Ab0340 multi-drug resistant ra is associated with higher baseline disease activity, multi-morbidity, and lower quality of life: analyses from the r4ra biopsy-driven clinical trial

Background We have recently described a fibroblast/stromal signature in patients with multi-drug resistant Rheumatoid Arthritis (MDR-RA). However, MDR-RA is known to be extremely heterogeneous, with multiple clinical and pathogenetic factors potentially contributing to multi-drug resistance. Objectives Define the association of MDR-RA with clinical and demographic factors. Methods Patients with multi-drug resistant RA (MDR-RA), defined as failure of 3x bDMARDs with a different mechanism of action (TNF-inhibitor, tocilizumab and rituximab) were identified from the R4RA clinical trial (n=40) and compared with first-line responders to either rituximab or tocilizumab (n=72) for: disease activity scores, including composite indexes and individual components; baseline demographics, including co-morbidities, and quality of life scores (HAQ and SF-36 domains); synovitis, assessed by ultrasound and immunohistochemistry. Results MDR-RA patients did not differ significantly from first-line responders in terms of age, disease duration and ethnicity, as shown in Table 1. MDR-RA patients were treated more often with a csDMARDs combination, while the number of previous anti-TNF did not differ. Baseline disease activity was significantly higher in MDR-RA compared to first-line responders. This difference was mainly driven by tender joints, while there were no significant differences for 28 swollen joints count, pain, and patient/physician global health scores (Table 1). Ultrasound scores and synovial pathotype distribution were not significantly different between MDR-RA and responders, but responders had a numerically higher power doppler score and significantly higher sub-lining macrophages, in line with the known association of synovial macrophages with treatment response. The incidence of individual comorbidities such as diabetes, hypercholesterolemia, hypertension, anxiety/depression, and obesity was non significantly different between MDR-RA and responders; however, the prevalence of multi-morbidities was significantly higher in MDR-RA patients, as 50% had more than 2 comorbidities compared to 22.8% of responders (p=0.0343). Finally, MDR-RA patients had significantly lower FACIT fatigue scores and worse scores for multiple SF-36 domains (physical functioning, emotional well-being, social functioning, and general health). Although the difference in baseline disease activity was mainly driven by tender joints, the longitudinal assessment of disease activity across 48 weeks showed persistently elevated tender and swollen joint counts, pain, and global health scores in MDR-RA patients compared with responders (Figure 1). Conclusion MDR-RA, defined as lack of response to 3x biologics with different mechanisms of action, is associated with worse disease activity baseline and multi-morbidity. There were no specific associations with pain scores, but MDR-RA had a huge impact on multiple quality-of-life domains. At follow-up, MDR-RA was associated with persistently elevated disease activity scores, including both higher tender and swollen joints, in keeping with persistently active inflammatory disease. Reference [1] Rivellese et al, Nat Med 28, 1256–1268 (2022) Table 1. MDR-RA (N=40) Responder (N=72) p value Age, 53.6 (14.1) 56.4 (11.9) 0.291 RA duration 14.9 (12.0) 12.3 (10.2) 0.254 Gender, F 35 (87.5%) 51 (70.8%) 0.077 csDMARDs <0.001 0 11 (27.5%) 50 (69.4%) 1 13 (32.5%) 6 (8.3%) 2 11 (27.5%) 12 (16.7%) >3 5 (12.5%) 4 (5.6%) Steroids 24 (60.0%) 36 (50.0%) 0.413 Previous anti-TNF 0.153 1 33 (82.5%) 47 (65.3%) 2 6 (15.0%) 22 (30.6%) >3 1 (2.5%) 3 (4.2%) CDAI 36.9 (14.0) 31.0 (13.0) 0.0305 DAS28 ESR 6.12 (1.05) 5.60 (1.21) 0.0191 ESR 33.5 (21.2) 32.6 (26.3) 0.839 CRP 21.5 (30.6) 21.9 (34.0) 0.946 TJC 28 15.5 (8.30) 11.2 (7.01) 0.00641 SJC 28 7.68 (4.81) 7.04 (5.64) 0.532 Pain (VAS ) 66.1 (21.8) 68.0 (23.4) 0.671 GH (VAS ) 70.0 (20.5) 66.5 (25.5) 0.437 Data shown as mean (SD) or n (%). Figure 1. Acknowledgements We thank all patients participating in the trial and the Precision Medicine Patient Advisory Group (PM-PAG) for their continuous support. The R4RA trial was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a partnership between the Medical Research Council (MRC) and the National Institute for Health and Care Research (NIHR) (grant no. 11/100/76). This study was further supported by NIHR (grant 131575) and MRC (MR/V012509/1). Disclosure of Interests None Declared.