Advanced Therapy in Early Crohn’s Disease: Evidence Outpaces Acceptance

Evidence continues to grow that patients with Crohn’s disease should be aggressively treated with advanced therapy as early as possible after diagnosis, rather than first turning to less-powerful corticosteroids.

Still, many clinicians aren’t yet with the program. An analysis of 2019-2023 insurance data found that nearly half of newly diagnosed patients with Crohn’s started out by taking corticosteroids (step-up therapy) instead of biologics and immunomodulators (top-down therapy).

There’s a significant risk to the step-up strategy, Marla Dubinsky, MD, of Mount Sinai Kravis Children’s Hospital in New York City, told MedPage Today. “Every day that we delay using advanced therapies in the patients that most need it is a day that we are not taking advantage of changing the trajectory of the disease,” she said.

Here’s a look at what we know about first-line therapy in Crohn’s.

Evidence Supports Top-Down Strategy

“Over the last 20 years, we’ve seen a lot of data suggesting that the earlier we treat [with advanced therapy], the better the outcomes,” said Gil Y. Melmed, MD, of Cedars-Sinai Inflammatory Bowel Disease Center in Los Angeles.

Multiple studies have supported the top-down approach, most notably the landmark PROFILE trial. In the randomized study, those in the top-down group were much more likely to reach sustained steroid-free and surgery-free remission at 48 weeks than those in the step-up group (79% vs 15%, P<0.0001). The top-down group also had fewer serious adverse events.

At the recent Digestive Disease Week meeting, researchers reported that 5-year follow-up data showed similar patterns. “I think our data suggest that not only is it more effective to treat with the most effective medications as soon as possible, it’s actually safer for patients,” Nurulamin Noor, MD, PhD, of the University of Cambridge in England, told MedPage Today at the time.

Nonetheless, Step-Up Therapy Persists

Despite the growing evidence for the top-down strategy, many newly diagnosed patients with Crohn’s are still being treated with the step-up approach, which relies on corticosteroids, 5-aminosalicylates, and thiopurines, Dubinsky said, “even though none of them change the trajectory of Crohn’s surgical rates, and none of them have proven to reduce complications over time.”

In fact, “steroids are the most likely inflammatory bowel disease [IBD] drugs to be associated with infections and death compared to any other therapeutic approach,” Stephen B. Hanauer, MD, of Northwestern University Feinberg School of Medicine in Chicago, told MedPage Today. “Once patients are started on steroids it creates two problems: managing side effects and initiating a steroid-sparing agent.”

How widespread is step-up therapy? A recent cohort study of patients newly diagnosed with Crohn’s from 2019 to 2023 found that 44% were treated with corticosteroids and 53% with advanced therapy.

“The idea that undertreated IBD is riskier than any of our riskiest therapy has really not penetrated the market as much as it should have,” Dubinsky said.

Some Insurers Still Resist Top-Down Strategy

Some insurers resist paying for highly expensive biologics for newly diagnosed patients even though research suggests that long-term costs are lower due to a reduced risk of hospitalization and surgeries, Hanauer explained.

According to Dubinsky, insurers may be willing to pay for some biologic options but not others. “What we try to say [to patients] is, ‘I don’t actually care what you start, just start whatever you can get your insurance to pay for, because all of our drugs are amazing.'” It helps that cheaper biosimilar products are now available, she added.

Tradition has played a role too, Melmed said. He noted that many gastroenterologists were trained to only turn to more powerful drugs after trying other approaches. Furthermore, patients may be hesitant to accept the need for advanced treatment.

Alternatives to Infliximab Are Available

There have also been fears about a higher risk of lymphoma in patients taking infliximab (Remicade), a biologic therapy that’s been around for about a quarter century, Dubinsky said. While the drug has a black box warning about serious infections and cancers such as lymphoma, a 2020 study said the “absolute risk of lymphoma with anti-TNF [tumor necrosis factor] use is low and benefits of adequate IBD control outweigh the potential risk of malignancy development.”

However, alternative biologics such as ustekinumab (Stelara), vedolizumab (Entyvio), and interleukin-23 inhibitors have appeared over the past 12 years, Dubinsky said. As a result, “there have been increased conversations about using [biologics] earlier, and the conversations were a lot easier because there was no black box warning, no infection warning, no malignancy warning.”

Early Therapy in Mild Cases May Be a Good Idea

About 20% of patients with Crohn’s will have mild inflammation and symptoms, and they’ll never progress to strictures and fistulas that usually require surgery, Melmed said. “Those patients may not need or don’t need advanced therapies,” he noted. “The problem is that we don’t know how to identify who those 20% are today at the time of their diagnosis.”

One challenge to treating milder cases is that reliable standards aren’t yet available to define who fits in that category, Dubinsky explained.

For now, she said, it’s better to err on the side of overtreating patients with milder disease via advanced therapies rather than undertreat patients with moderate-to-severe disease.