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Efficacy and Safety of Systemic Long-Term Treatments for Moderate-to-Severe Psoriasis: A Systematic Review and Meta-Analysis

      Psoriasis as a chronic inflammatory disease often requires effective long-term treatment; a comprehensive systematic evaluation of efficacy and safety of systemic long-term treatments in patients with moderate-to-severe psoriasis is lacking. Twenty-five randomized clinical trials were included. Results were pooled and quality of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). With respect to PASI 75 (psoriasis area and severity index), pooled risk ratios for infliximab (13.07, 95% confidence interval (CI): 8.60–19.87), secukinumab (11.97, 95% CI: 8.83–16.23), ustekinumab (11.39, 95% CI: 8.94–14.51), adalimumab (8.92, 95% CI: 6.33–12.57), etanercept (8.39, 95% CI: 6.74–10.45), and apremilast (5.83, 95% CI: 2.58–13.17) show superiority of biologics and apremilast in long-term therapy compared with placebo. With respect to the addressed safety parameters, no differences were seen between adalimumab, etanercept, or infliximab versus placebo. No placebo-controlled data on conventional treatments was identified. Head-to-head studies showed superior efficacy of secukinumab and infliximab versus etanercept and of infliximab versus methotrexate. A clear ranking is limited by the lack of long-term head-to-head trials. From the available evidence, infliximab, secukinumab, and ustekinumab are the most efficacious long-term treatments. Data on conventionals are insufficient. Further head-to-head comparisons and studies on safety and patient-related outcomes are needed to draw more reliable conclusions.
      AE
      adverse event
      b.i.d.
      twice daily
      CI
      confidence interval
      CsA
      cyclosporine A
      DLQI
      dermatology life quality index
      GRADE
      Grading of Recommendations Assessment, Development and Evaluation
      MD
      mean difference
      MTX
      methotrexate
      PASI
      psoriasis area and severity index
      PGA
      physician global assessment
      RCT
      randomized controlled trial
      RR
      risk ratio
      SAE
      serious adverse event

      Introduction

      Psoriasis vulgaris is a chronic inflammatory disease with a substantial impact on the patients’ quality of life (
      • Lee Y.W.
      • Park E.J.
      • Kwon I.H.
      • et al.
      Impact of psoriasis on quality of life: relationship between clinical response to therapy and change in health-related quality of life.
      ). Most studies focus on short-term induction periods. Placebo-controlled long-term studies are rare, and performing a meta-analysis of long-term data a challenge. However, to control and treat psoriasis, an effective and safe long-term therapy is required. In the current guidelines on systemic antipsoriatic treatment, four different conventional and four different biological therapies have been included (
      • Pathirana D.
      • Ormerod A.D.
      • Saiag P.
      • et al.
      European S3-guidelines on the systemic treatment of psoriasis vulgaris.
      ;
      • Nast A.
      • Boehncke W.H.
      • Mrowietz U.
      • et al.
      S3-guidelines for the treatment of psoriasis vulgaris. Update 2011.
      ). Recently, secukinumab, an IL-17 antagonist, and apremilast, an inhibitor of phosphodiesterase 4, were approved and/or recommended by the US Food and Drug Administration (
      • Food and Drug Administration
      ,
      • Food and Drug Administration
      ) and/or the Committee for Medicinal Products for Human Use of the European Medical Agency as new treatment options for psoriasis (
      • European Medicines Agency
      ,
      • Feldman S.R.
      • Gottlieb A.B.
      • Bala M.
      • et al.
      Infliximab improves health-related quality of life in the presence of comorbidities among patients with moderate-to-severe psoriasis.
      ).
      Existing systematic reviews and meta-analyses on the treatment of psoriasis have focused on induction therapy or do not include the recently approved treatments (
      • Spuls P.I.
      • Whitkamp L.
      • Bossuyt P.M.
      • et al.
      A systematic review of five systemic treatments for severe psoriasis: reply.
      ;
      • Woolacott N.
      • Hawkins N.
      • Mason A.
      Etanercept and efalizumab for the treatment of psoriasis: a systematic review.
      ;
      • Schmitt J.
      • Wozel G.
      Targeted treatment of psoriasis with adalimumab: a critical appraisal based on a systematic review of the literature.
      ;
      • Lucka T.C.
      • 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.
      ;
      • Liu Y.
      • Gong J.P.
      • Li W.F.
      Therapeutic effect and safety of ustekinumab for plaque psoriasis: a meta-analysis.
      ;
      • Meng Y.
      • Dongmei L.
      • Yanbin P.
      • et al.
      Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis.
      ;
      • Schmitt J.
      • Rosumeck S.
      • Thomaschewski G.
      • et al.
      Efficacy and safety of systemic treatments for moderate-to-severe psoriasis: meta-analysis of randomized controlled trials.

      GRADEpro. [Computer program on www.gradepro.org Version 3.2 for Windows. McMaster University, 2014

      ). In addition, existing reviews have not used the already established GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the quality of included studies.
      PASI (psoriasis area and severity index) is the most widely used score in psoriasis trials, making meta-analysis of existing trials possible. The Dermatology Life Quality Index (DLQI) is a widely accepted patient-oriented score used in many trials. In psoriasis trials in general, the reporting of safety is very little standardized. For this reason, safety aspects have been neglected in existing reviews. The committee for the update of the European psoriasis guidelines has selected the outcomes: (a) ‘number of patients with at least one adverse event (AE)’, (b) ‘number of patients with at least one serious AE (SAE)’, and (c) ‘withdrawal due to AE’ as relevant and sufficiently standardized outcomes to be extracted and considered for the assessment of treatments in the European Guidelines (consultation draft, date: 26 January 2015).
      The aim of this systematic review is to provide a comprehensive overview about evidence on the efficacy and/or safety of systemic treatments for moderate-to-severe psoriasis in long-term therapy in adult patients based on randomized controlled trials (RCTs).

      Results

      Systematic search yielded 5,663 results. After deduplication, 4,102 records remained and were screened by title and abstract. Three additional references were retrieved by hand search through reference lists. Overall, 48 articles were assessed for eligibility in full text, whereas 31 publications reporting on 25 independent RCTs met the inclusion criteria (Figure 1). Reasons for exclusion of articles are listed in Supplementary Material Table 1 online.
      Twenty-five studies with two to four study groups and a total of 11,279 randomized patients were included in the analysis. Ten trials were initially placebo-controlled, 11 trials had placebo and active treatment as control, and four trials had at least one active treatment as control. Three studies remained placebo-controlled until week 24 (
      • Gottlieb A.B.
      • Matheson R.T.
      • Lowe N.
      • et al.
      A randomized trial of etanercept as monotherapy for psoriasis.
      ;
      • Reich K.
      • Nestle F.O.
      • Papp K.
      • et al.
      Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial.
      ;
      • Asahina A.
      • Nakagawa H.
      • Etoh T.
      • et al.
      Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study.
      ) and were pooled to calculate a mean ‘placebo response’, which was used as a model for trials without long-term placebo control.
      The study sample size varied from 48 to 1,306. Thirty-one percent of all study subjects were female. All included trials performed intention-to-treat analysis.
      No studies investigating fumaric acid esters and cyclosporine A (CsA) in long-term treatment were available. Long-term data of direct comparisons of systemic therapies of up to 24 weeks were available for etanercept, infliximab, secukinumab, methotrexate (MTX), and acitretin. Detailed data on all included studies are presented in Supplementary Table 2.
      There is only one included head-to-head trial reporting efficacy data beyond 28 weeks of treatment for the comparison with etanercept and secukinumab (
      • Langley R.G.
      • Elewski B.E.
      • Lebwohl M.
      • et al.
      Secukinumab in plaque psoriasis—results of two phase 3 trials.
      ) (see Supplementary Material, Table 3). All summary of finding tables are presented as part of the Supplemental Material (Table 4).

      Risk of bias

      The risk of bias among the included studies was partly heterogeneous, rated with low risk or unclear risk of bias. Of the 25 included RCTs, 13 (52%) reported an adequate randomization method and 14 (56%) supplied sufficient information to assess whether allocation concealment was properly ensured. In three studies (12%), the blinding of participants and personnel was insufficient (open (
      • Barker J.
      • Hoffmann M.
      • Wozel G.
      • et al.
      Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1).
      ) or single blind (
      • Gisondi P.
      • Del Giglio M.
      • Cotena C.
      • et al.
      Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24-week, randomized, controlled, investigator-blinded pilot trial.
      ;
      • de Vries A.
      • Nijsten T.
      • Opmeer B.
      • et al.
      An independent prospective randomized controlled trial comparing the efficacy and cost effectiveness of infliximab and etanercept in 'high need' patients with moderate to severe chronic plaque type psoriasis.
      ) study design). In 21 studies (84%), the risk of attrition bias was low, as incomplete outcome data were sufficiently addressed. The risk of reporting bias was low in most of the studies (80%). The risk of bias for each study is presented in Supplementary Material Figure 1.

      Comparison of monotherapy versus placebo (at weeks 24–28)

      Placebo-controlled studies were identified for all biologics and for apremilast but not for conventional treatments. These drugs have been shown to be effective in long-term therapy compared with placebo up to week 28. With respect to the addressed safety parameters, no differences were seen between the biologics and placebo. Data on PASI 75 response are presented in Figure 2 (Forest plots of other outcomes are available in Supplementary Material Figure 2).
      Figure thumbnail gr2
      Figure 2Forest plot: Verum versus placebo—PASI 75 at weeks 24–28. CI, confidence interval; b.i.d., twice daily; b.i.w., twice weekly; EOW, every other week; PASI, psoriasis area and severity index; q.w., once weekly; w, week.
      Figure thumbnail gr3
      Figure 2Forest plot: Verum versus placebo—PASI 75 at weeks 24–28. CI, confidence interval; b.i.d., twice daily; b.i.w., twice weekly; EOW, every other week; PASI, psoriasis area and severity index; q.w., once weekly; w, week.

      Efficacy: assessor-oriented scores

      PASI 75

      All biologics and apremilast showed superior efficacy compared with placebo with respect to their PASI 75 response (Figure 2).
      The pooled risk ratio (RR) for infliximab (
      • Reich K.
      • Nestle F.O.
      • Papp K.
      • et al.
      Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial.
      ,
      • Reich K.
      • Nestle F.O.
      • 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.
      ;
      • Menter A.
      • Feldman S.R.
      • Weinstein G.D.
      • et al.
      A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis.
      ;
      • Feldman S.R.
      • Gottlieb A.B.
      • Bala M.
      • et al.
      Infliximab improves health-related quality of life in the presence of comorbidities among patients with moderate-to-severe psoriasis.
      ;
      • Torii H.
      • Nakagawa H.
      • Japanese Infliximab Study I
      Infliximab monotherapy in Japanese patients with moderate-to-severe plaque psoriasis and psoriatic arthritis. A randomized, double-blind, placebo-controlled multicenter trial.
      ;
      • Yang H.Z.
      • Wang K.
      • Jin H.Z.
      • et al.
      Infliximab monotherapy for Chinese patients with moderate to severe plaque psoriasis: a randomized, double-blind, placebo-controlled multicenter trial.
      ), secukinumab (Langley et al.,
      • European Medicines Agency
      ), ustekinumab (
      • Leonardi C.L.
      • Kimball A.B.
      • Papp K.A.
      • 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) [Erratum appears in Lancet. 2008 May 31;371(9627):1838].
      ;
      • Papp K.A.
      • Langley R.G.
      • 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).
      ;
      • Tsai T.F.
      • Ho J.C.
      • 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).
      ;
      • Igarashi A.
      • Kato T.
      • Kato M.
      • et al.
      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.
      ;
      • 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).
      ;
      • Janssen
      ,
      • Janssen
      ), adalimumab (
      • Gordon K.B.
      • Langley R.G.
      • Leonardi C.
      • et al.
      Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study.
      ;
      • Menter A.
      • Tyring S.K.
      • Gordon K.
      • et al.
      Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial.
      ;
      • Asahina A.
      • Nakagawa H.
      • Etoh T.
      • et al.
      Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study.
      ), etanercept (
      • Gottlieb A.B.
      • Matheson R.T.
      • Lowe N.
      • et al.
      A randomized trial of etanercept as monotherapy for psoriasis.
      ;
      • Leonardi C.L.
      • Powers J.L.
      • Matheson R.T.
      • et al.
      Etanercept as monotherapy in patients with psoriasis.
      ;
      • Krueger G.G.
      • Langley R.G.
      • Finlay A.Y.
      • et al.
      Patient-reported outcomes of psoriasis improvement with etanercept therapy: results of a randomized phase III trial.
      ;
      • Papp K.A.
      • Tyring S.
      • Lahfa M.
      • et al.
      A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction.
      ;
      • 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.
      ,
      • Tyring S.
      • Gordon K.B.
      • Poulin Y.
      • et al.
      Long-term safety and efficacy of 50 mg of etanercept twice weekly in patients with psoriasis.
      ;
      • van de Kerkhof P.C.
      • Segaert S.
      • Lahfa M.
      • et al.
      Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension.
      ;
      • Bagel J.
      • Lynde C.
      • Tyring S.
      • et al.
      Moderate to severe plaque psoriasis with scalp involvement: a randomized, double-blind, placebo-controlled study of etanercept.
      ;
      • Langley R.G.
      • Elewski B.E.
      • Lebwohl M.
      • et al.
      Secukinumab in plaque psoriasis—results of two phase 3 trials.
      , and apremilast (
      • Papp K.
      • Cather J.C.
      • Rosoph L.
      • et al.
      Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial.
      ) are 13.07 (95% confidence interval (95% CI): 8.60, 19.87, I2=0%), 11.97 (95% CI: 8.83, 16.23, I2=0%), 11.39 (95% CI: 8.94, 14.51, I2=0%), 8.92 (95% CI: 6.33, 12.57, I2=8%), 8.39 (95% CI: 6.74, 10.45, I2=0%), and 5.83 (95% CI: 2.58, 13.17), respectively, with low quality of evidence.

      PASI 90

      A higher probability to achieve a PASI 90 response compared with placebo at weeks 24–28 was seen with secukinumab (RR 40.15 (95% CI: 20.97, 76.89), I2=0%) (
      • Langley R.G.
      • Elewski B.E.
      • Lebwohl M.
      • et al.
      Secukinumab in plaque psoriasis—results of two phase 3 trials.
      ), ustekinumab (RR 31.63 (95% CI: 19.43, 51.51), I2=0%) (
      • Leonardi C.L.
      • Kimball A.B.
      • Papp K.A.
      • 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) [Erratum appears in Lancet. 2008 May 31;371(9627):1838].
      ;
      • Papp K.A.
      • Langley R.G.
      • 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).
      ;
      • Tsai T.F.
      • Ho J.C.
      • 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).
      ;
      • Igarashi A.
      • Kato T.
      • Kato M.
      • et al.
      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.
      ;
      • 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).
      ;
      • Janssen
      ,
      • Janssen
      ), infliximab (RR 31.00 (95% CI: 13.45, 71.46), I2=0%) (
      • Reich K.
      • Nestle F.O.
      • Papp K.
      • et al.
      Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial.
      2006;
      • Menter A.
      • Feldman S.R.
      • Weinstein G.D.
      • et al.
      A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis.
      ;
      • Feldman S.R.
      • Gottlieb A.B.
      • Bala M.
      • et al.
      Infliximab improves health-related quality of life in the presence of comorbidities among patients with moderate-to-severe psoriasis.
      ;
      • Torii H.
      • Nakagawa H.
      • Japanese Infliximab Study I
      Infliximab monotherapy in Japanese patients with moderate-to-severe plaque psoriasis and psoriatic arthritis. A randomized, double-blind, placebo-controlled multicenter trial.
      ;
      • Langley R.G.
      • Elewski B.E.
      • Lebwohl M.
      • et al.
      Secukinumab in plaque psoriasis—results of two phase 3 trials.
      ), adalimumab (RR 23.17 (95% CI: 12.51, 42.91), I2 = 0%) (
      • Gordon K.B.
      • Langley R.G.
      • Leonardi C.
      • et al.
      Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study.
      ;
      • Menter A.
      • Tyring S.K.
      • Gordon K.
      • et al.
      Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial.
      ;
      • Asahina A.
      • Nakagawa H.
      • Etoh T.
      • et al.
      Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study.
      ), etanercept (RR 19.14 (95% CI: 11.59, 31.60), I2=0%) (
      • Gottlieb A.B.
      • Matheson R.T.
      • Lowe N.
      • et al.
      A randomized trial of etanercept as monotherapy for psoriasis.
      ;
      • Leonardi C.L.
      • Powers J.L.
      • Matheson R.T.
      • et al.
      Etanercept as monotherapy in patients with psoriasis.
      ;
      • 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.
      ,
      • Tyring S.
      • Gordon K.B.
      • Poulin Y.
      • et al.
      Long-term safety and efficacy of 50 mg of etanercept twice weekly in patients with psoriasis.
      ;
      • van de Kerkhof P.C.
      • Segaert S.
      • Lahfa M.
      • et al.
      Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension.
      ;
      • Bagel J.
      • Lynde C.
      • Tyring S.
      • et al.
      Moderate to severe plaque psoriasis with scalp involvement: a randomized, double-blind, placebo-controlled study of etanercept.
      ), and apremilast (RR 13.00 (95% CI: 1.74, 97.25)) (
      • Papp K.
      • Cather J.C.
      • Rosoph L.
      • et al.
      Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial.
      ). The quality of the evidence for all results was low.

      PGA ‘clear/almost clear’

      Based on PGA (Physician Global Assessment) ‘clear/almost clear’, the biologics and apremilast are superior to placebo. The RRs are 13.13 (95% CI: 8.45, 20.38, I2=0), 9.91 (95% CI: 7.76, 12.66, I2=0), 9.84 (95% CI: 7.25, 13.36, I2=0%), 8.06 (95% CI: 5.89, 11.04, I2=0), 7.16 (95% CI: 5.35, 9.57, I2=0), and 5.00 (95% CI: 2.19, 11.41) for infliximab (
      • Reich K.
      • Nestle F.O.
      • Papp K.
      • et al.
      Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial.
      , 2006;
      • Menter A.
      • Feldman S.R.
      • Weinstein G.D.
      • et al.
      A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis.
      ;
      • Feldman S.R.
      • Gottlieb A.B.
      • Bala M.
      • et al.
      Infliximab improves health-related quality of life in the presence of comorbidities among patients with moderate-to-severe psoriasis.
      ;
      • Yang H.Z.
      • Wang K.
      • Jin H.Z.
      • et al.
      Infliximab monotherapy for Chinese patients with moderate to severe plaque psoriasis: a randomized, double-blind, placebo-controlled multicenter trial.
      ), ustekinumab (
      • Leonardi C.L.
      • Kimball A.B.
      • Papp K.A.
      • 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) [Erratum appears in Lancet. 2008 May 31;371(9627):1838].
      ;
      • Papp K.A.
      • Langley R.G.
      • 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).
      ;
      • Tsai T.F.
      • Ho J.C.
      • 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).
      ;
      • 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).
      ;
      • Janssen
      ,
      • Janssen
      ), secukinumab (
      • Langley R.G.
      • Elewski B.E.
      • Lebwohl M.
      • et al.
      Secukinumab in plaque psoriasis—results of two phase 3 trials.
      ), adalimumab (
      • Gordon K.B.
      • Langley R.G.
      • Leonardi C.
      • et al.
      Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study.
      ;
      • Menter A.
      • Tyring S.K.
      • Gordon K.
      • et al.
      Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial.
      ;
      • Asahina A.
      • Nakagawa H.
      • Etoh T.
      • et al.
      Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study.
      ), etanercept (
      • Gottlieb A.B.
      • Matheson R.T.
      • Lowe N.
      • et al.
      A randomized trial of etanercept as monotherapy for psoriasis.
      ;
      • Leonardi C.L.
      • Powers J.L.
      • Matheson R.T.
      • et al.
      Etanercept as monotherapy in patients with psoriasis.
      ;
      • van de Kerkhof P.C.
      • Segaert S.
      • Lahfa M.
      • et al.
      Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension.
      ;
      • Bagel J.
      • Lynde C.
      • Tyring S.
      • et al.
      Moderate to severe plaque psoriasis with scalp involvement: a randomized, double-blind, placebo-controlled study of etanercept.
      ;
      • Langley R.G.
      • Elewski B.E.
      • Lebwohl M.
      • et al.
      Secukinumab in plaque psoriasis—results of two phase 3 trials.
      ), and apremilast (
      • Papp K.
      • Cather J.C.
      • Rosoph L.
      • et al.
      Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial.
      ), respectively. All results have been assigned a low quality of evidence.

      Efficacy: patient-oriented scores

      DLQI

      Absolute reduction in mean DLQI. With a mean difference (MD) in absolute reduction in mean DLQI of 9.80 (95% CI: 8.19, 11.41), infliximab is statistically significantly superior to placebo in long-term treatment (high quality) (
      • Reich K.
      • Nestle F.O.
      • Papp K.
      • et al.
      Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial.
      ,
      • Reich K.
      • Nestle F.O.
      • 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.
      ).
      Compared with placebo, a higher reduction in absolute DLQI in the long-term treatment was found for adalimumab 80 mg every other week (MD 5.70 (95% CI: 3.13, 8.27), moderate quality) (
      • Asahina A.
      • Nakagawa H.
      • Etoh T.
      • et al.
      Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study.
      ), adalimumab with a loading dose of 80 mg and following 40 mg every other week (MD 4.20 (95% CI: 1.54, 6.86), low quality) (
      • Asahina A.
      • Nakagawa H.
      • Etoh T.
      • et al.
      Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study.
      ), and for adalimumab 40 mg every other week (MD 3.30 (95% CI: 0.56, 6.04), low quality) (
      • Asahina A.
      • Nakagawa H.
      • Etoh T.
      • et al.
      Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study.
      ). However, the effects were small for the last two dosing regimens.
      Percentage reduction in mean DLQI. Etanercept 50 mg twice weekly (b.i.w.) has been shown to be superior to placebo in long-term treatment with an MD in percentage DLQI reduction in 57.00 (95% CI: 38.52, 75.48, high quality) (
      • Gottlieb A.B.
      • Matheson R.T.
      • Lowe N.
      • et al.
      A randomized trial of etanercept as monotherapy for psoriasis.
      ).

      Safety

      Patients with at least one AE

      After long-term treatment, no differences were found between adalimumab and placebo in the number of patients with at least one AE (RR 1.04 (95% CI: 0.93, 1.16), moderate quality) (
      • Asahina A.
      • Nakagawa H.
      • Etoh T.
      • et al.
      Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study.
      ) and between infliximab and placebo (RR 1.15 (95% CI: 0.99, 1.34), moderate quality) (
      • Reich K.
      • Nestle F.O.
      • Papp K.
      • et al.
      Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial.
      , 2006).

      Patients with at least one SAE

      Compared with placebo, no differences in the risks of SAE were shown for adalimumab (RR 0.75 (95% CI: 0.14, 3.95), low quality) (
      • Asahina A.
      • Nakagawa H.
      • Etoh T.
      • et al.
      Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study.
      ), etanercept 50 mg once weekly (q.w.) (RR 0.64 (95% CI: 0.11, 3.70), moderate quality) (
      • Gottlieb A.B.
      • Matheson R.T.
      • Lowe N.
      • et al.
      A randomized trial of etanercept as monotherapy for psoriasis.
      ), and infliximab (RR 2.16 (95% CI: 0.65, 7.17), I2=0%, moderate quality) (
      • Reich K.
      • Nestle F.O.
      • Papp K.
      • et al.
      Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial.
      ,2006;
      • Yang H.Z.
      • Wang K.
      • Jin H.Z.
      • et al.
      Infliximab monotherapy for Chinese patients with moderate to severe plaque psoriasis: a randomized, double-blind, placebo-controlled multicenter trial.
      ).

      Withdrawal due to AE

      In comparison with placebo, no statistically significant differences in withdrawal due to AE in long-term treatment were found for adalimumab (RR 0.87 (95% CI: 0.24, 3.23), low quality) (
      • Asahina A.
      • Nakagawa H.
      • Etoh T.
      • et al.
      Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study.
      ), etanercept 50 mg q.w. (RR 0.32 (95% CI: 0.07, 1.53), moderate quality) (
      • Gottlieb A.B.
      • Matheson R.T.
      • Lowe N.
      • et al.
      A randomized trial of etanercept as monotherapy for psoriasis.
      ), and infliximab (RR 1.38 (95% CI: 0.55, 3.46), moderate quality) (
      • Reich K.
      • Nestle F.O.
      • Papp K.
      • et al.
      Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial.
      , 2006).

      Head-to-head comparisons of systemic treatments (at weeks 24–26)

      Five studies were identified providing long-term data of direct comparisons (see Supplementary Material Figure 3).

      Acitretin 0.4 mg kg-1 once daily (q.d.) versus etanercept 25 mg b.i.w.

      After long-term treatment, no statistically significant differences were found between acitretin and etanercept with respect to PASI 75 (RR 0.66 (95% CI: 0.29, 1.49)) and with respect to the number of patients with at least one AE (RR 5.48 (95% CI: 0.28, 107.62), very low quality for both outcomes) (
      • Gisondi P.
      • Del Giglio M.
      • Cotena C.
      • et al.
      Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24-week, randomized, controlled, investigator-blinded pilot trial.
      ).

      Acitretin 0.4 mg kg-1 q.d. versus combination of acitretin 0.4 mg kg-1 q.d. and etanercept 25 mg q.w.

      No differences were found between acitretin monotherapy and acitretin in combination with etanercept with respect to PASI 75 (RR 0.68 (95% CI: 0.29, 1.57)) and in the number of patients with at least one AE (RR 1.80 (95% CI: 0.18, 18.21), very low quality for both outcomes) (
      • Gisondi P.
      • Del Giglio M.
      • Cotena C.
      • et al.
      Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24-week, randomized, controlled, investigator-blinded pilot trial.
      ).

      Etanercept 25 mg b.i.w. versus combination of acitretin 0.4 mg kg-1 q.d. and etanercept 25 mg q.w.

      There are no differences in PASI 75 response between etanercept combined with acitretin and etanercept monotherapy after long-term treatment period (RR 1.02 (95% CI: 0.51, 2.04)). With respect to the number of patients with at least one AE, it is uncertain whether there is any difference (RR 0.28 (95% CI: 0.01, 6.38). The quality of evidence is very low for both outcomes (
      • Gisondi P.
      • Del Giglio M.
      • Cotena C.
      • et al.
      Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24-week, randomized, controlled, investigator-blinded pilot trial.
      ).

      Etanercept 50 mg b.i.w. for 12 weeks followed by 50 mg kg-1 q.w. versus combination of etanercept 50 mg b.i.w./q.w. and MTX 7.5–15 mg q.w.

      After long-term treatment, statistically significant differences with a small effect were observed in favor of the combination etanercept/MTX based on PASI 75 (RR 0.78 (95% CI: 0.69, 0.88), low quality), PASI 90 (RR 0.64 (95% CI: 0.51, 0.78), moderate quality), and PGA ‘clear/almost clear’ (RR 0.76 (95% CI: 0.66, 0.88), low quality). In contrast, a slightly increased risk for the occurrence of at least one AE was seen with the combination (RR 0.80 (95% CI: 0.70, 0.91), moderate quality), whereas no statistically significant difference was found for the number of patients with at least one SAE (RR 1.50 (95% CI: 0.25, 8.90), low quality) (
      • Gottlieb A.B.
      • Langley R.G.
      • Strober B.E.
      • et al.
      A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis.
      ).

      Etanercept 50 mg b.i.w. versus infliximab 5 mg kg-1

      After long-term treatment, etanercept was inferior to infliximab based on PASI 75 (RR 0.48 (95% CI: 0.26, 0.89), moderate quality) (
      • de Vries A.
      • Nijsten T.
      • Opmeer B.
      • et al.
      An independent prospective randomized controlled trial comparing the efficacy and cost effectiveness of infliximab and etanercept in 'high need' patients with moderate to severe chronic plaque type psoriasis.
      ).

      Etanercept 50 mg b.i.w./q.w. versus secukinumab 150–300 mg monthly

      After long-term treatment, there are small statistically significant differences in favor of secukinumab 150 mg based on PASI 75 (RR 0.80 (95% CI: 0.72, 0.89), moderate quality), PASI 90 (RR 0.67 (95% CI: 0.57, 0.79), high quality), and PGA ‘clear/almost clear’ (RR 0.74 (95% CI: 0.64, 0.86), moderate quality) (
      • Langley R.G.
      • Elewski B.E.
      • Lebwohl M.
      • et al.
      Secukinumab in plaque psoriasis—results of two phase 3 trials.
      ). Secukinumab 300 mg is superior to etanercept based on PASI 75 (RR 0.72 (95% CI: 0.65, 0.79), moderate quality), PASI 90 (RR 0.54 (95% CI: 0.46, 0.63), high quality), and PGA ‘clear/almost clear’ (RR 0.61 (95% CI: 0.53, 0.69), high quality) (
      • Langley R.G.
      • Elewski B.E.
      • Lebwohl M.
      • et al.
      Secukinumab in plaque psoriasis—results of two phase 3 trials.
      ).

      MTX 15–20  mg q.w. versus infliximab 5 mg kg-1

      MTX is inferior to infliximab in long-term treatment based on PASI 75 (RR 0.40 (95% CI: 0.33, 0.49)), PASI 90 (RR 0.29 (95% CI: 0.21, 0.41)), and PGA ‘clear/almost clear’ (RR 0.38 (95% CI: 0.31, 0.48), moderate quality for all outcomes) (
      • Barker J.
      • Hoffmann M.
      • Wozel G.
      • et al.
      Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1).
      ). With respect to quality of life, MTX and infliximab showed a percentage reduction in DLQI of 62% and 84%, respectively. Because of missing measures of variance, no effect estimate was calculated (
      • Barker J.
      • Hoffmann M.
      • Wozel G.
      • et al.
      Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1).
      ).

      Discussion

      This systematic review summarizes the evidence for efficacy and safety of systemic drugs in long-term treatment of moderate-to-severe psoriasis.
      Placebo-controlled studies could be identified for adalimumab, etanercept, infliximab, secukinumab, ustekinumab, and apremilast. Based on low quality of evidence, all biologics and apremilast have been shown to be clinically effective in long-term therapy compared with placebo. Patient relevant outcomes support this finding with high to low quality of evidence. With respect to the addressed safety outcomes, none of the results showed a statistically significant difference for adalimumab, etanercept, or infliximab compared with placebo. However, a trend of a less favorable safety profile of infliximab over placebo can be assumed from these data.
      For secukinumab, ustekinumab, and apremilast, no data for the selected safety outcomes were available.
      Head-to-head trials allow a much better direct comparison of efficacy and safety. However, the number of direct long-term comparisons is limited. With respect to efficacy, based on PASI 75, superiority of secukinumab over etanercept, of infliximab over MTX (dosages of 15–20 mg), and of infliximab over etanercept was shown in head-to-head trials of at least 24 weeks (moderate quality of evidence). As our addressed safety parameters were not provided in these studies, no conclusion with respect to safety was possible.
      In head-to-head comparisons, the combination of etanercept plus methotrexate has been found to be superior to etanercept monotherapy with a low to moderate quality of evidence. This effect was accompanied by a slight increase in AEs. Acitretin as a combination partner to etanercept low dose was shown to have some dose sparing potential compared with monotherapy with high-dose etanercept.
      For comparison of the other interventions, only indirect comparisons can be carried out. Summarizing the data from the indirect comparison for PASI 75 responses, the best results were seen for infliximab, secukinumab, and ustekinumab followed by adalimumab and etanercept. Apremilast showed the lowest PASI 75 response rate. Indirect comparisons of the DLQI data underline the superiority of infliximab over adalimumab. This ranking has been associated with limited strength as for indirect comparisons the assumption of clinical and methodological similarity of the included studies cannot be completely assured.
      Summarizing safety data is a critical issue; however, it is highly limited by feasibility due to a lack of standardised reporting. Further harmonization of reporting should be pursued; an excellent approach to harmonizing outcome reporting has been carried out for eczema and could be initiated for psoriasis safety reporting as well (
      • Schmitt J.
      • Spuls P.I.
      • Thomas K.S.
      • et al.
      The Harmonising Outcome Measures for Eczema (HOME) statement to assess clinical signs of atopic eczema in trials.
      ). A Cochrane review investigated the safety of biologic treatments in any indication, including non-antipsoriatic treatments such as abatacept and rituximab. The review showed an increased risk of tuberculosis reactivation (odds ratio 4.68, 95% CI: 1.18–18.60) compared with control. The rates of SAE, serious infections, lymphoma, and congestive heart failure were not significantly different. Pooling all these different biologics and different populations into one group is questionable (
      • Singh J.A.
      • Wells G.A.
      • Christensen R.
      • et al.
      Adverse effects of biologics: a network meta-analysis and Cochrane overview.
      ).
      Patient registries are another possible approach to generate long-term data on efficacy and especially safety.
      • Gniadecki R.
      • Bang B.
      • Bryld L.E.
      • et al.
      Comparison of long-term drug survival and safety of biologic agents in patients with psoriasis vulgaris.
      have published drug survival data from Danish psoriasis registry (DERMBIO), which showed longer drug survival on ustekinumab compared with the anti-TNF agents. Similar results were found by
      • van den Reek J.M.
      • Tummers M.
      • Zweegers J.
      • et al.
      Predictors of adalimumab drug survival in psoriasis differ by reason for discontinuation: long-term results from the Bio-CAPTURE registry.
      in the Dutch Bio-CAPTURE network, with better overall drug survival of ustekinumab over etanercept and a trend over adalimumab.

      Limitations

      In most of the long-term studies, the placebo groups were discontinued after induction. We performed an imputation approach to make long-term efficacy data of the drugs derived from original placebo-controlled studies suitable for meta-analyses. In this imputation approach, we calculated a mean placebo response of efficacy outcomes based on available placebo-controlled trials. The original sample size of the placebo group was also considered. We are aware that this imputation approach has been associated with uncertainties; consequently, we downgraded the quality of evidence.
      The assessment of safety remains a challenge. Reporting needs to be more standardised. Even when using the very broad categories number of patients with ‘at least one AE’, ‘at least one SAE’, and ‘withdrawal due to AE’, evidence is strongly limited. As we could not make assumptions on occurrence of AEs during long-term placebo treatment, imputations of placebo data for safety outcomes were not performed. In addition, among biologics, data reported in publications on ustekinumab and secukinumab were not suitable for analyzing our predefined safety outcomes, and conclusions on potential harms based on these parameters could not be drawn.
      More long-term head-to-head trials are needed to allow for comparisons of efficacy and safety with a higher validity. The RCT setting is preferable, as it generates the more robust data. Additional data will be generated from the ongoing patient registers providing information on safety and drug survival rates in the general patient population.

      Materials and Methods

      This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ). The selection of databases, eligibility criteria, outcomes of the review, and analyses methods were defined a priori in an internal protocol. Study selection, data extraction, and quality assessment were performed independently by two assessors. Any differences were solved by discussion and mutual agreement.

      Predefined eligibility criteria

      Published RCTs were included if they investigated one of the following treatments in commonly used dosages: acitretin, adalimumab, apremilast, CSA, etanercept, fumaric acid ester, infliximab, MTX, secukinumab, or ustekinumab. Comparison had to be done versus placebo, versus another included active treatment, or versus a combination of two included treatments. Data had to be available for a treatment duration of at least 24 weeks. Patient population consisted of adults suffering from moderate-to-severe plaque-type psoriasis. Studies had to report at least one efficacy or safety outcome for long-term treatment. No language restrictions were applied.

      Information sources and search

      Systematic literature searches were conducted in Medline, Medline in Process, and Embase using OvidSP platform. In addition, the Cochrane Library was searched via its online search platform. Search dates were from inception to 5 January 2015. The search strategy for Medline is presented in Supplementary Material Table 5. In addition, reference lists of relevant reviews and included studies were screened.

      Study selection and data extraction

      After exclusion of duplicates, titles and abstracts were screened for inclusion and exclusion. Potentially relevant articles were checked in full text for inclusion.
      Study characteristics (e.g. medication and dosage for intervention and control, number of randomized patients, trial and treatment duration, inclusion criteria, and sponsor), study population (e.g. age, sex, weight, previous treatment, disease severity), and study results of included trials were extracted using a standardized data extraction form. Efficacy and safety data were sought for one time point of long-term treatment, defined as a treatment of at least 24 weeks. Outcomes were PASI 75 (primary), PASI 90, PGA ‘clear/almost clear’, reduction in mean DLQI, patients with at least one AE, patients with at least one SAE, and withdrawal due to AE.

      Data analysis

      RRs with 95% CI for dichotomous data and MDs with 95% CI for continuous data were calculated for each study comparison. The effect estimates of the individual studies were pooled in the meta-analysis using a random-effects model (Review Manager 5.3.4). Inconsistencies among the estimates were quantified using the I2 test. Wherever heterogeneity among the included studies was substantial (
      • Higgins J.P.T.
      • Green S.
      ), study results were not pooled but presented individually.
      Limited placebo-controlled data were available for long-term treatment. Most of the placebo control arms did not continue beyond the induction period of usually 12 to 16 weeks. However, to calculate effect estimates, a placebo arm is necessary. Three included studies provided placebo data for up to week 24. The long-term placebo data of efficacy outcomes from these three studies were pooled to calculate a mean ‘placebo response’, which was used as a model for trials without long-term placebo control. Placebo data at week 24 were available for PASI 75, PASI 90, and PGA ‘clear/almost clear’ Table 1.
      Table 1Available placebo outcome data for week 24
      StudyComparator to placeboPlacebo response
      PASI 75PASI 90PGA 'clear/almost clear’
      Asahina et al. (2010)Adalimumab6/46 (13.0%)2/46 (4.3%)5/46 (10.9%)
      Gottlieb et al. (2003)Etanercept3/55 (5.5%)0/55 (0.0%)Not available
      Reich et al. (2005)Infliximab3/77 (3.9%)1/77 (1.3%)2/55 (3.6%)
      Total placebo response12/178 (6.7%)3/178 (1.7%)7/101 (6.9%)
      Abbreviations: PGA, Physician Global Assessment; PASI, psoriasis area and severity index.

      Quality of the evidence

      The quality of the individual included trials was assessed using the Cochrane Risk of Bias Tool (
      • Higgins J.P.
      • Altman D.G.
      • Gotzsche P.C.
      • et al.
      The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
      ). The available evidence and its quality were summarized using the GRADE approach (
      • Atkins D.
      • Best D.
      • Briss P.A.
      • et al.
      Grading quality of evidence and strength of recommendations.
      ) for each available outcome in each comparison. Using the GRADEprofiler software (Brozek et al., 2008), GRADE evidence profiles were developed for each available treatment comparison. The quality of the evidence for each comparison was categorized into one of the four categories, from ‘very low’ (+ - - -) to ‘high’ (+ + + +) based on the criteria risk of bias, inconsistency, indirectness, imprecision, publication bias, and large effects (
      • Balshem H.
      • Helfand M.
      • Schunemann H.J.
      • et al.
      GRADE guidelines: 3. Rating the quality of evidence.
      ). In addition to the general criteria for risk of bias, the quality was downgraded by two points if imputed placebo data were used for calculation of the effect estimate to reflect the limited validity of the results. Likelihood of publication bias was graded as ‘undetected’ for each outcome, although no analysis such as funnel plots or statistical tests for asymmetry could be carried out due to the small number of included studies for each comparison.

      Conflict of Interest

      Dr Nast has received honoraria for CME certified educational talks that received direct or indirect sponsoring from Abbott (now AbbVie) and Pfizer. The Division of Evidence-Based Medicine has received research grants from Pfizer. No other disclosures were reported.

      ACKNOWLEDGMENTS

      This review was accomplished during the update of the European psoriasis guidelines, which was supported financially by the European Dermatology Forum (EDF). There was no funding for the work on this manuscript itself. The EDF had no role in design and conduct of the study.

      Supplementary material

      Supplementary material is linked to the online version of the paper at http://www.nature.com/jid

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