Transcription
I'm really happy to be here. Uh, this is my third time at the AHA conference. Do I use this? This is my clicker. Um, so, uh, I'll be around today and tomorrow if you have questions you want to come up and ask me one-on-one. I'm I'm happy to answer those. I think we have a Q&A. Uh, Dr. Goyle and I have a Q&A after this talk. Um, and so if you have questions you want to ask the group, we're happy to answer them then, too.
>> [clears throat] >> Um, my talks today, I my first one I'm talking about is AIHA treatment or AIH treatment. Um, I'll be talking about medications, um, some treatment nuances, and then approaches to intolerant cases. And this is um, where I dug into my clinical experience over the last 10 to 15 years and just give some examples of how I've treated um patients that have had difficulties with some of the medications. Um, but I also want to open it up to you if if there are instances that you had um where you had intolerances and and sort of how it was dealt with or not dealt with. So, let's see if that works. Okay.
So, medications. So, the first thing I'm going to talk to you about is glucocorticoids. Um, this is a class of steroid. And the most common uh steroids, um, you know, when you hear about steroids, you tend to think, you know, what are they exactly? And I'll get into that in a second. But the ones that we're using, the glucocorticoids in general, we use prednisone in the United States, methylprednisolone, and budesonide. So, what is a steroid? See, is this pointer working? Oh, this is it's all these screens. All right. So I'll just I'll just talk.
Um, this for it's a little bit of a chemistry lesson I'm going to give you now. So if I haven't, it's been decades since I did chemistry, and some of you, it may have been even more than that. Um, what we're seeing on the left is a sort of a four-carbon ring, and that's the stair and steroids and sterile like cholesterol. So cholesterol really forms the backbone of what become uh steroids, and steroids are sort of the umbrella term, and glucocorticoids are under steroids. So, if you are recently diagnosed or if you've been on steroids and someone says, you know, you don't look, you don't look big. I thought steroids make you look really big. That's that's a different type of steroid. So, we are not talking about this. All right.
So, this is probably if you Google who is the most famous person to take steroids, this is what comes up. We have Arnold Schwarzenegger. This is before he was the the Terminator and the governor. And he used testosterone to get those muscles. Um, and that's what testosterone looks like. That's all you need to know. That's not what we're talking about. Okay. What we're talking about are these. In the top right, we have prednisone. That's what it looks like. That middle one on the right is methylprednisolone. And that complicated one on the bottom right is budesonide. That's all you really need to know for autoimmune hepatitis chemistry. Now, do you see how each of those has those? You see a pentagon and you see some hexagons? Uh, that's sort of all you need to know, and that that's the basis, and those little things that that come off. Um, my father-in-law is an organic chemist, so he would probably be mad at me for not explaining this in more detail, but um, those little things that come off, that's what makes it different. And you can see how testosterone looks somewhat like prednisone, but it's those little things that come off of the rings that make them different, and that's how they behave differently. So these these drugs can actually these these products can be made made in a lab. All right.
So here we have our prednisone molecule, and remember glucocorticoids are a type of steroid. So is um, say, estrogen, progesterone, and testosterone. Those are a type of steroid, but glucocorticoids are specific. Um, how do they come? What do they look like? So methylprednisolone, the the brand name is Solu-Medrol. So you may hear your physicians uh talking to you about Solu-Medrol. That's an IV form, and we can dose that anywhere from sort of 1 milligram in I in an IV to I I've used up to a gram um, particularly if if someone has um, rejection from a transplant, not AIH related necessarily, but um, these are sort of the dose ranges. Prednisone, this comes in pills. You can get a 1 milligram pill or what I've seen, I think, is up to a 20 milligram pill. The dose can range. I tend to, I have some patients on 1 milligram of prednisone. That's all they need. And when I'm starting out and moving from methylprednisolone to prednisone, sometimes I'll go up to 60 milligrams depending on the patient. Uh, the third one we'll see is budesonide. Budesonide also comes in pills. The doses, it's a narrow range. It'll be, they come in either 3 milligram tablets or 9 milligram tablets. And the dose ranges from 3, 6, or 9. It's very simple. Um, and it, I, if you, it actually is frustrating. I would like to be able to taper budesonide down to 1 milligram, but those pills don't exist. Uh, but a compounding pharmacy may be able to to do something for you there.
Um, this is this is the only math I'm going to talk about today in this lecture. This is what I call steroid math. 3 [clears throat] milligrams of budesonide is about 13 milligrams of prednisone. Um, I think Craig and Aparna and I could just debate this non-stop, but it's somewhere between 10 and 15. Does it matter exactly? It doesn't. It's It has to do with how much works for you. Um, and as I just said, if I could narrow, if I could decrease budesonide to 1 milligram, I actually think that would be great. Um, and that's about 10 milligrams of methylprednisolone. [clears throat]
All right. So this slide, I'm just contrasting prednisone and budesonide. So here we have prednisone on the left. So it can be used in a wide range of um, liver disease severity. So what Aparna showed you was the difference, the different um, presentations that you could have when you're diagnosed with autoimmune hepatitis. Asymptomatic, and you had a life insurance um, test, got enzymes, and they were up. Maybe you have jaundice, or maybe you are close to needing a liver transplant. We can use prednisone in in all of those. It's sort of like it would be what Oprah Winfrey would want to use. Everyone can get it. Um, they're easy to obtain, and they're cheap, right? There's no issues of getting prednisone at your drugstore. Very cheap. Costs a few dollars. And as I said, you can taper as small as 1 milligram. But there are side effects, and we'll go into that um, in in future slides. Um, they work well. If you could de, if if someone could develop a drug that worked as well as prednisone and had zero side effects, that's what we want, right? It's not whether prednisone works in some capacity. There's some people who uh may be non-responders to prednisone at all, but it probably works overall better than anything. And this is another thing that we could debate. How well does prednisone work? I don't, maybe we don't need to debate it, but it works very well. But the issue is it's not something you can take in the long term, or or it's, we we don't want you to be on it for the long term. Some people, that's that's the best option, but that's what we're trying to get people off of prednisone in the long term. Um, what about budesonide? Budesonide's also a glucocorticoid, but we can't use it in quite the same broad range. So it's limited to patients that don't have cirrhosis. And if you don't know whether you have cirrhosis, when I see a patient, someone that has jaundice when they're diagnosed, I don't like to use budesonide either because that tells me that there is some liver dysfunction. And why is this? The science behind this is you see that complicated thing in the bottom of your screen is the budesonide molecule. Budesonide is broken down by the liver into two uh different molecules that then don't really cause any problems. But if your liver is having trouble with its metabolism or metabolizing drugs, this budesonide molecule could then go sort of throughout your body. So we tend to use it if if someone doesn't have cirrhosis and they're not jaundiced. It's more difficult to find. Now, I will say that uh this is something that's changed over um my practice in medicine is that it's easier to find. I think if I had given this talk in 2010, this would be very hard to find and very expensive. But what I'm finding is that most most time when I prescribe budesonide, my patients don't have trouble finding it. Um, it is slightly more expensive than prednisone, but I think a month of budesonide, if you go on cost plus, maybe 30 or $40. So it's it's not breaking the bank. Um, and as I said, the tapers by three milligrams, and I find that frustrating. Um, it is, there are fewer side effects. Um, objectively, we see fewer side effects when I'm when I'm, if I'm able to move a p, move someone from prednisone to budesonide, people, some of these side effects that are associated with prednisone will go away. They don't always, depending on the dose, sometimes you can have a um, side effects on pred, on on budesonide um, but in general, they're fewer. And it works in some. So, uh, as like I said, prednisone works well. Budesonide um, there are times where I've tried it where it doesn't work. I move to prednisone, and that does work, even if patient, someone doesn't have jaundice or cirrhosis.
All right. So how do I use steroids? Um, so if I have a patient who is presents with their first um, sort of presenting symptoms with autoimmune hepatitis, they're hospitalized with jaundice. I don't know that my patient has autoimmune hepatitis yet. I know that they have jaundice, and I need to work that up. So, we get labs and a liver biopsy, as Aparna said in the last talk. Um, and this is where I'll use the IV version of a steroid. I'll use methylprednisolone, and I'll usually use it through 3 to 5 days around the time of the biopsy. If it's a weekend and I can't get the biopsy till Monday, I'll start it on the weekend. Um, there's some discussion on whether that will decrease the yield of the biopsy. And this is something that I learned from Craig years ago is no, it's fine. You'll still see the evidence if that's the cause of the disease. Start it as soon as you suspect. Um, if you find that the diagnosis is not on hepatitis, uh, a few days of steroids may cause a little bit of problem sleeping and some high blood sugars in the short term, but in the long term, you're going to be able to start treatment earlier. Um, so I'll use, I usually use IV methylprednisolone for a few days to make sure that one, this is and it's working, and I like to see those liver enzymes coming down while they're while someone's in the hospital, and then once I feel I feel good about it, um, I'll switch to oral prednisone on oral prednisone on discharge. What about uh, if someone's seeing me for an outpatient, they have elevated liver enzymes and their bilirubin's normal? So I'll do my workup, and that usually includes labs. I'm looking to make sure that it's uh, it's not viral hepatitis. There's not a drug-induced liver injury, and we'll talk about that in another talk. A liver biopsy, and often I'll start someone on budesonide or prednisone. Um, but this is where I, this is where I feel like I can use budesonide first.
All right. So that's a little bit about steroids. Now, what about the non-steroid immunosuppressants? I'll be telling you about what they are, when do I use them, how do I choose, and then do I need to monitor drug levels. So, and we heard about this in the last talk as well. Um, just to emphasize, anything that's important, uh, this is one of the things I learned in my first year of medical school. I was overwhelmed. So much information was coming at me, and uh, a wise person told me, anything that's important, you'll hear it more, you'll hear it enough times. Um, and so here I'm I'm saying something in a in a similar information in a different way, I think, and you're going to continue to hear about the different medications and the side effects and how we treat side effects and and taper medications. And I'm hoping over this uh, the next two days, something will resonate with you.
So what are the medications? We use azathioprine. The brand name is Imuran. I don't even think you can get that anymore, but maybe you can. We we use azathioprine. 6-MPP is what my um um GI colleagues tend to use. Uh, we don't tend to use that, but it's basically the same drug as azathioprine. Um, mycophenolate and um, uh, mycophenolic acid or Myfortic. For AIH, we tend to use mycophenolate, which is the brand name is CellCept. Um, but we could just easily use Myfortic. Um, on the right side, you see the sort of second-line or or third-line medications: tacrolimus, sirolimus, and cyclosporine. And I'll [clears throat] get into details about each of those in a second.
All right. So when do I use non-steroid immunosuppressants? Um, so this is, there's general practice and guidelines, and then there's sort of what we do as physicians and and why. And so I'll just tell you about my own experience and and what I like to do. So the the guidelines tell us we can start usually a few weeks after the initiation of steroids. So um, there's something called a TPMT. This is an enzyme that your body uses to process azathioprine or 6-MP. And we'll often check that at diagnosis to see whether azathioprine is a drug that can be used. But when to start this class of drugs, it's personalized, and it's okay to delay initiation. And as I found that I'm the longer I'm in medicine, I feel more and more comfortable delaying the start of the non-steroid immunosuppressants um until someone feels comfortable. Uh, could it be within two weeks? It can be, but often I'm starting it later than that, really because the months before and after a diagnosis of autoimmune hepatitis can be some of the quite, you know, the most challenging parts that someone's ever lived through. You're going through months of fatigue, jaundice, um, feeling unwell, difficulties at work, and then after the diagnosis, we're giving steroids at sometimes high doses that can also make you feel bad. To introduce yet another medication into the mix, it's it's often maybe a little bit too much, and so it's not really necessary. What I usually like to see is that things are improving. People understand what their um diagnosis [clears throat] is and and and how we can move forward with that. And then I'll usually start a non-steroid immunosuppressant. So I want people to start feeling better. And then the idea is that okay, now now that you're feeling better on the on the glucocorticoids, let's try to get you off of them. So in general, I try to start it within two months, but it, it really, this is something that um, I talk with my patients about um, when they feel comfortable.
Um, so these are the sort of the two main non-steroid immunosuppressants we use. So mycophenolate, this is a twice-daily medication. It, it's generally more potent than azathioprine and 6-MPP, but we could debate that. It doesn't require drug monitoring. Now, that doesn't mean that there shouldn't be drug monitoring. It's just we haven't developed a way to monitor this, and so we don't, and it's not safe in pregnancy. Um, azathioprine or 6-MPP, this is a once-daily drug. It's a little bit less potent. There is monitoring that we can do, so that's the TGN levels, and I'll talk to you about that in my next talk. Um, and it's acceptable in pregnancy. So, how do you choose among these? Um, well, if you don't have a, if you, if you don't know, you can let you know, your your provider can say, can can let you know which one they like to use and monitor that way. If you're someone that has difficulty taking a drug twice a day and really just needs that once-a-day drug, azathioprine is a better choice. If you are of childbearing potential, azathioprine is a better choice. Um, but there are, but but as you can see, it's it's a little bit less potent, azathioprine um, and uh, there can be side effects that you get with azathioprine that you don't get with mycophenolate, and in a future slide, I'll show you a little bit more about the details on their efficacy.
So what are the side effects? Both these medications can cause GI side effects, whether it's diarrhea, abdominal pain, nausea, vomiting, and infections. Underneath that are the sort of differences. So I do see that mycophenolate, it's it's more likely to cause some of the diseases associated with metabolic syndrome, particularly uh, high blood pressure, diabetes um, and this was actually, seeing more and more patients with with high blood pressure was one of the things um, on mycophenolate was one of the things that uh, made me think about looking into this more, and and and Craig and I actually did some research on looking at metabolic syndrome before and after a diagnosis of autoimmune hepatitis. Um, one of the things that we also see with mycophenolate, or I've seen, is is shingles. Um, and so I always recommend before starting mycophenolate, uh, to get the shingles vaccine, if it's available to you, and cold sores. I've seen many a lot of cold sore outbreaks. I tend not to see cold sore outbreaks or shingles as much within um, but it could happen there too. What do I see? What are the concerning things I see with azathioprine that are different from mycophenolate? Pancreatitis, 5 to 10% of people with azathioprine can get pancreatitis, and that can be severe. It can lead to a hospitalization. Anemia is is more common, I would say, with azathioprine than mycophenolate. And leukopenia, that's the that's the medical term for a low white blood cell count. And I see that routinely uh, with azathioprine. Uh, another thing I've seen with azathioprine is is drug fever. I have been yet to see that with mycophenolate.
So, did this come out? Okay. You guys can see it. So um, this is the CAMEO study. This is a graphical abstract. So all the journals now want us to do these so that you don't have to actually read it. You can just look at a picture and say, okay, I understand what this article is saying. So this is uh, the latest landmark study in autoimmune hepatitis. It came out in 2024. Um, and it was done in um, the Netherlands and in Belgium by uh, basically the equivalent of of Craig and Aparna and I, people that are really doctors that are interested in in treating autoimmune hepatitis and making people feel better. So they said, why don't we look at azathioprine and mycophenolate head-to-head? And what they did was people were on steroids uh, at at the start of the after a diagnosis, and half of the people got azathioprine, and half people got mycophenolate, and they followed them out for six months, and they wanted to see who had normal uh, ALT and IGG after 24 weeks. And and really, mycophenolate did much better than azathioprine. So you can see that there uh, it's something 50-some percent achieved this what primary response compared to azathioprine in the 20s. Um, so you'd say, well, should why should we use azathioprine at all? And what we're finding is that we're using more and more mycophenolate. Um, it's an effective drug um, and and it works well. But as I as I pointed out in that last slide, there are some reasons to use azathioprine. And this is where it can be personalized. So, what's my approach? Um, I provide when I see someone, I provide them with the data about the side effects and let I let people decide um, because both of them can work in the right patient.
So what if azathioprine and mycophenolate aren't enough? Um, as we heard in the last talk, we have tacrolimus, sirolimus, and cyclosporine. So these three medications are sort of the backbone for transplant immunosuppression. So they are more potent than azathioprine and mycophenolate. Um, they are the reason it was really the advent of cyclosporine that made it possible to do solid organ transplants. Um, now we typically use tacrolimus as the back as the main backbone, but I'm also a transplant hepatologist, and I use all three of these drugs in patients with liver transplants, mostly tacrolimus, but I still use sirolimus and cyclosporine sporadically. Um, these all require drug level monitoring, and what we're doing when we monitor these um levels is for both effect and toxicity, and and it can be really a narrow window there where you get the right effect without having toxicities of the medications, and the medications really do um, in the long term, can cause toxicity. Tacrolimus is probably the uh, the the best of these drugs as far as transplant goes, and we see it, it inherently causes kidney disease. So you cannot have kidney disease prior to taking tacrolimus, but the drug itself leads to kidney damage over the years. That leads to high blood pressure. Uh, frequently, we can see people can have a tremor. Uh, it's very common with tacrolimus to have a tremor. By decreasing the dose, sometimes that tremor can can decrease its intensity or go away. But sometimes even at very low doses of tacrolimus, I can't get the tremor to go away. Neuropathy. Um, I have a lot of patients who tacrolimus is working well for their liver, but they're getting progressive neuropathy, numbness in their hands and feet, and high potassium. Um, and that is one of the things, the the kidney disease and the high potassium are something that I monitor on labs, in addition to the tacrolimus level. So it, it requires, I, if if steroid, if if azathioprine and mycophenolate aren't enough, and we're using these medications, it really does, it cause, it requires more monitoring than those top medications do.
What about sirolimus? Um, I don't use this that often. When do I use this? I tend to use sirolimus when um, someone needs something that's more potent than azathioprine or mycophenolate, but maybe has kidney disease or had or or kidney disease was starting to develop on tacrolimus. Sirolimus has its own issues. Um, it causes poor wound healing, and it increases your risk for bacterial infections in ways that tacrolimus doesn't. So that's sort of why I put it on the second. Cyclosporine. It's really the least potent of the three. You can look at it as tacrolimus, but not quite as good. It has fewer side effects, but it's not quite as potent. But it's in the same class of medication as tacrolimus is. They're both calcineurin inhibitors, and so it can do the same thing that you see for tacrolimus.
Treatment nuances. So the picture you see on the right are the latest guidelines from the European Liver Society, and this is how they're recommending tapering steroids. Um, I tend to take a more practical approach. In general, I like to keep people on prednisone about 30 milligrams until the ALT is less than 100. And then once the ALT, and then I usually move to, that's five minutes. All right, I'll go through quick. It's fine. I usually go through about, and then I'll go to 20 milligrams. I usually keep people on 20 milligrams until the ALT is about 40, and then I start tapering, as you can see there. 15, 10, 7.5, 5, 2.5, and then off. I really, the, if we taper too quickly from from steroids, you can feel miserable. So I tend to do a taper every two to four weeks. How do I taper budesonide? In general, I keep people on 9 milligrams until the ALT is below 40, and then I'll taper about about three milligrams a month. And this can differ by provider. This can diff, and it really, it's an interactive based uh, or responsive to labs.
What about flares? I I tend to use prednisone or budesonide in the short term um, when there's a flare, and I'll also increase the dose of azathioprine or mycophenolate if possible. This is also a time where I may consider switching medications if the flare develops. Uh, particularly if if it's not in when I'm tapering medications and I see something like this. Uh, let's see there.
So, treatment nuance, managing side effects. How do we manage insomnia? So with the with steroids, insomnia, thin skin, high blood sugar, bone loss, cataracts. So, insomnia, really trying to decrease that dose. Taking steroids first thing in the morning may help some, but it might not. But that's usually the first thing I recommend. Thin skin, make sure that um, that your skin is not dry. You, the steroids in the long term can cause sort of thinning in the skin, more prone to cuts. Um, and so um, you want to make sure, try to keep the integrity of the skin good. High blood sugar. Again, trying to decrease that dose of steroids if possible. Um, and then this is where sort of nutrition is going to play a role. Um, cataracts, uh, I'm skipping bone loss for now, but cataracts is one of the things steroids can cause a different type of cataract than what you see with age. So, age tends to cause a posterior cataract, and um, steroids cause an anterior cataract. And sometimes when those line up, you can, someone can start steroids and then a few months later, they can't see because now the way that this the cataracts are lined up, you need cataract surgery, and that actually is a cure for it. Um, what about azathioprine or mycophenolate? I talked to you about the pancreatitis. Um, this is an issue. If pancreatitis occurs, that's usually when we're stopping. GI side effects, those can be tough. Um, Myfortic tends to have less uh, GI side effects than CellCept. So that's a switch that can be made, and and high blood pressure on mycophenolate um, is something that I'm watch.
All right. Immunosuppression withdrawal. When to think about this? And we touched a little bit this in the last talk. Um, what our guidelines say is two years after complete biochemical response. Once that occurs, I'll start. So that means normal labs. What is complete biochemical response? It should be normal labs. What we'll, what I'll do is I'll then minimize immunosuppression as much as I can with one drug only, and I like that drug not to be a steroid. So usually someone is on azathioprine about 50 milligrams or mycophenolate 250 milligrams twice daily. I have some patients that just take it once a day, 500. That's fine. Some we can consider a liver biopsy prior to withdrawal. Um, if I do withdraw, then I usually recommend monthly blood work um, because there's about an 80% chance of a flare after starting medication. Um, and so that's really up to you and your provider about whether you want, if you're in remission, if you're in complete biochemical response, and you want to try, um, that's, you know, that's up to you. If you don't want to try and just want to be maintain and stay on very minimal expression, that's fine, too. Um, let's see. Megan, do I have enough time to go over these or >> things? What's that? >> Yeah. Yeah, that's fine. This I I, the my last section is on um, intolerance and just sort of how I manage different side effects, and but I'm also happy to talk about it in the Q&A. I think that's a good part to segue. All right. Thank you everyone. [applause]