Deep analysis of the peripheral immune system in IBD reveals new insight in disease subtyping and response to mono or combination therapies.

Abstract: Background Inflammatory bowel disease (IBD) is a complex disease with variable presentation, progression and response to therapies. Current disease classification is based on subjective clinical phenotypes. The peripheral blood immunophenome can reflect local inflammation, thus we measured 39 circulating immune cell types in a large cohort of IBD and control subjects and performed immunotype:phenotype associations. Methods We performed FACS or CyTOF analysis on blood from 728 Crohn’s disease (CD), 464 ulcerative colitis (UC), and 334 non-IBD patients, with available demographics, endoscopic and clinical examinations and medication use. Results We observed few immune cell types commonly affected in IBD (lowered NK, B-cells, and CD45RA- CD8 T-cells). Generally, the immunophenome was distinct between UC and CD. Within disease subtype, there were further distinctions, with specific immune cell types associating with disease duration, behaviour and location. Thiopurine monotherapy altered abundance of many cell types, often in the same direction as disease association, while anti-TNF monotherapy demonstrated an opposing pattern. Concomitant use of an anti-TNF and thiopurine was not synergistic but rather additive. For example, thiopurine monotherapy use alone or in combination with anti-TNF was associated with a dramatic reduction in major subclasses of B-cells. Conclusions We present a peripheral map of immune cell changes in IBD related to disease entity and therapies as a resource for hypothesis generation. We propose the changes in B-cell subsets could affect antibody formation and potentially explain the mechanism behind the superiority of combination therapy through the impact of thiopurines on pharmacokinetics of anti-TNFs.