People have high plasma levels of interleukin-6 (IL6) and c-reactive protein years before they are diagnosed with inflammatory bowel diseases (IBD), researchers report in the June issue of Clinical Gastroenterology and Hepatology. These markers of systemic inflammation could be features of early-stage disease used to identify patients at risk.
Crohn’s disease (CD) and ulcerative colitis (UC) are believed to develop via inappropriate mucosal immune responses in genetically predisposed individuals. However, little is known about events that occur before people develop symptoms and are diagnosed with IBD. There has been evidence for a time lag between mucosal immune dysfunction and the development of symptoms.
Paul Lochhead et al conducted a nested case–control study of data from Nurses’ Health Study (NHS) cohorts to examine the association between blood markers of inflammation and later development of IBD.
They analyzed levels of levels IL6, and c-reactive protein (using a highly sensitive test) in blood specimens collected before diagnosis, from 83 persons with CD and 90 persons with UC, as well as 344 matched individuals without IBD (control subjects). Samples were collected between 1989 and 1990 from a total of 32,826 NHS participants (43–69 years old) and between 1996 and 1999 from a total of 29,611 NHSII participants (32–54 years old).
Compared with individuals in the lowest quintile of IL6 level, those in the highest quintile had an almost 5-fold increase in risk (odds ratio, 4.68) for CD and an odds ratio of 3.43 for UC. Individuals in the highest quintile of c-reactive protein level, compared with the lowest quintile, had an almost 3-fold increase in risk (odds ratio, 2.82) for CD and an odds ratio of 1.79 for UC.
The median time interval between blood collection and diagnosis of CD or UC was 6.6 and 6.8 years, respectively.
The authors conclude that subclinical inflammation may be a feature of a predisease state in IBD. Preclinical disease phases have defined by serologic markers in the absence of symptoms for other inflammatory disorders, such as rheumatoid arthritis and systemic lupus erythematosus.
There is evidence for IL6 signaling in gut mucosal immune homeostasis and the pathogenesis of IBD. Combinations of biomarkers of inflammation and genetic and serologic markers might be used to identify individuals at risk for IBD.
In an editorial that accompanies the article, Joana Torres et al state the study provides the first clear demonstration that systemic inflammation is present many years before diagnosis of IBD. Torres et al commend the study on its well-characterized cohort, quality control steps for case and phenotype ascertainment, detailed matching procedure, and careful statistical analyses adjusting for multiple confounding variables.
Studies are needed to reproduce the findings in a broader population. Nonetheless, the findings provide insights into the pathogenesis of CD and UC, and help identify potential windows for early treatment or disease prevention.