Conference Coverage

Are next-generation therapies for IBD ready? Are we making a difference?


A description of ulcerative colitis (UC) was first published by Wilkes in 1875. Infliximab was approved by the Food and Drug Administration for Crohn’s disease (CD) in 1998, 123 years later. However, in the following 20 years, there were eight new biologic or small-molecule agents approved for inflammatory bowel disease (IBD), with dozens more in the pipeline. These new mechanisms of action include janus kinase (JAK) inhibition, sphingosine 1 phosphate receptor 1 modulation, anti-integrins, and inhibition of the p19 subunit of interleukin-23.

Dr. Uma Mahadevan

Dr. Uma Mahadevan

Unfortunately, the rapid increase in drugs and mechanisms of action have not come with a strong understanding of which agent is most appropriate for which patient. Recent studies have tried to address parts of this question. First, we must define what the endpoints of therapy are – endoscopy, histology, or patient-reported outcomes? Then we need to understand how to achieve these endpoints. Combined immunosuppression with infliximab and azathioprine was superior to each alone in the SONIC trial (N Engl J Med. 2010;362:1383-95). The CALM study (Lancet. 2018;390:2779-89) looked at clinical management (escalation in therapy for moderate to severe CD by Crohn’s Disease Activity Index [CDAI]) and prednisone use versus a treat-to-target (T2T) approach which responded to C-reactive protein and fecal calprotectin. The T2T approach was statistically more likely to achieve endoscopic response at week 48 (45.9% vs. 30.3%). Early immunosuppression is also more likely to reduce hospitalization and surgery rates as shown in the REACT Trial (Lancet 2015;386:1825-34). This year at Digestive Disease Week, we can also add the VARSITY trial (Abstract 416A) which was a head-to-head comparison of vedolizumab to adalimumab for UC. After induction and maintenance therapy, vedolizumab was statistically more likely to induce clinical remission at week 52 than adalimumab, suggesting vedolizumab should be preferred as the first-line biologic in moderate to severe outpatient UC, particularly given its excellent safety profile.

Ustekinumab is Food and Drug Administration approved for CD. At this year’s DDW we saw that it is effective for induction and maintenance of remission in UC (Abstract 833) as well, and also has an excellent safety profile. JAK inhibitors have shown significant efficacy for UC, and more selective agents with primarily JAK1 inhibition are in studies for CD and UC. Adverse events of interest have included herpes zoster and thromboembolic events. Research has also been focusing on out-of-the-box therapies including fecal microbiota transplant for UC, dietary interventions for induction and maintenance of remission in IBD, and allogenic mesenchymal stem cells for perianal fistulizing CD.

With all of this new therapy, are we actually modifying disease history and avoiding surgery? The answer to that seems to be “yes.” Edward L. Barnes, MD, and colleagues (Abstract 708) used an insurance dataset to show that the rate of colectomy for UC has been reduced significantly between 2007 and 2016. While this may be, in part, attributable to biologic therapy, certainly change in practice guidelines, awareness of complications such as C. difficile, and enhanced disease monitoring have also played a role. Surgery itself should not be viewed as a failure. A limited ileocecal resection is more cost effective with equal or better quality of life at 1 year, compared with infliximab therapy, per the randomized LiRIC trial (Lancet Gastroenterol Hepatol 2017;2:785-92).

Therapy is evolving at a rapid pace, while the disease itself is increasing in incidence and prevalence around the world. To truly manage this patient population, we need to have a population-based intervention (diet, predictive biomarkers, etc.) to help reduce the number of people developing IBD, and a better understanding of when and how to use the mechanisms of action we already have to achieve and maintain remission in patients with IBD.

Dr. Mahadevan is professor of medicine, University of California at San Francisco Center for Colitis and Crohn’s Disease. She has disclosed receiving grant or research support from Tigenix, Pfizer, Genentech, and Celgene and being a consultant for Gilead, AbbVie, Bristol-Myers Squibb, Janssen, Takeda, and Lilly. Dr. Mahadevan made these comments during the AGA Institute Presidential Plenary at the annual Digestive Disease Week®.

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