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. The underpinning mechanism(s) of flare have been difficult to study because they occur unpredictably. Within both the BioRRA and BIO-FLARE studies, we have focussed on rheumatoid arthritis (RA) to establish a highly relevant human model that generates a ‘synchronised’ population of RA patients in clinical remission, approximately 50% of whom relapse within 6 months following treatment cessation, the other 50% maintaining drug-free remission. Using this experimental medicine approach we have conducted an in-depth analysis of circulating immune cell subsets and their mediators, as well as detailed investigation of the joint synovium, to dissect the molecular and cellular factors driving disease flare. Through this work we have identified key pathways and cellular mediators associated with RA disease flare, as well as those involved in drug-free remission. Our ultimate goal is to develop biomarkers that will underpin relapse prevention by appropriately targeted therapeutics, and targeted treatment withdrawal in patients most likely to maintain a drug-free remission. The knowledge generated in these studies may also provide clues to the transition from pre-RA to RA at disease onset, as well as provide potentially relevant understanding of other relapsing and remitting IMIDs, such as inflammatory bowel disease.