Rheumatol Ther (2021) 8:199–217 https://doi.org/10.1007/s40744-020-00261-0 ORIGINAL RESEARCH Efficacy and Safety of Ixekizumab in Patients with Psoriatic Arthritis and Inadequate Response to TNF Inhibitors: 3-Year Follow-Up (SPIRIT-P2) Ana-Maria Orbai . Jordi Gratacós . Anthony Turkiewicz . Stephen Hall . Eva Dokoupilova . Bernard Combe . Peter Nash . Gaia Gallo . Clinton C. Bertram . Amanda M. Gellett . Aubrey Trevelin Sprabery . Julie Birt . Lisa Macpherson . Vladimir J. Geneus . Arnaud Constantin Received: October 19, 2020 / Accepted: November 16, 2020 / Published online: December 5, 2020 Ó The Author(s) 2020 ABSTRACT intolerance to one or two tumor necrosis factor inhibitors. Purpose: Ixekizumab is a high-affinity mono- Methods: In the SPIRIT-P2 study (ClinicalTri- clonal antibody that selectively targets inter- als.gov ID: NCT02349295), patients were ran- leukin-17A. The objective of this study was to domized to placebo or ixekizumab 80 mg every assess the long-term efficacy and safety (to week 4 weeks (IXE Q4W) or every 2 weeks (IXE Q2W) 156) of ixekizumab in patients with active pso- following a 160-mg starting dose. During the riatic arthritis and inadequate response or extension period (weeks 24–156), patients maintained their original ixekizumab dose, and placebo patients received IXE Q4W or IXE Q2W (1:1). Exposure-adjusted incidence rates (IRs) Electronic supplementary material The online per 100 patient-years (PY) are presented. version of this article (https://doi.org/10.1007/s40744- 020-00261-0) contains supplementary material, which is Results: Of 363 patients enrolled in the study, available to authorized users. 310 entered the extension period. In all patients A.-M. Orbai (&) E. Dokoupilova Johns Hopkins University School of Medicine, Department of Pharmaceutical Technology, Faculty Baltimore, MD, USA of Pharmacy, Masaryk University, Brno, Czech e-mail: aorbai1@jhmi.edu Republic J. Gratacós B. Combe Rheumatology Department, Hospital Universitari CHU Montpellier and Montpellier University, Parc Taulı́, Sabadell, Barcelona, Spain Montpellier, France J. Gratacós P. Nash Medicine Department, Universitat Autònoma de School of Medicine, Griffith University, Brisbane, Barcelona, Sabadell, Barcelona, Spain Australia A. Turkiewicz G. Gallo  C. C. Bertram  A. M. Gellett  Rheumatology Associates Clinical Research Unit, A. T. Sprabery  J. Birt  L. Macpherson  V. J. Geneus Birmingham, AL, USA Eli Lilly and Company, Indianapolis, IN, USA S. Hall A. Constantin Monash University, Melbourne, VIC, Australia Hospital Pierre-Paul Riquet and Université Toulouse III, Toulouse, France E. Dokoupilova Medical Plus, s.r.o., Uherské Hradiště, Czech Republic 200 Rheumatol Ther (2021) 8:199–217 treated with IXE Q4W and IXE Q2W at week 0, Furthermore, clinical improvements responses persisted to week 156. At week 156, persisted up to 1 year during the clinical responses (observed) in patients treated extension period. with IXE Q4W and IXE Q2W were assessed [American College of Rheumatology (ACR) The objective of this study was to assess response criteria and minimal disease activity the long-term efficacy and safety (to week (MDA) criteria]: 84 and 85% showed 20% 156) of ixekizumab in the SPIRIT-P2 trial. improvement (ACR20); 60 and 58% showed What was learned from this study? 50% improvement (ACR50); 35 and 47% showed 70% improvement (ACR70), respec- The significant improvements observed tively; and 48 and 54% showed MDA. Placebo with ixekizumab at week 24 in SPIRIT-P2 patients re-randomized to ixekizumab also were sustained for up to 156 weeks across demonstrated sustained efficacy, as measured multiple endpoints in patients with by ACR and MDA responses. In the All Ixek- inadequate response or intolerance to one izumab Exposure Safety Population (n = 337), or two TNF inhibitors and adverse events with 644 PY of ixekizumab exposure, treatment- were consistent with the known safety emergent adverse events (TEAEs) were reported profile of ixekizumab. by 286 patients (44.4 IR). The most common The findings from SPIRIT-P2 suggest that TEAEs were upper respiratory tract infection ixekizumab is a long-term treatment (9.80 IR), nasopharyngitis (8.2 IR), sinusitis (6.2 option for patients with PsA who have IR), and bronchitis (4.5 IR). Serious adverse shown intolerance or had an inadequate events were reported by 42 (6.5 IR) patients response to one or two TNF inhibitors. (included 3 deaths and 10 infections). Conclusion: In this 156-week study of ixek- izumab, improvements in signs and symptoms of psoriatic arthritis and the safety profile remained consistent with those in previous DIGITAL FEATURES reports. This article is published with digital features, Trial registration: ClinicalTrials.gov identifier: including a summary slide, to facilitate under- NCT02349295. standing of the article. To view digital features for this article go to https://doi.org/10.6084/ Keywords: Efficacy; Interleukin-17A; Ixekizu- m9.figshare.13241459. mab; Psoriatic arthritis; Safety Key Summary Points INTRODUCTION Psoriatic arthritis (PsA) is an inflammatory, Why carry out this study? chronic, immune-mediated disorder present in In the phase 3 SPIRIT-P2 trial of 363 20–30% of patients with psoriasis [1, 2] and in patients with active psoriatic arthritis 0.05–1% of the general population [2]. PsA can (PsA) who had an inadequate response or lead to disease progression with musculoskeletal an intolerance to one or two tumor and extra-articular manifestations [3], resulting necrosis factor (TNF) inhibitors, in impaired function, reduced quality of life, and ixekizumab improved the signs and increased mortality [3, 4]. Treatments for PsA symptoms of PsA with superiority to include nonsteroidal anti-inflammatory drugs, placebo at 24 weeks. intra-articular or systemic glucocorticoids, con- ventional synthetic disease-modifying Rheumatol Ther (2021) 8:199–217 201 antirheumatic drugs (csDMARDs), and biologic the Classification Criteria for Psoriatic Arthritis agents, such as tumor necrosis factor (TNF) (CASPAR) with active PsA [17], defined as at inhibitors [5, 6]. Although TNF inhibitors are least three of 68 tender and three of 66 swollen often effective, 30–40% of patients with PsA have joints at screening and baseline, with active or only a partial response or become resistant or documented history of plaque psoriasis. Eligible intolerant to treatment [7, 8]. Furthermore, patients had been treated previously with at patients with an inadequate response to their least one csDMARD and had an inadequate first TNF inhibitor generally have lower response response (based on a minimum of 12 weeks of on their second or third TNF inhibitor [9]. For this therapy) or intolerance to one or two TNF substantial proportion of patients with prior inhibitors. Reasons for TNF inhibitor failure inadequate response, intolerance, or con- were not systematically collected. traindication to TNF inhibitors, well-tolerated treatments targeting an alternative mechanism Study Design of action and with persistent efficacy are of sig- nificant clinical value [10]. SPIRIT-P2 is a phase 3, randomized, double- Ixekizumab is a high-affinity monoclonal blind, PBO-controlled clinical study that com- antibody that selectively targets interleukin (IL)- prised two treatment periods: the double-blind 17A, a pro-inflammatory cytokine that mediates (weeks 0–24) and extension (weeks 24–156) joint damage [11]. Ixekizumab is approved for use periods. The methods have been reported in in active PsA, moderate-to-severe psoriasis, pedi- detail previously [in brief, see the electronic atric psoriasis (C 6 years with body supplementary material (ESM) file] [15, 18]. weight C 25 kg), ankylosing spondylitis, and Patients who participated in the extension non-radiographic axial spondyloarthritis [12, 13]. periods received ixekizumab 80 mg every Persistent efficacy over 3 years was observed 2 weeks (IXE Q2W) or every 4 weeks (IXE Q4W) in the SPIRIT-P1 trial, a phase 3 trial investi- until study completion or treatment discontin- gating ixekizumab treatment in patients with uation. Starting at week 32, and at all subse- active PsA who had not previously received quent visits during the extension period, biologic therapy for PsA or psoriasis [14]. patients were discontinued from study treat- SPIRIT-P2 is a phase 3 trial of 363 patients with ment for lack of efficacy if they failed to active PsA who had an inadequate response or demonstrate C 20% improvement from base- an intolerance to one or two TNF inhibitors. In line in tender and swollen joint counts. this study, ixekizumab improved the signs and The trial described was conducted in accor- symptoms of PsA with superiority to placebo dance with the Good Clinical Practice guide- (PBO) at 24 weeks [15]. Furthermore, clinical lines of the International Conference on improvements persisted up to 1 year during the Harmonisation and with the principles of the extension period [16]. In this article, the Declaration of Helsinki. The protocol and doc- authors report their evaluation of the long-term umentation was approved by the institutional efficacy and safety profile of ixekizumab in review board or independent ethics committee patients with prior inadequate response or at each investigational site prior to patient intolerance to TNF inhibitors through 3 years of screening (see ESM). All patients provided writ- treatment in SPIRIT-P2. ten informed consent prior to receiving inves- tigational product or undergoing study METHODS procedures. SPIRIT-P2 is registered at Clini- calTrials.gov (NCT02349295). Patients Outcomes Complete inclusion and exclusion criteria for SPIRIT-P2 have been reported previously [15]. Prespecified efficacy and health outcomes mea- Briefly, study participants were adults meeting sures were described previously [15, 16] and 202 Rheumatol Ther (2021) 8:199–217 include the percentage of patients achieving the weeks 16 and 24. As secondary analyses, missing following responses: American College of data were imputed using modified NRI (mNRI) Rheumatology (ACR) response criteria for categorical outcomes or modified baseline improvement of 20%, 50%, or 70% from base- observation carried forward (mBOCF) for con- line (ACR20/50/70); Leeds Enthesitis Index tinuous efficacy variables at all other (LEI = 0) and Leeds Dactylitis Index-Basic (LDI- timepoints. B = 0); C 0.35-point improvement in Health Safety analyses were performed on the All Assessment Questionnaire-Disability Index Ixekizumab Exposure Safety Population (AIESP; (HAQ-DI) score of [minimal clinically impor- IXE Q4W, IXE Q2W), which included all tant difference (MCID)]; as well as skin and nail patients who received at least one dose of outcomes, minimal disease activity (MDA; C 5 ixekizumab at any time during the 156-week of 7 of the Coates criteria [19]), and patient-re- study period, with baseline defined as the time ported outcomes. of first exposure to ixekizumab. Safety results Safety outcomes included the assessment of were summarized as the frequency and inci- adverse events (AEs), serious adverse events dence rate (IR) per 100 patient-years (PY) of (SAEs), and findings from physical examina- exposure to ixekizumab, using the entire dura- tions, vital signs, and laboratory studies. tion of exposure for the treatment period and Adverse events of special interest (AESIs) were expressed as a number of unique patients prespecified and previously discussed [20]. within a particular category of event. Additional details on the efficacy and safety Additional statistical methods, including outcomes assessed are available in the ESM file. detailed definitions for imputation methods, are described in the ESM. Statistical analyses Statistical Analyses were performed using SAS version 9.2 or higher (SAS Institute, Cary, NC, USA). Power calculations for the primary endpoint have been described previously [15]. The RESULTS Extension Period Population (EPP) included patients originally randomized to PBO who Patients were inadequate responders at week 16 and any patients remaining on PBO at week 24, all of Of 363 patients randomized to the PBO who were re-randomized 1:1 to receive IXE (n = 118), IXE Q4W (n = 122), or IXE Q2W Q2W or IXE Q4W (PBO/IXE Q2W and PBO/IXE (n = 123) study arms, 314 patients (87%) com- Q4W groups, respectively) for the duration of pleted the double-blind treatment period and the study or until discontinuation. Efficacy 310 entered the extension treatment period analyses were conducted on the intent-to-treat (weeks 24–156; ESM Fig. S1), as previously (ITT) population (ad hoc) randomly assigned to described [15]. Of the 310 patients who entered IXE Q2W or IXE Q4W at week 0 and on the EPP, the extension treatment period, 168 (54.2%) which included all patients who received at completed 156 weeks of treatment. Discontin- least one dose of ixekizumab during the exten- uation due to lack of efficacy was the most sion period (weeks 24–156). Efficacy results are common reason for patient discontinuation (94 summarized through week 156 as the number patients, 30.3%), with 75.5% of discontinua- and percentage of patients meeting response tions due to the mandatory discontinuation criteria for categorical variables or as the mean criteria (MDC; failure to demonstrate C 20% (standard deviation) change from baseline for improvement from baseline in tender and continuous variables. There were no compar- swollen joint counts [ACR20]) from baseline isons made between treatment groups. For effi- beginning at week 32. The majority of patients cacy variables, data were reported as observed. who discontinued due to MDC did so within Patients who received rescue therapy at week 16 the first year of treatment. At week 32, 23 of 310 were imputed as nonresponders (NRI) between patients (7.4%) discontinued due to MDC; Rheumatol Ther (2021) 8:199–217 203 between weeks 36 and 52, an additional 37 Q4W- and IXE Q2W-treated patients (Fig. 1). (11.9%) patients discontinued due to MDC; a Very low disease activity (7 of 7 MDA compo- further nine (2.9%) and two (0.6%) patients nents) response rates were also numerically discontinued due to MDC between weeks 52 similar between the IXE Q4W- and IXE Q2W- and 108 and weeks 108 and 156, respectively. treated patients (23 and 20%, respectively; ESM Baseline characteristics for the ITT popula- Fig. S2). As measured by Disease Activity Index tion [15] and for those who entered the exten- for Psoriatic Arthritis (DAPSA), at week 156, sion period [16] have been previously published. 41% of IXE Q4W- and 35% of IXE Q2W-treated In general, demographics and clinical charac- patients achieved low disease activity (LDA) and teristics for the ITT population were well bal- 33% of IXE Q4W- and 37% of IXE Q2W-treated anced among the study arms. Demographics patients achieved remission (ESM Fig. S2). As and clinical characteristics for the EPP were determined by a 28-joint Disease Activity Score comparable to those for the ITT population. using C-reactive protein \ 2.6, at week 156, Briefly, patients entering the extension period 67% of IXE Q4W-treated patients and 59% of were, on average, 51.8 years old, the majority IXE Q2W-treated patients had achieved remis- were white (92%), and slightly more than half sion (ESM Fig. S2). Response rates for composite were female (53%). Mean tender joint count was endpoints were lower but followed a similar 23 (of 68 joints) and swollen joint count was 12 pattern using the more conservative mNRI (of 66 joints). Within the EPP, 55% of patients approach (ESM Fig. S2). were inadequate responders to one TNF inhi- In patients with baseline dactylitis (LDI- bitor, 37% of patients were inadequate respon- B [ 0) and baseline enthesitis (LEI [ 0), IXE ders to two TNF inhibitors, and 9% of patients Q4W- and IXE Q2W-treated patients demon- showed intolerance to a TNF inhibitor [16]. strated persistent reductions through week 156 (Fig. 2). Complete resolution of dactylitis was Efficacy Outcomes achieved by 100% of IXE Q4W- and 91.7% of IXE Q2W-treated patients; however, observed Endpoints for the ITT population at week 108 data from the ITT population with baseline LDI- and week 156 are summarized in Table 1 (ob- B [ 0 are available for only 17 and 12 patients served) and ESM Table S1 (mNRI). As observed, in the IXE Q4W and IXE Q2W groups, respec- ACR20, ACR50, and ACR70 response rates in tively. Complete resolution of enthesitis was the ITT population were 84, 60, and 35%, achieved by 63% of IXE Q4W- and 79% of IXE respectively, in the IXE Q4W group and 85, 58, Q2W-treated patients (Table 1). Changes from and 47%, respectively, in the IXE Q2W group at baseline in LDI-B and LEI followed similar pat- week 156 (Fig. 1; Table 1). By mNRI analysis, the terns when missing data were imputed with ACR20, ACR50, and ACR70 response rates were mBOCF (Fig. 2). sustained to week 156: 55, 40, and 23% of IXE Among patients with baseline psoriasis, body Q4W-treated patients and 48, 34, and 25% of surface area (BSA) involvement C 3%, 79% of IXE Q2W-treated patients, respectively (ESM patients receiving IXE Q4W and 96% of those Table S1; Fig. 1). At week 156, patients on PBO receiving IXE Q2W achieved at least a 75% who were re-randomized to ixekizumab at week reduction in the baseline Psoriasis Area and 16 or 24 demonstrated ACR responses relatively Severity Index (PASI 75); 65 and 75% reached comparable with those of patients receiving PASI 90; and 51 and 64% attained PASI 100, continuous IXE treatment. ACR20, ACR50, and respectively, at week 156 (Table 1). PASI ACR70 response rates were 54, 41, and 24% of responses achieved at week 24 were maintained PBO/IXE Q4W-treated patients and 47, 36, and through the extension period (Fig. 3). Complete 12% of PBO/IXE Q2W-treated patients, respec- resolution of itch [Itch numeric rating scale tively (ESM Table S2). (NRS) = 0] in the ITT population with baseline At week 156, MDA (5 of 7 MDA components) psoriatic lesions involving C 3% BSA was was achieved by approximately 50% of the IXE achieved by 29 and 41% of IXE Q4W- and IXE Q2W-treated patients, respectively, at week 156 Table 1 Overview of efficacy at week 108 and week 156 (ITT population, observed data) 204 Efficacy outcomes Week 108 Week 156 IXE Q4W (n = 122) IXE Q2W (n = 123) IXE Q4W (n = 122) IXE Q2W (n = 123) Response rate, n/Nx (%) ACR20 64/78 (82.1) 52/62 (83.9) 56/67 (83.6) 45/53 (84.9) ACR50 47/74 (63.5) 36/62 (58.1) 39/65 (60.0) 31/53 (58.5) ACR70 25/79 (31.7) 26/61 (42.6) 24/68 (35.3) 24/51 (47.1) PASI 75a 39/47 (83.0) 29/32 (90.6) 34/43 (79.1) 27/28 (96.4) a PASI 90 33/47 (70.2) 24/32 (75.0) 28/43 (65.1) 21/28 (75.0) PASI 100a 23/47 (48.9) 21/32 (65.6) 22/43 (51.2) 18/28 (64.3) b NAPSI = 0 37/62 (60.0) 24/40 (60.0) 33/55 (60.0) 24/35 (68.6) c LEI = 0 30/44 (68.2) 28/43 (65.1) 24/38 (63.2) 30/38 (79.0) d LDI-B = 0 17/17 (100.0) 12/13 (92.3) 17/17 (100.0) 11/12 (91.7) e MDA 38/80 (47.5) 32/63 (50.8) 33/69 (47.8) 29/54 (53.7) e VLDA 14/80 (17.5) 11/63 (17.5) 16/70 (22.9) 11/55 (20.0) DAPSA LDA ([ 4 and B 14) 36/78 (46.2) 27/63 (42.9) 28/69 (40.6) 19/54 (35.2) DAPSA remission (B 4) 17/78 (21.8) 19/63 (30.2) 23/69 (33.3) 20/54 (37.0) f HAQ-DI C 0.35 39/70 (55.7) 35/56 (62.5) 37/60 (61.7) 30/50 (60.0) Itch NRS = 0a 10/47 (21.3) 12/32 (37.5) 12/42 (28.6) 11/27 (40.7) Change from baseline, mean (SD) NAPSIb - 15.9 (20.5) - 19.7 (20.1) - 16.6 (21.5) - 19.6 (20.3) c LEI - 2.0 (2.1) - 2.3 (1.6) - 1.8 (1.8) - 2.5 (1.6) LDI-Bd - 28.7 (21.2) - 54.7 (37.0) - 28.7 (21.2) - 54.7 (40.2) DAPSA - 38.1 (22.0) - 38.5 (22.7) - 38.7 (23.3) - 38.9 (23.5) DAS28-CRP - 2.7 (1.2) - 2.4 (1.1) - 2.8 (1.3) - 2.4 (1.1) Joint pain VAS - 33.4 (26.4) - 34.3 (25.8) - 37.9 (25.9) - 35.1 (26.0) Rheumatol Ther (2021) 8:199–217 Table 1 continued Efficacy outcomes Week 108 Week 156 IXE Q4W (n = 122) IXE Q2W (n = 123) IXE Q4W (n = 122) IXE Q2W (n = 123) HAQ-DI - 0.4 (0.6) - 0.5 (0.6) - 0.5 (0.6) - 0.5 (0.6) Itch NRS - 3.0 (3.0) - 4.2 (3.3) - 3.2 (3.1) - 4.4 (3.5) Fatigue severity NRS - 2.1 (2.8) - 3.3 (2.9) - 2.4 (2.9) - 2.5 (2.9) Rheumatol Ther (2021) 8:199–217 EQ-5D VAS 16.0 (21.8) 18.8 (17.8) 18.6 (20.1) 16.9 (18.7) WPAI-SHP Absenteeism - 3.9 (17.9) 2.1 (38.5) - 5.6 (23.4) 0.8 (30.5) Presenteeism - 30.0 (24.7) - 26.0 (24.0) - 28.3 (31.0) - 25.0 (20.2) Work productivity - 29.9 (26.7) - 26.9 (27.9) - 26.8 (35.3) - 18.7 (27.1) Activity impairment - 27.3 (28.3) - 24.3 (28.1) - 25.4 (30.0) - 24.0 (26.4) SF-36 MCS 3.8 (11.4) 4.9 (10.0) 4.4 (10.5) 5.6 (8.2) SF-36 PCS 8.1 (10.6) 10.0 (10.3) 9.1 (9.8) 10.3 (9.0) ACR American College of Rheumatology, BSA body surface area, DAPSA Disease Activity in Psoriatic Arthritis, DAS28-CRP 28-joint DAS using C-reactive protein, EQ-5D EuroQol 5-dimensions, HAQ-DI Health Assessment Questionnaire-Disability Index, ITT intent-to-treat; IXE Q2W ixekizumab 80 mg every 2 weeks, IXE Q4W ixekizumab 80 mg every 4 weeks, LDA low disease activity, LDI-B Leeds Dactylitis Index-Basic, LEI Leeds Enthesitis Index, MCS mental component summary, MDA minimal disease activity, NAPSI Nail Psoriasis Severity Index, NRS numeric rating scale, Nx number of patients with nonmissing data, PASI Psoriasis Area and Severity Index, PCS physical component summary, SD standard deviation, SF-36 Medical Outcomes Survey Short Form (36 items), VAS visual analog scale, VLDA very low disease activity, WPAI-SHP Work Productivity Activity Impairment-Specific Health Problem a Among patients with psoriasis and BSA involvement of C 3% at baseline b Among patients with baseline fingernail involvement c Among patients with baseline LEI [ 0 d Among patients with baseline LDI-B [ 0 e MDA defined as achieving 5/7 of the following MDA components: tender joint count B 1, swollen joint count B 1, PASI B 1 or BSA B 3%, patient pain VAS B 15, patient global disease activity VAS B 20, HAQ-DI B 0.5, and B 1 tender entheseal points. VLDA is defined as achieving 7/7 of of these components f Among patients with baseline HAQ-DI C 0.35 205 206 Rheumatol Ther (2021) 8:199–217 Fig. 1 American College of Rheumatology (ACR) and achieving five of the seven following MDA components: minimal disease activity (MDA) responses up to week 156, TJC B 1, SJC B 1, Psoriasis Area and Severity Index B 1 as observed and modified nonresponder imputation or body surface area B 3%, patient pain visual analog scale (mNRI). Intent-to-treat population randomized to ixek- (VAS) B 15, patient global disease activity VAS B 20, izumab at week 0. Starting at week 32, and at all Health Assessment Questionnaire–Disability Index B 0.5, subsequent visits during the extension period, patients were and B 1 tender entheseal points. ACR20/50/70 ACR discontinued from study treatment if they failed to response criteria improvement of 20, 50, or 70%, respec- demonstrate C 20% improvement from baseline in tender tively, IXE Q2W ixekizumab 80 mg every 2 weeks, IXE (TJC) and swollen (SJC) joint counts. MDA defined as Q4W ixekizumab 80 mg every 4 weeks (Table 1). In patients with baseline fingernail ixekizumab treatment (Fig. 4). Responses in psoriasis, measured by a modified version of the additional patient-reported quality-of-life out- Nail Psoriasis Severity Index (NAPSI) that comes, including Fatigue NRS, EuroQol 5-di- includes only fingernails (score range 0–40), mensions visual analog scale (VAS), and Work improvements in NAPSI observed at week 24 Productivity Activity Impairment-Specific persisted through week 156 (Fig. 2). At week Health Problem, were also sustained through 156, 60 and 69% of patients treated with IXE week 156 (Table 1). On average, about 10-point Q4W and IXE Q2W, respectively, achieved improvements from baseline in the Medical complete resolution of fingernail psoriasis Outcomes Survey Short Form (36 items) (SF- (Table 1). 36)–physical component summary and At week 156, improvements in physical approximately 5-point improvements in the SF- function measured by HAQ-DI MCID (C 0.35 36–mental component summary were reported improvement from baseline) occurred in 62% of by IXE-treated patients at week 156 (Table 1). IXE Q4W- and 60% of IXE Q2W-treated patients Improvements in the individual domains of the (with baseline HAQ-DI C 0.35) (Table 1). SF-36 at week 108 and week 156 were also Improvements from baseline in HAQ-DI observed (ESM Table S3). Improvements in the observed in the double-blind period persisted SF-36 vitality domain were consistent with through 156 weeks of extension-period improvements in the Fatigue NRS. Similarly, Rheumatol Ther (2021) 8:199–217 207 Fig. 2 Enthesitis, dactylitis, and nail psoriasis up to week was assessed in patients with fingernail psoriasis at baseline. 156 [observed and modified baseline observation carried Starting at week 32, and all subsequent visits during the forward (mBOCF)]. Intent-to-treat population random- extension, patients not demonstrating C 20% improve- ized to ixekizumab at week 0. Leeds Enthesitis Index (LEI) ment from baseline in both tender and swollen joint and Leeds Dactylitis Index–Basic (LDI-B) were assessed in counts were discontinued . IXE Q2W ixekizumab 80 mg patients with baseline LEI score [ 0 and LDI-B score [ 0, every 2 weeks, IXE Q4W ixekizumab 80 mg every 4 weeks respectively. Nail Area Psoriasis Severity Index (NAPSI) 208 Rheumatol Ther (2021) 8:199–217 Fig. 3 Psoriasis Area and Severity Index (PASI) responses failed to demonstrate C 20% improvement from baseline (observed and with mNRI). Intent-to-treat population in tender and swollen joint counts. IXE Q2W ixekizumab randomized to ixekizumab at week 0 with C 3% body 80 mg every 2 weeks, IXE Q4W ixekizumab 80 mg every 4 surface area of disease at baseline. Starting at week 32, and weeks, PASI 75/90/100 75/90/100% improvement from at all subsequent visits during the extension period, baseline on the PASI, respectively patients were discontinued from study treatment if they Rheumatol Ther (2021) 8:199–217 209 Fig. 4 Health Assessment Questionnaire-Disability Index HAQ-DI C 0.35. Starting at week 32, and all subsequent (HAQ-DI) minimal clinically important difference visits during the extension period, patients not demon- (MCID; observed and with mNRI) and HAQ-DI change strating C 20% improvement from baseline in tender and from baseline (observed and mBOCF) up to week 156. swollen joint counts were discontinued. IXE Q2W Intent-to-treat population randomized to ixekizumab at ixekizumab 80 mg every 2 weeks, IXE Q4W ixekizumab week 0. MCID was assessed in patients with baseline 80 mg every 4 weeks improvements in the SF-36 bodily pain domain who received at least one dose of study medi- correlated with improvements in joint pain cation reported one or more treatment-emer- VAS, with an approximate 37-point improve- gent adverse events (TEAEs) throughout 3 years ment from baseline in joint pain at week 156 of the study, with an IR of 44.4, with a similar (Table 1). distribution of patients in each treatment group (IXE Q4W, n = 141; IXE Q2W, n = 145). Most Safety TEAEs were mild or moderate in severity. The most common TEAEs (occurring in C 5% of A total of 337 patients with prior intolerance or patients in the AIESP; n = 337; IR per 100 PY) inadequate response to one or two TNF inhibi- were upper respiratory tract infection (IXE tors were included through the 3-year extension Q4W, 9.0 IR; IXE Q2W, 10.7 IR), nasopharyn- period of SPIRIT-P2. Patients treated with IXE gitis (IXE Q4W, 8.4 IR; IXE Q2W, 8.0 IR), Q4W (n = 168) and IXE Q2W (n = 169) sinusitis (IXE Q4W, 6.4 IR; IXE Q2W, 6.0 IR), accounted for 345.1 and 298.9 PY of exposure, bronchitis (IXE Q4W, 4.1 IR; IXE Q2W, 5.0 IR), respectively (Table 2). Overall, 85% of patients 210 Rheumatol Ther (2021) 8:199–217 Table 2 Adverse events per 100 patient-years of exposure Incidence ratea IXE Q4W (n = 168) IXE Q2W (n = 169) Overall Years 0–1 Years 1–2 Years Overall Years 0–1 Years Years (345.1 (143.4 (113.2 2–3 (298.9 (133.9 1–2 2–3 PY) PY) PY) (87.4 PY) PY) (92.9 (71.8 PY) PY) PY) TEAEs 141 (83.9) 133 (79.2) 84 (50.0) 57 (33.9) 145 (85.8) 136 (80.5) 72 (42.6) 48 (28.4) [40.9] [92.7] [74.2] [65.2] [48.5] [101.6] [77.5] [66.8] Mild 41 (24.4) 60 (35.7) 40 (23.8) 26 (15.5) 43 (25.4) 54 (32.0) 24 (14.2) 22 (13.0) [11.9] [41.8] [35.3] [29.7] [14.4] [40.3] [25.8] [30.6] Moderate 85 (50.6) 66 (39.3) 37 (22.0) 27 (16.1) 74 (43.8) 69 (40.8) 34 (20.1) 24 (14.2) [24.6] [46.0] [32.7] [30.9] [24.8] [51.5] [36.6] [33.4] Severe 15 (8.9) 7 (4.2) 7 (4.2) 4 (2.4) 28 (16.6) 13 (7.7) 14 (8.3) 2 (1.2) [4.3] [4.9] [6.2] [4.6] [9.4] [9.7] [15.1] [2.8] Discontinuations due 17 (10.1) 7 (4.2) 7 (4.2) 3 (1.8) 21 (12.4) 14 (8.3) 7 (4.1] 0 to adverse eventb [4.9] [4.9] [6.2] [3.4] [7.0] [10.5] [7.5] Serious adverse eventsb 19 (11.3) 7 (4.2) 10 (6.0) 5 (3.0) 23 (13.6) 9 (5.3) 12 (7.1) 3 (1.8) (5.5) [4.9] [8.8] [5.7] [7.7] [6.7] [12.9] [4.2] Deaths 1 (0.6) 0 0 1 (0.6) 2 (1.2) 0 2 (1.2) 0 [0.3] [1.1] [0.7] [2.2] Infections 112 (66.7) 91 (54.2) 52 (31.0) 32 (19.0) 101 (59.8) 84 (49.7) 49 (29.0) 31 (18.3) [32.5] [63.4] [45.9] [36.6] [33.8] [62.7] [52.8] [43.2] Serious infections 5 (3.0) 2 (1.2) 2 (1.2) 1 (0.6) 5 (3.0) 3 (1.8) 3 (1.8) 0 [1.4] [1.4] [1.8] (0.6) (3.0) [1.7] [2.2] [3.2] [1.1] Allergic reactions and 17 (10.1) 14 (8.3) 3 (1.8) 2 (1.2) 16 (9.5) 13 (7.7) 4 (2.4) 1 (0.6) hypersensitivities [4.9] [9.8] [2.7] [2.3] [5.4] [9.7] [4.3] [1.4] Anaphylaxis 0 0 0 0 0 0 0 0 Injection-site reactions 25 (14.9) 23 (13.7) 4 (2.4) 1 (0.6) 42 (24.9) 42 (24.9) 5 (3.0) 3 (1.8) [7.2] [16.0] [3.5] [1.1] [14.1] [31.4] [5.4] [4.2] Cerebrocardiovascular 2 (1.2) 0 0 2 (1.2) 7 (4.1) 0 7 (4.1) 0 eventsc [0.6] [2.3] [2.3] [7.5] Malignancies 7 (4.2) 3 (1.8) 3 (1.8) 2 (1.2) 2 (1.2) 0 2 (1.2) 0 [2.0] [2.1] [2.7] [2.3] [0.7] [2.2] Depression 6 (3.6) 4 (2.4) 2 (1.2) 0 4 (2.4) 2 (1.2) 2 (1.2) 0 [1.7] [2.8] [1.8] [1.3] [1.5] [2.2] Rheumatol Ther (2021) 8:199–217 211 Table 2 continued Incidence ratea IXE Q4W (n = 168) IXE Q2W (n = 169) Overall Years 0–1 Years 1–2 Years Overall Years 0–1 Years Years (345.1 (143.4 (113.2 2–3 (298.9 (133.9 1–2 2–3 PY) PY) PY) (87.4 PY) PY) (92.9 (71.8 PY) PY) PY) Inflammatory bowel diseased Reported by 1 (0.6) 0 1 (0.6) 0 0 0 0 0 investigator [0.3] [0.9] Confirmed by 0 0 0 0 0 0 0 0 adjudicatione Cytopenias 3 (1.8) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 0 0 [0.9] [1.4] [1.1] [0.3] [0.7] Hepatic events 14 (8.3) 8 (4.8) 6 (3.6) 2 (1.2) 12 (7.1) 8 (4.7) 2 (1.2) 2 (1.2) [4.1] [5.6] [5.3] [2.3] [4.0] [6.0] [2.2] [2.8] Values in table are presented as a number, with the percentage in parentheses and the IR per 100 PY in square brackets IR incidence rate, PY patient-years, TEAE treatment-emergent adverse event a Patients may have multiple events per category b Deaths are also included as serious adverse events and study treatment discontinuations due to adverse events c Cerebro-cardiovascular events have been adjudicated d Inflammatory bowel disease includes the following narrow terms: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, and ulcerative proctitis e Cases were reviewed by an independent committee of experts for adjudication and classified as ‘probable’ or ‘definite’ by Registre Epidemiologique des Maladies de l’Appareil Digestif (EPIMAD) criteria and urinary tract infection (IXE Q4W, 4.6 IR; recorded in the extension period. One female IXE Q2W, 2.7 IR). patient aged 64 years (IXE Q4W group) died The frequency of AEs leading to discontinu- from metastatic renal cell carcinoma on day 503 ation was slightly lower with IXE Q4W than of treatment. One male patient aged 65 years with IXE Q2W overall (n = 17 vs. n = 21). The IR (PBO/IXE Q2W group) with a history of chronic of discontinuations was also reasonably obstructive pulmonary disease and hyperten- stable over time in the IXE Q4W group (IR range sion died as a result of cardiopulmonary arrest 4.9–6.2) but more variable in the IXE Q2W on day 334 of treatment. One female patient group (IR range 0–10.5), with no events in the 2- aged 75 years (IXE Q2W group) died from to 3-year timeframe for IXE Q2W (Table 2). myocardial infarction on day 765 of treatment. Except for psoriatic arthropathy reported by two This patient had a history of chronic obstructive patients in the IXE Q4W group, all other AEs pulmonary disease, coronary artery disease, resulting in discontinuation were reported in hyperlipidemia, hypercholesterolemia, tran- one patient each (ESM Table S4). SAEs were sient ischemic attack, and previous myocardial reported by 19 (5.5 IR) IXE Q4W-treated infarction. None of the deaths were considered patients and 23 (7.7 IR) IXE Q2W-treated by the investigator to be related to the study patients (ESM Table S5). Three deaths were drug. 212 Rheumatol Ther (2021) 8:199–217 The IR of infections, reported as n (IR per 100 nonmelanoma skin cancer (NMSC). Malignan- PY), was 112 (32.5) and 101 (33.8) for IXE Q4W- cies excluding NMSC occurred in four patients and IXE Q2W-treated patients, respectively. in the IXE Q4W group and one patient in the Infections were more common during the first IXE Q2W group. year of treatment, after which the IR decreased Previously, a patient was reported in the over time. Ten serious infections were reported, double-blind treatment period as having SAEs of five in each IXE treatment group. These inclu- anal abscess and anal fistula considered by the ded pneumonia (one patient in each ixek- sponsor to be consistent with inflammatory izumab arm); diverticulitis, latent tuberculosis, bowel disease (IBD). Upon post hoc adjudica- lower respiratory tract infection, oral candidia- tion by an external committee of IBD special- sis (one patient each in the IXE Q4W arm); jaw ists, the event was determined to not be a abscess, anal abscess, perirectal abscess, and confirmed event of IBD [15]. A second patient, a esophageal candidiasis (one patient each in the 47-year-old woman (with a medical history IXE Q2W arm). Fifteen patients had Candida consistent with the presence of ulcerative coli- infections (high-level term): one patient (0.3 IR) tis) who was randomized to PBO at baseline and in the IXE Q4W arm and five patients (1.7 IR) in received IXE Q4W in the extension period, the IXE Q2W arm had oral candidiasis; two reported an event of ulcerative colitis. The patients in each arm had vulvovaginal can- external adjudication committee determined didiasis (1.2 IR per 100 PY each); one patient in that this event was not a confirmed event of each arm had genital candidiasis (0.6 IR IXE IBD. Q4W and 0.3 IR IXE Q2W); one patient in the Nine patients (2 [0.6 IR] in the IXE Q4W IXE Q2W arm had esophageal candidiasis (0.3 group and 7 [2.3 IR] in the IXE Q2W group) had IR); and two patients in the IXE Q4W arm had a cerebro-cardiovascular event confirmed by skin candida (0.6 IR). Nine patients had fungal external adjudication. All cerebrocardiovascular infections (high-level term): five patients (1.4 events in the IXE Q4W group occurred in years IR) in the IXE Q4W arm and four (1.3 IR) in the 2–3, and all events in the IXE Q2W group IXE Q2W arm. No case of Candida or fungal occurred during years 1–2 of the extension infection resulted in discontinuation; all were period. Depression was reported in ten patients mild to moderate and without deep organ (6 in the IXE Q4W arm and 4 in the IXE Q2W involvement. Five (1.7 IR) cases of herpes zoster arm), with a similar IR across both treatment in the IXE Q2W treatment group were observed, groups (Table 2). none of which resulted in treatment discontin- uation. No cases of active tuberculosis were reported. DISCUSSION The IR of hypersensitivity events, reported as n (IR per 100 PY), in the IXE Q4W and IXE Q2W The data reported in this study covers up to treatment groups was 17 (4.9) and 16 (5.4), 3 years of continuous treatment with ixek- respectively, and generally decreased from year izumab in a difficult-to-treat population of 1 to year 3. There were no reports of anaphy- patients with PsA who had an inadequate laxis. A total of 67 injection-site reaction (ISR) response or were intolerant to one or two TNF events were observed: 25 (7.2 IR) in the IXE inhibitors. Treatment with ixekizumab resulted Q4W treatment group and 42 (14.1 IR) in the in improvements in the signs and symptoms of IXE Q2W treatment group. The IR of ISRs PsA that persisted from week 24 through week decreased after the first year of treatment. 156. ACR20 responses (primary study endpoint) There were nine patients with malignancies: at week 24 (IXE Q4W, 71% and IXE Q2W, 67%; seven (2.0 IR) in the IXE Q4W treatment group observed), were maintained to week 156 (IXE and two (0.7 IR) in the IXE Q2W treatment Q4W, 84% and IXE Q2W, 85%; observed). group. The IRs of malignancies were constant Ixekizumab treatment was also associated with over time. Four patients in the IXE Q4W group resolution of enthesitis and improvement of and one patient in the IXE Q2W group had patient-reported physical and mental outcomes Rheumatol Ther (2021) 8:199–217 213 and plaque and nail psoriasis over the study observed with the IL-17A inhibitor secuk- duration. High rates of dactylitis resolution inumab (IR 1.9 in PsA) [28] and the TNF inhi- were also achieved in both groups, but the small bitors adalimumab (IR 2.8 in PsA) [29] and number of patients with dactylitis at baseline golimumab (IR 1.0 across indications) [30]. limits the scope of conclusions that can be ISRs have been noted with all US Food and drawn from these data. Drug Administration-approved self-in- The treat-to-target goals of MDA, DAPSA jectable biological agents [31]. None of the ISRs LDA, and DAPSA remission were achieved by with ixekizumab were considered to be serious approximately 50, 38, and 35% of patients, and all were mild or moderate in severity in this respectively, treated with ixekizumab through study. ISRs were numerically higher in the IXE week 156. Patients taking PBO who were re- Q2W (14.1 IR) arm than in the IXE Q4W (7.2 IR) randomized to ixekizumab treatment at week arm, with one discontinuation due to ISRs in 16 or 24 demonstrated comparable efficacy at each arm. In agreement with other studies of week 156 in joint and skin endpoints to patients ISRs with ixekizumab, reactions were typically on continuous ixekizumab treatment. Although tolerable, manageable, and decreased over time this clinical trial was not powered to detect [32]. statistical differences between the IXE Q2W and People with PsA have a two- to three-fold IXE Q4W treatment arms, there was no appar- increased risk of IBD [33, 34], and IBD is an AESI ent increased benefit with IXE Q2W relative to for the IL-17 inhibitor class of biologics [35, 36]. IXE Q4W (the approved dose for the treatment In this study, IBD events were infrequent (IXE of active PsA in patients who do not have Q4W, 0.3 IR; IXE Q2W, 0 IR). This is in line with coexisting moderate-to-severe psoriasis [12, 13]) the expected IR of IBD (Crohn’s disease or in arthritis-related measures. These 3-year data, ulcerative colitis) in patients with PsA both observed as well as mNRI, support the (0.03–0.11 IR) [33, 37, 38] and is consistent with long-term continued efficacy of ixekizumab for an integrated analysis demonstrating that the treatment of active PsA. among 8228 ixekizumab-treated patients with The safety profile of ixekizumab was gener- psoriasis, PsA, or axial spondyloarthritis, IBD ally consistent with that previously observed in was reported in \ 1% of the population [27]. patients with active PsA or moderate-to-severe The SPIRIT clinical trial program was unique psoriasis who received ixekizumab and with the in assessing the efficacy of ixekizumab in two double-blind treatment period of this study distinct patient populations. Three-year data [15, 16, 21–23]. Most TEAEs were mild or mod- from SPIRIT-P1, a phase 3 trial investigating erate in severity and the IR tended to decrease ixekizumab treatment in patients with active over time. Overall, the exposure-adjusted IR of PsA who had not previously received biologic discontinuations due to AEs was low and similar therapy for PsA or psoriasis, have recently been between ixekizumab treatment arms. published [14]. Patients with inadequate Treatments that modulate immune response response to one TNF inhibitor typically have may increase susceptibility to infection, but this decreased response to a second TNF inhibitor typically reduces after the first 6 months to [9, 39]. This population of patients with PsA, 1 year of treatment [24–27]. Throughout the over half of whom were inadequate responders 156-week treatment period, there were no to one TNF inhibitor and over a third were unexpected infections, and the IR tended to inadequate responders to two TNF inhibitors, decrease over time. Cases of candidiasis were presents specific challenges to clinicians but has more frequent with IXE Q2W than IXE Q4W, not been studied extensively in dedicated clin- and no event led to discontinuation. The over- ical trials. Efficacy data from SPIRIT-P2 assessing all IR for serious infections was low (IR range multiple characteristics of PsA, including 1.4–1.8) and was comparable to overall rates enthesitis, dactylitis, skin and nail psoriasis, and observed with ixekizumab treatment across patient-reported outcomes support ixekizumab several indications [27]. Furthermore, the IRs as a viable treatment option in this population for serious infections were comparable to those of patients with refractory disease. The efficacy 214 Rheumatol Ther (2021) 8:199–217 and safety findings of SPIRIT-P2 are similar with ACKNOWLEDGEMENTS the observations from SPIRIT-P1; however, as is expected in the more difficult patient popula- The authors would like to thank the patients for tion of SPIRIT P2, levels of response are slightly their involvement in the study. lower than in SPIRIT P1 [14]. Long-term efficacy and safety data from SPIRIT-P1 and -P2 indicate Funding. The studies described in this that ixekizumab is an effective treatment option manuscript were sponsored by Eli Lilly and for patients with active PsA across the multiple Company, which was involved in the study disease domains, even among patients who design, data collection, data analysis, and have had an inadequate response to one or two preparation of the manuscript. Eli Lilly and TNF inhibitors. Company also funded the journal’s Rapid Ser- One of the inherent limitations to the study vice Fees. design of this trial was the implementation of MDC at week 32. These criteria limit the gen- Medical Writing and Other Assis- eralizability of these data as they do not allow tance. Medical writing assistance was provided for fluctuation in PsA disease activity that is by Samantha Forster, PhD, CMPP, of ProScribe – often managed in the clinic with concomitant Envision Pharma Group, and was funded by Eli csDMARDs or steroids before discontinuing or Lilly and Company. ProScribe’s services com- switching a biologic DMARD. It should also be plied with international guidelines for Good acknowledged that the resulting patient popu- Publication Practice (GPP3). lation may partially contribute to the favorable outcomes observed in this study. This trial also Authorship. All named authors meet the did not include an assessment of radiographic International Committee of Medical Journal progression, the inhibition of which has been Editors (ICMJE) criteria for authorship for this shown previously with ixekizumab [21, 23], and article, take responsibility for the integrity of the prevention of which is important for joint the work as a whole, and have given their integrity. However, in a PsA population with a approval for this version to be published. high proportion of TNF inadequate responders, baseline X-ray data may be difficult to interpret. Authorship Contributions. All authors par- ticipated in the interpretation of study results and in the drafting, critical revision, and CONCLUSION approval of the final version of the manuscript. In conclusion, ixekizumab provided sustained Disclosures. Ana-Maria Orbai is a Jerome L. and clinically meaningful improvement in the Greene Foundation Scholar and is supported in signs and symptoms of active PsA for up to part by a research grant from the National 156 weeks among patients with an inadequate Institute of Arthritis and Musculoskeletal and response or intolerance to one or two TNF Skin Diseases of the National Institutes of inhibitors. The safety findings were consistent Health under award number P30-AR070254; is a with the known safety profile of ixekizumab. consultant for Eli Lilly and Company, Janssen, Overall, these results support the long-term use Novartis, Pfizer, and UCB Pharma; has received of ixekizumab among patients with PsA, research funding from Celgene, Janssen, and including those who may be more difficult to Novartis; and has been an investigator for treat due to prior inadequate response to TNF AbbVie, Celgene, Eli Lilly and Company, Gilead inhibitors. Sciences, and Novartis. Jordi Gratacós has received research grants or consulting fees from AbbVie, Celgene, Eli Lilly and Company, Jans- sen, Novartis, and Pfizer. Anthony Turkiewicz has received research grants or consulting fees from AbbVie, Eli Lilly and Company, Janssen, Rheumatol Ther (2021) 8:199–217 215 Novartis, and Pfizer and is on the speakers or independent ethics committee at each bureau for AbbVie, Eli Lilly and Company, investigational site prior to patient screening Janssen, Novartis, and Pfizer. Stephen Hall has (see ESM). All patients provided written received research funding from AbbVie, Bristol informed consent prior to receiving investiga- Myers Squibb, Celgene, Eli Lilly and Company, tional product or undergoing study procedures. Janssen, Pfizer, and UCB Pharma. Eva Dok- SPIRIT-P2 is registered at ClinicalTrials.gov oupilova received grant/research support from (NCT02349295). AbbVie, Affibody AB, Eli Lilly and Company, Galapagos, Gilead Sciences, GSK, Hexal AG, Data Availability. Eli Lilly and Company Merck, Novartis, Pfizer, R-Pharm, Sanofi-Aven- provides access to all individual participant data tis, and UCB Biopharma SPRL. Bernard Combe collected during the trial, after anonymization, has received grant/research support from with the exception of pharmacokinetic or Novartis, Pfizer, and Roche-Chugai; is a con- genetic data. Data are available to request sultant for AbbVie, Bristol Myers Squibb, Eli 6 months after the indication studied has been Lilly and Company, Janssen, Merck Sharp & approved in the US and EU and after primary Dohme, Novartis, Roche-Chugai, and UCB publication acceptance, whichever is later. No Pharma; and is on the speakers bureau of Bristol expiration date of data requests is currently set Myers Squibb, Eli Lilly and Company, Gilead once data are made available. Access is provided Sciences, Merck Sharp & Dohme, and Pfizer. after a proposal has been approved by an inde- Peter Nash is a consultant for AbbVie, Amgen, pendent review committee identified for this Bristol Myers Squibb, Celgene, Eli Lilly and purpose and after receipt of a signed data shar- Company, Hospira, Janssen, Merck Sharp & ing agreement. Data and documents, including Dohme, Novartis, Pfizer, Roche, Sanofi, and the study protocol, statistical analysis plan, UCB Pharma; is on the speakers bureau of clinical study report, and blank or annotated AbbVie, Amgen, Bristol Myers Squibb, Celgene, case report forms, will be provided in a secure Eli Lilly and Company, Hospira, Janssen, Merck data sharing environment. For details on sub- Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, mitting a request, see the instructions provided and UCB Pharma; and has received research at http://www.vivli.org. funding from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Hos- Open Access. This article is licensed under a pira, Janssen, Merck Sharp & Dohme, Novartis, Creative Commons Attribution-NonCommer- Pfizer, Roche, Sanofi, and UCB Pharma. Gaia cial 4.0 International License, which permits Gallo, Clinton C. Bertram, Amanda M. Gellett, any non-commercial use, sharing, adaptation, Aubrey Trevelin Sprabery, Julie Birt, Lisa distribution and reproduction in any medium Macpherson, and Vladimir J. Geneus are or format, as long as you give appropriate credit employees and shareholders of Eli Lilly and to the original author(s) and the source, provide Company. Arnaud Constantin has received a link to the Creative Commons licence, and consulting fees from AbbVie, Bristol Myers indicate if changes were made. The images or Squibb, Celgene, Janssen, Eli Lilly and Com- other third party material in this article are pany, Gilead Sciences, Medac, Merck Sharp & included in the article’s Creative Commons Dohme, Nordic Pharma, Novartis, Pfizer, Sanofi, licence, unless indicated otherwise in a credit and UCB Pharma. line to the material. If material is not included in the article’s Creative Commons licence and Compliance with Ethics Guidelines. The your intended use is not permitted by statutory trial described was conducted in accordance regulation or exceeds the permitted use, you with the Good Clinical Practice guidelines of will need to obtain permission directly from the the International Conference on Harmonisa- copyright holder. To view a copy of this licence, tion and with the principles of the Declaration visit http://creativecommons.org/licenses/by- of Helsinki. The protocol and documentation nc/4.0/. was approved by the institutional review board 216 Rheumatol Ther (2021) 8:199–217 REFERENCES 13. European Medicines Agency. Taltz 80 mg solution for injection in pre-filled syringe [summary of pro- duct characteristics]. https://www.medicines.org. 1. Alinaghi F, Calov M, Kristensen LE, et al. Prevalence uk/emc/product/7233/smpc. Accessed 29 Oct 2019. of psoriatic arthritis in patients with psoriasis: a systematic review and meta-analysis of observa- 14. Chandran V, van der Heijde D, Fleischmann RM, tional and clinical studies. J Am Acad Dermatol. et al. Ixekizumab treatment of biologic-naı̈ve 2019;80:251–265.e19. patients with active psoriatic arthritis: 3-year results from a phase III clinical trial (SPIRIT-P1). Rheuma- 2. Ritchlin CT, Colbert RA, Gladman DD. Psoriatic tology (Oxford). 2020;59:2774–84. arthritis. N Engl J Med. 2017;376:957–70. 15. Nash P, Kirkham B, Okada M, et al. Ixekizumab for 3. Gladman DD, Antoni C, Mease P, Clegg DO, Nash the treatment of patients with active psoriatic P. Psoriatic arthritis: epidemiology, clinical features, arthritis and an inadequate response to tumour course, and outcome. Ann Rheum Dis. 2005;64: necrosis factor inhibitors: results from the 24-week ii14–7. randomised, double-blind, placebo-controlled per- iod of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389: 4. Veale DJ, Fearon U. The pathogenesis of psoriatic 2317–27. arthritis. Lancet. 2018;391:2273–84. 16. Genovese MC, Combe B, Kremer JM, et al. Safety 5. Coates LC, Kavanaugh A, Mease PJ, et al. Group for and efficacy of ixekizumab in patients with PsA and Research and Assessment of Psoriasis and Psoriatic previous inadequate response to TNF inhibitors: Arthritis 2015 treatment recommendations for week 52 results from SPIRIT-P2. Rheumatology psoriatic arthritis. Arthritis Rheumatol. 2016;68: (Oxford). 2018;57:2001–11. 1060–71. 17. Taylor W, Gladman D, Helliwell P, et al. Classifi- 6. Gossec L, Smolen JS, Ramiro S, et al. European cation criteria for psoriatic arthritis: development League Against Rheumatism (EULAR) recommen- of new criteria from a large international study. dations for the management of psoriatic arthritis Arthritis Rheum. 2006;54:2665–73. with pharmacological therapies: 2015 update. Ann Rheum Dis. 2016;75:499–510. 18. Genovese MC, Combe B, Kremer JM, et al. Safety and efficacy of ixekizumab in patients with PsA and 7. Menegatti S, Bianchi E, Rogge L. Anti-TNF therapy previous inadequate response to TNF inhibitors: in spondyloarthritis and related diseases, impact on week 52 results from SPIRIT-P2. Rheumatology the immune system and prediction of treatment (Oxford). 2018;57:2001–11. responses. Front Immunol. 2019;10:382. 19. Coates LC, Fransen J, Helliwell PS. Defining mini- 8. Mease P. A short history of biological therapy for mal disease activity in psoriatic arthritis: a proposed psoriatic arthritis. Clin Exp Rheumatol. 2015;33: objective target for treatment. Ann Rheum Dis. S104–8. 2010;69:48–53. 9. Merola JF, Lockshin B, Mody EA. Switching bio- 20. Mease P, Roussou E, Burmester GR, et al. Safety of logics in the treatment of psoriatic arthritis. Semin ixekizumab in patients with psoriatic arthritis: Arthritis Rheum. 2017;47:29–37. results from a pooled analysis of three clinical trials. Arthritis Care Res (Hoboken). 2019;71:367–78. 10. Singh JA, Guyatt G, Ogdie A, et al. Special article: 2018 American College of Rheumatology/National 21. Mease PJ, van der Heijde D, Ritchlin CT, et al. Psoriasis Foundation guideline for the treatment of Ixekizumab, an interleukin-17A specific mono- psoriatic arthritis. Arthritis Rheumatol. 2019;71: clonal antibody, for the treatment of biologic-naive 5–32. patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo- 11. Kirkham BW, Kavanaugh A, Reich K. Interleukin- controlled and active (adalimumab)-controlled 17A: a unique pathway in immune-mediated dis- period of the phase III trial SPIRIT-P1. Ann Rheum eases: psoriasis, psoriatic arthritis and rheumatoid Dis. 2017;76:79–87. arthritis. Immunology. 2014;141:133–42. 22. Strober B, Leonardi C, Papp KA, et al. Short- and 12. Eli Lilly and Company. Taltz (ixekizumab) injec- long-term safety outcomes with ixekizumab from 7 tion, for subcutaneous use [prescribing informa- clinical trials in psoriasis: etanercept comparisons tion]. https://pi.lilly.com/us/taltz-uspi.pdf. and integrated data. J Am Acad Dermatol. Accessed 29 Oct 2019. 2017;76(432–40):e17. Rheumatol Ther (2021) 8:199–217 217 23. van der Heijde D, Gladman DD, Kishimoto M, et al. 33. Egeberg A, Mallbris L, Warren RB, et al. Association Efficacy and safety of ixekizumab in patients with between psoriasis and inflammatory bowel disease: active psoriatic arthritis: 52-week results from a a Danish nationwide cohort study. Br J Dermatol. phase III study (SPIRIT-P1). J Rheumatol. 2018;45: 2016;175:487–92. 367–77. 34. Makredes M, Robinson D, Bala M, Kimball AB. The 24. Kalb RE, Fiorentino DF, Lebwohl MG, et al. Risk of burden of autoimmune disease: a comparison of serious infection with biologic and systemic treat- prevalence ratios in patients with psoriatic arthritis ment of psoriasis: results from the Psoriasis Longi- and psoriasis. J Am Acad Dermatol. 2009;61: tudinal Assessment and Registry (PSOLAR). JAMA 405–10. Dermatol. 2015;151:961–9. 35. Hueber W, Sands BE, Lewitzky S, et al. Secuk- 25. Listing J, Gerhold K, Zink A. The risk of infections inumab, a human anti-IL-17A monoclonal anti- associated with rheumatoid arthritis, with its body, for moderate to severe Crohn’s disease: comorbidity and treatment. Rheumatology (Ox- unexpected results of a randomised, double-blind ford). 2013;52:53–61. placebo-controlled trial. Gut. 2012;61:1693–700. 26. Combe B, Rahman P, Kameda H, et al. Safety results 36. Targan SR, Feagan B, Vermeire S, et al. A random- of ixekizumab with 1822.2 patient-years of expo- ized, double-blind, placebo-controlled phase 2 sure: an integrated analysis of 3 clinical trials in study of brodalumab in patients with moderate-to- adult patients with psoriatic arthritis. Arthritis Res severe Crohn’s disease. Am J Gastroenterol. Ther. 2020;22:14. 2016;111:1599–607. 27. Genovese MC, Mysler E, Tomita T, et al. Safety of 37. Charlton R, Green A, Shaddick G, et al. Risk of ixekizumab in adult patients with plaque psoriasis, uveitis and inflammatory bowel disease in people psoriatic arthritis and axial spondyloarthritis: data with psoriatic arthritis: a population-based cohort from 21 clinical trials. Rheumatology (Oxford). 2020. study. Ann Rheum Dis. 2018;77:277–80. https://doi.org/10.1093/rheumatology/keaa189. 38. Li W-Q, Han J-L, Chan AT, Qureshi AA. Psoriasis, 28. Deodhar A, Mease PJ, McInnes IB, et al. Long-term psoriatic arthritis and increased risk of incident safety of secukinumab in patients with moderate- Crohn’s disease in US women. Ann Rheum Dis. to-severe plaque psoriasis, psoriatic arthritis, and 2013;72:1200–5. ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data. Arthritis 39. Mease PJ, Karki C, Liu M, et al. Discontinuation and Res Ther. 2019;21:111. switching patterns of tumour necrosis factor inhi- bitors (TNFis) in TNFi-naive and TNFi-experienced 29. Burmester GR, Panaccione R, Gordon KB, McIlraith patients with psoriatic arthritis: an observational MJ, Lacerda AP. Adalimumab: long-term safety in study from the US-based Corrona registry. RMD 23 458 patients from global clinical trials in Open. 2019;5:e000880. rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis 40. Schoels MM, Aletaha D, Alasti F, Smolen JS. Disease and Crohn’s disease. Ann Rheum Dis. 2013;72: activity in psoriatic arthritis (PsA): defining remis- 517–24. sion and treatment success using the DAPSA score. Ann Rheum Dis. 2016;75:811–8. 30. Thomas K, Flouri I, Repa A, et al. High 3-year goli- mumab survival in patients with rheumatoid 41. Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis disease activity measures: American Col- arthritis: real world data from 328 patients. Clin lege of Rheumatology recommendations for use in Exp Rheumatol. 2018;36:254–62. clinical practice. Arthritis Care Res (Hoboken). 2012;64:640–7. 31. Thomaidou E, Ramot Y. Injection site reactions with the use of biological agents. Dermatol Ther. 42. Coates LC, Gottlieb AB, Merola JF, Boone C, 2019;32:e12817. Szumski A, Chhabra A. Comparison of different remission and low disease definitions in psoriatic 32. Shear NH, Paul C, Blauvelt A, et al. Safety and tol- arthritis and evaluation of their prognostic value. erability of ixekizumab: integrated analysis of J Rheumatol. 2019;46:160–5. injection-site reactions from 11 clinical trials. J Drugs Dermatol. 2018;17:200–6.