Association between initial treatment strategy and progression to difficult-to-treat rheumatoid arthritis (D2T-RA): evidence from a 20-year-old real-world cohort.

BACKGROUND/OBJECTIVES: Despite major advances in rheumatoid arthritis (RA) management, a substantial proportion of patients evolve to difficult-to-treat RA (D2T-RA). We estimated the probability of progression to D2T-RA and assessed whether the initial choice of biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) is associated with this risk. METHODS: We retrospectively analysed 675 patients with established RA from the first consultation through all b/tsDMARD lines to the last follow-up or D2T-RA classification. Kaplan-Meier, log-rank and multivariable Cox regression analyses were performed to identify factors associated with D2T-RA progression. RESULTS: Of the 675 patients (mean follow-up of 217.1±131.16 months), 126 (18.7%) fulfilled the D2T-RA criteria. Tumour necrosis factor inhibitor (TNFi) accounted for most first-line and second-line treatments (81.0% and 53.2%). In the post-2000 subcohort (498 patients), no significant difference in D2T-RA risk was observed between TNFi and non-TNFi starters nor between TNFi-cycling or other mechanism of action (MoA)-switching strategies. Glucocorticoid exposure was independently associated with increased risk (HR 2.47, 95% CI 1.38 to 4.42) and delayed b/tsDMARD initiation with decreased hazard (HR 0.990, 95% CI 0.98 to 0.996). CONCLUSION: In this observational cohort, initial MoA choice was not associated with D2T-RA progression. Disease severity markers appeared more prominent than treatment strategies in driving refractory evolution. Validation in a prospective/randomised setting is required before potential transition into clinical practice.