Understanding Difficult-to-Treat Axial Spondyloarthritis in Real-World Practice

Axial spondyloarthritis (axSpA) management has improved substantially with the introduction of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), including tumor necrosis factor inhibitors, IL-17 inhibitors, and JNK inhibitors.

However, even with these advances, a subset of patients continues to experience persistent disease activity despite exposure to multiple targeted therapies. That’s why the concept of difficult-to-treat (D2T) disease, previously established in rheumatoid arthritis, is increasingly being explored in axSpA to better understand this therapeutic challenge.

A multicenter cross-sectional study published in Clinical Rheumatology in February 2026 used the BioSTaR registry to provide large real-world insight into this population. Here’s a brief overview of its key findings.

Design and Methodology

The Biological and Targeted Synthetic Disease-Modifying Antirheumatic Drugs Registry (BioSTaR) is a nationwide Turkish database that prospectively collects standardized clinical and treatment information from patients with inflammatory rheumatic diseases receiving targeted therapies.

Investigators analyzed data from 1,800 adults with axSpA recorded between February 2019 and January 2025, all of whom had received at least one biologic or targeted synthetic DMARD and met the Assessment of SpondyloArthritis International Society classification criteria for axSpA.

Prevalence of Difficult-to-Treat Disease

Patients were classified as having D2T axSpA using an extrapolated definition requiring failure of multiple b/tsDMARDs together with ongoing disease activity and perceived management difficulty. Among the 1,800 patients included in the registry, 204 met these criteria, corresponding to a prevalence of 11.3 percent.

Within the BioSTaR cohort, TNF inhibitors such as adalimumab and etanercept were the most frequently used agents, reflecting their earlier regulatory approval and longer clinical use in Turkey.

Clinical Features Associated with D2T axSpA

Several disease characteristics distinguished patients with difficult-to-treat disease from those who responded more effectively to therapy. Disease duration was significantly longer in the D2T group, suggesting that prolonged inflammatory exposure may contribute to treatment complexity. Radiographic axSpA was also more common in these patients and was associated with a 2.37-fold increase in the risk of D2T disease in a multivariate analysis.

Additionally, markers of disease activity were consistently higher among patients with D2T axSpA. Both BASDAI and ASDAS-CRP scores were elevated compared with non-D2T patients, indicating greater inflammatory burden. Each one-point increase in ASDAS-CRP increased the likelihood of D2T disease by approximately 1.62-fold.

Peripheral disease manifestations also appeared more frequently. Enthesitis was significantly more common in the D2T group, and the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) was higher overall. Each incremental increase in MASES modestly increased the probability of difficult-to-treat disease.

Extra-Musculoskeletal Manifestations and Comorbidities

Extra-musculoskeletal manifestations were also evaluated, including psoriasis, uveitis, and inflammatory bowel disease. Among these, psoriasis showed the strongest association with treatment difficulty. Its presence increased the risk of D2T axSpA by approximately 3.6-fold in a multivariate analysis.

Cardiometabolic comorbidities were also more prevalent among patients with D2T disease. Hypertension and cardiovascular disease occurred significantly more frequently in the D2T group. Hypertension was identified as an independent risk factor, increasing the likelihood of D2T disease by nearly twofold. Obesity also emerged as a contributor, with a roughly twofold increase in risk in multivariate modeling.

These associations highlight the interaction between systemic inflammation and cardiometabolic health. Obesity-related inflammatory signaling and vascular inflammation associated with hypertension may amplify immune pathways involved in axSpA and potentially impair treatment response.

Clinical Implications

The BioSTaR analysis demonstrates that approximately one in nine patients with axSpA receiving targeted therapy may meet criteria for difficult-to-treat disease. This phenotype is associated with longer disease duration, radiographic disease, higher inflammatory activity, enthesitis, psoriasis, and cardiometabolic comorbidities.

Recognition of these patterns may help clinicians identify patients at risk for treatment resistance and guide a more comprehensive management approach. Careful assessment of comorbid conditions and extra-musculoskeletal disease domains remains important when treatment response is suboptimal, particularly as newer therapeutic options continue to expand the treatment landscape for axSpA.

Reference:
Bodur H, Ataman Ş, Yurdakul FG, et al. Prevalence and risk factors of difficult-to-treat axial spondyloarthritis: Real-life evidence from the BioSTaR database. Clin Rheumatol. 2026;45(2):945-956. doi:10.1007/s10067-026-07926-1