Therapeutic management of vitiligo

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1 Minireview Submitted: Accepted: Conflict of interest None. DOI: /ddg Therapeutic management of vitiligo Rachela Bleuel, Bernadette Eberlein Department Dermatology and Allergy Biederstein, Technical University of Munich, Germany Summary Affecting 0.5 % of the world s population, vitiligo is an acquired skin disorder that poses major challenges in terms of dermatological care. Characterized by patchy depigmentation, the disease is frequently associated with cosmetic disfigurement and considerable psychological distress. The primary pathophysiological causes for the loss of functional melanocytes are thought to include genetic predisposition, autoimmune mechanisms, and oxidative stress. The present article highlights treatment recommendations contained in the European guidelines as well as those provided by recent reviews on vitiligo. Current therapeutic options are based on three approaches: (1) Regulation of the autoimmune response using topical and systemic immunomodulatory agents (corticosteroids and calcineurin inhibitors); (2) decrease in oxidative stress in melanocytes by means of topical and systemic antioxidants; and (3) activation of melanocyte regeneration using phototherapy (UVB in particular) and transplantation of pigment cells. In addition, patients should be educated in techniques for cosmetic camouflage. Following successful repigmentation, application of calcineurin inhibitors is recommended to prevent recurrences. Combination therapies of the aforementioned approaches are generally considered to be more successful than monotherapies. Early initiation of treatment is associated with a more favorable prognosis. Using the above treatment options, it may be possible to halt disease progression, stabilize depigmented lesions, and achieve repigmentation. Only in exceptional cases should permanent depigmentation be considered as a possible option. New insights into the pathogenesis of vitiligo will likely give rise to novel therapeutic approaches. Introduction Vitiligo is a chronic disease and the most common cause of cutaneous depigmentation. The loss of functional melanocytes in the epidermis and hair follicles usually starts between the ages of 10 and 30; both genders are equally affected [ 1 ]. Pathogenesis The exact cause of the loss of functional melanocytes in affected skin is not fully understood. A triggering event leads to a stress response in the skin, which initiates an autoimmune response against melanocytes in genetically predisposed individuals. The following four interdependent hypotheses on the pathophysiology have been investigated in numerous studies; drug-induced hypopigmentation caused by checkpoint inhibitors, on the other hand, is a phenomenon that has only recently been reported. 1. Genetic predisposition Twenty-five percent of patients with vitiligo have a positive family history. Siblings have a 6 % risk of developing the disease; twins, a 23 % risk [ 2 ]. In addition, numerous gene variants (> 40) have been identified in genome-wide association studies, which are associated with a vitiligo phenotype and encode immune-regulating proteins or melanocyte components [ 3 ]. 1309

2 2. Insufficient protective mechanisms against oxidative stress There is increasing evidence that some form of dysregulation prevents melanocytes from adequately responding to oxidative stress. It has been shown that affected patients exhibit increased levels of reactive oxygen species (ROS) induced by endogenous and exogenous stimuli, as well as decreased activity of antioxidant enzymes in the epidermis [ 4 ]. 3. Autoimmune response against melanocytes Given the association with other autoimmune disorders, it is safe to assume that there is an autoimmune mechanism that leads to the destruction of melanocytes by CD8 + T cells. Melanocytes attract these autoreactive T cells via the release of cytokines (including interferon- γ [IFN- γ ] and IFN- γ -inducing chemokines) in the skin [ 5 ]. 4. Neurochemical mediators as stimuli The neuronal hypothesis with regard to the pathogenesis in segmental vitiligo is based on the dermatomal distribution of vitiligo lesions and the assumption that nerve endings secrete neurochemical mediators cytotoxic to melanocytes. This is supported by increased perilesional neuropeptide levels, as well as the frequent onset of vitiligo following neurologic disorders. Recent observational studies, on the other hand, tend to suggest a cutaneous mosaic and propose segmental vitiligo to be a subvariant of non-segmental vitiligo [ 6 ]. 5. Checkpoint inhibitor-induced hypopigmentation Apart from other cutaneous side effects, about 16 % of melanoma patients on anti-ctla-4, anti-pd-1, and anti-pd-l1 antibody treatment also develop vitiligo-like hypopigmentation. Shown to be clinically distinct from vitiligo, these lesions present as multiple hypopigmented macules in light-exposed areas; there is no association with other autoimmune diseases and no positive family history of vitiligo [ 7 ]. Diagnosis and clinical presentation Clinically, vitiligo presents with asymptomatic, hypopigmented, sharply defined macules without signs of inflammation. The classification proposed at the Vitiligo Global Issues Consensus Conference in 2012 distinguishes between segmental (SV) and non-segmental (NSV) forms. The rare segmental form affects one or more dermatomes unilaterally. On the face, it is primarily the trigeminal region that is affected [ 8 ]. Non-segmental vitiligo usually occurs bilaterally and symmetrically. It can be further subdivided into generalized, acrofacial, mucosal, or localized variants. Two common phenotypes of NSV can be differentiated: phenotype I is characterized by prepubertal disease onset, a positive family history of vitiligo and premature hair graying, disseminated occurrence with frequent de- and repigmentation, and an association with halo nevi. Phenotype II, on the other hand, manifests itself after puberty, shows predominant involvement of the face and acral areas, and is associated with other autoimmune disorders [ 9 ]. Twenty percent of patients have another autoimmune condition (thyroid disease, psoriasis, rheumatoid arthritis, type 1 diabetes, alopecia areata, and others) [ 10 ]. The diagnosis is primarily made on clinical grounds and is based on history, clinical presentation, and family history (vitiligo, autoimmune disorders). Under Wood s light, one sees a blue/bright-white fluorescence of the depigmented skin [ 11 ] ; dermoscopy shows some remaining perifollicular pigmentation and telangiectases [ 12 ]. Laboratory tests for thyroid antibodies are routinely recommended [ 13 ]. Validated scores are useful for patient management and treatment monitoring. Recommended tools include the Vitiligo Extent Score (VES) (assessed by the physician) as well as the Self-Assessment Vitiligo Extent Score (SA-VES) and the dermatology quality of life index (DLQI) (assessed by the patient) [ 14, 15 ]. Consensus treatment recommendations by the European Dermatology Forum Current therapeutic approaches are based on the above-mentioned pathogenetic hypotheses, targeting three factors (Figure 1 ). However, there is still no curative treatment and the response to treatment is often limited. Early diagnosis may prevent disease progression in some cases. The primary goal is always repigmentation; secondary objectives include disease stabilization in order to stop the loss of functional melanocytes, as well as ensuring adequate psychosocial care and quality of life. The decision as to which treatment is the most appropriate in a given situation should be made on a case-by-case basis. Patients should be given realistic information about the probability of therapeutic success prior to treatment initiation. It is also important to explain that it may take several months for any response to treatment to occur and that proactive treatment may be necessary in the long run (Figure 2 ). Data from relevant studies suggests that combination therapies are generally more successful than monotherapies. Factors indicating a poor prognosis include early onset in childhood, disease duration of > 3 to 5 years, involvement of more than 30 % of the body surface area, and progressive disease [ 13, 16 ]. 1310

3 Figure 1 Pathogenesis and treatment options (modified after [16]). Figure 2 Treatment algorithm for vitiligo (modified after [1, 11, 13, 26]). 1311

4 1. Regulation of autoimmunity Topical immunomodulation: Topical corticosteroids (TCS) and calcineurin inhibitors (TCIs) are key components of evidence-based treatment; they result in repigmentation of sun-exposed areas in 75 % of cases. Once-daily application of class III TCS (e.g. mometasone furoate, methylprednisolone aceponate) to all affected areas is recommended for both children and adults. After no more than three months of continuous use, this should be switched to an intermittent regimen (for example, 15 days of treatment per month; maximum total treatment duration: six months). On the face and in areas particularly sensitive to corticosteroids, the use of TCIs (e.g. tacrolimus 0.1 % ointment BID for six months) is recommended in order to reduce adverse effects. Studies have shown no significant differences in the effectiveness of tacrolimus and pimecrolimus. Moderate exposure to sunlight is recommended as a supplementary measure. If TCIs prove to be effective, treatment may be extended beyond six months [ 13 ]. Systemic immunosuppression: in the majority of cases, oral corticosteroids can halt disease progression and trigger repigmentation. Three regimens have been described [ 17 ] : Oral mini-pulse therapy: dexamethasone on two consecutive days/week, starting with 2.5 mg daily. The ideal duration of treatment is three to six months; the daily dose can be increased to 5 10 mg dexamethasone equivalent [ 13 ]. Low-dose therapy: daily administration of prednisolone (0.3 mg/kg for two months) [ 18 ]. High-dose pulse therapy: Methylprednisolone (8 mg/kg IV) on three consecutive days [ 19 ]. Only few studies on the benefits of other immunosuppressants (cyclosporine, cyclophosphamide, methotrexate), biologics (TNF α inhibitors), and topical or systemic Janus kinase inhibitors (tofacitinib, ruxolitinib) in the treatment of vitiligo have been conducted. As they lack sufficient quality, no recommendation is possible. 2. Regulation of oxidative stress Topical antioxidants: Although studies are available on the use of topical antioxidants as monotherapy and in combination with phototherapy, the data thus obtained continues to be subject to controversial debate. There are many products with antioxidant enzymes (e.g. superoxide dismutase, catalase); so far, however, no recommendation for treatment has been issued [ 17 ]. Systemic antioxidants: Though the level of evidence is limited, some studies have shown oral antioxidants to have significant effects on repigmentation. Vitamin E (400 IU/day), Polypodium leucotomos (250 mg TID), and Ginkgo biloba (60 mg BID) seem to be beneficial, particularly in combination with phototherapy [ 20 ]. 3. Melanocyte regeneration and repigmentation Phototherapy: Phototherapy causes repigmentation through various mechanisms, including migration of melanocytes from perilesional skin and hair follicles, formation and melanization of melanosomes, and transfer of melanosomes into keratinocytes. Both photochemotherapy (PUVA) and UVB phototherapy (UVB 311 nm, excimer laser or lamp [UVB 308 nm]) can be employed in the treatment of vitiligo. PUVA therapy has been shown to be less effective and to be associated with more adverse effects than narrowband UVB therapy; in children, it has to be ensured that there is a clear indication for this therapeutic modality [ 13, 21 ]. Treatment with UVB 311 nm is given 2 3 times a week, initially at low doses ( mj/cm 2 ), followed by dose increases of 10 % to 20 % until the patient develops a pink erythema. Treatment is initially performed over a period of three months. If repigmentation occurs, it can be continued for a maximum of 24 months [ 13, 21 ]. Studies have demonstrated a response after six months (UVB 311 nm 74.2 % vs. PUVA 51.4 %) and after 12 months (UVB 311 nm 75 % vs. PUVA 61.6 %). The excimer laser (UVB 308 nm) has been shown to yield the best results in terms of repigmentation; however, this therapeutic option is only suitable for individual vitiligo lesions. Six months of narrowband UVB phototherapy proved to be most effective for vitiligo lesions on the face/in the nuchal region (44.2 %) and on the trunk (26.1 %) [ 13, 21 ]. Experimental approaches include combination therapies using the melanocyte stimulant afamelanotide [ 22 ]. Topical vitamin D3 analogues: Used as monotherapy, these agents have only weak repigmentation effects. Combination therapies with phototherapy or topical corticosteroids are associated with better outcomes [ 17 ]. Surgical treatment: This approach involves transplantation of pigmented tissue or cells. It is only recommended for patients with a history of stable disease for the past six to 24 months and should only be employed for smaller lesions. Transplantation is the treatment of first choice in patients with SV. The prognosis for lesions on the face and neck is particularly favorable. Various methods exist for tissue (punch grafts, blister grafts, split-thickness skin grafts, and hair follicle grafts) and cell transplantation (cultured melanocytes/epidermal cells or suspensions thereof). The surgical procedure is preferably followed by phototherapy for 3 4 weeks [ 23 ]. Cosmetics and patient management: Every patient should be trained by a specialized cosmetician in the use of camouflage to conceal vitiligo lesions. Techniques include 1312

5 self-tanning, pigmented foundations, and tattoos. Joining a self-help group and consultation with a psychologist can be part of the therapeutic management [ 13 ]. 4. Depigmentation In patients with recalcitrant, extensive disease (> 50 % of the body surface area) depigmentation is a therapeutic option. The chemical agent used is monobenzone 20 % cream, which is applied 2 3 times a day for 1 4 months until depigmentation is achieved. Exposure to sunlight should be avoided in the meantime; subsequently, the cream can be applied once or twice a week. Ruby lasers are a suitable treatment modality. Their wavelength of about 755 nm allows for selective destruction of melanin [ 24 ]. 5. Proactive treatment to prevent recurrences Taking prophylactic measures to prevent recurrences is advisable, even after successful repigmentation. In a study comparing proactive treatment with tacrolimus 0.1% ointment (twice a week) to placebo, the former was associated with a significantly lower recurrence rate after six months. Forty percent in the placebo group showed areas of depigmentation, compared to 9.7 % in the tacrolimus group [ 25 ]. Correspondence to Dr. med. Rachela Bleuel Department Dermatology and Allergy Biederstein Technical University of Munich, Germany Biedersteiner Strasse Munich, Germany rachela.bleuel@mri.tum.de References 1 Ezzedine K, Eleftheriadou V, Whitton M, van Geel N. Vitiligo. Lancet 2015 ; 386 : Alkhateeb A, Fain PR, Thody A et al. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res 2003 ; 16 : Shen C, Gao J, Sheng Y et al. Genetic Susceptibility to Vitiligo: GWAS Approaches for identifying vitiligo susceptibility genes and loci. Front Genet 2016 ; 7 : 3. 4 Schallreuter KU, Wood JM, Berger J. 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