Abstract Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a hyperinflammatory condition with multi-organ involvement, particularly affecting the cardiac and gastrointestinal systems. Although immunomodulatory therapy is standard, treatment approaches vary. This study aimed to evaluate treatment modalities in MIS-C such as methylprednisolone (MP), intravenous immunoglobulin (IVIG), anakinra and therapeutic plasma exchange (TPE) based on clinical severity and laboratory parameters in a prospectively followed cohort. Methods A total of 125 MIS-C patients were included in the study and followed for at least 6 months after discharge. Patients were stratified by severity and treated with various immunomodulatory regimens, including IVIG+MP, IVIG+MP+anakinra, and IVIG+MP+anakinra+TPE. Results Patients with mild disease and low inflammatory markers (median CRP 9 mg/dL, ferritin 192 µg/dL) received IVIG+MP. Those with higher inflammation (CRP 20–24 mg/dL, ferritin 308–846 µg/dL) without cardio-pulmonary support were treated with IVIG+low-dose-MP+anakinra. Patients with shock, macrophage activation syndrome, or bicytopenia received IVIG+high-dose-MP+anakinra. TPE was added in cases requiring cardio-pulmonary support. Most were discharged without corticosteroids or anakinra; only 11% received a short outpatient prednisolone taper. Conclusion The mid-term longitudinal assessment of MIS-C patients suggests that timely immunomodulatory therapies, guided by laboratory parameters, promote safe resolution of systemic inflammation and cardiac complications, and shorten treatment duration. Impact

Demonstrates that short-term, biomarker-guided use of anakinra and corticosteroids effectively controls hyperinflammation in MIS-C.

Highlights that prolonged corticosteroid therapy may not be necessary, even in severe cases.

Provides evidence of early cardiac recovery, including resolution of CAAs, without post-discharge steroids.

Supports a steroid-sparing treatment approach, reducing risks of long-term immunosuppression.

May inform future MIS-C treatment guidelines by minimizing the need for escalation therapy, ECMO, and related complications.