971 CLINICAL REPORT Absolute and Relative Psoriasis Area and Severity Indices (PASI) ActaDV for Comparison of the Efficacy of Ixekizumab to Etanercept and Placebo in Patients with Moderate-to-severe Plaque Psoriasis: An Integrated Analysis of UNCOVER-2 and UNCOVER-3 Outcomes Luis PUIG1, Martin DOSSENBACH2, Lovisa BERGGREN3, Anders LJUNGBERG4 and Claus ZACHARIAE5 1 Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 2Eli Lilly and Company, Vienna, Austria, 3Global Statistical Sciences, Lilly Deutschland GmbH, Bad Homburg, Germany, 4Eli Lilly and Company, Stockholm, Sweden, and 5Department of Dermatology and Allergy, Gentofte Hospital, University of Copenhagen, Denmark Acta Dermato-Venereologica Treatment goals defined by the absolute Psoria- SIGNIFICANCE sis Area and Severity Index (PASI) scores offer cer- tain advantages in the clinical setting. In order to Psoriasis treatment goals defined in terms of the absolute investigate potential treatment targets, this study Psoriasis Area and Severity Index (PASI) scores offer cer- evaluated absolute PASI outcomes relative to other tain advantages in the clinical setting, but a consensus on measures of response using data from two randomi- a treatment goal based on absolute PASI has not yet been zed clinical trials of patients with moderate-to-severe achieved. The current study was conducted in order to eva- psoriasis treated with ixekizumab, etanercept, or pla- luate different absolute PASI treatment targets relative to cebo (n=2,567). Response was assessed throughout other measures of the response to treatment based on the 12 weeks as the proportion of patients achieving ab- data derived from two large clinical studies of patients with solute PASI band cut-offs who also reached establis- moderate-to-severe plaque psoriasis. These data indicate hed response criteria. Most PASI band ≤2 responders that PASI ≤ 2 represents significantly meaningful clinical also achieved PASI 90 (70.1–100%), static Physician’s and health-related quality of life improvements and may be Global Assessment (0,1) (91.3–96.1%), Dermatology a suitable treatment target for moderate-to-severe plaque Life Quality Index (0,1) (63.0–67.7%), Patient Global psoriasis. Assessment of Disease Severity (0,1) (80.3–86.7%), ActaDV and Itch Numeric Rating Scale improvement ≥4 (87.2–87.6%). Agreement sharply decreased for less evaluating the severity and extent of psoriasis, which takes stringent PASI criteria. These data indicate that PASI into consideration the intensity of erythema, desquama- ≤2 represents significantly meaningful clinical and tion, and induration present as well as the percentage health-related quality of life improvements and may of body surface area involved for the head, trunk, and be a suitable treatment target for moderate-to-severe extremities (3, 4). An overall composite score from 0 to plaque psoriasis. 72 is calculated, with higher scores indicating greater disease severity (3, 4). In clinical studies, a reduction from Key words: ixekizumab; psoriasis; disease management. baseline in absolute PASI score of ≥75% (PASI 75) or Advances in dermatology and venereology Accepted Jun 25, 2019; E-published Jun 26, 2019 ≥ 90% (PASI 90) is recommended as a primary endpoint to Acta Derm Venereol 2019; 99: 971–977. assess the treatment efficacy by the European Medicines Agency (5). Moreover, PASI 75 and PASI 90 responses Corr: Martin Dossenbach, Eli Lilly and Company, Kölblgasse 8–10, AT- 1030, Vienna, Austria. E-mail: dossenbach_martin@lilly.com have been found to be positively associated with patients’ HRQoL assessments, indicative of clinically meaningful improvements in the disease activity (2, 6). However, P soriasis is a chronic inflammatory disease of the skin, nails, and joints that affects at least 100 mil- lion people worldwide (1). Typical cutaneous signs of the use of relative PASI measures has some limitations. Notably, calculation of the relative PASI requires know- ledge of the baseline disease status, which may not be the disease are erythematous raised lesions covered by known in routine clinical practice or other clinical settings white or silvery scales. Itching, stinging, and pain are where patients may switch from other treatments without common symptoms. Psoriasis can be associated with a washout period (7). Further, patients, particularly those several comorbidities, such as metabolic syndrome and with moderate-to-severe disease, may reach PASI 75 or cardiovascular disease, which add to its physical and PASI 90 relative to their initial disease status but still psychological burden, negatively affecting the patient’s have significant disease activity and HRQoL problems health-related quality of life (HRQoL) (1–3). (2, 6). As the absolute PASI has the advantage of being Optimal management of psoriasis requires well-defined indicative of the individual patient’s severity of disease at treatment goals based on reproducible and objective as- the time of analysis, independent of baseline PASI score, sessment methods of the disease severity. The Psoriasis use of alternative treatment targets based on the absolute Area and Severity Index (PASI) is a widely used tool for PASI scores have been proposed for assessment the ef- This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta doi: 10.2340/00015555-3245 Journal Compilation © 2019 Acta Dermato-Venereologica. Acta Derm Venereol 2019; 99: 971–977 972 L. Puig et al. fectiveness of new treatments (6). Previously, PASI ≤ 2, comparator etanercept, and placebo has been compared. Patients ≤ 3, and ≤ 5 have been suggested as potential therapeutic were randomly assigned 2:2:2:1 to receive subcutaneous 160 mg ix- ActaDV ekizumab (starting dose) followed by 80 mg every 2 weeks (Q2W) targets; however, the level of absolute PASI that could or 4 weeks (Q4W), etanercept 50 mg twice weekly, or placebo. serve as an optimal treatment target for clinical studies Efficacy measures of interest in the current analysis included and real-world use is currently unclear (2, 6−8). assessments of disease activity, including the proportion of patients To investigate this, we performed a post hoc analysis achieving PASI 75, PASI 90, and absolute PASI criteria of ≤ 1, of the pooled efficacy data from patients in two phase 3 ≤ 2, ≤ 3, and ≤ 5 following 1, 2, 4, 8, and 12 weeks of treatment. To gain further insight into the distribution of responses at each trials on ixekizumab, a high-affinity humanized mono- time point, absolute PASI response data from the original studies clonal antibody that selectively targets interleukin-17A, were regrouped into 6 non-overlapping categories representing for the treatment of moderate-to-severe plaque psoriasis the proportion of patients reaching absolute PASI bands: PASI = 0; Acta Dermato-Venereologica in adults. In the UNCOVER-2 and UNCOVER-3 trials, PASI > 0 to ≤ 1; PASI > 1 to ≤ 2; PASI > 2 to ≤ 3; PASI > 3 to ≤ 5; ixekizumab demonstrated a favorable safety profile and and PASI > 5. The proportion of patients per treatment group achieving each absolute PASI band criterion was assessed at each clear clinical benefits, with superior efficacy to both study endpoint in the induction phase. placebo and the tumor necrosis factor-alpha inhibitor Using data pooled across all treatments, the percentage overlap etanercept in terms of PASI 75, PASI 90, and PASI 100 between each population of absolute PASI band response and responses following a 12-week induction phase (9). The the populations of PASI 75, PASI 90, and sPGA responders at current analysis is based on the data collected throughout week 12 was also determined. Treatment response for the sPGA was considered as achieving scores of 0 (clear) or 1 (minimal di- 12 weeks of treatment (induction period) and aims to sease). Patient-reported outcomes reflective of HRQoL were also determine the degree of overlap in responders meeting examined in this manner and included the proportion of patients various absolute PASI and relative PASI criteria to showing improvement on the Dermatology Life Quality Index identify a level of absolute PASI that could serve as an (DLQI), the Itch Numeric Rating Scale (NRS), and the Patient alternative treatment goal. To further validate potential Global Assessment of Disease Severity (PatGA). The DLQI is a self-administered instrument that consists of 10 questions rating treatment targets, absolute PASI responders were also the impact of skin symptoms on various HRQoL domains over the evaluated against responders defined by another com- previous 7 days, for a possible composite score of up to 30 (10). monly used clinical index of disease severity, the static The current analyses used DLQI (0,1) as the response criterion, Physician’s Global Assessment (sPGA), and multiple indicative of no effect of psoriasis or psoriasis treatment on the patient-reported outcomes in order to determine the abso- patient’s life (11). The Itch NRS is an instrument comprising of one question, with scores from no itch to worst itch imaginable (from 0 lute PASI targets representing meaningful improvement ActaDV to 10) in the past 24 h (12). Treatment response was defined herein in disease activity and HRQoL. as a ≥4-point improvement from baseline on the Itch NRS. The PatGA is a single-item questionnaire in which the patient scores their symptoms on a 0–5 NRS (clear to severe), with a score of 0 METHODS or 1 set as the response criterion for this study. Patients Assessments of the 12-week response by baseline PASI This is a post hoc analysis of the pooled efficacy data from patients in two randomized, double-blind, placebo- and active- To determine whether the baseline PASI affected the response to controlled phase 3 clinical trials, UNCOVER-2 and UNCOVER-3 treatment, the proportion of patients reaching each absolute PASI (NCT01597245 and NCT01646177, respectively), comparing band criterion at week 12 were assessed after categorizing patients Advances in dermatology and venereology etanercept and ixekizumab efficacy and safety profiles in adult into groups with baseline PASI < 20 or baseline PASI ≥ 20. Mean patients with moderate-to-severe plaque psoriasis. The eligibility DLQI, PatGA, and Itch NRS at week 12 were also summarized criteria for the studies were similar and have been previously pu- overall and by baseline PASI category. blished (9). Briefly, the studies included patients ≥ 18 years of age with a confirmed diagnosis of chronic moderate-to-severe plaque Statistical analyses psoriasis ≥ 6 months prior to the baseline with a minimum 10% body surface area involvement, an sPGA score ≥ 3 (0–5 scale, in This was a post hoc analysis of pooled data collected from the order of increasing severity), and a PASI score ≥ 12 at screening intent-to-treat populations from two phase 3 clinical trials. The and baseline visits. Key exclusion criteria included any active or data cut-off date for this analysis was September 1, 2015. For cate- recent infections at baseline; erythrodermic, generalized pustular, gorical variables, missing data were imputed using non-responder or guttate forms of psoriasis; and prior exposure to etanercept (9). imputation (NRI) for binary endpoints or last-observation carried All studies were conducted with the approval of each center’s forward (LOCF) for continuous outcomes. NRI assumes that every institutional review board or independent ethics committee and patient who discontinues is a non-responder; LOCF assumes that in accordance with the guiding principles of the Declaration of discontinued patients will have the same efficacy response for the Helsinki. All patients provided written informed consent prior to remainder of the study. As the Q4W (every 4 weeks) ixekizumab enrollment. regimen is not approved for use in the European Union, the Q4W data are only included in the integrated analyses of all treatments combined, and data for Q2W (every 2 weeks) (the approved Study design, treatments, and endpoints dose) alone are otherwise shown in comparisons to placebo and The original designs for the two studies have been published etanercept treatment. previously (9). The current analysis is based on the data collected For comparisons between the proportions of patients meeting during the 12-week induction periods of these studies, where the absolute PASI criteria by treatment group, a Cochran-Mantel- response to the two treatment regimens of ixekizumab, the active Haenszel test stratified by study was performed. Two-sided statisti- www.medicaljournals.se/acta Absolute PASI as a measure for psoriasis 973 ActaDV Fig. 1. Patient disposition during the 12-week induction period of UNCOVER-2 and UNCOVER-3. Three additional patients who were randomized were excluded from the Psoriasis Area Severity Index (PASI) band analyses due to the missing baseline data. Ixekizumab 80 mg every 4 weeks (IXEQ4W) data are only included in the all-treatment- Acta Dermato-Venereologica combined analyses. ETN: etanercept; IXEQ2W: ixekizumab 80 mg every 2 weeks; PBO: placebo. (Data from Ref. 9). cal tests were performed where p < 0.05 was considered statistically of white males with the mean psoriasis duration > 18 significant. Due to the exploratory nature of these analyses, no years and mean body surface area involvement of > 26% correction for multiplicity was performed. To compare the absolute (Table I). Approximately 60% of patients had previously PASI measures to other well-established indices of disease severity and HRQoL, the percentage of patients reaching each criterion of received at least one form of systemic therapy for psoria- interest (PASI 75, PASI 90, sPGA [0,1], DLQI [0,1], PatGA [0,1], sis (Table I). The mean ± standard deviation (SD) baseline and Itch NRS improvement ≥ 4) who also reached each absolute PASI score across all treatment groups was 20.29 ± 7.76 PASI band cutoff was determined. For these analyses, all patients (range 12.0–63.0; median = 17.90). with data available at baseline and week 12 were pooled across treatment groups. Efficacy assessments based on absolute PASI and PASI band response rates RESULTS As previously reported in terms of the relative PASI Patient disposition response rates (9), the absolute PASI response rates for ixekizumab Q2W treatment were significantly higher A total of 2,570 patients participated in the two studies. ActaDV across the 12-week induction period compared to the Patient disposition and clinical details for the individual response rates for the placebo and etanercept treatment studies have been previously reported in detail (9). An groups (Fig. 2). Notably, by week 2, a significantly grea- overview of patient disposition of the combined studies ter proportion of patients in the ixekizumab treatment throughout the 12-week induction phase is provided in group reached PASI ≤ 1, and differences were sustained Fig. 1. For the current analyses, 3 subjects were excluded at all endpoints through 12 weeks (week 12 PASI ≤ 1 from the absolute PASI band analyses due to the missing response rates: 54.6% ixekizumab vs. 13.4% etanercept baseline values on several measures. vs. 0.8% placebo, p < 0.001; Fig. 2). Similar results were Table I shows selected summary demographics and obtained for PASI ≤ 2, ≤ 3, and ≤ 5, with significant diffe- Advances in dermatology and venereology baseline characteristics by treatment group for the com- rences in response to ixekizumab compared to etanercept bined studies. Across treatment groups, the patients had or placebo detected as early as week 1 for the absolute similar baseline characteristics, the majority comprising PASI ≤ 3 and ≤ 5 criteria (Fig. 2). Table I. Baseline demographics and clinical characteristics of patients with moderate-to-severe psoriasis: integrated analysis of UNCOVER-2 and UNCOVER-3 Placebo IXE Q2W Etanercept Characteristics n = 361 n = 736 n = 740 Age, years, mean ± SD 45.9 ± 12.12 45.1 ± 13.18 45.5 ± 13.33 Sex, male, n (%) 257 (71.2) 475 (64.5) 505 (68.2) Race, white, n (%) 325 (90.0) 691 (94.0) 682 (92.7) Body mass index (kg/m2), mean ± SD 30.52 ± 6.72 30.15 ± 7.08 30.98 ± 7.43 Psoriasis duration, years, mean ± SD 18.62 ± 12.60 18.06 ± 12.15 18.50 ± 12.11 Body surface area involvement, %, mean ± SD 28.0 ± 17.75 26.6 ± 16.66 26.8 ± 16.58 Static Physician’s Global Assessment, mean ± SD 3.6 ± 0.61 3.5 ± 0.61 3.5 ± 0.58 Dermatology Life Quality Index, mean ± SD 12.8 ± 7.10 12.4 ± 6.89 12.0 ± 6.95 Psoriasis Area and Severity Index score, mean ± SD 20.86 ± 8.37 20.07 ± 7.81 19.90 ± 7.53 Itch numeric rating scale, mean ± SD 6.4 ± 2.65 6.5 ± 2.56 6.4 ± 2.61 Previous systemic history, n (%) None 152 (42.1) 296 (40.2) 293 (39.6) Nonbiologic 133 (36.8) 298 (40.5) 311 (42.0) Biologic 35 (9.7) 54 (7.3) 59 (8.0) Nonbiologic and biologic 41 (11.4) 88 (12.0) 77 (10.4) IXE Q2W: ixekizumab 80 mg every 2 weeks; SD: standard deviation. Acta Derm Venereol 2019 974 L. Puig et al. ActaDV Fig. 2. Proportion of patients achieving absolute Psoriasis Area Severity Index (PASI) criteria from baseline through week 12 (non- responder imputation (NRI)) of UNCOVER-2 and UNCOVER-3. Percentages for each time point are color coded by treatment group. p-value from Cochran-Mantel-Haenszel test stratified by study. a) Placebo (PBO) at p < 0.001; b) vs Etanercept (ETN) at p < 0.001; c) vs PBO at p < 0.05; d) vs ETN Acta Dermato-Venereologica at p < 0.05. For simplicity, zero values are not labeled.; IXE Q2W: ixekizumab 80 mg every 2 weeks. Fig. 3 illustrates the differences in the distribution of a PASI 90 (70.1%) and sPGA (0,1) (91.3%) response, responses to each treatment in terms of non-overlapping but the level of agreement sharply decreased thereafter absolute PASI band categories. This breakdown of data for decreasingly stringent absolute PASI band criteria indicates that, compared to patients who received etaner- (Table II). cept or placebo, more patients treated with ixekizumab Regarding the patient-reported outcomes, across all were distributed across the lower absolute PASI catego- treatments combined, a high proportion of patients ries at all time points during the 12 weeks of treatment (81.8%) classified as absolute PASI=0 (PASI 100) re- (Fig. 3). For example, at week 12, 80.8% of patients in sponders at 12 weeks reached DLQI (0,1), indicative of the ixekizumab treatment group were categorized as ≤ 3 no impact of disease on patients’ lives (Table II). The responders compared to 34.8% in the etanercept group percentage overlap with DLQI (0,1) responders fell to and 3.7% in the placebo group, respectively. 67.7% and 63.0%, respectively, for absolute PASI >0 to ≤ 1 and > 1 to ≤ 2 responders, and continued to gradually Disease severity and HRQoL by absolute PASI response decrease with decreasing absolute PASI band ranges (Table II). In comparison, DLQI (0,1) was met by 67.2% category of PASI 75 and 73.4% of PASI 90 responders (Table II). The proportion of responders across all treatments at For the other HRQoL measures examined, the proportion ActaDV week 12 for each absolute PASI band criterion was of patients classified as absolute PASI = 0 responders at further examined relative to response on other disease 12 weeks who also reached PatGA (0,1) and Itch NRS severity indices (Table II). At week 12, of the patients (≥ 4 improvement) was 96.0% and 94.7%, respectively classified as absolute PASI band > 0 to ≤ 1 responders, (Table II). Of the patients with absolute PASI > 0 to ≤ 1 100% of patients also met PASI 90 and 96.1% met sPGA or > 1 to ≤  2 responses, 86.7% and 80.3%, respectively, (0,1), indicating excellent agreement between these re- were also classified as PatGA (0,1) responders, and > 87% sponse criteria. Similarly, the majority of patients with of patients in these absolute PASI categories also had a an absolute PASI > 1 to ≤ 2 response at week 12 also had ≥ 4-point improvement on the Itch NRS (Table II). How­ Advances in dermatology and venereology % Patients Week 1 Week 2 Week 4 Week 8 Week 12 Fig. 3. Comparison of relative response rates across Absolute PASI IXE IXE IXE IXE IXE treatment groups (non-responder imputation criteria Q2W ETN PBO Q2W ETN PBO Q2W ETN PBO Q2W ETN PBO Q2W ETN PBO (NRI)) using absolute Psoriasis Area Severity Index PASI = 0 0.0 0.0 0.0 1.5 0.0 0.0 8.2 0.4 0.0 24.7 2.8 0.8 39.0 6.4 0.3 (PASI) band criteria at 1, 2, 4, 8, and 12 weeks. The PASI >0 to <=1 0.1 0.0 0.0 1.1 0.0 0.0 5.2 0.7 0.3 13.7 3.1 0.0 15.6 7.0 0.6 PASI >1 to <=2 0.3 0.0 0.0 3.7 0.1 0.0 13.3 1.2 0.3 20.0 6.6 0.3 17.0 11.9 1.4 relative proportions of patients reaching each absolute PASI >2 to <=3 0.8 0.3 0.0 5.2 0.9 0.3 10.7 3.4 0.8 10.1 8.8 0.8 9.2 9.5 1.4 PASI criterion are shown by treatment group and time PASI >3 to <=5 4.5 0.4 0.0 14.0 2.0 0.3 17.1 8.9 1.1 12.4 13.5 2.2 8.4 15.9 2.5 point. ETN: etanercept; IXE Q2W: ixekizumab 80 mg PASI >5 94.3 99.3 100.0 74.5 97.0 99.4 45.5 85.4 97.5 19.1 65.2 95.9 10.8 49.3 93.8 every 2 weeks; PBO: placebo. www.medicaljournals.se/acta Absolute PASI as a measure for psoriasis 975 Table II. Patients who reached relative Psoriasis Area and Severity Index (PASI), static Physician’s Global Assessment (sPGA), and patient- reported outcome criteria at week 12 (NRI) as a percentage of those patients achieving each absolute PASI band (all treatments combined) ActaDV PASI 75 PASI 90 sPGA (0,1) DLQI (0,1) PatGA (0,1) Itch NRS ≥4b n = 2,567 n = 2,567 n = 2,567 n = 2,567 n = 2,567 n = 2,140 Absolute PASI = 0 Nx = 577 Nx = 577 Nx = 577 Nx = 577 Nx = 577 Nx = 473 n (%) reaching criterion 577 (100) 577 (100) 576 (99.8) 472 (81.8) 554 (96.0) 448 (94.7) Absolute PASI > 0 to ≤ 1 Nx = 279 Nx = 279 Nx = 279 Nx = 279 Nx = 279 Nx = 235 n (%) reaching criterion 279 (100) 279 (100) 268 (96.1) 189 (67.7) 242 (86.7) 205 (87.2) Absolute PASI > 1 to ≤ 2 Nx = 335 Nx = 335 Nx = 335 Nx = 335 Nx = 335 Nx = 275 n (%) reaching criterion 335 (100) 235 (70.1) 306 (91.3) 211 (63.0) 269 (80.3) 241 (87.6) Absolute PASI > 2 to ≤ 3 Nx = 201 Nx = 201 Nx = 201 Nx = 201 Nx = 201 Nx = 168 n (%) reaching criterion 201 (100) 41 (20.4) 143 (71.1) 112 (55.7) 135 (67.2) 133 (79.2) Absolute PASI > 3 to ≤ 5 Nx = 256 Nx = 256 Nx = 256 Nx = 256 Nx = 256 Nx = 216 n (%) reaching criterion 173 (67.6) 9 (3.5) 110 (43.0) 118 (46.1) 144 (56.3) 162 (75.0) Acta Dermato-Venereologica Absolute PASI >5a Nx = 919 Nx = 919 Nx = 919 Nx = 919 Nx = 919 Nx = 773 n (%) reaching criterion 51 (5.5) 0 (0) 48 (5.2) 139 (15.1) 138 (15.0) 237 (30.7) PASI 75 Nx = 1,616 Nx = 1,616 Nx = 1,616 Nx = 1,616 Nx = 1,616 Nx = 1,616 n (%) reaching criterion 1,616 (100) 1,141 (70.6) 1,403 (86.8) 1086 (67.2) 1332 (82.4) 1,173 (72.6) PASI 90 Nx = 1,141 Nx = 1,141 Nx = 1,141 Nx = 1,141 Nx = 1,141 Nx = 1,141 n (%) reaching criterion 1,141 (100) 1,141 (100) 1,095 (96.0) 838 (73.4) 1,017 (89.1) 866 (75.9) a Category includes patients with missing data. bItch numeric rating scale (NRS) ≥ 4 refers to improvement from baseline. %n= n/Nx*100; DLQI: Dermatology Life Quality Index; N: total number of patients in the analysis population; n: number of patients meeting the specified criteria; Nx: number of patients in each PASI category; PatGA: Patient Global Assessment. ever, the degree of overlap between > 2 to ≤ 3 or > 3 to ≤  5 response and these response criteria was substantially lower at 56.3–67.2% for PatGA (0,1) and 75.0–79.2% for Itch NRS (≥ 4) (Table II). Table III. Mean and mean change from baseline in DLQI, PatGA, Mean absolute DLQI, PatGA, and Itch NRS scores and Itch NRS at Week 12 (LOCF) by PASI band response (all treatments combined) are summarized by absolute PASI band criteria in Table III, and the overall means are plotted relative to absolute DLQIa PatGAb Itch NRSc n= 2,570 n= 2,570 n= 2,131 band criteria in Fig. 4. Absolute DLQI, PatGA, and Itch Mean (SD) Mean (SD) Mean (SD) NRS scores at week 12 correlated with the absolute PASI Absolute PASI = 0 criteria, with the impact of skin symptoms on HRQoL ActaDV Overall mean 0.73 (1.48) 0.39 (0.53) 0.53 (0.93) Mean change from baseline –9.80 (6.92) –3.45 (1.06) –6.53 (1.96) rated as less severe by patients in the absolute PASI ≤  2 Mean by baseline PASI category categories compared to patients in the absolute PASI > 2 Baseline PASI <20 0.97 (1.82) 0.45 (0.57) 0.75 (1.16) Baseline PASI ≥20 0.40 (0.68) 0.30 (0.47) 0.30 (0.57) categories (Fig. 4). Absolute PASI > 0 to ≤ 1 Assessment of the 12-week response by baseline PASI Overall mean 1.93 (2.52) 0.98 (0.63) 1.41 (1.71) Mean change from baseline –9.50 (7.32) –2.81 (1.21) –5.17 (2.43) < 20 versus baseline PASI ≥ 20 revealed no differences in Mean by baseline PASI category the percentage of patients reaching each absolute PASI Baseline PASI <20 Baseline PASI ≥20 2.11 (2.61) 1.53 (2.35) 1.05 (0.62) 0.82 (0.64) 1.45 (1.34) 1.33 (2.35) criterion between the two groups (Fig. 5). Furthermore, Absolute PASI > 1 to ≤ 2 when the mean absolute DLQI, PatGA, and Itch NRS Overall mean 2.00 (2.77) 1.23 (0.92) 1.56 (1.51) scores were assessed by these baseline PASI categories, Advances in dermatology and venereology Mean change from baseline –9.65 (7.13) –2.71 (1.32) –5.24 (2.01) Mean by baseline PASI category no consistent differences were observed (Table III). Baseline PASI <20 1.87 (2.32) 1.13 (0.91) 1.67 (1.61) Baseline PASI ≥20 2.27 (3.57) 1.43 (0.94) 1.33 (1.31) Absolute PASI > 2 to ≤ 3 Overall mean 3.55 (4.52) 1.52 (0.78) 2.26 (2.11) DISCUSSION Mean change from baseline –8.23 (6.41) –2.40 (1.15) –4.95 (2.39) Mean by baseline PASI category Relative PASI response criteria are commonly used in Baseline PASI <20 3.84 (4.94) 1.53 (0.80) 2.13 (1.94) Baseline PASI ≥20 2.61 (2.73) 1.50 (0.71) 2.63 (2.55) clinical trials and for comparing newer and older treat­ Absolute PASI > 3 to ≤ 5 ments but have limitations when applied in the daily Overall mean 3.24 (3.50) 1.61 (0.84) 2.21 (1.81) Mean change from baseline –8.67 (5.96) –2.36 (1.20) –4.88 (2.36) clinical practice. Treatment goals defined in terms of Mean by baseline PASI category absolute PASI avoid some of these limitations, but a Baseline PASI <20 3.26 (3.21) 1.61 (0.80) 2.17 (1.69) Baseline PASI ≥20 3.20 (4.40) 1.60 (1.00) 2.33 (2.15) consensus on the absolute PASI target that is clinically Absolute PASI > 5d meaningful has not been reached. The current study was 8.80 (7.13) 3.12 (1.29) 5.46 (2.93) Overall mean Mean change from baseline –3.89 (6.46) –0.97 (1.39) –2.01 (2.94) conducted to inform this discussion and to evaluate dif- Mean by baseline PASI category ferent absolute PASI treatment targets relative to other 8.24 (6.64) 3.13 (1.26) 5.58 (2.84) Baseline PASI <20 Baseline PASI ≥20 9.56 (7.67) 3.10 (1.34) 5.31 (3.04) measures of response based on data derived from two a Dermatology Life Quality Index (DLQI) has a possible composite score of 0–30 large clinical studies on patients with moderate-to-severe (least to most impact of skin symptoms on health-related quality of life (HRQoL)). b plaque psoriasis. Patient Global Assessment (PatGA) has possible scores from 0–5 numeric rating scale (NRS) (clear to severe). cItch NRS has scores from no itch to worst itch imaginable The ultimate treatment goal for psoriasis is clear or (from 0 to 10) in the past 24 h. dCategory includes patients with missing data. ITT: intention to treat; LOCF: last observation carried forward; PASI: Psoriasis almost clear skin, with many clinicians now advocating Area and Severity Index. robust treatment goals of ≥ 90% improvement over Acta Derm Venereol 2019 976 L. Puig et al. ActaDV Fig. 4. Mean Dermatology Life Quality Index (DLQI), Patient Global Assessment (PatGA), and Itch numeric rating scale (NRS) at week 12 Acta Dermato-Venereologica (last observation carried forward (LOCF)) by Psoriasis Area Severity Index (PASI) band response (all treatments combined). DLQI has a possible composite score of 0–30 (least to most impact of skin symptoms on health-related quality of life (HRQoL)). PatGA is scored from 0–5 NRS (clear to severe). Itch NRS is scored from no itch to worst itch imaginable (from 0 to 10) in the previous 24 h. PASI > 5 category includes patients with missing data. Data are from the intention-to-treat population (DLQI, PatGA) or a subpopulation with baseline Itch ≥4 (Itch NRS). N: total number of patients in the analysis population; Nx: number of patients in each PASI band category. base­line PASI, given the increased efficacy of the newer respondingly less overlap with the responders on these treatments (2, 6). With respect to PASI 90, the current HRQoL measures, indicating a substantial reduction in absolute PASI band analyses showed that both PASI > 0 patient satisfaction with increasing amounts of residual to ≤ 1 and > 1 to ≤ 2 responder populations exhibited good disease. This inverse relationship between PASI level overlap with the responder populations for PASI 90, as and HRQoL benefit was also observed between absolute well as for sPGA (0,1). In contrast, the levels of overlap DLQI, PatGA, and Itch NRS scores and absolute PASI for PASI > 2 to ≤ 3 and > 3 to ≤ 5 responder populations band response and is in broad agreement with previous with PASI 90 and sPGA (0,1) were markedly reduced, studies, which used a variety of HRQoL measures (13, indicating worse agreement between these criteria. These 17, 18). However, the baseline PASI level (baseline PASI data suggest that PASI ≤ 2 might serve as a potential < 20 versus PASI ≥ 20) did not substantially impact PASI alternative treatment goal for patients with plaque pso- response or HRQoL outcomes. These latter findings are riasis. In support of this conclusion, compared to other in line with our previous report on UNCOVER-2 and ActaDV absolute PASI levels, the PASI ≤ 2 response rates for UNCOVER-3 integrated populations, which found no ixekizumab, etanercept, and placebo treatment groups differences in PASI response between baseline PASI < 20 at 12 weeks in this pooled analysis most closely match and PASI ≥ 20 groups at 12 weeks and 156 weeks when the PASI 90 response rates previously published on the patients were examined by treatment group, indicating individual study populations (9). a consistent response to treatment regardless of the ba- Further, the current data suggest that absolute PASI seline disease severity (19). values in this range (i.e., ≤ 2) reflect clinically meaningful improvements in the patients’ HRQoL. Not surprisingly, Limitations a high proportion of patients achieving absolute PASI = 0 Advances in dermatology and venereology at 12 weeks also reached DLQI (0,1), PatGA (0,1), This study has a number of limitations. Notably, as this and Itch NRS ≥ 4, suggesting that skin-related HRQoL study used data from clinical trials on moderate-to-severe improvements were strongly associated with achieving psoriasis, the study populations were largely homoge- clear skin, which is consistent with previous reports neous in terms of baseline demographics and clinical cha- (13−16). Patients showing less than total skin clearance racteristics, including baseline PASI scores. With a mean at incrementally higher absolute PASI levels had cor- baseline PASI of 20.29, the strong agreement observed Fig. 5. Percentage of patients who reached each absolute Psoriasis Area Severity Index (PASI) band criterion at week 12 (non-responder imputation (NRI)) by baseline PASI (all treatments combined). Response has been categorized according to patients with baseline PASI score < 20 or ≥ 20. www.medicaljournals.se/acta Absolute PASI as a measure for psoriasis 977 between PASI ≤ 2 and PASI 90 response is to be expec- iris/handle/10665/204417. 2. Carretero G, Puig L, Carrascosa JM, Ferrándiz L, Ruiz-Villa- ted, and examining the absolute PASI in a more hetero- ActaDV verde R, de la Cueva P, et al. Redefining the therapeutic ob- geneous patient group with a broader range of base­line jective in psoriatic patients candidates for biological therapy. PASI values would further improve the evaluation of the J Dermatolog Treat 2018; 29: 334–346. 3. Schmitt J, Wozel G. The psoriasis area and severity index is absolute PASI treatment targets. An additional limitation the adequate criterion to define severity in chronic plaque- of using data from the UNCOVER clinical trials is that type psoriasis. Dermatology 2005; 210: 194–199. all patients met the inclusion criterion of baseline PASI 4. Fredriksson T, Pettersson U. Severe psoriasis – oral therapy with a new retinoid. Dermatologica 1978; 157: 238–244. ≥ 12, but it is not currently known if the findings are 5. European Medicines Agency. Guideline on clinical investiga- relevant to disease activity < 12. A recent prospective tion of medicinal products indicated for the treatment of observational study using the BioCAPTURE registry, psoriasis 2004 [retrieved 2018 Jan 10]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/ Acta Dermato-Venereologica inclusive of patients from clinical practice with baseline Scientific_guideline/2009/09/WC500003329.pdf. PASI scores < 10, has begun to examine this issue; its 6. Puig L. PASI90 response: the new standard in therapeutic findings suggest that defining treatment goals in terms efficacy for psoriasis. J Eur Acad Dermatol Venereol 2015; 29: 645–648. of absolute PASI may also have utility in patients with 7. Zheng J. Absolute Psoriasis Area and Severity Index: an mild disease according to the baseline PASI values (8). additional evaluation for clinical practice. Br J Dermatol 2017; 176: 576. 8. Zweegers J, Roosenboom B, van de Kerkhof PC, van den Reek Conclusion JM, Otero ME, Atalay S, et al. Frequency and predictors of a high clinical response in patients with psoriasis on biolo- Using data from clinical studies, the current study sup- gical therapy in daily practice: results from the prospective, ports the use of absolute PASI to define treatment goals multicenter BioCAPTURE cohort. Br J Dermatol 2017; 176: 786–793. as it can be used regardless of knowledge of the baseline 9. Griffiths CE, Reich K, Lebwohl M, van de Kerkhof P, Paul C, disease; thereby avoiding some of the limitations of the Menter A, et al. Comparison of ixekizumab with etanercept relative PASI measures. Specifically, the data suggest or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. that for most patients, PASI ≤ 2 is an attainable goal for Lancet 2015; 386: 541–551. the treatment of moderate-to-severe plaque psoriasis, on 10. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) – par with PASI 90 in terms of its association with clini- a simple practical measure for routine clinical use. Clin Exp Dermatol 1994; 19: 210–216. cal and HRQoL improvements, and may be a clinically 11. Hongbo Y, Thomas CL, Harrison MA, Salek MS, Finlay AY. relevant choice if the absolute PASI is used instead of Translating the science of quality of life into practice: What ActaDV the relative PASI. do dermatology life quality index scores mean? J Invest Dermatol 2005; 125: 659–664. 12. Kimball AB, Naegeli AN, Edson-Heredia E, Lin CY, Gaich C, Nikaï E, et al. Psychometric properties of the Itch Numeric ACKNOWLEDGMENTS Rating Scale in patients with moderate-to-severe plaque psoriasis. Br J Dermatol 2016; 175: 157–162. We thank the patients, their families, and the study personnel 13. Blauvelt A, Griffiths CEM, Lebwohl M, Mrowietz U, Puig L, who participated in these clinical trials. Eli Lilly and Company Ball S, et al. Reaching complete or near-complete resolution (Indianapolis, Indiana, USA) sponsored this study and the produc- of psoriasis: benefit and risk considerations. Br J Dermatol tion of this manuscript. Syneos Health provided medical writing 2017; 177: 587–590. (Kaye L. Stenvers) and editing (Teri Tucker, Antonia Baldo, Rod 14. Feldman SR, Bushnell DM, Klekotka PA, Scanlon M, Martin ML, Advances in dermatology and venereology Everhart) support. Wade SW, et al. Differences in psoriasis signs and symptom severity between patients with clear and almost clear skin The study was sponsored by Eli Lilly and Company, Indianapolis, in clinical practice. J Dermatolog Treat 2016; 27: 224–227. IN. 15. Viswanathan HN, Chau D, Milmont CE, Yang W, Erondu N, Conflicts of interest: LP has received consultancy/speaker’s Revicki DA, et al. Total skin clearance results in improve- honoraria from and/or participated in clinical trials sponsored by ments in health-related quality of life and reduced symptom Abbvie, Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, severity among patients with moderate to severe psoriasis. J Dermatolog Treat 2015; 26: 235–239. Celgene, Gebro, Janssen, Leo-Pharma, Eli Lilly and Company, 16. Strober B, Papp KA, Lebwohl M, Reich K, Paul C, Blauvelt A, Merck-Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, et al. Clinical meaningfulness of complete skin clearance in Sandoz, Samsung-Bioepis, Sanofi, and UCB. CZ has received psoriasis. J Am Acad Dermatol 2016; 75: 77–82. honoraria for lectures from Eli Lilly and Company, Leo Pharma, 17. Elewski BE, Puig L, Mordin M, Gilloteau I, Sherif B, Fox T, Novartis, and Pfizer; has consulted for and participated in advisory et al. Psoriasis patients with psoriasis Area and Severity boards for AbbVie, Almirall, Amgen, Eli Lilly and Company, Index (PASI) 90 response achieve greater health-related Janssen-Cilag, Novartis, and Takeda; and has been a clinical quality-of-life improvements than those with PASI 75–89 study investigator for AbbVie, Amgen, Boehringer Ingelheim, response: results from two phase 3 studies of secukinumab. Celgene, Eli Lilly and Company, Leo Pharma, MSD, Novartis, J Dermatolog Treat 2017; 28: 492–499. 18. Mattei PL, Corey KC, Kimball AB. Psoriasis Area Severity In- and Takeda. MD and AL are present or past employees and may dex (PASI) and the Dermatology Life Quality Index (DLQI): be shareholders of Eli Lilly and Company. 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