Childhood Vitiligo

CONTINUING MEDICAL EDUCATIONChildhood VitiligoNanette B. Silverberg, MD; Lisa Travis, MDGOALTo understand childhood vitiligo to better manage patients with the conditionOBJECTIVESUpon completion of this activity, dermatologists and general practitioners should be able to:1. Identify the variants of vitiligo.2. Discuss the genetic susceptibility of vitiligo.3. Describe the treatment options for vitiligo.CME Test on page 368.This article has been peer reviewed and approvedby Victor B. Hatcher, PhD, Professor of Medicine,Albert Einstein College of Medicine. Review date:May 2006.This activity has been planned and implementedin accordance with the Essential Areasand Policies of the Accreditation Council forContinuing Medical Education through thejoint sponsorship of Albert Einstein College ofMedicine and Quadrant HealthCom, Inc. AlbertEinstein College of Medicine is accredited bythe ACCME to provide continuing medical educationfor physicians.Albert Einstein College of Medicine designatesthis educational activity for a maximum of 1 AMAPRA Category 1 Credit TM . Physicians should onlyclaim credit commensurate with the extent of theirparticipation in the activity.This activity has been planned and produced inaccordance with ACCME Essentials.Dr. Silverberg is an investigator and speaker for Astellas Pharma Inc, and Novartis PharmaceuticalsCorporation. Dr. Travis reports no conflict of interest. The authors discuss off-label use of calcipotriene,corticosteroids, immunomodulators, methoxsalen, pseudolactase, psoralen and UVA, and topical calcineurininhibitors (pimecrolimus and tacrolimus). Dr. Hatcher reports no conflict of interest.Vitiligo is a common skin disorder in which pigmentis lost from the skin and adnexae. Halfof all cases begin before the age of 20 years.Until recently, there was a paucity of publisheddata regarding effective therapy of vitiligo.Current therapy is quite effective, and whilemany patients may not experience completerepigmentation, 50% to 75% repigmentation ofAccepted for publication November 7, 2005.Dr. Silverberg is Director, Pediatric and Adolescent Dermatology,and Dr. Travis is a resident, both from the Department ofDermatology, St. Luke’s-Roosevelt Hospital Center, New York,New York.Reprints: Nanette B. Silverberg, MD, Pediatric DermatologyDepartment, St. Luke’s-Roosevelt Hospital Center,1090 Amsterdam Ave, Suite 11D, New York, NY 10025(e-mail: nsilverberg@juno.com).vitiligo with recent onset routinely can be expectedwith available therapeutics.Cutis. 2006;77:370-375.Vitiligo vulgaris is a common pediatricproblem with a complex etiopathogenesis.1,2 Melanocytes are neural crest–derivedpigment-producing cells, which migrate duringembryogenesis from the neural crest and reside inthe skin by 8 to 10 weeks of gestation, later residingin the hair follicle. Pigment produced by melanocytesis stored in melanosomes within the cells andtransferred to keratinocytes via dendrites on themelanocyte cell surface.370 CUTIS ®

Childhood VitiligoFigure 1. Generalized vitiligoon the hands.Figure 2. Segmental vitiligo.Vitiligo is an acquired form of hypopigmentationor depigmentation in which pigment productionis halted or reduced. This may be attributedto autoimmune destruction of melanocytes, peroxidativedamage to melanocytes, or metabolicderangements within the melanocytes, whichinterfere with pigment production. 1 These variouspathogenic mechanisms may all result in the sameoutcome—apoptosis of the melanocyte. 3,4Clinically, lesions present as patches of hypopigmentationand depigmentation symmetricallylocated over the bony prominences, in theintertriginous location, and periorificially. Inaddition, sites such as the oral mucosa often aresilently involved. 1,5Vitiligo presents in a variety of ways. Generalized(Figure 1) and acrofacial vitiligo present withhypopigmented or depigmented patches symmetricallylocated periorificially and often involvingthe joints and bony prominences. The generalizedvariant, even when it begins in childhood, cancontinue to progress over a patient’s lifetime andcan result in complete depigmentation. Other variantsof childhood vitiligo include localized vitiligo,which usually has a good clinical prognosis, andsegmental vitiligo (Figure 2), a subtype of localizedvitiligo following a broad pattern of Blaschko lines.Most segmental cases will occur before the age of30 years. Segmental vitiligo of the body is the onlytype of localized disease that is difficult to repigment;however, facial segmental disease in children has a94% response rate to topical tacrolimus. 6 Trichromevitiligo is an unusual variant because some of theskin is fully depigmented, some is hypopigmented,VOLUME 77, JUNE 2006 371

Childhood Vitiligoand some has normal coloration. 7 Trichrome vitiligoresponds well to therapeutics. As with manyautoimmune illnesses, girls may be more commonlyaffected. 8Most subtypes of vitiligo are inherited through amultifactorial genetic modality; however, universalvitiligo appears to have an environmental trigger.Though this trigger has not been elucidated, autoimmunediathesis and exposure to environmentaltoxins such as dyes are suspected in universal disease. 9There are almost a dozen candidate susceptibilitygenes in vitiligo. These include polymorphismof the cytotoxic T-lymphocyte–associatedprotein 4 (CTLA4) gene, which plays a role in T-cellactivation 10 ; eukaryotic translation initiation factor4A1 (eIF4A1) 11 ; reduced expression of c-Kitand microphthalmia-associated transcription factor(MITF-M) genes involved in piebaldism andWaardenburg syndrome type II, respectively 12 ; HLAclass I and II loci, including DRB1*03, DRB1*04,and DRB1*07 13,14 ; low molecular weight polypeptideand transporters with antigen processing genes regionof the major histocompatibility complex 15 ; vitiligoCommon Therapies forVitiligo VulgarisCalcineurin inhibitors (eg, tacrolimus)with or without UV light*Calcipotriene with or withouttopical corticosteroids*Excimer laser (308 nm)*Intralesional corticosteroidsKhellin with or without UV lightMelageninNarrowband UVB with or without topical therapy*PseudocatalasePsoralen and UVA with or without calcipotrienePulsed oral corticosteroidsTopical corticosteroids*Vitamins*Most common therapies reviewed in the article.susceptibility loci on chromosomes 7 (autoimmunesusceptibility 2 [AIS2]) and 8 (AIS3), and systemiclupus erythematosus vitiligo related (SLEV1) onchromosome 17 16 ; melanocortin-1 receptor (MC1R);and agouti signaling protein (ASIP) genes. 17A family history of autoimmune disease, especiallythyroiditis and/or vitiligo, often is found inchildren with vitiligo. Concurrent autoimmunedisease is uncommon despite a high incidence ofthyroid antibodies. While the lifetime incidenceof clinically apparent second types of autoimmunedisease are not necessarily higher in children withvitiligo, the presence of a second autoimmuneendocrinopathy may exacerbate the vitiliginousdisease state. Furthermore, results of recent studieslooking at the presence of thyroid autoantibodies inchildren with vitiligo have suggested the incidenceof autoimmune thyroiditis is far higher than previouslythought, 18,19 thus screening for autoimmuneconditions such as thyroid disease, diabetes mellitus,and pernicious anemia should be performed at leastannually on children with active vitiligo.TreatmentNondermatologic interventions such as cosmetics arehelpful at hiding vitiligo. 1 They should be offered toall patients in the form of thick makeup that coversskin completely for special occasions and self-tannersthat reduce the cosmetic deficit and can be applied afew times per week. While cosmetics do not alter thecourse of disease, they have a psychological benefitfor the patient. Similarly, psychological interventionthrough therapy and hypnosis may be beneficial, evento young children. 20The dermatologic treatment of vitiligo hasexpanded and improved in the past 10 years. Surveysof practitioners in the past 10 years suggest thatonly 16% to 36% of practitioners will actively treatvitiligo, leaving patients little hope of recoveringtheir pigment. 21,22A variety of therapies are available (Table).Therapies are dually based; anti-inflammatory (ie,corticosteroids, immunomodulators) or antioxidant(ie, calcipotriene, pseudocatalase, vitamins) therapiesoften are paired with a therapy intended topromote pigmentation such as UV light or calcipotriene.While psoralen and UVA (PUVA) was thestandard of repigmentation for many years, it hasbeen replaced in safety and efficacy with the kinderand gentler narrowband (NB)-UVB.Topical corticosteroids have been the mainstayof therapy for vitiligo for decades. Repigmentationrates vary. Cho et al 23 described a group of 80 Koreanchildren with vitiligo and compared the childrenwith their adult vitiligo patient population. Results372 CUTIS ®

Childhood Vitiligoof this study revealed that children had a 64% repigmentationrate while adults had only a 57% repigmentationrate. Cockayne et al 24 described a similargroup of patients (10 children and 25 adults) withrepigmentation rates of 100% and 36% in childrenand adults, respectively. 24 Pediatric patients hadhead and neck disease, were dark skinned, and wereprimarily treated with high-potency steroid preparations.The first 2 characteristics (head and neckdisease, and dark skin type) appear to be associatedwith superior response to just about any treatment. 24Preparations of high-potency topical corticosteroidsmay show results in as few as 2 months 25 ; however,a 3- to 4-month trial is more traditional.Corticosteroid preparations have been fearedbecause of their side effects. High-potency andfluorinated products cause the worst side effects,but all topical corticosteroids may induce striae,atrophy, telangiectases, and hypopigmentationwhen applied to sensitive skin. Furthermore, onthe eyelids, topical corticosteroids can cause glaucomabecause of local absorption. Despite the riskfor adverse effects, short-course topical corticosteroidapplication has never been reported to havemajor side effects in published clinical trials onchildhood vitiligo. 1,25 The efficacy of these products,however, may be inferior to topical calcineurininhibitors. Lepe et al 25 looked at 20 children(mean age, 9.5 years) with fairly active vitiligo andtreated similar lesions with clobetasol or tacrolimusin a blinded fashion. There was a notable responseto clobetasol and tacrolimus; the mean percentageof repigmentation was 49.3% for clobetasol and41.3% for tacrolimus, making tacrolimus a topicaltherapy comparable in repigmentation efficacy tothe highest-potency steroid. 25Case reports published in 2002 and 2003described the efficacy of topical tacrolimus forvitiligo in both adult and pediatric patients. 26-28Beyond just good efficacy, tacrolimus is far saferfor eyelids, as well as intertriginous and genitalvitiligo, because tacrolimus will not induce atrophyof the treated skin or glaucoma. Furthermore,clinical results can be seen in as few as2 months 25 but are enhanced by extending theapplication time to at least 3 months. 6 Silverberget al 6 recently described a group of 57 childrenfrom 2 institutions in New York, New York, andChicago, Illinois, treated with topical tacrolimusointments 0.03% or 0.1% for a minimum 3-monthtrial. The response rate to topical tacrolimuswas 89% on the head and neck and 63% forthe body. It was better for twice-daily applicationthan once daily. Furthermore, the responserate for segmental vitiligo, a traditionallydifficult-to-treat variant, was 94% on the face, aremarkably high number. 6Kanwar et al 29 recently described a small groupof Indian children with vitiligo who mirrored thishigh response rate and boasted only a 12% rateof side effects such as pruritus or stinging. 29Tacrolimus is safe over large body surface areas andin just about any location where vitiligo occurs.It is not approved for mucosal application. Thereare limited data on the long-term risk for photocarcinogenesiswith topical tacrolimus and on thebiological risk for lymphoma. Blood levels for theseconditions would be unlikely in vitiligo becauseof the normal skin barrier. However, patients needto be told about animal studies with calcineurininhibitors, which suggest biological potential forcarcinogenesis. Localized hypertrichosis has beenreported with topical tacrolimus and patientsshould be warned of this risk, albeit temporary innature. 30 A few small case reports support the efficacyof pimecrolimus 1% cream and suggest it is aseffective as clobetasol 31,32 ; however, in our clinicalexperience, pimecrolimus is not as effective astacrolimus. Unfortunately, no head-to-head dataexist to support our experiences.When topical corticosteroids have been usedwith limited or no success, a combination ofcorticosteroids and topical calcipotriene can beeffectively used. Travis and Silverberg 33 reportedon 12 children with vitiligo; 10 responded toa clinical trial of topical corticosteroids (lowpotency for face and mid potency for body) andcalcipotriene. Of the children reported, 4 hadpreviously not responded to a 3- to 4-month trialof topical corticosteroids alone. The calcipotriene,therefore, may be added as an adjunct to corticosteroids,even if the corticosteroids are ineffectiveas monotherapy. 33 Calcipotriene also can be usedin combination with PUVA; however, conflictingresults have been published about their efficacy. 34More research is needed to corroborate the initialpositive data in topical calcipotriene in vitiligo.NB-UVB, a 311-nm UV light source, recentlycame into the spotlight as an alternative for phototherapyof vitiligo in children. Similar to theproposed mechanism for PUVA, the release of cytokinesand inflammatory mediators, which enhancesmelanocyte proliferation and migration, hasbeen proposed to be the mechanism of action forNB-UVB. A study by Westerhof and Nieuweboer-Krobotova 35 compared NB-UVB with topicalPUVA and found the former to be more successfulthan topical PUVA for treating extensivedisease, though the authors stated the differencewas probably not significant. Their results showedVOLUME 77, JUNE 2006 373

Childhood Vitiligo52 patients (67%) responded to twice-weeklyNB-UVB treatments versus 13 patients (46%) whoreceived twice-weekly topical PUVA treatments. 35Similar to the response with PUVA, lesions on theface and trunk responded better than those on thehands and feet. Overall, NB-UVB has demonstrateda better safety profile. Westerhof and Nieuweboer-Krobotova 35 found benefits of using NB-UVB overPUVA for long-term treatment, including the eliminationof photocontact allergenicity, phototoxicreactions, hyperkeratosis, and decreased erythema.Patients do not have to use methoxsalen, orally ortopically, when using NB-UVB. This eliminates theneed for protective eyewear outside of the office andthe risk for adverse effects from the psoralens. 1,35,36Njoo et al 36 studied the efficacy of NB-UVB in51 children with generalized vitiligo. The patientshad a mean age of 9.9 years and exhibited anaverage of 16% depigmentation. Twenty patientshad previously failed treatments. More than 75%overall repigmentation was seen in 27 patients(53%) with only 3 patients (6%) having completerepigmentation. 36 As with PUVA, the response toNB-UVB was dependent on the body site of thelesions; the best response was seen on the faceand neck followed by the trunk and proximalextremities. Response is best in patients withdarkly pigmented skin types and, over a year’s time,correlates with the level of compliance achievedwith the twice-weekly therapy. 36The excimer laser is a xenon chloride laseremitting a 308-nm coherent light, which repigmentsvitiliginous lesions similar to NB-UVBthrough emission of UV light. In a small studyincluding pediatric patients, 52.8% of lesionstreated with the excimer laser had 75% or morerepigmentation (71.5% for the face). 37 The efficacyof the excimer laser is similar to NB-UVBin that it works best on the head and neck andin patients with darker skin types. Small lesionsalso respond better to therapy than large lesions. 37The efficacy of the excimer laser is enhancedwhen combined with application of tacrolimus.Passeron et al 38 described 14 patients aged 12 to63 years who were treated twice-weekly with theexcimer laser for 24 sessions. One hundred percentof patients treated with a combination of theexcimer laser and tacrolimus had repigmentation.Seventy percent of the combination group hadmore than 75% repigmentation as compared with20% of the excimer laser–alone group. 38ConclusionChildhood vitiligo is a common and treatabledisorder. Despite the young age of the patient,therapy always should be offered. The selection oftherapy depends on the site and extent of disease.When initial therapy fails, alternatives alwaysshould be offered.REFERENCES1. Kovacs SO. Vitiligo. J Am Acad Dermatol. 1998;38:647-666.2. Halder RM, Grimes PE, Cowan CA, et al. Childhoodvitiligo. J Am Acad Dermatol. 1987;16:948-954.3. Lee AY, Youm YH, Kim NH, et al. Keratinocytes in thedepigmented epidermis of vitiligo are more vulnerableto trauma (suction) than keratinocytes in the normallypigmented epidermis, resulting in their apoptosis. Br JDermatol. 2004;151:995-1003.4. Wang X, Erf GF. Apoptosis in feathers of Smyth line chickenswith autoimmune vitiligo. J Autoimmun. 2004;22:21-30.5. Herane MI. Vitiligo and leukoderma in children. ClinDermatol. 2003;21:283-295.6. Silverberg NB, Lin P, Travis L, et al. Tacrolimus ointmentpromotes repigmentation of vitiligo in children: a reviewof 57 cases. J Am Acad Dermatol. 2004;51:760-766.7. Hann SK, Kim YS, Yoo JH, et al. Clinical and histopathologiccharacteristics of trichrome vitiligo. J Am AcadDermatol. 2000;42:589-596.8. Handa S, Dogra S. Epidemiology of childhood vitiligo: astudy of 625 patients from north India. Pediatr Dermatol.2003;20:207-210.9. Zhang XJ, Liu JB, Gui JP, et al. Characteristics of geneticepidemiology and genetic models for vitiligo. J Am AcadDermatol. 2004;51:383-390.10. Blomhoff A, Helen Kemp E, Gawkrodger DJ, et al. CTLA4polymorphisms are associated with vitiligo, in patientswith concomitant autoimmune diseases. Pigment Cell Res.2005;18:55-58.11. Lee AY, Kim NH, Park SW. All trans-retinoic acid(ATRA) elevated eukaryotic translation initiation factor4A1 (eIF4A1) mRNA in ATRA-responsive vitiliginousepidermis. Pigment Cell Res. 2004;17:659-667.12. Kitamura R, Tsukamoto K, Harada K, et al. Mechanismsunderlying the dysfunction of melanocytes in vitiligo epidermis:role of SCF/KIT protein interactions and the downstreameffector, MITF-M. J Pathol. 2004;202:463-475.13. Zhang XJ, Liang YH, Sun LD, et al. Association of HLAclass I alleles with vitiligo in Chinese Hans [letter].J Dermatol Sci. 2004;35:165-168.14. Tastan HB, Akar A, Orkunoglu FE, et al. Association ofHLA class I antigens and HLA class II alleles with vitiligo ina Turkish population. Pigment Cell Res. 2004;17:181-184.15. Casp CB, She JX, McCormack WT. Genes of the LMP/TAP cluster are associated with the human autoimmunedisease vitiligo. Genes Immun. 2003;4:492-499.374 CUTIS ®

Childhood Vitiligo16. Spritz RA, Gowan K, Bennett DC, et al. Novel vitiligosusceptibility loci on chromosomes 7 (AIS2) and8 (AIS3), confirmation of SLEV1 on chromosome 17, andtheir roles in an autoimmune diathesis. Am J Hum Genet.2004;74:188-191.17. Na GY, Lee KH, Kim MK, et al. Polymorphisms in themelanocortin-1 receptor (MC1R) and agouti signalingprotein (ASIP) genes in Korean vitiligo patients. PigmentCell Res. 2003;16:383-387.18. Iacovelli P, Sinagra JL, Vidolin AP, et al. Relevance ofthyroiditis and of other autoimmune diseases in childrenwith vitiligo. Dermatology. 2005;210:26-30.19. Kakourou T, Kanaka-Gantenbein C, Papadopoulou A,et al. Increased prevalence of chronic autoimmune(Hashimoto’s) thyroiditis in children and adolescentswith vitiligo. J Am Acad Dermatol. 2005;53:220-223.20. Silvan M. The psychological aspects of vitiligo. Cutis.2004;73:163-167.21. Ongenae K, Van Gell N, De Schepper S, et al. Managementof vitiligo patients and attitude of dermatologiststowards vitiligo. Eur J Dermatol. 2004;14:177-181.22. Njoo MD, Bossuyt PM, Westerhof W. Management ofvitiligo. results of a questionnaire among dermatologistsin The Netherlands. Int J Dermatol. 1999;38:866-872.23. Cho S, Kang HC, Hahm JH. Characteristics of vitiligo inKorean children. Pediatr Dermatol. 2000;17:189-193.24. Cockayne SE, Messenger AG, Gawkrodger DJ. Vitiligotreated with topical corticosteroids: children with headand neck involvement respond well. J Am Acad Dermatol.2002;46:964-965.25. Lepe V, Moncada B, Castanedo-Cazares JP, et al. Adouble-blind randomized trial of 0.1% tacrolimus vs0.05% clobetasol for the treatment of childhood vitiligo.Arch Dermatol. 2003;139:581-585.26. Grimes PE, Soriano T, Dytoc MT. Topical tacrolimusfor repigmentation of vitiligo. J Am Acad Dermatol.2002;47:789-791.27. Travis LB, Weinberg JM, Silverberg NB. Successful treatmentof vitiligo with 0.1% tacrolimus ointment. ArchDermatol. 2003;139:571-574.28. Tanghetti EA. Tacrolimus ointment 0.1% produces repigmentationin patients with vitiligo: results of a prospectivepatient series. Cutis. 2003;71:158-162.29. Kanwar AJ, Dogra S, Parsad D. Topical tacrolimus for treatmentof childhood vitiligo in Asians. Clin Exp Dermatol.2004;29:589-592.30. Prats Caelles I, Herranz Pinto P, de Ayala Casado EL, etal. Focal hypertrichosis during topical tacrolimus therapyfor childhood vitiligo. Pediatr Dermatol. 2005;22:86-87.31. Coskun B, Saral Y, Turgut D. Topical 0.05% clobetasolpropionate versus 1% pimecrolimus ointment in vitiligo.Eur J Dermatol. 2005;15:88-91.32. Mayoral FA, Gonzalez C, Shah NS, et al. Repigmentationof vitiligo with pimecrolimus cream: a case report.Dermatology. 2003;207:322-323.33. Travis LB, Silverberg NB. Calcipotriene and corticosteroidcombination therapy for vitiligo. Pediatr Dermatol.2004;21:495-498.34. Baysal V, Yildirim M, Erel A, et al. Is the combination ofcalcipotriol and PUVA effective in vitiligo? J Eur AcadDermatol Venereol. 2003;17:299-302.35. Westerhof W, Nieuweboer-Krobotova L. Treatment ofvitiligo with UV-B radiation vs topical psoralen plus UV-A.Arch Dermatol. 1997;133:1525-1528.36. Njoo MD, Bos JD, Westerhof W. Treatment of generalizedvitiligo in children with narrow-band (TL-01) UVB radiationtherapy. J Am Acad Dermatol. 2000;42(2 pt 1):245-253.37. Hadi SH, Spencer JM, Lebwohl M. The use of the 308-nmexcimer laser for the treatment of vitiligo. Dermatol Surg.2004;30:983-986.38. Passeron T, Ostovari N, Zakaria W, et al. Topical tacrolimusand the 308-nm excimer laser: a synergistic combinationfor the treatment of vitiligo. Arch Dermatol.2004;140:1065-1069.DISCLAIMERThe opinions expressed herein are those of the authors and do not necessarily represent the views of the sponsor or its publisher. Please review complete prescribinginformation of specific drugs or combination of drugs, including indications, contraindications, warnings, and adverse effects before administering pharmacologictherapy to patients.CONFLICT OF INTEREST STATEMENTThe Conflict of Interest Disclosure Policy of Albert Einstein College of Medicine requires that authors participating in any CME activity disclose to the audience anyrelationship(s) with a pharmaceutical or equipment company. Any author whose disclosed relationships prove to create a conflict of interest, with regard to theircontribution to the activity, will not be permitted to present.The Albert Einstein College of Medicine also requires that faculty participating in any CME activity disclose to the audience when discussing any unlabeled orinvestigational use of any commercial product, or device, not yet approved for use in the United States.VOLUME 77, JUNE 2006 375