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Summary: Background: In Phase 3 studies of ustekinumab, a fully human monoclonal IL‐12/23p40 antibody approved for moderate‐to‐severe Crohn's disease, patients entered a long‐term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM‐UNITI maintenance are reported. Methods: UNITI‐1 (TNF‐antagonist failures) and UNITI‐2 (conventional therapy failures) patients (N = 1281) entered IM‐UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose‐adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8–32). All Week 44 completers could enter the long‐term extension without further dose adjustment. Placebo patients discontinued following study unblinding. Results: A total of 718 patients (all treated) entered the long‐term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient‐years) were similar among all placebo and ustekinumab patients (Week 0‐96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed. Conclusions: Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355. [ABSTRACT FROM AUTHOR]

Background Adalimumab is used to treat moderate to severe Crohn's disease ( CD) and ulcerative colitis ( UC) when conventional therapies fail. Aim To update long-term adalimumab safety from CD and UC trials; the previous report was CD only, 3160 patients/3402 patient-years ( PYs). Methods Treatment-emergent adverse events ( AEs; first dose to 70 days after last dose/December 31, 2015) in adults in phase 2/3 and 3/3b trials and open-label extensions were coded using Medical Dictionary for Regulatory Activities (Med DRA-v18.1). Rates were assessed as events/100 (E/100 PYs). Results The database (16 trials; CD, N = 3606; UC, N = 1739) represented 4145 and 3397 PYs of exposure, respectively. For CD, incidences of any AEs with adalimumab were 60.8%-65.1%, depending on dose, and 71.5% with placebo; for UC, the incidences were 53.5%-54.8% and 56.1%, respectively. Rates of any AEs ( CD, 605 E/100 PYs; UC, 361 E/100 PYs), serious AEs ( CD, 36.1 E/100 PYs; UC, 18.9 E/100 PYs), and malignancies ( CD, 1.2 E/100 PYs; UC, 1.0 E/100 PYs) were similar between current and prior analyses. Apparent rate of opportunistic infections was lowered to 0.3 and 0.2 E/100 PYs for CD and UC, respectively, by recent Med DRA changes excluding oral candidiasis and tuberculosis. Standardised incidence ratios for malignancies were similar to the general population ( CD, 1.45 [95% CI, 0.90-2.22]; UC, 1.36 [95% CI, 0.84-2.07]). Demyelinating disorders were uncommon ( CD, 0.1 E/100 PYs; UC, <0.1 E/100 PYs). Conclusions Patients with moderately to severely active Crohn's disease or ulcerative colitis continued to experience acceptable safety with adalimumab, without new safety signals. [ABSTRACT FROM AUTHOR]

Background High concentration mesalazine formulations are more convenient than conventional low concentration formulations for the treatment of ulcerative colitis ( UC). Aim To compare the efficacy and safety of 1600 mg and 400 mg tablet mesalazine formulations. Methods Patients with mild-to-moderate active UC (Mayo Clinic Score >5; N=817) were randomised to 3.2 g of oral mesalazine, administered as two 1600 mg tablets once, or four 400 mg tablets twice daily. We hypothesised that treatment with the 1600 mg tablet was non-inferior (within a 10% margin) to the 400 mg tablet for induction of clinical and endoscopic remission at week 8. Open-label treatment with the 1600 mg tablet continued for 26-30 weeks based on induction response. Predictors of treatment response were also explored. Results At week 8, remission occurred in 22.4% and 24.6% of patients receiving the 1600 mg and 400 mg tablets, respectively (absolute difference −2.2%, 95% CI: −8.1% to 3.8%, non-inferiority P=.005). Endoscopic and histopathologic disease activity, leucocyte concentration and age were significantly associated with clinical remission ( P=.022, .042, .014 and .023, respectively). At week 38, 43.9% (296/675) of patients who continued treatment with the 1600 mg formulation were in remission, including 70.3% (142/202) of patients who received a reduced dose of mesalazine (1.6 g/d). The overall incidence of serious adverse events was low. Conclusions Induction therapy with 3.2 mg mesalazine using two 1600 mg tablets once-daily was statistically and clinically non-inferior to a twice-daily regimen using four 400 mg tablets ( NCT01903252). [ABSTRACT FROM AUTHOR]

Background Reliable tools for patient selection are critical for clinical drug trials. Aim To evaluate a consensus-based, standardised magnetic resonance enterography ( MRE) protocol for selecting patients for inclusion in Crohn's disease ( CD) multicenter clinical trials. Methods This study recruited 20 patients [Crohn's Disease Activity Index (CDAI) scores: <150 ( n = 8); 150-220 ( n = 4); 220-450 ( n = 8)], to undergo ileocolonoscopy and two MREs (with and without colonic contrast) within a 14-day period. Procedures were scored centrally using, Magnetic Resonance Index of Activity (Ma RIA), and both Crohn's Disease Endoscopic Index of Severity ( CDEIS) and Simplified Endoscopic Score ( SES- CD). Results 37 MREs were acquired. Both MREs were evaluable in 16 patients for calculation of test-retest and inter-reader reliability scores. The Ma RIA scores for the terminal ileum had excellent test-retest and inter-reader reliability, with correlations >0.9. The proximal ileum showed strong within-reader agreement (0.90-0.96), and fair between-reader agreement (0.59-0.72). MRE procedures were tolerable. Ma RIA scores correlated with CDEIS and SES- CD (0.63 and 0.71), but not with CDAI (0.34). MRE identified 3 patients with intra-abdominal complications, who would otherwise have been included in clinical trials. Furthermore, both MRE and ileocolonoscopy identified active bowel wall inflammation in 2 patients with CDAI <150, and none in 1 patient with CDAI > 220. Data quality was good/excellent in 85% of scans, and fair or better in 96%. Conclusions Magnetic resonance enterography of high-quality and reproducibility was feasible in a global multi- centre setting, with evidence for improved selectivity over CDAI and ileocolonoscopy in identifying appropriate CD patients for inclusion in therapeutic intervention trials. [ABSTRACT FROM AUTHOR]

Background Tumour necrosis factor alpha ( TNFα)-antagonism effectively treats ulcerative colitis (UC). The golimumab clinical programme evaluated subcutaneous (SC) and intravenous (IV) induction, and SC maintenance regimens, in TNFα-antagonist-naïve patients with moderate-to-severe active UC despite conventional treatment. Aim To evaluate dose-response relationship, select IV golimumab induction doses for continued development, and evaluate the safety and efficacy of selected doses. Methods Adults with Mayo scores of 6-12 and endoscopic subscores ≥2 were enrolled into this multicentre, randomised, double-blind, placebo-controlled, integrated Phase 2/3 dose-finding/dose-confirming study. In Phase 2, 176 patients were randomised (1:1:1:1) to a single IV infusion of placebo, 1-, 2- or 4-mg/kg golimumab. While Phase 2 data were analysed to select doses for continued development, 71 additional patients were randomised. Phase 3 enrolment stopped after 44 additional patients were randomised (1:1:1) to placebo, 2- or 4-mg/kg golimumab. Due to insufficient power for the Phase 3 primary endpoint analysis (clinical response at week 6), efficacy analyses are considered exploratory and include all randomised patients. Results No dose-response was observed in Phase 2; however, higher serum golimumab exposure was associated with greater proportions of patients achieving more favourable clinical outcomes, clinical response and greater improvement in Mayo scores compared with placebo-treated patients and those with lower serum concentrations. Among all randomised patients, numerically greater proportions were in clinical response at week 6 in the 2- and 4-mg/kg golimumab groups compared with placebo [44.0% (33/75) and 41.6% (32/77) vs. 30.1% (22/73)]. Conclusions Efficacy with single-dose golimumab IV induction was lower than expected and less than observed in the SC induction study. No new safety findings were observed. ClinicalTrials.gov Number, NCT00488774. [ABSTRACT FROM AUTHOR]

Background The general increased life expectancy is reflected in the age of patients with inflammatory bowel disease ( IBD). The knowledge about efficacy and safety of anti-tumour necrosis factor ( TNF) therapy in elderly is scarce and conflicting. Aim To assess the efficacy and safety of anti- TNF therapy in elderly patients taking into account eventual comorbidity. Methods Observational and retrospective single-centred study where 66 IBD patients initiating anti- TNF treatment at age ≥65 years (cases: ≥65 anti- TNF) were compared with 112 IBD patients initiating anti- TNF <65 years (controls <65 anti- TNF) and 61 anti- TNF naïve IBD patients treated with immunosuppressants ( IMS) and/or corticosteroids ( CS) ≥65 years (controls ≥65 IMS/ CS). Controls were matched to cases for IBD type, follow-up, disease duration and anti- TNF type. Comorbidity was assessed by using the Charlson Comorbidity Index ( CCI). Both efficacy and safety of treatment were adjusted for comorbidity. Results The short-term clinical response to anti- TNF at 10 weeks was significantly lower in cases: ≥65 anti- TNF (68% vs. 89%; P < 0.001), whereas at ≥6 months, differences were not significant (79.5% vs. 82.8%; P = 0.639). The risk for any severe adverse events was higher in cases: ≥65 anti- TNF than in controls <65 anti- TNF ( RR = 4.7; P < 0.001) or controls ≥65 IMS/ CS ( RR = 3.09; P = 0.0008). Age older than 65 and CCI > 0 were independent risk factors for malignancy and mortality regardless of the medication. Conclusion Elderly patients treated with anti- TNF have a lower rate of short-term clinical response and a higher rate of severe adverse events than the younger patients under the same treatment. [ABSTRACT FROM AUTHOR]

Background As treatment goals in Crohn's disease ( CD) evolve, targets now include clinical remission ( CR), mucosal healing ( MH) and biological remission [C-reactive protein normalisation ( CRPnorm)]. Aims To evaluate the association of baseline factors and treatment with the achievement of different composite remission parameters at week 26. Methods This post hoc analysis of the SONIC trial evaluated different composite remission measures at week 26 in a subgroup of patients with Crohn's disease activity index ( CDAI) scores, CRP, and endoscopic data available at baseline and week 26 ( N = 188). Assessed composite remission measures were: CR ( CDAI < 150) and MH (absence of any mucosal ulcerations), previously referred to as 'deep remission;' and alternative composite endpoints: CR + CRPnorm ( CRP < 0.8 mg/dL); CRPnorm + MH; and CR + CRPnorm + MH. Results Among analysed patients, 136/188 (72.3%) achieved CR and 90/188 (47.9%) achieved MH at week 26. All composite outcomes were significantly greater (Bonferroni significance level, P ≤ 0.016) with combination therapy (i.e. infliximab and azathioprine; 52.3-63.6%) vs. azathioprine monotherapy (12.9-29.0%; p ≤ 0.005 for all comparisons). Composite remission rates including MH were significantly greater with combination therapy (52.3-56.9%) vs. infliximab (25.6-32.3%; P ≤ 0.015 for all comparisons except CRPnorm + MH, P = 0.017) and vs. azathioprine monotherapy (12.9-20.4%; P ≤ 0.002 for all comparisons). Median serum trough infliximab concentrations among patients who achieved MH or CR + MH were greater when compared with those among patients who did not achieve MH ( P = 0.018) or CR + MH ( P = 0.053). Among the subgroup of patients with early Crohn's disease, MH alone or in combination with composite remission criteria significantly improved clinical outcomes of patients who received combination therapy. Conclusions Combination therapy was more effective in achieving various composite remission measures vs. azathioprine or infliximab monotherapy. These data illustrate that 'deep remission' is achievable with combination therapy in a high percentage of patients with early Crohn's disease. ClinicalTrials.gov number: NCT00094458. [ABSTRACT FROM AUTHOR]

Background Data for adalimumab in ulcerative colitis after prior use of infliximab are scarce. Aims To study adalimumab response rates and predictors of response in ulcerative colitis, including drug concentrations. Methods In this single centre cohort study 73 UC patients, previously exposed to infliximab, were assessed for response to adalimumab at weeks 12 and 52. Serum samples prior to week 12 were available and included in multivariate analysis to predict response. Results Overall clinical response at week 12 and 52 were 75% and 52%, respectively. Adalimumab was continued without need for dose escalation throughout year 1 in 16 patients, 22 needed dose escalation and 35 discontinued treatment within 1 year. Prior response to infliximab and early serum concentrations correlated with response. Receiver operator characteristic curve analysis yielded optimal adalimumab concentrations of 4.58 μg/mL for week 12 and 7.0 μg/mL for week 52. Independent predictors for response at week 12 were primary response to infliximab [odds ratio (OR) 8.33; 95% confidence interval (CI) 1.8-33.3; P = 0.006] and an adalimumab concentration ≥4.58 μg/mL at week 4 (OR 4.85; 95% CI 1.3-18.6; P = 0.009). Positive predictors for week 52 response were primary response to infliximab (OR 5.2; 95% CI 1.14-23.8; P = 0.034) and adalimumab concentration at week 4 of ≥7 μg/mL (OR 3.56; 95% CI 1.17-10.79; P = 0.025). Conclusion Prior response to infliximab and high early adalimumab serum concentrations predict week 12 and year 1 responses to adalimumab in ulcerative colitis. [ABSTRACT FROM AUTHOR]

Background A high proportion of patients with inflammatory bowel disease ( IBD) do not achieve clinical remission with the current therapies including mesalazine (mesalamine), immunossupresants ( IMS) and antibodies against tumour necrosis factor (anti- TNF). Moreover, IMS and anti- TNF involve a nonnegligible risk for infections and/or malignancies. The anti-adhesion molecules are one of the most interesting new treatments because of their gut-selectivity. Aim To review the physiopathology of the adhesion molecules and the current drugs targeting this mechanism. Methods We performed a literature review in PubMed and in clinicaltrials.gov using the terms 'anti-adhesion molecules', 'inflammatory bowel disease', 'natalizumab', 'vedolizumab', ' AMG181', 'Etrolizumab', ' PF-00547659', ' AJM300', 'Alicaforsen' and ' CCX282-B' up to November 2013. Results A total of eight drugs were found including those targeting the α4β1, α4β7 or αEβ7 integrins as well as the ICAM-1 and MAd CAM-1 addressins and the chemokine receptor 9. The rationale for these drugs is the blockade of gut-homing T lymphocytes and the ones targeting the α4β7/ MAd CAM-1 interaction presented the most promising results in luminal disease. Vedolizumab, an α4β7 antibody, has completed phase 3 trials with very positive results especially for ulcerative colitis. However, many questions remain unanswered such as the effect of these therapies in perianal disease and extraintestinal manifestations. Conclusions The blockade of the α4β7/ MAd CAM-1 interaction and especially vedolizumab is an effective and safe gut-specific treatment for IBD. Further studies are needed to clarify the efficacy and safety of the other anti-adhesion drugs and to define the specific indications of these therapies in the different scenarios of IBD. [ABSTRACT FROM AUTHOR]

Background Until recently, the management of ulcerative colitis ( UC) consisted of the stepwise use of mesalazine, corticosteroids and immunomodulators, or consideration of surgery. Anti-tumour necrosis factor ( TNF) agents are recent additions to the UC-treatment algorithm. Aim To provide clinicians with a review of the role of anti- TNFs in UC, discussing how the drug(s) were used in the past, their current use and to determine their future role. Methods The scientific literature was reviewed to evaluate data on the use of anti- TNFs in UC. Results In this review, we report how the management of UC has changed with the availability of anti- TNFs. The results from landmark anti- TNF trials have impacted clinical practice, leading to a readjustment of treatment goals. In addition, experience from clinical trials and local real-life cohorts have helped to clarify some misunderstandings in the management of UC. New anti- TNFs are on the horizon but questions still remain on the future role of anti- TNFs with regard to impact on disability, digestive damage and the possible development of risk matrices. Experiences from the use of anti- TNFs in Crohn's disease (for example, combination therapy and early treatment) now need to be addressed in UC. Conclusions The use of anti- TNFs in the management of UC has matured rapidly. Clinical experience has helped shape the current role of anti- TNFs, but more clinical research is needed to optimise their future role. [ABSTRACT FROM AUTHOR]

Background Tumour necrosis factor-alpha ( TNF-α) is an important mediator of the molecular cascade leading to chronic inflammation. TNF-α inhibitors have proven their safety and efficacy in the treatment of inflammatory diseases. Aim To review the non-malignant haematological adverse events, such as thrombocytopaenia, neutropaenia, hypercoagulability, pancytopaenia and aplastic anaemia in patients receiving TNF-α inhibitors. Methods We reviewed the literature by searching MEDLINE and EMBASE databases as well as references of all retrieved articles for the following terms: anti-tumour necrosis factor, anti- TNF, infliximab, adalimumab, certolizumab, etanercept, haematological complications, thrombocytopaenia, neutropaenia, anaemia, bone marrow and thrombosis. Results Thombocytopaenia is a very rare phenomenon and was associated with no serious adverse events. However, transient neutropaenia developed in up to 16% of cases. Patients with a previous history of neutropaenia on other therapies or baseline neutrophil count <4 × 109/L are at a particularly higher risk. The association between anti- TNF-α therapy and thrombosis is very nebulous due to the multitude of potential confounders. Only one case of primary eosinophilia has been reported with anti- TNF-α therapy. Conclusion Regular monitoring of the white blood cell count at baseline and with each infusion is recommended for patients on anti- TNF-α. Further studies to elucidate their interaction with the immune system are warranted. [ABSTRACT FROM AUTHOR]

Aim Diarrhoea with urgency is a debilitating long-term complication of ileal pouch anal anastomosis (IPAA) after a proctocolectomy. Somatostatin analogues are used to control diarrhoea and high-output ostomies. Hence, we designed a prospective, double-blind, crossover trial to explore the efficacy and tolerability of octreotide to reduce diarrhoea in adult patients with IPAA. Method Patients were randomized to octreotide subcutaneously (SC), 500 μg three times daily (t.i.d.), or matching placebo SC for 7 days. Responders (a reduction in stool frequency of three or more stools per 24-h period and with a reduction in stool frequency of at least 30% after 7 days of treatment compared with baseline; the primary end-point) remained in the same group and nonresponders could cross over to the alternative treatment for 7 days. Open-label octeotide LAR 30 mg was offered to all responders on day 14. Flexible pouchoscopy with biopsies was performed at baseline in all patients and was repeated on days 7 and 14 in patients with pouchitis. Results Fifteen patients (11 men, median age 52 years), all with ulcerative colitis, were randomized. Three patients were withdrawn for side effects during the blinded phase. Response was achieved by two of 12 and two of 11 patients treated with octreotide or placebo, respectively (including crossover, P = 0.9). The median stool frequency remained stable in both groups [Δoctreotide: 0 (IQR, −4 to 0), Δplacebo: −1 (IQR, −1 to 1), P = 0.45]. Octreotide had no effect on the modified pouch disease activity index (mPDAI), and pouchitis persisted in five of six subjects with pouchitis at onset. One subject received open-label octreotide LAR. Conclusion Octreotide has no clear beneficial effect on the stool pattern or on pouchitis severity in patients with high stool frequency after IPAA. [ABSTRACT FROM AUTHOR]

Background: Haptoglobin (Hp) is a haemoglobin-binding protein with immunomodulatory properties. Its gene (16q22) harbours a common polymorphism with two different alleles: Hp1 and Hp2. Genotype Hp22 has been shown to be over-represented in different immune diseases. Results in Crohn's disease (CD) are contradictory. Aims: To determine whether Hp plays a role in inflammatory bowel disease, both genetically and functionally Methods: 1061 patients with CD, 755 with ulcerative colitis (UC) and 152 with primary sclerosing cholangitis, as well as 452 healthy controls, were genotyped using touch-down PCR. To confirm association results, 464 CD trios and 151 UC trios were genotyped. Serum Hp concentrations were determined in 62 individuals of different genotype. Colitis was induced in mice with dextran sulphate sodium (DSS) and oxazolone (Oxa). Cytokine production was evaluated by mRNA quantification in colonic tissue and ELISA on supernatants of mesenteric lymph node cells. Results: Prevalence of Hp2 was higher in CD and UC than in controls. In the confirmatory cohorts, Hp2 was overtransmitted to the affected offspring. Serum Hp concentrations were higher in individuals with genotypes Hp11 and Hp21 than in those with Hp22 (1.38 vs 0.89 g/l). DSS- and Oxa-induced colitis were more severe in Hpdeficient mice than in control mice and accompanied by higher concentrations (although not statistically significantly different) of tissue mRNA for cytokines. Interleukin-17 production was significantly higher in the presence of Hpdeficient serum compared with wild-type serum. Conclusions: The Hp gene may play a role in susceptibility to inflammatory bowel disease. Its implication in other immune diseases underscores the common pathways between these diseases. Experimental models of colitis showed that Hp has a protective role in inflammatory colitis, most likely by inhibiting the production of Th1 and Th17 cytokines. INSET: Significance of this study. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2011; 34: 526-532 Summary Background Butyrate, a colonic metabolite of carbohydrates, is considered as the major energy source for the colonic mucosa. An impaired butyrate metabolism has been reported in ulcerative colitis (UC), however, the cause still remains unknown. Aim In the present study, we investigated whether higher butyrate concentrations could normalise the oxidation rate in UC. Furthermore, it was investigated whether carnitine could enhance the butyrate oxidation. Methods Mucosal biopsies from a total of 26 UC patients and 25 controls were incubated with 14C-labelled Na-butyrate and the produced 14CO2 was measured. First, the rate of oxidative metabolism was compared at three different concentrations of Na-butyrate (0.05 m m, 1 m m and 10 m m). Then, incubations of biopsies were performed with carnitine alone or combined with ATP. Results Overall, butyrate oxidation in UC was significantly lower than that in controls. The maximum rate of butyrate oxidation was achieved in UC and control subjects from 1 m m onwards. Increasing the butyrate concentration to a level to be present in the colonic lumen, i.e. 10 m m, did not increase the rate of butyrate oxidation in UC to the rate observed in controls. Addition of carnitine alone or combined with ATP caused no effects. Conclusions Saturation of butyrate kinetics was achieved from 1 m m in UC and control subjects. The rate of butyrate metabolism was significantly impaired in active ulcerative colitis. The addition of compounds interfering with the β-oxidation pathway had no effect on the butyrate metabolism in UC. [ABSTRACT FROM AUTHOR]

Background, Crohn's disease is a progressive condition, with most patients developing a penetrating or stricturing complication over time. A decade ago, treatment goals consisted of immediate symptomatic control. The introduction of anti-tumour necrosis factor (anti-TNF) therapies, however, has changed the way patients with Crohn's disease are treated. Over 10 years of clinical data and experience have demonstrated these therapies to be highly effective in Crohn's disease. Aim, To provide clinicians guidance on optimising treatment with anti-TNF therapies in Crohn's disease by introducing an evidence- and personal opinionbased treatment algorithm using infliximab initial anti-TNF therapy. Methods, Scientific literature was reviewed usingMEDLINE to evaluate data on clinical trials with infliximab in luminal and fistulising Crohn's disease. Results, The data from several landmark infliximab trials have changed clinical practice and led to a readjustment of treatment goals in Crohn's disease, allowing patients to achieve more than just symptomatic relief including sustained steroid-free remission. Infliximab induces complete mucosal healing and reduces the rates of hospitalisation and surgery. Based on diseaserelated risk factors, a treatment algorithm for infliximab is delineated in favour of a rapid step-up approach in patients at high risk for a disabling course of disease. Conclusion, Adopting the suggested treatment algorithm for infliximab into clinical routine is aimed to optimise outcomes for patients with Crohn's disease. [ABSTRACT FROM AUTHOR]

Background Crohn's disease (CD) is associated with impaired health-related quality of life (HRQoL). Certolizumab pegol, administered either every 2 weeks (q2w) or q4w, maintains efficacy in patients previously failing on the anti-TNF agent infliximab (WELCOME study). Aim To investigate the impact of certolizumab pegol administered q2w and q4w on work productivity and HRQoL in the WELCOME study. Methods Patients with loss of response to infliximab received open-label certolizumab pegol induction and were randomised to receive double-blind maintenance treatment with certolizumab pegol 400 mg either q4w or q2w through week 24, with a final evaluation at week 26. Work productivity and HRQoL were assessed using the Work Productivity and Activity Impairment:CD questionnaire and Inflammatory Bowel Disease Questionnaire respectively. Results Baseline HRQoL burden was representative of moderately to severely active CD. HRQoL, daily activity and work productivity improved in both treatment groups as early as week 6 and were maintained through week 26. Treatment benefits to HRQoL, daily activity and work productivity were similar between the certolizumab pegol q2w vs. q4w groups. Conclusions Certolizumab pegol therapy results in meaningful improvements in work productivity, daily activities and HRQoL in patients with active CD who previously responded to but either lost response or could not tolerate infliximab (ClinicalTrials.gov number: NCT00308581). [ABSTRACT FROM AUTHOR]

While some probiotic strains might have adjuvant effects in the therapy for inflammatory bowel diseases (IBD), these effects remain controversial and cannot be generalized. In this study, a dltD mutant of the model probiotic Lactobacillus rhamnosus GG (LGG), having a drastic modification in its lipoteichoic acid (LTA) molecules, was analysed for its effects in an experimental colitis model. Dextran sulphate sodium (DSS) was used to induce either moderate to severe or mild chronic colitis in mice. Mice received either phosphate-buffered saline (PBS), LGG wild-type or the dltD mutant via the drinking water. Macroscopic parameters, histological abnormalities, cytokine and Toll-like receptor (TLR) expression were analysed to assess disease activity. LGG wild-type did not show efficacy in the different experimental colitis set-ups. This wild-type strain even seemed to exacerbate the severity of colitic parameters in the moderate to severe colitis model compared to untreated mice. In contrast, mice treated with the dltD mutant showed an improvement of some colitic parameters compared to LGG wild-type-treated mice in both experimental models. In addition, treatment with the dltD mutant correlated with a significant down-regulation of Toll-like receptor-2 expression and of downstream proinflammatory cytokine expression in the colitic mice. These results show that molecular cell surface characteristics of probiotics are crucial when probiotics are considered for use as supporting therapy in IBD. [ABSTRACT FROM AUTHOR]

The transcription factor glioma-associated oncogene homolog 1 (GLI1) has a central function in gastrointestinal tract development and homeostasis. A non-synonymous single-nucleotide polymorphism (SNP) (rs2228226; Q1100E) in GLI1, which impairs GLI1 function in vitro, has been proposed as a risk factor for inflammatory bowel disease (IBD). In this study, we assessed the cumulative evidence for association of GLI1 with IBD. New genotype data for rs2228226 from New Zealand (907 controls, 990 IBD patients) and Belgian Caucasian case–control data sets (312 controls, 1214 IBD patients) were combined with data from the National Institute of Diabetes and Digestive and Kidney Diseases and three previously studied Caucasian case–control data sets. Meta-analysis of rs2228226 did not detect any association with ulcerative colitis (UC) (P=0.09, odds ratio (OR)=1.07, 95% confidence interval (CI)=0.92–1.24), Crohn's disease (CD) (P=0.29, OR=1.06, 95% CI=0.93–1.21) or overall IBD (P=0.15, OR=1.05, 95% CI=0.92–1.19). Our analyses of rs2228226 suggest that GLI1 is not a significant risk factor for IBD in Caucasians. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 31, 1296–1309 Background In the randomized, double-blind, placebo-controlled CHARM trial, adalimumab was more effective than placebo in maintaining clinical remission for patients with moderate-to-severe Crohn’s disease (CD) through 56 weeks. Aim To substantiate the long-term safety and clinical benefits of adalimumab through 2 years of therapy in CHARM and its open-label extension (ADHERE). Methods Patients entering ADHERE on blinded therapy received adalimumab 40 mg every other week (eow). Patients who had already moved to open-label adalimumab eow or weekly in CHARM continued their regimens. Data were analysed by originally randomized treatment group at CHARM baseline (adalimumab 40 mg eow, adalimumab 40 mg weekly, or placebo), regardless of whether patients entered ADHERE or received open-label adalimumab (eow or weekly). Results After up to 2 years of therapy, 37.6%, 41.9% and 49.8% of patients originally randomized to placebo, adalimumab eow and adalimumab weekly, respectively, were in clinical remission. All groups experienced sustained improvements on the Inflammatory Bowel Disease Questionnaire. Decreasing hazard rates for both all-cause and CD-related hospitalizations were observed over time. Over a 2-year period, the rates of serious adverse events and malignancies (33.3 and 1.1 events/100-patient-years respectively) were similar to those observed during the overall adalimumab CD clinical development programme. Conclusions Adalimumab demonstrated sustained maintenance of clinical remission, improvements in quality of life and reductions in hospitalization during long-term treatment for CD, with no new safety concerns identified. [ABSTRACT FROM AUTHOR]

Background Endoscopic dilatation of Crohn's diseaserelated strictures is an alternative to surgical resection in selected patients. The influence of disease activity and concomitant medical therapy on long-term outcomes is largely unknown. Aim and methods To study the long-term safety and efficacy of stricture dilatation in a single centre cohort. Results Between 1995 and 2006, 237 dilatations where performed in 138 patients (mean age 50.6613.4, 56% female) for a clinically obstructive stricture (<5 cm, 84% anastomotic). Immediate success of a first dilatation was 97% with a 5% serious complication rate. After a median follow-up of 5.8 years (IQR 3.0e8.4), recurrent obstructive symptoms led to a new dilatation in 46% or surgery in 24%. Niether elevated levels of C-reactive protein nor endoscopic disease activity predicted the need for new intervention. None of the concomitant therapies influenced the outcome. Conclusion This largest series ever reported confirms that long term efficacy of endoscopic dilatation of Crohn's disease outweighs the complication risk. Neither active disease at the time of dilatation nor medical therapy afterwards predict recurrent dilatation or surgery. [ABSTRACT FROM AUTHOR]

Background Adalimumab (ADA) and certolizumab pegol (CZP) have demonstrated efficacy in Crohn’s disease (CD) patients previously treated with infliximab (IFX). Aim To assess the efficacy and tolerability of a third anti-TNF in CD after failure of and/or intolerance to two different anti-TNF antibodies. Methods Crohn’s disease patients who received ADA or CZP after loss of response and/or intolerance to two anti-TNF agent were included in this retrospective study. Data were collected using a standardized questionnaire. Clinical response, duration, safety and reasons for discontinuation were assessed. Results Sixty-seven patients treated with CZP ( n = 40) or ADA ( n = 27) were included. A clinical response was observed in 41 (61%) at week 6 and 34 patients (51%) at week 20. The probability of remaining under treatment at 3 months, 6 months and 9 months was 68%, 60% and 45%, respectively. At the end of follow-up, the third anti-TNF had been stopped in 36 patients for intolerance ( n = 13), or failure ( n = 23). Two deaths were observed. Conclusions The treatment with a third anti-TNF (CZP or ADA) agent of CD patients, who have experienced loss of response and/or intolerance to two anti-TNF antibodies, has favourable short-term and long-term efficacy. It is an option to be considered in patients with no other therapeutic options. [ABSTRACT FROM AUTHOR]

The article discusses a study which examines the outcome of surgery for symptomatic Crohn's rectovaginal fistula (RVF) and the effect of therapy with antibody against tumour necrosis factor (TNF) on healing. The study shows that most patients achieve fistula closure but require more than one operation. It notes that 81 per cent of 52 patients achieve fistula closure and 56 per cent attain primary surgical success rate while 57 per cent achieve secondary surgical success rate.

Background and aims: This study evaluates the long-term safety of infliximab in patients with inflammatory bowel disease (IBD) treated with the drug over a 14-year period. Methods: The medical records of 734 patients with IBD treated with infliximab and 666 control patients not treated with infliximab were reviewed for adverse events. The time of onset and outcome, severity and concomitant medication were recorded. Results: Patients and controls were followed up for serious adverse events for a median time of 58 months (IQR 33-88) and 144 months (IQR 83-163), respectively. 112 severe adverse events occurred in 93 patients (13%) treated with infliximab and 157 occurred in 126 (19%) control patients (OR 1.33 (95% CI 0.56 to 3.00, p = 0.45). There was no difference between the two groups in mortality, malignancies and infection rate. Tuberculosis was diagnosed in two patients receiving infliximab who had negative skin tests at baseline whereas none of 16 patients with positive skin tests who received prophylaxis developed tuberculosis. Concomitant treatment with steroids was the only independent risk factor for infections in patients treated with infliximab (OR 2.69 (95% CI 1.18 to 6.12), p = 0.018). The most commonly observed systemic side effects were skin eruptions including psoriasiform eruptions in 150 patients (20%). Conclusions: Long-term infliximab treatment had a good overall safety profile in the patient cohort studied. [ABSTRACT FROM AUTHOR]

Background and aims: This observational study assessed the long-term clinical benefit of infliximab (IFX) in 614 consecutive patients with Crohn's disease (CD) from a single centre during a median follow-up of 55 months (interquartile range (IQR) 27-83). Methods: The primary analysis looked at the proportion of patients with initial response to IFX who had sustained clinical benefit at the end of follow-up. The long-term effects of IFX on the course of CD as reflected by the rate of surgery and hospitalisations and need for corticosteroids were also analysed. Results: 10.9% of patients were primary non-responders to IFX. Sustained benefit was observed in 347 of the 547 patients (63.4%) receiving long-term treatment. In 68.3% of these, treatment with IFX was ongoing and in 31.7% IFX was stopped, with the patient being in remission. Seventy patients (12.8%) had to stop IFX due to side effects and 118 (21.6%) due to loss of response. Although the yearly drop-out rates of IFX in patients with episodic (10.7%) and scheduled treatment (7.1%) were similar, the need for hospitalisations and surgery decreased less in the episodic than in the scheduled group. Steroid discontinuation also occurred in a higher proportion of patients in the scheduled group than in the episodic group. Conclusions: In this large real-life cohort of patients with CD, long-term treatment with IFX was very efficacious to maintain improvement during a median follow-up of almost 5 years and changed disease outcome by decreasing the rate of hospitalisations and surgery. [ABSTRACT FROM AUTHOR]

Background Budesonide exhibits similar efficacy to systemic glucocorticosteroids (GCSs) in Crohn’s disease (CD), but with fewer adverse events (AEs). Aim To evaluate budesonide’s safety profile in CD patients, in particular, incidences of clinically important AEs known to be associated with systemic GCSs. Methods Five 1-year, double-blind, placebo-controlled trials evaluating budesonide for mild-to-moderate CD were pooled for analysis. Results The highest incidence rates of AEs were gastrointestinal- and endocrine systems-related in both groups (budesonide 6 mg/day, n = 208; placebo, n = 209). Incidence rates were similar, except for higher incidence of endocrine disorders in budesonide versus placebo patients ( P = 0.0042) caused by a higher overall occurrence of cutaneous GCS symptoms ( P = 0.0036) in the budesonide group; differences in individual symptoms were nonsignificant. Percentage of patients with normal adrenal function was significantly lower at 13 weeks (three of five studies), but not at 52 weeks (two studies) in the budesonide versus placebo groups. Occurrence of clinically important or serious AEs associated with systemic GCSs, including sepsis, cataracts, adrenal insufficiency was rare and similar between groups. Conclusions Budesonide treatment for up to 1 year is well-tolerated in CD patients, with an AE profile similar to placebo and only rare occurrences of clinically important AEs associated with systemic GCSs. [ABSTRACT FROM AUTHOR]

Genetic predisposition is a risk factor for the development of inflammatory bowel diseases (IBDs). Disruption of the interleukin (IL)-10 pathway in mice causes intestinal inflammation similar to human IBD. Two common non-synonymous IL-10R1 variants, S138G and G330R, were cloned and expressed in HeLa and Ba/F3. A reduction in IL-10-induced STAT1 and STAT3 activation was seen for IL-10R1-S138G (but not IL-10R1-G330R) by phosphospecific western blotting in both cell types. When analyzing 52 world populations for the presence of IL-10R1 variants, a strong dissimilarity was found between major geographical regions. In addition, when 182 IBD–parent trios were genotyped for both variants, a reduced transmission of haplotype -7 (carrying the S138G variant allele) to offspring with ulcerative colitis (UC) was observed. This UC-protective effect of S138G was confirmed in a Hungarian cohort (n=185, allele frequency 11.6 versus 17.5%; P=0.017) but not in an independent Belgian cohort (n=666, allele frequency 15.9 versus 15.5%; P=0.8). In conclusion, the IL-10R1 S138G variant is a loss-of-function allele for IL-10-induced STAT1 and STAT3 activation but does not protect from UC susceptibility.Genes and Immunity (2009) 10, 84–92; doi:10.1038/gene.2008.72; published online 18 September 2008 [ABSTRACT FROM AUTHOR]

Background and aims: Anti-α4 integrin therapy with natalizumab is efficacious in refractory Crohn's disease and in multiple sclerosis, but carries an estimated 1/1 000 risk of progressive multifocal leukoencephalopathy (PML) caused by reactivation of latent JC virus infection. Athough anti-α4 integrin therapies are likely to be introduced in the clinic, screening for the risk of PML has not been developed. Methods: We prospectively collected urine, serum, plasma and bully coats from 125 patients with Crohn's disease, 100 control subjects with gastrointestinal (GI) disease, and 106 healthy volunteers. Four to eight weeks after this first sample collection, we additionally collected a set of urine, serum, plasma and bully coat samples from the 125 patients with Crohn's disease, and a next set of samples was collected 12-16 weeks after the first collection. JC viral loads were determined with quantitative real-time polymerase chain reaction (PCR), and JC virus seroprevalence with a specific enzyme-linked immunosorbant assay (ELISA). Results: The overall JC virus seroprevalence was 65%. JC virus DNA copies were detected in the urine from 29-44% of subjects, both those with Crohn's disease and controls. Median viral loads were significantly higher in patients with Crohn's disease who were immunosuppressed (7.36 × 106 copies/ml) compared to healthy volunteers (2.77 × 106 copies/ml) and compared to 01 controls (1.8 × 106 copies/ml). Clearance at any time point occurred in 4/107 (3.7%) subjects only. JC was found in two patients with Crohn's disease. Conclusions: The natural history of JC virus in patients with Crohn's disease is still unknown. Our study results show that JC virus latency and urine viral shedding is frequent in immunosuppressed patients with Crohn's disease. More prospective studies are needed in order to agree on possible recommendations concerning the exclusion of patients with JCV viraemia from anti-α4 integrin treatment. [ABSTRACT FROM AUTHOR]

Background Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the intestine, which frequently require surgery for complications or failure of medical therapy. Aim To seek evidence and provide direction for clinicians on optimal strategies to enable steroid free remission in inflammatory bowel disease. Methods Scientific literature was reviewed using MEDLINE with a specific focus on medical therapies for inducing and maintaining remission of CD and UC. The results were discussed at a roundtable meeting to reach a consensus on key issues. Results Several therapies have demonstrated efficacy for the treatment of active, moderate-to-severe CD and UC. These include agents, which induce remission [corticosteroids, infliximab and adalimumab (CD only)] or maintain remission and spare corticosteroids [azathioprine, mercaptopurine, methotrexate (CD only), infliximab and adalimumab (CD only)]. Wide variability exists in the use of these agents. Conclusion Treatment strategy algorithms are developed for use of these therapies that maximize remission and minimize corticosteroid dependence in patients with moderate-to-severe CD and UC. [ABSTRACT FROM AUTHOR]

We evaluated the effect of resistant starch (RS) and resistant starch with wheat bran (RS+WB) on the colonic ammonia metabolism in healthy volunteers using the biomarker 15N-lactose ureide (15N-LU). Particularly, it was investigated whether this biomarker allowed to estimate differences in the site of fermentation. Ten volunteers were included in a placebo-controlled crossover study. They consumed in random order 2 x 15 g RS/day for 2 weeks and placebo for 2 weeks separated by 2 weeks wash-out. At baseline, on the first day of each intake period and after each intake period, they consumed a 15N-labelled test meal and collected all urine in different fractions for 48 h. In ten other volunteers, the effect of 2 x 15 g RS/day and of 2 x 15 g RS + 2 x 6 g WB was compared. These volunteers collected urine and feces for 72 h. 15N-content of urine and feces was measured using combustion-isotope ratio mass spectrometry. RS exerted a significant decrease in cumulative urinary 15N-excretion which was different from placebo. The effect was most pronounced in the 6-24 h urine fraction which suggest fermentation in the proximal colon. The effect of RS+WB on cumulative urinary 15N-excretion was not significantly different from the effect of RS. A less pronounced decrease in the 6-24 h fraction was observed suggesting less fermentation in the proximal colon whereas no indications for more distal fermentation were observed. Since about 80% of the cumulative urinary 15N was recovered within 24 h, it was concluded that the biomarker 15N-LU was useful to monitor processes in the proximal colon rather than in the distal colon. [ABSTRACT FROM AUTHOR]

Background Dietary intervention with prebiotics can cause changes in the colonic microbiota and their metabolic activities. Aim To investigate whether the response to prebiotic dosing is influenced by the baseline metabolic activity of the colonic flora and bifidobacteria counts. Methods The 4-week effect of lactulose (10 g bid.; n = 29) and oligofructose-enriched inulin (10 g bid.; n = 19) was evaluated in healthy human volunteers. Lactose-[15N, 15N]-ureide was used to study the colonic NH3-metabolism. Urine (48 h) and faeces (72 h) were collected and analysed for p-cresol and 15N-content by gas chromatography–mass spectrometry and isotope ratio mass spectrometer, respectively. Faecal bifidobacteria were quantified by real-time polymerase chain reaction. Results After the 4-week prebiotic administration period, the urinary excretion of p-cresol and 15N was significantly decreased in both groups ( P < 0.05) corresponding to a significantly higher faecal excretion of 15N ( P < 0.05). The decrease in urinary 15N and p-cresol excretion significantly correlated with baseline 15N and p-cresol levels ( P < 0.05), indicating that subjects with higher baseline levels showed a higher response to prebiotic dosing. Furthermore, a significant correlation was seen between baseline bifidobacteria counts and the effect of prebiotic intake ( P < 0.05). Conclusion The response to prebiotic dosing, as indicated by the fate of NH3, p-cresol and bifidobacteria, is determined by the initial colonic conditions. [ABSTRACT FROM AUTHOR]

Objective:To investigate the influence of different pre- and probiotics on faecal β-glucuronidase and β-glucosidase activity, as one of the claimed beneficial effects of pre- and probiotics is the hypothesis that these substrates are able to reduce the production of toxic and carcinogenic metabolites by suppressing specific enzyme activities in the colon.Setting:Department of Gastrointestinal Research, University Hospital Gasthuisberg, KU Leuven, Belgium.Design and subjects:The effect was evaluated in a randomized, crossover study in 53 healthy volunteers who were randomly assigned to one of five treatment groups.Interventions:At the start and after a 4-week treatment period, the healthy volunteers collected faeces during 72 h. Lactulose and oligofructose-enriched inulin (OF-IN) were chosen as prebiotics, whereas Lactobacillus casei Shirota, Bifidobacterium breve and Saccharomyces boulardii were selected as probiotics. Two synbiotic combinations were evaluated as well. The enzyme activity was assessed spectrophotometricly.Results:Lactulose and OF-IN significantly decreased β-glucuronidase activity, whereas a tendency to a decreased β-glucuronidase activity was observed after L. casei Shirota and B. breve intake. To the contrary, B. breve increased β-glucosidase levels. Supplementation with the synbiotic did not appear to be more beneficial than either compound alone. No influence of S. boulardii was noted.Conclusions:Administration of lactulose, OF-IN, L. casei Shirota or B. breve resulted in a decrease of the β-glucuronidase activity, which is considered beneficial for the host.European Journal of Clinical Nutrition (2008) 62, 225–231; doi:10.1038/sj.ejcn.1602706; published online 28 February 2007 [ABSTRACT FROM AUTHOR]

Background: Adalimumab induced clinical remission after four weeks in patients with active Crohn's disease in the CLASSIC I trial. Objective: To evaluate long term efficacy and safety of adalimumab maintenance therapy in Crohn's disease in a follow-on randomised controlled trial (CLASSIC II). Methods: In the preceding CLASSIC I trial, 299 patients with moderate to severe Crohn's disease naive to tumour necrosis factor antagonists received induction therapy with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg, or placebo, at weeks 0 and 2. In all, 276 patients from CLASSIC I enrolled in CLASSIC II and received open-label adalimumab 40 mg at weeks 0 (week 4 of CLASSIC I) and 2; 55 patients in remission at both weeks 0 and 4 were re-randomised to adalimumab 40 mg every other week, 40 mg weekly, or placebo for 56 weeks. Patients not in remission at both weeks 0 and 4 were enrolled in an open-label arm and received adalimumab 40 mg every other week. With non-response or flare, these patients could have their dosages increased to 40 mg weekly. Patients in the randomised arm with continued non-response or disease flare could switch to open-label adalimumab 40 mg every other week and again to 40 mg weekly. The primary end point was maintenance of remission (CDAI < 150) in randomised patients through week 56. Results: Of 55 patients randomised at week 4, 79% who received adalimumab 40 mg every other week and 83% who received 40 mg weekly were in remission at week 56, v 44% for placebo (p<0.05). In all, 204 patients entered the open-label arm. Of these, 93 (46%) were in clinical remission at week 56. Adalimumab was generally well-tolerated in all patients. Conclusions: Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn's disease naive to anti-TNF treatment. [ABSTRACT FROM AUTHOR]

Background: Adalimumab, a fully human tumor necrosis factor (TNF) antagonist, is an effective treatment for patients with Crohn disease who are naive to the chimeric TNF antagonist, infliximab. No anti-TNF agent has been evaluated prospectively in patients with Crohn disease who had responded to another anti-TNF agent and then lost that response or were intolerant of the agent.Objective: To determine whether adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who have symptoms despite infliximab therapy or who cannot take infliximab because of adverse events.Design: 4-week, randomized, double-blind, placebo-controlled trial (November 2004 to December 2005).Setting: 52 sites in the United States, Canada, and Europe.Patients: 325 adults 18 to 75 years of age who had a history of Crohn disease for 4 months or more that was moderate to severe at baseline (Crohn's Disease Activity Index [CDAI] score, 220 to 450 points).Intervention: Patients were randomly assigned to receive induction doses of adalimumab, 160 mg and 80 mg, at weeks 0 and 2, respectively, or placebo at the same time points.Measurements: The primary end point was induction of remission at week 4. Decreases in CDAI score by 70 or more and 100 or more points (secondary end points) were also measured.Results: A total of 301 patients completed the trial. Twenty-one percent (34 of 159) of patients in the adalimumab group versus 7% (12 of 166) of those in the placebo group achieved remission at week 4 (P < 0.001). The absolute difference in clinical remission rates was 14.2 percentage points (95% CI, 6.7 to 21.6 percentage points). A 70-point response occurred at week 4 in 52% (82 of 159) of patients in the adalimumab group versus 34% (56 of 166) of patients in the placebo group (P = 0.001). The absolute difference in 70-point response rates was 17.8 percentage points (CI, 7.3 to 28.4 percentage points). Two of 159 patients in the adalimumab group and 4 of 166 patients in the placebo group discontinued treatment because of adverse events. No patients in the adalimumab group and 4 of 166 patients in the placebo group had a serious infection.Limitations: The trial did not directly compare alternative active treatments and did not evaluate maintenance of response or long-term immunogenicity of adalimumab.Conclusion: Adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who cannot tolerate infliximab or have symptoms despite receiving infliximab therapy. For more information on adalimumab in Crohn disease, click here. ClinicalTrials.gov registration number: NCT00105300. [ABSTRACT FROM AUTHOR]

Objective: To determine dysplasia and cancer in the 1991–2004 European Collaborative Inflammatory Bowel Disease (EC-IBD) Study Group cohort. Patients and Methods: A patient questionnaire and a physician per patient form were completed for each of the 1,141 inflammatory bowel disease patients (776 ulcerative colitis/365 Crohn’s disease) from 9 centers (7 countries) derived from the EC-IBD cohort. Rates of detection of intestinal cancer and dysplasia as well as extra-intestinal neoplasms were computed. Results: Patient follow-up time was 10.3 ± 0.8 (range 9.4–11) years. The mean age of the whole group of IBD patients was 37.8 ± 11.3 (range 16–76) years. Thirty-eight patients (3.3%; 26 with ulcerative colitis/12 with Crohn’s disease, 21 males/17 females, aged 61.3 ± 13.4, range 33–77 years), were diagnosed with 42 cancers. Cancers occurred 5.4 ± 3.3 (range 0–11) years after inflammatory bowel disease diagnosis. Colorectal cancer was diagnosed in 8 (1 Crohn’s disease and 7 ulcerative colitis patients – 0.3 and 0.9% of the Crohn’s disease and ulcerative colitis cohort, respectively) of 38 patients and 30 cancers were extra-intestinal. Four of 38 patients (10.5%) were diagnosed as having 2 cancers and they were younger compared to patients with one cancer (p = 0.0008). There was a trend for a higher prevalence of intestinal cancer in the northern centers (0.9%) compared to southern centers (0.3%, p = NS). Southern centers had more cases of extra-intestinal cancer compared to northern centers (2 vs. 3.8%, p = 0.08). Ten patients (0.9%; 8 with ulcerative colitis/2 with Crohn’s disease, 8 males, aged 62.3 ± 14.1 years) had colorectal dysplasia. Conclusions: In the first decade of the EC-IBD Study Group cohort follow-up study, the prevalence of cancer was as expected with most patients having a single neoplasm and an extra-intestinal neoplasm. In northern centers there was a trend for more intestinal cancers, while in southern centers there was a trend for more extra-intestinal cancers compared to northern centers. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background The natural course of Crohn's disease is characterized by flare-ups altered with periods of remission. The majority of Crohn's disease patients need surgery within 10 years of diagnosis. Major advances in treatment options over the past years have made our treatment goals more ambitious and modification of the natural course has become the ultimate endpoint. Aim To review the evidence of existing therapies for Crohn's disease for changing the natural history. Methods A Medline search was undertaken by using ‘natural history’, ‘Crohn's disease’, ‘therapy’ (corticosteroids, azathioprine, methotrexate, infliximab and enteral feeding), ‘surgery’, ‘hospitalizations’ and ‘mucosal healing’. Results Corticosteroids do not alter the disease course and maintenance therapy with corticosteroids should be avoided given their side effects. The immunomodulators azathioprine and methotrexate heal the mucosa but their onset of action is slow. Infliximab therapy introduces rapid mucosal healing and is associated with decreased hospitalizations and surgical interventions. Despite the fact that immunomodulators and infliximab are effective in maintaining clinical and endoscopic remission, there is little hard evidence at present that these therapies alter the natural history of the disease. The main reason being the fact that these therapies have so far been used only in refractory patients and that early initiation in the right patient is crucial in order to change the disease course. Conclusion Prospective studies should validate predictors of complicated disease and randomized studies in high-risk groups should be performed to answer if early introduction of immunomodulators or biological therapies slows down disease progression and alters natural history. [ABSTRACT FROM AUTHOR]

Background: An uncontrolled pilot study demonstrated that daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), might be effective for the treatment of active ulcerative colitis. Methods: A randomised, double blind, placebo controlled trial was conducted to evaluate the efficacy of daclizumab induction therapy in patients with active ulcerative colitis. A total of 159 patients with moderate ulcerative colitis were randomised to receive induction therapy with daclizumab 1 mg/kg intravenously at weeks 0 and 4, or 2 mg/kg intravenously at weeks 0, 2, 4, and 6, or placebo. The primary end point was induction of remission at week 8. Remission was defined as a Mayo score of 0 on both endoscopy and rectal bleeding components and a score of 0 or 1 on stool frequency and physician's global assessment components. Response was defined as a decrease from baseline in the Mayo score of at least 3 points. Results: Two per cent of patients receiving daclizumab 1 mg/kg (p = 0.11 v placebo) and 7% of patients receiving 2 mg/kg (p=0.73) were in remission at week 8, compared with 10% of those who received placebo. Response occurred at week 8 in 25% of patients receiving daclizumab 1 mg/kg (p=0.04) and in 33% of patients receiving 2 mg/kg (p=0.30) versus 44% of those receiving placebo. Daclizumab was well tolerated. The most frequently reported adverse events in daclizumab treated patients compared with placebo treated patients were nasopharyngitis (14.6%) and pyrexia (10.7%). Conclusion: Patients with moderate ulcerative colitis who are treated with daclizumab are not more likely to be in remission or response at eight weeks than patients treated with placebo. [ABSTRACT FROM AUTHOR]

Crohn's recurrence is the appearance of objective signs – defined radiologically, endoscopically or pathologically – of Crohn's disease in the bowel of a patient who has previously had a resection of all macroscopically diseased tissue. New lesions can be visualized endoscopically within weeks to months after ileal resection and ileocolonic anastomosis in the neoterminal ileum. The evolution of these lesions mimics the natural history of ileal Crohn's disease at the onset. If we are able to prevent recurrence of early lesions, we will probably interrupt the natural course of the disease. The drugs tested to date include different 5-aminosalicylate formulations, nitro-imidazole antibiotics, steroids and azathioprine. None of these therapies has convincingly been shown to prevent recurrent lesions. Metronidazole and ornidazole are effective, but cannot be used in the long-term because of side effects. Since there is a lag time of months to years between the development of recurrent lesions in the bowel and the recurrence of symptoms, we recommend performing imaging of the bowel 6 months after the operation to assess the severity of recurrence, and basing the further treatment strategy on this assessment. [ABSTRACT FROM AUTHOR]

Introduction: This study was designed to evaluate the safety of fontolizumab, a humanised anti-interferon y antibody, in patients with moderate to severe Crohn's disease (CD). Patients and methods: Forty five patients with a CD activity index (CDAI) of 250-450 were randomised in a double blind, placebo controlled, dose escalating fashion to receive single doses of fontolizumab (0.1, 1.0, and 4.0 mg/kg) or placebo. By day 29, patients with clinical response were re-randomised to receive three additional doses of one half their initial fontolizumab dose or placebo at four weekly intervals. Primary objectives were safety and tolerability. Secondary outcomes included assessments of immunogenicity, clinical activity, and potential pharmacodynamic surrogates. Results: Treatment was generally well tolerated. There were slightly more reports of chills, flu-like syndrome, asthenia, nausea, and vomiting in the 1.0 mg and 4.0 mg/kg fontolizumab cohorts. Two serious adverse events rated as worsening of CD occurred under fontolizumab. Antibodies to fontolizumab were confirmed in one patient. No differences in clinical activity parameters were noted between any of the active treatment groups and placebo, with the placebo group having a particularly favourable outcome (60% response and 40% remission). By day 29, a more enhanced decrease in median Crohn's disease endoscopic index of severity (p=0.02) and serum C reactive protein (p<0.001) was observed in the 4.0 mg/kg (n = 14) fontolizumab cohort compared with placebo (n = 10). Pharmacodynamic effects were observed by immunohistochemistry. Conclusions: Fontolizumab was well tolerated with minimal immunogenicity at doses of up to 4.0 mg/kg in patients with CD. A biological activity of fontolizumab is suggested. [ABSTRACT FROM AUTHOR]

Background Protein fermentation products, especially ammonia, are implicated in the pathogenesis of certain diseases. Aim To investigate the influence of lactulose and Saccharomyces boulardii cells on the composition of the intestinal microbiota and on the metabolic fate of ammonia by means of lactose-[15N, 15N]-ureide. Methods An at random, placebo-controlled, crossover study was performed in 43 healthy volunteers to evaluate the influence of lactulose and/or S. boulardii cells either administered as a single dose or after a 4-week intake period. Urine and faeces were collected. All samples were analysed for 15N-content by combustion-isotope ratio mass spectrometry . Real-time polymerase chain reaction was applied to determine the composition of the predominant faecal microbiota. Results A single administration of lactulose significantly decreased urinary 15N-excretion in a dose-dependent way. After long-term administration of lactulose, a significant reduction of the urinary 15N-excretion was observed, which was accompanied with a significant increase in the faecal 15N-output, more specifically more 15N was found in the bacterial fraction. A significant rise in the Bifidobacterium population was found after lactulose intake. No significant effects were observed after S. boulardii intake. Conclusion Dietary addition of lactulose can exert a bifidogenic effect accompanied by a favourable effect on the colonic NH3-metabolism. [ABSTRACT FROM AUTHOR]

Laboratory markers have been investigated in inflammatory bowel disease (IBD) for diagnostic and differential diagnostic purposes, for assessment of disease activity and risk of complications, for prediction of relapse, and for monitoring the effect of therapy. The introduction of biological therapies in IBD has renewed interest in inflammatory markers (especially C reactive protein (CRP)), given their potential to select responders to these treatments. Of all the laboratory markers, CRP is the most studied and has been shown to have the best overall performance. CRP is an objective marker of inflammation and correlates well with disease activity in Crohn's disease (CD). Increased CRP levels are associated with better response rates and normal CRP levels predict high placebo response rates in clinical trials with biologicals. However, despite the advantages of CRP over other markers, it is still far from ideal. Furthermore, CRP correlates less well with disease activity in patients with ulcerative colitis (UC) as compared with CD. Other laboratory markers, including erythrocyte sedimentation rate (ESR), leucocyte and platelet count, albumin, and α1 acid glycoprotein (orosomucoid), have been studied either less extensively in IBD or have proven to be less useful than CRP. Faecal markers seem promising and may be more specific in detecting gut inflammation in patients with established IBD. Promising results have been reported with the use of faecal calprotectin in CD as well as in UC. Recent data however suggest that the performance of the faecal calprotectin test is superior for UC than for CD. Taken together, laboratory markers are useful and should be part of the global management of our IBD patients. They are however not magic and until more data become available, the use of CRP and other laboratory markers should be seen as an additive tool to clinical observation and physical examination rather than a replacement. [ABSTRACT FROM AUTHOR]

Infliximab, the chimeric monoclonal IgG1 antibody to tumour necrosis factor, is indicated for refractory luminal and fistulizing Crohn's disease and extra-intestinal manifestations of inflammatory bowel disease. Recently, the active ulcerative colitis trials (ACT) studies have shown that infliximab is also efficacious to treat ulcerative colitis resistant to standard therapy. Induction with 5 mg/kg infliximab at weeks 0, 2 and 6 is advocated. The response to infliximab is improved when concomitant immunosuppressive therapy is given. As the majority of patients will relapse if not retreated, a long-term strategy is necessary. Although episodic therapy can be used, the optimal strategy is systematic maintenance treatment with 5 mg/kg intravenous (i.v.) every 8 weeks. Long-term maintenance therapy with infliximab results in a reduction of the rate of complications, hospitalizations and surgeries associated with Crohn's disease. Safety problems with the monoclonal antibody infliximab treatment mainly concern the formation of antibodies to infliximab, which may lead to infusion reactions, loss of response and serum sickness-like delayed infusion reactions. Latent tuberculosis needs to be screened for. The rate of other opportunistic infections is slightly increased mainly in patients treated concomitantly with immunosuppression. There is no evidence that malignancy rates in patients treated with antitumour necrosis factor strategies are increased. [ABSTRACT FROM AUTHOR]

4-1BB ligand (4-1BBL) expressed on antigen-presenting cells interacts with 4-1BB on activated T cells (especially CD8+ cells) and co-stimulates the latter to secrete cytokines and to proliferate. The role of 4-1BB−4-1BBL interaction was studied here in a model of colitis based on naive CD4+ T cell transfer to SCID mice, a disease model in which CD8 cells do not take part. We found that CD4+ T cells from 4-1BB-deficient mice, after transfer in SCID mice, proliferated more rapidly compared to wild-type CD4+ T cells. Mice reconstituted with naive CD4+ T cells from 4-1BB-deficient mice developed colitis, however, with a mixed Th1/Th2 response, in contrast to the Th1-type response in mice reconstituted with wild-type naive CD4+ T cells. Importantly, this altered cytokine response did not temper colitis severity. Although it has been reported previously that 4-1BB co-stimulation may contribute to regulatory T cell functioning, we found that CD4+CD25+ regulatory T cells from 4-1BB-deficient mice were perfectly able to prevent naive CD4+ T cell-induced colitis. In conclusion, our data provide evidence that 4-1BB−4-1BBL interaction modulates the effector CD4+ T cell-driven immune response and cytokine production in experimental colitis without affecting regulatory T cell function. [ABSTRACT FROM AUTHOR]