SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 273 ORIGINAL RESEARCH Reporting of Quality of Life in Clinical Trials of Biologics for Plaque Psoriasis: A Systematic Review Giselle Prado MDa, Anna Nichols MDb, PhD, Mercedes Florez-White MDc, Francisco Kerdel BSc, MBBSc,d aNational Society for Cutaneous Medicine, New York, NY bDepartment of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL cDepartment of Dermatology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL dFlorida Academic Dermatology Center, Coral Gables, FL Psoriasis vulgaris is a chronic relapsing and remitting inflammatory skin disease that affects 0.5-11.43% of the population worldwide.1 Psoriasis negatively impacts patients’ quality of life.2,3 For many patients, improved quality of life is as important as objective clinical improvement of psoriasis lesions.4 Many different tools have been created to evaluate the effect of chronic skin conditions on quality of life (e.g. Dermatology Life Quality Index, Skindex, SF-36, among others). The Dermatology Life Quality Index (DLQI) was first reported in 1994 and is a validated tool used to assess the effect of dermatologic conditions on quality of life.5,6 It is the most commonly used quality of life ABSTRACT Background: Psoriasis is a chronic remitting and relapsing skin disease. For many patients, improved quality of life (QoL) is as important as clinical improvement of lesions. Objective: To review reporting of Dermatology Life Quality Index (DLQI) in randomized controlled trials (RCTs) of biologics for adult patients with plaque psoriasis. Methods: A systematic review was conducted in 4 databases for RCTs that measured DLQI at baseline and endpoint. A data collection form was created for collecting study variables. Risk of bias was assessed using the Cochrane risk of bias tool. Results: Thirty-four RCTs enrolling 16,784 patients were included. Complete baseline and final mean DLQI data was retrieved for 24 studies (70.6%). The mean DLQI at baseline was reported in 79.4% of RCTs. The median at baseline was reported in 14.7% of RCTs. The mean DLQI at endpoint was reported in 23.5% of RCTs and the median DLQI at endpoint was reported in 5.9% of RCTs. The mean change in DLQI was reported in 64.7% of RCTs. Conclusions: DLQI was measured in most clinical trials assessing the efficacy of biologics for psoriasis. Studies did not adhere to uniform standards in publishing results, making analysis of the impact on DLQI challenging. INTRODUCTION https://www.google.com/maps/place/Florida+Academic+Dermatology+Centers/@25.763526,-80.25912,3a,75y,259h,90t/data=!3m7!1e1!3m5!1sG4ehzz2Ry9IwIWz-cQ6oAw!2e0!6s%2F%2Fgeo0.ggpht.com%2Fcbk%3Fcb_client%3Dmaps_sv.tactile%26output%3Dthumbnail%26thumb%3D2%26panoid%3DG4ehzz2Ry9IwIWz-cQ6oAw%26w%3D374%26h%3D75%26yaw%3D259%26pitch%3D0%26thumbfov%3D120%26ll%3D25.763525,-80.259120!7i13312!8i6656!4m7!1m4!3m3!1s0x88d9b775db0c5ffb:0x13f1ff27e25b3882!2s836+Ponce+De+Leon+Blvd,+Coral+Gables,+FL+33134!3b1!3m1!1s0x88d9b775db0c5ffb:0x6f3711e95685ddb9!6m1!1e1 SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 274 measure in clinical trials in dermatology.7 The DLQI is widely used due to its simplicity in scoring, quick completion in 2 minutes, among other reasons.8-10 The DLQI uses 10 questions to assess the effect of a skin condition on a patient’s symptoms and feelings, daily activities, leisure activities, work and school, personal relationships, and treatment.5 Respondents have the ability to rate the effect on quality of life as “not at all”, “a little”, “a lot”, and “very much.” This in turn is scored from 0-3 for each of the 10 questions for a total possible score of 30 points. These summary scores can be banded into different levels of severity. A summary score of 0-1 signifies no effect on quality of life, 2-5 a small effect, 6-10 a moderate effect, 11-20 a very large effect, and 21-30 an extremely large effect.11 Biologic therapy can lead to improvements in quality of life that are both statistically significant and clinically significant as seen when the banding concept of DLQI scores is applied.11 Thus, improving quality of life in patients with psoriasis should be of the utmost importance to clinicians. There are a variety of treatment options for moderate to severe plaque psoriasis and biologics have revolutionized the management of this disease. For patients with psoriasis treated with biologic therapy, there is a clear correlation between DLQI and PASI scores.12 At the time of writing this manuscript, six biologic medications were approved by the United States Food and Drug administration (FDA) for use in plaque psoriasis: adalimumab, etanercept, infliximab, ixekizumab, secukinumab, and ustekinumab. The use of these biologics for psoriasis is supported by data from randomized clinical trials (RCTs). Other reviews have examined the effect of biologic therapy on quality of life.13,14 However, new drugs have been approved since the prior studies were published and many of the originally approved drugs have been withdrawn from the market. This review presents an updated assessment of quality of life studies in psoriasis. Data Sources: We searched four computerized bibliographical databases for articles published since inception to August 2016: Pubmed, Cochrane Library CENTRAL, Ovid MEDLINE, and Embase. Search terms included: “Quality of Life,” “DLQI,” “Dermatology Life Quality Index,” “Dermatology quality of life index,” “psoriasis,” “randomized controlled trials,” “biologic therapy,” “biologic,” and the generic names for each of the drugs. The search was restricted to publications in English. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Prospero registration no. CRD42016046523). The search strategy used is given in Appendix 1. We reviewed trial registers (clinicaltrials.gov) and searched grey literature. Reference lists of all included studies and of recent reviews were also assessed. Electronic publications in advance of print were also included. Inclusion Criteria: We included double-blind, RCTs of patients with plaque psoriasis treated with FDA approved biologic treatments that measured DLQI at baseline and endpoint in adults (aged >18 years). Exclusion Criteria: The exclusion criteria were as follows: trials that included only a subtype of psoriasis, trials that only randomized patients with METHODS SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 275 concomitant psoriatic arthritis, studies that included any patient less than 18 years of age, articles where the change in DLQI values from baseline to endpoint could either not be reliably calculated or could not be obtained after requesting additional information from the author or study sponsor, and abstracts and posters where further data were not available upon contacting the author. Outcome measures: The primary outcome recorded was the mean DLQI score at baseline and endpoint. For studies with an open-label extension, the data were extracted only for the period of the study while it was randomized and controlled. For crossover trials, the data were extracted prior to the crossover. Data extraction and synthesis: One reviewer (G.P.) extracted data, another reviewer (A.N.) checked the extracted data for accuracy, and the reviewers met to discuss any disagreements. We created and piloted a data collection form for recording study design, DLQI scores, drug administered, dosing schedule, and quality of the methodology. Risk of bias was assessed using the Cochrane risk of bias tool independently by 2 reviewers (G.P. and A.N.). Disagreements were resolved by discussion. After screening 571 records, we identified 34 RCTs enrolling a total of 16,784 patients published between December 2003 and May 2016 that fit our inclusion and exclusion criteria. For these studies, 38 articles were retrieved, including those related to the original RCT publication as well as sub- analyses of the original RCT. Of the 34 original RCTs included, complete data, meaning baseline and final mean DLQI scores, was retrieved for 24 studies (70.6%). Of these 24 studies, 66.7% present unpublished data obtained from study authors and sponsors after contacting them for additional information. The mean DLQI at baseline was reported in 79.4% of studies (Table 1). The median at baseline was reported in 14.7% of the studies. The mean DLQI at endpoint was only reported in 23.5% of studies and the median DLQI at endpoint was reported in 5.9% of studies. The mean change in DLQI was reported in 64.7% of studies. Adalimumab. There were five RCTs comprising 1,918 patients that assessed DLQI data in patients treated with adalimumab. Of these studies, we obtained complete data for four RCTs (80%). The DLQI for the placebo group ranged from 8.4- 14.6 at baseline and 7.6-12.3 at endpoint. For those treated with adalimumab, the mean DLQI ranged from 8.4-14.6 at baseline and 2.0-5.0 at endpoint. Etanercept. There were eight RCTs comprising 2,968 patients that assessed DLQI data in patients treated with etanercept. Of these studies, we obtained complete data for four RCTs (50%). The DLQI for the placebo group ranged from 12.2-14 at baseline and 9.75-12.3 at endpoint. For those treated with etanercept, the mean DLQI ranged from 10-13.87 at baseline and 3.8-5.8 at endpoint. Infliximab. There were five RCTs comprising 1,639 patients that assessed DLQI data in patients treated with infliximab. Of these studies, we obtained complete data for four RCTs (80%). The DLQI for the placebo group ranged 10.5-14.4 at baseline and 11.2-13.1 at endpoint. For those treated with infliximab, the mean DLQI ranged from RESULTS SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 276 12.3-14.4 at baseline and 2.4-6.5 at endpoint. Ixekizumab. There were four RCTs comprising 4,008 patients that assessed DLQI data in patients treated with ixekizumab. Of these studies, we obtained complete data for all 4 RCTs (100%). The DLQI for the placebo group ranged from 10.81-12.8 at baseline and 10.26-11.6 at endpoint. For those treated with ixekizumab, the mean DLQI ranged from 10.36-13.4 at baseline and 1.9-4.66 at endpoint. Secukinumab. There were five RCTs comprising 3,294 patients that assessed DLQI data in patients treated with secukinumab. Of these studies, we obtained complete data for 2 RCTs (40%). The DLQI for the placebo group ranged from 12.0-13.4 at baseline and 10.9-11.5 at endpoint. For those treated with secukinumab, the mean DLQI ranged from 11.3-13.9 at baseline and 2.5-3.7 at endpoint. Ustekinumab. There were seven RCTs comprising 2,957 patients that assessed DLQI data in patients treated with ustekinumab. Of these studies, we obtained complete data for 6 RCTs (85.7%). The DLQI for the placebo group ranged from 10.5-15.2 at baseline and 9.7-14.7 at endpoint. For those treated with ustekinumab, the mean DLQI ranged from 10.5-16.1 at baseline and 2.1-4.8 at endpoint. Quality of Evidence for Included Studies. Appendix 2 provides an assessment of the risk of bias for the included studies. All studies were randomized controlled trials. Most studies limited the bias inherent to the trial by employing the use of random sequence generation, allocation concealment, and blinding of participants, personnel, and assessors. SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 277 Table 1: Summary of clinical trials investigating biologic therapy for patients with plaque psoriasis. Source Clinicaltrials .gov Number Interventions Trial Phase Tx End- point Week No. of PBO Pts at Base -line No. of PBO Pts at End- point No. of Tx Pts at Base -line No. of Tx Pts at End- point DLQI Measurement Reported in Publication Doses Studied Mean DLQI ± SD (SE) PBO Tx Baseline Endpoint Baseline Endpoint Asahina 201026 NCT003387 54 Adalimumab vs. PBO 2/3 16 & 24 138 138 123 122 Mean at baseline Mean change score with SD 40mg EOW 8.4 N/A 8.4 N/A 80mg at baseline then 40mg EOW 8.4 N/A 8.5 N/A 80mg EOW 8.4 N/A 8.8 N/A Gordon 201527* NCT014835 99 Adalimumab vs. Guselkumab vs. PBO 2 16 42 42 43 39 Mean change score with SD 80mg at baseline then 40mg EOW 14.6 ± 5.91 12.3 ± 7.66 14.6 ± 7.17 5.0 ± 7.41 Shikiar 200728/ Wallace 200529 N/A Adalimumab vs. PBO 2 12 104 104 95 94 Mean at baseline and endpoint with 95% CI Mean change score with 95% CI 80mg at baseline then 40mg EOW 12.2 (10.0- 14.4) 10.7 (9.1- 12.4) 13.3 (10.7- 15.8) 2.8 (1.0- 4.7) 80mg at baseline then 40mg/wk 12.2 (10.0- 14.4) 10.7 (9.1- 12.4) 13.6 (11.3- 15.9) 2.0 (0.3- 3.8) Revicki 200830 NCT002358 20 Adalimumab vs. MTX vs. PBO 3 12 & 16 53 53 108 103 Mean at baseline and endpoint with SD 80mg at baseline then 40mg 11.7 ± 7.0 7.6 ± 6.4 11.8 ± 6.6 2.5 ± 4.0 SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 278 Mean change score with 95% CI EOW Revicki 200731 NCT002378 87 Adalimumab vs. PBO 3 4 & 16 398 397 814 808 Mean at baseline and endpoint with SD Mean change score with 95% CI 80mg at baseline then 40mg EOW 11.4 ± 7.0 9.2 ± 7.1 11.3 ± 6.6 3.0 ± 4.5 Bachele z 201532/ Valenzu ela 201633* NCT012415 91 Etanercept vs. Tofacitinib vs. PBO 3 12 108 107 336 335 Mean at baseline and with SD and SE No. of pts with clinically meaningful decrease in DLQI 50mg twice/ wk 12.3 ± 7.1 10.3 12.7 ± 6.8 3.8 Strober 201134* NCT007105 80 Etanercept vs. Briakinumab vs. PBO 3 12 72 66 139 127 No. of pts with DLQI=0 at baseline and endpoint 50mg twice/ wk 13.61 ± 6.918 10.73 ± 6.9464 13.87 ± 7.848 4.78 ± 5.497 Leonardi 200335 N/A Etanercept vs. PBO 2 12 & 24 166 166 486 486 Mean at baseline with SE % Change with SE at wk 12 and 24 25mg / wk 12.8 (0.6) N/A 12.2 (0.5) N/A 25mg twice/ wk 12.8 (0.6) N/A 12.7 (0.5) N/A 50mg twice/wk 12.8 (0.6) N/A 11.3 (0.5) N/A SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 279 Gottlieb 200336/ Lowe 200237 N/A Etanercept vs. PBO 3 12 & 24 55 55 57 57 Mean at baseline % Change with SE at wk 24 25mg twice/ wk 14 N/A 10 N/A Krueger 200538 N/A Etanercept vs. PBO 3 12 193 193 390 390 Mean at baseline with SD No. of pts with clinically meaningful decrease in DLQI Graphical representation of % change 50mg / wk 12.2 ± 6.8 N/A 11.5 ± 7.2 N/A 50mg twice/wk 12.2 ± 6.8 N/A 11.4 ± 6.5 N/A Tyring 200639 NCT001114 49 Etanercept vs. PBO 3 12 307 307 311 311 Mean at baseline with SD % Change at wk 12 50mg twice/wk 12.5 ± 6.7 N/A 12.1 ± 6.7 N/A Reich 200940 N/A Etanercept vs. PBO 3 12 45 46 94 96 Mean at baseline and endpoint Mean change score % Change at wk 12 Graphical 50mg / wk 13.6 12.3 13.2 5.8 SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 280 representations of response ranges at baseline and endpoint, % of pts with DLQI= 0 or 1, and % of pts with clinically meaningful decrease in DLQI Gottlieb 201141* NCT006919 64 Etanercept vs. Briakinumab vs. PBO 3 12 68 68 141 141 No. of pts with DLQI=0 at baseline and endpoint 50mg twice/wk 13.05 9.75 12.40 4.39 Feldman 200542/ Gottlieb 200443 N/A Infliximab vs. PBO 2 10 51 51 198 198 Mean at baseline and endpoint with SD Median at baseline and endpoint with IQR Mean change score with SD % Change at wk 10 with SD 3mg/kg at wk 0, 2 , and 6 13.8 ± 6.6 11.2 ± 7.4 12.3 ± 7.3 3.4 ± 5.2 5mg/kg at wk 0, 2 , and 6 13.8 ± 6.6 11.2 ± 7.4 13.2 ± 7.0 2.8 ± 5.0 Feldman 200844/ Menter 200745* N/A Infliximab vs. PBO 2 10 208 200 625 619 Mean at baseline with SD Mean change 3mg/kg at wk 0, 2 , and 6 13.4 ± 7.34 12.8 ± 7.46 12.8 ±6.89 3.3 ± 4.87 5mg/kg at 13.4 ± 12.8 ± 13.1 2.5 ± SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 281 score with SD Median at baseline Graphical representations of median change score, % of pts with DLQI=0 at endpoint wk 0, 2 , and 6 7.34 7.46 ±7.01 3.83 Yang 201246 NCT011778 00 Infliximab vs. PBO 3 10 45 44 84 82 Mean at baseline and endpoint with SD Mean change score with SD Graphical representation of mean scores 5mg/kg at wk 0, 2 , and 6 14.4 ± 6.3 13.1 ± 5.7 14.4 ± 6.2 6.5 ± 6.5 Torii 201047 N/A Infliximab vs. PBO 3 10 & 14 19 16 35 34 Mean at baseline with SD Median at baseline Mean change score with SD No. of pts with DLQI=0 at 5mg/kg at wk 0, 2 , and 6 10.5 ± 6.8 N/A 12.7 ± 6.8 N/A SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 282 endpoint No. of pts with clinically meaningful decrease in DLQI Graphical representation of Mean change scores with SD Reich 200648* NCT011778 00 Infliximab vs. PBO 3 10 & 24 77 75 297 291 Mean at baseline with SD Mean change score with SD Graphical representation of % of pts with DLQI=0 at endpoint, response ranges at baseline and endpoint 5mg/kg at wk 0, 2, 6, then every 8 wk 11.8 ± 7.46 11.3 ± 8.10 12.7 ± 6.97 2.4 ± 4.16 Griffiths 201549* NCT015972 45 Ixekizumab vs. Etanercept vs. PBO 3 12 168 168 I: 698 E: 358 I: 698 E: 358 Mean at baseline with SD Mean change score with SE No. of pts with Ixekizumab 160mg at baseline then 80mg EOW 12.8 ± 7.24 10.6 ± 7.34 12.4 ± 6.86 1.9 ± 3.12 Ixekizumab 160mg at 12.8 ± 7.24 10.6 ± 7.34 11.6 ± 6.65 2.6 ± 4.48 SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 283 DLQI=0 at endpoint baseline then 80mg E4W Etanercept 50mg twice/wk 12.8 ± 7.24 10.6 ± 7.34 12.7 ± 7.03 4.7 ±5.35 Griffiths 201549* NCT016461 77 Ixekizumab vs. Etanercept vs. PBO 3 12 193 193 I: 771 E: 382 I: 771 E: 382 Mean at baseline with SD Mean change score with SE No. of pts with DLQI=0 at endpoint Ixekizumab 160mg at baseline then 80mg EOW 12.7 ± 7.0 10.5 ± 7.23 12.4 ± 6.93 2.0 ± 3.30 Ixekizumab 160mg at baseline then 80mg E4W 12.7 ± 7.0 10.5 ± 7.23 11.9 ± 6.97 2.4 ± 4.25 Etanercept 50mg twice/wk 12.7 ± 7.0 10.5 ± 7.23 11.5 ± 6.84 3.8 ± 4.75 Leonardi 201250* NCT011074 57 Ixekizumab vs. PBO 2 16 27 27 115 115 Mean at baseline with SD Mean change score with SD % of pts with DLQI=0 at endpoint 10 mg at wk 0, 2, 4, 8, 12, 16 10.81 ± 5.21 10.26 ± 6.92 10.61 ± 7.16 4.54 ± 6.04 25 mg at wk 0, 2, 4, 8, 12, 16 10.81 ± 5.21 10.26 ± 6.92 11.63 ± 7.19 4.66 ± 6.47 75 mg at wk 0, 2, 4, 8, 12, 16 10.81 ± 5.21 10.26 ± 6.92 11.10 ± 5.59 1.96 ± 3.27 150 mg at wk 0, 2, 4, 8, 12, 16 10.81 ± 5.21 10.26 ± 6.92 10.36 ± 5.81 2.15 ± 3.30 Gordon 201551* NCT014745 12 Ixekizumab vs. PBO 3 12 431 431 865 865 None in abstract 160mg at baseline 12.8 ± 7.11 11.6 ± 7.53 13.4 ± 7.02 2.0 ± 3.33 SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 284 then 80mg EOW 160mg at baseline then 80mg E4W 12.8 ± 7.11 11.6 ± 7.53 13.2 ± 7.02 2.3 ± 3.87 Augustin 201652 NCT009410 31 Secukinuma b vs. PBO 2 12 67 58 337 322 Mean at baseline with SD Median at baseline and endpoint with IQR Graphical representation of % of pts with DLQI= 0 or 1 150mg at baseline 12.5 ± 6.2 N/A 11.3 ± 6.9 N/A 150mg at baseline then E4W 12.5 ± 6.2 N/A 11.8 ± 7.1 N/A 150mg at baseline then wk 1, 2, and 4 12.5 ± 6.2 N/A 11.8 ± 6.7 N/A Thaci 201553/ Blauvelt 201654 NCT020749 82 Secukinuma b vs. Ustekinuma b 3 16 - - S: 331 U: 333 S: 331 U: 333 No. of pts with DLQI=0 or 1 at endpoint Secukinum ab 300mg weekly for wk 0-4 then E4W - - 13.4 ± 7.63 N/A Ustekinuma b 45 or 90mg at baseline, wk 4, then every 12 wk - - 13.2 ± 7.57 N/A Langley 201455 NCT013654 55 Secukinuma b vs. PBO 3 12 248 246 490 488 Mean at baseline and endpoint Mean change 300mg weekly for wk 0-4 then E4W 12.0 10.9 13.9 2.5 SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 285 score 150mg weekly for wk 0-4 then E4W 12.0 10.9 13.4 3.3 Langley 201455 NCT013585 78 Secukinuma b vs. Etanercept vs. PBO 3 12 326 324 980 973 Mean at baseline and endpoint Mean change score Secukinum ab 300mg weekly for wk 0-4 then E4W 13.4 11.5 13.3 2.9 Secukinum ab 150mg weekly for wk 0-4 then E4W 13.4 11.5 13.4 3.7 Etanercept 50mg twice/wk 13.4 11.5 13.4 5.5 Paul 201556 NCT016366 87 Secukinuma b vs. PBO 3 12 61 61 121 121 Paper did not report any DLQI data but DLQI was measured according to protocol on clinicaltrials.gov 300mg weekly for wk 0-4 then E4W N/A N/A N/A N/A 150mg weekly for wk 0-4 then E4W N/A N/A N/A N/A Leonardi 200857* NCT002679 69 Ustekinuma b vs. PBO 3 12 255 252 511 503 Mean at baseline with SD Mean change score with SD Median change score with IQR 45mg at baseline and wk 4 11.8 ± 7.41 11.2 ± 7.45 11.1 ± 7.09 3.1 ± 4.26 90mg at baseline and wk 4 11.8 ± 7.41 11.2 ± 7.45 11.6 ± 6.92 2.8 ± 3.64 SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 286 No. of pts with DLQI=0 or 1 at endpoint Papp 200858* NCT003074 37 Ustekinuma b vs. PBO 3 12 410 400 820 803 Mean at baseline with SD Mean change score with SD Median change score with IQR No. of pts with DLQI=0 or 1 at endpoint 45mg at baseline and wk 4 12.3 ± 6.86 11.8 ± 7.77 12.2 ± 7.07 2.9 ± 4.35 90mg at baseline and wk 4 12.3 ± 6.86 11.8 ± 7.77 12.6 ± 7.29 2.7 ± 4.01 Igarashi 201259 NCT007235 28 Ustekinuma b vs. PBO 2/3 12 32 31 126 123 Mean at baseline with SD Mean change score with SD Median change score No. of pts with DLQI=0 or 1 at endpoint 45mg at baseline and wk 4 10.5 ± 6.2 N/A 11.4 ± 6.5 N/A 90mg at baseline and wk 4 10.5 ± 6.2 N/A 10.7 ± 6.4 N/A Krueger 200760* NCT003202 16 Ustekinuma b vs. PBO 2 12 64 64 256 255 Mean at baseline with SD Mean change score with SD 45mg at baseline 12.0 ± 7.25 9.7 ± 7.10 11.9 ± 6.99 4.5 ± 6.24 90mg at baseline 12.0 ± 7.25 9.7 ± 7.10 13.4 ± 7.25 3.6 ± 5.10 45mg 12.0 ± 9.7 ± 12.6 ± 2.5 ± SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 287 Median change score with IQR No. of pts with DLQI=0 at endpoint weekly for 4 wk 7.25 7.10 6.63 3.75 90mg weekly for 4 wk 12.0 ± 7.25 9.7 ± 7.10 10.5 ± 6.73 2.1 ± 4.01 Zhu 201361* NCT010089 95 Ustekinuma b vs. PBO 3 12 162 159 160 158 Mean at baseline with SD Mean change score with SD 45mg at baseline and wk 4 13.1 ± 7.51 11.2 ± 7.88 13.7 ± 7.57 4.4 ± 5.39 Tsai 201162* NCT007473 44 Ustekinuma b vs. PBO 3 12 60 60 61 59 Mean at baseline with SD Mean change score with SD Median change score with IQR 45mg at baseline and wk 4 15.2 ± 6.95 14.7 ± 7.97 16.1 ± 6.09 4.8 ± 5.25 Papp 201663* NCT020544 81 Ustekinuma b vs. Risankizuma b 12 & 24 - - 40 40 Median at baseline Median % Change at wk 12 % of pts with DLQI=0 or 1 at wk 24 45 or 90mg at baseline, wk 4, wk 16 - - 15.8 ± 6.5 2.8 ± 4.3 Abbreviations: Week of treatment endpoint used for endpoint columns denoted in bold. *Denotes trials for which additional unpublished data was obtained after contacting authors and study sponsors. SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 288 &: and EOW: every other week. E4W: Every 4 weeks. IQR: Interquartile range. MTX: Methotrexate. N/A: Not available. - : Not applicable. SD: Standard Deviation. SE: Standard Error. PBO: PBO Pts: Patients. Tx: Treatment. Wk: Week. SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 289 Psoriasis can have a comparable negative effect on quality of life as cancer, myocardial infarction, and chronic lung disease.3 Patients with psoriasis have decreased work productivity, increased incidence of depression, and difficulties in personal relationships.15-17 Patients with more severe disease manifestations have even greater impairment in these areas of life.18 This disease results in cumulative life course impairment that influences how patients make major life decisions, develop social relationships, and pursue their life goals.19 Achieving significant improvements in quality of life measures should be the goal for any clinical trial assessing treatment efficacy in patients with psoriasis. It has previously been shown that biologic therapy significantly improves DLQI compared to conventional systemic therapy.20 Most clinical trials define efficacy and safety as primary endpoints and relegate quality of life measures as secondary endpoints. This systematic review demonstrates a clear improvement in quality of life, as evidenced by reductions in DLQI scores for patients with plaque psoriasis treated with biologics. The first generation of biologic therapies for plaque psoriasis were the TNF-alpha inhibitors (adalimumab, etanercept, and infliximab). More recently, the targeted therapies against interleukin (IL)-17 and IL- 12/23 have heralded a new era of biologic therapies. Although there were slight differences between the endpoint scores for the TNF-alpha inhibitors and the newer biologics, it is not clear whether these slight differences correspond to clinically significant differences in quality of life. Comparing the ranges of DLQI scores reported across the different drugs, most patients reported a “small effect” of their psoriasis symptoms on quality of life after treatment. When discussing improvement in quality of life, it is important to keep in mind the concept of minimal clinically important difference (MCID). MCID is defined as “the smallest difference in score in the domain of interest which patients perceive as beneficial and which would mandate, in the absence of troublesome side effects and excessive cost, a change in the patient’s management.”21 Taken from the patient’s perspective, this may mean a significant improvement in quality of life and symptomatology; while taken from the clinician’s perspective, this may mean a significant improvement in the treatment or prognosis of the disease. Several studies using different methodologies have attempted to determine the minimum clinically important change in DLQI score and results have ranged from 3-5.22 Four studies included in this review reported some measure of patients who achieved a meaningful decrease in DLQI (either number or percentage of patients). It is possible that the DLQI may not be the best quality of life metric for patients with psoriasis. The DLQI is a scale used to objectively quantify the effect of dermatologic conditions on quality of life. It was surprising to note that there were no significant differences in DLQI scores among the different biologic drugs. Most biologic drugs achieved a final DLQI of 2-5 after starting at a baseline of 8-14. The most recent clinical trials tout major differences in PASI scores as evidence for the efficacy of certain drugs over others. This difference in efficacy was not evident when looking at DLQI in isolation. The DLQI instrument as a measure of quality of life may not be DISCUSSION SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 290 sensitive enough to detect minor improvements attributable to increased skin clearance and then translate these improvements to effects on quality of life. Considering the minor differences in final DLQI scores among the different medications, it is important to keep in mind economic costs when prescribing a biologic therapy. The annual costs of these drugs range from $30,001 for infliximab to $69,762 for ixekizumab.23 Older TNF-alpha inhibitors such as adalimumab and etanercept are less expensive than the newer specific IL inhibitors. There are limited healthcare resources available and many patients struggle to afford their medications, therefore it is reasonable to utilize more affordable medications given the comparable effects on quality of life. A recent meta-analysis found no difference in risk of serious infections among different biologic therapies.24 However, newer medications offer less frequent dosing schedules, which can also augment perceived quality of life for patients. Our systematic review was extensive with a precisely executed search strategy and selection process. It serves as an up to date resource for quality of life data in clinical trials of psoriasis. The last similar review was published in 2006 with several drugs that are not currently available in the U.S.13 Additionally, the studies included in our review were all randomized controlled trials that are less susceptible to sources of bias. Our systematic review has some limitations. First, there was significant heterogeneity among the included studies in terms of length of study, characteristics of enrolled patients, and biologic therapy protocol. These studies were conducted with different objectives and comparison treatments across different trials. Although we originally planned to conduct a meta-analysis that would allow us to combine the results across several trials for each drug and thus compare drugs to one another, this proved to be impossible due to significant heterogeneity. Since we were unable to conduct the meta-analysis, it is not clear which drug is the most effective at improving quality of life. Future studies should determine whether clinically significant differences in quality of life (keeping in mind efficacy and cost-effectiveness) exist between the studied drugs. Second, most studies did not uniformly report DLQI data. In these cases, significant efforts were made to contact study authors and sponsoring companies for additional information. Many complied with our requests for further information. However, several study sponsors declined to provide unpublished data for use in this study. Poor reporting of quality of life data continues to be a significant problem in dermatology research25 and others have had similar experiences in which a lack of reporting guidelines for quality of life data resulted in data analysis difficulties.7 Conflict of Interest Disclosures: Dr. Kerdel receives honoraria from Amgen, Abbvie, Janssen, Lilly, Celgene, Actelion, Novartis, Leo, Regeneron, Sanofi, and Valeant. He also receives research grants from Amgen, Abbvie, Janssen, Lilly, Celgene, Actelion, Novartis, Pfizer, Regeneron, Sanofi, UCB, and AstroZeneca. Funding: None. Corresponding Author: Giselle Prado, MD National Society for Cutaneous Medicine, New York, NY drgiselleprado@gmail.com SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 291 References: 1. Michalek IM, Loring B, John SM. A systematic review of worldwide epidemiology of psoriasis. J Eur Acad Dermatol Venereol. 2016; 2. De arruda LH, De moraes AP. The impact of psoriasis on quality of life. Br J Dermatol. 2001;144 Suppl 58:33-6. 3. Rapp SR, Feldman SR, Exum ML, Fleischer AB, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999;41(3 Pt 1):401-7. 4. Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis. 2005;64 Suppl 2:ii18-23. 5. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-6. 6. Basra MK, Fenech R, Gatt RM, Salek MS, Finlay AY. The Dermatology Life Quality Index 1994-2007: a comprehensive review of validation data and clinical results. Br J Dermatol. 2008 Nov;159(5):997-1035. Epub 2008 Sep 15. 7. Ali FM, Cueva AC, Vyas J, et al. A systematic review of the use of quality- of-life instruments in randomized controlled trials for psoriasis. Br J Dermatol. 2016; 8. Loo WJ, Diba V, Chawla M et al. Dermatology Life Quality Index: influence of an illustrated version. Br J Dermatol 2003; 148:279–84. 9. Smith CH, Anstey AV, Barker JNWN et al. British Association of Dermatologists’ guidelines for biologic interventions for psoriasis. 2009. Br J Dermatol 2009; 161:987–1019. 10. Finlay AY, Basra MKA, Piguet V et al. Dermatology Life Quality Index (DLQI): a paradigm shift to patient-centered outcomes. J Invest Dermatol 2012; 132:2464–5. 11. Hongbo Y, Thomas CL, Harrison MA, Salek MS, Finlay AY. Translating the science of quality of life into practice: What do dermatology life quality index scores mean?. J Invest Dermatol. 2005;125(4):659-64. 12. Mattei PL, Corey KC, Kimball AB. Psoriasis Area Severity Index (PASI) and the Dermatology Life Quality Index (DLQI): the correlation between disease severity and psychological burden in patients treated with biological therapies. J Eur Acad Dermatol Venereol 2014; 28:333–7. 13. Katugampola RP, Lewis VJ, Finlay AY. The Dermatology Life Quality Index: assessing the efficacy of biological therapies for psoriasis. Br J Dermatol. 2007;156(5):945-50. 14. Reich K, Sinclair R, Roberts G, Griffiths CE, Tabberer M, Barker J. Comparative effects of biological therapies on the severity of skin symptoms and health- related quality of life in patients with plaque-type psoriasis: a meta-analysis. Curr Med Res Opin. 2008;24(5):1237- 54. 15. Korman NJ, Zhao Y, Roberts J, et al. Impact of psoriasis flare and remission on quality of life and work productivity: a real-world study in the USA. Dermatol Online J. 2016;22(7) 16. Shah K, Mellars L, Changolkar A, Feldman SR. Real-world burden of comorbidities in US patients with psoriasis. J Am Acad Dermatol. 2017;77(2):287-292.e4. 17. Darjani A, Heidarzadeh A, Golchai J, et al. Quality of life in psoriatic patients: a study using the short form-36. Int J Prev Med. 2014;5(9):1146-52. SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 292 18. Korman NJ, Zhao Y, Pike J, Roberts J. Relationship between psoriasis severity, clinical symptoms, quality of life and work productivity among patients in the USA. Clin Exp Dermatol. 2016;41(5):514-21. 19. Warren RB, Kleyn CE, Gulliver WP. Cumulative life course impairment in psoriasis: patient perception of disease-related impairment throughout the life course. Br J Dermatol. 2011;164 Suppl 1:1-14. 20. Jungo P, Maul JT, Djamei V, et al. Superiority in Quality of Life Improvement of Biologics over Conventional Systemic Drugs in a Swiss Real-Life Psoriasis Registry. Dermatology (Basel). 2017; 21. Jaeschke R, Singer J, Guyatt GH: Ascertaining the minimal clinically important difference. Control Clin Trials 1989; 10: 407–415. 22. Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data. Dermatology (Basel). 2015;230(1):27-33. 23. Feldman SR, Goffe B, Rice G, et al. The Challenge of Managing Psoriasis: Unmet Medical Needs and Stakeholder Perspectives. Am Health Drug Benefits. 2016;9(9):504-513. 24. Yiu ZZ, Exton LS, Jabbar-lopez Z, et al. Risk of Serious Infections in Patients with Psoriasis on Biologic Therapies: A Systematic Review and Meta-Analysis. J Invest Dermatol. 2016;136(8):1584- 91. 25. Le cleach L, Chassany O, Levy A, Wolkenstein P, Chosidow O. Poor reporting of quality of life outcomes in dermatology randomized controlled clinical trials. Dermatology (Basel). 2008;216(1):46-55. 26. Asahina A, Nakagawa H, Etoh T, Ohtsuki M. Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study. J Dermatol. 2010;37(4):299-310. 27. Gordon KB, Duffin KC, Bissonnette R, et al. A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque Psoriasis. N Engl J Med. 2015;373(2):136-44. 28. Shikiar R, Heffernan M, Langley RG, Willian MK, Okun MM, Revicki DA. Adalimumab treatment is associated with improvement in health-related quality of life in psoriasis: patient- reported outcomes from a phase II randomized controlled trial. J Dermatolog Treat. 2007;18(1):25-31. 29. Wallace K, Gordon K, Langley R, Chen D. Dermatologic quality of life in patients with moderate to severe plaque psoriasis receiving 48 weeks of adalimumab therapy. J Am Acad Dermatol 2005; 52 (Suppl 1): 180. 30. Revicki D, Willian MK, Saurat JH, et al. Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: results from a 16-week randomized controlled trial in patients with moderate to severe plaque psoriasis. Br J Dermatol. 2008;158(3):549-57. 31. Revicki DA, Willian MK, Menter A, et al. Impact of adalimumab treatment on patient-reported outcomes: results from a Phase III clinical trial in patients with moderate to severe plaque psoriasis. J Dermatolog Treat. 2007;18(6):341-50. 32. Bachelez H, Van de kerkhof PC, Strohal R, et al. Tofacitinib versus etanercept SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 293 or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial. Lancet. 2015;386(9993):552-61. 33. Valenzuela F, Paul C, Mallbris L, et al. Tofacitinib versus etanercept or placebo in patients with moderate to severe chronic plaque psoriasis: patient-reported outcomes from a Phase 3 study. J Eur Acad Dermatol Venereol. 2016;30(10):1753-1759. 34. Strober BE, Crowley JJ, Yamauchi PS, Olds M, Williams DA. Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol. 2011;165(3):661-8. 35. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349(21):2014-22. 36. Gottlieb AB, Matheson RT, Lowe N, et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol. 2003;139(12):1627-32. 37. Lowe N, Lebsack M Wande L. Psoriasis patients show improved quality of life when treated with Etanercept. Ann Dermatol Venereol 2002; 129: 1S762. 38. Krueger GG, Langley RG, Finlay AY, et al. Patient-reported outcomes of psoriasis improvement with etanercept therapy: results of a randomized phase III trial. Br J Dermatol. 2005;153(6):1192-9. 39. Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367(9504):29-35. 40. Reich K, Segaert S, Van de kerkhof P, et al. Once-weekly administration of etanercept 50 mg improves patient- reported outcomes in patients with moderate-to-severe plaque psoriasis. Dermatology (Basel). 2009;219(3):239-49. 41. Gottlieb AB, Leonardi C, Kerdel F, Mehlis S, Olds M, Williams DA. Efficacy and safety of briakinumab vs. etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol. 2011;165(3):652-60. 42. Feldman SR, Gordon KB, Bala M, et al. Infliximab treatment results in significant improvement in the quality of life of patients with severe psoriasis: a double-blind placebo-controlled trial. Br J Dermatol. 2005;152(5):954-60. 43. Gottlieb AB, Evans R, Li S, et al. Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2004;51(4):534-42. 44. Feldman SR, Gottlieb AB, Bala M, et al. Infliximab improves health-related quality of life in the presence of comorbidities among patients with moderate-to-severe psoriasis. Br J Dermatol. 2008;159(3):704-10. 45. Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2007;56(1):31.e1-15. 46. Yang HZ, Wang K, Jin HZ, et al. Infliximab monotherapy for Chinese patients with moderate to severe plaque psoriasis: a randomized, double-blind, placebo-controlled SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 294 multicenter trial. Chin Med J. 2012;125(11):1845-51. 47. Torii H, Nakagawa H. Infliximab monotherapy in Japanese patients with moderate-to-severe plaque psoriasis and psoriatic arthritis. A randomized, double-blind, placebo-controlled multicenter trial. J Dermatol Sci. 2010;59(1):40-9. 48. Reich K, Nestle FO, Papp K, et al. Improvement in quality of life with infliximab induction and maintenance therapy in patients with moderate-to- severe psoriasis: a randomized controlled trial. Br J Dermatol. 2006;154(6):1161-8. 49. Griffiths CE, Reich K, Lebwohl M, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to- severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386(9993):541-51. 50. Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366(13):1190-9. 51. Gordon K, Blauvelt A, Langley R. Ixekizumab for treatment of moderate- to-severe plaque psoriasis: 60-week results from a double-blind phase 3 induction and randomized withdrawal study (UNCOVER-1). 73rd Annual Meeting of the American Academy of Dermatology 2015: 20-24. 52. Augustin M, Abeysinghe S, Mallya U, et al. Secukinumab treatment of plaque psoriasis shows early improvement in DLQI response - results of a phase II regimen-finding trial. J Eur Acad Dermatol Venereol. 2016;30(4):645-9. 53. Thaçi D, Blauvelt A, Reich K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol. 2015;73(3):400-9. 54. Blauvelt A, Korman N, Mollon P, et al. Secukinumab treatment provides faster and more effective relief from patient-reported quality-of-life impact than ustekinumab in subjects with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2016;74(5):AB273. 55. Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis-- results of two phase 3 trials. N Engl J Med. 2014;371(4):326-38. 56. Paul C, Lacour JP, Tedremets L, et al. Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE). J Eur Acad Dermatol Venereol. 2015;29(6):1082-90. 57. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo- controlled trial (PHOENIX 1). Lancet. 2008;371(9625):1665-74. 58. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371(9625):1675-84. 59. Igarashi A, Kato T, Kato M, Song M, Nakagawa H. Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: long-term results from a phase 2/3 clinical trial. J Dermatol. 2012;39(3):242-52. SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 295 60. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356(6):580-92. 61. Zhu X, Zheng M, Song M, et al. Efficacy and safety of ustekinumab in Chinese patients with moderate to severe plaque-type psoriasis: results from a phase 3 clinical trial (LOTUS). J Drugs Dermatol. 2013;12(2):166-74. 62. Tsai TF, Ho JC, Song M, et al. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci. 2011;63(3):154-63. 63. Papp KA, Blauvelt A, Bukhalo M, et al. Selective blockade of Il-23p19 with Bi 655066 is associated with significant improvement in Qol outcomes compared with ustekinumab in patients with moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2016;74(5):AB275. SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 296 Appendix 1. Detailed search strategy. Search conducted on September 8th, 2016: Search conducted on August 30th, 2016: PubMed search Category Searc h Query Items found Quality of Life terms #1 Quality of life 278,988 #2 DLQI 795 #3 Dermatology life quality index 1,802 #4 Dermatology quality of life index 1,802 #5 (#1 OR #2 OR #3 OR #4) 279,007 Drug Terms #6 Secukinumab 213 #7 Adalimumab 5,323 #8 Infliximab 11,143 #9 Ixekizumab 102 #10 Ustekinumab 828 #11 Etanercept 6,676 #12 Biologic Therapy 516,999 #13 Biologic 1,386,2 14 #14 (#6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13) 1,871,1 08 Disease Term #15 Psoriasis 40,998 Design terms #16 Randomized Controlled Trials as Topic [MeSH Major Topic] 15,816 #17 "randomized controlled trials as topic" [MeSH Terms] 105,636 #18 Random Allocation [MeSH Terms] 87,192 #19 double blind method [MeSH Terms] 135,739 #20 "controlled clinical trial" [Publication Type] 503,881 #21 "randomized controlled trial" [Publication 418,036 SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 297 Type] #22 "clinical trials as topic" [MeSH Terms] 292,996 #23 "clinical trial" [Publication Type] 738,696 #24 (#16 or #17 or (#18 and (#19 or #22 or #23)) or #20 or #21) 607,554 #25 (((randomised and control and clinical and trial) or (randomized and control and clinical and trial))) 129,757 #26 ((((double or single or triple or treble) and (blind* or mask*) and (random*)))) 164,021 #27 (((random and allocat*) and control* and trial)) 22 #28 (#25 OR #26 OR #27) 258,498 #29 (#24 AND #28) 231,144 Language term #30 English [Language] 21,827, 863 Compilation of quality of life, drug terms, disease term, and design terms #31 (#5 AND #14 AND #15 AND #29 AND #30) 76 Search conducted on August 25th, 2016: Embase search Category Sear ch Query Hits Design terms #1 "randomized controlled trial (topic)"/exp 102,487 #2 "randomized controlled trial"/exp 410,524 #3 "randomization"/exp 70,729 #4 "double blind procedure"/exp 130,636 #5 [controlled clinical trial]/lim 607,113 #6 [randomized controlled trial]/lim 510,524 #7 "clinical trial"/exp 1,105,349 #8 "clinical trial (topic)"/exp 200,673 #9 #1 OR #2 OR #3 OR #4 OR #5 OR #6 783,138 #10 singl*:ab,ti OR doubl*:ab,ti OR treb*:ab,ti OR tripl*:ab,ti AND (blind*:ab,ti OR mask*:ab,ti) 212,673 #11 "placebo"/exp 292,811 #12 random* AND (clinical OR control*) AND trial OR (placebo* AND ("randomly 676,434 SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 298 allocated" OR (allocated AND random*))) #13 (#7 OR #8) AND (#10 OR #11 OR #12) 672,466 #14 #9 OR #13 890,573 Disease terms #15 ‘Psoriasis’ 63,602 Drug Terms #16 ‘Secukinumab’ 931 #17 ‘Adalimumab’ 21,275 #18 ‘Infliximab’ 37,012 #19 ‘Ixekizumab’ 467 #20 ‘Ustekinumab’ 3,014 #21 ‘Etanercept’ 23,852 #22 ‘Biologic Therapy’ 3,346 #23 ‘Biologic’ 76,906 #24 (#16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23) 123,128 Quality of Life Terms #25 DLQI 1,709 #26 ‘Dermatology life quality index’ 2,316 #27 ‘Dermatology quality of life index’ 63 #28 ‘Quality of Life’ 386,267 #29 (#25 OR #26 OR #27 OR #28) 386,734 Language Terms #30 [english]/lim 25,124,781 Final (#14 AND #15 AND #24 AND #29 AND #30) 461 Search conducted on August 25th, 2016: Ovid/MEDLINE search Categ ory Sear ch Query Hits Desig n terms #1 Randomized Controlled Trials as Topic/ 109,437 #2 Randomized Controlled Trial/ 428,678 #3 Random Allocation/ 88,489 #4 Double Blind Method/ 138,784 #5 controlled clinical trial.pt. 91,573 #6 randomized controlled trial.pt. 428,678 #7 Clinical Trial/ 504,873 #8 clinical trial.pt. 504,873 SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 299 #9 Clinical Trials as Topic/ 179,085 #10 1 or 2 or 3 or 4 or 5 or 6 698,072 #11 7 or 8 or 9 613,026 #12 ((singl* or doubl* or treb* or tripl*) and (blind* or mask*)).ab,ti. 150,294 #13 Placebos/ 33,637 #14 ((random* and (clinical or control*) and trial) or (placebo* and ("randomly allocated" or (allocated and random*)))).mp. [mp = title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier] 501,456 #15 12 or 13 or 14 555,680 #16 11 and 15 259,650 #17 10 or 16 713,005 Disea se terms #18 Psoriasis/ 29,520 Drug Terms #19 secukinumab.mp. 134 #20 Infliximab/ 8,053 #21 Adalimumab/ 3,520 #22 Ixekizumab.mp. 47 #23 Ustekinumab/ 439 #24 Etanercept/ 4,798 #25 Biologic Therapy/ 1,836 #26 Biologic.mp. 48,461 #27 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 61,907 Qualit y of Life Terms #28 DLQI.mp. 638 #29 Dermatology life quality index.mp. 879 SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 300 #30 Dermatology quality of life index.mp. 26 #31 Quality of Life/ 142,263 #32 28 or 29 or 30 or 31 142,443 Final #33 17 and 18 and 27 and 32 99 Cochrane Library search Categ ory Sear ch Query Hits #1 Psoriasis 4125 Qualit y of Life Terms #2 DLQI 320 #3 Dermatology life quality index 723 #4 Dermatology quality of life index 723 #5 Quality of Life 58281 #6 #2 or #3 or #4 or #5 58286 Drug Terms #7 secukinumab 150 #8 Infliximab 1371 #9 Adalimumab 1106 #10 Ixekizumab 27 #11 Ustekinumab 196 #12 Etanercept 1170 #13 Biologic Therapy 1322 #14 Biologic 2011 #15 #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 4728 Final #16 #1 and #6 and #15 234 SKIN September 2018 Volume 2 Issue 5 Copyright 2018 The National Society for Cutaneous Medicine 301 Appendix 2. Risk of bias table for the included studies. Low risk High risk Uncertain risk