Monochromatic excimer light 308 nm in the treatment of vitiligo: a pilot study

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1 /EADV(2003) 1,-3 ochromatic excimer light 30 nm in the treatment of vitiligo: a pilot study G Leone,* P lacovelli. A Paro Vidolin, Picardo Servizio di ototerapia, Istituto Dermatologico San Gallica, IRCCS, Via Elio Chianesi. 3, 001 Roma, Italy. *Corresponding author, tel ;fax ; gleone@ifo.it ABSTRACT Obiettive To study the efficacy and safety of mochromatic excimer light (EL) on 3 vitiligo patients referred to our clinico ethods In a pilot study, 3 patients (1 males, 20 females) with acrofacial (n = 21), focal (n =11), segmental (n = 1), and generalized (n = ) vitiligo were treated twice weekly with EL far a maximum period of months. Results Thirty-five patients (9%) showed signs of repigmentation within the first eight treatments. The treatment resulted in good repigmentation in 1 patients, and excellent repigmentation in 1 patients. Adverse events were limited to transient erythema. In addition, some patients (n = 3) t responding to prior narrow-band UVE (NH UVE) phototherapy showed good results with EL in our series. Conclusions Treatment with 30 nm EL far vitiligo may be more effective in ob.taining rapid repigmentation than phototherapy with NH UVE. The results in this study afe similar to those recently reported with a 30 nm excimer laser, but 30 EL could present some advantages: the possibility of treating larger areas compared to the 30 nm excimer laser, with shorter treatment times and better patient compliance. The overall good results and the early appearance of repigmentation contribute to reducing the cumulative exposure to UV radiation. Key words: mochromatic excimer light, narrow-band UVB, vitiligo Received: 2 September 2002, accepted 1 December 2002 Vitiligo is a common idiopathic acquired depigmentation disorder,l affecting 1-2% of the world population with predilection for age, sex or racial background, caused by selective destruction of melacytes. The disease is characterized by circumscribed white spots on the skin tending to enlarge centrifugally over time or, less frequentiy, to recover spontaneously at least in part.2 The exact pathogenesis is unkwn and several hypotheses bave beffi proposed.3 They include the autoimmune hypothesis, the autocytotoxic or self-destruction theory, where reactive oxygen species (ROS) and free radicals exert melacytotoxic activity, and the neuronal theory, which advocates the release of a chemical, toxic to the melacytes, from the dermal nerve endings. A genetic basis is supported by the familial cases of vitiligo: a family history is found in -3% of cases. There is w convincing evidence for the presence of oxidative stress in the skin of patients with vitiligo;. high concentrations of hydrogen peroxide together with low catalase levels bave been demonstrated in the epidermis.. A possible autoimmune mechanism has been considered as an increased incidence of auto antibodies and specific T cytotoxic lymphocytes bave been found in patients with active disease. urthermore, vitiligo is often associated with autoimmune disorders such as thyroid disease and diabetes mellitus.9 Various treatments bave been proposed.1o-12 The nsurgical modalities, considered first-line therapy, include corticosteroids (oral, topical and intralesional), oral or topical psoralens plus ultraviolet A (PUVA), and recently, narrow-band ultraviolet B (UVB) therapy. The surgical modalities consist of autologous transplantation and include split-thickness epidermal grafting, epidermal blister grafting, and grafting of cultured melacytes. Among the n-surgical modalities phototherapy is the treatment of choice far vitiligo with > 10% body 2003 European Academy of Dermatology and Venereology

2 32 Leone et al. involved.13 The goal of phototherapy is to stimulate melacytes present in the adjacent area to migrate and repopulate the vitiligius areas. Until a few years ago, PUVA therapy was the most popular treatment far vitiligo worldwide. Synthetic compounds such as -methoxypsoralen (-OP), -methoxypsoralen (-OP) and trimethylpsoralen (TP) afe used in modero photochemotherapy regimens in the form of topical agents (creams, gels and solutions) or orally, followed by exposure to natural sunlight (so-cal1edpuvasol) orto artificial UVA radiation (PUVA). Topical PUVA has to be dalle cautiously to avoid phototoxicity and koebnerization (appearance of new lesions at blistered sites). The limitations of PUVA include acute sideeffects such as nausea and phototoxic reactions, as well as longterm carcigenic risk. A recent retrospective study on systemic PUVA has pointed out that this treatment is only moderately effective in widespread vitiligo.1 Narrow-band UVB (NB UVB), with a peakemission at 1-3 nm, ismore recent and was initially used far psoriasis. This phototherapy was developed to remove the shorter, more erythemogenic, wavelengths and to use those that afe most efficient far clearing psoriasis.1 This light source has also been found useful in the treatment of vitiligo. Westerhof and Nieuweboer-Krobotoval compared NB UVB with topical PUVA and found that NB UVB was more effective in the treatment of vitiligo, with fewer side-effects. ore recently, Scherschun et al. I? bave confirmed favourable results with NB UVB used as motherapy. Treatment can begin with an initial dose corresponding to 0% of the minimal erythemal dose (ED) or with a fìxed dose based on the skin phototype of the patient followed by increments of 20% in each subsequent exposure, or every other exposure, unti! satisfactory erythema is achieved in the lesions. New UV sources that emit wavelengths effective far the treatment of vitiligo afe under intigation and bave been proposed: they may present some advantages aver conventional NB UVB phototherapy. or effective targeted phototherapy a new device has been introduced that emits NB UVB and delivers light to the skin through an optical fibre; interesting results in the treatment of vitiligo bave been described by Lotti et al.1 The 30 nm excimer laser has been successful1y tested recently far the treatment of limited plaque psoriasis The operational wavelength is close to that used in NB UVB. This laser offers some potential advantage in its ability to deliver high doses oflight to localized areas.21 A recent report on a trial using the 30 nm excimer laser in vitiligo has been published by Spencer et al.22 The authors conclude that the degree of repigmentation in a period of 2- weeks is much higher than that achieved with any other current vitiligo therapy and that the xen-chloride excimer laser may represent a new treatment modality far the management of stable vitiligo. The effectiveness of a new 30 nm mochromatic excimer source, with emission close to that used in NB UVB photo- therapy, has been described in the treatment of recalcitrant palmoplantar psoriasis.-z3;2 The mochromatic excimer light (30 nm EL) may present some advantages over the laser: lower power density and consequentiy reduced risk of accidents due to overexposure; larger irradiation field with the possibility to treat larger areas at a time, with shorter treatment duration. The aim of our pilot study was to intigate the effectiveness of this new source in the treatment of vitiligo. We have conducted a pilot open trial with EL on 3 vitiligo patients referring to our clinico Our results suggest that the 30 nm EL may represent a new therapeutic option for the management of vitiligo that may result in repigmentation of vitiligo lesions in a shorter rime as compared with current modalities. aterials and methods The source was a 30-nm XeCl EL device (EXCILITE()- DEKA ELA, Plorence, Italy). It produces a power density of mw/cm2 at a distance of 1 cm from skin and, at this fixed distance, the irradiation field covers an area of 0 cm2. This areahas a rectanguiar shape (3 cm x 1 cm). Thedevicecan be seen in fig. 1. A template with a series of holes and a shutter can be adapted on the device for the ED determination. Ali patients were phototested on rmally pigmented skin with 30 nm EL prior to treatment. Por ED determination a series of five increasing exposures, with 2% progression, was administered on the midback. Ali 3 patients were treated with EL as motherapy from arch 2002 to September Therapy was adrninistered twice a week, on n-consecutive days. The initial tluence for each patient was 0% of the ED. Dose increments at every other treatment were: 0% from treatment 1 to ; 30% from treatment to ; 20% constantly from treatment onwards. The dose was held constant when minimal asyrnptomatic erythema occurred in the lesions. If fig. 1 The mochromatic excimer light jeadv(2003) 1,-3

3 EL in the treatment of vitiligo 33 symptomatic erythema (burning, pain) or blistering developed, treatment was omitted (once or twice), and when treatment was resumed the last dose was decreased by 20%. Treatments were performed by a physician. Once % repigmentation was achieved, the frequency of treatments was tapered to once a week until complete repigmentation was achieved or until the protocol ( months) was completed. No topical treatment was applied to vitiligo areas during the treatment with 30 nm EL. When the face was irradiated the eyes were protected by UV-blocking goggles. In the case of vitiligo on the eyelids and in the orbital area, patients were instructed to keep their eyes shut during the treatments. Unaffected skin inside the irradiation field was shielded with surgical tape or with a high SP sunscreen applied prior to treatment to avoid unnecessary exposure and hyperpigmentation. Patients Al1 the patients were seen in the dermatology clinic, San Gallica Dermatological Institute, Rome, Italy. The patients were assessed for itzpatrick skin phototypes, overall disease duration, and history of previous therapy. Exclusion criteria were: treatment with phototherapy or PUVA during the previous 3 months; active disease; treatment with other medications (topical or systemic); face and/or dorsa of the hands totally depigmented; presence of spontaneous repigmentation; age < 1 years; skin type I. Patients characteristics can be seen in Table l. Patients who had had stable disease affecting more than 20% body surface and recent onset of the disease (less than years duration) were eligible for the study. Thirtyseven patients (1 men, 20 women) were included in the study. Table 1 Patient characteristics Patient. Sex Skin phototype Prior treatment with NB UVB Treatment location received().ji No. ofbeatments Appearance of repigmentation hands sternum scalp knees (forehead) axillae elbows back, hands trunk legs hands, trunk hands, knees, neck legs sternum axillae hands knees legs ~d1.! 3 ;-j EuropeanAcademyofDermatologyand Venereology JEADV(2003) 1,-3

4 3 Leone et al. Twenty-two patients presented with the acrofacial clinical subtype, 10 with focal vitiligo, one with segmental vitiligo, and four with generalized vitiligo. The last four patients had received and did t respond completely to NB UVB phototherapy. or this reason only one area was selected for treatment with 30 nm EL according to the patient's choice: these were, respectively, hands, face, limbs and trunk. The remaining vitiligo lesions, which were t treated, served as controllesions. The ages of the patients ranged from 1 to years (median 3 years). Twenty-two of the 3 patients had skin phototype III, and the remaining 1 patients had skin phototype. The ED on unaffected skin, determined with the EL device, as described earlier, ranged from 0. J/cm2 in skin type III to a maximum of 1.2 J/cm2 in skin type. Disease duration ranged from 2 months to years. Lesional photography was performed at the initial pretreatment visit, then monthly thereafter, and also when initial repigmentation first appeared. fig. 2 Patient with sparse lesions on the forehead, before treatment. Assessment of treatment efficacy Repigmentation was graded according to the percentage of repigmentation in the treated area: this was evaluated by two independent observers who compared photographs. The response to treatment was expressed as ' repigmentation' (score O), 'poor repigmentation' (between 1% and 2%, score 1), 'moderate repigmentation' (between 2% and 0%, score 2), 'good repigmentation' (between 1% and %, score 3), and 'excellent repigmentation' (more than %, score ). In most of the patients vitiligo was localized to more than one gite, so only 'overall' repigmentation grade was considered and t repigmentation grade related to the treated areas. Patients that showed less than 2% repigmentation or did t respond at ali after 3 months were excluded from the study. Informed written consent was obtained from the patients. All patients received a phototherapy information sheet. The study was approved by the Ethical Committee of the Institute. Results Thirty-three patients (9%) obtained an acceptable degree of repigmentation after 3 months; 21 (%) of these patients achieved 'good repigmentation' and 12 (32%) achieved 'excellent repigmentation'. At the end of the evaluation period the number ofpatients with grade repigmentation increased to 1 (9%). In the 'excellent repigmentation' group, two patients bave achieved complete repigmentation after 3 months and consequentiy the treatment was stopped: one patient had sparse lesions on the forehead (figs 2 and 3) and the other patient had sparse lesions on bolli legs. Distribution of patients on the basis of the degree of repigmentation obtained can be seen in Table 2. fig. 3 Same patient after eight treatments: almost complete repigmentation. Table 2 Repigmentation stare Repigmentation stare 3 months months 0(0%) 1 (1-2%) 2 (2-0%) 3 <1-%) (> %) In 3 patients (9%) repigmentation began within the first eight sessions (Table 1). Thirty-six patients bave completed the study. Only one patient did t respond to treatment and was excluded from the study after 3 months: the patient had generalized vitiligo, had already been treated with NB UVB, and the areas selected far treatment were the hands. o Certain anatomical sites responded better than others. Response rates based on vitiligo lesion sites afe given in Table 3. The best response was achieved with lesions located on the face, neck and trunk. Lesions located on the, back, arms o EuropeanAcademyofDermatologyand Venereology JEADV(2003) 1,-3

5 EL in the treatment of vitiligo 3 Table 3 Repigmentation months) by vitiligo areas (at No. of patlents Repigmentation grade Total Hands ace, Neck Trunk and legs also responded with good repigmentation. Lesions in the hands showed more than 0% repigmentation in two cases and response in one case. The cumulative dose ranged from 12. to 3 J/cm2 (mean 32 J/cm2). In the four patients with generalized vitiligo, the n- treated lesions (controllesions) did t show any sign of repigmentation. Side-effects Syrnptornatic erytherna was reported in seven patients (19%) between treatrnents 3 and. Treatrnent was suspended according to the phototherapy protocol and resurned when symptorns disappeared. Only erllients were used. Phototoxic or photoal1ergic reactions were t observed. Discussion The recent report by Spencer et al.22 has shown some advantages of targeted phototherapy with the 30 nm excimer laser: the rapidity of onset of repigmentation, the good overall response in terms of repigmented area, and the lower number oftreatments needed to achieve satisfactory repigmentation compared with conventional NB UVB. Ather important point is the possibility of selectively irradiating vitiligo patches without the involvement of the neighbouring healthy skin. Nevertheless the authors bave indicated that the major drawback may be the very small area of the irradiation field (2 x 2 cm) and consequently the lengthy treatment times in the case of larger lesions. With 30 nm EL we ted an early appearance of repigmentation in the majority of patients (3 patients) - between treatments and (Table 1). This finding is similar to that described with the 30-nm excimer laser. In addition, in patients that did t respond to prior treatment with NB UVB, pigmentation appeared between treatments and, except in ODe patient who did t respond to treatment. Table 2 shows that 12 patients (32%) experienced excellent repigmentation and 21 patients (%) good repigmentation after only 3 months of treatment. An interesting finding is that after months the results do t show striking differences: only six patients move from score 3 to score. This finding demonstrates that when patients do respond to the treatment they respond at the beginning; otherwise they do t respond at ali. This seems peculiar to this kind of treatment and is t always the case for conventional treatment with NB UVB, at least in our experience. In conventional NB UVB it is t uncommon to see a patient responding to treatment after 3 or months, even if after the first treatments hardly any pigmentation was seen. The percentage of patients achieving grade repigmentation after 3 months in this study (9%) is higher than that described in the firststudyon the efficacyofnb UVB.1 In that subset, % of patients repigmented more than % after 3 months of treatment and 3% did so after 12 months. Our results afe more similar to those described in recent reports on the use of NB UVB in adults1 and in children.2 In the series by Scherschun etal.,1 five of seven patients showed more than % repigmentation after a mean number of 19 treatments. In this series the skin types of the patients were and V. The possibility of a better response in terms of repigmentation of these skin types has been advocated by the authors. This may also be the case in our study where the skin phototypes of the patients were and. In the recent repòrt on the use of the 30-nm excimer laser in vitiligo,22 9% of the treated lesions achieved more than % repigmentation after six treatments and 1% after 12 treatments. The number of patients achieving repigmentation greater than % is higher in our study. Whether the difference in the output of the source, the differences in the treatment protocols and in the distribution of skin types between the two studies have contributed to the different response remains to be intigated. The generai advantages of NB UVB therapy also apply to 30 nm EL: absence of perilesional hyperpigmentation, photosensitizing agents t needed, etc. The findings concerning the response of different body sites to treatment afe in agreement with previous studies in vitiligo using narrow-band UVB, broad-band UVB, or oral PUVA therapy. Nevertheless, a satisfactory response on the hands was ted: two patients achieved grade 3 repigmentation. Even if this finding is t significant because of the limited number of patients that received treatment on the hands (n = 3), it may suggest the efficacy of higher NB UVB fluences on these locations that usually respond poorly to conventional treatment. The contraindications and risks (short-term and long-tetro) afe the same as with conventional NB UVB, but the possibility of obtaining satisfactory results in terms of repigmentation with significantly lower cumulativedoses is an important advantage. Our findings indicate that the use of new sources with high fluences for NB UVB phototherapy may shorten the 2003 European Academy ofdermatolory and VenereoloRY leadv (2003) 1,-3

6 3 Leone et al. of uv exposure, leading to a decrease in the dose-dependent side-effects typically associated with phototherapy. Our results with 30 nm EL show that the cumulative dose at the end of the treatment cycle is significantly lower than that reported in other studies with conventional NB UVB.1,1,2 The rapid onset of repigmentation may also play an important role in ameliorating patient motivation and compliance. In conventional NB UVB phototherapy, one reason for early interruption is difficulty in complying with the frequency of treatments. The possibility ofhaving biweekly and weekly treatments with the 30 nm EL was greatly appreciated by the patients. inally, three patients who did t respond to previous treatments with NB UVB showed excellent repigmentation after 30 nm EL therapy. This finding may be useful in the interpretation of the mechanism of action of 30 nm EL compared to conventional NB UVB. The difference in the mode of action of these two sources, which bave substantially the same spectra of emission, may be due to the ability of the 30 nm EL device to deliver higher energy fluences to the target tissue in less time. In other words, the induction of pigmentation by NB UVB may t obey the 'reciprocity law'. The major drawback of the device is the need to treat lesions, regardless of their shape or size, inside a fixed irradiation field at a fixed distance. In addition, the preparation of the patient with sunscreens or templates to protect adjacent healthy skin may be time-consuming: this is the case when smaller lesions afe treated. On the contrary, when larger areas afe treated two or three subsequent exposures afe needed but the irradiated area has to be accurately monitored to avoid double exposure on the borders. The results of this study indicate that 30 nm EL therapy may be a valuable option for treatment of stable vitiligo, with n-extensive lesions, limited to one or two body areas. In this case 30 nm EL may allow repigmentation in shorter times compared with traditional NBUVB, with exposure to lower cumulative doses. Nevertheless, the benefits of the 30 nm EL over conventional narrow-band UVB should be confirmed by a comparative trial on a larger series of patients. urther studies afe required to confirm the efficacy of this new source and the possible advantages bave to be critically evaluated, taking into consideration the higher costs of the treatment. Even if the efficacy of this new 30 nm excimer light source was identical to that ofnb UVB fluorescent tubes the final goal would be that of reducing considerably the cumulative dose, and this may of itself justify the higher cost of the treatment. References l Howitz J, Brodthagen H, Schwartz et al Prevalence of vitiligo. Arch Dermatol19; 113: Le Poole 1C, Das PK, Van den Wijngaard R et al. Review of the etiopathomechanism of vitiligo: a convergence theory. Exp Dermatol 1993; 2: Kovacs SO. Vitiligo. J Am Acad Dermato/199; 3: -. Ortonne JP, osher DB, itzpatrick TB. Viti/igo and Other Hypome/asis oj Hair and Skin. Plenum Press, New York, 193: 2-2. aresca V, Roccella, Roccella et a/. Increased sensitivity to peroxidative agents as a possible pathogenic factor of melacyte damage in vitiligo.j Int Dermato/199; 109: 0-3. Passi S, Grandinetti, aggio. Epidermal oxidative stress in vitiligo. Pigment Celi Res 199; Il: 1-. Schallreuter KU, Wood J, Berger J. Low catalase levels in the epidermis of patients with vitiligo. J Int Dermato/1991; 9: Schallreuter KU, oore J, Wood J et a/. In vivo and in vitto evidence for hydrogen peroxide (H2OJ accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase. J Int Dermato/ Symp Proc 1999; l: Kemp EH, Waterman EA, Weetman AP. Autoimmune aspects of vitiligo.autoimmunity 2001; 3: -. lo Njoo D, WesterhofW, Bos JD, Bossuyt P. The development of guidelines for the treatment of vitiligo. Arch Dermato/1999; 13: Il Shaffrali CG, Gawkrodger DJ. anagement of vitiligo. C/in Exp Dermato/2000; 2: Taneja A. Treatment of vitiligo. J Dermato/ Treat 2002; 13: Njoo D, Spuls PI, Bos JD et a/. Nonsurgical repigmentation therapies in vitiligo. Arch Dermato/199; 13: Kwok YKC, Anstey AV, Hawk JL. Psoralen photochemotherapy (PUVA) is only moderately effective in widespread vitiligo: a 10- year retrospective study. C/in Exp Dermato/2002; 2: Parrish JA, Jaenicke K. Action spectrum for phototherapy of psoriasis. J Int Dermato/191; : WesterhofW, Nieuweboer-Krobotova L. Treatmentofvitiligowith UV-H radiation vs topical psoralen plus UVA. Arch Dermato/199; 133: Scherschun L, Kim JJ, Lim HW. Narrow-band ultraviolet B is a useful and well tolerated treatment for vitiligo. J Am Acad Dermato/ 2001; : Lotti T, enchini G, Andreassi L. UV-H radiation microphototherapy. An elective treatment for segmental vitiligo. J Eur Acad Dermato/ Venereo/1990; 13: Asawanda P, Anderson R, Chang Y, Taylor CR. 30-nm excimer laser for the treatment of psoriasis. A dose-response study. Arch Dermato/2000; 13: Kemeny L, Bonis B. 30-nm excimer laser therapy for psoriasis. Arch Dermato/2001; 13: Spann CT, Barbagallo J, Weinberg J. Review ofthe 30-nm excimer laser in the treatment of psoriasis. Cutis 200 l; : Spencer J, Nossa R, Ajmeri J. Treatment of vitiligo with the 30-nm excimer laser: a pilot study. J Am Acad Dermato/2002; : JEADV(2003) 1,-3

7 El in the treatment of vitiligo 3 23 Campolrni P, avilia L, Lotti T et al. 30 nrn rchrornatic excirner light for the treatrnent of palmoplantar psoriasis. Int J ImmupatholPharmacol2002; 13 (Suppll): Cappugi P, avilia L, avilia C et al. 30 nrn rchrornatic excirner light in psoriasis: clinica! evaluation and study of cytokine levels in the skin.lnt] Immupatho/Pharmaco/2002; 13 (SuppI1): Njoo D, Bos JD, WesterhofW. Treatment of generalized vitiligo in children with narrow-band (TL-O1) UVB radiation therapy.] Am Acad Dermato/2000; 2: ]EADV(2003) 1,-3