ARTICLE
Auteur(s) : Modh Hanif Zulfakar, Michael Edwards, Charles Martin Heard
Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3XF,
United Kingdom
accepté le 14 Février 2007
Psoriasis
Psoriasis is a chronic inflammatory disorder of the skin, affecting
around 2% of the population [1, 2]. Its prevalence varies
throughout the world with the highest seen in the USA at 4.6% and
the lowest in Chinese populations at 0.4% [1]. There are several
different forms of the disease, the most common being psoriasis
vulgaris, in which the skin forms plaques which are thick and scaly
[3].
Genetic factors
The precise causative factors behind psoriasis have yet to be
identified although a genetic link has recently been established
and at present several genetic loci have been determined to confer
susceptibility to psoriasis [3]. Chromosomes 17q, 4q and 6p are
believed to be the main genetic loci involved. The disease also has
a unique association with the human leukocyte antigen Cw6
(HLA-Cw6), the only such association occurring in the HLA-C locus.
Individuals bearing this phenotype are 10 times more likely to
develop psoriasis. Much of the ongoing research has been focused on
the 300-kb PSORS1 locus, which accounts for 30-50% of the genetic
contribution to psoriasis [4]. Other genetic links to psoriasis
have been made to PSORS2, PSOR3, PSOR4, and PSOR5 loci in different
populations, although they are not as reproducible as PSORS1 [5].
Studies performed on Polish [6], Japanese [7] and American [8]
populations revealed an association of psoriasis with the KIR2DS1
gene which governs a stimulatory natural killer (NK) cells receptor
[6].
Inflammation factors
For many years psoriasis was thought to be a disease of disordered
keratinocyte proliferation and differentiation but during the 1990s
studies indicated that cellular immune infiltrates cause the
epidermal changes and therefore it is now considered a T-cell
mediated inflammatory disease [3]. In order to understand the
immune response in psoriasis, it is important to understand the
normal immune processes of the skin. Skin has been described as a
lymphoid organ as it has an effective immunological surveillance
system [5] throughout the skin working with lymph nodes and T
lymphocytes. This system includes antigen presenting cells,
cytokine-synthesizing keratinocytes, the epidermotrophic T cells,
dermal capillary endothelial cells, the draining nodes, [5] mast
cells, tissue macrophages, granulocytes, fibroblasts and
non-Langerhans APC [5] all these cells communicate via the release
of cytokines. Once activated by stimuli such as bacteria, UV light
and chemicals, the keratinocytes produce cytokines such as TNF-α.
This is a controlled process and imbalances lead to a number of
pathological states, including psoriasis [5].
For psoriasis to occur, a triggering factor is required in the
immune response in a particular area of the skin for the plaque to
form, which could be in the form of physical injury, inflammation,
rapid withdrawal of corticosteroid and bacterial/viral infections
[3]. Changes observed during the initiation may be explained by
immature dendritic cells present in the epidermis capturing and
internalising an antigen which is then presented on the cell
surface [5]. The specific antigen is unknown but research has
suggested that it could be bacterial or viral antigens or even
autoreactivity to proteins of the keratinocytes themselves [9].
These may include heat shock proteins [10]. The dendritic cell is
then able to stimulate T-cells in lymph nodes [5] which are then
activated in a multistep process which is started by binding
between ICAM-1 and the lymphocyte function-associated antigen LFA3
on DC with CD2 and LFA-1 on T cells [5]. The T-cell will receive a
primary stimulation which will lead to its activation and with
that, synthesis of mRNA for IL-2 and IL-2 receptors increases.
Further interaction or co-stimulation then occurs, a critical
process for optimisation of the T-cell activation and occurs via
non antigen-specific interaction. Also, the increased amount of
IL-2 from the activated T-cells and IL-12 from Langerhans cells
bind to receptors on activated T-cells, regulating the
transcription of cytokines which are responsible for
differentiation, maturation and proliferation of the T cells into
memory effector cells [5] e.g. IFN-α, TNF-α and IL-2. These T-cells
begin to migrate towards the skin where they accumulate around the
blood vessels of the dermis without entering the epidermis. This is
the first change seen between uninvolved skin and that of the
psoriatic lesion about to form [3]. The activation, expansion and
polarisation of the T-cells in psoriasis has also been linked to
cytokines such as IL-12, IL-15, IL-18 and IL-23 [11].
The first changes in skin will be seen when the acute psoriatic
lesion forms. This happens when larger numbers of lymphocytes
migrate into the skin, triggering epidermal hyperplasia. As the
epidermal hyperplasia occurs when the T cells, dendritic cells and
neutrophils infiltrate the epidermis, it has been suggested that
this process actually changes the epidermal basement layer between
keratinocytes, so that they can proliferate autonomously [3].
Nearly all the acute lesions will go on to become chronic
plaques. This occurs when equilibrium has been reached between
leukocyte infiltration and epidermal hyperplasia. At this point if
the patient does not receive treatment the cellular disease state
can remain for years [3]. These psoriatic plaques contain mature
dendritic cells, which express CD83+ and/or DC-Lysosomal associated
membrane protein+, and are located with T-cells in perivascular
accumulations within the epidermis. This system creates a mimic of
the T-cell regions of the lymph nodes and therefore it is
hypothesised that it may act like a secondary lymphoid tissue and
cause cellular immunity [3].
The T-cells present within the psoriatic plaque are usually LFA1
CD8+ but they may also express the αEβ7
integrin. The CD8+ cells in the epidermis and the CD4+ cells in the
dermis are highly active and have type 1 immune effector functions
and can be classified as type 1 cytotoxic (Tc1) and T
helper 1 (TH1) cell populations respectively [3]. The
activated T cells synthesise a number of cytokines such as TNF-α
and IFN-γ. The T cells which are activated do not always
differentiate as described earlier to the Tc1 and
TH1 cells but may also produce Natural Killer T cell (NK
T-cells), at this stage it is not known which type of T-cell is the
primary cause of inflammation seen in psoriasis [11]. The cytokines
produced can cause keratinocytes to express more than 100 genes
which may cause proliferation of keratinocytes [3]. Dendritic cells
are also present in psoriatic plaques in equal or greater number
than T-cells, especially CD11c+ (immature dendritic cells) which
are present in normal skin, but their expression is greatly
amplified in psoriatic skin. Mature DCs are also present, such as
CD83+ subsets. Dendritic cells like T-cells can produce many
products which also play a role in the pathophysiology of psoriasis
such as TNF, IFN and IL-23 [3].
Further evidence that psoriasis is mediated by T-cells has been
obtained from several observations. Normal skin taken from a
psoriasis-susceptible patient, grafted on an immunodeficient mouse,
began to show a psoriasis-like condition. It had also been observed
that graft or transplant patients with concurrent psoriasis showed
a marked improvement while undergoing therapy with cyclosporine, an
agent which inhibits T-cells [9].
From the above it can be seen that T cell activation and the
migration of leukocytes into the epidermis and dermis play a major
role in the formation of psoriatic plaques, but this is a normal
body response to an antigen, so why this develops into psoriasis
and why proliferation remains, is unclear. The specific genes which
are upregulated in psoriasis may play a part, these include:
- – Dendritic cells produce IL-23, act in T- cells to
produce IFN-γ [3].
- – Signal transducer and activator of transcription 1
(STAT1) is upregulated. This is induced by IFN-γ and causes the
production of over 65 pro- inflammatory products such as adhesion
molecules, chemokines and release of iNOS, which contribute to the
inward migration of leukocytes.
- – STAT3 has also been implicated. This is believed to be
a transducer of the keratinocyte hyperproliferation seen in
psoriasis. It is believed that this pathway is activated by
epidermal growth factors and IL-6 due to presence of receptors for
these on the keratinocyte [3].
- – Increased amounts of vasoactive peptide receptors have
been shown to be present in keratinocytes, believed to be induced
by TNF-α. This is believed to upregulate synthesis of IL-6 and IL-8
[5].
- – The vascularisation seen in psoriasis is believed to
be caused by vascular endothelial growth factor (VEGF) and IL-8,
which are released from the keratinocytes on the endothelium
[5].
Again, the pathophysiology of psoriasis is clearly complex with
many different pathways involved to form and maintain the psoriatic
plaques. The main problem seems to be the increased cell signalling
via chemokines and cytokines, that act on receptors to produce
upregulated gene expression and cause the proliferation of the
keratinocytes. The key ones are TNF-α, IFN-γ, IL, 1, 2, 6, 8, 12,
15, 17, 18, 23 and VEGF [12].
Treatment of psoriasis
At present the treatments available are for short term use and do
not completely control the symptoms [1] therefore there is a need
for treatments which can be tolerated for long term use to aid in
the control of this disease. Psoriasis is clearly a very complex
disease state and at present all that is really known, as with most
immunological diseases, is the cell types involved and the
processes that occur after initiation. The current problem in
psoriasis is that the precise cause of the disease remains unclear.
At present in psoriatic treatment there has been success with the
new biological treatments which target specific cytokines and
receptor targets to block certain processes [5]. Other than that
these specific target biological drugs, topically applied
corticosteroids and vitamin D analogues have provided the most user
friendly results for patients. Generally, the mechanism of action
for commonly prescribed drugs for psoriasis involves
immunomodulation/immunosupression, anti-inflammatory, and
antiproliferative actions.
For example, topical corticosteroids are available in several
classes of strength or potency. These immunomodulatory agents
possess anti-inflammatory, anti-proliferative, immunosuppressive
and vasoconstrictive effects. Anti-inflammatory and
immunosuppressive effects of corticosteroids are mediated by
modulation of corticosteroid-responsive genes, which then gives
rise to the effect of directly regulating gene transcriptions. This
includes genes involved in transcripting various pro-inflammatory
cytokines involved in psoriasis [13].
Meanwhile, vitamin D analogues (another anti-psoriatic agent
used widely), in particular those of Vitamin D3 and its
metabolites (e.g. calcitriol, calcipotriene) inhibit the
proliferation of keratinocytes and stimulate the differentiation of
cells. This would oppose hyperproliferation and the apparent lack
of differentiation of keratinocytes observed in psoriatic lesions.
Again, these agents act via interactions of Vitamin D-selective
receptors and regulating gene transcription [13]. Though these
agents can provide satisfactory control of the symptoms, they are
not suitable for long term use due to their side effects and
desensitization (e.g. corticosteroids), thus are only suitable to
control flares.
Another agent widely used in psoriasis is salicylic acid.
Although it does not have a direct effect on the aetiology of
psoriasis, it is used in conjunction with other anti-psoriatics to
counter the problem of delivering the drugs through the thickened
epidermal layer. The highly keratinized psoriatic scales/plaques
pose a significant barrier for permeation, thus, by untilizing the
keratolytic properties of salicylic acid, more drugs can be
delivered and the need for higher doses reduced. How salicylic acid
exerts its keratolytic effects is still not fully understood,
though it is believed that modification of intercellular cohesion
takes place, due to alteration of the structure of the stratum
corneum [14].
Eicosapentaenoic acid, EPA
In recent years there has been renewed focus on the use of
naturally occurring substances in a wide range of disease states.
EPA is a n-3 (or Omega 3), 21-carbon ‘essential’ fatty acid with 5
double bonds (figure
1) and is found predominantly in oily fish living in cold
waters, such as salmon and mackerel [1, 15].
Plants such as flax seed, walnut, canola and green leafy
vegetables contain alpha-linolenic acid (ALA) which is converted to
EPA and a further n-s polyunsaturated fatty acid docosahexaenoic
acid (DHA) (figure
1) through enzymatic reactions. This process, coupled with
consumption of marine plants such as algae and plankton, leads to
accumulation of these fatty acids as triacylglycerols in tissues of
marine mammals and fish. Extraction of oil from the flesh of cold
water fish yields the product commercially known as fish oil, as
opposed to that extracted from the liver of fish living in warmer
waters, which produces what is known as cod liver oil [16].
There are in fact a variety of fatty acids present in fish oil.
At least 50 different fatty acids ranging from C14 to
C24 in chain lengths, fatty acids with differing degrees
of saturation (saturated, mono-, polyunsaturated), position of
C-terminus (n-3, n-6), branching, different isomers, and other
characteristics. These fatty acids, including the Omega-3s are also
present in the phospholipids which constitute the cell membranes of
the fish, and are even more enriched in EPA and DHA compared to the
triacylgycerols, ranging from 40-55%. However, the phospholipids
are not considered as a viable source of EPA and DHA because of
their low amount (1-1.5% per body weight) and the difficult
extraction processes required [17].
In 1987 it was recognised that the indigenous Inuit population
of Greenland had a very low incidence of inflammatory diseases such
as psoriasis, asthma, congestive heart disease and rheumatoid
arthritis [18] which was associated with their high dietary intake
of EPA from oily fish. Since then, much effort has been made to
study the biochemical mechanism of action of n-3 fatty acids, with
most of the studies focussing on cardiovascular disease and the
role of n-3 as a cardioprotective agent [19-21]. However, the use
of high levels of EPA (and also DHA) has also been reported in
patients with numerous other chronic inflammatory and allergic
conditions (table 1) [15, 22].
Table 1 Inflammatory conditions responsive to
supplementation with Omega-3 long chain fatty acids [21]
|
Acute respiratory disease syndrome (ARDS)
|
|
Allergic diseases
|
|
Asthma
|
|
Atherosclerosis-related cardiovascular diseases
|
|
Inflammatory bowel diseases
|
|
Osteoarthritis
|
|
Psoriasis
|
|
Rheumatoid arthritis
|
|
Traumas of multiple aetiology
|
|
Viral and bacterial pneumonia
|
EPA and inflammation
The essential fatty acids are important for numerous physiological
processes and functions. They are used as substrates in the
biosynthesis of phospholipids that form the cellular membranes and,
more significantly, by cyclooxygenase (COX) and lipoxygenase (LOX)
to form eicosanoids during the inflammation process. Two isozymes,
15-lipoxygenase-1 and 15-lipoxygenase-2, exist, although the latter
has been implicated in interferon-gamma-induced inflammatory
processes in normal human epidermal keratinocytes and psoriatic
skin [23].
The eicosanoids play a central role in modulation and regulation
of cellular function, and leukotriene (LT), prostaglandin (PG),
tromboxane (TX) are important chemical inflammatory mediators which
help to protect the body from injury and noxious stimuli [24]. It
has been established that n-6 derived eicosanoids such as
arachidonic acid (AA) are pro-inflammatory and promote aggregation
of platelets, whereas the n-3 derived eicosanoids from EPA and DHA,
are less potent inflammatory mediators. Increased bioavailability
of n-3 fatty acids, e.g. as a consequence of dietary supplemention,
allows them to replace n-6 fatty acids as the major fatty acids in
the membranes and compete with n-6 for enzymes to produce less
potent eicosanoids [17]. Thus this will reduce the extent of
inflammation and promote an improvement in inflammatory diseases
[25]. An example of this is where AA, which is formed from n-6
fatty acid sources, uses the 5-lipoxygenase (5-LOX) enzyme to
produce LTB4 which causes leukocyte chemotaxis and
adherence. When sufficient levels of EPA are present it competes
with the AA for the 5-LOX to produce LTB5 which is at
least 10 times less potent that LTB4 [2] (figure 2). This is of
consequence in psoriasis as LTB4 has been shown to be
raised in psoriatic plaques and has chemotactic properties for the
infiltration of leucocytes. The addition of LTB4 has
also been shown to cause keratinocyte proliferation both in-vitro
and in-vivo but does not lead to complete features of a psoriatic
plaque, indicating that other factors (including those described
above) must also play a part [26].
EPA and psoriasis
Thus a rational basis exists for the use of EPA as a potential
treatment for psoriasis. Intravenous infusions with n-3 fatty acids
containing EPA were observed to lead to an increase in
LTB5 in psoriatic plaques within 4-7 days of starting
treatment, and on comparison with the control (patients infused
with n-6 fatty acids) did show improvements in psoriatic effects
without any severe side effects. In this trial, the researchers
employed 2 different lipid emulsions, one enriched with n-3 fatty
acids, and the other with n-6, infused twice daily for 10 days. A
total of 3 trials were conducted. Parameters investigated include
clinical parameters such as erythema, infiltration, desquamation,
subjective score and also biochemical index (generation of 5-series
leukotriene). The Psoriasis Area and Severity Index (PASI)-Score
was also employed to determine the severity of disease in each
participant both before and after treatment with the intravenous
lipid emulsions [2].
Oral dosing was found to provide some improvement in symptoms in
one study but further studies have shown no statistical effect on
stable plaques [15]. Several studies have been carried out on
topical application of n-3 fatty acids in psoriasis, the first one
was by Dewsbury during 1989 [27] in which she applied a MaxEPA 10%
in Unguentum Merck in a small trial of eleven patients, with eight
patients showing clinical improvements. A further study which used
a higher purity EPA, DCHA mixture (80% EPA-ethylester and 20%
DCHA-ethylester) compared to the fish oil mixes used previously,
did not show any improvement statistically compared to control. It
was hypothesised that this was due to pharmacokinetic properties
and the pure form not penetrating the skin as well as the mixed
fish oil [15]. Apart from these trials, application of fish oil
instead of EPA or its mixtures was also attempted by Escobar et al.
[28], who reported the benefits of fish oil in alleviating symptoms
of psoriasis and determined the efficacy of topically applied fish
oil in reducing psoriasis symptoms compared to liquid paraffin.
Both treatments were applied daily under occlusive dressing for 6
hours and the duration of treatment was for 4 weeks. The parameters
investigated were erythema, scaling, plaque thickness (induration)
and itching, on a weekly basis. It was found that both treatments
improved erythema and scaling compared to base values, while there
was a significant difference between the two treatments in
reduction of plaque thickness and scaling [29].
EPA and proinflammatory mediator release
Since these studies were carried out, further research into
psoriasis aetiology has taken place, which has concentrated on the
infiltration of leukocytes and the aberrant cell signalling that
occurs via cytokines and chemokines to cause the proliferation of
keratinocytes. As discussed earlier TNF-α is a key mediator in
psoriasis, as demonstrated by the fact that Infliximab (a
monoclonal antibody against TNF-α) has shown promise in treating
psoriasis [29]. EPA has also been shown to reduce TNF-α and IL-1
release by monocytes [15]. An inverse relationship was noted
between the % EPA content of mononuclear cell membrane content and
amount of TNF-α to a maximum of about 5% of membrane content, where
no further decrease is seen in TNF-α [30]. Both of these
pro-inflammatory agents are involved in the stimulation of T-cells,
especially TNF-α, which can cause production of numerous other
cytokines and chemokines involved in psoriasis. A decrease in their
production will lead to a decrease in T-cell activation and
therefore reduce proliferation of keratinocytes.
EPA has also been shown to impair the production of IL-12 and
IFN-γ during in vivo testing on mice [31]. In this study, plasma
levels of IFN-γ and IL-12 for groups of mice on five different
diets were compared. Those mice on EPA diets produced less IFN-γ
and IL-12 compared to those on olive oil diets. IFN-γ plays a key
role within psoriasis as it activates the STAT1 pathway, which is
responsible for the production of 65 pro inflammatory genes [3]. As
STAT1 is believed to be the main pathway by which pro-inflammatory
genes are expressed in psoriasis, any reduction in its activity
could help provide a reduction in symptoms of psoriasis and its
propagation into a chronic plaque.
As mentioned previously, the activation of T cells is a key step
in the initiation process of psoriasis and is required for
leukocyte migration to occur. Switzer et al. [31] have investigated
the effects of n-3 fatty acids on the apoptosis of CD4+ T-cells
which are found on the dermis of psoriatic plaques [3]. The T-cells
are characterised by the cytokines they produce, IL-2 and IFN-γ
[32]. The work concluded that n-3 fatty acids can cause the
polarisation and deletion of pro-inflammatory Th1 cells, possibly
as a result of alterations in membrane micro-domain fatty acid.
However, the authors did not determine which n-3 fatty acids are
implicated in this process and therefore cannot be certain if it is
an effect of EPA or other constituents of the oil used, therefore
more work is required to find the exact causative agent.
Finally, fatty acid binding protein (FABP) has been postulated
to serve as a lipid shuttle, solubilizing hydrophobic fatty acids
and delivering them to the appropriate metabolic system.
Epidermal-type FABP (E-FABP) is solely expressed in keratinocytes
but its specific role in the skin is not yet fully established.
E-FABP upregulation may be necessary during wound healing [33] and
its expression in dithranol irritation has been found to correlate
with the unimpaired skin barrier function [34]. Clearly the
activity of E-FABP is of potential of significance to the
distribution and activity of EPA within the epidermis.
EPA and inflammatory enzymes
COX-2 and LOX are the main inflammatory enzymes involved in
metabolism inside the skin, and are implicated in inflammatory
diseases such as psoriasis. Qualitative investigation using
immunocytochemistry methods has shown that EPA blocks these enzymes
in freshly excised porcine skin. In the experiment, the skin
sections were treated with fish oil, 2.5% ketoprofen and a mixture
of both, and immunohistochemistry staining protocol with COX-2 and
LOX antibodies was conducted on the skin at set time points.
Inhibition is determined by the reduction in the intensity of
staining after 24 hours. Treatment with a combination of both fish
oil and ketoprofen resulted in the most pronounced reduction in
COX-2 staining [35]. Ketoprofen is a known COX-2 inhibitor, while
EPA is thought to act by competition with arachidonic acid for
binding sites on COX-2; producing a less potent inflammatory
mediator; hence reduced inflammation (i.e. reduced staining) [17].
The same reduction was observed for LOX staining after treatment
with fish oil, again by production of less potent inflammatory
mediators derived from EPA (and DHA) [17].
Oxidised EPA
EPA is highly unsaturated and its oxidation to further compounds
occurs readily [36]. As the oxidation is very difficult to prevent,
it is very likely that the effects that EPA exert are actually
carried out by an oxidised product of EPA. Resolvin E1 is produced
in vivo at the vascular endothelial cell during what has been
termed as the resolution phase of inflammation [37]. Key events in
this process have also been found to be affected by currently used
drugs in inflammatory diseases such as aspirin, steroids, and
non-steroidal anti-inflammatory drugs. Resolvin E1 has been shown
to be a very potent agent at inhibiting TNF-α activation of the
NF-κB pathway, it reduces migration of splenetic dendritic cells
which express CD11c+ and reduce in vivo production of IL-12 [38].
Whether Resolvin E1 could be used in psoriasis is still unknown,
although it has been studied in other disease models such as asthma
[39] and colitis [40]. In its favour, a reduction in dendritic cell
migration is a good target in psoriasis, as the as they are a major
component of the cell migration into psoriatic skin, where they
produce cell signalling molecules, which can cause proliferation of
the psoriasis. The TNF-α activation of NF-κB is debatable, as there
have been recent research papers published which suggest that
activation of the NF- κB pathway has a positive role in controlling
keratinocyte growth, and therefore inhibiting its activation could
be detrimental to the psoriatic plaque [41]. However
corticosteroids, which are one of the most effective treatments for
psoriasis, block the NF-κ-B pathway and this is seen as
advantageous, due to the resultant reduction in TNF-α and IL-1
produced [13]. As a result, further work is required into the NF-κB
pathway to see if it is advantageous in psoriasis to target its
function, in the search for a target for more effective treatment.
In the skin, EPA (which is incorporated in the skin through
ingestion or topical and intravenous administration) is
subsequently metabolized by the enzyme 15-lipoxygenase (15-LOX)
found in the epidermis to 15(S)-hydroxyeicosapentaenoic acid
(15-HEPE) and 15(S)-hydroxyeicosatrienoic acid (15(S)-HETrE), both
monohydroxylated metabolites. As with EPA, these metabolites
compete with AA to produce less potent inflammatory mediators, thus
reducing the extent and severity of the inflammation process.
Research carried out by Vang & Ziboh even found these
metabolites to be more potent than the parent compound in relation
to this particular process, and also in inhibiting the growth of
prostatic cancer cells [42].
The investigation of oxidised derivatives of EPA is potentially
the most interesting in the field as, if a specific oxidised
metabolite of EPA could be identified which targets specific
functions within the inflammatory process involved in psoriasis, it
could create a very good treatment or lead compound for future
development. This would be better than using EPA alone as it would
have more specific effects than EPA, making it easier to prove
safety and efficacy to regulators. Depth profiling and the
metabolism of eicosapentaenoic acid in the skin was investigated.
Finite (30 μL) and infinite (1 mL) doses of fish oil and
a mixture of fish oil and 2.5% ketoprofen were applied to excised
porcine skin. In conditions where the skin is kept alive as long as
possible via use of a growth medium, lower amounts of EPA were
detected compared to non-growth-medium-sustained skin. Inversely,
the presence of 15-HEPE was only detected in the receptor phase of
the former, indicating that metabolism of EPA by viable skin
enzymes had occurred during permeation. The amount of 15-HEPE
correlated with the amount of EPA permeating through the epidermis,
as proven in samples dosed with 1ml solutions [43].
Depth profile analysis revealed that the greatest conversion of
EPA to 15-HEPE occurs at the basal layer of the skin, where
metabolic activity is highest. This finding is of particular
consequence to the treatment of psoriasis, where the lower layers
of the skin are in a state of hyperproliferation. With the presence
of 15-HEPE, a more potent anti-inflammatory, it is hypothesised
that this increase in growth can be arrested more effectively
[44].
Topical delivery of EPA
As with any therapeutic drug system, efficacy is only as good as
the efficiency of the delivery system. Oral and intravenous modes
of delivery are associated with wide distribution of the active
agent throughout the body and often extensive first pass
metabolism. The viable epidermis, the locus of psoriasis, is
avascular and receives nutrients (and therefore drug molecules) by
passive efflux from the microvasculature in the dermis.
Consequently the proportion of an administered dose arriving at the
desired site of action in the skin is typically very small.
Seemingly, the obvious solution is to use a topical delivery
system, in which the medication is applied directly to the affected
areas of skin. Of course anti-psoriasis topical preparations have
been around for some time, e.g. coal tar, dithranol. However,
effective topical delivery is dictated by a number of
physicochemical parameters associated with the formulation (e.g.
partition coefficient of the permeant, molecular size,
solubility/melting point, degree of ionization). Psoriasis plaques
are also dense and generally impenetrable to drugs and so some
regimens include the use of a keratolytic (or desmosomalytic)
agent, most notably salicylic acid, to make the plaque less
impenetrable.
The limited number of trials conducted so far have produced
mixed results and furthermore, have offered little evidence to
prove that substantial amounts of EPA were successfully delivered
to the viable epidermis. Only the blind trial which was carried out
gave an insignificant difference between control and treatment with
EPA, while the open label studies did produce an improvement in
symptoms [15]. One reason for this was suggested by Grimminger and
Mayser was that the blind trial used purer forms of EPA and DHA
than the open studies. Free long chain fatty acids are amphiphilic
and not well suited to dermal absorption, particularly in the
absence of a penetration-enhancing excipient in the formulation.
Furthermore, fatty acids have pro-inflammatory properties by virtue
of the free carboxylic acid groups, which could negate any
beneficial effects that EPA and DHA may have on psoriasis. On the
other hand, when applied as triacylglycerols (figure 1) the
proinflammatory response is diminished and skin absorption, and
even permeation, can occur [43, 44].
The trials that have been carried out with topical fish oil/EPA
need to be reviewed critically, as these involved a diversity of
different formulations (fish oil versus pure EPA, different bases
in the compounding) and differing amounts of EPA dosed. These
factors could explain the variability of the results obtained from
the trials. Indeed, no supporting data (in vitro or in vivo) was
provided proving that EPA had actually diffused into the skin, let
alone provide therapeutically useful amounts.
Another aspect of the use of fish oil/ EPA in topical
application is its potential as a carrier for other drugs used in
treatment of psoriasis or facilitating their delivery. It has been
determined that fish oils can act as permeation enhancers when used
in conjunction with topically delivered NSAIDs (ibuprofen and
ketoprofen) to increase the amount of NSAID delivered, with the
added advantage of using a vehicle which will have a local
anti-inflammatory effect, with the fish oils containing EPA
[43-45]. Further research evaluated the effectiveness of EPA
delivery from fish oil preparations, one containing just fish oil,
and a preparation of fish oil and ketoprofen. The results showed
that EPA did penetrate the skin as part of a fish oil mixture and
therefore its delivery topically could be a viable delivery route
with the right preparation of fish oil [42]. As observed in earlier
studies, EPA was found to enhance the penetration of ketoprofen and
vice-versa. This has been attributed to what is termed the ‘pull’
or ‘drag’ effect [45, 46]. This has been supported by a combination
of NMR spectral modulation and molecular modelling data that has
demonstrated particularly strong complexation between EPA or DHA
with ketoprofen [47].
A separate study by Puglia et al. [48] also investigated the
transcutaneous delivery of EPA from fish oil. Extracts from
Mediterranean fish such as sardines, mackerel and horse mackerel
were applied on human stratum corneum and epidermis (SCE) mounted
on Franz-type diffusion cells. Subsequently, they also looked at
UVB-induced erythema inhibition of fish oil preparations containing
ketoprofen, compared to fish oil or ketoprofen alone. It was again
shown that appreciable amounts of EPA were delivered from a fish
oil vehicle, and the greatest inhibitory effect against erythema
comes from the preparation containing both fish oil and ketoprofen.
This was attributed to the presence of two inhibitory compounds
(EPA and ketoprofen) and also the enhanced permeation that occurs
synergistically between the two. With this in mind, there is a
possibility that this phenomenon could be applied to other
antipsoriatic drugs, thus enhancing their delivery. For example,
this could be particularly useful with corticosteroids, as their
effectiveness becomes reduced the more they are used; and increased
permeation may make the doses delivered more effective and reduce
local side effects, as less product would need to be applied.
Adverse effects of topically applied EPA
In addition to the potential advantages of EPA and fish oils, there
are issues relating to whether its effects are all positive in
psoriasis. The production of PGE2 via COX-2 enzyme
counteracts the role of LTB4, as firstly it competes for
the AA from the 5-LOX enzyme, which leads to the activation of
TH1 cells. The production of PGE2 leads to
production of TH2 cells which do not release
pro-psoriatic cytokines such as IFN-γ, TNF-α but release cytokines
such IL-4 and IL-10 which are not involved with psoriasis [49]. The
blockade of PGE2 exacerbates psoriasis as can be shown
by the fact that treatment with NSAIDs in psoriatic patients tends
to worsen symptoms [50]. NSAIDs are potent blockers of the COX-2
but the effect could be due to the increased amount of AA available
to react with 5-LOX to produce LTB4, which could
exacerbate psoriasis. As can be seen in figure 2, EPA substitutes
for AA as a substrate of COX-2 which produces PGE2, to
produce a less potent prostaglandin PGE3, which may have
a detrimental effect on psoriasis.
Additionally, there may be compliance issues emanating from the
odour associated with a formulation containing fish oil, and
allergic reactions in sensitized patients. The problem with odour
could potentially be solved by using masking agents and addition of
antioxidants to prevent oxidation of the fish oil; however it is
more important to ensure such compounds do not retard the delivery
of the active constituents, thus defeating the purpose of using
fish oil in the first place.
Conclusion
Currently there are many unknowns about psoriasis aetiology and the
effects that blocking different cytokines have on the disease
progression. Furthermore, not enough is known about EPA effects on
cellular immunity other than via prostaglandin and leukotriene
synthesis [51] to fully understand the mode of action of EPA.
However, evidence so far suggests EPA does have a potential role in
the treatment of psoriasis, in particular for topical treatments,
either as an active anti-inflammatory agent by itself, or as a dual
action permeation enhancer for other anti-psoriatic treatments. The
challenges include optimising the delivery of EPA to the skin and
determining the derivatives of EPA which would give maximal
effects, and overcoming pharmacokinetic and formulation problems to
deliver EPA optimally to the intended target.
Acknowledgements
Financial support: none.
Conflict of interest: none.
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