Rethinking Histology as Treatment Target in Ulcerative Colitis

Liam Davenport

August 04, 2022

For patients who experience endoscopic remission of ulcerative colitis (UC), signs of active disease on histology did not affect their risk of clinical relapse, according to a large prospective study that reinforces a low endoscopy score as the treatment target.

In the study of more than 250 patients in endoscopic remission from UC, 19% experienced a clinical relapse within 1 year. The researchers found that a lower baseline endoscopy score was linked to a lower risk of relapse.

While histologic activity, as reflected in the Geboes Score, was not associated with clinical relapse, the presence of basal plasmacytosis independently doubled the risk of relapse.

"Our findings do not support the use of histology as a target for treatment in patients with ulcerative colitis who already achieved clinical and endoscopic remission," say Talat Bessissow, MD, McGill University Health Center, Montreal, Canada, and colleagues.

They add that the results "support the use of the Mayo endoscopic subscore of zero as the optimal target for endoscopic remission."

Further prospective data are needed to "define the role of histology activity and basal plasmacytosis in the management of ulcerative colitis," the authors write.

The study was published online in The American Journal of Gastroenterology.

Uncertain Role of Histology

Bessissow told Medscape Medical News, "Some studies have shown that histologic healing is associated with better long-term outcomes and less relapse, but this topic remains controversial because other studies have shown the opposite.

"Our study does not support histology as a treatment target," he continued, adding that therapy should not be changed solely on the basis of histology.

Bessissow clarified that although histology was not associated with less relapse over 1 year of follow-up, the role of histology on other, longer-term outcomes, such as surgery and colorectal cancer, still needs to be studied.

The natural history of UC is characterized by frequent relapse, the authors write, but "treating symptoms alone is not sufficient to prevent long-term complications."

This led to a shift toward using endoscopic healing as a therapeutic goal, a move that was aided by the advent of novel medical therapies, including biologic agents. Crucially, endoscopic healing is associated with improved long-term outcomes, as well as improved quality of life.

The authors continue, however, that a "significant proportion" of patients experience relapse despite achieving endoscopic healing, which "could be explained in part by the fact that up to 40% of patients in endoscopic healing will have ongoing active histologic disease."

However, in studies in which histologic activity was an endpoint, results have conflicted, and questions remain as to which parameters to include when assessing histologic activity.

Measuring the Predictive Values of Endoscopy and Histology

To investigate further, the researchers conducted a prospective observational study of consecutive adult patients with confirmed UC who presented to an endoscopy unit for colonoscopy for disease assessment or surveillance.

To qualify for the study, the patients' conditions had to have been in clinical remission for at least 3 months prior to the colonoscopy. They were excluded if they had undergone prior surgical resection, had experienced disease remission for a period of over 10 years, or had used oral or rectal steroids within 90 days, among other criteria.

During an initial colonoscopy, two biopsies were performed, with specimens taken from the rectosigmoid and, when possible, from the right and left colon. Blood and stool samples were taken, and demographic and clinical data were collected.

The study enrolled 253 patients. Almost half (47.4%) were younger than 50 years, and 46.3% were women. They were followed for 12 months, during which 19% developed clinical relapse, defined as a partial Mayo endoscopic score (MES) of >2.

When compared to patients with an MES of 0, the team found that patients with an MES of 1 or ≥2 were at higher risk of relapse, with an adjusted hazard ratio of 2.65 and 2.57, respectively.

Interestingly, a lower baseline MES also was associated with a lower risk of relapse, and patients with proctitis were more likely to experience relapse than those with pancolitis.

No Impact of Histology on Relapse Risk

Further analysis revealed that there was no association between clinical relapse and age, sex, disease extent, and C-reactive protein, hemoglobin, and albumin levels. However, there was a significant association between relapse and the occurrence of at least one relapse in the 2 years prior to enrollment.

While the mean baseline fecal calprotectin (FC) level was numerically higher in patients who experienced relapse in comparison with those who did not (306.9 µg/g vs 213.7 µg/g), the difference was not significant.

FC of >100 µg/g was, however, significantly associated with relapse, at an odds ratio of 2.26, although the association was no longer significant when using the False Discovery Rate test.

Active histology was no more common among those who experienced relapse than among those who did not. But with regard to histologic factors, the team found that the presence of basal plasmacytosis was associated with clinical relapse, at an adjusted odds ratio of 2.07.

On the other hand, a Geboes Score of ≥3.1, indicating the presence of epithelial neutrophils with or without crypt destruction or erosions, was not significantly associated with the risk of relapse, nor with the time to clinical relapse.

Clinical Implications

Approached for comment, Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at the Cleveland Clinic in Ohio, said that this is "the largest prospective study assessing histologic activity or remission to predict future disease relapse in ulcerative colitis."

He told Medscape Medical News that what the findings mean for clinical practice is that "patients who achieve an endoscopic and clinical remission are at a low likelihood of clinical relapse," and added that "these should be the 'treat-to-target' endpoints.

"Patients who have biopsy evidence, [such as] histologic activity based on the Geboes Score, do not require an escalation of therapy or a change in inflammatory bowel disease therapy," Regueiro said.

He noted, however, that one primary question remains: Aside from surveillance of dysplasia, is there a role for biopsy in cases of UC in which the Mayo score is 0?

"In my practice, I still take biopsies from a previously involved colitis segment, even if Mayo 0," he said.

"If there is histologic activity, I would not increase or optimize the current medications, but I also would not deescalate," Regueiro added. "I would keep the patient on a regular surveillance colonoscopy regimen, too."

No funding for the study has been reported. Bessissow has relationships with AbbVie, Alimentiv (formerly Robarts Inc), Amgen, Bristol-Myers-Squibb, Ferring, Gilead, Janssen, Merck, Pentax, Pfizer, Roche, Sandoz, Takeda, and Viatris. Other authors have disclosed numerous financial relationships. Regueiro has disclosed no such relationships.

Am J Gastroenterol. Published online July 21, 2022. Abstract

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