The mechanism of action of corticosteroids in psoriasis is not fully understoodThe different presentations of psoriasis require different approaches to treatment and appropriate prescriptions according to disease severity. The use of topical therapy remains a key component of the management of almost corticosteroids mechanism of action psoriasis psoriasis patients, and while mild disease is commonly treated only with topical agents, the use of stanozolol clenbuterol cycle therapy as adjuvant therapy in moderate-to-severe disease may corticosteroids mechanism of action psoriasis be helpful. This paper focuses on the cutaneous mechanisms of action of corticosteroids and on the currently available topical treatments, taking into account adverse effects, bioavailability, new combination treatments, and strategies to improve the safety of corticosteroids. National Center for Biotechnology InformationU. Didn't get the psorjasis
Mechanisms of action of topical corticosteroids in psoriasis. - PubMed - NCBI
Professor Egas Moniz, Lisbon, Portugal. The different presentations of psoriasis require different approaches to treatment and appropriate prescriptions according to disease severity. The use of topical therapy remains a key component of the management of almost all psoriasis patients, and 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.
This paper focuses on the cutaneous mechanisms of action of corticosteroids and on the currently available topical treatments, taking into account adverse effects, bioavailability, new combination treatments, and strategies to improve the safety of corticosteroids.
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 ].
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 Figure 1 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 therapies available for mild-to-moderate psoriasis involve a great number of different agents, including [ 3 , 7 , 8 ].
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 ].
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 ].
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 Table 1 [ 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 , Stoughton and Cornell classified corticosteroids potency according to their vasoconstrictive properties [ 3 , 11 , 17 ]. 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.
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.
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 ].
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.
Particularly, IL23 is important for the pathogenicity at later stages of T h 17 development. IL and IL share a common p40 subunit, which is covalently linked to either a p35 or p19 subunit forming IL or IL, respectively. IL, secreted by activated myeloid dendritic cells, will drive T-cell differentiation toward Th17 subset and also release IL, inducing T h 1 differentiation [ 26 ].
Th17 cells produce IL, which have potent keratinocyte proliferative ability. Anti-IL monoclonal antibodies AIN and LY 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 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 HSP But when the ligand binds to the receptor, this complex is disrupted and the GR migrates to the nucleus.
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 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 5q locus [ 32 ]. 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 Figure 2 [ 37 ].
Anti-inflammatory, immunosuppressive, and vasoconstrictive effects of topical corticosteroids [ 13 , 14 ]. The inflammatory process is controlled by the glucocorticoids' activity, enhancing the transcription of anti-inflammatory genes and decreasing the transcription of inflammatory genes Figure 3 [ 15 ]. Action of glucocorticoids in gene transcription adapted from [ 15 ]. 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. 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.
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 ]. 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 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. 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 ]. 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 ].
It is unquestionable that the expression and activity of several cytokines relevant to inflammatory diseases may be inhibited by treatment with glucocorticoids. 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.
Surprisingly, the edema was reduced in both strands of mice after administration of dexamethasone. 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. 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 ]. 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 A 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. 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. On the contrary, glucocorticoids reduce apoptosis and enhance neutrophils survival [ 15 ].
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.