild adverse events.

Benefits closely balanced with risks

Glycolic acid (2) Weak ModerateOnly evaluated in combination

with 4% HQ.Increased risk of skin desquamation.

Kojic acid (2) Weak Moderate Less effective as stand-alone.May be combined with 4% HQ for increased efficacy.

Risks and burden outweigh benefits

Parsley (1) Weak Moderate Similar efficacy and adverse eventsFormulation needs to be prepared by subjects, which increases burden of treatment.

Zinc sulfate (2) Strong High Less effective Risk for PIH.

Insufficient evidence to determine net benefit

Aloe vera (1) n/a Moderate NoneNo placebo or HQ comparison group. Used safely in pregnant patients.

Ascorbic Acid (1) n/a Moderate Similar or worse efficacyAscorbic acid readily degrades and needs to be combined with other agents.

Dioic Acid (1) n/a Moderate Similar efficacy Acneiform reaction from oily vehicle.

Ellagic acid and arbutin (1) n/a Moderate None No placebo or HQ comparison group.

Flutamide (1) n/a Moderate Similar efficacy Adverse event profile was not pro-vided. Risk of hormonal therapy not evaluated.



1166



demonstrated good clinical responses for both treatment arms.

In another open-label RCT, patients received azelaic acid of various concentrations (5%, 10% and 20%) with 3 different supplemental formulations.12 All 3 azelaic acid formulations improved colorimetric scores after 6 months of twice daily ap-plication. The most effective formulation contained 20% azelaic acid with 10% mandelic acid, 5% phytic acid, 5% 4-n-butyl res-orcinol, and 2% ferulic acid (Sesderma, Valencia, Spain). No AE profile was provided. Azelaic acid received a weak recommen-dation due to the poor study design of the included articles. Both studies had an open-label study design and one study com-pared combination formulations without comparing individual ingredients. The 2 identified studies use different concentrations of azelaic acid (range 5% to 20%), which also confounds results.

Cysteamine – strong recommendationCysteamine is approved by the U.S. Food and Drug Adminis-tration for the treatment of cystinosis and has been shown to inhibit melanogenesis at high concentrations.13,14 In 2 well-de-signed double-blind RCTs, 50 and 40 patients with melasma were treated with 5% cysteamine (Cysteamine®, Scientis Phar-ma SA, Geneva, Switzerland) or placebo daily for 4 months.13,14

In both studies, cysteamine significantly reduced MASI scores compared with placebo. In the second study, significant colo-rimetric differences were found favoring topical cysteamine compared with the placebo at 2 months and 4 months, and the Investigator’s Global Assessment (IGA) and patient feedback indicated positive efficacy of cysteamine. Patients reported erythema, dryness, itching, burning sensation, and irritation fol-lowing cysteamine therapy. Side effects were associated with prolonged exposure to the topical agent, and removing the cys-teamine by washing may decrease these side effects in patients. Clinical photos demonstrated diffuse skin brightening. Cyste-amine has not been directly compared with 4% HQ.

Cysteamine is reported to have anti-cancer and anti-melanoma effects, which may be beneficial compared with HQ.15,16 Cyste-amine may lead to diffuse skin brightening, and some patients report an unpleasant odor from cysteamine. Cysteamine is wide-ly used in Europe, but is not commercially available in the United States. As a stand-alone agent, cysteamine received a strong recommendation as it has a beneficial efficacy and safety profile.

Epidermal growth factor – weak recommendationThe topical application of EGF has been evaluated for the pro-motion of wound healing and prevention of post-inflammatory hyperpigmentation (PIH) after laser resurfacing of facial skin.17 In one double-blind, split-face RCT, 50 patients were treated with topical EGF serum (DNARenewal, Beverly Hills, CA) vs placebo on each designated side of the face, twice daily for 8 weeks.17

According to the Physician Global Aesthetic Improvement Scale,

DISCUSSIONHerein, we provided evidence-based recommendations on the safety and efficacy of topical medications for melasma (Table 2). The topical agents are presented below in alphabetical order in categories according to their risk and benefit to patients with melasma. According to ACP guidelines, a strong recommenda-tion may apply to most patients without reservations, whereas a weak recommendation differs according to an individual patient’s circumstances. As only RCTs were reviewed, all rec-ommendations were supported by moderate-quality (ie, one or more poorly designed RCT) or high quality of evidence (ie, one or more well designed RCT).

Multiple RCTs used 4% topical HQ as an active ingredient in combination therapies or comparison arms, but most of the literature on 4% HQ as a therapeutic modality was published before 2003. Cysteamine, TC, and TXA received the strongest recommendation of benefit. These medications had greater ef-ficacy and/or milder AE profiles compared with topical HQ. A full description of topical treatments is provided below, and the mechanisms of action are provided in Table 3.

Benefits Outweigh Risks and BurdenAzelaic acid – weak recommendationTwo poorly designed RCTs examined the efficacy of azelaic acid. In an open-label study, 29 patients received twice daily 20% az-elaic acid or 4% HQ for 8 weeks. 20% azelaic acid was more effective than 4% HQ according to the Melasma Area and Se-verity Index (MASI) score, but there is a significant bias in this study due to the open-label design.11 The clinical photographs

TABLE 3.

Mechanism of Action of Topical Agents

Mechanism of Action Drug

Tyrosinase inhibitor

Hydroquinone, Cysteamine, Kojic acid, Arbutin, Azelaic acid, Ascorbic acid, Ellagic acid, Aloe vera, Rumex occidnetalis, 4-n-butylresorcinol, Glycolic acid, EGF

Dopa oxidase inhibitor Mulberry extract

Peroxidase substrates / inhibitors Hydroquinone, Cysteamine

Increasing intracellular glutathione Cysteamine

Nuclear PPAR receptor agonist Dioic acid

Block plasmin pathway Tranexamic acid

Prevent Melanosome transferNiacinamide, Tretinoin, Dioic acid

Anti-hormonal Flutamide

Increase keratinocyte turnover Tretinoin, Glycolic acid

Cytotoxic Hydroquinone, Azelaic acid

UnknownZinc sulfate, Parsley, Lignin peroxidase



1167



there was an improvement in the melasma in 73.4% of patients on the EGF-treated side vs 13% on the placebo side. The average Melasma Quality of Life questionnaire score decreased from 42 to 33, with 73% of patients having an improvement in their score. No AEs were reported with use of either treatment.

While the authors concluded that topical EGF is a safe and effec-tive treatment for melasma, additional RCTs with greater power and validated outcome measures are needed to evaluate the ef-ficacy of topical EGF for melasma. Thus, topical EGF received a weak recommendation.

Hydroquinone (Liposomal) – weak recommendationOne double-blind RCT compared once daily treatment with 4% liposomal HQ (prepared by fusion method) to standard formula-tions of 4% HQ for 12 weeks, and demonstrated similar efficacy between the treatment regimens at week 4 following the end of the treatment course.18 AEs for liposomal HQ were not reported. As a result, any added benefit of liposomal vehicle is minimal.

Lignin peroxidase – weak recommendationOne split-face RCT compared the efficacy of twice daily lignin peroxidase (elure, Syneron Medical Ltd, Yokneam, Israel) in two cohorts of 30 patients over 12 weeks.19 In the first cohort, lignin peroxidase significantly improved MASI compared with no treatment. In the second cohort, there was no difference in MASI score between the lignin peroxidase and 4% HQ groups. Investigator grading indicated that lignin peroxidase resulted in improved skin texture. There were no AEs from either treatment. Lignin peroxidase improved patient melasma compared with no treatment.

Mulberry extract – weak recommendationOne single-blind RCT found that twice daily 75% mulberry extract oil for 8 weeks significantly improved patient MASI com-pared with placebo.20 Clinical photographs were consistent and showed decreased pigmentation following mulberry extract treatment. Patients treated with mulberry extract reported fewer AEs than the control group. Mulberry extract received a weak recommendation, as additional research is needed to establish the efficacy of mulberry extract for periods greater than 8 weeks and compared with HQ.

Niacinamide – weak recommendationNiacinamide, also known as vitamin B3, may decrease skin pigmentation by preventing melanosome transfer.21 One dou-ble-blind, split-face RCT of 27 patients compared the efficacy of 4% niacinamide (Nicomide-T Cream 4%, DUSA Pharmaceuticals Inc, Wilmington, MA) with 4% HQ every 3 hours during the day-time for 8 weeks.22 Both treatments reduced MASI significantly at week 8 compared with baseline. Niacinamide was associated with fewer and milder AEs. Colorimetric measures did not show statistical differences between both sides. However, according

to the IGA, good to excellent improvement was observed with niacinamide in 44% of patients compared with 55% with HQ. Niacinamide received a weak recommendation, but there is promising efficacy from a single study.

Rumex occidentalis (Western Dock) – weak recommendation One double-blind RCT compared the efficacy of twice daily 3% Rumex occidentalis (a perennial herb), 4% HQ, and placebo for 8 weeks in 45 patients.23 The placebo had no significant ef-fect, while the 3% Rumex occidentalis and 4% HQ significantly decreased MASI scores and colorimetric measures. Patients treated with Rumex occidentalis reported mild peeling. Clinical photographs demonstrated decreased pigmentation and diffuse skin brightening.23 Rumex occidentalis reduced patient melas-ma and may be worthy of future research.

Tranexamic acid – strong recommendationFive RCTs examined the use of topical TXA for patients with me-lasma. In one study of 60 patients, twice daily treatment with 6.5% TXA (Pazana Laboratory Asia Co., Ltd, Bangkok, Thailand) significantly improved melasma compared with vehicle at week 8.24 Clinical photographs showed improvement following TXA treatment, but mild pre-treatment severity. However, in another double-blind, split-face RCT, 5% TXA performed no better than the vehicle.25 Both treatment and control reduced melasma, but there was no difference in efficacy as determined by MASI and colorimetry. In a 60 patient double-blind study, 5% TXA vs 2% HQ twice daily both significantly decreased MASI.26 5% TXA was associated with higher patient satisfaction and less skin irrita-tion.26 In another split-face, double-blind study, 5% liposomal TXA (prepared by fusion method) had similar efficacy in re-ducing patient MASI score compared with 4% HQ after twice daily treatment for 12 weeks.27 Skin irritation only occurred in the 4% HQ treated group.27 In a split-face, double-blind study of twice daily 3% TXA vs 3% HQ and 0.01% dexamethasone, both treatments significantly reduced MASI scores.28 Photographs showed decreased pigmentation. There was no difference in treatment efficacy between groups, but topical application of 3% HQ and 0.01% dexamethasone was associated with an in-creased incidence of AEs.28

TXA had similar efficacy to HQ with a milder AE profile and received a strong recommendation. The efficacy of TXA is de-pendent on concentration dose when used as monotherapy. TXA is a lysine analogue and carries a theoretical risk for throm-bosis due to the anti-fibrinolytic effects. However, no evidence of increased clotting in low-risk patients was found in a recently published review of the safety and efficacy of oral TXA for me-lasma.29 Topical TXA likely has decreased vasculature circulation compared with oral administration, but the theoretical risk of blood clots remains. Clinicians may consider topical TXA as an alternative to HQ in patients without predispositions to throm-botic events.



1168



Triple combination therapy – strong recommendationFive RCTs have examined the efficacy of TC agents. One 211 patient double-blind RCT found that 4% HQ, 0.05% tretinoin, and 0.01% fluocinolone acetonide (FA) (Zhejiang Rishengchang Pharmaceutical Co., Ltd, Zhejiang, China) was more effective than placebo at clearing melasma based on the decreased in-dex of total target score.30 Another double-blind RCT of 32 patients found that daily 4% HQ, 0.05% tretinoin, and 0.05% dexamethasone had better investigator-rated outcomes than 4% HQ after 12 weeks.31 Erythema and scaling were more preva-lent following TC therapy (87.5% vs 43.7%). An open-label RCT of 119 patients found that once daily TC cream of 4% HQ, 0.05% tretinoin, and 0.01% FA (Tri-Luma®, Galderma, Lausanne, Swit-zerland) more effectively cleared melasma compared with twice daily 4% HQ, with 35% of patients achieving complete clear-ance on TC therapy compared with 5.1% in the HQ group.32 A 242 patient single-blind study evaluating the same treatment regimen similarly demonstrated reduced MASI score compared with 4% HQ.33 Patient photographs were consistent and showed improvement of melasma.33 In a single-blind 641 patient RCT, a TC hydrophilic cream containing 4% HQ, 0.05% tretinoin, and 0.01% FA more effectively cleared melasma compared with dual combination regimens of tretinoin plus HQ, tretinoin plus FA, or HQ plus FA.34 AEs of erythema, skin peeling, burning, and sting-ing sensation were mild and similar among all treatment arms.34

TC therapy was superior to 4% HQ with a similar AE profile and received a strong recommendation. TC therapies demonstrate the benefit of synergistic treatments in which HQ decreases melanogenesis, tretinoin increases keratinocyte turnover, and steroids reduce inflammation. Evidence from epidemiological studies and case reports has not revealed an increased risk of cancer but clinicians may consider limiting chronic exposure.9

If clinical goals have been achieved, a maintenance regimen of once or twice weekly TC therapy may minimize the risk for ochronosis.35,36 Relapse has been shown to occur in 50% of patients approximately 190 days following the establishment of a maintenance regimen compared with 58 days following abrupt cessation of therapy.35-37 For patients seeking a non-HQ therapeutic approach for the treatment of melasma due to HQ associated safety profile, we recommend against TC.

4-n-butylresorcinol – weak recommendationThree double-blind, split-face RCTs compared the efficacy of 4-n-butylresorcinol 0.1% cream or 0.3% serum with vehicle.38-40

In all 3 studies, 4-n-butylresorcinol significantly reduced skin pigmentation compared with vehicle based on colorimetric measures and clinical pigmentation score. In one study, the de-pigmenting effects of 4-n-butylresorcinol 0.3% serum increased until week 8 and then plateaued.40 The other two studies only compared the efficacy until week 8. Adverse events were mild in all three studies. Photographs showed improvement following 4-n-butylresorcinol topical therapies.38-40

4-n-butylresorcinol decreased skin pigmentation and may be a useful as a short-term treatment for melasma, but the long-term efficacy beyond 12 weeks is unclear. In vitro studies have indicated that 4-n-butylresorcinol was the most potent inhibitor of tyrosinase compared with HQ, arbutin, and kojic acid.41 4-n-butylresorcinol received a weak recommendation, as additional studies are needed to compare the efficacy of 4-n-butylresorcin-ol to establish the duration of effect greater than 8 to 12 weeks, and comparison studies to 4% HQ may provide additional strength of data.

Benefits Closely Balanced With Risks and BurdenGlycolic acid – weak recommendationGlycolic acid is believed to improve melasma by accelerating desquamation.42 Two RCTs examined the efficacy of combination 10% glycolic acid and 4% HQ for melasma.43,44 In a vehicle-con-trolled, double-blind RCT of 35 patients, twice daily application of a cream containing 10% buffered glycolic acid with 4% HQ, ascorbic acid, vitamin E, and sunscreen (Glyquin, ICN Phar-maceuticals, Costa Mesa, CA) was applied for 12 weeks.43 The combination 10% glycolic acid product significantly improved melasma compared with sunscreen-only control as determined by MASI and colorimetry.43 Another single-blind RCT compared daily 4% HQ alone with 4% HQ with 0.01% hyaluronic acid; 4% HQ with 10% glycolic acid; 4% HQ with 0.01% hyaluronic and 10% glycolic acid; or placebo.44 All 4 topical treatments improved melasma from baseline. The most significant decrease in melas-ma was measured following 4% HQ with 0.01% hyaluronic acid and 10% glycolic acid. Topical 4% HQ with supplemental glycolic acid was more irritating to skin than HQ alone. Post-treatment photographs showed localized skin brightening around the treatment site. Glycolic acid is weakly recommended as a supplement to 4% HQ, as the benefits and risk of skin desquamation should be carefully considered for each patient. Additionally, the RCTs do not directly compare the efficacy of glycolic acid alone with HQ alone. Glycolic acid supplementation had greater efficacy and more severe AEs compared with 4% HQ alone. Skin desqua-mation from glycolic acid may be minimized if patients apply a moisturizing cream concurrently.9 Glycolic acid appears best suited as adjunct therapy for melasma and not a primary, first-line approach.

Kojic acid – weak recommendationKojic acid is a tyrosinase inhibitor produced by several fungi species. Two poorly designed RCTs examined the use of kojic acid for melasma. In an 80-patient single-blind RCT, 4 different formulations of 1% kojic acid alone or in combination with 2% HQ and/or 0.1% betamethasone were tested.45 All 4 treatment groups significantly reduced MASI score after daily treatment for 12 weeks.45 The authors did not statistically compare inter-treatment efficacy but concluded that 1% kojic acid with 2% HQ



1169



had the best efficacy and 1% kojic acid with 0.1% betametha-sone was the least effective. 1% kojic acid, 2% HQ, and 0.1% betamethasone was associated with acneiform eruptions. In another RCT, daily 0.75% kojic acid with 2.5% ascorbic acid for 12 weeks was inferior to 4% HQ.46 Photographs demonstrated minimal efficacy for kojic acid as a stand-alone treatment. An-ecdotal clinical evidence suggests that compounding 12% HQ with 6% kojic acid may be an effective treatment not associated with diffuse skin brightening, but this formulation has not been studied in an RCT. Based upon the available published literature reviewed, kojic acid received a weak recommendation when combined with other agents, and evidence does not support recommendation as a stand-alone treatment for melasma.

Risks and Burden Outweigh BenefitsParsley – weak recommendationIn a poorly designed double-blind RCT, patients applied parsley or 4% HQ daily for 8 weeks.47 The patients in the parsley group had to self-brew 2.5 g of parsley in 125 ml of water. Both treat-ments significantly improved MASI from baseline. AEs in the parsley and 4% HQ group included irritation, redness, and itch-ing. As patients were required to self-prepare parsley extract to prevent treatment expiration, the use of parsley was weakly recommended. Additionally, differences in sample preparation may lead to variability in treatment results.

Zinc sulfate – strong recommendationZinc sulfate has been used to treat numerous skin conditions including acne vulgaris and warts. Two RCTs examined the use of once or twice daily 10% zinc sulfate for melasma.48,49 In both studies, topical application of 10% zinc sulfate reduced MASI score less effectively than 4% HQ. One study noted that patients treated with 4% HQ alone complained of greater skin irritation. However, 10% zinc sulfate resulted in PIH in 2 patients that re-solved with topical tretinoin treatment.49 As zinc sulfate was inferior to 4% HQ and carried a risk of PIH, we strongly do not recommend zinc sulfate for the treatment of melasma.

Insufficient Evidence to Determine Net BenefitAloe vera – no strength of recommendationOne double-blind study compared the efficacy of 2 aloe vera for-mulations (0.5% gel extract or 0.25% liposome-encapsulated gel extract) in 180 pregnant patients with pre-existing melasma.50

After 5 weeks, liposome-encapsulated aloe vera significantly improved patient MASI compared with the standard gel formu-lation. As there was no placebo or HQ control group, it is difficult to determine the relative efficacy of aloe vera. However, the net risk of AEs is likely low as the treatment was used in pregnant patients. The study did not describe the frequency of aloe vera application.

Ascorbic acid – no strength of recommendationIn a 16 patient, split-face, double-blind RCT, patients were less

satisfied with 5% L-ascorbic acid (La Roche-Posay, France) compared with 4% HQ after 16 weeks.51 Colorimetric analysis demonstrated no difference between treatment arms, and HQ was more irritating to the skin. Ascorbic acid is readily oxidized, which limits its use as a stand-alone treatment but may be com-bined with other topical agents.9

Dioic acid – no strength of recommendationOne open-label RCT of 96 patients compared twice daily 1% dioic acid with 2% HQ for 12 weeks. 1% dioic acid and 2% HQ improved MASI scores from baseline, but there was no signifi-cant difference between dioic acid and HQ.52 Patients treated with dioic acid had a higher incidence of acneiform reaction, which the authors attributed to an oily vehicle. An open-label design limited the strength of this study.

Ellagic acid and arbutin – no strength of recommendationIn an open-label RCT involving 29 patients, twice daily treatment with 1% synthetic ellagic acid, 1% arbutin, or plant extract with 1% natural ellagic acid significantly improved skin pigmenta-tion after 6 months without the occurrence of AEs.53 Limitations in the study design included the lack of blinding and lack of a placebo-control. Thus, additional research is needed before con-clusions can be drawn about ellagic acid and arbutin therapy for melasma.

Flutamide – no strength of recommendationOne double-blind study compared the efficacy of daily topi-cal 1% flutamide, an anti-androgenic drug, with 4% HQ over 4 months.54 Both treatments reduced MASI compared with base-line. Flutamide was more effective than HQ according to MASI and patient satisfaction but there was no difference between treatments when assessed using colorimetric analysis. The AE profile was not provided, and the safety of hormonal therapy should be evaluated before a recommendation can be made.

LIMITATIONSCurrently, there is no universally effective treatment for me-lasma, and some established topical agents carry significant safety risks that may reduce patient compliance and satisfac-tion. Topical HQ, the basis for many combination therapies, may be less effective in patients with darker skin phenotypes and is associated with ochronosis.9,55 Other novel agents have shown promising results, but are limited by small sample sizes, poor study design, and limited high quality published RCTs. When evaluating naturally-derived or compounded topical therapies, it is essential to consider the reproducibility of the chemical composition. Differences in treatment concentration or second-ary ingredients may have a significant impact on therapeutic efficacy. Additionally, several RCTs used natural agents pub-lished in non-English languages. These studies may have added to the literature, but we were unable to evaluate these studies.



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CONCLUSIONWe performed a systematic review of topical treatments for melasma. Strong evidence-based recommendations include cysteamine, TC, and TXA as first-line treatments for melasma. Cysteamine has excellent efficacy, is reported to have anti-cancer properties, and has no known risk for thrombosis or ochronosis. TC therapies and TXA are effective for melasma but carry theo-retical risks for ochronosis or thrombosis, respectively. Natural compounds are associated with low risk for AEs, but more re-search is needed to determine the efficacy, optimal formulation, and appropriate concentration of novel treatments.

For all topical agents, continued treatment and use of medi-cations is necessary as pigmentation may recur following treatment cessation. Future large RCTs with control arms us-ing standard-of-care treatments (ie, HQ or TC) are necessary to assess the relative risks and benefits of a novel agent. Current topical treatments mostly inhibit melanin formation and trans-fer, but do not target the vascular components of melasma, inflammation, or underlying disease etiology. We believe that synergetic combination approaches are likely to have greater ef-ficacy than stand-alone treatments. Future mechanistic research on the underlying etiology of melasma may facilitate the devel-opment of targeted approaches.

ACKNOWLEDGMENTSDr. Jagdeo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition, analysis, and interpretation of data: EA and JN. Drafting of the manuscript: EA. Critical revision of the manuscript for important intellectual content: JN and JJ.

DISCLOSURESDr. Jagdeo is a speaker for L’Oréal/Skinceuticals and a consul-tant for Scientis. Dr. Jagdeo is on the scientific advisory board for Sun Pharma/DUSA Pharmaceuticals, Inc. for the product Levulan® photodynamic therapy. No funding has been received for this article. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the U.S. Department of Veterans Affairs or the United States Government.

REFERENCES1. Kwon S-H, Hwang Y-J, Lee S-K, et al. Heterogeneous pathology of melasma

and its clinical implications. Int J Mol Sci. 2016;17(6):824.2. Ogbechie-Godec OA, Elbuluk N. Melasma: an up-to-date comprehensive re-

view. Derm Ther. 2017;7(3):305-318.3. Vázquez M, Maldonado H, Benmamán C, et al. Melasma in men. Int J Derm.

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Dermatol. 2011;65(4):689-697; quiz 698.5. Lee AY. Recent progress in melasma pathogenesis. Pigment Cell Melanoma

Res. 2015;28(6):648-660.6. Passeron T. Melasma pathogenesis and influencing factors–an overview of

the latest research. J Eur Acad Dermatol Venereol. 2013;27(s1):5-6.7. Jiang J, Akinseye O, Tovar-Garza A, et al. The effect of melasma on self-es-

teem: A pilot study. Int J Women Dermatol. 2018;4(1):38-42.

8. Pawaskar MD, Parikh P, Markowski T, et al. Melasma and its impact on health-related quality of life in Hispanic women. J Dermatol Treat. 2007;18(1):5-9.

9. Sheth VM, Pandya AG. Melasma: a comprehensive update: part II. J Am Acad Dermatol. 2011;65(4):699-714; quiz 715.

10. Qaseem A, Snow V, Owens DK, et al. The development of clinical practice guidelines and guidance statements of the American College of Physicians: summary of methods. Ann Intern Med. 2010;153(3):194-199.

11. Farshi S. Comparative study of therapeutic effects of 20% azelaic acid and hydroquinone 4% cream in the treatment of melasma. J Cosmet Dermatol. 2011;10(4):282-287.

12. Mazurek K, Pierzchala E. Comparison of efficacy of products containing az-elaic acid in melasma treatment. J Cosmet Dermatol. 2016;15(3):269-282.

13. Farshi S, Mansouri P, Kasraee B. Efficacy of cysteamine cream in the treat-ment of epidermal melasma, evaluating by Dermacatch as a new measure-ment method: a randomized double blind placebo controlled study. J Derma-tol Treat. 2018;29(2):182-189.

14. Mansouri P, Farshi S, Hashemi Z, et al. Evaluation of the efficacy of cys-teamine 5% cream in the treatment of epidermal melasma: a randomized double-blind placebo-controlled trial. Br J Dermatol. 2015;173(1):209-217.

15. Fujisawa T, Rubin B, Suzuki A, et al. Cysteamine suppresses invasion, me-tastasis and prolongs survival by inhibiting matrix metalloproteinases in a mouse model of human pancreatic cancer. PloS One. 2012;7(4):e34437.

16. Besouw M, Masereeuw R, van den Heuvel L, et al. Cysteamine: an old drug with new potential. Drug Discovery Today. 2013;18(15-16):785-792.

17. Lyons A, Stoll J, Moy R. A randomized, double-blind, placebo-Controlled, split-face study of the efficacy of topical epidermal growth factor for the treatment of melasma. J Drugs Dermatol. 2018;17(9):970-973.

18. Taghavi F, Banihashemi M, Zabolinejad N, et al. Comparison of therapeutic effects of conventional and liposomal form of 4% topical hydroquinone in patients with melasma. J Cosmet Dermatol. 2019;18(3):870-873.

19. Draelos ZD. A split-face evaluation of a novel pigment-lightening agent compared with no treatment and hydroquinone. J Am Acad Dermatol. 2015;72(1):105-107.

20. Alvin G, Catambay N, Vergara A, et al. A comparative study of the safety and efficacy of 75% mulberry (Morus alba) extract oil vs placebo as a topical treatment for melasma: a randomized, single-blind, placebo-controlled trial. J Drugs Dermatol. 2011;10(9):1025-1031.

21. Hakozaki T, Minwalla L, Zhuang J, et al. The effect of niacinamide on reduc-ing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol. 2002;147(1):20-31.

22. Navarrete-Solis J, Castanedo-Cazares JP, Torres-Alvarez B, et al. A double-blind, randomized clinical trial of niacinamide 4% vs hydroquinone 4% in the treatment of melasma. Dermatol Res Pract. 2011;2011:379173.

23. Mendoza CG, Singzon IA, Handog EB. A randomized, double-blind, placebo-controlled clinical trial on the efficacy and safety of 3% Rumex occidentalis cream vs 4% hydroquinone cream in the treatment of melasma among Fili-pinos. Int J Dermatol. 2014;53(11):1412-1416.

24. Viyoch J, Tengamnuay I, Phetdee K, et al. Effects of trans-4-(aminomethyl) cyclohexanecarboxylic acid/potassium azeloyl diglycinate/niacinamide topical emulsion in Thai adults with melasma: a single-center, randomized, double-blind, controlled study. Curr Ther Res Clin Exp. 2010;71(6):345-359.

25. Kanechorn Na Ayuthaya P, Niumphradit N, Manosroi A, et al. Topical 5% tranexamic acid for the treatment of melasma in Asians: a double-blind ran-domized controlled clinical trial. J Cosmet Laser Ther. 2012;14(3):150-154.

26. Atefi N, Dalvand B, Ghassemi M, et al. Therapeutic effects of topical tranexamic acid in comparison with hydroquinone in treatment of women with melasma. Dermatol Ther. 2017;7(3):417-424.

27. Banihashemi M, Zabolinejad N, Jaafari MR, et al. Comparison of therapeutic effects of liposomal Tranexamic Acid and conventional Hydroquinone on me-lasma. J Cosmet Dermatol. 2015;14(3):174-177.

28. Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising treatment for melasma. J Res Med Sci. 2014;19(8):753-757.

29. Bala HR, Lee S, Wong C, et al. Oral tranexamic acid for the treatment of melasma: a review. Dermatol Surg. 2018;44(6):814-825.

30. Gong Z, Lai W, Zhao G, et al. Efficacy and safety of fluocinolone acetonide, hydroquinone, and tretinoin cream in chinese patients with melasma: a ran-domized, double-blind, placebo-controlled, multicenter, parallel-group study. Clin Drug Investig. 2015;35(6):385-395.

31. Astaneh R, Farboud E, Nazemi MJ. 4% hydroquinone vs 4% hydroquinone, 0.05% dexamethasone and 0.05% tretinoin in the treatment of melasma: a comparative study. Int J Dermatol. 2005;44(7):599-601.

32. Ferreira Cestari T, Hassun K, Sittart A, et al. A comparison of triple combina-tion cream and hydroquinone 4% cream for the treatment of moderate to severe facial melasma. J Cosmet Dermatol. 2007;6(1):36-39.

33. Chan R, Park KC, Lee MH, et al. A randomized controlled trial of the effi-cacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4%



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cream in Asian patients with moderate to severe melasma. Br J Dermatol. 2008;159(3):697-703.

34. Taylor SC, Torok H, Jones T, et al. Efficacy and safety of a new triple-combi-nation agent for the treatment of facial melasma. Cutis. 2003;72(1):67-72.

35. Arellano I, Cestari T, Ocampo-Candiani J, et al. Preventing melasma recur-rence: prescribing a maintenance regimen with an effective triple combina-tion cream based on long-standing clinical severity. J Eur Acad Dermatol Venereol. 2012;26(5):611-618.

36. Hexsel D, Soirefmann M, Fernandes JD, et al. Objective assessment of erythema and pigmentation of melasma lesions and surrounding areas in long-term management regimens with triple combination. J Drugs Derma-tol. 2014;13(4):444-448.

37. Torok H, Taylor S, Baumann L, et al. A large 12-month extension study of an 8-week trial to evaluate the safety and efficacy of triple combination (TC) cream in melasma patients previously treated with TC cream or one of its dyads. J Drugs Dermatol. 2005;4(5):592-597.

38. Huh SY, Shin JW, Na JI, et al. The efficacy and safety of 4-n-butylresorcinol 0.1% cream for the treatment of melasma: a randomized controlled split-face trial. Annals Dermatol. 2010;22(1):21-25.

39. Huh SY, Shin JW, Na JI, et al. Efficacy and safety of liposome-encapsulated 4-n-butylresorcinol 0.1% cream for the treatment of melasma: a randomized controlled split-face trial. J Dermatol. 2010;37(4):311-315.

40. Khemis A, Kaiafa A, Queille-Roussel C, et al. Evaluation of efficacy and safety of rucinol serum in patients with melasma: a randomized controlled trial. Br J Dermatol. 2007;156(5):997-1004.

41. Kolbe L, Mann T, Gerwat W, et al. 4-n-butylresorcinol, a highly effective ty-rosinase inhibitor for the topical treatment of hyperpigmentation. J Eur Acad Dermatol Venereol. 2013;27 Suppl 1:19-23.

42. Kornhauser A, Coelho SG, Hearing VJ. Applications of hydroxy acids: clas-sification, mechanisms, and photoactivity. Clin Cosmet Investig Dermatol. 2010;3:135.

43. Guevara IL, Pandya AG. Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of me-lasma. Int J Dermatol. 2003;42(12):966-972.

44. Ibrahim ZA, Gheida SF, El Maghraby GM, et al. Evaluation of the efficacy and safety of combinations of hydroquinone, glycolic acid, and hyaluronic acid in the treatment of melasma. J Cosmet Dermatol. 2015;14(2):113-123.

45. Deo KS, Dash KN, Sharma YK, et al. Kojic acid vis-a-vis its combinations with hydroquinone and betamethasone valerate in melasma: a randomized, single blind, comparative study of efficacy and safety. Indian J Dermatol. 2013;58(4):281-285.

46. Monteiro RC, Kishore BN, Bhat RM, et al. A comparative study of the ef-ficacy of 4% hydroquinone vs 0.75% kojic acid cream in the treatment of facial melasma. Indian J Dermatol. 2013;58(2):157.

47. Khosravan S, Alami A, Mohammadzadeh-Moghadam H, et al. The effect of topical use of petroselinum crispum (parsley) versus that of hydroquinone cream on reduction of epidermal melasma: a randomized clinical trial. Holist Nurs Pract. 2017;31(1):16-20.

48. Iraji F, Tagmirriahi N, Gavidnia K. Comparison between the efficacy of 10% zinc sulfate solution with 4% hydroquinone cream on improvement of me-lasma. Adv Biomed Res. 2012;1:39.

49. Yousefi A, Khani Khoozani Z, Zakerzadeh Forooshani S, et al. Is topical zinc effective in the treatment of melasma? A double-blind randomized compara-tive study. Dermatol Surg. 2014;40(1):33-37.

50. Ghafarzadeh M, Eatemadi A. Clinical efficacy of liposome-encapsulated Aloe vera on melasma treatment during pregnancy. J Cosmet Laser Ther. 2017;19(3):181-187.

51. Espinal-Perez LE, Moncada B, Castanedo-Cazares JP. A double-blind ran-domized trial of 5% ascorbic acid vs. 4% hydroquinone in melasma. Int J Dermatol. 2004;43(8):604-607.

52. Tirado-Sánchez A, Santamaría-Román A, Ponce-Olivera RM. Efficacy of dioic acid compared with hydroquinone in the treatment of melasma. Int J Der-matol. 2009;48(8):893-895.

53. Ertam I, Mutlu B, Unal I, et al. Efficiency of ellagic acid and arbutin in melasma: a randomized, prospective, open-label study. J Dermatol. 2008;35(9):570-574.

54. Adalatkhah H, Sadeghi-Bazargani H. The first clinical experience on efficacy of topical flutamide on melasma compared with topical hydroquinone: a ran-domized clinical trial. Drug Des Devel Ther. 2015;9:4219-4225.

55. Nomakhosi M, Heidi A. Natural options for management of melasma, a re-view. J Cosmet Laser Ther. 2018:1-12.


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Copyright © 2019 CASE REPORT Journal of Drugs in Dermatology

SPECIAL TOPIC

Porokeratosis is a rare disorder of epidermal keratinization that encompasses several clinical forms, characterized by erythematous, an-nular plaques with an atrophic center and hyperkeratotic ridge-like border. The histopathological hallmark of porokeratosis is the cornoid lamella, a thin column of parakeratotic corneocytes embedded within the stratum corneum. There is no standard treatment regimen for porokeratosis. Current therapeutic modalities include topical agents, systemic medications, and surgical interventions that have variable efficacy. Here, we report a case of a patient with localized porokeratosis lesions on the face and extremities that resolved after one treatment session with carbon dioxide laser resurfacing combined with topical antioxidant serum containing L-ascorbic acid, alpha tocopherol, and ferulic acid. The diagnosis of porokeratosis was supported by the clinical presentation, dermoscopy, and in vivo skin imaging with optical coherence tomography and reflectance confocal microscopy. This case highlights the utility of using carbon dioxide laser to ablate porokeratosis lesions, as well as the clinical advantages offered by new noninvasive skin imaging modalities to examine, diagnose, and follow up skin pathologies.

J Drugs Dermatol. 2019;18(11):1174-1176.

ABSTRACT

INTRODUCTION

Porokeratosis is a disorder of epidermal keratinization that encompasses multiple clinical variants based on differ-ent patterns of distribution. It classically manifests as

one or more erythematous, annular plaques with an atrophic center and hyperkeratotic ridge-like border.1–3 The primary le-sion of classic porokeratosis starts as a small, light brown, scaly papule that spreads in a centrifugal manner and may slowly progress and coalesce into a sharply circumscribed plaque of various sizes and forms.4,5 The lesions are often asymptomatic but may be associated with pruritus.1 Porokeratosis lesions may affect any part of the body, including palmoplantar sur-faces and mucous membranes, but are more prevalent on the trunk and extremities.1,2

Porokeratosis may be classified as classic porokeratosis of Mibelli, linear porokeratosis, disseminated porokeratosis, disseminated superficial actinic porokeratosis, punctuate poro-keratosis, or porokeratosis palmaris et plantaris disseminata.1,3 The histopathological hallmark of porokeratosis is the cornoid lamella, characterized by a thin column of parakeratotic cor-neocytes embedded within the stratum corneum, forming an indentation within the epidermis.1,3,4 While the exact pathogen-esis of porokeratosis remains unclear, it may be acquired or hereditary, and is thought to be due to the clonal expansion of abnormal epidermal keratinocytes.1,4 The proliferation of abnormal clones may be triggered by extrinsic factors such

as irradiation, infective agents, mechanical trauma, and im-munosuppression.1 The differential diagnosis of porokeratosis includes actinic keratosis, seborrheic keratosis, psoriasis, lichen planus, Bowen’s disease, and squamous cell carcinoma.2,4

The overall prognosis of porokeratosis is favorable. However, a potential complication is an increased risk (estimated to be less than 10%) of malignant transformation of a porokeratosis lesion to a basal or squamous cell carcinoma.1,6 Risk factors include large lesion size, localization on the extremities, older age, and a long period of existence.1

There is no definitive or “gold standard” treatment regimen for porokeratosis, and current therapeutic approaches have variable efficacy and durability. Asymptomatic lesions are of-ten managed conservatively with sun protection, emollients, and clinical surveillance for signs of malignant degeneration.1

Current therapeutic modalities used to improve the signs and symptoms of porokeratosis include many topical, systemic, and surgical treatment options such as: 5-fluorouracil cream, topical vitamin D3 analogs, topical and systemic retinoids (eg, acitretin or isotretinoin), cryotherapy, dermabrasion, laser ablation, imiquimod, ingenol mebutate, topical diclofenac, can-tharidin, corticosteroids, topical tacrolimus, phototherapy, and surgical excision.3,4 A systematic review found that no random-ized controlled trials have been conducted to assess treatments

Successful Treatment of Porokeratosis With Ablative Fractional Carbon Dioxide Laser and Vitamin C, E, and Ferulic Acid Serum

Julie K. Nguyen MD,a,b Silvia Mancebo MD,a Brady Bleicher MD,b,c and Jared Jagdeo MD MSa,b

aDepartment of Dermatology, SUNY Downstate Medical Center, Brooklyn, NYBDermatology Service, VA New York Harbor Healthcare System – Brooklyn Campus, Brooklyn, NY

cDepartment of Dermatology, Mount Sinai Medical Center, New York, NY



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J.K. Nguyen, S. Mancebo, B. Bleicher, J. Jagdeo

of Mibelli was made. A skin biopsy was deferred. Although the lesions were asymptomatic, the patient was concerned about the aesthetic appearance and requested treatment.

The individual lesions were treated with ablative fractional CO2 laser resurfacing (Fraxel Repair, Solta Medical, Hayward, CA). Two days prior to the procedure, he was started on prophylaxis with valacyclovir (1 g twice daily for 7 days) and cephalexin (500 mg four times daily for 14 days). For each focal site of poro-keratosis, the lesion received three passes of the laser at 70 mJ with 35% coverage. An additional pass was performed at 50 mJ with 30% coverage along with feathering at the edges. A topical formulation of 15% L-ascorbic acid, 1% alpha-tocopherol, and 0.5% ferulic acid serum (C E Ferulic, SkinCeuticals Inc, Garland, TX) was applied immediately after the procedure, and the pa-tient was instructed to re-apply it twice daily for two days. At a two months follow-up visit, clinical examination of the affected areas showed complete clearance of the lesions (Figure 1D-F), and repeat in vivo imaging of the lesion on the forearm showed normal skin (images not shown).

DISCUSSIONThere is a paucity of clinical studies evaluating therapeutic mo-dalities for porokeratosis. The use of CO2 laser ablation for the treatment of porokeratosis has been previously documented in isolated case reports.3 Successful treatment of porokeratosis of Mibelli with the CO2 laser has been reported with good clini-cal and aesthetic outcomes, including histological confirmation of complete resolution of porokeratosis features and no evi-

for porokeratosis.3 Based on a limited number of case reports and cases series available in the literature, porokeratosis of Mibelli shows the best clinical outcomes after treatment with imiquimod cream.3

Herein, we report a case of a patient who had multiple lesions con-sistent with porokeratosis of Mibelli that were each successfully treated with a combination of ablative fractional carbon diox-ide (CO2) laser and topical application of an antioxidant serum. CASE REPORTA 51-year-old male with Fitzpatrick skin phototype 2 presented to dermatology clinic for evaluation of a chronic rash. He re-ported the occurrence of focal, red, scaly lesions on his left hand, face, and right arm. The onset of these lesions was un-clear, but they remained unchanged despite the use of topical clobetasol. His past medical history included celiac disease and hyperlipidemia, and medications included gemfibrozil. Physi-cal examination revealed three annular, pink, erythematous plaques (approximately 1.0 x 1.0 cm) with a raised scaly border distributed on the left dorsal hand, right forehead superior to the eyebrow, and right dorsal forearm (Figure 1A-C).

The lesion on the forearm was visualized under dermoscopy, optical coherence tomography (OCT), and reflectance confo-cal microscopy (RCM). Dermoscopy revealed the presence of a peripheral white rim and multiple dotted vessels over an erythematous center and superficial white scales (Figure 2A). OCT (VivoSight, Michelson Diagnostics Ltd, Kent, UK) showed a cornoid lamella (Figure 2B). RCM (VivaScope 3000, Caliber I.D., Rochester, NY) showed an atypical honeycomb pattern and ar-chitectural disarray at the corneal level (Figure 2C). Based on the clinical presentation and morphologic features identified on in vivo skin imaging modalities, the diagnosis of porokeratosis

FIGURE 2. (A) Dermoscopic image of a porokeratosis of Mibelli lesion revealing the presence of a peripheral white rim and multiple dotted vessels over a pink background and superficial white scales. (B) Optical coherence tomography of a cornoid lamella. (C) Reflectance confocal microscopy examination (single image) at the corneal level revealing hyper-refractile cells, an atypical honeycomb pattern, and architectural disarray.

FIGURE 1. Before (A, B, C) and after (D, E, F) photographs of isolated lesions of porokeratosis of Mibelli on the forehead, dorsal hand, and upper arm, respectively. All porokeratosis lesions were treated with a single session of ablative fractional carbon dioxide laser therapy followed by application of a topical antioxidant solution.(A) (B) (C)

(D) (E) (F)

(A) (B)

(C)



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J.K. Nguyen, S. Mancebo, B. Bleicher, J. Jagdeo

3. Weidner T, Illing T, Miguel D, Elsner P. Treatment of porokeratosis: a system-atic review. Am J Clin Dermatol. 2017;18(4):435-449.

4. Kanitakis J. Porokeratoses: An update of clinical, aetiopathogenic and thera-peutic features. Eur J Dermatology. 2014;24(5):533-544.

5. González S, ed. Reflectance Confocal Microscopy of Cutaneous Tumors. 2nd ed. Boca Raton, FL: CRC Press; 2017.

6. Sasson M, Krain AD. Porokeratosis and cutaneous malignancy: A review. Dermatologic Surg. 1996;22(4):339-342.

7. Groot DW, Johnston PA. Carbon dioxide laser treatment of porokeratosis of mibelli. Lasers Surg Med. 1985;5(6):603-606.

8. Rabbin P, Baldwin H. Treatment of Porokeratosis of Mibelli with CO2 laser va-porization versus surgical excision with split-thickness skin graft. J Dermatol Surg Oncol. 1993;19(3):199-202.

9. Hunziker T, Bayard W. Carbon dioxide laser in the treatment of porokeratosis. J Am Acad Dermatol. 1987;16(3 Pt 1):625.

10. Barnett JH. Linear porokeratosis: Treatment with the carbon dioxide laser. J Am Acad Dermatol. 1986;14(5):902-904.

11. Waibel JS, Mi QS, Ozog D, et al. Laser-assisted delivery of vitamin c, vitamin e, and ferulic acid formula serum decreases fractional laser postoperative recovery by increased beta fibroblast growth factor expression. Lasers Surg Med. 2016;48(3):238-244.

dence of recurrence at follow-up.7,8 CO2 laser treatment has also been used successfully in other types of porokeratosis, includ-ing linear porokeratosis.9,10 Besides the CO2 laser, the 585 nm pulsed-dye laser and Nd:YAG laser have been reported to be effective for various forms of porokeratosis.1

The use of ablative fractional CO2 laser for the treatment of porokeratosis of Mibelli has several advantages compared to other therapeutic options such as systemic agents or surgical excision, as it is minimally invasive, can be used to treat areas of extensive involvement, and lacks significant side effects. Furthermore, a single treatment session may be sufficient to achieve complete clearance and the potential for post-laser scarring can be minimized as the laser parameters can be cus-tomized.7 Postoperative application of vitamin C, E, and ferulic acid serum has been shown to promote more rapid wound heal-ing after fractional ablative laser treatment.11

This case report highlights the clinical utility of using real-time, high-resolution, non-invasive imaging techniques to establish a diagnosis of porokeratosis. In this case, by using OCT to iden-tify the cornoid lamella and using RCM to examine the distinct morphologic features of porokeratosis, we were able to confirm a diagnosis of porokeratosis, avoiding the need for an inva-sive biopsy for histopathological examination. The hallmark of dermoscopy diagnosis of porokeratosis is the presence of a pe-ripheral white rim, corresponding to the cornoid lamella, which can also be identified on OCT.1,5 On RCM imaging of porokera-tosis, the presence of sharp demarcation and hyper-refractile border at the level of the corneal layer corresponds in histopa-thology to the presence of the cornoid lamella.5

In conclusion, the use of the CO2 laser in porokeratosis of Mi-belli is a therapeutic modality that is minimally invasive, offers fast and durable results, delivers clinical results, and is asso-ciated with patient satisfaction. Clinicians should consider the use of ablative fractional CO2 laser to treat focal porokeratosis lesions with consideration of the size of the lesion, anatomical location, and risk of malignant transformation. To date, there are no treatment guidelines or universal consensus on the optimal treatment for porokeratosis, with the therapeutic arma-mentarium consisting of a variety of topical agents, systemic medications, and surgical modalities. The approach to treatment for porokeratosis should be individualized with consideration of the functional and aesthetic impact and patient preferences.

DISCLOSUREDr. Jagdeo is a consultant for SkinCeuticals-L'Oréal.

REFERENCES1. Sertznig P, Von Felbert V, Megahed M. Porokeratosis: present concepts.

J Eur Acad Dermatology Venereol. 2012;26(4):404-412.2. Ferreira FR, Santos LDN, Tagliarini FANM, Lira ML de A. Porokeratosis of

Mibelli--literature review and a case report. An Bras Dermatol. 2017;88(6 Suppl 1):179-182.


Jared Jagdeo MD MSE-mail:................……............................ [email protected]



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See tolerability and efficacy results at ALTRENOHCP.com.Model shown is for illustrative purposes only.

Adverse Reactions: The most common adverse reactions in clinical trials were application site dryness (4%), pain (3%), erythema (2%), irritation (1%) and exfoliation (1%).Nursing Women: It is not known whether topical administration of tretinoin could result in suffi cient systemic absorption to produce detectable concentrations in human milk. The developmental health benefi ts of breastfeeding should be considered along with the mother’s clinical need for ALTRENO and any potential adverse effects on the breastfed child from ALTRENO.To report SUSPECTED ADVERSE REACTIONS, contact Customer Service at 1-800-321-4576 or the FDA at 1-800-FDA-1088 or fda.gov/medwatch.Please see Brief Summary of Prescribing Information on preceding pages.References: 1. Altreno lotion [package insert]. Bridgewater, NJ: Ortho Dermatologics a division of Bausch Health Companies, Bridgewater, NJ 08807 USA. 2. Data on fi le. Ortho Dermatologics a division of Bausch Health Companies, Bridgewater, NJ 08807 USA.

Altreno is a trademark of Ortho Dermatologics’ affi liated entities. © 2019 Ortho Dermatologics’ affi liated entities. ALT.0070.USA.19

INDICATIONALTRENO™ (tretinoin) lotion, 0.05% is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older.IMPORTANT SAFETY INFORMATIONALTRENO is for topical use only. Not for ophthalmic, oral, or intravaginal use.Skin Irritation: Patients using ALTRENO may experience application site dryness, pain, erythema, irritation, and exfoliation. Depending upon the severity of these adverse reactions, instruct patients to use a moisturizer, reduce the frequency of the application of ALTRENO, or discontinue use. Avoid application of ALTRENO to eczematous or sunburned skin.Ultraviolet Light and Environmental Exposure: Minimize unprotected exposure to ultraviolet light, including sunlight and sunlamps. Warn patients with frequent sun exposure and those with inherent sensitivity to sunlight to exercise caution. Use sunscreen and protective clothing over treated areas when exposure cannot be avoided.Fish Allergies: ALTRENO contains soluble fi sh proteins. Use with caution in patients with known sensitivity or allergy to fi sh. Advise patients to contact their healthcare provider if they develop pruritus or urticaria.

the fi rst and only acne treatment that provides the proven effi cacy of tretinoin in a hydrating lotion.1,2

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BRIEF SUMMARY OF PRESCRIBING INFORMATION This Brief Summary does not include all the information needed to use ALTRENO safely and effectively. See full prescribing information for ALTRENO.

ALTRENO™ (tretinoin) lotion, for topical use Initial U.S. Approval: 1973

INDICATIONS AND USAGE

ALTRENO™ (tretinoin) lotion, 0.05% is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

Skin Irritation Patients using ALTRENO may experience application site dryness, pain, erythema, irritation, and exfoliation. Depending upon the severity of these adverse reactions, instruct patients to use a moisturizer, reduce the frequency of the application of ALTRENO, or discontinue use. Avoid application of ALTRENO to eczematous or sunburned skin.

Ultraviolet Light and Environmental Exposure Minimize unprotected exposure to ultraviolet light including sunlight and sunlamps during the use of ALTRENO. Warn patients who normally experience high levels of sun exposure and those with inherent sensitivity to sun to exercise caution. Use sunscreen products and protective clothing over treated areas when sun exposure cannot be avoided.

Fish AllergiesALTRENO contains soluble fish proteins. Use with caution in patients with known sensitivity or allergy to fish. Advise patients to contact their healthcare provider if they develop pruritus or urticaria.

ADVERSE REACTIONS

Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In 2 randomized, double-blind, vehicle-controlled trials, subjects age 9 years and older applied ALTRENO or vehicle once daily for 12 weeks. The majority of subjects were White (74%) and female (55%). Approximately 47% were Hispanic/Latino and 45% were younger than 18 years of age. Adverse reactions reported by ≥1% of subjects treated with ALTRENO and more frequently than vehicle are summarized in Table 1.

Table 1: Adverse Reactions Reported by ≥1% of Subjects Treated with ALTRENO and More Frequently than Vehicle

Adverse Reactions n (%)

ALTRENO N=767

Vehicle N=783

Application site dryness 29 (4) 1 (<1)

Application site pain1 25 (3) 3 (<1)

Application site erythema 12 (2) 1 (<1)

Application site irritation 7 (1) 1 (<1)

Application site exfoliation 6 (1) 3 (<1)1Application site pain defined as application site stinging, burning or pain.

Skin irritation was evaluated by active assessment of erythema, scaling, hypopigmentation, hyperpigmentation, itching, burning and stinging. The percentage of subjects who were assessed to have these signs and symptoms at any post baseline visit are summarized in Table 2.

Table 2: Application Site Tolerability Reactions at Any Post Baseline Visit

ALTRENO N=760

Mild/Mod/Severe

Vehicle N=782

Mild/Mod/Severe

Erythema 51% 44%

Scaling 49% 30%

Hypopigmentation 12% 10%

Hyperpigmentation 35% 35%

Itching 35% 28%

Burning 30% 14%

Stinging 21% 8%

USE IN SPECIFIC POPULATIONS

PregnancyRisk SummaryAvailable data from published observational studies of topical tretinoin in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are no data on ALTRENO use in pregnant women. The systemic levels following topical administration are lower than with administration of oral tretinoin; however, absorption of this product may result in fetal exposure. There are reports of major birth defects similar to those seen in infants exposed to oral retinoids, but these case reports do not establish a pattern or association with tretinoin-related embryopathy (see Data). Animal reproduction studies have not been conducted with ALTRENO. Topical administration of tretinoin in a different formulation to pregnant rats during organogenesis was associated with malformations (craniofacial abnormalities [hydrocephaly], asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) at doses up to 0.5 mg tretinoin/kg/day, approximately 2 times the maximum recommended human dose (MRHD) based on body surface area (BSA) comparison and assuming 100% absorption. Oral administration of tretinoin to pregnant cynomolgus monkeys during organogenesis was associated with malformations at 10 mg/kg/day (approximately 100 times the MRHD based on BSA comparison and assuming 100% absorption) (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. The background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

Data

Human DataWhile available studies cannot definitively establish the absence of risk, published data from multiple prospective controlled observational studies on the use of topical tretinoin products during pregnancy have




not identified an association with topical tretinoin and major birth defects or miscarriage. The available studies have methodologic limitations, including small sample size and in some cases, lack of physical exam by an expert in birth defects. There are published case reports of infants exposed to topical tretinoin during the first trimester that describe major birth defects similar to those seen in infants exposed to oral retinoids; however, no pattern of malformations has been identified and no causal association has been established in these cases. The significance of these spontaneous reports in terms of risk to the fetus is not known.

Animal DataTretinoin in a 0.05% gel formulation was topically administered to pregnant rats during organogenesis at doses of 0.1, 0.3 and 1 g/kg/day (0.05, 0.15, 0.5 mg tretinoin/kg/day). Possible tretinoin malformations (craniofacial abnormalities [hydrocephaly], asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) were observed at maternal doses of 0.5 mg tretinoin/kg/day (approximately 2 times the MRHD based on BSA comparison and assuming 100% absorption). These findings were not observed in control animals. Other maternal and reproductive parameters in tretinoin-treated animals were not different from control. For purposes of comparison of the animal exposure to human exposure, the MRHD is defined as 4 g of ALTRENO applied daily to a 60-kg person.Other topical tretinoin embryofetal development studies have generated equivocal results. There is evidence for malformations (shortened or kinked tail) after topical administration of tretinoin to pregnant Wistar rats during organogenesis at doses greater than 1 mg/kg/day (approximately 5 times the MRHD based on BSA comparison and assuming 100% absorption). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day (approximately 50 times the MRHD based on BSA comparison and assuming 100% absorption) was topically applied to pregnant rats during organogenesis. Supernumerary ribs have been a consistent finding in rat fetuses when pregnant rats were treated topically or orally with retinoids.

Oral administration of tretinoin during organogenesis has been shown to induce malformations in rats, mice, rabbits, hamsters, and nonhuman primates. Fetal malformations were observed when tretinoin was orally administered to pregnant Wistar rats during organogenesis at doses greater than 1 mg/kg/day (approximately 5 times the MRHD based on BSA comparison). In the cynomolgus monkey, fetal malformations were reported when an oral dose of 10 mg/kg/day was administered to pregnant monkeys during organogenesis (approximately 100 times the MRHD based on BSA comparison). No fetal malformations were observed at an oral dose of 5 mg/kg/day (approximately 50 times the MRHD based on BSA comparison). Increased skeletal variations were observed at all doses in this study and dose-related increases in embryo lethality and abortion were reported in this study. Similar results have also been reported in pigtail macaques.

Oral tretinoin has been shown to be fetotoxic in rats when administered at doses 10 times the MRHD based on BSA comparison. Topical tretinoin has been shown to be fetotoxic in rabbits when administered at doses 4 times the MRHD based on BSA comparison.

LactationRisk Summary

There are no data on the presence of tretinoin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. It is not known whether topical administration of tretinoin could result in sufficient systemic absorption to produce detectable concentrations in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ALTRENO and any potential adverse effects on the breastfed child from ALTRENO.

Pediatric UseSafety and effectiveness of ALTRENO for the topical treatment of acne vulgaris have been established in pediatric patients age 9 years to less than 17 years based on evidence from two multicenter, randomized, double-blind, parallel-group, vehicle-controlled, 12-week trials and an open-label pharmacokinetic study. A total of 318 pediatric subjects aged 9 to less than 17 years received ALTRENO in the clinical studies [see Clinical Pharmacology and Clinical Studies in full Prescribing Information].

The safety and effectiveness of ALTRENO in pediatric patients below the age of 9 years have not been established.

Geriatric UseClinical trials of ALTRENO did not include any subjects age 65 years and older to determine whether they respond differently from younger subjects.

NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityA 2-year dermal mouse carcinogenicity study was conducted with topical administration of 0.005%, 0.025% and 0.05% of a tretinoin gel formulation. Although no drug-related tumors were observed in surviving animals, the irritating nature of the drug product precluded daily dosing, confounding data interpretation and reducing the biological significance of these results.

Studies in hairless albino mice with a different formulation suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect was confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources.

The genotoxic potential of tretinoin was evaluated in an in vitro bacterial reversion test, an in vitro chromosomal aberration assay in human lymphocytes and an in vivo rat micronucleus assay. All tests were negative.

In dermal fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (approximately 2 times the MRHD based on BSA comparison and assuming 100% absorption), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day and above (approximately the MRHD based on BSA comparison and assuming 100% absorption) were observed.

PATIENT COUNSELING INFORMATIONAdvise the patient to read the FDA-approved patient labeling (Patient Information).

Distributed by: Ortho Dermatologics, a division of Bausch Health US, LLC. Bridgewater, NJ 08807 USA

U.S. Patent Number: 6,517,847

Altreno and Ortho Dermatologics are trademarks of Bausch Health Companies Inc. or its affiliates.© 2019 Bausch Health Companies Inc. or its affiliates. 04/2019ALT.0083.USA.19 9650300





Copyright © 2019 CASE REPORT Journal of Drugs in Dermatology

SPECIAL TOPIC

Background: Significant advances have been made in using lasers and intense pulse light sources to treat common vascular lesions such as telangiectasias. However, the treatment of leg telangiectasia, specifically, is more challenging because it involves the clearing of smaller veins as well as the larger feeding veins. The latest guidelines recommend use of short wavelength pulse-dyed lasers (PDL) as an option to treat telangiectasia cases that are unresponsive to sclerotherapy. Methods: A 29-year-old white woman presented with persistent telangiectasia, with multiple telangiectasias ranging from 1 cm to 20 cm in size involving the dorsal feet and both ankles and legs, which developed 10 years prior, associated with paresthesia. Test spots were treated with a 585-nm pulsed dye laser with various energy settings, and treatment was performed at 5.5 J/cm2 with spot size 10 mm and 0.5ms pulse duration. Results: Near complete clearance was achieved 1 month after the single treatment without adverse effects. Optical coherence tomog-raphy (OCT) imaging demonstrated a reduction of cutaneous blood flow after treatment. Discussion: We report successful treatment despite using settings that were previously reported to lack efficacy. This treatment resulted in considerable improvement in aesthetics and symptomatology. Also, OCT confirmed decreased vascular flow and bulging.Conclusion: Our results suggest there is still much to learn about the use of PDL in treating telangiectasias of the lower extremities, and that the ideal parameters warrant further investigation. Moreover, the novel use of OCT in auxiliary imaging for identification of treatment spots, as well as monitoring response at a microvascular level, holds great potential for wider application.

J Drugs Dermatol. 2019;18(11):1180-1182.

ABSTRACT

INTRODUCTION

Telangiectasias of the lower extremities are common. Sclerotherapy is the first-line treatment for telangiecta-sias, but significant advances have been made in using

lasers to treat these vascular lesions,1,2 including use of pulsed dye laser (PDL), potassium-titanyl-phosphate (KTP)-lasers, and longer wavelength lasers such as alexandrite lasers, diode la-sers (800 nm – 900 nm), and millisecond Nd:YAG lasers (1064 nm). Among these, short wavelength PDL has been viewed as a subpar treatment option for telangiectasia. There is also a per-haps unfounded consensus that longer wavelength PDL with higher fluences is better suited for treating vascular lesions of the lower extremities due to the vessels’ deeper location and larger diameter, respectively.3

In this report, we investigate the use of short wavelength PDL with low fluence levels in treating a patient with telangiecta-sia of the lower extremities that did not respond favorably to sclerotherapy. Additionally, we employed optical coherence tomography (OCT) imaging to identify the treatment area and

monitor treatment response at the microvascular level. We re-port successful treatment of lower extremity telangiectasia with a single session of 585-nm PDL therapy at low fluences in com-bination with OCT monitoring, which resulted in considerable improvement in aesthetics and symptomatology.

Case PresentationA 29-year-old Caucasian woman (Fitzpatrick skin type I) pre-sented with multiple telangiectasias ranging from 1 cm to 20 cm in size, involving the dorsal feet and both dorsal and ven-tral ankles and legs, which developed 10 years prior, associated with paresthesia. Two biopsies favored the diagnosis of es-sential telangiectasia. The patient had been previously treated with sclerotherapy, along with gabapentin 200mg nightly for paresthesias of the affected areas; but both provided only lim-ited improvement. She had noted frequent nosebleeds since childhood, but otherwise had no history of weight loss, fatigue, gastrointestinal bleeding, or neurological symptoms. No family history of similar symptoms was reported.

Successful Treatment of Lower Extremity Telangiectasias Using 585-nm Pulsed-Dye Laser at Low Fluence Combined

With Optical Coherence Tomography: A Case Report Ali Rajabi-Estarabadi MD, Caiwei Zheng BA, Natalie Williams BS, Samuel C. Smith MS, Keyvan Nouri MD,

Robert S. Kirsner MD PhDDepartment of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL



1181


A. Rajabi-Estarabadi, C. Zheng, N. Williams, et al

Three spots on the dorsum of the right foot were considered as test spots. Each spot measured approximately 1 cm x 1 cm. These spots were imaged using dynamic OCT to identify di-lated vessels and visualize blood flow at different skin depths. The sites were then treated with a 585-nanometer PDL with the energy set to 3.5 J/cm2, 4.5 J/cm2, and 5.5 J/cm2, respectively. A spot size of 10 mm was used due to the large size of the lesions, with a 0.5 ms pulse duration. The patient tolerated the proce-dure well. Post treatment instructions included sun avoidance and sunscreen use (SPF >30) on the treated areas. The use of gabapentin was unaltered. The patient returned for evaluation 4 weeks later. OCT demonstrated the most substantial decrease in blood flow and number of dilated vessels on the test spot treated with a fluence of 5.5 J/cm2. This result was also evident on visual inspection when comparing the 3 test spots.

The patient returned for the treatment of 3 additional area. Each area was treated once, each 1 month apart (Figure 1).

Fluence levels ranged from 4.5 J/cm2 to 5.5 J/cm2 depending on the location of the lesion, with a spot size of 10 mm and pulse duration of 0.5 ms. The results were documented photographi-cally both before and at 1 month follow-up. As seen in Figures 2a and 2b, near 100% clearance was achieved 1 month after the single treatment with no adverse effects reported. OCT imag-ing was also employed to compare blood flow of the lesion both before and one month after treatment, as shown in Figure 3. Blood flow data from OCT confirmed effective clearance. An evident drop in blood flow was seen at all measured depths after laser therapy. The highest blood flow was seen at a depth of 0.35 mm both before and after treatment. These data are re-ported in Figure 4.

FIGURE 1. Laser treatment areas. Session 1: anterior right & left shins. Session 2: posterior right and left shins. Session 3: dorsum of feet.

FIGURE 2. Blood flow data from OCT supports the effective clearance: drop in blood flow after treatment, particularly at 0.35mm in depth, where most blood vessels reside.

FIGURE 3. Near 100% clearance was achieved 1 month after the single treatment at that location, and no adverse effects were reported. OCT en face view shows decreased blood flow after 1 month.

FIGURE 4. Drop in blood flow after treatment, particularly at 0.35 mm in depth, where most blood vessels reside.

DISCUSSIONAlthough sclerotherapy remains the first-line treatment for leg telangiectasias, laser treatment is a promising alternative for those with contraindications, inadequate response, or intol-erable side effects such as purpura and hyperpigmentation.4

The use of PDL on lower extremity telangiectasias dates was originally reported in the 1990s; and some consensus had been reached based on previous studies and reports. For example, a shorter wavelength PDL of <600 nm has been recognized to yield the best results for facial telangiectasia because it is more efficacious in treating superficial vessels of small caliber, with diameters no larger than 1.0 mm.4-6 Treatment of telangiecta-sia of the lower extremities, however, involves vessels that are often larger in size and deeper beneath the thicker adventitial tissues and basal lamina, in addition to smaller more superfi-cial vessels, thus making treatment with a single laser difficult.4,6

Shorter wavelength (<600 nm) modalities such as KTP and LPDL have been reported to be most effective for narrow veins (<1 mm), while longer wavelength modalities such as alexandrite,



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A. Rajabi-Estarabadi, C. Zheng, N. Williams, et al

diode, and Nd:YAG have been recognized to be most effective for deeper veins.4

In terms of PDL, the 595-nm laser has traditionally been viewed as superior in treating leg veins than the original 585-nm la-ser.3 Studies also suggest a preference for treatments with longer pulse durations (typically 10 ms-100 ms) to target larger vessels and avoid common side effects, such as purpura, post-inflammatory hyperpigmentation, and hemosiderin deposition (Meesters et al).7 Additionally, most studies with PDL used flu-ences in the 10 J/cm2 to 20 J/cm2 range, and demonstrated that higher fluences are associated with an increased incidence of hyperpigmentation.8

This case is unique in that, despite using the previously discred-ited lower wavelength PDL (585-nm) with a short pulse duration (0.5 ms) and a relatively low energy density (5.5 J/cm2), near 100% clearance was achieved with only a single treatment. In fact, the results prove to be more efficacious compared with previous reports that are more in line with the existing param-eter consensus. The study by Garden reported perhaps the most favorable outcome, with 585-nm PDL at 1.5 ms and 16-20 J/cm2, having achieved 69±8% clearance after a single treatment.9 In comparison, our case achieved a higher clearance (nearly 100%) at a lower fluence (5.5 J/cm2).

Positive reports using the 595-nm PDL date back to 1997, when Hsia et al reported achievement of over 75% clearance in 64.7% of sites treated at 18 J/cm2 and in 52.9% of sites treated at 15 J/cm2 after a single treatment with the 595-nm PDL with a pulse duration of 1.5 ms.6 Buscher et al reported similar results with an average 67.5% clearance rate using the same laser and pulse duration with fluences of 20 J/cm2 and 24 J/cm2; but with 2 treatments needed to achieve this level of clearance.10 In 2003, Tanghetti reported even better results, with over 75% clearance in 80% of treated lesions at 16 J/cm2 with a 40 ms pulse duration after a single treatment.11 However, there was an increase in the incidence of temporary purpura, likely secondary to the use of higher fluences. Compared with the collective results using the 595-nm PDL, our case was able to achieve a greater clearance rate with a much lower fluence and pulse duration, with no no-table side effects.

Another unique aspect of this case is the employment of OCT. The use of OCT in dermatology is still novel but has already shown great promise. Recent studies have recommended OCT-based microangiography as a modality to provide high-resolution vas-cular maps, as well as direct visualization and quantitation of in vivo microvascular changes.12 Particularly in the treatment of telangiectasia, OCT has been reported to provide visualization of coagulation following intense pulsed light treatment, making OCT an attractive adjunct tool both before and after treatment.13 In this case, OCT imaging was useful in identifying treatment

spots as well as monitoring changes with treatment. OCT was also helpful in identifying small interconnecting vessels sur-rounding the treatment spots that were otherwise invisible to the naked eye and dermoscopy. Identification and treatment of these accessory vessels are speculated to have greatly reduced the need for multiple treatment sessions.

Our results suggest there is still much to learn about the use of PDL in treating telangiectasias of the lower extremities, and that the ideal parameters warrant further investigation. The excellent outcome achieved in this case was beyond expectation and, as such, necessitates more research in the application of low flu-ence, shorter wavelength PDL in the treatment of telangiectasia. Furthermore, the novel use of OCT in auxiliary imaging for iden-tification of treatment spots as well as monitoring response at a microvascular level holds great potential for wider application.

DISCLOSUREThe authors have no conflicts of interest.

REFERENCES1. Parlar B, Blazek C, Cazzaniga S, Naldi L, Kloetgen HW, Borradori L, Buettiker

U.Treatment of lower extremity telangiectasias in women by foam sclero-therapy vs. Nd:YAG laser: a prospective, comparative, randomized, open-label trial. J Eur Acad Dermatol Venereol. 2015.29(3)549-554.

2. Tepavcevic B, Matic P, Radak D. Comparison of sclerotherapy, laser, and ra-diowave coagulation in treatment of lower extremity telangiectasias. J Cos-met Laser Ther. 2012;14(5):239-242.

3. Reichert D. Evaluation of the long-pulse dye laser for the treatment of leg telangiectasias. Dermatol Surg. 1998;24(7):737-740.

4. Adamič M, Pavlovič MD, Troilius Rubin A, Palmetun-Ekbäck M, Boixeda P. Guidelines of care for vascular lasers and intense pulse light sources from the European Society for Laser Dermatology. J Eur Acad Dermatol Venereol. 2015;29(9):1661-1678.

5. Goldman MP, Fitzpatrick RF. Pulsed-dye laser treatment of leg telangiectasia: with and without simultaneous sclerotherapy. J Dermatol Surg Oncol. 1990. 16(4):338-44.

6. Hsia JAL, Zelickson B. Treatment of leg telangiectasia using a long-pulse dye laser at 595 nm. Lasers Surg Med. 1997. 20(1):1-5.

7. Meesters AA, Pitassi LH, Campos V, Wolkerstorfer A, Dierickx CC. Transcu-taneous laser treatment of leg veins. Lasers Med Sci. 2014;29(2):481-492.

8. Bernstein EF. The new-generation, high-energy, 595 nm, long pulse-duration, pulsed-dye laser effectively removes spider veins of the lower extremity. Lasers Surg Med. 2007;39(3):218-24.

9. Garden AB. Treatment of leg veins with high energy pulsed dye laser. Lasers Surg Med. 1996;8:34.

10. Buscher BA, McMeekin TO, Goodwin D. Treatment of leg telangiectasia by using a long-pulse dye laser at 595 nm with and without dynamic cooling device. Lasers Surg Med. 2000;27(2):171-175.

11. Tanghetti E, Sherr E. Treatment of telangiectasia using the multi-pass tech-nique with the extended pulse width, pulsed dye laser (Cynosure V-Star). J Cosmet Laser Ther. 2003;5(1):71-75.

12. Baran U, Choi WJ, Wang RK. Potential use of OCT-based microangiography in clinical dermatology. Skin Res Technol. 2016;22(2):238-246.

13. Ulrich M, Themstrup L, de Carvalho N, Manfredi M, Grana C, Ciardo S, Kästle R, Holmes J, Whitehead R, Jemec GB, Pellacani G, Welzel J. Dynamic optical coherence tomography in dermatology. Dermatology. 2016;232(3):298-311.


Ali Rajabi-Estarabadi MDE-mail:................……............................ [email protected]



A SUPPLEMENT TO

JDDDo You Know the Most Complete,

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Do You Know the Most Complete, Targeted Biologic for Psoriasis? The Answer May Surprise YouFunding Acknowledgement: This supplement to the Journal of Drugs in Dermatology is funded by Ortho Dermatologics.




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Copyright © 2019 FEATURED CONTENT Journal of Drugs in Dermatology

PIPELINE PREVIEWS

La Roche-Posay North American Foundation Call for Scientific Abstracts

The La Roche-Posay North American Foundation was established in 2005 to support outstanding candidates with promising projects in the field of clinical, biological or pharmacological research linked to dermatology. This competitive program is open to dermatology residents, fellows, and new practitioners (up to five years) in theUnited States.

All submitted applications will be evaluated by a scientific committee.

Three Grants: $10,000, $5,000 & $5,000

To be considered, submit 2 copies of your application in English.

• Abstract (1 page), research plan and budget (8 pages maximum)

• Curriculum Vitae of the applicant• A letter of support from mentor or chief of dermatology

All applications must be postmarked by December 31, 2019 to the

Secretariat GeneralLa Roche-Posay Laboratoire Dermatologique10 Hudson YardsNew York, NY 10001Attention: Tyler Steele Grants may also be submitted electronically to: [email protected]

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EPI Health, LLC Acquires Worldwide Rights to RHOFADE® from Aclaris Therapeutics, Inc.

EPI Health, LLC, a specialty pharmaceutical company committed to delivering innovative prescription therapies to dermatologists, today announced that it has acquired RHOFADE® (oxymetazoline hydrochloride) cream, 1% (RHOFADE) and related intellectual property assets from Aclaris Therapeutics, Inc. (Nasdaq: ACRS). RHOFADE (oxymetazoline hydrochloride) cream, 1% is indicated for the topical treatment of persistent facial erythema associated with rosacea in adults.

The National Rosacea Society (NRS) estimates that approximately 16 million Americans are affected by rosacea. Persistent facial redness (erythema) is cited as the most common sign of rosacea and may resemble a flushing or sunburn that does not go away. Typical triggers include sun exposure, stress, weather, food, and exercise.



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Issues and Considerations for Optimal Outcomes in Acne Management JOURNAL-BASED ENDURING CE ACTIVITY

To provide dermatology providers with a comprehensive, educational resource on the impact of acne scarring on patients of all skin types. Content will review the evaluation and classification by scar type, identification of patients at greatest risk for scarring, benefits and limits of current scar management strategies and overview of current understanding of topical and systemic retinoid use in the management of acne. Participants will have the potential to earn up to 2.0 hours of AMA PRA Category 1 Credit™ and ANCC credit.

Funded by an educational grant provided by Galderma Laboratories, L.P.

A SUPPLEMENT TO

JDD

December 2018 • Volume 17 • Issue 12 ( SUPPLEMENT)

Issues & Considerations for

Optimal Outcomes in Acne Management

LAST CHANCE




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November 2019



BRIEF SUMMARY OF PRESCRIBING INFORMATIONThis brief summary does not include all the information needed to use BRYHALI safely and effectively. See full prescribing information for BRYHALI.BRYHALI™ (halobetasol propionate) lotion, 0.01% for topical use Initial U.S. Approval: 1990INDICATIONS AND USAGEBRYHALI™ (halobetasol propionate) Lotion, 0.01% is indicated for the topical treatment of plaque psoriasis in adults.CONTRAINDICATIONSNone.WARNINGS AND PRECAUTIONSHypothalamic-Pituitary-Adrenal (HPA) Axis SuppressionBRYHALI has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis.Systemic effects of topical corticosteroids may include reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of treatment with the topical corticosteroid.The potential for hypothalamic-pituitary-adrenal (HPA) axis suppression with BRYHALI was evaluated in a study of 19 adult subjects with moderate to severe plaque psoriasis involving ≥20% of their body surface area (BSA). HPA axis suppression was reported for 1 (5.6%) subject at Week 4 and for 3 (15.8%) subjects at Week 8. All 3 subjects had normal HPA axis suppression test with discontinuation of treatment [see Clinical Pharmacology in full Prescribing Information]. Because of the potential for systemic absorption, use of topical corticosteroids, including BRYHALI, may require that patients be evaluated periodically for evidence of HPA axis suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of more potent corticosteroids, use over large surface areas, occlusive use, use on an altered skin barrier, concomitant use of multiple corticosteroid-containing products, liver failure, and young age. An adrenocorticotropic hormone (ACTH) stimulation test may be helpful in evaluating patients for HPA axis suppression.If HPA axis suppression is documented, attempt to gradually withdraw the drug, reduce the frequency of application, or substitute a less potent steroid. Manifestations of adrenal insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids.Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. Use of more than one corticosteroid-containing product at the same time may increase the total systemic exposure to corticosteroids. Pediatric patients may be more susceptible than adults to systemic toxicity from the use of topical corticosteroids due to their larger surface-to-body mass ratios [see Use in Specific Populations].Local Adverse ReactionsLocal adverse reactions from topical corticosteroids may include atrophy, striae, telangiectasias, burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, and miliaria. These may be more likely with occlusive use, prolonged use, or use of higher potency corticosteroids, including BRYHALI. Some local adverse reactions may be irreversible.Concomitant Skin Infections Use an appropriate antimicrobial agent if a skin infection is present or develops. If a favorable response does not occur promptly, discontinue use of BRYHALI until the infection has been adequately treated.Allergic Contact Dermatitis Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation. Consider confirmation of a clinical diagnosis of allergic contact dermatitis by appropriate patch testing. Discontinue BRYHALI if allergic contact dermatitis occurs.ADVERSE REACTIONSClinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In randomized, double-blind, multicenter, vehicle-controlled clinical trials, 426 adults with plaque psoriasis were treated with BRYHALI and had post-baseline safety data. Subjects applied BRYHALI once daily for up to eight weeks. Table 1 presents adverse reactions that occurred in at least 1% of subjects treated with BRYHALI and more frequently than in vehicle-treated patients.Table 1: Adverse Reactions Occurring in ≥1% of the Subjects Treated with BRYHALI through Week 8

BRYHALI (N=284)

Vehicle (N=142)

Adverse Reaction % %

Upper Respiratory Tract Infection 2% 1%

Application Site Dermatitis 1% 0

Hyperglycemia 1% 0

USE IN SPECIFIC POPULATIONSPregnancyRisk SummaryThere are no available data on BRYHALI use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.In animal reproduction studies, increased malformations, including cleft palate and omphalocele, were observed after oral administration of halobetasol propionate during organogenesis to pregnant rats and rabbits. The available data do not support relevant comparisons of systemic halobetasol propionate exposures achieved in the animal studies to exposures observed in humans after topical use of BRYHALI. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data

Animal DataHalobetasol propionate has been shown to cause malformations in rats and rabbits when given orally during organogenesis at doses of 0.04 to 0.1 mg/kg/day in rats and 0.01 mg/kg/day in rabbits. Halobetasol propionate was embryotoxic in rabbits but not in rats. Cleft palate was observed in both rats and rabbits. Omphalocele was seen in rats but not in rabbits.LactationRisk SummaryThere are no data on the presence of halobetasol propionate or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production after treatment with BRYHALI.Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BRYHALI and any potential adverse effects on the breastfed child from BRYHALI. Clinical ConsiderationsAdvise breastfeeding women not to apply BRYHALI directly to the nipple and areola to avoid direct infant exposure.Pediatric UseSafety and effectiveness of BRYHALI in pediatric patients under the age of 18 years have not been evaluated.Because of higher skin surface area to body mass ratios, pediatric patients are at a greater risk than adults of HPA axis suppression and Cushing’s syndrome when they are treated with topical corticosteroids. They are therefore also at greater risk of adrenal insufficiency during or after withdrawal of treatment. Adverse reactions including striae have been reported with use of topical corticosteroids in infants and children [see Warnings and Precautions].HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema [see Warnings and Precautions].Geriatric UseOf 284 subjects exposed to BRYHALI in clinical trials, 61 subjects were 65 years or older. Clinical trials of BRYHALI did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects.NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been performed to evaluate the carcinogenic potential of halobetasol propionate.Halobetasol propionate was not genotoxic in the Ames assay, in the sister chromatid exchange test in Chinese hamster somatic cells, in chromosome aberration studies of germinal and somatic cells of rodents, or in a mammalian spot test. Positive mutagenicity effects were observed in a mouse lymphoma gene mutation assay in vitro and in a Chinese hamster micronucleus test. Studies in rats following oral administration of halobetasol propionate at dose levels up to 0.05 mg/kg/day indicated no impairment of fertility or general reproductive performance.PATIENT COUNSELING INFORMATIONAdvise the patient to read the FDA-approved patient labeling (Patient Information).Manufactured for:Dow Pharmaceutical Sciences, a division of Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USABy:Valeant Pharmaceuticals International, Inc. Laval, Quebec H7L 4A8, Canada U.S. Patent Numbers: 6,517,847 and 8,809,307BRYHALI is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates.© 2018 Valeant Pharmaceuticals North America LLCBased on 9652102 November 2018 BRY.0032.USA.18

VALE5034 BRYHALIJournalAd JDD B/WPage Live: .125"fromTrim Fileformat:PDF/X-1A CarlingCommunications 3/14/19 Trim: 8.25"x10.875" Bleed: 8.50"x11.125”


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CHART A COURSE

SYMPTOMATIC RELIEF

FOR ADULTS WITH PLAQUE PSORIASIS

TO

The effi cacy of Class 1 halobetasol with safety proven for up to 8 weeks of dosing1,2

BRYHALIandthecheckmarkdesignaretrademarksofOrthoDermatologics’affiliatedentities.©2018AllRightsReserved.BRY.0025.USA.18 DISCOVER MORE AT BRYHALI.COM

STUDY RESULTS: 36.5%ofpatientsintrial1and38.4%intrial2achievedtreatmentsuccess*atweek8(primaryendpoint)vs8.1%and12.0%ofpatientswithvehicle,respectively(P<0.001inbothtrials).2

STUDY DESIGN: ThesafetyandefficacyofBRYHALILotionwereassessedin2prospective,multicenter,randomized,double-blind,phase3clinicaltrialsin430adultpatientswithmoderate-to-severeplaquepsoriasis.PatientsweretreatedwithBRYHALILotionorvehiclelotion,appliedoncedaily.Primaryefficacyendpointwastreatmentsuccessevaluatedatweek8.Secondaryefficacyendpointwastreatmentsuccessevaluatedatweeks2,4,6,and12(4 weeksposttreatment).Tertiaryefficacyendpointwasa2-gradeimprovementfrombaselineateachtimepointfortheindividualsignsofpsoriasis(erythema,plaqueelevation,andscaling).2

*Treatmentsuccesswasdefinedasatleasta2-gradeimprovementfrombaselineintheInvestigator’sGlobalAssessmentscore,andascoreof“clear”or“almostclear”(primaryendpointatweek8).2

References: 1.BRYHALILotion[prescribinginformation].Bridgewater,NJ.ValeantPharmaceuticalsNorthAmericaLLC.2.Dataonfile.

A NEW POTENCY CLASS OF STEROID LOTION

IndicationBRYHALI™(halobetasolpropionate)Lotion,0.01%isacorticosteroidindicatedforthetopicaltreatmentofplaquepsoriasisinadults.

Important Safety Information Warnings and Precautions

• BRYHALILotionhasbeenshowntosuppressthehypothalamic-pituitary-adrenal(HPA)axisduringtreatmentoruponcessationoftreatment;periodicevaluationmayberequired.

• SystemiceffectsoftopicalcorticosteroidsmayalsoincludeCushing’ssyndrome,hyperglycemia,andglucosuria.

• Childrenmaybemoresusceptibletosystemictoxicitywhentreatedwithtopicalcorticosteroids.

• Localadversereactionsmayincludeatrophy,striae,telangiectasias,hypopigmentation,andallergiccontactdermatitis.Somelocaladversereactionsmaybeirreversible.

• Useoftopicalcorticosteroidsmayincreasetheriskofposteriorsubcapsularcataractsandglaucoma.Ifvisualsymptomsoccur,considerreferraltoanophthalmologist.

• Useanappropriateantimicrobialagentifaskininfectionispresentoroccurs,andifpromptresponseisnotseen,discontinueuseuntilinfectionhasbeenadequatelytreated.

• DiscontinueBRYHALILotionifallergiccontactdermatitisoccurs.

Adverse Reactions

• Themostcommonadversereactions(≥1%)wereupperrespiratorytractinfection,applicationsitedermatitis,andhyperglycemia.

ToreportSUSPECTEDADVERSEREACTIONS,contactCustomerServiceat1-800-321-4576orFDAat1-800-FDA-1088.

Please see Brief Summary of full Prescribing Information on following page.

2 PIVOTAL PHASE 3 TRIALS

Continued results 4weeksposttreatment1

Signifi cant symptomatic relief asearlyasweek22

No increased epidermal atrophyobservedthrough8weeksoftreatment2

Localadversereactionsfromtopicalcorticosteroidsmayincludeatrophy,striae,telangiectasias,hypopigmentationandallergiccontact

dermatitis.Somelocaladversereactionsmaybeirreversible.

POTENT TO SUPERPOTENT CLEARANCE1:

BRYHALI(��)��%

TM

VALE5034 BRYHALIJournalAd JDD 4/CPage Live: .125"fromTrim Fileformat:PDF/X-1A CarlingCommunications 3/14/19Trim: 8.25"x10.875"Bleed: 8.50"x11.125”


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special focus · 2019-10-23 · continuing education: facial skin tightening with microfocused...

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