The Epidemiology and Treatment of Vitiligo: A Chinese Perspective

Vitiligo is an acquired skin disorder characterized by patchy depigmentation of the skin [1]. Vitiligo affects approximately 0.5% to 2% of the population worldwide, and the prevalence appears to be equal between men and women [2,3]. The pathogenesis of vitiligo is still not fully understood and mounting evidences have suggested that it might be related to autoimmunity and oxidative stress [4]. Although neither life-threatening nor symptomatic, the effect of vitiligo can be cosmetically and psychologically devastating, resulting in low selfesteem, poor body image and other negative effects [5-7]. In this review, we focus on the epidemiology and treatment of vitiligo in China.


Introduction
Vitiligo is an acquired skin disorder characterized by patchy depigmentation of the skin [1]. Vitiligo affects approximately 0.5% to 2% of the population worldwide, and the prevalence appears to be equal between men and women [2,3]. The pathogenesis of vitiligo is still not fully understood and mounting evidences have suggested that it might be related to autoimmunity and oxidative stress [4]. Although neither life-threatening nor symptomatic, the effect of vitiligo can be cosmetically and psychologically devastating, resulting in low selfesteem, poor body image and other negative effects [5][6][7]. In this review, we focus on the epidemiology and treatment of vitiligo in China.

Epidemiology Prevalence of vitiligo
Although vitiligo occurs worldwide, it is known that its prevalence varies between races and regions. Recent studies have revealed the prevalence from 0.06-2.28% . Howitz et al. [8] reported that the prevalence of vitiligo in Denmark was 0.38%. Mehta et al. [9] reported that the prevalence was 0.49% in rural areas of Indian and 1.78% in urban areas. Abdel-Hafez et al. [10] performed a survey in Upper Egypt and found the prevalence of vitiligo to be 1.2%. In USA, the prevalence of vitiligo was 0.74% [11]. Other studies have shown a prevalence of 0.17% in Italy [12], 0.5-1% in the French West Indies [13], and 0.28% in France [14]. In China, several studies have been performed and the prevalence of vitiligo ranged from 0.10 to 0.3% [15][16][17][18][19]. Lu et al. [15] conducted a survey in Shaanxi province, northwest China and found that the prevalence of vitiligo was 0.10%. In 2008, a population-based and dermatologist-confirmed survey was conducted in 6 cities in China and the prevalence of vitiligo was 0.56% [16].

Gender distribution
Discrepancy on prevalence of psoriasis in men and women has been reported. Most studies showed similar prevalence between men and women [3]. Lu et al. [15] reported vitiligo distributed equally in men and women. However, Wang et al. [16] found a higher prevalence in male than in female. The male to female ratio was 1.6:1, which is similar to that reported by McBurney [29]. In a hospital-based study, Boisseau-Garsaud et al. [13] found more female patients than male patients, suggesting that women are more concerned about vitiligo.

Age of onset
Although vitiligo can occur at any age, it is more common in young and middle-aged people. A study reported that the mean age of onset was 18.9 years [30], while another study found that the mean age of onset was 23.7 years old [31]. Furthermore, it was also reported that vitiligo occurred at 28.4 years old in men and 17.3 years old in women, suggesting that vitiligo occurs earlier in women than in men [18].

Type of vitiligo
Recently, new classification and nomenclatures have been proposed based on clinical features: segmental vitiligo (SV) and non-segmental vitiligo (NSV). The latter including the variants focal, generalized, acrofacial and universal vitiligo. In China, the NSV is the most common form. Wang et al. [16] reported that of 122 patients, 44 (36.1%) had focal vitiligo and 43 (35.3%) had generalized vitiligo. Universal vitiligo was found in 22 patients (18.0%) and acrofacial vitiligo was found in 10 patients (8.2%). Only 3 patients (2.5%) was segmental vitiligo. The types of vitiligo were similar between men and women. Similar results were obtained in other studies [18,31].

Genetics
The involvement of genetic factors in the susceptibility to vitiligo became evident in familial studies, which demonstrated that vitiligo segregates with a complex standard of multifactorial and polygenic inheritance [32][33][34][35][36][37][38]. A study reported that 20% of the patients had positive family history in first-degree relatives [33]. The relative risk of vitiligo in Denmark and India populations was 7 for parents, 12 for siblings, and 36 for off-spring. The relative risk of vitiligo for firstdegree relatives in increased 7 to 10 fold [36][37][38]. In China, 5%-20% patients with vitiligo had positive family history [17,18,31]. Sun et al. [18] reported that 128 patients out of 815 (15.7%) had positive family history, and the heritability degrees of vitiligo in the first-and seconddegree relatives were 59.6% and 55.2%, respectively. In another study, the positive family history was 9.8% [16]. reducing treatment side effects and improving the quality of life. As the treatment often extends over a long period of time, the treatment strategy should be fully discussed with the patient to obtain a good compliance.
Topical steroids, topical calcineurin inhibitors and UV therapy were widely used in China. Psoralen plus ultravoilet A (PUVA) therapy and broadband (BB)-UVB were less used because of the high risk of side effects. The combination treatments for vitiligo are recommended. Camouflaging was used in some patients with severe and stable vitiligo. Topical bleaching agents are rarely applied in China.

Topical treatments
Topical corticosteroids: Topical corticosteroids is the most prevalent treatment for vitiligo [39][40][41][42][43][44]. It is the first-line therapy for progressive vitiligo with less than 10% body surface area (BSA) involvements [39]. The best results were found on sun-exposed areas (face and neck) [45,46], in dark skin [47], and in recentdeveloped lesions [48]. Lesions on hands and feet usually had a poor response. A study assessed the effectiveness and safety of nonsurgical repigmentation therapies in localized and generalized vitiligo by means of a meta-analysis. The results revealed that Class 3 corticosteroids therapy was the most effective and safest therapy for localized vitiligo [45]. It may require a year or longer to note significant improvement [49]. Less than 50% of patients achieve greater than 75% repigmentation after 10 months of treatment [49]. Potent and very potent TCS were widely used for the treatment of vitiligo in China and skin side-effect reports were not common [39].

Topical calcineurin inhibitors:
The safety and efficacy of topical calcineurin inhibitors in patients with vitiligo has been evaluated in recent years [50][51][52][53][54][55][56][57][58][59][60][61]. Two left-right comparative studies showed that tacrolimus had similar effects to clobetasol propionate 0.05% in the treatment of pediatric patients [51,52]. Pimecrolimus was also effective [53]. In an open study comparing topical pimecrolimus and tacrolimus, both drugs showed similar effects [54]. In another open study, Lotti et al. [55] reported a higher response rate in tacrolimus group (61%) than in pimecrolimus group (54.6%). In a Chinese study, 83.9% patients treated with tacrolimus ointment were effective and 45.1% had complete or excellent response. It also showed that tacrolimus ointment was effective in both active and stable stages. Lesions on face and anogenital area had better response than other areas [56]. After the clinical trial, 61.7% of patients continued to use tacrolimus ointment, indicating that they were satisfied with the effects of tacrolimus and had a strong desire to continue the treatment [57]. Some studies showed that tacrolimus combined with narrowband UVB or 308-nm excimer laser therapy was superior to phototherapy alone or tacrolimus monotherapy [60,61]. The common side-effects of tacrolimus ointment were skin irritation (burning sensation, pruritus and erythema).

Vitamin D analogues:
Topical Vitamin D analogues such as calcipotriol, tacalcitol have been used as monotherapy or in combination with topical corticosteroids or phototherapy for the treatment of vitiligo [62][63][64][65]. However, the effects remained controversial. A right-left comparative study was performed to compare the efficacy and safety of topical calcipotriol (0.005%) and NB-UVB combination thrapy with NB-UVB alone in generalized vitiligo. The results showed that the effects of combination therapy were similar to NB-UVB monotherapy [66]. A similar results had been obtained in a study comparing calcipotriol and 308 nm excimer laser combination therapy and 308 nm excimer laser alone [67]. An open, uncontrolled trial was carried out to observe the effect of calcipotriol and betamethasone dipropionate combination therapy in the treatment of vitiligo. Patients were treated with topical calcipotriol 0.005%/betamethasone dipropionate 0.05% ointment twice a day. At the end of 12 weeks, 9.7% showed excellent response, 19.4% showed moderate response [64]. Phototherapy PUVA: Psoralen plus UVA therapy has been used to treat vitiligo for half a century. Oral or topical psoralen (solutions, creams or bath) was followed by UVA irradiation and it was effective for vitiligo [68]. Khellin plus UVA radiation (KUVA) was also reported to be effective for vitiligo [69]. Valkova [70] conducted a study to evaluate the efficacy of topical KUVA and systemic PUVA for vitiligo. It showed that topical KUVA required longer duration of treatment and higher UVA doses. No side effects were observed. In china, PUVA was less used for the treatment of vitiligo especially oral PUVA because of the high risk of side effects.
Narrowband UVB: Narrowband UVB represents a symbol of a specific UVB wave, 311 ± 2 nm. NB-UVB therapy was used for the treatment of vitiligo in 1990s [71][72][73]. Randomized, controlled trials have found that NB-UVB phototherapy is effective and safe for vitiligo [74,75]. Kishan [76] evaluted the efficacy and safety of NB-UVB in 150 vitiligo patients. The results showed 26(17.3%) patients achieved >75% repigmentation. 73 (48.7%) patients achieved 25-75% repigmentation. Adverse effects were minimal. Another randomized controlled study [77] compared the efficacy of NB-UVB with oral PUVA in the treatment of vitiligo. 56 patients were randomized in a 1:1 ratio to oral PUVA or NBUVB phototherapy. The median repigmentation achieved at the end of the six-month therapy course was 45% in the NB-UVB group and 40% in oral PUVA group. Less adverse effects was found in NB-UVB group (7.4%) than in PUVA group (57.2%). There was no significant difference in repigmentation. However, NB-UVB showed better tolerance and less side effects. In China, NB-UVB phototherapy is widely used because of its good efficacy safety profile. 308 nm excimer laser/light: 308 nm excimer laser/light therapy can radiate 308 nm UVB to targeted areas of vitiligo. It is useful for spotted and patched vitiligo lesions. 15-50% of 308 nm excimer lasertreated lesions showed excellent results (>75% repigmentation) [42]. A few studies have been conducted in China to evaluate the efficacy of 308 nm excimer laser/light in vitiligo treatment [78,79]. In one study, 36 patients with 44 vitiligo patches were treated using a 308 nm excimer laser. After 30 treatments 27/44 patches (61.4%) achieved more than 75% repigmentation [78]. Another study was performed [80] to compare the efficacy of 308 nm excimer laser with 308 nm excimer lamp in the treatment of vitiligo. Fourteen patients with a total of 48 lesions were treated. The results showed that 308 nm excimer laser with 308 nm excimer lamp had the similar effects [80].

Epidermal Grafting and surgical treatments
Skin grafts were first used for the treatment of vitiligo in the 1960s and became prevalent in 1980s. Five surgical methods are predominant, including: (i) split-thickness skin grafting; (ii) epidermal grafting; (iii) mini-grafting; (iv) autologous non-cultured melanocyte-keratinocyte cell transplantation/injection; and (v) autologous cultured melanocyte transplantation/injection. The UK guideline for management of vitiligo recommended that surgical treatment should be used only for cosmetically sensitive sites where there have been no new lesions, no Koebner's phenomenon and no extension of the lesion in the previous 12 months [40]. In China, autologous epidermal grafting was the most common surgical treatment for vitiligo [81]. Jin et al. [82] reported that 86.81% patients receiving autologous epidermal transplantation had satisfied repigmentation. Hyperpigmentation was found in 24.52% patients and hypopigmentation in 21.29% patients. Xu et al. [83] reported that successful repigmentation was obtained in 23 of the 24 patients who received autologous non-cultured epidermal cell suspension transplatation. Hong et al. [84] performed autologous cultured pure melanocytes transplantation in pediatric and adult patients. The results showed that 83.3% pediatric patients and 84.0% adult patients obtained satisfactory results (repigmentation of 50% or more).

Systemic treatment
The systemic therapies for vitiligo include oral corticosteroids, immunosuppresive agents, oral antioxidants and others. Corticosteroids can be used for short period of time in patients with progressive vitiligo. Kim et al. [85] studied the efficacy of low-dose oral corticosteroids for vitiligo. The initial dose was oral prednisolone 0.3 mg/kg for 2 months, then the dose reduced for half every month. After 5 month treatment, 70.4% patients showed repigmentation. Immunosuppressants have been evaluated in a limited number of studies and rarely used by Chinese dermatologists. Recently, topical and systemic antioxidants were tried in the treatment of vitiligo. Pseudocatalase, vitamin E, vitamin C, ubiquinone, lipoic acid, polypodium leucotomos, catalase⁄superoxide dismutase combination, and Ginkgo biloba have been used alone or, more frequently, in combination with phototherapy for vitiligo. The clinical effects need to be confirmed [86][87][88].

Conclusion
Vitiligo is a common acquired depigmenting skin disorder and has a negative impact on patients' quality of life. The prevalence of vitiligo in China varied from 0.1% to 0.56%. Topical steroids, topical calcineurin inhibitors, UVB therapy and autologous epidermal graft are the most used treatment for vitiligo.