Difficult-to- manage and treatment refractory axial Spondyloarthritis: Systematic review and meta-analysis of prevalence and determinants.

This systematic review and meta-analysis synthesized evidence on the prevalence and determinants of difficult-to-manage (D2M) and treatment-refractory (TR) axial spondyloarthritis (axSpA). A comprehensive literature search (PubMed/MEDLINE, Embase, Scopus, Web of Science, Cochrane Library) identified studies published from inception to August 2026. ASAS-aligned studies requiring failure of ≥2 b/tsDMARDs with different mechanisms plus persistent disease activity were included. Random-effects meta-analyses pooled prevalence estimates, odds ratios (ORs) for binary determinants, and standardized mean differences (SMDs) for continuous measures. Among 11 ASAS-aligned studies (5648 patients), pooled D2M-axSpA prevalence was 10.1% (95% CI 8.2-11.8%; I2 = 66%), with prospective multicenter studies yielding a stable estimate of 9-10%. Fibromyalgia was most strongly associated with D2M status (OR 3.32 [95% CI 1.93-5.72]), followed by HLA-B27 positivity (OR 1.74 [1.33-2.28]) and smoking (OR 1.31 [1.13-1.51]). Female sex showed no significant association (OR 1.42 [0.93-2.18]; I2 = 75.7%). Higher baseline BASDAI scores were observed in D2M patients; associations with age and disease duration were inconsistent. Extra-musculoskeletal manifestations showed non-significant trends. D2M-axSpA affects approximately one in ten patients, with true treatment-refractory disease representing a smaller subset. Fibromyalgia, smoking, and HLA-B27 positivity emerged as key associated factors, though cross-sectional designs preclude causal inference. These findings support the distinction between inflammatory and non-inflammatory mechanisms of persistent disease burden to guide clinical management.