Eur J Dermatol 2013; 23(1): 5-13

Review
Amit Aakash SHAH
Animesh A. SINHA
Department of Dermatology,
University at Buffalo and Roswell Park
Cancer Institute,
Clinical and Translational Research Center,
875 Ellicott St. Buffalo,
NY 14203,
USA

Reprints: A. A. Sinha
<[email protected]>

Article accepted on 9/24/2012

Oxidative stress and autoimmune skin disease

Antioxidants play the important role in our body of neutralizing free radicals and peroxides that are formed during normal physiologic events.
While these reactive oxygen species are necessary for numerous biological processes, when created in excess they can have deleterious effects.
The skin as an organ is constantly under attack by reactive oxygen species
from both endogenous and exogenous sources. The pathophysiology of
many autoimmune diseases is unknown and recently oxidative stress has
come to light as a possible triggering mechanism. Recent investigations
attempting to link autoimmune skin diseases and oxidative stress have
had varying degrees of success. In this article, we review the current
literature regarding antioxidants in alopecia areata, pemphigus vulgaris
and other blistering diseases, vitiligo, and psoriasis, and suggest possible
future studies and treatment options.
Key words: alopecia areata, antioxidant, autoimmune, free radicals,
oxidative stress, pemphigus vulgaris, reactive oxygen species, vitiligo

xidation reactions, such as those that produce

free radicals and peroxides (e.g. Superoxide, O2 ;
Hydrogen peroxide, H2 O2 ; Hydroxyl, OH, etc.)
are crucial to life. Free radicals participate in important
physiologic functions in the body, such as defense against
pathogens, signal transduction, and apoptosis [1]. However, when these reactive oxygen species (ROS) are created
in excess, or there is inadequate removal, they can lead
to oxidative stress, lipid peroxidation, dysregulated signal
transduction, pathologic changes to cell and tissue function
and even cell death [1, 2]. The skin is the major interface
between the environment and the body; therefore, it is under
constant exposure from chemical and physical elements
[3, 4]. It is most directly affected by ROS due to their generation from endogenous sources (enzyme activity; activated neutrophils) and environmental exposure (UV light;

doi:10.1684/ejd.2012.1884

Abbreviations:
AA
BP
CAT
CGD
DM 1
EBA
GSH
GSH-Px
MDA
NOX
PV
ROS
RA
SOD
SLE
TBARS
XO

alopecia areata
bullous pemphigoid
catalase
chronic granulomatous disease
diabetes mellitus type 1
epidermolysis bullosa acquisita
glutathione
glutathione peroxidase
malonyldialdehyde
NADPH oxidase
pemphigus vulgaris
reactive oxygen species
rheumatoid arthritis
superoxide dismutase
systemic lupus erythematosus
thiobarbituric acid reactive substances
xanthine oxidase

pollutants) [1, 2, 5]. Additionally, elevated oxidative stress

levels could be related to excessive physical and emotional
stress due to the burden of disease, medication regimen
and duration of treatment, age, and/or concurrent medical illnesses (gure 1). Antioxidants counteract the damage
caused by ROS by removing them from the hosts system,
converting them to safe molecules (H2 O, O2 , etc.), or preventing their formation. The major enzymatic antioxidants
of the skin include superoxide dismutase (SOD), catalase
(CAT), and glutathione peroxidase (GSH-Px) (table 1). The
main non-enzymatic antioxidants in the skin are vitamin
C, vitamin E, and glutathione (GSH) (table 1). Vitamin E
(tocopherol) is the most important of the non-enzymatic
antioxidants in the skin as it is the predominant physiologic
barrier antioxidant [1, 4, 6]; one molecule of tocopherol
has the ability to scavenge two peroxyl radicals [7, 8]. In

UV light, Pollutants,
Smoking,
Neutrophils,
Radiation, Disease,
Medication, Stress
etc.

ROS (e.g. Superoxide,

O2-; Hydrogen
peroxide, H2O2;
Hydroxyl, OH, etc.)

Mitochondrial
Activity

Pro-inflammatory
cytokines

AUTOIMMUNITY
?

Metabolic
Processes /
Cellular
Respiration

Lipid Peroxidation
Change in cell & tissue
function
Cell death

Apoptotic remnants

Figure 1. Possible role of reactive oxygen species in autoimmune disease manifestation.

(Afferent: light blue & Efferent: dark blue).

EJD, vol. 23, n 1, January-February 2013

To cite this article: Shah AA, Sinha AA. Oxidative stress and autoimmune skin disease. Eur J Dermatol 2013; 23(1): 5-13 doi:10.1684/ejd.2012.1884

Table 1. Antioxidants and oxidative stress markers and their

actions.
Antioxidant

Superoxide Dismutase (SOD)

Catalase (CAT)
Glutathione Peroxidase
(GSH-Px)
Glutathione (GSH)

Vitamin A
Vitamin C

Vitamin E

Uric Acid
Oxidative stress marker
Malonyldialdehyde (MDA)
NADPH Oxidase (NOX)
Xanthine Oxidase (XO)

Action

Converts Superoxide (O2 - )

O2 + H2 O2
Converts H2 O2 H2 O + O2
Converts 2GSH + H2 O2
H2 O + Glutathione disulfide
A reducing agent with the
ability to neutralize ROS.
Regeneration of Vitamin E
from oxidized state.
Radical trapping and cell
membrane protector from ROS.
Reducing agent acting as a
scavenger of ROS.
Regeneration of Vitamin E
from oxidized state.
Reducing agent acting as a
ROS scavenger. Protects cell
membrane from free radicals.
Neutralize free radicals.
Action
Product from the degradation
of lipids by ROS
Converts NADPH + O2
NADP+ + O2 - + H+
Converts hypoxanthine + H2 O
+ O2 xanthine + H2 O2
Converts xanthine + H2 O + O2
uric acid + H2 O2

healthy individuals, there is a balance between ROS and

antioxidant levels [1, 9]. During infections and inflammatory processes, however, there is an increase in ROS, leading
to oxidant/antioxidant disequilibrium.
In many autoimmune diseases, the details of pathogenesis
remain unclear and are thought to be multifactorial. Excessive oxidative stress is increasingly being recognized as
having a potentially key role in disease processes [10]. ROS
are physiological activators of transcription factors for certain pro-inflammatory cytokines, adhesion molecules and
cell cycle related genes. Furthermore, ROS can potentiate
cell death, and inefficient clearance of dying cells, with the
resultant accumulation of apoptotic remnants, may promote
the formation of autoantibodies, triggering and perpetuating the autoimmune cascade [10-12] (gure 1). Therefore,
ROS may play a role in not only in the pathogenesis of
autoimmune diseases but also in their progression and
severity [11].
The literature regarding the role of oxidative stress in skin
autoimmunity is incomplete and inconsistent, and to date
has not been systematically reviewed. The purpose of this
paper is to comprehensively evaluate and interpret the literature linking oxidative stress to autoimmune skin disease
and to provide guidance for further research. In particular,
we focus on several diseases - alopecia areata, pemphigus
vulgaris and other blistering diseases, vitiligo, and psoriasis
as model systems for investigation.

Autoimmune skin diseases

Alopecia areata
Alopecia areata (AA) is a non-scarring autoimmune skin
disease in which antibodies attack ones own hair follicles, leading to hair loss. It most commonly occurs on the
scalp, but any hair bearing area of the skin can be affected.
AA ranges from a singular round/oval patch of hair loss
(most likely on the scalp), to multiple patches, to complete scalp hair loss (alopecia totalis; AT), to complete
scalp and body hair loss (alopecia universalis; AU). The
prevalence of alopecia is approximately 0.1-0.2%, with an
overall lifetime risk of 1.7% [13-15]. The exact etiology
and pathogenesis of AA is unknown. The current consensus hypothesis for AA development involves hair follicle
immune privilege collapse and/or catagen phase overstimulation of the immune system leading to humoral and
cell-mediated autoimmune damage [14]. There have been
a variety of disease triggers cited in AA, including infections, stress, vaccinations, hormonal fluctuations, among
others [14, 16-18]. The role of oxidative stress, resulting in increased reactive oxygen species (ROS) and an
oxidant/antioxidant disequilibrium has been increasingly
examined in recent literature (tables 2-4).
A study by Naziroglu et al. (2000) evaluated the plasma and
RBC levels of vitamin E, beta carotene, thiobarbituric acid
reactive substances (TBARS) as lipid peroxidation status,
GSH, and GSH-Px in 37 alopecia patients and 34 agematched controls [19]. Of the 37 alopecia patients, 20 had
AA, 10 had AT, and 7 had AU, none of whom had received
any systemic therapy. The results showed a statistically significant decrease in beta carotene, GSH, and GSH-Px, and
a statistically significant increase in TBARS in alopecia
patients compared to controls. The levels of vitamin E were
lower in patients but not to a statistically significant degree.
Akar et al. (2002) looked at the TBARS, GSH-Px, and
SOD levels in the scalp of 10 AA patients and 10 control
patients [20]. The levels of TBARS, SOD, and GSH-Px
were increased to a statistically significant degree in AA
patients vs. controls. In addition, the four patients in early
phase disease (last episode of disease is less than 6 months
prior to sampling) had 2x higher levels than the six patients
in late phase disease. While the antioxidant values are the
opposite of the results of Naziroglu et al., Akar et al. contend that the elevated levels of the antioxidant enzymes
are due to excess production of free radicals in patients.
This may seem counterintuitive as increased free radicals
might be expected to lead to a decrease in antioxidants,
due to their consumption. The antioxidants in question are
produced within the body, so it is possible that increased
TBARS would lead to increased SOD and GSH-Px. A 2fold increase in TBARS, SOD, and GSH-Px was seen in
early vs. late phase disease, which could indicate a possible
positive correlation between disease activity and oxidative
stress.
Kim et al. (2010) aimed to assess the levels of free oxygen
radicals and antioxidant capacity as a whole in blood, using
a reactive oxygen metabolites (ROM) test and a biological
antioxidant potential (BAP) test [21]. Individual antioxidant
and free radicals were not measured. Sixteen AA patients
and sixteen healthy age-matched controls were tested. The
results showed a statistically significant decrease in the
EJD, vol. 23, n 1, January-February 2013

Table 2. Summary of studies involving antioxidant enzymes.

AA

PV

Vitiligo

Psoriasis

Akar et al. (n = 10)

Sravani et al. (n = 25)

Arican et al. (n = 16)

Yildirim et al. (n = 24)

Ines et al. (n = 36)

Koca et al. (n = 24)

Khan et al. (n = 30)

Yildirim et al. (n = 22)

Abdel Fattah et al. (n = 50)

Kadam et al. (n = 90)

Attwa et al. (n = 25)

Akar et al. (n = 10)

Ozturk et al. (n = 30)

Naziroglu et al. (n = 37)

Naziroglu et al. (n = 18)

Jalel et al. (n = 60)

Yildirim et al. (n = 22)

Yildirim et al. (n = 24)

Wozniak et al. (n = 67)

Ines et al. (n = 36)

Khan et al. (n = 30)

Yildirim et al. (n = 22)

Naziroglu et al. (n = 18)

Sravani et al. (n = 25)

Kadam et al. (n = 90)

Arican et al. (n = 16)

Ines et al. (n = 36)

Increase

SOD
Decrease

No Change
Increase

GSH-Px

Decrease

No Change
Increase

CAT

Decrease
No Change

antioxidant capacity and a statistically significant increase

in the free radical levels when comparing patients to
controls.
Koca et al. (2005) studied 24 AA patients and 20 age and
sex matched controls to look at the levels of MDA, nitric
oxide (NO), XO and SOD [22]. The authors found that
AA patients had significantly higher levels of MDA, XO,
and NO, and significantly lower levels of SOD compared
to control subjects, suggesting that the oxidant/antioxidant
ratio is greater in these patients. This study, however, did
not document if there is a compensatory increase in other
antioxidants, making it difficult to definitively conclude that
patients have an overall diminished antioxidant status.
Abdel Fattah et al. performed a case-control study looking
at SOD and MDA in 50 AA patients and 50 controls (25
patients with severe acne vulgaris and 25 healthy volunteers) [23]. The use of patient controls with acne was
to represent a positive control (patients under oxidative
stress). There were significant differences in SOD and MDA
between AA patients and the healthy controls; SOD was
decreased and MDA was increased. There were insignificant differences between the AA patients and the acne
vulgaris controls. Of the 50 patients with AA, 15 had a
disease duration of < 6 months and 35 had disease duration of > 6 months. There was a significant difference in the
SOD and MDA activity between the 2 groups; the shorter
the duration of the disease the higher the SOD levels and
EJD, vol. 23, n 1, January-February 2013

the lower the MDA levels. When comparing patients with

mono AA vs. poly AA vs. AT, this study found that the
more severe the disease status, the lower the SOD activity and the higher the MDA levels. In the 10 patients who
had scalp biopsies, Abdel Fattah et al. found positive correlations between tissue and blood SOD activity and tissue
and plasma MDA levels. Using the Severity of Alopecia
Tool (SALT) score as a guideline to assess the disease
severity, it was shown that there was a significant negative
correlation in regards to SOD activity and a significant positive correlation with MDA levels, meaning the worse the
disease, the lower the SOD activity and the higher the
MDA levels [23]. This study provides compelling evidence
(due to the high number of patients) that disease severity
and duration significantly change the oxidant/antioxidant
disequilibrium. However, this finding was based on data
linked to levels of SOD and MDA. This leaves open the
question of whether other antioxidant levels are also low, or
if there are compensatory changes in the other antioxidants.
The majority of studies in AA have shown that, in a snapshot
of time, AA patients with active disease have a disequilibrium of their oxidant/antioxidant status, supporting a link
between AA and oxidative stress (Summary tables 2-4). But
the nature of this link is yet to be fully determined; whether
oxidative stress causes primary manifestation or flare of
disease, or whether disease activity leads to an increase in
biomarkers of oxidative stress.

Table 3. Summary of Studies involving non-enzymatic antioxidants.

GSH

Vitamin E

Vitamin C

Vitamin A /
Beta-carotene

Uric Acid

TAS

AA

PV

Vitiligo

Psoriasis

Increase

Decrease

Naziroglu et al. (n = 37)

Naziroglu et al. (n = 18)

Yildirim et al. (n = 24)

Yildirim et al. (n = 24)

No Change
Increase

Yousefi et al. (n = 30)

-

Ozturk et al. (n = 30)

-

Ozturk et al. (n = 30)

-

Decrease

Naziroglu et al. (n = 37)

Naziroglu et al. (n = 18)

Khan et al. (n = 30)

Khan et al. (n = 30)

No Change
Increase

Ines et al. (n = 36)

-

Ines et al. (n = 36)

-

Decrease

No Change
Increase

Yousefi et al. (n = 30)

-

Khan et al. (n = 30)

-

Khan et al. (n = 30)

-

Decrease

Naziroglu et al. (n = 37)

Naziroglu et al. (n = 18)

No Change
Increase

Ines et al. (n = 36)

-

Ines et al. (n = 36)

-

Decrease

Yousefi et al. (n = 30)

No Change
Increase

Decrease

Jalel et al. (n = 60)

Kadam et al. (n = 90)

No change

Table 4. Summary of Studies involving oxidative stress markers.

AA

PV

Vitiligo

Psoriasis

Naziroglu et al. (n = 37)

Wozniak et al. (n = 67)

Akar et al. (n = 10)

Koca et al. (n = 24)

Naziroglu et al. (n = 18)

Ozturk et al. (n = 30)

Attwa et al. (n = 25)

Abdel Fattah et al. (n = 50)

Yildirim et al. (n = 24)

Yildirim et al. (n = 22)

Ines et al. (n = 36)

Kadam et al. (n = 90)

Khan et al. (n = 30)

Koca et al. (n = 24)

Decrease

No Change

Increase
TBARS
Decrease
No Change

Increase
MDA
Decrease
No Change
Increase
XO

EJD, vol. 23, n 1, January-February 2013

Pemphigus vulgaris and other blistering

diseases
Pemphigus vulgaris (PV) is an autoimmune skin disease in
which autoantibodies primarily bind desmoglein3 (DSG3)
and, in some cases, desmoglein1 (DSG1), two cell adhesion molecules expressed at the surface of keratinocytes.
Autoantibody binding interferes with cell-cell attachment
and leads to keratinocyte acantholysis by mechanisms that
are not yet fully understood [24]. The end result is an
intraepithelial blister. Most often, patients present with oral
mucosal lesions, but any epidermal area, mucosal and/or
cutaneous, can be involved. The incidence of PV is reported
to be from 0.5-5 per 100,000 people [25-27]. The etiology
of PV is still unknown and there are many reported triggering factors including medications, diet, and environmental
exposures [28-31]. A number of hypotheses have been
proposed regarding the pathogenesis of PV, including the
desmoglein compensation theory, the multiple hit hypothesis, the antibody induced apoptosis theory, and the basal
cell shrinkage hypothesis [24]. Oxidative stress, resulting
from an increase in ROS, has also been proposed as a contributory pathogenic mechanism. To our knowledge, there
have only been two published studies on antioxidant status
in PV patients (tables 2-4).
Naziroglu et al. (2003) looked into the plasma concentrations of vitamin A, beta carotene, vitamin E, GSH, GSH-Px,
catalase and MDA and the RBC values of GSH, GSHPx, Catalase and MDA [32]. This study evaluated 18 PV
patients who had no alcohol abuse problems and were not
receiving any systemic therapy, along with 18 age- and
gender-matched healthy controls. The authors found a significant decrease in the plasma concentrations of vitamin A,
beta carotene, vitamin E, GSH and catalase in PV patients
compared to the controls, and a significant increase in MDA.
In the RBCs there was a significant decrease in GSH, GSHPx and catalase, and a significant increase in MDA in the
PV patients. These findings support the case for an oxidant/antioxidant disequilibrium in PV patients. It should
be noted that this is one of the only studies to look into
vitamin A and PV, which may be relevant based on previous work linking vitamin A deficiency and disturbances in
epidermal growth and differentiation.
Yousefi et al. published a study in 2011 with 30 PV
patients and 30 healthy age/gender matched controls [33].
The patients were subdivided into three groups: cutaneous
involvement, mucocutaneous involvement, and mucosal
involvement. None were receiving treatment. Plasma levels
of GSH-Px, vitamin C, selenium, uric acid, and bilirubin
were tested. The authors found a significant decrease in uric
acid in patients vs. controls. The levels GSH-Px, vitamin
C, selenium, and bilirubin showed no statistical differences
between the patient and control goups, or between the three
clinical PV subsets. These results contrast directly with
those of Naziroglu et al.
NADPH oxidase (NOX) is an enzyme responsible for
the formation of several ROS. Chiriac et al. found that
skin cryosections incubated with IgG from bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA)
patients, or leukocytes from healthy donors exhibited
dermal-epidermal separation [34]. However, if the cryosections contained diphenylene iodonium (an inhibitor of
NADPH), or if chronic granulomatous disease (CGD)
granulocytes were used instead of healthy donor leukocytes,
EJD, vol. 23, n 1, January-February 2013

then there was no dermal-epidermal separation. While the

sample sizes in this study were small (EBA (n = 5), BP
(n = 5), CGD (n = 8)), the data support the role of NADPH
oxidase and, by inference, ROS in blister formation.
The limited number of studies in PV and other blistering
disorders, and the contradictory results among them make
it difficult to determine whether oxidative stress plays an
important role in PV (tables 2-4). Larger and more detailed
studies evaluating more comprehensive sets of antioxidants
in clinically defined patient subsets will be needed to draw
more definitive conclusions. In EBA and BP, it would be
beneficial to correlate more directly the antioxidant levels
in patients to disease activation and activity.

Vitiligo
Vitiligo is a skin disorder characterized by sections of
depigmented skin. It affects anywhere from 0.1-8% of the
population worldwide, with appearance at any age [35]. The
etiology is unknown, however, it is generally agreed that
there is a loss of function of melanocytes. Several (nonmutually exclusive) hypotheses have been suggested: an
immune-mediated attack on melanocytes; a neurochemical release from nerve endings resulting in melanocyte
destruction; accumulation of toxic metabolites from environmental exposure or intrinsic melanin synthesis pathways
resulting in melanocyte damage; dysregulation of biopterin
pathways leading to melanocyte cytotoxicity; and impaired
redox status or a defective free radical defense with toxicity
to melanocytes [35-37]. Most likely, there is a confluence
of etiologies which lead to active disease. Recently there
has been increased attention given to oxidative stress as a
pathogenetic mechanism. A number of studies have looked
into the putative role that oxidants/antioxidants may play
in vitiligo (tables 2-4).
A Turkish study by Yildirim et al. (2003) measured the
levels of SOD, GSH, MDA, and GSH-Px in 24 patients
with generalized vitiligo and 20 healthy controls. There
were significantly higher levels of SOD and MDA, and
significantly lower levels of GSH and GSH-Px in vitiligo
patients [38]. Similar findings were reported by Sravani et
al. [39] and Arican et al. [40]. Arican et al. and Sravani et
al. also found significantly lower levels of CAT in vitiligo
patients vs. controls [39, 40]. Furthermore, Sravani et al.
showed that both lesional and non-lesional skin in patients
had significantly lower CAT levels than controls [39]. This
dichotomy between SOD and CAT suggests that oxidative
stress may be increased in vitiligo patients in the form of
hydrogen peroxide, as SOD converts superoxide into oxygen and hydrogen peroxide and CAT converts hydrogen
peroxide into oxygen and water.
A Tunisian study [41] looking into MDA, vitamin A, vitamin E, GSH-Px, SOD, and CAT levels in 18 patients
with active vitiligo, 18 patients with stable vitiligo, and
40 control subjects aimed to determine if active disease is
associated with oxidative stress. The control group consisted of volunteers with any systemic or dermatologic
disease. The determination of vitiligo status (active vs. stable) was based on a patient questionnaire on the history
of disease. This study found that SOD and MDA were significantly increased and GSH-Px was significantly lower
in vitiliginous patients compared to controls. There was
no significant difference in the levels of vitamin A,

vitamin E, and CAT. Also, there was no significant difference between active and stable patients in any of the
levels measured. This study utilized a unique study design
comparing vitiligo patients to a control population with disease rather than disease free controls. However, without
knowing the illnesses affecting them and the disease activity status of the individuals comprising the control group,
these results seem un-interpretable. This study did attempt
to differentiate between active and stable disease. Although
no differences in oxidant/antioxidant markers were found,
this analysis represents a step in the right direction to understanding how oxidative stress impacts the pathogenesis of
vitiligo. Taking the model one step further and measuring
oxidant/antioxidant levels in patients in remission would
add another layer of depth in the oxidative stress model of
vitiligo etiology.
Ozturk et al. recruited 30 patients with generalized stable
vitiligo and 30 healthy controls and looked at the plasma
concentrations of several antioxidants and oxidants [42].
This study found a significantly increased level of MDA
in patients as well as a significant increase in GSH-Px,
which the authors suggest may have resulted from erythrocyte lysis due initially to decreased GSH-Px activity and
increased ROS levels in erythrocytes. They found no significant difference in the GSH and selenium levels between
patients and controls. Shin et al. [43] found the opposite,
showing significantly lower GSH levels and no significant
difference in MDA levels between 53 vitiligo patients and
65 controls. They further found that vitiligo patients who
smoked had a significantly lower GSH level compared to
non-smoking vitiligo patients.
A study done by Jalel et al. compared the total antioxidant status (TAS), using materials obtained from RANDOX,
and GSH-Px levels of 60 vitiligo patients vs 62 controls,
via blood sampling [44]. The vitiligo patients were divided
into 3 groups: patients without associated pathologies (VP,
25), diabetic vitiligo patients (DVP, 20), and dysthyroid
vitiligo patients (TVP, 15). The DVP had significantly
higher plasma glucose than the rest of the subjects and
the TVP had significantly higher TSH and lower T3 than
the control subjects, as expected. Thirty-five patients had
generalized vitiligo and 25 had focal disease. The authors
found a significantly lower TAS and GSH-Px levels in all
vitiligo patients vs. controls. Using a murine model, this
group also evaluated a variety of vitamins (A, C, and E)
and minerals (zinc and selenium) as treatments of vitiligo,
as this has shown positive results [45]. Forty mice were
divided into 5 groups of 8, all receiving a similar diet and
different combinations of treatments. Two groups (A & B)
received vitamins and minerals in some combination; group
C received a green tea decoction and minerals; group D
received just the green tea decoction; and group E was given
distilled water. The groups were scored for repigmentation
as: good (> 75%), moderate (25% - 74%), and bad (<25%).
All the mice in group E had bad scores. Groups A and B
had a majority of good scores. Group C had an even distribution, and Group D had mainly bad scores. These findings
suggest that supplementation with vitamins and minerals is
beneficial and adding these to current treatment regimens
could lead to superior clinical efficacy.
Khan et al. (2009) in India looked into the blood levels
of MDA, vitamin E, vitamin C, SOD, GSH-Px, and total
antioxidant activity in 30 vitiligo patients and 30 healthy
controls [46]. Inclusion criteria for patients were that they

10

had no progression of disease for the last year, less than

30% body surface involvement, and no more than 3 years
since the onset of disease manifestations. Results showed
that the levels of SOD, GSH-Px, vitamin C, vitamin E
and total antioxidant activity were significantly lower in
patients than in controls. MDA was significantly higher in
patients than in controls. These data support the assertion
that there is an antioxidant/oxidant imbalance in vitiligo
favoring oxidative stress. However, this study found that
SOD levels were lower in patients than in controls, which
contradicts previously published studies showing a higher
SOD level in patients [38, 40, 41]. So, while previous studies suggested that hydrogen peroxide was the main ROS
involved in causing oxidative damage, this may not be the
case.
While the literature in vitiligo may occasionally be contradictory for some values, overall the literature supports
consistent oxidative stress (tables 2-4). However, based on
work to date, it is unclear whether oxidative stress leads
to pathogenesis or whether the disease itself leads to an
antioxidant/oxidant imbalance. Longitudinal studies are
required to determine causality.

Psoriasis
Psoriais is an autoimmune inflammatory skin disease
presenting as inflammatory plaques on the skin due to
hyperproliferation of keratinocytes. The disease affects 13% of the population and commonly occurs on the elbows,
knees, scalp, and buttocks [47-49]. Psoriatic plaques can
vary in size from very minimal to involvement of the entire
surface of the skin. Lesions are likely to be triggered by
a variety of factors such as medications, stress, infections,
smoking, trauma, etc [48-50]. Oxidative stress has entered
the discussion recently as a potential elicitor of psoriasis.
Several studies have shown that there is an imbalance in
the antioxidant-oxidant equilibrium between psoriatics and
healthy controls. Yildirim et al. showed a statistically significant difference in SOD, GSH-Px, CAT, and tissue MDA
between patients and controls. SOD and GSH-Px were
significantly lower, while CAT and tissue MDA were significantly higher [51]. Kadam et al. found significantly lower
levels of CAT, SOD, and plasma total antioxidant status
in patients vs. controls, while serum MDA was significantly higher. Furthermore, when patients were classified
according to the Psoriasis Area and Severity Index (PASI),
those with higher PASI scores had a statistically significant
increased oxidative stress status [52]. Attwa et al. found
similar results regarding SOD and MDA between psoriasis
patients vs. controls, and similar results within the patient
group, based on PASI scores. They also found a highly statistically significant increase in MDA and decrease in SOD
when comparing smokers to non-smokers, in both the control and patient groups. In addition, a statistically significant
increase in PASI score was detected in smokers compared
to non-smokers [53]. Following treatment of patients with
topical corticosteroids for 11 days, Wozniak et al. found a
normalization of GSH-Px and TBARS in patients vs. controls. Before treatment, GSH-Px was significantly lower
and TBARS was significantly higher [54].
Collectively these data help to support a link between oxidative stress and psoriasis, and psoriasis disease severity.
Further studies tracking the antioxidant/oxidant status in
EJD, vol. 23, n 1, January-February 2013

patients over time will be needed to determine whether

changes in the oxidative stress status can be predictive of
changes in disease activity.

Synthesis
Our skin is the organ most targeted by ROS. While ROS perform necessary biological functions, their overproduction
can lead to unwanted consequences that are increasingly
being recognized as relevant in autoimmunity. Antioxidants
are our major defense mechanism against ROS. Without
antioxidants, free radicals and peroxides are uninhibited
from contributing to disease processes and accelerated
aging [55].
Oxidative stress can occur via various mechanisms. Exogenously, the skin is constantly targeted by environmental
factors (e.g. pollutants, smoking, UV light) that promote
the excessive generation of ROS which contribute to the
inflammatory cascade [2]. Endogenously, infections and
inflammation often increase the number of activated white
blood cells, which can lead to oxidant/antioxidant disequilibrium. Psychological stress can impact the balance of the
immune system by up-regulating and/or down-regulating
various levels of humoral and cellular responses [56], with
accompanying effects on oxidative stress.
The multifactorial etiology of autoimmune diseases makes
it extremely difficult to pinpoint and functionally define specific pathogenic factors. Nonetheless, oxidative stress has
recently become known as an important triggering event
in the emergence of various ailments, such as systemic
lupus erythematosus (SLE), rheumatoid arthritis (RA) and
diabetes mellitus type 1 (DM 1) [57-61]. As cutaneous surfaces are constantly under attack from ROS, autoimmune
diseases of the skin may be particularly affected by the
oxidant/antioxidant imbalance.
The majority of studies regarding autoimmune skin diseases
(specifically PV, AA, vitiligo, and psoriasis) and oxidative
stress have collectively found some significant differences
between patients and healthy controls. However, many of
the studies are limited in several ways. Very few track
patients longitudinally over time, making it difficult to
draw correlations between disease activity and oxidative
stress. Without this information there is no way of knowing
whether the establishment of disease states caused oxidant/antioxidant disequilibrium, or vice versa. Data should
be collected on more defined clinical subsets based on
patients distinguished on multiple clinical variables, e.g.
disease morphology, severity, activity, treatment response,
etc. Furthermore, there is little known about the interactions
of one ROS with another under physiologic conditions,
and even less is understood regarding the integrated networks of dysregulations that underlie disease conditions
[10]. Assessment of one, or limited sets of, antioxidants
can be misleading. Future studies would benefit from evaluating antioxidant status in total, as well as larger sets of
individual factors. Irradiation, environmental conditions,
illnesses, inflammation, smoking and alcohol consumption
have been shown to lead to an increase in free radical formation in the skin and their impact on these pathways will
need to be better studied [62]. Psychological evaluation of
subjects may also be useful to document, as stress can alter
the immune dynamic within the body [56]. It is known
EJD, vol. 23, n 1, January-February 2013

that stress hormones can lead to suppression and activation of various cytokine profiles, which is clearly relevant
to autoimmunity.
The current mainstay treatment for autoimmune skin
diseases centers on steroidal and/or non-steroidal immunosuppression. Clearly, continuous use of these drugs places
patients at risk for serious adverse side-effects. With further elucidation of the exact role that specific antioxidants
play in defined diseases, one can envision future therapeutic management strategies of skin disease that incorporate
high dose antioxidants as a possibility. In fact, preliminary studies with antioxidant intervention in a number of
autoimmune diseases (e.g. SLE, RA, DM 1) have shown
decreased oxidative stress markers with mixed clinical
results [58, 59, 63-65] (table 5). These findings suggest
antioxidants as a form of treatment in conjunction with
steroids could be beneficial. This strategy could help to
decrease the dosage of steroids/steroid sparing agents.
Oral supplementation with high dose antioxidants for skin
disease has had mixed results [9]. However, in order to
determine the value of what high dose actually is, we need
to better understand what normal intake should be. The
current recommended daily allowance for several antioxidants (e.g. vitamin E) is based on data that is over 50 years
old [66]. In fact, 96% of women and 93% of men do not
meet the dietary recommendations for vitamin E [66, 67].
Furthermore, as antioxidants are known to work synergistically, treatment with a single antioxidant may have limited
benefit, or possibly even a negative effect [68]. Thus, combinational therapeutic strategies should be explored.
Research into the topical application of vitamin C and E
in the treatment of skin disease and the prevention of skin
aging is ongoing and has been promising [1]. However,
there are still a number of obstacles to overcome. Individuals are likely to have different optimal antioxidant
levels in the skin, which may vary depending on age, diet,
stress, body site, skin type and illnesses, along with other
organic conditions and external factors [68]. Improving the
Table 5. Autoimmune disease and antioxidant intervention.
Disease

Intervention

SLE

Administration of Vitamin E & C vs. placebo was

associated with decreased lipid peroxidation, but
did not affect endothelial function [65].
Vitamin E with prednisolone showed
significantly lower anti-ds DNA antibody titers
when compared to prednisolone treatment alone
[59].
Vitamin E treatment showed significant analgesic
activity vs. placebo, furthermore when the
vitamin E treatment was stopped the analgesic
activity ceased as well [64].
Antioxidant enriched margarine was given for
10 weeks and clinical outcomes were measured
by Disease Activity Score (DAS). DAS
significantly decreased after the 10 weeks and
increased after a
4 week washout [63].
GSH and vitamin E were lower and MDA higher
in patients compared to healthy controls. After
vitamin E supplementation there was a significant
decrease in MDA and significant increase in GSH
and vitamin E. However, no significant changes
were observed in metabolic parameters [58].

RA

DM Type 1

11

solubility, permeability, and stability of antioxidants is

necessary, as antioxidants are inherently unstable and susceptible to photodegredation [1, 6, 62].
Topical microemulsions, composed of water, oil and surfactants, are under active development to overcome some
of the obstacles faced with topical antioxidant delivery [1].
We expect future clinical and mechanistic studies will provide improved guidance towards novel antioxidant based,
or aided, therapeutic regimens in the coming years.

Disclosure. Financial support: none. Conict of interest:
none.

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