Association Between Level of Fecal Calprotectin and Progression of Crohn's Disease

Abstract

Background & aims: Mucosal healing is associated with improved outcomes in patients with Crohn's disease (CD), but assessment typically requires ileocolonoscopy. Calprotectin can be measured in fecal samples to determine luminal disease activity in place of endoscopy-this measurement is an important component of the treat-to-target strategy. We investigated whether levels of fecal calprotectin are associated with subsequent CD progression.

Methods: We performed a retrospective study of 918 patients with CD (4218 patient-years of follow-up evaluation; median, 50.6 mo; interquartile range [IQR], 32.8-76.0 mo) managed at a tertiary medical center in Edinburgh, United Kingdom, from 2003 through 2015. Patients were included if they had 1 or more fecal calprotectin measurements made 3 months or more after their diagnosis. We collected clinical data and fecal calprotectin measurements and analyzed these data to identify factors associated with a composite outcome of progression in Montreal behavior, hospitalization, and resection.

Results: An increased level of fecal calprotectin at the index visit was associated with subsequent progression of CD, independent of symptoms or disease location. The median level of fecal calprotectin at the index visit was 432 μg/g (IQR, 1365-998 μg/g) in patients who reached the composite end point vs 180 μg/g (IQR, 50-665 μg/g) in patients who did not. In multivariable analysis, a cut-off value of 115 μg/g calprotectin identified patients who met the end point with a hazard ratio of 2.4 (95% CI, 1.8-3.1; P < .0001).

Conclusions: In a retrospective analysis of patients with CD, we found that measurements of fecal calprotectin made during routine monitoring can identify patients at risk for disease progression, independent of symptoms or disease location. It is therefore important to screen asymptomatic patients for mucosal inflammation and pursue complete resolution of inflammation.

Keywords: Biomarker; IBD; Noninvasive; Prognostic Factor.

Figure 1

Derivation of the cohort of patients with Crohn’s disease, fecal calprotectin (FC), and follow-up data. UC, ulcerative colitis.

Figure 2

Disease progression over time in the whole cohort as estimated by the empiric transition matrix method.

Figure 3

Kaplan–Meier plot of time to reach primary end point stratified by fecal calprotectin (FC) levels (A) greater than 250 μg/g and (B) greater than 115 μg/g at the index visit. The outcome of maintained digestive health is defined here as the inverse of the primary study end point (a composite of progression in Montreal behavior, hospitalization, or surgery). HR, hazard ratio.

Supplementary Figure 1

Comparison of Akaike Information Criterion (AIC) and the likelihood ratio test P value for Cox proportional hazards models at different thresholds of fecal calprotectin.

Supplementary Figure 2

Kaplan–Meier plot of time to reach primary end point stratified by fecal calprotectin (FC) greater than 115 μg/g at the index visit and by Montreal location. The outcome of maintained digestive health is defined here as the inverse of the primary study end point (a composite of progression in Montreal behavior, hospitalization, or surgery). (A) L1 ileal. (B) L2 colonic. (C) L3 ileocolonic. HR, hazard ratio.

Supplementary Figure 3

Kaplan–Meier plots of the 3 separate secondary outcome measures stratified by fecal calprotectin (FC) level greater than 115 μg/g. (A) Progression in Montreal behavior. (B) Surgery. (C) Hospitalization. HR, hazard ratio.

Supplementary Figure 4

Kaplan–Meier plots of the primary end point stratified by fecal calprotectin (FC) level greater than 115 μg/g and by the presence of symptoms at the index visit. The outcome of maintained digestive health is defined here as the inverse of the primary study end point (a composite of progression in Montreal behavior, hospitalization, or surgery). (A) Symptomatic (n = 227). (B) Not symptomatic (n = 377). (C) Unrecorded (n = 314). HR, hazard ratio.

Supplementary Figure 5

Kaplan–Meier plots of the primary end point stratified by fecal calprotectin (FC) level greater than 115 μg/g and by the quartile of time between diagnosis and first FC measurement. The outcome of maintained digestive health is defined here as the inverse of the primary study end point (a composite of progression in Montreal behavior, hospitalization, or surgery). (A) Time from diagnosis Q1 (0.2–1.3 y). (B) Time from diagnosis Q2 (1.3–6.3 y). (C) Time from diagnosis Q3 (6.3–15.3 y). (D) Time from diagnosis Q4 (15.3–50.8 y).

Supplementary Figure 6

Rolling median fecal calprotectin level by time since diagnosis stratified by subsequent progression in Montreal behavior.