With patients that are just diagnosed. These are the big questions. Um, but maybe if anybody wants to lead off as we start, we are going to do maybe virtually.

Okay. The first question that we had asked in the Q&A, um, is from Aaron and she said, "How can the AIH medical community better educate doctors across the US? It is difficult to find good and up-to-date care." Yeah. So, that's a tough question. Um, and you may have already heard that we, we struggle with this. I'll talk a little bit more about this tomorrow, but one of the things is I'm going to turn it back to you guys. So, one of the way that we educate doctors is through patients. And nothing gets me more excited when a patient comes into my office and they tell me how they grilled their emergency room doctor that they saw last week about autoimmune hepatitis. Um, almost as a badge of of of honor and and how belittling it was to that doctor. But they'll never forget what autoimmune hepatitis is. So I also want you to know that AHA goes to the major liver meeting here in North America. Uh, we pander directly to doctors. We talk to them. We give them materials. We have trifolds. We have a a huge amount of information online. So all of our friends and colleagues, if they will ever let me talk to them, I always talk about the AHA. Uh, that being said, I'm going to still flip it back to patients. You have to be talking to your doctors, your primaries, because I think that's one of the issues is it's not just your hepatologists or gastroenterologists, it's the other care providers as a part of your team. Other ideas? Again, we have two esteemed clinicians here that didn't know about us before, you know, maybe eight years ago. How else could we reach you in your office? How could we how could we promote more education?

You know, I I I think that one of what I've noticed is when new drugs are approved, there is often a very big push for education through lots of different venues, through CME events, through, you know, directly to patients, having more of these types of conferences. Um, so I think that, you know, part of it is supporting what we can do with clinical drug development and getting the next big thing out there. And then we do see it, you know, there's another autoimmune liver disease that just had two treatments, two new treatments approved in the past year. And the amount of education that has been done, this is for PBC, primary biliary cholangitis. The amount of education that I've seen done in the past year focused on this disease is is unbelievable. And you know, people that are endocrinologists now or primary care doctors, they do kind of recognize this more. I think with, you know, the approval Dr. Dr. Talisani was mentioning, um, steatohepatitis with MASH. I think that there's just more awareness now as well that liver tests are important. So, um, hopefully just recognizing and monitoring or just checking liver tests now is going to be more of a standard practice because there's more knowledge about it that that there will be naturally more education that way too. Um, but I don't have any other, I don't have any other brilliant ideas.

Yeah, it's it's a it's a quite it's a big challenge that that we have as physicians and particularly the three of us are we're at quaternary care centers. Um, and so my colleagues that I work with, we're all aware of autoimmune hepatitis, but if you're seeing, if you're a doctor and and you've never seen it before, that's quite challenging. And what I would say is it's not necessarily that that person needs to be the expert. I think they just need to refer to people who are experts. Not everyone needs to be an expert in everything. Um, but really knowing when to refer someone if you see abnormal liver enzymes. I think I think that's that's also an important move to make too.

Okay. And then, um, the next question is, is there a concern with delaying an immunosuppressant for 12 to 18 months, steroid only for that time? Um, yeah, I I feel like that's a that is autoimmune hepatitis is a personal disease and I feel like that's a personal question and um, using steroids for 12 to 18 months is possible. It's not ideal, but that's something that whoever wrote that question should be discussing with their doctor. Um, they don't like that situation, then seeking other opinions is also okay. It also depends on the dose of the steroid. The higher the dose, the more sort of um, side effects that can occur from that.

Um, and this person also asked about the Shingrix vaccine, if it would protect against shingles if you are already taking MMF.

So the the efficacy of the Shingrix vaccine, it is still effective and we do recommend that our patients that are immunosuppressed still receive the shingles vaccine. Um, there's some thought that if you are taking medicines to suppress your immune system that some of these vaccines will be less effective. But we have seen that in in our in lots of different conditions where people are immunosuppressed, you know, transplant patients, autoimmune hepatitis, other rheumatologic conditions, that this vaccine is still effective. And if cell is more potent, is the immunosuppression also more profound?

I I yeah, I that's an interesting question. I wouldn't necessarily say that Cellcept is more potent or what you're comparing that to if you're comparing that to azathioprine.

That's my word. So if you don't...

Okay. So I I maybe um I don't necessarily think that Cellcept is more potent. There's a few differences between Cellcept and azathioprine that are important. First, like Dr. Weinberg mentioned, azathioprine has been historically used. The onset of action. So azathioprine can take several weeks to become effective before you know, as opposed to Cellcept, which can be immediately effective. So maybe that's quite maybe that's part of the difference with how potency is described. Cellcept, when you give it, it works immediately. Azathioprine, when you start it, can take six weeks to achieve adequate um effective therapeutic levels in the body to to be effective. I think that the in the trials that have compared azathioprine and Cellcept, while we see that it is more effective at achieving biochemical remission, a lot of that difference is actually because of the poorer tolerability of azathioprine compared to Cellcept. So there was higher discontinuation rates of the azathioprine than there were of Cellcept. And if you take that into account, you know, it's probably relatively effective. That being said, I do have a similar practice as Dr. Weinberg where I am using Cellcept more because I I think it is better tolerated for most of our patients.

Oh, do you want to go ahead?

So, so I think I just want to highlight, you know, this is really important for patients. Is the three of us are probably going to disagree on some things as well. Um, and I'm not saying I'm not and I'm not saying they're disagreeing, but I think this highlights a really important issue for this disease. One of the challenges is that gap, right? So it's experiential. That's the level of evidence that we're working with with autoimmune hepatitis in a sense. And Dr. Weinberg has talked, you know, individuality. This is a heterogeneous disease. You have to apply individual principles. There is not a cookbook. Any of my patients have probably heard me say that 20 times. I don't have a cookbook. Um, I'm just out there freewheeling by the seat of my pants, just like you. But, but we're using your data to drive those decisions. And that's why I'm so transparent with patients. So, I I say that now because if you see things here in this these talks that are very different than what you experience at home, that may contribute to part of the problem. Um, uh, so I I apologize to Aparna for that. It's more the potency. Those are my words and it's a shorthand way for me just to say that I just I tend to see more viral infections with mycophenolate, but that may also be anecdotal. Um, and so that is one of the concerns that when someone is asking me which medication to choose, this is that's my experience is that this one, mycophenolate, can work better, but there's other side effects. And so what's what's neat about this is this is a talk that we can now I now am able to have with my patients, whereas when I was doing this 10 years ago, it was sort of like azathioprine and prednisone, and that's what we do. And if that doesn't work, then we'll do one of those other things and hope one of those works. But now we really have we have more choices. And so it's nice to see that evolution.

Any questions here?

Thank you. Um, how is a flare defined and what, how do you know you're in a flare unless you just happen to randomly come across your routine scheduled labs?

So a flare is really defined and it's by an increase in the liver enzymes. And now the three of us can debate endlessly, and we have, about what number is that that indicates, and we don't have a real answer for that, but the sort of the qualitative thing would be your enzymes are at around a certain level and then we see an increase by more than what we would expect on normal variability. And that's sort of what a flare is. But it, it could, but it's important to also know flares can happen for a variety of reasons that are not necessarily just you need more medication. If you have an illness, viral infection, um, if you get dehydrated for extended period of time, there are all sorts of things that are are you taking a medication that could lead to elevated liver enzymes also. So the context is also important for when liver enzymes go up. Um, and then, uh, but defining a flare is, uh, again, personalized.

And I think the other part of that is how do you know which is, it can be challenging, but I think one of the one of the things that you heard Dr. Weinberg say, that you heard me say, is that you will be monitoring liver tests carefully. So at the beginning of initiating treatment, you know, every two weeks, every week initially, every two weeks, every four weeks, you are getting liver tests checked. You should be getting liver tests checked once you're in this sort of maintenance phase, maybe every one to two months or so, eventually spacing it out. Um, you are having liver tests monitored fairly carefully. So often times it is asymptomatic. If you're having symptoms, without a doubt, you need to get liver tests checked. But oftentimes these these changes in the liver test may be completely without any associated symptoms and it is just detected when your your provider says, "Hey, you're due for re, you know, repeat routine blood test monitoring," and those results come back slightly elevated.

So, just to comment a little bit further, I'm just curious with the audience, how many of you felt like you've had a flare coming on? You've called your doctor and the doctor has either blown you off or said, "Okay, go get labs." Anybody like? So, what what is that feeling like? Is it just a change from baseline? Anybody want to share?

No.

Just how you felt? Um, I just felt some of my initial symptoms coming back, but I think it was caused by another medication, but the doctor, my hepatologist kind of blew me off and said, "I think we need to do a liver biopsy." And I was like, "What? What?" And so, I'm not taking the other medication. I'm getting my labs done again next week. It's been about a month and a half, but yeah, I just had those initial symptoms.

Yes. So, a change in baseline. And I'm I'm going to say for my practice, my patients will call in and say, "Hey, something's off." It's a very easy thing for me. I love data. They go to the lab for me. And I think that's also somewhat therapeutic in itself. Do you guys approach it any way different?

I sometimes have, sorry. I sometimes for actually all of my established patients with autoimmune hepatitis, I will always have just standing blood test orders because if our clinic is closed or they can't reach me, they can't reach our nurse for whatever reason and they feel a little bit off. I just, they know it's one of the counseling things that I provide our patients at the beginning. They know that they can go to the lab and they can get their blood test checked and and will be pinged with the results right away. So, um, you know, just just having that openness about that being your sort of autonomy to go to the to the lab to have your blood test checked if you don't feel well, I think is important.

Thank you for taking my question. Um, I have two quick ones. First of all, thank you. Thank you. Thank you. Thank you. Um, I'm the husband, I'm the husband of, um, my wife who was diagnosed about a year ago exactly. And, um, I realized how stressful it is on her. So I may have to make sure the stress level that I can bring and stress is not good. I understand that. But my question is, the stress level on a patient could affect this negatively or positively? Could you speak on that? And the last question is on biopsies. When does should it happen? Immediately or after treatment? Thank you.

Um, yeah. Do you want to comment? Well, let me maybe I can take your second question with the biopsies and then I don't have a great answer for stress, but I can try my best. Um, biopsies are recommended initially to help with the diagnosis of treatment. So, or diagnosis of the disease to help diagnose autoimmune hepatitis. That is the time where it's absolutely recommended. It is not standard of care to continue to do biopsies throughout the course of treatment unless there's uncertainty about what is going on in the liver. So if the liver tests are not responding to the treatments that have been provided, is there something else that's going on that was initially missed or, you know, could there be a new drug reaction with azathioprine or one of the other medications that we're using? So routine liver biopsies are not recommended. The only other time where we consider it is when there's discussion about stopping all immunosuppression medicines. So if you've been in biochemical remission for two years and there's discussions with your physicians about stopping the medications, then a biopsy might be recommended at that time. Um, stress is not good. I think that in in, you know, in lots of immune-mediated diseases, there is literature to suggest that stress can affect the immune system and can activate the immune system. I don't know how much is understood in autoimmune hepatitis. I know that there's a talk tomorrow that sort of talks about the mental health a little bit associated with with autoimmune hepatitis specifically. Um, but but I do think I I have had patients definitely say that, "Hey, I switched jobs. I haven't been sleeping well. It's been really stressful in my life," or, you know, whatever the stressors are, and I think that's why my liver tests are up and I don't have another reason for that. So I have anecdotally heard the same.

And one of the challenges we face with stress is that uh glucocorticoids, they can cause you to have more stress. Why do they do that? They can cause insomnia. If you're not sleeping well, it's you're going to have more stress. If your blood sugar is off, you're going to have more stress. So, it's part, it's the sort of it's the mental health aspect of it, but then you also have a medication that is not helping you. So, trying to reduce the dose of corticosteroid to the minimal amount necessary can also help with that too.

Hi everybody. Um, should I stand up or sitting down's okay?

No, you're fine.

Um, I just had a question. Um, no one really talks that much about seronegative autoimmune hepatitis. Um, and that's what I have. Um, and I've been seronegative the whole time. And, um, I was just wondering if you treat those patients differently because I, uh, I've had to go through like a few years of three different hepatologists and multiple biopsies and then finally a diagnosis this year. And it just seems like I'm on a lot of medication because it's kind of an atypical thing. And so I think they're just like, I'm on three different medicines, so you know, including prednisone. But I just wondered if if that is, I mean, no one really discusses it. They haven't even discussed it today. So I just thought I'd ask about it.

Um, so, uh, Craig and I talk about this a lot. Autoimmune hepatitis is a, it, it really, it's a heterogeneous disease. So it, and, um, you know, I would say what you're describing is, uh, one is a, is a percent of what we have as the umbrella term of autoimmune hepatitis. And the reason that we have that, that we call it autoimmune hepatitis has a lot to do with what we see on the biopsy and how we treat it. Um, and there's the majority sort of follow what Dr. Dr. Goyle showed with, um, uh, there's a, there's sort of a calculator, I guess, of an algorithm that we use. So you get a certain number of points for, you know, if you have antibodies and if you don't have viral hepatitis and what your liver enzymes are and what your IGG is. But I once, and, and there's also a biopsy component in the more complicated one. Um, and so if, if, if you have a biopsy finding that is consistent with sort of im, um, your immune system attacking your liver, um, but you don't have those antibodies, then we would tend to treat it the same way. I do think that it can be more difficult to diagnose because people are often physicians are often taught that you need to have these criteria, but there are, um, times when really it's, it's, it's, it's really coming down to the basics of, is this something that immunosuppression would help? And are there features, uh, on the biopsy that we would see? Um, I don't know if you guys have other thoughts too.

No. So I think if you, if you pull up this calculator that we sort of showed, if you put in all the points for everything besides antibodies, um, it's very hard to meet the definite diagnosis of AIH. You can, depending on what the IGG levels are. So it can be a very challenging diagnosis to make. I think the hope is that if it is seronegative hepatitis, that the treatment is still actually the same. We had somebody in person submit a question, um, asking where they can find out more information on side effects, uh, for medications like azathioprine, um, and that it seems like they're looking for a reliable source.

I will say that we do have at least on our website a list, but this is not an inclusive list. And so if the, the question is more specifically to your own symptoms, certainly I'd want you discussing with your doctor, but also realize the FDA puts a package insert with every drug. You can certainly look on those package inserts. You can Google that pretty easily and see if anything aligns. I will have patients that come in after we start a medication because they know certainly I'm going to be asking how they're tolerating it, and they're going to tell me about their increased gas, their joint pain, uh, you know, their increased hunger. Um, and we'll walk through those symptoms. But again, I think that's the, the overall vector there is to try to decide, is that medication fitting for them? Are those side effects, if they are related to disease or medication, and are they tolerable or do we need to make a, a major pivot? So that information is out there. The problem is there's a lot of symptoms already enriched in this disease. The question is, is it related to drug or not? And that is a really important question that we spend a lot of my clinic time discussing. Can I ask you all a question? Um, how many of you all have spoken with a pharmacist in your clinic before you started medications or after starting medications? Okay. So, not a lot. Yeah, maybe like 25%. Yeah, I think that is, you know, we, we're fortunate enough, again, we're, we're lucky that we're at these big referral centers, but we're fortunate enough to have a pharmacist embedded in our clinic. And one of the things that we've started to do in the past few years is include the pharmacist in sort of the counseling for all of the medications that we're giving for autoimmune hepatitis as well. So they will review the monitoring plan in terms of, you know, checking, you know, Dr. Weinberg mentioned monitoring for tacrolimus levels, cyclosporine levels, sirolimus levels, they'll go over that if those are started. They'll talk about the common side effects, they'll review vaccination status and vitamin D levels, things like that. So, um, it's been super beneficial for for a lot of our patients. And if it's, if you have access to it through the clinic, I think that's kind of cool to to take advantage of.

It's a luxury. It is a luxury.

Um, so I I find that the discerning side effects from medications is a humbling experience for me. And what I've learned over the years is that if if someone comes in and tells me, "I'm feeling different than I did last time I saw you and you started this medication," then my answer is it could be the medication. Um, even if that's not listed in the side effect profile. So, uh, just to give you a story, this was one of the things I was going to talk about, um, but I went over too long. Uh, one of my patients was started on azathioprine and a few weeks later he had very high fevers. And I had not seen that before within. And so the first thing I was concerned about was, um, does he have an infection because he's now on immunosuppressant. He's been on, um, you know, some sort of corticosteroid and now he's been on azathioprine for a few weeks. Um, but it turned out it was the azathioprine and that was the first time I'd seen an azathioprine-induced drug fever. I haven't seen it since. Um, but I had to, uh, you know, I didn't dismiss it just because I hadn't seen it. I said, "Okay. Now, knowing that he was on a steroid, I felt okay because we could keep the autoimmune hepatitis under control for a short time while we tried to figure out what else to use." Um, but it's, it's really important that you tell your provider, uh, whoever's treating your autoimmune hepatitis, that if you're feeling different, whether it's a flare or whether it's a side effect of medication, whether you're coming up coming down with with another illness. Um, because even if that, uh, side effect is not listed in the whole list of side effects, that it's possible you could be that person that has had that side effect and hasn't been reported before. Um, I have them. Um, first of all, in response to your comment about pharmacists, I learned that a lot of the pharmacies have a system that I talked to them and told them about the liver disease. So they flagged me so that if someone is filling a prescription that has adverse effects to the liver, they will at least prompt a conversation with me or the provider, which is kind of a nice little extra safety net because I do feel like a chemical experiment. Um, my question is, do you commonly see or ever see any cardiac effects from medicines? Um, I had a fairly severe case. I was on 60 milligrams of prednisone for quite a while. Within, uh, days of starting the azathioprine, I had atrial fibrillation and was hospitalized. And then within seven months, I had six cardioversions and ablation. And I still have, um, irregular heart arrhythmias that I think are to me feel like they're more associated with tacrolimus that I'm on. But I didn't know if other, if you see other patients that have cardiac side effects from this disease or these medicines.

Yes. No, we, we can see that and I'm sorry that you've, um, that you're going through that and have gone through that. Um, prednisone can increase your risk of developing atrial fibrillation. Um, I'm not, I haven't seen it do it, but again, that may be, that may happen as well. And tacrolimus can increase your risk of, um, all sorts of things among the metabolic syndrome spectrum, which can increase your risk of sort of cardiac events or, um, and there are other parts that can sort of do arrhythmia. So, yeah, there, that's why, you know, it's, that's why this, particularly tacrolimus, it's, it's not one of the first things that we'll, we'll jump to.

We probably have time for about one more. Um, somebody was asking here in person about, um, the levels, um, for enzyme levels for azathioprine. How often do you need to be tested for it? What are ideal levels? Um, can you go into a little bit more detail about that?

Oh, I I think I addressed that in my next talk. Yeah, we'll defer that one and we can talk a little bit.

There's...

Any more in person?

I know. So, we are planning for a break here at 10:30, but we'll probably just lead into the break, but so feel free to get up and restroom or or drinks or there's still food out as well.

Did you guys want to go?

Have there been any studies about, uh, diet and autoimmune hepatitis? I know there are with other autoimmune diseases.

I'm not aware of that.

Yeah.

So, uh, you're, you're with an organization now that's funding a diet study looking at fatigue. You'll learn more about it tomorrow. Uh, fatigue is a, as a side effect of disease. We're going to talk a lot more about, we're under the belief that Mediterranean diet may be impactful for some of the therapy or as a strategy for management side effects. There is some data. The problem is doing diet studies are really, really hard. Um, and and again, making sure patients adhere to diet, but also to do a crossover and see if they serve as their own control. Do they see an improvement? So there is literature that supports diet. Probably the most robust is Mediterranean, studied more in RA or rheumatoid arthritis or lupus as well. So and again, I I also pick all my patients' brains. This is the best way of forming hypotheses, um, what helps them symptoms and or when they have, we've talked about loss or remission or flare, uh, what, what were they eating or what were they consuming? So I think these are the things that we start to dissect.

I was also diagnosed with celiac at the same time, so I changed my diet, and it kept lupus and rheumatoid arthritis...

Yes.

Interesting. Yeah, the, the celiac is another celiac disease. I don't know if anybody wants to share any any other celiac patients that would like to admit it. Uh, we, we see a seropositivity for TTG and and celiac disease maybe in three to five percent of AIH patients, give or take a few percentage. Something that I always search for in all my patients. Um, but again, that's an important aspect of how diet can modify. Of course, celiac's one of the number one causes of abnormal liver tests in young males that are diagnosed with celiac as well. Um, so there's more to that than maybe meets the eye as well.

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Presenter Q&A for Session 1, Day 1

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