Inflammatory bowel disease (IBD) is a chronic inflammatory disease that can cause progressive functional and structural damage to the gastrointestinal tract. Medical therapies for IBD have traditionally focused on symptom control. While the use of oral aminosalicylates and corticosteroids can be effective in suppressing the inflammatory process and inducing symptomatic remission, this approach has not been shown to alter the natural history of IBD, reduce incidence of long-term complications or improve long-term patient outcomes. This fact, combined with the availability of other therapeutic approaches that can induce mucosal healing, has led clinicians and researchers to question whether symptom control is the most appropriate therapeutic goal in the treatment of IBD.
A paradigm shift
According to Edward V. Loftus Jr., M.D., a gastroenterologist specializing in IBD at Mayo Clinic's campus in Rochester, Minnesota, many experts are now advocating for a paradigm shift that emphasizes mucosal healing, rather than clinical remission, as the primary treatment objective. "Administering therapies directed at mucosal healing that may favorably modify the natural history of IBD when used in a treat-to-target approach is gaining acceptance," says Dr. Loftus.
Disease severity assessment tools
Dr. Loftus notes that it's important to recognize that accurate assessment of disease activity and severity in IBD continues to be challenging. Two widely used tools, the symptom-based Crohn's disease activity index (CDAI) and the Crohn's disease endoscopic index of severity (CDEIS), often paint very different pictures of disease activity.
"In patients with Crohn's disease undergoing treatment with prednisolone, research data shows a complete lack of correlation between the CDAI and the CDEIS," explains Dr. Loftus. "This suggests that focusing on severity of symptoms alone may be an inappropriate measure of therapeutic efficacy, because Crohn's disease symptoms are insensitive and nonspecific for bowel inflammation."
The presence of both inflammation and structural bowel damage in asymptomatic patients also underscores the utility of obtaining endoscopic evidence for mucosal healing, or other objective markers of inflammation, to guide therapeutic decisions and to evaluate their efficacy in IBD treatment trials.
"A focus on mucosal healing reduces the need for steroids, risk of hospitalization and surgery," says Dr. Loftus, "so treatment algorithms that incorporate endoscopy results into decision-making may do a better job of achieving long-term remission and reducing complications."
Initial research findings
The idea of using mucosal healing as an endpoint for assessing disease activity and remission in patients with IBD first gained attention when researchers showed that treatment with azathioprine and infliximab induced both symptomatic improvement and endoscopic remission in patients with Crohn's disease (CD). Since then, multiple studies have shown that evidence of mucosal healing after initial treatment is associated with a decreased colectomy risk and colorectal cancer risk in patients with ulcerative colitis (UC), and a decreased need for steroids and surgery in patients with CD.
Researchers studying various treat-to-target regimens have shown mucosal healing rates as high as 70 to 80 percent in patients with CD and 80 to 90 percent in patients with UC. The REACT trial was a cluster randomization trial that randomized practices to either an algorithmic approach to CD, where treatment was escalated every four weeks depending on symptoms, or a conventional approach. In results published in The Lancet in 2015, REACT showed that the algorithmic approach reduced complications over time when compared with conventional management.
The CALM study, presented in an abstract at Digestive Disease Week 2017, showed that an algorithmic approach based on driving down serum C-reactive protein and fecal calprotectin resulted in a much higher rate of mucosal healing than a conventional approach. "We will see more follow-up data on these patients going forward in terms of hospitalizations, need for surgeries and surgical complications," notes Dr. Loftus.
Key elements of the treat-to-target program
- The absence of mucosal ulceration is the primary therapeutic target.
- The desired target level should be established after baseline assessment of disease activity and maintained indefinitely, and it may be adjusted as needed to address comorbidities and drug-related risks.
- Symptoms and objective measures of inflammation (endoscopic or radiologic) should guide treatment decisions.
- Clinicians can dose escalate and combine therapies to improve efficacy.
- Clinicians should assess mucosal healing every six months, until the target is achieved, then every one to two years thereafter, adjusting the schedule according to degree of inflammation detected.
Additional questions and issues
Dr. Loftus notes that several questions still need to be answered in order to optimize this treatment algorithm for patients with IBD.
"At this point, we still need to define how much healing is really required to achieve positive outcomes," he explains. "We should also work to clarify the degree of incremental healing that can be achieved by dose escalation or switching therapies. And more work is needed to help us pinpoint the appropriate time interval between changes in therapy and subsequent reassessment."
For more information
Khanna, R. Early combined immunosuppression for the management of Crohn's disease (REACT): A cluster randomised controlled trial. The Lancet. 2015;386:1825.