Dermatol Ther (Heidelb) (2021) 11:885–905 https://doi.org/10.1007/s13555-021-00511-1 ORIGINAL RESEARCH Comparative Efficacy and Relative Ranking of Biologics and Oral Therapies for Moderate-to-Severe Plaque Psoriasis: A Network Meta-analysis April W. Armstrong . Ahmed M. Soliman . Keith A. Betts . Yan Wang . Yawen Gao . Luis Puig . Matthias Augustin Received: January 26, 2021 / Accepted: February 25, 2021 / Published online: March 31, 2021 Ó The Author(s) 2021 ABSTRACT options. This study assessed the short-term and long-term comparative efficacy of biologic and Introduction: The clinical benefits of biologic oral treatments for moderate-to-severe psoriasis. and oral treatments for moderate-to-severe pla- Methods: A systematic literature review identi- que psoriasis are well-established, but efficacy fied phase 2/3/4 randomized controlled trials outcomes can vary across therapies. Compara- (RCTs) through to 1 July 2020 for Food and tive efficacy analysis can be highly informative Drug Administration- or European Medicines in clinical settings with multiple therapeutic Agency-licensed treatments for moderate-to- severe psoriasis. Psoriasis Area and Severity Index (PASI) 75/90/100 response rates at the Supplementary Information The online version end of the primary response (short-term: 10–- contains supplementary material available at https:// 16 weeks from baseline) and maintenance peri- doi.org/10.1007/s13555-021-00511-1. ods (long-term: 48–52 weeks from baseline) were estimated using Bayesian network meta- A. W. Armstrong (&) Department of Dermatology, Keck School of analysis. Surfaces under the cumulative ranking Medicine, University of Southern California, HC4 curves (SUCRA) were estimated to present the 2000 1450 San Pablo, Health Sciences Campus, Los relative ranking of treatments. Angeles, CA 90033, USA Results: In the short term (N = 71 RCTs), the e-mail: aprilarmstrong@post.harvard.edu PASI 90 response rates were highest for ixek- A. M. Soliman izumab (72.9%, SUCRA 0.951), risankizumab AbbVie, Inc., 1 N. Waukegan Road, North Chicago, (72.5%, 0.940), and brodalumab (72.0%, 0.930), IL 60064, USA which were significantly higher than those for K. A. Betts  Y. Wang  Y. Gao guselkumab (65.0%, 0.795), secukinumab Analysis Group, Inc., 333 South Hope Street 27th (65.0%, 0.794), infliximab (56.8%, 0.702), cer- Floor, Los Angeles, CA 90071, USA tolizumab (400 mg: 49.6%, 0.607; 200 mg: L. Puig 42.2%, 0.389), ustekinumab (90 mg: 47.9%, Department of Dermatology, Hospital de la Santa 0.568; weight-based: 45.7%, 0.505; 45 mg: Creu i Sant Pau–Universitat Autònoma de 44.6%, 0.460), adalimumab (43.0%, 0.410), til- Barcelona, Carrer de Sant Quintı́, 89, 08041 Barcelona, Spain drakizumab (200 mg: 39.7%, 0.327; 100 mg: 37.2%, 0.268), etanercept (18.0%, 0.171), M. Augustin apremilast (12.4%, 0.090), and dimethyl fuma- Health Care Research in Dermatology and Nursing, rate (12.2%, 0.092). The PASI 100 response rates University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany were highest for ixekizumab (41.4%), 886 Dermatol Ther (Heidelb) (2021) 11:885–905 risankizumab (40.8%), and brodalumab What was learned from the study? (40.3%). In the long term (N = 11 RCTs), the PASI 90 rate was highest for risankizumab In the short term (N = 71 trials), the PASI (85.3%, SUCRA: 0.998), which were signifi- response rates were highest for cantly higher than those for brodalumab ixekizumab, risankizumab, and (78.8%, 0.786), guselkumab (78.1%, 0.760), brodalumab; in the long term (N = 11 ixekizumab (72.1%, 0.577), secukinumab trials), the PASI response rates were (67.0%, 0.450), ustekinumab (weight-based: highest for risankizumab. 55.0%, 0.252), adalimumab (51.6%, 0.176), and Ixekizumab, risankizumab, and etanercept (37.9%, 0.001). Risankizumab had brodalumab had the highest short-term the highest PASI 100 response rate (65.4%), efficacy, and risankizumab had the followed by brodalumab (55.7%) and guselk- highest long-term efficacy. umab (54.8%). Conclusions: Ixekizumab, risankizumab, and brodalumab had the highest short-term effi- cacy, and risankizumab had the highest long- term efficacy. DIGITAL FEATURES This article is published with digital features, Keywords: Biologic therapies; Network meta- including a summary slide, to facilitate under- analysis; Plaque psoriasis standing of the article. To view digital features for this article go to https://doi.org/10.6084/ Key Summary Points m9.figshare.14102903. Why carry out this study? INTRODUCTION A comparative efficacy analysis of the clinical benefits of biologic and oral Novel biologic therapies have shifted the treat- treatments for moderate-to-severe plaque ment paradigm for moderate-to-severe plaque psoriasis can help inform treatment psoriasis [1–3]. Anti-tumor necrosis factor (TNF) decisions when multiple therapeutic agents (e.g., etanercept, infliximab, and adali- options are available. mumab) and an anti-interleukin (IL) 12/23 agent (ustekinumab) were among the earliest This study assessed the short-term and biologic treatments licensed by the US Food and long-term comparative efficacy of biologic Drug Administration (FDA) and the European and oral treatments for moderate-to- Medicines Agency (EMA) for psoriasis. In recent severe plaque psoriasis licensed by the US years, biologic drugs targeting IL-17 (ixek- Food and Drug Administration or izumab, brodalumab, and secukinumab) and IL- European Medicines Agency using data 23 (risankizumab, guselkumab, and tildrak- from their phase 2, 3, or 4 randomized izumab) have become available and expanded controlled trials. the therapeutic options for psoriasis. Psoriasis Area and Severity Index (PASI) To facilitate the selection of appropriate 75/90/100 response rates at the end of the treatment regimens among the available can- primary response period (short-term: didates, it is important to evaluate multiple 10–16 weeks from baseline) and the aspects of each treatment, including the effi- maintenance period (long-term: cacy, safety, treatment adherence, and health- 48–52 weeks from baseline) were related quality of life (HRQoL), and to consider estimated using Bayesian network meta- the contraindications of the target patient analysis. population [4]. Specifically, the comparative efficacy data, particularly a high level of skin Dermatol Ther (Heidelb) (2021) 11:885–905 887 clearance as an outcome (i.e., a 90 or 100% guselkumab [8], ECLIPSE comparing guselk- reduction in Psoriasis Area and Severity Index umab with secukinumab [21], CLARITY com- [PASI 90, PASI 100, respectively]), are of key paring secukinumab with ustekinumab [22], interest. These efficacy outcomes have been and IMMerge comparing risankizumab with associated with improvement in HRQoL, psori- secukinumab [9]. Incorporating these studies in asis symptoms, and work productivity. For an indirect comparison of the PASI response example, Elewski et al. [5] reported that patients rates may not only improve the statistical power who achieved PASI 90–100 at week 12 in the to detect differences in both short- and long- ERASURE and FIXTURE trials were more likely term PASI response rates, but also enhance and to achieve a sustained response in HRQoL inform the evidence network for comparisons measured by the Dermatology Life Quality of long-term treatment efficacy. To this end, Index. Viswanathan et al. [6] showed that this study updated the NMA conducted by patients who achieved PASI 100 response at Armstrong et al. [14] by incorporating recently week 12 in a clinical trial had significantly lower published clinical trial data to provide a com- psoriasis symptom severity [6]. Feldman et al. prehensive assessment of the short-term and [7] showed that employed patients in the long-term PASI response rates, including PASI CLEAR trial who achieved at least PASI 90 had 90 and 100 as outcomes, associated with significantly lower work productivity loss and licensed treatments for moderate-to-severe pla- reduced annual indirect costs. Outcomes que psoriasis. assessing a high level of skin clearance have also become increasingly used in clinical develop- ment programs [8–11], making it possible to METHODS conduct an indirect comparison of such out- comes associated with various treatments. Data Source While several recent network meta-analyses (NMAs) have been conducted to compare the A systematic literature review (SLR) was con- relative efficacy of treatments for moderate-to- ducted to identify randomized controlled clin- severe plaque psoriasis, knowledge gaps still ical trials of treatments for moderate-to-severe exist [12–19]. First, PASI 100 results were not psoriasis through to 1 July 2020, which was an available in some of the recent NMAs [13, 15]. update of the SLR by Armstrong et al. [14]. The Second, such NMAs may lack sufficient statisti- search strategy is detailed in the Methods sec- cal power to detect potential differences tion of the electronic supplementary material. between treatments with the highest PASI 90 Eligible trials were required to (1) be a phase 2, and 100 response rates. Third, comparative 3, or 4 randomized clinical trial (RCT) on evidence assessing the long-term efficacy of treatments for moderate-to-severe plaque pso- treatments is limited due to the dearth of head- riasis among adults who were eligible for sys- to-head trials that did not implement crossover temic therapies or phototherapy; (2) include or re-randomization in the study design [14]. treatments and dosages licensed by the US FDA Expert opinions have stressed the importance of or the EMA; and (3) report at least one of the maintaining long-term skin clearance, even if efficacy outcomes of interest (PASI 75, 90, and short-term skin clearance is achieved [20]. 100; indicating the proportions of patients who Compared with the short-term PASI response, achieved at least a 75, 90, or 100% reduction in the long-term PASI response can additionally PASI) by the end of the primary response period reflect the variation in response over time, (short-term: 10–16 weeks from baseline) or the accounting for the gradual loss of response end of the maintenance period (long-term: among some patients. 48–52 weeks from baseline). For the long-term Recently, several large head-to-head trials NMA, trials were excluded if (1) patients swit- have been published that compare various ched to a different treatment during the post- novel treatments for psoriasis, including induction period compared with the induction IXORA-R comparing ixekizumab with period; (2) patients received a different dosage 888 Dermatol Ther (Heidelb) (2021) 11:885–905 during the post-induction period compared the end of the pre-specified primary assessment with the induction period, such that the entire period for the short-term NMA (weeks 10–16 treatment regimen considering both the after baseline) and the end of the pre-specified induction period and the post-induction period maintenance period for the long-term NMA was not licensed; or (3) patients were re-ran- (weeks 48–52 after baseline). The number nee- domized based on certain efficacy criteria, such ded to treat (NNT) for each treatment relative to as PASI 75, during the post-induction period. placebo by the end of the primary assessment As this is a post-hoc NMA of previously period was also calculated. These pre-specified published results of clinical trial data, no insti- periods for the primary assessment period and tutional board review was required. This article maintenance period were chosen because the is based on previously conducted studies and studies for the various medications were does not contain any new studies with human designed and a priori powered for those time participants or animals performed by any of the periods. Additionally, these time points often authors. corresponded to the primary or secondary end- points of the clinical trials. Comparators Statistical Analyses The comparators in this study included anti-IL- 23 agents (guselkumab 100 mg at weeks 0 and 4, NMA Models then every 8 weeks; risankizumab 150 mg at Bayesian probit NMAs [23] were implemented weeks 0 and 4, then every 12 weeks; tildrak- to jointly model the PASI 75, 90, and 100 izumab 100 mg and 200 mg at weeks 0 and 4, response rates. Due to the rich set of clinical then every 12 weeks), anti-IL-17 agents (bro- trials in the short-term network, a reference-arm dalumab 210 mg at weeks 0, 1, and 2, then adjustment was implemented to account for every 2 weeks; ixekizumab 160 mg at week 0, potential cross-trial heterogeneities in treat- 80 mg every 2 weeks until week 12, then 80 mg ment effects associated with the placebo every 4 weeks; secukinumab 300 mg at weeks 0, response rate of each trial [19, 24]. Additionally, 1, 2, 3, and 4, then every 4 weeks), anti-TNF a random-effects model was applied to the agents (adalimumab 80 mg at week 0, then short-term NMA to account for the potential 40 mg every 2 weeks starting at week 1; cer- heterogeneities that cannot be explained by tolizumab 400 mg at weeks 0, 2, and 4, then placebo response rates. For the long-term NMA, 200 mg or 400 mg every 2 weeks; etanercept a fixed-effects NMA model was fit due to the 25 mg twice-weekly/50 mg weekly; infliximab relative sparsity of the network. 5 mg/kg at weeks 0, 2 and 6, then every For each treatment, the posterior distribu- 8 weeks), an anti-phosphodiesterase type 4 tions of the PASI 75, 90, and 100 response rates inhibitor (PDE4) agent (apremilast 30 mg twice in the short term (10–16 weeks after baseline) daily after the initial titration schedule), an and the long term (48–52 weeks after baseline) anti-IL-12/23 agent (ustekinumab 45 mg, were summarized using posterior medians and 90 mg, or with a weight-based dosage 95% credible intervals (CrI). As the response [45 mg B 100 kg, 90 mg [ 100 kg] at weeks 0 rates were correlated, an overlap in two CrIs did and 4, then every 12 weeks), as well as dimethyl not rule out the possibility of a statistically sig- fumarate uptitrated to a maximum daily dose of nificance difference between two treatments. 720 mg for the treatment of moderate-to-severe Therefore, odds ratios (ORs) were used to for- plaque psoriasis. mally compare the PASI response rates between each pair of treatments and were summarized Outcomes using posterior medians and 95% CrIs. Addi- tionally, the treatments were ranked using the The outcomes were the proportions of patients surface under the cumulative ranking curve who achieved PASI 75, 90, and 100 response by (SUCRA) and mean rank with 95% CrI [25]. Dermatol Ther (Heidelb) (2021) 11:885–905 889 Medline, Embase, Cochrane, n=2,392 n=6,916 n=2,168 Duplicate, n=3,439 Exclusion codes i1, n=8,037 A – Reviews/editorials Screened based on tle, B – Populaon e1, n=7,324 abstract C – Study design A=2,216 D – Intervenon B=2,807 E – Animal/in-vitro C=1,680 F – Language/Non-English D=543 G – Conference abstract E=52 superseded by full-text F=26 H – Comparator i2, n=713 I – Outcomes Screened based on full J – Full text not obtained e2, n=364 text A=6 B=66 Hand searching, n=24 C=67 D=19 September 2018 update, F=6 n=59 G=172 H=10 December 2019 update, I=14 n=13 J=4 July 2020 update, n=19 i3, n=464 records covering 195 studies 71 studies included in the NMA 124 studies excluded from the NMA Fig. 1 Study screening and selection flow. e1 exclusion 1, e2 exclusion 2, i1 inclusion 1, i2 inclusion 2, i3 inclusion 3, NMA network meta-analysis For the short-term NMA, the NNT for each PASI 75, 90, and 100 response rates versus treatment relative to the placebo was calculated placebo. as the reciprocal of difference of a treatment in 890 Dermatol Ther (Heidelb) (2021) 11:885–905 Fig. 2 Evidence network for the network meta-analysis ACCEPT [54], LOTUS [55], PEARL [56], PHOENIX 1 (NMA) of the Psoriasis Area and Severity Index (PASI) [57], PHOENIX 2 [58], Igarashi et al. [59], VIP-U [60], response by the end of the primary response period (short- Zhou et al. [61], X-PLORE [62], VOYAGE-1 [63], term; 10–16 weeks after baseline). The included trials were: VOYAGE-2 [64], ORION [65], Ohtsuki et al. [66], Asahina et al. [27], Bissonnette et al. [28], REVEAL [29], ECLIPSE [21], Nakagawa et al. [67], Papp et al. [68], CHAMPION [30], Gordon et al. [31], Cai et al. [32], VIP AMAGINE-1 [69], AMAGINE-2 [70], AMAGINE-3 [33], Leonardi et al. [34], Papp et al. [35], van de Kerkhof [70], CIMPASI-1 [71], CIMPASI-2 [71], CIMPACT et al. [36], Gottlieb et al. [37], EXPRESS [38], EXPRESS II [72], NCT00245765 [73], NCT03051217 [74], reSUR- [39], SPIRIT [40], Chaudhari et al. [41], Torii et al. [42], FACE-1 [75], Papp et al. [76], reSURFACE-2 [75], Yang et al. [43], UNCOVER 1 [44], UNCOVER 2 [45], UltIMMa1 [77], IMMvent [78], IMMhance [79], Sus- UNCOVER 3 [45], IXORA-S [10], IXORA-R [8], talMM [80], IMMerge [9], BRIDGE [81], PSOR-008/ ERASURE [46], FEATURE [47], FIXTURE [46], JUNC- ESTEEM-1 [82], PSOR-009/ESTEEM-2 [83], PSOR-010/ TURE [48], CLEAR [49], CLARITY [11], VIP-S [50], LIBERATE [84], PSOR-005 [85], and Ohtsuki et al. [86]. ALLURE [51], ObePso-S [52], NCT03066609 [53], BIW Twice weekly, QW once weekly Dermatol Ther (Heidelb) (2021) 11:885–905 891 Additionally, the heterogeneity in treatment Table S1 in the electronic supplementary contrasts for the short-term NMA was summa- material. rized using (1) the posterior distribution mea- The posterior medians of the PASI 90 suring the effect of placebo response on response rates were highest for ixekizumab treatment contrasts and (2) the posterior distri- (median 72.9% [95% CrI 68.3%, 77.1%]), bution measuring the residual cross-trial vari- risankizumab (72.5% [68.1%, 76.7%]), and ance in treatment contrasts. brodalumab (72.0% [67.3%, 76.7%]), followed by guselkumab (65.0% [60.3%, 69.7%]), secuk- Computation inumab (65.0% [61.0%, 68.7%]), infliximab (56.8% [50.4%, 62.9%]), certolizumab 400 mg The posterior samples of the Bayesian NMA (49.6% [43.0%, 56.3%]), ustekinumab 90 mg models were drawn using the Markov Chain (47.9% [41.4%, 54.2%]), ustekinumab weight- Monte Carlo technique. Three parallel chains, based dosage (45.7% [41.2%, 50.3%]), ustek- each with 5000 adaptation iterations, 50,000 inumab 45 mg (44.6% [39.2%, 49.8%]), adali- burn-in iterations, 50,000 posterior simulations, mumab (43.0% [38.7%, 47.4%]), certolizumab and a thinning factor of 10, were implemented. 200 mg (42.2% [35.3%, 49.4%]), tildrakizumab Vague prior distributions were applied for all 200 mg (39.7% [33.2%, 46.8%]), tildrakizumab parameters, such that the posterior distributions 100 mg (37.2% [30.8%, 44.1%]), etanercept were driven primarily by the observed data. All (18.0% [14.5%, 22.2%]), apremilast (12.4% analyses were conducted in R statistical software [9.7%, 15.9%]), and dimethyl fumarate (12.2% (version 3.5.1; R Foundation for Statistical Com- [7.2%, 20.2%]) (Table 1). Similarly, the posterior puting, Vienna, Austria) and JAGS 4.3.0 (Free medians of the PASI 100 response rates were Software Foundation, Inc., Boston, MA, USA) highest for ixekizumab (median 41.4% [95% CrI 36.3%, 46.6%]), risankizumab (40.8% [36.1%, 46.0%]), and brodalumab (40.3% [35.2%, RESULTS 46.1%]). SUCRA and mean rank suggested a similar ranking of treatments as the median Literature Search PASI response rates. Ixekizumab, risankizumab, and brodalumab were associated with the A total of 464 publications covering 195 studies highest SUCRA (0.951, 0.940, and 0.930, were identified in the SLR through to 1 July respectively) and mean rank (1.8, 2.0, and 2.2, 2020, with 71 studies included in the NMAs and respectively) (Table 1; and ESM Fig. S1). 124 studies excluded from the NMAs (Fig. 1). All The posterior distributions of the pairwise 71 studies were included in the short-term ORs suggested that the PASI response rates were NMA, and 11 of the 71 studies were included in comparable between ixekizumab, risankizumab, the long-term NMA. Compared with the SLR and brodalumab, which were significantly conducted by Armstrong et al. [14], 52 addi- higher than those of all other treatments, tional records were identified, with 11 addi- including guselkumab and secukinumab, with tional studies qualifying for the short-term 95% probability (Table 2 [PASI 90 and 100]; ESM NMA and four additional studies qualifying for Table S2 [PASI 75]). Guselkumab and secuk- the long-term NMA. inumab were associated with significantly higher PASI response rates compared with infliximab, certolizumab (200 and 400 mg), Short-term Efficacy ustekinumab (45 mg, 90 mg, and weight-based), adalimumab, tildrakizumab (100 and 200 mg), A total of 71 eligible RCTs connecting 18 treat- etanercept, apremilast, and dimethyl fumarate, ment regimens were included in the NMA of with 95% probability. short-term PASI response rates (10–16 weeks The NNTs to achieve PASI 75, 90, or 100 for after baseline) (Fig. 2). A list of the trials inclu- each treatment relative to placebo are presented ded in the short-term NMA is included in in Fig. 3. The NNTs to achieve one additional 892 Dermatol Ther (Heidelb) (2021) 11:885–905 Table 1 Estimated response rates, SUCRA, and mean rank from the NMA of short-term PASI response Treatment Posterior median, % (95% CrI) SUCRAa Mean rank PASI 75 PASI 90 PASI 100 (95% CrI) Ixekizumab 160 mg at week 0, then 89.9 72.9 41.4 0.951 1.8 80 mg Q2W (87.3, 92.0) (68.3, 77.1) (36.3, 46.6) (1.0, 3.0) Risankizumab 150 mg at weeks 0, and 89.6 72.5 40.8 0.940 2.0 4, then Q12W (87.2, 91.8) (68.1, 76.7) (36.1, 46.0) (1.0, 3.0) Brodalumab 210 mg at weeks 0, 1, 89.4 72.0 40.3 0.930 2.2 and 2, then Q2W (86.7, 91.9) (67.3, 76.7) (35.2, 46.1) (1.0, 3.0) Guselkumab 100 mg at weeks 0, and 85.3 65.0 32.9 0.795 4.5 4, then Q8W (82.3, 88.1) (60.3, 69.7) (28.5, 37.7) (4.0, 5.0) Secukinumab 300 mg at weeks 0, 1, 2, 85.3 65.0 32.9 0.794 4.5 3, and 4, then Q4W (82.7, 87.6) (61.0, 68.7) (29.2, 36.7) (4.0, 5.0) Infliximab 5 mg/kg at weeks 0, 2, and 79.8 56.8 25.6 0.702 6.1 6, then Q8W (75.0, 84.0) (50.4, 62.9) (20.7, 31.0) (5.0, 7.0) Certolizumab 400 mg Q2W 74.4 49.6 20.1 0.607 7.7 (68.7, 79.5) (43.0, 56.3) (15.7, 25.2) (6.0, 11.0) Ustekinumab 90 mg at weeks 0, and 73.0 47.9 18.9 0.568 8.3 4, then Q12W (67.3, 77.9) (41.4, 54.2) (14.8, 23.5) (7.0, 12.0) Ustekinumab 45 mg B 100 kg, 71.1 45.7 17.4 0.505 9.4 90 mg [ 100 kg at weeks 0, and 4, (67.1, 74.9) (41.2, 50.3) (14.7, 20.6) (7.0, 12.0) then Q12W Ustekinumab 45 mg at weeks 0, and 70.1 44.6 16.7 0.460 10.2 4, then Q12W (65.3, 74.5) (39.2, 49.8) (13.5, 20.3) (8.0, 13.0) Adalimumab 80 mg at week 0, then 68.7 43.0 15.7 0.410 11.0 40 mg Q2W (64.7, 72.5) (38.7, 47.4) (13.2, 18.6) (8.0, 14.0) Certolizumab 400 mg at weeks 0, 2, 68.0 42.2 15.3 0.389 11.4 and 4, then 200 mg Q2W (61.3, 74.2) (35.3, 49.4) (11.4, 20.0) (8.0, 14.0) Tildrakizumab 200 mg at weeks 0, 65.7 39.7 13.8 0.327 12.4 and 4, then Q12W (59.1, 72.1) (33.2, 46.8) (10.3, 18.2) (9.0, 14.0) Tildrakizumab 100 mg at weeks 0, 63.3 37.2 12.4 0.268 13.4 and 4, then Q12W (56.5, 69.7) (30.8, 44.1) (9.2, 16.5) (11.0, 14.0) Etanercept 25 mg BIW/50 mg QW 40.2 18.0 4.1 0.171 15.1 (34.7, 45.9) (14.5, 22.2) (2.9, 5.5) (15.0, 16.0) Dermatol Ther (Heidelb) (2021) 11:885–905 893 Table 1 continued Treatment Posterior median, % (95% CrI) SUCRAa Mean rank PASI 75 PASI 90 PASI 100 (95% CrI) Apremilast 30 mg BID after initial 31.3 12.4 2.4 0.090 16.5 titration schedule (26.4, 36.8) (9.7, 15.9) (1.7, 3.4) (16.0, 17.0) Dimethyl fumarate (LAS 41008) 30.9 12.2 2.3 0.092 16.4 (21.4, 43.3) (7.2, 20.2) (1.1, 4.8) (15.0, 17.0) Placebo 5.3 1.1 0.1 0.000 18.0 (4.8, 5.8) (1.0, 1.3) (0.1, 0.1) (18.0, 18.0) BID twice daily, BIW twice weekly, CrI credible interval, NMA network meta-analysis, PASI Psoriasis Area and Severity Index, PASI 75, 90, 100 75, 90, or 100% decrease from baseline PASI, respectively, QW once weekly, Q2W once every 2 weeks, Q4W once every 4 weeks, Q8W once every 8 weeks, Q12W once every 12 weeks a SUCRA (surfaces under the cumulative ranking curves) measures the probability of a treatment being in the top ranks PASI 90 response were 1.39 (95% CrI 1.32, 1.49) [72.5%, 83.0%]), ixekizumab (72.1% [62.7%, for ixekizumab, 1.40 (1.32, 1.49) for risankizu- 80.1%]), secukinumab (67.0% [62.8%, 71.0%]), mab, and 1.41 (1.32, 1.51) for brodalumab. The ustekinumab (weight-based 55.0% [52.7%, NNTs to achieve one additional PASI 100 57.3%]), adalimumab (51.6% [41.8%, 61.3%]), response were 2.42 (95% CrI 2.15, 2.76) for and etanercept (37.9% [30.4%, 45.8%]) ixekizumab, 2.45 (2.18, 2.78) for risankizumab, (Table 2). Similarly, the posterior PASI 100 and 2.49 (2.18, 2.84) for brodalumab. response rates were highest for risankizumab The random-effects model with reference- (median: 65.4% [95% CrI 59.3%, 71.1%]), fol- arm adjustment revealed cross-trial hetero- lowed by brodalumab (78.1% [72.5%, 83.0%]) geneities in treatment contrasts. On the probit and guselkumab (54.8% [47.6%, 61.9%]). scale, each unit increase in the placebo PASI SUCRA and mean rank suggested a consistent response rate was associated with a statistically ranking of treatments as the PASI response significant decrease of 0.750 (95% CrI 0.534, rates, with risankizumab associated with a 1.008) in the difference between the active SUCRA of 0.998 and a mean rank of 1.0, fol- treatment and placebo. The residual cross-trial lowed by brodalumab and guselkumab (Table 3; variance of treatment contrasts on the probit ESM Fig. S2). scale was 0.014 (95% CrI 0.006, 0.028), which The posterior distributions of the pairwise differs from zero with 95% probability. odds ratios suggested that the PASI response rates associated with risankizumab were signif- Long-Term Efficacy icantly higher than all other treatments, including brodalumab, guselkumab, ixek- A total of 11 eligible RCTs connecting eight izumab, and secukinumab with 95% probability treatment regimens were included in the NMA (Table 4 [PASI 90 and 100] and Table S4 [PASI of long-term PASI response rates (48–52 weeks 75] in the electronic supplementary material). after baseline) (Fig. 4). A list of the trials inclu- Brodalumab and guselkumab were associated ded in the long-term NMA is shown in ESM with significantly higher PASI response rates Table S3. than ustekinumab, adalimumab, and etaner- The posterior PASI 90 response rates were cept with 95% probability. highest for risankizumab (median 85.3% [95% CrI 81.4%, 88.7%]), followed by brodalumab (78.8% [74.0%, 83.0%]), guselkumab (78.1% 894 Dermatol Ther (Heidelb) (2021) 11:885–905 Table 2 Pairwise odds ratio of achieving PASI 90 and 100 response in the short term (a) PASI 90: posterior median (95% CrI) 1.02 1.05 1.45 1.45 2.05 2.74 2.93 3.21 3.35 3.58 3.69 4.09 4.54 12.23 18.96 19.32 237.65 IXE (0.75, (0.75, (1.09, (1.12, (1.48, (1.92, (2.11, (2.44, (2.49, (2.67, (2.55, (2.83, (3.16, (8.74, (13.07, (10.03, (184.46, 1.38) 1.42) 1.90)* 1.89)* 2.86)* 3.87)* 4.11)* 4.18)* 4.56)* 4.74)* 5.34)* 5.85)* 6.52)* 17.19)* 27.06)* 36.18)* 305.82)* 0.98 1.02 1.42 1.42 2.00 2.68 2.86 3.13 3.27 3.49 3.61 3.99 4.44 11.96 18.51 18.84 232.00 (0.72, RIS (0.75, (1.07, (1.11, (1.43, (1.91, (2.05, (2.44, (2.43, (2.75, (2.54, (2.81, (3.14, (8.60, (13.27, (10.31, (182.92, 1.34) 1.37) 1.88)* 1.86)* 2.85)* 3.74)* 4.08)* 4.04)* 4.50)* 4.46)* 5.15)* 5.67)* 6.32)* 16.86)* 25.82)* 34.33)* 298.99)* 0.96 0.98 1.39 1.39 1.96 2.62 2.80 3.06 3.20 3.41 3.53 3.90 4.34 11.69 18.10 18.44 227.01 (0.70, (0.73, BRO (1.03, (1.06, (1.39, (1.86, (2.00, (2.39, (2.36, (2.61, (2.46, (2.74, (3.05, (8.35, (12.88, (9.99, (177.20, 1.33) 1.33) 1.88)* 1.87)* 2.84)* 3.72)* 4.06)* 3.99)* 4.49)* 4.57)* 5.13)* 5.63)* 6.29)* 16.77)* 25.81)* 34.08)* 298.73)* 0.69 0.71 0.72 1.00 1.41 1.89 2.02 2.21 2.31 2.46 2.55 2.82 3.13 8.43 13.06 13.30 163.75 (0.53, (0.53, (0.53, GUS (0.79, (1.01, (1.35, (1.46, (1.71, (1.72, (1.94, (1.79, (1.99, (2.22, (6.11, (9.36, (7.19, (129.80, 0.91)* 0.93)* 0.97)* 1.29) 1.99)* 2.63)* 2.85)* 2.88)* 3.15)* 3.14)* 3.61)* 3.98)* 4.45)* 11.82)* 18.24)* 24.30)* 209.20)* 0.69 0.71 0.72 1.00 1.41 1.88 2.01 2.21 2.31 2.46 2.54 2.81 3.12 8.42 13.06 13.30 163.55 (0.53, (0.54, (0.54, (0.78, SEC (1.05, (1.37, (1.50, (1.77, (1.77, (1.91, (1.81, (2.01, (2.23, (6.22, (9.26, (7.02, (132.86, 0.89)* 0.90)* 0.94)* 1.27) 1.90)* 2.58)* 2.74)* 2.72)* 3.02)* 3.13)* 3.56)* 3.91)* 4.35)* 11.46)* 18.04)* 24.50)* 200.72)* 0.49 0.50 0.51 0.71 0.71 1.34 1.43 1.56 1.64 1.74 1.80 1.99 2.21 5.97 9.26 9.43 115.96 (0.35, (0.35, (0.35, (0.50, (0.53, INF (0.91, (1.02, (1.13, (1.19, (1.25, (1.21, (1.34, (1.50, (4.18, (6.16, (4.73, (87.46, 0.68)* 0.70)* 0.72)* 0.99)* 0.95)* 1.94) 2.02)* 2.15)* 2.25)* 2.41)* 2.66)* 2.93)* 3.26)* 8.54)* 13.69)* 18.26)* 153.58)* 0.37 0.37 0.38 0.53 0.53 0.75 1.07 1.17 1.22 1.30 1.35 1.49 1.66 4.47 6.91 7.04 86.87 CZP (0.26, (0.27, (0.27, (0.38, (0.39, (0.51, (0.74, (0.85, (0.87, (0.96, (0.99, (1.01, (1.13, (3.10, (4.77, (3.76, (65.00, 400 0.52)* 0.52)* 0.54)* 0.74)* 0.73)* 1.10) 1.57) 1.62) 1.74) 1.79) 1.84) 2.20)* 2.45)* 6.52)* 10.10)* 13.28)* 116.86)* 0.34 0.35 0.36 0.50 0.50 0.70 0.93 1.10 1.15 1.22 1.26 1.39 1.55 4.18 6.48 6.60 81.22 UST (0.24, (0.25, (0.25, (0.35, (0.37, (0.49, (0.64, (0.79, (0.89, (0.88, (0.85, (0.93, (1.04, (2.91, (4.32, (3.33, (60.78, 90 0.47)* 0.49)* 0.50)* 0.69)* 0.67)* 0.99)* 1.35) 1.49) 1.46) 1.67) 1.86) 2.04) 2.27)* 5.96)* 9.48)* 12.64)* 106.95)* 0.31 0.32 0.33 0.45 0.45 0.64 0.85 0.91 1.04 1.11 1.15 1.27 1.42 3.82 5.91 6.02 74.07 (0.24, (0.25, (0.25, (0.35, (0.37, (0.47, (0.62, (0.67, UST_W (0.79, (0.88, (0.82, (0.91, (1.01, (2.80, (4.27, (3.27, (59.87, 0.41)* 0.41)* 0.42)* 0.59)* 0.56)* 0.88)* 1.17) 1.27) 1.40) 1.42) 1.62) 1.78) 1.98)* 5.25)* 8.13)* 10.96)* 92.48)* 0.30 0.31 0.31 0.43 0.43 0.61 0.82 0.87 0.96 1.07 1.10 1.22 1.35 3.65 5.66 5.76 70.97 (0.22, (0.22, (0.22, (0.32, (0.33, (0.44, (0.57, (0.69, (0.71, UST45 (0.80, (0.76, (0.84, (0.94, (2.62, (3.91, (3.00, (55.29, 0.40)* 0.41)* 0.42)* 0.58)* 0.56)* 0.84)* 1.15) 1.12) 1.26) 1.41) 1.58) 1.74) 1.93) 5.09)* 8.03)* 10.80)* 90.16)* 0.28 0.29 0.29 0.41 0.41 0.57 0.77 0.82 0.90 0.94 1.03 1.14 1.27 3.42 5.30 5.40 66.46 (0.21, (0.22, (0.22, (0.32, (0.32, (0.41, (0.56, (0.60, (0.70, (0.71, ADA (0.74, (0.82, (0.91, (2.51, (3.89, (2.99, (54.02, 0.37)* 0.36)* 0.38)* 0.51)* 0.52)* 0.80)* 1.04) 1.14) 1.14) 1.25) 1.43) 1.58) 1.76) 4.71)* 7.17)* 9.64)* 82.44)* 0.27 0.28 0.28 0.39 0.39 0.56 0.74 0.79 0.87 0.91 0.97 1.11 1.23 3.32 5.13 5.22 64.42 CZP (0.19, (0.19, (0.20, (0.28, (0.28, (0.38, (0.54, (0.54, (0.62, (0.63, (0.70, (0.74, (0.82, (2.25, (3.48, (2.76, (47.10, 200 0.39)* 0.39)* 0.41)* 0.56)* 0.55)* 0.82)* 1.01) 1.18) 1.22) 1.31) 1.35) 1.65) 1.84) 4.91)* 7.58)* 9.92)* 88.10)* 0.24 0.25 0.26 0.36 0.36 0.50 0.67 0.72 0.78 0.82 0.87 0.90 1.11 2.99 4.63 4.72 58.14 TIL (0.17, (0.18, (0.18, (0.25, (0.26, (0.34, (0.45, (0.49, (0.56, (0.58, (0.63, (0.61, (0.83, (2.05, (3.15, (2.49, (42.90, 200 0.35)* 0.36)* 0.36)* 0.50)* 0.50)* 0.75)* 0.99)* 1.07) 1.10) 1.19) 1.22) 1.35) 1.50) 4.43)* 6.83)* 8.91)* 79.58)* 0.22 0.23 0.23 0.32 0.32 0.45 0.60 0.65 0.71 0.74 0.79 0.81 0.90 2.70 4.18 4.25 52.37 TIL (0.15, (0.16, (0.16, (0.22, (0.23, (0.31, (0.41, (0.44, (0.50, (0.52, (0.57, (0.54, (0.67, (1.84, (2.82, (2.23, (38.46, 100 0.32)* 0.32)* 0.33)* 0.45)* 0.45)* 0.67)* 0.88)* 0.96)* 0.99)* 1.06) 1.09) 1.22) 1.21) 3.97)* 6.14)* 8.00)* 71.37)* 0.08 0.08 0.09 0.12 0.12 0.17 0.22 0.24 0.26 0.27 0.29 0.30 0.33 0.37 1.55 1.58 19.42 (0.06, (0.06, (0.06, (0.08, (0.09, (0.12, (0.15, (0.17, (0.19, (0.20, (0.21, (0.20, (0.23, (0.25, ETA (1.06, (0.82, (14.66, 0.11)* 0.12)* 0.12)* 0.16)* 0.16)* 0.24)* 0.32)* 0.34)* 0.36)* 0.38)* 0.40)* 0.44)* 0.49)* 0.54)* 2.23)* 2.98) 25.63)* 0.05 0.05 0.06 0.08 0.08 0.11 0.14 0.15 0.17 0.18 0.19 0.20 0.22 0.24 0.65 1.02 12.53 (0.04, (0.04, (0.04, (0.05, (0.06, (0.07, (0.10, (0.11, (0.12, (0.12, (0.14, (0.13, (0.15, (0.16, (0.45, APR (0.55, (9.39, 0.08)* 0.08)* 0.08)* 0.11)* 0.11)* 0.16)* 0.21)* 0.23)* 0.23)* 0.26)* 0.26)* 0.29)* 0.32)* 0.35)* 0.94)* 1.86) 16.95)* 0.05 0.05 0.05 0.08 0.08 0.11 0.14 0.15 0.17 0.17 0.19 0.19 0.21 0.24 0.63 0.98 12.31 (0.03, (0.03, (0.03, (0.04, (0.04, (0.05, (0.08, (0.08, (0.09, (0.09, (0.10, (0.10, (0.11, (0.12, (0.34, (0.54, DMF (6.83, 0.10)* 0.10)* 0.10)* 0.14)* 0.14)* 0.21)* 0.27)* 0.30)* 0.31)* 0.33)* 0.33)* 0.36)* 0.40)* 0.45)* 1.23) 1.81) 22.58)* 0.00 0.00 0.00 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.02 0.02 0.02 0.02 0.05 0.08 0.08 (0.00, (0.00, (0.00, (0.00, (0.00, (0.01, (0.01, (0.01, (0.01, (0.01, (0.01, (0.01, (0.01, (0.01, (0.04, (0.06, (0.04, PBO 0.01)* 0.01)* 0.01)* 0.01)* 0.01)* 0.01)* 0.02)* 0.02)* 0.02)* 0.02)* 0.02)* 0.02)* 0.02)* 0.03)* 0.07)* 0.11)* 0.15)* Dermatol Ther (Heidelb) (2021) 11:885–905 895 Table 2 continued (b) PASI 100: posterior median (95% CrI) 1.02 1.04 1.44 1.44 2.06 2.81 3.02 3.35 3.51 3.78 3.91 4.40 4.97 16.60 28.97 29.68 757.82 IXE (0.75, (0.76, (1.09, (1.12, (1.48, (1.95, (2.15, (2.52, (2.58, (2.80, (2.65, (2.96, (3.35, (11.31, (18.81, (13.28, (577.18, 1.37) 1.40) 1.87)* 1.86)* 2.89)* 4.04)* 4.32)* 4.39)* 4.85)* 5.05)* 5.84)* 6.51)* 7.41)* 24.53)* 43.85)* 65.14)* 990.53)* 0.98 1.02 1.41 1.41 2.01 2.75 2.95 3.27 3.43 3.69 3.84 4.31 4.86 16.26 28.31 28.96 740.37 (0.73, RIS (0.76, (1.07, (1.10, (1.43, (1.93, (2.09, (2.53, (2.52, (2.89, (2.63, (2.95, (3.33, (11.13, (19.11, (13.64, (571.56, 1.32) 1.35) 1.86)* 1.83)* 2.89)* 3.91)* 4.29)* 4.25)* 4.80)* 4.76)* 5.64)* 6.32)* 7.18)* 24.11)* 41.90)* 62.03)* 969.06)* 0.96 0.98 1.38 1.38 1.97 2.69 2.89 3.20 3.36 3.62 3.75 4.22 4.76 15.90 27.72 28.38 725.14 (0.71, (0.74, BRO (1.03, (1.06, (1.39, (1.88, (2.04, (2.48, (2.45, (2.74, (2.55, (2.88, (3.24, (10.83, (18.59, (13.25, (554.07, 1.32) 1.31) 1.86)* 1.84)* 2.87)* 3.88)* 4.26)* 4.19)* 4.78)* 4.86)* 5.61)* 6.27)* 7.15)* 23.92)* 41.87)* 61.27)* 966.46)* 0.69 0.71 0.72 1.00 1.43 1.95 2.10 2.32 2.44 2.62 2.72 3.05 3.45 11.54 20.10 20.57 525.70 (0.53, (0.54, (0.54, GUS (0.79, (1.01, (1.37, (1.49, (1.77, (1.79, (2.04, (1.86, (2.09, (2.36, (7.90, (13.48, (9.53, (405.28, 0.92)* 0.94)* 0.97)* 1.29) 2.04)* 2.78)* 3.04)* 3.06)* 3.40)* 3.39)* 4.01)* 4.48)* 5.11)* 17.12)* 29.95)* 44.18)* 687.95)* 0.69 0.71 0.73 1.00 1.43 1.95 2.09 2.32 2.43 2.62 2.71 3.05 3.45 11.52 20.10 20.57 524.92 (0.54, (0.55, (0.54, (0.78, SEC (1.05, (1.38, (1.53, (1.84, (1.83, (2.00, (1.88, (2.10, (2.37, (8.03, (13.28, (9.29, (413.98, 0.90)* 0.91)* 0.94)* 1.27) 1.95)* 2.74)* 2.92)* 2.90)* 3.27)* 3.40)* 3.96)* 4.42)* 5.02)* 16.66)* 29.79)* 44.71)* 662.55)* 0.49 0.50 0.51 0.70 0.70 1.36 1.47 1.63 1.71 1.84 1.90 2.14 2.42 8.08 14.10 14.44 368.24 (0.35, (0.35, (0.35, (0.49, (0.51, INF (0.91, (1.02, (1.14, (1.20, (1.28, (1.24, (1.38, (1.56, (5.33, (8.72, (6.18, (268.17, 0.68)* 0.70)* 0.72)* 0.99)* 0.95)* 2.04) 2.14)* 2.28)* 2.42)* 2.61)* 2.94)* 3.28)* 3.73)* 12.24)* 22.35)* 32.88)* 501.21)* 0.36 0.36 0.37 0.51 0.51 0.73 1.08 1.19 1.25 1.34 1.40 1.57 1.77 5.92 10.30 10.53 269.95 CZP (0.25, (0.26, (0.26, (0.36, (0.37, (0.49, (0.72, (0.84, (0.86, (0.95, (0.99, (1.02, (1.15, (3.84, (6.59, (4.81, (193.32, 400 0.51)* 0.52)* 0.53)* 0.73)* 0.72)* 1.10) 1.64) 1.69) 1.84) 1.91) 1.98) 2.43)* 2.75)* 9.22)* 16.19)* 23.41)* 376.86)* 0.33 0.34 0.35 0.48 0.48 0.68 0.93 1.11 1.16 1.25 1.29 1.46 1.64 5.49 9.58 9.81 250.71 UST (0.23, (0.23, (0.23, (0.33, (0.34, (0.47, (0.61, (0.77, (0.88, (0.86, (0.83, (0.93, (1.05, (3.57, (5.88, (4.21, (179.29, 90 0.46)* 0.48)* 0.49)* 0.67)* 0.65)* 0.98)* 1.39) 1.55) 1.52) 1.77) 2.00) 2.24) 2.54)* 8.38)* 15.16)* 22.26)* 343.10)* 0.30 0.31 0.31 0.43 0.43 0.61 0.84 0.90 1.05 1.13 1.17 1.32 1.49 4.97 8.66 8.86 226.37 (0.23, (0.24, (0.24, (0.33, (0.34, (0.44, (0.59, (0.64, UST_W (0.77, (0.86, (0.80, (0.90, (1.02, (3.41, (5.80, (4.11, (175.40, 0.40)* 0.40)* 0.40)* 0.57)* 0.54)* 0.87)* 1.19) 1.30) 1.46) 1.48) 1.73) 1.93) 2.20)* 7.34)* 12.86)* 19.08)* 293.98)* 0.28 0.29 0.30 0.41 0.41 0.58 0.80 0.86 0.95 1.08 1.11 1.25 1.42 4.73 8.25 8.44 215.68 UST (0.21, (0.21, (0.21, (0.29, (0.31, (0.41, (0.54, (0.66, (0.68, (0.77, (0.74, (0.82, (0.93, (3.17, (5.25, (3.73, (160.56, 45 0.39)* 0.40)* 0.41)* 0.56)* 0.55)* 0.83)* 1.17) 1.13) 1.29) 1.47) 1.68) 1.88) 2.14) 7.06)* 12.67)* 18.74)* 285.69)* 0.26 0.27 0.28 0.38 0.38 0.54 0.74 0.80 0.89 0.93 1.04 1.17 1.32 4.40 7.67 7.85 200.31 (0.20, (0.21, (0.21, (0.29, (0.29, (0.38, (0.52, (0.56, (0.67, (0.68, ADA (0.71, (0.80, (0.90, (3.01, (5.21, (3.71, (155.96, 0.36)* 0.35)* 0.37)* 0.49)* 0.50)* 0.78)* 1.05) 1.16) 1.16) 1.29) 1.51) 1.69) 1.93) 6.49)* 11.17)* 16.52)* 259.16)* 0.26 0.26 0.27 0.37 0.37 0.53 0.72 0.77 0.85 0.90 0.96 1.12 1.27 4.24 7.37 7.54 193.35 CZP (0.17, (0.18, (0.18, (0.25, (0.25, (0.34, (0.51, (0.50, (0.58, (0.60, (0.66, (0.71, (0.80, (2.67, (4.60, (3.40, (133.71, 200 0.38)* 0.38)* 0.39)* 0.54)* 0.53)* 0.81)* 1.01) 1.20) 1.25) 1.35) 1.40) 1.78) 2.02) 6.76)* 11.81)* 16.94)* 277.47)* 0.23 0.23 0.24 0.33 0.33 0.47 0.64 0.69 0.76 0.80 0.86 0.89 1.13 3.77 6.57 6.73 171.92 TIL (0.15, (0.16, (0.16, (0.22, (0.23, (0.30, (0.41, (0.45, (0.52, (0.53, (0.59, (0.56, (0.80, (2.38, (4.10, (3.02, (119.74, 200 0.34)* 0.34)* 0.35)* 0.48)* 0.48)* 0.73)* 0.98)* 1.08) 1.11) 1.21) 1.25) 1.41) 1.60) 6.03)* 10.52)* 15.01)* 247.87)* 0.20 0.21 0.21 0.29 0.29 0.41 0.56 0.61 0.67 0.71 0.76 0.79 0.89 3.34 5.83 5.95 152.35 TIL (0.13, (0.14, (0.14, (0.20, (0.20, (0.27, (0.36, (0.39, (0.45, (0.47, (0.52, (0.49, (0.62, (2.10, (3.60, (2.65, (105.19, 100 0.30)* 0.30)* 0.31)* 0.42)* 0.42)* 0.64)* 0.87)* 0.95)* 0.98)* 1.07) 1.11) 1.25) 1.25) 5.33)* 9.31)* 13.29)* 219.25)* 0.06 0.06 0.06 0.09 0.09 0.12 0.17 0.18 0.20 0.21 0.23 0.24 0.27 0.30 1.74 1.78 45.59 (0.04, (0.04, (0.04, (0.06, (0.06, (0.08, (0.11, (0.12, (0.14, (0.14, (0.15, (0.15, (0.17, (0.19, ETA (1.08, (0.77, (31.88, 0.09)* 0.09)* 0.09)* 0.13)* 0.12)* 0.19)* 0.26)* 0.28)* 0.29)* 0.32)* 0.33)* 0.37)* 0.42)* 0.48)* 2.77)* 4.04) 64.62)* 0.03 0.04 0.04 0.05 0.05 0.07 0.10 0.10 0.12 0.12 0.13 0.14 0.15 0.17 0.57 1.02 26.13 (0.02, (0.02, (0.02, (0.03, (0.03, (0.04, (0.06, (0.07, (0.08, (0.08, (0.09, (0.08, (0.10, (0.11, (0.36, APR (0.47, (18.02, 0.05)* 0.05)* 0.05)* 0.07)* 0.08)* 0.11)* 0.15)* 0.17)* 0.17)* 0.19)* 0.19)* 0.22)* 0.24)* 0.28)* 0.93)* 2.23) 38.41)* 0.03 0.03 0.04 0.05 0.05 0.07 0.09 0.10 0.11 0.12 0.13 0.13 0.15 0.17 0.56 0.98 25.54 (0.02, (0.02, (0.02, (0.02, (0.02, (0.03, (0.04, (0.04, (0.05, (0.05, (0.06, (0.06, (0.07, (0.08, (0.25, (0.45, DMF (11.96, 0.08)* 0.07)* 0.08)* 0.10)* 0.11)* 0.16)* 0.21)* 0.24)* 0.24)* 0.27)* 0.27)* 0.29)* 0.33)* 0.38)* 1.29) 2.12) 55.12)* 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.01 0.01 0.01 0.02 0.04 0.04 (0.00, (0.00, (0.00, (0.00, (0.00, (0.00, (0.00, (0.00, (0.00, (0.00, (0.00, (0.00, (0.00, (0.00, (0.02, (0.03, (0.02, PBO 0.00)* 0.00)* 0.00)* 0.00)* 0.00)* 0.00)* 0.01)* 0.01)* 0.01)* 0.01)* 0.01)* 0.01)* 0.01)* 0.01)* 0.03)* 0.06)* 0.08)* Values in table are presented as the pairwise odds ratio with the 95% credible interval in parenthesis. An odds ratio [ 1 indicates that the treatment in that row has a higher probability of achieving PASI response compared with the treatment in that column. An odds ratio \ 1 indicates that the treatment in that row has a lower probability of achieving PASI response compared with the treatment in that column ADA adalimumab, APR apremilast, BRO brodalumab, CZP 200 certolizumab 200 mg, CZP 400 certolizumab 400 mg, DMF dimethyl fumarate, ETA etanercept, GUS guselkumab, INF infliximab, IXE ixekizumab, PBO placebo, RIS risankizumab, SEC secukinumab, TIL 100 tildrakizumab 100 mg, TIL 200 tildrakizumab 200 mg, UST_W ustekinumab weight based, UST 45 ustekinumab 45 mg, UST 90 ustekinumab 90 mg a Denotes that 95% CrI excludes 1 896 Dermatol Ther (Heidelb) (2021) 11:885–905 NNT to achieve one PASI 75 response NNT to achieve one PASI 90 response NNT to achieve one PASI 100 response Ixekizumab 80 mg 1.18 (1.15, 1.22) 1.39 (1.32, 1.49) 2.42 (2.15, 2.76) Risankizumab 150 mg 1.19 (1.16, 1.22) 1.40 (1.32, 1.49) 2.45 (2.18, 2.78) Brodalumab 210 mg 1.19 (1.15, 1.23) 1.41 (1.32, 1.51) 2.49 (2.18, 2.84) Guselkumab 100 mg 1.25 (1.21, 1.30) 1.57 (1.46, 1.69) 3.05 (2.66, 3.52) Secukinumab 300 mg 1.25 (1.22, 1.29) 1.57 (1.48, 1.67) 3.05 (2.73, 3.44) Infliximab 5 mg/kg 1.34 (1.27, 1.43) 1.80 (1.62, 2.03) 3.93 (3.24, 4.86) Certolizumab pegol 400 mg 1.45 (1.35, 1.58) 2.06 (1.81, 2.39) 5.00 (3.98, 6.39) Ustekinumab 90 mg 1.48 (1.38, 1.61) 2.14 (1.89, 2.48) 5.31 (4.28, 6.81) Ustekinumab 45 mg ≤100 kg, 90 mg >100 kg 1.52 (1.44, 1.62) 2.25 (2.03, 2.49) 5.77 (4.87, 6.86) Ustekinumab 45 mg 1.54 (1.44, 1.67) 2.30 (2.05, 2.62) 6.01 (4.96, 7.45) Adalimumab 40 mg 1.58 (1.49, 1.68) 2.39 (2.16, 2.66) 6.39 (5.41, 7.61) Certolizumab pegol 200 mg 1.59 (1.45, 1.78) 2.43 (2.07, 2.93) 6.58 (5.03, 8.85) Tildrakizumab 200 mg 1.65 (1.50, 1.86) 2.59 (2.19, 3.12) 7.28 (5.52, 9.77) Tildrakizumab 100 mg 1.72 (1.55, 1.95) 2.77 (2.33, 3.36) 8.10 (6.11, 11.00) Etanercept 25 mg BIW / 50 mg QW 2.87 (2.46, 3.40) 5.91 (4.76, 7.48) 25.10 (18.35, 35.01) Apremilast 30 mg 3.85 (3.17, 4.73) 8.83 (6.79, 11.57) 43.74 (30.42, 63.06) Dimethyl fumarate 3.90 (2.63, 6.20) 8.99 (5.23, 16.34) 44.82 (21.08, 98.38) 1 5 10 50 1 5 10 50 1 5 10 50 Fig. 3 Estimated numbers needed to treat (NNTs) relative parenthesis. BIW Twice weekly, PASI 75, 90, 100 75, to placebo for short-term PASI response. Values are 90, or 100% decrease from baseline PASI, respectively, QW presented with the 95% credible interval (Crl) in once weekly DISCUSSION indirect comparison of eight active treatments. The large sample sizes of the newly included The results suggest that ixekizumab, risankizu- head-to-head trials, such as CLARITY (n = 1102) mab, and brodalumab were associated with and ECLIPSE (n = 1048) [21, 22], also made it significantly higher PASI response rates than the possible for the present long-term NMA to other licensed treatments in the short term, and detect statistical differences between that risankizumab was associated with signifi- treatments. cantly higher PASI response rates than the other In the short-term NMAs of this study, two licensed treatments in the long term. The anti-IL-17 agents (ixekizumab and brodalumab) results established the benefits of these treat- and an anti-IL-23 agent (risankizumab) were ments towards achieving a high level of skin associated with the most favorable efficacy clearance (PASI 100 and PASI 90). outcomes, including achievement of a high Compared with the prior NMA by Armstrong level of skin clearance. This result is consistent et al. [14], this study identified 11 additional with the findings of other recent NMAs for trials for the short-term PASI NMA and four moderate-to-severe plaque psoriasis. For exam- additional trials for the long-term PASI NMA. ple, Sbidian et al. [15] suggested that anti-IL-17 These additions included several large head-to- agents (ixekizumab, secukinumab, bimek- head trials between active treatments reporting izumab, and brodalumab), anti-IL-23 agents short-term PASI results, such as IXORA-R (risankizumab and guselkumab), and infliximab (n = 1027) and ECLIPSE (n = 1048) [8, 21]. The were significantly more effective, in terms of increase in statistical power made it possible to PASI 90 response rates, than ustekinumab and detect previously unidentified significant dif- other anti-TNF agents (adalimumab, cer- ferences in PASI response rates between the tolizumab, and etanercept). Mahil et al. [13] treatments. Specifically, the present study showed that in terms of achieving clear/nearly found statistically significantly higher short- clear skin status, ixekizumab was associated term PASI response rates associated with ixek- with the highest SUCRA value followed by izumab, risankizumab, and brodalumab com- risankizumab. Sawyer et al. [12] reported that pared with guselkumab following the addition the anti-IL-17 agents guselkumab and risanki- of the 11 recent trials. Furthermore, the four zumab were more efficacious than tildrak- newly added trials with long-term PASI results izumab, ustekinumab, anti-TNF agents, and extended the long-term NMA conducted by non-biologic systemic treatments. Tada et al. Armstrong et al. [14] and further connected [17] similarly reported that brodalumab, ixek- guselkumab and adalimumab to facilitate an izumab, and risankizumab were associated with Dermatol Ther (Heidelb) (2021) 11:885–905 897 Fig. 4 Evidence network for the NMA of PASI response AMAGINE-2 [70], ECLIPSE [21], VOYAGE-1 [63], by the end of the maintenance period (long-term; CLEAR [87], FIXTURE [46], CLARITY [22], IXORA-S 48–52 weeks after baseline). The included trials were: [88], UltIMMa1 [77], and IMMerge [9] the highest rates of PASI 90 and PASI 100 detect statistically significant differences response and the highest SUCRA values. between the three treatments. The long-term NMA suggested that PASI 90 This study benefits from the following and 100 response rates were highest for risan- strengths. First, the inclusion of newly pub- kizumab by the end of the maintenance period lished clinical trials permitted the addition of (PASI 90: 85.3%; PASI 100: 65.4%), followed by guselkumab and adalimumab into the long- brodalumab and guselkumab. To date, few term NMA and increased the sample sizes and studies have attempted an NMA comparing the statistical power for detection of differences in relative efficacy of treatments in the long term. PASI response rates between treatments in both Yasmeen et al. [16] found that risankizumab, the short-term and long-term NMAs. Second, brodalumab, and guselkumab were associated the use of the random-effects model adjusted with a higher probability of achieving a PASI for reference-arm response for the short-term response than other biologics, but did not NMAs addressed the potential heterogeneities 898 Dermatol Ther (Heidelb) (2021) 11:885–905 Table 3 Estimated response rates, SUCRA, and mean rank from the NMA of long-term PASI response Treatment Posterior median, % (95% CrI) SUCRAa Mean rank PASI 75 PASI 90 PASI 100 (95% Crl) Risankizumab 150 mg at weeks 0, and 93.6 85.3 65.4 0.998 1.0 4, then Q12W (91.2, 95.4) (81.4, 88.7) (59.3, 71.1) (1.0, 1.0) Brodalumab 210 mg at weeks 0, 1, 89.7 78.8 55.7 0.786 2.5 and 2, then Q2W (86.6, 92.3) (74.0, 83.0) (49.4, 61.8) (2.0, 4.0) Guselkumab 100 mg at weeks 0, and 89.3 78.1 54.8 0.760 2.7 4, then Q8W (85.6, 92.3) (72.5, 83.0) (47.6, 61.9) (2.0, 4.0) Ixekizumab 160 mg at week 0, 80 mg 85.4 72.1 47.2 0.577 4.0 Q2W until week 12, then 80 mg (78.5, 90.6) (62.7, 80.1) (37.0, 57.6) (2.0, 5.0) Q4W Secukinumab 300 mg at weeks 0, 1, 2, 81.8 67.0 41.5 0.450 4.9 3, and 4, then Q4W (78.5, 84.7) (62.8, 71.0) (37.0, 46.1) (4.0, 5.0) Ustekinumab 45 mg B 100 kg, 72.4 55.0 29.8 0.252 6.2 90 mg [ 100 kg at weeks 0, and 4, (70.2, 74.4) (52.7, 57.3) (27.6, 32.1) (6.0, 7.0) then Q12W Adalimumab 80 mg at week 0, then 69.4 51.6 26.9 0.176 6.8 40 mg Q2W (60.2, 77.5) (41.8, 61.3) (19.3, 35.7) (6.0, 7.0) Etanercept 50 mg BIW until week 12, 56.3 37.9 16.7 0.001 8.0 then QW (48.1, 64.2) (30.4, 45.8) (12.1, 22.4) (8.0, 8.0) a SUCRA measures the probability of a treatment being in the top ranks in treatment contrasts across trials, and insured included clinical trials were designed a priori for the validity for the statistical inference for the the assessments at these time points, these pre- short-term NMAs under a rich network. specified time points were chosen for this analysis. Second, the potential differences Limitations between patients with moderate-to-severe pla- que psoriasis in the clinical trials and the real This study is subject to the following limita- world, such as patient characteristics, adher- tions. First, NMAs rely on the transitivity ence, and persistence to treatments, may limit assumption, requiring that the study conduct the generalizability of the study results [26]. and patient populations be comparable across Third, due to the relative dearth of available trials. There may be observed or unobserved data, the long-term network is still sparse. factors, such as differences in study design, Fourth, while the long-term NMA was able to patient characteristics, and concomitant treat- assess the relative efficacy of treatments by ments, that may modify the treatment efficacy 48–52 weeks after baseline, direct evidence and influence the comparability of the clinical comparing the PASI response rates beyond trials in the NMAs. The assessment time points 1 year is lacking. Lastly, PASI may only repre- also varied across trials. However, as the sent one of the many aspects measuring the Table 4 Pairwise odds ratio of achieving PASI 90 and 100 response in the long term PASI 90 response: posterior median (95% CrI) RIS 1.57 (1.08, 2.28)a 1.63 (1.12, 2.37)a 2.25 (1.35, 3.73)a 2.86 (2.16, 3.82)a 4.76 (3.64, 6.29)a 5.48 (3.49, 8.61)a 9.56 (6.46, 14.28)a 0.64 (0.44, 0.92)a BRO 1.04 (0.71, 1.53) 1.44 (0.87, 2.34) 1.82 (1.36, 2.46)a 3.03 (2.37, 3.92)a 3.49 (2.21, 5.52)a 6.09 (4.07, 9.16)a 0.61 (0.42, 0.89)a 0.96 (0.66, 1.42) GUS 1.38 (0.82, 2.31) 1.76 (1.39, 2.25)a 2.92 (2.19, 3.94)a 3.36 (2.56, 4.42)a 5.88 (4.08, 8.50)a 0.44 (0.27, 0.74)a 0.70 (0.43, 1.15) 0.72 (0.43, 1.22) IXE 1.27 (0.81, 2.02) 2.11 (1.39, 3.26)a 2.43 (1.37, 4.33)a 4.24 (2.51, 7.26)a 0.35 (0.26, 0.46)a 0.55 (0.41, 0.74)a 0.57 (0.45, 0.72)a 0.79 (0.50, 1.23) SEC 1.66 (1.42, 1.95)a 1.91 (1.35, 2.71)a 3.34 (2.54, 4.41)a 0.21 (0.16, 0.28)a 0.33 (0.26, 0.42)a 0.34 (0.25, 0.46)a 0.47 (0.31, 0.72)a 0.60 (0.51, 0.71)a UST_W 1.15 (0.78, 1.69) 2.01 (1.47, 2.77)a Dermatol Ther (Heidelb) (2021) 11:885–905 0.18 (0.12, 0.29)a 0.29 (0.18, 0.45)a 0.30 (0.23, 0.39)a 0.41 (0.23, 0.73)a 0.52 (0.37, 0.74)a 0.87 (0.59, 1.28) ADA 1.75 (1.12, 2.73)a 0.10 (0.07, 0.15)a 0.16 (0.11, 0.25)a 0.17 (0.12, 0.25)a 0.24 (0.14, 0.40)a 0.30 (0.23, 0.39)a 0.50 (0.36, 0.68)a 0.57 (0.37, 0.89)a ETA PASI 100 response: posterior median (95% CrI) RIS 1.50 (1.08, 2.10)a 1.56 (1.11, 2.19)a 2.11 (1.32, 3.40)a 2.66 (2.06, 3.45)a 4.44 (3.49, 5.68)a 5.14 (3.29, 8.13)a 9.40 (6.30, 14.23)a 0.67 (0.48, 0.93)a BRO 1.03 (0.72, 1.48) 1.41 (0.88, 2.24) 1.77 (1.34, 2.34)a 2.96 (2.35, 3.73)a 3.42 (2.16, 5.49)a 6.26 (4.12, 9.60)a 0.64 (0.46, 0.90)a 0.97 (0.68, 1.38) GUS 1.36 (0.83, 2.22) 1.71 (1.37, 2.14)a 2.86 (2.18, 3.75)a 3.31 (2.50, 4.42)a 6.05 (4.15, 8.89)a 0.47 (0.29, 0.76)a 0.71 (0.45, 1.14) 0.74 (0.45, 1.20) IXE 1.26 (0.81, 1.95) 2.10 (1.40, 3.16)a 2.43 (1.37, 4.34)a 4.45 (2.60, 7.66)a 0.38 (0.29, 0.49)a 0.56 (0.43, 0.75)a 0.58 (0.47, 0.73)a 0.79 (0.51, 1.23) SEC 1.67 (1.43, 1.95)a 1.93 (1.34, 2.81)a 3.53 (2.62, 4.84)a 0.23 (0.18, 0.29)a 0.34 (0.27, 0.43)a 0.35 (0.27, 0.46)a 0.48 (0.32, 0.71)a 0.60 (0.51, 0.70)a UST_W 1.16 (0.78, 1.74) 2.11 (1.50, 3.04)a 0.19 (0.12, 0.30)a 0.29 (0.18, 0.46)a 0.30 (0.23, 0.40)a 0.41 (0.23, 0.73)a 0.52 (0.36, 0.74)a 0.86 (0.57, 1.29) ADA 1.83 (1.13, 2.95)a 0.11 (0.07, 0.16)a 0.16 (0.10, 0.24)a 0.17 (0.11, 0.24)a 0.22 (0.13, 0.38)a 0.28 (0.21, 0.38)a 0.47 (0.33, 0.67)a 0.55 (0.34, 0.88)a ETA Values in table are presented as the pairwise odds ratio with the 95% CrI. An odds ratio [ 1 indicates that the treatment in that row has a higher probability of achieving PASI response compared with the treatment in that column. An odds ratio \ 1 indicates that the treatment in that row has a lower probability of achieving PASI response compared with the treatment in that column ADA adalimumab, BRO brodalumab, ETA etanercept, GUS guselkumab, IXE ixekizumab, RIS risankizumab, SEC secukinumab, UST_W ustekinumab weight based a Denoted that 95% CrI excludes 1 899 900 Dermatol Ther (Heidelb) (2021) 11:885–905 efficacy of treatments for moderate-to-severe American Academy of Dermatology (AAD) Vir- plaque psoriasis. With additional data, future tual Meeting Experience (VMX). studies may consider comparisons of other measures of treatment efficacy, such as the res- Disclosures. April W. Armstrong serves as olution of itch, HRQoL, and treatment investigator and/or scientific advisor to AbbVie, adherence. BMS, Incyte, Leo, UCB, Janssen, Lilly, Novartis, Ortho Dermatologics, Sun, Dermavant, Der- mira, Sanofi, Regeneron, Pfizer, and Modmed. CONCLUSIONS Ahmed M. Soliman is an employee of AbbVie and owns AbbVie stock. Luis Puig has served as This study provides an up-to-date, comprehen- investigator and/or consultant or paid speaker sive indirect comparison of the relative efficacy to AbbVie, Almirall, Amgen, Biogen, Boehringer of licensed treatments for moderate-to-severe Ingelheim, Celgene, Janssen, Leo, Lilly, Merck, plaque psoriasis. Ixekizumab, risankizumab, Novartis, Pfizer, and UCB. Keith A. Betts, Yan and brodalumab were associated with the Wang, and Yawen Gao are employed by Anal- highest PASI response rates by the end of the ysis Group, Inc., which received payment from primary response period. Risankizumab was AbbVie Inc. for participation in this research. associated with the highest PASI response rates Matthias Augustin has served as consultant to by the end of the maintenance period. Future or paid speaker for clinical trials sponsored by research can take an integrative approach to companies that manufacture drugs used for the assess multiple aspects of each treatment, treatment of psoriasis, including AbbVie, Almi- including efficacy, safety, treatment adherence, rall, Amgen, Biogen, Boehringer Ingelheim, and HRQoL, and identify subgroups of patients Celgene, Centocor, Eli-Lilly, GSK, Janssen-Cilag, (using clinical, laboratory, and genomic data) Leo, Medac, Merck, MSD, Novartis, Pfizer, UCB, who can benefit the most from each biologic and Xenoport. No honoraria or payments were and oral treatment for moderate-to-severe pla- made for authorship. que psoriasis. Compliance with ethics guidelines. As this is a post-hoc NMA of previously published results ACKNOWLEDGEMENTS of clinical trial data, no institutional board review was required. This article is based on previously conducted studies and does not Funding. Sponsorship for this study and the contain any new studies with human partici- Rapid Service Fee were funded by AbbVie Inc. pants or animals performed by any of the authors. Authorship. All authors meet the Interna- tional Committee of Medical Journal Editors Data availability. The datasets analyzed (ICMJE) criteria for authorship for this article, during the current study are in the electronic take responsibility for the integrity of the work supplementary materials of the published as a whole, and have given their approval for article. this version to be published. Open Access. This article is licensed under a Medical writing and editorial assis- Creative Commons Attribution-NonCommer- tance. Editorial assistance in the preparation of cial 4.0 International License, which permits this article was provided by Dr. Shelley Batts of any non-commercial use, sharing, adaptation, Analysis Group, Inc. Support for this assistance distribution and reproduction in any medium was funded by AbbVie Inc. or format, as long as you give appropriate credit to the original author(s) and the source, provide Prior presentation. Portions of this research a link to the Creative Commons licence, and are planned to be presented at the 2021 indicate if changes were made. The images or Dermatol Ther (Heidelb) (2021) 11:885–905 901 other third party material in this article are 8. Blauvelt A, Papp K, Gottlieb A, Jarell A, Reich K, included in the article’s Creative Commons Maari C, et al. A head-to-head comparison of ixek- izumab vs. guselkumab in patients with moderate- licence, unless indicated otherwise in a credit to-severe plaque psoriasis: 12-week efficacy, safety line to the material. 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