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Introduction: Dual targeted therapy (DTT) may represent a therapeutic option in refractory Still’s disease; however, structured evidence remains limited.

Methods: We report two pediatric cases and conducted a systematic review of published reports describing the concurrent use of more than one biologic and/or targeted synthetic disease modifying antirheumatic drug in Still’s disease. Pediatric-onset and adult-onset Still’s disease were analyzed as predefined subgroups.

Results: In addition to our two original DTT cases, we identified 23 further patients with refractory Still’s disease treated with DTT, yielding a total of 25 cases, including 16 pediatric-onset and 9 adult-onset cases, with a mean of 4.3 prior treatment lines. Clinical improvement was reported in 17/25 patients, with remission documented in 10/25. Macrophage activation syndrome (MAS) was a frequent complication (9/25) but appeared less frequent after DTT initiation. In all patients with available paired data, markers of systemic inflammation declined markedly. Steroid-free status at last follow-up was achieved more frequently in pediatric-onset disease (9/16) than in adult-onset disease (1/9). No serious adverse events (SAEs) were observed in children, whereas SAEs occurred in adults (2/9).

Conclusion: Dual targeted therapy appears effective in refractory Still’s disease, even after multiple treatment failures. The lower frequency of MAS after DTT initiation and the steroid-sparing effect highlight its clinical potential and support the rationale for simultaneous targeting of multiple inflammatory pathways. Fewer AEs and more favorable outcomes in pediatric-onset disease likely reflect differences in treatment strategies, comorbidity burden, and possibly underlying biology, underscoring the need for careful patient selection and prospective evaluation.

Disclosures: The authors declare no conflicts of interest and received no specific funding for this work. Written informed consent for publication of the case reports was obtained.