Inflammatory Bowel Disease

,
The American Journal of Managed Care, August 2004, Volume 10, Issue 8

Inflammatory bowel disease is a complicated condition, includingCrohn's disease, ulcerative colitis, microscopic colitis, and indeterminatecolitis, that affects the intestine and several extraintestinalsites. There has been much debate regarding whether Crohn's diseaseand ulcerative colitis are distinct entities or if they exist alonga continuum of the same disease process. In this article, the pathogenicmechanisms and clinical manifestations of inflammatorybowel disease are reviewed, as well as treatment options. BecauseCrohn's disease and ulcerative colitis are chronic diseases, theyhave an important economic effect on our healthcare system andthe United States as a whole. Some newer and more expensivetreatment options may provide overall cost savings in select patientpopulations because of decreased use of healthcare resources.

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

Inflammatory bowel disease (IBD) includes Crohn'sdisease (CD), ulcerative colitis (UC), microscopiccolitis, and indeterminate colitis. Microscopic colitis,which includes collagenous and lymphocytic colitis,is characterized by a chronic lymphocytic infiltrate inthe absence of any endoscopic or radiographic abnormalities.1 Histologically, collagenous colitis is distinguishedfrom lymphocytic colitis by the presence of athickened subepithelial collagen band.1 Most IBD can becategorized as CD or UC. However, 8% to 13% of casesof IBD cannot be clearly categorized into CD or UC andare said to represent indeterminate colitis.2

There has been much debate regarding whether CDand UC are distinct entities or if they exist along a continuumof the same disease process. Crohn's disease ischaracterized by transmural inflammation involvingany part of the gastrointestinal tract, with skip lesionsoften present.3 The inflammation in UC involves onlythe mucosa and submucosa of the colon and extendsproximally from the rectum in a continuous fashion.3

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

EPIDEMIOLOGY

One to two million people in the United States haveIBD. In the United States, the incidence of CD is 3.6 to8.8 cases per 100 000 people, and the incidence of UCis 3 to 15 cases per 100 000 people.6 In contrast to UC,which shows a slight male predominance, CD appears tobe slightly more common among women.6 There is abimodal distribution in the population. Most individualsare diagnosed during a first peak between ages 15 and40 years, with a second peak occurring in individualsolder than 60 years,6 demonstrating that CD and UCcan affect people of all ages. Because physicians oftendo not consider IBD in the differential diagnosis in olderpatients, this group of patients may be misdiagnosed ashaving ischemic colitis or diverticulitis. Therefore, cliniciansshould consider IBD as a diagnosis in patients ofall ages.

All the races and ethnic groups in the world have CDand UC. The highest prevalence is seen in NorthAmerica and Europe.6 Whites are affected more oftenthan African Americans, who are affected more oftenthan Asians and Hispanics. There appears to be a gradientof increasing risk that correlates with how far onelives from the equator.6

During the past few decades, this racial gap has beenclosing, as there has been an increasing incidence ofIBD in Asians and African Americans.6 The incidenceof UC in Seoul, Korea, has increased 10-fold since themid 1980s, and South Asians who have migrated todeveloped countries are at increased risk for developingIBD.6 Among children living in the southeasternUnited States, CD and UC were found to be equallycommon among African Americans and whites.6 Thesepopulation findings indicate a dynamic distribution ofIBD among ethnic and racial groups, and the migrationfindings underscore the importance of environmentalfactors in the risk of IBD.

PATHOGENESIS

The pathogenesis of IBD is multifactorial. Affectedindividuals often have a genetic predisposition to developCD or UC. After disruption of the gastrointestinalmucosal barrier, a luminal antigen causes ongoing activationof the mucosal immune system, which leads totissue damage and the clinical features of IBD. TheFigure shows a schematic view of the pathogenesis ofCD and UC.

Genetic Predisposition

Studies have shown evidence for a genetic predispositionto IBD. First-degree relatives of patients with IBDhave a 4- to 20-fold increased risk and a 7% absoluterisk.7-9 Among family members with CD, there is strongconcordance within disease category and disease location.However, despite the evidence supporting a geneticpredisposition, most patients with IBD have no closerelatives with IBD.7-9 Monozygotic twins have a significantlyhigher concordance rate than dizygotic twins.The genetic contribution appears to be greater in CDthan in UC.7,8 Overall, the genetic predisposition to CDand UC appears to be multifactorial, as opposed to beinglinked to one specific gene.

Candidate Genes

IBD1

Several genes on different chromosomes have beenlinked to the development of CD and UC. The gene, which is located on chromosome 16, has beenlinked to CD.7 Early-onset CD has been associated witha specific locus on chromosome 5.7,10 In anotherstudy,11 the strongest association with the susceptibilitylocus on chromosome 5 was observed in patients withperianal CD.

CARD15

NOD2

CARD15

CARD15

CARD15

CARD15

CARD15

The most promising candidate gene is (alsoknown as ), which is expressed in macrophagesand paneth cells. The variant form of resultsin paradoxically reduced macrophage activation of theNF-κB pathway. One would expect this to result in adiminished inflammatory response. However, homozygotesfor this variant gene have a 20-fold increased riskof developing CD. Analysis of a recent study12 mayexplain this paradoxical response. This study showedthat recognizes muramyl dipeptide, the minimalbioactive peptidoglycan motif common to all bacteria.Therefore, in patients with variant ,bacterial antigens may bypass the host's initial immunedefenses (because of defects in peptidoglycan sensing)and result in increased stimulation of the mucosalimmune system. Recently, it has been noted thatpaneth cells, which are most numerous in the terminalileum and play an important role in antibacterialdefense in the intestine, express the gene.13Consequently, another intriguing hypothesis is that disruptionof this property of paneth cell function by variants may predispose patients to the developmentof ileal CD.13

Luminal Antigens

Studies in several different animal models havedemonstrated that luminal flora is required for IBD todevelop in a susceptible host. Genetically susceptible animalsthat are maintained in a germ-free environment frombirth do not develop immune system activation and colitis.When these same animals acquire luminal flora, theydevelop activation of their immune systems and colitis.14

A study15 in patients with CD after ileocecal resectiondemonstrated that luminal flora is necessary for thereactivation of CD. After segmental resection andreanastomosis, there was an 85% to 90% recurrence rateof CD. However, there was no evidence of recurrence inpatients with CD who had segmental resection andreanastomosis with a proximal diverting ileostomy. Inthe final part of the study, the ileostomy contents werereintroduced 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 luminalflora is necessary for the development of IBD.

Environmental Triggers

In a genetically predisposed host, an environmentaltrigger appears to precipitate the development of IBD.The environmental triggers implicated in the pathogenesisof IBD act by altering the luminal flora or disruptingthe mucosal barrier. Antibiotics and diet can alterthe luminal flora. Nonsteroidal anti-inflammatory drugsand acute infections can cause inflammation, whichresults in increased mucosal permeability.16 Stress andsmoking (in CD) can cause changes in blood flow andmucus secretion and thereby weaken the mucosal barrier.Although smoking may precipitate attacks of CD, itappears to be protective against flares of UC.17 In fact,nicotine patches are sometimes used for the treatmentof UC.18 In conclusion, all of these types of environmentaltriggers may allow luminal antigens to activatethe mucosal immune system.

Activation of the Mucosal Immune System

Environmental triggers can cause a persistent andexcessive activation of the mucosal immune system. It isunclear if this is due to a defect in the mucosal immunesystem 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 cellularimmunity and leads to the activation of macrophages,which produce tumor necrosis factor α (TNF-α), interleukin(IL) 1, and IL-6. These cytokines result ininflammation and consequent tissue destruction. InUC, the inflammatory response seems to be T helper2—mediated and results in crypt abscesses, whichcause tissue destruction.7 This dichotomy in pathogenesissupports the theory that CD and UC are separatedisease processes.

CLINICAL AND DIAGNOSTICFEATURES

Saccharomycescerevisiae

Although CD and UC have distinct clinical, laboratory,endoscopic, and histologic findings, there is someoverlap between these 2 diseases. In fact, as alreadynoted, 8% to 13% of patients with IBD are diagnosed ashaving indeterminate colitis because their clinical anddiagnostic findings are not specific for CD or UC.2 Otherpatients' disease is reclassified from UC to CD as theirdisease progresses. Serologic testing may aid in the differentiationbetween CD and UC. Anti— antibody is positive in approximately 40% to60% of patients with CD but in only 10% of patients withUC.19 Conversely, perinuclear antineutrophil cytoplasmicantibody is present in 60% to 80% of patients withUC but in only 10% of patientswith CD.19 The correct assignmentof patients to the categoriesof CD or UC becomesespecially important when consideringmedical and surgicaltreatment options. Table 1 providesa full description of theclinical and diagnostic featuresof CD and UC.20-22

INTESTINALCOMPLICATIONS

As a result of the transmuralinflammation seen in CD, thesepatients can develop fistulas,fissures, and strictures. Fistulasare abnormal communicationsbetween 2 loops of bowel,bowel and skin, or bowel andanother organ, such as thebladder. Strictures often lead tobowel obstruction. They can betreated with surgical resectionor strictureplasty.23 Patientswith CD and UC are vulnerableto severe hemorrhage and thepossibility of perforation.

Toxic megacolon is mostcommonly associated withUC, but it can occur in CD.Clinicians should suspecttoxic megacolon in a patientwith severe abdominal painand tenderness, abdominaldistension, decreased frequencyof bowel movements,rebound tenderness, fever,and tachycardia.24 Thesepatients should be treatedwith intravenous corticosteroids and decompression(nasogastric tube and rectal tube). Serial abdominal x-raysshould be done to monitor for worsening ofcolonic dilatation. Care should be taken to avoidantidiarrheal agents, narcotics, anticholinergic drugs,and hypokalemia, which may worsen the toxic megacolon.If toxic megacolon does not resolve promptlywith medical treatment, colectomy can be performedas the definitive treatment.24

Patients with CD and UC are at increased risk to developcolon cancer. The risk in UC is greatest in patientswith colonic inflammation that extends beyond thesplenic flexure. The risk of developing colon cancer forpatients with UC beyond the splenic flexure is roughly0.5% per year after 8 years of disease.25 In a large multicentertrial, the risk of colon cancer was 8% in patientswith CD at 22 years from onset and 7% in patients withUC at 20 years from onset.26,27

Screening colonoscopy should be performed every 2years after 8 years of colitis in patients with CD or UC.After 15 years, screening colonoscopy should be repeatedevery year. If low-grade dysplasia, dysplasia-associatedlesions or masses,28 or high-grade dysplasia isconfirmed by 2 pathologists, the affected individualshould have prophylactic colectomy because of the highrisk of developing colorectal carcinoma.

EXTRAINTESTINAL MANIFESTATIONS

The most frequent extraintestinal manifestations ofCD and UC affect the liver, bones, joints, skin, andeyes. These are often discovered before the intestinaldisease. One needs to take an extensive review of systemsand perform a full physical examination in thesepatients to detect these complicating conditions earlyin their course, as some of them respond well to treatment.Peripheral arthritis, erythema nodosum, andepiscleritis parallel the disease activity, while sacroiliitis,ankylosing spondylitis, pyoderma gangrenosum,anterior uveitis, and primary sclerosing cholangitisdo not. Therefore, it can be especially difficult toaccurately associate some of these findings with apatient's IBD diagnosis as they may occur while thepatient is in remission or after "curative" colectomyin a patient with UC. Table 2 provides a complete listof the extraintestinal manifestations of IBD and theirincidence.29,30

TREATMENT

Many advances have been made in the treatment ofCD and UC. The most important advances have been inanti—TNF-α, anti-α4 integrin, and probiotic therapy.7,31However, the treatment of IBD is based on a pyramidsystem, with most patients having mild or moderate diseaseand receiving aminosalicylates, and occasionallycorticosteroids, for disease flares.

All patients with IBD need multidimensional carebecause the disease can affect many aspects of life.Management should include nutrition, psychosocial support,and control of luminal disease and extraintestinalmanifestations. Nutritional support is especially importantfor patients with short-bowel syndrome and in children,who are at risk for growth retardation.7 Patientswith IBD should have close, long-term relationships withtheir healthcare providers. These patients shouldreceive symptomatic treatment for nausea, vomiting,diarrhea, and abdominal pain.7 However, antidiarrhealagents should not be used in active unstable disease.

Aminosalicylates

For decades, this class of drugs has been the mainstayof induction and maintenance of remission for patientswith CD and UC. Svartz 32 designed sulfasalazine(Azulfidine) to treat rheumatoid arthritis and noted thatit improved the associated abdominal pain and diarrheain some of these patients. Sulfasalazine is made up of sulfapyridineand 5-aminosalicylate (5-ASA) moietiesjoined by an azobond. In the colon, the bacterial flora(with azoreductase activity) cleave the bond and releasethe 5-ASA moiety, which acts locally to decrease inflammation.33 It blocks production of prostaglandins andleukotrienes, inhibits chemotaxis, scavenges oxygenradicals, and inhibits NF-κB. Sulfapyridine molecules areabsorbed in the colon and may achieve high serum levels.Most of the adverse effects of sulfasalazine can beattributed to sulfapyridine. For many years, sulfasalazinewas the first-line treatment for UC and CD affecting thecolon because it is effective and inexpensive. However,because some patients cannot tolerate the adverseeffects caused by the sulfapyridine moiety, severalingenious 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 cannottolerate sulfasalazine have an intolerance to the 5-ASAmoiety and therefore are unlikely to tolerate any of themedications from this class.34

mesalamine

The 5-ASA moiety is called when it isgiven by itself. "Unprotected" mesalamine is completelyabsorbed in the upper gastrointestinal tract. Therefore, 2oral preparations have been designed to "protect"mesalamine from absorption in the upper gastrointestinaltract and to deliver it to affected parts of the lowergastrointestinal tract. Mesalamine can be coated with anacrylic resin (Asacol). As the pH of the bowel increasesto greater than 7, this form of the drug is released in thedistal ileum and colon.35 Mesalamine in ethylcellulosemicrospheres (Pentasa) is delivered by sustained releasethroughout the intestines.35 Asacol and Pentasa may beespecially useful in CD because of their activity withinthe small intestine. Mesalamine is also available as a topicalenema (Rowasa)36,37 or in suppository form(Canasa).38,39 These formulations are useful in distal UCand CD and have minimal systemic adverse effects.

Two other aminosalicylates have been developed tocapitalize on the fact that cleavage of the azobond delivers5-ASA to the colonic mucosa. Olsalazine sodium(Dipentum) consists of two 5-ASA moieties connectedby an azobond, and balsalazide disodium (Colazal) is a5-ASA moiety attached to an inert molecule by anazobond.40 These 2 medications are effective in UCbecause, like sulfasalazine, their azobonds are cleavedby bacteria in the colon.

Corticosteroids.

Corticosteroids provide potent antiinflammatoryactivity for the induction of remission inCD and UC,7,31,41 but they are not effective for the maintenanceof remission. A response is usually seen within7 to 10 days. Chronic use is limited by serious adverseeffects, which correlate with the dose and the durationof treatment. In addition to the oral and intravenousroutes, corticosteroids can be given in enema form fortopical treatment of distal UC or CD.

The adverse systemic effects of corticosteroids haveprompted research into less toxic corticosteroid medications.Budesonide (Entocort EC) appears to havefewer systemic adverse effects because it has 90% first-passmetabolism by the liver. Although budesonide is aseffective as conventional corticosteroid treatment fordistal ileal and right colonic disease, it is less potent intransverse and distal colonic disease.42,43 As with othercorticosteroid treatments for CD and UC, budesonide isnot effective for the maintenance of remission.

Immunosuppressive Medications

The most commonly used medications in this classare azathioprine and its active metabolite 6-mercaptopurine.These medications are especially important forthe maintenance of remission in CD and UC. It maytake up to 6 months to observe a therapeutic response.7They are considered corticosteroid-sparing agentsbecause they are often used to maintain remission afterit is induced by corticosteroids. In this manner, corticosteroidsprovide coverage during the months beforethe delayed therapeutic response of azathioprine or 6-mercaptopurine occurs, and the corticosteroids can bediscontinued before their systemic toxicity accumulates.One study 44 suggested that 6-mercaptopurine iseffective in preventing postoperative recurrence in CD.

Azathioprine is a prodrug for 6-mercaptopurine,which can be converted into 6-methylmercaptopurineby the enzyme thiopurine methyltransferase (TPMT) or6-thioguanine by the enzyme hypoxanthine phosphoribosyltransferase.It is believed that 6-thioguanine isresponsible for its immunosuppressive effect and bonemarrow suppression. Most patients have wild-typeTPMT, but 11% have a heterozygous genotype withdecreased TPMT activity, and 0.3% have a homozygousgenotype with minimal TPMT activity. These patientswith decreased TPMT activity will accumulate higherlevels of 6-mercaptopurine and are more likely to haveshunting of 6-mercaptopurine toward the formation of6-thioguanine, which may accumulate and lead to bonemarrow suppression. Therefore, metabolite monitoringand enzyme genotyping may be helpful in predictingtoxicity and customizing therapy.45,46

Methotrexate is effective for induction and maintenanceof remission in CD.44,47 Cyclosporine has foundits niche in patients with severe UC.44 Approximately50% to 80% of patients refractory to intravenous corticosteroidtreatment may avoid colectomy with intravenouscyclosporine treatment.48 Uncontrolled clinicaldata have shown that cyclosporine is effective for treatingactive CD and for healing refractory CD fistulas, butcontrolled clinical trials have produced conflictingresults.49 Tacrolimus and mycophenolate mofetil areuseful second-line immunosuppressive options.

Antibiotics

pouchitis

Antibiotics probably work by changing the luminalflora and, consequently, diminishing activation of themucosal immune system. Metronidazole is effective foractive perianal and colonic CD.50 Moreover, it maydelay recurrence in CD if given for 3 months after surgicalresection and reanastomosis.51 Metronidazole isconsidered first-line therapy for a condition called,52 which is described in the "SurgicalTreatment" subsection of this section.

In open trials and a few controlled trials, ciprofloxacinhas been effective in the treatment of active CD. It isoften used in patients with perianal and fistulizing diseaseand has been used in combination with metronidazoleor as a single agent. However, the combination ofmetronidazole and ciprofloxacin has never beenshown to be more effective than either agent by itself.

Probiotics

Probiotics

Saccharomyces boulardi

Escherichia coli

One of the most interesting areas of IBD research isthe use of probiotics for the treatment of IBD. are defined as live microorganisms that havea beneficial effect on health by manipulating the microbialenvironment. By definition, this effect is beyondtheir inherent basic nutritional value.53 Lactobacilli,bifidobacteria, , nonpathogenic, enterococci, and streptococcihave been used as probiotics in various combinations.53

E coli

Streptococcus thermophilus

These beneficial effects have been proven in severalclinical studies. Nissle 1917, a probiotic formulationcontaining nonpathogenic , has been effective forthe maintenance of remission in UC.54 VSL-3, a probioticthat contains bifidobacteria, lactobacilli, and, has been effective for themaintenance of remission in UC and pouchitis.55Recently, VSL-3 has been shown to be effective for theprophylaxis of pouchitis.56 Therefore, probiotics havebeen proven to be effective in many clinical scenariosin IBD, but there is some ambiguity as to the specificways through which they are effective.

Anti-Tumor Necrosis Factor α Treatment

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

Infliximab has become an important option for thetreatment of refractory luminal and fistulizing CD.Unfortunately, 20% to 40% of patients receiving infliximabdevelop antibodies to infliximab, also known ashuman antichimeric antibodies.61-63 This antibody formationcorrelates with infusion reactions and a loss ofresponse to further treatment. Cotreatment with intravenoushydrocortisone or immunosuppressive medications,and dosing infliximab initially as infusions at 0, 2,and 6 weeks, decreases the risk of developing antibodiesto infliximab and becoming less responsive to infliximab.Therefore, it is now suggested that initialtreatment for luminal and fistulizing CD be given asinfusions at 0, 2, and 6 weeks, with some form ofimmunosuppression. Because many of the patientsreceiving infliximab have been refractory to the othertreatment options, infliximab can be used at 8-weekintervals to maintain remission in patients who remainresponsive.61-63 Infliximab treatment can be complicatedby serum sickness, hypersensitivity reaction, lupus-likereaction, and reactivation of tuberculosis.Therefore, patients should have a purified proteinderivative of tuberculin test before infliximab treatmentis initiated.61

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

Potential Treatment Options

The α4 integrins, which include α4β1 integrin andα4β7 integrin, are involved in the recruitment ofinflammatory cells. The α4β1 integrin is found onmonocytes and binds to vascular cell adhesion molecule1. The α4β7 integrin binds to mucosal addressincell adhesion molecule 1, which causes selective homingof leukocytes to intestinal tissue. These lymphocytesrelease various chemoattractant substances andresult in inflammation within the intestinal tissue.Natalizumab is a recombinant IgG4 humanized monoclonalantibody against α4 integrin. It blocks therecruitment of leukocytes. Recent placebo-controlledtrials showed a significant increase in clinical remissionwith 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 asa regulator of cellular metabolism, adipocyte differentiation,and macrophage lipid transport.67 In the colonicepithelium, it appears to have anti-inflammatory andantineoplastic activity.67 Expression of PPARγ isreduced in patients with UC, but not in patients withCD.67,68 Recent studies have demonstrated that thecommensal intestinal flora affects the expression ofPPARg in the colon68 and that PPARγ gene therapy canbe used to improve the endogenous anti-inflammatoryactivity of the colon.69 An open-label trial suggested thatrosiglitazone maleate, a PPARγ ligand, may be beneficialin patients with active UC.70 A randomized, placebo-controlledclinical trial is under way to evaluate PPARγligands in the treatment of UC that is refractory to conventionalmedical treatment.

Transdermal nicotine is effective for active left-sidedUC.18 Short-chain fatty acid enemas may be effective foractive distal UC, perhaps by providing nutrition for thedamaged colonocytes.71 There is evidence that fish oilmay be effective in treating patients with active UC andin preventing relapse in patients with CD.72,73Interleukin 10, IL-11, and anti—IL-12 have not shownany benefit in patients with CD or UC.46,61

Surgical Treatment

There are different approaches to the surgical managementof CD and UC. Because UC only involves therectum and colon, proctocolectomy is curative. In UC,there are 2 primary reasons for colectomy: malignancy(or dysplasia) and disease that is not controlled by medicaltreatment (including massive hemorrhage, perforation,toxic megacolon, and fulminant colitis).74 Years ago,total proctocolectomy with ileostomy was the surgery ofchoice. Although this surgical option is curative, thesepatients are faced with the inconvenience and comorbiditiesassociated with ileostomy care. Another option iscolectomy with ileorectal anastomosis. However, becauserectal mucosa is still present, these patients are atincreased risk of developing proctitis, and they need continuedscreening for rectal carcinoma. The most commonand popular option is ileal pouch—anal anastomosis. Inthis surgery, the ileum is formed into a pouch to maintaincontinence and attached to the anus. Pouchitis, inflammationof the ileal pouch, occurs in 20% to 50% ofpatients with an ileal pouch.75 Antibiotics and probioticsare effective treatment options for this complication.

Conversely, surgery in patients with CD is not curative.In CD, the indications for surgery are intestinalobstruction, internal fistulas or abscesses, perianal disease,toxic megacolon, severe disease refractory to medicaltherapy, malignancy (or dysplasia), and growthretardation.76 The clinical recurrence rate is approximately5% to 10% per year, and patients with CD oftenrequire repeated surgeries.76 At 10 years after their firstsurgery, 20% of these patients require another operation.The primary surgical principle in CD is to preserveas much bowel as possible because of the likelihood ofrepeated surgeries and the morbidities of short-bowelsyndrome.76 Although resection with anastomosis is themost common surgical procedure for CD strictures,strictureplasty has become an acceptable alternative forsmall-bowel strictures.23,76

CONCLUSIONS

In summary, IBD is a complicated inflammatory disease,which can affect the intestine and several extraintestinalsites. Crohn's disease and UC appear to havedifferent pathogenic mechanisms and important differencesin their clinical manifestations. Exciting developmentsin the past decade have given us a tremendousamount of insight into the pathogenesis and treatmentof CD and UC. Future research should provide us withadditional understanding of the pathogenesis of IBDand novel treatment options for this intriguing disease.

From Beth Israel Deaconess Medical Center and Harvard Medical School, Boston,Mass.

Address correspondence to: Noel B. Martins, MD, 41 Harley Drive, Apt. 10, Worcester,MA 01606. E-mail: nmartins@bidmc.harvard.edu.

J Clin Gastroenterol

1. Tremaine WJ. Collagenous colitis and lymphocytic colitis. .2000;30:245-249.

Inflammatory Bowel Disease

2. Marion JF, Rubin PH, Present DH. Differential diagnosis of chronic ulcerativecolitis and Crohn's disease. In: Kirsner JB, ed. . 5th ed.Philadelphia, Pa: WB Saunders Co; 2000:315-325.

Inflammatory Bowel Disease

3. Kirsner JB, ed. . 5th ed. Philadelphia, Pa: WBSaunders Co; 2000.

J ClinGastroenterol

4. Hay JW, Hay AR. Inflammatory bowel disease: costs-of-illness. . 1992;14:309-317.

J Clin Gastroenterol

5. Rubenstein JH, Chong RY, Cohen RD. Infliximab decreases resource use amongpatients with Crohn's disease. . 2002;35:151-156.

Gastroenterol Clin North Am

6. Loftus EV, Sandborn WJ. Epidemiology of inflammatory bowel disease.. 2002;31:1-20.

N Engl J Med

7. Podolsky DK. Inflammatory bowel disease. . 2002;347:417-429.

Gut

8. Tysk C, Lindberg E, Jarnerot G, et al. Ulcerative colitis and Crohn's disease inan unselected population of monozygotic and dizygotic twins: a study of heritabilityand the influence of smoking. . 1998;29:990-996.

N Engl J Med

9. Orholm M, Munkholm P, Langholz E, et al. Familial occurrence of inflammatorybowel disease. . 1991;324:84-88.

Nat Genet

10. Rioux JD, Daly MJ, Silverberg MS, et al. Genetic variation in the 5q31 cytokinegene cluster confers susceptibility to Crohn's disease. . 2001;29:223-228.

Gut

11. Armuzzi A, Ahmad T, Ling K-L, et al. Genotype-phenotype analysis of theCrohn's disease susceptibility haplotype on chromosome 5q31. .2003;52:1133-1139.

J Biol Chem

12. Girardin SE, Boneca IG, Viala J, et al. Nod2 is a general sensor of peptidoglycanthrough muramyl dipeptide (MDP) detection. . 2003;278:8869-8872.

Gastroenterology

13. Lala S, Ogura Y, Osborne C, et al. Crohn's disease and the NOD2 gene: a rolefor paneth cells. . 2003;125:47-57.

Infect Immun

14. Sellon RK, Tonkonogy S, Schultz M, et al. Resident enteric bacteria are necessaryfor the development of spontaneous colitis and immune system activation ininterleukin-10–deficient mice. . 1998;66:5224-5231.

Gastroenterology

15. D'Haens GR, Geboes K, Peeters M, et al. Early lesions of recurrent Crohn'sdisease caused by infusion of intestinal luminal contents into excluded ileum.. 1998;114:262-267.

Gut

16. Evans JM, McMahon AD, Murray FE, McDevitt DG, MacDonald TM. Nonsteroidalanti-inflammatory drugs are associated with emergency admission to hospitalfor colitis due to inflammatory bowel disease. . 1997;40:619-622.

Gut

17. Lindberg E, Tysk C, Andersson K, Jarnerot G. Smoking and inflammatorybowel disease: a case control study. . 1988;29:352-357.

Ann Intern Med

18. Sandborn WJ, Tremaine WJ, Offord KP, et al. Transdermal nicotine for mildlyto moderately active ulcerative colitis: a randomized, double-blind, placebo-controlledtrial. . 1997;126:364-371.

Am J Gastroenterol

19. Peeters M, Joossens S, Vermeire S, Vlietinck R, Bossuyt X, Rutgeerts P.Diagnostic value of anti–Saccharomyces cerevisiae and antineutrophil cytoplasmicautoantibodies in inflammatory bowel disease. . 2001;96:730-734.

Gastroenterol Endosc News

20. Kwon JH, Peppercorn MA, Farrell RJ. Diagnostic features of inflammatorybowel disease. . 2002;53:28-29.

Inflammatory Bowel Disease

21. Miner PB. Clinical features, course, laboratory findings, and complications inulcerative colitis. In: Kirsner JB, ed. . 5th ed.Philadelphia, Pa: WB Saunders Co; 2000:299-304.

Inflammatory Bowel Disease

22. Lashner BA. Clinical features, lab findings, and course of Crohn's disease. In:Kirsner JB, ed. . 5th ed. Philadelphia, Pa: WBSaunders Co; 2000:305-314.

Br J Surg

Br J Surg

23. Stebbing JF, Jewell DP, Kettlewell MG, Mortensen NJ. Recurrence and reoperationafter strictureplasty for obstructive Crohn's disease: long-term results [correctedtitle] [published correction appears in . 1996;83:131]. . 1995;82:1471-1474.

ClinGastroenterol

24. Fazio VW. Toxic megacolon in ulcerative colitis and Crohn's colitis. . 1980;9:389-407.

Gut

25. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerativecolitis: a meta-analysis. . 2001;48:526-535.

Gut

26. Gillen CD, Walmsley RS, Prior P, et al. Ulcerative colitis and Crohn's disease:a comparison of the colorectal cancer risk in extensive colitis. . 1994;35:1590-1592.

Gut

27. Sachar DB. Cancer in Crohn's disease: dispelling the myths [comment]. . 1994;35:1507-1508.

Gastroenterology

28. Blackstone MO, Riddell RH, Rogers BHG, Levin B. Dysplasia-associatedlesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis:an indication for colectomy. . 1981;80:366-374.

Gastroenterol Clin North Am

29. Su CG, Judge TA, Lichtenstein GR. Extraintestinal manifestations of inflammatorybowel disease. . 2002;31:307-327.

Medicine

30. Greenstein AJ, Janowitz HD, Sachar DB. The extraintestinal complications ofCrohn's disease and ulcerative colitis: a study of 700 patients. (Baltimore). 1976;55:401-412.

Gastroenterology

31. Sands BE. Therapy of inflammatory bowel disease. . 2000;118(suppl 1):S68-S82.

Acta MedScand

32. Svartz N. Salazopyrine: a new sulfanilamide preparation, A: therapeuticresults in rheumatic polyarthritis, B: therapeutic results in ulcerative colitis, C:toxic manifestations in treatment with sulfanilamide preparations. . 1942;110:577-596.

J Pharmacol Exp Ther

33. Peppercorn MA, Goldman P. The role of intestinal bacteria in the metabolismof salicylazosulfapyridine. . 1972;181:555-562.

Aliment Pharmacol Ther

34. Giaffer MH, O'Brien CJ, Holdsworth CD. Clinical tolerance to three 5-aminosalicylic acid releasing preparations in patients with inflammatory boweldisease intolerant or allergic to sulphasalazine. . 1992;6:51-59.

Gastroenterology

35. Prantera C, Cottone M, Pallone F, et al. Mesalamine in the treatment of mildto moderate active Crohn's ileitis: results of a randomized, multicenter trial.. 1999;116:521-526.

Gastroenterology

36. Sutherland LR, Martin F, Green S, et al. 5-Aminosalicylic acid enema in thetreatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.. 1987;92:1894-1898.

Gastroenterology

37. Biddle WL, Greenberger NJ, Swan JT, et al. 5-Aminosalicylic acid enemas:effective agent in maintaining remission in left-sided ulcerative colitis.. 1988;94:1075-1079.

Scand JGastroenterol

38. Campieri M, De Franchis R, Bianchi Porro G, Ranzi T, Brunetti G, BarbaraL. Mesalazine (5-aminosalicylic acid) suppositories in the treatment of ulcerativeproctitis or distal proctosigmoiditis: a randomized controlled trial. . 1990;25:663-668.

Am JGastroenterol

39. Hanauer S, Good LI, Goodman MW, et al. Long-term use of mesalamine(Rowasa) suppositories in remission maintenance of ulcerative proctitis. . 2000;95:1749-1754.

Gastroenterology

40. Green JR, Lobo AJ, Holdsworth CD, et al, Abacus Investigator Group.Balsalazide is more effective and better tolerated than mesalamine in the treatmentof acute ulcerative colitis. . 1998;114:15-22.

BMJ

41. Truelove SC, Witts LJ. Cortisone in ulcerative colitis: final report on a therapeutictrial. . 1955;2:1041-1048.

Gastroenterology

42. Greenberg GR, Feagan BG, Martin F, et al. Oral budesonide as maintenancetreatment for Crohn's disease: a placebo-controlled dose-ranging study.. 1996;110:45-51.

N Engl J Med

43. Thomson O, Cortot A, Jewell D, et al. A comparison of budesonide andmesalamine for active Crohn's disease. . 1998;339:370-374.

Am JGastroenterol

44. Sandborn WJ. A review of immune modifier therapy for inflammatory boweldisease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. . 1996;91:423-433.

Gastroenterology

45. Dubinsky MC, Lamothe S, Yang ITY, et al. Pharmacogenomics and metabolitemeasurement of 6-mercaptopurine therapy in inflammatory bowel disease.. 2000;118:705-713.

Med Clin North Am

46. Su C, Lichtenstein GR. Recent developments in inflammatory bowel disease.. 2002;86:1497-1523.

N Engl J Med

47. Feagan BG, Fedorak RN, Irvine EJ, et al, North American Crohn's StudyGroup Investigators. Comparison of methotrexate with placebo for the maintenanceof remission in Crohn's disease. . 2000;342:1627-1632.

Am J Gastroenterol

48. Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporine in ulcerative colitis:a five-year experience. . 1999;94:1587-1592.

Am J Gastroenterol

49. Egan LJ, Sandborn WJ, Tremaine WJ. Clinical outcome following treatment ofrefractory inflammatory and fistulizing Crohn's disease with intravenouscyclosporine. . 1998;93:442-448.

Gut

50. Sutherland L, Singleton J, Sessions J, et al. Double-blind placebo-controlledtrial of metronidazole in Crohn's disease. . 1991;32:1071-1075.

Gastroenterology

51. Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole treatmentfor prevention of Crohn's recurrence after ileal resection. .1995;108:1617-1621.

Dig Dis Sci

Gastroenterol Clin North Am

52. Madden MV, McIntyre AS, Nichols RJ. Double-blind crossover trial ofmetronidazole versus placebo in chronic unremitting pouchitis. .1994;39:1193-1196.53. Farrell RJ, Lamont JT. Microbial factors in inflammatory bowel disease.. 2002;31:41-62.

Lancet

54. Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon AT. NonpathogenicEscherichia coli versus mesalazine for the treatment of ulcerative colitis:a randomised trial. . 1999;354:635-639.

Aliment Pharmacol Ther

55. Venturi A, Gionchetti P, Rizzello F, et al. Impact on the composition of thefaecal flora by a new probiotic preparation: preliminary data on maintenancetreatment of patients with ulcerative colitis. . 1999;13:1103-1108.

Gastroenterology

56. Gionchetti P, Rizzello F, Helwig V, et al. Prophylaxis of pouchitis onset withprobiotic therapy: a double-blind, placebo-controlled trial. . 2003;124:1202-1209.

N Engl J Med

57. Targan SR, Hanauer SB, van Deventer SJH, et al, Crohn's Disease cA2 StudyGroup. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosisfactor α for Crohn's disease. . 1997;337:1029-1035.

Gastroenterology

58. Rutgeerts P, D'Haens G, Targan S, et al. Efficacy and safety of retreatmentwith anti–tumor necrosis factor antibody (infliximab) to maintain remission inCrohn's disease. . 1999;117:761-769.

N Engl J Med

59. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulasin patients with Crohn's disease. . 1999;340:1398-1405.

Gut

60. Probert CSJ, Hearing SD, Schreiber S, et al. Infliximab in moderately severeglucocorticoid resistant ulcerative colitis: a randomised controlled trial. . 2003;52:998-1002.

Gastroenterology

61. Sandborn WJ, Targan SR. Biologic therapy of inflammatory bowel disease.. 2002;122:1592-1608.

N Engl J Med

62. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on thelong-term efficacy of infliximab in Crohn's disease. . 2003;348:601-608.

Gastroenterology

63. Farrell RJ, Alsahli M, Jeen YT, et al. Intravenous hydrocortisone premedicationreduces antibodies to infliximab in Crohn's disease: a randomized controlledtrial. . 2003;124:917-924.

Gastroenterology

64. Sandborn WJ, Feagan BG, Hanauer SB, et al. An engineered human antibodyto TNF (CDP571) for active Crohn's disease: a randomized double-blind placebocontrolledtrial. . 2001;120:1330-1338.

Gastroenterology

65. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn's disease:a randomized, double-blind, placebo-controlled trial. . 2001;121:1088-1094.

N Engl J Med

Gastroenterology

66. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn's disease.. 2003;348:24-32.67. Wu GD. Is there a role for PPARγ in IBD? yes, no, maybe. . 2003;124:1538-1542.

Gastroenterology

68. Dubuquoy L, Jansson E, Deeb S, et al. Impaired expression of peroxisomeproliferatory–activated receptor γ in ulcerative colitis. . 2003;124:1265-1276.

Gastroenterology

69. Katayama K, Wada K, Nakajima A, et al. A novel PPARγ gene therapy to controlinflammation associated with inflammatory bowel disease in a murine model.. 2003;124:1315-1324.

Am J Gastroenterol

70. Lewis JD. An open-label trial of the PPARγ ligand rosiglitazone for activeulcerative colitis. . 2001;96:3323-3328.

Gut.

71. Breuer RI, Soergel KH, Lashner BA, et al. Short chain fatty acid rectal irrigationfor left-sided ulcerative colitis: a randomised, placebo controlled trial. 1997;40:485-491.

Am J Gastroenterol

72. Asian A, Triadafilopoulos G. Fish oil fatty acid supplementation in activeulcerative colitis: a double-blind, placebo-controlled, crossover study. . 1992;87:432-437.

N Engl J Med

73. Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Migliolo M. Effect ofan enteric-coated fish-oil preparation on relapses in Crohn's disease. . 1996;334:1557-1560.

Inflammatory Bowel Disease

74. Sachar DB. Indications for surgery in inflammatory bowel disease: a gastroenterologist'sopinion. In: Kirsner JB, ed. . 5th ed.Philadelphia, Pa: WB Saunders Co; 2000:611-615.

Inflammatory Bowel Disease

75. Dozois R, Kelly K. The surgical management of ulcerative colitis. In: KirsnerJB, ed. . 5th ed. Philadelphia, Pa: WB Saunders Co; 2000:626-657.

Inflammatory Bowel Disease

76. Strong S, Fazio V. The surgical management of Crohn's disease. In: Kirsner JB,ed. . 5th ed. Philadelphia, Pa: WB Saunders Co; 2000:658-709.