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Review
. 2025 Jan;31(1):90-104.
doi: 10.3350/cmh.2024.0821. Epub 2024 Nov 11.

Hard-to-treat autoimmune hepatitis and primary biliary cholangitis: The dawn of a new era of pharmacological treatment

Atsumasa Komori  1   2   3 , Yuki Kugiyama  2
Affiliations
Review

Hard-to-treat autoimmune hepatitis and primary biliary cholangitis: The dawn of a new era of pharmacological treatment

Atsumasa Komori et al. Clin Mol Hepatol. 2025 Jan.

Abstract

Patients with hard-to-treat autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) are defined a posteriori as those who do not show a sufficient response or are intolerant to pharmacological treatments, thus not achieving biochemical surrogate endpoints that are associated with long-term liver-related-event-free survival. The absence of a recently harmonized definition of 'complete biochemical response within 6 months (CBR≤6M)', which is defined as the normalization of serum transaminase and IgG levels below the upper limit of normal at ≤6 months after treatment initiation, is regarded as hard-to-treat AIH. The implementation of CBR≤6M, in turn, has been facilitating clinical trials, e.g., between azathioprine and mycophenolate mofetil, to reconsider appropriate first-line steroid sparing agents, leading to a reduction in the number of hard-to-treat AIH cases. Regarding PBC, one of the disseminated definitions of hard-to-treat patients is the absence of POISE criteria, which are evaluated at 12 months with serum alkaline phosphatase and bilirubin levels, after the introduction of ursodeoxycholic acid. Hard-to-treat PBC not meeting the POISE criteria has very recently been the target population for the U.S. FDA-approved second-line drugs, elafibranor and seladelpar. In future pharmacological treatment of AIH and PBC, the primary objective for AIH is likely to focus on lowering the number of hard-to-treat patients with personalized steroid sparing treatment regimens. A challenging goal in PBC treatment is the further optimization of treatment surrogate endpoints, even to the stricter alkaline phosphatase normalization, with which an indication of second- or later-line drugs might be expanded, but could ultimately lengthen patients' long-term survival.

Keywords: Autoimmune hepatitis; Primary biliary cholangitis; Treatment.

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Conflict of interest statement

Conflicts of Interest

A. Komori received grants as an investigator for clinical trials sponsored by GSK and Kowa Company and speaker and consulting honoraria from GSK and Kowa Company. There is no conflict of interest in Y. Kugiyama.

Figures

Figure 1.
Figure 1.
Future treatment strategies for hard-to-treat PBC from the “wait to fail approach” to the “personalized risk-stratifying approach”. LSM, liver stiffness measurement; PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid.
See this image and copyright information in PMC

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