Benjamin Cohen, MD, on Association of Postoperative Infection and TNF Inhibitors in IBD

In this podcast, Dr Cohen discusses his recent research into whether the use of tumor necrosis factor (TNF) inhibitors is associated with a higher rate of postoperative infection among patients with IBD.

Benjamin Cohen, MD, is Co-Section Head and Clinical Director for Inflammatory Bowel Disease at Cleveland Clinic.

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 Jimmy Limdi from the University of Manchester in the UK. Jimmy is our first non-US guest for IBD Drive Time, and he's going to go over the best of ECCO, the controlled and uncontrolled trials of existing therapies and safety. Jimmy, welcome to IBD Drive Time.

Jimmy Limdi, MD:
Thank you, Ray. Thank you for having me. It's an honor and privilege.

Dr Cross:
All right, let's jump right in. So the first study we're going to talk about is an oral presentation number one called SPARE, which is withdrawal of infliximab or anti-metabolite therapy in Crohn's patients in sustained remission on combination therapy. So Jimmy, can you give us an overview of the study design and the key findings?

Dr Limdi:
Yeah. Thanks, Ray. So yes, this was actually the opening presentation at ECCO this year, given by Edouard Louis. And quite a burning issue for practicing gastroenterologists, even if it wasn't about any new drug. Combination therapy, we know, has been the standard of care for moderate to severely active Crohn's disease ever since the publication of the SONIC trial. But the burning question for clinicians has been, how long does one continue combination therapy? Is it safe to continue combination therapy? Is there any harm associated with it? Are we overtreating our patients? Or indeed, is it even possible to deescalate therapy?

So this is actually the first randomized trial that actually addresses this issue. This was a European multicenter, unblinded RCT, wherein 211 patients, who were in deep remission, by the way, for their Crohn's disease, these patients were in deep remission, as assessed by ileocolonoscopy and small bowel imaging. And they were randomized to either continue with combination therapy, or to discontinue infliximab, that was arm B, and in arm C, they were allowed to discontinue their immunomodulator. These patients had a median disease duration of approximately six years, and I think it's important to say that about 50% of them had started their anti-TNF therapy within two years of their diagnosis. So they were being treated for moderate to severely active Crohn's disease fairly early in the course of therapy. The study primary aim was to assess relapse rates and time spent in remission over a two-year period following withdrawal of either infliximab or the anti-metabolite, in patients who had been on this treatment for over eight months, and also in corticosteroid-free remission for at least six months.

Following randomization, if these patients did relapse, they did have the opportunity to continue in the study, until such time that there was treatment failure. And treatment failure is defined either as the development of complications or inability to capture remission. Now, relapse, of course, was defined by clinical criteria, using the CDAI, and also biochemical criteria, wherein CRP more than five or a fecal calprotectin more than 250, or complications such as either an abdominal abscess greater than three centimeters, or intestinal obstruction, or a new fistula. These were treatment complications.

Now, the results of the study were quite interesting, actually. Now, the relapse rates in people who continued with combination therapy were 14%. There were 40% of people who discontinued infliximab who did actually relapse, and these relapse rates with azathioprine or immunomodulation was about 10%. So infliximab withdrawal, but not anti-metabolite withdrawal, was associated with a significantly higher risk of relapse. And then when they did escalate therapy, so in the group that was in arm A, which continued combination therapy, if they relapsed, for example, they were allowed to intensify their infliximab to 10 milligram per kg. In the group that discontinued infliximab, which was arm B, they could have another dose of infliximab. And then if necessary, escalate that dose to 10 milligrams per kg. And of course in arm C, which was discontinuation of the anti-metabolite, they could intensify to infliximab at 10 milligram per kg. So basically, if they did require to re-intensify treatment, they were able to recapture remission in nearly all patients after restarting infliximab.

In terms of exact figures, of the 39 patients who did relapse, 28 were re-treated and optimized. And in the combination group, one of two patients was able to recapture remission, 22 of 23 in the infliximab arm, and two of three in the discontinuation of the immunomodulator arm. Adverse events were few, very few, in single digits. So one case of tuberculosis and two severe infections, and there was no malignancy and no deaths.

So really, I think this is interesting and quite insightful, because it tells us that infliximab withdrawal is possible. And when it is done, or when someone deescalates infliximab from this combination therapy, it is possible to recapture remission. The question, of course, is would I do this in clinical practice, or how would one approach this in clinical practice? And I don't think that there is a one size that will fit all, but there are some caveats that must be remembered. Of course, this is the first controlled trial to demonstrate this, but we have known this for about a decade or so, through various other studies, including Edouard Louis's first publication in 2012, from the STORI trial, which was, of course, not controlled, but they were able to demonstrate that you can deescalate therapy.

But the selection of patients, I think, that matters the most. These patients were well-selected patients who were in deep endoscopic and also in biochemical remission, so they had achieved a deep level of remission. So achieving clinical, biochemical, endoscopic, and radiological remission is essential, before even such a consideration. But I guess if you have to do it, then whether it's cost-driven, or safety-driven, or patient-driven, or payer-driven, it is possible. One would then have to consider how one monitors these patients.

Dr Cross:
Really nice summary, Jimmy. And I think that, yeah, these are the patients that, I think I've learned this term from you, that have this precious remission, where they feel well, their scope looks great, their biomarkers are great. And we know it can be really hard to get patients to that outcome. And what we learned is, the immune modulator at that point probably doesn't make much of a difference, presuming they have reasonable drug levels. So I think we know that we can withdraw at some point the immune suppressant.

And then I guess the question in clinical practice, would you ever withdraw the anti-TNF? I think this does give us information, numbers, that we can quote our patients, so that we can give them the best shared decision-making. My personal bias is not to withdraw therapy, because you're not going to recapture everyone. And then we don't really have long, long-term results here to show that, for example, that you're not going to get immunogenicity based on that drug withdrawal.

And the other thing, this is a best case scenario of people that are maintaining a thiopurine anti-metabolite therapy, and there's still a fairly high rate of relapse. And if I was going to drop one, I'd probably drop the thiopurine, given the safety profile of that compared to the anti-TNF.

Dr Limdi:
I'm completely with you on that issue, that even I would probably withdraw the immunomodulator and not the infliximab. And that precious remission, what did it take to get there? That's very, very important, too, in order to be able to stay in that place. And yes, it's just an evolving story, and interesting to see what happens in the real manuscript.

Dr Cross:
Excellent study. We really enjoyed covering this. And by the way, that reminds me that we are sponsored by Advances in IBD and the Gastroenterology Learning Network. And Jimmy and I covered this for the IBD Education Group, of which MedEd Consultants is the parent company.

Let's go to the second paper. This is digital oral presentation 43, True North induction, rapidity of ozanimod-induced symptomatic response and remission in patients with moderate to severe UC. Very timely, given that the ozanimod was approved in the US this past fall.

Dr Limdi:
So, yeah, that's right. Thank you for introducing the second abstract, which, of course, is now a new molecule, new molecule to most of us, including us in the United Kingdom, at least outside of clinical trials. The clinical trial, the registrational trial, which has given it its approval, the True North study, for ozanimod, which is the first-in-class S1P modulator that we will see in IBD practice. Yeah, of course, it's now been published in a full manuscript form in the New England Journal. And this was a phase three, randomized, double blind, placebo-controlled trial in people with moderate to severely active Crohn's disease given ozanimod versus a placebo. And just remind our listeners, it had a 10-week induction period, and a 42-week maintenance period.

And overall, patients receiving ozanimod had higher rates of response and remission for their ulcerative colitis versus placebo. It was approximately 18% of people receiving ozanimod versus 6% getting placebo at week 10, and almost 40%, so 37% to be precise, achieving remission response versus placebo at week 52.

Of course, the abstract that we are discussing now is the one presented by Britta Siegmund, who is the incumbent president of ECCO, and presented this abstract on the rapidity of ozanimod-induced symptomatic response and remission in patients with moderate to severely active ulcerative colitis from the induction phase of the True North study. So nearly 1000 patients, just over a thousand patients, were randomized to receive ozanimod, either in cohort one or two, there were 600 patients in one and 367 patients in the second cohort. And what they assessed, really, was symptomatic response and remission, analyzed at each visit from week two to week 10, which was the end of induction, for that particular study.

So the remission, of course, was a hard endpoint at week 10, with a rectal bleeding score of zero, and a stool frequency less than or equal to one. Importantly, anti-TNF therapy had been used in 30% of patients in the first cohort and 40% of patients in the second cohort. So this is a treatment refractory cohort, with a mean disease duration of anything between six and seven years. So treatment refractory cohort of patients who have seen an anti-TNF in at least 30 to 40% of these patients, and at entry, a third of these patients had been receiving a corticosteroid. So nearly 70 or 73% of these patients were not on a corticosteroid.

And this is important, because the results of the study are quite interesting. What they found was that at week 10, there was symptomatic response was seen in the overall cohort by two weeks, as early as two weeks, in nearly 40% of these patients receiving ozanimod, versus about 20% receiving placebo. But when you actually delve into detail, it's kind of expected that anti-TNF-exposed patients seem to do less well than people who are anti-TNF-naive, and that was borne out in this study, so that in anti-TNF-naive patients, again, as early as at two weeks, clinical response was seen. And that was in nearly 40, just over 40% of patients, as opposed to placebo, where there was less, about 20%, just over 20%. But in the anti-TNF-exposed group, again at four weeks, as early as four weeks, a symptomatic response was noted.

When you look at symptomatic remission, which I repeat was people with a rectal bleeding score of zero and a stool frequency of less than or equal to one, so a really hard endpoint. By week five, again, they were able to demonstrate symptomatic remission in nearly just over 20% of patients with receiving ozanimod, as opposed to placebo, which was around 10 to 15%. But again, when you divide them into anti-TNF-naive and the anti-TNF-exposed groups, not unexpectedly, anti-TNF-naive patients did better, but still demonstrating remission in just over 20% by week four. This is remission by week four. And in the anti-TNF-exposed patients, by eight weeks showing clinical remission.

And these responses continue to improve over a period of time. So I think we need to see real world data. We need to see how you and I will, and real world experience will, or effectiveness data will actually, and efficacy data, will demonstrate how well this drug does. But it's quite encouraging to see that in a treatment refractory cohort, you can actually see response as early as week two, week four. But also I think there's another lesson here for us, that in a treatment refractory group, I think clinicians tend to give up on treatment sometimes if it's not seen to be working. So these patients, about 70% of who were not even receiving a corticosteroid, for them to actually achieve response and remission by weeks five and eight, I think is very useful data for a clinician.

So I guess the message here is that we do get excited about early response and early remission. It also teaches us to be patient, because week eight in patients with refractory disease, with utmost respect to our patients, I think they would be willing to wait often to achieve something as precious as a response and remission. So, yes, I think this data in that sense is quite interesting.

And of course, although we are not discussing the efficacy and the safety data here, the safety and data presented at UEGW recently, and also most recently at ECCO, are also very reassuring, in the sense that we are not really seeing any major adverse signals or even issues such as lymphopenia, which you expect, was about 3% of patients had an absolute lymphocyte count of less than 200. So in terms of where from week 10, I think these patients will probably do well. Of course, time will tell.

Dr Cross:
I just want to comment, and then maybe ask you a follow-up question. So the presumption with these drugs that affect leukocyte trafficking, like the S1P modulators and the anti-integrin, there's just been this thought that they take a long time to take effect. And this will really fly in the face of that, where this actually takes effect fairly quickly, so particularly in the bio-naive patients, where this drug is probably positioned the best. But I guess, Jimmy, in that more moderate patient, who's maybe less treatment-exposed, do we even need to give steroids to this patient-

Dr Limdi:
Absolutely.

Dr Cross:
... or if we can get the drug quickly, can we just get this started?

Dr Limdi:
Yeah, absolutely. And I think it is also giving us a new positioning, in a sense, for some of these small molecules. Yes, you're right, about the anti-integrin story, and actually, even some of the post-hoc data from GEMINI, which we are not discussing, do suggest earlier remission or response than we had expected from this class of therapy. But back to where we are, with S1P modulators, or even small molecules in general, I think we are looking at earlier induction. And they could actually be seen, and I think many of us do, at least with the existing small molecules, often use them as induction agents, because if you can see response within two weeks, as early as two weeks, I think I would be keen to convince my patient. And I suspect they will be happy about this, because no one really likes steroids. It is a drug we all should love to hate, if possible, and when necessary. So I think it is possible for us to aim to use these drugs as induction agents. Like I said, we had about 70% of these patients were not even on a corticosteroid. And they were in this group of people who had responses early as week two and four. So yeah, you're right. Absolutely.

Dr Cross:
So Jimmy, I think maybe the abstract that we generated the most interest from our group was the EARNEST abstract, so it's oral presentation 04, which is the largest randomized controlled trial to assess vedolizumab, or any biologic, for chronic pouchitis. So tell us about that study.

Dr Limdi:
Yeah. Thanks, Ray. That's a great introduction to the EARNEST study, because it is the largest double blind, randomized controlled trial for patients with chronic pouchitis for their ileal pouch-anal anastomosis for ulcerative colitis. And we really had only anecdotal data from small studies, so we know that even immunomodulators work. In a study of 14 patients on adalimumab, we know that works, infliximab, we've all used it for this group of patients. And indeed vedolizumab for pouchitis is not new. We have had a small publication, with n equals 18, I think, in Elementary Pharmacology Therapeutics about four or five years ago, which demonstrated it. But this is the first double blind, randomized controlled trial. So here, really, in earnest, we can see data from the EARNEST study.

And what they did, really, was to randomize patients, adult patients between the ages of 18 and 80, who had an IPAA for ulcerative colitis to receive either vedolizumab or placebo. At randomization, it's important to say that for the first four weeks, patients, all these patients, were given ciprofloxacin, but then they were randomized to vedolizumab in the standard induction and maintenance, and also, or placebo. And the primary endpoint for this study was an mPDAI remission at week 14, with important secondary endpoints, which were an mPDAI remission at week 34, and a PDAI, pouch disease activity index, remission, which includes histopathology, as we all know, at week 14 and at week 34. And then, of course, response using an mPDAI at both week 14 and 34, and importantly, quality of life as assessed by the IBDQ, and then the Cleveland Global Quality Of Life index scores. They did do some exploratory endpoints using the SES-CD. Of course, that's an endoscopy score that they employed in these patients with ulcerative colitis to see how it fares.

And the results were striking. The primary endpoint for the study was met, with a third of patients, 31% of patients, actually demonstrating PDAI remission as early as week 14, maintained at week 34 in 35% of patients. And then with response rates as high as 60%, so 62%, to be precise, in patients receiving vedolizumab as opposed to a third receiving placebo. And these rates, again, borne out at week 34, with 50%, 51%, again, to be precise, maintaining a clinical mPDAI response. And then also, a PDAI remission seen, a hard endpoint with histological healing, which was defined as a robust histopathology index of less than three, which actually in English means absence of neutrophils in the lamina propria. So this was achieved in a third of patients, again, 35% of patients by week 14, in those receiving vedolizumab, versus just under 10% receiving placebo, and was borne out at week 34, continued at 37% of patients receiving vedolizumab. So an excellent response and remission rate demonstrated by vedolizumab.

This was also sustained remission. So when they looked at sustained remission, which essentially means remission at week 14 and week 34, then a third of patients, so 27% of patients, had achieved an mPDAI remission through week 14 and 34. And the same number, 31%, had also achieved a PDAI remission. Reassuringly, there was greater histological remission in the vedolizumab group, and quality of life improvement also seen in the vedo group.

Adverse events were very few, in single digits, and nasopharyngitis, and headache or arthralgia, but all in less than 10 patients, so reinforcing our belief that vedolizumab has an excellent safety profile, even in this cohort of patients. So Simon Travis, my friend and colleague who presented this data on behalf of the investigators, concluded reasonably that vedolizumab had shown consistent treatment effect over placebo. And this, of course, being the first randomized trial of vedolizumab, does establish its place in this chronic active refractory cohort of patients with pouchitis.

Vedolizumab, by the way, now has received EMA approval in January for adult patients with moderate to severely active pouchitis. So it really is now there for us to use in this cohort.

Dr Cross:
So I think one of the reasons that our group was so excited about this was, we need more data, more trials, in the pouch world, even just getting the terminology correct. And so I was going to ask you, should this now be first line for antibiotic refractory pouchitis, and based on the regulatory agency in the UK, it seems like the answer to that would be yes.

Dr Limdi:
You're right, yes, it would be. And I think yes, we have always been able to use vedolizumab for first line, even in ulcerative colitis, unlike in Crohn's, where we cannot, by the way. But yes, we would use this as first line therapy, and I guess in individual payers, if they have an objection, you can still use an anti-TNF. It doesn't rule out the role of anti-TNF at all. But this is the first and most convincing data set, so it has to be given credit for having demonstrated what it has.

Dr Cross:
I agree, and it's the highest level of evidence. So I wanted to follow up with a question. This is something I struggle with in practice. You have a patient who's antibiotic-dependent. They may be doing well on ciprofloxacin 500 milligrams twice a day, with excellent control of their symptoms. And they come back, and you see that they're still on antibiotics. And we all feel a bit oogie that we have them on antibiotics. So, should I be giving that patient vedolizumab, or a biologic, or small molecule to facilitate antibiotic withdrawal? Or should I just keep them on antibiotics? Do you struggle with that as well, Jimmy?

Dr Limdi:
Yes, we do. We do. And in such instances, of course we have sometimes taken recourse to a short course of budesonide or beclomethasone in some instances. But of course the effect isn't sustained, and we know that we have to graduate to another level of therapy, which is typically immunomodulatory or, indeed, a biologic. And until now, we have been using either infliximab or adalimumab, and I think we would continue to do that, but this would give me greater confidence in actually using more effective therapy sooner in well-selected patients.

Dr Cross:
How about the patient who's doing okay on antibiotics, but they're stuck on them and can't get off? So cheaper antibiotic therapy with potential bacterial resistance, or much more expensive biologic therapy with potentially getting off antibiotics. So I don't know what to do with them.

Dr Limdi:
I think antibiotic-associated diarrhea, and C. difficile, and other infections, and other associations with antibiotics would probably steer me, there's potential for long term use, to a more effective form of therapy. And so I don't think I know the exact answer, but I would probably move to a biologic agent. And in this case, perhaps either vedolizumab or, if I cannot for insurance or payer reasons, then perhaps an anti-TNF biosimilar. What would you do, Ray? What is your best-

Dr Cross:
I'm going to start talking to my patients about it, once I have them out to six months or a year and considering a transition. And if they're happy with their antibiotics, I'll probably maintain. If they seem risk-averse to the antibiotics, something that's super safe like vedolizumab, we could certainly consider.

Jimmy, this has been wonderful, but the fun question that everyone looks forward to. So tell us something about yourself that the audience may not know.

Dr Limdi:
Oh, yeah. Okay. All my friends know it, all my professional colleagues don't. And it's perhaps less interesting to many people, but actually, I have always been, through school and university, more of a vocalist. So in fact, I had been approached to become a playback singer, for either Indian films or even in Western classical singing, and I have a graduate degree in music. But sadly, I think I spend much less time pursuing that passion, and have evolved a new interest over the last 20-odd years in tennis. So that, in sport, it remains my first love. But yes, as a vocalist, so everyone who knows me from school and childhood will know me more as a vocalist than even a medical doctor. Yeah, that's my story, I guess.

Dr Cross:
Very cool. It proves you can marry the right brain and the left brain. So Jimmy, it's been wonderful having you as a guest.

Dr Limdi:
It's been wonderful to be here.

Dr Cross:
We will have you back in the future for IBD Drive Time. Thank you.

Dr Limdi:
That will be an honor. Thank you very much, Ray. Thank you.