Standard Treatments
These include occlusive dressings, compression therapy, and intralesional corticosteroid injections.
Occlusive dressings
Occlusive dressings include silicone gel sheets and dressings, nonsilicone occlusive sheets, and Cordran tape. These measures have been used with varied success, and overall the quality of the studies has been suboptimal.[4] Antikeloidal effects appear to result from a combination of occlusion and hydration, rather than from an effect of the silicone.
Previous studies have shown that in patients treated with silicone occlusive sheeting with pressure worn 24 h/d for up to 12 months, 34% showed excellent improvement, 37.5% showed moderate improvement, and 28% demonstrated no or slight improvement.
Of patients treated with semipermeable, semiocclusive, nonsilicone-based dressings for 8 weeks, 60% experienced flattening of keloids, 71% had reduced pain, 78% had reduced tenderness, 80% had reduced pruritus, 87.5% had reduced erythema, and 90% were satisfied with the treatment.
Cordran tape is a clear surgical tape that contains flurandrenolide, a steroid that is uniformly distributed on each square centimeter of the tape, and it has been shown to soften and flatten keloids over time.
Compression therapy
Compression therapy involves pressure, which has long been known to have thinning effects on skin. Reduction in the cohesiveness of collagen fibers in pressure-treated hypertrophic scars has been demonstrated by electron microscopy.
Cellular mechanoreceptors may have an important role of compression therapy. Mechanoreceptors induce apoptosis and are involved in the integrity of the extracellular matrix. An increase in extracellular matrix rigidity produced by compression garments leads to a higher level of mechanoreceptor activity and therefore more cellular apoptosis. Migration, proliferation, and differentiation of cells has been shown to be affected by rigidity; therefore, the rigidity caused by compression may also inhibit the differentiation and proliferation of scar fibroblasts in vivo.[5, 6]
Compression treatments include button compression, pressure earrings, ACE bandages, elastic adhesive bandages, compression wraps, spandex or elastane (Lycra) bandages, and support bandages. In one study, button compression (2 buttons sandwiching the earlobe applied after keloid excision) prevented recurrence during 8 months to 4 years of follow-up observation.
Other pressure devices include pressure earrings and pressure-gradient garments made of lightweight porous Dacron, spandex (also known as elastane), bobbinet fabric (usually worn 12-24 h/d), and zinc oxide adhesive plaster. Overall, 60% of patients treated with these devices showed 75-100% improvement.
Corticosteroids
Corticosteroids, specifically intralesional corticosteroid injections, have been the mainstay of treatment. Corticosteroids reduce excessive scarring by reducing collagen synthesis, altering glucosaminoglycan synthesis, and reducing production of inflammatory mediators and fibroblast proliferation during wound healing. The most commonly used corticosteroid is triamcinolone acetonide (TAC) in concentrations of 10-40 mg/mL administered intralesionally with a 25- to 27-gauge needle at 4- to 6-week intervals.
Intralesional steroid therapy as a single modality and as an adjunct to excision has been shown to be efficacious in various studies. Response rates varied from 50-100%, with recurrence rates of 9-50% in completely resolved scars. When combined with excision, postoperative intralesional TAC injections yielded a recurrence rate of 0-100%, with most studies citing a rate of less than 50%. Complications of repeated corticosteroid injections include atrophy, telangiectasia formation, and pigmentary alteration.
A standardized corticosteroid therapy protocol has been shown to reduce the recurrence of keloids and hypertrophic scars after excision. Intralesional TAC injection was performed after removal of the sutures and then once every 2 weeks (total of 5 treatments). In addition, patients were instructed to apply corticosteroid ointment twice daily for 6 months to the wounds after suture removal. Only 3 (14.3%) of 21 keloids and 1 (16.7%) of 6 hypertrophic scars recurred.[7]
Aradi et al studied 21 earlobe keloids that were treated using keloidectomy with core fillet flap and given intraoperative intralesional steroid injections. This study showed an efficacy of 87.6%. Immediate recurrence was 9.5%, with an average of 29.9 months of follow up and with few complications encountered. Subjectively, 82.3% of patients were satisfied.[8]
Published data show molecular-based evidence of the clinical benefits of adding 5-fluorouracil to a steroid injection for improved scar regression and reduced recurrence of keloids. 5-Fluorouracil–induced G2 cell-cycle arrest and apoptosis may be associated with p53 activation and p21 up-regulation. 5-Fluorouracil significantly affects the treatment when combined with triamcinolone, leading to more significant cell proliferation inhibition, apoptosis, Col-1 suppression, and MMP-2 induction.[9]
Current and New Treatments
Current treatments for keloids and hypertrophic scars include intralesional IFN; 5-FU; doxorubicin; bleomycin; verapamil; retinoic acid; imiquimod 5% cream; tacrolimus; tamoxifen; botulinum toxin; TGF-beta3; rhIL-10; VEGF inhibitors; etanercept; mannose-6-phosphate inhibitors (M6P); onion extract; the combination of hydrocortisone, silicon, and vitamin E; PDT; intense pulsed light (IPL); UVA-1; combination butyrate and docosahexaenoic acid[10] ; and narrowband UVB.
IFN therapy, including IFN alfa, IFN beta, and IFN gamma, has been demonstrated in in vitro studies to reduce keloidal fibroblast production of collagen types I, III, and VI mRNA.
IFN alfa and IFN beta also reduce fibroblast production of glycosaminoglycans (GAGs), which form the scaffolding for the deposition of dermal collagen. IFN gamma enhances GAG production.
IFN alfa, IFN beta, and IFN gamma have been shown to increase collagenase activity. Studies have shown that IFN gamma modulates a p53 apoptotic pathway by inducing apoptosis-related genes. p53 is a protein synthesized following DNA damage. Once damage is repaired, p53 is degraded. Mutations of this protein are believed to predispose cells to hyperproliferation, possibly resulting in keloid formation. In addition, p53 is a potent suppressor of interleukin (IL)–6, a cytokine implicated in hyperproliferative and fibrotic conditions.
IFN injected into the suture line of keloid excision sites may be prophylactic for reducing recurrences. Berman and Flores reported statistically significant fewer keloid recurrences in a study of 124 keloid lesions after postoperative IFN alfa-2b injection treatment (5 million U, 1 million U injected per cm of scar) into keloid excision sites (18%) versus excision alone (51.1%) and TAC treatment (58.4%).[11]
Tredget et al showed a significant increase in the rate of scar improvement compared with the control period of time (P = .004) after injecting 9 patients with hypertrophic scars with 1 X 106 units of human recombinant IFN alfa-2b subcutaneously, daily for 7 days, and then 2 X 106 units administered 3 times per week for 24 weeks in total.[12] Scar assessment (P< .05) and scar volume (P< .05) also improved after 3 months of treatment. No recurrences were reported after stopping IFN therapy.
Conejo-Mir et al reported that 66% of keloids (n = 20) did not recur after 3 years of follow-up after treating 30 keloids with ultrapulse carbon dioxide laser ablation followed by sublesional and perilesional injections of 3 million IU of IFN alfa-2b 3 times per week.[13]
In a 2008 prospective study, Lee et al reported decreases in depth (81.6%, P = .005) and volume (86.6%, P = .002) treating 20 keloids with a combination of intralesional TAC and IFN alfa-2b compared with only a nonsignificant improvement (P = .281 and P = .245, respectively) obtained in 20 keloids treated with TAC alone.[14]
Notably, however, several studies have failed to demonstrate the efficacy of IFN alfa-2b for the treatment of keloids and hypertrophic scars, including a case series of 5 patients treated by Wong et al,[15] a case series by al-Khawajah of 22 patients with keloids using lower doses of IFN alfa-2b than in prior studies,[16] and a prospective randomized clinical trial by Davison et al in which 50 patients with keloids received intraoperative intradermal injections of IFN alfa-2b at 10 million U/mL or TAC at 40 mg/mL, both receiving an extra injection 1 week later.[17]
Hypertrophic scar intralesional injections of human recombinant IFN gamma at 200 mcg (6 X 106 U) per injection for 4 weeks have been reported by Pittet et al to be effective for relieving the symptoms in 6 of 7 patients and decreases in redness, swelling, firmness, and lesion area in 7 of 7 patients.[18] At week 16, the reappearance of symptoms was minimal in only 2 of 7 patients and a small increase in the lesion area occurred in 4 of 7 patients, although these lesions remained smaller than the original area.
5-Fluorouracil
5-FU, a pyrimidine analogue with antimetabolite activity, inhibits fibroblastic proliferation in tissue culture and is believed to reduce postoperative scarring by decreasing fibroblast proliferation. Its efficacy and safety have been reported when used as a monotherapy or when used in combination with other drugs (eg TAC) for the treatment of other fibrosing conditions, including infantile digital fibromatosis, knuckle pads, rheumatoid nodules, and adverse foreign body reaction and sarcoidal granulomatous complications after soft tissue filler injection. Some data suggest that 5-FU is effective in the treatment of hypertrophic scars and is somewhat effective in small keloids. Several studies have shown the effectiveness of 5-FU.
In a retrospective study of 1000 patients with hypertrophic scars and keloids over a 9-year period, the most effective regimen was found to be 0.1 mL of TAC (10 mg/mL) and 0.9 mL of 5-FU (50 mg/mL) up to 3 times a week.
A total of 85% of keloids showed more than 50% improvement in an open study by Kontochristopoulos et al in which 20 keloids were treated once weekly with intralesional 5-FU (50 mg/mL) for an average of 7 treatments, with a recurrence rate of 47% within 1 year of the treatment. The Ki-67 proliferative index was significantly reduced (P = .0001) after treatment.[19]
Nanda and Reddy treated 28 patients with multiple keloids in a prospective, randomized, uncontrolled clinical trial with weekly intralesional injections of 5-FU at 50 mg/mL and reported almost 80% of the patients showing more than 50% improvement. Regression from the periphery and flattening occurred in all patients. In 22 of 28 patients, the symptoms completely disappeared, while the rest showed a good response. Decrease in size was reported in 70% of the patients.[20]
5-FU in combination with other therapies significantly increases the efficacy over single modalities.
In a double-blind randomized study, 40 patients with keloids or hypertrophic scars received 8 weekly intralesional injections of TAC 10 mg/mL or a combination of TAC 4 mg/mL plus 5-FU 45 mg/mL. At week 12, both groups showed improvement; however, the lesions in the TAC plus 5-FU group had significantly greater pliability and less erythema, height, length, and width (P< .05) than the TAC group compared with baseline (P<.05).<ref>21</ref>
In a randomized clinical trial by Asilian et al, 69 patients with keloids and hypertrophic scars were treated with a combination of 5-FU (50 mg/mL), TAC (40 mg/mL), and a 585-nm flashlamp-pumped pulsed-dye laser (PDL) at 5-7.5 J/cm2, showing that it was more effective than the TAC and TAC plus 5-FU.[22] At week 12, a statistically significant reduction in length, height, and width was observed in all groups compared with baseline (P< .05). In a randomized clinical trial, Manuskiatti and Fitzpatrick found a statistically significant clinical improvement in keloidal and hypertrophic sternotomy scars using these 3 modalities separately and a combination of TAC and 5-FU compared with baseline. No difference was found between the 4 treatment modalities.[23]
5-FU was used to treat a patient with keloids and hypertrophic scars post facial dermabrasion. The patient received 6 intralesional injections of 5-FU with silicone sheets applied afterwards over a 3-month span. During 7 months of follow up, a significant improvement in the size, color, and texture of the scars was noticed. In addition, the pain and itching had fully resolved.[24]
Sadeghinia et al compared the use of intralesional TAC 40 mg/mL at 20 mg/cm2 of lesion and 5-FU (50 mg/ml) tattooing in a double blind study. Forty patients were randomized into 2 groups, which received the treatment every 4 weeks for 12 weeks. At week 44, both groups showed improvement in all parameters (erythema, pruritus, height, surface, and induration), but improvement was more significant in the 5-FU group (P< .05).[25]
Although some studies have shown good results, it appears triamcinolone is a better-tolerated and less toxic alternative to 5-FU in the management of keloids.[26]
Doxorubicin (Adriamycin)
Doxorubicin (Adriamycin) is a commonly used chemotherapeutic agent that irreversibly inactivates prolyl 4-hydroxylase in human skin fibroblasts and has been shown to inhibit collagen alpha-chain assembly.
Sasaki et al showed through sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis that doxorubicin, at a clinically therapeutic concentration of 12.5 µm, inhibits the assembly of collagen triple-helical molecules.[27] SDS-PAGE analysis of control cultures showed a large fraction of [3H]proline-labeled procollagen polypeptides in triple-helical conformation; however, after the addition of doxorubicin at 12.5 µm, a very small amount of intact alpha-chains were found. These results suggest that the impaired wound healing observed in cancer patients who receive doxorubicin may result from the inhibition of prolyl 4-hydroxylase.
Another mechanism of doxorubicin-induced inhibition of collagen synthesis includes the inhibition of the enzyme prolidase, which is key in the process of collagen resynthesis, cleaving imidodipeptides containing C-terminal, and making proline available for its recycling and further generation of new collagen. Muszynska et al demonstrated this process in cultured human skin fibroblasts, also suggesting that this inhibition is a posttranslational event.[28, 29]
Other agents such as doxycycline, other nonsteroidal anti-inflammatory drugs (ie, acetylsalicylic acid, sodium salicylate, phenylbutazone, indomethacin), daunorubicin, gentamicin, netilmicin, anthracycline)[30] are also capable of inhibiting prolidase in cultured human skin fibroblasts. Further studies are warranted to determine if doxorubicin or any of the above-mentioned agents can be useful to treat patients with excessive scarring.
Bleomycin
Bleomycin injections cause necrosis of keratinocytes with a mixed inflammatory infiltrate. Several studies have demonstrated that bleomycin can be used effectively to treat keloids and hypertrophic scars.
Bleomycin was given at a concentration of 1.5 IU/mL to 13 patients using the multiple-puncture method. Bleomycin was dripped onto the lesion, and then multiple punctures were made on the lesions using a syringe. Seven patients had complete flattening, 5 patients had highly significant flattening, and 1 patient had significant flattening. Likewise, Espana et al also reported complete flattening in 6 of 13 patients, highly significant flattening in 6 of 13 patients, and significant flattening in a single patient. Two patients presented a recurrence as a small nodule 10 and 12 months after the last infiltration.[31]
In another study of 31 keloids, patients were treated with 3-5 infiltrates of bleomycin within a 1-month period. Total regression occurred in 84% of the keloids, and both keloid volume and functional impairment were reduced.
Bodokh and Brun reported complete flattening in 69.4% of 36 patients with keloids and hypertrophic scars.[32] Saray et al obtained complete flattening in 73.3%, highly significant flattening in 6.7%, and moderate flattening in 6.7% of lesions after the administration of jet intralesional injections of bleomycin in 15 patients.[33]
In the only randomized clinical trial using the tattooing technique, with which smaller amounts of the drug are absorbed, thus minimizing systemic adverse effects, Naeini et al reported significantly better results with intralesional bleomycin compared with the control group (ie, combination of cryotherapy and TAC) in lesions larger than 100 mm2 (P = .03).[34] Local complications, such as hyperpigmentation, were observed in 75% of the patients.
Fifty patients with keloids and hypertrophic scars were treated with intralesional bleomycin. Three applications were given at 15-day intervals, and a fourth and final application was given 2 months after the third application. Complete flattening was observed in 44%, significant flattening in 22%, adequate flattening in 14%, and no flattening in 20%. Pruritus was relieved completely in 89% of patients.[35]
Manca et al have found that electroporation in combination with bleomycin is an effective treatment for keloids or hypertrophic scars or for those who are nonresponders to other treatments. In their study, 20 patients with keloids or hypertrophic scars had a median reduction of 87% in volume and 94% of the lesions showed volume reduction of more than 50%. Scar pliability and erythema scores were also significantly reduced. Less pruritus was observed in 89% of patients and pain was reduced in 94%.[36]
The combination of bleomycin and intralesional steroids such as triamcinolone has repeatedly shown good results. More recently, Camacho-Martinez et al designed a two-part study. They used 0.375 IU of bleomycin and 4 mg of triamcinolone acetonide to 1 cm2 and it was considered an acceptable procedure for the treatment of keloids. The best results were obtained in keloids larger than 1 cm2 or when divided into 1-cm2 square areas.[37]
Verapamil
Verapamil is a calcium channel blocker that blocks the synthesis and secretion of extracellular matrix molecules (eg, collagen, GAGs, fibronectin) and increases fibrinase.
In a study of 22 patients with keloids, patients were treated with surgical excision in combination with reconstruction with W-plasty or skin grafting and injection of verapamil (5 treatments of verapamil at 2.5 mg/mL-varying doses from 0.5-5 mL), depending on keloid size) over a 2-month period and were evaluated at 2-year follow-up. Two patients had keloids that decreased in size from the original lesion, 2 patients had hypertrophic scars, 4 patients had pruritus, and 1 patient had a keloid on the donor site (skin grafting site). The case series reported an average of 6.4 in patient satisfaction on a scale from 1 to 10.[38]
D’Andrea et al, from a case-control comparative study, reported resolution in 54% of the patients who had their keloids treated by a combination of surgical excision, silicon sheeting, and intralesional verapamil versus 18% in the control group without intralesional verapamil.[39] The recurrence rate was 36% in the active group after 18 months of follow up.
In a case series, Skaria reported complete resolution of 4 of 6 keloids and 1 of 2 hypertrophic scars at 1-year follow-up after surgical removal of the scar and further intralesional injection of verapamil at doses of 2.5 mg/mL.[40]
Lawrence reported 55% cured earlobe keloids in 52% of the patients after the combination of surgical excision, intralesional verapamil, and pressure earrings after an average of 28 months of follow-up.[41]
In a randomized clinical trial, Margaret Shanthi et al compared intralesional verapamil and intralesional TAC for the treatment of keloids and hypertrophic scars, reporting a reduction in vascularity, pliability, height, and width in both groups after 3 weeks of treatment. This result was maintained at 1 year after stopping the treatment. Although the rate of improvement was faster in the TAC group, overall, no difference was noted between the 2 groups.[42]
Ahuja et al studied 40 patients (48 scars) and compare the effects of triamcinolone and verapamil injections. This group concluded that even though the criterion standard first-line treatment is still triamcinolone, verapamil is almost equally effective, with very few adverse effects, and offers a therapeutic option to treat larger and recalcitrant scars.[43]
Retinoic acid
Retinoic acid decreases normal tonofilament and keratohyalin synthesis, increases the production of mucoid substances and the epidermal cell growth rate, and inhibits DNA synthesis in vitro.
In a clinical trial involving 21 patients with 28 keloids and hypertrophic scars, topical retinoic acid was applied for at least 3 months twice daily and showed favorable results in 77-79% of the lesions. This includes a decrease in the size and symptoms of the scar.[44]
In addition, because retinoids affect collagen metabolism, another study involving 9 females and 2 males with keloids treated with 0.05% tretinoin topically for 12 weeks showed a significant decrease in weight (P< .04) and size (P< .01) of the keloids when comparing the status of the lesions at the beginning of the study and at week 12.[45]
In vitro studies have demonstrated that retinoids can modulate collagen production and the proliferation of normal and keloidal fibroblasts. In vivo applications of 0.05% topical retinoic acid can lead to a reduction of hypertrophic scars in 50-100% of patients and of keloids in less than 20% of patients. The most common adverse effects reported have been photosensitivity, irritant contact dermatitis, and skin atrophy.
Retinoids can be used also as a preventive treatment. Kwon et al compared silicone gel and tretinoin cream use after studying 44 scars post surgery. They found that after 24 weeks of treatment, both therapeutic modalities were equally effective in preventing hypertrophic scars and keloids compared with the control group.[46]
Imiquimod
Imiquimod (1-[2-methylpropyl]-1H-imidazo[4,5-c]quinolin-4-amin) belongs to the family of imidazoquinolines. Imiquimod induces TNF-alpha, IFN-alpha and IFN-gamma, IL-1, IL-4, IL-5, IL-6, IL-8, and IL-12 and alters the expression of markers for apoptosis.
In one study, 13 keloids were treated with excision in combination with nightly applications of imiquimod 5% cream for 8 weeks. Ten patients with 11 keloids completed the 6-month study, and no keloids recurred after 6 months. Mild irritation was experienced with the application of imiquimod, and some patients needed a vacation period from the medication. Hyperpigmentation was experienced by more than half of the patients in the study.[47]
In 2 different pilot studies, imiquimod 5% cream was applied on postshaved or totally excised earlobe keloids. It was demonstrated that the recurrence rate on postshaved keloids was 0% after 12 months of follow-up and 75% recurrence-free after 24 weeks of parallel keloid excision. Although the presence of local adverse events did not affect the treatment, a resting period was needed.[48, 49]
In a different study, 15 patients with hypertrophic scars 2 months after breast surgery were treated with either petrolatum or imiquimod 5% cream. At 24 weeks, almost all the scars treated with imiquimod scored better after assessment with standardized scales. The results demonstrated that imiquimod treatment improved scar quality and color match after surgery.[50]
More recently, in study by Chuangsuwanich et al, 45 patients with excised keloids were treated with imiquimod 5% cream 2 weeks after the operation, on alternate nights, for 8 weeks.[51] After a follow-up period of 6-9 months, 10 of the keloids recurred (28.6% overall recurrence rate), with adverse effects found in 13 patients (37.1%). Interestingly, the keloids localized on the pinna had the lowest recurrence rate (2.9%) compared with those at the chest wall or neck (83.3% and 14.3%, respectively).
Tacrolimus
Tacrolimus is an immunomodulator that inhibits TNF-alpha. Gli -1, an oncogene, has been found to be overexpressed in fibroblasts of keloids. Inhibition of this oncogene may restore the natural apoptosis process and decrease proliferation of the ECM protein.[52] Rapamycin, a close analogue of tacrolimus, was used in an in vitro study and was found to inhibit the gli -1 oncogene, thus giving a rationale to initiate clinical trials of topical tacrolimus and rapamycin.
In an open-label pilot study, 11 patients used tacrolimus 0.1% ointment twice daily for 12 weeks on their keloids. Although the results were not statistically significant, the study showed a decrease in induration, tenderness, erythema, and pruritus for most patients.[53]
Kim et al observed the resolution of a keloid in a patient during a course of topical tacrolimus for atopic dermatitis.[52]
Sirolimus
Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a serine/threonine kinase that regulates collagen expression. By inhibiting mTOR, sirolimus blocks the response to IL-2 and decreases ECM deposition.[54] Similar to rapamycin, sirolimus inhibits Gli -1 signal transduction. mTOR kinases form 2 distinct multiprotein complexes, mTORC1 and mTORC2. In an in vitro and ex vivo study, 2 compounds, KU-0063794 and KU-0068650, were demonstrated to be potent and highly selective competitive inhibitors of mTORC1 and mTORC2 compared with rapamycin, which inhibits mTORC1 alone. The compounds have shown promising antifibrotic activity, with apparent no toxicity in vivo.[55]
A higher concentration of VEGF and higher blood vessel density has been found in the basal layer of the epidermis of keloidal tissue in comparison to normal skin. In co-cultured keloid keratinocytes and fibroblasts exposed to sirolimus, VEGF expression has shown to be down-regulated in a dose-dependent manner. Through inhibition of VEGF, sirolimus may control the expression profile of underlying dermal fibroblasts.
Tamoxifen
Tamoxifen, a synthetic nonsteroidal antiestrogen used to treat breast cancer, has been shown to inhibit proliferation of keloid fibroblasts and their collagen synthesis in monolayer cultures. Hu et al demonstrated that tamoxifen exhibits a dose-dependent and reversible inhibition of contraction of adult human dermal fibroblast in vitro.[56]
Tamoxifen has also been shown to reduce TGF-alpha, and its isoform TGF-alpha1, production by keloid fibroblasts in vitro. Mikulec et al have shown that keloid fibroblasts have significantly lower TGF-alpha1 production when exposed to 16 µmol/L of tamoxifen at day 2 of culture when compared with control keloid fibroblasts (P = .05).[57]
Botulinum toxin A
Botulinum toxin A (BTA) is a neurotoxin that causes a flaccid paralysis of the local musculature and reduces skin tension. This reduction in the skin tensile force during the course of wound healing may represent a novel therapeutic target for treating keloids.
In an in vitro study, 64% of cultured fibroblasts were found to be in the G0-G1 phase of the cell cycle when exposed to BTA, while 35.4% were in the proliferative phases (ie, G2, M, S). In comparison, cultured fibroblasts that were not exposed to BTA had the following distribution: 36% (G0-G1) and 64% (proliferative phases).[58] The effect of BTA on the cell cycle distribution of fibroblasts may indicate that BTA can improve the eventual appearance of and inhibit the growth of hypertrophic scars and keloids.
In a prospective, uncontrolled study evaluating the effects of BTA in the treatment of keloids, 12 keloids were injected intralesionally at a concentration of 35 U/mL, with the total dose varying from 70-140 U per session. Injections were given at 3-month intervals for a maximum of 9 months. At 1-year of follow up, the therapeutic outcomes were excellent (n = 3), good (n = 5), and fair (n = 4), with no patients failing therapy or showing signs of recurrence.[59]
Nineteen patients with hypertrophic scars received intralesional injections of BTA (2.5 U/mL at 1-mo intervals) for 3 months. All patients showed acceptable improvement of the scars at 6 months of follow up. The erythema, pruritus, and pliability scores were significantly lower post-BTA injections compared with baseline.[60]
In a case series, 12 patients (n=10 whites, n=01 Chinese, and n=01 South Asian) with keloids in different parts of the body (n=9 presternal; n=3 neck, thigh, and cheek), previously treated with conventional modalities, received between 20 and 100 units of BTA on each visit over the past 5 years (no frequency specified). Eight patients had concurrent alternating intradermal triamcinolone injections. Complete flattening of the keloids was obtained after a range of 2-43 months of repeated injections. Two of 12 patients had recurrences adjacent to previously treated areas. One patient developed atrophy, leading to ulceration and further recurrence.[61]
Intramuscular injections of BTA along with scar revision techniques on the face may help to reduce the development of a wider scar.[62]
Larger, randomized, controlled studies are warranted to determine the role of BTA in the treatment of keloids and hypertrophic scars.
TGF-beta and isomers
TGF-beta and its isomers have been shown to play a central role in fibrotic disorders characterized by excessive accumulation of interstitial matrix material in the lungs, kidneys, liver, and other organs. TGF-beta1 and TGF-beta2 have been shown to stimulate fibroblasts to produce collagen and have a direct and independent effect on the contraction of fibroblasts in vitro. However, TGF-beta3 may prevent scarring.
A study by Shah et al demonstrated that exogenous addition of TGF-beta3 reduces fibronectin and collagen types I and III deposition in the early stages of cutaneous rat wound healing and in overall wound scarring.[63]
A new antifibrotic product, avotermin (Juvista, Renovo; Manchester, United Kingdom) has been extensively studied. Avotermin is derived from human recombinant TGF-beta3. This product has shown promise in a phase I trial and 2 phase II trials completed in the United Kingdom. In these studies, wounds treated with avotermin showed a statistically significant improvement in scar appearance, with a response rate of greater than 70%. After analyzing safety data on more than 1500 human subjects, avotermin does not seem to have safety or tolerability issues for use in the prevention or reduction of scarring.
In a randomized, double-blind, placebo-controlled, within-patient, phase II trial to investigate the safety and efficacy of 200 ng per 100 μL per linear cm of wound margin of avotermin when administered twice following scar revision surgery, the overall analysis showed that the primary endpoint (ie, photographic evaluation by a lay panel over a period from week 6 to month 7 postsurgery using a visual analogue scale) was met (P = .038). Investigator assessment at 7 months postsurgery using a visual analogue scale also obtained statistical significance (P = .036). Approximately 75% of the 7-month scars assessed from avotermin-treated wounds were considered to have a structure more like normal skin compared with the placebo in the histopathological analysis.[64]
Bush et al evaluated 71 subjects (aged 18-45 y) who received avotermin at 50 or 200 ng/100 μL/linear centimeter of wound margin. Incisional wounds on the inner aspect of each upper arm were randomized to receive the following: no injection (standard wound care only), 1 intradermal injection of avotermin or placebo (immediately before surgery), or 2 injections of avotermin or placebo (immediately before surgery and 24 h later). Avotermin at 200 ng/100 μL/linear centimeter, administered once or twice, achieved significant improvements in scar appearance compared with controls (P< .02 for all comparisons). The 50-ng dose, administered twice, achieved significant improvements in scar appearance versus placebo (P = .043). Treatment was well tolerated.[65]
A double-blind, randomized study (ie, RN1001-0042) evaluated the efficacy and safety of 4 doses of avotermin given once. A total of 156 patients undergoing bilateral surgery to remove varicose leg veins by saphenofemoral ligation and long saphenous vein stripping were studied. Four different doses of avotermin were administered (5, 50, 200 or 500 ng per 100 µL, at 100 µL per linear cm of wound margin). The primary efficacy variable was lay panel Total Scar Score (ToScar) assessed between 6 weeks and 7 months. Avotermin 500 ng significantly improved groin scar appearance compared with placebo (mean lay panel ToScar difference 16·49 mm; P = .036). Avotermin 500 ng per 100 µL per linear cm of wound margin given once is well tolerated and significantly improves scar appearance.[65, 66, 67, 68, 69]
TGF therapy is currently being studied in ongoing clinical trials for use as an adjuvant treatment following excision of earlobe keloids.[70, 71, 72]
Epidermal growth factor
Epidermal growth factor (EGF) is a growth factor produced by platelets, macrophages, and monocytes and is activated by binding with the EGF receptor present on keratinocytes and fibroblasts.[73] It acts by stimulating keratinocyte proliferation and altering fibroblast activity, resulting in reduced healing time and improved tensile strength of scars.[74, 75] It has been found to be involved in wound healing. It is up-regulated early in the fetal period and is thought to be an important cytokine in scarless fetal healing.[76]
The role of recombinant human EGF (rhEGF) in scars is being investigated. In a murine full-thickness wound model, rhEGF decreased TGF-beta1 expression, suppressing collagen deposition and reducing cutaneous scars.[77]
rhEGF has also been studied in human studies. Shin et al evaluated the effects of rhEGF for scar prevention post thyroidectomy. The total Vancouver Scar Scale (VSS) was significantly lower in the treatment compared with the control group, although erythema, pigmentation, elasticity, and hydration were not significantly different.[78]
Hydrogel scaffold
Hydrogel scaffold is approved for used in Europe for improvement of wound healing and scarring and is available as an injectable porcine gelatin-dextran hydrogel scaffold.[79] Its approval is for injection of incisional sites immediately prior to closure. It is thought to function as a lattice for fibroblast adherence, leading to more regulated and organized distribution, with improved wound healing outcome.
Hydrogel scaffold has also been studied in the treatment of keloids. Berman et al studied 19 subjects with 26 ear keloids. They were treated with excision followed by injection with 3 mL of the scaffold per 2.5 cm of wound margin, along with wound margin approximation and closure.[80] At 12-month follow-up, the recurrence rate was 19.2%, and each of the recurrences measured less than 15% of the original volume, with 60% of the recurrences measuring less than 5%. As well, the average patient scar satisfaction on a scale of 1-10 was 9.9.
Other potential targets
Potential therapeutic targets include decapentaplegic homolog (Smad)3, high-mobility group box protein-1, and calcimycin.[113, 114, 115]
Laser Therapy
Ablative lasers
Carbon dioxide, argon laser, and Nd:YAG laser (1064 nm)
Ablation of keloids and hypertrophic scars using a carbon dioxide laser (10,600 nm) can cut and cauterize the lesion, creating a dry surgical environment with relatively minimal tissue trauma. When used as a single modality, the carbon dioxide laser was associated with recurrence rates of 39-92%, and when the carbon dioxide laser was combined with postoperative injected steroids, it was associated with recurrence rates of 25-74%.
A Korean study included 30 patients with hypertrophic scars treated with a combination of 3 different therapeutic modalities: 10600-nm ablative carbon dioxide laser (AFL), copper bromide laser (CBL), and intralesional TAC. At the end of the study, CBL achieved better outcomes for vascularity and pigmentation. AFL and AFL plus TAC were especially effective with regard to thickness and pliability. AFL produced epidermal resurfacing due to collagen remodeling. CBL plus TAC did not aggravate vascularity and pigmentation, suggesting that CBL may compensate for the erythema resulting from TAC. In conclusion, the combination of CBL, AFL, and intralesional TAC may provide a new treatment option for hypertrophic scars.[87]
Erbium:Yttrium aluminum garnet laser
(Er:YAG)
Er:YAG laser showed a decrease of 51.3% in redness, 50% in elevation, and 48.9% in hardness of keloids in one study after treating 21 keloids. The recurrence rate was not reported.[88]
Similar to the carbon dioxide laser, the argon 488-nm laser can induce collagen shrinkage via generation of excessive localized heat. The argon laser has demonstrated recurrence rates of 45-93%.
Nonablative lasers
Pulsed-dye laser (585 nm)
The 585-nm PDL provides photothermolysis, resulting in microvascular thrombosis. Beginning in the 1980s, authors noted that scars became less erythematous, more pliable, and less hypertrophic after treatment with the 585-nm PDL. The findings were later confirmed using objective measurements of erythema by reflectance spectrometry readings, scar height, and pliability measurements. Because of its efficacy, safety, and relatively low cost, the PDL remains the laser treatment of choice for hypertrophic scars. Multiple publications have continued to confirm the role of the 585-nm PDL for the treatment of keloids and hypertrophic scars.
In a randomized clinical trial, Manuskiatti et al treated 10 keloidal or hypertrophic median sternotomy scars with a 585-nm flashlamp-pumped PDL at fluences of 3, 5, and 7 J/cm2, and one segment was left untreated as a control.[23] They showed consistently better results in the treatment groups over the control. A trend was obtained towards lower fluences having more rapid onset of benefits and enhanced resolution of erythema, induration, and elevation of the scar. Multiple treatment sessions achieved greater clinical improvement.
Alster treated 44 bilateral, symmetric hypertrophic breast-reduction scars with a 585-nm PDL at 4.5-5.5 J/cm2 alone or in combination with intralesional TAC at 10-20 mg/mL injected immediately after the PDL irradiation.[89] All scars showed clinical improvement. The average pliability scores decreased by 50% after 2 sessions in both groups. The concomitant use of TAC reduced symptom scores by 70% compared with PDL alone (50%).
In a prospective, randomized clinical trial, Nouri et al treated 11 patients with 12 postoperative scars with 585-nm PDL at 3.5 J/cm2 versus no treatment.[90] The average overall improvement scores after one treatment was superior to the control (P = .0002). Vascularity improved 54% in treated halves, compared with 8% in controls. (P = .002). A total of 38% of halves returned to normal vascularity, compared with 0% in controls. Pliability improved 64% versus 1%, respectively (P = .002). A total of 62% of halves returned to normal pliability compared with 0% in control halves. The cosmetic appearance score was significantly better for the treated halves than for the untreated controls (7.3 vs 5.2; P = .016).
In contrast, Wittenberg et al found in a prospective, single-blinded, randomized, controlled study an overall reduction in blood flow (P = .001), volume (P = .02), and pruritus (P = .005) over time after a follow-up period of 4 months after treatment discontinuation, but no differences were noted among treatment and control groups treating hypertrophic scars with a 585-nm flashlamp-pumped PDL at 6.5-8 J/cm2 or silicone gel sheeting, or no treatment.[91]
Pulsed-dye laser (595 nm)
Two studies have demonstrated that the 585-nm PDL has more effectively cleared port-wine stains than the 595-nm PDL at the same settings. Murine studies determined that the beneficial effect of lasers inhibiting the scar tissue growth decreased as the wavelength of the laser was increased from 585 to 600 nm. Further studies are necessary to obtain similar conclusions in human tissue. However, longer wavelength (eg, 595 nm) is an alternative vascular-specific laser for dark-skinned patients, with higher amounts of epidermal melanin, which absorbs more readily the 585-nm wavelength, causing nonspecific damage to pigmented epidermis. Currently, 595-nm PDL systems incorporate in the handpiece a cryogen-spray cooling device, which permits safe and effective treatment of hypertrophic scars by raising the threshold for epidermal damage, avoiding the resultant epidermal necrosis when the skin surface temperatures exceeds 70°C immediately after PDL exposure.
In a prospective randomized clinical trial, Conologue et al treated 16 patients with postoperative scars immediately after suture removal with a 595-nm cryogen-cooled PDL at 8 J/cm2 and showed significant improvement (60%) versus the untreated control (-3%) in the average sum of all clinical parameters measured.[92] Improvement was noted in vascularity (69%) versus the control (0%) (P = .53) and in pliability (67%) compared with the control (-8%) (P = .337).
In order to compare the 0.45-millisecond (short) pulse width with the 40-millisecond (long) pulse width, Manuskiatti et al treated 19 patients with keloidal and hypertrophic sternotomy scars in a prospective randomized clinical trial, with a 595-nm PDL at 7 J/cm2 and a cryogen spray cooling device.[93] The short pulse width demonstrated greater overall improvement (P = .046) and scar pliability. Both pulse widths significantly reduced scar height compared with baseline; however, no differences were found between the groups. No effects were noted on scar erythema with either treatment. Both treatments were safe and effective in dark-skinned individuals.
Bellew et al randomly treated 15 hypertrophic scars with a 595-nm long-pulsed PDL at 7 J/cm2 with a concomitant skin-surface cooling device or with an IPL system with a 570-nm cut-off filter and a fluence of 40-45 J/cm2 and a triple pulse, reporting a mean improvement in the long-pulsed PDL group of 80% compared with 65% in the IPL group.[94] However, no statistical difference was noted between the 2 groups. Both systems are equally effective in improving the appearance of hypertrophic surgical scars. IPL minimizes the risk of purpura.
In contrast, however, Alam et al found no beneficial effect on clinical scar appearance at 6 weeks post treatment versus untreated control, after treating 20 patients with postoperative scars in a prospective, randomized, controlled trial using a 595-nm PDL at 7 J/cm2 and a 30-millisecond dynamic cooling spray.[95]
Neodymium:Yttrium, aluminum, garnet laser (1064 nm) (Nd:YAG)
Several studies, mostly case series, have been published on the Nd:YAG laser (1064 nm). A case series showed persistent flattening of keloids or hypertrophic scars in 5 (22.7%) of 22 scars 12 months after Nd:YAG treatment.[96] A clinical trial obtained a reduction in the size of the scars of 10% or greater in 8 (36.4%) of 22 patients treated with Nd:YAG at 3- to 4-week intervals.[97] The Nd:YAG laser appears to improve the cosmetic appearance of keloids and may be a superior treatment modality than PDL lasers.[98]
Author
Brian Berman, MD, PhD, Dermatologist and Partner, Skin and Cancer Associates; Professor Emeritus of Dermatology and Cutaneous Surgery, University of Miami, Leonard M Miller School of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Aclaris; Bifrontera; Aiviva; Pulse; Celumigen; Dermira; DUSA Sun Pharmaceutical; Exeltis, Ferndale; Galderma; GSK; Halscion; Klara; Leo; Medimetriks; Miragen; Novan; Novartis; Smith & Nephew; TopMD; Valeant Pharmaceuticals; Anacor; Aclaris; Menlo;<br/>Serve(d) as a speaker or a member of a speakers bureau for: Sun; Exeltis, Ferndale; Galderma; GSK; Halscion; Leo Pharmaceuticals; Medimetriks; Miragen; Novan; Novartis; Valeant Pharmaceuticals; Anacor; Clark; Aclaris; Sensus<br/>Received research grant from: Celumigen; Dermira; DUSA; Exeltis, Ferndale; Galderma; Leo; Menlo; Anacor; Clark; Pulse; Miragen; Sensus<br/>Received income in an amount equal to or greater than $250 from: Bifrontera; Aiviva; Pulse Biosciences; Dermira; DUSA; Sun; Menlo; Sirnaomics; Exeltis, Ferndale; Galderma; GSK; Halscion; Leo; Medimetriks; Miragen; Novan; Novartis; Smith & Nephew; TopMD; Valeant Pharmaceuticals; Anacor; Clark; Aclaris; Sensus.
Coauthor(s)
Andrea D Maderal, MD, Resident Physician, Department of Dermatology and Cutaneous Surgery, Jackson Memorial Hospital, University of Miami, Leonard M Miller School of Medicine
Disclosure: Nothing to disclose.
Martha H Viera, MD, Resident Physician, Department of Dermatology and Cutaneous Surgery, Jackson Memorial Hospital, University of Miami, Leonard M Miller School of Medicine
Disclosure: Nothing to disclose.
Sadegh Amini, MD, Dermatologist, Skin Cancer Associates; Voluntary Assistant Professor, Department of Dermatology and Cutaneous Surgery, University of Miami, Leonard M Miller School of Medicine.
Disclosure: Own stocks at NYSE for: AbbVie Inc.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Steven R Feldman, MD, PhD, Professor, Departments of Dermatology, Pathology and Public Health Sciences, and Molecular Medicine and Translational Science, Wake Forest Baptist Health; Director, Center for Dermatology Research, Director of Industry Relations, Department of Dermatology, Wake Forest University School of Medicine
Disclosure: Received honoraria from Amgen for consulting; Received honoraria from Abbvie for consulting; Received honoraria from Galderma for speaking and teaching; Received consulting fee from Lilly for consulting; Received ownership interest from www.DrScore.com for management position; Received ownership interest from Causa Reseasrch for management position; Received grant/research funds from Janssen for consulting; Received honoraria from Pfizer for speaking and teaching; Received consulting fee from No.
Chief Editor
Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Arash Taheri, MD, Research Fellow, Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Whitney Valins, MD, to the development and writing of the source articles.
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