N Hadzic et al. NEJM 2024; 390: 284-286.JAK Inhibition in STAT1 Gain-of-Function–Mediated Treatment-Resistant Autoimmune Hepatitis

In this case report, the authors describe a 21 month old who presented with jaundice and abnormal liver tests. Diagnostic evaluation identified high titers of LKM antibodies (1:10,520) along with liver biopsy findings consistent with type 2 autoimmune hepatitis (AIH). After 6 months of treatment with steroids and subsequently azathioprine, the patient continued with severe biochemical relapses and a liver biopsy showed only a partial response.

Subsequently, “genetic testing found the patient had a heterozygous c.821G→A p.(Arg274Gln) pathogenic variant in the gene encoding signal transducer and activator of transcription 1 (STAT1)… Functional assays in the patient repeatedly showed abnormally high STAT1 phosphorylation as compared with healthy controls; this confirmed an autosomal dominant STAT1 gain-of-function defect.”

Treatment with “baricitinib, an inhibitor of Janus kinase 1 (JAK1) and 2 (JAK2), was started. Within weeks, the patient’s aminotransferase levels normalized. ..A liver-biopsy sample that was obtained 4 months after the initiation of baricitinib therapy showed an absence of appreciable inflammation with residual mild fibrosis…She was weaned off mycophenolate and is continuing to receive daily baricitinib (8 mg) and prednisolone (2.5 mg) along with fluconazole and azithromycin for infection prophylaxis.”

My take: In children with refractory autoimmune hepatitis, genetic testing is worthwhile and may allow targeted therapy.

Related blog posts:

• Slim Pickings: Data for 2nd-Line Autoimmune Hepatitis Pediatric Therapy
• Online Aspen Webinar -COVID-19, Autoimmune Hepatitis (Part 8)
• Patterns and Puzzles with VEO-IBD This is a very good review and the image on this day has one of my favorite patient t-shirts. STAT gain-of-function defects can cause VEO-IBD picture as well.
• Autoimmune Hepatitis -Early Response Associated with Remission
• Autoimmune Hepatitis: Safety of Low Dose Steroids and Utility of Aminotransferases
• Predicting Outcomes in Childhood Autoimmune Hepatitis
• Why It Is Hard to Stop Immunosuppression with Autoimmune Hepatitis and Lower Bone Density with Fatty Livers
• Is It a Mistake to Use Budesonide for Autoimmune Hepatitis?