Hepatic Manifestations in Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome.

Abstract

Systemic juvenile idiopathic arthritis (sJIA) is a chronic inflammatory disease characterized by systemic features and arthritis. Macrophage activation syndrome (MAS) is a severe complication of sJIA often involving the liver. MAS confined predominantly to the liver, causing severe hepatitis, has been increasingly recognized. When liver MAS is the primary manifestation, significant hepatic injury can occur; therefore, differentiation from other forms of sJIA-related liver involvement, which may warrant distinct treatment approaches, is required. This study examined liver pathology in patients with sJIA-MAS and explored potential mechanisms. This retrospective case series analyzed data from 4 patients with sJIA-MAS who presented with liver dysfunction and underwent core liver biopsies at Cincinnati Children's Hospital Medical Center (2019-2024). Four patients (age range 4-15 years) had elevated transaminases, with 1 meeting MAS criteria and 3 diagnosed with subclinical MAS. Liver biopsies showed portal and sinusoidal inflammatory infiltrates of CD3+ CD8+ T cells and CD163+ macrophages, with extensive hepatocellular damage, including centrilobular parenchymal collapse, multifocal necrosis, and lymphocyte-mediated bile duct injury. One case revealed features of venoocclusive disease, a novel finding. Elevated serum chemokine (C-X-C motif) ligand 9 (CXCL9) and rapid response to emapalumab (anti-interferon γ [anti-IFN-γ]) in all patients suggested IFN-γ-driven liver pathology. This study underscores the critical roles of CD8+ T cells, macrophages, and IFN-γ in sJIA-MAS hepatitis. Future research should explore whether serum biomarkers of IFN-γ activity can differentiate sJIA-MAS from other liver pathologies, such as drug-induced liver injury (methotrexate- or anakinra-induced) and hepatic steatosis, to guide tailored therapies.