Treatment outcomes for people living with autoimmune hepatitis (AIH) are limited by a lack of specific therapies, as well as limited well-validated prognostic tools and clinical trial endpoints. We sought to identify predictors of outcome for people living with AIH. We evaluated the clinical course of people with AIH across 11 Canadian centres. Biochemical changes were analysed using linear mixed-effect and logistic regression. Clinical outcome was dynamically modelled using time-varying Cox proportional hazard modelling and landmark analysis. In 691 patients (median age 49 years, 75.4% female), with a median follow-up of 6 years (25th-75th percentile, 2.5-11), 118 clinical events occurred. Alanine aminotransferase (ALT) normalisation occurred in 63.8% of the cohort by 12 months. Older age at diagnosis (odd ratio [OR] 1.19, 95% CI 1.06-1.35) and female sex (OR 1.94, 95% CI 1.18-3.19) were associated with ALT normalisation at 6 months, whilst baseline cirrhosis status was associated with reduced chance of normalisation at 12 months (OR 0.52, 95% CI 0.33-0.82). Baseline total bilirubin, aminotransferases, and IgG values, as well as initial prednisone dose, did not predict average ALT reduction. At baseline, older age (hazard ratio [HR] 1.25, 95% CI 1.12-1.40), cirrhosis at diagnosis (HR 3.67, 95% CI 2.48-5.43), and elevated baseline total bilirubin (HR 1.36, 95% CI 1.17-1.58) increased the risk of clinical events. Prolonged elevations in ALT (HR 1.07, 95% CI 1.00-1.13) and aspartate aminotransferase (HR 1.13, 95% CI 1.06-1.21), but not IgG (HR 1.01, 95% CI 0.95-1.07), were associated with higher risk of clinical events. Higher ALT at 6 months was associated with worse clinical event-free survival. In people living with AIH, sustained elevated aminotransferase values, but not IgG, are associated with poorer long-term outcomes. Biochemical response and long-term survival are not associated with starting prednisone dose. Using clinical data from multiple Canadian liver clinics treating autoimmune hepatitis (AIH), we evaluate treatment response and clinical outcomes. For the first time, we apply mixed-effect and time-varying survival statistical methods to rigorously examine treatment response and the impact of fluctuating liver biochemistry on clinical event-free survival. Key to the study impact, our data is 'real-world', represents a diverse population across Canada, and uses continuous measurements over follow-up. Our results challenge the role of IgG as a marker of treatment response and if normalisation of IgG should remain an important part of the definition of biochemical remission. Our analysis further highlights that baseline markers of disease severity may not prognosticate early treatment response. Additionally, the initial prednisone dose may be less relevant for achieving aminotransferase normalisation. This is important for patients and treating clinicians given the relevance and importance of side effects.

中文翻译：

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自身免疫性肝炎的治疗反应和临床无事件生存期：加拿大多中心队列研究


自身免疫性肝炎 (AIH) 患者的治疗结果因缺乏特异性疗法以及经过充分验证的预后工具和临床试验终点有限而受到限制。我们试图找出 AIH 患者预后的预测因素。我们评估了加拿大 11 个中心的 AIH 患者的临床病程。使用线性混合效应和逻辑回归分析生化变化。使用时变 Cox 比例风险模型和界标分析对临床结果进行动态建模。在 691 名患者（中位年龄 49 岁，75.4% 为女性）中，中位随访时间为 6 年（第 25-75 个百分位，2.5-11），发生了 118 起临床事件。 12 个月时，63.8% 的队列患者丙氨酸转氨酶 (ALT) 恢复正常。诊断时年龄较大（比值比 [OR] 1.19，95% CI 1.06-1.35）和女性（OR 1.94，95% CI 1.18-3.19）与 6 个月时 ALT 正常化相关，而基线肝硬化状态与 ALT 正常化相关。 12 个月时正常化的机会（OR 0.52，95% CI 0.33-0.82）。基线总胆红素、转氨酶和 IgG 值以及初始泼尼松剂量并不能预测平均 ALT 降低。基线时年龄较大（风险比 [HR] 1.25，95% CI 1.12-1.40）、诊断时有肝硬化（HR 3.67，95% CI 2.48-5.43）和基线总胆红素升高（HR 1.36，95% CI 1.17- 1.58）增加了临床事件的风险。 ALT（HR 1.07，95% CI 1.00-1.13）和天冬氨酸转氨酶（HR 1.13，95% CI 1.06-1.21）长期升高与较高风险相关，但 IgG（HR 1.01，95% CI 0.95-1.07）则不然。的临床事件。 6 个月时较高的 ALT 与较差的临床无事件生存率相关。 在 AIH 患者中，转氨酶值持续升高（而非 IgG）与较差的长期预后相关。生化反应和长期生存与泼尼松起始剂量无关。我们利用加拿大多个治疗自身免疫性肝炎 (AIH) 的肝脏诊所的临床数据，评估治疗反应和临床结果。我们首次应用混合效应和时变生存统计方法来严格检查治疗反应以及肝脏生化波动对临床无事件生存的影响。研究影响的关键是，我们的数据是“真实世界”的，代表了加拿大各地的多元化人口，并在随访中使用连续测量。我们的结果挑战了 IgG 作为治疗反应标志物的作用，以及 IgG 正常化是否仍应作为生化缓解定义的重要组成部分。我们的分析进一步强调，疾病严重程度的基线标记可能无法预测早期治疗反应。此外，初始泼尼松剂量对于实现转氨酶正常化可能不太相关。考虑到副作用的相关性和重要性，这对于患者和治疗临床医生来说非常重要。