Clinical bottom line
Refractory enthesitis in axial spondyloarthritis (axSpA) remains a challenging clinical problem despite advances in biologic and targeted synthetic therapies. Emerging novel agents, including selective cytokine inhibitors and small molecules, show promise in reducing enthesitis severity and improving patient function, but evidence is still evolving. Imaging modalities such as ultrasound and MRI enhance detection and monitoring of enthesitis, supporting more tailored treatment approaches. Clinicians should consider novel therapies as adjuncts for patients with persistent enthesitis despite conventional biologics, while balancing efficacy with safety and cost-effectiveness.
What the evidence shows
Enthesitis, inflammation at tendon and ligament insertion sites, is a hallmark of axSpA and contributes significantly to pain and disability (Terlemez et al., 2021). Traditional biologics targeting tumor necrosis factor (TNF) have improved outcomes but some patients remain refractory, necessitating novel therapeutic options (Bittar et al., 2022). Recent reviews highlight emerging therapies targeting interleukin (IL)-17, IL-23, and Janus kinase (JAK) pathways as promising candidates for refractory enthesitis management (Dzhus et al., 2025; Bittar et al., 2022).
Imaging studies have advanced understanding of enthesitis distribution and severity. Radiographic and ultrasound assessments reveal trochanteric and pelvic enthesitis correlating with mobility impairment and disease activity (Akyıldız et al., 2025; ARP Rheumatology, 2026). Ultrasonography is particularly useful in non-radiographic axSpA for early enthesitis detection, guiding timely therapy escalation (Ozsoy-Unubol et al., 2018). However, imaging findings can lack specificity, as chronic changes may persist despite clinical remission (Braun et al., 2018).
Novel IL-17 inhibitors have demonstrated efficacy in reducing enthesitis scores and improving function in axSpA patients refractory to TNF inhibitors (Bittar et al., 2022). IL-23 blockade is under investigation, with preliminary data suggesting potential benefits but requiring further validation (Dzhus et al., 2025). JAK inhibitors offer oral administration convenience and have shown promise in controlling enthesitis and overall disease activity, though long-term safety data remain limited (Bittar et al., 2022).
Cost-effectiveness analyses emphasize the need for algorithmic screening and targeted therapy deployment to optimize resource use while maximizing patient benefit (Hodinka et al., 2018). Personalized treatment strategies incorporating clinical, imaging, and biomarker data may enhance outcomes in refractory enthesitis.
Caveats and uncertainty
Current evidence is limited by heterogeneity in enthesitis assessment methods, small sample sizes, and short follow-up durations in many studies. Imaging modalities, while sensitive, may detect subclinical changes of uncertain clinical relevance, complicating treatment decisions (Braun et al., 2018). The relative efficacy of novel agents specifically for enthesitis versus overall axSpA symptoms requires further clarification.
Long-term safety profiles of newer therapies, particularly JAK inhibitors, warrant ongoing surveillance given emerging concerns in other inflammatory diseases. Economic evaluations are often region-specific and may not generalize globally. Additionally, the interplay between enthesitis and other axSpA manifestations such as sacroiliitis and spondylitis complicates attribution of treatment effects.
How this may change practice
Clinicians managing axSpA patients with refractory enthesitis should consider integrating advanced imaging techniques like ultrasound to improve diagnostic accuracy and monitor therapeutic response. Novel biologics targeting IL-17 and emerging small molecules such as JAK inhibitors represent viable options when TNF inhibitors fail, though patient selection should be individualized.
Incorporating algorithmic screening tools may facilitate early identification of refractory enthesitis and optimize treatment sequencing. Multidisciplinary care involving rheumatologists, radiologists, and physiotherapists can enhance functional outcomes. Continued appraisal of evolving evidence and safety data is essential to refine therapeutic strategies.