APC: antigen-presenting cell
5-ASA: 5-aminosalicylic acid, mesalamine
FDA: Food and Drug Administration
HGPRT: hypoxanthine-guanine phosphoribosyl transferase
HPA: hypothalamic-pituitary-adrenal (axis)
IBD: inflammatory bowel disease
NSAID: nonsteroidal anti-inflammatory drug
PPAR-γ: peroxisome proliferator-activated receptor gamma
TGF: transforming growth factor
TH:T helper (lymphocyte)
TNF-α: tumor necrosis factor alpha
TPMT: thiopurine methyltransferase
XO: xanthine oxidase
INFLAMMATORY BOWEL DISEASE
Inflammatory bowel disease is a spectrum of remitting and relapsing, chronic, inflammatory intestinal conditions. IBD causes significant GI symptoms that include diarrhea, abdominal pain, bleeding, anemia, and weight loss. IBD conventionally is divided into two major subtypes: ulcerative colitis and Crohn disease.
Ulcerative colitis is characterized by confluent mucosal inflammation of the colon starting at the anal verge and extending proximally for a variable extent (e.g., proctitis, left-sided colitis, or pancolitis) (Ordas et al., 2012). Crohn disease, by contrast, is characterized by transmural inflammation of any part of the GI tract but most commonly the area adjacent to the ileocecal valve (Sartor, 2006). The inflammation in Crohn disease is not necessarily confluent, frequently leaving “skip areas” of relatively normal mucosa. The transmural nature of the inflammation may lead to fibrosis and strictures or fistula formation. IBD is often associated with extraintestinal manifestations involving the joints, skin, or eyes (Ott and Scholmerich, 2013). Primary sclerosing cholangitis is a serious but infrequent complication of ulcerative colitis in which inflammation and fibrostenosis occurs in the intra- and extrahepatic biliary tree (Williamson and Chapman, 2014). Chronic, severe IBD is associated with an increased risk for the development of colorectal cancer (Beaugerie and Itzkowitz, 2015).
A summary of proposed pathogenic events and potential sites of therapeutic intervention is shown in Figure 51–1. Both diseases are associated with an aberrant immune response to the commensal microbiota of the gut in genetically susceptible individuals (Sartor, 2006). Recent evidence of dysbiosis of the microbiome in IBD supports this theory (Bellaguarda and Chang, 2015). Nevertheless, Crohn disease and ulcerative colitis result from distinct pathogenic mechanisms at the level of mucosal immune activation (Xavier and Podolsky, 2007). Histologically, the transmural lesions in Crohn disease exhibit marked infiltration of lymphocytes and macrophages, granuloma formation, and submucosal fibrosis, whereas the superficial lesions in ulcerative colitis have lymphocytic and neutrophilic infiltrates.
Proposed pathogenesis of IBD and target sites for pharmacological intervention. Shown are the interactions among bacterial antigens in the intestinal lumen and immune cells in the intestinal wall. If the epithelial barrier is impaired, bacterial antigens can gain access to APCs such as dendritic cells in the lamina propria. These cells then present the antigen(s) to CD4+ lymphocytes and also secrete cytokines such as IL-12 and IL-18, thereby inducing the differentiation ...