International Journal of Dermatology 2009, 48, 86–90 © 2009 The International Society of Dermatology

86

AbstractBackground Vitiligo is an acquired, pigmentary skin disorder which is disfiguring and difficult

to treat. Phototherapy and application of topical corticosteroids are most commonly prescribed.

However, these therapies are often not effective and use of corticosteroids on the face may lead

to cutaneous atrophy, telangiectasia, and ocular complications.

Objective We sought to assess the efficacy of topical tacrolimus ointment in the treatment

of vitiligo.

Methods A prospective pilot study was performed of 30 patients with vitiligo. Patients were

treated with tacrolimus ointment for at least 4 months. Clinical responses were documented

during clinic visits, and by pretacrolimus and post-tacrolimus photography.

Results Twenty-five (83.3%) patients showed some repigmentation at the end of 4 months.

Patients with vitiligo for more than 5 years also responded well to tacrolimus ointment.

Repigmentation in active vitiligo was superior to that in stable vitiligo. 80% of patients with

segmental vitiligo of the head and neck showed some response to tacrolimus, but there was

no statistical significance between segmental and vulgaris vitiligo. The mean percentage of

repigmentation on the head and neck was greater than that on the trunk and extremities.

Four patients initially experienced burning on application.

Conclusions Topical tacrolimus ointment is an effective and well-tolerated alternative therapy

for vitiligo especially involving the head and neck.

Blackwell Publishing LtdOxford, UKIJDInternational Journal of Dermatology0011-90591365-4632© 2008 The International Society of DermatologyXXX Pharmacology and therapeuticsEfficacy and safety of tarcrolimus creamXu et al. Pharmacology and therapeuticsEfficacy and safety of tarcrolimus cream 0.1% in the treatment of vitiligo

Ai-E. Xu, BS, Di-Min Zhang, MM, Xiao-Dong Wei, BS, Bo Huang, MM, and Liang-Jun Lu, MM

From the Department of Dermatology, the Third Hospital of Hangzhou, Hangzhou, China

Correspondence

Ai.-E. Xu Department of Dermatology Third Hospital of Hangzhou Hangzhou China E-mail: xuaiehz@msn.com

Introduction

Vitiligo is an acquired pigmentary skin disorder with an esti-mated incidence of about 1% of world population affectingboth sexes equally.1,2 It is a disfiguring disease causing greatpsychosocial stress and is characterized clinically by the develop-ment of depigmented macules and patches that correspondhistologically to decreased or absent cutaneous melanocytes.The main mechanism of melanocyte destruction in vitiligois theorized to be an autoimmune lymphocytic attack onmelanocytes.1

Current treatment options aiming at repigmentation includethe application of potent topical corticosteroids and the admin-istration of phototherapy, either psoralen-UVA (PUVA) or,more recently, narrowband UVB.3–5 Although as many as64% patients respond at least partially to the application ofmedium-strength to potent topical corticosteroids,6 the risk ofcutaneous atrophy and telangiectasia, especially on the faceand in intertriginous areas, and of ocular adverse events whenapplied to periorbital sites, precludes the prolonged use oftopical corticosteroids. Besides the problem of compliance forregular hospital visits, narrow-band UVB treatment requiresexpensive equipment and trained personnel, and PUVA is

associated with a risk for cancer induction. So, the search fornewer therapeutic modalities continues.

Recently, successful treatment of vitiligo with the topicalcalcineurin inhibitors tacrolimus ointment 0.1% and 0.03%(Protopic®) or pimecrolimus cream 1% (Elidel®) has beenreported.7–9 Calcineurin-inhibitors act on T cells and mast cells,inhibiting T-cell activation and production of cytokines andpreventing the release of pro-inflammatory mediators in mastcells by degranulation.10 Tacrolimus ointment does not causethe atrophy, telangiectasia, or adverse potential ocular effectsof topical corticosteroids and limited application to the face andintertriginous areas.11 The present study was conducted in orderto assess the effect of tacrolimus ointment in treating vitiligo.

Materials and Methods

Study designThis was a prospective pilot study of response to treatment with

tacrolimus ointment of vitiligo in 30 patients conducted in 2005

and 2006.

Information collected in the routine clinical history included

patient sex, location and distribution of the disease, percentage of

depigmentation, age at onset, family history, and disease activity.

© 2009 The International Society of Dermatology International Journal of Dermatology 2009, 48, 86–90

87Xu et al. Efficacy and safety of tarcrolimus cream Pharmacology and therapeutics

Informed consent was obtained from all patients. Patients with a

known sensitivity to study drug or class of study drug and patients

who had used any other investigational agent in the last 30 days

were excluded as well as pregnant or breastfeeding women and

women with childbearing potential not using an adequate

contraception method.

Forty target lesions were selected to apply 0.1% tacrolimus

ointment (Protopic Ointment, Fujisawa Healthcare Inc) twice

a day. In all, 25 patients used tacrolimus ointment to treat only

involvement of the head and neck; two patients used the

tacrolimus ointment to treat vitiliginous sites only on the trunk

and/or extremities, including the hands; and three patients

applied the tacrolimus ointment for both head/neck and

body/extremities involvement.

No concomitant treatment was allowed and a washout period of

6 weeks was mandatory before topical tacrolimus was prescribed.

Patients were evaluated by the same observers at 4-weekly

intervals until 16 weeks and repigmentations were recorded.

During spring and summer months, patients were advised to apply

sunscreen of SPF 30 or higher with frequent reapplication and

incorporation of sun avoidance techniques (avoidance of midday

sun and wearing a hat). Safety was assessed by monitoring and

recording all adverse events throughout the study and by physical

examination, including visual evaluation of skin atrophy in target

lesions at each visit. Patients were asked to return all unused

medication at each visit and at the end of the study; the quantity

of returned medication was documented to assess patient

compliance.

Photography was done in a standard pose at baseline and at

4-week intervals thereafter to document the pattern and extent of

repigmentation. The area of repigmentation was analyzed by

serial mapping of body lesions. Depending on the extent of

repigmentation, the response to treatment was categorized

as marked to excellent (76–100%), moderate (51–75%), mild

(26–50%), minimal (1–25%), or no response. Patients were

followed up to 8 weeks after discontinuation of therapy to assess

the stability of pigmentation.

Statistical analysisStatistical analyses were performed using the analysis of

variance function and paired Student t-test with software.

Results

The mean age of the 30 patients was 22.3 ± 7.8 years (range7–40 years). There were 9 males and 21 females, and 25 ofthem were less than 30 years old. The majority of patients(80%) had vitiligo vulgaris, and 20% showed segmentalinvolvement. The mean duration of vitiligo before the initia-tion of therapy was 4 years (range: 0.25–14 years). There were7 patients with active vitiligo and 23 patients with stablevitiligo. None of the patients had any associated autoimmunedisease and no one had previously repigmented spontaneously.

Overall, 25 patients used tacrolimus ointment to treat onlyinvolvement of the head and neck; two patients used the tac-rolimus ointment to treat vitiliginous sites only on the trunkand/or extremities, including the hands; and three patientsapplied the tacrolimus ointment for both head/neck andbody/extremities involvement.

Twenty-five (83.3%) patients showed some repigmentationat the end of 4 months and the other five patents had noresponse. Initial repigmentation was noted in the sixth weekin the majority. One patient achieved excellent (100%) repig-mentation at the end of 14 weeks with twice daily tacrolimusointment 0.1%, and at the end of 16 weeks, another two patientsalso showed excellent repigmentation. Of these 25 patients,repigmentation was marked to complete in 6 (20%), moderatein 6 (20%), mild in 7 (23.3%) and minimal in 6 (20%) patients.

In all, 40 target lesions were treated. Among them, 10 lesionswere on the cheek, 7 lesions were on the forehead, 2 lesions wereon the eyebrow, 5 lesions were on the eyelid, 3 lesions were on theprenarse, 3 lesions were perioral, 5 lesions were on the neck,4 lesions were on the trunk, and 1 lesion was on the back of thehand. Of the 35 lesions in the head and neck regions treated, 33(94.3%) overall responded to tacrolimus ointment application.Of the 5 lesions with involvement of the trunk or extremities,only 20% responded at least partially to tacrolimus.

Excellent repigmentation was noted in 37.1% of patientswith head and/or neck involvement, but none with involve-ment of the trunk and/or extremities. The mean percentageof repigmentation within the treated vitiliginous areas was65% for the head/neck responders; the mean percentage ofrepigmentation on the trunk or extremities was 4% of the treatedvitiliginous areas, despite at least a 4-month trial in all patientswith trunk or extremity involvement. The mean percentage ofrepigmentation on the head/neck was statistically greaterthan that on the trunk and extremities (P < 0.01) Table 1.

The best repigmentation was observed in the lesions overthe face and areas with greater hair follicle density. Eyelidinvolvement tended to respond the most rapidly and com-pletely. Response to treatment was poor in lesions locatedover the trunk and hands. In our series, 20% of the patientsshowed segmental involvement, most commonly of the headand/or neck. Of all, 66.7% of patients with segmental vitiligoresponded at least partially to tacrolimus ointment, especiallythose with facial involvement (80%). But there was no statis-tical significance between segmental and vulgaris vitiligo ofthe head and neck.

Seven patients with active vitiligo had more or less respondedto tacrolimus ointment application, and excellent repigmenta-tion was noted in 28.8% of these patients. Of the 23 patientswith stable vitiligo, 18 (78.3%) responded to tacrolimusointment application, and excellent repigmentation was notedin 13.0% of these patients. The effect of topical application oftacrolimus ointment in active vitiligo was superior to that instable vitiligo (P < 0.05) Table 2.

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88 Pharmacology and therapeutics Efficacy and safety of tarcrolimus cream Xu et al.

In all, 10 patients had experienced their vitiligo for 5 yearsor longer (range: 5–14 years). Their mean age was 27.4 yearsand mean body surface area affected by the vitiligo was 21%.In all, two patients had lesions limited to the head/neckinvolvement, other eight on both the body and the head/neck.About 80% patients responded at least partially to therapy.Overall, these patients showed a mean extent of repigmenta-tion of 27% of nonfacial vitiliginous areas, and 49% repig-mentation of lesional skin on the head and/or neck. The meanrepigmentation rates did not vary statistically from that ofpatients with disease for less than 5 years.

Information about the pattern of repigmentation wasavailable in 25 responders. Almost all of the target lesionspresent over the face and neck showed repigmentation in adiffuse pattern characterized initially by hypopigmentation,both clinically and by Wood’s light examination, and subse-quently progression to full repigmentation. Repigmentation

was homogenous and of same color as that of patient skintype. The pattern of repigmentation was follicular in 42%target lesions on the trunk and extremities.

In all, 19 patients continued to apply tacrolimus ointmentas prophylatic therapy to previously affected sites to retainpigmentation, generally with application daily to every otherday. At least 3 patients using topical tacrolimus ointmentwere noted to have progression of the vitiligo at new sites inother areas on the body, suggesting that tacrolimus has nosystemic effect on the course of disease outside of the treatedareas.

Side-effects of therapy were minimal and limited to applica-tion site symptoms. 4 patients (13.3%) reported burning withinitial applications, but this subsided spontaneously and didnot necessitate stopping of therapy Figs 1 and 2.

Discussion

In this study, we have provided evidence that application oftacrolimus ointment promotes repigmentation of vitiligo.The better response of lesions of vitiliginous areas of the faceand neck compared with that of lesions on the trunk andextremities is consistent with both the increased folliculardensity on the face and neck and the superior response totacrolimus of dermatitis and psoriasis on the head and neckthan on the trunk and extremities.

Repigmentation for patients with long-term vitiligo is noto-riously difficult to achieve. However, patients with vitiligofor more than 5 years also responded well to tacrolimus

Table 1 Percentage repigmentation of different site

Repigmentation rate (%)Cheek (n = 10)

Forehead (n = 7)

Eyebrow (n = 2)

Eyelid (n = 5)

Prenarse (n = 3)

Perioral (n = 3)

Neck (n = 5)

Trunk (n = 4)

Hand (n = 1)

0 1 0 1 0 0 0 0 3 11–25 1 0 0 0 1 0 1 1 026–50 2 2 0 2 1 2 3 0 051–75 2 2 0 1 0 0 0 0 076–100 4 3 1 2 1 1 1 0 0

Table 2 Percentage repigmentation of different stage

Repigmentation rate (%)Progressive phase (n = 7)

Stable phase (n = 23)

0 0 51–25 1 526–50 2 551–75 1 576–100 3 3

Figure 1 Depigmentation of forehead before trial of tacrolimus 0.1% ointment (a) and after 4 months of twice daily application (b)

© 2009 The International Society of Dermatology International Journal of Dermatology 2009, 48, 86–90

89Xu et al. Efficacy and safety of tarcrolimus cream Pharmacology and therapeutics

ointment. Although the efficacy rate was slightly lower, therewas no statistical difference in mean response for patients withvitiligo of greater than or less than 5 years’ duration. Segmen-tal vitiligo has also been difficult to repigment. In our study,66.7% of patients with segmental vitiligo responded totacrolimus ointment, especially those with facial involvement(80%), suggesting that tacrolimus ointment is particularlyvaluable for this recalcitrant patient group.

Sliverberg et al. 12 have described the different response totacrolimus by season of initiation: response rate was 100%of patients who began in summer, 67% who began in spring,80% of who began in fall, and 61% who began in winter.Though response can occur independent of seasons, theresponse in the summer was statistically greater than that inthe winter (P < 0.05). Their results suggest that the combina-tion of tacrolimus ointment and UV light may be superiorto that of tacrolimus ointment alone, but that UV light is notnecessary for the beneficial effect of tacrolimus ointment.However, in our study, all of the patients’ treatment wasinitiated during the winter. We can imagine that if our patientsstarted therapy in summer, the results would be much better.

Follicular repigmentation is the predominant form ofrepigmentation of vitiligo,13 but in our trial, almost all of thepatients instead demonstrated increased pigmentation spreaddiffusely throughout the individual lesion, first as hypo-pigmentation and eventually as full repigmentation. Thisdiffuse pattern has recently been shown to be particularlycommon in response to topical corticosteroids, in contrast tothe follicular pattern, and in facial and segmental lesions.13

The many patients showing diffuse repigmentation supportsthe concept that a reservoir of persistent, dopa-negativemelanocytes in the depigmented epidermis of vitiligo isresponsible for the diffuse form of repigmentation.14,15

Tacrolimus, unlike topical corticosteroids, does not inter-fere with collagen synthesis and has no effect on keratinocyteproliferation in vitro.16 These findings correspond with theclinical experience of lack of atrophogenic effects in vivo,thereby allowing a longer period of use as generally requiredin the management of vitiligo. Also, the lack of risk of inducingocular cataracts or glaucoma with tacrolimus ointment use12

positions this new topical immunosuppressant as a particu-larly welcome agent for treating vitiligo of the eyelid.

In vitiligo, there is no abnormality of skin barrier functionsor inflammation to increase drug absorption. However, useof tacrolimus ointment for patients with vitiligo raises a poten-tial dilemma. UV light exposure has been a key elementin encouraging repigmentation of vitiliginous skin, whetherthrough use of PUVA or sun exposure. Chronic systemicimmunosuppression in patients with transplant is associatedwith an increased risk of nonmelanoma skin cancer, particu-larly in adult patients with previously sun-damaged skin.17

Although topical application of tacrolimus is not associatedwith systemic immunosuppression, the long-term risk of applica-tion of tacrolimus ointment to skin is unknown. Studies usingtacrolimus 0.1% ointment for up to 3 years in adults olderthan age 40 years with atopic dermatitis have not suggestedan increased risk of nonmelanoma skin cancer.18 Prolongedor unprotected UV light exposure would not be advisableconcurrent with tacrolimus ointment application. We suggestthat patients using the medication during months with sig-nificant sun exposure risk should be counseled about sunprotection and effective use of sunscreens while using themedication until additional years of experience showingsafety are accrued.

Silverberg et al. have described at least partial repigmenta-tion in 48 of 57 children with vitiligo treated with tacrolimusointment.12 Excellent repigmentation was noted in 47% ofpatients with head and/or neck involvement, but only in 25%with involvement of the trunk and/or extremities. Facial vitil-igo of the segmental type showed the best response rate. Ourstudy of 30 patients confirms their results.

As in other inflammatory and immunologically mediated skindisorders, the effective role of topical tacrolimus in the treat-ment of vitiligo may relate to its suppression of autoantibodyrecognition of cell-surface melanocyte antigens and inhibi-tion of subsequent cytotoxic T-lymphocyte reactions.19

Given its immunomodulatory properties and lack of cuta-neous side-effects seen with topical corticosteroids, tacrolimusis a potential therapeutic alternative for vitiligo of the headand neck even in pediatric patients with an improved benefit:risk ratio. Our early results of treatment vitiligo with topicaltacrolimus are promising. However, this is a pilot study andmore robust data need to be obtained in large double-blindcontrolled studies with long-term follow up to prove the safety,

Figure 2 (a) Depigmentation of nasolabial groove before initiation of tacrolimus 0.1% ointment. (b) Excellent repigmentation 4 months after initiating application of tacrolimus ointment 0.1% twice daily

International Journal of Dermatology 2009, 48, 86–90 © 2009 The International Society of Dermatology

90 Pharmacology and therapeutics Efficacy and safety of tarcrolimus cream Xu et al.

efficacy and stability of repigmentation with topical tacrolimusin the treatment of vitiligo. It will also be interesting to deter-mine whether longer periods of therapy or its combinationwith other therapeutic modalities could result in better responsein repigmentation.

References

1 Ortonne JP, Babadoran P, Fitzpatrick TB, et al. Hypomelanoses and hypermelanoses. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI. Fitzpatrick’s Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 2003: 839–846.

2 Kovacs SO. Vitiligo. J Am Acad Dermatol 1998; 38: 647–666.

3 Handa S, Pandhi R, Kaur I. Vitiligo: a retrospective comparative analysis of treatment modalities in 500 patients. J Dermatol 2001; 28: 461–466.

4 Njoo MD, Bos JD, Westerhof W. Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB radiation therapy. J Am Acad Dermatol 2000; 42: 245–253.

5 Stern RS, Liebman EJ, Vakeva L. Oral psorialen and ultraviolet-A light (PUVA) treatment of psoriasis and persistent risk of nonmelanoma skin cancer: PUVA follow-up study. J Natl Cancer Inst 1998; 90: 1278–1284.

6 Cho S, Kang HC, Hahm JH. Characteristics of vitiligo in Korean children. Pediatr Dermatol 2000; 17: 189–193.

7 Kostovic K, Pasic A. New treatment modalities for vitiligo: focus on topical immunomodulators. Drugs 2005; 65: 447–459.

8 Coskun B, Saral Y, Turgut D. Topical 0. 05% clobetasol propionate versus 1% pimecrolimus ointment in vitiligo. Eur J Dermatol 2005; 15: 88–91.

9 Lepe V, Moncada B, Castanedo-Cazares JP, et al. A

doubleblind randomized trial of 0.1% tacrolimus vs 0.05% clobetasol for the treatment of childhood vitiligo. Arch Dermatol 2003; 139: 581–585.

10 Marsland AM, Grimths CE. The macrolide immunosuppressants in Dermatology: mechanisms of action. Eur J Derm ato1 2002; 12: 618–622.

11 Paller AS. Use of nonsteroidal topical immunomodulators for the treatment of atopic dermatitis in the pediatric population. J Pediatr 2001; 138: 163–168.

12 Silverberg NB, Lin P, Travis L, et al. Tacrolimus ointment promotes repigmentation of vitiligo in children: a review of 57 cases. J Am Acad Dermatol 2004; 51 (5): 760–766.

13 Parsad D, Pandhi R, Dogra S, et al. Clinical study of repigmentation patterns with different treatment modalities and their correlation with speed and stability of repigmentation in 352 vitiliginous patches. J Am Acad Dermatol 2004; 50: 63–67.

14 Bartosik J, Wulf HC, Kobayasi T. Melanin and melanosome complexes in long standing stable vitiligo-an ultrastructural study. Eur J Dermatol 1998; 8: 95–97.

15 Tobin DJ, Swanson NN, Pittelkow MR, et al. Melanocytes are not absent in lesional skin of long duration vitiligo. J Pathol 2000; 191: 407–416.

16 Reitamo S, Rissanen J, Remitz A, et al. Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized trial. J Invest Dermatol 1998; 111: 396–398.

17 Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002; 47: 1–17.

18 Rico MJ, Naylor M, Elmets CA, et al. Treatment with tacrolimus ointment is not associated with an increase in non-melanoma skin cancer (Abstract). J Eur Acad Dermatol Venereol 2002; 16 (Suppl.): 138.

19 Plettenberg H, Assmann T, Ruzicka T. Childhood vitiligo and tacrolimus: immunomodulating treatment for an autoimmune disease. Arch Dermatol 2003; 139: 651–654.