Calcineurin Inhibitors in the Treatment of Adult Autoimmune Hepatitis: A Systematic Review

Abstract

Background and Aims:A considerable number of autoimmune hepatitis (AIH) patients completely or partially fail on first-line treatment. Several studies on the use of calcineurin inhibitors (CNIs) in the treatment of AIH have been published without focusing on indication. The aim was to assess the efficacy of CNIs in the treatment of adult AIH patients, specifically focusing on indication: first-line intolerant and with first-line insufficient response (failure to achieve or maintain remission), and with second versus third-line treatment. Methods: A literature search included studies on the use of CNIs in adult AIH. Patients with past or present use of CNIs from the Dutch AIH group cohort were added. The primary endpoint was biochemical remission while using CNIs. Secondary endpoints were biochemical response, treatment failure, and adverse effects. Results: Twenty studies from the literature and nine Dutch patients were included describing the use of cyclosporine in 59 and tacrolimus in 219 adult AIH patients. The CNI remission rate was 53% in patients with insufficient response to first-line treatment and 67% in patients intolerant to first-line treatment. CNIs were used as second-line treatment in 73% with a remission rate of 52% and as third-line treatment in 22% with a remission rate of 26%. Cyclosporine was discontinued in 13% and tacrolimus in 11% of patients because of adverse events. Conclusions: CNIs as rescue treatment in adult AIH patients are reasonably effective and safe both with insufficient response or intolerance to previous treatment. Prospective studies are needed.

Tacrolimus versus mycophenolate for autoimmune hepatitis patients with incomplete response on first line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial

“…To our knowledge this is the rst interventional study comparing two frequently used second-line therapies (albeit off-label) for AIH. Several retrospective studies have demonstrated a bene cial effect of both treatment strategies in patients with AIH and intolerance to azathioprine or for incomplete CR [14,[17][18][19][20][21][22][23][24][25][26]28]. Both drugs are registered and extensively used for the prevention of graft rejection in transplant recipients.…”

“…They studied the use of TAC for induction treatment of AIH and found a decrease of ALT in 80% of the patients. In several subsequently (relatively) small case series TAC was given as second line therapy for AIH, whereas remission rates differed between 20-92% [14,[17][18][19][20][21][22].…”

Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial

“…They studied the use of TAC for induction treatment of AIH and found a decrease in ALT in 80% of the patients. In several subsequent (relatively) small case series, TAC was given as second-line therapy for AIH, whereas remission rates differed between 20 and 92% [ 14 , 17 – 22 ].…”

“…The expected difference between groups was formulated in terms of relative risk derived from the expected cumulative incidences in the two groups according to previous literature. Papers on MMF for insufficient response in EU and North America reported 13%, 21% and 34% CR respectively, and review of the literature on TAC in adult AIH patients was also taken into account [ 22 , 23 , 25 , 36 ]. Assuming proportions of CR at the end of follow-up of 0.22 in the MMF group and 0.53 in the TAC group with a two-sided α of 0.05 significance level and power of 1 − β = 0.8 to determine the difference in proportions of 0.31, results, in N = 38 patients per group.…”

Recent advances in the diagnosis and management of autoimmune hepatitis

“…In contrast, AASLD guidelines support the use of tacrolimus or MMF as second-line treatment even though this recommendation was based mainly on a retrospective trial including very heterogeneous groups of AIH patients with not well-defined follow-up data who treated with various agents including tacrolimus [3,95]. Indeed, there are several similar published studies which have shown that calcineurin inhibitors (CNIs) are quite effective but strict monitoring is required due to their small therapeutic window resulting in significant toxicity in the long-term in about 25-55% of patients (neurotoxicity, renal injury, hypertension, diabetes, hyperlipidemia, and secondary malignancies) [96][97][98][99]. The net conclusion from these inconsistencies is that we need randomized-controlled trials to draw safe general conclusions on the use of 6-MP and CNIs in AIH patients with insufficient response and/or intolerance.…”