title: Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials.
abstract: BACKGROUND
  Ustekinumab and briakinumab, monoclonal antibodies to the shared p40 subunit of interleukin (IL)-12 and IL-23, have shown efficacy in treating chronic plaque psoriasis (CPP). Preliminary reports of major adverse cardiovascular events (MACEs) in psoriasis patients receiving anti-IL-12/23 agents have prompted concern.
  
  
  OBJECTIVE
  To evaluate a possible association between biologic therapies for CPP and MACEs via meta-analysis.
  
  
  METHODS
  Randomized controlled trials (RCTs) of anti-IL-12/23 (ustekinumab and briakinumab) agents and anti-tumor necrosis factor α (TNF-α) agents (adalimumab, etanercept, and infliximab) used in treating CPP were reviewed using the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Ovid MEDLINE from database inception to May 2011. The results of registered nonpublished completed studies were procured through abstract publications or poster presentations.
  
  
  METHODS
  Randomized, placebo-controlled, double-blind, monotherapy studies (with safety outcome data for MACE) of IL-12/23 antibodies and anti-TNF-α agents in adults. Studies of psoriatic arthritis were excluded.
  
  
  METHODS
  Two investigators independently searched data while 6 investigators reviewed the abstracted data.
  
  
  RESULTS
  A total of 22 RCTs comprising 10 183 patients met the predefined inclusion criteria. The primary outcome measure was MACE, a composite end point of myocardial infarction, cerebrovascular accident, or cardiovascular death during the placebo-controlled phase of treatment in patients receiving at least 1 dose of study agent or placebo. Absolute risk differences were used as an effect measure. There was no evidence of statistical heterogeneity across the studies using the I(2) statistic (I(2) = 0), allowing for combination of trial results using the Mantel-Haenszel fixed-effects method. During the placebo-controlled phases of the anti-IL-12/23 studies, 10 of 3179 patients receiving anti-IL-12/23 therapies experienced MACEs compared with zero events in 1474 patients receiving placebo (Mantel-Haenszel risk difference, 0.012 events/person-year; 95% confidence interval [CI], -0.001 to 0.026; P =.12). In the anti-TNF-α trials, only 1 of 3858 patients receiving anti-TNF-α agents experienced a MACE compared with 1 of 1812 patients receiving placebo (Mantel-Haenszel risk difference, -0.0005 events/person-year; 95% CI, -0.010 to 0.009; P = .94).
  
  
  CONCLUSIONS
  Compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti-IL-12/IL-23 antibodies or anti-TNF-α treatments. This study may have been underpowered to identify a significant difference.
authors.affiliation: Department of Dermatology, Baylor Research Institute, 3900 Junius St, Ste 125, Dallas, TX 75246, USA. caitriona.ryan@baylorhealth.edu
authors.forename: Caitriona
authors.initials: C
authors.lastname: Ryan
authors.forename: Craig L
authors.initials: CL
authors.lastname: Leonardi
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Kimball
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Strober
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Gordon
authors.forename: Richard G
authors.initials: RG
authors.lastname: Langley
authors.forename: James A
authors.initials: JA
authors.lastname: de Lemos
authors.forename: Yahya
authors.initials: Y
authors.lastname: Daoud
authors.forename: Derek
authors.initials: D
authors.lastname: Blankenship
authors.forename: Salahuddin
authors.initials: S
authors.lastname: Kazi
authors.forename: Dan H
authors.initials: DH
authors.lastname: Kaplan
authors.forename: Vincent E
authors.initials: VE
authors.lastname: Friedewald
authors.forename: Alan
authors.initials: A
authors.lastname: Menter
mesh_terms: D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D004311:Double-Blind Method; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects* / Q000627:therapeutic use; D007155:Immunologic Factors / Q000009:adverse effects* / Q000627:therapeutic use; D000069285:Infliximab; D018664:Interleukin-12; D053759:Interleukin-23; D008875:Middle Aged; D009203:Myocardial Infarction / Q000139:chemically induced*; D010919:Placebos; D011565:Psoriasis / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D012306:Risk; D020521:Stroke / Q000139:chemically induced*; D014409:Tumor Necrosis Factor-alpha; D000069549:Ustekinumab; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007155:Immunologic Factors; D053759:Interleukin-23; D010919:Placebos; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; C544528:briakinumab; D000069285:Infliximab; D000069549:Ustekinumab; D000068879:Adalimumab; D000068800:Etanercept