Dermatologic Therapy, Vol. ••, 2014, ••–•• Printed in the United States · All rights reserved
© 2014 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
REVIEW ARTICLE
Vitiligo nonsurgical treatment: a review of latest treatment researches Yanfei Zhang, Jessini Soranambal Mooneyan-Ramchurn, Nan Zuo, Yiguo Feng & Shengxiang Xiao Department of Dermatology, The Second Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
ABSTRACT: Vitiligo is a common depigmenting acquired disorder affecting about 1–2% of the world population, regardless of race, ethnic background, or gender. It is characterized by the appearance of milky white maculae because of a loss of melanocytes. The disfiguring nature of vitiligo causes high psychosocial morbidity. This is especially pronounced in populations with darker skin tone, likely because of the marked contrast. A variety of nonsurgical treatment regimens are currently employed in vitiligo. We reviewed the latest studies carried out on different nonsurgical treatment modalities used in vitiligo. All nonsurgical treatment aid to repigment or depigmentation the skin, however, many of them require a prolonged treatment course and may yield minimal results as well as carry unwanted side effects. There is a need for further research into the causes of vitiligo and into discovering better treatments. KEYWORDS: nonsurgical treatment, treatment, vitiligo
Background Vitiligo is a common depigmenting acquired disorder affecting about 1–2% of the world population, regardless of race, ethnic background, or gender. Approximately, 50% of the affected individuals develop the disease before the age of 20 (1) and about 25% prior to the age of 8 (2). The mean age of the onset of childhood vitiligo had been found to be between 4 and 5 years (2). It is characterized by the appearance of milky white maculae because of a loss of melanocytes (3). Studies have demonstrated that the disfiguring nature of vitiligo causes Address correspondence and reprint requests to: Feng Yiguo and Xiao Shengxiang, MD, PhD, Professors, The Second Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an 710004, Shaanxi Province, China, or email: [email protected] and [email protected].
high psychosocial morbidity (4–6). This is especially pronounced in populations with darker skin tone, likely because of the marked contrast (4,7). A variety of nonsurgical treatment regimens are currently employed in vitiligo. Here, we reviewed the latest studies carried out on nonsurgical treatment modalities used in vitiligo.
System administration Vitamin D deficiency or insufficiency had been demonstrated to be associated with almost all vitiligo patients (8). A pilot study done by Finamor et al. (9) found that daily dose of 35,000 IU of vitamin D was a safe and effective therapeutic approach for vitiligo. Methotrexate (MTX) is used in the treatment of autoimmune diseases to decrease the number of
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T cells capable of tumor necrosis factor α (TNFα) production, which is a key step in the development of vitiligo (10). Alghamdi and Khurrum’s (11) studies found that oral MTX (25 mg dose per week) was a safe and effective therapeutic approach for vitiligo, but because of the small uncontrolled pilot study, further research need to be carried out. Levamisole can be used as an immunomodifier for an effective treatment of vitiligo, 160 mg of levamisole weekly is safe and effective (12). In a retrospective study, low-dose oral minipulse dexamethasone (2.5 mg per day) is safe and effective for arresting progressive unstable vitiligo (13). Studies have shown that vitiligo appears to be an autoimmune disease involving T cell-mediated melanocyte destruction. Intramuscular injections of 15 mg alefacept (a fusion protein that blocks the growth of some types of T cells) for 12 weeks in four adult patients with widespread vitiligo did not show any repigmentation after 24 weeks follow-up. As a result of a small number of patients in the pilot study, further evaluation in larger studies may be required (14).
Topical therapy Topical steroids Potent topical steroids are considered first line therapy for localized vitiligo (15,16). These rarely achieve more than 50–75% repigmentation and are cumbersome, requiring multiple daily applications. They may require a year or more to note significant improvement (17,18). Less than 50% of patients achieve greater than 75% repigmentation after 10 months of therapy (17). Long-term use of topical corticosteroids can induce skin atrophy, but tretinoin can prevent this side effect, a placebocontrolled, paired-comparison, left-right study found that combined therapy with tretinoin plus topical corticosteroids is safe and effective for treatment of patients with vitiligo (19). It may be a new therapeutic approach to replace the use of corticosteroids alone. Topical calcineurin inhibitors Topical tacrolimus yields similar results to topical steroids. A study was performed by Silverberg et al. where patients with vitiligo were treated with tacrolimus 0.03% for children ages 2–15 years and tacrolimus 0.1% ointment for individuals 16 years
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or older, applied twice daily to all hypopigmented or depigmented lesions. Topical tacrolimus was effective for all skin tones and in all Fitzpatrick skin types, with superior efficacy on body lesions in individuals of Fitzpatrick types 3–4. Further, individuals with Fitzpatrick type 3–4 skin had shorter interval to greater than 75% improvement of lesions on the body, head, and neck. Recently, a study found that tacrolimus has better clinical efficacy during the active stages of vitiligo (20). Pimecrolimus, another calcineurin inhibitor, has been introduced for the treatment of nonsegmental vitiligo and it achieved more rapid repigmentation than topical steroids treatment (21). A pilot study done by Shim et al. (22) suggests that 1% pimecrolimus cream (twice daily for 3 months) is an effective and well-tolerated treatment for segmental childhood vitiligo. Tacrolimus 0.1% ointment and pimecrolimus 1% cream have defined roles in the treatment of vitiligo (23). Topical calcipotriol Vitamin D analogues have been used as monotherapy or in combination with phototherapy for the treatment of vitiligo. This possible mechanism prevents skin T cell infiltration (24), which is involved in the pathogenesis of vitiligo. However, the true effects of vitamin D analogues on vitiligo remain controversial.
Phototherapy and photochemotherapy Patients with extensive depigmentation may prefer treatment with light therapy because of the large surface area affected. Light therapies include: 1. oral or topical psoralens plus ultraviolet A radiation (PUVA), 2. narrowband ultraviolet B radiation (NB-UVB), 3. excimer laser. Ultraviolet (UV) radiation is considered the first line of therapy for vitiligo (25) that achieves partial repigmentation in 50–80% of patients (26). PUVA has long been a mainstay of treatment for vitiligo, but over the last decade NB-UVB has been increasing in use because of better repigmentation (27) and decreased incidence of phototoxic side effects (18,28). However, with both therapies, treatment may take many months, a year, or longer to
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achieve results (18,28,29). PUVA achieved a partial response in 60% of patients after a mean of 84.2 treatments (30). Patients treated with NB-UVB experienced a partial response at 4 weeks, but mean repigmentation was still less than 50% by 12 weeks (31). The 308 nm excimer laser is a newer treatment option, introduced in 2002, that can yield impressive results in an abbreviated timeframe (30). Nicolaidou et al. (29) reviewed the use of excimer laser and demonstrated that 15–50% of patients achieved greater than 75% repigmentation. Notably, excimer laser treatment periods were 15 weeks or less in the overwhelming majority of the studies analyzed (30). Additionally, there has been some evidence that excimer laser treatment causes faster, more complete repigmentation in patients with higher Fitzpatrick skin types (32,33). Evidence reveals that inactive melanocytes present in the outer sheaths of hair follicles are spared in individuals with vitiligo. Initiation of therapy then may induce maturation in these latent melanocytes followed by migration upwards along the hair follicle with ultimate dissemination in the epidermis (34). Perifollicular repigmentation in treated vitiligo and the fact that paucifollicular areas, such as the fingers and genitals, repigment poorly support this theory. There is some evidence that light treatments used in combination with topical agents improve outcomes (32).
PUVA The results of PUVA therapy vary considerably according to the site of vitiligo. The best results are obtained on the face, trunk, and proximal parts of extremities. PUVA treatments are used in combination with topical agents, such as calcipotriol, steroids, and tacrolimus.
NB-UVB Monotherapy with NB-UVB (311–312 nm) was introduced in 1997 as an effective treatment for generalized vitiligo, with better repigmentation and fewer adverse effects than PUVA (19). NB-UVB is considered as the first line of treatment for generalized vitiligo (8,9). Recently, a study found that hand-held NB-UVB phototherapy maybe feasible and effective for the treatment of vitiligo at home for patients with limited/early disease (37). Psoralen–NB-UVB is more efficacious than NB-UVB phototherapy, producing a greater percentage reduction in vitiligo area severity index scores and requiring a lesser cumulative dose and the response starts earlier (38). Afamelanotide is a potent and longer-lasting synthetic analogue of naturally occurring alpha-melanocyte stimulating hormone (α-MSH), which decreased in vitiligo, Grimes et al. (39) found that NB-UVB combined with afamelanotide is safe and effective and that afamelanotide represents a novel and potentially effective treatment for vitiligo, but still needs further studies. Treatment of localized nonsegmental vitiligo with intradermal 5-flurouracil (5-FU) injection combined with NB-UVB Intradermal 5-FU injection in combination with NB-UVB could be considered as a simple, safe, tolerable, and cheap technique for treatment of vitiligo. It shortens the duration of NB-UVB therapy and improves the outcome, repigmentation; except for acral lesions. Longer follow-up is needed. Despite those progresses, extremities and bony prominences remain usually resistant to all the current therapeutic approaches.
Broadband ultraviolet A (BB-UVA)
Effect of a preceding laser dermabrasion on the outcome of combined therapy of NB-UVB and potent topical steroid for treating nonsegmental vitiligo in resistant localizations
PUVA has been shown to be efficacious in the treatment of vitiligo, but when oral psoralens are contraindicated, what should we do next? A randomized controlled trial performed by El Mofty et al. (35) found that BB-UVA at a dose of 15 J/cm2 per session gives results for vitiligo that are comparable with PUVA, but still needs further studies. El-Mofty et al. (36) also found that BB-UVA was more effective than NB-UVB in the treatment of vitiligo. So BB-UVA may be considered as an alternative treatment line for vitiligo.
The laser-assisted dermabrasion significantly improves the repigmentation rate in vitiligo lesions when it precedes topical steroids associated with NB-UVB. Data concerning the combined used of topical steroid and UV on resistant extrafacial vitiligo are limited. The poor rate of repigmentation achieved in this study with this association stresses the need for further studies to assess the true interest of such a combination in those areas as compared with UV alone. Despite
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the high rate of repigmentation in such difficult areas, the high rate of side effects and the poor tolerance strongly limit its use in current practice.
Excimer laser Use of 308 nm excimer laser and topical calcipotriene in facial vitiligo The excimer laser has proved to be a useful tool in the treatment of vitiligo. Patients treated with excimer laser are achieving excellent results in a matter of a few months rather than many months to years. More data are needed to determine whether skin type, sex, or other hair follicle characteristics lend themselves to greater response to excimer therapy. Some research suggests that individuals with higher numerical Fitzpatrick skin type may respond to therapy more quickly and experience better outcomes than their lighter-skinned counterparts (32,33). The 308 nm excimer lamp and the 308 nm excimer laser exhibited similar efficacies in treating vitiligo (40).
Depigmentation Depigmentation therapy involves the removal of pigmented skin in a case of universal, extensive vitiligo. Q-switched laser therapy is more effective in patients with active vitiligo than patients with stable vitiligo and with no long-term side effects after a mean follow-up of 13 months (41), this study suggest for stable vitiligo, starting treatment as soon as possible when the vitiligo becomes active. Q-switched lasers should also be proposed as the first line of treatment when the surface that needs to be depigmented is limited in size (42). Q-switched neodymium-doped yttrium aluminium garnet (Nd : YAG) laser was quite effective and without any significant adverse effects in the treatment of universal vitiligo (43). Topical application of 20% monobenzyl ether of hydroquinone (MBEH) was also effective (44,45). Recently, a mouse model of vitiligo, successfully induced with MBEH, provided further evidence for MBEH to treatment of vitiligo (46). Psychological screening of vitiligo patients prior to initiating therapy is very important (44). Emotional instability, psychiatric instability, psychosis, suicidality, and fear of racial shifting must be excluded (44).
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Commentary Vitiligo is a condition caused by the destruction of melanocytes, resulting in areas of skin without pigmentation. The precise cause is still not known. Autoimmune, genetic, neural, self-destruction, growth factor deficiency, viral, and convergence theories may be the pathogenesis of vitiligo. There are many surgical and nonsurgical methods for the treatment of vitiligo. Nonsurgical treatment includes systemic therapy, topical medications, phototherapy, photochemotherapy, and combination therapies. Each treatment have certain indications and limitations. Oral medications are often used to control the development of vitiligo by immunosuppression or immune regulatory mechanisms. Levamisole, an immunomodulator and anthelmintic medication, may be used in the treatment of vitiligo because of its immunomodulatory function, but its adverse effects, such as myopathy and leukocytoclastic vasculitis, should be bear in mind. Potent topical steroids are considered first line of therapy for localized vitiligo. Topical tacrolimus and vitamin D yield similar results as topical steroids. Topical tacrolimus was found to be effective for all skin tones and in all Fitzpatrick skin types, with superior efficacy on body lesions in individuals of Fitzpatrick types 3–4. Further, individuals with Fitzpatrick type 3–4 skin had shorter interval to greater than 75% improvement of lesions on the body, head, and neck. Patients with extensive depigmentation may prefer treatment with light therapy because of the large surface area affected. PUVA has long been a mainstay of treatment for vitiligo, but when oral psoralens are contraindicated, BB-UVA may be an alternative therapy. But over the last decade, NB-UVB has been increasingly used because of better repigmentation and decreased incidence of phototoxic side effects. Hand-held NB-UVB phototherapy is more convenient to patients, but psoralen–NB-UVB is more efficacious than NB-UVB phototherapy. The surprisingly similar histochemical changes in response to PUVA in acral and nonacral lesions did not manifest with clinical repigmentation except in nonacral ones. Factors, such as inherent lower melanocyte density, lower melanocyte stem cell reservoirs, and/or lower baseline epidermal stem cell factor, may be considered as possible playmakers in this respect. NB-UVB is considered as the first line of treatment for generalized vitiligo. Combination approaches with several sources of UV and topical tacrolimus or pimecrolimus, or topical steroids, improved the
Vitiligo nonsurgical treatment
rate of repigmentation. Intradermal 5-FU injection in combination with NB-UVB could be considered as a simple, safe, tolerable, and cheap technique for treatment of vitiligo. It shortens the duration of NB-UVB therapy and improves the outcome and repigmentation except for acral lesions. Longer follow-up is needed. Despite those progresses, extremities and bony prominences remain usually resistant to all the current therapeutic approaches. Laser-assisted dermabrasion significantly improves the repigmentation rate in vitiligo lesions when it precedes topical steroids associated with NB-UVB. The excimer laser can induce repigmentation in an abbreviated timeframe without global exposure to radiation. The use of 308 nm excimer laser and topical calcipotriene in facial vitiligo showed greater than 75% repigmentation of facial lesions between 10 and 20 weeks. Certain areas are known to resist repigmentation, including hands and feet, lip-tip vitiligo, association with leucotrichia, and segmental vitiligo. Few reasons for resistance of the acral areas were suggested. The most popular theory is the relatively lower density or absence of pilosebaceous follicles, the reservoirs from which the melanocytes migrate. Relatively, less melanocyte density as well as higher chances of koebnerization over these friction and injury-prone anatomical sites may be another possible mechanism. Inactivated Notch-1 signaling in vitiliginous white hair and acral and segmental vitiligo consequent loss of epidermal and/or follicular active melanocytes may be the cause of their treatment resistance (47). Vitiligo potential repigmentation index (PRI) was introduced to assess the ability of vitiligo lesions to repigment under therapy (48), in patients with a higher PRI value, total body NB-UVB therapy has the best therapeutic effect, but lower PRI will probably not respond globally to repigmentation. For patients with universal, extensive vitiligo, depigmentation treatment rather than regimentation therapy was selected. Q-switched laser and Q-switched Nd : YAG laser are both quite effective and without any significant adverse effects in the depigmentation treatment of universal vitiligo, but for patients with active vitiligo, Q-switched laser is more effective. A variety of nonsurgical treatment regimens are currently employed in vitiligo. They aid to repigmentation or depigmentation of the skin; however, many of them require a prolonged treatment course and may yield minimal results as well
as carry unwanted side effects. Future goals should include developing strategies of treatment that do not require continuous, long-term drug applications i.e., to derive a better understanding of the specific antigenic triggers that may induce and sustain T cell activity in focal skin lesions. The progressive refinement of immune-targeted therapeutics, which has been enabled by the scientific studies of psoriasis, has now resulted in the ability to control most clinical disease signs and symptoms of psoriasis. Vitiligo and psoriasis vulgaris are both T cell-mediated autoimmune diseases. Hopefully, the approach taken to psoriasis pathogenic dissection and treatment will be a model for the approach to vitiligo.
Conflict of interest The authors have no conflict of interest to declare.
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Zhang et al. 13. Kanwar AJ, Mahajan R, Parsad D. Low-dose oral mini-pulse dexamethasone therapy in progressive unstable vitiligo. J Cutan Med Surg 2013: 17 (4): 259–268. 14. Bin Dayel S, AlGhamdi K. Failure of alefacept in the treatment of vitiligo. J Drugs Dermatol 2013: 12 (2): 159– 161. 15. Gawkrodger DJ, Ormerod AD, Shaw L, et al. Guideline for the diagnosis and management of vitiligo. Br J Dermatol 2008: 159: 1051–1076. 16. Whitton ME, Ashcroft DM, Gonzalez U. Therapeutic interventions for vitiligo. J Am Acad Dermatol 2008: 59: 713– 717. 17. Sanclemente G, Garcia JJ, Zuleta JJ, Diehl C, Correa C, Falabella R. A double-blind, randomized trial of 0.05% betamethasone vs. topical catalase/dismutase superoxide in vitiligo. J Eur Acad Dermatol Venereol 2008: 22 (11): 1359– 1364. 18. Parsad D, Kanwar AJ, Kumar B. Psoralen-ultraviolet A vs. narrow-band ultraviolet B phototherapy for the treatment of vitiligo. J Eur Acad Dermatol Venereol 2006: 20 (2): 175– 177. 19. Kwon HB, Choi Y, Kim HJ, Lee AY. The therapeutic effects of a topical tretinoin and corticosteroid combination for vitiligo: a placebo-controlled, paired-comparison, left-right study. J Drugs Dermatol 2013: 12 (4): e63–e67. 20. Du J, Wang XY, Ding XL, et al. Long-term efficacy and safety of tacrolimus ointment in the treatment of vitiligo. J Dermatol 2013: 40 (11): 935–936. 21. Choi CW, Chang SE, Bak H, et al. Topical immunomodulators are effective for treatment of vitiligo. J Dermatol 2008: 35: 503–507. 22. Shim WH, Suh SW, Jwa SW, et al. A pilot study of 1% pimecrolimus cream for the treatment of childhood segmental vitiligo. Ann Dermatol 2013: 25 (2): 168– 172. 23. Wong R, Lin AN. Efficacy of topical calcineurin inhibitors in vitiligo. Int J Dermatol 2013: 52 (4): 491–496. 24. Yamanaka KI, Kakeda M, Kitagawa H, et al. 1,24Dihydroxyvitamin D3 (tacalcitol) prevents skin T-cell infiltration. Br J Dermatol 2010: 162 (6): 1206–1215. 25. Falabella R, Barona MI. Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res 2008: 22: 42–65. 26. Vussuki E, Ziv M, Rosenman D, David M. [Long-term effects of PUVA therapy on Israeli patients with vitiligo]. Harefuah 2006: 145: 483–485. 27. Westerhof W, Nieuweboer-Krobotova L. Treatment of vitiligo with UV-B radiation vs topical psoralen plus UV-A. Arch Dermatol 1997: 133 (12): 1525–1528. 28. Bhatnagar A, Kanwar AJ, Parsad D, De D. Comparison of systemic PUVA and NB-UVB in the treatment of vitiligo: an open prospective study. J Eur Acad Dermatol Venereol 2007: 21 (5): 638–642. 29. Nicolaidou E, Antoniou C, Stratigos A, Katsambas AD. Narrowband ultraviolet B phototherapy and 308-nm excimer laser in the treatment of vitiligo: a review. J Am Acad Dermatol 2009: 60 (3): 470–477. 30. Falabella R, Barona MI. Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res 2009: 22 (1): 42–65. 31. Klahan S, Asawanonda P. Topical tacrolimus may enhance repigmentation with targeted narrowband ultraviolet B to treat vitiligo: a randomized, controlled study. Clin Exp Dermatol 2009: 34 (8): e1029–e1030.
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32. Kawalek AZ, Spencer JM, Phelps RG. Combined excimer laser and topical tacrolimus for the treatment of vitiligo: a pilot study. Dermatol Surg 2004: 30 (2 Pt 1): 130–135. 33. Goldinger SM, Dummer R, Schmid P, Burg G, Seifert B, Läuchli S. Combination of 308-nm xenon chloride excimer laser and topical calcipotriol in vitiligo. J Eur Acad Dermatol Venereol 2007: 21 (4): 504–508. 34. Cui J, Shen LY, Wang GC. Role of hair follicles in the repigmentation of vitiligo. J Invest Dermatol 1991: 97 (3): 410–416. 35. El Mofty M, Bosseila M, Mashaly HM, Gawdat H, Makaly H. Broadband ultraviolet A vs. psoralen ultraviolet A in the treatment of vitiligo: a randomized controlled trial. Clin Exp Dermatol 2013: 38 (8): 830–835. 36. El-Mofty M, Mostafa W, Youssef R, et al. BB-UVA vs. NB-UVB in the treatment of vitiligo: a randomized controlled clinical study (single blinded). Photodermatol Photoimmunol Photomed 2013: 29 (5): 239–246. 37. Eleftheriadou V, Thomas K, Ravenscroft J, Whitton M, Batchelor J, Williams H. Feasibility, double-blind, randomised, placebo-controlled, multi-centre trial of handheld NB-UVB phototherapy for the treatment of vitiligo at home (HI-Light trial: Home Intervention of Light therapy). Trials 2014: 15: 51. 38. Bansal S, Sahoo B, Garg V. Psoralen-narrowband UVB phototherapy for the treatment of vitiligo in comparison to narrowband UVB alone. Photodermatol Photoimmunol Photomed 2013: 29 (6): 311–317. 39. Grimes PE, Hamzavi I, Lebwohl M, Ortonne JP, Lim HW. The efficacy of afamelanotide and narrowband UV-B phototherapy for repigmentation of vitiligo. JAMA Dermatol 2013: 149 (1): 68–73. 40. Shi Q, Li K, Fu J, et al. Comparison of the 308-nm excimer laser with the 308-nm excimer lamp in the treatment of vitiligo – a randomized bilateral comparison study. Photodermatol Photoimmunol Photomed 2013: 29: 27– 33. 41. Komen L, Zwertbroek L, Burger SJ, van der Veen JP, de Rie MA, Wolkerstorfer A. Q-switched laser depigmentation in vitiligo, most effective in active disease. Br J Dermatol 2013: 169 (6): 1246–1251. 42. Boukari F, Lacour JP, Ortonne JP, Bahadoran P, Passeron T. Laser-assisted depigmentation for resistant vitiligo: a retrospective case series with long-term follow-up. J Eur Acad Dermatol Venereol 2014: 28 (3): 374–377. 43. Majid I, Imran S. Depigmentation therapy with Q-switched Nd: YAG laser in universal vitiligo. J Cutan Aesthet Surg 2013: 6 (2): 93–96. 44. Grau C, Silverberg NB. Vitiligo patients seeking depigmentation therapy: a case report and guidelines for psychological screening. Cutis 2013: 91 (5): 248–252. 45. Rordam OM, Lenouvel EW, Maalo M. Successful treatment of extensive vitiligo with monobenzone. J Clin Aesthet Dermatol 2012: 5 (12): 36–39. 46. Zhu Y, Wang S, Xu A. A mouse model of vitiligo induced by monobenzone. Exp Dermatol 2013: 22 (7): 499–501. 47. Seleit I, Bakry OA, Abdou AG, Dawoud NM. Immunohistochemical expression of aberrant Notch-1 signaling in vitiligo: an implication for pathogenesis. Ann Diagn Pathol 2014: 18 (3): 117–124. 48. Benzekri L, Ezzedine K, Gauthier Y. Vitiligo Potential Repigmentation Index: a simple clinical score that might predict the ability of vitiligo lesions to repigment under therapy. Br J Dermatol 2013: 168 (5): 1143–1146.
© 2014 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
REVIEW ARTICLE
Vitiligo nonsurgical treatment: a review of latest treatment researches Yanfei Zhang, Jessini Soranambal Mooneyan-Ramchurn, Nan Zuo, Yiguo Feng & Shengxiang Xiao Department of Dermatology, The Second Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
ABSTRACT: Vitiligo is a common depigmenting acquired disorder affecting about 1–2% of the world population, regardless of race, ethnic background, or gender. It is characterized by the appearance of milky white maculae because of a loss of melanocytes. The disfiguring nature of vitiligo causes high psychosocial morbidity. This is especially pronounced in populations with darker skin tone, likely because of the marked contrast. A variety of nonsurgical treatment regimens are currently employed in vitiligo. We reviewed the latest studies carried out on different nonsurgical treatment modalities used in vitiligo. All nonsurgical treatment aid to repigment or depigmentation the skin, however, many of them require a prolonged treatment course and may yield minimal results as well as carry unwanted side effects. There is a need for further research into the causes of vitiligo and into discovering better treatments. KEYWORDS: nonsurgical treatment, treatment, vitiligo
Background Vitiligo is a common depigmenting acquired disorder affecting about 1–2% of the world population, regardless of race, ethnic background, or gender. Approximately, 50% of the affected individuals develop the disease before the age of 20 (1) and about 25% prior to the age of 8 (2). The mean age of the onset of childhood vitiligo had been found to be between 4 and 5 years (2). It is characterized by the appearance of milky white maculae because of a loss of melanocytes (3). Studies have demonstrated that the disfiguring nature of vitiligo causes Address correspondence and reprint requests to: Feng Yiguo and Xiao Shengxiang, MD, PhD, Professors, The Second Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an 710004, Shaanxi Province, China, or email: [email protected] and [email protected].
high psychosocial morbidity (4–6). This is especially pronounced in populations with darker skin tone, likely because of the marked contrast (4,7). A variety of nonsurgical treatment regimens are currently employed in vitiligo. Here, we reviewed the latest studies carried out on nonsurgical treatment modalities used in vitiligo.
System administration Vitamin D deficiency or insufficiency had been demonstrated to be associated with almost all vitiligo patients (8). A pilot study done by Finamor et al. (9) found that daily dose of 35,000 IU of vitamin D was a safe and effective therapeutic approach for vitiligo. Methotrexate (MTX) is used in the treatment of autoimmune diseases to decrease the number of
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T cells capable of tumor necrosis factor α (TNFα) production, which is a key step in the development of vitiligo (10). Alghamdi and Khurrum’s (11) studies found that oral MTX (25 mg dose per week) was a safe and effective therapeutic approach for vitiligo, but because of the small uncontrolled pilot study, further research need to be carried out. Levamisole can be used as an immunomodifier for an effective treatment of vitiligo, 160 mg of levamisole weekly is safe and effective (12). In a retrospective study, low-dose oral minipulse dexamethasone (2.5 mg per day) is safe and effective for arresting progressive unstable vitiligo (13). Studies have shown that vitiligo appears to be an autoimmune disease involving T cell-mediated melanocyte destruction. Intramuscular injections of 15 mg alefacept (a fusion protein that blocks the growth of some types of T cells) for 12 weeks in four adult patients with widespread vitiligo did not show any repigmentation after 24 weeks follow-up. As a result of a small number of patients in the pilot study, further evaluation in larger studies may be required (14).
Topical therapy Topical steroids Potent topical steroids are considered first line therapy for localized vitiligo (15,16). These rarely achieve more than 50–75% repigmentation and are cumbersome, requiring multiple daily applications. They may require a year or more to note significant improvement (17,18). Less than 50% of patients achieve greater than 75% repigmentation after 10 months of therapy (17). Long-term use of topical corticosteroids can induce skin atrophy, but tretinoin can prevent this side effect, a placebocontrolled, paired-comparison, left-right study found that combined therapy with tretinoin plus topical corticosteroids is safe and effective for treatment of patients with vitiligo (19). It may be a new therapeutic approach to replace the use of corticosteroids alone. Topical calcineurin inhibitors Topical tacrolimus yields similar results to topical steroids. A study was performed by Silverberg et al. where patients with vitiligo were treated with tacrolimus 0.03% for children ages 2–15 years and tacrolimus 0.1% ointment for individuals 16 years
2
or older, applied twice daily to all hypopigmented or depigmented lesions. Topical tacrolimus was effective for all skin tones and in all Fitzpatrick skin types, with superior efficacy on body lesions in individuals of Fitzpatrick types 3–4. Further, individuals with Fitzpatrick type 3–4 skin had shorter interval to greater than 75% improvement of lesions on the body, head, and neck. Recently, a study found that tacrolimus has better clinical efficacy during the active stages of vitiligo (20). Pimecrolimus, another calcineurin inhibitor, has been introduced for the treatment of nonsegmental vitiligo and it achieved more rapid repigmentation than topical steroids treatment (21). A pilot study done by Shim et al. (22) suggests that 1% pimecrolimus cream (twice daily for 3 months) is an effective and well-tolerated treatment for segmental childhood vitiligo. Tacrolimus 0.1% ointment and pimecrolimus 1% cream have defined roles in the treatment of vitiligo (23). Topical calcipotriol Vitamin D analogues have been used as monotherapy or in combination with phototherapy for the treatment of vitiligo. This possible mechanism prevents skin T cell infiltration (24), which is involved in the pathogenesis of vitiligo. However, the true effects of vitamin D analogues on vitiligo remain controversial.
Phototherapy and photochemotherapy Patients with extensive depigmentation may prefer treatment with light therapy because of the large surface area affected. Light therapies include: 1. oral or topical psoralens plus ultraviolet A radiation (PUVA), 2. narrowband ultraviolet B radiation (NB-UVB), 3. excimer laser. Ultraviolet (UV) radiation is considered the first line of therapy for vitiligo (25) that achieves partial repigmentation in 50–80% of patients (26). PUVA has long been a mainstay of treatment for vitiligo, but over the last decade NB-UVB has been increasing in use because of better repigmentation (27) and decreased incidence of phototoxic side effects (18,28). However, with both therapies, treatment may take many months, a year, or longer to
Vitiligo nonsurgical treatment
achieve results (18,28,29). PUVA achieved a partial response in 60% of patients after a mean of 84.2 treatments (30). Patients treated with NB-UVB experienced a partial response at 4 weeks, but mean repigmentation was still less than 50% by 12 weeks (31). The 308 nm excimer laser is a newer treatment option, introduced in 2002, that can yield impressive results in an abbreviated timeframe (30). Nicolaidou et al. (29) reviewed the use of excimer laser and demonstrated that 15–50% of patients achieved greater than 75% repigmentation. Notably, excimer laser treatment periods were 15 weeks or less in the overwhelming majority of the studies analyzed (30). Additionally, there has been some evidence that excimer laser treatment causes faster, more complete repigmentation in patients with higher Fitzpatrick skin types (32,33). Evidence reveals that inactive melanocytes present in the outer sheaths of hair follicles are spared in individuals with vitiligo. Initiation of therapy then may induce maturation in these latent melanocytes followed by migration upwards along the hair follicle with ultimate dissemination in the epidermis (34). Perifollicular repigmentation in treated vitiligo and the fact that paucifollicular areas, such as the fingers and genitals, repigment poorly support this theory. There is some evidence that light treatments used in combination with topical agents improve outcomes (32).
PUVA The results of PUVA therapy vary considerably according to the site of vitiligo. The best results are obtained on the face, trunk, and proximal parts of extremities. PUVA treatments are used in combination with topical agents, such as calcipotriol, steroids, and tacrolimus.
NB-UVB Monotherapy with NB-UVB (311–312 nm) was introduced in 1997 as an effective treatment for generalized vitiligo, with better repigmentation and fewer adverse effects than PUVA (19). NB-UVB is considered as the first line of treatment for generalized vitiligo (8,9). Recently, a study found that hand-held NB-UVB phototherapy maybe feasible and effective for the treatment of vitiligo at home for patients with limited/early disease (37). Psoralen–NB-UVB is more efficacious than NB-UVB phototherapy, producing a greater percentage reduction in vitiligo area severity index scores and requiring a lesser cumulative dose and the response starts earlier (38). Afamelanotide is a potent and longer-lasting synthetic analogue of naturally occurring alpha-melanocyte stimulating hormone (α-MSH), which decreased in vitiligo, Grimes et al. (39) found that NB-UVB combined with afamelanotide is safe and effective and that afamelanotide represents a novel and potentially effective treatment for vitiligo, but still needs further studies. Treatment of localized nonsegmental vitiligo with intradermal 5-flurouracil (5-FU) injection combined with NB-UVB Intradermal 5-FU injection in combination with NB-UVB could be considered as a simple, safe, tolerable, and cheap technique for treatment of vitiligo. It shortens the duration of NB-UVB therapy and improves the outcome, repigmentation; except for acral lesions. Longer follow-up is needed. Despite those progresses, extremities and bony prominences remain usually resistant to all the current therapeutic approaches.
Broadband ultraviolet A (BB-UVA)
Effect of a preceding laser dermabrasion on the outcome of combined therapy of NB-UVB and potent topical steroid for treating nonsegmental vitiligo in resistant localizations
PUVA has been shown to be efficacious in the treatment of vitiligo, but when oral psoralens are contraindicated, what should we do next? A randomized controlled trial performed by El Mofty et al. (35) found that BB-UVA at a dose of 15 J/cm2 per session gives results for vitiligo that are comparable with PUVA, but still needs further studies. El-Mofty et al. (36) also found that BB-UVA was more effective than NB-UVB in the treatment of vitiligo. So BB-UVA may be considered as an alternative treatment line for vitiligo.
The laser-assisted dermabrasion significantly improves the repigmentation rate in vitiligo lesions when it precedes topical steroids associated with NB-UVB. Data concerning the combined used of topical steroid and UV on resistant extrafacial vitiligo are limited. The poor rate of repigmentation achieved in this study with this association stresses the need for further studies to assess the true interest of such a combination in those areas as compared with UV alone. Despite
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Zhang et al.
the high rate of repigmentation in such difficult areas, the high rate of side effects and the poor tolerance strongly limit its use in current practice.
Excimer laser Use of 308 nm excimer laser and topical calcipotriene in facial vitiligo The excimer laser has proved to be a useful tool in the treatment of vitiligo. Patients treated with excimer laser are achieving excellent results in a matter of a few months rather than many months to years. More data are needed to determine whether skin type, sex, or other hair follicle characteristics lend themselves to greater response to excimer therapy. Some research suggests that individuals with higher numerical Fitzpatrick skin type may respond to therapy more quickly and experience better outcomes than their lighter-skinned counterparts (32,33). The 308 nm excimer lamp and the 308 nm excimer laser exhibited similar efficacies in treating vitiligo (40).
Depigmentation Depigmentation therapy involves the removal of pigmented skin in a case of universal, extensive vitiligo. Q-switched laser therapy is more effective in patients with active vitiligo than patients with stable vitiligo and with no long-term side effects after a mean follow-up of 13 months (41), this study suggest for stable vitiligo, starting treatment as soon as possible when the vitiligo becomes active. Q-switched lasers should also be proposed as the first line of treatment when the surface that needs to be depigmented is limited in size (42). Q-switched neodymium-doped yttrium aluminium garnet (Nd : YAG) laser was quite effective and without any significant adverse effects in the treatment of universal vitiligo (43). Topical application of 20% monobenzyl ether of hydroquinone (MBEH) was also effective (44,45). Recently, a mouse model of vitiligo, successfully induced with MBEH, provided further evidence for MBEH to treatment of vitiligo (46). Psychological screening of vitiligo patients prior to initiating therapy is very important (44). Emotional instability, psychiatric instability, psychosis, suicidality, and fear of racial shifting must be excluded (44).
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Commentary Vitiligo is a condition caused by the destruction of melanocytes, resulting in areas of skin without pigmentation. The precise cause is still not known. Autoimmune, genetic, neural, self-destruction, growth factor deficiency, viral, and convergence theories may be the pathogenesis of vitiligo. There are many surgical and nonsurgical methods for the treatment of vitiligo. Nonsurgical treatment includes systemic therapy, topical medications, phototherapy, photochemotherapy, and combination therapies. Each treatment have certain indications and limitations. Oral medications are often used to control the development of vitiligo by immunosuppression or immune regulatory mechanisms. Levamisole, an immunomodulator and anthelmintic medication, may be used in the treatment of vitiligo because of its immunomodulatory function, but its adverse effects, such as myopathy and leukocytoclastic vasculitis, should be bear in mind. Potent topical steroids are considered first line of therapy for localized vitiligo. Topical tacrolimus and vitamin D yield similar results as topical steroids. Topical tacrolimus was found to be effective for all skin tones and in all Fitzpatrick skin types, with superior efficacy on body lesions in individuals of Fitzpatrick types 3–4. Further, individuals with Fitzpatrick type 3–4 skin had shorter interval to greater than 75% improvement of lesions on the body, head, and neck. Patients with extensive depigmentation may prefer treatment with light therapy because of the large surface area affected. PUVA has long been a mainstay of treatment for vitiligo, but when oral psoralens are contraindicated, BB-UVA may be an alternative therapy. But over the last decade, NB-UVB has been increasingly used because of better repigmentation and decreased incidence of phototoxic side effects. Hand-held NB-UVB phototherapy is more convenient to patients, but psoralen–NB-UVB is more efficacious than NB-UVB phototherapy. The surprisingly similar histochemical changes in response to PUVA in acral and nonacral lesions did not manifest with clinical repigmentation except in nonacral ones. Factors, such as inherent lower melanocyte density, lower melanocyte stem cell reservoirs, and/or lower baseline epidermal stem cell factor, may be considered as possible playmakers in this respect. NB-UVB is considered as the first line of treatment for generalized vitiligo. Combination approaches with several sources of UV and topical tacrolimus or pimecrolimus, or topical steroids, improved the
Vitiligo nonsurgical treatment
rate of repigmentation. Intradermal 5-FU injection in combination with NB-UVB could be considered as a simple, safe, tolerable, and cheap technique for treatment of vitiligo. It shortens the duration of NB-UVB therapy and improves the outcome and repigmentation except for acral lesions. Longer follow-up is needed. Despite those progresses, extremities and bony prominences remain usually resistant to all the current therapeutic approaches. Laser-assisted dermabrasion significantly improves the repigmentation rate in vitiligo lesions when it precedes topical steroids associated with NB-UVB. The excimer laser can induce repigmentation in an abbreviated timeframe without global exposure to radiation. The use of 308 nm excimer laser and topical calcipotriene in facial vitiligo showed greater than 75% repigmentation of facial lesions between 10 and 20 weeks. Certain areas are known to resist repigmentation, including hands and feet, lip-tip vitiligo, association with leucotrichia, and segmental vitiligo. Few reasons for resistance of the acral areas were suggested. The most popular theory is the relatively lower density or absence of pilosebaceous follicles, the reservoirs from which the melanocytes migrate. Relatively, less melanocyte density as well as higher chances of koebnerization over these friction and injury-prone anatomical sites may be another possible mechanism. Inactivated Notch-1 signaling in vitiliginous white hair and acral and segmental vitiligo consequent loss of epidermal and/or follicular active melanocytes may be the cause of their treatment resistance (47). Vitiligo potential repigmentation index (PRI) was introduced to assess the ability of vitiligo lesions to repigment under therapy (48), in patients with a higher PRI value, total body NB-UVB therapy has the best therapeutic effect, but lower PRI will probably not respond globally to repigmentation. For patients with universal, extensive vitiligo, depigmentation treatment rather than regimentation therapy was selected. Q-switched laser and Q-switched Nd : YAG laser are both quite effective and without any significant adverse effects in the depigmentation treatment of universal vitiligo, but for patients with active vitiligo, Q-switched laser is more effective. A variety of nonsurgical treatment regimens are currently employed in vitiligo. They aid to repigmentation or depigmentation of the skin; however, many of them require a prolonged treatment course and may yield minimal results as well
as carry unwanted side effects. Future goals should include developing strategies of treatment that do not require continuous, long-term drug applications i.e., to derive a better understanding of the specific antigenic triggers that may induce and sustain T cell activity in focal skin lesions. The progressive refinement of immune-targeted therapeutics, which has been enabled by the scientific studies of psoriasis, has now resulted in the ability to control most clinical disease signs and symptoms of psoriasis. Vitiligo and psoriasis vulgaris are both T cell-mediated autoimmune diseases. Hopefully, the approach taken to psoriasis pathogenic dissection and treatment will be a model for the approach to vitiligo.
Conflict of interest The authors have no conflict of interest to declare.
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