Advanced Therapies for Inflammatory Bowel Disease (IBD)

Podcast Transcript

Scott Steele: Butts & Guts, A Cleveland Clinic podcast exploring your digestive and surgical health from end to end. Hi, again everyone, and welcome to another episode of Butts & Guts. I'm your host, Scott Steele, the president of main campus and colorectal surgeon here at Cleveland Clinic in beautiful Cleveland, Ohio. And today I am super excited to have my friend and colleague, Dr. Benjamin Cohen, who is the co-section head and clinical Director for Inflammatory Bowel Disease in the Department of Gastroenterology, Hepatology, and Nutrition here at the Cleveland Clinic. Ben, thanks for joining us on Butts & Guts.

Dr. Benjamin Cohen: Thanks for having me, Scott.

Scott Steele: I know your background, but for all our listeners out there, can you give us a little bit more about where are you from, where did you train, and how did it come to the point that you're here at the Cleveland Clinic?

Dr. Benjamin Cohen: Sure. I grew up in New Jersey, so I'm a long-suffering New York Knicks fan. As a result of that, I did my medical school at Mount Sinai in New York, did my residency there, and then left to go to sunny San Diego for my GI fellowship training before ultimately going back to Mount Sinai, where I did my advanced IBD fellowship, and stayed on faculty there for nine years before coming out to Cleveland in 2020, right at the start of COVID. So the world has changed a lot since I've come here, but excited to be here and work with the really fantastic multidisciplinary team that we have at Cleveland Clinic.

Scott Steele: Today we're going to talk a little bit about advanced therapies for IBD, inflammatory bowel disease, and more specifically the use of biologics as a treatment option. So to start, can you give us an overview of what IBD is to our listeners who are not aware?

Dr. Benjamin Cohen: Sure. Inflammatory bowel diseases are a group of autoimmune inflammatory conditions where the immune system is essentially attacking the lining of the gut. And there are two types, defined as ulcerative colitis and Crohn's disease. Ulcerative colitis affects the colon or large intestine only, and it's a continuous inflammation beginning in the rectum and extending upwards. And it's more of a surface level inflammation that typically results in symptoms of rectal bleeding and diarrhea. Crohn's disease, on the other hand, can occur anywhere from the mouth to the anus. It can be discontinuous, affecting multiple areas with normal bowel in between, and it's a more full thickness inflammation that results in complications such as strictures, fistulas, or abscesses. And we'll talk a bit about treatment, but most of our advanced therapies are approved and work for both conditions, actually.

Scott Steele: When is the right time to seek treatment for IBD?

Dr. Benjamin Cohen: We've learned a lot in recent years that treating inflammation early is critically important. Uncontrolled inflammation can lead to progressive bowel damage that may not be reversible with medications and instead require surgical approaches. Also, our real world data has shown that our treatments may work best early in the disease course. And so for this reason it's important to both recognize and treat symptoms and inflammation early.

Scott Steele: Ben, there's people out there that may not need any treatment for IBD, they can just follow it. Can you talk about what percentage of the overall IBD patients that is and how is that the case?

Dr. Benjamin Cohen: Yeah, that's a really important question. We're not great at prognosticating who are the patients that are going to have progressive disease? And I actually was having this conversation with our advanced IBD fellow yesterday, that I find mild Crohn's disease to be one of the most difficult conditions, because we're very conditioned to, we have this hammer which is effective advanced therapies, and we want to hit every nail with the hammer, but that may not be the approach that we need.

So I think the key is really to stage disease activity when you first meet a patient, and that's going to occur through symptom assessment, lab markers of inflammation, cross-sectional imaging, doing an endoscopy, and from there you can see if there are factors that may portend a more severe course. So if you see large, deep ulcerations. On the other hand, if you have patients with a little bit of inflammation, maybe they're not very symptomatic at all, their biomarkers look normal, then I think it's reasonable in some cases to do a monitoring approach where we watch them close, so we don't let them just disappear and then come back five years later, finding out they've progressed, but we're periodically, within a year checking their lab biomarkers, reassessing their symptoms, and acting if we see any change.

The exact number of patients that may be, it's really hard to say. In Crohn's disease, I'd say it's in maybe the five to 10% range, although of course we're skewed at Cleveland Clinic, because we're seeing patients that are coming here for second and third opinions. Ulcerative colitis is a little bit different because we do have very effective medical therapy for mild ulcerative colitis that are 5-aminosalicylates, which are not systemically immunosuppressive in any way. So for patients with mild disease there, we can try that treatment first and see how they do.

Scott Steele: Truth or myth? Truth or myth? IBD most commonly occurs between the ages of 15 and 35.

Dr. Benjamin Cohen: Truth, I mean, IBD incidence does commonly peak in teens and young adults. However, there is a second incidence peak later in life, so older adults aren't immune to developing disease. And we can also see very early onset disease in young pediatric patients, so it can occur anywhere but commonly we are seeing it in ages 15 to 35.

Scott Steele: Ben, I often get asked, "Can I prevent this or at least reduce the risk of being diagnosed with IBD? Is there something? Or why don't we know exactly what causes this underlying condition?"

Dr. Benjamin Cohen: Yeah, I mean, I think there's a lot of work ongoing to try and understand what the exact pathogenesis is of IBD, but thus far I would say that there aren't any preventative measures we can take to reduce risk of developing disease. What I would say is that it's important to recognize warning sign symptoms when they occur, and to seek care early. And these warning sign symptoms could be rectal bleeding, iron deficiency anemia, unintentional weight loss, incontinence, pain, or diarrhea that wakes you up from sleep among other things. And then one factor where you may be thinking a little bit about things is if you have multiple first degree relatives with IBD, that would confer some increased genetic risk. But there's again, nothing specifically that we're doing beyond just paying attention to when patients may develop these warning sign symptoms.

Scott Steele: Okay. Let's jump a little bit now into biologics. And so how do biologics differ from more traditional IBD medications?

Dr. Benjamin Cohen: Biologics are advanced therapies for the treatment of IBD that are antibodies created to target specific proteins involved in inflammation. And this allows for a targeted immune suppression to reduce inflammation and allow the bowel to heal. And the first approved biologic for IBD was infliximab in the late 1990s. And since then we've had multiple classes of biologics, including other ones that target tumor necrosis factor, ones that target integrins, ones that target what are called interleukins 12 and 23, which are cell signaling molecules.

And then in addition to biologic drugs, we now have advanced therapies which are referred to as small molecules. And these are chemically synthesized compounds that are smaller in size compared to biologic molecules which allow them to be administered orally as compared to the traditional biologics which are either given subcutaneously or as infusions. And these small molecules have a very short half-life, which allows for a quicker onset of action and washout when stopping. And the classes of small molecules that patients may hear of are JAK inhibitors and S1P receptor modulators.

Scott Steele: As you're looking at a patient in front of you, what determines if that patient is a good candidate for biological therapy?

Dr. Benjamin Cohen: The indication for advanced therapies including biologics are moderate to severely active disease. So any patient with moderate to severely active, you see or Crohn's disease are good candidates for advanced therapy. Patients with mild ulcerative colitis or Crohn's that don't respond to conventional therapies also are good candidates. And again, as I mentioned before, the assessment of disease activity is really critically important. This is going to be a combination of patient symptoms, the lab markers of inflammation, imaging, and then endoscopy. And where we've evolved is that we don't rely just on patients' symptoms anymore because there can be a disconnect between the patients' symptoms and true, objective evidence of inflammation.

Scott Steele: Ben, how effective are biologics in treating IBD? And you mentioned a little bit about when and how do they go about either on maintenance or actually putting a patient into remission?

Dr. Benjamin Cohen: Our treatments are quite effective at improving inflammation and symptoms. And when you think about these medications as a first line therapy for patients, so they've never been on any other advanced therapy, the studies will generally show a response rate of around 50 to 70%. And then as a second line therapy, the response may drop somewhat, indicating that it's a harder to treat group. And our approved therapies can achieve both clinical and importantly, endoscopic remission, which is the end point that we increasingly desire. And the reason for that is the endoscopic remission reflects the bowel inflammation is healed and that this is going to translate to a more prolonged remission without complications.

And we think of the induction period and the maintenance period, as you were mentioning before, that maintenance period is typically after the first 12 weeks of treatment, and we can see increasing response in that time. So what I tell patients to expect is that if we do see an initial treatment response both in their symptoms, the markers of inflammation, the endoscopy, then we can do more things to try and optimize the effectiveness of the medicine to achieve even better results.

Scott Steele: With any treatment, there's potential side effects. Can you talk a little bit about that for biological treatment?

Dr. Benjamin Cohen: Yeah, so while all of our advanced therapies are generally safe, there are some safety concerns, and the nuances of the safety concerns can differ somewhat by the class. So generally speaking, since we're talking about medications that are mildly suppressing the immune system, infections are a concern. We recommend patients undergo routine vaccinations for preventable illnesses such as influenza, pneumonia, and shingles, and otherwise we advise patients to discuss with their treating physician if they have symptoms of possible infection such as fever.

The other side effects that patients are going to commonly ask us about are malignancies, including lymphoma, and lymphoma has been associated with biologics that block tumor necrosis factor. However, the absolute risk of lymphoma is exceedingly low, on the order of four to six and 10,000 patients in a year, when treated with one of these biologics alone. So compared to the effectiveness of the drugs, the benefits far outweigh the risk. And it's important to have open, honest discussions with patients to dispel any misconceptions about treatment risk so that they can make informed decisions. And really, we're fortunate now that we have so many different options for treatment, we can usually find a medication that's going to work for each patient's situation.

Scott Steele: So are these medications in isolation? Or you can combine them with other IBD medications?

Dr. Benjamin Cohen: While our advanced therapies are very effective, there is a treatment ceiling effect that we can't seem to break through. So we see the same level of response with each successive new drug that comes out. And for this reason, there has been a lot of interest in seeing if we can combine advanced therapies to help achieve a greater response. And some of the early studies of combination biologics have shown benefit, and there are larger studies underway currently. So I think the future is going to be utilizing a more personalized approach to treatment. So where we may immunophenotype a patient, for example, to understand which inflammatory pathways are driving disease in an individual patient, and then selecting one or more treatments that specifically target the primary cause of inflammation.

However, up to this point we've been using more of a shotgun approach. The real world evidence does help us select some treatments which may show more efficacy in specific scenarios such as perianal Crohn's disease, where we use the tumor necrosis factor inhibitor medications. So I think in terms of combination biologics, there's more to come. But the one scenario where we do use it in clinical practice now is patients that have concomitant extraintestinal manifestation. So if they may have, for example, rheumatoid arthritis along with their IBD, that we may be using two different biologics, one targeting each disease process in combination.

Scott Steele: Ben, are these drugs a little bit like a blood pressure pill or a pain pill when you take them, and you get immediate effect? Or how long do patients need to be on biological therapy before they start to see improvements in their IBD symptom?

Dr. Benjamin Cohen: I think it's really important to set clear expectations for patients when they start treatment. It can often take four to six months to fully see treatment response. However, it's important, as I said earlier, to monitor symptoms and lab markers of inflammation at earlier time points. If a patient is worsening or really having no response whatsoever, we may have to act sooner with regards to optimizing that medication, or switching, or referring to a surgeon. So I think my hope with many of these medications is that we'll see a response within the first few weeks, but we have to be monitoring the patient closely.

Scott Steele: Okay. So you put somebody on one of these biologic and it doesn't work. Is that like, "Rule out that entire class," and you got to switch to a different class of medications like you talked before? Or can you put them on another biologic?

Dr. Benjamin Cohen: It's a great question. Some biologics, particularly the tumor necrosis factor inhibitors, where patients can develop antibodies to a specific drug. So if patients develop antibodies to a drug, that's not necessarily meaning that they are not responding to that drug class. It just is they have developed a resistance to an individual drug. So you could go to another drug in the same class. However, with our newer biologic drugs, the ones that are in the interleukin 23 class, the ones that are in the anti-integrin class, antibodies are much less of a concern. So if somebody has what we consider a true non-response to a medication in that drug class, I would probably then switch to a different class of biologic or advanced therapy.

Scott Steele: As you know, there's certain patients that just don't respond, they end up needing surgery. Are there any safety considerations or considerations in general for patients that need surgery for IBD and are on these meds?

Dr. Benjamin Cohen: The safety of advanced therapies in the perioperative period has been a special interest of mine. There previously had been concern that advanced therapies may increase the risk of post-operative complications and infections. And for this reason, there had been recommendations on delaying surgeries or holding medications. However, we've performed a large prospective cohort study of nearly a thousand patients undergoing surgery for IBD, and patients on TNF blockers where there was the greatest concern, were not at any increased risk of post-operative infectious complications as compared to patients not on these medications. And the real driving factors around post-op complications were steroid exposure, smoking, diabetes, and for this reason, we really recommend basing the timing of surgery on those factors rather than the advanced therapy that patients are on.

Scott Steele: Looking ahead in the future, are there any new biological therapies or additional IBD treatment options on the horizon?

Dr. Benjamin Cohen: There are many new drug classes on the horizon as well as looking at combinations of medications that I discussed before. And we're really fortunate that we live in a time where there's been an explosion of available therapies for patients, so I think the future is really bright. One of the exciting phase three clinical trials that we're starting here now in both ulcerative colitis and Crohn's disease is looking at a class of medications that block TL1A. And there's a lot of optimism for that treatment approach. So I think it's important to talk with your treating physicians, get an idea for what clinical trials may be available, and there may be options even beyond the FDA approved drugs on the market.

Scott Steele: Okay. Now it's time for our quick hitters, a chance to get to know you a little bit better. So first of all, what is your favorite food?

Dr. Benjamin Cohen: Favorite food, chicken parmesan.

Scott Steele: Nice. We haven't had a chicken parmesan here in a while. What is your first car?

Dr. Benjamin Cohen: First car was a Honda Accord.

Scott Steele: Any color in particular?

Dr. Benjamin Cohen: It was green.

Scott Steele: My favorite color. And what is a place, Ben, you've traveled the world giving lectures that you said, "Hey, I'd like to go there again," or, "Is on my bucket list to go to?"

Dr. Benjamin Cohen: Bucket list to go to. The place I'd love to go back again is Japan, because when I went to Japan, this was now 10 years ago, I did not eat sushi, so I did not have an appreciation for what I was missing. And the only sushi that I had was at the fish market there, on my last few days there. So that's definitely where I would go back.

Scott Steele: Fantastic. And name one word to describe you.

Dr. Benjamin Cohen: Empathetic.

Scott Steele: Fantastic. And so give us a final take-home message to our listeners out there about advanced therapies in IBD.

Dr. Benjamin Cohen: I'd say the most important thing is that we really have learned the importance of treating inflammation early, so that we can prevent complications of disease. So it's really important to not ignore symptoms and signs of inflammation, and to talk to your doctor about treatment options. And when you do start treatment, to work with your doctor to define the treatment goals upfront, and put into place a monitoring plan so that you make sure your goals are reached.

Scott Steele: Fantastic advice. And to learn more about IBD treatment at the Cleveland Clinic, visit our website at clevelandclinic.org/IBD. That's clevelandclinic.org/IBD. You can also call us at 216.444.7000. That's 216.444.7000. Dr. Cohen, thanks so much for joining us on Butts & Guts.

Dr. Benjamin Cohen: Thanks so much for having me.

Scott Steele: That wraps things up here at Cleveland Clinic. Until next time, thanks for listening to Butts & Guts.