Laser in medicine, vol I, issue 1, October 2012 LASER TREATMENT OF SCARRING SKIN DISORDERS: FOCUS OF MORPHEA Jasmina Kozarev, M.D. Dermamedica Dr. Kozarev, Dermatology Laser Clinic, Sremska Mitrovica, Serbia Corresponding authors address: Jasmina Kozarev, MD, PhD Dr Kozarev Dermamedica Laser Center Vojvode Stepe bb, 22000 Sremska Mitrovica, Serbia t. +381 22612122 f. +381 22 636303 e-mail: [email protected] Web site: http//www.kozarevdermatology.com Keywords: morphea, fractional laser, control wounding, immune response. ABSTRACT Introduction Scar formation is an unfortunate consequence of many skin disorders. Morphea, typically start with the insidious onset of firm, violaceous or erythematous plaques. The plaques gradually enlarge with active, violaceous or erythematous borders and shiny, white, firm centers. Atrophic, sclerotic and depressed scars are the eventual sequelae. Numerous treatments have been tried, such as local corticosteroids, D-penicillamine, intravenous penicillin, intralesional interferon gamma, plasmapheresis, PUVA therapy, UVA1 phototherapy, PDL laser and in patients with severe disease, immunosuppressive and vasoactive drugs. The aim of this study was to determine whether fractional Er:YAG laser resurfacing of affected area would be effective in patients with localized scleroderma. Because mast cells also elaborate a variety of cytokines, the presence of mast cells following laser irradiation and accompanying tissue revascularization may provide an explanation for the therapeutic outcome following microvasculature destruction in terms of stimulating collagen remodeling. Materials and methods The cases are reported of five women patients presenting asymptomatic lesions: on the trunk, mammary region, and tibial region. Previous conventional therapies had failed. All patients had up to three similar cutaneous lesions. The lesions underwent punch biopsy, and the histopathological findings confirmed the diagnosis of morphea. Laboratory investigations showed no abnormalities. The treatment was performed once monthly into three sessions with fractional ErYAG laser resurfacing (scanning device in 1 Laser in medicine, vol I, issue 1, October 2012 turbo 4 mode, 10% of coverage, pulse width of 600 ms, fluence of 24J/cm2, and frequency of 20 Hz), without any other specific local therapy. Clinical and dermoscopic assessment of the lesions was performed before treatment, during follow-up and at treatment end point. Patients evaluated the treatment pain level after each of the three sessions. Results In all patients, the initial reactions to treatment consisted of erythema and minimal swelling, slight burning sensation but no significant pain. The erythema lasted between 2 and 10 days (mean, 4.6 days), and its severity was correlated with the initial erythema level. In all patients clinical, digital photography and dermoscopic assessment of the lesions before and at the treatment end point the therapy was highly effective. The only side-effect was a transient hyperpigmentation of the treated lesions in the leg area, with no systemic side effects observed during treatment. Also, blinded evaluation of global images supported an improvement in skin texture in all treated sites. Conclusion Following treatment, patients achieved complete clinical remission of the lesions, with a definitive improvement in the lesions' initial disfiguring features. Fractional ablative photothermolysis appears to be effective, and the outcome is predictable. Controlled trials are now necessary to confirm these preliminary results. 2 Laser in medicine, vol I, issue 1, October 2012 Introduction Morphea is a rare skin disease with yearly incidence rates of 25 per million (1). Although rare, morphea is invariably scarring, and 10 percent of affected patients develop functional disability as a result of the scars. It is a connective tissue disease limited to the skin, the subcutaneous tissue or even the underlying muscle. It is characterized by the appearance of single or of multiple sclerous patches with an ivory center and surrounded by a violaceous ring, indicating an inflammatory activity. Pigmentation disorders are sometimes present. It generally develops in three phases: inflammatory, edematous and then atrophic. The depth of sclerosis is variable and can reach the fascia and underlying muscle. The loss of sweat glands, hair follicles, and melanocytes compromises the ability of skin, to resist mechanical trauma, and to protect from UV radiation. There are five forms of localized scleroderma: plaques, generalized morphea, bullous morphea, linear morphea and morphea profunda. Three different laser sources are now available to be involved in morphea treatment protocol: vascular-specific pulsed dye laser (PDL) to reduce hyperemia, ablative fractional lasers to improve texture and pliability of the atrophic scar, and intense pulsed light (IPL) to correct scar dyschromia. Depending upon the constellation of patient symptoms and functional deficits, treatment of the morphea scar involves a number of modalities. Surgical incision or excision of the scar may be necessary, and defects are reconstructed with biologic skin substitutes, split- and full-thickness skin grafts, tissue rearrangement, tissue-expanded or pedicled flaps, and even free tissue transfer. Fractional laser resurfacing, first introduced in 2005 has been largely utilized for cosmetic indications, such as treatment of scars, photoaging, fine lines of the mouth and eyelids, and abnormal pigmentation. Ablative fractional Er-YAG laser beam targets intracellular water, leading to vaporization of tissue and denaturation of surrounding extracellular proteins. Fractional resurfacing is theoretically attractive in the management of morphea scars, because microscopic columns of abnormal dermis are vaporized or coagulated, which in turn stimulate collagen production and remodeling. These microscopic treatment zones (MTZs) produce by scanning fractional laser mode are 250 micrometers in diameter and 10 to 20% of coverage up to 200 micrometers in depth, leaving a significant amount of epidermis and dermis intact, to assist in rapid and controlled wound healing. Deeper, safe penetration with these ablative lasers may be possible by using turbo mode. This provides greater flexibility of Er:YAG laser fractional treatments. It allows fractional treatments to be accomplished from the keratinous layer to depths the practitioner deems necessary for the clinical application at hand. In comparison to full-surface ablative skin resurfacing, the fractionated very short pulse Er:YAG laser treatment provides very rapid reepithelization, with limited adverse side effects and reduces patient downtime to 4 days or less. Several recent reports have demonstrated the clinical value of fractional resurfacing in atrophic scar treatment, with dramatic results observed even in very old scars (2). 3 Laser in medicine, vol I, issue 1, October 2012 Material and method This was a retrospective study conducted at the Dr Kozarev Dermatology Laser Clinic in Serbia between March 2010 and March 2012. The patients included had to exhibit localized scleroderma in an inflammatory or atrophic phase (excluding those with linear morphea, generalized morphea, morphea profunda and systemic scleroderma) that had been active for at least one year despite high potency dermocorticosteroids or immunomodulators applied for more than two months. Five female patients aged between 34 and 67 years with biopsy-proven localized scleroderma (morphea) were studied. All patients had evidence of previous therapy non response with localization as asymptomatic lesions: on the trunk, mammary region, in the anterior tibial region of the right leg, and posterior tibial region. All patients had up to three similar cutaneous lesions. An active localized scleroderma was defined clinically by the inflammatory character of the peripheral border and by the extent of the central induration and confirmed histologically in all cases. The laboratory tests performed including a full blood count, urinalysis and liver function test, antinuclear antibody titre, C-reactive protein, erythrocyte sedimentation rate and additional tests for a range of antibodies: Hepatitic B and C antibodies, toxoplasma antibodies, anticentromere, anti-Sc 70, anti-dsDNA, and anti-RNP. In each patient the condition had previously failed to respond to potent topical corticosteroids, imiquimod cream, and/or PUVA bath photochemotherapy. Patients were required to discontinue all therapy at least two months before study initiation. The most affected sclerotic plaque of each patient was judged at baseline and then every 4 weeks during treatment. Sclerotic plaques were assessed by a clinical skin score (3). The clinical skin score assesses the degree of thickening and induration by palpation of the most affected part of the morphea plaque on an analogue scale graded from 10 (severe sclerosis, hard like a pressing hard wood) to 0 (normal skin elasticity with folding). In each patient all plaques was treated and the non affected skin on the contralateral side of the body were used as a control are which was scored at baseline and after therapy. Dermoscopic assessment of the lesions was performed before treatment, during follow-up and at treatment end point. Patients evaluated the treatment pain level after each of the three sessions using VAS score. A patient is asked to indicate his/her perceived pain intensity (most commonly) along a 100 mm horizontal line, and this rating is then measured from the left edge (4). The patient data are summarized in Table 1. 4 Laser in medicine, vol I, issue 1, October 2012 Table 1: Characteristics of patients with morphea treated with fractional Er:YAG laser Age/sex Duration of disease Number of lesions 34/F 1.5 years 3 Duration of previous therapy (months) 3 37/F 42/F 47/F 67/F 9 months 2 years 1 year 8 months 3 2 2 1 4 2 6 4 Previous therapy procedure Local corticosteroides PUVA Imiquimod Local corticoides PUVA Laser treatment was initiated with ErYAG fractional laser. Fractional laser treatment was started at least two months after discontinuation of the dermocorticosteroids, immunomodulators like imiquimod or other intralesional or light based therapy procedures. The treatment was performed once monthly into three sessions with fractional ErYAG laser resurfacing. (Dynamis SP, Fotona, SLO). A commercially available chill air cooling system (Zimmer Cryo 6 Unit, Germany) has been used to control pain and discomfort associated with procedure. During the procedure F- runner scanning device allowed precise control of ablation used in turbo 4 mode, 10% of coverage, pulse width of 600 ms, fluence of 24J/cm2, and frequency of 20 Hz), without any other specific local therapy. Results Fractional ErYAG laser treatment was well tolerated, with slight stinging phenomena during laser procedure. In all patients, the initial reactions to treatment consisted of erythema and minimal swelling in the treated areas; the patients reported a burning sensation but no significant pain. The erythema lasted between 2 and 10 days (mean, 4.6 days), and its severity was correlated with the initial erythema level. In all patients sclerosis regressed greatly, skin score markedly decreased and dermoscopy findings objectively showed a reduction of amount of cicatrisation, skin hardness and dischromia. At the end of the follow up period number of hair follicule in the treated zone increased greatly. In all patients clinical, digital photography and dermoscopic assessment of the lesions before and at the treatment end point the therapy was highly effective. The only side-effect was a transient hyperpigmentation of the treated lesions in the leg area, with no systemic side effects observed during treatment. Also, blinded evaluation of global images supported an improvement in skin texture in all treated sites. Laser treated control contralateral sites did not show any visible changes seen in the control biopsy. All patients evaluated therapy subjectively as effective and well tolerable and discomfort and personal dissatisfaction associated with the disease significantly decreased during therapy. 5 Laser in medicine, vol I, issue 1, October 2012 Finally, we did not observe recurrence or worsening of the disease within a follow-up of up to a year after treatment. Discussion Localized scleroderma is characterized by collagen accumulation and excessive sclerosis of the skin. The cause of this disease is unknown, collagen metabolism abnormalities are involved in the physiopathology of scleroderma, related in particular to the reduced synthesis of matrix metalloproteinases. On the basis of new insights into the key role of effector T cells in scleroderma, in particular Th-17, T-cell directed therapies are expected to have promising effects (5). The major complaints are tightness and itching and the disease is often complicated by contractures and cosmetic disfigurement. Numerous treatments have been tried, such as local corticosteroids, D-penicillamine, intravenous penicillin, intralesional interferon gamma, plasmapheresis, oral PUVA therapy or PUVA-bath photochemotherapy, UVA1 phototherapy and, in patients with severe disease, immunosuppressive and vasoactive drugs (6, 7). However, treatments have had only limited success or have caused considerable side-effects. Topical photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) is an experimental therapeutic approach, which is based on photosensitization of abnormal tissue by ALA-induced porphyrins and subsequent irradiation with red light, thus inducing cell injury via generation of singlet oxygen and other free radicals (8). Eisen and Alster showed positive clinical effect after 585nm pulse dye laser irradiation of hypertrophic scars and improvement if the sclerotic morphea plaques (9). To our knowledge, there have been no reports in the literature on the use of fractional Er;YAG laser in the treatment of morphea plaque. This small case study demonstrates an efficacy of ablative Er;YAG fractional laser treatment in localized scleroderma resistant to high potency topical corticosteroids, imiquimod and PUVA therapy with a very high response rate. The response to laser based treatment seems to be positive. High potent corticosteroids and immunosuppressive agents are effective in the early inflammatory phase. If no response is seen after 8 weeks, therapy may be changed to lesion limited-phototherapy (NB-UVB, BB-UVA, UVA1, or topical psoralen and UVA). We do not have data supporting efficacy of topical steroids, as the most commonly utilized therapy for active limited plaque morphea. There is no indication for topical steroids in the burnt-out phase of morphea (10). Because, spontaneous remissions of localized scleroderma are mentioned, treatment protocols are targeted at the active phase, stabilizing the size of current lesions and preventing the occurrence of new lesions. Possible outcomes of the inflammatory localized scleroderma lesions are scars which, although they can be treated in a number of ways, may have a negative psychological impact on social life and relationships. A 67-year-old woman presented with slightly erythematous, sclerotic patch with an ivory center on her left brest in March 2010 (Fig. 1A). The same area after two laser sessions and after a year in the end of the follow up period (Fig. 2A). 6 Laser in medicine, vol I, issue 1, October 2012 Fig 1a Fig 2a A 47-year-old woman presented with slightly 24 cm long and 14 cm wide atrophic morphea plaque in May 2010 (Fig. 3A). The same area after three laser sessions and after a year in the end of the follow up period (Fig. 4A). Fig 3a Fig 4a Role of matrix metalloproteinases and decreasing process of collagen degradation is in the middle of the hypotheses concerns abnormalities of the collagen metabolism of the external matrix by an increase in the production of type I and III collagen. The molecular impact of Er;YAG laser resurfacing on photodamaged or inflamed skin is evident. It had been clear that laser resurfacing eliminates much of the damaged collagen, and they demonstrated that it replaces the damaged fibers with what appeared to be a better matrix. Cutaneous wound healing is the interaction of a series of complex processes that lead to renovation, reconstruction, and a proportional restoration of the damaged skin’s elasticity. The profile of gene and protein alterations represents a well-organized and highly reproducible wound healing response. Epidermal resurfacing with the Er:YAG laser has impact on the dermal matrix via substantial dermal changes. Clinical effectiveness of laser skin resurfacing is based on the induction of synthesis of new collagen and other components of extracellular matrix. The goal of Er:YAG fractional laser treatment is transition from inflammatory to proliferative phase of tissue repair. In inflammatory phase, the principle cell is macrophage, which is responsible for degradation of damaged tissue (wound debridement). These cells stimulate influx and proliferation of fibroblasts by production of cytokines (11). In proliferative or fibroplastic phase myofibroblasts participate in active production of extracellular matrix components including collagen I and III (12). 7 Laser in medicine, vol I, issue 1, October 2012 We believe repetitive irradiation of human skin with Er:YAG laser could be a potentially useful method for modulation of chronic inflammatory response. The mechanisms of action of fractional ablative laser in the morphea treatment could be induction of collagenase activity, which need to be investigated. Whitby and Ferguson studied the distribution of growth factors in healing fetal wounds. They found platelet derived growth factor (PDGF) in fetal, neonatal and adult wounds, but transforming growth factor beta and basic fibroblast growth factor (bFGF) were not detected in the fetal wounds. They conclude that it may be possible to manipulate the adult wound to produce more fetal-like, scarless wound healing by therapeutically altering the levels of growth substances and their inhibitors (13). Another extracellular matrix glycoprotein tenascin is synthesized by fibroblasts that is present during embryogenesis but only sparsely distributed in adult’s dermal papilla. In the in healing wounds this protein is re-expressed, in the regenerating connective tissue area (14). Can we produce control wounding by using fractional ablative procedures? A number of experimental studies have suggested that mast cell degranulation may induce inflammatory response, fibroblast proliferation and collagen remodeling, which constitute the key steps of the wound healing process. Changes in the total mast cell number and percentage of degranulation were assessed during the inflammatory phase of repair (15). Pincherito et al. demonstrated that CO2 laser wounds are associated with greater levels of mast cell degranulation than scalpel wounds (16). Because mast cells also elaborate a variety of cytokines, the presence of mast cells following laser irradiation and accompanying tissue revascularization may provide an explanation for the therapeutic outcome following microvasculature destruction in terms of stimulating collagen remodeling. Conclusion Despite great advances, at present there is no “magic bullet” that can be used in the management of morphea plaque. Following treatment, patients achieved complete clinical remission of the lesions, with a great improvement in the lesions' initial disfiguring features. On the basis of the present results, fractional ablative photothermolysis appears to be effective, and the outcome is predictable. Prospective, double-blind placebo-controlled trials with larger numbers of patients are now necessary to confirm these preliminary results. 8 Laser in medicine, vol I, issue 1, October 2012 References 1. Marzano AV, Menni S, Parodi A, et al. Localized scleroderma in adults and children. Clinical and laboratory investigations on 239 cases. Eur J Dermatol. 2003; 13(2):171– 176. 2. Hasegawa, T. Matsukura, Y. Mizuno, Y. Suga, H. Ogawa, and S. Ikeda, Clinical trial of a laser device called fractional photothermolysis system for acne scars,” Journal of Dermatology, vol. 33, no. 9, pp. 623–627, 2006. 3. Seyger MMB, van den Hoogen FHJ, De Boo T, De Jong EMGJ. Reliability of two methods to assess morphea: skin scoring and the use of a durometer. J Am Acad Dermatol 1997; 37: 793 ± 796. 4. Revill SI, Robinson JO, Rosen M, Hogg MIJ. The reliability of a linear analogue for evaluating pain. Anaesthesia 1976;31:1191–8. 5. Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. N Engl J Med 2009; 361: 888–898. 6. Hunzelmann N, Scharffetter-Kochanek K, Hager C, Krieg T. Management of localised scleroderma. Sem Cutan Med Surg 1998; 17: 34 ± 40. 7. Kerscher M, Meurer M, Sander C, Volkenandt M, Lehmann P, Plewig G, RoÈcken M. PUVA bath photochemotherapy for localized scleroderma. Arch Dermatol 1996; 132: 1280 ± 1282. 8. Szeimies RM, Calzavara-Pinton P, Karrer S, Ortel B, Landthaler M. Topical photodynamic therapy in dermatology. J Photochem Photobiol 1996; 36: 213 ± 219. 9. Eisen D, Alster T. Use of a 585 nm pulse dye laser for the treatment of morphea. Dermatol Surg 2002:28:615-616. 10. Fett N, Werth VP. Update on morphea: Part II. Outcome measures and treatment. J Am Acad Dermatol 2011;64:231-42. 11. Leibovich SJ, Ross R. The role of the macrophage in wound repair. Am J Pathol 1975; 78:71–100. 12. Sappino AP, Schu¨ rch W, Gabbiani G. Differentiation repertoire of fibroblastic cells: Expression of cytoskeletal proteins as marker of phenotypic modulations. Lab Invest 1990;63: 144–161. 13. Whitby DJ, Ferguson MW: Immunohistochemical localization of growth factors in fetal wound healing. Dev Biol 147:207, 1991. 14. Bleacher JC et al: Fetal tissue repair and wound healing. Dermatol Clin 11(4):677, 1993. 15. Noli C, Miolo A (2001) The mast cell in wound healing. Vet Dermatol 12:303–313. 16. Pinheiro AL, Browne RM, Frame JW, Matthews JB. Mast cells in laser and surgical wounds. Braz Dent J. 1995;6(1):11-5. Conflict of Interests The authors report no conflict of interest and have not received any funding for research, education, or consulting from any laser companies. 9
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