Pharmacology and therapeutics

Efcacy of topical calcineurin inhibitors in vitiligo

Russell Wong1, BSc, and Andrew N. Lin2, MD, FRCPC

Faculty of Medicine and Dentistry, and Division of Dermatology and Cutaneous Sciences, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
2

Abstract
Topical tacrolimus and pimecrolimus are indicated for the treatment of atopic dermatitis, but they have been studied in many off-label uses. We reviewed the English language literature to dene their roles in treatment of vitiligo. Double-blind studies show that tacrolimus 0.1% ointment combined with excimer laser is superior to placebo, especially for UV resistant areas, such as bony prominences of the extremities. When used alone, tacrolimus 0.1% ointment is almost as effective as clobetasol propionate 0.05% ointment. Other studies suggest it can also be effective for facial lesions. Double blind studies show that pimecrolimus 1% cream combined with narrow band UVB is superior to placebo, especially for facial lesions. Additional studies would further clarify the role of topical calcineurin inhibitors in vitiligo.

Correspondence Dr Andrew N Lin, MD, FRCPC 2104 Clinical Sciences Building University of Alberta Edmonton Alberta Canada T6G 2G3 E-mail: anlin00@yahoo.com Presented in part at the 86th Annual Meeting, Canadian Dermatology Association, 2226 June 2011, Edmonton, Alberta, Canada. Conict of interest: Dr Lin has been a paid speaker for Astellas Pharma Canada Inc. American trade names: tacrolimus: PROTOPIC; pimecrolimus: ELIDEL.

Introduction Topical calcineurin inhibitors (TCIs) are indicated for the treatment of atopic dermatitis, but they have been evaluated in many other disorders.1 One of the beststudied off-labeled uses has been in vitiligo, for which both tacrolimus and pimecrolimus have been evaluated in double-blind studies, open studies, retrospective studies, and case reports. In this paper, we review these studies in order to dene their roles in the treatment of vitiligo. Materials and methods
We searched the English language literature in PUBMED, EMBASE, Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews since 1999, using the key words vitiligo OR leucoderma OR leukoderma AND macrolide OR calcineurin inhibitor OR immunomodulator OR tacrolimus OR pimecrolimus.
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Results
Tacrolimus ointment

Combined therapy with topical tacrolimus and excimer laser therapy appears to have a dened role in treating vitiligo, especially for lesions over bony prominences. In a double-blind study, 75% repigmentation was achieved in 50% of subjects treated with tacrolimus 0.1% ointment plus excimer laser, in contrast with 19% of subjects treated with placebo plus excimer laser.2 In another double-blind study, investigators found tacrolimus 0.1% ointment plus narrow-band UVB (NB-UVB) reduced the mean size of vitiligo lesions by 42.1%, while NB-UVB alone decreased lesions by 29% (P < 0.001).3 Two other double-blind studies presented conicting results. In one study, efcacy of tacrolimus plus NB-UVB was equal to placebo plus NBUVB,4 while another study showed that tacrolimus 0.1% ointment was superior to clobetasol 0.05%, as evaluated by computerized morphometric analysis of lesions but no signicant difference as evaluated by clinical evaluation.5
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In a single-blind study, investigators showed that tacrolimus 0.1% ointment plus excimer laser resulted in greater than 75% repigmentation in body sites where vitiligo is generally considered to be UV resistant, such as bony prominences and extremities, in 60% of patients; this end point was not achieved in any patients treated with excimer laser alone (P < 0.002).7 In one open, randomized study, combination treatment of 0.1% tacrolimus ointment plus 308-nm excimer light and 308-nm excimer light monotherapy are efcacious and tolerated well in treatment of vitiligo.8 Tacrolimus also appears to have a dened role in facial lesions. One open study of 110 patients demonstrated that greater than 75% repigmentation occurred in the face of 40% of patients, 23% in the extremities, 21.5% in the trunk, but only in 1% of lesions on the hands and feet and none in genital lesions.12 Additional studies are listed in Table 1231.
Pimecrolimus 1% cream

ment and of the neck with NB-UVB. Treatment with topical tacrolimus or pimecrolimus should be continued for three months in order to reach signicant levels of repigmentation.47 Discussion Vitiligo is a disorder of unknown etiology that results in depigmented macules and patches. It is likely an autoimmune phenomenon associated with underlying genetic predisposition.48 Topical corticosteroids have been shown to be effective as monotherapy in vitiligo, especially in head and neck lesions, with response rates of 64% in children.49 However, the head and neck are areas with skin that is among the thinnest of the body, and alternate therapies that do not cause atrophy would be welcome. Topical tacrolimus and, to a lesser extent, topical pimecrolimus appear to ll this need. As one open study of 110 patients demonstrated that >75% repigmentation occurred in the face of 40% of patients,12 and additional open and retrospective studies have shown efcacy in vitiligo, especially for facial lesions (Table 1), it appears that topical tacrolimus has a dened role in treating vitiligo lesions of the head and neck. Similarly, topical pimecrolimus has also shown favorable results for facial lesions, when combined with NBUVB in a double-blind study34 and excimer laser in a single-blind study.35 NB-UVB phototherapy is superior to ultraviolet A light phototherapy but should be reserved for patients who fail topical therapy and, when used alone, NBUVB phototherapy results in repigmentation rates of 41.6100%.49 Randomized controlled studies displayed that topical tacrolimus plus excimer laser has a special role in treating vitiligo lesions that are considered resistant to UVB therapy, such as bony prominences.3,7,8 In a position statement concerning potential photocarcinogenicity of TCIs, the European Dermatology Forum concluded that there is no conclusive evidence from rodent trials to indicate that long-term application of TCIs is photocarcinogenic. There is a need for further studies to investigate the validity of mouse models as well as long-term cohort studies in patients using TCIs.50 Conclusions Tacrolimus 0.1% ointment and pimecrolimus 1% cream have dened roles in the treatment of vitiligo. Strong evidence (double-blind studies) shows that tacrolimus 0.1% ointment combined with excimer laser is superior to placebo, especially for UV-resistant areas, such as bony
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Double-blind randomized controlled studies show mixed results regarding pimecrolimus 1% cream. One doubleblind study found that pimecrolimus 1% cream vs. placebo made no difference in repigmentation,32 while in another pimecrolimus 1% cream was less effective than clobetasol propionate 0.05% ointment,33 with both of these studies testing only non-facial lesions. An additional double-blind randomized controlled study showed pimecrolimus 1% cream plus NB-UVB was superior to placebo plus NB-UVB for facial lesions.34 Single-blind studies have shown a combination of 308-nm excimer laser plus pimecrolimus 1% cream to be superior to excimer laser only for facial lesions35 and that pimecrolimus 1% cream with microdermabrasion is superior to pimecrolimus 1% cream only.36 Six open studies showed favorable results, especially for facial lesions.6,3741 An open study comparing pimecrolimus 1% cream with mometasone furoate 0.1% cream found that they were equal for lesions on the face.40 Additionally, Coskun et al.41 found pimecrolimus 1% cream to be of equal efcacy to clobetasol propionate 0.05% ointment. Favorable results also occurred in one retrospective study42 and three case reports.4143 More information regarding major studies can be found in Table 2.3245
Other studies

Stinco et al.46 performed an open study in which patients were randomized to NB-UVB, tacrolimus 0.1% ointment, or pimecrolimus 1% cream, and were treated for 24 weeks. There were no statistically signicant differences in repigmentation for any anatomical site with all three treatments. The best results were seen for lesions of the face with pimecrolimus cream and tacrolimus ointInternational Journal of Dermatology 2013, 52, 491496

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Table 1 Summary of studies evaluating topical tacrolimus in vitiligo

Authors 10 weeks 12 weeks 12 weeks NB-UVB tacrolimus 0.1% ointment NB-UVB tacrolimus 0.1% ointment Excimer laser tacrolimus 0.1% BID

Design

No. of participants Intervention Results

Duration of study

40

Double-blind, controlled Double-blind, RCT Double-blind, RCT 8 weeks Clobetasol propionate 0.05% vs. tacrolimus 0.1% ointment Tacrolimus 0.1% vs. vehicle (petrolatum) Excimer laser tacrolimus 0.1% ointment BID

Excellent repigmentation observed in: 5/10 lesions treated with excimer laser + tacrolimus; and 2/10 in excimer laser only Tacrolimus side: mean reduction of 42.1% in lesion size. Placebo side: mean reduction of 29% in lesion size. Combination of tacrolimus + NB-UVB is greater than NB-UVB alone (P < 0.001) No statistical difference. Mean repigmentation of 49.24% with NB-UVB + tacrolimus 0.1% ointment, and 41.28% for NB-UVB + placebo

2013 The International Society of Dermatology 28 weeks 14 weeks 12 weeks Mean repigmentation with clobetasol propionate 0.05% was 49.3%, and 41.3% for tacrolimus ointment 0.1%. Tacrolimus 0.1% ointment is almost as effective as clobetasol propionate 0.05% and may be preferred due to decreased side effects Tacrolimus group: 16/20 repigmented; 7/20 at least moderate. Vehicle group: 11/20 experienced repigmentation; 4/20 at least moderate. Tacrolimus 0.1% ointment is a suitable alternative for localized lesions and facial lesions. Group A: 75% repigmentation seen in 16/23; 75% repigmentation seen in UV-sensitive areas in 10/ 13, and UV-resistant areas in 6/10. Group B: 75% repigmentation seen in 4/20; 75% repigmentation seen in UV-sensitive areas in 4/7, and UV-resistant areas in 0/13 Combined treatment: 30% excellent; 40% good; 25% moderate; 5% poor. Monotherapy: 25% excellent; 30% good; 35% moderate; 10% poor. 24 weeks Tacrolimus 0.1% and 308-nm excimer laser vs. 308-nm excimer laser only Tacrolimus 0.1% ointment vs. uticasone propionate 0.05% cream 24 weeks 52 weeks 16 weeks 52 weeks 16 weeks 24 weeks Tacrolimus 0.1% ointment BID Tacrolimus 0.03% or 0.1% ointment Tacrolimus 0.1% ointment vs. Class III topical steroid Tacrolimus group: 19 patients completed, mean repigmentation 15%. Fluticasone group: 21 completed, mean repigmentation 5%. Both groups displayed unsatisfactory repigmentation of segmental vitiligo. BID better than placebo (P = 0.016); BID vs. QD no difference (P = 0.055); QD vs. placebo no difference (P = 0.17) Combination treatment resulted in better repigmentation rates and decreased NB-UVB exposure Topical calcineurin inhibitors, vitiligo Tacrolimus 0.1% ointment QD vs. BID vs. placebo Tacrolimus 0.1% ointment + NB-UVB vs. NB-UVB alone Tacrolimus 0.03% (face) or 0.1% (body) + NB-UVB Tacrolimus 0.1% ointment occlusion Tacrolimus 0.1% ointment BID 12 weeks minimum 24 weeks Variable repigmentation in more than 70% of lesions. Face (73%), limbs (68%), trunk (53.5%). Extremities and genitals responded poorly Minimal repigmentation of the extremities with tacrolimus alone, but when occlusion was added (esp. hydrocolloid dressing) 80% displayed repigmentation. Hands, feet and lower legs were unresponsive Excellent repigmentation: 37.1% head and/or neck, 0% trunk and/or extremities; average 65% repigmentation in head/neck, average 4% repigmentation for trunk/extremity lesions 17/19 achieved repigmentation, 13/19 had excellent repigmentation of face and neck lesions. Hands, feet, ankles and wrists responded worst Head and neck: 47% had 76100% repigmentation. Trunk/extremities: 25% had 76100% repigmentation Tacrolimus is equal to topical steroids in promoting repigmentation. Patients with shorter disease duration responded better (P = 0.032) Pharmacology and therapeutics 493

Kawalek et al.2 Nordal et al.3 Mehrabi and Pandya4 Lepe et al.5

Double-blind, RCT

20 children

Lubaki et al.6

Double-blind, RCT

20

Passeron et al.7

Single-blind, RCT

14

Nistico et al.8

Open RCT

53

Kathuria et al.9

Open RCT

60

Radakovic et al.10 Majid11

17

Fai et al.12

Observerblinded RCT Prospective single-blind Open

80

110

Open

30

Hartmann et al.13 Xu et al.14

Open

30

Open

23

Retrospective

57 children

Grimes et al.15 Silverberg et al.21 Choi et al.22

Retrospective

79

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Five other open studies,1620 involving 151 participants, seven case studies2329 and one chart review30 support the use of tacrolimus ointment in the treatment of vitiligo, with one open study displaying inefcacy.31

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Table 2 Summary of studies evaluating topical pimecrolimus in vitiligo

No. of participants 20 Duration of study 24 weeks

Authors Dawid et al.32

Design Double-blind, RCT Double-blind, RCT

Intervention Pimecrolimus 1% cream BID vs. placebo Pimecrolimus 1% cream vs. clobetasol propionate 0.05% NB-UVB pimecrolimus 1% cream

Results Experimental: 3/14 poor; 11/14 absent. Control: 2/ 14 poor; 12/14 absent. Pimecrolimus is ineffective for body lesions; no facial lesions were evaluated Mean percentage of repigmentation was 57.7% for clobetasol and 32.1% for pimecrolimus. This difference was statistically signicant (P < 0.05). All lesions tested were on trunk or extremities Face and neck: experimental 4/14 excellent, 5/14 good; control 1/16 excellent, 3/16 good. On the face and neck, NB-UVB + pimecrolimus works better than NB-UVB + placebo. With pimecrolimus, lesions on the face responded superiorly to that of single laser (P = 0.004). Lesions on ngers and trunk showed no statistical difference Pimecrolimus only (60 lesions): 13 excellent; 7 good; 7 moderate; 33 poor. Pimecrolimus + microdermabrasion (60 lesions): 26 excellent; 9 good; 13 moderate; 12 poor. Combination therapy was superior to pimecrolimus monotherapy (P = 0.000) Seven lesions on the face had repigmentation >76%. Pimecrolimus works statistically better for face than upper limbs

Eryilmaz et al.33

16

8 weeks

Esfandiarpour et al.34

Double-blind, RCT

68

12 weeks

Hui-Lan et al.35

Single-blind, randomized prospective Single-blind, placebocontrolled, randomized

49

30 weeks

Excimer laser pimecrolimus 1% cream BID Pimecrolimus 1% cream microdermabrasion

Farajzadeh et al.36

65 children

30 weeks

Lubaki et al.6

Open

20

28 weeks

Pimecrolimus 1% cream BID

Six other open studies3741 involving 144 patients, patients from one retrospective study42 and three case studies4345 support the use of pimecrolimus 1% cream in the treatment of facial vitiligo.

prominences of the extremities. When used alone, it is almost as effective as clobetasol propionate 0.05% ointment. Other studies suggest it can be effective, especially for facial lesions. Strong evidence (double-blind studies) showed pimecrolimus 1% cream combined with NB-UVB is superior to placebo, especially for facial lesions. Additional studies would help to clarify the role of TCIs in vitiligo. References
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27 Prats Caelles I, Herranz Pinto P, de Ayala Casado EL, de Lucas Laguna R. Focal hypertrichosis during topical tacrolimus therapy for childhood vitiligo. Pediatr Dermatol 2005; 22: 8687. 28 Castanedo-Cazares JP, Lepe V, Moncada B. Repigmentation of chronic vitiligo lesions by following tacrolimus plus ultraviolet-B-narrow-band. Photodermatol Photoimmunol Photomed 2003; 19: 35 36. 29 Hartmann A, Brocker EB, Hamm H. Repigmentation of pretibial vitiligo with calcineurin inhibitors under occlusion. J Dtsch Dermatol Ges 2008; 6: 383385. 30 Silverberg JI, Silverberg NB. Topical tacrolimus is more effective for treatment of vitiligo in patients of skin of color. J Drugs Dermatol 2011; 10: 507510. 31 Ostovari N, Passeron T, Lacour J, Ortonne J. Lack of efcacy of tacrolimus in the treatment of vitiligo in the absence of UV-B exposure. Arch Dermatol 2006; 142: 252253. 32 Dawid M, Veensalu M, Grassberger M, Wolff K. Efcacy and safety of pimecrolimus cream 1% in adult patients with vitiligo: results of a randomized, double-blind, vehicle-controlled study. J Dtsch Dermatol Ges 2006; 4: 942946. 33 Eryilmaz A, Sekin D, Baba M. Pimecrolimus: a new choice in the treatment of vitiligo? J Eur Acad Dermatol Venereol 2009; 23: 13471348. 34 Esfandiarpour I, Ekhlasi A, Farajzadeh S, Shamsadini S. The efcacy of pimecrolimus 1% cream plus narrowband ultraviolet B in the treatment of vitiligo: a doubleblind, placebo-controlled clinical trial. J Dermatolog Treat 2009; 20: 1418. 35 Hui-Lan Y, Xiao-Yan H, Jian-Yong F, Zong-Rong L. Combination of 308-nm excimer laser with topical pimecrolimus for the treatment of childhood vitiligo. Pediatr Dermatol 2009; 26: 354356. 36 Farajzadeh S, Daraei Z, Esfandiarpour I, Hosseini SH. The efcacy of pimecrolimus 1% cream combined with microdermabrasion in the treatment of nonsegmental childhood vitiligo: a randomized placebo-controlled study. Pediatr Dermatol 2009; 26: 286291. 37 Boone B, Ongenae K, Van Geel N, et al. Topical pimecrolimus in the treatment of vitiligo. Eur J Dermatol 2007; 17: 5561. 38 Sendur N, Karaman G, Sani N, Savk E. Topical pimecrolimus: a new horizon for vitiligo treatment? J Dermatolog Treat 2006; 17: 338342. 39 Seira H, Farnaghi F, Firooz A, et al. Pimecrolimus cream in repigmentation of vitiligo. Dermatology 2007; 214: 253259. 40 Kse O, Arca E, Kurumlu Z. Mometasone cream versus pimecrolimus cream for the treatment of childhood localized vitiligo. J Dermatolog Treat 2010; 21: 133139. 41 Coskun B, Saral Y, Turgut D. Topical 0.05% clobetasol propionate versus 1% pimecrolimus ointment in vitiligo. Eur J Dermatol 2005; 15: 8891.

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42 Mayoral FA, Vega JM, Stavisky H, et al. Retrospective analysis of pimecrolimus cream 1% for treatment of facial vitiligo. J Drugs Dermatol 2007; 6: 517521. 43 Mayoral FA, Gonzalez C, Shah NS, Arciniegas C. Repigmentation of vitiligo with pimecrolimus cream: a case report. Dermatology 2003; 207: 322323. 44 Bilac DB, Ermertcan AT, Sahin MT, Ozturkcan S. Two therapeutic challenges: facial vitiligo successfully treated with 1% pimecrolimus cream and 0.005% calcipotriol cream. J Eur Acad Dermatol Venereol 2009; 23: 72 73. 45 Souza Leite RM, Craveiro Leite AA. Two therapeutic challenges: periocular and genital vitiligo in children successfully treated with pimecrolimus cream. Int J Dermatol 2007; 46: 986989. 46 Stinco G, Piccirillo F, Forcione M, et al. An open randomized study to compare narrow band UVB, topical pimecrolimus and topical tacrolimus in the treatment of vitiligo. Eur J Dermatol 2009; 19: 588593.

47 Lubaki LJ, Ghanem G, Vereecken P, et al. Time-kinetic study of repigmentation in vitiligo patients by tacrolimus of pimecrolimus. Arch Dermatol Res 2010; 302: 131 137. 48 Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: a comprehensive overview Part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. J Am Acad Dermatol 2011; 65: 473 491. 49 Felsten LM, Alikhan A, Petronic-Rosic V. Vitiligo: a comprehensive overview Part II: treatment options and approach to treatment. J Am Acad Dermatol 2011; 65: 493514. 50 Ring J, Barker J, Behrendt H, et al. Review of the potential photo-cocarcinogenicity of topical calcineurin inhibitors: position statement of the European Dermatology Forum. J Eur Acad Dermatol Venereol 2005; 19: 663671.

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