Update on the Management of Vitiligo

Amanda F. Nahhas, DO^1,2; Taylor L. Braunberger², MD; Iltefat H. Hamzavi², MD

¹Department of Dermatology, Beaumont-Farmington Hills, Detroit, MI, USA
²Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA

Conflict of interest:
Dr. Hamzavi is an investigator for Incyte Corporation, Clinuvel, Bayer, Estée Lauder, Unigen Inc., and Ferndale Laboratories. Dr. Nahhas and Dr. Braunberger are former sub-investigators for Ferndale Laboratories, Bayer, Estée Lauder, and Unigen Inc., with grants that were paid to the institution.

Abstract
Vitiligo is an acquired, autoimmune disease characterized by depigmented macules and patches on the skin, which occur secondary to melanocyte destruction. Available therapeutic options are broadly divided into medical, surgical and phototherapy, though treatment of vitiligo can be challenging. Early diagnosis and management can maximize treatment efficacy. The purpose of this discussion is to review updates in the management of vitiligo, including existing and emerging therapies.

Key Words:
medical management, phototherapy, treatment, vitiligo

Introduction

Vitiligo is an acquired, autoimmune disease characterized by depigmented macules and patches on the skin, which occur secondary to melanocyte destruction. Focal and segmental vitiligo patterns involve ≤10% body surface area (BSA) and are considered stable patterns. Generalized vitiligo typically involves ≥10% BSA, appears bilaterally in a symmetric distribution, and generally follows a relapsing and remitting disease course.

Treatment can be challenging, though available modalities of therapy include pharmacologic, surgical, and phototherapy. Appropriate characterization of vitiligo type, consideration of disease extent and duration, and efficacy of prior therapies can guide management and maximize treatment efficacy.

Medical Management

In early, stable, localized disease (≤12 months since onset), topical corticosteroids, topical immunomodulators, targeted narrowband ultraviolet B (NB-UVB) phototherapy, or a combination can be effective. In generalized, stable disease, topical corticosteroids or immunomodulators in combination with NB-UVB phototherapy are the mainstay of therapy. In patients with generalized, rapidly progressive vitiligo, a 3-month trial of pulsed oral corticosteroids may help induce stabilization.¹

Topical Therapies

Topical corticosteroids are effective agents in vitiligo due to their immunosuppressive and anti-inflammatory properties. Super-potent or potent corticosteroids are appropriate for treating the trunk and extremities, whereas mid-potency topical corticosteroids (or topical calcineurin inhibitors) are better suited for the face, neck, or intertriginous regions and in children. Cyclical application (1 week on and 1 week off for 6 months or for 5 days on and 2 days off ) can help avoid the cumulative adverse effects of topical corticosteroids, including skin atrophy, telangiectasias, and steroid-induced acne.¹ Treatment should not exceed 14 days in a month per package insert.²

Topical calcineurin inhibitors, such as tacrolimus (0.1%) or pimecrolimus (1%), are immunomodulatory, steroid-sparing agents that may be used anywhere with the exception of mucous membranes, and are nearly as effective as topical corticosteroids but more favorable with steroid-sparing properties.³ Twice daily use can promote disease stabilization and twice weekly applications may be considered for maintenance therapy.⁴ Topical calcineurin inhibitors may be used in combination with topical corticosteroids on ‘off’ days. Although tacrolimus poses a theoretical, long-term risk of carcinogenicity due to its immunosuppressive properties, no cases in humans have been reported.^1,5 In a mouse model investigating dermal photocarcinogenicity, topical 0.1% tacrolimus was associated with the development of lymphoma. An intra-individual left-right comparison study by Ostovari et al. involving 9 patients with generalized vitiligo found that repigmentation was optimized when topical calcineurin inhibitors were combined with UVB (308 nm excimer laser) exposure in all patients, whereas no repigmentation was observed on the side treated with topical 0.1% tacrolimus alone.⁶

Vitamin D analogs, such as topical calcipotriene, used in combination with phototherapy, may reduce time to repigmentation and the overall cumulative dose delivered.⁷

Oral Therapies

In progressive vitiligo, oral minipulse corticosteroid therapy (OMP) may be used to promote disease stabilization through immunosuppression. A typical regimen includes low-dose oral betamethasone or dexamethasone taken on 2 consecutive days per week for 3 to 6 months.¹ Lack of disease stabilization after 3 months of combination therapy (OMP plus NB-UVB phototherapy) warrants discontinuation of the OMP only and reevaluation at 3-month intervals.¹ Alternatively, upon failure of OMP, daily dosing with 20 mg of oral prednisone may be considered until disease progression has halted.⁸ In an early study published in 1993, 40 patients with extensive or rapidly progressive vitiligo were treated with 5 mg of betamethasone/ dexamethasone as a single oral dose on consecutive days weekly. Within 1 to 3 months, disease progression was arrested in 89% of the patients. In 2 patients, the dose was increased to 7.5 mg per day in order to halt disease progression. Within 2 to 4 months of treatment, 80% of patients noted increased spontaneous repigmentation that was maintained with continued therapy. Side effects consistent with oral corticosteroid use were observed in 42.5% of patients.⁹ In a study published in 2001, 29 patients with either progressive (n = 25) or stable (n = 4) vitiligo received 10 mg of oral dexamethasone on consecutive days weekly for 24 weeks. After an average of 18.2 ± 5.2 weeks, 88% (22 of 25) of patients with progressive vitiligo had arrest in disease activity. Side effects associated with oral corticosteroid use were observed in 69% of the patients studied.¹⁰ In a more recent study published in 2013, 444 patients with progressive vitiligo were treated with 2.5 mg of oral dexamethasone on consecutive days weekly. Using this regimen, arrest of disease progression was noted in 91.8% of these patients, with some repigmentation noted within 16.1 ± 5.9 weeks on average. Disease relapse occurred in 12.25% of patients, though the average disease-free survival until first relapse was 55.7 ± 26.7 weeks. Adverse effects consistent with oral corticosteroid use were observed in 9.2% of patients.¹¹ Side effects associated with any oral corticosteroid use (i.e., acne, weight gain, headache, nausea, and lethargy) should be reviewed with patients. There is evidence to suggest that confetti-like macules and koebnerization are good physical markers of instability.¹² These are markers the authors may use when deciding to initiate oral corticosteroid therapy.

Minocycline, through its anti-inflammatory, immunomodulatory, antioxidant, direct free radical scavenging, and anti-apoptotic properties, may be an effective therapy to arrest progression of vitiligo as well as induce repigmentation.^13-14 In a study involving patients with gradually progressive vitiligo (majority being of the generalized vitiligo type), patients were instructed to take 100 mg of oral minocycline daily. Of the 32 patients included in the study, 29 showed arrest of disease progression, with onset as early as 4 weeks after initiation of treatment in 10 of the 29 patients. Seven of 32 patients showed moderate to marked repigmentation.¹⁵ A randomized trial comparing 6-month treatment with oral dexamethasone (5 mg weekly, 2.5 mg given on 2 consecutive days per week) versus oral minocycline (100 mg daily) in 50 patients with unstable, generalized vitiligo showed there were no statistically significant differences in vitiligo disease activity scores and Vitiligo Area Scoring Index between groups.¹⁶ Another study compared 3-month treatment of oral minocycline (100 mg daily) with NB-UVB phototherapy (twice weekly) in 42 patients with unstable vitiligo and found a statistically significant improvement in repigmentation in the group treated with NB-UVB.¹⁷

Use of methotrexate, an immunomodulating systemic agent, has been shown to improve vitiligo in 1 of 3 patients with rapidly progressive, generalized vitiligo when administered in an uptitrating dose of 12.5-25 mg per week, as reported in a recently published case series. Repigmentation was noted as early as 6 weeks to 14 months in this patient, who had previously failed to respond to topical calcineurin inhibitors and phototherapy.¹⁸ A prospective, randomized trial was performed comparing 24-week treatment with oral methotrexate (10 mg weekly) versus OMP (dexamethasone, 5 mg weekly, 2.5 mg given on 2 consecutive days per week) in 50 patients with unstable vitiligo. New lesions developed in 6 of 25 patients in the methotrexate group and 7 of 25 patients in the OMP group, though the difference was not statistically significant. Both groups demonstrated similar reductions in vitiligo disease activity scores.¹⁹ Due to the limited availability of studies supporting its superior efficacy compared to other available treatments, use of methotrexate can be considered as a steroid-sparing agent in patients with vitiligo refractory to topical treatment and phototherapy.

The role of antioxidants in the treatment of vitiligo remains controversial. Based upon a systematic review of the literature performed by Speeckaert et al., the oxidative stress pathway is deregulated in patients with vitiligo, although it is not considered disease specific, but rather consistent with findings that are expected in an immune-mediated skin disorder. Furthermore, it was noted that increased oxidative stress in non-lesional skin may be specific to vitiligo.²⁰

Among the antioxidant therapies, oral Polypodium leucotomos (PL) extract has been studied in patients with generalized vitiligo due to its notable antioxidant and immunomodulatory properties. In a 26-week randomized clinical trial, patients received NB-UVB phototherapy (twice weekly) combined with either oral PL (250 mg thrice daily) (n = 25) or placebo (n = 24). Improvement in repigmentation was greatest in the group receiving oral PL and NB-UVB phototherapy and most prominent on the head and neck, which was statistically significant.²¹ A pilot, randomized, placebo-controlled clinical trial evaluated the effects of oral PL plus psoralen ultraviolet A (PUVA) versus placebo plus PUVA in 19 patients. Greater than 50% repigmentation was observed more frequently in the PL plus PUVA group compared to the placebo plus PL group.²²

Ginkgo biloba extract has been shown to have some antioxidant and anti-inflammatory properties and may help induce stabilization of vitiligo. In a placebo-controlled, double-blind study evaluating the efficacy of Ginkgo biloba extract in patients with gradually progressive vitiligo, 40 mg of oral Ginkgo biloba extract was administered to 24 patients 3 times daily for 6 months, while 18 patients received the placebo. Twenty patients in the active treatment and 8 patients in the placebo-controlled group had arrest in progression of disease, which was statistically significant. Ten patients in the active treatment group showed marked to complete repigmentation, compared to 2 patients in the placebo-controlled group.²³ A separate 12-week pilot clinical trial involving 11 patients showed that twice daily administration of 60 mg of oral Ginkgo biloba extract resulted in improved total Vitiligo Area Scoring Index measures and spreading as noted by Vitiligo European Task Force scores, with trends toward improvement of vitiligo lesion area and staging on Vitiligo European Task Force scores.²⁴ More clinical trials with larger cohorts are needed to better evaluate the efficacy of antioxidants, including Polypodium leucotomos and Ginkgo biloba extracts.

Phototherapy

NB-UVB is recommended in rapidly spreading vitiligo or extensive generalized vitiligo involving >5% to 10% of BSA.¹ Its immunosuppressive effects and ability to induce differentiation of melanocytes and production of melanin makes it an effective therapy.²⁵ A starting regimen of 200 mJ, delivered twice or thrice weekly, is appropriate in all phototypes, as it avoids risk of phototoxic reactions.²⁶ Once asymptomatic, when light pink erythema lasting less than 24 hours (the treatment endpoint) is no longer observed, the dose can be escalated in 10% to 20% increments until this endpoint is reestablished.²⁶ Patients should be warned of the risk of phototoxicity, and if this occurs, the next dose should be decreased or skipped, depending on the severity of the reaction. Alternatively, a fixed dosing schedule may be used that considers skin phototype differences in minimum erythema dose,²⁷ but this is only recommended in darker skin phototypes due to the increased risk of phototoxic reactions.²⁶

In patients with limited BSA of vitiligo (<10%) or in early, segmental disease, targeted phototherapy (excimer lasers and excimer lamps), is appropriate.^28,29 This approach avoids the generalized skin tanning effect induced by NB-UVB, although it does not address disease stabilization since clinically unaffected skin is not treated.¹

Either twice or thrice weekly phototherapy may be prescribed, as available comparison studies have not demonstrated superior efficacy in the final degree of repigmentation.^30,31 In studies using excimer laser, onset of repigmentation was observed earlier with thrice weekly dosing and repigmentation had greater dependence upon the total number of treatments, which likely can be extrapolated to NB-UVB phototherapy.^1,31

The Vitiligo Working Group recently released guidelines on the use of NB-UVB that advise the maximal acceptable delivered NB-UVB dose in a given treatment as 1500 mJ/cm² and 3000 mJ/cm² for the face and body, respectively.²⁶ In patients with skin phototypes IV-VI, the Vitiligo Working Group advises against defining an upper limit of NB-UVB dosing. In patients with skin phototypes I-III, a NB-UVB dosing upper limit is not suggested, as limited long-term studies are available to investigate the association between cumulative NB-UVB exposure and the potential for cutaneous malignancy, which remains a concern.²⁶ Skin phototype and photosensitivity may also be used to guide upper limits of NB-UVB dosing.¹

NB-UVB has become the preferred route of phototherapy as it has been demonstrated to be more efficacious, lacks a photosensitizer, requires a lower cumulative dose, and has fewer adverse effects compared to PUVA.³² NB-UVB is also safe in children and pregnant or lactating women.¹ PUVA may still be an option in darker skin phototypes and treatment refractory vitiligo.¹ Though concern exists, studies demonstrating increased risk of cutaneous malignancy with PUVA or NB-UVB are lacking. Recent literature suggests vitiligo may be protective against nonmelanoma and melanoma skin cancer.³³

Surgical Management

Surgical therapies may be considered in vitiligo that is local or generalized, stable, or untreated for over a year since onset; it is also appropriate in patients who have failed a 6-month course of topical therapy with or without phototherapy.¹ In generalized vitiligo, outcomes are less promising, which is attributable to the unstable disease course.

Disease stability is an important variable in surgical candidate selection. Published studies define stability as the lack of new or expanding depigmented patches for 6 months to 2 years. Other cutaneous markers of instability include the presence of koebnerization, confetti-like macules of depigmentation, trichrome pattern, or inflammatory borders.¹ Patient report, serial photography, and validated scoring systems such as the Vitiligo Area Severity Index, Vitiligo European Task Force assessment, and Vitiligo Disease Activity Score can be used to confirm stability.¹ In uncertain cases, a test punch graft in a stable, depigmented lesion may be performed.¹

Recipient site (RS) locations on the face and neck have the most favorable repigmentation outcomes, followed by the extremities (excluding digits), and then the trunk.³⁴ Acrofacial vitiligo (including distal fingertips and periungual and perioral areas) typically exhibits poor responses to repigmentation.³⁵ Skin overlying joints also has poor treatment responses due to susceptibility to trauma.³⁵ History of keloid formation, coagulopathy, and blood-borne infections should be considered, among other contraindications to surgery.¹ Surgical therapy can be divided into tissue- and cellular-based grafting techniques.

Tissue Grafting Techniques

Tissue grafting involves transfer of intact tissue from an area of normal, unaffected skin (donor site, DS) to an area of depigmented skin (RS). Many tissue grafting techniques are available, but suction blister epidermal grafting and minipunch grafting are the most widely utilized.

In suction blister epidermal grafting, blisters are raised, harvested, and transferred from a DS to RS. Suction blister epidermal grafting is useful for difficult to treat areas such as the eyelids.³⁶ Complications such as peripheral ‘halo’ depigmentation, milia, hypertrophy, and hyperpigmentation (especially in darker skin phototypes) may occur, including infection rarely.³⁷

Using minipunch grafting, grafts are transferred from DS into RS chambers approximately 5 to 10 mm apart from each other, with slightly larger DS punches taken to account for graft contracture. Complications such as cobblestoning, color mismatch, hypertrophic scarring, keloid formation, and graft rejection can occur at the RS, and depigmentation and scarring at the DS. Minipunch grafting is considered the easiest, fastest, and most cost-effective surgical treatment and, with the exception of the angle of the mouth, can be used anywhere.³⁸

Follicular unit transplant (FUT) capitalizes on the concept that pigmentation can be restored to affected vitiligo patches by targeting reservoirs of undifferentiated stem cells associated with hair follicles.³⁹ Epidermal removal (or ultraviolet radiation) can induce inactive melanocytes to convert to active melanocytes that can then migrate upwards to the epidermis from the outer root sheath to induce perifollicular repigmentation.⁴⁰ Donor grafts are typically harvested from the posterior-auricular or occipital scalp using the ‘strip method’ (also known as the FUT method), then dissected into follicular units and inserted with jeweler’s forceps into slits made at the RS using either a hair transplantation machine, curved cutting needle, or an 18-guage needle.⁴¹ FUT can be advantageous for hair-bearing sites, including difficult to treat areas such as the eyelashes.⁴²

Follicular unit extraction accomplishes hair follicle isolation via 1-mm punch biopsies that are subsequently transferred to RS chambers created via 1-mm punch biopsies, spaced approximately 3 to 10 mm apart.⁴¹ In contrast to FUT, follicular unit extraction is considered an easier procedure and is preferred when limited DS area is available and also favored as a spot-treatment for achromic areas that have not repigmented following FUT.⁴²

Cellular Grafting Techniques

Cellular grafting involves transferring melanocytes and keratinocytes from a DS to the RS as a suspension with or without the use of cell culture. Noncultured epidermal suspensions (also referred to as a melanocyte keratinocyte transplant procedure; NCES) has gained worldwide acceptance as a standard for vitiligo grafting, as it can be performed in a single office visit and does not require use of a laboratory.¹

The main advantage of NCES is the small DS area required to cover a large RS area, in a 1:10 ratio, respectively. An ultra-thin skin graft is harvested from the DS and following cell processing, a cellular suspension is formed and applied to a RS denuded to the dermal-epidermal junction by either dermabrasion or ablative carbon dioxide laser.

Hair follicle outer root sheath cell suspensions were somewhat recently introduced in 2009 by Vanscheidt and Hunziker.⁴³ This method involves the harvesting of hair follicles using the follicular unit extraction method, induction of cell separation using trypsin, incubation, centrifugation, and eventually application of collected cells to the RS. A notable drawback to hair follicle outer root sheath cell suspension is the low cell yield.⁴⁴

Treatment-Refractory Options

A lack of response, delineated by lack of stability or repigmentation following 3 and 6 months of combination therapy, respectively, should warrant consideration of other treatment modalities to improve dyschromia. Disease extent and impact on quality of life can guide treatment selection.

Camouflaging Agents

In vitiligo, camouflaging agents are broadly classified as temporary or permanent. Temporary treatment options include foundation and sunless-tanners, whereas permanent methods include micropigmentation (tattooing).⁴⁵ The ideal camouflaging agent is one that is waterproof, sweat resistant, opaque, and demonstrates good skin color match.⁴⁵

Camouflaging makeup foundations contain 25% more pigment compared to traditional makeup and are generally waterproof, decreasing the need for reapplication.⁴⁵ Dihydroxyacetone is a sunless tanning product that induces temporary staining of the skin by reacting with proteins in the stratum corneum to form brown chromophores termed melanoidins.⁴⁶ Dihydroxyacetone provides longer-lasting coverage (approximately 5 to 7 days),⁴⁷ though use may be limited by poor color match, allergic contact dermatitis,⁴⁸ and the potential cytotoxic effect on keratinocytes as seen in a recent in vitro study.⁴⁹

Micropigmentation (skin tattooing) is generally not recommended due to the risk of koebnerization and color variations over time, secondary to incorrect depth of pigment positioning, resulting in the need for re-application. Oxidation of tattoos containing metal oxides can also lead to a black discoloration, which can be difficult to remove.⁴⁵ Summer tanning can also lead to undesirable skin color contrasts.⁵⁰ Other reactions, including contact dermatitis, granulomatous reactions, and acquired transmission of herpes simplex virus, human immunodeficiency virus, hepatitis B and C, and secondary infections may also occur.⁴⁵

Depigmentation Therapies

In patients with extensive, treatment-refractory vitiligo involving greater than 50% of the BSA, depigmentation therapies can be considered.¹ Monobenzyl ether of hydroquinone (MBEH) is the only drug approved by the US Food and Drug Administration to induce depigmentation.¹ In areas of residual pigmentation, 20% MBEH can be applied twice daily. Lack of response after 4 months of therapy is an indication to increase to 30% MBEH, and if no response is observed by 6 months, MBEH should be discontinued.¹ Once complete depigmentation is achieved, applications can be reduced to a few times per week as maintenance. Complete depigmentation typically takes approximately 4 to 12 months, although darker skin phototypes may require longer treatment.¹ Side effects include irritant contact dermatitis⁵¹ and rarely conjunctival melanosis.⁵² Mequinol is a phenol derivative that may be used to achieve depigmentation, though onset of depigmentation is typically slower.¹

Laser-mediated depigmentation may be used to target remaining melanosomes in melanocytes through photothermolysis and photoacoustic effects.^53,54 The Q-switched ruby (694 nm), Q-switched alexandrite (755 nm), and Q-switched Nd:YAG lasers (532 nm), are most commonly used. This modality is usually reserved for treatment resistant areas on the hands and face. The potential for koebnerization associated with laser therapy can also be an asset to enhance depigmentation.⁵⁵

New Treatments in Vitiligo

Recent studies reveal the IFN-y-CXCL10 axis may be an effective target to treat vitiligo, which has given rise to a new class of targeted immunotherapies, the Janus kinase inhibitors.⁵⁶ Significant repigmentation has been reported following treatment with 2 oral Janus kinase inhibitors, tofacitinib⁵⁷ and ruxolitinib.⁵⁸ Topical ruxolitinib has also shown efficacy, especially with respect to facial repigmentation.⁵⁹ Combination with natural sunlight or NB-UVB may lead to improvements in their efficacy, as observed using oral tofacitinib.⁶⁰ Although these therapies appear promising, studies involving larger cohorts are needed to validate their efficacy. A multi-center phase II clinical trial (ClinicalTrials.gov Identifier: NCT03099304) involving the use of topical ruxolitinib in vitiligo is currently underway.

Afamelanotide, a synthetic alpha melanocyte stimulating hormone, requires the presence of melanocortin 1 receptor and supplementation with NB-UVB to stimulate melanoblast differentiation, and may be an effective new vitiligo therapy.⁶¹

Follow-Up

Frequent disease response monitoring is important to ensure appropriate management and allow for recognition of treatment failure early on, allowing for transition to alternative, potentially more effective therapies as needed. Generally, it is recommended that patients be reevaluated every 3 to 6 months until an effective, stable treatment regimen is established.¹ Due to the significant psychosocial burden experienced by patients with vitiligo, providers should be mindful of the importance of incorporating conversations addressing mental health into patient visits.

Conclusion

Vitiligo is a psychosocially debilitating disease requiring a multidisciplinary approach to treatment. Patients should be made aware of all of the options available geared at repigmentation and depigmentation prior to formulating a treatment plan. Frequent follow-up for disease monitoring and incorporation of discussions centered on quality of life impact can provide treatment guidance and allow for individualized care.

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