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Background & aimsThe 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.MethodsPatients 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.ResultsUsing 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.ConclusionsPatients receiving subcutaneous ustekinumab maintained clinical remission through 5 years. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

Background & aimsPregnant women with inflammatory bowel disease (IBD) may require biologic or thiopurine therapy to control disease activity. Lack of safety data has led to therapy discontinuation during pregnancy, with health repercussions to mother and child.MethodsBetween 2007 and 2019, pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States. The primary analysis was a comparison of 5 outcomes (congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infant infections) among pregnancies exposed vs unexposed in utero to biologics, thiopurines, or a combination. Bivariate analyses followed by logistic regression models adjusted for relevant confounders were used to determine the independent effects of specific drug classes on outcomes of interest.ResultsAmong 1490 completed pregnancies, there were 1431 live births. One-year infant outcomes were available in 1010. Exposure was to thiopurines (n = 242), biologics (n = 642), or both (n = 227) vs unexposed (n = 379). Drug exposure did not increase the rate of congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infections during the first year of life. Higher disease activity was associated with risk of spontaneous abortion (hazard ratio, 3.41; 95% confidence interval, 1.51-7.69) and preterm birth with increased infant infection (odds ratio, 1.73; 95% confidence interval, 1.19-2.51).ConclusionsBiologic, thiopurine, or combination therapy exposure during pregnancy was not associated with increased adverse maternal or fetal outcomes at birth or in the first year of life. Therapy with these agents can be continued throughout pregnancy in women with IBD to maintain disease control and reduce pregnancy-related adverse events. ClinicalTrials.gov, Number: NCT00904878.

Background & aimsPatients with Crohn's disease (CD), but not ulcerative colitis (UC), of shorter duration have higher rates of response to tumor necrosis factor (TNF) antagonists than patients with longer disease duration. Little is known about the association between disease duration and response to other biologic agents. We aimed to evaluate response of patients with CD or UC to vedolizumab, stratified by disease duration.MethodsWe analyzed data from a retrospective, multicenter, consortium of patients with CD (n = 650) or UC (n = 437) treated with vedolizumab from May 2014 through December 2016. Using time to event analyses, we compared rates of clinical remission, corticosteroid-free remission (CSFR), and endoscopic remission between patients with early-stage (≤2 years duration) and later-stage (>2 years) CD or UC. We used Cox proportional hazards models to identify factors associated with outcomes.ResultsWithin 6 months initiation of treatment with vedolizumab, significantly higher proportions of patients with early-stage CD, vs later-stage CD, achieved clinical remission (38% vs 23%), CSFR (43% vs 14%), and endoscopic remission (29% vs 13%) (P < .05 for all comparisons). After adjusting for disease-related factors including previous exposure to TNF antagonists, patients with early-stage CD were significantly more likely than patients with later-stage CD to achieve clinical remission (adjusted hazard ratio [aHR], 1.59; 95% CI, 1.02-2.49), CSFR (aHR, 3.39; 95% CI, 1.66-6.92), and endoscopic remission (aHR, 1.90; 95% CI, 1.06-3.39). In contrast, disease duration was not a significant predictor of response among patients with UC.ConclusionsPatients with CD for 2 years or less are significantly more likely to achieve a complete response, CSFR, or endoscopic response to vedolizumab than patients with longer disease duration. Disease duration does not associate with response vedolizumab in patients with UC.

Microbiota are thought to influence the development and progression of inflammatory bowel disease (IBD), but determining generalizable effects of microbiota on IBD etiology requires larger-scale functional analyses. We colonized germ-free mice with intestinal microbiotas from 30 healthy and IBD donors and determined the homeostatic intestinal T cell response to each microbiota. Compared to microbiotas from healthy donors, transfer of IBD microbiotas into germ-free mice increased numbers of intestinal Th17 cells and Th2 cells and decreased numbers of RORγt+ Treg cells. Colonization with IBD microbiotas exacerbated disease in a model where colitis is induced upon transfer of naive T cells into Rag1-/- mice. The proportions of Th17 and RORγt+ Treg cells induced by each microbiota were predictive of human disease status and accounted for disease severity in the Rag1-/- colitis model. Thus, an impact on intestinal Th17 and RORγt+ Treg cell compartments emerges as a unifying feature of IBD microbiotas, suggesting a general mechanism for microbial contribution to IBD pathogenesis.

CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. The LIBERTY studies aimed to demonstrate superiority of CT-P13 SC vs placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC). Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately to severely active CD or UC and inadequate response or intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks 0, 2, and 6. At week 10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until week 54 (maintenance phase) using prefilled syringes. (Co-) primary end points were clinical remission and endoscopic response (CD) and clinical remission (UC) at week 54 (all-randomized population). Overall, 396 patients with CD and 548 patients with UC received induction treatment. At week 54 in the CD study, statistically significant higher proportions of CT-P13 SC–treated patients vs placebo-treated patients achieved clinical remission (62.3% vs 32.1%; P <.0001) and endoscopic response (51.1% vs 17.9%; P <.0001). In the UC study, clinical remission rates at week 54 were statistically significantly higher with CT-P13 SC vs placebo (43.2% vs 20.8%; P <.0001). Achievement of key secondary end points was significantly higher with CT-P13 SC vs placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified. CT-P13 SC was more effective than placebo as maintenance therapy and was well tolerated in patients with moderately to severely active CD or UC who responded to CT-P13 IV induction. ClinicalTrials.gov , Numbers: NCT03945019 (CD) and NCT04205643 (UC). CT-P13 (infliximab, an anti–tumor necrosis factor therapy) is a biologic drug injected under the skin (ie, subcutaneously). Subcutaneous CT-P13 was more effective than a placebo and well tolerated in patients with moderate to severe Crohn's disease or ulcerative colitis. [ABSTRACT FROM AUTHOR]

Background & aimsCrohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects.MethodsWe performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony-stimulating factor 2-receptor β common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and granulocyte-macrophage colony-stimulating factor-responsive cells were defined by adenomatous polyposis coli (APC) time-of-flight mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and the expression and functions of gene products were compared.ResultsIn the discovery cohort, we associated CD with a frameshift mutation in CSF2RB (P = 8.52 × 10(-4)); the finding was validated in the replication cohort (combined P = 3.42 × 10(-6)). Incubation of intestinal lamina propria leukocytes with granulocyte-macrophage colony-stimulating factor resulted in high levels of phosphorylation of signal transducer and activator of transcription (STAT5) and lesser increases in phosphorylation of extracellular signal-regulated kinase and AK straining transforming (AKT). Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 after stimulation with granulocyte-macrophage colony-stimulating factor, compared with cells transfected with control CSF2RB, indicating a dominant-negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) had reduced responses to granulocyte-macrophage colony-stimulating factor and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance.ConclusionsIn a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB. Intestinal monocytes from carriers of this mutation had reduced responses to granulocyte-macrophage colony-stimulating factor, providing an additional mechanism for alterations to the innate immune response in individuals with CD.

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.

Summary: Background: Sarcopenia, a loss of skeletal muscle mass or function, affects up to 50% of patients with inflammatory bowel disease (IBD) and is associated with poor clinical outcomes including increased hospitalizations, need for surgery and post‐operative complications. Despite the high prevalence and clinical significance of sarcopenia in patients with IBD, few patients undergo routine muscle evaluation. Aim: The goal of this study was to review the mechanisms of sarcopenia in patients with IBD and understand novel modalities to assess and treat impaired muscle mass or function. Methods: Pubmed and Cochrane databases were searched including articles published up to February 2023 utilizing the following keywords: "inflammatory bowel disease", "IBD", "Crohn's disease", "ulcerative colitis", "sarcopenia", "myosteatosis", "muscle health", and "frailty". Results: The pathogenesis of sarcopenia in IBD is not well defined, however, there is evidence supporting the role of malabsorption, reduced protein intake, chronic inflammation, dysbiosis, decreased physical activity, medication effects and hormone signaling from visceral adiposity. Traditional sarcopenia assessment techniques include direct measurements on cross sectional imaging. However, given the time, cost and radiation exposure associated with cross sectional imaging, new bedside tools are now available to estimate muscle mass, including assessment of grip strength, mid upper arm circumference and body composition utilizing bioelectrical impedance analysis. In addition, novel biomarkers for assessing muscle mass and techniques utilizing point of care ultrasound have been proposed to make sarcopenia evaluation more streamlined in the IBD clinic. Conclusion: Sarcopenia is associated with poor clinical outcomes independent of IBD activity and therefore muscle health should be assessed in all IBD patients at routine intervals. Future studies to better our understanding of the pathophysiology as well as most effective management of sarcopenia in IBD will help guide clinical care and reduce disease related complications. [ABSTRACT FROM AUTHOR]

Summary: Background: Crohn's disease requires effective patient‐clinician communication for successful illness and medication management. Shared decision making (SDM) has been suggested to improve communication around early intensive therapy. However, effective evidence‐based SDM interventions for Crohn's disease are lacking, and the impact of SDM on Crohn's disease decision making and choice of therapy is unclear. Aim: To test the impact of SDM on choice of therapy, quality of the decision and provider trust compared to standard Crohn's disease care. Methods: We conducted a multi‐site cluster randomised controlled trial in 14 diverse gastroenterology practices in the US. Results: A total of 158 adult patients with Crohn's disease within 15 years of their diagnosis, with no prior Crohn's disease complications, and who were candidates to receive immunomodulators or biologics, participated in the study. Among these, 99 received the intervention and 59 received standard care. Demographics were similar between groups, although there were more women assigned to standard care, and a slightly shorter disease duration among those in the intervention group. Participants in the intervention group more frequently chose combination therapy (25% versus 5% control, p < 0.001), had a significantly lower decisional conflict (p < 0.05) and had greater trust in their provider (p < 0.05). Conclusions: With rapidly expanding medication choices for Crohn's disease and slow uptake of early intensive therapy, SDM can personalise treatment strategies and has the potential to move the field of Crohn's disease management forward with an ultimate goal of consistently treating this disease early and intensively in appropriate patients. Trial Registration: Evaluating a Shared Decision Making Program for Crohn's Disease, ClinicalTrials.gov Identifier NCT02084290 https://clinicaltrials.gov/ct2/show/NCT02084290. [ABSTRACT FROM AUTHOR]

Background: Cigarette smoking is associated with disease progression, poor outcomes, and increased biologic use in Crohn's Disease (CD). In this prospective study, we describe the structure and results of a pharmacist-driven smoking cessation program in an Inflammatory Bowel Disease (IBD) Specialty Medical Home. Methods: One pharmacist designed and implemented a collaborative drug therapy management (CDTM) program, which allowed the pharmacist to initiate and modify smoking cessation aids, monitor medication safety and efficacy, and provide behavioral counseling. Crohn's Disease patients who were current smokers and referred to the program were analyzed. Clinical and demographic data, disease activity, and smoking history were collected. The primary outcome was the proportion of patients in the enrolled group and the declined group who quit smoking at least once during the follow-up period. Secondary outcomes include demographic and clinical differences between enrolled and declined patients, and enrolled quitters and non-quitters. Results: Thirty-two patients were referred to the program and 19 participated. Over a median follow-up period of 305 [264-499] days, 42% (8/19) of enrolled patients quit smoking at least once. Fifteen percent (2/13) of declined patients quit smoking. Patients who continued to smoke had more instances of loss of response to a biologic, need to start a new biologic, or escalation of biologic therapy. The CDTM pharmacist was able to provide all necessary clinical services for smokers enrolled in the program. Conclusions: A pharmacist-led smoking cessation program in a specialty medical home is feasible. It may result in successful quit attempts and may optimize IBD medication use. [ABSTRACT FROM AUTHOR]

Whether preoperative treatment of inflammatory bowel disease (IBD) with tumor necrosis factor inhibitors (TNFis) increases the risk of postoperative infectious complications remains controversial. The primary aim of this study was to determine whether preoperative exposure to TNFis is an independent risk factor for postoperative infectious complications within 30 days of surgery. We conducted a multicenter prospective observational study of patients with IBD undergoing intra-abdominal surgery across 17 sites from the Crohn's & Colitis Foundation Clinical Research Alliance. Infectious complications were categorized as surgical site infections (SSIs) or non-SSIs. Current TNFi exposure was defined as use within 12 weeks of surgery, and serum was collected for drug-level analyses. Multivariable models for occurrence of the primary outcome, any infection, or SSI were adjusted by predefined covariates (age, sex, preoperative steroid use, and disease type), baseline variables significantly associated (P <.05) with any infection or SSI separately, and TNFi exposure status. Exploratory models used TNFi exposure based on serum drug concentration. A total of 947 patients were enrolled from September 2014 through June 2017. Current TNFi exposure was reported by 382 patients. Any infection (18.1% vs 20.2%, P =.469) and SSI (12.0% vs 12.6%, P =.889) rates were similar in patients currently exposed to TNFis and those unexposed. In multivariable analysis, current TNFi exposure was not associated with any infection (odds ratio, 1.050; 95% confidence interval, 0.716–1.535) or SSI (odds ratio, 1.249; 95% confidence interval, 0.793–1.960). Detectable TNFi drug concentration was not associated with any infection or SSI. Preoperative TNFi exposure was not associated with postoperative infectious complications in a large prospective multicenter cohort. [Display omitted] In the largest multicenter prospective surgical cohort on the topic, P rospective Cohort of U lcerative C olitis and Crohn's Disease Patients Undergoing Surgery to Identify Risk Factors for Post-Operative IN fection I (PUCCINI) showed that preoperative tumor necrosis factor inhibitor use was not associated with any postoperative infections, including surgical site infections. [ABSTRACT FROM AUTHOR]

Background: Active-comparator trials are important to inform patient and physician choice. We aimed to evaluate the efficacy and safety of monotherapy with either ustekinumab or adalimumab in biologic-naive patients with moderately to severely active Crohn's disease.Methods: We conducted a randomised, double-blind, parallel-group, active-comparator, phase 3b trial (SEAVUE) at 121 hospitals or private practices in 18 countries. We included biologic-naive patients aged 18 years or older with moderately to severely active Crohn's disease and a Crohn's Disease Activity Index (CDAI) score of 220-450, who had not responded to or were intolerant to conventional therapy (or were corticosteroid dependent) and had at least one ulcer of any size at baseline endoscopic evaluation. Eligible patients were randomly assigned (1:1; via an interactive web response system) to receive ustekinumab (approximately 6 mg/kg intravenously on day 0, then 90 mg subcutaneously once every 8 weeks) or adalimumab (160 mg on day 0, 80 mg at 2 weeks, then 40 mg once every 2 weeks, subcutaneously) through week 56. Study treatments were administered as monotherapy and without dose modifications. Patients, investigators, and study site personnel were masked to treatment group assignment. The primary endpoint was the proportion of patients who were in clinical remission (CDAI score <150) at week 52 in the intention-to-treat population (ie, all patients who were randomly assigned to a treatment group). This trial is registered with ClinicalTrials.gov, NCT03464136, and EudraCT, 2017-004209-41.Findings: Between June 28, 2018, and Dec 12, 2019, 633 patients were assessed for eligibility and 386 were enrolled and randomly assigned to receive ustekinumab (n=191) or adalimumab (n=195). 29 (15%) of 191 patients in the ustekinumab group and 46 (24%) of 195 in the adalimumab group discontinued study treatment before week 52. There was no significant difference between the ustekinumab and adalimumab groups in the occurrence of the primary endpoint; at week 52, 124 (65%) of 191 patients in the ustekinumab group versus 119 (61%) of 195 in the adalimumab group were in clinical remission (between-group difference 4%, 95% CI -6 to 14; p=0·42). Safety for both groups was consistent with previous reports. Serious infections were reported in four (2%) of 191 patients in the ustekinumab group and five (3%) of 195 in the adalimumab group. No deaths occurred through week 52 of the study.Interpretation: Both ustekinumab and adalimumab monotherapies were highly effective in this population of biologic-naive patients, with no difference in the primary outcome between the drugs.Funding: Janssen Scientific Affairs. [ABSTRACT FROM AUTHOR]

Although biologics have revolutionized the treatment of Crohn's disease (CD), an efficacy ceiling has been reached. Combining biologic therapies may improve remission rates. EXPLORER, a phase 4, single-arm, open-label study, evaluated triple combination therapy with vedolizumab (300 mg on day 1, weeks 2 and 6, and then every 8 weeks), adalimumab (160 mg on day 2, 80 mg at week 2, then 40 mg every 2 weeks), and methotrexate (15 mg weekly) in biologic-naïve patients with newly diagnosed, moderate- to high-risk CD. Endoscopic remission at week 26 (primary end point; Simple Endoscopic Score for CD ≤2), clinical remission at weeks 10 and 26 (secondary end point; Crohn's Disease Activity Index <150), and incidences of adverse events and serious adverse events were evaluated. Among 55 enrolled patients, the mean CD duration was 0.4 years, the mean baseline Simple Endoscopic Score for CD was 12.6, and the mean baseline Crohn's Disease Activity Index was 265.5. At week 26, 19 patients (34.5%) were in endoscopic remission. At weeks 10 and 26, 34 (61.8%) and 30 patients (54.5%), respectively, were in clinical remission. Post hoc Bayesian analysis showed that the probabilities that triple combination therapy produced a higher endoscopic remission rate (33.5%; 95% credible interval, 22.4–45.7) than placebo (14%), vedolizumab monotherapy (27%), or adalimumab monotherapy (30%) were 99.9% or higher, 86.3%, and 71.4%, respectively. Six patients had serious adverse events. Combination therapy resulted in endoscopic and clinical remission at week 26 in 34.5% and 54.5% of patients, respectively, with no safety signal related to the treatment regimen. This supports further evaluation of combination therapy in CD. ClinicalTrials.gov number: NCT02764762. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) treatment paradigms recommend objective disease activity assessment and reactive therapeutic drug monitoring (TDM) prior to changes in biologic therapy. We aimed to describe objective marker and TDM assessment in routine clinical practice prior to biologic therapeutic changes in adult IBD patients.Methods: TARGET-IBD is a prospective longitudinal cohort of over 2100 IBD patients receiving usual care at 34 US academic or community centers enrolled between June 2017 and October 2019 who received biologic therapy and had a dose change or biologic discontinuation for lack of efficacy. Objective markers of disease activity within 12 weeks prior included fecal calprotectin, C-reactive protein (CRP), endoscopy, computed tomography (CT) and magnetic resonance imaging (MRI). TDM data for infliximab or adalimumab was obtained.Results: 525 patients (71.4% Crohn's disease [CD], 28.6% ulcerative colitis [UC]) receiving biologic therapy underwent dose change (55.6%) or discontinuation (44.4%) for lack of efficacy. The majority were Caucasian (85.7%), 18-39 years old (52.2%), privately insured (81.5%), and at academic centers (73.7%). For dose changes, 67.5% had at least one objective disease activity assessment or TDM in the 12 weeks prior (CD 67.9%, UC 66.2%; P = 0.79). The most common objective marker was CRP in both CD (39.1%) and UC (54.5%). CRP and calprotectin were used significantly more in UC (P = 0.02 and P = 0.03). TDM was obtained in 30.7% (28.8% UC, 31.4% CD; P = 0.72) prior to dose change. For biologic discontinuation, 79.4% patients underwent objective assessment or TDM prior. In CD, CRP (46.3%) was most common, and CT (P = 0.03) and MRI (P < 0.001) were significantly more frequent than in UC. TDM was performed in 40.1% of patients (43.5% UC, 38.0% CD, P = 0.49) prior to discontinuation. Among all participants with dose change or discontinuation, endoscopy was performed in 29.3% with CD and 31.3% with UC. Academic care setting was associated with objective assessment before therapy change (OR 1.59, 95% CI 1.01-2.50).Conclusion: Nearly one-third of patients undergoing a biologic dose change or discontinuation do not undergo objective disease activity assessment or TDM. Assessment choice differs by disease. Future studies assessing the impact of such practices on long-term outcomes are needed. [ABSTRACT FROM AUTHOR]

Summary: Background: There is a need for improved risk stratification in Crohn's disease. Aim: To identify novel blood protein biomarkers associated with future Crohn's disease complications Methods: We performed a case‐cohort study utilising a paediatric inception cohort, the Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's disease (RISK) study. All patients had inflammatory disease (B1) at baseline. Outcomes were development of stricturing (B2) or penetrating (B3) complications. We assayed 92 inflammation‐related proteins in baseline plasma using a proximity extension assay (Olink Proteomics). An ensemble machine learning technique, random survival forests (RSF), selected variables predicting B2 and B3 complications. Selected analytes were compared to clinical variables and serology only models. We examined selected proteins in a single‐cell sequencing cohort to analyse differential cell expression in blood and ileum. Results: We included 265 patients with mean age 11.6 years (standard deviation [SD] 3.2). Seventy‐three and 34 patients, respectively, had B2 and B3 complications within mean 1123 (SD 477) days for B2 and 1251 (442) for B3. A model with 5 protein markers predicted B3 complications with an area under the curve (AUC) of 0.79 (95% confidence interval [CI] 0.76‐0.82) compared to 0.69 (95% CI 0.66‐0.72) for serologies and 0.74 (95% CI 0.71‐0.77) for clinical variables. A model with 4 protein markers predicted B2 complications with an AUC of 0.68 (95% CI 0.65‐0.71) compared to 0.62 (95% CI 0.59‐0.65) for serologies and 0.52 (95% CI 0.50‐0.55) for clinical variables. B2 analytes were highly expressed in ileal stromal cells while B3 analytes were prominent in peripheral blood and ileal T cells. Conclusions: We identified novel blood proteomic markers, distinct for B2 and B3, associated with progression of paediatric Crohn's disease. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a relapsing and remitting inflammatory disease of the colon with a variable course. Despite advances in treatment, only approximately 40% of patients achieve clinical remission at the end of a year, prompting the exploration of new treatment modalities. This review explores novel therapeutic approaches to UC, including promising drugs in various stages of development, efforts to maximize the efficacy of currently available treatment options, and non-medication-based modalities. Treatment approaches which show promise in impacting the future of UC management are highlighted. [ABSTRACT FROM AUTHOR]

Summary: Background: Vedolizumab, a gut‐selective α4β7 integrin antibody, is approved for moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). Aim: To report the final results from the vedolizumab GEMINI long‐term safety (LTS) study. Methods: The phase 3, open‐label GEMINI LTS study (initiated May 2009) enrolled patients with UC or CD from four prior clinical trials and vedolizumab‐naïve patients. Vedolizumab LTS was evaluated; efficacy and patient‐reported outcomes were exploratory endpoints. Results: Enrolled patients (UC, n = 894; CD, n = 1349) received vedolizumab 300 mg IV every 4 weeks; median cumulative exposure was 42.4 months (range: 0.03‐112.2) for UC and 31.5 months (range: 0.03‐100.3) for CD. Over 8 years, adverse events (AEs) occurred in 93% (UC) and 96% (CD) of patients, with UC (36%) and CD (35%) exacerbations most frequent. Serious AEs were reported for 31% (UC) and 41% (CD) of patients. Vedolizumab discontinuation due to AEs occurred in 15% (UC) and 17% (CD) of patients. There were no new trends for infections, malignancies, infusion‐related reactions, or hepatic events, and no cases of progressive multifocal leukoencephalopathy. Of the ten deaths (UC, n = 4; CD, n = 6), two were considered drug‐related by local investigators (West Nile virus infection‐related encephalitis and hepatocellular carcinoma). Continuous vedolizumab maintained clinical response long‐term, with 33% (UC) and 28% (CD) of patients in clinical remission at 400 treatment weeks. Conclusions: The safety profile of vedolizumab remains favourable with no unexpected or new safety concerns. These results further establish the safety of vedolizumab and support its long‐term use (NCT00790933/EudraCT 2008‐002784‐14). [ABSTRACT FROM AUTHOR]

Summary: Background: Direct comparisons are lacking between vedolizumab and tumour necrosis factor (TNF)‐antagonist therapy in Crohn's disease (CD). Aim: To compare safety and effectiveness of vedolizumab and TNF‐antagonist therapy in adult CD patients. Methods: Retrospective observational cohort (May 2014–December 2017) propensity score‐weighted comparison of vedolizumab vs TNF‐antagonist therapy (infliximab, adalimumab, certolizumab) in CD. Propensity scores were weighted for age, prior treatments, disease complications, extent and severity, steroid dependence, and concomitant immunosuppressive drug use. The primary outcome was comparative risk for infections or non‐infectious serious adverse events (requiring antibiotics, antivirals, antifungals, hospitalisation, or treatment discontinuation, or resulting in death). Secondary comparative effectiveness outcomes were clinical remission (resolution of CD‐related symptoms), steroid‐free clinical remission and endoscopic remission (absence of ulcers/erosions). Results: We included 1266 patients (n = 659 vedolizumab). Rates of non‐infectious serious adverse events (odds ratio [OR] 0.072, 95% confidence interval [CI] 0.012‐0.242), but not serious infections (OR 1.183, 95% CI 0.786‐1.795), were significantly lower with vedolizumab vs TNF‐antagonist therapy. Safety comparisons for non‐infectious serious adverse events remained significant after adjusting for differences in duration of exposure. No significant difference was observed between vedolizumab and TNF‐antagonist therapy for clinical remission (hazard ratio [HR] 0.932, 95% CI 0.707‐1.228), steroid‐free clinical remission (HR 1.250, 95% CI 0.677‐2.310) or endoscopic remission (HR 0.827, 95% CI 0.595‐1.151). TNF‐antagonist therapy was associated with higher treatment persistence compared with vedolizumab. Conclusions: There was a lower risk of non‐infectious serious adverse events, but not serious infections, with vedolizumab vs TNF‐antagonist therapy, with no significant difference for achieving disease remission. [ABSTRACT FROM AUTHOR]

Objectives: We performed a pathological pilot study to characterize the inflammation at the ileocolic anastomosis as Crohn's disease or ischemia. Methods and materials: Subjects were selected at random from a retrospective database of patients with Crohn's disease and who had undergone an ileocolic resection with subsequent endoscopic assessment of the anastomosis and neo-terminal ileum. Pathology slides from the anastomotic mucosa, either from targeted biopsies or subsequent ileocolic resections, were re-assessed histologically for features of ischemia and of Crohn's disease. Results: Twenty-nine specimens from 8 patients were reviewed, including 12 ileocolic resection specimens and 17 sets of endoscopic biopsies. Twenty-seven of the 29 specimens, accounting for all of the patients, had evidence of CD-like features. In contrast, only 2 specimens, accounting for 2 of 8 patients, had histologic features of ischemia, and both specimens also had Crohn's-like features. Conclusion: To our knowledge this is the first study to specifically evaluate the pathology of ileocolic anastomoses in Crohn's disease. It suggests that anastomotic inflammation is predominantly a manifestation of recurrent Crohn's disease rather than of postoperative ischemia. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The objective was to assess the efficacy and safety of GED-0301, an antisense oligodeoxynucleotide to Smad7, in active Crohn's disease (CD). METHODS: This phase 3, blinded study randomized patients (1:1:1:1) to placebo or 1 of 3 once-daily oral GED-0301 regimens: 160 mg for 12 weeks followed by 40 mg continuously or alternating placebo with 40 or 160 mg every 4 weeks through week 52. RESULTS: In all, 701 patients were randomized and received study medication before premature study termination; 78.6% (551/701) completed week 12, and 5.8% (41/701) completed week 52. The primary endpoint, clinical remission achievement (CD Activity Index score <150) at week 12, was attained in 22.8% of patients on GED-0301 vs 25% on placebo (P = 0.6210). At study termination, proportions of patients achieving clinical remission at week 52 were similar among individual GED-0301 groups and placebo. More placebo vs GED-0301 patients achieved endoscopic response (>50% decrease from baseline Simple Score for CD) at week 12 (18.1% vs 10.1%). Additional endoscopic endpoints were similar between groups at weeks 12 and 52. More placebo vs GED-0301 patients had clinical response (≥100-point decrease in the CD Activity Index score) at week 12 (44.4% vs 33.3%); at week 52, clinical response rates were similar. Adverse events were predominantly gastrointestinal and related to active CD, consistent with lack of clinical and endoscopic response to treatment. Two deaths occurred (GED-0301 total group) due to small intestinal obstruction and pneumonia; neither was suspected by the investigator to be treatment-related. DISCUSSION: GED-0301 did not demonstrate efficacy vs placebo in active CD. [ABSTRACT FROM AUTHOR]

Background and Aims 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. Methods 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. Results 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%]. Conclusions 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. [ABSTRACT FROM AUTHOR]

Ustekinumab is an effective treatment of Crohn's disease (CD). Of interest to patients is knowing how soon symptoms may improve. We analyzed ustekinumab response dynamics from the ustekinumab CD trials. Patients with CD received intravenous induction with ustekinumab ∼6 mg/kg (n = 458) or placebo (n = 457). Week 8 ustekinumab responders received subcutaneous ustekinumab 90 mg as the first maintenance dose or as an extended induction dose for nonresponders. Patient-reported symptom changes (stool frequency, abdominal pain, general well-being) within the first 14 days and clinical outcomes through week 44 were evaluated using the CD Activity Index. After ustekinumab infusion, stool frequency improvement was significantly (P <.05) greater than placebo on day 1 and for all patient-reported symptoms by day 10. In patients with no history of biologic failure or intolerance, cumulative clinical remission rates increased from 23.0% at week 3 to 55.5% at week 16 after the subcutaneous dose at week 8. Corresponding cumulative rates for patients with a history of biologic failure or intolerance increased from 12.9% to 24.1%. Neither change from baseline in CD Activity Index score nor week 8 ustekinumab pharmacokinetics were associated with week 16 response. Among all patients who received subcutaneous ustekinumab 90 mg q8w, up to 66.7% were in clinical response at week 44. Ustekinumab induction provided symptom relief by day 1 post-infusion. Following ustekinumab infusion and a subcutaneous 90 mg injection, clinical outcomes continued to increase through week 16 and up to week 44. Regardless of week 8 clinical status or ustekinumab pharmacokinetics, patients should receive additional treatment at week 8. ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355 [Display omitted] [ABSTRACT FROM AUTHOR]

Endoscopic assessment of disease activity is integral for evaluating treatment response in patients with Crohn's disease (CD). We aimed to define appropriate items for evaluating endoscopic activity and conventions for consistent endoscopic scoring rules in CD. A 2-round modified RAND/University of California at Los Angeles Appropriateness Method study was conducted. A panel of 15 gastroenterologists used a 9-point Likert scale to rate the appropriateness of statements pertaining to the Simple Endoscopic Score for CD, Crohn's Disease Endoscopic Index of Severity, and additional items relevant to endoscopy scoring in CD. Each statement was voted as appropriate, uncertain, or inappropriate based on the median panel rating and presence of disagreement. Panelists voted that it is appropriate for all ulcers to contribute to endoscopic scoring in CD, including aphthous ulcers, ulcerations at a surgical anastomosis, and anal canal ulcers (scored in the rectum). Endoscopic healing should reflect an absence of ulcers. Narrowing should be defined as a clear decrease in luminal diameter; stenosis should be defined by an impassable narrowing, and if occurring at the junction of 2 segments, scored in the distal segment. Scarring and inflammatory polyps were considered inappropriate for including in the affected area score. The optimal method for defining ulcer depth remains uncertain. We outlined scoring conventions for the Simple Endoscopic Score for CD and Crohn's Disease Endoscopic Index of Severity, noting that both scores have limitations. Therefore, we identified priorities for future research and steps for developing and validating a more representative endoscopic index in CD. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Aims: A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis [UC] or Crohn's disease [CD] has been reported. Here we further explore exposure--efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data. Methods: Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated. Exposure--efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 [Caverage ] as exposure measure. Results: Higher vedolizumab concentrations were associated with higher clinical remission rates; the exposure--efficacy relationship was steeper for UC than CD. Unadjusted analyses overestimated the relationship, more so for CD. From covariate-adjusted models, average probability of remission at Week 6 increased by approximately 15% for UC and 10% for CD between Caverage values of 35 and 84 µg/ml [5th and 95th percentiles, respectively]. On average, patients with higher albumin, lower faecal calprotectin [UC only], lower C-reactive protein [CD only], and no previous tumour necrosis factor-α [TNFα] antagonist use had a higher remission probability. Previous TNFα antagonist use had the greatest impact; remission probability was approximately 10% higher in treatment-naïve patients. Conclusions: Higher vedolizumab serum concentrations were associated with higher remission rates after induction therapy in patients with moderately to severely active UC or CD. This relationship is affected by several factors, including previous TNF α antagonist use. Prospective studies are needed to assess vedolizumab dose individualisation and optimisation. [ABSTRACT FROM AUTHOR]

Background and Aims: This 11-week Phase IIa induction study evaluated the efficacy and safety of eldelumab in patients with active Crohn's disease. Methods: Adults with Crohn's Disease Activity Index 220-450 were randomised 1:1:1 to placebo or eldelumab 10 or 20 mg/kg intravenously on Days 1 and 8, and alternate weeks thereafter. All patients underwent ileocolonoscopy at baseline. Patients with active inflammation according to the Simplified Endoscopic Score for Crohn's Disease criteria [the originally planned endoscopy cohort] underwent another ileocolonoscopy at Week 11 at the investigator's discretion. All ileocolonoscopies were centrally read. The primary objective was identification of the eldelumab target exposure for induction of remission [absolute Crohn's Disease Activity Index score < 150]. Rates of clinical response [reduction of = 100 from baseline or absolute score < 150 Crohn's Disease Activity Index], remission, and endoscopic improvements were also assessed. Results: A total of 121 patients were randomised. The eldelumab exposure-remission relationship was not significant at Week 11. Numerically higher remission and response rates were reported with eldelumab 20 mg/kg [29.3% and 41.5%, respectively] and 10 mg/kg [22.5% and 47.5%] versus placebo [20.0% and 35.0%]. A higher proportion of patients with a baseline Simplified Endoscopic Score for Crohn's Disease > 2 who received eldelumab achieved a 50% improvement in score and greater reductions from baseline endoscopy scores overall versus placebo. Adverse events were comparable across treatment groups. Conclusions: No exposure-remission relationship was seen with eldelumab. Eldelumab induction treatment demonstrated trends towards clinical and endoscopic efficacy. Safety was consistent with that reported previously. [ABSTRACT FROM AUTHOR]

Background and Aims: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: Inadequate response to infliximab [IFX] therapy in Crohn's disease [CD] may necessitate dose intensification. We evaluated safety and efficacy of high-dose IFX [HD IFX] [greater than 10 mg/ kg every 8 weeks] in CD and characterized predictors of response to HD IFX intensification. Methods: Electronic medical records were queried for CD patients between 2010 and 2012 who received HD IFX and were reviewed for history, medications, laboratory data, efficacy, and safety. Results: In all, 86 patients received HD IFX for CD at doses between 10 and 22.5 mg/kg every 4 to 7 weeks. In early HD IFX therapy [week 1-16], 25.8% and 59.1% experienced full and partial response, respectively. In later HD IFX therapy [week 38-100], 27.9% and 34.4% experienced full and partial response, respectively. Median serum IFX levels increased from 1.7 to 7.3 μ/mL [p = 0.017], and median C-reactive protein [CRP] values decreased from 20.5 at baseline to 4.7 mg/L after 16 weeks [p < 0.001]. Baseline CRP values were significantly elevated in the group that responded at 1-16 weeks compared with nonresponders [22.0 vs 3.5 mg/L, p < 0.01]. HD IFX therapy was discontinued in 26% and 7.3% of patients for inadequate response and adverse events, respectively. Eleven cases of infection required hospitalization for a serious infection rate of 7.41 events per 100 patient-years. Conclusions: HD IFX therapy may benefit CD patients who have failed standard doses of IFX. HD IFX therapy may be associated with more serious adverse events compared with standard dosing. Baseline CRP value may predict clinical response to HD IFX. [ABSTRACT FROM AUTHOR]

TNF antagonists have revolutionized the treatment of IBD. Nevertheless, between 30 and 45% of patients discontinue infliximab and other TNF antagonists over a 2- to 6-year period due to nonresponse, loss of response, or adverse events. Accordingly, the need for novel therapies grows each year. Recent studies have demonstrated the promise of new drugs with distinct modes of action for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). These include agents targeting leukocyte trafficking, therapies directed against IL-12/23 and Janus kinases (JAK), and antibodies against the classic inflammatory cytokine, IL-6. The anti-α4-integrin antibody, natalizumab, was the first effective antitrafficking agent for CD; however, its use has been greatly limited by the risk of progressive multifocal leukoencephalopathy. Therefore, second-generation antitrafficking agents have focused on restricting leukocyte blockade to the intestine through mechanisms interfering with α4β7-integrin and its interaction with mucosal addressin cellular adhesion molecule 1. IL-23 is a cytokine central to the adaptive immune responses that characterize IBD. Ustekinumab, targeting the p40 subunit of IL-12 and IL-23, and the oral JAK inhibitor tofacitinib have proven to be effective in phase 2 trials in CD and UC, respectively. In addition, antibodies targeting the proinflammatory cytokine IL-6 are being studied in CD. Each of the approaches described have promise as well as limitations, so it is likely that the search for novel agents in IBD will continue. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and aims More than 80% of Crohn's disease (CD) patients will require surgery. Surgery is not curative and rates of re-operation are high. Identification of genetic variants associated with repeat surgery would allow risk stratification of patients who may benefit from early aggressive therapy and/or post-operative prophylactic treatment. Methods CD patients who had at least one CD-related bowel resection were identified from the Prospective Registry in IBD Study at Massachusetts General Hospital (PRISM). The primary outcome was surgical recurrence. Covariates and potential interactions were assessed using the Cox proportional hazard model. Kaplan--Meier curves for time to surgical recurrence were developed for each genetic variant and analyzed with the log-rank test. Results 194 patients were identified who had at least 1 resection. Of these, 69 had two or more resections. Clinical predictors for repeat surgery were stricturing (HR 4.18, p = 0.022) and penetrating behavior (HR 3.97, p = 0.024). Smoking cessation was protective for repeat surgery (HR 0.45, p = 0.018). SMAD3 homozygosity for the risk allele was also independently associated with increased risk of repeat surgery (HR 4.04, p = 0.001). NOD2 was not associated with increased risk of surgical recurrence. Conclusion Stricturing and penetrating behavior were associated with increased risk of surgical recurrence, while smoking cessation was associated with a decreased risk. A novel association between SMAD3 and increased risk of repeat operation and shorter time to repeat surgery was observed. This finding is of particular interest as SMAD3 may represent a new therapeutic target specifically for prevention of post-surgical disease recurrence. [ABSTRACT FROM AUTHOR]

Objectives Activated granulocytes and monocytes may contribute to the pathogenesis of Crohn's disease (CD). In small, uncontrolled studies, granulocyte/monocyte apheresis (GMA) has shown promise in treating CD. We conducted a randomised, double-blind study to compare GMA with a sham procedure in patients with moderate to severe CD. Design Patients with active CD as defined by a Crohn's Disease Activity Index (CDAI) of 220-450 were randomly allocated in a 2:1 ratio to treatment with GMA using the Adacolumn Apheresis System ( JIMRO, Takasaki, Japan) or sham apheresis. Ten apheresis sessions were scheduled over a 9-week period, and efficacy was evaluated at week 12. The primary end point was the proportion of patients achieving clinical remission (CDAI score ≼150 without use of prohibited drugs). Results Clinical remission was achieved by 17.8% of patients in the GMA group (n=157) compared with 19.2% of those in the sham control group (n=78) (absolute difference -1.4% (95% CI-12.8% to 8.5%), p=0.858). Clinical response (defined as a ≽100-point decrease in CDAI) was achieved by 28.0% and 26.9% of patients in the GMA and sham groups, respectively (p=1.000). The two treatments produced similar changes from baseline in CDAI and quality of life, as well as in disease severity assessed endoscopically. The incidence and types of adverse events did not differ between groups. Conclusions GMA was well tolerated, but this study did not demonstrate its effectiveness over a sham procedure in inducing clinical remission or response in patients with moderate to severe CD. Clinical trial registration number Clinical Trials.gov identifier NCT00162942. [ABSTRACT FROM AUTHOR]

Crohn's disease and ulcerative colitis are heterogeneous conditions with highly variable courses of disease. Recent studies have focused on the time soon after diagnosis as a potential window of opportunity before which complicated disease behaviors have ensued and in which attaining adequate control of the inflammatory process might improve long-term outcomes. This review covers the use of immune suppression and biological therapy early in the course of inflammatory bowel disease. It includes the rationale for using these medications earlier, the features of early disease that may lead to improved outcomes with early intervention, the most optimal strategies for early treatment, the benefits of early intervention and the risks of this approach. In addition, we discuss the issue of which patients to choose for early intervention through risk stratification. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Crohn's disease and ulcerative colitis are heterogeneous conditions with highly variable courses of disease. Recent studies have focused on the time soon after diagnosis as a potential window of opportunity before which complicated disease behaviors have ensued and in which attaining adequate control of the inflammatory process might improve long-term outcomes. This review covers the use of immune suppression and biological therapy early in the course of inflammatory bowel disease. It includes the rationale for using these medications earlier, the features of early disease that may lead to improved outcomes with early intervention, the most optimal strategies for early treatment, the benefits of early intervention and the risks of this approach. In addition, we discuss the issue of which patients to choose for early intervention through risk stratification. [ABSTRACT FROM AUTHOR]

Objective The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn’s disease. Design In a double-blind, randomised, placebocontrolled 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 2310 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. Results 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 (ƒ¢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 4e10) showed a significant difference (mean DCDAI.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 DCDAI.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). Conclusions Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. INSET: Significance of this study. [ABSTRACT FROM AUTHOR]

OBJECTIVES:The objective of this study was to analyze the safety of long-term infliximab treatment, with/without concomitant immunomodulators, across Crohn's disease (CD) and ulcerative colitis (UC) clinical trials.METHODS:To maximize sample size, we pooled primary safety data across 10 CD or UC trials, including five randomized, controlled trials contributing data from patients who received intravenous infliximab 5 or 10 mg/kg (n=1,713; ±azathioprine) or placebo (n=406; ±azathioprine). Pooled incidences and 95% confidence intervals (CIs) were determined for mortality, infection, and malignancy. Standardized incidence ratios and 95% CIs were also determined for malignancies using the Surveillance, Epidemiology, and End Results database.RESULTS:We observed no increase in infections, serious infections, or malignancy with infliximab vs. placebo in these patients with inflammatory bowel disease (IBD). In patients with UC, but not CD, immunomodulator treatment (vs. treatment without immunomodulator) yielded a higher incidence (95% CI) of infections (120.07 (110.66, 130.08)/100 patient-years (pt-yrs) vs. 92.47 (84.54, 100.94)/100 pt-yrs). Among placebo-treated patients with CD, but not UC, those with immunomodulator use demonstrated a higher incidence (95% CI) of malignancy vs. no immunomodulator treatment (1.84 (0.22, 6.66)/100 pt-yrs vs. 0.00 (0.00, 0.00)/100 pt-yrs). Mortality and infection-related mortality appeared unaffected by infliximab or immunomodulator treatment.CONCLUSIONS:Infliximab treatment of IBD did not appear to affect incidences of infection, mortality, or malignancy. Relative to patients with no immunomodulator use, immunomodulator-treated UC patients demonstrated a higher incidence of infection and immunomodulator-plus-placebo-treated CD patients demonstrated a higher incidence of malignancy. [ABSTRACT FROM AUTHOR]

The placebo response is the efficacy attributable to a treatment that is thought to have no specific pharmacologic effect on the condition being treated. Although potentially helpful in clinical practice, high and unpredictable placebo response rates present a major impediment to the success of clinical trials in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Diverse factors contribute to the placebo response rates observed in clinical trials. These include patient characteristics, physician factors, frequency of study visits, characteristics of the outcome measures, concomitant treatments, regression to the mean, properties of the intervention and treatment setting, timing of the primary endpoint and natural history of the condition. Measures that may minimize the placebo response in IBD clinical trials include early timing of the primary endpoint, minimizing the number of study visits, restricting the patient population to those with documented inflammation (such as elevated biomarkers of inflammation or evidence of mucosal inflammation), including patients with more severe symptoms (i.e. greater disease activity) and enrolling patients with prior failure of immune modulators or biologics. Attempts to limit the placebo response in IBS studies have proven more difficult. Factors associated with higher placebo response rates in IBS studies include longer duration of treatment, greater number of office visits, frequency of administration of study intervention and overall treatment effect of the active agent under study. In the future, improved understanding of the factors that drive the placebo response rate should lead to more efficient study design and drug development. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Understanding patient-specific differences in risk tolerance for new treatments that offer improved efficacy can assist in making difficult regulatory and clinical decisions for new treatments that offer both the potential for greater effectiveness in relieving disease symptoms, but also risks of disabling or fatal side effects. The aim of this study is to elicit benefit-risk trade-off preferences for hypothetical treatments with varying efficacy and risk levels using a stated-choice (SC) survey. We derive estimates of “maximum acceptable risk” (MAR) that can help decisionmakers identify welfare-enhancing alternatives. In the case of children, parent caregivers are responsible for treatment decisions and their risk tolerance may be quite different than adult patients' own tolerance for treatment-related risks. We estimated and compared the willingness of Crohn's disease (CD) patients and parents of juvenile CD patients to accept serious adverse event (SAE) risks in exchange for symptom relief. The analyzed data were from 345 patients over the age of 18 and 150 parents of children under the age of 18. The estimation results provide strong evidence that adult patients and parents of juvenile patients are willing to accept tradeoffs between treatment efficacy and risks of SAEs. Parents of juvenile CD patients are about as risk tolerant for their children as adult CD patients are for themselves for improved treatment efficacy. SC surveys provide a systematic method for eliciting preferences for benefit-risk tradeoffs. Understanding patients' own risk perceptions and their willingness to accept risks in return for treatment benefits can help inform risk management decision making. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The Crohn's Disease Activity Index (CDAI) is used to judge efficacy in clinical trials. We explored the effect of CDAI response definitions for induction on study efficiency. METHODS: We analyzed primary CDAI data from induction studies in patients with mildly to moderately active Crohn's disease, not receiving concomitant aminosalicylates, corticosteroids, or immunomodulator therapy, and without fistulizing or stricturing complications. The 12 definitions of clinical response included: CDAI decrease from baseline by 50, 70, 100, or 150 points; decrease by 25% from baseline and by 70 or 100 points; CDAI <100 or 150 points; CDAI <150 points plus decrease by 70 or 100 points; CDAI <150 points at any time sustained for the duration of the trial; or decrease in the CDAI by 70 points for the last two consecutive visits. Response definitions were ranked according to ability to optimize the effect difference between treatment arms. The effect of time, baseline disease activity (CDAI 200–299 or ≥300 points), and previous surgical resections on response definitions were evaluated and ranked. Multivariate analysis on additional factors of age (<40 or ≥40 yr), gender and duration of disease (<2 or ≥2 yr) were performed to determine predictors of response when applied to these CDAI definitions. RESULTS: Treatment effect differences in placebo-controlled studies were maximized by response definitions that incorporated either a decrease CDAI ≥70 points for the last two consecutive visits or decrease in baseline CDAI ≥100 points, and remained optimal when evaluated for the composite effect of time, baseline activity, and prior resections. A decrease in baseline CDAI ≥100 points had some advantages over a decrease CDAI ≥70 points over two visits in terms of study efficiency, as it produced a lower control response rate and was not influenced by any of the baseline factors. CONCLUSION: Clinical trial efficiency for induction studies in patients with mildly to moderately active Crohn's disease can be improved by using either a decrease in CDAI by ≥70 points for the last two consecutive visits or a decrease in baseline CDAI by ≥100 points as the primary end point for the trial. These findings are valid for patients with ileocecal Crohn's disease not refractory to aminosalicylates, corticosteroids, immunomodulators, and biologics, and patients who do not have stricturing or penetrating complications. It is unclear if these CDAI response criteria would similarly increase study efficiency in trials that recruited patients with moderately to severely active disease, patients refractory to aminosalicylates, corticosteroids, immunomodulators, and biologics, and patients with stricturing or penetrating complications. [ABSTRACT FROM AUTHOR]