IBD Drive Time: Florian Rieder, MD, on Extraintestinal Manifestations

On the latest episode of IBD Drive Time, our host Dr Ray Cross discusses extraintestinal manifestations with Dr Rieder.
 

Florian Rieder, MD, is Vice Chair, Co-Director of the IBD section and Director of the Advanced IBD Fellowship program at the Department of Gastroenterology, Hepatology and Nutrition at the Cleveland Clinic, Cleveland.

TRANSCRIPT

Ray Cross, MD:
Welcome, everyone, to IBD Drive Time. I'm Raymond Cross from the University of Maryland School of Medicine, and I'm delighted to have my friend and colleague, Florian Rieder, from Cleveland Clinic here today to talk about extraintestinal manifestations. Flo, welcome to IBD Drive Time.

Florian Rieder, MD:
Thank you, Ray, for having us and thank you for developing this innovative format.

Dr Cross:
Thanks, Flo, and before I ask you the first question, I just want to remind our listeners that IBD Drive Time is sponsored by the Gastroenterology Learning Network and Advances in IBD. So Flo, let's get started. So for maybe our more novice listeners, how common are extraintestinal manifestations in IBD?

Dr Rieder:
Yeah. Ray, this is a very important question. And I think it's important because extraintestinal manifestations are greatly underappreciated when it comes to the treatment of inflammatory bowel diseases. And they're underappreciated, because first of all, they can affect many different organs; they can affect the eye, for instance, with uveitis; stomatitis in the mouth; then axial arthritis; peripheral arthritis; pancreas; liver; skin; or your vascular system, with thromboembolism.

And they're not only very widespread in your body potentially, but also they're very common, like you mentioned. So the frequency across inflammatory bowel disease population's around 40%, with a bit more frequent in Crohn's Disease and ulcerative colitis. And this is not where it ends. So multiple patients have more than one extraintestinal manifestation, some patients even have three or four. And then when you look at what type of extraintestinal manifestations are the most frequent, this is clearly driven by our joints, so arthritis and ankylosing spondylitis are the most common, and then skin manifestations, and then eye and liver.

Dr Cross:
And Flo, historically, we were taught in med school and residency that for extraintestinal manifestation, that there are some like aphthous ulcers, erythema nodosum, and the inflammatory arthritis that typically correlate with disease activity. In other words, when the patient's flaring. And then there's others like pyoderma, PSC [primary sclerosing cholangitis] and uveitis that are unrelated to disease activity. Do you think that's accurate, that classification?

Dr Rieder:
You're asking me a question that makes me wonder frequently, because the textbooks are written in the way you describe for probably decades. And it's interesting that you say you already learned the exact same thing in your medical school that I did, and that the current medical students learn. In my view, the data this is based on is actually much weaker than we think. So clear studies that look at luminal disease activity in inflammatory bowel disease, the degree of activity and the severity of extraintestinal manifestations are in fact lacking. And most information is available purely based on clinical symptoms of a flare in inflammatory bowel diseases.

And we know that this can be quite unreliable, particularly in Crohn's Disease. And we know that extraintestinal manifestation can occur even long before inflammatory bowel disease is diagnosed. So in the average is about half a year if they occur before, but in some patients even multiple years before you diagnose inflammatory bowel disease. And when you go down the list of the extraintestinal manifestations that I'd brought up very early on; peripheral arthritis, there is a belief they fluctuate with disease activity; axial arthritis, independent of disease activity; and then from the skin, erythema nodosum, with luminal disease activity; pyoderma, independent of it; and then aphthous stomatitis, with inflammatory activity.

But again, I think thorough studies here are clearly needed, and this is one of the drivers why we formed a national study group in inflammatory bowel diseases for extraintestinal manifestations through The Clinical Research Alliance at the Crohn’s Colitis Foundation that you and Millie Long lead together, to in fact get more information in that space, because it has tremendous impact on how we treat our patients. If the extraintestinal manifestation can be treated by treating the luminal disease, or if we need to treat it independently of the luminal disease.

Dr Cross:
Yeah, I agree. And I think that the longer I've been in practice, you just see exceptions to those rules that I mentioned. And you clearly pointed out that some things like inflammatory arthritis often can predate the diagnosis by years. We have many patients who are diagnosed with an atypical arthritis in adolescents, and now we're seeing them for Crohn's disease.

So I think you were alluding to this, or maybe I was thinking of this as you were talking, but we're trying to think about prognosticating patients, right? So who are the high risk patients? So who should we give highly effective treatment? That's what I call biologics and small molecules. Who should get them early? So do you think EIM should be a marker of more severe disease? Should they be getting these more effective therapies earlier in their course?

Dr Rieder:
So also very timely topic. And when you think about treat-to-target, and you mentioned early aggressive therapy for our patients with inflammatory bowel diseases, and what does not get mentioned in this treat-to-target algorithm is really extraintestinal manifestation. I don't think that extraintestinal manifestation in a clinical management override treatment of luminal disease. So the backbone of therapy should remain aggressive treatment of luminal disease. And in my view, in almost all instances or many instances, aggressive therapy early based on risk stratification for luminal disease progression.

If you have extraintestinal manifestations, however, it can affect your choice of therapy because for treating luminal disease, you often have multiple different options. And if you have luminal and extraintestinal manifestation, you focus on medications that can treat both effectively and at the same time. And if you have extraintestinal manifestations that are believed to fluctuate with luminal disease activity, you can perhaps focus more on luminal disease activity, but still keep in mind the extraintestinal manifestation.

Dr Cross:
So Flo, when we're thinking about high-risk patients and prognosticating which patients should get early, highly effective therapy with a biologic or a small molecule, are patients with EIMs a high-risk group? So should these patients be receiving these more effective drugs earlier in their disease course?

Dr Rieder:
It's an important question, Ray, and I do not use extraintestinal manifestation as a prognosticator for more severe disease. So as examples, if someone has peripheral arthritis and luminal disease, or someone has erythema nodosum and luminal disease, I do not treat the luminal disease any different in terms of the targets than I would do it in a patient without extraintestinal manifestation. However, what I do different is the choice of therapy may vary if the patient has extraintestinal manifestations or not, because some therapies cover both the EIM and the luminal disease, and some are more focused on luminal disease.

So specific examples here could be an anti-TNF that is known to work for most extraintestinal manifestations, as well as luminal disease. And then for instance, the other example is vedolizumab, a gut-selective medication that may work for extraintestinal manifestations that are linked to luminal disease activity, but may not work for extraintestinal manifestations that take an independent course. And then there is this patient group rate that you're well familiar with as an experienced clinician, where extraintestinal manifestations predominate the clinical picture. So patients where they have severe arthritis that have severe pyoderma with actually limited luminal disease activity. And then in these instances, it doesn't affect how I treat the luminal disease, but it affects the choice of medication, and I use it to also cover the extraintestinal manifestations.

Dr Cross:
Yeah, I agree. I practice very similarly and really tend to use the anti-TNFs and JAKs inhibitors for those that have predominant extraintestinal symptoms in general. I want to come to focus a little bit more on joints, because that's the most common manifestation we're going to see. And I know this is an area of research interest for you.

So Flo, let's focus a little bit on the joint. So I think we do a bad job at distinguishing old athlete arthritis like mine from inflammatory arthritis. So for the listener, how can they determine that a patient's symptoms are more suggestive or consistent with inflammatory arthritis?

Dr Rieder:
Yeah. So the most common, as you mentioned, extraintestinal manifestation is arthritis, particularly peripheral arthritis, and distinguishing these two that you mentioned, and I know you played a lot of football in your past, so you probably have put your joints through quite some activities in earlier years, it's not always easy to separate them. But I would first separate two big buckets; one is arthralgia without arthritis, so just joint pain without actual joint inflammation. And that's quite common, 10 to 15% or so of the patients have it. And then you have arthritis where you have organic findings of joint pain and swollen, tender joints.

Interestingly, Ray, how this is diagnosed in association with inflammatory bowel disease has not been well defined and has not been well recorded even in clinical trials. In a working group that we formed, that you are part of and sponsored by the Clinical Research Alliance from the Crohn's Colitis Foundation is now focusing on this peripheral arthritis, how to diagnose it, how to monitor it. And I want to give a shout out to Dr. Katie Falloon, who is leading this program nationally.

And in this setting, we just published a national consensus on how to diagnose, monitor and manage extraintestinal manifestation, including peripheral arthritis, and here the diagnostic criteria that were considered appropriate in a consensus panel where threefold; it was a joint pain and swollen and tender joints on exam; morning stiffness, joint pain, and swollen or tender joints on exam; or swollen tender joints on exam with exclusion of other etiologies. So in other words, it's a combination of patient symptoms, so the arthralgia together with objective findings on physical exam of the physician.

Dr Cross:
That's great. And you've made me a much better clinician through my participation in this consensus conference. I do a much better job at properly identifying these. So thanks to you for that. So you have a patient with Crohn's or ulcerative colitis, and they have swollen wrists and fingers, and they have two hours of morning stiffness, it gets better when they warm up. Do you do any additional diagnostic testing for those patients? Are you just pretty comfortable that that's going to be a spondyloarthropathy or inflammatory arthritis related to IBD?

Dr Rieder:
Yeah. So if they have no other etiologies that could explain this, like for instance, chronic arthritis, prior injuries in that joint, any signs of infection, I feel quite comfortable making the initial diagnosis of considering this arthropathy associated with inflammatory bowel diseases in the absence of other etiologies. And there was a big discussion in the consensus that you mentioned about who can actually make the diagnosis, because a gastroenterologist may not be comfortable doing that and may ask a rheumatologist to help.

But interestingly, the panel felt that an IBD specialist, as well as a rheumatologist, should have the ability to recognize this, but also should have the ability to clinically diagnose it. If I have any suspicious symptoms for this being something else, I will ask a rheumatologist, or I can use auxiliary testing, such as for instance, MRI or ultrasound. A plain x-ray will help with distinguishing this from chronic changes of the joint, because arthropathy associated with inflammatory bowel diseases is non-erosive, so you would have a normal x-ray, but still have joint swelling and diffusions and morning stiffness and so on. But long story short, the diagnosis for me is clinical, and I would be interested in what you do, Ray, unless I have suspicion for a different aetiology.

Dr Cross:
No, I agree. I don't do that several thousand dollars arthritis workup and HLA-B27 and things like that. I don't do it. I make a clinical diagnosis. And I think for those that are listening, if you're going to really pick one extraintestinal manifestation to get comfortable with, I would encourage you to really focus on arthritis because there's not enough rheumatologists. And even if you make friends with a rheumatologist, they don't always have access to see every patient. So I really think you have to feel comfortable giving a couple things to treat this. So Flo, what are you comfortable with clinically before you dial the rheumatologist? What therapies will you give? Other than therapies specific for treatment of the underlying IBD but just focusing on the joint itself, what do you use in these patients?

Dr Rieder:
Yeah, so for the joints themselves, I feel comfortable giving short courses of NSAIDs. By short course, I mean, 7 to 10 days of a non sterile anti-inflammatory drug. You can prefer COX-2 inhibitors that are supposed to be less problematic for inflammatory bowel diseases. Non-specific NSAIDs could potentially trigger flares, even though this is controversial, but I still give short courses of it, which is considered okay. Short term corticosteroids, irrespective of the luminal disease activity.

But then interestingly, Ray, a lot of drugs that treat intestinal inflammation, which would be the first step I would take, as you mentioned. A lot of drugs treat IBD and peripheral arthropathy, and one easy switch for instance, could be patients on 5-ASA with ulcerative colitis because sulfasalazine and the sulfur component that is added to the 5-ASA has been shown to work in peripheral arthritis quite well. And that's in fact how this drug was discovered for IBD. When patients came in with joint pain and ended up having diarrhea and sulfasalazine stopped the diarrhea. So this was a drug actually that came from the rheumatology world to IBD.

Then you have methotrexate that, at least in Crohn's disease, has, I think, convincing evidence that it works for both. And then anti-TNF, as we talked about earlier, is a drug that works very well for many inflammatory manifestations, extraintestinal manifestations of IBD. And ustekinumab has been shown to work in peripheral arthropathy. JAK inhibitors are now approved. There is not a lot of data in IBD arthropathy, but we know that from the rheumatology world, they work quite well.

And then certain surgeries may change, even though it is not a therapy option for extraintestinal manifestations in my view. But for instance, colectomy for UC has been shown to change joint pain. And when patients are on effective medications of the list that I just mentioned, so NSAIDs, steroids, sulfasalazine, and methotrexate, anti-TNF, ustekinumab or a JAK inhibitor, they don't get better on it, particularly if the luminal disease gets better but they continue to have joint pain, I send them to a rheumatologist because then I want to make sure I don't miss any other diagnoses that could cause it.

Dr Cross:
Yeah, I agree. I think that our listeners should feel pretty comfortable with... I tend to use COX-2 inhibitors. I feel really be comfortable with them and sulfasalazine can be a wonderful drug for arthritis, and often you don't even need... I do that dose escalation, 500 a day for a week, twice a day for a week, a gram twice a day for a week, then up to two grams twice a day, to try to avoid some of the side effects. And often patients don't even need to ramp up that high. So it's a great drug. We shouldn't forget about it.

And just for the listeners, remember that when you're adding on methotrexate, perhaps for someone who has some persistent joint pain that's not responding to their therapy that methotrexate doesn't have to be given 25 milligrams parenteral, it can be given low doses oral, starting at like seven and a half or ten milligrams once a week. So you don't have to give the high doses, although you're going to monitor them the exact same way as far as lab monitoring and stuff.

Dr Rieder:
Sorry. Can I ask you a quick-

Dr Cross:
Of course.

Dr Rieder:
How long are you comfortable giving COX-2 inhibitors in patients with IBD and peripheral arthropathy?

Dr Cross:
Certainly a short course is fine. I have some patients that are on it chronically, not necessarily twice daily, but here and there for breakthrough pain. I'm pretty comfortable with that. I'm not really worried about the long term use of those in our patients.

Dr Rieder:
Yeah. Yeah. I mean, I try to keep the courses short, but I'm sometimes wondering if I'm too conservative with it because it works extremely well for joint pain and this notion that they may drive a flare inflammatory bowel diseases may be overstated, but I tend to be on the conservative side. So it's interesting what you say. I may try longer courses.

Dr Cross:
Yeah. There's a clinical gastro hepatology article by Bill Sandborn that looked at two weeks for ulcerative colitis and there was absolutely no increase in flares. And then there was another, it wasn't celecoxib, it was a different COX-2 inhibitor, and it was in the Red Journals years ago that looked at 90 days of COX-2 inhibitor, and it wasn't associated with a flare. So I think it's pretty safe. So anyway, for the listeners, those are some things to focus on. Quick question, hidradenitis, Flo, is that an EIM? It seems like we're seeing more and more hidradenitis in our patients, so that is just one autoimmune begetting another autoimmune disease.

Dr Rieder:
Yeah. So hidradenitis is associated with inflammatory bowel diseases and you see it more frequent in IBD patients than in non-IBD patient. I would consider them extraintestinal manifestation. You can argue, like you say, these are two autoimmune diseases coming together, but this is in fact the case for probably for several of other extraintestinal manifestations as well, such as pyoderma and others. I think it's important to recognize, and particularly in the perianal area, this is sometimes not easy to distinguish from perianal disease.

And imaging could help experienced dermatologists. Dermatologists can help. And then assessing luminal disease activity. Sometimes we don't need to be able to distinguish because the medications that treat hidradenitis or treat for instance, perianal Crohn's Disease, have a large overlap. Anti-TNF work for both, ustekinumab works for both. And you can additionally add local therapies for hidradenitis in collaboration with dermatology. But this is something where I have a very low threshold to co-manage this with the dermatologist together, because it can become quite disfiguring in terms of scarring and irreversible skin changes that I try to avoid in the patients.

Dr Cross:
Yeah. These are difficult to treat patients, often difficult to treat, not always. Flo, this has been wonderful. I'm sure the listeners have learned a lot. I have. Before we wrap this up, a fun question, tell the audience something about yourself that they may not know.

Dr Rieder:
What they may know is that my life out of work is now dedicated to my kids. So I have a four year old and a six year old that dominate everything that I do outside of IBD. And I rediscovered building Lego, and they're now in the age where they have their own Lego boxes and are creative. And I love doing that with them. And now my wife is chiming in and we are having our own little set we are playing with at night.

Dr Cross:
You're probably using Lego building as a way to decompress and to decrease stress, so good for you, Flo.

Dr Rieder:
It's actually really good. It's helpful. It takes your mind of other things quite well.

Dr Cross:
For sure. Flo, this has been wonderful. Thanks for joining us. And we hope to have you again sometime soon.

Dr Rieder:
Yeah. Thank you, Ray. And thanks for spending all this time for educating our community and improving care of IBD patients.