Background The diagnostic delay in inflammatory bowel disease (IBD) is well known, yet the costs associated with diagnoses before IBD diagnosis have not yet been reported. This study explored societal costs and disease diagnoses 10 years before Crohn’s disease (CD) and ulcerative colitis (UC) diagnosis in Denmark. Methods This national register study included patients diagnosed between 2003 and 2015 identified in the Danish National Patient Registry (NPR) and controls who were individually matched on age and sex from the general population. Societal costs included health care services, prescription medicine, home care services, and labor productivity loss. Prediagnostic hospital contact occurring before CD or UC diagnosis was identified using the NPR. Average annual costs per individual were calculated before the patient’s first CD or UC diagnosis. A 1-sample t test was then applied to determine significance in differences between cases and controls. Results Among CD (n = 9019) and UC patients (n = 20,913) the average societal costs were higher throughout the entire 10-year period before the diagnosis date compared with the general population. The difference increased over time and equaled €404 for CD patients and €516 for UC patients 10 years before diagnosis and €3377 and €2960, respectively, in the year before diagnosis. Crohn’s disease and UC patients had significantly more diagnoses before their CD and UC diagnosis compared with the general population. Conclusions Compared with the general population, the societal costs and number of additional diagnoses among CD and UC patients were substantially higher in the 10-year period before diagnosis.

Interaction between the activating NKG2D receptor on lymphocytes and its ligands MICA, MICB, and ULBP1–6 modulate T and NK cell activity and may contribute to the pathogenesis of Crohn’s disease (CD). NKG2D ligands are generally not expressed on the cell surface of normal, non-stressed cells, but expression of MICA and MICB in CD intestine has been reported. In this exploratory study, we further characterize the expression of NKG2D and its ligands, including the less well-described ULBP4–6, in CD, and test if NKG2D ligand interactions are involved in the migration of activated T cells into the affected mucosal compartments. Intestinal tissue from CD patients and healthy controls were analyzed by flow cytometry, mass cytometry, and immunohistochemistry for expression of NKG2D and ligands, and for cytokine release. Furthermore, NKG2D-dependent chemotaxis of activated CD8+ T cells across a monolayer of ligand-expressing human intestinal endothelial cells was examined. Activated lymphocytes down-regulated NKG2D expression upon accumulation in inflamed CD intestine. NKG2D expression on CD56+ T and γδ T cells from inflamed tissue seemed inversely correlated with CRP levels and cytokine release. B cells, monocytes, mucosal epithelium, and vascular endothelium expressed NKG2D ligands in inflamed CD intestine. The expression of NKG2D ligands was correlated with cytokine release, but was highly variable between patients. Stimulation of vascular intestinal endothelial cells in vitro induced expression of NKG2D ligands, including MICA/B and ULBP2/6. Blockade of NKG2D on CD8+ T cells inhibited the migration over ligand-expressing endothelial cells. Intestinal induction of NKG2D ligands and ligand-induced down-regulation of NKG2D in CD suggest that the NKG2D-ligand interaction may be involved in both the activation and recruitment of NKG2D+ lymphocytes into the inflamed CD intestine.