编者按：第52届欧洲肝脏研究学会（EASL）年会期间，“Critical reflection on landmark papers 2016”专题围绕4篇具有里程碑意义的论文展开辩论，比利时鲁汶大学Frederik Nevens教授代表POISE研究团队，就2016年发表于《新英格兰医学杂志》的“A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis”一文发表观点。会后，本刊邀请Nevens教授介绍相关研究进展。

 

原发性胆汁性胆管炎：UDCA还是OCA？

 

“obeticholic acid is a very strong FXR agonist which means it is a much more powerful drug for getting rid of the toxic bile acids inside the liver.”

 

原发性胆汁性胆管炎（PBC）是一种胆汁淤积性肝病，熊去氧胆酸（UDCA）是其一线治疗药物。问题是，大约40%的患者对UDCA治疗反应不佳。如果治疗反应不佳，患者则有发生肝性并发症（如腹水和肝性脑病）的风险（15年后为50%）。因此，这种疾病亟需二线治疗药物。

 

据Nevens教授介绍，过去几年中，已经研发出新药奥贝胆酸（OCA），约50%对UDCA治疗应答不佳的患者对OCA治疗反应良好。OCA是强效FXR激动剂，去除肝脏内胆汁酸毒性作用更强。肝脏中的胆汁酸是这些患者的主要毒性原因。此外，FXR激动剂还具有其他作用，抗纤维化、抗炎，还可能抗动脉粥样硬化，以及从肠道吸收有毒化合物。因此，这种药物具有比UDCA更广泛的作用。

 

OCA皮肤瘙痒问题是否能克服？

 

“We have partially overcome the problem of pruritus by starting with lower doses and then increasing dosage if necessary.”

 

除肝脏相关问题以外，PBC患者的主要问题之一是出现皮肤瘙痒。临床试验发现，在基线治疗水平，60%的患者出现瘙痒。Ⅱ期临床研究显示，OCA可以降低碱性磷酸酶（ALP）水平，而ALT是预测患者结局的有效替代指标。但随之而来的问题是，应用高剂量OCA，患者会出现瘙痒症状，多数患者在治疗开始时就已出现瘙痒。Nevens教授指出，目前的试验设计旨在克服这一问题。

 

Nevens教授研究团队发现，从较低剂量（5 mg）开始，根据需求将剂量递增至10 mg。结果发现，约50%的患者在6个月后需要增量至10 mg；如此一年后，瘙痒引起的停药率仅为1%；长期随访发现，瘙痒引起的停药率仅为2%左右。所以，已经可以部分地克服瘙痒问题：以低剂量开始治疗，根据需求增加剂量，同时允许在治疗基线时就出现瘙痒症状的患者服用药物（如糖皮质激素）。

 

原发性硬化性胆管炎：norUDCA能否攻克难关？

 

“In the phase II study, we could prove that we could significantly reduce the ALP in patients receiving norUDCA.”

 

原发性硬化性胆管炎（PSC）是另一种胆汁淤积性肝病，主要影响患有炎症性肠病如克罗恩病的年轻男性。不幸的是，目前针对这种疾病没有好的治疗药物。许多患者应用UDCA，但研究已证实UDCA并不能改善患者的长期结局。

 

最近，Nevens教授作为共同作者研究norUDCA对PSC的治疗作用，norUDCA是UDCA的另一种形式。在Ⅱ期临床试验阶段，发现接受norUDCA治疗的患者ALP水平明显下降。因此，Ⅲ期临床试验将很快开始，以进一步证明Ⅱ期临床研究中观察到的积极作用。

 

英文原文：

 

First-line treatment for primary biliary cholangitis (PBC), a cholestatic liver disease, is ursodeoxycholic acid (urso). The problem is that in around 40% of patients, there is a poor response. If they do not respond well, they are at risk (50% after 15 years) for the development of major liver-linked complications, such as ascites and hepatic encephalopathy. So there is an urgent requirement for second-line treatment for this disease. Over the last couple of years, obeticholic acid has been developed, and where patients do not respond well to ursodeoxycholic acid, using obeticholic acid produces a response in around 50% of those patients. The difference between the drugs is that obeticholic acid is a very strong FXR agonist which means it is a much more powerful drug for getting rid of the toxic bile acids inside the liver. Bile acids in the liver are the main cause of toxicity in these patients. Additionally, FXR agonists have other beneficial effects including being antifibrotic, anti-inflammatory, perhaps anti-atherosclerotic, and for the absorption of toxic compounds from the gut. So this drug has a much broader spectrum of action than ursodeoxycholic acid.

 

One of the main problems (aside from liver-related issues) for patients with PBC is pruritus. From the trial, 60% of patients had pruritus at baseline. We know from the phase II studies that obeticholic acid has beneficial effects on alkaline phosphatase, which is a very good surrogate marker for the final outcome of patients. But the problem arose that at higher doses, pruritus occurs. Most patients already have pruritus at the onset of treatment. The design of the current trial aims to overcome that problem. We found that by starting with lower doses (5mg) and then increasing the dose to 10mg if necessary (which was found to be necessary in around 50% of patients after six months), the dropout rate due to pruritus after one year was only 1%. Also, during long-term follow-up, we can see that the dropout rate due to pruritus is only around 2%. So, in this trial, we have partially overcome the problem of pruritus by starting with lower doses and then increasing dosage if necessary, and allowing patients with pruritus at baseline to take medication such as corticosteroids.

 

Primary sclerosing cholangitis (PSC) is another cholestatic liver disease, which mostly affects young males with associated inflammatory bowel disease such as Crohn’s disease. Unfortunately, there are no good medications at present for this disease. Many use ursodeoxycholic acid, but that has been shown to not improve the long-term outcomes for these patients. Recently, I was a co-author of a study where we studied the positive effects of nor-ursodeoxycholic acid (norUrso), another form of ursodeoxycholic acid. In the phase II study, we could prove that we could significantly reduce the ALP in patients receiving norUrso, and consequently, a phase III study will start soon hopefully to prove the positive effects we observed in the phase II study.