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Improving rheumatoid arthritis comparative effectiveness research through causal inference principles: systematic review using a target trial emulation framework
  1. Sizheng Steven Zhao1,2,
  2. Houchen Lyu2,3,
  3. Daniel H Solomon2,4,
  4. Kazuki Yoshida2
  1. 1 Musculoskeletal Biology, Institute of Lifecourse and Medical Sciences, University of Liverpool, Liverpool, UK
  2. 2 Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Massachusetts, USA
  3. 3 Department of Orthopaedics, General Hospital of Chinese PLA, Beijing, China
  4. 4 Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr Sizheng Steven Zhao, Musculoskeletal Biology, Institute of Lifecourse and Medical Sciences, University of Liverpool, Liverpool, UK; s.zhao8{at}


Objectives Target trial emulation is an intuitive design framework that encourages investigators to formulate their comparative effectiveness research (CER) question as a hypothetical randomised controlled trial (RCT). Our aim was to systematically review CER studies in rheumatoid arthritis (RA) to provide examples of design limitations that could be avoided using target trial emulation, and how these limitations might introduce bias.

Methods We searched for head-to-head CER studies of biologic disease modifying anti-rheumatic drugs (DMARDs) in RA. Study designs were reviewed for seven components of the target trial emulation framework: eligibility criteria, treatment strategies, assignment procedures, follow-up period, outcome, causal contrasts of interest (ie, intention-to-treat (ITT) or per-protocol effect) and analysis plan. Hypothetical trials corresponding to the reported methods were assessed to identify design limitations that would have been avoided with an explicit target trial protocol. Analysis of the primary effectiveness outcome was chosen where multiple analyses were performed.

Results We found 31 CER studies, of which 29 (94%) had at least one design limitation belonging to seven components. The most common limitations related to: (1) eligibility criteria: 19/31 (61%) studies used post-baseline information to define baseline eligibility; (2) causal contrasts: 25 (81%) did not define whether ITT or per-protocol effects were estimated and (3) assignment procedures: 13 (42%) studies did not account for confounding by indication or relied solely on statistical confounder selection.

Conclusions Design limitations were found in 94% of observational CER studies in RA. Target trial emulation is a structured approach for designing observational CER studies that helps to avoid potential sources of bias.

  • rheumatoid arthritis
  • target trial emulation
  • causal inference
  • observational study
  • comparative effectiveness

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  • Handling editor Josef S Smolen

  • Twitter @stezhao, @DanielHSolomon, @kaz_yos

  • Contributors All authors contributed to study design, data interpretation, writing and review of the manuscript and approved the final version for publication.

  • Funding DHS was supported by grants from the National Institute of Health (NIH-P30-AR072577 (VERITY)). KY was supported by the Rheumatology Research Foundation Career Development Bridge Funding Award.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.