Idiopathic multicentric Castleman disease as a model of cytokine-driven immune dysregulation: clinical and translational insights from real-world anti–IL-6 therapy

Idiopathic multicentric Castleman disease (iMCD) is a rare and heterogeneous inflammatory disorder characterized by systemic immune dysregulation, generalized lymphadenopathy, and multi-organ involvement. Dysregulated cytokine signaling, particularly involving interleukin-6 (IL-6), plays a central role in disease pathogenesis and represents a validated therapeutic target. Over the past decade, the introduction of IL-6–directed therapies has significantly improved clinical outcomes; however, data from routine clinical practice remain limited due to disease rarity. This doctoral thesis explores iMCD as a model of cytokine-driven immune dysregulation through an integrated clinical and translational approach. The first part provides a comprehensive overview of Castleman disease, focusing on biological mechanisms, immune pathways, and the evolution of therapeutic strategies. Particular emphasis is placed on IL-6 signaling and its translational relevance in guiding targeted treatment. The second part presents a retrospective, multicenter real-world study conducted within a regional hematology network in Italy, evaluating the effectiveness and safety of siltuximab as first-line therapy in patients with iMCD. Clinical outcomes were assessed using international consensus diagnostic and response criteria. The study demonstrates high response rates, durable disease control, favorable survival outcomes, and a pronounced steroid-sparing effect in a heterogeneous real-world population. Treatment was generally well tolerated, and long-term therapy was feasible in responding patients. Overall, this work confirms the central role of IL-6–directed therapy in the management of iMCD and highlights the value of real-world evidence in rare diseases. By integrating biological insights with clinical outcomes, this thesis underscores the importance of translational research frameworks and collaborative networks in improving diagnosis, treatment, and long-term management of cytokine-driven inflammatory disorders.