**Background:** Acute liver failure (ALF) is a rare and potentially fatal complication of neonatal lupus erythematosus (NLE), caused by transplacental passage of maternal IgG antibodies against fetal liver antigens. No standardized treatment protocol exists for NLE-associated ALF. This case report describes a novel triple therapy protocol using exchange transfusion, intravenous immunoglobulin (IVIG), and steroids.
**Methods:** A full-term female infant was born to a primigravida mother with systemic lupus erythematosus and positive anti-Ro/SSA and anti-La/SSB antibodies. The mother had a lupus flare in the first trimester treated with 10 mg oral prednisone daily and stress dose steroids at delivery; azathioprine, hydroxychloroquine, and aspirin were continued during pregnancy. The infant received routine 1 mg intramuscular vitamin K after birth. On day of life (DOL) 5, screening electrocardiogram and echocardiogram were normal, but hypoalbuminemia and elevated transaminases were noted. On DOL 13, gastroenterology was consulted for cholestasis, worsening hepatitis, and persistent hypoalbuminemia. Infectious workup for herpes simplex virus, Epstein-Barr virus, cytomegalovirus, and HIV was negative. Creatine kinase, thyroid studies, cortisol, lactic acid, glucose, and abdominal ultrasound with Doppler were normal. On DOL 15, rheumatology confirmed cutaneous NLE (erythematous annular lesions on upper eyelids) and positive anti-Ro antibody (100 U/mL; negative anti-La). On DOL 18, ALF was diagnosed with INR 2.3, and an additional 5 mg subcutaneous vitamin K was given. On DOL 19, INR was 2.5 with elevated ferritin and normal ammonia. Liver biopsy was not performed to avoid delay. The patient was transferred to the intensive care unit. On DOL 20, she received double volume exchange transfusion using 500 mL of red blood cells constituted with fresh frozen plasma, followed by 1 g/kg IVIG and 2 mg/kg IV methylprednisolone. IV methylprednisolone was continued at 2 mg/kg daily. INR initially improved to 1.8 but rose to 2.1 on DOL 22, prompting a second dose of 1 g/kg IVIG. After improvement in bloodwork, wakefulness, and feeding, she was transferred to the acute care floor. On DOL 25, IV methylprednisolone was decreased to 1.5 mg/kg daily. She was transitioned to oral steroids on DOL 27 and weaned off by 2 months of life. She was discharged on DOL 29 on ursodiol and fat-soluble vitamins.
**Key Results:** Transaminases and INR normalized by DOL 29. Albumin normalized by DOL 55. Cholestasis resolved by DOL 74. Anti-Ro antibodies became undetectable 3 months after treatment. Cutaneous lesions resolved before the 3-month follow-up. A repeat abdominal ultrasound at 2 months was normal with no evidence of portal hypertension. The infant is currently healthy with no clinical concerns at 1 year of age. Laboratory values showed: total bilirubin peaked at 16.8 mg/dL on DOL 13 and decreased to 0.2 mg/dL by DOL 168; direct bilirubin peaked at 7.09 mg/dL on DOL 15 and fell to <0.20 mg/dL by DOL 111; AST peaked at 593 U/L on DOL 13 and normalized to 66 U/L by DOL 168; ALT peaked at 113 U/L on DOL 13 and normalized to 34 U/L by DOL 168; INR peaked at 2.5 on DOL 19 and normalized to 1.0 by DOL 74; albumin nadir was 1.7 g/dL on DOL 22 and normalized to 4.6 g/dL by DOL 168; anti-Ro antibody decreased from 100 U/mL on DOL 15 to <20 U/mL by DOL 168.
**Clinical Implications:** This case demonstrates that a triple therapy protocol of exchange transfusion, IVIG, and steroids can successfully treat ALF in NLE, leading to full recovery of liver function without sequelae. Given the high mortality reported in NLE-associated ALF (6 of 19 patients in a national registry died, with deaths occurring as early as DOL 6), the authors advocate for screening labs (ALT, total and direct bilirubin, INR, albumin, and anti-Ro antibodies) on DOL 1 in all neonates born to mothers with anti-Ro antibody autoimmune disease to enable early treatment. While further data are needed to generalize these results, this protocol offers a potential life-saving approach for a rare but devastating condition.