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Australasian Journal of Dermatology (2014) ••, ••–••
doi: 10.1111/ajd.12256
REVIEW ARTICLE
Vitiligo treatment update Benjamin S Daniel1 and Richard Wittal1,2 1
University of New South Wales, and 2Skin and Cancer Foundation, Sydney, New South Wales, Australia
ABSTRACT Vitiligo is a common depigmenting disease that can affect the skin and mucosal surfaces. Various treatments have been used over the years with varying repigmentation rates. This review looks at the evidence of commonly used therapies for vitiligo.
Table 1 Classification of vitiligo according to the Vitiligo Global Issues Consensus Conference (adapted from Ezzedine and colleagues2) Vitiligo or non-segmental vitiligo Acrofacial Mucosal Generalised Universal
Key words: management, treatment, vitiligo.
INTRODUCTION Vitiligo is a common acquired depigmenting skin disease affecting about 0.5 to 2% of the population.1 The treatment of vitiligo varies between countries, depending on the patients’ skin type and access to treatments and facilities. This review looks at the treatments for vitiligo and the evidence supporting their use. According to the 2012 classification and consensus nomenclature,2 there are three main types of vitiligo; namely, non-segmental vitiligo (NSV), segmental vitiligo and undetermined/unclassified vitiligo (Table 1). The term vitiligo includes the acrofacial, mucosal, generalised and mixed subtypes. The common differential diagnoses are listed in Table 2.
Quality of life (QoL) Vitiligo has a significant impact on QoL, affecting activities of daily living and personal relationships. Psychological counselling and support is necessary in the management of vitiligo, no matter how severe the disease. The effect on QoL is not directly proportionate to the extent of the disease and patients often worry that the disease will progress. Depression is common, affecting more than 50% of patients with vitiligo, especially single patients or women in the early years of the disease.3 Pre-existing low self-
Mixed Rare variants Segmental vitiligo Uni-segmental, bi-segmental or pluri-segmental Undetermined/unclassified vitiligo Focal Mucosal
More than one mucosal site affected Complete or almost complete depigmentation of skin/hair Combination of SV and NSV
Often follows a dermatomal or blaschkoid pattern Small localised macules that are not segmental or NSV One mucosal site affected
NSV, non-segmental vitiligo; SV, segmental vitiligo.
esteem, impaired self-perception, poor coping methods and inadequate social support contribute to the psychological impact of the disease.4 Due to time constraints, however, it may be appropriate for dermatologists to acknowledge the psychological impact of the disease by referring patients to a psychologist or counsellor who can address both the subjective and objective factors of the condition. Various therapeutic regimens impact on a patient’s QoL and should be considered when choosing an appropriate treatment.5 Patient support groups are an important avenue through which patients may find information about the disease and meet others with the same condition. The Vitiligo Association of Australia (www.vitiligo.org.au)6 is an active support group set up in 2010 to support patients and families with vitiligo. It has state branches which meet regularly and is associated with international vitiligo patient support groups.
Abbreviations: Correspondence: Dr Richard Wittal, University of New South Wales, Sydney, NSW, Australia. Email: [email protected] Benjamin S. Daniel, MBBS. Richard Wittal, FACD. Conflict of interest: none Submitted 29 August 2013; accepted 16 August 2014. © 2014 The Australasian College of Dermatologists
MBEH QoL RCT TCS TNF
monobenzyl ether of hydroquinone quality of life randomised controlled trial topical corticosteroids tumour necrosis factor
2 Table 2
BS Daniel and R Wittal Differential diagnoses for vitiligo
Pityriasis versicolor Idiopathic guttate hypomelanosis Tuberous sclerosis Piebaldism Discoid or systemic lupus erythematosus Sarcoidosis Scleroderma Post-inflammatory hypopigmentation/depigmentation: e.g. atopic dermatitis, psoriasis Post-traumatic depigmentation (e.g. scars, burns) Progressive macular hypomelanosis Cutaneous T-cell lymphoma Leprosy Pityriasis alba Melasma Naevus anemicus, naevus depigmentosus, halo naevus Leucoderma of variable causes: for example post-traumatic, melanoma associated leucoderma Amelanotic melanoma Lichen sclerosus et atrophicus Topical or drug-induced depigmentation
steroids but have a safer side-effect profile.14,15 Patients with vitiligo have greater amounts of interleukin -10, interferon-γ and tumour necrosis factor (TNF)-α in their skin compared to controls. Topical tacrolimus stimulates melanocyte growth and reduces TNF-α levels, resulting in repigmentation.16 It is particularly effective on the face and neck and when used in combination with phototherapy or occlusive dressings. It should be applied twice a day for a minimum of 6 months.17 The cost of topical tacrolimus usually limits its use in widespread disease.18–20 Unlike in other countries, most of the tacrolimus available in Australia has to be compounded in 0.03% and 0.1% concentrations. The quality and efficacy of the product is therefore variable, depending on the compounding pharmacists.
Topical vitamin D3 analogues Calcipotriol is effective when used in combination with TCS, especially in difficult-to-treat areas such as the eyelids.21,22 It is unknown if there is any significant advantage of using calcipotriol with phototherapy.23–25
Camouflage
Antioxidants
Cosmetic and tanning products conceal the patchiness of depigmented skin and improve the patients’ self-confidence and QoL. Camouflage does not treat the underlying disease and will not induce repigmentation. It is offered as conservative therapy for patients who do not wish to have treatment.7
Oxidative stress and free radicals are thought to play a role in the pathogenesis of vitiligo, with elevated levels of hydrogen peroxide in the epidermis of vitiliginous skin. Current studies are evaluating the evidence and safety of these antioxidants, including the naturally occurring glutathione. (Table 3) The evidence supporting the combination of some antioxidants with phototherapy is poor. An Australian randomised controlled trial (RCT) and other trials have failed to show any benefit in adding pseudocatalase to NBUVB.26,27 There is no additional benefit in applying topical superoxide dismutase to phototherapy alone.28 Topical steroids in the form of 0.05% betamethasone may be just as effective as topical catalase or dismutase superoxide in vitiligo.29 The combination of Polypodium leucotomos with NBUVB resulted in a higher rate of repigmentation than a placebo in the head and neck, especially in light-skinned individuals.30 An Italian RCT treated 35 patients with non-segmental vitiligo with NBUVB plus either oral antioxidants (two tablets which contained α-lipoic acid, vitamin C, vitamin E, polyunsaturated fatty acids and cysteine monohydrate) or placebo.31 A similar formulation is not currently available in Australia. After 2 months the treatment group had a statistically significant increased rate of catalase activity and reactive oxygen species production than the placebo group. At 6 months significant repigmentation was evident in 47% of those with antioxidants compared to 18% in the placebo group. Recent evidence suggests minocycline has antioxidant effects and may be potentially beneficial in vitiligo.35,36
MEDICAL THERAPIES Topical and oral corticosteroids Topical corticosteroids (TCS) are used as first-line therapy as monotherapy (e.g. in localised vitiligo), or in combination with phototherapy or other topical agents (e.g. in generalised vitiligo).8 Commonly prescribed TCS include betamethasone dipropionate, clobetasol dipropionate and mometasone furoate. Because of adverse effects and tachyphylaxis, TCS should not be used for longer than 3 months and steroid holidays should be encouraged.9,10 Sideeffects are generally not noticed with short bursts of TCS. Systemic corticosteroids halt disease progression and induce repigmentation when used at the onset or early stages of disease, in some cases resulting in complete repigmentation.11,12 Short pulses of systemic corticosteroids are used in international centres without long-term sideeffects. To stabilise rapidly expanding lesions within 1–4 months, an oral mini-pulse with dexamethasone 5–10 mg for 2 days per week (the equivalent of prednisolone 25–35 mg on Saturday and Sunday) can be used. This can be combined with NBUVB.13
Calcineurin inhibitors
Immunosuppressive agents
Tacrolimus and pimecrolimus, as monotherapy or in combination with phototherapy, are just as effective as topical
Despite its autoimmune nature, immunosuppressive therapies have not been shown to be significantly beneficial.
© 2014 The Australasian College of Dermatologists
Therapies for vitiligo Table 3
3
Evidence of antioxidants in vitiligo
Pseudocatalase
Superoxide dismutase and topical catalase or dismutase superoxide Polypodium leucotomos
Antioxidants (containing lipoic acid, vitamin C, vitamin E, polyunsaturated fatty acids and cysteine monohydrate)
Khellin
Phenylalanine
There are conflicting reports of the beneficial use of pseudocatalase, though RCTs, including an Australian study, have shown no additional benefit of pseudocatalase compared to NBUVB alone26,27 No proven benefit28,29
A RCT comparing Polypodium leucotomos with NBUVB to placebo found greater repigmentation in the head and neck area in light-skinned patients than in those exposed to the antioxidant30 RCT compared the NBUVB plus either oral antioxidants or placebo. After 2 months, the treatment group had a statistically significant increased rate of catalase activity and reactive oxygen species production than the placebo group. At 6 months, significant repigmentation was evident in 47% of those with antioxidants compared to 18% in the placebo group31 Used in systemic or topical forms in combination with UVA. It has comparable repigmentation rates as that of psoralens but with less phototoxicity32,33 Induces some repigmentation when used with UVA, though there are safety concerns over excess phenylalanine34
RCT, randomised controlled trial.
There are individual case reports of improvement with methotrexate37 and i.v. immunoglobulin,38 though a pilot study of methotrexate 25 mg/week for 6 months in six patients with generalised vitiligo failed to show any clinical improvement.39 Low-dose azathioprine is beneficial,40 with greater repigmentation after 4 months with azathioprine (0.6– 0.75 mg/kg/day) + PUVA than in PUVA alone (58 vs 25%, P < 0.001). RCT assessing cyclosporine and cyclophosphamide are lacking.41 One report indicated one of six patients treated with cyclosporine 6 mg/kg42 had a minimal to moderate response, while another case report reported some repigmentation on the face and forearms of a patient with pemphigus vulgaris treated with combination dexamethasone and cyclophosphamide pulse therapy.43 Vitiligo seems to have a protective benefit against melanoma and non-melanoma skin cancers. A large cohort study found the risk of melanoma and non-melanoma skin cancer was less than one-third that of patients without vitiligo.44
Figure 1 Previously depigmented area now shows follicular repigmentation with NBUVB.
Phototherapy Phototherapy is typically administered thrice per week and is more effective if commenced early on in the disease. It is used as first-line therapy in extensive disease. It can be used in combination with topical therapies such as corticosteroids, tacrolimus or calcipotriol.45 NBUVB is as effective as systemic PUVA but with fewer side effects.46,47 It produces a better colour match and often superior repigmentation with less erythema.48,49 About 56% of patients get 50% improvement in body surface area with NBUVB compared to 36% with PUVA.50 Using NBUVB with topical tacrolimus produces more than 50% repigmentation in the face, trunk and limbs.51 Acral regions and the genitals, however, do not respond as well. In a recent observational study, four patients with generalised vitiligo were treated with NBUVB and 4 monthly s.c. implants of 16 mg afamelanotide. Repigmentation occurred 2–40 days after the afamelanotide implant with only mild adverse effects reported.52 Though UVA alone can induce repigmentation, efficacy is enhanced when administered with psoralen, with reports of 100% repigmentation on the head and neck.53–55 In addition to its numerous adverse effects, oral PUVA is associated with hyperpigmentation and a noticeable difference between affected and unaffected skin (Fig. 1).50,56 Time is the major limitation with phototherapy,57 with some patients finding it difficult to attend centres with phototherapy facilities. Alternatively, patients have acquired their own UV machines or hand-held devices, which can be dangerous given the absence of supervision and monitoring. Unsupervised exposure to UV machines can increase the risk of all types of skin cancer and may not be beneficial in the long term. The advent of in-built safety mechanisms is important, but further studies are still required to assess the safety of these home UV machines. Targeted treatment with an excimer laser induces T-cell apoptosis and stimulates melanocyte development and progression along the hair follicle.58 The excimer laser and light sources are concentrated sources of NBUVB light that © 2014 The Australasian College of Dermatologists
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is useful for safely treating small localised areas of vitiligo. Two treatments are given weekly for about 6 weeks. The cost is set by the operator and there is no Medicare rebate. Repigmentation rates with an excimer laser are more rapid than NBUVB and are enhanced when used in combination with topical tacrolimus or steroids rather than as monotherapy.59 The excimer lamp is just as effective as excimer laser60 and can treat a larger area and is less expensive. Though the evidence is lacking, it is recommended that phototherapy should continue for at least 3 months to halt the disease and induce repigmentation. If the vitiligo responds, then treatment can continue for up to 1 year. Phototherapy should be ceased when there is no further response. There is no evidence supporting maintenance phototherapy.10
Measuring clinical response Clinical response can be monitored with objective methods such as clinical photographs and vitiligo area scoring index scores. Technological advances with computer imaging analysis software and accurate imaging techniques will better assess the efficacy of treatments with skin changes.
Microtattooing/tattooing Tattooing is useful for sites with a poor rate of repigmentation such as the lips, nipples and distal fingers. The tattoo colour often does not match the normal surrounding skin perfectly and may fade with time.
SURGICAL THERAPIES Surgical therapies are reserved for patients with stable disease who have failed medical treatments.61 They are typically used for difficult-to-treat areas such as the hands, feet, lips and nipples,62 and better results have been demonstrated in segmental rather than generalised vitiligo. The Koebner phenomenon should be explained to all patients before they embark on surgical therapies for vitiligo.63 Tissue grafting and cellular suspensions are the two main melanocyte transplantation techniques currently available for stable vitiligo. Stable vitiligo is defined as an absence of new areas of depigmentation or enlargement of existing areas for at least 6 months. Success rates with surgical therapies are dependent on patient selection, the stability of disease and the absence of the Koebner phenomenon. Tissue-grafting techniques include full thickness punch grafts, epidermal blister grafts and split-thickness grafts. Cellular grafting consists of cultured or non-cultured epidermal suspensions. Mini-grafting (punch grafting) is performed by transplanting 1–2 mm full thickness punch biopsies of normally pigmented skin into areas affected with vitiligo.62 It is time consuming and has potential adverse effects, including cobble-stoning and scarring, especially at the donor site (Fig. 2).64 © 2014 The Australasian College of Dermatologists
Figure 2
Punch grafting.
Epidermal blister or suction blister grafting is performed by inducing a blister in the depigmented recipient site with either liquid nitrogen or topical PUVA and removing the epithelium.62 Dermabrasion or similar blister formation by negative pressure suction is used at the donor site to remove the normally pigmented epithelium. Tissue grafting techniques are time-consuming, need training and often require special equipment such as vacuum equipment for blister formation. Split thickness grafts involve mechanical or chemical dermabrasion of the depigmented recipient skin to remove the superficial epithelium followed by a split-thickness biopsy of normally pigmented donor skin. The melanocytes from this biopsy are prepared using either cultured or noncultured means and transplanted to the dermabraded skin.62 A review of surgical autologous transplantation techniques looking at 63 studies found the highest mean success rates with split-thickness skin grafting (87%; 95% CI 82–91%) and epidermal blister grafting (87%; 95% CI 83–90%). The success rates of the other treatments varied between 13 to 53%.62 ReCell (Avita Medical Europe, Royston, UK), a harvesting kit used to prepare a non-cultured epidermal suspension from a split-thickness skin biopsy65 is effective in obtaining a good colour match66 but does not seem to be as effective compared to standard cellular grafting techniques (Fig. 3). Cultured melanocyte grafting is limited by expense, timing of procedure and results. Non cultured grafting can be performed faster with equivalent or better results without the use of a research laboratory.67 Cultured suspension also has potential risk of transmission of viral infections and the development of malignancy.
DEPIGMENTATION TECHNIQUES Depigmentation is reserved for patients with extensive or recalcitrant disease. Though there is no consensus as to the stage of disease that depigmentation should be initiated,68 it is usually offered if greater than 60% body surface area is
Therapies for vitiligo
5
Patchy depigmentation, repigmentation upon cessation, the need for ongoing sun avoidance, exposure to social stigmas and cultural ramifications are the major issues associated with depigmentation therapies. Systemic absorption of topical depigmentation agents can be toxic to melanocytes in other parts of the body such as the eyes.73
Treatment with biologics
Figure 3 Application of melanocyte cell suspension following dermabrasion.
involved or if visible areas such as the face and hands are affected.68 Repigmentation, especially after cessation of the depigmenting agent, can occur.69 Depigmenting therapies include monobenzyl ether of hydroquinone (MBEH), monomethyl ether of hydroquinone, 88% phenol, laser and cryotherapy. Though the exact mechanism of action of MBEH, also known as monobenzone or p-(benzyloxy)phenol, remains unknown, hypopigmentation is noticed after 3 months of application with complete depigmentation within 12 months.70 A retrospective study found complete depigmentation in up to 44% of patients treated with 20% MBEH, with hypopigmentation in a further 33%. No hypopigmentation occurred in 22% and one patient ceased treatment due to contact dermatitis. The strength of MBEH is determined by the response and reported adverse effects. 20% MBEH should be the initial strength, which can be decreased to 5% if contact dermatitis occurs. If no response is noticed after 3 months, then the strength can be gradually increased from 20 to 40%.71 In Australia, MBEH has to be compounded at a pharmacy. The quality and effectiveness of the product may vary, given it is non-standardised. Adverse effects include burning and itching, erythema, dryness, contact dermatitis and oedema, irregular patchy depigmentation with unpredictable hypopigmentation and hyperpigmentation and nail discolouration. Burning and itching may be alleviated by combining MBEH with emollients.70 Depigmentation with topical 4-methoxyphenol, also known as monomethyl ether of hydroquinone, mequinol or p-Hydroxyanisole occurs after 4 months,68 with slower response rates than with MBEH. Adverse effects include mild burning, itching, leucoderma and repigmentation after sun exposure.72 Lasers such as Q-switched alexandrite and ruby laser selectively destroy melanocytes inducing depigmentation.73 Eight patients who did not respond to 4-methoxyphenol received one treatment of Q-switched ruby laser (694 nm). Four (50%) reported pain and three had depigmentation.
Because of the higher levels of TNF-α in lesional and perilesional skin, it is thought that blocking TNF-α may reduce melanocyte destruction and promote melanocyte stem cell differentiation.74 This is supported by a case report in which a patient with ankylosing spondylitis had amelioration of his vitiligo when treated with infliximab.75 Despite this, infliximab, adalimumab and etanercept were not effective in a recent small case series.76 In fact, there is concern that biological agents and TNF-inhibitors worsen and trigger vitiligo.77,78 New onset vitiligo just 6 weeks after commencing infliximab for ulcerative colitis79 as well as worsening of existing vitiligo have been reported. Similarly, adalimumab has been implicated as a possible trigger for vitiligo.80,81 Clinical improvement with rituximab needs to be confirmed with larger studies. Further studies are required to determine whether a causal relationship between vitiligo and biologics exists and if there is a therapeutic role for TNF inhibitors.
Future therapies Gene therapy is a potential treatment in the future, with research into the pathophysiology of vitiligo and the methods and effectiveness of gene therapy and stem cell treatments.82 Ongoing studies are assessing the evidence and safety of combining phototherapy with various antioxidants such as piperidine, capsaicin, L-carnosine and curcumin.83 Other potential agents currently under investigation include statins, basic fibroblast growth factors, prostaglandin E2 analogues and COX-2 inhibitors. A trial assessing the effect of afamelanotide in 60 patients is underway. Promising results have been demonstrated in small or pilot studies with topical bimatoprost (0.03% twice/day), a prostaglandin F2-alpha analogue ophthalmic solution and topical photocil.84,85 CO2 laser, micrografting, microphototherapy, the utilisation of melanocytes from the outer root sheath of hair follicles and dressings post-vitiligo surgery are also being investigated.10,83 In the future, treatments or vaccines targeting specific components of the immune system such as heat shock proteins may be effective in preventing or halting disease.86 There is evidence that inducible heat shock proteins may prevent depigmentation.87 The chemokine CXCL 10 is elevated in the skin and serum of patients with vitiligo. The inhibition of CXCL 10 in mouse models results in repigmentation, suggesting a possible therapeutic target (Fig. 4).88 © 2014 The Australasian College of Dermatologists
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1st Line Conservave therapy
Counselling, psychological assistance, paent support groups
No treatment
Topical Corcosteroids Vitamin D analogues(e.g. calcipotriol) Calcineurin inhibitors(e.g. tacrolimus, pimecrolimus)
Limited disease
Camouflage and sunscreens 2nd Line Extensive disease
3rd Line
Phototherapy +/- topicals, anoxidants, khellin, phenylalanine
Surgical therapies(e.g. punch graing, autologous melanocyte transplantaon, split thickness gra, blister gra) or laser
Systemic immunosuppressive agents
In adults with extensive diseasere calcitrant to other therapies, consider depigmentaon
Figure 4
Treatment options for Vitiligo.
CONCLUSION Despite progress in recent years, treating vitiligo still remains challenging, requiring a systematic approach which addresses a patient’s needs, QoL and expectations. Future studies will advance our knowledge about the disease, its pathophysiology and genetics, and therapeutic options available to treat it.
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Parsad D, Kanwar A. Oral minocycline in the treatment of vitiligo – a preliminary study. Dermatol. Ther. 2010; 23: 305–7. Sandra A, Pai S, Shenoi SD. Unstable vitiligo responding to methotrexate. Indian J. Dermatol. Venereol. Leprol. 1998; 64: 309. Badilla A, Diaz C. [Remission of vitiligo during treatment with intravenous immunoglobulin: report of one case]. Rev. Med. Chil. 2011; 139: 484–8. Alghamdi K, Khurrum H. Methotrexate for the treatment of generalized vitiligo. Saudi Pharm J 2013; 21: 423–4. Radmanesh M, Saedi K. The efficacy of combined PUVA and low-dose azathioprine for early and enhanced repigmentation in vitiligo patients. J. Dermatolog. Treat. 2006; 17: 151–3. Whitton ME, Pinart M, Batchelor J et al. Interventions for vitiligo. Cochrane Database Syst. Rev. 2010; (1): CD003263. Gupta AK, Ellis CN, Nickoloff BJ et al. Oral cyclosporine in the treatment of inflammatory and noninflammatory dermatoses. A clinical and immunopathologic analysis. Arch. Dermatol. 1990; 126: 339–50. Dogra S, Kumar B. Repigmentation in vitiligo universalis: role of melanocyte density, disease duration, and melanocytic reservoir. Dermatol. Online J. 2005; 11: 30. Teulings HE, Overkamp M, Ceylan E et al. Decreased risk of melanoma and nonmelanoma skin cancer in patients with vitiligo: a survey among 1307 patients and their partners. Br. J. Dermatol. 2013; 168: 162–71. Akdeniz N et al. Comparison of efficacy of narrow band UVB therapies with UVB alone, in combination with calcipotriol, and with betamethasone and calcipotriol in vitiligo. J. Dermatolog. Treat. 2014; 25: 196–9. Bhatnagar A, Yavuz IH, Gunes Bilgili S et al. Comparison of systemic PUVA and NB-UVB in the treatment of vitiligo: an open prospective study. J. Eur. Acad. Dermatol. Venereol. 2007; 21: 638–42. Westerhof W, Nieuweboer-Krobotova L. Treatment of vitiligo with UV-B radiation vs topical psoralen plus UV-A. Arch. Dermatol. 1997; 133: 1525–8. Bhatnagar A, Kanwar AJ, Parsad D et al. Psoralen and ultraviolet A and narrow-band ultraviolet B in inducing stability in vitiligo, assessed by vitiligo disease activity score: an open prospective comparative study. J. Eur. Acad. Dermatol. Venereol. 2007; 21: 1381–5. 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: 175–7. Yones SS, Palmer RA, Garibaldinos TM et al. Randomized double-blind trial of treatment of vitiligo: efficacy of psoralenUV-A therapy vs narrowband-UV-B therapy. Arch. Dermatol. 2007; 143: 578–84. Fai D, Cassano N, Vena GA. Narrow-band UVB phototherapy combined with tacrolimus ointment in vitiligo: a review of 110 patients. J. Eur. Acad. Dermatol. Venereol. 2007; 21: 916–20. Grimes PE, Hamzavi I, Lebwohl M et al. The efficacy of afamelanotide and narrowband UV-B phototherapy for repigmentation of vitiligo. JAMA Dermatol. 2013; 149: 68–73. El-Mofty M, Mostafa WZ, Bosseila M et al. A large scale analytical study on efficacy of different photo(chemo)therapeutic modalities in the treatment of psoriasis, vitiligo and mycosis fungoides. Dermatol. Ther. 2010; 23: 428–34. Hann SK, Cho MY, Im S et al. Treatment of vitiligo with oral 5-methoxypsoralen. J. Dermatol. 1991; 18: 324–9. Lassus A, Halme K, Eskelinen A et al. Treatment of vitiligo with oral methoxsalen and UVA. Photodermatol 1984; 1: 170–3. Kwok YK, Anstey AV, Hawk JL. Psoralen photochemotherapy (PUVA) is only moderately effective in widespread vitiligo: a 10-year retrospective study. Clin. Exp. Dermatol. 2002; 27: 104– 10. © 2014 The Australasian College of Dermatologists
8 57.
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BS Daniel and R Wittal Scherschun L, Kim JJ, Lim HW. Narrow-band ultraviolet B is a useful and well-tolerated treatment for vitiligo. J. Am. Acad. Dermatol. 2001; 44: 999–1003. Do JE, Shin JY, Kim DY et al. The effect of 308nm excimer laser on segmental vitiligo: a retrospective study of 80 patients with segmental vitiligo. Photodermatol. Photoimmunol. Photomed. 2011; 27: 147–51. Alhowaish AK, Dietrich N, Onder M et al. Effectiveness of a 308-nm excimer laser in treatment of vitiligo: a review. Lasers Med. Sci. 2013; 28: 1035–41. 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. Parsad D, Gupta S. Standard guidelines of care for vitiligo surgery. Indian J. Dermatol. Venereol. Leprol. 2008; 74 (Suppl.): S37–45. Njoo MD, Westerhof W, Bos JD et al. A systematic review of autologous transplantation methods in vitiligo. Arch. Dermatol. 1998; 134: 1543–9. van Geel N, Speeckaert R, Taieb A et al. Koebner’s phenomenon in vitiligo: European position paper. Pigment. Cell Melanoma Res. 2011; 24: 564–73. Rusfianti M, Wirohadidjodjo YW. Dermatosurgical techniques for repigmentation of vitiligo. Int. J. Dermatol. 2006; 45: 411–7. Wood FM, Stoner ML, Fowler BV et al. The use of a noncultured autologous cell suspension and Integra dermal regeneration template to repair full-thickness skin wounds in a porcine model: a one-step process. Burns 2007; 33: 693–700. Cervelli V, De Angelis B, Balzani A et al. Treatment of stable vitiligo by ReCell system. Acta Dermatovenerol. Croat. 2009; 17: 273–8. Mulekar SV, Isedeh P. Surgical interventions for vitiligo: an evidence-based review. Br. J. Dermatol. 2013; 169 (Suppl. 3): 57–66. Alghamdi KM, Kumar A. Depigmentation therapies for normal skin in vitiligo universalis. J. Eur. Acad. Dermatol. Venereol. 2011; 25: 749–57. Oakley AM. Rapid repigmentation after depigmentation therapy: vitiligo treated with monobenzyl ether of hydroquinone. Australas. J. Dermatol. 1996; 37: 96–8. Mosher DB, Parrish JA, Fitzpatrick TB. Monobenzylether of hydroquinone. A retrospective study of treatment of 18 vitiligo patients and a review of the literature. Br. J. Dermatol. 1977; 97: 669–79. Jean Bolognia KL, Lapia BK, Somma S. Depigmentation therapy. Dermatol. Ther. 2001; 14: 29–34. Njoo MD, Vodegel RM, Westerhof W. Depigmentation therapy in vitiligo universalis with topical 4-methoxyphenol and the Q-switched ruby laser. J. Am. Acad. Dermatol. 2000; 42 (5 Pt 1): 760–9.
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Thissen M, Westerhof W. Laser treatment for further depigmentation in vitiligo. Int. J. Dermatol. 1997; 36: 386–8. Lv Y, Li Q, Wang L et al. Use of anti-tumor necrosis factor agents: a possible therapy for vitiligo. Med. Hypotheses 2009; 72: 546–7. Simon D, Hösli S, Kostylina G et al. Anti-CD20 (rituximab) treatment improves atopic eczema. J. Allergy Clin. Immunol. 2008; 121: 122–8. Alghamdi KM, Khurrum H, Taieb A et al. Treatment of generalized vitiligo with anti-TNF-alpha agents. J. Drugs Dermatol. 2012; 11: 534–9. Exarchou SA, Voulgari PV, Markatseli TE et al. Immunemediated skin lesions in patients treated with anti-tumour necrosis factor alpha inhibitors. Scand. J. Rheumatol. 2009; 38: 328–31. Lahita RG, Vernace MA. Vasculitis, vitiligo, thyroiditis, and altered hormone levels after anti-tumor necrosis factor therapy. J. Rheumatol. 2011; 38: 579–80. Ismail WA, Al-Enzy SA, Alsurayei SA et al. Vitiligo in a patient receiving infliximab for refractory ulcerative colitis. Arab. J. Gastroenterol. 2011; 12: 109–11. Posada C, Flórez A, Batalla A et al. Vitiligo during treatment of Crohn’s disease with adalimumab: adverse effect or co-occurrence? Case Rep. Dermatol. 2011; 3: 28–31. Smith DI, Heffernan MP. Vitiligo after the resolution of psoriatic plaques during treatment with adalimumab. J. Am. Acad. Dermatol. 2008; 58 (2 Suppl.): S50–2. Eleftheriadou V, Whitton ME, Gawkrodger DJ et al. Future research into the treatment of vitiligo: where should our priorities lie? Results of the vitiligo priority setting partnership. Br. J. Dermatol. 2011; 164: 530–6. Lotti TM, Hercogová J, Schwartz RA et al. Treatments of vitiligo: what’s new at the horizon. Dermatol. Ther. 2012; 25 (Suppl. 1): S32–40. Goren A, Salafia A, McCoy J et al. Novel topical cream delivers safe and effective sunlight therapy for vitiligo by selectively filtering damaging ultraviolet radiation. Dermatol. Ther. 2014; 27: 195-7. McCoy J, Goren A, Lotti T. In vitro evaluation of a novel topical cream for vitiligo and psoriasis that selectively delivers NB-UVB therapy when exposed to sunlight. Dermatol. Ther. 2013; 27: 117–20. Mosenson JA, Eby JM, Hernandez C et al. A central role for inducible heat-shock protein 70 in autoimmune vitiligo. Exp. Dermatol. 2013; 22: 566–9. Mosenson JA, Zloza A, Nieland JD et al. Mutant HSP70 reverses autoimmune depigmentation in vitiligo. Sci. Transl. Med. 2013; 5: 174ra28. Rashighi M, Agarwal P, Richmond JM et al. CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci. Transl. Med. 2014; 6: 223ra23.
Australasian Journal of Dermatology (2014) ••, ••–••
doi: 10.1111/ajd.12256
REVIEW ARTICLE
Vitiligo treatment update Benjamin S Daniel1 and Richard Wittal1,2 1
University of New South Wales, and 2Skin and Cancer Foundation, Sydney, New South Wales, Australia
ABSTRACT Vitiligo is a common depigmenting disease that can affect the skin and mucosal surfaces. Various treatments have been used over the years with varying repigmentation rates. This review looks at the evidence of commonly used therapies for vitiligo.
Table 1 Classification of vitiligo according to the Vitiligo Global Issues Consensus Conference (adapted from Ezzedine and colleagues2) Vitiligo or non-segmental vitiligo Acrofacial Mucosal Generalised Universal
Key words: management, treatment, vitiligo.
INTRODUCTION Vitiligo is a common acquired depigmenting skin disease affecting about 0.5 to 2% of the population.1 The treatment of vitiligo varies between countries, depending on the patients’ skin type and access to treatments and facilities. This review looks at the treatments for vitiligo and the evidence supporting their use. According to the 2012 classification and consensus nomenclature,2 there are three main types of vitiligo; namely, non-segmental vitiligo (NSV), segmental vitiligo and undetermined/unclassified vitiligo (Table 1). The term vitiligo includes the acrofacial, mucosal, generalised and mixed subtypes. The common differential diagnoses are listed in Table 2.
Quality of life (QoL) Vitiligo has a significant impact on QoL, affecting activities of daily living and personal relationships. Psychological counselling and support is necessary in the management of vitiligo, no matter how severe the disease. The effect on QoL is not directly proportionate to the extent of the disease and patients often worry that the disease will progress. Depression is common, affecting more than 50% of patients with vitiligo, especially single patients or women in the early years of the disease.3 Pre-existing low self-
Mixed Rare variants Segmental vitiligo Uni-segmental, bi-segmental or pluri-segmental Undetermined/unclassified vitiligo Focal Mucosal
More than one mucosal site affected Complete or almost complete depigmentation of skin/hair Combination of SV and NSV
Often follows a dermatomal or blaschkoid pattern Small localised macules that are not segmental or NSV One mucosal site affected
NSV, non-segmental vitiligo; SV, segmental vitiligo.
esteem, impaired self-perception, poor coping methods and inadequate social support contribute to the psychological impact of the disease.4 Due to time constraints, however, it may be appropriate for dermatologists to acknowledge the psychological impact of the disease by referring patients to a psychologist or counsellor who can address both the subjective and objective factors of the condition. Various therapeutic regimens impact on a patient’s QoL and should be considered when choosing an appropriate treatment.5 Patient support groups are an important avenue through which patients may find information about the disease and meet others with the same condition. The Vitiligo Association of Australia (www.vitiligo.org.au)6 is an active support group set up in 2010 to support patients and families with vitiligo. It has state branches which meet regularly and is associated with international vitiligo patient support groups.
Abbreviations: Correspondence: Dr Richard Wittal, University of New South Wales, Sydney, NSW, Australia. Email: [email protected] Benjamin S. Daniel, MBBS. Richard Wittal, FACD. Conflict of interest: none Submitted 29 August 2013; accepted 16 August 2014. © 2014 The Australasian College of Dermatologists
MBEH QoL RCT TCS TNF
monobenzyl ether of hydroquinone quality of life randomised controlled trial topical corticosteroids tumour necrosis factor
2 Table 2
BS Daniel and R Wittal Differential diagnoses for vitiligo
Pityriasis versicolor Idiopathic guttate hypomelanosis Tuberous sclerosis Piebaldism Discoid or systemic lupus erythematosus Sarcoidosis Scleroderma Post-inflammatory hypopigmentation/depigmentation: e.g. atopic dermatitis, psoriasis Post-traumatic depigmentation (e.g. scars, burns) Progressive macular hypomelanosis Cutaneous T-cell lymphoma Leprosy Pityriasis alba Melasma Naevus anemicus, naevus depigmentosus, halo naevus Leucoderma of variable causes: for example post-traumatic, melanoma associated leucoderma Amelanotic melanoma Lichen sclerosus et atrophicus Topical or drug-induced depigmentation
steroids but have a safer side-effect profile.14,15 Patients with vitiligo have greater amounts of interleukin -10, interferon-γ and tumour necrosis factor (TNF)-α in their skin compared to controls. Topical tacrolimus stimulates melanocyte growth and reduces TNF-α levels, resulting in repigmentation.16 It is particularly effective on the face and neck and when used in combination with phototherapy or occlusive dressings. It should be applied twice a day for a minimum of 6 months.17 The cost of topical tacrolimus usually limits its use in widespread disease.18–20 Unlike in other countries, most of the tacrolimus available in Australia has to be compounded in 0.03% and 0.1% concentrations. The quality and efficacy of the product is therefore variable, depending on the compounding pharmacists.
Topical vitamin D3 analogues Calcipotriol is effective when used in combination with TCS, especially in difficult-to-treat areas such as the eyelids.21,22 It is unknown if there is any significant advantage of using calcipotriol with phototherapy.23–25
Camouflage
Antioxidants
Cosmetic and tanning products conceal the patchiness of depigmented skin and improve the patients’ self-confidence and QoL. Camouflage does not treat the underlying disease and will not induce repigmentation. It is offered as conservative therapy for patients who do not wish to have treatment.7
Oxidative stress and free radicals are thought to play a role in the pathogenesis of vitiligo, with elevated levels of hydrogen peroxide in the epidermis of vitiliginous skin. Current studies are evaluating the evidence and safety of these antioxidants, including the naturally occurring glutathione. (Table 3) The evidence supporting the combination of some antioxidants with phototherapy is poor. An Australian randomised controlled trial (RCT) and other trials have failed to show any benefit in adding pseudocatalase to NBUVB.26,27 There is no additional benefit in applying topical superoxide dismutase to phototherapy alone.28 Topical steroids in the form of 0.05% betamethasone may be just as effective as topical catalase or dismutase superoxide in vitiligo.29 The combination of Polypodium leucotomos with NBUVB resulted in a higher rate of repigmentation than a placebo in the head and neck, especially in light-skinned individuals.30 An Italian RCT treated 35 patients with non-segmental vitiligo with NBUVB plus either oral antioxidants (two tablets which contained α-lipoic acid, vitamin C, vitamin E, polyunsaturated fatty acids and cysteine monohydrate) or placebo.31 A similar formulation is not currently available in Australia. After 2 months the treatment group had a statistically significant increased rate of catalase activity and reactive oxygen species production than the placebo group. At 6 months significant repigmentation was evident in 47% of those with antioxidants compared to 18% in the placebo group. Recent evidence suggests minocycline has antioxidant effects and may be potentially beneficial in vitiligo.35,36
MEDICAL THERAPIES Topical and oral corticosteroids Topical corticosteroids (TCS) are used as first-line therapy as monotherapy (e.g. in localised vitiligo), or in combination with phototherapy or other topical agents (e.g. in generalised vitiligo).8 Commonly prescribed TCS include betamethasone dipropionate, clobetasol dipropionate and mometasone furoate. Because of adverse effects and tachyphylaxis, TCS should not be used for longer than 3 months and steroid holidays should be encouraged.9,10 Sideeffects are generally not noticed with short bursts of TCS. Systemic corticosteroids halt disease progression and induce repigmentation when used at the onset or early stages of disease, in some cases resulting in complete repigmentation.11,12 Short pulses of systemic corticosteroids are used in international centres without long-term sideeffects. To stabilise rapidly expanding lesions within 1–4 months, an oral mini-pulse with dexamethasone 5–10 mg for 2 days per week (the equivalent of prednisolone 25–35 mg on Saturday and Sunday) can be used. This can be combined with NBUVB.13
Calcineurin inhibitors
Immunosuppressive agents
Tacrolimus and pimecrolimus, as monotherapy or in combination with phototherapy, are just as effective as topical
Despite its autoimmune nature, immunosuppressive therapies have not been shown to be significantly beneficial.
© 2014 The Australasian College of Dermatologists
Therapies for vitiligo Table 3
3
Evidence of antioxidants in vitiligo
Pseudocatalase
Superoxide dismutase and topical catalase or dismutase superoxide Polypodium leucotomos
Antioxidants (containing lipoic acid, vitamin C, vitamin E, polyunsaturated fatty acids and cysteine monohydrate)
Khellin
Phenylalanine
There are conflicting reports of the beneficial use of pseudocatalase, though RCTs, including an Australian study, have shown no additional benefit of pseudocatalase compared to NBUVB alone26,27 No proven benefit28,29
A RCT comparing Polypodium leucotomos with NBUVB to placebo found greater repigmentation in the head and neck area in light-skinned patients than in those exposed to the antioxidant30 RCT compared the NBUVB plus either oral antioxidants or placebo. After 2 months, the treatment group had a statistically significant increased rate of catalase activity and reactive oxygen species production than the placebo group. At 6 months, significant repigmentation was evident in 47% of those with antioxidants compared to 18% in the placebo group31 Used in systemic or topical forms in combination with UVA. It has comparable repigmentation rates as that of psoralens but with less phototoxicity32,33 Induces some repigmentation when used with UVA, though there are safety concerns over excess phenylalanine34
RCT, randomised controlled trial.
There are individual case reports of improvement with methotrexate37 and i.v. immunoglobulin,38 though a pilot study of methotrexate 25 mg/week for 6 months in six patients with generalised vitiligo failed to show any clinical improvement.39 Low-dose azathioprine is beneficial,40 with greater repigmentation after 4 months with azathioprine (0.6– 0.75 mg/kg/day) + PUVA than in PUVA alone (58 vs 25%, P < 0.001). RCT assessing cyclosporine and cyclophosphamide are lacking.41 One report indicated one of six patients treated with cyclosporine 6 mg/kg42 had a minimal to moderate response, while another case report reported some repigmentation on the face and forearms of a patient with pemphigus vulgaris treated with combination dexamethasone and cyclophosphamide pulse therapy.43 Vitiligo seems to have a protective benefit against melanoma and non-melanoma skin cancers. A large cohort study found the risk of melanoma and non-melanoma skin cancer was less than one-third that of patients without vitiligo.44
Figure 1 Previously depigmented area now shows follicular repigmentation with NBUVB.
Phototherapy Phototherapy is typically administered thrice per week and is more effective if commenced early on in the disease. It is used as first-line therapy in extensive disease. It can be used in combination with topical therapies such as corticosteroids, tacrolimus or calcipotriol.45 NBUVB is as effective as systemic PUVA but with fewer side effects.46,47 It produces a better colour match and often superior repigmentation with less erythema.48,49 About 56% of patients get 50% improvement in body surface area with NBUVB compared to 36% with PUVA.50 Using NBUVB with topical tacrolimus produces more than 50% repigmentation in the face, trunk and limbs.51 Acral regions and the genitals, however, do not respond as well. In a recent observational study, four patients with generalised vitiligo were treated with NBUVB and 4 monthly s.c. implants of 16 mg afamelanotide. Repigmentation occurred 2–40 days after the afamelanotide implant with only mild adverse effects reported.52 Though UVA alone can induce repigmentation, efficacy is enhanced when administered with psoralen, with reports of 100% repigmentation on the head and neck.53–55 In addition to its numerous adverse effects, oral PUVA is associated with hyperpigmentation and a noticeable difference between affected and unaffected skin (Fig. 1).50,56 Time is the major limitation with phototherapy,57 with some patients finding it difficult to attend centres with phototherapy facilities. Alternatively, patients have acquired their own UV machines or hand-held devices, which can be dangerous given the absence of supervision and monitoring. Unsupervised exposure to UV machines can increase the risk of all types of skin cancer and may not be beneficial in the long term. The advent of in-built safety mechanisms is important, but further studies are still required to assess the safety of these home UV machines. Targeted treatment with an excimer laser induces T-cell apoptosis and stimulates melanocyte development and progression along the hair follicle.58 The excimer laser and light sources are concentrated sources of NBUVB light that © 2014 The Australasian College of Dermatologists
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is useful for safely treating small localised areas of vitiligo. Two treatments are given weekly for about 6 weeks. The cost is set by the operator and there is no Medicare rebate. Repigmentation rates with an excimer laser are more rapid than NBUVB and are enhanced when used in combination with topical tacrolimus or steroids rather than as monotherapy.59 The excimer lamp is just as effective as excimer laser60 and can treat a larger area and is less expensive. Though the evidence is lacking, it is recommended that phototherapy should continue for at least 3 months to halt the disease and induce repigmentation. If the vitiligo responds, then treatment can continue for up to 1 year. Phototherapy should be ceased when there is no further response. There is no evidence supporting maintenance phototherapy.10
Measuring clinical response Clinical response can be monitored with objective methods such as clinical photographs and vitiligo area scoring index scores. Technological advances with computer imaging analysis software and accurate imaging techniques will better assess the efficacy of treatments with skin changes.
Microtattooing/tattooing Tattooing is useful for sites with a poor rate of repigmentation such as the lips, nipples and distal fingers. The tattoo colour often does not match the normal surrounding skin perfectly and may fade with time.
SURGICAL THERAPIES Surgical therapies are reserved for patients with stable disease who have failed medical treatments.61 They are typically used for difficult-to-treat areas such as the hands, feet, lips and nipples,62 and better results have been demonstrated in segmental rather than generalised vitiligo. The Koebner phenomenon should be explained to all patients before they embark on surgical therapies for vitiligo.63 Tissue grafting and cellular suspensions are the two main melanocyte transplantation techniques currently available for stable vitiligo. Stable vitiligo is defined as an absence of new areas of depigmentation or enlargement of existing areas for at least 6 months. Success rates with surgical therapies are dependent on patient selection, the stability of disease and the absence of the Koebner phenomenon. Tissue-grafting techniques include full thickness punch grafts, epidermal blister grafts and split-thickness grafts. Cellular grafting consists of cultured or non-cultured epidermal suspensions. Mini-grafting (punch grafting) is performed by transplanting 1–2 mm full thickness punch biopsies of normally pigmented skin into areas affected with vitiligo.62 It is time consuming and has potential adverse effects, including cobble-stoning and scarring, especially at the donor site (Fig. 2).64 © 2014 The Australasian College of Dermatologists
Figure 2
Punch grafting.
Epidermal blister or suction blister grafting is performed by inducing a blister in the depigmented recipient site with either liquid nitrogen or topical PUVA and removing the epithelium.62 Dermabrasion or similar blister formation by negative pressure suction is used at the donor site to remove the normally pigmented epithelium. Tissue grafting techniques are time-consuming, need training and often require special equipment such as vacuum equipment for blister formation. Split thickness grafts involve mechanical or chemical dermabrasion of the depigmented recipient skin to remove the superficial epithelium followed by a split-thickness biopsy of normally pigmented donor skin. The melanocytes from this biopsy are prepared using either cultured or noncultured means and transplanted to the dermabraded skin.62 A review of surgical autologous transplantation techniques looking at 63 studies found the highest mean success rates with split-thickness skin grafting (87%; 95% CI 82–91%) and epidermal blister grafting (87%; 95% CI 83–90%). The success rates of the other treatments varied between 13 to 53%.62 ReCell (Avita Medical Europe, Royston, UK), a harvesting kit used to prepare a non-cultured epidermal suspension from a split-thickness skin biopsy65 is effective in obtaining a good colour match66 but does not seem to be as effective compared to standard cellular grafting techniques (Fig. 3). Cultured melanocyte grafting is limited by expense, timing of procedure and results. Non cultured grafting can be performed faster with equivalent or better results without the use of a research laboratory.67 Cultured suspension also has potential risk of transmission of viral infections and the development of malignancy.
DEPIGMENTATION TECHNIQUES Depigmentation is reserved for patients with extensive or recalcitrant disease. Though there is no consensus as to the stage of disease that depigmentation should be initiated,68 it is usually offered if greater than 60% body surface area is
Therapies for vitiligo
5
Patchy depigmentation, repigmentation upon cessation, the need for ongoing sun avoidance, exposure to social stigmas and cultural ramifications are the major issues associated with depigmentation therapies. Systemic absorption of topical depigmentation agents can be toxic to melanocytes in other parts of the body such as the eyes.73
Treatment with biologics
Figure 3 Application of melanocyte cell suspension following dermabrasion.
involved or if visible areas such as the face and hands are affected.68 Repigmentation, especially after cessation of the depigmenting agent, can occur.69 Depigmenting therapies include monobenzyl ether of hydroquinone (MBEH), monomethyl ether of hydroquinone, 88% phenol, laser and cryotherapy. Though the exact mechanism of action of MBEH, also known as monobenzone or p-(benzyloxy)phenol, remains unknown, hypopigmentation is noticed after 3 months of application with complete depigmentation within 12 months.70 A retrospective study found complete depigmentation in up to 44% of patients treated with 20% MBEH, with hypopigmentation in a further 33%. No hypopigmentation occurred in 22% and one patient ceased treatment due to contact dermatitis. The strength of MBEH is determined by the response and reported adverse effects. 20% MBEH should be the initial strength, which can be decreased to 5% if contact dermatitis occurs. If no response is noticed after 3 months, then the strength can be gradually increased from 20 to 40%.71 In Australia, MBEH has to be compounded at a pharmacy. The quality and effectiveness of the product may vary, given it is non-standardised. Adverse effects include burning and itching, erythema, dryness, contact dermatitis and oedema, irregular patchy depigmentation with unpredictable hypopigmentation and hyperpigmentation and nail discolouration. Burning and itching may be alleviated by combining MBEH with emollients.70 Depigmentation with topical 4-methoxyphenol, also known as monomethyl ether of hydroquinone, mequinol or p-Hydroxyanisole occurs after 4 months,68 with slower response rates than with MBEH. Adverse effects include mild burning, itching, leucoderma and repigmentation after sun exposure.72 Lasers such as Q-switched alexandrite and ruby laser selectively destroy melanocytes inducing depigmentation.73 Eight patients who did not respond to 4-methoxyphenol received one treatment of Q-switched ruby laser (694 nm). Four (50%) reported pain and three had depigmentation.
Because of the higher levels of TNF-α in lesional and perilesional skin, it is thought that blocking TNF-α may reduce melanocyte destruction and promote melanocyte stem cell differentiation.74 This is supported by a case report in which a patient with ankylosing spondylitis had amelioration of his vitiligo when treated with infliximab.75 Despite this, infliximab, adalimumab and etanercept were not effective in a recent small case series.76 In fact, there is concern that biological agents and TNF-inhibitors worsen and trigger vitiligo.77,78 New onset vitiligo just 6 weeks after commencing infliximab for ulcerative colitis79 as well as worsening of existing vitiligo have been reported. Similarly, adalimumab has been implicated as a possible trigger for vitiligo.80,81 Clinical improvement with rituximab needs to be confirmed with larger studies. Further studies are required to determine whether a causal relationship between vitiligo and biologics exists and if there is a therapeutic role for TNF inhibitors.
Future therapies Gene therapy is a potential treatment in the future, with research into the pathophysiology of vitiligo and the methods and effectiveness of gene therapy and stem cell treatments.82 Ongoing studies are assessing the evidence and safety of combining phototherapy with various antioxidants such as piperidine, capsaicin, L-carnosine and curcumin.83 Other potential agents currently under investigation include statins, basic fibroblast growth factors, prostaglandin E2 analogues and COX-2 inhibitors. A trial assessing the effect of afamelanotide in 60 patients is underway. Promising results have been demonstrated in small or pilot studies with topical bimatoprost (0.03% twice/day), a prostaglandin F2-alpha analogue ophthalmic solution and topical photocil.84,85 CO2 laser, micrografting, microphototherapy, the utilisation of melanocytes from the outer root sheath of hair follicles and dressings post-vitiligo surgery are also being investigated.10,83 In the future, treatments or vaccines targeting specific components of the immune system such as heat shock proteins may be effective in preventing or halting disease.86 There is evidence that inducible heat shock proteins may prevent depigmentation.87 The chemokine CXCL 10 is elevated in the skin and serum of patients with vitiligo. The inhibition of CXCL 10 in mouse models results in repigmentation, suggesting a possible therapeutic target (Fig. 4).88 © 2014 The Australasian College of Dermatologists
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1st Line Conservave therapy
Counselling, psychological assistance, paent support groups
No treatment
Topical Corcosteroids Vitamin D analogues(e.g. calcipotriol) Calcineurin inhibitors(e.g. tacrolimus, pimecrolimus)
Limited disease
Camouflage and sunscreens 2nd Line Extensive disease
3rd Line
Phototherapy +/- topicals, anoxidants, khellin, phenylalanine
Surgical therapies(e.g. punch graing, autologous melanocyte transplantaon, split thickness gra, blister gra) or laser
Systemic immunosuppressive agents
In adults with extensive diseasere calcitrant to other therapies, consider depigmentaon
Figure 4
Treatment options for Vitiligo.
CONCLUSION Despite progress in recent years, treating vitiligo still remains challenging, requiring a systematic approach which addresses a patient’s needs, QoL and expectations. Future studies will advance our knowledge about the disease, its pathophysiology and genetics, and therapeutic options available to treat it.
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