Nature Reviews Rheumatology, Published online: 25 June 2025; doi:10.1038/s41584-025-01278-xOver the past decades, considerable progress has been made in the pharmacological treatment of immune-mediated joint diseases such as rheumatoid arthritis and psoriatic arthritis; however, treatment-resistant arthritis remains a major clinical challenge. To tackle insufficient treatment outcomes, further research into the underlying mechanisms and patterns of non-responsiveness is needed.