Okay. I want to welcome everybody for joining us for this month. This month's Hepatotoxicity SIG seminar series. We have the famous Dr. Einar Bjornsson, professor and chief of the Department of Internal Medicine at the Lantz Pitali University Hospital, Faculty of Medicine, University of Iceland. Einar is very well known to this audience for his work with the Icelandic registry on dilly when he does all things liver. He completed his gastroenterology and hepatology fellowship in 95 and a PhD from Sweden, I think the year before 94. Then he post-doc'ed at Ann Arbor for two years and he spent time at the Mayo Clinic 2008-2009 at Bethesda on sabbatical in Malaga, Spain. He's authored more than 400 publications, has a crazy Asian dex of 100, more than 39,000 Google citations. He has served as executive director of the editor of the Scandinavian Journal of Gastro, and currently he is an associate editor for the Journal of Hepatology. He is best known to his friends and colleagues for his insight into drug-induced liver injury and his fantastic humor and for smiling always. Thank you, Dr. Bjornsson, for joining us. Thank you very much, Lili, and I'd really like to thank the organizers for inviting me, giving me the opportunity to give this talk, and in particular to Lili. Just wanted to show you the main campus. It was in the summer, it's a very short time of the year, time of the year that is summer, but sometimes it's a little bit green, but our country is a country of ice and fire. We've had a lot of volcanoes not so far away from our house, and also the volcanoes, well, they have decreased in size. This is where it is, it's between Moscow and Washington, so that is maybe the reason why Ronald Reagan and Gorbachev came here in 1986. We're trying to do something about the COVID, but we won't go into more politics in this depressing times of politics. This is where I live. If you see in the circle, this is a capital metropolitan area of about 250,000. It's a big church in the circle, and I live across the street. Everybody who comes to Reykjavik, they will go to this big, very huge church, and I just, if any of the audience will be there, when you come up to the church, just call me, and I will come and see you within a few minutes, two minutes maybe. Anyway, we're going to talk about drug-induced liver injury. Just wanted to point you to the, you're all aware of the different types of drug-induced liver injury, direct hepatotoxicity, and mostly idiosyncratic, but this term, indirect hepatotoxicity, was introduced by Jay Hufnagel. In this paper, I was fortunate to write a little part of it, at least, a few years ago, and I remember when the reviewer didn't like this, his reviewer thought it was a controversial term, indirect hepatotoxicity, but I remember that Jay didn't like his remarks, so fortunately, this was published, and it's widely accepted nowadays. There's a specific type of immune-mediated drug-induced liver injury, the so-called third type, and based on immune-directed actions, mostly immune, but not only, what the drug does rather than what it is, and this is widely accepted, as I saw on the previous Twitter, the X, there were some slides from a meeting in Madrid, and you could only guess who the presenters were, came all the way from Malaga to Madrid, and I saw one slide, and they were introducing this indirect hepatotoxicity. Indirect liver injury. Why do I mention this at the beginning? Yes, we had, I think, infliximab is a good example of this indirect liver injury. So, in our prospective two-year study of daily in this country, we, like in other western countries, amazonic linoleic acid was the most common cause, but there were also azathioprine infliximab. These were associated with the most highest risk of delay. So, how frequent is daily? We, that's a difficult issue. We wonder if it, if you, if you calculated in patients who are hospitalized, have jaundice, liver failure, acute liver failure, or in the society, but I think, although it's quite rare, daily is commonly seen by hepatologists and gastronomers, and also other specialists, and for example, nowadays, oncologists, and they really need help from those who are, have more experience in the field, and approximately half of the drugs marketed in the United States can cause liver injury. I think it's a misunderstanding, like some people, that all drugs can cause. That's, I think, a misunderstanding, but, and to make it more, more, to give those people who are not involved in liver disease help, a helping hand is this fantastic database, or this is in the public domain, everybody too can, can work, learn from J. Hughes Nagelhaus. I know that he has spent a very, very long energetic time to, to create this, to help some people. And here is even an advertisement in the, on this liver talks to my talk, just to come to the topic of today. It's known that hepatobiliary disorders are the most common extra-intestinal manifestations in patients with inflammatory bowel disease. I think it's very important, and I don't think everybody that is dealing with patients with liver tests, how important it is to distinguish between chronic and acute liver injury. Most of the time, idiosyncratic DILI and indirect DILI is acute reaction. We are all aware of, of both large and small duct PSC. This is in the North American, Northern Europe population. There is also a, there is, there is also this phenomenon of IgG4-associated cholantitis. And actually at the Mayo Clinic, where they have the most reliable data on this, this entity, the, these patients have a higher risk of developing ulcerative colitis or inflammatory bowel disease. I actually have one of these, one patient with severe ulcerative colitis who had autoimmune pancreatitis. So, we have the acute liver injury in these patients and DILI is a high on that list. Reactivation of hepatitis B virus and other forms of DILI. Now, in the liver talks, you have categorized the drugs depending on how well liver injury is documented with the use of these drugs and in category A with more than 50 published cases. And actually in this category, most of them have more than a hundred cases, almost all. In this well-known culprit, these are the, those are azathioprine and sex MP, which for some reason is more widely used in, in the United States, whereas azathioprine is mostly used in Europe. And then infliximab, as I had mentioned, methotrexate, sulfasalazine, we'll come back to this. And now in category B, at least, is atalimumab, we come back to these drugs. First to mention the most widely drugs for mild, sometimes moderate colitis, mesalazine, I think, if liver injury is, even exists from these drugs, it's probably extremely rare. And according to this paper that was published in 2016, where we went through the drugs marketed in the US for documentation of liver injury, we could only come up with eight published cases, even though it was marketed in 1987. Sulfasalazine was previously widely used. It was actually introduced by a Swedish professor of internal medicine or gastroenterology, rheumatology, I'm sorry, Nanna Svartz, that showed that this was effective. But quite a lot of adverse effects. And I think sulfasalazine is very rarely used for the treatment of IBD nowadays. Because the effects are similar to 5-ASA. But when I started training in Gothenburg, Sweden, in the early 90s, these drugs were quite often used then. The classical presentation of hypersensitivity, often the RAS, fever, erythrofilia, and sporadic cases of granulomatosis hepatitis. Fulminant hepatitis has been reported, but trimetoprin sulfa, which is not used in IBD, is very, has a different characteristic, but it's a very well, well known characterized daily agent. Coming back to the drugs, which are still used nowadays, and even though we have had, we have all these new biological therapies, esotherm and sex-MP, both are well known causes of acute idiosyncratic, mostly cholestatic hepatitis. These are also dose dependent, where it's occurring in many patients after you dose increase. If you dose escalate, the DILI will appear. Can lead to sinusoidal obstruction and nodular generative hyperplasia. When I was working at the NIH, we were looking, yes, before I come to that, just want to point out that esotherapy was one of the agents we found in our prospective study. We could see that one out of 133 patients treated with esotherm induced liver injury, so it was quite a high risk compared to other idiosyncratic drugs. In the NIH period, where I spent 2014 to 2015, I looked at at these patients with suspected DILI due to thiopurines. And these were approximately the same proportion of patients with esothioprine and sex-MP were diagnosed or considered probable, very likely or definite. So the indication was IPD only in 55% was a little bit surprised to me. But the median dose was in the range where you treat IPD patients, 150 milligrams, but whereas when we treat patients with autoimmune hepatitis, this is usually in the range of 50 milligrams. It's a much lower dose needed there. So I don't think we see it as frequently there as in the IPD population. So the median latency to onset was 75 days and injury first arose after dose escalation in 59%, almost 60% of patients. So most of them presented with cell-limited cholestatic hepatitis, typically within three months before starting, after starting, sorry. And there was only one patient of this code that died to have the underlying cirrhosis. Interestingly, if you look at this graph from the paper, you see there is a wide range of latency and the blue dots are esothioprine cases and the red is sex-MP. And as you can see on the right side, most of the cases appeared quite a short time after the dose was increased in both types. And you could also see that most of them had canalicula cholestasis, if you looked at their lab. This was a phenomenon introduced by the late Zimmerman. And here you can see a patient with cholestatic hepatitis, a typical form, also has a nodular regenerative hypoplasia. And you can see on the lower side, the spots of the bile plugs in the bile ducts. Those of the audience that are familiar with treatment of inflammatory bowel disease patients, they know that sometimes the therapeutic levels of TGN are associated with poor therapeutic response if they have a low TGN levels. And whereas this sex-MMP had been a report to lead to threefold increased risk of liver injury. However, it is not so simple, because it also mentioned that around 90% of patients with super therapeutic high sex-MMP levels have no hepatotoxicity. And 40% of those who have low levels give a lot daily. So it's often very difficult to understand these idiosyncratic reactions. Strangely enough, when you have tested to change switching from ASA to sex-MMP after a daily episode, it has been reported to be possible in a large number of patients. According to the guidelines of the British Society of Gastroenterology, monitoring of blood count and liver test should be undertaken at some intervals after starting the drug, and then at three months interval after that. And as you maybe are aware of, I think probably that this can also lead to pancreatitis. A very well documented cause of acute pancreatitis. Coming to the liver injury-associated methotrexate, it's a complicated story. It's a very long story. We see it sometimes after intermittent use. This can be, for example, in oncological indications. But also after perioral treatment, when patients get 50 mg per week. But it's rather mild, rapidly reversible after discontinuation. It's the chronic injury that has been controversial, whether it's all related to muscle D, metabolic dysfunction associated with steatotic liver disease. It's a very difficult term. But probably most of the cases are associated with the chronic injury, fibrosis development with metabolic complications, diabetes and obesity. So, these drugs before, I've gone quickly through, so I will spend more time with the TNF-alpha antagonist. This is the drugs of our times, and we all have experience with these drugs. I think they are fantastic good drugs, and they have changed the lives of thousands of people around the world, giving relief of both rheumatoid arthritis, psoriasis and inflammatory bowel disease. So, as you know, they can lead to an abundance of lymphocyte by preventing normal suppression of B-cells. And more importantly for the liver injury, inhibition of TNF-alpha can lead to alteration of balance between the helper and regular T-cells that can result in delay. Just to show a schematic picture on the right, the effect of T-cells and regulatory T-cells, the balance between them can be altered. And firstly, we published a small series several years ago, and when we published the series, the largest series was from the Dealing Network. There were six cases from our friend Marwan Gabriel in Indianapolis, was the first author. He collected additional 28 cases from the literature. And from up until that time, it was not well documented which kind of patients were at risk and population studies were lacking. And we had 11 cases of TNF-alpha antagonists, and these were matched with a control group who were treated with these drugs, but did not develop liver injury. And there were two cases, there were two controls per cases, and they were matched for age, gender, and, yeah, age and gender and the indications that they were used for. And I think that's a very important thing because they, the indications can have an impact. So, but we didn't find any difference in dose of infliximab between those who developed liver injury and not any risk was associated with ANA prior to therapy. But what we found was that methotrexate concomitantly seemed to decrease the risk considerably. So, those who had duodeli, only one of them were on concomitant methotrexate. Most of these, you have to remember, most of these patients had a rheumatological indication. Whereas in the controls who did not develop, the majority were on these immunomodulators. I will come back to this issue a little bit later in the talk. Just to show you a graph of a 55-year-old woman with rheumatoid arthritis who who was found to develop up to 800 in ALT. And just by following the liver tests, she spontaneously recovered after a few weeks. And no steroids were required, of course. The other side, maybe I apologize for this picture, because I've shown it before. But this is an old case, which was a typical case of infliximab-induced liver injury with this intensive inflammation, plasma cells, you can see apoptosis, ballooning, just all signs of of severe liver injury. And you just can see the more than two months after discontinuation, there was no improvement. So, you can see here on the graph, it was detected in the middle of April. And we gave her steroids in the middle of or in the late June, because it didn't improve. And this is frequently seen in those who require steroids. They even can increase in the ALT levels can increase even long after you discontinue the drug. So, we wanted to look at the effect of to define the clinical phenotype. And this was a paper that was published in 2022, was online in 21. And we wanted to see the effect of corticosteroids. And, because this is what was mostly from case report or very, very short case series. And this is the paper where we divided this paper, we were able to find 36 cases of infliximab-induced liver injury. This is collected over a 10 year period in our institution. And for some reason, other people have not been able to collect this number of patients, but from this small country, we could put them together. And we can see that time to onset to peak of liver injury was, of course, higher in those who had because they required steroids, whereas those who did not require they normalized very shortly. And we want to describe the clinical and biochemical features. And also, we wanted to see the risk of relapse of hepatitis after stopping steroids, because many of these patients were autoimmune hepatitis-like. They had the so-called drug-induced autoimmune-like hepatitis. And to see if they were, we were able to treat them with other TNF-alpha inhibitors. So, these were the cohort. We collected them from 2010 to 2020. And the decision to treat the patient with corticosteroids was taken by an old hepatologist. And basically, these were those were treated who did not normalize the liver test after you discontinue the infliximab. And as you can see, the autoimmune features were taken into account, but they didn't seem to have such an impact on the treatment decision. So, before the invitation of corticosteroids, most patients were off the drug for several weeks without observing any improvement in liver tests. Thirty-six patients, they were interestingly, the majority, 78 percent, were females. But during the study period in our institution, approximately 50 percent of patients who received infliximab were of female gender. So, this was, the female gender seems to be a risk. Interestingly, most of the, in our series, most of the cases were rheumatological or dermatological cases, indications. Only eight percent of three cases were IPT. The reason for this, we'll come back to that in a minute. So, the median number of infliximab infusions before the onset of liver injury was four, very few, less than 20 percent developed this after five doses. The median dose of 300 milligrams, as I showed you earlier, the dose doesn't seem to be a risk factor for this type of liver injury. Eighty-one percent had hepatocellular injury. And cholestatic was rare since then. I've had one more case of an old lady who developed prolonged cholestatic injury from infliximab, but this is rare. Six patients had liver biopsies and the most common histological picture was unspecific hepatitis with mixed inflammatory cell infiltrates, and relatively similar to what is seen in autoimmune hepatitis. Half had mild to moderate fibrosis, not so on, it's not, it's quite similar to the patients with autoimmune hepatitis as shown earlier. So, the corticosteroid treatment was started in half of the cohort. One was concomitantly treated with azathioprine before you realized that this was a drug induced to autoimmune hepatitis. This, the azathioprine was later discontinued without any relapse of liver injury for several years of follow-up. I usually treated patients without jaundice with 30 milligrams of prednisolone tapering, five milligrams per week. And those who had jaundice at higher dose, 40 or 50 milligrams. And the median dose from onset, the median time from onset of liver injury to start off the treatment was 44 days. And those that tended to have higher peak ALT, and time from peak ALT to normalization of liver amps was low in those treated with corticosteroids. But as you know, this is a difficult comparison because those who normalize spontaneously, they will obviously have shorter time to normalization. This is a graph of showing the progression of ALT elevations in all patients. And the rule was a very rapid normalizations of liver tests. Of course, it's not randomized, but the observation of the, they all without exception, respond beautifully to steroids. We were able to see that 33% had ANA positivity in those who had ANA measured prior to developing DILI. But after presentation of DILI, 67% were either ANA positivity or ITG elevations. Six had elevated ITG levels. And most of them had also a positive ANA. Only one had smooth muscle antibodies. Thus, 69% had autoimmune features at diagnosis. Interestingly, in the 36 patients, a similar proportion of patients with autoimmune features were also observed in those who were treated or we considered them to require steroids. Whereas those not needing steroids were 74%. And obviously it didn't change management. So the reason why we started them with steroids was because they didn't normalize. They still had high ALT long time after discontinuation. So when I was at the Mayo Clinic in one of my sabbaticals, I looked at the impact of liver biopsy. This is in patients with this is in patients with classical autoimmune hepatitis. And I found that in 95% of the cases who had already increased autoantibodies or gamma globulins, the histology was compatible with autoimmune hepatitis. But 5% had atypical histology. But it didn't seem that it changed so much management. 86% of those who had atypical histology were treated with immunosuppression. So people didn't like that paper, the message, because they want to have their biopsies, want to look at biopsies and understand them. But this is some kind of data. And I knew that during the COVID period, it was not so easy to get people with suspected autoimmune hepatitis for liver biopsy. So they were treated with corticosteroids anyway. So just coming to end the discussion of our cohort of inflection map-induced DILI, this is a rather mild liver injury. Only 11% had jaundice. But in some of these cases, they needed to be treated also. One reason for treatment was that they needed another biological treatment and their responsible physicians didn't want to treat them and they still had liver injury. We were able to taper corticosteroid treatment in all patients. And no patient had a relapse, although some of them had autoimmune hepatitis-like picture. 75% were switched to another biological treatment, mostly Adalimumab, and none of these patients developed DILI after the second biological treatment. There was a study, multi-centered study, both American and European patients. They found a very high HLA genotype in these patients with HLA-B39 with an odds ratio of almost 40. There were no corrections made for multiple comparisons, and actually we could not reproduce it in our cohort. We were able to collect data on more than 80%. We didn't find this HLA-LL in anyone. We had, similar to the brunoid, a slight increase in DQB1 and DRB1 with a 2 to 3 odds ratio. It's also possible that the identified association could reflect the genetic predisposition to the underlying autoimmune disease, rather than due to the liver injury by infliximab. There is a small cohort from Portugal with seven cases due to infliximab, DILI cases, one Adalimumab, and all of these patients were treated with steroids, and they say that two require long-term treatment, but those who had stock treatment didn't relapse. They say here that infliximab was cautiously started in one case without recurrence, and this is a lack of data in the literature. We need more data on what happens if they get a retaliance. This is just one of the studies. I think in sake of time, I need to go over it quite quickly, some of the slides, but we need some more data to help us to understand this liver injury. Although in our cohort, the liver injury was quite mild. There have been at least 10 cases at least that have been reported to lead to liver transplant with a severe liver injury, and if you just look at one column in the table, you can see in the middle concomitant immunomodulators such as methotrexate or azathioprine. None of these patients were treated, so maybe that's a risk factor. This was indeed pointed out by Louise Meunier from Montpellier, who is an active researcher in this field. She pointed out to us that at least 92% of those were treated with infliximab monotherapy, and in their cohort, they found a similar rate of liver injury as we did in Iceland, one out of 160 IBD patients, and they were not, didn't have immunomodulator treatments concomitantly. They reviewed the literature and found 75 cases with IBD. Only 6-8% was treated with this combination therapy of infliximab and azathioprine, so I think it's a very clever thinking that this is probably a potential protective role against the risk of liver, infliximab-induced liver injury, and we found similarly with the methotrexate earlier. So, it's relatively common, mostly autoimmune-like. In our hands, about 50% required steroids, but acute liver failure has been reported. Adalimumab, which is one of the most profitable drugs marketed in the world, or at least in the US, when the Humira has lost the patent, it's in several different biosimilars. It has less often been reported to induce clinically apparent liver injury, though acute liver has been reported, but it can, like infliximab, drug-induced autoimmune-like hepatitis. We had a review of the literature a couple of years ago. We were able to come up with 10 cases, 90% were females, and most of them diagnosed within three months of the therapy. Most patients continued on steroids, but in those who were reported in the papers who had stopped immunosuppression, no relapse was observed. We have thought that those who had the drug-induced autoimmune-like hepatitis, that this is one of the distinguishing features, that they don't relapse. These are from the study. I actually had this patient last year, a 49-year-old woman who started Adalimumab for some vasculitis, cutaneous vasculitis. She was found to have elevated liver one and a half years later. She didn't normalize when we stopped the Adalimumab, so we started her on prednisolone. As you can see here, when starting the steroids, it went out quite rapidly. You see here on the bottom here, the liver test was normal, but actually she relapsed after I stopped the steroids. It is, although it should not be too categorical. In most of these patients, they do not relapse, but this just illustrates how important it is to follow these patients with liver tests after you stop the immunosuppression. I'm coming to the end, a few more slides, and we have some time for discussion. Vetilizumab is one of these good biological drugs when the people get adverse effects due to infliximab or fail infliximab and their effect stops. This binds to integrin and on monocyte inhibiting the ability to enter the intestinal epithelium has been linked to mixed and cholestatic liver enzyme. Although relatively few cases, I was only able to come up with three single cases, but one small series from an IBD center in London, they found four cases that are compatible with diludo. They didn't show any signs of primary sclerosing cholangiitis and the result after discontinuation of this drug in one case of retaliance was reported. I had one patient last summer, he had previously 74 year old man who was very healthy except the ulcerative colitis. He was put on vedelizumab 300 milligrams in cycles. He received two doses in the beginning of May and three weeks later and or two weeks later and had completely normal liver test prior to the start. He developed very severe cholestatic liver injury with jaundice in one month later and a value of 0.32. He had ALP of 774 and this just happened after we stopped the drug. He went up to 1000 and despite the cessation of the drug, we did a liver biopsy and you can see on the right here proliferation of bile ducts and severe inflammation. Here you can see a granuloma, granulomatosis hepatitis and these were expanded portal tracts and here you can see cholangiopathy with severe inflammatory cells very close to that the bile duct and this is the, you can see the expanded portal tract but the liver lobuli was not affected and here you can see the development of alkaline phosphatase similar to the liver injury induced by infleximab. The liver injury didn't seem to want to to stop so I was skeptical. I did the liver biopsy. I saw this inflammation so I started narcotic steroids and complete normalization directly after that. Finally ustekinumab is a very good drug as well and can heal fistula and do good things for our patients. Only two cases of DILI have been described there. It's not certain if it's hepatotoxic but we need more reports if we are going to believe that. Apart from these two cases no convincing reports of clinically apparent acute liver injury. New kids on the block tofaticinib and osanimod have not been associated with liver injury as far as we know from reports but the former has been associated with hepatitis B virus reactivation and the other with barcelonazoster. I just wanted to show you a very happy group of people to show that it's very interesting, very nice to study DILI. This is from the left Gerd Kullag from Zurich, Raúl Andrade from Madrid and and myself with Jay Hufnagel and Vincent Chen from a new star from Michigan. Here are young people from Iceland presenting their work and finally I want to acknowledge my collaborators during the years since I've been involved in this interesting expanding field. First of all Jay Hufnagel I worked for at the NIH so I learned a lot from him. Also Victor Navarro who created I think and helped Jay to create the liver talks at least in the beginning. Harsat Devarpavi from Bangalore in India who I work with and as well as Guru Aithal from Nottingham work with him in the ProEurope DILI. Nakasya Lassani from Indiana who is a tremendous energetic person and had the last SIG talk before me four weeks ago. Raúl Andrade and his wonderful wife Lucena Maribel Lucena. Finally Fernando Pessone from Argentina who is a good friend as well and a good collaborator and last but not least my PhD student who wrote his PhD on DILI Helgi Bjornsson who is now training in Gothenburg Sweden. Thank you very much for your attention. Fantastic talk Einar. Thank you for summarizing all this all these different drugs. I'm sorry we gave you such a broad task but it is such a common consult and it comes up so often at academic centers where you have IBD which is I'm sure you've seen the graphs the rates of IBD are growing it's not clear whether there's an environmental factor or whatnot on the first line and a very effective treatment remains these anti-TNFs so I don't think the problem's going anywhere. I want to welcome everyone to put in their questions or raise their hand if they have questions but I'm going to kick it off by asking you this. We are a big IBD center as well and a specific case that came up a few months ago for us was a patient who had come from the outside was a referral and had tried a bunch of different medications and the IBD doctor wanted to kind of peel everything away and try anti-TNF again. She thought it was indicated she wasn't sure that the patient was truly a non-responder and had had adequate anti-TNF treatment trial and the patient actually happens to have autoimmune hepatitis. So I guess the question is are you hesitant starting anti-TNF in somebody with actually in her case she was uncontrolled so they were trying to figure out you know if she needs to go on tacrolimus or whatnot because she didn't respond very well. Are you hesitant? Are you hesitant with? Yeah that's a very good question. Actually as I say in our cohort one out of approximately 150 cases who received the infliximal delivery injury so only a small proportion will develop that and I would not be hesitant to use it and I will find out very quickly if she does tolerate it or not. Usually it's not severe limb injury and the risk is very low and actually this has been reported and used in the treatment of very severe cases of autoimmune hepatitis when the steroids have been tried in oasathiopine, sex-mp, cell-sept, microphenylmorphotel and tacrolimus and then some of them have responded to infliximal and actually I was contacted by a friend in Turkey who was collecting cases from different centers in the world looking at this and they come up with 20 cases from different parts of the world and we had one case who my colleague had and he was able to reduce the steroids from 15 milligrams to seven and a half but using every fourth week infliximab but she has a normal liver test now. I think after the Alkep data and the liver failure I think everyone's a little scared of using it. But I think you should also be as scared of a patient with autoimmune hepatitis were not well controlled. Yeah I know but they wanted the indication for this would have been for the IBD. The IBD doctor wanted to treat that and she ended up treating it and didn't respond and right now she's on the JAK inhibitor the patient but that was we were debating this could this make the autoimmune hepatitis worse so I wanted your opinion or trigger it you know make it. Jay please go ahead. A great talk. I wonder if there's something special about infliximab. It seems to stand out much more than the others and it remember the X means that it's a chimeric monoclonal and I wonder whether we should just move away from infliximab and use other anti-TNFs in these situations and yes the anti-TNFs are the hot new thing for autoimmune hepatitis as well. I'm also impressed that maybe we should use steroids more often and sooner and that you don't let the disease go on to it's self-perpetuating. Yes I agree with that. I don't know why we have more liver injury due to infliximab. As compared to adalimumab yeah. But I think we have very few data on the recurrence of liver injury if you introduced infliximab again. I think it's because you have so many alternatives good drugs you can use instead. Yeah I think that's the other thing once you treat and control that autoimmune liver injury from drugs that you might be able to restart it. The question would be how long should the enzymes be normal before you stop the corticosteroids? Should that be the rule rather than a fixed course four or six weeks maybe four weeks after normal? That is a very very good question but this is not a problem because within a two or three weeks they respond so fantastically. I tried to use them for six to eight weeks to taper it down but they are normal within three or four five weeks so I just taper it down. I notice your taper is very fast. Your taper is pretty fast compared to what we do for hepatitis. Yes. And then I think Herb has a question along the same lines. Herb you want to ask it yourself? Dr. Bonkowski. Hi, my question was what has been your experience in restarting infliximab after DILI ascribed to infliximab? Have you done it and what has happened? No, I haven't done it so I don't think it's ethical to do it if you have other alternatives but I'm waiting for a report in the literature of somebody who has done it inadvertently or some so this is a lack of data but I haven't done it because I haven't needed it but it's a very good question Herb. I didn't see your face though. No, I've shared that. Maybe we could ask Raul to comment about this as well. Andrade. Is he in the audience? First of all, congratulations. I know it's a very nice talk. No, just a reflection because in my hospital we have in a database more than 1,000 people with IBD. We don't see really this kind of injury. Maybe it can occur and it's not reported in isolated cases but with our current, you know, aware of DILI and our network in the hospital, it is strange that there are no reports of DILI related to this compousing IBD patient and on the other hand, for example, rheumatologists or dermatologists either report this kind of injury. So maybe genetics or ethnic differences because the rates of DILI associated with infliximab, for example, in Iceland is really high. But I mean in Montpellier in the south of France, which is relatively close, just one and a half hour drive to Spain, they seem to have the same proportion. Are they so different from you, the Frenchman? I don't think so. Maybe different in some ways. Raul, Herb here, are all those patients kept on azathioprine and the infliximab added? Yes, yes, yes. Azathioprine may be one of the explanations, no? At least in IBD patients. It's pretty standard now because of the autoantibody formation, right? That they give them low dose methotrexate or azathioprine, don't get antibodies against the mouse component. Andrew? Hi, Einar. Very nice talk. I put something in the chat, but I'm actually more interested about that colostatic case that you had with the integrin inhibitor. And what do you think, do you think it's maybe an effect on the microbiome or do you think it's, how do you think this is, why do they have this sort of granulomatous hepatitis from an agent that should be limited to the intestine? Yeah, that's what you said. Everybody said the same thing about infliximab. How can that lead to liver injury? It's a peptide. A lot of things we do not understand. I was a little surprised to see this, but a very similar case was reported by, what's his name, Stein? Jonathan, do you know him? Yes, Jonathan Stein. Yeah, so he had a very remarkably similar with this long-standing cholestasis, but the pathophysiology is difficult to, it's not that very logical. Was there vanishing bile ducts? No. That's very interesting. It was a proliferating, proliferation of bile ducts. This needs to be better described, this chronic colostatic injury that's not vanishing bile duct syndrome can lead to liver transplant. Did the patient ever recover? Yes. He had steroids. He recovered in steroids and I thought the story had ended like that, but a few weeks after he stopped steroids, he developed a mild injury again cholestasis, not so severe. I treated him again and now he has normal liver tests. Maybe I should write this, try to get it published. The MRCP was, there's no, MRCP was normal. Exactly. Usually these kind of licular cholestatic cases are due to cytokines, right? So like the effect of cytokines, kind of like a Stouffer syndrome, like a perineoplastic syndrome that you have these cytokines circulating and it just kind of interferes with the effect of the transporters. But that's what the odd thing is. How does that lead to transplant? I guess if you have enough buildup of toxic bile acids over time, it's just interesting. I'm just speculating. Obviously nobody knows. Have you repeated a liver biopsy in that patient after the sort of recovery? You think I should do it? Well, it would certainly be of interest. I don't know if it's going to help the patient. No, it can help us, but you know, he has normal liver tests now and is feeling well. He responded to the vedelizumab in terms of the colitis and if he develops cholestatic injury again, I would certainly think about that. This guy is a very positive guy and he said he believed in the experts, so he did everything I wanted him to do. You might look for genetic, you know, maybe he's got some sort of a heterozygote mutation of the transporters that puts him at risk. But he had completely normal liver tests when he began, yeah. Is that possible to measure those? Well, you know, you can actually order genetic tests or panels that look for cholestatic genes, so maybe he's got a mild heterozygote that makes him more susceptible to injury due to medication. That's the question. That's a very good question, good suggestion. I'm trying to take you off of share screen so we can see you better. Einar, I missed this part. You treated the cholestatic guy with steroids? Yeah, this vedelizumab case, yeah, I didn't know what to do else. But when I saw all this inflammation in the portal tract, severe necroinflammation in the portal tracts, I decided to give him steroids. And, you know, liver tests, they normalized almost... You treated the histology, even though the... I treated the histology, yes. Yeah, I think that makes sense, even though the biochemistry was... If he didn't have any, if he hadn't had any inflammation, I would not have treated him. Yes, yes, yes, I agree with you. I agree with you there. Very interesting. I think we're done. Are there any other questions? This has been amazing, excellent talk. Thank you so much. Thank you, everybody, for joining from all over the world. It's always lovely to see everyone here once a month. I woke up this morning, and I felt I was going to an exam, but, but... You know the feeling. You'll get your grade in the mail. We're a bunch of pussycats. A plus, A plus. Thank you, everybody. Nice to see you guys. All right, bye-bye. Thank you, guys. Bye-bye. Thank you, thank you, Ina.

Hepatotoxicity

Dr. Einar Bjornsson

Drug-induced liver injury

Inflammatory bowel disease

Azathioprine

Infliximab

Biologics

Corticosteroids

TNF-alpha inhibitors

Methotrexate