Rapid Clinical Resolution in Patients with Indeterminate Pediatric Liver Failure and Immune Dysregulation Hepatitis Treated with Ruxolitinib

Abstract

IntroductionIndeterminate pediatric acute liver failure (iPALF) is a rare, life-threatening diagnosis associated with high rates of liver transplant and reduced survival. Immune dysregulation hepatitis shares many of the same clinical features as iPALF but is defined by an INR ≤ 1.5. Both present with progressive new-onset hepatocellular injury with predominant cytotoxic T-cell mediated inflammation and diffuse cytokine release. Importantly, the optimal medical therapy for these conditions of severe hepatic injury is not known. Here, we present two pediatric cases of steroid-refractory liver dysfunction where use of ruxolitinib, a JAK-STAT pathway inhibitor, led to significant clinical improvement. Case DescriptionsA 12-year-old male (patient A) presented with iPALF, while a 7-year-old female (patient B) presented with immune dysregulation hepatitis. Both patients had coagulopathy, transaminitis and hyperbilirubinemia (Table 1). Ischemia, toxin exposure, autoimmune hepatitis, and infection screens were negative. Immune evaluation demonstrated significantly elevated soluble IL-2 receptor, CXCL9, and sCD163, with mild hyperferritinemia (Table 1). Patient B had IgM EBV antibodies on repeat testing, which may have contributed to her immune dysregulation. Each patient’s next generation sequencing for inborn errors of immunity were negative. Both liver biopsies revealed a cytotoxic T-cell infiltrate, activated Kupffer cells, absence of iron, and absent plasma cell activity. During initial management, patient A received methylprednisolone 2 mg/kg daily, while patient B received 10 mg/kg daily before weaning to 2 mg/kg daily. Steroid-refractory disease was highlighted by ongoing liver damage on serial labs with worsening jaundice and fatigue. Both patients were transitioned to JAK-STAT inhibition with ruxolitinib. Patient A was loaded with 10 mg BID for one week before transitioning to 5 mg BID for 3 months, while patient B started and remained on 5 mg BID for 4 months. Both patients experienced rapid clinical improvement within one week and normalization of immune dysregulation on serial lab work by one month without need for further invasive interventions. Therapy was well tolerated without infectious or thrombotic complications.Table 1Maximum lab values prior to ruxolitinib initiationSoluble IL-2R (175.3–858.2 pg/mL)CXCL9 (< = 647 pg/mL)sCD163(<991 ng/mL)Ferritin (7–271 ng/mL)INRAST (< =60 U/L)ALT (10–49 U/L)Total Bilirubin (0.2–1.0 mg/dL)Patient A8664199731 0965971.62226275815.6Patient B243615 41881994291.43010228411.4Table 1. (abstract: 96) Selected laboratory test results. Values below or above reference are indicated with blue and red respectively. Not shown: IL-2, IL-4, IL-5, IL-8, IL-12, IL-13, IL-17 were normal. Fecal blood testing at baseline was negative. T cell memory population percentages were normal. T cell proliferation studies were normal. Pre-SCIG = pre-subcutaneous IgG (SCIG) treatment. Post-SCIG = post-SCIG treatment sample obtained after ~4 months of SCIG. n/a = sample not available. ConclusionThese cases suggest in iPALF and severe acute hepatitis where immune dysregulation is present, JAK-STAT inhibition may have benefit and deserves consideration for preventing disease progression and reducing morbidity and mortality.