Miguel Regueiro, MD: Bill and David, let's get to practical reality. You heard about the anti-TNFs [tumor necrosis factor medications]. Oftentimes, the payer will dictate the first therapy. At least in many parts of the country, often anti-TNF is the first-line or first treatment, and you can get in to the nuances, whether it's an IV [intravenous] or subcutaneous anti-TNF, which may have implications on your second. How do you decide, or what do you use second? When do you switch? When do you say this isn't working? Bill, I'll start with you. How do you consider when you're moving from one to another? When is that time, and what are you choosing next?
William J. Sandborn, MD: Many of us have worked on similar algorithms about how to think about this. In a patient who's getting a biologic and has symptoms, as a starting place, you want to know if the symptoms are a reflection of active disease. The gold standard for that is an endoscopic procedure or possibly a radiographic procedure, depending on the disease location. Increasingly, biomarkers can be a surrogate for endoscopy, but somehow, you need to be confident the patient has active disease: yes or no. If they do, that tells you the drug either isn't working or there's not enough drug.
Conversely, if there's no active disease, then switching the drug and dose escalating is not going to solve the problem, and you need to focus on what the cause of the problem is, which can be bile acid diarrhea, fat malabsorption, small intestinal bacterial overgrowth [SIBO]. You can have SIBO plus bile acid malabsorption or fat malabsorption, and it's essential to hunt hard for those things if you don't have active disease. Even if you do have active disease, you still might have those things. If the clinical history sets the patient up, they've had an ileal resection or they've had several ileal resections, that sets them up for bile acid malabsorption and for SIBO, so you still need to look. You wouldn't get off the hook just looking for that.
Then for active disease, you want to know, do they have antibodies to the drug and no drug, or do they have insufficient drug, or do they have plenty of drug? That's where therapeutic drug monitoring comes in; it's an essential part of that. If you have antibodies at high titer and low or undetectable drug, you're going to need to switch. If you have low drug and no antibodies, most likely you will want to dose escalate. If you have drug that is low but present and low titer antibodies, that’s a gamble whether you can overcome the immunogenicity. You can sometimes, but it's not as much of a slam dunk situation as if you don't have antibodies. Then, it depends on what your alternatives are.
We've also come to note that patients who have developed antibodies previously are at risk for developing antibodies again. There's evolving laboratory testing for HLA associations that predict this.
Don't stick your head in the sand. If you think that an anti-TNF is a good drug for this patient but they got antibodies already to 1 drug, don't give them another course of monotherapy and think you're going to win with optimization. You're probably not, and that patient, even at the extremes of age, probably should have a combination therapy. That's how I think about it. Then, if you're switching from an anti-TNF in Crohn disease, the drug that has had the best results with switching is ustekinumab. In ulcerative colitis [UC], it’s a tie between ustekinumab and tofacitinib, and there may be pluses or minuses in an individual patient. Both of those drugs in UC show a clear and unequivocal effect for induction and maintenance in failure patients, and other drugs show less benefit.
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