BACKGROUND. Pathologic Scars

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1 Medical and Rehabilitation Innovations Laser Therapy for Hypertrophic Scars & Keloids in Burns 2016

2 BACKGROUND Laser therapy has recently emerged as a promising option for treatment of hypertrophic scars and keloids associated with burns. Lasers (Light Amplification by Stimulated Emission of Radiation) are simply focused beams of light energy released in the form of photons which can be delivered continuously or in short high energy bursts or pulses. The theory behind using light to treat skin conditions started with the understanding of selective photothermolysis in , where specific targets in the skin could be destroyed via absorption of light by chromophores within a specific spatial confinement. Chromophores are biological molecules that can detect or capture light energy; common skin chromophores include hemoglobin, oxyhemoglobin, and melanin 2. Over the past decade, use of this information has led to substantial advancements in laser technology to treat cutaneous scars. Pathologic Scars Hypertrophic scars and keloids are cutaneous scars that result from surgery, traumatic wounds, and burns that can lead to functional impairments and cosmetic deformities. It is important to understand that there are distinct differences between these two types of scars. Hypertrophic scars result from overabundance of collagen deposits oriented parallel to the epidermal surface. They are characterized by diffuse redness or hyperemia from proliferation of capillary vessels. This increased perfusion supports continued growth of scar tissue, which increases scar thickness as well as pushing out the scar margins. In contrast, keloid tissue is largely composed of disorganized and excessive collagen deposits with limited vascularization. Keloids present as sharply elevated and irregularly shaped tumor-like skin growths that expand and invade beyond the initial wound boundaries. Hypertrophic scars undergo dynamic remodeling over the 6-18 months following injury, with some eventual reduction of redness and scar thickness and firmness over time. Keloid tissues, however, show no tendency to regress 3. These skin conditions affect millions of patients with an incidence of 4-16% being observed among different populations 4. Clinical symptoms associated with these scars include pain and pruritus (itching) along with restricted motion from scar related contractures, as well as the stigma and psychological stress of visible disfigurement. A variety of therapies have been utilized to treat hypertrophic scars and keloids, including physical therapy, compression garments, topical silicone gel, cryotherapy, topical or injected steroids, and a host of topical and ointments containing moisturizers, anti-pruritics, vitamins, and inflammatory modulators. These treatments are often prolonged, and can be uncomfortable and inconvenient. Many of these therapies have support within the burn care community, although none have been entirely effective. In fact, the prolonged duration and extremely variable course of burn scar maturation has made evaluation of any scar treatment very difficult. Definitive removal of hypertrophic scars and keloids and relief of significant scar contractures require surgery. However, surgery has many limitations. Surgery is invasive, costly, and painful. Only small mature scars can be excised completely, with primary closure or local flaps; larger wounds may require repeated skin grafting. Surgery is far less effective when performed on active scars, and patients must often wait months for scars to mature before surgery can be performed. And as such wounds heal, some recurrent scarring inevitably results. The recent emergence of laser therapy appears to offer a number of major advantages, which makes it a valuable addition to scar management strategies. 2 Paradigm Outcomes, Proprietary

3 Types of Lasers Lasers routinely used to treat scars are categorized into ablative and non-ablative groups. Ablative type lasers produce non-selective destruction of epidermis and scar tissue, while non-ablative lasers can target chromophores in the dermal layer without epidermal involvement. Currently there are four types of lasers that can be used in alternating or concurrent sessions based upon scar characteristics. These include Pulsed dye laser (PDL), fractional carbon dioxide (fco 2) laser, alexandrite and diode lasers, and intense pulse light (IPL). The following are brief summaries associated with each of the laser types. Pulsed Dye Laser (PDL) is a non-ablative laser that generates 585 nm and 595 nm wavelengths of light. This laser selectively destroys scar microvasculature through the targeting of the chromophore hemoglobin. This permits destruction of some of the proliferating capillaries that fuel scar hypertrophy, leading to dermal tissue anoxia/hypoxia causing neocollagenenesis and reduction in collagen deposition, fibroblast proliferation, and histamine release. PDL has been used for decreasing scar erythema and pruritus primarily, but has shown some benefit in reducing scar height and volume while improving texture and pliability of scars 6. One concern with use of PDL lies with potential involvement of other chromophores such as melanin that can cause collateral damage to the tissues. For this reason, PDL may be more effective in light-skinned individuals. Careful consideration is needed in patients with darker skin pigmentation. Fractional laser resurfacing uses an ablative laser that coagulates tiny columns of skin known as microscopic treatment zones (MTZ) with sparing of the tissues surrounding each MTZ wound. These tiny wounds then heal with little or no scarring, which reduces the overall mass of scar tissue and relieves some of the tension within the scar. It is believed that fractional lasers are significantly more effective per treatment particularly for hypertrophic and contracted scars 5. This type of laser includes fractional Carbon Dioxide CO 2 laser and erbium:yttrium aluminum garnet (Er:YAG) lasers. These lasers produce a grid-like pattern of MTZs that are 70 to 100 microns in diameter and adjustable to a controlled depth of microns. Alexandrite and diode lasers are similar to PDL using hemoglobin and melanin as their chromophores. Diode lasers were introduced in 1990s as light therapy to treat scars and keloids, while the long pulsed alexandrite laser is commonly used for removal of hair and follicular structures by destruction of stem cells in the hair follicles. Intense pulsed light (IPL) delivers focused light energy through a coupling gel that can be used to coagulate vascular lesions, treat hyperpigmentation, and remove hair follicles for cosmetic indications. Although IPL is not technically a laser, specific filters allow for selecting specific wavelengths of light that can lead to collagen stimulation, remove superficial leg veins, and treat rosacea. The exact mechanism of action is unknown currently, but this modality has been considered as an alternative to other more expensive aforementioned laser types when treating a variety of dermatologic conditions. Unfortunately, there is very little evidence of its efficacy in hypertrophic scars or keloids. 3 Paradigm Outcomes, Proprietary

4 LITERATURE SUMMARY Evidence of Efficacy Although there are many case studies and small series in the medical literature reporting beneficial results from various applications of laser therapies in managing pathologic scars, definitive evidence of efficacy of laser treatments for hypertrophic scars and keloids is still limited. This literature suffers from a number of shortcomings in design and performance, as well as the inherent difficulty in studying a condition as idiosyncratic, variable and prolonged as scar formation and maturation. Design problems include a high level of heterogeneity and less than optimal study quality; low case numbers in most prospective studies; follow up periods that are too short or inconsistent; lack of information on the duration of the scars and activity; absence of meaningful controls; great variations in scar location, laser protocols, and treatment intervals; as well as a lack of objectivity in outcomes measurements that can bias the assessment of therapeutic response 3. In addition, there are no studies comparing the effectiveness of laser therapy to each other or to other types of therapeutic modalities. Despite these shortcomings, however, accumulating experience with laser treatment of burn scars supports significant consensus among experts that laser treatment of specific conditions associated with pathologic scars can lead to reduction of erythema and improvement of severity of scar remodeling in hypertrophic scars 7. One Large Prospective Cohort Study Involving Laser for Hypertrophic Scars Perhaps the most important publication to date is the prospective study published in Annals of Surgery 2014 by Dr. Hultman et al to evaluate the long-term impact of laser therapies on remodeling in hypertrophic scars. 7 Authors reported on 147 burn patients with a mean age of 26.9 years, and burns of 16.1% total body surface area, studied a mean of 16 months after injury. Patients received 415 laser sessions: a mean of 2.8 sessions per patient. Outcome measures included both subjective (patient rated) and objective (physician rated) instruments including the Vancouver Scar Scale (VSS), which rates pigmentation, vascularity, pliability, and scar height; and the UNC4P Scar Scale, which documents patient scar-related symptoms such as pruritus, pain, paresthesia, and pliability. The study involved the use of a number of laser types including pulsed dye laser (PDL), fractional CO 2 laser, Noncoherent intense pulsed light (IPL.Nd:YAG/light sheer diode); and 755-nm wavelength Alexandrite laser. Results of the study demonstrated significant improvements in both objective and subjective characteristics of hypertrophic burn scars with reduction in both VSS and UNC4P scar assessment scores, while complications were rare and related primarily to anesthetic issues. Authors concluded that laser and light based therapies can be combined to treat hypertrophic burn scars successfully in the majority of patients. However, there were limitations to the study including inability to follow up with all patients limiting the sample size of the final cohort group; inconsistent and variable laser protocols; and use of outcome measures (e.g., VSS & UNC4P) that did not provide sufficient details to determine which scars may benefit from certain types of lasers. The study also lacked a control group to permit comparison of the natural history of these scars, which are known to improve over time. Finally, specific objective metrics such as scar thickness, color, and elasticity were not measured by tools such as ultrasound, chromometer, and curtometer which would have been more precise and more objective. It should be noted that patient satisfaction with laser treatments was uniformly very high. 4 Paradigm Outcomes, Proprietary

5 Meta-Analysis Review Other recent reports seem to provide similar conclusions. A meta-analysis that reviewed 28 published reports of laser treatment for scars found lasers produced a positive response in 71% of scar prevention treatments, 68% of hypertrophic scar treatments, and 72% of keloid treatments. 4 However, a majority of the studies reviewed did not include specifically burn patients and cannot be simply extrapolated to burn patients. In these and other recent reports, patient satisfaction with laser treatments was uniformly very high, and often exceeded the objective results measured by observers. 8 Treatment Indications and Timing As laser use has evolved, clinicians have broadened both the timing and indications for its use. One unique advantage of lasers is that they can be used to remove mature scars even years after injury, which most other scar treatments cannot do without surgical intervention. In addition, some observational studies seem to indicate that laser use early in the post-burn course, particularly the pulse-dye laser, can reduce the hyperemia of early inflammation and pre-emptively reduce subsequent scarring. To provide some guidance as to laser therapy in scar management, in early 2014 a laser scar treatment algorithm based on a recent consensus report was published in JAMA Dermatology outlining expert opinions regarding fractional ablative laser resurfacing and pulsed dye lasers. 5 In addition, Gold MH et al published updated international clinical recommendations and algorithm on scar management in the Journal of Dermatology Surgery. 10,11 The following is our assimilation of summary recommendations based upon expert consensus and expert opinion integrating both expert consensus publications. 5,10 However, it is important to remember that we will revisit this recommendation in the near future to keep up with the rapidly evolving area of laser therapy. Although it is anticipated that more liberal use of lasers will probably become mainstream in post-burn care, Paradigm will rely on evidence-based studies and publications to guide our position. 1. Lasers have no role for acute unhealed burns. Complete epithelialization of wounds (and skin grafts) must be attained before lasers can be used. 2. Laser therapy can be considered as indicated for those post traumatic, pathological scars unresponsive to silicone gel or sheeting, compression/pressure garment treatments, and other medical treatments for post traumatic scars. 3. Healed traumatic scars that demonstrate persistent erythematous discoloration greater than one (1) month with persistent clinical symptoms of pruritus and pain can be considered for laser therapy. Initial laser treatment of choice would be vascular laser types such as PDL. 4. Extensive hypertrophic burn scars that fail to improve with treatment with silicone gel or sheeting, compression/pressure garments, and/or onion extract preparations for eight to twelve (8-12) weeks may be considered for additional treatment with laser therapy. Fractional lasers are considered to be more effective than PDL or Q-witched Nd:YAG lasers for hypertrophic scar treatments. 5. Minor keloids that fail to improve within eight to twelve (8-12) weeks with silicone gel sheeting and intralesional corticosteroids may be considered for treatment with ablative fractional laser or PDL therapy. 5 Paradigm Outcomes, Proprietary

6 6. Major keloids that fail to improve with intralesional corticosteroids and 5-FU may be treated with ablative fractional laser or PDL therapy. 7. Ablative fractional laser treatment is considered to be more effective for scars that are thicker and associated with more restrictions. 8. PDL treatments should be applied for symptoms related to hypervascularity such as erythema, hyperemia, and pruritus associated with pathologic scars. 9. Ablative fractional laser treatments can be started after PDL treatments to improve scar texture (thickness) and pliability (stiffness). 10. Alexandrite laser therapy is effective for scar related folliculitis; and Intense pulsed light (IPL) can be used for dyschromia. 11. In general, complete laser treatment of a lesion will require two to four (2-4) individual laser treatment sessions with therapy intervals being four to eight (4-8) weeks (average six weeks) between sessions. PARADIGM POSITION Pathological scars such as hypertrophic scars and keloids are associated with burdensome symptoms that can impair clinical function as well as emotional wellbeing due to disfigurement. Although literature is currently limited in the number of high quality studies evaluating the efficacy of lasers in pathologic scars, the 2014 large prospective study reviewed above along with many other published case series, literature reviews, and meta-analyses support the use of laser therapy as an effective treatment option for specific scar related characteristics. However, it is also important to note that use of laser therapy in clinical settings for hypertrophic scars and keloids is an evolving technology with wide variation in frequency, timing, and techniques of use among burn centers. We anticipate that laser treatment will continue to grow in popularity and applications, and more quality studies will provide evidence-based standard of care for laser therapy in burn related scar management in the future. At the present time, Paradigm supports the use of laser therapies as a therapeutic option for hypertrophic scars and keloids with persistent clinical symptoms that are refractory to other conventional medical treatments such as silicone gel or sheeting and compression garments, etc. Furthermore, if and when laser therapy is considered or pursued, monitoring of the effectiveness of laser therapies should be performed using objective measurements of efficacy at laser treatment intervals/follow up. Available technology for specific characteristics of scar tissue include: Vascularity: Spectrophotometry or chromameter Perfusion: Doppler ultrasound flowmeter Pliability: Durometry Area/Size: Planimetry by standardized photography Thickness: Tissue ultrasound palpation systems (TUPS) 6 Paradigm Outcomes, Proprietary

7 Summary Paradigm Outcomes supports the use of laser therapy for refractory hypertrophic scars, although its use in keloids is limited to the indication criteria noted in the aforementioned indications and timing. In addition, when laser therapy is opted for, Paradigm strongly recommends monitoring the effectiveness and efficacy of the laser therapy via objective tools/tests. Our Help position is noted below. Help: Laser therapy has clearly been helpful in treatment of clinical symptoms associated with hypertrophic scars such as refractory pruritus, pain, and erythematous discoloration. In addition, laser therapy is helpful in improving texture and pliability of pathologic scars refractory to more conventional medical treatments. The success of laser treatments, while not absolute, certainly justifies its use for troublesome scar conditions. Hope: Pre-emptive use of lasers early in the course of healing can prevent formation and progression of pathologic scars. (Please note that it remains to be determined whether pre-emptive use of lasers to reduce the hyperemia and redness of burn wounds early in the course of healing can reduce subsequent scar formation and short circuit the time course and magnitude of burn scar healing.) Hype: Laser therapy will eliminate all scars, prevent contractures and disfigurements, and return normal skin function. (Please note that use of lasers has been widely presented in the popular media, with exaggerated claims of efficacy. Coupled with the mystique surrounding Star Wars technology, this information has sometimes led to a popular misconception that lasers are invariably successful in removing all scars. This is clearly not the case. As noted, scars respond significantly to laser treatment in 65-75% of cases, but even in the best cases, scars are never removed entirely. The extremely high level of patient satisfaction with laser treatments often exceeds objective measurements of improvement, suggesting significant psychological benefit, which has also contributed to the popularity of this form of therapy. All of this suggests that the public will increasingly regard lasers as a potential cure-all for burn and other scar conditions, and clinicians will see patients request these treatments. These impressions will have to be tempered by more objective assessments and realistic guidance from health care professionals in the future). 7 Paradigm Outcomes, Proprietary

8 ENDNOTES References 1. Anderson RR et al. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science 1983; 220: Hultman, MD; Yoshida, MD. UpToDate Resource 2016 topic: Laser therapy for hypertrophic scars and keloids November Brewin, MP et al. Prevention or treatment of hypertrophic burn scarring: A review of when and how to treat with the pulsed dye laser. Burns. 2014; 40: Jin, R, Huang et al. Laser therapy for prevention and treatment of pathologic excessive scars. Plastic and Reconstructive Surgery 2013; 132: Anderson, RR et al. Laser Treatment of traumatic scars with an emphasis on ablative fractional laser resurfacing: Consensus report. JAMA Dermatology, 2014; 150: Parrett BM et al. Pulsed dye laser in burn scars: current concepts and future directions. Burns 2010; 36: Hultman, CS et al. Laser Resurfacing and Remodeling of Hypertrophic Burn Scars: the results of a large prospective before-and-after cohort study with long term follow-up. Annals of Surgery 2014; 260: Jacobs, M; Roggy, D; Sood, R. 8Q8K8S A preliminary report of a prospective study evaluating outcomes of burn scars treated with laser therapy. J Burn Care Rehabil, 2016; 37:S Siwy, KG; Lee, K; Donelan, MB; Anderson, RR; Mileta, NR. Fractionated CO2 laser and burn scar contractures: evaluation of post treatment scar function and appearance. J Burn Care Res, 2016; 37:S Gold MH et al. Updated international clinical recommendations on scar management: part 1 evaluating the evidence. Dermatology Surgery 2014; 40: Gold MH et al. Updated international clinical recommendations on scar management: part 2. Algorithms for scar prevention and treatment. Dermatology Surgery 2014; 150:187 Acknowledgments Special thanks to Jeffrey Saffle, MD, Paradigm Medical Director; Paradigm ICMO group Chris Anderson & Laurie Anderson; and the Paradigm Outcomes Medical Affairs Leadership Michael Choo, MD, & Steven Moskowitz, MD Paradigm Management Services, LLC ( Paradigm ). No part of this publication may be reproduced, transmitted, transcribed, shared, disseminated, summarized, stored in a retrieval system, adapted, or translated into any language in any form by any means without the written permission of Paradigm. Trademarks, service marks, products names, company names or logos of Paradigm are protected by trademark and other laws of the United States, as well as international conventions and the laws of other countries. 8 Paradigm Outcomes, Proprietary