title: Using serum urate as a validated surrogate end point for flares in patients with gout: protocol for a systematic review and meta-regression analysis.
abstract: Gout is the most common inflammatory arthritis in men over 40 years of age. Long-term urate-lowering therapy is considered a key strategy for effective gout management. The primary outcome measure for efficacy in clinical trials of urate-lowering therapy is serum urate levels, effectively acting as a surrogate for patient-centred outcomes such as frequency of gout attacks or pain. Yet it is not clearly demonstrated that the strength of the relationship between serum urate and clinically relevant outcomes is sufficiently strong for serum urate to be considered an adequate surrogate. Our objective is to investigate the strength of the relationship between changes in serum urate in randomised controlled trials and changes in clinically relevant outcomes according to the 'Biomarker-Surrogacy Evaluation Schema version 3' (BSES3), documenting the validity of selected instruments by applying the 'OMERACT Filter 2.0'.
  
  
  
  A systematic review described in terms of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines will identify all relevant studies. Standardised data elements will be extracted from each study by 2 independent reviewers and disagreements are resolved by discussion. The data will be analysed by meta-regression of the between-arm differences in the change in serum urate level (independent variable) from baseline to 3 months (or 6 and 12 months if 3-month values are not available) against flare rate, tophus size and number and pain at the final study visit (dependent variables).
  
  
  
  This study will not require specific ethics approval since it is based on analysis of published (aggregated) data. The intended audience will include healthcare researchers, policymakers and clinicians. Results of the study will be disseminated by peer-reviewed publications.
  
  
  
  CRD42016026991.
authors.affiliation: Musculoskeletal Statistics Unit, Department of Rheumatology, The Parker Institute, Copenhagen University Hospitals, Bispebjerg and Frederiksberg, Frederiksberg, Denmark Department of Rheumatology, Odense University Hospital, Svendborg, Denmark.
authors.forename: Melanie B
authors.initials: MB
authors.lastname: Morillon
authors.affiliation: Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Lisa
authors.initials: L
authors.lastname: Stamp
authors.affiliation: Department of Medicine, University of Otago, Wellington, New Zealand.
authors.forename: William
authors.initials: W
authors.lastname: Taylor
authors.affiliation: JF Department of Rheumatology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Fransen
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Nicola
authors.initials: N
authors.lastname: Dalbeth
authors.affiliation: Department of Medicine, University of Alabama at Birmingham & Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, USA.
authors.forename: Jasvinder A
authors.initials: JA
authors.lastname: Singh
authors.affiliation: Musculoskeletal Statistics Unit, Department of Rheumatology, The Parker Institute, Copenhagen University Hospitals, Bispebjerg and Frederiksberg, Frederiksberg, Denmark.
authors.forename: Robin
authors.identifier: 0000-0002-6600-0631
authors.initials: R
authors.lastname: Christensen
authors.affiliation: Department of Rheumatology, St George Hospital, University of NSW, Sydney, New South Wales, Australia.
authors.forename: Marissa
authors.initials: M
authors.lastname: Lassere
mesh_terms: D015415:Biomarkers / Q000097:blood; D006073:Gout / Q000097:blood* / Q000175:diagnosis*; D006801:Humans; D015203:Reproducibility of Results; D012107:Research Design; D000078202:Systematic Reviews as Topic; D014527:Uric Acid / Q000097:blood*; D015201:Meta-Analysis as Topic
chemical_list: D015415:Biomarkers; D014527:Uric Acid
keywords: BIOMARKER; GOUT; OUTCOME; RHEUMATOLOGY; SURROGATE