Wednesday, January 21, 2009

Scars and Their Therapy – an Article Review

As I continue to catch up on my journal reading, I thought I would review and share this (full reference below) article with you on scars and current therapies.
The article begins by touching on the three stages of wound healing:   inflammation, proliferation, and matrix remodeling/scar formation.  Then goes on to discuss first the emerging scar-reducing therapies and then the currently available therapies.

The list and discuss the following as emerging scar-reducing therapies:
TGF-β Superfamily--
TGF-β has been studied as a potential scar-reducing agent since the 1980s.  TGF-β1, TGF-β2, and TGF-β3, have been demonstrated to have major roles in scar production.   Investigations of TGF-β as a scar-reducing agent have sought to simulate the fetal wound-healing environment by increasing the relative ratio of TGF-β3 to TGF-β1 and TGF-β2 to minimize scarring.  There are several ongoing Phase II clinical trials evaluating Juvista, human recombinant TGF-β3, with the next trials due to report in mid 2008. Although demonstrating positive preliminary efficacy with high safety, it remains to be seen with great anticipation what the long-term efficacy in larger trials will be compared with current therapy and what practical role if any TGF-β-modulating agents will play in future therapeutic protocols.
COX-2 Inhibitors and Nonsteroidal Antiinflammatory Drugs:
There has been growing interest in the role of the COX-2 pathway in scar reduction.  Topical application of a selective COX-2 inhibitor immediately after wounding resulted in a statistically significant reduction in local neutrophils, prostaglandin E2 levels, TGF-β1, collagen deposition, and scar formation in a mouse study.  Of note, it has been demonstrated that topical application of COX-2 inhibitors does not have a negative effect on wound reepithelialization.  There is conflicting evidence on the effect of constitutive inhibition of COX-1 and COX-2 on wound healing. One study has suggested that inhibition of COX-1 may cause delayed wound healing, whereas another study demonstrates no delay in wound healing.
Collagen Synthesis Inhibitors
Modulation of collagen metabolism is another potential target for preventing excessive scar formation. ……………. has shown modest benefit of scar reduction to date, and these remain agents of interest for further investigation.
Angiotensin-Converting Enzyme Inhibitors
It is well accepted in the cardiovascular literature that up-regulation of angiotensin-converting enzyme participates in adverse fibrous cardiac remodeling.   Recent studies have shown that a locally functioning tissue renin-angiotensin system operates in human skin.  It has been demonstrated that exogenous angiotensin II may accelerate wound healing in animal models.  ……… Further investigation of their role in scar reduction is warranted.
A recent study found that systemically administered minocycline significantly reduced the severity of hypertrophic scarring in a rabbit ear scar model.  The mechanism by which minocycline reduces scar formation in this model remains unanswered. …… Additional studies are needed to elucidate the mechanism of this intriguing agent.
Gene Therapy
There have been few published studies, limited to animal models, using gene therapy to investigate scar reduction. To date, fibroblasts have been used as the primary targets for a gene therapy approach to scar reduction. A major obstacle is that scarring is a very complicated process involving many different factors, and much of the outcome of scar formation is likely programmed by the early inflammatory response to wounding. Most studies to date have demonstrated modest or inconclusive results on scar formation.

They list and discuss the following as currently available scar-reducing therapies:
Topical and Intralesional Corticosteroid Injections
Triamcinolone is currently the most commonly used corticosteroid for the treatment of scars. When used as a monotherapeutic agent, studies show 50 to 100 percent efficacy of intralesional injection of triamcinolone.  However, many of these studies lack well-designed controls and standardized objective measures of scar outcome and thus are of limited value………
Use of intralesional 5-fluorouracil for treatment of hypertrophic scars has been shown to be effective in multiple studies.  However, most of these studies lack adequate controls and are of limited value. Combinations of 5-fluorouracil with intralesional corticosteroids and pulsed dye laser have been used to achieve better results than 5-fluorouracil as a monotherapy.  Notably, the combination of 5-fluorouracil with corticosteroids has been shown to decrease the side effects related to prolonged therapy with corticosteroids alone. …….
Bleomycin is an antibiotic with well-known antitumor, antibacterial, and antiviral activity.  Studies have shown that intradermal injection or the multipuncture method of bleomycin injection results in significant improvement in keloids and hypertrophic scars.  However, all of these studies involved a small sample size and lack well-designed controls and thus are of limited value.  ……
Adverse sequelae of bleomycin include hyperpigmentation (75 percent) and dermal atrophy in the skin surrounding treated scars (10 to 30 percent).  Further large controlled trials are needed to evaluate the efficacy of bleomycin.
Laser Therapy
Pulsed dye laser therapy has been shown to have positive efficacy in numerous studies, but many of these studies lack well-designed controls and are of limited value. The primary indication for pulsed dye laser is to reduce erythema. Pulsed dye laser therapy is based on the principle that hypervascularity plays a key role in scar appearance. ……
Common side effects of pulsed dye laser treatment include posttreatment purpura, which usually subsides after 7 to 10 days, and hyperpigmentation in 1 to 24 percent of patients.  ……… if further controlled trials support its efficacy.
Silicone Gel Sheets
Numerous studies have demonstrated the utility of silicone gel sheeting in treating hypertrophic scars but overall yield inconclusive evidence for its mechanism of action and efficacy in reducing existing scars.   Silicone gel sheeting has also been investigated for its potential utility in scar prophylaxis when applied in the postoperative period. Controlled studies investigating silicone gel sheeting applied to wounds immediately and 2 weeks postoperatively significantly decreased scar volume over controls in mirror-image incisional wounds. However, the largest controlled study demonstrated no improvement in scar prophylaxis.   A recent Cochrane review cites 13 trials involving 559 patients and concludes there is weak evidence of a benefit of silicone gel sheeting as a prevention for abnormal scarring in high-risk individuals, but most studies are of poor quality and highly susceptible to bias…….
Pressure Therapy
Pressure therapy has been a conservative management of scars since the 1970s,  despite a paucity of well-designed controlled clinical studies demonstrating its efficacy. ……..The largest randomized controlled trial showed no significant differences in scar reduction with pressure therapy compared with controls.
Current evidence does not support the efficacy of pressure treatment as a monotherapy for scar reduction. The appropriate role of pressure therapy in scar reduction protocols may be as an adjunctive treatment as part of a polytherapeutic strategy of scar management, but this must first be evaluated in clinical studies.
There have been many reports of cryotherapy used as a combination therapy with surgical excision for hypertrophic scar and keloid reduction.   Most of these studies are difficult to evaluate because of small sample sizes and lack of adequate controls. …… The main adverse effects reported were atrophic depressed scars and residual hypopigmentation (75 percent of cases).   ….. there is limited evidence for the long-term efficacy of cryotherapy for scar reduction.
Radiation therapy has been used in scar management primarily in the treatment of keloids, frequently being used as an effective adjunct to surgical excision.  Radiation likely mediates its effects on keloids through inhibition of proliferating fibroblasts and neovascular bud formation, resulting in decreased collagen production. 
Surgical excision in combination with radiotherapy is considered the most effective treatment available for severe keloids. There is limited and inconclusive evidence regarding optimal dosage, fractionation, indications for treatment, or timing of radiotherapy with respect to surgical procedures. However, a single dose given within 24 hours of excision appears to yield the highest cure rate in recurrent keloids. …….
Surgical Treatment
There are many different surgical strategies for scar revision, including excision with linear closure, excision with split- or full-thickness skin grafting, Z-plasty, W-plasty, and if all other options fail, excision followed by flap coverage. Tissue expansion and serial scar excision may be used to provide more tissue for advancement or local flap coverage of revised scars……

The article is well written and is a nice review of scar therapies.  I would have to agree with their conclusion that
There is a great need to use large controlled trials to examine currently available and emerging strategies of scar reduction to standardize scar treatment protocols and evaluate emerging agents that could potentially benefit patients with scars refractory to currently available treatments.   Two major shortcomings of current clinical studies include (1) a lack of well-designed controls and (2) a lack of standardized and comprehensive evaluative measurements of scar outcome.

Scars: A Review of Emerging and Currently Available Therapies; Plastic & Reconstructive Surgery. 122(4):1068-1078, October 2008; Reish, Richard G. M.D.; Eriksson, Elof M.D., Ph.D.

Other related posts:
Skin – Healing a Simple Wound/Laceration
Scar Prevention

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Anonymous said...

Do you know of any doctors who currently treat hypertrophic scars with bleomycin? I've read about this and it seems promising, but don't know how to go about finding a place for treatment.

rlbates said...

Sorry, I don't have any names to give you.