Real-World Clinical Management of Patients with Primary Biliary Cholangitis-A Retrospective Multicenter Study from Germany

Abstract

Background: Clinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany.

Objective: The aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option.

Methods: Diagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated.

Results: Overall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3% of patients, respectively. In 83.8% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60%, p = 0.005), Barcelona (13 vs. 34%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74%, p = 0.004; Barcelona: 50 vs. 84%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86%, p = 0.001).

Conclusion: Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients.

Keywords: autoantibodies; primary biliary cholangitis; second line therapy; treatment response; ursodeoxycholic acid.

Figure 1

Study flow diagram. In total, 763 patients with confirmed PBC from 10 independent hepatological referral centers were screened for study eligibility and real-world first-line UDCA treatment regimens and subsequent response rates at 12 months after the initiation of treatment were evaluated in 480 patients. Patients with an inadequate response to at least one of the response criteria (n = 116) were evaluated for hitherto available second-line treatment regimens and subsequent response rates at 12 months after treatment modification.

Figure 2

Management of patients with inadequate response to standard UDCA first-line treatment. The real-world management of 116 patients with inadequate response to standard first-line UDCA treatment according to at least one criterion is depicted, including patients without treatment modification (n = 39), increase of UDCA dosage (n = 35), addition of glucocorticoids (n = 6), bezafibrates (n = 28) or obeticholic acid (n = 4). Treatment response rates according to Paris-I, Paris-II, and Barcelona criteria and ALP levels ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN at 12 months after treatment modification, respectively; continuation of UDCA-monotherapy was analyzed. * p < 0.05, ** p < 0.01, not significant (ns) = p ≥ 0.05.

Figure 3

Evaluation of liver biochemistry. The course of liver biochemistry in patients with inadequate response to standard first-line UDCA treatment according to the subsequent individual management (A): no treatment modification (n = 39), (B): increase of UDCA dosage (n = 35), (C): addition of glucocorticoids (n = 6), (D): bezafibrates (n = 28) or (E): obeticholic acid (n = 4) is shown. The first bar represents the baseline values for alkaline phosphatase [ALP], bilirubin, aspartate aminotransferase [AST], alanine aminotransferase [ALT] and gamma-glutamyl transferase [gGT]. The second bar represents the laboratory results at 12 months after the initiation of standard first-line UDCA treatment. The third bar represents baseline values before the start of second-line treatment after different time periods under UDCA treatment. The fourth bar depicts the effect on liver biochemistry at 12 months after treatment modification. * p < 0.05, ** p < 0.01, *** p < 0.001, ns = p ≥ 0.05.