JPDS MAY 2023

Dapsone-induced hemolytic anemia in non-G6PD deficient leprosy patients receiving multidrug therapy in Southern Philippines Medical Center: A retrospective study Page 21 POSITION PAPERS Medical cannabis in dermatology Page 3 Stem cell therapy in dermatology Page 7 Volume 32 Issue 1 May 2023 ISSN 2094-201X The science of masculine beauty: Key principles and strategies for male aesthetic enhancement Page 13 Histology of acral lentiginous melanoma. A. Low power view (10x) with confluent nests of heavily pigmented and atypical melanocytes in the dermis. B. S100 positive melanocytes, with strong and diffuse nuclear expression within the dermis. C. HMB-45 positive melanocytes with strong and diffuse cytoplasmic expression within the dermis D. Melan-A positive pagetoid with strong and diffuse cytoplasmic expression within in the epidermis and confluent single melanocytes spanning the base of the epidermis. A B C D

EDITORIAL OFFICE #73 Malakas Street, Diliman, Quezon City 1100 Philippines (632) 8727 7309 • https://journal.pds.org.ph/ JPDS is indexed in the Western Pacific Rim Index Medicus (WPRIM) and HERDIN. ISSN: 2094-201X PHILIPPINE COPYRIGHT @ 2014 Philippine Dermatological Society. All rights reserved. No part of this publication may be reproduced, stored, or transmitted in any form or by any means without prior permission in writing from the copyright holder. DISCLAIMER The Philippine Dermatological Society and Editors cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed do not necessarily reflect those of the Philippine Dermatological Society and Editors, neither does the publication of advertisments constitute any endorsement by the Philippine Dermatological Society and Editors. All editorial staff are requested to disclose any potential conflict of interest, including current or recent financial relationships with any commercial entity whose products or services may be contained in the journal content. The competing interests are disclosed in our website. Journal of the Philippine Dermatological Society • Volume 32 Issue 1 • May 2023 Editorial Board 2023-2024 EDITOR-IN-CHIEF Hester Lim Bueser, MD, FPDS DEPUTY EDITOR Czarina P. Chavez, DipClinRes, MD, FPDS ASSOCIATE EDITORS Gisella U. Adasa, MD, FPDS, FPDSP-PDS Jonathan Nevin T. Yu, MD, FPDS, IFAAD Jay-V James G. Barit, MD, DPDS Elisa Rae Coo, MD, FPDS, FDSP-PDS Josef Symon Concha, MD, DPDS Tanya Perez-Chua, MD, FPDS, FDSP-PDS Melanie Joy Doria-Ruiz, MD, FPDS, MMHoA Lian C. Jamisola, MD, FPDS, APSV, MSPH Biostat Jennifer Lavina T. Ngo, MD-MBA, DPDS Ana Aurelia M. Santos, MD, FPDS Angeli Eloise E. Torres-Paulino, MD, FPDS Cybill Dianne C. Uy, MD, FPDS Terese Monette Aquino-Agas, MD, MClin Res, FPDS, FDSP-PDS EDITORIAL ADVISOR Camille Berenguer-Angeles, MD, FPDS COPYEDITORS LAYOUT ARTIST Jaryll Gerard L. Ampog Clarence Xlasi D. Ladrero Rodel C. Roño J Phil Dermatol Soc • May 2023 • ISSN 2094-201X i

Philippine Dermatological Society OFFICERS AND BOARD DIRECTORS 2023-2024 PRESIDENT Cynthia P. Ciriaco-Tan, MD, FPDS VICE PRESIDENT Maria Jasmin J. Jamora, MD, FPDS SECRETARY Camille Berenguer-Angeles, MD, FPDS TREASURER Antonio C. Sison, MD, FPDS IMMEDIATE PAST PRESIDENT Francisco D. Rivera IV, MD, FPDS MEMBERS Zharlah Gulmatico-Flores, MD, FPDS Claudine Rae Lagman-Javier, MD, FPDS Ma. Michellende Dolores G. Gatchalian, MD, FPDS Maria Cristina A. Puyat, MD, FPDS Maria Deanna S. Ramiscal, MD, FPDS Liza Marie R. Paz-Tan, MD, FPDS Mary Jane G. Uy, MD, FPDS Journal of the Philippine Dermatological Society • Volume 32 Issue 1 • May 2023 J Phil Dermatol Soc • May 2023 • ISSN 2094-201X ii

EDITORIAL 1 Artificial intelligence and the changing landscape of research Hester Gail Lim, MD, FPDS LET’S HEAR FROM A COLLEAGUE 3 Medical cannabis in dermatology: A position paper from the Philippine Dermatological Society Bryan Guevara, MD, FPDS, FDSP, Hester Gail Lim, MD, FPDS, Josef Symon S. Concha, MD, DPDS, Zharlah Gulmatico-Flores, MD, MMPHA, FPDS, Camille B. Angeles, MD,FPDS 7 Stem cell therapy in dermatology: A position paper from the Philippine Dermatological Society Bryan Guevara, MD, FPDS, FDSP, Hester Gail Lim, MD, FPDS, Josef Symon S. Concha, MD, DPDS, Zharlah Gulmatico-Flores, MD, MMPHA, FPDS, Camille B. Angeles, MD,FPDS CONTINUING MEDICAL EDUCATION 13 The science of masculine beauty: Key principles and strategies for male aesthetic enhancement Jonathan Nevin T. Yu, MD FPDS, Raphaela Martina C. Pineda, MD, DPDS, Katrina Ysabelle G. Sun, MD ORIGINAL ARTICLE 22 Dapsone-induced hemolytic anemia in nonG6PD deficient leprosy patients receiving multidrug therapy in Southern Philippines Medical Center: A retrospective study Camille Joyce J. Crisostomo, MD, DPDS, Karen Lee Alabado-Laurel, MD, FPDS, Angela E. Sison, MD, DPDS CASE REPORTS 27 A case of green nail syndrome secondary to P. aeruginosa and C. parapsilosis treated with topical nadifloxacin and oral fluconazole in a 31-year-old Filipino female Angeli Elaine A. Pangilinan MD, Nicole R. Rivera, MD, Leilani R. Senador, MD, FPDS 31 Treatment conundrum: A case of recalcitrant Epidermolysis Bullosa Acquisita (EBA) in a 50-yearold Filipino male Danelle Anne L. Santos, MD, Aira Monica R. Abella, MD, Danica-Grace Tungol, MD, DPDS, Leilani R. Senador, MD, FPDS 35 Oral sirolimus in the treatment of adult eruptive cherry angiomas Christine Lyka R. Sayson, MD, Aira Monica R. Abella, MD, Danielle Marlo R. Senador, MD, Leilani R. Senador, MD, FPDS, Gisella U. Adasa, MD, FPDS 39 Dermoscopic features and management strategy of a 10-year history acral lentiginous melanoma in a 55-year-old Filipino Alexis G. De las Alas, MD, Aira Monica R. Abella, MD, Kristy Elleza R. Evangelista, MD, FPDS, Gisella U. Adasa, MD, FPDS 43 Basal cell carcinoma arising on two variants of epidermal nevus: a case series Irene B. Cua, MD, DPDS, Arnelfa C. Paliza, MD, FPDS 47 Disseminated histoplasmosis in a 53-year-old HIV-negative Filipino male: A case report Dana Andrea D. Nery, MD Maria Katherina Lat-Herrin, MD, FPDS, FDSP-PDS, Mary Elizabeth Danga, MD, FPDS, FDSP-PDS 53 The great mimicker: A case report of an extensive pyoderma gangrenosum in a 39-year-old Filipino female treated with systemic corticosteroids and antibiotics Camille Joyce J. Crisostomo, MD, DPDS, Niña A. Gabaton, MD, FPDS 57 Plasma cell cheilitis in an elderly female: A case report Maria Isabel M. Belizario, MD, Jolene G. Dumlao, MD, FPDS, Johannes F. Dayrit, MD Table of Contents Journal of the Philippine Dermatological Society • Volume 32 Issue 1 • May 2023 J Phil Dermatol Soc • May 2023 • ISSN 2094-201X iii

Artificial intelligence and the changing landscape of research Hester Gail Lim, MD, FPDS1,2 Large language models (LLMs) are a subset of artificial intelligence (AI) trained on large quantities of text, enabling human-like interaction. These models are particularly adept at language-based tasks. ChatGPT (OpenAI, San Francisco, California) is a program based on one of the largest LLM subsets. In addition to its complex parameters, the pretraining has made it particularly adept at generating human-like text.1 It was made available to the public in November 2022.2 The use of LLMs can have a profound impact on written content creation, and research is no exception. With the ability to generate paragraphs of text based on simple prompts by the user, LLMs are increasingly used in creative writing, academic essays, and scientific writing. LLMs may hasten the literature review process and can quickly summarize data from multiple sources. It can improve the writing style, coherence, and readability of an article, which may be particularly helpful for non-native English speakers.3 However, certain risks must also be considered. Unlike human authors, LLMs cannot be held accountable for errors generated within the text.3,4 LLMs can generate text without a contextual understanding of the nature of the material, a capacity limited to human authors.3 As a result, the accuracy and scientific integrity of generated text cannot be ascertained. Lacking understanding, generated text may contain factual errors or fabrications, which may seem plausible to the casual reader. LLMs can even perpetuate scientific biases within the training data and skew responses toward inaccuracies.5 Furthermore, generated text may carry the risk of plagiarism.3,4 Zheng et al. tested ChatGPT’s accuracy by asking a question pertaining to an article published in 2022, beyond the scope of ChatGPT’s training database. Specific facts about the article were provided beforehand. The same question was asked five times. Each time, the question was answered J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 1 EDITORIAL plausibly but incorrectly, and each response elicited was different. The authors concluded that the generated text was convincing and plausible enough to a non-expert to be perceived as fact, despite the inherent errors.6 OpenAI states this limitation clearly on their website: “ChatGPT sometimes writes plausible-sounding but incorrect or nonsensical answers”.7 Differentiating between AI-generated and human-generated articles can be difficult and is perceived as a looming problem for editors and publishers. While a multitude of AI text detectors are available, these have varying degrees of accuracy. Detectors perceive patterns within generated text that indicate AI origin. Gao et al. used a GPT-2 detector to detect generated abstracts versus original abstracts. This detector had a specificity of 94% and a sensitivity of 86%. In comparison, blinded human reviewers were able to detect generated text accurately in only 68% of abstracts.8 Interestingly, AI text detectors appear to be less accurate when reviewing articles written by non-native English speakers.9 Users must also consider the ethical implications of authorship when utilizing AI. There are currently no guidelines in place to govern the use of AI within research writing. The Nature group of journals has explicitly prohibited using AI-generated content, stating that LLMs cannot be listed as co-authors. They further stated that any use of LLMs must be documented in the methodology or acknowledgments section. The Science family of journals has banned all AI-generated text, including images, figures, and graphics. Any detection of these in submissions will be perceived as scientific misconduct. This highlights the need for transparency when such systems are being utilized to avoid passing off AI-written text as that written by a human author, a term now being called ‘AIgiarism’.9 While the Journal of the Philippine Dermatological Society (JPDS) editorial process already includes screening

J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 2 REFERENCES 1. Shen Y, Heacock L, Elias J, Hentel KD, Reig B, Shih G, et al. ChatGPT and other large language models are double-edged swords. Radiology [Internet]. 2023;307(2):e230163. Available from: http://dx.doi.org/10.1148/radiol.230163 2. Marr B. A short history of ChatGPT: How we got to where we are today [Internet]. Forbes. 2023 [cited 2023 May 25]. Available from: https://www.forbes.com/sites/bernardmarr/2023/05/19/a-short-history-of-chatgpt-how-we-got-to-where-we-aretoday/?sh=362b3adb674f 3. Huang J, Tan M. The role of ChatGPT in scientific communication: writing better scientific review articles. Am J Cancer Res. 2023;13(4):1148–54. 4. Tools such as ChatGPT threaten transparent science; here are our ground rules for their use. Nature [Internet]. 2023;613(7945):612. Available from: http://dx.doi.org/10.1038/d41586-023-00191-1 5. Salvagno M, Taccone FS, Gerli AG. Can artificial intelligence help for scientific writing? Crit Care [Internet]. 2023;27(1):75. Available from: http://dx.doi.org/10.1186/s13054-023-04380-2 6. Zheng H, Zhan H. ChatGPT in scientific writing: A cautionary tale. Am J Med [Internet]. 2023; Available from: http://dx.doi. org/10.1016/j.amjmed.2023.02.011 7. Introducing ChatGPT [Internet]. Openai.com. [cited 2023 May 25]. Available from: https://openai.com/blog/chatgpt/ 8. Gao CA, Howard FM, Markov NS, Dyer EC, Ramesh S, Luo Y, et al. Comparing scientific abstracts generated by ChatGPT to real abstracts with detectors and blinded human reviewers. NPJ Digit Med [Internet]. 2023;6(1):75. Available from: http://dx.doi. org/10.1038/s41746-023-00819-6 9. Brainard J. Journals take up arms against AI-written text. Science [Internet]. 2023;379(6634):740–1. Available from: http://dx.doi. org/10.1126/science.adh2762 EDITORIAL submitted text for plagiarism, the editorial team has now included an additional level of screening with AI text detectors. Submitted manuscripts are run through at least two (2) different AI text detectors, and at least two (2) editors review those scoring highly for AI-generated text. We strongly discourage using LLMs in writing manuscripts, especially in the absence of full factual supervision by the author and transparency in the research process. While we recognize the potential benefits of LLMs in scientific writing, the role is assistive in nature and should not replace the expertise of a human author. As with the best of tools, strong human oversight remains necessary. Furthermore, critical thinking, contextual analysis, and the generation of new ideas are all unique to the human mind. Bypassing these in pursuit of generating more manuscripts or publications with great speed weakens these elements as cornerstones in the scientific process. This can lead to the gradual erosion of research quality, limiting true scientific progress. 1 Cebu Institute of Medicine 2Philippine Dermatological Society Research Committee Corresponding author Hester Gail Lim, MD, FPDS, [email protected] Conflict of interest None Source of funding None

LET'S HEAR FROM A COLLEAGUE Medical cannabis in dermatology A position paper from the Philippine Dermatological Society Bryan Guevara, MD, FPDS,FDSP,1 Hester Gail Lim, MD, FPDS,1 Josef Symon S. Concha, MD, DPDS,1 Zharlah Gulmatico-Flores, MD, MMPHA, FPDS,1 Camille B. Angeles, MD,FPDS1 KEY POINTS • Cannabis, also known as marijuana, is a psychoactive drug from the cannabis plant (Cannabis sativa). • While some countries have allowed the use of medical marijuana, the use of cannabis is currently illegal in the Philippines • Cannabis contains compounds called cannabinoids, such as cannabidiol (CBD) and tetrahydrocannabinol (THC). • Synthetic cannabinoids targeting specific receptors like cannabinoid receptor (CB) 1 and CB2 show potential for skin diseases, and it is crucial to know that these have a different chemical composition and potential effects compared to natural cannabinoids. • The cannabinoids can exert both agonist and antagonist effects on the skin’s own endocannabinoid system (ECS), which plays a role for the skin homeostasis. • The use of medical marijuana in dermatology gained the interest of researchers and clinicians for the treatment of autoimmune and inflammatory skin disorders. • The preliminary evidence suggests its potential benefit in the dermatologic conditions. • High-quality randomized controlled trials are still needed to determine the efficacy, treatment regimen, dosing, and safety before these products can be promoted in the treatment of dermatologic diseases. 1 Philippine Dermatological Society Research Committee Corresponding author Bryan Guevara, MD, FPDS,FDSP, [email protected] Conflict of interest None Source of funding None INTRODUCTION Marijuana, also known as cannabis or ‘weed’, refers to the dried flowers, stems, and seeds of the cannabis plant. The possession and use (either recreational or medical) of marijuana is currently illegal in the Philippines, while there has been recent interest within the legislature in favor of reevaluating the medical use of this plant.1 The plant Cannabis sativa contains over 100 pharmacologically active cannabinoids. These compounds include tetrahydrocannabinol (THC), which is impairing or mind-altering, and cannabidiol (CBD) which in contrast does not have mind-altering effects or does not cause a “high”.2 The therapeutic potential of cannabis and cannabinoids have gained public interest, including clinicians and researchers as the legalization and decriminalization of these products continues to expand to different countries. CANNABINOIDS AND THE SKIN Cannabinoids may be endogenous, plant-derived, or synthetic in origin, known respectively as endocannabinoids, phytocannabinoids, and synthetic cannabinoids. Endocannabinoids are produced endogenously and together with their receptors, cannabinoid receptor 1 (CB1), and cannabinoid receptor 2 (CB2), comprise the endocannabinoid system.3,4,5 CB1 is associated with the psychoactive effects of cannabinoids and is highly concentrated in the central nervous system and, to a lesser extent, in peripheral tissues.5,6 While, CB2 is associated with the immunomodulatory and anti-inflammatory properties and is expressed mostly in peripheral organs like J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 3

the skin.5,6,7 Both CB1 and CB2 have endogenous ligands on the skin, supporting that the skin has its own endocannabinoid system (ECS).3,4,5 The cannabinoids can exert both agonist and antagonist effects on the ECS, leading to activation or inhibition of keratinocyte proliferation, sebum production, hair production, and skin inflammation.5,8 The potential use of CB1 and CB2 selective agonists and antagonists can be utilized in a variety of dermatological conditions. MEDICAL USE OF CANNABIS IN DERMATOLOGIC CONDITIONS There is an increase of interest from the public in the use of cannabis, as these are marketed as “natural” alternatives for different dermatologic conditions. The medical use of cannabis in dermatologic conditions range from inflammatory, autoimmune, and other conditions (Table 1).9,10 The ECS plays an important role in skin homeostasis, which cannabinoids can be utilized for its immunomodulatory and anti-inflammatory effects. CLINICAL TRIALS Some selected dermatologic trials utilizing oral or topiJ Phil Dermatol Soc • November 2022 • ISSN 2094-201X 4 cal cannabinoids are summarized in Table 2. This review shows preliminary evidence of its beneficial effects for dermatologic conditions, particularly in inflammatory and autoimmune conditions. Palmitoylethanolamide (PEA), a molecule similar to endocannabinoids found in nature, has demonstrated potential in improving skin conditions like eczema and chronic pruritus,11 while lenabasum, a synthetic cannabinoid, has been the subject of clinical studies to evaluate its effectiveness in treating immune-mediated skin disorders.9 Table 1. Dermatologic conditions that may benefit from CBD.9,10 INFLAMMATORY CONDITIONS Acne vulgaris Asteatotic eczema Allergic contact dermatitis Atopic dermatitis Lichen simplex chronicus Prurigo nodularis Psoriasis Seborrheic dermatitis AUTOIMMUNE CONDITIONS Dermatomyositis Scleroderma (systemic sclerosis) OTHER CONDITIONS Calciphylaxis Epidermolysis bullosa Pyoderma gangrenosum Recalcitrant or chronic pruritus Trichotillomania Table 2. Efficacy and safety of cannabinoids in the treatment of dermatologic diseases: A review of clinical studies.12-18 AUTHORS CANNABINOID USED/STUDY SIZE DERMATOLOGICAL CONDITION STUDY DESIGN RESULTS Eberlein, et al. 200812 Emollient cream containing PEA n=2546 Atopic dermatitis Cohort study Decreased severity of skin inflammation, flare-ups, and use of topical steroids. Significant reduction in pruritus. Improved disease tolerance and sleep. No adverse effects. Yuan et al. 201413 Topical N-PEA n=60 Atopic dermatitis Phase II Prospective, randomized, double blind, placebo-controlled study Reduction in dryness, itching, and scaling. No adverse effects. Yuan et al. 201414 Topical N-PEA n=60 Asteatotic eczema Phase II Prospective, randomized, double blind, placebo-controlled study Improved scaling, dryness, and itching. Increased skin hydration. No adverse effects. Visse, et al. 201715 DMS-based dermatocosmetic lotion containing PEA n=100 Chronic pruritus Phase II Prospective, randomized, double blind, placebo-controlled study Decreased itch. No adverse effects. Spiera et al. 201716 Oral lenabasum n=42 Systemic sclerosis Phase II Prospective, randomized, double blind, placebo-controlled study Greater improvement in modified Rodnan score (a measure of skin thickness) compared to placebo. Mild fatigue in 4 subjects, dizziness in 2 subjects. Spiera et al. 202017 Oral lenabasum n=42 Systemic sclerosis Phase III Prospective randomized, double blind, placebo-controlled study Significant reduction in modified Rodnan score compared to placebo. Did not meet primary goal of improvement in American College of Rheumatology Combined Response Index in Diffuse Cutaneous Systemic Sclerosis. Dizziness and nausea common adverse effects. Werth et al. 202218 Oral lenabasum n=22 Skin predominant dermatomyositis Phase IIb Prospective, randomized, double blind, placebo-controlled study Improved erythema, scale, and itch compared to placebo. No adverse effects. PEA = palmitoylethanolamide, DMS =Derma Membrane Structure LET'S HEAR FROM A COLLEAGUE

These clinical trials have small study size, varying treatment regimens, and indications. Larger and high-quality randomized controlled trials are still recommended to determine the efficacy, treatment regimen, dosing, and safety before cannabis or cannabinoids can be promoted in treating certain dermatologic diseases. It is critical, however, to emphasize the potential significance of these findings in immune-mediated skin conditions like dermatomyositis and scleroderma, even if most of the research presented had small sample sizes. Large-scale clinical trials are difficult to undertake due to the rarity of these illnesses, but smaller studies can nevertheless offer insightful information about prospective therapeutic targets and available therapies. SAFETY DATA Topical cannabinoids are generally well-tolerated. The most reported adverse effects to topical N-PEA include stinging or burning upon application.13 Oral cannabinoids have a widely studied side effect profile. Cannabis and cannabinoid use is linked to hyperemesis, nausea, and vomiting. There are reports of synthetic cannabinoid use beJ Phil Dermatol Soc • November 2022 • ISSN 2094-201X 5 ing linked to anxiety, mood dysregulation, and psychosis. However, relatedness to the agent is not definite and these events may be dose and class dependent.19 Oral lenabasum has demonstrated a good safety profile in patients receiving treatment for dermatomyositis and scleroderma.18 The specificity of this synthetic compound in targeting CB2 receptors explains the lack of psychoactive effects among participants in the study.18 Furthermore, the increased risk of infection in some patients could be attributed to concomitant immunosuppressive use, most notably with mycophenolate mofetil.18 CONCLUSION Cannabinoids have shown promise in treating dermatologic conditions, especially immune-mediated skin diseases. There is a trend towards using a more targeted approach by utilizing synthetic cannabinoids to target immune cells rather than neural cells which bypasses its psychoactive effects. Regardless of its form, more data with higher level of evidence are needed before a strong recommendation can be made for the use of cannabis in our patients. REFERENCES 1. Republic Act No. 9165. An Act Instituting the Comprehensive Dangerous Drugs Act of 2002, Repealing Republic Act No. 6425, Otherwise Known as the Dangerous Drugs Act of 1972, as Amended, Providing its Funds Therefore, and for Other Purposes". Republic Act No. 9165 of June 7, 2002 (PDF). Retrieved March 1, 2023 from https://pdea.gov.ph/images/Laws/RA9165.pdf 2. Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and epilepsy. Neurotherapeutics. 2015;12(4):747-768. 3. Armstrong JL, Hill DS, McKee CS. Exploiting cannabinoid induced cytotoxic autophagy to drive melanoma cell death. J Invest Dermatol. 2015; 135(6):1629–1637. 4. Gaffal E, Cron M, Glodde N, et al. Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors. Allergy. 2013;68(8):994– 1000. 5. Nikan M, Nabavi SM, Manayi A. Ligands for cannabinoid receptors, promising anticancer agents. Life Sci. 2016;146: 124–130. 6. Basu S, Dittel BN. Unraveling the complexities of cannabinoid receptor 2 (CB2) immune regulation in health and disease. Immunol Res. 2011;51(1):26–38. 7. Karsak M, Gaffal E, Date R, et al. Attenuation of allergic contact dermatitis through the endocannabinoid system. Science. 2007;316(5830):1494–1497. 8. Ali A, Akhtar N. The safety and efficacy of 3% cannabis seeds extract cream for reduction of human cheek skin sebum and erythema content. Pak J Pharm Sci. 2015;28(4): 1389–1395. 9. Sheriff T, Lin MJ, Dubin D, Khorasani H. The potential role of cannabinoids in dermatology. J Dermatolog Treat. 2020 Dec;31(8):839- 845. doi: 10.1080/09546634.2019.1675854. Epub 2019 Oct 10. PMID: 31599175. 10. Sivesind TE, Maghfour J, Rietcheck H, Kamel K, Malik AS, Dellavalle RP. Cannabinoids for the treatment of dermatologic conditions. JID Innov. 2022 Jan 13;2(2):100095. doi: 10.1016/j.xjidi.2022.100095. PMID: 35199092; PMCID: PMC8841811. 11. Clayton P, Hill M, Bogoda N, Subah S, Venkatesh R. Palmitoylethanolamide: A Natural Compound for Health Management. Int J Mol Sci. 2021 May 18;22(10):5305. doi: 10.3390/ijms22105305. PMID: 34069940; PMCID: PMC8157570. 12. Eberlein B, Eicke C, Reinhardt HW, Ring J. Adjuvant Treatment of atopic eczema: Assessment of an emollient containing N-palmitoylethanolamine (ATOPA study). J Eur Acad Dermatol Venereol. 2008; 22(1): 73-82. [PMID: 18181976] 13. Yuan, J and Hwang S.W. (2014). Topical application of N-2-hydroxyetylpalmitide (Impromidine) for atopic dermatitis. Journal of Dermatological Treatment, 25(2), 144-147. LET'S HEAR FROM A COLLEAGUE

J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 6 14. Yuan C, Wang XM, Guichard A, Tan YM, Qian CY, Yang LJ, Humbert P. N-palmitoylethanolamine and N-acetylethanolamine are effective in asteatotic eczema: results of a randomized, double-blind, controlled study in 60 patients. Clin Interv Aging. 2014 Jul 17;9:1163-9. doi: 10.2147/CIA.S65448. PMID: 25071367; PMCID: PMC4111646. 15. Visse K, Blome C, Phan NQ, Augustin M, Stander S. Efficacy of body lotion containing palmitoylethanolamine in subjects with chronic pruritus due to dry skin: A dermatocosmetic study. Acta Derm Venereol. 2017; 97(5): 639-641. [PMID: 27983740] 16. Spiera R, Hummers L, Chung L, Frech T, Domsic R, Hsu V et al. OP0006 Safety and efficacy of lenabasum (JBT-101) in diffuse cutaneous systemic sclerosis subjects treated for one year in an open-label extension of trial jbt 101-ssc-001 [abstract]. Ann Rheum Dis 2018; 77:52. 17. Spiera R, Hummers L, Chung L, Frech TM, Domsic R, Hsu V, Furst DE, Gordon J, Mayes M, Simms R, Lafyatis R, Martyanov V, Wood T, Whitfield ML, Constantine S, Lee E, Dgetluck N, White B. Safety and Efficacy of Lenabasum in a Phase II, Randomized, PlaceboControlled Trial in Adults With Systemic Sclerosis. Arthritis Rheumatol. 2020 Aug;72(8):1350-1360. doi: 10.1002/art.41294. Epub 2020 Jul 17. PMID: 32336038; PMCID: PMC7497006. 18. Werth VP, Hejazi E, Pena SM, Haber J, Zeidi M, Reddy N, Okawa J, Feng R, Bashir MM, Gebre K, Jadoo AS, Concha JSS, Dgetluck N, Constantine S, White B. Safety and efficacy of lenabasum, a cannabinoid receptor type 2 agonist, in patients with dermatomyositis with refractory skin disease: A randomized clinical trial. J Invest Dermatol. 2022 Oct;142(10):2651-2659.e1. doi: 10.1016/j. jid.2022.03.029. Epub 2022 Apr 29. PMID: 35490744. 19. Eagleston LRM, Kalani NK, Patel RR, Flaten HK, Dunnick CA, Dellavalle RP. Cannabinoids in dermatology: a scoping review. Dermatol Online J. 2018 Jun 15;24(6):13030/qt7pn8c0sb. PMID: 30142706. LET'S HEAR FROM A COLLEAGUE

LET'S HEAR FROM A COLLEAGUE Stem cell therapy in dermatology A position paper from the Philippine Dermatological Society Bryan Guevara, MD, FPDS,FDSP,1 Hester Gail Lim, MD, FPDS,1 Josef Symon S. Concha, MD, DPDS,1 Zharlah Gulmatico-Flores, MD, MMPHA, FPDS,1 Camille B. Angeles, MD,FPDS1 1 Philippine Dermatological Society Research Committee Corresponding author Bryan Guevara, MD, FPDS,FDSP, [email protected] Conflict of interest None Source of funding None INTRODUCTION Stem cells (SC) are cells which have the capacity to give rise to specialized cell lineages, undergo self-renewal, and regenerate the tissue in which they are located.1 SC are categorized into either embryonic or somatic cells. Embryonic SC are pluripotent; thus, these cells have the potential to develop into progeny cells from all three germ layers (ectoderm, endoderm and mesoderm).2 Somatic SC, on the other hand, may be multipotent but majority are lineage-limited.3 As an organ, the skin exhibits regenerative capacity due to the different SC within. Skin SC are classified as somatic SC, with various subtypes.4 These include epidermal SC, follicular SC, melanocyte SC, sebaceous gland SC, mesenchymal SC-like cells, neural progenitor cells, and hematopoietic SC.5 These cells maintain skin homeostasis and regulate skin damage under physiological conditions. Of these SCs, epidermal stem cells (EPSCs) are of particular interest as they are numerous and accessible.6 Furthermore, compared to embryonic SCs, EPSCs are easy to obtain and are not hindered by ethical or political issues.7 As these cells demonstrate healing and regenerative capacities, the therapeutic potential of EPSCs is increasingly attracting the attention of dermatologists, and researchers. The bone marrow contains hematopoietic and mesenchymal SCs. The hematopoietic SC can be derived from the same donor or from an HLA-matched donor. Mesenchymal stem cells (MSCs) are multipotent adult SC derived from almost all tissues including bone marrow, umbilical cord, peripheral blood, and skin. In contrast to hematopoietic stem cells (HSCs), MSCs have low immunogenicity by virtue of their low MHC expression and also possess immunomodulatory effects, hence have utility in many diseases including inflammatory conditions.8 CURRENT EVIDENCE ON THE USE OF STEM CELL THERAPY IN DERMATOLOGICAL PRACTICE Stem cell therapy has been utilized in aesthetic and clinical dermatology, where some conditions have shown benefit from the use of these cells (Table 1). While results have been promising for the use of HSCs in various autoimmune diseases (pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, systemic sclerosis, systemic lupus erythematosus, and epidermolysis bullosa), currently, there are no existing clinical practice guidelines on the use of SC for dermatologic indications.9-20 Due to the regenerative capacity of SCs, their use has been particularly attractive in aesthetics. Numerous SC sources are available for use in regenerative medicine, including embryonic SC, induced pluripotent SC, and MSCs. The latter has been the most common source of SC therapy in aesthetics due to their relative availability, accessibility, and perceived lack of bioethical controversy.21 Adipose-derived stem cells (ASCs) are one type of MSC found in the stromal vascular fraction of adipose tissue, which has gained popularity due to the ease of collection and abundance.22 A method of isolating ASCs includes tumescent liposuction under local anesthesia, where the lipoaspirate is subjected to processing, filtration and may be further cultured in vitro.23 The final preparation of ASCs would depend on several factors, including harvesting mechanism, site of fat extraction, patient demographics, and history.24 J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 7

A review paper summarized select clinical trials evaluating the effects of SC for hair restoration in androgenetic alopecia.25 The studies included in the paper showed that ASCs were either injected intradermally directed to or applied to the scalp with a microneedle roller, wherein there were significant increase in the hair count. This review showed promising results; however, these are still preliminary due to limitations in study design, sample size and the varying treatment protocols used. An in vitro study of ASCs for scars has shown reduction in scar size with better color quality and pliability of the skin.26 Furthermore, ASCs combined with fractional therapy resulted in increased elasticity and hydration of the skin, thereby increasing overall satisfaction among subjects with photoaged skin and acne scars.27 A preclinical study also showed wrinkle reduction in the ASC treated group, with induced collagen and metalloproteinase production.28 Other preclinical studies also showed anti-aging properties of ASC by inhibiting melanin production after UV exposure, as well as antioxidant and trophic effects, which led to the restoration and rejuvenation of the skin.29,30 Another source of SCs in the application of aesthetic medicine is the bone marrow, where MSC can be isolated and would have excellent regenerative potential.24 However, this source would be more invasive hence the limitation of its use in aesthetic medicine. Other cell sources like amniotic fluid stem cells, umbilical cord blood stem cells, J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 8 or Wharton’s jelly MSCs also have applications in regenerative medicine.31,32 There is however, limited availability of cells for regenerative purposes and ethical issues, which hinders its wider use and acceptance. Adverse events reported on the use of ASC in aesthetic dermatology include transient redness and hematomas caused by the intradermal injections.26 Adverse events related to liposuction or fat harvesting are rare, as the amount of fat harvested is small or minimal. Meanwhile, infections were the most commonly reported adverse effect in a case series on HSCs for pemphigus vulgaris and foliaceus.12 However, adverse events may also be affected by the disease being treated, concurrent immunosuppressive agents administered, the type of stem cell, the method of administration and technique utilized. At present, there are no available large, randomized controlled trials or cohort group data from the field of aesthetic dermatology which can provide sufficient evidence to support the wide use of SCs among patients. Despite promising data from preclinical and small clinical studies, additional randomized controlled trials and standardization of treatment are needed to support the benefits of SCs. Furthermore, there is currently no clinical consensus on when to use these therapies. As of the moment, these therapies are typically regarded as experimental for rare diseases or used as a last resort for non-responders or in recalcitrant diseases. Table 1. Evidence for use of stem cell therapy in dermatological practice. INDICATION HIGHEST LEVEL OF EVIDENCE STEM CELL SOURCE OUTCOME Pemphigus vulgaris8 Case report Allogeneic hematopoietic stem cells Resolution of symptoms of pemphigus vulgaris was observed with sustained remission at 8-year follow up. Adjuvant therapy with cyclosporine, prednisolone, and anti-thymocyte globulin was initiated prior to HSC transplantation, with a 5-6 month taper. Side effects after procedure included malaise, mild pyrexia, and occasional skin rash. Pemphigus vulgaris9 Case series Allogeneic hematopoietic stem cells Resolution of symptoms of pemphigus vulgaris was observed 24 hours after treatment. No new lesions were seen after 6 months. There was no recurrence noted on all patients upon 8-year follow up. Pemphigus foliaceus10 Case report Autologous hematopoietic stem cells Cutaneous manifestations of pemphigus foliaceus gradually disappeared over 2 months and prednisone was tapered off within 4 months. Complete remission was observed on follow-up after 19 months. LET'S HEAR FROM A COLLEAGUE

J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 9 LET'S HEAR FROM A COLLEAGUE Pemphigus vulgaris and pemphigus erythematosus11 Open-label trial Autologous hematopoietic stem cells Skin lesions and complications gradually resolved in most patients. Adverse effects included pyrexia, allergy, infection, and elevation of enzymes. Only one patient died of severe sepsis and multiple organ failure. Systemic sclerosis1 Case series Autologous non-myeloablative hematopoietic stem cells Statistically significant improvement of modified Rodnan skin score was seen whereas cardiac, pulmonary function, and renal function remained stable without significant change. One patient with advanced disease died 2 years after the transplant from progressive disease. After median follow-up of 25.5 months, the overall and progression-free survival rates were 90 and 70% respectively. Systemic sclerosis13 Case series Autologous hematopoietic stem cells There was a major improvement in modified Rodnan skin score and overall function at final evaluation. Biopsies confirmed a statistically significant decrease of dermal fibrosis compared with baseline. Lung, heart, and kidney function remained clinically stable in general. Systemic sclerosis1 Open-label trial Autologous non-myeloablative hematopoietic stem-cells Follow-up 2 years after treatment showed improvements in modified Rodnan score and forced vital capacity. Systemic lupus erythematosus1 Case report CD34 purified autologous stem cells Clinical improvement was seen in a patient with severe SLE after highdose immunosuppressive therapy and autologous stem cell transplantation. Patient also showed a nine-month serological remission. Systemic lupus erythematosus16 Case report Autologous blood stem cells Hematopoietic regeneration was observed within 9 days. Twenty-one months after treatment, patient was in complete clinical remission with no signs of SLE-related disease activity. Pulmonary function also returned to normal. Systemic lupus erythematosus17 Case series Autologous stem cells Complete remission was prolonged and partial response was seen with dramatic clinical improvement in three out of six SLE patients. The remaining patients died due to serious infections in the early post transplantation period. Recessive dystrophic epidermolysis bullosa18 Case series Allogenic mesenchymal stromal cells Type VII collagen was replenished at the dermal–epidermal junction, which prevented blistering and improved wound healing in unconditioned patients. Recessive dystrophic epidermolysis bullosa19 Open label trial Allogenic mesenchymal stromal cells Improvement of appearance of erosions compared to baseline was seen. Recessive dystrophic epidermolysis bullosa20 Open label trial ABCB5+ mesenchymal stem cells Overall improvement of epidermolysis bullosa symptoms at 12 weeks was seen.

J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 10 LET'S HEAR FROM A COLLEAGUE STEM CELL PRACTICE IN THE PHILIPPINES The field of dermatology in the Philippines is still exploring the use of EPSC, which is a promising but upcoming area of study. The Philippine Dermatological Society Committee on Ethics and Research is encouraging institutions to conduct ethical research on the use of this therapy for both pathological and cosmetic purposes. However, it is important to note that there are other available therapies with more established evidence that should be attempted before considering SC therapy. While the Department of Health (DOH) is meticulous in ensuring the organization and sanitation of healthcare facilities, there is still room for improvement in defining the scope and evidence of SC therapy through ethically conducted local research. To regulate healthcare facilities that offer SC therapy in the Philippines, the DOH has established guidelines through Administrative Order No. 2013-0012.37 These guidelines should be updated and strengthened based on established and evolving standards from foreign governing bodies such as the US Food and Drug Administration. It is also important to educate physicians, patients, and the public on the potential risks and benefits of SC therapies, their appropriate and approved indications, and the availability of alternative therapies with stronger evidence. The governing agency must also monitor adverse events and report any unethical, illegal, or unregulated use of SC therapies while educating physicians and patients on how to report such incidents. The quality standards for the production of SC need to be regularly updated, and specific criteria must be met before being cleared for compassionate use. Third-party international reputable agencies should oversee such standards on a regular basis. Lastly, commercial facilities and basic science laboratories should be constantly encouraged to conduct safety and efficacy studies from preclinical (animal) studies to clinical trials to support the use of SC therapies in dermatology and other fields in medicine. Androgenetic alopecia25 Systematic review Adipose-derived stem cells All studies observed an increase in hair growth, but recognized the need for larger clinical studies to strengthen the evidence. Scar reduction26 Animal models Adipose-derived stem cells The study reported that scar size became significantly smaller with improvement in color closely resembling normal skin. An increase in scar flexibility was also noted in the group given ASC. Photoaging and acne scars27 Open label trial Adipose-derived stem cells An increase in skin elasticity and hydration with a decrease in transepidermal water loss, roughness and melanin index was seen in both acne scars and skin rejuvenation groups. Photoaging28 Animal models Adipose-derived stem cells Replica analysis showed a significant wrinkle reduction in the ASC group. Hyperpigmentation30 In vivo study Adipose-derived stem cells An increase in melanin formation was observed in the control group versus the ASC injection group as confirmed by Fontana-Masson and HMB-45 staining. Photoaging31 Animal models Adipose-derived stem cells Animal models showed suppression of glycation, antioxidation, and trophic effects. Wound healing33 Case series Adipose-derived regenerative cells The subjective improvement of scars is encouraging. Vitiligo34 Open label trial Non-cultured outer root sheath hair follicle cell suspension Improvement of vitiligo was seen with cellular grafting. However, the intervention technique needs further refinement and standardization to optimize outcomes. Alopecia areata35 Open label trial Adipose-derived stem cells Treatment was considered effective with increased hair density seen in subjects. Photoaging36 Animal models Adipose-derived stem cells Animal models showed an Increase in dermal thickness and collagen density in hairless mice.

J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 11 LET'S HEAR FROM A COLLEAGUE ACKNOWLEDGMENT The authors would like to thank Dr. Rosa Beatriz Diaz for proofreading this article. REFERENCES 1. Ramalho-Santos M, Willenbring H. On the origin of the term “Stem cell.” Cell Stem Cell. 2007;1:35–38. doi: 10.1016/j.stem.2007.05.013 2. Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 1961;14:213- 222. doi: 10.1667/rrav01.1 3. Shi C, Zhu Y, Su Y, Cheng T. Stem cells and their applications in skin-cell therapy. Trends Biotechnol. 2006;24:48-52 doi: 10.1016/j. tibtech.2005.11.003 4. Chu GY, Chen YF, Chen HY, Chan MH, Gau CS, Weng SM. Stem cell therapy on skin: Mechanisms, recent advances and drug reviewing issues. J Food Drug Anal. 2018;26(1):14-20. doi: 10.1016/j.jfda.2017.10.004 5. Yang R, Liu F, Wang J, Chen X, Xie J, Xiong K. Epidermal stem cells in wound healing and their clinical application. Stem Cell Res. Ther. 2019;10:229. doi: 10.1186/s13287-019-1312-z 6. Wang ZL, He RZ, Tu B, He JS, Cao X, Xia HS, et al. Drilling combined with adipose-derived stem cells and bone morphogenetic protein-2 to treat femoral head epiphyseal necrosis in juvenile rabbits. Curr Med Sci. 2018;38:277–288 doi: 10.1007/s11596-018- 1876-3 7. Khandpur S, Gupta S, Gunaabalaji DR. Stem cell therapy in dermatology. Indian J Dermatol Venereol Leprol. 2021;87(6):753-67. doi: 10.25259/IJDVL_19_20 8. Suslova IM, Theodoropoulos DS, Cullen NA, Tetarnikova MK, Tetarnikov AS, Kolchak NA. Pemphigus vulgaris treated with allogeneic hematopoietic stem cell transplantation following non-myeloablative conditioning. Eur Rev Med Pharmacol Sci. 2010;14(9):785-8. PMID: 21061838 9. Vanikar AV, Trivedi HL, Patel RD, Kanodia KV, Modi PR, Shah VR. Allogenic hematopoietic stem cell transplantation in pemphigus vulgaris: A single-center experience. Indian J Dermatol. 2012;57:9-11. doi: 10.4103/0019-5154.92667 10. 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Lisukov IA, Sizikova SA, Kulagin AD, Kruchkova IV, Gilevich AV, Konenkova LP, et al. High-dose immunosuppression with autologous stem cell transplantation in severe refractory systemic lupus erythematosus. Lupus. 2004;13(2):89-94. doi: 10.1191/0961203304lu491oa 18. Conget P, Rodriguez F, Kramer S, Allers C, Simon V, Palisson F, et al. Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin after intradermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa. Cytotherapy. 2010;12:429-431. doi: 10.3109/14653241003587637 19. Petrof G, Lwin SM, Martinez-Queipo M, Abdul-Wahab A, Tso S, Mellerio JE, et al. Potential of systemic allogeneic mesenchymal stromal cell therapy for children with recessive dystrophic epidermolysis bullosa. J Invest Dermatol. 2015;135(9):2319-21. doi: 10.1038/jid.2015.158 20. Kiritsi D, Dieter K, Niebergall-Roth E, Fluhr S, Daniele C, Esterlechner J, et al. Clinical trial of ABCB5+ mesenchymal stem cells for recessive dystrophic epidermolysis bullosa. JCI Insight. 2021;6(22):e151922. doi: 10.1172/jci.insight.151922. 21. Semsarzadeh N, Khetarpal S. Rise of stem cell therapies in aesthetics. Clin Dermatol. 2022;40(1):49-56. doi: 10.1016/j. clindermatol.2021.08.012

J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 12 LET'S HEAR FROM A COLLEAGUE 22. Pourang A, Rockwell H, Karimi K. New frontiers in skin rejuvenation, including stem cells and autologous therapies. Facial Plast Surg Clin North Am. 2020;28(1):101–117. doi: 10.1016/j.fsc.2019.09.009 23. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–228. 24. Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 2012;21:2724–52. doi: 10.1089/107632701300062859 25. Stefanis AJ, Groh T, Arenbergerova M, Arenberger P, Bauer PO. Stromal vascular fraction and its role in the management of alopecia: a review. J Clin Aesthet Dermatol. 2019;12:35–44. 26. Yun IS, Jeon YR, Lee WJ, Lee JW, Rah Dk, Tark, KC, et al. Effect of human adipose derived stem cells on scar formation and remodeling in a pig model: a pilot study. Dermatol Surg. 2012;38:1678–88. doi: 10.1111/j.1524-4725.2012.02495.x 27. Zhou BR, Zhang T, Jameel AAB, Xu Y, Xu Y, G SL, et al. The efficacy of conditioned media of adipose-derived stem cells combined with ablative carbon dioxide fractional resurfacing for atrophic acne scars and skin rejuvenation. J Cosmet Laser Ther. 2016;18:138–48. doi: 10.3109/14764172.2015.1114638. 28. Jeong JH, Fan Y, You GY, Choi TH, Kim S. Improvement of photoaged skin wrinkles with cultured human fibroblasts and adiposederived stem cells: a comparative study. J Plast Reconstr Aesthet Surg. 2015;68:372–81. doi: 10.1016/j.bjps.2014.10.045 29. Chang H, Park JH, Min KH, Lee RS, Kim EK. Whitening effects of adipose-derived stem cells: a preliminary in vivo study. Aesthetic Plast Surg. 2014;38(1):230–3. doi: 10.1007/s00266-013-0116-2 30. Zhang S, Dong Z, Peng Z, Lu F. Anti-aging effect of adipose-derived stem cells in a mouse model of skin aging induced by D-galactose. PLoS One. 2014;9(5):e97573. 31. Harris DT. Umbilical cord tissue mesenchymal stem cells: characterization and clinical applications. Curr Stem Cell Res Ther. 2013;8:394–399. doi: 10.2174/1574888x11308050006. 32. Dziadosz M, Basch RS, Young BK. Human amniotic fluid: a source of stem cells for possible therapeutic use. Am J Obstet Gynecol. 2016;214:321–7. doi: 10.1016/j.ajog.2015.12.061. 33. Condé-Green A, Marano AA, Lee ES, Reisler T, Price LA, Milner SM, et al. Fat Grafting and Adipose-Derived Regenerative Cells in Burn Wound Healing and Scarring: A Systematic Review of the Literature. Plast Reconstr Surg. 2016;137(1):302-312. doi: 10.1097/ PRS.0000000000001918. 34. Vinay K, Dogra S, Parsad D, Kanwar AJ, Kumar R, Minz RW, et al. Clinical and treatment characteristics determining therapeutic outcome in patients undergoing autologous non-cultured outer root sheath hair follicle cell suspension for treatment of stable vitiligo. J Eur Acad Dermatol Venereol. 2015;29(1):31-7. doi: 10.1111/jdv.12426. 35. Anderi R, Makdissy N, Azar A, Rizk F, Hamade A. Cellular therapy with human autologous adipose-derived adult cells of stromal vascular fraction for alopecia areata. Stem Cell Res Ther. 2018;9(1):141. doi: 10.1186/s13287-018-0889-y 36. Kim WS, Park BS, Park SH, Kim HK, Sung JH. Antiwrinkle effect of adipose-derived stem cell: Activation of dermal fibroblast by secretory factors. J Dermatol Sci. 2009;53(2):96-102. 37. Republic of the Philippines, Department of Health (Ona E). Administrative order no. 2013-0012: Rules and regulations governing the accreditation of health facilities engaging in human stem cell and cell-based or cellular therapies in the Philippines.

CONTINUING MEDICAL EDUCATION The science of masculine beauty: Key principles and strategies for male aesthetic enhancement Jonathan Nevin T. Yu, MD FPDS,1 Raphaela Martina C. Pineda, MD, DPDS,2 Katrina Ysabelle G. Sun, MD1 1 Skin and Cancer Foundation, Inc. 2Mount Sinai Department of Dermatology Corresponding author Jonathan Nevin T. Yu, MD, FPDS, [email protected] Conflict of interest None Source of funding None INTRODUCTION Recently, men and women have become increasingly interested in facial aesthetics. Although there is a frequent emphasis on female facial aesthetics, male facial aesthetics are gaining popularity.1 The top five cosmetic treatments performed on men in the United States were: Botulinum toxin A injections, laser skin resurfacing, laser hair removal, filler injections, and microdermabrasion.1 In this article for continuing medical education, we will examine the differences between male and female facial features, and the aesthetic differences between men of different ethnicities. We will also discuss skin care and nonsurgical therapies, such as neurotoxins, threads, injectable fillers, and lasers for enhancing the facial aesthetics of men. MALE VERSUS FEMALE FACIAL ATTRIBUTES SKIN In general, male skin is around 25% thicker than female skin, primarily due to differences in hormone levels. Androgens, which are more prevalent in males, stimulates the production of collagen and elastin fibers, resulting in thicker and firmer skin. However, among females during menopause, the decline in estrogen levels causes skin to thin out and become more fragile. Besides this, men create more sebum than women due to androgen hormones, this also occur but more noticeably after menopause in women. Men also have collagen that is thicker than women, which makes women more prone to premature aging. Due to higher muscle mass than females, rhytides are often deeper and more severe in men. Finally, men can be expected to have more wrinkles and rougher skin (Table 1; Figure 1).2 J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 13 Figure 1. Female vs male skin. Differences between Male and female skin on histology. An increase in connective tissue owing to the increase in collagen bundles in male skin compared to female skin. Table 1. Gender differences in the skin Male Female Thickness 25% thicker overall Constant thickness until menopause Collagen High collagen density Less collagen density Earlier signs of premature aging Sebum More Lessens during menopause Subcutaneous fat Less More Loss of collagen Initially the same rate Faster first 5 years of menopause Skeletal muscle mass More Lesser than men Skin elasticity Same Same

FACIAL SHAPE Regarding facial shape, there are numerous anatomical differences between male and female facial traits. One of the most distinguishing features between them is their facial shape.2 Men have a square face with a more prominent jawline, whereas women have a rounder, softer appearance with a less prominent jawline. The upper and lower facial dimensions of men are proportionally equal. This variance is due to the influence of hormones on bone formation and muscle mass.3 Men have prominent supraorbital ridges, which may be helpful as an anatomical reference for eyebrow placement. The male eyebrow is more horizontal than the female brow and lies lower along the orbital rim. Male orbital size is often more significant than female orbital size. Due to this, men typically show more prominent periocular alterations, particularly on the lower eyelids, which leads to the appearance of deep-set eyes. Men also have a more significant glabellar protrusion, while women's glabella stays flat. The height and width of the male forehead are more prominent than women, with a greater backward slope. A prominent mandibular ramus flexure characterizes the masculine jaw. Men also have a more pronounced, square chin that protrudes forward. The skeletal distinctions between men and women contribute to the square characteristics of the aging male face. Men often have less subcutaneous fat on their cheeks than women. As a result, male cheeks protrude anteriorly less than women (Table 2; Figure 2).2 The size and shape of the nose are additional distinguishing features. Women have smaller, more delicate noses with curved bridges, whereas men have larger, more prominent noses with straighter bridges. Men's lips tend to be thicker and less curved than women's, making them a crucial component of male facial beauty.2 ASIAN MEN VS. CAUCASIAN MEN Eye shape is one of the most noticeable variances between Asian and Caucasian men. Asian eyes are often smaller and almond-shaped, whereas Caucasian eyes are larger and rounder.4 The eyes, including its size, can change how the face looks overall, affecting the ideal male appearance in each culture. Caucasian men tend to have a facial shape to be more angular and acute, with a more prominent jawline and forehead. In contrast, Asian men have flatter, broader faces with a less prominent jawline and forehead (Figure 3). Moreover, Caucasians typically have smaller faces and greater vertical height. Asians have a more prominent face with a lower vertical height that is flat or concave in the J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 14 medial maxilla and lacks brow, nasal, and chin projection.5 Moreover, men's skin tone may affect their facial looks. Lighter skin tones are associated with a more feminine appearance.6 However, it is essential to note that there is no perfect skin tone for Asian or Caucasian men. Cultural and individual preferences for skin tone and standards of beauty may differ. PLANNING FOR MALE AESTHETIC TREATMENTS It is essential to understand the male aesthetic ideal when CONTINUING MEDICAL EDUCATION Male Female Facial Shape Squarer face Rounder face Eyebrows Heavier, overhanging horizontal Thinner, flared Mouth Wider Narrower Chin Stronger Softer Figure 2. Male vs Female. Table 2. Gender differences in the skull Male Female Larger and heavier skull Smaller and lighter skull Sloping, less rounded forehead (frontal bone) Rounded forehead (frontal bone) Prominent supraorbital ridge (brow) Smooth supraorbital ridge (brow) Square eye sockets (orbits) Round eye sockets (orbits) Blunt upper eye margins Sharp upper eye margins Square chin Pointed chin Vertical (acute) angle of the jaw Sloping (obtuse) angle of the jaw

planning aesthetic treatments.7 Clinicians must understand what makes men look and feel better to ensure success. The ideal male aesthetic is rooted in men exhibiting their motivations, goals, and concerns. It often differs significantly from women since men may have a unique perspective on what makes them look and feel attractive. For most men, the initial consultation to discuss their concerns should be done first without outright planning for a specific procedure.8 The initial consultation is essential because most men must become more familiar with procedures. Many male patients usually ask their physician for help deciding what kind of treatment they need with a particular concern. They prefer straightforward treatments that give instant results, have no downtime, and treatments that allow them to return to their routine and work immediately after a procedure. A multiracial, predominantly white male survey found that men prioritize 3 facial areas- hairline, periorbital area, and jawline.7 The focus of treatment in the periorbital area would commonly be the crow's feet and tear troughs. On the other hand, maintaining a masculine jawline by treating submental fullness and chin is also a priority for men. Eyelashes, lips, or perioral rhytids do not appear to be areas of concern for most men. J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 15 A common reason that men hesitate about cosmetic procedures is the fear of appearing feminized or losing their male characteristics. Some men say they are also reluctant to appear unnatural. Traditionally, male faces were considered more attractive if they were more masculine than the average. Masculine can be defined as a broader, more defined jawline, prominent chin, and lower, flatter eyebrows.9 However, conflicting studies have shown that male faces with feminine features are also preferred.4 A male with some feminine attributes shows that male facial attractiveness continuously evolves and involves striking a balance between femininity and masculinity. Aesthetic treatments are only successful if the patient is satisfied. Primarily, we must ensure that the desired results align with the patient's goals. Male aesthetic ideals involve aiming for individualized treatment while considering gender differences that influence aesthetic concerns and desires. MALE FACIAL AESTHETICS WITH NONSURGICAL INTERVENTIONS SKIN CARE Men are becoming cognizant of skincare's role in enhancing the quality and appearance of their skin, especially due to the increased use of social media and growing reliance on videoconferencing. Additionally, increasing online access to information and items enables male consumers to avoid in-person shopping. Men believe that their hectic lifestyle needs a streamlined approach to skincare that can be readily included in their shaving routine to maximize grooming time. A good skincare routine is essential for men, albeit many frequently disregard their skin's needs. This article will discuss essential male skincare ingredients, including sunscreens, moisturizers, keratolytics, hydroxy acids, retinoids, antioxidants, and pigment-lightening agents. A physician must emphasize adequate sun protection as a part of the male skin regimen. Men should understand that protecting the skin from cancer-causing ultraviolet rays will benefit them and help slow down the signs of photoaging. A broad-spectrum sunscreen with a minimum sun protection factor (SPF) 30 will provide adequate protection from ultraviolet (UV) A and B radiation. The Centers for Disease Control and Prevention has stated that men are 40% more likely to develop skin cancer than women.10 Additionally, the overall incidence of cutaneous malignancies such as melanoma, basal cell carcinoma, and squamous cell carAsian Male Caucasian Male Eyes Smaller, almond-shaped Larger, rounder Facial Shape Flatter and broader face, less prominent jawline and forehead More angular and acute face, more prominent jawline and forehead Figure 3. Typical Asian Man vs. Caucasian Man. CONTINUING MEDICAL EDUCATION

J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 16 cinoma is higher in men than in women. Gender differences in skin cancer incidence are due to sex-differing behavior patterns regarding men's vocation, making them more prone to sun exposure; therefore, sunscreen should be a vital component of their skin care.11,12 An essential part of educating patients on good and healthy skin habits is the benefit of using moisturizing agents and keratolytics. Educating male patients is vital since they usually have a much oiler skin type than women. Dead skin cells can lead to comedones, and acne production formation, therefore use of moisturizers that contain keratolytics helps in exfoliating and eliminating these cells. Moreover, these creams, ointments, or gels can help soften and improve the general texture of the skin.12,13 When selecting a type of moisturizer for men, it is essential to select one that feels comfortable and is appropriate for the patient's skin type to maintain good habits such as regular use. Hydroxy acids help reduce the appearance of fine lines, hyperpigmentation, and acne by exfoliation. They work by dissolving the bonds holding dead skin cells together and quickly removing them from the skin's surface. Some common hydroxy acids used in male skin care products are glycolic and salicylic. Ideally, alpha-hydroxy acids such as glycolic acid are preferred when a patient has a dry skin type since these are gentler on the skin and have the added benefit of skin lightening. Salicylic acid, on the other hand, is more suited for oiler skin types since it is fat-soluble and can penetrate deeper into the skin's pores.14 Retinoids are another essential component of a male skin care regimen. They function by increasing collagen formation, thereby reducing the appearance of fine lines and wrinkles. They also stimulate cell turnover, which helps minimize acne formation and enhance the skin's general texture and tone. It is crucial to advise patients on the correct administration of retinoids to prevent irritation.15 Patients should be instructed to apply a pea-sized amount uniformly to their entire face at bedtime. However, patients new to retinoids should begin with an application every other night and gradually increase to a daily application as their skin responds.16 Patients should be advised to avoid prolonged sun exposure during the day. Moreover, the application of a moisturizer can prevent inflammation and irritation. Antioxidants are another vital component of the male skin care regimen. They prevent skin damage caused by free radicals from the environment, which can contribute to premature aging and skin cancer. Some examples of commonly used antioxidants in male skin care products are vitamin C and E.17 Pigment lightening medications are prescribed for male patients with hyperpigmentation, which include dark patches and melasma. Hydroquinone, kojic acid, and azelaic acid are some examples that can lighten and level out the skin tone of dark spots.18 Incorporating all these essential components into a skin care regimen curated for the male patient can improve the patient's overall skin health and appearance. Dermatologists should educate male patients on the significance of skincare based on their skin type and recommend products suited to their specific needs and lifestyle.13,19 NEUROTOXINS Botulinum toxin A (BoNTA) is a popular cosmetic treatment used to improve the appearance of fine lines and wrinkles in both men and women. While BoNTA has traditionally been more prevalent among women, more men are now taking this treatment to enhance their appearance and boost their confidence. BoNTA blocks the nerve signals that cause the treated area's muscles to contract. The neurotoxin (BoNTA) binding to its receptor initiates a receptor-mediated endocytosis process, which results in the internalization of the neurotoxin.20 This internalization results in the BoNTA being contained inside vesicles.20 After internalization, the light chain is released from the vesicle. The light chain is then released from the vesicle and travels to the axon terminal, where it cleaves SNAP-25, the docking station for acetylcholine-containing vesicles.21 The cleavage of SNAP25 inhibits the formation of the SNARE complex, and therefore the vesicle cannot release acetylcholine to initiate muscle contraction.20 When these muscles cannot contract, the underlying skin remains wrinkle-free and smooth, resulting in a more youthful and rested appearance. It is recommended to administer BoNTA to treat horizontal forehead rhytids, glabellar complex, and periorbital or periocular rhytids. Men may be more vulnerable to wrinkles in these areas due to aging, UV exposure, and frequent facial expressions due to their greater muscle mass. When injected into the jawline and neck, it can provide a more masculine, squared-off appearance and define the jawline by relaxing the muscles that pull the lower face down. While men have stronger facial muscles than women, men typically require a more significant dose than women. Standard frontalis injection dosage ranges from 20 to 30 units22 distributed throughout 9 to 13 locations.23 Glabellar complex dosages may reach 30 units distributed between 5 injection spots, and doses for periorbital lines, CONTINUING MEDICAL EDUCATION

J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 17 may require 9 to 12 units distributed between 3 injection points.23 Most men have minor discomfort following the operation and can quickly resume their regular activities. Common BoNTA adverse effects include injection site pain, bruising, bleeding, edema, and erythema.24 Using a thinner needle and diluting the BoNTA with saline may assist in mitigating these adverse reactions. Furthermore, headaches, lethargy, nausea, flu-like symptoms, and ptosis have been described.25 The effects of botulinum toxin A typically last 3-4 months, after which the treatment must be repeated to maintain the desired results. As the muscles that cause wrinkles weaken over time, many patients eventually require fewer treatments. INJECTABLE FILLERS Injectable or dermal fillers are a common cosmetic treatment that restores lost facial volume due to age or other causes. Fillers such as hyaluronic acid, calcium hydroxylapatite, and poly-l-lactic acid function by restoring lost facial volume and adding volume to the treated area.26-28 By increasing the volume of the cheekbones, nose, jawline, and lips, these fillers can provide a more youthful and refreshed appearance. Men's facial structures are often more angular and defined than women’s, with a stronger jawline and more prominent cheekbones.26 In women, fillers are frequently used to enhance the lips and cheeks for volume and to fill in perioral and periocular rhytids. In contrast, men typically use fillers to augment the definition of the jawline and chin, filling in deeper lines and wrinkles around the mouth and nose. Enhancing the jawline and chin with fillers creates a more masculine, angular appearance.27,28 Another concern for men contemplating cosmetic augmentation is the cheek, given the significant paucity of subcutaneous fat in men. Overcorrection, mainly when an excessive volume is administered medially or laterally, can result in a feminine look. Care must be given when injecting men's lips, as overfilling, particularly the upper lip, is feminizing.28 When injecting fillers into men, it is essential to use a smaller volume than when injecting fillers into women to avoid creating a more feminine appearance. As the goal is to enhance the masculine features of the face rather than make a softer, more feminine appearance, the filler placement must be more precise. Men may require a different type of filler than women because their skin is typically thicker and less elastic.29,30 For the jawline, nose, and chin, a filler with a high ability to resist high shearing and compression is desirable.29 THREADS Thread lifting is a minimally invasive cosmetic procedure in which sutures, or threads, are used to lift and reposition the skin of the face, neck, and body.31-35 The thread technique provides a more youthful and revitalized appearance without requiring invasive surgical procedures. During a thread-lifting operation, the physician will use a small needle to insert biocompatible threads, such as polydioxanone (PDO), polylactic acid (PLLA), or polycaprolactone (PCA), into the skin.34 In addition to repositioning the skin, these threads are carefully designed to dissolve over time, stimulating collagen formation in the treated areas and boosting the threads' lifting and tightening benefits. Three types of absorbable threads are currently in use: Mono, Screw/Tornado, and Cog.35 Mono threads are smooth, barbless threads. This thread is typically implanted into the face in a mesh-like pattern to achieve tighter skin effects by enhancing and stimulating collagen around the thread. Monofilament threads are frequently used on neck lines, neck laxity, the forehead, and under the eyes. These threads are intended for attachment to a subcutaneous "anchoring point." Although monofilament threads effectively stimulate collagen production and synthesis, they are helpful for skin tightening, not lifting.35 Screw threads are sometimes referred to as Tornado threads. They frequently appear as single or double threads entangled around the inserting needle. These threads have a remarkable effect on the deflated areas of the skin. Intertwining threads have a more substantial impact than single threads, typically used for general face lifting.35 Cog threads are monofilament threads with barbs designed to attach to the skin's underside. Typically, these barbs are cut or molded as a thread component as a support structure to lift sagging tissues. Cog threads, unlike smooth mono threads, do not require anchoring points. Collagen formation will occur around both the threads and their barbs in the case of cog threads, making them the most effective for jawline lifting and slimming.35 The level at which these threads are inserted depends on the areas being treated and the desired level of lift. On the midface, for instance, where raising is needed, the needle is placed into the deep subcutaneous layer just above the superficial musculoaponeurotic system (SMAS).33 In contrast, a jawline lift is accomplished by putting the needle CONTINUING MEDICAL EDUCATION

J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 18 into the parotid-masseter region's subcutaneous fat toward the marionette line's origin.36 Anecdotally, the entry point for women is on the zygoma or slightly above it. In men, the insertion is usually 2 cm anterior to the superior border of the tragus. Gently pulling and securing the threads creates tension that lifts and tightens the skin. The operation typically lasts between 30 and 45 minutes and can be conducted under local anesthesia, allowing the patient to return to normal activities within a few days. The results of thread-lifting might last anywhere from several months to a year, depending on the patient and threads used. PDO threads can last between 6 and 12 months, PLLA threads up to 14 to 18 months (approximately one and a half years), and PCA threads take 16 to 24 months (about 2 years) to dissolve, with collagen stimulation lasting an additional year after the PCA threads have completely dissolved. Thread lifting is relatively safe yet contains certain dangers, as with any cosmetic operation. Infection, scarring, and thread migration are some dangers in which the threads shift from their initial position. It is vital to be familiar with the technique to minimize these dangers. The operation is safe and may be performed under local anesthetic, making it an attractive choice for individuals seeking non-invasive cosmetic enhancement. LASERS AND ENERGY BASED DEVICES Men typically seek laser and or energy-based devices (EBD) treatments to treat the following conditions: photodamage, acne scarring, loose neck/submental skin, hyperpigmentation, and facial rejuvenation.37 Men favor single or multiple procedures over a single day with little to no downtime compared to women.37 Several devices are currently available in the market depending on the indications and technology involved. Men who seek treatment for photodamage and facial rejuvenation using lasers/EBD typically are the ablative, non-ablative, or fractional laser type.38 Ablative lasers destroy the epidermis and part of the dermis to stimulate the wound healing process to lessen superficial pigmentation and fine wrinkles. Typical devices include CO2 (10,600 nm) and Er:YAG (2,940 nm) lasers. However, since this technology destroys the superficial to the upper layers of the skin, one expects significant downtime for male patients. Men with Fitzpatrick skin types III to VI are more prone to developing postinflammatory hyperpigmentation: thus, caution is advised when using ablative lasers.38 Nonablative lasers spare the epidermis and target the dermis to induce thermal remodeling and have little to no downtime compared to their ablative counterparts. Examples of these lasers/ EBD are the intense pulse light (500-1200 nm), Erbium glass (1,540-1550 nm) Alexandrite (700-825 nm), and Nd:YAG (1064 nm) systems. Fractionated lasers can be both ablative and non-ablative types, emitting an energy beam split into columns. These columns create areas of untreated skin, which promotes faster wound healing.39 The fractionated laser system has less downtime than ablative lasers and decreases the incidence of hyperpigmentation and are recommended in treating individuals with darker skin types.38 Men have acne that is often longer in duration, more severe, and treated later than women. As a result, men have more severe acne scarring.40 Lasers can be employed to smoothen out the scars and to stimulate collagen formation on the atrophic areas. Ablative resurfacing lasers selectively vaporize the skin surface to smoothen out the acne scars but with considerable downtime and an increased chance for hyperpigmentation in Asian men. Therefore, ablative and non-ablative fractional lasers were developed to mitigate untoward adverse events.41 Several energy-based devices can treat loose and saggy skin in men. A radiofrequency-based device uses a high frequency alternating current (0.3 to 10 MHz) to selectively heat dermal tissue to induce wound healing and neocollagenesis to tighten the skin.42 Another energy-based device, which employs microfocused ultrasound has also been shown to effectively treat saggy skin.43,44 CONCLUSION In conclusion, nonsurgical therapies, including neurotoxins, threads, injectable fillers, and the use of lasers/energy-based devices can improve the appearance of the male face. Different races have different ideas about how male faces should ideally look. For example, Western cultures often prefer angular, prominent faces, whereas Asian cultures prefer softer, rounder faces. One needs to take time with the initial male consult to balance what males perceive as ideal and what a dermatologist can achieve. Finally, a complete skincare regimen suited for a male patient’s goals and lifestyle should always align with the patient's aesthetic desires. Nevertheless, all races can benefit from these treatments, as they help mitigate signs of aging and create a youthful appearance. CONTINUING MEDICAL EDUCATION

J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 19 CONTINUING MEDICAL EDUCATION CME QUESTIONS 1. Which correctly describes male skin? a. Skin is 25% thicker than females b. More subcutaneous fat than females c. Sebum production decreases during menopause d. Less dense collagen than females 2. This is a minimally invasive cosmetic procedure in which specialized sutures are used to lift and reposition the skin of the face, neck, and body: a. Dermal filler b. Neurotoxin c. Thread lifting d. Liposuction 3. Which of the following statements is correct? a. Women’s lips tend to be thinner and less curved b. The upper and lower facial dimensions of males are proportionally equal c. Women’s expression lines are more profound because they have greater muscle mass d. As a result of androgen hormones, women produce more sebum than men 4. Around how many months do the effects of Botulinum Toxin A typically last? a. 1-2 months b. 3-4 months c. 1 year d. 5-6 months 5. Which products are considered pigment lightening agents that can be used to treat hyperpigmentation in male patients including dark spots and melasma? a. Hydroquinone b. Kojic acid c. Azelaic acid d. All of the above Answers to the quiz can be found on page 61.

J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 20 CONTINUING MEDICAL EDUCATION REFERENCES 1. Plastic surgery procedural statistics from the American Society of Plastic Surgeons. January 2020. Accessed March 24, 2023. https://www.plasticsurgery.org/news/plastic-surgery-statistics 2. Farhadian JA, Bloom BS, Brauer JA. Male Aesthetics: A Review of Facial Anatomy and Pertinent Clinical Implications. J Drugs Dermatol. 2015;14(9):1029-1034. 3. Lei X, Holzleitner IJ, Perrett DI. The Influence of Body Composition Effects on Male Facial Masculinity and Attractiveness. Front Psychol. 2019 Jan 4;9:2658. doi: 10.3389/fpsyg.2018.02658. PMID: 30662423; PMCID: PMC6328455. 4. Fakhro A, Yim HW, Kim YK, Nguyen AH. The Evolution of Looks and Expectations of Asian Eyelid and Eye Appearance. Semin Plast Surg. 2015;29(3):135-144. doi:10.1055/s-0035-1556847 5. Liew, S., Wu, W.T.L., Chan, H.H. et al. Consensus on Changing Trends, Attitudes, and Concepts of Asian Beauty. Aesth Plast Surg 40, 193–201 (2016). https://doi.org/10.1007/s00266-015-0562-0 6. Sebastián-Enesco C, Semin GR. The brightness dimension as a marker of gender across cultures and age. Psychol Res. 2020;84(8):2375-2384. doi:10.1007/s00426-019-01213-2 7. Keaney TC. "Man-some": A Review of Male Facial Aging and Beauty. Journal of Drugs in Dermatology : JDD. 2017 Jun;16(6):91-93. PMID: 29028860. 8. Handler MZ, Goldberg DJ. Cosmetic Concerns Among Men. Dermatol Clin. 2018 Jan;36(1):5-10. doi: 10.1016/j.det.2017.09.001. 9. Mastroluca E, Patalano M, Bertossi D. Minimally invasive aesthetic treatment of male patients: The importance of consultation and the lower third of the face. Journal of cosmetic dermatology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361772/#. Published July 2021. Accessed March 29, 2023 10. USCS data visualizations - CDC. Centers for Disease Control and Prevention. https://gis.cdc.gov/Cancer/USCS/#/AtAGlance/. Accessed March 31, 2023. 11. Roberts CA, Goldstein EK, Goldstein BG, Jarman KL, Paci K, Goldstein AO. Men's Attitudes and Behaviors About Skincare and Sunscreen Use Behaviors. J Drugs Dermatol. 2021;20(1):88-93. doi:10.36849/JDD.5470 12. Oblong JE. Male skin care: Shaving and moisturization needs. Dermatologic Therapy. 2012;25(3):238-243. doi:10.1111 /j.1529-8019.2012.01502 13. Liyanage A, Liyanage G, Sirimanna G, Schürer N. Comparative Study on Depigmenting Agents in Skin of Color. J Clin Aesthet Dermatol. 2022;15(2):12 14. Waller J, Dreher F, Maibach H, Weinstein G. The measurement of the relative potencies of several topical keratolytic ingredients. Journal of the American Academy of Dermatology. 2005;52(3). doi:10.1016/j.jaad.2004.10.374 15. Kornhauser A, Coelho SG, Hearing VJ. Applications of hydroxy acids: classification, mechanisms, and photoactivity. Clin Cosmet Investig Dermatol. 2010 Nov 24;3:135-42. doi: 10.2147/CCID.S9042. PMID: 21437068; PMCID: PMC3047947. 16. Kafi R, Kwak HS, Schumacher WE, et al. Improvement of naturally aged skin with vitamin A (retinol). Archives of Dermatology. 2007;143(5). doi:10.1001/archderm.143.5.606 17. Kligman AM. Guidelines for the use of topical tretinoin (retin-A) for photoaged skin. Journal of the American Academy of Dermatology. 1989;21(3):650-654. doi:10.1016/s0190-9622(89)70233-4 18. Michalak M. Plant-derived antioxidants: Significance in skin health and the aging process. International Journal of Molecular Sciences. 2022;23(2):585. doi:10.3390/ijms23020585 19. Makino ET, Jiang LI, Tan P, Cheng T, Mehta RC. Addressing Male Facial Skin Concerns: Clinical Efficacy of a Topical Skincare Treatment Product for Men. J Drugs Dermatol. 2018;17(3):301-306. 20. Westfall TC and Westfall DP. In Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. Chapter 8. The McGrawHill Companies, 2011. ISBN 9780071624428. 21. Benedetto AV. The cosmetic uses of Botulinum toxin type A. Int J Dermatol. 1999;38(9):641-655. doi:10.1046/j.1365- 4362.1999.00722.x 22. Lorenc ZP, Smith S, Nestor M, Nelson D, Moradi A. Understanding the functional anatomy of the frontalis and glabellar complex for optimal aesthetic botulinum toxin type A therapy. Aesthetic Plast Surg. 2013 Oct;37(5):975-83. 23. Sundaram H, Signorini M, Liew S, Trindade de Almeida AR, Wu Y, Vieira Braz A, Fagien S, Goodman GJ, Monheit G, Raspaldo H., Global Aesthetics Consensus Group. Global Aesthetics Consensus: Botulinum Toxin Type A--Evidence-Based Review, Emerging Concepts, and Consensus Recommendations for Aesthetic Use, Including Updates on Complications. Plast Reconstr Surg. 2016 Mar;137(3):518e-529e. 24. Rzany B, Dill-Müller D, Grablowitz D, Heckmann M, Caird D., German-Austrian Retrospective Study Group. Repeated botulinum toxin A injections for the treatment of lines in the upper face: a retrospective study of 4,103 treatments in 945 patients. Dermatol Surg. 2007 Jan;33(1 Spec No.):S18-25. 25. Satriyasa BK. Botulinum toxin (Botox) A for reducing the appearance of facial wrinkles: A literature review of clinical use and

pharmacological aspect. Clinical, cosmetic and investigational dermatology. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC6489637/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489637/. Published April 10, 2019. Accessed March 29, 2023. 26. Carruthers JDA, Glogau RG, Blitzer A; Facial Aesthetics Consensus Group Faculty. Advances in facial rejuvenation: botulinum toxin type a, hyaluronic acid dermal fillers, and combination therapies--consensus recommendations. Plast Reconstr Surg. 2008;121(5 Suppl):5S-30S. doi:10.1097/PRS.0b013e31816de8d0 27. Rho NK, Chang YY, Chao YY, et al. Consensus Recommendations for Optimal Augmentation of the Asian Face with Hyaluronic Acid and Calcium Hydroxylapatite Fillers. Plast Reconstr Surg. 2015;136(5):940-956. doi:10.1097/PRS.0000000000001706 28. Farhadian JA, Bloom BS, Brauer JA. Male Aesthetics: A Review of Facial Anatomy and Pertinent Clinical Implications. J Drugs Dermatol. 2015;14(9):1029-1034. 29. Choi MS. Basic rheology of dermal filler. Arch Plast Surg. 2020 Jul;47(4):301-304. doi: 10.5999/aps.2020.00731. Epub 2020 Jul 15. PMID: 32718107; PMCID: PMC7398800. 30. Molliard SG, Bétemps JB, Hadjab B, Topchian D, Micheels P, Salomon D. Key rheological properties of hyaluronic acid fillers: from tissue integration to product degradation. Plastic and Aesthetic Research. 2018; 5:17. http://dx.doi.org/10.20517/2347- 9264.2018.10 31. Cobo R. Use of Polydioxanone Threads as an Alternative in Nonsurgical Procedures in Facial Rejuvenation. Facial Plast Surg. 2020;36(4):447-452. doi:10.1055/s-0040-1714266 32. Hyejeong Lee, Kichan Yoon & Munjae Lee (2018) Outcome of facial rejuvenation with polydioxanone thread for Asians, Journal of Cosmetic and Laser Therapy, 20:3, 189-192, DOI: 10.1080/14764172.2017.1400167 33. Santorelli A, Cerullo F, Cirillo P, Cavallini M, Avvedimento S. Mid-face reshaping using threads with bidirectional convergent barbs: A retrospective study. J Cosmet Dermatol. 2021;20(6):1591-1597. doi:10.1111/jocd.14038. 34. Atiyeh, B.S., Chahine, F. & Ghanem, O.A. Percutaneous Thread Lift Facial Rejuvenation: Literature Review and Evidence-Based Analysis. Aesth Plast Surg 45, 1540–1550 (2021). https://doi.org/10.1007/s00266-020-02095-1 35. Yongtrakul, P., Sirithanabadeekul, P., & Siriphan, P. (2016). Thread Lift: Classification, Technique, and How to Approach the Patient. International Journal of Medical and Health Sciences, 10, 558-566. 36. Diaspro A, Luni M, Rossini G. Thread Lifting of the Jawline: A Pilot Study for Quantitative Evaluation. J Cutan Aesthet Surg. 2021 Jan-Mar;14(1):47-54. doi: 10.4103/JCAS.JCAS_41_20. PMID: 34084008; PMCID: PMC8149973. 37. Crispin MK, Hruza GJ, Kilmer SL. Lasers and Energy-Based Devices in Men. Dermatol Surg. 2017 Nov;43 Suppl 2:S176-S184. doi: 10.1097/DSS.0000000000001274. PMID: 29064982. 38. Houreld, N. N. (2019). The use of lasers and light sources in skin rejuvenation. Clinics in Dermatology, 37(4), 358-364. https://doi. org/10.1016/j.clindermatol.2019.04.008 39. Hantash, B.M., Bedi, V.P., Kapadia, B., Rahman, Z., Jiang, K., Tanner, H., Chan, K.F. and Zachary, C.B. (2007), In vivo histological evaluation of a novel ablative fractional resurfacing device. Lasers Surg. Med., 39: 96-107. https://doi.org/10.1002/lsm.20468 40. Agrawal DA, Khunger N. A Morphological Study of Acne Scarring and Its Relationship between Severity and Treatment of Active Acne. J Cutan Aesthet Surg. 2020;13(3):210-216. doi:10.4103/JCAS.JCAS_177_19 41. Yu JN, Abat K. Safety and efficacy of hybrid energy and trifractional technologies in the treatment of acne scars: An open-label clinical trial. J Cosmet Laser Ther. 2016;18(2):60-5. doi: 10.3109/14764172.2015.1063658. Epub 2016 Jan 28. PMID: 26820256. 42. Alster TS, Lupton JR. Nonablative cutaneous remodeling using radiofrequency devices. Clin Dermatol. 2007 Sep-Oct;25(5):487-91. doi: 10.1016/j.clindermatol.2007.05.005. PMID: 17870527. 43. Fabi SG. Noninvasive skin tightening: focus on new ultrasound techniques. Clin Cosmet Investig Dermatol. 2015 Feb 5;8:47-52. doi: 10.2147/CCID.S69118. PMID: 25709486; PMCID: PMC4327394. 44. Baumann L, Zelickson B. Evaluation of Micro-Focused Ultrasound for Lifting and Tightening Neck Laxity. J Drugs Dermatol. 2016 May 1;15(5):607-14. PMID: 27168269. CONTINUING MEDICAL EDUCATION J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 21

ORIGINAL ARTICLE Dapsone-induced hemolytic anemia in non-G6PD deficient leprosy patients receiving multidrug therapy in Southern Philippines Medical Center: A retrospective study Camille Joyce J. Crisostomo, MD, DPDS,1 Karen Lee Alabado-Laurel, MD, FPDS,1 Angela E. Sison, MD, DPDS1 ABSTRACT BACKGROUND Due to the high prevalence and incidence of leprosy in the Philippines, there is a continuing need to detect and document the occurrence of dapsone-induced hemolytic anemia. OBJECTIVE The aim of this study is to determine the incidence of dapsone-induced hemolytic anemia in non-glucose-6-phosphate dehydrogenase deficient leprosy patients receiving multidrug therapy (MDT) in Southern Philippines Medical Center. METHODOLOGY This is a retrospective study through chart review of leprosy patients treated with MDT regimen at Southern Philippines Medical Center from January 2016 to December 2018. The demographic profile, clinical characteristics, hemoglobin and hematocrit concentrations before and after initiation of MDT, the presence of symptoms of anemia, and the occurrence of dapsone-induced hemolytic anemia in leprosy patients were collected. The main outcome measure for this study was the incidence rate of dapsone- induced hemolytic anemia. Statistical-based analysis were used for continuous and categorical data which were summarized using means and standard deviations, and frequencies and percentages, respectively. RESULTS There was a decrease in the mean hemoglobin and hematocrit levels noted in the majority of patients after initiation of MDT from baseline 143.46 g/dl and 0.44, respectively, to 94 g/dl and 0.28 on the third month of MDT. The incidence rate of dapsone-induced hemolytic anemia during the 3-year period was 20 cases per 100. CONCLUISON The relatively high incidence rate of dapsone-induced hemolytic anemia highlights the importance of frequent monitoring of hemoglobin and hematocrit concentrations in leprosy patients being treated with multidrug therapy. KEYWORDS Hansen’s disease, leprosy, dapsone, hemolytic anemia 1 Department of Dermatology, Southern Philippines Medical Center, J. P. Laurel Ave., Bajada, Davao City, Philippines Corresponding author Camille Joyce J. Crisostomo, MD, DPDS [email protected] Conflict of interest None Source of funding None INTRODUCTION Leprosy, also known as Hansen’s disease, is a chronic granulomatous infection caused by Mycobacterium leprae, and recognized as a neglected tropical disease. Despite efforts to eliminate this debilitating disease, it is far from being eradicated in the Philippines. The prevalence of leprosy in the Philippines is less than 0.4 cases per 10,000 and approximately 1,700 new cases are identified each year according to the Department of Health (DOH).1 Likewise, Hansen’s disease belongs in the top 10 most common reasons for consult in the Southern Philippines Medical Center (SPMC) Department of Dermatology. Based on the institution’s census in 2018, there were 39 new cases of leprosy out of the 15,000 patients seen at the outpatient department with an average of 3 new patients per month. Therefore, the incidence rate and the prevalence rate of this disease in 2018 based on this data are 0.39, and 7.96 per 10,000, respectively.2 Based on a study by Guinto et al., the average annual mortality rate for lepromatous leprosy patients was 5.1 times higher than that of the general population.3 While leprosy is not often the immediate cause of death, sequelae from the disease and adverse events from medications can contribute to mortality. The multidrug therapy (MDT) is an efJ Phil Dermatol Soc • May 2023 • ISSN 2094-201X 22

fective regimen for the treatment of leprosy. This regimen includes rifampcin 600 mg monthly, clofazimine 300 mg monthly and 50 mg daily, and dapsone 100 mg daily for adults. The duration of treatment depends on the type of leprosy: 6 months for paucibacillary and 12 months for multibacillary leprosy. Adverse effects to these drugs are uncommon and are mostly related to dapsone.4 Dapsone (4’4’-diaminodiphenylsulfone), one of the drugs included in the MDT, has a bacteriostatic effect on Mycobacterium leprae by the inhibition of dihydrofolate synthetase enzyme.5 It has many adverse effects which include allergic reaction, exfoliative dermatitis, hemolytic anemia, jaundice, peripheral neuropathy, agranulocytosis, methemoglobinemia and dapsone hypersensitivity syndrome.6,7,8 Based on the data from the Department of Dermatology of SPMC, there was one (1) case of dapsone hypersensitivity syndrome out of twenty-six (26) leprosy patients treated with MDT in 2018. Hence, the incidence rate of this adverse drug reaction is 3.84 cases per 100.2 A study by Guragain et al. reported that four (4) patients died out of eighteen (18) cases secondary to dapsone adverse reaction.6 Hemolysis is the process of premature destruction or removal of erythrocytes from the circulation, which manifests as jaundice, cholelithiasis, anemia or isolated reticulocytosis.9,10 This can either be inherited or acquired. In drug-induced hemolytic anemia, certain medications may cause an immune response that eventually destroys the erythrocytes. The clinical and laboratory findings of this type of hemolytic anemia are identical to autoimmune hemolytic anemia but with the remission of the disease attributed to the discontinuation of the causative drug.11 Several laboratory tests are used to confirm the diagnosis of hemolytic anemia. Complete blood count is the first test requested to diagnose anemia. The most direct indicator of severity of hemolysis is the hemoglobin level.12 Another test is the reticulocyte count, which is usually elevated in individuals with hemolytic anemia secondary to the response of the bone marrow to compensate for the loss of red blood cells.9 Hemolytic anemia is suspected if there is anemia and reticulocytosis. Peripheral blood smear may reveal the presence of schistocytes or fragmented RBCs, which suggests intravascular hemolysis. Other laboratory findings suggestive of hemolysis include increased serum lactate dehydrogenase (LDH) and bilirubin, decreased haptoglobin, normal alanine aminotransferase (ALT) and hemosiderinuria. Direct and indirect Coombs tests may also reveal the presence of antibodies against red blood cells leading to its premature removal.13 ORIGINAL ARTICLE J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 23 Dapsone is primarily metabolized in the liver through N-acetylation and N-hydroxylation. Within the erythrocytes, the metabolite hydroxylamine, generates reactive oxygen species which are responsible for oxidation of oxyhemoglobin into methemoglobin. This process renders the erythrocytes senescent and these are removed prematurely by the spleen. Individuals with normal glucose-6-phosphat e dehydrogenase (G6PD) levels have the ability to reverse this oxidative damage by synthesis of glutathione within the erythrocytes. G6PD deficient patients are at increased risk of developing hemolytic anemia.8,14 However, the hemolytic process may also occur in patients without G6PD deficiency and occurs in a dose-dependent fashion.14 This adverse drug reaction can lead to morbidity and mortality if not diagnosed and treated early. A study conducted by Deps et al revealed that the dapsone used in the treatment of leprosy causes significant hemolytic anemia. The symptoms of hemolytic anemia were noted to appear within the first three (3) months of MDT regimen in the majority of patients (51%). In the study, the diagnosis of hemolytic anemia was made if the hemoglobin level was 12.7 g/dl or less for men and 11.5 g/dl or less for women, and/or the hematocrit level was less than 42% for men and 36% for women. At the end of the study, there was noted significant decrease in the mean hemoglobin and hematocrit concentrations.7 Another retrospective study by Guragain et al revealed that hemolytic anemia, along with jaundice and exfoliative dermatitis, were common adverse drug reactions in leprosy patients taking dapsone accounting for 22.22%.6 A study conducted in Indonesia reported that the incidence of hemolytic anemia after 3 months of MDT was 66.7% with a significant decreased in hemoglobin level and an increased reticulocyte count.5 In leprosy patients undergoing treatment with MDT, 83% were reported to have a decrease in hemoglobin concentration of more than or equal to 1 g/dl, and 16% of patients had a decrease in hemoglobin concentration more than or equal to 3 g/dl. In addition, decreasing the daily dose of dapsone led to an increase in the hemoglobin level. These findings suggest that dapsone-induced hemolytic anemia is dose-related.15 Due to the high incidence and prevalence of leprosy in the Philippines, there is a need for the clinicians to familiarize themselves with the occurrence of adverse drug reactions after initiation of MDT. To this date, there has been no published study in the Philippines on dapsone-related adverse events.

This study aims to determine the incidence of dapsone-induced hemolytic anemia in non-G6PD deficient leprosy patients receiving multidrug therapy in SPMC. Furthermore, we also aim to describe the dermatographic profile of leprosy patients seen at our center and determine their hemoglobin levels before and after initiation of MDT therapy. METHODOLOGY A descriptive study design was utilized for this study. This retrospective study was conducted using a chart review. Leprosy patients treated with MDT regimen for a minimum of 6 months at the Department of Dermatology in SPMC from January 2016 to December 2018 were included in the study. Exclusion criteria were the following: Leprosy patients diagnosed with G6PD deficiency and were given a treatment regimen without dapsone, those who had pre-existing anemia prior to initiation of MDT, those who started with MDT prior to the first consult, and those with incomplete data on the chart. Upon approval by the Ethics Board Committee, the names of the patients diagnosed with Hansen’s disease were retrieved from the leprosy central registry logbook, dermatopathology logbook and outpatient logbook of the department. Chart retrieval was requested from the SPMC medical records section. Demographic data, leprosy disease spectrum, as well as hemoglobin and hematocrit concentrations before and after initiation of therapy were gathered. We defined dapsone-induced hemolytic anemia as a hemoglobin level of 12.7 g/dl or lower for men and 11.5 g/dl or lower for women after initiation of therapy. These were the independent variables of the study. The main outcome of the study was the incidence rate of dapsone-induced hemolytic anemia in leprosy patients treated with multidrug therapy. Continuous data were summarized as means + standard deviations. Categorical data were summarized using frequencies and percentages. All statistical tests were done using Epi Info 7.2.2.6. RESULTS A total of eighty (80) leprosy patients treated with multidrug therapy (MDT) in the Department of Dermatology of Southern Philippines Medical Center from January 2016 to December 2018 were included in the study. A. DEMOGRAPHIC PROFILE Table 1 shows the demographic and clinical profiles of patients included in the study. The mean age of patients with leprosy J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 24 treated with MDT regimen was 34.29 ± 15.29 years old. There were sixty-three (63) male patients (78.75%) and seventeen (17) female patients (21.25%). The majority of patients had a lepromatous leprosy (LL) spectrum (52.50%), followed by borderline borderline leprosy (BB) (26.25%), and borderline lepromatous leprosy (BL) (11.25%). B. COMPARISON OF HEMOGLOBIN AND HEMATOCRIT LEVELS The hemoglobin and hematocrit levels of the patients before and after initiation of MDT is shown in Table 2. The baseline mean hemoglobin of patients was 143.46 ± 15.33 g/dL, and the baseline mean hematocrit was 0.44 ± 0.04. Based on the table shown, decreased hemoglobin and hematocrit were seen after 1 month of MDT. By the third month, the mean hemoglobin was 94.00 ± 28.40 g/dL, and the mean hematocrit was 0.28 ± 0.09. C. INCIDENCE OF DAPSONE-INDUCED HEMOLYTIC ANEMIA The incidence of dapsone-induced hemolytic anemia is shown in Table 3. The year with the highest incidence rate of dapsone-induced hemolytic anemia was during 2018. Nine (9) out of the twenty-six (26) total patients during that year had dapsone-induced hemolytic anemia comprising 34.62%. On the other hand, the incidence rate of hemolytic anemia for the year 2016 and 2017 were 9.38% and 18.18%, respectively. The average incidence rate of dapsone-induced hemolytic anemia for 2016-2018 was 20%. DISCUSSION Based on the results of the study, there was a decreasing trend Table 1. Demographic and clinical profiles of Hansen’s disease patients. Characteristics Values (n=80) Mean age ± SD, years 34.29 ± 15.29 Sex, frequency (%) Male 63 (78.75) Female 17 (21.25) Spectrum of leprosy, frequency (%) TT 1 (1.25) BT 6 (7.50) BB 21 (26.25) BL 9 (11.25) LL 42 (52.50) Histoid 1 (1.25) ORIGINAL ARTICLE

noted on the mean hemoglobin and hematocrit concentration of leprosy patients before and after initiation of MDT. The incidence rate of dapsone-induced hemolytic anemia among leprosy patients treated with MDT during 2016, 2017, and 2018 were 9.38%, 18.18%, and 34.62%, respectively. During the 3-year period, the incidence rate of this adverse drug reaction was 20%. All patients who developed hemolytic anemia manifested after 1 month of initiation of MDT with a mean difference of hemoglobin from baseline of 30.94 g/dl with the highest drop of 54 g/dl seen in one (1) patient. Eleven (11) out of sixteen (16) patients who developed dapsone-induced hemolytic anemia were male. The diagnosis of leprosy in many countries is more commonly seen in males than females with a ratio of 2:1.16 Currently, no study has reported any association between male sex and occurrence of dapsone-induced hemolytic anemia. However, it is known that G6PD deficiency is an X-linked recessive disorder. Hence, clinically significant hemolysis occurs more commonly in males. Fourteen (14) out of sixteen (16) patients who developed dapsone-induced hemolytic anemia had lepromatous leprosy (LL) spectrum. Although most of the patients included in the present study had LL spectrum (52.50%), a study by Rea et al. reported a decreased in mean J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 25 hemoglobin values in patients with erythema nodosum leprosum (ENL) reactions. This type of leprosy reaction occurs most often in lepromatous leprosy (LL) patients. However in the study, those who developed ENL before 6 months of antimicrobial treatment had passed were excluded to remove the possible influence of dapsone on hemoglobin values. ENL-associated anemia still has an unknown mechanism.17 Thirteen (13) out of sixteen (16) patients who developed hemolytic anemia were symptomatic. The most common symptoms were fever (62.50%), icteric sclera (43.75%), and weakness (25%). These symptoms manifested within a month of taking MDT which is compatible with the study conducted by Deps et al wherein majority of symptoms of hemolytic anemia were noted to appear within the first three months of therapy.7 However, not all patients who developed symptoms had hemolytic anemia. There were five (5) patients who had symptoms, such as fever and weakness, but with normal hemoglobin and hematocrit levels after initiation of MDT. Hence, the presence of symptoms in these patients may point to another cause which may include, but are not limited to, leprosy reactions. Although there are different causes of hemolytic anemia, a strong association was noted between dapsone and the development of hemolytic anemia in these patients considering the normal hemoglobin and hematocrit concentration before initiation of MDT and the onset of symptoms after MDT initiation. However, other laboratory tests, such as reticulocyte count, peripheral blood smear, bilirubin, haptoglobin, serum lactate dehydrogenase (LDH), ALT, urine hemosiderin, and Coomb’s test, that could help confirm the diagnosis of this condition, were not included in this study. Another limitation was that the data used in this study is a secondary data. Hence, the results of this study depend on the completeness of the chart. Those with incomplete data were not included in this study which resulted to a smaller sample size especially in month 2 and month 3 of treatment. Table 2. Hemoglobin and hematocrit levels of leprosy patients before and after starting MDT. Characteristics Hemoglobin (g/dL) Hematocrit Baseline (n=80) Month 1 (n=80) Month 2 (n=9) Month 3 (n=5) Baseline (n=80) Month 1 (n=80) Month 2 (n=9) Month 3 (n=5) Mean ± SD 143.46 ± 15.33 132.73 ± 18.38 113.44 ± 28.75 94.00 ± 28.40 0.44 ± 0.04 0.41 ± 0.06 0.34 ± 0.09 0.28 ± 0.09 Minimum 117.00 77.00 63.00 57.00 0.36 0.24 0.20 0.19 Maximum 178.00 164.00 144.00 119.00 0.51 0.50 0.44 0.36 Table 3. Incidence rate of dapsone-induced hemolytic anemia in leprosy patients treated with MDT at SPMC Dermatology from January 2016 to December 2018. Year Total number of new leprosy cases treated with MDT Total number of Dapsoneinduced hemolytic anemia Incidence rate of hemolytic anemia 2016 32 3 9.38% 2017 22 4 18.18% 2018 26 9 34.62% Total 80 16 20.00% ORIGINAL ARTICLE

Dapsone-induced hemolytic anemia is a life-threatening adverse drug reaction if not recognized and treated early. This study provides evidence on the incidence rate of dapsone-induced hemolytic anemia among non-G6PD deficient leprosy patients treated with MDT. Based on the results of the study, there is a high incidence rate of this adverse drug reaction that can often be overlooked. REFERENCES 1. Lauzon LC. Leprosy remains a hidden, persistent problem in the Philippines. National Nutrition Council. 2021 Jan 26. Available from: https:// nnc.gov.ph/regional-offices/visayas/region-viii-eastern-visayas/4653-leprosy-remains-a-hidden-persistent-problem-in-thephilippines 2. Leprosy central registry logbook. Southern Philippines Medical Center Department of Dermatology. 2018 (Unpublished) 3. Guinto R, Doull J, De Guia L. Mortality of persons with leprosy prior to sulfone therapy, Cordova and Talisay, Cebu, Philippines. Int J Lepr. 1954 Jul-Sep;22(3):273-84. PMID: 13232775. 4. Lastória JC, Abreu MA. Leprosy: a review of laboratory and therapeutic aspects--part 2. An Bras Dermatol. 2014 May-Jun;89(3):389-401. doi: 10.1590/abd1806-4841.20142460. PMID: 24937811; PMCID: PMC4056695. 5. Muhaira WT, Darmi M, Lubis RD. Hemolytic anemia incident in leprosy patients receiving multi-drug therapy at Haji Adam Malik Central Hospital, Medan-Indonesia. Bali Medical Journal. 2018;7(2). doi:10.15562/bmj.v7i2.774 6. Guragain S, Upadhayay N, Bhattarai BM. Adverse reactions in leprosy patients who underwent dapsone multidrug therapy: a retrospective study. Clin Pharmacol. 2017 Jun 29;9:73-78. doi: 10.2147/CPAA.S135846. PMID: 28721106; PMCID: PMC5500492. 7. Deps P, Guerra P, Nasser S, Simon M. Hemolytic anemia in patients receiving daily dapsone for the treatment of leprosy. Lepr Rev. 2012 Sep;83(3):305-7. PMID: 23356031. 8. Alungal J, Abdulla M, Kunnummal N, Sivadasan A. Dapsone-induced hypersensitivity syndrome, hemolytic anemia, and severe agranulocytosis. Int J Nutr Pharmacol Neurol Dis. 2015;5(3):113. doi:10.4103/2231-0738.158377. 9. Dhaliwal G, Cornett PA, Tierney LM Jr. Hemolytic anemia. Am Fam Physician. 2004 Jun 1;69(11):2599-606. PMID: 15202694. 10. Phillips J, Henderson AC. Hemolytic Anemia: Evaluation and Differential Diagnosis. Am Fam Physician. 2018 Sep 15;98(6):354-361. PMID: 30215915. 11. Garratty G. Drug-induced immune hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2009:73-9. doi: 10.1182/ asheducation-2009.1.73. PMID: 20008184. 12. Barcellini W, Fattizzo B. Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia. Dis Markers. 2015;2015:635670. doi: 10.1155/2015/635670. Epub 2015 Dec 27. PMID: 26819490; PMCID: PMC4706896. 13. Braunstein EM. Overview of Hemolytic Anemia. MSD Manual Professional Version. Published September 2022. Accessed May 16, 2023. https://www.msdmanuals.com/professional/hematology-and-oncology/anemias-caused-by-hemolysis/ microangiopathichemolytic-anemia. 14. Sago J, Hall R. Dapsone. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. 2012. Fitzpatrick’s Dermatology in General Medicine Eighth Edition. New York , NY: McGraw-Hill Companies. Inc; 2012: 2721-2726. 15. Byrd SR, Gelber RH. Effect of dapsone on haemoglobin concentration in patients with leprosy. Lepr Rev. 1991 Jun;62(2):171-8. doi: 10.5935/0305-7518.19910020. PMID: 1870379. 16. Walker S, Withington S, Lockwood D. Leprosy. In: Farrar J, Hotez P, Junghanss T, Kang G, Lalloo D, White N. 2014. Manson’s Tropical Infectious Diseases Twenty-third Edition. 2014: 506-518. 17. Rea TH. Decreases in mean hemoglobin and serum albumin values in erythema nodosum leprosum and lepromatous leprosy. Int J Lepr Other Mycobact Dis. 2001 Dec;69(4):318-27. PMID: 12035293. J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 26 CONCLUSION In conclusion, the results of this study highlight the importance of more frequent evaluation and monitoring of the hemoglobin and hematocrit concentrations of leprosy patients being treated with multidrug therapy to detect the presence of dapsone-induced hemolytic anemia. Early diagnosis and management of this condition can prevent further morbidity and mortality. ORIGINAL ARTICLE

A case of green nail syndrome secondary to P. aeruginosa and C. parapsilosis treated with topical nadifloxacin and oral fluconazole in a 31-year-old Filipino female Angeli Elaine A. Pangilinan MD,1 Nicole R. Rivera, MD,1 Leilani R. Senador, MD, FPDS1 ABSTRACT INTRODUCTION Pseudomonas aeruginosa is an opportunistic, gram-negative bacillus that can contaminate skin or open wounds to cause skin infections that are historically difficult to manage. The pathogenesis of green nail syndrome (GNS) begins with hyperhydration (occlusion, sweating, maceration) or destruction (microtrauma, dermatitis) of the epidermis thus disrupting the physical barrier, leading to the colonization and proliferation of P. aeruginosa. This case explores the off-label use of nadifloxacin, a fluoroquinolone approved for acne and bacterial skin infections in some countries, to treat a case of GNS. CASE REPORT This is a case of a 31-year-old Filipino female who presented with a four-month history of green discoloration of the lateral portion of the right thumbnail with a medical history of antiphospholipid antibody syndrome and rheumatoid arthritis. Clinical examination showed a dystrophic thumbnail with greenish discoloration, erythema and swelling around the base of the cuticle, and distal onycholysis. Laboratory findings revealed co-infection of P. aeruginosa and Candida parapsilosis. The patient was effectively treated with topical nadifloxacin and oral fluconazole. CONCLUSION This case highlights the possibility of fungal and polymicrobial infections in GNS and suggests a novel, easy-to-use, and cost-effective alternative treatment to GNS secondary to P. aeruginosa in the form of topical nadifloxacin. KEYWORDS green nail syndrome, nadifloxacin, Candida parapsilosis, Pseudomonas aeruginosa, onychomycosis 1 Department of Dermatology, Research Institute for Tropical Medicine 9002 Research Drive, Filinvest Corporate City, Alabang, Muntinlupa 1781, Philippines Corresponding author Angeli Elaine A. Pangilinan, MD, MBA, [email protected] Conflict of interest None Source of funding None INTRODUCTION Pseudomonas aeruginosa is an opportunistic, gram-negative bacillus that contaminates skin or open wounds to cause skin infections that are difficult to manage. Pseudomonas nail infection presents with a triad of green discoloration of the nail plate, proximal paronychia, and distolateral onycholysis.1 Risk factors include prolonged contact with a moist environment, history of trauma, immunocompromised state, frequent wet work, and a history of hyperhidrosis.1 This study explores the off-label use of nadifloxacin, a fluoroquinolone approved for acne and bacterial skin infections, to treat green nail syndrome (GNS). There are only a few published reports on treatment with this drug, proposing a novel, easy-to-use, and cost-effective alternative treatment to GNS secondary to P. aeruginosa. CASE SUMMARY A 31-year-old Filipino female presented with a four-month history of green discoloration of the lateral portion of the right thumbnail which was aggravated by frequent wet work, manicures, and excessive palmar sweating. No new medications were applied. In the interim, the patient noted an increase in size of discoloration, affecting the entire nail, hence consult at our clinic. She was undergoing immunosuppressive treatment for antiphospholipid antibody syndrome (APAS) and rheumatoid arthritis (RA), which may have compromised her immune system. Clinical examination showed a dystrophic right thumbnail with greenish discoloration, erythema and swelling around the base of the cuticle, and distal onycholysis. Dermoscopy presented a bright yellow green discoloration (Figure 1). There was distal onycholysis and J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 27 CASE REPORT

bright yellow green pigment on the ventral side of the nail plate (Figure 1). With the clinical and dermoscopic findings, a primary impression of GNS was made. The following diagnostics were done: bacterial gram stain culture and sensitivity (GS/ CS), 20% KOH, fungal culture and sensitivity of the affected nail as well as complete blood count, liver function tests, and creatinine level measurement. For the GS/CS, greenish discharge was collected on the distal nail bed beneath the free edge of the nail plate using a cotton pledget soaked in 0.9% normal saline solution. Results showed gram-positive cocci in pairs and in clusters, and bacterial culture had a moderate growth of P. aeruginosa (Table 1) as shown on Nutrient and MacConkey agar. The specimen for fungal culture was taken in the same manner, revealing growth of C. parapsilosis sensitive to fluconazole, andulafungin, caspofungin, micafungin, and voriconazole (Table 1). Clippings of the distal onycholytic nail were submitted for KOH which revealed yeast cells. Nadifloxacin 1% cream was applied on the dorsal nail plate, free nail edge, and the spaces between the nail plate and distal nail bed at bedtime and occluded with clingwrap overnight on weeks 1 to 8. Oral fluconazole 150-300 mg/ week was taken for 6 weeks. Figure 2 shows the patient’s thumbnail at weeks 1 to 8 of treatment with nadifloxacin and Figure 3 illustrates weeks 8 to 19 with fluconazole. There was disappearance of the green discoloration after applying nadifloxacin (Figure 2) and further elimination of the yellow discoloration after intake of fluconazole (Figure 3), thus attaining complete clinical cure. The patient was advised to avoid excessive immersion in water, to keep nails clean and dry, and to trim nails at 4-week intervals until regrowth. Twenty-four weeks after completion of treatment, the patient was instructed to undergo a repeat bacterial and Figure 1. Dermoscopy of the nail plate showed a bright yellow green discoloration of the nail plate with no visible blood vessels (A). Dermoscopy of the free edge demonstrated distal onycholysis and the presence of the pigment of the ventral side of the plate (B). J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 28 Table 1. Laboratory results. Gram Stain Pus cells/LPF Rare Epithelial cells/LPF Moderate Organisms/OIF Gram positive cocci in pairs and in clusters - Few Aerobic Culture and Sensitivity Test Moderate growth of Pseudomonas aeruginosa Interpretation Antibiotic Susceptibility aztreonam, levofloxacin, tobramycin, doripenem, piperacillin-tazobactam, ceftazidime, cefepime, imipenem, meropenem, amikacin, gentamycin, ciprofloxacin KOH wet mount Positive for yeast cells Fungal Culture Positive for Candida parapsilosis after 48 hours of incubation Interpretation Antifungal Susceptible andulafungin, caspofungin, fluconazole, micafungin, voriconazole Figure 2. Weeks 1 to 8 of treatment with topical nadifloxacin. First consult (A), 2 weeks (B), 4 weeks (C), 6 weeks (D), 8 weeks (E). CASE REPORT

fungal culture of the nail, however, she was not able to do so due to personal reasons. Although these should have been done to determine the definite cure rate, nadifloxacin has shown its efficacy in terms of partial clinical cure after eight (8) weeks, eliminating the greenish discoloration. Complete clinical cure resulted after the addition of fluconazole where the yellowish discoloration was eradicated. DISCUSSION This is a case of a 31-year-old Filipino female who presented with a four-month history of green discoloration of the right thumbnail with a medical history of antiphospholipid antibody syndrome and rheumatoid arthritis. Clinical examination showed a dystrophic thumbnail with greenish discoloration, erythema and swelling around the base of the cuticle, and distal onycholysis. Laboratory findings revealed co-infection of P. aeruginosa and C. parapsilosis which were effectively treated with topical nadifloxacin and oral fluconazole. The pathogenesis of GNS begins with hyperhydration (occlusion, sweating, maceration) or destruction (microtrauma, dermatitis) of the epidermis thus disrupting the physical barrier, leading to the colonization and proliferation of P. aeruginosa. 1 Rallis et al. enumerated the predisposing factors for GNS which are onycholysis, onychotillomania, microtrauma, chronic paronychia, chronic exposure to water, soaps or detergents, associated nail disorders, and an immunocompromised state.2 The patient is a housewife who engaged in frequent wet work and weekly manicures which caused nail trauma. She was undergoing immunosuppressive treatment for APAS and RA, which may have compromised her immune system. P. aeruginosa facilitates the spread of infection by producing collagenase, elastase, phospholipase, heat-stable thermolysin, vascular permeability factor, and fibrolysin.1 The bacteria digests keratin which explains the organism’s ability to invade the nail plate. The greenish hue is due to pyocyanin and pyoverdine that accumulate as P. aeruginosa is metabolized.1 There are no published guidelines and clinical trials for treating GNS.1 Therapies consist of topical antiseptics such as diluted acetic acid or sodium hypochlorite and oral antibiotics. Oral antibiotics such as ciprofloxacin are considered if topical antiseptics are unsuccessful, but they are not the first choice. The bacterial biofilm is approximately 1000 times less sensitive to antibiotics than isolated bacteria of the same species and the nail is not in contact with the nail bed so the antibiotic cannot reach the biofilm.3 Topical antibiotics have shown success, wherein 21 patients were successfully treated with 0.3% gentamycin administered nightly for 12 weeks.4 However, clinicians are wary that these are unlikely to adequately treat the infection and may lead to antibiotic resistance.1 While antibiotics proved to be effective, research shows increasing resistance to P. aeruginosa. 5 Hanberger et al. found that in five European countries, ciprofloxacin and gentamycin showed the highest incidence of resistance (37% resistant to ciprofloxacin in Portuguese ICUs and 46% resistant to gentamycin in French ICUs).5 Thus, there is a need for novel strategies to treatment. Topical nadifloxacin 1% cream is approved for the management of acne vulgaris and surgical site infections.6 It has broad spectrum activity against gram-positive (including MRSA), gram-negative, and anaerobic bacteria, making this a promising treatment for GNS.6 Due to its mechanism of action (binding to bacterial DNA gyrase and topoisomerase IV enzymes, inhibition of nor-A efflux pump, survival in acidic pH, anti-MRSA activity, and biofilms penetration), it has shown a very low chance of developing resistance.6 Two (2) HIV-positive patients with pseudomonas nail infection of three (3) weeks duration were successfully treated with nadifloxacin, applied daily on affected nails and observed complete clearance within six (6) weeks.2 Similarly, Müller et al. reported success with the treatment of two (2) immunocompetent patients with GNS by applying nadifloxacin.7 For the first case, nadifloxacin was applied daily on the nail plate for six (6) weeks.7 The co-infection with C. parapsilosis was treated with itraconazole 100 mg twice daily on weeks 1 and 5, demonstrating cure within 24 weeks.7 For the second case, nadifloxacin was applied daily on the nail plate for six (6) weeks.7 The nail plate was treated within 16 weeks of treatment.7 J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 29 Figure 3. Weeks 8 to 19 of fluconazole. Baseline (F), 13 weeks (G), 19 weeks (H). CASE REPORT

It is crucial to consider that polymicrobial and fungal infections may occur simultaneously, therefore, the identification of the etiology is imperative for appropriate treatment. In a study by Forouzan et al., the researchers concluded that while bacterial etiologies are common, fungal and polymicrobial infections may be more widespread than published literature suggests.8 Ohn et al. found that GNS was frequently associated with concomitant onychomycosis and speculated that onychomycosis is a predisposing factor to GNS because the nail spaces beneath the lateral folds are ideal for the growth of P. aeruginosa. 9 This study was prudent in requesting for the necessary laboratory tests, thus, clinicians must wisely identify the infectious agents involved when faced with a case of GNS. Fungal culture revealed a co-infection with C. parapsilosis. Studies show that Candida spp. were the most frequently isolated pathogens in onychomycosis and C. parapsilosis exhibits low phospholipase, proteinase, and biofilm formation activities.10 This confirms the need to perform antifungal susceptibility testing of yeasts from patients with onychomycosis. Based on the susceptibility test (Table 1), the patient was given fluconazole at 150 mg/cap per week for 12 weeks achieving partial clinical cure with nadifloxacin as seen from the disappearance of the green discoloration. According to Ghannoum, et al., “Fluconazole is used in the treatment of onychomycosis in adults at a weekly dose of 150 to 450 mg for 3 to 6 months for finger and toenail onychomycosis, respectively.”3 Treatment with fluconazole cleared the yellow discoloration achieving complete clinical cure. This case emphasizes the importance of appropriate work-up to diagnose possible co-infections in GNS and proposes topical nadifloxacin as an effective treatment modality. Further research is recommended to strengthen its effectiveness. CONCLUSION While GNS is rare, it is imperative to do appropriate workup to diagnose possible co-infection to initiate appropriate treatment. This study highlights the possibility of fungal and polymicrobial infections in GNS, and suggests a novel, easy-to-use, and cost-effective alternative treatment to GNS secondary to P. aeruginosa in the form of topical nadifloxacin. REFERENCES 1. Schwartz RA, Reynoso-Vasquez N, Kapila R. Chloronychia: The goldman-fox syndrome - implications for patients and healthcare workers. Indian J Dermatol [Internet]. 2020;65(1):1–4. Available from: http://dx.doi.org/10.4103/ijd.IJD_277_19 2. Rallis E, Paparizos V, Flemetakis A, Katsambas A. Pseudomonas fingernail infection successfully treated with topical nadifloxacin in HIV-positive patients: report of two cases. AIDS [Internet]. 2010;24(7):1087–8. Available from: http://dx.doi.org/10.1097/ QAD.0b013e32833819aa 3. Ghannoum, Mahmoud, et al. “Antifungals.” Kang, Sewon, et al. Fitzpatrick’s Dermatology. New York: McGraw-Hill Education, 2019. 3445. 4. Geizhals S, Lipner SR. Retrospective case series on risk factors, diagnosis and treatment of pseudomonas aeruginosa nail infections. Am J Clin Dermatol [Internet]. 2020;21(2):297–302. Available from: http://dx.doi.org/10.1007/s40257-019-00476-0 5. Hanberger H, Garcia-Rodriguez JA, Gobernado M, Goossens H, Nilsson LE, Struelens MJ. Antibiotic susceptibility among aerobic gram-negative bacilli in intensive care units in 5 european countries. French and Portuguese ICU Study Groups. JAMA [Internet]. 1999;281(1):67–71. Available from: http://dx.doi.org/10.1001/jama.281.1.67 6. Narayanan V, Motlekar S, Kadhe G, Bhagat S. Efficacy and safety of nadifloxacin for bacterial skin infections: results from clinical and post-marketing studies. Dermatol Ther (Heidelb) [Internet]. 2014;4(2):233–48. Available from: http://dx.doi.org/10.1007/ s13555-014-0062-1 7. Müller S, Ebnöther M, Itin P. Green nail syndrome (Pseudomonas aeruginosa nail infection): Two cases successfully treated with topical nadifloxacin, an acne medication. Case Rep Dermatol [Internet]. 2014;6(2):180–4. Available from: http://dx.doi. org/10.1159/000365863 8. Forouzan P, Cohen PR. Fungal viridionychia: Onychomycosis-induced chloronychia caused by Candida parapsilosis-associated green nail discoloration. Cureus [Internet]. 2021;13(12):e20335. Available from: http://dx.doi.org/10.7759/cureus.20335 9. Ohn J, Yu D-A, Park H, Cho S, Mun J-H. Green nail syndrome: Analysis of the association with onychomycosis. J Am Acad Dermatol [Internet]. 2020;83(3):940–2. Available from: http://dx.doi.org/10.1016/j.jaad.2020.01.040 10. Sav H, Baris A, Turan D, Altinbas R, Sen S. The frequency, antifungal susceptibility and enzymatic profiles of Candida species in cases of onychomycosis infection. Microb Pathog [Internet]. 2018;116:257–62. Available from: http://dx.doi.org/10.1016/j. micpath.2018.01.036 J Phil Dermatol Soc • November 2022 • ISSN 2094-201X 30 CASE REPORT

Treatment conundrum: A case of recalcitrant Epidermolysis Bullosa Acquisita (EBA) in a 50-year-old Filipino male Danelle Anne L. Santos, MD,1 Aira Monica R. Abella, MD,1 Danica-Grace Tungol, MD, DPDS,1 Leilani R. Senador, MD, FPDS1 ABSTRACT INTRODUCTION Epidermolysis Bullosa Acquisita (EBA) is a rare autoimmune blistering disease which presents in the skin and mucous membranes. The decrease in anchoring fibrils in the basement membrane zone causes separation of the epidermis from the dermis, resulting in its blistering presentation. The treatment plan will depend on the severity of the disease. The first-line treatment for mild EBA includes topical corticosteroids and immunomodulators such as dapsone and colchicine; while severe cases of EBA may be given intravenous immunoglobulins, systemic steroids, and immunosuppressants such as azathioprine and cyclophosphamide. CASE REPORT This is a case of a 50-year-old Filipino male who presented with a 2-year history of vesicles and tense bullae which evolved into papules, plaques and erosions with scarring and milia formation on the scalp and trauma-prone areas of the trunk and extremities. Clinical examination revealed multiple, well-defined, irregularly shaped erythematous papules and plaques with crusts, scales, erosions, pearl-like milia and scarring on the chest, back, upper, and lower extremities. The oral mucosa was moist with some ulcers on the tongue. Histopathologic examination using Hematoxylin and Eosin (H&E) stain revealed the absence of the epidermis with retention of dermal papillae suggestive of subepidermal clefting. Further examination with direct immunofluorescence (DIF) revealed monoclonal immunoglobulin (IgG) deposits demonstrating an intense linear fluorescent band at the dermoepidermal junction, consistent with Epidermolysis Bullosa Acquisita. Overall, the combined administration of prednisone, azathioprine, and colchicine resulted only in transient and incomplete resolution of lesions in this case of EBA. CONCLUSION The management of EBA is mostly supportive with the goal of minimizing complications. Combination treatments using steroids, colchicine, and azathioprine have been reported with various results. Its management remains challenging as most cases are refractory to treatment. KEYWORDS Epidermolysis Bullosa Acquisita, blistering disease, bullous disease, azathioprine, colchicine, prednisone, direct immunofluorescence study 1 Department of Dermatology, Research Institute for Tropical Medicine 9002 Research Drive, Filinvest Corporate City, Alabang, Muntinlupa 1781, Philippines Corresponding author Danelle Anne L. Santos, MD, [email protected] Conflict of interest None Source of funding None INTRODUCTION Epidermolysis Bullosa Acquisita (EBA) is a rare autoimmune blistering disease which presents in the skin and mucous membranes. Long-term remission in EBA patients is difficult to achieve. The combined administration of prednisone, azathioprine, and colchicine resulted only in transient and incomplete resolution of lesions in this case of EBA. CASE SUMMARY A 50-year-old Filipino male was initially seen via teledermatology with a 2-year history of vesicles and tense bullae which evolved into papules, plaques and erosions with scarring and milia formation on the scalp and trauma-prone areas of the trunk and extremities. The patient also experienced occasional constipation, for which no consult was sought. He was previously seen and managed by a private dermatologist who advised skin biopsy, but it was not done due to insufficient funds. He was then managed clinically as a case of pustular psoriasis and was prescribed bilastine 20 mg once a day for seven (7) days, amoxicillin + clavulanic acid 625 mg/capsule twice a day for 7 days, and isotretinoin 10 mg once a day for three (3) months. He was also prescribed clobetasol propionate ointment twice a day for two (2) weeks and mupirocin ointment twice a day for seven (7) days with minimal improvement; hence, consultation at our institution. J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 31 CASE REPORT

On initial consultation, clinical examination revealed multiple, well-defined, irregularly shaped erythematous papules and plaques with crusts, scales, erosions, pearllike milia, and scarring on the chest, back, upper, and lower extremities. The oral mucosa was moist with some ulcers on the tongue. Onycholysis and subungual hyperkeratosis were appreciated on the nails of the hands and feet, as well as onychomadesis on the first digit of the left foot (Figure 1). A 4-mm skin punch biopsy was taken from a fresh bulla for routine histologic examination and another specimen on perilesional skin for direct immunofluorescence (DIF). The histopathologic examination using Hematoxylin and Eosin (H&E) stain revealed the absence of the epidermis with retention of dermal papillae suggestive of subepidermal clefting. On high power view, sparse superficial perivascular infiltrates consisting of lymphocytes and eosinophils were also identified. The DIF revealed monoclonal immunoglobulin (IgG) deposits which demonstrated an intense linear fluorescent band at the dermoepidermal junction (Figure 2). Other diagnostic tests such as complete blood count, urinalysis, fasting blood sugar, lipid profile, kidney and liver function tests were all normal. With the clinical, histopathologic, and immunofluorescence findings, a diagnosis of epidermolysis bullosa acFigure 1. Baseline and follow-up photos while on medications. A. Initial consult. B. Week 4 of treatment on prednisone 30 mg/day. C. Week 12 of treatment on colchicine 1000 mcg/day and prednisone 30 mg/day. D. Week 20 of treatment on azathioprine 50 mg/day and prednisone 30 mg/day. E. Week 28 of treatment on azathioprine 150 mg/day and prednisone 20 mg/day. quisita was made. The patient was started on clindamycin 300 mg capsule every 6 hours for one (1) week to address an ongoing secondary bacterial infection, prednisone 40 mg once a day (0.6 mg/kg/day) and topical corticosteroids. Supportive management such as cetirizine, mupirocin 2% ointment and an oral gargle of sucralfate 4mg + aluminum hydroxide + magnesium hydroxide 60ml + diphenhydramine hydrochloride 12.5/5ml 30ml were also prescribed. For wound cleaning, mild soap and the use of normal saline solution (NSS) were advised. After the first two (2) weeks of medications with good compliance, there was minimal improvement, noted as flattening and drying of the lesions with no development of new bullae. However, upon the decrease of prednisone dose to 30 mg/day on week 4, new bullae developed and he was started on colchicine 500 mcg/day. The colchicine dose was gradually increased up to 2500 mcg/day by week 18. On week 20, the patient noted the appearance of new bullae on areas previously clear of lesions such as the trunk and back, despite being on colchicine 2500 mcg/day and prednisone 30 mg/day. Colchicine was shifted to azathioprine by week 21, initially at 50 mg/day then gradually increased to 150 mg/day. Around this time, the patient complained of increased frequency and severity of his constipation, J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 32 CASE REPORT

with pain on defecation. Colonoscopy was requested but it was not done due to financial constraints. Instead, supportive management such as fiber supplementation was advised. Skin care was also recommended which included avoidance of trauma and infection; as well as the use of Figure 2. A. Absence of the epidermis with retention of dermal papillae suggestive of subepidermal clefting (H&E, 4x); B. Sparse superficial perivascular infiltrates consisting of lymphocytes and eosinophils (H&E, 40x); C. Direct immunofluorescence studies showed (+) Linear IgG; D. Grade 3 and (+) Linear C3, Grade 2. Figure 3. Summary of medications given from weeks 0 to 28. the following topical corticosteroids on affected areas to facilitate healing: mometasone furoate 0.1% cream and hydrocortisone 1% cream for the face, and betamethasone valerate cream, halobetasol propionate 0.05% ointment, clobetasol propionate 0.05% ointment, and betamethasone dipropionate 0.05% ointment for the body. These topical corticosteroids were prescribed to be used alternately, every two (2) weeks to prevent tachyphylaxis and minimize unfavorable side effects. The patient was managed for a total of 32 weeks with minimal improvement, until he was lost to follow-up. DISCUSSION Being a rare disease entity, EBA is estimated to occur in only 0.08 to 0.5 cases per million individuals which only accounts for 5% of the total cases of autoimmune diseases affecting the basement membrane.1 The exact etiology of EBA is unknown, although it is largely associated with the presence of autoantibodies against type VII collagen, which is the major component of anchoring fibrils. The decrease in anchoring fibrils in the basement membrane zone causes separation of the epidermis from the dermis, resulting in the blistering presentation of the disease.2 As it is rarely seen, EBA may be misdiagnosed as other cutaneous diseases that present with vesicles and bullae. In this case, the patient was previously managed as a case of pustular psoriasis before being diagnosed with EBA at our institution. Another pitfall in the diagnosis of EBA is that clinical presentation may change over time. Vesicles and bullae may evolve into erosions and ulcerations, and one may fail to diagnose the patient as a blistering disease if the patient no longer presents with vesicles or bullae at the time of consultation. Thus, good history taking and clinical eye are of utmost importance in clinching the diagnosis. However, there are some cases where EBA may not present with blisters. Non-mechanobullous forms comprise the majority of EBA cases at 55%, while mechanobullous forms comprise only 38% and those with features of both, comprise 7%.3 The classical or mechanobullous form is characterized by the appearance of skin fragility and tense vesicles or bullae with scarring and milia formation; usually noted on the extensor surfaces and trauma-prone areas of the skin.3,4 In contrast, the non-classical or non-mechanobullous form lacks the appearance of blisters but may present with inflammation and urticaria which resolve without scarring and milia formation. This particular patient presented with the classical or mechanobullous form. J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 33 CASE REPORT

The management of EBA is mostly supportive with the goal of minimizing complications. The treatment plan will depend on the severity of the disease. The first-line treatment for mild EBA includes topical corticosteroids and immunomodulators, such as dapsone and colchicine. In severe cases of EBA, patients may be given intravenous immunoglobulins, systemic steroids, and immunosuppressants such as azathioprine and cyclophosphamide.1 Colchicine is usually the first immunomodulator of choice due to its relatively good safety profile and is initiated at dosages between 0.5 and 2.0 mg/day and then increased gradually.4,5 Colchicine acts by modifying collagen synthesis, resulting in structural alterations rendering EBA antigens unrecognizable by autoantibodies.6 In most studies, the therapeutic response was noted as early as 2 weeks.3,6,7 There were two (2) EBA cases reported, in which colchicine was administered initially at 2 mg/day, with total clearance of the lesions achieved at 8-12 weeks.7 However, caution must be taken when administering colchicine as it may lead to diarrhea and abdominal pain.3 Due to partial response, azathioprine was eventually prescribed in our patient, as immunosuppressants are recommended for severe and refractory cases. Azathioprine is usually given at doses between 50-150 mg/day. Its side effects include pancreatitis, fever, rash, malaise, nausea, diarrhea, leukopenia, and hepatitis.1,4 In one retrospective clinical REFERENCES 1. Miyamoto D, Gordilho JO, Santi CG, Porro AM. Epidermolysis Bullosa Acquisita. Anais Brasileiros de Dermatologia. 2022;97(4):409– 23. Available from: http//dx.doi.org/10.1016/j.abd.2021.09.010 2. Woodley, D., et al. "Epidermolysis Bullosa Acquisita". Kang, S. Fitzpatrick's dermatology. New York: McGraw-Hill Education; 2019. 971-991. 3. Kridin K, Kneiber D, Kowalski EH, Valdebran M, Amber KT. Epidermolysis Bullosa Acquisita: A comprehensive review. Autoimmunity Reviews. 2019;18(8):786–95. Available from: http//dx.doi.org/10.1016/j.autrev.2019.06.007 4. Koga H, Prost-Squarcioni C, Iwata H, Jonkman MF, Ludwig RJ, Bieber K. Epidermolysis Bullosa Acquisita: The 2019 update. Frontiers in Medicine. 2019;5. Available from: http//dx.doi.org/10.3389/fmed.2018.00362 5. Patel PM, Jones VA, Murray TN, Amber KT. A review comparing international guidelines for the management of bullous pemphigoid, pemphigoid Gestationis, mucous membrane pemphigoid, and epidermolysis bullosa acquisita. American Journal of Clinical Dermatology. 2020;21(4):557–65. Available from: http//dx.doi.org/10.1007/s40257-020-00513-3 6. Arora KP, Sachdeva B, Singh N, Bhattacharya SN. Remission of recalcitrant epidermolysis bullosa acquisita (EBA) with Colchicine Monotherapy. The Journal of Dermatology. 2005;32(2):114–9. Available from: http//dx.doi.org/10.1111/j.1346-8138.2005.tb00727.x 7. Megahed M, Scharffetter-Kochanek K. Epidermolysis bullosa acquisita ? successful treatment with Colchicine. Archives of Dermatological Research. 1994;286(1):35–40. Available from: http//dx.doi.org/10.1007/BF00375841 8. Kim SC, Kim JH, Kim YH. Epidermolysis Bullosa Acquisita: A retrospective clinical analysis of 30 cases. Acta Dermato Venereologica. 2011;91(3):307–12. Available from: http//dx.doi.org/10.2340/00015555-1065 9. Reddy H, Shipman AR, Wojnarowska F. Epidermolysis bullosa acquisita and inflammatory bowel disease: A review of the literature. Clinical and Experimental Dermatology. 2013;38(3):225–30. Available from: http//dx.doi.org/10.1111/ced.12114 analysis of 30 cases of EBA, one (1) patient was prescribed azathioprine 100 mg after being on a combination of methylprednisolone, dapsone, and colchicine for one (1) month with no remission.8 Combination treatments using steroids, colchicine, and azathioprine have been reported with various results. Pressing forward, the plan for this patient was to find the optimal dose of azathioprine. Moreover, a more indepth gastrointestinal investigation may be warranted in this case, given the association of EBA and inflammatory bowel diseases (IBD) and the patient’s history of constipation. A review of literature from 1969 to 2013 showed a total of 42 recorded cases of EBA co-existing with IBD; most were cases of Crohn’s disease due in part to the presence of type VII collagen autoimmunity in Crohn’s disease.9 CONCLUSION EBA is a rare bullous disease that is very difficult to manage, as exemplified in this particular case. The management of EBA remains challenging, as most cases are refractory to treatment and there are very few randomized controlled trials, given the rarity of the disease. Thus, proper documentation of cases with its corresponding treatment may help guide dermatologists in managing such a rare disease and eventually lead to the development of proper treatment guidelines and algorithms. J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 34 CASE REPORT

Oral sirolimus in the treatment of adult eruptive cherry angiomas Christine Lyka R. Sayson, MD,1 Aira Monica R. Abella, MD,1 Danielle Marlo R. Senador, MD,1 Leilani R. Senador, MD, FPDS,1 Gisella U. Adasa, MD, FPDS1 ABSTRACT INTRODUCTION Cherry angiomas are a common type of acquired vascular proliferation of the skin which manifest as single or multiple bright red spots that usually appear on the trunk and arms. They are generally asymptomatic; patients may opt to remove the lesions for cosmetic reasons and prevention of bleeding. Conventionally, most cherry angiomas are treated with curettage, laser, and electrosurgery. Herein, we report a case of multiple cherry angiomas managed alternatively with oral sirolimus. CASE REPORT A 47-year-old Filipino female presented with a 10-month history of gradually enlarging multiple bright-red papules and pedunculated nodules with a propensity to spontaneously bleed on gentle manipulation involving the scalp and forehead. Clinicopathological correlation suggests a diagnosis of eruptive cherry angiomas. The patient was started on oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor. CONCLUSION We present a case of a patient with eruptive cherry angiomas who experienced significant decrease in size and bleeding with treatment of oral sirolimus with minimal adverse effects. For patients with eruptive cherry angiomas, especially with contraindicated comorbidities, first-line therapeutic option treatments with oral sirolimus can be beneficial. KEYWORDS sirolimus, eruptive hemangiomas, cherry angiomas, vascular malformation 1Department of Dermatology, Research Institute for Tropical Medicine Corresponding author Christine Lyka R. Sayson, MD, [email protected] Conflict of interest None Source of funding None INTRODUCTION Cherry hemangiomas, also known as adult hemangiomas, senile angiomas or Campbell de Morgan spots, are the most common type of acquired vascular proliferation of the skin. These tend to increase in number and size with age.1,2 They usually occur in the third or fourth decade of life and present as small red macules that may appear on both sun-exposed and unexposed skin.2 Lesions present as multiple, bright red, dome-shaped papules measuring 1 to 5 mm in size on the trunk or upper limbs and rarely on hands, feet, and face.1 They are usually asymptomatic, but may bleed with trauma.3 Eruptive cherry angiomas are described as the development of multiple cherry angiomas.4 The etiology is not well-known, however, lesions may be associated with aging, pregnancy, climate, and exposure to chemicals.3 Other predisposing risk factors for the development of cherry angiomas include skin tumors and chronic immunosuppression that suggest imbalance of skin immune competence.5 Cherry angiomas are diagnosed clinically based on characteristic appearance and aided by dermoscopy with the characteristic features of red background, clustered red lacunae, and white surfaces.6 Histopathologic findings show thinned epidermis and many newly developed, polypoid, neovascularized capillaries that have thin narrow lumens along with prominent endothelial cells. The majority of patients have excellent prognosis since most lesions are asymptomatic.1 Some might have complications such as pain, bleeding, and recurring infections affecting quality of life.7 Removal of lesions are most often due to cosmetic reasons or for prevention of complications. Treatment modalities are mostly interventional and surgical including cryosurgery, electrosurgery, curettage, or pulsed dye laser.1 Ideal therapy for patients with vascular malformation would be targeting the cellular pathways involved in the vascular growth and proliferation. SiJ Phil Dermatol Soc • May 2023 • ISSN 2094-201X 35 CASE REPORT

rolimus, a mammalian target of rapamycin (mTOR) inhibitor, targets the regulation of angiogenesis and lymphangiogenesis leading to inhibition of tissue overgrowth.8 Studies reported sirolimus to be safe and effective in the treatment of complicated vascular anomalies.8,9 CASE SUMMARY A 47-year-old Filipino female presented with a 10-month history of a solitary, soft, erythematous papule on the right temporal scalp region after sustaining trauma. The lesion was associated with pruritus, pain, and bleeding with manipulation. It developed into a solitary well-defined, ovoid, smooth, erythematous pedunculated nodule measuring approximately 3x3mm. No interventions were done during this time. Two (2) months prior to consultation, lesions eventually increased in size and number evolving to multiple, well-defined, ovoid, smooth, erythematous nodules measuring approximately 0.5x1mm to 2x2mm now involving the right temporal region. The patient did not complain of any other systemic manifestations such as fever, weight loss, or lymphadenopathy. Patient is hypertensive and maintained on metoprolol. There were no similar lesions described in the family. On physical exam, there were multiple well-defined, ovoid, smooth, erythematous pedunculated aggregated nodules measuring approximately 3x3mm on the scalp and 8x10mm, in its largest diameter on the right temporal region. Dermoscopic examination showed clustered red lacunae and white surfaces on a red background (Figure 1). A 4-mm skin punch biopsy was obtained from the temporal region of the scalp and two (2) tissue samples from the right temple. Hematoxylin and eosin-stained (H&E) sections revealed extravasated red blood cells, numerous capillaries, and thrombosed blood vessels on the scalp. Hyperkeratosis of the stratum corneum and the dermis showed numerous capillaries lined by endothelial cells and dilated medium sized vessels on the right temporal region (Figure 2). These findings were consistent with a hemangioma. Initial laboratory evaluation included complete blood count, lipid profile, liver enzymes, blood urea nitrogen, creatinine, lactate dehydrogenase, peripheral blood smear, chest x-ray, whole abdomen ultrasound, and HIV antibody screening test. Results revealed slightly elevated liver enzymes, creatinine, and cholesterol, while the sonographic report showed cholelithiasis. Patient was prescribed phospholipids capsule and atorvastatin. The patient was initially started with oral sirolimus 1 mg/day for four (4) weeks. After three weeks of sirolimus 1 mg/day, there were increasing oral ulcers with a slight improvement in lesion size. Thus, dose was decreased to 0.5 mg/day. Patient was also given a mixture of sucralfate (4g), aluminum hydroxide and magnesium hydroxide susJ Phil Dermatol Soc • May 2023 • ISSN 2094-201X 36 Figure 1. Dermoscopy on initial consult showed clustered red lacunae (green arrows) and white surfaces on a red background. Figure 2. The dermis showed numerous capillaries lined by endothelial cells and dilated medium sized vessels (H&E, scanning view). CASE REPORT

pension (60 ml), diphenhydramine HCl 12.5 mg/5ml syrup (30 ml), in addition to topical application of benzocaine 20%, menthol 0.1% and zinc chloride 0.15% (Orajel). This regimen provided improvement in the size and number of oral ulcers. At the start of fourth week of treatment, there was a significant decrease in size of the lesions on the forehead and no new lesions were noted. Lower dose of 0.5 mg/day was continued for 14 weeks which showed further decrease in size of the lesions (Figure 3A-D) and no recurrence of oral ulcers. Repeat laboratory workup was done which revealed normal complete blood count, blood urea nitrogen, and creatinine. Cholesterol and liver enzyme levels had decreased from baseline. DISCUSSION Mammalian target of rapamycin (mTOR), a serine/threonine kinase, integrates the signals from phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT). PI3K/AKT/mTOR pathway is involved in cellular processes involving cellular catabolism and anabolism, cell motility, angiogenesis, and cell growth. The mTOR signaling pathway activates angiogenesis and lymphangiogenesis through increasing the expression of the vascular endothelial growth factor (VEGF). Tissue overgrowths leading to vascular anomalies develop when there are errors in the activation of the PI3K/AKT/ mTOR pathway.7,8 Figure 3. Baseline and follow-up photos while on oral sirolimus treatment. A. Initial consult B. Four weeks after initiation of treatment C. Eight weeks of treatment D. Fourteen weeks of treatment. Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. It has anti-proliferative, antiangiogenic, and immunosuppressive properties. The inhibition results in reduced protein synthesis, induction of apoptosis, cell migration inhibition and decreased expression of vascular endothelial growth factor (VEGF).10 By controlling ribosome biogenesis and protein synthesis, sirolimus combines signals from PI3K/AKT pathway to coordinate cell growth and proliferation.8 Sirolimus is considered one of the alternative options for complicated vascular anomalies including tufted angioma, kaposiform hemangioendotheliomas, and arteriovenous malformations.7,8 Systematic reviews on the efficacy and safety of topical and oral sirolimus demonstrated significant improvement in the treatment of vascular tumors related with venous malformations, lymphatic malformations, inflammatory/ autoimmune disorders, and neoplasm.10 Patients treated with sirolimus were observed to have reduction of symptoms and reduction of tumor size.8,9,10 The most common dosing for systemic treatment of sirolimus are initiated at 0.8 mg/m2 body surface twice daily for children and 1 mg twice daily for adults.10 A study used similar dosing regimens where efficacy of sirolimus were evaluated after 1 year of treatment. Reduction in the size of the lesions; reduction of pain, bleeding or oozing; or cessation of infections were observed within three (3) J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 37 CASE REPORT

months from the start of treatment.9 After stopping sirolimus, some patients had recurrence of symptoms, and when treatment was resumed improvements were noted again.8,9 Adverse effects reported with oral sirolimus include mucositis, lipid abnormalities, cytopenias, nausea and vomiting.10 In this case, reduced dose of 0.5 mg/day was given since the patient had oral ulcers on the second week of treatment. Oral ulcers, which eventually resolved, were the only adverse event seen in the patient. For complicated vascular tumors, studies have shown a wide range of treatment duration from 2 to 60 months.7,8 The patient completed 14 weeks of treatment with significant decrease in size of the lesions with minimal adverse effects. CONCLUSION Eruptive hemangiomas are the most common type of acquired vascular proliferation of the skin. As the patient REFERENCES 1. Qadeer HA, Singal A, Patel BC. Cherry Hemangioma. StatPearls Publishing; 2022. 2. Fernandez-Flores A, Colmenero I. Campbell de Morgan spots (cherry angiomas) show endothelial proliferation. Am J Dermatopathol [Internet]. 2018;40(12):894–8. Available from: http://dx.doi.org/10.1097/DAD.0000000000001216 3. Kim J-H, Park H-Y, Ahn SK. Cherry angiomas on the scalp. Case Rep Dermatol [Internet]. 2009;1(1):82–6. Available from: http:// dx.doi.org/10.1159/000251395 4. Betz-Stablein B, Koh U, Edwards HA, McInerney-Leo A, Janda M, Soyer HP. Anatomic distribution of cherry angiomas in the general population. Dermatology [Internet]. 2022;238(1):18–26. Available from: http://dx.doi.org/10.1159/000517172 5. Borghi A, Minghetti S, Battaglia Y, Corazza M. Predisposing factors for eruptive cherry angiomas: New insights from an observational study. Int J Dermatol [Internet]. 2016;55(11):e598–600. Available from: http://dx.doi.org/10.1111/ijd.13330 6. Gao J, Fei W, Shen C, Shen X, Sun M, Xu N, et al. Dermoscopic features summarization and comparison of four types of cutaneous vascular anomalies. Front Med (Lausanne) [Internet]. 2021;8:692060. Available from: http://dx.doi.org/10.3389/fmed.2021.692060 7. Sandbank S, Molho-Pessach V, Farkas A, Barzilai A, Greenberger S. Oral and topical sirolimus for vascular anomalies: A multicentre study and review. Acta Derm Venereol [Internet]. 2019;99(11):990–6. Available from: http://dx.doi.org/10.2340/00015555-3262 8. Adams DM, Trenor CC 3rd, Hammill AM, Vinks AA, Patel MN, Chaudry G, et al. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics [Internet]. 2016;137(2):e20153257. Available from: http://dx.doi.org/10.1542/ peds.2015-3257 9. Hammer J, Seront E, Duez S, Dupont S, Van Damme A, Schmitz S, et al. Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study. Orphanet J Rare Dis [Internet]. 2018;13(1):191. Available from: http://dx.doi.org/10.1186/s13023-018-0934-z 10. Swarbrick AW, Frederiks AJ, Foster RS. Systematic review of sirolimus in dermatological conditions. Australas J Dermatol [Internet]. 2021;62(4):461–9. Available from: http://dx.doi.org/10.1111/ajd.13671 ages, lesions tend to increase in number and size. Oral sirolimus was the treatment option for this case due to the increasing size and number of lesions. On the fourth week of treatment, there was a significant decrease in size and number of lesions. Oral sirolimus offers promising results to capillary hemangiomas not only in the pediatric group but may also be given to adult patients who have capillary hemangiomas. For complicated vascular anomalies, it is recommended to continue sirolimus treatment for 12 to 24 weeks with monthly follow-up to evaluate the progress and monitor for possible adverse effects. This report adds to the growing use of sirolimus in dermatological conditions. Further studies are still warranted, and more patients are needed to test the safety and efficacy of sirolimus. In the best knowledge of the authors, this is the first case report in the Philippines to successfully manage an adult patient with eruptive hemangiomas using oral sirolimus. J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 38 CASE REPORT

Dermoscopic features and management strategy of a 10-year history acral lentiginous melanoma in a 55-year-old Filipino Alexis G. De las Alas, MD,1 Aira Monica R. Abella, MD,1 Kristy Elleza R. Evangelista, MD, FPDS,2 Gisella U. Adasa, MD, FPDS2 ABSTRACT INTRODUCTION Acral lentiginous melanoma (ALM) is the most common type of cutaneous melanoma in Asians that is not associated with ultraviolet radiation (UV) exposure. Dermoscopy enables clinicians to distinguish between benign and malignant acral melanocytic lesions, with some dermoscopic characteristics playing a role in staging and have prognostic implications, which allows for appropriate surgical intervention. The difficulty of making an early diagnosis of ALM is highlighted by this case. ALM’s destructive nature, alongside the patient’s lack of awareness and vigilance, and healthcare access inequality, influences its prognosis. CASE REPORT This is a case of a long-standing acral lentiginous melanoma with no palpable lymphadenopathies in which it was not immediately detected through biopsy. Upon detection, wide excision with 2 cm margins and disarticulation of the 5th digit of the right foot reconstructed with a fasciocutaneous advancement flap with split thickness skin graft, grafted from the right anterior thigh was done. CONCLUSION Patient education and early detection is crucial in disease-specific survival. ALM often confers a poorer prognosis due to more advanced disease at the time of diagnosis. KEYWORDS Acral lentiginous melanoma, dermoscopy, parallel ridge pattern, BRAAFF checklist 1Department of Dermatology, Research Institute for Tropical Medicine
9002 Research Drive, Filinvest Corporate City, Alabang, Muntinlupa 1781, Philippines Corresponding author Alexis G. De las Alas, MD, [email protected] Conflict of interest None Source of funding None INTRODUCTION Acral lentiginous melanoma (ALM) is the most common type of cutaneous melanoma in Asians.1 Only 52 cases were recorded in the Philippine Dermatological Society (PDS) Health Information System (HIS) from 2011- 2016 due to its rarity. This may be due to the inconspicuous location of the lesion, alongside traumatic changes that can delay the diagnosis. Furthermore, ALM may be managed by other surgical specialties, which would not log cases in the PDS-HIS. 2 It accounts for 2-3% of all new melanomas and a sharp increase is seen in incidence per person year after the age of 80.1 If left untreated, life-threatening complications such as metastasis resulting in end organ damage can occur. Misdiagnosis is common in ALM due to its various clinical differentials. In these cases, dermoscopy can improve diagnostic accuracy by distinguishing between benign and malignant acral melanocytic lesions. Identifying dermoscopic features combined with increased awareness about the occurrence of ALM is essential in establishing an early diagnosis leading to increased survival rates and cure. CASE SUMMARY The patient is a 55-year-old Filipino male who initially presented with a 10-year history of a solitary, discrete, black macule on the upper plantar surface of the right foot. The patient previously worked as a farmer for 37 years with a notable history of trauma as the patient reportedly works barefooted. No consult was done, and no medications were taken nor applied. Over time, the lesion gradually increased in size, approximately measuring 2 x 3 cm, extending to the anterior lateral side of the upper plantar surface of the right foot, with areas of crusting, erosions, and excoriations, prompting the patient to seek private dermatology consult. On the first consult, the patient underwent an incisional biopsy revealing post inflammatory hyperpigmenJ Phil Dermatol Soc • May 2023 • ISSN 2094-201X 39 CASE REPORT

tation. Immunohistochemical staining with S100 was suggested but was not done. The patient was prescribed with topical antibiotic resulting in no improvement of the lesion. On the second consult 1 year ago, further increase in size of the lesion with persistence of crusts, erosions and excoriations were noted, hence another incisional biopsy was done. Results revealed ALM and the patient was then referred to our institution for further evaluations and management. Cutaneous examination revealed a solitary, well-defined, irregularly-shaped, tender, blue gray to black plaque with multiple areas of telangiectasias, erosions, excoriations, and ulcerations, measuring 7 x 5 cm, on the anterolateral aspect of the plantar surface of the right foot. (Figure 1). No palpable lymphadenopathies on the inguinal, popliteal, external iliac and obturator region were noted. Dermoscopy revealed multicomponent pattern consisting of a parallel ridge pattern, presence of irregular borders (Figure 2A), blue-white veil, hemorrhagic crusts, areas of ulceration and a white structureless area (Figure 2B). The tissue block was stained with S100, HMB 45 and Melan A for further evaluation (Figure 3) revealing the presence of heavily pigmented cells that formed nests in the superficial and deep dermis. After an interdisciplinary discussion, the patient underwent a wide excision with 2 cm margins and disarticulation of the 5th digit of the right foot (Figure 4A) and reconstruction was done with a fasciocutaneous advancement flap with a split thickness skin graft, grafted from the right anterior thigh (Figure 4B). The specimen was sent for a rush frozen section which showed a Breslow thickness of at least 7-8 mm. Both peripheral and deep margins of resected tissue specimen were negative for malignant melanocytic cells (Figure 4C). Laboratory work ups such as sentinel lymph node biopsy and chest/abdomen CT were ordered but were not done due to financial constraints. Following the American Joint Committee on Cancer (AJCC 8th Edition), the final pathologic diagnosis was Stage IIB - T4N0M0 signifying a mitotic rate of 2 per square mm with no lymphovascular invasion, indicating that the tumor depth invaded the reticular dermis. DISCUSSION ALM in skin of color typically presents as a macule progressing to a patch with variable light to dark brown pigment. It often has angular edges, following the ridges of the dermatoglyphics. As the lesion progresses and invades, it may become nodular and darkly pigmented, appearing J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 40 Figure 1. Cutaneous examination. Presence of a solitary, well-defined, irregularly shaped, tender, blue-gray to black plaque with multiple areas of telangiectasias, erosions, excoriations, and ulcerations, measuring 7 x 5 cm, on the anterolateral aspect of the plantar surface of the right foot. Figure 2. Dermoscopic findings. A. Presence of a parallel ridge pattern (enclosed in a red circle) and irregular borders (pointed by the blue arrows). B. Presence of a multicomponent pattern consisting of blue-white veil (enclosed in blue circles), hemorrhagic crusts (enclosed in yellow circle), areas of ulceration (pointed by the black arrow) and a white structureless area (pointed by the red arrow). Figure 3. Histopathologic findings. A. On low power view at 10x magnification, presence of heavily pigmented cells that formed confluent nests, varying in size and shape throughout the dermis. B. On S100 staining, a strong and diffuse nuclear expression of melanocytes in the dermis was present. C. On HMB 45 staining, the same level of staining of melanocytes in the superficial and deep dermis was present, signifying faulty maturation. D. On Melan A staining, cytoplasmic staining of melanocytes extending until the deep dermis was present. CASE REPORT

blue to black, with some presenting with ulceration.1 Given the unique features of acral sites, melanocytic lesions on the soles may present with many diagnostic challenges.3 Through naked eye alone, it is difficult to distinguish acral melanoma from benign lesions, hence, dermoscopy can be useful in formulating differential diagnoses on acral surfaces, thereby improving diagnostic accuracy in ALM. For ALM, the parallel ridge pattern, seen as a parallel linear pigmentation along the ridges of dermatoglyphics, is the hallmark dermoscopic pattern. The sensitivity and specificity of a parallel ridge pattern for diagnosing early ALM has been shown to be 86% and 99%, respectively.3 In a multicenter study in Japan by Saida et al, the presence of this pattern has shown to have high sensitivity and diagnostic accuracy in melanoma.4 Other dermoscopic patterns in ALM include: an irregular diffuse pigmentation, multicomponent pattern, blue-white veil, and ulceration.4,5 The emergence of validated dermoscopic algorithms can also be used as a guide in the management of pigmented acral lesions. Lallas et al. developed the BRAAFF checklist, a scoring system of six variables: blotches, ridge pattern, asymmetry of structures, asymmetry of colors, parallel furrow pattern, and fibrillar pattern.6 Our patient had dermoscopic findings of an irregular blotch, parallel ridge pattern, asymmetry of structures and colors, earning a BRAAFF score of 6. Lesions that score 1 or higher warrant evaluation for ALM.6 Another algorithm was created by Koga and Saida, incorporating the identification of the parallel ridge pattern or a lesion >7 mm in diameter without a typical benign pattern.7 Our patient presents with a parallel ridge pattern on dermoscopy and a lesion >7mm, thus performing a biopsy is warranted in this case. Additional stains were requested to further confirm the histopathologic diagnosis and establish an appropriate work up and management for this patient. Post-operatively, the patient was instructed to do daily wound care and intake of prescribed medications. The patient was advised to have an annual whole body skin examination,8 observation for the presence of satellite lesions on the post operative site, and follow-up visits with his medical oncology, plastic & general surgery, and dermatology specialists. Some dermoscopic features play a role in the AJCC staging system and have prognostic implications in melanoma. The presence of “shiny-white streaks", "milky-red areas" and a "blue-whitish veil" in dermoscopy was found to be highly associated with an ulceration in histology and a mitotic rate of more than 1/mm2. Also, the presence of ulceration further leads to classification into B of stage I, II and III tumors. In correlation with prognostic estimation, the presence of these dermoscopic features was found to be highly associated with distant metastases.9 The prognosis of ALM in Asians are affected by several factors, such as the duration of the lesion before diagnosis, Breslow thickness > 4.0 mm, high mitotic index, presence of vascular invasion, regional lymph node metastasis at diagnosis and its pathologic stage, along with its dermoscopic features.9,10 For this case, given the following factors, the patient has a prognosis of 53.3% and 27.4% for 5- and 10-year disease-specific survival rates, respectively.10 CONCLUSION The incidence of ALM is increasing worldwide. Here is a rare case of an ALM patient with a 10-year history. The patient presented with a chronic course of ALM, a condition where immediate management is crucial. In addition, our paper focuses on the importance of dermoscopy as diagnostic tool for ALM. The use of dermoscopy aids in the diagnosis of ALM, especially in early stages. Since the survival and prognosis of ALM depends on the early diagnosis, the need for patient education and increased doctor’s awareness of the clinical and dermoscopic features of ALM is vital for the cost-effective treatment and prevention of this deadly cancer. J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 41 Figure 4. Surgical Procedure. A. Wide excision with 2 cm margins and disarticulation of the 5th digit of the right foot. B. Fasciocutaneous advancement flap with split thickness skin graft, grafted from the right anterior thigh. C. Frozen section findings of Breslow thickness of at least 7-8 mm. Both peripheral and deep margins of resected tissue specimen were negative for malignant melanocytic cells. CASE REPORT

ACKNOWLEDGMENTS We would like to thank Dr. Anne Kristine Villalon of the Department of Surgery in Salve Regina General Hospital, for managing the patient and Dr. Johaness Dayrit of the Department of Dermatology in Research Institute for Tropical Medicine for interpreting the immunohistochemical stain results. REFERENCES 1. Brunsgaard E, Wu YP, Grossman D. Melanoma in Skin of Color: Part I. Epidemiology and clinical presentation. J Am Acad Dermatol [Internet]. 2022; Available from: http://dx.doi.org/10.1016/j.jaad.2022.04.056 2. Milana-Martinez JKT, Zabala DAR, Lim KAT, Lacuesta-Gutierrez MPM, Visitacion LR. Acral lentiginous melanoma treated by wide excision with split-thickness skin graft: case in images [Internet]. SPMC J Health Care Serv. 2017. Available from: http://n2t.net/ ark:/76951/jhcs8wut85 3. Tan A, Stein JA. Dermoscopic patterns of acral melanocytic lesions in skin of color. Cutis. 2019;103(5):274–6. 4. Saida T, Miyazaki A, Oguchi S, Ishihara Y, Yamazaki Y, Murase S, et al. Significance of dermoscopic patterns in detecting malignant melanoma on acral volar skin: results of a multicenter study in Japan: Results of a multicenter study in japan. Arch Dermatol [Internet]. 2004;140(10):1233–8. Available from: http://dx.doi.org/10.1001/archderm.140.10.1233 5. Kim SY, Yun SJ. Cutaneous melanoma in Asians. Chonnam Med J [Internet]. 2016;52(3):185–93. Available from: http://dx.doi. org/10.4068/cmj.2016.52.3.185 6. Lallas A, Kyrgidis A, Koga H, Moscarella E, Tschandl P, Apalla Z, et al. The BRAAFF checklist: a new dermoscopic algorithm for diagnosing acral melanoma. Br J Dermatol [Internet]. 2015;173(4):1041–9. Available from: http://dx.doi.org/10.1111/bjd.14045 7. Koga H, Saida T. Revised 3-step dermoscopic algorithm for the management of acral melanocytic lesions. Arch Dermatol [Internet]. 2011;147(6):741–3. Available from: http://dx.doi.org/10.1001/archdermatol.2011.136 8. Johnson MM, Leachman SA, Aspinwall LG, Cranmer LD, Curiel-Lewandrowski C, Sondak VK, et al. Skin cancer screening: recommendations for data-driven screening guidelines and a review of the US Preventive Services Task Force controversy. Melanoma Manag [Internet]. 2017;4(1):13–37. Available from: http://dx.doi.org/10.2217/mmt-2016-0022 9. Deinlein T, Arzberger E, Zalaudek I, Massone C, Garcias-Ladaria J, Oliveira A, et al. Dermoscopic characteristics of melanoma according to the criteria “ulceration” and “mitotic rate” of the AJCC 2009 staging system for melanoma. PLoS One [Internet]. 2017;12(4):e0174871. Available from: http://dx.doi.org/10.1371/journal.pone.0174871 10. Lv J, Dai B, Kong Y, Shen X, Kong J. Acral melanoma in Chinese: A clinicopathological and prognostic study of 142 cases. Sci Rep [Internet]. 2016;6:31432. Available from: http://dx.doi.org/10.1038/srep31432 J Phil Dermatol Soc • May 2023 • ISSN 2094-201X 42 CASE REPORT