Crohn disease presents “a number of challenges that I suspect are well known to all of you,” David T. Rubin, MD, FACG, told the attendees at the American College of Gastroenterology (ACG) session on “What’s New in GI Pharmacology” on Friday, October 22.

“There’s significant heterogeneity. There is no cure. We don’t have validated therapeutic biomarkers. Many clinical trial designs have an inherent bias in that many of the participants are patients who have already failed therapies for Crohn disease. And we see lots of primary nonresponse and loss of response” among patients with Crohn disease, he said.

Dr Rubin is the Joseph B. Kirsner professor of medicine, chief of the section of gastroenterology, hepatology, and nutrition, and codirector of the Digestive Diseases Center at the University of Chicago.

The inflammation that occurs in the patient with Crohn disease “is there to protect against real or perceived threats. The hope in treatment of Crohn disease is not to cure the disease but to reduce the inflammation and allow the body to essentially reset itself,” Dr Rubin explained

Complicating factors included the many phenotypes of Crohn disease, from extensive colonic disease to ileocolitis to perianal disease, he said. The clinician must also consider factors such as how sick the patient is, the prognosis, and biomarkers for benchmarking.

In general, Dr Rubin stated, “induction therapy is more intensive than maintenance therapy. Perianal disease also requires more intense therapy.” These points may seem obvious, but, he explained, they haven’t always been clearly delineated. He further noted that in determining dosages for pharmacotherapeutics in Crohn disease, “absorption and leakage matter, which can affect the ability to get drugs delivered. This is a very important consideration.”

The SONIC trial yielded important evidence regarding infliximab, Dr Rubin stated. “Interestingly, the results showed the level of infliximab was more important than whether a patient was on combination therapy. This tells us that we may be able to optimize infliximab levels as a monotherapy without including azathioprine.”

Using a treat-to-target approach and reactive therapeutic drug management (TDM) is “accepted and recommended,” Dr Rubin said. However, proactive TDM “is not yet supported by good evidence,” in terms of showing improved outcomes, but could be useful with patients who have failed other biologics and are at high risk of developing immunogenicity. Treat-to-target has shown significant results in clinical trials, he noted. The CALM trial, with a primary endpoint of endoscopic improvement, showed better outcomes in the treat-to-target arm, as did the STARDUST trial of ustekinumab.

It is also clear from existing studies and clinical practice that early treatment of Crohn disease is more likely to optimize response, Dr Rubin explained. Patients who begin treatment with anti-tumor necrosis factor (TNF) agents have been shown to be less likely to have surgery and to need treatment with steroids, and more likely to maintain response to therapy.

He also added, “the first therapy works best. This can be a major pushback with payers, who often want patients to be treated with conventional, nonbiologic treatments first before they go on to biologics.” A network meta-analysis of clinical trials in Crohn disease found that naïve patients treated with infliximab or adalimumab did best, he said. The SEAVUE trial of found that in biologic-naïve patients, both clinical remission and safety were equivalent in ustekinumab and adalimumab, while in patients who failed with anti-TNFs, ustekinumab showed superior results to vedolizumab.

The biggest challenge in Crohn disease may well be the treatment of perianal disease, which affects up to 20% of Crohn patients and has the most significant impact on quality of life. The best evidence of efficacy in treating perianal disease is with infliximab, although both vedolizumab and ustekinumab have also shown benefit.

Stem cell therapy, which is still in clinical trials, holds promise for treating perianal Crohn disease, Dr Rubin said. He also stressed, “Don’t forget to use antibiotics!” Patients with perianal Crohn disease who receive both biologic therapy and antibiotics show better outcomes.

There are many therapies in development along with stem cell treatment, including several  p19/IL 23 inhibitors, Dr Rubin noted. “In the future, we may find that combining some of these therapies will offer new options for patients with Crohn’s disease.”

--Rebecca Mashaw

Rubin, DT. Present and future treatments for Crohn’s disease. Presented at the American College of Gastroenterology postgraduate course and scientific meeting, October 22, 2021. Las Vegas, Nevada.