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Clinical Updates

Don Mehrabi, MD

Topical Immunomodulators for Vitiligo

Don Mehrabi

Thursday, February 07, 2008

Vitiligo is a skin condition that is characterized by depigmented macules or patches in a localized, segmental, or generalized distribution. The cause of vitiligo is unknown, but current hypotheses include neural-mediated destruction of melanocytes, oxidative destruction of melanocytes, and autoimmune destruction of melanocytes.

Current medical therapies focus on disrupting autoimmune melanocyte injury and primarily involve phototherapy with NB-UVB or PUVA, topical corticosteroids, and more recently, topical immunomodulators, namely tacrolimus and pimecrolimus. Although the effects of phototherapy and topical corticosteroids in the treatment of localized and generalized vitiligo are well documented, studies on the use of topical tacrolimus and pimecrolimus have shown mixed results to date.

Topical Tacrolimus

In addition to its immunosuppressive effects, topical tacrolimus has been shown to increase melanin biosynthesis and melanocyte migration in vitro.1,2 Its ability to reduce inflammation and thus counter the autoimmune destruction of melanocytes, in addition to its ability to induce melanin production/melanocyte migration, caused investigators to explore its use in the treatment of vitiligo.

Clinical application of topical tacrolimus for the treatment of localized and generalized vitiligo has been met with mixed results and most of the early studies were not controlled. In her initial report, Grimes reported moderate to excellent repigmentation of vitiligo areas in five out of six study participants. Later on, she reported repigmentation in 17 of 19 (89%) patients treated with topical tacrolimus in an open trial, but with statistically significant repigmentation only on head/neck areas.4 Similarly, Tanghetti reported partial repigmentation in 13 of 15 (87%) patients, but only patients with limited facial lesions achieved >75% repigmentation.5 In a later study of 22 Asian children, topical tacrolimus resulted in repigmentation in 19 (86.4%) patients, but the authors state that the best repigmentation was noted on facial areas. Other studies have also resulted in similar conclusions regarding the more substantial effect of topical tacrolimus in the repigmentation of facial areas7,8 (see Table 1). These reports have promoted the belief that topical tacrolimus is most effective in head and neck areas and that this effect was likely due to increased UV exposure in these areas.

Table 1.

Authors Publi-
cation Year
Trial Type Study Number of Patients Results
Grimes et al. 2002 Observation Topical tacrolimus alone 6 Moderate to excellent repigmentation in 5 out of 6 patients
Grimes et al. 2003 Observation Topical tacrolimus alone 19 89% response rate; statistically significant repigmentation only on face/neck areas
Tanghetti 2002 Observation Topical tacrolimus alone 15 87% response rate; >75% repigmentation only on face/neck areas
Kanwar et al. 2004 Observation Topical tacrolimus alone 22 86.4% response rate; best repigmentation noted in facial areas
Silverberget al. 2004 Retrospective Review Topical tacrolimus alone 57 89% response rate on face/neck; 63% response rate on trunk/extremities
Almiedaet al. 2004 Observation Topical tacrolimus alone 12 50% of patients with >50% repigmentation
Lepe et al. 2003 Comparative, Randomized Double-Blind Trial Topical tacrolimus vs. clobetasol 0.05% 20 Mean percentage of repigmentation: 49.3% for clobetasol vs. 41.3% for tacrolimus
Passeron et al. 2004 Comparative, Randomized Trial Excimer laser vs. Excimer laser + topical tacrolimus 14 Combination of excimer laser + topical tacrolimus was more effective than excimer laser alone
Ostavari et al. 2006 Observational Topical tacrolimus vs. Excimer laser + topical tacrolimus 9 Combination of excimer laser + topical tacrolimus was more effective than topical tacrolimus alone; topical tacrolimus monotherapy not supported in vitiligo treatment
Mehrabi and Pandya 2006 Randomized, Double-Blinded, Placebo-
controlled trial
NBUVB + petrolatum vs. NBUVB + topical tacrolimus 9 The addition of topical tacrolimus to NBUVB provided no additional benefit
Mayoral et al. 2003 Case Report Topical pimecrolimus alone 1 Near-complete repigmentation response noted within 5 months of therapy
Coskun et al. 2005 Comparative, intraindividual trial Topical pimecrolimus vs. clobetasol 0.05% 10 Similar rates and degree of repigmentation over trunk/acral areas
Sierafi et al. 2007 Observational Topical pimecrolimus alone 30 Mean percent repigmentation of 36% or less for all areas of the body
Boone et al. 2007 Observational Topical pimecrolimus alone 26 57.6% response rate; statistically significant decrease in median target area at 3 and 6 months
Dawid et al. 2006 Comparative, double-blind, intraindividual trial Topical pimecrolimus alone vs. vehicle 20 Treatment with topical pimecrolimus for body lesions was not effective

In a comparison study of 20 children, Lepe et al. reported repigmentation rates with topical tacrolimus comparable to clobetasol, suggesting that topical tacrolimus may serve as a viable alternative to corticosteroid use in children and in sensitive areas.9 In addition to the previous reports of the effectiveness of topical tacrolimus on facial areas, this report helped to establish topical tacrolimus as a corticosteroid-alternative treatment featuring similar results, an important consideration when treating facial skin that may be easily subjected to corticosteroid side effects. Again, these early reports did not feature a control group, an integral aspect of evidence-based medicine.

To explore the hypothesis that topical tacrolimus works best when subjected to ultraviolet radiation, several studies have been performed to evaluate this synergism. Initially, Passeron et al. reported a synergistic effect with a combination treatment 308 nm excimer laser and topical tacrolimus twice daily versus the excimer laser alone.10 On the other hand, studies specifically regarding tacrolimus plus a UV source versus tacrolimus alone have not been supportive for using topical tacrolimus alone and suggest that most of the repigmentation is due to UV exposure. In a comparison right/left trial with nine patients, Ostavari et al. showed poor repigmentation response in areas treated with topical tacrolimus, whereas areas treated with a combination of topical tacrolimus and excimer laser showed good to excellent repigmentation.11 In a pilot study of nine patients, Mehrabi and Pandya also reported no significant difference in areas treated with petrolatum and NB-UVB versus topical tacrolimus and NB-UVB over 12 weeks.12 However, their results showed a trend towards significance favoring the combination that may perhaps evolve over longer treatment periods.

These latter two studies would support that ultraviolet radiation is the primary cause of repigmentation, and that the addition of topical tacrolimus has no additional benefit. More reproducible studies are needed to substantiate whether the addition of topical tacrolimus to UV exposure has any benefit.

Topical Pimecrolimus

The use of topical pimecrolimus in the treatment of generalized and localized vitiligo has been less studied than topical tacrolimus, and the results have been mixed. In an initial case report on the use of topical pimecrolimus for the treatment of facial vitiligo, a near-complete repigmentation response was noted within 5 months of therapy.13 In a right/left comparison study, topical pimecrolimus and topical clobetasol 0.05% had comparable rates of repigmentation, most notably over the trunk and extremities versus acral areas; no facial lesions were included in this study.14

In studies with greater numbers of patients, topical pimecrolimus did result in repigmentation, although the degree of repigmentation was not substantial in most cases. In an observational study of 30 patients, Seirafi et al. showed pimecrolimus to result in some degree of repigmentation in vitiliginous areas on the face, trunk, and elbows, although the mean percent repigmentation was 36% or less for all areas of the body.15 In another study of 26 patients, a 57.6% response rate was noted with a statistically significant decrease in median target area at 3 and 6 months.16 To the contrary, one left/right comparison study of topical pimecrolimus and placebo failed to show any significant repigmentation in 20 patients.17 To date, there have been no studies evaluating the effect of topical pimecrolimus and UV exposure.

Discussion

Reports on the use of topical tacrolimus and pimecrolimus have been mixed. The current consensus is that these topical immunomodulators work well for facial and neck lesions with or without the presence of formal NB-UVB therapy. Perhaps the routine exposure of these anatomic areas to environmental ultraviolet sources results in this disparate effect. Although the synergy between the immunomodulators and environmental ultraviolet exposure leading to greater repigmentation of the facial/neck areas seems a worthy hypothesis, several studies have shown that the addition of topical tacrolimus to UVB exposure does not improve repigmentation over UVB alone.11,12 On the other hand, the isolated reports of excellent repigmentation results of using topical tacrolimus alone on facial areas, or in combination with the excimer laser on other areas, suggests that topical immunomodulators do have the ability to induce meaningful repigmentation in some areas.

At this point, it would be safe to conclude that current data warrants a trial of either topical tacrolimus or pimecrolimus for patients presenting with face and neck vitiligo. The low side-effect profile and comfort using these medications rather than strong topical corticosteroids on sensitive areas also make the topical immunomodulators an attractive option. The current data, however, do not seem to support using topical immunomodulators as a first-line treatment of vitiligo below the neck. Long-term safety is unknown: topical immunomodulators received a black box warning from the FDA recommending that they should not be used off-label in indications and conditions that predispose to skin cancer. Further controlled trials showing better efficacy and long-term safety are needed before this treatment can be recommended as initial therapy.

References

  1. Lan CC, Chen GS, Chiou MH, et al. FK506 promotes melanocyte and melanoblast growth and creates a favourable milieu for cell migration via keratinocytes: possible mechanisms of how tacrolimus ointment induces repigmentation in patients with vitiligo. Br J Dermatol.  2005;153:498-505.
  2. Kang HY, Choi YM. FK506 increases pigmentation and migration of human melanocytes. Br J Dermatol. 2006;155:1037-40.
  3. Grimes PE, Soriano T, Dytoc MT. Topical tacrolimus for repigmentation of vitiligo. J Am Acad Dermatol. 2002;47:789-91.
  4. Grimes PE, Morris R, Avaniss-Aghajani E, et al. Topical tacrolimus therapy for vitiligo: therapeutic responses and skin messenger RNA expression of proinflammatory cytokines. J Am Acad Dermatol. 2004;51:52-61.
  5. Tanghetti EA. Tacrolimus ointment 0.1% produces repigmentation in patients with vitiligo: results of a prospective patient series. Cutis. 2003;71:158-62.
  6. Kanwar AJ, Dogra S, Parsad D. Topical tacrolimus for treatment of childhood vitiligo in Asians. Clin Exp Dermatol.  2004;29:589-92.
  7. 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;51:760-6.
  8. Almeida P, Borrego L, Rodriguez-Lopez J, et al. Vitiligo. Treatment of 12 cases with topical tacrolimus. Actas Dermosifiliogr. 2005;96:159-63.
  9. 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.  2003;139:581-5.
  10. Passeron T, Ostovari N, Zakaria W, et al. Topical tacrolimus and the 308-nm excimer laser: a synergistic combination for the treatment of vitiligo. Arch Dermatol. 2004;140:1065-9.
  11. Ostovari N, Passeron T, Lacour JP, et al. Lack of efficacy of tacrolimus in the treatment of vitiligo in the absence of UV-B exposure. Arch Dermatol. 2006;142:252-3.
  12. Mehrabi D, Pandya AG. A randomized, placebo-controlled, double-blind trial comparing narrowband UV-B Plus 0.1% tacrolimus ointment with narrowband UV-B plus placebo in the treatment of generalized vitiligo. Arch Dermatol. 2006;142:927-9.
  13. Mayoral FA, Gonzalez C, Shah NS, et al. Repigmentation of vitiligo with pimecrolimus cream: a case report. Dermatology. 2003;207:322-3.
  14. Coskun B, Saral Y, Turgut D. Topical 0.05% clobetasol propionate versus 1% pimecrolimus ointment in vitiligo. Eur J Dermatol. 2005;15:88-91.
  15. Seirafi H, Farnaghi F, Firooz A, et al. Pimecrolimus cream in repigmentation of vitiligo.Dermatology. 2007;214:253-9.
  16. Boone B, Ongenae K, Van Geel N, et al. Topical pimecrolimus in the treatment of vitiligo. Eur J Dermatol. 2007;17:55-61.
  17. Dawid M, Veensalu M, Grassberger M, et al. Efficacy 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;4:942-6.

 

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