Liver transplant‐free survival according to alkaline phosphatase and GLOBE score in patients with primary biliary cholangitis treated with ursodeoxycholic acid

Abstract

Background: After 1 year of ursodeoxycholic acid (UDCA), patients with primary biliary cholangitis (PBC) may have a normal GLOBE score despite high alkaline phosphatase (ALP) levels. Aim:To assess the association between ALP and liver transplantation (LT)-free survival according to the GLOBE score Methods: Among 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.Results: After 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). Conclusion:The 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. How to cite this article: de Veer RC, Harms MH, Corpechot C, Thorburn D, Invernizzi P, Janssen HLA, et al. Liver transplant-free survival according to alkaline phosphatase and GLOBE score in patients with primary biliary cholangitis treated with ursodeoxycholic acid.

Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain?

“…Indeed, whereas normal ALP values in this population were consistently associated with a significant decrease in HR in the different subgroups studied, a concrete clinical benefit (ie, a significant increase in life expectancy without complications) was mainly found in the youngest patients, that is, before the age of 62 years, or those with high LSM, that is, ≥10 kPa, who together account for 60% of the study population. This inverse relationship between age and prognostic value of ALP under UDCA has been recently suggested 16 . The added value of a second-line therapy in PBC is likely to decrease with age, particularly beyond 70, especially if any ALP elevation is considered as a potential indication regardless of disease stage.…”

“…Very recently, it has been shown that, even in patients with an adequate response to UDCA, normal ALP levels or total bilirubin ≤0.6 ×ULN could be associated with a further reduction in the risk of death or LT 15,16 . However, the significance of this deep biochemical response in terms of absolute clinical benefit, that is, real gains in complication-free life expectancy, and not just risk reduction, needs to be further assessed.…”

“…[8][9][10][11] Currently, these adjunctive treatments are only considered when serum alkaline phosphatase (ALP) values remain above 1.5 (or 1.67 depending on the criteria used to define inadequate response) times the upper limit of normal (×ULN) or total bilirubin is elevated after 12 months of UDCA therapy. [12][13][14] Very recently, it has been shown that, even in patients with an adequate response to UDCA, normal ALP levels or total bilirubin ≤0.6 ×ULN could be associated with a further reduction in the risk of death or LT. [15,16] However, the significance of this deep biochemical response in terms of absolute clinical benefit, that is, real gains in complication-free life expectancy, and not just risk reduction, needs to be further assessed. Indeed, it remains unclear whether UDCA-treated patients with moderate persistent ALP elevation (ie, between 1.0 and 1.5 × ULN) or a bilirubin value between 0.6 and 1.0 × ULN should potentially be considered for second-line therapy.…”

Inflammasome and pyroptosis in autoimmune liver diseases

“…PBC and PSC are treated with ursodeoxycholic acid, the drug of choice for cholestatic liver disease ( 199 , 200 ). However, based on the response criteria, this treatment fails in approximately 25% to 50% of patients ( 201 ). Therefore, a large proportion of patients still do not have adequate treatment, and understanding the mechanisms of the proinflammatory pathway in AILDs and potential new therapeutic approaches is critical.…”

Open‐label, clinical trial extension: Two‐year safety and efficacy results of seladelpar in patients with primary biliary cholangitis

“…[23][24][25][26][27][28][29] Levels of ALP and TB, alone or together, can predict liver transplantation or death in patients with PBC, with lower levels of these markers being associated with better transplant-free survival. 25,27,29 Additional treatment options for PBC are needed due to many patients lacking a complete response with or intolerance to current treatments and/ or persistent clinical symptoms that impact quality of life. 3,4,9,18,30,31 Seladelpar is a first-in-class, potent and selective peroxisome proliferator-activated receptor (PPAR)δ agonist with many effects that impact PBC, including cholestasis, hepatocellular injury,…”