Feb. 09, 2019
Inflammatory bowel disease (IBD) is a chronic inflammatory disease that can cause progressive functional and structural damage to the gastrointestinal tract. IBD is a global disease with increasing prevalence. In this article, Mayo gastroenterologists provide an overview of new treatment approaches for Crohn's disease and ulcerative colitis.
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.
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. For patients with small bowel Crohn's disease, cross-sectional imaging such as computerized tomography enterography or magnetic resonance enterography may be a more appropriate modality to assess inflammation, extent and complications.
"A focus on mucosal or radiographic healing reduces the need for steroids, risk of hospitalization and surgery," says Dr. Loftus, "so treatment algorithms that incorporate endoscopy or enterography results into decision-making may do a better job of achieving long-term remission and reducing complications."
In addition to a treat-to-target approach, Talha A. Malik, M.D., M.P.H., notes that Mayo IBD specialists are also implementing and encouraging the development of a standardized approach to the management of IBD for Crohn's disease and ulcerative colitis that is systematic and evidence-based across all specialized IBD practices, clinics and centers. Dr. Malik is a gastroenterologist specializing in IBD at Mayo Clinic's campus in Arizona. "Our goal is to provide in-depth interpretation of test results, improved understanding of disease phenotype and severity, as well as management options that are consistent and driven by best research evidence."
The immunology of IBD is very complex, and drug targeting is complex. Within the United States, four anti-TNF agents are currently approved for the treatment of IBD — infliximab, adalimumab, certolizumab pegol and golimumab. Biosimilars to these anti-TNF agents have also been developed for use within the United States. Two anti-integrin biologics (natalizumab and vedolizumab) have been approved for use in IBD treatment. And ustekinumab, a biologic that targets cytokines interleukin-12 and interleukin-23 (IL-12 and IL-23), has been approved for Crohn's disease treatment.
According to Michael F. Picco, M.D., Ph.D., the approach to maximizing the effectiveness of these medications often includes therapeutic drug monitoring. Dr. Picco is a gastroenterologist specializing in IBD at Mayo Clinic's campus in Florida. "Among patients with an incomplete response to a particular medication, measuring serum levels of a drug can help gain insight into whether a dosing adjustment or a switch to another agent is needed," says Dr. Picco.
Approved in 2014 for both ulcerative colitis and Crohn's disease, vedolizumab blocks migration of leukocytes into the gut via a blockade of α4β7 integrin (the ligand of which is mucosal vascular addressin cell adhesion molecule 1) and can be considered as a first line agent. Due to its gut-selective approach, this drug may be a good choice for older patients or those with a history of immunosuppression or malignancy.
Approved in 2016 for Crohn's disease only, ustekinumab blocks inflammation produced through IL-12 and IL-23. This molecule, too, can be considered a first line biologic agent, for older adults in particular, and for those with a history of immunosuppression or malignancy and those who have already undergone treatment with anti-TNF agents.
Approved in 2018, tofacitinib is a selective Janus kinase (JAK) inhibitor and the first oral medication approved for treatment of moderate to severe ulcerative colitis. The Food and Drug Administration examined results from three controlled clinical trials to assess tofacitinib's efficacy and safety. In two placebo-controlled induction trials — OCTAVE Induction 1 and 2 — tofacitinib outperformed the placebo in achieving remission in patients with UC. Published results for these two eight-week placebo-controlled trials demonstrated that 10 mg of tofacitinib given twice daily induces remission in 17 to 18 percent of patients by week eight. Among responders at week eight, tofacitinib maintained remission in 34 to 41 percent of patients at the end of one year, with steroid-free remission rates that were 30 to 42 percent better than those seen with placebo.
According to Dr. Loftus, multiple other potential drugs are now in the development pipeline, including several molecules that are beginning or more than halfway through phase III trials. JAK inhibitors such as upadacitinib and filgotinib are being studied in phase II and III trials of ulcerative colitis and Crohn's disease. Both of these molecules are selective JAK1 inhibitors, and data from phase II trials demonstrated their effectiveness as treatments for moderate to severe Crohn's disease.
Etrolizumab, an anti-β7 integrin, was effective in moderate to severe ulcerative colitis in a phase II trial and so far in an open-label induction trial in phase III. It also looks promising in induction of moderate to severe Crohn's disease.
The anti-mucosal addressin cell adhesion molecule (MAdCAM) monoclonal antibody (renamed SHP647) was effective in ulcerative colitis but not in Crohn's disease in phase II trials.
The anti-p19 (anti-IL-23) antibodies, brazikumab and risankizumab, were effective in moderate to severe Crohn's disease in phase II trials. Another p19 antibody, mirikizumab, was recently shown in a phase II trial to be effective for moderate to severe ulcerative colitis.
The oral sphingosine 1-phosphate (S1P) receptor modulator, ozanimod, was effective for moderate to severe ulcerative colitis in a phase II trial and appeared promising for moderate to severe Crohn's disease in an open-label induction trial. Another S1P receptor modulator, etrasimod, was recently shown to be effective for clinical response, clinical remission and endoscopic response in a phase II trial of moderate to severe ulcerative colitis.
"With multiple agents with different mechanisms of action for our patients with IBD under study, the future looks bright," says Dr. Loftus.