indianjpaediatrdermatol13127-3481866_094018

Indian Journal of Paediatric Dermatology | Vol 13 | Issue 1 | January-April 2012 27

ADDRESS FOR CORRESPONDENCE Dr. Dilip Gude,

Intensivist & Research Coordinator, Department of Internal Medicine/Critical care, Princess Durru‑Shehvar Children’s

and General Hospital, Purani Haveli, Hyderabad, Andhra Pradesh, India E‑mail: [email protected]

hypothesis.[2] Defects in removal of toxic melanin precursors leading to accumulation of indole derivatives and free radicals which are melanotoxic form the crux of self‑destruct hypothesis.[3] Biochemical hypothesis suggests increased synthesis of hydrobiopterin, a cofactor of tyrosine hydroxylase which results in increased catecholamines and reactive oxygen species (ROS) toxic for melanocytes. Reduced catalase levels and higher/H2O2 concentrations in vitiliginous skin reinforce the biochemical hypothesis.[3]

While most‑earlier hypotheses had some if not complete basis to explain the pathophysiology of vitiligo, they were very unidimensional. The hypotheses were lacunate in explaining the fundamental basis in‑toto and were not evidence‑backed hence the need for newer theories that could better elucidate the disease. The newer perceptions of the components pertaining to the pathophysiology of vitiligo are detailed below.

geneticGenetically vitiligo has shown link with two independent association signals (rs11966200 and rs9468925) within the major histocompatibility complex (MHC) with high‑HLA susceptibility (the former linked to

introduction

With our perpetually evolving understanding of the pathophysiologic basis of vitiligo, we have been able to better manage the disorder by targeting its novel and hitherto unknown facets. A review of the disease’s current pathophysiologic perceptions and treatment modalities is presented.

PathoPhysiologic basis

Different hypotheses have been proposed explaining the pathophysiologic basis of vitiligo. Autoimmune hypothesis is based on the observation that other autoimmune diseases (e.g. autoimmune thyroid disease and type I diabetes mellitus) occur with higher incidence in vitiligo patients and that elevated serum levels of antibodies towards melanocytic antigens are found.[1] Altered reaction of melanocytes towards neuropeptides, catecholamines and their metabolites and aberrations in the expression of nerve growth factor (NGF) and neuropeptides comprise the neural

review artiCle

access this article onlineQuick response code

Website: ***

doi: ***

Vitiligo: Newer insights in pathophysiology and treatmentdilip gudeDepartment of Internal Medicine, Medwin Hospital, Nampally, Hyderabad, Andhra Pradesh, India

abStraCt

Despite decades of studies, vitiligo still evades us its exact pathophysiology and remains a challenge for clinicians. With a devastating cosmetic impact, the implications on the patient are dispiriting. A combination of the different proposed hypotheses may be responsible for its pathophysiologic basis. A variety of hypotheses that included autoimmune, neural, self‑destruct and biochemical means to explain the pathophysiologic basis of vitiligo were proposed. But they are increasingly giving way to newer theories that better delineate the basis of the disease and have paved way for different advancements in treatment accordingly. Our newer management modalities have bolstered our weaponry in fighting vitiligo. A review of the newer insights in to the pathophysiology and management of vitiligo is presented.

Key words: Autoimmune, pathophysiology, vitiligo

[Downloaded free from http://www.ijpd.in on Tuesday, March 17, 2015, IP: 180.246.92.51] || Click here to download free Android application for this journal

Avinash

Rectangle

Avinash

Rectangle

https://market.android.com/details?id=comm.app.medknow

aspire

Highlight

Gude: Vitiligo – Behind the screen

Indian Journal of Paediatric Dermatology | Vol 13 | Issue 1 | January-April 201228

HLA‑A3001, HLA‑B1302, HLA‑C0602 and HLA‑DRB1*0701 alleles[4]). Various genetic risk loci like 3p13 encompassing FOXP1 (rs17008723),[5] 6q27 encompassing CCR6 (rs6902119),[5] (rs2236313)[6] and RNASET2, FGFR1OP[6] and c6orf10‑BTNL2 (rs7758128)[7] have been incriminated in vitiligo. An elevated expression of a biological candidate gene, X‑box binding protein 1 (XBP1, located on chromosome 22) and its transcriptional modulation by a germ‑line regulatory polymorphism has an impact on the development of vitiligo. It is found in the lesional skins of vitiligo patients carrying the risk‑associated C allele‑rs2269577.[8] DDR1 is postulated as a susceptibility gene for vitiligo, implicating a defective cell adhesion in vitiligo pathogenesis.[9] A greater predisposition to vitiligo is found with homozygous deletion of GSTT1 and/or GSTM1.[10] Vitiligo is also believed to have a genetic predisposition for an altered catalase (SNP ‑mediated alteration of catalase structurally making it more susceptible to ROS).[11] FOXD3 (a primary regulator of melanoblast differentiation in the embryonic neural crest) is responsible for dysregulation of many genes involved in controlling cell cycle, cell division, cell growth, and proliferation leading to vitiligo.

lymphocyte mediatedOver‑expression of the B lymphocyte activating factor (BAF) may breakdown immune self‑tolerance in vitiligo. BAF activates self‑reactive B cells to produce auto‑antibodies against melanocytes, enhances CD4+ T cell helper effect on the activation of the CD8+ T cells and presents melanocyte antigen directly to the CD8+ T cells.[12] Antibodies to lamin A (VIT75, a melanocyte membrane antigen) are also raised in autoimmune vitiligo.[13] Higher/Th1/Th2 and IL‑2/IL‑4 ratios,[14] strong dependence on IFN‑γ and CXCR3[15] with significantly increased IL‑17 levels and decreased TGF‑β,[12] polymorphisms of genes of the IL19 cluster/receptors and IL20RB[16] have all been noted in vitiligo. Melanocyte specific CD8+ T cells (CD8+/CD45RO+ cells) and melanocyte disappearance in vitiligo directly correlate with disease activity.[17]

Organ transplantation is known to be a risk factor for vitiligo via increased melanocyte destruction caused by the autoimmune reactions triggered by chronic graft‑versus‑host disease (GVHD). In a study six cases of generalized vitiligo occurred after allogeneic hematopoietic cell transplantation (AHCT).[18] Another case‑report of vitiligo post‑combined liver‑kidney transplant was noted which was blamed on destruction of melanocytes by donor‑derived alloreactive cytotoxic T‑lymphocytes or antibodies transferred during

transplantation.[19] A patient with sickle‑cell disease, who received allogeneic HCT from his HLA identical vitiligo, affected further developed vitiligo.[20]

melanin/tyrosinase associatedThe characteristic depigmentation is produced by the haptogenic ortho‑quinones binding to tyrosinase (the enzyme that produces melanin) or other melanosomal proteins there by generating neo‑antigens responsible for a melanocyte‑specific delayed‑type hypersensitivity.[21] Melanocyte‑MART‑1 (melanoma antigen recognized by T‑cells) is found to correlate with the autoimmune mechanism in children with vitiligo.[22] Among the melanogenic mediators, stem cell factor (SCF) and endothelin‑1 (ET‑1) mRNA were significantly reduced in lesional as compared to perilesional epidermis.[23] Melanin, stratum corneum hydration and erythema index have been shown to be significantly low in vitiligo and epidermal barrier recovery is also considerably delayed.[24]

oxidative stress5,6‑Dihydroxyindole‑2‑carboxylic acid (DHICA)‑mediated antioxidation plays a critical role in the maintenance of immune hyporesponsiveness to melanosomal proteins.[25] In keratinocytes from perilesional vitiligo skin high levels of activated p38, NF‑kB p65 subunit, p53, and Smac/DIABLO proteins and low levels of ERK phosphorylation are found implying the role of oxidative stress in vitiligo.[26] There is evidence that superoxide dismutase (SOD) and malondialdehyde (MDA) levels are significantly higher and catalase (CAT) and glucose 6‑phosphate dehydrogenase (G6PD) levels significantly lower in vitiligo.[27] Abnormal synthesis and processing of tyrosinase‑related protein (TRP‑1) and its interaction with calnexin result in increased sensitivity of vitiligo melanocytes to oxidative stress and their early cell death.[28]

mitochondrial dysfunctionMitochondria have been proposed to be the target of different stimuli, such as reactive oxygen species generation, cytokines production, catecholamine release, alteration of Ca2+ metabolism, all of which are capable of inducing melanocyte degeneration. Reduction in cardiolipin level in the mitochondrial inner membrane, increase in the expression of HMG‑CoA reductase and level of cholesterol, modified expression of electron transport chain lipid‑dependent subunits and altered mitochondrial transmembrane potential have been noted in vitiligo.[29]

dna damageThere is evidence for increased DNA damage in vitiligo.





In a study that detailed cell cultures of epidermal melanocytes on 18 vitiligo patients, DNA damage was suggested by increased levels of 8‑oxoguanine, abnormal DNA binding due to nitration of p53 tumor suppressor protein by epidermal peroxynitrite (ONOO−),increased epidermal p53 (in-vitro and in-vivo) and p53 antagonist p76MDM2. Upregulation of DNA repair mechanisms such as short‑patch base‑excision repair via hOgg1 (8‑oxoguanine DNA glycosylase), apurinic/apyrimidinic endonuclease 1 (APE1), and polymerase‑β DNA repair is also found.[30]

apoptosisNACHT ‑leucine‑rich‑repeat protein‑1 (NALP1) (NLR family of proteins) plays a key role in spontaneous apoptosis and may be part of the APAF1 apoptosome. NALP1, part of the inflammasome cascade, is identified to play a significant role in vitiligo.[31] Apoptotic markers are significantly elevated in residual melanocytes in skin biopsies of patients with vitiligo. Serum IgG antibodies from vitiligo patients can penetrate into cultured melanocytes in vitro, and trigger apoptosis.[32]

homocysteineHomocysteine metabolism depends on both folic acid and vitamin B12, both of which are lowered in patients with vitiligo.[33] Elevated serum homocysteine levels are found in extensive vitiligo and may represent a severity marker.[34]

relation with thyroidSubstantial evidence shows that there is a significant association of vitiligo with thyroid dysfunction. In a study higher incidence of thyroid dysfunction was found in those with non‑segmental vitiligo compared to controls (11.8% vs. 4.3%).[35] The incidence of anti‑TPO antibodies in vitiligo is also noted to be high. A study showed that vitiligo (along with chronic urticaria and diffuse alopecia).[36] As vitiligo mostly manifests before the development of the thyroid disease, screening for thyroid functions and antibody levels could be of paramount benefit.

treatment

Response may be the best to medical therapies for lesions on the face and neck, followed by lesions on the proximal extremities and trunk, while those distributed over acral parts of extremities and non‑hairy areas, such as the wrist, feet, and male genitals, respond poorly. Unilateral segmental and clinically stable bilateral vitiligo and those refractory to medical

treatment may be candidates for surgical management. A review of the management options is elucidated.

topical corticosteroidsThe efficacy of topical corticosteroids is established. In a study moderate to high‑potency topical corticosteroids on children with vitiligo resulted in repigmentation in 64%, no change in 24%, and worsened lesions in 11%.[37] Another meta‑analysis found that corticosteroids resulted in more than 75% repigmentation of 56% of segmental vitiligo patients and 55% of generalized vitiligo patients.[38] A cyclical approach is proposed to minimize side effects and preserve clinical effectiveness wherein topical agents are altered every 6‑8 months.[39] With potent topical steroids, cutaneous side effects like atrophy, telangiectasia, and striae may occur. Systemic side effects like suppression of hypothalamic pituitary axis, hyperglycemia (and unmasking of latent diabetes mellitus) and rarely posterior sub‑capsular cataracts may also occur.

topical immunomodulatorsWith efficacy similar to that of topical steroids, immunomodulators have been promising in the management of vitiligo especially given the lesser side effects. In an observation, pimecrolimus 1% cream has shown almost full repigmentation of the lesions on eyelids and genitals.[40] FK506 (tacrolimus) in combination with endothelin (ET‑3) is shown to be effective in stimulating differentiation in neural crest cells which translates to better management in vitiligo.[41] Burning sensation, higher rate of infections like herpes simplex and eczema herpeticum, pruritus, erythema, and papules are the side effects encountered.

Psoralen+ultraviolet-aRepigmentation with Psoralen+Ultraviolet‑A (PUVA) is widely variable (rarely 100%) and darker skinned individuals have better repigmentation. Systemic PUVA (usually requiring 1‑3 years of therapy[42]) is reported to cause nausea, vomiting, phototoxic reactions and a possibly increased long‑term cutaneous malignancy risk. Topical PUVA limits those side effects although erythema, blistering and hyperpigmentation of normal, adjacent skin may be seen. Topical PUVA is comparable to narrowband UVB in the treatment of generalized vitiligo although the latter have fewer adverse effects and less cumulative UVB dose.[43]

narrowband uVbA number of studies confirm the safety and efficacy of narrowband UVB in children with generalized vitiligo with superior results on the face and neck and





in vitiligo present for a shorter duration. Response to thrice weekly therapy may be better than twice per week.

In a study low‑dose narrowband UVB‑activated pseudo‑catalase (PC‑KUS) showed a reduction in epidermal H2O2 and demonstrated a hundred per cent cessation in 98.6% and more than 75% repigmentation in 92.9% on the face/neck, 78.7% on the trunk, and 72.7% on the extremities.[44]

Combination therapy with UVB and calcineurin inhibitors may improve or accelerate repigmentation in patients with vitiligo.[45]

A variation of narrowband UVB, microphototherapy (focused only on areas affected) has been used to treat both segmental and non‑segmental vitiligo. A study showed that 70% achieved normal pigmentation in more than 75% of treated areas. In children with less than 30% body surface area (BSA) involvement this may be the ideal treatment modality.[46]

excimerThe 308‑nm excimer laser, wavelength of ultraviolet light close to that of narrowband UVB (311 nm), is an effective treatment for vitiligo, although impractical for widespread or large lesions.

A study showed that 308‑nm excimer laser therapy together with topical 1% pimecrolimus cream twice daily was compared with excimer laser therapy twice per week and it was found that 71% of the former and 50% of the latter achieved Grade 3 or 4 repigmentation.[47] In adults monochromatic excimer light (MEL) showed 95% of patients demonstrating some repigmentation and approximately 50% greater than 75% repigmentation. Than excimer, MEL has lower power density that translates in to reduced risk of overexposure, the possibility to treat larger areas at a time, and shorter treatment duration. These advantages recommend further studies in the application of MEL in children.[48] Adverse effects are that it may cause blisters (if the dose is too high), erythema and hyperpigmentation. Long‑term exposure to ultraviolet radiation ultimately may cause skin ageing and cancers.

helium-neon laserHelium‑neon (He‑Ne) laser augments melanocyte proliferation through enhanced α2β1 integrin expression, upregulates phosphorylated cyclic‑AMP response element binding protein (CREB) and suppresses mobility but increases attachment to

type IV collagen.[49] It is also proposed to repairing the damaged sympathetic nerves and improve the cutaneous circulation. A study of 40 segmental vitiligo patients treated with He‑Ne laser found marked repigmentation in 60% of patients and 100% recovery in 7.5% of patients.[50]

othersA combination therapy with tacalcitol ointment and sunlight exposure (unlike the ointment alone) improved postcervical, periocular, and periauricular vitiligo vulgaris. Vitamin D ligands alone or in different combinations may contribute to pigment restoration in vitiligo.[51]

Minocycline apart from antimicrobial effects, has anti‑inflammatory, immunomodulatory, and free‑radical scavenging actions that show benefit in vitiligo in arresting depigmentation/progress of the disease.[52]

A study on Ginkgo biloba showed that it has potential to stop progression of vitiligo, and improve total vitiligo area scoring index (VASI) score by 0.5 (an average repigmentation of vitiligo lesions of 15%). Ginkgo biloba also decreased vitiligo European task force (VETF) total vitiligo lesion area by 0.4% while it improved VETF staging score by 0.7 and the spreading score by 3.9.[53]

Elastic cationic niosomes (liposomes) delivery of tyrosinase plasmid (pMEL34) may result in a high tyrosinase gene expression and high tyrosinase and has great potential vitiligo gene therapy.[54]

Levamisole was shown to be simple, safe, and fairly effective remedy in managing limited and slow‑spreading vitiligo.[55]

L‑phenylalanine, an inhibitor of cytotoxic antibodies, supports the stimulation of melanin synthesis (apart from being its predecessor) and the migration of melanocytes from healthy into depigmented skin by solar irradiation. A study showed that L‑phenylalanine (especially in combination with high solar irradiation) showed impressive results (better on face than extremeties).[56]

Efalizumab showed promise in a patient with psoriasis and vitiligo[57] but was withdrawn from the market owing to risk of progressive multifocal leukoencephalopathy (PMLE) and fatal infections.

Vitamins such as vitamin B12 and folic acid plus sunlight have also been reported to be effective.[58]





surgical managementSegmental vitiligo patients are good candidates for surgical repigmentation. Epidermal grafting (autologous mini‑punch grafting, blister roof grafting) has shown promising results. A study showed that suction blister epidermal grafting obtained the best results in segmental subtypes, and in patients less than 20 years old.[59] Another study showed that suction blister autologous epidermal grafting could give results that were excellent in 85%, good in 10%, and poor in 5% and that it is rapid, safe (no scar formation or other complications), and effective treatment for stable childhood vitiligo (especially in refractory and stable children with small‑sized lesions).[60]

A comparison of mini‑punch grafting and split skin grafting (both followed by 3 months of PUVA) which included children as young as 10 years in chronic, stable, segmental vitiligo showed better results with split‑skin grafting, particularly over the face and extremities.[61] Combining blister roof transplantation (BRT) with khellin in liposomes and ultraviolet light (KLUV) in the treatment of recalcitrant vitiligo patches resulted in significant (>75%) patient satisfaction.[62]

depigmentationDepigmentation may be recommended (with hydroquinone 20%) if vitiligo affects more than 50% of the face or body and is recalcitrant to therapy. Mostly being permanent, depigmentation may also cause contact or irritant contact dermatitis (which responds to topical corticosteroids) and sun sensitivity.

conclusion

Adequate information and reassurance of young patients and their parents on the disease, investigation for thyroid dysfunction, avoidance of trigger factors, topical treatment (steroids/immunomodulators), UV radiation and laser form the cornerstones of the management of childhood vitiligo. Decent cosmetic outcomes and disease suppression may be achieved with cyclic therapy, early disease intervention and proper follow‑up. Clinicians need to be aware of the latest developments in pathophysiology and the mechanisms of ever evolving modalities of treatment to effectively curb the disease.

acKnoWledgments

I thank my colleagues and staff of the department of Internal medicine for their perpetual support.

references1. Ongenae K, Van Geel N, Naeyaert JM. Evidence for an

autoimmune pathogenesis of vitiligo. Pigment Cell Res 2003;16:90‑100.

2. HristakievaE,LazarovaR,LazarovN,StanimirovićA,ShaniJ.Markers for vitiligo related neuropeptides in human skin nerve fibers. Acta Med Croatica 2000;54:53‑7.

3. Forschner T, Buchholtz S, Stockfleth E. Current state of vitiligo therapy–evidence‑based analysis of the literature. J Dtsch Dermatol Ges 2007;5:467‑75.

4. Quan C, Ren YQ, Xiang LH, Sun LD, Xu AE, Gao XH, et al. Genome‑wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC. Nat Genet 2010;42:614‑8.

5. Jin Y, Birlea SA, Fain PR, Mailloux CM, Riccardi SL, Gowan K, et al. Common variants in FOXP1 are associated with generalized vitiligo. Nat Genet 2010;42:576‑8.

6. Quan C, Ren YQ, Xiang LH, Sun LD, Xu AE, Gao XH, et al. Genome‑wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC. Nat Genet 2010;42:614‑8.

7. Jin Y, Birlea SA, Fain PR, Gowan K, Riccardi SL, Holland PJ, et al. Genome‑wide analysis identifies a quantitative trait locus in the MHC class II region associated with generalized vitiligo age of onset. J Invest Dermatol 2011;131:1308‑12.

8. Ren Y, Yang S, Xu S, Gao M, Huang W, Gao T, et al. Genetic variation of promoter sequence modulates XBP1 expression and genetic risk for vitiligo. PLoS Genet 2009;5:e1000523.

9. Silva de Castro CC, do Nascimento LM, Walker G, Werneck RI, Nogoceke E, Mira MT. Genetic variants of the DDR1 gene are associated with vitiligo in two independent Brazilian population samples. J Invest Dermatol 2010;130:1813‑8.

10. Liu L, Li C, Gao J, Li K, Gao L, Gao T. Genetic polymorphisms of glutathione S‑transferase and risk of vitiligo in the Chinese population. J Invest Dermatol 2009;129:2646‑52.

11. Wood JM, Gibbons NC, Chavan B, Schallreuter KU. Computer simulation of heterogeneous single nucleotide polymorphisms in the catalase gene indicates structural changes in the enzyme active site, NADPH‑binding and tetramerization domains: A genetic predisposition for an altered catalase in patients with vitiligo? Exp Dermatol 2008;17:366‑71.

12. Lin X, Tian H, Xianmin M. Possible roles of B lymphocyte activating factor of the tumour necrosis factor family in vitiligo autoimmunity. Med Hypotheses 2011;76:339‑42.

13. Li Q, Lv Y, Li C, Yi X, Long HA, Qiao H, et al. Vitiligo autoantigen VIT75 is identified as lamin A in vitiligo by serological proteome analysis based on mass spectrometry. J Invest Dermatol 2011;131:727‑34.

14. Khan R, Gupta S, Sharma VK, Sharma A. WS/PP‑090‑07 T helper and T regulatory cytokines in vitiligo. International Immunology Meeting Abstracts 2010;22:ii145‑6.

15. Gregg RK, Nichols L, Chen Y, Lu B, Engelhard VH. Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase‑specific TCR transgenic mice. J Immunol 2010;184:1909‑17.

16. Kingo K, Reimann E, Karelson M, Rätsep R, Raud K, Vasar E, et al. Association analysis of genes of the IL19 cluster and their receptors in vitiligo patients. Dermatology 2010;221:261‑6.

17. Lang KS, Caroli CC, Muhm A, Wernet D, Moris A, Schittek B, et al. HLA‑A2 restricted, melanocyte‑specific CD8(+) T lymphocytes detected in vitiligo patients are related to disease





activity and are predominantly directed against MelanA/MART1. J Invest Dermatol 2001;116:891‑7.

18. Sanli H, Akay BN, Arat M, Koçyigit P, Akan H, Beksac M, et al. Vitiligo after hematopoietic cell transplantation: Six cases and review of the literature. Dermatology 2008;216:349‑54.

19. Bradley V, Kemp EH, Dickinson C, Key T, Gibbs P, Clatworthy MR. Vitiligo following a combined liver‑kidney transplant. Nephrol Dial Transplant 2009;24:686‑8.

20. Mellouli F, Ksouri H, Dhouib N, Torjmen L, Abdelkefi A, Ladeb S, et al. Possible transfer of vitiligo by allogeneic bone marrow transplantation: A case report. Pediatr Transplant 2009;13:1058‑61.

21. Westerhof W, Manini P, Napolitano A, d’Ischia M. The haptenation theory of vitiligo and melanoma rejection: A close‑up. Exp Dermatol 2011;20:92‑6.

22. Chen JP, Li HP, Jin SH, Zhang JT, Li J. [Detection of serum autoantibodies to melanocyte and correlation between melanoma antigen recognized by T‑cells and vitiligo in children]. Nan Fang Yi Ke Da Xue Xue Bao 2009;29:2107‑8, 2111.

23. Moretti S, Fabbri P, Baroni G, Berti S, Bani D, Berti E, et al. Keratinocyte dysfunction in vitiligo epidermis: Cytokine microenvironment and correlation to keratinocyte apoptosis. Histol Histopathol 2009;24:849‑57.

24. Liu J, Man WY, Lv CZ, Song SP, Shi YJ, Elias PM, et al. Epidermal permeability barrier recovery is delayed in vitiligo‑involved sites. Skin Pharmacol Physiol 2010;23:193‑200.

25. Liu XM, Zhou Q, Xu SZ, Wakamatsu K, Lei TC. Maintenance of immune hyporesponsiveness to melanosomal proteins by DHICA‑mediated antioxidation: Possible implications for autoimmune vitiligo. Free Radic Biol Med 2011;50: 1177‑85.

26. Becatti M, Prignano F, Fiorillo C, Pescitelli L, Nassi P, Lotti T, et al. The involvement of Smac/DIABLO, p53, NF‑kB, and MAPK pathways in apoptosis of keratinocytes from perilesional vitiligo skin: Protective effects of curcumin and capsaicin. Antioxid Redox Signal 2010;13:1309‑21.

27. Arican O, Kurutas EB. Oxidative stress in the blood of patients with active localized vitiligo. Acta Dermatovenerol Alp Panonica Adriat 2008;17:12‑6.

28. Jimbow K, Chen H, Park JS, Thomas PD. Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase‑related protein in vitiligo. Br J Dermatol 2001;144:55‑65.

29. Dell’Anna ML, Ottaviani M, Bellei B, Albanesi V, Cossarizza A, Rossi L, et al. Membrane lipid defects are responsible for the generation of reactive oxygen species in peripheral blood mononuclear cells from vitiligo patients. J Cell Physiol 2010;223:187‑93.

30. Salem MM, Shalbaf M, Gibbons NC, Chavan B, Thornton JM, Schallreuter KU. Enhanced DNA binding capacity on up‑regulated epidermal wild‑type p53 in vitiligo by H2O2‑mediated oxidation: A possible repair mechanism for DNA damage. FASEB J 2009;23:3790‑807.

31. Guerra L, Dellambra E, Brescia S, Raskovic D. Vitiligo: Pathogenetic hypotheses and targets for current therapies. Curr Drug Metab 2010;11:451‑67.

32. Ruiz‑Argüelles A, Brito GJ, Reyes‑Izquierdo P, Pérez‑Romano B, Sánchez‑Sosa S. Apoptosis of melanocytes in vitiligo results from antibody penetration. J Autoimmun 2007;29:281‑6.

33. Singh S, Singh U, Pandey SS. Increased level of serum Homocysteine in vitiligo. J Clin Lab Anal 2011;25:110‑2.

34. Silverberg JI, Silverberg NB. Serum homocysteine as a biomarker of vitiligo vulgaris severity: A pilot study. J Am Acad Dermatol 2011;64:445‑7.

35. Yang Y, Lin X, Fu W, Luo X, Kang K. An approach to the correlation between vitiligo and autoimmune thyroiditis in Chinese children. Clin Exp Dermatol 2010;35:706‑10.

36. ArtantaşS,GülU,KiliçA,GülerS.Skinfindingsinthyroiddiseases. Eur J Intern Med 2009;20:158‑61.

37. Kwinter J, Pelletier J, Khambalia A, Pope E. High‑potency steroid use in children with vitiligo: A retrospective study. J Am Acad Dermatol 2007;56:236‑41.

38. Ando I, Chi HI, Nakagawa H, Otsuka F. Difference in clinical features and HLA antigens between familial and non‑familial vitiligo of non‑segmental type. Br J Dermatol 1993;129: 408‑10.

39. Silverberg NB. Update on childhood vitiligo. Curr Opin Pediatr 2010;22:445‑52.

40. Souza Leite RM, Craveiro Leite AA. Two therapeutic challenges: Periocular and genital vitiligo in children successfully treated with pimecrolimus cream. Int J Dermatol 2007;46:986‑9.

41. Lan CC, Wu CS, Chen GS, Yu HS. FK506 (tacrolimus) and endothelin combined treatment induces mobility of melanoblasts: New insights into follicular vitiligo repigmentation induced by topical tacrolimus on sun‑exposed skin. Br J Dermatol 2011;164:490‑6.

42. Roelandts R. Photo(chemo) therapy for vitiligo. Photodermatol Photoimmunol Photomed 2003;19:1‑4.

43. Westerhof W, Nieuweboer‑Krobotova L. Treatment of vitiligo with UV‑B radiation vs topical psoralen plus UV‑A. Arch Dermatol 1997;133:1525‑8.

44. Schallreuter KU, Krüger C, Würfel BA, Panske A, Wood JM. From basic research to the bedside: Efficacy of topical treatment with pseudocatalase PC‑KUS in 71 children with vitiligo. Int J Dermatol 2008;47:743‑53.

45. Hossani‑Madani AR, Halder RM. Topical treatment and combination approaches for vitiligo: New insights, new developments. G Ital Dermatol Venereol 2010;145:57‑78.

46. Menchini G, Tsoureli‑Nikita E, Hercogova J. Narrow‑band UV‑B micro‑phototherapy: A new treatment for vitiligo. J Eur Acad Dermatol Venereol 2003;17:171‑7.

47. Hui‑Lan Y, Xiao‑Yan H, Jian‑Yong F, Zong‑Rong L. Combination of 308‑nm excimer laser with topical pimecrolimus for the treatment of childhood vitiligo. Pediatr Dermatol 2009; 26:354‑6.

48. Leone G, Iacovelli P, Paro Vidolin A, Picardo M. Monochromatic excimer light 308 nm in the treatment of vitiligo: A pilot study. J Eur Acad Dermatol Venereol 2003;17:531‑7.

49. Lan CC, Wu CS, Chiou MH, Chiang TY, Yu HS. Low‑energy helium‑neon laser induces melanocyte proliferation via interaction with type IV collagen: Visible light as a therapeutic option for vitiligo. Br J Dermatol 2009;161:273‑80.

50. Wu CS, Hu SC, Lan CC, Chen GS, Chuo WH, Yu HS. Low‑energy helium‑neon laser therapy induces repigmentation and improves the abnormalities of cutaneous microcirculation in segmental‑type vitiligo lesions. Kaohsiung J Med Sci 2008;24:180‑9.

51. Amano H, Abe M, Ishikawa O. First case report of topical tacalcitol for vitiligo repigmentation. Pediatr Dermatol 2008;25:262‑4.

52. Parsad D, Kanwar A. Oral minocycline in the treatment of vitiligo–a preliminary study. Dermatol Ther 2010;23:305‑7.





53. Szczurko O, Shear N, Taddio A, Boon H. Ginkgo biloba for the treatment of vitilgo vulgaris: An open label pilot clinical trial. BMC Complement Altern Med 2011;11:21.

54. Manosroi J, Khositsuntiwong N, Manosroi W, Götz F, Werner RG, Manosroi A. Enhancement of transdermal absorption, gene expression and stability of tyrosinase plasmid (pMEL34)‑loaded elastic cationic niosomes: Potential application in vitiligo treatment. J Pharm Sci 2010;99:3533‑41.

55. Pasricha JS, Khera V. Effect of prolonged treatment with levamisole on vitiligo with limited and slow‑spreading disease. Int J Dermatol 1994;33:584‑7.

56. Camacho F, Mazuecos J. Treatment of vitiligo with oral and topical phenylalanine: 6 years of experience. Arch Dermatol 1999;135:216‑7.

57. Fernandez‑Obregon AC. Clinical management with efalizumab of a patient with psoriasis and comorbid vitiligo. J Drugs Dermatol 2008;7:679‑81.

58. Juhlin L, Olsson MJ. Improvement of vitiligo after oral treatment with vitamin B12 and folic acid and the importance

of sun exposure. Acta Derm Venereol 1997;77:460‑2.

59. Gupta S, Kumar B. Epidermal grafting in vitiligo: Influence of age, site of lesion, and type of disease on outcome. J Am Acad Dermatol 2003;49:99‑104.

60. Hu JJ, Xu AE, Wu XG, Sun XC, Luo XY. Small‑sized lesions of childhood vitiligo treated by autologous epidermal grafting. J Dermatolog Treat 2012;23:219‑23.

61. Khandpur S, Sharma VK, Manchanda Y. Comparison of minipunch grafting versus split‑skin grafting in chronic stable vitiligo. Dermatol Surg 2005;31:436‑41.

62. de Leeuw J, Assen YJ, van der Beek N, Bjerring P, Martino Neumann HA. Treatment of vitiligo with khellin liposomes, ultraviolet light and blister roof transplantation. J Eur Acad Dermatol Venereol 2011;25:74‑81.

how to cite this article:***

Source of Support: Nil, Conflict of Interest: None declared


Avinash

Rectangle


indianjpaediatrdermatol13127-3481866_094018

Documents