Current Concepts In Treating Hypertrophic Scars And Keloids

Given that a keloid or hypertrophic scar may cause disfigurement, pruritus, pain and contractures that can result in deformity and disability, prevention is the first and most important step in the management of these scars. These authors discuss the pathophysiology of scar formation, risk factors, keys to prevention and available treatments for keloids or hypertrophic scars. Normal wound healing involves reepithelialization, angiogenesis, fibroblast hyperplasia, fibrin deposition, and production of tissue components such as collagen. New tissue, in the form of a scar, has a different architecture from the normal skin. A balance usually occurs between new tissue biosynthesis and degradation so patients avoid excess scar formation. An imbalance in this process can lead to a keloid or a hypertrophic scar.^1,2    Cutaneous scarring following skin trauma or a wound is a major cause of morbidity and disfigurement. Hypertrophic scars and keloids have very similar pathologic processes. By definition, hypertrophic scars do not extend beyond the initial site of injury while keloids typically project beyond the original wound margins. Hypertrophic scars may occur anywhere. However, keloids predominantly affect the ear lobe, neck and chest.^1,2    The prevalence rate of hypertrophic scarring in patients treated in burn centers may be as high as 70 percent.³ Other insults to the deep dermis, including lacerations, abrasions, piercings and vaccinations, can also cause scarring. The resultant disfigurement, pruritus, pain and contractures can dramatically affect a patient’s quality of life.²    The occurrence of keloids and hypertrophic scars has the highest incidence in the second to third decade of life. African-American populations are more susceptible to keloid formation.² Genetics and family history are strongly associated with the formation of keloid scars. More than 50 percent of all patients with keloids have a positive family history of keloid scarring.²

Understanding The Pathophysiology

We can categorize the process of wound healing into three overlapping phases. In the first inflammatory phase of wound healing (days one to three), macrophages enter the injury zone and phagocytize pathogens and tissue debris.    In the second proliferative phase (days four to 21), macrophages accumulate while endothelial cells and fibroblasts proliferate, and make new dermal tissue. Through the secretion of platelet-derived growth factor (PDGF) and transforming growth factor beta 1 (TGFb1), macrophages induce fibroblasts to proliferate and lay down type III collagen. An overactive second phase results in the formation of hypertrophic scars and keloids. Reepithelialization usually occurs in the first to second stage.    In the third remodeling phase (day 21 to year one), apoptosis occurs in a portion of the newly formed cells.^1,4-7 As the wound matures, the composition of the extracellular matrix changes. The type III collagen deposited in the proliferative phase slowly degrades and type I collagen replaces it. Type I collagen is oriented as small parallel bundles that differ from the basket weave orientation of collagen present in normal dermis. Within this abnormal collagenous network, there is an absence of hair follicles, sebaceous glands and sweat glands. The extent to which these changes in skin structure occur after cutaneous injury depends on the severity and extent of inflammation, and the depth of injury. The deeper cutaneous injuries give rise to more scar tissue.^1,4-6,8    Hypertrophic scars and keloids can be pruritic or tender. In the proliferative and remodeling phases, the scar may contract, causing tension on the surrounding skin and joints, and leading to deformity and reduction in joint range of motion. Large scars can cause severe interference with the function of extremities. The epidermis overlaying the scar is usually thinner than normal epidermis and more susceptible to breakage as a result of trauma.    The presence of a keloid or hypertrophic scar on feet may cause deformity. The foot cannot comfortably fit into shoes. Pressure and trauma from shoes or walking can cause pain or ulceration. Large scars sometimes result in severe disability.

A Guide To Scar Prevention

The primary goal in wound management is to help facilitate faster healing with less inflammation and prevent scar formation. The more quickly a wound heals, the less likely it is for scars to form. One usually repairs deep wounds involving the full thickness of the skin with stitches. Keep the wound edges beside each other for faster healing. Debride all necrotic tissues and remove all foreign bodies before wound closure. When there is a large, deep wound, a lack of adequate debridement and wound closure can lead to a higher risk of developing scars.^8-10 Reducing the tension on the wounds and preventing infection also helps in scar prevention.    Unlike deep wounds, superficial wounds (not involving full thickness of the skin) do not require closure of the wound edges. The goals of the treatment are to prevent infection and provide a better environment for faster reepithelialization of the wound. Providing a moist environment can occur through the use of an appropriate dressing. For large superficial wounds, using silver sulfadiazine cream underneath a gauze dressing is common. For small, superficial wounds, there are some commercially available dressings that are more convenient to use than the cream and gauze technique.^8-10    For scar prevention after surgery, it is important to keep the following keys in mind. 1. Close surgical wounds with minimal tension. 2. Incisions should not cross joint lines. 3. Incisions should follow skin creases whenever possible. Use a less traumatic surgical technique to reduce post-surgical inflammation.^8-10    After reepithelialization, the area should not be deeply erythematous or inflamed. Deep erythema and inflammation can signal fibroblast proliferation and collagen production. This soft tissue deposition causes the area to be indurated and thickened. More soft tissue deposition results in keloids and hypertrophic scars. Therefore, deep erythema and especially induration after wound healing can signal impending keloid or hypertrophic scar formation.^2,11 Suppression of inflammation and fibroblast activity immediately after reepithelialization may prevent scar formation.¹²

Current Insights On The Treatment Of Hypertrophic Scars And Keloids

Topical or intralesional corticosteroids can reduce the formation of hypertrophic scars by suppression of inflammation, TGFb1, TGFb2 and PDGF; inhibition of fibroblast growth, proliferation and collagen synthesis; and promotion of collagen degeneration.^1,2,13-16 Topical tretinoin (Retin-A) can potentiate the effect of topical corticosteroids. Combining the twice-a-week topical tretinoin and twice-a-day clobetasol (Temovate, GlaxoSmithKline) (a super potent topical corticosteroid) can prevent scar formation after superficial wounds such as superficial burn ulcers.¹² Employing an overnight occlusive dressing increases the effectiveness of clobetasol.¹⁷ One can also use glucocorticoid therapy for the prevention of scar recurrence following keloid or hypertrophic scar excision.^10,16,18-22 However, the risk of recurrence of a keloid after surgery is high, even with concomitant corticosteroid therapy. Therefore, surgery for keloids is rarely recommended.^18-20    Pressure garments or dressings, silicone gel sheeting or massage may also reduce the chance of hypertrophic scar or keloid formation by unknown mechanisms. However, the scientific evidence supporting these modalities is not very strong.^8-10 Flavonoids such as Contractubex gel (Merz Pharmaceuticals) and Mederma Skin Care Gel (Merz Pharmaceuticals), or onion extract are reportedly effective in the prevention of scar formation. Again, there is no strong evidence supporting these modalities.^8-10    The intralesional injection of corticosteroids can cause collagen degeneration, apoptosis of fibroblasts and atrophy of the scar tissue. Intralesional corticosteroids are the mainstay of treatment for keloids and hypertrophic scars.^23,24 One would inject triamcinolone acetonide 40 mg/mL (Kenalog, Bristol-Myers Squibb) in the hypertrophic scar or keloid with multiple punctures. Repeat the injection every three to four weeks until the hypertrophic area undergoes atrophy. Avoid injecting into the border of the lesion because it can cause atrophy of the surrounding normal skin.    Injection into the hard collagenous tissue of a scar may not always be easy. Cryotherapy of the scar before injection can make the tissue softer and the injection easier. Treatment with deep cryotherapy can cause necrosis and sloughing of the frozen tissue. It can help removal of very large elevated masses, but it is painful and traumatic.^8-10 Cryotherapy usually occurs via liquid nitrogen. However, other freezing agents may also be effective.

Other Possible Treatment Options

There are reports of efficacy for other treatment methods in hypertrophic scars and keloids.^8-10,25 Experienced physicians may use these modalities in selected cases.    Laser therapy. Pulsed dye laser is more effective in prevention or in early stages of scar formation. It is not effective for old lesions. Ablative lasers such as carbon dioxide laser are not better than surgical removal. They can burn and flatten small, elevated scars.^26-28    Radiotherapy. Superficial X-rays may be an adjuvant therapy after keloid excision. There is a potential risk of carcinogenesis.²⁹    Interferon. With intralesional injection of interferon (INF-α2b), common adverse effects include flu-like symptoms on injection.^30,31    5-fluorouracil (Carac Cream, Sanofi Aventis). With intralesional injection of 5-fluorouracil, common adverse effects include anemia, leukopenia and thrombocytopenia.^30,31    Bleomycin (Blenoxane, Teva Pharmaceuticals). We have found that this intralesional injection may result in necrosis and sloughing of the scar.    Scar revision (surgery). Scar revision occurs via excision with linear, tension-free closure, split- or full-thickness skin grafting, or shaving without closure. One may use it for hypertrophic scars. Recurrence rates are very high after keloid excision without adjuvant therapy with corticosteroids or radiotherapy.^18-20 The recurrence may result in formation of a new keloid larger than the originally treated one.    Imiquimod cream. Physicians have used imiquimod cream for prophylaxis and treatment. It may cause erythema, irritation and pruritus. There is some debate regarding efficacy of this treatment. In a study of 20 randomized, shaved keloids, Berman and colleagues assessed the use of imiquimod 5% or vehicle cream nightly for two weeks and subsequent use three times a week under occlusion for one month.³² At six months, the authors noted keloid recurrence rates of 37.5 percent in the imiquimod group and 75 percent in the vehicle group. However, they noted there was not enough statistical power to detect a significant difference in six-month keloid recurrence rates between the two treated groups.    Retinoic acid cream. Physicians have used retinoic acid cream for prophylaxis and treatment. There is limited data regarding the efficacy of this treatment. Janssen de Limpens studied the use of daily applications of a 0.05% solution of retinoic acid in 28 cases of intractable scars.²⁵ The author found a slight to marked reduction of the size of the scars and a decrease of complaints including itching in the majority of the cases.

In Conclusion

Hypertrophic scars and keloids are frustrating for patients. Despite decades of research, the pathophysiology of scar formation remains elusive. Therapeutic and preventive modalities for scars often lead to inconsistent and suboptimal results. Shortening the wound healing time as well as reducing inflammation during and after wound healing are the most important strategies for scar prevention. Early treatment of keloids and hypertrophic scars may prevent their growth and improve the outcomes. However, in some patients with large scars, especially in areas (like the feet) where surgical correction is not feasible, the prognosis of treatment may be limited.    Dr. Taheri is affiliated with the Department of Dermatology at the Center for Dermatology Research at the Wake Forest School of Medicine in Winston-Salem, NC.    Ms. Moustafa is affiliated with the Department of Dermatology at the Center for Dermatology Research at the Wake Forest School of Medicine in Winston-Salem, NC.    Dr. Mansoori is affiliated with the Department of Pathology at the Center for Dermatology Research at the Wake Forest School of Medicine in Winston-Salem, NC.    Dr. Feldman is affiliated with the Departments of Dermatology, Pathology and Public Health Sciences at the Wake Forest School of Medicine in Winston-Salem, NC.    Dr. Feldman is a consultant and speaker for Galderma Laboratories, Stiefel Laboratories/GlaxoSmithKline, Abbott Laboratories, Warner Chilcott, Janssen Pharmaceuticals, Amgen, Photomedex, Genentech, Biogen Idec, and Bristol-Myers Squibb. Dr. Feldman has received grants from Galderma Laboratories, Astellas Pharma, Abbott Laboratories, Warner Chilcott, Janssen Pharmaceuticals, Amgen, Photomedex, Genentech, Biogen Idec, Coria Laboratories/Valeant Pharmaceuticals, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol-Myers Squibb, Stiefel Laboratories/GlaxoSmithKline, Novartis Pharmaceuticals, Medicis Pharmaceutical, Leo Pharma, HanAll Pharmaceutical, Celgene, Basilea Pharmaceutica and Anacor Pharmaceuticals, and has received stock options from Photomedex. He is the owner of www.DrScore.com and a founder of Causa Research. References 1. Profyris C, Tziotzios C, Do V, I. Cutaneous scarring: Pathophysiology, molecular mechanisms, and scar reduction therapeutics Part I. The molecular basis of scar formation. J Am Acad Dermatol. 2012;66(1):1-10. 2. Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med. 2011;17(1-2):113-25. 3. Lawrence JW, Mason ST, Schomer K, Klein MB. Epidemiology and impact of scarring after burn injury: a systematic review of the literature. J Burn Care Res. 2012;33(1):136-46. 4. Broughton G, Janis JE, Attinger CE. Wound healing: an overview. Plast Reconstr Surg. 2006;117(7 Suppl):1e-32e. 5. Shih B, Garside E, McGrouther DA, Bayat A. Molecular dissection of abnormal wound healing processes resulting in keloid disease. Wound Repair Regen. 2010;18(2):139-53. 6. Kondo T, Ishida Y. Molecular pathology of wound healing. Forensic Sci Int. 2010;203(1-3):93-8. 7. Moulin V, Larochelle S, Langlois C, Thibault I, Lopez-Valle CA, Roy M. Normal skin wound and hypertrophic scar myofibroblasts have differential responses to apoptotic inductors. J Cell Physiol. 2004;198(3):350-8. 8. Wolfram D, Tzankov A, Pulzl P, Piza-Katzer H. Hypertrophic scars and keloids--a review of their pathophysiology, risk factors, and therapeutic management. Dermatol Surg. 2009;35(2):171-81. 9. Alster TS, West TB. Treatment of scars: a review. Ann Plast Surg. 1997;39(4):418-32. 10. Stucker FJ, Shaw GY. An approach to management of keloids. Arch Otolaryngol Head Neck Surg. 1992;118(1):63-7. 11. Wang J, Hori K, Ding J, Huang Y, Kwan P, Ladak A, et al. Toll-like receptors expressed by dermal fibroblasts contribute to hypertrophic scarring. J Cell Physiol. 2011;226(5):1265-73. 12. Taheri A. Topical clobetasol in combination with tretinoin is effective in prevention of scar formation after second degree skin burn. Skin Care Conference. Dezfoul, Iran 2008. 13. Fassler R, Sasaki T, Timpl R, Chu ML, Werner S. Differential regulation of fibulin, tenascin-C, and nidogen expression during wound healing of normal and glucocorticoid-treated mice. Exp Cell Res. 1996;222(1):111-6. 14. 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Prevention of earlobe keloid recurrence with postoperative corticosteroid injections versus radiation therapy: a randomized, prospective study and review of the literature. Dermatol Surg. 1996;22(6):569-74. 22. Rosen DJ, Patel MK, Freeman K, Weiss PR. A primary protocol for the management of ear keloids: results of excision combined with intraoperative and postoperative steroid injections. Plast Reconstr Surg. 2007;120(5):1395-400. 23. Ashley FL. Atrophy following cortisone injection for hypertrophic scar. Calif Med. 1973;119(2):65-6. 24. Mustoe TA, Cooter RD, Gold MH, Hobbs FD, Ramelet AA, Shakespeare PG, et al. International clinical recommendations on scar management. Plast Reconstr Surg. 2002;110(2):560-71. 25. Janssen de Limpens AM. The local treatment of hypertrophic scars and keloids with topical retinoic acid. Br J Dermatol. 1980;103(3):319-23. 26. Martin MS, Collawn SS. 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Treatment of keloid scars post-shave excision with imiquimod 5% cream: A prospective, double-blind, placebo-controlled pilot study. J Drugs Dermatol. 2009; 8(5):455-8.