[Show abstract][Hide abstract] ABSTRACT: Histopathology is potentially an important outcome measure in UC. Multiple histological disease activity (HA) indices, including the Geboes score (GS) and modified Riley score (MRS), have been developed; however, the operating properties of these instruments are not clearly defined. We assessed the reproducibility of existing measures of HA.
[Show abstract][Hide abstract] ABSTRACT: Laquinimod is an oral therapeutic agent under investigation for the treatment of Crohn's disease (CD), Huntington's disease, lupus nephritis and multiple sclerosis. This dose escalation study evaluated the safety and efficacy of laquinimod as induction therapy in patients with active moderate-severe CD.
[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: 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: Faecal calprotectin is a valuable noninvasive marker for inflammatory bowel disease (IBD). The aim of our study was to determine the correlation between six different calprotectin assays and compare their performance for diagnosis and follow up of IBD.
United European gastroenterology journal. 02/2014; 2(1):30-7.
[Show abstract][Hide abstract] ABSTRACT: Monitoring plasma concentrations of anti-tumor necrosis factor (TNF) agents could optimize treatment of patients with Crohn's Disease (CD). In a post -hoc analysis of data from a clinical trial, we compared the relationship between plasma concentrations of certolizumab pegol (CZP) and endoscopic and clinical response and remission to CZP therapy in patients with moderate to severe ileocolonic CD.
We analyzed data from the Endoscopic Mucosal Improvement in Patients with Active CD Treated with CZP trial, from 89 adult patients with active endoscopic CD (ulceration in ≥2 intestinal segments and CD Endoscopic Index of Severity [CDEIS] scores ≥8 points). Patients received subcutaneous CZP (400 mg) at weeks 0, 2, and 4 and then every 4 weeks up to week 52. Endoscopic evaluations were performed at weeks 0, 10, and 54. Blood samples were collected to measure CZP plasma concentrations at weeks 8 and 54. CZP quartiles at weeks 8 (n=80) and 54 (n=45) were correlated with endoscopic response (>5-point decrease in CDEIS from baseline) and remission (CDEIS <6) at weeks 10 and 54, respectively.
Higher concentrations of CZP at week 8 were associated with endoscopic response (P = .0016) and remission (P = .0302) at week 10 (n =45). At week 54, the rates of endoscopic remission correlated with plasma concentrations of CZP (P = .0206). There was a significant inverse relationship between plasma concentrations of CZP and baseline levels of C-reactive protein and body weight (P = .0014 and P = .0373, respectively).
Endoscopic response and remission are associated with higher plasma concentrations of CZP in in patients with moderate to severe ileocolonic CD. These results support the need to consider the pharmacokinetics of anti-TNF agents and therapeutic drug monitoring to optimize treatment. Clinicaltrials.gov no: NCT00297648.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 10/2013; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fistulizing Crohn’s disease represents an evolving, yet unresolved, issue for multidisciplinary management. Perianal fistulas are the most frequent findings in fistulizing Crohn’s disease. While enterocutaneous fistulas are rare, they are associated with considerable morbidity and mortality. Detailed evaluation of the fistula tract by advanced imaging techniques is required to determine the most suitable management options. The fundamentals of perianal fistula management are to evaluate the complexity of the fistula tract, and exclude proctitis and associated abscess. The main goals of the treatment are abscess drainage, which is mandatory, before initiating immunosuppressive medical therapy, resolution of fistula discharge, preservation of continence and, in the long term, avoidance of proctectomy with permanent stoma. The management of enterocutaneous fistulas comprises of sepsis control, skin care, nutritional optimization and, if needed, delayed surgery.
United European Gastroenterology Journal. 04/2013;
[Show abstract][Hide abstract] ABSTRACT: Management of Crohn's disease has traditionally placed high value on subjective symptom assessment; however, it is increasingly appreciated that patient symptoms and objective parameters of inflammation can be disconnected. Therefore, strategies that objectively monitor inflammatory activity should be utilised throughout the disease course to optimise patient management. Initially, a thorough assessment of the severity, location and extent of disease is needed to ensure a correct diagnosis, identify any complications, help assess prognosis and select appropriate therapy. During follow-up, clinical decision-making should be driven by disease activity monitoring, with the aim of optimising treatment for tight disease control. However, few data exist to guide the choice of monitoring tools and the frequency of their use. Furthermore, adaption of monitoring strategies for symptomatic, asymptomatic and post-operative patients has not been well defined. The Annual excHangE on the ADvances in Inflammatory Bowel Disease (IBD Ahead) 2011 educational programme, which included approximately 600 gastroenterologists from 36 countries, has developed practice recommendations for the optimal monitoring of Crohn's disease based on evidence and/or expert opinion. These recommendations address the need to incorporate different modalities of disease assessment (symptom and endoscopic assessment, measurement of biomarkers of inflammatory activity and cross-sectional imaging) into robust monitoring. Furthermore, the importance of measuring and recording parameters in a standardised fashion to enable longitudinal evaluation of disease activity is highlighted.
Journal of Crohn s and Colitis 04/2013; · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND & AIMS: Inter-observer differences in endoscopic assessments contribute to variations in rates of response to placebo in ulcerative colitis (UC) trials. We investigated whether centralized review of images could reduce these variations. METHODS: We performed a 10-week, randomized, double-blind, placebo-controlled, study of 281 patients with mildly to moderately active UC, defined by an Ulcerative Colitis Disease Activity Index (UCDAI) sigmoidoscopy score =2, that evaluated the efficacy of delayed-release mesalamine (Asacol™ 800 mg tablet) 4.8 g/day. Endoscopic images were reviewed by a single expert, central reader. The primary outcome was clinical remission (UCDAI, stool frequency and bleeding scores of 0, and no fecal urgency) at week 6. RESULTS: The primary outcome was achieved by 30.0% of patients given mesalamine and 20.6% of those given placebo-a difference of 9.4% (95% confidence interval [CI], -0.7% to 19.4%; P =.069). Significant differences in results from secondary analyses indicated the efficacy of mesalamine. Thirty-one percent of participants, all of whom had a UCDAI sigmoidoscopy score =2 as read by the site investigator, were considered ineligible by the central reader. Following exclusion of these patients the remission rates were 29.0% and 13.8% in the mesalamine and placebo groups respectively (difference 15%; 95% CI, 3.5%-26.0%, P =.011). CONCLUSIONS: Although mesalamine 4.8 g/day was not statistically different from placebo for induction of remission in patients with mildly to moderately active UC, based on an ITT analysis, the totality of the data support a benefit of treatment. Central review of endoscopic images is critical to the conduct of induction studies in UC.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Budesonide MMX is a novel oral formulation of budesonide that uses Multi-Matrix System (MMX) technology to extend release to the colon. This study compared the efficacy of budesonide MMX with placebo in patients with active, mild-to-moderate ulcerative colitis (UC). DESIGN: Patients were randomised 1:1:1:1 to receive budesonide MMX 9 mg or 6 mg, or Entocort EC 9 mg (budesonide controlled ileal-release capsules; reference arm) or placebo once daily for 8 weeks. The primary endpoint was combined clinical and endoscopic remission, defined as UC Disease Activity Index score ≤1 with a score of 0 for rectal bleeding and stool frequency, no mucosal friability on colonoscopy, and a ≥1-point reduction in endoscopic index score from baseline. RESULTS: 410 patients were evaluated for efficacy. Combined clinical and endoscopic remission rates with budesonide MMX 9 mg or 6 mg, Entocort EC and placebo were 17.4%, 8.3%, 12.6% and 4.5%, respectively. The difference between budesonide MMX 9 mg and placebo was significant (OR 4.49; 95% CI 1.47 to 13.72; p=0.0047). Budesonide MMX 9 mg was associated with numerically higher rates of clinical (42.2% vs 33.7%) and endoscopic improvement (42.2% vs 31.5%) versus placebo. The rate of histological healing (16.5% vs 6.7%; p=0.0361) and proportion of patients with symptom resolution (23.9% vs 11.2%; p=0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Adverse event profiles were similar across groups. CONCLUSION: Budesonide MMX 9 mg was safe and more effective than placebo at inducing combined clinical and endoscopic remission in patients with active, mild-to-moderate UC.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Hormone replacement therapy increases the risk of developing ulcerative colitis in postmenopausal women. Chronic intestinal inflammation predisposes to colon cancer development, but effects of female hormones on colitis-associated cancer development have not been examined. AIM: To investigate the role of female hormones in the dextran sodium sulfate (DSS)-azoxymethane (AOM) mouse model for colitis-associated cancer. DESIGN: We performed ovariectomies, or sham operations, on mice, and supplemented these animals with indicated hormones. Additionally, we used oestrogen receptor α or β (Erα or Erβ) mutant mice. To study colitis or colitis-associated cancer, we used DSS only, or DSS and AOM, respectively. RESULTS: Ovariectomy protects female mice against colitis-associated tumour development. Hormone replacement in ovariectomised mice with either oestradiol (E2), medroxyprogesterone acetate or a combination of both suggests that oestrogens are the ovary-derived factor that promotes tumour development in the context of inflammatory damage. E2-treated animals showed increased clinical symptoms and Il-6 production upon DSS-induced colitis and enhanced epithelial proliferation. Treatment with E2 markedly increased the numbers of polyps in ovariectomised mice and also strongly promoted tumour progression with all E2-treated animals developing at least one invasive adenocarcinoma, whereas, placebo-treated animals developed adenomas only. Using Er mutant mice, we find that the protumorigenic effect of oestrogen depends on both Erα and Erβ. CONCLUSIONS: Our results suggest that oestrogens promote inflammation-associated cancer development by impairing the mucosal response to inflammatory damage.
[Show abstract][Hide abstract] ABSTRACT: In recent years, many new agents have been evaluated for the treatment of inflammatory bowel disease. In this paper, we critically review recently published literature about these novel therapies, which have been the result of extensive research identifying molecular targets. Of the various biologicals and small molecules that have recently been tested in clinical trials, several demonstrated clinical efficacy with a tolerable safety profile. We discuss a number of them with specific focus on vedolizumab, a monoclonal antibody directed against the alpha4beta7 integrin on lymphocytes, ustekinumab, a monoclonal antibody against the p40 subunit of interleukin-12 and interleukin-23, and tofacitinib, a small molecule targeting Janus-activated kinase. Most likely, these three agents will find their way to the market and offer significant therapeutic alternatives for the management of Crohn's disease and/or ulcerative colitis.
Current Gastroenterology Reports 02/2013; 15(2):311.
[Show abstract][Hide abstract] ABSTRACT: We report the findings and outputs of an international expert opinion process to develop a definition of early Crohn's disease (CD) that could be used in future disease-modification trials. Nineteen experts on inflammatory bowel diseases held an international expert opinion meeting to discuss and agree on a definition for early CD to be used in disease-modification trials. The process included literature searches for the relevant basic-science and clinical evidence. A published preliminary definition of early CD was used as the basis for development of a proposed definition that was discussed at the expert opinion meeting. The participants then derived a final definition, based on best current knowledge, that it is hoped will be of practical use in disease-modification trials in CD.
The American Journal of Gastroenterology 12/2012; 107(12):1770-6. · 9.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treatment of inflammatory bowel disease has greatly improved with the development of targeted, monoclonal antibody–based therapies. Tumor necrosis factor antagonists are frequently used to treat patients with Crohn's disease or ulcerative colitis, but they have side effects and their efficacy often decreases with use. New, more effective drugs are therefore needed and in development. However, many agents that appeared to be promising in preclinical studies have failed to show efficacy in clinical trials. We discuss possible reasons for the failures of these reagents in trials, which include the high rate of response to placebo, an inadequate range of doses, inappropriate timing of end point measurements, the changing therapeutic environment, and the competitive trial system. We also review regulatory guidelines for end points and trial design and recommend ways to improve trials.
[Show abstract][Hide abstract] ABSTRACT: The clinical management of Crohn's disease (CD) has evolved in recent years from symptom control to healing of mucosal lesions. Mucosal healing, induced and maintained by immunomodulators and/or biologicals, has been shown to alter the disease course in patients with CD. As a consequence, long-term disease outcomes have been dramatically improved, in particular since the introduction of anti-tumor necrosis factor (TNF) agents. CD patients with active inflammation (ileocolonic ulcers and/or increased C-reactive protein levels) benefit most from treatment with TNF antagonists. Since healing of the inflamed mucosa is now considered an important treatment goal, endoscopic monitoring is gradually entering routine practice. Therefore, the mucosal appearance will more and more influence the therapeutic decision making process. Mucosal healing has also become an end-point in therapeutic trials. We will summarize some of the fundamental issues regarding mucosal healing and discuss data to support its clinical relevance in the management of CD.
Current drug targets 05/2012; 13(10):1248-51. · 3.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treatment with mesalamine to maintain endoscopic remission (mucosal healing) of ulcerative colitis (UC) has been shown to reduce the risk of relapse and is the recommended first-line maintenance therapy. To improve treatment adherence, a mesalamine formulation that can be administered once-daily, MMX(®) mesalamine (Lialda; Shire Pharmaceuticals LLC, Wayne, PA), was developed. This study was conducted to determine the efficacy and safety of once-daily MMX mesalamine compared with twice-daily delayed-release mesalamine (Asacol; Warner Chilcott, Dublin, Ireland) for maintaining endoscopic remission in patients with UC.
A multicenter, randomized, double-blind, 6-month, active-control trial was conducted to assess the non-inferiority of once-daily MMX mesalamine 2.4 g/day compared with twice-daily delayed-release mesalamine at a total daily dose of 1.6 g/day in patients with UC in endoscopic remission. The primary end point was maintenance of endoscopic remission at month 6 in the per-protocol (PP) population.
Overall, 826 patients were randomized and dosed. The primary objective (non-inferiority) was met. At month 6, 83.7 and 77.8% of patients receiving MMX mesalamine in the PP and intent-to-treat (ITT) populations, respectively, had maintained endoscopic remission compared with 81.5% (PP) and 76.9% (ITT) of patients receiving delayed-release mesalamine (95% confidence interval for difference: -3.9%, 8.1% (PP); -5.0%, 6.9% (ITT)). Time to relapse was not significantly different between the two treatment groups (log-rank test, P=0.5116 (PP); P=0.5455 (ITT)). The proportion of patients with adverse events was 37.1 and 36.0% in patients receiving MMX mesalamine and delayed-release mesalamine, respectively.
Once-daily dosing of MMX mesalamine 2.4 g/day was shown to be well tolerated and non-inferior to twice-daily dosing with delayed-release mesalamine 1.6 g/day for maintenance of endoscopic remission in patients with UC.
The American Journal of Gastroenterology 05/2012; 107(7):1064-77. · 9.21 Impact Factor