When doctors evaluate if a treatment is working for one of their patients with ulcerative colitis (UC), an inflammatory bowel disease that causes damage to the mucosal layer of the digestive tract, they will ask their patient about symptoms, such as bleeding, diarrhea and pain. But when researchers are evaluating the effectiveness of potential new treatments in a clinical trial, they need to include an objective assessment of disease activity as well.
So researchers are increasingly using endoscopy, a procedure using a flexible tube equipped with a video camera to look at patients’ digestive tracts, and examining tissue samples removed during a biopsy under a microscope to determine how well the mucosa is responding to an investigational therapy. In this Q&A, Dr. Keith Usiskin, executive director at Celgene, explains how by combining these two measurements, an assessment of mucosal healing can be made.
Why is mucosal healing important?
“Ulcerative colitis causes massive damage to the mucosa, weakening blood vessels and, eventually, leading to ulcers. Doctors and researchers are finding that achieving mucosal healing correlates with a better quality of life and other measurable benefits for patients with UC.
“For instance, studies have found that patients with UC in remission and with no signs of microscopic inflammation are less likely to be hospitalized or to experience relapse, in which their UC symptoms return. The data isn’t as strong as we’d like just yet, but we see a definite trend beginning to take shape.”
How is mucosal healing assessed in UC trials?
“Organizations conducting UC clinical trials assess mucosal healing often use both endoscopic appearance — what a gastroenterologist sees regarding redness, inflammation and ulcers during an endoscopy — and histological appearance — what a pathologist sees under a microscope regarding inflammation when they examine a tissue sample from a biopsy.”
Why are both endoscopies and biopsies needed to assess mucosal healing?
“While UC causes mucosal damage continuously, not every part of the mucosa is affected to the same extent. So endoscopies provide researchers with a bird’s eye view of the mucosa throughout the entire rectum and large intestine, including regions that are very inflamed and those that are less so.
“But endoscopic appearance doesn’t tell you everything. Studies have found that up to 24 percent of patients whose mucosa looks good in endoscopic assessments still have evidence of microscopic inflammation when a pathologist looks at a biopsy taken from the mucosa. That inflammation suggests the mucosa still is not fully healed and that the patient is at higher risk for relapses.”
What constitutes mucosal healing in these assessments?
“Defining mucosal healing remains one of the biggest challenges in UC clinical studies. The medical community and regulatory agencies have not come to a clear consensus on what constitutes mucosal healing in UC.
“Several scoring systems have been proposed for endoscopic and histologic assessments, but researchers have not decided which should be used. In Celgene’s studies, we use a widely used index for disease activity by endoscopic assessment in UC developed by researchers at the Mayo Clinic and a grading scale for histological assessment in UC developed by Dr. Karel Geboes at the University Hospitals Leuven in Belgium. We classify mucosal healing as a Mayo score less than or equal to one and a Geboes histologic score of less than two.”
What are the challenges in assessing mucosal healing?
“Clinician bias has been one of the most significant limitations in assessing mucosal healing. If the patient says they’re doing great, the clinician is more likely to report that the mucosa looks better, even if it seems the same as before starting treatment. The inverse can be true as well. We use central readers who do not know the patient’s health status to eliminate that bias. They can grade the endoscopies and biopsies based solely on their best judgment and experience.”
“The combination of endoscopy and pathology assessment of biopsies is key to the assessment of mucosal healing.”
Does the invasive nature of this assessment affect patient retention?
“Some patients are hesitant to enter a clinical trial if there are too many colonoscopies or endoscopies. Clinical researchers try to limit that when designing protocols for studies to minimize procedures that patients may find uncomfortable.
“We try to make it clear to patients what is expected of them when they sign up for a clinical trial and limit the burdens as much as possible. But we still have to make these assessments to determine the efficacy of potential new treatment options for UC.”
What could improve the assessment of mucosal healing?
“In the future, we may identify biomarkers that correlate with clinical symptoms, benefits and outcomes for patients with UC. Celgene is participating in an initiative to identify such biomarkers, and one day, noninvasive biomarkers may eliminate the need for endoscopy or biopsies. Imaging techniques such as MRIs and CT scans also may prove useful to assessing mucosal healing in future clinical trials and in the clinic. But right now, the combination of endoscopy and pathology assessment of biopsies is key to the assessment of mucosal healing for both scientific and regulatory purposes.”
To learn more about clinical trials for ulcerative colitis and other inflammatory bowel diseases, read “The Importance of Clinical Trials for Inflammatory Bowel Disease.”