Childhood vitiligo: treatment paradigms.

Childhood vitiligo differs from the adults by showing a higher incidence in females, segmental vitiligo being more common and less frequent association with other systemic autoimmune and endocrine disorders. Childhood vitiligo is often associated with a marked psychosocial and long lasting effect on the self-esteem of the affected children and their parents, hence an adequate treatment is very essential. Treatment of vitiligo is indeed a tough challenge for the dermatologists' more so in the background of childhood vitiligo. Although multiple therapeutic modalities are available in the therapeutic armamentarium, not all can be used in children. This brief report updates regarding various therapies available in the treatment of childhood vitiligo.

Introduction

Vitiligo is defined as an acquired cutaneous achromia characterized by milky white cutaneous macules of various sizes and shapes that tends to enlarge peripherally in course of time.[1] The prevalence of the disease varies between 0.1-4% of the world population.[2] Vitiligo usually presents itself in childhood or young adults, approximately half to one third of them develop this condition by 20 years of age and around 25% of them develop before 8 years with a mean age of onset varying between 4 and 5 years.[3] It spares no age, sex, or race. Many etiological hypotheses have been put forward to explain vitiligo, among which the most compelling one is a combination of genetic and immunologic factors, which interact with each other resulting in an autoimmune melanocyte destruction.[4]

Childhood vitiligo differs from the adults by showing a higher incidence in females, segmental vitiligo being more common and less frequent association with other systemic autoimmune and endocrine disorders.[5] Childhood vitiligo is often associated with a marked psychosocial and long lasting effect on the self-esteem of the affected children and their parents, hence an adequate treatment is very essential. Treatment of vitiligo is indeed a tough challenge for the dermatologists’ more so in the background of childhood vitiligo. Although multiple therapeutic modalities are available in the treatment armanterarium not all can be used in children. This brief report updates regarding various therapies available in the treatment of childhood vitiligo.

Therapies

The aim of treatment in vitiligo is to restore the normal appearance, morphology, and function of skin. Several treatment modalities are currently available; each having certain indications and limitations. The treatment can be broadly classified under medical and surgical modalities; Table 1 summarizes the current treatment available for childhood vitiligo. Treatment of vitiligo in children can be viewed in two phases: An initial phase to stop the progression of disease, and the next phase to induce repigmentation of the lesions. In children, medical therapy is often preferred. The review of literature done by Marion et al.[6] revealed that not many good studies have been done in the past to evaluate the efficacy of these treatment modalities in children with vitiligo.

Table 1

Current therapeutic modalities used for childhood vitiligo

Topical therapies

Corticosteroids

Topical steroids low, mid, or high potency are often the first line of treatment because they are easy and convenient mode of treatment used since many decades. Results of treatment outcome have been reported to be as moderately successful, particularly in patients with localized vitiligo.[7] The effectiveness of steroids could be due to their immunomodulatory effects; however, their efficacy in repigmentation of vitiliginous skin is not uniform, and often treatment period is prolonged by the time successful repigmentation is achieved. Accessible studies report a response rate between 45-60% in childhood vitiligo.[89] Meta-analysis by Morreli[10] inferred that potent topical steroids had the highest odds for success compared to placebo.

Long-term steroid usage and potency of steroid used in children is associated with epidermal atrophy, striae, telangiactesia, systemic absorption, glaucoma, tachyphylaxis, and hypothalamus pituitary axis (HPA axis) suppression. Cushing's syndrome and growth retardation are the most worrisome side effects in children and infants.[11]

Calcipotriol

Calcipotriol, a synthetic vitamin D3 analogue, have proved efficacious in psoriasis; however, it caused perilesional hyperpigmentation in treatment of psoriasis as one of its adverse effects. Keeping this in mind, researchers have tried to evaluate its efficacy in pigmentation of vitiligo. The exact mode of action of calcipotriol in vitiligo is debatable; however, it is possible that it exerts its action through 1,25 dihydrovitD3 receptors or by modifying the intracellular calcium homeostasis in melanocytes or through its immunomodulatory effects on T lymphocytes and others, hence preventing melanocyte destruction.[12-14] Parsad et al. first reported marked pigmentation in 55.6% of the treated children. In this study, calcipotriol was used as once-daily application on all lesions for varying periods. Summary of the studies done with calcipotriol is given in Table 2, all these were uncontrolled studies. The adverse effects due to calcipotriol are transient in the form of mild burning and irritation of the skin.

Table 2

Summary of studies done with calcipotriol

Calcipotriol has been used in combination with topical steroid in the treatment of vitiligo. There were 2 studies done with this combination. Travis et al.[15] studied 12 patients with vitiligo, (average age 13.1 years) in whom topical corticosteroids was applied in the morning and topical calcipotriene in the evening. Twelve patients (83%) responded to therapy, with an average of 95% repigmentation by body surface area. Four of the patients who responded had previously failed with topical steroids alone. Vitiligo lesions over eyelid and facial skin responded best in their study. None of them had adverse reactions to the treatment. They concluded that topical calcipotriene in combination with steroids can repigment vitiligo, even in those patients with topical corticosteroid failure. Kumaran et al.[16] also studied this combination efficacy in vitiligo in both adults and children and inferred that the repigmentation achieved with the combination treatment was faster, stable, and with very less adverse effects in comparison to either of the treatments used singly.

Calcineurin Inhibitors

Topical calcineurin inhibitors (TCI) have emerged as an important therapeutic modality in treatment of childhood vitiligo, having lesser side effects when compared to long-term topical steroids usage. Two common TCI used are tacrolimus and pimecrolimus.

The mechanism of action involves binding of tacrolimus to the immunophilin binding protein, thus blocking the calcineurin dephosphorylative activation of the nuclear factor of activated T cells, which translocates to nucleus initiating cytokine gene expression.

In vitro effects of tacrolimus include inhibition of T cell proliferation and production of cytokines including IL-2, IL-3, IL-4, IL-12, TNF, and IFN-g.[17] Pimecrolimus has a similar mechanism of action but less potent in comparison to tacrolimus because of its decreased protein binding capacity. Compared to healthy controls, patients with vitiligo have elevated IL-10, TNF-a, and IFN-g. Treatment with tacrolimus decreases tissue levels of TNF-α[18] and enhances melanocyte and melanoblast proliferation.[19]

Since the initial report of repigmentation in vitiliginous lesions by tacrolimus in adults (Grimes et al.), many new studies were done by Lepe et al.,[20] Kanwar et al.,[21] Silverberg et al.,[22] and others[2324] [Table 3] showing its similar efficacy in children. Ho et al.[23] undertook a prospective study in children aged 2-16 years with vitiligo, in which he compared tacrolimus with clobetasol propionate and placebo and showed the results were same in both treatment groups and better when compared to the placebo. Studies showing efficacy of pimecrolimus primarily in children are lacking; however, many studies studying a mixed population of children and adults[25-28] are available, which is summarized in Table 4.

Table 3

Summary of studies done with tacrolimus

Table 4

Summary of studies done with pimecrolimus

Side effects reported with these agents are: Burning sensation at the site of application, erythema, and transient pruritus.[21] Unlike topical corticosteroids, topical calcineurin inhibitors do not cause skin atrophy. In 2005, the Pediatric Advisory Committee of US FDA implemented a black box warning for tacrolimus and pimecrolimus due to the lack of long-term safety data and the potential risk of the development of malignancies. However, evidence of their causal relation to the development of skin cancer or lymphoma is still missing.

Systemic therapy

Stability of vitiligo followed by repigmentation is the primary end point in the treatment of childhood vitiligo. Often, the disease is unstable in many cases, thus requiring systemic treatment with oral corticosteroids. Systemic corticosteroids can arrest the progression of vitiligo and lead to repigmentation in a significant proportion of patients, but may also produce unacceptable side effects. Pasricha et al.[29] studied the effect of oral mini-pulse therapy with betamethasone in vitiligo patients (both children and adults) having extensive or fast-spreading disease and showed that progression of the disease was arrested in 89% of the treated patients and concluded that oral mini-pulse therapy with betamethasone/dexamethasone is an effective treatment modality to arrest the progression of vitiligo and also induces spontaneous repigmentation.

Phototherapy

Phototherapy has a time-honored place in the treatment of skin disease, more so in vitiligo. In recent years, a range of phototherapies is available: Ultraviolet (UV) A plus psoralen (PUVA), combined UVA plus UVB, and narrow-band UVB. Its role in children is limited by fear of long-term toxicity because of patients’ prolonged life expectancy after treatment; likelihood that repeated courses of treatment may be required for recurrent disease process, with an increasing risk of associated hazard; and the practical difficulties associated with delivering phototherapy in this age group.

Narrow band UVB

Narrow band UVB (TL01, 312 ± 2 nm) has proven to be efficacious in many of skin condition including vitiligo. Although much data of nbUVB exists in adults, there is a paucity of its reports in children. In children with vitiligo affecting ≥ 20% of body surface area, nbUVB has proved a safe option. Many studies recently carried out by Kanwar et al.,[30] Njoo et al.,[31] and Brazzelli et al.[32] have shown remarkable effects of nbUVB in childhood vitiligo patients. The results of these studies have been summarized in Table 5.

Table 5

Summary of studies done with nbUVB

The proposed mechanism of action of nbUVB is: Immunomodulatory effects, thereby halting the progress of the disease and stimulating the residual outer hair root sheath melanocytes.[33]

Initially, the treatments are started at 3 doses per week as it is difficult to estimate the minimal erythema dose in child, which is subsequently increased by 10% every sitting. Indian children having type IV or type V, Fitzpatrick skin types, can be safely started at 280 mJ, which was followed by Kanwar et al. However, presently there is insufficient data to provide recommendation for the safe maximum dose and duration of therapy of nbUVB in children.

Best repigmentation was noted on vitiligo lesions over face, trunk, disease of less duration, [Table 5].

Side effects of nbUVB include; minimal erythema, which is amenable to emollients and occasionally topical steroids and pruritus.[32]

Narrow band UVB has been used in combination with many topical therapeutic modalities like:

nbUVB and Pimecrolimus

Combination of the two has been studied in mixed population of both adults and children, and studies dealing with only children is lacking in literature. A double blind, placebo-controlled study by Esfandiarpour et al.[34] in both adults and children showed that the combination gave a better repigmentation on the facial lesions, and up to 50 - 100% pigmentation was seen in 63.3% who received combination therapy in comparison to only 25% who received placebo. They reported mild self-limiting side effects in for of minimal erythema and pruritus.

nbUVB with pseudocatalase

There are published reports that the epidermal accumulation of H2O2 is probably associated in the pathogenesis of vitiligo. Schallreuters[35] carried a retrospective analysis in a large group of children and adolescents who were treated with either nbUVB and pseudocatalase combination or nbUVB alone in vitiligo. They reported > 75% repigmentation of lesions everywhere, 70% had disease progression in nbUVB group. Pseudocatalase is a synthetic analogue of naturally-occurring catalase. Adverse effects reported included transient pruritus, hyperpigmentation, and sweating.

Psoralen Ultraviolet A

Psoralens (commonly used 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and 4,5¢, 8-trimethylpsoralen (TMP), belong to the family of naturally-occurring products known as furocoumarins. They demonstrate a higher ultraviolet light (UV) absorbance, thus used for enhancing the effect of UV light in skin disorders. The mechanism of action of PUVA is similar to that of nbUVB.[33]

Systemic PUVA or oral PUVA is contraindicated in children < 12 years of age, it is restricted to children of > 12 years and those who have widespread vitiligo (i.e., ≥ 20% BSA); however, topical PUVA can be safely used in children of 2 years and more who have up to 20% of their body affected.[36]

Haldar et al., Morelli et al., and Grimes et al. showed at least 75% repigmentation in about 60% of the treated children with systemic PUVA.[91036]

Side effects topical PUVA include sunburns, blistering, and perilesional hyperpigmentation.

Oral PUVA: Nausea, vomiting, abdominal pain, liver toxicity, cataracts, and risk of skin malignancy when used for longer durations (compared to nbUVB).[33]

L-Phenyalanine and UVA combination

Oral supplementation of L-Phenyalanine with UVA therapy have shown to be effective in children suffering from extensive vitiligo. Schuilps et al.[37] showed 50-100% repigmentation in 69% of children with no side effects.

PUVA and Calcipotriol

This combination, however, not strictly tried out in children per se, studies done in a mixed population of children, and adults have shown contradicting results.[3839]

PUVA Vs. nbUVB Vs. OMP

Rath et al.[40] compared different phototherapy methods PUVA, nb UVB and broadband UVB with an oral mini pulse of steroids (OMP) as an adjunct to determine the method with best tolerability and efficacy in 68 vitiligo patients (aged 10-50 yrs) with progressive disease. Clinical evaluation was done at 3 and 6 months on follow-up. They concluded that the oral steroids only had an added value and were not very effective by themselves; nbUVB was preferred over broadband UVB and nb UVB and PUVA showed comparable efficacy.

Safety is the primary concern in pediatric phototherapy. Full-time supervision should be provided by the physician, nurse, or phototherapy technician working in conjunction with parents while administering ultraviolet light to children. To avoid unnecessary corneal or cutaneous burns, therapists or parents may be required to stand at the partially-opened UV cabinet door to guarantee compliance with recommended goggles and safe positioning in the light unit. The genital areas must be well covered prior to receiving phototherapy. When administering UVB treatment, particularly to children under 5 years of age, parents can hold the glasses for the complete duration of therapy.

Targeted phototherapy with excimer laser

The excimer laser emits a wavelength of 308 nm, which is close to the range of nbUVB 312 ± 2 nm. The main advantage of excimer laser is, the therapy is targeted to the lesion only, thus sparing the normal skin from unwanted side-effects like photoaging etc. Al Otaibi et al.[41] conducted a controlled prospective trial in 34 patients with localized vitiligo (age 3-21 years), treatment was given twice-weekly for a period of 13 weeks with a spot size 15 and 25 mm and revealed that: Half of the children had at least 50% repigmentation, facial lesions responded better in comparison to other sites.

In a recent study by Cho et al.,[42] 40 lesions studied, half of them showed 50% repigmentation and 12.5% had > 75% repigmentation. Vitiligo lesions over sun-exposed areas responded better. Side-effects reported with this laser are perilesional hyperpigmentation, burns, and folliculitis.

Hui Lan et al.[43] compared the effect of excimer laser and pimecrolimus combination with excimer laser alone in Chinese children and showed that the combination gave a statistically significant repigmentation that was more evident on facial lesions.

Surgical modalities

Surgical therapy is not the first-line modality for treating childhood vitiligo. Those children with localized or segmental vitiligo, which is stable and not responding to conventional therapy, have been treated with surgical therapy.[44] Surgical treatments are not recommended in very young children because even the stable vitiligo lesions increase in size proportionately with increase in size with body growth. Various methods used for surgical replenishment of melanocytes include minipunch grafts, suction blister epidermal grafts (SBEG), thin Thiersch grafts, transplantation of epidermal cell suspension, cultured melanocyte suspension, and cultured epidermis.[45]

Among these, the use of SBEG has been widely studied in multiple uncontrolled prospective studies, retrospective studies, and clinical trials and has shown the best results. Two uncontrolled studies and review of other clinical trials by Gupta et al. showed more than 75% repigmentation in over 80% of children with vitiligo; the results were better than medical therapy and a better response in children than in adult patients.[4546] Mulekar et al.[47] studied the effect of non-cultured autologous epidermal transplantation in children and adolescents and showed a near-complete to complete repigmentation in 7 of 12 focal and 8 of 13 segmental vitiligo children. Sahni et al.[48] used the similar technique and observed 75-90% repigmentation after one year of procedure.

Cultured melanocyte transplantation is not feasible much to its cost factor and time consumption. Problems with surgical therapy include inability to treat large areas, transient hyperpigmentation of recipient or donor site, and risk of Koebner phenomenon at the graft site.

Cosmetic camouflage

Camouflage means concealment of the affected area by methods, which alters or obscures it. Properly counseled older children can use this as an effective add-on treatment. As childhood vitiligo is associated with significant social stigma, camouflage can help in temporarily decreasing the situation to a good extent. An ideal camouflage must be: Color matching, opaque to conceal the affected area, water- and sweat-resistant, easy to apply and stick on for a long time, non-allergenic, easy to be removed, efficacious, and more importantly cost-effective.[49]

Tedeschi et al.[50] demonstrated that proper makeup improved the quality of life in 15 children and adolescents (aged between 7–16 years) with skin conditions, 4 of whom had vitiligo. They concluded that cosmetic camouflage is a valid adjunctive tool to other therapies or an alternative when conventional treatments fail.

Cognitive therapy and psychological support

Childhood vitiligo with its profound psychological effects on both the child and parent, psychological approaches need to be assessed to see if they can help sufferers. Quality of life (QoL) and coping mechanisms may improve over time in patients with vitiligo. Cognitive behavioral therapy strategies rather than avoidance or concealment may be associated with better coping. Schwartz et al.[51] observed a higher frequency of shyness to change, fear for strangers, and predominant fear in children with vitiligo in comparison to healthy siblings. The child's perception about illness and difficulties in interaction with other children must be noted at every visit to the clinician and addressed accordingly.

Depigmentation

Monobenzyl ether of hydroquinone treatment is reserved for those patients with stable, extensive, and non-responsive vitiligo. With depigmentation, being permanent, it must be considered only in those patients who understand the aftermath of depigmentation.[36]

Summary

Although sufficient number of therapeutic modalities have been made available in the treatment of vitiligo, its response to any of them is far from satisfactory. With this brief report we come across as per evidence-based medicine, a properly randomized, double-blinded, placebo-controlled study is either lacking or very minimal as far as childhood vitiligo is concerned. Moreover, the number of children enrolled in the studies conducted was small or involved a mixed population of both adults and children. The best response seen was in lesions over face and neck in many of the studies.

Complete repigmentation of all the patches of vitiligo is almost always never achieved, and nearly 15-30% of patients never respond to any treatment at all. In most of the studies done so far, repigmentation of > 75% is taken as marked improvement, and the overall degree of repigmentation achieved was seldom > 60%. Hence, in a disease where excellent or complete repigmentation can be poor, proper patient selection is important. At first, the main aim of the treatment must be to arrest the spread of the disease by using of phototherapy or OMP as discussed earlier. The next step is to assess the severity and extent of involvement of vitiligo.

If the body surface area (BSA) involved in the child is < 20%, and the disease is not rapidly spreading, then topical therapy is first choice. Among the evidence available and reviewed here, topical steroids are time tested mode of treatment and proved to be efficacious, both potent and super potent steroid have given the same results. Only drawback of long-term topical steroid usage is its side effects. Topical calcineurin inhibitors are proving to be a boon recently, providing results similar to topical steroid, but their drawback is, it is costly and not recommended for children below 2 years of age.

A study, wherein clobetasol propionate was compared to tacrolimus, the results for the steroid was only slightly better. Hence, the first-line therapy could be topical steroids and TCI for lesions over face, neck, and genital areas. Not many studies are available on use of topical calcipotriol, those available have been studied only in a small group of children, hence it could be opted as an adjunct with other topical modalities.

If the BSA involved is > 20%, phototherapy should be considered; nbUVB is much safer in comparison to PUVA, hence should be the treatment of choice. Study by Kanwar et al. suggested that nbUVB is best in recent onset of vitiligo, arresting the disease progression and marked repigmentation in the lesions over face and neck. Combination of topical therapy and nbUVB has shown good results; this can be tried in few patients who fail to show a good response with nbUVB alone. However, the frequency and number of treatments necessary to increase the risk of developing a skin cancer remains unknown. Children with only focal lesions and not responding to topical therapy might do well with excimer laser.

Nowadays, surgical therapies in vitiligo are in vogue and show promising results in children, more with transplantation of suction blister grafts. Hence, future refinements in various techniques might help in repigmentation of all the patches in stable vitiligo. Rarely, there are situations wherein multiple modalities need to be added in the treatment of a given patient. Whatever said, therapy of childhood vitiligo still poses a big challenge even to the most experienced dermatologists, and future studies and research must be continued in perceiving to achieve the goal of a complete safe treatment package for this profound stigmatized condition in children.