Inflammation Is an Independent Risk Factor for Colonic Neoplasia in Patients With Ulcerative Colitis: A Case–Control Study

doi:10.1016/j.cgh.2013.06.023

Clinical Gastroenterology and Hepatology

Volume 11, Issue 12, December 2013, Pages 1601-1608.e4

https://doi.org/10.1016/j.cgh.2013.06.023 Get rights and content

Background & Aims

An association between inflammatory activity and colorectal neoplasia (CRN) has been documented in patients with ulcerative colitis (UC). However, previous studies did not address the duration of inflammation or the effects of therapy on risk for CRN. We investigated the effects of inflammation, therapies, and characteristics of patients with UC on their risk for CRN.

Methods

We collected data from 141 patients with UC without CRN (controls) and 59 matched patients with UC who developed CRN (cases), comparing disease extent and duration and patients' ages. We used a new 6-point histologic inflammatory activity (HIA) scale to score biopsy fragments (n = 4449). Information on medications, smoking status, primary sclerosing cholangitis, and family history of CRN were collected from the University of Chicago Inflammatory Bowel Disease Endoscopy Database. Relationships between HIA, clinical features, and CRN were assessed by conditional logistic regression.

Results

Cases and controls were similar in numbers of procedures and biopsies, exposure to steroids or mesalamine, smoking status, and family history of CRN. They differed in proportion of men vs women, exposure to immune modulators, and primary sclerosing cholangitis prevalence. In univariate analysis, HIA was positively associated with CRN (odds ratio [OR], 2.56 per unit increase; P = .001), whereas immune modulators (including azathioprine, 6-mercaptopurine, and methotrexate) reduced the risk for CRN (OR, 0.35; P < .01). HIA was also associated with CRN in multivariate analysis (OR, 3.68; P = .001).

Conclusions

In a case–control study, we associated increased inflammation with CRN in patients with UC. Use of immune modulators reduced the risk for CRN, indicating that these drugs have chemoprotective effects. On the basis of these data, we propose new stratified surveillance and treatment strategies to prevent and detect CRN in patients with UC.

Section snippets

Methods

A case–control study design was used to study UC patients drawn from IBD Endoscopy Database and IBD Registry, 2 databases that include all IBD patients seen at the University of Chicago. Patients with CRN, including flat low-grade dysplasia, high-grade dysplasia, or adenocarcinoma, were selected as cases. Patients with discrete polypoid dysplasia proximal to the area of colitis were excluded.

Controls without CRN were selected from the same databases by matching CRN cases on (1) histologic

Patient Characteristics

We identified 59 eligible cases of UC-related CRN between 1994 and 2005; 15 had CRC, 5 had high-grade dysplasia, 33 had low-grade dysplasia, and 6 were indefinite for dysplasia. The mean age of cases and controls at index date of CRN diagnosis was 47.1 years, with mean disease duration of 18.8 years. Cases were matched with 141 controls (2.4 controls per case). Cases and controls were similar in age and years since UC diagnosis and were perfectly matched in extent of disease. However, CRN cases

Discussion

In this case–control study we confirmed the association between increased degree of inflammation and subsequent neoplasia in patients with UC. This confirmation was achieved through our systematic approach, which used one of the largest patient cohorts to date, blinded re-reading of pathology, comprehensive assessments of risk factors and variables for each case, and elimination of confounders by using a matched case-control design. Our study also confirmed previous conclusions that male

Conclusions

This large U.S. study confirms that increased histologic degree of inflammation is associated with a greater risk for neoplasia in patients with UC and, importantly, adds to the understanding that risk increases with mean activity over time rather than with a single severe episode of disease. We also demonstrated that male sex is an important risk factor, and thiopurine exposure is associated with a significantly decreased CRN risk in UC. Furthermore, our data may explain discrepancies between

References (17)

R.B. Gupta et al.
Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study
Gastroenterology
(2007)
M. Rutter et al.
Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis
Gastroenterology
(2004)
D.T. Rubin et al.
Aminosalicylate therapy in the prevention of dysplasia and colorectal cancer in ulcerative colitis
Clin Gastroenterol Hepatol
(2006)
C.A. Siegel et al.
Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn's disease: a meta-analysis
Clin Gastroenterol Hepatol
(2009)
W.R. Connell et al.
Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease
Lancet
(1994)
J.A. Eaden et al.
The risk of colorectal cancer in ulcerative colitis: a meta-analysis
Gut
(2001)
S.H. Itzkowitz et al.
Inflammation and cancer IV: colorectal cancer in inflammatory bowel disease: the role of inflammation
Am J Physiol Gastrointest Liver Physiol
(2004)
R.H. Collins et al.
Colon cancer, dysplasia, and surveillance in patients with ulcerative colitis: a critical review
N Engl J Med
(1987)

There are more references available in the full text version of this article.

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: Conflicts of interest This author discloses the following: In the last 12 months, David Rubin has received grant support for investigator-initiated research from Warner Chilcott (formerly Procter and Gamble Pharmaceuticals). The remaining authors disclose no conflicts.

: Funding Supported in part by Warner Chilcott (formerly Procter and Gamble Pharmaceuticals), the Digestive Disease Research Core Center of the University of Chicago (DK42086), and the National Institutes of Health—National Institute of Diabetes and Digestive and Kidney Diseases (R01DK068271, R01DK061931), and the Cancer Research Foundation of Chicago.

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Original articleAlimentary tractInflammation Is an Independent Risk Factor for Colonic Neoplasia in Patients With Ulcerative Colitis: A Case–Control Study

Background & Aims

Methods

Results

Conclusions

Section snippets

Methods

Patient Characteristics

Discussion

Conclusions

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Clin Gastroenterol Hepatol

Lancet

The risk of colorectal cancer in ulcerative colitis: a meta-analysis

Gut

Inflammation and cancer IV: colorectal cancer in inflammatory bowel disease: the role of inflammation

Am J Physiol Gastrointest Liver Physiol

Colon cancer, dysplasia, and surveillance in patients with ulcerative colitis: a critical review

N Engl J Med

Original article
Alimentary tract
Inflammation Is an Independent Risk Factor for Colonic Neoplasia in Patients With Ulcerative Colitis: A Case–Control Study