Inadequate response to UDCA among PBC patients under routine care in the US: Rising serum bilirubin even in the normal range is a risk factor and subsequent clinical follow-up differs based on treatment response
Gordon SC, Zhang T, Bowlus CL, Lindor KD, Romanelli RJ, Haller IV, Anderson H, Vanwormer JJ, Boscarino JA, Schmidt MA, Daida YG, Sahota A, Vincent J, Wu KH, Trudeau S, Melkonian C, Rupp LB, and Lu M. Inadequate response to UDCA among PBC patients under routine care in the US: Rising serum bilirubin even in the normal range is a risk factor and subsequent clinical follow-up differs based on treatment response J Hepatol 2019; 70(1):e393-e394.
Background and aims: Ursodeoxycholic acid (UDCA)is a first line treatment in patients with primary biliary cholangitis (PBC)that is often followed by second-line therapy if there is inadequate response (IR). Previous analyses by the Fibrotic Liver Disease Consortium showed that pre-treatment total bilirubin, even within the normal range, is associated with increased risk of mortality. In the present study, we analyzed the effect of pre-treatment bilirubin and other covariates associated with the risk of IR, and compared follow-up care between patients with/without IR. Method: Baseline data were collected for PBC patients at time of UDCA initiation between 2006 and 2015. Total bilirubin was categorized as > 2, 2 > 1.5, 1.5 > 1.0, 1.0 > 0.7, 0.7 > 0.4, and ≤ 0.4 mg/dL. IR was defined using Paris II criteria 12 months after UDCA initiation. Logistic regression was used to estimate the adjusted risk for IR; model accuracy was assessed using area under the receiver operator characteristic curve (AUROC). Z-statistic was used to compare rates of follow-up care and treatment modification per person-year (PPY)between IR and non-IR patients. Results: Among 1578 UDCA treated patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander (ASINPI); 25% Hispanic), 706 (45%)had IR to UDCA at 12 months post-baseline. The multivariate model (AUROC = 0.79)showed that younger age, increasing alkaline phosphatase (ALP), low albumin, and a ratio of aspartate to alanine aminotransferase (AST/ALT)> 1.1 were independently associated with an increased risk of IR. Bilirubin—even in the high-normal (1.0 > 0.7)and mid-normal (0.7 > 0.4 mg/dL)ranges—was also significantly associated with increased risk of IR compared to low-normal levels (≤ 0.4 mg/dL; Figure). A sensitivity analysis that defined IR as ALp > 1.67xULN yielded similar results. Compared to responders, patients with IR were more likely to: discontinue UDCA (0.08 vs 0.04 PPY; p < 0.01); add obeticholic acid (0.023 vs 0.004 PPY; p < 0.01); and were more likely to see a specialist (5.12 vs 3.16 visits PPY; p < 0.01), undergo liver imaging (1.23 vs 0.56 tests PPY; p < 0.01), have liver-related laboratory testing (18.4 vs 10.2 tests PPY; p < 0.01), be hospitalized (0.11 vs 0.07 PPY; p < 0.01), and seek emergency care (0.13 vs 0.08 PPY; p < 0.01). Conclusion: Almost half of PBC patients (45%)in a routine clinical care cohort showed IR to UDCA. Baseline bilirubin > 0.4 mg/dL is associated with increasing risk of IR. Patients with IR had higher rates of specialist follow-up and health care utilization.