Dermot McGovern, MD, on Extraintestinal Manifestations in IBD

Dr McGovern discusses the results of a study he and colleagues conducted into the genetic and serological associations of extraintestinal manifestations among patients with inflammatory bowel disease. 

Dermot McGovern, MD, PhD, is director of Translational Medicine in the Inflammatory Bowel and Immunobiology Research Institute at Cedars-Sinai Medical Center in Los Angeles, where he directs the Cedars-Sinai Precision Medical Center and holds the Joshua and Lisa Greer Endowed Chair in IBD Genetics.

TRANSCRIPT:

Welcome to this podcast from the Advances in Inflammatory Bowel Disease Network. I'm your host, Rebecca Mashaw, and today we're joined by Dr. Dermot McGovern, who is the Director of Translational Medicine in the Inflammatory Bowel and Immunobiology Research Institute at Cedars-Sinai Medical Center in Los Angeles. He also directs the Cedars-Sinai Precision Medical Center and holds the Joshua and Lisa Greer Endowed Chair in IBD Genetics.

With all of that on your plate, we really appreciate your time to talk to us today about a recent study you did on extraintestinal manifestations in IBD. So to start with, why did you choose to conduct a study into EIMs?

Dr McGovern: Well, thank you, first of all, for having me on. I really appreciate it and the opportunity to talk about our study. I have been interested in the Action Test and Manifestations in IBD since I did my training. I did my PhD and my fellowship in Oxford in the UK, and my professor then, Derek Jewel, was very interested in in these manifestations.

So I think my first interest in these more systemic manifestations was triggered then. But you know, when I'm in my clinic with my IBD patients, I really try to think a little more holistically than just thinking about what's going on in their gut. And one of the most obvious sort of more holistic manifestations of their disease are these extraintestinal manifestations, but our work goes beyond that.

We really try to think of the patient in this whole or holistic way, because they do have either Crohn's disease or ulcerative colitis, but they have ...they’re humans beyond that. And the joint manifestations that we're going to talk about, and other manifestations that people think about as extraintestinal manifestations are one thing.

But we also think in the research that we're doing, can we think about their cardiovascular risk, their risk of developing cancer, things that we all worry about, but also some of these things may be more relevant to people who have ulcerative colitis or Crohn's disease. So I've always been interested in this area for scientific, but also for clinical reasons.

Rebecca Mashaw: Could you give us an overview of your investigation?

Dr McGovern: Sure. I think one of the things that we realized, studying genetics, is that the power is in getting numbers of participants in the studies. And so what we did—and I have to say this was, this has been a real labor of love, this took us a long time to get together.

And I think I must give a big shout out to Talin Haritunians, who's the other senior author on this, who's a professor in my group. Her persistence and optimism through this study really carried it through. Because we needed to try and get as many participants in the study, as I said.

So we have 4 cohorts, one from Cedars, one from the NIDDK IBD Genetics Consortium, and my longstanding collaborators there from Rutgers, Hopkins, University of Toronto, Montreal, Pittsburgh, and Mount Sinai-New York. Also the RISC cohort, which is the Pediatric Inception cohort, which was supported by the Crohn's and Colitis Foundation, and also SHARE, which was another consortium supported by the Helmsley Charitable Trust, and colleagues there at the Mayo Clinic, UNC, Mount Sinai again, Chicago, and Wash U. So we were able to get 12,000 subjects together into this study of European ancestry. And that’s a limitation of the study and perhaps something we can come back to a bit later. And we were able to define, of these subjects with ulcerative colitis and Crohn's disease, who had extraintestinal manifestations. So these all came from major centers with deep interest in IBD.

And so we studied specifically clinical factors associated with developing these, some serology in a subset of them, and also genetic factors. And the action test manifestations we were looking at were things affecting the liver, so primary sclerosing cholangitis— which is one of the major things that we see in our patients and with limited treatment options and something that we really need to understand more about—but also arthritis, both peripheral, so affecting the small joints, particularly the hands, but also some of the more central joints such as the spine and the sacroiliac joints, so ankylosing spondylitis; psoriasis, so that skin condition; and also in the eyes as well, uveitis and iritis. And so we just, we studied all of those individually but also brought them together to see if we could get more signals out of that.

And we found what we think were some interesting things. People with Crohn's disease were more likely to have extraintestinal manifestations than people with ulcerative colitis. Women were more likely to have these manifestations. They were more common in people with colonic disease, so large bowel inflammation, and people who'd had surgery or needed surgery for treating either their ulcerative colitis or Crohn's disease, and on the whole, smoking tended to increase the risk of developing these.

We found some serological associations. ANCA, which is one of the serological markers associated with colonic disease and nonresponse to anti-TNF therapy, was associated with these. And then in the genetics, we discovered some things around the HLA, the MHC, which we sort of knew. And also the genetic analysis pointed at some potential therapeutic opportunities, with these such as, well, things we knew about anti-TNFs, for example, or the JAK-STAT signaling pathways to the whole JAK inhibitors and we know that those are useful across these different manifestations. So that was that was very nice sort of positive internal control. And then a sort of intriguing result around something called IL-6— interleukin 6, which has previously been implicated the biology in the development of fibrosis and skin and so on.

So again, that was actually really interesting for us and people are beginning to think about, I've already thought about this in the past, but maybe not in a targeted way of using anti-IL6 type therapies across the immune-mediated diseases.

Yeah, so we were very pleased with the study. It confirms some things that we already knew, which was nice. That was a sort of positive internal control. And we discovered some new things. And I think we really highlighted that this is, studying these manifestations is a really important part of understanding the biology of IBD in general. But as I said, many of our patients suffer with these and often the symptoms of these are even more severe than the symptoms that they have from their gut disease. So trying to really understand what causes these is really important.

Rebecca Mashaw: In your experience, when a patient comes in to see you about their IBD, do they bring these things up? Do they know that this skin disorder that I seem to have may be related to this, or is this something that the clinician really has to probe for?

Dr McGovern: Yeah, it's a bit mixed. I think we do need some better education to tell our patients that these are the things that they should be thinking about. And there are some obvious things. If you have a big ulcer on your skin, you normally tell someone about that. It's pretty obvious. But I think more subtle things when people are perhaps getting that pain in their back, particularly, you know, early in the morning, it's stiff, they get out of bed that, you know. I know as we get all get a little older, that's true for a lot of us. But those are the sort of things that you should be mentioning. And actually on the health care side, we also need to educate our side of the partnership, which is to say we should be really asking these questions because I think that we probably don't capture this information as much as we should do.

And of course that's important for clinical reasons but it's also important for research. So I think that all around we would recognize that we need better education. One of the things that we're trying to do in that space and there's quite a lot of work going on here trying to improve the capture of this information, education around it.

So I think this is going to get better. And one of the things that we're doing at Cedars is we're starting a clinic for people with either ulcerative colitis or Crohn's disease who have these extraintestinal manifestations so that we can see them together with a rheumatologist, for example, and come up with a joint plan about managing both their gut and their symptoms and all that inflammation outside the gut as well.

Rebecca Mashaw: Now I understand that there are there are patients who once you get the gut settled down some of the EIMs also settle down— they're directly related to the IBD.  But sometimes they are not and I would think that's where the rheumatologist’s input would also be very helpful. So what's your experience been with your multidisciplinary approach to those issues?

Dr McGovern: Yeah, I think that you're absolutely right. So some of them settle down, you know, the big focus is on get on top of the inflammation in the gut and some of these things will resolve, but others don't.

And we need to think about what if we're going to take a medication approach, which of our drugs are effective for both gut and some of these other areas of inflammation? And previously, if we thought about what treatments we had for IBD, so in terms of talking about biologics or advanced therapies, we have the anti-TNFs, for example, and they are effective across some of these manifestations. So perhaps some of these discussions may not have been so important, but now we have drugs which are gut-selective, such as vedolizumab, and, you know, I think that's where your question becomes particularly important.

So if vedolizumab will treat the gut inflammation, is this a person where treating that gut inflammation, their other manifestations will go away? And this is the sort of work that I think really needs to be done going forward. And then as we get more and more different mechanisms of action, we've talked about the JAK inhibitors and there's other things coming down the pipe and already in the clinic, you know, some of them work in some of these other manifestations, some of them don't. And I think that's why it's really important that we increase the education around this, because if someone does have that inflammation in their back, for example, are they on the right treatment, which will help both their gut and their back inflammation?

Rebecca Mashaw: You mentioned that multiple serological associations were observed. Can you talk a little bit about those kinds of associations and how understanding those can approach clinical care?

Dr McGovern: Yeah, I mean, we identified a few serological associations. You know, I think probably the one which was most significant was the ANCA association with primary sclerosing cholangitis. So that fibrotic disease that is in the biliary tract in the liver.

And I think that the significance of this, and some of our results would be that, and this is what we're doing at the moment, is can we take those markers, perhaps together with some of the clinical factors and the genetics, to create models that identify people at risk of developing PSC and some of the other manifestations. Because again, that might help us with treatment choices, and also help us with screening strategies to identify people who are at risk of this. So, you know, we know where there is evidence that PSC, that primary sclerosing cholangitis is underdiagnosed in our IBD cases—we're missing cases of that. And so if we can develop a model which identifies people at higher risk of that and actually incorporate that into clinical practice and actively go looking for PSC, I think that would be a significant advance forward.

So that's one of the advances that I think the serological findings could help. The other is that perhaps some of the serological markers are reflective, there's some evidence now reflective of what's going on in the gut from a microbiome perspective. Now, it's not a microbiome study, but perhaps they reflect what's going on in the gut. And we have started to see microbiome associations now with some of these extraintestinal manifestations. So perhaps this is shedding a little bit more light in that direction as well.

And I've talked about the therapies that are currently in the clinic, but also things that are being developed. And I think that there's a lot of interest in targeting the microbiome when treating IBD. But again, if we start to understand the microbiome associations and so on with these extraintestinal manifestations, perhaps this introduces an opportunity there and understanding which individuals and what their microbiome or what their genetics or their serological profile is part of that sort of path towards more personalized or precision medicine, which is we think about markers—that whatever they may be that people have that would indicate that they are better candidates for one therapy versus another, basically. As opposed to the slightly less objective, more subjective approach that we have at the moment.

Rebecca Mashaw: I think that's the dream of every physician who treats patients with IBD is to have those tools so you can really target what's going to be the most effective treatment, because again my understanding is that the first treatment is always going to work the best and as you start cycling through treatments you're going to start to lose response.

Dr McGovern: Yeah the first treatment is your best chance of having a big response. It doesn't always work the best because of the reasons we just said. You sometimes may have the wrong mechanism, so identifying that right mechanism for that person who's sitting with you in the clinic as you're making those treatment choices together would be a major, major advance for us. There's a lot of work going on in this area using clinical genetics, proteomics, all the omics, using it.

We can't talk about this stuff without talking about AI and machine learning. So people are really trying to bring these big data sets together and really advanced statistical AI type approaches to really identify the signatures that we need in the clinic.

Rebecca Mashaw: Speaking of big data sets, your study was the largest multicohort data set to date, correct?

Dr McGovern: Studying specific specifically the EIMs, yes, absolutely. There are bigger data sets. We're part of the International IBD Genetics Consortium, for example, and there are studies coming out which will have more than 100,000 participants with IBD, which is great, absolutely great. we're trying to, you know, going forward, we're trying to line up this sort of clinical data, both the IBD or the gut data, but also these extraintestinal manifestation data as well so that we can continue to build on the study that we've done here with bigger cohorts.

Rebecca Mashaw: You mentioned early on that your cohort was almost all of European ancestry, and you said you’d go back to that topic. If that one of the next things that you need to do, is to start looking at mixed cohorts, or perhaps now maybe you need a cohort of all of people of African ancestry or Asian?

Dr McGovern: Yeah, yeah. So this is an absolute need for us. I mean, there clearly are social and ethical reasons why we need to be doing that, but there are very important scientific reasons why we should be doing that.

So our group with others have actually been pushing this for a number of years now. So we've been fortunate enough to work with great partners and participants and published the first, for example, genome-wide association study in African Americans, not looking at EIMs, but looking at IBD, the first whole genome sequencing in African Americans. We've done the first large study in Hispanics, Latinx community, and our whole genome sequencing study as a partnership with the University of Puerto Rico, University of Miami, Mount Sinai New York, and others, will be coming out soon as well. And we've also been fortunate to be participants in large East Asian studies. But these have really been in looking at the genetics of ulcerative colitis and Crohn's disease and together, of IBD. Not really so much in this space with the extraintestinal manifestations. So as we develop those cohorts, we are collecting that data, so we will be able to do those studies. And it's very, very important for us to make sure that the benefits that we talked about previously for precision medicine, personalized approach, don't make disparities that we see in health care greater. They need to do the opposite. They need to be a tool for us to start to narrow that gap. And, you know, that's very much the philosophy that we've adopted to try and, one of the tools to try and to reduce those disparities that we see.

And just one other thing I want to say in that space, that space at the moment is that actually, I just come back from Africa, and we've just founded a sub-Saharan African IBD research group. So I was privileged to work, to be at this meeting with groups from Nigeria, Ghana, Sierra Leone, Zimbabwe, Zambia, Kenya, and South Africa. We’ve started to collect samples and collect clinical information. And as you were seeing an evolution of these diseases in sub-Saharan Africa, start to collect that information and so on. So, you know, I think that and we want to collect the extraintestinal manifestation data clearly.

So, you know, we're really trying to push hard in that direction. and we just need to continue to work hard and make sure we're very diligent and persistent there.

Rebecca Mashaw: So there's much more research to be done.

Dr McGovern: There's always more research to be done we get answers and sometimes our studies throw up new questions for us to follow.

Rebecca Mashaw: That seems to happen most of the time yes.

Dr McGovern: Yeah that's the nature of medical research you push through one door and then you have other doors that you need to need to pursue. But yes, I mean, we're making really significant progress in the areas that we've talked about.

But for every genetic association we discover, we need to do functional work to find out what that genetic variation that we've identified is telling us about the disease and so on. So yes, plenty of work to be done.

Rebecca Mashaw: Are further thoughts for our listeners, and particularly for clinicians who are working with patients who have IBD?

Dr McGovern: You know, I think my clinical colleagues know this, but we should never forget the burden of disease that people carry with IBD and that it's not just restricted to the gut. So often these extraintestinal manifestations in the heat of the moment can be overlooked when you're trying to resolve the gut inflammation and so on. But I think, you know, my colleagues do this all the time, but we all need to be reminded to think holistically, you know, think about the partnership we have with our patients and that we should be asking them about, you know, the quality of their life. And the quality of their life is not always. driven by what's going on the gut if they've got very bad joint inflammation and can't do the things they want to do—work, exercise, be with their family, go out for that hike or whatever it may be—because of joint inflammation that that's as important as their gut inflammation to that person maybe you know having a bigger impact on the quality of life so we should we should always remember that.

Rebecca Mashaw: Well we really appreciate your time today and I look forward to talking to you again as more of your research comes up for publication.

Dr McGovern: Thanks for your time. Yeah yeah thank you very much appreciate you taking the time and the interest in our research so. It's very interesting, thanks so much.