16. Enfermedad Inflamatoria Intestinal

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Review Article

Medical Progress

I

NFLAMMATORY

B

OWEL

D

ISEASE

D

ANIEL

K. P

ODOLSKY

, M.D.

From the Gastrointestinal Unit and the Center for the Study of Inflam-matory Bowel Disease, Massachusetts General Hospital and Harvard Med-ical School, Boston.

N the decades since the major forms of idiopath-ic inflammatory bowel disease were defined onthe basis of clinical manifestations, investigators

have been challenged to identify the fundamental

pathophysiologic processes underlying these enigmaticdisorders, and clinicians have struggled to provide ef-fective therapy for the often dismaying clinical man-ifestations. Clinical experience has led to the generallyaccepted notion that Crohns disease and ulcerativecolitis are distinct, if not discrete, entities. However,

whether these are fundamentally different diseases orpart of a mechanistic continuum remains an unan-swered question, with both conceptual and practicalmanagement implications.

ETIOLOGY AND PATHOPHYSIOLOGY

Inflammatory bowel disease is thought to resultfrom inappropriate and ongoing activation of the mu-

cosal immune system driven by the presence of normalluminal flora. This aberrant response is most likelyfacilitated by defects in both the barrier function ofthe intestinal epithelium and the mucosal immunesystem.

Genetic Factors

Several clinical observations suggest that geneticfactors contribute to susceptibility to inflammatorybowel disease (Table 1). These include wide variationsin the incidence and prevalence of Crohns diseaseand ulcerative colitis among different populations, co-segregation of inflammatory bowel disease in rare kin-dreds with a variety of uncommon genetic disorders,and more directly, familial aggregation of inflamma-tory bowel disease. Multiple studies have suggestedthat first-degree relatives of an affected patient havea risk of inflammatory bowel disease that is 4 to 20times as high as that among the background popu-

I

lation; the absolute risk of inflammatory bowel dis-ease is approximately 7 percent among first-degreefamily members.

1,2

A substantially higher rate of dis-ease concordance has been observed in monozygotictwins than in dizygotic twins, especially in those withCrohns disease.

1

Collectively, these findings lend compelling sup-port to the inference that susceptibility is inheritedand that the genetic contribution to the developmentof disease is more important in Crohns disease thanin ulcerative colitis. However, the absence of simplemendelian inheritance suggests that multiple geneproducts contribute to a persons risk of inflammatorybowel disease.

Over the past 15 years, a wide variety of candidategenes have been studied. Most associations identifiedbetween specific candidate genes, including major-histocompatibility-complex loci, and inflammatorybowel disease have not been reproducible, have notshed new light on pathogenesis, or have not facilitateddiagnosis.

3-5

However, substantial progress has nowbeen made with use of the less biased approach of ge-nome-wide screening with microsatellite DNA mark-ers. Screening of DNA from members of kindreds

with multiple affected members identified an area ofapparent linkage on chromosome 16 among kindreds

with Crohns disease but not those with ulcerativecolitis.

6

Although the relative risk associated withthis putative locus, designated IBD1,

was small, theassociation was replicated in all but one independentstudy. These studies also provided evidence that in-flammatory bowel disease is linked to several othergenomic regions.

7-10

Most of these sites are equallylinked to both major forms of inflammatory boweldisease, suggesting that Crohns disease and ulcerativecolitis share many common genetic and, therefore,mechanistic features.

Detailed mapping of chromosome 16 has recentlyresulted in the identification of a gene responsible,at least in part, for this linkage.

11,12

This gene encodesa cytoplasmic protein designated NOD2 (also referredto as CARD 15 [caspase activation and recruitmentdomain]), which is expressed in macrophages and mayserve as a so-called pattern-recognition receptor forbacterial lipopolysaccharide, perhaps regulating nu-clear factor-

k

B activation and macrophage apoptosis.European and North American patients with Crohnsdisease, including those without a family history ofinflammatory bowel disease, are more likely to have

variants of NOD2 than are persons without Crohnsdisease. Paradoxically, these NOD2 variants appear

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Copyright 2002 Massachusetts Medical Society. All rights reserved.


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The New England Journal of Medic ine

to result in reduced macrophage activation of nucle-ar factor-

k

B in response to lipopolysaccharide. Per-sons who are homozygous for variant NOD2 mayhave a 20-fold or more increase in susceptibility toCrohns disease, with a particular predilection for il-eal disease.

13-15

Heterozygotes are also at increasedrisk. However, fewer than 20 percent of patients withCrohns disease are homozygous for these NOD2

variants. A putative locus associated with early-onsetCrohns disease appears to be present on chromo-some 5 in the vicinity of genes encoding a varietyof cytokine receptors.

16

Environmental Precipitants and Disease Cofactors

Whatever part genetic loci play in conferring sus-ceptibility to inflammatory bowel disease, studies ofidentical twins (in which only 45 percent of pairsof identical twins are concordant for Crohns disease)make it clear that the development of disease dependson additional factors. Among myriad factors studied,the most consistent are the use of nonsteroidal anti-

inflammatory drugs, which can lead to disease flares,possibly related to an altered intestinal barrier, andearly appendectomy, which is associated with a re-duced incidence of ulcerative colitis.

17,18

Smoking maymodify the phenotype; it protects against ulcerativecolitis but increases the risk of Crohns disease.

19,20

Accumulating evidence suggests that the luminalflora is a requisite and perhaps central factor in thedevelopment of inflammatory bowel disease. This in-ference is supported by studies in murine models ofcolitis established through genetic manipulation andreinforced by a variety of clinical observations in pa-tients (Table 2). For example, the development ofspontaneous colitis in rats and mice appears to re-quire the presence of luminal flora; colitis does notoccur in any of several mutant strains when they aremaintained in a germ-free environment, but it devel-ops rapidly when these mice are colonized by com-mensal bacteria.

21,22

Studies of murine models resonate with clinicalexperience. Broad-spectrum antibiotics and probiot-

*Although HLA antigens have been studied extensively, the resulting associations have been vari-ably reproducible.

The IBD1 locus encodes NOD2(also designated CARD 15

).

T

ABLE

1. E

VIDENCE

OF

G

ENETICALLY

D

ETERMINED

S

USCEPTIBILITY

TO

I

NFLAMMATORY

B

OWEL

D

ISEASE

.

Human studies

The prevalence varies among different populations.

The risk is increased among first-degree relatives of affected patients.

There is greater concordance among monozygotic than dizygotic twins.

Syndromes resembling inflammatory bowel disease cosegregate in families with rare genetic disorders(e.g., glycogen storage disease type IB, WiskottAldrich syndrome, HermanskyPudlaksyndrome).

There is usually concordance in the type and site of disease among members of families with multipleaffected members.

Numerous candidate genes have been identified with putative allelic associations with inflammatorybowel disease, including genes that encode HLA antigens,* tumor necrosis factor (promoter-sequence polymorphisms), mucin, interleukin-10, interleukin-1receptor antagonist, intercellu-lar adhesion molecule 1, kinin B1, inhibitor ofk

B kinase, and natural-resistanceassociated mac-rophage protein 2.

Screening with microsatellite DNA markers has identified genomic linkage on chromosomes 16(

IBD1

locus; linkage with Crohns disease only), 3, 5, 7, 12 (linkage with ulcerative colitis only),18, and 19 and the X chromosome.

Animal studies

Experiments in rodent lines with genetic alterations conferred by transgenic or gene-deletiontechniques led to the heritable development of inflammatory bowel diseaselike colitis.

Transgenic overexpression or deletion of a single gene by means of homologous recombination canlead to inflammatory bowel disease.

The phenotype resulting from a single genetic alteration is modulated by other genetic loci (e.g., theseverity and age at onset vary depending on the background strain).

No single gene is uniquely associated with the development of inflammatory bowel disease; colitisresults from alterations in a subgroup of genes that encode proteins involved in either the epi-thelial mucosal barrier or the mucosal immune response.

Genetic alteration confers susceptibility but is not sufficient to result in disease (e.g., mutant murinelines maintained in a germ-free state do not manifest inflammatory bowel disease).

Commensal bacteria are required for the development of inflammatory bowel disease in susceptiblehosts.




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ics have proven clinical efficacy in specific subgroupsof patients. Studies have demonstrated the presenceof an increased number of surface-adherent and intra-cellular bacteria in the colonic epithelium of patients

with inflammatory bowel disease.

23,24

Such observa-tions underscore the importance of further definingthe mechanisms of interaction between the normalmucosa and luminal microflora and their alterationin association with inflammatory bowel disease.

Immune Response and Inflammatory Pathways

The aggregate effect of genetic, environmental, andother processes is the sustained activation of mucosalimmune responses (Fig. 1). It remains unclear whetherthe immune system is activated as a result of an intrin-

sic defect (either constitutive activation or the failureof down-regulatory mechanisms) or because of con-tinued stimulation resulting from a change in theepithelial mucosal barrier.

25,26

Substantial progress has been made in character-izing immune-cell populations and inflammatory me-diators in patients with inflammatory bowel diseaseand murine models.

22,27

There is reasonable consensusthat the mucosa of patients with established Crohnsdisease is dominated by CD4+ lymphocytes with atype 1 helper-T-cell (Th1) phenotype, characterizedby the production of interferon-

g

and interleukin-2.In contrast, the mucosa in patients with ulcerative coli-tis may be dominated by CD4+ lymphocytes with anatypical type 2 helper-T-cell (Th2) phenotype, char-

T

ABLE

2. K

EY

F

EATURES

OF

M

AJOR

F

ORMS

OF

I

NFLAMMATORY

B

OWEL

D

ISEASE

.

F

EATURE

U

LCERATIVE

C

OLITIS

C

ROHN

S

D

ISEASE

Clinical features

FeverAbdominal painDiarrheaRectal bleeding

Weight lossSigns of malnutritionPerianal disease

Abdominal massGrowth failure in children and adolescents

Fairly commonVariesVery commonVery commonFairly commonFairly common

AbsentAbsentOccasional

CommonCommonFairly commonFairly commonCommonCommonFairly commonCommonCommon

Site

ColonIleumJejunumStomach or duodenumEsophagus

ExclusivelyNeverNeverNeverNever

2/3 of patients2/3 of patientsInfrequentInfrequentInfrequent

Intestinal complications

Stricture

FistulasToxic megacolonPerforationCancer

Unknown

AbsentUnknownUnknownCommon

Common

Fairly commonAbsentUncommonFairly common

Endoscopic findings

FriabilityAphthous and linear ulcersCobblestone appearancePseudopolypsRectal involvement

Very commonAbsentAbsentCommon

Very common

Fairly commonCommonCommonFairly commonFairly common

Radiologic findings

Distribution

Ulceration

FissuresStrictures or fistulas

Ileal involvement

Continuous

Fine, superficial

AbsentRare

Dilated (backwash ileitis)

Discontinuous, seg-mented

Deep, with submucosalextension

CommonCommon

Narrowed, nodular

Laboratory findings

Perinuclear-staining antineutrophilcytoplasmic antibodies

Anti

Saccharomyces cerevisiaeantibodies

70% of patients

Occasional

Occasional

50% of patients




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acterized by the production of transforming growthfactorb

(TGF-

b

) and interleukin-5 but not interleu-kin-4.

28

In murine models, the effects of the activationof Th1 cells may be enhanced by the concomitantdecrease in subgroups of suppressor T cells, variouslydesignated Th3 or Tr1, which produce the down-reg-ulatory cytokines interleukin-10 and TGF-

b

.

29

In-depth characterization of murine lines suggests

that the stereotypical Th1 cytokines activate macro-phages, which in turn, produce interleukin-12, inter-leukin-18, and macrophage migration inhibitor factorand thus further stimulate Th1 in a self-sustainingcycle. Just as important, activated macrophages pro-duce a potent mix of broadly active inflammatorycytokines, including tumor necrosis factor (TNF),interleukin-1, and interleukin-6.

Figure 1.

Pathogenesis of Inflammatory Bowel Disease.

Normal epithelium, with its highly evolved tight junctions and products of goblet-cell populations, most notably trefoil peptides

and mucin glycoproteins, provides an effective barrier against luminal agents. The integrity of the barrier may be compromised bygenetic variations in key molecular determinants, a diminished reparative response to injury, or exogenous agents, such as non-steroidal antiinflammatory drugs. Chronic, recurrent intestinal inflammation appears to result from stimulation of the mucosal im-

mune system by products of commensal bacteria in the lumen. Antigens from dietary sources may also contribute. Stimulation

may occur as a result of the penetration of bacterial products through the mucosal barrier, leading to their direct interaction withimmune cells, especially dendritic cells and lymphocyte populations, to promote a classic adaptive immune response. Alternatively,

bacterial products may stimulate the surface epithelium, possibly through receptors that are components of the innate immune-response system; the epithelium can, in turn, produce cytokines and chemokines that recruit and activate mucosal immune cells.Activation of classic antigen-presenting cells, such as dendritic cells, or direct stimulation through pattern-recognition receptors

promotes the differentiation of type 1 helper T cells (Th1) in patients with Crohns disease (shown here) or, possibly, atypical type 2helper T cells in patients with ulcerative colitis. The stereotypical products of Th1 promote a self-sustaining cycle of activation withmacrophages. In addition to producing the key cytokines that stimulate Th1 (interleukin-12, interleukin-18, and macrophage migra-

tion inhibitor factor), macrophages produce a mix of inflammatory cytokines, including interleukin-1, interleukin-6, and most nota-bly tumor necrosis factor, which target a broad variety of other types of cells. The latter include endothelial cells, which then facil-itate the recruitment of leukocytes to the mucosa from the vascular space, as well as fibroblasts and epithelium, modulating their

functional properties. Most important, these functions may be altered either by genetically determined variants, as exemplified bygerm-line mutations in the gene encoding NOD2, the product of the IBD1 locus, in some patients with Crohns disease, or by envi-ronmental factors.

Epithelial

barrier

Normal epithelium

Tumor necrosis factor

Interleukin-1

Interleukin-6

Interferon-

Macrophagemigration inhibitorfactor

Interleukin-12

Interleukin-18

Macrophage

Bacteria Type 1 helperT cell

Antigen-presenting

cell




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The activation of central immune-cell populationsis eventually accompanied by the production of a wide

variety of nonspecific mediators of inflammation (Fig.2). These include many other cytokines, chemokines,and growth factors as well as metabolites of arachi-

donic acid (e.g., prostaglandins and leukotrienes) andreactive oxygen metabolites such as nitric oxide.

24,27

These mediators enhance the inflammatory processitself and tissue destruction, which eventuate in theclinical manifestations of disease. Recruitment of ad-ditional leukocytes from the vascular space to sitesof disease activity is especially important in maintain-ing inflammation and depends on the expression ofadhesion molecules in the local microvasculatureand counterligands on the various leukocyte popu-lations.

30,31

TREATMENT

Treatment must begin with accurate diagnosis. The

diagnosis of inflammatory bowel disease depends onthe aggregate constellation of the clinical history,physical findings, and endoscopic, radiologic, and his-tologic features, as well as the results of routine lab-oratory tests (Table 2). Typically, these features per-mit a firm diagnosis of inflammatory bowel diseaseand distinction between ulcerative colitis and Crohnsdisease. However, in as many as 10 percent of pa-tients with inflammatory bowel disease that is limitedto the colon, it may not be possible to distinguishulcerative colitis from Crohns disease, at least initially;thus, these patients are considered to have indeter-minate colitis. Serologic markers, including perinu-clear-staining antineutrophil cytoplasmic antibodies,

present in up to 70 percent of patients with ulcerativecolitis, and anti

Saccharomyces cerevisiae

antibodies,present in 50 percent or more of those with Crohnsdisease.

32-35

Although these markers may help in thedifferential diagnosis of the few patients in whom thenature of colitis cannot be determined according tothe usual criteria, they are not recommended for rou-tine diagnosis.

The long-term management of inflammatory bow-el disease must be multidimensional and governed bythe type of disease and sites involved (Table 3). Ad-

junctive agents, such as antidiarrheal agents, that aredirected primarily at relieving symptoms rather thancontrolling inflammation itself can be important. El-emental diets have also been advocated as a primarytreatment for Crohns disease, but patients poor com-pliance often limits the practicality of this approach.

35,36

Proper nutrition and attention to related secondarycomplications such as osteoporosis resulting from mal-absorption, corticosteroid therapy, or both are alsoimportant. Supplemental nutrition is especially im-portant in the treatment of growth failure in children.Surgery can have an important role in management,

though a full consideration is beyond the scope of thisreview.

Notwithstanding the importance of other treat-ments, an expanding number and variety of drugsthat target the inflammatory processes broadly or se-

lectively are usually effective in controlling active dis-ease in most patients and in sustaining symptomaticremission for prolonged periods in many. In general,most clinicians use a stepped approach to therapy in

which more potent agents are added to the regimenif less active drugs fail to achieve an adequate response.

5-Aminosalicylic Acid

The 5-aminosalicylatebased compounds have re-mained mainstays of treatment for patients with mildto moderately active ulcerative colitis and Crohnsdisease since the recognition of the therapeutic effi-cacy of the prototypical agent sulfasalazine (see Sup-plementary Appendix 1, available with the full text

of this article at http://www.nejm.org). Early studiesdemonstrated that 5-aminosalicylate was the func-tionally active moiety of this sulfapyridine congener.5-Aminosalicylate may act by blocking the productionof prostaglandins and leukotrienes, inhibiting bacterialpeptideinduced neutrophil chemotaxis and adeno-sine-induced secretion, scavenging reactive oxygenmetabolites, and perhaps inhibiting the activation ofnuclear factor-

k

B.Over the past 15 years, a variety of newer 5-ami-

nosalicylatebased compounds have become avail-able.

37-43

In general, a 5-aminosalicylatebased agentshould be selected principally on the basis of diseaselocation. For patients with distal colonic disease, a sup-

pository or enema form will be most appropriate. Oralcompounds in which 5-aminosalicylic acid (mesal-amine) is conjugated to prevent absorption by thesmall bowel are appropriate for colonic disease. Theseinclude sulfasalazine, olsalazine (a 5-aminosalicylic aciddimer), and the recently approved balsalazide. Topicalformulations may be used alone or in combination

with oral formulations for patients with left-sidedcolonic disease. Oral formulations in which 5-amino-salicylic acid is in a slow-release or pH-dependent ma-trix can deliver therapeutic concentrations to the moreproximal small bowel or distal ileum, respectively, toexpand the spectrum of patients with Crohns disease

who may be treated with this class of agent. Mainte-nance treatment with a 5-aminosalicylic acid can beeffective for sustaining remission in ulcerative colitisbut is of questionable value in Crohns disease.

Corticosteroids

Corticosteroids have been commonly used when5-aminosalicylatebased compounds are inadequate.They presumably act through the same functionalproperties relevant to other inflammatory processes,




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though which among these may be especially impor-tant in inflammatory bowel disease has not been de-termined.

Topical corticosteroids (hydrocortisone enemas orfoam) can be used as an alternative to 5-aminosalicy-latebased compounds for patients with ulcerative

proctitis or distal ulcerative colitis. Oral prednisoneor prednisolone is used for moderately severe ulcer-ative colitis or Crohns disease, in doses ranging upto 60 mg per day for patients with the most severedisease. Intravenous administration is warranted forpatients who are sufficiently ill to require hospital-

Figure 2.

Common Cellular Pathways of Activation in Inflammatory Bowel Disease.

Activation of the protean transcriptional regulatory factor nuclear factor-

k

B (NF-

k

B) is acommon pathway central to cell activation and the production of diverse inflammatory me-

diators, including a variety of cytokines and chemokines. It also modulates resistance toprogrammed cell death (apoptosis). Several inflammatory factors implicated in inflamma-tory bowel disease activate NF-

k

B by eventually stimulating an intermediate kinase suchas NF-

k

Binducing kinase (NIK) or mitogen-activated protein kinase kinase 1 or 3 (MEKK1

or MEKK3) or by binding to receptor-interacting protein 2. These lead to phosphorylation ofthe inhibitor ofkB kinase (IKK) and subsequent dissociation of NF-kB (itself a dimer). NF-kBthen travels to the nucleus, where it can effect gene transcription. The phosphorylated con-

stituents are subject to degradation by proteosomes after ubiquitination. The spectrum ofmediators that activate this pathway includes inflammatory cytokines such as interleukin-1and tumor necrosis factor (TNF), which bind to their respective cell-surface receptors, as

well as microbial products such as lipopolysaccharide, which bind to cell-surface receptorsthat are members of the toll-like receptor family of pattern-recognition receptors. The path-way is also activated by NOD2 (also referred to as CARD 15), an intracytoplasmic receptor

that is activated by the entry, through mechanisms yet to be defined, of bacterial lipopoly-saccharide into the cytoplasm. NOD2 is the product of the IBD1 gene; germ-line mutations,

which are present in many patients with Crohns disease, appear to alter the activation ofthe NF-kB pathway. MyD88 denotes myeloid differentiation factor 88.

Bacterial

lipopolysaccharide

Geneenetranscriptionranscription

InterleukinsnterleukinsCytokinesytokinesChemokineshemokines

NF-F-B

NOD2OD2MyD88yD88MyD88MyD88

Toll-like

receptor

TNF and

receptor

Interleukin-1

and receptor

Antiapoptosis

Gene

transcription

Interleukins

Cytokines

Chemokines

NF-B

IBIB

NOD2

NIK, MEKK1,IK, MEKK1,or MEKK3r MEKK3NIK, MEKK1,or MEKK3

IKKKKcomplexomplexIKKcomplex

Receptor-interactingeceptor-interactingprotein 2rotein 2Receptor-interactingprotein 2




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ization; the majority of such patients, even those withfulminant ulcerative colitis, will have a response with-in 7 to 10 days. Optimal administration schedules foreither oral or intravenous corticosteroids have notbeen defined. Corticosteroids, irrespective of the routeof administration, should be continued only as longas needed to control acute inflammatory activity, sincethey have no proven maintenance benefit in the treat-ment of either ulcerative colitis or Crohns disease.Optimal tapering schedules have not been definedand are generally guided by clinical experience.44

Although corticosteroids are frequently, thoughnot invariably, effective, these effects must be balancedagainst their many and often serious side effects. Ingeneral, side effects correlate with the dose and du-ration of treatment. Some side effects may be partiallyoffset by careful management (e.g., early administra-tion of supplemental calcium, vitamin D, and bisphos-phonates to reduce corticosteroid-induced osteoporo-sis and careful monitoring of blood pressure and bloodglucose for corticosteroid-induced hypertension anddiabetes). For some patients, the side effects may bepartially circumvented by the use of budesonide, whichhas recently become available in the United States ina controlled-ileal-release formulation; an enema formis also available elsewhere.45-47 However, concern per-sists that patients who take budesonide for prolongedperiods remain at risk for systemic side effects; al-though first-pass metabolism may eliminate more than90 percent of the drug, budesonide has an affinity forthe glucocorticoid receptor that is 50 to 100 timesthat of prednisone. Moreover, its use is limited primar-ily to patients with distal ileal and right-sided colonic

disease, and its efficacy somewhat less than that of con-ventional corticosteroids.

Immunosuppressive and Immunoregulatory Agents

There is an expanding role for immunomodulatorydrugs in the care of patients with inflammatory boweldisease. These agents are generally appropriate for pa-tients in whom the dose of corticosteroids cannot betapered or discontinued. All these agents (as well ascorticosteroids) put patients at risk for opportunisticinfections.

Azathioprine and its active metabolite mercapto-purine have been the most extensively used immuno-suppressive agents, despite early hesitation arising fromconcern about an increased risk of lymphoma and oth-er side effects. Indeed, this issue remains unresolved,in part owing to uncertainty about the possibility ofa small, underlying increase in the risk of lymphomain patients with inflammatory bowel disease.48-50 Theactual mechanisms of action responsible for the ther-apeutic effect of these drugs remain largely unknownbut may include suppressing the generation of a spe-cific and long-lived subgroup of T cells, which mightaccount for the prolonged time needed to achieve atherapeutic response.

Clinical studies have shown that these agents areefficacious when they are given in adequate doses inpatients with ulcerative colitis or Crohns disease, al-lowing a gradual decrease in the corticosteroids andprolonging remission.51-53 The onset of benefit typ-ically takes several weeks and may require up to sixmonths, so that these drugs are not useful in the con-trol of acute disease activity and, conversely, should

TABLE 3. THERAPEUTIC OPTIONSFOR ULCERATIVE COLITISAND CROHNS DISEASE.

VARIABLE DISTAL ULCERATIVE COLITIS EXTENSIVE ULCERATIVE COLITIS CROHNS DISEASE

Mild disease Oral or rectal aminosalicylates Oral aminosalicylates Oral aminosalicylatesRectal corticosteroids Oral metronidazolePossibly oral budesonide or ciprofloxacin

Moderate disease Oral or rectal aminosalicylatesRectal cort icosteroids

Oral aminosalicylates Oral corticosteroids (budesonide for ilealor right-sided colonic disease)

Oral azathioprine or mercaptopurine

Severe disease Oral or parenteral corticosteroids Oral or parenteral corticosteroids Oral or parenteral corticosteroidsRectal corticosteroids Intravenous cyclosporine Subcutaneous or intravenous methotrexate

Intravenous infliximab

Refractory disease Oral or intravenous corticosteroids,in addition to oral azathioprine ormercaptopurine

Oral or intravenous cor ticosteroids,in addition to oral azathioprine ormercaptopurine

Intravenous infliximab

Perianal disease Oral antibiotic (metronidazole or cipro-floxacin)

Intravenous infliximabOral azathioprine or mercaptopurine

Remission Oral or rectal aminosalicylatesOral azathioprine or mercaptopurine

Oral aminosalicylatesOral azathioprine or mercaptopurine

Possibly oral azathioprine or mercaptopur-ine, mesalamine, metronidazole

Oral azathioprine or mercaptopurine




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be used only when prolonged therapy is planned.Although no firm guidelines for initiating the use ofthese agents have been established, many cliniciansconsider their use if it has not been possible to weanpatients from corticosteroids after six weeks.

Toxic effects, some quite serious, frequently limit theuse of azathioprine and mercaptopurine. Dose-relat-ed suppression of bone marrow is uniformly observed,and the white-cell count must be monitored closely

when therapy is initiated and periodically thereafter(typically every two to three months). Considerableprogress has been made in delineating the pathwaysof metabolism of mercaptopurine, and these findingshave highlighted the importance of genetic variants ofthe key enzyme thiopurine S-methyltransferase in de-termining susceptibility to life-threatening bone mar-row suppression.54-56 Approximately 0.1 percent of pa-tients are homozygous for a functionally null allele thatleads to the accumulation of toxic metabolites derived

from alternative degradative pathways. Neither bloodcounts nor metabolite concentrations reliably predictother toxic effects, which include pancreatitis anddrug-induced hepatotoxicity. In both instances, theseinitially asymptomatic effects are usually reversible withdiscontinuation of the medication and rapidly recur

with greater severity if treatment is resumed.Methotrexate is effective in the treatment of cor-

ticosteroid-dependent active Crohns disease and inmaintaining remission.57-59 Typically, the drug is ad-ministered as a weekly injection, either intramuscu-lar (15 mg per week) or subcutaneous (25 mg per

week), and the response becomes evident over a pe-riod of several weeks. The mechanism of action of

this agent also remains mostly uncertain. Aside fromthe generic risks of immunosuppression, methotrex-ate may lead to interstitial pneumonitis, which is firstmanifested by nonproductive cough and dyspnea,and there is a dose-related risk of hepatic fibrosis.

Cyclosporine can be effective in the treatment ofpatients with severe ulcerative colitis who are hospi-talized and otherwise in need of urgent proctocolec-tomy.60-62 This agent is presumed to work by block-ing lymphocyte activation. High doses can achieve atleast short-term control of disease sufficient to allowup to 80 percent of hospitalized patients who havebeen unresponsive to corticosteroids to be switchedto a tapering oral regimen of cyclosporine. Cyclospor-ine is usually added after an initial 7-to-10-day trialof intravenous high-dose corticosteroids. A recentstudy has shown essentially equivalent response ratesin patients given either cyclosporine or corticoster-oids as initial intravenous therapy after hospitaliza-tion.62 Although, as noted above, short-term controlof disease will result from the addition of cyclospor-ine in a substantial number of patients, approximately50 percent will undergo proctocolectomy within a

year as a result of either the inability to taper medi-cations or recurrent disease activity. Azathioprine ormercaptopurine may help sustain the cyclosporine-induced response. In general, cyclosporine should notbe used in the treatment of patients with Crohns

disease, with the possible exception of patients withsymptomatic and severe perianal or cutaneous fistu-las.63 Recent trials have suggested that the related com-pound tacrolimus, as well as mycophenolate mofetil,is also effective in the treatment of patients with in-flammatory bowel disease, though direct comparativestudies with cyclosporine have not been carried out.

Anti-TNF Therapy

The availability of the prototypical anti-TNF agentinfliximab has offered an important advance in ther-apy for patients with Crohns disease.64 Infliximabsmechanism of action is incompletely understood. Itseffectiveness suggests that TNF, a product of activat-

ed macrophages, may have a pivotal role among themany regulatory peptides with altered expression inassociation with inflammatory bowel disease.65,66 Thischimeric monoclonal antibody, composed of a com-plement-fixing human IgG1 constant region and amurine-derived antigen-binding variable region, bindssoluble TNF; however, its action is thought to de-pend in part on its ability to bind precursor cell-sur-face TNF, perhaps leading to monocyte apoptosis.

Two pivotal trials demonstrated the efficacy of in-fliximab in patients with Crohns disease.67,68 In thefirst, approximately two thirds of patients with mod-erately active Crohns disease who received a singleinfusion of infliximab had a significant reduction in

their score on a standard Crohns Disease ActivityIndex; of these, approximately half (one third of thetotal) achieved actual clinical remission. The response

was generally quite prompt (usually within two weeks).However, the durability of the response ranged froma few weeks to six months or more. This pattern ofresponse was mirrored in the second reported studyin which patients with perianal and cutaneous fistu-las received three infusions over a period of six weeks.Since this drug was approved for use in the UnitedStates, the experience in treating patients in routinepractice has largely resembled that observed in con-trolled studies.69-71

Important questions remain to be addressed to de-fine the most appropriate use of infliximab. Recentlycompleted trials suggest the effectiveness of serial ad-ministration of the drug to maintain the initial re-sponse, but this indication is not yet approved.72 Fur-thermore, although responses have been reported insmall numbers of patients with a variety of other in-testinal inflammatory conditions (e.g., Behets syn-drome), the usefulness of infliximab in patients withulcerative colitis remains uncertain.




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The optimal timing of infliximab administrationand the value of maintenance therapy must be deter-mined in rigorous studies, for several reasons. First,patients may not remain responsive to infliximab ther-apy indefinitely, and in some, the duration of responseafter an infusion becomes progressively shorter. Sec-ond, some patients who received infliximab during tri-als and who resumed treatment after a prolonged hia-tus had a serum sicknesslike reaction, suggesting that

the drug should not be used intermittently. Collec-tively, these two observations necessitate judicious useof this agent in patients with a lifelong condition.Third, the therapy is quite costly in terms of boththe cost of the drug itself and the logistics of infusingit (the average third-party reimbursement per dose ad-ministered to a 70-kg patient is more than $5,200).Fourth, though it is generally safe, serious complica-tions can ensue. In addition to occasional hypersensi-

TABLE 4. POTENTIAL THERAPEUTIC AGENTSFOR INFLAMMATORYBOWEL DISEASE.

AGENT RATIONALEOR TARGET STATUS

Growth hormone Stimulates production of insulin-likegrowth factor 1; trophic for theintestinal mucosa

Superior to placebo in patients withactive Crohns disease in a singletrial

Heparin Binds relevant growth factors (e.g.,fibroblast growth factor); blocksprothrombotic state; has anti-thrombotic activity

Some activity in suppressing activeulcerative colitis in multiple trials

Fish oil Modulates metabolism of arachidonicacid and its products

Reduced postoperative recurrenceof Crohns disease over a 2-yearperiod in a controlled trial

Nicotine patch Agent in tobacco that may accountfor the protective effect of smokingin patients with ulcerative colitis

Reduced some symptoms of ulcer-ative colitis but caused no objectivechanges in a controlled trial

Thalidomide Inhibits intracellular processingof tumor necrosis factor

Response in patients with activeCrohns disease in two pilot trials

Short-chain fattyacids

Presumptive optimal metabolic fuelfor colonic epithelium

Enema formulation improved distalulcerative colitis; results vary

Elemental diet Modulates antigenic load either di-

rectly or through altered flora

Improvement in active Crohns dis-

ease in multiple studiesMycophenolate

mofetilInhibits pathogenic T cell s Response in pat ients with Crohns

disease, but not ulcerative colitis, insmall series and controlled trials

Tacrolimus Inhibits activation pathways in lym-phocytes and other cell popula-tions

Benefit similar to that afforded by cy-closporine in small series; healingof fistulas

Interleukin-11 Enhances epithelial integrity Phase 23 studies in patients withCrohns disease

Interleukin-10 Down-regulates lymphocyte activa-tion

Minimal activity in patients withCrohns disease in phase 3 trials

Antiinterferon-g Antagonizes activation of macro-phages by interferon-g

Phase 2 trial in patients with Crohnsdisease

Antiinterleukin-12 Antagonizes interleukin-12 activationof type 1 helper T cells

Phase 2 studies in patients withCrohns disease

Keratinocyte growthfactor

Stimulates epithelial proliferation andrepair

Phase 2 studies in patients with ulcer-ative colitis

p38 Inhibitor Inhibits signal pathway leading tonuclear factor-kB Phase 12 studies in patients withCrohns disease

Antia4 integrin Inhibits leukocyte recruitment Variable activity in pat ients withCrohns disease in phase 3 studies

Antia4b7 integrin Inhibits leukocyte recruitment Phase 3 studies in patients with ulcer-ative colitis and Crohns disease

Bactericidalperme-ability-increasingprotein

Inhibits bacterial stimulation Phase 2 studies in patients withCrohns disease

Rosiglitazone Inhibits peroxisome-proli feratoractivated receptor-g

Phase 2 trial in patients with ulcer-ative colitis

Probiotic mixture Replaces pathogenic endogenousflora

Prevented pouchitis in studies ofpatients with ulcerative colitis; re-duced activity in Crohns disease




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tivity and infusion reactions, a number of deaths havebeen reported as a result of tuberculosis or sepsis.Complications have included the reactivation of tuber-culosis with atypical features; thus, all patients shouldbe screened for tuberculosis before beginning therapy.

Although a lupus-like syndrome has been reported in-frequently after treatment with infliximab, the clinicalsignificance of the more frequently detected antinucle-ar antibodies and antichimeric monoclonal antibodiesis uncertain. Finally, lymphoma has developed in asmall number of patients receiving infliximab, thougha causal relation has not been established.

A number of other agents that target TNF are inadvanced stages of clinical evaluation. These includeCDP571, a humanized monoclonal antibody in whichonly the small number of residues necessary to conferantigen specificity remain from the original murineantibody. The overall usefulness of CDP571 in clin-ical trials involving patients with active Crohns dis-

ease appears to be generally similar to that observedwith infliximab.73,74 These results contrast with thevery limited efficacy of etanercept, a fusion proteincomposed of the ligand-binding domain of the solu-ble receptor for TNF and an IgG common region, inpatients with Crohns disease.75

There has been recent interest in the use of thalid-omide in the treatment of Crohns disease, because ofits presumptive action in blocking the production ofTNF through the inhibition of intracellular path-

ways.76 Two small pilot trials have suggested thera-peutic effectiveness.77,78 However, given the infamoushistory of this agent as a teratogen, its use requiresrigorous supervision, including confirmation of ade-

quate contraception in patients of childbearing age.

Antibiotics and Probiotics

Empirical clinical experience has led to the recog-nition that antibiotics are useful in the treatment ofsubgroups of patients with Crohns disease.79 In con-trast, antibiotics have very limited use in patients withulcerative colitis, suggesting a differential role of theluminal flora in the two forms of inflammatory boweldisease.80 Metronidazole can be effective in the treat-ment of patients with Crohns disease who have per-ianal fistulas. However, high doses are usually neces-sary (up to 750 mg three times daily), and the sideeffects may be limiting, most notably neurotoxicity.Despite its lack of effectiveness in the treatment ofulcerative colitis, metronidazole can control colonic(but not small-bowel) Crohns disease. Ciprofloxacinand clarithromycin have been advocated as alterna-tives to metronidazole, but only small trials have beenreported.

The effectiveness of nonspecific antibiotics and ex-perimental evidence of the central role of the lumi-nal flora as an essential cofactor for the development

of disease in the susceptible host have provided animpetus to the development of alternative strategiesto manipulate the intestinal flora for therapeutic ben-efit. Probiotics, the administration of healthy bac-teria, appears to be one promising approach.81 Pa-

tients with pouchitis or active Crohns disease whowere treated with a mixture of commensal bacteriahad a positive therapeutic response; these findingsshould prompt increased efforts to define the valueof this approach, which could be free of systemic sideeffects.82

Investigational Agents

Advances in the understanding of the pathophys-iology of inflammatory bowel disease, even if theyare still incomplete, have led to great interest in theevaluation of a variety of new therapeutic agents withnovel actions (Table 4). The explication of the cyto-kine network in inflammatory bowel disease and the

seemingly central role of macrophage-produced in-terleukin-12, as described above, have led to ongoingtrials with antibodies against interleukin-12. Interleu-kin-10, a cytokine that generally down-regulates theactivation of Th1 cells, was found to have minimalactivity in Crohns disease.83-85 Preliminary studies ofinterleukin-11, a cytokine that is thought to act byenhancing the epithelial barrier as well as through theinhibition of inflammatory cytokines, showed an ap-parent benefit. Larger trials of interleukin-11 in pa-tients with ulcerative colitis and Crohns disease arein progress.86

Strategies that block the recruitment of leukocytesto the sites of mucosal inflammation have produced

promising results for example, a large-scale studyof patients with Crohns disease who were treated

with a monoclonal antibody directed against the a4integrin subunit. This integrin is part of a heterodimerthat functions as a homing molecule for mucosal lym-phocytes.87 Studies in both patients with ulcerativecolitis and those with Crohns disease are also under

way after the demonstration, in pilot studies, that achimeric antibody specific for the a4b7 integrin het-erodimer reduced disease activity in patients withmoderate-to-severe ulcerative colitis.88

Increasing attention is being directed at efforts toblock the intracellular signaling pathways central tothe activation of lymphocytes and macrophages withthe use of p38 antagonists and agents that target thetranscription factor nuclear factor-kB. A few patientshave already received a p38-blocking small molecule,

with apparent benefit. However, most of these agentsare in a relatively early stage of development,89 andthe overall safety of disrupting ubiquitous signalingmechanisms remains to be determined. In addition,a variety of more conventional agents, includinggrowth hormone,90 transdermal nicotine,91 fish oil,92




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and rosiglitazone,93 have been found to have someeffect in trials of variable sizes (Table 4). Finally, sev-eral patients with Crohns disease had a prolongedremission after undergoing allogeneic bone marrowtransplantation for unrelated reasons; this effect was

presumably the result of reconstitution with non-pathogenic T cells.94 However, this approach cannotbe considered established therapy.

CONCLUSIONS

Considerable progress has been made recently inboth defining the mechanisms underlying the devel-opment of inflammatory bowel disease and expand-ing the spectrum of effective therapies. It is reasonableto expect that, as the spectrum of genes that confersusceptibility to inflammatory bowel disease is iden-tified, attention will be focused on the mechanismsthrough which they lead to ulcerative colitis andCrohns disease. A definitive understanding will re-

quire the delineation of the nature of the interactionswith environmental factors, especially microflora.Progress in achieving these goals should lead to moreprecise genetic-based diagnosis, including presymp-tomatic risk assessment in family members of affectedpatients. In the interim, progress in our understand-ing of facets of the pathophysiology of inflammatorybowel disease has led to the development of usefulnew therapies.

The Center for the Study of Inflammatory Bowel Disease is supportedby funds from the National Institutes of Health (P30 DK43351).

I am indebted to Drs. Lawrence Friedman, Stephen Goldfinger,and Bruce Sands for comments and suggestions.

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of a humanized A4B7 antibody in ulcerative colitis (UC). Gastroenterology2000;118:Suppl 2:A874. abstract.89. Hommes D, van den Blink B, Plasse T, et al. Inhibition of stress-acti-

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disease after allogeneic marrow transplantation. Gastroenterology 1998;114:433-40.

Copyright 2002 Massachusetts Medical Society.

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16. Enfermedad Inflamatoria Intestinal

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