|Year : 2021 | Volume
| Issue : 2 | Page : 123-130
A comparative study in treatment of childhood vitiligo 0.03% tacrolimus versus 0.03% tacrolimus and topical steroids
Anandan Venkatesan1, Rashmi Sriram2, Sindhuja Balaji3, TK Anandhi4
1 Department of Dermatology, Government Stanley Medical College, Chennai, India
2 Department of Dermatology, BGS Global Institute of Medical Sciences, Bengaluru, Karnataka, India
3 Department of Dermatology, Chengalpattu Medical College, Chengalpattu, Tamil Nadu, India
4 Consultant Dermatologist, Everglow Dermacare Centre, Kanchipuram, Tamil Nadu, India
|Date of Submission||09-Nov-2019|
|Date of Decision||24-Dec-2019|
|Date of Acceptance||13-Aug-2020|
|Date of Web Publication||31-Mar-2021|
BGS Global Hospital, No 67, BGS Health and Education City, Uttarahalli Road, Kengeri, Bengaluru - 560 060, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Vitiligo is an idiopathic, acquired cutaneous achromia, characterized by circumscribed milky white macules. It develops before the age of 20 years in 50% of the patients and before the age of 10 years in 25% of the patients. Methods: This was a 2-year, prospective, comparative study conducted in vitiligo patients with 1 year of active intervention. Fifty patients in the age group of 2–14 years were enrolled in the study. Randomization was performed according to computer-generated random code. Patients with code A received treatment with 0.03% tacrolimus alone and patients with code B received treatment with 0.03% tacrolimus and topical steroids. The primary efficacy variable was the Vitiligo Area Severity Index (VASI), and the secondary efficacy parameter includes the Physician's Global Improvement Score which was computed at the end of the study. The statistical analysis was carried out using statistical software STATA 6.0. Results: Out of these 50 patients, 47 patients completed the study for a period of 1 year. The area-wise VASI reduction and VASI reduction in vitiligo types were analyzed in patients with code A and code B. The mean Physician's Global Assessment Score was 3.041 in the tacrolimus group, and it was 3.261 in the tacrolimus with steroid group. Conclusion: This shows that 0.03% tacrolimus can be effectively used as topical monotherapy in patients with localized stable vitiligo without the adverse effects of topical steroids.
Keywords: Childhood vitiligo, tacrolimus, topical steroids
|How to cite this article:|
Venkatesan A, Sriram R, Balaji S, Anandhi T K. A comparative study in treatment of childhood vitiligo 0.03% tacrolimus versus 0.03% tacrolimus and topical steroids. Indian J Paediatr Dermatol 2021;22:123-30
|How to cite this URL:|
Venkatesan A, Sriram R, Balaji S, Anandhi T K. A comparative study in treatment of childhood vitiligo 0.03% tacrolimus versus 0.03% tacrolimus and topical steroids. Indian J Paediatr Dermatol [serial online] 2021 [cited 2021 Jun 23];22:123-30. Available from: https://www.ijpd.in/text.asp?2021/22/2/123/312823
| Introduction|| |
Vitiligo is a common skin disorder affecting between 1% and 2% of the world population. In India and different countries across the globe, the incidence ranges from 0.1% to 8.8%. It affects 50% of the patients before 20 years of age and 25% before 10 years of age, resulting in a significant disease burden. It is characterized by completely depigmented milky white macules of varying sizes. Tacrolimus is a macrolide immunosuppressant that is approved for use in adult patients and pediatric patients above the age of two years. The repigmenting effect of tacrolimus has been reported to be site dependent, and the best results are seen on the face and neck. In fact, the site-dependent effect of tacrolimus gives an indirect support to the idea of combined role of topical tacrolimus and topical steroids. Therefore, the present study was done to compare the efficacy of 0.03% tacrolimus alone and 0.03% tacrolimus and mid-potent topical steroids in different types of vitiligo and if 0.03% tacrolimus alone can be used to avoid adverse effects of topical steroids.
| Methods|| |
This was a 2-year, prospective, comparative study conducted in vitiligo patients attending the Vitiligo Clinic, Department of Dermatology, Government Chengalpattu Medical College, Chengalpattu, from November 2010 to October 2012 (2 years). Fifty patients in the age group of 2–14 years were enrolled in the study. Institutional ethical committee clearance was taken (2508/MEI/2010). During the initial visit, the patient's demographic details including the name, age, sex, and residential address were noted. A detailed history regarding the onset, duration, and course of the disease, presence or absence of precipitating factors, family history, associated skin and systemic problems, treatment taken so far, and its outcome were recorded. Dermatological assessment of the disease was carried out noting down the sites of involvement, total body surface area (BSA) involved, total number of patches, size and distribution of the patches, and presence of white hair in the patch. Details regarding the margin of the patch, skin texture, presence or absence of perifollicular pigmentation, Koebner's phenomenon, and associated other skin and systemic problems were noted. Treatment was identified by a code number either A or B according to the treatment group. Patients who had received treatment with 0.03% tacrolimus alone were labeled as code A and patients who had received treatment with 0.03% tacrolimus and topical steroids were labeled as code B.
Inclusion criteria were age more than 2 years and <14 years, children free of chronic illness and systemic diseases, and vitiligo involving <20% BSA.
Patients with code A were advised to use 0.03% tacrolimus ointment twice daily morning and night. Patients with code B were advised to use 0.03% tacrolimus morning and topical steroid mometasone furoate 0.1% at night for 2 months continuously with a gap of 1 week from subsequent application to reduce the side effects associated with topical steroids. However, 0.03% tacrolimus was applied in the morning continuously unlike topical steroids.
The primary efficacy variable was the percentage change in depigmentation from baseline to the end of the study period. The secondary efficacy parameter includes the Physician's Global Improvement Assessment which was computed at the end of the study.
During the initial assessment, estimation of BSA involvement was assessed using the Vitiligo Area Scoring Index (VASI). The body was divided into the following mutually exclusive regions: face and neck, upper limbs (excluding hands), lower limbs (excluding feet), hands and feet, genitalia, and trunk. Buttocks were included with the lower extremities.
One hand unit, which encompasses the palm plus the volar surface of all the digits, is approximately 1% of total BSA and was used as a guide to estimate the baseline percentage of vitiligo involvement of any body region. To eliminate variation in hand size, we defined a hand unit to be the volar hand, including the fingers of a single investigator.
All the patients were followed up once in every 2 weeks, to look for any macular repigmentation, presence of new lesions, and presence of adverse effects. At each follow-up assessment, the extent of residual depigmentation within each affected patch which had been present at baseline was estimated to the nearest of one of the following percentages: 0%, 10%, 25%, 50%, 75%, 90%, or 100%. Any new depigmented patches that developed during the study were also estimated using the hand unit method and were included in the VASI calculation. For each body region, the VASI was determined by the product of the area of vitiligo in hand units (which were set at 1%/unit) and the extent of depigmentation within each hand unit measured patch.
The Physician's Global Improvement Assessment evaluated the overall change from baseline in VASI score on a five-point scale: 76%–100% – excellent improvement, 51%–75% – marked improvement, 26%–50% – definite improvement, 1%–25% – minimal improvement, and 0% – no change.
The primary efficacy parameter, VASI, was assessed at baseline and then in 2 months during follow-up for 12 months, and the secondary efficacy parameter, physician's global assessment, was evaluated only at the end of 12 months.
The statistical analysis was carried out using statistical software STATA 6.0 (Stata Corp LLC. Texas USA).
The categorical variables were expressed as frequency and percentage. The quantitative variables were expressed as mean and standard deviation. Descriptive statistics were used to evaluate baseline characteristics and adverse effects.
The group comparison for the categorical variables was analyzed using Chi-square test and quantity variables were analyzed using unpaired Student's t-test.
The change from baseline for the efficacy parameters within each treatment group was evaluated using the Student's t-test. P < 0.05 was considered as statistically significant.
| Results|| |
A total of 50 patients were enrolled in the study, with 25 patients who had received treatment with 0.03% tacrolimus only and 25 patients who had received treatment with 0.03% tacrolimus and topical steroids. All 50 patients were included in the safety analysis.
Out of these 50 patients, 47 patients had taken treatment for a period of one year. Three of these patients, 1 in the tacrolimus group and 2 in the tacrolimus with topical steroid group, left the study and their efficacy data were not included in the analysis. Most of the dropouts are between 8 and 12 weeks after commencing the treatment.
Out of the 25 patients enrolled for tacrolimus only (Group A) treatment, 13 were in the age group of 6–10 years. Out of the 25 patients enrolled for tacrolimus and topical corticosteroids (Group B), 19 were in the age group of 6–10 years. Out of the 25 patients enrolled for Group A treatment, 12 were males and other 12 were females.
The mean duration of vitiligo was 2.416 years in patients enrolled for Group A and 2.491 years in Group B.
Eighteen patients with focal vitiligo, 1 with segmental vitiligo, and 4 with acral vitiligo were included in the tacrolimus only treated group. Eight with focal vitiligo and 14 with acral vitiligo were included in the tacrolimus and topical corticosteroid group.
The mean total body VASI in the tacrolimus group at baseline was 0.1988 (taken as 100%), and in the tacrolimus with steroid group, it was 0.6154 (100%) with P < 0.05 which is statistically significant. The mean total body VASI in the tacrolimus group at the end of 2 months was 0.1931 (97.14%), and in the tacrolimus with steroid group, it was 0.6091 (98.98%) with P < 0.05 which is statistically significant. It shows that the onset of action was earlier in the tacrolimus and topical corticosteroid group. The mean total body VASI after 12 months of therapy with tacrolimus alone was 0.1363 (68.53%), and in the tacrolimus with steroid group, it was 0.4151 (67.45%) with P < 0.05 which is statistically significant [Figure 1].
|Figure 1: The mean total body VASI after 12 months of therapy with tacrolimus alone versus tacrolimus and steroids|
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The area-wise VASI reduction in tacrolimus versus tacrolimus and topical steroids is shown in [Table 1] and [Table 2], respectively [Figure 2] and [Figure 3].
|Table 1: The area-wise Vitiligo Area Severity Index reduction in tacrolimus|
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|Table 2: Area-wise Vitiligo Area Severity Index reduction in tacrolimus and topical steroids|
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The VASI reduction in vitiligo types of tacrolimus versus tacrolimus and topical steroids is displayed in [Table 3] and [Table 4], respectively [Figure 4] and [Figure 5].
|Table 3: Vitiligo Area Severity Index reduction in vitiligo type in tacrolimus|
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|Table 4: Vitiligo Area Severity Index reduction in vitiligo type in tacrolimus with steroids|
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|Figure 5: VASI reduction in vitiligo type in tacrolimus and topical steroids|
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Adverse effects included mainly burning sensation in about five patients in the tacrolimus only group, whereas in the tacrolimus with steroid group, it included atrophy in about six patients [Table 5] and [Figure 6].
|Figure 6: Adverse effects with tacrolimus alone versus tacrolimus and topical steroids|
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The mean Physician's Global Assessment Score was 3.041 in the tacrolimus group and it was 3.261 in the tacrolimus with steroid group (P = 0.657). Physician's global assessment showed that only 29.16% of the patients treated with tacrolimus alone had definite improvement, whereas 34.78% of the patients treated by tacrolimus with steroids had definite improvement. Physician's global assessment showed that only 12.5% of the patients treated with tacrolimus alone had excellent improvement, whereas 17.39% of the patients treated by tacrolimus with steroids had excellent improvement [Table 6] and [Figure 7].
|Table 6: Total reduction in Vitiligo Area Severity Index: Physician's global assessment|
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| Discussion|| |
This prospective comparative study explored the efficacy of 0.03% tacrolimus alone in comparison with 0.03% tacrolimus with topical corticosteroids (mometasone furoate) in patients suffering from vitiligo <10% of BSA involvement.
The prevalence of vitiligo in childhood (age <12 years) has been noted to be around one-quarter of vitiligo patients of all ages. Both sexes are equally affected. The female prevalence is higher due to greater concern about the cosmetic defect.
Vitiligo may develop at any age. The onset of the disease is usually below 10 years of age. The mean age of onset of childhood vitiligo in an Indian study was 6.2 years. Family members of the affected children have a higher incidence of vitiligo and other autoimmune diseases.
Vitiligo vulgaris is the most common clinical type in childhood vitiligo, followed by focal vitiligo and segmental vitiligo. Mucosal vitiligo is rare in children compared to adults. The rarest type seen in childhood is universal vitiligo.
The common initial site of onset of both nonsegmental vitiligo and segmental vitiligo in children is the face and neck. In nonsegmental vitiligo, initial lesions are periocular, perinasal, or perioral and gradually spread to other body parts. Perineum, perianal area, and in infancy, the diaper area may be the initial site of occurrence of lesions. Majority of the children have <20% body surface involvement.
Scalp leukotrichia is a frequent finding in children with vitiligo and their family members.
Koebner's phenomenon can be noted in both segmental and nonsegmental vitiligo in children, more commonly in the latter type. Koebner's phenomenon is more common in childhood vitiligo because of higher mobility and playfulness in this age group. The presence of Koebnerization is indicative of disease activity.
Emotional trauma and repression have been noted to be responsible for very sudden onset, rapid extension, and spread of lesion.
A positive family history, fewer lesions, <5% of BSA involvement, frequent segmental involvement, and greater difficulty in treatment but relatively better prognosis are the hallmarks of childhood vitiligo.
The course of childhood vitiligo is mostly stable or regressive; only a few patients experience progressive or recurrent disease. Complete spontaneous repigmentation of nonsegmental vitiligo is unusual. However, as compared to adults, the rate of spontaneous repigmentation is greater in children, especially in tropical countries and in summer months. Repigmentation may be diffuse, marginal, and perifollicular. Following onset, segmental vitiligo spreads fast only along the affected dermatome. Thereafter, it remains stationary for the rest of life.
Tacrolimus is a macrolide immunosuppressant that comes from the fungus Streptomyces tsukubaensis, which is a novel treatment for vitiligo. It binds to an immunophilin, FK binding protein-12, located in the cytoplasm of T-lymphocytes. The complex formed inhibits the phosphatase calcineurin. This inhibition prevents signal transduction which ultimately halts the transcription of cytokines interleukin-2 (IL-2), IL-3, IL-4, IL-5, IL-8, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and interferon-gamma. It also causes inhibition of histamine release from cutaneous mast cells. It causes impairment of synthesis of prostaglandin-D2, downregulation of FCeR1 on Langerhans cells, and inhibition of CD4 and CD8 lymphocyte migration. At molecular level, proliferation of both melanocytes and melanoblasts is significantly enhanced by tacrolimus. The concentration of stem cell factor in keratinocyte supernatant increases in a dose-dependent manner. Systemic absorption with topical tacrolimus is minimal. After single or multiple doses of 0.1% tacrolimus ointment, peak blood concentrations were in the range of 5–20 ng/ml. The absolute bioavailability of topical tacrolimus is unknown. Damaged skin has a higher rate of percutaneous absorption. Adverse effects include burning sensation, stinging, soreness, and pruritus. However, these agents are costly and may not be affordable by the families from low socioeconomic strata.
Mid-potent steroids are first-line therapies for children with localized vitiligo. Although high-potency steroids are more effective in vitiligo, these are not recommended for use in children. Available studies report a 45%–60% response rate to topical steroid in childhood vitiligo. According to Halder et al. and Cho et al., the response rate in children was 45% and 56%, respectively, with topical steroids alone. It requires long-term therapy for several months, increasing the chances of developing tachyphylaxis and local side effects such as atrophy, telangiectasia, hypertrichosis, and striae. There are risks of serious adverse effects such as glaucoma (prolonged application on periorbital vitiligo), suppression of hypothalamopituitary adrenal axis, and growth retardation with long-term use over large BSA. In order to avoid the adverse effects, interrupted therapy has to be given (application twice or once daily for 2 months followed by treatment-free period for 2 weeks if the treatment period is longer than 8 months). Hence, patients should be cautioned against prolonged inadvertent use of topical steroids.
The baseline demographic data and baseline characteristics in both the study groups, when compared, were similar.
The overall efficacy of 0.03% tacrolimus with topical corticosteroids (mometasone furoate) is slightly higher than 0.03% tacrolimus alone after the end of 12 months with better response at 4 months in the former. This shows that 0.03% tacrolimus can be effectively used as topical monotherapy in patients with localized stablevitiligo.
However, patients in the group of 0.03% tacrolimus with topical corticosteroids showed a significant reduction in total body VASI score in 4 months when compared 0.03% tacrolimus alone. The reduction in the former group is 16.92% when compared to 10.72% in the latter group at 4 months of the study period. This clearly shows that significant repigmentation occurs earlier in patients treated with 0.03% tacrolimus with topical corticosteroids.
Patients with focal vitiligo and segmental vitiligo showed a better clinical response to 0.03% tacrolimus with topical corticosteroids [Figure 8]a and [Figure 8]b. Patients with acral vitiligo did not respond to tacrolimus or tacrolimus and topical corticosteroids [Figure 9]a and [Figure 9]b. Facial vitiligo responded better with tacrolimus alone. Genital vitiligo responded better to tacrolimus and topical steroids. Vitiligo involving the upper limb and lower limbs showed better response with tacrolimus and steroids and minimal response with tacrolimus only.
|Figure 8: (a) Segmental vitiligo before treatment with tacrolimus and topical steroids. (b) Segmental vitiligo after treatment with tacrolimus and topical steroids|
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|Figure 9: (a) Acral vitiligo before treatment with tacrolimus and topical steroids. (b) Acral vitiligo after treatment with tacrolimus and topical steroids|
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The secondary efficacy parameters like physician's global assessment show results in favor of the tacrolimus and topical steroid-treated group.
Apart from transient burning, no serious adverse effects were noted in the tacrolimus group. Atrophy was noted in the tacrolimus and topical steroid group.
There were hyperpigmented borders seen in patients treated with tacrolimus and steroids which did not occur in patients treated with tacrolimus alone which showed homogenous pigmentation.
During the follow-up period of 3 months after completion of the study, none of the patients in either of the study groups showed clinical signs of relapse evidenced by the fact that VASI remains the same as that of 12 months.
Small sample size, lack of placebo control, and shorter duration of the study were the major limitations in this study.
| Conclusion|| |
0.03% tacrolimus alone can be effectively used as topical monotherapy for treating localized stable vitiligo. Facial vitiligo responds well to 0.03% tacrolimus alone and there is no need to add steroids topically as it increases the risk of atrophy. When mid-potent topical corticosteroids are combined with tacrolimus, there was a significant reduction in VASI score at an earlier date, when compared to tacrolimus alone. The overall efficacy of tacrolimus with steroids is 37.01%, which was only slightly higher than tacrolimus alone. Acral vitiligo does not respond to tacrolimus alone or tacrolimus with topical corticosteroids.
Combination of mid potent topical steroids and 0.03% tacrolimus was more effective than tacrolimus 0.03% alone in focal and segmental vitiligo. Vitiligo involving the upper limb and lower limbs showed better response with tacrolimus and topical steroids. Tacrolimus alone was safe as there were no serious systemic or cutaneous adverse effects apart from transient burning in a few patients unlike steroids which caused atrophy in few patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
We would like to thank Glaxosmithkline for the Sponsoring tacrolimus samples.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]