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ISSN: 1545 9616 February 2020 • Volume 19 • Issue 2 JDD

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Image credit page 205

IL-17 Pathway Blockade in Psoriasis

Expanded Utility for Ingenol Mebutate

Superficial Radiation for NMSC

Melasma’s Impact on QOL

Dermatologists’ Preparedness for Disasters

D PDT BE TR RI E C A S T E M R E

P N

1 T # #

B 1 1 Y S T D IS ER G MATOLO

LEVULAN® KERASTICK® + BLU-U® HAS BEEN TRUSTED IN THE TREATMENT OF MINIMALLY TO MODERATELY THICK ACTINIC KERATOSIS* FOR MORE THAN 17 YEARS.

*Of the face or scalp

TRUSTED IN MORE THAN 3 MILLION PATIENT TREATMENTS NATIONWIDE2 The proven in-office therapy 3, LEVULAN KERASTICK + BLU-U provides:

DEMONSTRATED EFFICACY DISTINCTIVE DELIVERY DEDICATED SUPPORT TEAM 10.875” Do Not Copy

Important Safety Information Penalties ApplyPatients should avoid exposure of the photosensitive treatment sites to sunlight or bright indoor light for 40 hours after LEVULAN LEVULAN® KERASTICK® (aminolevulinic acid HCl) for topical KERASTICK topical solution application. Advise patients to solution, 20%, plus blue light illumination using the BLU-U® Blue protect treated areas with light-opaque clothing, such as long Light Photodynamic Therapy Illuminator is indicated for the sleeves or a hat. Sunscreens will not protect the patient against treatment of minimally to moderately thick actinic keratoses of photosensitivity reactions caused by visible light. the face or scalp, or actinic keratosis of the upper extremities. Concomitant use of other known photosensitizing agents such Contraindicated in patients with cutaneous photosensitivity as St. John’s wort, griseofulvin, thiazide diuretics, sulfonylureas, at wavelengths of 400–450 nm, porphyria, known allergies to phenothiazines, sulfonamides, and tetracyclines might increase porphyrins, and/or known sensitivity to any of the components the photosensitivity reaction. of the LEVULAN KERASTICK. LEVULAN KERASTICK topical solution has not been tested on patients with inherited or The most common local adverse reactions (incidence ≥ 10%) acquired coagulation defects. were erythema, edema, stinging/burning, scaling/crusting, itching, erosion, hypo/hyperpigmentation, oozing/vesiculation/ Transient amnestic episodes have been reported during crusting, scaling, and dryness. In clinical trials, severe stinging postmarketing use of LEVULAN KERASTICK in combination and/or burning was reported by at least 50% of face and scalp with BLU-U Blue Light Photodynamic Therapy Illuminator. patients and 9% of upper extremity patients at some time Inform patients and their caregivers that LEVULAN KERASTICK during treatment. in combination with PDT may cause transient amnestic episodes. Advise patients to contact a healthcare provider if Please see a Brief Summary of the full Prescribing amnesia develops after treatment. Do not apply to the eyes Information on the following page. or to mucous membranes as irritation may be experienced. Excessive irritation may occur if LEVULAN KERASTICK is applied under occlusion for longer than 3 hours. Occlusion is References: 1. Symphony Health. Actinic Keratosis Total Patient Share. June 2018. 2. Data on file, Sun Pharma. LEVULAN KERASTICK (Prescribing Information). Sun Pharma; April 2018. used only in the treatment of lesions of the upper extremities. 3. LEVULAN KERASTICK topical solution should be applied by a qualified health professional to no more than 5 mm of perilesional skin surrounding each target lesion. During light SUN Dermatology is a division of Sun Pharmaceutical Industries, Inc. treatment, both patients and medical personnel should be © 2018 Sun Pharmaceutical Industries, Inc. All rights reserved. provided with blue blocking protective eyewear. PM-US-LEV-0190 12/2018

LEVULAN® KERASTICK® (aminolevulinic acid HCl) for Topical Solution, 20% In clinical trials, no non-cutaneous adverse events were found to be USE IN SPECIFIC POPULATIONS: Initial U.S. approval: 1999 consistently associated with LEVULAN KERASTICK photodynamic therapy. Pregnancy BRIEF SUMMARY OF PRESCRIBING INFORMATION Photodynamic Therapy Response: The constellation of transient local Limited available data with LEVULAN KERASTICK topical solution use in This Brief Summary does not include all the information needed to use symptoms of stinging and/or burning, itching, erythema and edema as a pregnant women are insufficient to inform a drug associated risk of adverse LEVULAN KERASTICK safely and effectively. See full prescribing information result of LEVULAN KERASTICK photodynamic therapy (PDT) was observed in developmental outcomes. Animal developmental toxicology studies were for LEVULAN KERASTICK. all clinical trials for actinic keratoses treatment. not conducted with aminolevulinic acid. LEVULAN KERASTICK solution has Local skin reactions at the application site were observed in 99% of low systemic absorption following topical administration, and the risk of INDICATIONS AND USAGE subjects treated with LEVULAN KERASTICK topical solution and BLU-U Blue maternal use resulting in fetal exposure to the drug is unknown. LEVULAN KERASTICK for topical solution, a porphyrin precursor, plus blue Light Photodynamic Therapy Illuminator. The most common local adverse Lactation light illumination using the BLU-U® Blue Light Photodynamic Therapy reactions (incidence ≥ 10%) were application site stinging/burning, There are no data on the presence of LEVULAN KERASTICK topical solution in Illuminator is indicated for the photodynamic therapy (treatment) of erythema, edema, scaling/crusting, hypo/hyperpigmentation, itching, either human or animal milk, the effects on the breastfed infant or on milk minimally to moderately thick actinic keratoses of the face or scalp, or erosion, oozing/vesiculation/crusting, dryness. actinic keratoses of the upper extremities. production. The developmental and health benefits of breastfeeding should In the trials for face and scalp lesions, severe stinging and/or burning at be considered along with the mother’s clinical need for LEVULAN KERASTICK DOSAGE AND ADMINISTRATION: one or more lesions during light treatment was reported by at least 50% topical solution and any potential adverse effects on the breastfeeding child The LEVULAN KERASTICK topical solution 20% is intended for direct of subjects. Severe stinging and/or burning also occurred during light from LEVULAN KERASTICK topical solution or from the underlying maternal application to individual lesions diagnosed as actinic keratoses and not to treatment in 9% of subjects receiving treatment for upper extremity lesions. condition. perilesional skin. This product is not intended for application by patients In trials for the face or scalp lesions, 99% of the active treatment group Pediatric Use or unqualified medical personnel. Application should involve lesions on and 79% of the vehicle group experienced erythema shortly after treatment. The safety and effectiveness in pediatric patients below the age of 18 have the scalp, face or upper extremities; multiple lesions can be treated within In the trial for the upper extremity lesions, 99% of LEVULAN KERASTICK not been established. Actinic keratosis is not a disease generally seen in the a treatment region, but multiple treatment regions should not be treated topical solution treatment group and 52% of the vehicle group experienced pediatric population. simultaneously. erythema on visit Days 2-3. Approximately 35% of LEVULAN KERASTICK The recommended treatment frequency is one application of the LEVULAN topical solution group had edema, while edema occurred in <1% of the Geriatric Use KERASTICK topical solution and one dose of illumination per treatment vehicle group. Both erythema and edema resolved to baseline or improved Of the 512 subjects in Phase 3 clinical trials of LEVULAN KERASTICK topical region per 8-week treatment session. Each individual LEVULAN KERASTICK by 4 weeks after therapy for face or scalp. Edema resolved by 4 weeks solution, 63% (321/512) were 65 years old and over, while 24% (123/512) applicator should be used for only one patient. and erythema resolved to baseline by 8 weeks for upper extremities. The were 75 years old and over. No overall differences in safety or substantial LEVULAN KERASTICK photodynamic therapy for actinic keratoses is a two- application of LEVULAN KERASTICK topical solution to perilesional skin differences in effectiveness were observed between these subjects and stage process involving application of the LEVULAN KERASTICK topical resulted in stinging, burning, erythema and edema similar to treated actinic younger subjects, but greater sensitivity of some older individuals cannot solution to the target lesions and then illumination with blue light using the keratosis be ruled out. BLU-U Blue Light Photodynamic Therapy Illuminator after 3 hours for upper Other Localized Cutaneous Adverse Experiences: Table 1 depicts the OVERDOSAGE extremity lesions or after 14-18 hours for face or scalp lesions. incidence and severity of cutaneous adverse events in trials for the face and scalp. Table 2 depicts the percentage of subjects with cutaneous adverse In the event that the drug is ingested, monitoring and supportive care CONTRAINDICATIONS reactions by the most severe grade reported in course of the trial for the are recommended. The patient should be advised to avoid incidental The LEVULAN KERASTICK for topical solution plus blue light illumination upper extremity lesions. exposure to intense light sources for at least 40 hours after ingestion. The using the BLU-U Blue Light Photodynamic Therapy Illuminator is consequences of exceeding the recommended topical dosage are unknown. TABLE 1 Post-PDT Cutaneous Adverse Events – ALA-018/ALA-019 For the Face and Scalp contraindicated in patients with cutaneous photosensitivity at wavelengths FACE SCALP There is no information on overdose of blue light from the BLU-U Blue Light LEVULAN LEVULAN of 400-450 nm, porphyria or known allergies to porphyrins, and in patients KERASTICK Vehicle + PDT KERASTICK Vehicle + PDT Photodynamic Therapy Illuminator following LEVULAN KERASTICK topical

Topical Solution + (n=41) Topical Solution + (n=21) solution application. with known sensitivity to any of the components of the LEVULAN KERASTICK. PDT (n=139) PDT (n=42) Mild/ Mild/ Mild/ Mild/ Degree of Severity Severe Severe Severe Severe WARNINGS AND PRECAUTIONS Moderate Moderate Moderate Moderate PATIENT COUNSELING Scaling/Crusting 71% 1% 12% 0% 64% 2% 19% 0% Pain 1% 0% 0% 0% 0% 0% 0% 0% Advise the patient to read the FDA-approved patient labeling (Patient Transient Amnestic Episodes Tenderness 1% 0% 0% 0% 2% 0% 0% 0% Itching 25% 1% 7% 0% 14% 7% 19% 0% Information). Transient amnestic episodes have been reported during postmarketing use Edema 1% 0% 0% 0% 0% 0% 0% 0% Ulceration 4% 0% 0% 0% 2% 0% 0% 0% of LEVULAN KERASTICK in combination with BLU-U Blue Light Photodynamic Bleeding/Hemorrhage 4% 0% 0% 0% 2% 0% 0% 0% Transient Amnestic Episodes Hypo/hyper-pigmentation 22% 20% 36% 33% Therapy Illuminator. Inform patients and their caregivers that LEVULAN Vesiculation 4% 0% 0% 0% 5% 0% 0% 0% Transient episodes of amnesia have been reported with LEVULAN KERASTICK KERASTICK in combination with PDT may cause transient amnestic Pustules 4% 0% 0% 0% 0% 0% 0% 0% Oozing 1% 0% 0% 0% 0% 0% 0% 0% in combination with BLU-U Blue Light Photodynamic Therapy Illuminator. episodes. Advise them to contact a healthcare provider if the patient Dysesthesia 2% 0% 0% 0% 0% 0% 0% 0% Advise patients and their families or caregivers to contact their healthcare

10.875” Scabbing 2% 1% 0% 0% 0% 0% 0% 0% develops amnesia after treatment. Erosion 14% 1% 0% 0% 2% 0% 0% 0% provider if memory impairment, confusion, or disorientation is observed. Excoriation 1% 0% 0% 0% 0% 0% 0% 0% Wheal/Flare 7% 1% 0% 0% 2% 0% 0% 0% Photosensitivity Skin disorder NOS 5% 0% 0% 0% 12% 0% 5% 0% Photosensitivity

After LEVULAN KERASTICK topical solution has been applied, the treatment Do Not Copy Advise patients that after LEVULAN KERASTICK topical solution has been site will become photosensitive and patients should avoid exposure of TABLE 2 Percentage of Subjects with Cutaneous Adverse Reactions by the Most Severe Grade Reported Post-Baseline – CP0108 For Upper Extremities applied, the treatment site will become photosensitive and that they should the photosensitive treatment sites to sunlight or bright indoor light (e.g., LEVULAN KERASTICK Vehicle + PDT avoid exposure of the photosensitive treatment sites to sunlight or bright examination lamps, operating room lamps, tanning beds, or lights at close Topical Solution + PDT Penalties(N=135) Apply(N=134) indoor light (e.g., examination lamps, operating room lamps, tanning proximity) for 40 hours. Exposure may result in a stinging and/or burning Degree of Severity Minimal/ Moderate/ Total Minimal/ Moderate/ Total beds, or lights at close proximity) for 40 hours. Advise patients to protect Mild Severe Mild Severe sensation and may cause erythema and/or edema of the lesions. Therefore, Edema 51% 4% 56% 7% 1% 8% treated lesions from the sun by wearing a wide-brimmed hat or similar before exposure to sunlight, patients should protect treated lesions from Erythema 35% 65% 100% 63% 12% 75% Hyper-pigmentation 64% 9% 73% 57% 10% 66% head covering of light-opaque material, and/or a long-sleeved shirt and/or the sun by wearing a wide-brimmed hat or similar head covering of light- Hypo-pigmentation 46% 4% 50% 50% 5% 55% gloves. Advise patients sunscreens will not protect against photosensitivity opaque material, and/or a long-sleeved shirt and/or gloves. Sunscreens will Oozing/Vesiculation/ Crusting 36% 5% 41% 8% 2% 10% reactions caused by visible light. It has not been determined if perspiration not protect against photosensitivity reactions caused by visible light. It has Scaling and Dryness 65% 22% 87% 58% 7% 64% can spread the LEVULAN KERASTICK topical solution outside the treatment Stinging/Burning 23% 73% 96% 23% 0% 23% not been determined if perspiration can spread the LEVULAN KERASTICK site to the eye or surrounding skin. topical solution outside the treatment site to the eye or surrounding skin. In the trial for upper extremity lesions, itching and scabbing occurred in If for any reason the patient cannot return for blue light treatment during Application of LEVULAN KERASTICK topical solution to perilesional areas of 8% and 4%, respectively, of the subjects in the LEVULAN KERASTICK the prescribed period after applying LEVULAN KERASTICK topical solution, photodamaged skin of the face, scalp or upper extremities may result in photodynamic therapy group. No subjects in the vehicle group reported advise patients to call the doctor. Advise patient to continue to avoid photosensitization. Upon exposure to activating light from the BLU-U, such itching or scabbing. exposure of the photosensitized lesions to sunlight or prolonged or intense photosensitized skin may produce a stinging and/or burning sensation and light for at least 40 hours. Advise patients to avoid certain medications that may become erythematous and/or edematous in a manner similar to that of Common (>2%, <10%) local cutaneous adverse reactions for face, scalp may enhance the phototoxic reaction to PDT. actinic keratoses treated with LEVULAN KERASTICK Photodynamic Therapy. and upper extremities in the LEVULAN KERASTICK topical solution group Because of the potential for skin to become photosensitized, the LEVULAN included wheal, scabbing, pustules, ulceration, bleeding, tenderness and Common Adverse Reactions KERASTICK topical solution should be used by a qualified health professional dysesthesia. Inform patients that treatment with LEVULAN KERASTICK topical solution to apply drug to no more than 5mm of perilesional skin surrounding the Uncommon (<2%) local cutaneous adverse reactions for face, scalp and plus BLU-U Blue Light Photodynamic Therapy Illuminator may result in target actinic keratosis lesions. If for any reason the patient cannot return upper extremities in the LEVULAN KERASTICK topical solution group were sensitivity to light, skin irritation and local skin reactions including erythema, for blue light treatment during the prescribed period after applying LEVULAN flaking, pain, peeling, perilesional pruritic rash, excoriation and blistering. edema, stinging/burning, scaling, crusting, oozing, vesiculation, wheal, KERASTICK topical solution, the patient should call the doctor. The patient scabbing, pustules, ulceration, itching, erosion, hypo/hyperpigmentation, Common (>2%, <10%) adverse reactions not limited to the application should also continue to avoid exposure of the photosensitized lesions to bleeding, tenderness, dysesthesia, and dryness. site for upper extremities and occurring more frequently in the LEVULAN sunlight or prolonged or intense light for at least 40 hours. If stinging and/or KERASTICK topical solution group than in the vehicle group were sinusitis, You are encouraged to report negative side effects of prescription drugs to burning is noted, exposure to light should be reduced. squamous cell carcinoma, and squamous cell carcinoma of skin. the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088. Irritation Postmarketing experience: LEVULAN, KERASTICK, BLU-U and DUSA are registered trademarks of DUSA The LEVULAN KERASTICK topical solution contains alcohol and is intended Pharmaceuticals, Inc., a Sun Pharma company. The following adverse reactions have been reported during post-approval for topical use only. Irritation may be experienced if this product is applied use of LEVULAN KERASTICK. Because these reactions are reported voluntarily ©2018 DUSA Pharmaceuticals, Inc. All rights reserved. to eyes or mucous membranes. Do not apply to the eyes or to mucous from a population of uncertain size, it is not always possible to reliably membranes. Excessive irritation may be experienced if this product is Manufactured for: DUSA Pharmaceuticals, Inc.® 25 Upton Drive, estimate their frequency or establish a causal relationship to drug exposure. applied under occlusion longer than 3 hours. Wilmington, MA 01887 Nervous system disorders: transient amnestic episodes Coagulation Defects For more information please contact: 1-877-533-3872 The LEVULAN KERASTICK for topical solution has not been tested on patients DRUG INTERACTIONS with inherited or acquired coagulation defects. There have been no formal studies of the interaction of LEVULAN KERASTICK www.levulan.com topical solution with any other drugs, and no drug-specific interactions were ADVERSE REACTIONS LAB-1442AW Rev E noted during any of the controlled clinical trials. It is, however, possible PM-US-LEV-0057 Because clinical trials are conducted under widely varying conditions, that concomitant use of other known photosensitizing agents such as St. adverse reaction rate observed in the clinical trials of a drug cannot be John’s wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, directly compared to rates in the clinical trials of another drug and may not sulfonamides and tetracyclines might increase the photosensitivity reaction reflect the rates observed in practice. of actinic keratoses treated with LEVULAN KERASTICK topical solution. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

SENIOR EDITORS Macrene Alexiades MD PhD Dee Anna Glaser MD Ronald L. Moy MD Gerhard Sattler MD Robert Baran MD C. William Hanke MD Keyvan Nouri MD James M. Spencer MD Joseph B. Bikowski MD William Levis MD Neil S. Sadick MD Susan H. Weinkle MD

SENIOR ASSOCIATE ASSOCIATE EDITORS Neil Alan Fenske MD Cleire Paniago-Pereira MD EDITORS Dale M. Abadir MD Rebecca Fitzgerald MD Anna C. Pavlick MD Kenneth Beer MD William Abramovits MD Alina A. Fratila MD Christopher R. Payne MD Martin Braun MD Andrew F. Alexis MD MPH Alejandro Camps Fresnada MD António Picoto MD Jeffrey Phillip Callen MD Shawn Allen MD Ellen C. Gendler MD Sheldon V. Pollack MD Jean Carruthers MD Rex A. Amonette MD Dore Gilbert MD Babar K. Rao MD James Q. Del Rosso DO Robert Anolik MD David J. Goldberg MD Wendy E. Roberts MD Lawrence F. Eichenfield MD Martha P. Arroyo MD Leonard H. Goldberg MD Amy E. Rose MD Patricia Farris MD Robin Ashinoff MD Robert H. Gotkin MD Steven Rosenberg MD Norman Goldstein MD Marc R. Avram MD Gloria F. Graham MD Lidia Rudnicka MD Aditya K. Gupta MD PhD David E. Bank MD John Hawk MD Bijan Safai MD Elizabeth Hale MD Jay G. Barnett MD Michael P. Heffernan MD Eli R. Saleeby MD Sherry H. Hsiung MD Eliot F. Battle Jr. MD William L. Heimer II MD Fitzgeraldo A. Sanchez-Negron MD Leon H. Kircik MD Richard G. Bennett MD N. Patrick Hennessey MD Miguel Sanchez-Viera MD Mark Lebwohl MD Diane S. Berson MD Alysa R. Herman MD Julie Schaffer MD Henry W. Lim MD Ronald R. Branacaccio MD George J. Hruza MD Bryan C. Schultz MD Flor Mayoral MD Rana Anadolu Brasie MD Shasa Hu MD Daniel Mark Siegel MD Maurizio Podda MD PhD Jeremy A. Brauer MD Mark J. Jaffe MD Arthur J. Sober MD Jeffrey Orringer MD Gary Brauner MD Do NotJared Copy Jagdeo MD Nicholas A. Soter MD Maritza Perez MD Neil Brody MD PhD PenaltiesS. BrianApply Jiang MD Jennifer Stein MD Kevin Pinski MD Lance H. Brown MD Bruce E. Katz MD Fernando Stengel MD Luigi Rusciani Scorza MD Isaac Brownell MD PhD Mark D. Kaufmann MD Hema Sundaram MD Ritu Saini MD Karen E. Burke MD PhD Amor Khachemoune MD Susan C. Taylor MD Jerome l. Shupack MD Mariano Busso MD Poong Myung Kim MD Emily Tierney MD Amy Taub MD Francisco M. Camacho-Martinez MD Christine Ko MD George-Sorin Tiplica MD PhD Danny Vleggaar MD Marian Cantisano-Zilkha MD David Kriegel MD Ella L. Toombs MD Brian Zelickson MD Alastair Carruthers MD Pearon G. Lang MD Irene J. Vergilis-Kalner MD Roger I. Ceilley MD Aimee Leonard MD Steven Wang MD Clay J. Cockerell MD Mary P. Lupo MD Ken Washenik MD PhD David E. Cohen MD Alan Matarasso MD Jeffrey Weinberg MD Julian S. Conejo-Mir MD Alan Menter MD Robert A. Weiss MD Elizabeth Alvarez Connelly MD Warwick L. Morison MD W. Phillip Werschler MD FEATURE EDITORS Ira Davis MD Rhoda S. Narins MD Ronald G. Wheeland MD Kendra G. Bergstrom MD Calvin Day MD Mark Naylor MD Jai Il Youn MD Joel L. Cohen MD Doris Day MD Kishwer S. Nehal MD John Zic MD Adam Friedman MD Jeffrey S. Dover MD Martino Neumann MD John A. Zitelli MD James L. Griffith MD Zoe Diana Draelos MD Nelson Lee Novick MD Marissa Heller MD Madeleine D. Duvic MD Jorge J. Ocampo Candiani MD Isaac Zilinsky MD Mohamed L. Elsaie MD Philip Orbuch MD Joseph C. English III MD Ariel Ostad MD

PAST CO-EDITORS-IN-CHIEF Elizabeth Hale MD (2004) Impact Factor Susan H. Weinkle MD (2005-2008) Impact Factor Score: 1.394* ® * Keyvan Nouri MD (2005-2008) Normalized Eigenfactor Score: 0.574 Article Influence Score: 0.378* Sherry H. Hsiung MD (2008) *Clarivate Analytics, Formerly the IP & Science Business of James M. Spencer MD (2009-2013) Thomson Reuters, June 2019 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

ORIGINAL ARTICLES 121 Effect of Calcipotriene/Betamethasone Dipropionate 0.005%/0.064% Foam on Target Lesions in Plaque Psoriasis: A Post-Hoc Analysis Karen A. Veverka PhD, Dharm S. Patel PhD, Tobias Anger, Jes B. Hansen PhD, James Del Rosso DO, and Leon H. Kircik MD

128 Intralesional Triamcinolone Acetonide in the Treatment of Traction Alopecia Laura N. Uwakwe MD, Brianna De Souza MD, Andrea Tovar-Garza MD, Amy J. McMichael MD

132 Real-World Clinical Experience With the IL-17 Receptor A Antagonist Brodalumab Miriam S. Bettencourt MD Do Not Copy 138 Clinical and Molecular Effects of Interleukin-17 Pathway Blockade in Psoriasis Lawrence Green MD, Jeffrey M.Penalties Weinberg MD, ApplyAlan Menter MD, Jennifer Soung MD, Edward Lain MD, Abby Jacobson

145 Multidisciplinary Real-World Experience With Bilastine, a Second Generation Antihistamine Charles W. Lynde MD FRCPC, Gordon Sussman MD FRCPC, Pierre-Luc Dion MD FRCPC, Lyn Guenther MD FRCPC, Jacques Hébert MD FRCPC, Jaggi Rao MD FRCPC, Tim Vander Leek MD FRCPC FAAAAI, Susan Waserman MSc FRCPC

156 Ingenol Mebutate: Expanded Utility Yasmin Khalfe BA and Theodore Rosen MD

163 Long-Term Efficacy and Safety of Superficial Radiation Therapy in Subjects With Nonmelanoma Skin Cancer: A Retrospective Registry Study William Roth MD, Robert E. Beer MD, Vivek Iyengar MD, Thomas Bender MD, Isabelle Raymond PhD

ORIGINAL ARTICLES (CONTD) 176 Randomized, Investigator-Blinded Study to Compare the Efficacy and Tolerance of a 650-microsecond, 1064-nm YAG Laser to a 308-nm Excimer Laser for the Treatment of Mild to Moderate Psoriasis Vulgaris Mark S. Nestor MD PhD, Daniel Fischer DO MS, David Arnold DO

184 Melasma’s Impact on Quality of Life Karen Kagha MD, Sabrina Fabi MD, Mitchel P. Goldman MD

188 Management of Residual Psoriasis in Patients on Biologic Treatment Wasim Haidari BS BA, Adrian Pona MD, and Steven R. Feldman MD PhD

BRIEF COMMUNICATIONS 195 A Survey of Dermatologists’ Preparedness for Natural and Manmade Disasters Emily C. Murphy BS, Timur Alptunaer, Samantha Noll MD, James Phillips MD, Adam J. Friedman MD Do Not Copy 198 Universal Protocol in Mohs Micrographic Surgery: Incorporating a “Time Out” Procedure in HistopathologicPenalties Interpretation Apply Nisreen Mobayed BS, Julie K. Nguyen MD, Jennifer C. Tang MD and C. William Hanke MD

CASE REPORTS 199 Successful Management of Anti-TNF-Induced Psoriasis Despite Continuation of Therapy in a Pyoderma Gangrenosum Patient Atrin Toussi BS BA, Stephanie T. Le MD, Virgina R. Barton MD, Chelsea Ma MD, Michelle Y. Cheng MD, Andrea Sukhov MD, Reason Wilken MD, Forum Patel MD, Elizabeth Wang MD, Emanual Maverakis MD

202 Combination Topical Chemotherapy for the Treatment of an Invasive Cutaneous Squamous Cell Carcinoma Rachel Fayne BA, Sonali Nanda MS, Anna Nichols MD PhD, John Shen MD

The ﬁ rst new retinoid molecule for the treatment of acne in 20+ years.1 THE POWER OF PRECISION Specifi cally targets RAR-γ, the most common retinoic Don't let acid receptor in the skin.2,3 POWERFUL EFFICACY* Their acne Be & WELL-TOLERATED In PIVOTAL Study 1,† the focus. >50% fewer inﬂ ammatory lesions on face and trunk at Week 12.2‡ Favorable tolerability on both the face and trunk areas, across 4 diff erent parameters.2 Most common adverse reactions (incidence ≥ 1%) Do Not Copy in patients treated with AKLIEF Cream were Penalties Apply application site irritation, application site pruritus (itching), and sunburn.4

IMPORTANT SAFETY INFORMATION Indication: AKLIEF® (trifarotene) Cream, 0.005% is a retinoid indicated for the topical treatment of acne vulgaris in patients 9 years of age and older. Adverse Events:The most common adverse reactions (incidence ≥ 1%) in patients treated with AKLIEF Cream were application site irritation, application site pruritus (itching), and sunburn. Warnings/Precautions: Patients using AKLIEF Cream may experience erythema, scaling, dryness, and stinging/ burning. Use a moisturizer from the initiation of treatment, and, if appropriate, depending upon the severity of these adverse reactions, reduce the frequency of application of AKLIEF Cream, suspend or discontinue use. Avoid application of AKLIEF Cream to cuts, abrasions or eczematous or sunburned skin. Use of “waxing” as a depilatory method should be avoided on skin treated with AKLIEF Cream. Minimize exposure to sunlight and sunlamps. Use sunscreen and protective clothing over treated areas when exposure cannot be avoided. You are encouraged to report negative side e ects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. * The exact process by which trifarotene ameliorates acne is unknown. † PIVOTAL Studies 1 & 2 Design2—First large-scale, multicenter, randomized Phase 3 clinical trials evaluating the e cacy and safety of topical therapy vs vehicle in both facial and truncal acne over 12 weeks. Patients: Screened and randomized to once-daily trifarotene cream 50 µg/gg/g (n=1,214) or vehicle (n=1,206). Primary endpoints: 1) absolute change in infl ammatory and non-infl ammatory lesion counts on the face from baseline to Week 12; 2) Investigator Global Assessment (IGA)§ success rate on the face. Secondary endpoints: 1) absolute change in infl ammatory and non-infl ammatory lesion counts on the trunk from baseline to Week 12; 2) Physician Global Assessment (PGA)§ success rate on the trunk. Success rate: Percentage of patients achieving IGA face rating of clear (0) or almost clear (1) and PGA trunk rating of clear (0) or almost clear (1) and at least a 2-grade change in IGA or PGA rating from baseline at a particular study visit. Safety endpoints: Incidence of adverse events and local tolerability (erythema, scaling, dryness, and stinging/burning). ‡ vs 44.8% reduction with vehicle; P<0.001 for face and vs 50% reduction with vehicle; P<0.001 for trunk.2 § The defi nitions of severity for the 5-point IGA (face) and PGA (trunk) scales were the same: 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate) and 4 (severe).2

Please see brief summary of full Prescribing Information on the next page. aklief.com/HCP

This advertisement prepared by Saatchi & Saatchi Wellness Client: Galderma Space: Size A Pubs: 1) JAMA Dermatology PP Contact: 2) JAAD (Journal of the American Angela Silva Product: Aklief Bleed: 8.5”x11.125” Academy of Dermatology)* 3) CUTIS Campaign: Trim: 7.875”x10.5” Telephone: 4) JDD (Journal of Drugs in Dermatology) 646-746-5253 Job #: B1162-003617-12 Safety: 7”x10” Issue: Publication Note: Guidelines for general identi cation only– Do not use as an insertion order. The following speci cations were used to produceDO this proofNOT and are included PRINT herewith as an aid to help you in faithfully reproducing it. Screen Angles: Y M C K Dot Shape: Round Square Elliptical Euclidean Software manufacturer of dot shape

IMPORTANT INFORMATION ABOUT AKLIEF® (trifarotene) Cream, 0.005%

BRIEF SUMMARY This summary contains important information about AKLIEF Cream. To help reduce your risk of developing these local skin reactions, when you It is not meant to take the place of your doctor’s instructions. Read this begin treatment with AKLIEF Cream, you should begin applying a information carefully before you start using AKLIEF Cream. Ask your doctor moisturizer on your skin as often as needed. or pharmacist if you do not understand any of this information or if you Tell your doctor if you develop symptoms of a local skin reaction. Your want to know more about AKLIEF Cream. For full Prescribing Information doctor may tell you to use AKLIEF Cream less often, or temporarily, or and Patient Information, please see the package insert. permanently stop your treatment with AKLIEF Cream. WHAT IS AKLIEF CREAM? These are not all of the possible side effects of AKLIEF Cream. For more AKLIEF Cream is a prescription medicine used on the skin (topical) to information, ask your doctor or pharmacist. treat acne vulgaris. Acne vulgaris is a condition in which the skin has blackheads, whiteheads, and pimples. You are encouraged to report negative side effects of prescription drugs to the FDA at www.fda.gov/medwatch or call 1-800-FDA-1088. You may also WHO IS AKLIEF CREAM FOR? contact GALDERMA LABORATORIES, L.P. at 1-866-735-4137. AKLIEF Cream is for use in people 9 years of age and older. It is not known if AKLIEF Cream is safe and effective in children younger than 9 years old. HOW SHOULD I USE AKLIEF CREAM? • Use AKLIEF Cream exactly as your doctor tells you to use it. Apply Do not use AKLIEF Cream for a condition for which it was not a thin layer of AKLIEF Cream over the affected areas one (1) time prescribed. Do not give AKLIEF Cream to other people, even if they have each day, in the evening. the same symptoms you have. It may harm them. APPLYING AKLIEF CREAM: WHAT SHOULD I TELL MY DOCTOR BEFORE USING AKLIEF CREAM? • Wash the area where the cream will be applied and pat dry. Before you use AKLIEF Cream, tell your doctor if you: • If you receive a sample tube of AKLIEF Cream, follow your doctor’s • have skin problems, including eczema, cuts or sunburn. instructions about how much to apply • are pregnant or planning to become pregnant. It is not known if • AKLIEF Cream comes in a pump. Press down on (depress) the AKLIEF Cream will harm your unborn baby. Pump one (1) time to dispense a small amount of AKLIEF Cream • are breastfeeding or plan to breastfeed. It is not known if AKLIEF and spread a thin layer over your face (forehead, cheeks, nose, Cream passes into your breast milk. Breastfeeding women and chin). Avoid contact with your eyes, lips, mouth and the should use AKLIEF Cream on the smallest area of skin and for the corners of your nose. Press down on the pump two (2) times to shortest time needed while breastfeeding. Do not apply AKLIEF dispense enough AKLIEF Cream to apply a thin layer to cover Cream to the nipple and areola to avoid contact with your baby. your upper trunk (the area of your upper back that you can reach, Talk to your doctor about the best way to feed your baby if you shoulders, and chest). One (1) more pump may be used to apply use AKLIEF Cream. a thin layer of AKLIEF Cream to your middle and lower back, if acne is present. Tell your doctor about all of the medicines you take, including prescrip- • When you begin treatment with AKLIEF Cream, you should begin tion and over-the-counter medicines, vitamins, and herbal supplements. applying a moisturizer on your skin as often as needed. Especially tell your doctor if you use any other medicine for acne. HOW SHOULD I STORE AKLIEF CREAM? WHAT SHOULD I AVOID WHILE USING AKLIEF CREAM? Do Not Copy • Store AKLIEF Cream at room temperature, 68° to 77° F (20° to 25° C). • Minimize exposure to sunlight. You should avoid using • Keep AKLIEF Cream away from heat. sunlamps, tanning beds, and ultraviolet light during Penalties Apply treatment with AKLIEF Cream. If you have to be in sunlight or are • If you received a sample tube of AKLIEF Cream from your doctor, sensitive to sunlight, use a sunscreen with SPF (sun protection keep the tube tightly closed. factor) of 15 or more, and wear protective clothing and a Keep AKLIEF Cream and all medicines out of the reach of wide-brimmed hat to cover the treated areas. children. • You should avoid using AKLIEF Cream on skin areas with cuts, WHAT ARE THE INGREDIENTS OF AKLIEF CREAM? abrasions, eczema, or on sunburned skin. Active ingredient: trifarotene • You should avoid using skin products that may dry or irritate your skin such as medicated or abrasive soaps and Inactive ingredients: allantoin, copolymer of acrylamide and cleansers, cosmetics that have strong skin drying effects sodium acryloyldimethyltaurate, dispersion 40% in isohexadecane, and products containing high levels of alcohol. cyclomethicone, 5% ethanol, medium-chain triglycerides, phenoxyethanol, propylene glycol, purified water. • You should avoid the use of “waxing” as a hair removal method on skin treated with AKLIEF Cream. WHERE SHOULD I GO FOR MORE INFORMATION ABOUT AKLIEF CREAM? WHAT ARE THE POSSIBLE SIDE EFFECTS OF AKLIEF CREAM? • Talk to your doctor or pharmacist. The most common side effects of AKLIEF Cream include: • Visit www.AKLIEF.com or call 1-866-735-4137. application site (skin) irritation, itching and sunburn. ©Galderma Laboratories, L.P. All Rights Reserved. All trademarks are the AKLIEF Cream may cause serious side effects including: property of their respective owners. • Local skin irritation. Local skin reactions are common with AKLIEF GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USA Cream, are most likely to happen during the first four (4) weeks Revised: 9/19 of treatment and may decrease with continued use of AKLIEF Cream. Signs and symptoms of local skin reaction include: o Redness o Dryness o Scaling o Stinging or burning

References: 1. AKLIEF Press Release. Federal Drug Administration approval 2019. 2. Tan J, Thiboutot D, Popp G, et al. Randomized phase 3 evaluation of trifarotene 50 µg/g cream treatment of moderate facial and truncal acne. J Am Acad Dermatol. 2019;80(6):1691-1699. 3. Fisher GJ, Harvinder ST, Xiao J, et al. Immunological identification and functional quantitation of retinoic acid and retinoid x receptor proteins in human skin. J Biol Chem. 1994;269(32):20629-20635. 4. AKLIEF (trifarotene) Cream 0.005% [Prescribing Information]. Ft Worth, TX: Galderma Laboratories, L.P.; October 2019.

©2020 Galderma Laboratories, L.P. All Rights Reserved. All trademarks are the property of their respective owners. USMP/AKL/0098/1119 Galderma Laboratories, L.P., 14501 N. Freeway, Fort Worth, TX 76177 aklief.com/hcp Printed in USA 1/20

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LETTERS TO THE EDITOR 207 Skin Cancer Epidemiology and Sun Protection Behaviors Among Native Americans M.E. Logue MD, A. Smidt MD, M. Berwick PhD MPH

209 Is Dupilumab an Immunosuppressant? Adrian Cuellar-Barboza MD, Matthew Zirwas MD, Steven R. Feldman MD PhD

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INDICATION RHOFADE cream is indicated for the topical treatment of persistent facial erythema associated with rosacea in adults.

IMPORTANT SAFETY INFORMATION AND WARNINGS WARNINGS AND PRECAUTIONS Potential Impacts on Cardiovascular Disease Alpha-adrenergic agonists may impact blood pressure. RHOFADE cream should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease, orthostatic hypotension, and uncontrolled hypertension or hypotension. Advise patients with cardiovascular disease, orthostatic hypotension, and/or uncontrolled hypertension/hypotension to seek immediate medical care if their condition worsens.

Potentiation of Vascular Insuffi ciency RHOFADE cream should be used with caution in patients with cerebral or coronary insuffi ciency, Raynaud’s phenomenon, thromboangiitis obliterans, scleroderma, or Sjögren’s syndrome. Advise patients to seek immediate medical care if signs and symptoms of potentiation of vascular insuffi ciency develop.

Risk of Angle Closure Glaucoma RHOFADE cream may increase the risk of angle closure glaucoma in patients with narrow-angle glaucoma. Advise patients to seek immediate medical care if signs and symptoms of acute angle closure Do Not Copy glaucoma develop.

Penalties Apply CONTRAINDICATIONS There are no contraindications for RHOFADE cream.

ADVERSE REACTIONS The most common adverse reactions >1% for See results with RHOFADE cream RHOFADE cream were: application-site dermatitis 2%, worsening inﬂ ammatory lesions of rosacea 1%, Not an actual patient BEFORE AFTER application-site pruritus 1%, application-site erythema Day 1: Predose Day 29: Hour 12 1%, and application-site pain 1%.

erythema associated with rosacea References: 1. RHOFADE® cream full Prescribing Information 2018. in adults* Unretouched photos of clinical trial subject. Individual results may vary. At hours 3, 6, 9, and 12 on Day 29 of clinical trials, a >2-grade improvement in per- *Based on Symphony Health PHAST data recording the number of prescriptions written between July 2017 sistent facial erythema was seen in 12% to 18% of subjects using RHOFADE cream vs 5% to 9% using vehicle. The most common side eff ects at the application site include: and October 2019. Data on fi le. EPI Health, LLC dermatitis, worsening of rosacea pimples, itching, redness, and pain.1 These are not © RHOFADE is a registered trademark of EPI HEALTH, LLC. all the possible side eff ects of RHOFADE cream. Individual results may vary. [RHO-JA-1119] EPIH_19_0119_JournalAd_M02 Colors: 4C Spread ad + Brief PI for Journal of Drugs in Dermatology - January Issue Bleed: .125” Trim size: 8.25” w x 10.875” h Live: .125” File built at 100% Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

INDICATION RHOFADE cream is indicated for the topical treatment of persistent facial erythema associated with rosacea in adults.

Penalties Apply CONTRAINDICATIONS There are no contraindications for RHOFADE cream.

For topical use only. Not for oral, ophthalmic, or intravaginal use. Please see full Prescribing Information for RHOFADE cream is the #1 prescribed RHOFADE cream at rhofadehcp.com and Brief Summary attached. topical treatment for persistent facial erythema associated with rosacea References: 1. RHOFADE® cream full Prescribing Information 2018. in adults* Unretouched photos of clinical trial subject. Individual results may vary. At hours 3, 6, 9, and 12 on Day 29 of clinical trials, a >2-grade improvement in per- *Based on Symphony Health PHAST data recording the number of prescriptions written between July 2017 sistent facial erythema was seen in 12% to 18% of subjects using RHOFADE cream vs 5% to 9% using vehicle. The most common side eff ects at the application site include: and October 2019. Data on fi le. EPI Health, LLC dermatitis, worsening of rosacea pimples, itching, redness, and pain.1 These are not © RHOFADE is a registered trademark of EPI HEALTH, LLC. all the possible side eff ects of RHOFADE cream. Individual results may vary. [RHO-JA-1119] Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

RHOFADE® (oxymetazoline HCI) cream, 1% BRIEF SUMMARY—PLEASE SEE THE RHOFADE® CREAM PACKAGE Monoamine Oxidase Inhibitors INSERT FOR FULL PRESCRIBING INFORMATION. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines. INDICATIONS AND USAGE RHOFADE cream is indicated for the topical treatment of persistent facial USE IN SPECIFIC POPULATIONS erythema associated with rosacea in adults. Pregnancy Risk Summary DOSAGE AND ADMINISTRATION For topical use only. Not for oral, ophthalmic, or intravaginal use. There are no available data on RHOFADE cream use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Prime the RHOFADE cream pump before using for the first time. To do so, with A literature article describing intranasal decongestant use in pregnant women the pump in the upright position, repeatedly depress the actuator until cream identified a potential association between second-trimester exposure to is dispensed and then pump three times. Discard the cream from priming oxymetazoline (with no decongestant exposure in the first trimester) and actuations. It is only necessary to prime the pump before the first dose. renal collecting system anomalies. In animal reproduction studies, there RHOFADE cream tubes do not require priming. were no adverse developmental effects observed after oral administration Apply a pea-sized amount of RHOFADE cream, once daily in a thin layer to of oxymetazoline hydrochloride in pregnant rats and rabbits at systemic cover the entire face (forehead, nose, each cheek, and chin) avoiding the eyes exposures up to 3 times and 73 times, respectively, the exposure associated and lips. Wash hands immediately after applying RHOFADE cream. with the maximum recommended human dose (MRHD). The estimated background risks of major birth defects and miscarriage for the indicated CONTRAINDICATIONS population are unknown. All pregnancies have a background risk of birth None. defect, loss, or other adverse outcomes. In the U.S. general population, the WARNINGS AND PRECAUTIONS estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Potential Impacts on Cardiovascular Disease Alpha-adrenergic agonists may impact blood pressure. RHOFADE Clinical Considerations cream should be used with caution in patients with severe or unstable Fetal/Neonatal Adverse Reactions or uncontrolled cardiovascular disease, orthostatic hypotension, Following repeated use of oxymetazoline hydrochloride solution nasal and uncontrolled hypertension or hypotension. Advise patients with spray for the treatment of nasal congestion at a dose 5 times higher than cardiovascular disease, orthostatic hypotension, and/or uncontrolled recommended, one case of fetal distress was reported in a 41-week pregnant hypertension/hypotension to seek immediate medical care if their patient. The fetal distress resolved hours later, prior to the delivery of the condition worsens. healthy infant. The anticipated exposures for the case are 8- to 18-fold higher Potentiation of Vascular Insufficiency than plasma exposures after topical administration of RHOFADE cream. RHOFADE cream should be used with caution in patients with cerebral Human Data or coronary insufficiency, Raynaud’s phenomenon, thromboangiitis No adequate and well-controlled trials of RHOFADE cream have been obliterans, scleroderma, or Sjögren’s syndrome. Advise patients to seek conducted in pregnant women. Across all clinical trials of RHOFADE cream, immediate medical care if signs and symptoms of potentiation of vascular two pregnancies were reported. One pregnancy resulted in the delivery of insufficiency develop. a healthy child. One pregnancy resulted in a spontaneous abortion, which Risk of Angle Closure Glaucoma was considered to be unrelated to the trial medication. RHOFADE cream may increase the risk of angle closure glaucoma in patients Lactation with narrow-angle glaucoma. Advise patients to seek immediate medical care No clinical data are available to assess the effects of oxymetazoline on if signs and symptoms of acute angle closure glaucoma develop. the quantity or rate of breast milk production, or to establish the level of ADVERSE REACTIONS oxymetazoline present in human breast milk post-dose. Oxymetazoline was detected in the milk of lactating rats. The developmental and health benefits Clinical Studies Experience of breastfeeding should be considered along with the mother’s clinical need Because clinical trials are conducted under varying conditions, adverse for RHOFADE cream and any potential adverse effects on the breastfed child reaction rates observed in the clinical trials of a drug cannot be directlyDo Not fromCopy RHOFADE cream or from the underlying maternal condition. compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pediatric Use PenaltiesSafety Apply and effectiveness of RHOFADE cream have not been established A total of 489 subjects with persistent facial erythema associated with in pediatric patients below the age of 18 years. rosacea were treated with RHOFADE cream once daily for 4 weeks in 3 controlled clinical trials. An additional 440 subjects with persistent facial Geriatric Use erythema associated with rosacea were also treated with RHOFADE cream One hundred and ninety-three subjects aged 65 years and older received once daily for up to one year in a long-term (open-label) clinical trial. Adverse treatment with RHOFADE cream (n = 135) or vehicle (n = 58) in clinical trials. reactions that occurred in at least 1% of subjects treated with RHOFADE No overall differences in safety or effectiveness were observed between cream through 4 weeks of treatment are presented in the table below: subjects ≥ 65 years of age and younger subjects, based on available data. Clinical studies of RHOFADE cream did not include sufficient numbers of Adverse Reactions Reported by ≥ 1% of Subjects Through 4 Weeks of subjects aged 65 and over to determine whether they respond differently Treatment in Controlled Clinical Trials from younger subjects. Pooled Controlled Clinical Trials OVERDOSAGE Adverse Reaction RHOFADE Cream Vehicle RHOFADE cream is not for oral use. If oral ingestion occurs, seek medical (N = 489) (N = 483) advice. Monitor patient closely and administer appropriate supportive Application-site dermatitis 9 (2%) 0 measures as necessary. Accidental ingestion of topical solutions (nasal sprays) containing imidazoline derivatives (e.g., oxymetazoline) in children has Worsening inflammatory lesions 7 (1%) 1 (< 1%) resulted in serious adverse events requiring hospitalization, including nausea, of rosacea vomiting, lethargy, tachycardia, decreased respiration, bradycardia, hypotension, Application-site pruritus 5 (1%) 4 (1%) hypertension, sedation, somnolence, mydriasis, stupor, hypothermia, drooling, and coma. Keep RHOFADE cream out of reach of children. Application-site erythema 5 (1%) 2 (< 1%) Application-site pain 4 (1%) 1 (< 1%) In the long-term (open-label) clinical trial, the rates of adverse reactions over a one-year treatment period were as follows: worsening inflammatory lesions of rosacea (3%), application-site dermatitis (3%), application-site pruritus (2%), application-site pain (2%), and application-site erythema (2%). Subjects with persistent erythema along with inflammatory lesions were allowed to use additional therapy for the inflammatory lesions of rosacea. RHOFADE is a registered trademark of EPI HEALTH, LLC. DRUG INTERACTIONS Anti-hypertensives/Cardiac Glycosides Patented. U.S. Patent Numbers: U.S. 7,812,049; U.S. 8,420,688; U.S. 8,815,929; U.S. 8,883,838; U.S. 9,974,773; and U.S. 10,335,391. Alpha-adrenergic agonists, as a class, may impact blood pressure. Caution Made in the U.S.A. in using drugs such as beta-blockers, anti-hypertensives and/or cardiac glycosides is advised. Caution should also be exercised in patients receiving alpha-1 adrenergic receptor antagonists such as in the treatment of cardiovascular disease, benign prostatic hypertrophy, or Raynaud’s disease.

doi:10.36849/JDD.2020.4750 February 2020 121 Volume 19 • Issue 2 Copyright © 2020 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Effect of Calcipotriene/Betamethasone Dipropionate 0.005%/0.064% Foam on Target Lesions in Plaque Psoriasis: A Post-Hoc Analysis Karen A. Veverka PhD,ª Dharm S. Patel PhD,ª Tobias Anger,B Jes B. Hansen PhD,B James Del Rosso DO,c and Leon H. Kircik MDd ªLEO Pharma, Madison, NJ BLEO Pharma, Ballerup, Denmark cJDR Dermatology Research/Thomas Dermatology, Las Vegas, NV dIcahn School of Medicine at Mount Sinai, New York, NY Indiana University Medical Center, Indianapolis, IN; Physicians Skin Care, PLLC, Louisville, KY

ABSTRACT

Objective: Investigate the effect of fixed-combination calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) foam on target lesion severity in plaque psoriasis. Design: Post-hoc analysis was conducted on data from a Phase 3, randomized, double-blind, multicenter clinical study of Cal/BD foam in the treatment of psoriasis vulgaris for 4 weeks (PSO-FAST; NCT01866163). Participants: In PSO-FAST, 426 patients (≥18 years) with psoriasis vulgaris (≥mild severity) were randomized 3:1 to Cal/BD foam (n=323) or vehicle foam (n=103), applied once daily. Measurements: Assessments included (1) target lesion severity (redness, scaliness, and thickness) at baseline and weeks 1, 2, and 4; and (2) the proportion of patients with ≥50% reduction in total sign score (TSS-50) from baseline at weeks 1, 2, and 4. Results: A greater proportion of patients achieved considerable improvement (a score of 0 or 1) in the severity of target lesions after 4 weeks of treatment with Cal/BD foam vs vehicle foamDo at Notweek 4 Copy(redness: 76.2% vs 21.4%; P<.001; scaliness: 91.3% vs 61.2%; P<.001; and thickness: 83.3% vs 35.0%; P<.001, respectively). Rapid onset of efficacy was observed as early as week 1. Significantly more patients also achieved TSS-50 at week 4 with PenaltiesCal/BD foam vs vehicle Apply foam for their target lesions regardless of treatment area, including the elbows and knees (P<.05 for all). Conclusions: Significant improvements in target lesion severity were achieved with up to 4 weeks of treatment with once-daily Cal/BD foam for adults with plaque psoriasis versus vehicle foam, with rapid onset of efficacy observed at week 1.

J Drugs Dermatol. 2020;19(2)121-126. doi:10.36849/JDD.2020.4750

INTRODUCTION soriasis is a common, chronic, inflammatory skin disease ly appear as areas of scaly skin, red raised areas on the skin, that affects approximately 7 million adults in the United dry skin, and crusty plaque features that contribute to the bur- States and many more worldwide.1,2 The characteristic den of the disease and are associated with the worst quality of P 5 scaling and erythematous plaques of the disease can be dis- life from psoriasis for patients. Disease severity in psoriasis figuring and, in addition, painful, or severely pruritic.3 In fact, is determined by the amount of redness, scaliness, and thick- psoriasis can be detrimental to the physical, social, and psycho- ness of the lesions, either across different body regions or on social well-being of the individual, so much so that the disutil- a predefined target lesion, or both. The Psoriasis Area and Se- ity and deterioration in quality of life felt by these patients can verity Index (PASI) is the gold standard for measuring psoriasis often be comparable to other serious chronic diseases, accord- severity.6,7 ing to a systemic literature review.4,5 Morphologic evaluation of these plaques or skin lesions is important in diagnosis and in There is no cure for plaque psoriasis at the present time, classification of the psoriasis subtype within the disease spec- leaving the goal of treatment to be achievement of complete trum. Plaque psoriasis, for example, the most common form clearance of skin symptoms and improvement in the patient’s of the disease—manifests as well-defined, sharply demarcated, quality of life.8 Despite a rapidly evolving treatment landscape erythematous plaques of varying size.3 These lesions common- for psoriasis, topical corticosteroids and vitamin D3 analogues Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

122 Journal of Drugs in Dermatology K.A. Veverka, D.S. Patel, T. Anger, et al February 2020 • Volume 19 • Issue 2

are still very relevant and remain the backbone of treatment 29%; 3=30%-49%; 4=50%-69%; 5=70-89%; 6=90%-100%) and the for most patients with plaque psoriasis. Combination formu- severity of clinical signs. Each patient also had a target lesion of lations of these agents have become the preferred option ≥5 cm at its longest axis, scored by the physician as ≥1 (score because of their enhanced efficacy and minimized toxicity.9-11 range, 0-4) each for redness, thickness, and scaliness, for a total The fixed-combination formulation of calcipotriene 0.005% score of ≥4, using the same scale as for the mPASI (see Supple- plus betamethasone dipropionate 0.064% (Cal/BD) foam is mental Table 1). one such combination product that has demonstrated efficacy and a favorable safety profile in several large, randomized, The primary efficacy endpoint in the original study was the clinical studies.12-17 In PSO-FAST, a randomized Phase 3 study proportion of patients at week 4 who achieved treatment suc- of 426 patients with at least mild severity psoriasis, signifi- cess, defined as a rating of “clear” or “almost clear,” plus cantly more patients treated with Cal/BD foam than those in a minimum 2-grade improvement, according to the PGA. the vehicle group achieved treatment success, defined as an improvement from at least moderate disease at baseline to a Post-Hoc Analyses rating of “clear” or “almost clear,” or from mild disease to a rat- The objective of this post-hoc analysis was to evaluate the clini- ing of “clear,” at week 4, according to scores on the Physician’s cal sign severity of the target lesion after once-daily application Global Assessment (PGA; also referred to as the Investigator’s of Cal/BD foam for 4 weeks. The severity of the clinical signs Global Assessment).17 Cal/BD foam also significantly reduced of redness, scaliness, and plaque thickness for the target lesion the modified PASI (mPASI) score (modified PASI excludes the was assessed using a 5-point scale based on mPASI assessment head) and increased the proportion of patients achieving 75% (0=none; 1=mild; 2=moderate; 3=severe; 4=very severe; Supple- improvement in PASI score (PASI-75); in addition, it provided mental Table 1). Response to treatment was assessed by (1) the significantly greater itch relief than vehicle foam.17 proportion of patients achieving “clear” or “almost clear” rat- ings for each of lesion redness, scaliness, and plaque thickness; While assessment of psoriasis disease severity and treatment and (2) the proportion of patients achieving a ≥50% reduction in response across overall body regions is important, we sought total sign score (TSS-50), in which TSS is the sum of the scores to gain insight into the impact of Cal/BD foam formulation on for the 3 components of redness, scaliness, and thickness at the appearance of psoriasis at the lesion level, addressing the weeks 1, 2, and 4 of treatment. inherent redness, scaliness, and thickness of psoriaticDo plaques Not Copy that patients find so troubling. This understanding could pro- Statistical Analyses vide a more comprehensive evaluation of disease severityPenalties and The Apply outcomes above were compared between treatment groups a more tangible assessment of treatment benefits that the pa- using the Cochran-Mantel-Haenszel method, adjusted for pooled tients can “see” and “feel.” The PSO-FAST study had shown that centers. Missing values were imputed as non-responders, and the rate of treatment success at the target lesion was higher for subgroup analyses by location of target lesion were additionally Cal/BD vs the vehicle foam,17 but little else was reported for the performed. treatment outcome at the target lesion. Therefore, a post-hoc analysis of the target lesion data from the PSO-FAST Phase 3 RESULTS study was conducted. A total of 426 patients were randomized in the study (Cal/BD foam, n=323; foam vehicle, n=103). The majority of the patients METHODS (97%) completed the study. Patient demographics and baseline Study Design, Objectives, and Patient Population characteristics were similar between treatment groups and have PSO-FAST was a Phase 3, randomized, double-blind, multicenter been previously reported (Table 1).17 The mean age for the study study conducted in the United States (NCT01866163). The details population was 51 years (range, 18-87 years); most patients of study methodology, patient selection, endpoints, and pro- were male (59.4%) and white (85.9%) and had moderate-to-se- spective statistical analyses have been previously described.17 vere psoriasis (84.7%). Mean disease duration was 15.9 years (range, 1-67 years). With regard to the target lesion, the major- Eligible patients were ≥18 years of age, with a clinical diagnosis ity of patients (~88%-95%) had moderate to very severe clinical of psoriasis vulgaris of the trunk and/or limbs of at least mild signs at baseline. The majority of the target lesions were located severity, according to the PGA score for disease severity. Pa- on the limbs (67.4%) and the trunk (20.7%), with a lesser percent- tients were randomized 3:1 to once-daily, fixed-combination Cal/ age located on the knee (3.8%) and elbow (8.2%). BD foam or foam vehicle for 4 weeks. At baseline, patients had between 2% and 30% of their body surface area (ie, trunk and After 4 weeks of treatment, significantly more patients using limbs) affected by the disease and had an mPASI score of ≥2, Cal/BD foam had a rating of “none” or only “mild” for redness calculated from the investigator’s assessment of the extent of (76.2% vs 21.4%; P<.001), scaliness (91.3% vs 61.2%; P<.001), and disease (rated as 0=no involvement; 1=less than 10%; 2=10%- thickness (83.3% vs 35.0%; P<.001) of their target lesion area as Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

123 Journal of Drugs in Dermatology K.A. Veverka, D.S. Patel, T. Anger, et al February 2020 • Volume 19 • Issue 2

TABLE 1. compared with the patients using vehicle foam (Figure 1). No- Patient Demographics and Baseline Characteristics tably, these improvements were observed as early as week 1 Cal/BD Vehicle All (Figure 1). The improvements in the overall target lesion severity foam foam (n=426) were also evident when the different treatment areas —limbs, (n=323) (n=103) trunk, and elbows or knees—were assessed separately at week Median age, years (range) 52 (18-87) 46 (19-79) 51 (18-87) 4 (Supplemental Figure 1). Male, n (%) 204 (63.2) 49 (47.6) 253 (59.4) Race, n (%) Specifically, more patients in the Cal/BD foam group had no White 276 (85.4) 90 (87.4) 366 (85.9) signs or only mild signs of redness, scaliness, and thickness of Black or African American 24 (7.4) 6 (5.8) 30 (7.0) the target lesion at the limbs (75.3% vs 22.2%, 94.0% vs 63.9%, Other 23 (7.1) 7 (6.8) 30 (7.0) 84.2% vs 38.9%, respectively), trunk (82.6% vs 15.8%, 91.3% vs 57.9%, 88.4% vs 26.3%, respectively), and elbows or knees Mean body mass index, 32.0 (16-62) 33.1 (19-59) 32.3 (16-62) kg/m2 (range) (69.2% vs 25.0%, 76.9% vs 50.0%, 69.2% vs 25.0%, respectively) at week 4 (Supplemental Figure 1). In terms of the TSS assess- Fitzpatrick skin type, n (%) ment for redness, scaliness, and thickness at the target lesion, I 16 (5.0) 4 (3.9) 20 (4.7) significantly more patients achieved TSS-50 with Cal/BD foam II 83 (25.7) 25 (24.3) 108 (25.4) than with the foam vehicle at week 4 (81.4% vs 23.3%, P<.001); III 92 (28.5) 39 (37.9) 131 (30.8) in some patients, significant improvements were observed as IV 89 (27.6) 21 (20.4) 110 (25.8) early as week 1 (Figure 2). Consistently, higher proportions of V 33 (10.2) 9 (8.7) 42 (9.9) patients achieved TSS-50 at week 4 with Cal/BD foam than with VI 10 (3.1) 5 (4.9) 15 (3.5) vehicle foam for the target lesion, regardless of the target lesion Mean duration of psoriasis location (limbs: 81.9% vs 26.4%, P<.001; trunk: 85.5% vs 15.8%, 16.3 (1-67) 14.9 (1-53) 15.9 (1-67) vulgaris, years (range) P<.001; elbows or knees: 71.8% vs 16.7%, P<.05) (Figure 3). Mean BSA, % (SD) 7.4 (6.4) 8.0 (7.0) 7.5 (6.5) DISCUSSION PGA score, n (%) This post-hoc analysis showed that, with a once-daily regimen Mild 50 (15.5) 15 (14.6) 65 (15.3) of Cal/BD foam for 4 weeks, the majority of patients achieved Moderate 244 (75.5) 75 (72.8)Do 319 (74.9) Not Copy either clearance of their target lesion or a reduction in target Severe 29 (9.0) 13 (12.6)Penalties 42 (9.9) lesion Apply severity to a rating of mild. In many patients, the improve- Mean mPASI score (range) 7.4 (2-37) 7.9 (2-47) 7.5 (2-47) ments to the target lesion occurred rapidly, within 1 week. The Target lesion location, n (%) proportion of patients who were able to achieve at least a 50% Limbs 215 (66.6) 72 (69.9) 287 (67.4) reduction in the severity of the redness, scaliness, and thickness Trunk 69 (21.4) 19 (18.4) 88 (20.7) of the target lesion (measured by TSS) was also greater with Elbow 25 (7.7) 10 (9.7) 35 (8.2) Cal/BD foam than with vehicle foam, and this reduction could occur as early as week 1 and regardless of the location of the Knee 14 (4.3) 2 (1.9) 16 (3.8) treatment area. Target lesion severity, n (%)

Redness Psoriasis characteristics such as scaliness of the skin, red raised Mild 19 (5.9) 5 (4.9) 24 (5.6) areas on the skin, dry skin, and crusted plaque areas are the Moderate 194 (60.1) 55 (53.4) 249 (58.5) features that most patients consider to be the most common Severe/Very severe 110 (34.1) 43 (41.7) 153 (35.9) symptoms of this condition.18 In the original report of PSO-FAST, Scaliness complete resolution of the clinical signs in the target lesion was Mild 44 (13.6) 8 (7.8) 52 (12.2) achieved at week 4 in significantly more patients using Cal/BD foam than in those in the vehicle foam group: redness (32.6% Moderate 170 (52.5) 62 (60.2) 232 (54.5) vs 3.0%), scaliness (70.0% vs 18.2%), and thickness (57.5% vs Severe/Very severe 109 (33.7) 33 (32.0) 142 (33.3) 4.0%).17 Findings from our post-hoc analysis not only showed Thickness consistent general findings but also demonstrated improve- Mild 29 (9.0) 7 (6.8) 36 (8.4) ments for target lesions across treatment areas. This study Moderate 194 (60.1) 63 (61.2) 257 (60.3) provided evidence that, for many patients, redness, scaliness, Severe/Very severe 100 (31.0) 33 (32.0) 133 (31.2) and thickness can be effectively managed at the plaque level BSA=body surface area; SD=standard deviation. with the once-daily Cal/BD foam. Even psoriasis on knees and elbows was significantly more improved with Cal/BD foam than with vehicle foam. Knee and elbow involvement represented a PreviousFigure Legends Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

Figure 1. Proportion of patients achieving improvements (overall lesion score of 0 or 1) in redness, scaliness, and thickness of target lesion severity with Cal/BD foam. 124 Figure 2. Proportion of patients achieving at least a 50% reduction in total sign score (TSS-50) at each visit with Cal/BD foam. Journal of Drugs in Dermatology K.A. Veverka, D.S. Patel, T. Anger, et al Figure 3. Proportion of patientsFebruary achieving 2020 at •least Volume a 50% 19 reduction • Issue in 2total sign score (TSS-50) at each visit for target lesion by location.

Supplemental Figure 1. Proportion of patients achieving improvements (overall lesion score of 0 or 1) in redness, scaliness, and thickness of the target lesion at week 4 by location. FIGURE 1. Proportion of patients achieving improvements (overall lesion score of 0 or 1) in redness, scaliness, and thickness of target lesion Figureseverity 1. with Proportion Cal/BD offoam. patients achieving improvements (overall lesion score of 0 or 1) in redness, scaliness, and thickness of target lesion severity with Cal/BD foam.

small percentage of selection as target lesion locations in this FIGURE 2. Proportion of patients achieving at least a 50% reduction in clinical study setting, but in real-world practice, psoriasis of the total sign score (TSS-50) at each visit with Cal/BD foam. knees and elbows may be more common, hence representing Figure 2. Proportion of patients achieving at least a 50% reduction in total sign score (TSS-50) at each visit with Cal/BD foam. an unmet need for more evidence of treatment outcome.19 A recent open-label study, initiated by the investigators, has, in fact, similarly demonstrated significant improvement in target lesions at the knees and elbows, accumulating further evidence for the use of Cal/BD foam to treat psoriasis in these areas.20

Common limitations of post-hoc analyses, such as Dotesting Not of Copy data for hypotheses that were not pre-specified before the data collection in the original study, apply to this analysis.Penalties Indeed, Apply the statistical analysis plan for the original study did not include comparisons of target lesion assessments, as evaluated here. Nonetheless, the current results were consistent with those of the original study in terms of the efficacy of Cal/BD foam in treating patients with mild, moderate, and severe chronic plaque A once-daily regimen of Cal/BD foam for up to 4 weeks provided psoriasis.17 Larger studies are needed to validate the current re- considerable and rapid improvements in target lesion severity sults with regard to target lesions. Additional research initiatives in chronic plaque psoriasis. Overall, the findings of this post-hoc investigating any potential correlation between target lesion analysis provide more insight into the benefits of treatment with and overall treatment outcomes may yield useful and practical Cal/BD foam at the level of the individual psoriatic plaque, ad- clinical evidence for the management of psoriasis. dressing characteristics that are most bothersome to patients.

FIGUREFigure 3. Proportion3. Proportion of patientsof patients achieving achieving at leastat least a 50% a 50% reduction reduction in totalin total sign sign score score (TSS-50) (TSS- 50)at each at each visit visit for targetfor target lesion lesion by location. by location.

125 Journal of Drugs in Dermatology K.A. Veverka, D.S. Patel, T. Anger, et al February 2020 • Volume 19 • Issue 2

betamethasone dipropionate aerosol foam versus ointment in patients These results may be considered by patients and physicians with psoriasis vulgaris: a randomized Phase II study. J Dermatolog Treat. when making treatment decisions. 2016;27(2):120-127. 1 7. Leonardi C, Bagel J, Yamauchi P, et al. Efficacy and safety of calcipotriene plus betamethasone dipropionate aerosol foam in patients with psoria- DISCLOSURES sis vulgaris: a randomized Phase III study (PSO-FAST). J Drugs Dermatol. 2015;14(12):1468-1477. Drs Patel, Veverka, Anger, and Hansen are employees of LEO 18. Feldman SR. Disease burden and treatment adherence in psoriasis patients. Pharma. Dr Kircik has served as a research investigator, speak- Cutis. 2013;92(5):258-263. er, and consultant for LEO Pharma, Inc. Dr. Del Rosso has served 19. Wu JJ, Veverka KA, Lu M, et al. Real-world experience of calcipotriene and betamethasone dipropionate foam 0.005%/0.064% in the treatment of adults as an advisor, speaker, and clinical research investigator for LEO with psoriasis in the United States. J Dermatolog Treat. 2019;30(5):454-460. Pharma. 20. Del Rosso JQ, Kircik LH. The effect of calcipotriene-betamethasone dipropionate aerosol foam versus vehicle on target lesions in moderate severity plaque psoriasis: focus on elbows and knees. J Drugs Dermatol. ACKNOWLEDGMENTS 2019;18(4):358-361. P-value communications provided medical writing, editing, and AUTHOR CORRESPONDENCE publication assistance and was funded by LEO Pharma. LEO Pharma was responsible for the design and conduct of the study Leon H. Kircik MD and provided all administrative, technical, and material support E-mail:...... ……...... [email protected] for the trial. REFERENCES 1. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol. 2014;70(3):512-516. 2. Parisi R, Symmons DP, Griffiths CE, et al. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133(2):377-385. 3. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58(5):826-850. 4. Moller AH, Erntoft S, Vinding GR, et al. A systematic literature review to compare quality of life in psoriasis with other chronic diseases using EQ-5D- derived utility values. Patient Relat Outcome Meas. 2015;6:167-177. 5. Griffiths CEM, Jo SJ, Naldi L, et al. A multidimensional assessmentDo ofNot the Copy burden of psoriasis: results from a multinational dermatologist and patient survey. Br J Dermatol. 2018;179(1):173-181. 6. Chalmers RJG. Assessing psoriasis severity and outcomes Penaltiesfor clinical trials Apply and routine clinical practice. Dermatol Clin. 2015;33(1):57-71. 7. Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis. 2005;64 (suppl 2):ii65-ii73. 8. Mrowietz U, Kragballe K, Reich K, et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. Arch Dermatol Res. 2011;303(1):1-10. 9. Davis SA, Feldman SR. Combination therapy for psoriasis in the United States. J Drugs Dermatol. 2013;12(5):546-550. 10. Iversen L, Lange MM, Bissonette R, et al. Topical treatment of psoriasis: questionnaire results on topical therapy accessibility and influence of body surface area on usage. J Eur Acad Dermatol Venereol. 2017;31(7):1188-1195. 11. American Academy of Dermatology Work G, Menter A, Korman NJ, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol. 2011;65(1):137-174. 12. Lebwohl M, Tyring S, Bukhalo M, et al. Fixed combination aerosol foam calcipotriene 0.005% (Cal) plus betamethasone dipropionate 0.064% (BD) is more efficacious than Cal or BD aerosol foam alone for psoriasis vulgaris: a randomized, double-blind, multicenter, three-arm, Phase 2 study. J Clin Aesthet Dermatol. 2016;9(2):34-41. 13. Stein Gold L, Lebwohl M, Menter A, et al. Aerosol foam formulation of fixed combination calcipotriene plus betamethasone dipropionate is highly efficacious in patients with psoriasis vulgaris: pooled data from three randomized controlled studies. J Drugs Dermatol. 2016;15(8):951-957. 14. Menter A, Gold LS, Koo J, et al. Fixed-combination calcipotriene plus betamethasone dipropionate aerosol foam is well tolerated in patients with psoriasis vulgaris: pooled data from three randomized controlled studies. Skinmed. 2017;15(2):119-124. 15. Paul C, Stein Gold L, Cambazard F, et al. Calcipotriol plus betamethasone dipropionate aerosol foam provides superior efficacy vs gel in patients with psoriasis vulgaris: randomized, controlled PSO-ABLE study. J Eur Acad Der- matol Venereol. 2017;31(1):119-126. 16. Koo J, Tyring S, Werschler WP, et al. Superior efficacy of calcipotriene and Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

126 Journal of Drugs in Dermatology K.A. Veverka, D.S. Patel, T. Anger, et al February 2020 • Volume 19 • Issue 2

SUPPLEMENTALSupplemental Figure FIGURE 1. 1.Proportion Proportion of of patients patients achieving achieving improvements improvements (overall (overall lesion lesion score score of of 0 0or or 1) 1) in in redness,redness, scaliness, scaliness, and and thickness of thethickness target lesionof the targetat week lesion 4 by atlocation. week 4 by location.

SUPPLEMENTAL TABLE 1. Severity Score for Redness, Thickness, and Scaliness

Severity Score

0=none (no erythema) 1=mild (faint erythema, pink to very light red) Redness 2=moderate (definite light red erythema) 3=severe (dark red erythema) 4=very severe (very dark red erythema) 0=none (no scaling) 1=mild (sparse, fine-scale lesions, only partially covered) Scaliness 2=moderate (coarser scales, most of lesions covered) 3=severe (entire lesion covered with coarse scales) 4=very severe (very thick coarse scales, possibly fissured)Do Not Copy 0=none (no plaque elevation) 1=mild (slight, barely perceptible elevation) Penalties Apply Thickness 2=moderate (definite elevation but not thick) 3=severe (definite elevation, thick plaque with sharp edge) 4=very severe (very thick plaque with sharp edge) Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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Intralesional Triamcinolone Acetonide in the Treatment of Traction Alopecia Laura N. Uwakwe MD,ª Brianna De Souza MD,B Andrea Tovar-Garza MD,c Amy J. McMichael MDb aDepartment of Dermatology, Columbia University Irving Medical Center, New York, NY bDepartment of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC cDepartment of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX

ABSTRACT

Traction alopecia (TA) is a form of hair loss caused by continuous and prolonged tension to the hair, most commonly seen in Black/Af- rican American women and children who wear hairstyles that pull excessively at the frontotemporal hairline. Dermatologists have recommended the use of intralesional triamcinolone acetonide injections (ILK) to decrease the inflammatory process, however, evidence- based proof is lacking in the literature. In this case series, we evaluate the effectiveness and safety of ILK in the TA management of 6 African American women. A retrospective chart review was done of patients with a diagnosis of TA, who were treated with ILK at an academic dermatology clinic, yielding 6 patients. Management of TA was assessed by comparing the photographs for changes in hair density along the frontotemporal hairline. ILK with a concentration of 5 mg/mL, was administered in areas of low hair density along the frontotemporal hairline at 6 to 8-week intervals, for 3 successive visits. All subjects demonstrated visible increase in hair density along the frontotemporal hairline following their first or second treatment, and no severe adverse effects were observed or reported. The use of ILK is currently an effective and safe method of treating TA, particularly in the early to mid-stages. Common adverse effects are pain, and subsequent transient atrophy at the injection site. The transient atrophy is not an indication to stop treatment. Avoidance of treating dented areas is sufficient to allow it to revert. Patient education is pivotal in the prevention and management of TA. It is imperative that dermatologists caution against grooming practices that exert tension on the hairline.

J Drugs Dermatol. 2020;19(2)128-130. doi:10.36849/JDD.2020.4635 Do Not Copy BACKGROUND Penalties Apply raction alopecia (TA) is a form of hair loss secondary on histology.6,7 The histological findings can also vary depend- to repetitive and/or prolonged tension to a hair follicle ing on the stage of the disease. Early findings on histology over an extended period of time. This typically results include trichomalacia, normal number of terminal hairs, pre- T 1,2 from wearing tight hairstyles, or an acute traumatic event. As served sebaceous glands, and increased number of telogen the etiology is mechanical trauma of the hair follicle, it can oc- and catagen hairs.8 Late disease findings include a decreased cur in any ethnic/racial demographic or gender. It has been ob- number of terminal hair follicles which have been replaced by served in ballerinas, as well as Sikh Indian males, all of whom fibrous tracts, vellus hairs, and retained sebaceous glands.8 wear hairstyles that exert tension on the frontotemporal hairline. However, most cases of TA occur in women of African de- Recommended treatment for TA includes the use of minoxidil scent.1,3 and intralesional steroid injections. However, evidence-based proof of the efficacy of ILK in the improvement of TA has not The diagnosis of TA can be made clinically, as well as through been reported in the literature. In this case series, we evaluate the histological examination of a scalp biopsy. The earliest the efficacy and safety of intralesional triamcinolone acetonide signs of TA are perifollicular erythema and pruritus with or injections (ILK) when used with topical minoxidil in the man- without surrounding papules and pustules.4 The fringe sign of agement of TA in 6 African American women. TA is a clinical finding characterized by the presence of retained hair along the frontal and/or temporal hairline, and it has been METHODS shown to have high sensitivity for detecting early and late dis- A retrospective chart review was performed in patients carry- ease of TA.5 On dermoscopy, one may observe reduced hair ing a diagnosis of TA, who were seen at an active hair disorder density with an absence of follicular openings in late stages, clinic between January 2016 and December 2017. All patients and in earlier stages an absence of hairs with preserved fol- who were treated with ILK, and whose treatment progress were licular openings outlined in brown, particularly at the periphery recorded with photographs were included. Those who used of the patch of affected scalp, corresponding to the pigmented minoxidil as an adjunct treatment were also noted. The man- basal cell layer of the follicular infundibulum that can be seen agement of TA was assessed by comparing the changes in hair Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

129 Journal of Drugs in Dermatology L.N. Uwakwe, B. De Souza, A. Tovar-Garza, A.J. McMichael February 2020 • Volume 19 • Issue 2

TABLE 1. Summary of Treatment Results in Study Subjects. Results of our cohort of African American females with traction alopecia (TA) following treatment with intralesional triamcinolone acetonide. Study Demographics and History Post Treatment with Steroid Injections Subject History of Traction Increase in Hair Age Total # of Injections Minoxidil Used? Other Treatments Side Effects Styles? Growth? 1 61 Yes 3 Yes Yes None 2 32 Yes 1 Yes doxycycline Yes Itch 3 24 Yes 4 Yes Yes None 4 50 Yes 3 Yes Yes None 5 35 Yes 3 Yes Yes None

6 58 Yes 3 No Yes None

density along the frontotemporal hairline. All patients had been None of the subjects reported any serious adverse effects from instructed to avoid tension-related hair care practices. the injections. The subject that received only one ILK treatment and continued dual therapy on minoxidil and doxycycline re- RESULTS ported itch initially, which was improved with the use of a topical Of the TA patients seen, 6 met the criteria for our observational steroid. study. All 6 were African American females presenting for evaluation of frontotemporal hair loss, with ages ranging from 32 DISCUSSION to 61 years. All subjects reported a history of hairstyling that This study shows that ILK, when used in conjunction with topical exerted tension to the frontotemporal hairline at some point in minoxidil, is effective in halting TA progression, and in improv- their lives, whether it was recent, during childhood, or both. The ing frontotemporal hair density in patients with TA. Our patients clinical diagnosis of TA was established through the presence of reported no adverse systemic effects from the injections that are the fringe sign. Five subjects had 3 to 4 ILK injectionsDo done Not at 6 Copycommonly associated with corticosteroids, and only one patient to 8-week intervals, performed at a concentrationPenalties of 5 mg/mL, Applyreported itch in the frontotemporal hairline, a symptom which is while one subject (Subject #2) received only one treatment with more likely a side effect of the topical minoxidil or a manifesta- ILK (Table 1) also at a concentration of 5 mg/mL. Injections were tion of the TA pathology itself. done both at the border of the hair loss in the frontotemporal hairline and extending backwards to include the normal density Only one study describing the treatment of TA is available in the hair. Subjects concurrently used topical minoxidil 5% daily, and literature, and it only reports on outcomes with topical minoxidil one subject (Subject #2) also took oral doxycycline. All subjects use.9 Intralesional steroids have been used in the treatment of reported the cessation of all hair care practices that exert ten- many dermatologic conditions, including scarring and nonscar- sion to the frontotemporal hairline, including tight ponytails, ring forms of alopecia. Its effectiveness is believed to be due its tight hair braiding/weaving, twisting of locks, use of scarves to anti-inflammatory effects. Intralesional triamcinolone acetonide tie hair down, and the use of hair gel on the frontotemporal hair- is particularly favored as the glucocorticoid agent of treatment line. All subjects demonstrated a visible increase in hair density in TA and several other dermatologic conditions because of along the frontotemporal hairline following their third treatment its prolonged duration of action (which is longer than that of (Figure 1). other triamcinolone salts).10 Furthermore, steroids administered intralesionally have the unique benefit of inserting a high con- FIGURE 1. Photographs of study subject at baseline, following the first centration of medication to the affected area, more than would treatment with triamcinolone acetonide, and following the second be possible from topical or oral steroids, while avoiding adverse treatment, respectively. systemic side effects. Side effects of intralesional corticosteroid injection include pain (due to the volume of fluid injected into the lesion, as well as the location of the injection—frontotemporal scalp tends to be the most sensitive area of the scalp), atrophy, and pigmentary changes at the site of injection.10

It is believed that subclinical inflammation may be a key component to the pathophysiology of the early stages of TA, which would explain the effectiveness of ILK in the treatment of TA. Some believe that the histological findings in cases of TA in the Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

130 Journal of Drugs in Dermatology L.N. Uwakwe, B. De Souza, A. Tovar-Garza, A.J. McMichael February 2020 • Volume 19 • Issue 2

7. Billero V, Miteva M. Traction alopecia: the root of the problem. Clin Cosmet literature may be skewed towards late stage disease, a stage Investig Dermatol. 2018;11:149-159. doi:10.2147/CCID.S137296. where signs of inflammation are not usually histologically ap- 8. Mirmirani P, Khumalo NP. Traction alopecia: how to translate study data for 11 public education--closing the KAP gap? Dermatol Clin. 2014;32(2):153-161. parent. However, in a study by Whiting, 24 patients with TA 9. Khumalo NP, Ngwanya RM. Traction alopecia: 2% topical minoxidil shows were identified, and histological findings included significant promise. Report of two cases. J Eur Acad Dermatol Venereol. 2007;21(3):433- 434. lympho-histiocytic inflammation around 14% of the lower and 10. Firooz A, Tehranchi-Nia Z, Ahmed AR. Benefits and risks of intralesional cor- 38% of the mid and upper hair follicles in this cohort.12 Sig- ticosteroid injection in the treatment of dermatological diseases. Clin Exp nificant scarring was also present around 50% of the lower and Dermatol. 1995;20(5):363-370. 11. Goldberg LJ. Cicatricial marginal alopecia: is it all traction? Br J Dermatol. 12 around 86% of the mid and upper follicles in this group. In our 2009;160(1):62-68. study, clinical signs of inflammation, such as pustules, erythe- 12. Whiting DA. Cicatricial alopecia: clinico-pathological findings and treatment. Clin Dermatol. 2001;19(2):211-225. ma, and flaking were not appreciated, however treatment with anti-inflammatory agents proved to be quite effective. Despite AUTHOR CORRESPONDENCE the scarring that can be seen, this study suggests that existing hair follicles can be recruited to grow terminal hairs with treat- Laura N. Uwakwe MD ment, at least in the early to mid-stage cases. E-mail:...... ……...... [email protected]

We recommend treatment with ILK at a concentration of 5mg/ mL, to minimize risk of atrophy. Injections can be performed at intervals of 6 to 8 weeks, and a total of 3 treatments should be sufficient to determine if response will occur. Additionally, daily use of topical minoxidil 5%, and avoidance of traction at the hairline will likely maximize positive outcomes, as the minoxidil presumably prolongs the anagen phase of the growing hairs. As minoxidil can cause mild hypertrichosis, scalp irritation, or mild shedding early in treatment, these possible side effects should be discussed with patients before prescribing this medication. Finally, we recommend that all patients with TA for whom treatment is started have baseline and follow-upDo photo Not- Copy graphs taken. Photographic record of progress can be helpful to both clinicians and patients to fully appreciate the effectivenessPenalties Apply of treatment. DISCLOSURES The author, Amy J. McMichael, is a consultant for the following companies: Allergan, eResearch Technology, Inc., Galderma, Guthey Renker, Johnson & Johnson, Keranetics, Merck & Co., Inc., Merz Pharmaceuticals, Proctor & Gamble, Samumed, and Incyte. Amy J. McMichael receives grants from Allergan and Proctor & Gamble and has conducted research for Samumed. Amy J. McMichael receives royalties from UpToDate. The authors Laura Uwakwe, Andrea Tovar-Garza, and Brianna De Souza have no conflicts to disclose. REFERENCES 1. Khumalo NP, Jessop S, Gumedze F, Ehrlich R. Determinants of marginal traction alopecia in African girls and women. J Am Acad Dermatol. 2008;59(3):432-8. 2. Whiting DA. Traumatic alopecia. Int J Dermatol. 1999;38 Suppl 1:34-44. 3. Billero V, Miteva M. Traction alopecia: the root of the problem. Clin Cosmet Investig Dermatol. 2018;11:149-159. 4. Callender VD, McMichael AJ, Cohen GF. Medical and surgical therapies for alopecias in black women. Dermatol Ther. 2004;17(2):164-76. 5. Samrao A, Price VH, Zedek D, Mirmirani P. The “Fringe Sign”-A useful clinical finding in traction alopecia of the marginal hair line.Dermatol Online J. 2011;17(11):1. 6. Tosti A, Miteva M, Torres F, Vincenzi C, Romanelli P. Hair casts are a dermoscopic clue for the diagnosis of traction alopecia. Br J Dermatol. 2010;163(6):1353-5. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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doi:10.36849/JDD.2020.4774 February 2020 132 Volume 19 • Issue 2 Copyright © 2020 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Real-World Clinical Experience With the IL-17 Receptor A Antagonist Brodalumab Miriam S. Bettencourt MD Bettencourt Skin Center/Advanced Dermatology & Cosmetic Surgery, Henderson, NV; University of Nevada, Las Vegas, NV

ABSTRACT

Psoriasis is a chronic, inflammatory, remitting/relapsing autoimmune dermatologic condition that manifests with scaly, erythematous plaques. It has a significantly negative effect on patient quality of life, as well as increasing their risk of numerous comorbid diseases. Patients are typically treated initially with topical steroids, retinoids, and vitamin D derivatives followed by phototherapy and systemic treatments, including oral, subcutaneous or intravenous immunomodulatory drugs, if needed.

Psoriasis is driven by T-cell activation and associated with the secretion of proinflammatory cytokines and a dysregulated interleukin- 23/T helper 17 (Th-17) inflammatory response. Eleven biologic therapies and 6 biosimilars that target the 3 main immunological pathways—tumor necrosis factor-α (TNF-α), interleukin 23 (IL-23), and IL-17, are approved for the treatment of plaque psoriasis. While most demonstrate similar effectiveness in clinical trials, patient response in real-world settings is varied. Thus, it is important that the clinician understand the mechanism of action of these drugs as well as their safety profile, unique benefits, and limitations. They must also consider the patient’s disease presentation, severity, and comorbid conditions when determining the most appropriate therapy.

This article focuses on the IL-17 inhibitors, secukinumab, ixekizumab, and brodalumab, highlighting their unique mechanisms of action and their efficacy and safety in a real-world clinical setting.

J Drugs Dermatol. 2020;19(2)132-136. doi:10.36849/JDD.2020.4774 Do Not Copy INTRODUCTION Penalties Apply soriasis is a chronic, inflammatory, remitting/relapsing Studies conducted in mice demonstrate that removing either autoimmune dermatological condition characterized IL-23 or IL-17 decreases the progression of psoriasis.5,6 Mice Pby scaly, erythematous plaques. Patients with psoriasis injected with monoclonal antibodies targeting IL-17 blocked, experience a significantly reduced quality of life due to or neutralized, downstream signaling of this cytokine and discomfort from the physical symptoms as well as disability decreased epidermal hyperplasia.5 and disfigurement. They also have a higher risk of comorbid conditions, including psoriatic arthritis (PsA), cardiovascular Similarly, genetically modifying mice to not express IL- disease, inflammatory bowel disease, metabolic syndrome, 23 or IL-17 receptors significantly reduced psoriatic lesion chronic kidney disease, mood disorders, including depression, development upon stimulation with the lesion-causing tumor and malignancy.1 promoter 12-O-tetradecanoylphorbol-13-acetate.7 This greater understanding of the immune-mediated pathology of the While the etiology of psoriasis is unknown, there have disease has led to the development of monoclonal antibodies been many recent advances in the understanding of its and fusion proteins that block specific cytokines or cytokine pathogenesis. We now know that psoriasis is a T-cell mediated receptors involved in psoriatic inflammation. disease involving a dysregulated inflammatory response of the interleukin (IL) 23/T-helper (Th)-17 pathway. In this process, IL- Currently available biologics are the TNF-α inhibitors infliximab, 23 is overproduced by dendritic cells and keratinocytes, which adalimumab, certolizumab, and etanercept; the IL-12/13 stimulates Th17 cells within the dermis to produce and release inhibitor ustekinumab; the IL-17 inhibitors secukinumab and additional inflammatory cytokines. This, in turn, activates ixekizumab; the IL-17 receptor blocker brodalumab; and the an inflammatory cascade of downstream effector molecules IL-23 inhibitors guselkumab, tildrakizumab, and risankizumab- including IL-17A, IL-17F, IL-22, IL-21, and tumor necrosis rzaa.1 Biosimilars to infliximab, adalimumab, and etanercept factor-α (TNF-α), which is responsible for the keratinocyte are also available. hyperproliferation that results in the characteristic scaly plaques.2-4 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

133 Journal of Drugs in Dermatology M.S. Bettencourt February 2020 • Volume 19 • Issue 2

TABLE 1. IL-17 Inhibitor Dosing, Mechanism of Action, Adverse Events2

IL-17 Inhibitor Dosage Mechanism of Action Common Side Effects 300 mg at week 0, 1, 2, 3, 4; Selectively binds to and inhibits IL-17A, Nasopharyngitis, diarrhea, upper Secukinumab then 300 mg every 4 weeks preventing binding to the IL-17 receptor. respiratory tract infections 160 mg at week 0, then 80 Nasopharyngitis, upper respiratory tract mg every 2 weeks until Selectively binds to IL-17A, preventing Ixekizumab infections (URI), injection site reactions, week 12; then 80 mg week binding to the IL-17 receptor. headaches, and arthralgias every 4 weeks. Specifically binds to the anti-IL-17 receptor. Thus, it blocks the binding of subunits IL-17A, Nasopharyngitis, upper respiratory 210 mg at week 0, 1, 2, IL-17F, IL-17C, IL-17A/F and IL-25 to the receptor, tract infections, headaches, and arthralgias; Brodalumab then 210 mg every 2 weeks significantly inhibiting the pro-inflammatory mild, self-resolving neutropenia during signaling cascade that leads to psoriasis. induction phase.

Source: Silfvast-Kaiser A, Paek SY, Menter A. Anti-IL17 therapies for psoriasis. Expert Opin Biol Ther. 2018.

In clinical trials of these biologics, between 49% and 91% of to consider the high rate of suicidal ideation in patients with patients achieved 90% reduction on the Psoriasis Area and psoriasis, particularly those with severe disease.14 Severity Index (PASI) score from baseline, with most trials demonstrating a nearly 70% or higher improvement.8 A recent analysis of the brodalumab phase 2 and phase 3 clinical trials and their long-term extensions found no IL-17 Inhibitors causal relationship between brodalumab treatment and SIB. Brodalumab is the only IL-17 receptor blocker given that The analysis found a comparable rate of SIB between the secukinumab and ixekizumab inhibit only IL-17 A. The 3 are brodalumab and ustekinumab groups throughout the 52- indicated for the treatment of moderate-to-severe plaque week controlled phases (0.20 vs 0.60 per 100 patient-years). psoriasis in adult patients.9-11 Table 1 highlights their mechanismDo Not InCopy addition, the authors noted that there is no correlation of action, dosing, and observed adverse events. between IL-17 inhibition and SIB.15 Nonetheless, the labeling for Penaltiesbrodalumab Apply carries a warning regarding the risk of suicide and The 3 biologics all demonstrate direct action against the SIB, and the US Food and Drug Administration requires a Risk 1L-17A pathway. However, while ixekizumab and secukinumab Evaluation and Mitigation Strategy (REMS) for SIB.9 selectively bind to and inhibit IL-17A, preventing binding to the IL-17 receptor, brodalumab specifically binds to the anti-IL-17 Rapid Onset of Action receptor, blocking the binding of subunits IL-17A, IL-17F, IL-17C, These biologics are particularly notable for their early onset of IL-17A/F, and IL-25.9-11 This is important given evidence that IL- action, which is important given the significant quality of life 17F and IL-17C demonstrate greater elevation in psoriasis than impact of a psoriatic flare.16 In the phase 3 randomized, double- IL-17A.12 blind, FIXTURE trial comparing secukinumab to placebo or etanercept, the median time to a 50% reduction in the baseline The most common adverse effects in clinical trials of these 3 PASI score with the approved 300 mg dose was 3 weeks with drugs included mild-to-moderate nasopharyngitis, headache, secukinumab versus 3.9 weeks with etanercept (P<0.001). A upper respiratory tract infections, and arthralgia.9-11 Cases significantly higher percentage of patients also reached a PASI of transient, self-resolving neutropenia without associated 90 at 12 weeks compared to those on etanercept (54.1% vs infection were also reported in the clinical trials of brodalumab.9 20.7%, P<0.001).17 Depression and suicidal ideation and behavior (SIB) were reported during the phase 3 clinical studies for brodalumab, Ixekizumab was investigated in the phase 3 UNCOVER-1, with 3 completed suicides in brodalumab-treated patients. -2, and -3 randomized, double-blind, trials against placebo, The majority occurred during the long-term, open-label phase and etanercept. In the UNCOVER-2 and 3, which compared of the studies.13 It is important to note, however, that clinical ixekizumab to placebo and etanercept, ixekizumab trials for ixekizumab or secukinumab excluded patients with demonstrated significantly greater efficacy against etanercept, a history of psychiatric events or prior suicide attempts, while with 89.7% in the UNCOVER-2 trial reaching PASI 75 at 12 the brodalumab trials did not. In addition, brodalumab trial weeks, 70.7% PASI 90, and 40.5% PASI 100 compared to 41.6%, participants were predominantly middle-aged white males, 18.7%, and 5.3%, respectively, in the etanercept cohort. Similar who carry the greatest risk for suicide.13 It is also important results were observed in the UNCOVER-3 trial. Significant Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

134 Journal of Drugs in Dermatology M.S. Bettencourt February 2020 • Volume 19 • Issue 2

improvement was seen as early as week 1 in the UNCOVER-2 or tolerability. However, there is no guidance as to sequencing and -3 trials, with a 50% PASI 75 response by week 4, and a 50% of therapies. Instead, the guidelines note that “not all switches PASI 90 response by week 8.18 may result in improvement and that, at this time, there are insufficient data to make more specific recommendations.”22 Two phase 3 studies (AMAGINE-2 and AMAGINE-3) of This requires that clinicians personalize treatment for patients brodalumab found that that at week 12, 44% of brodalumab based on the patients’ individual symptoms and history.22 patients on the 300 mg dosage versus 22% of ustekinumab patients in AMAGINE-2, and 37% vs 19% in AMAGINE-3, The median treatment duration for patients on biologics is obtained PASI 100 scores (P<0.001). The median time to less than a year, with loss of efficacy the most common reason a response in both studies was significantly shorter with for failure.23 At that point, most clinicians either increase the brodalumab than with ustekinumab (P<0.001), with at least a dosage or switch to another biologic. The evidence regarding 50% improvement in PASI scores realized at less than 2 weeks, the efficacy of switching patients from a previous biologic to and a 75% improvement at 4 weeks.19 an IL-17, whether they were responders or non-responders, is emerging. Sub-analyses of phase 3 trials of the IL-17 inhibitors A recent systematic review of 27 studies examining the time to demonstrate significant response in patients switched from onset of action for IL-17 and IL-23 inhibitors found brodalumab a previous biologic to an IL-17. A sub-analysis of four phase 3 210 mg every 2 weeks produced the shortest time to 25% trials of secukinumab found that at week 12, 55.2% of previous and 50% of patients achieving PASI90 (3.5 and 6.2 weeks, biologic users and 42% of previous non-responders achieved respectively). That compared to 4.1 and 7.4 weeks, respectively, PASI 90 at the 300 mg dose.24 for ixekizumab 160mg every 2 weeks, and 4.6 and 8.1 weeks, respectively, for ixekizumab 160 mg every 4 weeks.20 Sub-analyses of the 2 phase 3 clinical trials for ixekizumab found that at week 12, 91.5% of the biologic-experienced and Meanwhile, a review of available data on adalimumab, 87.7% of the biologic-naïve patients treated with the 80 mg infliximab, ustekinumab, etanercept, brodalumab, ixekizumab, every two weeks achieved a PASI 90.25 and secukinumab found that brodalumab had the quickest time to a clinically meaningful response (defined as time for Papp et al recently published a study examining the efficacy 25% of patients to achieve a PASI 75 or a 50% reductionDo Not in ofCopy switching from ustekinumab to brodalumab based on mean baseline PASI), with a calculated time of 2.1 weeks. That AMAGINE-2 and AMAGINE-3. At week 12, 40.9% and 39.5% of was followed by 2.4 weeks for ixekizumab, and 3.0Penalties weeks for biologic-naive Apply and -experienced patients achieved PASI 100 secukinumab.16 on brodalumab 300 mg compared with 21.1% and 17.0% on ustekinumab (both P<0.001). In patients in whom prior biologics We speculate that the observed efficacy and speed of onset for had been successful or failed, 41.7% and 32.0% on brodalumab brodalumab may be related to its unique mechanism of action, achieved PASI 100, compared with 21.1% and 11.3% with which prevents the cycle of inflammation and proliferation that ustekinumab. There were no differences in tolerability.26 leads to the classic cutaneous features of psoriasis resulting in almost compete resolution of the genomic, histological, and While there is good evidence of the benefits of switching clinical features of the disease. betweenTNF α-inhibitors given the length of time they have been on the market, and between TNFα-inhibitors and several other Switching Biologics biologics, there is far less evidence as to the outcomes when The National Psoriasis Foundation recommends a “treat-to- switching between IL-17 inhibitors.27 A 12-week, multicenter, target” approach for the disease, with a preferred “acceptable” retrospective study of switching 31 patients who failed on response at 3 months after treatment initiation either body secukinumab to ixekizumab found that 22 (71%) achieved PASI surface area (BSA) 3% or less or BSA improvement 75% or 75 or sPGA of 0/1 after 12 weeks of ixekizumab.28 more from baseline; and the target response at 3 months after treatment initiation and during 6 months maintenance Just one study to date has examined the efficacy of switching evaluation of BSA 1% or less.21 from ixekizumab or secukinumab to brodalumab. This was an open-label trial of 40 patients (34 of whom completed the study) Treatment guidelines from the American Academy of with moderate-to-severe psoriasis, all of whom had previously Dermatology and the National Psoriasis Foundation also failed secukinumab or ixekizumab for at least 3 months. emphasize the importance of patient quality-of-life and patient Patients were switched to brodalumab 210 mg at weeks 0, 1, preferences in treatment decisions.22 The guidelines note that and 2, followed by 210mg every 2 weeks to week 16. At week 16, all therapies for psoriasis, including biologics, may be switched 76% of patients achieved a PASI-75; 50% a PASI-90; and 32% a with a biologic with the goal of improved efficacy, safety, and/ PASI 100. In addition, 71% achieved an sPGA of 0 or 1.29 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

135 Journal of Drugs in Dermatology M.S. Bettencourt February 2020 • Volume 19 • Issue 2

Clinical Experience with Brodalumab 8% demonstrated evidence of immunogenicity. Those with Although clinical trial data is essential to establishing the the highest levels (1.7%) had reduced responses compared to efficacy and safety of a new compound, the strict requirements negative patients.33 for trial participation rarely mirror the patients that clinicians treat on a daily basis. Thus, it is important to establish that the The patients highlighted here, as well as dozens more we have results observed in clinical trials also apply to the real-world treated during the past 2 years, have remained in complete setting. remission with maintenance therapy with brodalumab with no adverse physical or psychological effects. Since its approval in 2017, we have treated numerous patients with moderate-to-severe psoriatic disease resistant to topical DISCUSSION and other systemic treatments, including other biologics, with The elucidation of the underlying molecular pathways associated brodalumab. They include patients who were naïve to biologic with plaque psoriasis and the subsequent development of therapy; failed on biologic therapy (defined as a decrease targeted biologics, has completely changed the management in PASI score of less than 50% that necessitates a change in of the disease and improved the quality of life for millions of treatment regimen);30 or failed on another IL-17. We have been patients. However, there remain high failure rates with these struck with the rapidity with which patient symptoms resolved, drugs, necessitating switching patients to new therapies. and with the effect on self-reported quality of life. We have seen excellent response in our practice when switching One patient had a history of psoriasis and psoriatic arthritis non-responders to systemic therapies, including biologics, (PsA) for 33 years that was resistant to topical and systemic to the IL-receptor blocker brodalumab. Studies find it has the therapies, including etanercept, adalimumab, and apremilast. fastest onset of action of all IL-17 inhibitors and even other She presented with a severe flare affecting 10% of her biologics, which we attribute to its unique mechanism of action. body surface area (BSA). Within 1 month of treatment with brodalumab, BSA involvement dropped to 1% and she reported Within 1-month of starting our patients on brodalumab, we significant improvement in joint pain. observed a complete or near complete remission, which has been maintained for 6 months or more One patient with severe plantar psoriasis that Doaffected Not Copy her mobility, as well as significant erythema and pruritis, DISCLOSURES demonstrated complete resolution of all symptomsPenalties after 2 Dr Apply Bettencourt has received Consultancy fees from Ortho doses of brodalumab. Another patient with a 15-year history of Dermatologics. psoriasis presented with a BSA of 40% with severe erythema, scaling, and generalized pruritis. Her disease was having ACKNOWLEDGMENTS a significant effect on her mood and quality of life and she The author would like to thank Judi Miller, SRxA, McLean, had recently started on antidepressants. At 1 month after her VA for assistance with literature research, manuscript editing first injection of brodalumab, she had 100% skin clearance. and submission. Ms. Miller’s work was supported by Ortho During her most recent visit with us, she reported significant Dermatologics. improvement in her quality of life, joint pain, sleep, and had discontinued her antidepressants. We have also treated several REFERENCES patients who failed on an IL-17 inhibitor yet who achieved 1. von Csiky-Sessoms S, Lebwohl M. What's new in psoriasis. Dermatol Clin. 2019;37(2):129-136. complete remission on brodalumab with no evidence of 2. Silfvast-Kaiser A, Paek SY, Menter A. Anti-IL17 therapies for psoriasis. Expert immunogenicity. Opin Biol Ther. 2018. 3. Cai Y, Fleming C, Yan J. New insights of T cells in the pathogenesis of psoriasis. Cell Mol Immunol. 2012;9(4):302-309. The issue of immunogenicity is an important one when 4. Fitch E, Harper E, Skorcheva I, et al. Pathophysiology of psoriasis: recent considering biologics for any immune-mediated disease advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep. 2007;9(6):461- 467. given its contribution to primary or secondary failure, or 5. Nakajima K, Kanda T, Takaishi M, et al. Distinct roles of IL-23 and IL-17 in inadequate response.31 Phase 3 clinical trials for secukinumab, the development of psoriasis-like lesions in a mouse model. J Immunol. 2011;186(7):4481-4489. brodalumab, and ixekizumab demonstrated very low rates 6. Krueger JG, Fretzin S, Suarez-Farinas M, et al. IL-17A is essential for cell of immunogenicity. In the FIXTURE and ERASURE trials activation and inflammatory gene circuits in subjects with psoriasis. for secukinumab, 0.4% and 0.3%, respectively, of patients J Allergy Clin Immunol. 2012;130(1):145-154 e149. 7. Martin DA, Towne JE, Kricorian G, et al. The emerging role of IL-17 in the demonstrated anti-secukinumab antibodies at week 60, with pathogenesis of psoriasis: preclinical and clinical findings.J Invest Dermatol. no significant loss of efficacy.17 Anti-brodalumab antibodies 2013;133(1):17-26. 8. Kim WB, Jerome D, Yeung J. Diagnosis and management of psoriasis. were detected in 1.8% and 2.3% of participants at week 52 in Canadian family physician Medecin de famille canadien. 2017;63(4):278-285. its clinical trials, but were also not associated with any lack of 9. SILIQ [prescribing information]. Valeant Pharmaceuticals North America: Bridgewater, NJ;2017. efficacy.32 Among patients receiving ixekizumab every 2 weeks, Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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10. TANTZ [prescribing information]. Eli Lilly:Indianapolis, Ind.;2016. 11. COSENTYX [prescribing information]. Novartis:East Hanover, NJ; 2019. In. 12. Armstrong AW, Read C, Leonardi CL, et al. IL-23 versus IL-17 in the pathogenesis of psoriasis: there is more to the story than IL-17A. J Drugs Dermatol. 2019;18(supp 2):s202-s208. 13. Hashim PW, Chen T, Lebwohl MG, et al. What lies beneath the face value of a box warning: a deeper look at brodalumab. J Drugs Dermatol. 2018;17(8):s29-s34. 14. Singh S, Taylor C, Kornmehl H, et al. Psoriasis and suicidality: A systematic review and meta-analysis. J Am Acad Dermatol. 2017;77(3):425-440 e422. 15. Lebwohl MG, Papp KA, Marangell LB, et al. Psychiatric adverse events during treatment with brodalumab: Analysis of psoriasis clinical trials. J Am Acad Dermatol. 2018;78(1):81-89.e85. 16. Papp KA, Lebwohl MG. Onset of action of biologics in patients with moderate-to-severe psoriasis. J Drugs Dermatol. 2017;17(3):247-250. 1 7. Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis — results of two phase 3 trials. N Eng J Med. 2014;371(4):326-338. 18. Griffiths CE, Reich K, Lebwohl M, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386(9993):541-551. Dermpath Slide Study 19. Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Eng J Med. 2015;373(14):1318-1328. Test your Dermpath knowledge! 20. Egeberg A, Andersen YM, Halling-Overgaard A. Systematic review on rapidity of onset of action for interleukin-17 and interleukin-23 inhibitors for Flip through the Slide Study psoriasis. J Eur Acad Dermatol Venereol. 2019;doi:10.1111/jdv.15920. 2 1. Armstrong AW, Siegel MP, Bagel J, et al. From the Medical Board of the made up of 100 random slides National Psoriasis Foundation: treatment targets for plaque psoriasis. J Am Acad Dermatol. 2017;76(2):290-298. and read through 22. Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad each diagnoses Dermatol. 2019;80(4):1029-1072. 23. Levin AA, Gottlieb AB, Au SC. A comparison of psoriasis drug failure rates and reasons for discontinuation in biologics vs conventional systemic therapies. J Drugs Dermatol. 2014;13(7):848-853. 24. Griffiths CE, Papp K, Zaldivar ER, et al. Secukinumab shows efficacy in subjects regardless of previous exposure to biologic therapy: A pooled subanalysis from four phase 3 clinical trials in psoriasis. J Am Acad Dermatol. 2015;72(5)Suppl 1:AB251. Do Not Copy 25. Gottlieb AB, Lacour JP, Korman N, et al. Treatment outcomes with ixekizumab in patients with moderate-to-severe psoriasis who have or have not received prior biological therapies: an integrated analysis of two PhasePenalties III randomized ApplyVisit dermatologyinreview.com/dermpath/ studies. J Eur Acad Dermatol Venereol. 2017;31(4):679-685. 26. Papp KA, Gordon KB, Langley RG, et al. Impact of previous biologic use on the efficacy and safety of brodalumab and ustekinumab in patients with moderate-to-severe plaque psoriasis: integrated analysis of the randomized controlled trials AMAGINE-2 and AMAGINE-3. Br J Dermatol. Dermatopathology resources of Derm In-Review 2018;179(2):320-328. brought to you by our educational partner 2 7. Qiang JK, Shahbaz A, Kim W, et al. Effectiveness of sequential use of biologics in the treatment of moderate to severe psoriasis in real world Canadian academic clinical practice: A cohort study. J Am Acad Dermatol. 2016;74(1):176-177. 28. Georgakopoulos JR, Phung M, Ighani A, et al. Biologic switching between interleukin 17A antagonists secukinumab and ixekizumab: a 12- week, multicenter, retrospective study. J Eur Acad Dermatol Venereol. 2019;33(1):e7-e8. 29. Kimmel G, Chima M, Kim HJ, et al. Brodalumab in the treatment of moderate- to-severe psoriasis in patients who have previously failed treatment with anti-interleukin-17A therapies. J Am Acad Dermatol. 2019;doi: https://doi. org/10.1016/j.jaad.2019.05.007. 30. Mrowietz U, Kragballe K, Reich K, et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. Arch Dermatol Res. 2011;303(1):1-10. 3 1. Yiu ZZN, Griffiths CEM. Interleukin 17-A inhibition in the treatment of psoriasis. Expert Rev Clin Immunol. 2016;12(1):1-4. 32. Bagel J, Lebwohl M, Israel RJ, et al. Immunogenicity and Skin Clearance Recapture in Clinical Studies of Brodalumab. J Am Acad Dermatol. 2019;doi: For more information, e-mail us at https://doi.org/10.1016/j.jaad.2019.05.094. 33. Blauvelt A, Langley RG, Gordon K. Ixekizumab, a novel anti-IL-17A antibody, [email protected] exhibits low immunogenicity during long-term treatment in patients with psoriasis. J Am Acad Dermatol. 2016;74(5):AB258. AUTHOR CORRESPONDENCE

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doi:10.36849/JDD.2020.4645 February 2020 138 Volume 19 • Issue 2 Copyright © 2020 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Clinical and Molecular Effects of Interleukin-17 Pathway Blockade in Psoriasis Lawrence Green MD,ª Jeffrey M. Weinberg MD,B Alan Menter MD,c Jennifer Soung MD,D Edward Lain MD,E Abby Jacobsonf aGeorge Washington University School of Medicine, Washington, DC BIcahn School of Medicine at Mount Sinai, New York, NY cBaylor Scott & White, Dallas, TX DSouthern California Dermatology, Santa Ana, CA EAustin Institute for Clinical Research, Pflugerville, TX fOrtho Dermatologics, Bridgewater, NJ

ABSTRACT

The interleukin-17 (IL-17) pathway plays a crucial role in the development of psoriasis. Briefly, naive T cells differentiate into helper T (Th17) cells through interaction with activated dendritic cells in the presence of IL-23, Th17 cells produce IL-17 cytokines, and keratinocytes stimulated by IL-17 ligands lead to aberrant differentiation and proliferation that promote production of proinflammatory chemokines and further recruitment of inflammatory cells, setting up a positive feedback loop. Currently, 3 US Food and Drug Administration– approved agents to treat psoriasis affect the IL-17 pathway: brodalumab, secukinumab, and ixekizumab. Brodalumab is a fully human IL-17 receptor A antagonist that blocks signaling of multiple downstream inflammatory cytokines involved in psoriasis. Secukinumab and ixekizumab selectively bind to and neutralize only IL-17A. Pharmacologic effects in patients with psoriasis include decreased keratinocyte hyperproliferation, reduced epidermal thickening, decreased inflammatory markers, and resolution of histologic and genomic features of psoriasis. In clinical trials, therapeutic doses of brodalumab, secukinumab, and ixekizumab have demonstrated skin clearance efficacy by psoriasis area and severity index and static physician’s global assessment scores at 12 weeks. The immunomodulation of these agents is associated with a favorable safety profile. Overall, the clinical improvement and normalization of genetic hallmarks of psoriasis provide a strong case for the unique role ofDo IL-17 receptorNot Copyblocking as a therapeutic mechanism of action to treat psoriasis. Understanding the unique mechanisms by which treatments interact with the IL-17 pathway to inhibit downstream proinflammatory signal cascade can help physicians make informed treatmentPenalties decisions Apply when selecting the appropriate medication for patients.

J Drugs Dermatol. 2020;19(2)138-143. doi:10.36849/JDD.2020.4645

INTRODUCTION soriasis is a chronic, inflammatory, immune-mediated genetic) that trigger the aberrant immune response and result- systemic disease with an estimated prevalence of 3.2% ing cascade of immunologic events in psoriasis pathology are Pin the United States among individuals >20 years of age.1 still not completely defined. It is characterized by abnormal proliferation of keratinocytes, increased dermal vascularity, and dermal infiltration of multiple The current understanding of the complex pathophysiology inflammatory cells and by clinical presentation of erythema, in- associated with psoriasis has spurred the development of a duration, and scaling.2,3 Psoriasis has multiple symptoms with a variety of important new therapeutic agents that selectively substantial effect on both physical and emotional health-related target proinflammatory cytokines (eg, IL-17, IL-23, TNFα) rather quality of life, as well as a number of comorbid conditions.4-6 than suppressing the immune system in its entirety, resulting in favorable efficacy and safety profiles compared with those of A complex series of immunologic events results in the forma- less-selective immunosuppressive agents.3 This review focuses tion of psoriatic plaques as well as the underlying systemic on the central role of the IL-17 pathway in psoriasis pathophysi- inflammation characteristic of psoriasis. Central to this process ology and the clinical and molecular effects of the blockade of is the keratinocyte activation of dendritic cells. Inflammatory this pathway in the context of psoriasis treatment. dendritic cells release interleukin-23 (IL-23) and IL-12 to activate helper T (Th17) cells, Th1 cells, and Th22 cells, which in turn pro- Overview of the Central Role of the IL-17 Pathway in Psoriasis duce psoriatic cytokines, including IL-17, tumor necrosis factor For many years, the Th1 pathway had been considered the α (TNFα), and IL-22.7-9 The initial causes (environmental and/or primary driver in psoriasis.10 Research over the last decade, Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

139 Journal of Drugs in Dermatology L. Green, J.M. Weinberg, A. Menter, et al February 2020 • Volume 19 • Issue 2

however, has demonstrated that pathogenic T cells producing FIGURE 1. Expression of interleukin-17 (IL-17) isoforms in psoriatic high levels of IL-17 in response to IL-23 play a central role in skin.20 *P<0.01 for lesional versus nonlesional skin. mRNA, messenger the pathogenesis of psoriasis.10 Activation of native immune RNA. cells results in production of proinflammatory cytokines (eg, TNFα and interferon-α), which stimulate myeloid dermal dendritic cells to produce IL-12 and IL-23.3,9 These cytokines induce activation of T cells and differentiation into Th17 and Th1 cells, with greater differentiation into the Th17 lineage in the presence of IL-23.9,11 Th17 cells produce IL-17A, IL-17F, IL-21, IL-22, and TNFα.3 In addition to Th17-propagated cytokines, other ligands of the IL-17 receptor implicated in the proinflammatory cascade include IL-17C and IL-17E.11,12

Keratinocytes stimulated by IL-17 ligands result in aberrant differentiation and proliferation that promote the production of synergistic actions are similar to those of IL-17A, and the specif- proinflammatory chemokines, characterized by a self-ampli- ic IL-17 receptor it interacts with shares a subunit (IL-17 receptor fying inflammatory response.13 IL-17A recruits immune cells A) in common with that of IL-17A, IL-17F, and IL-17A/F.14,15,17,19 to psoriatic lesions by enhancing keratinocyte chemokine expression, including chemokine (C-C motif) ligand 20 (which Messenger RNA levels (Figure 1) and protein levels of IL-17A, mediates recruitment of myeloid dendritic cells and Th17 cells) IL-17F, and IL-17C are highly upregulated in psoriatic skin.20 Ad- and chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL3, CXCL5, ditionally, IL-17E has been shown to be produced at elevated CXCL6, and CXCL8 (which drive neutrophil recruitment), thus levels in keratinocytes located within psoriatic plaques, further perpetuating the inflammatory process.14,15 IL-17A also down- supporting the role of IL-17 cytokines in the immunopathologic regulates the expression of filaggrin, which binds to keratin mechanisms of psoriasis.12 IL-17 receptor A expression, how- fibers in epithelial cells, supporting the disruption of skin barri- ever, is no different among nonlesional and lesional psoriatic er function.3 Neutrophils, mast cells, and Tc17 cells, all of which skin.20 Furthermore, increased levels of both Th17 cells and IL-17 are found in psoriatic lesions, also produce IL-17A.16 Do Not Copyhave been found in the blood as well as skin lesions in patients Penalties Applywith psoriasis.21,22 A proposed pathobiologic model of psoria- IL-17C–stimulated endothelial cells lead to increased TNFα, and sis suggests that a self-sustaining feedback loop is established, IL-17C/TNFα–stimulated keratinocytes have similar inflamma- in which production of IL-17 in psoriasis pathogenesis leads to tory gene response patterns as those induced by IL-17A/TNFα, aberrant skin cell differentiation and proliferation (Figure 2).11 contributing to a positive proinflammatory feedback loop be- Through the proinflammatory feedback mechanisms described tween endothelial cells and the epidermis.17 IL-17A, IL-17C, and previously, chronic activation of IL-17 signaling ultimately leads TNFα additively and synergistically amplify the proinflamma- to the signs and symptoms of psoriasis.16 tory effects of one another.11 IL-17E, also known as IL-25, signals via the IL-17 receptor A and IL-17 receptor B subunits and is over- Inhibition of the IL-17 Pathway in Psoriasis expressed in keratinocytes located within psoriatic plaques.12 The central role of IL-17 in the pathogenesis of psoriasis makes Keratinocyte-derived IL-17E has been implicated in plaque for- it an attractive therapeutic target, and there are multiple ap- mation and hyperproliferation. IL-17E–mediated macrophage proaches to inhibition of IL-17–mediated signaling. Mechanisms activation leads to enhanced inflammation through recruitment of action involve direct antagonism of IL-17 as well as indirect, of immune cells, including monocytes and neutrophils.18 upstream approaches.23-25 Currently, 3 approved agents affect the IL-17 pathway directly, either by binding to the IL-17A ligand Rationale for Targeting the IL-17 Pathway in Psoriasis (secukinumab and ixekizumab) or by binding to IL-17 receptor The IL-17 family of cytokines interact with the transmembrane A (brodalumab).21,26 Brodalumab is a fully human anti–IL-17 re- receptors (IL-17 receptors A, B, C, D, and E).14 These IL-17 receptor A monoclonal antibody that binds IL-17 receptor A with ceptors are expressed on keratinocytes, dendritic cells, and a high affinity and prevents the signaling of multiple cytokines in- variety of immune cells and mediate response to IL-17 cyto- volved in psoriasis (IL-17A, IL-17F, IL-17A/F, and IL-17E [IL-25]).21,27 kines.15 IL-17A, IL-17F, and the IL-17A/F heterodimer share the Brodalumab undergoes selective, direct binding to IL-17 re- same IL-17 receptor for signaling, resulting in downstream gene ceptor A, resulting in inhibition of the induction of multiple activation and proinflammatory activity.16,19 IL-17C is also pres- downstream inflammatory factors (Figure 3).11,25,27,28 ent in psoriatic lesions, localizing in keratinocytes, endothelial cells, and leukocytes, and is the most abundant IL-17 cytokine In contrast to brodalumab, secukinumab and ixekizumab target in psoriatic skin.17 The effects of IL-17C on TNFα production and IL-17A, an IL-17 cytokine isoform that propagates inflammation Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

140 Journal of Drugs in Dermatology L. Green, J.M. Weinberg, A. Menter, et al February 2020 • Volume 19 • Issue 2

FIGURE 2. Proposed model for the role of IL-17 in psoriasis pathogenesis11 and IL-23/Th17–mediated effects on epidermal keratinocytes in psoriatic skin. The broad downstream effects of increased IL-23 and IL-17 signaling on various immune cell populations and keratinocyte biology are shown.10 Blocking ligand interaction with IL-17 receptor A has been shown to reduce inflammatory markers upstream of the IL-17 signal cascade, including IL-23 and an IL-12 subunit, indicating the potential for a negative feedback loop within the IL-17 signal cascade.28,34 CCL, chemokine (C-C

motif) ligand; IFN-γ, interferon-γ; IL, interleukin; Tc, cytotoxic T cell; Th, helper T cell; TNF, tumor necrosis factor.

Pharmacologic Effects of IL-17 Pathway Inhibition in Psoriasis FIGURE 3. Inhibition of downstream inflammatory processes due to In early-phase human studies, brodalumab normalized psori- brodalumab blockade of IL-17 receptor A.11,25,27,28 IL, interleukin. atic gene expression profiles and led to significantly decreased keratinocyte hyperproliferation, reduced epidermal thickening, and fewer numbers of infiltrating T cells in the skin of patients Do Not withCopy psoriasis.28,33 Within 1 week, expression of IL-23 and IL-12 subunit genes was reduced, indicating that brodalumab may Penaltiesreduce Apply inflammatory markers upstream of IL-17 receptor A.28,34 Within 2 weeks, IL-17A, IL-17C, and IL-17F were downregulated in a dose-dependent manner.28 In a punch biopsy subset of patients enrolled in three phase 3 clinical trials of brodalumab, extensive improvement in clinical features of psoriasis was accompanied by near-complete resolution of histologic and genomic features of psoriasis, including a transcriptome of lesional skin that resembled nonlesional skin after brodalumab treatment.34

In an early study of secukinumab that included patients with plaque psoriasis, reductions in clinical disease activity were associated with reductions of histomorphologic signs of acanthosis and epidermal hyperplasia and changes in gene expression of IL-17A pathway markers.35 For example, expression of via the IL-17 receptor.15,26,29 Ixekizumab is a humanized monoclo- IL-17A and IL-22 was markedly reduced after secukinumab ther- nal antibody that selectively binds with IL-17A and inhibits its apy, as was the area occupied by dermal IL17A+CD3+ T cells.35 interaction with the IL-17 receptor.26,30 Secukinumab is a high- affinity, fully human monoclonal antibody that selectively binds Skin lesions from patients with psoriasis in a phase 1 study of and neutralizes IL-17A.29 Fully human monoclonal antibodies, ixekizumab demonstrated significant dose-dependent reduc- such as brodalumab and secukinumab, have no murine se- tions from baseline in keratinocyte proliferation, hyperplasia, quence, whereas humanized monoclonal antibodies contain epidermal thickness, and dermal and epidermal infiltration by T murine sequence–derived complementarity-determining re- cells and dendritic cells.36 These changes were accompanied by gions engrafted into human-derived V regions.31 Of note, fully decreased expression of cytokines from multiple T-cell subsets, human monoclonal antibodies may have a lower potential for including interferon-γ, IL-17A/F, and IL-22 and the dendritic cell immunogenicity than humanized monoclonal antibodies.32 cytokine IL-23.36 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

141 Journal of Drugs in Dermatology L. Green, J.M. Weinberg, A. Menter, et al February 2020 • Volume 19 • Issue 2

TABLE 1. Efficacy and Safety Profile of IL-17 Receptor Inhibitors at 12 Weeks of Treatment in Patients With Psoriasis Serious Adverse sPGA 0/1, PASI 75, PASI 100, Drug Study Dose Events, n (%) n (%) n (%) n (%) 210 mg Q2W Brodalumab AMAGINE-139 168 (75.7) 185 (83.3) 93 (41.9) 4 (1.8) (n=222) 210 mg Q2W Brodalumab AMAGINE-238 481 (78.6) 528 (86.3) 272 (44.4) 6 (1.0) (n=612) 210 mg Q2W Brodalumab AMAGINE-338 497 (79.6) 531 (85.1) 229 (36.7) 9 (1.4) (n=624) 80 mg Q2W Ixekizumab UNCOVER-137 354 (81.8) 386 (89.1) 153 (35.3) 20 (1.7) (n=433) 80 mg Q2W Ixekizumab UNCOVER-240 292 (83.2) 315 (89.7) 142 (40.5) -- (n=351) 80 mg Q2W Ixekizumab UNCOVER-337 310 (80.5) 336 (87.3) 145 (37.7) -- (n=385) 300 mg Q4Wa Secukinumab ERASURE29 160 (65.3) 200 (81.6) 70 (28.6) -- (n=245) 300 mg Q4Wa Secukinumab FIXTURE29 (n=323) 202 (62.5) 249 (77.1) 78 (24.1) 4 (1.2)

PASI 75 and 100, psoriasis area severity index 75% and 100% improvement; Q2W, every 2 weeks; Q4W, every 4 weeks; sPGA 0/1, static physician’s global assessment score of 0 or 1. aAfter once-weekly dosing for 5 weeks.

Clinical Efficacy of IL-17 Pathway Blockade in Psoriasis the pathogenesis of psoriasis. For example, among the TNFα- In clinical trials, therapeutic doses of brodalumab, secukinumDo Not- blockingCopy agents, efficacy rates by PASI 75 in phase 3 studies ab, and ixekizumab have all demonstrated substantial skin (range, 10-16 weeks) were 49%, 71%, and 80% for etanercept, clearance efficacy following 12 weeks of treatmentPenalties by psoriasis adalimumab, Apply and infliximab, respectively.41-43 Interestingly, af- area and severity index (PASI) and static physician’s global as- ter 50 weeks of therapy in a phase 3 clinical trial of infliximab, sessment (sPGA) scores (Table 1).26,29,37-40 During the long-term the efficacy rate by PASI 75 was reduced to 61%.43 Of note, both extension phases (range, 52-60 weeks) in many of these trials, secukinumab and ixekizumab were superior to etanercept in efficacy was maintained in large percentages of patients. For terms of sPGA or modified PGA, PASI 75, PASI 90, and PASI example, in AMAGINE-1, among those receiving brodalumab 100 in their respective phase 3 trials that included an etan- 210 mg every 2 weeks who had PASI 90% improvement re- ercept arm.29,40 In the AMAGINE-2 and AMAGINE-3 studies, sponse (PASI 90) and PASI 100 at week 12, 78.3% and 67.5% brodalumab 210 mg was superior to ustekinumab, a mono- achieved PASI 90 and PASI 100, respectively, at week 52.39 In clonal antibody against IL-12 and IL-23, in terms of sPGA score AMAGINE-2 and AMAGINE-3, PASI 75, PASI 90, and PASI 100 of 0 or 1 response, PASI 75, and PASI 100.38 Furthermore, in rates at week 52 among those receiving brodalumab 210 mg a study evaluating time to achieve clinically meaningful out- every 2 weeks were 80%, 75%, and 56%, respectively, in AMAG- comes (defined as time for 25% of patients to achieve PASI INE-2 and 80%, 73%, and 53%, respectively, in AMAGINE-3.38 75), brodalumab exhibited the most rapid onset of efficacy (2.1 Maintenance of response to ixekizumab was demonstrated in weeks), followed by the other IL-17 inhibitors ixekizumab (2.4 UNCOVER-3; PASI 75, PASI 90, and PASI 100 rates were 80%, weeks) and secukinumab (3.0 weeks), whereas adalimumab, 71%, and 52%, respectively, at week 60.37 The 52-week efficacy ustekinumab, and etanercept achieved onset of efficacy at 4.6, rates for secukinumab ranged from approximately 75% to 80% 4.6, and 6.6 weeks, respectively.44 and 60% to 65% for PASI 75 and PASI 90, respectively, and the 52-week efficacy rate for PASI 100 was ~40% in the ERASURE Safety Overview of IL-17 Pathway Blockade in Psoriasis and FIXTURE trials.29 As summarized in the updated 2019 joint American Academy of Dermatology and National Psoriasis Foundation guidelines The efficacy results for brodalumab, secukinumab, and ixeki- of care for the management and treatment of psoriasis with zumab, all of which act within the IL-17 pathway cascade (by biologics, the safety profile of IL-17 inhibitors is well established binding to the IL-17 receptor A [brodalumab] or the IL-17A li- and understood.45 IL-17 inhibitors are associated with an in- gand [secukinumab and ixekizumab]), compare very favorably creased risk of infection and are not recommended in patients with those of other biologics that target different pathways in with a history of inflammatory bowel disease (IBD) but are not Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

142 Journal of Drugs in Dermatology L. Green, J.M. Weinberg, A. Menter, et al February 2020 • Volume 19 • Issue 2

associated with an increased risk of malignancy and may be ma, Eli Lilly, and Novartis. Jeffrey M. Weinberg serves as an used in patients with hepatitis B or C infections.45 As shown investigator for Boehringer Ingelheim, LEO Pharma, and Novar- in Table 1, the rates of serious adverse events with brodalum- tis and serves as a speaker for and/or advisor to AbbVie, Amgen, ab, secukinumab, and ixekizumab ranged from 1.0% to 1.8%, Celgene, Eli Lilly, LEO Pharma, and Novartis. Alan Menter has comparable to the rates reported with placebo.29,37-40 The most received compensation from or served as an investigator, con- common adverse events reported with these agents included sultant, advisory board member, or speaker for AbbVie, Allergan, nasopharyngitis, upper respiratory tract infection, headache, Amgen, Anacor, Boehringer Ingelheim, Celgene, Dermira, Eli and arthralgia.29,37,38 Lilly, Galderma, Janssen Biotech, LEO Pharma, Merck, Neothet- ics, Novartis, Pfizer, Regeneron, Symbio/Maruho, Vitae, and In a systematic review of clinical trials of patients with pso- Xenoport. Jennifer Soung has served as an investigator, con- riasis or psoriatic arthritis, Candida infections were reported sultant, advisory board member, or speaker for AbbVie, Actavis, in 4.0% of patients treated with brodalumab, 1.7% of patients Actelion, Allergan, Amgen, Boehringer Ingelheim, Cassiopeia, treated with secukinumab, and 3.3% of patients treated with Celgene, Dr. Reddy, Eli Lilly, Galderma, GSK, Janssen, Kadmon, ixekizumab compared with 0.3%, 2.3%, and 0.8% in those re- LEO Pharma, Menlo, National Psoriasis Foundation (nonprofit), ceiving placebo, ustekinumab, or etanercept, respectively.46 Novan, Novartis, Ortho Dermatologics, Pfizer, Regeneron, and The majority of Candida infections in anti–IL-17 biologic clinical UCB. Edward Lain has received compensation from or served as trials occurred in the oral cavity and were of mild severity.47 an investigator, consultant, advisory board member, or speaker Exacerbation of IBD has also been reported in trials of anti– for AbbVie, Allergan, Boehringer Ingelheim, Celgene, Dermira, IL-17 agents in psoriasis, including 1 case of Crohn disease Eli Lilly, Galderma, LEO Pharma, Neothetics, Novartis, Pfizer, with brodalumab.48 In a study of ixekizumab, incidence rates Sol-Gel, Endo Pharmaceuticals, Dr Reddy, Kadmon, Thync Glob- of Crohn disease and ulcerative colitis were 0.10 and 0.20 per al, Cassiopeia, Menlo, UCB, Kiniksa, Glenmark, Sienna, Sebacia, 100 patient-years, respectively, and were 0.11 and 0.15 per 100 BMS, Vanda, Chemocentryx, Brickell, Aclaris, and Novan. Abby patient-years, respectively, in a study of secukinumab.48 On the Jacobson is an employee of Ortho Dermatologics and holds basis of these observations, caution should be used in patients stock and/or stock options in Bausch Health. with possible or diagnosed IBD.48 ACKNOWLEDGMENT SUMMARY Do Not ThisCopy study was sponsored by Ortho Dermatologics. Editorial The IL-17 pathway plays a crucial role in the immunopathogene- assistance was provided under the direction of the authors by sis and development of psoriasis. Currently, 3 US FoodPenalties and Drug Angela Apply Cimmino, PharmD, Rebecca Slager, PhD, and David Administration–approved agents affect this pathway for treat- Boffa, ELS, of MedThink SciCom, with support from Ortho Der- ment of psoriasis (brodalumab, secukinumab, and ixekizumab) matologics. with others in development (bimekizumab).49 Brodalumab is a highly selective IL-17 receptor A antagonist that blocks mul- REFERENCES tiple downstream inflammatory cytokines that are elevated in 1. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol. 2014;70(3):512-516. psoriasis, including IL-17C and IL-17E, which may correlate with 2. Meephansan J, Subpayasarn U, Komine M, Ohtsuki M. Pathogenic role of the observed efficacy of brodalumab. Secukinumab and ixeki- cytokines and effect of their inhibition in psoriasis. Chiriac A, ed. An Interdis- zumab selectively bind to and neutralize only IL-17A. Inhibition ciplinary Approach to Psoriasis: London, UK: InTech Open; 2017. 3. Silfvast-Kaiser A, Paek SY, Menter A. Anti-IL17 therapies for psoriasis. Expert of the IL-17 pathway with these agents results in improvements Opin Bil Ther. 2019;19(1):45-54. in clinical, histologic, and genetic characteristics of psoriasis. 4. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and atten- The immunomodulation produced by these agents has been tion to comorbidities. J Am Acad Dermatol. 2019;80(4):1073-1113. associated with a favorable safety profile. Overall, the clinical im- 5. Prussick RB, Miele L. Nonalcoholic fatty liver disease in patients with psoriasis: a consequence of systemic inflammatory burden?Br J Dermatol. provement and normalization of genetic hallmarks of psoriasis 2018;179(1):16-29. provide a strong case for the unique role of IL-17 receptor block- 6. Takeshita J, Grewal S, Langan SM, et al. Psoriasis and comorbid diseases: ing as an important therapeutic mechanism of action in treating epidemiology. J Am Acad Dermatol. 2017;76(3):377-390. 7. Baliwag J, Barnes DH, Johnston A. Cytokines in psoriasis. Cytokine. psoriasis. Understanding the unique mechanisms by which 2015;73(2):342-350. each of these biologics interacts with the IL-17 pathway to inhibit 8. Kim J, Krueger JG. The immunopathogenesis of psoriasis. Dermatol Clin. 2015;33(1):13-23. downstream proinflammatory signal cascade will be of bene- 9. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361(5):496-509. fit to dermatologists in making informed treatment decisions. 10. Hawkes JE, Chan TC, Krueger JG. Psoriasis pathogenesis and the development of novel targeted immune therapies. J Allergy Clin Immunol. 2017;140(3):645-653. 11. Martin DA, Towne JE, Kricorian G, et al. The emerging role of IL-17 in the DISCLOSURES pathogenesis of psoriasis: preclinical and clinical findings.J Invest Dermatol. 2013;133(1):17-26. Lawrence Green has served as an investigator, consultant, or 12. Senra L, Stalder R, Alvarez Martinez D, Chizzolini C, Boehncke WH, Brembilla speaker for Amgen, AbbVie, Bausch Health, Celgene, Sun Phar- NC. Keratinocyte-derived IL-17E contributes to inflammation in psoriasis.J Invest Dermatol. 2016;136(10):1970-1980. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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13. Giunta A, Ventura A, Chimenti MS, Bianchi L, Esposito M. Spotlight on ix- and UNCOVER-3): results from two phase 3 randomised trials. Lancet. ekizumab for the treatment of moderate-to-severe plaque psoriasis: design, 2015;386(9993):541-551. development, and use in therapy. Drug Des Devel Ther. 2017;11:1643-1651. 4 1. Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to 14. Gooderham M, Posso-De Los Rios CJ, Rubio-Gomez GA, Papp K. Interleu- severe psoriasis: A randomized, controlled phase III trial. J Am Acad Derma- kin-17 (IL-17) inhibitors in the treatment of plaque psoriasis: a review. Skin tol. 2008;58(1):106-115. Therapy Lett. 2015;20(1):1-5. 42. Papp KA, Tyring S, Lahfa M, et al. A global phase III randomized controlled 15. Kirkham BW, Kavanaugh A, Reich K. Interleukin-17A: a unique pathway in trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid ar- Br J Dermatol. 2005;152(6):1304-1312. thritis. Immunology. 2014;141(2):133-142. 43. Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance ther- 16. Girolomoni G, Mrowietz U, Paul C. Psoriasis: rationale for targeting interleu- apy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind kin-17. Br J Dermatol. 2012;167(4):717-724. trial. Lancet. 2005;366(9494):1367-1374. 1 7. Johnston A, Fritz Y, Dawes SM, et al. Keratinocyte overexpression of IL-17C 44. Papp KA, Lebwohl MG. Onset of action of biologics in patients with moder- promotes psoriasiform skin inflammation. J Immunol. 2013;190(5):2252- ate-to-severe psoriasis. J Drugs Dermatol. 2017;17(3):247-250. 2262. 45. Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care 18. Senra L, Mylonas A, Kavanagh RD, et al. IL-17E (IL-25) enhances in- for the management and treatment of psoriasis with biologics. J Am Acad nate immune responses during skin inflammation.J Invest Dermatol. Dermatol. 2019;80(4):1029-1072. 2019;139(8):1732-1742.e17. 46. Saunte DM, Mrowietz U, Puig L, Zachariae C. Candida infections in patients 19. Lowes MA, Russell CB, Martin DA, Towne JE, Krueger JG. The IL-23/T17 with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and pathogenic axis in psoriasis is amplified by keratinocyte responses.Trends their practical management. Br J Dermatol. 2017;177(1):47-62. Immunol. 2013;34(4):174-181. 4 7. Frieder J, Kivelevitch D, Fiore CT, Saad S, Menter A. The impact of biologic 20. Johansen C, Usher PA, Kjellerup RB, Lundsgaard D, Iversen L, Kragballe agents on health-related quality of life outcomes in patients with psoriasis. K. Characterization of the interleukin-17 isoforms and receptors in lesional Expert Rev Clin Immunol. 2018;14(1):1-19. psoriatic skin. Br J Dermatol. 2009;160(2):319-324. 48. Hohenberger M, Cardwell LA, Oussedik E, Feldman SR. Interleukin-17 inhibi- 2 1. Roman M, Chiu MW. Spotlight on brodalumab in the treatment of moder- tion: role in psoriasis and inflammatory bowel disease. J Dermatolog Treat. ate-to-severe plaque psoriasis: design, development, and potential place in 2018;29(1):13-18. therapy. Drug Des Devel Ther. 2017;11:2065-2075. 49. Papp KA, Merola JF, Gottlieb AB, et al. Dual neutralization of both interleukin 22. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17, Th22, and 17A and interleukin 17F with bimekizumab in patients with psoriasis: Results Th1 cells are increased in psoriasis. J Invest Dermatol. 2010;130(5):1373- from BE ABLE 1, a 12-week randomized, double-blinded, placebo-controlled 1383. phase 2b trial. J Am Acad Dermatol. 2018;79(2):277-286 e210. 23. Leonardi CL, Gordon KB. New and emerging therapies in psoriasis. Semin Cutan Med Surg. 2014;33(2 suppl 2):S37-41. 24. Chiricozzi A, Romanelli P, Volpe E, Borsellino G, Romanelli M. Scanning the AUTHOR CORRESPONDENCE Immunopathogenesis of Psoriasis. Int J Mol Sci. 2018;19(1). 25. Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Lawrence Green MD Nat Rev Drug Discov. 2012;11(10):763-776. 26. Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 mono- E-mail:...... ……...... [email protected] clonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366(13):1190-1199. 2 7. Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-reDo Not- Copy ceptor antibody for psoriasis. N Engl J Med. 2012;366(13):1181-1189. 28. Russell CB, Rand H, Bigler J, et al. Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti-IL-17Penalties receptor Apply monoclonal antibody. J Immunol. 2014;192(8):3828-3836. 29. Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis- -results of two phase 3 trials. N Engl J Med. 2014;371(4):326-338. 30. Liu L, Lu J, Allan BW, et al. Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A. J Inflamm Res. 2016;9:39-50. 3 1. Harding FA, Stickler MM, Razo J, DuBridge RB. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs. 2010;2(3):256-265. 32. Silberstein S, Lenz R, Xu C. Therapeutic Monoclonal antibodies: what headache specialists need to know. Headache. 2015;55(8):1171-1182. 33. Papp KA, Reid C, Foley P, et al. Anti-IL-17 receptor antibody AMG 827 leads to rapid clinical response in subjects with moderate to severe psoriasis: results from a phase I, randomized, placebo-controlled trial. J Invest Dermatol. 2012;132(10):2466-2469. 34. Tomalin LE, Russell C, Garcet S, et al. IL-17 receptor A inhibition with brodalumab rapidly normalizes molecular and cellular phenotype of patients with moderate-to-severe psoriasis vulgaris. 27th European Academy of Derma- tology and Venereology Congress; September 16-18, 2018; Paris, France. 35. Hueber W, Patel DD, Dryja T, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2(52):52ra72. 36. Krueger JG, Fretzin S, Suárez-Fariñas M, et al. IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis.J Allergy Clin Immunol. 2012;130(1):145-154.e149. 3 7. Gordon KB, Blauvelt A, Papp KA, et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375(4):345-356. 38. Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373(14):1318- 1328. 39. Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, double- blind, placebo-controlled study of brodalumab in patients with moderate-to- severe plaque psoriasis. Br J Dermatol. 2016;175(2):273-286. 40. Griffiths CE, Reich K, Lebwohl M, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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doi:10.36849/JDD.2020.4835 February 2020 145 Volume 19 • Issue 2 Copyright © 2020 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Multidisciplinary Real-World Experience With Bilastine, a Second Generation Antihistamine Charles W. Lynde MD FRCPC,a Gordon Sussman MD FRCPC,B Pierre-Luc Dion MD FRCPC,c Lyn Guenther MD FRCPC,d Jacques Hébert MD FRCPC,e Jaggi Rao MD FRCPC,f Tim Vander Leek MD FRCPC FAAAAI,g Susan Waserman MSc FRCPCh aDepartment of Medicine, University of Toronto, Toronto, ON, Canada BDivision of Allergy/Clinical Immunology, University of Toronto, Toronto, ON, Canada cDivision of Dermatology, Université Laval, Québec, Québec, Canada; CISSS de Chaudière-Appalaches – Hôtel-Dieu de Lévis, Lévis, Québec, Canada dWestern University, London, ON. Royal College of Physicians and Surgeons of Canada, EDepartment of Medicine, Université Laval, Québec, Canada fDivision of Dermatology, University of Alberta, Edmonton, Alberta, Canada gDepartment of Pediatrics, Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada hDivision of Clinical Immunology & Allergy, Department of Medicine, McMaster University, Hamilton, ON, Canada

ABSTRACT

Introduction: Allergic conditions frequently require treatment with antihistamines. First-generation antihistamines can potentially interfere with restful sleep, cause “morning after” effects, impair learning and memory, and reduce work efficiency. Second-generation antihistamines, such as bilastine, have been demonstrated to decrease allergy symptoms effectively without causing night-time sleep disturbances and related adverse events. Method: A real-world case project was developed to help optimize patient care by recognizing the role bilastine can play for allergic conditions where antihistamine treatment is needed.Do The presentedNot Copy real-world patient cases conducted by the panel members are supported with evidence from the literature, wherePenalties available. Any discussion Apply concerning off-label use should be considered an expert opinion only. Results: The real-world cases presented here used bilastine in conditions such as perennial and seasonal allergic rhinitis, chronic urticaria, as well as urticarial vasculitis and pruritus associated with inflammatory skin conditions. The treated patients were between 9 and 76-years old providing information on a full spectrum of patients that require treatment with antihistamines. Conclusions: The presented real-world cases using the second-generation antihistamine, bilastine, demonstrated favorable outcomes for the treated patients. While effectively relieving symptoms, the antihistamine was reported to be safe and well-tolerated.

J Drugs Dermatol. 2020;19(2)145-154. doi:10.36849/JDD.2020.4835

INTRODUCTION llergic conditions, such as seasonal allergic rhinitis that decrease allergy symptoms effectively, while potentially (SAR), perennial allergic rhinitis (PAR), and urticaria increasing quality of life and reducing night-time sleep distur- (both acute and chronic) are frequently treated with bances.4 One of these new second-generation AHs approved for A 1,2 antihistamines (AHs). Most first-generation AHs have a long the treatment of various allergic conditions such as SAR and history and were introduced decades before clinical pharmacol- chronic spontaneous urticaria (CSU) is bilastine (Blexten, Aralez ogy studies, and randomized controlled trials were required by Pharmaceuticals Canada Inc.).5-7 Bilastine is available by pre- regulatory agencies.2 Consequently, first-generation AHs that scription; it is not derived from nor is it a metabolite of another were previously approved for use are assumed to be safe and AH, has a rapid one-hour onset of action and provides sustained effective.2 However, physicians have become aware these first- efficacy.5-9 This AH does not penetrate the brain, is scarcely me- generation AHs cause impairment and potentially interfere with tabolized and does not interact with cytochrome P450.6,7 For the restful sleep, cause hangovers or “morning after” effects, im- treatment of allergic conditions in adults and adolescents over pair learning and memory, and reduce work efficiency.3 Addi- 12 years of age, a daily oral dose of bilastine 20 mg is recom- tionally, various second-generation AHs have been developed mended.7 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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This current real-world case project serves as a mechanism to If yes, describe. What (if any) are the special circumstances re- help optimize patient care by recognizing the role bilastine can lated to this particular case and what lessons are learned? play in the treatment of a broad range of conditions such as SAR, PAR, urticarial vasculitis as well as both chronic and induc- During a one-day authorship meeting, the panel presented their ible urticarias. Additionally, the project explores where bilastine cases, followed by a group discussion, after which the authors can manage pruritus due to skin conditions, such as in atopic decided which of the real-world cases using bilastine were dermatitis (AD), which may require adjunctive AH use to skin- included in the manuscript. The publication was developed, re- care and AD treatment. viewed by the panel members, and prepared for publication.

METHODS Antihistamines for Treatment of Allergic Conditions A real-world case-based approach was used to explore the role First-generation AHs bilastine can play in the treatment of conditions that require AHs have been in use since 1940 for various allergic conditions.1 AH use. These real-life patient cases are coupled with evidence The first generation AHs were discovered by Bovet and Staub from the literature. Recommendations given by the panel reflect in 1937 and have anticholinergic and sedative activity.1,10,11 AHs the use of bilastine for these conditions and demonstrate how act as inverse agonists rather than antagonists of histamine patients can benefit from its use. Any discussion concerning H1-receptors, which are members of the superfamily of G-pro- off-label use should be considered an expert opinion only. tein-coupled receptors (GPCRs).10 The older first-generation AHs penetrate readily into the brain to cause sedation, drowsiness, The target audience for this publication are physicians, such as fatigue, impaired concentration, and memory, possibly by neg- allergists and dermatologists, who treat patients with condi- atively impacting rapid-eye-movement (REM) sleep.10,12,13 These tions requiring AHs. first-generation AHs may cause detrimental effects on learning and examination performance in children, may impair the LITERATURE REVIEW ability of adults to work and drive, and their use should be dis- A literature review was conducted to explore the role of sec- couraged.10,12 Both the Allergic Rhinitis and its Impact on Asthma ond-generation AHs, and to assess their value for patients (ARIA) guidelines14 and the European Academy of Allergy and with conditions requiring AHs. Databases searched were: EM- Clinical Immunology (EAACI) / Global Allergy and Asthma Euro- BASE, MEDLINE, CINAHL, PubMed, The Cochrane Library,Do RCPNot peanCopy Network (GA2 LEN)/ European Dermatology Forum (EDF)/ Guidelines Database, and DARE. The searches were conducted World Allergy Organization (WAO) guidelines for the manage- February 24–25, 2019, and included guidelines and Penaltiesother publi- ment Apply of urticaria13 recommend (strong recommendation, high cations in the English language, which were dated from 2000 quality evidence) the use of second-generation, non-sedating to 2019. References selected further included evidence on bilas- AHs and discourage the use of first-generation AHs. tine and its use in the presented cases. Medical subject heading terms were used in various combinations in the literature Many physicians still combine a second-generation AH in the searches and included: 1st and 2nd generation AHs use, specifi- morning with a sedating first-generation AH at night to enhance cally bilastine; efficacy for conditions requiring AHs; allergic sleep. Staevska et al. compared levocetirizine with or without rhinoconjunctivitis, chronic urticaria, safety of AHs; elimination; nightly hydroxyzine, and noted the two treatments were equally tolerance; anticholinergic effects; cardiotoxicity; metabolism; effective in decreasing symptoms, quality of life improvement, AHs interaction with other drugs; drowsiness using AHs and and lack of nighttime disturbance; however, hydroxyzine in- use of AHs during various activities (such as driving and flying a creased daytime somnolence.4 plane); adverse events; effects of its use in populations of various age groups and impact on quality of life. A media audit of US coverage of transport accidents from 1996 to 2008 in which first-generation AHs were implicated, revealed ROLE OF THE PANEL 54 fatalities.12 The authors suggested this was likely a gross un- An expert panel (authors) of allergists and dermatologists who derestimation of the true figure because these were only media commonly treat patients with bilastine was established to pres- reported events.12 A similar audit performed on second-genera- ent real-life case studies covering conditions including SAR, tion AHs found no articles that associated these AHs as a cause PAR, urticarial vasculitis, urticaria and pruritus due to various of transport accidents.12 causes, such as AD. The panel members used a template for their case studies, which asked the following questions: What Second-generation AHs are the case and the impact of the condition? What are the treat- Second generation AHs cause less sedation because of their ment options, and what treatment(s) were previously used? limited penetration of the blood-brain barrier.10 They are highly Why might bilastine work in this case, where does it fit and what selective for the histamine H1-receptor and have minimal an- were the results of bilastine use? Did any adverse events occur? ticholinergic effects.10 The second-generation AHs commonly Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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TABLE 2. Chronic Spontaneous and Inducible Urticaria No and Type Author/Year Type and Length of Treatment Results of Patients Bilastine significantly reduced the total symptom scores from day 2 Placebo,bilastine 20 mg, N = 516 with onwards compared to placebo. Bilastine was safe and well-tolerated as Zuberbier, 201035 levocetrizine 5 mg. Oral, QD CSU compared with placebo. Comparison with levocetirizine indicated both for 4 weeks. treatments to be equally efficacious. N = 197 with All efficacy variables improved during treatment, and long-term treat- CSU or pru- Bilastine 20 mg, Oral, QD for ment for 52 weeks was safe and well-tolerated. Yagami, 201734 ritus associ- 52 weeks. Bilastine improved symptoms of both conditions early in treatment, and ated with skin the efficacy was maintained throughout the 52 weeks. diseases. N = 115 with Bilastine 20 mg, Oral, QD for Bilastine demonstrated efficacy for the relief of pruritus associated with CSU, eczema/ 8 weeks. urticaria and other skin diseases in dermatitis, Non-responder patients (<30% Serra, 201932 adults, with a good safety profile. Up-dosing to 40mg in non-responding prurigo or improvement in pruritus score patients after 2 weeks of treatment was efficacious without any safety cutaneous at week 2) were up-dosed to concerns. pruritus 40mg, QD from week 2. N = 29 with Bilastine 20, 40 and 80 mg, CSU who had Oral, QD for 6 weeks. Bilastine 20 mg was effective in relieving the symptoms of CSU. Up- not At 2 weeks patients without dosing to double the licensed dose of bilastine appeared to be sufficient Weller, 201833 responded a complete response (UAS7 for the majority of CSU patients. sufficiently to ≤ 3) were up-dosed by an ad- A proportion of the severely affected patients benefited from 80 mg. licensed doses ditional 20 mg QD of other AHs Bilastine 20 mg up-dosed to N = 20 with 40 and 80 mg daily each for Bilastine 20 mg was effective (P<0.0001) in reducing CTT. Up-dosing to Krause, 201331 cold contact 7 days with 14-day washout Do Not80 Copymg significantly P( <0.04) increased its effectiveness without sedation. urticaria (CCU) periods compared to placebo in a 12-weekPenalties study. Apply Antihistamine (AH); Critical Temperature Thresholds (CTT); Urticaria Activity Score (UAS)

The efficacy of bilastine in SAR and PAR has been confirmed in at work and school.29 CSU is characterized by the appearance several studies comparing bilastine to either placebo alone or to of spontaneously occurring pruritic erythematous wheals that placebo and other AHs (Table 1).15,25-28 generally resolve in less than 24 hours.30 These wheals may appear daily for more than 6 weeks; in 50% of cases, associated The Kuna et al. trial was a double-blind, randomized, controlled angioedema or severe associated swelling occurs.30 CSU has a study performed in patients suffering from SAR to determine prevalence of 0.5-1% of the general population, occurring most- the efficacy and safety of bilastine 20 mg compared to cetiri- ly in women; the peak age of onset is 20-40 years, and 10-50% zine 10 mg, and placebo.15 The mean total symptom scores may have the disease longer than 5 years.3 were reduced in the bilastine and cetirizine treated groups to a similar, and significantly greater extent, compared with pla- International urticaria guidelines recommend second-genera- cebo. Bilastine demonstrated a significantly lower incidence of tion AHs as first-line treatment.13,29 As a second-step in therapy, somnolence and fatigue compared to cetirizine.15 An additional before resorting to other treatments, these second-generation multicenter study evaluated bilastine (20 mg), desloratadine (5 AHs have been recommended at high doses (up to 4x thera- mg) or placebo treatment in 721 patients with SAR.25 After 14 peutic dose) based on studies showing the benefit of a higher days of treatment, both nasal and non-nasal symptoms had sig- dosage of 2nd generation antihistamines and expert opinion.29 nificantly decreased in those patients who received the drugs compared to placebo.25 Bilastine has been assessed in multiple clinical trials involving patients with chronic urticaria (Table 2).31-35 In a double-blind, Chronic urticaria controlled clinical trial with placebo and levocetirizine in pa- Chronic spontaneous urticaria and other chronic forms of urti- tients with CSU, the total symptom score was reduced from the caria are disabling, impair quality of life and affect performance second day of treatment with bilastine, bilastine showed better Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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used in Canada for treatment of symptoms in allergic rhinitis the effects of alcohol and lorazepam or cause the impaired per- and urticaria are desloratadine, cetirizine, fexofenadine, lorata- formance of tasks related to flying.5,6,17,19 In clinical trials where dine, rupatadine and bilastine. Even though these are all 2nd bilastine was administered at doses of up to 40 mg once daily, generation antihistamines they have different attributes. For it did not affect psychomotor performance and did not affect the example, cetirizine can cause somnolence in some individuals, subjects’ driving performance in a standard car driving test.6,20 fexofenadine has a relatively short duration of action and may be required to be taken twice daily for all-round daily protection Bilastine fits many of the properties for an ideal AH, described and loratadine, desloratadine, as well as rupatadine, are exten- by the ARIA guidelines: Potent and selective activity at H1 re- sively metabolized within the liver by the group of enzymes ceptors, rapid onset and long duration of action, and efficacy belonging to the P450 cytochrome system10,15 in PAR and SAR. Other beneficial properties include a lack of interactions with cytochrome P450, lack of sedation, cognitive or Bilastine is a newer second-generation AH that is rapidly ab- psychomotor impairment, no anticholinergic activity, no cardiac sorbed without being metabolized and has a bioavailability of safety concerns, and no potential for tachyphylaxis.21 60%.16 In vitro, this AH has a high selectivity for the H1-receptor and no antagonism against other receptors such as serotonin, Seasonal and Perennial Allergic Rhinitis muscarinic M3-receptors, adrenoceptors and H2- and H3-recep- Allergic rhinitis tors.16 Since bilastine is not metabolized, no dose adjustment Allergic rhinitis is a chronic condition mostly occurring in chil- is required in patients with hepatic impairment.17 Bilastine has dren, adolescents, and young adults.22 Prevalence of 10%–25% a rapid onset of action, within one hour, and a long duration has been shown in a cross-sectional study among four world of action, greater than twenty-six hours.17,18 With regards to bi- geographic regions: Asia, Europe, the Americas, and Africa.22 lastine and safety, at the recommended dose of 20 mg daily, Symptoms are more intense during spring and autumn;22 al- treatment-emergent adverse reactions with bilastine, including lergens provoke symptoms such as nasal itching, sneezing, somnolence, are equal to placebo.17 Bilastine does not cross the rhinorrhea, and nasal obstruction frequently leading to reduced blood-brain barrier, and therefore at the 20 mg dose, it does not quality of life.22-24 Histamine, released by mast cells and baso- affect functional performance, the ability to drive, potentiate phils, is responsible for the symptoms.7,22-24

TABLE 1. Do Not Copy Seasonal Allergic Rhinitis, Perennial Allergic Rhinitis Studies No and Type Penalties Apply Author/Year Type and Length of Treatment Results of Patients Placebo, bilastine 20 mg, Significantly superior to placebo and comparable to cetirizine in reliev- Kuna P, 200915 N = 681 - SAR cetirizine 10 mg. ing symptoms of SAR. Lower incidence of total AEs, somnolence, Oral, QD for 14 days fatigue and drug-related AEs compared to cetirizine. Placebo, Bilastine 20 mg, Significantly fewer symptoms compared to placebo and comparable to Bachert C, 200925 N = 721 - SAR Desloratadine 5 mg, desloratadine both for efficacy and safety. Oral, QD for 14 days Placebo, Bilastine 20 mg, Cetirizine 10 mg. Oral, QD for 4 weeks. An open-label A post-hoc analysis indicated that bilastine and cetirizine were similarly Sastre J, 201228 N = 650 - PAR extension phase evaluated the effective and more effective than placebo. safety of bilastine 20 mg ad- Bilastine was safe and well-tolerated over a 1-year treatment period. ministered to patients (n=513) for one year. Significantly superior to placebo and comparable to fexofenadine in Placebo – oral QD, Bilastine relieving symptoms of PAR. Bilastine showed a rapid onset of action, Okubo K, 201726 N = 765 - PAR 20mg – oral QD, Fexofenadine and total nasal symptom score was significantly greater than fexofena- 60 mg – oral BID for 14 days. dine on day 1. Bilastine 20mg – oral for 12 Bilastine was safe, well-tolerated, and effective for patients with SAR N = 58 SAR/ N Okubo K, 201727 weeks (SAR and PAR) and 1 and PAR. The observed improvement was maintained for 1 year in PAR = 64 PAR year (PAR only). patients, with no loss of drug efficacy. N = 509 children (aged Placebo, Bilastine 10mg – oral Novak Z, 201637 2 to >12) – AR Bilastine had a safety and tolerability profile similar to that of a placebo. for 12 weeks or chronic urticaria Bilastine was safe and well-tolerated over a 1-year treatment period. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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results than placebo, and bilastine had a safety profile similar is presently off-label in the pediatric population; however, phase to placebo.35 3 clinical data demonstrates that bilastine is safe for use in children as young as 2 years of age.37 As well, bilastine was recently Long-term treatment with bilastine has also been investigated approved in Europe for children age 6 – <12 years of age and in in an open-label, single-arm, one-year safety study.34 This study Mexico for children 2 – <12 years of age. The panel members demonstrated that bilastine significantly reduced all rash and proposed a liquid pediatric formulation of the AH is needed, es- itch symptoms at the first time point (2 weeks), and this response pecially for use in children down to 2 years of age. was maintained throughout the 52 weeks showing that bilastine does not cause tachyphylaxis. Throughout the treatment period CSU and dermatographism or angioedema bilastine was well tolerated with only 2.5% of patients reporting Table 4 shows three cases: A 19-year-old female with CSU and mild or moderate bilastine-related adverse events and only two dermatographism (Case 3), a 24-year-old female with CSU and reports of somnolence similar to placebo-treated patients.34 angioedema (Case 4), and a 12-year-old male with an 8-month history of daily urticaria and intermittent angioedema (Case 5). Bilastine was also investigated in three up-dosing studies in patients with CSU and cold contact urticaria.31-33 At doses of 40 The patient described in case 4 had previously used oral diphen- and 80 mg, bilastine further improved upon the symptom score hydramine 25 mg, sometimes up to 3 times/day (TID), which outcomes for urticaria patients. Since bilastine is a non-brain only controlled pruritus and swelling for a few hours. After one penetrating antihistamine it is an ideal AH for up dosing the month of bilastine use, her condition had cleared after which daily dose four-fold in difficult-to-treat urticaria.8 the AH was used PRN. Her quality of life dramatically improved, positively impacting her study, quality of sleep, social life, and Pruritus associated with dermatological conditions self-image. According to the panel members, the sedation The involvement of histamine in pruritus associated with caused by using first-generation AHs is not helpful in treating various skin conditions varies. For example, histamine H1‐re- pruritus and should be discouraged because of potentially seri- ceptor-induced pruritus in AD is lower than that in patients with ous side effects.1-6,12 CSU.34,36 Two studies that included patients with CSU or pruritus associated with skin diseases showed that bilastine is effective Inducible urticaria: cold urticaria and cholinergic urticaria in reducing itch scores for skin conditions such as AD,Do prurigo Not TableCopy 5 presents two cases with inducible urticaria: A 29-year- and cutaneous pruritus (Table 2).34,32 One of these studies al- old female with cold contact urticaria (Case 6) and a 22-year-old lowed for 52 weeks of treatment, and no loss of drugPenalties sensitivity male Apply with cholinergic urticaria (Case 7). The patient in Case 6 at 20 mg once daily was seen.34 received previous treatment with cyproheptadine 16 mg, cetirizine 40 mg, and at bedtime doxepin 75 mg, which caused This second-generation AH is effective for chronic pruritus sedation and systemic side effects. After changing her medica- related to skin diseases such as AD and demonstrates that tion to bilastine 40 mg twice daily, the patient had fewer and less second-generation AHs may be an effective adjunct to AD treat- severe outbreaks and no systemic symptoms. ment, in addition to patient education, a primary skincare plan, the use of moisturizers, and topical anti-inflammatory therapy. The correct diagnosis for the 22-year-old male with cholinergic urticaria took a long time; in fact, before proper diagnosis, the Real-Life Cases patient was even treated (unsuccessfully) for conditions such The cases presented here by the authors focused on the use of as scabies and AD. However, with the combination of proper bilastine in conditions such as SAR, PAR, and chronic urticaria, education on his condition, and bilastine 20 mg daily used as as well as less common but challenging conditions such as urti- needed, this patient has recovered the confidence to exercise carial vasculitis and pruritus in skin conditions. again, thereby improving his QoL significantly. The panel agreed that education on cholinergic urticaria and its differential diag- Advisors discussed the use of AHs, then presented, reviewed, noses is crucial for successful treatment. and critiqued the various cases. A final consensus vote (75% consensus needed) on the cases revealed a unanimous consen- Urticarial vasculitis sus on ten different cases for inclusion in the publication. Table 6 presents case 8 about a 43-year-old female with urticarial vasculitis, which is difficult to diagnose from a biopsy. Conse- SAR and PAR quently, for over 8 years after the first symptoms occurred, Table 3 discusses a 21-year-old female with PAR (Case 1) and a numerous biopsies showed negative results. Eventually, how- 9-year-old boy with a pet allergy and a history of seasonal al- ever, confirmation of the condition from a biopsy was obtained; lergies (Case 2). Both patients tolerated bilastine very well and the patient’s condition improved significantly after she was pre- had a rapid response to treatment with no adverse events re- scribed bilastine. ported. The panel members noted that in cases 2 and 5 bilastine Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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TABLE 3. Case Studies of Patients with Allergic Rhinitis

Why Bilastine Disease Follow up/ No Case and Issues Previous Treatment Was Chosen Management Learning Points 21-year-old female with PAR has rhinorrhea, sneezing and nasal obstruction, ocular symptoms, SOB on exercise, fatigue, lack OTC antihistamines, taken Because of published Bilastine 20 mg QD. of energy and difficulty to concentrate. Her on a PRN basis – were se- efficacy data and Patient significantly Consider treating daily symptoms occur mostly in the morn- dating; but she did like the innocuous profile improved; reduction with bilastine 20 mg ing and at home. Previous allergy workup effect. Nasal steroids were (no cardiovascular of nasal symptoms, until all symptoms 1 = allergy to dust mites. Review of systems tried but dropped due to nor CNS effects and no ocular or pul- are gone – usually 1 = unremarkable; family history positive for local irritation (burning and minimal potential monary symptoms; or 2 months up to 6 allergies. She reduced dust in her home and bleeding). for interaction with medication well months had no pets. Physical examination showed other drugs). tolerated. large and pale turbinates, no polyps; con- junctival redness; no wheezing on forced expiration. Bilastine 10 mg (half a tablet), upon 9-year-old boy (58.5 inches/87 pounds and breakout (approx blood work normal) has a pet allergy and every 5 days, reacts when exposed to the family’s dog. He which fits with the has had SAR since age 5 and has symp- pharmacokinetics of toms yearly from May-Sept, skin prick test bilastine), used for conducted March, 2017 (age 7) and tested all breakouts during positive for tree mix, ragweed and weed the month of the mix. When closely interacting with the fam- condition. ily dog he develops hives on the face, neck it is effective for the Hives and itch and eyes (Figures Case 2-1, Case 2-2): treatment of urticaria completely resolve - 1st breakout 2 days after puppy came and allergic rhinitis, Continue to take within twenty min- 2 home: red itchy swollen eye with raised None bilastine also has ro- bilastine 10 mg as utes of treatment red hives below the eye. bust pediatric safety needed each time. No lon- - 2nd breakout 5 days later: red blotchy data Casein this 2 Patient same Details: Photo is from third breakout – hives on face and neck. ger has an impact patches on neck and face. population. on daily activities, - 3rd breakout 5 days later: red blotchy Do Not Copy social life and sleep patches on neck and face. disturbance. After - 4th breakout 8 days later: red blotches on Penalties Apply each treatment he face. returns to normal The condition has been present for 1 month within 20 minutes and impacts on his daily activities, social life and is extremely and quality of sleep (due to itching). happy with the outcome (Figure Case 2-3). Antihistamine (AH); Central nervous system (CNS); Over-the-counter (OTC); Perennial allergic rhinitis (PAR); Seasonal allergic rhinitis (SAR); Shortness of breath (SOB); Once a day (QD); Twice a day (BID); Three times a day (TID); Four times a day (QID); Oral (PO); As needed (PRN)

Before treatment

CASECase 2 Patient 2 PATIENT Details: Photo DETAILS: is from third breakout Photo – hivesis from on face third and neck breakout. – hives on face and neck.

Before treatment 20 minutes after treatment Before treatment

151 Journal of Drugs in Dermatology C.W. Lynde, G. Sussman, P-L Dion, et al February 2020 • Volume 19 • Issue 2

TABLE 4. Case Studies of Chronic Spontaneous Urticaria and Angioedema

Why Bilastine Disease Follow up/ No Case and Issues Previous Treatment Was Chosen Management Learning Points 19-year-old female with CSU and dermatographism, sometimes accompanied by Fewer hives, less swollen lips and face, symptoms started 2 Bilastine 20 mg BID swelling and pruri- months ago. She studies long hours and Cetirizine 20 mg am and started 2 weeks tus. She sleeps bet- Because of its ef- has frequent viral infections. School and diphenhydramine 50 mg ago. She was ter, is less tired and 3 ficacy, and minimal sleep are affected by pruritus and medica- at bedtime. Prednisone on instructed to stop better able to study. sedation. tion related fatigue. She is embarrassed to two occasions. medication when She still has some be out when there is a rash and swelling. symptoms resolve. dermatographism, When rash is gone her skin still welts upon which is improving. rubbing. Replaced diphenhydramine with bilastine 20 mg BID x 7 days. Upon Diphenhydramine 25 mg Good prior experi- 24-year-old female university student with follow-up bilastine Fast onset and PO, sometimes up to TID. ence with similar CSU and angioedema. More than 12-week was increased to 40 clearance, less Controls pruritus and swell- cases. Effective, history of hives on the trunk and extremi- mg BID x 30 days, hives, swelling and ing for a few hours then safe, tolerable and ties, with substantial swelling of the lips on after which the intensity of pruritus. 4 lesions and swelling recur. reliable. a daily basis (Figures: Photo Case 4-1, Case condition cleared Improved study Medication takes hours to It is a prescription 4-2, Case 4-3). Very itchy, adversely affecting (Figure: Photo Case productivity, sleep, work; patient feels sedated medication (drug daily activities, social life, self-image and 4-4), then bilastine social life and self- with decreased daytime coverage). sleep. 20 mg QD x 30 days image. productivity. followed by PRN. Referral for allergy testing and care by family physician. Bilastine, 20 mg QD x 3 months resulted Almost symptom in marked improve- free for up to 2 Desloratadine,Do Not minimal Copyim- ment, symptoms months (mild 12-year-old male (54.3 inches/89 pounds) provement. Bilastine 20mg are less intense, re- swelling ~2x/mo). 20 minutes after treatmentPrevious treatment with an 8-month history of daily urticaria, QD was started by primary solve more quickly, Bilastine restarted to 5 Penalties Applywith desloratadine intermittent angioedema (lips, eyes), signifi- care physician 3 months now breakouts are prevent these symp- unsuccessful. cantly impacting his daily activities. prior to presentation in this 1-3 times per week. toms (20 mg QD or clinic. Dose increased to BID). Bilastine was 20 mg QD or BID. well tolerated with Condition and qual- no adverse effects. ity of life improved. Chronic spontaneous urticaria (Case 3: CSU and dermatographism (Susan Waserman) Case 4: CSU with angioedema (Jaggi Rao) Case 5: CSU and angioedema (Tim

Vander Leek). Once a day (QD);Twice a day (BID); Three times a day (TID); Four times a day (QID); Oral (PO); As needed (PRN) Case 4-1 Case 4-2 Case 4-3 Case 4-4

20 minutes20 minutesafter20 minutes treatment after aftertreatment treatment

CASE 4 BEFORE CASE 4 AFTER

152 Journal of Drugs in Dermatology C.W. Lynde, G. Sussman, P-L Dion, et al February 2020 • Volume 19 • Issue 2

TABLE 5. Case Studies of Patients With Inducible Urticaria

Why Bilastine Disease Follow up/ No Case and Issues Previous Treatment Was Chosen Management Learning Points 29-year-old female with cold contact urticaria symptoms which started to occur ~5 Cetirizine replaced years ago and are getting worse with time. by bilastine 40 mg Cyproheptadine 16 mg On several occasions, patient experienced BID. Clinical caused such sedation that a generalized urticarial rash, which was response – very she had to stop medication. accompanied, on two events, with dyspnea good in terms of: Follow-up ice cube Cetirizine 40 mg gave a clini- Effective and less 6 and dizziness. According to Wanderer’s - Significant test gave minimal cal response; however, she sedation. classification based on severity: Type III (one reduction of response. reduced the dose because or more episodes associated with symp- number of attacks of serious side effects. At toms and signs indicative of respiratory or and their severity bed time doxepine 75 mg. cardiovascular compromise). The condition - No more sys- negatively impacted her QoL. Ice cube test– temic symptoms clearly positive. 22-year-old male with cholinergic urti- Educated re: caria presented with recurrent itchy, small, disease urticarial wheals post-exercise and stress, Previously treated as Controls the Bilastine 20 mg PO Bilastine 20 mg PO which go away after 2-3 hours. Bothers him scabies (ineffective) and condition well, no BID, episodically 7 BID, as needed con- at the gym, makes him self-conscious. Clini- also treated as AD with sedation or mood when he feels he trolled the disease cally cholinergic urticaria (not painful). He topical steroids (no help). disturbance. needs it. effectively. has seen several physicians (walk-in clinics) and no one is certain what he has. Case 6: Cold urticaria (Jacques Hebert) Case 7: Cholinergic urticaria (Charles Lynde). Quality of life (QoL); atopic dermatitis (AD); Twice daily (BID); Oral (PO)

TABLE 6. Case Study of a Patient With Urticarial Vasculitis

Do Not CopyWhy Bilastine Disease Follow up/ No Case and Issues Previous Treatment Was Chosen Management Learning Points Penalties Apply Condition has improved (however, patient was 43-year-old female presented with urticarial reluctant to reduce vasculitis. She has a history of ulcerative dapsone). colitis and sclerosing cholangitis. Colectomy Good control Cetirizine, desloratadine for high-grade dysplasia followed in 2011. with bilastine + (for years), dapsone added In 2010, started to have urticarial plaques on Cetirizine/deslorata- dapsone (except in 2011 to improve control. face/trunk/limbs. Lesions present but little dine were replaced for a few outbreaks Continue bilastine as Was well controlled on pruritus. by bilastine 80 mg each year when needed + dapsone 8 that combination (except QD to improve under psychologi- is continued for 14 when under psychological Many previous biopsies were negative for drowsiness and cal stress). Impact days. stress she developed a few urticarial vasculitis (finally positive in 2018). maintain efficacy. of skin condition: lesions). She complained of Low C3-C4. Impact of skin condition: Daily daily activities (no); drowsiness. activities (yes); professional life (yes), social professional life life (yes), self-image (ves), sleep disturbance (no), social life (no), (no). self-image (no), sleep disturbance (no); No adverse events. Case 8: Urticarial vasculitis (Pierre-Luc Dion) (Table 6). Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

153 Journal of Drugs in Dermatology C.W. Lynde, G. Sussman, P-L Dion, et al February 2020 • Volume 19 • Issue 2

TABLE 7. Case Studies of Patients With Inducible Urticaria

Why Bilastine Disease Follow up/ No Case and Issues Previous Treatment Was Chosen Management Learning Points Refractory pruritus Protopic, nerisone, sys- Bilastine (20 mg 76-year-old retired male presented with unresponsive to Refractory pruritus tem steroids, doxepin, OD) in addition constant itching without a skin eruption other AHs; depen- of unknown etiology, loratadine, rupatadine, to bb-UVB/twice (pruritus of unknown origin) except for dant on UVB 2x/ which is dependent refrigerated lotion. Tried BB a week. UVB was occasional dry skin in the winter for 4.5 week. In Japan, on UVB may respond 9 UVB reduced pruritus, but discontinued and years. Itching was worse in the winter even bilastine is indicated to bilastine mono- worsened when decreased pruritus controlled if his skin was adequately moisturized. Skin for pruritus and it therapy, allowing for to once a week. He became with bilastine 20mg biopsy: Superficial perivascular dermatitis. has several studies UVB to be discon- dependant on phototherapy OD for a month; no QOL: Hard to concentrate due to itch. showing efficacy in tinued for 2 years. adverse events. pruritus. Bilastine, 20 mg/day (on medication for 2 months); flutica- 63-year-old female with AD, asthma, allergic sone nasal spray. rhinosinusitis, pruritic and heat/sun sensitiv- Improvements Primary skin care ity. AD exacerbated with heat/sun exposure; Other antihistamines started 1 day after plan in AD is impor- blistering type of reaction. Patient avoided Desloratadine, diphenhydr- have not been taking bilastine – tant. The AH may be 10 light exposure, wore gloves, used bandages, amine, clobetasol propio- significantly effective itchiness and facial an effective adjunct felt “poisoned” by the condition, which has nate. in controlling skin puffiness reduced, to AD treatment to a severe impact on daily activities, sleep, eruptions. improvement in control pruritus. mood and self-image. Location of lesions QoL leading to im- and erythema: Arms, legs, neck. provement in mood and self- image; less drowsy. Pruritus: Case 9: Pruritus of unknown origin (Lyn Guenther), Dermatitis/eczema Case 10: Atopic dermatitis (Gordon Sussman) Quality of life (QOL); Broad band (BB); atopic dermatitis (AD)

Pruritus of unknown cause and pruritus associated withDo AD Not panelCopy suggested a minimum of 2–3 months with no condition Table 7 discusses two patients with pruritus: In case 9, the pa- activity or symptoms before discontinuing bilastine, after which tient presents with pruritic symptoms due to an unknownPenalties cause, the Apply AH is taken as needed. In SAR an AH is to be taken for the while case 10 involves a patient with AD-related pruritus. For duration of the pollen season, and those with PAR can take it these patients, education on their conditions, avoidance of pru- indefinitely. In those patients with CSU the time they need to ritic triggers, and the implementation of a primary skincare plan take AH varies considerably. Generally we treat until the disease using a moisturizer were essential to improving their condition. is gone. Second-generation AHs can sometimes help to treat pruritus related to AD, but not the AD itself. In case 10, bilastine is shown as The panel members concluded that their task is not only to an effective adjunct to AD treatment to control pruritus. Howev- teach about the risks of first-generation sedating AHs but also er, adherence to therapy is important for success. Again, panel to educate healthcare providers (including primary care phy- members emphasized that the sedation caused by using first- sicians) and their patients on how and why they should use generation AH is not helpful in treating pruritus and can also second-generation AHs. cause serious side effects.1-6,12 The authors stated: “Bilastine is not available in the US, but it Suggestions for bilastine use is in Canada, and we find it effective.” Although guidelines from Second generation AHs such as bilastine may work, even when the US recommend second-generation AHs, due to lack of avail- other AHs do not. The effective clinical response in many of the ability, the choices are more limited.38 presented patient cases was achieved not because treatment with first-generation AHs are ineffective but because the patient CONCLUSIONS could not tolerate the first generation AH. It must be recognized Second-generation AHs are thoroughly investigated in clinical that first-generation AHs have serious side effects significantly pharmacology studies and randomized controlled trials. Every and negatively impacting QoL. day clinical practice can pose challenges when selecting an effective and safe AH for the treatment of allergic conditions.The The panel members recommended that for pruritic conditions, real-world cases presented here applied bilastine in conditions bilastine is continued until all symptoms subside, usually, 1 to such as SAR, PAR, chronic urticaria, and less common but chal- 2 months duration, up to 6 months, or longer if necessary. The lenging conditions such as urticarial vasculitis and pruritus in Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

154 Journal of Drugs in Dermatology C.W. Lynde, G. Sussman, P-L Dion, et al February 2020 • Volume 19 • Issue 2

PDF. inflammatory skin conditions. This second-generation AH, bilas- 18. Horak F, Zieglmayer P, Zieglmayer R, Lemell P. The effects of bilastine com- tine, was shown to be effective in relieving symptoms, was safe pared with cetirizine, fexofenadine, and placebo on allergen-induced nasal and ocular symptoms in patients exposed to aeroallergen in the Vienna Chal- and well tolerated even when used over a prolonged period. lenge Chamber. Inflamm Res. 2010;59(5):391-398. 19. Valk PJ, Simons R, Jetten AM, Valiente R, Labeaga L. Cognitive performance DISCLOSURES effects of bilastine 20 mg during 6 hours at 8000 ft cabin altitude. Aerosp Med Hum Perform. 2016;87(7):622-627. The authors have no conflicts of interest to declare. 20. Conen S, Theunissen EL, Van Oers AC, Valiente R, Ramaekers JG. Acute and subchronic effects of bilastine (20 and 40 mg) and hydroxyzine (50 mg) on actual driving performance in healthy volunteers. J Psychopharmacol. Some of the settings for bilastine use in this article are consid- 2011;25(11):1517-1523. ered ‘off-label’. Use of bilastine in off-label settings is left up to 2 1. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organiza- the discretion of the treating health care professional after care- tion, GA(2)LEN and AllerGen). Allergy. 2008;63 Suppl 86:8-160. ful clinical evaluation. 22. Passali D, Cingi C, Staffa P, Passali F, Muluk NB, Bellussi ML. The International Study of the Allergic Rhinitis Survey: outcomes from 4 geographical regions. Asia Pac Allergy. 2018;8(1):e7. ACKNOWLEDGMENT 23. Juniper EF, Rohrbaugh T, Meltzer EO. A questionnaire to measure quality of The authors acknowledge and thank Anneke Andriessen PhD for life in adults with nocturnal allergic rhinoconjunctivitis. J Allergy Clin Immu- nol. 2003;111(3):484-490. her invaluable assistance with preparing this manuscript. 24. Skoner DP. Allergic rhinitis: definition, epidemiology, pathophysiology, detection, and diagnosis. J Allergy Clin Immunol. 2001;108(1 Suppl):S2-8. REFERENCES 25. Bachert C, Kuna P, Sanquer F, et al. Comparison of the efficacy and safety of bilastine 20 mg vs desloratadine 5 mg in seasonal allergic rhinitis patients. 1. Kuna P, Jurkiewicz D, Czarnecka-Operacz MM, et al. The role and choice Allergy. 2009;64(1):158-165. criteria of antihistamines in allergy management - expert opinion. Postepy 26. Okubo K, Gotoh M, Asako M, et al. Efficacy and safety of bilastine in Japa- Dermatol Alergol. 2016;33(6):397-410. nese patients with perennial allergic rhinitis: A multicenter, randomized, 2. Simons FE, Simons KJ. Histamine and H1-antihistamines: celebrating a cen- double-blind, placebo-controlled, parallel-group phase III study. Allergol Int. tury of progress. J Allergy Clin Immunol. 2011;128(6):1139-1150 e1134. 2017;66(1):97-105. 3. Sussman G, Hebert J, Gulliver W, et al. Insights and advances in chronic 2 7. Okubo K, Gotoh M, Togawa M, Saito A, Ohashi Y. Long-term safety and ef- urticaria: a Canadian perspective. Allergy Asthma Clin Immunol. 2015;11(1):7. ficacy of bilastine following up to 12 weeks or 52 weeks of treatment in 4. Staevska M, Gugutkova M, Lazarova C, et al. Night-time sedating H1 -an- Japanese patients with allergic rhinitis: Results of an open-label trial. Auris tihistamine increases daytime somnolence but not treatment efficacy in Nasus Larynx. 2017;44(3):294-301. chronic spontaneous urticaria: a randomized controlled trial. Br J Dermatol. 28. Sastre J, Mullol J, Valero A, Valiente R, Bilastine Study G. Efficacy and safety 2014;171(1):148-154. of bilastine 20 mg compared with cetirizine 10 mg and placebo in the treat- 5. Farre M, Perez-Mana C, Papaseit E, et al. Bilastine vs. hydroxyzine: occupa- ment of perennial allergic rhinitis. Curr Med Res Opin. 2012;28(1):121-130. tion of brain histamine H1 -receptors evaluated by positron emission tomog- 29. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA(2)LEN/EDF/WAO guide- raphy in healthy volunteers. Br J Clin Pharmacol. 2014;78(5):970-980.Do Not Copyline for the definition, classification, diagnosis and management of urticaria. 6. Garcia-Gea C, Martinez-Colomer J, Antonijoan RM, Valiente R, Barbanoj Allergy. 2018;73(7):1393-1414. MJ. Comparison of peripheral and central effects of single and repeated 30. Kaplan AP. Chronic urticaria: pathogenesis and treatment. J Allergy Clin Im- oral dose administrations of bilastine, a new H1 antihistamine:Penalties a dose-range Applymunol. 2004;114(3):465-474; quiz 475. study in healthy volunteers with hydroxyzine and placebo as control treat- 3 1. Krause K, Spohr A, Zuberbier T, Church MK, Maurer M. Up-dosing with bi- ments. J Clin Psychopharmacol. 2008;28(6):675-685. lastine results in improved effectiveness in cold contact urticaria. Allergy. 7. Sadaba B, Azanza JR, Gomez-Guiu A, Rodil R. Critical appraisal of bilastine 2013;68(7):921-928. for the treatment of allergic rhinoconjunctivitis and urticaria. Ther Clin Risk 32. Serra E, Campo C, Novak Z, et al. Efficacy and safety of bilastine in reducing Manag. 2013;9:197-205. pruritus in patients with chronic spontaneous urticaria and other skin dis- 8. Church MK, Labeaga L. Bilastine: a new H1 -antihistamine with an op- eases: an exploratory study. J Dermatolog Treat. 2019:1-9. timal profile for updosing in urticaria.J Eur Acad Dermatol Venereol. 33. Weller K, Church MK, Hawro T, et al. Updosing of bilastine is effective in 2017;31(9):1447-1452. moderate to severe chronic spontaneous urticaria: A real-life study. Allergy. 9. Kawauchi H, Yanai K, Wang DY, Itahashi K, Okubo K. Antihistamines for al- 2018;73(10):2073-2075. lergic rhinitis treatment from the viewpoint of nonsedative properties. Int J 34. Yagami A, Furue M, Togawa M, Saito A, Hide M. One-year safety and ef- Mol Sci. 2019;20(1). ficacy study of bilastine treatment in Japanese patients with chronic spon- 10. Church MK, Church DS. Pharmacology of antihistamines. Indian J Dermatol. taneous urticaria or pruritus associated with skin diseases. J Dermatol. 2013;58(3):219-224. 2017;44(4):375-385. 11. Staub A, Bovet D. Action de la thymoxyethyldiethylamine (929F) et des 35. Zuberbier T, Oanta A, Bogacka E, et al. Comparison of the efficacy and safety ethers phenoliques sur le choc anaphylactique. C R Soc Biol. 1937;125:818– of bilastine 20 mg vs levocetirizine 5 mg for the treatment of chronic idio- 821. pathic urticaria: a multi-centre, double-blind, randomized, placebo-controlled 12. Church MK, Maurer M, Simons FE, et al. Risk of first-generation H(1)-antihis- study. Allergy. 2010;65(4):516-528. tamines: a GA(2)LEN position paper. Allergy. 2010;65(4):459-466. 36. van Zuuren EJ, Apfelbacher CJ, Fedorowicz Z, Jupiter A, Matterne U, Weis- 13. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA(2) LEN/EDF/WAO shaar E. No high level evidence to support the use of oral H1 antihistamines Guideline for the definition, classification, diagnosis, and management of as monotherapy for eczema: a summary of a Cochrane systematic review. urticaria: the 2013 revision and update. Allergy. 2014;69(7):868-887. Syst Rev. 2014;3:25. 14. Brozek JL, Bousquet J, Baena-Cagnani CE, et al. Allergic rhinitis and its Im- 3 7. Novak Z, Yanez A, Kiss I, et al. Safety and tolerability of bilastine 10 mg ad- pact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. ministered for 12 weeks in children with allergic diseases. Pediatr Allergy 2010;126(3):466-476. Immunol. 2016;27(5):493-498. 15. Kuna P, Bachert C, Nowacki Z, et al. Efficacy and safety of bilastine 20 mg 38. Seidman MD, Gurgel RK, Lin SY, et al. Clinical practice guideline: Allergic compared with cetirizine 10 mg and placebo for the symptomatic treatment rhinitis. Otolaryngol Head Neck Surg. 2015;152(1 Suppl):S1-43. of seasonal allergic rhinitis: a randomized, double-blind, parallel-group study. Clin Exp Allergy. 2009;39(9):1338-1347. 16. Corcostegui R, Labeaga L, Innerarity A, Berisa A, Orjales A. Preclinical pharmacology of bilastine, a new selective histamine H1 receptor antago- AUTHOR CORRESPONDENCE nist: receptor selectivity and in vitro antihistaminic activity. Drugs R D. 2005;6(6):371-384. 1 7. BLEXTEN®. (Product Monograph) December 13 2018. Aralez Pharmaceuti- Charles W. Lynde MD FRCPC cals Canada Inc. In:Available from: https://pdf.hres.ca/dpd_pm/00047806. E-mail:...... ……...... [email protected] Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

doi:10.36849/JDD.2020.4731 February 2020 156 Volume 19 • Issue 2 Copyright © 2020 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Ingenol Mebutate: Expanded Utility Yasmin Khalfe BA and Theodore Rosen MD Department of Dermatology, Baylor College of Medicine, Houston, TX

ABSTRACT

Ingenol mebutate (IM) is a novel drug that was developed for the treatment of actinic keratosis (AK). The drug works by a dual mechanism of action -- a rapid induction of cell death by necrosis along with a delayed neutrophil-mediated cellular cytotoxicity response.¹ Currently, IM is available as a 0.015% or 0.05% topical gel and has only been FDA-approved for the treatment of actinic keratosis. However, IM has also been extensively used off-label, and found to be efficacious in the treatment of multiple other skin disorders. In this review, we discuss the current literature that provides evidence for the successful use of ingenol mebutate as treatment for dermatologic disorders beyond actinic keratosis.

J Drugs Dermatol. 2020;19(2)156-161. doi:10.36849/JDD.2020.4731

INTRODUCTION Bowen’s Disease ngenol mebutate (IM), brand name Picato®, is derived from Bowen’s Disease (BD), also known as squamous cell carcino- the sap of Euphorbia peplus, a plant used for centuries as ma in situ, is an intra-epidermal malignancy with the potential a natural remedy for skin conditions. IM works by a dual to progress to invasive squamous cell carcinoma at a risk of I 4 mechanism of action. First it induces rapid cell death by necro- 3-5%. The lesions are usually asymptomatic and present as sis, followed by neutrophil-mediated, antibody-dependentDo celNot- well-defined,Copy scaly patches or plaques. Treatment options in- lular cytotoxicity.1 This mechanism allows the drug to not only clude surgery, photodynamic therapy, cryotherapy, topical kill cells rapidly, but also prevent recurrence. IM Penaltieswas initially fluorouracil Apply and imiquimod. There is, however, limited data to developed to treat actinic keratosis (AK), a common skin cancer guide the definitive choice of therapy. Because actinic keratosis precursor. In randomized control studies, investigators demon- is a pre-malignant precursor of SCC, IM’s effectiveness against strated effective clinical and histologic clearance of AK with IM AK suggests efficacy against BD. In fact, in a Phase I/II clini- treatment.2 The Food and Drug Administration approved IM for cal study, Ramsay et al studied the effectiveness of E. peplus treatment of AK in January 2012, and currently it is available sap (in which IM is an active compound) on nonmelanoma skin commercially as a 0.015% or 0.05% topical gel.3 cancers (NMSC).5 The investigators found that 94% of patients with an intraepithelial carcinoma treated with E. peplus sap had There are multiple advantages to IM therapy compared to other a complete clinical response at 1-month post-treatment which treatments, as the latter can require high compliance, longer decreased to 75% at 15 months follow up. For SCC’s, the re- treatment courses, and access to provider-administered thera- sults showed a complete clinical response rate of 75% after 1 pies. Ingenol mebutate, by contrast, is a viable treatment option month and 50% after 15 months.5 Since then, multiple cases of as a topical therapy that can be patient, or caretaker admin- BD treated with commercial IM have been reported. istered. Another major advantage is that IM requires fewer applications and has a shorter treatment duration than other In one of the first cases reported, Braun et al treated a 74-year- topical drugs which can result in improved adherence.2 With old man with two lesions on his trunk consistent with BD.6 The these advantages and its effective mechanism of action, IM has patient was given 0.05% IM, and two months post-treatment the potential to be a valuable therapeutic drug for disorders the lesions had completely cleared clinically and histopatholog- other than AK. In the past few years, investigators have recog- ically. Similarly, Salleras et al reported 3 separate cases in which nized this potential and have reported IM use as an off-label IM was used to treat Bowen’s Disease: An 80-year-old woman treatment for multiple illnesses. Numerous case reports and with a large BD lesion in the pre-tibial area failed treatment with studies have been recently published demonstrating the novel photodynamic therapy and imiquimod 5% cream, so IM 0.05% use of the drug. This review summarizes the current literature was applied twice, 24 hours apart.7 The patient had local reac- and synthesizes evidence for the use of ingenol mebutate as tions that cleared gradually, and histopathologic clearance was treatment for dermatologic disorders beyond actinic keratosis. noted at 9 weeks. The second case was of a 73-year-old woman Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

157 Journal of Drugs in Dermatology Y. Khalfe, T. Rosen February 2020 • Volume 19 • Issue 2 with BD on the thigh. IM 0.05% was applied twice, 24 hours case reports discussed which all showed complete clearance of apart. Histological clearance was noted at 4 weeks. Lastly, an BD, the cure rate in this study was relatively lower. Nine of the 87-year-old woman with pre-auricular lesion diagnosed as BD 17 patients (52.9%) showed a complete response. When con- was treated with 3 applications of 0.015% IM, each 24 hours sidering patients treated with IM alone, only 1 patient showed apart. Ensuing inflammation resolved, and histologic resolu- a complete response, and 4 showed partial response. However, tion was verified 4 weeks post-treatment. when fractional CO2 laser pretreatment was employed, all patients had some response, with 8/9 patients (88.9%) having a Two additional cases of successful 0.05% IM have been report- complete response. ed. Lee et al reported a 79-year-old woman with a BD plaque on her calf treated with 0.05% IM for 3 consecutive days.8 LSR’s Taken together, these studies demonstrate the potential ef- peaked between day 3 and 6, but 10-weeks post treatment, all fectiveness of IM in treating BD. While the 10 case reports of lesions clinically resolved, and biopsies showed no evidence of solely IM treatment all showed complete clearance of BD in BD. A separate report of a 73-year-old male with a BD lesion on both males and females around 70-80 years old, the study by the dorsum of the hand was also treated with 0.05% IM, but for Lee et al did not demonstrate as impressive efficacy with only 2 consecutive days.9 The patient had complete clinical remis- IM gel (only 12.5% in male and female patients ages 36-85). sion at 6 weeks follow up. However, when patients received a pretreatment fractional CO2 laser, almost 90% showed complete clearance. Thus, the In terms of 0.015% IM, Rallis et al report treating a 75-year-old addition of fractional CO2 laser prior to IM treatment may be man with numerous AK’s on his face and scalp as well as a reasonable. Additionally, the use of an occlusive dressing in lesion on the ear that was confirmed intraepidermal SCC on elderly populations who need physician-directed treatment in- biopsy.10 The patient was scheduled for cryosurgery and pre- stead of patient-directed treatment is a valid consideration. scribed 0.015% IM daily for 3 consecutive days for AK’s. Two months later, all AK lesions as well as the BD lesion had com- Superficial Basal Cell Carcinoma pletely resolved. When asked, the patient stated he applied Basal cell carcinoma (BCC) is the most common skin cancer in IM to the in-situ SCC in the same fashion as AKs. No recur- the world.14 UV radiation from sunlight is the most important rence was seen 5 months post-treatment. Similarly, Alkhalaf et risk factor for BCC. The incidence increases with age, however al used 0.015% IM to treat an 82-year-old Caucasian manDo with Not Copythe BCC incidence among younger women has been increasing 4 chest plaques diagnosed as BD.11 Due to patient preference recently.14 Superficial BCC (sBCC), in particular, is defined as for non-surgical treatment and physician-directedPenalties treatment, basaloid Apply cells confined to the epidermis or most superficial der- IM 0.015% was applied to each lesion and covered with an oc- mis. Such lesions commonly appear as scaly, non-firm patches clusive dressing for 1 day. Three months later, treatment was or papules often with a shiny quality.15 Traditional treatments repeated with bandage kept on for 2 days. At 6-months, 2 le- include excisional surgery and curettage/electrodesiccation as sions went into clinical remission, and the other 2 lesions were well as second-line therapies such as topical imiquimod, 5-fluo- treated once more for complete resolution. rouracil, photodynamic therapy, and cryosurgery. For patients in which surgery is unsuitable or against patient preference, ef- The use of Fractional CO2 laser prior to IM treatment has also fective topical options are imperative. IM has recently shown to been studied with promising results. In a case report by Chae be an effective alternative for sBCC. et al, a 68-year-old woman with histopathology-confirmed BD on her shin underwent pretreatment of CO2 fractional laser to One such study is the Phase I/II clinical study by Ramsay et al.5 promote transcutaneous drug delivery.12 She was instructed to Investigators found that the E. peplus sap containing IM was apply 0.05% IM for 2 consecutive days. Four weeks post-treat- effective against sBCC; in lesions <16 mm, the complete clini- ment, the erythematous plaque disappeared, and skin biopsy at cal response rate in this study was 78%. In another Phase II 3-months showed only irregular acanthosis with dermal fibro- study, Siller et al evaluated the safety of 2 applications of IM sis. Two years of follow-up showed no recurrence. at 3 concentration (0.0025%, 0.01% and 0.05%) in patients with histologically confirmed sBCC.16 The study was randomized, To evaluate effectiveness of IM in BD treatment and compare double blinded and vehicle controlled. Patients were all Cauca- IM efficacy alone or with ablative fractional laser pretreatment, sian and mostly males (73%) with an average age of 59 (range, a study was done in 2018 in which 19 patients were treated for 36-77). The patients were treated on either day 1 and 2 or day 1 biopsy-confirmed BD.13 Patients with facial lesions were given and 8 using randomly assigned 0.0025%, 0.01% or 0.05% IM, or 0.015% gel for 3 consecutive days and non-facial lesions re- a matching vehicle gel. The best outcome was seen in patients ceived 0.05% gel for 2 consecutive days. Nine patients received who received 2 applications of 0.05% IM on day 1 and 2 consec- pretreatment fractional CO2 laser. Two patients of the 10 who utively, as 63% (5/8) had histological clearance at day 85. Only received solely IM were lost to follow up. In contrast to previous 13% of patients who received treatment on day 1 and 8 had Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

158 Journal of Drugs in Dermatology Y. Khalfe, T. Rosen February 2020 • Volume 19 • Issue 2

complete clearance suggesting that treatment on consecutive complete resolution was observed. Ten weeks post-treatment, days is imperative to successful clearance of sBCC with IM gel. biopsy showed clearance by moderate depth, but remaining lesion was observed, so a second application of 0.015% IM was Similar success of IM treating sBCC was found in a retrospec- performed. Ten weeks later, biopsy showed complete resolution tive chart review by Bettencourt et al.17 Investigators looked at 7 on histology. patients with sBCC treated with 0.05% IM. The patients included 3 males and 4 females ages 47 to 75 whose lesions were all lo- Similarly, Diluvio et al reported successful use of 0.015% and cated on the trunk. Patients applied medication once daily until 0.05% IM in treating both pigmented and non-pigmented sBCC 2 tubes of 0.05% IM gel were empty. One patient was treated for in a case series of 4 patients.22 A 50-year-old Caucasian man 2 days, two were treated for 4 days, and the four were treated with a neck tumor and an 80-year-old Caucasian man with an for 7 days. Patients experienced LSR’s that resolved at 2 weeks. abdominal tumor showed dermoscopy findings of pigmented All sBCC’s resolved clinically at 2-4 weeks post-treatment, and sBCC. Based on the location of lesions, the former patient was repeat biopsy of 4 patients confirmed histologic clearance. Fol- treated with 0.015% IM once daily for 3 consecutive days, and low up every 3 months up to 14 months showed no suspicious the latter patient had 0.05% IM once daily for 2 consecutive lesions. days. One month later, no BCC-related dermoscopic criteria was seen for either patient. Histologic examination confirmed Multiple subsequent case reports of patients with sBCC show results, and no recurrence was seen during a 6-month period. similar findings. In a report by Cantisani et al, a 79-year-old The two patients with non-pigmented sBCC were a 50-year-old Caucasian man had multiple NMSC and AK.18 The patient was woman with preauricular lesion and a 56-year-old woman with treated with 0.05% IM applied for 2 consecutive days for both multiple trunk lesions. 0.015% IM was applied once daily for AK and a sBCC on his back. Complete resolution of the sBCC 3 consecutive days for the former patient and 0.05% IM was was noted 3 months post-treatment. applied once daily for 2 consecutive days for the latter. In the patient with the preauricular lesion, no BCC related dermo- Stieger et al reported a case of a 30-year-old woman with scopic criteria was seen one-month post-treatment. Histologic Gorlin-Goltz syndrome previously treated with conventional exam confirmed the results, and no recurrence was observed surgery, Mohs surgery, cryotherapy, laser ablation, photody- in 6 months follow-up. However, in the patient with multiple namic therapy, imiquimod 5%, 5-FU, and vismodegibDo systemic Not trunkCopy lesions, dermoscopy one month later showed complete therapy.19 The patient stopped the latter due to side effects, and regression of 2 lesions but only partial in the other 2 lesions, BCC recurred within 3 months. The patient requestedPenalties alterna- so Apply another cycle of treatment was repeated. Complete clinical tive therapy so 0.05% IM was prescribed. IM was applied for 2 resolution was observed confirmed by histological exam; no consecutive days leading to local inflammatory reaction which recurrence was seen in 6 months. Overall, 3 patients had com- healed after 2 weeks. The superficial BCC’s showed complete plete remission after single course, and one patient completely healing clinically with no recurrence up to 8 months post-treat- healed after two courses showing good efficacy and tolerance ment. of IM in both pigmented and non-pigmented sBCC.

In the largest case series reported, 20 patients with superficial Both concentrations of 0.015% and 0.05% IM have shown to BCC’s were treated with IM.20 The patients included 12 males be effective against sBCC on the trunk, extremities, and face/ and 8 females with a median age of 65 (range, 53-83). Eight scalp. Successful treatment has been demonstrated in both patients had back lesions, eight had trunk lesions, two had arm male and female patients in an age range of 30-80. In terms lesions, one had a shoulder lesion, and one had a leg lesion. of treatment schedule, the literature supports a course of 2-3 Patients were treated once daily with 0.05% IM for 2 consecu- consecutive days of daily treatment rather than multiple days tive days as in previous reports. In all 20 patients, LSR’s lasted between treatments. about 2 weeks. Two months post-treatment, all patients showed complete clinical and dermoscopic clearance. Six months post- Nodular Basal Cell Carcinoma treatment continued total clearance was reported with no Few studies have proven IM to be an effective treatment for recurrence. forms of BCC beyond the superficial variety. Two cases of treated nodular BCC (nBCC) have been reported in the literature. In terms of 0.015% IM Jung et al showed histologically proven successful treatment of sBCC.21 Investigators treated an The first was of a 100-year-old bed-bound woman with a large 84-year-old Korean woman with a forehead patch consistent nodule on her cheek confirmed as nBCC by histology.23 Because with sBCC on histologic examination. Due to age and patient she was not a good surgical candidate, she was treated with preference, 0.015% IM was applied once daily for 4 consecu- IM 0.015% applied daily for 3 consecutive days. This treatment tive days. LSR lasted 2 weeks, and 2 months after treatment, was repeated 3 consecutive months. Tumor size reduced, and Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

159 Journal of Drugs in Dermatology Y. Khalfe, T. Rosen February 2020 • Volume 19 • Issue 2

6 months later the regimen was repeated for 4 more months of FMF lesions. consecutively. The nBCC completely disappeared, and no recurrence happened 6 months later. Overall topical IM in the 7 reported cases proved to be an effective treatment for MF. Additionally, in a study of 11 male In another report, investigators treated a 66-year-old man with patients, IM 0.05% showed to be an effective adjuvant therapy a nBCC on his temple.24 He was given IM 0.015% once daily for MF and FMF. However, because of the small number of pa- for 3 consecutive days. By Day 37, the lesion had clinically tients, furthers studies with appropriate placebo control are cleared. Taken together, these cases show the effectiveness of needed. IM in treating not only superficial BCC but nodular BCC as well. However, due to the small number of cases, an optimal dosing Anogenital Warts regimen for nBCC remains uncertain. Anogenital warts (AW) are caused by the human papillomavirus, most often types 6 and 11. HPV is the most common sexually Mycosis Fungoides transmitted disease worldwide.29 Treatment guidelines from the Mycosis fungoides (MF) is the most common cutaneous T cell CDC recommend patient-applied imiquimod cream, podofilox lymphoma. MF is diagnosed by skin biopsy and immunohis- gel, or sinecatechins; provider-administered treatments include tochemistry, and typical treatment options include ultrapotent surgery, cryotherapy or trichloroacetic acid.30 However, only topical corticosteroids, phototherapy, radiation, and chemo- surgical therapies have clearance rates approaching 100%, and therapy.25 management is difficult as lesions recur. Multiple studies in recent years have examined IM efficacy in this disorder. Ignatavo and Chang assessed the effect of topical IM on MF lesions.26 Three patients with stage IA MF had previously re- Schopf et al studied the effects of IM in 17 patients (15 males ceived standard therapeutic intervention. One MF lesion was and 2 females) with median age 51 (range, 21-70) who had selected on the trunk or extremities that was a comparable size AGW clinically diagnosed and confirmed by biopsy.31 0.015% of < 50 cm2 and CAILS score of 20. Investigators applied 0.015% IM was used on 4 patients, and 0.05% was used on 13 patients. IM once daily for 3 days consecutively then continued pulse Results showed that 16/17 patients had clearance of AGW. In treatment with 0.05% IM on a 3-week basis for 12 weeks. Target 13/17 cases, one treatment was enough; one patient required 2 lesions were evaluated every 3 weeks, and lesions wereDo biop Not- applicationsCopy for clearance of AGW, while two patients required sied at baseline and after 6 weeks before reapplication of IM. 3 applications. These patients had longer history of AGW, and Results showed a mean CAILS of 20.33 before treatmentPenalties and lesions Apply were more fibrotic and indurated. One patient (on CAILS of 1 on week 24 of treatment. A partial response (50%) cyclosporine A) showed a partial response. Overall, a single ap- was seen in 1 patient after 6 weeks and the other after 9 weeks. plication of IM was efficacious in over 76% of cases, and AGW However, 100% of treated MF lesions were in complete remis- remained in remission for up to 240 days post-treatment. sion at the end of the 24-week follow-up period. As ablative therapy for AGW can often only be done under In a study by Lebas et al, three male patients with longstanding general anesthesia, another case series observed the effects and extensive MF and one with folliculotropic MF (FMF) stage of IM application prior to ablative therapy.32 Two patients with T2 were treated with IM.27 A single target lesion was selected, genital warts at the glans penis and anal skin were treated. A and 0.05% IM was applied twice with 1 week between appli- small drop of 0.05% IM was applied to all visible warts. Within cations. Patients continued methotrexate therapy. The patients 24 hours both patients had pain and grey discoloration of warts had adverse effects of burning and crusting for 3-5 days. How- managed with ibuprofen. The treated warts were ablated after ever, biopsies post-treatment showed no signs of MF or FMF in 48 hours. Within 1 week, erosions resolved with satisfactory all patients. cosmetic outcome and no scarring. There was no recurrence in a 3-month period. In both patients, 0.05% IM was a beneficial Lebas et al later published a prospective pilot evaluation in option for ablating AGW without anesthesia. which ten male patients with longstanding, extensive MF and one with FMF who received methotrexate for at least 6 months In a larger study, Larsen et al examined the safety, efficacy and were treated with IM as adjuvant therapy.28 Eleven target le- recurrence of IM 0.05% in patients with 2-20 external AGW.33 sions were selected in each patient, and 0.05% IM was applied Of the 40 patients that received treatment, 83% of the patients twice with 1 week between applications. Biopsies were taken were men, and the median age was 36. IM 0.05% was applied of 10 lesions before and 2 months post-treatment. The mean on Day 1. If the patient did not have clearance by day 15 or 29, CAILS score was reduced by 59% compared with 5% for the treatment was repeated. Patients attended up to 7 visits on day controls, and a complete or partial clearance of histologic fea- 1, 3, 15, 29, and 43 and a follow up 12 weeks after day 29 or 43. tures was observed in 6/10 (60%) of MF lesions and 4/10 (40%) Efficacy was evaluated by complete clearance of AGW, reduc- Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

160 Journal of Drugs in Dermatology Y. Khalfe, T. Rosen February 2020 • Volume 19 • Issue 2

tion in AGW count 14 days after last treatment, and recurrence bilateral legs were confirmed DSAP by histology. Previous rate evaluated 12 weeks after complete clearance. 22 patients treatments of TCA, imiquimoid 5% and tretinoin 0.1% were inef- received 1 application, 8 patients received 2 applications, and fective. The patient was prescribed IM 0.05% for 2 days over the 10 patients received 3 applications. All patients had erosions right lower leg and followed up on days 3, 15, 30, and 60. By day and erythema, almost all had exudate, and ~80% had blister- 30, there was marked reduction in scaling with post-inflamma- ing with LSR’s returning to baseline by day 15. Five patients tory erythema, and on day 60 erythema had faded with reduced withdrew due to pain and kissing lesions. Complete clearance scaling. Overall the DSAP lesions were effectively treated with of AGW 14 days after last treatment was seen in 43.6% of pa- minimal discomfort and good cosmetic response. tients. There was a lower clearance rate with AGW duration >4 years, and a higher clearance rate for AGW counts <10. The re- In these two case reports of women in their late 40-50’s, both currence rate was 57.1%. Despite this, the median reduction in 0.05% and 0.015% IM were effective in treating porokeratosis. AGW count in 14 days after last treatment was 90.9%, showing While further studies are needed to support these conclusions, IM was efficacious in reducing the AGW count. IM could be a valuable alternative treatment for porokeratosis.

Collectively, all 59 patients in these studies treated with IM CONCLUSION 0.05% had a reduction in AGW lesions, with or without com- While ingenol mebutate has only been FDA-approved for the plete clearance. Additionally, the use of IM prior to ablative treatment of actinic keratosis, multiple other skin disorders therapy proved to be a valuable option for treatment without have been treated successfully off-label with IM. Evidence anesthesia. Although IM appears promising, its optimal treat- to support IM use is greatest for Bowen’s Disease, superficial ment regimen for AGW remains unknown. basal cell carcinoma and anogenital warts, as numerous case reports and controlled studies have been published in recent Porokeratosis years. Literature also exists suggesting efficacy of IM in treat- Porokeratosis is a rare skin disorder characterized by epider- ing mycosis fungoides and porokeratosis; because of the fewer mal keratinization and a distinct cornoid lamella. Multiple number of cases, further studies are imperative to determine an porokeratosis variants exist including disseminated super- appropriate IM dosing regimen. IM gel offers a topical therapy ficial actinic porokeratosis (DSAP), porokeratosis of Mibelli, with multiple advantages including a short treatment course. Al- linear porokeratosis, and others. Malignant transformationDo Not is thoughCopy local skin reactions are extremely common, and in fact, possible. Generally, sun protection and close surveillance for expected, they have been found to resolve promptly and with malignancy is sufficient management, but treatmentPenalties can be in- good Apply cosmetic outcome. IM may well prove to be a valuable op- dicated for preventative measures. Treatment of local disease tion for patients whose individual situations call for innovative can be done with ablative measures or topical therapy (includ- and creative intervention. ing steroids, 5-fluoruracil, imiquimod 5%, and retinoids).34 However, no randomized clinical trials have been done assess- DISCLOSURES ing treatment options, and no standard guidelines have been The authors report no relevant conflicts of interest. established. Because IM can target keratinocyte proliferation, it is justifiable that it may be effective against porokeratosis. REFERENCES 1. Rosen RH, Gupta AK, Tyring SK. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion ne- In the first case reported of IM therapy for porokeratosis, Kin- crosis followed by lesion-specific immune response. J Am Acad Dermatol. dem et al treated a woman in her 50’s with an 8-year history 2012;66(3):486-493. of porokeratosis of Mibelli confirmed clinically and histopatho- 2. Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366(11):1010-9. logically.35 The patient had unsuccessful previous treatments 3. Ali FR, Wlodek C, Lear JT. The role of ingenol mebutate in the treatment of including aminolevulinic acid, electrocoagulation, 5-fluoro- actinic keratoses. Dermatol Ther (Heidelb). 2012;2(1):8. 4. Jaeger AB, Gramkow A, Hjalgrim H, et al. Bowen disease and risk of sub- uracil, topical betamethasone and calcipotriol, CO2 laser, and sequent malignant neoplasms: A population-based cohort study of 1147 pa- imiquimod. She was also treated with pulsed dye laser and tients. Arch Dermatol. 1999;135(7):790-793. 5. Ramsay JR, Suhrbier A, Aylward JH, et al. The sap from Euphorbia pep- diclofenac sodium 3% gel; none of the treatments achieved re- lus is effective against human nonmelanoma skin cancers. Br J Dermatol. mission. Investigators gave the patient 0.015% IM once daily 2011;164(3):633-636. for 3 days. She received this treatment twice separated by 1 6. Braun SA, Homey B, Gerber PA. Successful treatment of Bowen disease with ingenol mebutate. Hautarzt. 2014;65(10):848-850. month. Three weeks after the second course, the lesion largely 7. Salleras Redonnet M, Quintana Codina M. Ingenol mebutate gel for the cleared with satisfactory cosmetic results. At 4 months, the pa- treatment of Bowen's disease: a case report of three patients. Dermatol Ther. 2016;29(4):236-239. tient showed no signs of recurrence and was pain-free. 8. Lee JH, Lee JH, Bae JM, et al. Successful treatment of Bowen's disease with ingenol mebutate 0.05% gel. J Dermatol. 2015;42(9):920-921 9. Mohanna MT, Hofbauer GF. Bowenoid actinic keratosis and Bowen's disease Another successful case reported a 47-year-old woman with treated successfully with ingenol mebutate. Dermatology. 2016;232 Suppl DSAP.36 Multiple erythematous annular scaling papules on 1:14-6. 10. Rallis E, Liakopoulou A, Christodoulopoulos C. Ingenol mebutate for the Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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treatment of intraepidermal squamous cell carcinoma. J Clin Aesthet Der- matol. 2017;10(7):12-13. 11. Alkhalaf A, Hofbauer GF. Ingenol Mebutate 150 mg as physician-directed treatment of Bowen's Disease under occlusion. Dermatology. 2016;232 Suppl 1:17-9. 12. Chae JB, Park JT, Kim BR, et al. A case of Bowen's Disease successfully Derm In-Review welcomes our treated with ingenol mebutate gel. Ann Dermatol. 2017;29(4):523-524. 13. Lee DW, Ahn HH, Kye YC, et al. Clinical experience of ingenol mebutate gel for the treatment of Bowen's disease. J Dermatol. 2018;45(4):425-430. advertising supporters and thanks 14. Verkouteren JAC, Ramdas KHR, Wakkee M, et al. Epidemiology of basal cell carcinoma: scholarly review. Br J Dermatol. 2017;177(2):359-372. 15. Chen CC, Chen CL. Clinical and histopathologic findings of superficial basal them for their commitment to cell carcinoma: A comparison with other basal cell carcinoma subtypes. J Chin Med Assoc. 2006;69(8):364-371. 16. Siller G, Rosen R, Freeman M, et al. PEP005 (ingenol mebutate) gel for the resident education. topical treatment of superficial basal cell carcinoma: results of a randomized phase IIa trial. Australas J Dermatol. 2010;51(2):99-105. 1 7. Bettencourt MS. Treatment of superficial basal cell carcinoma with ingenol mebutate gel, 0.05%. Clin Cosmet Investig Dermatol. 2016;9:205-209. 18. Cantisani C, Paolino G, Cantoresi F, et al. Superficial basal cell carcinoma successfully treated with ingenol mebutate gel 0.05%. Dermatol Ther. 2014;27(6):352-354. 19. Stieger M, Hunger RE. Ingenol mebutate treatment in a patient with Gorlin Syndrome. Dermatology. 2016;232 Suppl 1:29-31. 20. Izzi S, Sorgi P, Piemonte P, et al. Successfully treated superficial basal cell carcinomas with ingenol mebutate 0.05% gel: Report of twenty cases. Der- matol Ther. 2016;29(6):470-472. 2 1. Jung YS, Lee JH, Bae JM, et al. Superficial basal cell carcinoma treated with two cycles of ingenol mebutate gel 0.015. Ann Dermatol. 2016;28(6):796- 797. 22. Diluvio L, Bavetta M, Di Prete M, et al. Dermoscopic monitoring of efficacy of ingenol mebutate in the treatment of pigmented and non-pigmented basal cell carcinomas. Dermatol Ther. 2017;30(1):10.1111/dth.12438. Epub 2016 Nov 12. 23. Iannazzone SS, Ingordo V. Nodular basal cell carcinoma of the face successfully treated with ingenol mebutate 0.015% gel. Dermatol Pract Concept. 2018;8(2):129-131. 24. Del Rosso JQ. Ingenol mebutate topical gel A status report on clinical use beyond actinic keratosis. J Clin Aesthet Dermatol. 2016;9(11 SupplDo 1):S3-S11. Not Copy 25. Wilcox RA. Cutaneous T-cell lymphoma: 2011 update on diagnosis, risk-strat- ification, and management.Am J Hematol. 2011;86(11):928-948. Thank you also 26. Ignatova D, Chang YT, Hoetzenecker W, et al. Ingenol mebutatePenalties for mycosis Apply fungoides. Br J Dermatol. 2019. 2 7. Lebas E, Libon F, Quatresooz P, et al. Plaque/patch stage mycosis fungoides to our successfully treated with ingenol mebutate. Journal of the American Acad- emy of Dermatology. 2016;74(5, Supplement 1):AB181. educational partner 28. Lebas E, Arrese J, Libon F, et al. Prospective pilot evaluation of the efficacy and safety of adjuvant topical ingenol mebutate gel for localized patch/ Aurora Diagnostics plaque-stage mycosis fungoides. Journal of the American Academy of Der- matology. 2018;79(3, Supplement 1):AB230. for their continued 29. de Camargo CC, Tasca KI, Mendes MB, et al. Prevalence of anogenital warts in men with HIV/AIDS and associated factors. Open AIDS J. 2014;8:25–30. support of the 30. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexu- ally transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015; 64(RR-03):1-137. Dermpath 3 1. Schopf RE. Ingenol mebutate gel is effective against anogenital warts – a case series in 17 patients. J Eur Acad Dermatol Venereol. 2016;30(6):1041-1043. components of 32. Braun SA, Gerber PA. Ingenol mebutate for the management of genital warts in sensitive anatomic locations. J Am Acad Dermatol. 2017;77(1):e9-e10. Derm In-Review. 33. Larsen HK, Banzhaf CA, Thomsen SF, et al. An exploratory, prospective, open-label trial of ingenol mebutate gel 0.05% for the treatment of external anogenital warts. J Eur Acad Dermatol Venereol. 2018;32(5):825-831. 34. Williams GM, Fillman EP. Porokeratosis. In: StatPearls. Treasure Island (FL): StatPearls Publishing LLC; 2019. 35. Kindem S, Serra-Guillen C, Sorni G, et al. Treatment of porokeratosis of Mi- belli with ingenol mebutate: a possible new therapeutic option. JAMA Der- matol. 2015;151(1):85-86. 36. Anderson I, Routt ET, Jim On SC. Disseminated superficial actinic porokeratosis treated with ingenol mebutate gel 0.05. Cutis. 2017;99(3):E36-E39.

JDD Podcasts present the latest journal content related to advances in drugs, NEW EPISODE - CME AVAILABLE devices and treatment methods in Picking on Pruritus as a Problematic Clinical dermatology, in a new convenient Biomarker in Autoimmune Connective Tissue Diseases audio format. From article abstracts Drs. Gideon Smith and Adam Friedman to interviews, JDD Podcasts provide a fresh perspective of the peer reviewed Pruritus is the worst – plain and simple. However we have only content you have come to rely on just scratched the surface with respect to why it happens in a from JDD (Journal of Drugs in multitude of clinical scenarios and what it could be telling us Dermatology). other then “SCRATCH ME.” In this edition of the JDD Podcast, Dr. Gideon Smith, assistant professor of dermatology at Harvard Hosted by Adam Friedman, MD and Medical school, Vice Chair for Clinical Affairs in Dermatology, and released monthly, each episode will Director of the Connective Tissue Diseases Clinic and Fellowship feature an interview with, and practical joins us to pick apart his recent study in the JDD October 2019 pearls from, the principal investigator edition, Characterizing Pruritus in Autoimmune Connective Tissue of a high-profile JDD manuscript in a Diseases. Tune in to learn how not all itch is created equal in the convenient audio format. Each podcast autoimmune connective tissue world. Determine what questions will place the selected article into a can help guide management and therapy selection. Hear how to clinically useful perspective that is easy connect with rheumatology to forge a long lasting partnership, to listen to in the office or on the go. just like itchy and scratchy. Do Not Copy Penalties Apply www.jddonline.com/category/podcast Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

doi:10.36849/JDD.2020.4647 February 2020 163 Volume 19 • Issue 2 Copyright © 2020 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Long-Term Efficacy and Safety of Superficial Radiation Therapy in Subjects With Nonmelanoma Skin Cancer: A Retrospective Registry Study William Roth MD,a Robert E. Beer MD,B Vivek Iyengar MD,c Thomas Bender MD,D Isabelle Raymond PhDe aDermatology and Dermatological Surgery, Boynton Beach, FL BBalfour Dermatology, Brentwood, CA cDermatology Associates, Tinley Park, IL DAdvanced Dermatology and Skin Care Centre, Mobile, AL ESensus Healthcare, Boca Raton, FL

ABSTRACT

Background: Low-dose superficial radiation therapy (SRT) effectively treats nonmelanoma skin cancer (NMSC) without requiring invasive excision. SRT is especially safe and effective among the elderly who comprise most patients with basal cell and squamous cell carcinomas (BCCs and SCCs). Objective: To demonstrate the long-term safety and efficacy of SRT for treating NMSC with a new generation device. Methods: A retrospective chart review was performed at four clinical study sites. The study population included male and female patients (N=516) treated with SRT for NMSC (N=776) including BCCs (n=448) and SCCs (n=328) prior to January 2015 with long-term follow-up records. Results: The overall mean (SD) total treatment dosage was 4652.33 (366.34) cGy (range, 3636.6 to 5455 cGy) administered over a mean of 12.3 (1.85) sessions. The overall Kaplan-Meier survival probability estimate (95% CI) was 0.989 (0.980, 0.998) at 24 months, 0.989 (0.969, 1.000) at 60 months, and 0.989 (0.942, 1.000) at 85 months. There were six recurrences of BCCs (n=4) and SCCs (n=2). The most common adverse event was hypopigmentation. Limitations: Retrospective study design and some incompleteDo Not data. Copy Conclusion: It is estimated that 98.9% of nonmelanomaPenalties skin cancers Apply will not recur after 85 months following superficial radiation therapy.

J Drugs Dermatol. 2020;19(2)163-168. doi:10.36849/JDD.2020.4647

INTRODUCTION onmelanoma skin cancer (NMSC) comprises basal performed as an office procedure without anesthesia,11 minimal cell carcinoma (BCC), squamous cell carcinoma (SCC), risk of infection and superior cosmetic outcomes.12 Recovery is Nand numerous less common skin tumors.1 NMSCs are rapid with no or minimal downtime or lifestyle restrictions. SRT the commonest form of malignancy among Caucasians2 and its has been shown to be safe and very effective among elderly incidence continues to rise worldwide.3 Although Mohs surgery who comprise the majority of patients with NMSC.8,13 has traditionally been regarded as the gold-standard for treating NMSC,4 it may not be suitable for the elderly due to frailty, The objective of this retrospective chart review was to further limited life-expectancy, and comorbidities.5-7 demonstrate the long-term efficacy of SRT for treating NMSCs with a new generation device. Superficial radiation therapy (SRT) comprises low energy X-rays produced by units generally operating in the 50 to METHODS 150 kV range. SRT was the standard of care for office-based Seven clinical centers across the US that treated NMSCs with radiation treatment of NMSCs for more than 100 years but SRT for at least 5 years were contacted to participate. Sites were declined during the 1980s due to an increase in the popular- required to have treated at least 50 patients with ≥5-year fol- ity of Mohs micrographic surgery and because there were no low-up. Three sites declined or did not respond. The study was new devices to replace older ones;8 however, the use of SRT is therefore conducted in four clinical practices, where three of the currently seeing a resurgence following the reintroduction of four investigators were also Mohs surgeons. Retrospective chart newer, easy-to-use SRT equipment.9 Low-dose SRT effectively reviews identified 516 subjects treated for 776 histologically treats NMSC without requiring invasive excision.10 SRT can be confirmed, primary, cutaneous NMSC lesions. Relevant clinical Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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Journal of Drugs in Dermatology W. Roth, R.E. Beer, V. Iyengar, et al February 2020 • Volume 19 • Issue 2

TABLE 1. information regarding patient demographics, tumor characteristics, treatment parameters, and adverse events was recorded Comorbidities of Subjects Treated with SRT along with evidence of latent adverse events and lesion recur- n rence at follow-up. One site excluded data from patients treated Significant Cardiovascular Disease 54 13 for lower legs that were reported in another publication. Initial Diabetes 44 and recurrent lesions were staged according to the American Anticoagulation Therapy 36 Joint Committee on Cancer staging system for NMSCs.14 Immunosuppressed 22

Study Population Congestive Heart Failure 21 The study population included male and female patients treat- Leg Edema 16 ed with SRT for NMSC prior to January 2015; had one or more Chronic Obstructive Pulmonary Disease 15 lesions treated with a minimum 5 mm space between lesion History of MRSA 11 margins; and for whom the required long-term retrospective Dementia 10 data was available. All subjects were treated with the same de- Hypertension 10 vice (SRT-100™, Sensus Healthcare, Boca Raton, FL). Cancer/Non-Hodgkin’s Lymphoma 6 Peripheral Vascular Disease 5 Statistical Analysis Because of the variation in follow-up duration among patients, Coronary Bypass Surgery 4 Kaplan-Meier survival probability estimates were used to deter- Stasis Dermatitis 4 mine the recurrence rates for all tumors. Kaplan-Meier estimates Bleeding Disorder 3 were calculated across available follow-up data and reported as Kidney Dialysis 3 recurrence probability and 95% confidence intervals by follow- History of Stroke 2 up year. Lupus 1 Polymyalgia 1 Ethics Staphylococcal Infection in Treatment Area 1 The study protocol was determined to meet the conditions for exemption under 45 CFR 46.101(b)(4) by a commercialDo IRBNot Copy (Western Institutional Review Board (WIRB), Puyallup, WA). ClinicalTrials.gov Identifier: NCT03693937. PenaltiesTABLE Apply 2. RESULTS Lesion Location Location, n (%) All (n=776) BCC (n=448) SCC (n=328) Demographics and Clinical Characteristics Nose 179 (23) 151 (34) 28 (8) The 516 subjects included in the analysis were treated for 776 NMSCs. Subjects were male (n=293; 57%) and female (n=223; Lower leg 118 (15) 44 (10) 74 (23) 43%) with a mean (SD) age of 79 (8.7) years (range, 42 to 100 Forehead 76 (10) 44 (10) 32 (10) years). Most were 60 to 79 years old (46%) years and 80 to 89 Ear 71 (9) 49 (11) 22 (7) years old (43%). Among subjects for whom race was recorded Cheek 65 (8) 41 (9) 24 (7) (n=283; 55%), all were Caucasian. Most subjects (n=366; 71%) Scalp 51 (7) 14 (3) 37 (11) were treated for single lesions and the remainder were treated Lower arm 49 (6) 9 (2) 40 (12) for multiple lesions. Comorbid illnesses were recorded for 173 Body Trunk 36 (5) 24 (5) 12 (3) subjects (33.5%), many of whom had multiple comorbidities Hand 25 (3) 1 (<1) 24 (7) (Table 1). Neck 24 (3) 17 (4) 7 (2) Among the 776 lesions, 448 (58%) were diagnosed as BCCs and Upper arm 22 (3) 9 (2) 13 (4) 328 (42%) were diagnosed as SCCs. Subtype diagnosis was re- Chin 17 (2) 12 (3) 5 (2) ported for 330 of the 448 BCC lesions (74%), and for 186 of the Lips 15 (2) 12 (3) 3 (1) 328 SCC lesions (57%). The predominant BCC subtypes were Temple 7 (1) 7 (2) -- nodular (49%), infiltrative (16%), superficial (11%), and infiltra- Foot 6 (1) 4 (<1) 2 (1) tive + superficial (11%). The predominant SCC subtypes were Upper leg 5 (1) 3 (<1) 2 (1) in situ/Bowen’s disease (42%), well-differentiated (20%), and Eyelid 5 (1) 5 (1) -- keratoacanthoma (10%). All but ten lesions were new. Recurrent Chest 4 (<1) 2 (<1) 2 (1) BCCs (n=7) were previously treated with electrosurgery (n=2) and excision (n=1). Recurrent SCCs (n=3) were previously treat- Face 1 (<1) -- 1 (<1) ed with curettage and electrodesiccation. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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TABLE 3. outlier. The mean treatment margin for SCC lesions (n=308) was Follow-up Duration 7.9 (2.8) mm (range, 2.5 to 12 mm). The margins were kept the Months All NMSCs, n (%) BCC, n (%) SCC, n (%) same throughout the course of treatment. <6 71 (9) 43 (10) 28 (9) 6 – 12 96 (13) 59 (13) 37 (11.5) Energy was recorded for nearly all treated NMSCs (n=759). A 13 – 23 77 (10) 40 (9) 37 (11.5) treatment energy of 50 KV was applied to most lesions (91%) 24 – 35 90 (12) 55 (13) 35 (11) across both subtypes. Fewer lesions were treated with 70 (8%) or 100 KV (1%). For two BCC and two SCC lesions, the treat- 36 – 47 130 (17) 60 (14) 70 (22) ment energy was recorded as both 50 and 70 KV and were not 48 – 59 176 (23) 110 (25) 66 (20) included in the summary. Overall, 694 (91%) lesions received ≥60 118 (16) 70 (16) 48 (15) SRT fractions without interruption during the entire course of treatment while 79 lesions (29 BCC; 40 SCC) required treatment The mean (SD) lesion size was reported for 763 NMSCs (98%). breaks. The mean duration of these breaks was 16.2 days and Across all NMSC lesions, mean lesion size was 1.56 cm (1.1) most frequent duration was 14 days (38%) and 21 days (17%). (range, 0.3 to 6.5 cm), with 538 lesions (70.5%) <2 cm and 225 (29.5%) ≥2 cm. Most lesions were located on the head and neck. Immediate Efficacy The distribution and frequency of lesion locations is summa- The overall cure rate was defined as the percentage of NMSC le- rized in Table 2. sions attaining complete cure immediately following the course of SRT treatment. Complete cure data was available for 760 Superficial Radiation Therapy Variables treated lesions (98%). Treatment variables were available for 763 lesions for which the full SRT treatment protocol was completed. Incomplete Nine of the 760 NMSC lesions (5 SCC and 4 BCC), occurring in treatments were primarily due to patient non-compliance or six patients, with two patients having two lesions each, did not unrelated patient death prior to treatment completion. For one demonstrate complete cure; however, only one of these nine lesion, treatment was prematurely stopped due to severe pain lesions received the full SRT treatment. Incomplete treatments at the treatment site. As a result of early SRT termination, eight were due to patient non-compliance (n=4), or reasons unrelated lesions did not attain complete cure immediately Dofollowing Not Copyto NMSC or SRT (n=4). The individual with the one fully treated treatment completion. Follow-up was limited-to-none for these lesion was sent to oculoplastic surgeon (due to lesion location) lesions and they were excluded from the treatment Penaltiesanalyses. forApply follow-up, and the final outcome for the lesion is unknown. When the cure rate was calculated regardless of whether the Lesions (n=763) were treated with a mean total dose of 4652.33 full treatment protocol was completed, the overall cure rate was (366.34) cGy (range, 3636.6 to 5455 cGy) over a mean of 12.3 98.82% for all lesions (N=760). (1.85) SRT fractions (range, 6 to 18). Across all treated NMSCs, the most frequent number of total SRT fractions was 12, occur- Treatment Follow-up ring for about one-half of all lesions. Fractions were administered The most recent follow-up visit since the last SRT was recorded three times weekly for most lesions (84%) over a mean of (29.2) for 768 NMSCs (99%); however, no evaluation was reported for days (range, 10 to 60 days). ten lesions resulting final evaluable set of 758 NMSCs (437 BCCs and 321 SCCs). The distribution of follow-up duration for all le- The mean time dose fractionation (TDF) factor for all lesions sions is summarized in Table 3. Overall, the mean post-treatment was 99.11 (2.29; range, 87.5-116). The low TDF factor of 87.5 was follow-up was 36.5 (21.6) months (range, 1 to 85 months). due to one subject completing only 11 of 12 planned treatments. One BCC lesion with an outlier TDF of 130 was excluded from Recurrence the analysis but it is worth noting this patient was treated for a There were six recurrences among the 759 treated lesions for small infiltrative BCC. The higher TDF reflects a prior standard of which the presence or absence of a recurrence was reported, of practice together with the infiltrative quality and white appear- which one was inconclusive. That lesion had a 3x3 mm crusted ance of the lesion and the physicians’ belief that this high dose plaque at the site that made determination of recurrence uncer- was appropriate for a lesion that clinically had some features of tain. If all six lesions were included, the long-term cure rate was a sclerosing basal cell carcinoma. There was some initial bleed- 99.21% (recurrence rate 0.79%). If the questionable recurrence ing and mild hypopigmentation following treatment, but the is removed from the calculation, the long-term cure rate was overall outcome was positive. 99.34% (recurrence rate 0.66%).

The mean treatment margins for BCC lesions (n=433) was 6.8 Data regarding recurrent lesions is summarized in Table 4. Le- (2.6) mm (range, 1.5 to 23.5 mm). The 23.5 mm margin was an sions recurred after a mean of 13.3 months (range, 3 to 24 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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TABLE 4. Patient Demographics and Clinical Characteristics of Recurring Lesions Last Immediate Latent Age Diagnosis New or Recurrence Subject Gender Location Size (cm) Follow-up Adverse Adverse (yrs) Subtype Recurring (months) (months) Events Events redness, scaling: 3x3 BCC, 1 male 87 eyelid 0.3 new 9 9 mm crusted none infiltrative plaque on lesion redness; 2 female 94 BCC nose 2.5 recurring 9 18 moist; none ulcerated hypopigmentation BCC, right inflammation; 3 male 80 2.8 new 11 45 which later infiltrative cheek ulceration worsened; atrophy SCC, well-differ- right inflammation; 4 male 87 2.2 new 3 59 hypopigmentation entiated, lower leg crusting KA Type SCC, well-differ- inflammation; 5 male 84 lower leg 1.3 new 24 58 hypopigmentation entiated, crusting KA Type BCC, inflammation; 6 male 84 nose 0.5 new 24 65 hypopigmentation infiltrative crusting Subject 1. Recurrence inconclusive. Patient sent for follow-up with oculoplastic surgeon. Subject 2. Recurrent lesions previously treated with excision demonstrated complete cure following SRT treatment completion but recurred 9 months later. Treated with Mohs surgery. Outcome unknown as patient has since deceased. Subject 3. Lesion not involved in hypopigmented area but close enoughDo and Notof same pathology Copy to be considered a recurrence. Patient immunosuppressed and on renal dialysis with extensive skin cancers over the face, trunk and extremities. Recurrence treated with electrosurgery. Subject 4. Biopsy showed SCC KA-type lesion. It was noted that keratoacanthomas can occur in traumatized areas and are not unusual after excisions. As it was unclear if this was a recurrence or stimulation of new growth, it was conservativelyPenalties considered aApply recurrence. The lesion was retreated with electrosurgery. Subject 5. Patient had extensive skin cancers on the legs. This lesion occurred 2 years post-SRT on the edge of the radiated area and was therefore considered a recurrence. The lesion was treated with Mohs surgery Subject 6. The recurrent lesion was very extensive although the skin appeared normal microscopically. It was believed that the recurrence was due to inadequate treatment margins. The lesion was treated with Mohs surgery.

months). AEs and latent AEs were reported for each recurrent 1.000) at 60 months, and 0.982 (0.945, 1.00) at 85 months. For le- lesion; however, none were noted as serious. Recurrent lesions sions ≥2 cm, the survival probability was 0.983 (0.963, 1.000) at were subsequently treated with Mohs surgery (n=3), electrosur- 24 months, 0.983 (0.930, 1.000) at 60 months, and 0.983 (0.803, gery (n=2), or lost to follow-up (n=1). 1.00) at 85 months. Although a limited number of recurrences were noted, a multivariate Cox regression analysis was con- Kaplan-Meier Probability Estimates of Lesion Recurrence ducted to assess the potential influence of gender, age, NMSC The overall Kaplan-Meier survival probability estimate (95% CI) type, lesion size, and treatment margin, which failed to demon- was 0.989 (0.980, 0.998) at 24 months, 0.989 (0.969, 1.000) at 60 strate any significant association with recurrence-free survival. months, and 0.989 (0.942, 1.000) at 85 months (Table 5). Surviv- al probability for BCCs were 0.988 (0.975, 1.000) at 24 months, Safety 0.988 (0.960, 1.000) at 60 months, and 0.988 (0.930, 1.000) at 85 One of the four participating study sites (n=130 subjects) did not months (Table 5). The survival probability estimates for SCCs note any immediate or latent adverse events (AEs) in the medi- were 0.991 (0.979, 1.000) at 24 months, 0.991 (0.962, 1.000) at 60 cal charts. One site (n=350 subjects) noted radiation dermatitis months, and 0.991 (0.910, 1.000) at 85 months (Table 5). for six treated lesions from two subjects.

Survival probability estimates (95% CI) were also calculated A third study site noted AEs for all treated lesions (n=74) consist- based on lesion size. For lesions <2 cm in diameter, the survival ing of redness alone or in combination with one or more events probability was 0.982 (0.982, 1.00) at 24 months, 0.982 (0.971, of scaly, itchy, hot, and moist. Other noted AEs included ulcer- Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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TABLE 5. Kaplan-Meier Survival Probability Estimates DISCUSSION All Nonmelanoma Skin Cancers Superficial radiation therapy has been used to treat NMSC for Survival 95% Confidence over a century with low recurrence rates and favorable cosme- Month Probability Interval Limit sis.10 The objective of this study was to further demonstrate the Estimate Lower Upper long-term efficacy of SRT for treating NMSCs with a new gen- 12 0.993 0.987 0.999 eration device. The results of this present study revealed overall 24 0.989 0.980 0.998 cure rates of 98.9% at 24, 60, and 85 months. This compares fa- 36 0.989 0.979 0.999 vorably with the cure rates of 98.1% at 24 months and 95.0% at 60 months10 and 97.4% after 36 months13 reported by others. 48 0.989 0.977 1.000 60 0.989 0.969 1.000 Higher cure rates in the present study could be partly due to 72 0.989 0.943 1.000 more optimal treatment parameters including a higher number 85 0.989 0.942 1.000 of doses (fractions) and/or dosing frequency. Recent consensus guidelines15 suggest treatment recommendations should Basal Cell Carcinoma Lesions be speci¬fic for anatomical locations and that changes in SRT Survival 95% Confidence fractionation schemes by increased number and time between Month Probability Interval Limit treatments have led to better outcomes.16-18 The treatment mar- Estimate Lower Upper gins were also kept consistent throughout the duration of the 12 0.991 0.981 1.000 treatment and TDF was kept between 90 and 110, which is within 19 24 0.988 0.975 1.000 the suggested therapeutic window. Another reason cure rates 36 0.988 0.974 1.000 may have been higher is patient selection. As three of the four study investigators were Mohs surgeons, it is possible they se- 48 0.988 0.971 1.000 lected patients who were more ideally suited for SRT versus 60 0.988 0.960 1.000 patients better suited for Mohs surgery. 72 0.988 0.930 1.000 85 0.988 0.930 1.000Do Not OtherCopy possible reasons for higher cure rates includes site selection, which was biased toward sites with long-term data and the Squamous Cell Carcinoma Lesions Penaltiesavailability Apply of staff to collect patient information. The retrospec- Survival 95% Confidence tive nature of the study also increased the possibility that some Month Probability Interval Limit lesion recurrences were lost to follow-up. Still, there were six Estimate Lower Upper recurrences that were noted at follow up. One lesion was recur- 12 0.999 0.988 1.000 rent prior to SRT, which made it a higher risk of recurring,20 but 24 0.991 0.979 1.000 other lesions were not. It is difficult to say why some lesions 36 0.991 0.978 1.000 recurred and regression analysis failed to demonstrate any significant associations. Importantly, recurring lesions were all 48 0.991 0.974 1.000 subsequently treated successfully with other modalities. 60 0.991 0.962 1.000

72 0.991 0.911 1.000 AEs were inconsistently noted in medical charts and varied be- 85 0.991 0.910 1.000 tween sites. We suspect some site recorded all AEs and others only recorded unexpected AEs. Expected AEs with SRT include ation (n=6; 8%) and latent AEs included burning, itching, pain transient redness and scaliness at the treatment site. More (n=5), hyperpigmentation (n=2), scarring (n=2), and radiogenic significant AEs and latent AEs responded to treatment and even- ulceration (n=1). tually resolved.

The fourth study site noted AEs for all NMSC lesions treated at Superficial radiation therapy is currently recommended as an al- the site (n=225) consisting of inflammation alone or together ternative to surgery for primary BCCs and SCCs of the head and with crusted and ulcerated skin. Other AEs included one in- neck,21 particularly when surgery may result in functional deficits stance of each of the following: mucositis, hypopigmentation, or poor cosmetic outcomes.7,15,22 The National Comprehensive and hair loss. Latent AEs included hypopigmentation (n=173; Cancer Network® Guidelines recommend radiotherapy for pa- 77%), atrophy (n=10), acute pain (n=2), Staphylococcal infection tients with BCC and SCC who are not candidates for surgery, requiring antibiotics (n=1), mucositis (n=1), epistaxis (n=1), and or over 60 years of age because of concerns about long-term minor hair loss (n=1). sequelae;23,24 however, radiation therapy is contraindicated in Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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10. Cognetta AB, Howard BM, Heaton HP, Stoddard ER, Hong HG, Green WH. genetic conditions predisposing to skin cancer (basal cell nevus Superficial x-ray in the treatment of basal and squamous cell carcinomas: a syndrome, xeroderma pigmentosum) and connective tissue dis- viable option in select patients. J Am Acad Dermatol. 2012;67:1235-1241. 23,24 11. McGregor S, Minni J, Herold D. Superficial radiation therapy for the treat- eases (scleroderma). Recent consensus guidelines suggest ment of nonmelanoma skin cancers. J Clin Aesthet Dermatol. 2015;8:12-14. SRT should be used as first-line therapy for treating appropriate 12. Piccinno R, Tavecchio S, Benzecry V. Superficial radiotherapy for non-melanoma skin cancer of the lip: a 44-year Italian experience. J Dermatolog Treat. types of NMSC tumors, such as primary BCC, SCC, significant 2019;11:1-17. SCC in situ,15 which were made up the majority of the lesions in 13. Roth WI, Shelling M, Fishman K. Superficial radiation therapy: a viable non- the current study. These results would support this statement surgical option for treating basal and squamous cell carcinoma of the lower extremities. J Drugs Dermatol. 2019;18:130-134. and highlight that cure rates can be as effective as surgery for 14. Farasat S, Yu SS, Neel VA, Nehal KS, Lardaro T, Mihm MC, Byrd DR, Balch appropriate lesion and patient. Furthermore, SRT has been CM, Califano JA, Chuang AY, Sharfman WH, Shah JP, Nghiem P, Otley CC, 13 Tufaro AP, Johnson TM, Sober AJ, Liégeois NJ. A new American Joint Com- shown to be a viable treatment option in frail, elderly patients mittee on Cancer staging system for cutaneous squamous cell carcinoma: who represent a large proportion of patients with NMSCs. SRT creation and rationale for inclusion of tumor (T) characteristics. J Am Acad Dermatol. 2011;64:1051-1059. may be preferable to surgery in this population due to comor- 15. Nestor MS, Berman B, Goldberg D, Cognetta AB Jr, Gold M, Roth W, Cock- bidities and limited life expectancy.25,26 erell CJ, Glick B. Consensus guidelines on the use of superficial radiation therapy for treating nonmelanoma skin cancers and keloids. J Clin Aesthet Dermatol. 2019;12:12-18. CONCLUSION 16. Fitzpatrick PJ, Thompson GA, Easterbrook WM, Gallie BL, Payne DG. Basal Superficial radiation therapy is an effective and well-tolerated and squamous cell carcinoma of the eyelids and their treatment by radiotherapy. Int J Radiat Oncol Biol Phys. 1984;10:449-454. treatment for nonmelanoma skin cancers. These results add to 1 7. Tsao MN, Tsang RW, Liu FF, Panzarella T, Rotstein L. Radiotherapy manage- the existing evidence demonstrating the safety and long-term ment for squamous cell carcinoma of the nasal skin: the Princess Margaret Hospital experience. Int J Radiat Oncol Biol Phys. 2002;52:973-979. efficacy of SRT for treating NMSC. 18. Zaorsky NG, Lee CT, Zhang E, Keith SW, Galloway TJ. Hypofractionated radiation therapy for basal and squamous cell skin cancer: a meta-analysis. DISCLOSURES Radiother Oncol. 2017;125:13-20. 19. Orton CG, Ellis F. A simplification in the use of the NSD concept in practical Dr. Raymond is a full-time Sensus Healthcare employee who radiotherapy. Br J Radiol. 1973;46:529-537. receives a salary and own stock in the company. Drs. Roth, 20. Gillard M, Wang TS, Johnson TM. Nonmelanoma Cutaneous Malignan- cies. In: Chang AE GP, Hayes DF, Kinsella T, Pass HI, Schiller JH, Stone RM, Iyengar, Bender, and Beer received honoraria from Sensus Strecher V, , ed. Oncology: An Evidence-Based Approach. Berlin/Heidelberg, Healthcare for their participation in this study. Germany: Springer Science & Business Media; 2007. 2 1. Grossi Marconi D, da Costa Resende B, Rauber E, de Cassia Soares P, Fer- ACKNOWLEDGMENT nandes JM Jr, Mehta N, Lopes Carvalho A, Kupelian PA, Chen A. Head and Do Not Copyneck non-melanoma skin cancer treated by superficial X-ray therapy: an This study was sponsored by Sensus Healthcare, Boca Raton, analysis of 1021 cases. PLoS One. 2016;11:e0156544. 22. Mendenhall WM, Amdur RJ, Hinerman RW, Cognetta AB, Mendenhall NP. FL. The authors acknowledge the editorial assistancePenalties of Dr. Carl ApplyRadiotherapy for cutaneous squamous and basal cell carcinomas of the head S. Hornfeldt, Apothekon, Inc., and statistical analyses by Elvi- and neck. Laryngoscope. 2009;119:1994-1999. 23. Bichakjian CK, Olencki T, Aasi SZ, Alam M, Andersen JS, Berg D, Bowen ra Cawthon, Regulatory Insight during the preparation of this GM, Cheney RT, Daniels GA, Glass LF, Grekin RC, Grossman K, Higgins manuscript. Dr. Raymond is a full-time Sensus Healthcare em- SA, Ho AL, Lewis KD, Lydiatt DD, Nehal KS, Nghiem P, Olsen EA, Schmults CD, Sekulic A, Shaha AR, Thorstad WL, Tuli M, Urist MM, Wang TS, Wong ployee who receives a salary and own stock in the company. SL, Zic JA, Hoffmann KG, Engh A. Basal cell skin cancer, Version 1.2016, Drs. Roth, Iyengar, Bender, and Beer received honoraria from NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. Sensus Healthcare for their participation in this study. 2016;14:574-597. 24. Bichakjian CK, OlenckiT, Aasi SZ, al e. Squamous cell skin cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. October 5, 2017. Available: REFERENCES https://www.nccn.org/professionals/physician_gls/recently_updated.aspx. Accessed 04-19-19. 1. Griffin LL, Ali FR, Lear JT. Non-melanoma skin cancer.Clin Med (Lond). 25. Linos E, Parvataneni R, Stuart SE, Boscardin WJ, Landefeld CS, Chren MM. 2016;16:62-65. Treatment of nonfatal conditions at the end of life: nonmelanoma skin can- 2. Apalla Z, Lallas A, Sotiriou E, Lazaridou E, Ioannides D. Epidemiological cer. JAMA Intern Med. 2013;173:1006-1012. trends in skin cancers. Dermatol Pract Concept. 2017;7:1-6. 26. Linos E, Chren MM, Stijacic Cenzer I, Covinsky KE. Skin cancer in U.S. el- 3. Leiter U, Keim U, Eigentler T, Katalinic A H, olleczek B, Martus P, Garbe C. derly adults: does life expectancy play a role in treatment decisions? J Am Incidence, mortality, and trends of nonmelanoma skin cancer in Germany. Geriatr Soc. 2016;64:1610-1615. J Invest Dermatol. 2017;137:1860-1867. 4. Gualdi G, Monari P, Apalla Z, Lallas A. Surgical treatment of basal cell carcinoma and squamous cell carcinoma. G Ital Dermatol Venereol. 2015;150:435- AUTHOR CORRESPONDENCE 447. 5. Garcovich S, Colloca G, Sollena P, Andrea B, Balducci L, Cho WC, Bernabei R, Peris K. Skin cancer epidemics in the elderly as an emerging issue in Isabelle Raymond PhD geriatric oncology. Aging Dis. 2017;8:643-661. E-mail:...... ……...... [email protected] 6. Čeović R, Petković M, Mokos ZB, Kostović K. Nonsurgical treatment of nonmelanoma skin cancer in the mature patient. Clin Dermatol. 2018;36:177-187. 7. Newlands C, Currie R, Memon A, Whitaker S, Woolford T. Non-melanoma skin cancer: United Kingdom National Multidisciplinary Guidelines. J Laryn- gol Otol. 2016;130:S125-132. 8. Cognetta AB Jr, Wolfe CM, Goldberg DJ, Hong HG. Practice and educational gaps in radiation therapy in dermatology. Dermatol Clin. 2016;34:319-333. 9. SRT-100™. Sensus Healthcare, Boca Raton, FL. Available: https://www.sensu- shealthcare.com/superficial-radiation-therapy/srt-100/. Accessed 04-29-19. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

doi:10.36849/JDD.2020.3641 February 2020 170 Volume 19 • Issue 2 Copyright © 2020 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Pneumatic Delivery of Hyaluronan for Skin Remodeling: A Comparative Review Yuri Vinshtok MD,a Daniel Cassuto MD,b Inna Belenky PhDc aPerfAction Technologies, Rehovot, Israel BPrivate practice, Milano, Italy cIndustry scientific expert, Israel

ABSTRACT

Jet Volumetric Remodeling (JVR) utilizes the principle of superficial soft tissue delivery of fluids, such as hyaluronic acid (HA) and other therapeutic materials. Dermal delivery of HA activates fibroblasts increasing collagen and elastin synthesis with a long-lasting dermal remodeling and thickening effect. JVR-injected HA causes immediate and diffuse skin hydration resulting in an aesthetically pleasing aspect. JVR technology is able to target different layers during the same treatment with only minor side effects. The article reviews JVR delivery of hyaluronan in comparison to current skin remodeling treatmentFigures modalities. J Drugs Dermatol. 2020;19(2)170-175. doi:10.36849/JDD.2020.3641 Figure 1. Intradermal distribution of JVR-injected hyaluronic acid (HA). Figure 2. Histological analysis of dermal glycosaminoglycans (GAGs) after JVR-injected HA. Figure3. US images of JVR-injected normal saline (NS). Figure 4. Histological findings after intradermal JVR injection of HA.

INTRODUCTION FIGURE 1. Intradermal distribution of JVR-injected hyaluronic acid (HA). Aging visibly affects the skin appearance and is FocalFigure vacuolization1. Intradermal presents distribution dispersion of of JVR HA -withoutinjected a hyaluronic mechanical acid (HA). Focal vacuolization presents dispersion of HA without a due to two main factors: environmental (extrinsic) separationmechanical of the separation collagen bundlesof the collagen (Courtesy bundles of Dr. E. (CourtesyLoeb). of Dr. E. Loeb). Mand genetic (intrinsic), resulting in decreasedDo derNot- Copy mal thickness and diminished fibroblast activity of the aging skin. UV exposure specifically reduces collagen synthesisPenalties and Apply causes its degeneration.1,59

Therefore, the main goal for correction of the skin thickening is to successfully stimulate collagen and elastin synthesis in the dermis. Various energy-base devices (EBD) (thermal, light, infrared, radio-frequency) can stimulate collagen synthesis and tightening leading to thicker and firmer skin, whilst restoring elastin with the EBD has not been definitely demonstrated yet. Micro-needling, dermal fillers, dermal threads and platelet rich plasma have been also reported as effective for wrinkles reduction and tightening effect.1-3

Jet Volumetric Remodeling (JVR) utilizes the principle of superficial soft tissue delivery of fluids, such as hyaluronic acid and other therapeutic materials. A pneumatically accelerated jet There are a growing number of publications describing clinical penetrates the epidermis through a small entry point and im- efficacy of JVR method in skin thickening and other aesthetic mediately disperses the fluid in a 3-D way.4,42 The accelerated indications.Figure 2. Histological The aim of thisanalysis paper of is dermal to review glycosaminoglycans JVR delivery of (GAGs) after JVR-injected HA (Hale-staining). (A) Untreated skin: dispersion of the fluid particles creates multiple nano-traumas hyaluronanblue staining in indicatescomparison GAGs to incurrent dermis; skin (B) remodelingUV-aged skin: treat decrease- of GAGs in dermis; (C) UV-treated skin after JVR: increase of to the surrounding tissues fibers (Figure 1). An activated repair mentGAG modalities.s in dermis (Boisnic 2009). results in dermal thickening and strengthening over time.5 JVR technology (EnerJet, PerfAction Technologies, Rehovot, Israel) Biological Effect accurately controls depth and volume of the delivery allowing Progressive degrading of collagen and elastin fibers results in for optimal penetration and distribution as needed through the gradual reduction in dermis thickness and reduced density of treatment. retinacula cutis.6,7 EBDs promote collagen remodeling through

(A) (B) (C)

Figure 3. US images of JVR-injected normal saline (NS). (A) NS penetrates temporal soft tissue down to fat layer immediately after injection; (B) NS spread below frontal SMAS immediately after injection; (C) Continuing NS dispersion 15 minutes after injection.

171 Journal of Drugs in Dermatology Y. Vinshtok, D. Cassuto, I. Belenky February 2020 • Volume 19 • Issue 2

TABLE 1. Comparative Histopathology Data on Dermal Remodeling Effects Non-ablative Ablative Biological process JVR IPL RF US Fillers Micro-needling lasers lasers Fibroblast stimulation ↑5,11 ↑12-16 ↑13,18 ↑19 ↑20 ↑27 ↑30-32 ↑1,3,33 Collagen remodeling/ ↑5 ↑13,17 ↑13,18 ↑13,19 ↑20-26 ↑27-29 n/a n/a contraction Skin hydration ↑5,11 n/a n/a n/a n/a n/a ↑31 n/a ↑ - indicates presence; JVR – Jet Volumetric Remodeling; IPL – Intensive Pulsed Light; RF – Radio Frequency; US - ultrasound

activation of the heat-shock protein mechanism and/or by direct FIGURE 3. US images of JVR-injected normal saline (NS). damage to the skin inducing inflammatory healing repair. (A)

However, the naturally occurring mechanism of the strengthening mesenchymal tissues is different. In muscles correct exercise causes micro-tears in the myosin fibers inducing a re- pairing mechanism leading to significant strengthening of the muscle without inflammation. JVR technology provides a similar kind of nanoscopic tears to the dermal matrix, well below the threshold of the inflammatory healing response, avoiding the side effects associated with inflammation unlike most EBDs. JVR-induced dermal remodeling and thickening was demonstrated in the human skin samples after administration of hyaluronan.9 In-vitro studies indicated 48% increase of collagen synthesis by dermal fibroblasts after JVR treatment of the UV-aged human skin.10 The effect also increased collagen level Do Not CopyB(B) in the superficial-to-middle dermis. A comparative summary of the different histology findings is visible in TablePenalties 1, including Apply fibroblast stimulation, collagen remodeling and skin hydration.

Figures DermalFigure 1. Intradermal delivery distribution of HA of by JVR- JVRinjected activates hyaluronic acidfibroblasts (HA). increasing collagenFigure 2. Histological and elastin analysis synthesisof dermal glycosaminoglycans with a long-lasting (GAGs) after dermal JVR-injected thick HA.- Figure3. US images of JVR-injected normal saline (NS). eningFigure 4. Histologicaleffect.11 findingsHA particles after intradermal dispersed JVR injection through of HA. the dermis by

the pneumatic force also improve skin hydration. Glycosami- noglycansFigure 1. Intradermal (GAGs) distribution ofare JVR -injectedincreased hyaluronic withacid (HA). further Focal vacuolization improvement presents dispersion of of HA without a mechanical separation of the collagen bundles (Courtesy of Dr. E. Loeb). collagen elastin and moisture retention.10 Biochemical analysis of GAG content showed a 57% increase after a single JVR delivery of hyaluronan to the UV-aged skin sample (Figure 2).

C(C)

FIGURE 2. Histological analysis of dermal glycosaminoglycans (GAGs) after JVR-injected HA (Hale-staining). (A) Untreated skin: blue staining indicates GAGs in dermis; (B) UV-aged skin: decrease of GAGs in

dermis; (C) UV-treated skin after JVR: increase of GAGs in dermis (Boisnic 2009). Figure 2. Histological analysis of dermal glycosaminoglycans (GAGs) after JVR-injected HA (Hale-staining). (A) Untreated skin: blue staining indicates GAGs in dermis; (B) UV-aged skin: decrease of GAGs in dermis; (C) UV-treated skin after JVR: increase of (A)GAG s in dermis (Boisnic 2009). (B) (C)

(A) (B) (C)

172 Journal of Drugs in Dermatology Y. Vinshtok, D. Cassuto, I. Belenky February 2020 • Volume 19 • Issue 2

TABLE 2. Comparative Data on the Penetration Depth

Non-ablative Ablative Fractional Fractional Technology JVR IPL* RF US Micro-needling* lasers* lasers* RF RF needles* Penetration 0.05-0.5 1-3 mm20 0.5-3.5 1-5 mm9 0.1-2 mm13,17,38 1-5 mm25 0.6 mm26 1.5-7.8 mm27,28 up to 3 mm3 depth mm13,37 3-6 mm25 mm50 *depends on the light wavelength; **depends on the needle length

Depth of Penetration after a single session. Histopathology examination following Lasers’ and light-sources’ penetration through the skin is limit- several TriPollar RF treatments in periorbital and perioral ar- ed by many factors: energy density, skin type, scattering, pulse eas revealed 49% increase in dermal thickening. The increase diameter et al, while radio-frequency devices depend greatly appears to be due to focal thickening of collagen fibers.21,38 As on the tissue hydration and impedance. for HIFU, histometric analysis of the skin samples two months after the treatment showed 23%-thickness increase of the der- For JVR, the depth of penetration is directly related to pneumatic mis.27 Dermal fillers, such as poly-L-lactic acid, HA, and calcium pressure generating delivery of liquid into the tissue. Published hydroxyapatite can increase collagen production.30-32 In these evidence shows penetration of the injected fluid down to 5 mm publications, the comparison was done between treated and of depth and distributing it across the different skin layers.10,35 untreated skin from non-specified sites. In our series, the skin However, the latest generation of this technology allows even from the same area was compared before and after treatment deeper penetration -- through the superficial skin, subcutane- and results revealed positive effect on the dermal thickness. ous fat layer and fascia -- as being demonstrated by ultrasound (US) (Figure 3). Histological findings after multiple JVR treatments with hyaluronic acid showed an increased amount of collagen and In comparison to JVR, ablative lasers and sublative radio fre- increased dermal thickness.9 At four months after the treatment, quency (RF) (Table 2) usually do not penetrate the deeper dermis. regeneration of dermal structures, “notable augmentation of Non-ablative RFs can heat up skin and subcutaneous layers collagen type III and increased fibroblasts migration” were but their impact is limited.25 High-intensity focused ultrasoundDo Not shownCopy (Figure 4). Overall, there was a 175% increase of the der- (HIFU) penetrates below the skin but its action is destructive, mis thickness in comparison to baseline.9 Clinically the authors causing scarring rather than regeneration.27 Furthermore,Penalties once reported Apply a full Fitzpatrick–Goldman Wrinkle class reduction in RF and HIFU are in proximity of the bony surfaces, the pain can face and neck and palpably thicker and visually more homoge- be intolerable and limits the treatment efficacy. neous skin in the chest and dorsal hands.

Assessment of Thickening Effect Ultrasound Assessment Several recent studies have shown that skin thicknesses, as The importance of ultrasound for dermal assessment is steadily

well as the dermal density is important indicators of the re- increasing and gains recognition.Figure Unlike 4. Histological histology, findings after theintradermal mea JVR- injection of HA. Hematoxylin-eosin–stained specimen of 39-years old male generation process associated with the energy-based aesthetic surements are made on live skintaken that at baseline was (A)not and undergone4 months after JVR (B)any shows increased number and density of collagen fibers. No evidence of inflammatory infiltrate or dermo-epidermal separation is present at treated site (Levenberg 2010). technologies. modification or processing. Therefore,A the findings represent

Histology Assessment Quantitative assessment of skin thickening after JVR has been FIGURE 4. Histological findings after intradermal JVR injection of measured by histology, showing focal thickening of collagen HA. Hematoxylin-eosin–stained specimen of 39-years old male taken fibers, increase in the number of dermal fibroblasts and focal at baseline (A) and 4 months after JVR (B) shows increased number upturn of elastin fibers.21 and density of collagen fibers. No evidence of inflammatory infiltrate or dermo-epidermal separation is present at treated site (Levenberg Figure 4. Histological findings after intradermal JVR injection of HA. Hematoxylin-eosin–stained specimen of 39-years old male 2010).taken at baseline (A) and 4 months after JVR (B) shows increased number and density of collagen fibers. No evidence of The ability to remodel skin and increase dermal thickness was inflammatory infiltrate or dermo-epidermal separation is present at treated site (Levenberg 2010). (A) (B) proven for the following modalities - Er:YAG laser,13 pulsed A B dye laser,14 1320 nm Nd:YAG laser,37 intense pulse light (IPL),36 fractional RF needles,52 poly-L-lactic acid filler,30 and calcium hydroxyapatite.32 Abdominal skin therapy with 1064 nm Nd:YAG laser demonstrated thickening and reorganization of collagen fibers within the laser-exposed lower reticulum and fibro-septal system.41 Use of 1440 nm Nd:YAG laser for the neck contouring resulted in average 31% increase in skin thickness 3 months

173 Journal of Drugs in Dermatology Y. Vinshtok, D. Cassuto, I. Belenky February 2020 • Volume 19 • Issue 2

TABLE 3. Comparative Data on Maximum Increase in Dermal Thickening Non-ablative Ablative Technology JVR RF US Fillers lasers lasers 23%#27, Maximum increase in dermal thickening 250%*5 17%*40, 6%*41 10.3%*39 23-25%#27,28 4%#58 49%#21 *assessed by ultrasound methods; #assessed by histopathology analysis

more of a true skin thickness. Furthermore, ultrasound allows Side effects associated with JVR are limited to occasional bruis- for repeated follow-up of the same portion of skin, which obvi- ing and rare pinpoint post-inflammatory hyperpigmentation.9,34 ously cannot be the case with histology. The occurrence rate is operator-related and mainly associated with miscalculated use of excessive injection pressure due to Ultrasound assessment and quantitative analysis by Kobus5 in inexperienced operator. Unnecessarily high pressure causes patients after JVR therapy demonstrated significant P( <.05) in- untoward deep penetration, bruising, and pain. Furthermore, crease in dermal thickness in different facial regions. The most it may induce more damage to the dermis than needed, well substantial effect was noted in the upper lip area, where the beyond the threshold that causes inflammation during the thickness had increased by an average of 1.3 mm. At the end healing process. This could increase the risk of pinpoint post- of the 6-month follow-up, the biggest difference was noted inflammatory hyperpigmentation in sensitive skin types. around the eyes, where the skin remained thicker by an average of 0.77 mm over baseline, which represented average 2.5-times Unlike JVR, lasers have been reported to cause diffuse post- increase. inflammatory hyperpigmentation, scarring, infection, and permanent hypopigmentation.40,44 IPL, although considered Ablative lasers showed a 10.3% increase in skin thickness three less harmful due to the filtration of ultraviolet radiation is also months after single treatment.39 HIFU generated an increase of linked to blistering, hypo- or hyperpigmentation, and scarring.48 23-25% two months after single treatment.27,28 Bipolar RF tech- Electromagnetic radiation of RF devices (monopolar, bi-polar, nology showed a 49% increase after 7 treatments.21 For Nd:YAG and fractional) is converted to thermal energy and may pro- laser, the ultrasound measurements demonstrated aDo 31% Notin- duceCopy erythema, edema, skin breakdown, and scarring.8,21 HIFU crease after 6 months.43 Comparative changes in the dermal uses ultrasound beams to induce cellular damage and tissue thickness are presented in Table 3. Penaltiescoagulation Apply which may induce temporary side effects of skin erythema, swelling and bruising.28 Summary of the side effects Safety is presented in Table 4. Patients seeking aesthetic improvement are concerned by efficacy and safety of the treatment. A low pain and risk profile Pain Level with minimal chances for side effects is definitely a desirable JVR treatment procedures produce minimal pain and discom- combination. fort for which no pre-treatment medication or local anesthesia required.11,34,35,53,54 The fluid jet penetrates the skin in 30 ms (av- Side Effects erage measurement; unpublished data) possibly explaining the American Society for Aesthetic Plastic Surgery emphasizes relatively low stimulation of pain receptors. While needle in- bruising, redness, and swelling pain as the main risks following jection produces a uniform vertical damage, the jet disperses the device-based aesthetic procedures. immediately after penetrating the epidermis losing pressure

TABLE 4. Comparative Clinical Data on Side Effects Ablative/ Fractional Non-ablative Micro- Technology JVR Fractional IPL RF RF/ US lasers needling lasers Needles PIH, crusting, scarring, Bruising, PIH, Bruising, PIH, crusting, dyschromia PIH, Crusting, scaling, PIH, crusting, prolonged dis- Bruising, PIH, Side effects PIH8-10,21 scaling, prolonged blistering, blistering, burns, scaling, comfort, inflam- scarring3,33 blistering20,38,43,45 discomfort, burns46,48 inflammation8,48 blistering49-52 mation28 infection39,40,44,46

174 Journal of Drugs in Dermatology Y. Vinshtok, D. Cassuto, I. Belenky February 2020 • Volume 19 • Issue 2

TABLE 5. Comparative Data on Procedural Pain Level (VAS score) Non-ablative Fractional RF Micro- Technology JVR Ablative lasers RF Fractional RF US lasers Needles needling Average VAS 2-316 Fractional: Bi-polar 6.7**56, 235 3.6-6.7*55 5.0550 5.68 - 6.5329 23 score 5.4–6.443 RF: 1.147 3.6 - 4.423 *with cold air; **after 10% lidocaine cream

now? A systematic review of the literature. J Plast Reconstr Aesthet Surg. while the particles are scattered across the dermis or the deep- 2018;71(1):1-14 er layers (Figure1). Therefore, the pain stimulus is much lower 4. Kim BJ, Yoo KH, Kim MN. Successful treatment of depressed scars of the forehead secondary to herpes zoster using subdermal minimal surgery tech- than with the traditional injection. nology. Dermatol Surg. 2009;35(9):1439-40. 5. Kobus KF, Dydymski T. Quantitative dermal measurements following treat- Comparing to JVR, most EBD treatments are more painful and ment with AirGent. Aesthet Surg J. 2010;30(5):725-9. 6. Bonta M, Daina L, Muţiu G. The process of ageing reflected by histological require topical or local anesthesia (Table 5). Ablative lasers and changes in the skin. Rom J Morphol Embryol 2013, 54(3 Suppl):797–804. HIFU appeared to be the least tolerable. The pain of CO2 laser 7. Tsukahara K, Tamatsu Y, Sugawara Y et al. Relationship between the depth of facial wrinkles and the density of the retinacula cutis. Arch Dermatol. is measured up to 6.7 on Visual Analog Scale (VAS), even with 2012;148(1):39-46. skin cooling by cold air.55 HIFU and Microfocused Ultrasound 8. Greene RM, Green JB. Skin tightening technologies. Facial Plast Surg. 2014;30(1):62-7. (MFU) require pain killers, nerve blocks, pre-treatment local an- 9. Levenberg A, Halachmi S, Arad-Cohen A. Clinical results of skin remodel- esthesia, and in some cases, conscious sedation.28 Fractional ing using a novel pneumatic technology. Int J Dermatol. 2010;49(12):1432-9. non-ablative laser is associated with less pain, though it also 10. Boisnic S. Anti-aging effect of treatment by Perf-Action's Airgent in human skin maintained in survival. Gredeco white paper 2010. needs topical and cold air anesthesia.0 Pain at fractional RF 11. Han TY, Lee JW, Lee JH et al. Subdermal minimal surgery with hyal- treatments is reported to range from “moderate” to “intoler- uronic acid as an effective treatment for neck wrinkles. Dermatol Surg. 2011;37(9):1291-6. 23,25,56,57 able”, which requires the use of anesthesia. Non-ablative 12. de Angelis F, Kolesnikova L, Renato F et al. Fractional nonablative 1540-nm high-energy RF Thermage requires topical lidocaine applied pri- laser treatment of striae distensae in Fitzpatrick skin types II to IV: clinical 57 and histological results. Aesthet Surg J. 2011;31(4):411-9. or to the treatment. Only IPL reported to have mild transient 13. Alam M, Hsu TS, Dover JS et al. Nonablative laser and light treatments: discomfort during treatment, similar to JVR though with much histology and tissue effects - a review. Lasers Surg Med. 2003;33(1):30-9. lower benefit per session.25 14. Zelickson BD, Kilmer SL, Bernstein E et al. Pulsed dye laser therapy for sun Do Not Copydamaged skin. Lasers Surg Med. 1999;25(3):229-36. 15. Sarnoff, D. Ultrasonic and histologic findings using a 1440-nm Nd:YAG laser CONCLUSION Penalties Applyfor neck contouring and skin tightening. Materials of Annual Meeting of the American Society of Laser Surgery and Medicine. April 2013; Boston, MA. Since its introduction, JVR has being proven efficacious for 16. Hong JS, Park SY, Seo KK et al. Long pulsed 1064 nm Nd:YAG laser treat- dermal remodeling, using kinetic energy generated by the ment for wrinkle reduction and skin laxity: evaluation of new parameters. Int J Dermatol. 2015;54(9):e345-50. mechanical pressure. JVR is capable of remodeling many su- 1 7. Tanaka Y, Matsuo K, Yuzuriha S. Objective assessment of skin rejuvenation perficial soft tissue layers during the same treatment. While using near-infrared 1064-nm neodymium: YAG laser in Asians. Clin Cosmet other EBD may temporarily improve skin turgor by an imme- Investig Dermatol. 2011;4:123-30. 18. Alster TS, Bellew SG. Improvement of dermatochalasis and periorbital rhyt- diate edema, the JVR-injected HA solution causes immediate ides with a high-energy pulsed CO2 laser: a retrospective study. Dermatol and diffuse skin hydration resulting in an aesthetically pleasing Surg. 2004;30(4):483-7. 19. Britt CJ, Marcus B. Energy-Based Facial Rejuvenation: Advances in Diagno- aspect. Review of published data shows that JVR is effective in sis and Treatment. JAMA Facial Plast Surg. 2017;19(1):64-71. improving dermal thickness up to two-fold. Fractional devices 20. Zelickson BD, Kist D, Bernstein E et al. Histological and ultrastructural evaluation of the effects of a radiofrequency-based nonablative dermal remodeling can be aggressive and effective, but lack capability of treating device: a pilot study. Arch Dermatol. 2004;140(2):204-9. all superficial soft tissue layers. JVR technology is able to target 2 1. Kaplan H, Gat A. Clinical and histopathological results following TriPollar ra- different layers during the same treatment with only minor side diofrequency skin treatments. J Cosmet Laser Ther. 2009;11(2):78-84. 22. Alexiades-Armenakas M, Rosenberg D, Renton B et al. Blinded, random- effects if any. JVR’s safety profile looks by far more advanta- ized, quantitative grading comparison of minimally invasive, fractional geous and causes less concern than EBD. radiofrequency and surgical face-lift to treat skin laxity. Arch Dermatol. 2010;146(4):396-405. 23. Lee HS, Lee DH, Won CH et al. Fractional rejuvenation using a novel bipolar DISCLOSURES radiofrequency system in Asian skin. Dermatol Surg. 2011;37(11):1611-9. 24. Kist D, Burns AJ, Sanner R et al. Ultrastructural evaluation of multiple pass Drs. Vinshtok and Cassuto are employed by PerfAction Technol- low energy versus single pass high energy radio-frequency treatment. ogies and claim no conflicts of interests. Dr. Belenky claims no Lasers Surg Med. 2006;38(2):150-4. conflict of intersects. 25. Sadick N. Tissue tightening technologies: fact or fiction.Aesthet Surg J. 2008;28(2):180-8. 26. Mulholland R, Ahn D, Kreindel M et al. Fractional Ablative Radio-Frequency REFERENCES Resurfacing in Asian and Caucasian Skin: A Novel Method for Deep Radiofre- quency Fractional Skin Rejuvenation. Journal of Cosmetics, Dermatological 1. Mehta-Ambalal SR. Neocollagenesis and neoelastinogenesis: from the labo- Sciences and Applications. 2012;2(3):144-150. ratory to the clinic. J Cutan Aesthet Surg. 2016;9(3):145-151. 2 7. Suh DH, Choi JH, Lee SJ et al. Comparative histometric analysis of the ef- 2. Buck DW, Alam M, Kim JY. Injectable fillers for facial rejuvenation: a review. fects of high-intensity focused ultrasound and radiofrequency on skin. J Cos- J Plast Reconstr Aesthet Surg. 2009;62(1):11-8. met Laser Ther. 2015;17:230–6. 3. Ramaut L, Hoeksema H, Pirayesh A et al. Microneedling: where do we stand 28. 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juvenation: A Review. Facial Plast Surg. 2016;32(3):269-75. 58. Kim J. Effects of Injection Depth and Volume of Stabilized Hyaluronic Acid 29. Fabi SG. Noninvasive skin tightening: focus on new ultrasound techniques. in Human Dermis on Skin Texture, Hydration, and Thickness. Arch Aesthetic Clin Cosmet Investig Dermatol. 2015;5(8):47-52. Plast Surg. 2014;20(2):97-103. 30. Donofrio L, Weinkle S. The third dimension in facial rejuvenation: a review. 59. Bodendorf MO, Willenberg A, Anderegg U et al. Connective tissue response J Cosmet Dermatol. 2006;5(4):277-83. to fractionated thermo-ablative Erbium: YAG skin laser treatment. Int J Cos- 3 1. Meran S, Thomas D, Stephens P et al. Involvement of hyaluronan in regula- met Sci. 2010;32(6):435-45. tion of fibroblast phenotype. J Biol Chem. 2007;31;282(35):25687-97. 60. rbium: YAG skin laser treatment. Int J Cosmet Sci. 2010;32(6):435-45. 32. Eviatar J, Lo C, Kirszrot J. Radiesse: Advanced Techniques and Applica- tions for a Unique and Versatile Implant. Plast Reconstr Surg. 2015;136(5 AUTHOR CORRESPONDENCE Suppl):164S-170S. 33. Aust MC, Fernandes D, Kolokythas P et al. Percutaneous collagen induction therapy: an alternative treatment for scars, wrinkles, and skin laxity. Plast Yuri Vinshtok MD Reconstr Surg. 2008;121(4):1421-9. E-mail:...... ……...... [email protected] 34. Mashiko T, Abo Y, Kuno S et al. A novel facial rejuvenation treatment using pneumatic injection of non-cross-linked hyaluronic acid and hypertonic glu- cose solution. Dermatol Surg. 2015;41(6):755-8. 35. Levenberg A. Controlled Corticosteroid Introduction Using Superficial Thera- peutic Pressure for the Treatment of Keloids. PerfAction white paper 2013. 36. Luo D, Cao Y, Wu D et al. Impact of intense pulse light irradiation on BALB/c mouse skin-in vivo study on collagens, matrix metalloproteinases and vascular endothelial growth factor. Lasers Med Sci. 2009;24(1):101-8. 3 7. Goldberg DJ. Non-ablative subsurface remodeling: clinical and histologic evaluation of a 1320-nm Nd:YAG laser. J Cutan Laser Ther. 1999;1(3):153-7. 38. Sachdeva S. Nonablative fractional laser resurfacing in Asian skin--a review. J Cosmet Dermatol. 2010;9(4):307-12. 39. Tierney EP, Hanke CW, Petersen JP et al. Clinical and echographic analysis of ablative fractionated carbon dioxide laser in the treatment of photodamaged facial skin. Dermatol Surg. 2010;36:2009-21. 40. Fournier N, Dahan S, Barneon G et al. Nonablative remodeling: clinical, histologic, ultrasound imaging, and profilometric evaluation of a 1540 nm Er:glass laser. Dermatol Surg. 2001;27(9):799-806. 4 1. Sasaki GH. Quantification of human abdominal tissue tightening and contraction after component treatments with 1064-nm/1320-nm laser-assisted lipolysis: clinical implications. Aesthet Surg J. 2010;30(2):239-45. 42. Lee JW, Kim BJ, Kim MN et al. Treatment of acne scars using subdermal minimal surgery technology. Dermatol Surg. 2010;36(8):1281-7. 43. Wind BS, Kroon MW, Meesters AA et al. Non-ablative 1,550 nm fractional laser therapy versus triple topical therapy for the treatment of melasma: a randomized controlled split-face study. Lasers Surg Med. 2010;42(7):607-12.Do Not Copy 44. Tierney EP, Hanke CW, Watkins L. Treatment of lower eyelid rhytids and laxity with ablative fractionated carbon-dioxide laser resurfacing: Case series and review of the literature. J Am Acad Dermatol. 2011;64(4):730-40.Penalties Apply 45. Bak H, Kim BJ, Lee WJ et al. Treatment of striae distensae with fractional photothermolysis. Dermatol Surg. 2009;35(8):1215-20. 46. Harris K, Ferguson J, Hills S. A comparative study of hair removal at an NHS hospital: Luminette intense pulsed light versus electrolysis. J Dermatolog Treat. 2014;25(2):169-73. 4 7. Harth Y. Painless, safe and efficacious noninvasive skin tightening, body contouring, and cellulite reduction using multisource 3DEEP radiofrequency. J Cosmet Dermatol. 2015;14(1):70-5. 48. Dierickx CC. The role of deep heating for noninvasive skin rejuvenation. Lasers Surg Med. 2006;38(9):799-807. 49. Wilson KA. Versatile e-matrix provides minimally invasive rejuvenation for all skin types. The Aesthetic Guide - Clinical Roundtable (Supplement) 2010:2-8. 50. Naouri M, Mazer JM. Non-insulated microneedle fractional radiofrequency for the treatment of scars and photoaging. Eur Acad Dermatol Venereol. 2016;30(3):499-502. 5 1. Hantash BM, Ubeid AA, Chang H et al. Bipolar fractional radiofrequency treatment induces neoelastogenesis and neocollagenesis. Lasers Surg Med. 2009;41(1):1-9. 52. Hantash BM, Renton B, Berkowitz RL et al. Pilot clinical study of a novel minimally invasive bipolar microneedle radiofrequency device. Lasers Surg Med. 2009;41(2):87-95. 53. Patel T, Tevet O. Effective treatment of acne scars using pneumatic injection of hyaluronic acid. J Drugs Dermatol. 2015;14(1):74-6. 54. Cassuto D. Effective Treatment of Striae Distensae using Pneumatic Injec- tion of Hyaluronic Acid. PerfAction white paper, 2014 55. Raulin C, Grema H. Single-pass carbon dioxide laser skin resurfacing combined with cold-air cooling: efficacy and patient satisfaction of a prospective side-by-side study. Arch Dermatol. 2004;140(11):1333-6. 56. Wang LZ, Ding JP, Yang MY et al. Treatment of facial post-burn hyperpigmentation using micro-plasma radiofrequency technology. Lasers Med Sci. 2015;30(1):241-5. 5 7. Fitzpatrick R1, Geronemus R, Goldberg D et al. Multicenter study of non- invasive radiofrequency for periorbital tissue tightening. Lasers Surg Med. 2003;33(4):232-42. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

doi:10.36849/JDD.2020.4769 February 2020 176 Volume 19 • Issue 2 Copyright © 2020 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Randomized, Investigator-Blinded Study to Compare the Efficacy and Tolerance of a 650-microsecond, 1064-nm YAG Laser to a 308-nm Excimer Laser for the Treatment of Mild to Moderate Psoriasis Vulgaris Mark S. Nestor MD PhD,a,b Daniel Fischer DO MS,a David Arnold DOa ªCenter for Clinical and Cosmetic Research, Aventura, FL bDepartment of Dermatology and Cutaneous Surgery, Department of Surgery, Division of Plastic Surgery, University of Miami Miller School of Medicine, Miami, FL

ABSTRACT

Background: Phototherapy is a safe and effective modality for the treatment of mild to moderate psoriasis. Objectives: To compare the efficacy and safety of the 650-microsecond, 1064-nm pulsed YAG laser with the excimer laser for the treatment of mild to moderate psoriasis vulgaris of the arms and legs. Methods: Eligible subjects (n=15) aged 54.3 ± 11.7 years enrolled in a randomized, investigator-blinded study. Psoriatic plaques on one side of the body were treated with the 650-microsecond laser and plaques on the other side were treated with the 308-nm excimer laser. Subjects made up to 15 visits, twice weekly, or fewer if full clearance was achieved. Efficacy and tolerance were evaluated by the mPASI scores and local skin reactions, respectively. Results: Both devices showed efficacy in treating psoriatic plaques. Differences between the two devices were not significant for redness, thickness, scaliness, mPASI scores for arms and legs, and overall mPASI scores for the treated psoriatic plaques on each side of the body. The investigator-assessed scores for erosion/ulceration, vesicles, erythema, scaling, edema, and atrophy were low and identical for both sides of the body. Conclusion: The efficacy and tolerance of the 650-microsecondDo Not laser Copyis equivalent to that of the excimer laser for the treatment of mild to moderate psoriasis vulgaris of the arms and legs.Penalties Apply J Drugs Dermatol. 2020;19(2)176-183. doi:10.36849/JDD.2020.4769

INTRODUCTION urrent options for the treatment of psoriasis include duced in 2009 by Khatri and colleagues who used the laser systemic and topical modalities. Systemic therapies in- to remove unwanted hair.10 Since then, other investigators clude immune inhibitors, immune modulators and, for have used the 650-microsecond laser to treat skin of color,11,12 C 1 13 14 15 moderate to severe disease, biological agents. Primarily, for onychomycosis, facial telangiectasias, and acne. The ad- mild to moderate psoriasis, topical treatments comprise oint- vantage of the 650-microsecond laser is that treatment does ments, medicated bath with diastase or herbal extracts, and not require cooling or anesthesia because the pulse duration phototherapy. Phototherapy is safe, effective, and does not in- is shorter than or equal to the thermal relaxation time of the cur the side effects of systemic medications.2 therapeutic target. This feature minimizes scarring, pigmentary changes, thermal damage to surrounding tissues, and discom- The 308-nm excimer laser is considered first-line phototherapy fort during or after treatment.15 The 650-microsecond laser has for topical plaque psoriasis.2 The efficacy and safety of this laser received FDA approval for the treatment of psoriasis. has been extensively evaluated for the treatment of psoriasis.3-9 The advantage of the excimer laser is its ability to treat psoriatic The primary objective of this study was to compare the ability lesions with high doses of monochromatic radiation while spar- of the 650-microsecond, 1064-nm pulsed YAG laser (LightPod ing unaffected skin.2 Three protocols have been developed to Neo®, Aerolase Corp., Tarrytown, NY) to clear psoriatic plaques optimize treatment: the minimal erythema dose, the induration, with that of the 308-nm excimer laser (XTRAC Velocity 400®, and the minimal blistering dose.7 PhotoMedex, Inc., Montgomeryville, PA). Plaques were located on the limbs of subjects with mild-to-moderate psoriasis vul- A novel 650-microsecond 1064-nm Nd: YAG laser was intro- garis. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

177 Journal of Drugs in Dermatology M.S. Nestor, D. Fischer, D. Arnold February 2020 • Volume 19 • Issue 2

The secondary objective was to compare the tolerance and Study Design safety of the two lasers during treatment. In this investigator-blinded study, psoriatic plaques were randomized to receive one of the two laser treatments. The study METHODS was IRB- approved and all subjects provided signed informed Subjects consent. Target areas on the right and left sides of the body were Eligible subjects (n=15) were healthy and included 11 males and thoroughly cleaned before laser therapy with either the 650-mi- 4 females aged 54.3 ± 11.7 (mean ± SD) years. Subjects were crosecond laser on one side or the 308-nm excimer laser on Caucasian (n = 10), black or African American (n = 5), and Fitz- the other side. A non-blinded individual treated each psoriatic patrick skin types II through VI (II = 1, III = 4, IV = 5, V = 3, VI = 2). plaque according to the randomization scheme. Subjects made up to 15 treatment visits, twice weekly, or fewer if full clearance Inclusion Criteria was achieved. Subjects were photographed at visits shown in Eligible subjects had a clinical diagnosis of mild to moder- the Table 1. ate plaque psoriasis (psoriasis vulgaris) of at least 6 months duration. The disease involved the limbs, was amenable to Treatment Parameters phototherapy, and comprised 4 or more psoriatic plaques. The The 650-microsecond laser settings were the following: lens modified Psoriasis Area and Severity Index (mPASI) score was type 5 to 6 mm, energy mode 7 to 8, and pulse width 650 mi- at least 2 and the defined treatment area was confined to only croseconds. Fluence ranged from 24 to 41 J/cm2. Each subject 2% to 30% of the body surface area (BSA). Women of child-bear- received multiple passes per treatment session. For the excimer ing potential tested negative for pregnancy, were not breast laser, median dose (fluence) ranged from 0.60 to 0.96 J/cm2 and feeding, and were willing to practice a reliable method of con- median body surface area treated ranged from 800 to 1410 cm2. traception during the study. Multiple passes were not required.

Exclusion Criteria Assessments Subjects not eligible for the study had an unstable form of pso- The Physician’s Global Assessment (PGA) was performed on riasis (eg, guttate, erythrodermic, pustular); other inflammatory each subject by the investigator at the screening visit to deter- skin disease that could confound the evaluation of psoriasis vul- mine the severity of disease. The investigator also determined garis; pigmentation, scarring, pigmented lesions, or sunburnDo Not in theCopy Body Surface Area (BSA) involvement at baseline and the the treatment area. Other grounds for exclusion were planned end-of-study visits. Adverse events and concomitant medica- prolonged exposure to natural or artificial sunlight;Penalties history of tions Apply were monitored at each visit. Subjects completed the Itch hypersensitivity to any component of the test product; history by Numerical Rating Scale (NRS) at visits 2, 5, 8, 11, 14, 16, and of hypercalcemia, vitamin D toxicity, severe renal insufficiency, 17 and the investigator completed the modified Psoriasis Area or severe hepatic disorder; undergoing systemic treatment with and Severity Index (mPASI) and Local Skin Reaction (LSR) with a biological therapies 4 to 16 weeks prior to randomization; use of Visual Analog Scale (VAS) at study visits 2, 5, 8, 11, 14, 16, and 17. systemic immunosuppressant therapies within 4 weeks prior to Visit 1/baseline and during the trial; use of phototherapy (pso- Physician’s Global Assessment ralen + ultraviolet A radiation [PUVA] and ultraviolet B radiation The PGA (Table 2) is the investigator’s or designee’s impression [UVB]) within 4 weeks prior to Visit 1/baseline and during the of the disease at a single time point using a defined, 5-point, trial; use of topical treatments (eg, corticosteroids, vitamin D static scale (clear, almost clear, mild, moderate, or severe). The analogs, retinoids, salicylic acid, pimecrolimus, tacrolimus, an- PGA represents the average lesion severity on the limbs. The as- thralin, tar) with a possible effect on psoriasis within 2 weeks sessment is based on the condition of the disease at the time of prior to Visit 1/baseline; clinical signs of skin infection with bac- evaluation (eg, during the baseline visit), and not in relation to teria, viruses, or fungi; HIV infection; chronic or acute medical the condition at a previous visit. condition which, in the opinion of the investigator, may have posed a risk to the safety of the subject, or may have interfered Body Surface Area (BSA) Involvement with the assessment of safety or efficacy in the trial; required For each subject, the investigator assessed the extent of psori- the use of any concomitant medication, which, in the opinion atic involvement on the limbs at visits specific to the Schedule of the investigator, had the potential to cause an adverse effect (Table 1). The total psoriatic involvement on the limbs (excluding when given with the investigational product or would interfere genital and intertriginous areas) was recorded as a percentage with the interpretation of trial results; initiation of, or expected of the total BSA, assuming that the surface of the subject’s full, changes to, concomitant medication that may affect psoriasis; flat palm (including the five digits) is approximately 1% of the or participation in another clinical trial; or received an investiga- total BSA. This information was used to estimate the area on the tional product or non-marketed drug substances within 30 days limbs to be treated with the lasers. prior to screening. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

178 Journal of Drugs in Dermatology M.S. Nestor, D. Fischer, D. Arnold February 2020 • Volume 19 • Issue 2

TABLE 1. Schedule of Visits, Treatments, and Assessments Visit Procedure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Screen x

Define Tx area x x

Laser Tx xxxxxxxxxxxxxxx PGA x Itch x x x x x x x BSA x x mPASI x x x x x x x Photography x x x x x x x x LSR (VAS) x x x x x x x Adverse events x x x x x x x Concomitant medications x x x x x x x x Tx = treatment; PGA = Physicians Global Assessment; BSA = Body Surface Area; mPASI = Modified Psoriasis Area and Severity Index; LSR = local skin reaction; VAS = Visual Analogue Scale.

TABLE 2. Characteristics of the Physician Global Assessment (PGA) Scores Score Description Plaque thickening = no elevation or thickening of normal skin Scaling = no evidence of scaling 0 (clear) Erythema = none (no residual red coloration but post-inflammatory hypo or hyperpigmentation may be present) Plaque thickening = none or possibleDo thickening Not Copybut difficult to ascertain whether there is a slight elevation above normal skin level 1 (almost clear) Scaling = none or residual surfacePenalties dryness and scaling Apply Erythema = light pink coloration Plaque thickening = slight but definite elevation 2 (mild) Scaling = fine thin scales partially or mostly covering lesions Erythema = light red coloration Plaque thickening = moderate elevation with rounded or sloped edges 3 (moderate) Scaling = coarse scale layer at least partially covering most lesions Erythema = definite red coloration

Plaque thickening = marked and very marked elevation typically with hard or sharp edges 4 (severe) Scaling = non-tenacious or thick tenacious scale predominates, covering most or all of the lesions Erythema = very bright red coloration, extreme red coloration; deep red coloration

TABLE 3. Scale for the Severity of Psoriatic Lesions Score Redness Thickness Scaliness 0 (none) no erythema no plaque elevation no scaling sparse, fine-scale lesions, only 1 (mild) faint erythema, pink to very light red slight, barely perceptible elevation partially covered

2 (moderate) definite light red erythema definite elevation but not thick coarser scales, most of lesions covered

definite elevation, thick plaque with entire lesion 3 (severe) dark red erythema sharp edge covered with coarse scales

179 Journal of Drugs in Dermatology M.S. Nestor, D. Fischer, D. Arnold February 2020 • Volume 19 • Issue 2

Modified Psoriasis Area and Severity Index (mPASI) Local Skin Reaction (LSR) Assessment With Visual Analog Scale The severity of the psoriatic lesions on the arms and legs was (VAS) recorded for redness, thickness, and scaliness (Table 3). For each The LSR involved signs assessed by the investigator and symp- clinical sign, a single score reflected the average severity of all toms reported by the subject. The investigator assessed the psoriatic lesions on the arms or the legs. treatment and immediate surrounding areas for perilesional erosion/ulceration, vesicles, erythema, scaling, edema, and The extent of psoriatic involvement was recorded for the arms atrophy. The most severe intensity of each LSR category was and legs using the following scale: graded according to the scale in Table 4. The subjects assessed burning and pain after application. Parameter Arms Legs Redness 3 1 Itch by Numerical Rating Scale (NRS) Thickness 2 1 The intensity of psoriatic itch within the previous 24 hours was Scaling 2 1 graded by the subject according to a 10-point numerical rating scale (NRS) in which 0 = no itch at all and 10 = the worst itch one Subtotal 7 3 can imagine. Weighting factor 0.2 0.4 Weighted intensity 1.4 1.2 Statistics No. of handprints/body region 1 1 Since much of the data consisted of small whole numbers, data Area affected (%) 5 1.2 were analyzed using non-parametric statistics with P=0.05 as PASI area score/extent 1 1 the cutoff value for significance. Differences were evaluated for Weighted intensity x area score 1.4 1.2 significance by the Wilcoxon Signed Rank test. mPASI score 1.4 + 1.2 = 2.6 RESULTS Calculation of mPASI score Twelve subjects (80%) completed the study. One subject with- Redness, thickness, and scaling were all graded according to drew because of a change in work schedule that interfered with the scale 0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = very study visits. Two other subjects were lost to follow-up. severe. The weighting factor for the arms was 20% (0.2)Do and Notfor Copy the legs was 40% (0.4). In all cases the median number of hand- Body Surface Area prints per arm and per leg was 1. The extent of involvementPenalties was The Apply median BSA at baseline (n=15) was 2.00, ranging from 2.0 0% to 10%, so the area score was 1 in all cases. to 4.0. At the end of the study (n=12), the median BSA was 2.25 and values ranged from 2.0 to 4.0. The median BSA at the end of An example is shown below. study did not differ significantly from baseline.

* † Average of arms and legs Involvement (%) mPASI Scores 0 0 The median mPASI scores of the arms and legs are shown in 1 < 10 Tables 5 and 6. Differences between the 650-microsecond and 2 10-20 excimer lasers were not significant for redness, thickness, 3 30-49 scaliness, mPASI scores for arms and legs, and mPASI scores. Overall mPASI scores for 650-microsecond vs. excimer lasers 4 50-69 throughout the study period are shown in the Figure 1. Values 5 70-89 decreased rapidly until visit 10 when they leveled off at 1.3 and 6 90-100 decreased to 1.2 at the end of the study. *includes back of hands. †includes buttocks and top of feet.

TABLE 4. Local Skin Reaction Categories (Lesional and Peri-Lesional Areas) Erosion/ Atrophy Score Vesicles Erythema Scaling Edema Ulceration (thinning) 0 (absent) none none none none none none 1 (mild) barely visible barely visible barely visible barely visible barely palpable barely visible

2 (moderate) distinct distinct distinct distinct easily palpable distinct

180 Journal of Drugs in Dermatology M.S. Nestor, D. Fischer, D. Arnold February 2020 • Volume 19 • Issue 2

TABLE 6. The mPASI Parameters and Scores for Legs Redness Thickness Scaliness mPASI Overall mPASI Visit 650-mcs Excimer 650-mcs Excimer 650-mcs Excimer 650-mcs Excimer 650-mcs Excimer

(Baseline) 2.0 2.0 2.0 2.0 2.0 2.0 2.4 2.4 2.8 2.8 5 1.5 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.3 2.5 8 1.5 1.5 1.5 2.0 1.5 2.0 2.0 2.2 1.6 1.6 11 1.5 1.5 1.5 2.0 1.0 1.5 1.8 2.0 1.3 1.3 14 1.5 2.0 1.5 2.0 1.5 1.0 2.0 2.0 1.3 1.3 16 1.5 2.0 1.5 2.0 1.5 1.5 2.0 2.0 1.3 1.3 17 (EOS) 1.5 1.0 1.5 1.0 1.5 1.0 1.8 1.6 1.2 1.2 P value 0.650 (ns) 0.3125 (ns) 1.000 (ns) 0.7500 (ns) 1.000 (ns)

*Wilcoxon signed rank test.

TABLE 5. The mPASI Median Scores for Arms Redness Thickness Scaliness mPASI Visit 650-mcs Excimer 650-mcs Excimer 650-mcs Excimer 650-mcs Excimer (Baseline) 2.0 2.0 2.0 2.0 2.0 2.0 1.2 1.2 5 2.0 2.0 2.0 2.0 2.0 2.0 1.1 1.0 8 2.0 1.5 2.0 2.0 2.0 2.0 1.1 1.0 11 2.0 1.5 2.0 2.0 2.0 2.0 1.0 1.0 14 2.0 2.0 2.0 2.0 2.0 1.0 1.1 1.0 16 2.0 1.5 Do 2.0Not Copy1.0 2.0 1.0 1.1 0.8 17 (EOS) 1.5 1.0 1.5 1.5 1.5 1.5 0.9 0.9 P value* 0.1250 (ns) Penalties1.000 (ns) Apply 0.500 (ns) 0.1250 (ns) *Wilcoxon signed rank test.

TABLE 7. Median Local Skin Reactions (Maximum Value) for the Lesional and Perilesional Areas on Both Sides of the Body Lesional Area Perilesional Area Visit Erosion/ Erosion/ Vesiculation Erythema Scaling Edema Atrophy Vesiculation Ulceration Ulceration Baseline 0.0 (0) 0.0 (0) 0.0 (1) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 5 0.0 (1) 0.0 (0) 0.0 (2) 0.0 (3) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 8 0.0 (2) 0.0 (0) 0.0 (0) 0.0 (3) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 11 0.0 (2) 0.0 (0) 0.0 (2) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 14 0.0 (2) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 16 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0)

Local Skin Reactions Median local skin reactions for the lesional and perilesional ar- treatment with the excimer laser. The subject had erythema and eas are shown in Table 7. Since visual inspection revealed that tenderness at the treated lesions. median reaction scores were identical on both sides of the body, values are not separated according to the laser. Median reac- Although pain during or after treatment was significantly greater tion scores were zero for each reaction parameter. Maximum for the 650-microsecond laser (P=0.0002), no subject withdrew values ranged from 0 to 2 for erosion/ulceration and erythema from the study for this reason. and from 0 to 3 for scaling. One subject was burned during Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

181 Journal of Drugs in Dermatology M.S. Nestor, D. Fischer, D. Arnold February 2020 • Volume 19 • Issue 2

Itch Scores Tolerance of both laser treatments was excellent as shown by Median itch scores are shown in Figure 2. Since visual inspec- the Table 7 data. Erosion/ulceration and erythema were 1 or 2 tion revealed that median values were identical for both lasers, and scaling was 3 in some cases. Although pain during and after values are not separated according to the laser. Values varied treatment was greater with the 650-microsecond laser than with from 2 to 4 during the initial visits and decreased to 2 by the end the excimer laser (Table 8), this did not discourage any subject of the study. The median itch score at the end of the study was from completing the study. significantly lower than the baseline value P( =0.0156). A recent roundtable discussion12 includes the experience of one DISCUSSION author (Dr. Nazanin Saedi) on the use of the 650-microsecond The efficacy of the 650-microsecond laser has been shown to laser for treating plaque psoriasis. The author states, “I've had be equivalent to that of the excimer laser for the treatment of really good experience with plaque psoriasis patients who have mild to moderate psoriasis vulgaris of the arms and legs. Dif- either failed topical therapy, have hard-to-treat areas, or been ferences were not significant for redness, thickness, scaliness, sick or non-compliant with topicals. We see improvement short- mPASI scores for arms and legs, and overall mPASI scores. As ly after initial treatment. For example, I had a woman, skin type shown in Figure 1, the median overall mPASI scores for both II, with it (psoriasis) on the ear. I used the 6-mm spot at level six lasers were identical for all except treatment 4. As expected, the and four passes. A week after her first treatment there's barely values decreased rapidly until visit 10 when they leveled off at anything left.” This preliminary finding agrees with the results of 1.3 and decreased 1.2 at the end of the study. the present study.

The 650-microsecond Nd:YAG 1064nm laser offers unique fea- TABLE 8. tures not available in other devices. Its 650-microsecond pulse Pain Assessments duration causes minimal pain during treatment of skin of color Pain VAS without anesthetic or skin cooling. Since the pulse duration is Visit (Median, IQR]) shorter than the thermal relaxation time of both the skin and 650-mcs Excimer blood vessels, the therapeutic target is heated more rapidly than Baseline 39.5 (58.4) 0.0 (1.1) the rate heat is conducted to the surrounding skin, thus reduc- Do Not Copying damage and lowering the risk of pigmentary alterations.14 5 59.0 (62.7) 1.0 (3.0) The 650-microsecond laser also delivers energy in a collimated 8 56.0 (46.7) 1.0Penalties (2.2) Apply beam, so the operator may vary handpiece-to-skin distance 11 17.5 (59.5) 2.0 (7.3) without changing the fluence. This enhances both efficacy and 14 74.0 (81.0) 1.5 (6.6) safety during treatment and renders treatment less dependent 16 36.5 (77.6) 2.0 (2.0) on operator technique.16 Clinical examples of the treatment of VAS = Visual Analog Scale; IQR = interquartile range (75th percentile – 25th psoriasis with the 650-microsecond laser are shown in Figures percentile). 3 through 5.

FIGURE 1. Overall mPASI scores for 650-microsecond vs. excimer lasers after the indicated treatments. EOS = end of study.

3 2.8 2.8 2.5 Overall mPASI score 2.5 2.3

2 1.6 1.6 1.5 1.3 1.3 1.3 1.3 1.3 1.3 1.2 1.2

1 mPASI Score

0.5

0 0 4 7 10 14 15 EOS No. of treatments

Aerolase Excimer

182 Journal of Drugs in Dermatology M.S. Nestor, D. Fischer, D. Arnold February 2020 • Volume 19 • Issue 2

FIGURE 2. Itch scores (median) by Numerical Rating Scale (0 = no itch; 10 = worst possible itch) at each treatment visit. A trend toward reduction in subject-rated itch with continued treatment is apparent. MedianMedian Itch Scores Scores 4 4

2 2 2 Itch Score

baseline 5 8 11 14 16 17 Visit

FIGURE 3. Left knee of a 65-year-old black male before (left) and after (right) 15 treatments (24 J/cm2, multiple passes) with the The strength of the present study is its comparison with the ex- 650-microsecond, 1064-nm pulsed YAG laser. cimer laser, the current first-line phototherapy for the treatment of mild to moderate psoriasis vulgaris. Results are nearly identical throughout the study and treatment-related adverse events were not observed. Limitations are the small number of patients and the short follow-up time. The encouraging results justify additional studies with more patients and longer follow-up time. Do Not Copy CONCLUSION PenaltiesThe Apply efficacy and tolerance of the 650-microsecond laser has been shown to be equivalent to that of the excimer laser for the treatment of mild to moderate psoriasis vulgaris of the arms FIGURE 4. Left elbow of a 57-year-old white male before (left) and and legs. after (right) 15 treatments (28 J/cm2, multiple passes) with the 650-microsecond, 1064-nm pulsed YAG laser. DISCLOSURES Dr. Nestor has received research grants from Aerolase and is a consultant to Aerolase. Drs. Fischer and Arnold have no disclosures. REFERENCES 1. Sbidian E, Chaimani A, Garcia-Doval I, et al. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane Da- tabase Syst Rev. 2017; Dec 22;12:CD011535. 2. Zhang P, Wu MX. A clinical review of phototherapy for psoriasis. Lasers Med Sci. 2018;33:173-180. 3. Bónis B, Kemény L, Dobozy A, et al. 308 nm UVB excimer laser for psoriasis. FIGURE 5. Left hand of a 60-year-old white male before (left) and Lancet. 1997;350(9090):1522. 4. Taibjee SM, Cheung ST, Laube S, Lanigan SW. Controlled study of ex- after (right) 15 treatments (28 J/cm2, multiple passes) with the cimer and pulsed dye lasers in the treatment of psoriasis. Br J Dermatol. 650-microsecond, 1064-nm pulsed YAG laser. 2005;153:960-966. 5. He YL, Zhang XY, Dong J, et al. Clinical efficacy of a 308 nm excimer laser for treatment of psoriasis vulgaris. Photodermatol Photoimmunol Photomed. 2007;23:238-241. 6. Mudigonda T, Dabade TS, Feldman SR. A review of protocols for 308 nm excimer laser phototherapy in psoriasis. J Drugs Dermatol. 2012;11:92-97. 7. Abrouk M, Levin E, Brodsky M, et al. Excimer laser for the treatment of psoriasis: safety, efficacy, and patient acceptability. Psoriasis (Auckl). 2016;6:165-173. 8. Higgins E, Ralph N, Ryan S, et al. A randomised half body prospective study of low and medium dose regimens using the 308 nm excimer laser in the Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

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treatment of localised psoriasis. J Dermatolog Treat. 2017;28:8-13. 9. Fritz K, Salavastru C. The 308 nm excimer laser for the treatment of psoriasis and inflammatory skin diseases.Hautarzt. 2018;69:35-43. 10. Khatri KA, Lee RA, Goldberg LJ, Khatri B, Garcia V. Efficacy and safety of a 0.65 millisecond pulsed portable ND: YAG laser for hair removal. J Cosmet Laser Ther. 2009; 11: 19-24. 11. Cook-Bolden F. A novel 0.65 millisecond pulsed 1064 nm laser to treat skin of color without skin cooling or anesthetics. J Drugs Dermatol. 2011; 10(12 Suppl): s10-1. 12. Burgess C, Chilukuri S, Campbell-Chambers DA, et al. Practical applications for medical and aesthetic treatment of skin of color with a new 650-microsecond laser. J Drugs Dermatol. 2019;18:s138 - s143. 13. Hochman LG. Laser treatment of onychomycosis using a novel 0.65-millisecond pulsed Nd: YAG 1064-nm laser. J Cosmet Laser Ther. 2011;13:2-5. 14. Rose AE, Goldberg DJ. Successful treatment of facial telangiectasias using a micropulse 1,064-nm neodymium-doped yttrium aluminum garnet laser. Dermatol Surg. 2013;39:1062-1066. 15. Gold MH, Goldberg DJ, Nestor MS. Current treatments of acne: medications, lights, lasers, and a novel 650-μs 1064-nm Nd: YAG laser. J Cosmet Dermatol. 2017;16:303-318. 16. Roberts WE, Henry M, Burgess C, et al. Laser treatment of skin of color for medical and aesthetic uses with a new 650-microsecond nd:yag 1064nm laser. J Drugs Dermatol. 2019;18:s135-s137.

AUTHOR CORRESPONDENCE

Mark Nestor MD PhD E-mail:...... ……...... [email protected]

Do Not Copy

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doi:10.36849/JDD.2020.4663 February 2020 184 Volume 19 • Issue 2 Copyright © 2020 ORIGINAL ARTICLE Journal of Drugs in Dermatology SPECIAL TOPIC Melasma’s Impact on Quality of Life Karen Kagha MD,a Sabrina Fabi MD,B Mitchel P. Goldman MDB aLoma Linda University Medical Center, Department of Dermatology, Loma Linda, CA BUniversity of California, San Diego; Cosmetic Laser Dermatology, San Diego, CA

ABSTRACT

Melasma is a commonly acquired condition that mostly affects women with Fitzpatrick skin types III-VI with prominent brown pigmentation with or without an underlying erythema. Despite multiple treatment options, melasma can be challenging given its chronic and relapsing nature. The objective of this article is to review the quality of life impact of melasma and offer suggestions for enhancing the melasma specific quality of life scale.

J Drugs Dermatol. 2020;19(2)184-187. doi:10.36849/JDD.2020.4663

INTRODUCTION elasma is a commonly acquired hyperpigmentation Increased erythema and telangiectasias suggest that there may disorder that most frequently occurs in women with be a vascular component to melasma while another smaller Fitzpatrick skin types III-VI with an average onset study suggests neural involvement as a possibility.1,4,7 M 1,2,3 between 20-30 years of age. The most commonly affected groups include Hispanic, Asian, and patients of African descent Etiology/Pathogenesis in areas with more intense UV exposure.1,4 Men can also be Melasma is a complex multifactorial condition that has a ge- affected by the condition, but account for less than twenty per- netic predisposition. The pathogenesis is not fully understood, cent.1,3 In the United States alone, over 5 million peopleDo are Not af- butCopy increased stem cell factor, which binds the tyrosine kinase fected by melasma.4 The etiology is multifactorial with several receptor, c-kit, has been shown to play a role.1,2 Alterations in known exacerbating factors including pregnancy,Penalties hormonal Wnt Apply signaling pathway, α-melanocyte-stimulating hormone, contraceptives, intense UV exposure, and thyroid disorders.1,4 barrier dysfunction, increased oxidative stress, increased Interestingly in a study in Argentinian women that developed mast cells, and fatty acid abnormalities have also been impli- melasma during pregnancy or while taking oral contraceptives, cated.1,2,10 Furthermore, visible light has been noted to play a there was a 70% incidence of thyroid abnormalities.5 Less com- role in worsening melasma. In fact, one study examined hyper- monly, phototoxic medications, cosmetics (especially those pigmentation at 7 time points over two weeks and noted that that contain oil of bergamot as a masking fragrance), and stress darker skin types had a darker and more sustained hyperpig- have also been cited as exacerbating factors.4,6 Melasma is mentation from visible light when compared to UVA1.11 Another characterized by irregularly shaped light to dark brown macules study showed sustained pigmentation from visible light wave- and patches with a symmetric distribution most commonly on length 415 nm after less than two hours of sun exposure.2,11,12 the malar region, chin, and forehead.1,4 Underlying hypervascu- Melasma also has a vascular component that could influence larity may occur in a significant number of patients.7, 8 pigmentation. Specifically, vascular endothelial growth factor is an angiogenic growth factor that is the likely cause of in- The centrofacial pattern is the most common form of melas- creased vascularity within melasma patches.7 ma that has a distribution of hyperpigmented patches on the forehead, cheeks, upper lip, and nose.4 The less common man- Epidemiology dibular pattern of melasma is characterized by hyperpigmented Melasma is a skin condition that affects men and women of patches along the mandible ramus and tends to occur later in many different skin types. Prevalence of melasma ranges life with women more commonly presenting in their forties.2 from 8.8% in Latina women in the United States to up to 40% There is some speculation that the mandibular subtype of me- of women and 20% of men in Southeast Asia.4,13 A survey of lasma should instead be considered a form of poikiloderma Arab-American women living in the United States found of civatte since this pattern often occurs in postmenopausal melasma to be the 5th most common skin condition affecting women with signs of actinic damage.4 Non-facial melasma, 14.5% of people, while another multicenter study found that which is more commonly seen in postmenopausal women, has African Americans were more likely to have a positive family also been reported to affect the forearms and upper back.1,4,9 history.4,14,15 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

185 Journal of Drugs in Dermatology K. Kagha, S. Fabi, M.P. Goldman February 2020 • Volume 19 • Issue 2

Histology tion condition is sometimes dismissed as simply a cosmetic Histological features of melasma include epidermal and der- concern while other skin conditions such as psoriasis are not. mal melanin with varying quantities related to the severity of One commentary even suggests that inadequate treatment of the hyperpigmentation. There is no increase in melanocytes psoriasis should be considered a box warning, a spin on a term but there is an increase in the number of melanosomes, size of that the US Food and Drug Administration uses to highlight po- the cells, and elongation of dendrites.1 It was initially thought tentially harmful prescription medications.23 When examining that areas that illuminate under a Woods lamp have epidermal the effects that melasma has on QOL, a similar sensitivity of the involvement while areas that do not light up have dermal in- psychosocial impact and disease burden should be given, as it volvement. However, more recent research suggests that this typically affects the face which is harder to conceal than other may not be completely accurate.4,16 Other histologic features of parts of the body. melasma include an increase in mast cells, solar elastosis, and dermal blood vessels.1 Several scales have been used to capture the QOL effects on various skin conditions including the Dermatology Life Qual- Treatment ity Index (DLQI) and SKINDEX-16. Interestingly, a Singaporean The treatment of melasma requires a multimodal approach with study used the DLQI scale to compare the QOL effects from me- a focus on skin lightening, improving the vascular component lasma to that of other skin conditions. The study results showed and strict broad spectrum photoprotection. High protection fac- that the DLQI of melasma was lower than vitiligo, lichen planus, tor sunscreen decreases the intensity of melasma and reduces bullous pemphigoid, acne scarring, and pityriasis rosacea.24 the incidence during pregnancy by over 90%.6,17,18 The gold stan- This data only further supports the need for a melasma specific dard of treatment includes hydroquinone with broad spectrum QOL scale in order to truly capture the effects that melasma has photoprotection, but a variety of therapies have been used. In on patients. Because the DLQI considers physical symptoms efforts to stunt the growth of melanocytes, inhibit the forma- that are not relevant to pigmentary disorders, such as pain and tion of melanosomes and increase their destruction, several pruritus, this comparison data that does not use a melasma therapies have included topical retinoids, azaleic acid, kojic specific scale can be misleading and potentially result in mini- acid, chemical peels, tranexamic acid, mequinol, melatonin, mizing disease burden. glutathione, cysteamine, flutamide, methimazole, polypodium leucotomos, and a multitude of lasers.1,16,19,20 TranexamicDo acid Not is GivenCopy this need for a melasma specific QOL scale, Balkrishnan a fibrinolytic agent that effectively treats melasma with down- and colleagues created a Melasma QOL scale that consists of stream effects that impede melanin synthesis, decreasePenalties mast 10 Apply questions to measure the QOL impact of melasma based on cells, and inhibit angiogenesis.1 Lasers have shown benefit in a Likert scale.2 The MelasQOL was developed by modifying the improving melasma and can be implemented as a treatment SKINDEX-16 and using the melasma and discoloration ques- option for patients who have not responded to topical or oral tionnaire.4 Balkrishnan et al conducted a survey on 102 women therapy. Fractional resurfacing is FDA approved for melasma with melasma and found the life areas most impacted included and patients treated with this have shown improvement.21 In- social life, recreation and leisure, and emotional well-being.16 tense pulse light (IPL) therapy has also been beneficial for the The impact on a patient’s emotional well-being can subsequent- hyperpigmentation and vascular component associated with ly have a negative effect on social functioning, productivity at melasma.7 Copper bromide lasers have been useful in treating work or school, and lowered self-esteem.16 Additionally when melasma, especially in patients with increased vascularity.21 asked about their QOL in regard to work, family relationships, social life, sexual relationships, recreation and leisure, physi- Despite the variety of treatment options, treating melasma cal health, money matters, and emotional well-being, many presents a unique challenge that is often chronic and relapsing. patients felt that these areas in their life would improve if they did not have melasma.16 Melasma is a chronic condition that Quality of Life Scales and Discussion can be extremely difficult to manage with expensive treatment Although the weight that patients with melasma carry can- options that are typically not 100% successful. Simply dismiss- not be measured by the same traditional physical endpoints ing melasma as a cosmetic condition serves as a detriment to as other chronic diseases such as diabetes or cardiac disease, patients and discourages the quest for finding tailored therapy the psychosocial effects are undeniable. Melasma is a highly plans that can at least minimize the burden of disease for each visible skin condition that has been shown to negatively im- patient.6 pact a patient’s quality of life (QoL), similar to acne.1,2,4 This pigmentation disorder is a chronic condition that occurs in a Pollo et al notes that currently only one specific QoL measure relatively young population. Patients with melasma report feel- for melasma is available and points out that this scale did not ings of frustration, embarrassment, and depression stemming follow the classic construction stages for psychometric instru- from the presence of their melasma.1,22 This chronic pigmenta- ments (it was constructed from previous questionnaires and Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

186 Journal of Drugs in Dermatology K. Kagha, S. Fabi, M.P. Goldman February 2020 • Volume 19 • Issue 2

TABLE 1. not the symbolic perceptions of the patient).25 Furthermore, the original study reports that given the available study population MelasQoL Disease-Specific Questionnaire for Assessing the Quality of Life of Patients With Melasma demographics, information was not collected from ethnicities in which melasma is more prevalent.16 The scale has since Answers: On a Likert scale of 1 (not bothered at all) to 7 (bothered all the time), the subject rates feelings on the following: been translated and validated in additional languages including Spanish, Brazilian Portuguese, French, and Turkish but more Regarding their melasma, patients rate how they feel about: work still remains to be done.26 Specifically, melasma affects 1. The appearance of your skin condition. all skin types but occurs more commonly in darker skin types 2. Frustration due to the appearance of your skin condition. including East Asians (Japanese, Korean and Chinese), Indian, 3. Embarrassment about the appearance of your skin condition. 6 Pakistani, Middle Eastern, African, and Hispanic. One study in 4. Feeling depressed about your skin condition. Washington DC surveyed 2000 black patients and showed that 5. The effects of your skin condition on your interactions with pigmentary disorders other than vitiligo were the third most others (e.g.: interactions with family, friends, close relation- commonly cited skin disorders.27 The most common problem ships etc.). among this subset of patients was post-inflammatory hyper- 6. The effects of your skin condition on your desire to be with pigmentation followed by melasma.6,27 Another study reviewed people 7. medical records of patients in New York City and found dys- 7. Your skin condition making it hard to show affection. chromia including post-inflammatory hyperpigmentation and 8. Skin discoloration making you feel unattractive to others. melasma to be the second most common diagnosis in black 9. Skin discoloration making you feel less vital or productive. patients at 19.9%.28 Future health related QOL studies should in- 10. Skin discoloration affecting your sense of freedom. clude a diverse group of ethnicities in order to further elucidate the impact on QOL in the most commonly affected populations. The total score ranges from 10 to 70

A recent pilot study by Jiang and colleagues notes that while TABLE 2. studies have used MelasQOL to measure QOL in patients, not Rosenberg Scale Self Esteem many studies have specifically measured the effect of melasma Answers: Strongly Agree, Agree, Disagree, Strongly Disagree on self-esteem.29 According to Pollo and colleagues, the current 1. On the whole, I am satisfied with myself. MelasQOL potentially compromised instrument precisionDo Notby Copy using a smaller number of questions to represent psychological 2. At times I think I am no good at all. effects of melasma as it relates to self-esteem comparedPenalties to its Apply3. I feel that I have a number of good qualities. impact on social relationships, leisure, profession, and physical 4. I am able to do things as well as most other people. appearance.30 Having a scale that fully captures all of the QOL 5. I feel I do not have much to be proud of. effects of melasma is not only important for clinical research, 6. I certainly feel useless at times. but it will serve as an asset to patients by validating the strug- 7. I feel that I'm a person of worth, at least on an equal plane gles that they endure regularly with this condition. Jiang et al with others. suggests using a validated tool such as the Rosenberg scale 8. I wish I could have more respect for myself. (see Table 2) in a diverse population of patients with melasma.29 9. All in all, I am inclined to feel that I am a failure. Physicians often use physical changes in skin condition to ob- 10. I take a positive attitude toward myself. jectively evaluate response to treatment; however, physicians should consider more than just physical changes when evaluating the efficacy of their treatment methods. Of note, melasma severity index (MASI) scores did not correlate with the nega- patients had an improvement in QOL and more willingness to tive effects on HRQOL, suggesting that even a small amount of be in social situations, participate in outdoor activities, have a melasma can be significantly distressing to the patient.16,29 This more positive outlook on life, and have an increase in self confi- only further emphasizes the need to enhance the MelasQOL to dence after successful treatment with oral tranexamic acid and reflect these important factors. triple combination cream.29 Although there is no perfect “cure”, making an improvement is enough to make the patient feel sig- Furthermore, updates made to the MelasQOL scale should in- nificantly satisfied. In fact, Wilson et al found that subjects were clude a response to treatment category. Pre and post therapy significantly satisfied with approximately 50% improvement in QoL must be assessed in clinical studies for melasma, especial- facial hyperpigmentation and melasma after treatment with a ly considering that disease severity alone does not fully capture 1927 nm diode laser with and without topical hydroquinone.32 the concerns of the patient. One study noted an improvement This further emphasizes the idea that offering patients some- in patients treated with serial glycolic acid peels every 3 weeks thing has a positive effect on QOL versus doing nothing, which and 20% azaleic acid cream.31 Another pilot study reported can feel discouraging and hopeless. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

187 Journal of Drugs in Dermatology K. Kagha, S. Fabi, M.P. Goldman February 2020 • Volume 19 • Issue 2

14. El-Essawi D, Musial JL, Hammad A, et al. A survey of skin disease and skin- Finally, while it may be best to distinguish from the QoL scale, related issues in Arab Americans. J Am Acad Dermatol 2007;56:933-8. willingness to pay is another important measure of disease 15. Ortonne JP, Arellano I, Berneburg M, et al. A global survey of the role of ultraviolet radiation and hormonal influences in the development of melasma. burden that should be considered in future melasma clini- J Eur Acad Dermatol Venereol 2009;23:1254-62. cal studies.33 A study conducted in Germany on patients with 16. Balkrishnan R, McMichael AJ, Camacho FT, et al. Development and valida- rosacea found that 25.7% would pay €100 ($130) for a sustain- tion of a health-related quality of life instrument for women with melasma. Br J Dermatol 2003;149:572-7. able cure, 27.1% would pay €500 ($650), 21.4% would pay up 1 7. Miot HA, Miot LD. Re: Topical 10% zinc sulfate solution for treatment of to €1000 ($1300), and 19% would pay greater than or equal to melasma. Dermatol Surg 2009;35:2050-1. 18. Lakhdar H, Zouhair K, Khadir K, et al. Evaluation of the effectiveness of a 33 €1000 ($1300). Since data shows that even a small amount of broad-spectrum sunscreen in the prevention of chloasma in pregnant wom- melasma may be significantly distressing to a patient, willing- en. J Eur Acad Dermatol Venereol 2007;21:738-42. 19. Goh CL, Chuah SY, Tien S, et al. Double-blind, placebo-controlled trial to eval- ness to pay may be another important tool combined with QOL uate the effectiveness of polypodium leucotomos extract in the treatment of and self-esteem assessment used to further assess the impor- melasma in Asian skin: a pilot study. J Clin Aesthet Dermatol 2018;11:14-19. 20. Goldman MP, Gold MH, Palm MD, et al. Sequential treatment with triple tance of adequately treating these patients. combination cream and intense pulsed light is more efficacious than sequential treatment with an inactive (control) cream and intense pulsed light CONCLUSION in patients with moderate to severe melasma. Dermatol Surg 2011;37:224- 33. Overall, melasma presents as a unique chronic and often recur- 2 1. Sheth VM, Pandya AG. Melasma: a comprehensive update: part II. J Am ring pigment disorder that mostly commonly affects women of Acad Dermatol 2011;65:699-714. 22. Ikino JK, Nunes DH, Silva VP, et al. Melasma and assessment of the quality dark skin types. This condition has a significant impact on QOL of life in Brazilian women. An Bras Dermatol 2015;90:196-200. and self-esteem in ways that may not be fully captured by the 23. Kagha KC, Blauvelt A, Anderson KL, et al. A boxed warning for inadequate psoriasis treatment. Cutis 2016;98:206-07. 2003 MelasQOL assessment tool. Several enhancements to this 24. Harumi O, Goh CL. The effect of melasma on the quality of life in a sample of assessment tool can be made in order to better serve patients women living in Singapore. J Clin Aesthet Dermatol 2016;9:21-4. suffering with this condition. 25. Pollo CF, Miot LDB, Meneguin S, et al. Development and validation of a multidimensional questionnaire for evaluating quality of life in melasma (HRQ- melasma). An Bras Dermatol 2018;93:391-96. DISCLOSURES 26. Lieu TJ, Pandya AG. Melasma quality of life measures. Dermatol Clin 2012;30:269-80, viii. Dr. Fabi has conducted research studies and consulted for 2 7. Halder RM, Grimes PE, McLaurin CI, et al. Incidence of common dermato- SkinMedica, Colorscience, Lumenis, and Solta. Dr. Goldman ses in a predominantly black dermatologic practice. Cutis 1983;32:388, 90. Goldman has conducted research studies and consulted for 28. Alexis AF, Sergay AB, Taylor SC. Common dermatologic disorders in skin of color: a comparative practice survey. Cutis 2007;80:387-94. SkinMedica, SkinCeuticals, Isdin, Topix, Cell ResearchDo Corpora Not- 29.Copy Jiang J, Akinseye O, Tovar-Garza A, et al. The effect of melasma on self-es- tion, Lumenis, and Solta. Dr. Kagha has no conflicts of interest teem: A pilot study. Int J Womens Dermatol 2018;4:38-42. 30. Pollo CF, Meneguin S, Miot HA. Evaluation instruments for quality of life to declare. Penalties Applyrelated to melasma: an integrative review. Clinics (Sao Paulo) 2018;73:e65. 3 1. Dayal S, Sahu P, Dua R. Combination of glycolic acid peel and topical 20% REFERENCES azelaic acid cream in melasma patients: efficacy and improvement in quality of life. J Cosmet Dermatol 2017;16:35-42. 1. Grimes PE, Ijaz S, Nashawati R, et al. New oral and topical approaches for 32. Wilson MJV, Jones IT, Bolton J, et al. The safety and efficacy of treatment the treatment of melasma. Int J Womens Dermatol 2019;5:30-36. with a 1,927-nm diode laser with and without topical hydroquinone for facial 2. Ogbechie-Godec OA, Elbuluk N. Melasma: an up-to-date comprehensive re- hyperpigmentation and melasma in darker skin types. Dermatologic Surgery view. Dermatol Ther (Heidelb) 2017;7:305-18. 2018;44:1304–10. 3. Sarkar R, Ailawadi P, Garg S. Melasma in Men: A review of clinical, etiologi- 33. Moustafa F, Lewallen RS, Feldman SR. The psychological impact of rosa- cal, and management issues. J Clin Aesthet Dermatol 2018;11:53-59. cea and the influence of current management options.J Am Acad Dermatol 4. Sheth VM, Pandya AG. Melasma: a comprehensive update: part I. J Am Acad 2014;71:973-80. Dermatol 2011;65:689-97. 34. Balkrishnan R, McMichael AJ, Camacho FT, et al. Development and valida- 5. Lutfi RJ, Fridmanis M, Misiunas AL, et al. Association of melasma with thy- tion of a health-related quality of life instrument for women with melasma. roid autoimmunity and other thyroidal abnormalities and their relationship to Br J Dermatol. 2003;149:572-7. the origin of the melasma. J Clin Endocrinol Metab 1985;61:28-31. 6. Handel AC, Miot LD, Miot HA. Melasma: a clinical and epidemiological review. An Bras Dermatol 2014;89:771-82. AUTHOR CORRESPONDENCE 7. Zaleski L, Fabi S, Goldman MP. Treatment of melasma and the use of intense pulsed light: a review. J Drugs Dermatol 2012;11:1316-20. Karen Kagha MD 8. Wu DC, Fitzpatrick RE, Goldman MP. Confetti-like sparing: a diagnostic clinical feature of melasma. J Clin Aesthet Dermatol 2016;9:48-57. E-mail:...... ……...... [email protected] 9. Freitag FM, Cestari TF, Leopoldo LR, et al. Effect of melasma on quality of life in a sample of women living in southern Brazil. J Eur Acad Dermatol Venereol 2008;22:655-62. 10. Passeron T, Picardo M. Melasma, a photoaging disorder. Pigment Cell Mela- noma Res 2018;31:461-65. 11. Mahmoud BH, Ruvolo E, Hexsel CL, et al. Impact of long-wavelength UVA and visible light on melanocompetent skin. J Invest Dermatol 2010;130:2092- 7. 12. Duteil L, Cardot-Leccia N, Queille-Roussel C, et al. Differences in visible light-induced pigmentation according to wavelengths: a clinical and histological study in comparison with UVB exposure. Pigment Cell Melanoma Res 2014;27:822-6. 13. 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;143:424-5. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

Management of Residual Psoriasis in Patients on Biologic Treatment Wasim Haidari BS BA,ª Adrian Pona MD,ª and Steven R. Feldman MD PhDa,b,c ªCenter for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC BDepartment of Pathology, Wake Forest School of Medicine, Winston-Salem, NC cDepartment of Social Sciences & Health Policy, Wake Forest School of Medicine, Winston-Salem, NC

ABSTRACT

While biologics are highly effective, most psoriasis patients do not achieve complete skin clearance with their biologic monotherapy. How to achieve complete skin clearance in psoriasis patients who fail their biologic is not well characterized. To describe treatment approaches in psoriasis patients who fail to achieve complete clearance from their biologic, we modeled and assessed the efficacy, cost, and safety of three treatment approaches– adding a topical agent with their biologic, escalating the biologic dose, and switching to a different biologic. Efficacy of each approach was obtained from literature identifying complete clearance defined as 100% improvement in Psoriasis Area and Severity Index and/or Physician’s Global Assessment score of clear. Cost of each treatment approach was calculated using medication wholesale acquisition cost obtained from Medi-Span Price Rx. Safety was assessed by adverse event (AE) rates. Complete clearance in patients not cleared on their initial biologic was achieved when adding calcipotriene/betamethasone dipropionate (Cal/BD) foam (28%), switching to guselkumab (20%), and switching to infliximab (15.8%). Adding Cal/BD foam to the initial biologic ($3,780 per additional patient cleared) was a less costly approach compared to the lowest cost dose escalation (guselkumab; $73,370 per additional patient cleared) or switching the initial failed biologic to the lowest cost alternative biologic (infliximab; $88,250 per additional patient cleared). There were no treatment-related or serious AEs when adding Cal/BD foam. Adding a topical agent may be an efficacious, low cost, and safe approach to achieve complete clearing in psoriasis patients who previously failed to clear on their biologic. Do Not Copy J Drugs Dermatol. 2020;19(2)188-194. doi:10.36849/JDD.2020.3989 Penalties Apply

INTRODUCTION METHODS soriasis impacts patients’ quality of life as much as other A systematic literature review was performed using MEDLINE major chronic diseases, including cancer.1,2 Advance- to find articles discussing treatment approaches for moderate- Pments in the treatment of psoriasis, particularly biolog- to-severe plaque psoriasis patients who fail to achieve complete ics, have allowed for better symptom control, reduction of ad- skin clearance on their biologic. Articles describing total psoria- verse effects, and improved patient satisfaction, albeit at higher sis clearance, defined as 100% improvement in Psoriasis Area cost.3 Biologic therapies have increased the ability of psoriasis and Severity Index (PASI 100) and/or Physician’s Global Assess- patients to achieve complete skin clearance.5 However, some ment score of 0 (PGA 0), were considered. We then characterized patients may fail to respond to their biologic agent, and most the efficacy, cost, and safety of each approach to manage residu- do not achieve complete clearance.4,11-14 Complete psoriasis al psoriasis in patients who failed to achieve complete psoriasis clearing is desirable as complete clearance is associated with clearing on their biologic. fewer symptoms and better quality of life compared to less than complete psoriasis clearing.5 Efficacy Efficacy for adding a topical agent as an adjunct was obtained There is no clear consensus about how to treat patients who from a published report.17 We did not identify a similar report fail to achieve complete clearing with a biologic. Treatment ap- describing the efficacy of escalating the dose of a biologic in proaches include adding a topical agent, escalating the dose of psoriasis subjects who previously failed to achieve complete biologic, or switching to a different biologic. We characterized skin clearance. However, since 18.6% of psoriasis subjects re- the different treatment approaches for patients with psoriasis ceiving ustekinumab 45 mg were able to achieve PASI 100 and who improve but do not clear with their biologic treatment; we 29.5% of psoriasis subjects were able to achieve PASI 100 on 90 assessed efficacy, cost, and safety of each treatment approach mg of ustekinumab, we estimated that an additional 10.9% of using a model informed by the available literature. psoriasis subjects would achieve PASI 100 on ustekinumab 90 5 16. Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial. Br J Dermatol. 2018;178(1):114-123. 17. Bagel J, Zapata J, et al. A prospective, open-label study evaluating adjunstive calcipotriene 0.005%/betamethasone dipropionate 0.064% foam in psoriasis patients with inadequate response to biologic therapy. J Drugs Dermatol. 2018;17(8):845-850. 18. Bagel J, Gold LS. Combining topical psoriasis treatment to enhance systemic and phototherapy: a review of the literature. J Drugs Dermatol. 2017;16(12):1209-1222. 19. Mrowietz U, Bachelez H, Burden AD, et al. Secukinumab for moderate to severe palmoplantar pustular psoriasis: Results of the 2PRECISE study. J Am Acad Dermatol. 2019;80(5):1344-1352. 20. Strohal R, Chimenti S, et al. Etanercept provides an effective, safe and flexible short- and long-term treatment regimen for moderate-to-severe psoriasis: a systematic review of current evidence. J Dermatolog Treat. 2013; 24(3):199-208.

AUTHOR CORRESPONDENCE5 16. Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase WasimIII NAVIGATE Haidari trial.BS BA Br J Dermatol. 2018;178(1):114-123. E-mail: [email protected] 17. Bagel J, Zapata J, et al. A prospective, open-label study evaluating adjunstive calcipotriene 0.005%/betamethasone dipropionate 0.064% foam in psoriasis patients with inadequate response to biologic therapy. J Drugs Dermatol. 6 Previous Page Contents Zoom In Zoom Out Search Issue Cover Next Page 2018;17(8):845-850. | | | Medication cost/duration of study | | | 18. Bagel J, Gold LS. Combining topical psoriasis treatment to enhance systemic and phototherapy: a review of the literature. J Drugs Dermatol. 2017;16(12):1209-1222. Figure 1: Number needed to treat equation. 6 19. Mrowietz U, Bachelez H, Burden AD, et al. Secukinumab for moderate to severe palmoplantar pustular psoriasis: Results of the 2PRECISE study. J Am Acad Dermatol. 2019;80(5):1344-1352. Medication cost/duration of study = (Cost/unit of medication) x (Number of medication 20. Strohal R, Chimenti S, et al. Etanercept provides an effective, safe and flexible short- and longNumber-term treatment Needed regimen to Treat (NNT) to achieve clearance in for moderate-to-severe psoriasis: a systematic review of current evidence. J Dermatolog Treatunits administered during study). 2013; 24(3):199-208. 189 one additional patient = (Number of subjects in the study) / (percentage of subjects achieving clearance) AUTHOR CORRESPONDENCE Journal of Drugs in Dermatology W. = (Cost/unit of medication) x (Number of medication CostHaidari, of EffectivelyA. Pona, S.R. Clearing Feldman One Biologically Naiive units administered during study)Subject with Standard Biologic Dosing Wasim Haidari BS BA February 2020 • Volume 19 • Issue 2 E-mail: [email protected] Cost= (NNT) of Effectively * (Medication Clearing cost/duration One Biologically of study) Naiive Subject with Standard Biologic Dosing

Figure 2:= Estimating (NNT) cost* (Medication per additional patient cost/duration cleared when of adding study) a topical agent to the initial biologic. FIGURE 1. Number needed to treat equation. FIGURE 2. Estimating cost per additional patient cleared when adding Figure 1: Number needed to treat equation. a topicalEstimated agent costto the of initial effectively biologic. clearing one additional subject with dose escalation, previously not achieving complete clearance on standard dosing Number Needed to Treat (NNT) to achieve clearance in Estimated cost of effectively clearing one additional one additional patient = (Number of subjects in the study) / Cost= (Cost per ofadditional Effectively patient Clearing cleared One Biologically Naiive Subjectsubject with Standarddose escalation, Biologic previously Dosing) x 2not achieving (percentage of subjects achieving clearance) =complete (Cost of Cal/BD clearance foam) on xstandard (NNT to achievedosing clearance for one additional= (Cost of patient) Effectively Clearing One Biologically Naiive Subject with Standard Biologic Dosing) x 2

Figure 4: Switching to another biologic calculations.

FigureFIGURE 2: Estimating 3. Dose cost escalation per additional approach patient cleared calculations. when adding a topical agent to the initial biologicFIGURE. 4. Switching to another biologic calculations.

Figure 4: Switching to another biologic6 calculations. Cost of new biologic loading dose Medication cost/duration of study = (Cost/unit of medication) x (Number of units Costadministed of new during biologic loading loading phase dose with new biologic) Cost per additional patient cleared == (Cost/unit of medication) x (Number of medication (Cost of Cal/BD foam) x (NNT to achieve clearance for one = (Cost/unit of medication) x (Number of units additionalunits administered during study) patient) administed during loading phase with new biologic) Figure 3: Dose escalation approach calculations. Cost of Effectively Clearing One Biologically Naiive Subject with Standard Biologic Dosing

= (NNT) * (Medication cost/duration of study)

Cost per additional patient cleared with switch to another

biologic = (Cost of new biologic loading dose) x (NNT) Estimated cost of effectively clearing one additional Cost per additional patient cleared with switch to another subject with dose escalation, previously not achieving biologic complete clearance on standard dosing = (Cost of new biologic loading dose) x (NNT) = (Cost of Effectively Clearing One Biologically Naiive Figure 3: Dose escalation approach calculations. Subject with Standard Biologic Dosing) x 2 to another biologic approaches (Figure 1). In order to calculate Do Not Copy the cost per additional cleared patient with addition of a topical Achieving Clearance by Switch to a Different Biologic or Addition of a Topical Agent PenaltiesTable agent1Apply: approach, the cost of Cal/BD foam was multiplied by NNT mg (29.5%-18.6% = 10.9%)12 Since we could not find dose esca- to achieve clearance for one additional patient (Figure 2). Figure 4: Switching to another biologic calculations. lation clearing rates for other drugs, this rate also was appliedTable 1: Achieving Clearance by Switch to a Different Biologic or Addition of a Topical Agent for adalimumab, ixekizumab, and guselkumab dose escalations. Dose Escalation Approach Lastly, the rate of complete clearing for switching to another bio- Psoriasis clearance data on standard biologic dosing were Cost of new biologic loading dose logic was obtained from previous reported studies.15,16 available for adalimumab, ustekinumab, ixekizumab, and = (Cost/unit of medication) x (Number of units 11- 14 administed during loading phase with new biologic) guselkumab. These studies reported number of subjects and Cost Considerations percentage of patients achieving PASI 100 allowing for the cal- In order to compare the cost per additional patient cleared for culation of number needed to treat (NNT) to effectively clear the different approaches, we assumed that the cost on the first one biologically naïve subject with standard biologic dosing biologic is their baseline cost and we determined the additional (Figure 1). Cost/unit of medication for adalimumab, ustekinum- cost. ab, ixekizumab, and guselkumab was obtained using available medication wholesale acquisition cost data retrieved from Medi- Adding a Topical Agent Span Price Rx.9 Using the description of intervention completed TheCost cost perfor additionaltopical Cal/BD patient foam cleared (Enstilar, with LEO switch Pharma to another Inc.), ob- in the studies, we counted the number of medication units ad- biologic tained from Medi-Span Price Rx, is $1,050 for 60 g.9 Patients in ministered over the duration of the study. Then, using the cost/ = (Cost of new biologic loading dose) x (NNT) the study evaluating Cal/BD foam efficacy in psoriasis patients unit of medication and total number of medication units admin- with inadequate response to biologic therapy received Cal/BD istered during the study, medication cost/duration of study was foam once daily for 4 weeks.17 The 28% of patients achieved total determined (Figure 3). The next step was to calculate the cost of clearance of plaque psoriasis as early as week 4; we made an effectively clearing one biologically naive subject with standard

assumption that 60 g supply of Cal/BD foam is sufficient to last 4 biologic dosing. In order to do this, medication cost/duration of weeks if applied once daily as reported in the study.18 NNT to ef- study and previously determined NNT were multiplied (Figure Table 1: Achieving Clearance by Switch to a Different Biologic or Addition of a Topical Agent fectively clear one additional patient with topical treatment not 3). Lastly, to estimate the cost of effectively clearing one ad- achieving complete clearance on initial biologic was determined ditional subject with dose escalation, previously not achieving in the same manner as for the dose escalation and switching clearance on standard dosing, we made an assumption that it Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

190 Journal of Drugs in Dermatology W. Haidari, A. Pona, S.R. Feldman February 2020 • Volume 19 • Issue 2

would be double the cost of effectively clearing one biologically secondary endpoint and reported serious AE described in the naive subject with standard biologic dosing (Figure 3). studies to assess safety.

Switching to Another Biologic Approach Cost Considerations RESULTS Studies evaluating switching to another biologic approach Complete clearance in those not initially cleared on their biologic reporting clearance as PASI 100 or PGA 0 were identified for was achieved in 28% (n=7) of subjects when adding calcipotri- infliximab and guselkumab only.15,16 Similar to dose escalation ene/betamethasone dipropionate (Cal/BD) foam, 20% (n=135) approach, the number of subjects in the study and percentage of patients switching to guselkumab, and 15.8% (n=179) switch- of patients achieving clearance were used to determine NNT to ing to infliximab (Table 1).15-17 These rates represent clearance achieve clearance in one additional patient (Figure 1). We as- beyond what was accomplished by the initial biologic. There sumed that the baseline cost on the first biologic would equal were limited data reporting efficacy of dose escalation in patient the cost of the switched biologic except the additional cost of populations failing an initial biologic; we have estimated around loading dose of the new biologic. To determine the additional 10.9% patients would achieve clearance with dose doubling of cost with this approach, we needed to estimate cost of the new adalimumab, ustekinumab, ixekizumab, and guselkumab. biologic loading dose. For infliximab, the loading dose of 5 mg/ kg is administered at weeks 0, 2, and 6. We used the price of In addition to patient’s baseline cost of initial biologic, adding a reconstituted 100 mg intravenous infliximab solution ($1,167) topical agent costs $3,780 per additional patient cleared (Table obtained from Medi-Span Price Rx,9 and the average weight was 1). Adding a topical agent is less costly than biologic dose esca- assumed to be 80 kg, which would require a 400 mg infliximab lation or switching biologic approaches. Guselkumab is the least dose. The cost/unit of medication ($1,167*4 = $4,668) was mul- costly option for achieving clearance with dose escalation with tiplied by the number of medication units (three) administered $73,370 being the added cost of effectively clearing one addi- during loading period of infliximab: $4,668*3 = $14,004 to esti- tional subject, whereas adalimumab is the most costly option at mate cost of the new biologic loading dose. Multiplying this cost $290,900 per additional patient cleared (Table 2). Switching the by the NNT provides additional cost required to effectively clear initial failed biologic to infliximab ($88,225 per additional patient one more patient not achieving complete clearance on initial cleared) is least costly switching intervention; guselkumab was biologic: $14,004 x 6.3 = $88,225 when switching to infliximab estimated to cost $108,590 per additional patient cleared (Table (Figure 4). Do Not 1).Copy No other studies were identified that reported complete psoriatic clearance after switching biologics. In the study evaluating switching to guselkumab, patientsPenalties were Apply administered guselkumab at weeks 0 and 4 during the loading Time to clearing was shortest for adding a topical agent ap- phase after an inadequate response to ustekinumab. We mul- proach as patients achieved total clearance of plaque psoriasis tiplied the cost/unit of medication ($10,859) by the number of as early as week 4.17 Time to clearance for dose escalation would medication units (two) administered during loading period to be expected to be more than 24-28 weeks, as it takes 24 weeks estimate cost of the new biologic loading dose.9,16 NNT and cost to achieve clearance on adalimumab and guselkumab stan- of effectively clearing one additional patient not achieving com- dard dosing, and 28 weeks to reach clearance on ustekinumab plete clearance on initial biologic was determined in the same and ixekizumab standard dosing (Table 3). Time to clearance manner as for the switch to infliximab (Figure 4). with switching to infliximab is 26 weeks while it’s 36 weeks for switching to guselkumab, although we made an assumption in For addition of topical treatment, the added cost was the price of this paper that switch to guselkumab would also clear patients Cal/BD foam when adding topical as an adjunct to the patient’s in 26 weeks.15,16 existing biologic therapy. For the dose escalation approach, the added cost is the same as cost of standard maintenance bio- Lastly, serious AE were evaluated as another secondary end- logic dosing as we have estimated dose escalation to double point to assess safety of treatments. Adding Cal/BD foam is the price of standard dose (Figure 3). For the switch to another safer than dose escalation or switching to another biologic, as biologic approach, assuming the maintenance cost of the new there were no treatment-related AE or serious AE when adding biologic is equal to the baseline cost of the initial biologic, the a topical agent to biologic monotherapy.17 AE rates for biologic added cost is simply the cost of the new biologic loading dose. dose escalation are expected to be at least as high as rates (1.7% – 4.9% serious AE) reported in studies evaluating standard bio- Time to Clearance and Safety logic dosing.11-14 3.7% and 6.7% of patients experienced serious Secondary endpoints include time to clearing and adverse event AE in studies evaluating switching to infliximab and switching to rates. To determine time to clearing, we evaluated the time guselkumab, respectively (Table 3).15,16 (number of weeks) it took patients to achieve psoriasis clearance on different treatments. Lastly, we looked at AE rates as another Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

191 Journal of Drugs in Dermatology W. Haidari, A. Pona, S.R. Feldman February 2020 • Volume 19 • Issue 2

TABLE 1. Achieving Clearance by Switch to a Different Biologic or Addition of a Topical Agent Additional Cost to Cost Key Re- Effec- of Biologic NNT to sults (% of tively Clear Loading Achieve Number Patients Another Treatment Previous Duration Dose or Clearance Study Design of Intervention Achiev- Patient not Approach Therapy (Weeks) Cost of in one Subjects ing Either Achieving Topical Additional PASI 100 or Complete Agent Patient PGA0) Clearance on Initial Biologic Received infliximab (5mg/kg) at weeks Switching to Gottlieb et P, MC, 179 Etanercept 0, 2, 6, 14, 26 15.8 $14,004 6.3 $88,225 infliximab al., 2012 OL and 22 after a 2-week washout period Patients with IR to ustekinumab (45 or 90mg) administered at weeks 0 and 4 were Switching to Langley et Ustekinum-Do Not Copy R, DB 135 randomized 36 20 $21,718 5.0 $108,590 guselkumab al., 2017 ab Penaltiesafter 12- Apply week washout period and received guselkumab 100mg at weeks 0, 4, 12, 20, 28 Received Cal/BD foam Ustekinum- once daily ab (52%), for 4 weeks, adalim- followed by Adding umab (20%), a main- a topical Bagel et P, OL 25 secukinum- tenance 16 28 $1,050 3.6 $3,780 agent / Cal/ al., 2018 ab (20%), regimen of 2 BD foam etanercept consecutive (4%), ixeki- days weekly zumab (4%) for an additional 12 weeks P- Prospective; Open-label- OL; MC- Multicenter; R- Randomized; DB- Double Blind; PGA- Physician Global Assessment; PASI- Psoriasis Area and Severity Index; Cal/BD foam – Calcipotriene/Betamethasone Dipropionate foam; IR – Incomplete Response Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

192 Journal of Drugs in Dermatology W. Haidari, A. Pona, S.R. Feldman February 2020 • Volume 19 • Issue 2

TABLE 2. Achieving Clearance Through Dose Escalation Cost of Est. Cost # of Effectively of Ef- Medi- Clearing Percent- Med. fectively cation One Bio- Age of Cost Cost Clearing Number Units logically Duration Patients Per per One Ad- Biologic Author Intervention of Admin- NNT Naive (weeks) Achiev- Unit of Dura- ditional Subjects istered Subject ing PASI Med. tion of Subject Over with 100 Study With Dose Duration Standard Escala- of Sstudy Biologic tion* Dosing Adalimumab Menter 80mg at week 0, Adalimumab et al., then 40mg EOW 334 24 24.9 14 $5,174 $72,437 4.0 $290,900 $581,800 2008 starting one week after initial dose Ustekinumab Papp 45mg at weeks 0 Ustekinumab et al., 397 28 18.6 4 $11,002 $44,009 5.4 $236,600 $473,200 and 4, then every 2008 12 weeks Ixekizumab 160mg initial Gordon loading dose Ixekizumab et al., 195 28 49.50 9 $5,368 $48,312 2.0 $97,600 $195,200 at week 0; then 2016 80mg every 4 weeks Guselkumab Blauvelt 100mg at weeks Guselkumab et al., 0 and 4, followed 329 24 44.4 3 $10,859 $32,578 2.2 $73,370 $146,740 2017 by injections Do Not Copy every 12 weeks Penalties Apply

TABLE 3. Summary of Primary and Secondary Endpoints of Treatment Approaches to Manage Residual Psoriasis

Primary Endpoints Secondary Endpoints

Additional Cost Required to Percentage of Effectively Clear One Addi- Time to Patients Anticipated Treatment Approach tional Patient Not Achieving Clearing Adverse Event Rates to Clear With Complete Clearance on (Weeks) Approach Initial Biologic Adalimumab dose escalation 10.9 $290,900 >24 * Ustekinumab dose escalation 10.9 $236,600 >28 Serious AE were seen in 2% of patients*

Ixekizumab dose escalation 10.9 $97,600 >28 1.7% of patients experienced serious AE*

4.9% of patients experienced at least one Guselkumab dose escalation 10.9 $73,370 >24 serious AE*

3.7% experienced serious adverse events, Switching to infliximab 15.8 $88,225 26 which were considered to be solved without sequelae

Switching to guselkumab 20 $108,590 36 6.7% of patients had at least one serious AE

No treatment-related AE and no serious AE Adding Cal/BD foam to biologic 28 $3,780 4 were reported in the study

193 Journal of Drugs in Dermatology W. Haidari, A. Pona, S.R. Feldman February 2020 • Volume 19 • Issue 2

DISCUSSION dosing interval and/or increasing the medication dose per single Although biologics are highly efficacious treatment options for administration. Dose escalation, although perhaps the simplest psoriasis, initial therapy with a biologic usually fails to result in strategy, creates an economic burden as doubling the dosage complete skin clearance.4 To address incomplete psoriasis clear- likely doubles the cost.8 Dose escalation approach to achieve ance, healthcare providers may add a topical medication while clearance in one additional patient is more costly than switching continuing the initial biologic, increase the dose of the initial to another biologic or adding a topical (Figure 5). Although we biologic, or switch to a different biologic.6 were able to estimate the successful clearance of residual psoriasis by dose escalating a biologic, our estimate was based on an An alternative for patients who have not achieved complete assumption, as there were no studies evaluating dose escala- clearing with biologic monotherapy may be to add a topical tion in patient population failing initial biologic. Our estimation agent. Adding topical agents as an adjunct to biologics can im- was a reasonably conservative approach because clinical trials prove clinical response in psoriasis patients who did not achieve try to identify the effective dose. complete clearance.18 When comparing all treatment options for patients with psoriasis who failed to achieve complete clearance If patients with psoriasis fail to achieve complete skin clear- after their initial biologic, adding Cal/BD foam is the least-costly ance from their initial biologic, they may switch to a different approach to achieve clearing of residual psoriasis in patients on biologic.7, 1 0 Switching to another biologic agent can be effective biologic treatment and was considerably less costly compared for patients who have failed the first biologic.7, 1 0 Lack of efficacy to the lowest cost dose escalation (guselkumab; $73,370 per ad- of a specific biologic may not necessarily equate to resistance ditional patient cleared) or switching the initial failed biologic to other biologics (Table 1).4 When clearing one additional pa- to the lowest cost alternative biologic (infliximab; $88,225 per tient, switching to guselkumab ($108,590 per additional patient additional patient cleared). Patients may be hesitant to use a cleared) is $20,365 more costly biologic to substitute than switch- topical as they have often failed topicals before going on bio- ing to infliximab ($88,225 per additional patient cleared) after an logics. However, adding a topical with the best patient friendly initial failed biologic. However, previous failed therapy in those properties (once daily, fast acting, effective treatment) will in- switched to infliximab (etanercept) was different than previous crease chances that the patient will adhere to the treatment. failed biologic in those switched to guselkumab (ustekinumab). Based on the available evidence, adding a topical to a biologic When you have a patient who has improved9 considerably, you 6.7% of patients had at least one Switching to guselkumab can provide for complete clearing20 and may be a safe andDo$108,590 lower Not knowCopy they are not36 a completeserious treatment AE failure. Switching does cost alternative in managing patients with psoriasis who failed not guarantee better outcomes; some patients could experience Adding Cal/BD foam to No treatment-related AE and no to achieve completebiologic clearance from28 their initial biologic.Penalties$3,780 worsening Apply of their4 psoriasisserious or no AE improvement. were reported in the Other study potential Cal/BD foam – Calcipotriene/Betamethasone Dipropionate foam; AE – Adverse Eventproblems associated with switching include the economic bur- Dose*These escalation AE rates may reported assist are for in studies clearing evaluating a patient’s standard residualbiologic dose pso - den on a patient, the time to achieve complete clearance once

riasis. Dose escalation for a biologic includes shortening of the initiated on a new biologic, and the length of time for a patient’s

Figure 5. Added Cost Required to Achieve Clearance in One Additional Patient Based on Treatment Approach (this cost is in addition to patient’s baseline cost) FIGURE 5. Added Cost Required to Achieve Clearance in One Additional Patient Based on Treatment Approach (this cost is in addition to patient’s baseline cost)

Ixekizumab dose escalation

Ustekinumab dose escalation

Adalimumab dose escalation

Guselkumab dose escalation

Switching to guselkumab

Switching to infliximab

Adding Cal/BD foam

$0.00Additional $50,000.00 cost required $100,000.00 to achieve $150,000.00 clearance $200,000.00 in one additonal $250,000.00 patient $300,000.00 for each treatment approach

194 Journal of Drugs in Dermatology W. Haidari, A. Pona, S.R. Feldman February 2020 • Volume 19 • Issue 2

52-week results from a randomised, double-blind, placebo-controlled trial insurance company to approve their new biologic; while waiting (PHOENIX 2). The Lancet. 2008;371(9625):1675-1684. for an insurance company to approve a new biologic, patients 13. Gordon KB, Blauvelt A, Papp KA, et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375(4):345-356. continue to suffer from their residual psoriasis. Navigating 14. Blauvelt A, Papp KA, Griffiths CE, et al. Efficacy and safety of guselkumab, through new insurance paperwork, when switching from a drug an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: that was already authorized to a new one, also entails greater Results from the phase III, double-blinded, placebo- and active comparator- cost to the physician’s practice, a cost that we did not include in controlled VOYAGE 1 trial. J Am Acad Dermatol. 2017;76(3):405-417. our model. A limitation in this study is that the estimate of cost 15. Gottlieb AB, Kalb RE, Blauvelt A, et al. The efficacy and safety of infliximab in patients with plaque psoriasis who had an inadequate response to etan- for switching a biologic may be low as failing one drug may ercept: results of a prospective, multicenter, open-label study. J Am Acad make it more likely patients would fail a second one. Dermatol. 2012;67(4):642-650. 16. Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: CONCLUSIONS results of the randomized, double-blind, phase III NAVIGATE trial. Br J Der- matol. 2018;178(1):114-123. Adding a topical agent may be an effective, low cost, and safe 1 7. Bagel J, Zapata J, et al. A prospective, open-label study evaluating adjunstive approach to achieve clearing in patients with psoriasis who fail calcipotriene 0.005%/betamethasone dipropionate 0.064% foam in psoria- to achieve complete clearance from an initial biologic. sis patients with inadequate response to biologic therapy. J Drugs Dermatol. 2018;17(8):845-850. 18. Bagel J, Gold LS. Combining topical psoriasis treatment to enhance sys- DISCLOSURES temic and phototherapy: a review of the literature. J Drugs Dermatol. 2017;16(12):1209-1222. This study received a research grant from LEO Pharma Inc. Dr. 19. Mrowietz U, Bachelez H, Burden AD, et al. Secukinumab for moderate to Steven Feldman has received research, speaking and/or consult- severe palmoplantar pustular psoriasis: Results of the 2PRECISE study. J Am Acad Dermatol. 2019;80(5):1344-1352. ing support from a variety of companies including Galderma, 20. Strohal R, Chimenti S, et al. Etanercept provides an effective, safe and flex- GSK/Stiefel, Almirall, LEO Pharma, Boehringer Ingelheim, ible short- and long-term treatment regimen for moderate-to-severe pso- Mylan, Celgene, Pfizer, Valeant, Abbvie, Samsung, Janssen, Lil- riasis: a systematic review of current evidence. J Dermatolog Treat. 2013; 24(3):199-208. ly, Menlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, AUTHOR CORRESPONDENCE Sun Pharma, Suncare Research, Informa, UpToDate, and Na- tional Psoriasis Foundation. He is founder and majority owner Wasim Haidari BS BA of www.DrScore.com and founder and part owner of Causa Re- E-mail:...... ……...... [email protected] search, a company dedicated to enhancing patients’ adherenceDo Not Copy to treatment. Penalties Apply Wasim Haidari and Dr. Adrian Pona have no conflicts to disclose. REFERENCES 1. Rapp SR, Feldman SR, Exum M, et al. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 2017;41(3):401-407. 2. Takeshita J, Grewal S, Langan SM, et al. Psoriasis and comorbid diseases: Epidemiology. J Am Acad Dermatol. 1999;76(3):377-390. 3. Smith J, Cline A, Feldman SR. Advances in Psoriasis. South Med J. 2017;110(1):65-75. 4. Hu Y, Chen Z, Gong Y, Shi Y. A Review of Switching Biologic Agents in the Treatment of Moderate-to-Severe Plaque Psoriasis. Clin Drug Investig. 2018;38(3):191-199. 5. Strober B, Papp KA, Lebwohl M, et al. Clinical meaningfulness of complete skin clearance in psoriasis. J Am Acad Dermatol. 2016;75(1):77-82 e77. 6. Mrowietz U, de Jong EM, Kragballe K, et al. A consensus report on appropriate treatment optimization and transitioning in the management of moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol. 2014;28(4):438-453. 7. Kerdel F, Zaiac M. An evolution in switching therapy for psoriasis patients who fail to meet treatment goals. Dermatol Ther. 2015;28:390-403. 8. Shahwan KT, Kimball AB. Managing the dose escalation of biologics in an era of cost containment: the need for a rational strategy. Int J Womens Derma- tol. 2016;2(4):151-153. 9. Medi-Span Price Rx. Third-party provider of drug pricing information. Ac- cessed 03/15/2019. 10. Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol. 2019. 11. Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Derma- tol. 2008;58(1):106-115. 12. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

doi:10.36849/JDD.2020.4741 February 2020 195 Volume 19 • Issue 2 Copyright © 2020 BRIEF COMMUNICATION Journal of Drugs in Dermatology SPECIAL TOPIC A Survey of Dermatologists’ Preparedness for Natural and Manmade Disasters Emily C. Murphy BS,a,b Timur Alptunaer MD,c,d Samantha Noll MD,c,d James Phillips MD,c,d Adam J. Friedman MDa aDepartment of Dermatology, The George Washington School of Medicine and Health Sciences, Washington, DC BGeorgetown University, School of Medicine, Washington, DC cDepartment of Emergency Medicine, George Washington University Hospital, Washington, DC DDisaster and Operational Medicine, The George Washington School of Medicine and Health Sciences, Washington, DC

INTRODUCTION atural and manmade disasters cause a range of dermatologic manifestations, including secondary infec- FIGURE 1. Responses to survey question, “Do you think disaster tions after a flood,1 irritation from blistering agents preparedness should be included in dermatology training?” stratified N by training (in versus out of residency), age (18-34 years versus 35 used in chemical warfare,2 or acute and chronic effects of cuta- years and older), practice type (non-academic versus academic). neous radiation syndrome.3 Recognizing and managing these The percentages are based on the total number of respondents per disaster sequelae require diagnostic acumen, knowledge on question. reporting, and short- and long-term management strategies. However, a 2003 survey revealed that 88% of dermatologists felt unprepared to respond to a biological attack.4 Years later, this survey herein examines whether the dermatology field has advanced in its bioterrorism preparedness. We additionally assessed dermatologists’ preparedness for natural, Dochemical, Not Copy and radiological/nuclear disasters, as well as their perceptions about the appropriateness of disaster training in dermatology.Penalties Apply Our IRB-approved survey was disseminated via the Orlando Dermatology Aesthetic and Clinical Conference listserv. Sta- tistical analyses were performed using chi-square tests, with a p-value less than 0.05 considered statistically significant. The percentages reported are based on the total number of respondents per question.

Of the 1,677 emails sent, 959 opened the email, 296 clicked the patients affected by natural events (78.2%), intentional chemi- link, and 256 completed the survey; 14 participants did not hold cal exposures (52.7%), and natural biological events (50.9%). MD/DO licenses and were excluded from the analysis (N=242). Fewer respondents reported being comfortable with uninten- Survey data on demographics and disaster preparedness are tional chemical exposures (47.3%), intentional biological attacks presented in Table 1. More females (61.0%) than males (38.6%) (34.6%), and nuclear/radiological injuries (16.4%). Forty-one completed the survey. Dermatologists of all ages were includ- percent received training during medical school, 37.5% during ed, with the largest group being between 25 and 34 years old residency, and 42.9% after residency; 16.1% of respondents ad- (45.0%). Thirty-two percent were in residency and 67.8% were ditionally reported receiving training through the military. The beyond residency. Forty-one percent worked in academic prac- most common training mediums were lectures/conferences tices, 30.4% were employees of group practices/health systems, (59.4%), self-directed learning (34.4%), and field-based training 26.3% were private practice owners, and 2.5% reported other/ (26.6%). mixed practices. Seventy-five percent thought disaster preparedness/response Only 28.9% received training in disaster preparedness/re- should be part of dermatology training, while 25.3% reported sponse; the likelihood of training did not significantly vary that it should not, most commonly because they felt it is not by practice type, age, or residency status. Of the trained re- important (58.6%) or that they have other educational priorities spondents, the majority would be comfortable caring for (46.6%). Compared to non-academic dermatologists, academic Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

196 Journal of Drugs in Dermatology E.C. Murphy, T. Alptunaer, S. Noll, et al February 2020 • Volume 19 • Issue 2

TABLE 1. Number and Percentage of Responses [n(%)] to Survey Questions Regarding Demographic Factors and Disaster Preparedness/Response. The total number of respondents (N) and responses (for questions where multiple answers were allowed) are reported. The percentages are based on the total number of respondents per question. Examples of each disaster type were provided in the survey as described by question 6 in the table. Question Answer n (%) Demographics Female 147(61.00) 1. What is your gender? (N=241) Male 93(38.59) Non-binary 1(0.41) 18-24 years 1(0.41) 25-34 years 109(45.04) 2. What is your age? (N=242) 35-54 years 86(35.54) 55 years or older 46(19.01) In training 79(32.24) 3.How many years have you been in practice after residency? 1-10 years 85(34.69) (N=245) 11-20 years 28(11.43) 21 years or more 53(21.63) An owner of a solo practice? 40(16.67) An equity owner of a group practice? 23(9.58) An employee of a group practice, hospital, or health care system? 73(30.42) 4. Are you… (N=240) An employee of an academic institution? 98(40.83) Mixed practice/other type of practice: military n=2; contractor, public and 6(2.50) private, volunteer county clinic, researcher, n=1 each Disaster Dermatology

5. Have you received training in disaster preparedness or Yes 70(28.93) response? (N=242) No 172(71.07) DoNatural Not events Copy (e.g. earthquakes, tsunamis, or floods)? 43(78.18) Unintentional chemical exposures (industrial or environmental accidents)? 26(47.27) PenaltiesIntentional chemical Apply exposures (e.g. blistering agents or caustic/acidic 6. Based on your training, would you be comfortable caring for 29(52.73) patients affected by… (check all that apply) agents)? (N=55 respondents who received training, 154 responses) Natural biological events (e.g. viral or bacterial outbreaks)? 28(50.91) Intentional biological attacks (e.g. anthrax spores, smallpox virus, or plague)? 19(34.55) Nuclear/radiological injuries? 9(16.36) During medical school 23(41.07) 7. When did you receive training in disaster preparedness or During residency 21(37.50) response (check all that apply)? (N=56 respondents who received training, 77 responses) After residency 24(42.86) Other time: military n=9 9(16.07) Lecture or conference 38(59.38) Webinar 12(18.75) Field-based training 17(26.56) 8. How were you trained on disaster preparedness or response Self-directed learning 22(34.38) (check all that apply)? (N=64 respondents who received training, 108 responses) Research/review articles 3(4.69) Textbooks 8(12.50) Other type of training: course n=3; government work, military, n=2 each; 8(12.50) decontamination team n=1

9. Do you believe disaster preparedness and response should be Yes 174(74.68) part of dermatology training? (N=233) No 59(25.32) I feel adequately prepared on this topic. 5(8.62) I do not feel it is an important topic for dermatologists to learn about. 34(58.62) 10. Why do you believe disaster preparedness and response should not be included in dermatology training? I do not feel dermatologists should be involved in disaster responses. 16(27.59) (N=58 respondents who answered "No" to question 9, 89 I have other educational priorities. 27(46.55) responses) Other reason: no interest among dermatologists n=3; intern year topic n=2; 7(12.07) topic for first responders, topic for emergency medicine residents n=1 each Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

197 Journal of Drugs in Dermatology E.C. Murphy, T. Alptunaer, S. Noll, et al February 2020 • Volume 19 • Issue 2

FIGURE 2. Word cloud based on respondents’ free response answers prepared for a disaster. Encouragingly, though, 75% reported to the question, “Please enter any comments.” The comments were that disaster preparedness should be part of dermatology train- summarized into general themes and a word cloud was created based ing, thus a formal training program is sorely needed to meet on the number of times each theme was discussed, with larger text this demand. reflecting more common themes. Irrelevant comments, such as not applicable or none, were excluded from the word cloud. There were 44 DISCLOSURES relevant comments leading to 24 themes. The word cloud was created using Matlab R2018a (MathWorks, Natick, MA). Abbreviations: The authors have no conflicts of interest to declare. American Academy of Dermatology (AAD); Continuing Medical Education (CME). REFERENCES 1. Tempark T, Lueangarun S, Chatproedprai S, Wananukul S. Flood-related skin diseases: a literature review. Int J Dermatol. 2013;52(10):1168-1176. doi:10.1111/ijd.12064 2. Farmer K, Proano L, Madsen JM, Partridge R. Introduction to Chemical Di- sasters. In: Ciottone’s Disaster Medicine. 2nd ed. Philadelphia, PA: Elsevier; 2016:639-643. https://www-clinicalkey-com.proxy1.library.jhu.edu/#!/content/book/3-s2.0-B9780323286657001102. Accessed October 6, 2018. 3. Molé DM. Introduction to Nuclear and Radiological Disasters. In: Ciot- tone’s Disaster Medicine. 2nd ed. Philadelphia, PA: Elsevier; 2016:615-620. https://www-clinicalkey-com.proxy1.library.jhu.edu/#!/content/book/3-s2.0- B9780323286657001059. Accessed October 9, 2018. 4. Carroll C, Balkrishnan R, Khanna V, Feldman S. Bioterrorism preparedness in the dermatology community. Arch Dermatol. 2003;139(12):1657-1658.

AUTHOR CORRESPONDENCE

practitioners were less likely to report that disaster prepared- Adam J. Friedman MD FAAD ness should be included in dermatology training (64.2% versus E-mail:...... ……...... [email protected] 82.1%; P=0.0022; Figure 1). Dermatologists under 35 years of age were also less likely to feel that disaster preparedness should be part of their training compared to older practitioners (68.3% versus 80.1%; P=0.0266; Figure 1). A similarDo trend Not Copy existed for dermatology residents, with only 66.7% reporting that disaster preparedness should be part of their trainingPenalties com- Apply pared to 78.5% of dermatologists beyond residency, but the p-value did not reach significance P( =0.0527; Figure 1).

A common theme discussed in participants’ comments was that dermatologists should be prepared for bioterrorism- related cutaneous disease (n=4), especially for anthrax- or smallpox-related disease (Figure 2). Others discussed that disaster preparedness would be a useful addition to dermatology training (n=5), possibly via the American Academy of Derma- tology (n=3); yet, some respondents expressed reservations about dermatologists’ willingness to participate in a disaster response (n=3) (Figure 2).

Similar to the 2003 survey which showed that few dermatologists received adequate bioterrorism preparedness training,4 our survey found that a large percentage of dermatologists still have not received any type of disaster training. To examine training adequacy, we further evaluated dermatologists’ ability to manage the outcomes of specific disasters. We found that even with training, many dermatologists feel ill-prepared to manage patients affected by disasters, especially biological attacks and nuclear/radiological events. Given over 70% have not received training and the trained practitioners are still un- comfortable, the dermatology community is likely inadequately Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

doi:10.36849/JDD.2020.4800 February 2020 198 Volume 19 • Issue 2 Copyright © 2020 BRIEF COMMUNICATION Journal of Drugs in Dermatology SPECIAL TOPIC Universal Protocol in Mohs Micrographic Surgery: Incorporating a “Time Out” Procedure in Histopathologic Interpretation Jennifer C. Tang MDa and C. William Hanke MDB aDr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL BLaser and Skin Surgery Center of Indiana, Indianapolis, IN

INTRODUCTION n 1999, the Institute of Medicine’s (IOM) first report, “To section number (Table 1). The time out process should occur Err Is Human”, brought forth the issue of medical error in prior to slide being placed on the microscope and agreed upon Ipatient care.1 In this publication, the IOM recognized that by Mohs surgeon and second participant. The procedure must mistakes or failures to prevent mistakes were mostly caused by be performed before reading each slide in order to facilitate ac- flawed systems, processes, and conditions. It outlined a four- curate map marking. tiered approach to improve safety including: 1) development of leadership, research, tools, and protocols to enhance the knowl- Histologic interpretation error has been found to be a major cause edge base on safety, 2) a nationwide public mandatory report- of tumor recurrence in two studies.4,5 Hruza found that techni- ing system and encouraging voluntary participation to identify cal errors, including histologic interpretation errors, accounted and learn from errors, 3) oversight organizations, professional for more than 75% of cases of local recurrence.4 Campbell et al. groups, health care purchasers to raise performance standards also reported that surgeon interpretation error was highly as- and expectations, and 4) implementation of safety systems in sociated with tumor recurrence.5 Given that slide interpretation the healthcare organization to ensure delivery of safe practice. accounts for the majority of recurrences following Mohs micro- This was the first roadmap towards a safer health system. graphic surgery, safeguards should be implemented to improve the process. A standardized time out procedure reduces vari- The Joint Commission adopted a formal Sentinel Event Policy to ables that could lead to wrong slide or wrong patient error. We assist office-based surgery practices to improve safety and learn recommend the time out procedure during slide interpreta- from serious adverse events when they occur. To reduceDo errors, Not tionCopy as a safety initiative among Mohs micrographic surgeons. the Joint Commission implemented the use of Universal Proto- TABLE 1. col to prevent wrong-site, wrong-person, or wrong-procedurePenalties ApplyChecklist for Mohs Surgery Histopathology Time Out (this informa- surgery.2 In dermatology, the addition of preoperative biopsy- tion is called out verbally during the timeout) site photography has been helpful in site identification. In a 1. Patient’s Name survey study of 722 Mohs surgeons, 89% reported photographs 2. Diagnosis and location as the most useful tool to decrease risk of wrong-site surgery.3 3. Stage Letter or Number (ie, A, B, C, etc. or 1, 2, 3, etc.) Surgical specialties have incorporated Universal Protocol, con- 4. Section Number (ie, 1 of 2, 2 of 2, etc.) sisting of a verification process, surgical site marking, and time out immediately prior to procedure. The time out is designed DISCLOSURES to ensure correct patient identity, correct scheduled procedure, The authors have reported no conflicts. and correct surgical site. The pre-procedure verification process and surgical site marking include the patient, nursing staff, and REFERENCES Mohs surgeon by confirming patient's name and date of birth, 1. Kohn L, Corrigan J DM, ed. To Err Is Human: Building a Safer Health System. Washington DC: Committee on Quality of Health Care in America, Institute reviewing pathology report and photographs if available, and of Medicine, National Academies Press; 1999. involving the patient in site identification. We believe a time out 2. The Joint Commission. Universal Protocol. https://www.jointcommission. process during interpretation of Mohs histopathology sections org/standards_information/up.aspx. Accessed June 18, 2017. 3. Nemeth SA, Lawrence N. Site identification challenges in dermatologic would minimize mapping errors that could lead to persistence surgery: A physician survey. J Am Acad Dermatol. 2012;67(2):262-268. or recurrence of cancer, as well as over-resection of tissue. doi:10.1016/j.jaad.2012.03.016. 4. Hruza GJ. Mohs micrographic surgery local recurrences. J Dermatol Surg Oncol. 1994;20(9):573-577. Often times several patients’ slides are prepared simultane- 5. Campbell T, Armstrong AW, Schupp CW, Barr K, Eisen DB. Surgeon error and slide quality during Mohs micrographic surgery: Is there a relationship with ously to maximize efficiency. As a result, several sets of slides tumor recurrence? J Am Acad Dermatol. 2013;69(1):105-111. doi:10.1016/j. are completed at the same time for the surgeon to read. The jaad.2013.02.016. combination of multiple patients with possibly more than one AUTHOR CORRESPONDENCE slide each further compounds the risk for error. The time out procedure should involve at least two people: Mohs surgeon, Jennifer Tang MD fellow, resident, histology technician, or nurse. The verbal con- E-mail:...... ……...... [email protected] firmation should include patient’s name, diagnosis, stage, and Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

Successful Management of Anti-TNF-Induced Psoriasis Despite Continuation of Therapy in a Pyoderma Gangrenosum Patient Atrin Toussi BS BA,a,b Stephanie T. Le MD,a Virgina R. Barton MD,ª Chelsea Ma MD,ª Michelle Y. Cheng MD,ª Andrea Sukhov MD,c Reason Wilken MD,d Forum Patel MD,ª Elizabeth Wang MD,e Emanual Maverakis MDª ªUniversity of California, Davis, Department of Dermatology, Sacramento, CA BUniversity of California, Davis, School of Medicine, Sacramento, CA cUniversity of Colorado, Denver, Department of Dermatology, Denver, CO DNew York University, Langone Health, Department of Dermatology, New York, NY EStanford University School of Medicine, Department of Dermatology, Redwood City, CA

ABSTRACT

Pyoderma gangrenosum is an inflammatory, neutrophil-mediated disorder that is difficult to treat. Tumor necrosis factor and other inflammatory mediators are among the most promising therapeutic targets. We present a case of a 60-year-old woman with recalcitrant pyoderma gangrenosum treated with adalimumab, who paradoxically developed psoriasis. Secukinumab, an interleukin-17 inhibitor, was added to her regimen, resulting in successful treatment of her psoriasis. Secukinumab was later replaced by methotrexate, resulting in remission of both pyoderma gangrenosum and maintenance of a psoriasis-free state. We conclude that paradoxically induced psoriatic lesions can resolve with adjunct therapy despite continuation of anti-tumor necrosis factor agents. J Drugs Dermatol. 2020;19(2)199-201. doi:10.36849/JDD.2020.4662Do Not Copy Penalties Apply INTRODUCTION yoderma gangrenosum (PG) is a rare, ulcerating, in- PG included adalimumab 40 mg twice monthly and a multidrug flammatory skin disease that commonly arises at sites combination of mycophenolate mofetil and cyclosporine, which Pof minor trauma, a phenomenon known as pathergy. she had previously responded well to. Upon presentation, adali- Although its etiology is mostly unknown, T cell activation, ab- mumab was increased to 40 mg weekly alongside adjuvant normal neutrophil migration, and tumor necrosis factor (TNF), therapy, which resulted in remission of her PG flare (Figure 1b). and interleukin (IL)-17 signaling appear to play major roles in She then continued this regimen as maintenance therapy (Fig- pathogenesis.1-3 ure 2).

Despite their therapeutic efficacy in psoriasis, TNF inhibitors, such as adalimumab, have been implicated in paradoxical anti- FIGURE 1. Pyoderma gangrenosum of the leg. (A) Our patient TNF-induced psoriasis. In these cases, it is commonly thought developed a lower extremity ulcer with undermined borders and peripheral erythema. Granulation tissue and neutrophilic exudates that the offending TNF inhibitor should be immediately discon- are present at the ulcer base. (B) The ulcer resolved on a regime tinued. However, we demonstrate that anti-TNF agents can be of adalimumab 40 mg weekly, cyclosporine 100 mg twice daily, and continued for treatment of underlying disease in the setting of mycophenolate mofetil 500 mg twice daily, leaving an atrophic scar. paradoxical psoriasis. We also demonstrate the utility of adjunct treatment, specifically secukinumab and methotrexate, in (A) (B) the respective induction and maintenance of remission from anti-TNF-induced psoriasis. CASE REPORT A 60-year-old woman with a history of severe, relapsing PG requiring multi-drug therapy presented with an ulcer at the site

of a recent skin biopsy (Figure 1a). Her treatment regimen for Figure 1.

Figure 1.

200 Journal of Drugs in Dermatology A. Toussi, S.T. Le, V. R. Barton, et al February 2020 • Volume 19 • Issue 2

FIGURE 2. Timeline of medication changes from 2014 to 2019, not When adalimumab (40 mg weekly) was approved by her in- to scale. Regions in blue denote pyoderma gangrenosum flares. surance, it was restarted with the addition of methotrexate Regions in yellow denote psoriasis flare. Medications of interest are prophylactically to prevent another episode of adalimumab- denoted in red. Other than those noted in the text, some medications induced psoriasis. With this combination, her PG symptoms were either self-discontinued or insurance changes necessitated went into remission without evidence of psoriasiform lesions their discontinuation. Note that cyclosporine and mycophenolate for greater than one year to date (Figure 2). mofetil were titrated down in 2018 until replaced by adalimumab and methotrexate. ADA = adalimumab, CsA = cyclosporine, Pred = DISCUSSION prednisone, MMF = mycophenolate mofetil, MTX = Methotrexate, SEC = secukinumab. Treatment of Pyoderma Gangrenosum PG is a complex and multifactorial neutrophilic dermatosis ADA ADA ADA requiring multi-drug therapy.4,5 It is estimated to occur in ap- MTX MTX proximately 3 to 10 people per million per year.6 Although CsA CsA 7 Pred this disease is traditionally difficult to diagnose, recent diag- MMF MMF MMF nostic guidelines have been proposed.8,9 Currently, there are SEC SEC two randomized controlled trials (RCTs), multiple cohort stud- May Dec Jul Feb Sep Apr Nov Jun Jan ies , and limited open-label and case-control studies detailing 2014 2015 2016 2017 2018 2019 treatment.10,11 In these, systemic steroids are most often used, PG are Insurance changes PG remission followed by cyclosporine and biologics, with equivalent efficacy Psoriasis onset noted between prednisolone and cyclosporine.10

Nine months after starting her modified regimen, she returned Infliximab, a TNF antagonist, is typically used in refractory cases to clinic with several new, well-demarcated, erythematous post- of PG.10 Additional studies have documented PG remission with auricular plaques. She was treated with topical corticosteroids similar biologics, including adalimumab, etanercept, anakinra, for presumed seborrheic dermatitis. Over the course of two and ustekinumab, but responses are often partial.12,13 In addi- months, the lesions expanded to include well-demarcated, ery- tion to partial response, TNF inhibitors can have unanticipated thematous scaling plaques on her arms, trunk, scalp, and lower side effects, including paradoxical psoriasis. In fact, psoriasis is extremities (Figure 3a). Evaluation for fungal etiologiesDo with Not theCopy third leading skin complication of anti-TNF therapy, behind KOH staining was negative. A diagnosis of adalimumab-induced xerosis and atopic dermatitis.14 And while there are over one psoriasis was favored, and she was started on secukinumab.Penaltieshundred Apply reported cases of TNF inhibitor-induced psoriasis,15 ours is the first to demonstrate this phenomenon in a PG pa- FIGURE 3. Adalimumab-induced psoriasis. (A) Nine months after tient. increasing adalimumab, our patient developed well-demarcated, erythematous plaques distributed to the arms, trunk, and lower Treatment of TNF-Inhibitor Induced Psoriasis extremities. The background was digitally darkened, but the When TNF-inhibitor paradoxical reactions occur, the first step in cutaneous lesions were not altered. (B) Within one month of initiating management is commonly thought to be discontinuation of the secukinumab, there was complete resolution of the psoriasiform offending agent. However, current literature provides conflicting lesions. data on this point. A recent review of anti-TNF-induced psoriasis (A) (B) recommends switching to a different agent or class of medications only in the setting of uncontrolled underlying disease.16 Another review of 222 cases of paradoxical psoriasis found that nearly 40% of patients continue therapy with either the same or a different TNF inhibitor and 74% of these patients achieve complete remission of their paradoxical psoriasis.17 As a result, in at

Figure 3. least some cases of paradoxical psoriasis with controlled un- Within weeks of starting secukinumab, her psoriasis resolved derlying disease, patients can seemingly tolerate the causative despite remaining on adalimumab concurrently (Figure 3b). At TNF inhibitor. Our case demonstrates that paradoxical psoriatic this point, she had complications with insurance coverage and lesions can resolve in patients who continue the offending anti- underwent numerous lapses in follow up visits, necessitating TNF agent with the addition of a second immunosuppressive multiple medication changes (Figure 2). She later transitioned therapy, even in the setting of uncontrolled underlying disease. to secukinumab-only therapy but when her PG symptoms returned, secukinumab was discontinued and she was treated Here we illustrated the efficacy of secukinumab and,

insteadFigure 3. with a multidrug regimen of prednisone, cyclosporine, subsequently, methotrexate as adjunct agents in treating TNF-

201 Journal of Drugs in Dermatology A. Toussi, S.T. Le, V. R. Barton, et al February 2020 • Volume 19 • Issue 2

gangrenosum. Dermatol Online J. 2014;20(6). established for the induction and maintenance of remission from 6. Langan SM, Groves RW, Card TR, Gulliford MC. Incidence, mortality, and paradoxical psoriasis in the setting of uncontrolled underlying disease associations of pyoderma gangrenosum in the United Kingdom: a 18,19 retrospective cohort study. J Invest Dermatol. 2012;132(9):2166-2170. disease while maintaining anti-TNF therapy. 7. Le ST, Wang JZ, Alexanian C, et al. Peristomal pyoderma gangrenosum: An exceedingly rare and overdiagnosed entity? J Am Acad Dermatol. 2019;81(1):e15. Secukinumab has been used to treat recalcitrant anti-TNF in- 8. Maverakis E, Ma C, Shinkai K, et al. Diagnostic criteria of ulcerative pyo- duced psoriasis, but is not typically a first-line agent.16 As an derma gangrenosum: a Delphi consensus of international experts. JAMA IL-17 inhibitor, it is suited to treat both psoriasis and anti-TNF- Dermatol. 2018;154(4):461-466. 9. Maverakis E, Le ST, Callen J, et al. New validated diagnostic criteria for pyo- induced psoriasis, which evidently must also be mediated by derma gangrenosum. J Am Acad Dermatol. 2019;80(4):e87-e88. IL-17 producing Th17 cells.20 In addition to secukinumab’s effica- 10. Partridge ACR, Bai JW, Rosen CF, Walsh SR, Gulliver WP, Fleming P. Ef- fectiveness of systemic treatments for pyoderma gangrenosum: a sys- cy in psoriasis, its mechanism of action is also implicated in PG tematic review of observational studies and clinical trials. Br J Dermatol. treatment, as IL-17 mediates neutrophil migration and homeo- 2018;179(2):290-295. stasis.21,22 Additionally, IL-17 and its receptor are overexpressed 11. Patel F, Fitzmaurice S, Duong C, et al. Effective strategies for the management of pyoderma gangrenosum: a comprehensive review. Acta Derm Ve- in PG lesions and a greater ratio of IL-17-producing Th17 cells is nereol. 2015;95(5):525-531. seen in PG patients.23 For these reasons, IL-17 targeted therapy 12. Brooklyn TN, Dunnill MGS, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled 24,25 in PG has already been suggested. trial. Gut. 2006;55(4):505-509. 13. Sivamani RK, Goodarzi H, Garcia MS, et al. Biologic therapies in the treatment of psoriasis: a comprehensive evidence-based basic science and clini- In our case, secukinumab was initiated for anti-TNF-induced cal review and a practical guide to tuberculosis monitoring. Clin Rev Allergy psoriasis with the hope of also controlling the patient’s PG. In Immunol. 2013;44(2):121-140. the end, while secukinumab induced remission of psoriasis, it 14. Hellstrom AE, Farkkila M, Kolho KL. Infliximab-induced skin manifestations in patients with inflammatory bowel disease.Scandinavian journal of gastro- only temporarily alleviated PG symptoms. One possible reason enterology. 2016;51(5):563-571. for this failure is that PG pathophysiology does not solely rely 15. Wollina U, Hansel G, Koch A, Schönlebe J, Köstler E, Haroske G. Tumor necrosis factor-α inhibitor-induced psoriasis or psoriasiform exanthemata. Am on IL-17 signaling and other inflammatory pathways are likely J Clin Dermatol. 2008;9(1):1-14. involved. Towards this end, new investigations of PG-associat- 16. Li SJ, Perez-Chada LM, Merola JF. TNF inhibitor-induced psoriasis: proposed algorithm for treatment and management. Journal of Psoriasis and Psoriatic ed conditions suggest it to be a disease of the innate immune Arthritis. 2018;4(2):70-80. system in which inflammasomes activate IL-8.1 As a result, IL-17 1 7. Denadai R, Teixeira FV, Steinwurz F, Romiti R, Saad-Hossne R. Induction or therapy may not be sufficient for all cases of PG. exacerbation of psoriatic lesions during anti-TNF-α therapy for inflammatory bowel disease: A systematic literature review based on 222 cases. J Crohns Do Not CopyColitis. 2013;7(7):517-524. Lastly, we examine methotrexate, a folate antimetabolite and di- 18. Kirkham B, Mease PJ, Nash P, et al. AB0945 Secukinumab efficacy in patients with active psoriatic arthritis: pooled analysis of four phase 3 trials by hydrofolate reductase inhibitor. It is a commonly citedPenalties systemic Applyprior anti-tnf therapy and concomitant methotrexate use. Ann Rheum Dis. agent used to induce remission of mild to severe psoriasis as 2018;77(Suppl 2):1597. 16,26 19. Farhangian ME, Feldman SR. Immunogenicity of biologic treatments for well as in anti-TNF-induced psoriasis. Our case demonstrates psoriasis: therapeutic consequences and the potential value of concomitant that as an adjunctive medication, methotrexate can effectively methotrexate. Am J Clin Dermatol. 2015;16(4):285-294. prevent the development of anti-TNF-induced psoriasis in a pa- 20. Yiu ZZ, Griffiths CE. Interleukin 17-A inhibition in the treatment of psoriasis. Expert Rev Clin Immunol. 2016;12(1):1-4. tient with a history of this paradoxical reaction. 2 1. Krstic A, Mojsilovic S, Jovcic G, Bugarski D. The potential of interleukin-17 to mediate hematopoietic response. Immunol Res. 2012;52(1-2):34-41. 22. Ye P, Rodriguez FH, Kanaly S, et al. Requirement of interleukin 17 receptor CONCLUSION signaling for lung Cxc chemokine and granulocyte colony-stimulating factor Anti-TNF-induced psoriasiform lesions fully remit with adjunct expression, neutrophil recruitment, and host defense. Int J Clin Exp Med. 2001;194(4):519-528. secukinumab therapy despite continuation of anti-TNF therapy. 23. Marzano AV, Fanoni D, Antiga E, et al. Expression of cytokines, chemokines These lesions stay in remission with adjunct methotrexate ther- and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet's syndrome. Clin Exp Immunol. apy. 2014;178(1):48-56. 24. Goodarzi H, Sivamani RK, Garcia MS, et al. Effective strategies for the man- DISCLOSURES agement of pyoderma gangrenosum. Adv Wound Care. 2012;1(5):194-199. 25. Caproni M, Antiga E, Volpi W, et al. The Treg/Th17 cell ratio is reduced in All authors have no relevant conflicts of interest to disclose. the skin lesions of patients with pyoderma gangrenosum. Br J Dermatol. 2015;173(1):275-278. REFERENCES 26. Haustein UF, Rytter M. Methotrexate in psoriasis: 26 years' experience with low-dose long-term treatment. J Eur Acad Dermatol Venereol. 1. Ahn C, Negus D, Huang W. Pyoderma gangrenosum: a review of pathogen- 2000;14(5):382-388. esis and treatment. Expert Rev Clin Immunol. 2018;14(3):225-233. 2. Wang EA, Steel A, Luxardi G, et al. Classic ulcerative pyoderma gangrenosum is a T cell-mediated disease targeting follicular adnexal structures: a AUTHOR CORRESPONDENCE hypothesis based on molecular and clinicopathologic studies. Front Immu- nol. 2017;8:1980. 3. Maverakis E, Goodarzi H, Wehrli LN, Ono Y, Garcia MS. The etiology of para- Emanual Maverakis MD neoplastic autoimmunity. Clin Rev Allergy Immunol. 2012;42(2):135-144. E-mail:...... ……...... [email protected] 4. Wang EA, Maverakis E. The rapidly evolving lesions of ulcerative pyoderma gangrenosum: a timeline. Int J Dermatol. 2018;57(8):983-984. 5. Sharon V, Burrall B, Patel F, et al. Multimodal therapy of idiopathic pyoderma Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

doi:10.36849/JDD.2020.2228 February 2020 202 Volume 19 • Issue 2 Copyright © 2020 CASE REPORT Journal of Drugs in Dermatology SPECIAL TOPIC Combination Topical Chemotherapy for the Treatment of an Invasive Cutaneous Squamous Cell Carcinoma Rachel Fayne BA,*a Sonali Nanda MS,*a Anna Nichols MD PhD,a John Shen MDb aDepartment of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL bShen Dermatology, Temecula, CA *These two authors contributed equally.

ABSTRACT

Introduction: Standard of care for squamous cell carcinoma (SCC) is usually surgical, with either excision or Mohs micrographic surgery. However, surgery may not be ideal for elderly patients with numerous lesions, who are poor surgical candidates or who refuse surgery. Topical 5-fluorouracil (5-FU) and imiquimod have been studied off-label as monotherapies in the treatment of SCC in situ with promising results. However, long-term tumor-free survival rates are still less than with surgical management. Methods: We report a case of biopsy-proven invasive SCC in an 86-year-old Caucasian male with history of multiple actinic keratoses and no previous skin cancers. The patient declined surgical treatment due to concerns about cosmetic outcomes. A combination of topical 5% imiquimod cream, 2% 5-FU solution, and 0.1% tretinoin cream was used five nights per week under occlusion for a treatment goal of 30 total applications. The patient was evaluated in clinic every 2 weeks during which the site was treated with cryotherapy. The patient reported burning pain associated with treatment and only completed 24 of the 30 applications. Results: Follow-up biopsy 15 months after completing topical treatment revealed dermal scar with no evidence of residual carcinoma. Conclusion: Topical combination therapy with imiquimod, 5-FU, and tretinoin with intermittent, brief cryotherapy effectively treated a small, invasive SCC in this select patient who deferred surgery. Prospective randomized-controlled clinical trials to assess the role of combination topical treatment for invasive SCCs are warranted.

J Drugs Dermatol. 2020;19(2)202-204. doi:10.36849/JDD.2020.2228 Do Not Copy Penalties Apply INTRODUCTION tandard of care for the treatment of SCC is either surgical in diameter, on his right posterior ear (Figure 1A). Pathology excision, Mohs micrographic surgery or radiation therapy confirmed invasive SCC described as atypical squamous cells S(RT) in cases where surgery is not ideal.1 Outcomes for with scattered mitotic figures extending in strands within the patients with SCC are excellent in terms of survival.1 However, dermis. The epidermis demonstrated papillomatosis with pseu- surgery may not be the best option for patients with numer- do-horn cyst formation (Figure 2A-B). The patient was extremely ous or extensive lesions, elderly patients, or patients who are concerned with the cosmetic outcome of surgical treatment and concerned about their cosmetic outcome. Less invasive treat- sought alternative options, thus a non-surgical treatment plan ment options include injectable medications such as 5-FU, was employed using a combination of off-label topical treat- methotrexate, bleomycin and interferon, photodynamic thera- ments used frequently as monotherapy for superficial BCC or py (PDT), cryotherapy or RT.2,3 Several topical medications have SCC in situ in patients who defer surgery. The treatment goal been used off-label to treat SCC in situ, including the topical chemotherapeutic agent 5-FU, which interferes with DNA syn- FIGURE 1. (A) The right posterior ear of an 86-year-old Caucasian male thesis, and the topical immunomodulator imiquimod, which with a 3 mm pink papule with superficial crusting. (B) Clinical resolution regulates the immune response.4-7 However, long-term tumor- of the lesion seen 15 months after initial biopsy was taken. free survival rates are lower than with surgery.7 Here, we present a case of biopsy-proven SCC treated with a combination topical regimen that resulted in clinical resolution of the lesion during the 25-month follow-up period. CASE An 86-year-old Caucasian male with a previous history of actinic keratoses on the scalp, and no prior history of skin cancer, presented with a tender, crusted pink papule, approximately 3 mm Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

203 Journal of Drugs in Dermatology R. Fayne, S. Nanda, A. Nichols, J.Shen February 2020 • Volume 19 • Issue 2

FIGURE 2. (A-B) Histologic image of the lesion seen in Figure 1A. many patients accumulate numerous skin,1 cancers in their life- Extending in strands within the dermis are atypical squamous cells time, often on the face and other cosmetically sensitive areas with scattered mitotic figures. The overlying epidermis demonstrates and may not want to undergo invasive procedures for every papillomatosis with pseudo-horn cyst formation, consistent with lesion. Surgical management may also leave patients with un- squamous cell carcinoma. (C-D) Histologic image of the lesion seen wanted scars, which has been demonstrated to significantly in Figure 1B, demonstrating no residual evidence of carcinoma. Within 14 the dermis is a focus of fibrosis with randomly oriented collagen affect psychosocial functioning. This was of particular concern bundles, consistent with dermal cicatrix. for our patient. Thus, there is a need for non-invasive treatment options. Current non-surgical options for the treatment of SCC include PDT, cryotherapy, and RT.3 Topical medications like imiquimod and 5-FU have been studied off-label for SCC in situ, and, in several small reports, invasive SCC.

Imiquimod acts at the level of the toll-like receptors (TLRs) on antigen-presenting cells, initiating a cascade of events that leads to increased production of IFN-γ, a potent inhibitor of angiogenesis, and Fas receptor-ligand pro-apoptotic signaling, which culminates in caspase activation and cell death.15 Imiqui- mod has been studied for the treatment of SCC in situ, and, in several small case series for the treatment of invasive SCC. In one case series, 4 patients with SCC in situ and 6 with invasive or recurrent invasive SCC underwent treatment with 5% imiqui- was 30 total applications of 2% 5-FU solution, 5% imiquimod mod cream 5 times per week for 16 weeks. Of the 6 patients with cream, and 0.1% tretinoin cream under occlusion 5 nights per invasive SCC, 4 demonstrated complete regression and 2 dem- week. Every two weeks the patient was evaluated in clinic and onstrated partial regression by the end of treatment and without the lesion was treated with local cryotherapy at a distance of 6 recurrence for a mean follow-up period of 31 months.16 In an- mm from the lesion for 1 second and with 1 freeze-thaw cycle. other, two patients with SCC in situ and one with invasive SCC After 24 treatments, the patient developed burning painDo on Nothis wereCopy treated with 5% imiquimod cream nightly for six weeks, posterior ear and discontinued treatment. and follow-up biopsy demonstrated no residual carcinoma or Penaltiescarcinoma Apply in situ.17 At 15-months follow up, physical exam of the right posterior ear demonstrated a pink to skin-colored scar (Figure 1B). A repeat 5-FU functions as an antimetabolite, binding to thymidylate biopsy at that time revealed a focus of fibrosis with randomly synthetase and inhibiting conversion of deoxyuridine to thymi- oriented collagen bundles within the dermis consistent with a dine. This targets highly mitotic, neoplastic cells, reducing DNA dermal cicatrix, residual carcinoma was not detected (Figure 2C- synthesis and leading to cell death.15 Topical 5-FU has not yet D). been reported for the treatment of invasive SCC or SCC in situ. Intralesional and topical 5-FU is often used to treat keratoacan- DISCUSSION thomas,18,19 a variant of SCC, and is approved for the treatment Skin cancer is the most common cancer in the United States, of superficial BCC.2,3 with approximately 9,500 cases diagnosed every day,8,9 and its incidence is on the rise.10 SCC is associated with very low Both imiquimod and 5-FU commonly induce local side effects, mortality if detected and treated early, with standard of care be- including erythema and symptoms of burning, pain, and itching. ing surgical excision or Mohs micrographic surgery.1 However, Rarely, imiquimod can induce like flu-like symptoms.20,21 Despite not all patients are ideal surgical candidates. Older patients are these known side effects, many patients still report a preference a particularly important population to consider, given that in- of topical therapy over surgery.22 In addition to patient prefer- creased age is a known risk factor for the development of SCC.1 ence and avoiding known potential surgical complications, Although it has been shown that this population can safely un- topical therapy is also less costly to the patient.23 dergo Mohs micrographic surgery,11 it is well-known that elderly patients suffer from slower wound healing.12 One recent study Because topical imiquimod and 5-FU are not approved for SCC shows that approximately one third of patients over 80 and one in situ or invasive SCC, data regarding long-term tumor-free sur- half of patients over 90 had no residual carcinoma after initial vival is limited. Imiquimod and 5-FU are approved treatments for biopsy. Taking this into account along with relative patient lon- superficial basal cell carcinoma (BCC), and studies have shown gevity, age may be a significant consideration before excision that individually, these topical therapies may yield significant of facial non-melanoma skin cancers, including SCC.13 Further, long-term tumor-free survival rates for superficial BCC, but they Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

204 Journal of Drugs in Dermatology R. Fayne, S. Nanda, A. Nichols, J.Shen February 2020 • Volume 19 • Issue 2

randomised controlled trial. Lancet Oncol. 2014. 15(1):96-105. are still less effective than surgery when used as monothera- 8. Guy, G.P., Jr., et al., Vital signs: melanoma incidence and mortality trends py.4,5 Because these two drugs act through distinct mechanisms and projections - United States, 1982-2030. MMWR Morb Mortal Wkly Rep, 2015. 64(21): p. 591-6. of action, combination therapy is a reasonable means to opti- 9. Rogers, H.W., et al., Incidence Estimate of Nonmelanoma Skin Cancer (Ke- mize outcomes for patients who wish to avoid surgery.21 ratinocyte Carcinomas) in the U.S. Population, 2012. JAMA Dermatol. 2015. 151(10):1081-6. 10. Muzic, J.G., et al., Incidence and trends of basal cell carcinoma and cutane- The third topical agent used, tretinoin, is known to interfere with ous squamous cell carcinoma: a population-based study in olmsted county, carcinogenesis and apoptosis. It is a retinoid, or a vitamin-A de- Minnesota, 2000 to 2010. Mayo Clin Proc. 2017. 92(6):890-898. 11. Regula, C.G., et al., Functionality of patients 75 years and older undergo- rivative, that acts on nuclear retinoic acid receptors in order to ing mohs micrographic surgery: a multicenter study. Dermatol Surg. 2017. control cellular proliferation and differentiation.15 Topical treti- 43(7):904-910. 12. Rogers EM, et al. Comorbidity scores associated with limited life expectancy noin has been studied for its potential role as a chemopreventive in the very elderly with nonmelanoma skin cancer. J Am Acad Dermatol. agent for BCC and SCC, but thus far has been proven ineffective 2018. 78(6):1119-1124. [24]. One study in renal transplant patients, with increased risk 13. Chauhan R, et al. Age at Diagnosis as a relative contraindication for intervention in facial nonmelanoma skin cancer. JAMA Surg. 2018. 153(4):390-392. for SCC, showed that a combination of topical tretinoin and low 14. Sobanko, JF, et al. Importance of physical appearance in patients with skin dose systemic retinoids, in an attempt to lessen toxicity associ- cancer. Dermatol Surg. 2015. 41(2):183-8. 15. Micali G, et al. Topical pharmacotherapy for skin cancer: part I. Pharmacol- ated with high dose systemic retinoids, reduced the number of ogy. J Am Acad Dermatol. 2014. 70(6):965 e1-12; quiz 977-8. existing SCCs and reduced risk of new SCCs.25 While efficacy of 16. Peris K, et al., Imiquimod treatment of superficial and nodular basal cell carcinoma: 12-week open-label trial. Dermatol Surg. 2005. 31(3):318-23. topical tretinoin as monotherapy for SCC has not been studied, 1 7. Nouri K, C. O'Connell, and M.P. Rivas, Imiquimod for the treatment of a combination of topical tretinoin, imiquimod and 5-FU, each Bowen's disease and invasive squamous cell carcinoma. J Drugs Dermatol. with their distinct mechanisms of action, may provide improved 2003. 2(6): p. 669-73. 18. Goette DK. Treatment of keratoacanthoma with topical fluorouracil. Arch Der- long-term tumor free survival compared to single-drug regi- matol. 1983. 119(11):951-3. mens for patients with invasive SCC. 19. Kiss N, et al. Intralesional therapy for the treatment of keratoacanthoma. Dermatol Ther. 2019. 32(3):e12872. 20. Arits AH, et al. Photodynamic therapy versus topical imiquimod versus topi- We present a patient with invasive SCC successfully treated with cal fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial. Lancet Oncol. 2013. 14(7):647-54. combination topical therapy consisting of 5% imiquimod cream, 2 1. Shaw FM and M.A. Weinstock, Comparing topical treatments for basal cell 2% 5-FU solution, and 0.1% tretinoin cream. Previous reports of carcinoma. J Invest Dermatol. 2018. 138(3):484-486. 22. Tinelli M, et al. What determines patient preferences for treating low risk the use of single-drug topical therapy with imiquimod or 5-FU in basal cell carcinoma when comparing surgery vs imiquimod? A discrete the treatment of SCC in situ shown promising results,Do however Not Copychoice experiment survey from the SINS trial. BMC Dermatol. 2012. 12:19. the success rates were still lower than surgical management. 23. Yoon J, et al. Impact of topical fluorouracil cream on costs of treating keratinocyte carcinoma (nonmelanoma skin cancer) and actinic keratosis. J Am We demonstrate that the combination of these threePenalties medica- ApplyAcad Dermatol. 2018. 79(3): p. 501-507 e2. tions provided an excellent outcome in our case, although the 24. Weinstock MA, et al. Tretinoin and the prevention of keratinocyte carcinoma (Basal and squamous cell carcinoma of the skin): a veterans affairs random- follow-up was only 25 months. Prospective randomized clinical ized chemoprevention trial. J Invest Dermatol. 2012. 132(6):1583-90. trials are needed to support these findings, which may offer pa- 25. Rook AH, et al., Beneficial effect of low-dose systemic retinoid in combina- tients a non-surgical alternative to the current standard of care. tion with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients. Transplantation. 1995. 59(5):714-9. DISCLOSURES AUTHOR CORRESPONDENCE The authors have no potential conflicts of interest, financial -in terests, relationships or affiliations relevant to the subject of this Rachel Fayne submission. E-mail:...... ……...... [email protected] REFERENCES 1. Nehal KS, Bichakjian CK. Update on keratinocyte carcinomas. N Engl J Med. 2018;379(4):363-374. 2. Chitwood K, J. Etzkorn, and G. Cohen, Topical and intralesional treatment of nonmelanoma skin cancer: efficacy and cost comparisons.Dermatol Surg. 2013;39(9):1306-16. 3. Collins, A., J. Savas, and L. Doerfler. Nonsurgical treatments for nonmelanoma skin cancer. Dermatol Clin. 2019. 37(4):435-441. 4. Williams, H.C., et al., Surgery versus 5% imiquimod for nodular and superficial basal cell carcinoma: 5-year results of the SINS randomized controlled trial. J Invest Dermatol. 2017. 137(3):614-619. 5. Jansen, M.H.E., et al., Five-Year results of a randomized controlled trial comparing effectiveness of photodynamic therapy, topical imiquimod, and topical 5-fluorouracil in patients with superficial basal cell carcinoma.J Invest Dermatol. 2018. 138(3): p. 527-533. 6. Quirk, C., et al., Sustained clearance of superficial basal cell carcinomas treated with imiquimod cream 5%: results of a prospective 5-year study. Cutis. 2010. 85(6): p. 318-24. 7. Bath-Hextall, F., et al., Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

Recurrent Squamous Cell Carcinoma Arising Within a Linear Porokeratosis Amelia M. Abbott-Frey BA, Alexandra J. Coromilas MD, George W. Niedt MD, Jesse M. Lewin MD Columbia University Department of Dermatology, New York, NY

ABSTRACT

Here we report a case of linear porokeratosis with recurrent malignant degeneration to squamous cell carcinoma (SCC) recurring six years after excision of initial SCC. A 79-year-old woman presented with a friable tumor located within a longstanding lesion on her posterior thigh. Six years prior, she was diagnosed with SCC arising within the same lesion, which had been surgically excised with negative margins. Physical examination revealed a 3.5 x 2.7 cm friable tumor on the left proximal posterior thigh. The tumor was located within a hyperpigmented and erythematous scaly linear plaque within a line of Blaschko, extending from the left buttock to the left distal posterior thigh. Two 4 mm punch biopsies were performed: one of the erythematous plaque on the left buttock and one from the friable tumor on the left posteromedial thigh. Histology from the left buttock revealed a cornoid lamella consistent with porokeratosis and the left posteromedial thigh revealed SCC. The patient underwent Mohs micrographic surgery with negative margins, followed by a linear repair. Porokeratosis is a disorder of epidermal keratinization that has been associated with malignant degeneration, although such cases are rare. The risk of recurrence of SCC arising within a porokeratosis is unknown. This case emphasizes the importance of ongoing monitoring for malignant degeneration within these lesions.

J Drugs Dermatol. 2020;19(2)205-206. doi:10.36849/JDD.2020.4640

CASE REPORT 79-year-old woman with a history of hypertensionDo andNot thigh.Copy The patient subsequently underwent 1 stage of Mohs mi- hypothyroidism presented with a friable tumor within crographic surgery with complete tumor extirpation, followed Aa lesion on the left buttock and posterior Penaltiesthigh which by Apply a linear repair. has been present for her entire life. She was diagnosed with squamous cell carcinoma (SCC) arising within the linear plaque FIGURE 2. Histology demonstrates a column of porokeratosis (cornoid six years prior, which was surgically excised with negative mar- lamella) overlying the epidermis. There is an underlying infiltrate of lymphocytes. gins. Physical examination revealed a hyperpigmented and erythematous scaly linear plaque within a line of Blaschko, extending from the left buttock to the left distal posterior thigh (Figure 1). There was a 3.5 x 2.7 cm friable tumor on the proximal posterior thigh within the linear plaque.

FIGURE 1. Friable tumor within a linear hyperpigmented plaque extending from the left buttock to left distal posterior thigh.

FIGURE 3 AND 4. Histology (low and high power) demonstrates skin with psoriasiform epidermal hyperplasia and atypical keratinocytes at all levels of the epidermis. There is underlying diffuse inflammation.

Two 4 mm punch biopsies were performed: one of the erythematous plaque on the left buttock and one from the friable tumor on the left posteromedial thigh. Histology revealed a cornoid lamella consistent with porokeratosis on the left buttock (Figure 2) along with SCC in situ (Figures 3 and 4) on the posteromedial Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

206 Journal of Drugs in Dermatology A.M. Abbott-Frey, A.J. Coromilas, G.W. Niedt, J.M. Lewin February 2020 • Volume 19 • Issue 2

DISCUSSION Porokeratosis is a disorder of epidermal keratinization. There are several clinical variants of porokeratosis including porokeratosis of Mibelli, punctate porokeratosis, disseminated superficial porokeratosis, disseminated superficial actinic porokeratosis, porokeratosis plantaris palmaris et disseminate, and linear porokeratosis. Histologically these lesions are characterized by a cornoid lamella, which is a compact column of parakerato- sis. Although porokeratosis has historically been viewed as a JDD benign lesion, there is evidence that these lesions may demonstrate malignant transformation. Research suggests that malignant degeneration occurs in about 7.5-11% of porokerato- Facial Skin T ses, commonly presenting as Bowen’s disease, SCC, or basal ighte 1,2 U nin cell carcinoma. The risk of malignancy is hypothesized to be Con ltras g W sider oun ith M ation d and ic related to abnormal DNA ploidy in cells of the cornoid lamella s f or De rofo Patie rma cuse 3 nt S e l Fil d as well as aberration of the p53 protein. lectio lers: n a nd Outc omes Linear porokeratosis (LP) is an uncommon form of porokeratosis that is typically congenital, though lesions may arise in adulthood. LP’s follow Blaschko lines and are most often unilat- eral; however, they can rarely be generalized.3 Of all variants of porokeratosis, LP carries the highest risk for malignant transfor- STILL mation, estimated to occur in up to 19% of cases.1 Our patient’s lesion was clinically consistent with LP, which was confirmed AVAILABLE histologically. She had multiple risk factors for malignant transformation including a large, long-standing lesion, and location on the extremity.3-4 Other known risk factors for malignantDo Not Copy transformation include sun exposure, immunosuppression, and ionizing radiation.1,2,4,5 While there are a few casesPenalties in the Apply literature of multiple squamous cell carcinomas arising within linear porokeratosis, to our knowledge this is the first case to present with recurrence of a malignancy treated six years prior. This case highlights the importance of regular monitoring and surveillance for malignant degeneration in patients with large and long-standing linear porokeratosis. Facial Skin Tightening With DISCLOSURES Microfocused Ultrasound None of the authors have any conflicts of interest, financial, or and Dermal Fillers otherwise. Considerations for Patient Selection REFERENCES and Outcomes 1. Sasson, M, Krain, A. Porokeratosis and cutaneous malignancy: a review. Dermatol Surg. 1996;22:339-42. 2. Maubec E, Duvilard P, Margulis A. Common skin cancers in porokeratosis. Br J Dermatol. 2005;152:1389–91. Available now in the JDD CME Library: 3. Sertznig P, von Felbert V, Megahed M. Porokeratosis: present concepts. JEADV. 2012;26:404-412. www.JDDonline.com/CME 4. Otsuka F, Umebayashi Y, Watanabe S, Kawashima M, et al.Porokeratosis large skin lesions are susceptible to skin cancer development: histological and cytological explanation for the susceptibility. J Cancer Res Clin Oncol. 1993;119:295–400. This continuing education enduring activity is supported 5. Bencini PL, Tarantino A, Grimalt R, Ponticelli C, et al. Porokeratosis and im- by an educational grant provided by munosuppression. Br J Dermatol. 1995;132:74–8. Merz North America, Inc. AUTHOR CORRESPONDENCE

Skin Cancer Epidemiology and Sun Protection Behaviors Among Native Americans

To the Editor,

e read, with interest, Maarouf et al’s study, Skin cancer to other regions, which is also believed to be attributable to the epidemiology and sun protection behaviors among high UV intensity environment. This phenomenon may play a Native Americans (J Drugs Dermatol. 2019; 18(5):420- role in Southwestern states seeing much lower rates of melano- W 3,4 423), which provided insight regarding sun protective behaviors ma despite rates of non-melanoma skin cancer remaining high. among American Indians (AIs).1 At the University of New Mexico (UNM) School of Medicine Department of Dermatology we are Most important, we agree with the emphasis on improving AI ac- particularly invested in using such data to address the healthcare cess to skin cancer screenings and sun safety education. Although disparities we observe regarding New Mexican AI access to care. It skin cancer incidence is lower among minority populations, includ- is unclear whether the authors were aware of a very similar study ing AIs, the mortality rate is higher.5 This coincides with lower rates we published in 2016.2 Our cross-sectional study included 429 par- of skin cancer screenings and commonly held misconceptions re- ticipants, 38% non-Hispanic White (NHW), and 50% AI, in two rural garding skin cancer development within these populations. These New Mexican/Navajo Nation border towns. We sought to inventory issues are further exacerbated by healthcare disparities and sub- skin cancer risk reduction behaviors among AIs. We found AIs 38% standard access to health education.6 less likely than NHWs to have high sun protective scores. A higher proportion of NHWs used sunscreen, wore sunglasses, and had AI communities represent unique populations which need to be physician skin checks when compared to AIs (P<0.001). given special considerations in efforts to decrease the health and economic burdens of melanoma and NMSC. We believe continued We disagree with Maarouf et al’s assumption of a Fitzpatrick Skin work including behavioral inventories may provide cultural data to Type (FST) III-V score for the AI population. FST scores are defined enhance awareness projects and early detection practices. We look by how the skin reacts to the sun. Maarouf et al’s data actually re- forward to future research and thank the authors for their contribu- futes their own assumption: among AIs, the rate of redness and tion to the small but hopefully growing body of data specific to this peeling following sun exposure was 90% and 82%, respectively.Do Not population.Copy Anecdotally, in our clinics we similarly find AIs often report easily burning with sun exposure. Because of this, we were notPenalties surprised M.E. Apply Logue MD to see that reflected in their data. The problem with basing FST University of New Mexico Department of Dermatology scores on ethnicity, especially among the AI population, lies in the broad variation in skin tone determined by both an individual’s A. Smidt MD native tribal region and ancestry, which can be complex in post- University of New Mexico Department of Dermatology colonial America. M. Berwick PhD MPH We do not believe data comparison between AIs and FST III-V University of New Mexico Department of Internal Medicine populations is statistically valuable, nor is it reasonable to assume AIs have more sun exposure; we found no statistically significant References: difference (P>0.05) regarding childhood sunburns, time outside, 1. Maarouf M, Zullo SW, DeCapite T, Shi VY. Skin cancer epidemiology and or using shade, sleeves, and hats between AIs and NHWs. Ob- sun protection behaviors among Native Americans. J Drugs Dermatol. servationally, while the concept of “sun protective clothing” may 2019;18(5):420-423. 2. Logue ME, Hough T, Leyva Y, Kee J, Berwick M. Skin cancer risk reduction not have a shared meaning, AIs wear more conservative cloth- behaviors among American Indian and non-Hispanic white persons in rural ing. Dr. Jaron Kee, a member of our research team and the Diné new mexico. JAMA Dermatol. 2016;152(12):1382-1383. doi:10.1001/jamader- (Navajo) tribe, provided invaluable insight, particularly regarding matol.2016.3280 traditional Diné sunblock (mixed herbs and clay) and clothing (near 3. New Mexico Tumor Registry | The University of New Mexico. https:// full coverage) that have been widely used in their sheep herding nmtrweb.unm.edu/. Accessed September 1, 2019. 4. United States Cancer Statistics | Cancer | CDC. https://www.cdc.gov/cancer/ culture for generations. AI populations are influenced to vary- uscs/index.htm. Published August 20, 2019. Accessed September 1, 2019. ing degrees by Western culture and practices, and behaviors can 5. Wu X-C, Eide MJ, King J, et al. Racial and ethnic variations in incidence and change drastically on a generational timeline. A point of interest survival of cutaneous melanoma in the United States, 1999-2006. Journal regarding Western cultural influence: our data found no statisti- of the American Academy of Dermatology. 2011;65(5, Supplement 1):S26. cally significant difference in using tanning beds, which was the e1-S26.e13. doi:10.1016/j.jaad.2011.05.034 6. Jacobsen AA, Galvan A, Lachapelle CC, Wohl CB, Kirsner RS, Strasswim- least practiced behavior for both groups. This may be due to the mer J. Defining the Need for Skin Cancer Prevention Education in Uninsured, high UV intensity environment of the Southwest. As Maarouf et Minority, and Immigrant Communities. JAMA Dermatol. 2016;152(12):1342- al mentioned, and recent data shows, sun protective behaviors 1347. doi:10.1001/jamadermatol.2016.3156 are generally more commonplace in the Southwest compared Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

Response

To the Editor,

We thank Lo et al for their interest in our article, “Skin cancer epide- thus difficult to generalize their usage. Both parties agree that it miology and sun protection behaviors among Native Americans.”1 is important to consider traditional and modern aspects of behav- Our program at the University of Arizona shares a similar goal to iors and sun safety strategies available to a broad Native American identify and decrease potential dermatologic disparities affecting population. Guided by Shannon Zullo’s observations on the Navajo Native Americans (NA). reservation, we specifically designed our study to investigate the qualities Native American participants value in their sunscreen us- It is important to note that our inclusion criteria aimed to identify age, and we believe that it is a strength of our study. a unique patient population of adult Native American members of federally recognized tribes with a history of living on a reservation. We acknowledge that our study is limited by the anonymity of clini- These criteria allowed us to reach a segment of the Native Ameri- cal data (eg, Fitzpatrick score, eye, and hair color) due to design. can population that had a higher likelihood of receiving care from Our group appreciates and encourages collaboration between re- the Indian Health Service or Tribal Health clinics, as their services searchers interested in illuminating Native American dermatologic are only available to registered Native American members of feder- health disparities. Furthermore, the body of Native American der- ally recognized tribes.2 Our cohort differed from the commenter’s matologic research could also benefit from an examination of the study3 was not an appropriate comparison model. Reservation Na- heterogenicity of skin conditions and care practices among differ- tive Americans are understudied in research, and we believe that ent NA tribes and geographic regions. We look forward to future a strength of our study is a subject group that features a mean studies and thank the New Mexico team for their thoughtful com- length of time living on a reservation of 20 years. Furthermore, the ments and contribution to the literature. referenced ‘sun-behavior score’3 did not appear to be methodologi- cally defined in the commenter’s article with specific criteria, which Shannon W. Zullo MS made it difficult to compare their results directly to ours. University of Arizona College of Medicine Do Not Tucson,Copy AZ We wholeheartedly agree with the commenters that Native Ameri- can patients fall on a wide spectrum of Fitzpatrick skinPenalties scores as a Vivian Apply Y. Shi MD result of regional and national variation amongst tribes. However, University of Arizona, Department of Medicine when our data showed high rates of our cohort reporting photo- Division of Dermatology toxicity with associated redness (90%) or peeling (82%), it seemed Tucson, AZ worthy of discussion, considering that Fitzpatrick Skin Phototyping Scores I-III are often cited as burning most readily.4 Due to our sur- References: vey collection methods, which was largely sampled from Arizona, 1. Maarouf M, Zullo SW, DeCapite T, Shi VY. Skin cancer epidemiology and our cohort had an increased likelihood of having higher Fitzpatrick sun protection behaviors among native americans. J Drugs Dermatol. scores (III+) and also experiencing heightened sun exposure given 2019;18(5):420-423. 2. Indian Health Service. Indian Health Manual: Chapter 1 - Eligibility for ser- the UV index present in the region. We clearly acknowledged that vices. https://www.ihs.gov/ihm/pc/part-2/p2c1/. Updated June 28, 2017. Ac- this was a discussion item with limitations, but we believe the ex- cessed October 24, 2019. ploration of high phototoxicity rates in our cohort was warranted. 3. Logue ME, Hough T, Leyva Y, Kee J, Berwick M. Skin cancer risk reduction According to the Centers for Disease Control, Native Americans behaviors among american indian and non-hispanic white persons in Rural have the second highest incidence of melanoma5 and previous data New Mexico. JAMA Dermatology. 2016;152(12):1382-1383. 4. Coups EJ, Stapleton JL, Hudson SV, Medina-Forrester A, Natale-Pereira A, has also shown that NA individuals are more likely to be diagnosed Goydos JS. Sun protection and exposure behaviors among Hispanic adults at a significantly higher stage of melanoma than non-Hispanic in the United States: differences according to acculturation and among His- Whites.6 panic subgroups. BMC Public Health. 2012;12:985. 5. U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visual- While we greatly appreciate Dr. Kee’s insight on Navajo sun safety izations Tool, based on November 2018 submission data (1999-2016): U.S. Department of Health and Human Services, Centers for Disease Control and habits, we would like to caution the commenters on utilizing anec- Prevention and National Cancer Institute. https://gis.cdc.gov/Cancer/USCS/ dotal observations. One of our study authors, Shannon Zullo, is a DataViz.html. Updated June 2019. Accessed October 20, 2019. member of the Navajo Nation who grew up on the reservation in a 6. Baldwin J, Janitz AE, Erb-Alvarez J, Snider C, Campbell JE. Prevalence and sheep-herding family. In her experience, the customs of conserva- mortality of melanoma in Oklahoma among racial groups, 2000-2008. The tive attire and red clay sunscreen have become less common, and Journal of the Oklahoma State Medical Association. 2016;109(7-8):311-316 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

Is Dupilumab an Immunosuppressant? Adrian Cuellar-Barboza MD,a Matthew Zirwas MD,b Steven R. Feldman MD PhDc ªDepartment of Dermatology, University Hospital “Dr. José E. González”, Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico bOhio University, Columbus, OH cDepartment of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC

ABSTRACT

Atopic dermatitis (AD) is a chronic, immune-related, inflammatory skin disease that significantly reduces quality of life. In severe AD, systemic immunosuppressants are often utilized, though they do not target specific biologic pathways of AD. A non-immunosuppressive treatment may offer the possibility of high efficacy with better safety. Dupilumab, the only FDA-approved biologic for AD (approved for adults and adolescents 12 and older), is a fully human monoclonal IgG4ҡ antibody that inhibits IL-4 and IL-13 signal. To date, there is no evidence that dupilumab has immunosuppressive effects. On the contrary, by decreasing Staphylococcus colonization and partially normalizing the skin microbiome, likely via direct effects on the innate immune system, dupilumab appears to improve immunologic protection against infections. To date, no study has reported reactivation of latent infections (such as hepatitis B or tuberculosis, invasive fungal infection or unusual opportunistic infections) or progression of malignancy in association with dupilumab. Data on dupilumab’s safety is limited by the short follow-up time in most trials and the relatively low number of patients treated to date. Keeping those limitations in mind and based on current best evidence, it appears that dupilumab may enhance innate immune function in patients with AD.

J Drugs Dermatol. 2020;19(2)209-210. doi:10.36849/JDD.2020.4722

Do Not Copy topic dermatitis (AD) is a chronic, immune-related, microbial diversity.2 Furthermore, IL-4 reduces antimicrobial inflammatory skin disease that significantlyPenalties reduces peptide Apply (AMP) production in the skin, which is a key component Aquality of life. In severe AD, systemic immunosuppres- of the innate immune system.5 Combining these observations sants (which inhibit the immune system’s ability to fight infec- suggests that the decrease in cutaneous Staphylococcus tions and malignancy)— such as prednisone, cyclosporine, caused by dupilumab could be due in part to increased AMP methotrexate, azathioprine, and mycophenolate mofetil— are production triggered by IL-4 blockade. often utilized, though they do not target specific biologic pathways of AD, and their long-term use is limited by moderate In a population-based claims data study of patients with AD, efficacy and adverse events.1 Narrower, better targeted, non- the incidence of serious infections was 7.5 per 1,000 (7.18-7.89) immunosuppressive treatment may offer the possibility of high among systemic non-biologic users compared to 2.6 per 1,000 efficacy with better safety. (0.45-14.3) among dupilumab users.1 To date, no study has reported reactivation of latent infections (such as hepatitis B or The underlying immune mechanisms of AD are becoming tuberculosis, invasive fungal infection or unusual opportunistic better understood. Interleukin 4 (IL-4) and IL-13 play key roles infections) or progression of malignancy in association with as evidenced by the genes for these signaling proteins being dupilumab. linked to AD. Dupilumab, the only FDA-approved biologic for AD (approved for adults and adolescents 12 and older), is a fully In conclusion, there is no evidence that dupilumab has human monoclonal IgG4ҡ antibody that inhibits IL-4 and IL-13 immunosuppressive effects. On the contrary, by decreasing signal transduction by binding to the shared α subunit of the Staphylococcus colonization and partially normalizing the skin IL-4 and IL-13 receptors.2 microbiome, likely via direct effects on the innate immune system, dupilumab appears to improve immunologic protection AD is a risk factor for Staphylococcus infections.3 Dupilumab against infections. Data on dupilumab’s safety is limited by the reduces the incidence of skin infections and eczema herpeticum short follow-up time in most trials and the relatively low number in adults with moderate-to-severe AD by over 50%.4 While of patients treated to date. Keeping those limitations in mind this might be related to an improvement in the skin barrier and based on current best evidence, it appears that dupilumab integrity due to decreased scratching, dupilumab also changes is not an immunosuppressant and the substantial decrease in the cutaneous microbiome, even in non-lesional skin, with infection rates makes it reasonable to say that dupilumab may a reduction in Staphylococcus density and an increase in enhance innate immune function in patients with AD. Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

DISCLOSURES Steven R. Feldman has received research, speaking and/ or consulting support from a variety of companies including Galderma, GSK/Stiefel, Almirall, Leo Pharma, Boehringer A top practice management and career building resource for Residents and Young Dermatologists Ingelheim, Mylan, Celgene, Pfizer, Valeant, Abbvie, Samsung, Janssen, Lilly, Menlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, Next Steps in Derm UpToDate, and National Psoriasis Foundation. He is founder and majority owner of www.DrScore.com and founder and part Content Highlights owner of Causa Research, a company dedicated to enhancing patients’ adherence to treatment. Matthew Zirwas has received Derm In- Review Pop Quiz – Each Friday, a new research, speaking and/or consulting support from a variety of Pop Quiz question is posted to the Next Steps in companies including Abbvie, Aerolase, Aclaris, Aructis, Asana, Derm website, courtesy of Derm In-Review! Test your AsepticMD , Avillion, DS Biopharma, Fit Bit, Foamix, Genench knowledge each week with these questions! / Novartis, Incyte, Janssen, L’Oreal, Leo, Lilly, Menlo, Ortho Derm, Pfizer, Regeneron / Sanofi, and UCB. Adrian Cuellar- Patient Buzz Series - Do you ever field odd-ball patient questions and wonder where the information they Barboza has no conflicts to disclose. presented came from? The monthly “Patent Buzz” series addresses recent dermatology news from the consumer References press and provides background on the conditions and 1. Schneeweiss MC, Perez-Chada L, Merola JF. Comparative safety of systemic immuno-modulatory medications in adults with atopic dermatitis. J Am Acad treatments your patients may ask about at their next Dermatol. 2019. doi: 10.1016/j.jid.2019.05.024. [Epub ahead of print]. office visit. Find the latest in the series under the Derm 2. Callewaert C, Nakatsuji T, Knight R, Kosciolek T, Vrbanac A, Kotol P, Ardeleanu Topics section on NextStepsinDerm.com M, Hultsch T, Guttman-Yassky E, Bissonnette R, Silverberg JI, Krueger J, Menter A, Graham NMH, Pirozzi G, Hamilton JD, Gallo RL. IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus ColonizationDo Not and CopyJDD Editorial Highlights – Editorial highlights each Increases Microbial Diversity in Atopic Dermatitis. J Invest Dermatol. 2020 month from the Journal of Drugs in Dermatology (JDD), Jan;140(1):191-202. 3. Aliyu S, Cohen B, Liu J, Larson E. Prevalence and risk factors forPenalties bloodstream Applyas well as podcasts and the “Ask the Investigator” series. infection present on hospital admission. J Infect Prev. 2018;19(1):37-42. 4. Fleming P, Drucker AM. Risk of infection in patients with atopic dermatitis Genoderms Made Ludicrously Easy: Tumor treated with dupilumab: A meta-analysis of randomized controlled trials. J Am Acad Dermatol. 2018;78(1):62-69.e1. Syndromes Webinar: Dr. Finch brings a special 5. Bao L, Shi VY, Chan LS. IL-4 up-regulates epidermal chemotactic, angiogenic, webinar presentation from his wildly popular book, and pro-inflammatory genes and down-regulates antimicrobial genes in vivo Genoderms Made Ludicrously Easy. In this webinar, Dr. and in vitro: Relevant in the pathogenesis of atopic dermatitis. Cytokine. 2013;61(2):419-425. Justin Finch reviews the clinical spectrum of genetic disorders with malignant potential and examines key dermatologic clues to the diagnosis of genetic tumor AUTHOR CORRESPONDENCE syndromes, including PTEN hamartoma syndromes, Reed syndrome, Gardner syndrome, Rombo syndrome Steven R. Feldman MD PhD and others. The discussion of important clinical features E-mail:...... ……...... [email protected] is facilitated by high-yield visual mnemonic cartoons.

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@NextSteps_Derm @nextstepsinderm @NextStepsinDerm

If you would like to contribute to Next Steps in Derm, visit https://nextstepsinderm.com/contributor/ or email us at [email protected] and a team member will get back with you Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page BE AN GET TO KNOW ORIGINAL.GET TO KNOW Don’t settle for imitations. #1 provider Choose the of skin TM GET TO KNOW FASTER GET TO KNOW ACCUREP TREATMENTS TECHNOLOGYTM tightening treatments worldwide. ACCUREP UpFASTER to 25% faster Optimized treatment TREATMENTStreatment time with TECHNOLOGYalgorithm with site theUp new to Total25% fasterTip 4.0*. Optimizedspecific real-time treatment tuning. treatment time with FASTER TREATMENTS - Up to 25% faster treatment algorithm with site the new Total Tip 4.0*.time with the Total Tip 4.0*. specific real-time tuning. 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ENHANCED EASIERFaster treatments that deliver consistent outcomes and provide patient comfort USER EXPERIENCE TO NAVIGATEFaster treatments that deliver consistent outcomes and provide patientDo comfort Not Copy *With 33% larger surface area as compared to Total Tip 3.0. Lighter, ergonomic handpiece All comparisonsLarge are to touchscreenthe Thermage CPT™ with system and its components. with multi-directional vibration. userF friendlyASTER interface. 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Thermage FLX® INDICATION • The radiofrequency energy only delivery components of the Thermage FLX® system and accessories are indicated for use in: dermatologic and general surgical procedures for electrocoagulation and hemostasis; non-invasive treatment of periorbital wrinkles and rhytids including upper and lower eyelids; and non-invasive treatment of wrinkles and rhytids.

• The simultaneous application of radiofrequency energy and skin vibration by the Thermage ORIGINATOR. INNOVATOR. LEADER. ® FLX system and accessories are indicated for use in dermatologic and general surgical procedures [email protected] | 877.782.2286 | +1.510.786.6946 for electrocoagulation and hemostasis; non-invasive treatment of periorbital wrinkles and rhytids; non- invasive treatment of wrinkles and rhytids; temporary improvement in the appearance of cellulite; relief of minor muscle aches and pains; relief of muscle spasms; and temporary improvement of local circulation (blood circulation). Solta Medical is a global leader in the aesthetic industry providing innovative products such as Liposonix®, VASERlipo®, VASER® ultrasonic systems, Thermage® radiofrequency and Isolaz® acne therapy systems, and the Clear + Brilliant®, Clear + Brilliant pèlo® and Fraxel® lasers. ®/TM are trademarks of Bausch Health Companies Inc. or its af liates. ©2019 Bausch Health Companies Inc.or its af liates. TRM.0092.USA.19 Previous Page | Contents | Zoom In | Zoom Out | Search Issue | Cover | Next Page

PIPELINE PREVIEWS

ALASTIN Skincare® Announces Issuance of Third U.S. 18th World Congress on Cancers of the Skin Patent for Their Revolutionary TransFORM Body Treat- ment With TriHex Technology® The 18th World Congress on Cancers of the Skin (WCCS) will be held in Buenos Aires, Argentina, June 24-27, 2020. This event ALASTIN Skincare®, Inc. - a specialty aesthetics company is organized by Colegio Ibero Latinoamericano de Dermatolo- dedicated to developing and marketing innovative, clinically- gia (CILAD) and co-sponsored by The Skin Cancer Foundation tested physician dispensed skin care products, announces that (SCF). Participating in this extraordinary scientific event offers the United States Patent and Trademark Office has issued a physicians a unique opportunity to interact with distinguished third U.S. Patent covering ALASTIN's innovative science and international faculty and learn about breakthrough discoveries products. U.S. Patent No. 10,493,011 is entitled, "Peptide Com- in the prevention, diagnosis and treatment of all types of skin positions and Methods for Ameliorating Skin Laxity and Body cancer. The scientific program structure includes symposiums, Contour." This patent is directed to the composition and uses forums, conferences and round table discussions. related to ALASTIN's breakthrough TransFORM Body Treat- ment, when used alone as well as when used in conjunction About The World Congress on Cancers of the Skin with body-shaping procedures. The World Congress on Cancers of the Skin is held in a different country every two years and is sponsored jointly by The Skin As the leader in peri-procedure skincare, the issuance of ALAS- Cancer Foundation and dermatological organizations from the TIN's third formulation patent supports the brand's position as host country. Since 1983 the Congress highlighted melanomas the fastest growing professionally dispensed skincare compa- and nonmelanomas, new advances in diagnosis and new per- ny in the U.S. aesthetic market. spectives in the treatment of skin cancer.

Visit www.alastin.com to find a physician retailer near you. WHERE: Do Not CentroCopy de Convenciones Buenos Aires Av. Pres. Figueroa Alcorta 2099, 1112 CABA, Argentina Cutera ExcelV+ Penalties Apply WHEN: With design input from leading dermatologists, excel V+ is Wednesday, June 24, 2020 – Saturday, June 27, 2020 the latest generation laser technology for the treatment of All important information, including specific times, can be found vascular and benign pigmented lesions and skin revitalization at https://www.wccs2020.com/ concerns. By combining two clinically proven wavelengths, the 532 nm LBO and Cutera’s pioneered 1064 nm Nd:YAG, TICKETS: providers can treat more than 20 indications on the face and Fees to attend range from $200-700 USD body, from challenging vascular and pigmentary issues to today’s most common concerns such as rosacea, leg veins, CONTACTS: and our signature Laser Genesis procedure. The excel V+ Media Inquiries: Arielle Grabel features several new enhancements, including a large 16 (646-583-7987; [email protected]) mm spot size for 2X faster treatments, 50% more power with Event Coordination: Staci Pierson the 532 nm wavelength, and two new revenue streams with (646-583-7978; [email protected]) the Green Genesis and the Dermastat 532 nm treatments. Combined with its solid-state design, no consumable model, About The Skin Cancer Foundation intra-pulse autocalibration, and adjustable sapphire contact The Skin Cancer Foundation is the only global organization cooling, the new excel V+ provides the power, precision, solely devoted to the prevention, early detection and treatment and performance to put your practice ahead of the rest. of skin cancer. The mission of the Foundation is to decrease the incidence of skin cancer through public and professional Learn more about excel V+ at www.cutera. com/excelVplus. education and research. Since its inception in 1979, the Foundation has recommended following a complete sun protection regimen that includes seeking shade and covering up with clothing, including a wide-brimmed hat and UV- blocking sunglasses, in addition to daily sunscreen use. For more information, visit SkinCancer.org.

Erratum

Dear Editor,

ue to a processing error, the order of authors in the STILL article “Dietary Lycopene Protects SKH-1 Mice Against DUltraviolet B-Induced Photocarcinogenesis” in the De- cember issue (J Drugs Dermatol. 2019;18(12):1244) was incor- AVAILABLE rect. The correct order of authors should be as follows:

Xueyan Zhou MD MS,a,b Karen E. Burke MD PhD,a Yongyin Wang PhD,a,c Huachen Wei MD PhDa,d

Sincerely,

Karen E. Burke MD PhD Clinical Insights About the Role of Skin pH in Do Not CopyInflammatory Dermatological Penalties Apply Conditions

Supported by an unrestricted educational grant from the International Dermatology Education Foundation

BRIEF SUMMARY OF PRESCRIBING INFORMATION USE IN SPECIFIC POPULATIONS This brief summary does not include all the information needed to use BRYHALI safely and Pregnancy effectively. See full prescribing information for BRYHALI. Risk Summary BRYHALI® (halobetasol propionate) lotion, 0.01% for topical use There are no available data on BRYHALI use in pregnant women to inform a drug- Initial U.S. Approval: 1990 associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. INDICATIONS AND USAGE In animal reproduction studies, increased malformations, including cleft palate and BRYHALI® (halobetasol propionate) Lotion, 0.01% is indicated for the topical treatment of omphalocele, were observed after oral administration of halobetasol propionate during organogenesis to pregnant rats and rabbits. The available data do not support relevant plaque psoriasis in adults. comparisons of systemic halobetasol propionate exposures achieved in the animal studies CONTRAINDICATIONS to exposures observed in humans after topical use of BRYHALI. None. The background risk of major birth defects and miscarriage for the indicated population is WARNINGS AND PRECAUTIONS unknown. In the U.S. general population, the estimated background risk of major birth Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to BRYHALI has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis. 20%, respectively. Systemic effects of topical corticosteroids may include reversible HPA axis suppression with Data the potential for glucocorticosteroid insufficiency. This may occur during treatment or upon Animal Data withdrawal of treatment with the topical corticosteroid. Halobetasol propionate has been shown to cause malformations in rats and rabbits when The potential for hypothalamic-pituitary-adrenal (HPA) axis suppression with BRYHALI was given orally during organogenesis at doses of 0.04 to 0.1 mg/kg/day in rats and evaluated in a study of 19 adult subjects with moderate to severe plaque psoriasis involving 0.01 mg/kg/day in rabbits. Halobetasol propionate was embryotoxic in rabbits but not in ≥20% of their body surface area (BSA). HPA axis suppression was reported for 1 (5.6%) rats. Cleft palate was observed in both rats and rabbits. Omphalocele was seen in rats but subject at Week 4 and for 3 (15.8%) subjects at Week 8. All 3 subjects had normal HPA axis not in rabbits. suppression test with discontinuation of treatment [see Clinical Pharmacology in full Lactation Prescribing Information]. Risk Summary Because of the potential for systemic absorption, use of topical corticosteroids, including There are no data on the presence of halobetasol propionate or its metabolites in human BRYHALI, may require that patients be evaluated periodically for evidence of HPA axis milk, the effects on the breastfed infant, or the effects on milk production after suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis treatment with BRYHALI. suppression include the use of more potent corticosteroids, use over large surface areas, Systemically administered corticosteroids appear in human milk and could suppress occlusive use, use on an altered skin barrier, concomitant use of multiple corticosteroid- growth, interfere with endogenous corticosteroid production, or cause other untoward containing products, liver failure, and young age. An adrenocorticotropic hormone (ACTH) effects. It is not known whether topical administration of corticosteroids could result in stimulation test may be helpful in evaluating patients for HPA axis suppression. sufficient systemic absorption to produce detectable quantities in human milk. If HPA axis suppression is documented, attempt to gradually withdraw the drug, reduce the The developmental and health benefits of breastfeeding should be considered along with frequency of application, or substitute a less potent steroid. Manifestations of adrenal the mother’s clinical need for BRYHALI and any potential adverse effects on the breastfed insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis child from BRYHALI. function is generally prompt and complete upon discontinuation of topical corticosteroids. Clinical Considerations Systemic effects of topical corticosteroids may also include Cushing’s syndrome, Advise breastfeeding women not to apply BRYHALI directly to the nipple and areola to avoid hyperglycemia, and glucosuria. Use of more than one corticosteroid-containing product at direct infant exposure. the same time may increase the total systemic exposure to corticosteroids. Pediatric Pediatric Use patients may be more susceptible than adults to systemic toxicity from the use of topical Safety and effectiveness of BRYHALI in pediatric patients under the age of 18 years have corticosteroids due to their larger surface-to-body mass ratios [see Use in not been evaluated. Specific Populations]. Because of higher skin surface area to body mass ratios, pediatric patients are at a greater Local Adverse Reactions risk than adults of HPA axis suppression and Cushing’s syndrome when they are treated Local adverse reactions from topical corticosteroids may include atrophy, striae, with topical corticosteroids. They are therefore also at greater risk of adrenal insufficiency telangiectasias, burning, itching, irritation, dryness, folliculitis, acneiform eruptions, during or after withdrawal of treatment. Adverse reactions including striae have been hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection,Do Notand reportedCopy with use of topical corticosteroids in infants and children [see Warnings miliaria. These may be more likely with occlusive use, prolonged use, or use of higher and Precautions]. potency corticosteroids, including BRYHALI. Some local adverse reactions may HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, be irreversible. Penaltiesand Apply intracranial hypertension have been reported in children receiving topical Concomitant Skin Infections corticosteroids. Manifestations of adrenal suppression in children include low plasma Use an appropriate antimicrobial agent if a skin infection is present or develops. If a cortisol levels and an absence of response to ACTH stimulation. Manifestations of favorable response does not occur promptly, discontinue use of BRYHALI until the infection intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema has been adequately treated. [see Warnings and Precautions]. Allergic Contact Dermatitis Geriatric Use Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to Of 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 heal rather than noting a clinical exacerbation. Consider confirmation of a clinical diagnosis older to determine whether they respond differently from younger subjects. of allergic contact dermatitis by appropriate patch testing. Discontinue BRYHALI if allergic contact dermatitis occurs. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility ADVERSE REACTIONS Long-term animal studies have not been performed to evaluate the carcinogenic potential Clinical Trials Experience of halobetasol propionate. Because clinical trials are conducted under widely varying conditions, adverse reaction Halobetasol propionate was not genotoxic in the Ames assay, in the sister chromatid rates observed in the clinical trials of a drug cannot be directly compared to rates in the exchange test in Chinese hamster somatic cells, in chromosome aberration studies of clinical trials of another drug and may not reflect the rates observed in clinical practice. germinal and somatic cells of rodents, or in a mammalian spot test. Positive mutagenicity In randomized, double-blind, multicenter, vehicle-controlled clinical trials, 426 adults with effects were observed in a mouse lymphoma gene mutation assay in vitro and in a Chinese plaque psoriasis were treated with BRYHALI and had post-baseline safety data. Subjects hamster micronucleus test. applied BRYHALI once daily for up to eight weeks. Table 1 presents adverse reactions that Studies in rats following oral administration of halobetasol propionate at dose levels up to occurred in at least 1% of subjects treated with BRYHALI and more frequently than in 0.05 mg/kg/day indicated no impairment of fertility or general reproductive performance. vehicle-treated patients. PATIENT COUNSELING INFORMATION Table 1: Adverse Reactions Occurring in ≥1% of the Subjects Treated with Advise the patient to read the FDA-approved patient labeling (Patient Information). BRYHALI through Week 8 Manufactured for: BRYHALI Vehicle Bausch Health US, LLC (N=284) (N=142) Bridgewater, NJ 08807 USA By: Adverse Reaction % % Bausch Health Companies Inc. Upper Respiratory Tract Infection 2% 1% Laval, Quebec H7L 4A8, Canada U.S. Patent Numbers: 6,517,847 and 8,809,307 Application Site Dermatitis 1% 0 BRYHALI is a trademark of Ortho Dermatologics’ affiliated entities. ©2019 Ortho Dermatologics’ affiliated entities. Hyperglycemia 1% 0 Based on 9652102 October 2019 BRY.0135.USA.19

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Indication 2 PIVOTAL PHASE 3 TRIALS BRYHALI® (halobetasol propionate) Lotion, 0.01% is a corticosteroid Do Not Copyindicated for the topical treatment of plaque psoriasis in adults. 1 POTENT TO SUPERPOTENT CLEARANCE : Important Safety Information Penalties ApplyWarnings and Precautions 4 weeks post treatment1 Continued results • BRYHALI Lotion has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis during treatment or Signifi cant symptomatic relief as early as week 22 upon cessation of treatment; periodic evaluation may be required. • Systemic eff ects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. No increased epidermal atrophy • Children may be more susceptible to systemic toxicity when observed through 8 weeks of treatment2 treated with topical corticosteroids. • Local adverse reactions may include atrophy, striae, Local adverse reactions from topical corticosteroids may include telangiectasias, hypopigmentation, and allergic contact atrophy, striae, telangiectasias, hypopigmentation and allergic dermatitis. Some local adverse reactions may be irreversible. contact dermatitis. Some local adverse reactions may be irreversible. • Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. If visual symptoms occur, consider referral to an ophthalmologist. STUDY RESULTS: 36.5% of patients in trial 1 and 38.4% in trial 2 achieved treatment success at week 8 (primary endpoint) vs 8.1% and 12.0% of patients with vehicle, respectively (P<0.001 • Use an appropriate antimicrobial agent if a skin infection is present in both trials).2 or occurs, and if prompt response is not seen, discontinue use STUDY DESIGN: The safety and effi cacy of BRYHALI Lotion were assessed in 2 prospective, until infection has been adequately treated. multicenter, randomized, double-blind, phase 3 clinical trials in 430 adult patients with • Discontinue BRYHALI Lotion if allergic contact dermatitis occurs. moderate-to-severe plaque psoriasis. Patients were treated with BRYHALI Lotion or vehicle lotion, applied once daily. Primary effi cacy endpoint was treatment success evaluated at week Adverse Reactions 8. Secondary effi cacy endpoint was treatment success evaluated at weeks 2, 4, 6, and The most common adverse reactions (≥1%) were upper respiratory 12 (4 weeks post treatment). Tertiary effi cacy endpoint was a 2-grade improvement from • baseline at each time point for the individual signs of psoriasis (erythema, plaque elevation, tract infection, application site dermatitis, and hyperglycemia. and scaling).2 To report SUSPECTED ADVERSE REACTIONS, contact Customer Treatment success was defi ned as at least a 2-grade improvement from baseline in the Service at 1-800-321-4576 or FDA at 1-800-FDA-1088. Investigator’s Global Assessment score, and a score of “clear” or “almost clear” (primary endpoint at week 8).2 References: 1. BRYHALI Lotion [prescribing information]. Bridgewater, NJ. Please see Brief Summary of full Prescribing Information on Bausch Health US, LLC. 2. Data on fi le. following page.

VALE6706 BRYHALI Journal Ad JDD 4/C Page Live: .125" from Trim File format: PDF/X-1A Carling Communications 1/13/20 Trim: 8.25"x10.875" Bleed: 8.5”x11.125