European Journal of Pharmacology 623 (2009) S17–S25

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European Journal of Pharmacology

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Review

Infliximab therapy for patients with inflammatory bowel disease: 10 years on

Gert Van Assche ⁎, Séverine Vermeire, Paul RutgeertsDivision of Gastroenterology, University of Leuven Hospitals, Herestraat 49, B-3000 Leuven, Belgium

⁎ Corresponding author. Tel.: +32 16344225; fax: +E-mail address: gert.vanassche@uzleuven.be (G. Van

0014-2999/$ – see front matter © 2009 Elsevier B.V. Aldoi:10.1016/j.ejphar.2009.10.025

a b s t r a c t

a r t i c l e i n f o

Article history:Accepted 30 September 2009Available online 18 October 2009

Keywords:Crohn's diseaseUlcerative colitisBiological therapyAnti-TNF therapyInfliximabEndoscopyDisease out comeMedical therapy

The advent of infliximab a decade ago has drastically changed the treatment paradigm for patients withinflammatory bowel diseases (IBD). Controlled evidence supports the use of this anti-TNF antibody to treatluminal and fistulizing Crohn's disease, ulcerative colitis, pediatric Crohn's disease and extraintestinalmanifestations of IBD. For all IBD indications induction with infliximab 5 mg/kg IV at weeks 0–2–6, followedby q8 week scheduled maintenance is advocated. Novel treatment goals such as mucosal healing and thereduction of hospitalizations and surgeries, have been achieved by infliximab and open the perspective ofdisease modification. The benefit to risk ratio of infliximab is comparable to that of other immunosuppressivetreatments such as azathioprine, provided patients are correctly selected and followed. Despite this progress,optimal treatment strategies are still debated. Recent evidence supports the ‘top down’ use of infliximab inpatients naive to azathioprine or methotrexate, but the lack of clinically useful predictors of a debilitatingdisease course hinders the selection of patients eligible for early biological intervention. Secondary loss ofresponse or intolerance due to immunogenicity is intrinsic to the use of therapeutic antibodies, and fuels thecontroversy over the combination of anti-TNF agents with traditional immunosuppressives.

32 16344419.Assche).

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© 2009 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S172. Infliximab for refractory luminal Crohn's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S183. Infliximab for perianal fistulizing Crohn's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S184. Infliximab for ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S195. Pediatric inflammatory bowel disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S196. Infliximab for extraintestinal manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S197. Step up or top down infliximab therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S198. Mucosal healing as a therapeutic endpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S209. The role of combination infliximab and immunosuppressive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S20

10. Optimal treatment schedules long term . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S2111. Can infliximab ever be stopped? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S2112. Safety of infliximab in patients with inflammatory bowel disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S2213. Conclusions and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S23Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S23References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S23

1. Introduction

Infliximab, a chimeric monoclonal IgG1 anti-TNF antibody, was thefirst biological therapy to be introduced in the treatment of patientswith inflammatory bowel disease a decade ago. Since then anti-TNFtherapy has dramatically changed our concept of treating refractoryCrohn's disease and more recently also of ulcerative colitis (UC).

Inflammatory bowel diseases are chronic inflammatory illnessesaffecting the intestinal tract. Crohn's disease typically occurs in theright colon and in the terminal ileum, but can affect the entiregastrointestinal tract. Ulcerative colitis only affects the colon, and thediagnosis of indeterminate of unclassified colitis is reserved forchronic colitis with endoscopic and histologic features of Crohn'sdisease and ulcerative colitis. The exact pathogenesis of inflammatorybowel disease is unknown. The most recent hypothesis states thatgenetically predisposed subjects lose tolerance to intestinal micro-biota and as a consequence their innate and adaptive immune system

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unleach an uncontrolled inflammatory reaction resulting in tissuedamage and loss of organ function (Baumgart and Sandborn, 2007).Hitherto unidentified environmental factors and intestinal dysbiosismost likely catalyze this uncontrolled inflammation. Most patientswith Crohn's disease have a progressive disease course leading tocomplications and necessitating surgery for strictures or abscesses(Beaugerie et al., 2006; Loly et al., 2008). Conventional, non biologicaltherapies, have failed to change the long term outcomes of patientswith Crohn's disease. Systemic corticosteroids are an effectiveinduction agent for luminal Crohn's disease, but large populationbased studies have shown that one year after the introduction ofcorticosteroids most patients are either steroid dependent, steroidrefractory or have been operated on (Munkholm et al., 1994; Faubionet al., 2001 ). Topical steroids such as budesonide have an improvedsafety profile but they are not efficacious for long termmaintenance ofremission. Azathioprine and methotrexate are efficacious long termtreatment options and spare steroids (Present et al., 1980; Candyet al., 1995; Feagan et al., 1995; Feagan et al., 2000), but despite theincreasing use of azathioprine in the last 20 years the rates of Crohn'sdisease related surgery has not declined. In a French referral centercohort analyzing patients from 1978 to 2002 the cumulativeprobability of using azathioprine in a 5-year period rose from 0.13to 0.56 without affecting the cumulative need for surgery (0.35 to 0.34over 5 years). However, it needs to be said that only 9% of patientsneeding surgery had taken azathioprine for more than 3 months(Cosnes et al., 2002). Conventional treatment of perianal fistulizingCrohn's disease, one of the most debilitating Crohn's diseasecomplications, consists of surgical drainage, antibiotics and azathio-prine, but controlled evidence is lacking (Sandborn et al., 2003).Ulcerative colitis is characterized by a more variable disease courseand a recent analysis of the prospective Norwegian IBSEN cohort hasshown that after an initial disease flare 55% of patients are wellcontrolled with aminosalicylates or no therapy for at least a 5-yearperiod (Solberg et al., 2009). However, chronically active steroiddependent disease and fulminant steroid refractory ulcerative colitisrepresent major challenges to clinicians and patients alike. Theevidence supporting the use of azathioprine in ulcerative colitis ismore limited, although Ardizzone et al. demonstrated that azathio-prine is superior to 5-ASA in maintaining steroid free clinical andendoscopic remission (Ardizzone et al., 2006). For patients withfulminant ulcerative colitis failing IV corticosteroids cyclosporine at adose of 2 to 4 mg/kg IV is an adequate medical rescue before totalcolectomy (Lichtiger et al., 1994; Van Assche et al., 2003a,b). However,avoidance of colectomy long term after rescue with cyclosporine is lessthan 50% (Moskovitz et al., 2006; Campbell et al., 2005) andcyclosporine carries a sizable mortality risk, particularly due toopportunistic infections (Colombel et al., 2004a,b; Arts et al., 2004).

Biological therapy with anti-TNF agents thus created greatexpectation to further solve the clinical shortcomings of conventionaltherapy. Immunogenicity and primary as well as secondary non-response, however, were identified as new challenges.

Like all bio-engineered therapeutic proteins infliximab inducesanti-drug antibodies in patients. This immunogenicity interferes withlong term outcomes as it is associated with loss of efficacy andintolerance due to infusion reactions (Baert et al., 2003). Morehumanized anti-TNF antibodies, such as the human IgG1, adalimumab,and the humanized and pegylated Fab fragment, certolizumab, haveshown efficacy in Crohn's disease (Hanauer et al., 2006; Colombelet al., 2007; Sandborn et al., 2007a; Schreiber et al., 2005, 2007) andhave recently opened new perspectives to patients but all issues havenot been resolved. Indeed, still 20–30% of patients with refractoryCrohn's disease (Targan et al., 1997; Hanauer et al., 2002; Present et al.,1999) and 30–40% (Rutgeerts et al., 2005) of those with refractoryulcerative colitis do not respond to anti-TNF treatment (primaryfailures). Moreover, humanization of therapeutic antibodies has notsolved the problem of immunogenicity and secondary loss of response

to anti-TNF agents. Finally, anti-TNF therapies are associated with anincreased risk of infectious complications and possibly of non-Hodgkin's lymphoma. At this moment, however, despite ongoingdevelopmental programs, anti-TNF agents still are the only biologicalsapproved to treat inflammatory bowel disease in Europe.

This review will focus on the current evidence supporting the useof infliximab to treat patients with inflammatory bowel disease. Inaddition, we will analyze to what extent infliximab can be consideredas a disease modifying agent. Finally we will describe optimaltreatment schedules when using infliximab in real life clinicalpractice.

2. Infliximab for refractory luminal Crohn's disease

Infliximab is administered to patients with Crohn's disease andulcerative colitis as an intravenous infusion at a dose of 5 mg/kg bodyweight at weeks 0, 2 and 6, followed by 5 mg/kg infusions every8 weeks for maintenance.

The efficacy of infliximab for the treatment of refractory luminalCrohn's disease has been proven in several randomized clinical trials.In the pivotal trial by Targan et al., 65% of patients responded to asingle infusion of infliximab (defined as a 70 point drop of the Crohn'sdisease activity index, or CDAI) and 30% achieved remission ( CDAIscore b150) (Targan et al., 1997). A dose response effect was notobserved in this trial. However, at week 12 37% of patients hadrelapsed, but were not retreated in this trial. In the larger (n=573)ACCENT 1 trial (Hanauer et al., 2002) 58% of patients responded byweek 2 and 27% achieved remission. After the full loading dose atweeks 0–2–6 a significant 10% increment of clinical response wasobserved (from 59 to 69%, Pb0.035) and has justified the use of threeinfusion infliximab induction therapy in Crohn's disease. The efficacyof infliximab to maintain remission of luminal Crohn's disease wasdemonstrated in two controlled trials. In the first trial by Rutgeertset al. patients received 10 mg/kg infliximab or placebo q8weeks untilweek 36 after active induction therapy (Rutgeerts et al., 1999).Significantly more patients in the 10 mg/kg infliximab group main-tained remission (53% vs. 20%, Pb0.013). The ACCENT I maintenancetrial randomized patients two weeks after receiving one infusion ofinfliximab at 5 mg/kg to placebo, or IFX infusions at 2–6–14–22–30–38and 46 weeks (Hanauer et al., 2002). The trial had two maintenancearms on active drug. The low dose group received infliximab 5 mg/kg atweeks 2–6 and thereafter and the high dose group received 5 mg/kg atweeks 2–6 and 10 mg/kg thereafter. Clinical remission rates at week 30for patients with an initial response at week 2 were 44% in 5 mg/kg and45% in the 10 mg/kg group (Pb0.02 IFX overall). Also in this trial, thesteroid free remission was more prevalent in patients treated with IFX(29% vs. 9% for placebo, OR 4.2 95% CI 1.5–11.5, P=0b0.01).

Is surgical outcome affected by infliximab treatment? The risk ofseptic complications following intestinal surgery in patients treatedwith infliximab is not increased (Marchal et al., 2004; Colombel et al.,2004a,b).

3. Infliximab for perianal fistulizing Crohn's disease

Infliximab was shown to be effective in two large placebo-controlled trials for patients with perianal fistulizing disease. In thefirst, induction trial 5 mg/kg infusions at weeks 0, 2, and 6 resulted incomplete fistula closure (defined as cessation of all drainage on 2visits 4 weeks apart) in 17/31 (55%) of cases (Present et al., 1999),significantly more than placebo (13%). Higher dose infusions of10 mg/kg were not more effective (38% remission). The median timeto loss of response was 12 weeks. The larger ACCENT II trial confirmedthe efficacy for induction of fistula response and remission (69%fistula response, defined as cessation of drainage from N50% of fistulaorifices, or 195/282 at 14 weeks), and subsequently randomizedresponders to receive 5 mg/kg every 8 weeks, or placebo (Sands et al.,

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2004). At week 54, 33/91 (36%) patients treated with 5 mg/kginfliximab were in remission compared to 19/98 (19%) on placebo(P=0.009). Response rates were 46% in the infliximab group and 23%for placebo (P=0.01). Maintenance infliximab reduced hospitaliza-tions and surgeries (Lichtenstein et al., 2005a,b). The difference in thesurgical incidence could be attributed to the major surgeries (bowelresections, derivating ostomies), but the rates of incision and drainageof abscesses or placement of seton drains in the fistula track wasidentical. Subsequently, several uncontrolled studies reported on theefficacy of infliximab to ameliorate inflammatory lesions visualizedwith pelvic magnetic resonance imaging (MRI) or endo-analultrasound (Van Assche et al., 2003a,b). However, these studies alsoindicated that complete obliteration of fistula track after long terminfliximab therapy was rarely observed.

4. Infliximab for ulcerative colitis

The initial experience with open-label use of infliximab forpatients with ulcerative colitis was mixed (Chey, 2001; Regueiroet al., 2006), but placebo-controlled trials have proven thatinfliximab is an effective therapy for refractory ulcerative colitisand for rescue of steroid-resistant pre-surgical ulcerative colitis. TheACT trials have shown that induction with IV infliximab 5 mg/kg atweeks 0, 2 and 6 followed by scheduled maintenance therapy every8 weeks is effective in refractory moderate-to-severe ulcerativecolitis to improve disease related symptoms, to induce remission,to heal the mucosa and to decrease the need for steroids over54 weeks (Rutgeerts et al., 2005). In ACT-1 and ACT-2 trialsinfliximab induced remission in up to 39% of patients at a dose of5 mg/kg and significant clinical response in up to 69%. Again no doseresponse was observed between 5 and 10 mg/kg. After one year oftreatment still more than 30% of patients were in remission andsustained remission was achieved in 20% of patients after one year of8-weekly IFX treatment. Endoscopic response with completemucosal healing or only mild residual lesions was observed inabout 60% of patients. Approximately 30% of patients were failingoral corticosteroids in both trials and experienced similar clinicalefficacy as compared to those failing other medical therapies. Inaddition, infliximab decreased ulcerative colitis-related hospital-izations at week 30 in the ACT trials. The total number ofhospitalizations in the infliximab-treated group was significantlylower than in the placebo group (19 vs. 44, Pb0.01).

In patients with acute severe ulcerative colitis resistant to highdoses of glucocorticosteroids a single infusion of infliximab 5 mg/kgreduced the need for colectomy from 67% with placebo to 29%(P=0.017). Significantly more patients treated with placebo (14/21)required surgical colectomy by three months as compared to thosetreatedwith a single dose of infliximab 5 mg/kg (7/24) (Jarnerot et al.,2005). Preliminary results from a cohort of patients treated at theMount Sinai hospital in New York suggest that patients receivinginfliximab followed by cyclosporine or vice versa have a substantialrisk of serious adverse events including mortality (Maser et al., 2007),but the data from the Hôpital St Louis in Paris, France (Leblanc et al.,2009), suggest that successive use of both agents is a valuable andrelatively safe option. Although infliximab prevented colectomy in theACT-1 and ACT-2 trials (Sandborn et al., 2009), data on long termavoidance of colectomy with infliximab are not yet available.

Is surgical outcome affected by infliximab treatment? Ferranteet al. recently reported on a single center experience of colectomiesfor patients with ulcerative colitis. Patients treated with infliximabwere not more likely to experience septic complications after pouchsurgery, although most procedures were elective rather than urgentrescues (Ferrante et al., 2009). In an earlier publication, however, fromthe colorectal surgery group at the Mayo Clinic, Rochester, MN, anincreased risk of infectious postoperative complications was found ina group of infliximab-treated patients as compared to controls

(Selvasekar et al., 2007). Other retrospective cohorts and thecontrolled Scandinavian trial have not confirmed this increasedcomplication risk.

5. Pediatric inflammatory bowel disease

Infliximab has been approved for the treatment of refractoryCrohn's disease in children. The efficacy of IFX as an induction regimein children or adolescents with Crohn's disease has not been assessedin a randomized placebo-controlled trial. Evidence to support the useof infliximab in pediatric Crohn's disease is inferred from arandomized, dose-blind, open-label trial (Baldassano et al., 2003),and the open-label induction arm of the REACH study (Hyams et al.,2007). The REACH study demonstrated that in children andadolescents on concomitant immunosuppression, with response toinfliximab induction therapy, scheduled maintenance with infliximab5 mg/kg q8 weeks is effective at maintaining clinical remission(Hyams et al., 2007). Moreover, maintenance infliximab therapy issteroid sparing (Hyams et al., 2007; Cezard et al., 2003; Markowitzet al., 2006), and has a benefit on growthwith improvement of growthvelocity (Hyams et al., 2007; Borrelli et al., 2004; Walters et al., 2007),which is a crucial outcome in the pediatric population. As in adults,maintaining remission over time may require dose escalation or areduction in dosing interval (Hyams et al., 2007; Serrano et al., 2001).No controlled trial evaluating the efficacy of infliximab in pediatriculcerative colitis has been published.

6. Infliximab for extraintestinal manifestations

Articular disease is themost frequent extraintestinal manifestationof inflammatory bowel disease. Axial and large joint arthropathy inpatients with Crohn's disease and UC can be classified in the group ofdiseases known as spondylarthritis. The evidence supporting the useof infliximab for spondylarthritis in Crohn's disease is largely based onopen-label studies. However, the efficacy of infliximab to treatspondylarthritis in general has been proven in randomized controlledtrials and in clinical practice articular symptoms in patients withCrohn's disease and spondylarthritis respond well to infliximabtherapy (Van den Bosch et al., 2002; Zochling et al., 2006; Braun et al.,2002; Gorman et al., 2002; Van der Heijde et al., 2005). Erythemanodosum, a painful nodular skin lesion occurring in clusters most oftenon the legs, are a sign of active inflammation and respond well totreatment of underlying inflammatory bowel disease activity, includinginfliximab therapy. Pyoderma gangrenosum is a feared complication ofCrohn's disease and ulcerative colitis characterized by ulcerating sterileskin wounds with frequent secondary infection. A multicentre,randomized, placebo-controlled trial of 30 patients, including 19patients with inflammatory bowel disease demonstrated the efficacyof infliximab to treat pyoderma gangrenosum (Brooklyn et al., 2006).Two weeks after one infusion of infliximab 5 mg/kg 46% had improvedcompared to 6% with placebo (P=0.025). Interestingly, 90% of patientswith a short duration since the onset of pyoderma (b12 weeks)responded compared to less than 50% of patients with lesions olderthan 3 months.

An unpublished pilot trial indicated that primary sclerosingcholangitis does not improve with infliximab therapy, althoughprimary sclerosing cholangitis is not a contraindication to infliximabtherapy in patients with active inflammatory bowel disease.

7. Step up or top down infliximab therapy

Drugs targeted at interrupting the inflammatory cascadework bestin patients with a high burden of inflammation. Patients with Crohn'sdisease aremore likely to have an inflammatory phenotype early on inthe course of Crohn's disease. Nevertheless, the majority of patientswith Crohn's disease develop a disabling disease course leading to

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complications and surgery (Beaugerie et al., 2006; Loly et al., 2008),and specifically young patients (b40 years) or patients with perianallesions at diagnosis are at risk for debilitating complications.However, for an individual patient predicting a disabling diseasecourse and thus the need formore advancedmedical therapy has beendifficult. Therefore, starting immunosuppressives with the first or atleast with the second course of corticosteroids has become generalpractice in young patients with Crohn's disease. A recently publishedclinical strategy trial from Belgium and the Netherlands randomized133 patients with active Crohn's disease naive to steroids and naive toazathioprine to either a conventional step up strategy with fullcourses of steroids (prednisolone or budesonide) and introduction ofazathioprine when they flared after tapering or became dependent onsteroids (D'Haens et al., 2008). Patients in the top down arm receivedthree infusions of infliximab and were started on azathioprine atinduction. From week 6 azathioprine was continued as a mono-therapy and infliximab was only administered upon flare. Until oneyear after the start of therapy steroid free remission was morefrequent in the early combined immunosuppressives group [61.5% vs.42.2%, difference 19.4% (95%CI 2.4–36.3, Pb0.05)]. Also the mediantime to relapse was longer in the early combined immunosuppres-sives (‘top down’) group: 329·0 days, IQR: 91.0-not reached vs. 174.5days, IQR 78·5–274·0, P=0·03. The trial also confirmed that inpatients who need corticosteroids to control their Crohn's diseasemore than two thirds are treated with azathioprine after 2 years. As acaveat, it should be noted that this unblinded study is liable to theintrinsic observer bias associated with an open-label trial.

8. Mucosal healing as a therapeutic endpoint

Endoscopy with mucosal biopsies is arguably the gold standard forestablishing a diagnosis of inflammatory bowel disease. However, therole of endoscopy in assessing the efficacy of medical therapy ininflammatory bowel disease is more controversial. In Crohn's diseaseendoscopic healing is usually assessed with the Crohn's diseaseEndoscopic Index of Severity (CDEIS) (Mary and Modigliani, 1989) orthe more recently developed Simplified Endoscopic Score for Crohn'sdisease (SES-CD) (Daperno et al., 2004). Both scores assess inflam-mation in all segments of the colon and terminal ileum, but the SES-CD scores focuses on mucosal ulcerations. Finally, complete disap-pearance of mucosal ulcerations has been used to evaluate the efficacyof infliximab. Steroid therapy is not effective at inducing endoscopichealing (Modigliani et al., 1990; Olaison et al., 1990; Frøslie et al., 2007),but uncontrolled evidence suggests that azathioprine induces endo-scopic improvement when used long term (D'Haens et al., 1999;Lemann et al., 2006).

The ACCENT I study included an endoscopic sub-study in 99 patientsrecruited from 25 preselected sites (Rutgeerts et al., 2006). In this study,patients were treated with infliximab 5 or 10 mg/kg, or placebo, for1 year. At week 54, more patients who received systematic 8-weeklyinfliximab retreatment (combined dose levels) exhibited completemucosal healing than those who received a single 5 mg/kg infliximabinfusion andepisodic therapyuponflare thereafter (Rutgeerts et al., 2004,2006). In an open-label early intervention trial, combined infliximab andazathioprine therapy induced clearly more endoscopic healing of ulcersthan standard step up therapy (73% vs. 30%, Pb0.001) (D'Haens et al.,2008). In the blinded double-dummy controlled SONIC trial comparingazathioprine monotherapy (2.5 mg/kg/d), infliximab monotherapy(5 mg/kg) and combined infliximab plus azathioprine the total disap-pearance of mucosal ulcers was most frequently observed in thecombined infliximab and azathioprine group at week 26 (44% IFX+azathioprine vs. 19% azathioprine (Pb0.001)) and patients with mucosallesions at inclusion were more likely to benefit from infliximab therapy(Sandborn et al., 2008).

In ulcerative colitis, a diversity of endoscopic scores has beenvalidated, but recently the Mayo Endoscopic activity score (Schroeder

et al., 1987) is used in most clinical trials. This score has 4 grades fromnormal mucosa to severe disease. In the two randomized, double-blind, placebo-controlled Active Ulcerative Colitis Trials (ACT-1 andACT-2) endoscopic healing was integrated in the primary endpoint ofdisease remission. Mucosal healing was defined as endoscopy sub-score of zero (complete healing) or 1 (partial healing). At weeks 8 and30 mucosal healing, in each study and at week 54 in ACT-1, occurredin significantly more patients in the infliximab-treated groups than inthe placebo groups (P≤0.009 for all comparisons).

Although, the efficacy of infliximab for inducing endoscopichealing in patients with Crohn's disease and ulcerative colitis isproven, the impact of mucosal healing on long term outcomes is morecontroversial.

In ACCENT I, patientswith Crohn's diseasewho exhibited completemucosal healing both short and long term had significant reductionsin the number of hospitalizations, procedures, surgeries, and days ofintensive care unit stay, compared with patients who exhibited onlytransient or no healing (Rutgeerts et al., 2006). In a large single centercohort, endoscopic mucosal healing was also associated with areduction of major abdominal surgeries. The surgical rate was 9.3%(7/75) in healed patients with scheduled maintenance infliximab and22.2% (6/27) in those with persistent mucosal ulcerations (Schnitzleret al., 2009a,b). However, no prospective, controlled trial hasevaluated the impact on long term outcomes of intensifying medicaltherapy in those inflammatory bowel disease patients with lack ofmucosal healing. Therefore, at present, all evidence supporting a rolefor endoscopic healing in guiding themedical or surgical managementof patients with Crohn's disease is indirect.

9. The role of combination infliximab andimmunosuppressive therapy

The marketing authorization in Europe (the European “labeling”)and theECCO treatment guidelineshavepositioned infliximabas secondor third line immunosuppressive therapy in patients failing steroidsand/or azathioprine (Travis et al., 2006).As a consequencemostpatientshave been treated with a combination of infliximab and a purineanalogue ormethotrexate, analogous to the use in rheumatoid arthritis.However, contrary towhat has been shown in rheumatoid arthritiswithmethotrexate, a therapeutic synergism of combined therapy withtraditional immunosuppressives (azathioprine/6-mercatopurine orMTX) and anti-TNF antibodies had never been clearly demonstratedin patients with inflammatory bowel disease until very recently. Themain rationale to use combined therapy in inflammatory bowel diseasewas the intrinsic potential of infliximab to induce anti-drug antibodies(immunogenicity). Immunosuppressives were shown to decrease thedevelopment of neutralizing anti-infliximab antibodies when this drugwasused in anepisodic, on-flare strategy [Baert et al., 2003; Farrell et al.,2003]. Also, infliximab serum levelswere significantly higher in patientswith concomitant immunosuppressive therapy (Baert et al., 2003).More recently it became clear that this protective effect ismuch less if atall present when patients are treated with infliximab in a scheduledmaintenance regimen (Hanauer et al., 2004; Maser et al., 2006;Vermeire et al., 2007). This was recently confirmed in a large Belgianreferral center cohort where concomitant azathioprine ormethotrexatetherapy did not influence long term outcomes of infliximab treatment(Schnitzler et al., 2009a,b). Recently, a prospective open-label trialdemonstrated that withdrawing immunosuppressives from patientswith Crohn's disease and in remission with combined infliximab andimmunosuppressives therapy for at least 6 months did not affectefficacy over 2 years of follow up, but tended to decrease IFX troughlevels (Van Assche et al., 2008). The trial indicated that the impact ofwithdrawing anti-metabolites in patients treated with scheduledinfliximab maintenance therapy has no or only limited risk of loss ofefficacy, although IFX trough levels were generally lower afterinterruption of immunosuppressives and this warrants further long

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term follow up. All patients in the trial had received combinationtherapy for at least 6 months and most had failed azathioprine beforestarting infliximab. In addition, preliminary data from a recent Canadiancollaborative trial showed no additional clinical benefit of methotrexate25 mg/week in combination with maintenance every 8 weeks inflix-imab over infliximab therapy alone.

In recent years and with the data from early intervention trials,anti-TNF agents have been used more early in the disease courseincluding in patients naive to azathioprine and this patientpopulation has a different profile. Preliminary data from the large(n=508) blinded double-dummy controlled SONIC trial comparingazathioprine monotherapy (2.5 mg/kg/d), infliximab monotherapy(5 mg/kg) and combined infliximab plus azathioprine have beenreleased (Sandborn et al., 2008). At 26 weeks the steroid freeremission rates in patients receiving combined immunosuppressivetherapy with infliximab and azathioprine were higher than in thoseon infliximab monotherapy (57% vs. 45%, PN0.05) and these werealso higher than remission rates in patients with azathioprinemonotherapy (45% vs. 30%, Pb0.01). The difference between thethree groups persisted through one year of treatment. A course ofsteroids was allowed in all patients until week 12 to compensate forthe slow onset of the therapeutic effect of azathioprine. Also, the totaldisappearance of mucosal ulcers was highest in the combinedinfliximab and azathioprine group (44% IFX+azathioprine vs. 19%azathioprine (Pb0.001)). Infliximab serum levels from the SONICtrial have not yet been publically released. Since all patients in SONICwere naive to azathioprine and in the absence of pharmacokineticdata, it is logical to assume that at least azathioprine may actsynergistically with infliximab to induce clinical remission and tomaintain that over 6 months. However, the downside of immuno-suppressive synergism is toxicity and this will be discussed further.

10. Optimal treatment schedules long term

Optimizing therapy starts with selecting the ideal patient. Inclinical trials and also in open-label experience about 30% of patientswith inflammatory bowel disease have failed to respond to infliximaband clear predictors of response could improve the benefit to risk ratioof anti-TNF therapy. Unfortunately, the prime candidate responder toinfliximab still needs to be profiled. Large cohort studies haveidentified pure colonic disease, with a non-stricturing and non-penetrating phenotype and with increased CRP as predictors ofresponse to infliximab. Although preliminary, the SONIC trialprovided the first controlled evidence that patients with increasedCRP and/or mucosal lesions at endoscopy, clearly benefit more frominfliximab therapy (Sandborn et al., 2008). Also patients onimmunosuppressive therapy were more likely to respond shortterm to infliximab in cohort studies (Vermeire et al., 2002). It isunclear if the benefit of concomitant immunosuppressive therapy is aresult of decreased immunogenicity, selection of patients with aninflammatory phenotype or synergistic activity. Most of the data onpredictors of response to infliximab focused on short term efficacy; ina recently published large cohort of patients with Crohn's diseasetreated with infliximab and a median follow up of 55 months at asingle referral center, the concomitant immunosuppressive therapydid not improve long term results of infliximab (Schnitzler et al.,2009a,b). For clinical practice, selecting patients with ongoinginflammation reflected by an increased CRP and/or mucosal ulcera-tions appears the most valuable strategy at this moment.

Of all biological agents, the secondary loss of response to infliximabhas been best characterized since this compound has been used inclinical practice for more than a decade. With episodic on-flare use ofinfliximab patients run a clear risk of developing antibodies toinfliximab. Several treatment strategies such as systematicmaintenancetherapy, concomitant immunosuppression and prophylactic systemicsteroids, decrease the incidence of anti-drug antibody formation (Baert

et al., 2003; Farrell et al., 2003; Maser et al., 2006; Hanauer et al., 2006).Antibodies to infliximab are neutralizing and are associated withdecreased drug serum levels and shorter duration of response (Baertet al., 2003; Farrell et al., 2003; Maser et al., 2006). In the ACCENT I trial38% of patients in the episodic arm and 11% in the scheduledmaintenance arm developed antibodies to infliximab (Hanauer et al.,2004). Of interest, concomitant immunosuppressives only reduced theinduction of antibodies to infliximab in patients treated episodically, butnot in those on scheduled maintenance therapy (Hanauer et al., 2006).The findings from ACCENT I were confirmed in a retrospective cohort atthe Mount Sinai Hospital in Toronto. In this cohort antibodies toinfliximab correlated with low trough levels, with CRP and with theabsence of long term remission (Maser et al., 2006). Also, a decrease indrug levels may be driven by mechanisms other than the induction ofanti-drug antibodies. Antibodies to therapeutic proteinsmay not alwaysreflect the full extent of immunogenicity since the classic solid phaseELISAs can only reliablymeasure anti-drug antibodieswhen drug serumlevels are very low. Also differences between the assays impair thecomparison between individual cohorts. Drug trough levels, therefore,also reflect the degree of drug degradation andmay be amore clinicallyrelevant surrogate marker of bioactivity. IFX drug levels correlate withthe presence of antibodies to infliximab and with duration of response,but this correlation is not absolute (St Clair et al., 2002; Maser et al.,2006).

For patients with inflammatory bowel disease more relevant thanthe underlying mechanism is their chance of needing and respondingto accelerated dosing due to secondary loss of response. From clinicaltrials we can infer some of this information.

In the maintenance trial with infliximab, ACCENT I, increasing thedose from 5 to 10 mg/kg (30% of patients) and from 10 to 15 mg/kgrestored response in 62% and in 69% of patients respectively (Hanaueret al., 2002). Also, in a single center patient cohort in Leuven of 547patients with Crohn's disease followed for almost 5 years, 66% (75/108) patients who shortened their dose interval regained clinicalresponse until the end of follow up (Schnitzler et al., 2009a,b).Conversely, 22% of 547 primary responders, lost response to infliximabdespite interventions in the treatment schedule and every year 5% ofpatients discontinued infliximab therapy. The two main strategies fordose intervention are: (1) increasing drug exposure by decreasing thedosing interval or increasing the dose or (2) changing to another drug.To some extent the therapeutic intervention can be tailored to theindividual patient. If patients report no response whatsoever to theprevious dose of an anti-TNF agent, increasing the dose at the nextadministration appears more logical. Whereas in patients with agradual shortening of the duration of response, decreasing the intervalis a valid option. Switching to another anti-TNF agent is now an optionin the treatment of patients with Crohn's disease and should beconsidered in patients losing response or becoming intolerant to thefirst anti-TNF agent. However, in the GAIN trial with adalimumabspecifically designed to include patients with loss of response to orintolerant to infliximab, remission rates 4 weeks after high doseadalimumab induction were lower as compared to an earlier dosefinding trial, CLASSIC 1 (Sandborn et al., 2007a,b,c; Hanauer et al.,2006). This observation needs to be confirmed, but exhaustingtreatment options with the first anti-TNF compound by interval and/or dose optimization, should always be considered.

11. Can infliximab ever be stopped?

With the increasing use of purine analogues in the first line andanti-TNF agents in the second line, the majority of patients withCrohn's disease and a growing proportion of patients with ulcerativecolitis, are treated with immunosuppressives in maintenance. There-fore, the question arises if patients can stop these immunosuppressiveswithout risking early disease flares or complicated disease. Immuno-suppressive dependency is only a concern if safety is at stake and as

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discussed further, immunosuppressives may carry a small but signifi-cant risk of lymphoma and of serious infections.

Preliminary data from a GETAID trial indicate that in patients inclinical remission with infliximab maintenance therapy for at least1 year, interrupting this therapy leads to clinical relapse in almost halfof the patients after a median follow up of 12 months (Louis et al.,2009). Predictors of early relapse in this trial with 115 patientsincluded increased CRP or endoscopic activity at the time of stoppinginfliximab. Final results of this important trial are awaited.

12. Safety of infliximab in patients with inflammatorybowel disease

Anti-TNF agents such as infliximab have immunomodulatoryproperties. Even if ex vivo experiments have shown that humanlymphocyte function is not affected by infliximab (Cornillie et al.,2001), recent experience has revealed a limited but real risk ofserious infections. In the long term clinical trials ACCENT I andACCENT II, evaluatingmaintenance therapy in luminal and fistulizingCrohn's disease, respectively the incidence of serious infections wasbetween 3% and 6% and similar for patients treated with infliximabfollowed by placebo or by infliximab maintenance for a year(Hanauer et al., 2002; Sands et al., 2004). Also in the large placebo-controlled trials ACT-1 and ACT-2 in active ulcerative colitis a 2.5%–6.6% serious infection rate was reported with no increase in theinfliximab group of patients (Rutgeerts et al., 2005). Nevertheless,after the drug had been approved for clinical use in Crohn's diseaseand rheumatoid arthritis a limited but definite risk of opportunisticinfections particularly with pathogens residing intracellularly be-came apparent. Reactivation of latent tuberculosis was first reportedto be associated with infliximab use in 2001 (Keane et al., 2001), butit is now recognized that the occurrence of intracellular andgranulomatous infections, such as tuberculosis, histoplasmosis orCMV is a class effect of all anti-TNF agents (Bongartz et al., 2006;Peyrin-Biroulet et al., 2008). Most patients with inflammatory boweldisease receive a combined immunomodulator regimen also contain-ing purine analogues, methotrexate or steroids. The large (more than10,000 patient-years as of August, 2005) TREAT registry, whichfollows North American patients started either on infliximab or onalternative immunomodulatory treatment, revealed that the risk ofserious infections in infliximab-treated patients is mainly linked toconcomitant use of systemic steroids (Lichtenstein et al., 2005a,b).Also, in a recent safety analysis comparing an unselected singlecenter cohort of infliximab-treated patients with those on traditionaltherapy including steroids and anti-metabolites, the concomitant useof systemic steroids inferred a risk of serious infections (OR 2.7, 95%CI 1.2–6.1) (Fidder et al., 2009). Retrospective evidence frominflammatory bowel disease patients treated with traditionalimmunosuppressives and with infliximab at the Mayo clinic,indicates that cumulative use of immunosuppressives increases therisk of opportunistic infections (Toruner et al., 2008).

Acute infusion reactions to infliximab are generally mild tomoderate, but may preclude further treatment and often herald lossof efficacy since they are associated with ATI induction (Fidder et al.,2009). Severe reactions with anaphylaxis on the contrary areexceedingly rare and are allergic, IgE mediated phenomena. Delayedinfusion reactions occur usually in patients with a longer intervalbetween infusions and are associatedwith rapid clearance of the drug.In the ACCENT I trial 4.5% of the infliximab and 2.7% of the placeboinfusions were associated with an infusion reaction. Also, 2.4% of thepatients (14/573) met the definition of a delayed hypersensitivityreaction (Hanauer et al., 2002). In the cohort reported by Baert et al.the presence of antibodies to infliximabwas clearly associatedwith anincreased risk of infusion reactions and subsequent loss of response(Baert et al., 2003). In this cohort a total of 27% of patients developedinfusion reactions with episodic, on-flare infliximab therapy. In a

recent safety cohort reported by Fidder et al. 115/682 or 17% ofinflammatory bowel disease patients developed an acute infusionreaction and 7% a delayed-type hypersensitivity reaction. Both acuteand delayed reactions occurred early on in the treatment (after amedian of 2 to 3 infusions) and were linked to episodic therapy andthe absence of induction therapy in a multivariate analysis (Fidderet al., 2009).

The risk of malignancy in patients exposed to infliximab iscontroversial. In contrast to clinical trial data with infliximab andadalimumab in rheumatoid arthritis, A meta-analysis of placebo-controlled trials of anti-TNF therapies for Crohn's disease (includinginfliximab, adalimumab, certolizumab, etanercept, onercept, andCDP571) did not observe an increased risk of cancer among patientstreated with anti-TNF therapy compared to placebo (Peyrin-Birouletet al., 2008). The denominator of placebo exposed patients was smallin most of these trials. Two recent cohort studies attempted to assessthe risk difference between standard immune suppressive therapyand infliximab therapy in clinical practice. In an age, sex, andimmunosuppressives matched control analysis at several Italiansites, Biancone et al. found no increase of malignancy with infliximabcompared to standard therapy in 404 patients with inflammatorybowel disease patients (relative risk 1.4) (Biancone et al., 2006).

A similar effort comparing a cohort of infliximab exposed patientsfrom a large single center experience with long term follow up(3775patient-years in the infliximab group) found no increasedmalignancy risk in anti-TNF treated patients as compared to controls(Fidder et al., 2009). The discussion on the malignancy risk of anti-TNFagents in inflammatory bowel disease has recently focused onlymphoma. In a meta-analysis of the available literature for the 8905patients (21,178patient-years) the observed rate of NH lymphomawas3.2× higher than expected ( SIR 3.2, 95% CI 1.5 – 6.9) (Siegel, 2008). Incontrast to longstanding rheumatoid arthritis, inflammatory boweldisease per se does not infer a specific risk of lymphoma (Lewis et al.,2001), but the majority of patients who developed NHL were receivingcombination therapywith anti-TNF and thiopurines. There have been atleast 16 cases of hepatosplenic T-cell lymphoma (HSTCL) occurring inthe setting of combined infliximab and thiopurine therapy (Mackey etal., 2007). This rare form of NHL presents with hepatomegaly andsplenomegaly andotherwise vague symptoms. The courseof thediseaseis notoriously aggressive and often fatal. Two of the HSTCL cases werediagnosed after the patients had switched from infliximab to adalimu-mab and one additional case has been reported in a patient exposed toadalimumab as the sole anti-TNF agent and to azathioprine. The HSTCLoccurred predominantly in a younger population (age range 12–40 years, average age 23) and 15 of the 16 were male (Mackey et al.,2007; Rosh et al., 2007). There have been at least 9 additional casesreported among patients treated only with thiopurine therapy (Rosh etal., 2007). Likewise, several cases have been reported in patients whohave received an organ transplant. HSTCL occurring in the setting ofinflammatory bowel disease in the absence of immunosuppressivetherapy have not been reported to the best of our knowledge. Thereports of 16 cases of a rare lymphoma in recent years and in youngmales on anti-TNF therapy suggest an increased evidence, but it isunclear at present whether the risk is particularly associated withcombination therapy rather than with anti-TNF monotherapy orthiopurine monotherapy.

Antinuclear antibody (ANA) formation has been reported in 56% ofCrohn's disease patients treated with infliximab (Vermeire et al.,2003) and in 19% treated with adalimumab (Sandborn et al., 2007a).The clinical relevance of ANA induction by anti-TNF agents is unclear,and lupus like disease has been reported in patients treated with allanti-TNF agents. In clinical trials and post-marketing safety cohortsthe prevalence of drug related lupus with infliximab has beenbetween 0.2 and 0.6% (Fidder et al., 2009). Drug related lupus shouldbe suspected in patients with IBD treated with anti-TNF agents whopresent with arthralgias, myalgias, serositis, facial rash and high ANA

Table 2Treatment goals achieved by infliximab in IBD.

Treatment goal Crohn's disease Ulcerative colitis

Induction of clinical remission ✓ ✓

Maintenance of clinical remission ✓ ✓

Steroid sparing ✓ ✓

Endoscopic healing ✓ ✓

Fistula closure (perianal) ✓ NAAvoidance of hospitalizations ✓ ✓

Avoidance of surgery ✓ ✓

Improvement in quality of life ✓ ✓

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titers (particularly anti dsDNA). Occurrence of these symptoms incombination with high ANA titers often necessitates interruption ofanti-TNF therapy which usually results in complete resolution ofsymptoms. However, the symptoms recur when a patient is re-exposed to the same anti-TNF (De Bandt et al., 2005). It is currentlyunclear if switching to a second anti-TNF is a valuable option inpatients with positive ANA and symptoms suggestive of drug relatedlupus.

Neurologic side effects of biological therapies used in inflam-matory bowel disease include demyelinating disease and opticneuritis with anti-TNF agents and JC virus related progressivemultifocal leukencephalopathy with natalizumab. A history ofdemyelinating disease or optic neuritis constitutes a contraindicationfor the initiation of anti-TNF therapy, and patients developing thesedisorders with anti-TNF therapy should be permanently discontinued(Gupta et al., 2005). Worsening of severe congestive heart failure(NYHA class III–IV) is a class effect of anti-TNF agents and advancedcardiac failure constitutes a contraindication for these therapies(Dinesh et al., 2004). Eczematous skin lesions are an emergingobservation in patients treated with anti-TNF agents in a maintenanceschedule. A recent analysis from a large single center experiencefound skin lesions ranging from dry itchy skin to psoriasis like eczemaand palmo-plantar pustulosis in up to 20% of patients, more often inwomen (OR 1.9, 95% CI 1.242.85) (Fidder et al., 2009). Most patientscan be helped with topical therapy.

In the relatively young population affected by inflammatory boweldisease, questions about pregnancies and fertility are very relevant.Since ulcerative colitis and Crohn's disease are chronically relapsingconditions and disease control benefits pregnancy outcomes, mostpatients continue some form of maintenance therapy duringpregnancy. The experience with the use of infliximab beforeconception and during pregnancy has accumulated in the last5 years. The outcomes of pregnancies in mothers who deliberatelyused infliximab during pregnancy suggest no increased risk ofcongenital malformation or growth retardation (Mahadevan et al.,2005). Monoclonal IgG1 antibodies don't cross the placental barrier inearly pregnancy but do appear in the serum of the newborn babywhen administered in the last trimester (Vasiliauskas et al., 2006).Despite the presence of infliximab in the serum of babies born tomothers using infliximab throughout pregnancy, preliminary datasuggest that the efficacy of common vaccinations is not affected.Infliximab does not appear in human breast milk.

13. Conclusions and future perspectives

Since infliximab has been introduced in clinical practice, the drughas earned its place in the treatment paradigm of inflammatory

Table 1Indications and contra-indication for infliximab in inflammatory bowel disease.

Indications Contra-indications

Crohn's disease Ulcerative colitis

Active luminalCD in adults

Active outpatient UC AbsoluteActive infectionAbdominal abscess

Active fistulizingCD in adults

Severe steroid refractory UC History of lymphomaHistory of demyelinating diseaseor optic neuritis

Pediatric Crohn'sdisease

Refractory pouchitisa Severe heart failureColonic high grade dysplasiaor colorectal cancer

Extraintestinal manifestations of IBD RelativeSpondylarthritis History of malignancyErythema nodosuma andpyoderma gangrenosuma

Pure fibrostenotic CD

Uveitisa Perianal abscess

a No controlled data available.

bowel disease. Luminal and fistulizing Crohn's disease in adults andchildren, refractory ulcerative colitis and most extraintestinalmanifestations complicating inflammatory bowel disease are indica-tions for infliximab (Table 1). Three infusion induction and scheduledq8 week maintenance therapy is the optimal treatment strategy inboth ulcerative colitis and Crohn's disease since it maximises longterm response. Selecting patients with a high a priori likelihood ofresponse to biological agents also improves the benefit to risk profile.Novel treatment goals achieved by infliximab include the preventionof hospitalizations and surgery and endoscopic healing (Table 2).However, despite ten years of experience with infliximab in clinicalpractice not all controversies have been solved. These include theneed for concomitant immunosuppressive therapy in all patients,discontinuing infliximab in patients with a durable response, thelong term benefit of early top down intervention and the need toachievemucosal healing in every patient. In recent years fully humananti-TNF antibodies have entered clinical practice and have broad-ened the therapeutic options for patients with inflammatory boweldisease. However, further development of orally absorbed smallmolecules and agents targeting alternative pathways in the immunesystem and with an optimal benefit to risk profile should beencouraged.

Conflicts of interest

Gert Van Assche and Séverine Vermeire have received grant supportand/or speaker's fees fromAbbott, Schering-Plough, Centocor, and UCB.

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