Large-scale clustering of longitudinal faecal calprotectin and C-reactive protein profiles in inflammatory bowel disease
Authors: Constantine-Cooke Nathan , Vestergaard Marie Vibeke , Plevris Nikolas , Monterrubio-Gómez Karla , Ramos Belinchón Clara , Ong Solomon , Elford Alexander T. , Gros Beatriz , Sazonovs Aleksejs , Jones Gareth-Rhys , Jess Tine , Vallejos Catalina A. , Lees Charlie W. 
Published: November 2024

Background

Crohn’s disease (CD) and ulcerative colitis (UC) are highly heterogeneous, dynamic and unpredictable, with a marked disconnect between symptoms and intestinal inflammation. Attempts to classify inflammatory bowel disease (IBD) subphenotypes to inform clinical decision making have been limited. We aimed to describe the latent disease heterogeneity by modelling routinely collected faecal calprotectin (FC) and CRP data, describing dynamic longitudinal inflammatory patterns in IBD.

Methods

In this longitudinal study, we analysed patient-level post-diagnosis measurements of FC and CRP in two European cohorts. Latent class mixed models were used to cluster individuals with similar longitudinal profiles. Associations between cluster assignment and baseline characteristics were quantified using multinomial logistic regression. Differences in advanced therapy use across clusters were also explored. Finally, we considered uncertainty in cluster assignments with respect to follow-up length and the overlap between FC and CRP clusters. We included 1036 patients in the FC discovery analysis (Lothian) with a total of 10545 FC observations (median 9 per subject, IQR 6–13), and 7880 patients in the replication (Denmark). The CRP discovery analysis consisted of 1838 patients with 49364 measurements (median 20 per subject; IQR 10–36), with 10041 patients in the replication cohort.

Findings

Eight distinct clusters of inflammatory behaviour over time were identified in the FC and CRP analysis for the Scottish cohort. This model was then applied to the Danish replication cohort, with similar patterns observed in both the Scottish and Danish populations. The clusters, FC1–8 and CRP1–8, were ordered from the lowest cumulative inflammatory burden to the highest. The clusters included groups with high diagnostic levels of inflammation which rapidly normalised, groups where high inflammation levels persisted throughout the full seven years of observation, and a series of intermediates including delayed remitters and relapsing remitters. CD and UC patients were unevenly distributed across the clusters. In UC, male sex was associated with the poorest prognostic cluster (FC8). The use and timing of advanced therapy was associated with cluster assignment, with the highest use of early advanced therapy in FC1. Of note, FC8 and CRP8 captured consistently high patterns of inflammation despite a high proportion of patients receiving advanced therapy, particularly for CD individuals. We observed that uncertainty in cluster assignments was higher for individuals with short longitudinal follow-up, particularly between clusters capturing similar earlier inflammation patterns. There was broadly poor agreement between FC and CRP clusters in keeping with the need to monitor both in clinical practice.

Interpretation

Distinct patterns of inflammatory behaviour over time are evident in patients with IBD. Cluster assignment is associated with disease type and both the use and timing of advanced therapy. These data pave the way for a deeper understanding of disease heterogeneity in IBD and enhanced patient stratification in the clinic.