1/7 CLINICAL REPORT An Analysis of Patient-reported Outcomes in IXORA-S: Comparing ActaDV Ixekizumab and Ustekinumab over 52 Weeks in Moderate-to-severe Psoriasis Lluís PUIG1, Mark LOMAGA2, Kristin HOLLISTER3, Yves DUTRONC3, Lovisa BERGGREN4 and Peter VAN DE KERKHOF5 Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain, 1 DermEdge Research and Probity Medical Research, Mississauga, Ontario, Canada, 3Eli Lilly and Company, Indianapolis, IN, USA, 4HaaPACS 2 GmbH, Schriesheim, Germany (formerly), and 5Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Acta Dermato-Venereologica Patient-reported outcomes are valuable for asses- sing new psoriasis therapies. This study investigated SIGNIFICANCE patient-reported outcomes in patients with moderate- While skin clearance is the goal of psoriasis treatment, pa- to-severe plaque psoriasis treated with ixekizumab tients and practitioners also state the need for improve- or ustekinumab, dosed according to their respective ments in patients’ quality of life. These improvements are labels, for 52 weeks (IXORA-S-NCT02561806). Patient- evaluated by various patient-reported outcomes. The re- reported outcomes investigated included patient global sults of this study showed that ixekizumab-treated patients assessment, pruritus, skin pain, health-related quality had significantly greater improvements in patient-reported of life, and work productivity. Ixekizumab-treated outcomes compared with ustekinumab-treated patients patients reported greater improvements in patient- across multiple assessments at or before week 12, with the reported outcomes sooner after treatment compared responses being maintained to week 52. As most patients with ustekinumab-treated patients, and maintain­ in the IXORA-S trial achieved high levels of skin clearance, ed great­ er improvements in patient global assess- the trial results presented here reflect the important im- ment scores (ixekizumab 0.72, ustekinumab 1.19; provements in everyday quality of life that come with skin p < 0.001), rates of Dermatology Life Quality Index (0, clearance. 1) (ixekizumab 71.3%, ustekinumab 56.6%, p < 0.01), and 36-item Short-form Health survey physical compo- week 12 primary endpoint, and continuing through to ActaDV nent summary score change from baseline (ixekizumab 5.53, uste­ kinumab 3.28; p < 0.05) at week 52. While week 52, ixekizumab was found to be more effective than clinically meaning­ful improvements in patient-reported ustekinumab, as assessed by Psoriasis Area and Severity outcomes resulted with either treatment, ixekizumab Index (PASI) 75/90/100 and the static Physician’s Global provided more rapid improvements in patient-reported Assessment (sPGA) (0, 1) response rates, and safety out- out­comes and superior outcomes for some assess- comes were comparable (12, 13). Improvements in PROs, ments through one year of treatment, while maintain- including Itch Numeric Rating Scale (NRS) minimal ing statistically superior improvements in skin seve- clinically important difference rates and Dermatology rity, as assessed by either physicians or patients. Life Quality Index (DLQI) scores of (0, 1), were also Advances in dermatology and venereology Key words: patient-reported outcomes; health-related quality statistically significantly greater for ixekizumab-treated of life; ixekizumab; ustekinumab. patients compared with ustekinumab-treated patients as Accepted Nov 16, 2020; Epub ahead of print Nov 25, 2020 early as weeks 2 and 24 (12). The aim of the current study was to assess whether ixekizumab treatment lead to great­ Acta Derm Venereol 2020; 100: adv00344. er and more rapid improvements in PROs, compared with Corr: Lluís Puig, Department of Dermatology, Hospital de la Santa Creu i ustekinumab treatment, through to week 52 of IXORA-S. Sant Pau, Universitat Autònoma de Barcelona Medical School, Mas Casa- novas 90, ES-08041 Barcelona, Spain. E-mail: lpuig@santpau.cat MATERIALS AND METHODS R esolution of skin plaques is the key endpoint for any psoriasis trial; however, patients and physicians also state the need for equal improvements in patients’ quality Study design IXORA-S (NCT02561806) was a phase 3b, multicentre, ran- domized, double-blinded, double-dummy, active comparator, and of life, as measured by patient-reported outcomes (PROs) parallel-group trial (12, 13). Patients were randomized 1:1 to re- (1–3). Because psoriasis affects patients both physically ceive ixekizumab (IXE; 160 mg starting dose, 80 mg every 2 weeks and psychologically (4–9), for new therapeutics it is va- through to week 12, 80 mg every 4 weeks through to week 52) or luable to examine PROs in the context of skin clearance. ustekinumab (UST; dosed per label, patients ≤ 100.0 kg received 45 mg and patients > 100.0 kg received 90 mg at weeks 0 and 4, IXORA-S was a phase 3, head-to-head trial compar­ then every 12 weeks through to week 52). This study reports the ing ixekizumab, a high-affinity monoclonal antibody outcomes from baseline to week 52 using validated tools to assess that selectively targets interleukin (IL)-17A (10), with clinical disease severity and patient-reported outcomes (PROs). ustekinumab, an antibody that targets IL-12/23 (11). At Some PROs were previously reported for weeks 0–24 (12). The This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta doi: 10.2340/00015555-3700 Society for Publication of Acta Dermato-Venereologica Acta Derm Venereol 2020; 100: adv00344 2/7 L. Puig et al. primary endpoint of the study was to assess the proportion of Statistical analysis patients achieving a PASI 90 response at week 12 (12). For continuous variables, mean and standard deviation (SD) are ActaDV reported; for binary variables both absolute and relative frequen- Study population cies are reported. Continuous variables were compared using the Wilcoxon rank sum test. Missing values for continuous variables Key inclusion and exclusion criteria have been reported previously were imputed using modified baseline observation carried forward (12). Of note, eligible study participants were required to have a (mBOCF) (24). Binary variables were compared using Fisher’s baseline PASI ≥ 10; to have previously failed, had a contraindica- exact test. Missing values for binary variables were imputed using tion, or exhibited an intolerance to at least one systemic therapy; non-responder imputation. All statistical tests were 2-sided. p-value and no prior treatment with ustekinumab, ixekizumab, or any other < 0.05 were considered statistically significant. No multiplicity interleukin (IL)-17 or IL-12/23 antagonists. adjustments were performed for these analyses. All analyses were performed using SAS Version 9.4 (Cary, NC: SAS Institute Inc; Acta Dermato-Venereologica Ethical compliance 2014.) and were pre-specified except for the analysis of Itch NRS Study protocols were approved by applicable Ethical Review score distribution over time. Boards (ERB) (study number NCT02561806). The study was performed in accordance with the Council for International Or- ganizations of Medical Sciences International Ethical Guidelines RESULTS and the principles of the Declaration of Helsinki. Baseline demographics and patient characteristics were well balanced between the ixekizumab (n = 136) and Outcome measures ustekinumab (n = 166) treatment arms (Table I). Baseline Psoriasis Area and Severity Index (PASI). PASI scores range from PASI, PtGA, and sPGA were indicative of moderate-to- 0 (no psoriasis) to 72 (most severe disease). severe disease activity. Baseline itch NRS and skin pain Static Physician’s Global Assessment. Physician’s assessment rated VAS scores were also moderate in severity. Baseline on a 6-point scale (0: clear; 1: minimal; 2: mild; 3: moderate; 4: severe; 5: very severe). DLQI total scores were aligned with moderate-to-severe Patient Global Assessments (PtGA). Patient-administered, scale disease (DLQI>10) (25). SF-36 MCS and PCS indicated rated on a 0 (clear) to 5 (severe) numerical rating scale (NRS). a moderate impact on patient HRQoL. Itch numerical rating scale (NRS). A validated patient-reported Both patient and physician assessments of disease NRS assessing itch severity on a 0 (no itch) to 10 (worst itch severity were investigated using evaluation of sPGA imaginable) scale (14). A minimal clinically important difference (Fig. 1A) and PtGA (Fig. 1B), respectively, over a (MCID) is an improvement ≥ 4 among patients who reported an period of 52 weeks. Patients in both treatment groups ActaDV Itch NRS score ≥ 4 at baseline (15). demonstrated rapid improvements in PtGA and sPGA Skin pain visual analogue scale (VAS). A patient-reported tool as- sessing current skin pain on a 0-mm (no pain) to 100-mm (severe skin pain) horizontal scale. Table I. Baseline patient demographics and clinical characteristics Dermatology Life Quality Index (DLQI). A validated patient- Ustekinumab Ixekizumab administered questionnaire with 10 questions spanning 6 domains (n = 166) (n = 136) (symptoms and feelings; daily activities; leisure; work and school; Age, years, mean (SD) 44.0 (13.3) 42.7 (12.7) personal relationships; and treatment) with a total score ranging Sex, male, n (%) 112 (67.5) 90 (66.2) from 0 to 30 (16, 17); scores of 0 or 1 (0, 1) represent no impact Race, white, n (%) 157 (95.7) 125 (93.3) of disease on health-related quality of life (HRQoL) (18). Weight, kg, mean (SD) 89.4 (24.8) 85.8 (20.3) Advances in dermatology and venereology Weight, >100.0 kg, n (%) 45 (27.1) 31 (23.0) Medical outcomes study 36-item Short-Form health survey (SF- BMI, kg/m2, mean (SD) 29.7 (7.0) 28.8 (5.6) 36). SF-36 assesses 8 domains: physical functioning, role-physical, PASI score, mean (SD) 19.8 (9.0) 19.9 (8.2) role-emotional, bodily pain, vitality, social functioning, mental PtGA score, mean (SD) 4.0 (0.9) 4.1 (1.0) health, and general health (19, 20). Composite physical health sPGA score, mean (SD) 3.6 (0.6) 3.6 (0.7) (PCS) and mental health (MCS) component scores were derived % BSA, mean (SD) 27.5 (16.7) 26.7 (16.5) Duration of psoriasis (years), mean (SD) 18.2 (12.0) 18.0 (11.1) from the individual domains. Lower scores denote greater im- Itch NRS, mean (SD) 6.2 (2.6) 6.3 (2.7) pairments in quality of life. The acute (one-week recall) version DLQI score, mean (SD) 12.0 (7.3) 11.1 (7.2) of the scale was used. Skin pain VAS, mean (SD) 39.4 (30.8) 42.9 (33.3) European Quality of Life – 5 Dimensions – 5 Level (EQ-5D-5L) 36-item Short-Form Health survey and European Quality of Life for Psoriasis (EQ-PsO). The EQ- MCS, mean (SD) 46.5 (11.9) 47.1 (11.5) PCS, mean (SD) 48.4 (9.8) 47.3 (9.5) 5D-5L measures dimensions of mobility, self-care, usual activities, European Quality of Life – 5 Dimensions pain/discomfort, and anxiety/depression. Scores were converted UK, mean (SD) 0.7 (0.2) 0.7 (0.2) into a single summary index by crosswalking the data using UK PsO, mean (SD) 0.7 (0.2) 0.7 (0.2) population-based index scores (21). The EQ-PsO adds 2 additional VAS, mean (SD) 67.4 (22.4) 66.3 (22.2) psoriatic disease-specific dimensions (skin irritation (itching) and WPAI:PsO self-confidence) to the standard EQ-5D-5L questionnaire (22). In Absenteeism, mean (SD) 4.3 (14.9) 3.1 (10.7) Presenteeism, mean (SD) 21.7 (29.1) 22.1 (28.4) addition, the 100-mm VAS was used for patient reporting of current Work Impairment, mean (SD) 22.8 (30.1) 23.8 (29.8) health state, with 100-mm indicating “best imaginable health state” Activity Impairment, mean (SD) 29.8 (28.4) 28.2 (30.6) and 0-mm indicating “worst imaginable health state”. SD: standard deviation; BMI: body mass index; PASI: Psoriasis Area and Work Productivity and Activity Impairment Questionnaire for Severity Index; PtGA: patient global assessments; sPGA: static Physician’s Psoriasis (WPAI:PsO). The WPAI:PsO evaluates 4 dimensions: Global Assessment; BSA: body surface area; NRS: numerical rating scale; DLQI: Dermatology Life Quality Index; VAS: visual analogue scale; MCS: mental health absenteeism, presenteeism, work productivity loss, and activity component score; PCS: physical health component score; PsO: psoriasis; WPAI:PsO: impairment (23). Higher scores indicate greater impairment. Work Productivity and Activity Impairment Questionnaire for Psoriasis. www.medicaljournals.se/acta IXORA-S patient-reported outcomes over 52 weeks 3/7 4 A 5 B UST PtGA ActaDV UST sPGA (N=166) IXE PtGA *** 4 (m ean, m BO CF) 3 IXE sPGA (N= 136) (m ea n, m BOCF) *** ‡ 3 ‡ sPGA P tG A 2 *** *** *** ‡ 2 ‡ *** *** *** *** *** ** ‡ ** ** *** † ‡ ‡ † ‡ † † ‡ 1 † 1 Acta Dermato-Venereologica 0 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week Week Fig. 1. Static Physician’s Global Assessment (sPGA) and patient global assessments (PtGA) among patients with psoriasis treated with ixekizumab (IXE) or ustekinumab (UST) for 52 weeks. PtGA: †p < 0.01, ‡p < 0.001 UST vs IXE; sPGA: **p < 0.01, ***p < 0.001 UST vs IXE. p-values derived from Wilcoxon rank sum test. mBOCF: modified baseline-observation carried forward. scores (as assessed by change from baseline) during the To further investigate the severity of pruritus that had first 12 weeks, which continued through to week 52 for not resolved, individual itch NRS response rate levels PtGA (IXE 0.72 ± 0.94 (mean ± SD), UST 1.19 ± 1.21) were defined and overlaid (Fig. 3). Itch NRS scores ≤ 2 and sPGA (IXE 0.64 ± 0.92, UST 1.14 ± 1.20). PtGA and and ≤ 1 (including 0) were reported by similar numbers sPGA scores in the ixekizumab treatment group were of ixekizumab-treated and ustekinumab-treated pa- statistically significantly more improved, compared with tients at week 12 (≤ 2: IXE n = 99, 72.8%, UST n = 119, the ustekinumab treatment group, at all post-baseline as- 71.7%; ≤ 1: IXE n = 83, 61.0%, UST n = 97, 58.4%). sessments. Of note, both sPGA and PtGA scores within The percent­ages for Itch NRS scores reported at week treatments exhibited numerically similar trends, indicat­ 12 for both treatment groups increased slightly, but with ing that patient and physician disease perspectives were some fluctuation, throughout the maintenance period. similar for these assessments. At week 52, 76.5% (n = 104) of ixekizumab-treated Pruritus is one of the leading symptoms in patients patients and 70.5% (n = 117) of ustekinumab-treated ActaDV with chronic plaque psoriasis. Patients treated with patients rated their pruritus ≤ 2, and 64.0% (n = 87) of ixekizumab reported greater improvements in Itch NRS ixekizumab-treated patients and 61.4% (n = 102) of sooner after treatment compared with ustekinumab ustekinumab-treated patients rated their pruritus ≤ 1. In (12), but by week 52, improvements in itch severity summary, pruritus reductions were observed earlier in were not different between treatment groups (Fig. 2A; patients treated with ixekizumab, although by week 24, IXE–5.01 ± 2.96, UST –4.55 ± 2.85). A similar trend was similar responses were seen in both treatment groups and seen for the proportion of patients achieving Itch NRS maintained until week 52. MCID (improvement ≥ 4, Fig. 2B). A statistically signifi- Skin pain improved rapidly from baseline in both cantly greater proportion of ixekizumab-treated patients treatment groups (12) and persisted throughout the main- Advances in dermatology and venereology achieved Itch NRS (0) early in treatment compared with tenance period (Fig. 4A). At week 52, the mean change ustekinumab-treated patients (Fig. 2C), but by week 52, from baseline in skin pain VAS score was –36.54 for similar proportions of patients in each treatment group ixekizumab-treated patients and –31.79 for ustekinumab- reported complete resolution of their itch symptoms (IXE treated patients. Complete resolution of skin pain was 41.2%, n = 56, UST 34.3%, n = 57). achieved by 48.5% (n = 66) of ixekizumab-treated A Week B 100 C 100 0 4 8 12 16 20 24 28 32 36 40 44 48 52 90 90 Response Rate (NRI) * Response Rate (NRI) 0 ** ( 4 Improvement) UST 80 80 Itch NRS MCID Change from Baseline *** Itch NRS (0) -1 (N=166) 70 70 (Mean, mBOCF) IXE (N=136) 60 *** 60 -2 50 50 * Itch NRS * * *** 40 40 -3 *** 30 30 *** * -4 20 20 *** 10 10 -5 0 0 * ** 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52 -6 Week Week Fig. 2. (A) Change in Itch numerical rating scale (NRS) scores, and (B) the proportions of patients achieving Itch NRS minimal clinically important difference (MCID) (≥ 4 improvement) or (C) Itch NRS (0) when treated with ixekizumab or ustekinumab for 52 weeks. Achievement of Itch NRS MCID was investigated in patients who had Itch NRS scores ≥ 4 at baseline. Itch NRS scores and proportion of patients achieving Itch NRS MCID previously reported for weeks 0–24 (12) *p < 0.05, **p < 0.01, ***p < 0.001, all vs UST by (A) Wilcoxon rank sum or (B & C) Fisher’s exact test. mBOCF: modified baseline-observation carried forward; NRI: non-responder imputation. Acta Derm Venereol 2020 4/7 L. Puig et al. ActaDV Acta Dermato-Venereologica Fig. 3. Response rates for individual Itch numerical rating scale (NRS) scores for (A) ixekizumab-treated and (B) ustekinumab-treated patients through to week 52. Coloured areas: itch NRS responses. Solid vertical line: end of induction period (primary endpoint). Dotted vertical lines: active injections administered during the maintenance period. All patient visits during the maintenance period are represented on the x-axis. Due to missing data at some time-points, total response rates do not always add up to 100, as indicated by the white space at the top of each area plot. A Week B 100 0 4 8 12 16 20 24 28 32 36 40 44 48 52 90 Response Rate (NRI) 0 80 Skin Pain VAS (0) UST (N=166) Change from Baseline IXE (N=136) 70 (Mean, mBOCF) -10 60 Skin Pain VAS ** * * 50 ** * 40 -20 * 30 *** 20 ** -30 10 ** 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 -40 Week ActaDV * Fig. 4. Change in (A) skin pain visual analogue scale (VAS) and (B) the proportions of patients achieving Skin Pain VAS (0) when treated with ixekizumab (IXE) or ustekinumab (UST) for 52 weeks. *p < 0.05, **p < 0.01, ***p < 0.001, all vs UST by (A) Wilcoxon rank sum or (B) Fisher’s exact test. Skin pain VAS scores previously reported for weeks 0–24 (12). mBOCF: modified baseline observation carried forward; NRI: non- responder imputation. patients and 41.0% (n = 68) of ustekinumab-treated in the ixekizumab treatment group, at all post-baseline patients at week 52 (Fig. 4B). assessments (Fig. 5B). At week 52, 71.3% (n = 97) Improvements in HRQoL, as assessed by DLQI, were of ixekizumab-treated patients and 56.6% (n = 94) of statistically significantly greater for ixekizumab-treated ustekinumab-treated patients reported minimal-to-no Advances in dermatology and venereology patients within the first month of treatment (week 2 impact of their disease (DLQI [0, 1]). DLQI component IXE: –6.34, UST: –3.55; week 4 IXE: –7.79, UST: scores are shown in Table SI1. –5.72; Fig. 5A); however, DLQI change from baseline scores were similar at assessed time-points thereafter. DLQI (0, 1) rates were statistically significantly greater 1 https://doi.org/10.2340/00015555-3700 A 0 UST (N=166) B 100 IX E ( N=1 3 6) Change from Baseline Response Rate(NRI) -2 80 DLQI Tot al Score (mean, mBOCF) ** * ** DLQI (0,1) -4 60 *** -6 40 *** *** -8 20 ** - 10 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week Week Fig. 5. Change in (A) Dermatology Life Quality Index (DLQI) total scores and (B) the proportion of patients achieving DLQI (0, 1) for patients with psoriasis treated with ixekizumab (IXE) or ustekinumab (UST) for 52 weeks. DLQI (0, 1) results previously reported for weeks 0–24 (12). **p < 0.01, ***p < 0.001, both vs UST by Wilcoxon rank sum test. mBOCF: modified baseline-observation carried forward; NRI: non-responder imputation. www.medicaljournals.se/acta IXORA-S patient-reported outcomes over 52 weeks 5/7 A 7 B 7 ActaDV * Change from Baseline 6 6 Change from Baseline * * (mean,mBOCF) (mean, mBOCF) 5 5 SF-36 MCS * SF-36 PCS 4 4 3 3 2 2 U S T (N = 1 6 6 ) 1 1 IX E ( N = 1 3 6 ) 0 0 Acta Dermato-Venereologica 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week Week Fig. 6. Change in 36-item Short-Form Health survey (SF-36) (A) physical and (B) mental component summaries for patients with psoriasis treated with ixekizumab (IXE) or ustekinumab (UST) for 52 weeks. *p < 0.05 vs UST by Wilcoxon rank sum test. mBOCF: modified baseline- observation carried forward. HRQoL was also investigated using SF-36 and EQ-5D. Table II. Changes in quality of life outcomes reported by patients with psoriasis treated with ixekizumab (IXE) or ustekinumab Patients treated with ixekizumab reported statistically (UST) for 52 weeks significantly greater improvements in SF-36 PCS change Change from Week 12 Week 24 Week 52 from baseline at all post-baseline assessments, including baseline Mean (SD) Mean (SD) Mean (SD) week 52 (IXE: 5.53, UST: 3.28; Fig. 6A). No statistical EQ-5D-5L UK Index Score differences were seen between treatment groups in SF-36 UST 0.1237 (0.217) 0.1190 (0.212) 0.1258 (0.221) IXE 0.1682 (0.226) 0.1612 (0.228) 0.1599 (0.242) MCS change from baseline (Fig. 6B). Individual SF-36 EQ-PsO Index Score domains are shown in Table SII1. UST 0.1173 (0.160) 0.1210 (0.152) 0.1204 (0.159) Improvements in EQ-5D-5L index score, EQ-PsO IXE EQ-5D VAS 0.1512 (0.165)* 0.1561 (0.159)* 0.1421 (0.177) index score, and EQ-5D VAS were observed in both UST 10.10 (22.7) 10.72 (22.7) 12.52 (22.1) treatment groups (Table II). While statistically signifi- IXE 13.56 (22.3) 15.38 (22.4) 13.38 (22.5) cantly greater improvements in the EQ-PsO Index Score *p < 0.05 vs UST by Wilcoxon rank sum test. SD: standard deviation; EQ-5D-5L: European Quality of Life – 5 Dimensions – 5 ActaDV were reported for ixekizumab-treated patients at weeks Level; EQ-PsO: European Quality of Life for Psoriasis; VAS: visual analogue scale. 12 (IXE: 0.1512, UST: 0.1173) and 24 (IXE: 0.1561, UST: 0.1210), all other EQ-5D results were comparable between the 2 treatment groups. Finally, rapid improvements in work productivity and activity impairment, as assessed by the WPAI:PsO questionnaire, were observed in both treatment groups A B Advances in dermatology and venereology 5 UST 0 (N=166) Change from baseline Change from baseline IXE (N=136) -5 (mean, mBOCF) (mean, mBOCF) Presenteeism Absenteeism 0 -10 -15 -5 -20 -10 -25 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week Week C 0 D 0 Work Productivity Loss Change from baseline Change from baseline Fig. 7. Change in the domains Activity Impairment of the Work Productivity and -5 -5 (mean, mBOCF) (mean, mBOCF) Activity Impairment Question­ naire for Psoriasis (WPAI:PsO) -10 -10 Impairment for patients with psoriasis treated with ixekizumab -15 -15 (IXE) or ustekinumab (UST) for 52 weeks including (A) Absenteeism, (B) -20 -20 Presenteeism, (C) Work Productivity Loss, and (D) Activity Impairment. -25 -25 mBOCF: modified baseline-observation 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52 carried forward. Week Week Acta Derm Venereol 2020 6/7 L. Puig et al. (Fig. 7) with no statistical differences observed in any A strength of this analysis is the inclusion of disease- WPAI:PsO domains between the 2 treatment groups. specific validated PRO measures to highlight the patient ActaDV perspective in psoriasis. DISCUSSION Conclusion Overall, in these analyses, treatment with ixekizumab Ixekizumab treatment resulted in greater improvements resulted in greater improvements in PROs, compared at or before week 12 across the majority of PRO mea- with ustekinumab treatment, early in treatment. However, sures, compared with ustekinumab treatment; both treat- both treatments resulted in important clinical improve­ ments resulted in clinically meaningful improvements for ments in PROs for patients, which were maintained patients across the PROs assessed, and these responses Acta Dermato-Venereologica through to week 52. In patients treated with ixekizumab, were maintained through to 52 weeks (12). improvements in disease activity (sPGA and PtGA) and HRQoL remained statistically significantly superior, vs ustekinumab, throughout the maintenance period ACKNOWLEDGEMENTS (including week 52). Brian S. Comer, PhD, and Chenyun Tan, PharmD, for medical It is not uncommon for discordances to be observed writing assistance during the preparation of this manuscript. Kan- between physician and patient-reported outcomes (26, nan R MSc, MTech for editorial assistance during the preparation 27). Disease severity assessments in this study allowed of this manuscript. Russel Burge for his advice on PRO measures. for an observational comparison of patient-reported and Conflicts of interest: LP reports receipt of honoraria or consultation physician-reported subjective measures. Overlap (within fees from Abbvie, Almirall, Amgen, Baxalta, Biogen, Boehringer treatment groups) between sPGA and PtGA scores Ingelheim, Celgene, Gebro, Janssen, Leo Pharma, Lilly, Merck Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Sandoz, throughout the study indicate similarities between phy- Samsung-Bioepis, Sanofi, and UCB. ML reports receipt hono­raria sician and patient perception of disease severity. While and/or consultation fees from Abbvie, Amgen, Bristol Myers other studies have indicated discordant scoring between Squibb, Boehringer Ingelheim, Dermira, Janssen, Leo Pharma, patient and physician scales (26, 27), IXORA-S has Lilly, Merck Serono, Novartis, Pfizer, Regeneron, Sandoz, Sun provided an example of alignment between the 2 scales. Pharma, Sanofi, and UCB. KH and YD are employees and share­ High physician-reported disease severity is associated holders of Eli Lilly and Company. LB was a former employee of HaaPACS GmbH on behalf of Eli Lilly and Company. PvdK with a greater severity of patient-reported symptoms ActaDV reports fees for consultancy service or lectureships from Celgene, (pruritus, pain), HRQoL, and impact on work productiv­ Almirall, Abbvie, Amgen, Eli Lilly, Novartis, Janssen Pharmaceu- ity (9). Furthermore, improvements in clinical responses tica, Leo Pharma, Bristol Myers Squibb and Dermavant. are associated with improvements in PROs (28, 29). As published previously, 52.2% and 76.5% patients treated REFERENCES with ixekizumab achieved PASI100 (completely clear skin) and PASI90 by week 52, respectively, vs 35.5% and 1. Feldman SR, Malakouti M, Koo JY. Social impact of the bur- den of psoriasis: effects on patients and practice. Dermatol 59.0%, respectively, of patients treated with ustekinumab Online J 2014; 20: 13030/qt48r4w8h2. (13). PRO results presented here illustrate greater im- 2. Reich K, Mrowietz U. Treatment goals in psoriasis. J Dtsch Advances in dermatology and venereology provements in ixekizumab-treated patients, particularly Dermatol Ges 2007; 5: 566–574. 3. Strober B, Papp KA, Lebwohl M, Reich K, Paul C, Blauvelt A, early in treatment, compared with ustekinumab-treated et al. Clinical meaningfulness of complete skin clearance in patients. Given that the majority of patients treated in psoriasis. J Am Acad Dermatol 2016; 75: 77–82.e77. IXORA-S achieved PASI90 or PASI100, it follows that 4. Kimball AB, Jacobson C, Weiss S, Vreeland MG, Wu Y. The psychosocial burden of psoriasis. Am J Clin Dermatol 2005; these patients would report clinically significant improve­ 6: 383–392. ments in a number of PROs, as reflected in the results of 5. Bhosle MJ, Kulkarni A, Feldman SR, Balkrishnan R. Quality the current study. of life in patients with psoriasis. Health Qual Life Outcomes 2006; 4: 35. 6. Lewis-Beck C, Abouzaid S, Xie L, Baser O, Kim E. Analysis of the Study limitations and strength relationship between psoriasis symptom severity and quality of life, work productivity, and activity impairment among patients Limitations of this study include lack of a placebo arm, with moderate-to-severe psoriasis using structural equation potentially biasing PROs, and the relatively short trial modeling. Patient Prefer Adherence 2013; 7: 199–205. 7. Weiss SC, Kimball AB, Liewehr DJ, Blauvelt A, Turner ML, duration. Changes in quality of life may require longer Emanuel EJ. Quantifying the harmful effect of psoriasis on treatment periods in order for the benefits of treatment health-related quality of life. J Am Acad Dermatol 2002; to peak, as opposed to outcomes assessing itch or pain. 47: 512–518. 8. Young M. The psychological and social burdens of psoriasis. In addition, these medications possess differences in Dermatol Nurs 2005; 17: 15–19. their peak onset of efficacy, as previously noted (12); 9. Korman NJ, Zhao Y, Pike J, Roberts J. Relationship between therefore, the timing of peak improvements in PROs psoriasis severity, clinical symptoms, quality of life and work productivity among patients in the USA. Clin Exp Dermatol and their association with peaks in clinical efficacy may 2016; 41: 514–521. differ between the 2 treatments. 10. Liu L, Lu J, Allan BW, Tang Y, Tetreault J, Chow CK, et al. www.medicaljournals.se/acta IXORA-S patient-reported outcomes over 52 weeks 7/7 Generation and characterization of ixekizumab, a humani- measures in the assessment of psoriasis patients: results of zed monoclonal antibody that neutralizes interleukin-17A. J a phase II study. Health Qual Life Outcomes 2006; 4: 71. ActaDV Inflam Res 2016; 9: 39–50. 21. Swinburn P, Lloyd A, Boye KS, Edson-Heredia E, Bowman L, 11. Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary Janssen B. Development of a disease-specific version of the P, Yeilding N, et al. Efficacy and safety of ustekinumab, a EQ-5D-5L for use in patients suffering from psoriasis: les- human interleukin-12/23 monoclonal antibody, in patients sons learned from a feasibility study in the UK. Value Health with psoriasis: 52-week results from a randomised, double- 2013; 16: 1156–1162. blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 22. Pickard AS, Gooderham M, Hartz S, Nicolay C. EQ-5D health 371: 1675–1684. utilities: exploring ways to improve upon responsiveness in 12. Reich K, Pinter A, Lacour JP, Ferrandiz C, Micali G, French psoriasis. J Med Econ 2017; 20: 19–27. LE, et al. Comparison of ixekizumab with ustekinumab in 23. Lebwohl MG, Kavanaugh A, Armstrong AW, Van Voorhees AS. moderate-to-severe psoriasis: 24-week results from IXORA- US perspectives in the management of psoriasis and psoriatic S, a phase III study. Br J Dermatol 2017; 177: 1014–1023. arthritis: patient and physician results from the population- 13. Paul C, Griffiths CEM, van de Kerkhof PCM, Puig L, Dutronc based multinational assessment of psoriasis and psoriatic Acta Dermato-Venereologica Y, Henneges C, et al. Ixekizumab provides superior efficacy arthritis (MAPP) survey. Am J Clin Dermatol 2016; 17: 87–97. compared to ustekinumab over 52-weeks of treatment: re- 24. Gordon KB, Blauvelt A, Papp KA, Langley RG, Luger T, Ohtsuki sults from IXORA-S, a phase 3 study. J Am Acad Dermatol M, et al. Phase 3 trials of ixekizumab in moderate-to-severe 2019; 80: 70–79.e3. plaque psoriasis. N Engl J Med 2016; 375: 345–356. 14. Shikiar R, Bresnahan BW, Stone SP, Thompson C, Koo J, Re- 25. Mrowietz U, Kragballe K, Reich K, Spuls P, Griffiths CE, Nast vicki DA. Validity and reliability of patient reported outcomes A, et al. Definition of treatment goals for moderate to severe used in psoriasis: results from two randomized clinical trials. psoriasis: a European consensus. Arch Dermatol Res 2011; Health Qual Life Outcomes 2003; 1: 53. 303: 1–10. 15. Kimball AB, Naegeli AN, Edson-Heredia E, Lin CY, Gaich C, 26. Schafer I, Hacker J, Rustenbach SJ, Radtke M, Franzke N, Nikai E, et al. Psychometric properties of the Itch Numeric Augustin M. Concordance of the Psoriasis Area and Severity Rating Scale in patients with moderate-to-severe plaque Index (PASI) and patient-reported outcomes in psoriasis psoriasis. Br J Dermatol 2016; 175: 157–162. treatment. Eur J Dermatol 2010; 20: 62–67. 16. Basra MK, Fenech R, Gatt RM, Salek MS, Finlay AY. The Der- 27. Lebwohl MG, Bachelez H, Barker J, Girolomoni G, Kavanaugh matology Life Quality Index 1994–2007: a comprehensive A, Langley RG, et al. Patient perspectives in the management review of validation data and clinical results. Br J Dermatol of psoriasis: results from the population-based multinational 2008; 159: 997–1035. assessment of psoriasis and psoriatic arthritis survey. J Am 17. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) – Acad Dermatol 2014; 70: 871–881.e871–830. a simple practical measure for routine clinical use. Clin Exp 28. Edson-Heredia E, Banerjee S, Zhu B, Maeda-Chubachi T, Dermatol 1994; 19: 210–216. Cameron GS, Shen W, et al. A high level of clinical response 18. Hongbo Y, Thomas CL, Harrison MA, Salek MS, Finlay AY. is associated with improved patient-reported outcomes in Translating the science of quality of life into practice: What psoriasis: analyses from a phase 2 study in patients treated do dermatology life quality index scores mean? J Invest with ixekizumab. J Eur Acad Dermatol Venereol 2016; 30: Dermatol 2005; 125: 659–664. 864–865. ActaDV 19. Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 Health sur- 29. Viswanathan HN, Chau D, Milmont CE, Yang W, Erondu N, vey: manual and interpretation guide. Boston: The Health Revicki DA, et al. Total skin clearance results in improve- Institute, New England Medical Center; 1993. ments in health-related quality of life and reduced symptom 20. Shikiar R, Willian MK, Okun MM, Thompson CS, Revicki severity among patients with moderate to severe psoriasis. DA. The validity and responsiveness of three quality of life J Dermatolog Treat 2015; 26: 235–239. Advances in dermatology and venereology Acta Derm Venereol 2020