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Interleukin-17 inhibitors. A new era in treatment of psoriasis and other skin diseases.

ABSTRACT: Psoriasis is a chronic skin disease caused by the excessive secretion of inflammatory cytokines. Available therapeutic options include biologic drugs such as tumor necrosis factor alpha inhibitors and interleukin 12/23 (IL-12/23) inhibitors. The recent discovery of IL-17, which contributes to development of psoriasis, opened new possibilities for further treatment modalities. Currently, one anti-IL17 biological agent is approved for the treatment - a fully human monoclonal antibody that targets IL-17A (secukinumab). Further clinical trials, including a humanized IgG4 specific for IL-17 (ixekizumab) and a fully human antibody that targets the IL-17 receptor A (brodalumab).

SUBMITTER: Wasilewska A

PROVIDER: S-EPMC5004212 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Interleukin-17 inhibitors. A new era in treatment of psoriasis and other skin diseases.

Wasilewska Agnieszka A Winiarska Marta M Olszewska Małgorzata M Rudnicka Lidia L

Postepy dermatologii i alergologii 20160816 4

Psoriasis is a chronic skin disease caused by the excessive secretion of inflammatory cytokines. Available therapeutic options include biologic drugs such as tumor necrosis factor alpha inhibitors and interleukin 12/23 (IL-12/23) inhibitors. The recent discovery of IL-17, which contributes to development of psoriasis, opened new possibilities for further treatment modalities. Currently, one anti-IL17 biological agent is approved for the treatment - a fully human monoclonal antibody that targets ...[more]

PMID: 27605893

Similar Datasets

Inflammatory bowel disease in patients with psoriasis treated with interleukin-17 inhibitors.

Project description:Background:Interleukin 17 (IL-17) inhibitors provide an excellent treatment option for patients with psoriasis and psoriatic arthritis, resulting in high levels of efficacy for skin clearance and joint improvement. Safety has also been established in clinical trials for this group of biologic agents; however, rare case reports of exacerbation or induction of inflammatory bowel disease (IBD) have been reported in the literature. No causal relationship has been established. When IL-17 inhibitors were investigated for the management of IBD, no benefit was found and worsening of disease was noted for some patients. IBD is more common in patients with psoriasis and, therefore, it remains unknown if these drugs cause de novo IBD or if the reported cases of IBD in patients on IL-17 therapy is due to the background risk in this predisposed population who may have already had an underlying or subclinical disease. Methods/Results:A literature search was conducted for the terms 'IL-17 inhibitor,' 'ixekizumab,' 'secukinumab,' 'brodalumab' and 'inflammatory bowel disease,' 'ulcerative colitis,' and 'Crohn's disease' in PubMed and Google Scholar. Cases of new-onset or exacerbation of IBD were identified in the literature along with postmarketing pharmacovigilance data. These cases will be reviewed in this paper. Conclusions:IL-17 inhibitors have proven efficacy for the treatment of psoriasis and psoriatic arthritis with a strong safety profile. However, rare cases of IBD onset and exacerbation in patients on IL-17 inhibitors have been reported in the literature, highlighting the need to select patients and therapeutic choices appropriately when treating this population.

| S-EPMC7185907 | biostudies-literature

Interleukin-17 Inhibitors for the Treatment of Ankylosing Spondylitis.

Project description:Tumor necrosis factor inhibitor (TNFi) has been applied in the treatment of ankylosing spondylitis (AS) for many years but still with an unmed need due to inefficacy or intolerance. Current treatment guideline recommended the use of IL-17 inhibitors over a second TNFi in patients with primary nonresponse to the first TNFi. We herein review the present available IL-17 inhibitors including secukinumab (SEC), ixekizumab (IXE), brodalumab and bimekizumab (BKZ) in clinical trials of AS. Therapeutic response and safe profile have been discussed in detail for each drug. Overall, IL-17 inhibitors were proved to be alternatives for biologic disease-modifying anti-rheumatic drugs (bDMARDs) in AS, which might be safer for tuberculosis while candida infection should be monitored in long term treatment.

| S-EPMC9524761 | biostudies-literature

Psoriasis: Association of interleukin-17 gene polymorphisms with severity and response to treatment.

Project description:Psoriasis is a chronic, inflammatory disease with a complex pathogenesis that is not yet fully understood. Although it is a multifactorial disease, the genetic factor has a major role in the pathogenesis of psoriasis. Genome wide association studies have identified over 50 genetic loci associated with psoriasis risk. Beside TNF-α or IL-23, the IL-17 family is a newer group that has proven implications in the pathogenesis of psoriasis. The most important members of the family, with pro-inflammatory qualities, are IL-17A and IL-17F. These interleukins are produced by a varied number of cells, but by far the most important are Th17 cells. Of the patients 20-30% present moderate-to-severe psoriasis, therefore, systemic medication (phototherapy, methotrexate, cyclosporine, acitretin or biologic agents) is mandatory. The necessity of an individualized treatment plan, for each patient, is imperative in order to establish the best strategy for non-responders to classical treatment or to other biologic treatments. The discovery of Th17 pathway improved the treatment and prognosis of psoriasis. Anti-psoriatic agents against IL-17 or its receptors are a novel group of biologic agents; these include ixekizumab, secukinumab and brodalumab. Polymorphisms of IL-17 family have been correlated with the severity and response to treatment in psoriasis, and also with the risk of inflammatory, infectious, autoimmune or neoplastic pathologies. The significant difference in the presence or absence of susceptibility loci in different population is due to genetic background and environmental factors that have a major impact on disease predisposition. In this study, we reviewed the importance and influence of the IL-17 polymorphisms as predictors of response to treatment and severity of the disease.

| S-EPMC6639965 | biostudies-literature

Increased expression of interleukin-17 pathway genes in nonlesional skin of moderate-to-severe psoriasis vulgaris.

Project description:BackgroundPsoriasis vulgaris is an inflammatory immune-mediated disease, with lesional skin characterized by sharply demarcated, erythematous scaly plaques. Uninvolved psoriatic skin appears clinically similar to normal skin. However, it has been hypothesized that inflammatory cytokines, e.g. interleukin (IL)-17, may affect any organ or tissue having a vascular supply; thus, distant uninvolved skin could be exposed to increased circulating IL-17.ObjectivesTo establish comparative genomic profiles between noninvolved skin and normal skin, in particular, determining immune abnormalities in distant uninvolved skin.MethodsWe performed a meta-analysis on three gene array studies, comparing the nonlesional (NL) psoriatic skin transcriptome with normal gene expression. We investigated immunological features of noninvolved skin, particularly linked to IL-17 signalling.ResultsWe detected 252 differentially expressed gene transcripts in uninvolved skin compared with normal skin; multiple immune-related genes, including IL-17-downstream genes, were upregulated. Increased expression of IL-17-signature genes (e.g. DEFB4 and S100A7) was associated with an increased number of CD3+, CD8+ and DC-LAMP+ cells in NL skin vs. normal controls. Inducible T-cell costimulator (ICOS) expression was detected only in a few T-cells within NL skin.ConclusionsOur data described the genomic profile in NL skin, characterizing the immune activation that was mainly attributed to IL-17 signalling.

| S-EPMC4720589 | biostudies-literature

Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation

Project description:To understand the overall function of IL-17RD and IL-17RC in IL-17A signaling, RNAseq was performed with WT, Il17rc KO, and Il17rd KO primary mouse keratinocytes following IL-17A treatment along with untreated WT control. Keratinocyte from neonatal WT, Il17rd KO, and Il17rc KO mice were cultured and stimulated with IL-17A (100 ng/mL, PeproTech) for 8h.

2019-04-17 | GSE129176 | GEO

Interleukin 23 in the skin: role in psoriasis pathogenesis and selective interleukin 23 blockade as treatment.

Project description:Plaque psoriasis is one of the most common autoimmune skin diseases and is characterized by erythematous, scaly plaques. Many highly effective, targeted therapies have been developed as a result of an improved understanding of the pathogenesis of psoriasis. Using agents that target the central interleukin (IL)-23/IL-17 immune axis, this once difficult-to-treat disease is now among the most effectively treated autoimmune diseases with major clinical improvements possible in around 90% of patients. In this article, we outline the immune mechanisms responsible for the development of psoriasis and provide an overview of the novel IL-23 antagonists being used to manage this chronic skin disease.

| S-EPMC5956648 | biostudies-literature

Sequential interleukin-17 inhibitors for moderate-to-severe plaque psoriasis who have an IL-17 inhibitors failure in a resource limited country: An economic evaluation.

Project description:BackgroundBiologics has been known to be effective for patients with psoriasis. However, optimal treatment pathways and their cost-effectiveness are limited in a resource-limited country. This study assessed the cost-effectiveness of different sequential biologics for moderate-to-severe plaque psoriasis.MethodA hybrid model from a societal perspective was used. Model inputs were derived from network meta-analysis, clinical trials, and published literature. Three different sequential biologic treatments were assessed; Sequence 1; 1st Interleukin-17 (IL-17) inhibitor (secukinumab) followed by 2nd IL-17 inhibitors (ixekizumab or brodalumab), then 3rd IL-23 inhibitor (guselkumab), Sequence 2; ixekizumab followed by secukinumab or brodalumab, then guselkumab, and Sequence 3; brodalumab followed by ixekizumab or secukinumab, then guselkumab. Methotrexate or ciclosporin was used as standard of care (SoC).ResultsAll three different sequential biologic therapies could gain total quality-adjusted life year (QALY), but they had higher cost than SoC. Sequence 1 had the lowest incremental cost-effectiveness ratio (ICER) compared to SoC at 621,373 THB/QALY (19,449 $/QALY). ICER for Sequence 2 was 957,258 THB/QALY (29,962 $/QALY), while that for Sequence 3 was 1,332,262 THB/QALY (41,700 $/QALY). Fully incremental analysis indicated that Sequence 3 was dominated by Sequence 1 and Sequence 2. ICER for Sequence 2 was 7,206,104 THB/QALY (225,551 $/QALY) when compared to Sequence 1.ConclusionAt the current willingness-to-pay of 160,000 THB/QALY, no sequential IL-17 inhibitor was cost-effective compared to SoC. Secukinumab followed by ixekizumab or brodalumab then guselkumab (Sequence 1) may be the most appropriate option compared with other treatments.

| S-EPMC11315331 | biostudies-literature

Interleukin-17 in Chronic Inflammatory Neurological Diseases.

Project description:A critical role for IL-17, a cytokine produced by T helper 17 (Th17) cells, has been indicated in the pathogenesis of chronic inflammatory and autoimmune diseases. A positive effect of blockade of IL-17 secreted by autoreactive T cells has been shown in various inflammatory diseases. Several cytokines, whose production is affected by environmental factors, control Th17 differentiation and its maintenance in tissues during chronic inflammation. The roles of IL-17 in the pathogenesis of chronic neuroinflammatory conditions, multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), Alzheimer's disease, and ischemic brain injury are reviewed here. The role of environmental stimuli in Th17 differentiation is also summarized, highlighting the role of viral infection in the regulation of pathogenic T helper cells in EAE.

| S-EPMC7283538 | biostudies-literature

Unprocessed Interleukin-36α Regulates Psoriasis-Like Skin Inflammation in Cooperation With Interleukin-1.

Project description:Generalized pustular psoriasis is a severe skin disease characterized by epidermal hyperplasia, neutrophil-rich abscesses within the epidermis, and a mixed inflammatory infiltrate in the dermis. The disease may be caused by missense mutations in the IL-36 receptor antagonist, IL-36Ra. Curiously, the related IL-1Ra has therapeutic effects in some of these latter patients. Here, using an experimental mouse model of psoriasiform skin inflammation, we demonstrate in vivo connections between IL-36 and IL-1 expression. After disease initiation, IL-36α-deficient mice exhibited dramatically diminished skin pathology, including absence of epidermal neutrophils, reduced keratinocyte acanthosis, and less dermal edema. In contrast, IL-36β and IL-36γ knockout mice developed disease indistinguishable from that of wild-type mice. The endogenous IL-36α was not processed through proteolysis. Although IL-36α expression was strongly induced in an IL-1 signaling-dependent manner during disease, expression of IL-1α was also dependent upon IL-36α. Hence, after being upregulated by IL-1α, IL-36α acts through a feedback mechanism to boost IL-1α levels. Analyses of double knockout mice further revealed that IL-36α and IL-1α cooperate to promote psoriasis-like disease. In conclusion, IL-1α and IL-36α form a self-amplifying inflammatory loop in vivo that in patients with insufficient counter regulatory mechanisms may become hyper-engaged and/or chronic.

| S-EPMC4648684 | biostudies-literature

Signalling of multiple interleukin (IL)-17 family cytokines via IL-17 receptor A drives psoriasis-related inflammatory pathways.

Project description:BackgroundThe interleukin (IL)-23/IL-17 immune axis is of central importance in psoriasis. However, the impact of IL-17 family cytokines other than IL-17A in psoriasis has not been fully established.ObjectivesTo elucidate the contribution of IL-17 family cytokines in psoriasis.MethodsTo address the expression and localization of IL-17 family cytokines, lesional and nonlesional skin samples from patients with psoriasis were analysed by several complementary methods, including quantitative polymerase chain reaction, immunoassays, in situ hybridization and immunohistochemistry. Mechanistic studies assessing the functional activity of IL-17 family cytokines were performed using ex vivo cultured human skin biopsies and primary human keratinocytes.ResultsWe demonstrated that IL-17A, IL-17F, IL-17A/F and IL-17C are expressed at increased levels in psoriasis lesional skin and induce overlapping gene expression responses in ex vivo cultured human skin that correlate with the transcriptomic signature of psoriasis skin. Furthermore, we showed that brodalumab, in contrast to ixekizumab, normalizes gene expression responses induced by the combination of IL-17A, IL-17F, IL-17A/F and IL-17C in human keratinocytes.ConclusionsSeveral IL-17 ligands signalling through IL-17RA are overexpressed in psoriasis skin and induce similar psoriasis-related inflammatory pathways demonstrating their relevance in relation to therapeutic intervention in psoriasis.

| S-EPMC8453543 | biostudies-literature

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