Abstract Introduction Systemic inflammation in children with sickle cell disease (SCD) presents diagnostic challenges, as overlapping features of vaso-occlusive crises, infection, and potential autoinflammatory processes can be difficult to distinguish. We report a 3-year-old boy with SCD (HbSS) who developed prolonged systemic inflammation and culture-negative arthritis, ultimately managed as a systemic juvenile idiopathic arthritis (sJIA)-like disease. Diagnostic uncertainty required close multidisciplinary team…