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Miguel Regueiro, MD
Professor of Medicine
Chair of the Digestive Disease & Surgery Institute
Cleveland Clinic, Cleveland


This month, I look at how our understanding of the role of genetics in inflammatory bowel disease has evolved and discuss one aspect of last year’s landmark trial that spurred the FDA approval of risankizumab (Skyrizi, AbbVie) for moderate to severe Crohn’s disease.

About 20 years ago, as we began to sequence the human genome, there was excitement in all of medicine—including among IBD clinicians—about the possibility of gene sequencing in driving precision medicine. Find the relevant genetic mutation, the thinking went, and we could develop a custom treatment that would make our patient’s life better.

As the first study I discuss shows, this is only part of the story. Obviously, our genetics plays a role in health outcomes, but so do our lifestyles and the environment in which we live—facts that were underappreciated two decades ago. Now we accept that genes, environment and lifestyle all play roles in IBD. The good news is that this knowledge enables us to encourage patients to adopt healthier lifestyles and diets, which are always good ideas, and also are important as part of treatment.

The other study looks at the maintenance phase of the landmark FORTIFY trial, which led to risankizumab’s approval as a treatment for moderate to severe CD in June 2022. The main FORTIFY trial showed that risankizumab induced remission by 12 weeks. This maintenance study shows that it maintains remission through one year. We don’t know yet whether risankizumab also will be approved as a treatment for ulcerative colitis, but in any case, it is great to have a new medication for CD.


Genetics and IBD

Am J Gastroenterol 2023;118(3):511-522

This study tracked the experience of 707 people with CD and 1,576 people with UC in the United Kingdom using the UK Biobank cohort. Some patients in the cohort had a higher genetic risk for developing IBD than others.

To find effects of lifestyle on genetic risk for severe IBD, the investigators reviewed the cohort’s responses on six lifestyle choices (diet, smoking status, alcohol consumption, sleep, physical activity and body mass index), categorizing the patients into three groups based on healthy choices: favorable, intermediate and unfavorable.

On its own, a genetic predisposition more than doubled the risk for developing IBD. The hazard ratio (HR) was similar for CD and UC (HR, 2.24; 95% CI, 1.75-2.86 and HR, 2.15; 95% CI, 1.82-2.53, respectively). Combining genetic risk and an unhealthy lifestyle, however, dramatically increased the chances of developing IBD (CD: HR, 4.40; 95% CI, 2.91-6.66 and UC: HR, 4.44; 95% CI, 3.34-5.91).

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In contrast, people with a genetic predisposition who had a healthier lifestyle halved their risk for IBD (CD: HR, 2.33; 95% CI, 1.58-3.44 and UC: HR, 2.05; 95% CI, 1.58-2.66). However, this cohort consisted of only respondents with European ancestry, decreasing the applicability of the results to the general population.


Risankizumab and Endoscopic Remission at One Year

Lancet 2022;399[10340]:2031-2046

The FORTIFY trial is the maintenance phase of the previous ADVANCE and MOTIVATE trials, which established that risankizumab could induce endoscopic remission in CD. FORTIFY enrolled 712 patients who had taken part in the earlier trials, who received either 180 mg (n=179) or 360 mg (n=179) of risankizuamb or placebo (n=184) over 12 months. Dosing occurred every eight weeks.

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At the one-year mark, after some patients had withdrawn from various trial arms, the 360-mg dose was especially efficacious at maintaining clinical remission and endoscopic rates compared with placebo. The investigators found that clinical remission, as defined per the Crohn’s Disease Activity Index, was reached in 52% of participants taking the 360-mg dose versus 41% of the placebo arm (P=0.0054).

—Compiled and written by Marcus A. Banks

This article is from the April 2023 print issue.