ALIMENTARY TRACT: CLINICAL REVIEW

CurrentTherapeuticRecommendationsInfliximabforUlcerativeColitis

Eric Hung Shen, MD and Kiron Moy Das, MD, PhD

Abstract: Randomized, controlled studies have shown that inflix-imab, the chimeric anti-tumor necrosis factor alpha (TNF-a) anti-body, is effective for the treatment of active and fistulizing Crohn'sdisease.I-3 Because infliximab is beneficial in patients with Crohn'sdisease, in whom other therapies have failed, it has been postulatedthat infliximabmay also be helpful in patients with ulcerative colitis.Many investigators have studied the effectiveness of infliximab inu\cerative colitis, mainly in patients who are refractory to corticoste-roids. Unfortunately, these studies have not yielded a conc\usive an-swer to the efficacy of infliximab in inducing remission in patientswith severeulcerative colitis. However, somehavereported excellentresults and others less effective, with the overall databeing inconclu-sive. Thepurpose ofthis review is to summarizethe current literatureon the use of infliximab in u\cerative colitis, as well as to provideinsight into the possible mechanisms of why it may or may not workin these difficult-to-treatpatients.

Key Words: u\cerative colitis, infliximab

(J C/in GastroenteroI2004;38:741-745)

UIcerative colitis is a chronic inflammatory process, whichdiffusely affects the superficial mucosa of the colon and

extends proximally from the anal verge up to the cecum. Themainstay therapy for u1cerative colitis includes sulfasalazineand one of its metabolites, 5-arninosalicylate, as well as otheragents, such as corticosteroids or immunomodulators. As a lastresort, surgery can be done in patients with severe disease.

Following oral adrninistration, sulfasalazine bypassessmall bowel absorption and 5-aminosalicylate is released inthe colon by bacterial action.4,5 Sulfasalazine, as well as vari-ous preparations of 5-arninosalicylate are effective in inducing

From the Crohn's and Colitis Center ofNew Jersey, Division ofGastroenter-

ology and Hepatology, Robert Wood Johnson Medical School, NewBnmswick, New Jersey.

Reprints: Kiron M. Das, MD, The Crohn's and Colitis Center ofNew Jersey,

Department of Gastroenterology and Hepatology, Robert Wood JohnsonMedical School, 1 Robert Wood Johnson Place, MEB 478, New Bruns-

wick, NJ 08901 (e-mail: daskm@umdnj.edu).Copyright «:>2004 by Lippincott Williams & Wilkins

J C/in Gastroenterol ·Volume 38, Number 9, October 2004

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and maintaining rernission.6-9 Immunomodulators, such as6-mercaptopurine and azathioprine, are also effective in main-taining rernission in most patients with u1cerative colitis.IO-12However, many patients often experience a flare-up of theirdisease, necessitating the use of oral or intravenous corticoste-roids. Chronic use of steroids is known to cause many adverseeffects. AIso, a significant proportion of patients will becomeresistant to steroids.13 The remaining options in these patientsinclude cyclosporine or surgery. Cyclosporine can be effectivein a subset of patients with fulminant colitis; however, 18%to43% fail to respond, and most ofthose who do respond initiallywill eventually need a colectomy.14-16 The use of cyclosporineis also associated with high1y toxic side effects including renalinsufficiency, infection, seizures, and hypertension. Occa-sional fatalities have been noted also. Many physicians have,therefore, become wary ofusing cyclosporine and have begunto look at infliximab as a last altemative medical option in pa-

tients with steroid-dependent and refractory disease.

BASIC MECHANISM OF INFLAMMATION ININFLAMMATORY BOWEL DISEASE

The etiologies of Crohn's disease and u1cerative colitisare unknown. Both genetic and environrnental factors playim-portant roles.17,18Autoimmunity, in particular, has been em-phasized in the pathogenesis ofulcerative colitis.19-22A mas-

sive B and T Iymphocyte infiltration in the mucosa, inappro-priate production of antibodies, and T cell dysfunctions arecentral factors in the pathophysiology of inflammatory boweldisease. There are also polymorphonuclear cells and macro-phages that are recruited at the site of active inflammation.Theactivated Iymphocytes and macrophages produce variouscy.tokines and inflanunatory mediators, which then, in tum,re-cruit more inflanunatory cells.

Cytokines are signaling proteins. Several, includingin-terleukin (IL) 1, IL-6, IL-8, TNF-a., and interferon-'Y(IFN-'Y),are involved in the inflanunatory process, and, hence, theyareidentified as "pro-inflanunatory cytokines." Other inflamma-tory mediators, such as leukotriene B4, prostaglandin E2.platelet activating factor, and thromboxane are increasedinthetissue ofpatients with active inflammatory bowel disease.18

Shen and Das / CIinGastroentero/·Volume 38, Number 9, October 2004

The cytokine profiles of ulcerative colitis and Crohn 'sdisease are usually different. This is reflected by the differentcytokines thatthe CD4+T cells, T helperl (Thl), and T helper2(Th2)produce.ln Crohn's disease, an over-expression ofThl-related pro-inflammatory cytokines, such as lFN-"f and TNF-a, is evident.18 ln contrast, ulcerative colitis is associated with

a dysregulated Th2 response and production oflL-4 and 5 re-sulting in stimulation ofhumoral immunityy,19-21

TNF-a has multiple biologic properties related to in-flammation and proliferation. Activation of TNF-a inducespro-inflammatory cytokines, such as lL-l and 6, enhances leu-kocyte rnigration by increasing endotheliallayer permeability,amplifies expression of adhesion molecules by endothelialcells and leukocytes, and activates neutrophil and eosinophilfunctional activity.

ROLE OF TNF-a IN ULCERATIVE COLlTIS

Although the Th2 type of immune response is predorni-nant in ulcerative colitis, it has been shown that TNF-a mayalso play a role in its pathogenesis. Patients with ulcerativecolitis may have increased levels ofTNF-a in colonic mucosa,stools, and plasma, which correlate with disease activity.23-25It has also been shown that concentrations of soluble TNF-a

receptors p55 and p75 are increased in the urine ofthese pa-tients and that these levels correlate with disease severity.26

The cotton-top tamarin is an animal model that demon-strates the association between TNF-a and ulcerative colitis.

The tamarin is an animal that spontaneously develops ulcer-ative colitis, presenting with symptoms of diarrhea and weightloss that improves afier receiving arninosalicylates or cortico-steroids.27 These animais can develop the same complicationsthat humans do, including colonic adenocarcinoma and scle-rosing choJangitis. 1t has been shown that the fecaJ concentra-tions of TNF-a are increased in these animaIs and treatment

with CDP 571 (a chimeric monoclonal antibody directed againstTNF-a) results in rapid clinicaI and histologic improvement.27Using the above evidence to support the use of an anti- TNF-aantibody in ulcerative colitis, Evans et ai published the firststudy using CDP 571 in patients with active disease.28

MODE OF ACTION OF INFLlXIMABÚ1ÍÜXiDNJhJs '" cóimcnc 3Ob:'.7JVE-uJDPDSÇ..IDP.DPdPLHI

antibody composed of 75% human protein and 25% mouseprotein. lt binds to TNF-o. with h\gh 'dflln\t'j ?tM clft:ctivt:ryinhibits its action by blocking soluble as well as transmem-brane TNF-a. Mechanisms ofaction include neutralization ofTNF, Iysis of activated TNF-a-producing immune cells, andinduction of apoptosis in activated macrophages and Tcells.29-31Thebinding ofinfliximab to TNF-a inhibits the se-cretion of ?ro-inflammatory Th\ cytokinessuch as IL-6 and 8,lCAM-l, and lFN-"f.

742

USE OF INFLlXIMAB IN ULCERATIVE COLlTISThe first study using anti-TNF-a therapy in ulcerative

colitis was published in 1997.28ln that open label study, 15patients with rnild to moderate disease were given a single5-mg/kg infusion ofCDP 571 and were followed for 8 weeks.There was a significantreduction in the Powell-Tuck scoreat 1week afier infusion, but this effect did not last past 2 weeks.There was no significant difference in the sigmoidoscopicap-pearance or in the number ofliquid stools.

Chey et aI, in 2001, reported an open-Iabeltrial of8 pa-tients who werebeing admitted for elective colectomyto con-trol their disease.32Each patient received a single infusion of5-mg/kg infliximab.They founda dramaticresponseto inflix-imab with alI 8 patients. The patients improved clinically andhistologically within 1week of the infusion, with results last-ing up to 5 months.However, this study has been criticized onmany factors. Theaverage age ofthe patientswas60 years old,which is a slightlyolder population than what is normally seen.AIso, 4 patients had characteristics of Crohn's disease ratherthan ulcerative colitis, which would temper the results seen inthis study. Chey and his colleagues later extended this trial to16 patients.33ln this group, clinical, endoscopic, and histo-logic improvement were seen in 14 patients (88%) afier asingle infusion of infliximab. Surgery was avoided in 6 of 7surgical candidates (86%). Clinical remission was maintainedin 14of 16patients (88%) for at least 4 months and in 4 (25%)for 6 to 1Omonths.

The first randornized double blind, placebo-controlledtrial using infliximab in severe steroid-refractory ulcerativecolitis was done by Sands et ai in 2001.34The study was ini-tially designed to enroll 60 patients but was terrninated, pre-maturely, due to slow recruitment. Ofthe II patients enrolled,8 received infliximabin various concentrations(three received5 mg/kg, three 10 mg/kg, and two 20 mglkg), and 3 patientsreceived placebo. Four of 8 patients who received infliximabresponded (50%), compared with none ofthose who receivedplacebo. Ali ofthe patients who receivedplacebo underwent acoJectomy by 2 weeks.

Kaser et allooked at 6patients with activesteroidrefrac-tory ulcerative colitis in an open-Iabel trial.35Ali of the pa-tients improved afier a single infusion of infliximab 5 mg/kg.Two of 6 patientsrelapsed by week4 but the remaining4 con-tinued to be in clinical rernission during the entire follow-up

~;P?fJ~The first studyto look at the use of infliximabin children

was done cy Mamu1a et ai in 2002.36lt was a retrospectiveanalysis involving 9 patients (median age 14years old), 7 ofwhich had a clinical response, as measured by the PhysicianGlobal Assessment (77%). Corticosteroid use was discontin-ued in 6 of8 patients (75%). Ofnote, 2 patientsexperiencedaninfusion reaction.

Kolm et ai performed an open-Iabel trial using a singleinfusion of infliximab, 5 mg/kg, in 13 steroid-refractorypa-

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tients with ulcerative colitis.37 Of the 13 patients, 10 had aclinical response to therapy (77%). Nine out ofthe 10 patientswho responded remained in remission for a mean of 10months. All of the responders were able to discontinue corti-costeroids during the mean follow-up period.

A retrospective chart review was done by Actis et aI in2002, involving 8 steroid refractory patients who received 1 ormultiple infusions of infliximab.38 Four of 8 initially re-sponded (50%). The 4 who did not respond underwent imme-diate colectomy. Two of the initial responders remained inclinical rernission for up to 7 months.

Su et allooked at the use of single or multiple infusionsofinfliximab in 27 active ulcerative colitis patients.39 Ofthe 27patients, 12 patients achieved rernission (44%) and 6 had a

partial response (22%), for a total of 18 out of 27 who re-sponded (66%). Five ofthe 9 non-responders underwent col-ectomy within 40 days of the last infliximab infusion. Half ofthe original responders experienced a total of 19 relapses, with95% ofthose relapses responding to repeat infusions. Lookingat the differences in characteristics between responders andnon-responders, Su found that patients with steroid-refractorydisease were far less likely to respond than those without thedisease (33% vS. 83%, P = 0.026). Ofthe 10 steroid-dependentpatients, 6 were able to reduce their dosage whereas 3 wereable to completely discontinue their steroids.

The second randomized, double-blind, placebo-controlled trial was performed by Probert et a1.40In this studyof 43 patients, 23 received 2 infusions ofinfliximab 5 mg/kg atweek Oand week 2 and 20 received placebo. Those who did notrespond by week 6 were offered open-label treatment with in-fliximab 10 mg/kg. After 6 weeks, there were no statisticaldifferences between the rates of rernission in the infliximab

and placebo groups (39% [9/23] vS. 30% [6/20]). There wasalso no difference in the sigmoidoscopic end points. Ofthe 20patients who were eligible to receive the open-label infusion of

Us;ng Inflix;mab ;n U/cerat;ve Colit;s

infliximab, clinical rernission was achieved in 3 out of 11 pa-tients who had received prior treatmentwith infliximab (37%)anü in 1 of9 patients woo had not (11%).

The most recent published study involving the use ofinfliximab in ulcerative colitis was an open-label trial, per-formed by Gomet et aI, looking at 30 patients who receivedsingle or multiple infusions of infliximab.41At day 7 clinicalresponse occurred in 21 out of 28 patients (75%), with com-plete rernission in 12 of 28 (43%). However, at 1month postthe last infusion the response rate was 50%, with complete re-rnission in 32%. Among the 22 responders, the probability ofrelapse was deterrnined to be 73% at 6 months. Concornitantuse of antimetabolites was associated with a lower rate of re-lapse (P < 0.04).

Table 1 summarizes the various published studies, in-cluding the date, number of patients, type of study, length offollow-up, and response rate.

OUR EXPERIENCEWITH ULCERATIVECOLlTISWe have administered single or multiple doses of inflix-

imab to 11 patients, 8 with u1cerative colitis and 3 with inde-terrninate colitis. Four patients received a single infusion ofinfliximab (5 mg/kg) and 7 received between 2 and 8 infusions.All of these patients did not respond adequately to steroids.Overall, 5 of 11 patients (45%) responded to infliximabtherapy. Of the patients with ulcerative colitis, 3 of 8 (38%)showed an excellent response to the infliximab, with 1 patientstill in rernission 1.5 years after a single infusion of infliximab.This patient is currendy on conventional therapy and did notsubsequendy require steroids. Of the 3 patients with indeter-minate colitis, 2 showed a good response to an induction dos-ing ofinfliximab. Ofnote, 3 of8 patients with ulcerative colitisor indeterminate colitis who did not respond to infliximabneeded a colectomy for control of their disease. In contrast, 2

18

TABLE1. UsingIntliximabin UlcerativeColitis

Number Type of Response RemissionAuthor Date of Patients Study Follow-up Rate Rate

Chey33 2001 16 Retrospective 2:4 months 88% 88%Sands34 2001 11 Randomized, double-blind, placebo 10 weeks 50% vs. 0"10* NAKasers 2001 6 Retrospective 5.5 months 100% 66%Mamula36 2002 9 Retrospective 13 months 77% NAKohn37 2002 13 Retrospective 12 months 77% 69%Actis38 2002 8 Retrospective 9 months 50% 25%SU39 2002 27 Retrospective Up to 16 months 66% 44%Probert4O 2003 43 Randomized, double-blind, placebo 6 weeks 39% versus 30%* 27% vs. 11%"Gornet41 2003 30 Retrospective Up to 24 months 75% at week I 43% aI week IOur experience 2004 1i Retrospeclive Up 104 years 45% 36%

*Infliximab versus placebo.

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Shen ono Dos J Clin CostroenteroJ.VoJume 38, Number 9, October 2004

ofthe responders who were scheduled for colectomy were ableto avoid surgery with the use of infliximab.

CONCLUSIONThe treatment of moderate to severe ulcerative colitis

can be a challenging problem, especially when conventionaltherapieshave failed.Variouscytokinesappearto mediate mu-cosal inflammation, and an imbalance of pro-inflammatoryandanti-inflammatorycytokines seemsto play a critical role ininflammatorybowel disease. Although ulcerative colitis, un-likeCrohn's disease, is associatedwith activation ofTh2 cells,several studies have reported a Thl type of response with in-creased IFN-"{and TNF-a production in the mucosa of manyof these patients.z2-25It is possible that the therapeutic re-sponsein ulcerative colitis depends on the type of immune im-balance,and that clinical improvement occurs only in patientswith an overproductionofTNF-a.

The lack of randomized, placebo-controlled studies us-ing infliximabfor ulcerative colitis prevents the rational use ofthedrug in ulcerativecolitis. Because the overall response rateseemsto be about 40% to 50%, it cannotbe recommended forroutineuse. Efficacy of infliximab for long-term use in ulcer-ativecolitis is unknown. There is some evidence that some ofthepatients with steroid refractory disease may be more resis-tantto infliximab,but this needs to be evaluatedfurther.Largerrandomized studies need to be performed before we can addinfliximab to our armamentarium of agents that are effectivefor the treatment of ulcerative colitis, particularly for thosewho are refractory to conventional therapies. Perhaps pre-assessmentofthe cytokine profile in the colonic biopsy tissuemay provide clinical guidance for the use of infliximab in asubgroupof patients with ulcerative colitis.

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Copyright 2004. Lippincott Williams and Wilkins, Inc.Reproduced by permission. Further reproduction pro-hibited without consent of authors and publisher.

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