David Rubin, MD, on Optimizing Anti-TNFs for IBD

Dr Rubin reviews the impact of anti-tumor necrosis factors on the treatment of inflammatory bowel disease and how today it remains a valuable tool in the armamentarium of therapies.

David Rubin, MD, is the Joseph B Kirsner Professor In Medicine, chief of Gastroenterology, Hepatology and Nutrition, and director of the Digestive Diseases Center at the University of Chicago School of Medicine.

TRANSCRIPT:

Hi, it’s Dr David Rubin from the University of Chicago. I'm at the Advances in IBD meeting 2023 in Orlando, Florida. It's the 22nd year of this meeting, remarkably, and this morning, I gave a lecture on optimizing anti-TNF therapy. I spoke about how anti-TNF therapy was a revolution in IBD being the first therapy that was approved by the FDA for moderate to severe Crohn's disease in 1998 when they approved iniximab. And, of course, subsequently, we have a variety of additional subcutaneous anti-TNF therapies and biosimilars now to both infliximab and adalimumab, and most recently, the FDA approval of subcutaneous infliximab for maintenance therapy in both Crohn's disease and ulcerative colitis.

I spoke about all that we've learned with the anti-TNF therapies in our field, how effective these therapies have been for our patients with Crohn's and UC, the data we also have for perianal fistulizing Crohn's disease with infliximab, and how we can approach patients with Crohn's or ulcerative colitis when we choose an anti-TNF therapy. We've now learned a lot about how to optimize these treatments. We know, for example, that there are some factors that predict the likelihood of loss of response, as well as the likelihood of development of antidrug antibodies or what we call immunogenicity. Those factors include men more than women; we now know very well in a variety of different and important research studies that people who are overweight or obese, and especially actually, those who have fat around their viscera, are more likely to lose response or require higher amounts of drug. And we've also learned that smokers are more likely to lose response and develop antidrug antibodies, and people with high inflammatory markers are at higher risk, both for increased clearance of drug and the development of immunogenicity and antidrug antibodies. So one of my main messages in this lecture was for people to understand what's the risk of that individual patient in front of you, that when you're going to prescribe an anti-TNF drug, that the patient may not respond completely, or they may respond, but then lose response, as well as the possibility that they're going to develop anti-drug antibodies.

I also spoke about how we've learned to prevent these by, for example, using concomitant immunomodulators. Of course, the data primarily exists with Infliximab, but we've come to appreciate the value of using an immunomodulator like a thiopurine in combination with infliximab, and probably with adalimumab and the others, at least during the induction phase of management, as well as we've learned how to commitPpatients to maintenance therapy, and to monitor the disease, and in some cases, monitor the drug levels in order to keep people on therapy as we move forward.

I reviewed the evolving data on therapeutic drug monitoring anti-TNFs. And I pointed out to the audience that especially for high-risk patients, the ones I've already mentioned, who have high inflammatory burdens or high likelihood of clearance of drug too rapidly, that doing a intraloading or premaintenance drug level—so a week 6 drug level with infliximab and probably a week 4 or week 6 level with adalimumab—can actually guide you in early dose optimization and dose escalation going into maintenance with the presumption that that will prevent loss of response. I say presumption because those studies are still ongoing. But it certainly makes sense to know if the drug level is less than a certain amount early.  You're going to want to try to avoid loss of response later by increasing the dose, which we know correlates to an increased drug level subsequently.

So what are the levels? Well, you want an infliximab level of 17 or more prior to the third loading dose at week 6. And with adalimumab, it's a little less well defined, But I would say you want a level that's also more than 15 or 20 before your week 4 or week 6 loading phase and maintenance dosing. We also talked a bit about how to approach loss of response, and this has to do with the patient who's either symptomatic, where reactive drug monitoring makes sense, where's the drug, is there no drug left, or if there is drug have developed antidrug antibodies, and whether you can optimize dosing, cycle to another therapy in class if they have antidrug antibodies, or swap to an entirely different mechanism to try and recapture.

I pointed out to the audience that the majority of loss of response with anti-TNF is not due to immunogenicity, but rather, the mechanism stops working, and the disease presumably moves right through that mechanism, and we need a different treatment strategy— very important point now that we have so many other options to think about for our patients. So all in all, we've made some incredible progress thinking about how to use anti-TNFs in our patients with IBD. It is still a very important treatment option for people with Crohn's and colitis, and we should know as much as possible about how, when we choose this option, we want it to work, and we want it to last, and we've made some great progress in that area. Thank you very much.