Breaking Through the Therapeutic Ceiling: the Future of Inflammatory Bowel Disease

Breaking through the “therapeutic ceiling” in inflammatory bowel disease (IBD) that causes many patients to struggle to achieve and sustain remission is one of the biggest issues facing the practice of gastroenterology, said Dr Adam Cheifetz, as he opened second day of the Interdisciplinary Autoimmune Summit (IAS) virtual meeting on April 27.

Dr Cheifetz is director of the Center for Inflammatory Bowel Disease at Beth Israel Deaconess Medical Center in Boston and associate professor at Harvard Medical School.

In projecting the future of gastroenterology, Dr Cheifetz said that treatment with new combinations of therapies—including combining biologics and/or small molecules—and the application of therapeutic drug monitoring (TDM) should play significant roles. “We’re trying to treat smarter; to treat earlier with the most effective therapies; to treat deeper, reaching for biochemical and endoscopic improvement; to use treat to target for tight control; and to treat more effectively through TDM,” he said.

Dr Cheifetz explained that TDM is the measurement of trough concentrations of drug levels, particularly with tumor necrosis factor inhibitors (TNFis), to maintain optimum biologic therapy. Achieve threshold drug concentrations for TNFis has been shown to be “better than empirically dose optimizing” patients.

Dr Stephen Hanauer, the Clifford Joseph Barborka Professor of Medicine at the Feinberg School of Medicine and medical director of the Digestive Health Center at Northwestern University in Chicago, explained, “In rheumatology, in induction and maintenance dosing, you never had the issues with immunogenicity that we’ve encountered. But in IBD, when we started with infliximab, it was a single infusion. Then we were left with a whole cohort of patients who developed antidrug antibodies. We had to learn from that.”

He continued, “Infliximab was our only drug for 4 or 5 years until the next TNFi came along. So we were forced to learn how to use these drugs in the best ways. That’s where the concept of monitoring came into clinical play for us.” 

TNFis are now often used in combination with methotrexate and other immunomodulators, Dr Cheifetz stated. “We have really good data from trials that with combination therapy, particularly infliximab with azathioprine, patients do better” than if they are treated with either drug as monotherapy.

“Rheumatology has been teetering on this issue of combination for a while,” Dr Joseph Merola, associate professor in the department of dermatology and the division of rheumatology at Harvard Medical School and Brigham & Women’s Hospital in Boston, said. Dr Hanauer commented, “Well, let me make it more complicated. When we analyze those combination trials what we see is the boost in the drug levels from the combination.”

Dr Cheifetz added, “There’s fear in GI of low drug concentrations,” which are associated with higher rates of antidrug antibodies and loss of response. He also noted that TDM and combination therapy can be very important in the field of dermatology, too, particularly with hidradenitis suppurativa, which he described as a “very aggressive” disease whose patients clear drug more quickly and require high doses.

“There is data in not just IBD, but also other fields, that proactive TDM is effective.” Proactive TDM, he explained, involves checking drug trough concentrations before patients show any loss of response to ensure that the drug levels are appropriate. Dr Hanauer explained that one reason doses of these medications, when used in IBD, are almost twice those administered in other IMIDs is because “there is more immune tissue in the gut” and patients eliminate a great deal of drug in the stool.

Dr Joel Gelfand, professor of dermatology and epidemiology at the University of Pennsylvania Perelman School of Medicine, commented that in his field, “a lot of patients who lose response to biologics are really underdosed, I think.” Dr Alexis Ogdie, associate professor of medicine and epidemiology in the Perelman School of Medicine, added that this is also a problem with some of the interleukin inhibitors, such as IL-17s and IL-23s, used in a variety of immune-mediated inflammatory disorders (IMIDs.)

More personalized induction therapy that uses a pharmacokinetic dashboard to predict needed drug concentrations will likely provide better outcomes, Dr Cheifetz said. He referenced a study showing that 80% of patients with who received 5 mg/kg of infliximab during induction needed higher doses to reach the appropriate drug concentration; even some 60% of those dosed at 10 mg/kg needed more. “High rates of drug clearance, C-reactive protein, low albumin, all contribute to patients needing more drug during induction, when it’s most important.”

Dr Hanauer commented that there is “uniform acceptance of reactive TDM,” or checking drug concentrations and antibodies when patients begin to show loss of response. Dr Cheifetz replied, “Why wait?” He added, “In our field we’re trending to check levels once during induction to help predict what’s needed. I check at least once a year in maintenance.”

Combining biologics holds promise for treating IBD as well as extraintestinal manifestations. The VEGA study showed that patients on the combination of the IL-23 inhibitor guselkumab with the TNFi golimumab had better response than those on either drug as monotherapy. However, Dr Hanauer asked, “Are payers going to pay for this?” Dr Merola agreed. “It’s great in theory to combine these drugs but cost is a big issue.” He further noted that the safety of combined biologics, as in the VEGA trial, is comparable to safety shown in other drug trials.

Dr Hanauer discussed the goal of providing precision medicine to patients with IBD. “We used to talk about IBD as two buckets—one for Crohn’s disease and one for ulcerative colitis. Now IBD is seen a spectrum, with overlaps, like you see in dermatology. But we lack any biomarkers that distinguish between phenotypes.” With more than 150 genetic polymorphisms associated with IBD, he asked, “how do we personalize care?”

Treating these diseases earlier in their course is one key to ensuring better outcomes, the panelists agreed. Dr Hanauer said, “It’s been found that if you treat optic neuritis aggressively you can prevent progression to the development of multiple sclerosis. Our goal to reduce progression of disease by treating to rigorous targets in IBD.” He added that IBD is “moving away from patient-reported outcomes as targets; instead we set out to treat to endoscopic or histologic targets.” Dr Ogdie added, “We still want those PROs because you want the patient to feel better, but we struggle a lot for other outcome measures in rheumatology.”

Dr Gelfand commented, “There is often a long delay before a patient with psoriasis gets the first biologic —10 years or more. Should we treat patients with milder disease more aggressively upfront?” A major barrier to this course is, again, payers, the panelists agreed. “Even now third-party payers are making patients fail therapies” that may not have been the best choice, Dr Hanauer said, and second-line therapies often do not work as well.

In IBD, the focus is on trying to stratify patients at presentation by their risk of progression. “We have separated disease activity—how the patient feels today—and disease severity, or how likely the patient is to progress,” Dr Hanauer explained. “But most of our determinants for progression are clinical—age, comorbidities, phenotypic presentation— not based on biomarkers. So one of our biggest needs is for biomarkers to help predict response.”

He expressed optimism about the potential role for artificial intelligence. “We’re incorporating this into our practice now, into colonoscopic screening. AI can now describe the pattern of disease in IBD much better than individuals. I think this is going to help us break through that therapeutic ceiling.”

—Rebecca Mashaw

Reference:

Cheifetz AS, Hanauer SB. The future of IBD. Presented at: Interdisciplinary Autoimmune Summit. April 27, 2023. Virtual