Explore the vast range of titles available.

ObjectiveAlthough 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.DesignIn 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.ResultsBased 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.ConclusionsThe 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.

In this 52-week randomized trial, the α 4 β 7 integrin antibody vedolizumab was effective in treating ulcerative colitis. There were not significantly more adverse events with vedolizumab than with placebo, but the trial was not large or long enough to fully assess safety. Ulcerative colitis is a chronic inflammatory bowel disease characterized by symptoms of bloody diarrhea, abdominal cramps, and fatigue. 1 Current medical therapy has important limitations. Aminosalicylates 2 – 4 are only modestly effective; glucocorticoids can cause unacceptable adverse events and do not provide a benefit as maintenance therapy. Tumor necrosis factor (TNF) antagonists, although efficacious, 5 , 6 predispose patients to serious infection. 7 Thus, new treatment strategies are needed. The migration of leukocytes into inflamed intestinal tissue is highly regulated by specific molecular mechanisms. The α 4 β 7 integrin, 8 a cell-surface glycoprotein variably expressed on circulating B and T lymphocytes, interacts with mucosal addressin-cell . . .

In this 52-week randomized trial, the α 4 β 7 integrin antibody vedolizumab was effective in treating Crohn's disease. The incidence of serious adverse events was higher with vedolizumab than with placebo. Crohn's disease is a chronic inflammatory bowel disease. 1 Current treatments include glucocorticoids, immunosuppressive agents (i.e., azathioprine, mercaptopurine, or methotrexate), and tumor necrosis factor (TNF) antagonists. 1 – 3 Many patients do not have a response to therapy, 4 and treatments are associated with important toxic effects. 5 , 6 Natalizumab, a monoclonal antibody that modulates gut and brain lymphocyte migration by antagonizing α 4 β 1 and α 4 β 7 integrin–mediated interactions, 7 is efficacious in the treatment of multiple sclerosis 8 , 9 and Crohn's disease. 10 – 12 Its use in patients with Crohn's disease has been limited by the development in some patients of progressive multifocal . . .

Intestinal barrier defects are common in patients with inflammatory bowel disease (IBD). To identify which components could underlie these changes, we performed an in-depth analysis of epithelial barrier genes in IBD.MethodsA set of 128 intestinal barrier genes was selected. Polygenic risk scores were generated based on selected barrier gene variants that were associated with Crohn's disease (CD) or ulcerative colitis (UC) in our study. Gene expression was analyzed using microarray and quantitative reverse transcription polymerase chain reaction. Influence of barrier gene variants on expression was studied by cis-expression quantitative trait loci mapping and comparing patients with low- and high-risk scores.ResultsBarrier risk scores were significantly higher in patients with IBD than controls. At single-gene level, the associated barrier single-nucleotide polymorphisms were most significantly enriched in PTGER4 for CD and HNF4A for UC. As a group, the regulating proteins were most enriched for CD and UC. Expression analysis showed that many epithelial barrier genes were significantly dysregulated in active CD and UC, with overrepresentation of mucus layer genes. In uninflamed CD ileum and IBD colon, most barrier gene levels restored to normal, except for MUC1 and MUC4 that remained persistently increased compared with controls. Expression levels did not depend on cis-regulatory variants nor combined genetic risk.ConclusionsWe found genetic and transcriptomic dysregulations of key epithelial barrier genes and components in IBD. Of these, we believe that mucus genes, in particular MUC1 and MUC4, play an essential role in the pathogenesis of IBD and could represent interesting targets for treatment.

Fecal calprotectin is a marker of inflammation in inflammatory bowel disease (IBD). Since mucosal healing has become a goal of treatment in IBD we examined how reliably calprotectin levels reflect mucosal disease activity.MethodsIn all, 126 IBD patients and 32 irritable bowel syndrome (IBS) patients needing colonoscopy delivered a sample of feces prior to the start of bowel cleansing. Besides collection of symptom scores and blood tests, experienced endoscopists recorded the Simple Endoscopic Score for Crohn's Disease (SES-CD) and the Crohn's Disease Endoscopic Index of Severity (CDEIS) in Crohn's disease (CD) patients and the Mayo endoscopic score in ulcerative colitis (UC) patients. Stool samples were shipped for central calprotectin PhiCal Assay (enzyme-linked immunosorbent assay [ELISA]). Correlation analysis was done with Pearson statistics.ResultsThe median (interquartile range [IQR]) fecal calprotectin levels were 175 (44–938) μg/g in CD, 465 (61–1128) μg/g in UC, and 54 (16–139) μg/g in IBS. Correlations were significant with endoscopic disease scores in both CD and in UC. Using ROC statistics, a cutoff value of 250 μg/g indicated the presence of large ulcers with a sensitivity of 60.4% and a specificity of 79.5% (positive predictive value [PPV] 78.4%, negative predictive value [NPV] 62.0%) in CD. Levels ≤250 μg/g predicted endoscopic remission (CDEIS ≤3) with 94.1% sensitivity and 62.2% specificity (PPV 48.5%, NPV 96.6%). In UC, a fecal calprotectin >250 μg/g gave a sensitivity of 71.0% and a specificity of 100.0% (PPV 100.0%, NPV 47.1%) for active mucosal disease activity (Mayo >0). Calprotectin levels significantly correlated with symptom scores in UC (r = 0.561, P < 0.001), but not in CD.ConclusionsFecal calprotectin levels correlate significantly with endoscopic disease activity in IBD. The test appears useful in clinical practice for assessment of endoscopic activity and remission.

In this randomized trial involving adults with Crohn's disease in whom anti–tumor necrosis factor therapy had failed, ustekinumab, an antibody against interleukin-12 and 23, was associated with increased response rates, as compared with placebo. Crohn's disease is a chronic inflammatory bowel disease. 1 One third of patients do not have a response to initial treatment with tumor necrosis factor (TNF) antagonists (primary nonresponse) 2 – 6 ; another one third have a transient response 2 , 4 , 6 and require dose escalation or a switch to another therapy (secondary nonresponse). 7 , 8 Patients with primary nonresponse are unlikely to benefit from another TNF antagonist. Patients with secondary nonresponse who switch to a second TNF antagonist are less likely to have a response than are patients who have not received a TNF antagonist. 4 , 6 These represent difficult clinical problems. Preclinical studies . . .

In this randomized trial comparing infliximab, azathioprine, and combination therapy in adults with moderate-to-severe Crohn's disease, infliximab and combination therapy were superior to azathioprine. Adverse events were similar in the three groups. In this randomized trial comparing infliximab, azathioprine, and combination therapy in adults with moderate-to-severe Crohn's disease, infliximab and combination therapy were superior to azathioprine. Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract that is defined by relapsing and remitting episodes, with progression over time to complications of stricture, fistulas, or abscesses. 1 Symptoms of mild-to-moderate disease are treated with mesalamine, budesonide, or systemic corticosteroids. 2 , 3 The therapeutic benefit of corticosteroids is frequently offset by side effects of prolonged exposure. 4 In addition, systemic corticosteroids and budesonide are not effective for maintenance therapy. 5 – 7 Azathioprine and 6-mercaptopurine are frequently prescribed for patients in whom first-line therapies fail — in particular, those who are dependent on or do not have a response to systemic corticosteroids. . . .

ObjectivePouchitis is the most common complication after colectomy with ileal pouch-anal anastomosis (IPAA) for UC and the risk is the highest within the 1st year after surgery. The pathogenesis is not completely understood but clinical response to antibiotics suggests a role for gut microbiota. We hypothesised that the risk for pouchitis can be predicted based on the faecal microbial composition before colectomy.DesignFaecal samples from 21 patients with UC undergoing IPAA were prospectively collected before colectomy and at predefined clinical visits at 1 month, 3 months, 6 months and 12 months after IPAA. The predominant microbiota was analysed using community profiling with denaturing gradient gel electrophoresis followed by quantitative real-time PCR validation.ResultsCluster analysis before colectomy distinguished patients with pouchitis from those with normal pouch during the 1st year of follow-up. In patients developing pouchitis, an increase of Ruminococcus gnavus (p<0.001), Bacteroides vulgatus (p=0.043), Clostridium perfringens (p=0.011) and a reduction of two Lachnospiraceae genera (Blautia (p=0.04), Roseburia (p=0.008)) was observed. A score combining these five bacterial risk factors was calculated and presence of at least two risk factors showed a sensitivity and specificity of 100% and 63.6%, respectively.ConclusionsPresence of R. gnavus, B. vulgatus and C. perfringens and absence of Blautia and Roseburia in faecal samples of patients with UC before surgery is associated with a higher risk of pouchitis after IPAA. Our findings suggest new predictive and therapeutic strategies in patients undergoing colectomy with IPAA.

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. 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. 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). 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. Genentech.

In this observational study of patients who received multiple infusions of infliximab for Crohn's disease refractory to conventional treatment, antibodies against infliximab developed in 61 percent of patients. Antibodies decreased infliximab concentrations and the duration of response. Antibodies were less likely to develop in patients who were also receiving immunosuppressive agents. Infliximab (Remicade, Centocor), a chimeric monoclonal IgG1 antibody against tumor necrosis factor, has been approved for the treatment of moderate-to-severe Crohn's disease in patients who have an inadequate response to conventional therapy and for the management of enterocutaneous fistulas. A single intravenous infusion induced a response at four weeks in 50 to 81 percent of patients with refractory luminal disease and induced remission in 25 to 48 percent. 1 The response can be maintained with repeated infusions. 2 In patients with fistulizing disease, four weeks after the last of three infusions, at weeks 0, 2, and 6, 38 to 55 percent of . . .