M e d i c a l an d M a i n t e n a n c e

Tre a t m e n t s fo r V i t i l i g o
Thierry Passeron, MD, PhD

KEYWORDS
 Vitiligo  Medical treatments  Topical steroids  Calcineurin inhibitors  Sytemic steroids
 Methotrexate

KEY POINTS
 Medical treatments alone, or in combination with phototherapy, are key approaches for treating
nonsegmental vitiligo and, to a lesser extent, for treating segmental vitiligo.
 The treatments can be useful for halting disease progression and have proved effective for inducing
repigmentation and decreasing the risk of relapses.
 Although the treatments have some side effects and limitations, vitiligo often induces a marked
decrease in the quality of life of affected individuals and in most cases the risk:benefit ratio is in
favor of an active approach.
 Systemic and topical agents targeting the pathways involved in the loss of melanocytes and in the
differentiation of melanocyte stem cells should provide even more effective approaches in the near
future, thanks to the increased knowledge of the pathophysiology of vitiligo.

INTRODUCTION complete depigmented lesions, however, and

repigmentation may be difficult in lesions of
There are 3 aims needed for the optimal care of some patients while their vitiligo remains inactive
vitiligo patients: first, halting the disease progres- for years. Recent transcriptomic analysis showed
sion; then, allowing complete repigmentation of an impaired Wnt signaling pathway in vitiligo le-
lesional areas; and, finally, preventing relapses. sions preventing the differentiation of melanocyte
There is still no therapeutic panacea for vitiligo stem cells.4 Fibroblasts of some areas, such as
but current options can lead to significant hands and feet, produce Wnt inhibitors.5 This
improvement of vitiligo lesions. Some areas, might contribute to a defect in melanocyte differ-
such as the face, usually respond well to therapies entiation and could explain the difficulties for
whereas they remain mostly ineffective for others, repigmenting those localizations. So far the best
such as hands and feet. Recent advances in the way to stimulate the differentiation of melanocytes
understanding of the pathophysiology of vitiligo is ultraviolet (UV) radiation. Recent data have
foster new therapeutic opportunities. One of the shown that the action of UV on melanocyte stem
most promising is the demonstration of the key cells is mediated by Wnt proteins.6 Thus, stimu-
role of the interferon gamma (INF-g)/Janus kinase lating the Wnt pathway by using topical agents
(JAK)/CXCL10 pathway in the depigmentation might allow repigmenting even difficult-to-treat
process of vitiligo.1 Targeting this pathway might areas. Although phototherapy and surgery remain
provide effective therapeutic approaches, as sug- useful approaches for vitiligo, systemic or topical
gested by recent cases reports (discussed medical therapies are important alone or com-
later).2,3 The immune reaction is absent of bined for optimal treatment of most vitiligo cases
[Link]

Department of Dermatology and INSERM U1065, Team 12, C3M, Archet 2 Hospital, University Hospital of Nice,
150 Route de Ginestière, Nice 06200, France
E-mail address: passeron@[Link]

Dermatol Clin 35 (2017) 163–170

[Link]
0733-8635/17/Ó 2016 Elsevier Inc. All rights reserved.
164 Passeron

and, in light of recent pathophysiologic advances, and the high rate of relapses, the use of such an
they offer encouraging options for the near future. approach remains controversial.

HALTING DISEASE PROGRESSION Methotrexate

The course of vitiligo is unpredictable. An active The first case supporting the use of methotrexate
phase, however, can be clinically detected. Medi- in vitiligo was reported in a woman treated with
cal history of the vitiligo, reporting a rapid onset 7.5 mg per week for rheumatoid arthritis. She
and ongoing extension of depigmented lesions, had a 6-month history of rapidly progressing viti-
is highly suggestive of active disease. Wood ligo. She stopped developing new lesions after
lamp examination is of great importance because 3 months of treatment.15 More recently, the effi-
it can show blurred and hypochromic borders of cacy of methotrexate (10 mg per week) was
lesions that are associated with ongoing depig- compared with OMP dexamethasone (5 mg per
menting process.7 The presence of a confetti week with 2.5 mg taken on 2 consecutive days)
sign was recently reported to be also associated in a prospective randomized open-label study in
with a marked spreading of vitiligo lesions within 52 vitiligo patients.16 After 6 months of treatment,
the following months.8 Several medical ap- 6 of 25 patients developed new lesions with meth-
proaches have been proposed for halting or otrexate compared with 7 of 25 patients with OMP.
decreasing the progression of active vitiligo. Both groups had also a similar reduction in vitiligo
disease activity score. The investigators
Systemic Steroids concluded that both drugs are equally effective
in controlling the disease activity of vitiligo. The
Systemic corticosteroids (high-dose pulsed
data evaluating the use of methotrexate in vitiligo,
therapy, minipulsed regimen, or daily oral low
however, remain limited.
dose) have been reported to rapidly arrest
spreading vitiligo and to induce repigmentation.9
Minocycline
Low-dose oral prednisolone (0.3 mg/kg) taken
daily for 2 months10 and a high dose of intravenous Minocycline was proposed for treating vitiligo
methylprednisolone (8 mg/kg) administered on 3 because of its anti-inflammatory, immunomodula-
consecutive days11 were evaluated in open-label tory, and free-radical scavenging properties. An
clinical studies. Both regimens were reported to initial open-label study reported an arrest in dis-
halt disease progression in more than 85% of ease progression in 29 of 32 patients treated
cases and to induce some repigmentation in with 100 mg per day of minocycline.17 The same
more than 70% of cases. Most studies have eval- group further reported a prospective randomized
uated oral minipulse (OMP) betamethasone or trial comparing OMP (5 mg per week) with minocy-
dexamethasone using 5 mg twice a week on 2 cline (100 mg per day)18; 50 patients with active
consecutive days usually for 3 months12 to vitiligo were included. After 6 months of treatment,
6 months.13 The progression of disease was both groups showed a significant decrease in viti-
stopped in more than 85% of cases but a marked ligo disease activity score from 4.0 to 1.64  0.86
repigmentation was observed in less than 7% of (P<.001) and from 4.0 to 1.68  0.69 (P<.001), for
cases. Side effects included weight gain, minocycline and OMP, respectively. The differ-
insomnia, acne, agitation, menstrual disturbance, ence between the 2 groups was not statistically
and hypertrichosis. The prevalence of side effects significant (P 5 .60). Minocycline (100 mg per
ranged from 12%12 to 69%.13 A large retrospec- day) was also compared with narrow-band (Nb)-
tive study confirmed these results, showing an ar- UVB (twice weekly) in a prospective comparative
rest of disease activity in 91.8% of cases.14 trial performed in 42 patients with active vitiligo.19
Adverse reactions, such as weight gain, lethargy, After 3 months of treatment, only 23.8% of pa-
and acneiform eruptions, were observed in 9.2% tients still had active lesions with Nb-UVB
of patients. Relapses after discontinuation of the compared with 66.1% with minocycline (P<.05).
treatment are not rare. In 138 children treated Patients in the Nb-UVB group also showed signif-
with OMP of methylprednisolone for 6 months, icantly higher repigmentation compared with
34.8% had relapses over a period of 1 year. The those in minocycline group. Both studies lacked
rate of relapses was higher in children below an untreated group to assess the evolution of viti-
10 years of age (47.4%). Thus, systemic cortico- ligo without treatment. These results need further
steroids seem to halt disease progression in evaluation, but Nb-UVB seems more important
most cases. No prospective randomized trial for halting disease progression and has the main
against placebo, however, has been performed advantage of also promoting more efficient repig-
yet. Given the significant potential for side effects mentation of vitiligo lesions.
 Medical and Maintenance Treatments for Vitiligo 165

REPIGMENTATION THERAPIES month double-blind randomized trial compared

Corticosteroids 0.1% tacrolimus and 0.05% clobetasol propionate
in children with vitiligo.28 This study confirmed that
Intralesional corticosteroids were first reported for
tacrolimus stimulates vitiligo repigmentation; how-
use in vitiligo 30 years ago. The pain associated
ever, tacrolimus ointment was not superior to clo-
with injection and the risk of cutaneous atrophy
betasol in extent of repigmentation. These results
(observed in approximately one-third of patients)
were confirmed by a prospective randomized trial
was against further use of this approach.20
comparing tacrolimus 0.1%, clobetasol propio-
Recently, a series of 9 patients with localized viti-
nate, and placebo.29 Tacrolimus and clobetasol
ligo were successfully treated with intralesional in-
propionate showed similar efficacy and both pro-
jections of triamcinolone acetonide, 3 mg/mL
vided significantly better repigmentation
(0.05–0.1 mL for each site), every 4 to 6 weeks
compared with placebo. Facial lesions responded
with an average duration of the treatment of
faster and better compared with nonfacial lesions.
4 months (maximum 7 months).21 Skin atrophy
Twice-daily application of 0.1% tacrolimus pro-
was seen in 1 patient and menstrual irregularity re-
vided better results compared with once-daily ap-
ported in 2 patients. A meta-analysis of nonsur-
plications.30 The same results were obtained in an
gical approaches for treating vitiligo reported
open intraindividual study performed with 1%
equal efficacy of intralesional and topical ste-
pimecrolimus cream.31 Again, 0.05% clobetasol
roids.22 Taking into account the side effects of
propionate induced a comparable rate of repig-
intralesional steroids, the use of topical forms
mentation to a topical calcineurin inhibitor. The
should thus be preferred. Systemic steroids can
best results were observed on sun-exposed areas.
be beneficial for halting systemic progression of
An intraindividual prospective comparative study
active vitiligo but they have limited efficacy in
has shown that tacrolimus monotherapy in the
repigmenting the lesions.13
absence of UV has little or no repigmenting poten-
Topical corticosteroids are useful for small,
tial in vitiligo.32 An open randomized study
localized areas and remain one of the gold stan-
compared topical pimecrolimus and topical tacro-
dard treatments for vitiligo. Meta-analyses
limus to Nb-UVB for treating vitiligo.33 The investi-
confirmed their effectiveness for localized viti-
gators did not find statistically significant
ligo.23 Steroid-induced repigmentation occurs
differences in repigmentation among the 3 groups.
within 1 to 4 months of treatment in a perifollicular
It is now demonstrated, however, that best results
pattern and from the margins of the lesions. Side
are achieved when phototherapy is combined with
effects include epidermal atrophy, steroid-
these topical treatments (Fig. 1) (See Samia Esmat
induced acne, rosacea, telangiectasia, ecchymo-
and colleagues article, “Phototherapy and
ses, and striae. Atrophy was observed in 14%
Combination Therapies for Vitiligo,” in this issue).
and 21%, respectively (mean), of patients treated
with potent versus very potent corticosteroids.24
Corticosteroids of low potency, however, show Other Topical Medical Treatments
no therapeutic effect at all. Furthermore, suppres-
Topical vitamin D analogs have been proposed
sion of the hypothalamic-pituitary-adrenal axis
alone or combined with phototherapy for treating
may occur after prolonged applications on large
vitiligo. A prospective, right/left comparative,
areas. To minimize the incidence of these side ef-
open-label study showed that calcipotriol in
fects, it is recommended to use topical steroids on
monotherapy is not effective for vitiligo.34
limited skin areas; to avoid prolonged use on sen-
There are several conflicting results on the use
sitive areas, such as face and body folds; and to
of topical antioxidants for treating vitiligo. In most
use them once daily for only 6 to 8 weeks followed
cases, however, topical antioxidants are used in
by a treatment-free interval of several weeks
combination with phototherapy. One prospective
because mild steroid-induced skin atrophy is
intraindividual study compared 0.05% betametha-
reversible. Other schedules of intermittent therapy
sone to topical catalase/dismutase superoxide.35
(3 weeks on and 1 week off and 5 days a week)
After 10 months of treatment, there was no statis-
have also been proposed.25 To minimize side ef-
tical differences between the 2 groups (P 5 .79),
fects, treatment should be discontinued if there
with mean repigmentation of 18.5% with betame-
is no visible improvement after 3 months.
thasone and 12.4% with topical catalase/dismut-
ase superoxide. Although the rationale for using
Topical Calcineurin Inhibitors
topical antioxidants in vitiligo is strong, the data
Early observations suggested that tacrolimus and remain limited and controversial. One possible
pimecrolimus may be effective treatments for explanation is the difficulty of delivering active
both localized and generalized vitiligo.26,27 A 2- antioxidants into the skin. Double-blind
166 Passeron

Fig. 1. Vitiligo of the leg and knee (A) before treatment and (B) after 30 sessions of 308-nm excimer laser com-
bined with twice-daily applications of 0.1% of tacrolimus ointment.

placebo-controlled studies are mandatory to observe rapid repigmentation. Potent topical ste-
further investigate the real efficacy of such an roids and calcineurin inhibitors have proved their
approach for treating vitiligo. efficacy and are the best options for repigmenting
localized vitiligo.36,37 Topical steroids or calci-
INDICATIONS AND LIMITATIONS OF USING neurin inhibitors can also be proposed for
MEDICAL APPROACHES FOR TREATING segmental vitiligo, although they are less effective
VITILIGO than in nonsegmental forms.38 They can be useful
before surgical approaches, however, because
The use of systemic treatments, such as systemic they can reduce the size of the area to graft and
corticosteroids or methotrexate, can induce po- sometimes completely repigment the lesions
tential serious side effects. The limited data actu- (Fig. 2).
ally available for their efficiency in treating vitiligo Due to the risk of atrophy when using potent or
should prompt caution on their use in current prac- very potent topical steroids for a long period, their
tice. Their use remains controversial and should be efficacy has to be assessed after 3 months.
limited to active vitiligo to halt the disease. Peri- Although data remain limited, intermittent therapy
odic monitoring of their efficacy and tolerance with application 5 days a week can be proposed
are important. Although comparative data are to decrease the risk of atrophy. On sensitive areas,
limited, the good safety profile of Nb-UVB, its abil- such as folds, neck, and face (and mostly eyelids),
ity to decrease disease progression, and its effec- twice-daily application of topical calcineurin inhibi-
tiveness for also inducing repigmentation should tors are preferred.28 Calcineurin inhibitors are
make Nb-UVB the first-line option for halting dis- significantly more effective on sun-exposed areas
ease progression. or when combined with phototherapy (See Samia
Vitiligo usually requires several months for repig- Esmat and colleagues article, “Phototherapy and
mentation and patients have to be informed about Combination Therapies for Vitiligo,” in this issue).
the length of the treatment to avoid premature Avoidance of UV light is suggested, however, by
discontinuation of the treatment; many expect to the package insert. This recommendation was
 Medical and Maintenance Treatments for Vitiligo 167

Fig. 2. (A) Segmental vitiligo affecting the V1 segment of the face before treatment and (B) partial repigmenta-
tion after 1 year of twice-daily applications of 0.1% of tacrolimus ointment and sun exposures. The repigmenta-
tion remains incomplete but allows decreasing the size of the surgical graft.

based on mouse models and on the immunosup- calcineurin inhibitors have been used for vitiligo
pression that can be induced when a high quantity alone or combined with phototherapy for more
of calcineurin inhibitors penetrates through the skin than 10 years without any indication of risk. Taken
and reaches systemic levels. The mouse models together, these data are reassuring concerning
have strong limitations, however, when drawing the use of topical calcineurin inhibitors combined
definitive conclusions, and reassuring data on the with UV exposures in vitiligo patients; however, a
use of topical calcineurin inhibitors have since total follow-up of 20 to 25 years may be required
been reported.39,40 Moreover, penetration of high to be completely reassured concerning a potential
quantities of calcineurin inhibitors can mostly be increased risk of skin cancers. Thus, the risk:bene-
observed when used over large surfaces in atopic fit ratio needs to be discussed with patients when
dermatitis patients where the skin barrier is altered, topical calcineurin inhibitors are proposed. A treat-
which is not the case for vitiligo skin. Topical ment algorithm is proposed in Fig. 3.

ViƟligo
In all cases medical camouflaging can be helpful
Psychological support if needed

Non-
Segmental Universalis
segmental

Ac ve ongoing
Medical Surgical Discuss
depigmenta on
approaches approaches depigmenta on of the
?
remaining pigmented
areas
Topical steroids YES NO
or topical Consider Are the lesions
calcineurin As first-line or phototherapy or localized or
inhibitors; a er medical systemic steroids diffuse?
Phototherapy treatment to try hal ng the
alone or be er disease
combined progression LOCALIZED
Topical steroids or topical
calcineurin inhibitors
alone, or be er combined with sun
exposure or excimer laser or lamp

DIFFUSE
Phototherapy
alone, or be er combined with
topical treatment (at least in
difficult to treat areas)

Complete or almost complete repigmenta on achieved ?

YES NO
Consider maintenance therapy Reconsider protocol

Fig. 3. Treatment algorithm.

168 Passeron

PREVENTING VITILIGO RELAPSES Afamelanotide

After successful repigmentation, the rate of relapse Afamelanotide is a melanocortin-1 receptor
in vitiligo patches is approximately 40%.41 In atopic agonist. A prospective randomized trial provided
dermatitis, proactive treatment with topical ste- encouraging results when afamelanotide, adminis-
roids or calcineurin inhibitors has demonstrated ef- trated monthly by subcutaneous implants, was
ficacy to decrease flares of the disease.42 In a 2- combined with UVB (repigmentation rate of
center, prospective randomized study, the use of 48.64% at day 168) compared with UVB alone
biweekly application of 0.1% tacrolimus ointment (repigmentation rate of 33.26%).47 Only 17 of 28
was compared with placebo43; 35 patients with patients completed the study in the combination
72 nonsegmental vitiligo lesions who achieved at arm (39.3% dropout) compared with 24 of 27 pa-
least 75% of repigmentation after phototherapy, tients (11.1% dropout) in the UVB-only arm. The
topical treatment, or a combination approach most frequent side effects were nausea (18%)
were included. After 6 months, 40% of lesions and fatigue (11%). Better results were obtained,
showed depigmentation in the placebo group however, in dark-skinned patients. The potent tan-
compared with 9.7% with tacrolimus (P 5 .0075). ning of the nonlesional skin is also a limitation in fair-
The tolerance was good and the side effects limited skinned patients because it increases the contrast
to transient erythema and stinging or burning sen- between healthy and lesional skin. Additional
sations. This study shows that twice-weekly appli- studies are clearly required to determine the indica-
cations of 0.1% of tacrolimus are effective for tions and the limitations of this approach.48
decreasing vitiligo relapses.
According to the data available in atopic derma- Janus Kinase Inhibitors
titis and the comparable efficacy of topical ste-
The IFN-g/JAK/CXCL10 pathway seems to play a
roids and tacrolimus for treating vitiligo, it may be
key role in the depigmentation process of vitiligo.1
hypothesized that topical steroids could also be
Every component of this pathway represents a po-
effective for preventing vitiligo relapse. Many
tential therapeutic target.49 For now, clinical data
questions remain. How long should this preventive
are limited to 2 case reports using JAK inhibitors.
treatment be continued? Are applications 3 times
IFN-g signals through its receptor, which activates
per week more effective than only 2 times per
JAK1 and JAK2 to induce the transcription of
week and thus could they further reduce the risk
CXCL10, which is important in vitiligo pathogen-
of relapse? The author proposed this maintenance
esis. The first clinical response was reported using
treatment only in patients with active vitiligo or pa-
a JAK1/JAK3 inhibitor, called tofacitinib, which is
tients who already had relapses after having
Food and Drug Administrant approved for the
achieved repigmentation and continues this pro-
treatment of rheumatoid arthritis.2 A 50-year-old
active approach for at least 6 months without
woman with vitiligo nonresponsive to topical treat-
any sign of disease activity. Further studies are
ments was treated with 3 mg per day of tofacitinib
clearly required, however, to answer to these
for 3 weeks and then 5 mg per day (daily dose for
questions.
rheumatoid arthritis is 10 mg). An almost-complete
repigmentation was achieved after 5 months of
POTENTIAL EMERGING MEDICAL treatment. The second case was a 35-year-old
TREATMENTS man with vitiligo and alopecia areata.3 He received
Topical Prostaglandins oral ruxolitinib during a phase 2 trial for alopecia
areata. Ruxolitinib is a JAK1/JAK2 inhibitor
Prostaglandin E2 can stimulate the proliferation of approved for treating myelofibrosis and polycy-
melanocytes and melanogenesis.44 Two open- themia vera. After 20 weeks of treatment, he repig-
label prospective studies tested twice-daily appli- mented from 0.8% to 51% on his face.
cation of topical prostaglandin E2 in the treatment Unfortunately, the repigmentation was completely
of localized and stable vitiligo; 15 of the 24 patients gone 12 weeks after the discontinuation of the
in the first study45 and 20 of the 56 patients in the treatment. Prospective randomized trials are now
second trial46 achieved repigmentation of greater required for assessing the long-term efficacy and
than 75% after 6 months of treatment. The toler- the safety of such approaches but they seem of
ance was good in both studies. Those results great interest, especially for active vitiligo.
need confirmation but they are potentially inter-
esting because the mechanism of action of prosta- SUMMARY
glandins probably differs from the current
therapeutic approaches and may be combined Medical treatments alone or in combination with
with them to enhance the repigmentation rate. phototherapy are key approaches for treating
 Medical and Maintenance Treatments for Vitiligo 169

nonsegmental vitiligo and to a lesser extent for 11. Seiter S, Ugurel S, Tilgen W, et al. Use of high-dose
treating segmental vitiligo. They can be useful for methylprednisolone pulse therapy in patients with
halting disease progression and have proved progressive and stable vitiligo. Int J Dermatol
effective for inducing repigmentation and more 2000;39:624–7.
recently to decrease the risk of relapses. They 12. Pasricha JS, Khaitan BK. Oral mini-pulse therapy
have some side effects and limitations that have with betamethasone in vitiligo patients having exten-
to be discussed with patients. Vitiligo often in- sive or fast-spreading disease. Int J Dermatol 1993;
duces a marked decreased in the quality of life of 32:753–7.
affected individuals, however, and the risk:benefit 13. Radakovic-Fijan S, Furnsinn-Friedl AM,
ratio is in favor of an active approach in most Honigsmann H, et al. Oral dexamethasone pulse
cases. Thanks to increased knowledge of the treatment for vitiligo. J Am Acad Dermatol 2001;44:
pathophysiology of vitiligo, systemic and topical 814–7.
agents targeting more specifically the pathways 14. Kanwar AJ, Mahajan R, Parsad D. Low-dose oral
involved in the loss of melanocytes and also in mini-pulse dexamethasone therapy in progressive
the differentiation of melanocyte stem cells should unstable vitiligo. J Cutan Med Surg 2013;17:259–68.
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approaches. sponding to methotrexate. Indian J Dermatol Vene-
reol Leprol 1998;64:309.
16. Alghamdi K, Khurrum H. Methotrexate for the treat-
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