Researchers at Icahn School of Medicine at Mount Sinai found that up to one-third of patients with ulcerative colitis who achieve mucosal healing still experience increased stool frequency, and suggest that its underlying cause could be long-term damage to the colon, not histological activity.
The study, “Discrepancies between patient-reported outcomes, and endoscopic and histological appearance in UC,” was recently published in Gut.
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood. Blood in the stool is reported in more than 90 percent of UC patients with active disease, and is associated with ulceration of the mucosa and loss of the internal membranes’ integrity.
The therapeutic target in inflammatory bowel diseases (Crohn’s disease and ulcerative colitis) is now mucosal healing, as confirmed by endoscopy alone or a combination of endoscopy and histology (microscopic examination of the tissues), rather than just treating symptoms. This treatment goal is also referred to as endoscopic mucosal healing — generally defined as the absence of inflammatory and ulcerative lesions in the gut, as seen in endoscopy.
However, Jean-Frédéric Colombel, MD, of the Division of Gastroenterology at the Icahn School of Medicine at Mount Sinai in New York City, and colleagues saw in a previous study that endoscopic mucosal healing does not always match patient-reported persistent symptoms. This led the researchers to try to understand if active histological inflammation was continuing in some patients.
In a retrospective analysis of data from an observational, multicenter study of 103 patients with UC, they compared rectal bleeding and stool frequency symptom subscores, using the Mayo Clinic Score (MCS), with the endoscopic subscore (MCSe) and histology. Fecal calprotectin (a biochemical measurement of the protein calprotectin in the stool), C reactive protein (CRP) and inflammatory cytokine expression, all well-established biomarkers of inflammation, were also evaluated in mucosal biopsies from these patients.
“What we found in these two studies … was that even if patients were able to reach the endpoints of endoscopic and histological healing … between 20% and 30% are still [experiencing] an increased number of stools, which … is sometimes associated with urgency, and even incontinence in some patients — a most disturbing symptom for patients with UC,” Colombel said in a news release.
Across different definitions of mucosal healing, a larger proportion of UC patients reported abnormal stool frequency, ranging from 25 percent to 39 percent, than rectal bleeding, ranging from 10 percent to 24 percent.
Fecal calprotectin and inflammatory cytokine expression were higher in patients with active disease than in patients with mucosal healing, but no significant differences were seen between patients when the researchers considered the increasingly rigorous definitions of mucosal healing.
These findings confirmed that histological activity does not explain the persistence of symptoms in UC patients with endoscopic remission.
Colombel suggests that the underlying cause of persistently increased stool frequency in patients showing both endoscopic and histological healing may be long-term, disease-related damage to the colon.
“Very often, sometimes following several years of disease activity, there is damage caused to the colon, with lack of plasticity, elasticity and [pliability],” he said. “Instead of being very elastic, it cannot adapt to the volume of stools, becoming very stiff and narrowed … and then patients are not able to control the number of stools, and unfortunately, this is not measured at all using endoscopy or histology.”
Other hypotheses are nerve and muscle damage, Colombel said, but still need to be tested.
“We need to understand the underlying mechanism that is driving this, and eventually [develop] new treatments that can address both mucosal healing and symptom relief,” he said. “Of course, we shouldn’t dismiss that fact that in most patients there is good correlation [between healing and relief].”