Zenas Yiu

Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

Drug survival reflects a drugs effectiveness, safety, and tolerability. We assessed the drug survival of biologics used to treat psoriasis in a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register (BADBIR)). The survival rates of the first course of biologics for 3,523 biologic-naive patients with chronic plaque psoriasis were compared using survival analysis techniques and predictors of discontinuation analyzed using a multivariate Cox proportional hazards model. Data for patients on adalimumab (n=1,879), etanercept (n=1,098), infliximab (n=96), and ustekinumab (n=450) were available. The overall survival rate in the first year was 77%, falling to 53% in the third year. Multivariate analysis showed that female gender (hazard ratio (HR) 1.22; 95% confidence interval (CI): 1.09-1.37), being a current smoker (HR 1.19; 95% CI: 1.03-1.38), and a higher baseline dermatology life quality index (HR 1.01; 95% CI: 1.00-1.02) were predictors of discontinuation. Presence of psoriatic arthritis (HR 0.82; 95% CI: 0.71-0.96) was a predictor for drug survival. As compared with adalimumab, patients on etanercept (HR 1.63; 95% CI: 1.45-1.84) or infliximab (HR 1.56; 95% CI: 1.16-2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37-0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival. The results of this study will aid clinical decision making when choosing biologic therapy for psoriasis patients.

British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017

The overall aim of the guideline is to provide evidence-based recommendations on the use of biologic therapies (adalimumab, etanercept, infliximab, ixekizumab, secukinumab and ustekinumab) in adults, children and young people for the treatment of psoriasis; consideration is given to the specific needs of people with psoriasis and psoriatic arthritis. Biologic therapies have now been in use for over 10 years, and with accrued patient-years exposure and clinical experience, many areas that were covered in previous versions of the guideline are now part of the Summary of Product Characteristics (SPC) and/or routine care so that specific recommendations are redundant (see Toolkit A: Summary of licensed indications and posology for biologic therapy, in Supporting information 2). Therefore, in this update we focus on areas where there has been a major change in the evidence base or clinical practice, where practice is very varied and/or where clear consensus or guidelines are lacking (see section 3.1 in Supporting information 1).

Demographics and disease characteristics of patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register

The British Association of Dermatologists Biologic Interventions Register (BADBIR) is a prospective, observational cohort designed to assess the long‐term safety of biologic and conventional systemic therapies used for adults with moderate‐to‐severe psoriasis in the U.K. and Republic of Ireland.

Quantitative Evaluation of Biologic Therapy Options for Psoriasis: A Systematic Review and Network Meta-Analysis

Multiple biologic treatments are licensed for psoriasis. The lack of head-to-head randomized controlled trials makes choosing between them difficult for patients, clinicians, and guideline developers. To establish their relative efficacy and tolerability, we searched MEDLINE, PubMed, Embase, and Cochrane for randomized controlled trials of licensed biologic treatments for skin psoriasis. We performed a network meta-analysis to identify direct and indirect evidence comparing biologics with one another, methotrexate, or placebo. We combined this with hierarchical cluster analysis to consider multiple outcomes related to efficacy and tolerability in combination for each treatment. Study quality, heterogeneity, and inconsistency were evaluated. Direct comparisons from 41 randomized controlled trials (20,561 participants) were included. All included biologics were efficacious compared with placebo or methotrexate at 3–4 months. Overall, cluster analysis showed adalimumab, secukinumab, and ustekinumab were comparable in terms of high efficacy and tolerability. Ixekizumab and infliximab were differentiated by very high efficacy but poorer tolerability. The lack of longer term controlled data limited our analysis to short-term outcomes. Trial performance may not equate to real-world performance, and so results need to be considered alongside real-world, long-term safety and effectiveness data. These data suggest that it is possible to discriminate between biologics to inform clinical practice and decision making (PROSPERO 2015:CRD42015017538).

Impact of Biologic Therapies on Risk of Major Adverse Cardiovascular Events in Patients with Psoriasis: Systematic Review and Meta-analysis of Randomised Controlled Trials

Concerns have been raised regarding an increased risk of major adverse cardiovascular events (MACEs) (myocardial infarction, cerebrovascular accident or cardiovascular death) in patients treated with anti‐interleukin (IL)‐12/23 agents for moderate‐to‐severe psoriasis. We aimed to examine the risk of MACEs in adult patients with plaque psoriasis that are exposed to biologic therapies via a meta‐analysis of randomized controlled trials (RCTs). Data were obtained from systematic searches in the Cochrane Library, MEDLINE and Embase, U.S. Food and Drug Administration, European Medicines Agency, individual pharmaceutical companies online search platforms and five trials registers (up to 31 March 2016). We selected RCTs reporting adverse events in adults with plaque psoriasis receiving at least one licensed dose of biologic therapy, conventional systematic therapy or placebo. We calculated Peto odds ratios (ORs) with 95% confidence intervals (CIs) and calculated I2 statistics to assess heterogeneity. Overall, 38 RCTs involving 18 024 patients were included. No MACEs were observed in 29 studies, while nine RCTs reported 10 patients experiencing MACEs. There was no statistically significant difference in risk of MACEs associated with the use of biologic therapies overall (OR 1·45, 95% CI 0·34–6·24); tumour necrosis factor‐α inhibitors (adalimumab, etanercept and infliximab) (OR 0·67, 95% CI 0·10–4·63); anti‐IL‐17A agents (secukinumab and ixekizumab) (OR 1·00, 95% CI 0·09–11·09) or ustekinumab (OR 4·48, 95% CI 0·24–84·77). No heterogeneity was observed in these comparisons. In conclusion, the limited existing evidence suggests that licensed biologic therapies are not associated with MACEs during the short randomized controlled periods in clinical trials.

Risk of Serious Infections in Patients with Psoriasis on Biologic Therapies: A Systematic Review and Meta-Analysis

A comprehensive evaluation of the risk of serious infections in biologic therapies for psoriasis is lacking. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and prospective cohort studies reporting serious infections in people taking any licensed biologic therapy for psoriasis compared with those taking placebo, nonbiologic therapy, or other biologic therapies. The quality of the studies was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. No significant heterogeneity was detected in data from 32 RCTs (n = 13,359 participants) and one cohort study (n = 4,993 participants). In adults, low- to very-low-quality RCT data showed no significant difference between any biologic therapy and placebo at weeks 12–16 (overall pooled Peto odds ratio = 0.71, 95% confidence interval = 0.36–1.41) and weeks 20–30 (odds ratio = 2.27, 95% confidence interval = 0.45–11.49). No significant differences were found in any of the other comparisons in underpowered RCT data. Prospective cohort study data of low quality suggests that only adalimumab (adjusted hazard ratio [adjHR] = 2.52, 95% confidence interval = 1.47–4.32) was associated with a significantly higher risk of serious infection compared with retinoid and/or phototherapy in adults. No association between biologic therapies and serious infections in patients with psoriasis who were eligible for RCTs was detected. Further observational studies are needed to inform the uncertainty around this risk in the real world.

Interleukin 17-A inhibition in the treatment of psoriasis

Interleukin (IL) 17-A appears to be integral to the pathogenesis of chronic plaque psoriasis. Recent clinical trials have shown that blockade of this cytokine with the biologic therapies—secukinumab, ixekizumab and brodalumab—have led to unprecedented treatment efficacy for psoriasis. In addition, their dual efficacy towards psoriatic arthritis increases their potential clinical utility and they promise to be an important treatment option for patients who have tumour necrosis factor inhibitor resistant disease. Here, we present the evidence for the high treatment efficacy of the IL-17A inhibitors but also discuss some potential questions and areas of research needed, including the lack of evidence behind the drug survival, immunogenicity and safety profile.

Safety of biological therapies for psoriasis: effects on reproductive potential and outcomes in male and female patients

The effects of biological therapies for psoriasis on pregnancy outcomes and lactation, and male fertility and mutagenicity are common concerns in the clinical setting. There is relatively little evidence to guide the clinician and patient. Here, we review the safety profile of the commonly used biological therapies for psoriasis in individuals of reproductive potential. Safety data were derived from large‐scale registries, adverse event reporting databases, clinical trials and case reports. We assessed the effect of each therapy on adverse pregnancy outcomes including congenital malformations, and lactation with maternal administration, and male fertility and potential mutagenicity with paternal administration. We provide applicable guidance to inform clinician and patient before and after conception.

Novel Oral Therapies for Psoriasis and Psoriatic Arthritis

Several classes of new oral therapy are in use or in development for the treatment of psoriasis. Despite the high efficacy of biologics, new oral therapies remain important as patients generally prefer this mode of administration and they offer an alternative risk–benefit profile. In this review, we discuss the novel modes of action of these drugs, including modulation of cellular pathways involving diverse targets such as Janus kinase, phosphodiesterase 4, sphingosine 1-phosphate, A3 adenosine receptor and rho-associated kinase 2. We review the available evidence around licensed drugs (apremilast) and drugs that are advanced (tofacitinib) or early (ponesimod, baricitinib, peficitinib, INCB039110, CF101, KD025) in the development pipeline. The key limitations of these oral therapies are their modest efficacy profile (apremilast, ponesimod) and the limitations of their safety profile (tofacitinib, ponesimod), while the evidence for the early pipeline drugs are at phase II level only. Potential niches of current unmet needs include apremilast for patients with concomitant psoriatic arthritis, as combination treatments with biologic therapies, and/or for patients in whom multiple biologic therapies have failed due to immunogenicity and secondary inefficacy. The present knowledge gap regarding these novel drugs includes the need for longer clinical trials or observational studies to evaluate safety, and randomised phase III trials for the early pipeline drugs. We conclude that further research and data are necessary to conclusively establish the role of these agents in the current psoriasis treatment paradigm.

Efficacy and safety of emerging immunotherapies in psoriasis.

Psoriasis is a common chronic inflammatory disease of the skin. Current biologic therapies are highly effective in the treatment of psoriasis, transforming the lives of patients with this significantly disabling disease. Advances in the understanding of the immunological pathogenesis of psoriasis have led to the development of new biologic therapies, targeting specific inflammatory cytokines upregulated in psoriasis. These include the IL-17 antagonists, secukinumab, brodalumab and ixekizumab; the IL-23 antagonists, guselkumab and tildrakizumab; and the oral small molecule therapies, tofacitinib and apremilast. Here, we review evidence for the efficacy and safety of these novel psoriasis therapies, providing clinicians with an overview of the next era in immunotherapy for psoriasis.