DIFFERENCE IN THE EFFECTS OF TOPICAL TACROLIMUS 0.

1%
AMONG VITILIGO PATIENTS WITH SKIN TYPES IV AND V.

BY:
ASIS MIRCHANDANI (07120110051)

FACULTY OF MEDICINE
UNIVERSITAS PELITA HARAPAN
2013

INTRODUCTION

1.1 Background
Many studies have shown promising results on the efficacy of topical tacrolimus 0.1% in
treating vitiligo. One such study tested the efficacy and safety of topical tacrolimus 0.1% in
the treatment of face and neck vitiligo. The repigmentation percentage reached to 30.6% in
the targeted areas (neck and face).1 Another study by Udompataikul et al. also shows results
favouring topical tacrolimus 0.1% in the treatment of vitiligo.2 In spite of evidence suggesting
good results with topical tacrolimus, its role as a monotherapeutic agent for the treatment of
vitiligo is still in doubt. One study showed no significant increase in repigmentation in
patients with additional topical tacrolimus theraphy to NB-UVB treatment when compared to
NB-UVB theraphy alone.3
Evidence favor topical tacrolimus as a good agent for vitiligo especially for those
depigmented patches on the neck and head. One study that was different to many was that of
Silverberg and Silverberg. This study revealed that although topical tacrolimus is effective in
treating vitiligo generally, there is a difference in the reaction to the treatment in patients with
varying Fitzpatrick skin type.4
Fitzpatrick skin type scale is a clinical and research tool used in dermatology to classify
patients based on their tendency to tan or burn in response to sun exposure. It is divided into
six categories (I-VI) where skin type I easily burns and never tans when exposed to the sun.
Skin types V and VI are not classified with their ability to tan or burn, but rather with their
skin color. Brown people are classified in category V while black people in VI. Asians are
usually classified in categories III, IV and V. 5,6,7
Although the incidence rate of vitiligo is only 0.1% to 2%, it is important to investigate
further into this topic as studies have shown an increased tendency of depression and mood
disorders amongst vitiligo patients.8,9 Moreover, topical immunomodulators are more cost
friendly compared to other methods of treatment such as NB-UVB and Excimer light.
Keeping in mind the skin type of Indonesians (IV &V) and the depressive tendencies of
vitiligo patients, it is quite appropriate that this research is done to evaluate the efficiency of
treatment by using topical tacrolimus 0.1% as a monotheraphy.

Hence the topic: DIFFERENCE IN THE EFFECTS OF TOPICAL TACROLIMUS

0.1% AMONG VITILIGO PATIENTS WITH SKIN TYPES IV AND V.
1.2 Research question
The research question would be:
Is there a difference in the effects of topical tacrolimus 0.1% among vitiligo patients with
skin type IV and V?
1.3 Aims and objectives
1. General aim:
Knowing the difference in the effects of topical tacrolimus 0.1% among vitiligo
patients with skin types IV and V.
2. Specific aim
Assessing the difference in the effects of topical tacrolimus 0.1% among vitiligo
patients with skin types IV and V.
1.4 Significance of study
1. Scientifically
Expands the knowledge and understanding of tacrolimus and its effects on vitiligo
and will be useful for future research.
2. Practically
Increasing the efficacy of treatment of vitiligo patients using tacrolimus and other
mwans of repigmentation.

LITERATURE REVIEW

2.1 Melanin and melanin production

Melanocytes are cells that produce pigment which are derived from the neural crest
embryonically. They are cells that reside in various parts of the human body: epidermis,
cochlea, eye, hair follicle and the meninges. Some site specific melanocytes are: melanocyte
stem cells (undifferentiated cells present at the bulge of the hair follicle), cutaneous
melanocytes (melanocytes found in the basal layer of the epidermis) and hair-follicle
melanocytes. The main function of melanocytes is the production of melanin, an indole
derivative of 3, 4 di-hydroxyl-phenylalanine (DOPA) which are stored in melanosomes (a
membrane bound organelle present in melanocytes).10 The main function of melanin is
protecting the skin from phototoxic damage and to determine the characteristic skin color.11
Melanogenesis is the process of melanin synthesis and distribution in the epidermis. It
involves several key steps: transcription of proteins required for melanogenesis, melanosome
biogenesis, sorting of melanogenic proteins into melanosomes, transport of melanosomes to
the tips of melanocyte dendrites and transfer of melanosome to the keratinocytes. Disruption
of any of these following steps leads to hypopigmentation.10
Melanocytes produce two types of melanin: eumelanin (dark, brown-black, and insoluble)
and pheomelanin (light, red-yellow and soluble). Melanins are formed in melanosomes
through a series of oxidative steps.10 The main function of melanin is to provide protection
against UV-induced DNA damage by absorbing and scattering UV radiation (280400 nm).
Accordingly, energy absorption by melanin is maximal in this portion of the electromagnetic
spectrum, and decreases gradually across the visible light spectrum. UV absorbed by melanin
is converted into heat, a less toxic form of energy.12

Fig Melanin biosynthesis

2.2 Vitiligo: Depigmentation disorder of the skin

Vitiligo is an acquired idiopathic hypomelanotic skin disorder. It is characterised by
depigmented macules which is caused by loss of cutaneous melanocytes.13 It has a prevalence
of about 0.5% -1% in the world population. 14 Although its occurrence is not common
amongst the general population, it is a psychologically devastating and a recalcitrant skin
disorder.15
AETIOLOGY AND PATHOGENESIS
Vitiligo is a multifactorial disease and till date its aetiology is poorly understood, although
four hypotheses have been proposed for the pathogenesis of vitiligo. Firstly, the autoimmune
hypothesis focuses on melanocyte destruction through immunologic processes. This
hypothesis suits best clinically to the Non-Segmental type of vitiligo. Secondly, the neural
hypothesis suggests that a neurochemical factor released from nerve endings or from skin
cells destroy melanocytes and hence causes depigmentation. This hypothesis is usually
related to Segmental type of vitiligo as its clinical picture usually shows depigmentation in a
certain dermatome pattern. The third hypothesis involves melanocyte death caused by
monobenzone-like substances which maybe exogenous or endogenous (noradrenaline,
semiquinones of oestrogen). The final hypothesis is the impaired redox hypothesis.
Melanocyte cell death can be caused by excessive levels of free radicals or by impaired free
radical defences.
A genetic predisposition renders melanocytes in vitiligo patents to be more susceptible
towards precipitating factors than normal healthy melanocytes. The current accepted
pathogenesis of vitiligo is a bipolar approach involving the autoimmune mechanism and the
cytotoxic free radicals on genetically susceptible vitiligo melanocytes.

The immune mediated damage

The autoimmune hypothesis of vitiligo can be supported by various research evidences.
Firstly, vitiligo often correlates and is present along with other autoimmune disorders such as
thyroid diseases, diabetes mellitus, adrenal insufficiency, psoriasis, lupus erythematosus,
lichen planus, alopecia areata, myasthenia gravis, pernicious anemia, rheumatoid arthritis).
Moreover, organ-specific circulating autoantibodies are often present, even in the absence of
autoimmune disorders other than vitiligo. Specific melanocyte autoantibodies have also been
found in Non Segmental vitiligo patients, such as autoantibodies against thyrosinase, and
thyrosinase related proteins 1 and 2, Pmel17/gp100 (melanosomal matrix glycoprotein) and
the surface receptor MCHR1 (melanin-concentrating hormone receptor 1).
T-cell infiltrates have been found in the depigmented areas of Non-segmental vitiligo patients
which includes CD4+, CD8+ T-cells as well as CD68+ macrophages. Infiltrating T-cells kill
melanocytes in the skin and hence causes the depigmentation in vitiligo patients. The
antigens that are targeted in NSV patients include Tyrosinase, gp100, MART-1, TRP-2, P
protein and to a lesser extent TRP-1. In cases of vitiligo, melanocytic cells express a part of
their melanosome as MHC class II. These epitopes are likely not to have peripheral tolerance,
which means that they are susceptible to an autoimmune destruction. They are targets for CD
4+ T-cells which recruit adjacent cytotoxic CD8+ T-cells which causes melanocytic cell
death. Other factors may also contribute to this process. Keratinocytes present their own
antigens or melanocyte antigens in a MHC class II manner. Langerhans cells also act as an
antigen presenting cell for T-cell activation. Langerhans cells have been found in lesional skin
in Non-segmental vitiligo patients.
After antigen presentation to the T-cell receptor of a T-lymphocyte, the phospholipase C
pathway is activated, with subsequent inositol trisphosphate (IP3) production and hydrolysis
of phosphoinositol- containing lipids in the plasma membrane. IP3 induces calcium release
from the endoplasmic reticulum and increased intracellular calcium stimulates activation of
the calmodulin complex, which binds calcineurin. The activated calcineurin complex
dephosphorylates the cytoplasmic nuclear factor of activated T-cells (NFATc) and
dephosphorylated NF-ATc is translocated to the nucleus [182]. The production of activator
protein-1, another transcriptional factor, is promoted by protein kinase C. Both transcriptional
factors are necessary for the production of IL-2. This pro-inflammatory cytokine leads to Tcell activation.

The cytotoxic damage

The second hypothesis accepted as the pathogenesis of vitiligo is the impaired redox
hypothesis. A cellular homeostasis is present in the skin to prevent damage caused by
excessive high levels of free radicals. Some of these reactive oxygen species are singlet
oxygen (1O2), superoxide anion(O2.-), hydroxyl radicals(OH.), hydrogen peroxide(H2O2),
peroxynitrite anion(OONO-), and nitric oxide(NO). The defences for these reactive oxygen
species are a set of enzymes which acts as anti-oxidants. They are superoxide dismutase,
catalase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase, thioredoxin
reductase, thioredoxin peroxidase and methionine sulfoxide reductases A and B. It is when
there is an imbalance in the production and clearance of these reactive oxygen species that
oxidative stress occurs which in turn causes cytotoxic cellular damage.
Epidermal sources of endogenous ROS such as growth factors have been identified. Growth
factors such as TNF alpha, basic fibroblast growth factor, IL-6, IL-1 alpha have been
identified in skin of vitiligo patients.
H2O2 production also arises from several enzymatic activities: epidermal monoamine oxidase
A activity, NADPH (reduced nicotinamide adenine dinucleotide phosphate) oxidase activity
from neutrophils and macrophages, photo-oxidation of epidermal-6-biopterin, degradation of
purin bases to uric acid by xanthine oxidase, epidermal inducible nitric oxide synthases
activity. Exogenous sources such as phenols, ortho- and para-quinols as well as UV
(ultraviolet)A, UVB and X-rays can generate H2O2.16 H2O2 deactivates catalase, thioredoxin
reductase and methionine sulfoxide reductases A.xiii As a proof, low activity of
these enzymes is well documented in vitiligo skin. This affects the entire epidermal antioxidant defence machinery and increases in turn the H2O2 pool.
Gene expression of glutathione-S-transferase (GST) is remarkably repressed in vitiligo skin
and this impairs the adaptative cellular response to various stressors, namely H2O2, 4
hydroxy-2-nonenal (a stable product of lipid peroxidation, easily reacting with proteins and
DNA) and mild UV irradiation.17
A consequence of the oxidation of the essential cofactor (6R)-L-erythro-5, 6,7,8
tetrahydrobiopterin (6BH4) and its isomer 7BH4 to 6- and 7-biopterin by H2O2 is that all the
essential cofactor-dependent enzymes, such as tyrosine hydroxylase, phenylalanine

hydroxylase, tryptophan hydroxylase and nitric oxide synthases, are deactivated as well as
mechanisms involved in 6BH4 recycling.xiii Perturbed 6BH4 synthesis/recycling/regulation
influences catecholamine synthesis and degradation.18 An overproduction of the cofactor
6BH4 in association with elevated GTP-cyclohydrolase I enzyme activity has been
demonstrated in both the pigmented and repigmented epidermis of NSV patients19, with
increased catecholamine synthesis and degradation via catecholamine-O-methyl-transferase
and monoamine oxidase A activities.xv Monoamine oxidase A, the degrading enzyme for
noradrenaline, produces H2O2 as a reaction product from the oxidation of this
catecholamine.20 As a proof, high levels of catecholamines have been documented in plasma
and urine of NSV patients, particularly in the early active phase of the disease.21,22 H2O2mediated deactivation of acetylcholinesterase and butyrylcholinesterase induces high
acetylcholine levels in vitiligo epidermis.23,24
POMC (proopiomelanocortin) cleavage by prohormone convertases as well as structure and
function of POMC-derived peptides such as Alpha-Melanocyte Stimulating Hormone (AlphaMSH) and Beta- endorphin are affected by H2O2-mediated oxidation25 and this may explain
the reduction of Alpha-MSH epidermal levels in vitiligo.26 Increased ROS production in
vitiligo may be due to impairment of mitochondria, which represent the major site for the
generation of cellular oxidative stress.27 The expression and function of the mitochondrial
electron transport chain (ETC) complexes is strictly dependent on the lipid component of the
inner mitochondrial membrane and particularly on cardiolipin (CL).28 An impaired assembly
or recycling of CL is associated with mitochondrial defects.29,30 Peripheral blood mononuclear
cells (PBMCs) of patients with active vitiligo show increased ROS generation and
compromised antioxidant capacity, with increased superoxide dismutase activity, reduced
catalase activity, and decreased GSH and vitamin E levels31. Moreover, the CL level in the
mitochondrial inner membrane is reduced, the level of cholesterol is increased32 and an
increase in the activity of the mitochondrial malate dehydrogenase, a Krebs cycle enzyme,
has also been detected in PBMCs of active vitiligo patients.33

CLASSIFICATION
A recent consensus on vitiligo by the international federation of pigment cell societies
classified vitiligo based on clinical presentation into two major subgroups: Segmental vitiligo
(SV), Non-segmental vitiligo (NSV). Non- segmental vitiligo includes clinical variants such
as generalized vitiligo, acrofacial vitiligo and universal vitiligo. There is another subgroup of
vitiligo known as the focal vitiligo. This may in time evolve to be a segmental vitiligo or a
non-segmental vitiligo.34

Table 1: Bordeaux VGICC classification and consensus nomenclature. xiii

CLINICAL PRESENTATION

Vitiligo is a hypopigmentation disorder with appearance of white patches on the skin which is
caused by the loss of functioning melanocytes. xii Through immunohistochemical studies, a
complete loss of melanocytes in the dermal-epidermal junction of the involved vitiligo skin
was seen as a result of antibodies specific for several melanocytes antigen.xi,xii Although
recent studies suggest that poorly functioning melanocytes have been isolated and cultured in
vitro from these white patches on the skin.xi the widely accepted pathomechanism in the
destruction of functioning melanocytes is due to the infiltrating autoantibodies attacking the
surface antigens of the melanocytes or the cytotoxic T cells causing direct destruction to the
melanocytes.35 However, recent studies suggest that the cause of the loss of functioning
melanocytes in the lesion areas are Apoptosis and melanocytorrhagy.36,37
In Non-segmental vitiligo (NSV), lesions are mostly bilateral and symmetrical. They usually
progress and the lesions become bigger and more widespread. Depigmentation of the hair
follicles also occurs in the later stages of the disease. This usually indicates a poorer
prognosis than when hair follicles remain unchanged. Usually a family history of vitiligo or
autoimmunity is present. Personal medical history such as autoimmunity (thyroid disease,
diabetes mellitus and etc.) may also be present.38,xi,xii,xiii The characteristic sign of NSV is
Koebners phenomenon. Koebners phenomenon is defined as the development of lesions at
sites of specifically traumatized uninvolved skin of patients with cutaneous diseases. In a
study relating Koebners phenomenon to vitiligo, most of the post-traumatic lesions that
occur in vitiligo is related to areas of repeated frictions that occur during washing, dressing,
personal care, sports and occupational activity.39 Halo nevi, nevi surrounded by a ring of
depigmentation, may precede the vitiligo appearance.xi
In Segmental vitiligo (SV), lesions are usually unilateral. They often follow the dermatome
(skin innervated by the sensory fibres of the cranial or spinal nerves pattern and also a pattern
of the Blaschko lines (lines which follow the dorso-ventral embryonic development of the
cellular components of the skin.)40 SV usually begins in the childhood years and has a rapid
onset. It stabilises within 1-2 years. The face is usually involved and leukotrichia (white hair)
appears early in the onset of Segmental vitiligo.xvii

2.3 Tacrolimus: Treatment for vitiligo

Tacrolimus (FK506, Protopic) is a potent immunosuppressive macrolide which is

traditionally used to prevent allograft rejection of kidney, heart, and liver transplant. It is
derived from the metabolite of Streptomyces Tsukubaensis. Tacrolimus is available in two
forms: topical and systemic. The systemic tacrolimus is available as injections and oral
tablets. The advantage of a topical preparation is that it easily penetrates into the epidermis
layer which makes it an effective treatment for vitiligo.41 Also topical tacrolimus causes less
skin atrophy and is safer for application on the face than topical glucocorticoids. Some of the
adverse effects of topical tacrolimus include: Transient erythema, burning, pruritus and etc.42
Topical tacrolimus is available in two preparations: 0.03% and 0.01%. Topical tacrolimus is
more effective in children above 2 years old while the 0.01% preparation is more effective for
adults with vitiligo.43
Recent studies have showed that tacrolimus induces repigmentation among vitiligo patients
through three mechanisms. Firstly, it inhibits the autoimmune hypothesis of non-segmental
vitiligo. Tacrolimus binds to a cytosol protein known as the cytosolic 12-KDa macrophillin
FK506 (FKBP). This complex increases the immune Th2 responses and also inhibits
calcineurin mediated phosphorylation of NF-AT (inflammatory transcription factor). This in
turn reduces pro-inflammatory cytokines such as IL2, IL3, IL4, IL5, TNF alpha, and gamma
interferon which reduces T cell activation and in turn reduces autoimmunity.44,45,46,47,48
Secondly, topical tacrolimus offers reactive oxygen species protection by increasing
glutathione levels on the vitiligo patients.49 Tacrolimus also reduces the levels of inducible
oxide synthase (INOS) which in turn reduces nitrogen oxide levels (NO).50 Finally, topical
tacrolimus induces melanocyte proliferation and migration. Topical tacrolimus activates the
MAPK pathway, which causes an upstream of enzymes such as TRP-1 and thyrosinase which
is essential for melanin production. This causes the melanocyte stem cells in the bulb of the
hair follicles to proliferate and migrate.51

CONCEPTUAL FRAMEWORK, HYPOTHESIS, OPERATIONAL DEFINITION

3.1 Theoretical framework

VITILIG
O
Genetically
susceptible
to Vitiligo

Genetically
susceptible has
reduction of GST
expression

Melanocyte
antigen
presentation to T

Defense
mechanism
against H2O2
and ROS
Increased
productio
n of H2O2

Increased
oxidation of
cofactor 6HB4
Affected
cleavage of
POMC

Defense
mechanism
against ROS

Increased
catecholamine
production and
degradation

Activation of
Phospholipase C

Production
of IP3

Calcium
release from
ER

Intracellular
calcium
Calmodulin binds
with Calcineurin

DEPIGMENTATIO
N

TACROLIM
US3.2 Conceptual framework

Dephosphorylati
on of NFATc

Pro
inflammatory
cytokines
Activation of T
cells

Koebners
phenomenon
Sun exposure
Genetics
Phototoxic
injury

Repigmentation in
vitiligo patients
with Fitzpatrick
skin type IV

(Confounding

(Dependent
variable)

Topical Tacrolimus
0.1% applied twice
daily.
(Independent
variable)

Repigmentation in
vitiligo patients
with Fitzpatrick
skin type V
(Dependent
variable)

Controlled Variable

Age
Vitiligo type (Non-segmental
vitiligo)
Time of exposure
Frequency of exposure

3.3 Hypothesis
There a difference in the effects of administration of topical tacrolimus 0.1% on vitiligo
patients with skin type IV and V.
3.4 Operational definition
a. Vitiligo
Vitiligo is an acquired idiopathic hypomelanotic skin disorder which is characterised by
depigmented macules caused by loss of cutaneous melanocytes.
b. Non-segmental Vitiligo (NSV)
Non-segmental vitiligo is characterised by depigmented macules that vary in size from a few
to several centimetres in diameter. It often involves both sides of the body with tendency
toward symmetrical distribution. Body hairs remain spared and usually remain pigmented
although it may lose pigmentation with disease progression.
c. Topical Tacrolimus 0.1%
Topical tacrolimus is an immunosuppressive macrolide used in the treatment of vitiligo. In
this research, topical tacrolimus is applied twice a day for 6 months on non-segmental vitiligo
patients.
d.Fitzpatrick skin type
It is a numerical classification schema for the color of the skin to classify different types of
skin by observing their responses to UV light. Its score is determined by a questionnaire
given to the patient.

e. VASI score
It is a quantitative score develop for the measurement of disease extent and severity of
vitiligo. The total body VASI scored is calculated using the formula:
VASI=

( hand units ) (residual depigmentation)

allbody sites

One hand unit (which includes the surface area of the palm including all its digits) is
equivalent to approximately 1% of the total surface area of the body. The residual
depigmentation can be approximated to the nearest following percentages: 100%-complete
depigmentation, 90%-specs of pigment present, 75%-depigmented areas exceed pigmented

areas, 50%-depigmented areas are equal to the pigmented areas, 25%-pigmented areas
exceed depigmented areas, 10%-specs of depigmented areas.

RESEARCH METHOD

4.1 Design
The experimental method will be used as the design in this research. Topical tacrolius 0.1%
will be the intervention given to the two groups of non-segmental vitiligo patients.
4.2 Time and place
This research will be hospital based and will be done in the out-patient clinic of dermatology
in Rumah Sakit Cipto Mangunkusumo (RSCM). The duration of the research will last for 6
months.
4.3 Population and sample
The populations that will be considered for the sampling of this research are non-segmental
vitiligo patients (both male and female) between the ages of 18-65 years old. They should fit
into the Fitzpatrick classification for skin types of IV and V.
4.4 Inclusion and exclusion criteria

Inclusion
o Non segmental vitiligo patients aged between 18-65 years old with Fitzpatrick
skin type IV and V.
Exclusion
o Patients who are allergic to Topical Tacrolimus 0.1%
o Patients with previously prescribed Topical Tacrolimus 0.1%
o Patients with other underlying autoimmune diseases (SLE, Thyroid diseases
and etc.)
o Patients diagnosed with HIV and malignancy and also those who are treated
for these two diseases
o Patients who have other underlying skin conditions

4.5 Sample size

2( Z + Z)2 S 2
( x 1x 2)2
4.6 Sampling method
4.7 Research procedure
The research will take place in Rumah Sakit Cipto Mangunkusomo (RSCM) for a duration of
6 months. First a sample frame will be collected. The non-segmental patients who come for
consultation and check up to the out-patient department that fits in the sample criteria will be
recorded. A random sampling will be done on the available population. The patients selected
for the research will be contacted for a follow up to check for their availability for the
research. Once the sample is available and ready for the research, they will be called upon to
the hospital for briefing and allergic testing to ensure a safety in the research. The patients are
also checked for their VASI score (Vitiligo Area Severity Index). Once all the procedures are
done. The patients are briefed on what they are to do during the six months. The patient is to
apply topical tacrolimus 0.1% on all their white patches twice a day, once in the morning and
the second time in the evening. Care must be taken on the second application as if applied
immediately before sleeping, the medication may be in vain due to contact with the bed, ned
sheets and etc. Should there be any adverse effects with application of this ointment, the
patient should return for s follow up. After 6 months, the patients are told to return and their
VASI scored rechecked. The results are then tabulated, processed and analyzed.
4.8 Data management and analysis
T- test
4.9 Ethics
Informed consent?

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