INTRODUCTION

Vitiligo is a commonly acquired, idiopathic, heritable depigmentary disorder of skin and/or mucous membrane. It is a chronic disease of great social and cosmetic concern. The prevalence of vitiligo in India varies from 0.1% to 8.8%.[1] The diagnosis of vitiligo is usually clinical. It is characterized by depigmented macules due to the selective destruction of melanocytes.[2] Several factors have been proposed for the disease such as autoimmune hypothesis, oxidative stress theory, genetic factors, autocytotoxicity, neurohumoral hypothesis, and melanocytorrhagy.[3] As it is often recalcitrant to medical treatment alone, many surgical techniques and modifications have been used to treat stable recalcitrant vitiligo ever since 1964.[4] Stability of vitiligo has been defined by various authors as the duration varying from 6 months to 2 years during which there is no new lesion, no enlargement of the existing lesion, and no Koebnerization.[567]

Though a lot of surgical treatment modalities are available for vitiligo, patients are often apprehensive to undergo extensive procedure such as grafting. Therapeutic wounding of lesion helps in stimulation of melanocytes of the surrounding area and hair follicles to migrate, proliferate, and repigment the skin.[5] Needling followed by topical application of 5% 5-fluorouracil (5-FU), a combination of medical and surgical modalities, provides a promising, effective, and safe modality of treatment.

The aim of this study was to assess the efficacy and safety of topical 5% 5-FU with needling versus 5% 5-FU alone in stable vitiligo.

MATERIALS AND METHODS

Follow-up

Patients were followed for 3 months after the last session. Assessment was done at baseline and thereafter every month using clinical photographs and by subjective assessment score of repigmentation [Table 1]. A CONSORT flowchart showing participant status through the trial is given in Figure 1.

Table 1 Grading of repigmentation

Repigmentation	Grade	Response
Absent	G0	No response
<25%	G1	Poor
25%–50%	G2	Good
50%–75%	G3	Very good
>75%	G4	Excellent

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Figure 1

CONSORT flowchart showing participant status through the trial

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RESULTS

Both Group A and Group B patients were comparable in terms of age (P = 0.06) and sex distribution (P = 0.791). The mean age in Group A and Group B was 29.4 and 24.2 years, respectively. We found vitiligo to be more prevalent in females comprising 18 (60%) patients in Group A and 19 (63.3%) patients in Group B. The mean duration of vitiligo was 7.25 years in Group A and 5.90 years in Group B. The most common morphological type in our study was vitiligo vulgaris (37 of 60, 61.7%) followed by focal vitiligo (12 of 60, 20%). More details regarding the clinical characteristics of both the groups are mentioned in Table 2.

After 1 month of therapy, initiation of repigmentation was noted in 76 patches (65%) in Group A and 45 patches in Group B (38.7%) (P < 0.0001) [Table 3].

At the end of 6 months, a statistically significant difference was observed between the two groups with better outcome in Group A, in which 47% of the patches had excellent response (>75% repigmentation) and 46.2% had very good response (50%–75% repigmentation). In Group B, 4.3% patches had excellent response and 8.6% had very good response (P = 0.03) [Table 3]. Loss of pigmentation was not seen in any patient.

Ulceration of lesions was seen in two patients in Groups A and B. Pain, erythema, and itching were more common in Group A, but no statistically significant difference was observed between the groups with regard to the adverse effects (P = 0.25) [Table 3]. Koebner’s phenomenon was not seen in any patient.

Site-wise analysis revealed that excellent response was most often seen in patches over the trunk followed by head and neck and limbs in both the groups. None of the acral lesions showed excellent response to any of the treatments [Figure 2].

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Figure 2

Excellent response with respect to location of the patch

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DISCUSSION

Vitiligo is an autoimmune disease produced as a result of interaction of environmental, genetic, and neural factors, leading to the destruction of melanocytes and appearance of depigmented macules. Vitiligo has a profound psychosocial impact on life, inculcating lowered self-esteem in patients.[9] In an Indian study of 30 patients, it was found that 10% patients of vitiligo had depression, one had anxiety, and one had suicidal ideation.[10] It is thus important to provide them with best possible modality of treatment and help them to cope up better. Therapy for vitiligo has to be chosen based on the nature and stability of disease, extent of involvement, age of the patient, and so on, from a myriad of medical and surgical modalities.

Tsuji and Hamada[11] introduced the method of application of 5-FU after therapeutic wounding as the treatment of vitiligo. Topical 5-FU has been used earlier either alone or in combination with dermabrasion and lasers.[1213] FU show selective and differential cytotoxicity toward epidermal cells. Melanocytes are less vulnerable to fluorouracil than keratinocytes. The mechanism of repigmentation suggested that 5-FU causes overstimulation of melanocytes of follicles, which migrates during epithelialization and induces pigmentation.[14] It is found in in vitro studies that 5-FU in low concentration selectively destroys keratinocytes in 3 weeks, whereas melanocytes continue to multiply and form pigment.[13]

Needling induces strong inflammatory response and local edema, leading to increased intercellular spaces of the basal layer. Active melanocytes migrate from pigmented epidermis through these spaces. The inflammatory mediators such as leukotrienes C4 and D4 and matrix metalloproteinases from keratinocytes help in melanocyte migration and proliferation.[1215] Several trials combining microneedling with another treatment modality have shown improved effectiveness in achieving regimentation in vitiligo. These also demonstrated lesser duration of treatment with reduced side effects.[8161718]

Our study constituted patients of age varying from 11 to 43 years, and the mean age of Group A and Group B patients was 29.4 and 24.2 years, respectively. A female predominance was observed in our study (60% in Group A and 63.3% in Group B). Similar study conducted by George et al.[13] noted female predominance in their study. A higher number of female patients have been found in clinico-epidemiological studies of vitiligo conducted by Handa and Dogra[19] and Gandhi et al.[20] This probably reflects the increased social stigma of vitiligo in female patients, and thus early treatment-seeking behavior.

Vitiligo vulgaris (61.7%) was the most common morphological pattern, followed by focal vitiligo (20%) in our study. These findings are consistent with a study conducted by Shashikiran et al.[18] who observed vitiligo vulgaris in 58% patients. George et al.[13] also found maximum number of patients of vitiligo vulgaris (73.3%) followed by focal vitiligo (26.7%).

At the end of 1 month, initiation of repigmentation in the form of erythema over the patches started in 76 patches (65%) of group A and 45 patches of group B (38.8%). However, Mina et al.[8] reported a start of repigmentation within 6 weeks in 44% patches of vitiligo treated with 5-FU combined with microneedling. The response to needling appears to be faster than effect of fluorouracil combined with microdermabrasion as studied by Garg et al.[21] who noted the start of repigmentation in 50% patches within 2 months. The faster response after needling could be due to the better penetration of the topical drug after needling.

At the end of 6 months, excellent repigmentation (>75% repigmentation) was noted in 47% patches of Group A and only 4.3% patches of Group B patients, whereas <50% repigmentation was seen in 6.8% and 87% patches of Group A and Group B respectively [Figures 3 and 4]. The results of our study are comparable to a study conducted by Shashikiran et al.[18] in which more than 75% repigmentation was reported in 49% of the patches. However, they noticed <50% repigmentation in 25% patches in their study. Mina et al.[8] noted excellent repigmentation in 48% patches treated with combined microneedling and 5-FU.

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Figure 3

G4 response (>75% repigmentation) in a vitiligo patch over the lower limb: (A) at baseline; (B) at 6 months

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Figure 4

G3 response (50%–75% repigmentation) in a vitiligo patch over the elbow: (A) at baseline; (B) at 6 months

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Similar result was reported by Yones et al.[22] in a study of efficacy of dermabrasion plus topical 5-FU in stable vitiligo, in which they found excellent repigmentation in 45% patients.

A study conducted by George et al.[13] on the efficacy of laser dermabrasion followed by topical 5-FU in the treatment of stable vitiligo found nearly complete repigmentation in 40% patients.

Santosh et al.[23] found that after 3 months of treatment of vitiligo with 5-FU after microneedling of the lesion, approximately 60% of patients (30) had hyperpigmentation in the vitiligo lesions. There was almost complete pigmentation in very small patches; larger ones had less pigmentation and 40% (20) did not have any pigmentation from the previous state.

Only one patient of 27 (3.7%) showed excellent improvement in vitiligo patch treated with microneedling with dermapen after 5-FU application in an Egyptian study. Approximately 70% patients showed some improvement in the color of lesions. These patients showed 18.5% improvement when treated with microneedling alone.[24] Ghiya et al.[25] reported excellent response in 60% children of stable localized vitiligo treated with 5-FU solution followed by dermaroller. The high response rate can be attributed to the fact that patients received treatment every 15 days for 6 months.[25]Table 4 compares the various trials involving 5-FU after therapeutic wounding in vitiligo.

In our study, maximum number of truncal lesions showed the best response, and acral lesions were the least responsive. This was consistent with the results of Shashikiran et al.[18] Leukotrichia and bony locations have been linked to the poor response of treatment in literature.[29]

In our study, pain was experienced by 12 (40%) patients of Group A and none of the patients in Group B, whereas erythema, itching, and ulceration were observed in few patients of both the groups. The adverse effects of erythema, itching, and ulceration were in accordance with a study by Shashikiran et al.[18] However, they recorded pain during the procedure in all the patients (100%). The lesser occurrence of pain in our study can be attributed to the use of topical anesthetic sprayed before the procedure. Mina et al.[8] observed ulceration in 4% patients, which is consistent with our findings. Sethi et al.[26] reported erythema and serous discharge in all patients, formation of pseudomembrane, and hypertrophic scarring in their study. Loss of pigmentation was not seen in any of our patients probably due to the short follow-up period after the intervention. No systemic side effect was reported in our study, thereby making use of topical FU along with needling safe and effective therapeutic modality in the treatment of vitiligo.

Limitations of our study included an unblinded design and a short follow-up period. This study also did not evaluate the efficacy of the intervention on mucosal vitiligo. Further, we did not use any tool that measures changes in vitiligo from the patient’s perspective. The use of a 26-gauge needle might be economically convenient but it is prone to produce an inferior wound than a dermaroller or a dermapen.

We found that needling followed by topical application of 5-FU has much higher efficacy than 5-FU alone in vitiligo. It is a useful therapy in poor responders to conventional therapy. However, the stability of repigmentation has to be analyzed with longer period of follow up.