The Biologic Onset of Crohn's Disease: A Screening Study in First Degree Relatives

Summary

Participation Requirements

Description

Crohn's Disease (CD) is a form of inflammatory bowel disease (IBD) that affects the gastrointestinal tract. CD is a chronic, remitting, and relapsing disease that is rarely diagnosed at or near its biological onset. In routine clinical practice, CD diagnosed at the pre-clinical stage is largely by c...

Crohn's Disease (CD) is a form of inflammatory bowel disease (IBD) that affects the gastrointestinal tract. CD is a chronic, remitting, and relapsing disease that is rarely diagnosed at or near its biological onset. In routine clinical practice, CD diagnosed at the pre-clinical stage is largely by chance during routine screening procedures. Current evidence suggests these earlier diagnoses lead to better treatment outcomes and may even offer clues to better understand the disease's etiology and pathogenesis. Consequently, diagnosing CD at an early stage may offer several advantages including better response to medical treatment; possible avoidance of long term complications and surgery; and long term cost savings. In the last several years it has become apparent that Crohn's Disease tends to evolve over time from an inflammatory disease to a fibrosing one due to the repeated healing and repair cycles. The fibrosing found in CD is similar to that of other diseases that affect organs like the liver and pancreas. Extensive fibrosis (build-up of excessive scar tissue) does not respond to drug therapy and must be treated with surgery; therefore, surgical intervention (e.g., intestinal resection) is a treatment modality common to CD patients largely due to this indication. Ideally, Crohn's Disease should be diagnosed before this irreversible damage takes place and while the disease is still responsive to medical therapy; however, the disease only comes to medical attention in the presence of symptoms most often associated with severe bowel damage such as obstructions and strictures. Even still, the presence of these symptoms does not always lead to prompt diagnosis. Additionally, this evidence indicates that CD has already run a long course before it becomes symptomatic and further supports the need for earlier diagnosis. An efficient screening strategy for Crohn's Disease has yet to be identified. To date, colonoscopy is considered the gold-standard as there are no noninvasive tests that can conclusively screen for disease. Screening the general population has been shown to be inefficient due to the overall risk of developing the disease so it is crucial to determine the populations at the greatest risk. Crohn's Disease has proven to have a strong genetic component. Referral center studies published in the last several years have shown that 5-15% of patients with CD have a family history of the disease; therefore, family members of CD patients may constitute an ideal population for screening. Familial studies have focused mostly on first-degree relatives [FDR] and have found that this group is at a higher risk for developing the disease than the general population. In addition, a landmark study published in 2003 showed that >40% of asymptomatic first-degree relatives of CD patients [CD-FDR] had elevated fecal calprotectin-an intestinal inflammation marker that closely reflects disease activity in CD patients-with values between those of healthy controls and FDR's with diagnosed disease. Additional abnormalities such as, Anti-Saccharomyces Cerevisae Antibodies [ASCA] positivity and elevated inflammatory markers-have also been reported in asymptomatic first-degree relatives at a greater proportion than the known risk of developing the disease. Recently, at another institution, the investigators conducted an ileocolonoscopy-based screening study in 38 first-degree relatives of patients with Crohn's Disease. Identified first-degree relatives were carefully excluded in the presence of digestive symptoms or a medical history that contained possible causes of intestinal inflammation. The healthy control group consisted of 10 age and sex-matched individuals who were scheduled for a colonoscopy due to unrelated reasons (e.g., colon cancer screening or rectal bleeding) and whose results were found to be normal. In both groups, tissue, blood, and stool samples were collected. Median values for fecal calprotectin (FC) and histology were significantly greater in first-degree relatives when compared to the healthy controls. Additionally, colonoscopy identified three different phenotypes within the first-degree relative population: 1) normal, or superimposable to controls; 2) minor lesions (aphthae or small superficial erosions), and 3) typical features of Crohn's Disease. These findings were confirmed with histological scoring that resulted in three highly separated clusters. That preliminary research supports the idea that screening within this high-risk population allows for earlier diagnosis. Validating these results on a larger scale and with less invasive methods may lead to the development of a screening strategy that can be implemented as part of routine clinical practice. Additionally, more research is needed to further characterize the novel phenotype identified as it may hold crucial clues to the pathogenesis of the disease. This study seeks to detect asymptomatic, first-degree relatives of patients with established Crohn's Disease in hopes of catching the disease at or near its biologic onset (pre-clinical stage). Screening will be done using the PillCam™ COLON 2 capsule endoscopy system. Capsule findings will be reviewed by Dr. Sorrentino and Dr. Nguyen at the central site. These findings will then be verified using proven ileocolonoscopy methods. Blood, stool, and tissue specimens will be collected for research-related testing and to be stored for further research. Healthy-controls will be enrolled for comparison purposes. The goal of this study is to validate the preliminary data from our pilot study using a multi-center approach.

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