Emerging Insights in Keloid Pathogenesis and Therapeutics

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Emerging Insights in Keloid Pathogenesis and Therapeutics
Author(s)
Noelle Desir, BA
Iain Noel Encarnacion, MS
Susan C. Taylor, MD

Keloids are fibroproliferative lesions caused by aberrant wound healing in predisposed individuals.1 While keloids have been reported in patients of all races and ethnicities, they most commonly develop in individuals of African or Asian descent.2 Often associated with symptoms such as pain and itching, keloids can be disfiguring and result in poorer quality of life.3 There is a paucity of research on keloid pathogenesis and efficacious therapeutics, particularly in patients with skin of color (SOC). Herein, we outline the current research on keloid treatment and highlight promising new therapies ranging from innovative intralesional techniques to advanced laser-based and biologic therapies.

Deficiencies in Skin of Color Research

Although keloids are 17 times more prevalent in patients with SOC,4 there is a considerable lack of focus on this population in the literature.5 Studies on keloids that include individuals with SOC often group patients of all skin types together, and subgroup analyses are not always performed.6,7 As a result, dermatologists may face considerable challenges in providing effective treatments for keloids in patients with SOC. With few evidence-based options available, patients with SOC who have keloids continue to experience impairments in quality of life.

Common Keloid Therapies

There currently is no gold-standard treatment for keloids. Common therapeutic modalities include intralesional corticosteroids (ILCs), antineoplastic agents and neuromodulators, laser-based devices, and surgical therapies (eg, excision), as well as combined medical and surgical techniques.8

Intralesional Corticosteroids—Minimally invasive ILCs are the first-line treatment in all patients with keloids, regardless of skin phototype. Because keloid formation results from trauma to the skin, ILCs often are recommended to minimize further skin damage.5 One meta-analysis found that ILCs have demonstrated success rates of 50% to 100%9; however, these studies frequently combine ILCs with other treatment modalities, and few studies have focused on the efficacy of ILC monotherapy in patients with SOC.6,10-13

Antineoplastic Agents and Neuromodulators—Certain antineoplastic agents (eg, 5-fluorouracil [5-FU] and bleomycin) and neuromodulators (eg, botulinum toxin A [BTA]) also have been studied in keloid management.8

5-Fluorouracil frequently is combined with ILCs such as triamcinolone (TAC). Combined therapy is more effective than TAC monotherapy in scar height reduction.14,15 Rates of adverse events such as dyspigmentation, atrophy, and telangiectasias also were lower in patients who received combined therapy.14,15 A systematic review found that intralesional bleomycin may be more effective than TAC alone, 5-FU alone, TAC combined with 5-FU, and TAC combined with cryotherapy; however, hyperpigmentation was a common adverse event, occurring in roughly 70% (42/60) of patients.16,17 Additionally, a 2024 meta-analysis evaluated 20 randomized controlled trials comprising 1114 patients treated with intralesional TAC, 5-FU, BTA, verapamil, and/or bleomycin. Botulinum toxin A and TAC plus 5-FU were found to have outstanding therapeutic efficacy for keloids, and rates of adverse events were similar among users of TAC, 5-FU, BTA, and TAC plus 5-FU.18

While antineoplastic agents and BTA may be promising keloid therapies, further studies demonstrating their efficacy and safety profiles are necessary, particularly regarding dyspigmentation as a potential adverse event, as this may be of concern in patients with darker phototypes.

Laser Therapies—Of all treatment modalities, laser-based keloid therapies have been the most robustly studied in SOC. The 2 main types are ablative (eg, CO2, Er:YAG) and nonablative (eg, pulsed dye, Nd:YAG) lasers. Ablative lasers rapidly heat water molecules within the skin, thereby vaporizing the skin cells in a controlled precise process that reduces scar tissue by removing layers of skin. Nonablative lasers target hemoglobin in blood vessels, reducing oxygen supply and inducing collagen remodeling without damaging the epidermis.19

For patients with SOC, lasers carry a risk for postinflammatory hyperpigmentation.20 To address this risk, recent advancements in laser technology and procedural protocols have aimed to minimize the number of passes and utilize cooling devices21; however, many of these recommendations are based on retrospective reviews and small case series. A 2024 meta-analysis comprising 550 patients found that the combination of fractional CO2 laser therapy and 5-FU was the most effective intervention, markedly reducing Vancouver Scar Scale and pliability scores as well as keloid thickness.22 Conversely, pulsed dye lasers were the least effective in terms of improving scar thickness, pigmentation, and pliability when compared to other treatments.

Randomized controlled trials of laser-based therapies in patients with SOC are lacking in the literature. Future studies should focus on calibrating laser-based therapies for those with darker skin tones and examine the efficacy and adverse effects of ablative and nonablative lasers in patients with SOC.

Promising New Keloid Therapies

Keloid disease pathogenesis is incompletely understood, but several new therapeutic targets have been highlighted in the literature, including dupilumab, pentoxifylline, sirtuin 6 (SIRT6) modulators, remdesivir, and needle-assisted electrocoagulation plus pharmacotherapy.

Dupilumab—An anti–IL-4 and IL-13 monoclonal antibody, dupilumab was first approved for the treatment of severe atopic dermatitis. Its use has broadened since its approval, and keloids have been identified as a potential therapeutic target. A 2019 case study described a 53-year-old Black man with severe atopic dermatitis and chronic keloids that regressed with systemic dupilumab therapy.23 This prompted a follow-up case-control study using real-time polymerase chain reaction testing to evaluate Th2 gene expression (IL-4R, IL-13, and CCL18) of lesional and nonlesional tissue in 3 Black patients with chronic keloids and no concurrent atopic dermatitis vs 5 healthy Black controls.Despite the limited sample size, a significant increase in IL-13 and the Th2 chemokine CCL18 was found in patients with keloids compared to controls (P<.05), suggesting that the entire integument of patients with severe keloids is abnormal.23 This finding supports the use of systemic treatments for chronic and multifocal keloid disease. Several subsequent case reports have corroborated the efficacy of systemic and/or intralesional dupilumab.24,25 However, some studies have reported contradictory findings, suggesting the need for high-quality clinical trials.26,27

Pentoxifylline—Pentoxifylline is a methylated xanthine derivative and a nonspecific phosphodiesterase ­inhibitor used to treat claudication from peripheral artery disease. It also inhibits the proliferation and rate of collagen synthesis of fibroblasts from keloids in vitro.28,29 A 2019 retrospective, open-label pilot study analyzed postsurgical keloid recurrence in 45 patients with 67 unique keloids that were stratified into low- and high-risk groups based on clinical factors including multiple symptomatic keloids, history of recurrence, and family history.30 Both the low- and the high-risk groups were treated with 40 mg/mL intralesional triamcinolone acetonide monthly for 6 months; however, some of the high-risk keloids also received pentoxifylline 300 mg 3 times daily for 6 months. There was a statistically significant decrease in keloid recurrence rate between the high-risk group treated with pentoxifylline and the low-risk group for whom pentoxifylline was not prescribed (P=.015).

Similarly, a randomized clinical trial comparing the efficacy of combination intralesional pentoxifylline and intralesional triamcinolone vs monotherapy with pentoxifylline or triamcinolone found the most significant improvement in the combination cohort with reduction in keloid height (P=.04), pliability (P=.003), and vascularity (P=.05).31 These findings highlight the need for supplementary studies on the use of pentoxifylline for keloid therapy.

SIRT6 Modulators—SIRT6 modulators are an exciting future therapeutic target. In a recent case-control study evaluating the histologic milieu of keloid tissue vs normal skin specimens, the researchers found that selective overexpression of SIRT6 via the use of a recombinant adenovirus in keloid fibroblasts attenuated proliferation, invasion, and collagen synthesis while fostering apoptosis, likely through the suppression of MAPK/ERK pathway activity.32

Remdesivir—The antiviral drug remdesivir has been reported to have pharmacologic activities in a wide range of fibrotic diseases, including keloids. A 2024 study explored the potential effect and mechanisms of remdesivir on skin fibrosis both in vitro and in rodents.33 Remdesivir was found to decrease skin fibrosis and attenuate the gross weight of keloid tissues in vivo, suppress fibroblast activation and autophagy both in vivo and in vitro, dampen fibroblast activation by the TGF-β1/Smad signaling pathway, and inhibit fibroblasts autophagy by the PI3K/Akt/mTOR signaling pathway. These results demonstrate the therapeutic potential of remdesivir for keloid management.

Needle-Assisted Electrocoagulation Plus Pharmacotherapy—A novel needle-assisted electrocoagulation technique combined with pharmacotherapy (corticosteroid and 5-FU injections) was effective in a Chinese clinical trial involving 6 patients with keloids.34 Investigators used Vancouver Scar Scale and both Patient and Observer Scar Assessment Scale scores to grade patients’ scars before treatment and 1 month after the first treatment cycle. They found that ablation combined with pharmacotherapy significantly reduced all 3 scores without any obvious adverse events (P=.004, P=.006, and P=.017, respectively). This novel combination treatment may serve as a safe and effective therapeutic approach for keloid removal.

Final Thoughts

Emerging treatments offer promising new horizons in keloid management; however, the lack of robust, high-quality clinical trials, especially those focusing on SOC, underscores a pressing need for comprehensive and inclusive studies. There is much work to be done to close the existing knowledge gap, and future studies must be more intentional with recruitment, assuring that the patients who are disproportionately affected by these lesions are represented in study populations.

References
  1. Téot L, Mustoe TA, Middelkoop E, eds. Textbook on Scar Management: State of the Art Management and Emerging Technologies. Springer; 2020.
  2. Davis SA, Feldman SR, McMichael AJ. Management of keloids in the United States, 1990-2009: an analysis of the National Ambulatory Medical Care Survey. Dermatol Surg. 2013;39:988-994. doi:10.1111/dsu.12182
  3. Kassi K, Kouame K, Kouassi A, et al. Quality of life in black African patients with keloid scars. Dermatol Reports. 2020;12:8312. doi:10.4081/dr.2020.8312
  4. Delaleu J, Charvet E, Petit A. Keloid disease: review with clinical atlas. part I: definitions, history, epidemiology, clinics and diagnosis. Ann Dermatol Venereol. 2023;150:3-15. doi:10.1016/j.annder.2022.08.010
  5. Bronte J, Zhou C, Vempati A, et al. A comprehensive review of non-surgical treatments for hypertrophic and keloid scars in skin of color. Clin Cosmet Investig Dermatol. 2024;17:1459-1469. doi:10.2147/CCID.S470997
  6. Davison SP, Dayan JH, Clemens MW, et al. Efficacy of intralesional 5-fluorouracil and triamcinolone in the treatment of keloids. Aesthet Surg J. 2009;29:40-46. doi:10.1016/j.asj.2008.11.006
  7. Azzam OA, Bassiouny DA, El-Hawary MS, et al. Treatment of hypertrophic scars and keloids by fractional carbon dioxide laser: a clinical, histological, and immunohistochemical study. Lasers Med Sci. 2016;31:9-18. doi:10.1007/s10103-015-1824-4
  8. Ekstein SF, Wyles SP, Moran SL, et al. Keloids: a review of therapeutic management. Int J Dermatol. 2021;60:661-671. doi:10.1111/ijd.15159
  9. Morelli Coppola M, Salzillo R, Segreto F, et al. Triamcinolone acetonide intralesional injection for the treatment of keloid scars: patient selection and perspectives. Clin Cosmet Investig Dermatol. 2018;11:387-396. doi:10.2147/CCID.S133672
  10. Kant SB, van den Kerckhove E, Colla C, et al. A new treatment of hypertrophic and keloid scars with combined triamcinolone and verapamil: a retrospective study. Eur J Plast Surg. 2018;41:69-80. doi:10.1007/s00238-017-1322-y
  11. Cohen AJ, Talasila S, Lazarevic B, et al. Combination cryotherapy and intralesional corticosteroid versus steroid monotherapy in the treatment of keloids. J Cosmet Dermatol. 2023;22:932-936. doi:10.1111/jocd.15520
  12. Tawaranurak N, Pliensiri P, Tawaranurak K. Combination of fractional carbon dioxide laser and topical triamcinolone vs intralesional triamcinolone for keloid treatment: a randomised clinical trial. Int Wound J. 2022;19:1729-1735. doi:10.1111/iwj.13775
  13. Belie O, Ugburo AO, Mofikoya BO, et al. A comparison of intralesional verapamil and triamcinolone monotherapy in the treatment of keloids in an African population. Niger J Clin Pract. 2021;24:986-992. doi:10.4103/njcp.njcp_474_20
  14. Khalid FA, Mehrose MY, Saleem M, et al. Comparison of efficacy and safety of intralesional triamcinolone and combination of triamcinolone with 5-fluorouracil in the treatment of keloids and hypertrophic scars: randomised control trial. Burns. 2019;45:69-75. doi:10.1016/j.burns.2018.08.011
  15. Asilian A, Darougheh A, Shariati F. New combination of triamcinolone, 5-Fluorouracil, and pulsed-dye laser for treatment of keloid and hypertrophic scars. Dermatol Surg. 2006;32:907-915. doi:10.1111/j.1524-4725.2006.32195.x
  16. Kim WI, Kim S, Cho SW, et al. The efficacy of bleomycin for treating keloid and hypertrophic scar: a systematic review and meta-analysis. J Cosmet Dermatol. 2020;19:3357-3366. doi:10.1111/jocd.13390
  17. Kabel A, Sabry H, Sorour N, et al. Comparative study between intralesional injection of bleomycin and 5-fluorouracil in the treatment of keloids and hypertrophic scars. J Dermatol Dermatol Surg. 2016;20:32-38.
  18. Yang HA, Jheng WL, Yu J, et al. Comparative efficacy of drug interventions for keloids: a network meta-analysis. Ann Plast Surg. 2024;92(1S suppl 1):S52-S59. doi:10.1097/SAP.0000000000003759
  19. Preissig J, Hamilton K, Markus R. Current laser resurfacing technologies: a review that delves beneath the surface. Semin Plast Surg. 2012;26:109-116. doi:10.1055/s-0032-1329413
  20. Bin Dakhil A, Shadid A, Altalhab S. Post-inflammatory hyperpigmentation after carbon dioxide laser: review of prevention and risk factors. Dermatol Reports. 2023;15:9703. doi:10.4081/dr.2023.9703
  21. Kaushik SB, Alexis AF. Nonablative fractional laser resurfacing in skin of color: evidence-based review. J Clin Aesthet Dermatol. 2017;10:51-67.
  22. Foppiani JA, Khaity A, Al-Dardery NM, et al. Laser therapy in hypertrophic and keloid scars: a systematic review and network meta-analysis. Aesthetic Plast Surg. Published May 17, 2024. doi:10.1007/s00266-024-04027-9
  23. Diaz A, Tan K, He H, et al. Keloid lesions show increased IL-4/IL-13 signaling and respond to Th2-targeting dupilumab therapy. J Eur Acad Dermatol Venereol. 2020;34:E161-E164. doi:10.1111/jdv.16097
  24. Min MS, Mazori DR, Lee MS, et al. Successful treatment of keloids and hypertrophic scars with systemic and intralesional dupilumab. J Drugs Dermatol. 2023;22:1220-1222. doi:10.36849/JDD.6385
  25. Wittmer A, Finklea L, Joseph J. Effects of dupilumab on keloid stabilization and prevention. JAAD Case Rep. 2023;37:103-105. doi:10.1016/j.jdcr.2023.05.001
  26. Luk K, Fakhoury J, Ozog D. Nonresponse and progression of diffuse keloids to dupilumab therapy. J Drugs Dermatol. 2022;21:197-199. doi:10.36849/jdd.6252
  27. Tirgan MH, Uitto J. Lack of efficacy of dupilumab in the treatment of keloid disorder. J Eur Acad Dermatol Venereol. 2022;36:E120-E122. doi:10.1111/jdv.17669
  28. Berman B, Duncan MR. Pentoxifylline inhibits the proliferation of human fibroblasts derived from keloid, scleroderma and morphoea skin and their production of collagen, glycosaminoglycans and fibronectin. Br J Dermatol. 1990;123:339-346. doi:10.1111/j.1365-2133.1990.tb06294.x
  29. Berman B, Duncan MR. Pentoxifylline inhibits normal human dermal fibroblast in vitro proliferation, collagen, glycosaminoglycan, and fibronectin production, and increases collagenase activity. J Invest Dermatol. 1989;92:605-610.
  30. Tan A, Martinez Luna O, Glass DA 2nd. Pentoxifylline for the prevention of postsurgical keloid recurrence. Dermatol Surg. 2020;46:1353-1356. doi:10.1097/DSS.0000000000002090
  31. Serag-Eldin YMA, Mahmoud WH, Gamea MM, et al. Intralesional pentoxifylline, triamcinolone acetonide, and their combination for treatment of keloid scars. J Cosmet Dermatol. 2021;20:3330-3340. doi:10.1111/jocd.14305
  32. Zhou T, Chen Y, Wang C, et al. SIRT6 inhibits the proliferation and collagen synthesis of keloid fibroblasts through MAPK/ERK pathway. Discov Med. 2024;36:1430-1440. doi:10.24976/Discov.Med.202436186.133
  33. Zhang J, Zhang X, Guo X, et al. Remdesivir alleviates skin fibrosis by suppressing TGF-β1 signaling pathway. PLoS One. 2024;19:E0305927. doi:10.1371/journal.pone.0305927
  34. Zhao J, Zhai X, Xu Z, et al. Novel needle-type electrocoagulation and combination pharmacotherapy: basic and clinical studies on efficacy and safety in treating keloids. J Cosmet Dermatol. doi:10.1111/jocd.16453
Article PDF
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Author and Disclosure Information

Noelle Desir is from Weill Cornell Medical College, New York, New York. Iain Noel Encarnacion is from Eastern Virginia Medical School, Norfolk. Dr. Taylor is from the Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Noelle Desir and Iain Noel Encarnacion have no relevant financial disclosures to report. Dr. Taylor has served as a consultant, advisory board member, investigator, and/or speaker for AbbVie, Allergan Aesthetics, Arcutis, Armis Biopharma, Avita Medical, Beiersdorf, Biorez, Bristol-Myers Squibb, Cara Therapeutics, Catalyst Medical Education, Concert Pharmaceuticals, Croma-Pharma GmbH, Dermsquared, Dior, Eli Lilly and Company, EPI Health, Estée Lauder, Evolus, Galderma, GloGetter, Hugel America, Incyte, Johnson & Johnson Innovate Medicine, LearnSkin, L’Oreal USA, Medscape, MJH Life Sciences, Pfizer, Piction Health, Sanofi, Scientis US, UCB, and Vichy Laboratories. She also serves on the board of directors for Mercer Strategies; has received stock options for Armis Biopharma, GloGetter, and Piction Health; and has received royalties from McGraw-Hill.

Correspondence: Susan C. Taylor, MD, Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104 (susan.taylor@pennmedicine.upenn.edu).

Cutis. 2024 November;114(5):137-139. doi:10.12788/cutis.1122

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Noelle Desir, BA
Iain Noel Encarnacion, MS
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Iain Noel Encarnacion, MS
Susan C. Taylor, MD
Author and Disclosure Information

Noelle Desir is from Weill Cornell Medical College, New York, New York. Iain Noel Encarnacion is from Eastern Virginia Medical School, Norfolk. Dr. Taylor is from the Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Noelle Desir and Iain Noel Encarnacion have no relevant financial disclosures to report. Dr. Taylor has served as a consultant, advisory board member, investigator, and/or speaker for AbbVie, Allergan Aesthetics, Arcutis, Armis Biopharma, Avita Medical, Beiersdorf, Biorez, Bristol-Myers Squibb, Cara Therapeutics, Catalyst Medical Education, Concert Pharmaceuticals, Croma-Pharma GmbH, Dermsquared, Dior, Eli Lilly and Company, EPI Health, Estée Lauder, Evolus, Galderma, GloGetter, Hugel America, Incyte, Johnson & Johnson Innovate Medicine, LearnSkin, L’Oreal USA, Medscape, MJH Life Sciences, Pfizer, Piction Health, Sanofi, Scientis US, UCB, and Vichy Laboratories. She also serves on the board of directors for Mercer Strategies; has received stock options for Armis Biopharma, GloGetter, and Piction Health; and has received royalties from McGraw-Hill.

Correspondence: Susan C. Taylor, MD, Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104 (susan.taylor@pennmedicine.upenn.edu).

Cutis. 2024 November;114(5):137-139. doi:10.12788/cutis.1122

Author and Disclosure Information

Noelle Desir is from Weill Cornell Medical College, New York, New York. Iain Noel Encarnacion is from Eastern Virginia Medical School, Norfolk. Dr. Taylor is from the Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Noelle Desir and Iain Noel Encarnacion have no relevant financial disclosures to report. Dr. Taylor has served as a consultant, advisory board member, investigator, and/or speaker for AbbVie, Allergan Aesthetics, Arcutis, Armis Biopharma, Avita Medical, Beiersdorf, Biorez, Bristol-Myers Squibb, Cara Therapeutics, Catalyst Medical Education, Concert Pharmaceuticals, Croma-Pharma GmbH, Dermsquared, Dior, Eli Lilly and Company, EPI Health, Estée Lauder, Evolus, Galderma, GloGetter, Hugel America, Incyte, Johnson & Johnson Innovate Medicine, LearnSkin, L’Oreal USA, Medscape, MJH Life Sciences, Pfizer, Piction Health, Sanofi, Scientis US, UCB, and Vichy Laboratories. She also serves on the board of directors for Mercer Strategies; has received stock options for Armis Biopharma, GloGetter, and Piction Health; and has received royalties from McGraw-Hill.

Correspondence: Susan C. Taylor, MD, Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104 (susan.taylor@pennmedicine.upenn.edu).

Cutis. 2024 November;114(5):137-139. doi:10.12788/cutis.1122

Article PDF
CT114005137.pdf
Article PDF
CT114005137.pdf

Keloids are fibroproliferative lesions caused by aberrant wound healing in predisposed individuals.1 While keloids have been reported in patients of all races and ethnicities, they most commonly develop in individuals of African or Asian descent.2 Often associated with symptoms such as pain and itching, keloids can be disfiguring and result in poorer quality of life.3 There is a paucity of research on keloid pathogenesis and efficacious therapeutics, particularly in patients with skin of color (SOC). Herein, we outline the current research on keloid treatment and highlight promising new therapies ranging from innovative intralesional techniques to advanced laser-based and biologic therapies.

Deficiencies in Skin of Color Research

Although keloids are 17 times more prevalent in patients with SOC,4 there is a considerable lack of focus on this population in the literature.5 Studies on keloids that include individuals with SOC often group patients of all skin types together, and subgroup analyses are not always performed.6,7 As a result, dermatologists may face considerable challenges in providing effective treatments for keloids in patients with SOC. With few evidence-based options available, patients with SOC who have keloids continue to experience impairments in quality of life.

Common Keloid Therapies

There currently is no gold-standard treatment for keloids. Common therapeutic modalities include intralesional corticosteroids (ILCs), antineoplastic agents and neuromodulators, laser-based devices, and surgical therapies (eg, excision), as well as combined medical and surgical techniques.8

Intralesional Corticosteroids—Minimally invasive ILCs are the first-line treatment in all patients with keloids, regardless of skin phototype. Because keloid formation results from trauma to the skin, ILCs often are recommended to minimize further skin damage.5 One meta-analysis found that ILCs have demonstrated success rates of 50% to 100%9; however, these studies frequently combine ILCs with other treatment modalities, and few studies have focused on the efficacy of ILC monotherapy in patients with SOC.6,10-13

Antineoplastic Agents and Neuromodulators—Certain antineoplastic agents (eg, 5-fluorouracil [5-FU] and bleomycin) and neuromodulators (eg, botulinum toxin A [BTA]) also have been studied in keloid management.8

5-Fluorouracil frequently is combined with ILCs such as triamcinolone (TAC). Combined therapy is more effective than TAC monotherapy in scar height reduction.14,15 Rates of adverse events such as dyspigmentation, atrophy, and telangiectasias also were lower in patients who received combined therapy.14,15 A systematic review found that intralesional bleomycin may be more effective than TAC alone, 5-FU alone, TAC combined with 5-FU, and TAC combined with cryotherapy; however, hyperpigmentation was a common adverse event, occurring in roughly 70% (42/60) of patients.16,17 Additionally, a 2024 meta-analysis evaluated 20 randomized controlled trials comprising 1114 patients treated with intralesional TAC, 5-FU, BTA, verapamil, and/or bleomycin. Botulinum toxin A and TAC plus 5-FU were found to have outstanding therapeutic efficacy for keloids, and rates of adverse events were similar among users of TAC, 5-FU, BTA, and TAC plus 5-FU.18

While antineoplastic agents and BTA may be promising keloid therapies, further studies demonstrating their efficacy and safety profiles are necessary, particularly regarding dyspigmentation as a potential adverse event, as this may be of concern in patients with darker phototypes.

Laser Therapies—Of all treatment modalities, laser-based keloid therapies have been the most robustly studied in SOC. The 2 main types are ablative (eg, CO2, Er:YAG) and nonablative (eg, pulsed dye, Nd:YAG) lasers. Ablative lasers rapidly heat water molecules within the skin, thereby vaporizing the skin cells in a controlled precise process that reduces scar tissue by removing layers of skin. Nonablative lasers target hemoglobin in blood vessels, reducing oxygen supply and inducing collagen remodeling without damaging the epidermis.19

For patients with SOC, lasers carry a risk for postinflammatory hyperpigmentation.20 To address this risk, recent advancements in laser technology and procedural protocols have aimed to minimize the number of passes and utilize cooling devices21; however, many of these recommendations are based on retrospective reviews and small case series. A 2024 meta-analysis comprising 550 patients found that the combination of fractional CO2 laser therapy and 5-FU was the most effective intervention, markedly reducing Vancouver Scar Scale and pliability scores as well as keloid thickness.22 Conversely, pulsed dye lasers were the least effective in terms of improving scar thickness, pigmentation, and pliability when compared to other treatments.

Randomized controlled trials of laser-based therapies in patients with SOC are lacking in the literature. Future studies should focus on calibrating laser-based therapies for those with darker skin tones and examine the efficacy and adverse effects of ablative and nonablative lasers in patients with SOC.

Promising New Keloid Therapies

Keloid disease pathogenesis is incompletely understood, but several new therapeutic targets have been highlighted in the literature, including dupilumab, pentoxifylline, sirtuin 6 (SIRT6) modulators, remdesivir, and needle-assisted electrocoagulation plus pharmacotherapy.

Dupilumab—An anti–IL-4 and IL-13 monoclonal antibody, dupilumab was first approved for the treatment of severe atopic dermatitis. Its use has broadened since its approval, and keloids have been identified as a potential therapeutic target. A 2019 case study described a 53-year-old Black man with severe atopic dermatitis and chronic keloids that regressed with systemic dupilumab therapy.23 This prompted a follow-up case-control study using real-time polymerase chain reaction testing to evaluate Th2 gene expression (IL-4R, IL-13, and CCL18) of lesional and nonlesional tissue in 3 Black patients with chronic keloids and no concurrent atopic dermatitis vs 5 healthy Black controls.Despite the limited sample size, a significant increase in IL-13 and the Th2 chemokine CCL18 was found in patients with keloids compared to controls (P<.05), suggesting that the entire integument of patients with severe keloids is abnormal.23 This finding supports the use of systemic treatments for chronic and multifocal keloid disease. Several subsequent case reports have corroborated the efficacy of systemic and/or intralesional dupilumab.24,25 However, some studies have reported contradictory findings, suggesting the need for high-quality clinical trials.26,27

Pentoxifylline—Pentoxifylline is a methylated xanthine derivative and a nonspecific phosphodiesterase ­inhibitor used to treat claudication from peripheral artery disease. It also inhibits the proliferation and rate of collagen synthesis of fibroblasts from keloids in vitro.28,29 A 2019 retrospective, open-label pilot study analyzed postsurgical keloid recurrence in 45 patients with 67 unique keloids that were stratified into low- and high-risk groups based on clinical factors including multiple symptomatic keloids, history of recurrence, and family history.30 Both the low- and the high-risk groups were treated with 40 mg/mL intralesional triamcinolone acetonide monthly for 6 months; however, some of the high-risk keloids also received pentoxifylline 300 mg 3 times daily for 6 months. There was a statistically significant decrease in keloid recurrence rate between the high-risk group treated with pentoxifylline and the low-risk group for whom pentoxifylline was not prescribed (P=.015).

Similarly, a randomized clinical trial comparing the efficacy of combination intralesional pentoxifylline and intralesional triamcinolone vs monotherapy with pentoxifylline or triamcinolone found the most significant improvement in the combination cohort with reduction in keloid height (P=.04), pliability (P=.003), and vascularity (P=.05).31 These findings highlight the need for supplementary studies on the use of pentoxifylline for keloid therapy.

SIRT6 Modulators—SIRT6 modulators are an exciting future therapeutic target. In a recent case-control study evaluating the histologic milieu of keloid tissue vs normal skin specimens, the researchers found that selective overexpression of SIRT6 via the use of a recombinant adenovirus in keloid fibroblasts attenuated proliferation, invasion, and collagen synthesis while fostering apoptosis, likely through the suppression of MAPK/ERK pathway activity.32

Remdesivir—The antiviral drug remdesivir has been reported to have pharmacologic activities in a wide range of fibrotic diseases, including keloids. A 2024 study explored the potential effect and mechanisms of remdesivir on skin fibrosis both in vitro and in rodents.33 Remdesivir was found to decrease skin fibrosis and attenuate the gross weight of keloid tissues in vivo, suppress fibroblast activation and autophagy both in vivo and in vitro, dampen fibroblast activation by the TGF-β1/Smad signaling pathway, and inhibit fibroblasts autophagy by the PI3K/Akt/mTOR signaling pathway. These results demonstrate the therapeutic potential of remdesivir for keloid management.

Needle-Assisted Electrocoagulation Plus Pharmacotherapy—A novel needle-assisted electrocoagulation technique combined with pharmacotherapy (corticosteroid and 5-FU injections) was effective in a Chinese clinical trial involving 6 patients with keloids.34 Investigators used Vancouver Scar Scale and both Patient and Observer Scar Assessment Scale scores to grade patients’ scars before treatment and 1 month after the first treatment cycle. They found that ablation combined with pharmacotherapy significantly reduced all 3 scores without any obvious adverse events (P=.004, P=.006, and P=.017, respectively). This novel combination treatment may serve as a safe and effective therapeutic approach for keloid removal.

Final Thoughts

Emerging treatments offer promising new horizons in keloid management; however, the lack of robust, high-quality clinical trials, especially those focusing on SOC, underscores a pressing need for comprehensive and inclusive studies. There is much work to be done to close the existing knowledge gap, and future studies must be more intentional with recruitment, assuring that the patients who are disproportionately affected by these lesions are represented in study populations.

Keloids are fibroproliferative lesions caused by aberrant wound healing in predisposed individuals.1 While keloids have been reported in patients of all races and ethnicities, they most commonly develop in individuals of African or Asian descent.2 Often associated with symptoms such as pain and itching, keloids can be disfiguring and result in poorer quality of life.3 There is a paucity of research on keloid pathogenesis and efficacious therapeutics, particularly in patients with skin of color (SOC). Herein, we outline the current research on keloid treatment and highlight promising new therapies ranging from innovative intralesional techniques to advanced laser-based and biologic therapies.

Deficiencies in Skin of Color Research

Although keloids are 17 times more prevalent in patients with SOC,4 there is a considerable lack of focus on this population in the literature.5 Studies on keloids that include individuals with SOC often group patients of all skin types together, and subgroup analyses are not always performed.6,7 As a result, dermatologists may face considerable challenges in providing effective treatments for keloids in patients with SOC. With few evidence-based options available, patients with SOC who have keloids continue to experience impairments in quality of life.

Common Keloid Therapies

There currently is no gold-standard treatment for keloids. Common therapeutic modalities include intralesional corticosteroids (ILCs), antineoplastic agents and neuromodulators, laser-based devices, and surgical therapies (eg, excision), as well as combined medical and surgical techniques.8

Intralesional Corticosteroids—Minimally invasive ILCs are the first-line treatment in all patients with keloids, regardless of skin phototype. Because keloid formation results from trauma to the skin, ILCs often are recommended to minimize further skin damage.5 One meta-analysis found that ILCs have demonstrated success rates of 50% to 100%9; however, these studies frequently combine ILCs with other treatment modalities, and few studies have focused on the efficacy of ILC monotherapy in patients with SOC.6,10-13

Antineoplastic Agents and Neuromodulators—Certain antineoplastic agents (eg, 5-fluorouracil [5-FU] and bleomycin) and neuromodulators (eg, botulinum toxin A [BTA]) also have been studied in keloid management.8

5-Fluorouracil frequently is combined with ILCs such as triamcinolone (TAC). Combined therapy is more effective than TAC monotherapy in scar height reduction.14,15 Rates of adverse events such as dyspigmentation, atrophy, and telangiectasias also were lower in patients who received combined therapy.14,15 A systematic review found that intralesional bleomycin may be more effective than TAC alone, 5-FU alone, TAC combined with 5-FU, and TAC combined with cryotherapy; however, hyperpigmentation was a common adverse event, occurring in roughly 70% (42/60) of patients.16,17 Additionally, a 2024 meta-analysis evaluated 20 randomized controlled trials comprising 1114 patients treated with intralesional TAC, 5-FU, BTA, verapamil, and/or bleomycin. Botulinum toxin A and TAC plus 5-FU were found to have outstanding therapeutic efficacy for keloids, and rates of adverse events were similar among users of TAC, 5-FU, BTA, and TAC plus 5-FU.18

While antineoplastic agents and BTA may be promising keloid therapies, further studies demonstrating their efficacy and safety profiles are necessary, particularly regarding dyspigmentation as a potential adverse event, as this may be of concern in patients with darker phototypes.

Laser Therapies—Of all treatment modalities, laser-based keloid therapies have been the most robustly studied in SOC. The 2 main types are ablative (eg, CO2, Er:YAG) and nonablative (eg, pulsed dye, Nd:YAG) lasers. Ablative lasers rapidly heat water molecules within the skin, thereby vaporizing the skin cells in a controlled precise process that reduces scar tissue by removing layers of skin. Nonablative lasers target hemoglobin in blood vessels, reducing oxygen supply and inducing collagen remodeling without damaging the epidermis.19

For patients with SOC, lasers carry a risk for postinflammatory hyperpigmentation.20 To address this risk, recent advancements in laser technology and procedural protocols have aimed to minimize the number of passes and utilize cooling devices21; however, many of these recommendations are based on retrospective reviews and small case series. A 2024 meta-analysis comprising 550 patients found that the combination of fractional CO2 laser therapy and 5-FU was the most effective intervention, markedly reducing Vancouver Scar Scale and pliability scores as well as keloid thickness.22 Conversely, pulsed dye lasers were the least effective in terms of improving scar thickness, pigmentation, and pliability when compared to other treatments.

Randomized controlled trials of laser-based therapies in patients with SOC are lacking in the literature. Future studies should focus on calibrating laser-based therapies for those with darker skin tones and examine the efficacy and adverse effects of ablative and nonablative lasers in patients with SOC.

Promising New Keloid Therapies

Keloid disease pathogenesis is incompletely understood, but several new therapeutic targets have been highlighted in the literature, including dupilumab, pentoxifylline, sirtuin 6 (SIRT6) modulators, remdesivir, and needle-assisted electrocoagulation plus pharmacotherapy.

Dupilumab—An anti–IL-4 and IL-13 monoclonal antibody, dupilumab was first approved for the treatment of severe atopic dermatitis. Its use has broadened since its approval, and keloids have been identified as a potential therapeutic target. A 2019 case study described a 53-year-old Black man with severe atopic dermatitis and chronic keloids that regressed with systemic dupilumab therapy.23 This prompted a follow-up case-control study using real-time polymerase chain reaction testing to evaluate Th2 gene expression (IL-4R, IL-13, and CCL18) of lesional and nonlesional tissue in 3 Black patients with chronic keloids and no concurrent atopic dermatitis vs 5 healthy Black controls.Despite the limited sample size, a significant increase in IL-13 and the Th2 chemokine CCL18 was found in patients with keloids compared to controls (P<.05), suggesting that the entire integument of patients with severe keloids is abnormal.23 This finding supports the use of systemic treatments for chronic and multifocal keloid disease. Several subsequent case reports have corroborated the efficacy of systemic and/or intralesional dupilumab.24,25 However, some studies have reported contradictory findings, suggesting the need for high-quality clinical trials.26,27

Pentoxifylline—Pentoxifylline is a methylated xanthine derivative and a nonspecific phosphodiesterase ­inhibitor used to treat claudication from peripheral artery disease. It also inhibits the proliferation and rate of collagen synthesis of fibroblasts from keloids in vitro.28,29 A 2019 retrospective, open-label pilot study analyzed postsurgical keloid recurrence in 45 patients with 67 unique keloids that were stratified into low- and high-risk groups based on clinical factors including multiple symptomatic keloids, history of recurrence, and family history.30 Both the low- and the high-risk groups were treated with 40 mg/mL intralesional triamcinolone acetonide monthly for 6 months; however, some of the high-risk keloids also received pentoxifylline 300 mg 3 times daily for 6 months. There was a statistically significant decrease in keloid recurrence rate between the high-risk group treated with pentoxifylline and the low-risk group for whom pentoxifylline was not prescribed (P=.015).

Similarly, a randomized clinical trial comparing the efficacy of combination intralesional pentoxifylline and intralesional triamcinolone vs monotherapy with pentoxifylline or triamcinolone found the most significant improvement in the combination cohort with reduction in keloid height (P=.04), pliability (P=.003), and vascularity (P=.05).31 These findings highlight the need for supplementary studies on the use of pentoxifylline for keloid therapy.

SIRT6 Modulators—SIRT6 modulators are an exciting future therapeutic target. In a recent case-control study evaluating the histologic milieu of keloid tissue vs normal skin specimens, the researchers found that selective overexpression of SIRT6 via the use of a recombinant adenovirus in keloid fibroblasts attenuated proliferation, invasion, and collagen synthesis while fostering apoptosis, likely through the suppression of MAPK/ERK pathway activity.32

Remdesivir—The antiviral drug remdesivir has been reported to have pharmacologic activities in a wide range of fibrotic diseases, including keloids. A 2024 study explored the potential effect and mechanisms of remdesivir on skin fibrosis both in vitro and in rodents.33 Remdesivir was found to decrease skin fibrosis and attenuate the gross weight of keloid tissues in vivo, suppress fibroblast activation and autophagy both in vivo and in vitro, dampen fibroblast activation by the TGF-β1/Smad signaling pathway, and inhibit fibroblasts autophagy by the PI3K/Akt/mTOR signaling pathway. These results demonstrate the therapeutic potential of remdesivir for keloid management.

Needle-Assisted Electrocoagulation Plus Pharmacotherapy—A novel needle-assisted electrocoagulation technique combined with pharmacotherapy (corticosteroid and 5-FU injections) was effective in a Chinese clinical trial involving 6 patients with keloids.34 Investigators used Vancouver Scar Scale and both Patient and Observer Scar Assessment Scale scores to grade patients’ scars before treatment and 1 month after the first treatment cycle. They found that ablation combined with pharmacotherapy significantly reduced all 3 scores without any obvious adverse events (P=.004, P=.006, and P=.017, respectively). This novel combination treatment may serve as a safe and effective therapeutic approach for keloid removal.

Final Thoughts

Emerging treatments offer promising new horizons in keloid management; however, the lack of robust, high-quality clinical trials, especially those focusing on SOC, underscores a pressing need for comprehensive and inclusive studies. There is much work to be done to close the existing knowledge gap, and future studies must be more intentional with recruitment, assuring that the patients who are disproportionately affected by these lesions are represented in study populations.

References
  1. Téot L, Mustoe TA, Middelkoop E, eds. Textbook on Scar Management: State of the Art Management and Emerging Technologies. Springer; 2020.
  2. Davis SA, Feldman SR, McMichael AJ. Management of keloids in the United States, 1990-2009: an analysis of the National Ambulatory Medical Care Survey. Dermatol Surg. 2013;39:988-994. doi:10.1111/dsu.12182
  3. Kassi K, Kouame K, Kouassi A, et al. Quality of life in black African patients with keloid scars. Dermatol Reports. 2020;12:8312. doi:10.4081/dr.2020.8312
  4. Delaleu J, Charvet E, Petit A. Keloid disease: review with clinical atlas. part I: definitions, history, epidemiology, clinics and diagnosis. Ann Dermatol Venereol. 2023;150:3-15. doi:10.1016/j.annder.2022.08.010
  5. Bronte J, Zhou C, Vempati A, et al. A comprehensive review of non-surgical treatments for hypertrophic and keloid scars in skin of color. Clin Cosmet Investig Dermatol. 2024;17:1459-1469. doi:10.2147/CCID.S470997
  6. Davison SP, Dayan JH, Clemens MW, et al. Efficacy of intralesional 5-fluorouracil and triamcinolone in the treatment of keloids. Aesthet Surg J. 2009;29:40-46. doi:10.1016/j.asj.2008.11.006
  7. Azzam OA, Bassiouny DA, El-Hawary MS, et al. Treatment of hypertrophic scars and keloids by fractional carbon dioxide laser: a clinical, histological, and immunohistochemical study. Lasers Med Sci. 2016;31:9-18. doi:10.1007/s10103-015-1824-4
  8. Ekstein SF, Wyles SP, Moran SL, et al. Keloids: a review of therapeutic management. Int J Dermatol. 2021;60:661-671. doi:10.1111/ijd.15159
  9. Morelli Coppola M, Salzillo R, Segreto F, et al. Triamcinolone acetonide intralesional injection for the treatment of keloid scars: patient selection and perspectives. Clin Cosmet Investig Dermatol. 2018;11:387-396. doi:10.2147/CCID.S133672
  10. Kant SB, van den Kerckhove E, Colla C, et al. A new treatment of hypertrophic and keloid scars with combined triamcinolone and verapamil: a retrospective study. Eur J Plast Surg. 2018;41:69-80. doi:10.1007/s00238-017-1322-y
  11. Cohen AJ, Talasila S, Lazarevic B, et al. Combination cryotherapy and intralesional corticosteroid versus steroid monotherapy in the treatment of keloids. J Cosmet Dermatol. 2023;22:932-936. doi:10.1111/jocd.15520
  12. Tawaranurak N, Pliensiri P, Tawaranurak K. Combination of fractional carbon dioxide laser and topical triamcinolone vs intralesional triamcinolone for keloid treatment: a randomised clinical trial. Int Wound J. 2022;19:1729-1735. doi:10.1111/iwj.13775
  13. Belie O, Ugburo AO, Mofikoya BO, et al. A comparison of intralesional verapamil and triamcinolone monotherapy in the treatment of keloids in an African population. Niger J Clin Pract. 2021;24:986-992. doi:10.4103/njcp.njcp_474_20
  14. Khalid FA, Mehrose MY, Saleem M, et al. Comparison of efficacy and safety of intralesional triamcinolone and combination of triamcinolone with 5-fluorouracil in the treatment of keloids and hypertrophic scars: randomised control trial. Burns. 2019;45:69-75. doi:10.1016/j.burns.2018.08.011
  15. Asilian A, Darougheh A, Shariati F. New combination of triamcinolone, 5-Fluorouracil, and pulsed-dye laser for treatment of keloid and hypertrophic scars. Dermatol Surg. 2006;32:907-915. doi:10.1111/j.1524-4725.2006.32195.x
  16. Kim WI, Kim S, Cho SW, et al. The efficacy of bleomycin for treating keloid and hypertrophic scar: a systematic review and meta-analysis. J Cosmet Dermatol. 2020;19:3357-3366. doi:10.1111/jocd.13390
  17. Kabel A, Sabry H, Sorour N, et al. Comparative study between intralesional injection of bleomycin and 5-fluorouracil in the treatment of keloids and hypertrophic scars. J Dermatol Dermatol Surg. 2016;20:32-38.
  18. Yang HA, Jheng WL, Yu J, et al. Comparative efficacy of drug interventions for keloids: a network meta-analysis. Ann Plast Surg. 2024;92(1S suppl 1):S52-S59. doi:10.1097/SAP.0000000000003759
  19. Preissig J, Hamilton K, Markus R. Current laser resurfacing technologies: a review that delves beneath the surface. Semin Plast Surg. 2012;26:109-116. doi:10.1055/s-0032-1329413
  20. Bin Dakhil A, Shadid A, Altalhab S. Post-inflammatory hyperpigmentation after carbon dioxide laser: review of prevention and risk factors. Dermatol Reports. 2023;15:9703. doi:10.4081/dr.2023.9703
  21. Kaushik SB, Alexis AF. Nonablative fractional laser resurfacing in skin of color: evidence-based review. J Clin Aesthet Dermatol. 2017;10:51-67.
  22. Foppiani JA, Khaity A, Al-Dardery NM, et al. Laser therapy in hypertrophic and keloid scars: a systematic review and network meta-analysis. Aesthetic Plast Surg. Published May 17, 2024. doi:10.1007/s00266-024-04027-9
  23. Diaz A, Tan K, He H, et al. Keloid lesions show increased IL-4/IL-13 signaling and respond to Th2-targeting dupilumab therapy. J Eur Acad Dermatol Venereol. 2020;34:E161-E164. doi:10.1111/jdv.16097
  24. Min MS, Mazori DR, Lee MS, et al. Successful treatment of keloids and hypertrophic scars with systemic and intralesional dupilumab. J Drugs Dermatol. 2023;22:1220-1222. doi:10.36849/JDD.6385
  25. Wittmer A, Finklea L, Joseph J. Effects of dupilumab on keloid stabilization and prevention. JAAD Case Rep. 2023;37:103-105. doi:10.1016/j.jdcr.2023.05.001
  26. Luk K, Fakhoury J, Ozog D. Nonresponse and progression of diffuse keloids to dupilumab therapy. J Drugs Dermatol. 2022;21:197-199. doi:10.36849/jdd.6252
  27. Tirgan MH, Uitto J. Lack of efficacy of dupilumab in the treatment of keloid disorder. J Eur Acad Dermatol Venereol. 2022;36:E120-E122. doi:10.1111/jdv.17669
  28. Berman B, Duncan MR. Pentoxifylline inhibits the proliferation of human fibroblasts derived from keloid, scleroderma and morphoea skin and their production of collagen, glycosaminoglycans and fibronectin. Br J Dermatol. 1990;123:339-346. doi:10.1111/j.1365-2133.1990.tb06294.x
  29. Berman B, Duncan MR. Pentoxifylline inhibits normal human dermal fibroblast in vitro proliferation, collagen, glycosaminoglycan, and fibronectin production, and increases collagenase activity. J Invest Dermatol. 1989;92:605-610.
  30. Tan A, Martinez Luna O, Glass DA 2nd. Pentoxifylline for the prevention of postsurgical keloid recurrence. Dermatol Surg. 2020;46:1353-1356. doi:10.1097/DSS.0000000000002090
  31. Serag-Eldin YMA, Mahmoud WH, Gamea MM, et al. Intralesional pentoxifylline, triamcinolone acetonide, and their combination for treatment of keloid scars. J Cosmet Dermatol. 2021;20:3330-3340. doi:10.1111/jocd.14305
  32. Zhou T, Chen Y, Wang C, et al. SIRT6 inhibits the proliferation and collagen synthesis of keloid fibroblasts through MAPK/ERK pathway. Discov Med. 2024;36:1430-1440. doi:10.24976/Discov.Med.202436186.133
  33. Zhang J, Zhang X, Guo X, et al. Remdesivir alleviates skin fibrosis by suppressing TGF-β1 signaling pathway. PLoS One. 2024;19:E0305927. doi:10.1371/journal.pone.0305927
  34. Zhao J, Zhai X, Xu Z, et al. Novel needle-type electrocoagulation and combination pharmacotherapy: basic and clinical studies on efficacy and safety in treating keloids. J Cosmet Dermatol. doi:10.1111/jocd.16453
References
  1. Téot L, Mustoe TA, Middelkoop E, eds. Textbook on Scar Management: State of the Art Management and Emerging Technologies. Springer; 2020.
  2. Davis SA, Feldman SR, McMichael AJ. Management of keloids in the United States, 1990-2009: an analysis of the National Ambulatory Medical Care Survey. Dermatol Surg. 2013;39:988-994. doi:10.1111/dsu.12182
  3. Kassi K, Kouame K, Kouassi A, et al. Quality of life in black African patients with keloid scars. Dermatol Reports. 2020;12:8312. doi:10.4081/dr.2020.8312
  4. Delaleu J, Charvet E, Petit A. Keloid disease: review with clinical atlas. part I: definitions, history, epidemiology, clinics and diagnosis. Ann Dermatol Venereol. 2023;150:3-15. doi:10.1016/j.annder.2022.08.010
  5. Bronte J, Zhou C, Vempati A, et al. A comprehensive review of non-surgical treatments for hypertrophic and keloid scars in skin of color. Clin Cosmet Investig Dermatol. 2024;17:1459-1469. doi:10.2147/CCID.S470997
  6. Davison SP, Dayan JH, Clemens MW, et al. Efficacy of intralesional 5-fluorouracil and triamcinolone in the treatment of keloids. Aesthet Surg J. 2009;29:40-46. doi:10.1016/j.asj.2008.11.006
  7. Azzam OA, Bassiouny DA, El-Hawary MS, et al. Treatment of hypertrophic scars and keloids by fractional carbon dioxide laser: a clinical, histological, and immunohistochemical study. Lasers Med Sci. 2016;31:9-18. doi:10.1007/s10103-015-1824-4
  8. Ekstein SF, Wyles SP, Moran SL, et al. Keloids: a review of therapeutic management. Int J Dermatol. 2021;60:661-671. doi:10.1111/ijd.15159
  9. Morelli Coppola M, Salzillo R, Segreto F, et al. Triamcinolone acetonide intralesional injection for the treatment of keloid scars: patient selection and perspectives. Clin Cosmet Investig Dermatol. 2018;11:387-396. doi:10.2147/CCID.S133672
  10. Kant SB, van den Kerckhove E, Colla C, et al. A new treatment of hypertrophic and keloid scars with combined triamcinolone and verapamil: a retrospective study. Eur J Plast Surg. 2018;41:69-80. doi:10.1007/s00238-017-1322-y
  11. Cohen AJ, Talasila S, Lazarevic B, et al. Combination cryotherapy and intralesional corticosteroid versus steroid monotherapy in the treatment of keloids. J Cosmet Dermatol. 2023;22:932-936. doi:10.1111/jocd.15520
  12. Tawaranurak N, Pliensiri P, Tawaranurak K. Combination of fractional carbon dioxide laser and topical triamcinolone vs intralesional triamcinolone for keloid treatment: a randomised clinical trial. Int Wound J. 2022;19:1729-1735. doi:10.1111/iwj.13775
  13. Belie O, Ugburo AO, Mofikoya BO, et al. A comparison of intralesional verapamil and triamcinolone monotherapy in the treatment of keloids in an African population. Niger J Clin Pract. 2021;24:986-992. doi:10.4103/njcp.njcp_474_20
  14. Khalid FA, Mehrose MY, Saleem M, et al. Comparison of efficacy and safety of intralesional triamcinolone and combination of triamcinolone with 5-fluorouracil in the treatment of keloids and hypertrophic scars: randomised control trial. Burns. 2019;45:69-75. doi:10.1016/j.burns.2018.08.011
  15. Asilian A, Darougheh A, Shariati F. New combination of triamcinolone, 5-Fluorouracil, and pulsed-dye laser for treatment of keloid and hypertrophic scars. Dermatol Surg. 2006;32:907-915. doi:10.1111/j.1524-4725.2006.32195.x
  16. Kim WI, Kim S, Cho SW, et al. The efficacy of bleomycin for treating keloid and hypertrophic scar: a systematic review and meta-analysis. J Cosmet Dermatol. 2020;19:3357-3366. doi:10.1111/jocd.13390
  17. Kabel A, Sabry H, Sorour N, et al. Comparative study between intralesional injection of bleomycin and 5-fluorouracil in the treatment of keloids and hypertrophic scars. J Dermatol Dermatol Surg. 2016;20:32-38.
  18. Yang HA, Jheng WL, Yu J, et al. Comparative efficacy of drug interventions for keloids: a network meta-analysis. Ann Plast Surg. 2024;92(1S suppl 1):S52-S59. doi:10.1097/SAP.0000000000003759
  19. Preissig J, Hamilton K, Markus R. Current laser resurfacing technologies: a review that delves beneath the surface. Semin Plast Surg. 2012;26:109-116. doi:10.1055/s-0032-1329413
  20. Bin Dakhil A, Shadid A, Altalhab S. Post-inflammatory hyperpigmentation after carbon dioxide laser: review of prevention and risk factors. Dermatol Reports. 2023;15:9703. doi:10.4081/dr.2023.9703
  21. Kaushik SB, Alexis AF. Nonablative fractional laser resurfacing in skin of color: evidence-based review. J Clin Aesthet Dermatol. 2017;10:51-67.
  22. Foppiani JA, Khaity A, Al-Dardery NM, et al. Laser therapy in hypertrophic and keloid scars: a systematic review and network meta-analysis. Aesthetic Plast Surg. Published May 17, 2024. doi:10.1007/s00266-024-04027-9
  23. Diaz A, Tan K, He H, et al. Keloid lesions show increased IL-4/IL-13 signaling and respond to Th2-targeting dupilumab therapy. J Eur Acad Dermatol Venereol. 2020;34:E161-E164. doi:10.1111/jdv.16097
  24. Min MS, Mazori DR, Lee MS, et al. Successful treatment of keloids and hypertrophic scars with systemic and intralesional dupilumab. J Drugs Dermatol. 2023;22:1220-1222. doi:10.36849/JDD.6385
  25. Wittmer A, Finklea L, Joseph J. Effects of dupilumab on keloid stabilization and prevention. JAAD Case Rep. 2023;37:103-105. doi:10.1016/j.jdcr.2023.05.001
  26. Luk K, Fakhoury J, Ozog D. Nonresponse and progression of diffuse keloids to dupilumab therapy. J Drugs Dermatol. 2022;21:197-199. doi:10.36849/jdd.6252
  27. Tirgan MH, Uitto J. Lack of efficacy of dupilumab in the treatment of keloid disorder. J Eur Acad Dermatol Venereol. 2022;36:E120-E122. doi:10.1111/jdv.17669
  28. Berman B, Duncan MR. Pentoxifylline inhibits the proliferation of human fibroblasts derived from keloid, scleroderma and morphoea skin and their production of collagen, glycosaminoglycans and fibronectin. Br J Dermatol. 1990;123:339-346. doi:10.1111/j.1365-2133.1990.tb06294.x
  29. Berman B, Duncan MR. Pentoxifylline inhibits normal human dermal fibroblast in vitro proliferation, collagen, glycosaminoglycan, and fibronectin production, and increases collagenase activity. J Invest Dermatol. 1989;92:605-610.
  30. Tan A, Martinez Luna O, Glass DA 2nd. Pentoxifylline for the prevention of postsurgical keloid recurrence. Dermatol Surg. 2020;46:1353-1356. doi:10.1097/DSS.0000000000002090
  31. Serag-Eldin YMA, Mahmoud WH, Gamea MM, et al. Intralesional pentoxifylline, triamcinolone acetonide, and their combination for treatment of keloid scars. J Cosmet Dermatol. 2021;20:3330-3340. doi:10.1111/jocd.14305
  32. Zhou T, Chen Y, Wang C, et al. SIRT6 inhibits the proliferation and collagen synthesis of keloid fibroblasts through MAPK/ERK pathway. Discov Med. 2024;36:1430-1440. doi:10.24976/Discov.Med.202436186.133
  33. Zhang J, Zhang X, Guo X, et al. Remdesivir alleviates skin fibrosis by suppressing TGF-β1 signaling pathway. PLoS One. 2024;19:E0305927. doi:10.1371/journal.pone.0305927
  34. Zhao J, Zhai X, Xu Z, et al. Novel needle-type electrocoagulation and combination pharmacotherapy: basic and clinical studies on efficacy and safety in treating keloids. J Cosmet Dermatol. doi:10.1111/jocd.16453
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