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Topical pimecrolimus in the treatment of vitiligo

European Journal of Dermatology. Volume 17, Number 1, 55-61, January-February 2007, Therapy

DOI : 10.1684/ejd.2007.0093

Summary

Author(s) : Barbara Boone, Katia Ongenae, Nanny Van Geel, Sander Vernijns, Stefanie De Keyser, Jean-Marie Naeyaert , Department of Dermatology, University Hospital of Ghent, De Pintelaan 185, 9000 Ghent, Belgium.

Summary : Although the treatment of vitiligo has improved during the last decade, therapy is still not satisfactory for many patients. Recently topical calcineurin inhibitors were introduced in the treatment of atopic dermatitis. Considering the autoimmune hypothesis of vitiligo pathogenesis, the use of these topical calcineurin inhibitors seems reasonable. Most clinical vitiligo trials have been performed with tacrolimus and show beneficial effects. Concerning the value of pimecrolimus in the treatment of vitiligo only few data are available. Therefore we performed an open pilot study in 26 patients to evaluate the efficacy and safety of 1% pimecrolimus in the treatment of vitiliginous lesions in the head and neck region. In 13 of 26 (50%) evaluated target lesions, repigmentation was noted after a 6 month treatment period with a median percentage of repigmentation of 72.9% (interquartile range: 30.5-98.3%). Duration of vitiligo and total affected body surface area tended to be inversely correlated with the success rate of treatment. Side effects were mainly limited to a burning sensation at the application site. Despite the promising results of topical immunomodulators in the treatment of vitiligo, prudence is in order, as long-term follow up studies are still lacking.

Keywords : efficacy, pimecrolimus, safety, topical immunomodulator, vitiligo

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ARTICLE

Auteur(s) : Barbara Boone, Katia Ongenae, Nanny Van Geel, Sander Vernijns, Stefanie De Keyser, Jean-Marie Naeyaert

Department of Dermatology, University Hospital of Ghent, De Pintelaan 185, 9000 Ghent, Belgium

accepté le 4 Octobre 2006

Vitiligo is an acquired depigmenting disorder characterized by loss of functional melanocytes. It is estimated that about 0.5 to 1% of the world’s population suffers from vitiligo with an uneven distribution over different continents, probably to be explained by different rates of inbreeding [1, 2]. The onset of vitiligo is usually in childhood or young adulthood. Men and women are equally affected. The course of the disease is usually unpredictable, but is often slowly progressive. Depending on the extent of the lesions, vitiligo can be classified into two main categories: generalized and localized. Generalized vitiligo is the most common presentation with milky white patches in a symmetrical distribution. Patients with vitiligo have an increased risk of developing autoimmune diseases. Thyroid disorders are most commonly associated with vitiligo [3]. Although vitiligo is asymptomatic and does not adversely affect mortality and physical morbidity, it may cause a considerable psychosocial stress and potential psychiatric comorbidity, with effects on the person’s self-esteem [4]. The etiology of vitiligo is still largely unknown. Several theories have been proposed. The autoimmune hypothesis is the most important and popular. This theory is supported by the clinical association of vitiligo with autoimmune disorders, the frequent detection of circulating auto-antibodies to surface and cytoplasmatic antigens of melanocytes and the finding of activated T-cells in the periphery of actively progressing lesions in some vitiligo patients [1, 5, 6].Although different treatment options of vitiligo are available, no curative therapy exists. Treatment of vitiligo aims at stabilization and/or repigmentation of the lesions. Standard nonsurgical therapeutic options include topical corticosteroids, topical calcipotriol, photochemotherapy (PUVA) or narrow band UV-B phototherapy. Surgical modalities are based on autologous grafting of non-lesional epidermis or cultured melanocytes to depigmented areas [7]. Furthermore, cosmetic camouflage and supplementation of antioxidants are adjuvant therapeutic options. Patients with extensive vitiligo can be further depigmented with monobenzyl ether of hydroquinone [3, 8, 9].As all treatment modalities are limited by adverse effects or poor efficacy, new therapies are needed. Recently, tacrolimus ointment (FK 506, Protopic^®, Astellas) and pimecrolimus cream (SDZ ASM 981, Elidel^®, Novartis) have been introduced in the treatment of the disorder. They were originally developed for the treatment of inflammatory skin disorders and both are FDA/EMEA approved for use in atopic dermatitis. Tacrolimus and pimecrolimus are topical ascomycin immunomodulating macrolactams and act as calcineurin inhibitors affecting the activation/maturation of T-cells and subsequently inhibit the production of various Th1 and Th2 type of cytokines as IL-2, IL-3, IL-4, IL-5, IL-10, GMCS-factor, TNFα and IFNγ [5, 6, 10, 11]. This mechanism may interfere with the autoimmune mediated destruction of melanocytes by activated T-cells in vitiligo lesions. However, as the lymphocytic infiltrate in perilesional skin is not present in all vitiligo patients, other mechanisms may play a role in TIM (topical immunomodulator) induced repigmentation. Recently in vitro evidence of a direct interaction between tacrolimus and keratinocytes creating a favourable milieu for melanocytic growth and migration has been obtained [12]. Most clinical trials investigating the use of TIMs in the treatment of vitiligo have been performed with tacrolimus and show beneficial effects (table 4). The aim of our open proof of concept study was to evaluate the efficacy and safety profile of pimecrolimus as a treatment modality in vitiligo patients. In addition a review of the literature concerning the treatment of vitiligo with TIMs is presented.

Materials and methods

( Table 1 )( Table 2 )( Table 3 )( Table 4 )A prospective, open proof of concept study was conducted at the department of dermatology at the university hospital of Ghent. Approvement by the Ethical Committee was obtained (October 23^th 2003, project 2003/275) and all participants provided signed informed consent. In May 2004 a total of 26 patients were recruited for a 6 month trial. All patients were at least 6 years old with active or stable (not expanding during the last year) vitiligo and at least lesions in the head or neck region. Other body parts could be affected. Patients with segmental/focal vitiligo or with generalized vitiligo explosively expanding or spontaneously regressing during 3 months before study onset were excluded. Previous topical treatment was interrupted at least 2 weeks before inclusion, whereas photo(chemo)therapy was stopped at least 1 month before study onset. Detailed history and clinical examination were performed at the baseline visit.

The total vitiligo affected area was estimated by using the patient’s palm as a template representing 1% of the body surface area. A reference lesion in the head and neck region was chosen and investigated with Wood light. Digital pictures of the lesion were taken. To obtain an accurate measurement of the size of the reference lesion the contours were traced on transparent sheets at baseline and follow up visits in 20 of 26 patients. These sheets were scanned at a predefined resolution and analyzed using a digital image analysis software (Matlab; Mathworks, Inc, Natik, Mass) as previously described [13].

Patients were asked to apply topical pimecrolimus twice daily, primarily over the reference lesion and optionally at other affected body sites. During the spring and summer patients were advised to avoid sun exposure and to apply sunscreen of at least SPF 20 with frequent reapplication.

Follow up visits were scheduled 3 and 6 months after the baseline visit. At that moment a clinical and Wood light assisted assessment of repigmentation of the reference lesion was made by the clinician. Doubt about possible repigmentation was interpreted as absence of repigmentation. Following clinical and Woodlight assessment, the reference lesion was traced on a transparent sheet and by means of digital analysis software the surface area of the lesion was measured. Subsequently the percentage of area reduction or repigmentation in the reference lesion during the trial could be calculated. This percentage of repigmentation was the main parameter to measure treatment efficacy. Finally, patients were questioned about adverse effects.

Descriptive and explorative statistical analyses were performed. Changes in pigmentation were evaluated with a Wilcoxon Ranked Sign test with a p-value less than 0.05 indicating statistical significance. In order to identify prognostic factors of disease improvement multiple linear and logistic regression was performed.
Table 1 Demographic data

	Number (Percentage)	Mean (SD)	Median (IQR)
Sex (n = 26)
Male	8 (30.8%)
Female	18 (69.2%)
Vitiligo activity (n = 26)
Active	16 (61.5%)
Stable	10 (38.5%)
Depigmentation of scars (n = 26)
Present	11 (42.3%)
Absent	15 (57.7%)
Halo nevi (n = 26)
Present	3 (11.5%)
Absent	23 (88.5%)
Thyroid disease (n = 26)
Present	4 (15.4%)
Absent	22 (84.6%)
Other autoimmune diseases (n = 26)
Present	0 (0%)
Absent	26 (100%)
Family history of vitiligo (n = 26)
Present	8 (30.8%)
Absent	18 (69.2%)
Family history of autoimmune diseases (n = 26)
Present	5 (19.2%)
Absent	21 (80.8%)
Previous vitiligo treatment (n = 26)
Yes	23 (88.5%)
No	3 (11.5%)
Phototype (n = 26)
I	1 (3.8%)
II	4 (15.4%)
III	21 (80.8%)
Age (years) (n = 26)		36.4 (18.1)	35.5 (19.0-53.0)
ARRAY(0x2ed19c)
Duration of vitiligo (years) (n = 26)		12.8 (10.0)	8 (5.0-18.0)

Table 2 Clinical assessement of total vitiligo affected area at baseline (palm = 1%)

	Mean (SD) %	Median (IQR) %
Head and neck (n = 26)	1.5 (1.8)	1.0 (0.5-2.0)
Trunk (n = 26)	4.7 (6.1)	3.0 (0.5-5.5)
Upper limbs (n = 26)	2.9 (2.5)	2.0 (1.0-5.0)
Lower limbs (n = 26)	1.6 (1.8)	0.8 (0.3-2.5)
Total affected area (n = 26)	10.7 (9.0)	8.4 (3.3-15.5)

Table 3 Clinical assessment of repigmentation of the target lesion

	Number (percentage)	Number (percentage)
Month 3	Month 6
Repigmentation (clinical) (n = 26)	10 (38.5%)	13 (50.0%)
Repigmentation (Woodlight) (n = 26)	13 (50.0%)	15 (57.7%)
Mean period to initial repigmentation (± SD) (n = 26)	6.9 (± 2.4) weeks	7.4 (± 2.8) weeks

Table 4 Case reports and clinical studies on tacrolimus in the treatment of vitiligo

Tacrolimus
Reference	Study design	Number of patients	Study duration	Treatment regimen	Materials and methods	Results	Adverse effects
Mehrabi D [42] 2006	Randomized, placebo-controlled, double-blind trial	9	12 weeks	0.1% tacrolimus + UVB versus placebo + UVB	2 paired vitiligo patches, digital photography, computerized area measurement	No statistically significant difference	Redness, pruritus, burning (most likely related to light therapy)
Ostovari N [43] 2006	Comparative prospective, non blind, pilot study	9	12 weeks	0.1% tacrolimus + UVB versus 0.1% tacrolimus	2 paired vitiligo patches, digital photography, 6-point scale for grading repigmentation by 2 investigators	No repigmentation with tacrolimus monotherapy	Erythema (most likely related to light therapy)
Almeida P [44] 2005	Open pilot study	12	8 months	0.1% tacrolimus twice daily	Digital photography, 3-point scale for grading repigmentation	Good to excellent repigmentation in 50% of patients	Pruritus at initial application
Kanwar AJ [45] 2004	Open pilot study	25 children	12 weeks	0.03% tacrolimus twice daily	Digital photography, serial mapping of body lesions, 3-point scale for grading repigmentation	Complete repigmentation in 57.9% of patients, best results in face and hear bearing sites	Pruritus and burning
Silverberg N [46] 2004	Retrospective review	57 children	3 months	0.03% or 0.1% tacrolimus once or twice daily	Digital photography, 3-points scale for grading repigmentation	At least partial repigmentation in 84% of patients, best results in head and neck region	Burning at initial application
Passeron T [17] 2004	Comparative, prospective, randomized, intra-individual study	14	12 weeks	0.1% tacrolimus + excimer laser versus excimer laser	2 to 5 paired lesions, digital photography, 6- points scale for grading repigmentation	Combination therapy is superior to excimer laser monotherapy	Erythema, bullae (most likely related to light therapy)
Kawalek A [18] 2004	Prospective, double-blind, placebo-controlled study	8	10 weeks	0.1% tacrolimus + excimer laser versus placebo + excimer laser	24 symmetric patches, photography, 4-point scale for grading repigmentation	Significantly greater degree of repigmentation when treatment with combination therapy	Excimer: erythema, blistering Tacrolimus: tingling, burning, erythema
Grimes P [10] 2004	Open prospective study	23	24 weeks	0.1% tacrolimus twice daily	6-points disease severity scale	Varying levels in 89% of patients, best result head and neck region	Burning, stinging, pruritus, verruca vulgaris
Lepe V [14] 2003	Randomized, double-blind, comparative trial	20 children	2 months	0.1% tacrolimus versus 0.05% clobetasol propionate	2 symmetrical lesions, color slides, morphometric digitalized computer program	Tacrolimus almost as effective as clobetasol propionate	Clobetasol propionate: atrophy, telangiectasia Tacrolimus: burning
Travis L [47] 2003	Case report	3	2 to 4 months	0.1% tacrolimus twice daily	Lesions on face and eyelids	Complete repigmentation in 100% of patients	None
Castanedo-Cazares [48] 2003	Case report	1	4 months	0.1% tacrolimus + UV-B	Lesions on face	Percentage of repigmentation area: 95%	Not mentioned
Tanghetti E [49] 2003	Open pilot study	15	1.5 to 9.5 months	0.1% tacrolimus twice daily (+ sunlight exposition in some patients)	4-points scale for grading overall repigmentation	At least partial repigmentation in 87% of patients	None
Grimes P [50] 2002	Open pilot study	6	1 to 5 months	0.03% or 0.1% tacrolimus twice daily	Application on all vitiliginous lesions, 4-points scale for grading overall repigmentation	Moderate to excellent repigmentation in 83% of patients	Burning and stinging at initial application, tinea corporis
Smith D [51] 2002	Case report	1	18 months	0.1% tacrolimus twice daily	Lesions on face	90% repigmentation in face and scalp region	Not mentioned

Results

A total of 26 Causasian patients (8 males and 18 females) with a median age of 35.5 years was recruited for participation in a study with a mean (± SD) study duration of 186 (± 17) days. No patients were lost during follow up. The duration of vitiligo varied from 2 to 38 years with a median of 8 years. In 16 (61.5%) patients vitiligo was actively spreading during the past year. Depigmentation of scars was noticed in 11 (42.3%) patients whereas halo naevi were present in 3 (11.5%) patients. Twenty one (80.8%) patients could be categorized as phototype III whereas 4 (15.4%) patients were classified as phototype II and only one (3.8%) patient as phototype I. Based on history, thyroid disease was present in 4 (15.4%) patients. No other autoimmune diseases were associated. A family history of vitiligo was noticed in 8 (30.8%) patients. A family history of autoimmune disease was present in 5 (19.2%) patients (4 thyroid disease, 1 Crohn’s disease). In total, 23 (88.5%) patients had used topical and/or photo(chemo)therapy before the introduction of pimecrolimus cream with limited or no improvement. Three patients had no prior therapy (table 1).

The median total affected body surface area at baseline was 8.4% ranging from 1.1% to 38.0% which indicates a broad vitiligo severity spectrum of the participants. The median affected area in head and neck region amounted to 1% with an interquartile range from 0.5 to 2.0% (table 2).

Repigmentation of the target lesion was clinically marked in 10 of 26 (38.5%) patients after 3 months and in 13 of 26 (50.0%) patients after 6 months. Assessment of repigmentation with Woodlight revealed even better results with repigmentation in 13 of 26 (50.0%) patients after 3 months and in 15 of 26 (57.7%) patients after 6 months. The mean (± SD) period to initial repigmentation ran up to 7.4 (± 2.8) weeks (table 3).

At baseline the median surface area of the reference lesion in head and neck region was 5.8 cm² (interquartile range (IQR) 3.3-16.8 cm²). At month 3 the median target lesion area was statistically significantly reduced to 3.6 cm² (IQR 0.7-12.0 cm²) (Wilcoxon Ranked Sign test, p = 0.0023) with a median relative area reduction of 26.2% (IQR 16.8-47.4%). At month 6 the median target lesion area was further reduced to 1.4 cm² (IQR 0.0-9.4 cm²), a statistically significant reduction versus baseline (Wilcoxon Ranked Sign test, p = 0.0007) with a median relative area reduction of 72.9% (IQR 30.5-98.3%) versus baseline ( (figure 1) ). Only 1 of 20 (5%) patients presented with enlargement of the initial reference lesion, whereas stabilization (repigmentation < 10%), reduction and even complete disappearance of the lesion were noticed in 3 of 20 (15%), 11 of 20 (55%) and 5 of 20 (25%) patients respectively.

Due to the small sample size of the pilot study no statistically significant predictors of response rate could be identified. However, some tendencies were noted. Duration of vitiligo and total affected body surface area influenced treatment outcome. The shorter the duration of vitiligo and the smaller the total affected body surface area, the better the probability on repigmentation.

Side effects of therapy were mainly limited to application site symptoms. Twelve of 26 (46.2%) patients mentioned a burning sensation at initial application, for which therapy was not discontinued. At the end of the study 2 of 26 (8%) patients developed an acneiform eruption at the application site.

Discussion

Since 2002 several case reports and small studies on the use of TIMs in vitiligo have been published (tables 4 and 5)( Table 5 ). Most studies have been performed with tacrolimus and show beneficial results, mainly in the head and neck region. This may be explained by the greater density of hair follicles in these areas and thus the greater melanocyte reservoir. Moreover, the head and neck are sun-exposed areas and UV therapy is a well-known treatment option of vitiligo. One randomized, double blind, left-right comparative trial has been conducted and showed tacrolimus to be almost as effective as clobetasol propionate in the treatment of vitiligo [14]. The first report on pimecrolimus in the treatment of vitiligo was published in 2003. A patient with lesions on the face treated with 1% pimecrolimus during 5 months showed repigmentation of more than 90% [15]. Equal efficacy of 1% pimecrolimus versus 0.05% clobetasol propionate was found in one trial [16].

In our study 26 vitiligo patients were asked to apply 1% pimecrolimus twice daily over a 6 month period, which is longer than the follow up time in most similar studies so far. Moreover, digital image analysis software was used in order to obtain objective repigmentation area measurements instead of the commonly used subjective repigmentation scaling scores. Clinical assessment revealed repigmentation of the target lesion on the face or neck in 10 of 26 (38.5%) patients after 3 months and in 13 of 26 (50.0%) patients after 6 months. Objective measurement of the target lesion showed a median relative area reduction of 26.2% and 72.9% after 3 and 6 months respectively. Based on these results, patients with a good initial response to pimecrolimus treatment should be encouraged to continue therapy as further improvement can be expected.

Two prospective studies showed the synergistic effect of tacrolimus ointment and 308-nm excimer laser treatment [17, 18]. However, it is still uncertain whether combination of topical immunomodulators with UV treatment is safe in the long-term with respect to photocarcinogenesis. Systemic treatment with tacrolimus in organ transplant patients increases the risk for the development of cutaneous cancer. This finding has led to the restriction of UV exposure during topical treatment with TIMs. In animal studies a combination of topical immunomodulators with ultraviolet exposure revealed an enhanced risk of the development of skin cancer. However animal models are a poor predictor of human carcinogenesis. Moreover, studies in humans with inflammatory skin disease treated with topical immunomodulators show there is no evidence that the combination of UV and TIMs is more carcinogenic than UV alone [19, 20]. Studies in mouse skin have shown that pimecrolimus and tacrolimus applications even can protect against UV induced damage on DNA [21-23]. In addition, in patients with vitiligo the occurrence of non-melanoma skin cancer is uncommon and the important tumor suppressor p53 is upregulated, suggesting an inherent resistence to the development of cutaneous malignancies in vitiliginous skin [24, 25]. Postmarketing epidemiological studies to assess the long-term risk of skin cancer in patients treated with topical pimecrolimus are underway. Until further evidence is available an adequate UV protection should be advised and a combination therapy of TIM and UV should only be performed in controlled settings.

As not all vitiligo patients show repigmentation upon pimecrolimus treatment, it would be interesting to know if certain predictors of considerable disease improvement exist. We were not able to identify statistically significant predictors, but some tendencies were noted. An inverse correlation between duration of the disease and total affected body surface area versus response rate was noted. The correlation between short vitiligo duration and promising response rate upon pimecrolimus therapy has already been noticed by another open pilot study conducted by Sendur N et al. [26]. Studies with larger series are required to support these findings and to identify other possible predictors in order to enable the physician to select those vitiligo patients with a high probability of successful treatment with pimecrolimus.

As vitiligo tends to be chronic and requires quite a long therapeutic course to achieve satisfactory results, tolerability and safety are important issues. Few side effects were mentioned by patients participating in our study. Twelve patients mentioned a burning sensation upon initial application which resolved after a few days. This application site reaction is the most frequently reported side effect upon treatment with topical immunomodulators. However, the incidence is lower in the vitiligo population compared to the atopic dermatitis population. This is probably due to the presence of an intact epidermis in vitiligo patients versus the excoriated skin of an atopic dermatitis patient [6]. At the end of the study two patients developed an acneiform eruption at the application site. While not previously observed in vitiligo trials with TIM treatment, this adverse event has occasionally been observed in atopic dermatitis patients treated with both tacrolimus [27-29] and pimecrolimus [30, 31]. Although skin infections did not occur within our study population, molluscum contagiosum infection during the treatment of vitiligo with tacrolimus has been reported [32]. However, treatment with TIMs has not been associated with a statistically significant increase of skin infections in patients with atopical dermatitis [33-35]. Analogously there is no increased incidence of systemic infections in patients treated with topical calcineurin inhibitors [36].

Controversy exists concerning the possible association between the use of topical immunomodulators and the occurrence of malignancies in humans. Since January 2006 a black box warning for tacrolimus and pimecrolimus has been enacted by the FDA because of concerns of potential safety risks including skin cancer and lymphoma. However there is no evidence of a causal relation between the sporadically reported lymphomas and the use of a topical calcineurin inhibitor. As a small percentage of patients treated with TIMs have a significant absorption of these agents [27, 37] and phase 4 studies have only just begun to enroll patients, conclusive safety data will only be available after many years [19, 34, 36, 38]. It should be noted that most studies with TIMs are conducted in patients with atopic dermatitis in which the barrier function of the skin is disturbed. In vitiligo the barrier function of the skin is normal which results in a lesser degree of penetration of TIMs. Moreover, due to a higher lipophilicity, pimecrolimus has a more skin-selective profile than tacrolimus, which theoretically results in a lower potential for systemic immunosuppression and the development of cancer [39].

Despite above mentioned safety issues, we demonstrated pimecrolimus to be a useful alternative in the treatment of vitiligo in the head and neck region. Treatment of vitiligo with pimecrolimus (and tacrolimus) enables the physician to circumvent side effects of currently available therapeutic options [8]. Most importantly, topical immunomodulators have an advantage over topical corticosteroids as they do not induce atrophy, striae and telangiectasia. Moreover, application of topical steroids to the eyelids can cause glaucoma and cataracts whereas this has not been reported to treatment with TIMs [40, 41]. Unfortunately topical calcineurin inhibitors are up to 10 times more expensive than corticosteroids.
Table 5 Case reports and clinical studies on pimecrolimus in the treatment of vitiligo

Pimecrolimus
Reference	Study design	Number of patients	Study duration	Treatment regimen	Materials and methods	Results	Adverse effects
Coskun B [16] 2005	Comparartive prospective, non blind trial	10	2 months	1% pimecrolimus versus 0.05% clobetasol propionate	2 paired vitiligo patches digital photography, 4-points scale for grading repigmentation	Comparable rate of repigmentation	Clobetasol propionate: telangiectasia, atrophy Pimecrolimus: burning
Mayoral F [15] 2003	Case report	1	5 months	1% pimecrolimus	Lesions on the face, scalp, trunk (+ atopic dermatitis)	Percentage of repigmentation: >90%	None

Conclusion

Data from case reports and smaller pilot studies investigating the use of topical calcineurin inhibitors in the treatment of vitiligo are promising. However, placebo-controlled prospective studies with larger patient series should be conducted in order to further investigate the efficacy of pimecrolimus in the treatment of vitiligo. Trials comparing the efficacy of pimecrolimus versus corticosteroids could help to resolve the present disagreement on the topic. Identification of predictors of considerable disease improvement would enable the physician to select those vitiligo patients with a high probability of successful treatment with pimecrolimus. As vitiligo has an important effect on the psychological well-being of a patient, quality of life scales should be included in future trials. It is also unknown whether a relapse will occur when pimecrolimus treatment is stopped and whether continuous or intermittent therapy will be needed. Moreover, safety issues concerning the treatment with topical immunomodulators are still pending and vitiligo tends to be chronic and requires quite a long therapeutic course to achieve satisfactory results. Therefore long-term follow up studies are required. Awaiting larger studies, the use of topical pimecrolimus in the treatment of vitiligo could be an alternative in the treatment of head and neck lesions where chronic use of potent corticosteroids is contra-indicated.

Acknowledgements

Financial support: Medication was kindly provided by Novartis Belgium. Statistical analysis was performed in collaboration with Novartis Belgium and General Biometric Services and Consulting (Ghent). The authors thank M. Dierick, and M. De Backer, for their support and assistance in completing this trial.

Conflict of interest: None

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