Secondary Logo

Journal Logo

FEATURE ARTICLES

Vitiligo

A Comprehensive Overview

Stiegler, Julia; Brickley, Sylvana

Author Information
Journal of the Dermatology Nurses’ Association: 1/2 2021 - Volume 13 - Issue 1 - p 18-27
doi: 10.1097/JDN.0000000000000589

Abstract

BACKGROUND

Vitiligo is an acquired chronic disease of depigmented white macules and patches that result from destruction of melanocytes in the affected skin. Vitiligo is common and affects approximately 1% of the world population (Whitton et al., 2016). The disease has no prominent sex predilection. Onset may occur from shortly after birth until late adulthood, although over half of individuals are affected before the age of 20 years (Taïeb & Picardo, 2009; Porter et al., 1979). Flat white lesions of vitiligo can appear on any area of skin. The disease favors symmetric involvement of the face (particularly periorificial), hands, ankles, groin, and skin folds, with a predilection for sites of friction. Although the lesions of vitiligo are typically asymptomatic, the psychosocial impact and physical disfigurement of the condition are devastating to many patients and represent a significant healthcare burden. Treatments may restore pigment, but there is no cure.

Pathogenesis

Although the complex pathogenesis of vitiligo is incompletely understood, this multifactorial disease results in an absence of epidermal melanocytes in affected skin. The host immune system plays a clear role in disease pathogenesis with Th1, Th17, cytotoxic T cells, regulatory T cells, and dendritic cells found in affected tissues, as well as key mediators interferon-γ and interleukin-22 (Gregg et al., 2010; Klarquist et al., 2010; Lili et al., 2012; Rätsep et al., 2008). It is hypothesized that cytotoxic CD8+ T cells are the predominant cell type that attack melanocytes in vitiligo, leading to loss of function (Benzekri & Gauthier, 2017; Harris & Rashighi, 2018). Repigmentation of vitiligo is dependent on a viable melanocyte reservoir. Unaffected melanocytes, found deep in the hair follicle units of depigmented epidermis and at the periphery of vitiligo lesions, serve to repigment affected skin (Falabella & Barona, 2009). In many patients, repigmentation is possible if these melanocytes are stimulated with the appropriate topical or oral medications, often in combination with ultraviolet (UV) light (Falabella & Barona, 2009).

Genes play a significant role in the pathogenesis of vitiligo; however, these influences are complex and interact with nongenetic factors. A twin study of vitiligo in European-derived Whites found a 23% concordance of vitiligo in monozygotic twins, underscoring the importance of nongenetic factors (Alkhateeb et al., 2003). More recently, genome-wide association studies have identified 48 distinct genetic loci and a few specific genes that account for 22.5% of vitiligo heritability in European-derived Whites (Spritz & Andersen, 2017). Nearly all of the identified genes encode proteins involved in apoptosis, melanocyte function, and immunoregulation. These genetic findings underscore the autoimmune basis of vitiligo, which has been associated with other autoimmune diseases such as pernicious anemia, thyroid disease, Addison disease, systemic lupus erythematosus, rheumatoid arthritis, adult-onset Type 1 diabetes, and even psoriasis (Spritz & Andersen, 2017).

CLINICAL PRESENTATION

The most common presentation of vitiligo is depigmented or hypopigmented macules or patches that may vary in size from a few millimeters to several centimeters and are surrounded by normal skin. Well-developed lesions of vitiligo are completely depigmented with well-demarcated borders and may vary in shape from oval or round to linear or irregular. If hair-bearing areas are involved, the hair may turn white.

Physical Examination

During the physical examination of suspected vitiligo, the astute clinician must differentiate hypopigmented from depigmented skin. A Wood's lamp is a type of UV lamp that may be used for this purpose. Hypopigmented skin has decreased pigmentation because of a reduction in melanocytes or melanin. Depigmented skin represents the absence of functional melanocytes (Benzekri et al., 2012). Under a Wood's lamp, depigmented skin fluoresces a brilliant bright white whereas hypopigmented skin does not (Benzekri et al., 2012). As vitiligo is a depigmenting condition, the clinician can expect to observe bright white fluorescence of depigmented areas. Notable exceptions to this rule include areas of early vitiligo and the trichrome vitiligo variant, which may exhibit hypopigmented macules or patches next to depigmented lesions. Active lesions of nonsegmental vitiligo (NSV) may have a depigmented appearance with poorly or well-defined borders (Benzekri & Gauthier, 2017). An increased number of depigmented patches over sites of trauma, such as elbows, hands, and knees, represent the Koebner phenomenon (KP), a common finding in vitiligo (van Geel et al., 2019). Confetti-like depigmentation, trichromic and hypochromic lesions with poorly defined borders, inflammatory borders, itch, and leukotrichia are also associated with disease activity; however, more data are needed to establish their utility as potential markers (van Geel et al., 2019).

Koebner Phenomenon

A characteristic trait of vitiligo is the KP also known as “isomorphic response.” KP is defined as the development of lesions at the site of traumatized, previously uninvolved skin (Goh & Pandya, 2017) and is common in dermatologic diseases such as psoriasis and lichen planus. The KP is named after a German dermatologist, Heinrich Koebner (1838–1904), who observed that his patients with psoriasis developed new lesions at sites of trauma (Kobner, 1877). KP is estimated to occur in 21%–62% of patients with vitiligo (van Geel et al., 2011). KP helps to explain why vitiligo often presents in areas of friction and skin movement, such as the nasolabial folds, lateral canthi, eyelids, penis, shins, elbows, and the perioral region (van Geel et al., 2019). Patients may report KP by history, and careful examination may reveal linear macules of depigmentation at sites of friction or abrasions (Goh & Pandya, 2017).

Classifications of Vitiligo

In 2011, the Vitiligo European Taskforce convened at the Vitiligo Global Issues Consensus Conference and revised the classification of vitiligo. Table 1 below summarizes the classification of vitiligo according to the taskforce's consensus statement (Ezzedine, Diallo et al., 2012). The Vitiligo European Taskforce also recommended that the term vitiligo “vulgaris” not be used as it conveys a negative connotation, although “vulgaris” is synonymous with “common.” Many authors have attempted to classify vitiligo; however, for the purposes of this review, one classification was chosen for clarity.

TABLE 1 - Classification and Consensus Nomenclature of Vitiligo According to the VETF, 2011
Category of Vitiligo Subtype
Nonsegmental vitiligo Acrofacial
Mucosal (more than one mucosal site)
Generalized
Universal
Mixed
Segmental vitiligo Unisegmental, bisegmental, or plurisegmental
Undetermined/unclassified vitiligo Focal
Mucosal (one mucosal site in isolation)

Vitiligo is classified based on clinical presentation into two major forms, segmental vitiligo (SV) and NSV (Ezzedine, Diallo et al., 2012). Rare clinical variants of vitiligo such as focal, inflammatory, confetti-like or “punctate,” and trichrome have been reported but are difficult to definitively classify because they may fit into the general clinical spectrum of disease (Ezzedine, Diallo et al., 2012). Trichrome, inflammatory borders, and confetti-like lesions are considered potential markers of active lesions (Goh & Pandya, 2017; van Geel et al., 2019).

NSV has been used as umbrella term for different clinical subtypes of vitiligo that are clearly distinct from SV, including acrofacial, generalized, mucosal, and universal (Ezzedine, Diallo et al., 2012). NSV is characterized by depigmented macules that vary in size from a few to several centimeters in diameter, located on both sides of the body with a tendency towards symmetrical distribution. Acrofacial vitiligo affects the distal extremities and face. Generalized vitiligo implies more widespread distribution and more areas of involvement (Ezzedine, Diallo et al., 2012; Hann & Nordlund, 2000). Universal vitiligo involves complete or nearly complete depigmentation of skin; sometimes, body hair, oral mucosa, and/or genital mucosae are involved. Mixed vitiligo is when features of SV and NSV are present, often first presenting as SV and then progressing to NSV (Goh & Pandya, 2017).

SV is categorized into unisegmental, bisegmental, and plurisegmental subtypes. SV is typically associated with rapid onset and leukotrichia (Ezzedine, Diallo et al., 2012). Other authors have defined SV as a unilateral patch of depigmentation that does not cross the midline (Goh & Pandya, 2017). The face is most commonly affected in SV, followed by the trunk, neck, extremities, and scalp (Goh & Pandya, 2017).

Undetermined or unclassified types of vitiligo that are in the clinical spectrum of disease but excluded from other categories include focal vitiligo and mucosal vitiligo (Ezzedine, Diallo et al., 2012). Focal vitiligo describes a long-standing, depigmented lesion that does not progress to NSV or SV after 2 years (Ezzedine, Diallo et al., 2012; Goh & Pandya, 2017). The diagnosis of focal vitiligo should be considered after ruling out all other causes of focal hypopigmentation, such as nevus depigmentosus or trauma-induced leukoderma (Ezzedine, Lim et al., 2012; Goh & Pandya, 2017). Isolated mucosal vitiligo is rare but has been reported. Rare cases of lichen sclerosus simultaneously occurring with vitiligo and a vitiligoid variant of lichen sclerosus have been reported as well (Cooper et al., 2008; Dennin et al., 2018; Weisberg et al., 2008). Therefore, a biopsy may be warranted to confirm the diagnosis of vitiligo in patients presenting with depigmented macules isolated to the mucosa.

Punctate, inflammatory, and trichrome vitiligo are other rare clinical variants that may fall into the clinical spectrum of disease. Punctate vitiligo is characterized by depigmented confetti-like macules affecting any area of the body and should be differentiated from idiopathic guttate hypomelanosis (Falabella et al., 1988). These confetti-like macules have been reported as a marker of rapidly progressing disease (Goh & Pandya, 2017). When coinciding with NSV, punctate vitiligo should be classified as NSV; however, if observed in isolation, it should be referred to as punctate vitiligo (Ezzedine, Lim et al., 2012). Inflammatory vitiligo describes erythema sometimes seen at the borders of lesions and is thought to be a marker of disease activity (Benzekri et al., 2012; Goh & Pandya, 2017). Trichrome vitiligo is characterized by a combination of intermixed hypopigmented, normal, and depigmented skin. Trichrome vitiligo has been reported as a marker of rapid progression (Goh & Pandya, 2017; van Geel et al., 2011).

DIFFERENTIAL DIAGNOSIS AND DIAGNOSTIC EVALUATION

Differential Diagnosis

The differential diagnosis for depigmented macules, as seen in vitiligo, includes discoid lupus erythematosus, scleroderma, albinism, piebaldism, lichen sclerosus, medication- or chemical-induced leukoderma, and onchocerciasis (Bolognia et al., 2018). Mucosal vitiligo with isolated genital involvement should be evaluated with biopsy to rule out lichen sclerosus (Ezzedine, Diallo et al., 2012). The differential diagnosis for hypopigmented macules, as seen in the trichrome variant and early lesions of vitiligo, includes tinea versicolor, pityriasis alba, postinflammatory hypopigmentation, nevus depigmentosus, nevus anemicus, idiopathic guttate hypomelanosis, morphea, and mycosis fungoides (Bolognia et al., 2018).

Diagnostic Evaluation

A skin biopsy is rarely necessary to make the diagnosis of vitiligo but would show a lack of melanocytes in the affected skin. Wood's lamp examination is a widely accepted and cost-effective tool to differentiate the depigmented lesions of vitiligo from hypopigmented lesions.

Depending on patient history and a thorough review of systems, thyroid-stimulating hormone, antithyroid peroxidase antibody, free T4, antinuclear antibody, complete blood count with differential, and/or fasting blood glucose may be indicated to assess for comorbidities. Most patients do not have an accompanying autoimmune disease, and routine laboratory monitoring in asymptomatic patients is not recommended (Kroon et al., 2012).

PROGNOSIS

Vitiligo typically shows an insidious onset, and the natural progression of the disease is unpredictable. It may show slow spread with periods of stabilization or rapid evolution. Vitiligo may stabilize for years only to progress without clear cause (Rodrigues et al., 2017). SV typically reaches the full extent of involvement within 1–2 years and rarely spreads further. Spontaneous remission is rare with the exception of SV. However, the presence of halo nevi and leukotrichia in SV portends a higher likelihood of progression to mixed vitiligo (Ezzedine, Diallo et al., 2012).

Disease progression is clinically characterized by the appearance of new hypopigmented or depigmented macules, centrifugal enlargement of existing lesions, or both (Bolognia et al., 2018). Inflammatory vitiligo, trichrome vitiligo, peripheral hypopigmentation, and lesions with poorly defined borders are considered markers of high disease activity, and aggressive treatment should be considered (Benzekri et al., 2012; Goh & Pandya, 2017).

ASSOCIATED CONDITIONS

Association With Other Autoimmune Diseases

Patients with vitiligo have been found to have a higher incidence of autoimmune diseases such as thyroiditis, Type 1 diabetes, lupus, Addison disease, pernicious anemia, and alopecia areata (Spritz & Andersen, 2017). Many vitiligo susceptibility genes that encode proteins with immunoregulatory and apoptotic functions have been associated with other autoimmune diseases that vitiligo is epidemiologically associated with (Spritz & Andersen, 2017). Thyroid dysfunction was found in one large study to precede the onset of vitiligo (Kroon et al., 2012). A focused review of systems, medical history, and physical examination should be used to guide laboratory evaluation for autoimmune diseases.

Association With Melanoma

Vitiligo-like depigmentation may be seen in the setting of melanoma, and case reports have associated this with metastatic disease (Cho et al., 2009; Duhra & Ilchyshyn, 1991; Kiecker et al., 2006; Ortonne et al., 1978). It is presumed that the vitiligo-like depigmentation is secondary to an immune response against melanoma. The association is notable enough that, when an older adult presents with new-onset vitiligo, providers should complete a full skin examination to assess for suspicious pigmented lesions. Vitiligo can be triggered by melanoma immunotherapy including PD-1 and BRAF inhibitors and is considered a good prognostic sign (Hua et al., 2016).

FU1
FIGURE 1.:
Scattered depigmented macules of vitiligo. Photos Courtesy of A. Borger. Used with patient permission.
FU2
FIGURE 2.:
Scattered depigmented macules of vitiligo on the dorsal hand. Evidence of Koebner phenomenon be appreciated at the fingertips where there is depigmentation.
FU3
FIGURE 3.:
Depigmented patches on the upper and lower eyelids. This periocular location is very common in vitiligo. Photos Courtesy of A. Borger. Used with patient permission.
FU4
FIGURE 4.:
A and B, Depigmented macules and patches of the bilateral axillae.

Surprisingly, patients with vitiligo have a threefold lower probability of developing skin cancer, both melanoma and nonmelanoma types, compared with matched peers, despite exposure to higher levels of UV radiation (Paradisi et al., 2014; Spritz & Andersen, 2017; Teulings et al., 2013). At least six confirmed vitiligo loci encode melanocyte components or regulators of melanocyte function (Spritz & Andersen, 2017). These vitiligo loci have been implicated in both normal pigmentary variation and risk of melanoma, and all have shown a remarkable inverse relationship between the risk of vitiligo and melanoma (Jin et al., 2016; Spritz & Andersen, 2017). Further studies to elucidate the precise relationship between vitiligo and a lower melanoma risk are needed.

Association With Halo Nevi

Halo nevi are common through adolescence and have a striking clinical association with vitiligo. Two main theories regarding the association between halo nevi and vitiligo exist: (a) Halo nevi are a risk factor for developing vitiligo, and (b) halo nevi are an early sign of vitiligo (Barona et al., 1995). However, some cases of vitiligo clearly spare melanocytic nevi, so the precise relationship between the two remains to be fully elucidated (Jouary & Taieb, 2010).

TREATMENT

Early and aggressive treatment of vitiligo is associated with better outcomes, yet overall, treatment is only moderately effective (Harris & Rashighi, 2018). Some patients will choose to forego treatment based on personal preference; nevertheless, treatment should be offered to all patients (Rodrigues et al., 2017). Currently, there are no treatments with the indication of inducing repigmentation in vitiligo that are approved by the U.S. Food and Drug Administration (FDA). Most treatments used today target inflammation in a nonspecific manner and are used off-label to induce repigmentation of affected skin (Rodrigues et al., 2017). The only FDA-approved treatment for vitiligo is monobenzyl ether of hydroquinone cream, a depigmenting agent used to permanently lighten unaffected skin in rare cases of severe recalcitrant vitiligo.

Optimal treatment of vitiligo depends on the subtype of disease, percentage of body surface area (BSA) involved, effect on quality of life, and the patient's perception of the risk-to-benefit ratio (Rodrigues et al., 2017). Disease location and activity warrant consideration when determining an appropriate treatment plan. The aim of treatment is to prevent further destruction of melanocytes and enable stimulation of the growth and proliferation of existing melanocytes, leading to repigmentation (Bishnoi & Parsad, 2018).

A recent Cochrane review examined a wide range of interventions including topical treatments, surgical methods, and psychological therapies (Whitton et al., 2015). The quality of the examined studies was poor to moderate at best, most studies had fewer than 50 participants, and very few studies specifically included children (Whitton et al., 2016). The best evidence from individual trials showed short-term benefits from topical corticosteroids (TCSs) and various forms of UV radiation combined with topical preparations (Whitton et al., 2016). Further studies are needed to assess psychological interventions.

Topical Therapies

Initial therapy for vitiligo with minimal BSA involvement (<5%) includes TCSs and/or topical calcineurin inhibitors (TCIs). The site of the lesion and age of the patient should be considered when selecting a topical agent (Rodrigues et al., 2017). Potent or ultrapotent (Class I or II) TCSs are appropriate for treating the nonintertriginous torso and extremities of adults; less potent TCSs are less efficacious in this setting (Rodrigues et al., 2017). Children with vitiligo should be treated with midpotency TCSs or TCIs, depending on body location (Rodrigues et al., 2017). TCIs are recommended as a first-line treatment for the face, neck, and intertriginous areas of adults and children because of the potential for TCS-induced cutaneous atrophy, telangiectasia, and striae formation (Dillon et al., 2017; Rodrigues et al., 2017; Taieb et al., 2013). Regimens that include daily or twice-daily application of TCSs with “days off” in a cyclical fashion are commonly employed to avoid adverse effects of TCSs, although formal evidence to support this practice is lacking (Rodrigues et al., 2017).

Phototherapy

When vitiligo is extensive, rapidly spreading, or unresponsive to topical treatments, phototherapy alone or in combination with topical treatment is the mainstay of therapy. Whole-body phototherapy with narrowband UV-B (NB-UVB) or psoralen plus UV-A (PUVA) is indicated for extensive disease (>5%–10% BSA) and rapidly spreading diseases (Rodrigues et al., 2017). NB-UVB is the preferred method of phototherapy as it is at least as effective as PUVA with lower risks of burning and skin cancer (Bae et al., 2017; Rodrigues et al., 2017). NB-UVB phototherapy is also more widely available than PUVA and does not require pretreatment with ingestion of psoralen, which causes nausea at therapeutic doses and posttreatment sun sensitivity of the eyes and skin. The recent Cochrane review deemed PUVA to be inferior to NB-UVB in achieving >75% repigmentation in vitiligo, reinforcing the preference for NB-UVB (Whitton et al., 2015).

Phototherapy combined with topical treatment is preferred when >5%–10% BSA is affected or when focal areas are nonresponsive to topical treatment alone (Rodrigues et al., 2017). For localized diseases such as focal or acrofacial vitiligo, small NB-UVB phototherapy units or excimer laser may be preferred (Rodrigues et al., 2017). The greatest response to phototherapy should be anticipated on the face and neck (Bae et al., 2017).

Phototherapy sessions are needed for two to three sessions per week for at least 12 weeks to determine efficacy and then should be continued for at least several months in responders. Long-term phototherapy should be encouraged in responders to enhance treatment response (Bae et al., 2017). Patients should be counseled to not apply any topical products or sunscreens before phototherapy and should be vigilant about sun protection (Rodrigues et al., 2017). In-office phototherapy can be expensive and time consuming, so a home phototherapy unit may be considered for patients who wish to continue phototherapy long-term.

Surgical Treatment

Referral to a plastic surgeon or board-certified dermatologist for surgical treatment may be indicated for focal, stable vitiligo lesions that are recalcitrant to other therapies and cause the patient significant emotional distress. Surgical techniques include punch grafting, epidermal blister grafting, or cellular grafts that are used in concert with other ongoing treatments. The presence of unstable vitiligo lesions is a contraindication for surgical treatment (Benzekri et al., 2012).

Oral Treatment

For rapidly progressing NSV, oral pulse steroids with or without phototherapy may be warranted to slow or halt progression of the disease (Kanwar et al., 2013; Lee et al., 2016; Pasricha & Khaitan, 1993; Whitton et al., 2015).

EMERGING THERAPIES

A number of emerging therapies exist for vitiligo. Janus kinase (JAK) inhibitors, afamelanotide, and topical prostaglandins are potentially promising future therapies at the time of this writing.

Tofacitinib and ruxolitinib are JAK inhibitors that have shown promising regimentation in adult patients with vitiligo (Craiglow & King, 2015; Joshipura et al., 2018; Rothstein et al., 2017). JAK inhibitors are a class of medications that act on the JAK-signal transducer and activator of transcription pathway to block downstream cytokine-mediated signaling, which plays an important role in normal cell growth and immunoregulation (Cinats et al., 2018). A complete discussion of the JAK-signal transducer and activator of transcription pathway and the various processes through which it is implicated in autoimmune and malignant processes is outside the scope of this article and has been extensively reviewed prior (Borie et al., 2003; Darnell & Levy, 2002; Hirahara et al., 2016; Villarino et al., 2017).

Afamelanotide

Afamelanotide is a synthetic analog of alpha-melanocyte-stimulating hormone and melanocortin-1 receptor agonist that stimulates melanogenesis and is administered via subcutaneous implant (Lim et al., 2015). Afamelanotide is currently only FDA approved to treat erythropoietic protoporphyria. In 2015, a randomized multicenter trial reported that treatment of NSV with a combination of subcutaneous afamelanotide implant with NB-UVB therapy (n = 28) resulted in clinically apparent, statistically significant repigmentation compared with NB-UVB monotherapy alone (n = 27; Lim et al., 2015). Notable adverse events included erythema in both groups and minor infections and nausea in the combination therapy group. Other, less common cutaneous events included hyperpigmentation of unaffected skin, which was subjectively reported by all patients in the combination therapy group. No hyperpigmentation of unaffected skin was reported in the NB-UVB monotherapy group, suggesting that afamelanotide caused the hyperpigmentation of unaffected skin (Lim et al., 2015).

JAK Inhibitors

Ruxolitinib is a selective JAK1/JAK2 inhibitor available in oral and topical formulations (Cinats et al., 2018). Oral ruxolitinib is FDA approved for use in myelofibrosis and polycythemia vera (Cinats et al., 2018). Research on more selective JAK isoforms that inhibit a narrower range of cytokines is ongoing (Cinats et al., 2018).

Tofacitinib, a JAK1/JAK3 inhibitor, is also available in both oral and topical formulations. The oral formulation is FDA approved for the treatment of rheumatoid arthritis but has also been used off-label in various immune regulated disorders including alopecia areata. Recent case series and case reports have found that tofacitinib improved vitiligo disease severity when used topically or orally (Cinats et al., 2018; Craiglow & King, 2015; Kim et al., 2018).

Topical and oral JAK inhibitors are not currently FDA approved for the treatment of vitiligo. The most common adverse event of oral tofacitinib is infection. Unfortunately, oral tofacitinib has also been associated with an increased risk of malignancy (Cinats et al., 2018; McKesey & Pandya, 2019). Although oral JAK inhibitors have been shown to be effective in treating vitiligo in case series, the side effect profiles, including reported increased rates of infection and malignancy associated with oral tofacitinib and blood dyscrasias associated with oral ruxolitinib, potentially limit their use in a nonfatal condition such as vitiligo (Kim et al., 2018; Liu et al., 2017).

Topical formulations of JAK inhibitors are promising as they presumably will have fewer systemic side effects than oral formulations. Recent case series have shown promising results regarding topical formulations of JAK inhibitors for the treatment of vitiligo. In a recent study, 11 patients with facial vitiligo were treated for 2–4 months with tofacitinib 2% cream twice daily in conjunction with NB-UVB 3 times weekly. The investigators reported a mean improvement of 70%; however, they did not utilize a control group (McKesey & Pandya, 2019). In a case series of 10 patients treated for generalized vitiligo with oral tofacitinib, suction blister sampling revealed that the autoimmune response was inhibited during treatment in both responding and nonresponding lesions. This finding suggests that light was required for melanocyte regeneration in combination with oral tofacitinib (Liu et al., 2017). It is hypothesized that photoactivation is required to stimulate melanocytes to leave their stem cell niche and migrate to the epidermis while tofacitinib suppresses the autoimmune response (Kim et al., 2018). When used in conjunction with JAK inhibitors, the dose of NB-UVB phototherapy needed to stimulate repigmentation has been observed to be much lower than the dose required to achieve a similar effect with NB-UVB alone (Kim et al., 2018).

Phase 3 clinical trials investigating the use of topical ruxolitinib 1.5% cream in the treatment of vitiligo are ongoing (National Institutes of Health, 2020). Phase 2 clinical trials for topical ruxolitinib showed promising results, with 58% of subjects achieving at least 50% improvement of their vitiligo and 52% of subjects achieving at least 75% improvement after 1 year (Rosmarin et al., 2020).

Prostaglandin E2

Prostaglandin E2 (PGE2) is synthesized in skin and regulates melanocyte proliferation, in addition to affecting keratinocytes and Langerhans cells. PGE2 causes melanocyte proliferation and is commercially available as a gel. Preliminary studies have suggested that topical PGE2 may be effective in the treatment of vitiligo (Kapoor et al., 2009; Parsad et al., 2002). Although interesting, further studies are needed to confirm these results.

CONTROVERSIAL THERAPIES

Systemic antioxidants and pseudocatalase with NB-UVB have been examined for their utility in treating vitiligo; however, further studies are needed to determine their utility.

Pseudocatalase

Pseudocatalase cream has been proposed to work as a topical oxygen radical scavenger in the skin. Studies from Schallreuter and colleagues found that topical application of pseudocatalase enhanced repigmentation when combined with NB-UVB (Schallreuter et al., 2002, 1999, 1995). However, subsequent studies by different investigators were unable to reproduce these findings (Bakis-Petsoglou et al., 2009; Naini et al., 2012; Patel et al., 2002). Further research is needed to establish the utility of pseudocatalase as a potential treatment for vitiligo.

Systemic Antioxidants

Some providers may recommend use of systemic antioxidants on the hypothesis that vitiligo results from a deficiency of natural antioxidant mechanisms (Dell'Anna et al., 2007). Selenium, methionine, tocopherols, ascorbic acid, B12, folic acid, L-phenylalanine, Vitamin E, zinc sulphate, and ubiquinone are sometimes used (Dell'Anna et al., 2007; Falabella & Barona, 2009; Whitton et al., 2015). To date, no controlled clinical trials have been performed to validate the use of systemic antioxidants alone for the treatment of vitiligo. One randomized, double-blind, placebo-controlled, multicenter trial (n = 35) compared supplementation with an antioxidant pool that contained α-lipoic acid, Vitamins C and E, and polyunsaturated fatty acids combined with NB-UVB phototherapy with NB-UVB alone (Dell'Anna et al., 2007). No statistically significant difference in treatment response was found between the two groups (p = .226; Dell'Anna et al., 2007; Whitton et al., 2015).

PSYCHOSOCIAL AND CULTURAL CONSIDERATIONS

The unpredictable disease course and physical disfigurement associated with vitiligo are challenging for patients and may lead to psychological devastation and social stigmatization (Nguyen et al., 2016; Rzepecki et al., 2018). Although vitiligo is not life threatening, the social and psychological ramifications of the condition can be profound. Vitiligo may cause significant psychological morbidity, and patients have reported associated feelings of embarrassment, anxiety, and shame (Porter et al., 1979). The unpredictable and often unstable disease course and measures needed to cover up their disease with clothing and/or cosmetic products may create a perpetual psychological burden for patients (Nguyen et al., 2016). Many patients live in constant fear that their vitiligo will progress (Rzepecki et al., 2018).

In some cultures, vitiligo is a highly stigmatized disorder. This stigmatization may have significant psychosocial impacts. In Saudi Arabia, over 50% (n = 898) of surveyed individuals reported they would not consider marrying someone with vitiligo and were concerned the condition could be contagious (Nguyen et al., 2016). Depression has been found to be 5 times more likely among patients with vitiligo (p < .001; Rzepecki et al., 2018). The association of depression with vitiligo may be culturally influenced. Various studies found that the prevalence of depression associated with vitiligo ranged from 16.2% in Singapore to 31% in Italy, >50% in Arab societies, and 59% of Indian individuals (Nguyen et al., 2016). The ideal skin tone may vary between these cultures, which could contribute to the differences in reported prevalence of depression. Vitiligo is also more visible in darker skin types, which may contribute to these results. Clinicians should consider a holistic approach to treating vitiligo that includes consideration of the psychosocial and emotional impact of the disease on the patient.

From the Nursing Perspective

It is important to remember that, for most patients with vitiligo, although benign, the disease is a lifelong battle and may have significant psychosocial and emotional ramifications. It is important that nurses evaluate the individual impact on each patient with vitiligo to determine what level of treatment the patient feels is necessary and suitable. In the future, more research is needed to evaluate standardized rating tools that can help nurses assess the personal impact that vitiligo may have on a patient's life. One potential area of future research for nurses is to study the psychosocial impact of vitiligo and patient perception and adherence to various treatment modalities.

FU5

REFERENCES

Alkhateeb A., Fain P. R., Thody A., Bennett D. C., Spritz R. A. (2003). Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Research, 16(3), 208–214. 10.1034/j.1600-0749.2003.00032.x
Bae J. M., Jung H. M., Hong B. Y., Lee J. H., Choi W. J., Lee J. H., Kim G. M. (2017). Phototherapy for vitiligo: A systematic review and meta-analysis. JAMA Dermatology, 153(7), 666–674. 10.1001/jamadermatol.2017.0002
Bakis-Petsoglou S., Le Guay J. L., Wittal R. (2009). A randomized, double-blinded, placebo-controlled trial of pseudocatalase cream and narrowband ultraviolet B in the treatment of vitiligo. British Journal of Dermatology, 161(4), 910–917. 10.1111/j.1365-2133.2009.09252.x
Barona M. I., Arrunátegui A., Falabella R., Alzate A. (1995). An epidemiologic case–control study in a population with vitiligo. Journal of the American Academy of Dermatology, 33(4), 621–625.
Benzekri L., Gauthier Y. (2017). Clinical markers of vitiligo activity. Journal of the American Academy of Dermatology, 76(5), 856–862. 10.1016/j.jaad.2016.12.040
Benzekri L., Gauthier Y., Hamada S., Hassam B. (2012). Clinical features and histological findings are potential indicators of activity in lesions of common vitiligo. British Journal of Dermatology, 168(2), 265–271. 10.1111/bjd.12034
Bishnoi A., Parsad D. (2018). Clinical and molecular aspects of vitiligo treatments. International Journal of Molecular Sciences, 19(5), 1509. 10.3390/ijms19051509
Bolognia J., Schaffer J., Cerroni L. (2018). Dermatology. Elsevier.
Borie D. C., Si M. S., Morris R. E., Reitz B. A., Changelian P. S. (2003). JAK3 inhibition as a new concept for immune suppression. Current Opinion in Investigational Drugs, 4(11), 1297–1303.
Cho E. A., Lee M. A., Kang H., Lee S. D., Kim H. O., Park Y. M. (2009). Vitiligo-like depigmentation associated with metastatic melanoma of an unknown origin. Annals of Dermatology, 21(2), 178–181. 10.5021/ad.2009.21.2.178
Cinats A., Heck E., Robertson L. (2018). Janus kinase inhibitors: A review of their emerging applications in dermatology. Skin Therapy Letter, 23(3), 5–9.
Cooper S. M., Ali I., Baldo M., Wojnarowska F. (2008). The association of lichen sclerosus and erosive lichen planus of the vulva with autoimmune disease: A case–control study. Archives of Dermatology, 144(11), 1432–1435. 10.1001/archderm.144.11.1432
Craiglow B. G., King B. A. (2015). Tofacitinib citrate for the treatment of vitiligo: A pathogenesis-directed therapy. JAMA Dermatology, 151(10), 1110–1112. 10.1001/jamadermatol.2015.1520
Darnell J. E., Levy D. E. (2002). STATs: Transcriptional control and biological impact. Nature Reviews Molecular Cell Biology, 3(9), 651–662. 10.1038/nrm909
Dell'Anna M. L., Mastrofrancesco A., Sala R., Venturini M., Ottaviani M., Vidolin A. P., Leone G., Calzavara P. G., Westerhof W., Picardo M. (2007). Antioxidants and narrow band-UVB in the treatment of vitiligo: A double-blind placebo controlled trial. Clinical and Experimental Dermatology: Clinical Dermatology, 32(6), 631–636. 10.1111/j.1365-2230.2007.02514.x
Dennin M. H., Stein S. L., Rosenblatt A. E. (2018). Vitiligoid variant of lichen sclerosus in young girls with darker skin types. Pediatric Dermatology, 35(2), 198–201. 10.1111/pde.13399
Dillon A. B., Sideris A., Hadi A., Elbuluk N. (2017). Advances in vitiligo: An update on medical and surgical treatments. The Journal of Clinical and Aesthetic Dermatology, 10(1), 15–28.
Duhra P., Ilchyshyn A. (1991). Prolonged survival in metastatic malignant melanoma associated with vitiligo. Clinical and Experimental Dermatology, 16(4), 303–305. 10.1111/j.1365-2230.1991.tb00383.x
Ezzedine K., Diallo A., Léauté-Labrèze C., Séneschal J., Prey S., Ballanger F., Alghamdi K., Cario-André M., Jouary T., Gauthier Y., Taieb A. (2012). Halo naevi and leukotrichia are strong predictors of the passage to mixed vitiligo in a subgroup of segmental vitiligo. British Journal of Dermatology, 166(3), 539–544. 10.1111/j.1365-2133.2011.10709.x
Ezzedine K., Lim H. W., Suzuki T., Katayama I., Hamzavi I., Lan C. C. E., Goh B. K., Anbar T., Silva de Castro C., Lee A. Y., Parsad D., van Geel N., Le Poole I. C., Oiso N., Benzekri L., Spritz R., Gauthier Y., Hann S. K., Picardo M., Taieb A.; Vitiligo Global Issue Consensus Conference Panelists (2012). Revised classification/nomenclature of vitiligo and related issues: The Vitiligo Global Issues Consensus Conference. Pigment Cell & Melanoma Research, 25(3), E1–E13. 10.1111/j.1755-148X.2012.00997.x
Falabella R., Barona M. I. (2009). Update on skin repigmentation therapies in vitiligo. Pigment Cell & Melanoma Research, 22(1), 42–65. 10.1111/j.1755-148X.2008.00528.x
Falabella R., Escobar C. E., Carrascal E., Arroyave J. A. (1988). Leukoderma punctata. Journal of the American Academy of Dermatology, 18(3), 485–494. 10.1016/s0190-9622(88)70071-7
Goh B. K., Pandya A. G. (2017). Presentations, signs of activity, and differential diagnosis of vitiligo. Dermatologic Clinics, 35(2), 135–144. 10.1016/j.det.2016.11.004
Gregg R. K., Nichols L., Chen Y., Lu B., Engelhard V. H. (2010). Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase-specific TCR transgenic mice. Journal of Immunology, 184(4), 1909–1917. 10.4049/jimmunol.0902778
Hann S. K., Nordlund J. J. (2000). Clinical features of generalized vitiligo. In Vitiligo: a monograph on the basic and clinical science (Vol. 1, pp. 35–49).
Hirahara K., Schwartz D., Gadina M., Kanno Y., O'Shea J. J. (2016). Targeting cytokine signaling in autoimmunity: Back to the future and beyond. Current Opinion in Immunology, 43, 89–97.
Hua C., Boussemart L., Mateus C., Routier E., Boutros C., Cazenave H., Viollet R., Thomas M., Roy S., Benannoune N., Tomasic G., Soria J. C., Champiat S., Texier M., Lanoy E., Robert C. (2016). Association ofvitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatology, 152(1), 45–51.
Jin Y., Andersen G., Yorgov D., Ferrara T. M., Ben S., Brownson K. M., Holland P. J., Birlea S. A., Siebert J., Hartmann A., Lienert A., van Geel N., Lambert J., Luiten R. M., Wolkerstorfer A., Wietze van der Veen J. P., Bennett D. C., Taïeb A., Ezzedine K., Spritz R. A. (2016). Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nature Genetics, 48(11), 1418–1424. 10.1038/ng.3680
Joshipura D., Alomran A., Zancanaro P., Rosmarin D. (2018). Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib: A 32-week open-label extension study with optional narrow-band ultraviolet B. Journal of the American Academy of Dermatology, 78(6), 1205–1207.e1. 10.1016/j.jaad.2018.02.023
Jouary T., Taieb A. (2010). Halo nevi and vitiligo. In Taieb A., Picardo M. (Eds.), Vitiligo  (pp. 61–64). Springer-Verlag.
Kanwar A. J., Mahajan R., Parsad D. (2013). Low-dose oral mini-pulse dexamethasone therapy in progressive unstable vitiligo. Journal of Cutaneous Medicine and Surgery, 17(4), 259–268. 10.2310/7750.2013.12053
Kapoor R., Phiske M. M., Jerajani H. R. (2009). Evaluation of safety and efficacy of topical prostaglandin E2 in treatment of vitiligo. British Journal of Dermatology, 160(4), 861–863. 10.1111/j.1365-2133.2008.08923.x
Kiecker F., Hofmann M., Sterry W., Trefzer U. (2006). Vitiligo-like depigmentation as a presenting sign of metastatic melanoma. Journal of the European Academy of Dermatology and Venereology, 20(9), 1135–1137. 10.1111/j.1468-3083.2006.01628.x
Kim S. R., Heaton H., Liu L. Y., King B. A. (2018). Rapid repigmentation of vitiligo using tofacitinib plus low-dose, narrowband UV-B phototherapy. Journal of the American Academy of Dermatology, 154(3), 370–371. 10.1001/jamadermatol.2017.5778
Klarquist J., Denman C. J., Hernandez C., Wainwright D. A., Strickland F. M., Overbeck A., Mehrotra S., Nishimura M. I., Le Poole I. C. (2010). Reduced skin homing by functional Treg in vitiligo. Pigment Cell & Melanoma Research, 23(2), 276–286. 10.1111/j.1755-148X.2010.00688.x
Kobner H. (1877). Zur atiologie der psoriasis. Vjschr Dermatologist, 3(559).
Kroon M. W., Joore I. C. K. W., Wind B. S., Leloup M. A. C., Wolkerstorfer A., Luiten R. M., Bos J. D., Geskus R. B., van der Veen J. P. W. (2012). Low yield of routine screening for thyroid dysfunction in asymptomatic patients with vitiligo. British Journal of Dermatology, 166(3), 532–538. 10.1111/j.1365-2133.2011.10717.x
Lee J., Chu H., Lee H., Kim M., Kim D. S., Oh S. H. (2016). A retrospective study of methylprednisolone mini-pulse therapy combined with narrow-band UVB in non-segmental vitiligo. Dermatology (Basel, Switzerland), 232(2), 224–229. 10.1159/000439563
Lili Y., Yi W., Ji Y., Yue S., Weimin S., Ming L. (2012). Global activation of CD8+ cytotoxic T lymphocytes correlates with an impairment in regulatory T cells in patients with generalized vitiligo. PLoS One, 7(5) e37513. 10.1371/journal.pone.0037513
Lim H. W., Grimes P. E., Agbai O., Hamzavi I., Henderson M., Haddican M., Linkner R. V., Lebwohl M. (2015). Afamelanotide and narrowband UV-B phototherapy for the treatment of vitiligo: A randomized multicenter trial. JAMA Dermatology, 151(1), 42–50. 10.1001/jamadermatol.2014.1875
Liu L. Y., Strassner J. P., Refat M. A., Harris J. E., King B. A. (2017). Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure. Journal of the American Academy of Dermatology, 77(4), 675–682.e1. 10.1016/j.jaad.2017.05.043
McKesey J., Pandya A. G. (2019). A pilot study of 2% tofacitinib cream with narrowband ultraviolet B for the treatment of facial vitiligo. Journal of the American Academy of Dermatology, 81, 646–648. 10.1016/j.jaad.2019.04.032
Naini F. F., Shooshtari A. V., Ebrahimi B., Molaei R. (2012). The effect of pseudocatalase/superoxide dismutase in the treatment of vitiligo: A pilot study. Journal of Research in Pharmacy Practice, 1(2), 77–80. 10.4103/2279-042X.108375
National Institutes of Health. (2020). A study of INCB018424 phosphate cream in subjects with vitiligo. https://clinicaltrials.gov/ct2/show/NCT03099304
Nguyen C. M., Beroukhim K., Danesh M. J., Babikian A., Koo J., Leon A. (2016). The psychosocial impact of acne, vitiligo, and psoriasis: A review. Clinical, Cosmetic and Investigational Dermatology, 9, 383–392. 10.2147/CCID.S76088
Ortonne J. P., Gauthier Y., Guillet G., Gauthier O. (1978). Dépigmentation cutanée associée au mélanome malin [Hypomelanosis of the skin and malignant melanoma (author's translation)]. Annales de Dermatologie et de Venereologie, 105(12), 1043–1052.
Paradisi A., Tabolli S., Didona B., Sobrino L., Russo N., Abeni D. (2014). Markedly reduced incidence of melanoma and nonmelanoma skin cancer in a nonconcurrent cohort of 10,040 patients with vitiligo. Journal of the American Academy of Dermatology, 71(6), 1110–1116. 10.1016/j.jaad.2014.07.050
Parsad D., Pandhi R., Dogra S., Kumar B. (2002). Topical prostaglandin analog (PGE2) in vitiligo—A preliminary study. International Journal of Dermatology, 41(12), 942–945. 10.1046/j.1365-4362.2002.01612.x
Pasricha J. S., Khaitan B. K. (1993). Oral mini-pulse therapy with betamethasone in vitiligo patients having extensive or fast-spreading disease. International Journal of Dermatology, 32(10), 753–757. 10.1111/j.1365-4362.1993.tb02754.x
Patel D. C., Evans A. V., Hawk J. L. M. (2002). Topical pseudocatalase mousse and narrowband UVB phototherapy is not effective for vitiligo: An open, single-centre study. Clinical and Experimental Dermatology, 27(8), 641–644. 10.1046/j.1365-2230.2002.01142.x
Porter J., Beuf A. H., Nordlund J. J., Lerner A. B. (1979). Psychological reaction to chronic skin disorders: A study of patients with vitiligo. General Hospital Psychiatry, 1(1), 73–77. 10.1016/0163-8343(79)90081-1
Rashighi M., Harris J. E. (2017). Vitiligo pathogenesis and emerging treatments. Dermatologic Clinics, 35(2), 257–265. 10.1016/j.det.2016.11.014
Rätsep R., Kingo K., Karelson M., Reimann E., Raud K., Silm H., Vasar E., Kõks S. (2008). Gene expression study of IL10 family genes in vitiligo skin biopsies, peripheral blood mononuclear cells and sera. The British Journal of Dermatology, 159(6), 1275–1281. 10.1111/j.1365-2133.2008.08785.x
Rodrigues M., Ezzedine K., Hamzavi I., Pandya A. G., Harris J.; Vitiligo Working Group (2017). Current and emerging treatments for vitiligo. Journal of the American Academy of Dermatology, 77(1), 17–29. 10.1016/j.jaad.2016.11.010
Rosmarin D., Pandya A. G., Lebwohl M., Grimes P., Hamzavi I., Gottlieb A. B., Butler K., Kuo V., Sun K., Ji T., Howell M. D., Harris J. E. (2020). Ruxolitinib cream for treatment of vitiligo: A randomised, controlled, phase 2 trial. Lancet (London, England), 396(10244), 110–120. https://doi.org/10.1016/S0140-6736(20)30609-7
Rothstein B., Joshipura D., Saraiya A., Abdat R., Ashkar H., Turkowski Y., Sheth V., Huang V., Au S. C., Kachuk C., Dumont N., Gottlieb A. B., Rosmarin D. (2017). Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib. Journal of the American Academy of Dermatology, 76(6), 1054–1060.e1. 10.1016/j.jaad.2017.02.049
Rzepecki A., McLellan B., Elbuluk N. (2018). Beyond traditional treatment: The importance of psychosocial therapy in vitiligo. Journal of Drugs in Dermatology, 17(6), 688–691.
Schallreuter K. U., Moore J., Behrens-Williams S., Panske A., Harari M. (2002). Rapid initiation of repigmentation in vitiligo with Dead Sea climatotherapy in combination with pseudocatalase (PC-KUS). International Journal of Dermatology, 41(8), 482–487. 10.1046/j.1365-4362.2002.01463.x
Schallreuter K. U., Moore J., Wood J. M., Beazley W. D., Gaze D. C., Tobin D. J., Marshall H. S., Panske A., Panzig E., Hibberts N. A. (1999). In vivo and in vitro evidence for hydrogen peroxide (H2O2) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase. The Journal of Investigative Dermatology. Symposium Proceedings, 4(1), 91–96. 10.1038/sj.jidsp.5640189
Schallreuter K. U., Wood J. M., Lemke K. R., Levenig C. (1995). Treatment of vitiligo with a topical application of pseudocatalase and calcium in combination with short-term UVB exposure: A case study on 33 patients. Dermatology (Basel, Switzerland), 190(3), 223–229. 10.1159/000246690
Spritz R. A., Andersen G. H. (2017). Genetics of vitiligo. Dermatologic Clinics, 35(2), 245–255. 10.1016/j.det.2016.11.013
Taieb A., Alomar A., Böhm M., Dell'Anna M. L., De Pase A., Eleftheriadou V., Ezzedine K., Gauthier Y., Gawkrodger D. J., Jouary T., Leone G., Moretti S., Nieuweboer-Krobotova L., Olsson M. J., Parsad D., Passeron T., Tanew A., van der Veen W., van Geel N., Whitton M.; Union Européenne des Médecins Spécialistes (UEMS) (2013). Guidelines for the management of vitiligo: The European Dermatology Forum consensus. The British Journal of Dermatology, 168(1), 5–19. 10.1111/j.1365-2133.2012.11197.x
Taïeb A., Picardo M. (2009). Clinical practice. Vitiligo. The New England Journal of Medicine, 360(2), 160–169. 10.1056/NEJMcp0804388
Teulings H. E., Overkamp M., Ceylan E., Nieuweboer-Krobotova L., Bos J. D., Nijsten T., Wolkerstorfer A. W., Luiten R. M., van der Veen J. P. W. (2013). Decreased risk of melanoma and nonmelanoma skin cancer in patients with vitiligo: A survey among 1307 patients and their partners. The British Journal of Dermatology, 168(1), 162–171. 10.1111/bjd.12111
van Geel N., Speeckaert R., Taieb A., Picardo M., Böhm M., Gawkrodger D. J., Schallreuter K., Bennett D. C., van der Veen W., Whitton M., Moretti S., Westerhof W., Ezzedine K., Gauthier Y.; VETF Members (2011). Koebner's phenomenon in vitiligo: European position paper. Pigment Cell & Melanoma Research, 24(3), 564–573. 10.1111/j.1755-148X.2011.00838.x
van Geel N., Grine L., De Wispelaere P., Mertens D., Prinsen C., Speeckaert R. (2019). Clinical visible signs of disease activity in vitiligo: A systematic review and meta-analysis. Journal of the European Academy of Dermatology and Venereology: JEADV, 33(9), 1667–1667. 10.1111/jdv.15604
Villarino A. V., Kanno Y., O'Shea J. J. (2017). Mechanisms and consequences of JAK–STAT signaling in the immune system. Nature Immunology, 18(4), 374–384.
Weisberg E. L., Le L. Q., Cohen J. B. (2008). A case of simultaneously occurring lichen sclerosus and segmental vitiligo: Connecting the underlying autoimmune pathogenesis. International Journal of Dermatology, 47(10), 1053–1055. 10.1111/j.1365-4632.2008.03623.x
Whitton M., Pinart M., Batchelor J. M., Leonardi-Bee J., Gonzalez U., Jiyad Z., Eleftheriadou V., Ezzedine K. (2016). Evidence-based management of vitiligo: Summary of a Cochrane systematic review. The British Journal of Dermatology, 174(5), 962–969. 10.1111/bjd.14356
Whitton M. E., Pinart M., Batchelor J., Leonardi-Bee J., González U., Jiyad Z., Eleftheriadou V., Ezzedine K. (2015). Interventions for vitiligo. The Cochrane Database of Systematic Reviews, 2, CD003263. 10.1002/14651858.CD003263.pub5
Keywords:

Vitiligo

Copyright © 2020 by the Dermatology Nurses’ Association.