Evaluating the Optimum Number of Biopsies to Assess Histological Inflammation in Ulcerative Colitis

A Retrospective Cohort Study

Robert Battat; Niels Vande Casteele; Rish K. Pai; Zhongya Wang; Guangyong Zou; John W. D. McDonald; Marjolijn Duijvestein; Jenny Jeyarajah; Claire E. Parker; Tanja Van Viegen; Sigrid A. Nelson; Brigid S. Boland; Siddharth Singh; Parambir S. Dulai; Mark A. Valasek; Brian G. Feagan; Vipul Jairath; William J. Sandborn

Disclosures

Aliment Pharmacol Ther. 2020;52(10):1574-1582. 

In This Article

Discussion

Histological remission is an emerging treatment target in ulcerative colitis that is associated with improved patient outcomes relative to symptom- and endoscopy-based targets. Accordingly, considerable interest exists for including biopsy protocols into clinical trials. The most common procedure consists of collecting two biopsies from the rectosigmoid colon at baseline with repeat sampling conducted at the end of the induction or maintenance periods. However, the optimum biopsy sampling method has not been adequately evaluated. Specifically, the ideal number of biopsies and the effects of sampling multiple colonic locations relative to sampling only the rectosigmoid have not been determined.

The primary finding of the current study is that two rectosigmoid biopsies is the minimum number of samples required for reliable histological assessment when using the RHI and VAS. A pre-defined threshold for agreement was used, and this was met by both the 2- and 3-biopsy sampling methods, but not the 1-biopsy sampling method. In contrast, three rectosigmoid biopsies were required to reliably assess histological inflammation when using the GS. Although numerical cross-instrument comparisons are not valid since the instruments are scored on different scales, we speculate that the lesser degree of agreement observed with the GS relative to the RHI may be because the instrument was not developed as an evaluative instrument. In contrast, the RHI was generated as a continuous outcome measure using accepted methodological principles of index development including specific item generation, item selection and formal reliability, and responsiveness testing.

Exploratory subgroup analysis based on endoscopic disease activity suggested that in patients with active disease (Mayo Clinic Endoscopic Subscore ≥1), a minimum of three rectosigmoid biopsies may be required for reliable assessment of histological disease activity when using the RHI and VAS. However, this finding should be interpreted with caution given the relative imprecision of the estimates and sample size.

Another secondary finding was that when the RHI reference score calculated using rectosigmoid biopsies was compared to the RHI reference score calculated using biopsies from the transverse or ascending colon, the threshold for acceptable agreement was not met. Furthermore, using all locations and the maximum number of biopsies available to assess histological remission resulted in reduced histological remission rates estimates compared to using the rectosigmoid colon alone. This observation, which may reflect variable colonic healing following treatment and sampling strategies, has potential implications for both clinical practice and drug development since the most common practice is to exclusively obtain rectosigmoid biopsies based on the notion that disease activity in the rectosigmoid is a surrogate of the most severe disease activity elsewhere in the colon. Our results do not support this hypothesis and suggest that comprehensive sampling of more proximal colonic segments may be a more appropriate, conservative approach. However, the findings of this secondary analysis are limited by the sample size; of the patients with >3 rectosigmoid biopsies available, only 42% (21/50) and 32% (16/50) had biopsies collected from the ascending and transverse colon respectively. Data from rigorously designed, adequately powered studies are required to definitively address the role of colonic location with respect to biopsy procurement strategies in ulcerative colitis. Furthermore, while previous studies[4,11,12,20,21] have demonstrated that histological remission is a predictor of reduced risk of relapse in ulcerative colitis, longitudinal studies are needed to determine whether proximal, compared to distal, biopsies are relatively more predictive of outcome.

Construct validity for histological scores was analysed and significant correlations existed between histological scores and rectal bleeding, stool frequency, and endoscopic scores. This was true for both the RHI and GS, which further validates these indices as endpoints in clinical trials.

A limitation of the current study is that it was based on a relatively small sample; 46 patients were included in the primary analysis. Moreover, due to the retrospective nature of the study design, we were unable to standardise the decision to perform either flexible sigmoidoscopy or colonoscopy and the biopsy sampling methods. Nevertheless, a substantial number of biopsies (n = 287) were assessed, and blinded central reading was employed since unblinded evaluations have been demonstrated to affect both endoscopic and histological disease activity estimates.[22,23]

Given that histological remission has been independently associated with improved clinical outcomes and low placebo rates,[9,12,22,24,25] the US Food and Drug Administration has suggested redefining "mucosal healing" to include histological remission.[26] This has prompted the development of standardised histological scoring systems and their routine inclusion in RCTs.[27–31] Currently, evaluation of histology in ulcerative colitis clinical trials is exclusively based on biopsies taken from the rectosigmoid colon. While sampling all colonic segments for assessment of histological inflammation may provide a more detailed evaluation of colonic remission rates than isolated sampling of the rectosigmoid alone, implementation of colonoscopy and segmental sampling in trials could have major consequences and future studies are needed to address this important question.

In summary, this study demonstrates that compared to a 4-biopsy reference standard, at minimum two, and preferably three, biopsies are required to reliably assess histological disease activity in a single colonic segment using the RHI. However, further studies are needed to confirm the number of biopsies needed in patients with active endoscopic disease and whether sampling from multiple colonic locations affects this endpoint.

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