Inflammatory Bowel Disease

Published Online: August 01, 2004
Noel B. Martins, MD; and Mark A. Peppercorn, MD

Inflammatory bowel disease is a complicated condition, including Crohn's disease, ulcerative colitis, microscopic colitis, and indeterminate colitis, that affects the intestine and several extraintestinal sites. There has been much debate regarding whether Crohn's disease and ulcerative colitis are distinct entities or if they exist along a continuum of the same disease process. In this article, the pathogenic mechanisms and clinical manifestations of inflammatory bowel disease are reviewed, as well as treatment options. Because Crohn's disease and ulcerative colitis are chronic diseases, they have an important economic effect on our healthcare system and the United States as a whole. Some newer and more expensive treatment options may provide overall cost savings in select patient populations because of decreased use of healthcare resources.

(Am J Manag Care. 2004;10:544-552)

Inflammatory bowel disease (IBD) includes Crohn's disease (CD), ulcerative colitis (UC), microscopic colitis, and indeterminate colitis. Microscopic colitis, which includes collagenous and lymphocytic colitis, is characterized by a chronic lymphocytic infiltrate in the absence of any endoscopic or radiographic abnormalities.1 Histologically, collagenous colitis is distinguished from lymphocytic colitis by the presence of a thickened subepithelial collagen band.1 Most IBD can be categorized as CD or UC. However, 8% to 13% of cases of IBD cannot be clearly categorized into CD or UC and are said to represent indeterminate colitis.2

There has been much debate regarding whether CD and UC are distinct entities or if they exist along a continuum of the same disease process. Crohn's disease is characterized by transmural inflammation involving any part of the gastrointestinal tract, with skip lesions often present.3 The inflammation in UC involves only the mucosa and submucosa of the colon and extends proximally from the rectum in a continuous fashion.3

Because CD and UC are chronic diseases, they have an important economic effect on both the healthcare system and the United States as a whole. The direct cost (medical care, medications, tests, and procedures) of CD in the United States in 1990 was $6561 per patient, and the direct cost of UC was $1488 per patient.4 In addition to these direct costs, there are indirect costs, such as absence from work, decreased earnings, premature death, and changes in quality of life. After adjusting for productivity losses, the annual cost for CD and UC in the United States has been estimated at $1.8 to $2.6 billion.4 During the past decade, some expensive treatment options have been developed. One study 5 looked at the effect of infliximab use on resource utilization in patients with CD and found that treatment with infliximab (especially among those with fistulas) resulted in decreased use of surgical services and fewer hospitalizations. Consequently, some of our newer and more expensive treatment options may provide overall cost savings in select patient populations because of decreased use of healthcare resources.


One to two million people in the United States have IBD. In the United States, the incidence of CD is 3.6 to 8.8 cases per 100 000 people, and the incidence of UC is 3 to 15 cases per 100 000 people.6 In contrast to UC, which shows a slight male predominance, CD appears to be slightly more common among women.6 There is a bimodal distribution in the population. Most individuals are diagnosed during a first peak between ages 15 and 40 years, with a second peak occurring in individuals older than 60 years,6 demonstrating that CD and UC can affect people of all ages. Because physicians often do not consider IBD in the differential diagnosis in older patients, this group of patients may be misdiagnosed as having ischemic colitis or diverticulitis. Therefore, clinicians should consider IBD as a diagnosis in patients of all ages.

All the races and ethnic groups in the world have CD and UC. The highest prevalence is seen in North America and Europe.6 Whites are affected more often than African Americans, who are affected more often than Asians and Hispanics. There appears to be a gradient of increasing risk that correlates with how far one lives from the equator.6

During the past few decades, this racial gap has been closing, as there has been an increasing incidence of IBD in Asians and African Americans.6 The incidence of UC in Seoul, Korea, has increased 10-fold since the mid 1980s, and South Asians who have migrated to developed countries are at increased risk for developing IBD.6 Among children living in the southeastern United States, CD and UC were found to be equally common among African Americans and whites.6 These population findings indicate a dynamic distribution of IBD among ethnic and racial groups, and the migration findings underscore the importance of environmental factors in the risk of IBD.


The pathogenesis of IBD is multifactorial. Affected individuals often have a genetic predisposition to develop CD or UC. After disruption of the gastrointestinal mucosal barrier, a luminal antigen causes ongoing activation of the mucosal immune system, which leads to tissue damage and the clinical features of IBD. The Figure shows a schematic view of the pathogenesis of CD and UC.


Genetic Predisposition

Studies have shown evidence for a genetic predisposition to IBD. First-degree relatives of patients with IBD have a 4- to 20-fold increased risk and a 7% absolute risk.7-9 Among family members with CD, there is strong concordance within disease category and disease location. However, despite the evidence supporting a genetic predisposition, most patients with IBD have no close relatives with IBD.7-9 Monozygotic twins have a significantly higher concordance rate than dizygotic twins. The genetic contribution appears to be greater in CD than in UC.7,8 Overall, the genetic predisposition to CD and UC appears to be multifactorial, as opposed to being linked to one specific gene.

Candidate Genes

Several genes on different chromosomes have been linked to the development of CD and UC. The IBD1 gene, which is located on chromosome 16, has been linked to CD.7 Early-onset CD has been associated with a specific locus on chromosome 5.7,10 In another study,11 the strongest association with the susceptibility locus on chromosome 5 was observed in patients with perianal CD.

The most promising candidate gene is CARD15 (also known as NOD2), which is expressed in macrophages and paneth cells. The variant form of CARD15 results in paradoxically reduced macrophage activation of the NF-κB pathway. One would expect this to result in a diminished inflammatory response. However, homozygotes for this variant gene have a 20-fold increased risk of developing CD. Analysis of a recent study12 may explain this paradoxical response. This study showed that CARD15 recognizes muramyl dipeptide, the minimal bioactive peptidoglycan motif common to all bacteria. Therefore, in patients with variant CARD15, bacterial antigens may bypass the host's initial immune defenses (because of defects in peptidoglycan sensing) and result in increased stimulation of the mucosal immune system. Recently, it has been noted that paneth cells, which are most numerous in the terminal ileum and play an important role in antibacterial defense in the intestine, express the CARD15 gene.13 Consequently, another intriguing hypothesis is that disruption of this property of paneth cell function by CARD15 variants may predispose patients to the development of ileal CD.13

Luminal Antigens

Studies in several different animal models have demonstrated that luminal flora is required for IBD to develop in a susceptible host. Genetically susceptible animals that are maintained in a germ-free environment from birth do not develop immune system activation and colitis. When these same animals acquire luminal flora, they develop activation of their immune systems and colitis.14

A study15 in patients with CD after ileocecal resection demonstrated that luminal flora is necessary for the reactivation of CD. After segmental resection and reanastomosis, there was an 85% to 90% recurrence rate of CD. However, there was no evidence of recurrence in patients with CD who had segmental resection and reanastomosis with a proximal diverting ileostomy. In the final part of the study, the ileostomy contents were reintroduced into the distal ileum in these patients, which resulted in recurrence of the CD within 1 week. Both of these observations support the belief that luminal flora is necessary for the development of IBD.

Environmental Triggers

In a genetically predisposed host, an environmental trigger appears to precipitate the development of IBD. The environmental triggers implicated in the pathogenesis of IBD act by altering the luminal flora or disrupting the mucosal barrier. Antibiotics and diet can alter the luminal flora. Nonsteroidal anti-inflammatory drugs and acute infections can cause inflammation, which results in increased mucosal permeability.16 Stress and smoking (in CD) can cause changes in blood flow and mucus secretion and thereby weaken the mucosal barrier. Although smoking may precipitate attacks of CD, it appears to be protective against flares of UC.17 In fact, nicotine patches are sometimes used for the treatment of UC.18 In conclusion, all of these types of environmental triggers may allow luminal antigens to activate the mucosal immune system.

Activation of the Mucosal Immune System

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