Gastroenterologists now have many more options for medical management of inflammatory bowel disease (IBD) than 30 years ago, when therapeutics were largely limited to 5-aminosalicylates (5-ASAs) and corticosteroids, Jean-Frédéric Colombel, MD, said in his keynote address to the Crohn’s & Colitis Congress on January 21.

However, he stressed, even the most effective therapies achieve a net benefit for fewer than half of patients with ulcerative (UC) and Crohn’s disease (CD) after induction. “We are plateauing,” Dr Colombel stated.

Dr Colombel is professor of medicine and director of the Susan and Leonard Feinstein IBD Center, and director of the Leona M. and Harry B. Helmsley Charitable Trust IBD Center at the Icahn School of Medicine at Mount Sinai in New York.

“We have set more ambitious goals for IBD treatment, such as mucosal and histologic healing, yet our patients remain at high risk for surgery—up to 25% of patients with Crohn’s disease,” he said. “So where should we go from here?”

First, Dr Colombel said, “we need to make the most of what we have. There is a huge gap between knowledge and practice, and inequality of care. Studies show that very few IBD patients are started on biologics, and more concerning, up to 63% of patients with IBD are managed on steroids.”

The “3 pillars” of early treatment, treat-to-target, and tight control of disease must be applied to achieve improvement in overall rates of remission. “We know that drugs are most effective in Crohn’s disease when begun early,” he stated. “Patients whose disease remains under tight control do better and more often achieve deep remission.” How to achieve tight control is a matter of some debate, Dr Colombel added, noting that “the jury is still out” on the effectiveness of proactive therapeutic drug monitoring in maintaining remission.

“The market in ulcerative colitis does not reflect existing science,” he said. “We have seen from study results that vedolizumab is superior to adalimumab, yet few patients begin their treatment for UC with vedolizumab.”

Finding and using biomarkers to help risk-stratify patients and predict which patients are likely to respond to certain therapies is limited in practice, Dr Colombel explained. The HLA-DQA1*05 gene has direct implications for therapy, because this gene predisposes patients to develop antidrug antibodies to tumor necrosis factor-alpha inhibitors (TNFi). “We need to embrace the concept of personalized medicine,” he said.

Dr Colombel made “a plea for rational combinations” of therapeutics. “Rheumatologists and dermatologists are already doing this but in IBD, there’s almost nothing.  We have only retrospective data,” he said, emphasizing the need for more prospective studies of drug combinations.

One such study is in progress, he noted. The EXPLORER study is enrolling newly diagnosed patients with CD at high risk of complications. It is designed to investigate the safety and efficacy of vedolizumab, adalimumab, and methotrexate in combination, and the de-escalation to vedolizumab monotherapy over time. Dr Colombel said some data from this study should be available soon.

“The concept of rational combination therapy is to find medications with complementary mechanisms of action,” he explained. “To do that, we must know more about modes of action for all of our therapeutics.”

Finding new therapeutic targets should also be a priority, Dr Colombel said. “We should consider revisiting IBD pathogenesis; maybe it’s time to target other factors, such as the microbiota.” This includes study of fecal microbiotal transplantation (FMT) as a possible therapeutic mechanism, in addition to bacteriophage therapy, improving barriers, and investigation of B-cell involvement in IBD.

 “We should also investigate the impact of intervention at the preclinical phase, define new pathways, and identify new therapeutic targets,” Dr Colombel stated. ““We must embrace the paradigm of prevention.”

--Rebecca Mashaw

Reference:

Colombel JF. Keynote presentation: Breaking the ceiling of IBD therapies. Presented at: Crohn’s & Colitis Congress. January 21, 2022. Virtual