Vitiligo
Salient features
|
·
The most frequent depigmenting disorder,
affecting 1% of the population worldwide ·
Characterized by progressive autoimmune-mediated
destruction of epidermal melanocytes ·
Typical presentation: patches of white skin and
hair ·
Cause of physiological and social stigma among
affected individuals ·
Increased risk for other autoimmune diseases,
unpredictable evolution and unsatisfactory therapeutic outcomes |
Vitiligo
is an acquired disorder characterized by circumscribed depigmented macules and
patches that result from a progressive loss of functional epidermal melanocytes.
Epidemiology
Worldwide
vitiligo affects approximately 0.5–2% of the general population. Vitiligo can begin at any age but in the majority of cases
becomes apparent between the age of 20 and 30 years. Although
patients with vitiligo may attribute the onset of their disease to specific
life events (e.g. physical injury, sunburn, emotional distress, illness,
pregnancy), with the exception of the Koebner phenomenon, there is no proof
that these factors cause or precipitate vitiligo.
Aetiology
Different factors of vitiligo pathogenesis
Pathogenesis
Vitiligo
is a multifactorial disorder related to both genetic and nongenetic factors. It
is generally agreed that there is an absence of functional melanocytes in
vitiligo skin and that the loss of histochemically recognizable melanocytes is
the result of their destruction.
Pathogenic
hypotheses for vitiligo
A
primary challenge is the fact that what is referred to as vitiligo likely represents a heterogeneous group
of diseases with different genetic backgrounds and environmental triggers.
The
immune system clearly plays a central role, in particular Th1 and Th17 cells,
along with cytotoxic T cells, regulatory T cells, and dendritic cells; key
mediators include interferon-γ (IFN-γ), C-X-C chemokine ligand 10 (CXCL10), and
interleukin-22 (IL-22).
Intrinsic
defects of melanocytes and exogenous triggers may also play a role in vitiligo
development. In addition, oxidative stress has been investigated as a
pathogenic factor that could activate the immune response in vitiligo and
underlie impaired WNT signaling that prevents melanoblast differentiation.
Accumulating data highlight the complexity of vitiligo, with involvement of
multiple cell types, including keratinocytes, fibroblasts, and stem cells as
well as immune cells.
These
hypotheses are not mutually exclusive and the various pathways may converge to
induce the disappearance of melanocytes from the skin and hair follicles.
However, the exact cascade of events remains to be elucidated.
Proposed model for the pathogenesis of vitiligo
Inherited
genetic risk and environmental insults (e.g. monobenzyl ether of hydroquinone
[MBEH], 4-tertiary butyl phenol [4-TBP]) induce melanocyte stress, exemplified
by endoplasmic reticulum (ER) stress. Stressed melanocytes signal to local
innate and resident skin cell types via exosomes containing antigen and
damage-associated molecular patterns (DAMPs), soluble heat shock protein 70
(HSP70), and other factors. These signals activate several cell types, some of
which migrate to the draining lymph nodes and stimulate T cells, which secrete
interferon-γ (IFN-γ). IFN-γ signals through the IFN-γ receptor (IFN-γR) on
keratinocytes and/or other cells; this involves phosphorylation of the
transcription factor STAT1 by Janus kinase (JAK) 1 and 2. Phosphorylated STAT 1
homodimerizes and then translocate in to the nucleus, where IFN-γ dependent
genes such as CXCL10 (C-X-C chemokine ligand 10) are transcribed. Auto reactive
CD8+ T cells
that express C-X-C chemokine receptor 3 (CXCR3) follow secreted CXCL10 to the
skin, where they kill melanocytes. Approaches targeting this IFN-γ-STAT-CXCL10
axis that drives melanocyte destruction (e.g. with JAK inhibitors or antibodies
against CXCR3) hold promise as potential treatments for vitiligo. ROS, reactive
oxygen species; STAT1, signal transducer and activator of transcription 1;
TYRP-1, tyrosinase related protein 1.
Double strike
hypothesis in vitiligo
In
2010, Michelsen proposed a thesis known as double strike hypothesis in
vitiligo, i.e. vitiligo is caused by a least two different major patho-mechanisms:
an antibody based patho-mechanism and a T cell-based patho-mechanism. The
antibody-based patho-mechanism is dominant in diffuse vitiligo, while the
T-cell based patho-mechanism is dominant
in localised vitiligo.
Pathology
Epidermis – complete absence of melanocytes
and melanin pigment
A skin biopsy is rarely necessary to confirm
the diagnosis of vitiligo. Generally, histology shows a marked absence of
melanocytes and melanin in the epidermis of lesional areas. Histochemical
studies show a lack of dopa- positive melanocytes in the basal layer of the
epidermis. There is sparse dermal, perivascular and perifollicular lymphocytic
infiltrates at the margins of early vitiligo lesions and active lesions,
consistent with cell mediated immune process destroying melanocytes in
situ.
Clinical Features
The
most common presentation of vitiligo is totally amelanotic (i.e. milk- or
chalk-white) macules and patches with fairly homogeneous depigmentation
surrounded by normal skin. The lesions can be round, oval, irregular or linear
in shape. The borders are usually well-defined and convex, as if the
depigmenting process were “invading” the surrounding normally pigmented skin. However, at their onset or when actively spreading, areas
of vitiligo may be more ill-defined and hypo- rather than depigmented.
Lesions enlarge centrifugally over time at a rate that can be slow
or rapid. Vitiligo macules and patches range from millimetres to centimetres in
diameter and often have variable sizes within an area of involvement and fuse
with neighbouring lesions to form complex patterns. In lightly
pigmented individuals, the lesions may be subtle or in apparent without Wood’s
lamp examination or tanning of uninvolved skin. In darkly pigmented patients,
the contrast between vitiliginous areas and the surrounding skin is striking. Vitiligo
is usually asymptomatic, but pruritus is sometimes noted, especially within
active lesions.
Vitiligo
often demonstrate a predilection for sun exposed regions, body folds and
periorificial areas, although it can develop anywhere on the body. Depigmented
macules are usually first noted on the sun- exposed areas of skin, such as face
or dorsa of hands. These areas are prone to sunburn. Interestingly, it has a
predilection for sites that are normally relatively hyper pigmented, such as
the face, dorsal aspect of the hands and body folds (nipples, areola, axillae,
umbilicus, groins and sacral and anogenital regions). Areas subjected to
repeated friction and traumas are also likely to be affected, for example hips,
digits, dorsa of hands and feet, flexor wrists, elbows, knees, dorsal ankles
and shins. Facial vitiligo typically occurs around the eyes, nostrils and mouth
(i.e. periorificial). Vitiligo on the palms, soles, lips and oral mucosa in
lightly pigmented individuals may not be evident without wood’s lamp
examination.
Clinical
classification of vitiligo
Two major forms are generally
recognized: (1) segmental, which usually does not
cross the midline; and (2) non-segmental, also
simply called “vitiligo” without qualification. Mixed vitiligo
refers to segmental and non-segmental forms occurring in the same patient
The
non-segmental form includes all cases not classified as segmental and is
divided into three general types: localized, generalized and universal.
The following classification scheme divides vitiligo into two
major types, localized and generalized
Distribution
of amelanotic skin lesions in vitiligo
Localized
· Focal vitiligo: characterized by the presence of one or few macule (s) in
one area that are not segmentally distributed; considered a precursor form of
GV.
· The
segmental form (uni‐, bi‐, or pluri segmental): characterized by one
or more macules involving one or rarely multiple segments of the body having unilateral segmental/band‐shaped distribution that does not cross the midline.
·
Mucosal vitiligo: a term reserved for depigmentation of mucous membrane
alone.
Generalized
· Vulgaris: multiple
scattered patches that are widely distributed in a more or less symmetrical
pattern; the most common presentation of GV
· Acrofacial or lip-tip
type: periungual involvement of one or more digits may be associated with lip
depigmentation; however, either can be an isolated
finding.
·
Mixed: combination of
segmental and generalized (acrofacial and/or vulgaris) types
· Universal: Complete
or nearly complete depigmentation of the whole body, although a few pigmented
areas always remain; the most severe form of GV.
Overall, >90% of vitiligo
patients have the vulgaris or acrofacial variants of the generalized type. In
the remainder, localized vitiligo is more common than mixed or universal
vitiligo. Segmental vitiligo is more common in children than adults, accounting
for ~15–30% of vitiligo in pediatric patients and typically remains
localized and often stabilizes within the
first year of onset, the depigmented lesions persisting unchanged for many
years.
As
vitiligo often spares follicular melanocytes, the
hairs in the patches frequently remain normally pigmented, but in older lesions
the hairs too are often amelanotic. Leukotrichia (depigmentation of hair within
vitiligo macules) is due to destruction of the melanocyte reservoir within the
hair follicle, therefore, predicting a poor therapeutic response. The occurrence of leukotrichia does not correlate with
disease activity. Rarely, follicular vitiligo presents
with leukotrichia in the absence of depigmentation of the surrounding
epidermis. Although vitiligo of the scalp, eyebrows, and eyelashes usually
presents as one or more localized patches of white or grey hair (poliosis),
scattered white hairs due to involvement of individual follicles or even total
depigmentation of all scalp hair may occur. In general, spontaneous
repigmentation of depigmented hair in vitiligo does not occur.
Specific Rare Clinical Phenotypes
·
Quadrichrome vitiligo is characterized by the presence
of a fourth colour (dark brown) at sites of perifollicular repigmentation. It
is more often encountered in patients with darker skin photo types.
·
Pentachrome vitiligo—the occurrence of five shades of
color: (1) white, (2) tan, (3) medium brown [unaffected skin], (4) dark brown and (5) black.
·
Confetti vitiligo or vitiligo ponctué— an
unusual clinical presentation of vitiligo, is characterized by multiple, tiny punctate-like discrete depigmented macules on normal
skin, sometimes superimposed upon a hyper pigmented macule.
·
Red vitiligo—the depigmented lesions have a
raised red border and may be pruritic, which is referred to as inflammatory
vitiligo
· Blue vitiligo— Blue
vitiligo
can result when vitiligo develops in areas already affected by post
inflammatory dermal hyper pigmentation, the blue–gray appearance of the skin,
which corresponds histologically with the absence of epidermal melanocytes and
presence of numerous dermal melanophages.
· Hypochromic
vitiligo (vitiligo
minor) was recently described in patients with skin types V and VI. They
presented with persistent hypo pigmented macules in a seborrheic distribution,
with lesions coalescing on the face and scattered on the neck, trunk, and
scalp. A few individuals had additional achromic macules, and there was no
history of prior inflammatory lesions. Decreased melanocyte density was noted
histologically.
· Although a hyper pigmented margin around a macule of leukoderma has been said to be specific for vitiligo, this is not a common feature.
One
of the manifestations of vitiligo is the isomorphic Koebner phenomenon (IKP),
characterized by the development of vitiligo in sites of trauma (e.g. a
laceration, burn or abrasion). The IKP is more common in patients with
progressive non-segmental vitiligo, but it can also affect those with segmental
vitiligo. There appears to be a minimal threshold of injury required for the
IKP to occur, bringing into question the hypothesis that minor trauma, such as
friction from clothes (in the absence of true injury), can induce vitiligo
lesions.
Comorbid Associations
Although most vitiligo patients are otherwise healthy, generalized
vitiligo which is an autoimmune disease is
often associated with a variety of other autoimmune diseases,
especially in patients with a family history of vitiligo and other forms of
autoimmunity. The most prevalent associated
autoimmune disease is autoimmune thyroid dysfunction, either hypothyroidism
(Hashimoto's thyroiditis) or hyperthyroidism (Grave's disease). Autoimmune
thyroid disease occurs in ~15% of adults and ~5–10% of children with vitiligo. Other less
frequently associated
autoimmune conditions are rheumatoid arthritis, psoriasis, type 1 diabetes
mellitus (usually adult-onset), pernicious anaemia, systemic lupus erythematosus,
and Addison's disease. Halo melanocytic nevi, alopecia
areata, and lichen sclerosus are additional autoimmune skin conditions that may
be associated with vitiligo.
Vitiligo
and ocular disease
The uveal tract (iris, ciliary body, and
choroid) and retinal pigment epithelium contain pigment cells. Uveitis is the most significant ocular abnormality
associated with vitiligo. Vogt–Koyanagi–Harada (VKH)
syndrome, a multiorgan disorder that affects pigmented structures, such as the eyes,
inner ear, meninges and skin andis characterized by vitiligo,especially
of the face or sacral region + meningismus
+poliosis +
uveitis + dysacusis (otic involvement) + alopecia areata. The
aseptic meningitis may be due to destruction of leptomeningeal melanocytes. The
disease appears in the fourth to fifth decade and is more common in women and
in persons with dark pigmentation.
Histologic
examination of amelanotic skin, which classically appears after the
extracutaneous symptoms, demonstrates an infiltrate consisting primarily of CD4+ lymphocytes, suggesting a prominent role for
cell-mediated immunity.
Alezzandrini syndrome is
a rare disorder characterized by unilateral whitening of scalp hair, eyebrows,
and eyelashes as well as ipsilateral depigmentation of facial skin and visual
changes. In the affected eye, there is decreased visual acuity and an atrophic
iris. The pathogenesis of Alezzandrini syndrome is unknown, but it is believed
to be closely related to VKH syndrome.
Childhood vitiligo
Vitiligo
commonly starts in children, who are more likely to show segmental vitiligo. Although vitiligo vulgaris is the most common clinical type
observed in children, the frequency of segmental vitiligo (~15–30%) is
significantly increased compared to that in adults (<5–10%). The incidence
of associated endocrinopathies is less than in the adult vitiligo population.
Between 30 and 40% of patients have a positive family history of vitiligo in a parent, sibling, or child and those with a
positive family history are more likely to develop vitiligo before 7 years of
age.
Depigmentation Other Than Vitiligo
In patients with vitiligo, local loss of pigment may
occur around pigmented nevi, the so-called halo phenomenon and often progress to spontaneous
disappearance of the nevus, presumably via lymphocyte-mediated destruction of
nevus cells.
The diagnosis of vitiligo is based
essentially on clinical examination. The distribution, age of onset and hyper
pigmented border will suggest the diagnosis. The
presence of a family history of vitiligo, the Koebner phenomenon, leukotrichia
or associated autoimmune disorders such as thyroid disease can help to support
a clinical diagnosis of vitiligo.
Wood’s light examination
Examination
with the Wood’s light in a dark room accentuates the hypo pigmented areas (vitiligo
area appears brighter and the normal skin appears darker) and is useful for
examining patients with light complexions. The axillae, anus, and genitalia
should be carefully examined. These areas are frequently involved but often
clinically non apparent without the Wood’s light.
Laboratory
Given the
association between vitiligo and other autoimmune diseases, several screening
laboratory tests are helpful, including T4 and TSH levels, antinuclear
antibodies, fasting
blood glucose, complete blood count with indices (pernicious anemia), ACTH
stimulation test for Addison disease, if suspected. Clinicians should also consider
testing for serum antithyroglobulin and antithyroid peroxidase antibodies,
particularly when patients have signs and symptoms suggestive of thyroid
disease.
Assessment of stability of vitiligo
Scoring system in vitiligo
The
onset of vitiligo is usually insidious. Many patients
become aware of the depigmented macules and patches, especially in sun-exposed
areas, during the summer when tanning increases the contrast between involved
and uninvolved skin. It is postulated that there is progressive, uniform
loss of pigment until a discrete white macule is apparent, which is followed by
centrifugal enlargement. Clinical erythema or
pruritus rarely precedes vitiligo.
The course of vitiligo is unpredictable. It becomes more
extensive by the appearance of new depigmented macules, enlargement of
pre-existing lesions, or both processes. Peripheral hypo
pigmentation and poorly defined borders appear to be predictive of active
vitiligo. A spotty pattern of depigmentation may also represent a marker of
progressive disease. The natural course of generalized vitiligo is usually one of
slow spread, sometimes
extending rapidly over a period of several months and then remains
stabilized for a long period of time. Rarely, total body involvement develops
within a few weeks or even days. In contrast, segmental vitiligo usually
reaches its full extent within 1–2 years and remains restricted to the initial
segmental area. Some degree of sun-induced or spontaneous repigmentation of
vitiligo is not uncommon, but complete and stable repigmentation is rare. Spontaneous
re-pigmentation is unpredictable, often clinically insignificant, and tends to
be cosmetically unacceptable. It occurs in fewer than 50% of patients, most commonly
in younger patients and in sun-exposed areas, where natural sunlight may act as
an inducing agent. In clinical practice, the most frequently encountered
pattern of repigmentation is perifollicular, though other patterns, such as
marginal, diffuse, or combined may also occur. When the hairs within
an area of vitiligo are depigmented, the former pattern is not observed. Some clinical parameters such as
a long duration of the disease, occurrence of Koebner's phenomenon,
leukotrichia, and mucosal involvement indicates of poor prognosis.
The presence of clinical markers
including trichrome sign, confetti-like depigmentation, and Koebner phenomenon
in vitiligo patients is associated with worse prognosis and rapid disease
progression, a recent study in the journal JAMA Dermatology has suggested. The
study further found that patients with multiple clinical markers may require more
intensive treatment.
MANAGEMENT
Vitiligo pathogenesis
begins with altered melanocytes that exhibit an elevated cellular stress
response. This triggers autoimmunity, which targets melanocytes for
destruction, resulting in focal depigmentation. Repigmentation requires the
growth and migration of melanocytes, typically from hair follicles. Thus, there
are 3 goals to consider during the treatment of vitiligo: (1) reducing
melanocyte stress, (2) suppressing autoimmune targeting of melanocytes and (3)
promoting melanocyte regeneration. Current treatments, including topical
immunosuppressants, phototherapy, and surgical approaches, partially address
these goals in overall nontargeted ways.
Indications for
treatment
Treatment is necessary for
patients in whom the disease causes emotional and social distress. Vitiligo in
individuals with fair complexions is usually not a significant cosmetic
problem. The condition becomes more apparent in the summer months when tanning
accentuates normal skin. Tanning may be prevented with sunscreens that have an
SPF of 15 or higher. Vitiligo is a significant cosmetic problem in people with
dark complexions.
The aims of vitiligo treatment are repigmentation and
stabilization of the depigmentation process. Although
there is still no therapeutic panacea for vitiligo, available options can lead
to satisfactory results. The choice of therapy depends on the extent,
location, and activity of disease as well as the patient’s age, skin type, and
motivation to undergo treatment. In general, a period of at least 2–3 months is
required to determine whether a particular treatment is effective. The areas of
the body that typically have the best response to medical therapy are the face,
neck, mid extremities and trunk, while the distal extremities and lips are the
most resistant to treatment.
Mechanism of
repigmentation
The
goal of treatment is to restore melanocytes to the skin. Therapy involves
stimulating melanocytes within the hair follicle to proliferate and migrate
back into depigmented skin. Depigmented skin is devoid of melanocytes in the
epidermis. Repigmentation is caused by activation and migration of melanocytes
from a melanocytic reservoir located in the outer root sheath of hair
follicles. Therefore skin with little or no hair (hands and feet) or with white
hair responds poorly to treatment. Inactive DOPA-negative amelanotic
melanocytes in the outer root sheath are still present. These cells can be
activated by treatment to acquire enzymes for melanogenesis. They proliferate
and mature as they migrate up the hair follicle into the epidermis and spread centrifugally.
When a vitiliginous spot repigments, it repigments from the follicle and
spreads outward and/or at the periphery of the
lesions. This process is slow and requires at least 6 to 12 months of
treatment. After therapeutic repigmentation, the rate
of recurrent depigmentation of vitiligo lesions is ~40%.
Treatment perspective
All
treatment options have limited success. For generalized vitiligo, phototherapy
with narrow-band UVB (NB-UVB) radiation is most effective with the fewest side
effects. Topical corticosteroids are the preferred drugs for localized
vitiligo. They may be replaced by topical immunomodulators, which display
comparable effectiveness and fewer side effects. The effectiveness of vitamin D
analogues is controversial with limited data but they are felt to be the least
effective topical treatment. The excimer laser is an alternative to UVB therapy
especially for localized vitiligo. Surgical therapy can be very successful, but
requires an experienced surgeon and is very demanding of time and facilities,
thus limiting its widespread use.
Corticosteroids
Topical
glucocorticoids
Corticosteroids
(TCSs) are used as first-line therapy. Children respond better than adults.
Head and neck lesions respond better. Topical corticosteroids are useful for
localized areas of vitiligo.
Approximately half of patients with vitiligo affecting ≤20% of the body
surface area achieved >75% repigmentation with either class 1 (super potent)
or class 2–3 (high-potency) topical corticosteroids. Typically ultra-potent
formulations are required for reliable efficacy, and most published studies
have evaluated the class I steroid clobetasol. It should be applied twice daily
and is preferable to use an intermittent regimen as cycles of 1 week on
treatment followed by 1 week off treatment for up to 6 months to avoid local
side effects (skin atrophy, telangiectasia, striae, hypertrichosis and acneform
eruptions). For childhood vitiligo, a class II potency steroid with a good
safety profile, like mometasone, is a good choice. Lower potency steroids do
not have strong evidence to support their use. Treatment should be discontinued
if there is no visible improvement after 2 months.
Systemic corticosteroids
Systemic corticosteroids can arrest rapidly spreading
vitiligo and lead to repigmentation in a significant proportion of patients,
but they may also produce unacceptable side effects. Oral mini pulse therapy
with 5 mg of betamethasone/dexamethasone is reported to arrest the progression
and induce spontaneous repigmentation in some vitiligo patients. To minimize
the side effects, betamethasone as a single oral dose is taken after breakfast
on 2 consecutive days per week. The progression of the disease is arrested in
89% of patients with active disease, whereas some patients needed an increase
in the dosage to 7.5 mg/day to achieve a complete arrest of lesions. Within 2
to 4 months, 80% of the patients started having spontaneous repigmentation of
the existing lesions that progressed with continued treatment.
Topical
calcineurin inhibitors
Topical application
of tacrolimus 0.1% ointment or pimecrolimus 1% cream twice daily initially for 6 months can lead to
repigmentation of vitiligo, with response rates in paediatric
patients similar to those achieved with topical corticosteroids. The
best results are obtained when these agents are used for facial and neck lesions and combined with sun exposure, with
the latter suggesting a synergistic effect. In addition, topical calcineurin
inhibitors (TCIs) have been shown to enhance repigmentation when used together
with narrowband UVB phototherapy or the 308 nm excimer laser. Topical tacrolimus
can also be used in conjunction with topical corticosteroids on a rotational basis or as maintenance therapy after
repigmentation. These medications are well tolerated and can be used for
prolonged periods without steroid-like side effects. They are slightly less
effective than corticosteroids. Nightly occlusion may enhance the effect on arm
and leg lesions that were previously nonresponsive to topical therapy.
Vitamin D3 analogues
Calcitriol
and calcipotriene are topical vitamin D3 analogues. As monotherapy,
they are inferior to TCS. When combined with TCSs, repigmentation rates
increase, and there is a greater stability of repigmentation compared with
either as monotherapy.
Photo (chemo) therapy
Narrowband UVB
Narrowband
UVB (NB-UVB) has become the first-line treatment for adults and children ≥6
years of age with generalized vitiligo, especially if it involves ≥5% of the
body surface area or cosmetically sensitive areas that typically respond to
treatment. Narrow-band
ultraviolet B light phototherapy is superior to ultraviolet A light
phototherapy. Therapy should be stopped if no colour returns after 3 months.
Patients who respond usually keep their pigment. Patients who have actively
spreading vitiligo should not be treated; treatment does not halt the spread of
the disease.
The starting dose of NB-UVB ranges from 100–250 mJ/cm2, which is increased in increments of 10–20% at each
subsequent exposure until mild, asymptomatic lesional erythema is achieved. Treatments
are administered 2–3 times per week, but not on two consecutive days.
Approximately 9 months of therapy are required to achieve maximal regpigmentation;
at least 3 months of treatment are warranted before the condition can be
classified as non-responsive. Better results occur in younger patients.
Short-term side effects include pruritus and xerosis; long-term side effects
(e.g. cutaneous carcinogenesis) have not been described.
The
advantages of NB-UVB over psoralen plus UVA (PUVA) therapy include shorter
treatment times, a lack of gastrointestinal side effects, reduced phototoxic
reactions and no need for post-treatment photo protection; in addition, NB-UVB
can be used in children, pregnant or lactating women, and individuals with
hepatic or kidney dysfunction. Furthermore, NB-UVB produces less accentuation
of the contrast between depigmented and normally pigmented skin.
Psoralen plus UVA
Psoralen
photo chemotherapy involves the use of psoralens combined with UVA light.
Psoralens can be administered orally (oral PUVA) or applied topically (topical
PUVA), followed by exposure to either UVA light or natural sunlight (PUVASOL).
Oral PUVA treatments
using 8-MOP (0.4–0.6 mg/kg) are typically administered two times weekly. For
patients with vitiligo, the initial dose of UVA is usually 0.5–1.0 J/cm2, which is gradually increased until minimal
asymptomatic erythema of the involved skin occurs. To reduce the risk of the
Koebner phenomenon, significant erythema (photo toxicity) is avoided. 5-MOP has
about the same response rate as 8-MOP in repigmenting vitiligo, but a lower
incidence of photo toxicity as well as less nausea and vomiting.
The response rate to PUVA is variable. PUVA resulted in
greater than 90% repigmentation in only 8% of patients, usually inhomogeneous
and weak repigmentation. The total number of PUVA
treatments required is generally 50–300. Until more data are available, it seems
wise to recommend 1000 J/cm2 as the
maximum cumulative (P) UVA dose and 300 as the maximum number of UVA
treatments.
PUVASOL
(psoralens
+ natural sunlight) can be used in sunnier climates, according to the
same principles as for PUVA. Less phototoxic oral psoralens such as 5-MOP are
preferred, to avoid phototoxic reactions. As with oral
psoralens, it may require ≥15 treatments to initiate response and ≥100 to
finish.
Topical (paint) PUVA is
more difficult to perform because of the high risk of photo toxicity and
subsequent blistering or koebnerization. A low concentration (≤0.1%) of
psoralen should be used, which requires dilution of the commercially available
preparation. Approximately 20–30 minutes after applying the topical cream or
ointment onto the lesions, the patient should be exposed to initial UVA doses
of no more than 0.25 J/cm2, with the same
fractional increments until mild erythema is achieved in the treated sites.
Lasers and
related light devices
Excimer laser and lamp
The
operational wavelength of the 308 nm excimer laser and lamp is close to that of
NB-UVB and is
approved by the FDA for treating localised vitiligo. The
therapeutic benefit of the excimer laser for vitiligo has been investigated in
multiple studies, and, overall, 20–50% of lesions achieve ≥75% repigmentation;
the excimer lamp appears to have similar efficacy. Only a few studies have
directly compared excimer laser to NB-UVB, and some but not all showed superior
results with the former modality. This may be explained by the excimer laser’s
higher irradiance (power per unit area), which is thought to stimulate
melanocyte development.
Localized patches of
vitiligo are treated one to three times weekly with the excimer laser,
typically for a total of 24 to 48 sessions; the repigmentation rate depends on
the total number of sessions, not their frequency. In practice, twice weekly
treatments for a total of ~40 sessions are thought to be optimal. As with other
vitiligo therapies, facial and neck lesions respond better than those on the
distal extremities and overlying bony prominences. This treatment produces optimal aesthetic results,
with minor contrast between normal and affected skin. The excimer laser is similar to classical NB-UBV
treatments, with the advantage of fewer side effects because only one lesion is
treated at a time. Most patients who respond do not develop new areas of
pigment loss. The appearance of new or enlarged macules indicates the possible
beginning of treatment failure. Excimer laser
is safe to use in children who have vitiligo. Totally repigmented macules
should remain filled with 85% certainty; those incompletely repigmented are
likely to reverse and depigment. Erythema and
(rarely) blistering represent potential side effects.
Helium–neon laser
The
helium–neon laser emits a wavelength (632.8 nm) in the red visible light range
that can enhance melanocyte proliferation and melanogenesis in vitro. In a study performed in 30 patients with
segmental vitiligo, 20% of lesions achieved ≥75% repigmentation after a mean of
79 treatment sessions, which were administered once or twice weekly.
Surgical therapies
For
vitiligo patients who fail to respond to medical therapy, surgical treatment
with autologous transplantation techniques may be an option. The general
selection criteria for autologous transplantation are stable disease for at
least 6 months, an unsatisfactory response to medical therapy, absence of the
Koebner phenomenon, a positive minigrafting test (retention/spread of pigment
at the recipient site and no koebnerization at the donor site after 2–3
months), no tendency for scar or keloid formation, and age above 12 years. PUVA may be required after the procedure to unify the color between the
graft sites.
Surgical
methods have been proposed as a therapeutic option in patients with stable
vitiligo (e.g. segmental vitiligo). These surgical techniques are based on a
common basic principle: to transplant autologous melanocytes from a normal
pigmented area to the affected depigmented skin. Different surgical techniques
for repigmenting vitiligo have been gradually devised and include tissue grafts
(full‐thickness punch grafts, split‐thickness grafts, suction blister
grafts) and cellular grafts (cultured melanocytes, cultured epithelial sheet
grafts and non‐cultured epidermal cellular grafts). Lately, the use of hair
follicle outer root sheath cells has been introduced and Grafting
of individual hairs to repigment vitiligo leukotrichia has also
been successfully performed. The
three tissue grafting methods (full‐thickness punch grafts, split‐thickness grafts, suction blister
grafts) seem to have comparable success rates in inducing repigmentation.
Cellular grafting techniques were in general found to be nearly as effective,
although the percentages of patients in whom repigmentation was achieved were
slightly lower than with the tissue grafting techniques. However, cellular
grafting can be used to treat larger areas and has in general better cosmetic
results compared to tissue grafts. Furthermore, adverse events seem to be less
frequent with cellular grafts than with punch or split‐skin grafts.
Combination therapy
Combination
therapy may produce higher rates of repigmentation compared to traditional
monotherapies. Examples include phototherapy
following surgical procedures as well as combining TCIs and/or topical
corticosteroids with NB-UVB or excimer laser therapy. Although topical vitamin
D derivatives are relatively ineffective as monotherapy, these agents may
result in additional repigmentation when used in conjunction with phototherapy.
Micropigmentation
The
technique of permanent dermal micropigmentation utilizes a non-allergenic iron
oxide pigment to camouflage recalcitrant areas of vitiligo. This tattooing
method is especially useful for sites known to have a poor rate of
repigmentation with currently available treatments (e.g. the lips, nipples and
distal fingers). Although the colour may not match
perfectly with the normal surrounding skin and can fade over time, the result
is immediate and can represent a dramatic aesthetic improvement.
Depigmentation
Depigmentation represents a treatment option
for patients who have widespread vitiligo with only a few areas of normally
pigmented skin in exposed sites. Patients with more than 50% involvement of
the skin surface may choose to remove the remaining normal skin pigment. The objective of depigmentation is
“one” skin color for patients. The patients must be carefully chosen,
i.e. adults who recognize that their appearance will be altered significantly
and who understand that depigmentation requires lifelong strict photo
protection (e.g. sunscreens, clothing, and umbrellas). The most commonly used
agent is 20% monobenzyl ether of hydroquinone (MBEH). The end-stage color of
depigmentation with MEH is chalk-white, as in vitiligo macules. The patient who
may want bleaching with MEH is typically a skin phototype IV to VI. An
occasional patient may wish to take 30–60 mg β-carotene per day to impart an
off-white color to the vitiliginous skin.
Monobenzone destroys melanocytes and can cause contact
dermatitis. Therefore, an open application test can
be performed before more widespread application; monobenzone should be
applied to a single pigmented spot daily for 1 week. Thereafter larger
pigmented areas are treated twice daily for 1 year or longer. Application for 3
to 4 years may be necessary. Patients may note an inflammatory response within
the pigmented skin but not in the white skin. The monobenzone can be diluted to
a 10%, 5%, or lower concentration for these patients. A group VI topical
steroid may also be used to control inflammation.
Depigmentation is usually done in regions to limit drug
absorption. Start with the face and upper extremity areas and then treat lower
extremity sites. Truncal areas are last, and many patients choose to leave
their trunk its normal colour.
It typically takes 1–3 months to initiate a response, and
a loss of pigment can occur at distant sites. Although depigmentation from MBEH
is considered permanent, repigmentation (especially perifollicular in areas
with pigmented hairs) can be seen following a sunburn or even intense sun
exposure. Monomethyl ether of hydroquinone (MMEH) in
a 20% cream can be used as an alternative to MBEH. Side effects include contact dermatitis, exogenous
ochronosis, and leukomelanoderma en confetti.
Depigmentation via Q-switched rubyand Q-switched
alexandrite laser therapy was reported to achieve faster depigmentation than
that achieved with a bleaching agent and this laser
has also been used in combination with topical 4-methoxyphenol to induce
depigmentation. Lastly, depigmentation with the Q-switched alexandrite laser
has been described.
Psychological
support
The
impact of vitiligo on quality of life is severe in many affected individuals,
and it is critical for physicians to recognize this aspect of the condition and
address their patients’ psychological needs. Although a “magic” treatment is
not yet available, there is always something beneficial that can be done for
vitiligo patients. They first need to know what their skin disorder is.
Explaining the nature of the disease process and the potential and limits of
available therapies is important and more productive than a fatalistic attitude
that there is no cure and vitiligo is “only” a cosmetic disorder. Even helping
patients to conceal the condition so that it is not visible can be part of the
management plan. The use of support groups and, if indicated, psychological counselling
are important supplementary therapies.
Additional
controversial therapies
Pseudocatalase with narrowband UVB
The
rationale for this treatment is based on the hypothesis that accumulation of
hydrogen peroxide leads to pathogenic inactivation of catalase in the skin of
patients with vitiligo. In an open uncontrolled study, complete repigmentation
of lesions on the face and hands was observed in 90% of patients (30 of 33)
treated with topical pseudocatalase and calcium twice daily plus UVB twice
weekly, with initial repigmentation at 2–4 months.
Systemic antioxidant therapy
The
rationale for this approach rests on the hypothesis that vitiligo results from
a deficiency of natural antioxidant mechanisms. Although to date not validated
by controlled clinical trials, selenium, methionine, tocopherols, ascorbic
acid, and ubiquinone are sometimes helpful.
Potential emerging treatments
Ablative laser treatment followed by narrowband UVB plus
topical 5-fluorouracil or corticosteroids
In
difficult-to-treat sites (e.g. distal extremities, over bony prominences),
erbium:YAG laser ablation of vitiligo lesions followed by NB-UVB therapy twice
weekly for 3–4 months, plus topical application of either 5-fluorouracil or a
potent corticosteroid, was found to result in significantly greater
repigmentation than treatment with NB-UVB ± the topical corticosteroid.
Similar studies have shown that treatment of recalcitrant vitiligo
lesions with an ablative fractional carbon dioxide laser led to greater
efficacy of subsequent therapy with NB-UVB , outdoor sun, and/or a potent
topical corticosteroid. In order to minimize koebnerization, these approaches
should be reserved for patients with stable vitiligo.
Topical prostglandins
Preliminary
studies have suggested the utility of topical prostaglandin E2 and latanoprost (an analogue of prostaglandin
F2) in the treatment of vitiligo. Although
interesting, these results require confirmation.
Afamelanotide
Afamelanotide
is a α-melanocyte stimulating hormone (α-MSH) analogue that stimulates melanogenesis and
melanocyte proliferation by binding to the melanocortin-1 receptor (MC1R). A
recent randomized controlled study found that the addition of afamelanotide
(monthly subcutaneous implants) to NB-UVB therapy increased the speed and
extent of repigmentation compared to NB-UVB alone in patients with generalized
vitiligo, especially those with skin types IV–VI. However,
afamelanotide-induced excessive tanning of non-lesional skin can increase the
contrast with lesional skin, thereby reducing cosmetic acceptance in lightly pigmented
patients. Additional studies are needed to determine the indications and
limitations of afamelanotide therapy for vitiligo.
Janus kinase (JAK) inhibitors
Administration
of the JAK inhibitors ruxolitinib and tofacitinib has been reported to lead to
repigmentation of vitiligo. Further investigation is needed to determine how
approaches targeting the IFN-γ–JAK–STAT1
signaling pathway that drives melanocyte destruction can be utilized to treat
vitiligo.
General outline of management for vitiligo: therapy
options, according to the clinical features
|
Type of vitiligo |
Level |
Usual management |
|
SV or limited NSV
(<2–3% of body surface) |
First line |
Avoidance of
triggering factors, local therapies (corticosteroids, calcineurin inhibitors) |
|
Second line |
Localized NB‐UVB therapy, especially excimer monochromatic
lamp or laser |
|
|
Third line |
Consider surgical
techniques if repigmentation cosmetically unsatisfactory on visible areas |
|
|
NSV |
First line |
Avoidance of triggering/aggravating factors.
Stabilization with NB‐UVB therapy, at least 3months. Optimal duration at least 9 months, if
response. Combination with systemic/topical therapies, including
reinforcement with localized UVB therapy, possible. |
|
Second line |
Systemic steroids
(e.g. 3–4‐month mini pulse
therapy) or immunosuppressants if rapidly progressing disease or absence of
stabilization under NB‐UVB |
|
|
Third line |
Graft in nonresponding
areas especially with high cosmetic impact. However, Koebner phenomenon
limits the persistence of grafts. Relative contraindication in areas such as
dorsum of hands |
|
|
Fourth line |
Depigmentation
techniques (hydroquinone monobenzyl ether or 4‐methoxyphenol alone or associated with Q‐switched ruby laser) in nonresponding widespread (>50%) or
highly visible recalcitrant facial/hands vitiligo |
·
A no treatment option (zero line) can be considered in patients
with a fair complexion after discussion. For children, phototherapy is limited
by feasibility in the younger age group and surgical techniques are rarely
proposed before prepubertal age. There is no current recommendation applicable
to the case of rapidly progressive vitiligo, not stabilized by ultraviolet (UV)
therapy. For all subtypes of disease or lines of treatment, psychological
support and counselling, including access to camouflage instructors is needed.
NSV, non segmental vitiligo; SV, segmental vitiligo; NB‐UVB, narrowband UVB.
