Dalekos, George Ν.

Background and Aims: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. Approach and Results: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7–21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7–59.9, p < 0.001) when these 2 conditions were met. Conclusions: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

INTRODUCTION: Treatment of primary biliary cholangitis (PBC) can improve the GLOBE score. We aimed to assess the association between changes in the GLOBE score (ΔGLOBE) and liver transplantation (LT)–free survival in patients with PBC who were treated with ursodeoxycholic acid (UDCA). METHODS: Among UDCA-treated patients within the Global PBC cohort, the association between ΔGLOBE (ΔGLOBE 0–1 : during the first year of UDCA, ΔGLOBE 1–2 : during the second year) and the risk of LT or death was assessed through Cox regression analyses. RESULTS: Overall, 3,775 UDCA-treated patients were included; 3,424 (90.7%) were female, the median age was 54.0 (interquartile range [IQR] 45.9–62.4) years, and the median baseline GLOBE score was 0.25 (IQR −0.47 to 0.96). During a median follow-up of 7.2 (IQR 3.7–11.5) years, 730 patients reached the combined end point of LT or death. The median ΔGLOBE 0–1 was −0.27 (IQR −0.56 to 0.02). Cox regression analyses, adjusted for pretreatment GLOBE score and ΔGLOBE 0–1 2 , showed that ΔGLOBE was associated with LT or death (adjusted hazard ratio 2.28, 95% confidence interval 1.81–2.87, P < 0.001). The interaction between baseline GLOBE score and ΔGLOBE 0–1 was not statistically significant ( P = 0.296). The ΔGLOBE 1–2 was associated with LT or death (adjusted hazard ratio 2.19, 95% confidence interval 1.67–2.86, P < 0.001), independently from the baseline GLOBE score and the change in GLOBE score during the first year of UDCA. DISCUSSION: UDCA-induced changes in the GLOBE score were significantly associated with LT-free survival in patients with PBC. While the relative risk reduction of LT or death was stable, the absolute risk reduction was heavily dependent on the baseline prognosis of the patient.

SummaryBackgroundAfter 1 year of ursodeoxycholic acid (UDCA), patients with primary biliary cholangitis (PBC) may have a normal GLOBE score despite high alkaline phosphatase (ALP) levels.AimTo assess the association between ALP and liver transplantation (LT)‐free survival according to the GLOBE scoreMethodsAmong patients with a normal or elevated GLOBE score in the Global PBC cohort, the association between ALP after 1 year of UDCA and the risk of LT/death was assessed. The LT‐free survival was compared with that of a matched general population.ResultsAfter 1 year of UDCA, ALP was associated with the risk of LT/death (aHR 1.31, 95% CI 1.003–1.72, p = 0.048) among 2729 patients with a normal GLOBE score. The 10‐year LT‐free survival among these patients with an ALP >2.0 × ULN was 94.0% (95% CI 90.1–97.9) for those <50 years, and 82.6% (95% CI 76.5–88.7) for those ≥50 years, which was significantly lower (p = 0.040) and similar (p = 0.736) to that of the matched population, respectively. The 10‐year LT‐free survival in patients ≥50 years with normal GLOBE score and normal ALP (90.8%, 95% CI 87.7–93.9) was significantly higher (p = 0.022) than the matched population. Among 1045 patients with an elevated GLOBE score, ALP was associated with LT/death only in those <50 years (aHR 1.38, 95% CI 1.06–1.81, p = 0.016).ConclusionThe LT‐free survival of patients with PBC with a normal GLOBE score is optimal in case of normal ALP levels, also in relation to the general population. Despite their generally favourable prognosis, an elevated ALP level may still indicate a need for add‐on therapy.

Changes over time in the presenting features and clinical course of patients with primary biliary cholangitis are poorly described. We sought to describe temporal trends in patient and disease characteristics over a 44‐year period across a large international primary biliary cholangitis cohort of 4,805 patients diagnosed between 1970 and 2014, from 17 centers across Europe and North America. Patients were divided into five cohorts according to their year of diagnosis: 1970‐1979 (n = 143), 1980‐1989 (n = 858), 1990‐1999 (n = 1,754), 2000‐2009 (n = 1,815), and ≥2010 (n = 235). Age at diagnosis, disease stage, response to ursodeoxycholic acid, and clinical outcomes were compared. Mean age at diagnosis increased incrementally by 2‐3 years per decade from 46.9 ± 10.1 years in the 1970s to 57.0 ± 12.1 years from 2010 onward (P < 0.001). The female to male ratio (9:1) and antimitochondrial antibody positivity (90%) were not significantly variable. The proportion of patients presenting with mild biochemical disease (according to Rotterdam staging) increased from 41.3% in the 1970s to 72.2% in the 1990s (P < 0.001) and remained relatively stable thereafter. Patients with a mild histological stage at diagnosis increased from 60.4% (1970‐1989) to 76.5% (1990‐2014) (P < 0.001). Correspondingly, response to ursodeoxycholic acid according to Paris‐I criteria increased; 51.7% in the 1970s and 70.5% in the 1990s (P < 0.001). Recent decades were also characterized by lower decompensation rates (18.5% in the 1970s to 5.8% in the 2000s, P < 0.001) and higher 10‐year transplant‐free survival (48.4%, 68.7%, 79.7%, and 80.1% for each respective cohort; P < 0.001). Conclusion: In recent decades, a pattern of primary biliary cholangitis presentation consistent with an older age at diagnosis alongside reduced disease severity has been noted; the observed trends may be explained by an increase in routine testing of liver function and/or a changing environmental trigger. (Hepatology 2018;67:1920‐1930).