Aida Pašić

Krešimir Kostović

Romana Èeović

Zrinjka Paštar

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10Treatment of Vitiligo with Narrow-Band UVB and Topical Gel Containing Catalase and Superoxide DismutaseKrešimir Kostović, Zrinjka Paštar1, Aida Pašić, Romana ČeovićUniversity Department of Dermatology and Venereology, Zagreb University Hospital Center; 1Health Department, Ministry of Defense, Zagreb, CroatiaCorresponding author: Krešimir Kostović, MDUniversity Department of Dermatologyand VenereologyZagreb University Hospital CenterŠalata 4HR-10000 ZagrebCroatia kreso.kostovic@zg.htnet.hrReceived: December 2, 2006Accepted: January 25, 2007SUMMARY Narrow-band UVB has been reported to be efﬁcacious in patients with vitiligo. The epidermis of patients with vitiligo showed reduction in the levels of catalase, in association with high levels of hydrogen peroxidase (H2O2) that is toxic for melanocytes. Based on these ﬁndings, we studied the efﬁcacy and safety of a topical gel containing catalase and superoxide dismutase (Vitix®) in combination with narrow-band UVB. The study included 22 patients of which 19 completed the 6-month study period. Patients applied the gel containing catalase and superoxide dismutase twice a day and received narrow-band UVB 3 times per week. Two different dermatologists evaluated the grade of repigmentation by photograph comparison. At the end of therapy, more than 50% of overall repigmentation was noticed in 11 of 19 (57.9%) patients. More than 75% repigmentation was recorded in three (15.79%), 26%-50% repigmentation in six (31.58%) patients and 1%-25% repigmentation in one (5.26%) patient, whereas one (5.26%) of 19 patients showed no repigmentation at all. The best response was achieved on the face and neck, with more than 50% repigmentation observed in 11 of 14 (78.6%) patients. Development of new lesions was not observed. Adverse events were mild and transient. The study showed that the combination therapy of narrow-band UVB and gel containing catalase and dismutase is a therapeutic option that could be considered in the management of vitiligo. Further evaluation of this combination in multicenter, double-blind, placebo-controlled studies should be undertaken.KEY WORDS: vitiligo treatment, narrow-band UVB, catalaseINTRODUCTION Vitiligo is an acquired idiopathic hypomelanot-ic disorder characterized by sharply demarcated depigmented macules of variable size and shape (1). The incidence is 1%-2% without sexual pre-dilection (2,3). Functional melanocytes disappear from the lesional area of the epidermis although some authors have shown that melanocytes are still present even in the long-standing disease (4). The exact pathogenesis of vitiligo remains un-known. Several hypotheses on the pathogenesis exist, e.g., autoimmune, neural, self-destruction and biochemical, however, none is fully explana-Acta Dermatovenerol Croat             2007;15(1):10-14         ORIGINAL SCIENTIFIC ARTICLE11ACTA DERMATOVENEROLOGICA CROATICAtory (3,5). The biochemical hypothesis on the melanocyte destruction in vitiligo in part refers to excessive production of oxidation products such as hydrogen peroxidase (H2O2) and low catalase activity in keratinocytes of the involved and unin-volved epidermis (3,6-8), which was demonstrat-ed in vivo and in vitro (6,7). The overproduction of H2O2 is the result of high levels of monoamine oxidase A and of a defective recycling of tetrahy-drobiopterin, which is an essential cofactor for the hydroxylation of phenylalanine to tyrosine via phe-nylalanine hydroxylase (9). The H2O2 overproduc-tion could also account for the low catalase activity in keratinocytes (9). According to this hypothesis, we conducted a study to investigate the efﬁcacy and safety of a topical formulation containing catalase and super-oxide dismutase (Vitix®) in combination with nar-row-band UVB phototherapy in 22 patients.PATIENTS AND METHODS Study design The study was open and uncontrolled. Patients were screened at a preliminary visit. Reviews were made monthly at each visit. The duration of the study was 6 months. Patients Nineteen patients with vitiligo (6 males and 13 females) from the outpatient clinic of the Univer-sity Department of Dermatology and Venereology, Zagreb University Hospital Center, were included in the study. Three patients dropped out because of their non-compliance and not because of ad-verse effects. The mean age of study patients was 29.28, range 15-71 years.  The clinical vulgaris subtype was present in 14, acrofacial type in 3 pa-tients, and segmental and focal type in one patient each.  According to Fitzpatrick classiﬁcation, nine pa-tients had skin type IV, seven had skin type II and three had skin type III. The mean duration of the disease was 6.23 years, ranging from 3 months to 21 years. Family history was positive in three (15.7 %) cases. Twelve patients were previously treat-ed: eight with topical corticosteroids, and four with PUVA therapy. Seven patients did not receive any therapy. Patients using medical treatment for viti-ligo at the time of the study, patients with a history of skin cancer, dysplastic nevi, photosensitivity or using photosensitizing medicines, with psychiatric or epileptic disorders, renal failure, known sub-stance allergies, and pregnant and breast-feeding patients were not included in the study. All patients were healthy and used no additional treatment. Treatment protocol Patients were assessed and instructed to ap-ply the skincare gel product containing catalase and superoxide dismutase from the plant Cu-cumis melo (Vitix®, Life Science Inv. Ltd.) to the affected skin twice a day for the study period of six months. During the treatment period, patients were also exposed to the narrow-band UVB three times per week. The UVB source was a Wald-mann-UV7001K. The ﬁrst dose was 0.25 mJ/cm2. Doses were gradually increased depending on the patient’s response to the previous exposure. Dur-ing the treatment, the eyes were protected by UV-blocking goggles. All patients kept their underwear on in order to shield the genitals from the narrow-band UVB exposure. Patients applied Vitix® gel much before taking phototherapy. Evaluation of the treatment Patients were seen monthly for clinical follow up, close-up photo-documentation and reassess-ment. Therapeutic response was expressed as 0% (no repigmentation), 1%-25% (poor), 26%-50% (moderate), 51%-75% (good) and 76%-100% (excellent) repigmentation. The repigmentation grade was estimated by two different dermatolo-gists who compared the photographs. The total number of treatments, cumulative narrow-band UVB dose, and adverse effects were recorded.RESULTS The χ2-test and Mann-Whitney test were used on statistical evaluation. The level of signiﬁcance was set at p<0.05. Twenty-two eligible patients were enrolled in the study. Three patients dropped out because of their non-compliance and not be-cause of adverse effects, and 19 patients were evaluated for therapeutic efﬁcacy. The mean num-ber of narrow-band UVB exposures was 68.89 (range 63-74). The mean total UVB dose per pa-tient was 41.67 J/cm2 (range 30.10-67.65 J/cm2). The ﬁrst repigmentation occurred between the 6th and 26th exposure (mean 12.6 exposure).   At the end of the 6-month therapy, more than 50% of overall repigmentation was noticed in 11 of 19 (57.9%) patients. Of these, three (15.79%) patients showed more than 75% (excellent) re-pigmentation, six of 19 (31.58%) patients showed Kostović et al.     Acta Dermatovenerol CroatTreatment of vitiligo      2007;15(1):10-14 1226%-50% (moderate) repigmentation, one (5.26%) patient showed 1%-25% (poor) repigmentation, and one (5.26%) patient showed no repigmenta-tion at all.      Certain anatomic sites responded better than the others. The best response was achieved in the lesions located on the face and neck, followed by proximal extremities and trunk. Lesions on the hands and feet were most refractory to treatment. More than 50% repigmentation on the face and neck was recorded in 11 of 14 (78.6%) patients. Of these, ﬁve (35.7%) patients showed excellent re-pigmentation (Fig. 1). More than 50% repigmenta-tion on proximal extremities and trunk was record-ed in nine of 17 (52.9%) patients. Of these, ﬁve (29.4%) patients showed excellent repigmentation. More than 50% repigmentation on the hands and feet was observed in ﬁve of 13 (38.5%) patients. Excellent repigmentation on the hands and feet was seen in two (15.4%) patients (Fig. 2).   There was no signiﬁcant correlation between the disease duration and repigmentation grade (p=0.311), type of the skin and repigmentation grade (p=0.223), and previous therapy and repig-mentation (p=0.477).  The development of new lesions was not re-corded in our patients. Laboratory evaluation of serum and urine was unremarkable.  Thirteen of 19 (68.4%) patients reported mild ery-thema on depigmented areas, one (5.26%) patient reported mild erythema with stinging and itching at the site of Vitix® gel application, and ﬁve patients were free from side effects.DISCUSSION Although vitiligo is asymptomatic and does not affect mortality and physical morbidity, depigmen-tation on visible areas leads to severe cosmetic disﬁgurement and may cause considerable psy-Figure 1.A) Vitiligo on the face of an 18-year-old female patientFigure 2.A) Vitiligo on the dorsum of the hands of a 30-year-old female patientFigure 1.B) Almost complete repigmentation after 6-month therapyFigure 2.B)  Excellent repigmentation after 6-month therapyACTA DERMATOVENEROLOGICA CROATICAKostović et al.     Acta Dermatovenerol CroatTreatment of vitiligo      2007;15(1):10-14 13Czarnecka-Operacz and Silny    Acta Dermatovenerol CroatSpeciﬁc immunotherapy in atopic dermatitis  2006;14(4):chological distress. Patients with vitiligo have nu-merous treatment options available, but not all pa-tients respond to the current treatment methods. Even among patients who respond to the treat-ment, there is a high potential for relapse.  Phototherapeutic options (narrow-band UVB and PUVA) are relatively efﬁcacious in the treat-ment of generalized vitiligo. They are generally limited by the requirement of long-term treatment on a twice or three times a week basis for 12 months or even longer. Narrow-band UVB (311 nm) is considered as the ﬁrst-choice therapy for adults and children with generalized vitiligo (5,10). Narrow-band UVB is equally or more efﬁcacious than PUVA (11,12). Various studies report more than 75% repigmentation in 12.5%-75% of pa-tients after one year of UVB narrow-band treat-ment (13-18). The advantages of narrow-band UVB over oral PUVA therapy include the following: shorter treat-ment time; no systemic effects since oral drugs are not required; less burning incidents; less con-trast formation between depigmented and normal pigmented skin: no need of post-treatment eye photoprotection; and allowed use in children and pregnant and lactating women (5,19). The mecha-nism of action of narrow-band UVB phototherapy in vitiligo is not completely understood. It induces local immunosuppression, stimulates the produc-tion of melanocyte-stimulating hormone, and in-creases melanocyte proliferation and melanogen-esis (20). Nowadays, there is accumulating evidence that the increased oxidative stress exists in the entire epidermis of these patients. Oxidation prod-ucts such as hydrogen peroxide (H2O2) are toxic for melanocytes (7). The involved and uninvolved epidermis of patients with vitiligo showed a consis-tent reduction in the levels of catalase, a scaven-ger for highly reactive substances, in association with high levels of H2O2 (8). Based on these ob-servations, a low-molecular weight complex called pseudocatalase has been synthesized. It has been hypothesized that epidermal H2O2 can be re-moved with topical application of a narrow-band UVB-activated pseudocatalase cream and such a combination has been tried in the treatment of vitiligo. In an uncontrolled study, 33 patients with vitiligo were treated with a twice-a-day application of pseudocatalase, calcium and narrow-band UVB twice a week. Complete repigmentation on the face and dorsum of the hands appeared in 90% of treated patients over a mean of 15 months (9). In another open, uncontrolled study, topical pseu-docatalase in combination with narrow-band UVB showed no clear evidence of efﬁcacy and there was even a slight tendency to worsening of the pa-tients’ vitiligo. The treatment period was 6 months (21). Thus, the use of pseudocatalase in the treat-ment of vitiligo remains a controversial issue.  In our study, at the end of 6-month therapy, 11 (57.9%) patients achieved more than 50% repig-mentation. Only two (10.52%) patients showed poor or no repigmentation at all. The face and neck showed the best repigmentation response (78.6% of patients had more than 50% repigmen-tation). Lesions on the hands and feet were most refractory to treatment, yet our patients showed better results in these areas (38.5% of patients achieved 50% repigmentation) than patients in other studies where narrow-band UVB therapy was used (12,13,16,17). The duration of our study was not sufﬁcient to achieve complete therapeutic response and this is probably the reason why only three (15.79%) patients achieved more than 75% overall repigmentation. For example, in the study by Westerhof et al., only 8% of patients showed more than 75% repigmentation of the lesional skin at 3 months (18). However, at 12 months of treat-ment, 63% of patients showed more than 75% re-pigmentation on the lesional skin.  There is no consensus whether better re-sponse to the narrow-band UVB treatment cor-relates with a shorter duration of the disease or darker skin type. We found no correlation between the rate of response and disease duration or skin type.   In our study, no progression of the disease was observed during the treatment period. Vitix® gel was well tolerated and only one patient report-ed mild erythema with stinging and itching at the application site.  The manufacturer claims that this formulation, containing two free radical scavengers (catalase and superoxide dismutase) is an effective catalyst for the removal of H2O2 from the skin. However, another report indicates that Vitix® does not have a capacity to reduce H2O2 (22). Although our study was open and uncontrolled, most of the repigmen-tation observed could probably be attributed to the narrow-band UVB therapy, however, an additional effect of Vitix® gel is quite possible.  In conclusion, the present study showed that the combination therapy with narrow-band UVB and topical catalase and dismutase of a natural origin (Vitix®) is a therapeutic option that could be considered in the management of vitiligo. Further ACTA DERMATOVENEROLOGICA CROATICAKostović et al.     Acta Dermatovenerol CroatTreatment of vitiligo      2007;15(1):10-14 14 ACTA DERMATOVENEROLOGICA CROATICAevaluation of this combination in multicenter, dou-ble-blind, placebo-controlled studies should be undertaken. 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Treatment of Vitiligo with Narrow-Band UVB and Topical Gel Containing Catalase and Superoxide Dismutase

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