Second-line tacrolimus and mycophenolate mofetil in difficult-to-treat autoimmune hepatitis

Abstract

Introduction:

Azathioprine with corticosteroids is the first-line treatment for patients with autoimmune hepatitis (AIH). However, around 20% of patients require treatment alternatives, and second-line therapy for AIH is less well defined due to a lack of randomized controlled trials. We evaluated the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy.

Methods:

We performed a retrospective analysis of second-line therapies with MMF or tacrolimus for patients with AIH. Biochemical parameters were collected at the change of therapy, after 6 and 12 months, and at the last follow-up.

Results:

In total, 84/455 (18%) patients with AIH required second-line therapies, and 59 patients received MMF (47 patients) or tacrolimus (12 patients). Complete biochemical remission was achieved at a similar proportion in the tacrolimus group compared with MMF after 12 months (70.0% vs. 51.7%). In the subgroup of patients with insufficient response to first-line therapy, the rate of complete biochemical remission after 12 months was 70% in the tacrolimus group and 31% in the MMF group. Patients in the tacrolimus group had a higher mean ALT values compared with the MMF group and a higher prevalence of cirrhosis at the start of second-line therapy (50% vs. 19.1%).

Conclusions:

MMF and tacrolimus are effective and well-tolerated second-line therapies for AIH and should be part of the individualized second-line treatment algorithm of AIH. A trial of MMF is warranted after failure of first-line therapy. However, tacrolimus seems to be a safe and effective second-line option in patients with more advanced and aggressive disease.

INTRODUCTION

Autoimmune hepatitis (AIH) is a chronic liver disease leading to cirrhosis and liver failure if treated inadequately. Immunosuppressive therapy consists of corticosteroids and azathioprine (AZA) as first-line treatment.¹,² Unfortunately, about 20% of patients remain refractory or intolerant to standard therapy.³,⁴ Randomized controlled trials evaluating second-line therapies in AIH are missing; thus, current recommendations rely on retrospective studies and expert consensus. Current guidelines suggest stratifying difficult-to-treat patients into those (i) intolerant or (ii) with insufficient response to AZA.¹,²,⁵ Mycophenolate mofetil (MMF) and tacrolimus (TAC) are used as alternatives in difficult-to-treat patients. The CAMARO trial compared the effectiveness of MMF versus AZA as first-line therapy, showing MMF to be equally effective in treatment-naïve AIH compared with AZA, with fewer adverse events.⁶ This raises the question of whether AZA and MMF should be used sequentially in difficult-to-treat AIH or if more potent immunosuppressive drugs, such as TAC, should be initiated after failure of one first-line drug. Especially in patients with insufficient response to first-line therapy, it is unclear if MMF has sufficient immunosuppressive potency.⁷ We aimed to assess MMF and TAC as second-line therapies in difficult-to-treat AIH to provide real-world evidence in this challenging population.

METHODS

Adult AIH patients treated at Charité—Universitätsmedizin Berlin, a German high-volume center, between 2007 and 2025, were retrospectively analyzed. The study complied with the Declaration of Helsinki and was approved by the local ethics committee (EA2/252/22). AIH was diagnosed according to current guidelines.¹,²,⁸ The primary endpoint was complete biochemical remission (normalization of AST, ALT, and IgG). Secondary endpoints included the safety of MMF and TAC, the need for concomitant steroid therapy, and the clinical outcome. Insufficient response was defined as failure to achieve complete remission after 6 months of optimized first-line therapy. Adverse events were documented by the treating physician by review of symptoms and collected from patients' charts; however, not systematically assessed.

RESULTS

In our cohort of adult AIH patients, 18% (84/455) required second-line therapies, of which 13% (59/455) received second-line treatment with MMF (47 patients) or TAC (12 patients) (Figures 1A, B). Baseline characteristics were similar between the 2 groups (Supplemental Table S1, http://links.lww.com/HC9/C265), with a higher rate of cirrhosis in the initial histology in the TAC group (33.3% vs. 6.4%). First-line therapy was discontinued in the MMF group in 51.1% due to adverse events (AE) and 44.7% due to insufficient response (IR). In the TAC group, all 12 patients stopped first-line treatment due to IR. In the MMF group, the mean prednisolone dose was 12.5 mg (IR) and 10 mg (AE), and the mean AZA dose was 125 mg (IR) and 100 mg (AE). In the TAC group, the mean prednisolone was 15 mg, and the mean AZA dose was 100 mg. At the start of second-line therapy, 50% of patients had cirrhosis in the TAC group compared with 19.1% in the MMF group (p=0.036) (Supplemental Table S1, http://links.lww.com/HC9/C265). Median aminotransferase levels at the start of second-line therapy were higher in the TAC group (TAC: median ALT 4.1 × ULN, AST 1.8 × ULN; MMF: ALT 1.6 × ULN, AST 1.3 × ULN) (Supplemental Table S1, http://links.lww.com/HC9/C265).

FIGURE 1.

(A) Sankey flow diagram of the therapeutic regimen in our AIH cohort. (B) Flowchart of patients treated with MMF or TAC according to the indication for second-line therapy. (C) Treatment response to second-line AIH treatment with MMF or TAC. Complete biochemical remission: normalization of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and immunoglobulin G (IgG). Insufficient response: no complete biochemical remission. MMF group all patients (left panel), only patients with IR (middle panel), and the TAC group (right panel). (D) Decrease ALT levels presented as upper limit of normal (ULN) during second-line AIH treatment with MMF (left panel) or TAC (right panel). AE: adverse events to first-line treatment; IR: insufficient response to first-line treatment. Abbreviations: AIH, autoimmune hepatitis; IR, insufficient response; MMF, mycophenolate mofetil; TAC, tacrolimus.

In the MMF group, the rate of complete biochemical remission was 45.5% (15/33) after 6 months, 51.7% (15/29) after 12 months, and 73.3% (22/30) at last follow-up (Figure 1C). In the TAC group, after 6 months, complete biochemical remission was observed in 36.4% (4/11) of patients, after 12 months in 70% (7/10), and in 71.4% (5/7) at last follow-up (Figure 1C). Normalization of aminotransferase levels occurred in 36% (4/11) at 6 months and 70% (7/10) at 12 months in the TAC group. In the MMF group, normalized aminotransferases were found in 54.5% (18/33) at 6 months and 55.2% (16/29) at 12 months. In the subgroup of patients that had liver cirrhosis (MMF: n=9, TAC: n=6), the rate of complete biochemical remission after 12 months was 50% in the TAC group and 16.7% in the MMF group.

Patients who received second-line therapies due to IR, after 6 months of treatment, both groups had a similar rate of response of 36%–38%. After 12 months, the rate of complete biochemical remission was lower in the MMF group at 31% compared with 70% in the TAC group and similar at last follow-up (69%–71%). The patients in the MMF group who ended first-line therapy due to adverse events (AE) showed complete biochemical remission rates of 52.6% (10/19) after 6 months, 67% (10/15) after 12 months, and 75% (12/16) at last follow-up.

Second-line treatment was initiated together with steroids in 90% of cases. After 12 months, concomitant steroid treatment was given in 56.5% (13/23) in the MMF group and 88.9% (8/9) in the TAC group. At last follow-up, 46.7% (14/30) in the MMF group and 71.4% (5/7) in the TAC group needed concomitant steroids (prednisolone dose: 2.5–7.5 mg/d). A total of 14/47 (29.8%) patients in the MMF group ended second-line therapy. The reasons for discontinuation were insufficient response (n=5), AE (n=5), remission (n=1), and 3 patients had other reasons. In the TAC group, 5 patients stopped second-line treatment, in 2 patients due to side effects (impaired renal function, n=1; fatigue, n=1) and 2 patients due to IR. A full list of reported AE is shown in Supplemental Table S2, http://links.lww.com/HC9/C266.

DISCUSSION

Difficult-to-treat patients contribute substantially to the disease burden of AIH,⁹ and require individualized therapy. It is unclear whether patients who do not respond to AZA should receive MMF or be escalated directly to a more potent agent such as TAC. In our cohort, both MMF and TAC achieved comparable rates of complete remission with a similar rate of adverse events. Notably, TAC-treated patients had a higher prevalence of cirrhosis and higher aminotransferase levels, suggesting the efficacy of TAC, particularly in more aggressive disease. In our study, both MMF and TAC were effective second-line options in AIH. Our findings support an initial trial of MMF after first-line failure with AZA, while highlighting TAC as a valuable option for patients with advanced or aggressive disease to prevent progression.

Supplementary Material

hc9-10-e0921-s001.docx ^{(20.6KB, docx)}

hc9-10-e0921-s002.docx ^{(18.2KB, docx)}