Rapid Response of Biologic Treatments of Moderate-to-Severe Plaque Psoriasis: A Comprehensive Investigation Using Bayesian and Frequentist Network Meta-analyses

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Plaque psoriasis is a chronic, inflammatory skin disease with an estimated prevalence of 1.5–5% in the general population [1, 2]. Psoriasis significantly impairs patients’ quality of life [1, 2], underscoring the need for timely and effective treatments.

Biologic therapies have transformed the treatment of moderate-to-severe psoriasis and have markedly improved multiple patient outcomes [3, 4]. Several biologics are available, including inhibitors of interleukin (IL)-17 (brodalumab, ixekizumab, secukinumab), IL-12/-23 (ustekinumab), IL-23 (guselkumab, risankizumab, tildrakizumab), or tumor necrosis factor (adalimumab, certolizumab pegol, etanercept, infliximab) [5, 6]. These biologics are approved for patients with moderate-to-severe plaque psoriasis based on efficacy and safety established in phase 3, double-blind, randomized, controlled trials (RCTs).

Rapid efficacy is important to patients and clinicians [4, 7‐10], but head-to-head comparisons of biologics are rare, and none conducted to date have had speed of onset as a primary objective. We present a comprehensive network meta-analysis (NMA) that indirectly compares rapid response rates at early time points (≤ 12 weeks of treatment) for 11 approved biologics for moderate-to-severe psoriasis. Bayesian and Frequentist NMA (BNMA and fNMA, respectively) were used to investigate Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) response from phase 3 RCTs identified by systematic literature review.

Inclusion criteria for the studies with available data to include in the NMA have previously been reported and are listed in Electronic Supplementary Material (ESM) Table 1. These studies included patients who were ≥ 18 years of age with moderate-to-severe psoriasis.

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

PASI 75, PASI 90, and PASI 100 endpoints (≥ 75, ≥ 90, and 100% improvement in PASI score, respectively) were analyzed at weeks 2, 4, 8, and 12, and missing values were handled using nonresponder imputation (NRI) in all studies, with the exception of four studies (CIMPACT [11], CIMPASI-1 [12], CIMPASI-2 [12], CLARITY [13]) that reported endpoints based on multiple imputation (MI). DLQI (0,1) status, where (0,1) indicates no effect/no impact on patient's life, was assessed at week 12, and missing values were handled using NRI in all studies, except for five studies (CIMPASI-1 [12], CIMPASI-2 [12], CLARITY [13], CLEAR [14], ERASURE [15]) that used last observation carried forward and one study (FIXTURE [15]) that did not mention how missing values were treated. When required data were imputed differently (e.g., MI vs. NRI) or analyzed (mixed model for repeated measures vs. analysis of covariance) differently, they were included in the data analysis based on the assumption that the impact of the chosen imputation/analytical method was negligible for treatment effects.

Based on the BNMA analysis, IL-17 antagonists showed the most rapid treatment effects, with ixekizumab and brodalumab being similar for rapid skin and quality of life responses (Figs. 1, 2, 3; Tables 1, 2).

Ixekizumab and brodalumab showed more rapid treatment effects on PASI 75 response rates at weeks 2, 4, and 8 compared with all other biologics included in the analysis (Figs. 1, 2; Table 1). At week 12, ixekizumab and risankizumab had the most rapid treatment effects; the distribution for ixekizumab overlapped with risankizumab, and the distribution for risankizumab overlapped with brodalumab, secukinumab, infliximab, and guselkumab (Figs. 1, 2; Table 1).

Similarly, ixekizumab and brodalumab showed more rapid treatment effects on PASI 90 response rates at weeks 2, 4, 8, and 12 than did all of the other biologics included in the analysis (Figs. 1, 2; Table 1). Ixekizumab and brodalumab had the most rapid treatment effects at week 2, brodalumab had the most rapid treatment effects at week 4, and ixekizumab and brodalumab had the most rapid treatment effects at weeks 8 and 12 where distributions overlapped (Figs. 1, 2; Table 1). Ixekizumab and brodalumab had no overlap but were followed at week 4 by infliximab and secukinumab and at week 8 by secukinumab, infliximab, and risankizumab, and distributions did overlap for those treatments. At week 12, distributions for ixekizumab and brodalumab overlapped, and the distribution for brodalumab overlapped with risankizumab, which in turn overlapped with secukinumab and infliximab (Figs. 1, 2; Table 1).

Ixekizumab and brodalumab showed the most rapid treatment effects for PASI 100 at weeks 4 and 12, and brodalumab showed the most rapid treatment effects at week 8 (Table 1; ESM Figs. 1, 2).

Average (i.e., posterior mean) relative treatment effect was greatest for ixekizumab, brodalumab, and secukinumab on the DLQI (0,1) response rates at week 12, where distributions overlapped for these three treatments (Fig. 3; Table 2).

Results from fNMA were consistent with those from BNMA, with similar treatment rankings for PASI 75/90/100 at weeks 2, 4, 8, and 12 and for DLQI (0,1) at week 12. PASI 90 at week 12 rankings are presented (Table 3). Ixekizumab and brodalumab were ranked highest compared with the other biologics included in the fNMA analysis. Network diagrams are presented for PASI 90 at week 12 (Fig. 4). In Fig. 4, lines represent direct comparisons using RCTs, and numbers represent the number of RCTs included in each comparison.

In this comprehensive NMA of phase 3 RCTs, ixekizumab and brodalumab provided the most rapid and highest clinical response of PASI 75, PASI 90, or PASI 100 as early as week 2 compared to other biologic treatments (secukinumab, ustekinumab, guselkumab, adalimumab, and etanercept). DLQI (0,1) response rate distributions at week 12 overlapped for ixekizumab, brodalumab, and secukinumab. BNMA and fNMA results showed similar relative effect estimates with comparable treatment rankings. These findings align with previously published reports of rapid clinical improvement for patients with moderate-to-severe psoriasis treated with ixekizumab or brodalumab [48‐50].

Rapid improvements in skin and the ability to feel better quickly are important treatment attributes of a psoriasis therapy. These are important patient preferences for treatments and are ranked among the highest desired priorities in multiple reports [2, 4, 9, 10, 51, 52]. However, rapid effect is also tied to longer-term outcomes, including skin improvement, quality of life, and reduction in itch [50, 53‐55], though it must be noted that an association between rapid effect and long-term outcomes was not assessed in this analysis. It is also important to note that each patient has different treatment expectations [51, 56] and that the alignment of individual patient needs with physician goals may improve adherence and satisfaction with therapy [56].

Several limitations to this study should be considered. NMA differs from a traditional meta-analysis in that it is not an analysis of only head-to-head studies of the same intervention with the same comparator. NMA relies on a network of evidence from RCTs where relevant treatments are connected by trials, and this provides a combination of direct and indirect comparisons for analysis of the comparative effects of many interventions [57]. RCTs are considered to be the gold standard for treatment comparisons and provide valuable clinical data, and the studies included in the analyses are assumed to be generally similar and consistent; however, heterogeneity still may exist. There may be clinical differences (participants, populations [naïve versus experienced], duration of follow-up, and mode of administration) and methodological differences (study design, approaches to analysis, and imputation methods) that may not be aligned due to the availability of or clarity in the published data. For example, an insufficient number of RCTs included in this analysis had DLQI (0,1) response rates available at time points earlier than week 12; the threshold for NMA inclusion was not met and, thus, earlier quality of life response was not evaluated. This may contribute to selection and reporting bias. The way endpoints were imputed was clear in the majority of studies included in the analysis; however, the imputation method used for DLQI (0,1) missing values was not mentioned in one study (FIXTURE [15]). Another important caveat is that quality of life was limited in this report by what the DLQI tool could capture in the narrow RCT population. Our focus was limited to the first 12 weeks of treatment, and as such, long-term quality of life impacts of psoriasis and costs associated with disease management were not examined. Safety and patient-reported outcomes data, including those related to quality of life, were not examined in this report. The NMA results presented here are not direct comparisons and should be interpreted with caution if used to inform future treatment choices. Finally, results cannot be generalized by class because not all members of the IL-17 superfamily of cytokines were shown to be rapid in this analysis and there was some overlap between these and members of different classes, such as IL-23.

Overall, this NMA demonstrates that ixekizumab and brodalumab provide the most rapid skin clearance and quality of life improvement within 12 weeks compared with other leading biologic treatments for patients with moderate-to-severe psoriasis, including secukinumab, an IL-17 antagonist, and biologics that inhibit the IL-12/-23, IL-23, or TNF pathways.