Inflammatory and Immune Cytoprofiles of Active Ulcerative Colitis from Crohn’s Disease—Insights from Multivariable Modeling

Differentiating active ulcerative colitis (UC) from Crohn’s disease (CD) is one of the unmet needs addressed by biomarkers in inflammatory bowel disease (IBD). The immune landscapes of UC and CD differ, justifying the search for discriminatory markers and novel therapy targets among their mediators. Herein, 27 systemic cytokines were measured using flow cytometry-based methodology in 138 IBD patients, with an additional 21 being determined in 67 of the patients. Their discriminatory power was assessed individually and as exploratory multivariable signatures generated using logistic regression, hierarchical clustering, and principal component analysis. Eotaxin-1, macrophage inflammatory protein (MIP)-1β, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) showed fair discriminatory potential, while multivariable models performed better. Interleukin (IL)-1β, IL-4, and MIP-1α were strongly associated with CD, whereas IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), MIP-1β, and TRAIL were associated with UC. Active UC was characterized by mediators linked to eosinophil-, mastocyte-, and neutrophil-driven inflammation and tissue repair (eotaxin-1, IL-5, growth-regulated oncogene (GRO), MIP-1β, stem cell factor (SCF), GM-CSF, IL-1 receptor antagonist, TRAIL, stem cell growth factor (SCGF)-β, and cutaneous T cell-attracting chemokine (CTACK)), whereas active CD was associated with Th1/Th17 immunity, myeloid activation, fibrosis, angiogenesis, and neuroimmune remodeling (IL-1β, IL-12p70, IL-15, ‘regulated on activation, normal T-cell expressed and secreted’ (RANTES), MIP-1α, stromal cell-derived factor (SDF)-1α, nerve growth factor β (β-NGF), and leukemia inhibitory factor (LIF)). In conclusion, integrated circulating immune signatures identify several understudied cytokines as potential contributors to disease-specific pathways and show potential in distinguishing active UC from CD warranting further mechanistic studies and independent validation in larger cohorts.