IBD Monitor Issue

VOLUME 10 NUMBER 2 2009

EditorS-in-ChiEf

Stephen Hanauer, Chicago, IL, USA

Jack Satsangi, Edinburgh, UK

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INFLAMMATORY BOWEL DISEASEExpert commentary on advances in the understanding and management of inflammatory bowel disease

MONITOR

LEading artiCLES

Mucosal Healing and Treatment Efficacy in IBD

Gert van Assche, Séverine Vermeire, and Paul Rutgeerts

Management of Lack and Loss of Response to Anti-Tumor

Necrosis Factor TherapyAnne Christine W Vos,

Herma H Fidder, Gijs R van den Brink, and Daniel W Hommes

Management of Postoperative Crohn’s DiseaseJoseph Rodemann

and Miguel Regueiro

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Editor-in-Chief

Stephen Hanauer, MD University of Chicago, Chicago, IL, USA

Jack Satsangi, MBBS, DPhil Western General Hospital, Edinburgh, UK

Clinical Editors

Federico Balzola, MD Azienda Ospedaliera San Giovanni Battista di Torino, Turin, Italy

Charles Bernstein, MD University of Manitoba, Winnipeg, MB, Canada

Gert Van Assche, MD, PhD University Hospital of Leuven, Leuven, Belgium

Editorial Advisory Board

Zane Cohen, PhD Mount Sinai Hospital, Toronto, ON, Canada

Jean-Frédéric Colombel, MD Hôpital Huriez, Lille, France

Anders Ekbom, PhD Karolinska Institute, Stockholm, Sweden

Brian Feagan, MD University of Western Ontario, London, ON, Canada

Claudio Fiocchi, MD The Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, OH, USA

John O’Leary, MD Coombe Women’s Hospital, Dublin, Ireland

Paul C Rutgeerts, MD Universitaire Ziekenhuizen Leuven, UZ Gasthuisberg, Leuven, Belgium

Ernest G Seidman, MD Hôpital Sainte-Justine, Université de Montréal, Montreal, QC, Canada

Stephan Targan, MD Cedars-Sinai Medical Center, Los Angeles, CA, USA

William J Tremaine, MD Mayo Clinic, Rochester, MN, USA

Contents

y Leading Articles

Mucosal Healing and 35 Treatment Efficacy in IBDGert van Assche, Séverine Vermeire, and Paul Rutgeerts

Management of Lack and Loss of Response 43 to Anti-Tumor Necrosis Factor TherapyAnne Christine W Vos, Herma H Fidder, Gijs R van den Brink, and Daniel W Hommes

Management of Postoperative 52 Crohn’s DiseaseJoseph Rodemann and Miguel Regueiro

y Clinical Reviews

Clinical Observations and Research 61

Therapeutics Research 63

Prognosis and Assessment 66

Pathogenesis 66

Epidemiology 71

yMeeting Report

Digestive Disease Week 2009 73 (DDW 2009): Key Updates in IBD Clinical ResearchUma Mahadevan and Fernando Velayos

RT698_2_REM_IBD_10_2_07.indd 1 1/12/09 15:33:34

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FACuLty disCLosuREsThe following are the financial relationships declared by the journal’s Editorial Board:stephen Hanauer: Abbott, Alevan, Amgen, Asahi, Astra Zeneca, Bristol Myers Squibb, Centocor, Chemocentryx, Elan, Ferring, Genentech, GSK, Novartis, Otsuka, McNeil PPC, Millennium Pharmaceuticals, Procter & Gamble, Prometheus, Salix, Shire, Therakos, and UCB Pharma.Jack satsangi: Abbott and Novartis.Federico Balzola: None to declare.Charles Bernstein: Abbott Canada, Axcan Pharma, Shire Canada, and UCB Canada.Gert Van Assche: Not yet received.Zane Cohen: Not yet received.Jean-Frédéric Colombel: Abbott, ActoGeniX NV, Astra Zeneca, Berlex, Boehringer-Ingelheim, Bristol Meyers Squibb, Cellerix SL, Chemocentryx, Centocor, Cosmo Technologies, Danone France, Elan, Falk Pharma, Ferring, Genentech, Giuliani SpA, Given Imaging, Glaxo Smith Kline, Intestinal Biotech Development, Millenium Pharmaceuticals, Neovacs SA, Ocera Therapeutics, Otsuka American Pharmaceuticals, PDL Biopharma, Pfizer, RiboVax Boitech, Schering-Plough, Shire, Synta, Teva Pharmaceuticals, Therakos, UCB Pharma, and Wyeth.Anders Ekbom: None to declare.Brian Feagan: Abbott, AstraZeneca, Berlex, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Centocor, CombinatoRx, Elan/Biogen, ISIS, Janssen-Ortho, Millennium, Napo Pharma, Novartis, Osiris, Otsuka, Procter & Gamble, Protein Design Labs, Santarus, Schering Canada, Schering-Plough, Serono, Synta, Teva Pharmaceuticals, Tillotts, and UCB Pharma.Claudio Fiocchi: None to declare.John o’Leary: None to declare.Paul C Rutgeerts: Abbott, Centocor, Schering-Plough, and UCB Pharma.Ernest G seidman: Not yet received.stephan targan: Berlex, Bristol Myers Squibb, Elan, Gilead Science, Procter & Gamble, Prometheus, Salix, Santarus, and UCB Pharma.william J tremaine: Procter & Gamble, NPS Pharmaceuticals, and SLA Pharma.

EditoRiAL PoLiCyIBD Monitor is an independent journal published by Remedica Medical Education and Publishing. Editorial control is the sole responsibility of the Editors-in-Chief, Editorial Advisory Board, and the Clinical Editors. Before publication, all material submitted to the journal is subjected to rigorous review by the Editors-in-Chief, Editorial Advisory Board, Clinical Editors, and/or independent reviewers for suitability of scientific content, scientific accuracy, scientific quality, and conflict of interest.

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Remedica Medical Education and Publishing Ltd., Commonwealth House, 1 New Oxford Street, London, WC1A 1NU, UK.Tel: +44 (0)20 7759 2999 Fax: +44 (0)20 7759 2951Email: [email protected]

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LEAdinG ARtiCLE

| LEADING ARTICLE

| MUCOSAL HEALING AND TREATMENT EFFICACy IN IBD 35

Address for correspondence: Gert van Assche, MD, PhD, Department of Gastroenterology, Leuven University Hospitals, 49 Herestraat, Leuven, Belgium. Email: [email protected]

Endoscopy is arguably the gold standard for establishing, with as much certainty as possible, a diagnosis in IBD. However, the role of endoscopy in assessing the efficacy of medical therapy in IBD is more controversial. Improvement of signs and symptoms has been the primary outcome parameter of IBD trials, and endoscopic assessment has often been omitted from the trial design. However, there may be reasons to consider endoscopic evaluation of novel treatment strategies, other than to simply corroborate data on short-term clinical response or induction of remission. Crohn’s disease is frequently associated with complications, and surgery is inevitable in up to 70% of patients. Repeated bowel resections are necessary in 30% of Crohn’s disease patients, carrying an inherent risk of short bowel syndrome. Fulminant and poorly controlled ulcerative colitis (UC) also necessitates total proctocolectomy in many patients. Next to steroid-free clinical remission, avoiding surgery and associated complications may become the ultimate aim for every IBD therapy.

The introduction of biological therapies has undoubtedly led to better outcomes for patients who have refractory disease, and these therapies are associated with rapid mucosal healing. If we are to be more ambitious concerning our treatment goals

and incorporate mucosal healing as a primary aim, we need to answer the following questions:

Can mucosal healing be achieved and maintained with •medical therapy in IBD?Does mucosal healing change both the short- and long-•term outcomes of IBD?Is relapse of symptomatic activity related to failure of •bowel healing in IBD?

Endoscopic assessment of disease activityUlcerative colitisIn UC, multiple endoscopic scores of disease severity have been independently developed and are used in clinical trials (Table 1) [1,2]. The full Mayo score encompasses criteria of stool frequency, rectal bleeding, findings at endoscopy, and physician’s global assessment. The total score can vary between 0 and 12, and the endoscopic subscore between 0 and 3 (Figure 1). Other scores also assess endoscopic disease severity in UC and, in general, use comparable criteria such as friability, ulcers, and changes in vascular pattern. In clinical trials with biological agents such as infliximab, the Mayo

Mucosal Healing and Treatment Efficacy in IBD Gert van Assche, MD, PhD, Séverine Vermeire, MD, PhD, and Paul Rutgeerts, MD

Department of Gastroenterology, Leuven University Hospitals, Leuven, Belgium

Mucosal healing has long been incorporated into the assessment of treatment efficacy in ulcerative colitis; however, in Crohn’s disease this concept has only recently emerged after the evaluation of biological therapies in clinical trials. Systemic steroids do not induce mucosal healing in Crohn’s disease, but purine analogues and anti-tumor necrosis factor (anti-TNF) agents do have the potential to heal mucosal ulcerations. Evidence for mucosal healing has now been provided for the anti-TNF agents infliximab, adalimumab, and certolizumab. For infliximab, mucosal healing is associated with a reduction in hospitalizations and surgeries. However, the benefit of treating patients with IBD more intensively until they achieve mucosal healing has not been proven. In clinical practice, assessing mucosal healing should be considered in patients with persistent symptoms despite adequate therapy and when treatment discontinuation is being considered. Inflamm Bowel Dis Monit 2009;10(2):35–42.

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endoscopic score developed by Schroeder et al. has been used to evaluate therapeutic efficacy. Endoscopic activity of at least 2 on the Mayo scale (moderate disease, see Table 1) was an inclusion criterion for two large trials of infliximab in moderate to severe UC: ACT-1 (Active UC Trial-1) and ACT-2 [3]. In these trials, endoscopic remission was defined as a score of 0 or 1, indicating healed mucosa or mild disease with mild friability and distortion of the vascular pattern without mucosal defects.

Crohn’s diseaseIn contrast to UC, the extent and severity of mucosal lesions in Crohn’s disease is considered to be an unreliable predictor of success with standard medical treatment. Because several colonic and ileal segments can be affected with a high degree of variability, endoscopic severity scores need to incorporate weighting factors for both the degree of involvement of all segments and lesion severity (see Table 2).

Crohn’s disease endoscopic index of severityIn the late 1980s, pioneering work on the development of an endoscopic severity score for Crohn’s disease and UC was performed by the French Groupe d’Etudes Thérapeutiques sur les Affections Inflammatoires Digestives (GETAID). For a period of 2 years, patients undergoing ileocolonoscopy at 13 academic medical centers were included in a prospective trial. The group evaluated and validated the importance of nine predefined lesions: pseudopolyps, healed ulcerations, erythema, mucosal edema, aphthoid ulcerations, superficial and deep ulcerations, and stenoses (ulcerated or non-ulcerated). The index was refined by incorporating the percentage of disease involvement

in all of the endoscopic segments (ileum, right colon, transverse colon, left and sigmoid colon, and rectum) and the percentage of ulcerated mucosa. This resulted in the development of the Crohn’s disease endoscopic index of severity (CDEIS) [4–6].

The CDEIS correlated well with a global evaluation of lesion severity, measured on a visual analogue scale, and was found to have excellent interobserver agreement. However, the correlation of the CDEIS with the most widely used clinical score, the Crohn’s disease activity index (CDAI), was weak [6]. At the present time, the CDEIS is still the most widely used severity index in clinical trials, despite its shortcomings and the time-consuming scoring system.

Simple endoscopic score for Crohn’s diseaseMore recently, Daperno et al. have reported on a simplified endoscopic severity index for Crohn’s disease, which emphasizes the importance of ulcerations [7]. Ulcerations are considered to reflect disease severity, and are more liable to change with therapy as they occur in actively inflamed mucosa. Rather than using the penetration of ulcerations in the bowel wall (deep versus superficial in the CDEIS), Daperno et al. looked at the size of the ulcers (aphthoid <0.5 mm, large 0.5–2 mm, very large >2 mm). Their “simple endoscopic score for Crohn’s disease” (SES-CD) has good interobserver agreement and correlates well with the CDAI and C-reactive protein (CRP) assessments. The Kappa (κ) coefficient value is a measure of agreement between two independent observers, where a score of >0.6 indicates good agreement and a score ≥0.8 indicates excellent interobserver agreement. κ values for the SES-CD vary from 0.6 to 1.0 for the different subscores. The interclass κ value between the

Figure 1. Different grades of the endoscopic component of the Mayo scoring system for ulcerative colitis activity. 0: normal or healed mucosa; 1: mild friability and faded vascular pattern; 2: absent vascular pattern, erosions, and marked friability; 3: frank ulcers and/or spontaneous bleeding.

2 310

Table 1. Endoscopic scores used in ulcerative colitis.

0 1 2 3

Powell-Tuck [1] No bleeding Bleeding on light touch Spontaneous bleeding

Sutherland [2] Normal Mild friability Moderate friability Exudation, spontaneous bleeding

Schroeder (Mayo) [3] Normal Faded vascular pattern, mild friability

Loss of vascular pattern, erosions, friability

Ulcers of spontaneous bleeding

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| LEADING ARTICLE


CDEIS and SES-CD was >0.9, indicating excellent agreement between the two indices. Despite good agreement with clinical and biological outcomes, both the CDEIS and SES-CD tend to overestimate disease in patients with extensive colitis, and underestimate endoscopic severity in patients with ileitis and limited colonic involvement. It is unclear whether patients with localized but severe colitis have a more favorable outcome. Therefore, relative changes from baseline in endoscopic indices may better reflect mucosal healing in these patients.

Crohn’s disease postoperative endoscopic recurrence scoreRutgeerts et al. have developed an endoscopic disease severity score specifically for postoperative Crohn’s disease recurrence in the neoterminal ileum [8]. This score, which ranges from 0–4, measures the extent and severity of ulcerations and other mucosal lesions at the ileocolonic anastomosis and higher up in the ileum (see Table 2). In the original publication, this was shown to be the best predictor of re-operation amongst a panel of clinical and biological parameters. Since then, the score has been used in most trials that have investigated the maintenance of surgical remission.

Endoscopic ileal lesions can appear as early as 3 months after the anastomosis has been constructed, and precede clinical and

surgical recurrence. In general, medical therapy that is considered to be beneficial for the maintenance of surgical remission, such as metronidazole and azathioprine, decreases and/or delays the recurrence of endoscopic lesions [9,10]. However, none of the postoperative prevention trials have had a follow-up of >2 years, or included a sufficient number of patients to be able to define a correlation between endoscopic and surgical recurrence.

Mucosal healing and medical therapy in ulcerative colitisMucosal healing in UC can be assessed with flexible sigmoidoscopy. This procedure is generally well tolerated and requires limited bowel preparation. Mucosal healing in UC has been more widely associated with success of medical therapy [1,2], although it is not entirely clear whether patients who achieve full endoscopic remission with standard therapies such as aminosalicylates and glucocorticosteroids will have better long-term outcomes than those without healing.

The two randomized, double-blind, placebo-controlled trials ACT-1 and ACT-2 have evaluated the efficacy of intravenous infliximab (5 mg/kg at weeks 0, 2, and 6 then every 8 weeks for up to 54 weeks) in 364 adults with moderate-to-severe,

Table 2. Endoscopic scores used in Crohn’s disease.

Crohn’s disease endoscopic index of severity (CDEIS): range 0–50 [4].

Ileum Right Transverse Left+sigmoid Rectum

Deep ulceration (score 0–12)

Superficial ulceration (score 0–12)

Surface area ulcerated (cm, maximum 10)

Surface area affected (cm, maximum 10)

Sum of all totals per segment is divided by the number of segments examined +3 (if ulcerated stenosis present) +3 (if non-ulcerated stenosis present).

Simple endoscopic score for Crohn’s disease (SES-CD): score range 0–56 [7].

Ileum Right Transverse Left+sigmoid Rectum

Presence + size of ulcers (score 0–3)

Surface ulcerated (score 0–3)

Surface affected (score 0–3)

Presence and type of stenosis (score 0–3)

Crohn’s disease postoperative endoscopic recurrence score (neo-terminal ileum) [32].

Observation Score

No recurrence 0

<5 aphthous lesions or lesions confined to the anastomosis 1

>5 aphthous lesions with normal mucosa between lesions or skip areas of larger lesions

2

Diffuse aphthous ileitis with diffusely inflamed mucosa 3

Diffuse inflammation with large ulcers, nodules and/or narrowing 4

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active UC [3]. Mucosal healing was defined as an endoscopy subscore of zero (complete healing) or 1 (partial healing), and this was incorporated in the Mayo activity score used in the assessment of the primary endpoint. Mucosal healing, at weeks 8 and 30 in each study and at week 54 in ACT-1, occurred in significantly more patients in the infliximab-treated groups than in the placebo groups (p≤0.009 for all comparisons). In addition, infliximab decreased UC-related hospitalizations at week 30 in the ACT trials. The total number of hospitalizations in the infliximab-treated group was significantly lower than that in the placebo group (19 vs. 44; p<0.01).

Crohn’s disease medical therapy and mucosal healingStandard therapies, including aminosalicylates, antibiotics, and glucocorticosteroids, do not heal the bowel mucosa in Crohn’s disease [8,11,12]. In a French collaborative study, patients received high doses of prednisolone (1 mg/kg/day) until clinical remission was achieved (3–7 weeks) [6]. Although 92% of patients achieved clinical remission, only 29% (38 of 131) also exhibited endoscopic remission according to the CDEIS. Endoscopic lesions worsened in 9% of patients treated with prednisolone, despite symptomatic improvement [8]. This landmark study showed that although glucocorticosteroids are very effective at controlling symptoms in the short term, they do not initiate restoration of mucosal integrity in the ileum and the colon. In a recently reported Norwegian inception cohort, the use of steroids to control Crohn’s disease decreased the likelihood of mucosal healing at 1 year [12]. Whether this observation was due to a higher disease activity or a direct effect of steroid therapy is unclear.

“Multiple endoscopic scores of UC disease activity are in use in clinical trials”

In contrast to the lack of mucosal healing with glucocorticosteroids, a number of studies have indicated that purine analogues are associated with both clinical improvement and endoscopic healing. D’Haens and colleagues conducted an open-label trial of azathioprine in patients with severe post-surgical recurrence of ileal disease that was refractory to glucocorticosteroid treatment [13]. They found that ≥6 months of azathioprine therapy at adequate doses resulted in healing of severe lesions (complete healing in six of 15 patients [40%], and near-complete healing in five of 15 [33%]). In a subsequent open-label study, the same authors reported similar data on healing with azathioprine in Crohn’s disease patients outside of the postoperative setting [14]. Mucosal healing with azathioprine was addressed more systematically in a

French study, which was part of a randomized, azathioprine-withdrawal trial in Crohn’s disease [15]. Colonoscopy was performed in 45 patients at inclusion. Sixteen patients (36%) had complete mucosal healing and 53% had no ulcers, with positive correlation between endoscopic CDEIS scores and clinical CDAI scores (p=0.034). With regard to methotrexate, open-label experience in a limited cohort of patients with Crohn’s disease has provided evidence for the association between clinical response and endoscopic and histological healing [16].

The advent of biological therapies has introduced new perspectives to the role of endoscopic healing as an outcome parameter of Crohn’s disease therapy. Dramatic endoscopic improvement was reported in the first pilot trial with infliximab [17]. In an endoscopic substudy of another trial (n=30), mucosal healing accompanied the clinical improvement achieved with infusions of infliximab (5, 10, or 20 mg/kg) [18]. Moreover, a good correlation was demonstrated between improvements in CDAI and CDEIS scores as early as 4 weeks after the first infusion. The disappearance of ulcers was evenly distributed in all ileocolonic segments, with resolution of ulcers ranging from 74% in the ileum to 96% in the rectum. Mucosal healing was confirmed histologically with disappearance of the inflammatory infiltrate in infliximab-treated patients.

“The CDEIS is presently the most widely used Crohns disease endoscopic

severity index in clinical trials”

The ACCENT I (A Crohn’s Disease Clinical Study Evaluating Infliximab in a New Long-Term Treatment Regimen) study included an endoscopic substudy in 99 patients recruited from 25 selected centers [19–21]. In this study, patients were treated with infliximab 5 or 10 mg/kg, or placebo, for 1 year. At week 54, a greater proportion of patients who received systematic 8-weekly infliximab retreatment (combined dose levels) exhibited complete bowel healing compared with those who received a single 5 mg/kg infliximab infusion and episodic therapy upon flare thereafter [19]. In the trial, healing was defined as the complete disappearance of all ulcers from the colon and the ileum; this is considered to accurately reflect the inflammatory state of the mucosa. However, the CDEIS used by other trials also incorporates erythema, edema, and stenosis; therefore, the data from ACCENT I cannot be directly compared with previous observations. Even if infliximab therapy does result in early and dramatic mucosal healing, the endoscopic data from ACCENT I also confirmed clinical observations on the rapid re-appearance of frank ulcerations in patients with a disease flare after a period of remission with the anti-tumor necrosis factor (anti-TNF) agent. The relatively low number of patients with mucosal healing after 1 year of episodic,

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| LEADING ARTICLE


on-demand treatment proves that the beneficial effect of infliximab on the ileal and colonic mucosa is only temporary.

In an open-label, Dutch–Belgian collaborative trial, known as the “Step-up/Top-down” trial, early combined infliximab induction and azathioprine maintenance (the “top-down” regimen) without the use of steroids, resulted in a higher proportion of endoscopic healing (absence of ulcers) than standard systemic steroids followed by azathioprine maintenance (71% [17 of 24 patients] vs. 30% [six of 20 patients]; p<0.001) [22].

“Standard therapies, including aminosalicylates, antibiotics, and

glucocorticosteroids, do not heal the bowel mucosa in Crohn’s disease”

Preliminary data from the large (n=508), blinded, double-dummy, controlled SONIC (Study of Immunomodulator-Naive patients in Crohn’s Disease) trial comparing azathioprine monotherapy, infliximab monotherapy (2.5 mg/kg/day), and combined infliximab plus azathioprine therapy have been released [23]. At 26 weeks, the steroid-free remission rates in patients receiving combined immunosuppressive therapy with infliximab and azathioprine were higher than with infliximab monotherapy (57% vs. 45%; p<0.05) and these were also higher than remission rates in patients on azathioprine monotherapy (45% vs. 30%; p<0.01). Of interest, the total disappearance of mucosal ulcers was also highest in the combined infliximab and azathioprine group (44% in the infliximab plus azathioprine group vs. 19% in the azathioprine monotherapy group; p<0.001) and patients with mucosal lesions at inclusion were more likely to benefit from infliximab therapy.

For the humanized anti-TNF Fab fragment certolizumab pegol, endoscopic healing was demonstrated in an open-label trial [19]. Preliminary data indicated that after 1 year of treatment with certolizumab pegol 400 mg every 4 weeks, 55% of 89 patients experienced endoscopic remission (CDEIS <7) [24].

Preliminary data from a randomized, placebo-controlled trial exploring the mucosal healing potential of the fully human monocolonal anti-TNF antibody, adalimumab, in active ileocolonic Crohn’s disease have recently been presented [25]. In this trial, 135 patients received open-label induction therapy

with 160/80 mg of adalimumab at weeks 0/2 and were then randomized to adalimumab 40 mg or placebo every 2 weeks. The absence of mucosal ulcers at week 12 (primary endpoint) was observed in 27.4% (17 of 62) of adalimumab-treated patients versus 13.1% (eight of 61) of placebo recipients (p=0.06). After 1 year, a significant difference between the two groups was observed with absence of ulcers (complete mucosal healing) in 24.2% of adalimumab-treated patients compared with none of the placebo recipients (p<0.001) (Table 3 and Figure 2).

Mucosal healing and disease outcomesThe impact of mucosal healing with medical therapy on outcomes in patients with Crohn’s disease has only been well studied for infliximab. As previously described, systematic 8-weekly treatment with infliximab induces complete mucosal healing in nearly half of the patients treated [20]. Patients who exhibited complete mucosal healing in either the short- or long-term had significant reductions in the number of hospitalizations, procedures, surgeries, and days of intensive care unit stay compared with patients who exhibited only transient or no healing. This has been confirmed by an analysis of the ACCENT I trial data (which was designed to evaluate the role of infliximab in maintenance treatment).

In UC, Carbonnel and colleagues found an association between endoscopic disease severity and the need for colectomy and/or the response to intensive medical therapy [26]. However, in a controlled trial with infliximab, endoscopic disease severity did not predict the need for colectomy [27]. In addition, no association between endoscopic healing and outcome of infliximab therapy was found in multivariate analysis of a single-center cohort by Ferrante and colleagues [28]. Outcome predictions are difficult to establish from ACT-1 and ACT-2, since all patients were required to have moderately or severely active endoscopic disease at baseline in these studies. Preliminary data suggest a modest but significant effect of scheduled infliximab maintenance therapy on the long-term prevention of colectomy.

Mucosal healing and time to relapseIt was hoped that novel therapies would be able to reset the “immunostat” of the bowel. In other words, after induction therapy and a short period of maintenance, the effect could be preserved even after the cessation of therapy. This has not been confirmed either in formal studies or in clinical practice.

The GETAID group demonstrated that prolonging glucocorticosteroid treatment until the colonic mucosa had healed did not result in better long-term outcomes after tapering

Table 3. Drug therapy and mucosal healing in Crohn’s disease.

No or limited healing

Important but slow healing

Important and rapid healing

Aminosalicylates

Antibiotics

Glucocorticoids

Azathioprine

6-Mercaptopurine

Methotrexate

Infliximab

Adalimumab

(Certolizumab pegol)

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and cessation of the glucocorticosteroids [8]. Patients who achieved clinical remission with and without colonic healing had similar relapse-free intervals. The data are somewhat similar for azathioprine-induced mucosal healing. Lémann et al. reported on a randomized, double-blind, placebo-controlled, multicenter, azathioprine-withdrawal trial in Crohn’s disease [15]. Patients who were in clinical remission on azathioprine for ≥42 months were randomized to either continue with azathioprine or to receive placebo for 18 months. Twelve relapses were observed during the 18-month period. Kaplan–Meier estimates of the 18-month relapse rate were 21.8±6.3% for placebo and 7.9±4.4% for azathioprine. This study did not establish equivalence, but the relapse rate on placebo was low (approximately 22%). Endoscopic healing did not predict absence of relapse [15]. An extended follow-up of this patient cohort was recently reported [29]. A clinical relapse rate of up to 60% was found at 54 months of follow-up in patients who discontinued azathioprine; however, no endoscopic data were provided in the study. D’Haens et al. followed-up patients from the ACCENT I endoscopy substudy after completion of the 54-week trial [18]. Patients were stratified according to the degree of healing at a 54-week endoscopy. The mean relapse-free survival intervals were 20 weeks for patients with complete healing, 19 weeks for patients with partial healing, and just 4 weeks for patients without healing.

Mucosal healing as a specific endpoint in clinical trialsThe CDAI, which has been used by virtually all recent Crohn’s disease clinical trials, and most clinical scores of UC activity include several subjective parameters. This subjective content is undoubtedly at least partially responsible for the high response

rates seen with placebo in several trials. Therefore, biological outcome parameters such as CRP levels in Crohn’s disease and endoscopic healing in both Crohn’s disease and UC have been advocated in the evaluation of novel therapeutic agents. The healing capacity of these drugs is an objective endpoint that reduces the placebo effect, leading to a lower required sample size. However, to date, no prospective, controlled trial has evaluated the impact on long-term outcomes of intensifying medical therapy in those IBD patients with a lack of mucosal healing. Therefore, at present, all evidence supporting a role for endoscopic healing in guiding the medical or surgical management of patients with Crohn’s disease is indirect.

“Preliminary data from clinical trials with infliximab, certolizumab pegol,

and adalimumab have demonstrated endoscopic healing in IBD patients”

In routine clinical practice, endoscopic follow-up of Crohn’s disease patients who achieve remission with standard or novel therapies cannot be advocated. However, endoscopy is useful in patients who present with persistent symptoms despite a good clinical response. Indeed, post-inflammatory irritable bowel syndrome (IBS) is a common cause of diarrhea and abdominal cramps. In a Swedish study, 57% of Crohn’s disease patients and 33% of UC patients with longstanding clinical and endoscopic remission had persistent or relapsing IBS-like symptoms [30]. In addition, abdominal pain and bloating with normal CRP levels raises the suspicion of a critical stenosis. Hence, ileocolonoscopy can be of key importance in the pre-operative decision-making process, and as well as in postoperative situations. Flexible

Figure 2. Endoscopic images of a colon in a patient with Crohn’s disease treated with scheduled maintenance adalimumab. On the left-hand panel, a scar of a healed serpinginous ulcer is obvious. Pseudopolyps can be seen in the right-hand panel.

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sigmoidoscopy offers a reliable assessment of disease severity in UC and is generally well tolerated. Therefore, the threshold to evaluate treatment efficacy in UC is lower for most physicians, and this option should be discussed with patients. Moreover, most published guidelines advocate endoscopic dysplasia surveillance in patients with longstanding disease; this also allows assessment of endoscopic healing. The value of endoscopic surveillance has not been substantiated by high-quality controlled evidence; however, at this time, there is insufficient evidence that endoscopic mucosal healing in UC abrogates the need for continued endoscopic dysplasia surveillance.

The results of a recently published large, single-center cohort study confirmed the abovementioned clinical trial data with infliximab of an association between endoscopic healing and durable clinical remission [9]. In initial responders to infliximab, complete mucosal healing (defined as the absence of ulcers) was identified in 45% of 183 patients, and partial healing (defined as clear improvement but residual ulcers) in and additional 22%. Furthermore, mucosal healing was associated with a decreased need for major abdominal surgery.

other markers of mucosal healingAs ileocolonoscopy entails a significant burden to patients with Crohn’s disease – given the need for complete bowel preparation, sedation, and the discomfort of the procedure – alternative tools to assess mucosal inflammation and healing have been studied. Fecal markers, such as calprotectin, accurately reflect active mucosal inflammation, particularly in UC, and correlate with the endoscopic appearance. Trials to evaluate the use of calprotectin as a marker of mucosal healing after medical therapy are ongoing and a Finnish prospective study in 15 patients has reported a decrease in fecal calprotectin and endoscopic activity after treatment with infliximab [10]. If fecal calprotectin indeed correlates well with endoscopic improvement, using fecal markers as biological endpoints would become feasible.

For the small intestine, an organ that is mostly hidden from classical endoscopy, wireless capsule endoscopy (WCE) may prove to be a valuable assessment tool in the future. However, the specificity and the correlation with clinical activity of lesions detected with capsule endoscopy needs to be better determined. The findings from a recently reported, open-label, prospective trial indicated that a response to medical therapy resulted only in improvement in the number of large ulcers in the ileal mucosa as judged by WCE [31]. This finding emphasizes that the significance of smaller ulcerations visualized with WCE needs to be better defined. Computed tomography and magnetic resonance imaging enteroclysis are other emerging tools in the assessment of transmural ileal disease, but prospective data on the impact of medical therapy on transmural lesions are not available.

Additional prospective data are needed before these newer techniques replace classical endoscopy as the gold standard for assessing mucosal healing in IBD.

ConclusionIn clinical trials, endoscopic mucosal healing has matured as a marker of the anti-inflammatory action of newer biological therapies and of immunosuppression in Crohn’s disease and UC. Infliximab-induced remission is associated with the disappearance of mucosal ulcers and with reduced hospitalizations, procedures, surgeries, and intensive care admissions in both diseases. However, it is not clear whether, in clinical practice, the achievement of mucosal healing should be assessed in all patients who respond to medical treatment. Complete mucosal healing may delay relapse after discontinuation of therapy as it predicts a longer duration of response, but it is by no means a sign of disease cure.

disclosuresDrs van Assche, Rutgeerts, and Vermeire have received research support and/or honoraria from Abbott, Centocor, Schering-Plough, and UCB Pharma. Dr van Assche has also received honoraria from Ferring Pharmaceuticals.

References 1. Powell-Tuck J, Day DW, Buckell NA et al. Correlations between defined sigmoidoscopic

appearances and other measures of disease activity in ulcerative colitis. Dig Dis Sci 1982;27:533–7.

2. Higgins PD, Schwartz M, Papili J et al. Is endoscopy necessary for the measurement of disease activity in ulcerative colitis? Am J Gastroenterol 2005;100:355–61.

3. Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–76.

4. Mary Jy, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut 1989;30:983–9.

5. Landi B, Anh TN, Cortot A et al. Endoscopic monitoring of Crohn’s disease treatment: a prospective, randomized clinical trial. The Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives. Gastroenterology 1992;102:1647–53.

6. Cellier C, Sahmoud T, Froguel E et al. Correlations between clinical activity, endoscopic severity, and biological parameters in colonic or ileocolonic Crohn’s disease. A prospective multicentre study of 121 cases. The Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives. Gut 1994;35:231–5.

7. Daperno M, D’Haens G, Van Assche G et al. Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc 2004;60:505–12.

8. Modigliani R, Mary Jy, Simon JF et al. Clinical, biological, and endoscopic picture of attacks of Crohn’s disease. Evolution on prednisolone. Groupe d’Etude Thérapeutique des Affections Inflammatoires Digestives. Gastroenterology 1990;98:811–8.

9. Schnitzler F, Fidder H, Ferrante M et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn’s disease. Inflamm Bowel Dis 2009;15:1295–301.

10. Sipponen T, Savilahti E, Kärkkäinen P et al. Fecal calprotectin, lactoferrin, and endoscopic disease activity in monitoring anti-TNF-alpha therapy for Crohn’s disease. Inflamm Bowel Dis 2008;14:1392–8.

11. Olaison G, Sjödahl R, Tagesson C. Glucocorticoid treatment in ileal Crohn’s disease: relief of symptoms but not of endoscopically viewed inflammation. Gut 1990;31:325–8.

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

13. D’Haens G, Geboes K, Ponette E et al. Healing of severe recurrent ileitis with azathioprine therapy in patents with Crohn’s disease. Gastroenterology 1997;112:1475–81.

14. D’Haens G, Geboes K, Rutgeerts P. Endoscopic and histologic healing of Crohn’s (ileo-) colitis with azathioprine. Gastrointest Endosc 1999;50:667–71.

15. Lémann M, Mary Jy, Colombel JF et al.; Groupe D’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif. A randomized, double-blind, controlled withdrawal trial in Crohn’s disease patients in long-term remission on azathioprine. Gastroenterology 2005;128:1812–8.

16. Kozarek RA, Patterson DJ, Gelfand MD et al. Methotrexate induces clinical and histological remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989;110:353–6.

17. van Dullemen HM, van Deventer SJ, Hommes DW et al. Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995;109:129–35.

18. D’Haens G, van Deventer S, van Hogezand R et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology 1999;116:1029–34.

19. Hanauer SB, Feagan BG, Lichtenstein GR et al.; ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–9.

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

21. Rutgeerts P, Diamond RH, Bala M et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc 2006;63:433–42.

22. D’Haens G, Baert F, van Assche G et al.; Belgian Inflammatory Bowel Disease Reseach Group; North-Holland Gut Club. Early combined immunosuppresion or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008;371:660–7.

23. Colombel JF, Hébuterne X. Endoscopic mucosal improvement in patients with active Crohn’s disease treated with certolizumab pegol: first results of the MUSIC clinical trial. Am J Gastroenterol 2008;103:A1107 (Abstr.).

24. Sandborn WJ, Rutgeerts P, Reinisch W et al. SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Am J Gastroenterology 2008;103:S436 (Abstr.).

25. Rutgeerts P, D’Haens G, Van Assche G. Adalimumab induces and maintains mucosal healing in patients with moderate to severe Crohn’s disease. First results of the EXTEND trial. Gastroenterology 2009;136:A116 (Abstr.).

26. Carbonnel F, Gargouri D, Lémann M et al. Predictive factors of outcome of intensive intravenous treatment for attacks of ulcerative colitis. Aliment Pharmacol Ther 2000;14:273–9.

27. Järnerot G, Hertervig E, Friis-Liby I et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005;128:1805–11.

28. Ferrante M, Vermeire S, Katsanos KH et al. Predictors of early response to infliximab in patients with ulcerative colitis. Inflamm Bowel Dis 2007;13:123–8.

29. Treton X, Bouhnik y, Mary Jy et al.; Groupe D’Etude Thérapeutique Des Affections Inflammatoires Du Tube Digestif (GETAID). Azatioprine withdrawal in patients with Crohn’s disease maintained on prolonged remission: a high risk of relapse. Clin Gastroenterol Hepatol 2009;7:80–5.

30. Simrén M, Axelsson J, Gillberg R et al. Quality of life in inflammatory bowel disease in remission: the impact of IBS-like symptoms and associated psychological factors. Am J Gastroenterol 2002;97:389–96.

31. Efthymiou A, Viazis N, Mantzaris G et al. Does clinical response correlate with mucosal healing in patients with Crohn’s disease of the small bowel? A prospective, case-series study using wireless capsule endoscopy. Inflamm Bowel Dis 2008;14:1542–7.

32. Rutgeerts P, Geboes K, Vantrappen G et al. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990;99:956–63.

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LEAdinG ARtiCLE

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| MANAGEMENT OF LACK/LOSS OF RESPONSE TO ANTI-TNF THERAPy 43

Address for correspondence: Daniel W Hommes, MD, PhD, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. Email: [email protected]

Until the late 1990s, the treatment of Crohn’s disease predominantly involved the use of steroids, 5-aminosalicylates (5-ASAs), and antimetabolites. However, patients often fail to achieve and maintain response and remission with these therapies. The majority of patients eventually need corticosteroids to manage the disease, and these are associated with potentially serious side effects [1].

In 1998, Lapidus et al. compared the cumulative risk of surgery in Crohn’s disease patients diagnosed during the time-period 1960–1974 with that in patients diagnosed in 1975–1980. The cumulative risk of major surgery was nearly 50% in both groups, demonstrating a lack of progress in the treatment of Crohn’s disease [2]. The introduction of anti-tumor necrosis factor-α (anti-TNF-α) therapy represents a remarkable success story in the treatment of Crohn’s disease in many ways. Response and remission rates (discussed later) have been impressive and patients report an improved quality of life [3]. In addition, the healing of endoscopic lesions [4,5] and reduction of chronic inflammatory infiltrates has been achieved [4,6].

To date, three anti-TNFs have been approved by the US Food and Drug Administration (FDA) for the treatment of refractory Crohn’s disease:

Infliximab: a chimeric monoclonal IgG1 antibody.•Adalimumab: a humanized IgG1• antibody. Certolizumab: a pegylated Fab’ fragment. •

working mechanism of anti-tnFAll three approved anti-TNF agents are known to neutralize soluble TNF-α [7], which is an essential Th1 cytokine produced by monocytes and T cells [8].

Etanercept, a soluble TNF receptor fusion protein, is an effective drug for the treatment of rheumatoid arthritis (RA) and also efficiently neutralizes TNF-α [7,9,10]. Surprisingly, etanercept is not beneficial in Crohn’s disease [11], suggesting that neutralizing soluble TNF-α is not the sole mechanism of action of the anti-TNF agents that are efficacious in Crohn’s disease. One of the differences between infliximab and etanercept is that infliximab induces apoptosis in lamina propria

Management of Lack and Loss of Response to Anti-Tumor Necrosis Factor TherapyAnne Christine W Vos, Herma H Fidder, MD, PhD, Gijs R van den Brink, MD, PhD, and Daniel W Hommes, MD, PhD

Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands

The introduction of biologics has proven a significant breakthrough in the treatment of Crohn’s disease. At the present time, three anti-tumor necrosis factor (anti-TNF) agents are approved by the US Food and Drug Administration for the treatment of Crohn’s disease: infliximab, adalimumab, and certolizumab. Although anti-TNF therapy has been widely studied in clinical trials and found to be effective in Crohn’s disease, approximately one-third of patients do not respond to induction therapy, and around one-third of initial responders lose their response after several months of treatment. In this review, factors associated with lack of response (primary non-responders) and loss of response (secondary non-responders) are discussed. Identifying factors associated with lack and/or loss of response could be helpful in the selection of patients who are likely to benefit from anti-TNF therapy. This could attenuate morbidity and side effects, and reduce costs. Inflamm Bowel Dis Monit 2009;10(2):43–51.

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T cells [12], whereas etanercept does not [13]. Moreover, infliximab, but not etanercept, binds to membrane-bound TNF-α (mTNF), which can be cleaved by TNF-α-converting enzyme (TACE) to generate soluble TNF-α. Upon binding to mTNF, infliximab induces antibody-dependent cellular cytotoxicity (ADCC) and cell lysis [14]. Mitoma et al. have described the induction of “reverse signaling” through mTNF by infliximab and adalimumab (but not etanercept), leading to cell cycle arrest in Jurkat T cells [15,16]. Certolizumab does not induce apoptosis, but, like infliximab and adalimumab, does inhibit lipopolysaccharide-induced interleukin-1β (IL-1β) production by monocytes [7]. Infliximab induces apoptosis in monocytes from Crohn’s disease patients with active disease [17]. Furthermore, it reduces vascular cell adhesion molecule-1 (VCAM-1) and CD40 expression on mucosal endothelium, thereby disrupting the CD40–CD40L-dependent interaction between T cells and the endothelium [18]. Infliximab also influences wound healing; it increases tissue inhibitor of metalloproteinase-1 (TIMP-1) production and thus reduces matrix metalloproteinase (MMP) activity, and has been shown to inhibit myofibroblast migration in vitro [19].

Response and lack of response (primary non-responders) in clinical trials The efficacy and safety of anti-TNF therapy has been widely evaluated in several clinical studies (Table 1). In clinical trials, response is generally defined as a reduction on the Crohn’s Disease Activity Index (CDAI) of 70 points (70-point response) or 100 points (100-point response) between baseline and 4 weeks in non-fistulizing disease. In this review, response is defined as a reduction of 70 points on the CDAI unless stated otherwise. In fistulizing disease, a response is said to be achieved when a decrease of ≥50% in the number of draining

fistulas after 10 weeks is observed. Remission is defined as a CDAI score <150 [3,20].

Targan et al. reported overall response rates at week 4 of 65% in patients treated with infliximab and 17% in the placebo group [3]. In ACCENT I (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen), 58% of the participants responded to infliximab at week 2 [21]. In SONIC (Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease), much higher response rates were observed in patients who were previously naïve to immunomodulators and biologics, and who had a short disease duration [22].

The response rates of anti-TNF-naïve patients treated with adalimumab were assessed in the CLASSIC I (Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn’s Disease I) trial [20]. After 4 weeks, clinical response rates of 54% (in recipients of adalimumab 40 mg at week 0 and adalimumab 20 mg at week 2 [adalimumab 40/20 mg]) and 59% (adalimumab 80/40 mg and 160/80 mg) were seen.

The clinical response rates of patients receiving certolizumab pegol were evaluated in the PRECISE 1 (Pegylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy 1) trial [23]. At week 4, the response rate was 44% in all patients. The 100-point response rate at week 6 after full induction therapy in patients with a C-reactive protein (CRP) level >10 mg/L (primary endpoint) was 37% compared with 26% in the placebo group (p=0.04). Patients who had received anti-TNF therapy within the previous 3 months and those who had a hypersensitivity or lack of response to a first anti-TNF dose were excluded from this trial.

Infliximab, adalimumab, and certolizumab all appeared to be safe in the trials described above. Overall, around one-third of patients treated with infliximab, 45% of patients treated with adalimumab, and 56% of patients treated with certolizumab failed to show a clinical response at week 4 or week 6 after full

Table 1. Percentage of patients showing a clinical response (70-point reduction from baseline on the Crohn’s disease activity index) or remission after 2 and 4 weeks.

Anti-TNF Trial (n) [reference]

Response week 2 (placebo group)

Remission week 2 (placebo group)

Response week 4 (placebo group)

Remission week 4 (placebo group)

Infliximab Targan et al. (108) [3]

ACCENT I (573) [21]

61% (17%)

58% (21%)

27% (4%) 65% (17%) 33% (4%)

Adalimumab CLASSIC I (299) [20]

44–55% (30%) 14–24% (14%) 54–59% (37%) 18–36% (12%)

Certolizumab PRECISE 1 (662) [23]

35% (25%) 13% (8%) 44% (33%) 19% (11%)

ACCENT I: A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen; CLASSIC I: Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn’s Disease I; PRECISE 1: Pegylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy 1; TNF: tumor necrosis factor.

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induction therapy. It is difficult to directly compare the results of different studies because there are no head-to-head trials. It is not known whether these primary non-responders represent a specific group of patients. Patients who do not show a response after a first infusion of infliximab also fail to show a response after subsequent infusions [3,24], suggesting that the lack of response is stable over time. In general, although many clinical trials have shown the efficacy and safety of anti-TNF therapy in Crohn’s disease patients, there is a relatively large group of patients displaying no response after 4 weeks (primary non-responders).

Factors associated with lack of responseSeveral associations between lack of response and genetic, demographic, and clinical factors have been described. Factors associated with response are summarized in Table 2. Most studies to date have focused on infliximab since most experience has been obtained with this anti-TNF agent.

Genetic factors Polymorphisms in genes coding for TNF-α, TNF-β, and the TNF receptor (TNFR) have been widely studied, with investigations focusing on response to anti-TNF. No associations between the TNFR or the TNFA gene and response to anti-TNF were identified in four separate studies [25–28]. In contrast, a polymorphism in the TNF-β (lymphotoxin-α; LTA) region was demonstrated to be associated with poor response in one study [24]. Furthermore, an association between a polymorphism in a disintegrin and metalloproteinase domain-17 (ADAM-17 or TACE; discussed above) and clinical response has been described [28].

“30–60% of patients treated with biologics fail to show a clinical response at weeks

4–6 after full induction therapy”

In two studies published in 2002, no association was observed between the Crohn’s disease susceptibility gene nucleotide oligomerization domain 2/caspase recruitment domain 15 (NOD2/CARD15) and response to infliximab [29,30]. However, an association between a polymorphism in the Fcγ receptor IIIA (FcγRIIIA) and response to infliximab therapy was observed in a study by Louis et al. [31]. Fc receptors are expressed on monocytes, natural killer cells, and B cells, and are important for ADCC. In the study by Louis et al., patients with the FcγRIIIA –158 V/V genotype and an elevated CRP level before treatment were found to have better responses to infliximab after 4 weeks than patients with the V/F and F/F genotypes [31]. However, the same investigators tested this

association in a larger group of 344 patients enrolled in the ACCENT I study and were unable to confirm this relationship [32]. Although not significant, a larger reduction in CRP levels was observed in patients with the V/V genotype.

Clinical factorsMartinez-Borra et al. identified an association between serum TNF-α levels and response to infliximab in patients with fistulizing Crohn’s disease [33]. Cytokine concentration was determined at weeks 0, 2, 4, 6, 8, and 10. Patients with high TNF-α concentrations (mean 201 pg/mL) before and during infliximab treatment showed poor responses compared with patients with lower TNF-α concentrations (mean 14 pg/mL). In this instance, it may have been that patients with high TNF-α levels before treatment needed a higher dose of anti-TNF. However, high TNF-α levels could not explain all cases of lack of response in the study. TNF-α could not be detected in the serum of five patients who had a complete lack of response. In contrast, a trend towards a better response was observed in patients with luminal disease and higher levels of TNF-α in a study by Louis et al., although this result was not statistically significant (p=0.06) [25]. Higher response rates in patients with elevated CRP levels (>5 mg/mL) prior to infliximab therapy compared with those with normal CRP levels (<5 mg/mL) before therapy were also described in that investigation.

Although solid evidence is lacking, the relationship between genetics and response to infliximab suggests that there may be different groups of Crohn’s disease patients, possibly with different types of disease – perhaps some with a type of disease in which TNF-α is not the dominant factor. The hypothesis that there are different types of disease was proposed by Vasiliauskas et al. [34,35]. The presence of serum perinuclear antineutrophil cytoplasmic antibody (pANCA) is mainly associated with ulcerative colitis (UC), but 10–15% of Crohn’s disease patients also express pANCA. These patients usually have a more UC-like disease phenotype than Crohn’s disease patients who predominantly express anti-Saccharomyces cerevisae antibody (ASCA). The latter is associated with a more aggressive type of Crohn’s disease with small-bowel involvement and fistula formation. In this respect, the absence or presence of ASCA and pANCA serum antibodies may signify different types of mucosal inflammation.

In a study of 279 Crohn’s disease patients, ASCA and pANCA status was scored blindly prior to anti-TNF therapy. Although not significant (p=0.067), a trend towards a poorer response was found in patients with positive pANCA and negative ASCA status [36]. Another study in 59 patients found a significant association between speckled ANCA (sANCA; defined as the presence of diffuse speckled staining over the whole neutrophil upon indirect immunofluorescence staining) and a better response to anti-TNF, compared with those with pANCA or cytoplasmic ANCA (cANCA) expression [24].

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Effect of concurrent immunosuppression and disease durationThe effect of early combined immunosuppression (infliximab and antimetabolites; “top down”) versus conventional therapy in newly diagnosed Crohn’s disease patients was recently evaluated in an open-label, randomized trial [37]. Significantly higher response and remission rates were seen in patients

receiving early combined immunosuppression after 1 year. In addition, similar results were recently observed in patients naïve to immunomodulators and biologics [22]. In the latter study (SONIC), patients were treated with azathioprine and placebo, infliximab and placebo, or infliximab and azathioprine. The remission rates at week 26 were 31%, 44%, and 58%, respectively, indicating that early combined immunosuppression

Table 2. Predictors of reponse to infliximab.

Genetic Factors

Study [reference] n (Crohn’s disease patients)

Factor Association with response? p value

Taylor et al. [24] 59 LTA gene (LTA 1-1-1-1-haplotype) Yes → negative association 0.007

Louis et al. [25]

Pierik et al. [26]

Mascheretti et al. [27]

Dideberg et al. [28]

226

344

90 and 444

222

–308 TNF gene polymorphism

TNFRI and TNFRII

TNFRI, TNFRII, and TNFA polymorphisms

TNF gene

No

No

No

No

Dideberg et al. [28] 222 TACE haplotype Yes → positive association 0.045

Vermeire et al. [29]

Mascheretti et al. [30]

245

534

NOD2/CARD15

NOD2/CARD15

No

No

Louis et al. [31]

Louis et al. [32]

200

344

FcyRIIIa (V/V genotype)

FcyRIIIa (V/V genotype)

Yes → positive association

No

0.003

Clinical and demographic factors

Study [reference] n (Crohn’s disease patients)

Factor Association with response? p value

Martinez-Borra et al. [33] 36 High serum TNF-α levels Yes → negative association <0.05

Louis et al. [25] 226 High CRP levels (>5 mg/L) before infliximab treatment

Yes → positive association 0.004

Esters et al. [36] 279 Positive pANCA and negative ASCA status No (trend towards poor response) 0.067

Taylor et al. [24] 59 pANCA status Yes → negative association 0.003

D’Haens et al. [37]* 133 Early combined immunosuppression (infliximab and azathioprine)


Lionetti et al. [38]

Kugathasan et al. [39]

22

15

Short disease duration

Pediatric Crohn’s disease



<0.05

<0.01

Vermeire et al. [41] 240 Young age

Luminal Crohn’s disease

Concurrent immunosuppression




0.018

0.046

0.0022

Arnott et al. [42]

Parsi et al. [43]

74

100




Yes → positive association (in inflammatory Crohn’s disease)

0.034

0.007

Arnott et al. [42]

Parsi et al. [43]

74

100

Smoking

Smoking

Yes → negative association

Yes → negative association

0.005

0.004

Schnitzler et al. [44] 614 Concurrent azathioprine, CRP level at baseline, and disease duration

No

Lemann et al. [45]** 113 Concurrent azathioprine in azathioprine-naïve patients


ASCA: anti-Saccharomyces cerevisiae antibody; CRP: C-reactive protein; LTA: lymphotoxin-α; NOD2/CARD15: nucleotide oligomerization domain 2/caspase recruitment domain 15; pANCA: perinuclear antineutrophil cytoplasmic antibody; TACE: TNF-α-converting enzyme; TNF: tumor necrosis factor; TNFR: TNF receptor.

*Early use of infliximab + azathioprine versus conventional therapy was evaluated in this study. **Use of azathioprine + placebo versus azathioprine + infliximab was evaluated in this study.

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in naïve patients is more effective than infliximab monotherapy. These findings suggest that a short disease duration might favor a better response. This issue has also been addressed by others [38,39]. Longer duration of disease is more frequently associated with stricture formation and fibrosis, and this type of disease is difficult to treat. In addition, there is evidence that the cytokine profile in Crohn’s disease changes over time, switching from a typical Th1 to a more Th2-like disease [40], which could also influence the efficacy of anti-TNF therapy.

“Genetics, disease type and duration, smoking, and concurrent immunosuppression

may influence the response to anti-TNFs”

Several demographic and clinical parameters have been studied with regard to their influence on response to anti-TNF. Vermeire et al. performed a logistic regression analysis in a cohort of 240 patients and found that young age, luminal Crohn’s disease, and concomitant immunosuppressive therapy were independent predictors of a better response [41]. The role of concomitant immunosuppression has also been addressed by other investigators [42,43]. In a prospective study, patients treated with immunomodulators were found to have better short-term and long-term responses to infliximab [42]. Parsi et al. also observed an association between concurrent immunosuppressive therapy and response [43]. Of 100 Crohn’s disease patients, 50 were treated with concurrent immunosuppressive therapy, of whom 76% showed a response. In contrast, 50 patients did not receive any concurrent immunosuppression; among these patients, 58% showed a response, although this was not statistically significant (p=0.06) and the two groups showed the same duration of response [43]. This difference was more evident in patients with inflammatory Crohn’s disease; in this group, 74% of the patients on concurrent immunosuppression showed a clinical response, compared with 39% of the patients not on concurrent immunosuppression.

In contrast, no association between immunomodulators and prolonged duration of response or higher remission rate was seen in a recent study by Schnitzler et al. [44]. Lémann et al. reported higher remission rates in patients treated with a combination of azathioprine and infliximab, especially in the patient group naïve to azathioprine and biologics [45]. However, in patients who had formerly used azathioprine for >6 months with active disease and who were treated with azathioprine and infliximab, the remission rate was lower than in azathioprine-naïve patients, suggesting that azathioprine-naïve patients particularly benefit from such an approach.

SmokingA strong adverse effect of smoking on response rates to anti-TNF treatment has been observed [42,43]. In a group of 100 Crohn’s

disease patients, 77% of non-smokers responded to infliximab, whereas only 49% of smokers showed a clinical response [43].

Summary In conclusion, there are several factors associated with a lack of response to anti-TNF treatment. Firstly, the lack of response may be genetically determined. Secondly, patients with a poor initial response to infliximab potentially have a different type of disease; these patients might not benefit from anti-TNF therapy since TNF-α may not be the dominant factor in their type of Crohn’s disease. Finally, smoking, disease duration, and concurrent immunosuppression may influence the response to anti-TNFs. In summary, studies show conflicting results and more research needs to be undertaken to identify predictive factors.

Management of lack of responseThere are few data on patients treated with a second anti-TNF agent after failing to respond to the first anti-TNF tried. One study included four infliximab non-responders, of whom one showed a clinical response to adalimumab [46]. Another study included six primary infliximab non-responders, three of whom responded to adalimumab [47].

The use of agents targeting other sites in the inflammatory cascade may be considered in the case of non-response, for example natalizumab (an antibody against the cellular adhesion molecule α4 integrin). Subgroup analysis of the ENCORE (Efficacy of Natalizumab in Crohn’s disease Response and Remission) trial revealed that there was no difference in efficacy between anti-TNF-naïve patients and patients who had previously received anti-TNF therapy but failed to respond [48]. The efficacy of ustekinumab (an antibody directed against IL-12 and IL-23) in Crohn’s disease has recently been studied and found to be particularly effective in patients who had previously received infliximab [49]. Vedolizumab (an antibody against α4β7 integrin) is currently being evaluated in a Phase III trial for the treatment of Crohn’s disease.

Loss of response in clinical trials (secondary non-responders)In addition to those who do not respond, a considerable proportion of patients who do initially respond lose their response after several months of anti-TNF treatment. Loss of response is generally defined as a history of initial response followed by a lack of improvement or worsening of symptoms, including increased stool frequency, fever, rectal bleeding, daily abdominal pain, and recurring drainage from a previously non-draining fistula [50]. Furthermore, a significant number of patients become intolerant to anti-TNF agents; this is

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characterized by acute (during or within 24 h post-treatment) or delayed (occurring 24 h to 15 days post treatment) reactions.

Rutgeerts et al. assessed remission and response rates in patients who initially responded after 8 weeks of treatment with infliximab [51]. After 36 weeks, 72% of initial responders still showed a clinical response (meaning there was a loss of response in 28%). After 44 weeks, 62% patients continued to show a response (loss of response in 38%). The mean time to loss of response was >48 weeks (vs. 37 weeks in placebo recipients). The long-term benefit of infliximab (median follow-up 55 months) was assessed by Schnitzler et al. [44]. A total of 647 patients were evaluated, of whom 547 showed a clinical response at week 10 and were followed until the end of the study. At the end of follow-up, 63% of the patients continued to show clinical benefit. In 13%, treatment was discontinued because of side effects, and in 22% it was discontinued because of a loss of response.

“Loss of response is generally defined as a history of initial response

followed by a lack of improvement or worsening of symptoms”

Response rates after 26 and 56 weeks in week-4 responders to adalimumab were evaluated in CHARM (Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance) as secondary endpoints [52]. After 26 weeks, 55% maintained a response, indicating that there was a loss of response in approximately 45%. At week 56, 43% (adalimumab 40 mg every other week recipients) and 49% (adalimumab 40 mg weekly recipients) showed a response, representing a loss of response in approximately 55% of patients. However, 81% of week-26 responders maintained response up to week 56. Of the week-4 responders, 40% (adalimumab every other week recipients) and 47% (weekly recipients of adalimumab) were in remission, compared with 17% in the placebo group, at 26 weeks. After 56 weeks, remission rates were 36–41%, compared with 12% in the placebo group. Adverse events leading to discontinuation of the study drug (with exacerbation of Crohn’s disease being the most common event) occurred in 6.9% (adalimumab every other week recipients) and 4.7% (adalimumab weekly recipients) compared with 13.4% of the placebo group. Patients who were previously treated with infliximab but who lost response also responded to adalimumab in this trial, but this response rate were lower than that in patients who were naïve to anti-TNF therapy.

Schreiber et al. assessed response rates at week 26 (primary endpoint) in patients treated with certolizumab pegol who showed a 100-point response at week 6 (428 of 668 patients [64%] overall) [53]. Patients were stratified by CRP level at baseline

(<10 mg/L or >10 mg/L) and response rates were evaluated at week 26. At this time-point, 62% of week-6 responders in the CRP >10 mg/L group still showed a response (vs. 34% in the placebo group); thus, 38% patients had lost response. In the intention-to-treat population (n=425), 63% of week-6 responders still had a response at week 26 in the certolizumab group compared with 36% of the placebo group. The remission rate at week 26 among week-6 responders was 48% in the certolizumab group and 29% in the placebo group. Serious adverse events occurred in 6% of the certolizumab group and in 7% of the placebo group. The most frequently occurring adverse events were the same in the two groups. Twenty-four percent of the patients had previously been treated with infliximab, but those with a primary lack of response were excluded from this study. Response rates in infliximab-naïve patients were higher than those in patients who had previously received infliximab.

Factors associated with loss of response Approximately 40–55% of patients who initially respond to anti-TNF therapy lose this response at a certain time-point. Loss of response may be disease- or drug-related. Disease-related factors include stricturing and abscess formation. Infections should first be excluded before a patient is considered to be a secondary non-responder. Drug-related factors include the formation of neutralizing antibodies against antibodies or altered clearance of the drug.

Antibodies to infliximabThe formation of antibodies to infliximab (ATI) has been found to be associated with infusion reactions and a shorter duration of response [54,55]. Farrell et al. performed a randomized clinical trial to investigate the association between hydrocortisone premedication and the formation of ATI [54]. They concluded that pretreatment with intravenous hydrocortisone significantly reduced ATI levels in Crohn’s disease patients receiving infliximab infusions, but it did not reduce the formation of ATI or the number of infusion reactions. Overall, 73% of patients who lost an initial response to infliximab were positive for ATI, whereas none of the continuous responders were ATI-positive. Of the patients on concurrent immunosuppressive therapy, 24% were positive for ATI, compared with 63% of those not treated with immunosuppressive agents (i.e. placebo recipients). Another study found that concurrent immunomodulators conferred protection against the formation of ATIs; however, this association was only found in patients receiving episodic infliximab therapy, and not in those receiving scheduled therapy [56]. A role for immunosuppressive therapy in reducing the formation of ATI was also confirmed by Baert et al. [55].

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Antibodies to adalimumabAntibodies to adalimumab (ATA) have been found to be associated with non-response to adalimumab in a retrospective study in patients with active Crohn’s disease [57]. In addition, the formation of ATA is associated with reduced levels of adalimumab and reduced duration of response in RA [58]. In a cohort study of 253 RA patients, the efficacy of adalimumab and formation of ATA were evaluated in anti-TNF-naïve patients and anti-TNF (infliximab)-exposed patients (switchers) who discontinued treatment because of a loss of response [59]. Switchers with ATI developed ATA more frequently than anti-TNF-naïve patients, and anti-TNF-naïve patients had a better response to adalimumab. However, the response to adalimumab was limited in switchers without ATI, suggesting that there may be different types of non-responders and that switching to a second TNF because of loss of response in patients without ATI may not be effective. Perhaps supporting this suggestion, the same group reported an association between IL-10 polymorphisms and the formation of ATA in a prospective study [60].

Antibodies to certolizumabIn the PRECISE 2 study, 58 (9%) of the 668 included patients developed antibodies against certolizumab. No clear relationship between duration of response and antibody formation was identified [53]. In a 12-week study, nine of 73 patients (12.3%) had detectable antibodies against certolizumab [61]. In addition, certolizumab plasma concentrations were lower in those with detectable antibody levels. However, response rates at week 12 (the primary endpoint) were the same in patients who were positive and negative for antibodies to certolizumab.

SummaryThe role of antibodies against antibodies in the long-term efficacy of anti-TNFs is controversial. Measurement of the incidence and levels of antibodies against antibodies is highly dependent on the type of assay used, type of dosage regimen, and timing of measurement. Moreover, measuring antibodies against antibodies is very complex. In a recent systematic review, the incidence of ATI and their effect on infliximab efficacy and safety were evaluated [62]. The authors emphasized that it is more or less impossible to compare the results of different studies because of differences in study design and the use of various techniques to establish ATI incidence and levels. Nevertheless, they concluded that ATI formation is, to some extent, associated with a reduced duration of response and infusion reactions but not with serious adverse reactions. They also concluded that the formation of ATI has little clinical relevance overall. A more useful method for predicting loss of response could be to measure the drug trough level, which may reflect bioactivity. This has been found to predict clinical outcome, with low infliximab trough levels demonstrated to be associated with loss of response [63].

Management of loss of responseDose intensificationFor patients with low trough drug serum levels, it may be effective to shorten the treatment intervals. Maintaining adequate plasma drug trough levels has been demonstrated to be beneficial in maintaining response [64]. In ACCENT I, the infliximab dose was increased from 5 mg/kg to 10 mg/kg in secondary non-responders, and 88% of patients had a clinical response after this increase [21]. In the follow-up study by Schnitzler et al., 71% of those needing an increase in dose and/or re-induction at weeks 0, 2, and 6, 62% of the patients needing a dose increase and shortening of dose interval, and 29% of those with a shortened interval were able to go back to the standard dosage regimen [44]. This is probably also the case for adalimumab and certolizumab. Adalimumab dosing can be increased from 40 mg every other week to 40 mg weekly [65]. Loss of response to certolizumab can be controlled by giving a supplemental dose, as is currently being assessed in the PRECISE 4 study [66].

Switching to another anti-TNFAnother option in case of failure of sustained response is switching to another anti-TNF agent. Remission and response rates after 4 weeks in patients receiving adalimumab previously treated with infliximab, but who lost response (n=164) or became intolerant (n=190) to infliximab, were assessed in a randomized, placebo-controlled trial [50]. At week 4, 52% (vs. 34% of placebo recipients) achieved a response, and 21% (vs. 7% of placebo recipients) achieved remission, indicating that adalimumab is an acceptable alternative in this group of patients [52].

The efficacy of certolizumab in patients previously treated with infliximab but who lost response or became intolerant to infliximab is currently being evaluated in WELCOME (26-Week Open-label Trial Evaluating the Clinical Benefit and Tolerability of Certolizumab Pegol Induction and Maintenance in Patients Suffering from Crohn’s Disease with Prior Loss of Response or Intolerance to Infliximab). A total of 539 patients are included in this ongoing trial, with 62% showing a clinical response at week 6, comparable with the rates found in the PRECISE 2 study [67].

Switching to another anti-TNF agent seems to be a good option, but it may be that there are different groups of secondary non-responders, and that some patients might not benefit from such an approach. Unfortunately, much remains unknown about the causes of loss of response, and so far no predictive factors for loss of response have been identified.

Concluding remarksLack and loss of response to anti-TNF therapy represent an obstacle in the treatment of Crohn’s disease. Predictive factors for lack and loss of response are needed to select patients for a particular therapeutic approach. This may improve treatment, minimize side effects, and reduce morbidity. Many studies

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have been undertaken to identify predictive factors for lack and loss of response to anti-TNF. Genetic, clinical, and demographic factors have been proposed to play a role in lack of response. FcγRIIIa, TACE, and LTA are possible genetic factors, while a young age, luminal Crohn’s disease, short duration of disease, and concurrent immusuppression are possible clinical factors. Patients with a lack of response can switch to another anti-TNF or to a biologic with another mechanism of action. Although controversial, the formation of antibodies against antibodies has been associated with loss of response. The use of concurrent immunosuppressive drugs may reduce the formation of these antibodies against antibodies. Dose intensification in patients with low drug trough levels and switching to another anti-TNF might also be good options in patients with loss of response.

A better understanding of the complex pathogenesis of Crohn’s disease and the working mechanism of anti-TNF agents could help to identify predictive factors for the response to anti-TNFs and would allow the selection of patients for specific management strategies.

disclosuresDr Hommes has served as an advisor to Abbott, Centocor, Schering Plough, and UCB. In addition, Dr Hommes has received financial support for research from Abbott, Centocor, Schering Plough, and UCB. Drs Vos, Fidder, and van den Brink have no relevant financial interests to disclose.

References1. Lichtenstein GR, Feagan BG, Cohen RD et al. Serious infections and mortality in

association with therapies for Crohn’s disease: TREAT Registry. Clin Gastroenterol Hepatol 2006;4:621–30.

2. Lapidus A, Bernell O, Hellers GR et al. Clinical course of colorectal Crohn’s disease: a 35-year follow-up study of 507 patients. Gastroenterology 1998;114:1151–60.

3. Targan SR, Hanauer SB, van Deventer SJ et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. N Engl J Med 1997;337:1029–36.

4. D’Haens G, Van Deventer S, Van Hogezand R et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology 1999;116:1029–34.

5. van Dullemen HM, van Deventer SJ, Hommes DW et al. Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2) Gastroenterology 1995;109:129–35.

6. Baert FJ, D’Haens GR, Peeters M et al. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn’s ileocolitis. Gastroenterology 1999;116:22–8.

7. Nesbitt A, Fossati G, Bergin M et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents Inflamm Bowel Dis 2007;13:1323–32.

8. Schreiber S, Nikolaus S, Hampe J et al. Tumour necrosis factor alpha and interleukin 1beta in relapse of Crohn’s disease. Lancet 1999;353:459–61.

9. Moreland LW, Schiff MH, Baumgartner SW et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999;130:478–86.

10. Moreland LW, Baumgartner SW, Schiff MH et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997;337:141–7.

11. Sandborn WJ, Hanauer SB, Katz S et al. Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001;121:1088–94.

12. ten Hove T, van Montfrans C, Peppelenbosch MP et al. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn’s disease. Gut 2002;50:206–11.

13. Van den Brande JM, Braat H, van den Brink GR et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology 2003;124:1774–85.

14. Scallon BJ, Moore MA, Trinh H et al. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995;7:251–9.

15. Mitoma H, Horiuchi T, Hatta N et al. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha. Gastroenterology 2005;128:376–92.

16. Mitoma H, Horiuchi T, Tsukamoto H et al. Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells: comparison among infliximab, etanercept, and adalimumab. Arthritis Rheum 2008;58:1248–57.

17. Lügering A, Schmidt M, Lügering N et al. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspase-dependent pathway. Gastroenterology 2001;121:1145–57.

18. Danese S, Sans M, Scaldaferri F et al. TNF-alpha blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation: a novel anti-inflammatory mechanism of infliximab in Crohn’s disease. J Immunol 2006;176:2617–24.

19. Di Sabatino A, Pender SLF, Jackson CL et al. Functional Modulation of Crohn’s disease myofibroblasts by anti-tumor necrosis factor antibodies. Gastroenterology 2007;133:137–49.

20. Hanauer SB, Sandborn WJ, Rutgeerts P et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006;130:323–33.

21. Hanauer SB, Feagan BG, Lichtenstein GR et al.; ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–9.

22. Sandborn W, Rugeerts P, Reinisch W et al. SONIC: a randomized, double-blind controlled trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Inflamm Bowel Dis 2008;14(Suppl 3);Abstr P087.

23. Sandborn WJ, Feagan BG, Stoinov S et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007;357:228–38.

24. Taylor KD, Plevy SE, yang H et al. ANCA Pattern and LTA haplotype relationship to clinical responses to anti-TNF antibody treatment in Crohn’s disease. Gastroenterology 2001;120:1347–55.

25. Louis E, Vermeire S, Rutgeerts P et al. A positive response to infliximab in Crohn disease: association with a higher systemic inflammation before treatment but not with –308 TNF gene polymorphism. Scand J Gastroenterol 2002;37:818–24.

26. Pierik M, Vermeire S, Steen KV et al. Tumour necrosis factor-alpha receptor 1 and 2 polymorphisms in inflammatory bowel disease and their association with response to infliximab. Aliment Pharmacol Ther 2004;20:303–10.

27. Mascheretti S, Hampe J, Kühbacher T et al. Pharmacogenetic investigation of the TNF/TNF-receptor system in patients with chronic active Crohn’s disease treated with infliximab. Pharmacogenomics J 2002;2:127–36.

28. Dideberg V, Théâtre E, Farnir F et al. The TNF/ADAM 17 system: implication of an ADAM 17 haplotype in the clinical response to infliximab in Crohn’s disease. Pharmacogenet Genomics 2006;16:727–34.

29. Vermeire S, Louis E, Rutgeerts P et al. NOD2/CARD15 does not influence response to infliximab in Crohn’s disease. Gastroenterology 2002;123:106–11.

30. Mascheretti S, Hampe J, Croucher PJ et al. Response to infliximab treatment in Crohn’s disease is not associated with mutations in the CARD15 (NOD2) gene: an analysis in 534 patients from two multicenter, prospective GCP-level trials. Pharmacogenetics 2002;12:509–15.

31. Louis E, El Ghoul Z, Vermeire S et al. Association between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn’s disease. Aliment Pharmacol Ther 2004;19:511–9.

32. Louis EJ, Watier HE, Schreiber S et al. Polymorphism in IgG Fc receptor gene FCGR3A and response to infliximab in Crohn’s disease: a subanalysis of the ACCENT I study. Pharmacogenet Genomics 2006;16:911–4.

33. Martínez-Borra J, López-Larrea C, González S et al. High serum tumor necrosis factor-alpha levels are associated with lack of response to infliximab in fistulizing Crohn’s disease. Am J Gastroenterol 2002;97:2350–6.

34. Vasiliauskas EA, Plevy SE, Landers CJ et al. Perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn’s disease define a clinical subgroup. Gastroenterology 1996;110:1810–9.

35. Vasiliauskas EA, Kam Ly, Karp LC et al. Marker antibody expression stratifies Crohn’s disease into immunologically homogeneous subgroups with distinct clinical characteristics. Gut 2000;47:487–96.

36. Esters N, Vermeire S, Joossens S et al. Serological markers for prediction of response to anti-tumor necrosis factor treatment in Crohn’s disease. Am J Gastroenterol 2002;97:1458–62.


www.ibdmonitor.com

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37. D’Haens G, Baert F, van Assche G et al.; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008;371:660–7.

38. Lionetti P, Bronzini F, Salvestrini C et al. Response to infliximab is related to disease duration in paediatric Crohn’s disease. Aliment Pharmacol Ther 2003;18:425–31.

39. Kugathasan S, Werlin SL, Martinez A et al. Prolonged duration of response to infliximab in early but not late pediatric Crohn’s disease. Am J Gastroenterol 2000;95:3189–94.

40. Kugathasan S, Saubermann LJ, Smith L et al. Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease. Gut 2007;56:1696–705.

41. Vermeire S, Louis E, Carbonez A et al. Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn’s disease. Am J Gastroenterol 2002;97:2357–63.

42. Arnott ID, McNeill G, Satsangi J. An analysis of factors influencing short-term and sustained response to infliximab treatment for Crohn’s disease. Aliment Pharmacol Ther 2003;17:1451–7.

43. Parsi MA, Achkar JP, Richardson S et al. Predictors of response to infliximab in patients with Crohn’s disease. Gastroenterology 2002;123:707–13.

44. Schnitzler F, Fidder H, Ferrante M et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort. Gut 2009;58:492–500.

45. Lémann M, Mary Jy, Duclos B et al. Infliximab plus azathioprine for steroid-dependent Crohn’s disease patients: a randomized placebo-controlled trial. Gastroenterology 2006;130:1054–61.

46. Seiderer J, Brand S, Dambacher J et al. Adalimumab in patients with Crohn’s disease – safety and efficacy in an open-label single centre study. Aliment Pharmacol Ther 2007;25:787–96.

47. Ho GT, Smith L, Aitken S et al. The use of adalimumab in the management of refractory Crohn’s disease. Aliment Pharmacol Ther 2008;27:308–15.

48. Targan SR, Feagan BG, Fedorak RN et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology 2007;132:1672–83.

49. Sandborn WJ, Feagan BG, Fedorak RN et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 2008;135:1130–41.

50. Sandborn WJ, Rutgeerts P, Enns R et al. Adalimumab Induction Therapy for Crohn Disease Previously Treated with Infliximab: a randomized trial. Ann Intern Med 2007;146:829–38.

51. Rutgeerts P, D’Haens G, Targan S et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999;117:761–9.

52. Colombel JF, Sandborn WJ, Rutgeerts P et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132:52–65.

53. Schreiber S, Khaliq-Kareemi M, Lawrance IC et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007;357:239–50.

54. Farrell RJ, Alsahli M, Jeen yT et al. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology 2003;124:917–24.

55. Baert F, Noman M, Vermeire S et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348:601–8.

56. Maser EA, Villela R, Silverberg MS et al. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol 2006;4:1248–54.

57. West RL, Zelinkova Z, Wolbink GJ et al. Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn’s disease. Aliment Pharmacol Ther 2008;28:1122–6.

58. Bartelds GM, Wijbrandts CA, Nurmohamed MT et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis 2007;66:921–6.

59. Bartelds GM, Wijbrandts CA, Nurmohamed MT et al. Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-TNF naive patients: a cohort study. Ann Rheum Dis 2009; [Epub ahead of print].

60. Bartelds GM, Wijbrandts CA, Nurmohamed MT et al. Anti-adalimumab antibodies in rheumatoid arthritis patients are associated with interleukin-10 gene polymorphisms. Arthritis Rheum 2009;60:2541–2.

61. Schreiber S, Rutgeerts P, Fedorak RN et al.; CDP870 Crohn’s Disease Study Group. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology 2005;129:807–18. Erratum in: Gastroenterology 2005;129:1808.

62. Cassinotti A, Travis S. Incidence and clinical significance of immunogenicity to infliximab in Crohn’s disease: a critical systematic review. Inflamm Bowel Dis 2009;15:1264–75.



65. Feagan BG, Panaccione R, Sandborn WJ et al. Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn’s disease: results from the CHARM study. Gastroenterology 2008;135:1493–9.

66. Sandborn WJ, Hanauer SB, Rutgeerts P et al. Re-induction and maintenance therapy with subcutaneous certolizumab pegol in patients with Crohn’s disease following treatment failure: PRECISE 4 results. Gastroenterology 2007;132(Suppl 1):Abstr T1274.

67. Vermeire S, Abreu M, D’Haens G et al. Efficacy and safety of certolizumab pegol in patients with active Crohn’s disease who previously lost response or were intolerant to infliximab: open label induction. Preliminary results of the WELCOME study. Gastroenterology 2008;134(Suppl 1):P-81.

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LEAdinG ARtiCLE

Address for correspondence: Miguel Regueiro, MD, Division of Gastroenterology, Hepatology & Nutrition, University of Pittsburgh Medical Center, 200 Lothrop Street, PUH-C Wing Mezzanine Level, Pittsburgh, PA 15213, USA. Email: [email protected]

Crohn’s disease is a chronic, relapsing, inflammatory disorder of unknown etiology that can involve the entire gastrointestinal tract. Crohn’s disease affects approximately 500 000 patients in the US and frequently requires both medical and surgical management [1]. Approximately 80% of Crohn’s disease patients will require surgery in their lifetime [2]. While surgery removes the diseased intestine, it is not curative and recurrence is common. In Crohn’s disease patients who have undergone a resection due to disease, the endoscopic recurrence rate of disease at 1 year is 70–90% [3,4]. A much smaller proportion of patients have clinical recurrence of disease at 1 year – as low as 20–37% [3,4].

The wide range of postoperative recurrence rates cited in the literature is due to the heterogeneity of the studies in terms of definitions of recurrence (i.e. clinical or endoscopic), time to recurrence, and indication for surgery (i.e. perforating or stricturing disease). The postoperative management of Crohn’s disease patients offers a challenge for physicians in terms of diagnosing recurrence, minimizing risk factors for recurrence, and selecting patients for therapies to prevent recurrence.

definition of recurrenceHistorically, the definition of Crohn’s disease recurrence after surgery has relied upon clinical symptoms. Most patients who have recurrence by these definitions will not have symptoms, that is, clinical recurrence of Crohn’s disease [3]. Crohn’s disease recurrence postoperatively is usually clinically silent until another complication develops that requires surgery.

The postoperative Crohn’s disease patient serves as a unique model to gain insight into the natural course of Crohn’s disease. Most newly diagnosed Crohn’s disease patients present with disease that is well advanced and have apparent intestinal structural damage (i.e. stenosis, strictures, and/or penetrating disease). It is not known why Crohn’s disease patients do not develop signs and symptoms at the first instance of intestinal inflammation years before diagnosis. To that end, monitoring postoperative recurrence by the development of clinical symptoms is problematic. Most mucosally active Crohn’s disease recurs at or immediately proximal to the ileocolonic anastomosis within the first 1 year after surgery and is clinically silent [4]. Unfortunately, most clinical trials still define postoperative recurrence by clinical symptoms. The 1-year clinical relapse or recurrence rates measured by the Crohn’s

Management of Postoperative Crohn’s DiseaseJoseph Rodemann, MD, and Miguel Regueiro, MD

Inflammatory Bowel Disease Center and Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

The majority of patients with Crohn’s disease require surgery at some point. Postoperative Crohn’s disease recurrence is common after intestinal resection. The optimal management strategy for postoperative recurrence of Crohn’s disease is controversial. In the absence of universally adopted guidelines, clinicians and patients must discuss and balance the risks and benefits of postoperative pharmacotherapy. Those at a low risk of disease recurrence may not require treatment. On the other hand, patients with more aggressive disease and a high risk of recurrence may be best treated early in the postoperative period with an immunomodulator or anti-tumor necrosis factor agent. Ideally, postoperative treatment decisions would be made using predictable, reliable, and reproducible clinical prediction criteria that would guide treatment. This article reviews the data on postoperative Crohn’s disease – including definitions of postoperative recurrence, surveillance of postoperative recurrence, risk factors, and medications for prevention of recurrence. Inflamm Bowel Dis Monit 2009;10(2):52–60.

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| MANAGEMENT OF POSTOPERATIVE CROHN’S DISEASE 53

disease activity index (CDAI) is the most common primary endpoint of postoperative clinical trials. Therefore, utilizing the CDAI to define postoperative recurrence will underestimate postoperative Crohn’s disease recurrence [5].

Postoperative endoscopic recurrenceThe finding of endoscopically evident Crohn’s disease in the neoterminal ileum is now recognized as the best predictor of disease progression and need for future surgery. In the landmark study by Rutgeerts et al., a cohort of 89 Crohn’s disease patients undergoing ileocolonic resection were prospectively assessed by ileocolonoscopy and monitored for clinical and surgical recurrence [6]. This study found the strongest predictor of recurrent Crohn’s disease to be the severity of endoscopic lesions found on colonoscopy 1 year after surgery. Endoscopic recurrence after resection was graded using the scoring system devised for this study (Table 1, Figure 1). Patients with mild or inactive disease (i0, i1) rarely had symptoms at 1 year and 80% of these patients continued to have mild

or absent endoscopic recurrence at 3 years. Patients with severe endoscopic disease (i3, i4) were much more likely to have clinical recurrence at 1 year; 92% of these patients had progressive, severe endoscopic disease at 3 years with a high likelihood for reoperation. The intermediate (i2) group was between these two groups clinically and endoscopically (33% of these patients progress to i4 lesions at 3 years). These data indicate that the most important predictor of Crohn’s disease recurrence after operation is the severity of endoscopic lesions. Therefore, we believe that routine colonoscopy 6 months to 1 year after intestinal resection is important for the evaluation of endoscopic recurrence, regardless of clinical symptoms.

non-endoscopic assessments of postoperative recurrenceStudies indicate that clinical assessment tends to miss many patients who have endoscopic recurrence of disease. Multiple tests have been evaluated for assessing postoperative recurrence including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) concentration, fecal calprotectin level, fecal lactoferrin level, and wireless capsule endoscopy (WCE).

ESR is noted to be more sensitive in patients with active Crohn’s colitis, but does not appear to be a reliable test for clinical postoperative recurrence [7]. CRP levels can correlate with disease activity but conflicting reports make this assessment unreliable as the primary test for clinical disease recurrence; however, higher levels of CRP may suggest a more severe recurrence of disease [8–10].

Fecal calprotectin and lactoferrin levels appear to be more predictive of endoscopic disease activity than other surrogate markers [8,11]. A small study that followed the values of fecal lactoferrin and calprotectin in patients with Crohn’s disease before and after ileocolonic resection found that these values correlated well with each other and were elevated with

Table 1. Endoscopic recurrence score [6].

Endoscopic score

Definition

i0 No lesions

i1 ≤5 Aphthous lesions

i2 >5 Aphthous lesions with normal mucosa between the lesions or skip areas of larger lesions or lesions confined to the ileocolonic anastomosis

i3 Diffuse aphthous ileitis with diffusely inflamed mucosa

i4 Diffuse inflammation with already larger ulcers, nodules, and/or narrowing

Remission: endoscopic score of i0 or i1; recurrence: endoscopic score of i2–i4.

Figure 1. Endoscopic recurrence of Crohn’s disease after resection was graded using the scoring system devised by Rutgeerts et al. (Table 1) [6]. A: Mild disease with ≤5 aphthous lesions (score: i1); B: Severe endoscopic disease with diffuse aphthous ileitis and inflamed mucosa (score: i3); C: Severe endoscopic disease with diffuse inflammation with large ulcers and stenosis (score: i4). A B C

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recurrent disease [12]. Unfortunately, these are not available for routine testing everywhere.

Wireless capsule endoscopy (WCE) has been employed to detect the recurrence of postoperative Crohn’s disease. Bourreille et al. performed ileocolonoscopy and WCE in 32 patients 6 months after ileocolonic resection. Both modalities were 100% specific at identifying endoscopic recurrence, but colonoscopy had a superior sensitivity of 90% versus 62–76% for WCE [13]. Pons Beltrán et al. assessed 22 patients for Crohn’s disease recurrence after resection using colonoscopy and WCE, and found similar rates of detection of endoscopic neoterminal ileal recurrence; in addition, there were 10 other patients who had recurrence that was proximal to the reach of colonoscopy detected using the combined modalities [14]. The authors suggested in their analysis that WCE is better than colonoscopy at detecting disease recurrence. Biancone et al. assessed 22 patients 1 year after ileocolonic resection for Crohn’s disease with colonoscopy, WCE, and small intestine contrast ultrasonography (SICUS). Although all patients were in clinical remission at 1 year, colonoscopy detected recurrence in 21 of the 22 patients, SICUS detected recurrence in 22 of 22 (one false-positive), and WCE detected recurrence in 16 of 17 patients (five patients were unable to complete WCE due to the risk of capsule retention) [15]. These results indicate that with the proper training and technology, WCE and SICUS may have a role in non-invasive detection of Crohn’s disease recurrence after surgery.

Risk factors for recurrenceThere are several factors that influence the likelihood of a patient experiencing recurrent Crohn’s disease postoperatively. The best studied risk factors include cigarette smoking, disease behavior and phenotype, number of intestinal resections, and surgical technique. The age at disease onset, gender, and family history have also been studied for their ability to predict the postoperative recurrence of Crohn’s disease. While there are trends to suggest a young age at onset may be a risk factor, gender has not been associated with an increased risk of postoperative recurrence. Family history of Crohn’s disease has been reported with varying results; either no added risk [16], or a significant risk factor [17,18].

Several studies have implicated cigarette smoking as causing an increased risk of postoperative Crohn’s disease recurrence. One study of 174 patients displayed a significant increase in the risk of clinical recurrence at 10 years in patients who smoke cigarettes (70% vs. 41% in nonsmokers; p<0.005) [19]. An even higher risk was seen in women who smoke (odds ratio [OR] 2.1). A review of 59 patients who had undergone ileocolonic resection for Crohn’s disease revealed that smokers had an increased risk of clinical recurrence compared with non-smokers (50% vs. 25%, OR 2.96; p<0.02). Smokers also appeared to

have clinical recurrence earlier than non-smokers (p≤0.001) [20]. Another study reviewed the records of 400 patients who underwent excisional surgery for a complication of Crohn’s disease [21]. Smokers required more glucocorticoids (93% vs. 82%; p=0.002) and immunosuppressive medication (39% vs. 25%; p=0.002) than non-smokers [18,21]. The results displayed a higher risk of recurrent surgical Crohn’s disease in female smokers. A review involving 267 patient demonstrated that patients who have undergone ileocecal resection for Crohn’s disease who stop smoking reduce their risk for reoperation at 10 years (45% vs. 61%; p=0.016) [17].

“Endoscopic evidence of Crohns disease in the neoterminal ileum is the best predictor of disease recurrence”

Disease phenotype – perforating versus non-perforating disease – has been evaluated as a risk factor for recurrent Crohn’s disease. Greenstein et al. found that patients with a perforating indication for initial resection tended to have recurrent perforating disease that required subsequent resections [22]. Two studies found that perforating disease led to reoperation sooner than non-perforating disease [23,24]. A meta-analysis of 13 studies involving 3044 patients in which the incidence of recurrence and indication of reoperation for recurrent Crohn’s disease were evaluated indicated a higher recurrence rate in perforating disease (HR 1.50; p=0.002), but there was a high degree of heterogeneity between studies [25].

Surgical techniques have been investigated for their potential impact on disease recurrence. The type of anastamosis has been evaluated in several studies [26,27]. A retrospective study of 141 patients who underwent ileocolonic resection for Crohn’s disease found a significantly lower surgical recurrence rate in those with a handsewn side-to-side anastamosis compared with a stapled end-to-side anastamosis (p<0.05) [27]. However, another study evaluated 139 patients who underwent ileocolonic resection with side-to-side or end-to-end anastamosis. Endoscopic recurrence was found in 37.9% of patients with side-to-side anastamosis and in 42.5% of patients with an end-to-end anastamosis (p=0.55) [28]. Laparoscopic ileocolonic resection was compared with open ileocolonic resection in a group of 92 patients followed over 5 years [29]. Surgical recurrence of disease was no different between the groups at 5 years (29.1% open vs. 27.7% laparoscopic; p=0.914) although the rate of intestinal obstruction was significantly higher in the open group. One study compared stapled end-to-end anastamosis to sutured end-to-end anastamosis and found a higher rate of surgical disease recurrence at 5 years in patients with the sutured anastamosis (3% vs. 24%; p=0.007) [30].

Other risk factors for recurrence, including the pathological findings in resected tissue, genetic mutations, and the use

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of perioperative blood transfusion, have been studied. A retrospective study of 130 patients with Crohn’s disease requiring an operation for their disease suggested that the presence of granulomas is a risk for recurrent clinical recurrence at 5 years (62% vs. 81%; p=0.003) [31]; however, two other studies indicated that the presence of granulomas was actually predictive of a decrease in clinical disease recurrence [32,33]. The number of granulomas in samples of the large bowel and anus in a sample of 79 patients was predictive of a good outcome, but was of no prognostic significance in the small bowel [33]. Myenteric plexitis of the proximal resection margin correlated with higher endoscopic recurrence at 3 months (75% vs. 41%; p=0.008) and at 1 year (93% vs. 59%; p=0.041) in a study of 32 patients [34]. In a study of 70 patients undergoing surgery for Crohn’s disease, the presence of the NOD2/CARD15 gene variants was associated with more frequent postoperative recurrence (OR 3.63) and earlier reoperation (p=0.03) [35]. A pooled analysis of 622 patients evaluated over 5 years could not detect a difference between surgical recurrence in patients with or without perioperative blood transfusion (26.9% with transfusion vs. 25.2% without transfusion; p=0.456) [36].

Medical therapies to prevent recurrenceSeveral medications have been studied for the prevention of postoperative Crohn’s disease recurrence. We will review the data on 5-aminosalicylates, antibiotics, probiotics, budesonide, 6-mercaptopurine and azathioprine, infliximab, and experimental agents. Due to a growing body of literature on the thiopurine analogues in postoperative Crohn’s disease, we provided a more detailed review of these studies and a table that outlines the key features of the data.

5-Aminosalicylic acid (5-ASA) agentsClinical trials have investigated the efficacy of 5-ASA agents in postoperative Crohn’s disease, with varying results. One study of 569 patients over 2 years indicated that sulfasalazine had no significant prophylactic effect on postoperative clinical Crohn’s disease recurrence (p=0.08) [37]. Another study indicated that 3 g/day sulfasalazine was successful at decreasing postoperative clinical Crohn’s disease recurrence at 1 year (16% vs. 28%; p<0.01) [38]. Four studies have indicated that 5-ASA compounds have a positive effect on the prevention of postoperative Crohn’s disease recurrence [39–42]. Three of these studies evaluated 3 g/day mesalamine compared with placebo, with two finding improved clinical outcomes following ≥1 year on therapy [39,40]. In a study of 163 patients followed for a maximum of 72 months, decreased symptomatic recurrence (clinical plus either radiological or endoscopic recurrence) was displayed in the group receiving mesalamine (31% recurrence in the

treatment group vs. 41% in the control group; p=0.031) [39]. The relative risk of recurrent Crohn’s disease was calculated to be 0.628. A study of 87 patients displayed a decrease in the severity and frequency of endoscopic lesions at 12 months in the mesalamine recipients (24% in the treatment group vs. 56% in the placebo group, OR 4.1; p<0.004) [40]. The third study of 3 g/day mesalamine followed 106 patients for 3 months and found endoscopic recurrence in 50% of the treatment group and 63% of the placebo group (p=0.16) [41]. Another study of 95 patients found that 2.4 g/day mesalamine significantly improved endoscopic recurrence at 12 months compared with placebo (29% vs. 60%; p=0.002) and decreased the severity of recurrence [42]. In an evaluation of mesalamine 4 g/day versus placebo in 318 patients followed for a total of 18 months, the clinical recurrence of postoperative Crohn’s disease was similar between the two groups (24.5% in the treatment group vs. 31.4% in the placebo group; p=0.10) [43]. Similarly, another evaluation of 3 g/day mesalamine versus placebo in 246 patients did not find a significant difference between the two groups in terms of clinical recurrence with 25% recurrence in the treatment group and 36% recurrence in the placebo group (p=0.056) [44]. Another study assessed whether the dosing of mesalamine had any effect on postoperative Crohn’s disease recurrence at 12 months. When comparing patients receiving 2.4 g versus 4.0 g of mesalamine per day, overall endoscopic recurrence was more significant in the lower dose mesalamine group (62% vs. 46%; p<0.04) but a difference was not seen in patients with more severe disease recurrence [45]. In summary, the results of all of the studies of 5-ASA are disparate and collectively offer no or minimal reduction in postoperative Crohn’s disease recurrence with 5-ASA.

AntibioticsTwo studies indicate that the neoterminal ileum must be exposed to the intestinal flora in order for Crohn’s disease to recur after surgery [46,47]. These findings have led to the study of antibiotics in the prevention of postoperative Crohn’s disease. Metronidazole and ornidizole have both been evaluated in prospective, placebo-controlled trials.

“Smoking and perforating disease are key risk factors for postoperative

disease recurrence”

In the first study, 60 patients were assigned to receive 20 mg/kg/day metronidazole orally versus placebo starting 1 week after ileocecal resection of Crohn’s disease. At 12 weeks, recurrence was visualized endoscopically in 75% of patients receiving placebo versus 52% of those on metronidazole (p=0.09), with severe recurrence seen in 43% versus 13% of patients (p=0.02), respectively. Clinical recurrence at 1 year

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was statistically significantly reduced, with a recurrence rate of 25% in the placebo group and 4% in the metronidazole group (p=0.044) [48]. In the second study, ornidazole 500 mg orally twice daily (not currently available in the US) was compared with placebo in 80 patients within 1 week of ileocecal resection. Endoscopic recurrence at 1 year was 79% in the placebo group versus 53.6% in the ornidizole group (OR 0.31; p=0.037). Clinical recurrence was 37.5% in the placebo group compared with 7.9% in the ornidazole group at 1 year (OR 0.14; p=0.0046) [49]. Both of these antibiotics were discontinued more frequently than placebo due to side effects.

Both metronidazole and ornidazole appear to have a role in preventing postoperative Crohn’s disease recurrence. The limitation with nitromidazole antibiotics is that the majority of patients cannot tolerate these treatments, and that the medications must be continued long-term in order to prevent recurrence.

ProbioticsTwo prospective studies have evaluated strains of Lactobacillus to prevent postoperative Crohn’s disease recurrence [50,51]. Twelve billion CFU/day of Lactobacillus GG were compared with placebo for 1 year in 45 patients who underwent ileocecal resection for Crohn’s disease. At 1 year, the clinical recurrence rate was 16.6% in the Lactobacillus group compared with 10.5% in placebo recipients, which was a statistically insignificant difference (p=0.948). Endoscopic recurrence at 1 year was 60% in the Lactobacillus group versus 35.3% for placebo (p=0.297) [50]. A larger study evaluated 98 patients receiving Lactobacillus johnsonii or placebo for 6 months following ileocecal resection. Endoscopic recurrence at 6 months was 64% in the placebo group compared with 49% in the Lactobacillus group (OR 1.79; p=0.15) [51]. Clinical recurrence was similar in the two groups. Both studies used smaller numbers of bacteria than have been used to treat other gastrointestinal disorders. These studies indicate that probiotics probably do not have a role in preventing the postoperative recurrence of Crohn’s disease.

BudesonideBudesonide has been evaluated in two prospective, randomized, placebo-controlled trials in postoperative Crohn’s disease. In the first, 169 patients were given 6 mg/day budesonide or placebo for 1 year after ileocecal resection [52]. Endoscopic recurrence at 3 months was 47% in the placebo group versus 21% in the budesonide group, with no significant difference between the two groups (p=0.11). At 1 year, there remained no difference in endoscopic recurrence between the groups, with 32% recurrence in the treatment group and 65% in the placebo group (p=0.047). Another study evaluated budesonide 3 mg/day versus placebo, administered for 1 year following ileocecal resection in 83 subjects. Endoscopic or clinical recurrence was 57% in the treatment group and 70% in the treatment group at 12 months,

which was not statistically significant (p=0.15) [53]. These studies indicate that there is no role for budesonide as a primary therapy to prevent recurrence of Crohn’s disease postoperatively.

Azathioprine/6-mercaptopurine6-mercaptopurine (6-MP) and azathioprine (AZA) are effective steroid-sparing and maintenance treatments for moderate-to-severe Crohn’s disease. Given the limited treatment options in the postoperative setting, many physicians will administer thiopurine analogues in an attempt at reducing postoperative Crohn’s disease recurrence [54]. To date, there have been four controlled trials and one meta-analysis evaluating these immunomodulators for the prevention of postoperative Crohn’s disease (Table 2).

“Thiopurine analogues are widely used in the management of

postoperative Crohns disease”

Two of the postoperative 6-MP/AZA studies were positive and demonstrated a reduction in post-surgical reccurence whereas two of the studies were negative and did not report a benefit compared with placebo or 5-ASA [55–58]. Although the two positive 6-MP/AZA studies have been reported as demonstrating a reduction of postoperative Crohn’s disease recurrence, there are a few important caveats when considering the results. In the study by Hanauer et al., there were methodological flaws in the design and analysis of the trial, which attenuate the positive claims of the study (Table 2) [56]. The conclusion of the study was that 6-MP 50 mg was more effective than placebo at preventing postoperative recurrence, but this is not supported by robust results. The other positive study by D’Haens et al. was a well performed study that administered an induction course of metronidazole for 3 months to all patients [57]. Although the study was positive, the endoscopic endpoint was not met at 3 months, which may have been due to the metronidazole effect in the placebo group. Additionally, the 1-year endoscopic recurrence rate was still quite high in the AZA group (43.8%) and barely met statistical significance compared with placebo (69%; p=0.048).

To date, the meta-analysis by Peyrin-Biroulet et al. provides the most comprehensive overview of 6-MP/AZA for the prevention of postoperative Crohn’s disease [59]. Although the meta-analysis concluded that 6-MP/AZA is more effective than placebo or mesalamine, the benefit appears modest. Specifically, the thiopurine analogues were only 8% more effective than the controls at preventing 1-year clinical recurrence and 13% more effective at 2 years. Similarly, 6-MP/AZA was only 15% more effective at preventing significant endoscopic recurrence (≥i2) but not effective at preventing very severe endoscopic recurrence (i3 or i4). In practical terms, considering how many patients one

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| LEADING ARTICLE


Tabl

e 2.

6-M

erca

ptop

urin

e an

d az

athi

oprin

e stu

dies

in p

osto

pera

tive

Croh

n’s d

iseas

e.

Au

thors

, ye

ar

[ref

eren

ce]

Stu

dy

des

ign

, p

atie

nt

nu

mb

erM

edic

atio

nEn

dp

oin

tsRe

sults

Lim

itatio

ns/

note

s

Han

auer

et a

l. 20

04 [5

5]Ra

ndom

ized

, dou

ble-

dum

my,

dou

ble-

blin

d

131

patie

nts

enro

lled

6-M

P 50

mg,

5-

ASA

3 g,

or

plac

ebo

Clin

ical

, end

osco

pic,

or

rad

iogr

aphi

c re

curr

ence

at

24 m

onth

s

Posi

tive

stud

y

Clin

ical

, end

osco

pic,

and

rad

iogr

aphi

c re

curr

ence

at 2

4 m

onth

s:

6-M

P: 5

0%, 4

3%, a

nd 3

3%, r

espe

ctiv

ely;

5-

ASA

: 58%

, 63%

, and

46%

, res

pect

ivel

y;

plac

ebo:

77%

, 64%

, and

49%

, res

pect

ivel

y

95%

CIs

all

over

lap

Auth

ors’

con

clus

ion:

6-M

P w

as m

ore

effe

ctiv

e th

an p

lace

bo a

t pre

vent

ing

clin

ical

and

en

dosc

opic

rec

urre

nce

over

2 y

ears

No

sing

le e

ndpo

int

95%

CIs

all

over

lap

Subt

hera

peut

ic 6

-MP

leve

ls

No

valid

ated

Cro

hn’s

dis

ease

act

ivity

sco

re

may

hav

e re

sulte

d in

clin

ical

rel

apse

(77%

) hi

gher

than

end

osco

pic

rela

pse

(64%

); th

is is

un

prec

eden

ted

and

usua

lly e

ndos

copi

c re

laps

e is

sig

nific

antly

hig

her

than

clin

ical

rel

apse

Hig

h w

ithdr

awal

rat

e: 5

6% b

efor

e st

udy

end;

onl

y 69

% o

f the

enr

olle

d st

udy

popu

latio

n w

ere

eval

uabl

e

Ardi

zzon

e et

al

. 200

4 [5

4]Pr

ospe

ctiv

e, o

pen-

labe

l, ra

ndom

ized

142

patie

nts

AZA

2 m

g/kg

or

5-A

SA 3

gC

linic

al r

elap

se

(CD

AI >

200)

2

year

s af

ter

surg

ery

Neg

ativ

e st

udy

Clin

ical

rec

urre

nce

rate

: AZA

17%

, 5-A

SA 2

8% (p

=0.

2)

No

diffe

renc

e in

tim

e to

rel

apse

(p=

0.86

)

Ope

n-la

bel,

othe

rwis

e a

wel

l don

e st

udy

Her

farth

et a

l. 20

06 [5

8]D

oubl

e-bl

ind,

do

uble

-dum

my,

ra

ndom

ized

co

ntro

lled

trial

79 p

atie

nts

(onl

y 37

en

rolle

d du

e to

ea

rly te

rmin

atio

n)

AZA

2–2.

5 m

g/kg

/da

y or

5-A

SA 4

g/d

ayEn

dosc

opic

re

curr

ence

at

1 ye

ar (≥

i2)

Neg

ativ

e st

udy

Endo

scop

ic r

ecur

renc

e ra

te: A

ZA

17%

, 5-A

SA 3

7% (p

=0.

27)

Trea

tmen

t fai

lure

equ

ally

hig

h:

AZA

(nin

e of

18

patie

nts)

, 5-A

SA

(nin

e of

19

patie

nts)

(p=

1.0)

Adve

rse

even

ts le

adin

g to

with

draw

al:

AZA

33%

, 5-A

SA 1

1%

Stop

ped

prem

atur

ely

due

to in

terim

ana

lysi

s fin

ding

that

the

hypo

thes

is c

ould

not

be

test

ed w

ith th

e pl

anne

d sa

mpl

e si

ze

70%

of t

he 7

9 pa

tient

s co

mpl

etin

g th

e st

udy

had

an a

dver

se e

vent

D’H

aens

20

08 e

t al.

[56]

Dou

ble-

blin

d,

rand

omiz

ed c

ontro

lled

trial

; ope

n-la

bel f

or

met

roni

dazo

le in

al

l pat

ient

s fo

r th

e fir

st 3

mon

ths

81 p

atie

nts

All r

ecei

ved

3 m

onth

s of

met

roni

dazo

le

250

mg

thre

e-tim

es

daily

follo

wed

by

AZA

100–

150

mg/

day

or p

lace

bo

Endo

scop

ic

recu

rren

ce (≥

i2)

Posi

tive

stud

y (1

-yea

r end

poin

t)

Endo

scop

ic r

ecur

renc

e at

3 m

onth

s: A

ZA

34%

, pla

cebo

53%

(p=

0.11

)

Endo

scop

ic r

ecur

renc

e at

1 y

ear:

AZA

43

.7%

, pla

cebo

69%

(p=

0.04

8)

The

3-m

onth

end

osco

pic

recu

rren

ce m

ay

be a

ffect

ed b

y m

etro

nida

zole

but

the

1-ye

ar

resu

lts s

houl

d no

t hav

e be

en a

ffect

ed

No

stat

istic

al d

iffer

ence

in e

ndos

copi

c re

curr

ence

at 3

mon

ths

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would need to treat (i.e. the number needed to treat [NNT]) to prevent one postoperative recurrence, the benefit of 6-MP/AZA is marginal. Specifically, in order to prevent clinical recurrence in one patient at 1 year postoperatively, 13 patients would need to be treated with a purine analogue (NNT=13) and, at 2 years, eight patients (NNT=8). To prevent endoscopic recurrence in one patient at 1 year postoperatively would require seven patients being treated (NNT=7). More importantly, the results from the meta-analysis failed to show a benefit over placebo or 5-ASA at preventing very severe endoscopic recurrence (i3 or i4). The most severe endoscopic recurrence has been well correlated with future clinical recurrence and ultimately the need for additional surgery. The meta-analysis also reported a significant rate of withdrawal due to adverse events in the 6-MP/AZA group (17.2%, range 10–22%) compared with controls (9.8%; p=0.02). The purine analogues may prevent postoperative clinical recurrence but requires treatment of many patients to realize the benefit – something that may not be possible due to the high rate of side effects. Therefore, the purine analogues have not convincingly demonstrated reduction of very severe postoperative endoscopic recurrence, which translates into a failure to alter the natural course of postoperative Crohn’s disease.

InfliximabAnti-tumor necrosis factor (anti-TNF) agents have become the mainstay therapy for patients with moderate-to-severe Crohn’s disease not responding to conventional treatment. Until recently, these agents had not been tested in a randomized manner for the prevention of postoperative Crohn’s disease. The first published report of success with infliximab for preventing the postoperative recurrence of Crohn’s disease was the description of a 23-year-old female started on a standard dose of infliximab (5 mg/kg) at 2 weeks after sigmoid resection. She was continued on infliximab, receiving a dose at 2 and 6 weeks after surgery, followed by dosing every 8 weeks. After 4 years of follow-up, the patient remained in clinical, endoscopic, radiological, and histological remission [60].

A series of seven patients who underwent surgical resection for complication of Crohn’s disease were administered open-label infliximab and followed for 2 years [61]. None (0%) of the seven treated patients had clinical or endoscopic disease recurrence at 2 years while 12 of 16 patients (75%) who did not receive infliximab had a recurrence. Recently, a randomized, placebo-controlled trial evaluated the efficacy of infliximab for postoperative Crohn’s disease prevention. Twenty-four patients undergoing ileocecal resection were randomized to infliximab (5 mg/kg at 0, 2, and 6 weeks, and every 8 weeks thereafter) or placebo for 1 year [62]. Most of the patients had penetrating/fistulizing disease and approximately 25% had more than two surgeries prior to entry into the trial. Infliximab significantly decreased endoscopic recurrence (9.1% vs. 84.6%

with placebo; p=0.0006) and histological recurrence (21.3% vs. 84.6% with placebo; p=0.01) at 1 year, with a trend towards a decrease in clinical recurrence (p=0.38). Adverse events were similar in both groups (eight receiving infliximab and 11 receiving placebo). Larger studies are required to confirm these findings, but infliximab may be an effective therapy in preventing endoscopic recurrence for those with a very high risk for postoperative recurrence, for example in those with penetrating disease and multiple surgeries.

Other therapiesSeveral other therapies have been studied for the prevention of postoperative Crohn’s disease recurrence. Interleukin-10 (IL-10) displays inhibitory effects on inflammatory cells and has the potential to prevent inflammation. Recombinant human IL-10 (Tenovil; Schering-Plough Research Institute, Kenilworth, NJ, USA) was compared with placebo in 65 patients who had recently undergone ileocecal resection for Crohn’s disease [63]. At 3 months, no difference was found in endoscopic recurrence between patients receiving Tenovil (47%) compared with placebo (52%). The severity of endoscopic lesions was also similar between the two groups, indicating little effect in preventing disease recurrence. Another therapy evaluated in postoperative Crohn’s disease was enteral feeding. A non-randomized trial of 39 patients undergoing intestinal resection for Crohn’s disease compared the effect of enteral nutrition (elemental or polymeric) with that of a regular diet on clinical recurrence of Crohn’s disease postoperatively [64]. The rate of clinical recurrence of Crohn’s disease appeared to be decreased by the use of enteral nutrition (46% vs. 75%; p=0.017).

ConclusionA majority of patients with Crohn’s disease will require surgical resection during their lifetime. We can inform patients about the risk factors for recurrence of postoperative Crohn’s disease and their role in prevention. It is important to detect the recurrence of postoperative Crohn’s disease at an early stage in order to prevent long-term complications.

Several treatments have been researched for the prevention of postoperative Crohn’s disease. There is currently no standard of care established for postoperative prevention, and management decisions are made based on the risk of postoperative recurrence. Known risk factors for postoperative Crohn’s disease recurrence include active smoking, young age, penetrating/perforating disease, and two or more surgical resections. We would consider low-risk patients to be those without these risk factors or those with long-standing Crohn’s disease who come to their first surgery for a short stricture (<10 cm). We typically withhold postoperative treatment in low-risk patients, but will perform a colonoscopy 6–12 months later. If there is significant endoscopic recurrence (≥i2), then we

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| LEADING ARTICLE


recommend treatment with 6-MP/AZA or an anti-TNF agent. We consider all patients with risk factors for recurrence as high risk and would administer medication postoperatively. Which treatment to employ is debatable but we believe it should include one of the following three options:

Metronidazole in combination with 6-MP/AZA.•6-MP/AZA monotherapy.•An anti-TNF with or without 6-MP/AZA. •

The relatively unimpressive data on the ability for 6-MP/AZA monotherapy to alter the natural course of Crohn’s disease postoperatively may ultimately lead to a “top down” approach with a biological agent after surgery. Larger studies are desperately needed to determine the efficacy and safety of anti-TNF therapy postoperatively. It is our practice to administer an anti-TNF postoperatively if a patient has been on 6-MP/AZA pre-operatively or in patients who are at the highest risk for recurrence, i.e. those with perforating/penetrating complications or those who have had two or more intestinal resections. Regardless of the postoperative treatment strategy employed, it is important to assess for disease recurrence before a complication arises and another surgery is required. Therefore, we recommend that an ileocolonoscopy be performed on all patients 6–12 months after surgery with careful inspection of the surgical anastamosis and neoterminal ileum.

disclosuresDr Regueiro has acted as a consultant for Abbott, Axcan, Centocor, Elan, Procter & Gamble, Salix, Shire, and UCB. Dr Rodemann has no financial interests to disclose.

References1. Loftus EV, Schoenfeld P, Sandborn WJ. The epidemiology and natural history of Crohn’s

disease in population-based patient cohorts from North America: a systematic review. Aliment Pharmocol Ther 2002;16:51–60.

2. Olaison G, Sjödahl R, Tagesson C. Glucocorticoid treatment in ileal Crohn’s disease: relief of symptoms but not of enodoscopically viewed inflammation. Gut 1990;31:325–8.

3. Rutgeerts P, Geboes K, Vantrappen G et al. Natural history of recurrent Crohn’s disease at the ileocolonic anastamosis after curative surgery. Gut 1984;25:665–72.

4. Olaison, G, Smedh K, Sjödahl R. Natural course of Crohn’s disease after ileocolonic resection: endoscopically visualised ileal ulcers preceeding symptoms. Gut 1992;33:331–5.

5. Viscido A, Corrao G, Taddei G et al. “Crohn’s disease activity index” is inaccurate to detect the post-operative recurrence in Crohn’s disease. A GISC (Gruppo Italiano per lo Studio dol Colon e del Retto) study. Ital J Gastroenterol Hepatol 1999;31:274–9.

6. Rutgeerts P, Geboes K, Vantrappen G et al. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990;99:956–63.

7. Sachar DB, Smith H, Chan S et al. Erythrocytic sedimentation as a measure of clinical activity in inflammatory bowel disease. J Clin Gastroenterol 1986;8:647–50.

8. Jones J, Loftus EV Jr, Pannaccione R et al. Relationships between disease activity and serum and fecal biomarkers in patients with Crohn’s disease. Clin Gastroenterol Hepatol 2008;6:1218–24.

9. Chamouard P, Richert Z, Meyer N et al. Diagnostic value of C-reactive protein for predicting activity level of Crohn’s disease. Clin Gastroenterol Hepatol 2006;4:882–7.

10. Koelewijn CL, Schwartz MP, Samsom M et al. C-reactive levels during a relapse of Crohn’s disease are associated with the clinical course of the disease. World J Gastroenterol 2008;14:85–9.

11. Sipponen T, Savilahti E, Kolho KL et al. Crohn’s disease activity assessed by fecal calprotectin and lactoferrin; correlation with Crohn’s disease activity index and endoscopic findings. Inflamm Bowel Dis 2008;14:40–6.

12. Lamb CA, Mohiuddin MK, Gicquel J et al. Faecal calprotectin or lactoferrin can identify postoperative recurrence in Crohn’s disease. Br J Surg 2009;96:663–74.

13. Bourreille A, Jarry M, D’Halluin P et al. Wireless capsule endoscopy versus ileocolonoscopy for the diagnosis of postoperative recurrence of Crohn’s disease: a prospective study. Gut 2006;55:978–83.

14. Pons Beltrán V, Nos P, Bastida G et al. Evaluation of postsurgical recurrence in Crohn’s disease: a new indication for capsule endoscopy? Gastrointest Endosc 2007;66:553–40.

15. Biancone L, Calabrese E, Petruzziello C et al. Wireless capsule endoscopy and small intestinal contrast ultrrasonography in recurrence of Crohn’s disease. Inflamm Bowel Dis 2007;13:1256–65.

16. Chardavoyne R, Flint GW, Pollack S et al. Factors affecting recurrence following resection for Crohn’s disease. Dis Colon Rectum 1986;29:495–502.

17. Ryan WR, Allan RN, yamamoto T et al. Crohn’s disease patients who quit smoking have a reduced risk of reoperation for recurrence. Am J Surg 2004;187:219–25.

18. Unkart JT, Anderson L, Li E et al. Risk factors for surgical recurrence after ileocolonic resection of Crohn’s disease. Dis Colon Rectum 2008;51:1211–6.

19. Sutherland LR, Ramcharan S, Bryant H et al. Effect of cigarette smoking on recurrence of Crohn’s disease. Gastroenterology 1990;98:1123–8.

20. Kane SV, Flicker M, Katz-Nelson F. Tobacco use is associated with accelerated clinical recurrence of crohn’s disease after surgically induced remission. J Clin Gastroenterol 2005;39:32–5.

21. Cosnes J, Corbonnel F, Beaugerie L. Effects of cigarette smoking on the long-term course of Crohn’s disease. Gastroenterology 1996;110:424–31.

22. Greenstein AJ, Lachman P, Sachar DB et al. Perforating and non-perforating indications for repeated operations in Crohn’s disease: evidence for two clinical forms. Gut 1988; 29:588–92.

23. Lautenbach E, Berlin JA, Lichtenstein GR. Risk factors for early postoperative recurrence of Crohn’s disease. Gastroenterology 1998;115:259–67.

24. Avidan B, Sakhnini E, Lahat A et al. Risk factors regarding the need for a second operation in patients with Crohn’s disease. Digestion 2005;72:248–53.

25. Simillis C, yamamoto T, Reese GE et al. A meta-analysis comparing incidence of recurrence and indication for reoperation after surgery for perforating versus nonperforating Crohn’s disease. Am J Gastroenterol 2008;103:196–205.

26. Caprilli R, Corrao G, Taddei G et al. Prognostic factors for postoperative recurrence of Crohn’s disease. Gruppo Italiano per lo Studio del Colon e del Retto (GISC). Dis Colon Rectum 1996;39:335–41.

27. Scarpa M, Ruffolo C, Bertin E et al. Surgical predictors of recurrence of Crohn’s disease after ileocolonic resection. Int J Colorectal Dis 2007;22:1061–9.

28. McLeod RS, Wolff, BG, Ross S et al. Recurrence of Crohn’s disease after ileocolonic resection is not affected by anastamotic type: results of a multicenter, randomized, controlled trial. Dis Colon Rectum 2009;52:919–27.

29. Bergamaschi R, Pessaux P, Arnaud JP. Comparison of conventional and laparosocopic ileocolonic resection for Crohn’s disease. Dis Colon Rectum 2003;46:1129–33.

30. yamamoto T, Bain IM, Mylonakis E et al. Stapled functional end to end anastamosis versus sutured end to end anastamosis after ileocolonic resection in Crohn’s disease. Scand J Gastroenterol 1999;34:708–13.

31. Anseline PF, Wlodarczyk J, Murugasu R et al. Presence of granulomas is associated with recurrence after surgery of for Crohn’s disease: experience of a surgical unit. Br J Surg 1997;84:78–82.

32. Glass RE, Baker WN. Role of granuloma in recurrent Crohn’s disease. Gut 1976;176:75–7.

33. Chambers TJ, Morson BC. The granuloma in Crohn’s disease. Gut 1979;20:269–74.

34. Ferrante M, De Hertogh G, Hlavaty T et al. The value of myenteric plexitis to predict early postoperative Crohn’s disease recurrence. Gastroenterology 2006;130:1595–606.

35. Alvarez-Lobos M, Arostegui JI, Sans M, et al. Crohn’s disease patients carrying Nod2/CARD15 gene variant have an increase and early need for first surgery due to structuring disease and higher rate of surgical recurrence. Ann Surg 2005;424:693–700.

36. Hollaar GL, Gooszen HG, Post S et al. Perioperative blood transfusion does not prevent recurrence in Crohn’s disease. A pooled analysis. J Clin Gastroenterol 1995;21:134–8.

37. Summers RW, Switz DM, Sessions JT et al. National cooperative Crohn’s disease study: results of drug treatment. Gastroenterology 1979;77:847–69.

38. Ewe K, Herfarth C, Malchow H et al. Postoperative recurrence of Crohn’s disease in relation to radicality of operation and sulfasalazine prophylaxis: a multicenter trial. Digestion 1989;42:224–32.

39. Mcleod RS, Wolff BG, Steinhart AH et al. Prophylactic mesalamine treatment decrease postoperative recurrence of Crohn’s disease. Gastroenterology 1995;109:404–13.


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40. Brignola C, Cottone C, Pera A et al. Mesalamine in the prevention of endoscopic recurrence after intestinal resection for Crohn’s disease. Gastroenterology 1995:108:345–9.

41. Florent C, Cortot A, Quandale P et al. Placebo-controlled clinical trial of mesalazine in the prevention of early endoscopic recurrences after resection for Crohn’s disease. Eur J Gastroenterol Hepatol 1996;8:229–33.

42. Caprilli R, Andreoli A, Capurso L et al. Oral mesalazine (5-aminosalicylic acid; Asacol) for the prevention of post-operative recurrence of Crohn’s disease. Gruppo Italiano per lo Studio del Colon e del Retto (GISC). Aliment Pharmacol Ther 1994;8:35–43.

43. Lochs H, Mayer M, Fleig WE et al. Prophylaxis of postoperative relapse in Crohn’s disease with mesalamine: European Cooperative Crohn’s Disease Study VI. Gastroenterology 2000;118:264–73.

44. Sutherland LR, Martin F, Bailey RF et al. A randomized placebo-controlled, double-blind trial of mesalamine in the maintenance of remission of Crohn’s disease. Gastroenterology 1997;112:1069–77.

45. Caprilli R, Cottone M, Tonelli F et al. Two mesalazine regimens in the prevention of the post-operative recurrence of Crohn’s disease: a pragmatic, double-blind, randomized controlled trial. Aliment Pharmacol Ther 2003;17:517–23.

46. Rutgeerts P, Goboes K, Peeters M et al. Effect of faecal stream diversion on recurrence of Crohn’s disease in the neoterminal ileum. Lancet 1991;338:771–4.

47. D’Haens GR, Geboes K, Peeters M et al. Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 1998;114:262–7.

48. Rutgeerts P, Hiele M, Geboes K et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 1995;108:1617–21.

49. Rutgeerts P, Van Assche G, Vermeire S et al. Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2005;128:856–61.

50. Prantera C, Scribano ML, Falasco G et al. Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn’s disease: a randomised controlled trial with Lactobacillus GG. Gut 2002;51:405–9.

51. Marteau P, Lemann M, Seksik P et al. Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn’s disease: a randomised, double blind, placebo controlled GETAID trial. Gut 2006;55:842–7.

52. Hellers G, Cortot A, Jewell D et al. Oral budesonide for prevention of postsurgical recurrence in Crohn’s disease. The IOIBD Budesonide Study Group. Gastroenterology 1999;116:294–300.

53. Ewe K, Böttger T, Buhr HJ et al. Low-dose budesonide treatment for prevention of postoperative recurrence of Crohn’s disease: a multicentre randomized placebo-controlled trial. German Budesonide Study Group. Eur J Gastroenterol Hepatol 1999:11:277–82.

54. Domènech E, Mañosa M, Bernal I et al. Impact of azathioprine on the prevention of postoperative Crohn’s disease recurrence: results of a prospective, observational, long-term follow-up study. Inflamm Bowel Dis 2008;14:508–13.

55. Ardizzone S, Maconi G, Sampietro GM et al. Azathioprine and mesalamine for the prevention of relapse after conservative therapy for Crohn’s disease. Gastroenterology 2004;127:730–40.

56. Hanauer SB, Korelitz BI, Rutgeerts P et al. Postoperative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology 2004:127:723–9.

57. D’Haens GR, Vermiere S, Van Assche G et al. Therapy of metronidazole with azathioprine to prevent postoperative recurrence of Crohn’s disease: a controlled randomized trial. Gastroenterology 2008;135:1123–9.

58. Herfarth H, Tjaden C, Lukas M et al. Adverse events in clinical trials with azathioprine and mesalamine for prevention of postoperative recurrence of Crohn’s disease. Gut 2006;55:1525–6.

59. Peyrin-Biroulet L, Deltenre P, Ardizzone S et al. Azathioprine and 6-mercaptopurine for the prevention of post-operative recurrence in Crohn’s disease: a meta-analysis. Am J Gastroenterol 2009;104:2089–96.

60. Sorrentino D, Terrosu G, Avellini C et al. Prevention of postoperative recurrence of Crohn’s disease by infliximab. Eur J Gastroenterol Hepatol 2006;18:457–9.

61. Sorrentino D, Terrosu G, Avellini C et al. Infliximab with low-dose methotrexate for prevention of postsurgical recurrence of ileocolonic Crohn disease. Arch Intern Med 2007;167:1804–7.

62. Regueiro M, Schraut W, Baidoo L et al. Infliximab prevents Crohn’s disease recurrence after ileal resection. Gastroenterology 2009;136:441–50.

63. Colombel JF, Rutgeerts P, Malchow H et al. Interleukin 10 (Tenovil) in the prevention of postoperative recurrence of Crohn’s disease. Gut 2001;49:42–6.

64. Esaki M, Matsumoto T, Hizawa K et al. Preventive effect of nutritional therapy against postoperative recurrence of Crohn disease, with reference to findings determined by intra-operative enteroscopy. Scand J Gastroenterol 2005;40:1431–7.

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CLiniCAL REViEws

| CLINICAL REVIEWS

| CLINICAL OBSERVATIONS AND RESEARCH 61

Clinical ReviewsExpert Commentary on Recent Key Papers Prepared by Federico Balzola, MD, Charles Bernstein, MD, and Gert Van Assche, MD, PhD

CLiniCAL oBsERVAtions And REsEARCH

suboptimal rates of cervical testing among women with inflammatory bowel diseaseLong MD, Porter CQ, Sandler RS et al. Clin Gastroenterol Hepatol 2009;7:549–53.

This investigation evaluated rates of cervical screening in women with IBD over a 10-year period in 33 US states. Overall, 70.4% of >9000 IBD cases underwent cervical testing at least once every 3 years, compared with 65.2% of >25 000 control subjects. The authors’ conclusion was that women with IBD were tested for cervical abnormalities at suboptimal rates; however, the rate of cervical testing was not less than that for the controls.

Using the PharMetrics Patient-Centric Database (IMS Health, Watertown, MA, USA), data on 9356 women with IBD and 25 849 matched controls from the period 1996–2005 were accessed. This database included insurance claims from 87 health plans from 33 US states. All females aged 20–64 years with ≥36 months of continuous health plan enrollment were eligible for inclusion in the study. Controls were matched to patients by age, geographic residence, insurance plan, and Medicaid exposure. Chronic immunosuppressant use was defined as filling at least two prescriptions of purine analogues, methotrexate, or anti-tumor necrosis factor-α agents – a somewhat liberal definition of chronic use.

Of the IBD patients, 70.4% underwent cervical testing at least once every 3 years as did 65.2% of controls. On regression analysis, the main factor associated with increased cervical testing among women with IBD was having a primary care doctor (odds ratio [OR] 1.37, 95% confidence interval [CI] 1.19–1.59); an even stronger likelihood was identified when including gynecologists with primary care physicians (OR 2.95, 95% CI 2.51–3.46). Factors associated with reduced testing were Medicaid insurance (OR 0.28, 95% CI 0.19–0.41), use

of immunosuppressant therapy (OR 0.81, 95% CI 0.74–0.88), and an age >40 years (with significant reduction for every 10 years over the age of 40 years). It should be noted that prior hysterectomy could not be controlled for in the analysis; this is a factor of importance as women age. There were no differences in outcomes for women with ulcerative colitis versus women with Crohn’s disease.

While the authors concluded that women with IBD are tested for cervical abnormalities at suboptimal rates, they were not tested any less frequently than controls; therefore, suboptimal cervical testing is not specific to IBD. Nonetheless, particularly for female IBD patients receiving immunosuppressant medication, cervical testing should be increased.

Address for reprints: MD Long, University of North Carolina, Chapel Hill, NC 27599–7080, USA. Email: [email protected]

Fatigue and health-related quality of life in pediatric inflammatory bowel diseaseMarcus SB, Strople JA, Neighbors K et al. Clin Gastroenterol Hepatol 2009;7:554–61.

Fatigue and health-related quality of life (HRQoL) in children with IBD were examined in this questionnaire study. Patient- and parent-reported measures of fatigue and HRQoL were collected for both IBD and control children. Disease activity was also assessed in the IBD patients. Children with primarily inactive IBD had increased fatigue and a lower health-related QoL than healthy controls. Furthermore, their fatigue scores were not different to those of pediatric patients with rheumatological diseases or cancer.

Seventy children with IBD and 157 healthy controls (all aged 10–17 years) and their parents completed the Pediatric Quality of Life Inventory (PedsQL) Multidimensional Fatigue Scale (higher scores imply less fatigue), the PedsQL 4.0 Generic Core Scale (a generic health-related quality of life [QoL] scale, where higher scores imply greater QoL), and the Children’s Depression

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Inventory: Short form (CDI:S). Children with IBD completed the IMPACT III QoL questionnaire (higher scores imply better QoL). Disease activity was determined by the Pediatric Crohn’s Disease Activity Index (PCDAI; higher scores imply greater disease activity) and the Physician Global Assessment for ulcerative colitis (UC; scores ranged from 35–100 and a score of >65 implied depression).

While the mean PCDAI score was 0 in the 52 Crohn’s disease patients and 56% of UC patients were in remission, the mean PedsQL Multidimensional Fatigue Scale score was 73.9±16.8 in IBD versus 82.2±12.3 in healthy controls (p<0.001). Both the general fatigue subscale and sleep/rest fatigue subscale scores were lower in IBD patients than in the controls. The mean PedsQL 4.0 Generic Core Scale score was 76.7±14.2 in the IBD cohort versus 85.9±10.4 in the controls (p<0.001). There was a strong correlation between the PedsQL Multidimensional Fatigue Scale and the PedsQL 4.0 Generic Core Scale (Pearson correlation coefficient r=0.8; p<0.001). There was a direct relationship between fatigue score and Crohn’s disease activity (r=–0.48; p=0.001). There was an inverse relationship between Peds QL Multidimensional Fatigue Scale scores and the Depression Inventory Short form scores, which suggests a direct relationship between fatigue and depression (r=–0.43; p<0.0001). There was a direct relationship between fatigue scores and age, with no relationship between fatigue and sex, ethnicity, socioeconomic status, body mass index (BMI), disease duration, or use of various medications.

Children with primarily inactive IBD had increased fatigue and a lower health-related QoL than healthy controls. The effect sizes were moderate-to-large, suggesting that the results are clinically relevant. However, their fatigue scores were not different to those for pediatric patients with rheumatological diseases or cancer. The cause of fatigue and lower QoL in these children, most of whom were in remission, is unclear.

Address for reprints: SB Marcus, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Memorial Hospital, 2300 Children’s Plaza, Box 65, Chicago, IL 60614, USA. Email: [email protected]

Patients’ attitudes to medicines and adherence to maintenance treatment in inflammatory bowel diseaseHorne R, Parham R, Driscoll R et al. Inflamm Bowel Dis 2009;15:837–44.

This cross-sectional survey of members of the UK National Association for Colitis and Crohn’s Disease questioned patients’ beliefs about maintenance therapy and adherence to maintenance therapy. Of the entire cohort, just 48% were classified as identifying the maintenance

treatment as being both of high necessity and having low concerns about the medications, which suggests that greater patient education to allay their concerns about the medications prescribed and the relative importance of their use is needed.

A cross-sectional survey was randomly sent to 5900 members of the 29 500-membered UK National Association for Colitis and Crohn’s Disease (NACC), of whom 1871 (32%) responded. The survey questioned beliefs about maintenance therapy and adherence to maintenance therapy. Adherence was assessed using a four-item Medication Adherence Report Scale (MARS), where patient with a score of 4–16 was classified as a low adherer and >16 was classified as a high adherer. Subjects’ beliefs about medication prescribed for IBD and attitudes to medicine in general were assessed using a “Beliefs about Medicines Questionnaire” (BMQ). The BMQ comprises two subscales including, firstly, an assessment of the subject’s perception of the necessity of a prescribed medication and, secondly, an evaluation of their concerns about potential adverse effects of taking the medicine.

Of the respondents, 49% had ulcerative colitis (UC), 45% had Crohn’s disease, and 6% had other forms of colitis. High necessity of the maintenance treatment was reported by 90% and 52% had low concerns about the medication. Of the entire cohort, 48% could be classified as identifying the maintenance treatment as being both of high necessity and having low concerns about the medications. Low adherence was reported by 29% of participants. For IBD-specific medications, 28% reported unintentional non-adherence at least sometimes (forgetting to take medications) and 32% reported intentional non-adherence. Deliberate medication stoppage at least sometimes was reported by 9%. Concerns about maintenance IBD therapy was reported by 48%. Of those with concerns, 73% were concerned about long-term effects of the medication and 52% were concerned about dependency on the medication. Only 16% held the view that medications in general were harmful, but 31% thought that there was overuse of medications. Low adherence was associated with a younger age, a disease duration of >5 years, and fewer than three (versus three or more) outpatient visits in the previous year. Treatment attitudes such as an ambivalent attitude or being skeptical or indifferent were all highly predictive of low adherence. Low adherence was associated with doubts about personal needs for maintenance therapy and the potential adverse effects of such therapy. For specific medications, subjects prescribed steroids reported the highest concerns about their medication, which was significantly different than the extent of concerns about using 5-aminosalicylates (5-ASA), but not different than concerns expressed regarding using immunosuppressives. The lowest adherence rates were evident among those prescribed steroids compared with either of the other two medication classes.

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This study shows that there is ample room for patient education in helping to allay their concerns about the medications prescribed and the relative importance of their use, as well as room for reducing practical barriers to adherence.

Address for reprints: R Horne, Centre for Behavioural Medicine, Department of Practice and Policy, School of Pharmacy, University of London, Mezzanine Floor, BMA House, Tavistock Square, London, WC1H 9JP, UK. Email: [email protected]

Patient trust-in-physician and race are predictors of adherence to medical management in inflammatory bowel diseaseNguyen GC, LaVeist TA, Harris ML et al. Inflamm Bowel Dis 2009;15:1233–9.

The authors of this cross-sectional study evaluated predictors of adherence to medical management in 120 black and 115 white IBD patients recruited from a single outpatient clinic in Baltimore, MD, USA. Trust-in-physician, race, and age were significant predictors of adherence to medication after adjusting for confounding factors.

This was a cross-sectional study of 120 black people and 115 white people with IBD recruited from an outpatient clinic at Johns Hopkins University Medical Center, Baltimore, MD, USA. Self-reported medication adherence was measured using the Hill-Bone Compliance Scale, a Trust-In-Physician Scale was administered, and quality of life (QoL) was measured using the Short IBD Questionnaire (SIBDQ). The Hill-Bone Compliance Scale was adapted for an IBD population where scores could range from 10–40 and a score of <16 was considered adherent.

A total of 65% were considered adherent to medication. Higher adherence correlated with greater trust-in-physician (r=–0.3; p<0.0001), increasing age (r=–0.19; p=0.01), and worsening health-related QoL (r=–0.18; p=0.01). Adherence was higher among white patients (80%) than black patients (50%; p<0.0001). The adjusted odds ratio of adherence among black versus white patients was 0.29 (95% confidence interval 0.13–0.64). After adjusting for employment, income, health insurance, marital and socioeconomic status, as well as immunosuppressive therapy, trust-in-physician, race, and age remained significant predictors of adherence. The trust-in-physician score was slightly worse among black patients than white patients (p=0.06).

The authors concluded that trust-in-physician was a potentially modifiable predictor of adherence to IBD medical therapy. The racial differences in adherence also merit further exploration so as to find ways to narrow the gap.

Address for reprints: GC Nguyen, 600 University Avenue, Suite 437, Toronto, ON M5G 1X5, Canada. Email: [email protected]

tHERAPEutiCs REsEARCH

Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn’s disease: a meta-analysisSiegel CA, Marden SM, Persing SM et al. Clin Gastroenterol Hepatol 2009;7:874–81.

Concerns have been raised that anti-tumor necrosis factor (anti-TNF) agents may increase the risk of non-Hodgkin’s lymphoma (NHL). These authors conducted a meta-analysis to determine the rate of NHL in adult Crohn’s disease patients treated with anti-TNFs, and compared this rate with that of a population-based registry and a population of immunomodulator-treated Crohn’s disease patients. They found the use of anti-TNF agents in conjunction with immunomodulators to be associated with an increased risk of NHL; however, they state that absolute rate of these events is low and should be weighed against the substantial benefits of treatment.

Crohn’s disease patients do not appear to have an increased risk of lymphoma, but Crohn’s disease patients treated with immunomodulators such as azathioprine and 6-mercaptopurine (6-MP) may have up to a four-fold increased risk. Crohn’s disease that is refractory to steroids and immunomodulator drugs requires the use of anti-tumor necrosis factor (anti-TNF) drugs (infliximab, adalimumab, and certolizumab pegol). The use of these therapies has resulted in concerns of a possible association with an increased risk of lymphoma, in particular of non-Hodgkin’s lymphoma (NHL; up to a 1.5% absolute annual risk).

In this article, the authors describe a meta-analysis to evaluate the NHL rate among adult Crohn’s disease patients treated with anti-TNF drugs. A total of 26 studies involving 8905 patients were included; nine were randomized controlled trials, three were cohort studies, and 14 were case series. Patients were a mean age of 36.9 years and had a mean duration of Crohn’s disease of 9.3 years. Overall, 22 studies involved infliximab, three involved adalimumab, and one involved certolizumab; 66% of participants were also taking immunomodulators. The mean follow-up time was 74 weeks, with a dropout rate of 0–33%. The expected rate of NHL among subjects not exposed to anti-TNF agents was derived from two sources: the Surveillance Epidemiology & End Results (SEER) cancer registry and a previously published meta-analysis of patients treated with 6-MP or azathioprine [1]. Relative

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rates of NHL were calculated as standardized incidence ratios (SIRs). There were a total of 13 lymphomas in 21 178 patient-years of observation (6.1 NHL per 10 000 patient-years). The mean patient age was 52 years. Twelve of the patients with NHL were treated with infliximab, and one with adalimumab. At least four of the patients had received only one infusion of anti-TNF agent. Nine of 13 of the NHL patients had current or prior exposure to 6-MP or azathioprine. The SIR was 3.23 when compared with the expected rate of NHL in all age groups combined in the SEER registry, and male patients were found to have a higher rate of NHL. When compared with the observed rate of NHL in the study of Kandiel et al. [1], the SIR was 1.7. The authors additionally performed a sensitivity analysis, excluding anti-TNF studies that had a dropout rate >15%, and found an increased absolute risk of NHL of 9.4 per 10 000 patient-years with a SIR of 9.4 (95% confidence interval 1.8–12.3). The NHL rate increased as patients got older and the SIR reached statistical significance in men aged 55–64 years.

In summary, the reported rate of NHL in patients exposed to anti-TNF agents is not statistically higher that that reported for patients treated with immunomodulators [1], although the heterogeneity of the studies included in the present meta-analysis should be kept in mind. It appears that exposure to a combination of an anti-TNF agent and an immunomodulator is the key factor associated with the increased risk of NHL. The absolute rate of these events should be weighed against the substantial benefits associated with treatment, with the prospective that further data will provide a more accurate assessment.1. Kandiel A, Fraser AG, Korelitz BI et al. Increased risk of lymphoma among

inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 2005;54:1121–5.

Address for reprints: CA Siegel, Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA. Email: [email protected]

Absence of infliximab in infants and breast milk from nursing mothers receiving therapy for Crohn’s disease before and after delivery Kane S, Ford J, Cohen R et al. J Clin Gastroenterol 2009;43:613–6.

The objective of this study was to determine whether infliximab was transferred to the newborns during gestation and/or breastfeeding in pregnant women. Three women who were taking the drug until week 25–32 of gestation and again at 3–14 days postpartum were studied. Infliximab levels were undetectable in the sera of newborns and breast milk in the mothers. It is likely

that infliximab is not transferred to the breast milk in nursing mothers.

Three patients diagnosed with Crohn’s disease were followed prospectively while using infliximab during their pregnancies. They received 5 mg/kg of infliximab at regular intervals until week 25–32 of gestation and then resumed treatment at 3–14 days postpartum. The levels of infliximab postpartum in maternal serum was 74.3 µg/mL (6 days post-infliximab), 62.6 µg/mL (5 days post-infliximab infusion), and 60.0 µg/mL (43 days post-infliximab), respectively. Infliximab was undetectable in the sera of the newborn children. Infliximab was also undetectable in the breast milk of the mothers (at 5–43 days post-infliximab). This makes it likely that infliximab is not transferred to the breast milk in nursing mothers. Even if present in breast milk, it is unknown what effect infliximab would have on nursing babies.

These data corroborate case reports already in the literature and suggest that if infliximab is necessary for the mother it is reasonable to withhold it 8 weeks before delivery. It remains largely unknown whether infliximab has an adverse effect on the developing fetus (while it is administered prior to 32 weeks gestation); however, preliminary reports seem to suggest no immediate apparent adverse effects on the newborn.

Address for reprints: S Kane, Department of Medicine, Mayo Clinic College of Medicine, 200 First Street South West, Rochester, MN 55905, USA. Email: [email protected]

Adalimumab for the treatment of fistulas in patients with Crohn’s diseaseColombel JF, Schwartz DA, Sandborn WJ et al. Gut 2009;58:940–8.

The efficacy of adalimumab for the treatment of perianal fistulas in patients with Crohn’s disease has not been studied in a dedicated clinical trial. This article reports on the long-term effects of adalimumab treatment on perianal disease in patients included in a large, placebo-controlled trial that primarily evaluated luminal disease. Cessation of drainage occurred significantly more often in patients in the combined adalimumab treatment groups compared with the placebo group, and this fistula remission was maintained in most patients in an open-label extension study with adalimumab for an additional 1 year.

The chimeric monoclonal anti-tumor necrosis factor-α (anti-TNF-α) antibody, infliximab, has been used for approximately 10 years to treat patients with fistulizing Crohn’s disease, based on data from two randomized controlled trials with cessation of drainage from fistula orifices as the primary endpoint. Due to the lack of efficacy or of controlled evidence supporting the use

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of other medical therapies, as well as the potential debilitating consequences of extensive surgery, infliximab is now used as a second-line agent for this indication. Adalimumab is a human anti-TNF-α antibody that is approved for the treatment of refractory luminal Crohn’s disease. However, despite encouraging open-label evidence, no controlled data supporting the use of adalimumab in fistulizing disease were available until the present study appeared.

The article reports on a subpopulation of patients who entered CHARM (Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance) with one or more actively draining perianal fistulas. The CHARM trial was designed to evaluate the long-term efficacy of adalimumab in the treatment of luminal Crohn’s disease. All patients received 80 mg adalimumab at week 0 and 40 mg adalimumab 2 weeks later; patients were subsequently randomized at week 4 to receive placebo, adalimumab 40 mg every other week, or adalimumab 40 mg weekly for 1 year. Patients were allowed to “step over” to open-label adalimumab, but only on the basis of luminal disease flares. Cessation of drainage from fistulas was designated a predefined endpoint for 117 of 854 patients who had draining fistulas at baseline. In addition, the mean number of days with actively draining fistulas was calculated assuming that, between treatment visits, the draining status would not change. From week 16 of the trial until its end at week 56, significantly more patients achieved cessation of drainage from all orifices in the combined adalimumab groups compared with the placebo group. At week 56, 33% of patients in the combined adalimumab groups and 13% in the placebo group had no draining fistulas. Moreover, the mean number of draining fistulas per day was significantly lower in both adalimumab groups compared with the control group (combined adalimumab 0.88, placebo 1.34; p<0.01). Of interest, in the open-label extension study, most patients who achieved fistula remission in CHARM maintained this remission. Using a non-responder imputation analysis, 29 of 70 (41%) evaluable patients were in remission at 1 year and 22 of 70 (31%) at 60 weeks later (after one additional year of open-label therapy). The adverse event profile was similar for both patients who received placebo and those who received adalimumab.

This article provides the first controlled evidence supporting the use of adalimumab in fistulizing Crohn’s disease. However, important limitations apply. The CHARM trial was designed and conducted as a trial for luminal disease and treatment decisions were based on luminal symptoms only. Secondly, all patients received open-label adalimumab induction and thus this study does not prove that adalimumab is an induction agent for fistulizing Crohn’s disease. Finally, the numbers of patients still in their unblinded stratum at week 56 were low (n=16 for placebo, n=12 for adalimumab every other week). More data would therefore be welcome to reinforce this observation. However, a clear advantage of adalimumab maintenance therapy is observed in this analysis and it should be noted that

>50% of patients in all groups had previously been exposed to another anti-TNF-α agent.

Address for reprints: J-F Colombel, Hôpital Claude Huriez, Centre Hospitalier Universitaire de Lille, Rue Michel Polonovski, 59037 Lille, France. Email: [email protected]

infliximab rescue therapy after cyclosporin failure in steroid-refractory ulcerative colitisMañosa M, López San Román A, Garcia-Planella E et al. Digestion 2009;80:30–5.

Cyclosporine induces clinical remission in steroid-refractory ulcerative colitis (UC); however, a significant proportion of patients fail to respond to cyclosporine and require rescue medical therapies or urgent colectomy. The outcome of UC patients with an acute flare of UC refractory to both intravenous steroids and cyclosporine who were treated with infliximab as a rescue therapy in clinical practice was evaluated by Mañosa and colleagues.

Sixteen patients with steroid-refractory ulcerative colitis (UC) were treated with cyclosporine and either failed to respond or relapsed. Cyclosporine was dosed to blood levels of 200–400 ng/mL. Treatment with cyclosporine either failed to achieve remission or the patients relapsed soon after the cyclosporine was withdrawn. Oral cyclosporine was not used as a bridge therapy to azathioprine, although the report later states that at the time of infliximab initiation, 12 of 16 patients were using thiopurines.

Within a median of 19 days (range 5–30 days) after cyclosporine discontinuation, infliximab at a dose of 5 mg/kg with the usual three-dose induction regimen was started. Thirteen patients initially responded but only six of these 13 received maintenance infusions. After a median time of 195 days from initiation of infliximab, six (37.5%) patients required colectomy. All who required colectomy underwent the surgery within 8 months of starting infliximab. There were no deaths but one patient had septic arthritis.

This report, like others, shows that infliximab can serve as rescue therapy for some patients with active UC who have failed on steroids and cyclosporine. However, patients received varied approaches to both the cyclosporine and infliximab therapies and hence nothing definitive can be concluded. While either cyclosporine or infliximab can be used as rescue therapies when the other agent has failed in severe UC, the colectomy rates are generally 40–50% at 1 year and the risk of serious infection seems too high to warrant this approach routinely.

Address for reprints: E Domènech, IBD Unit, Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, 5a planta edifici general, Ctra. del Canyet, s/n, ES-08916 Badalona, Spain. Email: [email protected]

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PRoGnosis And AssEssMEnt

Fecal calprotectin complements routine laboratory investigations in diagnosing childhood inflammatory bowel diseaseQuail MA, Russell RK, Van Limbergen JE et al. Inflamm Bowel Dis 2009;15:756–9.

The utility of fecal calprotectin in the diagnostic work-up of children with IBD was evaluated in this study. Its role alongside standard blood tests used in IBD was also assessed. The investigators found that fecal calprotectin was significantly more likely to be raised than any of the commonly employed blood tests at IBD diagnosis. They conclude that fecal calprotectin measurement is a significant advance when used alongside routine blood tests in the diagnosis of pediatric IBD.

Fecal calprotectin is a neutrophil cytosolic protein with antimicrobial properties. It is present at an increased concentration in stool in those with gastrointestinal inflammation. The normal fecal calprotectin level in children aged 4–17 years is <50 µg/g, although neonatal levels are higher, at a median of 167 µg/g. The test for fecal calprotectin is simple and noninvasive, and is therefore of considerable value in the pediatric population in which the diagnosis of IBD may be difficult and a delay to diagnosis is common.

In this study, the authors aimed to evaluate the diagnostic utility of fecal calprotectin in addition to standard IBD blood tests. They enrolled 29 males and 19 females with IBD (33 with Crohn’s disease, 24 with a panenteric disease; five with ulcerative colitis [UC] and 10 with IBD type unspecified). Participants were diagnosed using standard criteria; stool cultures were obtained in all patients to exclude enteric infection. The median age at diagnosis was 11.2 years (interquartile range 8.7–13 years). Stool samples were obtained from all patients at diagnosis and before the initiation of any IBD-specific treatment. Fecal calprotectin was measured by the PhyCal Test (Calpro, Oslo, Norway) and a positive calprotectin result was considered to be >50 µg/g. A full blood count (FBC), C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), and liver function tests (LFTs) were available for 47 patients at diagnosis. The fecal calprotectin concentration was raised in 46 of 48 patients (96%; median value 750 µg/g) and it was significantly more likely to be abnormal compared with all other individual blood tests. Of 45 patients tested, 32 (71.1%) had an abnormal ESR; 19 of 38 (50%) had an abnormal CRP level, 29 of 46 (63%) had a raised platelet count, 12 of 45 (26.7%) had hypoalbuminemia, and 38 of 46

(82.6%) patients had an abnormal hemoglobin concentration. Seven of 47 (14.9%) patients had raised calprotectin levels without abnormalities in the abovementioned blood tests and all patients had at least one abnormal blood test and/or raised calprotectin levels at diagnosis.

In summary, the authors found that fecal calprotectin is abnormal in the majority of children with IBD at diagnosis and it can be abnormal when the disease is insufficient to cause increases in systemic inflammatory markers. However, fecal calprotectin is not a specific test for IBD. As a consequence, the combination of blood and fecal markers may be the most effective screening strategy to select patients who require further endoscopic assessment.

Address for reprints: PM Gillett, Consultant Paediatric Gastroenterologist, Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, EH9 1LF, UK. Email: [email protected]

PAtHoGEnEsis

Crohn’s disease: the hot hypothesisPeyrin-Biroulet L, Oussalah A, Bigard MA. Med Hypotheses 2009;73:94–6.

In this article, Peyrin-Biroulet et al. review the evidence for a protective role of sunlight and endogenous/dietary vitamin D in the development of Crohn’s disease, including in vivo studies demonstrating a therapeutic effect of vitamin D in ameliorating the severity of colitis. The authors conclude that vitamin D supplementation and/or heliotherapy may be useful in the treatment of Crohn’s disease, although additional investigations into such treatments are required.

The pathogenesis of Crohn’s disease remains largely unknown but the contribution of luminal bacteria flora, and of genetic, environmental, and immune regulatory factors with a Th1-type cytokine profile, is evident in the initiation and perpetuation of the disease. Epidemiological studies have highlighted that low vitamin D levels are linked with autoimmune disorders including multiple sclerosis, type 1 diabetes, and rheumatoid arthritis. Interestingly, a recent study demonstrated that only 22% of Crohn’s disease patients had optimal serum levels of vitamin D, suggesting a similar possible etiological role for this vitamin in IBD [1].

Cutaneous synthesis after sunlight exposure and diet are the main sources of vitamin D. With regard to diet, fatty fish, shitake mushrooms, and reindeer meat are three dietary sources that are rich in this vitamin. In terms of sunlight, the unusual geographic distribution of Crohn’s disease prevalence (a “North to South gradient”) and an increased prevalence in those with

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a birth period during the winter have been proposed as factors associated with an increased risk for developing Crohn’s disease. For these reasons, the present authors hypothesized that sunlight and vitamin D levels exert a protective effect against the development of Crohn’s disease.

In a review of the evidence, the authors describe how vitamin D appears to play an important role in the function of the immune system by regulating Toll-like receptor signaling, antimicrobial effector pathways, and the innate response. Moreover, the vitamin has been shown to inhibit dendritic cell maturation and T cell differentiation, to upregulate production of Th2 cytokines (interleukin-4 [IL-4] and IL-10), and to downregulate IL-12. Some animal studies have shown a therapeutic effect of vitamin D in ameliorating the severity of induced colitis in IL-10-mutant mice. Other studies have shown that, in patients, vitamin D status may be inversely associated with Crohn’s disease activity.

Discussing these findings, the authors hypothesized that in the case of vitamin D deficiency, some microbes might trigger intestinal inflammation due to dysregulation of the immune system. They conclude that vitamin D supplementation and heliotherapy may be a potential tool in the treatment of Crohn’s disease with the possible effects of modifying its natural course. Further studies are required to investigate these intriguing findings.1. Leslie WD, Miller N, Rogala L et al. Vitamin D status and bone density in recently

diagnosed inflammatory bowel disease: the Manitoba IBD Cohort Study. Am J Gastroenterol 2008;103:1451–9.

Address for reprints: L Peyrin-Biroulet, Inserm, U724, and Department of Hepato-Gastroenterology, University Hospital of Nancy, Allée du Morvan, 54511 Vandoeuvre-lès-Nancy, France. Email: [email protected]

Role of Klebsiella and collagens in Crohn’s disease: a new prospect in the use of low-starch dietRashid T, Ebringer A, Tiwana H et al. Eur J Gastroenterol Hepatol 2009;21:843–9.

Crohn’s disease is thought to arise from a complex interaction between environmental, genetic, immuno-logical, and infectious factors. This review article discusses evidence to support a role for Klebsiella pneumonie in the etiology of Crohn’s disease. In addition, the use of low-starch diet to reduce or eradicate such potential causative infectious agents is evaluated.

IBD, in particular Crohn’s disease, results from a complex interaction between environmental, genetic, immunological, and infectious factors. Microbiological, molecular, and serological evidence support the role of Klebsiella pneumonie (KP) in the etiology of Crohn’s disease and the authors of this article reviewed the involvement of the microbe in Crohn’s disease.

Recent findings have shown increased synthesis of collagens type I, III, and V, and overexpression of human leukocyte antigen (HLA) class I molecules in the bowel lesions of Crohn’s disease patients. Enzymatic products from KP (nitrogenase reductase, pullulanase pulD, and pulA) share molecular homologies with HLA-B27 molecules, the trihelical structures of collagens type I, III, and IV, and myosin. Furthermore, significantly elevated levels of antibodies against KP and autoantibodies to collagens type I, III, IV, and V have been observed in patients with Crohn’s disease compared with healthy controls. These autoantibodies have a pathological effect on the intestinal mucosa and eventually lead to the characteristic lesions of established Crohn’s disease. It is suggested by the authors that a low-starch diet could help in decreasing the bulk of microbial load in the bowel. Dietary starch consists of approximately 30% by weight of amylase and 70% of the branched carbohydrate polymer amylopectin. Amylase is completely hydrolyzed during digestion, but amylopectin is incompletely hydrolyzed. The latter passes through the ileo-cecal valve and acts as a substrate for bacterial proliferation. Thus, eradication of one causative microbe such as KP via a low-starch diet, with or without the use of antibiotics, could represent a new therapeutic strategy in the management of Crohn’s disease. This proposed strategy needs to be validated in prospective, randomized controlled trials; however, these intriguing observations about KP mimicry with several collagens should help advance our understanding of the etiology of Crohn’s disease.

Address for reprints: A Ebringer, Professor of Immunology, School of Biomedical and Health Sciences, King’s College London, London, SE1 9NN, UK. Email: [email protected]

interleukin-25 inhibits interleukin-12 production and th1 cell-driven inflammation in the gutCaruso R, Sarra M, Stolfi C et al. Gastroenterology 2009;136:2270–9.

The precise phenotype of the T cells causing uncontrolled inflammation in the human gut is not known, but an imbalance between Th1, Th2, and Th17 cells resulting from activation by dendritic cells has been observed in human and experimental IBD. In this article, Caruso et al. provide evidence from patients and from mice that interleukin-25 (IL-25, also known as IL-17E) dampens the secretion by CD14+ monocytes of IL-23 and IL-12, the main stimuli of Th17- and Th1-driven inflammation, respectively.

A normal immunological balance and uncontrolled gut inflammation are both characterized by an intensive cross-talk between monocytic dendritic cells and lymphocytes in the intestinal mucosa. Regulatory cross-talk leads to intestinal

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tolerance to luminal antigen, a desirable situation in general, but persistent excitatory cross-talk leads to IBD. The main instigating cytokines of T-effector responses are interleukin-12 (IL-12) and IL-23, which drive the Th1 and Th17 responses, respectively. IL-25 (also known as IL-17E, secreted by CD14+ monocytic cells, has been shown to dampen Th1/Th17 responses and, as a consequence, to control inflammation. The precise cell type upon which IL-25 exerts its main effects is unknown but evidence strongly suggests that it interferes with the monocyte-induced T cell differentiation and activation.

In the current study, researchers from Italy and the UK addressed the question of whether IL-25 acts to suppress excitatory cytokine release from human mucosal CD14+ cells and has the potential to ameliorate chemical- or hapten-induced colitis in mice. The experiments in mucosal CD14+ cells indicated that although patients with IBD (24 with Crohn’s disease and nine with UC) harbored more of these cells, the percentage of CD14+ cells expressing the IL-25 receptor (IL-25R) did not differ between IBD and control patients. Cells were then exposed short-term (30 min) to increasing doses of IL-25, followed by lipopolysaccharide conditioning. A dose-dependent inhibition of IL-12/p40 mRNA expression was observed. Subsequent experiments with the optimal dose of IL-25 (50 ng/mL) confirmed that IL-12 p70 (the full protein) and IL-23 secretion was decreased.

Next, the efficacy of IL-25 to prevent peptidoglycan (PGN)-induced colitis in mice was determined. PGN-mediated colitis was associated with an increase in IL-12 and in Th1 (rather than Th17) cytokines. The administration of IL-25 at the time of colitis induction resulted in attenuation of the disease and of the proinflammatory cytokines. This concided with an increase in the production of IL-13 (an archetype Th2 cytokine). However, anti-IL-13 antibodies did not eliminate the protective effect of IL-25.

The article then goes on to report the role of IL-25 in the therapeutic setting in murine colitis. Colitis was induced in Balb/c mice with trinitrobenzene sulphonic acid (TNBS). In this Th1-predominant model, IL-25, administered 1 day after colitis induction, significantly reduced histological inflammation and the production of IL-12 and interferon-γ. Of interest, the same suppressive effect of IL-25 was observed in oxazolone-induced colitis, a colitis model driven by Th1-independent mechanisms. Finally, the authors turned to mucosal biopsies of patients with IBD to show that IL-25 RNA expression was decreased in actively inflamed mucosa and upregulated in healed mucosa. Immunhistochemistry revealed the main source of IL-25 in the gut mucosa to be the subepithelial macrophage-like cells, with weak expression in epithelial cells.

Taken together, the results of this study provide evidence for a regulatory role for IL-25 in several colitis models. The fact that a therapeutic effect was observed in a diversity of models, with very different cytokine profiles, suggests that

the mechanism by which IL-25 inhibits gut inflammation transgresses the Th1-mediated inflammatory pathways and acts by silencing cells of the innate immune system, possibly CD14+ cells. Unfortunately, the authors were unable to unravel the mechanism by which IL-25 exerts its therapeutic effect. In addition, as IL-25 in the therapeutic setting was given very soon (1 day) after colitis induction, the observed protective effect needs to be tested in animals with fully established colitis. Nevertheless, IL-25 is a molecule to look out for in the future, as it may present a therapeutic target in patients with IBD.

Address for reprints: G Monteleone, Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Università Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy. Email: [email protected]

the corticotropin-releasing factor system in inflammatory bowel disease: prospects for new therapeutic approachesPaschos KA, Kolios G, Chatzaki E. Drug Discov Today 2009;14:713–20.

There is increasing evidence that stress plays a role in the development of IBD. The corticotropin-releasing factor (CRF) system is key in brain–gut interaction and is known to be involved in the inflammatory process within the gastrointestinal tract. The present authors review the role of the CRF system in IBD pathogenesis.

Ulcerative colitis (UC) and Crohn’s disease are precipitated by a complex interaction between environmental, genetic, and immune regulatory factors, and microbial exposure. A higher rate of IBD is seen in Northern, industrialized countries and IBD demonstrates an inverse relationship with the degree of sanitation. Furthermore, a great deal of data has suggested that stress plays a crucial role in IBD; whether stress represents a causative factor or is a consequence of IBD development remains debatable, since disease symptoms can themselves cause stress, whereas psychosocial stress might trigger or perpetuate the inflammatory cascade through neuro-immunological interaction.

The corticotrophin-releasing factor (CRF) system is of key importance in the brain–gut interaction. It consists of four peptides: CRF and urocortin 1 (Ucn 1), which have affinity for CRF1 receptor primarily expressed in the brain and pituitary; and Ucn 2 and 3, which bind selectively to the CRF2 receptor expressed in the central nervous system and muscles. Multiple reports show that CRF receptors are additionally expressed in proximity to their ligands in intestinal cells and may contribute to the regulation of intestinal motility through a peripheral mechanism such us the formation of autocrine/paracrine regulatory loops. For example, activation of CRF receptors expressed in goblet cells of rat mucosa resulted in mucin release.

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| PATHOGENESIS 69

In addition, peripherally administrated CRF and Ucn 1 were found to regulate colonic motility and fecal excretion (inducing diarrhea) in rats and these effects were reversed by specific CRF1 antagonists. CRF receptors have also been detected in immune cells including macrophages, lymphocytes, and mast cells; thus, the CRF system may be involved in inflammatory pathways, in parallel with its stress-associated immune role through the hypothalamic–pituitary–adrenal axis. In fact, in rat models, locally secreted CRF endogenous ligands may play a pro-inflammatory role by binding to CRF1 receptors. Conversely, Ucns may act as endogenous anti-inflammatory agents by binding to CRF2 receptors. Recent findings in individuals with IBD strengthen the animal data by showing an enhanced CRF expression in the colon of patients, both in inflammatory and epithelial cells. As a consequence, the CRF system may become potential target for novel therapeutic strategies. Synthetic CRF1 antagonists such as antalarmin, CP-154,526, CRA-1000, NBI-35965, and NBI-27014 have been shown to alleviate colonic activity induced by stress or restraint in animal models, and additionally lack systemic adverse effects that arise via the immune system. These are proposed as potential therapeutic strategies for irritable bowel syndrome. Further studies are needed to elucidate the effects of these agents on pro-inflammatory pathways in order to develop new therapeutic approaches for IBD patients.

Address for reprints: E Chatzaki, Laboratory of Pharmacology, Faculty of Medicine, Laboratory of Pharmacology, Democritus University of Thrace (DUTH), Dragana, Alexandroupolis 68100, Thrace, Greece. Email: [email protected]

Amelioration of colitis by genetically engineered murine regulatory t cells redirected by antigen-specific chimeric receptorElinav E, Adam N, Waks T et al. Gastroenterology 2009;136:1721–31.

Regulatory T cells (Tregs ) are interesting targets for therapeutic intervention as they are known to dampen inflammation in most tissues. The authors of this article describe a new methodology in mice whereby endogenous Tregs were genetically engineered to recognize metabolites of a colitis-inducing agent. The investigators demonstrate that they are able to specifically direct Tregs to the site of inflammation in the colon, and that the cells are capable of long-term suppression of inflammation in the diseased colon. This cell therapy with genetically modified T cells is not ready for use in patients but provides an interesting perspective for future investigations.

Regulatory T cells (Tregs ), formerly known as suppressor T cells, are essential guardians that keep excessive inflammation including autoimmune phenomena at bay. Tregs are numerically

deficient in patients with IBD and amelioration of murine colitis is associated with an increase in Treg number. Adoptive transfer (immune cell transfer from a donor animal to a recipient animal) of Tregs ameliorates colitis. In patients, a clinical response to anti-tumor necrosis factor-α (anti-TNF-α) agents coincides with an increase in the number of circulating Tregs in the blood. Therefore, Tregs have received a lot of attention as a potential therapeutic target in IBD. One problem with Tregs is that most of them are not directed against a specific antigen and therefore large numbers of specific cells need to be transferred. In this article, Elinav et al. describe a new methodology for enriching Tregs in the inflamed mouse colon where they can exert their suppressor activity.

Murine CD4+CD25+Tregs (the archetype natural Treg ) were isolated from Balb/c splenic cells with a CD4+CD25+ cell-selection kit. Cells were than transduced with retroviruses encoding anti-trinitrophenol (TNP)-specific receptor complexes that can activate T cells through co-stimulatory molecules. TNP is a metabolite of trinitrobenzene sulphonic acid (TNBS). This chemical agent can behave as a hapten and, when rectally administered, induces a severe distal colitis in mice. The researchers went on to expand the transduced Tregs to obtain enough cells for therapeutic use in mice. They also demonstrated that transduced Tregs were suppressing interferon-γ secretion by effector T cells, a sign of regulatory activity. In vivo adoptive transfer of Tregs transduced to be activated by TNP, improved mortality from TNBS-induced colitis in Balb/c mice and ameliorated endoscopic and microscopic appearance. Of interest, a bell-shaped dose effect with a narrow therapeutic margin was observed for the number of cells transferred to colitic mice. Transfer of 1.5×105 cells gave an optimal therapeutic effect whereas transferring 2.5×105 cells was ineffective. The authors speculate that, with a higher dose, more contaminating effector T cells were co-transferred but no direct evidence of this was provided. Finally, in vitro experiments were performed to investigate the molecular mechanism underlying the suppressive effect of the transduced Tregs. The suppressive effect was not affected by inhibiting interleukin-10 and transforming growth factor-β (two cytokines commonly implicated in Treg function). However, cell–cell contact was demonstrated to be important; in transwell experiments where direct cell contact is prevented, the suppressive effect of Tregs on effector T cells partially disappeared.

The main strength of this study is the description of a new methodology for generating Tregs with a specific epitope orientation that retains their bioactivity in vivo and in vitro. The therapeutic efficacy of these cells in a colitis model opens new avenues for research. However, several limitations apply and should be kept in mind before these results can be translated into novel treatments for patients. Firstly, human Treg populations are not identical to those in mice. Secondly, as the authors correctly discuss, in most human immune disorders – and IBD is no exception – the causative antigen is not known.

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However, Tregs activated by a commonly occurring antigen in the gastrointestinal mucosa may also dampen inflammation, even if this antigen is not the cause of IBD. Finally, cell therapy with retrovirally engineered cells is still considered higly experimental and safety of potentially transferring retroviral material needs to be explored further.

Address for reprints: Z Eshhar, Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. Email: [email protected]

increased short- and long-term risk of inflammatory bowel disease after Salmonella or Campylobacter gastroenteritisGradel KO, Nielsen HL, Schønheyder HC et al. Gastroenterology 2009;137:495–501.

This retrospective analysis suggests that the short- and long-term risks of IBD after an initial diagnosis of Salmonella or Campylobacter gastroenteritis is increased. The data analyzed were population-based and case-controlled. The small but significant increase in the long-term risk of IBD (1% absolute risk increase) that was identified deserves further study.

Although it seems very likely that intestinal dysbiosis is implicated in the pathogenesis of Crohn’s disease and possibly also of ulcerative colitis, a causative pathogen has not been identified. In this study from Aarhus, Denmark, the association between Salmonella and Campylobacter gastroenteritis and the short- and long-term development of IBD was investigated in using a laboratory registry of stool cultures. The study was population-based with data searched based on the Danish social security number, enabling the identification of all healthcare-related information for a given individual. Case series and non-population-based data had previously suggested a link between infectious gastroenteritis and the onset of Crohn’s disease.

This retrospective study was designed as a case-controlled trial comparing patients who had culture-proven Campylobacter and Salmonenella enteritis with an age- and sex-matched control group, with the intent to assess the subsequent risk of IBD in the short- and long-term. The study group consisted of all patients in a defined region of Northern Denmark with a first-time culture diagnosis of Campylobacter or Salmonella infection between 1999 and 2003. Patients with pre-existing IBD or with a diagnosis of IBD at the time of positive culture were excluded. For every subject, two age-, sex-, and geographical location-matched control individual were selected. Individuals with pre-existing IBD were excluded from the control group. All new diagnoses of IBD were retrieved from the database and data on hospitalization related to the index infectious gastroenteritis

were gathered. Finally, information on comorbid diseases in the index and control individuals was recorded.

A total of 13 148 exposed patients and twice as many unexposed subjects were identified. Infected patients were more likely to have comorbid disease. After the index infection, 107 patients were diagnosed with IBD versus 73 unexposed controls. The hospitalization rate was 28% in the total group of exposed patients and this rose to 45% in patients who were later diagnosed with IBD. However, the increased number of hospital contacts in the latter group was not concentrated in the months following the original infectious enteritis. A Kaplan–Meier analysis of new cases of IBD up to 15 years after the original infectious event showed a steep increase in new diagnoses in the first year after the infectious event, whereas in the unexposed group, only one case of IBD was detected. Of the 39 patients with a new IBD diagnosis within 1 year, 74% were hospitalized in relation to their Salmonella/Campylobacter gastroenteritis. From 2 years after inclusion onwards, the incidence of IBD rose in both groups but eventually only 0.5% of controls developed IBD versus 1.5% of exposed individuals. The absolute risk difference in the long-term (including the first year with the most pronounced increase of IBD diagnosis) was 1%. Excluding the first year after diagnosis, the hazard ratio (relative risk) of IBD in the exposed group compared with the controls was 1.9 (95% confidence interval 1.4–2.6).

These results show that patients with a documented Salmonella or Campylobacter gastroenteritis are at an increased risk of IBD, particularly within 1 year after diagnosis. Of course, the retrospective nature of this trial introduces a major limitation to the interpretation of the results – as the authors rightfully mention. Smoldering subclinical IBD may have been exacerbated by the infection and this may have triggered the diagnosis. In addition, the gastroenteritis may have been more symptomatic in these patients, prompting a stool culture. Another consideration is that it can be difficult to endoscopically differentiate an infectious colitis from IBD. The high hospitalization rate in patients with an infection and subsequent diagnosis of IBD may suggest that the threshold for culture was lower in this group due to more severe symptoms. Indeed, a Salmonella or Campylobacter enteritis with milder symptoms may be diagnosed as a more common viral enteritis and remain undiagnosed. Whether the severity of infectious gastroenteritis determines the later risk of IBD is a possibility that is certainly suggested by the results of the current study.

Notwithstanding the abovementioned caveats, the long-term data and the population-based approach generate an interesting hypothesis that could change our concept of the pathogenesis of IBD. However, confirmatory and, if possible, prospective data are needed before we can conclude that a single symptomatic gastroenteritis triggers IBD.

Address for reprints: HL Nielsen, Department of Infectious Diseases, Mølleparkvej 4, Aalborg Hospital, Aarhus University Hospital, DK-9000 Aalborg, Denmark. Email: [email protected]

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EPidEMioLoGy

time trends in therapies and outcomes for adult inflammatory bowel disease, northern California, 1998–2005Herrinton LJ, Liu L, Fireman B et al. Gastroenterology 2009;137:502–11.

Time trends and differences across medical centers in the care for adult IBD patients were investigated in this analysis. From 1998 to 2005, there was a reduction in prolonged steroid use and hospitalization in Crohn’s disease, but the rate of surgery remained constant. In ulcerative colitis, the results were also mixed with increased prolonged steroid use but reduced hospitalizations and surgeries. Over time, there was a shift in care from gastroenterologists toward primary care physicians.

This study involved 2892 subjects with Crohn’s disease and 5895 subjects with ulcerative colitis (UC) who attended one of 16 clinics that are part of the Kaiser Permanente health maintenance organization in Northern California, USA, between 1998 and 2005. Of the Crohn’s disease patients, 77% were white, while 67% of the UC patients were white. Of the total population, 63% were <50 years of age. There was a slight female predominance in the Crohn’s disease group with an equal sex ratio in UC.

The number of gastroenterologists in the health organization increased over the years of the study, by 46%. Despite this increase, the rate of visits to gastroenterologists over time declined, while the rate of visits for IBD diagnoses to primary care physicians increased by >350% for each disease. Hence, over time, there was a shift in care from gastroenterologists toward primary care physicians. Over time in Crohn’s disease, there was a reduction of 7% in 5-aminosalicylate (5-ASA) use, a reduction of 36% in prolonged (>120 days) steroid use, and an increase of 43% in immunomodulator use. Over time in UC, there was an increase of 20% in 5-ASA use, an increase of 27% of prolonged steroid use, and an increase of 150% in immunomodulator use. By 2005, 5% of Crohn’s disease subjects used infliximab, with negligible use in UC. There was a reduction in hospitalization of 33% for Crohn’s disease and 29% for UC. There was also a decline in surgery rates of 50% for UC but no significant change in the rate in Crohn’s disease.

Hence, some positive trends have emerged in managing Crohn’s disease in terms of less prolonged steroid use and a lower rate of hospitalization, but the constant rate of surgery is a concern. In UC, the results are also mixed with increased prolonged steroid use but reduced hospitalizations and

surgeries. It is possible that patients are choosing to defer surgery longer in favor of prolonged steroids or that the shift to primary care medicine away from specialist medicine may have led to this trend.

Address for reprints: LJ Herrinton, Division of Research, Kaiser Permanente Northern California, 2000 Broadway Avenue, Oakland, CA 94612, USA. Email: [email protected]

Association between early-life factors and risk of child-onset Crohn’s disease among Victorian children born 1983–1998: a birth cohort studyPonsonby AL, Catto-Smith AG, Pezic A et al. Inflamm Bowel Dis 2009;15:858–66.

The present investigators examined changes in pediatric Crohn’s disease incidence over a 15-year period (1983–1998), and aimed to identify perinatal characteristics associated with Crohn’s disease risk, using an Australian state birth database. The risk for Crohn’s disease was greater in those born during the second half of the 15-year study period (1992–1998). Perinatal characteristics associated with higher Crohn’s disease risk included an urban location, higher socioeconomic status, a married mother, and a congenital abnormality. However, the increased disease incidence among more recent births was not accounted for by changes in these perinatal factors. Thus, other factors are likely to be involved.

Pediatric Crohn’s disease, like the disease in adults, is a serious immunological disorder. Its etiology remains unclear. The present authors have previously reported data showing that the incidence of pediatric-onset Crohn’s disease increased from 0.13 per 100 000 child-years in 1971 to 2.01 per 100 000 child-years in 1990, a >10-fold increase [1]. This increase was more marked in urban than in rural regions. In the present study, the authors utilized data from the Victorian Perinatal Data Collection Unit, which started in 1982 and collects data on every birth of 20 weeks’ gestation or birth weight >400 g in a birth record database. A total of 1 005 054 live births in Victoria, Australia, from 1983–1998, were evaluated in order to examine the following:

Temporal trends in Crohn’s disease incidence.•How maternal and infant exposures predicted subsequent •Crohn’s disease incidence.The extent to which the recent temporal change in Crohn’s •disease incidence could be explained by changes in perinatal factors over time (a proportional hazards model).

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For the births during the entire time-period studied (1983–1998), the crude pediatric Crohn’s disease incidence rate was 2.01 (95% confidence interval [CI] 1.79–2.27) per 100 000 person-years. The factors positively associated with Crohn’s disease were as follows: a married mother, high socioeconomic advantage index, older maternal ages, any interventional delivery, and a congenital abnormality. Furthermore, living in an urban area at birth was associated with a higher Crohn’s disease risk for males (hazard ratio [HR] 2.29; 95% CI 1.41–3.72) but not for females. In a comparison of the 1992–1998 and 1983–1991 periods, the increase in Crohn’s disease incidence among the later versus the earlier births remained evident after adjustment for sex, maternal age, marital status, socioeconomic status, interventional births, proportion of first-born children

or congenital abnormality. The calculated HR was 1.54 (95%

CI 1.17–2.04; p=0.002) for births during 1992–1998 compared

with the 1983–1991 group. Sibling exposure (number of days

“exposed” to siblings) during the first 6 years of life was not

associated with Crohn’s disease risk.

In conclusion, it is probable that antenatal, perinatal, and/or

postnatal factors not measured in this study are increasing over

time and are driving the temporal increase in pediatric-onset

Crohn’s disease incidence. Further analysis of these factors

needs to be undertaken.1. Phavichitr N, Cameron DJ, Catto-Smith AG. Increasing incidence of Crohn’s disease

in Victorian children. J Gastroenterol Hepatol 2003;18:329–32.

Address for reprints: A-L Ponsonby, Murdoch Childrens Research Institute, Royal Childrens Hospital, Flemington Road, Parkville, VIC, Australia 3052. Email: [email protected]

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Digestive Disease Week (DDW) 2009 featured several important presentations about the optimal medical management of patients with IBD. Novel methods of determining disease activity, safety of medications with respect to impact on colorectal cancer and pregnancy, optimizing efficacy and duration of medical therapy, and effects on outcomes other than clinical remission (e.g. mucosal healing and fistula closure) were all discussed and are summarized below.

diagnosticsDetermining if patient symptoms correlate with disease activity in IBD can be difficult and often patients undergo repeated imaging tests and colonoscopies. One study reported at DDW 2009 showed that patients with ulcerative colitis (UC) have 39% more radiation exposure than the background population (baseline is 1.8 mSv), and that patients with Crohn’s disease have 157% more radiation exposure, 75% of which is due to computed tomography (CT) scans [1]. One way to minimize radiation exposure is to use more ultrasonography and magnetic resonance imaging (MRI) to determine disease activity. In a study presented by Lenze et al., 30 patients with suspected strictures underwent ultrasonography, MRI, and positive emission tomography (PET) scanning, the results of which were compared with endoscopy. Endoscopy found 37 strictures, while PET identified 29, MRI 30, and ultrasonography 25 [2]. Ultrasonography had the highest sensitivity for detecting fibrostenosis. The authors suggest that MRI and ultrasonography are preferable first options due to the lack of radiation, although the imaging modality selected will of course be dependent on the expertise of the institution.

An alternative method to determine inflammatory activity is assessment of fecal calprotectin. However, its use is limited by cost, availability, and the protracted time required to obtain the results. In a study of 527 consecutive subjects (99 UC, 233 Crohn’s disease, 107 irritable bowel syndrome, and 88 healthy controls), stool testing (1286 samples) for fecal calprotectin was performed using a commercially available monoclonal antibody enzyme-linked immunosorbent assay (ELISA) and a one-step, semi-quantitative, immunochromatographic, office-based rapid strip test device [3]. The sensitivity of the ELISA versus office-based test for Crohn’s disease (89.2% vs. 86%) and UC (86.4% vs. 82.3%) and the specificity of the two tests for Crohn’s disease (87.2% vs. 83.1%) and UC (83.1% vs. 79.2%) were similar, suggesting that the office-based assay was as effective, cheaper, and quicker (10 min) than the ELISA [3].

outcomesVitamin deficiencies such as B12 and folate deficiencies have been thought to be a consequence of disease activity in IBD. New data on vitamin D raise the question of whether vitamin D deficiency actually drives inflammatory activity. A retrospective analysis of 494 patients (58.7% female; 266 Crohn’s disease and 209 UC patients) determined nadir vitamin D levels [4]. The mean duration of disease was inversely proportional to the nadir vitamin D levels (p<0.05). There was also a significant inverse relationship between both Harvey Bradshaw Index for Crohn’s disease and Mayo score for UC and vitamin D levels. The authors concluded that vitamin D had a role in reducing disease activity through its immunomodulatory action. Another study from France attempted to determine whether geographic distribution

Digestive Disease Week 2009 (DDW 2009): Key Updates in IBD Clinical Research

Chicago, iL, usA, 30 May–4 June, 2009Uma Mahadevan, MD, and Fernando Velayos, MD, MPH

UCSF Center for Colitis and Crohn’s Disease, San Francisco, CA, USA

Previous meeting reports are available free from

www.ibdmonitor.com

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of Crohn’s disease and UC is influenced by sun exposure [5]. Sunshine exposure data was provided by month and by French region from 1984–2002. A total of 14 213 new patients with Crohn’s disease and 12 452 with UC were registered by five health insurance funds. Age- and gender-adjusted Crohn’s disease incidence rates increased as local ultraviolet light doses decreased. The authors concluded that low sunlight exposure could be a risk factor for Crohn’s disease (but not for UC), again highlighting the possible role of vitamin D.

Colorectal cancer rates in patients with UC and Crohn’s colitis are higher than those in the baseline population. Mesalamine agents may potentially have a chemopreventative effect [6]. Whether this is inherently due to the mechanism of action of mesalamine or to simply reducing inflammation – a known risk factor for colorectal cancer in UC – is not known. A study from the Groupe d’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID group) in France reported that IBD patients with longstanding extensive colitis who were receiving thiopurines had a 3.5-fold decreased risk of colorectal advanced neoplasia, suggesting that perhaps a reduction in inflammation was the key to reducing rates of neoplasia [7].

“In-office ultrasound and fecal calprotectin determination may allow rapid determination

of the level of inflammation”

There is also great interest in comparing surgical outcomes among medical hospitals. Recent data using the National Inpatient Sample in the US show that surgical mortality in UC is lower among centers with the highest colectomy case-volume [8]. While these data suggest that this surgery should be performed in high-volume rather than in low-volume centers, the question has not been studied in other populations. A retrospective cohort study using the Premier Perspective Rx, a database of 167 predominantly small-to-medium hospitals around the US, investigated this issue and found no association between hospital surgical volume and mortality rate [9]. In fact, the hospitals with the highest tertile volume had the highest mortality rate (7.4%), compared with medium-volume (3.3%), and low-volume (3.9%) hospitals. These data underscore that hospital case-volume alone is unlikely to be a reliable marker for helping patients choose where to have surgery for UC and should not be a key determinant for policy makers aiming to improve surgical outcomes in this patient population [9].

Pregnant women with IBD are often concerned about the effect of medications on their newborn’s outcomes. A national prospective registry of pregnant women with IBD reported their interim results at this year’s DDW. Target enrollment is 600 women; 404 were enrolled as of May 29, 2009, of whom 237 completed their pregnancy and were available for analysis.

The rate of any complication, congenital malformation, preterm birth, low birth weight, or neonatal intensive care unit (ICU) stay was not different based on exposure to azathioprine/6-mercaptopurine or biological therapy [10]. Another study looked at placental transfer of certolizumab in pregnant women [11]. Prior data demonstrated that infliximab, an immunoglobulin G1 antibody, crossed the placenta and was present in the infant at levels higher than in the mother at birth [12]. As certolizumab is a Fab’ fragment and does not have an Fc receptor, transfer was hypothesized to be passive. In two patients who received certolizumab at 2 weeks and 1 week prior to delivery, respectively, the corresponding maternal certolizumab levels on the day of birth were 19 and 60 µg/mL. The respective cord blood levels (which are nearly equal to newborn levels) were 1.65 and 0.94 µg/mL, demonstrating that transfer to the newborn was minimal. If rates of birth defects are equal among anti-tumor necrosis factor (anti-TNF) agents, based on available evidence, certolizumab – if available in that country – would be the preferred agent in pregnant women owing to minimal transfer to the newborn.

The safety of biologics in pregnancy is being studied across multiple disciplines as the use of the drugs increase. One sobering study published by Carter et al. [13] reported 61 anomalies in 41 children exposed to anti-TNF agents (22 etanercept and 18 infliximab) in utero. The authors suggested that a pattern of anomalies consistent with VACTERL syndrome was seen, as 19 of 34 (56%) anomalies were components of VACTERL, although only one patient had the actual syndrome. While this study has been criticized for the lack of a denominator (number of women treated with anti-TNFs) among other statistical flaws, its findings certainly warrant further research.

Clinical trialsInfliximabThe SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease) trial reported its 50-week results [14]. Patients with Crohn’s disease who were naïve to immunomodulators or biologics were randomized to azathioprine 2.5 mg/kg daily (n=170), infliximab 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks (n=169), or to azathioprine plus infliximab (n=169). The primary endpoint was clinical remission (Crohn’s disease activity index [CDAI] <150 and off corticosteroids) at week 26. At this time-point, the rates of remission were 30%, 44%, and 57%, respectively. Infliximab alone was superior to azathioprine alone (p=0.006), and combination therapy was superior to infliximab alone (p=0.022) and azathioprine alone (p<0.001). Of the 508 patients who entered the study, 317 patients were still in the trial at week 30 (patients who were non-responders tended to drop out). Of those patients, 280 chose to enter the study extension and 242

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of the 280 patients completed the study extension. At 50 weeks, when patients who did not enroll in the extension were counted as non-responders, the results remained similar with remission rates of 24%, 35% (p=0.028 vs. azathioprine), and 46% (p=0.035 vs. infliximab, p<0.001 vs. azathioprine), respectively. When only patients who enrolled in the extension (n=280) were assessed, the respective remission rates were 55%, 61% (p=0.324 vs. azathioprine), and 72% (p=0.065 vs. infliximab alone; p=0.010 vs. azathioprine alone). The rates of any adverse events and serious adverse events were not higher in the infliximab or combination therapy group compared with the azathioprine alone group. Overall, these data suggest that in the patient with moderate-to-severe Crohn’s disease who is naïve to immunomodulators and biological agents, combination therapy is superior to either therapy alone. Immunogenicity as well as synergy between azathioprine and infliximab may play a role.

The issue of whether azathioprine can be discontinued at 6 months without impacting remission rates, as suggested by a prior study [15], is not answered by the SONIC study design. One French study did attempt to determine if infliximab could be discontinued without adversely affecting the disease course [16]. In that prospective study, 115 patients on infliximab plus azathioprine for >1 year, in steroid-free remission for ≥6 months, had their infliximab discontinued. A Kaplan–Meier curve found that 57% of patients relapsed by 12 months. The median time to relapse was 6.5 months and the majority of patients could be retreated with infliximab without infusion reactions. Patients with no endoscopic or serological (C-reactive protein) markers of inflammation were less likely to relapse (17%) at 1 year. In patients already on infliximab, the measurement of infliximab levels in a symptomatic individual were found to impact upon treatment decisions in 73% of cases [17]. In that study of 155 patients with symptoms despite infliximab therapy, when antibodies to infliximab were present, changing the anti-TNF agent was helpful in 92% of cases, while increasing infliximab was effective in only 17%. Among patients with subtherapeutic drug concentrations, increasing the infliximab dose was effective in eliciting a response in 86% of patients while changing the anti-TNF agent was effective in 40%. When there were no detectable antibodies to infliximab and levels were therapeutic, if endoscopy demonstrated active disease the authors recommended trying a drug with a different mechanism of action. If no active disease was seen on evaluation, then it was indicated that strictures, infection, and irritable bowel syndrome should be considered.

AdalimumabThe ADHERE (Additional Long-Term Dosing with Humira® to Evaluate Sustained Remission and Efficacy in Crohn’s disease) study looked at patients randomized to adalimumab and in remission at week 56 of the CHARM (Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance)

study and followed them for an additional 2 years. At 3 years, 83% of patients in the last observation carried forward (LOCF) group were still in remission [18].

The CARE (Crohn’s Patients Treated with Adalimumab: Results of a Safety and Efficacy) study, which was also open-label, followed 945 patients given adalimumab 160/80 mg induction dosages and 40 mg dosages every other week. At week 12, patients with a disease flare could receive adalimumab 40 mg weekly. Patients with arthralgias, arthritis, oral apthous ulcers, sacroiliitis, and erythema nodosum had a significant reduction in these extraintestinal manifestations by week 20 of the study [19]. Patients with fistulas had a 26% rate of complete closure of fistulas by week 20. This was higher in the biologic-naïve group (33%) compared with those who had prior infliximab use (22%) [20].

“Adalimumab and certolizumab are effective in patients who have lost response

or who are intolerant to infliximab”

Finally, the EXTEND (Extend the Safety and Efficacy of Adalimumab Through Endoscopic Healing) trial examined rates of mucosal healing with adalimumab. All patients (n=135) received adalimumab 160 mg at week 0 and 80 mg at week 2. At week 4, they were randomized to continue adalimumab 40 mg every 2 weeks or to receive placebo. The primary endpoint was complete endoscopic mucosal healing at week 12. In the intention-to-treat analysis, 13.1% of patients who received induction and then placebo had complete mucosal healing compared with 27.4% of the maintenance adalimumab group (p=0.056). At week 52, the results were 0% and 24.2%, respectively (p<0.001). While these results certainly suggest that adalimumab use is associated with mucosal healing, the lack of significance at week 12 may simply reflect the fact that all patients received induction adalimumab 160/80 mg [21].

CertolizumabThe WELCOME (26-Week Open-label Trial Evaluating the Clinical Benefit and Tolerability of Certolizumab Pegol Induction and Maintenance in Patients Suffering from Crohn’s Disease with Prior Loss of Response or Intolerance to Infliximab) trial assessed the efficacy of certolizumab pegol in Crohn’s disease patients who had lost response or become intolerant to infliximab [22]. Overall, 539 patients with moderate-to-severe Crohn’s disease received certolizumab pegol 400 mg at weeks 0, 2, and 4. The primary endpoint was response at week 6. Patients were then randomized to either certolizumab pegol 400 mg every 4 weeks or 400 mg every 2 weeks. At week 6, 62% of patients had a reduction in their CDAI score of 100 points and 39% were in clinical remission. At week 26, 30% of patients receiving fortnightly certolizumab pegol and 29% of patients receiving

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certolizumab pegol every 4 weeks were in clinical remission. While this suggests that certolizumab every 2 weeks is not superior to certolizumab every 4 weeks in the patient naïve to the drug, there is likely a role for fortnightly dosing in patients who are losing response to dosing every 4 weeks.

summaryThis year’s DDW solidified our understanding of biological therapy and pointed to new areas for further study. In-office ultrasound and fecal calprotectin determination may allow us to rapidly determine the level of inflammation in a patient, and provide appropriate therapy (and reduce radiation exposure). Pregnant women with IBD should be able to continue their therapy during pregnancy without an increase in adverse events. Infliximab in combination with azathioprine is more effective than either agent alone in the patient naïve to the two therapies. In a patient losing response to infliximab, measuring drug levels will help to guide therapy. Mucosal healing has now been demonstrated with all three currently approved biological agents. Both adalimumab and certolizumab are effective in patients who have lost response or who are intolerant to infliximab. As we move forward, we anticipate new mechanisms of action to add to our IBD armamentarium.

disclosuresDr Mahadevan serves as a consultant to Abbott, Centocor, Elan pharmaceuticals, Procter & Gamble, Shire, and UCB. Dr Velayos serves as a consultant to Centocor, Shire, Procter & Gamble, and UCB.

References1. Kroeker K, Lam S, Birchall IW et al. Patients with IBD are exposed to potentially serious

excesses of ionizing radiation. Gastroenterology 2009;136(5 Suppl. 1):Abstract 650.

2. Lenze F, Wessling J, Bremer J et al. Detection and differentiation of inflammatory versus fibromatous Crohn’s disease strictures – results of a prospective comparison of 18F-FDG-PET/CT, MR-enteroclysis and transabdominal ultrasound vs. endoscopic/histologic evaluation. Gastroenterology 2009;136(5 Suppl. 1):Abstract 654.

3. Shastri y, Schröder O, Stein J. Comparative evaluation of a new semi-quantitative, rapid, office-based strip test with an ELISA-based assay for measuring fecal calprotectin to assess intestinal inflammation: prospective multicenter clinical study. Gastroenterology 2009;136(5 Suppl. 1):Abstract 187.

4. Bosworth B, Iroku U, Cohen M et al. Serologic vitamin D levels correlate with IBD disease activity. Gastroenterology 2009;136(5 Suppl. 1):Abstract W1174.

5. Nerich V, Monnet E, Boutron-Ruault MC et al. Geographic distribution of inflammatory bowel disease (IBD) in France and sunlight exposure. Gastroenterology 2009;136 (5 Suppl. 1):Abstract 115.

6. Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol 2005;100:1345–53.

7. Beaugerie L, Seksik P, Bouvier A et al. Thiopurine therapy is associated with a three-fold decrease in the incidence of advanced colorectal neoplasia in IBD patients with longstanding extensive colitis: results from the CESAME Cohort. Gastroenterology 2009;136(5 Suppl. 1):Abstract 281.

8. Kaplan GG, McCarthy EP, Ayanian JZ et al. Impact of hospital volume on postoperative morbidity and mortality following a colectomy for ulcerative colitis. Gastroenterology 2008;134:680–7.

9. Velayos FS, Maselli J, Lindenauer P et al. Imapct of hospital volume, surgeon volume, and missed quality measures on post-operative mortality following colectomy for ulcerative colitis. Gastroenterology 2009;136(5 Suppl. 1):Abstract 155.

10. Mahadevan U, Martin CF, Sandler RS et al. A multi-center national prospective study of pregnancy and neonatal outcomes in women with inflammatory bowel disease exposed to immunomodulators and biologic therapy. Gastroenterology 2009;136(5 Suppl. 1): Abstract 562.

11. Mahadevan U, Abreu M. Certolizumab use in pregnancy: low levels detected in cord blood. Gastroenterology 2009;136(5 Suppl. 1):Abstract 960.

12. Mahadevan U, Terdiman JP, Church J et al. Infliximab levels in infants born to women with inflammatory bowel disease. Gastroenterology 2007;132(4 Suppl. 2):Abstract 144.

13. Carter JD, Ladhani A, Ricca LR et al. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol 2009;36:635–41.

14. Sandborn W, Rutgeerts PJ, Reinisch W et al. One year data from the SONIC study: a randomized, double-blind trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Gastroenterology 2009;136(5 Suppl. 1):Abstract 751f.

15. D’Haens G, Baert F, van Assche G et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008;371:660–7.

16. Louis E, Vernier-Massouille G, Grimaud J-C et al Infliximab discontinuation in Crohn’s disease patients in stable remission on combined therapy with immunosuppressors: a prospective ongoing cohort study. Gastroenterology 2009;136(5 Suppl. 1):Abstract 961.

17. Afif W, Loftus EV, Faubion WA et al. Clinical utility of measuring infliximab and human anti-chimeric antibody levels in patients with inflammatory bowel disease. Gastroenterology 2009;136(5 Suppl. 1):Abstract 962.

18. Rutgeerts P, Colombel JF, Sandborn WJ et al. Maintenance of long-term remission in patients with moderately to severely active Crohn’s disease treated for 3 years with adalimumab: results from the open-label ADHERE study. Gastroenterology 2009;136 (5 Suppl. 1):Abstract W1092.

19. Louis E, Lofberg R, Reinisch W. Adalimumab reduces extraintestinal manifestations in patients with Crohn’s disease in the CARE trial. Gastroenterology 2009;136(5 Suppl. 1): Abstract S1131.

20. Lofberg R, Louis E, Reinisch W et al. Adalimumab induces sustained fistula healing in both anti-TNF-naïve and anti-TNF-experienced patients with Crohn’s disease: the CARE trial. Gastroenterology 2009;136(5 Suppl. 1):Abstract S1144.

21. Rutgeerts P, D’Haens, GR, Van Assche GA et al. Adalimumab induces and maintains mucosal healing in patients with moderate to severe ileocolonic Crohn’s disease – first results of the EXTEND trial. Gastroenterology 2009;136(5 Suppl. 1):Abstract 751e.

22. Sandborn W, Vermeire S, D’Haens GR et al. WELCOME: a randomized, double-blind, controlled trial comparing certolizumab pegol 400 mg every 2 weeks with every 4 weeks for maintenance of response and remission in patients with moderate to severe Crohn’s disease with secondary failure to infliximab. Gastroenterology 2009;136(5 Suppl. 1): Abstract 143.

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