Tacrolimus and mycophenolate mofetil as second-line treatment in autoimmune hepatitis: Is the evidence of sufficient quality to develop recommendations?

Abstract

Background: The standard management of autoimmune hepatitis (AIH) is based on corticosteroids, alone or in combination with azathioprine. Second-line treatments are needed for patients who have refractory disease. However, high-quality data on the alternative management of AIH are scarce.

Aim: To evaluate the efficacy and safety of tacrolimus and mycophenolate mofetil (MMF) and the quality of evidence by using the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE).

Methods: A systematic review and meta-analysis of the available data were performed. We calculated pooled event rates for three outcome measures: Biochemical remission, adverse events, and mortality, with their corresponding 95% confidence intervals (CI).

Results: The pooled biochemical remission rate was 68.9% (95%CI: 60.4-76.2) for tacrolimus, and 59.6% (95%CI: 54.8-64.2) for MMF, and rates of adverse events were 25.5% (95%CI: 12.4-45.3) for tacrolimus and 24.1% (95%CI: 15.4-35.7) for MMF. The pooled mortality rate was estimated at 11.5% (95%CI: 7.1-18.1) for tacrolimus and 9.01% (95%CI: 6.2-12.8) for MMF. Pooled biochemical remission rates for tacrolimus and MMF in patients with intolerance to standard therapy were 56.6% (CI: 43.4-56.6) vs 73.5% (CI: 58.1-84.7), and among non-responders were 59.1% (CI: 48.7-68.8) vs 40.8% (CI: 32.3-50.0), respectively. Moreover, the overall quality assessments using GRADE proved to be very low for all our outcomes in both treatment groups.

Conclusion: Tacrolimus and MMF are in practice considered effective for patients with AIH who are non-responders or intolerant to first-line treatment, but we found no high-quality evidence to support this statement.

Keywords: Autoimmune hepatitis; Efficacy; Grading of Recommendations Assessment, Development and Evaluation approach; Meta-analysis; Second-line; Systematic review.

Figure 1

PRISMA flow diagram of the articles retrieved by systematic literature search. AIH: Autoimmune hepatitis.

Figure 2

Assessment of methodological quality (risk of bias) of articles identified in the systematic literature search and included in our meta-analysis.

Figure 3

The pooled event rate of biochemical remission in the tacrolimus group with risk of bias assessment per study. Heterogeneity: Q = 16.25, degree of freedom = 8 (P = 0.039); I² = 50.76%. Test for overall effect: Z = 4.21 (P < 0.0001). A: Failure to develop and apply appropriate eligibility criteria (inclusion of control population); B: Flawed measurement of both exposure and outcome; C: Failure to adequately control confounding; D: Incomplete follow-up. CI: Confidence interval.

Figure 4

The pooled event rate of biochemical remission in the mycophenolate mofetil group with risk of bias assessment per study. Heterogeneity: Q = 29.72, degree of freedom = 15 (P = 0.013); I² = 49.52%. Test for overall effect: Z = 3.85 (P = 0 < 0.0001). A: Failure to develop and apply appropriate eligibility criteria (inclusion of control population); B: Flawed measurement of both exposure and outcome; C: Failure to adequately control confounding; D: Incomplete follow-up. CI: Confidence interval.

Figure 5

The publication bias of included studies for biochemical remission in (A) tacrolimus and (B) mycophenolate mofetil groups.