Comparing the Efficacy and Tolerability of Biologic Therapies in Psoriasis

An Updated Network Meta-analysis

S.K. Mahil; M.C. Ezejimofor; L.S. Exton; L. Manounah; A.D. Burden; L.C. Coates; M. de Brito; A. McGuire; R. Murphy; C.M. Owen; R. Parslew; R.T. Woolf; Z.Z.N. Yiu; O.A. Uthman; M.F. Mohd Mustapa; C.H. Smith

Disclosures

The British Journal of Dermatology. 2020;183(4):638-649. 

In This Article

Abstract and Introduction

Abstract

Background: The rapid expansion of psoriasis biologics has led to an urgent need to understand their relative efficacy and tolerability to inform treatment decisions better and, specifically, to inform guideline development.

Objectives: To update a 2017 meta-analysis on the comparative efficacy and tolerability of biologic treatments for psoriasis.

Methods: We searched the MEDLINE, PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs), published up to 7 September 2018, of 11 licensed, NICE-approved biologics targeting tumour necrosis factor (adalimumab, etanercept, infliximab, certolizumab pegol), interleukin (IL)-12/IL-23p40 (ustekinumab), IL-17A (secukinumab, ixekizumab), IL-17RA (brodalumab) and IL-23p19 (guselkumab, tildrakizumab, risankizumab). A frequentist network meta-analysis ascertained direct or indirect evidence comparing biologics with one another, methotrexate or placebo. This was combined with hierarchical cluster analyses to consider efficacy (≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) or Physician's Global Assessment 0 or 1; PASI 75; Dermatology Life Quality Index improvement) and tolerability (drug withdrawal due to adverse events) outcomes at 10–16 weeks, followed by assessments of study quality, heterogeneity and inconsistency.

Results: We identified 62 RCTs presenting data on direct comparisons (31 899 participants). All biologics were efficacious compared with placebo or methotrexate at 10–16 weeks. Hierarchical cluster analyses revealed that adalimumab, brodalumab, certolizumab pegol, guselkumab, risankizumab, secukinumab, tildrakizumab and ustekinumab were comparable with respect to high short-term efficacy and tolerability. Infliximab and ixekizumab clustered together, with high short-term efficacy but relatively lower tolerability than the other agents, although the number of drug withdrawal events across the network was low, so these findings should be treated with caution.

Conclusions: Using our methodology we found that most biologics cluster together with respect to short-term efficacy and tolerability, and we did not identify any single agent as 'best'. These data need to be interpreted in the context of longer-term efficacy, effectiveness data, safety, posology and drug acquisition costs when making treatment decisions.

Introduction

Psoriasis is a chronic inflammatory skin disease that affects 2–4% of individuals worldwide,[1] and is associated with increased mortality and multimorbidity.[2] An improved understanding of the molecular pathogenesis of psoriasis has led to the introduction of powerful targeted biologic therapies, which have transformed patient outcomes.[3] Eleven biologics are now licensed for use in Europe and the USA that target tumour necrosis factor (TNF) (adalimumab, certolizumab pegol, etanercept, infliximab), interleukin (IL)-12/IL-23p40 (ustekinumab), IL-17A (ixekizumab, secukinumab), IL-17 receptor (brodalumab) and IL-23p19 (guselkumab, risankizumab, tildrakizumab).[4,5] This rapid expansion of treatment options has led to an urgent need for comparative efficacy research to inform clinical decision making.

Head-to-head randomized trials are considered the gold standard for comparative evidence, and active-comparator trial data are becoming increasingly available.[6] However, randomized controlled trials (RCTs) involving all possible pairwise combinations of biologics, or a simultaneous direct comparison of multiple agents, are not feasible. To address this, a network meta-analysis (NMA) can synthesize direct and indirect evidence from multiple RCTs simultaneously.[7] The relative efficacy of two treatments can be estimated even if no studies compare them directly. Indirect evidence from studies comparing treatments with a common reference arm is used. If head-to-head trial data are available, pooled estimates derived from direct and indirect evidence can provide greater precision compared with using direct evidence alone. The treatments can also be ranked to produce a hierarchy. NMAs are thus a powerful source of evidence for informing clinical guidelines and practice.

Recent NMAs have assessed the relative efficacy of newer biologics with respect to Psoriasis Area and Severity Index (PASI) response, for example at least 90% improvement in PASI from baseline (PASI 90).[8–19] Patient-reported outcomes such as change in Dermatology Life Quality Index (DLQI) and treatment tolerability measures are also vital considerations for clinical decision making. These data can be synthesized in a hierarchical cluster analysis, whereby outcomes related to both efficacy and tolerability are analysed simultaneously.[20]

Although not performed in many recent NMAs,[8–11,14–17,19] hierarchical cluster analysis may help inform treatment choice as it identifies clusters of agents that are similar with regard to both outcomes.[12,13,18] Our last NMA in 2017 included six biologics.[18,21] As the number of biologics has nearly doubled since that study, we updated the NMA and hierarchical cluster analyses using the outcome set defined by our multistakeholder guideline development group. These findings, which have in part informed the updated British Association of Dermatologists (BAD) clinical guidelines,[22] provide a comprehensive evidence base to support clinicians when choosing from the expanded range of biologics.

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