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.

EPIDEMIOLOGY

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.

PATHOGENESIS

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

Environmental triggers can cause a persistent and excessive activation of the mucosal immune system. It is unclear if this is due to a defect in the mucosal immune system or continued stimulation of the immune system. In CD, the T helper 1 immune response becomes overactive.⁷ This response plays an important role in cellular immunity and leads to the activation of macrophages, which produce tumor necrosis factor α (TNF-α), interleukin (IL) 1, and IL-6. These cytokines result in inflammation and consequent tissue destruction. In UC, the inflammatory response seems to be T helper 2–mediated and results in crypt abscesses, which cause tissue destruction.⁷ This dichotomy in pathogenesis supports the theory that CD and UC are separate disease processes.

CLINICAL AND DIAGNOSTIC FEATURES

Although CD and UC have distinct clinical, laboratory, endoscopic, and histologic findings, there is some overlap between these 2 diseases. In fact, as already noted, 8% to 13% of patients with IBD are diagnosed as having indeterminate colitis because their clinical and diagnostic findings are not specific for CD or UC.² Other patients' disease is reclassified from UC to CD as their disease progresses. Serologic testing may aid in the differentiation between CD and UC. Anti–Saccharomyces cerevisiae antibody is positive in approximately 40% to 60% of patients with CD but in only 10% of patients with UC.¹⁹ Conversely, perinuclear antineutrophil cytoplasmic antibody is present in 60% to 80% of patients with UC but in only 10% of patients with CD.¹⁹ The correct assignment of patients to the categories of CD or UC becomes especially important when considering medical and surgical treatment options. Table 1 provides a full description of the clinical and diagnostic features of CD and UC.^20-22

INTESTINAL COMPLICATIONS

As a result of the transmural inflammation seen in CD, these patients can develop fistulas, fissures, and strictures. Fistulas are abnormal communications between 2 loops of bowel, bowel and skin, or bowel and another organ, such as the bladder. Strictures often lead to bowel obstruction. They can be treated with surgical resection or strictureplasty.²³ Patients with CD and UC are vulnerable to severe hemorrhage and the possibility of perforation.

Toxic megacolon is most commonly associated with UC, but it can occur in CD. Clinicians should suspect toxic megacolon in a patient with severe abdominal pain and tenderness, abdominal distension, decreased frequency of bowel movements, rebound tenderness, fever, and tachycardia.²⁴ These patients should be treated with intravenous corticosteroids and decompression (nasogastric tube and rectal tube). Serial abdominal x-rays should be done to monitor for worsening of colonic dilatation. Care should be taken to avoid antidiarrheal agents, narcotics, anticholinergic drugs, and hypokalemia, which may worsen the toxic megacolon. If toxic megacolon does not resolve promptly with medical treatment, colectomy can be performed as the definitive treatment.²⁴

Patients with CD and UC are at increased risk to develop colon cancer. The risk in UC is greatest in patients with colonic inflammation that extends beyond the splenic flexure. The risk of developing colon cancer for patients with UC beyond the splenic flexure is roughly 0.5% per year after 8 years of disease.²⁵ In a large multicenter trial, the risk of colon cancer was 8% in patients with CD at 22 years from onset and 7% in patients with UC at 20 years from onset.^26,27

Screening colonoscopy should be performed every 2 years after 8 years of colitis in patients with CD or UC. After 15 years, screening colonoscopy should be repeated every year. If low-grade dysplasia, dysplasia-associated lesions or masses,²⁸ or high-grade dysplasia is confirmed by 2 pathologists, the affected individual should have prophylactic colectomy because of the high risk of developing colorectal carcinoma.

EXTRAINTESTINAL MANIFESTATIONS

The most frequent extraintestinal manifestations of CD and UC affect the liver, bones, joints, skin, and eyes. These are often discovered before the intestinal disease. One needs to take an extensive review of systems and perform a full physical examination in these patients to detect these complicating conditions early in their course, as some of them respond well to treatment. Peripheral arthritis, erythema nodosum, and episcleritis parallel the disease activity, while sacroiliitis, ankylosing spondylitis, pyoderma gangrenosum, anterior uveitis, and primary sclerosing cholangitis do not. Therefore, it can be especially difficult to accurately associate some of these findings with a patient's IBD diagnosis as they may occur while the patient is in remission or after "curative" colectomy in a patient with UC. Table 2 provides a complete list of the extraintestinal manifestations of IBD and their incidence.^29,30

TREATMENT

Many advances have been made in the treatment of CD and UC. The most important advances have been in anti–TNF-α, anti-α4 integrin, and probiotic therapy.^7,31 However, the treatment of IBD is based on a pyramid system, with most patients having mild or moderate disease and receiving aminosalicylates, and occasionally corticosteroids, for disease flares.

All patients with IBD need multidimensional care because the disease can affect many aspects of life. Management should include nutrition, psychosocial support, and control of luminal disease and extraintestinal manifestations. Nutritional support is especially important for patients with short-bowel syndrome and in children, who are at risk for growth retardation.⁷ Patients with IBD should have close, long-term relationships with their healthcare providers. These patients should receive symptomatic treatment for nausea, vomiting, diarrhea, and abdominal pain.⁷ However, antidiarrheal agents should not be used in active unstable disease.

Aminosalicylates

For decades, this class of drugs has been the mainstay of induction and maintenance of remission for patients with CD and UC. Svartz ³² designed sulfasalazine (Azulfidine) to treat rheumatoid arthritis and noted that it improved the associated abdominal pain and diarrhea in some of these patients. Sulfasalazine is made up of sulfapyridine and 5-aminosalicylate (5-ASA) moieties joined by an azobond. In the colon, the bacterial flora (with azoreductase activity) cleave the bond and release the 5-ASA moiety, which acts locally to decrease inflammation.³³ It blocks production of prostaglandins and leukotrienes, inhibits chemotaxis, scavenges oxygen radicals, and inhibits NF-κB. Sulfapyridine molecules are absorbed in the colon and may achieve high serum levels. Most of the adverse effects of sulfasalazine can be attributed to sulfapyridine. For many years, sulfasalazine was the first-line treatment for UC and CD affecting the colon because it is effective and inexpensive. However, because some patients cannot tolerate the adverse effects caused by the sulfapyridine moiety, several ingenious methods have been developed to deliver the 5-ASA moiety to affected parts of the small and large intestine. Between 10% and 20% of patients who cannot tolerate sulfasalazine have an intolerance to the 5-ASA moiety and therefore are unlikely to tolerate any of the medications from this class.³⁴

The 5-ASA moiety is called mesalamine when it is given by itself. "Unprotected" mesalamine is completely absorbed in the upper gastrointestinal tract. Therefore, 2 oral preparations have been designed to "protect" mesalamine from absorption in the upper gastrointestinal tract and to deliver it to affected parts of the lower gastrointestinal tract. Mesalamine can be coated with an acrylic resin (Asacol). As the pH of the bowel increases to greater than 7, this form of the drug is released in the distal ileum and colon.³⁵ Mesalamine in ethylcellulose microspheres (Pentasa) is delivered by sustained release throughout the intestines.³⁵ Asacol and Pentasa may be especially useful in CD because of their activity within the small intestine. Mesalamine is also available as a topical enema (Rowasa)^36,37 or in suppository form (Canasa).^38,39 These formulations are useful in distal UC and CD and have minimal systemic adverse effects.

Two other aminosalicylates have been developed to capitalize on the fact that cleavage of the azobond delivers 5-ASA to the colonic mucosa. Olsalazine sodium (Dipentum) consists of two 5-ASA moieties connected by an azobond, and balsalazide disodium (Colazal) is a 5-ASA moiety attached to an inert molecule by an azobond.⁴⁰ These 2 medications are effective in UC because, like sulfasalazine, their azobonds are cleaved by bacteria in the colon.

Corticosteroids. Corticosteroids provide potent antiinflammatory activity for the induction of remission in CD and UC,^7,31,41 but they are not effective for the maintenance of remission. A response is usually seen within 7 to 10 days. Chronic use is limited by serious adverse effects, which correlate with the dose and the duration of treatment. In addition to the oral and intravenous routes, corticosteroids can be given in enema form for topical treatment of distal UC or CD.

The adverse systemic effects of corticosteroids have prompted research into less toxic corticosteroid medications. Budesonide (Entocort EC) appears to have fewer systemic adverse effects because it has 90% first-pass metabolism by the liver. Although budesonide is as effective as conventional corticosteroid treatment for distal ileal and right colonic disease, it is less potent in transverse and distal colonic disease.^42,43 As with other corticosteroid treatments for CD and UC, budesonide is not effective for the maintenance of remission.

Immunosuppressive Medications

The most commonly used medications in this class are azathioprine and its active metabolite 6-mercaptopurine. These medications are especially important for the maintenance of remission in CD and UC. It may take up to 6 months to observe a therapeutic response.⁷ They are considered corticosteroid-sparing agents because they are often used to maintain remission after it is induced by corticosteroids. In this manner, corticosteroids provide coverage during the months before the delayed therapeutic response of azathioprine or 6-mercaptopurine occurs, and the corticosteroids can be discontinued before their systemic toxicity accumulates. One study ⁴⁴ suggested that 6-mercaptopurine is effective in preventing postoperative recurrence in CD.

Azathioprine is a prodrug for 6-mercaptopurine, which can be converted into 6-methylmercaptopurine by the enzyme thiopurine methyltransferase (TPMT) or 6-thioguanine by the enzyme hypoxanthine phosphoribosyltransferase. It is believed that 6-thioguanine is responsible for its immunosuppressive effect and bone marrow suppression. Most patients have wild-type TPMT, but 11% have a heterozygous genotype with decreased TPMT activity, and 0.3% have a homozygous genotype with minimal TPMT activity. These patients with decreased TPMT activity will accumulate higher levels of 6-mercaptopurine and are more likely to have shunting of 6-mercaptopurine toward the formation of 6-thioguanine, which may accumulate and lead to bone marrow suppression. Therefore, metabolite monitoring and enzyme genotyping may be helpful in predicting toxicity and customizing therapy.^45,46

Methotrexate is effective for induction and maintenance of remission in CD.^44,47 Cyclosporine has found its niche in patients with severe UC.⁴⁴ Approximately 50% to 80% of patients refractory to intravenous corticosteroid treatment may avoid colectomy with intravenous cyclosporine treatment.⁴⁸ Uncontrolled clinical data have shown that cyclosporine is effective for treating active CD and for healing refractory CD fistulas, but controlled clinical trials have produced conflicting results.⁴⁹ Tacrolimus and mycophenolate mofetil are useful second-line immunosuppressive options.

Antibiotics

Antibiotics probably work by changing the luminal flora and, consequently, diminishing activation of the mucosal immune system. Metronidazole is effective for active perianal and colonic CD.⁵⁰ Moreover, it may delay recurrence in CD if given for 3 months after surgical resection and reanastomosis.⁵¹ Metronidazole is considered first-line therapy for a condition called pouchitis,⁵² which is described in the "Surgical Treatment" subsection of this section.

In open trials and a few controlled trials, ciprofloxacin has been effective in the treatment of active CD. It is often used in patients with perianal and fistulizing disease and has been used in combination with metronidazole or as a single agent. However, the combination of metronidazole and ciprofloxacin has never been shown to be more effective than either agent by itself.

Probiotics

One of the most interesting areas of IBD research is the use of probiotics for the treatment of IBD. Probiotics are defined as live microorganisms that have a beneficial effect on health by manipulating the microbial environment. By definition, this effect is beyond their inherent basic nutritional value.⁵³ Lactobacilli, bifidobacteria, Saccharomyces boulardi, nonpathogenic Escherichia coli, enterococci, and streptococci have been used as probiotics in various combinations.⁵³

These beneficial effects have been proven in several clinical studies. Nissle 1917, a probiotic formulation containing nonpathogenic E coli, has been effective for the maintenance of remission in UC.⁵⁴ VSL-3, a probiotic that contains bifidobacteria, lactobacilli, and Streptococcus thermophilus, has been effective for the maintenance of remission in UC and pouchitis.⁵⁵ Recently, VSL-3 has been shown to be effective for the prophylaxis of pouchitis.⁵⁶ Therefore, probiotics have been proven to be effective in many clinical scenarios in IBD, but there is some ambiguity as to the specific ways through which they are effective.

Anti-Tumor Necrosis Factor α Treatment

Many discoveries in this class of therapy have been made in the past 5 years. Studies ^57-59 conducted in the mid to late 1990s confirmed a benefit for infliximab in fistulizing an active luminal CD. In open trials, there have been reports of benefit in patients with UC. However, a recent randomized trial showed no efficacy of infliximab in steroid-resistant UC.⁶⁰ Infliximab, which received FDA approval for the treatment of CD in 1998, is a chimeric monoclonal IgG1 antibody against TNF-α. It is a chimera of 75% human protein and 25% murine protein, which selectively targets the TNF-α molecule. Although it was initially believed to act via binding to soluble TNF-α, it primarily acts by binding membrane-bound TNF-α and inducing cell lysis by antibody-dependent cell-mediated cytotoxicity or complement fixation and apoptosis.⁶¹

Infliximab has become an important option for the treatment of refractory luminal and fistulizing CD. Unfortunately, 20% to 40% of patients receiving infliximab develop antibodies to infliximab, also known as human antichimeric antibodies.^61-63 This antibody formation correlates with infusion reactions and a loss of response to further treatment. Cotreatment with intravenous hydrocortisone or immunosuppressive medications, and dosing infliximab initially as infusions at 0, 2, and 6 weeks, decreases the risk of developing antibodies to infliximab and becoming less responsive to infliximab. Therefore, it is now suggested that initial treatment for luminal and fistulizing CD be given as infusions at 0, 2, and 6 weeks, with some form of immunosuppression. Because many of the patients receiving infliximab have been refractory to the other treatment options, infliximab can be used at 8-week intervals to maintain remission in patients who remain responsive.^61-63 Infliximab treatment can be complicated by serum sickness, hypersensitivity reaction, lupus-like reaction, and reactivation of tuberculosis. Therefore, patients should have a purified protein derivative of tuberculin test before infliximab treatment is initiated.⁶¹

Because infliximab, which is 25% murine, has enough immunogenicity to induce the formation of antibodies to infliximab in 20% to 40% of patients, other medications have been studied that may be less immunogenic. CDP571 antibody is a humanized monoclonal antibody against TNF-α. It is composed of 95% human protein and 5% murine protein. Although it has a lower incidence of antibody formation and infusion reactions, it appears to be slightly less effective.^46,61,64 Etanercept is 100% human; consequently, treatment is not limited by the formation of antibodies against it. Although it has a clear role in the treatment of rheumatoid arthritis, it has not been found to be effective in the treatment of CD or UC.^61,65

Potential Treatment Options

The α4 integrins, which include α4β1 integrin and α4β7 integrin, are involved in the recruitment of inflammatory cells. The α4β1 integrin is found on monocytes and binds to vascular cell adhesion molecule 1. The α4β7 integrin binds to mucosal addressin cell adhesion molecule 1, which causes selective homing of leukocytes to intestinal tissue. These lymphocytes release various chemoattractant substances and result in inflammation within the intestinal tissue. Natalizumab is a recombinant IgG4 humanized monoclonal antibody against α4 integrin. It blocks the recruitment of leukocytes. Recent placebo-controlled trials showed a significant increase in clinical remission with 2 doses of natalizumab (3 mg/kg of body weight) given 4 weeks apart.^46,61,66

Peroxisome proliferator–activated receptor γ (PPARγ) is a nuclear hormone receptor that functions as a regulator of cellular metabolism, adipocyte differentiation, and macrophage lipid transport.⁶⁷ In the colonic epithelium, it appears to have anti-inflammatory and antineoplastic activity.⁶⁷ Expression of PPARγ is reduced in patients with UC, but not in patients with CD.^67,68 Recent studies have demonstrated that the commensal intestinal flora affects the expression of PPARg in the colon⁶⁸ and that PPARγ gene therapy can be used to improve the endogenous anti-inflammatory activity of the colon.⁶⁹ An open-label trial suggested that rosiglitazone maleate, a PPARγ ligand, may be beneficial in patients with active UC.⁷⁰ A randomized, placebo-controlled clinical trial is under way to evaluate PPARγ ligands in the treatment of UC that is refractory to conventional medical treatment.

Transdermal nicotine is effective for active left-sided UC.¹⁸ Short-chain fatty acid enemas may be effective for active distal UC, perhaps by providing nutrition for the damaged colonocytes.⁷¹ There is evidence that fish oil may be effective in treating patients with active UC and in preventing relapse in patients with CD.^72,73 Interleukin 10, IL-11, and anti–IL-12 have not shown any benefit in patients with CD or UC.^46,61

Surgical Treatment

There are different approaches to the surgical management of CD and UC. Because UC only involves the rectum and colon, proctocolectomy is curative. In UC, there are 2 primary reasons for colectomy: malignancy (or dysplasia) and disease that is not controlled by medical treatment (including massive hemorrhage, perforation, toxic megacolon, and fulminant colitis).⁷⁴ Years ago, total proctocolectomy with ileostomy was the surgery of choice. Although this surgical option is curative, these patients are faced with the inconvenience and comorbidities associated with ileostomy care. Another option is colectomy with ileorectal anastomosis. However, because rectal mucosa is still present, these patients are at increased risk of developing proctitis, and they need continued screening for rectal carcinoma. The most common and popular option is ileal pouch–anal anastomosis. In this surgery, the ileum is formed into a pouch to maintain continence and attached to the anus. Pouchitis, inflammation of the ileal pouch, occurs in 20% to 50% of patients with an ileal pouch.⁷⁵ Antibiotics and probiotics are effective treatment options for this complication.

Conversely, surgery in patients with CD is not curative. In CD, the indications for surgery are intestinal obstruction, internal fistulas or abscesses, perianal disease, toxic megacolon, severe disease refractory to medical therapy, malignancy (or dysplasia), and growth retardation.⁷⁶ The clinical recurrence rate is approximately 5% to 10% per year, and patients with CD often require repeated surgeries.⁷⁶ At 10 years after their first surgery, 20% of these patients require another operation. The primary surgical principle in CD is to preserve as much bowel as possible because of the likelihood of repeated surgeries and the morbidities of short-bowel syndrome.⁷⁶ Although resection with anastomosis is the most common surgical procedure for CD strictures, strictureplasty has become an acceptable alternative for small-bowel strictures.^23,76

CONCLUSIONS

In summary, IBD is a complicated inflammatory disease, which can affect the intestine and several extraintestinal sites. Crohn's disease and UC appear to have different pathogenic mechanisms and important differences in their clinical manifestations. Exciting developments in the past decade have given us a tremendous amount of insight into the pathogenesis and treatment of CD and UC. Future research should provide us with additional understanding of the pathogenesis of IBD and novel treatment options for this intriguing disease.