When and How to Switch Therapies in Crohn's Disease

Stephen B. Hanauer, MD: Once we determine our therapeutic strategy, be it for low-risk or moderate- to high-risk individuals, it’s important that we monitor for both symptoms as well as biologic evidence of response. That can include biomarkers such as C-reactive protein or calprotectin. We will also intermittently endoscope the patient with a colonoscopy or repeat the imaging to make certain that we’re really achieving our ultimate goal, which is to heal the mucosa, which we think will prevent the progression of the disease.

Each therapy is different. It has a different onset of action, mechanism of action, and time to response. We’ll reassess depending on the individual therapy. With corticosteroids, we expect clinical improvement quite rapidly, within days, and certainly within a week or two. Similarly, with the TNF inhibitors, we usually expect a more rapid response for patients. Some of the other mechanisms of action may take a little bit longer. For instance, the anti-integrin therapies may take a number of weeks, or even a month, or 2, or several, to have an effect. And then finally, with our recent addition of ustekinumab, we’re anticipating pretty rapid responses, usually within the first few weeks of treatment.

When we’re looking at loss of response to biologics, it’s important for us to, first and foremost, be certain that they actually have lost response, that their symptoms are not due to conditions outside of the Crohn’s disease, such as infections or bile salt diarrhea. Once we’ve established that the loss of response is really due to active inflammation, then we will typically measure drug levels of the biologics. We then have 3 separate situations. If there is a lot of drug on board and the patients are not responding, we usually switch classes. On the other hand, if there’s no or little drug on board in the presence of anti-drug antibodies, that’s when we’ll switch to another agent within the same class. And finally, if there are low levels of the drug and no anti-drug antibodies, we simply increase the dose to optimize the levels.

William J. Sandborn, MD: A really critical question at this point in time is what to do with patients with Crohn’s disease who’ve received anti-TNF therapy and have had a primary nonresponse, have lost response, or have become intolerant to treatment. There are several strategies for this. One is to actually switch within the anti-TNF class. I think that that’s most effective in patients for whom you’ve employed therapeutic drug monitoring, and you’ve demonstrated that the patient developed immunogenicity or anti-drug antibodies to the first anti-TNF. And those patients, if you switch an anti-TNF to another anti-TNF, tend to do fairly well. On the other hand, if you have a sufficient amount of anti-TNF drug on board and the patient is still symptomatic and has endoscopic findings, then really changing mechanisms of action becomes critical.

There are several classes of drugs now that we can do that with. One is the anti-integrin agent, vedolizumab, or anti-alpha 4/beta 7, and the other is the anti—interleukin-12/23 agent that’s targeted to the P450 sub unit shared by those 2 cytokines, and that’s ustekinumab. So, each of those drugs, vedolizumab and ustekinumab, has been evaluated in patients who are intolerant or have failed TNF blockers. And each of them has been shown to be effective. I would say that vedolizumab takes longer to work in that patient population, so it’s more of a long-term play. It may take 10 weeks or longer to really show a benefit. But then, eventually, patients with a TNF failure can do quite well on vedolizumab.

The anti-cytokine agent, ustekinumab, works relatively quickly in patients with anti-TNF failure and can be used for both induction or, if it has been given intravenously, long-term maintenance, where it’s given subcutaneously. It clearly is effective in both patients who are anti—TNF naïve and failed anti-TNFs. So, we really have several excellent options.

Transcript edited for clarity.