Nonsegmental vitiligo update - Dermatologica Sinica

DERMATOLOGICA SINICA xxx (2016) 1e4

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REVIEW ARTICLE

Nonsegmental vitiligo update Masutaka Furue 1, *, Takafumi Kadono 2 1 2

Department of Dermatology, Kyushu University, Fukuoka, Japan Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received: Mar 25, 2016 Revised: Jun 23, 2016 Accepted: Jul 5, 2016

Nonsegmental vitiligo is an acquired leukoderma characterized by the destruction of melanocytes. Autoimmunity is the most widely accepted hypothesis to explain the pathogenesis of nonsegmental vitiligo. Increased oxidative stress and decreased expression of E-cadherin may facilitate the loss of melanocytes. Because vitiligo preferentially affects cosmetically sensitive regions such as the face, hands, and genital area, it imposes significant psychological and social burdens. In this review, we discuss recent topics in the epidemiology, pathogenesis, genetic background, and therapeutic advances of nonsegmental vitiligo. Copyright © 2016, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: epidemiology genetic background nonsegmental vitiligo pathogenesis therapy

Introduction Vitiligo is an acquired depigmenting disorder that should be differentiated from congenital hypopigmentation such as albinism, piebaldism, dyschromatosis symmetrica hereditaria, and nevus depigmentosus.1e3 Idiopathic guttate hypomelanosis, tinea versicolor, and chemically induced leukoderma caused by phenols, catechols, and rhododendrol should also be distinguished from authentic vitiligo.1,3e5 Segmental vitiligo affecting a unilateral dermatome-like cutaneous segment is less frequent than nonsegmental or generalized vitiligo.6 Occasionally, both nonsegmental and segmental vitiligo appear in one patient (mixed type).6 Dysregulation of the nervous system is hypothesized to be the cause of segmental vitiligo.6

Epidemiology The prevalence of vitiligo is estimated at less than 1%.2e4,6,7 A precise population-based epidemiological study by Howitz et al8 revealed that the prevalence of vitiligo was 0.38% (179/47,033) in Denmark, peaking at 60e69 years of age with a male to female ratio of 1:1.13. Although selection bias should be considered in patient-

Conflict of interest: The authors declare that they have no financial or non-financial conflicts of interest related to the subject matter or materials discussed in this article. * Corresponding author. Department of Dermatology, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812e8582, Japan. E-mail address: [email protected] (M. Furue).

based studies, vitiligo was found in 1134 (1.68%) of 67,448 Japanese dermatological patients, peaking at 66e75 years of age with a male to female ratio of 1:1.37.9 Women are generally affected by vitiligo more than (or equal to) men.1,10 In another study of 912,986 Japanese dermatological patients, congenital and acquired depigmented disorders affected 1748 (0.2%) and 6359 (0.7%) patients, respectively, and 60% of total depigmented disorders consisted of vitiligo.7 In Korea, the annual prevalence of vitiligo determined by hospital-visiting rate was 0.12% to 0.13%, with a male to female ratio of 1:1.31 over a 3-year period.11

Pathogenesis While the pathogenesis of nonsegmental vitiligo remains poorly understood, autoimmune stress and oxidative stress are currently considered to work synergistically in the apoptosis or destruction of melanocytes (Figure 1).1,3,12 Both humoral and cellular immunity are involved in the development of nonsegmental vitiligo. Autoantibodies are variably detected against pigment cell antigens such as tyrosinase and tyrosinase-related protein 1 and 2.1 At the center of a vitiligo lesion, complete loss of melanocytes is observed. Infiltration of macrophages, T cells and neutrophils is demonstrated, especially in progressing perilesional skin. The majority of epidermotropic T cells express cutaneous lymphocyte antigen (skin-homing receptor) with an increased CD8/CD4 ratio and interferon g production.1,13e16 Interferon g is known to inhibit melanogenesis and to induce apoptosis of melanocytes (Figure 1).15 Furthermore, interferon a-2a-induced nonsegmental vitiligo occurs

http://dx.doi.org/10.1016/j.dsi.2016.07.001 1027-8117/Copyright © 2016, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Furue M, Kadono T, Nonsegmental vitiligo update, Dermatologica Sinica (2016), http://dx.doi.org/10.1016/ j.dsi.2016.07.001

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M. Furue, T. Kadono / Dermatologica Sinica xxx (2016) 1e4

Figure 1 Pathogenesis of nonsegmental vitiligo. Lesional skin of vitiligo lacks melanocytes. Melanocyte cell death has multiple causes. Cellular and humoral immunity appear to be involved in this cytotoxic process. The perilesional skin harbors multicellular infiltrates comprising CD4þ T cells, CD8þ T cells, macrophages, and neutrophils. CD8þ T cells together with released interferon-g are cytotoxic to melanocytes. Loss of E-cadherin induces detachment and apoptosis of melanocytes. Increased oxidative stress (reactive oxygen species; ROS) is detected in lesional skin, which facilitates apoptosis of E-cadherin-deficient melanocytes. In addition, elevated ROS levels oxidize constituent enzymes in melanocytes, such as tyrosinase, which may accelerate the production of anti-oxidized tyrosinase autoantibodies. The activation of Langerhans cells is also observed in lesional skin, which may facilitate cellular and humoral immunity. More than 36 susceptible genes are reported. Six genes (LPP, HLA Class I gene region, IL2RA, IKZF4, C1QTNF6, and RNASET2-FGFR1OP-CCR6) are shared between Caucasian and Chinese populations. Nonsegmental vitiligo is associated with other autoimmune diseases such as Hashimoto’s thyroiditis and pernicious anemia. Four genes (PTPN22, RERE, IFIH1, and CTLA4) are associated with vitiligo in patients with other autoimmune diseases. Several microRNAs are also reported to be up- or downregulated in nonsegmental vitiligo.

in the treatment of Behçet's disease.16 It should be noted that even in normal appearing skin of patients with nonsegmental vitiligo, melanocytes tend to lack expression of E-cadherin; a molecule essential to the adhesion of melanocytes to surrounding basal keratinocytes.17 This abnormality is associated with the detachment of the melanocytes from the basal to suprabasal layers in the epidermis, leading to apoptosis of melanocytes (Figure 1).17 Increased oxidative stress (excessive reactive oxygen species) with mitochondrial swelling is detected in the lesional keratinocytes of nonsegmental vitiligo (Figure 1).12,17 Low levels of antioxidant enzymes have also been detected in the serum of vitiligo patients.12 The inflammasome protein, nucleotide-binding domain and leucine-rich repeat containing protein 1 (NLRP1), is a key enzyme to mediate the activation of interleukin (IL)-1b. The NLRP1 and IL-1b immunostaining in the perilesional skin of nonsegmental vitiligo is significantly associated with progressive disease.18 Oxidative stress causes extensive alterations in conformation and function of tyrosinase, which increases the antigenicity of oxidized tyrosinase.19 In lesional skin, Langerhans cells are increased in number and activated so that they may facilitate the antigen-presenting process against the oxidized melanocyte antigens.12,19,20 Additionally, oxidative stress or mechanical friction further accelerates the detachment and apoptosis of melanocytes with insufficient expression of E-cadherin (Figure 1).17 This may explain the frequent occurrence of Koebner's phenomenon in vitiligo.21e23 Furthermore, decreased levels of copper and zinc may be related to melanogenesis and oxidative stress because these

trace elements, which are considered as antioxidants, are integral parts of many metalloenzymes that are essential in the process of melanogenesis.24 MicroRNAs (miRs) are short noncoding RNA molecules that regulate gene expression, and contribute to biological processes including apoptosis, cell cycle progression, and differentiation. To date, nearly 2500 miRs have been found in humans.25 In lesional skin, miR-1, miR-133a and miR-133b are significantly upregulated compared with controls in normal skin.26 Other studies have shown that miR-16, miR-451, miR-224-3p and miR-4712-3p are overexpressed and that miR-574-3p, miR-1274A, miR-3940-5p are downregulated in the blood of nonsegmental vitiligo patients compared with healthy controls (Figure 1).27,28 Different series of miRs are likely to be operative in situ and in the circulation to regulate the pathomechanism of vitiligo. Genetic background and comorbidity Genetic background also plays a pivotal role in the pathogenesis of nonsegmental vitiligo. Concordance rate of vitiligo was 23% among 22 monozygotic twin-pairs compared with 0% among dizygotic twin-pairs.10 The reported frequency of vitiligo among first-degree relatives of 2078 Caucasian vitiligo probands was 18 times that of the general population.10 As reviewed intensively, recent genomewide association and linkage studies have suggested at least 36 susceptibility loci in Caucasian populations.29,30 Chinese populations have nine susceptibility loci, six of which are shared with Caucasian populations: LPP, HLA Class I gene region, IL2RA, IKZF4,



C1QTNF6, and RNASET2-FGFR1OP-CCR6.29,30 Vitiligo is significantly associated with other autoimmune diseases such as Hashimoto's thyroiditis, pernicious anemia, Addison's disease, diabetes mellitus, systemic lupus erythematosus, and inflammatory bowel disease.1,10,30,31 Comorbidity of vitiligo with lichen sclerosus and antitumor necrosis factor a treatment are also reported.32e34 Four genes, PTPN22, RERE, IFIH1, and CTLA4, are recognized vitiligo susceptibility loci for patients with systemic autoimmune diseases (Figure 1).29 Vitiligo is known to appear in animals such as pigs, horses, and chickens.35 Therapeutic approach Because vitiligo preferentially affects cosmetically sensitive regions such as the face, hands, and genital area, it imposes significant psychological and social burdens.7,36 Therapeutic guidelines have been published in different countries, with similar concepts and evidence.6,7,37e39 Beneficial effects are evident in topical corticosteroids and topical calcineurin inhibitors; phototherapies including narrowband ultraviolet B (UVB), psoralen plus ultraviolet A (PUVA), and excimer light; oral steroid minipulse; surgical procedures with punch or epidermal grafting; and camouflage.6,7,37e41 Repigmentation is assumed to occur due to the migration of melanocytic stem cells present in the lower part of the bulge (perifollicular repigmentation) and/or the direct migration of perilesional melanocytes (edge repigmentation).38 Several international scales have been developed to measure the severity (Vitiligo Extent Score),42 quality of life (Vitiligo Impact Patient Scale),43 and patient-reported outcome evaluation (Vitiligo Noticeability Scale).44 Although narrowband UVB has been reported to be more effective than PUVA,45 a recent meta-analysis could not prove the superiority as evaluated by >75% repigmentation.41 Treatment with topical calcipotriol and oral PUVA resulted in significantly higher percentages of both initial (81%) and complete pigmentation (63%), compared with placebo and PUVA (7% and 15%, respectively).46 Similarly, the addition of topical tacalcitol to narrowband UVB improved the extent of repigmentation and increased the response rate more than narrowband UVB alone.47 Recent systematic reviews have also reported that the combination therapy with topical calcineurin inhibitors and narrowband UVB or 308 nm excimer laser/light irradiation are more effective for vitiligo than monotherapy with narrowband UVB or 308 nm excimer laser/light irradiation.48,49 Oral minipulse of betamethasone plus narrowband UVB was significantly superior to treatment with oral minipulse of betamethasone alone.50 However, the abovementioned standard treatments do not fully satisfy the quality of life of patients in our daily clinics. Novel therapeutic approaches are definitely necessary. In this context, oral tofacitinib, a Janus kinase 1/3 inhibitor, may be a promising agent in the near future.51 In conclusion, recent clinical, genetic, and experimental studies further stress the significance of autoimmunity and oxidative milieu in the pathogenesis of vitiligo. New drugs targeting the immune response in combination with antioxidant agents may enhance the therapeutic potential with or without conventional treatments. References 1. Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: a comprehensive overview. Part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. J Am Acad Dermatol 2011;65:473e91. 2. Yaghoobi R, Omidian M, Bagherani N. Vitiligo: a review of the published work. J Dermatol 2011;38:419e31. 3. Ezzedine K, Eleftheriadou V, Whitton M, et al. Vitiligo. Lancet 2015;386:74e84. 4. Lerner AB. On the etiology of vitiligo and gray hair. Am J Med 1971;51:141e7.

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5. Yagami A, Suzuki K, Sano A, et al. Rhododendrol-induced leukoderma accompanied by allergic contact dermatitis caused by a non-rhododendrol skin-lightening agent, 5,50 -dipropylbiphenyl-2,20 -diol. J Dermatol 2015;42: 739e40. €hm M, et al. Guidelines for the management of viti6. Taieb A, Alomar A, Bo ligo: the European Dermatology Forum consensus. Br J Dermatol 2013;168: 5e19. 7. Oiso N, Suzuki T, Wataya-Kaneda M, et al. Guidelines for the diagnosis and treatment of vitiligo in Japan. J Dermatol 2013;40:344e54. 8. Howitz J, Brodthagen H, Schwartz M, et al. Prevalence of vitiligo. Epidemiological survey on the Isle of Bornholm, Denmark. Arch Dermatol 1977;113: 47e52. 9. Furue M, Yamazaki S, Jimbow K, et al. Prevalence of dermatological disorders in Japan: a nationwide, cross-sectional, seasonal, multicenter, hospital-based study. J Dermatol 2011;38:310e20. 10. Alkhateeb A, Fain PR, Thody A, et al. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res 2003;16:208e14. 11. Lee H, Lee MH, Lee DY, et al. Prevalence of vitiligo and associated comorbidities in Korea. Yonsei Med J 2015;56:719e25. 12. Colucci R, Dragoni F, Moretti S. Oxidative stress and immune system in vitiligo and thyroid diseases. Oxid Med Cell Longev 2015;2015:631927. 13. Le Poole IC, van den Wijngaard RM, Westerhof W, et al. Presence of T cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am J Pathol 1996;148:1219e28. 14. Shin J, Lee JS, Kim MR, et al. New suggestive clue to the mechanism of vitiligo: inflammatory vitiligo showing prominent leukocytoclasis at the erythematous rim. J Dermatol 2013;40:488e90. 15. Yang L, Wei Y, Sun Y, et al. Interferon-gamma inhibits melanogenesis and induces apoptosis in melanocytes: A pivotal role of CD8þ cytotoxic T lymphocytes in vitiligo. Acta Derm Venereol 2015;95:664e70. 16. 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45. Bhatnagar A, Kanwar AJ, Parsad D, et al. Comparison of systemic PUVA and NBUVB in the treatment of vitiligo: an open prospective study. J Eur Acad Dermatol Venereol 2007;21:638e42. 46. Ermis O, Alpsoy E, Cetin L, et al. Is the efficacy of psoralen plus ultraviolet A therapy for vitiligo enhanced by concurrent topical calcipotriol? A placebocontrolled double-blind study. Br J Dermatol 2001;145:472e5. 47. Leone G, Pacifico A, Iacovelli P, et al. Tacalcitol and narrow-band phototherapy in patients with vitiligo. Clin Exp Dermatol 2006;31:200e5. 48. Yazdani Abyaneh M, Griffith RD, Falto-Aizpurua L, et al. Narrowband ultraviolet B phototherapy in combination with other therapies for vitiligo: mechanisms and efficacies. J Eur Acad Dermatol Venereol 2014;28:1610e22. 49. Bae JM, Hong BY, Lee JH, et al. The efficacy of 308-nm excimer laser/light (EL) and topical agent combination therapy versus EL monotherapy for vitiligo: a systematic review and meta-analysis of randomized controlled trials (RCTs). J Am Acad Dermatol 2016;74:907e15. 50. Rath N, Kar HK, Sabhnani S. An open labeled, comparative clinical study on efficacy and tolerability of oral minipulse of steroid (OMP) alone, OMP with PUVA and broad/narrow band UVB phototherapy in progressive vitiligo. Indian J Dermatol Venereol Leprol 2008;74:357e60. 51. Craiglow BG, King BA. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed therapy. JAMA Dermatol 2015;151:1110e2.
