This study examines how synovial monocytes contribute to persistent inflammation in childhood-onset arthritis. Patient samples, cellular experiments and computational analyses were combined to investigate the effects of inflammatory signalling and interactions with synovial fibroblasts. The results implicate the IL-6/JAK/STAT pathway and cell–cell contact in shaping monocyte behaviour. Analyses of synovial signalling and circulating inflammatory markers, including clustering and random-forest methods, connect the experimental findings to variation between patients. The work illustrates how clinical observations, immunology and statistical learning can inform one another when investigating disease mechanisms and potential therapeutic targets.