[Show abstract][Hide abstract] ABSTRACT: Background
Tofacitinib, a novel, oral Janus kinase inhibitor, demonstrated a dose-dependent efficacy for induction of clinical response and remission in patients with active ulcerative colitis (UC). The objective of the current study was to determine the effect of tofacitinib on patient-reported outcomes (PROs).Methods
Eligible patients (¿18 years of age) with a diagnosis of active UC (total Mayo score of 6-12 points and moderately-to-severely active disease on sigmoidoscopy) were randomized in a 2:2:2:3:3 ratio to receive oral tofacitinib 0.5 mg, 3 mg, 10 mg, or 15 mg, or placebo twice daily (BID) for 8 weeks. PROs were assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Inflammatory Bowel Disease Patient-Reported Treatment Impact (IBD PRTI) survey.ResultsAt Week 8, mean IBDQ total scores had improved relative to baseline across all five treatment groups (baseline range 123.2-134.5; Week 8 range 149.6-175.4). Improvement from baseline was significantly greater (P¿=¿0.001) for tofacitinib 15 mg BID versus placebo. For tofacitinib 15 mg BID, most patients reported satisfaction or extreme satisfaction, definite preference for tofacitinib, and definite willingness to use tofacitinib again on the IBD PRTI at week 8. Patients achieving endoscopic remission (Mayo endoscopy score of 0) had significantly higher IBDQ scores and favorable PRTI scores than those not achieving endoscopic remission.Conclusions
Short-term treatment with tofacitinib BID was associated with dose-dependent improvement in health-related quality of life and patient preferences for tofacitinib. The results complement previously reported efficacy and safety data for the Phase II study. (NCT 00787202, November 6, 2008).
[Show abstract][Hide abstract] ABSTRACT: Objectives:Measurement of the component of fibrosis in Crohn's disease (CD) may have important therapeutic implications. The aim of this study was to characterize the Magnetic Resonance Imaging (MRI) findings that are differentially associated with the presence of fibrosis and those associated with inflammatory activity, using the pathological analysis of surgically resected intestinal lesions as reference standard.Methods:MRI studies with identical imaging protocol of 41 CD patients who underwent elective bowel resection within 4 months before surgery were reviewed. MRI evaluated wall thickening, edema, ulcers, signal intensity at submucosa at 70 s and 7 min after gadolinium injection, stenosis, and pattern of enhancement in each phase of the dynamic study and changes on this pattern over time. Pathological inflammatory and fibrosis scores were classified into three grades of severity.Results:In all, 44 segments from 41 patients were analyzed. The pathological intensity of inflammation was associated with the following MRI parameters: hypersignal on T2 (P=0.02), mucosal enhancement (P=0.03), ulcerations (P=0.01), and blurred margins (P=0.05). The degree of fibrosis correlated with the percentage of enhancement gain (P<0.01), the pattern of enhancement at 7 min (P<0.01), and the presence of stenosis (P=0.05). Using percentage of enhancement gain, MRI is able to discriminate between mild-moderate and severe fibrosis deposition with a sensitivity of 0.94 and a specificity of 0.89.Conclusions:MRI is accurate for detecting the presence of severe fibrosis in CD lesions on the basis of the enhancement pattern.Am J Gastroenterol advance online publication, 27 January 2015; doi:10.1038/ajg.2014.424.
The American journal of gastroenterology. 01/2015;
[Show abstract][Hide abstract] ABSTRACT: Interleukin 13 (IL-13) is thought to play a key role as an effector cytokine in UC. Anrukinzumab, a humanised antibody that inhibits human IL-13, was evaluated for the treatment of UC.
In a multicentre, randomised, double-blind, placebo-controlled study, patients with active UC (Mayo score ≥4 and <10) were randomised to anrukinzumab 200, 400 or 600 mg or placebo. Patients received five intravenous administrations over 14 weeks. The primary endpoint was fold change from baseline in faecal calprotectin (FC) at Week 14. Secondary endpoints included safety, pharmacokinetics and IL-13 levels.
The modified intention-to-treat population included 84 patients (21 patients/arm). Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo. The study had a high dropout rate, in part, related to lack of efficacy. The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score, clinical response, clinical remission and proportion of subjects with mucosal healing. An increase in serum total IL-13 (free and bound to anrukinzumab) was observed for all anrukinzumab groups but not with placebo. This suggests significant binding of anrukinzumab to IL-13. The safety profile was not different between the anrukinzumab and placebo groups.
A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13.
ClinicalTrials.gov number NCT01284062.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
[Show abstract][Hide abstract] ABSTRACT: Abstract The purpose of this review is to provide a practical appraisal of the usefulness of magnetic resonance enterography in the management of Crohn's disease and the potential utilities that this imaging modality may have in clinical research. Also, we review some basic technical considerations that clinicians should know to understand the value and limitations of the technique. Lastly, we outline the future trends and potential contributions of new technological advances in the field of magnetic resonance imaging that can improve the classic magnetic resonance enterography technique.
Scandinavian Journal of Gastroenterology 01/2015; 50(1):66-73. · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe endoscopic lesions (SEL) in patients with colonic Crohn's disease (CD) have been linked to higher risk of colectomy. The aims of this study were to reassess the predictive value of colonoscopy compared against MRI for requirement of resection surgery in patients with CD and determine the influence of current therapeutic options.
In this single-centre, observational, prospective, longitudinal study, patients with an established diagnosis of CD and suspected activity were included. After baseline assessment, including colonoscopy and MRI, patients were followed until resection surgery or the end of study.
112 patients were eligible for analysis. Ulcers were present in 94/112 (84%) of patients at colonoscopy (SELs in 51/112 (46%)) and stenosis in 38/112 (34%). MRI identified ulcers in 79/112 (71%) of patients, stenosis in 36/112 (32%) and intra-abdominal fistulae in 20/112 (18%). Surgical resection requirements (29/112 (26%)) were not associated with the presence of SELs at colonoscopy. The presence of stenosis (p<0.001) or intra-abdominal fistulae (p<0.001) at MRI correlated with a higher risk of surgery. In the multivariate analysis, perianal disease (OR 9 (2 to 39), p=0.003), stenosis (OR 3.4 (1 to 11), p=0.04) and fistulae at MRI (OR 10.6 (2 to 46), p=0.002) increased the risk of abdominal resection surgery, while months under immunomodulators (OR 0.94 (0.90 to 0.98), p=0.002) and/or antitumor necrosis factor (anti-TNF) therapy (OR 0.97 (0.94 to 1), p=0.04) during follow-up decreased this risk.
Perianal disease, stenosis and/or intra-abdominal fistulae at MRI independently predict an increased risk of resection surgery in patients with CD, whereas immunosuppressants and/or anti-TNF therapy reduce such risk. Under current therapeutic strategies, the presence of SELs is not a predictor of resection surgery in patients with CD.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
[Show abstract][Hide abstract] ABSTRACT: & Aims: There is a need for a scoring system that provides a comprehensive assessment of structural bowel damage, including stricturing lesions, penetrating lesions, and surgical resection, that measures disease progression. We developed the Lémann Index and assessed its ability to measure cumulative structural bowel damage in patients with Crohn's disease (CD).
[Show abstract][Hide abstract] ABSTRACT: Increased understanding of the pathogenesis of inflammatory bowel diseases (IBD) has led to new therapeutic strategies. One of these is to target the molecules that regulate interactions between leukocytes and endothelial cells at sites of inflammation (mainly leukocyte integrins and endothelial cell adhesion molecules of the immunoglobulin superfamily). These molecules have been validated as therapeutic targets for IBD; several have shown efficacy and 2 have been approved by the Food and Drug Administration for treatment of IBD. Natalizumab, the first anti-integrin antibody tested for treatment of IBD, blocks the α4 subunit. Although it is effective, its clinical use has been limited by its association with risk for progressive multifocal leukoenkephalopathy. Other, allegedly more selective, drugs that affect leukocyte recruitment in the gastrointestinal tract have been developed or are under investigation, and could increase safety. These include vedolizumab and AMG 181 (antibodies against α4β7), etrolizumab (anti-β7), and PF-00547659 (anti-mucosal vascular addressin cell adhesion molecule 1). Other agents have been developed to block α4 (the small molecule AJM300), CCR9 (the small molecule CCX282-B), and CXCL10 (the antibody eldelumab). We review the scientific rationale for inhibiting interactions between leukocytes and endothelial cells to reduce intestinal inflammation, and analyze the clinical studies that have been carried out to test these new molecules, with particular attention to safety. We propose an evidence-based clinical positioning of this class of drugs.
[Show abstract][Hide abstract] ABSTRACT: Dersalazine sodium is an inhibitor of platelet activator factor with potential efficacy in patients with ulcerative colitis through an alternative mechanism of action. The study was a first proof of clinical safety and activity of dersalazine sodium in patients with ulcerative colitis.
[Show abstract][Hide abstract] ABSTRACT: Background & Aims
Tofacitinib, an orally administered Janus kinase inhibitor, blocks signaling through γ-chain–containing cytokines (interleukins 2, 4, 7, 9, 15, and 21). We performed a phase 2 trial to measure its efficacy in patients with moderate-to-severe active Crohn’s disease.
Patients (n = 139, ≥18 y old) with moderate-to-severe active Crohn’s disease were randomly assigned to groups given 1 mg (n=36), 5 mg (n=34), or 15 mg (n=35) tofacitinib or placebo (n=34), twice daily for 4 weeks, at 48 centers in 12 countries. The primary endpoint was the proportion of clinical responders at week 4 (decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥70 points [Response-70]). Secondary endpoints included clinical remission (CDAI score <150 points) at week 4.
A clinical response was observed in 36% (P = .467), 58% (P = .466), and 46% (P ≥ .999) of patients given the 1, 5, and 15 mg doses of tofacitinib, compared with 47% of patients given placebo. Clinical remission was observed in 31% (P = .417), 24% (P = .776), and 14% (P = .540) of patients given the 1, 5, and 15 mg doses of tofacitinib, compared with 21% of patients given placebo. The 15 mg dose of tofacitinib reduced levels, from baseline, of C-reactive protein and fecal calprotectin. Adverse and serious adverse events were similar among groups. Dose-dependent increases in low- and high-density lipoprotein cholesterol were observed in patients given the 5 or 15 mg doses of tofacitinib.
There were no significant differences in percentages of patients with moderate-to-severe active Crohn’s disease who achieved clinical responses (Response-70) or clinical remission following 4 weeks administration of tofacitinib (1, 5, or 15 mg) or placebo twice daily. However, a large percentage of patients given placebo achieved Response-70 or remission. Reductions in C-reactive protein and fecal calprotectin among patients given the 15 mg dose of tofacitinib indicate its biologic activity. ClinicalTrials.gov Number NCT00615199.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 09/2014; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The genetic analysis of ulcerative colitis (UC) has provided new insights into the etiology of this prevalent inflammatory bowel disease. However, most of the heritability of UC (>70%) has still not been characterized. To identify new risk loci for UC we have performed the first genome-wide association study (GWAS) in a Southern European population and undertaken a meta-analysis study combining the newly genotyped 825 UC patients and 1,525 healthy controls from Spain with the six previously published GWAS comprising 6,687 cases and 19,718 controls from Northern European ancestry. We identified a novel locus with genome-wide significance at 6q22.1 (rs2858829, P=8.97 x 10(-9), OR (95% CI)=1.12 (1.08-1.16)) that was validated with genotype data from a replication cohort of the same Southern European ancestry consisting in 1,073 cases and 1,279 controls (combined P=7.59 x 10(-10), OR (95% CI)=1.12 (1.08-1.16)). Furthermore, we confirmed the association of 33 reported associations with UC and we nominally validated the GWAS results of nine new risk loci (P<0.05, same direction of effect). SNP rs2858829 lies in an intergenic region and is a strong cis-eQTL for FAM26F gene, a gene that is shown to be selectively upregulated in UC colonic mucosa with active inflammation. Our results provide new insight into the genetic risk background of UC, confirming that there is a genetic risk component that differentiates from Crohn's Disease, the other major form of inflammatory bowel disease.
Human Molecular Genetics 07/2014; · 6.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To develop a consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease (pCD), based on best available evidence.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to determine the accuracy of advanced endoscopy for prediction of relapse in ulcerative colitis, in comparison with serum and fecal biomarkers.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: It goes back to 1932 when Dr. Burrill Bernard Crohn and co-workers published their landmark paper, describing regional ileitis as a disease entity. However, clinical trial research has been developing rather slowly in luminal Crohn's disease. It took until the early seventies before the first randomized clinical trial was set up by the National Co-operative Crohn's Disease Study (NCCDS) group. Although the efforts of this group triggered a first wave of clinical trials in Crohn's disease, the lack of guidelines for conducting a clinical trial in this research area resulted in a variety of study designs and much criticism. Besides having a rather small sample size and a short follow-up time, they were often characterized by vague and subjective assessment of disease activity and treatment response.
Following the advent of a new and very potent drug class in the late nineties, the anti-TNF agents, investigators started to re-think their study protocols and the first guidelines were set up by the regulatory authorities.
Over the last 15 years, clinical trials in luminal Crohn's disease have been evolving significantly. Inclusion criteria have been shifting from clinical scores such as Crohn's Disease Activity Index (CDAI) to more objective disease activity parameters such as biomarkers (C-reactive protein and faecal calprotectin) and endoscopic lesions. Primary endpoints have been developing from clinical response to corticosteroid-free remission and more ambitious end-points such as mucosal healing.
In this paper, we will give a historical overview on clinical trials in luminal Crohn's disease, before and within the biologic era, and provide insight into how they have shaped our current understanding of trial designs in Crohn's disease.
Journal of Crohn s and Colitis 05/2014; · 3.56 Impact Factor