Pigment International

REVIEW ARTICLE
Year
: 2022  |  Volume : 9  |  Issue : 1  |  Page : 14--24

Management of childhood vitiligo − a brief review


Sahana P Raju, Sumit Kaur, Eswari Loganathan 
 Department of DVL, Bangalore Medical College and Research Institute, Bengaluru, Karnataka, India

Correspondence Address:
Dr. Eswari Loganathan
Department of DVL, Bangalore Medical College and Research Institute, Bengaluru, Karnataka, Pincode: 560002
India

Abstract

Vitiligo comprises of one of the commonest reasons for a dermatology consultation in the pediatric age group, worldwide. The incidence of childhood vitiligo varies from 1% to 8%, making it a significant pediatric condition. Various theories have been put forward to explain the occurrence of depigmentation in vitiligo, of which genetic factors play a predominant role in childhood vitiligo. The various modalities of treatment of childhood vitiligo are reviewed in this article. The management of vitiligo is extremely challenging, more so in the pediatric age group, as it can lead to significant psychologic trauma and dysregulation of social development in a child. The goals of management of childhood vitiligo should be aimed at addressing all these issues and achieving an optimum result out of the available modalities.



How to cite this article:
Raju SP, Kaur S, Loganathan E. Management of childhood vitiligo − a brief review.Pigment Int 2022;9:14-24


How to cite this URL:
Raju SP, Kaur S, Loganathan E. Management of childhood vitiligo − a brief review. Pigment Int [serial online] 2022 [cited 2022 Jun 29 ];9:14-24
Available from: https://www.pigmentinternational.com/text.asp?2022/9/1/14/345304


Full Text



 INTRODUCTION



Vitiligo is a chronic debilitating depigmentation disorder with a multifactorial etiology. Childhood vitiligo is a distinct portion of vitiligo, which often differs in its clinical characteristics and response to treatment when compared with adult vitiligo. Characteristic differences include the higher rates of instability as well as repigmentation and the frequent occurrence of segmental vitiligo in children.[1]

Childhood vitiligo is also known to be associated with various autoimmune conditions, the most common of which is autoimmune thyroiditis.[2] Alopecia areata, atopic disorders, halo nevi, celiac disease, type 1 diabetes, and Addison disease are other reported autoimmune disorders.[3]

Achieving complete repigmentation in vitiligo is challenging, but not uncommon. A combination of therapies is usually tried before clinical response occurs. In this article, we review all available forms of treatment, including topical therapy, systemic medications, phototherapy, surgical therapy, and other measures for childhood vitiligo. However, large randomized control trials involving pediatric patients with vitiligo evaluating these therapies are not available. The study protocols used by these studies vary extensively and usually a combined population of adults and children are considered in these studies. Here, we attempt to analyze the existing data and decide the modality of treatment based on the extent of disease, sites involved, and response obtained.

 PATHOMECHANISMS



Complex and multifarious hypotheses have been proposed to explain the onset of vitiligo in children, some of them being the autoimmune theory, oxidative stress theory, genetic theory, neurohumoral theory, and melano-cytorrhagy theory.3 As family history of vitiligo is an important predisposing factor and almost one-fifth of the patients have at least one close relative affected, it can be said that genetic factors play an important role in childhood vitiligo.[4] Some of the significant genes involved are: TYRP1 (tyrosinase-related protein 1), MITF (melanocyte-inducing transcription factor), P38 MAPK (P38 mitogen-activated protein kinase), POMC (pro-opio-melanocortin), LEF1 (lymphoid enhancer-binding factor 1), and CAT genes (catalase gene).[4] Recently, a “convergence theory” was described which consolidated all existing theories into a single summary of vitiligo etiology.[5]

 CLASSIFICATION



The classification based on the Vitiligo Global Issues Consensus Conference is explained in [Figure 1]. [6] The purpose of differentiating various types of vitiligo serves multiple purposes, as each category has a different prognosis, and therefore, an important consideration for patient management. Some of the types and clinical characteristics of childhood vitiligo encountered by us are depicted in [Figure 2]. The prognosis of segmental vitiligo deserves a special mention, as it commonly occurs in children. This type usually has a better prognosis, is known to stabilize early, and responds better to surgical modalities with a reduced risk of recurrence.{Figure 1}{Figure 2}

 TREATMENT MODALITIES



The two main objectives to be achieved when treating vitiligo are: stabilization of active disease and promotion of repigmentation. The duration, extent and severity of disease, presence of Koebner phenomenon, and association with other autoimmune conditions have to be considered before deciding upon the plan of action. Incomplete and transient repigmentation have been reported to occur in children with a disease of duration of <2 years.[7]

 TOPICAL THERAPY



In general, localized vitiligo and limited area involvement (<20% of body surface area) are managed with topical therapy.

Topical corticosteroids

Mid-potent topical corticosteroids (TCs) are considered as the first-line therapy for children with localized vitiligo. Local side effects (e.g., atrophy, telangiectasia, hypertrichosis, striae, acneiform eruption, and glaucoma with periorbital usage) and systemic side effects (e.g., suppression of hypothalamic-pituitary-adrenal axis, Cushing syndrome, tachyphylaxis, and growth retardation) can be prevented by using TCs for less than 2 to 4 months.[8] Topical potent steroids such as mometasone furoate can be used as once daily application for a period of 3 months if given on daily basis or <6 months if given with gaps (15 days per month for 6 months).[9]

Topical calcineurin inhibitors

Topical calcineurin inhibitors (TCIs) such as tacrolimus and pimecrolimus are advocated for use in areas with thin skin like eyelids where potential side effects of corticosteroids are high. TCI can be safely used even in the highest strength for children >2 years.[10] TCI monotherapy is particularly useful for the treatment of face and neck lesions.[11]

A black box warning was issued for tacrolimus and pimecrolimus for the potential risk of the development of malignancies though clear cut evidence is lacking. The efficacy of TCIs was shown to be better during active stage of the disease, with shorter disease duration and over head and neck lesions along with a minimum side-effect profile.[12] Twice daily applications of topical tacrolimus 0.1% cream, or pimecrolimus 1% cream for a period of 10 to 12 weeks with moderate but daily sun exposure is recommended.[10] The common adverse effects include pruritus, burning sensation, and erythema which generally subside spontaneously as the treatment progress.[13]

Calcipotriol

Calcipotriol, a synthetic vitamin D3 analog when used in psoriasis, was reported to cause perilesional hyperpigmentation. This finding made the basis of its use in vitiligo. It is known to have immunomodulatory and melanocyte upregulation properties.[14] In a study conducted on 18 pediatric patients of vitiligo who were treated with 50 μg/g of topical calcipotriol twice daily, 77.8% showed repigmentation, among which 21.4% had complete repigmentation.[15] Another study in pediatric vitiligo in which marked to complete repigmentation occurred in 55% patients, recommended exposure to sunlight after application of calcipotriol.[15] Combination therapy with corticosteroids is an effective and safe option in sun-exposed areas.

JAK-STAT inhibitors

Blockade of JAK inhibits interferon gamma signaling and expression of CXCL-10 in keratinocytes, and hence prevents the development of depigmentation.[16] Topical tofacitinib, a JAK1/3 inhibitor, and ruxolitinib, a JAK1/2 inhibitor, are available as 2% and 1.5% cream, respectively. A study conducted on 12 patients with vitiligo using ruxolitinib 1.5% cream applied twice daily showed 76% improvement in facial VASI score and a 23% improvement in overall Vitiligo Area and Severity Index (VASI) score in 44% patients.[17] Mild adverse effects such as application site pruritus and acne are known to occur.[18] Others such as JAK1/3 inhibitor (ATI-50002), ritlecitinib (JAK3 inhibitor), and brepocitinib (JAK1 and TYK2 inhibitors) combined with phototherapy are also under trial.[17] The efficacy was better in sun-exposed areas, facial lesions, concomitant narrow band UVB (NBUVB) therapy, and Fitzpatrick skin types IV to VI.[19]

Decapeptide

Basic fibroblast growth factor (bFGF)-related decapeptide solution is a new drug discovered in Indian studies.[20] It is a sequence of amino acids derived from bFGF which is a mitogen stimulating the growth as well as migration of melanocytes and hence helps in repigmentation. It is used topically once a day and better repigmentation rates were observed when used in combination with tacrolimus 0.1% ointment.[21] In a study by Davinder et al. comparing the repigmentation rates of a combination of bFGF and tacrolimus versus tacrolimus in 120 patients of stable vitiligo, the combination group showed greater than 50% repigmentation in 66.7% patients compared to 39.2% in the tacrolimus group.[21]

Bimatoprost

Bimatoprost is a prostaglandin F which stimulates human melanocyte dendricity.[22] Although bimatoprost can be safely used in eyelash hypotrichosis in children, we were unable to find studies regarding its use in childhood vitiligo.[23] Jha et al. reported a case of stable localized periorbital vitiligo with no response to tacrolimus and topical steroids, which showed some benefit with bimatoprost 0.03% ophthalmic solution.[22] Some of the common adverse events reported are conjunctival hyperemia, dryness and pruritis, burning sensation in the eye, eyelid pigmentation, and visual disturbances.[24]

Combination therapy

A combination of TCs and TCIs is usually the preferred therapy, with 0.1% tacrolimus cream being favored for the head and neck regions, and 0.1% mometasone cream (cycles of intermittent application, usually 2 months on and off cycles) for the body. Certain anatomical sites such as elbows, knees, or anterior shin in older children can be treated with 0.05% clobetasol propionate cream for short periods of time[25] [Figure 3].{Figure 3}

The various topical agents used in childhood vitiligo are summarized in [Table 1].{Table 1}

 SYSTEMIC AGENTS



Corticosteroids

Corticosteroids are known to halt the progression of vitiligo by decreasing the antibody titers against melanocytes thereby suppressing complement mediated cytotoxicity.[34] The most popularly used form of systemic corticosteroids is the oral minipulse (OMP) therapy, where long acting steroids are given in a suprapharmacologic and intermittent manner to lessen the adverse effects. Betamethasone in a dose of 5 to 7.5 mg/week (0.1 mg/kg body weight) or dexamethasone in the dose of 2.5 to 10 mg/week (0.3 to 0.4 mg/kg body weight) is given on 2 consecutive days in a week for 3 to 6 months.[35] Pasricha and Khaitan studied 36 patients of vitiligo, out of which 89% had complete arrest in progression of disease and 80% had repigmentation with OMP therapy.[36] Majid et al. compared the efficacy of OMP using methylprednisolone, in addition to topical fluticasone in pediatric vitiligo and achieved complete remission in more than 90% patients.[37]

A few minor adverse events such as headache, acne, weight gain, insomnia, increase in appetite, lethargy, and hypertrichosis have been known to occur with short-term therapy. Corticosteroids also tend to increase the rates of susceptibility to infections in children through immune suppression when given for more than 2 weeks. The most common side effects known to occur in children are vomiting, behavioral changes, sleep disturbances, and an increased risk of fractures. Rarely, manifestations of Hypothalamus-Pituitary axis (HPA) axis suppression such as hypoglycemia, electrolyte imbalances, joint pain, and myalgia may manifest even with a course of steroid therapy as short as 2 weeks.[38]

Children on oral corticosteroids must be frequently monitored for growth velocity. Some of the risk factors for growth retardation in children on corticosteroids include long-term therapy for more than 6 months, daily regime of steroids, and use of dexamethasone or betamethasone.[38]

Methotrexate

Methotrexate is an antimetabolite drug whose action in vitiligo is possibly due to the suppression of tumor necrosis factor alpha-induced nuclear factor kappa B activation.[39] Studies on adult patients with vitiligo have showed that it is as effective as OMP with betamethasone, when combined with Narrow Band Ultra-Violet B therapy (NBUVB), in halting the progression of the disease and repigmentation rates.[40] Another study in 20 adult patients showed cessation of disease activity in 90% of patients with unstable treatment resistant vitiligo, and repigmentation in 70% cases.[41] Although methotrexate has been safely used in the treatment of childhood psoriasis, pityriasis rubra pilaris, morphea, and juvenile dermatomyositis, there are no studies showing its efficacy in childhood vitiligo.[42]

Azathioprine

Azathioprine is an immunomodulatory drug which acts by inhibiting the de novo purine synthesis.[43] In a study comparing the betamethasone OMP versus azathioprine in progressive vitiligo in adults, it was found that arrest of disease progression occurred late in azathioprine group, compared to OMP group.[44] Another study demonstrated the early and augmented onset of repigmentation in adult patients of vitiligo treated with low-dose azathioprine and psoralen ± UVA (PUVA).[45] Although there is a paucity of studies on the use of azathioprine in childhood vitiligo, it may be mainly used as a steroid sparing agent in progressive vitiligo, where longer durations of corticosteroids are indicated. Side effects such as nausea, headache, indigestion, cutaneous viral infections, and respiratory tract infections are reported with its use.[46]

Mycophenolate mofetil

Mycophenolate mofetil (MMF) suppresses the activity of T and B lymphocytes by inhibiting the enzyme inosine monophosphate dehydrogenase involved in de novo protein synthesis. A pilot study comparing MMF and OMP in progressive nonsegmental vitiligo in adults showed earlier and higher relapse rates in MMF group, along with development of serious side effects such as leucopenia and transaminitis.[47] Cost is also a restraining factor when prescribing MMF. Though MMF is used in the treatment of pediatric nephrotic syndrome and renal transplant regimens in children, there are no studies justifying its use in children.[48]

Cyclosporine

Cyclosporine has a role in the treatment of vitiligo, though its immunosuppressive activity (inhibition of nuclear factor of activated T cells and interleukin 2). In a study by Taneja et al. on the efficacy of cyclosporine in adult patients with progressive vitiligo, 61% of the patients showed an arrest in progression and 81% had repigmentation. This study concluded that in addition to its immune modulatory action, cyclosporine could also directly activate melanogenesis.[49] In another study by Mehta et al. comparing the efficacy of OMP and cyclosporine, it was found that cyclosporine used in a dose of 3 mg/kg/day for 4 months, resulted in earlier stabilization of disease compared to OMP.[50] Although there are no studies of use of cyclosporine in childhood vitiligo, it has been effectively used in recalcitrant pediatric dermatoses such as atopic dermatitis, psoriasis, and alopecia areata.[51]

Apremilast

Apremilast is a phosphodiesterase 4 inhibitor which induces differentiation and proliferation of melanocytes through activation of cyclic adenosine monophosphate pathway and also has anti-inflammatory properties. A pilot study by Huff and Gottwald showed that a patient with chronic recalcitrant vitiligo reported a 60% to 70% improvement in pigmentation after 13 months of treatment with apremilast in a dose of 30 mg twice a day.[52] Albeit the use of apremilast in childhood vitiligo is not explored, it has proven to be safe in other pediatric dermatoses. Saporito successfully treated an 8-year-old child of atopic dermatitis with apremilast 30 mg daily.[53] A phase 2 open label study demonstrated that apremilast can be safely used in pediatric patients with moderate to severe plaque psoriasis.[53] Common side effects include nausea, vomiting, headache, diarrhea, weight loss, and depression.[54]

Janus kinase inhibitors

As discussed previously, Janus kinase (JAK) inhibitors such as tofacitinib and ruxolitinib have immune modulatory and repigmentation properties. Joshipura et al. studied the effect of 5 mg tofacitinib twice a day for 12 weeks on a patient of generalized vitiligo and observed repigmentation over UV-exposed areas.[55]

Gianfaldoni et al. compared the effects of NBUVB versus tofacitinib 10 mg per day combined with NBUVB in adult patients with vitiligo and observed higher repigmentation rates in the combined group.[56] Minor adverse events such as diarrhea, weight gain, upper respiratory tract infections, and arthralgia have been reported. Though studies regarding use of oral JAK inhibitors in children with vitiligo are not available, oral tofacitinib and ruxolitinib have been used safely in pediatric alopecia areata, graft versus host disease, leukemia, lymphoma, and juvenile idiopathic arthritis.[57]

Vitamin D and other antioxidants

Vitamin D

The antioxidant and antiapoptotic properties of vitamin D offer a protective mechanism in vitiligo patients who are predisposed for its deficiency. The addition of vitamin D has proven beneficial in children with normal and decreased vitamin D levels.[58] It can also be used in combination with topical tacrolimus. In accordance with Indian Academy of Pediatrics guidelines, 400 and 600 IU of vitamin D can be supplemented in infants and children with normal vitamin D levels, respectively.[59]

Other antioxidants

The oxidative stress theory in the pathogenesis of vitiligo involves a decrease in antioxidants and an increase in oxidative stress markers such as malondialdehyde. Kim et al. demonstrated that the outcome of refractory childhood facial vitiligo could be improved by concomitant antioxidant therapy and conventional vitiligo treatment.[60] The recommended daily intake of a few antioxidants in children are mentioned in [Table 2].[61]{Table 2}

The various systemic agents used for the management of childhood vitiligo and their common adverse effects are summarized in [Table 3].{Table 3}

 PHOTOTHERAPY



Phototherapy forms the cornerstone of management of vitiligo as ultraviolet (UV) rays have a dual modality of action, causing immunosuppression as well as stimulation of melanocytes.

PUVA therapy

Photochemotherapy, either with oral or topical psoralens, forms an important therapeutic modality in childhood vitiligo. It involves ingestion or topical application of photo-sensitizing agents (8-methoxypsoralen, 5-methoxypsoralen, and 4,5,8-trimethylpsoralen) and subsequent exposure to UVA light (320–400 nm). The indications in children are unstable vitiligo, vitiligo involving >10% bovine serum albumin (BSA), focal vitiligo, not responding to other modalities of treatment. The recommendations by Indian Association of Dermatologists, Venereologists and Leprologists (IADVL) suited for darker skin types involve ingestion of 0.6 mg/kg 8-MOP (Methoxalen) or 1.2 mg/kg 5-MOP with an initial treatment dose of 2 to 3 J/cm2.[64] In a study by Ersoy-Evans et al., out of eight children of vitiligo treated with PUVA, 57% of them had repigmentation.[65] Adverse effects can be either short term such as erythema, blister formation, and swelling can occur after PUVA therapy, or long-term consequences such as photo-aging, pigmentary changes, lentiginosis, actinic damage, and the risk of nonmelanoma skin cancers can occur. Also because PUVA therapy can induce cataract formation in children, it is relatively contra-indicated below 12 years of age.[66]

Bath PUVA: This method employs a very dilute solution of psoralen in water. The advantages of this method are that it avoids an uneven distribution of pigment and decreases the occurrence of systemic side effects of oral PUVA.[64]

PUVASol: Here the source of UV radiations is solar energy from the sun. It is not recommended for use in children as the amount of UV light titrated on the skin cannot be controlled and it allows infrared and visible light, which can prove to be harmful.[64]

Topical PUVA and topical PUVA Sol: About 0.01% to −0.1% of 8-MOP in a cream or lotion formulation is used here and the area irradiated after half an hour. It is indicated in children with depigmented patches involving less than 5% BSA.[64]

 NBUVB



NBUVB in the range of 311 to 313 nm is a well-tolerated and currently the preferred form of phototherapy in children. In accordance with the Vitiligo Working Group’s phototherapy recommendations, a standard fixed dose of 150 to 200 mJ/cm2must be started, with an increment of 10% to 20% per session. The patients can be asked to come in twice a week for therapy and a minimum of 18 to 36 sessions are necessary before deeming it unresponsive to treatment.[67] It is recommended that the maximum duration of NBUVB use in children should not exceed 12 months. In a study by Kanwar and Dogra, 75% of patients had complete repigmentation at the end of 1 year of therapy, whereas 20% had moderate and 5% had mild repigmentation.[68] Certain areas such as trunk, face, neck, and back are known to respond faster than other areas. The distinct advantages of NVUVB include lesser risk of phototoxic reactions, brief treatment sessions, no perilesional hyperpigmentation, and lesser color disparity between lesional and normal skin. It also does not have the systemic side effects associated with PUVA therapy and posttreatment eye protection is not warranted.

Home-based phototherapy

Home-based phototherapy (HBPT) was initially introduced for the treatment of psoriasis and later expanded for use in vitiligo. The obvious advantages include the ease of administration to the patients, the reduction in number of hospital visits, and increased patient compliance. However, one of the chief concerns with HBPT includes overtreatment resulting in increased incidence of side effects.[69]

Handheld UVB devices such as combs have shown efficacy in the treatment of focal and nonsegmental vitiligo in adult patients, and shown to be safe.[70]

Excimer laser

The 308 nm xenon-chloride monochromatic light has undue advantages in treatment of focal vitiligo. It spares the uninvolved skin from unwanted side effects of radiation. Also, excimer lamp avoids the cramped atmosphere inside an NBUVB chamber which is a better choice for children. It can be used to treat vitiligo involving less than 10% BSA. It was also demonstrated that excimer laser acts synergistically with topical tacrolimus.[71] Up to 20 sittings with an excimer lamp can be tried, before switching to alternate therapy.

The various forms of phototherapy used are summarized in [Table 4].{Table 4}

Some of the other, less commonly use compounds which have photosensitizing properties, when used along with phototherapy are khellin and phenyl-alanine.

Practical considerations in children

Practical obstacles have to be considered when treating children with phototherapy. The fact that continuous photoprotection is essential, for at least 48 hours, around the clock might not be feasible. Also, weekly treatments imply absenteeism from school. For younger children, it is recommended that an adult attender must remain with the child, inside the phototherapy chamber, with the necessary photoprotective measures.[74]

Although corticosteroids and phototherapy form the main modalities of treatment in childhood vitiligo, corticosteroid use is limited by its side effects and phototherapy does not terminate the destruction of melanocytes and affect the disease process per se which warrants the use of other immune-suppressive agents.

 SURGICAL THERAPY



Surgical modalities of treatment for childhood vitiligo are restricted only to those lesions unresponsive to the above modalities discussed, and in those with a stable disease for at least 1 year. The key challenge faced is the maintenance of immobility postoperatively which is difficult in young children.[75] The various methods available include tissue methods such as mini punch grafts, suction blister epidermal grafts (SBEG), split skin grafts, and cellular techniques such as epidermal cell suspension transplant, cultured melanocyte transplant, and cultured epidermis. Among these methods, the best studied and most convenient technique for children and adolescents is the SBEG. Studies showed over 75% repigmentation rates over face and lips with SBEG.[75] Some studies on efficacy of noncultured epidermal cell suspension also showed repigmentation rates of 75% to 90% in childhood segmental vitiligo.[76]

 DEPIGMENTATION



Depigmentation therapy with monobenzyl ether of hydroquinone can be cautiously advocated in older children with extensive, treatment resistant vitiligo, who can understand the repercussions of the therapy.[77]

 PSYCHOTHERAPY



Vitiligo disrupts the quality of life in children and has been known to cause depression, anxiety, low self-esteem, interference with emotional maturation, and other psychosocial hinderances.[78] Children with visible and exposed lesions of vitiligo, especially over the face, must be observed and screened for any psychosocial impairments and counseled appropriately. Various forms of psychotherapy, including cognitive behavioral therapy, hypnosis has been utilized to improve their quality of life to a certain extent.[78]

 NEWER AGENTS



Many new emerging therapies are still in the pipeline and need further trails to prove their efficacy and safety especially in pediatric age group. Piperine is a phytochemical derived from Piper nigrum which acts by stimulating melanocyte proliferation as well as dendrite formation in vitro and is reported to be more effective with UVR. It has also observed to decrease time taken for repigmentation.[79],[80]

Photocil (alpha-glucosyl hesperidin + diethylaminohydroxybenzoyl hexyl benzoate) cream has been developed and tried in adults to selectively filter out nontherapeutic UV radiation and deliver only NBUVB from natural sunlight.[81]

Afamelanotide, an α-melanocyte-stimulating hormone agonist given as subcutaneous injection, when combined with phototherapy, has been shown to cause repigmentation in a randomized multicenter trial in adults.[82]

Many other newer medications such as l-carnitine, l-carnosine, capsaicin, cucumis melo, and Prostaglandin E2 (PGE2) analogs are under trial but studies in children are still lacking.[83]

 CONCLUSION



Vitiligo is one of the commonest dermatologic disorders described in childhood. Evaluation of the child for other autoimmune diseases and early management is the key to prevent long-term consequences. Although the protocol described in [Figure 4] is most frequently followed, there is a lack of clear-cut consensus for the management of childhood vitiligo, as treatment has to be tailored according to each patient’s needs. A holistic approach to the child is required, not only to improve their physical appearance, but also to improve their psychologic well-being.{Figure 4}

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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