Loss of biochemical response at any time worsens outcomes in UDCA-treated patients with primary biliary cholangitis

Abstract

Background & aims: Biochemical response to ursodeoxycholic acid (UDCA) therapy is associated with good prognosis in people living with primary biliary cholangitis (PBC). Biochemical response is typically assessed early in disease and it is not known what proportion of patients lose previously attained biochemical response, nor whether this impacts long-term liver transplant (LT)-free survival.

Methods: We identified all UDCA-treated patients with PBC from the Canadian Network for Autoimmune Liver disease with biochemical measurements at 1 year, and evaluated their liver biochemistry over time. Inadequate biochemical response was defined as serum alkaline phosphatase ≥1.67x the upper limit of normal or abnormal serum total bilirubin at 1 year of UDCA therapy and all time points thereafter. Multistate Markov models were used to estimate transition rates between biochemical response states and from each state to LT or death. Results were validated in an external cohort (GLOBAL PBC registry).

Results: A total of 823 patients from eight centers were included. Mean age at diagnosis was 53 years, 91% were female, 33% had inadequate biochemical response to UDCA at 1 year (n = 269). Patients who retained initial adequate response had lower rates of LT or death compared to patients who subsequently lost response (relative rate 0.102, 95% CI 0.047-0.223). Patients who regained adequate response had lower rates than patients who did not (0.016, 95% CI 0.001-0.568), and patients who lost response once more (0.010, 95% CI 0.001-0.340). Patients who regained adequate response for a third time also had lower rates than patients who did not (0.151, 95% CI 0.040-0.566). Analyses in the GLOBAL PBC registry (n = 2,237) validated these results.

Conclusion: Loss of biochemical response at any time is associated with heightened risks of LT or death in people living with PBC. Achievement of biochemical response is an important goal throughout follow-up, regardless of biochemical response profile early in therapy.

Impact and implications: Early biochemical response to ursodeoxycholic acid is associated with good prognosis in patients with primary biliary cholangitis (PBC). Our work demonstrates that patients with PBC transition between biochemical response states over time, and that these transitions correspond with changes in risk of liver transplantation or death. Clinicians should re-evaluate risk and optimize treatment decisions for patients with PBC throughout follow-up, regardless of early biochemical response to therapy.

Keywords: UDCA; alkaline phosphatase; liver transplantation; prognostication; total bilirubin.

Graphical abstract

Fig. 1

Multistate model of the transitions between UDCA response states over time. This figure outlines biochemical response states through which patients progressively transition in the multistate model. Patients enter the model as IR-1 or AR-1 and progress through states sequentially or remain in a state if no change. Patients may transition to liver transplantation or death from any state at any point in time. For example, a patient with inadequate response at 1 year will begin as IR-1. This patient will transition to AR-1 when they achieve adequate response. This patient’s state will change to IR-2 if they transition back to inadequate response and will change to AR-2 if they achieve adequate response once again. The patient’s state will change to IR-3 if they transition back to inadequate response for a third time and will transition to AR-3 if they achieve adequate response for a third time. State changes beyond the fourth instance of inadequate response are absorbed into the IR-4+ state. We applied a composite endpoint of liver transplantation or death and patients without one of these two events were censored at last known date alive. Patients can transition to liver transplantation or death from any state at any point in time. AR-, adequate response; IR-, inadequate response; LT, liver transplantation; UDCA, ursodeoxycholic acid.

Fig. 2

Study flowchart for the original and validation cohorts. The same exclusion criteria were applied to both cohorts; exclusion criteria which resulted in 0 patients being excluded are not included in the figure for the validation cohort. Patients from Toronto were excluded from the validation cohort because they were present in the original cohort. AIH, autoimmune hepatitis; CaNAL, Canadian Network for Autoimmune Liver disease; GAVE, gastric antral vascular ectasia; GPBC, Global PBC Study group; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; HPS, hepatopulmonary syndrome; HRS, hepatorenal syndrome; LT, liver transplantation; PBC, primary biliary cholangitis; SBP, spontaneous bacterial peritonitis; UDCA, ursodeoxycholic acid.

Fig. 3

Estimated percentage of patients in each response state over time, whole cohort. Estimated percentage of patients in each response state over time in the main cohort, derived from the fitted transition probability matrix of the multistate model. Pie chart represents the breakdown of states at 5 years, corresponding to the dashed vertical line in the rectangular figure. The pie chart represents the 5-year values reported in the text. AR-, adequate response; IR-, inadequate response; LT, liver transplantation; UDCA, ursodeoxycholic acid.

Fig. 4

Estimated mean time spent in each state from 1 to 15 years after UDCA initiation, by UDCA response status at 1 year. Patients with inadequate response to UDCA at 1 year were estimated to remain in their IR-1 state for an additional mean of 3.4 years (95% CI 3.0-3.8). If these patients achieve adequate biochemical response, they were expected to retain this response and remain in AR-1 for 4.5 years (95% CI 4.1-4.9). Patients with adequate response at 1 year were estimated to remain in their AR-1 state for an additional 6.6 years (95% CI 6.1-7.0). A patient with inadequate response to UDCA at 1 year will enter the IR1 state, and any subsequent achievement of biochemical response moves them to the AR-1 state. A patient with adequate response to UDCA at 1 year will enter the AR-1 state, and any subsequent loss of response moves them to the IR-2 state. The time a patient is estimated to spend in each state was defined by the integral of the transition probability matrix from 1 to 15 years after UDCA initiation. AR-, adequate response; IR-, inadequate response; LT, liver transplant; UDCA, ursodeoxycholic acid.

Fig. 5

Over time, adequate response is always associated with better liver transplant-free survival. (A) Original cohort; (B) validation cohort. Clock-reset Kaplan Meier curves of survival probability from each UDCA response state. Follow-up time begins 1 year after UDCA initiation. Patients transition from one curve to the next at the time of their state change. Patients are censored at last date known alive or at the time of state change. Log-rank p <0.01 all pairwise comparisons to previous state. p values are corrected for multiple comparisons using the Benjamini-Hochberg method. AR-, adequate response; IR-, inadequate response; UDCA, ursodeoxycholic acid.