Psoriasis pathogenesis and the development of novel targeted immune therapies.
ABSTRACT: Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell-mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a "feed forward" inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management.
Project description:Psoriasis, an inflammatory skin disease, and psoriatic arthritis (PsA), an inflammatory arthritis, share clinical, genetic, and pathogenic factors and may be summed as one disease, the psoriatic disease. Interleukin (IL)-17 plays a major role in the development of both psoriasis and PsA. IL-23 is important in the proliferation and maintenance of IL-17, and therefore, cytokines of the IL-23/IL-17 axis attracted much interest as therapeutic targets in psoriasis and PsA. Therapeutic agents targeting the IL-23/IL-17 axis have been proven to be very effective in psoriasis and PsA, some are already in the therapeutic armamentarium and others are in the development. Some agents, target IL-23 and others IL-17 and include anti-IL-12/IL-23 p40 (ustekinumab, briankizumab), anti-IL-23p19 (guselkumab, tildrakizumab, risankizumab, brazikumab, mirikizumab), anti-IL-17A (secukinumab, ixekizumab), dual anti-IL-17A and anti-IL-17F (bimekizumab), or anti-IL-17 receptor (brodalumab) monoclonal antibodies. Janus tyrosine kinase(JAK) inhibitors also directly affect IL-23 and, thus, IL-17. After the first-generation pan-JAK inhibitors have been shown efficacy (tofacitinib, baricitinib), new-generation selective JAK inhibitors (filgotinib, upadacitinib) are under investigation in psoriasis and PsA.
Project description:Psoriasis is a chronic, inflammatory, immune-mediated skin condition that affects 3 to 4% of the adult US population, characterized by well-demarcated, erythematous plaques with silver scale. Psoriasis is associated with many comorbidities including cardiometabolic disease and can have a negative impact on quality of life. The current armamentarium of psoriasis treatment includes topical therapies, phototherapy, oral immunosuppressive therapies, and biologic agents. Over the past 2 decades, there has been rapid development of novel biologic therapies for the treatment of moderate-to-severe plaque psoriasis. This article will review the role of IL-12, IL-23, and IL-17 in the pathogenesis of psoriasis and the monoclonal antibodies (ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, and risankizumab) that target these cytokines in the treatment of this disease.
Project description:INTRODUCTION:New generation biologics, including interleukin (IL)-17 and IL-23 inhibitors, have delivered higher rates of skin clearance than older treatments in head-to-head studies. However, studies comparing these new biologics directly to one another are limited. OBJECTIVES:To compare the short-term efficacy of available (or imminently available) biologic and non-biologic systemic therapies for treating patients with moderate-to-severe plaque psoriasis. METHODS:A systematic review was undertaken to identify randomised controlled trials evaluating biologic treatments, apremilast and dimethyl fumarate. MEDLINE, MEDLINE In-Process, Embase and the Cochrane Library were searched from the 1st January 2000 to 22nd November 2018. A Bayesian network meta-analysis (NMA) using a random-effects multinomial likelihood model with probit link and meta-regression to adjust for cross-trial variation in placebo responses compared the efficacy of interventions at inducing different levels of Psoriasis Area and Severity Index (PASI) response during the induction period. A range of sensitivity analyses was undertaken. RESULTS:Seventy-seven trials (34,816 patients) were included in the NMA. The base-case analysis showed that all active treatments were superior to placebo. IL-17 inhibitors, guselkumab and risankizumab were found to be more efficacious than tildrakizumab, ustekinumab, all TNF inhibitors and non-biologic systemic treatments at inducing all levels of PASI response. In addition, brodalumab, ixekizumab and risankizumab were significantly more efficacious than secukinumab; no significant difference was found in the comparison with guselkumab. The greatest benefit of brodalumab, ixekizumab, guselkumab, and risankizumab was seen for PASI 90 and PASI 100 response. Results were consistent across all analyses. CONCLUSIONS:In the NMA brodalumab, ixekizumab, risankizumab and guselkumab showed the highest levels of short-term efficacy. There were differences in efficacy between treatments within the same class. Longer-term analyses are needed to understand differences between these drugs beyond induction in what is a life-long condition.
Project description:INTRODUCTION:Rapid improvement of psoriasis is valued by patients and should be considered to be an important factor in treatment selection. We investigated Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) response rates within the first 12 weeks of treatment to compare the rapid response of 11 biologic therapies for moderate-to-severe psoriasis using Bayesian and Frequentist network meta-analyses (NMA). METHODS:A systematic literature review was conducted to identify phase 3, double-blind, randomized, controlled trials for adult patients with moderate-to-severe psoriasis treated with interleukin (IL)-17 (brodalumab, ixekizumab, secukinumab), IL-12/-23 (ustekinumab), IL-23 (guselkumab, risankizumab, tildrakizumab), or tumor necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, infliximab). Outcome measures extracted from 32 publications were ? 75, ? 90, or 100% improvement in PASI score (PASI? 75,?PASI?90, or PASI 100, respectively) at weeks 2, 4, 8, and 12 and DLQI (0,1), where score (0,1) indicates no effect on patient's life, at week 12. Bayesian NMA (BNMA) used fixed-treatment effect and random-baseline effect, normal independent models. Frequentist NMA (fNMA) was conducted as sensitivity analyses to test the robustness of the findings. RESULTS:Based on BNMA and fNMA, brodalumab and ixekizumab showed the most rapid treatment effects on PASI 75 at weeks 2, 4, and 8 and on PASI 90 and PASI 100 at weeks 2, 4, 8, and 12; ixekizumab overlapped with risankizumab on PASI 75 at week 12. Brodalumab, ixekizumab, and secukinumab yielded higher DLQI (0,1) gains at week 12 compared to all of the other biologics studied. Additional measures of quality of life were not assessed in this report. CONCLUSIONS:Ixekizumab and brodalumab provide the most rapid response and earliest clinical benefit at week 2 among all of the biologics studied, including other biologic treatments such as secukinumab, ustekinumab, guselkumab, adalimumab, and etanercept. BNMA and fNMA results showed similar relative effect estimates and treatment rankings. FUNDING:Eli Lilly and Company.
Project description:Background:The role of interleukin-12 (IL-12), interleukin-23 (IL-23), and interleukin-17 (IL-17) has been recognized in psoriasis pathogenesis, and new drugs targeting this axis have already been developed which may provide a new therapeutic approach for patients with moderate to severe psoriasis. Objective:To compare the direct and indirect evidences of the efficacy and safety of brodalumab, secukinumab, ixekizumab, ustekinumab, guselkumab, tildrakizumab, and risankizumab in the short-term treatment of moderate to severe plaque psoriasis using network meta-analysis (NMA). Methods:A comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for the available relevant studies. NMA was conducted by Stata 15.0 software using relative risks (RR) with 95% confidence interval to assess the clinical effectiveness and safety. Ranked the efficacy and safety for each drug accordance with the surface under the cumulative ranking curve (SUCRA). Results:This meta-analysis included 28 studies. All the interventions performed better than placebo in short-term achievement. Based on the result of SUCRA, ixekizumab 80?mg every 2 weeks ranked the highest in short-term achievement of PASI 75 (SUCRA?=?93.0%). Brodalumab 210?mg ranked the highest in short-term achievement of PASI 100 (SUCRA?=?85.0%). Secukinumab 300?mg ranked the highest in short-term achievement of sPGA 0/1 or IGA 0/1 or PGA 0/1 (SUCRA?=?98.1%). In terms of having a risk of adverse events, the rates were higher in brodalumab, secukinumab, ixekizumab, and ustekinumab 45?mg compared with placebo. Ixekizumab 80?mg every 4 weeks ranked the highest in the risk of adverse events during short-term treatment (SUCRA?=?4.5%). Guselkumab 50?mg ranked the highest in the risk of serious adverse events during short-term treatment (SUCRA?=?25.9%). Ixekizumab 80?mg every 4 weeks ranked the highest in the risk of discontinuations due to adverse events during short-ter treatment (SUCRA?=?10.7%). Conclusions:IL-17, IL-12/23, and IL-23 inhibitors had high efficacy in the achievement of PASI 75, PASI 100, and sPGA 0/1 or IGA 0/1 or PGA 0/1 in moderate to severe plaque psoriasis after 12 or 16 weeks of treatment. IL-17 inhibitors showed superior efficacy. However, its clinical safety was poor. Risankizumab appeared to have relatively high efficacy and low risk. The clinical tolerance of other biological agents needs to be further observed.
Project description:Psoriasis is a chronic disease that requires long-term treatment. Consequently, understanding the safety and tolerability of any potential treatment over time is critical to effective prescribing. The biologic agents currently available for the treatment of psoriasis target a number of different inflammatory cytokines involved in psoriasis disease pathogenesis. The monoclonal antibodies tildrakizumab, guselkumab and risankizumab target the p19 subunit that is specific to interleukin (IL)-23. This article reviews published data on the safety of these IL-23p19 inhibitors in patients with psoriasis compared with other currently available biologic therapies. Data from randomized, placebo- and active-controlled phase 3 clinical trials show tildrakizumab, guselkumab and risankizumab to have a favourable risk-benefit profile in patients with moderate to severe psoriasis. No significant safety concerns have been observed for any of these IL-23p19 inhibitors in the data published to date. The most commonly reported adverse events (AEs) associated with these agents in phase 3 studies were upper respiratory tract infections. No increase was seen in rates of serious infections, malignancies or major adverse cardiovascular events, with no signals suggestive of an elevated risk of opportunistic infections, active tuberculosis or reactivation of latent tuberculosis infection, mucocutaneous Candida infections, triggering or worsening of inflammatory bowel disease, demyelinating disorders or suicidal ideation. Selectively targeting IL-23p19 may help avoid AEs that have been associated with biologic agents with other mechanisms of action. Data from long-term extension studies and patient registries will further establish the safety profile of IL-23p19 inhibitors for the treatment of moderate to severe psoriasis in routine practice.
Project description:The development of several highly effective biologic drugs in the past decade has revolutionized the treatment of moderate-to-severe plaque psoriasis. With increased understanding of the immunopathogenesis of psoriasis, the emphasis has turned toward more specific targets for psoriasis drugs. Although the complex immunological pathway of psoriasis is not yet completely understood, current models emphasize the significant importance of interleukin (IL)-23 and IL-17. Several biologic drugs targeting these cytokines are now in various stages of drug development. Drugs targeting IL-23 include BI-655066, briakinumab, guselkumab, tildrakizumab, and ustekinumab. Drugs targeting IL-17 include brodalumab, ixekizumab, and secukinumab. While many of these have shown safety and good efficacy in clinical trials of moderate-to-severe plaque psoriasis, long-term safety is still to be established.
Project description:OBJECTIVE:The aim of this study was to evaluate the budget impact of introducing tildrakizumab for moderate-to-severe plaque psoriasis from a US health plan perspective. METHODS:A budget impact model estimated costs before and after the adoption of tildrakizumab to a hypothetical US health plan with 1 million covered lives over 5 years. Additionally, the model included adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, secukinumab, ustekinumab, and apremilast; biosimilars were not included. Model input data were obtained from the published literature, clinical trials, and prescription data. Market uptake for tildrakizumab was assumed as 1% annually over 5 years. Patients initiating or switching treatments required induction dosing; all others treated required maintenance dosing. The model compared the total annual costs for tildrakizumab versus treatment without tildrakizumab to calculate budget impact in 2018 US dollars. Scenarios exploring alternative assumptions for adverse events and market uptake rates were assessed, and a one-way sensitivity analysis was conducted. RESULTS:Within a health plan of 1 million members with an estimated 1048 patients receiving biologics or apremilast for psoriasis, the total annual health plan cost after introducing tildrakizumab decreased by $5585, $137,025, $205,538, $274,051, and $342,563 in years 1-5, respectively, resulting in a cumulative reduction of $964,763 over 5 years. The impact on total cost was largely due to drug acquisition costs. The incremental per member per month (PMPM) cost reductions were negligible in year 1, $0.01 in year 2, $0.02 in years 3-4, and $0.03 in year 5. Scenario and sensitivity analyses confirmed the model robustness. CONCLUSIONS:The introduction of tildrakizumab with a 1% annual uptake over 5 years has the potential to reduce the cost of treating patients with moderate-to-severe plaque psoriasis for a US health plan.
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.
Project description:<h4>Introduction</h4>A range of treatments are available for moderate-to-severe psoriasis; however, there remains a paucity of direct comparisons of these in head-to-head trials. Network meta-analyses (NMA) allow comparisons of these to support clinical decision making. This systematic literature review assesses the methodological quality of NMAs available for moderate-to-severe psoriasis and compares their methods and results. Their validity and applicability for current practice is also assessed.<h4>Methods</h4>A systematic review of published NMAs of at least two biologics for moderate-to-severe psoriasis was undertaken. Embase, MEDLINE, MEDLINE In-Process, and the Cochrane Library were last searched on 19 February 2020. The quality of NMAs was assessed using the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) criteria. NMA methodology, funding, and results were compared and differences in results explored.<h4>Results</h4>Twenty-five analyses evaluating up to 19 different treatments at 8-24 weeks, and two analyses at 1 year, were included. Psoriasis Area Severity Index (PASI) response was assessed in 23, facilitating comparisons between NMAs. All NMAs met at least half of the ISPOR criteria. The major limitations were explaining the rationale for methodology, exploring effect modifiers, and consistency between direct and indirect estimates. The analyses differed in model type (Bayesian or frequentist), analysis of PASI response (binomial or multinomial), and analysis of different treatment doses (separate or pooled). PASI results were broadly similar, except for the Cochrane Collaboration NMA which provided lower estimates of treatment efficacy versus placebo. This analysis differed methodologically from others, including pooling data for different doses.<h4>Conclusions</h4>Based on PASI 90 at induction, the majority of recent NMAs came to similar conclusions: interleukin (IL) 17 inhibitors (brodalumab, ixekizumab, secukinumab), IL-23 inhibitors (guselkumab and risankizumab) and infliximab were most efficacious, supporting the validity of NMAs in this clinical area. Decisions should be made using high-quality, up-to-date NMAs with assumptions relevant to clinical practice.