S4320 The Last Resort: A Case of Relapsing Autoimmune Hepatitis Responsive to Cyclophosphamide Salvage Therapy

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Introduction: Management of autoimmune hepatitis (AIH) is challenging for patients who either fail to respond or experience adverse effects with first line therapies. Existing literature is limited and demonstrates variable efficacy for salvage therapies. Here, we present a case of refractory AIH with sustained response to cyclophosphamide. Case Description/Methods: A 54-year-old woman with history of systemic lupus erythematosus on hydroxychloroquine and previously diagnosed AIH on mycophenolate mofetil, tacrolimus, and prednisone presented to the hospital due to worsening fatigue and rising liver tests. She was initially diagnosed with AIH 2 years prior with positive serologies (anti-smooth muscle antibody 1:160; immunoglobulin G 1948 mg/dL) and classic liver biopsy findings (Figure 1A/B). She had severe, refractory disease and had previously been treated with azathioprine and rituximab, in addition to the off label use of belimumab. Despite aggressive therapy, her liver tests continued to rise leading to her admission (Table 1). On arrival, her vital signs and physical exam were unremarkable. An extensive laboratory evaluation revealed total bilirubin 3.9 mg/dL, AST 480, ALT 207, alkaline phosphatase 199, and INR 1.38. Her total IgG was 2,178, and she tested negative for infectious etiologies (CMV, EBV, HIV, HBV, HCV, HAV). A repeat liver biopsy showed portal and lobular inflammation with severe interface activity and clusters of plasma cells highlighting sites of hepatocyte necrosis (Figure 1C/D), consistent with active AIH. The patient was treated with methylprednisolone for 2 days before initiating cyclophosphamide. She remained on stable doses of oral prednisone and tacrolimus, and her mycophenolate mofetil was replaced with 6-mercaptopurine. She completed an additional 5 cycles of cyclophosphamide at a dose of 1000mg per infusion. Follow-up at 1, 4, and 9 months demonstrated normalization of liver tests with gradual resolution of fatigue and her prednisone was able to be tapered (Table 1). Discussion: Cyclophosphamide for refractory AIH has not been previously described. Here we present a case of refractory AIH achieving remission following 6 cycles of cyclophosphamide therapy. At lower doses, cyclophosphamide’s role as an alkylating agent may drive AIH remission via downregulation of Th1 and cytotoxic T-cells leading to a reduction in pro-inflammatory cytokine release. Further evaluation into the role of cyclophosphamide for refractory AIH should be investigated.Figure 1.: A, C: Portal tract expansion with mononuclear inflammatory cell infiltrate (black arrows), and interface hepatitis (yellow arrows). B, D: Lobular inflammation with clusters of mononuclear inflammatory cells including plasma cells highlighting sites of hepatocyte necrosis (green arrows). Table 1. - Timeline of liver test fluctuations with initial diagnosis occurring in August 2021 and elevations in LFTs in June 2022, February 2023, and May 2023 requiring readmissions and up-titration of immunosuppressive medications Date Total Bilirubin Alkaline Phosphatase ALT AST Total IgG (If available) Immunosuppressive Regimen Aug-21 25.4 178 740 1377 1948 Prednisone 60 mg Daily Aug-21 4.8 93 63 34 Prednisone Taper (5 Week), Azathioprine 100 mg (new) Dec-21 0.6 134 123 225 Azathioprine 200 mg (increased) Mar-22 0.5 72 118 241 1800 Azathioprine 200 mg, Tacrolimus 1 mg BID (new) June-22 5.3 149 703 1045 2360 Readmission: Tacrolimus 1 mg BID, Prednisone Taper (40mg), Mycophenolate Mofetil 1000 mg BID (new) Aug-22 0.6 66 89 90 1400 Tacrolimus 1 mg BID, Prednisone Taper at 10mg daily, Mycophenolate Mofetil 1500 mg BID (increased) Dec-22 0.8 87 223 134 2000 Tacrolimus 1 mg BID, Mycophenolate Mofetil 1500 mg BID, Rituximab (new) Feb-23 4.4 128 341 522 2359 Readmission: methylprednisolone 60 mg IV → prednisone 40 mg daily → 20 mg on discharge (with taper), Tacrolimus 1 mg BID, Mycophenolate Mofetil 1500 mg BID. May-23 3.9 199 207 480 2178 Readmission: methylprednisolone 60 mg IV → prednisone 20 mg daily at discharge, tacrolimus 2 mg BID (increased), and cyclophosphamide 750 mg IV. June-23 1.6 151 201 214 Prednisone 20 mg daily, tacrolimus 2 mg BID, Cyclophosphamide 1000 mg IV (increased; administered every 4 weeks to complete 5 more doses) Aug-23 1.0 128 128 290 Prednisone 17.5 mg daily, tacrolimus 2 mg BID, cyclophosphamide 1000 mg IV every 4 weeks to complete 3 more doses Oct-23 0.7 135 88 98 Prednisone 17.5 mg daily, tacrolimus 2 mg BID, cyclophosphamide 1000 mg IV (last dose completed on 10/16/2024) Nov-23 0.8 116 60 65 Prednisone 17.5 mg daily, tacrolimus 2 mg BID, started 6MP 25 mg/day x14 days, then increased to 50 mg/day Feb-24 0.7 128 31 37 Prednisone 7.5 mg daily, tacrolimus 2 mg BID; 6MP 50 mg/day (new) April-24 0.5 95 32 51 Prednisone 5 mg daily, tacrolimus 2 mg BID, and 6MP 50 mg/day

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