Vitiligo: Management and prognosis

INTRODUCTION — Vitiligo is a common, acquired, autoimmune, chronic disorder of pigmentation characterized by the development of white macules on the skin due to loss of epidermal melanocytes [1,2]. The depigmented areas are often symmetrical and usually increase in size with time. Given the contrast between the white patches and areas of normal skin, the disease is most disfiguring in darker skin types and has a profound impact on the quality of life of children and adults [3,4]. Patients with vitiligo often experience stigmatization, isolation, and low self-esteem [5-8].

Although there is no cure for the disease, the available treatments may halt the progression of the disease and induce varying degrees of repigmentation, with acceptable cosmetic results in many cases. This topic review will discuss the management of vitiligo. The pathogenesis, clinical features, and diagnosis of vitiligo are discussed separately. Other pigmentation disorders are also discussed separately.

●(See "Vitiligo: Pathogenesis, clinical features, and diagnosis".)y

●(See "Acquired hypopigmentation disorders other than vitiligo".)

●(See "Pigmentary mosaicism (hypomelanosis of Ito)".)

PATIENT EVALUATION — The evaluation of the patient with vitiligo involves a detailed history and a complete skin examination to assess disease severity and individual prognostic factors.

History and physical examination — Important elements of history include:

●Age at onset of lesions

●Family history of vitiligo and/or other autoimmune diseases

●Rate of progression or spread of lesions

●Presence of concomitant diseases

●Current medications and supplements

●Occupation (exposure to chemicals)

●Effects of disease on the quality of life

These aspects of the history influence the diagnostic work-up, therapeutic interventions for stabilization and repigmentation, long-term follow-up, and prognosis.

A full-body skin examination should be performed to assess [9]:

●Type of vitiligo (segmental, nonsegmental)

●Extent of the disease, with particular attention to sites of vitiligo predilection, such as the lips and perioral area, periocular areas, dorsal surface of the hands, fingers, flexor surface of the wrists, elbows, axillae, nipples, umbilicus, sacrum, inguinal/anogenital regions, and knees

●Mucosal involvement

●Koebner phenomenon

●Poliosis (leukotrichia)

●Trichrome and confetti pattern

The percentage of the body area involved can be estimated by the so-called 1 percent rule or "palm method." In both children and adults, the palm of the hand (including the fingers) is approximately 1 percent of the total body surface area (TBSA), while the palm (excluding the fingers) is approximately 0.5 percent of the TBSA. An alternative method is the "rule of nines":

●Each leg represents 18 percent of the TBSA.

●Each arm represents 9 percent of the TBSA.

●The anterior and posterior trunk each represent 18 percent of the TBSA.

●The head and neck represent 9 percent of the TBSA.

●The genital area represents 1 percent of the TBSA.

Setting the goals of treatment — The goals of treatment for vitiligo should be set with the individual patient or parents/caregivers, in the case of children, based upon the patient's age and skin type; the extent, location, and degree of disease activity; and the impact of the disease on the patient's quality of life. An open discussion with the patient about the limitations of treatment may be helpful to create realistic expectations.

Nonsegmental vitiligo, which is the most common type of vitiligo, has an unpredictable course, and treatment is often challenging. However, multiple therapies, including topical agents, light therapies, and autologous grafting procedures, have demonstrated efficacy for repigmentation [10]. The response to treatments is generally slow and may be highly variable among patients and among different body areas in the same patient. The best outcomes are often achieved in darker skin types (Fitzpatrick IV to VI), although satisfactory results are also often seen in lighter skin types (Fitzpatrick II, III) [11]. Facial and truncal lesions respond best to treatment, while acral areas are extremely difficult to treat. Optimal repigmentation often correlates with the density of spared hair follicles within the affected site. The highest density of hair follicles is found on the face, while the lowest density areas include acral sites, such as the hands, feet, and volar surfaces [12]. (See 'Nonsegmental vitiligo involving <10 percent of the body surface area' below and 'Nonsegmental vitiligo involving 10 to 40 percent of the body surface area' below and 'Nonsegmental stable vitiligo involving >40 percent of the body surface area' below.)

Segmental vitiligo is a less common type of vitiligo. It often begins in childhood and has a much more predictable course. In the vast majority of patients, there is minimal progression after one or two years of disease onset. While segmental vitiligo may be more therapeutically challenging compared with nonsegmental disease, the best outcomes are achieved with autologous grafting procedures. (See 'Segmental vitiligo' below.)

OUR APPROACH

General considerations — Our approach to the management of patients with vitiligo is generally consistent with published guidelines [13-15]. Topical, systemic, and light-based therapies are available for stabilization and repigmentation of vitiligo (table 1) [16-20]. Treatment modalities are chosen in the individual patient, based on:

●Disease severity

●Disease activity (stable [no increase in size of existing lesions and absence of new lesions in the previous three to six months] versus progressive disease)

●Patient preference (including cost and accessibility)

●Response evaluation

Combination therapies, such as phototherapy plus topical or oral corticosteroids, calcineurin inhibitors, or, less commonly, vitamin D analogues, appear to be more effective than single therapies [21]. Despite treatment, however, vitiligo has a highly unpredictable course, and the long-term persistence of repigmentation cannot be predicted [21].

Camouflage, if desired, can be beneficial during treatment or as an alternative to treatment for patients with vitiligo affecting exposed areas, such as the face, neck, and hands. (See 'Camouflage' below.)

Stabilization of rapidly progressive disease

Systemic glucocorticoids — For patients who experience rapid progression of vitiligo, with depigmented macules spreading over a few weeks or months, we suggest low-dose oral glucocorticoids as first-line therapy for the stabilization (cessation of spread) of the disease (table 1). Oral prednisone is given at the dose of 5 to 10 mg per day in children and 10 to 20 mg per day in adults for a maximum of two weeks. If needed, treatment can be repeated in four to six weeks. In adult patients, alternatives to oral prednisone include oral minipulse therapy with dexamethasone 2.5 mg on two consecutive days weekly for an average of three months or intramuscular triamcinolone 40 mg in a single administration. Treatment with triamcinolone can be repeated in four to six weeks for a maximum of three injections.

Stabilization therapy can be given alone or in combination with phototherapy. In our experience, for patients with active, disseminated disease affecting multiple anatomic sites, concurrent initiation of systemic corticosteroids and narrowband ultraviolet B (NBUVB) phototherapy may be more effective than oral corticosteroids alone. The disease is expected to stabilize in one to three months. (See 'Phototherapy' below.)

Evidence for the efficacy of systemic glucocorticoids in halting the spread of vitiligo is limited to a few uncontrolled studies [22-24]:

●In one study, 81 patients were treated with prednisolone 0.3 mg/kg per day for two months, and then the dose was progressively reduced in the subsequent three months [22]. Control of disease progression was achieved in approximately 90 percent of patients and repigmentation in 74 percent of patients.

●In another study, 40 patients with extensive or rapidly spreading vitiligo were treated with oral minipulses of betamethasone or dexamethasone (5 mg in single dose) on two consecutive days per week for several months. After one to three months, vitiligo progression was arrested in 32 of 36 patients with active disease [23].

●A retrospective study assessed 40 patients with vitiligo receiving either oral minipulse dexamethasone 4 mg on two consecutive days per week plus NBUVB and topical clobetasol (n = 25) or NBUVB plus clobetasol (n = 15). Disease arrest was achieved in 23 of 25 patients (92 percent) in the dexamethasone minipulse group compared with 8 of 15 patients (53 percent) in the control group [25].

It is important to note that oral corticosteroids alone are not effective as a repigmenting therapy for progressing vitiligo. In a small, open-label trial, 86 patients with progressive nonsegmental vitiligo were treated with oral minipulses of betamethasone (0.1 mg/kg twice weekly on two consecutive days for three months followed by 1 mg every month for the following three months) alone or in combination with psoralen plus ultraviolet A (PUVA), NBUVB, or broadband ultraviolet B (UVB) [26]. At six months, marked or moderate improvement was achieved in 15 percent of patients treated with corticosteroids alone versus 85 percent of patients treated with corticosteroids plus PUVA, 81 percent of those treated with corticosteroids plus NBUVB, and 33 percent of those treated with corticosteroids plus broadband UVB.

Phototherapy — In both adults and children in whom systemic corticosteroids are contraindicated, targeted UVB phototherapy or NBUVB phototherapy may be used alone to stabilize active vitiligo [27]. NBUVB is administered two to three times weekly. NBUVB requires six months to one year of treatment to achieve optimal outcomes for stabilization and repigmentation. (See 'Narrowband ultraviolet B phototherapy' below.)

Other — Systemic immunosuppressants, such as cyclosporine, methotrexate, and mycophenolate mofetil, have been used in a few patients with active vitiligo as an alternative to systemic corticosteroids [28-31]. In a randomized study that included 50 patients with active vitiligo, mycophenolate mofetil given at a dose of up to 2 g per day for six months was as effective as dexamethasone minipulses (2.5 mg on two successive days a week) [28]. While the frequency of adverse effects was similar in both groups, two patients discontinued treatment due to mycophenolate-related complications.

Two studies reported stabilization of vitiligo using minocycline 100 mg daily for three to six months [32,33]. Suggested mechanisms for minocycline's therapeutic effect in stabilizing vitiligo include inhibition of free radical formation and cytokine production [34].

Nonsegmental vitiligo involving <10 percent of the body surface area

Localized disease — In patients with nonsegmental stable vitiligo (no increase in size of existing lesions and absence of new lesions in the previous three to six months) that involves less than 10 percent of the total body surface area (TBSA) and is limited to the face, neck, trunk, or extremities (picture 1A-B), mid- to high-potency topical corticosteroids (groups 2 to 4 (table 2)) or topical calcineurin inhibitors are first-line therapies [14,35]. Topical ruxolitinib is a therapeutic option for patients with poor or no response to topical corticosteroids or topical calcineurin inhibitors but can also be considered a first-line topical agent in select patients. Ruxolitinib 1.5% cream is the first therapy to be approved by the US Food and Drug Administration (FDA) for vitiligo after monobenzyl ether of hydroquinone (which is approved for final depigmentation in extensive vitiligo):

●Topical corticosteroids – Mid- to high-potency topical corticosteroids are applied to the involved skin twice and once daily, respectively. Agents with negligible systemic or local side effects, such as mometasone furoate, are preferred [14]. Superpotent corticosteroids (eg, clobetasol) provide substantial efficacy for repigmentation of trunk and extremity lesions.

There are no studies evaluating the optimal duration of treatment with topical corticosteroids. In the author's experience, topical corticosteroids can be used safely for two months, interrupted for one month, and then resumed for an additional two or three months. Others suggest a discontinuous scheme (eg, once-daily application for 15 days per month for six months) [13,14,36].

Patients must be monitored closely for adverse effects of topical corticosteroids, which include skin atrophy, telangiectasias, hypertrichosis, and acneiform eruptions. Limited quantities should be prescribed. (See "Topical corticosteroids: Use and adverse effects".)

●Topical calcineurin inhibitors – The topical calcineurin inhibitors tacrolimus (0.03% in children and 0.1% in adults) and pimecrolimus 1% are preferred to topical corticosteroids for patients with limited vitiligo involving the face or areas at high risk for skin atrophy (eg, intertriginous areas, genitals).

Topical calcineurin inhibitors are generally applied twice daily. They can also be used in combination with a topical corticosteroid for the first month or two, applying each one once daily.

The efficacy of tacrolimus and pimecrolimus alone or in combination with other therapies for the treatment of nonsegmental vitiligo has been evaluated in several randomized trials and meta-analyses including either adults or children with vitiligo [37-42]:

•In a randomized trial, 100 children (55 children with facial vitiligo and 45 children with nonfacial vitiligo) were treated with a topical corticosteroid (clobetasol propionate 0.05%), tacrolimus 0.1%, or placebo for six months [43]. Among children with facial vitiligo, the success rate (defined as repigmentation >50 percent) was the same in the topical corticosteroid and tacrolimus groups (58 percent). However, among children with nonfacial vitiligo, the success rate was higher in the topical corticosteroid group compared with the tacrolimus group (39 versus 23 percent). The success rate in the placebo group was 7 percent.

•In a randomized trial that included 42 adult patients with facial vitiligo, tacrolimus 0.1% ointment applied twice daily induced ≥75 percent repigmentation of the target lesion at week 24 in 65 percent of patients in the tacrolimus group compared with 0 percent of patients in the vehicle group [42].

•In a 12-week, open, randomized study, 53 patients with vitiligo were treated with 308 nm monochromatic excimer light (MEL) twice weekly plus 0.1% tacrolimus and oral vitamin E daily, 308 nm MEL twice weekly plus daily oral vitamin E, or daily oral vitamin E alone [44]. At the end of the study, good to excellent repigmentation was achieved in 70 percent of patients in the MEL plus tacrolimus and vitamin E group, 55 percent of those in the MEL plus vitamin E group, and in none of the patients in the vitamin E group.

•In an open trial, 40 children with nonsegmental, focal, or segmental vitiligo were treated with 0.1% mometasone furoate cream once daily or 1% pimecrolimus cream twice daily for three months [45]. Moderate or marked responses were seen in 11 patients (55 percent) in the mometasone furoate group and in 7 patients (35 percent) in the pimecrolimus group, but the difference was not statistically significant.

The use of topical calcineurin inhibitors does not seem to be associated with an increased risk for skin or systemic malignancies [46-49]. Labeling recommends that these agents should not be used in combination with ultraviolet light therapy. However, a retrospective, cohort study of 25,694 patients with vitiligo who received topical calcineurin inhibitors or phototherapy for six weeks or more between 2001 and 2019 did not show an increase in skin cancer [50].

●Topical ruxolitinib – Topical ruxolitinib is a Janus kinase (JAK) inhibitor approved by the US FDA in July 2022 and by the European Medicines Agency (EMA) in February 2023 for the treatment of nonsegmental vitiligo affecting ≤10 percent of the body surface area (BSA), including the face, in patients ≥12 years [51]. It can be used as first- or second-line treatment in any patient with vitiligo meeting the FDA-approved criteria.

Topical ruxolitinib 1.5% cream is applied as a thin layer to the affected areas twice daily (maximum dose 60 g per week) for up to 52 weeks [52]. Due to the safety concerns listed in a boxed warning in the prescribing information, patients should be monitored for efficacy and adverse effects [51]. Treatment should be discontinued if no response is noted in six months.

The efficacy of topical ruxolitinib versus placebo for vitiligo has been evaluated in one phase 2, randomized trial and two phase 3, randomized trials:

•In a randomized, phase 2 trial, 157 adult patients with vitiligo involving at least 0.5 percent of facial BSA and at least 3 percent of nonfacial BSA were treated with ruxolitinib cream (1.5% twice daily, 1.5% once daily, 0.5% once daily, or 0.15% once daily) or vehicle [53]. After 24 weeks, more patients receiving ruxolitinib 1.5% twice daily and once daily achieved the primary endpoint (≥50 percent improvement in the facial Vitiligo Area Scoring Index [F-VASI]) compared with vehicle (45, 50, and 3 percent, respectively). Treatment was generally well tolerated. The most common treatment-related adverse events were pruritus at the application site (3 to 19 percent) and acne (3 to 18 percent).

•In two multinational, phase 3, randomized trials of identical design, 674 patients aged 12 years and older with nonsegmental vitiligo involving 10 percent or less of TBSA applied 1.5% ruxolitinib cream or vehicle twice daily to all depigmented areas on the face and body for 24 weeks [52]. After 24 weeks, all patients could apply ruxolitinib for an additional 28 weeks. At 24 weeks, the proportion of patients achieving the primary endpoint of 75 percent reduction in the facial Vitiligo Area Scoring Index (F-VASI-75) was 30 and 31 percent in the ruxolitinib groups and 7 and 11 percent in the vehicle groups. A 50 percent improvement in the total Vitiligo Area Scoring Index (T-VASI-50) was achieved in 21 and 24 percent of patients in the ruxolitinib groups and 5 and 7 percent in the vehicle groups. Adverse events occurred in 46 and 50 percent of patients in the ruxolitinib groups and 39 and 34 percent in the vehicle groups and were generally mild or moderate. Adverse events occurring through week 52 in the ruxolitinib groups included acne at the site of application (6 and 7 percent), nasopharyngitis (5 and 6 percent), and pruritus at the site of application (4 and 5 percent). Serious adverse events occurred in 3 and 1 percent of patients in the ruxolitinib groups versus 2 and 0 percent of patients in the vehicle group. Adverse events leading to discontinuation of the trial agent occurred in less than 1 percent of subjects. Plasma concentrations of ruxolitinib were stable through week 40 and well below the half-maximal concentration associated with myelosuppression.

The repigmentation rates and time to repigmentation achieved with topical ruxolitinib appear to be similar to those observed with topical corticosteroids and topical calcineurin inhibitors, although no head-to-head, randomized studies have compared topical ruxolitinib with topical corticosteroids or topical calcineurin inhibitors. Cost may limit the use of topical ruxolitinib, especially in resource-limited settings.

Disseminated disease — For patients with disseminated areas of depigmentation affecting multiple anatomic sites but with overall involvement of less than 5 or 10 percent of the TBSA, the use of topical corticosteroids may be unpractical. For these patients, we suggest whole body NBUVB phototherapy as first-line therapy. NBUVB phototherapy is administered two to three times weekly. In the author's experience, less than 50 treatments are usually sufficient to achieve optimal outcomes.

Recalcitrant disease — For recalcitrant, stable vitiligo involving less than 5 to 10 percent of the TBSA that does not respond to topical therapies, treatment options include targeted phototherapy with excimer laser, NBUVB phototherapy, oral PUVA photochemotherapy, and autologous grafting procedures.

Targeted phototherapy — For patients with limited disease affecting 2 to 3 percent of TBSA that does not respond to topical corticosteroids or topical calcineurin inhibitors, targeted UVB phototherapy, if available, is a therapeutic option. Targeted phototherapy is typically administered two to three times weekly. In the author's experience, targeted phototherapy has demonstrated efficacy for the treatment of limited areas of vitiligo involvement (picture 2) [54].

Targeted phototherapy uses 308 nm monochromatic excimer lamps or lasers. These devices deliver high-intensity light only to the affected areas while avoiding exposure of the healthy skin and lowering the cumulative UVB dose. (See "Targeted phototherapy".)

A systematic review of six randomized trials (411 patients with 764 lesions) found that excimer lamps and excimer lasers were equally effective in inducing ≥50 and ≥75 percent repigmentation [55]. Although the repigmentation may occur more rapidly with more frequent weekly treatments (eg, three times per week), the final result appears to be related to the overall number of treatment sessions rather than their frequency [56].

As with NBUVB, targeted phototherapy can be used in combination with topical therapies, including tacrolimus ointment and topical corticosteroids [14,57]. However, the pooled analysis of two studies comparing targeted phototherapy plus topical tacrolimus with targeted phototherapy alone failed to find a statistically significant difference between the two treatment modalities in achieving >50 and >75 percent repigmentation (relative risk [RR] 1.6, 95% CI 0.76-3.39 and RR 2.39, 95% CI 0.64-8.96, respectively) [40].

Psoralen plus ultraviolet A photochemotherapy — Topical or oral psoralen plus ultraviolet A (PUVA) photochemotherapy is a viable option for patients with limited disease that does not respond to phototherapy with NBUVB and topical agents, and when targeted phototherapy is not available. Treatment is given twice weekly, with an interval of 48 hours between sessions [58]. PUVA and NBUVB show comparable efficacy [59]. However, the adverse effect profile of PUVA is significant and includes xerosis, photoaging, and cataracts. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)

Transplantation procedures — Surgical therapies have been used for vitiligo for the past 25 years and remain viable options for patients with stable, localized vitiligo areas that have been unresponsive to medical intervention, including topical agents and NBUVB phototherapy [60]. They are often combined with phototherapy to expedite repigmentation in the grafted areas [61].

The scope of transplantation procedures is the transfer of a reservoir of healthy melanocytes to vitiliginous skin for proliferation and migration into areas of depigmentation. Techniques used for the treatment of vitiligo include [60]:

●Autologous suction blister grafts [62,63]

●Minigrafts or punch grafts, including 1 mm punch grafts [64-66]

●Split-thickness grafts [67,68]

●Laser ablation plus cultured epidermal suspensions [69-71]

●Autologous noncultured epidermal cell preparations, including the Jodhpur technique [72-74]

●Hair follicle transplantation [75-77]

●Autologous melanocyte cultures [78,79]

While all these techniques have proven successful, most are technically challenging and expensive. One millimeter punch grafts, however, can be performed with ease and without the need for special devices or equipment.

Factors that influence the outcome of transplantation techniques include age, site of lesion, and type of vitiligo. In a series of 117 patients, the best results were achieved for patients younger than age 20 and patients with segmental vitiligo; the grafting site did not significantly affect the outcome [80].

Evidence for efficacy of transplantation procedures for vitiligo is based on multiple randomized and observational studies. A systematic review of randomized trials and observational studies of autologous transplantation methods for vitiligo concluded that maximal repigmentation occurred in patients treated with split-thickness grafting and epidermal suction blister grafting [81]. Both treatment groups achieved success rates of 90 percent repigmentation.

Other studies have reported the benefits of transplantation of autologous melanocyte cultures and epidermal suspensions containing both melanocytes and keratinocytes [69,72,82]. In one randomized trial comparing autologous noncultured epidermal cell suspension with suction blister grafts in 41 patients, a repigmentation ≥75 percent was achieved in over 85 percent of lesions in both treatment groups [72]. However, more lesions in the noncultured epidermal cell suspension group achieved a 90 to 100 percent repigmentation compared with those in the suction blister group (70 versus 27 percent).

Transplantation procedures are contraindicated for patients with a history of hypertrophic scars or keloids. Adverse effects of these treatments include cobblestoning, scarring at both donor and recipient sites, graft depigmentation, and graft displacement. Suction blister grafts and split-skin grafts may be associated with the Koebner phenomenon at the donor site, a complication of major clinical importance since it results in the development of new vitiligo lesions [37].

Other adverse effects include hypopigmentation, hyperpigmentation, and infection at both donor and recipient sites. Punch grafting or minigrafting adverse effects include lack of color blending and matching with the surrounding normal skin, cobblestoning, and "polka dot" appearance [83].

Nonsegmental vitiligo involving 10 to 40 percent of the body surface area

Narrowband ultraviolet B phototherapy — For adults and children with nonsegmental vitiligo involving 10 to 40 percent of the TBSA, we suggest whole body NBUVB phototherapy as first-line therapy (picture 3). Due to its lack of systemic toxicity and its good safety profile in both children and adults, NBUVB phototherapy has emerged as the treatment of choice for patients with vitiligo involving >10 percent of the BSA and has largely replaced PUVA [15]. NBUVB can be used for both stabilization and repigmentation of vitiligo (picture 3). (See 'Stabilization of rapidly progressive disease' above.)

NBUVB involves the use of ultraviolet lamps with a peak emission of approximately 311 nm [84]. These shorter wavelengths provide higher energy fluences and induce less cutaneous erythema compared with broadband UVB. NBUVB induces local immunosuppression and apoptosis; stimulates the production of melanocyte-stimulating hormones, basic fibroblasts, growth factor, and endothelin I; and increases melanocyte proliferation and melanogenesis [84-86]. (See "UVB phototherapy (broadband and narrowband)".)

Administration — NBUVB is administered two to three times per week for an average of 9 to 12 months. We use an initial dose of 200 mJ/cm²; in the absence of perceptible erythema, dose increments of 10 to 20 percent of the last used dose are administered at each subsequent session, until a mild, asymptomatic erythema lasting <24 hours is achieved [15].

Follicular areas of repigmentation usually begin to appear after 15 to 20 NBUVB treatments (picture 4). If patients are responding well with continued repigmentation, treatment can be maintained beyond 9 to 12 months and up to 24 months or 200 sessions and then tapered off.

Mid-potency topical corticosteroids or topical calcineurin inhibitors can be intermittently used in combination with phototherapy.

Home phototherapy — Home NBUVB phototherapy is an option for patients unable to travel to the clinician's office for weekly treatments [87,88]. Whole-body or portable, handheld units are available on the market (sample brand names include Daavlin, National Biological Solarc Systems). It is of paramount importance that patients should be provided with detailed instructions on the use of the home phototherapy units and return for in-office clinician follow-up on a regular basis.

Efficacy — The efficacy of NBUVB for the treatment of vitiligo is supported by multiple randomized trials and meta-analyses:

●A meta-analysis of three randomized trials comparing oral PUVA with NBUVB found a 60 percent nonstatistically significant higher proportion of participants achieving >75 percent repigmentation in the NBUVB group compared with the oral PUVA group [37]. The additive effect of tacrolimus ointment (0.1%) applied once daily combined with NBUVB in the treatment of vitiligo has been evaluated in one randomized trial [89]. In this study, 40 patients with stable, symmetrical vitiligo were treated with tacrolimus ointment 0.1% on one side of their body and a placebo ointment on the other side plus whole-body NBUVB two or three times weekly for at least three months. In 27 of 40 patients, a greater reduction in the target lesion area was seen in the side treated with tacrolimus compared with the side treated with NBUVB alone (42 versus 29 percent). However, a possible increase in the risk of skin cancer with this combination therapy cannot be excluded.

●A 2017 meta-analysis of 35 randomized and nonrandomized studies including 1428 patients compared the repigmentation rates of NBUVB and PUVA by treatment duration [90]. For NBUVB, a ≥75 percent repigmentation was achieved by 13, 19, and 36 percent of patients at 3, 6, and 12 months of treatment, respectively. For PUVA, ≥75 percent repigmentation was achieved by 9 percent of patients at 6 months and 14 percent of patients at 12 months. The results of this meta-analysis suggest that phototherapy should be continued for at least 12 months to achieve a maximal response.

Only a few small, observational studies have evaluated the duration of repigmentation in patients with vitiligo treated with phototherapy. In a small, observational study of 11 patients followed up for two years after treatment with NBUVB phototherapy, five maintained areas of repigmentation and six experienced complete or partial relapse of vitiligo at previously repigmented sites [91]. In another study including 15 children treated with NBUVB phototherapy and followed up for a mean of 12 months after completing treatment, six showed stable repigmentation, four showed further improvement, and three showed complete or partial regression of the pigmentation achieved with treatment [92].

Second-line therapy

Psoralen plus ultraviolet A photochemotherapy — Historically, photochemotherapy with topical or systemic psoralen plus ultraviolet A (PUVA) radiation was the "gold standard" treatment for the repigmentation of vitiligo. However, PUVA has been largely replaced by NBUVB phototherapy. (See "UVB phototherapy (broadband and narrowband)".)

PUVA is associated with substantial adverse effects, including phototoxicity and gastrointestinal discomfort, and requires patients to use ocular protection for 12 to 24 hours following treatment. Although a long-term risk of skin cancer has been shown in psoriasis patients [93], a survey that included 1307 vitiligo patients and their partners did not show an increase risk of skin cancer for patients treated with PUVA therapy compared with their partners [94]. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)

Nonsegmental stable vitiligo involving >40 percent of the body surface area

Phototherapy — Phototherapy with NBUVB is the first-line therapy for patients with extensive nonsegmental stable (no increase in size of existing lesions and absence of new lesions in the previous three to six months) vitiligo involving greater than 40 percent of the TBSA. The suggested regimen and duration of treatment are similar to that discussed above for patients with more limited disease. (See 'Narrowband ultraviolet B phototherapy' above.)

Oral PUVA may be used as a second-line therapy for adult patients with extensive disease. (See 'Psoralen plus ultraviolet A photochemotherapy' above.)

Depigmentation — For patients with extensive, recalcitrant vitiligo affecting 40 percent or more of the BSA that does not respond to repigmentation regimens and for patients with extensive vitiligo who do not desire undergoing repigmentation treatments, depigmentation of residual, normally pigmented areas may be an option [95].

Monobenzone — Since the 1950s, monobenzyl ether of hydroquinone (monobenzone) at concentrations of 20% or higher has been used as a depigmenting agent for patients with extensive vitiligo [96,97]. Monobenzone causes permanent destruction of melanocytes and induces depigmentation locally and remotely from the sites of application [95].

Depigmentation therapy is usually initiated with monobenzone 10% cream for one month and then continued with monobenzone 20% cream. Monobenzone is applied on the areas of residual pigmentation once or twice daily; we typically treat exposed areas first. These sites include the face, neck, upper extremities, chest, and lower legs. Depigmentation usually begins at distant sites (where the drug has not been applied) after three to six months of continued use. Depigmentation therapy may require one to three years to achieve optimal outcomes.

Adverse effects of monobenzone are dose dependent and include irritant contact dermatitis, pruritus, severe xerosis, alopecia, and premature hair graying. Irritant contact dermatitis and pruritus usually respond to topical and systemic steroids.

Monobenzone should never be used as a lightening agent in patients with disorders of pigmentation other than vitiligo. It will induce vitiligo in such patients [95].

Other depigmenting agents — Other topical agents that have been used for depigmentation include 4-methoxyphenol (mequinol) 20% cream [98] and 88% phenol solution. Adverse effects of mequinol include burning, pruritus, and contact dermatitis. Cardiac toxicity is a potential serious complication resulting from systemic absorption of phenol. (See "Chemical peels: Procedures and complications", section on 'Special precautions for phenol peels'.)

Segmental vitiligo — Topical corticosteroids, topical calcineurin inhibitors, or targeted phototherapy are the first-line therapy for limited segmental vitiligo. NBUVB phototherapy can be used for more extensive disease affecting multiple dermatomes. (See 'Targeted phototherapy' above.)

For patients with stable, segmental vitiligo that does not respond to topical or light therapies, autologous grafting is a second-line option [99]. Long-term repigmentation has been reported in patients with segmental vitiligo with autologous melanocyte transplantation [100]. (See 'Transplantation procedures' above.)

RESPONSE ASSESSMENT — Patients are usually re-evaluated in three to six months of starting treatment. Photographs should be taken with a standardized technique [101] before starting treatment and at each follow-up visit to evaluate the degree of repigmentation. The initial response to treatment is in most cases indicated by the appearance of perifollicular areas of repigmentation in the vitiliginous patch, which usually begins 8 to 12 weeks after the initiation of treatment or after 15 to 20 narrowband ultraviolet B (NBUVB) sessions (picture 4). Some patients may show a diffuse repigmentation pattern or a combination of diffuse and perifollicular [102,103].

MAINTENANCE TREATMENT — In patients who respond well to treatment and achieve optimal repigmentation, therapies can be gradually tapered and then discontinued. However, some patients may require maintenance treatment. Intermittent use of topical corticosteroids or topical calcineurin inhibitors (eg, twice weekly) and phototherapy (eg, one session every other week) may be used as long-term maintenance treatments.

In a randomized, double-blind, placebo-controlled study of 35 vitiligo patients (16 given placebos and 19 given tacrolimus), twice-weekly use of tacrolimus 0.1% was effective for maintenance therapy of white patches previously repigmented [104].

For patients who relapse after stopping treatment or during the maintenance phase, another cycle of active treatment, including topical agents and/or phototherapy, depending on the disease extent, can be administered.

ADJUNCTIVE THERAPIES — There are several adjunctive therapies that have been used to treat vitiligo, including topical vitamin D3 analogues, vitamins, and plant extracts. We generally do not routinely use such treatments due to the lack of sufficient evidence of efficacy.

Topical vitamin D analogues — The benefit of topical vitamin D3 analogues in the treatment of vitiligo is controversial. A few small, randomized trials evaluated the role of calcipotriol and tacalcitol in combination with psoralen plus ultraviolet A (PUVA), narrowband ultraviolet B (NBUVB), or natural sunlight for the treatment of nonsegmental vitiligo with conflicting results [105-107]:

●In a prospective, right-left, 24-week, comparative study including 24 patients with vitiligo, there were no statistically significant differences between the sides treated with NBUVB monotherapy and the sides treated with NBUVB plus calcipotriol [106].

●In another right-left, comparative study, 35 patients with generalized vitiligo applied calcipotriol 0.05 mg/g cream or placebo to the reference lesions one hour before PUVA treatment twice weekly [105]. Lesions on the side treated with calcipotriol plus PUVA had a fourfold increase in the likelihood of achieving greater than 75 percent repigmentation sooner than the side treated with placebo plus PUVA (mean number of PUVA sessions 9 and 12, respectively).

Dietary supplements — Oral supplementation with antioxidants and vitamins is often used as an adjunctive treatment for vitiligo, usually in combination with phototherapy. However, there is limited evidence from high-quality studies to support their use [108]:

●Vitamins – A few small, uncontrolled studies have reported stabilization and repigmentation in vitiligo patients treated with ultraviolet B (UVB) phototherapy and high-dose vitamin supplementation, vitamin C, vitamin B12, and folic acid [109,110].

●Alpha-lipoic acid – Alpha-lipoic acid is an organosulfur compound derived from octanoic acid. It is widely available as an over-the-counter nutritional supplement and has been marketed as an antioxidant. The efficacy of alpha-lipoic acid in vitiligo was demonstrated in one randomized trial including 35 patients with nonsegmental vitiligo [111]. In this study, twice-daily oral supplementation with alpha-lipoic acid, vitamin E, polyunsaturated fatty acids, and cysteine monohydrate combined with NBUVB twice weekly for six months resulted in significantly more patients (47 versus 18 percent) achieving >75 percent repigmentation compared with phototherapy alone. In addition, repigmentation occurred earlier with lower cumulative UVB dose. Biochemical evaluations at two and six months showed increased catalase activity, decreased intracellular reactive oxygen species production, and reduced membrane peroxidation in the combination treatment group. Despite these promising results, further studies are needed to confirm the benefit of alpha-lipoic acid supplementation in the management of vitiligo.

●Ginkgo biloba – Extracts from the Ginkgo biloba leaf have long been used in traditional Chinese medicine to treat various conditions, including cutaneous, neurologic, and vascular disorders. The two main groups of active constituents responsible for G. biloba's medicinal effects are terpene lactones (ginkgolides and bilobalides) and ginkgo flavone glycosides, which are present in varying concentrations in the leaf of the ginkgo tree. (See "Clinical use of ginkgo biloba".)

An in vitro investigation of a G. biloba extract documented its effect in protecting human melanocytes from hydrogen peroxide-induced oxidative stress by activating the transcription factor nuclear erythroid 2-related factor (Nrf2). Nrf2 regulates the expression of a number of genes involved in the cellular defense against oxidative stress [112]. Only a few investigations have evaluated ginkgo's use in the management of vitiligo:

•A small, randomized trial reported that the spread of vitiligo was arrested in 20 of 25 subjects receiving 40 mg of G. biloba extract three times daily for six months but in none of 22 subjects in the placebo group [113]. In addition, 10 patients in the active treatment group, but only two in the placebo group, showed >75 percent repigmentation.

•Another pilot study found significant improvements in the total Vitiligo Area Scoring Index (T-VASI) and Vitiligo European Task Force assessment in 12 participants following 12 weeks of supplementation with twice-daily G. biloba extract [114]. In addition to repigmentation, active depigmentation ceased in all patients with acrofacial vitiligo.

●Polypodium leucotomos – In one randomized trial, NBUVB in combination with oral extracts of Polypodium leucotomos, a tropical fern with antioxidant and immunomodulator properties, was more effective than NBUVB alone in inducing repigmentation of vitiligo in the head and neck area (50 versus 19 percent) after 25 weeks [115]. No difference was noted in other body areas.

Microneedling — Microneedling, a technique that uses a device that creates microchannels in the dermis, has been used alone or in combination with topical agents (eg, tacrolimus, topical fluorouracil, trichloroacetic acid) in a limited number of patients with refractory vitiligo with some success [116].

INVESTIGATIONAL THERAPIES

Afamelanotide — Afamelanotide, a potent and longer-lasting synthetic analog of naturally occurring alpha-melanocyte-stimulating hormone (MSH), is a novel intervention for vitiligo [117,118]. Its use is based upon the demonstration of defects in the melanocortin system in patients with vitiligo, including decreased circulating and lesional skin levels of alpha-MSH [119]. Afamelanotide is delivered as a subcutaneous, bioresorbable implant that promotes melanocyte proliferation and melanogenesis.

The safety and efficacy of afamelanotide implants combined with narrowband ultraviolet B (NBUVB) were assessed in an observational study of four patients with generalized vitiligo [117]. Patients were treated three times weekly with NBUVB for one month and then administered a series of four monthly implants containing 16 mg of afamelanotide. Follicular and confluent areas of repigmentation were evident within two days to four weeks after the initial implant. Afamelanotide induced fast and deep repigmentation as well as diffuse hyperpigmentation in all cases. In a subsequent randomized trial including 55 patients with skin type III to VI and vitiligo involving 15 to 50 percent of the body surface area (BSA), patients in the NBUVB plus afamelanotide group achieved a greater repigmentation than patients in the NBUVB monotherapy group at five months (49 versus 33 percent, respectively) [118].

Prostaglandin E2 — Prostaglandin E2 (PGE2) is a potentially beneficial treatment for localized, stable vitiligo. PGE2 controls the proliferation of melanocytes by means of stimulant and immunomodulatory effects. In a consecutive series of patients with stable vitiligo, repigmentation occurred in 40 of 56 patients treated with PGE2 0.25 mg/g gel twice daily for six months [120]. The response was excellent in 22 of 40 patients, with complete repigmentation observed in 8 patients.

Prostaglandin F2 analogues

Bimatoprost — Bimatoprost, a synthetic analog of prostaglandin F2-alpha approved for the topical treatment of glaucoma and hypotrichosis of the eyelashes, is associated with hyperpigmentation of periocular skin caused by increased melanogenesis [121]. The efficacy of bimatoprost in the treatment of vitiligo was initially evaluated in a preliminary study of 10 patients with localized vitiligo treated with bimatoprost 0.03% ophthalmic solution twice daily for four months [122]. Of the 10 patients, 3 had 100 percent repigmentation, 3 had 75 to 99 percent repigmentation, and 1 patient had 50 to 75 percent repigmentation. The best responses were observed on the face.

A subsequent proof-of-concept, randomized trial compared the efficacy of bimatoprost 0.03% ophthalmic solution alone and in combination with a topical steroid (mometasone) with mometasone alone in 32 patients with nonsegmental, nonfacial, stable vitiligo involving <5 percent of the BSA [123]. At 20 weeks, none of the patients achieved the prespecified endpoint of 50 to 75 percent repigmentation. However, in a post-hoc analysis using a less stringent definition of response (25 to 50 percent repigmentation), patients treated with bimatoprost, either alone or with mometasone, achieved a greater repigmentation in the neck and trunk than patients treated with mometasone alone.

Latanoprost — Latanoprost, a prostaglandin F2-alpha analogue used in the treatment of glaucoma, was found to induce skin pigmentation in guinea pigs [124,125]. In a study that included 22 patients with bilateral and symmetric vitiligo lesions stable for the last three months, latanoprost was found to be superior to placebo and comparable with NBUVB in inducing skin repigmentation [124].

Janus kinase inhibitors — In several case reports, the oral Janus kinase (JAK) inhibitors tofacitinib and ruxolitinib, approved for the treatment of rheumatoid arthritis and myelofibrosis, respectively, have shown efficacy for the treatment of vitiligo [126,127]. In a pooled analysis of nine studies including 45 patients treated with tofacitinib and ruxolitinib, 26 patients (58 percent) had a good response (>50 percent repigmentation), 10 (22 percent) had a partial response (<50 percent/some repigmentation), and 9 (20 percent) had no response [128]. The best response was achieved for facial vitiligo.

SKIN CANCER RISK — Multiple studies have assessed the risk of melanoma and nonmelanoma skin cancers in patients with vitiligo [94,129]. A meta-analysis of five retrospective cohort studies including nearly 230,000 patients with vitiligo did not find an increased risk of nonmelanoma skin cancer or melanoma in the areas affected by vitiligo or in nonaffected skin in patients treated with phototherapy compared with patients not treated with phototherapy [130].

PSYCHOLOGIC INTERVENTIONS — The patient's ability to cope with a lifelong disease should be carefully evaluated at the time of treatment planning. Psychologic support should be offered to patients if needed. High-quality studies evaluating the efficacy of psychologic interventions in the management of patients with vitiligo are lacking. One small, randomized trial found that cognitive-behavioral therapy in addition to conventional therapies was effective in improving the quality of life, self-esteem, and perceived body image in adult patients with vitiligo and even influenced the course of the disease itself [131].

CAMOUFLAGE — Cosmetic camouflage can be beneficial for patients with vitiligo affecting exposed areas, such as the face, neck, and hands. Camouflage may be used during treatment and may also be an option for patients with focal or segmental vitiligo who do not desire repigmentation treatment.

Camouflage products include foundation-based cosmetics and self-tanning products containing dihydroxyacetone (DHA). DHA-based products are the most popular because they provide lasting color for up to several days and are not immediately rubbed off onto clothing.

Tattooing or micropigmentation should be avoided, given the risk of koebnerization and oxidation of tattoo pigment causing further dyschromia. (See "Vitiligo: Pathogenesis, clinical features, and diagnosis", section on 'Koebner phenomenon'.)

PROGNOSIS — Vitiligo is a chronic disease with a highly unpredictable course. Early-onset vitiligo appears to be associated with involvement of a greater body surface area and increased rate of disease progression [132]. Despite treatment, most patients experience alternating periods of pigment loss and disease stability for their entire life. Occasionally, patients may experience spontaneous repigmentation.

Organ-specific autoantibodies are common in vitiligo. Patients who develop thyroid organ-specific autoantibodies have an increased risk of developing subclinical or overt autoimmune thyroid disease [133,134]. (See "Vitiligo: Pathogenesis, clinical features, and diagnosis", section on 'Associated disorders'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vitiligo".)

SUMMARY AND RECOMMENDATIONS

●Goals of treatment – Vitiligo is a chronic, relapsing disease. The goals of treatment include the stabilization of active disease and the repigmentation of depigmented patches. However, the response to treatments is slow and may be highly variable among patients and among different body areas in the same patient. (See 'Patient evaluation' above.)

●Stabilization of rapidly progressive disease – For patients with rapidly progressive, nonsegmental vitiligo (ie, depigmented macules spreading over a few weeks or months), we suggest oral glucocorticoids and/or narrowband ultraviolet B (NBUVB) as first-line therapy for the stabilization (cessation of spread) of the disease (Grade 2C). However, NBUVB is a reasonable alternative for patients who do not tolerate glucocorticoids. Oral glucocorticoids are not indicated for repigmentation of progressive vitiligo.

In our experience, patients with disseminated and rapidly progressive disease affecting multiple anatomic sites may benefit from concurrent initiation of systemic corticosteroids and NBUVB phototherapy. (See 'Stabilization of rapidly progressive disease' above.)

●Management of nonsegmental vitiligo – The approach to the treatment of stable vitiligo depends on the extent of the disease:

•Vitiligo involving <10 percent of the body surface area:

-Localized disease – For patients with limited disease that involves <10 percent of the body surface area (BSA) and is localized, we suggest mid- to high-potency topical corticosteroids or topical calcineurin inhibitors as initial therapy rather than NBUVB (Grade 2C). Topical corticosteroids can be used safely for two to three months, interrupted for one month, and then resumed for an additional two or three months. Topical calcineurin inhibitors are preferred to topical corticosteroids for body areas at increased risk of atrophy. Topical ruxolitinib, a Janus kinase (JAK) inhibitor approved for the treatment of nonsegmental vitiligo affecting ≤10 percent of the BSA, is a therapeutic option for patients who have not responded to topical corticosteroids or topical calcineurin inhibitors and can also be considered a first-line therapy in the appropriate patient. (See 'Localized disease' above.)

-Disseminated disease – Patients with limited but disseminated disease, for whom the use of topical therapies may be unpractical, are best treated with NBUVB phototherapy. (See 'Disseminated disease' above.)

-Recalcitrant disease – For patients with limited, stable, recalcitrant disease that does not respond to initial therapy, therapeutic options include targeted phototherapy, psoralen plus ultraviolet A (PUVA) photochemotherapy, and surgical procedures that involve the autologous transplantation of healthy melanocytes in depigmented areas. The choice among these treatments depends on availability, clinical judgment, and patient preference. (See 'Recalcitrant disease' above.)

•Vitiligo involving 10 to 40 percent of the body surface area – For patients with moderate to extensive disease involving 10 to 40 percent of the BSA, we suggest phototherapy with NBUVB rather than PUVA as initial therapy (Grade 2C). NBUVB phototherapy is administered two to three times per week for 9 to 12 months or up to 200 treatments. Topical corticosteroids or topical calcineurin inhibitors may be intermittently used in combination with NBUVB phototherapy. (See 'Nonsegmental vitiligo involving 10 to 40 percent of the body surface area' above.)

•Vitiligo involving >40 percent of the body surface area – We suggest NBUVB phototherapy rather than PUVA as first-line therapy for patients with extensive disease who desire repigmentation treatment (Grade 2C). Depigmentation of residual pigmented areas with monobenzyl ether of hydroquinone (monobenzone) can be offered for patients with recalcitrant disease that does not respond to repigmentation regimens and for those with extensive vitiligo who do not desire undergoing repigmentation treatments. (See 'Nonsegmental stable vitiligo involving >40 percent of the body surface area' above and 'Depigmentation' above.)

●Management of segmental vitiligo – Therapeutic options for stable, segmental vitiligo include topical therapies (eg, topical corticosteroids, topical calcineurin inhibitors), targeted phototherapy, and surgical therapy. (See 'Segmental vitiligo' above and 'Transplantation procedures' above.)