肿瘤免疫疗法通过再次激活免疫抑制，恢复免疫系统的免疫监视功能，从而达到抗肿瘤作用，但会破坏机体免疫耐受平衡，从而出现免疫相关不良反应。免疫检查点抑制剂（ICIs）近年来在实体肿瘤治疗领域得到了广泛应用，是当前抗癌治疗的明星药物，ICI相关药物性肝损伤 （ILICI） 已成为免疫抗肿瘤时代不可回避的问题，因此日益受到关注和重视。

 

第57届欧洲肝病研究学会年会（EASL2022）暨2022年国际肝脏大会^TM（ILC 2022）上，法国巴黎Paul Brousse医院肝胆中心Eleonora De Martin教授主持了关于免疫检查点抑制剂相关肝损伤话题的专家论坛。《国际肝病》有幸在现场采访了Eleonora De Martin教授，请她从ILICI的危险因素、皮质类固醇使用策略、ILICI管理重点和未来研究方向等方面，展开深入的交流和探讨。

 

 

《国际肝病》

请您介绍免疫检查点抑制剂（ICIs）相关性肝炎有哪些危险因素？其中最值得临床医师注意的是什么？

 

Eleonora De Martin教授：这个问题很难回答，因为唯一已经证实的是自身免疫性疾病会增加患ICI诱导的肝炎的风险，更普遍来说，会增加ICI免疫相关不良事件的风险。自身免疫性肝病虽然不是ICI的禁忌证，但用药前需筛查。如果患者患有其他自身免疫性疾病，应加以控制。 

 

一个德国研究团队去年发表了一篇有趣的论文，发现巨细胞病毒（CMV） IgG阳性和CMV反应性CD4效应记忆T细胞的患者，患ICI诱导肝炎的风险增加。研究者建立了一个结合这些指标的模型，具有良好的特异性和灵敏度。但这一发现是基于接受抗PD-1和抗CD4联合治疗的转移性黑色素瘤患者的特殊人群，所以它们虽有希望，但不能在临床实践中使用。遗憾的是，目前我们还没有确定可以常规使用的特定危险因素。

 

英文原文：

 

: What are the risk factors for checkpoint inhibitor induced immune-mediated hepatotoxicity？Among them, what is the most noteworthy for clinicians?

 

Dr De Martin: This is a tough question because the only thing that has been demonstrated is that if you have an autoimmune disease, you have an increased risk of developing immune checkpoint inhibitor (ICI)-induced hepatitis, and more in general, immune-related adverse events to ICI. This is not a contraindication for the use of these drugs, but you need to screen for autoimmune liver diseases. If you have another autoimmune disease, the disease should be controlled.

 

There was an interesting paper published last year by a German group that found that patients with cytomegalovirus (CMV) IgG-positive and CMV-reactive CD4 effector memory T-cells had an increased risk of developing ICI-induced hepatitis. They found a model combining these variables that had good specificity and sensitivity, but their findings were based on a special population of patients with metastatic melanoma treated with a combination of anti-PD-1 and anti-CD4. So they are promising results, but it is not something that we currently use in clinical practice. At the moment, we unfortunately haven’t identified specific risk factors that could be used routinely.

 

《国际肝病》

ICIs的肝毒性管理以及皮质类固醇的作用是复杂且存有争议的。您对此有什么见解？

 

Eleonora De Martin教授：目前，肿瘤科医师根据常见不良事件评价标准（CTCAE ）中的严重程度使用皮质类固醇。对于2 级（中度肝损伤）患者，从0.5~1.0 mg/kg/天的剂量开始。这是很大的皮质类固醇剂量，因为如果与急性自身免疫性肝炎相比，在严重情况下，类固醇剂量才从每天1mg/kg开始。自身免疫性肝炎的严重程度由凝血障碍的存在（INR≥1.5）来定义。可以说，根据严重程度评分，类固醇使用剂量确实很大。我认为我们需要重新考虑严重程度评分。如果将CTCAE评分与美国药物肝损伤研究网络 （DILIN）评分比较，例如3级肝损伤，对于CTCAE评分，只需要达到转氨酶升高至正常上限的5~20倍，而对于DILIN评分，还要求胆红素升高至>2.5 mg/dL、需要住院治疗。

 

根据我的经验，患者其实可以自行改善。在我们的64例CTCAE评分3级甚至4级的患者中，50%都可以自行改善。遗憾的是，我们无法确定转氨酶的合适界值，以确定何时使用皮质类固醇。这是未来需要研究的内容。当然，对于黄疸或严重肝炎（如凝血障碍）患者，应该使用皮质类固醇。或者根据随后进行的肝功能检测来指导皮质类固醇的应用。因此，我认为不应立即使用皮质类固醇，而是等上约一周时间，期间每48小时做一次肝功能测试并观察。如果肝功能检测显示相关指标不断升高，应使用皮质类固醇。我再强调一下，我们应该保持冷静，等一等，不要一开始就用大剂量皮质类固醇。有时候只是时间问题。

 

英文原文：

 

: The management of liver toxicity of ICIs and the role of steroids is complex and controversial. What's your opinion on this aspect？

 

Dr De Martin: Currently, the oncologists base their choice to introduce corticosteroids on the CTCAE classification of severity. If you have a patient with a hepatitis of Grade 2, you should start at 0.5-1.0 mg/kg/day, which is a huge dose of corticosteroids, because if you compare with patients with acute autoimmune hepatitis, if they are severe, you start with 1mg/kg daily, and the severity for immune hepatitis is defined by the presence of coagulopathy (INR equal or >1.5). Basically, based on this severity score that they use, the dosage of steroids that they use are really massive. I think we need to rethink the severity score, and when you compare it with the drug-induced liver injury network (DILIN) score, a Grade 3, for example, for the CTCAE score, you have just transaminases between 5 and 20 times the limit of upper normal, while on the DILIN, you need to also have a high bilirubin (>2.5 mg/dl) and you need to be hospitalized.

 

In my experience, and this has been found in other groups as well, patients can improve spontaneously. In our series of 64 patients with a CTCAE of Grade 3 or higher, 50% improved spontaneously, even with a Grade 4. Unfortunately, we couldn’t define a proper cutoff of transaminases, and this is something for future study in order to define when to introduce the corticosteroids. Of course, if you have jaundice, or a really severe hepatitis (as defined by coagulopathy, as I said), you should introduce corticosteroids. Otherwise, the evolution of liver tests over time should guide you as to whether or not you should introduce corticosteroids. So for example, you should not jump to steroids straight away but wait around one week doing liver tests every 48 hours and see. If the liver tests trend higher and higher, you should introduce steroids. Once again, you need to stay cool and wait a little bit, and not start on massive steroid doses. As I said, sometimes it is just a matter of time.

 

《国际肝病》

ICIs引起的药物相关肝损伤管理的重点是什么？有哪些新的进展？

 

Eleonora De Martin教授：我认为，当肿瘤科医师对怀疑ICI诱发肝炎的患者进行评估时，第一要排除急性肝炎的其他致病因素。要检查全部肝炎病毒，而不仅仅是HBV和HCV，比如HEV。还需要检查是否患有自身免疫性疾病。需要了解患者是否在使用其他有潜在肝脏毒性的药物，如抗生素。有时患者会服用补充剂或非处方药，因此在确诊ICI诱发肝炎之前，需要完善所有检查。

 

第二，需要评估是否需要做肝活检。这也是有争议的。活检很重要。我们对所有3级或以上肝炎患者做了活组织检查。重要的是要清楚这种毒性类型不是自身免疫性肝炎，因为它不具有和自身免疫性肝炎相同的组织学特征。对于病情复杂、最严重病例和类固醇难治患者，活检对于鉴别诊断很重要。

 

第三，开始使用皮质类固醇后，要监测患者应答。有研究发现，使用皮质类固醇后ALT下降的中位时间约为11天。要稍微等一等，如果患者没有应答，应该引入第二种免疫抑制剂。我倾向使用霉酚酸酯（MMF）。根据我的经验以及文献中的案例，这真的很有效。对于无应答的更严重病例，也可以使用他克莫司等。如果患者有应答，应该减少免疫抑制剂的使用，并在某一点停用。

 

第四，这是关于再次用药的问题。对于转移性肿瘤，可能没有其他选择，所以应就重新引入ICI的利弊进行多学科讨论。最重要的是，在使用联合治疗或抗PD-1治疗出现首次肝毒性后，避免采取抗CD4治疗。因为已有充分证据证明，重新引入抗CD4，肝炎复发风险很高。同时，需要对患者进行严格监测，因为没有肝炎复发的预后因素。唯一的问题是引入ICI和肝炎发作的间隔时间。间隔越短，肝炎复发风险越高。所以这需要一个多学科的讨论，来决定是否要采取应对再次用药的策略。

 

总之，确诊ICI诱发的肝炎，需要进行非常仔细的鉴别诊断。如果不确定是最严重的病例或对皮质类固醇无应答的病例，请进行肝活检。评估患者病情严重程度，看他们是否对类固醇有应答，或者是否需要2线或3线免疫抑制剂。如果患者有应答，可以进行多学科探讨，确定是否可以重新引入ICI。

 

英文原文：

 

: What are the key points on management of ILICI（Immune-mediated liver injury caused by ICIs）？Could you please update us with lated progress on it if any？

 

Dr De Martin: I think the first thing to do when the oncologist assesses a patient for the suspicion of ICI-induced hepatitis is to exclude all other causes of acute hepatitis. You need to check for all viruses, not only B and C. You need to check for hepatitis E, for example (we have had a couple of cases of that). You need to check for autoimmune diseases, if you haven’t done it before. You need to know if the patient has received other drugs that are potentially toxic for the liver - the general practitioner may have prescribed an antibiotic, for example. You really need to make a differential diagnosis. Sometimes patients will take supplements or non-prescription medications, so you really need to check for all of that before concluding that you have a true ICI-induced hepatitis. This is the first point.

 

The second point is that you need to see if there is a need for liver biopsy. This is also controversial. It is important to biopsy. We biopsy a lot - all the patients with Grade 3 or higher hepatitis. This is important to understand that this type of toxicity is not an autoimmune hepatitis, as it doesn’t have the same histological characteristics of autoimmune hepatitis. Right now, I think a biopsy is important for the differential diagnosis if the condition is complicated, so for the most severe cases and cases that are steroid refractory.

 

The other point is, that if you start the corticosteroids, you need to monitor your patients for response, which will be the majority of cases. Allow time. There was a paper that found that the median time for ALT to decrease after the introduction of corticosteroids was about 11 days. You need to wait a little bit, and if you find that the patient is not responding, you should introduce a second immunosuppressive drug. The one I prefer is mycophenolate mofetil (MMF). In my experience, and also in cases in the literature, it is really effective. Otherwise, for the more severe cases that are not responding, you can also use tacrolimus. There are some other drugs, but I am not going to go into them.

 

Then the other point is if the patient is responding, you should decrease immunosuppression and stop it at a certain point. There is the question of a rechallenge. When faced with metastatic cancer, there may not be an alternative, so you should have a multidisciplinary discussion about the pros and cons of reintroducing an ICI. The thing that is most important is to avoid an anti-CD4 after first toxicity of a combination therapy or an anti-PD-1 therapy, because it has been well-demonstrated that if you reintroduce an anti-CD4, the risk of hepatitis recurrence is really high.

 

Secondly, you need to monitor your patient very strictly, because there are no prognostic factors for the recurrence of hepatitis. The only thing is the time between the ICI introduction and the hepatitis onset. The shorter the time, the higher the risk of hepatitis recurrence. But you cannot deny these only oncological possible treatments for these patients. So, as I said, it is a multidisciplinary discussion in order to decide if you want to rechallenge your patient or not.

 

In conclusion, make sure that it is really an ICI-induced hepatitis with a really careful differential diagnosis. Do a liver biopsy if you are not sure in the most severe cases or cases not responding to corticosteroids. Evaluate the severity and see if they are responding to steroids or need a second or third line of immune suppression. If they do respond, you can discuss with your team whether you can or cannot reintroduce an ICI.

 

《国际肝病》

ICI造成的肝损伤是免疫新时代抗肿瘤疗法中不可回避的问题，因此，随着精准医学的发展，ICI在多种肿瘤中的应用越来越多，其免疫相关肝毒性的发生率将继续上升。您认为未来关于 ILICI的研究方向是什么？

 

Eleonora De Martin教授：我认为我们不能依赖于临床或组织学甚至放射学参数，而是需要找到分子生物标志物，因为它们具有真正的异质性。我们需要找到生物标志物，鉴别肝功能指标升高但可自行改善患者，以及真正将进展为严重毒性的患者。我们需要寻找更多的免疫生物标志物，明确需要皮质类固醇、需要二线治疗的患者以及再次用药后复发患者的特征。

 

英文原文：

 

: Liver injury caused by ICIs is unavoidable in anti-tumor practice in the new era of immunotherapies. With the development of precision medicine, ICIs will be more and more used in most cancers, and incidence of immune-related hepatotoxicity will continue to rise. Accordingly, what do you think is the future research direction of ILICI?

 

Dr De Martin: I think we really need molecular biomarkers. This is a really heterogeneous population, so you cannot rely on clinical or histological or even radiological parameters. We really need to find biomarkers, even to differentiate those patients who will progress to severe toxicity from those patients who will just have a raise in liver function tests that will improve spontaneously. We need to look at more immunological biomarkers to characterize patients in need of corticosteroids, in need of a second-line therapy, and also who would have a recurrence after rechallenge.