BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (the BIO-FLARE study): protocol for a non-randomised longitudinal cohort study

Abstract

Background: Our knowledge of immune-mediated inflammatory disease (IMID) aetiology and pathogenesis has improved greatly over recent years, however, very little is known of the factors that trigger disease relapses (flares), converting diseases from inactive to active states. Focussing on rheumatoid arthritis (RA), the challenge that we will address is why IMIDs remit and relapse. Extrapolating from pathogenetic factors involved in disease initiation, new episodes of inflammation could be triggered by recurrent systemic immune dysregulation or locally by factors within the joint, either of which could be endorsed by overarching epigenetic factors or changes in systemic or localised metabolism.

Methods: The BIO-FLARE study is a non-randomised longitudinal cohort study that aims to enrol 150 patients with RA in remission on a stable dose of non-biologic disease-modifying anti-rheumatic drugs (DMARDs), who consent to discontinue treatment. Participants stop their DMARDs at time 0 and are offered an optional ultrasound-guided synovial biopsy. They are studied intensively, with blood sampling and clinical evaluation at weeks 0, 2, 5, 8, 12 and 24. It is anticipated that 50% of participants will have a disease flare, whilst 50% remain in drug-free remission for the study duration (24 weeks). Flaring participants undergo an ultrasound-guided synovial biopsy before reinstatement of previous treatment. Blood samples will be used to investigate immune cell subsets, their activation status and their cytokine profile, autoantibody profiles and epigenetic profiles. Synovial biopsies will be examined to profile cell lineages and subtypes present at flare. Blood, urine and synovium will be examined to determine metabolic profiles. Taking into account all generated data, multivariate statistical techniques will be employed to develop a model to predict impending flare in RA, highlighting therapeutic pathways and informative biomarkers. Despite initial recruitment to time and target, the SARS-CoV-2 pandemic has impacted significantly, and a decision was taken to close recruitment at 118 participants with complete data.

Discussion: This study aims to investigate the pathogenesis of flare in rheumatoid arthritis, which is a significant knowledge gap in our understanding, addressing a major unmet patient need.

Trial registration: The study was retrospectively registered on 27/06/2019 in the ISRCTN registry 16371380 .

Keywords: DMARD cessation; DMARD withdrawal; Flare; Pathogenesis; Remission; Rheumatoid arthritis.

Fig. 1

RA Aetiopathogenesis. Environmental factors act upon genetic predisposition to cause breach of tolerance (transition A); Unknown factors act on an individual with pre-RA to trigger active RA (transition B); Treatment induces remission (transition C); Unknown factors trigger flare (transition D). Colours denote what is well investigated (green), the focus of the study (orange) and additional processes that this study could inform (pink)

Fig. 2

The BIO-FLARE Study overview with estimated patient numbers. Recruitment numbers are extrapolated from data observed in the BioRRA study [5] and other published studies of DMARD withdrawal [13, 14]. Sample collection will occur at baseline, 2, 5, 8, 12 and 24 weeks after DMARD withdrawal, and also at the time of arthritis flare if this occurs

Fig. 3

Participant journey through the study. If the DAS28-CRP ≥ 2.4 at the screening visit, the participant is referred back to their own rheumatology team, remaining on DMARDs. All remaining participants stop their DMARDs at day 0 and are followed up with routine visits, or patient requested ad-hoc visits for 24 weeks or until the point of flare