BJD British Journal of Dermatology. Summary. What s already known about this topic? CLINICAL TRIALS

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1 CLINICAL TRIALS BJD British Journal of Dermatology A prospective randomized controlled trial comparing infliximab and etanercept in patients with moderateto-severe chronic plaque-type psoriasis: the Psoriasis Infliximab vs. Etanercept Comparison Evaluation (PIECE) study A.C.Q. de Vries, 1 H.B. Thio, 2 W.J.A. de Kort, 3 B.C. Opmeer, 4 H.M. van der Stok, 1 E.M.G.J. de Jong, 5 B. Horvath, 6 J.J.V. Busschbach, 7 T.E.C. Nijsten 2 and Ph.I. Spuls 1 1 Department of Dermatology and 4 Clinical Research Unit, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands 2 Department of Dermatology and 7 Medical Psychology and Psychotherapy Section, Erasmus Medical Center, 3015 CA, Rotterdam, the Netherlands 3 Department of Dermatology, Amphia Hospital, Molengracht 21, 4818 CK Breda, the Netherlands 5 Department of Dermatology, UMC St Radboud, Rene Descartesdreef 1, 6525 GL Nijmegen, the Netherlands 6 Department of Dermatology, UMC Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands Linked Comment: Burden. Br J Dermatol 2017; 176:565. Summary Correspondence Anna-Christa Quinta de Vries. a.q.devries@amc.uva.nl Accepted for publication 5 July 2016 Funding sources The study was funded by a programme grant from The Netherlands Organization for Scientific Research-Medical Sciences (NWO-MW; project ). The funders had no involvement in the study design, data collection, analysis and interpretation, the writing of the report, or the decision to submit the paper for publication. The protocol is available from the authors upon request. Conflicts of interest See Appendix 1. DOI /bjd Background There are currently no independent data available comparing infliximab and etanercept for the treatment of psoriasis. Objectives To compare these biologics without funding from pharmaceutical companies. Methods Overall, 50 patients were randomized to etanercept (n = 23) 50 mg subcutaneously twice weekly or infliximab (n = 25) 5 mg kg 1 intravenously at week 0, 2, 6, 14 and 22. After 24 weeks, 19 patients stopped and 22 continued treatment and were followed up to week 48. The primary outcome was 75% improvement of Psoriasis Area and Severity Index (PASI 75) at week 24. The secondary outcomes included PASI 75 at week 6 (onset of action) and week 12, Investigator s Global Assessment (IGA), Patient Global Assessment, impact on quality of life (Skindex-17 and SF-36), Treatment Satisfaction Questionnaire of Medication, duration of remission, maintenance treatment and safety. Results At week 24, PASI 75 was achieved in 72% (infliximab) vs. 35% (etanercept) (P = 001). The onset of action was achieved in 52% (infliximab) and 4% (etanercept). At week 12, 76% (infliximab) and 22% (etanercept) achieved PASI 75 (P < 0001). At week 24, IGA clear or almost clear was observed in 76% (infliximab) and 30% (etanercept) (P = 001). Skindex-17 symptom score was significantly better for infliximab. Maintenance treatment achieved PASI 75 for 67% (n = 6) infliximab vs. 50% (n = 5) etanercept, at week 48 (P = 065). Mild adverse events were reported in 76% (infliximab) vs. 66% (etanercept). Conclusions Infliximab showed a rapid and significant higher level of efficacy until week 24 compared with etanercept. Long-term data showed no significant differences between both groups at week 48. Safety parameters were comparable. What s already known about this topic? Etanercept and infliximab are both effective and safe treatments for psoriasis. No comparative long-term data are available that are independent from pharmaceutical companies. 624 British Journal of Dermatology (2017) 176, pp British Association of Dermatologists

2 Psoriasis infliximab vs. etanercept comparison evaluation, A.C.Q. de Vries et al. 625 What does this study add? The onset of action and physician-reported efficacy for week 12 and 24 is significantly better for infliximab. There was less of a difference in efficacy for patientreported outcomes. Long-term data show no significant differences, based on the duration of remission after stopping treatment and maintenance treatment until week 48. Randomized controlled trials (RCTs) are required to compare the efficacy and safety of different biologics. There are only three published head-to-head trials that demonstrate that ustekinumab and briakinumab are both superior to etanercept, and that guselkumab is superior to adalimumab. 1 3 To our knowledge, no investigator-initiated comparative clinical trials for biologics have been completed independently of pharmaceutical companies. A systematic review by Schott et al. 4 showed that financial support by pharmaceutical companies influenced multiple aspects of the trials. Our objective was to perform an investigator-initiated independent RCT comparing infliximab vs. etanercept, in order to study short- and long-term efficacy, including patient-reported outcomes and safety in psoriasis. Patients and methods Design This was a multicentre, single-blind, investigator-initiated, RCT comparing infliximab and etanercept in the treatment of moderate-to-severe chronic plaque-type psoriasis. The trial was conducted in the Netherlands at the departments of dermatology of the Academic Medical Center of Amsterdam, Erasmus Medical Center of Rotterdam, Radboud University Medical Center of Nijmegen, University Medical Center of Groningen and the nonacademic centre of the Amphia Hospital of Breda. After screening for eligibility, patients were randomized (1 : 1) either to infliximab or etanercept and initially treated for 24 weeks (induction phase). At the end of the induction phase, patients stopped treatment or continued treatment if they preferred. All patients were followed up to 48 weeks; for those whose treatment was stopped, the duration of remission [time to 50% loss of the obtained Psoriasis Area and Severity Index (PASI) improvement and/or need to retreat with ultraviolet (UV) and/or systemic therapy] was evaluated in the 24- week follow-up period. If the treatment was continued, the effectiveness and safety were assessed in a 48-week maintenance treatment period. The trial was approved by the medical ethics committee and performed according to Good Clinical Practice Guidelines and the Declaration of Helsinki. Written informed consent was obtained before any study-related procedures were carried out. This report adheres to the Consolidated Standards of Reporting Trials statement and the Template for Intervention Description and Replication checklist. 5 7 The trial was prospectively registered on the Dutch Trial Register (NTR 1559; Participants Consecutive patients (18 75 years of age) with moderate-tosevere chronic plaque-type psoriasis defined as PASI 10 and/or body surface area (BSA) 10 and/or PASI 8 plus a Skindex-29 score 35 [moderate/severe impaired quality of life (QoL)] were included. Additionally, patients must have failed or were contraindicated for and/or intolerant to UV therapy, and methotrexate or ciclosporin according to the indication and reimbursement criteria for the Netherlands. The washout period was 2 weeks for topical and UV therapy and 4 weeks for systemic therapies. Patients were excluded for the following reasons: if they were pregnant (or planning a pregnancy); breastfeeding; malignancy in the previous 10 years; active/chronic infections including tuberculosis; demyelinating disease; congestive heart failure; allergy and/or hypersensitivity to study drugs; live vaccination in the previous 3 months; if they had severe liver function disorders (more than two times the upper limit of the parameters) and/or kidney function disorders (more than 15 times the upper limit of the parameters), or if they had been treated with infliximab or etanercept in the past and stopped because of a lack of efficacy (at least 12 weeks treatment and/or three infusions), contraindication or adverse events. Urine and blood tests were performed at screening, week 6, 12, 24 and every 8 weeks during follow-up. 8 Additionally, measurements of hepatitis B and C, serum pregnancy test, tuberculin skin test and chest X-ray for excluding (latent) tuberculosis, and an electrocardiogram were performed. At baseline, demographic data and disease characteristics were recorded, and women who could potentially be pregnant underwent a urine pregnancy test. Initially, the trial design planned for patients to stop treatment at week 24 in order to allow the duration of remission to be assessed. However, many patients wished to continue treatment after 24 weeks. Additional data emerged showing that antibody formation and infusion reactions may be increased when restarting infliximab after a treatment-free interval of more than 16 weeks. 9,10 Therefore, we amended the design and agreed to allow patients to continue treatment up to week 48 according to patient preference and physician opinion British Association of Dermatologists British Journal of Dermatology (2017) 176, pp

3 626 Psoriasis infliximab vs. etanercept comparison evaluation, A.C.Q. de Vries et al. Interventions and procedures Etanercept 50 mg was self-administered by subcutaneous injection twice weekly and infliximab 5 mg kg 1 was administered intravenously during 2 3-h inpatient visits at week 0, 2, 6 and every 8 weeks thereafter. If the response was insufficient (less than 50% improvement in PASI) or the patient experienced adverse events that made discontinuation necessary up to week 12, patients could switch to the other treatment arm. At week 12, nonresponders (less than 50% improvement in PASI) could cross over to the other study arm. A low potent corticosteroid ointment for the hands and genitals and desoximetasone lotion and moisturizers for the scalp were allowed. Outcomes Outcomes were assessed at baseline, week 6, 12, 24, 32, 40 and 48. The primary outcome was the difference between the infliximab and etanercept groups in 75% improvement of PASI (PASI 75) at week 24. Secondary outcomes included the following: the difference in PASI (at 12 weeks) between the groups; the proportion of patients achieving an Investigator s Global Assessment (IGA) of almost clear or clear ; Patient s Global Assessment (PaGA) of good or totally under control ; mean change in BSA, QoL [Skindex-17 and SF-36 Short Form Health Survey (Medical Outcomes Study 36- Item)] 11 and Treatment Satisfaction Questionnaire of Medication (TSQM) (all assessed at week 12 and 24) and onset of action (the proportion of patients reaching PASI 75 at week 6). Secondary safety outcomes included the number and severity (mild, moderate or severe) of adverse events and their relation to treatment, which were all assessed at each visit. All adverse events were grouped into one of 11 categories. For patients who discontinued study medication at week 24, the mean duration of remission (50% loss of the obtained PASI improvement and/or need to retreat) was assessed at week 32, 40 and 48. However, for patients who continued study treatment after week 24, PASI, IGA and PaGA were assessed to collect data on maintenance treatment. The IGA is a 5-point scale ranging from 0 (clear) to 4 (severe disease). The PaGA is a 4-point scale ranging from 0 (psoriasis totally under control) to 3 (psoriasis not totally under control). The Skindex-17 assesses dermatology-specific symptoms (range 0 10) and psychosocial impact (range 0 24), with higher scores indicating more significantly impaired QoL. 12 The generic SF-36 consists of a physical and mental component. 13,14 Treatment satisfaction was measured by the mean TSQM score (on a 5 7-point Likert scale), which included global satisfaction, efficacy, adverse events and convenience domains. 15 The combined score was transformed to a scale ranging from 0 (extremely dissatisfied) to 100 (extremely satisfied). A score above 666 was considered satisfied and a score above 833 was considered very satisfied. 16 British Journal of Dermatology (2017) 176, pp Data on neutralizing antibodies, treatment trough concentrations, cost-effectiveness and nail psoriasis will be published separately. Randomization and blinding The adequate generation of an unpredictable allocation sequence and concealment of allocation was achieved using a secure online internet facility (the TEN-ALEA Clinical Trial Data Management System, provided by the Trans European Network and was performed in the coordinating centre by the main investigators. The sequence was generated in random block sizes of two and four to ensure it was unknown and not predictable by the investigators involved in randomizing participants. Efficacy outcomes were carried out by trained assessors who were blinded to treatment allocation. Safety assessments were not blinded. Patients were not blinded to treatment allocation and all statistical analyses were performed blinded. Statistical analysis The trial was designed to detect a difference in PASI 75 between groups. We hypothesized that after 12 weeks, 75% of the patients on infliximab would achieve PASI 75 vs. 50% of the patients on etanercept. For the trial to have 80% power and 5% significance (two-sided), allowing for 10% dropout, 120 participants were needed. Missing data for the primary end point were imputed using the last observation carried forward. Analyses were carried out according to the intention-totreat (ITT) principle, apart from the longer-term data where a per protocol analysis (PPA) was performed. No interim analysis was performed. SPSS 20.0 for Windows (IBM, Armonk, NY, U.S.A.) was used. Baseline, demographic and outcome variables were reported as proportions (%) or means for categorical and continuous variables, respectively. The efficacy data (PASI score) were calculated as relative risk (RR) with 95% confidence intervals (CIs). Other differences were tested using Pearson s v 2 -test (or Fisher s exact test as appropriate) for categorical variables, and Student s t-test or the Mann Whitney U-test for continuous variables, conditional on the distribution. P 005 (twosided) were considered statistically significant. QoL questionnaires were tested according to standard methods ,17 Differences in the incidence of adverse events were tested using Poisson regression, expressed as incidence rate ratios (IRRs). Results Recruitment and baseline characteristics Between April 2009 and June 2011, 53 patients were screened for eligibility, of which 48 were randomized; 25 patients were to receive infliximab and 23 patients were to receive etanercept (Fig. 1). A total of 48 patients were available for the ITT analysis at week 24. Despite a recruitment period that 2016 British Association of Dermatologists

4 Psoriasis infliximab vs. etanercept comparison evaluation, A.C.Q. de Vries et al. 627 Fig 1. Flowchart showing randomization of patients and progress throughout the study. A total of 53 patients were assessed for eligibility. Two patients withdrew informed consent and one patient was diagnosed with latent tuberculosis and therefore not randomized. A total of 50 patients were randomized. Two patients were late exclusions, one because of earlier ineffective etanercept use and one because of a squamous cell carcinoma of the skin in their medical history. Before week 12, one patient in the infliximab group switched to the etanercept group, because of a reactive arthritis after 2 weeks of treatment. Another patient in the infliximab group was withdrawn from the study because of an erythroderma at week 4. In the etanercept group, one patient was withdrawn from the study because of neutropenia (week 8) and one because of a fear of needles (week 4). At week 12, two patients in the infliximab group switched to etanercept and three patients in the etanercept group switched to infliximab, according to their Psoriasis Area and Severity Index (PASI) score. However, four patients from the etanercept group, who were nonresponders at week 12 and therefore allowed to switch to infliximab, preferred continuation of etanercept therapy. Between week 12 and 24, when no switch was allowed, one patient on infliximab was lost to follow-up, two patients receiving etanercept were withdrawn from the study because of adverse events (AEs) and one because of inefficacy. Overall, 23 patients receiving infliximab and 18 patients receiving etanercept reached week 24, according to per protocol analysis (PPA). The duration of remission was analysed for 19 patients who discontinued the study medication at week 24, 12 in the infliximab group and seven in the etanercept group. One patient in the etanercept group was withdrawn from the study because of an AE (liver enzyme elevations, three times the upper limit) at week 24. Eight patients in the infliximab group and five in the etanercept group needed retreatment before week 48. Four patients receiving infliximab and one receiving etanercept reached week 48 without retreatment. Maintenance treatment was analysed for 22 patients PPA who continued the medication at week 24, 11 with infliximab and 11 with etanercept. By week 48, two patients in the infliximab group discontinued the study medication, one because of PASI increase (inefficacy and withdrawal of informed consent) (week 36) and one because of liver dysfunction (three times the upper limit of the parameters) (week 32). In the etanercept group, one patient dropped out at week 40 because of noncompliance for a study visit (no show). Nine patients in the infliximab group and 10 in the etanercept group completed the medication until week 48. ITT, intention to treat; LTFU, lost to follow-up British Association of Dermatologists British Journal of Dermatology (2017) 176, pp

5 628 Psoriasis infliximab vs. etanercept comparison evaluation, A.C.Q. de Vries et al. was longer than planned and increased efforts to recruit more participants, it was not possible to recruit the 120 patients planned before the trial was closed. A total of 19 patients discontinued the study drug at week 24 PPA, 12 who were receiving infliximab and seven who were receiving etanercept, in accordance with the initial protocol. Baseline characteristics of included patients were comparable across treatment groups and shown in Table 1. Clinical response For the primary outcome, 72% of the patients receiving infliximab achieved PASI 75 at week 24 compared with 35% of the patients receiving etanercept (RR 21, 95% CI ) (Table 2). A similar difference was observed at week 12 [76% in the infliximab group vs. 22% in the etanercept group (RR 35, 95% CI )]. There were significant differences in some other secondary outcomes at week 24. IGA was clear or almost clear in 76% of the patients receiving infliximab compared with 30% of patients receiving etanercept (P < 001), and BSA was 78% in the infliximab group vs. 46% in the etanercept group. However, there was no significant difference in the proportion of patients achieving a PaGA of good or totally under control at 24 weeks (88% vs. 70% for infliximab and etanercept, respectively; P = 012). The proportion of patients reaching PASI 75 by week 6, as a measure of the speed of onset of action, was achieved by 52% in the infliximab group compared with 43% in the etanercept group. Other outcomes are shown in Table 2. Quality of life and treatment satisfaction The mean Skindex-17 symptoms score was significantly lower in the infliximab group [week 12: 39 vs. 24, respectively (P = 002) and week 24: 46 vs. 30 (P = 002)]. No significant difference was seen for the psychosocial domain, for the generic SF-36 or for any of the aspects of the TSQM (Table 3). Follow-up after 24 weeks The mean duration of remission for patients who discontinued their study medication at 24 weeks PPA was 155 weeks (SD 805) for infliximab (n = 12) and 137 weeks (SD 117) for etanercept (n = 6) (P = 07) (Table 4). For patients who continued study treatment after week 24, 73% (eight of 11) on infliximab and 46% (five of 11) on etanercept achieved PASI 75 (P = 039) at week 24. At week 48, six of nine patients (67%) on infliximab and five of 10 patients (50%) on etanercept achieved PASI 75 (P = 065). Safety There were significantly more adverse events in the infliximab group (201 vs. 148, P = 003) (Table 5). Most adverse events British Journal of Dermatology (2017) 176, pp Table 1 Demographics and baseline characteristics of the included participants in both groups were mild, with severe adverse events accounting for only 5% in the infliximab group and 7% in the etanercept group. Circulatory disorders and abnormalities in blood count had a significant higher IRR for infliximab. In both groups, one serious adverse event was reported, which was unlikely to be related to the study drugs. Discussion Infliximab (n = 25) Etanercept (n = 23) Mean age, years (SD) 459 (139) 424 (132) Female sex n (%) 7 (28) 10 (44) Mean duration of psoriasis, 215 (129) 179 (106) years (SD) Psoriatic arthritis, n (%) 2 (8) 3 (13) Familiar with psoriasis 20 (80) 18 (78) unguium, n (%) Prior therapy, n (%) Methotrexate 24 (96) 23 (100) Ciclosporin 19 (76) 17 (74) PUVA 11 (44) 11 (48) UVB 24 (96) 23 (100) Acitretin 5 (20) 8 (35) Adalimumab 1 (4) 2 (9) Alefacept 0 0 Efalizumab 0 1 (4) Etanercept 2 (8) 2 (9) Infliximab 0 0 Other a 8 (32) 14 (61) Disease activity, mean (SD) PASI 178 (97) 159 (51) BSA 281 (215) 213 (131) IGA 32 (052) 33 (065) PaGA 296 (020) 278 (042) Skindex-17 Symptoms 77 (18) 75 (20) Psychosocial 145 (65) 117 (65) SF-36 Physical component 366 (112) 406 (105) Mental component 456 (107) 456 (103) PUVA, psoralen combined with ultraviolet A; UVB, ultraviolet B; PASI, Psoriasis Area and Severity Index; BSA, body surface area; IGA, Investigator s Global Assessment; PaGA, Patient s Global Assessment. a Other treatments were fumaric acid, dithranol, day care treatment and V-Beam laser. Our primary outcome showed a significantly higher PASI 75 response in the infliximab group compared with those in the etanercept group after 24 weeks. This difference is particularly striking given that the dosage of etanercept (50 mg twice weekly) is higher than the recommended dosage of 50 mg once weekly, or twice weekly for only 12 weeks, as stated in the Dutch, German and European S3-guidelines for psoriasis and the summary of product characteristics. 8, British Association of Dermatologists

6 Psoriasis infliximab vs. etanercept comparison evaluation, A.C.Q. de Vries et al. 629 Table 2 Clinical responses at week 12 and 24 (intention to treat) Variable Week 12 IFX (n = 25) ETA (n = 23) P-value Week 24 IFX (n = 25) ETA (n = 23) Improvement PASI score Absolute reduction, mean (SD) 148 (96) 91 (60) 002 a 154 (98) 107 (45) 004 a Relative reduction, mean (SD) 798% (178) 529% (240) 0 a 8417% (134) 672% (171) 0 a PASI 100 (at least 100%), n (%) 1 (4) 0 (0) 1 b 2 (8) 0 (0) 049 b PASI 90 (at least 90%), n (%) 5 (20) 0 (0) 005 b 10 (40) 1 (4) 0 c PASI 75 (at least 75%), n (%) 19 (76) 5 (22) 0 b 18 (72) 8 (35) 001 c PASI 50 (at least 50%), n (%) 24 (96) 14 (61) 0 b 25 (100) 20 (87) 010 b BSA absolute reduction, mean (SD) 215 (212) 93 (126) 004 d 240 (219) 130 (117) 007 d BSA relative reduction, mean (SD) 643% (350) 63% (1231) 0 d 775% (267) 465% (618) 0 d Improvement IGA Absolute reduction, mean (SD) 192 (10) 122 (10) 002 a 212 (08) 156 (08) 003 a Relative reduction, mean (SD) 573% (270) 326% (292) 0 a 653% (215) 453% (207) 0 a Clear or almost clear (IGA < 2), n (%) 17 (68%) 2 (9%) 0 c 19 (76%) 7 (30%) 0 c Improvement PaGA Absolute reduction, mean (SD) 17 (07) 13 (09) 005 a 20 (07) 15 (08) 001 a Relative reduction, mean (SD) 593% (216) 449% (291) 006 a 687% (237) 514% (279) 003 a Psoriasis totally or good under control (PaGA < 2), n (%) 19 (76) 13 (56) 015 c 22 (88) 16 (70) 012 IFX, infliximab; ETA, etanercept; PASI, Psoriasis Area and Severity Index; BSA, body surface area; IGA, investigators global assessment; PaGA, patient s global assessment. a t-test for independent groups. b Fisher s exact test. c v 2 -test. d Mann Whitney U-test for independent groups. P-value Table 3 Effect on quality of life and treatment satisfaction at week 12 and 24 (intention to treat) Week 12 Week 24 Variable IFX (n = 25) ETA (n = 23) P-value a IFX (n = 25) ETA (n = 23) P-value a Skindex-17 Absolute reduction (SD) Symptoms 39 (17) 24 (25) (25) 30 (22) 002 Psychosocial 52 (50) 35 (40) (67) 47 (43) 006 Relative reduction, % (SD) Symptoms 528 (205) 315 (332) (299) 389 (251) 001 Psychosocial 359 (419) 399 (416) (511) 451 (424) 069 SF-36 Absolute improvement (SD) Physical 77 (97) 89 (106) (11. 9) 99 (105) 032 Mental 14 (117) 05 (78) (91) 22 (99) 058 TMSQ, mean (SD) Global satisfaction 735 (203) 732 (187) 073 Efficacy 750 (197) 747 (146) 071 Adverse events 833 (273) 922 (179) 011 Convenience 706 (170) 781 (253) 022 Treatment Medication Satisfaction Questionnaire (TMSQ) is not performed at week 0, therefore no reduction at week 12 measurable. IFX, infliximab; ETA, etanercept. a P-values were calculated by using t-test. This observed superiority of infliximab may be explained, at least partly, by the following: the different mechanisms of these two drugs; the induction phase of infliximab with frequent initial dosing (week 0, 2 and 6); the infliximab dosage prescribed per kg body weight; the different route of administration and the difference in self-administration (etanercept) and hospital outpatient (infliximab) treatment. Infliximab also showed a more rapid onset of action. Nast et al., 21 who defined the onset of action as the weighted mean time until 25% of the patients achieved PASI 75, showed a mean weighted time of 35 weeks for infliximab and 66 weeks for etanercept. In our study, only 4% on etanercept reached PASI 75 after 6 weeks, whereas 52% in the infliximab group achieved a PASI 75 by week British Association of Dermatologists British Journal of Dermatology (2017) 176, pp

7 630 Psoriasis infliximab vs. etanercept comparison evaluation, A.C.Q. de Vries et al. Table 4 Clinical responses after week 24 (per protocol) Treatment group Variable IFX ETA P-value Drug discontinuation at 12 (48) 7 (30) week 24, n (%) PASI at week 24, 29 (23) 44 (21) 017 a mean (SD) Patients with PASI 75, 8 (67) 2 (29) 017 a n (%) Duration of remission 155 (805) 137 (117) 070 a (weeks), mean (SD) Drug continuation at 11 (44) 11 (48) week 24, n (%) PASI at week 24, 20 (16) 43 (18) 001 a mean (SD) Patients with PASI 75, 8 (73) 5 (46) 039 b n (%) Patients at week 32, n PASI at week 32, 17 (19) 34 (22) 007 a mean (SD) Patients with PASI 75, 8 (73) 5 (46) 039 b n (%) Patients at week 40, n 9 11 PASI at week 40, 15 (20) 45 (39) 005 a mean (SD) Patients with PASI 75, 6 (67) 5 (46) 041 b n (%) Patients at week 48, n 9 10 PASI at week 48, 35 (44) 46 (36) 057 a mean (SD) Patients with PASI 75, 6 (67) 5 (50) 065 b n (%) IFX, infliximab; ETA, etanercept; PASI, Psoriasis Area and Severity Index. a t-test. b Fisher s exact test. Other published studies demonstrated higher response rates for etanercept compared with our data (PASI 75 was achieved by 45 50% of patients treated with etanercept after 12 weeks and by 60% after 24 weeks) Comparative data reported by Griffiths et al. 2 and Gottlieb et al. 1 showed PASI 75 for 675% and 56% of patients treated with etanercept 50 mg twice weekly after 12 weeks, respectively. However, our infliximab data were generally consistent with the current literature Comparison of our IGA and PaGA data shows that in the etanercept group, more patients than investigators assessed their psoriasis as good or totally under control after 24 weeks, suggesting that PaGA does not correlate well with the IGA and PASI. However, the assessment in the infliximab group was comparable between the investigators and patients. Other published data have shown that the self-administered PASI score correlates well with PASI (r = 091). 28,29 Both infliximab and etanercept improved QoL to a clinically relevant extent after 12 and 24 weeks, which is in agreement with other RCTs. 24,30 32 The global TSQM scores ranged between 70 and 80 at week 24 and were categorized as satisfied for both treatments. The convenience domain was in British Journal of Dermatology (2017) 176, pp favour of etanercept. This finding is in line with a previous study that showed a median convenience score of 778 for etanercept and 667 for infliximab (no comparison). 16 This could be because patients were able to self-administer etanercept at home and therefore had fewer hospital visits. The lower number of adverse events may also have contributed to this. There was no significant difference in the duration of remission [infliximab 155 weeks (n = 12) vs. etanercept 137 weeks (n = 6)] in patients who stopped treatment at week 24. Langley et al. 33 summarized the evidence for duration of remission for biologics and reported a post-treatment clinical benefit with infliximab of median 47 months after 6 weeks and median 3-month treatment with etanercept 50 mg twice weekly after 12 weeks. They suggested that the long-term benefits of infliximab may be limited by neutralizing antibodies. In this small comparative study, maintenance treatment showed no significant difference in mean PASI between infliximab (n = 9) and etanercept (n = 10). However, these data need to be interpreted with caution as this was not a prespecified outcome and the number of patients in each group was very low. An increase in mean PASI was observed after 32 weeks of etanercept and 40 weeks of infliximab, which corresponds to the data by Lucka et al. 34 that reported a trend towards a loss of efficacy for etanercept and infliximab after 24 weeks. Tyring et al. 24 reported maintenance treatment of etanercept 50 mg twice weekly that showed a PASI 75 for 60% and 63% at week 36 and 48, respectively. Also, a decrease in efficacy was reported during follow-up, with 51% of patients scoring a PASI 75 after 96 weeks of treatment. From the results shown here, we can conclude that both treatments are effective and recommended for moderate-tosevere psoriasis. Although infliximab showed a significantly superior short-term clinical response with a faster onset of action, the improvement in QoL (except Skindex-17 symptom score) and treatment satisfaction were comparable. Treatment choice can be made based on physician and patient preferences, taking into account the differences in the efficacy and safety of these two treatments. Treatment dissatisfaction is common among patients with psoriasis. Umar et al. 35 published a study assessing the extent to which matching physicians treatment recommendations to patients treatment preferences is associated with an improvement in treatment satisfaction. An approach based on preference matching showed an increase in patient satisfaction in the management of psoriasis. The experience of the physician in prescribing biologics and shared decision making, taking into account patient preferences and treatment satisfaction, may lead to one treatment being preferred over another. 36 To date, European and Dutch guidelines express no preference for prescribing biologics and patients and physicians can make the choice in partnership. 8,37 This RCT was not financially supported by the pharmaceutical industry and all aspects of the trial are free of influence 2016 British Association of Dermatologists

8 Psoriasis infliximab vs. etanercept comparison evaluation, A.C.Q. de Vries et al. 631 Table 5 Adverse events (intention to treat) Treatment group Variable IFX ETA P-value Total no. of patients Total no. of patients with adverse events, n (%) 24 (96) 23 (100) 100 a Total no. of adverse events a Serious adverse events, n (%) 1 (05) 1 (07) Gastrointestinal (stomach pain) (week 11) a Cardiac (angina pectoris) (week 45) a Adverse events leading to drug discontinuation b Reactive arthritis 1 Erythroderma 1 Liver dysfunction 1 Neutropenia 1 Exacerbation of psoriasis 1 Severity of the adverse events, n (%) Mild 153 (761) 98 (662) 004 a Moderate 34 (169) 39 (264) 003 a Severe 10 (50) 11 (74) 034 a Treatment-related adverse events (probably or 16 (8) 18 (12) 019 a definitely), c no of adverse events, n (%) Categorized adverse events, no. of adverse events, n (%) IFX ETA Incidence rate ratio P-value d CI Common cold/flu 29 (144) 26 (176) No. of patients 15 (60) 11 (48) Neurological disorders 23 (114) 13 (88) No. of patients 10 (40) 10 (44) Respiratory disorders 7 (35) 11 (74) No. of patients 6 (24) 6 (26.) Circulatory disorders 18 (90) 6 (41) No. of patients 8 (32%) 4 (17) Gastrointestinal disorders 14 (70) 12 (81) No. of patients 10 (40) 4 (17) Urinary tract disorders 9 (45) 4 (27) No. of patients 6 (24) 4 (17) Muscular disorders 20 (100) 13 (88) No. of patients 11 (44) 8 (35) Skin diseases 30 (149) 23 (155) No. of patients 14 (56) 13 (56) Injection-site or infusion reactions 6 (30) 2 (14) No. of patients 6 (24) 2 (9) Significant abnormalities in blood count 17 (85) 6 (41) No. of patients 12 (48) 5 (22) Other adverse events 22 (109) 31 (209) No. of patients 16 (64) 13 (56) Adverse events were classified as serious, mild, moderate and severe according to predefined definitions (see Patients and methods section). Incidence rate ratio: ratio infliximab vs. etanercept. IFX, infliximab; ETA, etanercept; CI, confidence interval. a v 2 -test. b Fisher s exact test. c Treatment-related adverse events classified as probably or definitely by the safety assessor. d Wald v 2 -test. from pharmaceutical companies. Well-designed comparison studies evaluating predefined outcomes, including patientreported outcomes, with short- and long-term data are valuable and contribute to better-informed shared decision making and personalized medicine. In such studies, the results are discussed in the context of the existing literature. Limitations of our study include the reduced sample size, increasing the likelihood of type II error. However, statistically significant differences were observed for the primary outcome and registry studies have shown similar PASI 75 data for infliximab after 10 and 24 weeks of treatment. 26 It proved more difficult than expected to recruit patients, which may have been due to several reasons. 38 Despite an initial rapid increase, the number of patients in need of biologics has decreased since the early years of this type of treatment. Furthermore, concurrent (pharmaceutical) trials have been ongoing and new biologics have become available, which physicians and patients may have preferred over etanercept and infliximab British Association of Dermatologists British Journal of Dermatology (2017) 176, pp

9 632 Psoriasis infliximab vs. etanercept comparison evaluation, A.C.Q. de Vries et al. Lastly, the inclusion criteria had to conform to the new guidelines for biologics, which require UV therapy in addition to methotrexate or ciclosporin, rather than methotrexate and ciclosporin, which considerably reduced the number of suitable patients. More comparative trials investigating dosage reduction, intermittent treatment and combination treatments are needed. A core outcome set 39 for psoriasis trials including patientreported outcomes would further improve evidence-based decision making. Acknowledgments We are indebted to C.A.C. Prinsen and M.E. Schram (Academic Medical Center, Amsterdam) as blinded observers. C. Dekkers (Amphia Hospital, Breda), the research nurses at Erasmus Medical Center, Rotterdam and P. van L umig (UMC St. Radboud, Nijmegen) for recruiting patients for this study. This study was partly presented at the 23rd European Academy of Dermatology and Venereology congress (8 12 October 2014, Amsterdam, the Netherlands). References 1 Gottlieb AB, Leonardi C, Kerdel F et al. Efficacy and safety of briakinumab vs. etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol 2011; 165: Griffiths CE, Strober BE, van de Kerkhof P et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 2010; 362: 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: Schott G, Pachl H, Limbach U et al. The financing of drug trials by pharmaceutical companies and its consequences: part 2: a qualitative, systematic review of the literature on possible influences on authorship, access to trial data, and trial registration and publication. Dtsch Arztebl Int 2010; 107: Schulz KF, Altman DG, Moher D; the CONSORT Group. 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10 Psoriasis infliximab vs. etanercept comparison evaluation, A.C.Q. de Vries et al Gottlieb AB, Evans R, Li S et al. Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, doubleblind, placebo-controlled trial. J Am Acad Dermatol 2004; 51: 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: Langley RG, Gordon KB. Duration of remission of biologic agents for chronic plaque psoriasis. J Drugs Dermatol 2007; 6: Lucka TC, Pathirana D, Sammain A et al. Efficacy of systemic therapies for moderate-to-severe psoriasis: a systematic review and meta-analysis of long-term treatment. J Eur Acad Dermatol Venereol 2012; 26: Umar N, Schaarschmidt M, Schmieder A et al. Matching physicians treatment recommendations to patients treatment preferences is associated with improvement in treatment satisfaction. J Eur Acad Dermatol Venereol 2013; 27: Lecluse LL, de Groot M, Bos JD, Spuls PI. Experience with biologics for psoriasis in daily practice: switching is worth a try. Br J Dermatol 2009; 161: Pathirana D, Ormerod AD, Saiag P et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol 2009; 23 (Suppl. 2): Treweek S, Mitchell E, Pitkethly M et al. Strategies to improve recruitment to randomised controlled trials. Cochrane Database Syst Rev 2010; 4:MR Williamson PR, Altman DG, Blazeby JM et al. Developing core outcome sets for clinical trials: issues to consider. Trials 2012; 13:132. Appendix 1 Novartis. He has received educational grants from Abbvie, Janssen, Pfizer and Biogen/Idec. W.J.A.K. has acted as a medical advisor for Novartis. H.M.S. has been involved in performing clinical trials with Abbvie, Pfizer, Novartis, Janssen, BioClinic, Amgen and Leo Pharma. E.M.G.J.J. has received research grants for the independent research fund for the Department of Dermatology of University Medical Centre St Radboud, Nijmegen, the Netherlands from Abbvie, Pfizer and Janssen and also acted as consultant and/or paid speaker for and/or participated in research sponsored by companies that manufacture drugs used for the treatment of psoriasis including Abbvie, Janssen, MSD and Pfizer. B.H. has received an Unrestricted Educational Grant from Abbvie Investigator Initiated Study and been involved in studies by Janssen and Abbvie in addition to performing clinical trials with Novartis, Solenne B.V. and acted as a consultant for Abbvie, Janssen, Philips, Galderma. T.E.C.N. has received research grants for the independent research fund of the Department of Dermatology of Erasmus MC, Rotterdam, the Netherlands from Abbvie, Leo Pharma, MSD, Pfizer and Janssen and has also acted as consultant and/or paid speaker for and/or participated in research sponsored by companies that manufacture drugs used for the treatment of psoriasis including Abbvie, Leo Pharma, Galderma, Janssen, MSD and Pfizer. Ph.I.S. has, in the past, acted as a consultant for Leo Pharma, Abbvie and Novartis and has previously received an independent research grant from Schering Plough and from Leo Pharma. She has been involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of psoriasis. Conflicts of interest H.B.T. has been a consultant and invited speaker for Biogen/ Idec, Janssen, Abbvie, Pfizer, MSD, Leo Pharma, Teva and 2016 British Association of Dermatologists British Journal of Dermatology (2017) 176, pp