Treatment of Refractory Pediatric Autoimmune Hepatitis With Rituximab

**Background:** Autoimmune hepatitis (AIH) is a progressive inflammatory liver disorder characterized by elevated aminotransferases, hypergammaglobulinemia, autoantibodies, and interface hepatitis on histology. Standard immunosuppression with steroids and azathioprine induces biochemical remission in 80%–90% of patients, but 10%–20% are refractory. Refractory disease can progress to cirrhosis and end-stage liver disease requiring transplantation. While AIH is predominantly T cell-mediated, evidence supports a key role for B cells. Rituximab, a monoclonal antibody against CD20, has been used successfully in adults with refractory AIH, but pediatric experience is limited to one prior report of two patients. This case series reports two additional pediatric patients treated with rituximab for refractory AIH.

**Methods:** This is a retrospective case series of two pediatric patients with refractory AIH treated at a single center. Patient 1 was a 5-year-old female with morphea and vitiligo who presented with elevated aminotransferases, jaundice, and fever. Antinuclear antibody titer was 1:5120 and liver–kidney microsomal antibody titer was >1:10,240. Liver biopsy showed active chronic hepatitis with patchy bridging necrosis consistent with AIH type 2. She was initially treated with prednisone and azathioprine and achieved clinical remission, but had persistent elevation of aminotransferases and biopsy-proven active AIH (grade II, stage II) despite 6 weeks of prednisone 1 mg/kg/day. She was then treated with rituximab 375 mg/m² followed by 1 g/kg IVIG. Patient 2 was an 18-year-old female with steroid-dependent AIH and arthritis diagnosed in 2015. She was initially treated with high-dose prednisone and azathioprine but never achieved biochemical remission. Mycophenolate mofetil was added, but she had recurrent flares. Azathioprine was discontinued and tacrolimus started with brief normalization before another flare. Liver biopsy showed chronic hepatitis with grade IV, stage III AIH. She was switched to sirolimus but could not wean below 20 mg prednisone daily due to persistently elevated aminotransferases. She was then treated with rituximab 375 mg/m² followed by 1 g/kg IVIG. Dosing intervals for rituximab were based on laboratory trends (aminotransferases and CD19 counts).

**Key Results:** Patient 1 demonstrated good response with near normalization of aminotransferases after rituximab initiation. Despite B-cell repletion, dramatic reduction in aminotransferases continued, and repeat rituximab doses were administered based on laboratory trends. After remission, she continued to receive rituximab and IVIG infusions every 6–8 months based on aminotransferases and CD19 counts. Since starting rituximab 5 years ago, her AIH has remained well-controlled. Patient 2 received four rituximab and IVIG infusions over the first year. Her aminotransferases markedly improved, and she exhibited improved energy levels and reduced joint pain. At follow-up, she remains on maintenance with rituximab, adjunctive sirolimus, and low-dose prednisone (7.5 mg daily) and has not required admission for a disease flare in the year and a half since starting rituximab. No adverse events were reported in either patient.

**Clinical Implications:** This case series adds to the limited pediatric experience with rituximab for refractory AIH. Both patients showed significant improvement in liver enzymes and clinical symptoms without adverse events, supporting rituximab as a salvage therapy for children with AIH that does not respond to standard immunosuppression. The findings underscore the important role of B cells in AIH pathogenesis and suggest that B-cell depletion may be an effective treatment strategy. Given that 10%–20% of patients are refractory to standard therapies and 10%–15% will develop end-stage liver disease requiring transplantation, alternative treatment modalities are critical. Furthermore, 14%–44% of patients with AIH have additional autoimmune comorbidities, and these patients may represent a more difficult-to-treat subgroup that could benefit from B-cell depleting therapies. Although rituximab has not yet been endorsed as second-line therapy in AIH, this report demonstrates efficacy without adverse events with dosing interval based on laboratory parameters. Further studies are needed to define the efficacy of B-cell modulation in AIH and develop new treatment strategies.