Use of Tacrolimus Ointment in Vitiligo Alone or in Combination Therapy

S. Berti, MD¹; G. Buggiani, MD^1,2; T. Lotti, MD^1,2
1. Department of Pediatric Medicine, Anna Meyer Children’s Hospital of Florence, Florence, Italy
2. Department of Dermatological Sciences, University of Florence, Florence, Italy

ABSTRACT

Current treatments for vitiligo are largely unsatisfactory. Topical corticosteroids and phototherapy (narrow-band UVB and psoralen+UVA) are the most prescribed, however, these therapies are often not effective and have important side-effect, especially when used for a long time. Many studies have reported the efficacy and safety of tacrolimus ointment in adults and children with vitiligo, particularly when located on the head and neck. Successful treatment is possible when it is combined with other therapies, such as narrow-band UVB, microphototherapy, helium-neon laser, or narrow-band excimer laser.

Key Words: corticosteroids, phototherapy, tacrolimus, vitiligo

Vitiligo, an acquired pigmentary skin disorder affecting 1% of the world’s population, is characterized by depigmented macules that correspond histologically with reduced or absent cutaneous melanocytes.1 Although the mechanism of melanocyte dysfunction and disappearance is still unclear, there are 2 major theories regarding its pathogenesis: the autoimmune theory and the autotoxicity theory.2 Current treatments, e.g., topical corticosteroids, narrow-band UVB (NBUVB), and psoralen+UVA (PUVA), are the most prescribed,3 but are not often effective, and corticosteroids aplied to the face may lead to cutaneous atrophy, telangiectasia, and ocular complications. NBUVB treatment requires expensive equipment and trained personnel, and PUVA has been associated with a risk of carcinogenesis.3 Phototherapy and corticosteroids have limited effectiveness, particularly on the acral regions.4

Immunomodulators, such as tacrolimus ointment 0.1% and 0.03% (Protopic®, Astellas), and pimecrolimus cream 1% (Elidel®, Novartis) are approved for treating atopic dermatitis in adult patients and pediatric patients over 2 years of age.2 Tacrolimus can be used as an alternative to topical steroids in many other forms of dermatitis, such as vitiligo. This ointment does not cause the atrophy, telangiectasia, or adverse ocular effects of topical corticosteroids, which has limited application to the face and intertriginous areas.1

Tacrolimus acts on T cells and mast cells, inhibiting T cell activation and the production of proinflammatory cytokines, such as Tumor Necrosis Factor (TNF), whose levels are higher in vitiligo lesional skin.5 Moreover, it prevents the release of proinflammatory mediators in mast cells by degranulation.1 Recently, the successful treatment of vitiligo with tacrolimus has been reported (See Table 1).

Xu et al.1 studied 30 vitiligo patients who were treated with tacrolimus ointment for 4 months or more. Of these, 83.3% patients showed some repigmentation at the end of 4 months. In particular, 1 patient achieved excellent (100%) repigmentation at the end of 14 weeks, and another 2 patients exhibited 100% repigmentation at the end of 16 weeks. Of these 25 patients, repigmentation was graded as complete in 20%, moderate in 20%, mild in 23.3%, and minimal in 20%. Of the patients with segmental vitiligo of the head and neck, 80% showed the some response, but there was no statistical significance between segmental and vulgaris vitiligo. Patients who had vitiligo for more than 5 years also responded well. Repigmentation is notoriously difficult to achieve. The mean percentage of repigmentation on the head and neck was greater than that seen on the trunk and extremities. The only reported side-effect was initial burning on application in 4 patients. The study found that tacrolimus was a safe and effective therapy for vitiligo, especially when it involved the head and neck.

Reference	Evidence
Xu, et al.1	83.3% (25/30) repigmentation: 12% excellent 20% complete 20% moderate 23.3% mild 20% minimal
Choi, et al.2	69.3% repigmentation: (no difference of disease location or age of onset; better response in short-duration disease)
Hartmann, et al.4	81% repigmentation on face 80% repigmentation on extremities (when in occlusion)
Table 1: Recent studies on the treatment of vitiligo with tacrolimus ointment

In 2008, Choi et al.2 studied 79 patients; 52 were treated with tacrolimus and 27 with topical corticosteroids. Topical immunomodulators were found to be as effective as topical steroids and patient response was faster than that once obtained by topical steroids. The patients studied were then divided in 3 groups according to the location of vitiligo lesions: 59 had lesions on the face, 53 on the hands, and 23 on the feet. After treatment, 38 showed repigmentation on the face, 31 on the hands, and 9 on the feet. The investigators could not find any statistically significant differences in the ratio of lesions, which showed response among these 3 groups. They further divided their study into 2 groups: long-duration (>12 months) and short-duration (<12 months). The short-duration group showed a higher rate of response that was statistically significant. There was no statistical difference between the group of younger (i.e., <18 years of age) and older (i.e., >18 years of age) patients. The faster response of topical immunomodulators may be related to their effects on melanocytes, i.e., the proliferation of melanocytes is enhanced by a tacrolimustreated keratinocyte supernatant, which is rich with stem cell factor and matrix metallopeptidase-9.2 These results coincide with those of Lepe et al.7 who, in a study of 20 patients, documented that clobetasol and tacrolimus showed more than 75% repigmentation in 5 patients. There were no statistically significant differences between these 2 treatments (p>0.05).

In a placebo-controlled 12-month prospective study of 31 vitiligo patients, Hartmann et al.4 documented the safety and efficacy of tacrolimus, even in those with disease of long-standing duration and in those who received long-term treatment. Tacrolimus may significantly improve the quality of life of affected patients. In the region beyond the face and neck, additional occlusion with polyurethane foil or hydrocolloid dressing may significantly enhance the therapeutic results and may shorten the time until the start of repigmentation. When tacrolimus was applied occlusively, repigmentation was documented in 81% of patients with facial lesions, and in 80% of patients with lesions on the extremities.

Many studies suggest the associated use of tacrolimus with other therapeutic options to improve the rate of repigmentation.8-10 Lotti et al.8 studied 458 patients with vitiligo that affected less than 10% of their skin surface. A 311nm narrow-band microphototherapy (Bio Skin®, Cropper Medical) was given alone or in combination with topical treatment, (i.e., tacrolimus, pimecrolimus, betamethasone dipropionate 0.05%, calcipotriol, or phenylalanine cream). The investigators reported that targeted combination therapies in vitiligo were remarkably more effective than a single treatment. Fai et al.9 studied 110 patients with chronic and refractory vitiligo in a period of 30 months, and suggested that the combination of topical tacrolimus with NBUVB phototherapy as an alternative approach that could be highly effective for the treatment of refractory vitiligo located on the face, trunk, and limbs. However, longterm data and randomized controlled trials on a large number of patients are required.

The association of tacrolimus with NBUVB excimer laser has been reported to improve the repigmentation rate, but it is associated with the possibility of unexpected burns.10 Recently, an association between helium-neon laser and topical tacrolimus has been proposed to be effective without infringing on the issue of additional photocarcinogenic risk. Since the underlying repigmentation mechanisms of these 2 modalities are different, it is reasonable to propose that combining them may produce better clinical results.11 It is important to remember that NBUVB, microphototherapy, UVB narrow-band excimer laser, and helium-neon laser still have the potential to produce skin cancer. In fact they are effective for treating vitiligo, especially when combined with tacrolimus ointment. Based on the evidence, these treatment options appear to be safe and well tolerated, even though they may have carcinogenic potential, which is extremely important for children affected by vitiligo.

Silverberg et al.12 reported that the use of tacrolimus ointment is an effective alternative treatment for vitiligo in children, particularly involving head and neck areas. Kanwar et al. studied 25 Asian children with vitiligo (i.e., 54.5% had vitiligo vulgaris, 40.9% had focal vitiligo, and 4.5% had segmental vitiligo). In this study, application with topical 0.03% tacrolimus applied twice daily for 12 weeks was shown to be an effective and well-tolerated treatment. Response was graded as complete (i.e., >75% repigmentation) in 57.9% of the patients, moderate (i.e., 50%-75% repigmentation) in 26.3%, mild (i.e., <50% repigmentation) in 15.7%, and 3 patients had no response. Side-effects, such as pruritus and burn, which was noted in only 3 patients, were minimal.13

Conclusion

Tacrolimus ointment is effective and safe for treating vitiligo, especially when it is located on the head and neck, or when the disease is long-lasting. Childhood vitiligo can be successfully treated with tacrolimus, sparing the adverse events seen from topical corticosteroids. Although topical application is not associated with systemic immunosuppression, the long-term risk from the application of tacrolimus ointment to the skin is still unknown. Further studies with topical tacrolimus for the treatment of vitiligo with long-term follow-up are necessary to better evaluate the safety, efficacy, and stability of repigmentation, especially when associated with focused UVB microphototherapy.

References

1. Xu AE, Zhang DM, Wei XD, et al. Efficay and safety of tacrolimus cream 0.1% in the treatment of vitiligo. Int J Dermatol 48(1):86-90 (2009 Jan).
2. Choi CW, Chang SE, Bak H, et al. Topical immunomodulators are effective for treatment of vitiligo. J Dermatol 35(8):503-7 (2008 Aug).
3. Hercogová J, Buggiani G, Prignano F, et al. A rational approach to the treatment of vitiligo and other hypomelanoses. Dermatol Clin 25(3):383-92 (2007 Jul).
4. Hartmann A, Bröcker EB, Hamm H. Occlusive treatment enhances efficacy of tacrolimus 0.1% ointment in adult patients with vitiligo: results of a placebo-controlled 12-months prospective study. Acta Derm Venereol 88(5):474-9 (2008)
5. Grimes PE, Morris S, Avaniss-Aghajani E, et al. Topical tacrolimus therapy for vitiligo: therapeutic responses and skin messenger RNA expression of proinflammatory cytokines. J Am Acad Dermatol 51(1):52-61 (2004 Jul).
6. Kostovic K, Pasic A. New treatment modalities for vitiligo: focus on topical immunomodulators. Drugs 65(4):447-59 (2005)
7. Lepe V, Moncada B, Castanedo-Cazares JP, et al. A double-blind randomized trial of 0.1% tacrolimus vs 0.05% clobetasol for the treatment of childhood vitiligo. Arch Dermatol 139 (5):581-85 (2003 May).
8. Lotti T, Buggiani G, Troiano M, et al. Targeted and combination treatments for vitiligo. Comparative evaluation in 458 subjects. Dermatol Ther 21(Suppl 1):S20-6 (2008 Jul).
9. Fai D, Cassano N, Vena GA. Narrow-band UVB phototherapy combined with tacrolimus ointment in vitiligo: review of 110 patients. J Eur Acad Dermatol Venereol 21(7):916-20 (2007 Aug).
10. Passeron T, Ostovari N, Zakaria W, et al. Topical tacrolimus and the 308nm excimer laser: a synergistic combination for treatment of vitiligo. Arch Dermatol 140(9):1065-9 (2004 Sep).
11. Lan C, Wu C, Chen G, et al. Helium-neon laser and topical tacrolimus combination therapy: novel treatment option for vitiligo without additional photocarcinogenic risk. J Eur Acad Dermatol Venereol (2008 Jun 23).
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 51(5):760-6 (2004 Nov).
13. Kanwar AJ, Dogra S, Parsad D. Topical tacrolimus for treatment of vitiligo in Asians. Clin Exp Dermatol 29(6):589-92 (2004 Nov).

In this issue:

1. Treatments for Scalp Psoriasis with Emphasis on Calcipotriol Plus Betamethasone Dipropionate Gel (Xamiol®)
2. Use of Tacrolimus Ointment in Vitiligo Alone or in Combination Therapy
3. Update on Drugs and Drug News - May 2009