IBD Drive Time: Jordan Axelrad, MD, on Communicating Risks to Patients With IBD

Drs Raymond Cross and Jordan Axelrad provide guidance to clinicians about the best ways to put risks—both of uncontrolled IBD and of therapies—into perspective for patients.

Raymond Cross, MD, is Medical Director, The Center for Inflammatory Bowel and Colorectal Diseases​, The Melissa L. Posner Institute for Digestive Health and Liver Disease at Mercy Medical Center​, in Baltimore, Maryland​. Jordan Axelrad, MD, is an associate professor at the NYU Grossman School of Medicine and codirector of the Inflammatory Bowel Disease Center at NYU Langone Health in New York City.

IBD Risk Communication: Absolute vs Relative Risk in Discussing Therapies and Adverse Events

• Inflammatory bowel disease (IBD) therapies; FDA warnings; immunosuppression setting: Jordan Axelrad, MD, emphasized distinguishing relative risk from absolute risk when discussing treatment-related adverse events in patients with IBD. He noted that some risks may rise with cumulative exposure or during periods of multiple concurrent immunosuppressive therapies, while overall event incidence often remains “very, very low.”
• Absolute risk framing; patient counseling approach: Dr Axelrad stated that he prefers communicating risk using absolute numbers rather than relative risk multipliers because patients may perceive statements such as a “10-fold increased risk” as alarming without context. As an example, he contrasted a general population event rate of 2 per 100,000 patients with 20 per 100,000 in patients with IBD, emphasizing that the absolute risk remains exceptionally low.
• Contextualizing adverse-event risk with real-world comparisons: Raymond Cross, MD, and Dr Axelrad discussed grounding treatment risk in familiar comparisons, including breast cancer risk, motor vehicle fatality risk, choking risk, and heart disease mortality. Dr Axelrad noted that adverse events related to IBD therapies may involve only “a handful of cases” per 10,000 treated patients.

Dr Cross: Welcome, everyone, to IBD Drive Time. I'm Raymond Cross from Mercy Medical Center in Baltimore, Maryland. I'm delighted to have my friend and colleague, Jordan Axelrad, who's, I think, our fourth or fifth time return guest to IBD Drive Time, and we're going to talk about communicating risks in patients with IBD. Jordan, welcome back.

Dr Axelrad: Thanks, Ray. Thanks for having me back.

Dr Cross: So let's jump right in, Jordan. When discussing risks of treatment and conversely of poorly controlled disease, how do you communicate this to patients? So in other words, do you talk about absolute versus relative risk? Do you ground this with risks that patients have in real life? What are your tips?

Dr Axelrad: Yeah. So I think there's a couple of really key considerations when evaluating risk. The first is really distinguishing relative from absolute risk. So for example, therapies often increase the relative risk of certain adverse events compared to like the general unexposed population, but the absolute number, the absolute incidence of whatever we're talking about, events or so forth, remains very, very low. And so, and also risks are time dependent, right? So certain risks may increase with duration of cumulative exposure, whereas others may be highest in the early phases of therapy, during periods of maybe we're using multiple immunosuppressions at once.

And then we also, of course, have drugs that have FDA warnings. And so all of that needs to really be contextualized. My general approach to communicating risk is usually in absolute numbers, because I think that that's easiest for patients to understand rather than me just saying, oh, you have a 10-fold increased risk. That can sound very scary. But if the event rate is only... in the general population is 2 in 100,000 patients, and in IBD patients is 20 in 100,000 patients, that absolute risk is still exceptionally low.

Dr Cross: Yeah, correct. It's like the...You know, when they came out with the scare about proton pump inhibitors and dementia, and I think like the absolute risk was something like 0.1% difference. And then of course that was debunked, but it didn't generate any news because negative studies don't generate any news. So, and, and do you ground it in real with real life risks? Like one of the things I'll tell patients after I go over risk, I'll say something like, and to put that in context, a woman's life, a woman's risk of getting breast cancer in her life is 1 in 8. A man's risk of getting breast cancer is about 1 in 10. Your risk of dying in a car accident is about 1 in 100. Your risk of dying from choking is like 1 in 1500. Like, do you do any of that in practice?

Dr Axelrad: Yeah, I'll usually talk about death from heart disease, which for men is 1 in 4, for example, that's often quoted. So when we talk about adverse events of IBD therapies, which every single patient, of course, is super concerned about, putting it into context that we're talking about a handful of cases generally in 10,000 treated patients, totally different comparisons.

Dr Cross: And for the listeners, if you want to find some good grounding risks that give you a comparator with lymphoma, you can go to, there's a website called Risk of Dying, and it gives you these different numbers. So you can find a couple that are easy to remember that are somewhat ludicrous, but it sometimes decreases tension with patients.

So let's talk about cancer, because I think patients are very afraid of cancer, more so than any potential complication. But what cancers... increased in patients with IBD irrespective of their immune suppression.

Dr Axelrad: Yeah. So remember that cancer risk is strongly influenced by individual factors—age, family history, comorbidities, smoking. All of that is going to influence overall cancer risk and in some ways more than IBD. So there are several cancers that are increased in patients with IBD. Of course, the one we know most is colorectal cancer. That's primarily increased in folks with colitis, obviously colon involvement, and also substantially increased in patients who also have concomitant primary sclerosing cholangitis, PSC, which, of course, additionally increases the risk of cholangiocarcinoma. and HCC as well. So PSC is really kind of a premalignant condition, particularly of the colon and of the bile ducts.

Other cancers that are increased in patients with IBD include small bowel adenocarcinoma in patients with ileal Crohn's disease. Although again, we're talking about a handful of cases in 10,000 patients with ileal Crohn's disease. Anal cancers for folks who have perianal Crohn's, and very rarely intestinal lymphomas, again, more so in patients with Crohn's disease. But other than colorectal cancer, all of those other risks are quite low.

Dr Cross: And I just want to, for the listeners out there, the small bowel adenocarcinoma is real. And if you practice IBD long enough, you're going to see them. And just a reminder that if you have a patient who has a stricture and, you know, often we're going to try a medication before offering surgery and we could debate whether that's the right thing to do or not. But if that patient doesn't respond, particularly a patient who's a middle or older age, that patient's absolutely going to have surgery. I've had two patients who have had adenocarcinomas within strictures. And thank goodness we didn't cycle through multiple meds trying to get a response. And we were able to get that out. And they both did quite well. So don't forget about what Jordan brought up there.

Now, you mentioned what cancers are increased in our patients, Jordan. Which of our therapies are associated with an increased risk of cancer?

Dr Axelrad: So again, same as with cancers in the setting of active IBD. Patient-level factors will also be important in overall cancer risk in the setting of IBD therapies with the same things, family history, smoking, et cetera. So we know that there are several cancers linked with thiopurine use, and these include nonmelanoma skin cancer—so basal and squamous cell carcinomas—lymphoma, and also in some studies, genitourinary cancers as well. So these risks, again, overall, in the general population, for example, the risk of lymphoma is about 2 in 10,000. In IBD, it goes up a little bit. And then in the setting of thiopurines, we're talking about 4 to 6 cases in 10,000 treated patients. So again, the overall absolute incidence is quite low, although increased about 1- to 2-fold compared to the general population. So that's important to keep in mind.

Anti-TNFs have also been associated with certain types of cancers. So some studies have linked it with melanoma and also independently with lymphoma. But what we know is that the lymphoma risk is increased in patients who are on an anti-TNF plus a thiopurine. That's where we tend to see the highest risk. Again, in patients who are on anti-TNF with a thiopurine, that risk is about 10 in 10,000 treated patients. So maybe anywhere between 3 and 5 times in the unexposed population. So keeping that in perspective that the relative risk is much higher, but absolute numbers, it's still a very rare event.

All of our other classes of drugs, there's really not consistent data linking IBD therapies with cancers. And I would say JAK inhibitors are maybe an evolving area where particularly in older adults from the rheumatoid arthritis population, we saw that there were more nonmelanoma skin cancers and potentially some other rare cancers that have not been seen in the IBD population. And that's really in the setting of JAK inhibitors.

Dr Cross: So I want to remind the listeners that IBD Drive Time is the official podcast of the AIBD Network. We are on Spotify and Apple Podcasts. You can find us and listen in regularly.

Jordan, all of our therapies, I call them advanced therapies—but that's probably not a good word. It should be highly effective therapies—but all of them are associated with a higher risk of infection. How do you... When you're thinking about that, and increasingly when we look at our pivotal trials and we look at adverse events, you start to see this trend that the placebo patients actually have more adverse events and they can have more infections. And how do you tease out what the disease itself is doing as far as driving infection risk? And then what are the additive effects of corticosteroids?

Dr Axelrad: Yeah. So really important. So first, this is an important, you know, IBD Drive Time because we're talking about cancers and infection, which generally patients ask us about as number one to way before they ask us how quickly are they going to start feeling better and so forth from our drugs. So as you mentioned, IBD itself contributes to an increased risk of infection. So patients with fistulizing disease, especially perianal or intraendominal involvement, at increased risk of abscess formation. Active inflammation predisposes individuals to GI infections like C. difficile. There are also other infections, you know, beyond the gut that are increased in patients with IBD, again, irrespective of IBD therapy exposure—respiratory and urinary tract infections. Some studies have shown that just IBD itself increases the risk of those. So there is a balance between infections in the setting of IBD, active IBD, and then the infection risk from IBD therapies.

So of course, corticosteroids are associated with the largest increase in infection risk. They really substantially increase the risk of infection in a dose- and duration-dependent manner for essentially every infection, bacterial, viral, and other opportunistic infections. So that is the reason when I talk with patients about why we want to start more highly effective, advanced therapies is because not only will it mitigate the risks of infection in the setting of active IBD, but also allows us to avoid steroids, right? These meds are meant to be steroid-sparing, which patients don't always associate corticosteroids with such high risks of infection.

Dr Cross: And you were involved in the Swedish study with the additive effects of steroids. And if I'm summarizing that right, basically any therapy that a patient was on, if they're on concurrent steroids, it's doubled or tripled the risk of serious infection. Am I summarizing that correctly?

Dr Axelrad: Exactly. And when you looked at the therapies compared to each other, advanced therapies in particular, that really the infection risks are actually quite similar. You know, we tend to associate anti-TNF and JAK inhibitors with perhaps an increased risk of infection. But when you adjust it for underlying IBD activity and corticosteroid exposure, the risks of serious infection are pretty similar across advanced IBD therapies. And it was really the corticosteroid that was driving the large infection risk and, you know, double to 4-fold, depending on the situation, increased the risk of serious infection with corticosteroids.

Dr Cross: And when you and I were at ECCO, we also reviewed a French study, I think it was the Getaid group, that looked at that, too. And it was... similar. Even patients who were on nothing or 5-ASAs, their serious infection rate was very similar to a JAK. And the differences between what we think we know are incredibly safe, IL-23 inhibitors, anti-integrins, there really wasn't that much difference. It's two really big cohorts with really reputable data sets suggesting that the safety pyramid is actually steroids and underlying disease activity bad, and everything else is more safer and really to the top.

Dr Axelrad: Agreed,

Dr Cross: Okay. So let's talk a little bit about cardiovascular events, which is becoming an area of increasing interest in IBD, sort of a nontraditional risk factor for cardiovascular disease and thromboembolic risk, which we've known for a long time has been associated with IBD. So which therapies, if any, are associated with higher MACE and higher VTE?

Dr Axelrad: Yeah. So as you already mentioned, active inflammation is a significant risk factor for venous thromboembolism, also arterial events as well. So we already know that IBD activity, another way of thinking about risks of adverse events, IBD is bad, active IBD is bad.

Corticosteroids increase the risk of VTE and cardiovascular events in a dose-dependent manner, we know that. And really from our therapies, it's only JAK inhibitors that have some association with VTE and major adverse cardiovascular events, MACE. And that really stems from the study ORAL surveillance, which was an open-label, randomized, noninferiority trial, not in IBD, but in rheumatoid arthritis, comprising older adults over the age of 50 with at least one cardiovascular risk factor. So a very different population, perhaps, than the average IBD patient. And in that study, they saw tofacitinib. which is not typically our JAK inhibitor of choice anymore, was associated with an increased dose-dependent risk of major cardiovascular events and VTE.

Dr Cross: And, you know, Jordan, you're getting big enough that people are going to just remember you as Jordan. We don't have to say your last name, but so everyone knows who Marla is. And she summarizes things so well at times that make it very digestible for patients. And what she reminded me from that study is that in that study, if you didn't have a history of baseline cardiovascular disease, you did not have an increased risk of events on tofacitinib. If you were under 65 and you never smoked, you didn't have a higher rate of malignancy. And those were primarily lung cancers that were the big ones. And if you didn't have a history of VTE or PE, you didn't have any increased risk of those events either. So that's very helpful for your patients. You have to go through ORAL surveillance when you're talking about a JAK. And I think we extrapolate UPA and TOFA together because I don't think UPA is any safer than TOFA. It's just more effective. And when you tell them that, I think it's very reassuring.

Dr Axelrad: I agree. And I think that IBD cohorts tend to be younger, tend to have fewer baseline cardiovascular risk factors. And so generalizing ORAL surveillance, which resulted in the black box warning on JAK inhibitors, to patients with IBD who perhaps are really receiving upadacitinib, you know, it just needs context. And what we already established and chatted about is that active IBD is the largest risk factor for VTE and cardiovascular events. And so again, this is a risk-benefit balance that needs to be shared with patients. And I think to the FDA's credit, they actually, I think, acknowledged the nuance of that when they updated the label to give us a little bit more leeway in prescribing JAKs, because these are really good, really good forms of therapy.

Dr Cross: So I got, I have two scenarios for Jordan, and then I'm going to ask him a fun question, because we like to fund questions. Before I do that, just a reminder to everyone that the next AIBD regional will be April 30^th…I'm sorry, May 30th and May 31st in Portland. First time we're going out to Portland. So my colleague Tina Ha will be leading that with Anthony Sophia. So that'll be a fun meeting to go out to Portland.

Jordan, I'm going to give you two scenarios.So the first one is a 65-year-old woman with breast cancer diagnosed 3 years ago, in remission. She's now diagnosed with moderately active ulcerative pancolitis. What treatment—or maybe give me a couple of treatments —would you choose? And I'm going to flip the scenario a little bit in a second. So remember that.

Dr Axelrad: The most important thing here as far as cancer risk goes is not whatever you and I are about to prescribe this patient. It's her personal history of having breast cancer, right? So that's the largest risk of cancer, not whatever we're about to do. It's her history of breast cancer. The other is because we have data in cancer risk of patients who have histories of cancers exposed to IBD therapies, largely from both ICARE in France or in Europe, I should say, and also the SAFIRE registry, which is co-led by Steve Itzkowitz and myself, we've learned that our IBD therapies don't appear to increase the risk of new or recurrent cancers in patients with histories of cancers who will already be at high risk or higher risk, I should say. So in this setting, I usually let the patient as characteristics, right? The disease activity and severity of that individual patient, what they need for their IBD, guides my selection. So if I thought this patient had severe disease and needed infliximab, I would use infliximab. If I thought this patient would do well with vedolizumab, I would use vedolizumab.

I think there's a temptation to use vedolizumab in this patient cohort because we intuit it's our safest advanced therapy. But again, we have a lot of data now that the therapies really similarly don't increase the risk of most cancers, and there's been no signal for breast cancer. So I would let the IBD guide my decision, not the history of cancer. And I do think, though, in a patient who's more moderate, a vedo, an IL-23 inhibitor, an S1P receptor modulator, that don't have any link with cancer, would be totally appropriate.

Dr Cross: And if this patient had more of a Mayo-3 endoscopy, you'd have no issue using whatever you needed, and that could include a JAK inhibitor.

Dr Axelrad: Yep, I agree.

Dr Cross: I wanted to give a little preview here for this—Jordan actually has a really nice review article that’ll be published soon in the American Journal of Gastro or the red journal that really summarizes all of this really nicely in about 6 or 7 pages so a really nice review that's going to be published.

So last scenario: 55-year-old man with hypertension, hyperlipidemia, prior DVT during a flare of Crohn's. He has inflammatory ileocolonic Crohn's, moderately active despite adalimumab with therapeutic drug levels of 14. What treatment would you choose?

Dr Axelrad: Yeah, I think that a couple of considerations here. I think you could go with a JAK inhibitor, perhaps. And I know the VTE history was thrown in there, but you mentioned that it was in the setting of active Crohn's. What we know is that active IBD is the largest risk factor, especially if it's provoked VTE. That's a much safer scenario in which to consider a JAK inhibitor.

As far as this particular patient with a high drug level or okay drug level, I should say, for adalimumab, you could consider JAK. You could consider even infliximab. You could also consider an IL-23 inhibitor. I think actually all of those in some ways could be considered for this particular scenario, but I wouldn't let the history of VTE, especially a provoked VTE in the setting of disease flare, disease activity, I wouldn't let that detract my ability to use a JAK.

Dr Cross: Now, if this patient had been on both adalimumab and an IL-23 inhibitor, probably the best therapy would be a JAK. If you're going to use that with the prior DVT, are you asking your hematologist to give something for DVT prevention while they're on the JAK?

Dr Axelrad: Yeah, so usually our hematology colleagues are substantially less worried about this than we are, right? Their risk tolerance for things is a little bit different. For patients with provoked DVT, that's more than 6 months in the rearview mirror,most patients are not requiring any sort of anticoagulation or antiplatelet therapy for prevention or anything like that. I think when disease is very active and there's a history of unprovoked DVT and we want to use a JAK inhibitor and maybe the patient is an active smoker, using an estrogen-containing OCP, you know, other risk factors, that's someone we may want to consider for something preventative on board.

Dr Cross: Yeah, I think our hematologist here at Mercy, I usually ask, she's so good at getting them in quickly for me. I sense the pattern is, well, they had a bad flare before and had a DVT. I'm going to treat them. And it's not so much because of the JAK. It's because they had a DVT when they were flaring before. And then once you cool down their disease, I think we could pull off their treatment and I think that probably makes a lot of sense.

All right, Jordan—fun question. I've asked you a bunch of fun questions but what's your favorite hobby?

Dr Axelrad: Okay so we're not going to talk about using points for travel? I mean to be very boring one of my favorite hobbies is playing tennis. I'm probably going to go out and play tennis for about an hour right after this chat.  But coming back to the points is that this is not promotion…

Dr Cross: OR pickleball when you're 55.

Dr Axelrad: Yeah, or pickleball when you're 55. I like to play on clay because you can't play pickleball on clay. So it's a little tricky. You could, but you will fall down very quickly. Yeah, you won't really be playing much. But what I'll say about the points and credit card and travel is that, and this is not promotional, is that there's a credit card out there that allows you to get points for your mortgage or your rent payments. If you're like me and you live in New York City, that tends to be the largest thing you pay for every month. So all those points left on the table, you got to think about that, right?

Dr Cross: Yeah, you do. All right, Jordan, this has been great. Thanks for doing this. For the listeners, this has been IBD Drive Time, the official podcast of the AIBD Network. Thanks, Jordan.

Dr Axelrad: Thanks, Ray. Good to see you.