Poly‐refractory Rheumatoid Arthritis: An Uncommon Subset of Difficult to Treat Disease with Distinct Inflammatory and Non‐inflammatory Phenotypes

Objectives To investigate the prevalence of poly‐refractory RA defined as failure of all biologic (b)/targeted synthetic (ts)‐DMARDs. To further investigate whether Persistent inflammatory refractory RA (PIRRA) and non‐inflammatory refractory RA (NIRRA) patients, determined by objective ultrasound (US) synovitis, have distinct clinical phenotypes in both EULAR difficult‐to‐treat Rheumatoid Arthritis (D2T‐RA) and poly‐refractory RA groups. Methods A cross‐sectional study of 1591 RA patients on biologic b/tsDMARDs that evaluated D2T‐RA criteria and subclassified as poly‐refractory if inefficacy/toxicity to at least one drug of all classes. PIRRA was defined if US synovitis in ≥1 swollen joint (SJ) and NIRRA if absent. Univariate tests and multivariate logistic regression were conducted to investigate factors associated with poly‐refractory, PIRRA, and NIRRA phenotypes. Results 122/1591 were excluded due to missing data. 247/1469 (16.8%) had D2T‐RA and only 40/1469 (2.7%) poly‐refractory RA. This latter group had higher DAS‐28‐CRP (median 5.4 vs 5.02, p<0.05), CRP levels (median 13 vs 5mg/l, p<0.01), and smoking (ever) rates (20% vs 4%, p<0.01) compared to other D2T patients. Smoking was associated with poly‐refractory RA (OR= 5.067, 95% CI [1.774‐14.472], p=0.002). Of 107 D2T‐RA patients with recent US, 61 (57%) were PIRRA and 46 (43%), NIRRA. NIRRA patients had elevated BMI (median 30 vs 26, p<0.001) and higher fibromyalgia prevalence (15% vs 3%, p<0.05), lower SJ count (median: 2 vs 5, p<0.001) and lower CRP levels (5 vs 10, p<0.01). Conclusion Only 2.7% of D2T‐RA failed all classes of b/tsDMARDs. Among D2T‐RA, under 60% had objective signs of inflammation, representing a target for innovative strategies. image