Patient Risk, Not Disease Duration, Key to Timing Biologics in IBD

Becky McCall

November 17, 2021

The decision to Initiate biologics early in the treatment of Crohn's disease (CD) and ulcerative colitis (UC) should be based on complication risk, not on the assumption that earlier treatment produces better results, new research suggests.

Results of a meta-analysis of randomized controlled trials show that "the proportional biologic/placebo treatment effect on remission and response to biologics was not influenced by disease duration in UC or CD patients," the investigators note.

"Patients with Crohn's disease treated with biologics early on show over 40% remission rate, compared to around 30% for those with disease of 20 years or more," study investigator Shomron Ben-Horin, MD, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel, told Medscape Medical News.

The rates of remission with both biologics and placebo were higher for patients with short-duration CD compared with patients with disease of longer duration. However, for patients with UC, the remission rates with both biologics and placebo were similar regardless of disease duration.

"Our findings support the use of biologics in patients with Crohn's disease early after diagnosis if they are at high risk of disease progression and complications, but not just to achieve better efficacy," Ben-Horin said.

The meta-analysis was published online in Gastroenterology.

Getting the Timing Right

Ben-Horin led the research with an international group of investigators who assessed individual data from 6168 patients with CD and 3227 patients with UC. The patients were participants in 25 placebo-controlled trials.

For patients with CD, the odds ratio (OR) of achieving remission with biologics in comparison with placebo was 1.47 (95% CI, 1.01 – 2.15) for short-duration disease (≤18 months), which was not so different from the OR for longer-duration disease (>18 months) (OR, 1.43; 95% CI, 1.19 – 1.72).

"These results remained similar when tested for other disease duration cutoffs or when accounting for individual patients' characteristics, such as whether patients were previously exposed to biologics or not," said Ben-Horin.

For patients with UC, the OR for remission with biologics in comparison with placebo was 1.82 (95% CI, 1.12 – 2.97) for those with short-duration disease and 2.21 (95% CI, 1.79 – 2.72) for those with long-duration disease.

What the optimal timing is for using biologics for patients with inflammatory bowel disease (IBD), which includes both CD and UC, and whether all patients with these conditions need them are very pertinent questions, said Ben-Horin.

About a decade ago, the treatment of IBD changed. At that time, patients were initially treated with immunomodulators or steroids; biologics were used onlyif those treatments failed. More recently, a top-down approach has been followed, in which biologics are brought in at the beginning of the treatment protocol, said Ben-Horin.

This top-down approach has been widely adopted to prevent complications, such as intestinal strictures, bowel obstruction, or fistulas, which can increase the odds that patients with CD will require surgery, he added.

Although treatment with biologics was more effective when initiated earlier than later, data to support this were limited, prompting the investigators to conduct the current review.

"A substantial fraction of patients with Crohn's disease may be better off with biologics first if they are at a high risk of complications, for example, smokers, patients with extensive disease, or those with perianal fistula. But this may not be necessarily true for those with a low risk of complications," said Ben-Horin.

For patients with UC, "the lack of better efficacy with biologics in short-duration disease forces us to rethink our protocols of an early start of biologics," he added.

Possible Reasons for the Early Response

The reasons for the higher response to both placebo and biologics for patients with early CD are unknown.

"It may be that there is plasticity in Crohn's disease early in the course of disease, where the tissue is more amenable to return to normal whether the patient is on placebo or treatment," said Ben-Horin.

He suspects that the more likely explanation is that the placebo response is higher in patients with CD of short duration.

"When we looked at levels of C-reactive protein, this was reduced by biologics at similar magnitude in early- and late-disease patients," Ben-Horin said. He noted that more studies are needed to better understand disease dynamics with these conditions.

Commenting on the findings for Medscape Medical News, Stephen B. Hanauer, MD, from Northwestern University Feinberg School of Medicine, in Chicago, Illinois, noted that they "absolutely support earlier intervention for moderate-severe Crohn's disease from diagnosis, rather than waiting for transmural progression that will make disease more refractory to any mechanism of action.

"Unfortunately, the average duration of disease in biologic trials is often close to 10 years, which implies a more refractory population," Hanauer said.

"Furthermore, in the United States, clinicians and patients are hampered by inability to gain third-party authorization for biologics or advanced oral agents, such as JAK inhibitors or S1P modulators, until failure of so-called conventional agents despite labeling indication for moderate-severe disease," he added.

Ben-Horin has received consultancy and/or advisory board fees from AbbVie, Novartis, Schering-Plough, Janssen, Celltrion, GSK, Pfizer, Galmed, and Takeda and research support from AbbVie, Janssen, Celltrion, Galmed, and Takeda. Hanauer is a consultant and speaker for AbbVie, Janssen, and Takeda.

Gastroenterology. Published online October 29, 2021. Abstract

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