IBD Landmarks Studies Review - Gut 2009

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Landmark data inearly IBD patients:

time to change your practice?

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LANDMARK DATA INEARLY IBD PATIENTS:TIME TO CHANGEYOUR PRACTICE?

The articles in this Satellite are based onpresentations made at a Satellitesymposium held on 20 October 2008 inVienna, Austria.

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PapersManagement of inflammatory bowel disease: 1

lessons learned over the decadesW Reinisch

The who, when and how of 3treating ulcerative colitis

P J Rutgeerts

Infliximab in Crohn’s disease: translating 6landmark data into clinical practice

J-F Colombel

Infliximab in inflammatory bowel disease: 9bring the future to your practice today

R Panaccione

BMJ_Schering_Plough_Satellites_contents:BMJ_Schering_Plough_Satellites_contents 07/04/2009 19:21 Page 1

Management of inflammatorybowel disease: lessons learnedover the decadesWalter Reinisch

Correspondence to:Professor Walter Reinisch,Austrian IBD Study Group,Medical University of Vienna,Vienna, Austria; [email protected]

Over the past decade, important lessons have beenlearned regarding the management of inflamma-tory bowel disease (IBD), leading to a reassessmentof treatment goals which should now includereducing surgeries and hospitalisations, achievingremission off corticosteroids, improving quality oflife (QoL), and optimising treatment. Thesestringent end points should be achieved to changeultimately the natural course of the disease.

It is now clear that Crohn’s disease (CD) andulcerative colitis (UC) are progressive diseases thatare not simply characterised by periods of activity(flares) and remission; nor is it sufficient simply totreat the symptoms of IBD. Furthermore, theefficacy and safety of conventional therapies, suchas corticosteroids and thiopurines, has been over-estimated. It is no longer acceptable for patients toreceive long term or repeated courses of corticos-teroids as these drugs have no impact on diseasecourse and are associated with increased risk ofmortality.1 By optimising the use of the currentbiologics, it is possible to achieve corticosteroid-freeremission and, more importantly, improve andmaintain patients’ overall QoL.

BIOLOGIC THERAPYBiologic therapies have been available for 10 years,of which the first was infliximab. Infliximab wasapproved for use in CD in the USA in 1998 and inthe EU in 1999. Infliximab is now indicated for CD(luminal and fistulising) and UC.2 Use of inflix-imab in Europe has progressed from being a thirdline to a second line treatment, and since 2007 ithas been approved for use in paediatric CD. Duringthe past 10 years, several important lessons havebeen learned regarding the use of biologic therapy,including the need for:

c Proper induction therapy

c Proper maintenance therapy

c Mucosal healing as a treatment end point

c Immunogenicity management for all biologics

THREE DOSE INDUCTION THERAPYWhen infliximab was first used in 1998, single doseinduction therapy was used. Adopting a three doseinduction strategy has been shown to result insuperior clinical outcomes.3 Orlando et al evaluatedthe predictors of response to infliximab in a largecohort of patients with luminal and/or fistulising

CD (n = 573).4 In this study, patients receivedeither a single infliximab infusion (5 mg/kg) orthree infusions at 0, 2 and 6 weeks. Patients werefollowed up for 6 months and clinical response andremission assessed. Clinical response was definedas a reduction of >70 points on the Crohn’sDisease Activity Index (CDAI) at 12 weeks andclinical remission was defined as CDAI ,150 inpatients with luminal disease.4 It was shown that asingle infliximab infusion inversely correlated withclinical response and remission and was a predictorof a worse clinical response compared with threescheduled induction infusions.4

SCHEDULED MAINTENANCE THERAPYClinical studies have shown that scheduled inflix-imab maintenance treatment is more effective thanepisodic treatment. In particular, ACCENT I (ACrohn’s disease Clinical study Evaluating inflix-imab in a New long term Treatment regimen)demonstrated that compared with episodic treat-ment, patients with CD receiving scheduledinfliximab treatment (at weeks 0, 2 and 6, thenevery 8 weeks) were more likely to:

c Be in remission5

c Maintain response for a longer period of time5

c Reduce and discontinue corticosteroid use5

c Have greater rates of mucosal healing3

In the case of infliximab, there is a dramaticreduction of immunogenicity from episodic toscheduled treatment which renders its immuno-genicity similar to other biologics. The issue ofconcomitant immunosuppression is of less impor-tance with scheduled maintenance treatment.3 6

MUCOSAL HEALING AS A TREATMENT END POINTIt is now clear that treating the underlying causesof IBD is essential and achieving mucosal healing isan important treatment end point to strive for.Mucosal healing is associated with better long termoutcomes and ACCENT I demonstrated that allrandomised CD patients at 54 weeks treated withinfliximab scheduled therapy had significantlyhigher rates of mucosal healing compared withepisodic therapy. Additionally, ACCENT I demon-strated that patients who achieved mucosal healingat both visits (week 10 and 54) had a much lowerincidence of hospitalisations and surgeries com-pared with no healing: 0% vs 46% for hospitalisa-

Landmark data in early IBD patients: time to change your practice?

Satellites 2009:1–2 1

tions and 0% vs 8% for surgeries.7 The importanceof mucosal healing has also been demonstrated inUC. A combined analysis of the Active UlcerativeColitis Trials 1 and 2 (ACT 1 and ACT 2) hasshown that patients with UC who achievedmucosal healing at week 8 were significantly morelikely to achieve and maintain clinical remission atweek 30 (48.3%) compared with those with nomucosal healing (9.5%, p,0.01).8

SUMMARYIn the last decade, understanding has progressed inthe management of IBD and the use of biologics. Itis now recognised that three dose inductiontherapy with infliximab is far superior to one doseinduction, and scheduled treatment is better thanepisodic treatment. It is also understood thattreatment goals for patients should go beyondsymptomatic remission and aim for mucosalhealing, and this may be accomplished by movingfrom treating refractory disease to treating thecondition earlier.

The articles in this BMJ Satellite will focus onevidence to improve and re-examine currentclinical practice in treating CD and UC. Thearticles will help answer the most pressing ques-tions on managing IBD, such as how to optimiseUC treatment and how new data can changepractice in CD. Gastroenterologists will be chal-lenged to implement immediately changes to their

treatment approaches which could help improveoverall outcomes and potentially change thenatural course of IBD.

Competing interests: Consultancies: AstraZeneca, Ferring, AbbottLaboratories, Schering-Plough, Centocor, Elan, UCB, Novartis,Otsuka, PDL, Sanochemia, AESCA; Honoraria: Ferring, Schering-Plough, AstraZeneca, Abbott Laboratories, Centocor, Elan, UCB,Novartis, Otsuka, PDL, AESCA; Grants Received: Abbott Laboratories,AESCA, UCB.

REFERENCES1. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infections

and mortality in association with therapies for Crohn’s disease:TREAT registry. Clin Gastroenteral Hepatol 2006;4:621–30.

2. RemicadeH (infliximab). Summary of Product Characteristics (SPC).July 2008.

3. Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison ofscheduled and episodic treatment strategies of infliximab in Crohn’sdisease. Gastroenterology 2004;126:402–13.

4. Orlando A, Colombo E, Kohn A, et al. Infliximab in the treatment ofCrohn’s disease: predictors of response in an Italian multicentreopen study. Digest Liver Dis 2005;37:577–83.

5. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenanceinfliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet2002;359:1541–9.

6. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importanceof antibody responses to infliximab after maintenance or episodictreatment in Crohn’s disease. Clin Gastroenterol Hepatol2004;2:542–53.

7. Rutgeerts P, Malchow H, Vatn MH, et al. Mucosal healing inCrohn’s disease patients is associated with reduction inhospitalizations and surgeries. Gastroenterology2002;123:43.[abstract M2138].

8. Sandborn WJ, Lichtenstein GR, Colombel JF, et al. Infliximabtherapy reduces hospitalizations in ulcerative colitis patients.Am J Gastroenterol 2005;100:S–312.


2 Satellites 2009:1–2

The who, when and how of treatingulcerative colitisPaul J Rutgeerts

Correspondence to:Professor Paul Rutgeerts,Department of Medicine,University of Leuven, Leuven,Belgium; [email protected]

The traditional treatment paradigm for ulcerativecolitis (UC) is based on a step-up approach in whichtherapies with the least toxicity are utilised early andsubsequent therapies are added because of lack ofresponse or toxicity. This approach, however, maynot represent the most optimal treatment forpatients. Another approach is to add a structuredtime frame to when therapies are effective orineffective and when to advance therapy which willallow for better management of UC.1

Currently, 5-aminosalicylic acid (5-ASA) is stillthe mainstay of treatment for UC. In a proportionof patients, however, it will be necessary to initiatecorticosteroid treatment in order to control thedisease. Although some patients will respond tocorticosteroids, many will either become refractoryand not respond to high corticosteroid doses orbecome corticosteroid dependent, respond but flareup when corticosteroids are tapered. In corticoster-oid dependent patients, immunomodulators suchas azathioprine (AZA) are introduced first; if thereis still no response, this is followed by biologictherapy with infliximab. In corticosteroid refrac-tory patients, many physicians may want to treatdirectly with biological therapy.1

EVIDENCE FOR USING INFLIXIMAB IN ULCERATIVECOLITIS

Clinical efficacyActive Ulcerative Colitis Trials 1 and 2 (ACT 1 andACT 2) were randomised, double blind, placebocontrolled studies that evaluated the effect ofinfliximab in adults (n = 364 in each study) withmoderate to severe UC, despite treatment withconcurrent medications. Patients received inflixi-mab (5 mg/kg or 10 mg/kg) or placebo infusions atweeks 0, 2 and 6 and then every 8 weeks throughweek 46 (ACT 1) or week 22 (ACT 2). Patientswere followed through week 54 in ACT 1 andweek 30 in ACT 2. The Mayo score wasdetermined at weeks 0, 8, and 30 for both studiesand at week 54 in ACT 1. Clinical response wasdefined as a decrease from baseline in the totalMayo score of at least 3 points and at least 30%,with an accompanying decrease in the subscore forrectal bleeding of at least 1 point or an absolutesubscore for rectal bleeding of 0 or 1. Clinicalremission was defined as a total Mayo score of 2points or lower, with no individual subscoreexceeding 1 point.2

Clinical response was achieved by significantlymore patients at weeks 8, 30 and 54 (ACT 1) in theinfliximab 5 mg/kg and 10 mg/kg groups comparedto placebo. In ACT 1, at 54 weeks, 45.5%, 44.3%

and 19.8% of patients treated with infliximab 5mg/kg, 10 mg/kg or placebo, respectively, had aclinical response. In ACT 2, at week 30, 47.1%,60%, and 26% of patients treated with infliximab 5mg/kg, 10 mg/kg or placebo, respectively, had aclinical response. Similar results were observed inpatients achieving clinical remission with signifi-cantly more patients achieving it in the infliximabgroups. In ACT 1, at 54 weeks, 34.7%, 34.4% and16.5% of patients treated with infliximab 5 mg/kg,10 mg/kg or placebo, respectively, achieved clinicalremission. In ACT 2, at week 30, 25.6%, 35.8% and10.6% of patients treated with infliximab 5 mg/kg,10 mg/kg or placebo, respectively, achieved clinicalremission.2

Corticosteroid-free remissionInfliximab therapy allows patients with UC toachieve corticosteroid-free remission. In ACT 1,61.0% of patients were receiving corticosteroids atbaseline (median daily dose 20 mg/day).2 Theproportion of patients who were in clinicalremission (total Mayo score of 2 points or lower,with no individual subscore exceeding 1 point) andhad discontinued corticosteroids at week 30 wassignificantly higher with infliximab 5 mg/kg thanwith placebo (24.3% vs 10.1%, respectively;p = 0.03), and this was maintained through toweek 54 (25.7% vs 8.9%, p = 0.006) (fig 1). Inaddition, the median daily corticosteroid dose in

Figure 1 Clinical remission and off corticosteroids atweeks 30 and 54.2



infliximab treated patients decreased dramaticallycompared with patients receiving placebo. After aninitial drop, the median dose in the placebo groupremained the same as baseline throughout theremainder of the study.2

Mucosal healingMucosal healing is an important treatment objec-tive when assessing the efficacy of UC treatments.In UC, mucosal healing is assessed by the Mayoscore of endoscopic activity. Mucosal healing isachieved with a subscore of 0 or 1 and activedisease is scored with an endoscopy score of 2 to 3.A score of 0 is when the mucosa becomescompletely normal, with normal vascularisationand no friability. A score of 1 shows abnormalvascular pattern and some friability but noerosions, ulcerations or active bleeding. Score 2has important friability with some erosions andscore 3 is when there are ulcers, mainly superficial,and the presence of active bleeding.

Infliximab rapidly induces mucosal healing inpatients with UC. In ACT 1, patients receivinginfliximab were significantly more likely to havemucosal healing at weeks 8, 30 and 54. When usinga Mayo endoscopic subscore of 0 or 1, approxi-mately 62% of patients receiving infliximab 5 mg/kg achieved mucosal healing at week 8 comparedwith 33.9% of placebo patients (p,0.001). Superiormucosal healing with infliximab was maintainedthrough to week 30 (50.4% vs 24.8%, respectively)and week 54 (45.5% vs 18.2%, respectively)(p,0.001 vs placebo for both time points).2 Whenmore stringent criteria were applied to determinecomplete mucosal healing (Mayo endoscopic sub-score 0—normal mucosa), mucosal healing wasachieved in 22.3% of infliximab patients and 12.4%of placebo patients at week 8 and 32.2% and15.7%, respectively, at week 54.3

Hospitalisations and surgeryThe incidences of hospitalisations and colectomywere assessed in ACT 1 and ACT 2. The rate ofhospitalisations decreased by 50% with infliximabcompared with placebo. Through week 54, therewere 40 hospitalisations per 100 patient-years inthe placebo group and 20 per 100 patient-yearswith infliximab (p = 0.003).4 More importantly,significant reductions in colectomy rates were alsoseen with infliximab. A post hoc analysis of ACT 1and ACT 2 has shown that the colectomy rate forpatients with placebo was 14.8% compared with9.5% with infliximab (p = 0.035).4

TRANSLATING CLINICAL DATA TO CLINICALPRACTICEThe ACT 1 and ACT 2 studies demonstrated theeffectiveness of infliximab in UC and provided thedata necessary to support the approval of inflix-imab for UC. In Europe, infliximab is currentlyindicated for the treatment of moderate-to-severeactive UC in patients who have had an inadequateresponse to conventional therapy, including corti-costeroids and AZA or 6-mercaptopurine (6-MP),or who are intolerant to or have medical contra-indications for such therapies.5 The use of inflix-imab has also been suggested in guidelines. TheEuropean Crohn’s and Colitis Organization’s(ECCO) guidelines for the management of UCrecommend infliximab in oral steroid refractoryand in thiopurine intolerant or refractory UC.6

How do we apply clinical trial information in reallife clinical practice?ACT 1 and ACT 2 clearly showed the effectivenessof infliximab in the short term and up to 1 year inpatients with moderate-to-severe UC.3 However,data on long term efficacy are scarce. A recentstudy, however, has evaluated the long termefficacy of infliximab. The results of this studycan be applied to clinical practice since the studyused an approach to more everyday clinical practiceby analysing a subgroup of outpatients whoreceived infliximab for refractory UC outside theACT 1 trial.7

The study conducted by Ferrante et al aimed todetermine the long term clinical outcomes ofinfliximab in 121 patients (median age 38 years)with refractory UC and to identify predictors ofsustained clinical response and colectomy. Theextent of inflammation was similar to that in theACT trials. Patients with left-sided colitis andproctitis were included with those with extensivecolitis as these patients are also good candidates forinfliximab treatment. Most patients were receivingconcomitant mesalamine therapy, and many hadreceived previous treatment with intravenoussteroids or cyclosporine. The primary efficacyoutcome was colectomy-free survival, and thesecondary outcome measures were sustained clin-ical response and serious adverse events. Patientsreceived either a single dose of infliximab 5 or10 mg/kg or an induction scheme with infliximabat weeks 0, 2 and 6. The majority of patients (75%)showed a clinical response to infliximab inductionand received maintenance therapy with infusionsevery 8 weeks. The remaining patients receivedepisodic therapy.7

Patients were followed up for a median period of33 months.7 Overall, 63% of patients (n = 121)treated with infliximab showed short term(4 weeks) clinical response. Forty-one per cent ofpatients had a complete clinical response (absenceof diarrhoea and blood) and 22% had a partialclinical response (marked clinical improvement butstill persistent rectal blood loss).7 Short termmucosal healing was assessed in 70 patients(58%) both before and 4–10 weeks after the first

Key findings of ACT 1 and ACT 2

c In UC, infliximab:– Reduced disease activity– Allowed for corticosteroid-free remission– Achieved complete mucosal healing– Significantly reduced the rates of hospitalisation and surgery



infliximab infusion and was defined as a Mayoendoscopic subscore of 0 or 1. Of these, 53%achieved mucosal healing.7 Of the 81 patientsachieving short term clinical response, 68% had asustained clinical response during the median 33.4month follow-up.

During the median follow-up of 33 months, 17%of patients (n = 21) required a colectomy, with amedian time to colectomy of 7.6 months.7 Ananalysis of the predictors of colectomy revealedthat absence of short term clinical response,absence of short term mucosal healing, a highbaseline C-reactive protein (CRP >5 mg/l) andabsence of short term CRP drop (.50% or tonormal) all predicted the need for colectomy.7 Thisstudy had an acceptable number of adverse events.Thirteen patients experienced acute infusion reac-tions and eight patients experienced a delayedhypersensitivity reaction, resulting in treatmentdiscontinuation in four patients. Serious adverseevents, which were mainly hospitalisations for aninflammatory event (six), occurred in 11 patients.

PROPER PATIENT SELECTION FOR INFLIXIMAB:CONSIDERATIONS FOR TOMORROWIn the ACT studies, the reduction in colectomyrate compared with placebo4 suggests that the

potential to use infliximab much earlier may have apositive impact on the course of persistently activeUC. Similarly, in acute presurgical colitis, thecolectomy rate has been shown to be significantlylower with infliximab (29%) than placebo (67%).8

It is unlikely, however, that the earlier introduc-tion of infliximab in patients with acute severecolitis will be practical because these patients oftenhave an indolent disease course characterised byvery sudden and often unexpected, severe, acuteflare-up, which cannot be controlled with intrave-nous corticosteroids.

More data are needed on the use of infliximab inimmunomodulator-naive patients and a trial initia-tive is ongoing (UC-SUCCESS)9 as well as incorticosteroid-naive UC pts with another plannedtrial (MUNIX).

The results from these new studies may provideguidance to some unanswered questions on themanagement of moderate-to-severe active UC,such as:

c Is early disease different?

c Does earlier treatment result in better out-comes?

c Is monotherapy or combination therapy abetter option to induce remission?

Competing interests: Consultancies: Abbott Laboratories,Centocor, Schering-Plough, UCB, Elan, PDL, NovImmune; Honoraria:Abbott Laboratories, Centocor, Schering-Plough, UCB, Elan, PDL,NovImmune; Grants received: Abbott Laboratories, Centocor,Schering-Plough, UCB.

REFERENCES1. Panaccione R, Rutgeerts P, Sandborn WJ, et al. Review article:

treatment algorithms to maximize remission and minimizecorticosteroid dependence in patients with inflammatory boweldisease. Aliment Pharmacol Ther 2008;28:674–88.

2. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab forinduction and maintenance therapy for ulcerative colitis. N Engl J Med2005;353:2462–76.

3. Data on file, Centocor. Inc.4. Sandborn W, Rutgeerts P, Feagan BG, et al. Infliximab reduces

colectomy in patients with moderate to severe ulcerative colitis:colectomy analysis ACT 1 and ACT 2. Gut 2007;56(suppl III):pA26.

5. RemicadeH (infliximab). Summary of Product Characteristics (SPC).Schering-Plough. Accessed July 2008.

6. Travis SPL, Stange EF, Lemann M, et al. Gassull and for theEuropean Crohn’s and Colitis Organisation (ECCO). J Crohn’s Colitis2008;2:24–62.

7. Ferrante M, Vermeire S, Fidder H, et al. Long-term outcome afterinfliximab for refractory ulcerative colitis. J Crohn’s Colitis2008;2:219–25.

8. Jarnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescuetherapy in severe to moderately severe ulcerative colitis: arandomized, placebo-controlled study. Gastroenterology2005;128:1805–11.

9. Clinical trials website. Efficacy & safety of infliximab monotherapyvs combination therapy vs aza monotherapy in ulcerative colitis (part1) maintenance vs intermittent therapy for maintaining remission(part 2) (study P04807AM2). http://www.clinicaltrials.gov/ct2/show/nct00537316?term=p04807&rank=1. (Accessed 20 January2009).

Predictors of need for colectomy

c Absence of:– Short term clinical response– Short term mucosal healing

c Baseline CRP >5 mg/lc No short term CRP drop .50% or to normal

Summary

c Patient selection is key when deciding to use infliximab.c The current infliximab label and ECCO guidelines help depict appropriate UC

patients for infliximab therapy:– Moderate-to-severe active UC in patients who have had an inadequate

response to conventional therapy, including corticosteroids and AZA or 6-MP, or who are intolerant to or have medical contraindications for suchtherapies.

– Oral steroid refractory and thiopurine intolerant or refractory UC patients.c Infliximab will provide greater benefit in the right patients, and timely

intervention may reduce colectomy rates and hospitalisations.c Avoiding colectomy is important as it is not a cure for UC and is associated

with serious complications.c Treatment decisions should be guided by the status of the mucosa.

– Mucosal healing is an important treatment end point and represents a newtherapeutic target in helping with patient selection.



Infliximab in Crohn’s disease:translating landmark data intoclinical practiceJean-Frederic Colombel

Correspondence to:Professor Jean-Frederic Colombel, Departmentof Hepatogastroenterology,University of Lille, Lille, France;[email protected]

A considerable amount of clinical data has beengathered evaluating the benefits of infliximab inpatients with Crohn’s disease (CD). These evolvingclinical data, which have been obtained in patientswith different disease duration and different previousdrug exposures, are being used to gradually build anddevelop a treatment paradigm for CD (fig 1).1–5

ACCENT I (A CROHN’S DISEASE CLINICAL TRIALEVALUATING INFLIXIMAB IN A NEW LONG TERMTREATMENT REGIMEN)The ACCENT I trial showed that scheduled main-tenance infliximab treatment is more effective thanepisodic treatment.

ACCENT I, the largest study in patients withsymptomatic CD, not only demonstrated thatinfliximab is an effective maintenance treatment,but that scheduled infliximab treatment is morebeneficial than episodic treatment. In ACCENT I,after an initial infliximab 5 mg/kg infusion, 573patients with CD (Crohn’s Disease Activity Index(CDAI) >220) were randomised to receive eitherepisodic treatment (infliximab 5 mg/kg infusionfollowed by placebo infusions at weeks 0, 2 and 6,then every 8 weeks) or scheduled treatment(infliximab 5 mg or 10 mg/kg at weeks 0, 2 and6, then every 8 weeks).2 6 At week 14 or later,patients who responded at any time to infliximaband then worsened were eligible to cross over toactive episodic treatment with infliximab 5, 10 or15 mg/kg for patients originally assigned to episo-dic, 5 mg/kg scheduled and 10 mg/kg scheduledtreatment strategies, respectively. Patients receiv-ing 5-aminosalicylic acid (5-ASA), corticosteroidsor azathioprine/6-mercaptopurine (AZA/6-MP)were eligible to enter the study.2

The number of hospitalisations per 100 patientswas significantly lower in patients who receivedinfliximab 5 mg/kg scheduled therapy through54 weeks compared with episodic treatment (24vs 38; p = 0.047). There was a similar impact onsurgery rates. By week 54, only 3% of patients hadsurgeries with scheduled therapy compared with7% treated with episodic treatment (p = 0.004).2

GETAID (GROUPE D’ETUDE THERAPEUTIQUE DESAFFECTIONS INFLAMMATOIRES DU TUBEDIGESTIF)The GETAID trial showed that infliximab should not beused as a bridge to immunomodulators and infliximab ismore effective in AZA-naıve patients.

The concept of bridging involves maintainingthe effect of AZA with infliximab. In the GETAIDtrial, patients (n = 113) with active CD despiteprednisone given for at least 6 months werestratified into two groups: those that were receiv-ing but failed to respond to AZA/6-MP for morethan 6 months, and those that were AZA/6-MPnaıve. Patients were randomised to inductiontherapy with infliximab 5 mg/kg or placebo atweeks 0, 2 and 6. All patients received stable dosesof AZA/6-MP for 52 weeks. The primary end pointwas clinical remission (CDAI ,150) off corticos-teroids at week 24. At weeks 12 and 24, signifi-cantly more patients receiving infliximab plusAZA/6-MP were in corticosteroid-free clinicalremission than those receiving AZA/6-MP alonein both AZA failures and AZA-naıve patients. Theeffect of infliximab on clinical remission wasgreater in AZA-naıve patients than in AZA failures.This suggests that earlier infliximab use may bebeneficial in CD patients. Additionally, the trialdemonstrated that the bridge strategy does notwork because the efficacy in week 12 (in bothstrata) was not maintained over the course of theyear, but declined rapidly.3

SUTD (STEP-UP TOP-DOWN)The SUTD trial showed that early treatment withinfliximab is more effective than conventional therapy.

This SUTD showed that more intensive treat-ment early in the course of the disease results inbetter outcomes. The SUTD trial compared theeffectiveness of early use of combined immunosup-pression (infliximab/AZA) ‘‘top-down’’ therapywith conventional ‘‘step-up’’ therapy in patientswith active CD.5 In this 2 year, open-label trial,patients (n = 133) with CD diagnosed within theprevious 4 years who had not previously receivedcorticosteroids, antimetabolites or biologic therapywere randomised to receive aggressive top-downcombined immunosuppression (infliximab 5 mg/kgat weeks 0, 2 and 6 in combination with AZA) orconventional step-up therapy (in sequence, induc-tion with oral corticosteroids, followed by AZA,then infliximab if patients remained symptomaticon the previous treatment).5 The primary outcomemeasure was remission without corticosteroids orbowel resection at weeks 26 and 52.5 Secondary endpoints included time to relapse (CDAI .200 and/orthe need for bowel resection and/or the need foradding additional treatment according to assigned



regimen) and mucosal healing. At week 26, 60% ofpatients in the top-down group were in remissionwithout corticosteroids and without surgical resec-tion compared with 35.9% of patients in the step-upgroup.5 The median time to relapse was longer forpatients in the top-down group (329 days) thanthose in the step-up group (174.5 days) (p = 0.031)(fig 2).5

Importantly, endoscopic examination revealedthat 73.1% of patients receiving top-down therapyhad no mucosal ulcers after 2 years compared withonly 30.4% receiving step-up therapy. At the end of2 years, 75% of patients in the step-up group werereceiving immunomodulators and 25% receivedinfliximab because they had active disease over the2 years.5

SONIC (STUDY OF BIOLOGIC- ANDIMMUNOMODULATOR NAIVE PATIENTS INCROHN’S DISEASE)The SONIC trial showed that an infliximab basedtreatment strategy is superior for AZA-naıve patientsand earlier use of infliximab is beneficial.

SONIC is a landmark trial for the management ofCD. In this trial, 508 patients with moderate-to-severe CD who were either corticosteroid dependent

or requiring a second (or greater) round of steroidswithin 1 year or were 5-ASA or budesonide failureswere enrolled.4 All patients were naıve to bothimmunomodulators and biologics. Patients wererandomised to receive AZA 2.5 mg/kg capsules plusplacebo infusions (n = 170), infliximab 5 mg/kginfusions (at week 0, 2 and 6, then every 8 weeks)plus placebo capsules (n = 169), or infliximab 5 mg/kg infusions plus AZA 2.5 mg/kg capsules (n = 169).The primary end point was corticosteroid-freeremission defined as CDAI ,150 points and offcorticosteroids for >3 weeks.7 The major secondaryend point was mucosal healing (complete absence ofmucosal ulcerations in the colon and terminal ileumas assessed by video endoscopy) at week 26.4

Endoscopy was performed at baseline and at week26. At baseline, the median disease duration wasshort (2.2 years) and the median C-reactive protein(CRP) value was relatively high (1.0 mg/dl).4

At week 26, the proportion of patients incorticosteroid-free clinical remission was signifi-cantly greater with infliximab monotherapy andinfliximab plus AZA combination therapy com-pared with AZA monotherapy (57%, 44% and31%, respectively) (fig 3). The difference betweenthe infliximab monotherapy and infliximab plusAZA combination therapy was statistically sig-nificant (p = 0.022). In addition, more patientsexperienced complete mucosal healing whilereceiving the infliximab monotherapy (30%,p = 0.023) and infliximab plus AZA combinationtherapy (44%, p,0.001) than AZA monotherapy

Figure 1 Infliximab trials demonstrating effect in different patient types.1–5 5-ASA,5-aminosalicylic acid; AZA, azathioprine; CS, corticosteroids; IS, immunosuppressors;6-MP, 6 mercaptopurine.

Figure 2 SUTD: Time to relapse after successful induction at week 14. Reproducedfrom D’Haens G et al5 with permission from Elsevier.

Figure 3 SONIC: Clinical remission withoutcorticosteroids at week 26.7 AZA, azathioprine; CDAI,Crohn’s Disease Activity Index; IFX, infliximab.

Figure 4 SONIC: Mucosal healing at week 26.7 AZA,azathioprine; IFX, infliximab.



(17%). There was no significant difference betweenthe two infliximab groups (p = 0.055) (fig 4).7

Importantly, corticosteroid-free remission wassignificantly improved in patients with higherinflammatory burden at baseline as demonstratedby CRP values and endoscopic lesions. In patientswith high baseline CRP values (>0.8 mg/dl), ahigher proportion of those receiving infliximab plusAZA combination therapy (63.5%, p,0.001) andinfliximab monotherapy (47.5%, p = 0.004) were insteroid-free remission compared with those receivingAZA monotherapy (27.6%).8 In patients withnormal baseline CRP values (,0.8 mg/dl), therewas no statistically significant difference in the rateof clinical remission between the treatment groups.Similar findings were made in patients with noendoscopic lesions at baseline.8 Significantly morepatients in the infliximab groups with endoscopiclesions at baseline achieved corticosteroid-free remis-sion compared with those in the AZA monotherapygroup (p(0.003). This may be important when itcomes to choosing the right patient for therapy.Furthermore, in the subgroup of patients with bothhigh CRP and mucosal lesions at baseline, thedifference in the rate of corticosteroid-free clinicalremission between AZA monotherapy and inflix-imab plus AZA combination therapy was even larger(28.0% vs 68.8%, p,0.001).8 These data suggest astrong benefit from using CRP and/or endoscopiclesions as identifiers when selecting CD patients forinfliximab therapy.

LESSONS FOR CLINICAL PRACTICESo how do the clinical trial findings relate toclinical practice? It is now clear from ACCENT Ithat patients failing on corticosteroids and AZAshould receive infliximab. Whether infliximabshould be used as monotherapy or in combinationwith AZA is still uncertain.

The SUTD study revealed that early, aggressive,top-down use of infliximab is more effective than

conventional step-up therapy. This top-downapproach may be useful in patients who arediagnosed earlier in the disease course.

SONIC has shown that for AZA-naıve patientswith active CD, infliximab monotherapy should beused as a second line treatment. In patients withparticularly active CD, infliximab/AZA combina-tion therapy may be the most effective strategy.Whether the combination therapy should bemaintained after 6 months or whether patientsshould continue to receive infliximab or AZAmonotherapy is still unknown.

The data clearly demonstrate that earlier treat-ment with infliximab is more effective in AZA-naıve patients. In addition, patients with particu-larly active disease (high CRP and/or endoscopiclesions) are likely to gain a strong benefit fromearly infliximab treatment. CRP and mucosallesions, therefore, are important identifiers ofpatients with CD suitable for early infliximabtreatment.

Competing interests: Consultancies: Boehringer Ingelheim, OtsukaAmerica Pharaceuticals, Protein Design Labs, Grunenthal GmbH,Pharmion, UCB, UCB/CellTech, Berlex/Schering, Centocor, Schering-Plough, Elan, Abbott Laboratories, Bristol-Meyers Squibb, ShirePharmaceuticals: Honoraria: Centocor, Schering-Plough, AbbottLaboratories, Elan, Ferring, UCB; Grants received: Giuliani,AstraZeneca, Danisco, Sanofi, Ferring, Association Francois Aupetit,Institut National de la Sante et de la Recherche Medicale, Fonds deRecherche, Societe Nationale Francaise de Gastroenterologie, LilleUniversity, International Organisation of Inflammatory Bowel Disease.

REFERENCES1. Targan SR, Hanauer SB, van Deventer SJH, et al. A short-term

study of chimeric monoclonal antibody cA2 to tumor necrosis factora for Crohn’s disease. N Engl J Med 1997;337:1029–35.

2. Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison ofscheduled and episodic treatment strategies of infliximab in Crohn’sdisease. Gastroenterology 2004;126:402–13.

3. Lemann M, Mary JY, Duclos B, et al. Infliximab plus azathioprinefor steroid-dependent Crohn’s disease patients: a randomised,placebo-controlled trial. Gastroenterology 2006;130:1054–61.

4. Colombel JF, Rutgeerts P, Reinisch W, et al. SONIC: a randomized,double-blind, controlled trial comparing infliximab and infliximab plusazathioprine to azathioprine in patients with Crohn’s disease naive toimmunomodulators and biologic therapy. Gut 2008;57(suppl 2):A1.

5. D’Haens G, Baert F, van Assche G, et al. Early combinedimmunosuppression or conventional management in patients withnewly diagnosed Crohn’s disease: an open randomised trial. Lancet2008;371:660–7.

6. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenanceinfliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet2002;359:1541–9.

7. Sandborn WJ, Rutgeerts P, Reinisch W, et al. SONIC: arandomized, double-blind, controlled trial comparing infliximab andinfliximab and azathioprine to azathioprine in patients with Crohn’sdisease naıve to immunomodulators and biologic therapy. ACG2008; Abstract 29.

8. Colombel JF, Rutgeerts P, Reinisch W, et al. SONIC: a randomized,double-blind, controlled trial comparing infliximab and infliximab plusazathioprine to azathioprine in patients with Crohn’s disease naive toimmunomodulators and biologic therapy. J Crohn’s Colitis2009;3:S45–6.

Key clinical trial messages

c ACCENT I: Scheduled maintenance infliximab treatment is more effective thanepisodic treatment.

c GETAID: Infliximab should not be used as a bridge to immunomodulators.c SUTD: Early treatment with infliximab is more effective than conventional

therapy.c SONIC:

– Infliximab monotherapy or combination therapy is more effective thanAZA monotherapy.

– An infliximab based treatment strategy is superior for AZA-naıve patients.– High CRP and/or extensive mucosal lesions are patient identifiers for

early infliximab therapy.



Infliximab in inflammatory boweldisease: bring the future to yourpractice todayRemo Panaccione

Correspondence to:Professor Remo Panaccione,Inflammatory Bowel DiseaseClinic, University of Calgary,Calgary, Alberta, Canada;[email protected]

The findings of clinical trials such as SONIC (StudyOf biologic- and immunomodulator Naıve patientsIn Crohn’s disease) helped confirm that it is nowtime for all gastroenterologists to consider earlybiologic therapy as part of their inflammatory boweldisease (IBD) treatment paradigm. Treatments thatchange the natural disease course in ulcerative colitis(UC) and Crohn’s disease (CD) are needed in theabsence of a cure. Treatment of the symptoms aloneis no longer acceptable as this does not affect thedisease progression. In UC, for example, cross-sectional analyses of population-based studies havedemonstrated that despite symptomatic treatments,40–50% of patients will continue to have moderatelyactive disease that impacts upon quality of life(QoL).1 Furthermore, over time, a significant propor-tion of UC patients with uncontrolled disease and/or complications will require surgical resection.

The symptomatic treatment of CD has alsolargely proven to be ineffective in changing thenatural course of disease and its complications.Despite immunomodulators being used for over25 years, there has been no significant decrease insurgical rates or intestinal complications inpatients with CD.2 Most patients with CD startwith an inflammatory phenotype.3 Uncontrolledinflammation likely leads to complications such asstructuring/penetrating fistulising disease, whichtranslates into a cumulative increase in surgicalrate. Therefore, the use of disease modifyingtreatments such as biologics in both CD and UCshould be considered. The treatment goals in IBD

have evolved. From a patient’s perspective, theirfocus for outcomes is to get better, have theirsymptoms subside, and improve their QoL so thatthey can return to their normal daily routine.

Gastroenterologists observe the abnormallaboratory parameters and abnormal mucosa andshould therefore strive to not only improvesymptoms but also to normalise abnormal labora-tory values and heal the mucosa which in essencereflects a healthier end organ. Economic data showthat if the best drugs are used early and often, thenthere is a huge impact from society’s perspective(indirect costs) with regard to reduced hospitalisa-tions and surgery and increased work productivity.

MUCOSAL HEALING: AN IMPORTANT TREATMENTEND POINT IN IBDThe primary goal of IBD treatment must be tochange the underlying course of the disease and tostrive for normalisation of the bowel. This requiresadopting mucosal healing as a treatment end pointto assess the effectiveness of treatment and as aprognostic marker of long term disease. Althoughevidence of the powerful effect that biologics haveon the mucosa highlights the importance ofmucosal healing, conventional treatments alsoinduce mucosal healing in a small proportion ofpatients.4 The important point is that mucosalhealing, regardless of the agent which induces it, isassociated with improved outcomes. This is high-lighted by a Norwegian, population based cohortstudy that looked at the effect of mucosal healing

Figure 1 Long termmucosal healing reducessurgery rates. Reproducedfrom Frøslie et al4 withpermission from Elsevier.CD, Crohn’s disease; MH,mucosal healing; UC,ulcerative colitis.



on resection and colectomy rates in patients withUC and CD between 1990 and 1994, beforebiologic therapy was available.4 The study foundthat across the therapeutic classes, long termmucosal healing was associated with decreasedsurgery over time compared with no mucosalhealing (fig 1).4 This demonstrates that it isimportant that mucosal healing be achieved andmaintained.

Importantly, mucosal healing also predicts sus-tained clinical outcomes. In the SUTD (Step-upTop-down) study, clinical outcomes in patientsachieving mucosal healing (simple endoscopy score(SES) 0; no ulcers) were compared with thosepatients with endoscopic activity (SES 1–9) at year2.5 Treatment-naıve patients with CD (n = 133)were randomised to receive infliximab/azathioprine(AZA) combination therapy or conventional man-agement for 2 years. Data were then collected for 2more years after the study, during which timepatients were treated at the discretion of theirclinician.5 In patients who had mucosal healing (0SES) at year 2, a significantly greater proportion(69.6%) were in stable clinical remission off corti-costeroids and with no flares in the subsequent year

3 and 4 follow-up compared with patients withoutmucosal healing (38.1%, p = 0.036).5 Importantly,this remission was sustained when patients did nottake infliximab during the year 3 and 4 follow-up(fig 2).5 This shows that achieving early, completemucosal healing using biologic therapy predictssignificantly higher clinical remission rates in sub-sequent years.

Mucosal healing is considered to be importantenough that other biologic agents have beenevaluated to achieve this end point. In an open labelstudy evaluating the effects of certolizumab onmucosal healing, 61.5% of patients achieved endo-scopic response (Crohn’s Disease Endoscopic Indexof Severity (CDEIS) .5) and 42.3% achievedendoscopic remission (CDEIS ,6) at week 10.When looking at the very hard end point of completemucosal healing defined as a CDEIS ,3 (someinflammation present), 11.3% achieved this endpoint.6 The patients in this study were from a verymature population compared with those in theSONIC trial. In SONIC, complete mucosal healingwas defined as complete absence of mucosal ulcera-tions; the mucosa is completely normal. At6 months, 44% of patients treated withinfliximab+AZA and 30% treated with infliximabmonotherapy achieved this end point.7 These resultshave set the bar for what is possible and what otheragents need to strive for in terms of mucosal healing.

Mucosal healing following surgeryFollowing resection, 73% of patients will experienceendoscopic recurrence within the first year.8 Thispatient population has been treated with manydifferent therapies without impressive resultsbecause the lesions come back and symptoms recur,which may lead to physicians waiting to treatsymptoms. In a small, randomised, controlled trial of23 patients, there was a significant effect on mucosalhealing with infliximab treatment following resec-tion.9 Four weeks after surgery, patients receivedeither infliximab 5 mg/kg at weeks 0, 2 and 6 andthen every 8 weeks or standard care (5-aminosa-licylic acid (5-ASA), AZA, etc). At 1 year, 90% ofpatients receiving infliximab achieved endoscopic

Figure 2 Mucosal healing predicts sustained clinical response.5 CD, Crohn’s disease; SES, simple endoscopy score; TNF, tumour necrosis factor.

Figure 3 Time-bound Crohn’s disease treatment algorithm.11 AZA, azathioprine; MTX,methotrexate; TNF, tumour necrosis factor.



remission compared with 15.4% of patients treatedwith standard care (p = 0.0006). Similar results wereobserved with infliximab achieving completeabsence of CD in colonoscopy at 1 year (80% vs7.7%, p = 0.0009).9 This shows the impressive resultsof infliximab in very early disease as these patientswere treated just after resection.

SHOULD WE USE BIOLOGIC THERAPY EARLIER?Over the past few years, a number of post hocanalyses have confirmed that the early use ofbiologics improves clinical outcomes. In the adali-mumab study CHARM (Crohn’s trial of the fullyHuman antibody Adalimumab for RemissionMaintenance), the highest remission rates at week26 were found in patients with the shortest diseasedurations (,2 years).10 Similar results were seenwith certolizumab pegol in PRECISE 2 (PEGylatedAntibody Fragment Evaluation in Crohn’s DiseaseSafety and Efficacy).11

The SONIC trial, however, is a landmark,randomised controlled trial assessing the robust-ness of the early use of infliximab in CD. Thisrandomised, controlled study showed that wheninfliximab is used to treat early CD, it significantlyimpacts overall remission rates. The therapeuticgain almost doubled just by treating patientsearlier compared with other infliximab studiesin mature patient populations. SONIC showsthat there is a ‘‘window of opportunity’’ when

infliximab treatment is most effective. Earlytreatment will improve clinical outcomes andpotentially change the natural course of disease.Certain patients, particularly those with veryactive disease (high inflammatory burden andmucosal lesions) at baseline are likely to gain themost benefit.7 Furthermore, it has been shown thatinfliximab/AZA combination therapy providesgreater improvements than infliximab monother-apy in the short term, although it remains unclearwhether this effect extends into the long term. It isstill necessary to determine if other biologictherapies perform in a similar fashion as infliximabwithin randomised trials.

Evidence suggests that infliximab rather thanAZA should be the therapy of choice in AZA-naıvepatients with CD who are still active despitecorticosteroids. Patients who have a large inflam-matory burden and severe disease and are notresponding to steroids are suitable for biologictherapy. Based on the data, combination therapyshould be used in biologic/AZA-naıve patients,certainly in the short term (6 months). If patientsare failing on an immunosuppressant (AZA/6-mercaptopurine (6-MP)), it would be inappropriateto continue this therapy along with a biologic asthe patient has already not responded to thismechanism of action. In clinical practice, for AZA/6-MP failures, it is appropriate to start treatmentwith infliximab or another biologic. If there is aresponse within 12–24 weeks, the immunosup-pressant can likely be withdrawn.12

CURRENT TREATMENT PARADIGMSThe clinical evidence demonstrates benefit withinfliximab early in the course of IBD. The reality,however, is current regulatory restrictions in somecountries dictate that patients must fail certaintherapies before infliximab is introduced. If this isthe case, clinicians must re-evaluate where drugsare going to work and what the outcomes will be.The overriding treatment goal should be to achievecorticosteroid-free remission in all patients. Earlytreatment with infliximab can achieve this asdemonstrated in SONIC. Chronic, or repeated,corticosteroid use should no longer be considered avalid option. With this goal in mind, time-boundtreatment algorithms have been established for bothCD and UC that aim to maximise remission andminimise corticosteroid dependence (figs 3 and 4).13

Competing interests: Consultancies: AstraZeneca, Ferring, AbbottLaboratories, Byk Solvay, Schering-Plough, Shire Pharmaceuticals,Centocor, Elan, Prometheus, GlaxoSmithKline, UCB, Procter & Gamble,Bristol-Myers Squibb; Honoraria: Ferring, Axcan, Jansen, Schering-Plough, Shire Pharmaceuticals, Procter & Gamble; Grants received:Ferring, Axcan, Jansen, Schering-Plough, Shire Pharmaceuticals,Procter & Gamble.

REFERENCES1. Langholz E, Munkholm P, Davidsen M, et al. Course of ulcerative

colitis: analysis of changes in disease activity over years.Gastroenterology 1994;107:3–11.

2. Cosnes J, Nion-Larmurier I, Beaugerie L, et al. Impact of theincreasing use of immunosuppressants in Crohn’s disease on theneed for intestinal surgery. Gut 2005;54:237–41.

Figure 4 Time-bound ulcerative colitis treatment algorithm.11 5-ASA, 5-aminosalicylicacid; AZA, azathioprine; IFX, infliximab.

Summary

c Early use of infliximab is important in CD and can improve outcomes.c Studies are underway to determine if early use of infliximab will also benefit

patients with UC.c Mucosal healing with timing of therapy will lead to the best outcomes and

change the natural course of disease.



3. Cosnes J, Cattan S, Blain A, et al. Long-term evolution of diseasebehavior of Crohn’s disease. Inflamm Bowel Dis 2002;8:244–50.

4. Frøslie KF, Jahnsen J, Moum BA, et al. Mucosal healing ininflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412–22.

5. Baert F, Moortgat RN, van Assche G, et al. Mucosal healingpredicts sustained clinical remission in early Crohn’s disease.J Crohn’s Colitis 2008;2:7.

6. Colombel JF, Hebuterne X. Endoscopic mucosal improvement inpatients with active Crohn’s disease treated with certolizumabpegol: first results of the MUSIC clinical trial. Am J Gastroenterol2008;103:A–1107.

7. Colombel J-F, Rutgeerts P, Reinisch W, et al. SONIC: a randomized,double-blind, controlled trial comparing infliximab and infliximab plusazathioprine to azathioprine in patients with Crohn’s disease naive toimmunomodulatorsandbiologictherapy.JCrohn’sColitis2009;3:S45–6.

8. Rutgeerts P, Geboes K, Vantrappen G, et al. Predictability of thepostoperative course of Crohn’s disease. Gastroenterology1990;99:956–63.

9. Regueiro M, Schraut W, Baidoo L, et al. Infliximab for preventionof Crohn’s disease (CD) recurrence affer ileal resection. Am JGastroenterol 2008;103:S412.

10. Schreiber S, Reinisch W, Colombel JF, et al. Early Crohn’s diseaseshows high levels of remission to therapy with adalimumab: sub-analysis of CHARM. Gastroenterology 2007;132:A-147.

11. Schreiber S, Colombel JF, Danes J, et al. Recent onset Crohn’sdisease shows higher remission rates and durablity of response totreatment with subcutaneous monthly certolizumab pegol: resultsfrom the analysis of the PRECISE 2 phase III study. Gut2006;55(suppl II):A131.

12. Van Assche G, Magdelaine-Beuzelin C, D’Haens G, et al.Withdrawl of immunosuppression in Crohn’s disease treated withscheduled infliximab maintenance: a randomized trial.Gastroenterology 2008;134:1861–8.

13. Panaccione R, Rutgeerts, Sandborn WJ, et al. Review article:treatment algorithms to maximize remission and minimizecorticosteroid dependence in patients with inflammatory boweldisease. Aliment Pharmacol Ther 2008;28:674–88.



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IBD Landmarks Studies Review - Gut 2009