A Critical Appraisal of Nonsurgical Modalities for Managing Hypertrophic Scars and Keloids Rajeev B

View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector Formosan Journal of Surgery (2015) 48,49e56

Available online at www.sciencedirect.com ScienceDirect

journal homepage: www.e-fjs.com

REVIEW ARTICLE A critical appraisal of nonsurgical modalities for managing hypertrophic scars and keloids Rajeev B. Ahuja a,*, Pallab Chatterjee b, Vybhav Deraje a

a Department of Burns, Plastic, Maxillofacial and Microvascular Surgery, Lok Nayak Hospital and Associated Maulana Azad Medical College, New Delhi, India b Department of Surgery, Command Hospital Air Force, Bangalore, India

Received 10 November 2014; received in revised form 20 January 2015; accepted 26 January 2015 Available online 13 March 2015

KEYWORDS Summary The nature of hypertrophic scars and keloids can be unpredictable even to the hypertrophic scar; most experienced physicians. Predicting the susceptibility and severity of these disorders is keloid; difficult. The availability of numerous treatment options which yield various results make keloid diathesis deciding on a course of treatment difficult. Further complicating the selection of treatment options are the numerous industry-driven publications that seem biased and are supported by marketing strategies for related products. Physicians often end up using a treatment modality that is not particularly objective or supported by a high level of evidence. Reviewing liter- atureonthistopiccanbedaunting.Thisstudyattemptstoclarifythecomplex fibroproliferative disorder of skin wound healing by briefly describing its pathophysiology, ca- tegorizing patients into distinct groups based on their clinical behavior, and analyzing relevant evidence for each treatment modality. Copyright ª 2015, Taiwan Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved.

1. Introduction the International Advisory Panel on scar management published a revision of the recommended practices pro- 1,2 The unpredictability of hypertrophic scars (HTSs) and ke- moted by the first advisory panel in 2002, resulting in loids can confuse the most experienced physicians. In 2014, new treatment algorithms. However, the numerous treatment options available, combined with contrasting data, continue to make deciding on a course of treatment difficult. Based on a review of existing data, this study attempts Conflicts of interest: none. to rationalize treatment options after observing the clinical * Corresponding author. Department of Burns, Plastic, Maxillofa- behavior of scars and examining the evidence associated cial and Microvascular Surgery, Lok Nayak Hospital and Associated with various modalities, traditional as well as emerging, Maulana Azad Medical College, New Delhi 110 002, India. E-mail address: [email protected] (R.B. Ahuja). used to treat excessive scarring.

2. Discussion

2.1. Pathophysiology and clinical behavior

Skin damage can result in scars when the wound healing process is disrupted. This can be divided into three distinct but overlapping phases: inflammation, proliferation, and remodeling. A scaffold of the extracellular matrix (ECM) is deposited by fibroblasts during the proliferative phase, forming a structural framework that bridges the wound and enables vascular ingrowth. The recruitment and proliferation of fibroblasts and the production of the ECM are influenced by the following fibrogenic growth factors: platelet-derived growth factor, insulin-like growth factor, transforming growth factors b1 and b2 (TGF-b1 and TGF- b2), and basic fibroblast growth factor.3 These fibrogenic growth factors upregulate ECM production, increase the rates of proliferation and/or migration of the fibroblasts, and inhibit the production of proteases required for main- taining the balance between production and degradation. The ECM is degraded during the final maturation or remodeling phase, and immature Type III collagen trans- forms into mature Type I collagen. ECM degradation occurs through the action of collagenases, proteoglycanases, and other proteases released by mast cells, macrophages, Figure 1 A patient with extensive post-burn hypertrophic endothelial cells, and fibroblasts. Either excessive synthesis scarring of trunk and neck with contracture. of collagens, fibronectins, and proteoglycans by fibroblasts caused by the absence of apoptotic signals or deficient matrix degradation and remodeling may lead to keloid formation and hypertrophic scarring. In addition, recent evidence suggests that the severity of inflammation or the type of immune response may predis- pose to excess scar formation.4 Fibroblasts produce increased amounts of collagen when adverse wound healing factors are present, such as increased skin tension (except ear lobes), delayed wound healing, and wound infection, which prolong the inflammatory response. Experimental evidence suggests that a prolonged inflammatory period with immune cell infiltration increases fibroblast activity with greater and more sustained ECM deposition, leading to keloid formation.4 In addition, the type of immune response can affect fibrogenesis. Development of a T helper, Th2 response, promotes fibrogenesis, whereas predominance of a Th1 response attenuates tissue fibrosis.5 This may explain why keloid scars spread beyond the margins of the original wound, whereas hypertrophic scars, in which the immune Figure 2 A child with postsurgical keloid on sternum cell infiltrations decrease over time, remain within the following cardiac surgery. original wound margins and often regress with time.4 Hypertrophic scars (Fig. 1) and keloids (Fig. 2) that develop following skin damage represent the ends of a actin-containing myofibroblasts, whereas keloidal scars spectrum of healing by scarring (Fig. 3). However, patients have coarse collagen fibers with fewer a-smooth muscle who develop keloids spontaneously and have a family his- actin-containing myofibroblasts.6 tory of keloids may be presumed to have a “keloid diath- Skin pigmentation is one of the major risk factors for the esis” (Fig. 4) a term introduced by Burd and Huang.6 development of keloids. Keloids are observed in people of Patients with a keloid diathesis may have a history of all races, except albinos. People with dark skin are more multiple scarring, and the high recurrence rate makes such susceptible to keloid formation, with a reported incidence scarring appear as a benign fibroproliferative tumor. rate of 6e16% in African populations.7 The fact that this Structurally and biochemically, hypertrophic scars have condition never occurs in albinos, or on the palms or soles, more Type III collagen compared with keloidal scars, which is testimony to the fact that keloids are associated with contain a higher Type I:Type III collagen ratio. Hypertrophic increased skin pigmentation. There is increased sensitivity scars have fine collagen fibers with more a-smooth muscle to melanocyte-stimulating hormone (MSH) which leads to a Evidence appraisal for treatment of hypertrophic scars 51

Figure 3 A schematic representation of authors’ understanding of the spectrum of ﬁbroproliferative disorders of wound healing. “Keloid diathesis” is viewed as a benign ﬁbroproliferative tumor and hence depicted in the same spectrum, yet detached from the mainstream healing process.

The clinical management of scarring is complicated by a lack of precise characterization of each scar category, interchangeable use of the terms hypertrophic scars and keloids, a lack of appreciating keloid diathesis as an inde- pendent entity, and the availability of few therapeutic in- terventions that are supported by well-designed prospective studies involving adequate control groups. Moreover, there is no animal model for studying the bio- logical behavior of keloids in humans, thus our understanding of this subject is hampered.

2.2. Critical appraisal of current therapies for hypertrophic scars and keloids

2.2.1. Pressure therapy Pressure therapy has been used for both prophylaxis and treatment of hypertrophic scars and keloids since the 1970s. Although the underlying mechanism of action is poorly understood, possible mechanisms of action are Figure 4 A patient with extensive keloids on the chest and decreased collagen synthesis by limiting oxygen supply and 9 breasts representing “keloid diathesis”. increased apoptosis of fibroblasts. Recommendations for the amount of pressure and the duration of therapy are based on empirical observations, and support providing a 20-fold increase in the likelihood of keloid formation. continuous pressure of 25e40 mmHg administered for at Furthermore, keloid forming tendency is also increased in least 23 hours per day for >6 months, while the scar is still puberty and pregnancy (because of increased MSH activity). active. A recent study observed that 20e25 mmHg was Taylor et al8 reported that a-MSH, which is produced by more effective than 10e15 mmHg in treating hypertrophic melanocytes, could increase TGF-b secretion and inhibit scars.10 However, according to a meta-analysis in 2009, no interferon (IFN)-a production by activating T cells, thus change in global scar scores was observed by pressure stimulating the multiplication of fibroblasts. therapy, and only a small (but statistically significant) 52 R.B. Ahuja et al. improvement was observed in scar height.11 Pressure recruitment, not specifying the drug dose per unit of the therapy is limited by the ability to adequately fit the scar, defining the end point of each injection inaccurately, garment to the wounded area and by reduced compliance or applying an inappropriate frequency of injections.22 In caused by side effects such as maceration and odor in hot addition, none of these studies has segregated scars and humid climates. Despite these limitations, some au- accompanied by a keloid diathesis, which pathophysiolog- thors have reported the effectiveness of pressure therapy ically behave quite differently.6 Ahuja and Chatterjee22 in pediatric age groups.12 In addition, postoperative pres- attempted to approach related trials more objectively by sure applied with pressure earrings reportedly reduces clearly defining the parameters for scar recruitment and recurrence rates markedly after surgical repair of earlobe injection. They established a relationship between a drug keloids.13 volume of 1.5 ml and a scar area of approximately 6 cm2 to Currently, the recommended clinical use of pressure ensure complete blanching of the lesion at the endpoint of garments is restricted to deep dermal wounds that have injection without exceeding the safe dose for TAC. All scars healed spontaneously over weeks, grafted wounds sur- received 0.7e0.9 ml of the drug (TAC) at the initial stages rounded by a deep dermal wound that have been allowed to and 1e1.5 ml as they softened. However, because of a lack heal spontaneously over weeks, hypertrophic wounds in of strong supporting evidence, Ahuja and Chatterjee rec- children and young adults, wounds in people with dark skin, ommended that the proposed 3-week injection schedule, and wounds in anatomical locations where compression can based on previous studies, should be reviewed to determine be applied.14 Ogawa (2010)15 recommended pressure ther- a more frequent regimen. A Chinese study proposed the use apy alone for contracture-free hypertrophic scars that of a combination of 5-fluorouracil (5-FU) (50 mg/ml) and would otherwise improve by physiologic scar maturation. A triamcinolone (40 mg/ml) at weekly intervals in a pro- large multicentric trial is necessary to determine optimal spective trial.23 approach, but the authors’ personal experience is in line Response rates with intralesional steroids are reported with the aforementioned recommendations. Currently, this from 50% to 100% and recurrence rates from 9% to 50%.24 is the only option available for managing widespread Combining TAC with 5-FU, pulsed dye laser (PDL), and postburn hypertrophic scarring (Fig. 1). cryotherapy has been reported to be more beneficial than TAC monotherapy, although few randomized controlled 2.2.2. Silicone-based products trials (RCTs) have tested these modalities.15 For older le- The mechanism of action of silicone-based products on sions, TAC was combined with cryotherapy for greater and scar tissue is unknown. Some researchers have suggested more marked response rates and is currently the most that silicone may penetrate the skin, but others have dis- widely used modality in Europe.12 The success rate of this missed this idea.16 Normalization of transepidermal water approach reportedly increased because larger volumes of loss was suggested as the likely underlying mechanism.17 A TAC could be injected into the scar following softening Cochrane review recently concluded that most related caused by cryotherapy.12 A study in 2006 concluded that studies have been of poor quality; therefore, the efficacy of TAC injections alone were effective in reducing the volume silicone gel sheets remains unclear.18 Nevertheless, the of lesions in most patients.25 Our experience validates this current guidelines on scar management regard silicone gel report for hypertrophic scars and keloids (without a sheeting as the first-line therapy for linear hypertrophic or diathesis).22 widespread burn hypertrophic scars and minor keloids.1 A Injecting the steroid sufficiently below the epidermis is study by Nast et al19 recommended that silicone sheets be crucial, or epidermal atrophy and extravasation in the applied for 12e24 hours per day over a period of surrounding tissue may ensue. Other adverse effects 12e24 weeks, beginning 2 weeks after the wounding. Sili- include telengiectasias, hypopigmentation, and pain at the con gels are equally or more effective than silicone gel injection site.12 Currently, intralesional TAC is the therapy sheets, and they are most commonly used with pressure of choice for small hypertrophic scars and recent-onset therapy. keloids.2

2.2.3. Intralesional triamcinolone injection 2.2.4. Cryotherapy Intralesional triamcinolone acetonide (TAC) is regarded as Cryotherapy with liquid nitrogen has been used either as a the gold standard in the management of less extensive monotherapy or in combination with intralesional TAC for hypertrophic scars and keloids and has been in use since the treating keloids.15 Traditional cryotherapy combined with 1960s. Synthetic corticosteroids decrease the production of intralesional TAC augments therapeutic efficacy. In an RCT, inflammatory cytokines, chemokines, and lysosomal en- Layton et al26 reported that early vascular lesions respon- zymes, and inhibit fibroblast proliferation.20 Furthermore, ded significantly more effectively to cryosurgery than late scars treated with TAC exhibit decreased levels of the lesions. Cryotherapy acts by inducing vascular damage, proteinase inhibitors a-2-macroglobulin and a-2-antitrypsin leading to anoxia and ultimately tissue necrosis. Approxi- in the scar, leading to decreased collagenase (matrix met- mately three to six sessions are typically necessary (at 3e4- alloproteinase 1) degradation.21 week intervals) to generate appropriate responses and Generally, 3e4 TAC injections (40 mg/ml) delivered via a postintervention healing. Commonly occurring side effects 25-26 g needle or dermojet, every 3e4 weeks are suffi- include permanent hypo- and hyperpigmentation, blis- cient, although occasionally the course may continue for 6 tering, and postoperative pain.27 months or more. Most studies on intralesional injections for Compared with contact probes, intralesional cryoprobes scarring can be criticized for one or more technical lapses (administered by needling) have an increased efficacy with of the trial, such as not defining the scar age for a shorter re-epithelialization period. Cryotherapy is Evidence appraisal for treatment of hypertrophic scars 53 effective for treating small keloids that are resistant to Nevertheless, its ability to treat thick keloids may be conventional treatment techniques. Har-Shai et al28 re- limited because its efficacy decreases with the thickness of ported a scar volume reduction of 70% for earlobe keloids the scar.35 and 60% for keloids on the upper back, shoulders, and chest Ablative or nonablative fractional and microfractional following a single cryotherapy session. The only adverse laser resurfacing procedures for correcting the abnormal event noted by the authors was minimal hypopigmentation, texture and pliability of a burn scar have been used and are with a nonresponse rate of <3%. a focus of ongoing research.36 Similarly, intense pulsed light therapy has also been investigated in alleviating burn scar 2.2.5. Intralesional verapamil dyschromia and chronic folliculitis.37 However, based on In 1990, Lee and Ping29 demonstrated that calcium channel the recently published German guidelines for treating blockers such as verapamil cause decreased extracellular excessive scarring, PDL is primarily recommended for matrix production in scars. Another study by Boggio et al30 reducing erythema in highly vascularized red scars, and for in 2011 demonstrated that verapamil depolymerizes actin treating severe pruritus. According to these guidelines, filaments to modify fibroblast morphology with a conse- treatment with conventional CO2 or Erbium-YAG lasers may quent increase in procollagenase secretions. Other studies be recommended for the ablation of inactive hypertrophic have reported using intralesional verapamil for treating scars.19 At a minimum, laser therapies can be combined burn scars and earlobe keloids. Margaret Shanthi et al31 with other commonplace treatments in managing burns were first to report that intralesional verapamil may be as scars. effective as TAC in treating hypertrophic scars and keloids. An RCT conducted by Ahuja and Chatterjee22 concluded 2.2.7. Intralesional antimitotic drugs that verapamil is almost as effective as TAC and offers Antineoplastic agents, such as 5-FU, bleomycin, and mito- several therapeutic possibilities in addition, such as use mycin C (MC), are used in the management of hypertrophic with triamcinolone in an alternating fashion or even scars and keloids. In particular, 5-FU has recently shown simultaneously in the treatment of larger or multiple scars. some efficacy in the treatment of keloids and HTS.38 It acts They also recommended administering a dose of 1.5 ml of by inhibiting DNA synthesis, thereby increasing fibroblast verapamil (2.5 mg/ml) per 6 cm2 area of lesion, injected apoptosis. Haurani et al39 combined 5-FU with a surgical every 3e4 weeks. Lesions generally require seven to eight excision of keloids, which failed to respond to intralesional sessions of injections (2e3 sessions more than when using TAC alone; only 19% of them recurred after 1 year of follow- triamcinolone injections) and show no major adverse up. Most studies have used the high-dose version of 5-FU reactions.22 therapy (40e50 mg/ml) to destroy the keloid. A low-dose therapy that involves using 1.4e3.5 mg/ml of 5-FU has 2.2.6. Lasers been shown to produce excellent results.40 In addition, A vascular-specific pulse dye laser (PDL) to treat hyper- there is enough evidence to support the use of a combi- trophic scars is rarely used in the clinical environment; nation of TAC (40 mg/ml) and 5-FU (50 mg/ml) in a 1:9 however, it has become the standard of care in some major ratio.41 burns centers.32 Lasers have been used either to prevent or Bleomycin sulfate, another antineoplastic agent, was treat hypertrophic scars by selective destruction of scar found to directly inhibit collagen synthesis through microvasculature through targeted photothermolysis. decreased stimulation by TGF-b1.42 Most studies have Other mechanisms for achieving clinical efficacy include demonstrated notable improvements in scar height and decreased cellular activity resulting from anoxia or colla- pliability, as well as reduction in erythema, pruritus, and genolysis by laser-stimulated cytokine release. pain after three to five injections (by using multiple needle Historically, the 585 nm PDL has been shown to effec- puncture or jet injections) of bleomycin (1.5 IU/ml) with a tively improve the pliability and texture of hypertrophic maximum of 2 ml/cm2 of skin.43 However, this option is scars, as well as reduce the erythema and associated more expensive compared with steroids and 5-FU. Appar- symptoms of pain and pruritus33; however, some recent ently, bleomycin is a promising alternative to 5-FU; how- studies do not agree with these findings.32 A study by Alster ever, cautious handling is necessary because of its toxicity and Nanni33 reported that an average of two to three and additional relevant studies are warranted. treatment sessions with an energy range of 4.5e6.5 J/cm2 Mitomycin C is an antineoplastic agent that inhibits DNA was required to reduce the scar surface area, and only one synthesis. Most studies on MC have been small and uncon- to two sessions were necessary to alleviate the symptoms. trolled, with a high degree of methodological variability. Treatment intervals of approximately six weeks were rec- Few data on hypertrophic scarring are available, and most ommended. Optimal results were obtained when the lasers data on keloids are based on clinical experience in post- were applied early. Following on from this study, the operative management.36 Additional studies are necessary 595 nm PDL has recently been found to have even greater for establishing this therapy. efficacy34; however, more RCTs are required to test its Based on the aforementioned data, we recommend efficacy and indications. The side effects are generally using antitumor drugs only for keloid diathesis and keloidal mild and predominantly include purpura, typically persist- scars which are resistant to other measures. The side ef- ing for 7e14 days. Depending on the energy density fects may include pain, hyperpigmentation, skin irritation, employed, vesicles and crusts may occur.12 In another and ulceration. Contraindications are anemia, leukopenia, study the 1064 nm Nd:YAG laser has recently shown thrombocytopenia, pregnancy, bone marrow depression, promise. The underlying mechanisms of action may be and infection. No systemic side effects have been similar to PDL, but the Nd:YAG reaches greater depths. reported.36,38e43 54 R.B. Ahuja et al.

2.2.8. Radiotherapy laser removal of tattoos. In addition, such creams are Superficial X-rays, electron beams, and low- or high-dose effective when used in combination with intralesional brachytherapy have been used as an adjunct to surgical TAC.54 removal of keloids, with favorable results in reduced 44,45 recurrence. Radiation mediates its effects on keloids 2.2.11. Botulinum toxin A through inhibition of neovascular buds and proliferating fi- Botulinum toxin A (BTA) immobilizes local muscles to broblasts, resulting in decreased collagen production. A reduce skin tension. Reduction of the tensile force during dose of 12 Gy divided into six to 10 fractions, applied daily the course of cicatrization in addition to effective regula- or every second day starting 24 hours after surgery, is tion of the balance between fibroblast proliferation and 19 currently recommended. The side effects include hypo- cellular apoptosis may represent a novel therapeutic option and hyperpigmentation, erythema, telangiectasia, and at- for the aesthetic improvement of postsurgical scars. Gass- 46 rophy. As radiation entails risks regarding carcinogenesis, ner et al55 demonstrated that administering BTA injections particularly in areas such as the breasts or thyroid, it should into the musculature adjacent to the wound (15 U and 2 cm 46 be used with caution, even if the risk is low. Even after incision length) within 24 hours after wound closure resul- e radiotherapy and surgery, a recurrence rate of 9 72% has ted in enhanced wound healing and less noticeable scars been reported, which generally depends on the total dose compared with a placebo. Other studies have advocated 44 of radiation and duration of follow-up. We suggest that injecting BTA 4e7 days prior to surgery.12 Recently, intra- radiation therapy should be reserved for keloid diathesis lesional BTA was proposed for treating established keloids alone because other modalities can adequately treat HTS in a prospective, uncontrolled study.56 BTA was injected and keloidal scars. at 3-month intervals for 9 months at a concentration of 35 U/ml. The total dose ranged from 70 to 140 units per 2.2.9. Immunomodulators session. At the 1-year follow-up, eight out of 12 patients Imiquimod cream (5%) acts topically by modifying the im- showed favorable-to-excellent results with no failures. mune response, and works by stimulating IFNs that increase Within the follow-up period of 1 year, no signs of recur- collagen breakdown. Additionally, imiquimod alters the rence were observed in any of the patients. However, expression of apoptosis-associated genes, and is reportedly another objective evaluation of BTA-treated keloids that effective in preventing recurrence of earlobe keloid after entails using optical profilometry revealed no changes in 47 excision. However, a high recurrence rate reported in scarring compared with the baseline characteristics.57 another study and contrasting data make this option Additional in-depth studies are required before this 5,47,48 questionable. comparatively expensive therapy can be suggested for the a IFN- 2b therapy can decrease the synthesis of Type I treatment of excessive scarring.36 and Type III collagen and it directly antagonizes the effects of TGF-b and histamine.49 One study showed that the systemic administration of IFN-a2b resulted in improved out- 3. Conclusions comes in seven out of nine patients.50 However, intralesional IFN injections have not been shown to have Hypertrophic scars, keloids, and scars of a keloid diathesis any effect.51 In addition, adverse effects are common with behave distinctly. A keloid diathesis should be considered a IFN treatment, including flu-like symptoms and pain on different entity because it behaves in the manner of a injection.49 benign fibroproliferative tumor of wound healing. Although In 2009, Ferguson et al52 summarized the results of three the treatment strategies are common for all scars, we double-blind, placebo-controlled trials with intradermal believe that antimitotic therapy (e.g., 5-FU) or radio- avotermin (recombinant TGF-b3). However, in 2011, after therapy should be reserved for a keloid diathesis; however, avotermin failed to hit its primary and secondary endpoints 5-FU may be rarely necessary for treating resistant keloidal in a Phase III trial, Renovo, the company manufacturing scars. Almost all hypertrophic scars and keloids can be avotermin, concluded that the efficacy of avotermin may managed using TAC or verapamil injections, and softening be insufficient in demonstrating significant benefits.53 We by cryotherapy can hasten response in long-standing scars. currently do not recommend the use of IFN or imiquimod; Compression garments and silicone gel or sheets are however, IFN may be a promising option in future for invariably used as adjuncts, although the supporting evi- treating resistant keloids or extensive hypertrophic scars. dence is not strong. Furthermore, pressure therapy and silicone sheets are the only modalities available in pre- 2.2.10. Onion extracts (Extractum cepae) venting and treating extensive postburn hypertrophic Extractum cepae has flavonoids (quercetin and kaempferol) scarring. Emerging therapies, such as BTA or IFN, have not that may play a role in scar reduction by inhibiting fibro- been subjected to large-scale RCTs, and avotermin has blast proliferation. It is hypothesized that these inhibitory failed to demonstrate adequate response in Phase III trials. effects may be mediated through the inhibition of TGF-b1 Creams with a combination of onion extracts and heparin and TGF-b2 by quercetin. Considerable industry-driven continue to be used extensively, although supporting evi- data have yielded contrasting results, thus diminishing the dence has emerged only recently and is still weak. Lasers credibility of using such drugs. However, recent studies are primarily used to diminish the hyperemic response or have shown that scar creams containing onion extracts can treat scar folliculitis. An informed approach is necessary to significantly improve scar height and associated symptoms effectively manage scar hypertrophy. Preventing hyper- compared with a placebo. They also appear to be effective trophy by following the surgical principles of wound healing in preventing unaesthetic scars in patients who undergo is critical. Evidence appraisal for treatment of hypertrophic scars 55

References 23. Wu XL, Gao Z, Song N, Liu W. Clinical study of auricular keloid treatment with both surgical excision and intralesional injection of low-dose 5-fluorouracil and corticosteroids. 1. Gold MH, McGuire M, Mustoe TA, et al. Updated international Zhonghua Yi Xue Za Zhi. 2009;28:1102e1105. clinical recommendations on scar management: part 2- 24. Robles DT, Berg D. Abnormal wound healing: keloids. Clin algorithms for scar prevention and treatment. Dermatol Dermatol. 2007;25:26e32. Surg. 2014;40:825e831. 25. Muneuchi G, Suzuki S, Onodera M, Ito O, Hata Y, Igawa HH. 2. Mustoe TA, Cooter RD, Gold MH, et al. International clinical Long-term outcome of intralesional injection of triamcinolone recommendations on scar management. Plast Reconstr Surg. acetonide for the treatment of keloid scars in Asian patients. 2002;110:560e571. Scand J Plast Reconstr Surg Hand Surg. 2006;40:111e116. 3. Kiristy CP, Lynch AB, Lynch SE. Role of growth factors in 26. Layton AM, Yip J, Cunliffe WJ. A comparison of intralesional cutaneous wound healing: A review. Crit Rev Oral Biol Med. triamcinolone and cryosurgery in the treatment of acne ke- 1993;4:729e760. loids. Br J Dermatol. 1994;130:498e501. 4. Brown JJ, Bayat A. Genetic susceptibility to raised dermal 27. Atiyeh BS. Nonsurgical management of hypertrophic scars: scarring. Br J Dermatol. 2009;161:8e18. evidence-based therapies, standard practices, and emerging 5. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat methods. Aesthetic Plast Surg. 2007;31:468e494. Rev Immunol. 2004;4:583e594. 28. Har-Shai Y, Sabo E, Rohde E, Hyams M, Assaf C, 6. Burd A, Huang L. Hypertrophic response and keloid diathesis: Zouboulis CC. Intralesional cryosurgery enhances the invo- two very different forms of Scar. Plast Reconstr Surg. 2005; lution of recalcitrant auricular keloids: a new clinical 116:150ee157e. approach supported by experimental studies. Wound Repair 7. Niessen FB, Spauwen PH, Schalkwijk J, Kon M. On the nature Regen. 2006;14:18e27. of hypertrophic scars and keloids: a review. Plast Reconstr 29. Lee RC, Ping JA. Calcium antagonists retard extracellular Surg. 1999;104:1435e1458. matrix production in connective tissue equivalent. J Surg Res. 8. Taylor AW, Yee DG, Nishida T, Namba K. Neuropeptide regu- 1990;49:463e466. lation of immunity: the immunosuppressive activity of alpha- 30. Boggio RF, Freitas VM, Cassiola FM, Uryabashi M, Machado- melanocyte-stimulating hormone (alpha-MSH). Ann N Y Acad Santelli GM. Effect of a calcium channel clocker (verapamil) Sci. 2000;917:239e247. on the morphology, cytoskeleton and collagenase activity of 9. Reno` F, Sabbatini M, Lombardi F, et al. In vitro mechanical human skin fibroblasts. Burns. 2011;37:616e625. compression induces apoptosis and regulates cytokines release 31. Margaret Shanthi FX, Ernest K, Dhanraj P. Comparison of in hypertrophic scars. Wound Repair Regen. 2003;11:331e336. intralesional verapamil with intralesional triamcinolone in the 10. Candy LH, Cecilia LT, Ping ZY. Effect of different pressure treatment of hypertrophic scars and keloids. Indian J Der- magnitudes on hypertrophic scar in a Chinese population. matol Venereol Leprol. 2008;74:343e348. Burns. 2010;36:1234e1241. 32. Brewin MP, Lister TS. Prevention or treatment of hypertrophic 11. Anzarut A, Olson J, Singh P, Rowe BH, Tredget EE. The burn scarring: a review of when and how to treat with the effectiveness of pressure garment therapy for the prevention pulsed dye laser. Burns. 2014;40:797e804. of abnormal scarring after burn injury: a meta-analysis. J 33. Alster TS, Nanni CA. Pulsed dye laser treatment of hypertro- Plast Reconstr Aesthet Surg. 2009;62:77e84. phic burn scars. Plast Reconstr Surg. 1998;102:2190e2195. 12. Gauglitz GG. Management of keloids and hypertrophic scars: 34. Vrijman C, van Drooge AM, Limpens J, et al. Laser and intense current and emerging options. Clin Cosmet Investig Dermatol. pulsed light therapy for the treatment of hypertrophic scars: 2013;6:103e114. a systematic review. Br J Dermatol. 2011;165:934e942. 13. Bran GM, Brom J, Hormann K, Stuck BA. Auricular keloids: 35. Akaishi S, Koike S, Dohi T, Kobe K, Hyakusoku H, Ogawa R. Nd: combined therapy with a new pressure device. Arch Facial YAG Laser treatment of keloids and hypertrophic scars. Plast Surg. 2012;14:20e26. Eplasty. 2012;12:e1. 14. Engrav LH, Heimbach DM, Rivara FP, et al. 12-Year within- 36. Gold MH, Berman B, Clementoni MT, Gauglitz GG, Nahai F, wound study of the effectiveness of custom pressure Murcia C. Updated international clinical recommendations on garment therapy. Burns. 2010;36:975e983. scar management: part 1-evaluating the evidence. Dermatol 15. Ogawa R. The most current algorithms for the treatment and Surg. 2014;40:817e824. prevention of hypertrophic scars and keloids. Plast Reconstr 37. Erol OO, Gurlek A, Agaoglu G, Topcuoglu E, Oz H. Treatment Surg. 2010;125:557e568. of hypertrophic scars and keloids using intense pulsed light(- 16. Ahn ST, Monafo WW, Mustoe TA. Topical silicone gel: a new IPL). Aesthetic Plast Surg. 2008;32:902e909. treatment for hypertrophic scars. Surgery. 1989;106:781e786. 38. Shridharani SM, Magarakis M, Manson PN, Singh NK, Basdag B, 17. Mustoe TA. Evolution of silicone therapy and mechanism of Rosson GD. The emerging role of antineoplastic agents in the action in scar management. Aesthetic Plast Surg. 2008;32: treatment of keloids and hypertrophic scars. Ann Plast Surg. 82e92. 2010;64:355e361. 18. O’Brien L, Jones DJ. Silicone gel sheeting for preventing and 39. Haurani MJ, Foreman K, Yang JJ, Siddiqui A. 5-Fluorouracil treating hypertrophic and keloid scars. Cochrane Database treatment of problematic scars. Plast Reconstr Surg. 2009; Syst Rev. 2013;9:CD003826. 123:139e148. 19. Nast A, Eming S, Fluhr J, et al. German S2k guidelines for the 40. Liu W, Wu X, Gao Z, Song N. Remodelling of keloid tissue into therapy of pathological scars (hypertrophic scars and keloids). normal-looking skin. J Plast Reconstr Aesthet Surg. 2008;61: J Dtsch Dermatol Ges. 2012;10:747e762. 1553e1554. 20. Roques C, Teót L. The use of corticosteroids to treat keloids: a 41. Darougheh A, Asilian A, Shariati F. Intralesional triamcinolone review. Int J Low Extrem Wounds. 2008;7:137e145. alone or in combination with 5-fluorouracil for the treatment 21. Rockwell WB, Cohen IK, Ehrlich HP. Keloid and hypertrophic of keloid and hypertrophic scars. Clin Exp Dermatol. 2009;34: scars. a comprehensive review. Plast Recontr Surg. 1989;84: 219e223. 827e837. 42. Espanã A, Solano T, Quintanilla E. Bleomycin in the treatment 22. Ahuja RB, Chatterjee P. Comparative efficacy of intralesional of keloids and hypertrophic scars by multiple needle punc- verapamil hydrochloride and triamcinolone acetonide in hy- tures. Dermatol Surg. 2001;27:23e27. pertrophic scars and keloids. Burns. 2014;40:583e588. 56 R.B. Ahuja et al.

43. Naeini FF, Najafian J, Ahmadpour K. Bleomycin tattooing as a 51. Davison SP, Mess S, Kauffman LC, Al-Attar A. Ineffective promising therapeutic modality in large keloids and hyper- treatment of keloids with interferon alpha-2b. Plast Reconstr trophic scars. Dermatol Surg. 2006;32:1023e1030. Surg. 2006;117:247e252. 44. Ragoowansi R, Cornes PG, Moss AL, Glees JP. Treatment of 52. Ferguson MW, Duncan J, Bond J, et al. Prophylactic adminis- keloids by surgical excision and immediate postoperative tration of avotermin for improvement of skin scarring: three single-fraction radiotherapy. Plast Reconstr Surg. 2003;111: double-blind, placebo-controlled, phase I/II studies. Lancet. 1853e1859. 2009;373:1264e1274. 45. Guix B, Henriquez I, Andre´s A, Finestres F, Tello JI, 53. Renovo stock demolished by Justiva trial failure. Pharma Martinez A. Treatment of keloids by high-dose-rate brachy- Times Available from: http://www.pharmatimes.com/ therapy: A seven-year study. Int J Radiat Oncol Biol Phys. Article/11-02-15/Renovo_stock_demolished_by_Justiva_ 2001;50:167e172. trial_failure.aspx. Last accessed 21 Jan 2015. 46. Ogawa R, Mitsuhashi K, Hyakusoku H, Miyashita T. Post- 54. Koc E, Arca E, Surucu B, Kurumlu Z. An open, randomized, operative electron-beam irradiation therapy for keloids and controlled, comparative study of the combined effect of hypertrophic scars: retrospective study of 147 cases followed intralesional triamcinolone acetonide and onion extract gel for more than 18 months. Plast Reconstr Surg. 2003;111: and intralesional triamcinolone acetonide alone in the 547e555. treatment of hypertrophic scars and keloids. Dermatol Surg. 47. Berman B, Harrison-Balestra C, Perez OA, et al. Treatment of 2008;34:1507e1514. keloid scars post-shave excision with imiquimod 5% cream: a 55. Gassner HG, Brissett AE, Otley CC, et al. Botulinum toxin to prospective, double-blind, placebo-controlled pilot study. J improve facial wound healing: a prospective, blinded, Drugs Dermatol. 2009;8:455e458. placebo-controlled study. Mayo Clin Proc. 2006;81: 48. Caçaõ FM, Tanaka V, Messina MC. Failure of imiquimod 5% 1023e1028. cream to prevent recurrence of surgically excised trunk ke- 56. Zhibo X, Miaobo Z. Intralesional botulinum toxin type A in- loids. Dermatol Surg. 2009;35:629e633. jection as a new treatment measure for keloids. Plast 49. Leventhal D, Furr M, Reiter D. Treatment of keloids and hy- Reconstr Surg. 2009;124:275ee277e. pertrophic scars: a meta-analysis and review of the literature. 57. Gauglitz GG, Bureik D, Dombrowski Y, Pavicic T, Ruzicka T, Arch Facial Plast Surg. 2006;8:362e368. Schauber J. Botulinum toxin A for the treatment of keloids. 50. Ladak A, Tredget EE. Pathophysiology and management of the Skin Pharmacol Physiol. 2012;25:313e318. burn scar. Clin Plast Surg. 2009;36:661e674.