Clinical dermatology Original article

doi: 10.1111/j.1365-2230.2005.02037.x

Tacalcitol and narrow-band phototherapy in patients with vitiligo

G. Leone, A. Pacico, P. Iacovelli, A. Paro Vidolin and M. Picardo
Phototherapy Unit, S. Gallicano Dermatological Institute, IRCCS, Rome, Italy

Summary

Background. Vitiligo is a skin disease characterized by loss of normal pigmentation in the skin. Several treatments exist but none is really effective. Recently, perturbations of calcium homeostasis in vitiliginous epidermis have been described. Aim. Based on these ndings, the aim of this prospective, randomized, open-label study was to compare the effectiveness of narrow-band ultraviolet B (NB-UVB) phototherapy alone and the combination of NB-UVB and topical application of the vitamin D3 analogue tacalcitol in the treatment of vitiligo. Methods. In total, 32 subjects with generalized vitiligo and symmetrical lesions were enrolled in the study. Subjects were instructed to apply tacalcitol ointment daily to the lesion on the side randomly selected to receive combination therapy. All subjects received NB-UVB phototherapy on a twice-weekly schedule. Results. Addition of topical tacalcitol to NB-UVB treatment improved the extent of repigmentation and increased the response rate in patients with vitiligo compared with NB-UVB treatment alone. Conclusion. Application of tacalcitol ointment in combination with twice-weekly NBUVB phototherapy is an effective alternative treatment for patients with generalized vitiligo.

Introduction
Vitiligo is an acquired cutaneous depigmentation disorder affecting approximately 12% of the world population with no predilection for age, gender or ethnic background. Familial occurrence is found in about 30% of patients.1 Although not life-threatening, vitiligo is a disguring disorder and can have deep psychological consequences.2 The progressive depigmentation of the skin that characterizes vitiligo is associated with loss of melanocytes from the basal layer of the epidermis. Present therapies require many months to years of treatment and sometimes result in disappointing outcomes. Phototherapy with the photosensitizer psoralen

Correspondence: Dr Giovanni Leone, MD, Phototherapy Unit, S. Gallicano Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy. E-mail: gleone@ifo.it Conict of interest: none declared. Accepted for publication 10 October 2005

plus ultraviolet A (PUVA) is an effective treatment, but carries a potential risk of various skin cancers such as squamous cell carcinoma and malignant melanoma.3 An alternative to PUVA therapy is narrow-band ultraviolet B (NB-UVB) phototherapy using lamps that have a maximum emission at 311312 nm. NB-UVB treatment is generally administered twice weekly and does not require photosensitizers. As with many other treatments, PUVA and NB-UVB therapies generally result in good repigmentation on the face but less frequently improve the pigmentation on the hands and feet.46 In several studies evaluating the combination of PUVA and the topical vitamin D3 analogue calcipotriol for the treatment of psoriasis, hyperpigmentation on the psoriatic plaques was observed as an adverse reaction.7 This observation suggested that the combination of PUVA and topical calcipotriol might be effective in the treatment of vitiligo.8 A related vitamin D3 analogue, tacalcitol, inhibits keratinocyte proliferation and induces their differentiation. In addition, it appears to

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Tacalcitol and vitiligo G. Leone et al.

modulate inammatory and immunological mediators in the skin that may be involved in the aetiology of psoriasis. No signicant systemic drug absorption has been observed after application of tacalcitol to the skin,9 and several studies have demonstrated its efcacy in the treatment of psoriasis.10 Tacalcitol is currently approved for the treatment of mild to moderate psoriasis and is available in Europe as a 4 lg g ointment. Unlike calcipotriol, tacalcitol has not yet been evaluated in combination with phototherapy in the treatment of vitiligo patients. In this open-label study we compared the safety and efcacy of NB-UVB therapy in combination with topical tacalcitol vs. NB-UVB therapy alone for treatment of patients with generalized vitiligo.

Patients and methods

This study was a randomized, prospective, assessorblinded, bilateral-paired study of tacalcitol in combination with NB-UVB vs. NB-UVB alone for treatment of generalized vitiligo in adults. This study was conducted at the Phototherapy Unit of S. Gallicano Institute, Rome, from January 2003 to January 2004. The medical ethics committee of the institute approved the study protocol, and all subjects provided written informed consent. Inclusion criteria were: vitiligo with symmetrical distribution, lesions stable for at least 6 months before enrolment, > 20% of body surface area affected and disease duration of 1 year minimum to 5 years maximum. Exclusion criteria were: age < 18 years, treatment with phototherapy, PUVA or sun exposure in the previous 3 months, presence of spontaneous repigmentation and segmental vitiligo. In total, 32 subjects (11 men, 21 women; mean age 35.8 years, range 1854) with generalized vitiligo were enrolled in the study. For each subject, a bilateral pair of symmetrical lesions was selected for treatment, and one side (left or right) was randomly assigned to receive combination therapy. The 32 lesion pairs (64 lesions) evaluated in the study were located on the face (12 pairs), axillae (10 pairs), elbows (5 pairs), knees (3 pairs) and forearms (2 pairs). Subjects were instructed to apply tacalcitol ointment once daily each evening at the standard dose of 10 mg 4 cm2 (as measured by a microdosator), to the assigned areas. Tacalcitol ointment 4 lg g (Vellutan) was generously provided by Abiogen Pharma (Pisa, Italy). All vitiliginous lesions were treated twice weekly with NB-UVB, starting with 70% of the minimal erythema dose (MED) on unaffected skin. On alternating treatment

days, the doses were increased by the following increments: 30% increase of MED from treatments 14, 20% increase from treatments 48, and 10% constantly from treatment 8 onwards. The dose was held constant when minimal asymptomatic erythema occurred on the lesions. If symptomatic erythema (burning, pain) or blistering developed, treatment was withheld and the last dose used was decreased by 20% when treatment was resumed. Treated areas were evaluated for repigmentation and were assessed in a blinded manner by a single observer at baseline and at the end of the study. Repigmentation was recorded as none (score 0), moderate (< 50%, score 1), good (5080%, score 2) and excellent (> 80%, score 3), depending on the extent of repigmentation for any specic lesion. A score of 2 or higher was considered a successful treatment response. Photographs were taken before treatment, every 4 weeks and at the end of the study. Treatment was continued for up to 6 months. All subjects completed the 6 months of therapy in a compliant manner and all were included in the statistical analysis for efcacy.
Statistical analysis

Analysis of repigmentation percentage with a nonparametric paired test found a signicant difference between treated and nontreated lesions; P < 0.05 was considered statistically signicant. Because this was a right left bilateral lesion comparison study, differences in age, gender and ethnic origin were not considered in the treatment comparison.

Results
As shown in Table 1, the study population was subdivided into three groups according to treatment

Table 1 Mean time to repigmentation by response category and treatment group. Mean time to repigmentation Response category Treatment group n Days SD (minmax) 25 39 29 25 0 0 (30120) (60180) (90150) (120180) (150150) (180 > 180)

Good responders Tacalcitol + NB-UVB 23 55 NB-UVB alone 23 130 Responders Tacalcitol + NB-UVB 7 111 NB-UVB alone 7 159 Non-responders Tacalcitol + NB-UVB 2 150 NB-UVB alone 2 195

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2.5

2.0

Mean Score

1.5

1.0

0.5

NT P = n.s. Rsq = 0.0530 T P < 0.05 Rsq = 0.2831 0 1 2 3 4 Duration of disease (years) 5 6

0.0

Figure 1 Response to treatment according to duration of disease

(T, tacalcitol + NB-UVB; NT, NB-UVB alone),

Repigmentation Score 3.0 2.5

* *

2.0 Mean 1.5 1.0 0.5 0.0 0 1 2 3 4 Time (months) 5 6

* * * *
T NT

*P < 0.0005

Figure 3 Baseline (a) and post-treatment (b) photographs of symmetrical vitiligo lesions located on the face of one patient. The left side has been treated with NB-UVB + tacalcitol, the right side has been treated with NB-UVB alone.

Figure 2 Time course of repigmentation score (T, tacalcitol + NB-

UVB; NT, NB-UVB alone),

results and rapidity of repigmentation: good responders (23 subjects, 72%), responders (7 subjects, 22%) and nonresponders (2 subjects, 6%). All subjects experienced some degree of repigmentation regardless of treatment type and no new lesions occurred on any of the subjects during the treatment period. Response to both treatments was related to the duration of the disease (Fig. 1; Table 1); those achieving good response had shorter disease duration. Throughout the observation period, lesions treated with combination therapy showed signicantly (P < 0.0005) higher repigmentation scores compared with lesions treated with NB-UVB alone (Fig. 2). Lesions treated with combination therapy showed a

more pronounced onset of repigmentation, both in the size of the area affected and in the time to repigmentation onset. In subjects who responded to combination therapy, repigmentation was observed within 3 months. As expected, the face showed good repigmentation with combination therapy (Fig. 3; Table 2). However, even lesions affecting elbows, which generally respond poorly to phototherapy alone, responded well to the combination of topical tacalcitol ointment and NB-UVB (Fig. 4). Combination therapy was generally well-tolerated by all subjects at all sites with minimal side-effects, including mild erythema and itching. Mild irritation and desquamation following the application of the ointment was noted occasionally in the 12 subjects treated on the face. In all 12 subjects, these effects subsided after several days of treatment.

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Table 2 Patients skin type, MED and degree of repigmentation related to location of the lesions. Score at end of the study Skin type II IV III II III III IV II III III II III III IV II III III IV III II III IV II II II II II II II III II IV MED J cm2 0.45 1 0.6 0.3 0.45 0.3 0.8 0.3 1 0.6 0.3 0.3 0.45 1 0.2 0.45 0.6 1.2 0.3 0.6 0.2 1 0.45 0.3 0.8 0.6 0.2 0.45 0.45 0.8 0.3 0.2 T+ NB-UVB 2 3 3 2 3 3 3 2 2 3 2 3 3 3 2 3 3 3 3 2 3 3 2 2 2 1 2 2 1 2 2 3

Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

Age 25 42 18 32 22 53 47 36 33 21 28 30 22 49 37 53 27 29 22 47 25 51 45 41 47 54 27 38 30 39 23 54

Sex M F F M M F F F M M F F F M M M F F F M F F F F F M M F F F F F

Location Elbows Axillae Axillae Axillae Face Face Face Knees Face Knees Elbows Axillae Elbows Forearms Face Face Elbows Face Face Axillae Face Face Knees Face Elbows Face Axillae Axillae Axillae Axillae Forearms Axillae

NB-UVB 1 2 2 1 2 1 1 1 1 2 1 1 2 1 1 2 2 2 2 1 1 1 1 1 1 0 2 1 0 1 1 2

Figure 4 Baseline (a) and post-treatment (b) photographs of two symmetrical vitiligo lesions located on the elbows of one subject. Left elbow, treatment with tacalcitol + NB-UVB; right elbow, NB-UVB alone.

MED, minimal erythema dose.

Discussion
Current therapeutic options for vitiligo are limited by inconsistent and incomplete responses, relapses and side-effects of treatments. Phototherapeutic options are generally limited by the requirement that long-term treatment takes place on a twice weekly or three times weekly basis over a period ranging from many months to years. Highly variable response rates are seen for the standard modalities, averaging approximately 51% for PUVA. With an optimum side-effect prole and an average response rate of 62%, NB-UVB is one of the most efcacious treatments, but 612 months of treatment are needed before optimum results are seen.11,12

Although previous studies showed an unfavourable clinical response to tacalcitol alone,13 our results showed that combination treatment with NB-UVB and tacalcitol signicantly improves repigmentation in vitiligo patients compared with phototherapy alone. With combination therapy, repigmentation occurred earlier and after lower cumulative UVB dosages. Notably, most patients who exhibited a fair clinical response to the combination therapy had been resistant to previous PUVA or topical corticosteroid therapy. These preliminary results indicate that tacalcitol ointment improves response to NB-UVB in subjects with vitiligo, decreasing the time to onset of repigmentation. The effectiveness of tacalcitol ointment on vilitiginous lesions may be mediated by modication of calcium metabolism at the cellular level by means of the hypothetical action of tacalcitol on

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1,25-dihydroxy vitamin D3-receptor expression on melanocytes and keratinocytes. This could contribute to the restoration of calcium homeostasis that seems to be altered in melanocytes from vitiliginous skin.14 18 Furthermore, vitamin D3 has been shown to have immunomodulatory effects on T cells and other immunocompetent cells such as macrophages or neutrophils. Therefore, vitamin D3 might inhibit T-cell-mediated melanocyte destruction as shown in vitiligo during immunotherapy for melanoma.19,20 In addition, experiments by Katayama et al. suggest that tacalcitol upregulates c-Kit expression by melanocytes exposed to linear polarized infrared and solar irradiation. The increased efcacy of NB-UVB phototherapy in combination with topical tacalcitol observed in our study might arise in part from the upregulation by tacalcitol of c-Kit mRNA expression in irradiated melanocytes.13,21 Our study suggests that the cumulative dose of NBUVB needed to achieve satisfactory repigmentation could be considerably reduced with combination therapy. The dosage increments used for phototherapy in this study were selected based on previous experience with NB-UVB alone; however, based on the results with our study population, combination therapy with tacalcitol ointment should permit the use of even lower NBUVB dosages in the future. Consistent with results of studies showing a long history of vitiligo (> 5 years) to be an indicator of poor response to treatment, our analysis showed that patients with recent-onset disease had better response to combination treatment than those with longer duration. Notably, NB-UVB therapy in combination with topical tacalcitol was effective in treating areas such as elbows and knees, which have been considered generally refractory to treatment. In conclusion, our study suggests that treatment with NB-UVB phototherapy in combination with tacalcitol enhances the extent of repigmentation and decreases the time to repigmentation in subjects with vitiligo. In addition, lower cumulative doses of NB-UVB radiation were required when phototherapy was given in combination with topical tacalcitol. Larger prospective studies demonstrating statistical signicance of this novel therapeutic association are needed in order to delineate further the efcacy of phototherapy combined with tacalcitol for treatment of vitiligo.

References
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Acknowledgement
We thank Barbara J. Rutledge PhD, for editing assistance.

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who do not respond to PUVA alone: a preliminary study. J Am Acad Dermatol 2001; 44: 6347. 20 Parsad D, Saini R, Verma N. Combination of PUVAsol and topical calcipotriol in vitiligo. Dermatology 1998; 197: 16770.

21 Norris A, Todd C, Graham A et al. The expression of the c-kit receptor by epidermal melanocytes may be reduced in vitiligo. Br J Dermatol 1996; 134: 299306.

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