PO:07:098 | Reasons for treatment failure and their synovial correlate among patients with difficult-to-treat rheumatoid arthritis

Alessandro Giollo¹, Mariangela Salvato¹, Francesca Frizzera¹, Kiren Khalid¹, Lorenzo Di Luozzo¹, Carlo Garaffoni², Maria Capita², Marianna Tamussin², Giovanni Lanza², Marny Fedrigo³, Annalisa Angelini³, Roberta Ramonda¹, Ettore Silvagni², Andrea Doria¹ | ¹UOC Reumatologia Padova, Italy; ²UOC Reumatologia Ferrara, Italy; ³UOC Patologia cardiovascolare Padova, Italy; ⁴UOC Anatomia Patologica Ferrara, Italy

Background. EULAR difficult-to-treat rheumatoid arthritis (D2TRA) is defined by treatment failure of two classes of biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). However, treatment failure can result from inefficacy or adverse events (AEs), thus introducing a potential caveat in the definition of D2TRA. The aim of the study was to investigate whether D2TRA resulting from treatment inefficacy exhibits distinct synovial pathology compared to that arising from AEs.

Materials and Methods. The MATRIX-D2T was a prospective cohort, multi-centre study that included RA patients with moderate to high disease activity undergoing ultrasound-guided synovial tissue biopsy (UGSTB) at two institutions. Patients were eligible for inclusion if they fulfilled the EULAR D2TRA definition. The main tissue outcome was the Krenn Synovitis Score (KSS, ranging from 0 to 9); secondary outcomes included the main synovial pathotypes (lymphomyeloid, diffuse myeloid, pauci-immune fibroid), immunohistochemistry scores, and the count of lymphoid aggregates. The exposures comprised the number (1 to 5) of b/tsDMARDs that failed due to inefficacy (inefficacy score) or AEs (AEs score). All regression analyses were adjusted for disease duration.

Results. Among 132 patients undergoing USGTB during the study period, 42 patients met the study criteria and were included (mean (SD) age 58 (11) years, duration 15 (10) years, females 62%). The median (IQR) number of failed b/tsDMARDs was 3 (2 to 5), and for csDMARDs, it was 2 (1 to 4). The median (IQR) probability of inefficacy:AE for treatment failure was 72% (40 to 86%). Inefficacy score was weakly correlated with PhGA (p=0.289, p=0.039) and not correlated with disease activity, duration, age, or PROMs; the AE score was not correlated with patients’ characteristics. In multivariable regression (Table 1), the inefficacy score was significantly and inversely associated with KSS, while the AE score was not. The quadratic term did not strengthen the association, nor was there interaction between inefficacy and AE scores or inefficacy scores and ACPA. A similar association with lymphoid aggregate count was close to significance. Immunohistochemistry analysis revealed CD34 and alfa-SMA were significantly and inversely associated with the inefficacy score. There was a trend for pauci-immune fibroid pathotype enrichment in patients with a higher probability of inefficacy and, likewise, a decreased frequency of lymphomyeloid pathotype (Figure); this trend was not seen for the AE scores. Sensitivity analysis of primary vs. secondary inefficacy and serious AEs vs. drug intolerance was underpowered to detect significant differences in KSS and other outcomes.

Conclusions. Compared to adverse events, inefficacy as the reason for D2TRA was moderately associated with the severity of synovitis. The higher occurrence of the pauci-immune fibroid pathotype and stromal density enriched with myofibroblasts and endothelial cells suggests exhausted synovial inflammation in some D2TRA patients with multidrug inefficacy.