Interpreting Biomarker Discordance in Inflammatory Bowel Disease: Beyond Fecal Calprotectin and C-Reactive Protein

Treat-to-target management in inflammatory bowel disease (IBD) combines symptoms, fecal and serum biomarkers, endoscopy, histology, and cross-sectional imaging, but these measures frequently diverge. Discordance may reflect analytical variation, timing, disease location, phenotype, comorbidity, or partially non-overlapping biological processes. We performed a critical narrative review using a structured PubMed/MEDLINE search, supplemented by citation chaining and publisher searches. Guidelines, systematic reviews, diagnostic studies, cohorts, randomized trials, and selected mechanistic studies were prioritized. Fecal calprotectin (FC) and lactoferrin primarily reflect intestinal neutrophilic inflammation, whereas C-reactive protein (CRP) and related serum indices reflect a nonlocalizing systemic response. The fecal immunochemical test (FIT) detects gastrointestinal bleeding, and leucine-rich alpha-2 glycoprotein (LRG) remains promising but insufficiently standardized. We distinguish five biological biomarker domains—namely, fecal–neutrophil; serum–systemic; epithelial/barrier; restitution/resolution; and fibrosis/extracellular matrix (ECM) remodeling—from symptoms and clinical indices, pharmacologic measurements, and phenotype-directed reference assessments. Circulating barrier, repair, and matrix-turnover markers remain investigational. Reactive therapeutic drug monitoring (TDM) for anti-tumor necrosis factor (anti-TNF) agents has the most mature evidence. Vedolizumab and ustekinumab show exposure–response associations, but actionable thresholds are unvalidated, and clinical TDM is not established for newer biologics or oral small molecules. After objective confirmation of disease activity, the framework may support phenotype-directed therapeutic decisions but is not a validated algorithm. Clinically important disagreement should prompt assessment of sampling, assay, timing, infection, medication-related confounding, and pretest probability before phenotype-directed endoscopy, histology, imaging, or reactive TDM is selected. A single discordant result should neither trigger treatment escalation nor exclude active or structural disease.