National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, United Kingdom; University Hospitals Birmingham, Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom.
Duke Clinical Research Institute, Durham, North Carolina.
Clin Gastroenterol Hepatol. 2021 Jun;19(6):1248-1257. doi: 10.1016/j.cgh.2020.07.032. Epub 2020 Jul 22.
BACKGROUND & AIMS: Serum alkaline phosphatase (ALP) and the enhanced liver fibrosis (ELF) score are used as endpoints in trials of patients with primary sclerosing cholangitis (PSC). We aimed to quantify inter- and intra-individual variation in levels of ALP and the ELF score over time, and evaluated their association with fibrosis progression.
We analyzed data from 234 patients with large-duct PSC enrolled in a 2-year, phase 2b placebo-controlled trial of simtuzumab. Participants were assessed by laboratory tests every 4 weeks, and liver biopsies collected at time of screening, week 48, and week 96.
Serum levels of ALP and ELF scores did not differ significantly between simtuzumab and placebo groups, so the data were pooled. Median per-patient variations in ALP between clinic visits were approximately 12% over 12 weeks, 20% over 48 weeks, and 20% over 96 weeks. Reductions, unrelated to study intervention, of more than 40% in ALP were observed in 10.9% of patients with baseline activity greater than 2-fold the upper limit of normal (ULN) and 12.5% of patients with more than 3-fold the ULN at 1 year. At 2 years, reductions of more than 40% in ALP were observed in 15.8% of patients with baseline activity greater than 2-fold the ULN and 17.9% of patients with more than 3-fold the ULN. Among the 209 patients with Ishak fibrosis stage 0-4 at baseline, serum ALP activity did not associate with development of cirrhosis or with a 2-point increase in fibrosis stage at 2 years. In contrast, the median per-patient variation in ELF scores between clinic visits was approximately 3% over 12 weeks, 4% over 48 weeks, and 4% over 96 weeks. Elevated ELF scores at baseline and at weeks 12, 24 and 48, each associated with development of cirrhosis at 2 years (odds ratio >2.75; P < .01 for all timepoints). ELF scores at baseline and weeks 12, 24 and 48, also associated with a 2-point increase in fibrosis stage at 2 years (odds ratios all greater than 2; P < .01 for all timepoints).
In an analysis of data from patients with large-duct PSC enrolled in a prospective trial, we found large interindividual and intraindividual variations in serum ALP activity. Serum ALP activity did not associate with disease progression over a 2-year period. Variations in ELF score were smaller, and scores determined at multiple timepoints associated with fibrosis progression and development of cirrhosis.
血清碱性磷酸酶（ALP）和增强型肝纤维化（ELF）评分被用作原发性硬化性胆管炎（PSC）患者临床试验的终点。我们旨在定量分析 ALP 水平和 ELF 评分随时间的个体内和个体间变化，并评估它们与纤维化进展的关系。
我们分析了 234 例接受大导管 PSC 治疗的患者的数据，这些患者参加了为期 2 年的 simtuzumab 安慰剂对照 2b 期临床试验。参与者每 4 周进行一次实验室检查，并在筛查时、第 48 周和第 96 周采集肝活检。
simtuzumab 组和安慰剂组的血清 ALP 水平和 ELF 评分无显著差异，因此将数据合并。12 周内，每位患者的 ALP 个体内变化中位数约为 12%，48 周内为 20%，96 周内为 20%。基线时 ALP 活性高于正常上限（ULN）2 倍的患者中，有 10.9%观察到超过 40%的 ALP 降低，基线时 ALP 活性高于 ULN 3 倍的患者中，有 12.5%观察到超过 40%的 ALP 降低。在第 2 年时，基线时 ALP 活性高于 ULN 2 倍的患者中，有 15.8%观察到超过 40%的 ALP 降低，而基线时 ALP 活性高于 ULN 3 倍的患者中，有 17.9%观察到超过 40%的 ALP 降低。在基线时患有 Ishak 纤维化分期 0-4 的 209 例患者中，血清 ALP 活性与肝硬化的发展或 2 年内纤维化分期增加 2 分均无相关性。相比之下，12 周内，每位患者的 ELF 评分个体内变化中位数约为 3%，48 周内为 4%，96 周内为 4%。基线和第 12、24 和 48 周时升高的 ELF 评分与第 2 年时肝硬化的发展相关（所有时间点的优势比>2.75；P<.01）。基线和第 12、24 和 48 周时的 ELF 评分也与第 2 年纤维化分期增加 2 分相关（所有时间点的优势比均大于 2；P<.01）。
在对参加前瞻性试验的大导管 PSC 患者数据的分析中，我们发现血清 ALP 活性存在较大的个体内和个体间差异。在 2 年期间，血清 ALP 活性与疾病进展无相关性。ELF 评分的变化较小，多个时间点的评分与纤维化进展和肝硬化的发展相关。
