UC: Symptoms Often Persist Despite Histologic Healing

Pam Harrison

September 16, 2016

Patients with ulcerative colitis (UC) do not necessarily achieve complete relief of symptoms, especially with respect to stool frequency (SF), even when they do achieve endoscopic and histologic healing, according to results from an observational study published online September 2 in Gut.

"Whether active histological inflammation in patients with endoscopic healing drives the persistence of symptoms in a subset of patients has not been evaluated," Jean-Frederic Colombel, MD, from the Icahn School of Medicine at Mount Sinai, New York City, and colleagues write.

"Our work highlights the possibility that it may be very difficult for a therapy to achieve complete remission of symptoms even in the presence of endoscopic and histological healing."

The EMBARK cohort consisted of 103 patients with UC who had no prior therapeutic intervention. All patients underwent a full ileocolonoscopy, and clinical disease activity was evaluated using the Mayo Clinic Score (MCS). As the authors note, rectal bleeding (RB), SF, and Mayo endoscopic subscores (MCSe) are all separate components of the Mayo Clinic Score.

"Disease severity, as measured by the total MCS, was mild in the EMBARK patient population (median=4, mean=4.5±3.8) with 60% (61/103) of patients having inactive disease as measured by endoscopy," the authors write.

However, the authors found that there was not a consistent relationship between scores and symptoms. "With increasing symptom scores, the proportion of patients without evidence of endoscopic activity (MCSe=0) decreased, but a proportion of patients without endoscopic activity still had more severe symptoms," the authors explain.

Specifically, a small proportion of patients (5%) still had more severe symptoms of RB in the absence of endoscopic activity, as did 18% of patients who reported severe symptoms of SF. The sensitivity and specificity of each of the two symptoms and the two symptoms together to predict endoscopic healing, as defined by a MCSe score or 0 to 1, also varied considerably.

Table. Comparison of RB and SF With Endoscopic Healing (MCSe = 0/1)

Symptom Score Positive Predictive Value Negative Predictive Value Sensitivity Specificity
RB = 0 85.5% 70.8% 77% 81%
SF = 0 95% 63.5% 62.3% 95.2%
RB + SF = 0 94.3% 58.8% 54.1% 95.2%

Mucosal Healing

Investigators also looked at different categories of mucosal healing and found that almost one quarter of patients with a MCSe of 0 or 1 had a RB score of 1 or more, whereas 6% of patients in the same category had a RB score of 2 or more. "In the same patient group, 39% of patients had an SF score ≥1 and 25% reported an SF≥2," the authors write. "A similar trend was observed in patients with MCSe=0."

"Notably," they write, "the majority of patients with MCSe=0 had inactive histology, and the addition of histological inactivity to endoscopy did not change the rate of patients reporting symptoms."

Biomarker Analysis

Investigators also assessed levels of fecal calprotectin, C-reactive protein, and other known biomarkers of inflammation and found that patients with higher endoscopy scores of 2 or 3 had significantly higher levels of fecal calprotectin compared with those who met criteria for mucosal healing (P < .01).

C-reactive protein levels were also higher in patients with a higher MCSe score compared with those whose scores indicated mucosal healing (P < .01).

As expected, only a small proportion (7%) of patients with no evidence of endoscopic disease reported RB, although significantly more of them reported abnormal SF. "[W]e found that symptom scores generally correlated well with endoscopic scores, but some patients still exhibited persistent symptoms while having endoscopic scores of 0 or 1," the authors conclude.

"Given that the persistence of symptoms greatly impacts patient quality of life, it is vital to understand the underlying mechanisms that drive them and eventually work towards treatment regimens that can address both mucosal healing and symptom relief," he adds.

Dr Colombel has received research funding from AbbVie, Genentech, Janssen and Janssen, and Takeda. He has also served as a consultant or speaker for AbbVie, Amgen, Boehringer Ingelheim, Celgene Corporation, Celltrion, Enterome, Ferring, Genentech, Janssen Pharmaceuticals, Medimmune, Merck & Co, Pfizer, Protagonist, Second Genome, Seres, Shire, Takeda, and Theradiag, and has received stock options from Intestinal Biotech Development and Genfit. Three coauthors are employees of Genentech, a member of the Roche group, and own Roche stock. Another coauthor has received payment to his institution from Genentech for the central pathology review in this manuscript, and his institution has received payment for his central pathology review services from Shire, Novartis, Centocor, and Galapagos. Another coauthor serves as an advisory board member for AbbVie, Janssen Pharmaceuticals, and Boehringer Ingelheim Pharma and serves as a consultant for Celgene, Connecticut Children's Medical Center, Genentech, Janssen Pharmaceuticals, Shire, and Velocity Pharmaceutical Development.

Gut. Published online September 2, 2016. Full text

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