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Original article
Novel methodology to discern predictors of remission and patterns of disease activity over time using rheumatoid arthritis clinical trials data
  1. RA-MAP Consortium
  1. Correspondence to Dr Brian D M Tom; brian.tom{at}mrc-bsu.cam.ac.uk; Professor Deborah Symmons; deborah.symmons{at}manchester.ac.uk

Abstract

Objectives To identify predictors of remission and disease activity patterns in patients with rheumatoid arthritis (RA) using individual participant data (IPD) from clinical trials.

Methods Phase II and III clinical trials completed between 2002 and 2012 were identified by systematic literature review and contact with UK market authorisation holders. Anonymised baseline and follow-up IPD from non-biological arms were amalgamated. Multiple imputation was used to handle missing outcome and covariate information. Random effects logistic regression was used to identify predictors of remission, measured by the Disease Activity Score 28 (DAS28) at 6 months. Novel latent class mixed models characterised DAS28 over time.

Results IPD of 3290 participants from 18 trials were included. Of these participants, 92% received methotrexate (MTX). Remission rates were estimated at 8.4%(95%CI 7.4%to9.5%) overall, 17%(95%CI 14.8%to19.4%) for MTX-naïve patients with early RA and 3.2% (95% CI 2.4% to 4.3%) for those with prior MTX exposure at entry. In prior MTX-exposed patients, lower baseline DAS28 and MTX reinitiation were associated with remission. In MTX-naïve patients, being young, white, male, with better functional and mental health, lower baseline DAS28 and receiving concomitant glucocorticoids were associated with remission. Three DAS28 trajectory subpopulations were identified in MTX-naïve and MTX-exposed patients. A number of variables were associated with subpopulation membership and DAS28 levels within subpopulations.

Conclusions Predictors of remission differed between MTX-naïve and prior MTX-exposed patients at entry. Latent class mixed models supported differential non-biological therapy response, with three distinct trajectories observed in both MTX-naïve and MTX-exposed patients. Findings should be useful when designing future RA trials and interpreting results of biomarker studies.

  • DAS28 trajectories
  • latent class mixed models
  • methotrexate
  • randomised controlled trial
  • remission
  • rheumatoid arthritis

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: http://creativecommons.org/licenses/by/4.0

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Footnotes

  • Collaborators See RA-MAP Consortium Membership in online supplementary material 1.

  • Contributors The RA-MAP contributing authors have (1) substantially contributed to the conception or design of the work; or the acquisition, analysis or interpretation of data for the work; and have been involved in the (2) drafting the work or revising it critically for important intellectual content; and have given (3) final approval of the version to be published; and have (4) agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding This study was funded by the MRC/ABPI Inflammation and Immunology Initiative Grant (MRC reference numbers: G1001516 and G1001518). BDMT is supported by the UK Medical Research Council (Unit Programme numbers: MC_UP_1302/3 and MC_UU_00002/2). DS was an NIHR Senior Investigator.

  • Competing interests Although the UK RA-MAP Consortium is the author, there are a number of individuals (ie, contributors) to this paper, some of whom may have competing interests through their industry affiliation, research funding or consultancy activities. We have uploaded a file listing the contributors and their competing interests if any in the online supplementary material 1.

  • Patient consent Not required.

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

  • Data sharing statement The individual participant data from the 18 clinical trials are not available for sharing due to the agreement made with the companies/investigators who agreed for their non-biological arm(s) data to be used in this work.