Prevalence and clinical factors associated with difficult-to-manage axial spondyloarthritis: a multicentre Italian cohort study with meta-analysis

Background: The concept of difficult-to-manage axial spondyloarthritis (D2M-axSpA) has recently been introduced to describe patients with a persistent disease burden despite appropriate treatment. However, its real-world prevalence and associated clinical features remain insufficiently characterised. Objective: To estimate the prevalence of D2M and treatment-refractory (TR) axSpA in routine clinical practice, identify factors associated with D2M, and assess the consistency of selected D2M-associated features across different cohorts. Design and methods: A cross-sectional study was conducted in 252 patients with axSpA from two Italian tertiary centres. The 2024 Assessment of Spondyloarthritis International Society consensus-based definition was applied to identify D2M and TR axSpA. Clinical, laboratory and imaging characteristics were compared between D2M and non-D2M patients. Factors independently associated with D2M were evaluated using multivariable logistic regression. To explore consistency across populations, an exploratory meta-analysis was performed using harmonised data from the published Argentinian Reuma-Check cohort. Results: Among 252 patients with axSpA, 16 (6.3%) fulfilled the definition of D2M, and 8 (3.2%) met criteria for TR axSpA. Patients with D2M exhibited higher disease activity (Axial Spondyloarthritis Disease Activity Score 2.50 ± 0.62 vs 1.24 ± 0.65; p < 0.001), greater axial pain (2.50 ± 2.75 vs 0.80 ± 1.63; p = 0.017) and worse global assessments (Patient Global Assessment 3.20 vs 1.16; p < 0.001). In multivariable analysis, fibromyalgia (odds ratios (OR) 5.5, 95% confidence interval (CI): 1.2–25.6) and a history of uveitis (OR 3.3, 95% CI: 1.0–11.1) were independently associated with D2M status. Current nonsteroidal anti-inflammatory drug (NSAID) use (OR 3.8, 95% CI: 1.2–11.9) was also associated with D2M, most likely reflecting higher symptom burden rather than a causal relationship. Meta-analytic findings identified psoriasis (risk ratios (RR) 2.17; p = 0.008), smoking (RR 1.53; p = 0.045), uveitis (RR 2.45; p = 0.044) and radiographic structural damage (RR 1.84; p = 0.004) as consistent features associated with D2M axSpA. Conclusion: D2M axSpA was identified in approximately 6.3% of patients, while 3.2% fulfilled criteria for TR axSpA. Fibromyalgia, NSAID use and uveitis were independently associated with the D2M phenotype, whereas meta-analytic evidence highlighted additional associations with psoriasis, smoking and structural damage. These findings support the multifactorial nature of D2M axSpA, in which both inflammatory and non-inflammatory mechanisms contribute to disease complexity.