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INTRALESIONAL APPROACHES
INTRALESIONAL APPROACHES
IL therapies are first-line treatments for keloids and hypertrophic scars.1 IL therapies are able to effectively deliver active ingredients directly to the site of the keloid, minimizing systemic side effects. Various IL therapies have been evaluated for the treatment of keloids, including corticosteroids, 5-fluorouracil (5-FU), verapamil, interferon (IFN), bleomycin, and botulinum toxin-A (BTX-A). The IL technique has also been used to deliver cryotherapy, and, more recently, for the insertion of a hydrogel scaffold to incision sites for prevention of keloid scars.
Corticosteroids IL steroids are the mainstay of keloid management. Steroids function by several
mechanisms, including inhibiting inflammatory cell migration and activation, reducing profibrotic mediators during wound healing, and by altering glycosaminoglycan synthesis.2 They also reduce blood supply to the wound through vasoconstriction,3 and inhibit transcription of nitric oxide synthase leading to inhibition of collagen synthesis by fibroblasts.4 Triamcinolone acetonide (TAC) is the steroid most commonly employed, and is administered at a concentration ranging from 10 to 40 mg/mL, at intervals of 4 to 6 weeks. The medication is typically administered using a 30-gauge needle with goal of needle insertion within the papillary dermis.
As monotherapy for treatment of keloids, studies have reported efficacy rates ranging from 50% to 100%, though with recurrence rates of up to 50%. IL TAC has also been used extensively as adjuvant therapy post-excision. When combined with excision, recurrence rates are generally reported to be less than 50%.2 The frequency and timing of adjuvant therapy injections have not been clearly defined, and a small study by Hayashi et al., suggested a new protocol for adjuvant therapy post-excision.5 The authors treated 21 keloids and 6 hypertrophic scars with IL TAC 10 mg/mL at suture removal, and then every 2 weeks, for a total of 5 treatments, in conjunction with topical steroids twice daily. They had a recurrence rate of only 14.3% for keloids and 16.7% for hypertrophic scars. Another study specifically evaluating IL TAC as adjuvant therapy after excision of earlobe keloids reported an efficacy of 87.6%, and a recurrence rate of 9.5% over a follow-up period of 29.9 months.6
Adverse reactions to IL steroids are generally mild. These may include pain or burning with injection, telangiectasia, atrophy, and pigmentary changes, which are cosmetically bothersome to patients and a limiting aspect of repeated therapy.7 Darougheh et al., reported atrophy and telangiectasias in 37% of patients treated with IL TAC.8 More rarely, necrosis and ulceration may occur.
5-Fluorouracil 5-FU is another effective treatment for keloids. 5-FU is a fluorinated pyrimidine that functions as an antimetabolite by inhibiting thymidylate synthase, thereby preventing ribonucleic acid (RNA) synthesis and function.8 5-FU may also function by blocking collagen synthesis,9 and has been found to lead to decreased expression of TGF-beta in keloidal tissue.10 More commonly used as a chemotherapeutic agent, 5-FU has been studied extensively in the treatment of keloids, either as monotherapy, in conjunction with IL corticosteroids, or as adjuvant therapy.
As monotherapy, IL 5-FU is typically administered weekly at a concentration of 50 mg/mL, with generally no more than 2-mL injection performed at a visit.11 In one study by Kontochristopoulos et al., 20 subjects with keloids were treated with weekly IL 5- FU 50 mg/mL, at an average volume of 0.2 to 0.4 mL/cm2.10 Eighty-five percent of
subjects had more than 50% improvement, with most improvement in small and previously untreated lesions, and recurrence was reported in 47%. The most frequent side effects were pain, hyperpigmentation, and sloughing; blood monitoring for changes in complete blood count, liver function tests, and renal function was performed, and did not reveal any alterations. Another study by Nanda and Reddy, found a similar response with greater than 50% improvement in most patients, and none of the 28 keloids treated recurred during a 24-week follow- up period.12
IL 5-FU is also an effective therapy in combination with IL steroids. A randomizedcontrolled trial of 150 subjects evaluated IL TAC alone or in combination with 5-FU.8 Subjects were randomized to one of two groups: group A, IL TAC 10 mg/mL, and group B, IL TAC 4 mg/mL with 5-FU 45 mg/mL. Both groups received weekly injections for a total of eight injections. Good to excellent results were reported in 84% of group B as compared to 68% of group A, and complications were reduced in group B (8%) as compared to group A (24%).8 In a systematic review comparing IL 5-FU to IL steroids, 5-FU was found to be effective as monotherapy, though only the combination of 5-FU with TAC was found to be superior to TAC alone.13
Finally, 5-FU can also be used as adjuvant therapy post-excision. In a study by Haurani et al., surgical excision was combined with monthly IL 5-FU 50 mg/mL, and resulted in a recurrence rate of 19% at 1-year follow-up.14 In a meta-analysis including five publications, keloid recurrence was statistically lower in patients who received 5- FU postsurgical excision as compared to those who did not, while TAC was found to be ineffective at lowering keloid recurrence.15
Local reactions are common, including erythema, pain, burning, hyperpigmentation and ulceration, though these side effects may be ameliorated with the addition of TAC to 5-FU.16 Systemic side effects are generally not seen, and they have not been reported with use for this indication.
Verapamil Verapamil is a calcium channel blocker that is used in the treatment of keloids. It has been shown to stimulate collagenase in keloidal tissue, resulting in reduced collagen and reduction of fibrous tissue formation.17 It is typically administered at a concentration of 2.5 mg/mL, though the interval of administration has not been well defined.
IL verapamil as monotherapy was found to have efficacy rates similar to IL TAC with fewer side effects, though the rate of achieving efficacy was slower in onset.17 Verapamil has also been studied as adjuvant therapy post-excision, though a recent randomized-controlled trial by Danielsen et al., found a significantly higher recurrence rate with IL verapamil as compared to IL TAC, resulting in early termination of the study.18
Interferon IFNs are antifibrotic and antiproliferative cytokines that assist in the antitumoral and antiviral immune response.19 IFNs inhibit fibroblast proliferation and collagen synthesis, and increase expression of collagenase.20
As monotherapy, IL IFN-alpha-2b was found to be ineffective in the treatment of 22 keloids in one study.21 Side effects were common, with seven patients withdrawing from the study because of severe local pain during injection. IL IFN may be more beneficial in combination with TAC. One study found a statistically significant decrease in size from baseline when IL IFN-alpha-2b was administered twice weekly in combination with TAC every 2 weeks, whereas TAC every 2 weeks alone did not produce a significant size decrease.22 IFN has also been studied as an adjuvant to excision, where recurrence rates were lower (18.7%) than with TAC as adjuvant therapy (58.4%) and excision alone (51.1%).23
Adverse reactions are common, and include generalized flu-like symptoms, pain on injection, local redness, and swelling.20 Systemic symptoms may be improved by pretreatment with acetaminophen.
Bleomycin Bleomycin is a cytotoxic antibiotic with antineoplastic, antibacterial, and antiviral properties. In dermatology, it is most commonly used for the treatment of recalcitrant warts, but has also been studied for the treatment of keloids.24 In vitro, administration of bleomycin to fibroblasts has been shown to result in decreased collagen synthesis and increased apoptosis.25
Bleomycin is administered at a dose of 1.5 U/mL through a multiple needle puncture approach after local anesthesia of the area is performed with IL lidocaine. In one study of 13 subjects receiving bleomycin 1.5 U/mL every 1 to 4 months, complete flattening was noted in 53.8% of subjects, and in the remaining subjects there was a greater than 75% resolution in scar thickness.26 At 12 months, there was a 15.4% rate of recurrence. In another study by Saray and Gulec, bleomycin was injected into 15 keloids or hypertrophic scars that had been previously unresponsive to IL steroids through a jet injection technique.25 After local anesthesia, multiple injections of bleomycin 1.5 U/mL were administered via a jet injector spaced 0.5 mm apart, with a maximum volume of 3.5 mL injected per session every 4 weeks until cosmetic improvement. Complete flattening is shown in 73.3% of lesions, and there were no recurrences during followup.25
A common side effect of IL bleomycin therapy is pain, and therefore, local anesthesia is generally required prior to the procedure. Other potential side effects include ulceration, crusting, transient hyperpigmentation, and dermal atrophy.24 No systemic
toxicities have been reported with IL administration.25
Botulinum Toxin-A BTX-A is a neurotoxin that mediates its effects by preventing exocytosis of acetylcholine, thereby blocking neuromuscular transmission and resulting in muscle flaccidity.27 Traditionally used for rejuvenation and facial rhytides, it has also been noticed clinically to improve appearance of scars.28 The mechanism of its effects in keloids may be related to reducing tensile forces across the wound, a factor known to be involved in keloid pathogenesis.29 BTX-A has also been found in vitro to drive fibroblasts into the resting phase of the cell cycle.30
BTX-A has been evaluated clinically for the treatment of keloids, though exact injection parameters have not been clearly defined. In one study by Zhibo and Miaobo, BTX-A was administered via 24-gauge needle to 12 patients with keloids; total dose ranged from 70 to 140 U per session.31 They reported excellent results in 25%, good results in 42%, and fair in 33%. Another study examined IL BTX-A injections in 19 patients at a concentration of 2.5 U/cm2 monthly for 3 months; at 6 months, all patients had acceptable improvement and high satisfaction.27 BTX-A may possibly represent a promising treatment for keloids when used in the appropriate setting, though further studies are needed and widespread use may be limited by its cost.
Intralesional Cryotherapy Cryotherapy has long been used for the treatment of keloids. Cryotherapy freezes the keloidal tissue, leading to direct cellular injury with intracellular ice crystal formation, disrupting the intracellular organelles and plasma membrane.32 Traditionally, cryotherapy was administered as a spray, which has been reported to be beneficial,33 though one common and cosmetically displeasing side effect resulting from this procedure is hypopigmentation, as melanocytes are more sensitive to cold destruction than fibroblasts.32
IL cryotherapy was developed to prevent this side effect. It can be performed via several methods, including injection with a 20-gauge needle, multiple 18-gauge needle injections, or an IL cryoprobe. IL administration directly applies the cryogen to the core of the keloid, minimizing cellular damage to epidermal components, including melanocytes.32 van Leeuwen et al., treated 29 keloids with IL cryotherapy, and found an average volume decrease of 63% after 12 months, and a recurrence rate of 24%.34
There is still a significant risk of hypopigmentation, particularly with darker skin types,35 and a recent study evaluating temperature changes of the overlying epidermis using this technique found that the outer surface of the scar still reached temperatures below โ20ยฐC, colder than the freezing temperature of melanocytes.36 In one study, the
hypopigmentation recovered in most keloids within 12 months.34
Hydrogel Scaffold Device A novel therapy for the prevention of keloid recurrence post-excision is the use of a hydrogel scaffold. This scaffold is composed of a porcine gelatin-dextran hydrogel scaffold injected into the wound immediately prior to skin closure.37 It may function as a scaffold or lattice for fibroblasts, resulting in more appropriate migration and proliferation. This scaffold is currently approved in Europe for improvement of scarring. In one study of 26 ear keloids, the keloids were excised and then a maximum of 3 mL per 2.5 cm of the hydrogel scaffold was injected into the wound margin, followed by wound approximation and closure.38 The recurrence rate was 19.2%, and patient scar satisfaction was very high. Further studies and US approval are needed before this approach could be widely adopted.