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.

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.

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.

Autoimmune hepatitis (AIH) is an immunoinflammatory chronic liver disease with dynamic and rather heterogeneous disease manifestations. A trend of increasing prevalence of AIH has been observed worldwide, along with a relative increase in the percentage of male patients. AIH is characterized and diagnosed based on serum biochemistry and liver histology: elevated aminotransferases and serum immunoglobulin G (IgG), the presence of serum anti-nuclear antibody or anti-smooth muscle antibody, and interface lympho-plasmacytic hepatitis. Clinical manifestations differ among disease subtypes with distinct time-frames, i.e., AIH with a chronic insidious onset, and acute-onset AIH (the diagnosis of which is often challenging due to the lack of typical serum findings). The absence of disease-specific biomarkers or histological findings may expand the disease phenotype into drug-induced AIH-like liver injury. Corticosteroids and azathioprine are recommended first-line treatments for AIH. The complete normalization of aminotransferases and serum IgG is an essential treatment response to ensure long-term overall survival. An incomplete response or intolerance to these drugs is considered an indication for second-line treatment, especially with mycophenolate mofetil. Life-long maintenance treatment is required for the majority of patients, but the few who achieve prolonged and stringent biochemical remission with lower alanine aminotransferase and IgG within the normal range may be able to discontinue the medications. In the future, the quality of life of AIH patients should be managed by personalized medicine, including the appropriate selection and dosing of first-line therapy and perhaps alternating with potential therapeutics, and the prediction of the success of treatment withdrawal.