Defining Difficult-to-Treat Rheumatoid Arthritis in Routine Care: Comparative Performance of Published Criteria and Description of Early and Late D2T-RA Phenotypes.

BACKGROUND: Despite advances in treat-to-target strategies, a subset of patients with rheumatoid arthritis (RA) remains refractory to multiple therapies and is classified as difficult-to-treat RA (D2T-RA). Although the European Alliance of Associations for Rheumatology (EULAR) has proposed classification criteria for D2T-RA, these patients remain variably identified in real-world practice due to heterogeneous applications. We compared different published applications of the EULAR D2T-RA criteria and proposed a temporal framework to distinguish early from late D2T-RA. METHODS: Using data from the Ontario Best Practices Research Initiative (OBRI), a longitudinal real-world RA registry, we evaluated four literature-derived adaptations of the EULAR D2T-RA definition among patients initiating their first advanced therapy. These definitions differed in disease activity requirements, follow-up duration, and treatment count thresholds. We assessed prevalence, agreement between definitions, and explored different temporal anchors for classifying early versus late D2T-RA. RESULTS: Among 1,121 RA patients (mean age 56.0; 80.7% female; mean disease duration was 8.4 years), 202 (18%) fulfilled at least one of the four D2T-RA definitions. Prevalence varied substantially across definitions, ranging from 5.5% (definition 4) to 11.7% (definition 2). Definitions 1 and 2, which incorporated multiple disease-activity measures, identified the largest proportion of patients, whereas definition 4, defined solely by initiation of a third advanced therapy, was most restrictive. Overlap between definitions was modest, with only 44% of patients meeting all Definitions 1-3, whereas Definition 4 identified a distinct group with no overlap with the other definitions, suggesting that these classification approaches capture different patient subsets and are not interchangeable. In temporal analyses, anchoring the D2T-RA onset to the initiation of the first advanced therapy, a two-year threshold-selected for its clinical relevance and balanced groups sizes- classified (~40%) of patients as early and (~60%) as late D2T-RA. CONCLUSION: The applications of D2T-RA criteria are not interchangeable and vary widely in patient capture. A two-year threshold anchored to the first initiation of advanced therapy offered a clinically balanced early-late D2T-RA framework. Harmonized, multidimensional definitions incorporating disease activity and temporal stratification are needed to improve phenotyping, prognostication and cross-study comparability.