1. Introduction
Psoriasis
is a lifelong, chronic, and immune-mediated systemic disease with
preferential skin involvement, which affects approximately 1–3% of the
Caucasian population [
1,
2].
Psoriasis may appear at any age; however, over 75% of patients belong
to a clear subgroup, that develops the disease before the age of 40
(type 1 or early-onset psoriasis) [
3,
4].
The most common clinical variant is plaque-type psoriasis,
characterized by erythematous scaly plaques, round or oval, variable in
size, frequently located in scalp, lower back, umbilical region,
intergluteal cleft, knees, and elbows [
1,
5,
6].
As a clinically heterogeneous disease, psoriasis presents several
degrees of severity and a wide array of presentations in different
patients [
7].
Approximately 80% of psoriasis patients have mild disease, with skin
plaques usually covering less than 10% of the body surface area (BSA).
However, some patients have moderate to/or severe disease, with greater
than 10% of the BSA involvement [
3,
6].
The
different presentations of psoriasis require a variable approach to
treatment and the current treatment concept advocates that the type of
therapy prescribed should be appropriated to disease severity. Although
there is a wide range of therapies available for the treatment of
psoriasis, either systemic or topical agents, the use of topical therapy
()
remains a key component of the management of almost all psoriasis
patients. While mild disease is commonly treated only with topical
agents, the use of topical therapy as adjuvant therapy in
moderate-to-severe disease may also be helpful and can potentially
reduce the amount of phototherapy or systemic agent required to achieve
satisfactory disease control.
Topical therapy for management of psoriasis.
Topical therapies available for mild-to-moderate psoriasis involve a great number of different agents, including [
3,
7,
8]
emollients;
tars;
dithranol;
topical retinoids (Tazarotene);
calcineurin inhibitors (pimecrolimus and tacrolimus);
keratolytics (salicylic acid, urea);
topical vitamin D analogues (calcitriol, tacalcitol, and calcipotriol);
topical corticosteroids.
Since
their introduction to dermatology, more than 50 years ago, topical
corticosteroids have become the mainstay of treatment of various
dermatoses including psoriasis, mainly due to their immunosuppressive,
anti-inflammatory and antiproliferative properties, which makes this
class of drugs an useful therapy for this immune-mediated disease [
9,
10].
Although
topical corticosteroids are an integral part of the psoriasis
therapeutic armamentarium, limitations due to the occurrence of
well-known cutaneous adverse effects such as atrophy, striae and/or
telangiectases, and also potential systemic adverse events prevent their
optimal long-term and extensive utilization. Therefore, strategies such
as the weekend-only/pulse therapy regimen or combining topical
corticosteroids with other topical agents may improve their efficacy and
safety profile over longer periods [
11,
12].
The
purpose of the therapy is to reduce the extent and severity of
psoriasis to the point at which it is no longer detrimental to a
patient's quality of life. Treatment choice should always be tailored to
match the individual patient's needs and his expectations. When
employed under these circumstances, a topical treatment regimen is more
likely to produce a satisfactory clinical outcome [
3,
8].
2. Currently Available Topical Corticosteroids for Treatment of Psoriasis
Corticosteroids
remain first-line treatment in the management of all grades of
psoriasis, both as monotherapy or as a complement to systemic therapy.
They are available in a wide range of preparations including gel, cream,
ointment, foam, lotion, oil and spray, and a new and innovative vehicle
() [
3,
16].
Corticosteroid classification system, adapted from [
12].
According
to Cornell and Stoughton, we know that the vehicle can directly modify a
preparation's therapeutic and adverse effects by changing the
pharmacokinetics of the topical corticoid molecule. Therefore, the
development of an improved vehicle for corticosteroids is at the
forefront of dermatologic research [
16,
17].
Although
the decision of the agent depends on patient's choice, distribution of
disease and local availability, bioassays comparing vehicles and
corticoid molecules have demonstrated that ointments are the most
effective, followed by creams and lotions. A recent study with
clobetasol has suggested spray vehicle to be slightly more efficacious
than other vehicles. Besides the important role of specific factors
involved in the formulation of the spray, this greater efficacy may be
due to increased patient compliance with an odorless, easy to apply, low
residue, and elegant vehicle [
3,
16,
18].
In 1985, Stoughton and Cornell classified corticosteroids potency according to their vasoconstrictive properties [
3,
11,
17].
While in the USA there are seven potency groups, the UK considers four
classes: mild (class IV), moderately potent (class III), potent (class
II), and very potent (class I) [
3,
11,
19,
20].
Lower-potency
corticosteroids are particularly recommended to apply on the face,
groin, axillary areas, and in infants and children, whereas mid- and
higher-potency corticosteroids are commonly used as initial therapy on
all other areas in adults. Superpotent corticosteroids are mainly used
for stubborn, cutaneous plaques or lesions on the palms, soles, and/or
scalp [
11,
21,
22].
Regardless of the inexistence of studies to prove the assurance of
topical corticosteroid use on the scalp beyond 4 weeks, in general,
high-potency topical corticosteroids can be successfully and safely
used. The reason for that safety is possibly due to the presence of
dense vascularization and abundance of adnexal structures on the scalp
that minimize the possibility of tachyphylaxis and side effects such as
skin atrophy [
23,
24].
As
an initial therapy to achieve a faster improvement of lesions, in
clinical practice, potent and superpotent corticosteroids are often
used; however, they should not be used for more than 2 weeks and the
patient should be under close surveillance [
3,
11,
20,
25].
Psoriasis
is a clinically heterogeneous disease, and its individual presentation
can make the selection of the most appropriated treatment difficult. To
overcome the variable nature of the disease and also the several options
of treatment, there are currently two sets of guidelines from Germany [
22] and USA [
6]
available for the different forms of topical treatment, which allow = a
more effective therapy decision and to decide when patients move from
topical to systemic treatment [
7]. However, there are huge differences between recommendations from different countries [
7,
9]. While German guidelines [
22]
recommend a combination of topical steroids with salicylic acid (broad
combination is possible; care must be taken regarding steroid side
effects), USA guidelines [
6]
suggest the use of topical steroids as monotherapy in mild-to-moderate
psoriasis or in combination with other topical agents, UV light or
systemic agents in moderate-to-severe disease [
7].
3. Cutaneous Mechanisms of Action of Topical Corticosteroids
Psoriasis
is an autoinflammatory and in some aspects an autoimmune disease of the
skin. Both keratinocytes and leukocytes are actively involved in the
immunopathology of the disease. Neutrophils, plasmacytoid dendritic
cells (DCs), and CD11c
+ (myeloid) DCs are present in
psoriatic lesions as part of the innate immunity. Acquired immunity is
diverted towards a T helper 1 (T
h1) CD4
+ cells-mediated response producing IFN-
γ, TNF-
α, and interleukin-2 (IL-2), along with T cytotoxic (T
C) CD8
+ cells [
2]. Recently, T
h17 cells have been suggested to be involved in the pathogenesis of psoriasis synthesizing IL-17A, IL-17F, and IL-22. T
h17 cells' differentiation, proliferation, and survival are dependent on IL-6, TGF, IL-1
β, IL-23, and IL-21. Particularly, IL23 is important for the pathogenicity at later stages of T
h17
development. IL-23 and IL-12 share a common p40 subunit, which is
covalently linked to either a p35 or p19 subunit forming IL-12 or IL-23,
respectively. IL-23, secreted by activated myeloid dendritic cells,
will drive T-cell differentiation toward Th17 subset and also release
IL-12, inducing T
h1 differentiation [
26]. IL-17A leads to joint pathology due to its potential activity of inducing RANKL and its synergistic effect with IL-1
β and TNF-
α.
Th17 cells produce IL-22, which have potent keratinocyte proliferative
ability. IL-22, along with IL-17, induces STAT3 activation and
cytokine/chemokine production, showing that way, an important role in
the physiopathology of psoriasis. Anti-IL-17 monoclonal antibodies
(AIN457 and LY2439821) may be useful in patients with psoriasis and
autoimmune arthritis, as showed by successful experiments in animal
models. Further clinical trials with these anti-IL-17 monoclonal
antibody preparations in psoriasis and psoriatic arthritis are necessary
[
27].
Corticosteroids act in two different ways at the cellular level, divided into genomic and nongenomic pathways.
The
genomic pathway refers to the glucocorticoid receptor (GR) and to its
activation by cortisol, subsequent receptor homodimerization, and
binding to glucocorticoid-responsive elements (GREs). When the ligand is
absent, the glucocorticoid receptor accumulates in the cytoplasm
complexing with proteins, including the large heat shock proteins HSP90
and HSP70. But when the ligand binds to the receptor, this complex is
disrupted and the GR migrates to the nucleus. Upon dimerisation of GR
and binding to a palindromic promoter sequence, the glucocorticoid
response elements, the transcription of genes with anti-inflammatory
functions such as tyrosine amino transferase (TAT), phosphoenolpyruvate
carboxykinase (PEPCK), IL-10,
β-adrenergic receptor,
IL-1-receptor antagonist, and dual-specificity protein phosphatase 1
(DUSP-1) are promoted. GC negatively regulates the expression of
proinflammatory genes by transrepression, for example, cytokines, growth
factors, adhesion molecules, nitric oxide, prostanoids, and other
autacoids [
28]. Further, coactivators or corepressors help modifying the structure of chromatin, enabling the DNA transcription [
29]. The cortisol-glucocorticoid receptor complex may interact with nuclear factor-
κB leading to its transrepression (NF-
κB) [
30,
31]. The latter mechanism apparently requires lower cortisol levels than the mechanism involving the GRE [
32].
The
nongenomic pathway takes membrane-bound receptors and second messengers
into account, and it is responsible for the rapid effects of
glucocorticoids that occur in a few minutes. This pathway does not
require
de novo protein synthesis and acts by modulating the
level of activation and responsiveness of target cells, such as
monocytes, T cells, and platelets [
33,
34].
The glucocorticoid receptor is encoded by the
GR gene, localized to chromosome 5q31-32 locus [
32]. Posttranscriptional processing includes splicing of exon 9, yielding either
GRα mRNA or
GRβ mRNA [
35]. Glucocorticoid receptor
α isoform is responsible for the known actions of cortisol, whereas glucocorticoid receptor
β isoform appears to play a regulatory role. An increase of the
β/
α isoforms ratio in a cell generates glucocorticoid resistance [
36].
Glucocorticoids
possess numerous functions such as anti-inflammatory, antimitotic,
apoptotic, vasoconstrictive and immunomodulatory functions. These
properties are closely associated with their efficacy in the skin
disease treatment () [
37].
Anti-inflammatory, immunosuppressive, and vasoconstrictive effects of topical corticosteroids [
13,
14].
Anti-Inflammatory Properties —
The
inflammatory process is controlled by the glucocorticoids' activity,
enhancing the transcription of anti-inflammatory genes and decreasing
the transcription of inflammatory genes () [
15].
Action of glucocorticoids in gene transcription (adapted from [
15]).
Glucocorticoids
induce the expression of annexin A1 (also known as lipocortin 1;
encoded by ANXA 1) and ALXR (the annexin A1 receptor) by mechanisms
still not known. Annexin A1 is a protein mainly located on basal
keratinocytes of the basement membrane. Although in normal skin annexin
A1 has been identified within cytoplasm, in diseased skin the
intracellular localization of annexin A1 is apparently modified. In
lesional psoriatic skin, annexin A1 appears only in the cell membrane,
suggesting a translocation of the protein. This transition may occur to
promote the binding of annexin A1 to phospholipids, therefore reducing
the production of inflammatory prostanoids [
37].
Annexin A1 inhibits phospholipase A
2 (PLA
2),
thus blocking the synthesis of arachidonate-derived eicosanoids
(prostaglandins, prostacyclins, leukotrienes, and thromboxanes) [
32]. This blocking is furthered by the repression of glucocorticoid-mediated cyclooxygenase 2 transcription [
38–
41].
It remains unclear if the reduction of these substances levels come
first and then plaque resolution, or if the normalization of prostanoid
levels follows plaque clearance [
37].
Exogenous
and endogenous annexin A1 may regulate the innate immune cells
activities controlling its levels of activation. Annexin A1 signals
throw a formyl peptide receptor 2 (FPR2, ALXR in humans). Despite the
activation of ALXR singnalling can occur by the annexin A1 autocrine,
paracrine, and juxtacrine functions, the juxtacrine interaction seems to
be the mechanism by which the anti-inflammatory process occurs.
Concerning the innate response, it seems that the upregulation of the
annexin A1 expression by leukocytes induced by glucocorticoids may be
responsible for the inhibition of leukocytes response. Glucocorticoids
also increase the secretion of annexin A1 by macrophages and the annexin
A1 secreted by mast cells and monocytes, promotes the clearance of
apoptotic neutrophils by macrophages. Endogenous annexin A1 is also
released from apoptotic neutrophils and acts on macrophages promoting
phagocytosis and removal of the apoptotic cells. The ALXR may be one
mediator of this mechanism. Contrasting with the innate immunity, the
adaptive immune system seems to act in a different way. Activation of T
cells results in the release of annexin A1 and in the expression of
ALXR. Although, glicocorticoids may reduce the annexin A1 expression
within T-cell exposure as a consequence, there is an inhibition of
T-cell activation and T cells differentiate into T helper 2 [
42,
43].
Glucocorticoids induce expression of the MAPK
phosphatase 1 (MKP-1). MAPK phosphatase 1 owes its anti-inflammatory
properties to the interference in the MAPK pathway. MAPK phosphatase 1
dephosphorylates and hence further inactivates c-Jun (the terminal
kinase in the MAPK pathway). The inactivation of MAPKs and also of
MAPK-interacting kinase by MKP-1 is due to the inhibition of PLA
2 activity mediated by glucocorticoids [
32].
If
glucocorticoids induce MKP-1 to suppress the inflammation, it seems
that glucocorticoids resistance in some inflammatory diseases could be
related to defects in the expression, or function, of MKP-1. It has been
described in some inflammatory diseases that c-jun N terminal kinase
and p38 activities are increased, becoming possible targets for clinical
intervention. Possible mechanisms for glucocorticoids resistance may be
associated with a failure in the inhibition of c-jun N terminal kinase
and p38 because these kinases negatively regulate GR function. For
example, an initial defect in glucocorticoids-induced MKP-1
expression/activity might increase MAPK activity, thus impairing the GR
function. As a consequence of this failure, an increase in transcription
of proinflammatory genes, or in the instability of the mRNAs, may
occur. Alternative to the hyperactive MAPK pathway, a reduced number of
activated GR within the nucleus or a lack of interaction with the basal
transcription process may be a reason for steroid resistance. It can be
relevant, concerning the glucocorticoid tachyphylaxia, whether these
mechanisms can be implicated [
44,
45].
c-Jun
is a transcription factor recognized to form homodimers and
heterodimers with c-Fos, the latter combination resulting in the
activator protein 1 (AP-1). Both c-Jun homodimer and AP-1 heterodimer
are associated with transcription of inflammatory and immune genes.
There is also evidence of direct protein-protein interactions between
the glucocorticoid receptor and c-Jun homodimers and AP-1 heterodimers,
conferring to the nongenomic pathway of cortisol a large share of the
anti-inflammatory action of glucocorticoids [
31]. Other genomic mechanisms include the direct repression of the NF-
κB transcription factor by the glucocorticoid receptor. NF-
κB
binds to DNA and induces transcription of genes encoding cytokines,
chemokines, complement proteins, cell-adhesion, molecules and
cyclooxygenase 2 [
46], all associated with inflammation.
It
is unquestionable that the expression and activity of several cytokines
relevant to inflammatory diseases may be inhibited by treatment with
glucocorticoids. These cytokines include IL-1, IL-2, IL-3, IL-6, IL-11,
TNF-
α, GM-CSF, and chemokines that “call” inflammatory cells to
the site of inflammation, namely, IL-8, RANTES, MCP-1, MCP-3, MCP-4,
MIP-1
α, and eotaxin. Furthermore, the inflammatory process receptors, such as NK
1 and NK
2-receptors,
are involved in the transcription of genes coding for these mediated
inflammatory receptors by glucocorticoids activity. The glucocorticoids
suppressive effects are related with inhibition of cytokine gene
expression by inhibiting the transcription factors that regulate their
expression, rather than binding to their promoter regions [
15].
Regarding
genomic and nongenomic pathways, it seems that the nongenomic pathway
stands out powerful enough to mediate the anti-inflammation process by
itself. In an experiment, the
GR mouse gene was mutated so that the glucocorticoid receptor lost the ability to dimerize, and thus bind DNA. In these
GRdim/dim
mice, glucocorticoids were only allowed to act via the nongenomic
pathway. A phorbol 12-myristate 13-acetate- (PMA-) mediated ear edema
was then induced in both wild-type and
GRdim/dim
mice. Surprisingly, the edema was reduced in both strands of mice after
administration of dexamethasone. Additionally, dexamethasone suppressed
serum TNF-
α and IL-6, and lipopolysaccharide (LPS)-induced transcription of TNF-
α, IL-6, IL-1
β, and cyclooxygenase 2 genes in both wild-type and mutant mice [
47].
Nitric
oxide (NO) has a relevant function in multiple systems modeling
physiological and pathological processes in the skin, namely,
vasodilation, immunomodulation, inflammation, and oxidative damage to
cells and tissues. Thereby, NO represents another possible target for
glucocorticoids. The synthesis of NO is dependent of the nitric oxid
synthases (NOS), a family of enzymes with three isoforms, the
constitutive endothelial eNOS, neuronal nNOS, and the inducible iNOS.
While glucocorticoids restrain the induction of iNOS, they do not
produce any effect over eNOS and nNOS activity.
It is
thought that inhibition of NO by glucocorticoids occurs only in the
presence of high NO levels, caused by inflammatory substances such as
lipopolysaccharides or cytokines, in a similar way to the COX system.
The nitric oxide synthases' inhibitors appear to be related with the NO
role in erythema and oedema formation in psoriasis. Moreover, iNOS was
found in lesional psoriatic skin [
37,
48].
The
modulation of mast cell numbers and activity has been suggested as an
additional mechanism for the anti-inflammatory properties. These cells
have numerous pro-inflammatory mediators, as histamine and
prostaglandins, which are released, in response to mast cell
degranulation. Thereby, we may obtain an anti-inflammatory action by
inhibiting this mast cell reaction. The use of glucocorticosteroids
diminishes the number of mast cell in the skin, which is responsible for
reducing histamine content in the treated skin [
37,
49].
Antiproliferative Properties —
Another
beneficial action of the topical glucocorticoids is their antimitotic
activity, which has been suggested as providing positive results in the
treatment of psoriasis, where cell turnover rate of the skin is
substantially elevated. Studies on normal and psoriatic skin suggest
that topical glucocorticoids decrease the number of epidermal mitoses.
Dexamethasone may have an anti-proliferative effect over the A549 cell
line, which is associated with an increase of annexin A1 [
37].
It would be of interest to find out whether the antimitotic power of
glucocorticoids is caused by these effects on annexin A1 in order to
develop new therapeutic tools and diminish the skin thinning.
Apoptotic and Antiapoptotic Properties —
Eosinophils
and lymphocytes are also an aim of glucocorticoids therapy. These drugs
decrease the survival of both types of cells, leading to programmed
cell death or apoptosis. The apoptosis of eosinophils appears to be
related with a blockade of the IL-5 and GM-CSF effects, of which
eosinophils are dependent. On the contrary, glucocorticoids reduce
apoptosis and enhance neutrophils survival [
15].
Vasoconstrictive Properties —
Although
associated with an unclear mechanism, the vascular action has been
proposed to be part of the anti-inflammatory effects of glucocorticoids,
since there is a reduction in blood flow to the inflamed site.
Vasoconstriction, also termed “blanching,” when related to skin surface,
forms the basis of the standard assay for evaluation of the potency of
topical glucocorticoids [
37].
Immunosuppressive Properties —
The
regulation of several aspects of immune-cell function is also pertinent
to the cutaneous function of glucocorticoids, conferring an additional
benefit in treatment of dermal diseases. In addition to inhibiting
humoral factors involved in the inflammatory response and the leukocyte
migration to sites of inflammation, glucocorticoids interfere with the
function of endothelial cells, granulocytes, and fibroblasts. Therefore,
glucocorticoids commonly repress maturation, differentiation, and
proliferation of all immune cells, including DCs and macrophages.
Suppressing dendritic cells and macrophages, and consequently the
production of T helper 1-cell-inducing cytokine interleukin-12 (IL-12),
glucocorticoids generate a shift in adaptive immune responses from a T
h1 type to a T
h2 type. Furthermore, these drugs may amplify delayed-type hypersensitivity [
13].
3.1. Systemic Adverse Effects of Topical Corticosteroids
Considering
the broad array of interactions between glucocorticoids and specific
and nonspecific molecular targets within the cell (),
it is expectable that prescribing corticosteroids may produce a wide
range of undesirable adverse effects. This has led, in fact, to a
“steroid phobia” among patients [
50]. The adverse effects of glucocorticoids tend to be more severe with systemic rather than with topical treatment [
51].
Nevertheless, glucocorticoid topical therapy for cutaneous and
pulmonary (nasal administration) diseases is known to be associated with
systemic adverse reactions [
52,
53].
The
impaired barrier function in psoriatic skin facilitates the cutaneous
penetration of the topical corticosteroid independently from its
potency. The concomitant vasodilatation in psoriatic vessels increases
the possibility of topical corticosteroids to reach the systemic
vessels. A large extent of body surface and long-term use of topical
corticosteroids may conduct to a higher concentration of corticosteroids
in the blood, leading to systemic side effects. The risk of systemic
side effects associated with chronic topical corticosteroid use
increases with high-potency formulations.
As
anti-inflammation is one of the main goals in the treatment of
psoriasis, it should be noted that the lack of immune function, a state
of immunosuppression, brings about opportunistic infections that the
human organism would otherwise efficiently deal with. Among these, there
are infections caused by
Candida spp., or reinfections caused by previously latent virus, like
Cytomegalovirus [
51]. Endogenous hypercortisolism may also account for these infections [
54].
Overt cataract and glaucoma may also develop [
55,
56],
due to the effects that glucocorticoids have on the endocrine and
cardiovascular systems. Glaucoma is a consequence of an increased
intraocular pressure. Exogenous corticosteroids are not inactivated by
11
β-hydroxysteroid dehydrogenase, so they actually activate the mineralocorticoid receptor allowing ENaCs to increase serum Na
+ levels and causing hypertension [
57]. Other glucocorticoids cardiovascular adverse effects include a hypercoagulability state and dyslipidemia [
58,
59]. The correlation with the glucose metabolism is notorious, since glucocorticoids may aggravate previous diabetes mellitus [
51].
Indeed, the United States of America's National Health and Wellness
Survey (NHWS) identified psoriasis to be associated with cardiovascular
risk factors such as hypertension, hypercholesterolemia, and diabetes [
60]. Glucocorticoids promote hepatic gluconeogenesis [
51]. Glucose-6-phosphatase, a key enzyme in the gluconeogenesis pathway, is encoded by the
G6Pase gene. The
G6Pase
gene promoter includes a glucocorticoid-responsive element (GRE), this
way augmenting the gluconeogenesis rate after glucocorticoid receptor
activation [
61]. Glucocorticoids concomitantly generate iatrogenic Cushing's syndrome and adrenal insufficiency [
62].
High levels of glucocorticoids in the bloodstream imbalance the
hypothalamus-pituitary-adrenal axis equilibrium and suppress the ACTH
levels, as a result of a negative regulatory effect on ACTH release. It
leads to adrenal cortex atrophy and, thereafter, to complications like
hypogonadism, inhibition of growth, or osteoporosis [
51].
Osteoporosis is a serious complication of glucocorticoid treatment, particularly when affecting trabecular bone [
63].
The pathophysiology underlying osseous degradation is related to the
upregulation of the receptor activator of nuclear factor kappa-B ligand
(RANKL) mRNA by glucocorticoids, helping osteoclasts to differentiate
and therefore degrading bone. On the other hand, osteoprotegerin (OPG)
gene transcription is repressed [
51].
Myopathy
and muscle atrophy are also possible adverse effects of glucocorticoid
treatment. It was found that proteolysis is augmented in myocytes, due
to a glucocorticoid-mediated increase in the transcription of
genes-encoding proteins linked to the ubiquitin-proteasome pathway [
64].
Glucocorticoids may also aggravate previous psychiatric disorders [
65]. Accordingly, the NHWS places depression as a comorbidity significantly associated with psoriasis [
60].
3.2. Cutaneous Adverse Effects of Topical Corticosteroids
The
very first contact that the patient has with topical corticosteroids is
mostly through skin. Although corticosteroids help mitigate psoriatic
lesions, cutaneous side effects are numerous and not rare. Skin atrophy,
striae rubrae distensae and perturbed cicatrization are the most
common. Hypertrichosis, steroid acne, perioral dermatitis, erythema, and
telangiectasia may also occur. Erythema and telangiectasia together
with skin atrophy may lead to permanent rubeosis steroidica (). Hyperpigmentation is rarer than the above-mentioned adverse effects [
51].
Purpura, milia and rubeosis steroidica induced by superpotent topical corticosteroids.
Glucocorticoids-mediated
skin atrophy involves thinning of the epidermis and dermis (and even
hypodermis), resulting in increased water permeability and, thus, in
increased transepidermal water loss [
66,
67]. The thinning is caused by a decreased proliferative rate of keratinocytes and dermal fibroblasts [
68]. The origin of the decreased proliferation lies in collagen turnover. Transforming growth factor
β (TGF-
β) is a signaling molecule that, among other actions, promotes production of collagen, using Smad proteins as second messengers [
69]. Activated GR negatively regulates Smad3 through a protein-protein interaction, in this way, blocking expression of the
COL1A2 gene, which encodes a type I collagen chain [
70]. Type I collagen represents roughly 80% of the total share of skin collagen [
51]. Therefore, glucocorticoids reduce collagen turnover through blocking of TGF-
β actions. Coincidentally, TGF-
β plays a central role in the epithelial-to-mesenchymal transition (EMT), an essential mechanism for cicatrization [
71–
73]. Glucocorticoids also diminish synthesis of epidermal lipids [
67].
Furthermore, glucocorticoids reduce collagenases, which are part of the
matrix metalloproteinases (MMPs) and tissue inhibitors of the
metalloproteinases TIMP-1 and TIMP-2. Striae formation, which occurs in
hypercortisolism and may occur after long-term topical treatment with
glucocorticoids, may be explained by the skin tensile strength
determined by type I and type III collagens [
74–
77].
The thinning of epidermis caused by glucocorticoids' long-term topical
treatment appears also to be related with the repression of K5–K14
keratin genes, which are markers of the basal keratinocytes.
Additionally, these drugs inhibit K6–K16 keratin genes, markers of
activated keratinocytes, therefore promoting impaired wound healing.
Special
attention should be paid when applying topical corticosteroids in the
presence of an infection, as there is a risk of exacerbation. Topical
corticosteroids can inhibit the skin's ability to fight against
bacterial or fungal infections. A common example of this inhibition is
seen when a topical steroid is applied to an itchy groin rash. If this
is a fungal infection, the rash gets redder, itchier, and spreads more
extensively than a normal mycosis. The result is a tinea incognito, a
rash with bizarre pattern of widespread inflammation [
78].
Glucocorticoids'
adverse effects are an obstacle to psoriasis treatment. Abolishing
these reactions and at the same time maintaining glucocorticoids
efficacy has been a challenge to researchers. Selective glucocorticoid
receptor agonists (SEGRAs or, alternatively, dissociating
glucocorticoids), nitrosteroids, and liposomal glucocorticoids are under
development [
79]. To this date, we still rely on conventional glucocorticoids.
4. Bioavailability of Topical Corticosteroids
The
type of psoriasis and drug metabolism in the skin are the main factors
that influence bioavailability of topical corticosteroids.
Alterations
in the epidermal permeability barrier may contribute to psoriasis, as
evidenced by the enhanced transepidermal water loss. Recently, an
association between the gene of psoriasis and variations in the late
cornified envelope gene loci has been confirmed, establishing a relation
between an alteration of the permeability in the epidermis and the
pathogenesis of the disease [
80].
There is also the 500 Dalton rule for the skin penetration of chemical
compounds and drugs, which states that molecules above that weight are
not capable of crossing the stratum corneum [
81].
For instance, topical tacrolimus (802 Da) is not effective in chronic
plaque-type psoriasis but it is useful in psoriasis in the face or
intertriginous areas, in pustular psoriasis [
82], and when combined with descaling agents [
83–
86].
Skin acts as a barrier due to its physicochemical properties [
87]
and to the enzymes present in the keratinocytes (cytochrome P450
enzymes), which inactivate some topical corticosteroids and metabolize
others in more active substances [
88].
Corticosteroids are lipophilic and readily migrate through the cell
membrane to bind the corticoid receptor thus forming dimers, which then
migrate to the cell nucleus inducing the therapeutic effect by
regulating gene expression [
89].
Fluticasone propionate and methylprednisolone aceponate are very
lipophilic, and due to that they have an increased bioavailability; but
while the first one is hydrolyzed in an inactive substance, the last one
is hydrolyzed by cutaneous esterase's in a more active metabolite [
10].
One
of the most important points to achieve the success in treatment is to
choose the best corticosteroid formulation according to each patient.
There is an array of manufactured vehicles including creams, ointments,
lotions, foams, oils, gels, solutions, drops, shampoos, sprays, and
tape; the efficacy rates between them are roughly comparable [
90]. For example, scalp, foams, gels, or sprays may be more easy to apply, and so, a better result is expected.
The
vehicle has a therapeutic effect; scalp lipogel without active
ingredients showed response rates of over 20% in scalp psoriasis [
91].
Also a 15%–47% response to placebo was described with emollients in
psoriatic patients, but it is already known that hydration improves
signs and symptoms of psoriasis [
6,
21].
Ointments
are composed by more than 70%, of lipids, lipid-rich creams by 70% and
creams only 15% to 25%. In contrast to what was assumed, a recent study
with betamethasone with a low-lipid content formulation showed a higher
efficiency than high-lipid concentrated creams and ointments, confirming
the need of tailor therapies to individual patients and the impact of
bioavailability of specific components of the vehicles. We can add
specific ingredients to increase bioavailability; for instance,
propylene glycol is a percutaneous absorption enhancer of hydrocortisone
[
10].
The
volume of the prescription should be planned considering the frequency
and the effective dose; the fingertip unit is used as a pattern for the
topical agent required. Dressings are also used, enhancing the drug
delivery, and this choice depends on local availability and patient
preference [
92].
When
applied in a higher concentration, or multiple times a day, the levels
of a corticoid (triamcinolone acetonide) in the stratum corneum of the
skin, after 24 h, were the same as in a lower dose and a less frequent
application [
10].
Topical
treatments in psoriasis should be specific to each topographic region,
and steroids are absorbed at different rates in different parts of the
body as follows:
eyelids and genitals absorb 30%;
face absorbs 7%;
armpit absorbs 4%;
forearm absorbs 1%;
palm absorbs 0,1%;
sole absorbs 0,05%.
Vitamin D analogues and low-potency steroids in a cream base are indicated for psoriasis of the face or flexures [
93].
The scalp skin has very specific properties, it is covered by hair and
sebaceous glands are abundant; therefore, a large proportion of the drug
applied is wasted and adhered to the hair not having contact with the
scalp. New vehicles are proposed to improve the treatment of scalp
psoriasis such as calcipotriol-betamethasone dipropionate scalp lipogel [
91], clobetasol propionate and betamethasone valerate foam [
94], clobetasol propionate shampoo [
95], and clobetasol propionate 0.05% spray [
96].
Combined
treatments with different biological targets are already accepted,
usually having an additive or synergistic effect. These treatments act
by adding the effects on different targets (T-cell functions, innate
immunity, epidermal differentiation, and proliferation), reducing the
side effects and managing recalcitrant lesions. Topical therapies can be
used during the phase that the systemic treatment is suboptimal [
10].
5. New Combination Treatment of Topical Corticosteroids
Combination
therapy has emerged with the development of new noncorticosteroid
preparations, but before the merge we have to make sure that the two
combinations are compatible, synergistic, and safe. As an example,
calcipotriol is just compatible with tar gel and halobetasol propionate
preparations and it has a superior effect when combined with halobetasol
ointment. Halobetasol decreased the irritant dermatitis caused by
calcipotriol [
97,
98].
Also ammonium lactate is compatible with hydrocortisone valerate and
halobetasol propionate, and it has been shown to protect against skin
atrophy [
10,
99].
Salicylic
acid, vitamin D analogues and retinoids, with different mechanisms of
action, are usually combined with topical corticosteroids. Concerning
polytherapy versus fixed-dose combinations, the last one requires less
frequent applications and has a higher adherence from the patients.
5.1. Topical Vitamin D Analogues and Corticosteroids
These agents were found in the sequence of the discovery that oral vitamin D had a therapeutic effect on psoriatic plaques [
100].
While
vitamin D has mainly antiproliferative (epidermal) effects,
corticosteroids have mainly anti-inflammatory (dermal) effects.
The
vitamin D analogues correct epidermal hyperproliferation, abnormal
angiogenesis, and keratinization and induces apoptosis in inflammatory
cells by acting through vitamin D receptors present on keratinocytes and
lymphocytes. They also modulate the decrease of IL-1 and IL-6 levels,
the reducing of CD45RO and C8
+ T cells. They inhibit the epithelial cell growth by increasing transforming growth factor-
β1 and -
β2 levels [
101]. Many of these effects protect skin from the cutaneous atrophy caused by corticosteroids [
102].
Vitamin
D analogues and corticosteroids are the combining topical agents of
choice in psoriasis showing a superior efficacy when compared with
monotherapy [
20].
The
most common side effects are skin irritation, dryness, peeling,
erythema, and edema, which can occur in up to 35% of the patients.
Adverse effects will diminish along the time.
At the moment, three vitamin D analogues are approved for the treatment of psoriasis: calcitriol, calcipotriol, and tacalcitol.
The
corticosteroids effects can be diminished by administrating
calcipotriol 0.03% once daily in the morning plus betamethasone valerate
once daily in the evening [
103].
Calcipotriol
is the vitamin D analogue most widely accepted for the combination
therapy with corticosteroids, although not all corticosteroids can be
mixed with calcipotriol due to incompatibilities [
97].
A combined ointment with calcipotriol and betamethasone dipropionate is
already being used and showing good results, giving to the patient's
skin stability and optimal delivery of both substances. Cutaneous
atrophy caused by this ointment is similar to the corticosteroid alone
during a 4-week treatment period [
104,
105]. Recent data says that the combination has proved to be superior in efficacy than the individual components alone [
106].
This
combination of calcipotriol and betamethasone dipropionate is approved
for use in trunk and extremities, but it is not recommended for face,
intertriginous areas, and scalp. Although this combination has now been
developed as an oily lipogel indicated for scalp psoriasis, showing the
same efficacy, safety, and tolerability as the ointment [
91,
107].
5.2. Topical Salicylic Acid and Corticosteroids
Salicylic
acid is a topical keratolytic used in the treatment of a variety of
papulosquamous lesions such as psoriasis. Its mechanism of action is
still unclear, but it is believed to act by inducing disruption of
keratinocyte-keratinocyte binding and softening of the stratum corneum
by decreasing its pH [
108].
Salicylic
acid has a filtering effect reducing the efficacy of UVB therapy, so it
should not be applied before treatment. Due to scarce data, it should
not be applied during pregnancy [
3].
Usually, salicylic acid is safe; however, with long-term use in large skin areas, systemic salicylic acid toxicity can occur [
108].
Studies
with tritiated triamcinolone acetonide, desoximetasone, and
hydrocortisone 17-valerate showed that salicylic acid enhance the
efficacy of these corticosteroids by increasing their penetration in
skin. This faster penetration of corticosteroids in skin does not occur
when mixed with other ingredients such as camphor, menthol, phenol, or
urea.
Fixed-dose combinations such as
salicylic acid and betamethasone propionate or salicylic acid with
diflucortolone are already available in some countries and they show
similar efficacy. They both appear to be efficacious and well tolerated
during short-term period treatment of plaque psoriasis and their use is
recommended for limited areas of skin: for thick, scaly, and psoriatic
plaques [
10].
5.3. Topical Tazarotene and Corticosteroids
Tazarotene
was the first topic retinoid found to be effective for mild-to-moderate
psoriasis and it is available in cream or gel form.
Tazarotene
is a retinoid derivate which binds the retinoic acid receptor (RAR) in a
class-specific manner, preferentially binding RAR-
γ and RAR-
β than RAR-
α [
109].
This regulation of transcription result in reduced keratinocyte
proliferation, normalized keratinocyte differentiation, and decreased
inflammation. Its protective role against cutaneous atrophy from
corticosteroid induction, may be important already shown by the retinoid
tretinoin [
110].
This retinoid may cause skin irritation in up to 30% of users [
111],
and this irritation was more pronounced in patients receiving
tazarotene plus corticosteroids than in those receiving calcipotriol [
112].
Retinoids may reduce UVB tolerance, and tazarotene has proven to be more efficacious than UVB alone [
113].
As the systemic retinoids, tazarotene is contraindicated in pregnancy.
It
is not indicated to prescribe tazarotene mixed with corticosteroids.
Although tazarotene showed to be chemically compatible with a number of
topical corticosteroids, no experiment testing over two weeks of
treatment has been performed [
114].
7. Comments
Mild-to-moderate
psoriasis can be controlled with topical therapy; however, topical
therapy should be administrated with adjunctive therapy in severe and
extended psoriasis.
Glucocorticoid research is an
ongoing process with the development of hyperselective therapeutic
agents acting at different stages of the psoriasis inflammatory
response. One of the most desired targets of the new drugs is to induce
selective transrepression. The development of selectivity in a molecular
level may bear less on efficacy.
Tachyphylaxis is the
rapidly decreasing response to topical corticosteroids. After corrected
and sustained use of topical steroids, the capillaries in the dermis do
not constrict as well as before, requiring higher doses or more
frequent applications of steroids to achieve the former results. The
ability of the blood vessels to constrict as before eventually returns
to normal after stopping therapy. The common and known clinical
perception of tachyphylaxis may also be significantly related to issues
of compliance outside the study group, or to vessels flare unrelated to
therapy. Du Vivier and Stoughton, in 1975, were the first describing the
persistence and recurrence of psoriasis in patients who were previously
treated with topical corticosteroids with a successful result [
121]. The question remains if this is a truly clinical entity or if it is just due to a nonadherence to the topical regimen.
Rebound
caused by abruptly withdrawal, or ending of steroid therapy by the
individual him/herself, can result in sudden worsening of psoriasis.
Furthermore, the psoriasis may return more aggressively. A localized or a
mild form of psoriasis may become generalized, or a generalized form
can be precipitated as pustular or erythrodermic form, when patients do
not wean gradually off of corticosteroids.
The
treatment should be tailored in an individual manner, prescribing to
each patient the most suitable vehicle. Despite ointments being
clinically more effective in psoriasis symptoms, what really matters is
the desire of the patient, and the way he/she adheres to the topical
treatment.
Each patient will adhere “better” to a
different vehicle, some will prefer ointments, others gel or spray, and
others will prefer occlusion therapy.
Tight
supervision during the treatment with topical corticosteroids by giving
support and answers to patient concerns must be provided, and this can
make the difference between a successful treatment and a worsening of
the disease.
