Safety of 0.1% topical tacrolimus in the treatment of vitiligo

Vitiligo is a common, acquired, discoloration of the skin, characterized by well circumscribed, ivory or chalky white macules which are flush to the skin surface. The hair over the lesion may be either normal or white (poliosis) 1. Vitiligo usually begins in childhood or young adulthood; approximately one half of those with vitiligo acquire the disease before the age of 20 years and the incidence decreases with increasing age2. Vitiligo is a multifactorial polygenic disorder with a complex pathogenesis. Although several theories have been proposed to explain the loss of epidermal melanocyte in vitiligo, the exactcause remains unknown3. Phototherapy and applications of topical steroids are most commonly prescribed. However, these are not always effective and corticosteroids on the face may lead to cutaneous atrophy, telangiectasias and ocular (applied to periorbital region) complications. Successful treatment of vitiligo with topical calcineurin inhibitors has been reported. Tacrolimus, a macrolide immune suppressant that comes from the fungus Streptomyces tsukuba is used as novel treatment option for vitiligo4,5. This drug act on T cells and mast cells inhibiting T cell activation the release of pro-inflammatory mediators in mast cells by degranulation. Tacrolimus therapy does not cause atrophy, telengiactesia and ocular side effects like topical steroids, when applied

to face and intertriginous areas 6 .Inclinical trials, the common adverse effects were burning, pruritus, and erythema of skin.Burning sensation at the site of application is by far the most frequently reported adverse effect and is found in roughly 37 to 46% of adults and children treated with 0.03% tacrolimus,and 26 to 58% of those treated with 0.1% tacrolimus ointment 7 .Particular attention has been paid to skin infections as a potential complication of topical treatment with an immunosuppressive agent.Viral, fungal, and bacterial infections have all been reported 8 .Apart from mild to moderate burning, erythema, and pruritus, the use of tacrolimus ointment can cause folliculities,acne, Kaposi's varicelliform eruptions, eczema herpeticum and herpes simplex infections.Increased skin sensitivity to hot and cold and alcohol intolerance have also been reported 9 .Occurrence of recurrent skin tags, rosacea like granulomatous eruptions, rosaceiform dermatitis, mucosal hyperpigmentation, tinea incognito, molluscumcontagiosumand verruca vulgarishave recently been reported.The cutaneous viral infection in particular is alarming and may be caused by local immunosuppressions 10 .Although there is a theoretic concern that topical immunomodulatory therapy with tacrolimus and pimecrolimus may increase the risk of cancer, there is no evidence to date to suggest an increased risk of cutaneous or visceral cancer.The European Agency for the Evaluation of Medicinal Products has not recommended any change in labeling or approval of these topical agents.There may still be clinical situations where such off-label treatment is seen as a lesser risk than available alternatives such as oral administration of an immunosuppressant, and limited data on safety are emerging 11 .There are numerous treatment options available for vitiligo but none is universally safe.Very recently topical tacrolimus 0.1% is being produced and marketed in our country but its safety has not been studied in our population yet.This study is designed to observe the safety of using topical tacrolimus 0.1% in patients of vitiligo.

Materials and Methods
A clinical trial was conducted in the department of Dermatology and Venereology, BMC, Dhaka.Study period of the trial was January 2010 to July 2010 and patients with vitiligo (focal and segmental) were the study population.Finally thirty patients, who matched the inclusion criteria, were selected for the study.Sampling technique was purposive type.History and physical findings were recorded in a structured questionnaire.Ethical approval was taken from ethical Committee of BMC, Dhaka.

Procedure of data collection:
A total number of thirty subjects of vitiligo were primarily selected from thedepartment of Dermatology and Venereology, BMC, Dhaka and complete history, general physical and dermatological examinations was done for all enrolled subjects.For women of reproductive age reproductive history, menstrual history, lactation and pregnancy plan was carefully judged.Before inclusion in the study, all the participants and parents of children wereelaborately informed about the natural history and the prognosis of the disease, proper application procedures for the therapy, possible therapeutic outcomes and adverse effects associated with therapy, so that they can make independent decision about their participation.They were assured of strict privacy and secrecy of information on all occasions as such necessary measures were taken before hand.Photographs of all lesions and clinical assessment at baseline and follow-up visit after three months were taken for subsequent assessment and further comparison.Each individual lesion was treated with tacrolimus 0.1% ointment twice daily for three months.Generally, the repigmentation was recorded every 4 weekly for three months and outcome measures graded as none (no repigmentation), mild (less than 50% repigmentation), moderate (50-75% regimentation), and complete (more than 75% repigmentation).Observation and results of the clinical study and statistical analysis were presented by suitable chart, tables, graphics and diagram.

Result
This study was carried out on thirty vitiligo (focal and segmental) patients for a period of 12 weeks at the department of Dermatology and Venereology, BMC, Dhaka.Majority of patients suffering from vitiligo 20(66.6%)were under the age of 40 years.The highest percentage 13(43.3%)was in the age of 11-20 years.Sex ratio revealed higher in case of female 18(60%), with a male-female ratio 1:1.5(table-I).Table II showed

Discussion
In this study, 43.3% subjects were within the age group of 11-20 years and 20% were in the age group of 21-30 years which mostly correlates with the findings of many other study, like the percentage of subjects in the age group of 11-20 years was 46% in one study12 and 29.7% in another study 13.Sex ratio revealed higher in case of female (60%), with a male-female ratio 1:1.Nobody discontinued the therapy for serious adverse effects.In this study dermatological adverse effects were infrequent and mild, so all the patients completed the therapy.This study found that topicaltacrolimus 0.1% ointment to be safe in the treatment of vitiligo, with reduction in the number of vitiligenous spots by increased repigmentation significantly.

Conclusion:
This study reflects that topicaltacrolimus ointment 0.1% is a safe topical therapeutic option for the treatmentvitiligo.Proper selection of patient as well as appropriate topical use of drug for adequate duration responds well to reduce the number and size of vitiligenous spots with minimum adverse effects.
Inclusion criteria: * Vitiligo patients of both sex and above 2 years of age.* Patient who had not received any treatment for vitiligo (both systemic and topical) in the previous 2 months prior to inclusion.* Vitiligoof focal and segmental.Exclusion criteria: * Pregnant women and lactating mother.* Known case of tacrolimus hypersensitivity.* Vitiligouniversalis with widespread involvement.
Figure I: Distribution of the subjects by adverse effects.
These are the clinical adverse effects of topical tacrolimus described in the literature which includes pruritus, irritation, burning and erythema of skin.No serious adverse events occurred during the 12 week study.The symptoms are mild intensity that concurs with the references; as we find burning sen-sation found in 13.3%11, 3.5%21 of cases and pruritus and burning in 12% 20 of cases.