Brian G. Feagan

We did a randomised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn's disease who respond to a single infusion of infliximab.573 patients with a score of at least 220 on the Crohn's disease activity index (CDAI) received a 5 mg/kg intravenous infusion of infliximab at week 0. After assessment of response at week 2, patients were randomly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group I), repeat infusions of 5 mg/kg infliximab at the same timepoints (group II), or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg (group III). The prespecified co-primary endpoints were the proportion of patients who responded at week 2 and were in remission (CDAI <150) at week 30 and the time to loss of response up to week 54 in patients who responded. Analyses of the co-primary endpoints were by intention to treat.335 (58%) patients responded to a single infusion of infliximab within 2 weeks. At week 30, 23 of 110 (21%) group I patients were in remission, compared with 44 of 113 (39%) group II (p=0.003) and 50 of 112 (45%) group III (p=0.0002) patients. Thus, patients in groups II and III combined were more likely to sustain clinical remission than patients in group I (odds ratio 2.7, 95% CI 1.6-4.6). Throughout the 54-week trial, the median time to loss of response was 38 weeks (IQR 15 to >54) and more than 54 weeks (21 to >54) for groups II and III, respectively, compared with 19 weeks (10-45) for group I (p=0.002 and p=0.0002, respectively). Infliximab safety was consistent with that seen in other trials of infliximab in Crohn's disease and rheumatoid arthritis. In particular, the incidence of serious infections was similar across treatment groups.Patients with Crohn's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if infliximab treatment is maintained every 8 weeks.

Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, is an established treatment for Crohn's disease but not ulcerative colitis.Two randomized, double-blind, placebo-controlled studies--the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)--evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2.In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P<0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P< or =0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P<0.001 for both comparisons).Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo. (ClinicalTrials.gov numbers, NCT00036439 and NCT00096655.)

Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis.We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P<0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups.Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).

The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown.In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52.At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%).Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).

Infliximab, a monoclonal antibody against tumor necrosis factor, is an effective maintenance therapy for patients with Crohn's disease without fistulas. It is not known whether infliximab is an effective maintenance therapy for patients with fistulas.We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least three months' duration. Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6. A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54. The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent randomization.The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, P<0.001). At week 54, 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36 percent of patients in the infliximab maintenance group (P=0.009).Patients with fistulizing Crohn's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.

OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a “treat-to-target” clinical management strategy using an evidence-based expert consensus process. METHODS: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7–10 on a 10-point rating scale (where 10=agree completely). RESULTS: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn’s disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit)andendoscopic remission (defined as a Mayo endoscopic subscore of 0–1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit;andendoscopic remission, defined as resolution of ulceration at ileocolonoscopy,orresolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients’ quality of life.

Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy.We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150).The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups.Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).

The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease.In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response.59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (CDAI (SD) =33.9 (19.7), 95% credible interval -4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4-10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (-1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected).Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo.This trial was registered at ClinicalTrial.gov with the number NCT01009281.

Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy.

Most patients who have active Crohn's disease are treated initially with corticosteroids. Although this approach usually controls symptoms, many patients become resistant to or dependent on corticosteroids, and long exposure is associated with an increased risk of mortality. We aimed to compare the effectiveness of early use of combined immunosuppression with conventional management in patients with active Crohn's disease who had not previously received glucocorticoids, antimetabolites, or infliximab.We did a 2-year open-label randomised trial at 18 centres in Belgium, Holland, and Germany between May, 2001, and January, 2004. We randomly assigned 133 patients to either early combined immunosuppression or conventional treatment. The 67 patients assigned to combined immunosuppression received three infusions of infliximab (5 mg/kg of bodyweight) at weeks 0, 2, and 6, with azathioprine. We gave additional treatment with infliximab and, if necessary, corticosteroids, to control disease activity. 66 patients assigned to conventional management received corticosteroids, followed, in sequence, by azathioprine and infliximab. The primary outcome measures were remission without corticosteroids and without bowel resection at weeks 26 and 52. Analysis was by modified intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00554710.Four patients (two in each group) did not receive treatment as per protocol. At week 26, 39 (60.0%) of 65 patients in the combined immunosuppression group were in remission without corticosteroids and without surgical resection, compared with 23 (35.9%) of 64 controls, for an absolute difference of 24.1% (95% CI 7.3-40.8, p=0.0062). Corresponding rates at week 52 were 40/65 (61.5%) and 27/64 (42.2%) (absolute difference 19.3%, 95% CI 2.4-36.3, p=0.0278). 20 of the 65 patients (30.8%) in the early combined immunosuppression group had serious adverse events, compared with 19 of 64 (25.3%) controls (p=1.0).Combined immunosuppression was more effective than conventional management for induction of remission and reduction of corticosteroid use in patients who had been recently diagnosed with Crohn's disease. Initiation of more intensive treatment early in the course of the disease could result in better outcomes.

In a randomized, double-blind, placebo-controlled trial, we evaluated the efficacy of certolizumab pegol in 662 adults with moderate-to-severe Crohn's disease. Patients were stratified according to baseline levels of C-reactive protein (CRP) and were randomly assigned to receive either 400 mg of certolizumab pegol or placebo subcutaneously at weeks 0, 2, and 4 and then every 4 weeks. Primary end points were the induction of a response at week 6 and a response at both weeks 6 and 26.

In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown.

See Sparrow MP et al on page 209 and Yacyshyn B et al on page 215 in the February 2007 issue of CGH. See Sparrow MP et al on page 209 and Yacyshyn B et al on page 215 in the February 2007 issue of CGH. Ulcerative colitis (UC) is a common gastrointestinal disorder in adults. Recent advances in pathophysiology, immunology, and pharmaceutical science have resulted in a large number of medications including biologic agents with potential application to the treatment of UC. Clinical development of these drugs requires well-controlled trials evaluating safety and efficacy. The first randomized controlled trial in UC dates back to 1955 when cortisone was shown to be effective for the treatment of active disease. Further experience in clinical trial design for UC during the last 50 years has led to the creation of a large number of disease-specific measures of disease activity. Natural history studies have allowed the classification of UC patients into subpopulations based on anatomic extent of disease, severity of disease, and prolonged treatment with corticosteroid therapy. Currently, important differences exist among investigators and regulatory agencies in the use of measures of response. This article presents the consensus of an international group of specialists on classification, treatment indications, and clinical trial efficacy end points for the medical therapy of UC. The need for a systematic evaluation of the outcomes used for clinical trials in UC came about from perceived inconsistencies in regulatory decision making. This issue was identified by a few individuals who are regularly involved in the design and implementation of randomized controlled trials of therapy for this disorder. The clinical trials task force of the International Organization of Inflammatory Bowel Disease (IOIBD) initiated this process of developing a systematic review in 2003. Studies were selected for inclusion if they (1) first described a measurement instrument, (2) modified or validated an existing instrument, or (3) provided an illustrative example of the use of a measurement in a clinical trial (in some instances for regulatory approval). The task force met initially in person for discussion. The results were summarized in a draft manuscript by the primary authors (G.D. and W.J.S.) and discussed at the annual IOIBD meetings in 2004 and 2005. The manuscript was then circulated to the entire IOIBD membership; the leadership of the European Crohn’s and Colitis Organization (ECCO); the leadership of 3 groups of investigators who conduct clinical trials in inflammatory bowel disease (IBD) in the United States (the clinical alliance of the Crohn’s and Colitis Foundation of America), Canada (the clinical network of the Crohn’s and Colitis Foundation of Canada), and France (the Groupe d’Etude Thérapeutique des Affections Inflammatoires Digestives); and to pharmaceutical companies who conduct clinical trials in UC including Abbott Laboratories, Ardeypharm, Asahi Kasei Medical, AstraZeneca, Axcan Pharma, Centocor, Elan, Dr. Falk Pharma, Ferring Pharmaceuticals, Giuliani SPA, Otsuka Pharmaceuticals, Proctor & Gamble Pharmaceuticals, Protein Design Labs, Salix Pharmaceuticals, Shire Pharmaceuticals, Schering AG, Schering Plough Corporation, and UCB. The manuscript was again extensively edited and revised and then discussed by the entire IOIBD membership at the annual general meeting in 2006. Following that meeting, additional revisions were made, and the review was submitted for publication. External peer review by the journal Gastroenterology led to a final revision that is presented below. Consensus statements can be classified with respect to the strength of the evidence supporting the conclusions (level 1, randomized controlled trials; level 2, well-designed cohort and case control studies; level 3, expert opinion based on observational data).1Kitching A. Sackett D. Yusef S. Approaches to evaluating evidence. BMJ Books, Oxford, UK1998Google Scholar There have been no randomized controlled trials or subexperimental studies that have compared the utility of the different measures of outcome for determining the disease activity of UC, and virtually none of the instruments discussed below have been validated (defined as the extent to which a scale measures what it is intended to measure).2Guyatt G.H. Sackett D.L. Cook D.J. Evidence-Based Medicine Working GroupUsers’ guides to the medical literature. II. How to use an article about therapy or prevention. A. Are the results of the study valid?.JAMA. 1993; 270: 2598-2601Google Scholar No formal quantitative process was used to reach the conclusions outlined below. Rather, the authors reviewed the relevant medical literature and considered factors such as clinical relevance, use in multiple clinical trials, use in clinical trials that lead to regulatory approval, and others in forming an expert opinion. Thus, the evidence summarized in this review is all level 3. The scores described below are based on signs and symptoms for which no standard definitions have been developed. A “bowel movement” for instance could be any trip to the bathroom with passage of fecal material through the anus, but some patients with severe disease may be incontinent making the definition unsuitable.3Rao S.S. Holdsworth C.D. Read N.W. Symptoms and stool patterns in patients with ulcerative colitis.Gut. 1988; 29: 342-345Google Scholar The upper limit of normal for stool frequency is quite variable and may be up to 3 or 4 stools per day. Thus, defining an increased stool frequency may require a comparison to a patient’s “normal” stool frequency, which could be preferable to setting an absolute number of stools per day. On the other hand, the “normal” number of bowel movements for any individual patient can also vary considerably. The same is true for “fecal urgency” and “abdominal pain,” often interpreted as combined cramps and dull discomfort. The authors recommend that, in the future, more stringent definitions be discussed and developed. In 1955, Truelove and Witts reported the results of a placebo-controlled trial of oral cortisone for treating active UC. The authors described an instrument to measure disease activity subsequently named the Truelove and Witts Severity Index,4Truelove S.C. Witts L.J. Cortisone in ulcerative colitis Final report on a therapeutic trial.BMJ. 1955; 2: 1041-1048Google Scholar composed of 6 variables: number of stools per day; blood in stools; temperature; pulse; hemoglobin; and erythrocyte sedimentation rate (ESR) (see Supplementary Table 1 online at www.gastrojournal.org). Clinical remission was defined as 1 or 2 stools per day without blood, absence of fever or tachycardia, a normal hemoglobin or “returning towards normal,” a normal ESR or “returning towards normal,” and gaining weight. To be included in this category, patients were expected to show all of the above features. No change or worse was described as “self-explanatory.” All intermediate cases were defined as “improved.” This instrument has multiple limitations. Most notably, neither the Truelove and Witts Severity Index nor the definitions of “clinical remission,” “improvement,” and “no change” or “worsening” have been validated, and it is not quantitative, ie, no disease severity score is generated. Although the Truelove and Witts Severity Index is useful to broadly classify patients and therefore can be used as an entry or exclusion criteria for clinical trials, it is not sufficiently discriminative to measure changes in disease activity.4Truelove S.C. Witts L.J. Cortisone in ulcerative colitis Final report on a therapeutic trial.BMJ. 1955; 2: 1041-1048Google Scholar In 1978, Powell-Tuck et al reported the results of a controlled comparison of oral prednisolone 10 mg 4 times daily vs 40 mg once daily for the treatment of active UC. The authors described a disease activity measure subsequently named the Powell-Tuck Index,5Powell-Tuck J. Bown R.L. Lennard-Jones J.E. A comparison of oral prednisolone given as single or multiple daily doses for active proctocolitis.Scand J Gastroenterol. 1978; 13: 833-837Google Scholar including 10 clinical variables: general health, abdominal pain, bowel frequency, stool consistency, bleeding, anorexia, nausea or vomiting, abdominal tenderness, extraintestinal complications (eye, mouth, joint, skin), and temperature (see Supplementary Table 2 online at www.gastrojournal.org). The scores range from 0 to 20 points. One variation of the Powell-Tuck Index includes sigmoidoscopic appearance (0–2 points), increasing the total maximum score to 22 points (see Supplementary Table 2 online at www.gastrojournal.org). Remission was defined as a score of 0, and improvement was defined as a decrease in the baseline score ≥2 points. Neither the Powell-Tuck Index nor the definitions of remission and improvement have been validated. Each of the 10 clinical variables was correlated with the sigmoidoscopic appearance in a patients’ cohort.6Powell-Tuck J. Day D.W. Buckell N.A. Wadsworth J. Lennard-Jones J.E. Correlations between defined sigmoidoscopic appearances and other measures of disease activity in ulcerative colitis.Dig Dis Sci. 1982; 27: 533-537Google Scholar Rectal bleeding, abdominal pain, bowel frequency, stool consistency, and well-being correlated best with endoscopic changes. The sigmoidoscopic appearance contributes little to the variance of the Powell-Tuck Index score7Higgins P.D. Schwartz M. Mapili J. Zimmermann E.M. Is endoscopy necessary for the measurement of disease activity in ulcerative colitis?.Am J Gastroenterol. 2005; 100: 355-361Google Scholar because only 2 points of the maximum 22 points come from sigmoidoscopy. The 7 patient self-reported items (general health, abdominal pain, bowel frequency, stool consistency, bleeding, anorexia, nausea or vomiting) correlate well with the total index score.8Maunder R.G. Greenberg G.R. Comparison of a disease activity index and patients’ self-reported symptom severity in ulcerative colitis.Inflamm Bowel Dis. 2004; 10: 632-636Google Scholar A cut-off of <3.5 points correlates with Patient-Defined Remission (see below).9Higgins P.D.R. Schwartz M. Mapili J. Krokos I. Leung J. Zimmerman E.M. Patient defined dichotomous end points for remission and clinical improvement in ulcerative colitis.Gut. 2005; 54: 782-788Google Scholar In 1988, Rachmilewitz et al reported the results of a controlled comparison of coated mesalamine (Claversal; Smith Kline Beecham, United Kingdom) and sulfasalazine for the treatment of active UC. In this trial, the authors described an instrument subsequently named the Clinical Activity Index (CAI)10Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial.BMJ. 1989; 298: 82-86Google Scholar composed of 7 variables: number of stools, blood in stools, investigator’s global assessment of symptomatic state, abdominal pain or cramps, temperature due to colitis, extraintestinal manifestations, and laboratory findings (see Supplementary Table 3 online at www.gastrojournal.org). The scores ranging from 0 to 29 points (higher scores meaning more severe disease) have been validated in one study11Rutgeerts P. International Study GroupComparative efficacy of coated, oral 5-aminosalicylic acid (Claversal) and sulphasalazine for maintaining remission of ulcerative colitis.Aliment Pharmacol Ther. 1989; 3: 183-191Google Scholar in which clinical remission was defined as a CAI score ≤4 points. In 1992, Seo described an activity index (AI)12Seo M. Okada M. Yao T. Ueki M. Arima S. Okumura M. An index of disease activity in patients with ulcerative colitis.Am J Gastroenterol. 1992; 87: 971-976Google Scholar based on evaluation of 18 clinical, laboratory, and endoscopic variables that were prospectively collected from 72 patients during 85 clinical relapses. A multivariable regression analysis was used to develop an equation that best predicted the Truelove and Witt’s Severity Index classification (mild, moderate, severe) for each patient. Five variables were defined: bloody stool, bowel movements, ESR, hemoglobin, and serum albumin. The AI is calculated as follows: AI = 60 × bloody stool + 13 × bowel movements + 0.5 × ESR − 4 × hemoglobin − 15 × albumin + 200. Scores range from approximately 50 to 250 points. Activity index scores <150 points, 150–200 points, and >200 points correspond to mild, moderate, and severely active disease, respectively, as classified by the Truelove and Witts Severity Index. In a subsequent study performed in patients with severe UC, an AI score <180 points after 2 weeks of intravenous corticosteroids predicted remission. Conversely, a score >200 predicted colectomy.13Seo M. Okada M. Yao T. Okabe N. Maeda K. Oh K. Evaluation of disease activity in patients with moderately active ulcerative colitis: comparisons between a new activity index and Truelove and Witts classification (comments).Am J Gastroenterol. 1995; 90: 1759-1763Google Scholar, 14Seo M. Okada M. Yao T. Matake H. Maeda K. Evaluation of the clinical course of acute attacks in patients with ulcerative colitis through the use of an activity index.J Gastroenterol. 2002; 37: 29-34Google Scholar The AI significantly predicted response to infliximab or need for colectomy in a clinical trial.15Jarnerot G. Hertervig E. Friis-Liby I. Blomquist L. Karlen P. Granno C. Vilien M. Strom M. Danielsson A. Verbaan H. Hellstrom P.M. Magnuson A. Curman B. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study.Gastroenterology. 2005; 128: 1805-1811Abstract Full Text Full Text PDF Scopus (915) Google Scholar The AI also correlates significantly with endoscopic findings.16Seo M. Okada M. Maeda K. Oh K. Correlation between endoscopic severity and the clinical activity index in ulcerative colitis.Am J Gastroenterol. 1998; 93: 2124-2129Google Scholar A cut-off of <120 points correlates with Patient-Defined Remission (see below).9Higgins P.D.R. Schwartz M. Mapili J. Krokos I. Leung J. Zimmerman E.M. Patient defined dichotomous end points for remission and clinical improvement in ulcerative colitis.Gut. 2005; 54: 782-788Google Scholar A decrease of >30 points from baseline correlates with Patient-Defined Significant Improvement (see below).9Higgins P.D.R. Schwartz M. Mapili J. Krokos I. Leung J. Zimmerman E.M. Patient defined dichotomous end points for remission and clinical improvement in ulcerative colitis.Gut. 2005; 54: 782-788Google Scholar In 1993, Hanauer et al reported the results of a placebo-controlled trial of sustained release mesalamine (Pentasa; Ferring, Copenhagen, Denmark, and Shire, Basingstoke, United Kingdom) for the treatment of active UC. In this trial, the authors utilized a Physician Global Assessment (PGA).17Hanauer S. Schwartz J. Robinson M. Roufail W. Arora S. Cello J. Safdi M. Pentasa Study GroupMesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial.Am J Gastroenterol. 1993; 88: 1188-1197Google Scholar The PGA is an arbitrarily designed, multicomponent measure of disease activity that uses the physician’s assessment of improvement or worsening in clinical status based on disease activity and symptom severity as compared with baseline (see Supplementary Table 4 online at www.gastrojournal.org). Scores range from 1 to 6 points, with higher scores meaning more severe disease, and treatment success was defined as a PGA score of 1 or 2, whereas treatment benefit was defined as any improvement of PGA score over baseline and remission as a PGA score of 1. The PGA and the definitions of treatment success, benefit, or remission have not been validated. In 1990, Lichtiger et al reported the results of a pilot trial of intravenous cyclosporine for the treatment of severely active steroid-refractory UC. In this trial, the authors described a modified Truelove and Witts Severity Index (MTWSI), also referred to as the Lichtiger Index.18Lichtiger S. Present D.H. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis (comment).Lancet. 1990; 336: 16-19Google Scholar Eight variables determine the Lichtiger Index: diarrhea (number of daily stools), nocturnal stools, visible blood in stool (percentage of movements), fecal incontinence, abdominal pain/cramping, general well-being, abdominal tenderness, and need for antidiarrheals (see Supplementary Table 5 online at www.gastrojournal.org). The scores range from 0 to 21 points. Clinical response was initially defined as a score reduction from baseline of ≥50%.18Lichtiger S. Present D.H. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis (comment).Lancet. 1990; 336: 16-19Google Scholar Subsequently, clinical response was defined as a Lichtiger Index score <10 points on 2 consecutive days.19Lichtiger S. Present D.H. Kornbluth A. Gelernt I. Bauer J. Galler G. Michelassi F. Hanauer S. Cyclosporine in severe ulcerative colitis refractory to steroid therapy.N Engl J Med. 1994; 330: 1841-1845Google Scholar Recently, remission was defined as a Lichtiger Index score ≤3.20Targan S.R. Salzberg B.A. Mayer L. Hommes D. Hanauer S. Mahadevan U. Reinisch W. Plevy S.E. Dignass A.U. Van Assche G. Buchman A. Mechkov G. Krastev Z. Lowder J.N. A phase I-II study: multiple dose levels of visilizumab are well tolerated and produce rapid and sustained improvement in ulcerative colitis patients refractory to treatment with IV steroids (IVSR-UC).Gastroenterology. 2005; 128 (abstr)Google Scholar Neither the Lichtiger Index nor the definitions of clinical response or remission have been validated. In 1998, Hanauer et al reported a placebo-controlled trial of budesonide enemas for active distal UC in which they described a disease activity measure subsequently named the Investigators Global Evaluation.21Hanauer S.B. Robinson M. Pruitt R. Lazenby A.J. Persson T. Nilsson L.G. Walton-Bowen K. Haskell L.P. Levine J.G. US Budesonide Enema Study GroupBudesonide enema for the treatment of active, distal ulcerative colitis and proctitis: a dose-ranging study.Gastroenterology. 1998; 115: 525-532Google Scholar The Investigators Global Evaluation is an arbitrarily designed, multicomponent measure using the physician’s assessment of disease severity based on disease activity and symptom severity compared with baseline (see Supplementary Table 6 online at www.gastrojournal.org). The scores range from 0 to 4 points, with remission defined as ≤3 bowel movements per day, no blood in stools, no urgency, no abdominal pain or painful evacuations, and a sigmoidoscopic inflammation grade of 0. Neither the Investigators Global Evaluation nor the definition of remission has been validated. In 1998, Walmsley et al described an instrument to measure disease activity named the Simple Clinical Colitis Activity Index (SCCAI).22Walmsley R.S. Ayres R.C. Pounder R.E. Allan R.N. A simple clinical colitis activity index.Gut. 1998; 43: 29-32Google Scholar Investigators adapted the 10 items of the Powell-Tuck Index and added 3 additional items: sigmoidoscopic assessment,5Powell-Tuck J. Bown R.L. Lennard-Jones J.E. A comparison of oral prednisolone given as single or multiple daily doses for active proctocolitis.Scand J Gastroenterol. 1978; 13: 833-837Google Scholar nocturnal bowel movements, and urgency of defecation. Furthermore, the general well-being score from the Harvey and Bradshaw index of Crohn’s disease was substituted for the general health question of the Powell-Tuck Index.23Harvey R.F. Bradshaw J.M. A simple index of Crohn’s disease activity.Lancet. 1980; 1: 514Google Scholar In the study that evaluated 57 patients during 63 assessments, multivariable regression analysis was used to develop an equation that contained 6 variables that best predicted the Powell-Tuck Index classification: bowel frequency (day), bowel frequency (night), urgency of defecation, blood in stool, general well-being, and extracolonic manifestations (see Supplementary Table 7 online at www.gastrojournal.org). Scores range from 0 to 19 points. Although clinical remission and response criteria were not defined in the original study, a cut-off of <2.5 points has been shown to correlate with Patient-Defined Remission,9Higgins P.D.R. Schwartz M. Mapili J. Krokos I. Leung J. Zimmerman E.M. Patient defined dichotomous end points for remission and clinical improvement in ulcerative colitis.Gut. 2005; 54: 782-788Google Scholar and a decrease of >1.5 points from baseline correlates with Patient-Defined Significant Improvement (see below).9Higgins P.D.R. Schwartz M. Mapili J. Krokos I. Leung J. Zimmerman E.M. Patient defined dichotomous end points for remission and clinical improvement in ulcerative colitis.Gut. 2005; 54: 782-788Google Scholar In 2002, Levine et al reported the results of a controlled trial of balsalazide for the treatment of active UC. In this trial, the authors described an instrument to measure disease improvement based on individual symptom scores24Levine D.S. Riff D.S. Pruitt R. Wruble L. Koval G. Sales D. Bell J.K. Johnson L.K. A randomized, double-blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis.Am J Gastroenterol. 2002; 97: 1398-1407Google Scholar including rectal bleeding, patient functional assessment, stool frequency, abdominal pain, sigmoidoscopic grade, and PGA (see Supplementary Table 8 online at www.gastrojournal.org). The scores for each item range from 0 to 3 points (normal to severe). Improvement was defined as a reduction from baseline of ≥1 grade in rectal bleeding and at least one of the other assessed symptoms. Improvement based on individual symptom scores has not been validated as a measure of disease activity. In 2005, Feagan et al reported the results of a placebo-controlled trial of anti-α4β7 integrin antibody (MLN-02) for the treatment of active UC. In this trial, the Ulcerative Colitis Clinical Score (UCCS) was described.25Feagan B.G. Greenberg G.R. Wild G. Fedorak R. Pare P. McDonald J.W.D. Dube R. Cohen A. Steinhardt H. Landau S. Aguzzi R.A. Fox I.H. Vandervoort M.K. Treatment of ulcerative colitis with a humanized antibody to the α4β7 integrin.N Engl J Med. 2005; 352: 2499-2507Google Scholar This instrument consists of 4 items: stool frequency, rectal bleeding, subject’s (patient’s) functional assessment, and PGA (see Supplementary Table 9 online at www.gastrojournal.org). This instrument is a modification of the Mayo Score (see below).26Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis A randomized study.N Engl J Med. 1987; 317: 1625-1629Google Scholar Scores range from 0 to 12 points with higher scores meaning more active disease. Clinical remission was defined as a UCCS score of 0 or 1 and a modified endoscopic Baron score of 0 or 1 (see below) and no rectal bleeding. Clinical response was defined as an improvement of 3 points or more on the UCCS. Neither the UCCS nor the definitions of clinical remission or clinical response have been validated. In 2005, Higgins et al described an index named Patient-Defined Remission.9Higgins P.D.R. Schwartz M. Mapili J. Krokos I. Leung J. Zimmerman E.M. Patient defined dichotomous end points for remission and clinical improvement in ulcerative colitis.Gut. 2005; 54: 782-788Google Scholar Investigators asked 56 patients the survey question, “Is your ulcerative colitis in remission (not active)?” to which only yes or no answers were accepted. At a return visit between 1 and 14 months later, subjects were again asked whether they were in remission and whether their UC was better or worse than at their previous visit on a 7-point Likert scale (1, much better; 2, some better; 3, a little better; 4, about the same; 5, a little worse; 6, some worse; 7, much worse). Subjects who reported being either much better or some better were defined as significantly improved. Those who were a little better, about the same, or one of the 3 levels of worsening were not considered significantly improved. Patient-Defined Remission had good sensitivity (86%) and specificity (76%) for a “regulatory definition of remission” defined by investigators as a composite of a modified Baron endoscopic score graded 0–2 (absence of friability) and absence of visible blood reported by the patient. Truelove and Witts performed serial sigmoidoscopic assessments during a placebo-controlled trial of cortisone for the treatment of active UC. Sigmoidoscopic appearance was classified as (1) normal or near normal (defined as slight hyperemia or only slight granularity), (2) improved, or (3) no change or worse.4Truelove S.C. Witts L.J. Cortisone in ulcerative colitis Final report on a therapeutic trial.BMJ. 1955; 2: 1041-1048Google Scholar The absence of definitions for the endoscopic descriptors may create interobserver variability. In a cross-sectional study, Baron et al specifically evaluated the interobserver variability in describing the appearance of the rectosigmoid mucosa using a rigid proctoscope in patients with UC. The endoscopic disease activity was rated using a 4-point scale (0–3) (see Supplementary Table 10 online at www.gastrojournal.org)27Baron J.H. Connell A.M. Lennard-Jones J.E. Variation between observers in describing mucosal appearances in proctocolitis.BMJ. 1964; 1: 89-92Google Scholar that was mainly based on the severity of bleeding. Notably, ulceration was not assessed. Interobserver variation was calculated for all variables and was the highest for “graded” variables such as “redness.” However, the best agreement was reached for “friability” (bleeding to light touch). Powell-Tuck et al performed serial sigmoidoscopic assessments during a controlled trial of oral prednisolone for the treatment of active UC. The sigmoidoscopic appearance was described using a 3-point scale (0–2), again with focus on “bleeding” as a predominant endoscopic feature (see Supplementary Table 2 online at www.gastrojournal.org).5Powell-Tuck J. Bown R.L. Lennard-Jones J.E. A comparison of oral prednisolone given as single or multiple daily doses for active proctocolitis.Scand J Gastroenterol. 1978; 13: 833-837Google Scholar Rachmilewitz performed serial endoscopic assessments during a controlled comparison of coated mesalamine and sulfasalazine for the treatment of active UC. In this trial, an instrument consisting of 4 items was described: granulation scattering reflected light, vascular pattern, vulnerability of mucosa, and mucosal damage (mucus, fibrin, exudates, erosions, and ulcer) (see Supplementary Table 11 online at www.gastrojournal.org).10Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial.BMJ. 1989; 298: 82-86Google Scholar Scores range from 0 to 12 points. Endoscopic remission was defined as an endoscopic index score of 0–4 points. The instrument has not been validated. Hanauer et al performed serial endoscopic assessments during a placebo-controlled trial of sustained release mesalamine (Pentasa; Ferring and Shire) for the treatment of active UC. They described the Sigmoidoscopic Index.17Hanauer S. Schwartz J. Robinson M. Roufail W. Arora S. Cello J. Safdi M. Pentasa Study GroupMesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial.Am J Gastroenterol. 1993; 88: 1188-1197Google Scholar Its 5 variables were erythema, friability, granularity/ulceration, mucopus, and disappearance of mucosal vascular pattern. Each variable was assigned a value from 0 to 3 (0, normal; 1, mild; 2, moderate; 3, severe). The total scores for the Sigmoidoscopic Index range from 0 to 16 points. Sigmoidoscopic remission was defined as a Sigmoidoscopic Index score of 0 to 4 points, which has not been validated. Lémann et al28Lemann M. Galian A. Rutgeerts P. Van Heuverzwijn R. Cortot A. Viteau J.M. Elewaut A. Belaiche J. Froguel E. Modigliani R. Comparison of budesonide and 5-aminosalicylic acid enemas in active distal ulcerative colitis.Aliment Pharmacol Ther. 1995; 9: 557-562Google Scholar and later Hanauer et al21Hanauer S.B. Robinson M. Pruitt R. Lazenby A.J. Persson T. Nilsson L.G. Walton-Bowen K. Haskell L.P. Levine J.G. US Budesonide Enema Study GroupBudesonide enema for the treatment of active, distal ulcerative colitis and proctitis: a dose-ranging study.Gastroenterology. 1998; 115: 525-532Google Scholar performed serial endoscopic assessments during a comparative trial with budesonide and 5-ASA enemas and during a placebo-controlled trial of budesonide enemas for the treatment of active distal UC. The authors described the Sigmoidoscopic Inflammation Grade Score,21Hanauer S.B. Robinson M. Pruitt R. Lazenby A.J. Persson T. Nilsson L.G. Walton-Bowen K. Haskell L.P. Levine J.G. US Budesonide Enema Study GroupBudesonide enema for the treatment of active, distal ulcerative colitis and proctitis: a dose-ranging study.Gastroenterology. 1998; 115: 525-532Google Scholar, 28Lemann M. Galian A. Rutgeerts P. Van Heuverzwijn R. Cortot A. Viteau J.M. Elewaut A. Belaiche J. Froguel E. Modigliani R. Comparison of budesonide and 5-aminosalicylic acid enemas in active distal ulcerative colitis.Aliment Pharmacol Ther. 1995; 9: 557-562Google Scholar which was a 4-point scale (0–3): 0, normal mucosa; 1, edema and/or loss of visible mucosal vascularity, granularity; 2, friability (defined as visible, induced bleeding on examination), petechiae; and 3, spontaneous hemorrhage, visible ulcers. No definition of improvement in sigmoidoscopic inflammation was identified. Schroeder et al performed serial flexible proctosigmoidoscopic assessments during a placebo-controlled trial of oral delayed release mesalamine (Asacol; Procter & Gamble

This analysis of Crohn's disease patients treated with infliximab in ACCENT I compared episodic and scheduled treatment strategies under conditions that simulate clinical practice.After 5 mg/kg infliximab at week 0, 573 patients were randomized to infusions at weeks 2 and 6 and every 8 weeks until week 46 of placebo (episodic), infliximab 5 mg/kg at weeks 2 and 6 followed by 5 mg/kg (5 mg/kg scheduled) every 8 weeks, or infliximab 5 mg/kg at weeks 2 and 6 followed by 10 mg/kg (10 mg/kg scheduled) every 8 weeks. At or after week 14, treatment could be given with a dose of infliximab 5 mg/kg higher upon loss of response.The efficacy of scheduled infliximab therapy was better than episodic treatment. Crohn's Disease Activity Index (CDAI) scores were consistently significantly better in the 10 mg/kg scheduled maintenance group from weeks 10 to 54, and response and remission rates (combined scheduled) were significantly higher from weeks 10 to 30. A greater proportion of patients achieved complete mucosal healing at week 54 (P = 0.041). A lower proportion developed antibodies to infliximab in the scheduled groups than in the episodic group (9% [5 mg/kg], 6% [10 mg/kg], 28% [episodic], respectively). Scheduled strategy patients had fewer Crohn's disease-related hospitalizations (P = 0.014) and surgeries (P = 0.01) than episodic strategy patients.The scheduled infliximab groups, particularly the 10 mg/kg group, had better CDAI and Inflammatory Bowel Disease Questionnaire (IBDQ) responses than those in the episodic group. Both scheduled groups had fewer hospitalizations, higher rates of mucosal healing, and fewer developed antibodies than those in the episodic group, with no increase in side effects.

Although corticosteroids are highly effective in improving symptoms of Crohn's disease, they may have substantial toxicity. In some patients, attempts to discontinue corticosteroids are unsuccessful.We conducted a double-blind, placebo-controlled multicenter study of weekly injections of methotrexate in patients who had chronically active Crohn's disease despite a minimum of three months of prednisone therapy. Patients were randomly assigned to treatment with intramuscular methotrexate (25 mg once weekly) or placebo for 16 weeks. The patients also received prednisone (20 mg once a day), which was tapered over 10 weeks unless their condition worsened. The primary outcome measure was clinical remission at the end of the 16-week trial. Remission was defined by the discontinuation of prednisone and a score of < or = 150 points on the Crohn's Disease Activity Index.A total of 141 patients were randomly assigned in a 2:1 ratio to methotrexate (94 patients) or placebo (47 patients). After 16 weeks, 37 patients (39.4 percent) were in clinical remission in the methotrexate group, as compared with 9 patients (19.1 percent) in the placebo group (P = 0.025; relative risk, 1.95; 95 percent confidence interval, 1.09 to 3.48). The patients in the methotrexate group received less prednisone overall than those in the placebo group (P = 0.026). The mean (+/- SE) score on the Crohn's Disease Activity Index after 16 weeks of treatment was significantly lower in the methotrexate group (162 +/- 12) than in the placebo group (204 +/- 17, P = 0.002). The changes in quality-of-life scores and serum orosomucoid concentrations were similar. In the methotrexate group, 16 patients (17 percent) withdrew from treatment because of adverse events (including asymptomatic elevation of serum aminotransferase in 7 and nausea in 6), as compared with 1 patient (2 percent) in the placebo group.In a group of patients with chronically active Crohn's disease, methotrexate was more effective than placebo in improving symptoms and reducing requirements for prednisone.

Natalizumab, a humanized monoclonal antibody against alpha4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue.We conducted two controlled trials to evaluate natalizumab as induction and maintenance therapy in patients with active Crohn's disease. In the first trial, 905 patients were randomly assigned to receive 300 mg of natalizumab or placebo at weeks 0, 4, and 8. The primary outcome was response, defined by a decrease in the Crohn's Disease Activity Index (CDAI) score of at least 70 points, at week 10. In the second trial, 339 patients who had a response to natalizumab in the first trial were randomly reassigned to receive 300 mg of natalizumab or placebo every four weeks through week 56. The primary outcome was a sustained response through week 36. A secondary outcome in both trials was disease remission (a CDAI score of less than 150).In the first trial, the natalizumab and placebo groups had similar rates of response (56 percent and 49 percent, respectively; P=0.05) and remission (37 percent and 30 percent, respectively; P=0.12) at 10 weeks. Continuing natalizumab in the second trial resulted in higher rates of sustained response (61 percent vs. 28 percent, P<0.001) and remission (44 percent vs. 26 percent, P=0.003) through week 36 than did switching to placebo. Serious adverse events occurred in 7 percent of each group in the first trial and in 10 percent of the placebo group and 8 percent of the natalizumab group in the second trial. In an open-label extension study, a patient treated with natalizumab died from progressive multifocal leukoencephalopathy, associated with the JC virus, a human polyomavirus.Induction therapy with natalizumab for Crohn's disease resulted in small, nonsignificant improvements in response and remission rates. Patients who had a response had significantly increased rates of sustained response and remission if natalizumab was continued every four weeks. The benefit of natalizumab will need to be weighed against the risk of serious adverse events, including progressive multifocal leukoencephalopathy. (ClinicalTrials.gov numbers, NCT00032786 and NCT00032799.)

Background & Aims: Long-term safety data for infliximab and other therapies in Crohn’s disease (CD) are needed. Methods: We prospectively evaluated patients for prespecified safety-related outcomes. Results: As of August 2004, 6290 patients were enrolled; 3179 received infliximab (5519 patient-years), 87% of whom received at least 2 infusions, and 3111 received other therapies (6123 patient-years). The mean length of follow-up evaluation was 1.9 years. More infliximab-treated patients had moderate-to-severe (30.8% vs 10.3%) or severe-fulminant (2.5% vs .6%) CD, and had surgical (17.5% vs 13.8%) or medical (14.4% vs 9.1%) hospitalizations in the previous year. More patients were taking prednisone (27.4% vs 16.1%), immunomodulators (49.4% vs 32.2%), or narcotic analgesics (9.8% vs 5.4%) when compared with those receiving other therapies (P < .001, all comparisons). The mortality rates were similar for infliximab- and non–infliximab-treated patients (.53 per 100 patient-years vs .43; relative risk, 1.24; 95% confidence interval [CI], .73–2.10). In multivariate logistic regression analysis, only prednisone was associated with an increased mortality risk (odds ratio [OR], 2.10; 95% CI, 1.15–3.83; P = .016). Although the unadjusted analysis showed an increased risk for infection with infliximab use, multivariate logistic regression analysis suggested that infliximab was not an independent predictor of serious infections (OR, .99; 95% CI, .64–1.54). Factors independently associated with serious infections included prednisone use (OR, 2.21; 95% CI, 1.46–3.34; P < .001), narcotic analgesic use (OR, 2.38; 95% CI, 1.56–3.63; P < .001), and moderate-to-severe disease activity (OR, 2.11; 95% CI, 1.10–4.05; P = .024). Conclusions: Mortality rates were similar between infliximab- and non–infliximab-treated patients. The increased risk for serious infection observed with infliximab likely was owing to disease severity and prednisone use. Background & Aims: Long-term safety data for infliximab and other therapies in Crohn’s disease (CD) are needed. Methods: We prospectively evaluated patients for prespecified safety-related outcomes. Results: As of August 2004, 6290 patients were enrolled; 3179 received infliximab (5519 patient-years), 87% of whom received at least 2 infusions, and 3111 received other therapies (6123 patient-years). The mean length of follow-up evaluation was 1.9 years. More infliximab-treated patients had moderate-to-severe (30.8% vs 10.3%) or severe-fulminant (2.5% vs .6%) CD, and had surgical (17.5% vs 13.8%) or medical (14.4% vs 9.1%) hospitalizations in the previous year. More patients were taking prednisone (27.4% vs 16.1%), immunomodulators (49.4% vs 32.2%), or narcotic analgesics (9.8% vs 5.4%) when compared with those receiving other therapies (P < .001, all comparisons). The mortality rates were similar for infliximab- and non–infliximab-treated patients (.53 per 100 patient-years vs .43; relative risk, 1.24; 95% confidence interval [CI], .73–2.10). In multivariate logistic regression analysis, only prednisone was associated with an increased mortality risk (odds ratio [OR], 2.10; 95% CI, 1.15–3.83; P = .016). Although the unadjusted analysis showed an increased risk for infection with infliximab use, multivariate logistic regression analysis suggested that infliximab was not an independent predictor of serious infections (OR, .99; 95% CI, .64–1.54). Factors independently associated with serious infections included prednisone use (OR, 2.21; 95% CI, 1.46–3.34; P < .001), narcotic analgesic use (OR, 2.38; 95% CI, 1.56–3.63; P < .001), and moderate-to-severe disease activity (OR, 2.11; 95% CI, 1.10–4.05; P = .024). Conclusions: Mortality rates were similar between infliximab- and non–infliximab-treated patients. The increased risk for serious infection observed with infliximab likely was owing to disease severity and prednisone use. Crohn’s disease (CD) is characterized by recurrent inflammation at any location in the gastrointestinal tract. The pharmacologic management of CD is based on the location, extent, and disease severity.1Rutgeerts P. van Assche G. Vermeire S. Optimizing anti-TNF treatment in inflammatory bowel disease.Gastroenterology. 2004; 126: 1593-1610Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 2Hanauer S.B. Drug therapy inflammatory bowel disease.N Engl J Med. 1996; 334: 841-848Crossref PubMed Scopus (449) Google Scholar, 3Podolsky D.K. Inflammatory bowel disease.N Engl J Med. 2002; 347: 417-429Crossref PubMed Scopus (3222) Google Scholar Therapeutic options include aminosalicylates, antibiotics, and immunosuppressive agents such as corticosteroids, antimetabolite immunomodulators (eg, 6-mercaptopurine, azathioprine, methotrexate), and infliximab. Infliximab has been proven to be efficacious in patients with either luminal4Targan S.R. Hanauer S.B. van Deventer S.J.H. et al.Crohn’s Disease cA2 Study GroupA short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease.N Engl J Med. 1997; 337: 1029-1035Crossref PubMed Scopus (3116) Google Scholar, 5Rutgeerts P. Feagan B.F. Lichtenstein G.R. et al.Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease.Gastroenterology. 2004; 126: 402-413Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar, 6Hanauer S.B. Feagan B.G. Lichtenstein G.R. et al.Maintenance infliximab for Crohn’s disease the ACCENT I randomized trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3726) Google Scholar, 7Rutgeerts 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: 761-769Abstract Full Text Full Text PDF PubMed Scopus (1079) Google Scholar or fistulizing CD.8Present D.H. Rugeerts P. Targan S. et al.Infliximab for the treatment of fistulas in patients with Crohn’s disease.N Engl J Med. 1999; 340: 1398-1405Crossref PubMed Scopus (2506) Google Scholar, 9Sands B.E. Anderson F.H. Bernstein C.N. et al.Infliximab maintenance therapy for fistulizing Crohn’s disease.N Engl J Med. 2004; 350: 876-885Crossref PubMed Scopus (1921) Google Scholar The use of corticosteroids is associated with a high incidence of both short- and long-term side effects including Cushing’s syndrome, osteoporosis, diabetes, and infection.10Stuck A.E. Minder C. Frey F.J. Risk of infectious complication in patients taking glucocorticosteroids.Rev Infect Dis. 1989; 11: 954-963Crossref PubMed Scopus (692) Google Scholar, 11Yang Y.X. Lichtenstein G.R. Corticosteroids in Crohn’s disease.Am J Gastroenterol. 2002; 97: 803-823Crossref PubMed Google Scholar The use of immunomodulators is complicated by a delayed onset of action and side effects including bone marrow suppression, hepatotoxicity, and pancreatitis.12Sandborn W.J. A review of immune modifier therapy for inflammatory bowel disease azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate.Am J Gastroenterol. 1996; 91: 423-433PubMed Google Scholar Because both corticosteroids and immunomodulators have broad effects on the immune system, patients treated with these drugs may be at increased risk for serious or fatal infections.13Aucott J.N. Glucocorticoids and infection.Endocrinol Metab Clin North Am. 1994; 23: 655-670PubMed Google Scholar, 14Klein N.C. Go C.H. Cunha B.A. Infections associated with steroid use.Infect Dis Clin North Am. 2001; 15: 423-432Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Infliximab, which specifically targets tumor necrosis factor-α, also is associated with adverse events including infections. In large controlled clinical trials of infliximab in patients with CD, the percentage of patients with serious infections ranged from 4.0% to 4.6% and the mortality rate ranged from .7% to 1.3%.6Hanauer S.B. Feagan B.G. Lichtenstein G.R. et al.Maintenance infliximab for Crohn’s disease the ACCENT I randomized trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3726) Google Scholar, 9Sands B.E. Anderson F.H. Bernstein C.N. et al.Infliximab maintenance therapy for fistulizing Crohn’s disease.N Engl J Med. 2004; 350: 876-885Crossref PubMed Scopus (1921) Google Scholar The occurrence of infliximab-related adverse events, including serious opportunistic infections such as tuberculosis, listeriosis, histoplasmosis, and death, also has been documented in reports of open-label trials or retrospective trials.15Colombel J.F. Loftus E.V. Tremaine W.J. et al.The safety profile of infliximab in patients with Crohn’s disease the Mayo Clinic experience in 500 patients.Gastroenterology. 2004; 126: 19-31Abstract Full Text Full Text PDF PubMed Scopus (851) Google Scholar, 16Ricart E. Panaccione R. Loftus E.V. et al.Infliximab for Crohn’s disease in clinical practice at the Mayo Clinic the first 100 patients.Am J Gastroenterol. 2001; 96: 722-729Crossref PubMed Google Scholar, 17Cohen R.D. Tsang J.F. Hanauer S.B. Infliximab in Crohn’s disease first anniversary clinical experience.Am J Gastroenterol. 2000; 95: 3469-3477Crossref PubMed Google Scholar, 18Farrell R.J. Shah S.A. Lodhavia P.J. et al.Clinical experience with infliximab therapy in 100 patients with Crohn’s disease.Am J Gastroenterol. 2000; 95: 3490-3497Crossref PubMed Google Scholar Gastroenterologists remain concerned about the safety of CD treatments. Recognizing that registries are useful in evaluating safety by prospectively following-up large numbers of patients in real-world clinical settings for an extended time and representing cohorts of patients with the same disease who are treated with different drugs, we established a registry, The Crohn’s Therapy, Resource, Evaluation, and Assessment Tool (TREAT). The TREAT Registry is a large-scale, ongoing, observational registry that was designed to examine the safety of CD therapies, including infliximab. The TREAT Registry is a prospective, observational, multicenter, long-term registry of North American patients with CD. The registry was initiated in 1999 to evaluate the clinical safety outcomes of various treatment regimens, including infliximab, in the management of CD. Approximately 350 gastroenterologists from both community-based and academic practice settings were each to enroll up to 150 patients for a target enrollment of at least 5000 patients. Most physicians were identified from the membership list of the Crohn’s and Colitis Foundation Association. Patients were treated at the discretion of their physicians (ie, there was no defined treatment protocol). Physician participation in the registry could be withdrawn if patient enrollment requirements were not met, complete data were not submitted, a physician was leaving the practice, or if a physician elected to discontinue participation. The design of the TREAT Registry was approved by institutional review boards. All patients provided written informed consent. Physicians or their designees were paid a small honorarium on a per-patient basis as compensation for participating in the registry. Centocor, Inc. (Malvern, PA), the manufacturer of infliximab, sponsored the TREAT Registry, but all data were collected, collated, managed, and analyzed by Ovation Research Group (Highland Park, IL), an independent research organization, under the supervision and guidance of an Advisory Committee comprising several authors of this publication (G.R.L., B.G.F., R.D.C., B.A.S., and W.J.S.), and the TREAT medical monitor (R.H.D.). Patients must have had a diagnosis of CD and could not be participating in any clinical trial. Initially, patients younger than 18 years of age participated but the protocol subsequently was amended to limit enrollment to those age 18 years or older. In this ongoing registry, data are collected at enrollment and then on a semiannual basis (each January and July). Data collection will continue for a minimum of 5 years. Patient demographic information and physicians’ assessments of overall patient health were collected at enrollment. Physicians assessed disease severity (remission, mild-moderate, moderate-severe, or severe-fulminant) according to the American College of Gastroenterology Guidelines.19Hanauer S.B. Sandborn W. Practice Parameters Committee of the American College of GastroenterologyManagement of Crohn’s disease in adults.Am J Gastroenterol. 2001; 96: 635-643Crossref PubMed Google Scholar The follow-up data included assessment of disease severity, medication use, adverse events, dates of infliximab infusions, and outcomes of each infusion. The start and stop dates for other medications were not collected. Serious adverse events (SAEs) and changes in pregnancy status were collected as they occurred. Physicians were required to report SAEs within 24 hours of occurrence. A detailed description of the SAE including dates of onset and resolution; designation that the SAE was expected or unexpected; the seriousness and intensity of the SAE; the relationship of the SAE to the underlying CD; concomitant CD medications or surgical procedures for CD; and the treatment and outcome of the SAE, was collected. Baseline demographic and disease characteristics are summarized for the cohort of all patients combined and by treatment cohort. The cohort of patients who received infliximab within 12 weeks before enrollment, who were scheduled to receive infliximab within 30 days of enrollment, or who received infliximab at some other point in the registry was termed infliximab-treated patients. Because it is not possible to document infliximab administration before participation in the registry, only patients who met the criteria outlined previously are considered infliximab-treated. Patients who did not receive infliximab during the registry are termed other-treatments-only patients. Means and SDs were calculated for continuous variables (age, body mass index, and years between CD diagnosis and enrollment). Frequencies and percentages were generated for categoric outcomes (sex, race, involved intestinal segment[s], disease severity, use of immunomodulators, use of prednisone, use of narcotic analgesics, and health resource use). Corticosteroid use represented prednisone use exclusively; immunomodulator use represented the use of azathioprine, 6-mercaptopurine, and/or methotrexate. The Student t test was used to test for equality of means across treatment groups. The χ2 test was used to evaluate the association between treatment group and categoric variables. The primary analyses evaluated the rates of death and rates of serious infection among medication categories. If a patient had multiple serious infections, then the first serious infection was considered for this analysis. For each event, the rate of the events per 100 person-years was calculated for each medication category (infliximab vs other treatments) as the quotient of the total number of on-therapy events and patient-years of exposure to medication multiplied by 100. Two different definitions of exposure time were used: (1) total exposure to infliximab was defined as the time between the first infliximab infusion through the date of the last follow-up evaluation, and (2) exposure to infliximab was defined as having received infliximab within 3 months. Patients could accumulate exposure time in both infliximab and other-treatments-only categories, depending on infliximab start and stop dates. A Poisson regression analysis, accounting for within-patient correlations and as implemented by the GENMOD procedure in SAS (SAS Institute Inc., Cary, NC), tested for the differences in event rates between medication categories. In these analyses, a 2-sided P value of .05 was considered statistically significant. Multivariable regression modeling was used to explore the effects of baseline demographic characteristics (age, sex, race, diseased segment[s], disease severity, and years between diagnosis and enrollment in the TREAT Registry) and medication use as predictors of death and serious infection. For mortality analyses, CD medications, designated as ever used were obtained from all available 6-month periods ( January–June and July–December) that occurred between enrollment and the time of death. Medication use during the period in which the death occurred was included in this analysis. For analysis of serious infection, CD medication ever used was obtained from all available 6-month periods that occurred from enrollment through the period before the onset of the serious infection. Medication use during the period in which the infection occurred was not included in these analyses because medication start and stop dates were not collected for any medications other than infliximab. Therefore, it was unknown whether the medication was given in response to the event, or whether the medication caused the event. After examining the unadjusted models, demographic characteristics and medication ever used between enrollment and the event were included in a multivariate logistic model.20Hosmer D.W. Lemeshow S. Applied logistic regression. John Wiley & Sons, Inc, New York1998Google Scholar The Cox proportional hazards model with time-varying covariates also was used to assess the risk for an event in a given period based on drug use in the prior period. Because the core results identifying risk factors were consistent between the 2 approaches, results from the logistic regression are presented. The data collected through August 23, 2004, were analyzed using SAS software, version 8.02 or higher of the SAS System for Windows. No adjustments were made for multiple comparisons. Through August 2004, 6290 CD patients from 212 centers were enrolled from both community (82%) and academic (18%) centers. Most patients were female (58%) and Caucasian (89%), with an average age of 43 ± 14.7 years. The population was distributed almost equally between those who had been treated with infliximab (N = 3179, 50.5%) and those who had not. More than 85% of patients treated with infliximab had received at least 2 infusions. Among patients who received infliximab, a median of 5 (range, 1–32) infusions were received. Most patients (86%) received infliximab 5 mg/kg. Among the patients who had received at least 2 infusions, the average time between infusions was 61.2 ± 78.1 days. Approximately 16% of patients took budesonide and .5% of patients took cyclosporine at some point while enrolled in the registry. Infliximab-treated patients were younger than patients in the other-treatments-only group (P < .001), but did not differ with regard to sex or race (Table 1). Seventy-four patients who were younger than 18 years of age were enrolled, but their enrollment was discontinued when the protocol was amended to include only patients age 18 or older.Table 1Baseline Patient DemographicsCharacteristicAll patientsInfliximab treatedaInfliximab-treated patients are those patients who received infliximab within 12 weeks before enrollment, who were scheduled to receive infliximab within 30 days of enrollment, or who received infliximab at some other point in the registry.Other treatments onlyP valuebP value from t test (continuous variables) or χ2 test (categoric variables).Total patients, N6290 (100.0%)3179 (50.5%)3111 (49.5%)Age at enrollment, y Mean ± SD42.5 ± 14.740.3 ± 13.944.7 ± 15.3<.001Sex, N Female3619 (57.5%)1842 (57.9%)1777 (57.1%).24 Male2559 (40.7%)1289 (40.5%)1270 (40.8%) Unknown112 (1.8%)48 (1.5%)64 (2.1%)Race, N Caucasian5601 (89.0%)2823 (88.8%)2778 (89.3%).25 African American421 (6.7%)228 (7.2%)193 (6.2%) Asian24 (0.4%)15 (.5%)9 (.3%) Hispanic81 (1.3%)39 (1.2%)42 (1.4%) Other42 (.7%)22 (.7%)20 (.6%) Unknown/missing121 (1.9%)52 (1.6%)69 (2.2%)BMI at enrollment, kg/m2 Mean ± SD26.6 ± 16.626.6 ± 17.126.5 ± 16.1.91BMI, body mass index.a Infliximab-treated patients are those patients who received infliximab within 12 weeks before enrollment, who were scheduled to receive infliximab within 30 days of enrollment, or who received infliximab at some other point in the registry.b P value from t test (continuous variables) or χ2 test (categoric variables). Open table in a new tab BMI, body mass index. Patients in the infliximab-treated group differed significantly from patients in the other-treatments-only group with regard to intestinal segment(s) affected by disease, disease severity, health resource use in the year before enrollment, and medication use at enrollment (P < .0001 for all) (Table 2). Patients who received infliximab, compared with patients who received other treatments only, were more likely to have both their ileum and colon involved (43.2% vs 35.4%, respectively), and to have moderate-to-severe or severe-to-fulminant disease at enrollment (33.3% vs 10.9%, respectively). Hospitalization in the year before enrollment for either surgical (17.5% vs 13.8%) or medical (14.4% vs 9.1%) management also was more frequent among infliximab-treated patients compared with patients who received other treatments only. Patients in the infliximab-treated group were more likely to be receiving prednisone (27.4% vs 16.1%), immunomodulators (49.4% vs 32.2%), and narcotic analgesics (9.8% vs 5.4%) at enrollment.Table 2Baseline Disease CharacteristicsCharacteristicAll patientsInfliximab treatedaInfliximab-treated patients are those patients who received infliximab within 12 weeks before enrollment, who were scheduled to receive infliximab within 30 days of enrollment, or who received infliximab at some other time during the registry.Other treatments onlyP valuebP value from t test (continuous variables) or χ2 test (categoric variables).Total patients, N6290 (100.0%)3179 (50.5%)3111 (49.5%)Years between diagnosis and enrollment Mean ± SD10.8 ± 10.210.7 ± 9.810.9 ± 10.6.45Diseased segment(s), N Ileum only1806 (28.7%)799 (25.1%)1007 (32.4%)<.001 Colon only1767 (28.1%)895 (28.2%)872 (28.0%) Ileum and colon2475 (39.3%)1374 (43.2%)1101 (35.4%) Unknown/missing242 (3.8%)111 (3.5%)131 (4.2%)Disease severity, N RemissioncRemission refers to patients who are asymptomatic or without inflammatory sequelae and refers to patients who have responded to acute medical intervention or who have undergone surgical resection without evidence of residual disease. Patients requiring corticosteroids to maintain well-being are considered to be steroid-dependent and are not in remission.1535 (24.4%)387 (12.2%)1148 (36.9%)<.001 Mild/moderatedMild to moderate disease applies to ambulatory patients who are able to tolerate oral alimentation without manifestations of dehydration, toxicity (high fevers, rigors, prostration), abdominal tenderness, painful mass, obstruction, or >10% weight loss.3081 (49.0%)1592 (50.1%)1489 (47.9%) Moderate/severeeModerat-to-severe disease applies to patients who have failed to respond to treatment for mild to moderate disease or those with more prominent symptoms of fevers, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia.1299 (20.7%)979 (30.8%)320 (10.3%) Severe/fulminantfSevere-fulminant disease applies to patients with persistent symptoms despite the introduction of corticosteroids, or individuals presenting with high fever, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess.99 (1.6%)81 (2.5%)18 (.6%) Unknown/missing276 (4.4%)140 (4.4%)136 (4.4%)Health resource use in year before enrollment Surgical admissions, N985 (15.7%)557 (17.5%)428 (13.8%)<.001 Medical admissions, N741 (11.8%)459 (14.4%)282 (9.1%)<.001Medication use at enrollment Prednisone, N1372 (21.8%)870 (27.4%)502 (16.1%)<.001 Immunomodulators, N (%)2575 (40.9%)1572 (49.4%)1003 (32.2%)<.001 Narcotic analgesics, N (%)480 (7.6%)313 (9.8%)167 (5.4%)<.001a Infliximab-treated patients are those patients who received infliximab within 12 weeks before enrollment, who were scheduled to receive infliximab within 30 days of enrollment, or who received infliximab at some other time during the registry.b P value from t test (continuous variables) or χ2 test (categoric variables).c Remission refers to patients who are asymptomatic or without inflammatory sequelae and refers to patients who have responded to acute medical intervention or who have undergone surgical resection without evidence of residual disease. Patients requiring corticosteroids to maintain well-being are considered to be steroid-dependent and are not in remission.d Mild to moderate disease applies to ambulatory patients who are able to tolerate oral alimentation without manifestations of dehydration, toxicity (high fevers, rigors, prostration), abdominal tenderness, painful mass, obstruction, or >10% weight loss.e Moderat-to-severe disease applies to patients who have failed to respond to treatment for mild to moderate disease or those with more prominent symptoms of fevers, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia.f Severe-fulminant disease applies to patients with persistent symptoms despite the introduction of corticosteroids, or individuals presenting with high fever, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess. Open table in a new tab Patients were followed-up for a mean of 1.9 ± .96 years (median, 1.77 y; range, .5–4.91 y), and as of August 2004, approximately 79% of patients were participating actively in the registry. Patient discontinuations are outlined in Figure 1. Fifty-five (.87%) of the 6290 patients died. Of these 55 patients, 29 had received infliximab. Mortality rates were similar for patients who had received infliximab and those who had not: .53 per 100 patient-years vs .43 per 100 patient-years (relative risk [RR] [95% confidence interval (CI)] = 1.24 [.729–2.102]; P = .43). Similar rates were observed when patients were assessed by exposure to infliximab within the past 3 months. Sixteen patients died within 3 months of receiving an infliximab infusion (mortality rate per 100 patient-years, .41) compared with 39 who died who were not in this time frame (mortality rate, .50) (RR [95% CI] = .83 [.466–1.494]; P = .54). Without adjusting for other factors, patients who died were older (odds ratio [OR], 1.07 for each 1-year increase in age; P < .001) and had a longer duration of disease (OR, 1.06 for each 1-year increase in CD duration; P < .001). When medications were analyzed without adjusting for other factors, the use of prednisone (OR, 2.13; P = .007) and narcotic analgesics (OR, 1.84; P = .044) were associated with increased mortality. In the adjusted model, only age (OR, 1.07; P < .001), duration of CD (OR, 1.03; P = .006), and use of prednisone (OR, 2.10; P = .016) remained independent predictors of death. The use of infliximab was not a significant predictor of mortality in either the unadjusted or adjusted models (Table 3). The reported causes of death among patients are shown in a Table included in online supplementary materials (see Supplemental Table 1 at www.cghjournal.org).Table 3Predictors of MortalityPredictor variableAll patients(N = 6290)Deaths(N = 53aData representing patient status between registration and June 30, 2004, were used in the logistic regression analysis because this is the timeframe for which there is complete information or medication usage. Two patients died after June 30, 2004.)Unadjusted resultsAdjusted resultsOR (95% CI)cOR reported as OR per year increase in age.P valuebP value from Wald χ2 test.OR (95% CI)cOR reported as OR per year increase in age.P valuebP value from Wald χ2 test.Age Mean ± SD42 ± 14.759 ± 16.11.072 (1.053–1.092)cOR reported as OR per year increase in age.<.0011.072 (1.050–1.094)<.001Sex Male/unknown2671.94%—— Female3619.77%.825 (.480–1.418).49.733 (.415–1.293).28Race Non-Caucasian/unknown689.73%—— Caucasian5601.86%1.182 (.469–2.980).720.734 (.284–1.900).52Diseased segment(s) Ileum and colon24751.01%—— Ileum only1806.78%.766 (.397–1.477).43.891 (.449–1.768).74 Colon only1767.74%.726 (.371–1.424).35.866 (.419–1.789).70 Unknown242.41%.407 (.055–3.014).38.698 (.082–5.927).74Years between diagnosis and enrollment Mean ± SD11 ± 10.219 ± 15.71.062 (1.040–1.084)<.0011.030 (1.008–1.052).006Severity at baseline Remission1535.65%—— Mild3081.71%1.097 (.518–2.322).811.266 (.562–2.852).57 Moderate/severe13981.29%1.989 (.915–4.324).0832.256 (.900–5.653).083 Unknown2761.09%1.676 (.458–6.128).443.223 (.776–13.387).11Infliximab No3111.80%—— Yes3179.88%1.097 (.638–1.885).741.015 (.531–1.942).96Prednisone No3894.59%—— Yes23961.25%2.134 (1.237–3.683).0072.096 (1.147–3.832).016Immunomodulators No25261.03%—— Yes3764.72%.695 (.404–1.193).19.731 (.398–1.340).31Narcotic analgesics No5085.73%—— Yes12051.33%1.836 (1.018–3.312).0441.787 (.946–3.379).074a Data representing patient status between registration and June 30, 2004, were used in the logistic regression analysis because this is the timeframe for which there is complete information or medication usage. Two patients died after June 30, 2004.b P value from Wald χ2 test.c OR reported as OR per year increase in age. Open table in a new tab Among the 6253 patients who had adequate follow-up data for this analysis, 106 patients (1.70%) had a serious infection. Without adjusting for other factors, the rate of serious infections for the 69 patients who had received infliximab was significantly higher than that of 37 patients who were not treated with infliximab (1.37 per 100 patient-years vs .65; RR [95% CI], 2.15 [1.442–3.210]; P < .001). Without adjustment for other factors, there was a significantly higher rate of serious infection within 3 mon

Background & AimsIn the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergo remission, and have mucosal healing. We investigated the association between early improvement (based on endoscopy) and subsequent clinical outcome.MethodsPatients underwent endoscopic evaluations at weeks 0, 8, 30, and 54 (ACT-1 only), and were categorized into 4 subgroups by week 8 (Mayo endoscopy subscore, 0–3). The association of week 8 endoscopy subscores, subsequent colectomy risk, symptoms and corticosteroid use outcomes were analyzed. Mucosal healing was defined as a Mayo endoscopy subscore of 0 (normal) or 1 (mild).ResultsInfliximab-treated patients with lower week 8 endoscopy subscores were less likely to progress to colectomy through 54 weeks of follow-up evaluation (P = .0004). This trend was not observed among patients given placebo (P = .47). Patients with lower endoscopy subscores achieved better symptomatic and corticosteroid use outcomes at weeks 30 and 54 (P < .0001, infliximab; P < .01, placebo). Among patients who achieved clinical response at week 8, trends in subsequent clinical outcomes by week 8 endoscopy subscores were generally consistent with that for the overall patient population; no trends were observed among patients who achieved clinical remission.ConclusionsThe degree of mucosal healing after 8 weeks of infliximab was correlated with improved clinical outcomes including colectomy. Similar trends were observed for all outcomes except colectomy among the subgroup with clinical response at week 8. The degree of mucosal healing at week 8 among those in clinical remission did not predict subsequent disease course. In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergo remission, and have mucosal healing. We investigated the association between early improvement (based on endoscopy) and subsequent clinical outcome. Patients underwent endoscopic evaluations at weeks 0, 8, 30, and 54 (ACT-1 only), and were categorized into 4 subgroups by week 8 (Mayo endoscopy subscore, 0–3). The association of week 8 endoscopy subscores, subsequent colectomy risk, symptoms and corticosteroid use outcomes were analyzed. Mucosal healing was defined as a Mayo endoscopy subscore of 0 (normal) or 1 (mild). Infliximab-treated patients with lower week 8 endoscopy subscores were less likely to progress to colectomy through 54 weeks of follow-up evaluation (P = .0004). This trend was not observed among patients given placebo (P = .47). Patients with lower endoscopy subscores achieved better symptomatic and corticosteroid use outcomes at weeks 30 and 54 (P < .0001, infliximab; P < .01, placebo). Among patients who achieved clinical response at week 8, trends in subsequent clinical outcomes by week 8 endoscopy subscores were generally consistent with that for the overall patient population; no trends were observed among patients who achieved clinical remission. The degree of mucosal healing after 8 weeks of infliximab was correlated with improved clinical outcomes including colectomy. Similar trends were observed for all outcomes except colectomy among the subgroup with clinical response at week 8. The degree of mucosal healing at week 8 among those in clinical remission did not predict subsequent disease course.

Little is known about the efficacy of golimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF) -α, for treatment of ulcerative colitis (UC). We evaluated subcutaneous golimumab induction therapy in TNF-α antagonist-naïve patients with moderate-to-severe UC despite conventional treatment.We integrated double-blind phase 2 dose-finding and phase 3 dose-confirmation trials in a study of 1064 adults with UC (Mayo score: 6-12; endoscopic subscore ≥ 2; 774 patients in phase 3). Patients were randomly assigned to groups given golimumab doses of 100 mg and then 50 mg (phase 2 only), 200 mg and then 100 mg, or 400 mg and then 200 mg, 2 weeks apart. The phase 3 primary end point was week-6 clinical response. Secondary end points included week-6 clinical remission, mucosal healing, and Inflammatory Bowel Disease Questionnaire (IBDQ) score change.In phase 2, median changes from baseline in the Mayo score were -1.0, -3.0, -2.0, and -3.0, in the groups given placebo, 100 mg/50 mg, 200/100 mg, and 400/200 mg golimumab, respectively. In phase 3, rates of clinical response at week 6 were 51.0% and 54.9% among patients given 200 mg/100 mg and 400 mg/200 mg golimumab, respectively, vs 30.3% among those given placebo (both, P ≤ .0001). Rates of clinical remission and mucosal healing and mean changes in IBDQ scores were significantly greater in both golimumab groups vs the placebo group (P ≤ .0014, all comparisons). Rates of serious adverse events were 6.1% and 3.0%, and rates of serious infection were 1.8% and 0.5%, in the placebo and golimumab groups, respectively. One patient in the 400 mg/200 mg group died as a result of surgical complications of an ischiorectal abscess.Treatment with subcutaneous golimumab induces clinical response, remission, and mucosal healing, and increases quality of life in larger percentages of patients with active UC than placebo. ClinicalTrials.gov Number: NCT00487539.

See commentary on page 462. See commentary on page 462. Patients with ulcerative colitis or Crohn’s colitis have an increased risk of colorectal cancer (CRC). Most cases are believed to arise from dysplasia, and surveillance colonoscopy therefore is recommended to detect dysplasia. Detection of dysplasia traditionally has relied on both examination of the mucosa with targeted biopsies of visible lesions and extensive random biopsies to identify invisible dysplasia. Current U.S. guidelines recommend obtaining at least 32 random biopsy specimens from all segments of the colon as the foundation of endoscopic surveillance.1Farraye F.A. Odze R.D. Eaden J. et al.AGA Medical Position Statement on the Diagnosis and Management of Neoplasia in Inflammatory Bowel Disease.Gastroenterology. 2010; 138: 738-745Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar, 2Farraye F.A. Odze R.D. Eaden J. et al.AGA Technical Review on the diagnosis and management of colorectal dysplasia in inflammatory bowel disease.Gastroenterology. 2010; 138: 746-774Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar, 3Leighton J.A. Shen B. Baron T.H. et al.ASGE Guidelines: endoscopy in the diagnosis and treatment of inflammatory bowel disease.Gastrointest Endosc. 2006; 63: 558-565Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Itzkowitz S.H. Present D.H. Crohn's and Colitis Foundation of America Colon Cancer in IBD Study GroupConsensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease.Inflamm Bowel Dis. 2005; 11: 314-321Crossref PubMed Scopus (518) Google Scholar However, much of the evidence that provides a basis for these recommendations is from older literature, when most dysplasia was diagnosed on random biopsies of colon mucosa.5Bernstein C.N. Shanahan F. Weinstein W.M. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis?.Lancet. 1994; 343: 71-74Abstract PubMed Scopus (521) Google Scholar With the advent of video endoscopy and newer endoscopic technologies, investigators now report that most dysplasia discovered in patients with inflammatory bowel disease (IBD) is visible.6Rutter M.D. Saunders B.P. Wilkinson K.H. et al.Most dysplasia in ulcerative colitis is visible at colonoscopy.Gastrointest Endosc. 2004; 6: 334-339Abstract Full Text Full Text PDF Scopus (248) Google Scholar, 7Rubin D.T. Rothe J.A. Hetzel J.T. et al.Are dysplasia and colorectal cancer endoscopically visible in patients with ulcerative colitis?.Gastrointest Endosc. 2007; 65: 998-1004Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar Such a paradigm shift may have important implications for the surveillance and management of dysplasia. The evolving evidence regarding newer endoscopic methods to detect dysplasia has resulted in variation among guideline recommendations from organizations around the world.1Farraye F.A. Odze R.D. Eaden J. et al.AGA Medical Position Statement on the Diagnosis and Management of Neoplasia in Inflammatory Bowel Disease.Gastroenterology. 2010; 138: 738-745Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar, 2Farraye F.A. Odze R.D. Eaden J. et al.AGA Technical Review on the diagnosis and management of colorectal dysplasia in inflammatory bowel disease.Gastroenterology. 2010; 138: 746-774Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar, 3Leighton J.A. Shen B. Baron T.H. et al.ASGE Guidelines: endoscopy in the diagnosis and treatment of inflammatory bowel disease.Gastrointest Endosc. 2006; 63: 558-565Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Itzkowitz S.H. Present D.H. Crohn's and Colitis Foundation of America Colon Cancer in IBD Study GroupConsensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease.Inflamm Bowel Dis. 2005; 11: 314-321Crossref PubMed Scopus (518) Google Scholar, 8Van Assche G. Dignass A. Bokemeyer B. et al.Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations.J Crohns Colitis. 2013; 7: 1-33Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 9Cairns S.R. Scholefield J.H. Steele R.J. et al.Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002).Gut. 2010; 59: 666-689Crossref PubMed Scopus (895) Google Scholar, 10Cancer Council Australia Colonoscopy Surveillance Working PartyClinical Practice Guidelines for Surveillance Colonoscopy—in adenoma follow-up; following curative resection of colorectal cancer; and for cancer surveillance in inflammatory bowel disease. Cancer Council Australia, Sydney2011Google Scholar We therefore sought to develop unifying consensus recommendations addressing 2 issues: (1) How should surveillance colonoscopy for detection of dysplasia be performed? (2) How should dysplasia identified at colonoscopy be managed? An international multidisciplinary group representing a wide spectrum of stakeholders and attitudes regarding IBD surveillance (Appendix 1, available online at www.giejournal.org) developed these recommendations following a process that adhered to suggested standards for guideline development from the Institute of Medicine and others and that incorporated the GRADE methodology.11Graham R. Mancher M. Wolman D.M. et al.Clinical Practice Guidelines We Can Trust. National Academy of Sciences, Washington, DC2011Crossref Google Scholar, 12Woolf S.H. Schunemann H.J. Eccles M.P. et al.Developing Clinical Practice Guidelines: types of evidence and outcomes; values and economics, synthesis, grading, and presentation and deriving recommendations.Implementation Sci. 2012; 7: 1-12Crossref Scopus (164) Google Scholar, 13Guyatt G.H. Oxman A.D. Vist G.E. et al.GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.BMJ. 2008; 336: 924-926Crossref PubMed Google Scholar, 14Schunemann H.J. Wiercioch W. Etxeandia I. et al.Guidelines 2.0: systematic development of a comprehensive checklist for a successful guideline enterprise.CMAJ. 2014; 186: E123-E142Crossref PubMed Scopus (391) Google Scholar Details regarding the development process are provided in Figure 1 and Appendix 2. A systematic review was performed for each focused clinical question. The search strategy is shown in Appendix 3, and the full synthesis of evidence reviewed by panelists is presented in Appendix 4. All appendices are available online at www.giejournal.org. The strength of recommendation, provided for each recommendation, reflects the level of confidence that desirable effects of an intervention outweigh undesirable effects. Strong recommendations mean panelists are confident that the desirable effects outweigh the undesirable effects; therefore, most informed patients would choose the recommended management, and clinicians would provide the intervention to most patients. Conditional recommendations mean the desirable and undesirable effects of the intervention are closely balanced or appreciable uncertainty exists regarding the balance; therefore, informed patients’ choices will vary according to their values and preferences, with many not wanting the intervention, and clinicians must ensure that patients’ care is in keeping with their values and preferences.13Guyatt G.H. Oxman A.D. Vist G.E. et al.GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.BMJ. 2008; 336: 924-926Crossref PubMed Google Scholar A subgroup of panelists developed a set of terms for colonoscopic findings in IBD surveillance to establish uniformity in communication. Descriptive phrases, modified from the Paris Classification,15The Paris classification of superficial neoplastic lesions: esophagus, stomach, and colon.Gastrointest Endosc. 2003; 58: S3-S43Abstract Full Text Full Text PDF PubMed Scopus (1774) Google Scholar were recommended for adoption (Table 1). Modifications included the addition of terms for ulceration and border of the lesion. It was agreed that the terms dysplasia-associated lesion or mass (DALM), adenoma-like, and non-adenoma-like should be abandoned. The term endoscopically resectable indicates that (1) distinct margins of the lesion could be identified, (2) the lesion appears to be completely removed on visual inspection after endoscopic resection, (3) histologic examination of the resected specimen is consistent with complete removal, and (4) biopsy specimens taken from mucosa immediately adjacent to the resection site are free of dysplasia on histologic examination.Table 1Terminology for Reporting Findings on Colonoscopic Surveillance of Patients With Inflammatory Bowel Disease (modified from Paris Classification15The Paris classification of superficial neoplastic lesions: esophagus, stomach, and colon.Gastrointest Endosc. 2003; 58: S3-S43Abstract Full Text Full Text PDF PubMed Scopus (1774) Google Scholar)TermDefinitionVisible dysplasiaDysplasia identified on targeted biopsies from a lesion visualized at colonoscopy PolypoidLesion protruding from the mucosa into the lumen ≥2.5 mmPedunculatedLesion attached to the mucosa by a stalkSessileLesion not attached to the mucosa by a stalk: entire base is contiguous with the mucosa NonpolypoidLesion with little (<2.5 mm) or no protrusion above the mucosaSuperficial elevatedLesion with protrusion but <2.5 mm above the lumen (less than the height of the closed cup of a biopsy forceps)FlatLesion without protrusion above the mucosaDepressedLesion with at least a portion depressed below the level of the mucosa General descriptorsUlceratedUlceration (fibrinous-appearing base with depth) within the lesionBorder Distinct borderLesion’s border is discrete and can be distinguished from surrounding mucosa Indistinct borderLesion’s border is not discrete and cannot be distinguished from surrounding mucosaInvisible dysplasiaDysplasia identified on random (non-targeted) biopsies of colon mucosa without a visible lesion Open table in a new tab The goal of this section is to define the optimal method(s) of detecting colon dysplasia in patients with IBD. Detection of dysplasia, which is the immediate goal of surveillance colonoscopy, was chosen as the primary endpoint, with the understanding that detection of dysplasia is not clearly documented to improve clinical outcomes such as CRC incidence or mortality. Only histologic diagnoses of low-grade or high-grade dysplasia were considered; diagnoses of indefinite for dysplasia were excluded. Current guideline recommendations regarding the need for serial surveillance colonoscopy in patients with IBD were accepted, and other issues such as the appropriate surveillance interval or risk stratification1Farraye F.A. Odze R.D. Eaden J. et al.AGA Medical Position Statement on the Diagnosis and Management of Neoplasia in Inflammatory Bowel Disease.Gastroenterology. 2010; 138: 738-745Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar, 2Farraye F.A. Odze R.D. Eaden J. et al.AGA Technical Review on the diagnosis and management of colorectal dysplasia in inflammatory bowel disease.Gastroenterology. 2010; 138: 746-774Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar, 3Leighton J.A. Shen B. Baron T.H. et al.ASGE Guidelines: endoscopy in the diagnosis and treatment of inflammatory bowel disease.Gastrointest Endosc. 2006; 63: 558-565Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Itzkowitz S.H. Present D.H. Crohn's and Colitis Foundation of America Colon Cancer in IBD Study GroupConsensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease.Inflamm Bowel Dis. 2005; 11: 314-321Crossref PubMed Scopus (518) Google Scholar, 8Van Assche G. Dignass A. Bokemeyer B. et al.Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations.J Crohns Colitis. 2013; 7: 1-33Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 9Cairns S.R. Scholefield J.H. Steele R.J. et al.Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002).Gut. 2010; 59: 666-689Crossref PubMed Scopus (895) Google Scholar, 10Cancer Council Australia Colonoscopy Surveillance Working PartyClinical Practice Guidelines for Surveillance Colonoscopy—in adenoma follow-up; following curative resection of colorectal cancer; and for cancer surveillance in inflammatory bowel disease. Cancer Council Australia, Sydney2011Google Scholar were not addressed. Recommendations are listed in Table 2 and appear individually hereafter with the proportion of panelists in agreement, the strength of the recommendation, and the quality of evidence. A summary of the evidence and discussion regarding the recommendation follows each statement.Table 2Summary of Recommendations for Surveillance and Management of Dysplasia in Patients With Inflammatory Bowel DiseaseDetection of dysplasia on surveillance colonoscopy1.When performing surveillance with white-light colonoscopy, high definition is recommended rather than standard definition (strong recommendation, low-quality evidence).2.When performing surveillance with standard-definition colonoscopy, chromoendoscopy is recommended rather than white-light colonoscopy (strong recommendation, moderate-quality evidence).3.When performing surveillance with high-definition colonoscopy, chromoendoscopy is suggested rather than white-light colonoscopy (conditional recommendation, low-quality evidence).4.When performing surveillance with standard-definition colonoscopy, narrow-band imaging is not suggested in place of white-light colonoscopy (conditional recommendation, low-quality evidence).5.When performing surveillance with high-definition colonoscopy, narrow-band imaging is not suggested in place of white-light colonoscopy (conditional recommendation, moderate-quality evidence).6.When performing surveillance with image-enhanced high-definition colonoscopy, narrow-band imaging is not suggested in place of chromoendoscopy (conditional recommendation, moderate-quality evidence).Management of dysplasia discovered on surveillance colonoscopy7.After complete removal of endoscopically resectable polypoid dysplastic lesions, surveillance colonoscopy is recommended rather than colectomy (strong recommendation, very low-quality evidence).8.After complete removal of endoscopically resectable nonpolypoid dysplastic lesions, surveillance colonoscopy is suggested rather than colectomy (conditional recommendation, very low-quality evidence).9.For patients with endoscopically invisible dysplasia (confirmed by a GI pathologist) referral is suggested to an endoscopist with expertise in IBD surveillance using chromoendoscopy with high-definition colonoscopy (conditional recommendation, very low-quality evidence). Open table in a new tab Statement 1: When performing surveillance with white-light colonoscopy, high definition is recommended rather than standard definition. (80% agreement; strong recommendation; low-quality evidence) High-definition (1080 system) endoscopy provides image signals of higher pixel density than standard definition (480 system), with faster line scanning on high-definition monitors, leading to sharper images with fewer artifacts.16Subramanian V. Ragunath K. Advanced endoscopic imaging: a review of commercially available technologies.Clin Gastroenterol Hepatol. 2014; 12: 368-376Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar A high-definition system includes a high-definition endoscope, processor, cabling, and monitor. A retrospective observational study found that dysplasia was discovered in approximately twice as many patients undergoing high-definition colonoscopy (n = 203) compared with a cohort undergoing standard-definition colonoscopy (n = 154): adjusted prevalence ratio = 2.2 (95% confidence interval [CI], 1.1-4.5).17Subramanian V. Ramappa V. Telakis E. et al.Comparison of high definition with standard white light endoscopy for detection of dysplastic lesions during surveillance colonoscopy in patients with colonic inflammatory bowel disease.Inflamm Bowel Dis. 2013; 19: 350-355Crossref PubMed Scopus (87) Google Scholar Given that most dysplastic lesions are visible,6Rutter M.D. Saunders B.P. Wilkinson K.H. et al.Most dysplasia in ulcerative colitis is visible at colonoscopy.Gastrointest Endosc. 2004; 6: 334-339Abstract Full Text Full Text PDF Scopus (248) Google Scholar, 7Rubin D.T. Rothe J.A. Hetzel J.T. et al.Are dysplasia and colorectal cancer endoscopically visible in patients with ulcerative colitis?.Gastrointest Endosc. 2007; 65: 998-1004Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar the improved visualization and lack of negative effects with high-definition endoscopy justified a strong recommendation for its use. In addition, patients likely would strongly desire high-definition colonoscopy because of the belief that visualization and examination are improved. The cost of purchasing new high-definition endoscopic equipment is a consideration. However, high-definition colonoscopy already is widely used in endoscopic units. Statement 2: When performing surveillance with standard-definition colonoscopy, chromoendoscopy is recommended rather than white-light colonoscopy. (85% agreement; strong recommendation; moderate-quality evidence) Chromoendoscopy involves the application of dye to the colon mucosa, thereby providing contrast enhancement to improve visualization of epithelial surface detail. Methylene blue and indigo carmine, the agents most commonly used, are applied to the colon mucosa via a catheter or the colonoscope biopsy or water jet channel,18Soetikno R. Subramanian V. Kaltenbach T. et al.The detection of nonpolypoid (flat and depressed) colorectal neoplasms in patients with inflammatory bowel disease.Gastroenterology. 2013; 144: 1349-1352.e6Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar and accentuate the changes in epithelial surface topography.19Kaltenbach T. Sano Y. Friedland S. et al.American Gastroenterological Association (AGA) Institute Technology Assessment on Image Enhanced Endoscopy.Gastroenterology. 2008; 134: 327-340Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar We identified 8 trials that used standard-definition colonoscopy and compared chromoendoscopy with white-light colonoscopy alone (Table 3).20Kiesslich R. Fritsch J. Holtmann M. et al.Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.Gastroenterology. 2003; 124: 880-888Abstract Full Text Full Text PDF PubMed Scopus (761) Google Scholar, 21Kiesslich R. Goetz M. Lammersdorf K. et al.Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis.Gastroenterology. 2007; 132: 874-882Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar, 22Chiorean M.V. Helper D.J. Saxena R. et al.Targeted biopsies using chromoendoscopy can replace random biopsies in patients with IBD at high risk for colorectal neoplasia.Gastroenterology. 2012; 142: S339Abstract Full Text PDF Google Scholar, 23Rutter M.D. Saunders B.P. Schofield G. et al.Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis.Gut. 2004; 53: 256-260Crossref PubMed Scopus (495) Google Scholar, 24Marion J.F. Waye J.D. Present D.H. et al.Chromoendoscopy-targeted biopsies are superior to standard colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial.Am J Gastroenterol. 2008; 103: 2342-2349Crossref PubMed Scopus (246) Google Scholar, 25Matsumoto T. Nakamura S. Jo Y. et al.Chromoscopy might improve diagnostic accuracy in cancer surveillance for ulcerative colitis.Am J Gastroenterol. 2003; 98: 1827-1833Crossref PubMed Scopus (106) Google Scholar, 26Hlavaty T. Huorka M. Koller T. et al.Colorectal cancer screening in patients with ulcerative and Crohn's colitis with use of colonoscopy, chromoendoscopy and confocal endomicroscopy.Eur J Gastroenterol Hepatol. 2011; 23: 680-689Crossref PubMed Scopus (71) Google Scholar, 27Gunther U. Kusch D. Heller F. et al.Surveillance colonoscopy in patients with inflammatory bowel disease: Comparison of random biopsy vs. targeted biopsy protocols International.J Colorectal Dis. 2011; 26: 667-672Crossref PubMed Scopus (0) Google Scholar The proportion of patients with dysplasia was 0% to 10% greater with chromoendoscopy in the individual studies, but the difference was not significant in any study. Meta-analysis revealed a significantly greater proportion of patients with dysplasia by using chromoendoscopy (relative risk [RR] = 1.8 [1.2-2.6] and absolute risk increase = 6% [3%-9%]). Meta-analysis of the 2 randomized, parallel-group trials also confirmed a significant increase with chromoendoscopy in the proportion of patients with dysplasia (RR = 2.3 [1.1-4.6], absolute increase = 8% [2%-15%]). The number of dysplastic lesions identified was greater with chromoendoscopy in all studies (Table 3), and in the 4 tandem studies in which all patients had both chromoendoscopy and white-light examination, the number of dysplastic areas discovered increased almost 2-fold (RR = 1.9, 1.4-2.7) with chromoendoscopy. Chromoendoscopy significantly increased the duration of colonoscopy by a mean of 11 minutes (range 9-12 minutes).Table 3Proportion of Patients With Dysplasia and Number of Visible Dysplastic Lesions Identified in Studies Comparing Chromoendoscopy Versus White-Light ColonoscopyStudyStudy typePatients with dysplasia/all patientsRR (95% CI)Absolute risk increase (95% CI)No. of visible dysplastic lesionsChromoendoscopyWhite-lightChromoendoscopyWhite-lightKiesslich20Kiesslich R. Fritsch J. Holtmann M. et al.Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis.Gastroenterology. 2003; 124: 880-888Abstract Full Text Full Text PDF PubMed Scopus (761) Google ScholarRandomized parallel-group13/846/812.1 (0.8-5.2)8% (-2% to 18%)3210Kiesslich21Kiesslich R. Goetz M. Lammersdorf K. et al.Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis.Gastroenterology. 2007; 132: 874-882Abstract Full Text Full Text PDF PubMed Scopus (460) Google ScholarRandomized parallel-group11/804/732.5 (0.8-7.5)8% (-1% to 17%)192Marion24Marion J.F. Waye J.D. Present D.H. et al.Chromoendoscopy-targeted biopsies are superior to standard colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial.Am J Gastroenterol. 2008; 103: 2342-2349Crossref PubMed Scopus (246) Google ScholarProspective tandem22/10212/1021.8 (0.96-3.5)10% (0% to 20%)3513Rutter23Rutter M.D. Saunders B.P. Schofield G. et al.Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis.Gut. 2004; 53: 256-260Crossref PubMed Scopus (495) Google ScholarProspective tandem7/1002/1003.5 (0.8-16.4)5% (-1% to 11%)92Matsumoto25Matsumoto T. Nakamura S. Jo Y. et al.Chromoscopy might improve diagnostic accuracy in cancer surveillance for ulcerative colitis.Am J Gastroenterol. 2003; 98: 1827-1833Crossref PubMed Scopus (106) Google ScholarProspective tandem12/5712/571.0 (0.5-2.0)0% (-2% to 2%)188Hlvaty26Hlavaty T. Huorka M. Koller T. et al.Colorectal cancer screening in patients with ulcerative and Crohn's colitis with use of colonoscopy, chromoendoscopy and confocal endomicroscopy.Eur J Gastroenterol Hepatol. 2011; 23: 680-689Crossref PubMed Scopus (71) Google ScholarProspective tandem and additional cohort4/302/453.0 (0.6-15.4)9% (-5% to 23%)62Gunther27Gunther U. Kusch D. Heller F. et al.Surveillance colonoscopy in patients with inflammatory bowel disease: Comparison of random biopsy vs. targeted biopsy protocols International.J Colorectal Dis. 2011; 26: 667-672Crossref PubMed Scopus (0) Google ScholarRetrospective two-group2/500/505.0 (0.3-101.6)4% (-3% to 11%)20Chiorean22Chiorean M.V. Helper D.J. Saxena R. et al.Targeted biopsies using chromoendoscopy can replace random biopsies in patients with IBD at high risk for colorectal neoplasia.Gastroenterology. 2012; 142: S339Abstract Full Text PDF Google ScholarProspective tandemNo per-patient data given (N = 63)4118SCENIC meta-analysis1.8 (1.2-2.6)6% (3%-9%)RR, Relative risk; CI, confidence interval; SCENIC, Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations. Open table in a new tab RR, Relative risk; CI, confidence interval; SCENIC, Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations. An economic analysis concluded that chromoendoscopy with targeted biopsies was less costly and more effective than white-light colonoscopy with random biopsies,28Konijeti GG, Shrime MG, Ananthakrishnan A, et al. Cost-effectiveness analysis of chromoendoscopy for colorectal cancer surveillance in patients with ulcerative colitis. Gastrointest Endosc. Epub 2013 Nov 18.Google Scholar suggesting that chromoendoscopy should be used in place of white-light endoscopy when surveillance colonoscopy is performed. The cost-effectiveness of chromoendoscopy increased with increasing surveillance interval, suggesting that varying the surveillance interval based on the risk of CRC may be appropriate and could increase the cost effectiveness of surveillance colonoscopy. However, when surveillance is performed, even if performed less frequently than currently recommended in lower-risk patients, the best technique should be used. Although chromoendoscopy increases the yield of dysplasia compared with standard-definition white-light colonoscopy, whether the additional lesions identified with chromoendoscopy are associated with the same increased risk for CRC as the visible and invisible dysplasia identified in older studies is not known. Data from the Surveillance, Epidemiology and End-Results Medicare-linked database of patients ≥67 years old revealed that interval cancers 6 to 36 months after colonoscopy occurred in a much higher proportion of patients with IBD (15.1% with Crohn’s disease and 15.8% with ulcerative colitis) than patients without IBD (5.8%),29Wang Y.R. Cangemi J.R. Loftus Jr., E.V. et al.Rate of early/missed colorectal cancers after colonoscopy in older patients with or without inflammatory bowel disease in the United States.Am J Gastroenterol. 2013; 108: 444-449Crossref PubMed Scopus (61) Google Scholar suggesting that clinically relevant areas of neoplasia may be missed with current colonoscopic surveillance. Potential barriers to use of chromoendoscopy also were considered. These include the additional preparation and time required for chromoendoscopy, need to train endoscopists in this technique, need to develop quality measures and assess performance after training, procedure-related costs, and barriers to reimbursement (eg, lack of procedure code for chromoendoscopy in the United States). These issues were discussed in detail by a subgroup of the panel, and their report will appear in a separate publication. Statement 3: When performing surveillance with high-definition colonoscopy, chromoendoscopy is suggested rather than white-light colonoscopy. (84% agreement; conditional recommendation; low-quality evidence) A prospective, tandem study that used high-definition colonoscopy in 75 patients with IBD found that dysplasia was identified in significantly more patients undergoing chromoendoscopy than white-light colonoscopy alone: 16 (21%) versus 7 (9%); P = .007.30Picco M.F. Pasha S. Leighton J.A. et al.Procedure time and the determination of polypoid abnormalities with experience: implementation of a chromoendoscopy program for surveillance colonoscopy for ulcerative colitis.Inflamm Bowel Dis. 2013; 19: 1913-1920PubMed Google Scholar Ten dysplastic lesions were identified on the initial white-light examination, and an additional 12 were discovered on the subsequent chromoendoscopic examination. Despite the significant difference in favor of chromoendoscopy, the strength of this recommendation is conditional because of its reliance on only one relatively small observational study whose primary aim was to assess chromoendoscopy training and performance. Statement 4: When performing surveillance with standard-definition colonoscopy, narrow-band imaging (NBI) is not suggested in place of white-light colonoscopy. (84% agreement; conditional recommendation; low-quality evidence) Currently available endoscope-based image-enhancement technologies include NBI (Olympus, Tokyo, Japan), i-scan (Pentax, Tokyo, Japan), and Fuji Intelligent Chromo Endoscopy (Fujinon, Tokyo, Japan).16Subramanian V. Ragunath K. Advanced endoscopic imaging: a review of commercially available technologies.Clin Gastroenterol Hepatol. 2014; 12: 368-376Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar NBI, which uses filters to provide narrow bands of blue and green light wavelengths,16Subramanian V. Ragunath K. Advanced endoscopic imaging: a review of commercially available technologies.Clin Gastroenterol Hepatol. 2014; 12: 368-376Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar is the only one of these technologies that has been studied in IBD surveillance and thus the only one considered in this recommendation. A randomized, crossover study of 42 patients found no significant difference between NBI and standard-definition whi

Background & Aims: Interleukin-12 and interleukin-23 are inflammatory cytokines implicated in Crohn's disease pathophysiology. Ustekinumab is a monoclonal antibody against the p40 subunit of interleukin-12/23. Methods: We performed a double-blind, cross-over trial of the clinical effects of ustekinumab in 104 patients with moderate-to-severe Crohn's disease (population 1). Patients were given subcutaneous placebo at weeks 0–3, then ustekinumab at weeks 8–11; subcutaneous ustekinumab at weeks 0–3, then placebo at weeks 8–11; intravenous placebo at week 0, then ustekinumab at week 8; or intravenous ustekinumab at week 0, then placebo at week 8. Furthermore, an open-label trial evaluated the effects of 4 weekly subcutaneous injections or 1 intravenous infusion of ustekinumab in 27 patients who were primary or secondary nonresponders to infliximab (population 2). Results: In population 1, clinical response rates for the combined groups given ustekinumab and placebo were 53% and 30% (P = .02), respectively at weeks 4 and 6, and 49% and 40% (P = .34), respectively at week 8. In a subgroup of 49 patients who were previously given infliximab (neither primary nor secondary nonresponders), clinical response to ustekinumab was significantly greater than the group given placebo (P < .05) through week 8. In population 2, the clinical responses at week 8 to subcutaneous and intravenous ustekinumab were 43% and 54%, respectively. There was no increase in the number of adverse or serious adverse events in patients given ustekinumab through week 8 compared with placebo. Conclusions: Ustekinumab induced a clinical response in patients with moderate-to-severe Crohn's disease, especially in patients previously given infliximab. Background & Aims: Interleukin-12 and interleukin-23 are inflammatory cytokines implicated in Crohn's disease pathophysiology. Ustekinumab is a monoclonal antibody against the p40 subunit of interleukin-12/23. Methods: We performed a double-blind, cross-over trial of the clinical effects of ustekinumab in 104 patients with moderate-to-severe Crohn's disease (population 1). Patients were given subcutaneous placebo at weeks 0–3, then ustekinumab at weeks 8–11; subcutaneous ustekinumab at weeks 0–3, then placebo at weeks 8–11; intravenous placebo at week 0, then ustekinumab at week 8; or intravenous ustekinumab at week 0, then placebo at week 8. Furthermore, an open-label trial evaluated the effects of 4 weekly subcutaneous injections or 1 intravenous infusion of ustekinumab in 27 patients who were primary or secondary nonresponders to infliximab (population 2). Results: In population 1, clinical response rates for the combined groups given ustekinumab and placebo were 53% and 30% (P = .02), respectively at weeks 4 and 6, and 49% and 40% (P = .34), respectively at week 8. In a subgroup of 49 patients who were previously given infliximab (neither primary nor secondary nonresponders), clinical response to ustekinumab was significantly greater than the group given placebo (P < .05) through week 8. In population 2, the clinical responses at week 8 to subcutaneous and intravenous ustekinumab were 43% and 54%, respectively. There was no increase in the number of adverse or serious adverse events in patients given ustekinumab through week 8 compared with placebo. Conclusions: Ustekinumab induced a clinical response in patients with moderate-to-severe Crohn's disease, especially in patients previously given infliximab. See Maser EA et al on page 1112 in CGH. See Maser EA et al on page 1112 in CGH. Conventional therapy for moderate-to-severe Crohn's disease includes corticosteroids and immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate.1Hanauer S.B. Sandborn W. The Practice Parameters Committee of the American College of Gastroenterology Management of Crohn's disease in adults.Am J Gastroenterol. 2001; 96: 635-643Crossref PubMed Google Scholar, 2Travis S.P. Stange E.F. Lemann M. et al.European evidence based consensus on the diagnosis and management of Crohn's disease: current management.Gut. 2006; 55: i16-i35Crossref PubMed Scopus (602) Google Scholar Patients who fail to respond to conventional therapies are treated with anti–tumor necrosis factor (TNF) antibodies.1Hanauer S.B. Sandborn W. The Practice Parameters Committee of the American College of Gastroenterology Management of Crohn's disease in adults.Am J Gastroenterol. 2001; 96: 635-643Crossref PubMed Google Scholar, 2Travis S.P. Stange E.F. Lemann M. et al.European evidence based consensus on the diagnosis and management of Crohn's disease: current management.Gut. 2006; 55: i16-i35Crossref PubMed Scopus (602) Google Scholar Approximately one third of anti-TNF–naive patients experience primary nonresponse to anti-TNF therapy.3Targan S.R. Hanauer S.B. van Deventer S.J. 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: 1029-1035Crossref PubMed Scopus (3075) Google Scholar, 4Hanauer S.B. Feagan B.G. Lichtenstein G.R. et al.Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3629) Google Scholar, 5Hanauer S.B. Sandborn W.J. Rutgeerts P. et al.Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC I trial.Gastroenterology. 2006; 130: 323-333Abstract Full Text Full Text PDF PubMed Scopus (1440) Google Scholar, 6Colombel J.F. Sandborn W.J. Rutgeerts P. et al.Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial.Gastroenterology. 2007; 132: 52-65Abstract Full Text Full Text PDF PubMed Scopus (1843) Google Scholar, 7Sandborn W.J. Feagan B.G. Stoinov S. et al.Certolizumab pegol for the treatment of Crohn's disease.N Engl J Med. 2007; 357: 228-238Crossref PubMed Scopus (965) Google Scholar, 8Schreiber S. Khaliq-Kareemi M. Lawrance I. et al.Certolizumab pegol maintenance therapy for Crohn's disease.N Engl J Med. 2007; 357: 239-250Crossref PubMed Scopus (919) Google Scholar Of initial anti-TNF therapy responders, an additional one third subsequently lose response or become intolerant (secondary nonresponse),4Hanauer S.B. Feagan B.G. Lichtenstein G.R. et al.Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3629) Google Scholar, 6Colombel J.F. Sandborn W.J. Rutgeerts P. et al.Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial.Gastroenterology. 2007; 132: 52-65Abstract Full Text Full Text PDF PubMed Scopus (1843) Google Scholar, 8Schreiber S. Khaliq-Kareemi M. Lawrance I. et al.Certolizumab pegol maintenance therapy for Crohn's disease.N Engl J Med. 2007; 357: 239-250Crossref PubMed Scopus (919) Google Scholar requiring dose escalation or switching to another anti-TNF agent.9Rutgeerts P. Feagan B.G. Lichtenstein G.R. et al.Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease.Gastroenterology. 2004; 126: 402-413Abstract Full Text Full Text PDF PubMed Scopus (864) Google Scholar, 10Sandborn W.J. Rutgeerts P. Enns R. et al.Adalimumab induction therapy for Crohn's disease previously treated with infliximab: a randomized trial.Ann Intern Med. 2007; 146: 829-838Crossref PubMed Scopus (863) Google Scholar Anti-TNF therapy response rates among secondary nonresponders who switch within the class are generally lower than those among anti-TNF–naive patients.6Colombel J.F. Sandborn W.J. Rutgeerts P. et al.Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial.Gastroenterology. 2007; 132: 52-65Abstract Full Text Full Text PDF PubMed Scopus (1843) Google Scholar, 8Schreiber S. Khaliq-Kareemi M. Lawrance I. et al.Certolizumab pegol maintenance therapy for Crohn's disease.N Engl J Med. 2007; 357: 239-250Crossref PubMed Scopus (919) Google Scholar, 10Sandborn W.J. Rutgeerts P. Enns R. et al.Adalimumab induction therapy for Crohn's disease previously treated with infliximab: a randomized trial.Ann Intern Med. 2007; 146: 829-838Crossref PubMed Scopus (863) Google Scholar Additional therapeutic options with novel mechanisms of action are needed for moderate-to-severe Crohn's disease, particularly for patients who fail anti-TNF agents. Interleukin-12 and interleukin-23 have been implicated in the pathophysiology of Crohn's disease,11Peluso I. Pallone F. Monteleone G. Interleukin-12 and Th1 immune response in Crohn's disease: pathogenetic relevance and therapeutic implication.World J Gastroenterol. 2006; 12: 5606-5610PubMed Google Scholar, 12Neurath M.F. IL-23: a master regulator in Crohn disease.Nat Med. 2007; 13: 26-28Crossref PubMed Scopus (197) Google Scholar and a recent genome-wide association study found a significant association between Crohn's disease and a gene that encodes a subunit of the receptor for interleukin-23.13Duerr R.H. Taylor K.D. Brant S.R. et al.A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.Science. 2006; 314: 1461-1463Crossref PubMed Scopus (2462) Google Scholar Naive CD4+ T cells differentiate into 4 subsets: T-helper 1 (Th1), Th2, Th17 (Thinterleukin-17), and regulatory T cells. Interleukin-12, a heterodimer of p40 and p35 subunits, induces differentiation of naive CD4+ T cells into Th1 cells,14Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity.Nat Rev Immunol. 2003; 3: 133-146Crossref PubMed Scopus (2975) Google Scholar which produce interferon-γ and mediate cellular immunity. Interleukin-23, a heterodimer of the same p40 subunit and a p19 subunit, induces differentiation of naive CD4+ T cells into Thinterleukin-17 cells,15Iwakura Y. Ishigame H. The IL-23/IL-17 axis in inflammation.J Clin Invest. 2006; 116: 1218-1222Crossref PubMed Scopus (816) Google Scholar, 16Kastelein R.A. Hunter C.A. Cua D.J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation.Annu Rev Immunol. 2007; 25: 221-242Crossref PubMed Scopus (640) Google Scholar which produce interleukin-17, interleukin-17F, interleukin-6, and TNFα to mediate cellular immunity. Monoclonal antibody neutralization of interleukin-12/23 via the shared p40 subunit is effective in treating animal models of colitis.17Neurath M.F. Fuss I. Kelsall B.L. et al.Antibodies to interleukin 12 abrogate established experimental colitis in mice.J Exp Med. 1995; 182: 1281-1290Crossref PubMed Scopus (1196) Google Scholar, 18Elson C.O. Cong Y. Weaver C.T. et al.Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice.Gastroenterology. 2007; 132: 2359-2370Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, 19Becker C. Dornhoff H. Neufert C. et al.Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis.J Immunol. 2006; 177: 2760-2764Crossref PubMed Scopus (198) Google Scholar, 20Yen D. Cheung J. Scheerens H. et al.IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6.J Clin Invest. 2006; 116: 1310-1316Crossref PubMed Scopus (1272) Google Scholar Furthermore, a human immunoglobulin (Ig)G1 monoclonal antibody to the interleukin-12/23 p40 subunit, ABT-874 (J695), was reported to possibly induce clinical response and remission in a phase 2 study of patients with active Crohn's disease.21Mannon P.J. Fuss I.J. Mayer L. et al.Anti-interleukin-12 antibody for active Crohn's disease.N Engl J Med. 2004; 351: 2069-2079Crossref PubMed Scopus (750) Google Scholar Further research is needed to elucidate the role of interleukin-12 and interleukin-23 in other pathogenic disease processes and to determine whether the common p40 subunit has biologic activities that are separate and distinct from the p35 and p19 subunits of the respective cytokines either as heterodimers or monomers. Ustekinumab is a fully human IgG1 monoclonal antibody that targets the interleukin 12/23 shared p40 subunit. Anti–interleukin-12/23 therapy with ustekinumab has shown efficacy in psoriasis22Leonardi C.L. Kimball A.B. Papp K.A. et al.Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1).Lancet. 2008; 371: 1665-1674Abstract Full Text Full Text PDF PubMed Scopus (1400) Google Scholar, 23Papp K.A. Langley R.G. Lobwohl M. et al.Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 2).Lancet. 2008; 371: 1675-1684Abstract Full Text Full Text PDF PubMed Scopus (1255) Google Scholar, 24Krueger G.G. Langley R.G. Leonardi C. et al.A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis.N Engl J Med. 2007; 356: 580-592Crossref PubMed Scopus (702) Google Scholar and has been evaluated in multiple sclerosis.25Kasper L.H. Everitt D. Leist T.P. et al.A phase I trial of an interleukin-12/23 monoclonal antibody in relapsing multiple sclerosis.Curr Med Res Opin. 2006; 22: 1671-1678Crossref PubMed Scopus (41) Google Scholar Here we report the results of a randomized, placebo-controlled, phase 2a induction trial of ustekinumab in patients with moderate-to-severe Crohn's disease. This trial was conducted between May 2004 and October 2006. The protocol was approved by the institutional review board at each center. All patients gave written informed consent. Eligible patients were adults with moderate-to-severe Crohn's disease of at least 6 weeks' duration and a Crohn's disease activity index (CDAI) score of 220–450 points (range, 0–600 points; greater scores indicate more severe disease).26Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn's disease activity index National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (3035) Google Scholar Crohn's colitis, ileitis, or ileocolitis was confirmed by radiography or endoscopy. Ineligible patients were those testing positive for a tuberculin skin test and patients with short-bowel syndrome, an ostomy, obstructive symptoms with strictures, current or recent opportunistic infection or abscess, cancer, recent treatment with any investigational agent or an anti-TNF agent including infliximab within the past 16 weeks. Concomitant use of 5-aminosalicylates, antibiotics, prednisolone at a maximum daily dose of 20 mg, azathioprine, 6-mercaptopurine, or methotrexate was permitted. Concomitant medication doses remained constant, except corticosteroids, which could be tapered by 2.5 mg/wk after week 8. Two populations were studied. Population 1 had received at least one of the following: 5-aminosalicylates, antibiotics, corticosteroids, azathioprine, 6-mercaptopurine, or methotrexate; submaximal infliximab doses or regimens (ie, only 1–2 induction doses of infliximab 5 mg/kg, or maintenance doses of infliximab 5 mg/kg every 8 weeks without shortening the dosing interval or escalating to infliximab 10 mg/kg, or infliximab intolerance); or other anti-TNFα agents. Population 2 comprised nonresponders to a 3-dose induction of infliximab 5 mg/kg (primary nonresponders) or initial responders who lost response during every-8-week maintenance therapy, despite dose escalation to 10 mg/kg (secondary nonresponders), as determined by the investigator. This was a double-blind, placebo-controlled, parallel-group, cross-over study. Cross-over to the alternate therapy occurred at week 8. Patients were randomly assigned (1:1:1:1) to 1 of 4 groups: subcutaneous placebo at weeks 0, 1, 2, and 3, then 90 mg ustekinumab at weeks 8, 9, 10, and 11; subcutaneous 90 mg ustekinumab at weeks 0, 1, 2, and 3, then placebo at weeks 8, 9, 10, and 11; intravenous placebo at week 0, then 4.5 mg/kg ustekinumab at week 8; or intravenous 4.5 mg/kg ustekinumab at week 0, then placebo at week 8. This was an open-label study. Patients were assigned randomly (1:1) to either subcutaneous 90 mg ustekinumab at weeks 0, 1, 2, and 3, or intravenous 4.5 mg/kg ustekinumab at week 0. No additional treatment was administered at week 8. Randomization in both study populations was performed centrally using an adaptive randomization procedure that was stratified by investigative site. Clinical response was defined as a reduction of at least 25% and 70 points in the CDAI score from week 0.4Hanauer S.B. Feagan B.G. Lichtenstein G.R. et al.Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3629) Google Scholar, 27Sandborn W.J. Feagan B.G. Hanauer S.B. et al.A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease.Gastroenterology. 2002; 122: 512-530Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar Clinical remission was defined as an absolute CDAI score of less than 150 points, and 100-point response was defined as a reduction of at least 100 points from week 0 in the CDAI score.26Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn's disease activity index National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (3035) Google Scholar, 27Sandborn W.J. Feagan B.G. Hanauer S.B. et al.A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease.Gastroenterology. 2002; 122: 512-530Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar Patients in both populations were followed up for safety and efficacy through week 28. Data for CDAI scores were collected from patient diaries; clinical assessments, adverse events, and concomitant medications were recorded; and laboratory tests, including assessment of the C-reactive protein concentration, were performed throughout the study. Blood samples were drawn at weeks 0, 16, 28, and 54 for assessment of antibodies to ustekinumab using an antigen-bridging enzyme immunoassay. The primary end point was clinical response at week 8 in population 1, defined as a reduction of 25% or more and 70 points or more from the baseline CDAI score. Secondary end points included clinical response at weeks 4 and 6, and clinical remission and 100-point response at weeks 4, 6, and 8. Other end points included clinical response, 100-point response, and clinical remission at week 16, a time point 8 weeks after the first dose of ustekinumab in patients who initially had been assigned to placebo from week 0 through week 8. Patients who had a prohibited change in their concomitant Crohn's disease medication, a Crohn's disease–related surgery, or who discontinued study medication for lack of therapeutic effect were considered not to have achieved clinical response, clinical remission, or 100-point response from the time of event onward. Patients with insufficient data to calculate their CDAI score were considered not to have achieved clinical response, clinical remission, or 100-point response at that time point. The intent-to-treat population included all randomized patients. Comparisons between the placebo (subcutaneous and intravenous combined) and ustekinumab (subcutaneous and intravenous combined) groups were made for each end point using a 2-sided, 0.05-level Cochran–Mantel–Haenszel chi-square test, stratified by route of administration. Comparisons of each end point through week 8 by route of administration were made between placebo and ustekinumab using a 2-sided, 0.05-level Fisher's exact test. Prespecified subgroup analyses were as follows: baseline bodyweight (<60 kg, ≥60 to <75 kg, or ≥75 kg); Crohn's disease duration (≤5 y, >5 to ≤15 y, or >15 y); C-reactive protein (<0.6 mg/dL or ≥0.6 mg/dL); and previous use (yes, no) or concomitant use (yes, no) of corticosteroids, 5-aminosalicylate compounds, azathioprine, 6-mercaptopurine, methotrexate, anti-TNF agents, or antibiotics. Odds ratios and corresponding 95% confidence intervals were determined to compare the proportion of patients in clinical response at week 8 in the combined ustekinumab and combined placebo groups. Summaries of adverse events and antibodies to ustekinumab were based on data for all patients who received at least one dose of study medication and were based on the actual treatment received. For the primary end point of clinical response at week 8 in population 1, we planned to recruit 25 patients each into the subcutaneous and intravenous ustekinumab and placebo groups, yielding a total sample size of 100 patients. Combining the subcutaneous and intravenous routes of administration for both the ustekinumab and placebo groups, 100 patients would provide 82% power to detect a difference in clinical response rates of 30% assuming a 70% rate of clinical response for ustekinumab and a 40% rate of clinical response for placebo. No power calculations were performed for population 2. The steering committee of academic investigators and Centocor contributors designed this study. Centocor bioanalytic staff created the clinical database and performed the statistical analyses. All authors interpreted the data, and prepared and approved the report for submission.

Selective blockade of interactions between leukocytes and vascular endothelium in the gut is a promising strategy for the treatment of inflammatory bowel diseases.We conducted a multicenter, double-blind, placebo-controlled trial of MLN02, a humanized antibody to the alpha4beta7 integrin, in patients with active ulcerative colitis. We randomly assigned 181 patients to receive 0.5 mg of MLN02 per kilogram of body weight, 2.0 mg per kilogram, or an identical-appearing placebo intravenously on day 1 and day 29. Eligible patients also received concomitant mesalamine or no other treatment for colitis. Ulcerative colitis clinical scores and sigmoidoscopic assessments were evaluated six weeks after randomization.Clinical remission rates at week 6 were 33 percent, 32 percent, and 14 percent for the group receiving 0.5 mg of MLN02 per kilogram, the group receiving 2.0 mg per kilogram, and the placebo group, respectively (P=0.03). The corresponding proportions of patients who improved by at least 3 points on the ulcerative colitis clinical score were 66 percent, 53 percent, and 33 percent (P=0.002). Twenty-eight percent of patients receiving 0.5 mg per kilogram and 12 percent of those receiving 2.0 mg per kilogram had endoscopically evident remission, as compared with 8 percent of those receiving placebo (P=0.007). For the minority of patients in whom an MLN02 antibody titer greater than 1:125 developed, incomplete saturation of the alpha4beta7 receptor on circulating lymphocytes was observed and no benefit of treatment was identifiable.In this short-term study, MLN02 was more effective than placebo for the induction of clinical and endoscopic remission in patients with active ulcerative colitis.

Quality of life (QOL), a subjective index of health perception and function, embraces physical, social, and emotional performance but has not had a prominent role in clinical trials of inflammatory bowel disease (IBD). To test the robustness of the Inflammatory Bowel Disease Questionnaire (IBDQ), a disease-specific QOL index, this study assessed its validity, reliability, and responsiveness during a multicenter trial.Three hundred five patients with stable Crohn's disease received cyclosporin or placebo for 18 months. IBDQ and dimensional scores (bowel, social, systemic, and emotional) were correlated with disease activity (Crohn's disease activity index [CDAI] and Harvey-Bradshaw index). Concordance of IBDQ scores was tested in 280 stable subjects. Linear regression evaluated change in IBDQ scores over time.IBDQ scores correlated highly with CDAI (r = -0.67; P < 0.0001). The reliability coefficient for IBDQ score was 0.70 vs. 0.66 for CDAI and 0.55 for Harvey-Bradshaw index. Regression line slopes of IBDQ scores were significantly different in patients who deteriorated from those who remained stable ([b] < 0.15; P < 0.0001). QOL scores were lower in patients who required surgery.The IBDQ is a valid reliable assessment tool that reflects important changes in the health status of patients with IBD. The IBDQ is a robust measure of therapeutic efficacy and should be used in future clinical trials in IBD.

The objective of this study was to contribute long-term safety data for infliximab and other therapies in Crohn's disease (CD).We prospectively evaluated CD patients enrolled in the large, observational Crohn's Therapy, Resource, Evaluation, and Assessment Tool registry, established to compare infliximab safety with conventional nonbiological medications in CD.A total of 6,273 patients were enrolled and evaluated on or before 23 February 2010; 3,420 received infliximab (17,712 patient-years; 89.9% received ≥ 2 infusions) and 2,853 received other-treatments-only (13,251 patient-years). Mean length of patient follow-up was 5.2 years. More infliximab- than other-treatments-only-treated patients had moderate-to-severe (30.6% vs. 10.7%) or severe-to-fulminant (2.5% vs. 0.6%) disease severity (P < 0.001). In the year before enrollment, more infliximab- than other-treatments-only-treated patients required surgical intervention (17.4% vs. 13.6%), medical hospitalization (14.2% vs. 8.8%), prednisone (47.8% vs. 31.4%), immunomodulators (52.0% vs. 32.1%), and narcotic analgesics (17.3% vs. 9.1%). Patient mortality was similar for infliximab- and other-treatments-only-treated patients (0.58 vs. 0.59/100 patient-years). In multivariate logistic regression analyses, treatment with prednisone (hazard ratio (HR) = 2.14, 95% confidence interval (CI) = 1.55, 2.95; P < 0.001) or narcotic analgesics (HR = 1.79, 95% CI = 1.29, 2.48; P < 0.001) and age (HR = 1.08, 95% CI = 1.07, 1.09; P < 0.001) were associated with increased mortality risk. Neither infliximab nor immunomodulator treatment was associated with increased mortality risk. Factors independently associated with serious infections included moderate-to-severe disease activity (HR = 2.24, 95% CI = 1.57, 3.19; P < 0.001), narcotic analgesic treatment (HR = 1.98, 95% CI = 1.44, 2.73; P < 0.001), prednisone therapy (HR = 1.57, 95% CI = 1.17, 2.10; P = 0.002), and infliximab treatment (HR = 1.43, 95% CI = 1.11, 1.84; P = 0.006).Mortality was similar between infliximab- and other-treatments-only-treated CD patients. An increased risk of serious infection with infliximab was observed, although CD severity and use of prednisone or narcotic analgesics carried higher risks.

Patients with Crohn's disease often have relapses. Better treatments are needed for the maintenance of remission. Although methotrexate is an effective short-term treatment for Crohn's disease, its role in maintaining remissions is not known.We conducted a double-blind, placebo-controlled, multicenter study of patients with chronically active Crohn's disease who had entered remission after 16 to 24 weeks of treatment with 25 mg of methotrexate given intramuscularly once weekly. Patients were randomly assigned to receive either methotrexate at a dose of 15 mg intramuscularly once weekly or placebo for 40 weeks. No other treatments for Crohn's disease were permitted. We compared the efficacy of treatment by analyzing the proportion of patients who remained in remission at week 40. Remission was defined as a score of 150 or less on the Crohn's Disease Activity Index.Forty patients received methotrexate, and 36 received placebo. At week 40, 26 patients (65 percent) were in remission in the methotrexate group, as compared with 14 (39 percent) in the placebo group (P=0.04; absolute reduction in the risk of relapse, 26.1 percent; 95 percent confidence interval, 4.4 percent to 47.8 percent). Fewer patients in the methotrexate group than in the placebo group required prednisone for relapse (11 of 40 [28 percent] vs. 21 of 36 [58 percent], P=0.01). None of the patients who received methotrexate had a severe adverse event; one patient in this group withdrew because of nausea.In patients with Crohn's disease who enter remission after treatment with methotrexate, a low dose of methotrexate maintains remission.

Vedolizumab is a gut-selective antibody to α4β7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab.Safety data (May 2009-June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model.In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1-1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy.Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period.NCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT00790933.

GASTROENTEROLOGY 2002;122:512-530

Background & AimsSubcutaneous golimumab, a fully human monoclonal antibody to tumor necrosis factor-α (TNFα), was evaluated as maintenance therapy in TNFα antagonist-naive adults with moderate-to-severe active ulcerative colitis, despite conventional therapy, who responded to golimumab induction therapy.MethodsWe performed a phase 3, double-blind trial of patients who completed golimumab induction trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment, eg, PURSUIT). Patients who responded to induction therapy with golimumab (n = 464) were assigned randomly to groups given placebo or injections of 50 or 100 mg golimumab every 4 weeks through week 52. Patients who responded to placebo in the induction study continued to receive placebo. Nonresponders in the induction study received 100 mg golimumab. The primary end point was clinical response maintained through week 54; secondary end points included clinical remission and mucosal healing at both weeks 30 and 54.ResultsClinical response was maintained through week 54 in 47.0% of patients receiving 50 mg golimumab, 49.7% of patients receiving 100 mg golimumab, and 31.2% of patients receiving placebo (P = .010 and P < .001, respectively). At weeks 30 and 54, a higher percentage of patients who received 100 mg golimumab were in clinical remission and had mucosal healing (27.8% and 42.4%) than patients given placebo (15.6% and 26.6%; P = .004 and P = .002, respectively) or 50 mg golimumab (23.2% and 41.7%, respectively). Percentages of serious adverse events were 7.7%, 8.4%, and 14.3% among patients given placebo, 50 mg, or 100 mg golimumab, respectively; percentages of serious infections were 1.9%, 3.2%, and 3.2%, respectively. Among all patients given golimumab in the study, 3 died (from sepsis, tuberculosis, and cardiac failure, all in patients who received 100 mg golimumab) and 4 developed active tuberculosis.ConclusionsGolimumab (50 mg or 100 mg) maintained clinical response through week 54 in patients who responded to induction therapy with golimumab and had moderate-to-severe active ulcerative colitis; patients who received 100 mg golimumab had clinical remission and mucosal healing at weeks 30 and 54. Safety was consistent with that reported for other TNFα antagonists and golimumab in other approved indications. ClinicalTrials.gov number: NCT00488631. Subcutaneous golimumab, a fully human monoclonal antibody to tumor necrosis factor-α (TNFα), was evaluated as maintenance therapy in TNFα antagonist-naive adults with moderate-to-severe active ulcerative colitis, despite conventional therapy, who responded to golimumab induction therapy. We performed a phase 3, double-blind trial of patients who completed golimumab induction trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment, eg, PURSUIT). Patients who responded to induction therapy with golimumab (n = 464) were assigned randomly to groups given placebo or injections of 50 or 100 mg golimumab every 4 weeks through week 52. Patients who responded to placebo in the induction study continued to receive placebo. Nonresponders in the induction study received 100 mg golimumab. The primary end point was clinical response maintained through week 54; secondary end points included clinical remission and mucosal healing at both weeks 30 and 54. Clinical response was maintained through week 54 in 47.0% of patients receiving 50 mg golimumab, 49.7% of patients receiving 100 mg golimumab, and 31.2% of patients receiving placebo (P = .010 and P < .001, respectively). At weeks 30 and 54, a higher percentage of patients who received 100 mg golimumab were in clinical remission and had mucosal healing (27.8% and 42.4%) than patients given placebo (15.6% and 26.6%; P = .004 and P = .002, respectively) or 50 mg golimumab (23.2% and 41.7%, respectively). Percentages of serious adverse events were 7.7%, 8.4%, and 14.3% among patients given placebo, 50 mg, or 100 mg golimumab, respectively; percentages of serious infections were 1.9%, 3.2%, and 3.2%, respectively. Among all patients given golimumab in the study, 3 died (from sepsis, tuberculosis, and cardiac failure, all in patients who received 100 mg golimumab) and 4 developed active tuberculosis. Golimumab (50 mg or 100 mg) maintained clinical response through week 54 in patients who responded to induction therapy with golimumab and had moderate-to-severe active ulcerative colitis; patients who received 100 mg golimumab had clinical remission and mucosal healing at weeks 30 and 54. Safety was consistent with that reported for other TNFα antagonists and golimumab in other approved indications. ClinicalTrials.gov number: NCT00488631.

Background & AimsThere is an increasing need for new treatments for patients with Crohn’s disease (CD) in whom previous therapy with tumor necrosis factor (TNF) antagonists has failed. We performed a placebo-controlled, phase 3, double-blind trial to evaluate the efficacy and safety of vedolizumab, an antibody against the integrin α4β7, as induction therapy.MethodsPatients with moderately to severely active CD (CD activity index [CDAI] score, 220–400 points) were assigned randomly to groups given vedolizumab (300 mg) or placebo intravenously at weeks 0, 2, and 6. The primary analysis involved 315 patients with previous TNF antagonist failure (ie, an inadequate response to, loss of response to, or intolerance of ≥1 TNF antagonists); we determined the proportion of patients in clinical remission (CDAI, ≤150 points) at week 6. Secondary analyses evaluated outcomes at weeks 6 and 10 in this population and in the overall population (N = 416), which included patients naive to TNF antagonist therapy (n = 101).ResultsAmong patients who had experienced previous TNF antagonist failure, 15.2% of those given vedolizumab and 12.1% of those given placebo were in remission at week 6 (P = .433). At week 10, a higher proportion of this population given vedolizumab was in remission (26.6%) than those given placebo (12.1%) (nominal P = .001; relative risk, 2.2; 95% confidence interval, 1.3–3.6). A higher proportion of patients with previous TNF antagonist failure given vedolizumab also had a CDAI-100 response (≥100-point decrease in CDAI score from baseline) at week 6 than those given placebo (39.2% vs 22.3%; nominal P = .001; relative risk, 1.8; 95% confidence interval, 1.2–2.5). Adverse event results were similar among all groups.ConclusionsVedolizumab was not more effective than placebo in inducing clinical remission at week 6 among patients with CD in whom previous treatment with TNF antagonists had failed. The therapeutic benefits of vedolizumab in these patients were detectable at week 10. ClinicalTrials.gov number: NCT01224171. There is an increasing need for new treatments for patients with Crohn’s disease (CD) in whom previous therapy with tumor necrosis factor (TNF) antagonists has failed. We performed a placebo-controlled, phase 3, double-blind trial to evaluate the efficacy and safety of vedolizumab, an antibody against the integrin α4β7, as induction therapy. Patients with moderately to severely active CD (CD activity index [CDAI] score, 220–400 points) were assigned randomly to groups given vedolizumab (300 mg) or placebo intravenously at weeks 0, 2, and 6. The primary analysis involved 315 patients with previous TNF antagonist failure (ie, an inadequate response to, loss of response to, or intolerance of ≥1 TNF antagonists); we determined the proportion of patients in clinical remission (CDAI, ≤150 points) at week 6. Secondary analyses evaluated outcomes at weeks 6 and 10 in this population and in the overall population (N = 416), which included patients naive to TNF antagonist therapy (n = 101). Among patients who had experienced previous TNF antagonist failure, 15.2% of those given vedolizumab and 12.1% of those given placebo were in remission at week 6 (P = .433). At week 10, a higher proportion of this population given vedolizumab was in remission (26.6%) than those given placebo (12.1%) (nominal P = .001; relative risk, 2.2; 95% confidence interval, 1.3–3.6). A higher proportion of patients with previous TNF antagonist failure given vedolizumab also had a CDAI-100 response (≥100-point decrease in CDAI score from baseline) at week 6 than those given placebo (39.2% vs 22.3%; nominal P = .001; relative risk, 1.8; 95% confidence interval, 1.2–2.5). Adverse event results were similar among all groups. Vedolizumab was not more effective than placebo in inducing clinical remission at week 6 among patients with CD in whom previous treatment with TNF antagonists had failed. The therapeutic benefits of vedolizumab in these patients were detectable at week 10. ClinicalTrials.gov number: NCT01224171.

Background & Aims: A randomized placebo-controlled trial evaluated the efficacy of natalizumab induction therapy in patients with Crohn’s disease. Methods: Patients (N = 509) with moderately to severely active Crohn’s disease and active inflammation characterized by elevated C-reactive protein concentrations were randomized (1:1) to receive natalizumab 300 mg or placebo intravenously at Weeks 0, 4, and 8. The primary end point was induction of response (≥70-point decrease from baseline in the Crohn’s Disease Activity Index score at Week 8 sustained through Week 12). Additional efficacy end points included the proportion of patients with sustained remission (Crohn’s Disease Activity Index score <150 points) and response or remission over time. Results: Response at Week 8 sustained through Week 12 occurred in 48% of natalizumab-treated patients and 32% of patients receiving placebo (P < .001). Sustained remission occurred in 26% of natalizumab-treated patients and 16% of patients receiving placebo (P = .002). Week 4 response rates were 51% for natalizumab and 37% for placebo (P = .001). Responses remained significantly higher at subsequent assessments (P < .001) in natalizumab-treated patients. Natalizumab-treated patients also had significantly higher remission rates at Weeks 4, 8, and 12 (P ≤ .009). The frequency and types of adverse events were similar between treatment groups. Conclusions: Natalizumab induced response and remission at Week 8 that was sustained through Week 12. Response and remission rates for natalizumab were superior to those for placebo at Weeks 4, 8, and 12, demonstrating the early and sustained efficacy of natalizumab as induction therapy in patients with elevated C-reactive protein and active Crohn’s disease. Natalizumab was well tolerated in this study. Background & Aims: A randomized placebo-controlled trial evaluated the efficacy of natalizumab induction therapy in patients with Crohn’s disease. Methods: Patients (N = 509) with moderately to severely active Crohn’s disease and active inflammation characterized by elevated C-reactive protein concentrations were randomized (1:1) to receive natalizumab 300 mg or placebo intravenously at Weeks 0, 4, and 8. The primary end point was induction of response (≥70-point decrease from baseline in the Crohn’s Disease Activity Index score at Week 8 sustained through Week 12). Additional efficacy end points included the proportion of patients with sustained remission (Crohn’s Disease Activity Index score <150 points) and response or remission over time. Results: Response at Week 8 sustained through Week 12 occurred in 48% of natalizumab-treated patients and 32% of patients receiving placebo (P < .001). Sustained remission occurred in 26% of natalizumab-treated patients and 16% of patients receiving placebo (P = .002). Week 4 response rates were 51% for natalizumab and 37% for placebo (P = .001). Responses remained significantly higher at subsequent assessments (P < .001) in natalizumab-treated patients. Natalizumab-treated patients also had significantly higher remission rates at Weeks 4, 8, and 12 (P ≤ .009). The frequency and types of adverse events were similar between treatment groups. Conclusions: Natalizumab induced response and remission at Week 8 that was sustained through Week 12. Response and remission rates for natalizumab were superior to those for placebo at Weeks 4, 8, and 12, demonstrating the early and sustained efficacy of natalizumab as induction therapy in patients with elevated C-reactive protein and active Crohn’s disease. Natalizumab was well tolerated in this study. CME quiz on page 2001.Crohn’s disease involves persistent recruitment of leukocytes into gut tissue, coupled with dysregulated activation of immune cell function. The α4 integrins, heterodimeric glycoproteins expressed on the surface of most leukocytes, are key molecules involved in the adhesion of leukocytes to vascular endothelium and their subsequent migration into surrounding tissue.1Lobb R.R. Hemler M.E. The pathophysiologic role of alpha 4 integrins in vivo.J Clin Invest. 1994; 94: 1722-1728Crossref PubMed Scopus (361) Google Scholar, 2Giancotti F.G. A structural view of integrin activation and signaling.Dev Cell. 2003; 4: 149-151Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Agents that inhibit interactions between α4 integrins on circulating immune cells and their vascular endothelial cell receptors would be expected to decrease the migration of these cells through the endothelium, thereby decreasing chronic inflammation.3von Andrian U.H. Engelhardt B. a4 Integrins as therapeutic targets in autoimmune disease.N Engl J Med. 2003; 348: 68-72Crossref PubMed Scopus (258) Google ScholarNatalizumab is a humanized immunoglobulin G4 monoclonal antibody against α4 integrins, which may make it less immunogenic than chimeric antibodies. Previous studies have suggested that natalizumab may be effective as induction therapy for patients with moderately to severely active Crohn’s disease.4Gordon F.H. Lai C.W. Hamilton M.I. Allison M.C. Srivastava E.D. Fouweather M.G. Donoghue S. Greenlees C. Subhani J. Amlot P.L. Pounder R.E. A randomized placebo-controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn’s disease.Gastroenterology. 2001; 121: 268-274Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar, 5Ghosh S. Goldin E. Gordon F.H. Malchow H.A. Rask-Madsen J. Rutgeerts P. Vyhnalek P. Zadorova Z. Palmer T. Donoghue S. Natalizumab Pan-European Study GroupNatalizumab for active Crohn’s disease.N Engl J Med. 2003; 348: 24-32Crossref PubMed Scopus (767) Google Scholar, 6Sandborn W.J. Colombel J.F. Enns R. Feagan B.G. Hanauer S.B. Lawrance I.C. Panaccione R. Sanders M. Schreiber S. Targan S. van Deventer S. Goldblum R. Despain D. Hogge G.S. Rutgeerts P. International Efficacy of Natalizumab as Active Crohn’s Therapy (ENACT-1) Trial GroupEvaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial GroupNatalizumab induction and maintenance therapy for Crohn’s disease.N Engl J Med. 2005; 353: 1912-1925Crossref PubMed Scopus (809) Google Scholar Patients with moderate to severe disease (Crohn’s Disease Activity Index [CDAI] scores ≥220 to ≤450) enrolled in the phase 3 induction trial ENACT-1 (N = 905) received 3 infusions of natalizumab (300 mg) or placebo over 8 weeks.6Sandborn W.J. Colombel J.F. Enns R. Feagan B.G. Hanauer S.B. Lawrance I.C. Panaccione R. Sanders M. Schreiber S. Targan S. van Deventer S. Goldblum R. Despain D. Hogge G.S. Rutgeerts P. International Efficacy of Natalizumab as Active Crohn’s Therapy (ENACT-1) Trial GroupEvaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial GroupNatalizumab induction and maintenance therapy for Crohn’s disease.N Engl J Med. 2005; 353: 1912-1925Crossref PubMed Scopus (809) Google Scholar Response was defined as a reduction of ≥70 points from Week 0 in the CDAI score, whereas remission was defined as a CDAI score <150 points.7Best W.R. Becktel J.M. Singleton J.W. Kern F. Development of a Crohn’s disease activity index National Cooperative Crohn’s Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (2974) Google Scholar A clinical response at Week 10 was observed in 56% of patients treated with natalizumab and 49% of patients receiving placebo (P =.051). Remission occurred at Week 10 in 37% of natalizumab-treated patients and 30% of patients receiving placebo (P = .124). However, analyses in subgroups of patients, including those with active inflammation at baseline characterized by a C-reactive protein (CRP) concentration above the upper limit of normal (ULN [>2.87 mg/L]), demonstrated clinically and statistically significant differences in response and remission rates. Among the patients in the ENACT-1 trial with CRP concentrations above the ULN (n = 660; 73% of the total population), 58% of natalizumab-treated patients and 45% of patients in the placebo group experienced a clinical response at Week 10 (P = .007), while 40% and 28%, respectively, entered clinical remission (P = .014).6Sandborn W.J. Colombel J.F. Enns R. Feagan B.G. Hanauer S.B. Lawrance I.C. Panaccione R. Sanders M. Schreiber S. Targan S. van Deventer S. Goldblum R. Despain D. Hogge G.S. Rutgeerts P. International Efficacy of Natalizumab as Active Crohn’s Therapy (ENACT-1) Trial GroupEvaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial GroupNatalizumab induction and maintenance therapy for Crohn’s disease.N Engl J Med. 2005; 353: 1912-1925Crossref PubMed Scopus (809) Google ScholarAlthough the ENACT-1 trial did not meet the primary end point of response at Week 10 with statistical significance in the overall population, the efficacy of natalizumab as a maintenance therapy in patients who responded to induction therapy was clearly demonstrated in the ENACT-2 trial. Significantly more patients sustained response and remission at every assessment beginning at Week 20 through Week 60 (receiving a total duration of 15 months of natalizumab therapy, including the 3 months in the ENACT-1 trial).6Sandborn W.J. Colombel J.F. Enns R. Feagan B.G. Hanauer S.B. Lawrance I.C. Panaccione R. Sanders M. Schreiber S. Targan S. van Deventer S. Goldblum R. Despain D. Hogge G.S. Rutgeerts P. International Efficacy of Natalizumab as Active Crohn’s Therapy (ENACT-1) Trial GroupEvaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial GroupNatalizumab induction and maintenance therapy for Crohn’s disease.N Engl J Med. 2005; 353: 1912-1925Crossref PubMed Scopus (809) Google ScholarThe ENCORE (Efficacy of Natalizumab in Crohn’s disease Response and Remission) trial was designed to confirm the hypothesis generated from the subgroup analysis of the ENACT-1 trial that natalizumab is effective as an induction therapy in patients with moderately to severely active Crohn’s disease and active inflammation characterized by elevated CRP concentrations.Patients and MethodsSelected investigators and employees of Elan Pharmaceuticals, Inc (San Diego, CA), and Biogen Idec (Cambridge, MA) designed the ENCORE study. The investigator authors had access to all data, participated in the analysis and interpretation of these data, and were members of the publication committee. The manuscript was written by a publication committee (with the assistance of a medical writer), which included authors from the group of investigators. The authors verified the completeness and accuracy of these data and analyses. The publication committee approved the final manuscript.PatientsThis global, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was conducted at 114 centers between March 2004 and March 2005. Institutional review boards or ethics committees at each participating center approved the protocol before study initiation. All patients gave written informed consent.Men and women, 18 years of age or older, with moderately to severely active Crohn’s disease (based on clinical evaluation and CDAI scores ≥220 to ≤450) and objective evidence of inflammation as confirmed by elevated CRP concentrations were eligible. Elevated CRP concentrations were defined as >2.87 mg/L (ULN) as assessed by the study central laboratory at the screening visit. Patients were required to have at least a 6-month history of Crohn’s disease, and radiologic or endoscopic studies were required within the previous 36 months or following prior surgical resection to confirm the diagnosis. Concurrent therapies for Crohn’s disease, including stable doses of 5-aminosalicylates, prednisone or an equivalent corticosteroid (≤20 mg/day), budesonide (≤6 mg/day), azathioprine, 6-mercaptopurine, methotrexate, and antibiotics, were permitted. Patients were excluded if they had short-bowel syndrome, an ostomy, a total colectomy, a stricture with obstructive symptoms, draining fistulas, an abdominal abscess, had received anti–tumor necrosis factor therapy within the previous 12 weeks, or had ever previously been treated with natalizumab.Study DesignPatients were screened for eligibility and randomized 7–14 days later at the baseline (Week 0) visit to receive 3 intravenous infusions of natalizumab 300 mg or placebo (1:1 ratio) at Weeks 0, 4, and 8 and followed up until Week 12 for safety and efficacy assessments. Randomization was stratified by site, and assignment to treatment was centrally performed. The patients, site staff, and study investigators were all blinded to treatment assignment. Response was defined as a reduction of ≥70 points in the CDAI score from Week 0, whereas remission was defined as a CDAI score <150 points.7Best W.R. Becktel J.M. Singleton J.W. Kern F. Development of a Crohn’s disease activity index National Cooperative Crohn’s Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (2974) Google ScholarPatient Schedule, Efficacy, and Safety EvaluationsPatients were assessed at Weeks −2, 0, 4, 8, and 12. The CDAI score was calculated at Weeks 0, 4, 8, and 12; scores ranged from 0 to 600, with higher scores indicating more severe disease activity.7Best W.R. Becktel J.M. Singleton J.W. Kern F. Development of a Crohn’s disease activity index National Cooperative Crohn’s Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (2974) Google Scholar The Inflammatory Bowel Disease Questionnaire (IBDQ)8Irvine E.J. Feagan B. Rochon J. Archambault A. Fedorak R.N. Groll A. Kinnear D. Saibil F. McDonald J.W. Canadian Crohn’s Relapse Prevention Trial Study GroupQuality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease.Gastroenterology. 1994; 106: 287-296Abstract PubMed Google Scholar and Short Form-36 (SF-36)9Brazier J.E. Harper R. Jones N.M. O’Cathain A. Thomas K.J. Usherwood T. Westlake L. Validating the SF-36 health survey questionnaire: new outcome measure for primary care.BMJ. 1992; 305: 160-164Crossref PubMed Scopus (3278) Google Scholar were administered at Weeks 0 and 12 to assess health-related quality of life. At each visit, adverse events (AEs) and concomitant medications were recorded and samples were collected for laboratory evaluations. Safety assessments included vital signs, physical examinations, hematology, serum biochemistry, urinalysis, and determination of the presence of anti-natalizumab antibodies. Serum samples for determination of natalizumab concentration and presence of anti-natalizumab antibodies were collected at baseline and Weeks 4, 8, and 12 or at the time of study discontinuation if before Week 12. A positive anti-natalizumab antibody test was defined as a concentration ≥.5 μg/mL in a validated enzyme-linked immunosorbent assay at any time point. The study design and prespecified study end points for ENCORE are shown in Figure 1 and Table 1.Table 1Prespecified Study End PointsPrimary end point •Proportion (%) achieving a clinical response, defined as a ≥70-point decrease in baseline (Week 0) CDAI score, at both Weeks 8 and 12Secondary end points •Proportion (%) achieving clinical remission, defined as a CDAI score <150, at both Weeks 8 and 12 •Proportion (%) achieving a clinical response, defined as a ≥70-point decrease in baseline (Week 0) CDAI score, at Week 12 •Proportion (%) achieving clinical remission, defined as a CDAI score <150, at Week 12Tertiary end points •Proportion (%) achieving a ≥100-point decrease in baseline (Week 0) CDAI score at both Weeks 8 and 12 •Proportion achieving a clinical response (as defined previously) at both Weeks 4 and 8 •Proportion achieving a clinical remission (as defined previously) at both Weeks 4 and 8 •Time to clinical response, defined as a ≥70-point decrease in baseline (Week 0) CDAI score •Time to clinical remission, defined as a CDAI score of <150 •Proportion (%) achieving a clinical response (as defined previously) at Week 8 •Mean change from baseline (Week 0) CDAI score at Weeks 4, 8, and 12 •To compare the effects of natalizumab vs placebo on changes in inflammatory markers, including CRP and platelets •Mean change from baseline (Week 0) platelet count at Weeks 4, 8, and 12 •Mean change from baseline (Week 0) CRP level at Weeks 4, 8, and 12 •To evaluate the effects of natalizumab on quality of life, as measured by the IBDQ and SF-36 health survey •Mean change in IBDQ from baseline (Week 0) at Week 12 •Mean change in the SF-36 or its components from baseline (Week 0) at Week 12Safety end points (analyses were conducted in all randomized patients receiving at least a part of 1 infusion) •The number and proportion of patients with AEs •Assessment of clinical laboratory parameters •Assessment of vital signs Open table in a new tab Statistical AnalysisIt was planned to randomize 462 patients (231 to natalizumab and 231 to placebo) in this clinical trial. This sample size was determined using a 2-sided, 2-sample comparison of proportions at the 5% level of significance. The sample size provided 90% power to detect a difference between a placebo response rate of 40% and a natalizumab response rate of 55%. The primary analysis evaluated the proportion of patients achieving a clinical response at both Weeks 8 and 12. Secondary analyses evaluated the proportion of patients achieving a clinical remission at both Weeks 8 and 12 and those in response or remission at Week 12. Treatment effect was analyzed using logistic regression adjusting for disease severity (CDAI score <330 or ≥330) at baseline. A CDAI score of 330 was prespecified by the study investigators as an arbitrary indicator of a more severe disease state. Logistic regression and log-rank tests were used as appropriate to provide nominal P values for secondary end points. The distributions of time to clinical response and time to remission utilized the Kaplan–Meier method, and treatment group comparisons used the Cox proportional hazards model. If a patient’s CDAI score could not be evaluated at a given time point because of missing data or an incomplete study assessment, the patient was considered a treatment failure for that time point. Once a patient was withdrawn early from the study, received rescue intervention, or discontinued use of study drug due to an AE, that patient was considered a treatment failure at all time points subsequent to the failure date. For continuous efficacy data, the last-observation-carried-forward approach was used to replace missing data. Data collected at time points after the failure date were replaced by the last available data on or before the failure date. All statistical analyses were performed with SAS for Windows version 8.2 (SAS Institute, Inc, Cary, NC).ResultsPatient CharacteristicsA total of 832 patients were screened; of these, 509 were eligible for randomization at Week 0 (Figure 2). The most common reason for a patient to fail screening was a CRP concentration below the ULN, which occurred in 171 patients (21% of the entire population screened for the trial). Patients were randomly assigned to receive placebo (250 patients) or natalizumab (259 patients). Data for all patients receiving study drug were included in the safety analysis (N = 510). One patient received a single infusion of natalizumab despite not being randomized and thus was excluded from efficacy analyses (N = 509 randomized). Baseline characteristics between both treatment groups were similar (Table 2). Overall, 39 patients (15%) in the natalizumab group and 42 patients (17%) in the placebo group withdrew prematurely from the study.Figure 2Enrollment, treatment, and outcome of patients in the ENCORE trial.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 2Demography and Baseline CharacteristicsCharacteristicPlacebo (N = 250)Natalizumab (N = 259)Mean age (y)37.738.1Gender, N (%) Female148 (59)154 (59) Male102 (41)105 (41)Race, N (%) Black6 (2)3 (1) White236 (94)247 (95) Asian1 (<1)1 (<1) Hispanic1 (<1)1 (<1) Other6 (2)7 (3)Mean weight (kg)74.471.9Mean height (cm)170.4170.1Mean body mass index (kg/m2)25.724.8Mean duration of disease (mo)120.3121.4Disease location, N (%) Ileal65 (26)56 (22) Colonic65 (26)69 (27) Ileocolonic120 (48)134 (52)Mean (SD) baseline CDAI score299.5 (63.19)303.9 (64.80) CDAI score <330, N (%)178 (71)174 (67) CDAI score ≥330, N (%)71 (28)84 (32) Missing, N (%)1 (<1)1 (<1)Mean (SD) baseline CRP level (mg/L)23.4 (27.93)23.0 (27.82) ≤2.87, N (%)18 (7)14 (5) >2.87, N (%)232 (93)245 (95)Mean (SD) baseline albumin level (g/L)36.8 (4.94)36.7 (4.92)Mean (SD) baseline platelet count (×109/L)368.3 (122.03)380.7 (115.41)Smoking status >10/day, N (%)48 (19)57 (22)Concomitant Crohn’s disease medication or diet, N (%)227 (91)247 (95) 5-ASA compounds120 (48)128 (49) Immunosuppressants96 (38)97 (37) Corticosteroids94 (38)109 (42) Antibiotics13 (5)17 (7) Diet4 (2)3 (1)Prior use of anti–tumor necrosis factor agents, N (%)112 (45)130 (50)Reason for discontinuation, N (%) AE/intolerant35 (31)35 (27) Unresponsive37 (33)44 (34) Other40 (36)51 (39) Open table in a new tab EfficacyResponse and remissionThe primary end point, response at Week 8 sustained through Week 12, occurred in 48% (124 of 259) of natalizumab-treated patients compared with 32% (81 of 250) of patients receiving placebo (P < .001) (Figure 3A). The secondary end point, remission at Week 8 sustained through Week 12, occurred in 26% (68 of 259) of patients randomized to receive natalizumab and 16% (40 of 250) of patients who received placebo (P = .002) (Figure 3B). Analyses of the proportion of patients in response and remission at Week 12 (secondary end point) demonstrated significant differences with natalizumab treatment compared with placebo. At Week 12, 60% (155 of 259) of patients receiving natalizumab vs 44% (109 of 250) of those administered placebo were in response (P < .001) and 38% (97 of 259) vs 25% (63 of 250), respectively, were in remission (P = .001) (Figure 3A and B).Figure 3The primary end point was induction of response (≥70-point decrease from baseline CDAI score) at Week 8 that was sustained through Week 12. (A) Proportion of patients with a clinical response (≥70-point decrease from baseline CDAI score). The secondary end points were induction of remission (CDAI score <150) at Week 8 that were sustained through Week 12 and the proportion of patients in response or remission at Week 12. (B) Proportion of patients in clinical remission (CDAI score <150). (C) Proportion of patients with ≥100-point decrease from baseline CDAI score. Significant differences between the treatment groups are noted.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Treatment effect was evident as early as the first assessment. Response rates at Week 4 were 51% (133 of 259) for natalizumab and 37% (92 of 250) for placebo (P = .001), and these responses remained significantly higher at Weeks 8 and 12 (P < .001) in patients receiving natalizumab (Figure 3A). Patients receiving natalizumab also had significantly higher remission rates as early as Week 4 and, again, remission rates remained significantly higher at Weeks 8 and 12 (P ≤ .009) (Figure 3B). A more stringent response criterion is a decrease of ≥100 points from baseline in the CDAI score.10Su C. Lichtenstein G.R. Krok K. Brensinger C.M. Lewis J.D. A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn’s disease.Gastroenterology. 2004; 126: 1257-1269Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar The proportion of patients with a 100-point response at Week 8 and sustained through Week 12 was higher for patients in the natalizumab group compared with those in the placebo group (39% [102 of 259] for natalizumab vs 22% [56 of 250] for placebo; P < .001) (Figure 3C). The difference in 100-point response rates between the natalizumab and placebo groups was evident as early as the first assessment at Week 4 (39% [101 of 259] for natalizumab compared with 27% [67 of 250] for placebo; P = .004) and was also statistically significant at Weeks 8 and 12 (Figure 3C).At baseline, the mean (±SD) CDAI scores for patients in the natalizumab and placebo treatment groups were similar (303.9 [±64.80] vs 299.5 [±63.19], respectively) (Table 2). The median (minimum, maximum) CDAI scores were also similar (286 [147, 472] for natalizumab vs 287 [149, 483] for placebo). The differences in mean decrease in CDAI score from baseline were significantly greater at Weeks 4, 8, and 12 in the natalizumab group compared with the placebo group (P < .001). At Week 4, patients receiving natalizumab had a mean 83-point decrease in their CDAI scores. CDAI scores continued to decrease throughout the study in natalizumab-treated patients. The greatest improvement in CDAI score was observed 4 Weeks following the third infusion (at Week 12) (−117.9 [±104.55] for natalizumab compared with −68.3 [±99.34] for placebo) (Table 3). Similar effects were observed in the median decrease from baseline in CDAI. The median time to clinical response for patients in the natalizumab treatment group was 31 days (95% confidence interval, 30–56 days) compared with 57 days (95% confidence interval, 57–64 days) for patients receiving placebo (P < .001). The median time to clinical remission was 86 days (95% confidence interval, 85 undeterminable days) for patients receiving natalizumab and was undeterminable (95% confidence interval, 87 undeterminable days) for those receiving placebo. The distribution of time to remission was statistically significantly different between treatment groups in favor of natalizumab (P = .002).Table 3Change From Baseline in CDAI Score Over TimeWeek of visitPlacebo (N = 250)Natalizumab (N = 259)P valueaP value refers to differences in the CDAI score change from baseline.NMeanSDMedianMinimum, MaximumNMeanSDMedianMinimum, Maximum4249−50.184.71−50.0−352, 202258−83.087.03−78.0−352, 153<.0018249−65.896.88−53.0−352, 177258−104.494.47−102.5−373, 153<.00112249−68.399.34−66.0−400, 171258−117.9104.55−113.5−385, 155<.001NOTE. Last observation carried forward was used to replace the missing data. Also, the data collected at the time points after the failure date (the earliest of early discontinuation, start date of rescue intervention, or onset date of AEs that led to discontinuation of study drug) were replaced by the last available data before the failure date using last observation carried forward.a P value refers to differences in the CDAI score change from baseline. Open table in a new tab Health-related quality of lifeThe mean (±SD) total IBDQ scores at baseline were similar (123.6 [±31.06] points for natalizumab vs 122.5 [±28.44] points for placebo). At Week 12, a greater improvement in mean (±SD) total IBDQ score was observed among patients in the natalizumab group compared with those in the placebo group (26.7 [±32.34] points vs 15.2 [±28.92] points, respectively; P < .001). Significant improvement was also observed in all 4 dimensions of the IBDQ (data not shown).Effects on laboratory parametersDuring the study, mean CRP concentrations consistently decreased from baseline values for patients who received natalizumab, while CRP concentrations remained essentially unchanged, or slightly increased, for those who received placebo. Patients in the natalizumab group exhibited significantly lower mean CRP concentrations compared with patients receiving placebo at all time points, and by Week 12, mean CRP concentrations were 15.0 (±25.66) for natalizumab-treated patients compared with 24.7 (±31.82) mg/L for patients receiving placebo (P < .001) (Figure 4A). Evidence of a treatment effect is further seen when examining the number of patients with normalization of CRP (to levels <2.87 mg/L) during the study. At Week 12, 23% (56 of 245) of natalizumab-treated patients had CRP concentrations below the ULN compared with 8% (18 of 232) of patients receiving placebo (P < .001).Figure 4(A) Mean serum CRP concentration (mg/L) at each visit. (B) Mean platelet count (×10 9/L) at each visit. (C) Mean serum albumin concentration (g/L) at each visit. P values reflect a statistically significant difference between treatment groups.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Total platelet count, another acute phase reactant that correlates with the degree of inflammation in moderately to severely active Crohn’s disease, was assessed throughout the study.11Kapsoritakis A.N. Koukourakis M.I. Sfiridaki A. Potamianos S.P. Kosmadaki M.G. Koutroubakis I.E. Kouroumalis E.A. Mean platelet volume: a useful marker of inflammatory bowel disease activity.Am J Gastroenterol. 2001; 96: 776-781Crossref PubMed Google Scholar Patients receiving natalizumab exhibited consistent decreases in mean platelet counts throughout the study, while the levels in those patients receiving placebo remained virtually unchanged (Figure 4B). The proportion of patients who had platelet counts restored to the normal range (130–400 × 109/L) by Week 12 was 55% (53 of 96) for patients randomized to natalizumab and 25% (20 of 81) for those administered placebo (P < .001 for Weeks 8 and 12, P = .131 for Week 4).Mean serum albumin concentrations increased over time in natalizumab-treated patients, whereas mean concentrations decreased postbaseline for patients

<h2>Abstract</h2> This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice Committee. The paper was approved by the Committee on May 18, 2003, and by the AGA Governing Board on July 25, 2003.

The efficacy of arthroscopic surgery for the treatment of osteoarthritis of the knee is unknown.We conducted a single-center, randomized, controlled trial of arthroscopic surgery in patients with moderate-to-severe osteoarthritis of the knee. Patients were randomly assigned to surgical lavage and arthroscopic débridement together with optimized physical and medical therapy or to treatment with physical and medical therapy alone. The primary outcome was the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score (range, 0 to 2400; higher scores indicate more severe symptoms) at 2 years of follow-up. Secondary outcomes included the Short Form-36 (SF-36) Physical Component Summary score (range, 0 to 100; higher scores indicate better quality of life).Of the 92 patients assigned to surgery, 6 did not undergo surgery. Of the 86 patients assigned to control treatment, all received only physical and medical therapy. After 2 years, the mean (+/-SD) WOMAC score for the surgery group was 874+/-624, as compared with 897+/-583 for the control group (absolute difference [surgery-group score minus control-group score], -23+/-605; 95% confidence interval [CI], -208 to 161; P=0.22 after adjustment for baseline score and grade of severity). The SF-36 Physical Component Summary scores were 37.0+/-11.4 and 37.2+/-10.6, respectively (absolute difference, -0.2+/-11.1; 95% CI, -3.6 to 3.2; P=0.93). Analyses of WOMAC scores at interim visits and other secondary outcomes also failed to show superiority of surgery.Arthroscopic surgery for osteoarthritis of the knee provides no additional benefit to optimized physical and medical therapy. (ClinicalTrials.gov number, NCT00158431.)

Corticosteroids are the most efficacious drugs for inducing remission in active Crohn's disease, but their benefits are frequently offset by serious side effects. Budesonide is a corticosteroid with high topical antiinflammatory activity but low systemic activity because of extensive hepatic metabolism. We investigated the efficacy and safety of an oral controlled-ileal-release preparation of budesonide in patients with active Crohn's disease involving the ileum or ileum and proximal colon.

Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be “diagnostic modality driven”: for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. (Inflamm Bowel Dis 2011)

Persistent disease activity is associated with a poor prognosis in inflammatory bowel disease (IBD). Therefore, monitoring of patients with intent to suppress subclinical inflammation has emerged as a treatment concept. As endoscopic monitoring is invasive and resource intensive, identification of valid markers of disease activity is a priority. The objective was to evaluate the diagnostic accuracy of C-reactive protein (CRP), fecal calprotectin (FC), and stool lactoferrin (SL) for assessment of endoscopically defined disease activity in IBD.Databases were searched from inception to November 6, 2014 for relevant cohort and case-control studies that evaluated the diagnostic accuracy of CRP, FC, or SL and used endoscopy as a gold standard in patients with symptoms consistent with active IBD. Sensitivities and specificities were pooled to generate operating property estimates for each test using a bivariate diagnostic meta-analysis.Nineteen studies (n=2499 patients) were eligible. The pooled sensitivity and specificity estimates for CRP, FC, and SL were 0.49 (95% confidence interval (CI) 0.34-0.64) and 0.92 (95% CI 0.72-0.96), 0.88 (95% CI 0.84-0.90) and 0.73 (95% CI 0.66-0.79), and 0.82 (95% CI 0.73-0.88) and 0.79 (95% CI 0.62-0.89), respectively. FC was more sensitive than CRP in both diseases and was more sensitive in ulcerative colitis than Crohn's disease.Although CRP, FC, and SL are useful biomarkers, their value in managing individual patients must be considered in specific clinical contexts.

Interleukin 10 (IL-10) is an anti-inflammatory, immunomodulatory cytokine that regulates mucosal inflammation. This study evaluated the safety, tolerance, and efficacy of recombinant human IL-10 (rhuIL-10) for mild to moderately active Crohn's disease.We conducted a 24-week multicenter, prospective, randomized, double-blind, placebo-controlled, and sequential-escalating-dose study. Ninety-five patients with Crohn's Disease Activity Index of 200-350, not presently undergoing corticosteroid, mesalamine, or immunosuppressive therapy, were treated with subcutaneous rhuIL-10 (1, 5, 10, or 20 microg/kg) or placebo once daily for 28 consecutive days. Patients were followed up for 20 weeks after treatment. Evaluation of safety and tolerance was the first objective, and efficacy was the second objective.Adverse effects were dose-related, mild-to-moderate in severity, and reversible. Asymptomatic and reversible anemia and thrombocytopenia were observed at higher doses. No withdrawal or delayed adverse effects were evident during 20 weeks of follow-up. At the end of treatment (day 29), intent-to-treat analysis showed that 23.5% (confidence interval [CI], 6.8%-49.9%) of patients receiving 5 micro/kg rhuIL-10 experienced clinical remission and endoscopic improvement; 0% (CI, 0%-14.8%) of patients in the placebo group did. Higher doses of recombinant human IL-10 were less effective than 5 microg/kg. No rhuIL-10 serum accumulation and no antibody against IL-10 were detected after 4 weeks.Subcutaneous rhuIL-10 administered daily for 28 days to patients with mild to moderately active Crohn's disease is safe, well-tolerated, and shows clinical and endoscopic improvement.

Variability in endoscopic assessment necessitates rigorous investigation of descriptors for scoring severity of ulcerative colitis (UC).To evaluate variation in the overall endoscopic assessment of severity, the intra- and interindividual variation of descriptive terms and to create an Ulcerative Colitis Endoscopic Index of Severity which could be validated.A two-phase study used a library of 670 video sigmoidoscopies from patients with Mayo Clinic scores 0-11, supplemented by 10 videos from five people without UC and five hospitalised patients with acute severe UC. In phase 1, each of 10 investigators viewed 16/24 videos to assess agreement on the Baron score with a central reader and agreed definitions of 10 endoscopic descriptors. In phase 2, each of 30 different investigators rated 25/60 different videos for the descriptors and assessed overall severity on a 0-100 visual analogue scale. κ Statistics tested inter- and intraobserver variability for each descriptor. A general linear mixed regression model based on logit link and β distribution of variance was used to predict overall endoscopic severity from descriptors.There was 76% agreement for 'severe', but 27% agreement for 'normal' appearances between phase I investigators and the central reader. In phase 2, weighted κ values ranged from 0.34 to 0.65 and 0.30 to 0.45 within and between observers for the 10 descriptors. The final model incorporated vascular pattern, (normal/patchy/complete obliteration) bleeding (none/mucosal/luminal mild/luminal moderate or severe), erosions and ulcers (none/erosions/superficial/deep), each with precise definitions, which explained 90% of the variance (pR(2), Akaike Information Criterion) in the overall assessment of endoscopic severity, predictions varying from 4 to 93 on a 100-point scale (from normal to worst endoscopic severity).The Ulcerative Colitis Endoscopic Index of Severity accurately predicts overall assessment of endoscopic severity of UC. Validity and responsiveness need further testing before it can be applied as an outcome measure in clinical trials or clinical practice.

Background & AimsThe efficacy of infliximab for treating patients with ulcerative colitis has been established.MethodsThe Active Ulcerative Colitis Trial (ACT)-1 and ACT-2 randomized, double-blind, placebo-controlled studies evaluated infliximab induction and maintenance therapy in moderately to severely active ulcerative colitis. Overall, 728 patients received placebo or infliximab (5 or 10 mg/kg) intravenously at weeks 0, 2, and 6, then every 8 weeks through week 46 (ACT-1) or 22 (ACT-2). Colectomy, hospitalization, and surgery/procedure data through 54 weeks after the first infusion were obtained from ACT-1, ACT-2, and associated data sources. In the prespecified analysis, all data were combined to ascertain time to colectomy. Kaplan–Meier product-limit method was used to estimate the cumulative incidence of colectomy, and log-rank test was used to compare the combined infliximab group and placebo.ResultsEighty-seven percent (630 of 728) of patients had complete colectomy follow-up; 13% (98 of 728) of patients had a median follow-up of 6.2 months. The cumulative incidence of colectomy through 54 weeks was 10% for infliximab and 17% for placebo (P = .02), yielding an absolute risk reduction of 7%. Compared with placebo, fewer ulcerative colitis-related hospitalizations and surgeries/procedures per 100 patient-years of treatment occurred with infliximab therapy: 40 vs 20 (P = .003) and 34 vs 21 (P = .03), respectively. Serious adverse events occurring in infliximab-treated patients included serious infections, tuberculosis, histoplasmosis, listeriosis, and malignancy.ConclusionsPatients with moderately to severely active ulcerative colitis treated with infliximab were less likely to undergo colectomy through 54 weeks than those receiving placebo. The efficacy of infliximab for treating patients with ulcerative colitis has been established. The Active Ulcerative Colitis Trial (ACT)-1 and ACT-2 randomized, double-blind, placebo-controlled studies evaluated infliximab induction and maintenance therapy in moderately to severely active ulcerative colitis. Overall, 728 patients received placebo or infliximab (5 or 10 mg/kg) intravenously at weeks 0, 2, and 6, then every 8 weeks through week 46 (ACT-1) or 22 (ACT-2). Colectomy, hospitalization, and surgery/procedure data through 54 weeks after the first infusion were obtained from ACT-1, ACT-2, and associated data sources. In the prespecified analysis, all data were combined to ascertain time to colectomy. Kaplan–Meier product-limit method was used to estimate the cumulative incidence of colectomy, and log-rank test was used to compare the combined infliximab group and placebo. Eighty-seven percent (630 of 728) of patients had complete colectomy follow-up; 13% (98 of 728) of patients had a median follow-up of 6.2 months. The cumulative incidence of colectomy through 54 weeks was 10% for infliximab and 17% for placebo (P = .02), yielding an absolute risk reduction of 7%. Compared with placebo, fewer ulcerative colitis-related hospitalizations and surgeries/procedures per 100 patient-years of treatment occurred with infliximab therapy: 40 vs 20 (P = .003) and 34 vs 21 (P = .03), respectively. Serious adverse events occurring in infliximab-treated patients included serious infections, tuberculosis, histoplasmosis, listeriosis, and malignancy. Patients with moderately to severely active ulcerative colitis treated with infliximab were less likely to undergo colectomy through 54 weeks than those receiving placebo.

<h2>Summary</h2><h3>Background</h3> Etrolizumab is a humanised monoclonal antibody that selectively binds the β7 subunit of the heterodimeric integrins α4β7 and αEβ7. We aimed to assess etrolizumab in patients with moderately-to-severely active ulcerative colitis. <h3>Methods</h3> In this double-blind, placebo-controlled, randomised, phase 2 study, patients with moderately-to-severely active ulcerative colitis who had not responded to conventional therapy were recruited from 40 referral centres in 11 countries. Eligible patients (aged 18–75 years; Mayo Clinic Score [MCS] of 5 of higher [or ≥6 in USA]; and disease extending 25 cm or more from anal verge) were randomised (1:1:1) to one of two dose levels of subcutaneous etrolizumab (100 mg at weeks 0, 4, and 8, with placebo at week 2; or 420 mg loading dose [LD] at week 0 followed by 300 mg at weeks 2, 4, and 8), or matching placebo. The primary endpoint was clinical remission at week 10, defined as MCS of 2 or less (with no individual subscore of >1), analysed in the modified intention-to-treat population (mITT; all randomly assigned patients who had received at least one dose of study drug, had at least one post-baseline disease-activity assessment, and had a centrally read screening endoscopic subscore of ≥2). This study is registered with ClinicalTrials.gov, number NCT01336465. <h3>Findings</h3> Between Sept 2, 2011, and July 11, 2012, 124 patients were randomly assigned, of whom five had a endoscopic subscore of 0 or 1 and were excluded from the mITT population, leaving 39 patients in the etrolizumab 100 mg group, 39 in the etrolizumab 300 mg plus LD group, and 41 in the placebo group for the primary analyses. No patients in the placebo group had clinical remission at week 10, compared with eight (21% [95% CI 7–36]) patients in the etrolizumab 100 mg group (p=0·0040) and four (10% [0·2–24]) patients in the 300 mg plus LD group (p=0·048). Adverse events occurred in 25 (61%) of 41 patients in the etrolizumab 100 mg group (five [12%] of which were regarded as serious), 19 (48%) of 40 patients in the etrolizumab 300 mg plus LD group (two [5%] serious), and 31 (72%) of 43 patients in the placebo group (five [12%] serious). <h3>Interpretation</h3> Etrolizumab was more likely to lead to clinical remission at week 10 than was placebo. Therefore, blockade of both α4β7 and αEβ7 might provide a unique therapeutic approach for the treatment of ulcerative colitis, and phase 3 studies have been planned. <h3>Funding</h3> Genentech.

The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohn's disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.

The quantitative relationships between instruments and assays that measure clinical, endoscopic, and biologic disease activity in patients with Crohn's disease are poorly characterized. This study evaluated the correlations between the Crohn's Disease Activity Index (CDAI), the Simple Endoscopic Score for Crohn's Disease (SES-CD), serum high-sensitivity C-reactive protein (hsCRP) (both phenotype and genotype) and interleukin-6 (IL-6), and fecal calprotectin and lactoferrin.A total of 164 patients with Crohn's disease undergoing colonoscopy were enrolled. The CDAI and SES-CD scores, serum hsCRP and IL-6, CRP and IL-6 genotypes, and fecal calprotectin and lactoferrin were measured.There were no significant associations between the CDAI and SES-CD scores (Spearman rank correlation coefficient, 0.15) or between the CDAI scores and the serum concentrations of hsCRP and IL-6, or the fecal concentrations of calprotectin and lactoferrin. In contrast, the serum hsCRP and IL-6 concentrations and the fecal calprotectin and lactoferrin concentrations were significantly higher in patients with more severe endoscopic disease activity (SES-CD score > 7 points) (P < .001 for all comparisons). The CRP 717 mutant homozygote and heterozygote status was associated with significantly lower concentrations of hsCRP (P = .02). There was a trend toward higher hsCRP concentrations in the CRP 286 heterozygous adenine mutant-type mutant genotype, but this did not reach statistical significance.Serum and fecal biomarker concentrations are associated with endoscopic but not clinical disease activity in patients with Crohn's disease. Stimulated hsCRP concentration is affected significantly by select genetic polymorphisms.

Background The interleukin-23 pathway is implicated genetically and biologically in the pathogenesis of Crohn's disease. We aimed to assess the efficacy and safety of risankizumab (BI 655066, Boehringer Ingelheim, Ingelheim, Germany), a humanised monoclonal antibody targeting the p19 subunit of interleukin-23, in patients with moderately-to-severely active Crohn's disease. Methods In this randomised, double-blind, placebo-controlled phase 2 study, we enrolled patients at 36 referral sites in North America, Europe, and southeast Asia. Eligible patients were aged 18–75 years, with a diagnosis of Crohn's disease for at least 3 months, assessed as moderate-to-severe Crohn's disease at screening, defined as a Crohn's Disease Activity Index (CDAI) of 220–450, with mucosal ulcers in the ileum or colon, or both, and a Crohn's Disease Endoscopic Index of Severity (CDEIS) of at least 7 (≥4 for patients with isolated ileitis) on ileocolonoscopy scored by a masked central reader. Patients were randomised 1:1:1 using an interactive response system to a double-blind investigational product, and stratified by previous exposure to TNF antagonists (yes vs no). Patients received intravenous 200 mg risankizumab, 600 mg risankizumab, or placebo, at weeks 0, 4, and 8. The primary outcome was clinical remission (CDAI <150) at week 12 (intention-to-treat population). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02031276. Findings Between March, 2014, and September, 2015, 213 patients were screened, and 121 patients randomised. At baseline, 113 patients (93%) had been previously treated with at least one tumour necrosis factor (TNF) antagonist (which had failed in 96 [79%]). At week 12, 25 (31%) of 82 risankizumab patients (pooled 41 patients in 200 mg and 41 patients in 600 mg arms) had clinical remission versus six (15%) of 39 placebo patients (difference vs placebo 15·0%, 95% CI 0·1 to 30·1; p=0·0489). Ten (24%) of 41 patients who received 200 mg risankizumab had clinical remission (9·0%, −8·3 to 26·2; p=0·31) and 15 (37%) of 41 who received the 600 mg dose (20·9%, 2·6 to 39·2; p=0·0252). 95 (79%) patients had adverse events (32 in the placebo group, 32 randomised to 200 mg risankizumab, 31 randomised to 600 mg risankizumab); 18 had severe adverse events (nine, six, three); 12 discontinued (six, five, one); 24 had serious adverse events (12, nine, three). The most common adverse event was nausea and most common serious adverse event was worsening of underlying Crohn's disease. No deaths occurred. Interpretation In this short-term study, risankizumab was more effective than placebo for inducing clinical remission in patients with active Crohn's disease. Therefore, selective blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in Crohn's disease. Funding Boehringer Ingelheim.

Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease.In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809.This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events.Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality.AbbVie Pharmaceuticals.

Ozanimod (RPC1063) is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract.We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Patients were randomly assigned, in a 1:1:1 ratio, to receive ozanimod at a dose of 0.5 mg or 1 mg or placebo daily for up to 32 weeks. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. The primary outcome was clinical remission (Mayo Clinic score ≤2, with no subscore >1) at 8 weeks.The primary outcome occurred in 16% of the patients who received 1 mg of ozanimod and in 14% of those who received 0.5 mg of ozanimod, as compared with 6% of those who received placebo (P=0.048 and P=0.14, respectively, for the comparison of the two doses of ozanimod with placebo). Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory. Clinical response (decrease in Mayo Clinic score of ≥3 points and ≥30% and decrease in rectal-bleeding subscore of ≥1 point or a subscore ≤1) at 8 weeks occurred in 57% of those receiving 1 mg of ozanimod and 54% of those receiving 0.5 mg, as compared with 37% of those receiving placebo. At week 32, the rate of clinical remission was 21% in the group that received 1 mg of ozanimod, 26% in the group that received 0.5 mg of ozanimod, and 6% in the group that received placebo; the rate of clinical response was 51%, 35%, and 20%, respectively. At week 8, absolute lymphocyte counts declined 49% from baseline in the group that received 1 mg of ozanimod and 32% from baseline in the group that received 0.5 mg. The most common adverse events overall were anemia and headache.In this preliminary trial, ozanimod at a daily dose of 1 mg resulted in a slightly higher rate of clinical remission of ulcerative colitis than placebo. The trial was not large enough or of sufficiently long duration to establish clinical efficacy or assess safety. (Funded by Receptos; TOUCHSTONE ClinicalTrials.gov number, NCT01647516.).

Background & AimsWe studied the reliability of the previously described Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and validated it with an independent cohort of investigators.MethodsWe created a new library of 57 videos of flexible sigmoidoscopy and stratified them based on disease severity. Twenty-five investigators were each randomly assigned to assess 28 videos (which included 4 duplicates to assess intraobserver reliability). Investigators were blinded to clinical details except for 2 of 4 duplicated videos (to assess the impact of knowledge of symptoms on assessment). Three descriptors (“vascular pattern”, “bleeding”, and “erosions and ulcers”) comprising the UCEIS were scored with a visual analogue scale (VAS) to assess overall severity. Intrainvestigator and interinvestigator agreement was characterized by κ statistical analysis; reliability ratios were used to compare VAS and UCEIS scores.ResultsThere was a high level of correlation between UCEIS scores and overall assessment of severity (correlation coefficient, 0.93). Internal consistency (Cronbach α analysis) was 0.86. Intrainvestigator and interinvestigator reliability ratios for UCEIS scores were 0.96 and 0.88, respectively. Intrainvestigator agreement in determination of the UCEIS score was good (κ = 0.72), with individual descriptors ranging from a κ of 0.47 (for bleeding) to 0.87 (for vascular pattern). Interinvestigator agreement in determination of UCEIS scores was moderate (κ = 0.50), with descriptors ranging from a κ of 0.48 (for bleeding) to 0.54 (for vascular pattern). Intrainvestigator variability in determining UCEIS scores did not change appreciably when a video was presented with clinical details.ConclusionsThe UCEIS and its components show satisfactory intrainvestigator and interinvestigator reliability. Among investigators, the UCEIS accounted for a median of 86% of the variability in evaluation of overall severity on the VAS when assessing the endoscopic severity of UC and was unaffected by knowledge of clinical details. We studied the reliability of the previously described Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and validated it with an independent cohort of investigators. We created a new library of 57 videos of flexible sigmoidoscopy and stratified them based on disease severity. Twenty-five investigators were each randomly assigned to assess 28 videos (which included 4 duplicates to assess intraobserver reliability). Investigators were blinded to clinical details except for 2 of 4 duplicated videos (to assess the impact of knowledge of symptoms on assessment). Three descriptors (“vascular pattern”, “bleeding”, and “erosions and ulcers”) comprising the UCEIS were scored with a visual analogue scale (VAS) to assess overall severity. Intrainvestigator and interinvestigator agreement was characterized by κ statistical analysis; reliability ratios were used to compare VAS and UCEIS scores. There was a high level of correlation between UCEIS scores and overall assessment of severity (correlation coefficient, 0.93). Internal consistency (Cronbach α analysis) was 0.86. Intrainvestigator and interinvestigator reliability ratios for UCEIS scores were 0.96 and 0.88, respectively. Intrainvestigator agreement in determination of the UCEIS score was good (κ = 0.72), with individual descriptors ranging from a κ of 0.47 (for bleeding) to 0.87 (for vascular pattern). Interinvestigator agreement in determination of UCEIS scores was moderate (κ = 0.50), with descriptors ranging from a κ of 0.48 (for bleeding) to 0.54 (for vascular pattern). Intrainvestigator variability in determining UCEIS scores did not change appreciably when a video was presented with clinical details. The UCEIS and its components show satisfactory intrainvestigator and interinvestigator reliability. Among investigators, the UCEIS accounted for a median of 86% of the variability in evaluation of overall severity on the VAS when assessing the endoscopic severity of UC and was unaffected by knowledge of clinical details.

We determined the effects of adalimumab maintenance treatment on the risks of hospitalization and surgery in Crohn's disease (CD).A total of 778 patients with CD were randomized to placebo, adalimumab 40 mg every other week or adalimumab 40 mg weekly, all after an 80-mg/40-mg adalimumab induction regimen. All-cause and CD-related hospitalizations and major CD-related surgeries were compared between the placebo and adalimumab groups (every other week, weekly, and both combined) using Kaplan-Meier analysis and Cox proportional hazard models.Both 3- and 12-month hospitalization risks were significantly lower for patients who received adalimumab. Hazard ratios for all-cause hospitalization were 0.45, 0.36, and 0.40 for the adalimumab every other week, weekly, and combined groups, respectively (all P < .01 vs placebo). Hazard ratios for CD-related hospitalization were 0.50, 0.34, and 0.42, respectively (all P < .05). Cox model estimates demonstrated adalimumab every other week and weekly maintenance therapies were associated with 52% and 60% relative reductions in 12-month, all-cause hospitalization risk, and 48% and 64% reductions in 12-month risk of CD-related hospitalization. The combined adalimumab group was associated with 56% reductions in both all-cause and CD-related hospitalization risks. Fewer CD-related surgeries occurred in the adalimumab every other week, weekly, and combined groups compared with placebo (0.4, 0.8, and 0.6 vs 3.8 per 100 patients; all P < .05).Patients with moderate-to-severe CD treated with adalimumab had lower 1-year risks of hospitalization and surgery than placebo patients.

Previous Canadian recommendations have addressed severe UC in the hospitalized patient,9Bitton A. Buie D. Enns R. et al.Treatment of hospitalized adult patients with severe ulcerative colitis: Toronto consensus statements.Am J Gastroenterol. 2012; 107 (author reply 195): 179-194Crossref PubMed Scopus (122) Google Scholar and these guidelines present recommendations for the nonhospitalized patient with mild to severe active UC.

Background & Aims:This study determined the effectiveness of tacrolimus for the treatment of Crohn’s disease fistulas.Methods:The study was a randomized, double-blind, placebo-controlled, multicenter clinical trial. Forty-eight patients with Crohn’s disease and draining perianal or enterocutaneous fistulas were randomized to treatment with oral tacrolimus 0.2 mg · kg−1 · day−1 or placebo for 10 weeks. The primary outcome measure was fistula improvement as defined by closure of ≥50% of particular fistulas that were draining at baseline and maintenance of that closure for at least 4 weeks. A secondary outcome measure was fistula remission as defined by closure of all fistulas and maintenance of that closure for at least 4 weeks.Results:Forty-three percent of tacrolimus-treated patients had fistula improvement compared with 8% of placebo-treated patients (P = 0.004). Ten percent of tacrolimus-treated patients had fistula remission compared with 8% of placebo-treated patients (P = 0.86). Adverse events significantly associated with tacrolimus, including headache, increased serum creatinine level, insomnia, leg cramps, paresthesias, and tremor, were managed with dose reduction.Conclusions:Oral tacrolimus 0.2 mg · kg−1 · day−1 is effective for fistula improvement, but not fistula remission, in patients with perianal Crohn’s disease. Adverse events associated with tacrolimus can be managed by dose reduction. Lower doses of tacrolimus should be evaluated.

Although most treatment algorithms in inflammatory bowel disease (IBD) begin with classifying patients according to disease severity, no formal validated or consensus definitions of mild, moderate, or severe IBD currently exist. There are 3 main domains relevant to the evaluation of disease severity in IBD: impact of the disease on the patient, disease burden, and disease course. These measures are not mutually exclusive and the correlations and interactions between them are not necessarily proportionate. A comprehensive literature search was performed regarding current definitions of disease severity in both Crohn's disease and ulcerative colitis, and the ability to categorize disease severity in a particular patient. Although numerous assessment tools for symptoms, quality of life, patient-reported outcomes, fatigue, endoscopy, cross-sectional imaging, and histology (in ulcerative colitis) were identified, few have validated thresholds for categorizing disease activity or severity. Moving forward, we propose a preliminary set of criteria that could be used to classify IBD disease severity. These are grouped by the 3 domains of disease severity: impact of the disease on the patient (clinical symptoms, quality of life, fatigue, and disability); measurable inflammatory burden (C-reactive protein, mucosal lesions, upper gastrointestinal involvement, and disease extent), and disease course (including structural damage, history/extension of intestinal resection, perianal disease, number of flares, and extraintestinal manifestations). We further suggest that a disease severity classification should be developed and validated by an international group to develop a pragmatic means of identifying patients with severe disease. This is increasingly important to guide current therapeutic strategies for IBD and to develop treatment algorithms for clinical practice.

OBJECTIVES: To assess the safety and efficacy of brodalumab, a human anti-interleukin-17 receptor monoclonal antibody, in patients with moderate-to-severe Crohn’s disease (CD). METHODS: Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study in patients with moderate-to-severe CD and evidence of active inflammation. Patients were randomized 1:1:1:1 to receive brodalumab (210, 350, or 700 mg at baseline and week 4) or placebo. The primary end point was proportion of patients achieving Crohn’s disease activity index (CDAI) remission (≤150) at week 6. Secondary end points included proportion of patients with CDAI response (reduction from baseline of ≥100) at week 6 and change from baseline in CDAI at week 6. RESULTS: The study was terminated early based on an imbalance in worsening CD in active treatment groups. At the time of termination, 130 patients had been randomized. At week 6, remission rates were 3% (210 mg), 15% (350 mg), 9% (700 mg), and 3% (placebo) and CDAI response occurred in 16% (210 mg), 27% (350 mg), 15% (700 mg), and 13% (placebo) of patients. Mean change in CDAI at week 6 was −8.7 (95.3) (210 mg), −35.4 (105.6) (350 mg), −0.6 (105.9) (700 mg), and −28.2 (86.0) (placebo). Besides worsening of CD, overall incidences of adverse events were similar across treatment groups. CONCLUSIONS: Treatment with brodalumab resulted in a disproportionate number of cases of worsening CD in patients with active CD and no evidence of meaningful efficacy. These analyses did not suggest additional safety risks of brodalumab beyond worsening of CD symptoms in patients with active CD.

Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease.We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed.In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Elevated liver aminotransferase levels were more common with ozanimod.Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.).

Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone.In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50.Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62-2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated.The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. ClincialTrials.gov number, NCT00132899.

We analyzed data collected during the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) to assess relationships between serum concentrations of infliximab and outcomes of adults with moderate-to-severe ulcerative colitis.We compared serum concentrations of infliximab with outcomes of 728 patients with moderately-to-severely active ulcerative colitis who participated in ACT-1 or ACT-2; efficacy data were collected at weeks 8, 30, and 54 (for ACT-1 only). Relationships between serum concentration of infliximab and efficacy outcomes were assessed using trend, logistic regression, and receiver operating characteristic curve analyses. We also evaluated factors that affected the relationship between exposure and response.Median serum concentrations of infliximab at weeks 8, 30, and/or 54 were significantly higher in patients with clinical response, mucosal healing, and/or clinical remission than in patients who did not meet these response criteria. There were statistically significant relationships between quartile of infliximab serum concentration and efficacy at these time points (P < .01). Infliximab therapy was effective for a smaller proportion of patients in the lowest quartile, and these patients had lower serum levels of albumin and a higher incidence of antibodies to infliximab than patients in other quartiles. Although the relationship between exposure to infliximab and response varied among patients, approximate serum concentrations of 41 μg/mL infliximab at week 8 of induction therapy and 3.7 μg/mL at steady-state during maintenance therapy produced optimal outcomes in patients.Serum concentrations of infliximab are associated with efficacy in patients with moderate-to-severe ulcerative colitis; however, complex factors determine the relationship between exposure to this drug and response. A prospective evaluation of the value of measuring serum concentrations of infliximab should be performed before these data can be included in patient management strategies. Clinicaltrials.gov numbers: NCT00036439 and NCT00096655.

<h3>Objective</h3> Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn9s disease (CD). <h3>Design</h3> We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study. <h3>Results</h3> 180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p&lt;0.0001) with 10 mg twice daily after both induction and maintenance treatments. <h3>Conclusions</h3> Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib. <h3>Trial registration numbers</h3> NCT01393626 and NCT01393899.

Patients with ulcerative colitis or Crohn’s colitis have an increased risk of colorectal cancer (CRC). Most cases are believed to arise from dysplasia, and surveillance colonoscopy therefore is recommended to detect dysplasia. Detection of dysplasia traditionally has relied on both examination of the mucosa with targeted biopsies of visible lesions and extensive random biopsies to identify invisible dysplasia. Current U.S. guidelines recommend obtaining at least 32 random biopsy specimens from all segments of the colon as the foundation of endoscopic surveillance.

<h3>Objective</h3> Although the Geboes score (GS) and modified Riley score (MRS) are commonly used to evaluate histological disease activity in UC, their operating properties are unknown. Accordingly, we developed an alternative instrument. <h3>Design</h3> Four pathologists scored 48 UC colon biopsies using the GS, MRS and a visual analogue scale global rating. Intra-rater and inter-rater reliability for each index and individual index items were measured using intraclass correlation coefficients (ICCs). Items with high reliability were used to develop the Robarts histopathology index (RHI). The responsiveness/validity of the RHI and multiple histological, endoscopic and clinical outcome measures were evaluated by analyses of change scores, standardised effect size (SES) and Guyatt9s responsiveness statistic (GRS) using data from a clinical trial of an effective therapy. <h3>Results</h3> Inter-rater ICCs (95% CIs) for the total GS and MRS scores were 0.79 (0.63 to 0.87) and 0.80 (0.69 to 0.87). The correlation estimates between change scores in RHI and change score in GS and MRS were 0.75 (0.67 to 0.82) and 0.84 (0.79 to 0.88), respectively. The SES and GRS estimates for GS, MRS and RHI were: 1.87 (1.54 to 2.20) and 1.23 (0.97 to 1.50), 1.29 (1.02 to 1.56) and 0.88 (0.65 to 1.12), and 1.05 (0.79 to 1.30) and 0.88 (0.64 to 1.12), respectively. <h3>Conclusions</h3> The RHI is a new histopathological index with favourable operating properties.

Selective blockade of lymphocyte-vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the alpha4beta7 integrin, in patients with active Crohn's disease.Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (>or=70-point decrement in the Crohn's Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score <or=150) and with an enhanced clinical response (>or=100-point decrement in CDAI). Human anti-human antibody levels were measured.Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively (P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohn's disease.This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohn's disease.

<h3>Background & Aims</h3> Most patients with Crohn's disease (CD) eventually require an intestinal resection. However, CD frequently recurs after resection. We performed a randomized trial to compare the ability of infliximab vs placebo to prevent CD recurrence. <h3>Methods</h3> We evaluated the efficacy of infliximab in preventing postoperative recurrence of CD in 297 patients at 104 sites worldwide from November 2010 through May 2012. All study patients had undergone ileocolonic resection within 45 days before randomization. Patients were randomly assigned (1:1) to groups given infliximab (5 mg/kg) or placebo every 8 weeks for 200 weeks. The primary end point was clinical recurrence, defined as a composite outcome consisting of a CD Activity Index score >200 and a ≥70-point increase from baseline, and endoscopic recurrence (Rutgeerts score ≥i2, determined by a central reader) or development of a new or re-draining fistula or abscess, before or at week 76. Endoscopic recurrence was a major secondary end point. <h3>Results</h3> A smaller proportion of patients in the infliximab group had a clinical recurrence before or at week 76 compared with the placebo group, but this difference was not statistically significant (12.9% vs 20.0%; absolute risk reduction [ARR] with infliximab, 7.1%; 95% confidence interval: −1.3% to 15.5%; <i>P</i> = .097). A significantly smaller proportion of patients in the infliximab group had endoscopic recurrence compared with the placebo group (30.6% vs 60.0%; ARR with infliximab, 29.4%; 95% confidence interval: 18.6% to 40.2%; <i>P</i> < .001). Additionally, a significantly smaller proportion of patients in the infliximab group had endoscopic recurrence based only on Rutgeerts scores ≥i2 (22.4% vs 51.3%; ARR with infliximab, 28.9%; 95% confidence interval: 18.4% to 39.4%; <i>P</i> < .001). Patients previously treated with anti-tumor necrosis factor agents or those with more than 1 resection were at greater risk for clinical recurrence. The safety profile of infliximab was similar to that from previous reports. <h3>Conclusions</h3> Infliximab is not superior to placebo in preventing clinical recurrence after CD-related resection. However, infliximab does reduce endoscopic recurrence. ClinicalTrials.gov ID NCT01190839.

Background Oral 5‐aminosalicylic acid (5‐ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. Previously, it was found that 5‐ASA drugs in doses of at least 2 g/day, were more effective than placebo but no more effective than SASP for inducing remission in ulcerative colitis. This updated review includes more recent studies and evaluates the efficacy and safety of 5‐ASA preparations used for the treatment of mild to moderately active ulcerative colitis. Objectives The primary objectives were to assess the efficacy, dose‐responsiveness and safety of oral 5‐ASA compared to placebo, SASP, or 5‐ASA comparators for induction of remission in active ulcerative colitis. A secondary objective of this systematic review was to compare the efficacy and safety of once daily dosing of oral 5‐ASA with conventional (two or three times daily) dosing regimens. Search methods A computer‐assisted literature search for relevant studies (inception to July 9, 2015) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies. Selection criteria Studies were accepted for analysis if they were randomized controlled clinical trials of parallel design, with a minimum treatment duration of four weeks. Studies of oral 5‐ASA therapy for treatment of patients with active ulcerative colitis compared with placebo, SASP or other formulations of 5‐ASA were considered for inclusion. Studies that compared once daily 5‐ASA treatment with conventional dosing of 5‐ASA (two or three times daily) and 5‐ASA dose ranging studies were also considered for inclusion. Data collection and analysis The outcomes of interest were the failure to induce global/clinical remission, global/clinical improvement, endoscopic remission, endoscopic improvement, adherence, adverse events, withdrawals due to adverse events, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5‐ASA versus placebo, 5‐ASA versus sulfasalazine, once daily dosing versus conventional dosing, 5‐ASA versus comparator 5‐ASA, and 5‐ASA dose‐ranging. Placebo‐controlled trials were subgrouped by dosage. SASP‐controlled trials were subgrouped by 5‐ASA/SASP mass ratios. Once daily versus conventional dosing studies were subgrouped by formulation. 5‐ASA‐controlled trials were subgrouped by common 5‐ASA comparators (e.g. Asacol, Claversal, Salofalk and Pentasa). Dose‐ranging studies were subgrouped by 5‐ASA formulation. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention‐to‐treat basis. Main results Fifty‐three studies (8548 patients) were included. The majority of included studies were rated as low risk of bias. 5‐ASA was significantly superior to placebo with regard to all measured outcome variables. Seventy‐one per cent of 5‐ASA patients failed to enter clinical remission compared to 83% of placebo patients (RR 0.86, 95% CI 0.82 to 0.89). A dose‐response trend for 5‐ASA was also observed. No statistically significant differences in efficacy were found between 5‐ASA and SASP. Fifty‐four per cent of 5‐ASA patients failed to enter remission compared to 58% of SASP patients (RR 0.90, 95% CI 0.77 to 1.04). No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5‐ASA. Forty‐five per cent of once daily patients failed to enter clinical remission compared to 48% of conventionally dosed patients (RR 0.94, 95% CI 0.83 to 1.07). Eight per cent of patients dosed once daily failed to adhere to their medication regimen compared to 6% of conventionally dosed patients (RR 1.36, 95% CI 0.64 to 2.86). There does not appear to be any difference in efficacy among the various 5‐ASA formulations. Fifty per cent of patients in the 5‐ASA group failed to enter remission compared to 52% of patients in the 5‐ASA comparator group (RR 0.94, 95% CI 0.86 to 1.02). A pooled analysis of 3 studies (n = 1459 patients) studies found no statistically significant difference in clinical improvement between Asacol 4.8 g/day and 2.4 g/day used for the treatment of moderately active ulcerative colitis. Thirty‐seven per cent of patients in the 4.8 g/day group failed to improve clinically compared to 41% of patients in the 2.4 g/day group (RR 0.89; 95% CI 0.78 to 1.01). Subgroup analysis indicated that patients with moderate disease may benefit from the higher dose of 4.8 g/day. One study compared (n = 123 patients) Pentasa 4 g/day to 2.25 g/day in patients with moderate disease. Twenty‐five per cent of patients in the 4 g/day group failed to improve clinically compared to 57% of patients in the 2.25 g/day group (RR 0.44; 95% CI 0.27 to 0.71). A pooled analysis of two studies comparing MMX mesalamine 4.8 g/day to 2.4 g/day found no statistically significant difference in efficacy (RR 1.03, 95% CI 0.82 to 1.29). There were no statistically significant differences in the incidence of adverse events between 5‐ASA and placebo, once daily and conventionally dosed 5‐ASA, 5‐ASA and comparator 5‐ASA formulation and 5‐ASA dose ranging (high dose versus low dose) studies. Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache and worsening ulcerative colitis. SASP was not as well tolerated as 5‐ASA. Twenty‐nine percent of SASP patients experienced an adverse event compared to 15% of 5‐ASA patients (RR 0.48, 95% CI 0.37 to 0.63). Authors' conclusions 5‐ASA was superior to placebo and no more effective than SASP. Considering their relative costs, a clinical advantage to using oral 5‐ASA in place of SASP appears unlikely. 5‐ASA dosed once daily appears to be as efficacious and safe as conventionally dosed 5‐ASA. Adherence does not appear to be enhanced by once daily dosing in the clinical trial setting. It is unknown if once daily dosing of 5‐ASA improves adherence in a community‐based setting. There do not appear to be any differences in efficacy or safety among the various 5‐ASA formulations. A daily dosage of 2.4 g appears to be a safe and effective induction therapy for patients with mild to moderately active ulcerative colitis. Patients with moderate disease may benefit from an initial dose of 4.8 g/day.

Inflammatory bowel diseases (IBD) - Crohn's disease (CD) and ulcerative colitis (UC) - significantly impact quality of life and account for substantial costs to the health care system and society.To conduct a comprehensive review and summary of the burden of IBD that encompasses the epidemiology, direct medical costs, indirect costs and humanistic impact of these diseases in Canada.A literature search focused on Canadian data sources. Analyses were applied to the current 2012 Canadian population.There are approximately 233,000 Canadians living with IBD in 2012 (129,000 individuals with CD and 104,000 with UC), corresponding to a prevalence of 0.67%. Approximately 10,200 incident cases occur annually. IBD can be diagnosed at any age, with typical onset occurring in the second or third decade of life. There are approximately 5900 Canadian children <18 years of age with IBD. The economic costs of IBD are estimated to be $2.8 billion in 2012 (almost $12,000 per IBD patient). Direct medical costs exceed $1.2 billion per annum and are driven by cost of medications ($521 million), hospitalizations ($395 million) and physician visits ($132 million). Indirect costs (society and patient costs) total $1.6 billion and are dominated by long-term work losses of $979 million. Compared with the general population, the quality of life patients experience is low across all dimensions of health.The present review documents a high burden of illness from IBD due to its high prevalence in Canada combined with high per-patient costs. Canada has among the highest prevalence and incidence rates of IBD in the world. Individuals with IBD face challenges in the current environment including lack of awareness of IBD as a chronic disease, late or inappropriate diagnosis, inequitable access to health care services and expensive medications, diminished employment prospects and limited community-based support.

Oral 5-aminosalicylic (5-ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. Previously, it was found that 5-ASA drugs were more effective than placebo but had a statistically significant therapeutic inferiority relative to SASP. This updated review includes more recent studies and evaluates the effectiveness, dose-responsiveness, and safety of 5-ASA preparations used for maintenance of remission in quiescent ulcerative colitis.The primary objectives were to assess the efficacy, dose-responsiveness and safety of oral 5-ASA compared to placebo, SASP, or 5-ASA comparators for maintenance of remission in quiescent ulcerative colitis. A secondary objective was to compare the efficacy and safety of once daily dosing of oral 5-ASA with conventional (two or three times daily) dosing regimens.A literature search for relevant studies (inception to 9 July 2015) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies.Studies were accepted for analysis if they were randomized controlled trials with a minimum treatment duration of six months. Studies of oral 5-ASA therapy for treatment of patients with quiescent ulcerative colitis compared with placebo, SASP or other 5-ASA formulations were considered for inclusion. Studies that compared once daily 5-ASA treatment with conventional dosing of 5-ASA and 5-ASA dose ranging studies were also considered for inclusion.The primary outcome was the failure to maintain clinical or endoscopic remission. Secondary outcomes included adherence, adverse events, withdrawals due to adverse events, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5-ASA versus placebo, 5-ASA versus sulfasalazine, once daily dosing versus conventional dosing, 5-ASA versus comparator 5-ASA formulation, and 5-ASA dose-ranging. Placebo-controlled trials were subgrouped by dosage. Once daily versus conventional dosing studies were subgrouped by formulation. 5-ASA-controlled trials were subgrouped by common 5-ASA comparators (e.g. Asacol and Salofalk). Dose-ranging studies were subgrouped by 5-ASA formulation. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention-to-treat basis.Forty-one studies (8928 patients) were included. The majority of included studies were rated as low risk of bias. Ten studies were rated at high risk of bias. Seven of these studies were single-blind and three studies were open-label. However, two open-label studies and four of the single-blind studies utilized investigator performed endoscopy as an endpoint, which may protect against bias. 5-ASA was significantly superior to placebo for maintenance of clinical or endoscopic remission. Forty-one per cent of 5-ASA patients relapsed compared to 58% of placebo patients (7 studies, 1298 patients; RR 0.69, 95% CI 0.62 to 0.77). There was a trend towards greater efficacy with higher doses of 5-ASA with a statistically significant benefit for the 1 to 1.9 g/day (RR 0.65; 95% CI 0.56 to 0.76) and the > 2 g/day subgroups (RR 0.73, 95% CI 0.60 to 0.89). SASP was significantly superior to 5-ASA for maintenance of remission. Forty-eight per cent of 5-ASA patients relapsed compared to 43% of SASP patients (12 studies, 1655 patients; RR 1.14, 95% CI 1.03 to 1.27). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome for the placebo and SASP-controlled studies was high. No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5-ASA. Twenty-nine per cent of once daily patients relapsed over 12 months compared to 31% of conventionally dosed patients (8 studies, 3127 patients; RR 0.91, 95% CI 0.82 to 1.01). Eleven per cent of patients in the once daily group failed to adhere to their medication regimen compared to 9% of patients in the conventional dosing group (6 studies, 1462 patients; RR 1.22, 95% CI 0.91 to 1.64). There does not appear to be any difference in efficacy among the various 5-ASA formulations. Forty-four per cent of patients in the 5-ASA group relapsed compared to 41% of patients in the 5-ASA comparator group (6 studies, 707 patients; RR 1.08, 95% CI 0.91 to 1.28). A pooled analysis of two studies showed no statistically significant difference in efficacy between Balsalazide 6 g and 3 g/day. Twenty-three per cent of patients in the 6 g/day group relapsed compared to 33% of patients in the 3 g/day group (216 patients; RR 0.76; 95% CI 0.45 to 2.79). One study found Balsalazide 4 g to be superior to 2 g/day. Thirty-seven per cent of patients in the 4 g/day Balsalazide group relapsed compared to 55% of patients in the 2 g/day group (133 patients; RR 0.66; 95% CI 0.45 to 0.97). One study found a statistically significant difference between Salofalk granules 3 g and 1.5 g/day. Twenty-five per cent of patients in the Salofalk 3 g/day group relapsed compared to 39% of patients in the 1.5 g/day group (429 patients; RR 0.65; 95% CI 0.49 to 0.86). Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache, dyspepsia, and nasopharyngitis. There were no statistically significant differences in the incidence of adverse events between 5-ASA and placebo, 5-ASA and SASP, once daily and conventionally dosed 5-ASA, 5-ASA and comparator 5-ASA formulations and 5-ASA dose ranging studies. The trials that compared 5-ASA and SASP may have been biased in favour of SASP because most trials enrolled patients known to be tolerant to SASP which may have minimized SASP-related adverse events.5-ASA was superior to placebo for maintenance therapy in ulcerative colitis. However, 5-ASA had a statistically significant therapeutic inferiority relative to SASP. Oral 5-ASA administered once daily is as effective and safe as conventional dosing for maintenance of remission in quiescent ulcerative colitis. There does not appear to be any difference in efficacy or safety between the various formulations of 5-ASA. Patients with extensive ulcerative colitis or with frequent relapses may benefit from a higher dose of maintenance therapy. High dose therapy appears to be as safe as low dose and is not associated with a higher incidence of adverse events.

<h3>Context</h3>Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority.<h3>Objective</h3>To determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease.<h3>Design, Setting, and Patients</h3>Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohn's Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively.<h3>Interventions</h3>Patients with a Crohn's Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted.<h3>Main Outcome Measure</h3>Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease.<h3>Results</h3>For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease.<h3>Conclusion</h3>In these trials, treatment with omega-3 free fatty acids was not effective for the prevention of relapse in Crohn disease.<h3>Trial Registration</h3>clinicaltrials.gov Identifiers: EPIC-1: NCT00613197, EPIC-2: NCT00074542

The traditional management of Crohn's disease, which is based on progressive, step-wise treatment intensification with re-evaluation of response according to symptoms, does not improve long-term outcomes of Crohn's disease and places patients at risk for bowel damage. The introduction of novel therapies and the development of new approaches to treatment in rheumatoid arthritis led to better outcomes for patients. Prominent among these is a "treat to target" strategy that is based on regular assessment of disease activity by using objective clinical and biological outcome measures and the subsequent adjustment of treatments. This approach is complementary to the concept of early intervention in high-risk patients. This review evaluates current literature on this topic and proposes a definition for the concept of treating to targets for Crohn's disease.

Although low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohn's disease (CD), the clinical relevance of ATI in patients with adequate infliximab concentrations is uncertain. We evaluated this question using an assay sensitive for identification of ATI in the presence of infliximab.In an observational study, 1487 trough serum samples from 483 patients with CD who participated in four clinical studies of maintenance infliximab therapy were analysed using a fluid phase mobility shift assay. Infliximab and ATI concentrations most discriminant for remission, defined as a C-reactive protein concentration of ≤ 5 mg/L, were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission.Based upon analysis of 1487 samples, 77.1% of patients had detectable and 22.9% had undetectable infliximab concentrations, of which 9.5% and 71.8%, respectively, were positive for ATI. An infliximab concentration of > 2.79 μg/mL (area under the curve (AUC) = 0.681; 95% CI 0.632 to 0.731) and ATI concentration of < 3.15 U/mL (AUC = 0.632; 95% CI 0.589 to 0.676) were associated with remission. Multivariable analysis showed that concentrations of both infliximab trough (OR 1.8; 95% CI 1.3 to 2.5; p < 0.001) and ATI (OR 0.57; 95% CI 0.39 to 0.81; p = 0.002) were independent predictors of remission.The development of ATI increases the probability of active disease even at low concentrations and in the presence of a therapeutic concentration of drug during infliximab maintenance therapy. Evaluation of strategies to prevent ATI formation, including therapeutic drug monitoring with selective infliximab dose intensification, is needed.

BackgroundAlthough metronidazole and ciprofloxacin are used to treat perianal Crohn's disease (CD), no placebo-controlled trials have been performed.

MEDI2070 is a human monoclonal antibody that selectively inhibits interleukin 23 (IL23), a cytokine implicated in the pathogenesis of Crohn's disease (CD). We analyzed its safety and efficacy in treatment of CD in a phase 2a study.We conducted a double-blind, placebo-controlled study of 119 adults with moderate to severe CD failed by treatment with tumor necrosis factor antagonists. Patients were randomly assigned (1:1) to groups given MEDI2070 (700 mg) or placebo intravenously at weeks 0 and 4. Patients received open-label MEDI2070 (210 mg) subcutaneously every 4 weeks from weeks 12 to 112. The CD Activity Index was used to measure disease activity.The primary outcome, clinical response (either a 100-point decrease in CD Activity Index score from baseline or clinical remission, defined as CD Activity Index score <150) at week 8 occurred in 49.2% of patients receiving MEDI2070 (n = 59) compared with 26.7% receiving placebo (n = 60; absolute difference, 22.5%; 95% confidence interval, 5.6%-39.5%; P = .010). Clinical response at week 24 occurred in 53.8% of patients who continued to receive open-label MEDI2070 and in 57.7% of patients who had received placebo during the double-blind period and open-label MEDI2070 thereafter. The most common adverse events were headache and nasopharyngitis. Higher baseline serum concentrations of IL22, a cytokine whose expression is induced by IL23, were associated with greater likelihood of response to MEDI2070 compared with placebo.In a phase 2a trial of patients with moderate to severe Crohn's disease who had failed treatment with tumor necrosis factor antagonists, 8 and 24 weeks of treatment with MEDI2070 were associated with clinical improvement. ClinicalTrials.gov ID: NCT01714726.

The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. We assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis.This phase 2b/3, double-blind, randomised, placebo-controlled trial including two induction studies and one maintenance study was done in 341 study centres in 40 countries. Eligible patients were aged 18-75 years with moderately to severely active ulcerative colitis for at least 6 months before enrolment (induction study A: inadequate clinical response, loss of response to or intolerance to corticosteroids or immunosuppressants, naive to tumour necrosis factor [TNF] antagonists and vedolizumab [biologic-naive]; induction study B: inadequate clinical response, loss of response to or intolerance to any TNF antagonist or vedolizumab, no TNF antagonist or vedolizumab use within 8 weeks before screening [biologic-experienced]). Patients were randomly assigned 2:2:1 to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once per day for 11 weeks. Patients who had either clinical remission or a Mayo Clinic Score response at week 10 in either induction study entered the maintenance study. Patients who received induction filgotinib were rerandomised 2:1 to continue their induction filgotinib regimen or to placebo. Patients who received induction placebo continued receiving placebo. The primary endpoint was clinical remission by Mayo endoscopic, rectal bleeding, and stool frequency subscores at weeks 10 and 58. For the induction studies, efficacy was assessed in all randomised patients who received at least one dose of study drug or placebo within that study. For the maintenance study, efficacy was assessed in all patients randomised to any filgotinib treatment group in the induction studies who received at least one dose of study drug or placebo in the maintenance study. Patients who received placebo throughout the induction and maintenance study were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of the study drug or placebo within each study. This trial is registered with ClinicalTrials.gov, NCT02914522.Between Nov 14, 2016, and March 31, 2020, we screened 2040 patients for eligibility. 659 patients enrolled in induction study A were randomly assigned to receive filgotinib 100 mg (n=277), filgotinib 200 mg (n=245), or placebo (n=137). 689 patients enrolled into induction study B were randomly assigned to receive filgotinib 100 mg (n=285), filgotinib 200 mg (n=262), or placebo (n=142). 34 patients in induction study A and 54 patients in induction study B discontinued the study drug before week 10. After efficacy assessment at week 10, 664 patients entered the maintenance study (391 from induction study A, 273 from induction study B). 93 patients continued to receive placebo. 270 patients who had received filgotinib 100 mg in the induction study were randomly assigned to receive filgotinib 100 mg (n=179) or placebo (n=91). 301 patients who had received filgotinib 200 mg in the induction study were randomly assigned to receive filgotinib 200 mg (n=202) or placebo (n=99). 263 patients discontinued treatment in the maintenance study. At week 10, a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A 26·1% vs 15·3%, difference 10·8%; 95% CI 2·1-19·5, p=0·0157; induction study B 11·5% vs 4·2%, 7·2%; 1·6-12·8, p=0·0103). At week 58, 37·2% of patients given filgotinib 200 mg had clinical remission versus 11·2% in the respective placebo group (difference 26·0%, 95% CI 16·0-35·9; p<0·0001). Clinical remission was not significantly different between filgotinib 100 mg and placebo at week 10, but was significant by week 58 (23·8% vs 13·5%, 10·4%; 0·0-20·7, p=0·0420). The incidence of serious adverse events and adverse events of interest was similar between treatment groups. In the induction studies, serious adverse events occurred in 28 (5·0%) of 562 patients given filgotinib 100 mg, 22 (4·3%) of 507 patients given filgotinib 200 mg, and 13 (4·7%) of 279 patients given placebo. In the maintenance study, serious adverse events were reported in eight (4·5%) of 179 patients given filgotinib 100 mg, seven (7·7%) of 91 patients in the respective placebo group, nine (4·5%) of 202 patients in the filgotinib 200 mg group, and no patients in the respective placebo group. No deaths were reported during either induction study. Two patients died during the maintenance study; neither was related to treatment.Filgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis.Gilead Sciences.

Vedolizumab, an anti-α(4)β(7) integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing.To characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic-pharmacodynamic relationship using population modelling.Data from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data.Vedolizumab pharmacokinetics was described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half-life of vedolizumab was 25.5 days; linear clearance (CL(L)) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution (V(c)) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (%CV) were 35% for CLL and 19% for V(c); residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CL(L).Population pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2); NCT01224171 (GEMINI 3).

Background & AimsWe evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn’s disease (CD).MethodsWe performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo; or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily; or 24 mg upadacitinib once daily and were evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using the multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%.ResultsAmong the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo. Endoscopic remission was achieved by 10% (P < .1 vs placebo), 8%, 8% (P < .1 vs placebo), 22% (P < .01 vs placebo), and 14% (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections vs placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol levels compared with patients in the placebo group.ConclusionsIn a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients compared with placebo. Upadacitinib’s benefit/risk profile supports further development for treatment of CD. (Clinicaltrials.gov, Number: NCT02365649) We evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn’s disease (CD). We performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo; or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily; or 24 mg upadacitinib once daily and were evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using the multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%. Among the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo. Endoscopic remission was achieved by 10% (P < .1 vs placebo), 8%, 8% (P < .1 vs placebo), 22% (P < .01 vs placebo), and 14% (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections vs placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol levels compared with patients in the placebo group. In a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients compared with placebo. Upadacitinib’s benefit/risk profile supports further development for treatment of CD. (Clinicaltrials.gov, Number: NCT02365649)

The inflammatory bowel diseases ulcerative colitis and Crohn's disease are chronic, relapsing disorders of the gastrointestinal tract. Collectively, these conditions can result in debilitating physical and psychosocial symptoms for patients and affect society through loss of schooling, absenteeism, and health-care costs. More than 2 million Europeans and 1·5 million North Americans have inflammatory bowel disease (IBD), with the majority of health-care costs driven by medication. The cause of IBD is unknown, but it is considered to be the result of an inappropriate immune response against environmental factors, including luminal and microbial antigens, in genetically susceptible hosts.1de Souza HS Fiocchi C Immunopathogenesis of IBD: current state of the art.Nat Rev Gastroenterol Hepatol. 2016; 13: 13-27Crossref PubMed Scopus (820) Google Scholar Over the past decade, large-scale genome-wide association studies have identified more than 200 genetic loci associated with IBD, some of which are shared with other chronic autoimmune diseases. The majority of loci are shared across diverse ancestral groups, apart from major European risk variants such as NOD2 (the first identified mutation that mediates immune response to gut bacteria) and IL23R, which are not present in east Asians.2Jostins L Ripke S Weersma RK et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (3227) Google Scholar However, this large investment in genetics has not yet resulted in direct benefit on patient outcomes, either through identification of risk-stratification tools for disease progression or for predicting response to therapy, resulting in renewed interest in understanding the effects of environmental exposures. Epidemiological studies of migrant populations have shown that the offspring of individuals immigrating from regions with low IBD prevalence in Asia to the developed world have similarly high incidence of IBD compared with children of non-immigrants, indicating that risk might be triggered by earlier life exposure to environmental antigens.3Benchimol EI Mack DR Guttmann A et al.Inflammatory bowel disease in immigrants to Canada and their children: a population-based cohort study.Am J Gastroenterol. 2015; 110: 553-563Crossref PubMed Scopus (149) Google Scholar The rising incidence observed in newly industrialised nations is associated with striking dietary changes, including increased exposure to processed food, refined sugars, dairy, and less plant-based fibres.4Windsor JW Kaplan GG Evolving epidemiology of IBD.Curr Gastroenterol Rep. 2019; 21: 40Crossref PubMed Scopus (116) Google Scholar In China, since the first reported case of IBD in 1956, more than 260 000 people are now living with IBD—a rise paralleled with westernisation of diet and culture.5Kaplan GG Ng SC Globalisation of inflammatory bowel disease: perspectives from the evolution of inflammatory bowel disease in the UK and China.Lancet Gastroenterol Hepatol. 2016; 1: 307-316Summary Full Text Full Text PDF PubMed Scopus (115) Google Scholar Other environmental exposures linked to an increased risk for development of IBD include smoking in Crohn's disease, childhood antibiotic exposure, non-steroidal drugs, stress, and the hygiene hypothesis;6Ananthakrishnan AN Epidemiology and risk factors for IBD.Nat Rev Gastroenterol Hepatol. 2015; 12: 205-217Crossref PubMed Scopus (882) Google Scholar protective factors include smoking in ulcerative colitis, appendectomy, and breastfeeding. In The Lancet Gastroenterology & Hepatology, the GBD 2017 Inflammatory Bowel Disease Collaborators report global prevalence, mortality, and overall burden of IBD from 195 countries and territories between 1990 and 2017, using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017.7GBD 2017 Inflammatory Bowel Disease CollaboratorsThe global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet Gastroenterol Hepatol. 2019; (published online Oct 21)https://doi.org/10.1016/S2468-1253(19)30333-4Google Scholar Similar to observations reported in a systematic review of cohort studies in The Lancet in 2018,8Ng SC Shi HY Hamidi N et al.Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.Lancet. 2018; 390: 2769-2778Summary Full Text Full Text PDF PubMed Scopus (2432) Google Scholar incidence has stabilised in the west, but prevalence increased because of improved survival. Conversely, the authors report rapidly rising incidence rates in newly industrialised countries in South America, eastern Europe, Asia, and Africa, which are likely yet to peak, but lower prevalence. Furthermore, the rise in earlier onset IBD means longer disease duration and potentially more complex disease into adulthood and old age, bringing associated challenges of managing IBD in an ageing population, with concurrent comorbidity and risk of treatment-related adverse events. Reassuringly, reductions in mortality were observed (eg, the age-standardised death rate decreased from 0·61 [95% uncertainty interval 0·55–0·69] per 100 000 population in 1990 to 0·51 [0·42–0·54] in 2017), with improved survival attributed by the authors to timelier introduction of biological agents, colon cancer surveillance, and better surgical techniques. Collectively, more than 6·8 million people are estimated to be living with IBD worldwide. This burden to patients and society will require investment into research to better understand the interplay of genes, the microbiome, and the environment, to address traditional paradigms of chronic disease prevention. Enhanced understanding of the very early stages of IBD from preclinical samples might eventually offer possibilities for disease prevention in high-risk individuals (eg, first-degree relatives) through manipulation of the microbiome or dietary therapies.9Torres J Burisch J Riddle M Dubinsky M Colombel JF Preclinical disease and preventive strategies in IBD: perspectives, challenges and opportunities.Gut. 2016; 65: 1061-1069Crossref PubMed Scopus (51) Google Scholar The Crohn's and Colitis Canada Genetic, Environmental, Microbial (GEM) Project, which is prospectively enrolling first-degree relatives of Crohn's disease probands with biomarker collection and environmental history exposure, might provide novel insights into such preclinical disease pathways. Ultimately, the goal is to either interrupt these diseases preclinically in high-risk individuals—an approach that has recently shown promise in type 1 diabetes10Herold KC Bundy BN Long SA et al.An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes.N Engl J Med. 2019; 381: 603-613Crossref PubMed Scopus (330) Google Scholar—or to develop primary prevention strategies based on dietary interventions. The study by the GBD 2017 Inflammatory Bowel Disease Collaborators shows that data from large-scale population epidemiology studies are essential for providing insights into the cause of IBD that will ultimately result in a cure. VJ has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genetech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Topivert, and Celltrion; and speaker's fees from Takeda, Janssen, Shire, Ferring, AbbVie, and Pfizer. BGF has received consulting fees from Abbott/AbbVie, AdMIRx, Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport, Aptevo Therapeutics, Asta Pharma, AstraZeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, Galapagos, Galen/Atlantica, GiCare Pharma, Gilead, Gossamer Pharma, GlaxoSmithKline, Inception IBD, Intact Therapeutics, JnJ/Janssen, Kyowa Kakko Kirin, Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestlé, Nextbiotix, Novonordisk, ParImmune, Parvus Therapeutics, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Qu Biologics, Rebiotix, Receptos, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma, Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared, and Zyngenia; speaker's fees from Abbott/AbbVie, JnJ/Janssen, Lilly, Takeda, Tillotts, UCB Pharma; grant/research support from AbbVie, Amgen, AstraZeneca/MedImmune, Atlantic Pharmaceuticals, Boehringer Ingelheim, Celgene Corporation, Celltech, Genentech/Hoffmann-La Roche, Gilead Sciences, GlaxoSmithKline, Janssen Research & Development, Pfizer, Receptos/Celgene International, Sanofi, Santarus, Takeda Development Center Americas, Tillotts Pharma, and UCB; is a member of the scientific advisory board for Abbott/AbbVie, Allergan, Amgen, AstraZeneca, Atlantic Pharma, Avaxia Biologics, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Elan/Biogen, Galapagos, Genentech/Roche, JnJ/Janssen, Merck, Nestlé, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma, and UCB Pharma; and is a member of the board of directors for Robarts Clinical Trials. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017The prevalence of IBD increased substantially in many regions from 1990 to 2017, which might pose a substantial social and economic burden on governments and health systems in the coming years. Our findings can be useful for policy makers developing strategies to tackle IBD, including the education of specialised personnel to address the burden of this complex disease. Full-Text PDF Open Access

BackgroundVedolizumab is a gut-selective biologic that has shown efficacy in ulcerative colitis (UC) and Crohn's disease (CD). We studied the pharmacokinetics, pharmacodynamics, safety, tolerability, and efficacy of a new formulation of vedolizumab produced by an improved manufacturing process.

The aim was to evaluate long-term efficacy, quality of life, and safety in ulcerative colitis patients who received infliximab during the ACT-1 and -2 extension studies.Adults with moderate-to-severely active ulcerative colitis in the 54-week ACT-1 and 30-week ACT-2 studies who achieved benefit from infliximab were eligible to participate in extension studies and receive up to 3 additional years of therapy. Patients received randomized study medication until all sites were unblinded; placebo-treated patients were discontinued. Patients receiving 5 or 10 mg/kg infliximab continued to receive open-label infliximab every 8 weeks. Patients receiving infliximab 10 mg/kg could decrease to 5 mg/kg; patients receiving infliximab 5 mg/kg could increase to 10 mg/kg if response was lost.A total of 229 of 484 infliximab-treated patients from the ACT-1 and ACT-2 main studies entered the long-term extensions. Overall, 70 (30.6%) patients discontinued infliximab infusions for adverse events (24 [10.5%]), lack of efficacy (11 [4.8%]), required a colectomy (1 [0.4%]), or for other reasons (34 [14.8%]). Proportions of patients whose Physician's Global Assessment scores were indicative of no or mild disease (score = 0 or 1) were maintained during the extension studies; 76.5% at Extension week 0 and ranged between 90.0% and 94.3% through Extension week 152. Improvement in Inflammatory Bowel Disease Questionnaire scores observed in the main studies was maintained. During the long-term extension, the infliximab safety profile was consistent with that of the main studies; no new or unexpected safety signals were observed.Long-term treatment with infliximab for up to 3 additional years was effective and well tolerated.

Interobserver differences in endoscopic assessments contribute to variations in rates of response to placebo in ulcerative colitis (UC) trials. We investigated whether centralized review of images could reduce these variations.We performed a 10-week, randomized, double-blind, placebo-controlled study of 281 patients with mildly to moderately active UC, defined by an Ulcerative Colitis Disease Activity Index (UCDAI) sigmoidoscopy score ≥2, that evaluated the efficacy of delayed-release mesalamine (Asacol 800-mg tablet) 4.8 g/day. Endoscopic images were reviewed by a single expert central reader. The primary outcome was clinical remission (UCDAI, stool frequency and bleeding scores of 0, and no fecal urgency) at week 6.The primary outcome was achieved by 30.0% of patients treated with mesalamine and 20.6% of those given placebo, a difference of 9.4% (95% confidence interval [CI], -0.7% to 19.4%; P = .069). Significant differences in results from secondary analyses indicated the efficacy of mesalamine. Thirty-one percent of participants, all of whom had a UCDAI sigmoidoscopy score ≥2 as read by the site investigator, were considered ineligible by the central reader. After exclusion of these patients, the remission rates were 29.0% and 13.8% in the mesalamine and placebo groups, respectively (difference of 15%; 95% CI, 3.5%-26.0%; P = .011).Although mesalamine 4.8 g/day was not statistically different from placebo for induction of remission in patients with mildly to moderately active UC, based on an intent-to-treat analysis, the totality of the data supports a benefit of treatment. Central review of endoscopic images is critical to the conduct of induction studies in UC; ClinicalTrials.gov Number, NCT01059344.

Although tumor necrosis factor (TNF) antagonists have shown clear benefits over conventional treatments for inducing and maintaining clinical remission in both Crohn's disease and ulcerative colitis, a high proportion of patients lose response over time. Given the scarce alternative of treatments when treatment failure occurs, it is highly desirable to optimize both initial response and long-term continuation of TNF antagonists. One of the most well-characterized factors associated with loss of response to these agents is the development of immunogenicity, whereby the production of neutralizing antidrug antibodies accelerates drug clearance, leading to subtherapeutic drug concentrations and, ultimately, to treatment failure. However, other patient-related factors, such as sex and/or body size, and disease severity, including TNF burden and serum albumin concentration among others, also may influence the pharmacokinetics of these agents. Nevertheless, the evidence generated to date about these complex interactions is scarce, and further prospective studies evaluating their influence on the pharmacokinetics of TNF antagonists are needed. Drug adjustment empirically based on clinical symptoms often is inaccurate and may lead to suboptimal outcomes. Recent evidence shows that maintenance of an optimal therapeutic drug concentration is associated with improved clinical outcomes. Therefore, incorporation of therapeutic drug monitoring into clinical practice may allow clinicians to optimize treatment by maintaining effective drug concentrations over time.

It is important to have clear goals for treating inflammatory bowel disease in clinical practice and in research. Conventional end points for trials in ulcerative colitis and Crohn’s disease have been based on composite indices, such as the Mayo Clinic Score and the Crohn’s Disease Activity Index; these indices incorporate symptoms, signs, and findings from laboratory tests and sometimes endoscopic assessments. Although definitions of clinical response and remission have been based on these indices for regulatory purposes, they are difficult to apply to practice because they are complex and not intuitive to clinicians. This has caused a disconnect between clinical trials and practice. Recently, the use of composite indices in trials has been reevaluated in Food and Drug Administration–sponsored Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics workshops due to concerns about the validity of the indices. Alternative measures of outcome and definitions of response are being developed. Patient-reported outcomes are psychometric instruments created and defined by patients to quantify symptoms. A combination of end points, comprising patient-reported outcomes and objective evaluation of inflammation by endoscopy, offers a clinically meaningful and scientifically valid alternative to existing composite indices. Unlike composite indices, response definitions based on endoscopy and patient-reported outcomes can be readily applied in practice. This convergence of outcome assessment in clinical trials and practice could expedite implementation of “treat-to-target” algorithms, in which therapy is progressively intensified until a specific treatment goal is reached. This approach could improve patient care by reducing rates of disease-related complications, surgery, and hospitalization. It is important to have clear goals for treating inflammatory bowel disease in clinical practice and in research. Conventional end points for trials in ulcerative colitis and Crohn’s disease have been based on composite indices, such as the Mayo Clinic Score and the Crohn’s Disease Activity Index; these indices incorporate symptoms, signs, and findings from laboratory tests and sometimes endoscopic assessments. Although definitions of clinical response and remission have been based on these indices for regulatory purposes, they are difficult to apply to practice because they are complex and not intuitive to clinicians. This has caused a disconnect between clinical trials and practice. Recently, the use of composite indices in trials has been reevaluated in Food and Drug Administration–sponsored Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics workshops due to concerns about the validity of the indices. Alternative measures of outcome and definitions of response are being developed. Patient-reported outcomes are psychometric instruments created and defined by patients to quantify symptoms. A combination of end points, comprising patient-reported outcomes and objective evaluation of inflammation by endoscopy, offers a clinically meaningful and scientifically valid alternative to existing composite indices. Unlike composite indices, response definitions based on endoscopy and patient-reported outcomes can be readily applied in practice. This convergence of outcome assessment in clinical trials and practice could expedite implementation of “treat-to-target” algorithms, in which therapy is progressively intensified until a specific treatment goal is reached. This approach could improve patient care by reducing rates of disease-related complications, surgery, and hospitalization. Inflammatory bowel disease (IBD) is caused by immune dysregulation of the digestive tract1Ordas I. Eckmann L. Talamini M. et al.Ulcerative colitis.Lancet. 2012; 380: 1606-1619Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 2Baumgart D.C. Sandborn W.J. Crohn's disease.Lancet. 2012; 380: 1590-1605Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar that results in chronic inflammation. Consequently, symptoms of abdominal pain, diarrhea, and bleeding occur that result in impaired quality of life. Although medical therapy is focused on controlling inflammation, disease activity is assessed in clinical trials by composite indices that predominantly measure signs and symptoms. In clinical practice, assessment of symptoms predominates. Thus, our traditional approach to treatment focuses more on the consequences of inflammation rather than the inflammatory process itself. This situation is not ideal, because there is a substantial overlap between the symptoms of IBD and other conditions, such as irritable bowel syndrome, bile salt diarrhea, steatorrhea, bacterial overgrowth, and scarring, that are unlikely to respond to anti-inflammatory therapy.3Bruining D.H. Sandborn W.J. Do not assume symptoms indicate failure of anti-tumor necrosis factor therapy in Crohn's disease.Clin Gastroenterol Hepatol. 2011; 9: 395-399Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Furthermore, it is well established that the Crohn’s Disease Activity Index (CDAI), which is heavily weighted toward symptoms, correlates poorly with endoscopy.4Cellier 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 Therapeutiques des Affections Inflammatoires Digestives.Gut. 1994; 35: 231-235Crossref PubMed Google Scholar Although there is a better correlation between symptoms and endoscopy in ulcerative colitis (UC), in many circumstances assessment of symptoms alone lacks sufficient precision for decision making. Based on these observations, we contend that an evolution in the measurement of IBD disease activity is needed that emphasizes development and use of disease activity indices that incorporate validated independent measures of both symptoms and inflammation into a coprimary end point.5Kirshner B. Guyatt G. A methodological framework for assessing health indices.J Chronic Dis. 1985; 38: 27-36Abstract Full Text PDF PubMed Scopus (978) Google Scholar Previous reviews6Sandborn W.J. Feagan B.G. Hanauer S.B. et al.A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease.Gastroenterology. 2002; 122: 512-530Abstract Full Text Full Text PDF PubMed Google Scholar, 7D'Haens G. Sandborn W.J. Feagan B.G. et al.A review of activity indices and efficacy endponts for clinical trials of medical therapy in adults with ulcerative colitis.Gastroenterology. 2007; 132: 763-786Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar have characterized the clinical, endoscopic, and composite indexes historically used in IBD clinical trials. Existing instruments are predominantly symptom based, are in most instances empirically derived, and do not adequately assess either symptoms from the patient’s perspective or the underlying inflammatory process. At present, there are no patient-reported outcome (PRO) or clinician-reported outcome (ClinRO) instruments that have been created according to the guidance of the US Food and Drug Administration (FDA).8US Food and Drug Administration. US Food and Drug Administration (FDA) guidance for industry: patient-reported outcome measures use in medical product development to support labeling claims. 2009. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf.Google Scholar Valid PROs, based on items generated from qualitative patient interviews, must be both reliable and responsive to clinically meaningful changes in health status. Clinically useful PROs should be both easily administered and readily interpretable by patients and clinicians.9US Food and Drug Administration. Gastroenterology regulatory endpoints and the advancement of therapeutics (GREAT II) workshop; October 21–22, 2013; Bethesda, MD.Google Scholar Similarly, a ClinRO for IBD trials must be a reliable measure of mucosal inflammation with well-defined operating properties.9US Food and Drug Administration. Gastroenterology regulatory endpoints and the advancement of therapeutics (GREAT II) workshop; October 21–22, 2013; Bethesda, MD.Google Scholar Examples of PROs that meet FDA standards for other conditions include the VVSymQ score (BTG International Ltd, London, England, UK), which was the primary end point in trials that led to the approval of Varithena (polidocanol injectable foam; Provensis Ltd) for treatment of varicose veins.10Todd III, K.L. Wright D. VANISH-2 Investigator GroupThe VANISH-2 study: a randomized, blinded, multicenter study to evaluate the efficacy and safety of polidocanol endovenous microfoam 0.5% and 1.0% compared with placebo for the treatment of saphenofemoral junction incompetence.Phlebology. 2014; 29: 608-618Crossref PubMed Scopus (14) Google Scholar VVSymQ is a PRO based on daily patient assessment of the symptoms of varicose veins determined to be most important to patients: heaviness, achiness, swelling, throbbing, and itching. Similarly, the modified Myelofibrosis Symptom Assessment Form PRO, in addition to spleen volume, led to the approval of Jakafi (Incyte Corporation, Wilmington, DE) (ruxolitinib) for myelofibrosis.11Mesa R.A. Gotlib J. Gupta V. et al.Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial.J Clin Oncol. 2013; 31: 1285-1292Crossref PubMed Scopus (56) Google Scholar The modified Myelofibrosis Symptom Assessment Form is a cumulative daily diary that scores the core symptoms of myelofibrosis (abdominal discomfort, pain under the left ribs, night sweats, itching, bone/muscle pain, and early satiety). Clinical trials in rheumatoid arthritis offer an example of coprimary end points in trials for regulatory approval. Cimzia (UCB, Inc, Brussels, Belgium) (certolizumab pegol) was approved in 2009 for trials in rheumatoid arthritis that included the coprimary end point of ACR20 (a composite index of swollen joint count, tender joint count, physician’s assessment of disease activity, and patient’s assessment of physical function and levels of acute phase reactant) and the mean change from baseline in the modified total Sharp score of joint radiographs at week 54.12Keystone E. Heijde D. Mason Jr., D. et al.Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.Arthritis Rheum. 2008; 58: 3319-3329Crossref PubMed Scopus (344) Google Scholar The major secondary end point was a PRO: the Disability Index of the Health Assessment Questionnaire. It is important to recognize that simple composite measures that assess both PRO and ClinRO elements, such as a physician’s global assessment,13Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.N Engl J Med. 1987; 317: 1625-1629Crossref PubMed Google Scholar are problematic because the concepts being evaluated are highly heterogeneous, making it difficult to assign a single measure of disease activity.9US Food and Drug Administration. Gastroenterology regulatory endpoints and the advancement of therapeutics (GREAT II) workshop; October 21–22, 2013; Bethesda, MD.Google Scholar As a response to this situation, an evolution in thinking has emerged contending that the degree of inflammation should be measured by clinicians using objective instruments such as endoscopy (and potentially in the future histology and cross-sectional imaging) and that the patients’ experience should be assessed by a validated PRO. Definitions of response and remission used for study end points should require improvement in both of these domains as a coprimary end point. This concept is attractive because it reflects clinical practice, in which in a typical patient encounter, physicians ask patients such questions as “How many stools are you having?”, “How frequently do you experience abdominal pain?”, and “Are you seeing blood in your bowel movements?”. Subsequently, clinicians objectively assess disease activity with endoscopy or potentially other measures of inflammation. In essence, this construct specifies that clinicians integrate both the patient experience and objectively measured disease activity before formulating a treatment plan or determining whether treatment goals have been met. Given these considerations, it is notable that most existing practice guidelines are exclusively symptom based. For example, the 2009 American College of Gastroenterology guidelines for management of Crohn’s disease (CD) defined remission as patients with an absence of symptoms; mild to moderate disease as ambulatory patients without systemic toxicity, dehydration, tenderness, <10% weight loss, obstruction, or abdominal mass; and fulminant disease as patients with severe symptoms including fever, those with complications such as bowel obstruction, and those failing to respond to therapy.14Lichtenstein G.R. Hanauer S.B. Sandborn W.J. Management of Crohn’s disease in adults.Am J Gastroenterol. 2009; 104: 465-483Crossref PubMed Scopus (438) Google Scholar Ultimately, such definitions have limited value in clinical practice because they are imprecise and not based on objective and practicable criteria. Alternatively, definitions of response and remission based on the composite disease activity indices that up until now have been routinely used for regulatory approval have not become accepted for use in patient care due to their complexity and apparent lack of face validity. Commensurate with our understanding of the limitations of our traditional outcome measures and disease definitions has been the developing concept that therapy in IBD should be based on specific, well-defined treatment targets that include both resolution of inflammation and symptoms. Treatment strategy trials in which the efficacy and safety of multilevel therapeutic algorithms are evaluated for their ability to achieve specific goals of therapy (“treat to target”) have recently been initiated in IBD. The intent of these studies is to identify therapeutic strategies that will reduce the long-term burden of IBD. This review outlines the literature that describes the evolution currently taking place in assessment of treatment goals in clinical trials and clinical practice. In patients with UC, important reductions in rates of colorectal cancer and colectomy have been observed over the past several decades.15Vester-Andersen M.K. Prosberg M.V. Jess T. et al.Disease course and surgery rates in inflammatory bowel disease: a population-based, 7-year follow-up study in the era of immunomodulating therapy.Am J Gastroenterol. 2014; 109: 705-714Crossref PubMed Scopus (25) Google Scholar However, much of this improvement appears to come from the widespread use of mesalamine for induction and maintenance therapy in patients with mild to moderate UC and/or the widespread practice of surveillance colonoscopy, with little evidence that the prognosis for patients with moderate to severe UC who require corticosteroid therapy has improved.16Langholz E. Munkholm P. Davidsen M. et al.Course of ulcerative colitis: analysis of changes in disease activity over years.Gastroenterology. 1994; 107: 3-11Abstract Full Text PDF PubMed Google Scholar, 17Leijonmarck C.E. Persson P.G. Hellers G. Factors affecting colectomy rate in ulcerative colitis: an epidemiologic study.Gut. 1990; 31: 329-333Crossref PubMed Google Scholar, 18Hendriksen C. Kreiner S. Binder V. Long term prognosis in ulcerative colitis—based on results from a regional patient group from the county of Copenhagen.Gut. 1985; 26: 158-163Crossref PubMed Google Scholar, 19Hoie O. Wolters F.L. Riis L. et al.Low colectomy rates in ulcerative colitis in an unselected European cohort followed for 10 years.Gastroenterology. 2007; 132: 507-515Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 20Jess T. Riis L. Vind I. et al.Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark.Inflamm Bowel Dis. 2007; 13: 481-489Crossref PubMed Scopus (206) Google Scholar, 21Faubion Jr., W.A. Loftus Jr., E.V. Harmsen W.S. et al.The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study.Gastroenterology. 2001; 121: 255-260Abstract Full Text Full Text PDF PubMed Google Scholar, 22Turner D. Walsh C.M. Steinhart A.H. et al.Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression.Clin Gastroenterol Hepatol. 2007; 5: 103-110Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar In CD, approximately 50% of patients develop disease-related complications such as a stricture, fistula, or abscess that frequently require surgery within 10 years of diagnosis.23Peyrin-Biroulet L. Loftus Jr., E.V. Colombel J.F. et al.The natural history of adult Crohn's disease in population-based cohorts.Am J Gastroenterol. 2010; 105: 289-297Crossref PubMed Scopus (252) Google Scholar, 24Solberg I.C. Vatn M.H. Hoie O. et al.Clinical course in Crohn's disease: results of a Norwegian population-based ten-year follow-up study.Clin Gastroenterol Hepatol. 2007; 5: 1430-1438Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar For example, the cumulative probability of surgery was not different between 2 Spanish cohorts of patients with newly diagnosed CD that were accrued from 1994 to 1997 and from 2000 to 2003.25Domenech E. Zabana Y. Garcia-Planella E. et al.Clinical outcome of newly diagnosed Crohn's disease: a comparative, retrospective study before and after infliximab availability.Aliment Pharmacol Ther. 2010; 31: 233-239PubMed Google Scholar Similarly, 2 nationwide inpatient cohorts of patients with CD in the United Sates from 1993 to 2004 and from 1998 to 2005 did not show a decrease in the overall rate of surgery.25Domenech E. Zabana Y. Garcia-Planella E. et al.Clinical outcome of newly diagnosed Crohn's disease: a comparative, retrospective study before and after infliximab availability.Aliment Pharmacol Ther. 2010; 31: 233-239PubMed Google Scholar, 26Cannom R.R. Kaiser A.M. Ault G.T. et al.Inflammatory bowel disease in the United States from 1998 to 2005: has infliximab affected surgical rates?.Am Surg. 2009; 75: 976-980PubMed Google Scholar, 27Jones D.W. Finlayson S.R. Trends in surgery for Crohn's disease in the era of infliximab.Ann Surg. 2010; 252: 307-312Crossref PubMed Scopus (35) Google Scholar One potential explanation for these observations is that the use of clinical symptoms as a treatment target fails to ensure that the underlying inflammation is adequately controlled, without which complications ensue. As noted previously, the traditional outcome measures in UC trials consist of composite instruments that incorporate symptoms, laboratory criteria, and sigmoidoscopic findings. The end points in the trial by Truelove and Witts of cortisone in patients with UC was based on symptoms, laboratory results, and a 3-point endoscopy scale that were required to be met independently.28Truelove S.C. Witts L.J. Cortisone in ulcerative colitis; final report on a therapeutic trial.Br Med J. 1955; 2: 1041-1048Crossref PubMed Google Scholar These scores were not validated. Subsequently, multiple UC and CD composite clinical indices were used from 1960 to 1990.6Sandborn W.J. Feagan B.G. Hanauer S.B. et al.A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease.Gastroenterology. 2002; 122: 512-530Abstract Full Text Full Text PDF PubMed Google Scholar, 7D'Haens G. Sandborn W.J. Feagan B.G. et al.A review of activity indices and efficacy endponts for clinical trials of medical therapy in adults with ulcerative colitis.Gastroenterology. 2007; 132: 763-786Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar, 29Rutgeerts P. Geboes K. Vantrappen G. et al.Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract Full Text PDF PubMed Google Scholar None of these scores were completely validated. Our review will focus on indices that have been used for regulatory approval between 2005 and 2014 (Table 1).Table 1Indices Used for Regulatory Approval From 2005 to 2014IndicesDescriptorsUC Baron score (endoscopic items)Spontaneous bleeding, friability, moisture, distensibility, valves, vascular patternaWith >60% interobserver agreement. MBS (endoscopic items)Normal mucosa (0), granular with an abnormal vascular pattern (1), friable (2), microulcerations with spontaneous bleeding (3), gross ulceration (4)Endoscopic response: improvement by 2 grades in the MBSEndoscopic remission: MBS score of 0 MCS (endoscopic and clinical items)Stool frequency, rectal bleeding, physician’s global assessment, endoscopic severityRange: 0–12Complete response: MCS score of 0 in all subscoresPartial response: substantial but incomplete improvement in the subscores Partial MCSStool frequency and rectal bleeding UCEISVascular pattern (1–3), bleeding (1–4), erosions and ulcers (1–4)CD CDAISeverity of abdominal pain, general well-being, frequency of liquid stool, extraintestinal manifestations, need for antidiarrheal drugs, presence of an abdominal mass, body weight, hematocritRange: 0–600Clinical response: reduction from baseline of 70 to 100 pointsClinical remission: <150 HBIAbdominal pain, abdominal mass, general well-being, extraintestinal manifestations, number of liquid stools for the previous dayRemission score: <5, correlates with CDAI score <150 CDEISDeep ulcerations, superficial ulcerations, percentage of involved mucosa, percentage of ulcerated mucosa in 5 segments, and global evaluation of lesion severityComplete remission: score ≤3Remission: <6Response: decrease of >5 points SES-CDPresence and size of ulcer, extent of ulcerated surface, extent of affected surface, presence and type of narrowings3 levels for each descriptor in 5 segmentsRemission: 0–2a With >60% interobserver agreement. Open table in a new tab Baron et al explored the interrater agreement of 8 endoscopic scoring descriptors in the first endoscopic index validation study30Baron J.H. Connell A.M. Lennard-Jones J.E. Variation between observers in describing mucosal appearances in proctocolitis.BMJ. 1964; 1: 89-92Crossref PubMed Google Scholar (Table 1). Categorical score items (friability, bleeding) had higher agreement (90% and 87%, respectively) than continuous score items (erythema, granularity) (30% and 47%, respectively). Agreement was not adjusted for chance, the score was not validated against clinical symptoms, and no definition of endoscopic remission was given. The Baron score was developed using rigid sigmoidoscopy, and friability was determined by touching the mucosa with a cotton swab inserted through the rigid instrument. Subsequently, the Baron score was used with fiber-optic scopes and then video endoscopes. In 2005, the Baron score was empirically modified by Feagan et al; the modified Baron score (MBS) has 5 grades (0–4).31Feagan B.G. Greenberg G.R. Wild G. et al.Treatment of ulcerative colitis with a humanized antibody to the a4b7 integrin.N Engl J Med. 2005; 352: 2499-2507Crossref PubMed Scopus (440) Google Scholar The modification removed qualitative assessment of different levels of bleeding (moderately, severely) and defined the 4 levels by categorical items (normal, granular, friable, bleeding, ulcerated). Endoscopic response is defined as an improvement of 2 grades in the MBS, and endoscopic remission is defined as an MBS score of 0. The Mayo Clinic Score (MCS) is a composite instrument that includes both endoscopic and clinical items.13Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.N Engl J Med. 1987; 317: 1625-1629Crossref PubMed Google Scholar The MCS (range, 0–12 points) was created empirically for a clinical trial in patients with mild to moderate UC. The items and severity levels were based on the investigators’ clinical experience. The MCS consists of 4 descriptors: stool frequency, rectal bleeding, physician’s global assessment, and assessment of endoscopic severity based on fiber-optic flexible sigmoidoscopy (Table 1). Complete response is defined as an MCS score of 0 in all subscores. Partial response is defined as “substantial but incomplete improvement in the subscores.” The index has been used in multiple clinical trials of mesalamine, budesonide MMX, infliximab, adalimumab, and golimumab.13Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.N Engl J Med. 1987; 317: 1625-1629Crossref PubMed Google Scholar, 31Feagan B.G. Greenberg G.R. Wild G. et al.Treatment of ulcerative colitis with a humanized antibody to the a4b7 integrin.N Engl J Med. 2005; 352: 2499-2507Crossref PubMed Scopus (440) Google Scholar, 32Rutgeerts P. Sandborn W.J. Feagan B.G. et al.Infliximab for induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2005; 353: 2462-2476Crossref PubMed Scopus (1765) Google Scholar, 33Sandborn W.J. Feagan B.G. Marano C. et al.Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis.Gastroenterology. 2014; 146 (quiz e14–e15): 85-95Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 34Sandborn W.J. van Assche G. Reinisch W. et al.Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.Gastroenterology. 2012; 142 (e1–3): 257-265Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar, 35Sandborn W.J. Travis S. Moro L. et al.Once-daily budesonide MMX(R) extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study.Gastroenterology. 2012; 143 (e1–2): 1218-1226Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Some trials have modified the instrument such that mild friability is scored as a 2 rather than a 1 on the Mayo endoscopic subscore36Rutgeerts P. Colombel J.F. Reinisch W. et al.Infliximab induces and maintains mucosal healing in patients with active ulcerative colitis: the ACT trial experience.Gut. 2005; 54: A58Google Scholar (Figure 1). The MCS has important limitations; it is a composite score that assimilates items (symptoms and endoscopy) that are not logically combinable and are not easy to appropriately weight. These properties increase measurement variability and decrease statistical efficiency.9US Food and Drug Administration. Gastroenterology regulatory endpoints and the advancement of therapeutics (GREAT II) workshop; October 21–22, 2013; Bethesda, MD.Google Scholar As a response to these limitations, the MCS has been adapted to functionally create coprimary end points for trials by separating its subcomponents into symptom-based and endoscopic criteria of response and remission. In 2 clinical trials that compared infliximab with placebo in patients with moderate to severe UC, clinical response was defined as a reduction in the MCS of at least 3 points and a decrease of 30% from the baseline score, with a decrease of at least 1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1.32Rutgeerts P. Sandborn W.J. Feagan B.G. et al.Infliximab for induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2005; 353: 2462-2476Crossref PubMed Scopus (1765) Google Scholar Clinical remission was defined as a MCS of ≤2 and no subscore >1. Mucosal healing was defined as an endoscopic subscore of 0 or 1. Partial MCSs have been defined as 3-item (stool frequency, rectal bleeding, and physician’s global assessment) and 2-item (stool frequency and rectal bleeding) instruments.37Lewis J.D. Chuai S. Nessel L. et al.Use of the noninvasive components of the Mayo score to assess clinical response in ulcerative colitis.Inflamm Bowel Dis. 2008; 14: 1660-1666Crossref PubMed Scopus (108) Google Scholar These instruments, which do not include endoscopy, have good correlation with the full MCS. The 2-item MCS only includes items that are reported by patients and from a practical perspective comprises a PRO. This evolution in using the MCS illustrates the desire to independently assess symptoms and inflammation defined by endoscopy. The score has not been completely validated. The CDAI has been the primary outcome measure for clinical trials since publication of the National Cooperative Crohn’s Disease Study trial in 1979.38Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Google Scholar, 39Summers R.W. Switz D.M. Sessions Jr., J.T. et al.National Cooperative Crohn's Disease Study: results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Google Scholar The CDAI was created by regressing 18 clinical items identified by physicians (ie, abdominal pain, pain awakening patient from sleep, appetite), physical signs (ie, average daily temperature, abdominal mass), use of medication (ie, loperamide or opiate use for diarrhea), and laboratory tests (ie, hematocrit) against the dependent variable of a 4-point global rating o

Probiotic formulations of single species of bacteria have not been effective in preventing the recurrence of Crohn's disease after surgery. We investigated the ability of VSL#3, a mixture of 8 different bacterial probiotic species, to prevent Crohn's disease recurrence after surgery in a multicenter, randomized, double-blind, placebo-controlled trial.Within 30 days of ileocolonic resection and re-anastomosis, patients with Crohn's disease were randomly assigned to groups given 1 sachet of VSL#3 (900 billion viable bacteria, comprising 4 strains of Lactobacillus, 3 strains of Bifidobacterium, and 1 strain of Streptococcus salivarius subspecies thermophilus) (n = 59) or matching placebo (n = 60). Colonoscopy was performed at days 90 and 365 to evaluate the neoterminal ileum for disease recurrence and obtain mucosal biopsies for cytokine analysis. Patients from both groups with either no or mild endoscopic recurrence at day 90 received VSL#3 until day 365. The primary outcome was the proportion of patients with severe endoscopic recurrence at day 90.At day 90, the proportion of patients with severe endoscopic lesions did not differ significantly between VSL#3 (9.3%) and placebo (15.7%, P = .19). The proportions of patients with non-severe lesions at day 90 who had severe endoscopic recurrence at day 365 were 10.0% in the early VSL#3 group (given VSL#3 for the entire 365 days) and 26.7% in the late VSL#3 group (given VSL#3 from days 90 through 365) (P = .09). Aggregate rates of severe recurrence (on days 90 and 365) were not statistically different, 20.5% of subjects in the early VSL#3 group and 42.1% in the late VSL#3 group. Patients receiving VSL#3 had reduced mucosal inflammatory cytokine levels compared with placebo at day 90 (P < .05). Crohn's disease activity index and inflammatory bowel disease quality of life scores were similar in the 2 groups.There were no statistical differences in endoscopic recurrence rates at day 90 between patients who received VSL#3 and patients who received placebo. Lower mucosal levels of inflammatory cytokines and a lower rate of recurrence among patients who received early VSL#3 (for the entire 365 days) indicate that this probiotic should be further investigated for prevention of Crohn's disease recurrence. Clinical trials.gov number: NCT00175292.

Background & AimsUstekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn’s disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab’s pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy.MethodsWe collected data on serum concentrations of ustekinumab and efficacy from induction studies of patients with moderate to severe CD given ustekinumab for 8 weeks following a single intravenous dose (either 130 mg or approximately 6 mg/kg). We collected the same data from a maintenance study of patients with a response to ustekinumab in the induction study who then received subcutaneous injections (90 mg) every 8 or 12 weeks for 44 weeks. At week 44 of the maintenance study (52 weeks after treatment began), patients were evaluated for the primary endpoint of clinical remission (defined as a CD activity index score below 150 points), endoscopic markers of efficacy, and serum level of C-reactive protein. Ustekinumab concentration data were categorized into quartiles and relationships between exposure and response were assessed. Optimal concentration cutoff values were evaluated using receiver operating characteristic curve analysis.ResultsSerum concentrations of ustekinumab over time were proportional to dose and did not differ significantly between the induction studies. In the maintenance study, ustekinumab concentration reached the steady state by the second maintenance dose; the median trough concentration was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals. Ustekinumab serum concentrations associated with rates of clinical remission and endoscopic efficacy endpoints, correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators. Trough concentrations of ustekinumab of 0.8 (or even up to 1.4 μg/mL) or greater were associated with maintenance of clinical remission in a higher proportion of patients than patients with lower trough concentrations.ConclusionsIn an analysis of data from Phase 3 studies of patients with moderate to severe CD, we found serum concentrations of ustekinumab to be proportional to dose and associate with treatment efficacy. Concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators. Clinicaltrials.gov no. NCT01369329 (UNITI 1), NCT01369342 (UNITI 2), and NCT01369355 (IM-UNITI). Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn’s disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab’s pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy. We collected data on serum concentrations of ustekinumab and efficacy from induction studies of patients with moderate to severe CD given ustekinumab for 8 weeks following a single intravenous dose (either 130 mg or approximately 6 mg/kg). We collected the same data from a maintenance study of patients with a response to ustekinumab in the induction study who then received subcutaneous injections (90 mg) every 8 or 12 weeks for 44 weeks. At week 44 of the maintenance study (52 weeks after treatment began), patients were evaluated for the primary endpoint of clinical remission (defined as a CD activity index score below 150 points), endoscopic markers of efficacy, and serum level of C-reactive protein. Ustekinumab concentration data were categorized into quartiles and relationships between exposure and response were assessed. Optimal concentration cutoff values were evaluated using receiver operating characteristic curve analysis. Serum concentrations of ustekinumab over time were proportional to dose and did not differ significantly between the induction studies. In the maintenance study, ustekinumab concentration reached the steady state by the second maintenance dose; the median trough concentration was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals. Ustekinumab serum concentrations associated with rates of clinical remission and endoscopic efficacy endpoints, correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators. Trough concentrations of ustekinumab of 0.8 (or even up to 1.4 μg/mL) or greater were associated with maintenance of clinical remission in a higher proportion of patients than patients with lower trough concentrations. In an analysis of data from Phase 3 studies of patients with moderate to severe CD, we found serum concentrations of ustekinumab to be proportional to dose and associate with treatment efficacy. Concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators. Clinicaltrials.gov no. NCT01369329 (UNITI 1), NCT01369342 (UNITI 2), and NCT01369355 (IM-UNITI).

Patients with Crohn's disease commonly develop ileal and less commonly colonic strictures, containing various degrees of inflammation and fibrosis. While predominantly inflammatory strictures may benefit from a medical anti-inflammatory treatment, predominantly fibrotic strictures currently require endoscopic balloon dilation or surgery. Therefore, differentiation of the main components of a stricturing lesion is key for defining the therapeutic management. The role of endoscopy to diagnose the nature of strictures is limited by the superficial inspection of the intestinal mucosa, the lack of depth of mucosal biopsies and by the risk of sampling error due to a heterogeneous distribution of inflammation and fibrosis within a stricturing lesion. These limitations may be in part overcome by cross-sectional imaging techniques such as ultrasound, CT and MRI, allowing for a full thickness evaluation of the bowel wall and associated abnormalities. This systematic literature review provides a comprehensive summary of currently used radiologic definitions of strictures. It discusses, by assessing only manuscripts with histopathology as a gold standard, the accuracy for diagnosis of the respective modalities as well as their capability to characterise strictures in terms of inflammation and fibrosis. Definitions for strictures on cross-sectional imaging are heterogeneous; however, accuracy for stricture diagnosis is very high. Although conventional cross-sectional imaging techniques have been reported to distinguish inflammation from fibrosis and grade their severity, they are not sufficiently accurate for use in routine clinical practice. Finally, we present recent consensus recommendations and highlight experimental techniques that may overcome the limitations of current technologies.

Background & AimsThe efficacy and safety of vedolizumab, a humanized immunoglobulin G1 monoclonal antibody against the integrin α4β7, were demonstrated in multicenter, phase 3, randomized, placebo-controlled trials in patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease. We analyzed data from 1 of these trials to determine the effects of vedolizumab therapy in patients with UC, based on past exposure to anti–tumor necrosis factor-α (TNF) antagonists.MethodsWe performed a post hoc analysis of data from the GEMINI 1 study, collected from 464 patients who received vedolizumab or placebo but had not received a previous TNF antagonist (naive to TNF antagonists) and 367 patients with an inadequate response, loss of response, or intolerance to TNF antagonists (failure of TNF antagonists). Predefined outcomes of GEMINI 1 were evaluated in these subpopulations.ResultsAt Week 6, there were greater absolute differences in efficacy between vedolizumab and placebo in patients naive to TNF antagonists than patients with failure of TNF antagonists, although the risk ratios (RRs) for efficacy were similar for each group. Week 6 rates of response to vedolizumab and placebo were 53.1% and 26.3%, respectively, among patients naive to TNF antagonists (absolute difference, 26.4%; 95% confidence interval [CI], 12.4–40.4; RR, 2.0; 95% CI, 1.3–3.0); these rates were 39.0% and 20.6%, respectively, in patients with failure of TNF antagonists (absolute difference, 18.1%; 95% CI, 2.8–33.5; RR, 1.9; 95% CI, 1.1–3.2). During maintenance therapy, the absolute differences were similar but the RR for efficacy was higher for patients with failure of TNF antagonists than for patients naive to TNF antagonists, for most outcomes. Week 52 rates of remission with vedolizumab and placebo were 46.9% and 19.0%, respectively, in patients naive to TNF antagonists (absolute difference, 28.0%; 95% CI, 14.9–41.1; RR, 2.5; 95% CI, 1.5–4.0) and 36.1% and 5.3%, respectively, in patients with failure of TNF antagonists (absolute difference, 29.5%; 95% CI, 12.8–46.1; RR, 6.6; 95% CI, 1.7–26.5). No differences in adverse events were observed among groups.ConclusionsVedolizumab demonstrated significantly greater efficacy as induction and maintenance therapy for UC than placebo in patients naive to TNF antagonists and patients with TNF antagonist failure. There were numerically greater treatment differences at Week 6 among patients receiving vedolizumab who were naive to TNF antagonists than patients with TNF antagonist failure. ClinicalTrials.gov no: NCT00783718. The efficacy and safety of vedolizumab, a humanized immunoglobulin G1 monoclonal antibody against the integrin α4β7, were demonstrated in multicenter, phase 3, randomized, placebo-controlled trials in patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease. We analyzed data from 1 of these trials to determine the effects of vedolizumab therapy in patients with UC, based on past exposure to anti–tumor necrosis factor-α (TNF) antagonists. We performed a post hoc analysis of data from the GEMINI 1 study, collected from 464 patients who received vedolizumab or placebo but had not received a previous TNF antagonist (naive to TNF antagonists) and 367 patients with an inadequate response, loss of response, or intolerance to TNF antagonists (failure of TNF antagonists). Predefined outcomes of GEMINI 1 were evaluated in these subpopulations. At Week 6, there were greater absolute differences in efficacy between vedolizumab and placebo in patients naive to TNF antagonists than patients with failure of TNF antagonists, although the risk ratios (RRs) for efficacy were similar for each group. Week 6 rates of response to vedolizumab and placebo were 53.1% and 26.3%, respectively, among patients naive to TNF antagonists (absolute difference, 26.4%; 95% confidence interval [CI], 12.4–40.4; RR, 2.0; 95% CI, 1.3–3.0); these rates were 39.0% and 20.6%, respectively, in patients with failure of TNF antagonists (absolute difference, 18.1%; 95% CI, 2.8–33.5; RR, 1.9; 95% CI, 1.1–3.2). During maintenance therapy, the absolute differences were similar but the RR for efficacy was higher for patients with failure of TNF antagonists than for patients naive to TNF antagonists, for most outcomes. Week 52 rates of remission with vedolizumab and placebo were 46.9% and 19.0%, respectively, in patients naive to TNF antagonists (absolute difference, 28.0%; 95% CI, 14.9–41.1; RR, 2.5; 95% CI, 1.5–4.0) and 36.1% and 5.3%, respectively, in patients with failure of TNF antagonists (absolute difference, 29.5%; 95% CI, 12.8–46.1; RR, 6.6; 95% CI, 1.7–26.5). No differences in adverse events were observed among groups. Vedolizumab demonstrated significantly greater efficacy as induction and maintenance therapy for UC than placebo in patients naive to TNF antagonists and patients with TNF antagonist failure. There were numerically greater treatment differences at Week 6 among patients receiving vedolizumab who were naive to TNF antagonists than patients with TNF antagonist failure. ClinicalTrials.gov no: NCT00783718.

Summary Background The Crohn's Disease Activity Index ( CDAI ) is a measure of disease activity based on symptoms, signs and a laboratory test. The US Food and Drug Administration has indicated that patient reported outcomes ( PRO s) should be the primary outcome in randomised controlled trials for Crohn's disease ( CD ). Aim As no validated PRO exists for CD , to investigate whether CDAI diary card items could be modified for this purpose. Methods Data from a trial of rifaximin‐extended intestinal release were used to identify cut‐points for stool frequency, pain and general well‐being using receiver operating characteristic curves with CDAI &lt;150 as criterion. The operating properties of 2‐ and 3‐item PRO were evaluated using data from a trial of methotrexate in CD . Regression analysis determined PRO 2 and PRO 3 scores that correspond to CDAI ‐defined thresholds of 150, 220 and 450 and changes of 50, 70 and 100 points. Results Optimum cut‐points for CDAI remission were mean daily stool frequency ≤1.5, abdominal pain ≤1, and general well‐being score of ≤1 (areas under the ROC curve 0.79, 0.91 and 0.89, respectively). The effect estimates were similar using 2‐ and 3‐item PRO s or CDAI . PRO 2 and PRO 3 values corresponding to CDAI scores of 150, 220 and 450 points were 8, 14, 34 and 13, 22, 53. The corresponding values for CDAI changes of 50, 70 and 100, were 2, 5, 8 and 5, 9, 14. Responsiveness to change was similar for both PRO s. Conclusion Patient reported outcomes derived from CDAI diary items may be appropriate for use in clinical trials for CD .

Summary Background Fibrotic stricture is a common complication of Crohn's disease ( CD ) affecting approximately half of all patients. No specific anti‐fibrotic therapies are available; however, several therapies are currently under evaluation. Drug development for the indication of stricturing CD is hampered by a lack of standardised definitions, diagnostic modalities, clinical trial eligibility criteria, endpoints and treatment targets in stricturing CD . Aim To standardise definitions, diagnosis and treatment targets for anti‐fibrotic stricture therapies in Chron's disease. Methods An interdisciplinary expert panel consisting of 15 gastroenterologists and radiologists was assembled. Using modified RAND /University of California Los Angeles appropriateness methodology, 109 candidate items derived from systematic review and expert opinion focusing on small intestinal strictures were anonymously rated as inappropriate, uncertain or appropriate. Survey results were discussed as a group before a second and third round of voting. Results Fibrotic strictures are defined by the combination of luminal narrowing, wall thickening and pre‐stenotic dilation. Definitions of anastomotic (at site of prior intestinal resection with anastomosis) and naïve small bowel strictures were similar; however, there was uncertainty regarding wall thickness in anastomotic strictures. Magnetic resonance imaging is considered the optimal technique to define fibrotic strictures and assess response to therapy. Symptomatic strictures are defined by abdominal distension, cramping, dietary restrictions, nausea, vomiting, abdominal pain and post‐prandial abdominal pain. Need for intervention (endoscopic balloon dilation or surgery) within 24‐48 weeks is considered the appropriate endpoint in pharmacological trials. Conclusions Consensus criteria for diagnosis and response to therapy in stricturing Crohn's disease should inform both clinical practice and trial design.

Background Endoscopic assessment of mucosal disease activity is routinely used to determine eligibility and response to therapy in clinical trials of ulcerative colitis. The operating properties of the existing endoscopic scoring indices are unclear. Objectives A systematic review was undertaken to evaluate the development and operating characteristics of endoscopic scoring indices for the evaluation of ulcerative colitis. Search methods We searched MEDLINE, Embase and CENTRAL from inception to 5 July 2016. We also searched references and conference proceedings (Digestive Disease Week, United European Gastroenterology Week, European Crohn’s and Colitis Organization). Selection criteria Any study design (e.g. randomized controlled trials, cohort studies, case series) that evaluated endoscopic indices for evaluation of ulcerative colitis disease activity were considered for inclusion. Eligible participants were adult patients (> 16 years), diagnosed with ulcerative colitis using conventional clinical, radiologic and endoscopic criteria. Data collection and analysis Two authors independently reviewed the studies identified from the literature search. These authors also independently extracted and recorded data on the number of patients enrolled; number of patients per treatment arm; patient characteristics including age and gender distribution; endoscopic index; and outcomes such as reliability (intra‐rater and inter‐rater), validity (content, construct, criterion), responsiveness and feasibility. Any disagreements regarding study inclusion or data extraction were resolved by discussion and consensus with a third author. Risk of bias was assessed by determining whether assessors were blinded to clinical information and whether assessors scored the endoscopic index independently. We also assessed the methodological quality of the validation studies using the COSMIN checklist Main results A total of 23 reports of 20 studies met the pre‐defined inclusion criteria and were included in the review. Of the 20 included validation studies, 19 endoscopic scoring indices were assessed, including the Azzolini Classification, Baron Score, Blackstone Endoscopic Interpretation, Chinese Grading System of Ulcerative Colitis, Endoscopic Activty Index, Jeroen Score, Magnifying Colonoscopy Grade, Matts Score, Mayo Clinic Endoscopic Subscore, Modified Baron Score, Modified Mayo Clinic Endoscopic Subscore, Osada Score, Rachmilewtiz Endoscopic Score, St. Mark's Index, Ulcerative Colitis Colonoscopic Index of Serverity (UCCIS), endoscopic component of the Ulcerative Colitis Disease Activity Index (UCDAI), Ulcerative Colitis Endoscopic Index of Severity (UCEIS), Witts Sigmoidoscopic Score and Watson Grade. The individuals who performed the endoscopic scoring were blinded to clinical and/or histologic information in ten of the included studies, not blinded to clinical and/or histologic information in one of the included studies, and it was unclear whether blinding occurred in the remaining nine included studies. Independent observation was confirmed in four of the included studies, unclear in five of the included studies, and non‐applicable (since inter‐rater reliability was not assessed) in the remaining eleven included studies. The methodological quality (COSMIN checklist) of most of the included studies was rated as 'good' or 'excellent'. One study that assessed responsiveness was rated as 'fair'. The inter‐rater reliability of nine endoscopic scoring indices including the Baron Score, Blackstone Endoscopic Interpretation, Endoscopic Activity Index, Matts Score, Mayo Clinic Endoscopic Subscore, Osada Score, UCCIS, UCEIS, Watson Grade was assessed in seven studies, with estimates of correlation, ƙ, ranging from 0.44 to 0.97. The iIntra‐rater reliability of seven endoscopic scoring indices including the Baron Score, Blackstone Endoscopic Interpretation, Matts Score, Mayo Clinic Endoscopic Subscore, Osada Score, UCCIS and UCEIS was assessed in three studies, with estimates of correlation, ƙ, ranging from 0.41 to 0.86. No studies assessed content validity. Three studies evaluated the criterion validity of three endoscopic scoring indices including the Rachmilewitz Endoscopic Score, Magnifying Colonoscopy Grade and the UCCIS. These indices were correlated with objective markers of disease activity including albumin, blood leukocytes, C‐reactive protein, fecal calprotectin, hemoglobin, mucosal interleukin‐8 concentration and platelet count. Correlation estimates ranged from r = ‐0.19 to 0.83. Thirteen endoscopic scoring indices were tested for construct validity in 13 studies. Estimates of correlation between the endoscopic scoring indices and other measures of disease activity ranged from r = 0.27 to 0.93. Two studies explored the responsiveness of four endoscopic scoring indices including the Mayo Endoscopic Subscore, Modified Baron Score, Modified Mayo Endoscopic Subscore and UCEIS. One study concluded that the Modified Baron Score, Modified Mayo Endoscopic Subscore and UCEIS had similar responsiveness for detecting disease change in ulcerative colitis. The other included study concluded that the UCEIS may be the most accurate endoscopic scoring tool. None of the included studies formally assessed feasibility. Authors' conclusions While the UCEIS, UCCIS and Mayo Clinic Endoscopic Subscore have undergone extensive validation, none of these instruments have been fully validated and only two studies assessed responsiveness. Further research on the operating properties of these indices is needed given the lack of a fully‐validated endoscopic scoring instrument for the evaluation of disease activity in ulcerative colitis.

OBJECTIVES: We assessed potential associations between malignancy and antitumor necrosis factor therapy in patients with Crohn's disease (CD), as this relationship is currently poorly defined. METHODS: Utilizing data from the Crohn's Therapy, Resource, Evaluation, and Assessment Tool (TREAT™) Registry, a prospective cohort study examining long-term outcomes of CD treatments in community and academic settings, infl uences of baseline patient/disease characteristics and medications were assessed by survival analysis and multivariate models. Standardized incidence ratios and exact 95 % confi dence intervals were determined as the ratio of events observed (TREAT) vs. expected (general population of USA). RESULTS: As of 23 February 2010, 6,273 CD patients (infliximab during registry=3,420 (during or within 1 year before registry=3,764); other-treatments-only: 2,509), were enrolled and, on average, had been followed for 5.2/7.6 years, respectively, for all/currently active patients. Crude cancer incidences were similar between infliximab- and other-treatments-only-exposed patients. Multivariate Cox regression analysis demonstrated that baseline age (hazard ratio (HR)=1.59/10 years;P<0.001), disease duration (HR=1.64/10 years;P=0.012), and smoking (HR=1.38;P=0.045) but neither immunosuppressive therapy alone (HR=1.43;P=0.11), infliximab therapy alone (HR=0.59;P=0.16), nor their combination (HR=1.22,P=0.34) were independently associated with the risk of malignancy. When compared with the general population, no significant increase in incidence was observed in any malignancy category. In an exposure-based analysis, use of immunosuppressants alone (odds ratio=4.19) or in combination with infliximab (3.33) seemed to be associated with a numerically, but not significantly, greater risk of malignancy than did treatment with infliximab alone (1.96) relative to treatment with neither. CONCLUSIONS: In the TREAT Registry, age, disease duration, and smoking were independently associated with increased risk of malignancy. Although results for immunosuppressant use were equivocal, no significant association between malignancy and infliximab was observed.

Following induction/maintenance treatment in the UNITI/IM-UNITI studies of ustekinumab for Crohn's disease, patients entered a long-term extension for up to 5 years from induction. Efficacy through 152 and safety through 156 weeks are reported.At IM-UNITI Week 44, 567 ustekinumab-treated patients entered the long-term extension and continued to receive blinded subcutaneous ustekinumab on their assigned dose interval, without any subsequent dose adjustment. Placebo-treated patients discontinued after study unblinding [after IM-UNITI Week 44 analyses]. Efficacy data in the long-term extension [LTE] were collected every 12 weeks [q12w] before unblinding and then at q12w/q8w dosing visits.Through Week 156, 29.6% of ustekinumab-treated patients discontinued. In an intent-to-treat analysis of randomised patients from IM-UNITI Weeks 0-152, 38.0% of ustekinumab induction responders receiving the drug q12w and 43.0% q8w were in remission at Week 152. Among patients entering the long-term extension in their original randomised groups, 61.9% of q12w and 69.5% of q8w patients were in remission at Week 152. Across all ustekinumab-treated patients [randomised and non-randomised] entering the long-term extension, remission rates at Week 152 were 56.3% and 55.1% for q12w and q8w, respectively. Safety events [per 100 patient-years] were similar among all ustekinumab-treated patients entering the long-term extension and placebo [overall adverse events 389.70 vs 444.17; serious adverse events, 18.97 vs 19.54; serious infections, 4.21 vs 3.97]. Rates of antibodies to ustekinumab through Week 156 remained low, 4.6% in all randomised ustekinumab-treated patients; lowest among patients in the original randomised q8w group [2/82, 2.4%].Continued treatment with subcutaneous ustekinumab maintained clinical response and remission through 3 years in a majority of patients who responded to induction therapy and was well-tolerated. ClinicalTrials.gov number NCT01369355.

Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease.ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete.Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug.Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease.AbbVie.

<h3>Background</h3> Crohn9s disease (CD) is a chronic disabling and progressive IBD. Only strategies looking beyond symptoms and based on tight monitoring of objective signs of inflammation such as mucosal lesions may have the potential for disease modification. Endoscopic evaluation is currently the gold standard to assess mucosal lesions and has become a major therapeutic endpoint in clinical trials. Several endoscopic indices have been proposed to evaluate disease activity; unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response and endoscopic remission in CD. <h3>Methods</h3> In these recommendations from the International Organization for the Study of Inflammatory Bowel Disease, we first reviewed all technical aspects of available endoscopic scoring systems in the literature. Second, in order to achieve consensus on endoscopic definitions of remission and response in trials, a two-round vote based on a Delphi method was performed among 14 specialists in the field of IBDs. <h3>Results</h3> At the end of the voting process, the investigators ranked first a &gt;50% decrease in Simple Endoscopic Score for Crohn9s Disease (SES-CD) or Crohn9s Disease Endoscopic Index of Severity for the definition of endoscopic response, and an SES-CD 0–2 for the definition of endoscopic remission in CD. All experts agreed on a Rutgeerts’ score i0–i1 for the definition of endoscopic remission after surgery.

Background & AimsVedolizumab is a gut-selective monoclonal antibody for the treatment of moderately to severely active Crohn’s disease (CD). We performed a prospective study of endoscopic, radiologic, and histologic healing in patients with CD who received vedolizumab therapy.MethodsWe performed a phase 3b, open-label, single-group study of 101 patients with at least 3 months of active CD (a CD Activity Index [CDAI] score of 220–450, a simple endoscopic score for CD [SES-CD] of 7 or more, 1 or more mucosal ulcerations [identified by endoscopy], and failure of conventional therapy) from March 2015 through December 2017. Among the patients enrolled, 54.5% had previous failure of 1 or more tumor necrosis factor (TNF) antagonists and 44.6% had severe endoscopic disease activity (SES-CD scores above 15) at baseline. Participants received vedolizumab (300 mg intravenously) at weeks 0, 2, and 6, and then every 8 weeks thereafter, for 26 weeks (primary study) or 52 weeks (substudy, 56 patients). The primary endpoint at week 26 was endoscopic remission (SES-CD score of 4 or less); other endpoints included endoscopic response (50% reduction in SES-CD), radiologic remission (magnetic resonance index of activity score below 7), and histologic response (modified global histologic disease activity score of 4 or less).ResultsAt week 26, 11.9% of patients were in endoscopic remission (95% confidence interval [CI] 6.3–9.8); at week 52, 17.9% of the patients were in endoscopic remission (95% CI 8.9–30.4). Higher proportions of patients naïve to TNF antagonists achieved endoscopic remission than patients with TNF-antagonist-failure at weeks 26 and 52. Higher proportion of patients with moderate CD (SES-CD scores, 7–15) achieved endoscopic remission at weeks 26 and 52 than patients with severe CD (SES-CD scores above 15). The proportion of patients with complete mucosal healing increased over time, with greater rates of healing in the colon than in the ileum. Remission was detected by magnetic resonance enterography in 21.9% of patients at week 26 (95% CI 9.3–40.0) and in 38.1% at week 52 (95% CI 18.1–61.6). At week 26, 24.4% of patients had a histologic response in the colon (95% CI 15.3–35.4) and 28.3% of patients had a histologic response in the ileum (95% CI 17.5–41.4). At week 52, 20.5% of patients had a histologic response in the colon (95% CI 9.8–35.3) and 34.3% of patients had a histologic response in the ileum (95% CI 19.1–52.2). There were no notable safety issues, including worsening of extraintestinal manifestations.ConclusionsIn a phase 3b trial, we found that 26 and 52 weeks of treatment with vedolizumab (300 mg, at weeks 0, 2, and 6, and then every 8 weeks thereafter) induces endoscopic, radiologic, and histologic healing in patients with moderately to severely active CD. ClinicalTrials.gov no: NCT02425111. Vedolizumab is a gut-selective monoclonal antibody for the treatment of moderately to severely active Crohn’s disease (CD). We performed a prospective study of endoscopic, radiologic, and histologic healing in patients with CD who received vedolizumab therapy. We performed a phase 3b, open-label, single-group study of 101 patients with at least 3 months of active CD (a CD Activity Index [CDAI] score of 220–450, a simple endoscopic score for CD [SES-CD] of 7 or more, 1 or more mucosal ulcerations [identified by endoscopy], and failure of conventional therapy) from March 2015 through December 2017. Among the patients enrolled, 54.5% had previous failure of 1 or more tumor necrosis factor (TNF) antagonists and 44.6% had severe endoscopic disease activity (SES-CD scores above 15) at baseline. Participants received vedolizumab (300 mg intravenously) at weeks 0, 2, and 6, and then every 8 weeks thereafter, for 26 weeks (primary study) or 52 weeks (substudy, 56 patients). The primary endpoint at week 26 was endoscopic remission (SES-CD score of 4 or less); other endpoints included endoscopic response (50% reduction in SES-CD), radiologic remission (magnetic resonance index of activity score below 7), and histologic response (modified global histologic disease activity score of 4 or less). At week 26, 11.9% of patients were in endoscopic remission (95% confidence interval [CI] 6.3–9.8); at week 52, 17.9% of the patients were in endoscopic remission (95% CI 8.9–30.4). Higher proportions of patients naïve to TNF antagonists achieved endoscopic remission than patients with TNF-antagonist-failure at weeks 26 and 52. Higher proportion of patients with moderate CD (SES-CD scores, 7–15) achieved endoscopic remission at weeks 26 and 52 than patients with severe CD (SES-CD scores above 15). The proportion of patients with complete mucosal healing increased over time, with greater rates of healing in the colon than in the ileum. Remission was detected by magnetic resonance enterography in 21.9% of patients at week 26 (95% CI 9.3–40.0) and in 38.1% at week 52 (95% CI 18.1–61.6). At week 26, 24.4% of patients had a histologic response in the colon (95% CI 15.3–35.4) and 28.3% of patients had a histologic response in the ileum (95% CI 17.5–41.4). At week 52, 20.5% of patients had a histologic response in the colon (95% CI 9.8–35.3) and 34.3% of patients had a histologic response in the ileum (95% CI 19.1–52.2). There were no notable safety issues, including worsening of extraintestinal manifestations. In a phase 3b trial, we found that 26 and 52 weeks of treatment with vedolizumab (300 mg, at weeks 0, 2, and 6, and then every 8 weeks thereafter) induces endoscopic, radiologic, and histologic healing in patients with moderately to severely active CD. ClinicalTrials.gov no: NCT02425111.

Objectives Here, we present the reported incidence rates of inflammatory bowel disease (IBD) in patients receiving treatment with secukinumab for psoriasis (PsO), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), in a pooled analysis of 21 clinical trials. Methods Data from all patients who had received at least one dose of secukinumab were included. Safety analyses were conducted to evaluate cumulative IBD rates as well as per-year rates, by indication. Crohn’s disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) events were analysed using exposure-adjusted incidence rates (patient incidence rates per 100 patient-years (PY)). Results A total of 7355 patients with a cumulative exposure of 16 226.9 PY were included in the pooled analysis. Among 5181 patients with PsO, there were 14 cases of UC, 5 cases of CD and 1 case of IBDU, with exposure adjusted incidence rates (EAIRs) of 0.13, 0.05 and 0.01, respectively. Of these 20 cases, 14 were new-onset. In 1380 patients with PsA, there were 3 cases of UC, 3 cases of CD and 2 cases of IBDU (EAIRs 0.08, 0.08 and 0.05); 7 of these represented new-onset cases. Among 794 patients with AS, there were 4 cases of UC, 8 cases of CD and 1 case of IBDU (EAIRs 0.2, 0.4 and 0.1); 9 were new-onset cases. In the per year analysis, the EAIRs for each indication did not increase over time with secukinumab treatment. Conclusions In this pooled secukinumab safety analysis of 7355 patients across 21 clinical trials, cases of IBD events (including CD, UC and IBDU) were uncommon.

The GEMINI long-term safety [LTS] study is a continuing phase 3 trial investigating the safety and efficacy of vedolizumab, an α4β7 integrin antagonist for ulcerative colitis [UC] and Crohn’s disease. We provide an interim analysis of efficacy in patients with UC. Patients from the C13004 and GEMINI 1 studies and a cohort of vedolizumab-naïve patients received open-label vedolizumab every 4 weeks. Interim data were collected from May 22, 2009 to June 27, 2013. Clinical response and remission, evaluated using partial Mayo scores, and health-related quality of life [HRQL] were assessed for up to 152 weeks of cumulative treatment in the efficacy population. As of June 27, 2013, 63% of the efficacy population [n = 532/845] were continuing treatment. Among patients who responded to vedolizumab induction and had data available, 88% [n = 120/136] were in remission after 104 weeks of exposure (96% [n = 70/73] after 152 weeks). Among patients who withdrew from every-8-week vedolizumab maintenance in GEMINI 1 [n = 32] before week 52, increased dosing to every 4 weeks in GEMINI LTS resulted in response and remission rates of 41% and 28%, respectively, after 52 weeks, an increase from 19% and 6%, respectively, from before the dose increase. Similar benefits were demonstrated regardless of prior tumour necrosis factor-antagonist exposure. Durable benefits on HRQL were also observed. Patients with UC experienced clinical and HRQL improvements with continued vedolizumab treatment. Increased dosing frequency to every 4 weeks was beneficial in patients who had loss of response to 8-weekly dosing.

We conducted a systematic review with meta-analysis to estimate rates and trends of colectomy in patients with ulcerative colitis (UC), and of primary and re-resection in patients with Crohn's disease (CD), focusing on contemporary risks.Through a systematic review until September 3, 2019, we identified population-based cohort studies that reported patient-level cumulative risk of surgery in patients with UC and CD. We evaluated overall and contemporary risk (after 2000) of surgery and analyzed time trends through mixed-effects meta-regression.In patients with UC (26 studies), the overall 1-, 5-, and 10-year risks of colectomy was 4.0% (95% CI, 3.3-5.0), 8.8% (95% CI, 7.7-10.0), and 13.3% (95% CI, 11.3-15.5), respectively, with a decrease in risk over time (P < .001). Corresponding contemporary risks were 2.8% (95% CI, 2.0-3.9), 7.0% (95% CI, 5.7-8.6), and 9.6% (95% CI, 6.3-14.2), respectively. In patients with CD (22 studies), the overall 1-, 5-, and 10-year risk of surgery was 18.7% (95% CI, 15.0-23.0), 28.0% (95% CI, 24.0-32.4), and 39.5% (95% CI, 33.3-46.2), respectively, with a decrease in risk over time (P < .001). Corresponding contemporary risks were 12.3% (95% CI, 10.8-14.0), 18.0% (95% CI, 15.4-21.0), and 26.2% (95% CI, 23.4-29.4), respectively. In a meta-analysis of 8 studies in patients with CD with prior resection, the cumulative risk of a second resection at 5 and 10 years after the first resection was 17.7% (95% CI, 13.5-22.9) and 31.3% (95% CI, 24.1-39.6), respectively.Patient-level risks of surgery have decreased significantly over time, with a 5-year cumulative risk of surgery of 7.0% in UC and 18.0% in CD in contemporary cohorts. This decrease may be related to early detection and/or better treatment.

Vedolizumab is a gut-selective α4β7 integrin antagonist therapy for ulcerative colitis and Crohn's disease. The GEMINI long-term safety [LTS] trial is an ongoing open-label study investigating the safety of vedolizumab. We present interim exploratory analyses of efficacy in patients with Crohn's disease.Patients from the C13004, GEMINI 2 and GEMINI 3 studies and vedolizumab-naïve patients could enrol in GEMINI LTS and received vedolizumab every 4 weeks. Data were collected from May 22, 2009 to June 27, 2013. Outcomes of clinical response and remission, defined by the Harvey-Bradshaw Index, and health-related quality of life [HRQL] were assessed for up to 152 weeks of treatment in the efficacy population.Among patients with response at week 6 in GEMINI 2 who received vedolizumab continuously, 83% [n=100/120] and 89% [n=62/70] of patients with available data were in remission after 104 and 152 weeks, respectively. Increased dosing frequency from every 8 weeks [GEMINI 2] to every 4 weeks [GEMINI LTS] improved outcomes in patients who had withdrawn early from GEMINI 2, with 47% [n=27/57] experiencing clinical response and 32% [n=18/57] in remission at week 52 of GEMINI LTS [up from 39% and 4% before the dose increase]. Similar improvements were observed regardless of prior tumour necrosis factor [TNF] antagonist exposure. Long-term benefits of HRQL were also observed.The clinical benefits of vedolizumab continued with long-term treatment regardless of prior TNF antagonist exposure. Increased dosing frequency might improve outcomes in patients who lose response to conventional 8-weekly dosing.

Background & AimsInterleukin 23 contributes to the pathogenesis of ulcerative colitis (UC). We investigated the effects of mirikizumab, a monoclonal antibody against the p19 subunit of interleukin 23, in a phase 2 study of patients with UC.MethodsWe performed a trial of the efficacy and safety of mirikizumab in patients with moderate to severely active UC, enrolling patients from 14 countries from January 2016 through September 2017. Patients were randomly assigned to groups given intravenous placebo (N = 63), mirikizumab 50 mg (N = 63) or 200 mg (N = 62) with exposure-based dosing, or mirikizumab 600 mg with fixed dosing (N = 61) at weeks 0, 4, and 8. Of assigned patients, 63% had prior exposure to a biologic agent. Clinical responders (decrease in 9-point Mayo score, including ≥2 points and ≥35% from baseline with either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 who had received mirikizumab were randomly assigned to groups that received maintenance treatment with mirikizumab 200 mg subcutaneously every 4 weeks (N = 47) or every 12 weeks (N = 46). The primary endpoint was clinical remission (Mayo subscores of 0 for rectal bleeding, with 1-point decrease from baseline for stool frequency, and 0 or 1 for endoscopy) at week 12. A multiple testing procedure was used that began with the 600-mg dose group, and any nonsignificant comparison result ended the formal statistical testing procedure.ResultsAt week 12, 15.9% (P = .066), 22.6% (P = .004), and 11.5% (P = .142) of patients in the 50-mg, 200-mg, and 600-mg groups achieved clinical remission, respectively, compared with 4.8% of patients given placebo. The primary endpoint was not significant (comparison to 600 mg, P > .05). Clinical responses occurred in 41.3% (P = .014), 59.7% (P < .001), and 49.2% (P = .001) of patients in the 50-mg, 200-mg, and 600-mg groups, respectively, compared with 20.6% of patients given placebo. At week 52, 46.8% of patients given subcutaneous mirikizumab 200 mg every 4 weeks and 37.0% given subcutaneous mirikizumab 200 mg every 12 weeks were in clinical remission.ConclusionsIn a randomized trial of patients with UC, mirikizumab was effective in inducing a clinical response after 12 weeks. Additional studies are required to determine the optimal dose for induction of remission. Mirikizumab showed durable efficacy throughout the maintenance period. Clinicaltrials.gov, Number NCT02589665 Interleukin 23 contributes to the pathogenesis of ulcerative colitis (UC). We investigated the effects of mirikizumab, a monoclonal antibody against the p19 subunit of interleukin 23, in a phase 2 study of patients with UC. We performed a trial of the efficacy and safety of mirikizumab in patients with moderate to severely active UC, enrolling patients from 14 countries from January 2016 through September 2017. Patients were randomly assigned to groups given intravenous placebo (N = 63), mirikizumab 50 mg (N = 63) or 200 mg (N = 62) with exposure-based dosing, or mirikizumab 600 mg with fixed dosing (N = 61) at weeks 0, 4, and 8. Of assigned patients, 63% had prior exposure to a biologic agent. Clinical responders (decrease in 9-point Mayo score, including ≥2 points and ≥35% from baseline with either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 who had received mirikizumab were randomly assigned to groups that received maintenance treatment with mirikizumab 200 mg subcutaneously every 4 weeks (N = 47) or every 12 weeks (N = 46). The primary endpoint was clinical remission (Mayo subscores of 0 for rectal bleeding, with 1-point decrease from baseline for stool frequency, and 0 or 1 for endoscopy) at week 12. A multiple testing procedure was used that began with the 600-mg dose group, and any nonsignificant comparison result ended the formal statistical testing procedure. At week 12, 15.9% (P = .066), 22.6% (P = .004), and 11.5% (P = .142) of patients in the 50-mg, 200-mg, and 600-mg groups achieved clinical remission, respectively, compared with 4.8% of patients given placebo. The primary endpoint was not significant (comparison to 600 mg, P > .05). Clinical responses occurred in 41.3% (P = .014), 59.7% (P < .001), and 49.2% (P = .001) of patients in the 50-mg, 200-mg, and 600-mg groups, respectively, compared with 20.6% of patients given placebo. At week 52, 46.8% of patients given subcutaneous mirikizumab 200 mg every 4 weeks and 37.0% given subcutaneous mirikizumab 200 mg every 12 weeks were in clinical remission. In a randomized trial of patients with UC, mirikizumab was effective in inducing a clinical response after 12 weeks. Additional studies are required to determine the optimal dose for induction of remission. Mirikizumab showed durable efficacy throughout the maintenance period. Clinicaltrials.gov, Number NCT02589665

There is a great unmet need for new therapeutics with novel mechanisms of action for patients with Crohn's disease. The ADVANCE and MOTIVATE studies showed that intravenous risankizumab, a selective p19 anti-interleukin (IL)-23 antibody, was efficacious and well tolerated as induction therapy. Here, we report the efficacy and safety of subcutaneous risankizumab as maintenance therapy.FORTIFY is a phase 3, multicentre, randomised, double-blind, placebo-controlled, maintenance withdrawal study across 273 clinical centres in 44 countries across North and South America, Europe, Oceania, Africa, and the Asia-Pacific region that enrolled participants with clinical response to risankizumab in the ADVANCE or MOTIVATE induction studies. Patients in ADVANCE or MOTIVATE were aged 16-80 years with moderately to severely active Crohn's disease. Patients in the FORTIFY substudy 1 were randomly assigned again (1:1:1) to receive either subcutaneous risankizumab 180 mg, subcutaneous risankizumab 360 mg, or withdrawal from risankizumab to receive subcutaneous placebo (herein referred to as withdrawal [subcutaneous placebo]). Treatment was given every 8 weeks. Patients were stratified by induction dose, post-induction endoscopic response, and clinical remission status. Patients, investigators, and study personnel were masked to treatment assignments. Week 52 co-primary endpoints were clinical remission (Crohn's disease activity index [CDAI] in the US protocol, or stool frequency and abdominal pain score in the non-US protocol) and endoscopic response in patients who received at least one dose of study drug during the 52-week maintenance period. Safety was assessed in patients receiving at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03105102.712 patients were initially assessed and, between April 9, 2018, and April 24, 2020, 542 patients were randomly assigned to either the risankizumab 180 mg group (n=179), the risankizumab 360 mg group (n=179), or the placebo group (n=184). Greater clinical remission and endoscopic response rates were reached with 360 mg risankizumab versus placebo (CDAI clinical remission was reached in 74 (52%) of 141 patients vs 67 (41%) of 164 patients, adjusted difference 15% [95% CI 5-24]; stool frequency and abdominal pain score clinical remission was reached in 73 (52%) of 141 vs 65 (40%) of 164, adjusted difference 15% [5-25]; endoscopic response 66 (47%) of 141 patients vs 36 (22%) of 164 patients, adjusted difference 28% [19-37]). Higher rates of CDAI clinical remission and endoscopic response (but not stool frequency and abdominal pain score clinical remission [p=0·124]) were also reached with risankizumab 180 mg versus withdrawal (subcutaneous placebo; CDAI clinical remission reached in 87 [55%] of 157 patients, adjusted difference 15% [95% CI 5-24]; endoscopic response 74 [47%] of 157, adjusted difference 26% [17-35]). Results for more stringent endoscopic and composite endpoints and inflammatory biomarkers were consistent with a dose-response relationship. Maintenance treatment was well tolerated. Adverse event rates were similar among groups, and the most frequently reported adverse events in all treatment groups were worsening Crohn's disease, arthralgia, and headache.Subcutaneous risankizumab is a safe and efficacious treatment for maintenance of remission in patients with moderately to severely active Crohn's disease and offers a new therapeutic option for a broad range of patients by meeting endpoints that might change the future course of disease.AbbVie.

The IM-UNITI study and long-term extension (LTE) evaluated the long-term efficacy, safety, and immunogenicity of subcutaneous ustekinumab maintenance therapy in patients with Crohn's disease. Here, we report the final results of IM-UNITI LTE through 5 years.Patients completing safety and efficacy evaluations at week 44 of the maintenance study were eligible to participate in the LTE and continue the treatment they were receiving. Unblinding occurred after completion of maintenance study analyses (August 2015), and patients receiving placebo were discontinued from the study after unblinding. No dose adjustment occurred in the LTE. Efficacy assessments were conducted every 12 weeks until unblinding and at dosing visits thereafter through week 252. Serum ustekinumab concentrations and antidrug antibodies were evaluated through weeks 252 and 272, respectively.Using an intent-to-treat analysis of all patients randomized to ustekinumab at maintenance baseline, 34.4% of patients in the every-8-weeks group and 28.7% in the every-12-weeks group were in clinical remission at week 252. Corresponding remission rates among patients who entered the LTE were 54.9% and 45.2%. Overall, adverse event rates (per 100 patient-years) from maintenance week 0 through the final visit generally were similar in the placebo and combined ustekinumab groups for all adverse events (440.3 vs 327.6), serious adverse events (19.3 vs 17.5), infections (99.8 vs 93.8), and serious infections (3.9 vs 3.4). Serum ustekinumab concentrations were maintained throughout the LTE. Antidrug antibodies occurred in 5.8% of patients who received ustekinumab during induction and maintenance and continued in the LTE.Patients receiving subcutaneous ustekinumab maintained clinical remission through 5 years. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

<h3>Background & Aims</h3> Clinical remission, defined by a composite of patient reported outcomes and Mayo endoscopy subscore (MES) 0 or 1 is a recommended treatment target in patients with ulcerative colitis (UC). We estimated whether incorporating more rigorous remission definitions, of endoscopic remission (MES 0) and histologic remission, affects risk of relapse. <h3>Methods</h3> Through a systematic review, we identified cohort studies in adults with UC in clinical remission that reported a minimum 12-month risk of clinical relapse, based on MES (0 vs 1) and/or histologic disease activity, in patients with endoscopic remission. Using random effects meta-analysis, we calculated relative and absolute risk of clinical relapse in patients with UC achieving different treatment targets. <h3>Results</h3> In a meta-analysis of 17 studies that included 2608 patients with UC in clinical remission, compared to patients achieving MES 1, patients achieving MES 0 had a 52% lower risk of clinical relapse (relative risk, 0.48; 95% CI, 0.37–0.62). The median 12-month risk of clinical relapse in patients with MES 1 was 28.7%; the estimated annual risk of clinical relapse in patients with MES 0 was 13.7% (95% CI, 10.6–17.9). In a meta-analysis of 10 studies in patients in endoscopic remission (MES 0), patients who achieved histologic remission had a 63% lower risk of clinical relapse vs patients with persistent histologic activity (relative risk, 0.37; 95% CI, 0.24–0.56). Estimated annual risk of clinical relapse in who achieved achieving histologic remission was 5.0% (95% CI, 3.3–7.7). <h3>CONCLUSIONS</h3> In a systematic review and meta-analysis of patients with UC in clinical remission, we observed that patients achieving more rigorous treatment endpoints (endoscopic and histologic remission) have a substantially lower risk of clinical relapse compared with patients achieving clinical remission.

Altered gut microbiota composition and function have been associated with inflammatory bowel diseases, including ulcerative colitis (UC), but the causality and mechanisms remain unknown.We applied 16S ribosomal RNA gene sequencing, shotgun metagenomic sequencing, in vitro functional assays, and gnotobiotic colonizations to define the microbial composition and function in fecal samples obtained from a cohort of healthy individuals at risk for inflammatory bowel diseases (pre-UC) who later developed UC (post-UC) and matched healthy control individuals (HCs).Microbiota composition of post-UC samples was different from HC and pre-UC samples; however, functional analysis showed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified more than 22,000 gene families that were significantly different between HC, pre-UC, and post-UC samples. Of these, 237 related to proteases and peptidases, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia and other potentially beneficial taxa and directly correlated with known proteolytic taxa, such as Bacteroides vulgatus. High elastase activity was confirmed in Bacteroides isolates from fecal samples. The bacterial contribution and functional significance of the proteolytic signature were investigated in germ-free adult mice and in dams colonized with HC, pre-UC, or post-UC microbiota. Mice colonized with or born from pre-UC-colonized dams developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC-colonized mice.We have identified increased fecal proteolytic activity that precedes the clinical diagnosis of UC and associates with gut microbiota changes. This proteolytic signature may constitute a noninvasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with antiproteases.

Background & AimsGuselkumab, a selective p19 interleukin-23 antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis. This study evaluated the efficacy and safety of guselkumab in patients with moderately to severely active Crohn’s disease with inadequate response or intolerance to conventional or biologic therapy.MethodsGALAXI-1, a phase 2, double-blind, placebo-controlled study, randomized patients 1:1:1:1:1 to intravenous guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo. Change from baseline in Crohn’s Disease Activity Index score (primary end point), clinical remission, clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, endoscopic response (major secondary end points), and safety in guselkumab-treated patients vs placebo were evaluated through week 12. Ustekinumab was a reference arm.ResultsOf 309 patients evaluated, approximately 50% had disease refractory to prior biologic therapy. At week 12, significantly greater reductions in Crohn’s Disease Activity Index from baseline (least squares means: 200 mg: –160.4, 600 mg: –138.9, and 1200 mg: –144.9 vs placebo: –36.2; all, P < .05) and significantly greater proportions of patients achieved clinical remission in each guselkumab group vs placebo (Crohn’s Disease Activity Index <150; 57.4%, 55.6%, and 45.9% vs 16.4%; all, P < .05). Greater proportions of patients receiving guselkumab achieved clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, and endoscopic response at week 12 vs placebo. Efficacy of ustekinumab vs placebo was also demonstrated. Safety event rates were generally similar across treatment groups.ConclusionsAt week 12, all 3 dose regimens of guselkumab induced greater clinical and endoscopic improvements vs placebo, with a favorable safety profile. ClinicalTrials.gov, Number: NCT03466411. Guselkumab, a selective p19 interleukin-23 antagonist, is approved for the treatment of plaque psoriasis and psoriatic arthritis. This study evaluated the efficacy and safety of guselkumab in patients with moderately to severely active Crohn’s disease with inadequate response or intolerance to conventional or biologic therapy. GALAXI-1, a phase 2, double-blind, placebo-controlled study, randomized patients 1:1:1:1:1 to intravenous guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo. Change from baseline in Crohn’s Disease Activity Index score (primary end point), clinical remission, clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, endoscopic response (major secondary end points), and safety in guselkumab-treated patients vs placebo were evaluated through week 12. Ustekinumab was a reference arm. Of 309 patients evaluated, approximately 50% had disease refractory to prior biologic therapy. At week 12, significantly greater reductions in Crohn’s Disease Activity Index from baseline (least squares means: 200 mg: –160.4, 600 mg: –138.9, and 1200 mg: –144.9 vs placebo: –36.2; all, P < .05) and significantly greater proportions of patients achieved clinical remission in each guselkumab group vs placebo (Crohn’s Disease Activity Index <150; 57.4%, 55.6%, and 45.9% vs 16.4%; all, P < .05). Greater proportions of patients receiving guselkumab achieved clinical response, Patient Reported Outcomes-2 remission, clinical-biomarker response, and endoscopic response at week 12 vs placebo. Efficacy of ustekinumab vs placebo was also demonstrated. Safety event rates were generally similar across treatment groups. At week 12, all 3 dose regimens of guselkumab induced greater clinical and endoscopic improvements vs placebo, with a favorable safety profile. ClinicalTrials.gov, Number: NCT03466411.

<h2>Summary</h2><h3>Background</h3> Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P_2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. <h3>Methods</h3> In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes <i>vs</i> no), baseline corticosteroid use (yes <i>vs</i> no), and baseline disease activity (modified Mayo score [MMS]; 4–6 <i>vs</i> 7–9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. <h3>Findings</h3> Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients <i>vs</i> ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients <i>vs</i> nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. <h3>Interpretation</h3> Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. <h3>Funding</h3> Arena Pharmaceuticals.

Despite the introduction of new monoclonal antibodies and oral therapies for the treatment of ulcerative colitis, clinical remission rates remain low, underscoring the need for innovative treatment approaches. We assessed whether guselkumab plus golimumab combination therapy was more effective for ulcerative colitis than either monotherapy.We did a randomised, double-blind, controlled, proof-of-concept trial at 54 hospitals, academic medical centres, or private practices in nine countries. Eligible adults (aged ≥18 to 65 years) had a confirmed diagnosis of ulcerative colitis at least 3 months before screening and moderately-to-severely active ulcerative colitis (Mayo score 6-12) with a centrally-read baseline endoscopy subscore of 2 or higher. Patients were randomly assigned (1:1:1) using a computer-generated randomisation schedule to combination therapy (subcutaneous golimumab 200 mg at week 0, subcutaneous golimumab 100 mg at weeks 2, 6, and 10, and intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab monotherapy 100 mg every 8 weeks for 32 weeks), golimumab monotherapy (subcutaneous golimumab 200 mg at week 0 followed by subcutaneous golimumab 100 mg at week 2 and every 4 weeks thereafter for 34 weeks), or guselkumab monotherapy (intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab 100 mg every 8 weeks thereafter for 32 weeks). The primary endpoint was clinical response at week 12 (defined as a ≥30% decrease from baseline in the full Mayo score and a ≥3 points absolute reduction with either a decrease in rectal bleeding score of ≥1 point or a rectal bleeding score of 0 or 1). Efficacy was analysed in the modified intention-to-treat population up to week 38, which included all randomly assigned patients who received at least one (partial or complete) study intervention dose. Safety was analysed up to week 50, according to study intervention received among all patients who received at least one (partial or complete) dose of study intervention. This trial is complete and is registered with ClinicalTrials.gov, NCT03662542.Between Nov 20, 2018, and Nov 15, 2021, 358 patients were screened for eligibility, of whom 214 patients were randomly assigned to combination therapy (n=71), golimumab monotherapy (n=72), or guselkumab monotherapy (n=71). Of the 214 patients included, 98 (46%) were women and 116 (54%) were men and the mean age was 38·4 years (SD 12·0). At week 12, 59 (83%) of 71 patients in the combination therapy group had achieved clinical response compared with 44 (61%) of 72 patients in the golimumab monotherapy group (adjusted treatment difference 22·1% [80% CI 12·9 to 31·3]; nominal p=0·0032) and 53 (75%) of 71 patients in the guselkumab monotherapy group (adjusted treatment difference 8·5% [-0·2 to 17·1; nominal p=0·2155). At week 50, 45 (63%) of 71 patients in the combination therapy group, 55 (76%) of 72 patients in the golimumab monotherapy group, and 46 (65%) of 71 patients in the guselkumab monotherapy group had reported at least one adverse event. The most common adverse events were ulcerative colitis, upper respiratory tract infection, headache, anaemia, nasopharyngitis, neutropenia, and pyrexia. No deaths, malignancies, or cases of tuberculosis were reported during the combination induction period. One case of tuberculosis was reported in the combination therapy group and one case of colon adenocarcinoma was reported in the guselkumab monotherapy group; both occurred after week 12. Two deaths were reported after the final dose of study intervention (poisoning in the combination therapy group and COVID-19 in the guselkumab monotherapy group).Data from this proof-of-concept study suggest that combination therapy with guselkumab and golimumab might be more effective for ulcerative colitis than therapy with either drug alone. These findings require confirmation in larger trials.Janssen Research and Development.

Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis.We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment.Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment.To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint.F Hoffmann-La Roche.