A Patient-Centered Focus in Crohn’s Disease Management

Crohn’s disease is an inflammatory disease of the gastrointestinal tract. In the past 25 years, there have been several advancements in therapeutics to treat this condition. How does one position therapies to treat patients with Crohn’s disease? According to experts, therapy for the disease needs to be tailored as a patient-centered approach. To learn more about optimal positioning of agents as first- or second-line therapies in treating Crohn’s disease, Medscape spoke with Waseem Ahmed, MD, assistant professor of medicine, Crohn’s and Colitis Center; Division of Gastroenterology & Hepatology, University of Colorado School of Medicine, Aurora, Colorado; and Adam S. Cheifetz, MD, director of the Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, and professor of medicine, Harvard Medical School, Boston, Massachusetts. Read on for their insights.This interview has been edited for length and clarity. 
Several gastroenterology societies regularly contribute guidelines regarding both the medical and surgical management of Crohn’s disease. These include guidelines from the American Gastroenterological Association, the American College of Gastroenterology, and the European Crohn’s and Colitis Organisation, among others. Clinicians, however, cannot rely solely on these guidelines, according to experts. 
“While guidelines are evidence-based and are recommendations from experts in their respective fields, [Crohn’s] patients should be managed on an individual basis rather than simply a standardized approach. Shared decision-making, an approach of integrating patient perspectives and preferences into medical decision making, in conjunction with guidance from the medical team, is preferred,” said Waseem Ahmed, MD. “The field of IBD continues to rapidly change, and so it is further difficult to solely rely on guidelines for guidance with the regular development of practice-changing breakthroughs in IBD.”
According to Ahmed, therapies for Crohn’s disease include both medical and dietary considerations. Dietary therapies for Crohn’s disease include several different diets focusing on the consumption of certain foods thought to attenuate inflammation and the avoidance of specific foods thought to trigger it. Ahmed said examples of diets demonstrating efficacy in the treatment of Crohn’s disease include the Mediterranean diet, the Crohn’s Disease Exclusion Diet, and exclusive enteral nutrition. Medical therapies for Crohn’s disease largely act on the immune system, targeting specific pathways which are dysregulated and thought to contribute to uncontrolled inflammation seen in IBD.
“Medical therapies range from biologics, which are protein-based therapies delivered directly into the bloodstream via infusion or injection, to small molecules, which can be ingested and are directly absorbed via the gastrointestinal tract. Examples of these include the biologics infliximab, adalimumab, and risankizumab and the small molecule upadacitinib,” said Ahmed.
According to Adam S. Cheifetz, MD, there are several classes of biologics that have various mechanisms of action, and that there are anti–tumor necrosis factor alpha (TNF) agents, including infliximab and adalimumab, that block a protein TNF; anti-integrin agents, like vedolizumab, that prevent certain inflammatory cells from exiting the bloodstream and entering the intestines; and agents that block specific interleukins (IL), including risankizumab, which blocks IL-23, and ustekinumab, which blocks IL-12/23. 
Cheifetz remarked that clinicians often, in conjunction with anti-TNF therapies, use immunomodulators such as methotrexate and thiopurines as an adjunct, because they decrease the risk of a patient developing antibodies to an anti-TNF agent and thereby improve the efficacy of these agents. Many clinicians still use corticosteroids, but importantly, said Cheifetz, these agents should only ever be used to induce remission; they can’t maintain remission. 
Ahmed pointed out that it is first important to distinguish patients with mild Crohn’s disease from those with moderate to severe disease, as the latter are at increased risk for eventual disease complications such as hospitalization and surgery. “While patients with mild Crohn’s disease may be able to maintain disease control with intermittent use of budesonide (a localized steroid) or a specific dietary therapy, patients with moderate to severe Crohn’s disease more commonly need to commit to a long-term medical therapy,” said Ahmed.
In patients who require long-term medical therapy for Crohn’s disease, positioning therapies is quite challenging. “There are limited head-to-head clinical trials comparing patient outcomes using individual therapies for Crohn’s disease,” said Ahmed. He pointed out that only recently have there been high-level data to assist in making these decisions, such as the SEAVUE trial, which demonstrated similar efficacy between two biologics (adalimumab and ustekinumab) in moderate to severe, biologic-naive Crohn’s disease, and the SEQUENCE trial, which demonstrated the noninferiority of risankizumab to ustekinumab in achieving clinical remission and superiority in achieving endoscopic remission in patients with moderate to severe Crohn’s disease with previous exposure to TNF antagonists. 
“Further head-to-head clinical trials are necessary to delineate the positioning of therapies in Crohn’s disease,” said Ahmed. “While these are eagerly anticipated, clinicians must also rely on real-world comparative data and network meta-analyses, an indirect comparison of clinical trial outcomes between medical therapies, to further substantiate this knowledge gap.”
According to Cheifetz, when he talks to patients about choice of medication, first and foremost he looks at how effective the medication is at inducing and maintaining clinical remission, though endoscopic improvement and mucosal healing are also important. “Does it have efficacy in perianal disease? Can it control extraintestinal manifestations like arthritis? Are there other associated conditions to consider, like psoriasis? The other major thing I think about and discuss with the patient is the safety of the medications,” said Cheifetz.
Several patient- and disease-related factors are considered when choosing among therapies for Crohn’s disease. According to Ahmed and Cheifetz, patient factors include preference, treatment modality (injection, infusion, or pill), drug cost and payer coverage, drug safety, risk for immunogenicity, patient age, and individual patient comorbidities which may be implicated with use of a specific therapy. Disease factors, they said, include location of disease; disease activity; high-risk disease factors, including the presence of a fistula or perianal disease; the presence or absence of extraintestinal manifestations of Crohn’s disease or separate immune disorders which may require medical therapy; and previous drug exposures, among others.
How do the side effects of the drugs factor into the positioning of medications for Crohn’s disease? ” One of the things that I think is important when talking about risks and benefits is that the risks of any of these advanced therapies are very, very rare,” said Cheifetz. “But uncontrolled Crohn’s disease has a high risk for complication. A patient with uncontrolled Crohn’s disease has about an 80% risk of developing a complication like a stricture or a fistula and has a 30%-50% chance of ending up with surgery.”
Cheifetz said he would love to say that positioning Crohn’s therapies is algorithmic, but it’s not. “That is what makes treating patients with Crohn’s challenging,” he said. “It is fun and exciting that we have all these agents, but we really don’t know exactly where to position them, and it does come down to individual patients. Ideally, what I refer to as the holy grail of treating Crohn’s disease and IBD is to be able to determine, a priori, which medication will work for the individual patient, to be able to really personalize the care of IBD.”
Waseem Ahmed, MD, has disclosed no relevant financial relationships. 
Adam S. Cheifetz, MD, has disclosed the following relevant financial relationships:  Serve(d) as a consultant for: AbbVie; AegirBio; Artizan Biosciences; Prometheus; Fzata, Adiso; Bristol Myers Squibb; Clario; Food is Good; Fresenius Kabi; Janssen; Lilly; Pfizer; Procise; Spherix; Samsung  Serve(d) as a speaker or a member of a speakers bureau for: AbbVie; Bristol Myers Squibb