INN-289 (CROHN'S)


Crohn’s Disease

Inflammatory bowel disease (IBD), is characterized as an inflammatory disorder, mainly of the colon and small intestine. Two major types of IBD exist: Crohn’s disease (CD) and ulcerative colitis (UC).


The incidence of CD in North America is about 3.1–20.2 per 100,000 and has a prevalence of 201 per 100,000 population. Based on epidemiological, genetic and immunologic data, CD is known to be a heterogeneous disorder and has multifactorial etiology with genetics and the environment playing a complex role in disease manifestation.


Crohn’s disease is characterized by transmural inflammation, a type of injury that spans the entire depth of the intestinal wall, which is distinctly different compared to UC. Another important distinction with CD is that any part of the intestine can be involved and the disease could affect any part of the gastrointestinal tract from mouth to perianal area. A quarter of patients have colitis only, while 25% have ileitis only and 50% have ileocolitis, which involves the ileum and colon.


Risk factors for CD have been studied extensively with various hypotheses including genetic mutations, smoking history, diet, lifestyle (sleep, stress and exercise duration), and appendectomy (higher incidence of CD) and certain medications.


Diarrhea is the most common symptom of active CD because decreasing absorption of water and increasing excretion of electrolytes in these patients. In ileocolitis, the symptoms could include right lower quadrant abdominal pain, fever and diarrhea, mimicking appendicitis. More severe CD, can result in severe malabsorption and steatorrhea along with low-grade (inflammatory process) or high-grade fever (infectious process).


The introduction and advent of newer anti-tumor necrosis factor agents and other monoclonal antibodies to gut-specific targets has dramatically changed the paradigm for CD treatment over the last decade. Although these agents have revolutionized the way CD is treated, there are limitations (tolerance, side effects, and infection) to all of these agents and newer treatments are in development.


One area of emerging science is the intestinal microbiome and IBD, as the gut microbiota of CD patients had been shown to have potentially reduced bacterial diversity compared to normal controls. There have been studies showing the higher prevalence of certain strains of bacteria over others which should influence disease manifestation and is an active area of research. These bacteria among other pathogens and multifactorial toxins could affect the epithelial integrity and barrier of the intestine, causing downstream effects causing inflammation and injury.

Mechanism

Intestinal tight junctions control the passage of large molecules such as intact proteins, particles and cells through the paracellular space. This passive transport is known as intestinal paracellular permeability, and while it accounts for only 10% of total protein uptake it serves as the major portal for intact protein and antigen delivery into the body. Protein entry is in close proximity to the submucosal lymphocytes, which comprise 80% of immunoglobulin producing cells in the human body.


Increased intestinal paracellular permeability leads to antigen presentation for processing and antibody response. Tight junctions in other organs have a similar function: the regulation of paracellular transport. In the capillary endothelia of the blood brain barrier, tight junctions are the anatomical barrier interfacing blood and CNS.


Tight junction dysfunction has been implicated in a host of disease states, including a variety of autoimmune diseases. Ischemia - reperfusion injury also appears to be associated with tight junction dysfunction, while many cytokines, bacterial toxins, infections, and drugs have also been implicated in tight junction injury or destruction.