The Toronto IBD Global Endoscopic Reporting [TIGER] Score: A Single, Easy to Use Endoscopic Score for Both Crohn's Disease and Ulcerative Colitis Patients.

BACKGROUND AND AIMS: We constructed the Toronto IBD Global Endoscopic Reporting [TIGER] score for inflammatory bowel disease [IBD]. The aim of our study was to develop and validate the TIGER score against faecal calprotectin [FC], C-reactive protein [CRP], and IBD Disk. METHODS: A cross-sectional study was performed among 113 adult patients (60 Crohn's disease [CD] and 53 ulcerative colitis [UC]). In the development and usability phase, blinded IBD experts reviewed and graded ileocolonoscopy videos. In the validity phase the TIGER score was compared with: [1] the Simple endoscopic Score for CD [SES-CD] and the Mayo endoscopic score in CD and UC, respectively; [2] FC and CRP; and [3] IBD Disk. RESULTS: Inter-observer reliability of the TIGER score per segment between reviewers was excellent: interclass correlation coefficient [ICC] = 0.94 [95% CI: 0.92-0.96]. For CD patients, overall agreement per segment between SES-CD and TIGER was 91% [95% CI: 84-95] with kappa coefficient 0.77 [95% CI: 0.63-0.91]. There was a significant correlation between TIGER and CRP [p <0.0083], and TIGER and FC [p <0.0001]. In addition, there was significant correlation between TIGER and IBD Disk [p <0.0001]. For UC patients, overall agreement per segment between Mayo endoscopic score and TIGER was 84% [95% CI: 74%-90%] and kappa coefficient 0.60 [95% CI: 0.42-0.808]. There was a significant correlation between TIGER and FC [p <0.0001]. There was a significant correlation between TIGER and IBD Disk [p <0.0001]. CONCLUSIONS: The TIGER score is a reliable and simple novel endoscopic score that can be used for both CD and UC patients and captures full endoscopic disease burden.

Canadian association of gastroenterology clinical practice guideline for the management of Luminal Crohn's Disease

Crohn's disease (CD) is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. We provide guidance for treatment of ambulatory patients with mild to severe active luminal CD. We performed a systematic review to identify published studies of the management of CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent. Optimal management of CD requires careful patient assessment, acknowledgement of patient preferences, evidence-based use of existing therapies, and thorough assessment to define treatment success.

Higher Adalimumab Drug Levels are Associated with Mucosal Healing in Patients with Crohn's Disease.

BACKGROUND AND AIMS: The current approach to managing the loss of response to anti-tumour necrosis factor (TNF) agents is generally empirical. Prior studies have suggested that adalimumab levels of >4.9 µg/mL are required to achieve clinical remission. Our aim was to identify an optimal adalimumab level to achieve endoscopic healing in Crohn's disease (CD). METHODS: A cohort of 60 CD patients treated with adalimumab between 2005 and 2013 were reviewed for the study. Demographic and clinical information was obtained from chart review and patient interview. Disease activity was determined using the Harvey-Bradshaw index (HBI), ileocolonoscopy reports and C-reactive protein (CRP) levels. Clinical remission was defined as HBI <5. Endoscopic remission/mucosal healing (MH) was defined as the absence of any ulceration in all ileocolonic segments. Trough adalimumab levels and adalimumab antibody levels were tested using a liquid-phase mobility shift assay. RESULTS: Lower median CRP was significantly associated with MH 1.2mg/dl vs no MH 14.4mg/dl (p = 6.93×10(-6)). Higher adalimumab trough level was significantly associated with MH (median 14.7 µg/mL in those with MH vs 3.4 µg/mL in those without, p = 6.25×10(-5)). Higher adalimumab trough level was also significantly associated with the combined outcome of clinical and endoscopic remission (median 13.0 vs 4.8 µg/mL, p = 5.36×10(-3)). A cut-off of 8.14 µg/ml best discriminated subjects with MH from those without MH, with sensitivity and specificity of 91.4 and 76.0%, respectively (positive and negative predictive values 84.2 and 86.4%, respectively). CONCLUSIONS: Higher adalimumab levels were significantly associated with MH. This study suggests that attaining MH alone or a combined outcome of clinical and endoscopic remission is more likely to occur in those patients who achieve an adalimumab trough level of at least 8.14 µg/mL.

Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus

BACKGROUND & AIMS:: The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC. METHODS: A systematic literature search identified studies on the management of UC. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a working group of specialists. RESULTS: The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti-tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes. CONCLUSIONS: Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.(AU)

Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease.

BACKGROUND: Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy. AIM: The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed. METHODS: The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. RESULTS: Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. CONCLUSIONS: Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials.

Impact of Clostridium difficile colitis on 5-year health outcomes in patients with ulcerative colitis.

BACKGROUND: Clostridium difficile colitis (CDC) is associated with an increased short-term mortality risk in hospitalised ulcerative colitis (UC) patients. We sought to determine whether CDC also impacts long-term risks of adverse health events in this population. AIM: To determine whether CDC also impacts long-term risks of adverse health events in this population. METHODS: A population-based retrospective cohort study was conducted of UC patients hospitalised in Ontario, Canada between 2002 and 2008. Patients with and without CDC were compared on the rates of adverse health events. The primary outcomes were the 5-year adjusted risks of colectomy and death. RESULTS: Among 181 patients with CDC and 1835 patients without CDC, the 5-year cumulative colectomy rates were 44% and 33% (P = 0.0052) and the 5-year cumulative mortality rates were 27% and 14% (P < 0.0001) respectively. CDC was associated with a higher adjusted 5-year risk of mortality [adjusted hazard ratio (aHR) 2.40, 95% CI 1.37-4.20], but not of colectomy (aHR 1.18, 95% CI 0.90-1.54). CDC impacted mortality risk both during index hospitalisation (adjusted odds ratio 8.90, 95% CI 2.80-28.3) as well as over 5 years following hospital discharge among patients who recovered from their acute illness (aHR 2.41, 95% CI 1.37-4.22). Colectomy risk was not influenced by CDC in this cohort. CONCLUSION: Clostridium difficile colitis is associated with increased short-term and long-term mortality risks among hospitalised ulcerative colitis patients. As colectomy risk is not similarly impacted by Clostridium difficile colitis, factors predictive of death among C. difficile-infected ulcerative colitis patients require elucidation.

Relationship between social support and autonomic function during a stress protocol in ulcerative colitis patients in remission.

BACKGROUND: The relationship of psychological stress to relapse in ulcerative colitis (UC) is inconsistent. This may be due to a failure to identify patient characteristics, such as social support, which moderate the transduction of stress from the central nervous system to the immune system. In this study we tested the hypothesis that social support enhances parasympathetic modulation of heart rate in UC. METHODS: An indirect measure of autonomic function (heart rate variability; HRV) was measured in 108 patients with UC in remission during a standard protocol involving periods of stress, paced breathing, and relaxation. Social support was measured with the Social Support Questionnaire. RESULTS: After controlling for age, which is strongly related to HRV, both satisfaction with social support (F = 5.7, significance = 0.002) and its interaction with age (F = 7.8, significance <0.001) were associated with high-frequency HRV, which measures parasympathetic modulation of heart rate. Social support was associated with higher levels of high-frequency HRV at almost all points in the stress protocol. Neither age nor social support was associated with differences in the LF/HF ratio, which measures sympathetic modulation of heart rate. CONCLUSIONS: Social support is related to parasympathetic activity in UC. Given previous evidence of an antiinflammatory role for the parasympathetic nervous system, this suggests that autonomic function could serve as a mediating link between social support and reduced inflammatory activity.

Validating Crohn's disease activity indices for use in assessing postoperative recurrence.

BACKGROUND: The Crohn's Disease Activity Index (CDAI) has been used in medical trials with scores <150 indicative of remission. Its value in assessing postoperative recurrence is unknown. The objective of this study was to explore the utility of the CDAI in determining the presence or absence of symptomatic disease recurrence in patients having previously undergone ileocolic resection for Crohn's disease. METHODS: Ninety-three patients underwent clinical and colonoscopic evaluation within 12 months of ileocolic resection. Endoscopic appearance was assessed using the Rutgeerts score (i0-i4). Symptomatic disease recurrence was defined by the composite of symptom severity warranting therapy and an endoscopic score ≥ i2. CDAI scores were calculated. Comparisons were made using the receiver operator curve (ROC). RESULTS: Thirty-nine (42%) patients had recurrent disease (22% symptomatic, 20% endoscopic only) at 12 months. Median CDAI for symptomatic recurrence was 198 (interquartile range [IQR]: 106-293), 80 for asymptomatic subjects (IQR 35-115). The area under the ROC curve for symptomatic disease and CDAI was 0.78 (95% confidence interval [CI] 0.64-0.91). Recurrence was best predicted by a CDAI of ≥ 148 (sensitivity 70%, specificity 81%). A strong linear relationship existed between the CDAI and Inflammatory Bowel Disease Questionnaire (r = 0.82). CONCLUSIONS: The CDAI performs reasonably well in the postoperative setting and 150 appears the best cutpoint for indicating symptomatic disease. However, it is likely not suitable for use as the primary outcome measure. These data suggest that a combination of symptom assessment plus endoscopic evidence of recurrence should remain the gold standard definition for assessing outcomes in postoperative CD trials.

Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis.

BACKGROUND AND AIMS: Antibodies to infliximab reduce serum infliximab with loss of clinical benefit, but undetectable trough serum concentrations of infliximab may occur without antibody formation. The relationship between trough serum infliximab and clinical outcomes was evaluated in acute ulcerative colitis. METHODS: In a cohort of 115 patients with ulcerative colitis treated with three-dose induction followed by scheduled maintenance infliximab, rates of clinical remission, colectomy, antibodies to infliximab and trough serum infliximab were determined. RESULTS: Rates of remission were 32% at week 10 and 37% at week 54. Colectomy occurred in 40% of patients, at a median of 5.3 (IQR 1.9-12.1) months. Detectable trough serum infliximab was present in 39% of patients and, among patients with undetectable infliximab, 41% were antibody positive and 20% were antibody negative. For antibody-positive and antibody-negative patients, rates of remission (18% vs 14%), endoscopic improvement (25% vs 35%) and colectomy (52% vs 59%) were not different. A detectable serum infliximab was associated with higher rates of remission (69% vs 15%; p<0.001) and endoscopic improvement (76% vs 28%, p<0.001). An undetectable serum infliximab predicted an increased risk for colectomy (55% vs 7%, OR 9.3; 95% CI 2.9 to 29.9; p<0.001). Concurrent immunosuppression was not associated with clinical outcomes. CONCLUSIONS: For patients with ulcerative colitis treated with infliximab, a detectable trough serum infliximab predicts clinical remission, endoscopic improvement and a lower risk for colectomy. An undetectable trough serum infliximab, irrespective of antibody status, is associated with less favourable outcomes.

Detecting colorectal cancer by 1H magnetic resonance spectroscopy of fecal extracts.

Colorectal cancer is one of the most common cancers in the western world. Its early detection has been found to improve the prognosis of the patient, providing a wide window of opportunity for successful therapeutic interventions. However, current diagnostic techniques all have some limitations; there is a need to develop a better technique for routine screening purposes. We present a new methodology based on magnetic resonance spectroscopy of fecal extracts for the non-invasive detection of colorectal cancer. Five hundred twenty-three human subjects (412 with no colonic neoplasia and 111 with colorectal cancer, who were scheduled for colonoscopy or surgery) were recruited to donate a single sample of stool. One-dimensional (1)H magnetic resonance spectroscopy (MRS) experiments were performed on the supernatant of aqueous dispersions of the stool samples. Using a statistical classification strategy, several multivariate classifiers were developed. Applying the preprocessing, feature selection and classifier development stages of the Statistical Classification Strategy led to approximately 87% average balanced sensitivity and specificity for both training and monitoring sets, improving to approximately 92% when only crisp results, i.e. class assignment probabilities > or =75%, are considered. These results indicate that (1)H magnetic resonance spectroscopy of human fecal extracts, combined with appropriate data analysis methodology, has the potential to detect colorectal neoplasia accurately and reliably, and could be a useful addition to the current screening tools.

MAST3: a novel IBD risk factor that modulates TLR4 signaling.

Inflammatory bowel disease (IBD) is a chronic disorder caused by multiple factors in a genetically susceptible host. Significant advances in the study of genetic susceptibility have highlighted the importance of the innate immune system in this disease. We previously completed a genome-wide linkage study and found a significant locus (IBD6) on chromosome 19p. We were interested in identifying the causal variant in IBD6. We performed a two-stage association mapping study. In stage 1, 1530 single-nucleotide polymorphisms (SNPs) were selected from the HapMap database and genotyped in 761 patients with IBD. Among the SNPs that passed the threshold for replication, 26 were successfully genotyped in 754 additional patients (stage 2). One intronic variant, rs273506, located in the microtubule-associated serine/threonine-protein kinase gene-3 (MAST3), was found to be associated in both stages (pooled P=1.8 x 10(-4)). We identified four MAST3 coding variants, including a non-synonymous SNP rs8108738, correlated to rs273506 and associated with IBD. To test whether MAST3 was expressed in cells of interest, we performed expression assays, which showed abundant expression of MAST3 in antigen-presenting cells and in lymphocytes. The knockdown of MAST3 specifically decreased Toll-like receptor-4-dependent NF-kappaB activity. Our findings are additional proofs of the pivotal role played by modulators of NF-kappaB activity in IBD pathogenesis.

Traditional corticosteroids for induction of remission in Crohn's disease.

BACKGROUND: Historically, corticosteroids have been the most commonly used class of medication for induction of remission in Crohn's disease (CD). Corticosteroids down regulate production of inflammatory cytokines and interfere with NF-kappaB production, thereby blunting inflammatory response. OBJECTIVES: The primary objective was to systematically review the efficacy and safety of traditional corticosteroids (given orally or intravenously) for induction of remission in CD. SEARCH STRATEGY: The following electronic databases were searched: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders (IBD/FBD) Group Specialized Trial Register, and ClinicalTrials.gov. No language restrictions were applied. Reference lists of trials and review articles, as well as recent proceedings from major gastroenterology meetings were manually searched. SELECTION CRITERIA: Randomized, controlled clinical trials of traditional, systemic corticosteroids for the induction of remission of active CD were included in this review. Control groups included patients receiving either placebo or 5-aminosalicylates (5-ASA). The study population included patients of any age with active CD (as defined by the study authors or validated clinical activity indices), receiving any formulation of systemically available corticosteroid by any oral or parenteral methods of delivery. The primary outcome was induction of remission of CD. Secondary outcomes included clinical response, change in mean CDAI, adverse events and the proportion of patients withdrawing due to adverse events. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality using Jadad's criteria. A random or fixed effects model was chosen based on an assessment of heterogeneity, and studies were weighted using the DerSimonian & Laird or the Mantel-Haenszel method accordingly. Meta-analysis was performed using RevMan 4.2.10 software. MAIN RESULTS: Two studies compared corticosteroids to placebo and six studies compared corticosteroids to 5-ASA. Corticosteroids were found to be significantly more effective than placebo at inducing remission in CD (RR 1.99; 95% CI 1.51 to 2.64; P < 0.00001). Corticosteroids were found to be more effective than 5-ASA at inducing remission in studies with long follow-up duration (i.e. > 15 weeks; RR 1.65; 95% CI 1.33 to 2.03; P < 0.00001). Corticosteroids induced adverse events in a higher proportion of patients than placebo (RR 4.89; 95% CI 1.98 to 12.07; P = 0.0006), or low-dose 5-ASA (RR 2.38; 95% CI 1.34 to 4.25; P = 0.003). No difference existed in the proportion of patients experiencing adverse events when steroids were compared to high-dose 5-ASA. Steroids did not induce more study withdrawals due to adverse events than either placebo or 5-ASA. AUTHORS' CONCLUSIONS: Corticosteroids are effective for induction of remission in patients with CD, particularly when used for more than 15 weeks. Although corticosteroids cause more adverse events than either placebo or low-dose 5-ASA, these adverse events did not lead to increased study withdrawal in the included studies. Further information is required to determine the optimal duration of treatment and tapering protocol to maximize the efficacy of treatment with corticosteroids. Additionally, further study is required to determine whether corticosteroids are more effective in patients with certain phenotypes or when administered intravenously.

An SNP linkage scan identifies significant Crohn's disease loci on chromosomes 13q13.3 and, in Jewish families, on 1p35.2 and 3q29.

Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.

Severe paediatric ulcerative colitis: incidence, outcomes and optimal timing for second-line therapy.

BACKGROUND: Despite the predominance of extensive disease in children with ulcerative colitis, data concerning severe paediatric ulcerative colitis are sparse. We reviewed rates and predictors of response to intravenous-corticosteroid therapy in a single-centre cohort with long-term follow-up. METHODS: 99 children (49% males; age 2-17 years) were hospitalised (1991-2000) for treatment of severe ulcerative colitis (90% extensive; 49% new onset ulcerative colitis). Clinical, laboratory and radiographic data were reviewed. A population-based subset was used to assess incidence. Predictors of corticosteroid response were analysed using univariate and multivariate analyses at days 3 and 5 of therapy. Colectomy rates were calculated using Kaplan-Meier survival analyses. RESULTS: 28% (95% CI, 23 to 34%) of children with ulcerative colitis resident in the Greater Toronto Area required admission for intravenous corticosteroid therapy, of whom 53 (53%; 95% CI, 44 to 63%) responded. Several predictors were associated with corticosteroid failure, but in multivariable modelling only C-reactive protein [OR = 3.5 (1.4 to 8.4)] and number of nocturnal stools [OR = 3.2 (1.6 to 6.6)] remained significant at both days 3 and 5. The Pediatric Ulcerative Colitis Activity Index (PUCAI), Travis and Lindgren's indices strongly predicted non-response. Radiographically, the upper range of colonic luminal width was 40 mm in children younger than 11 years versus 60 mm in older patients. Cumulative colectomy rates at discharge, 1 year and 6 years were 42%, 58% and 61%, respectively. CONCLUSIONS: Children with ulcerative colitis commonly experience at least one severe exacerbation. Response to intravenous corticosteroids is poor. The PUCAI, determined at day 3 (>45 points) should be used to screen for patients likely to fail corticosteroids and at day 5 (>70 points) to dictate the introduction of second-line therapies.

Omega 3 fatty acids (fish oil) for maintenance of remission in ulcerative colitis.

BACKGROUND: Omega-3 fatty acids (n-3, fish oil) have been shown to have anti-inflammatory properties. Therefore, n-3 therapy may be beneficial in chronic inflammatory disorders such as ulcerative colitis. OBJECTIVES: To systematically review the efficacy and safety of n-3 for maintaining remission in ulcerative colitis (UC). SEARCH STRATEGY: The following databases were searched from their inception without language restriction: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Healthstar, PubMed, and ACP journal club. Experts were contacted for unpublished data. SELECTION CRITERIA: Randomized placebo-controlled trials (RCT) of fish oil for maintenance of remission in UC were included. Studies must have enrolled patients (of any age group) who were in remission at the time of recruitment, and were followed for at least six months. The intervention must have been fish oil given in pre-defined dosage. Co-interventions were allowed only if they were balanced between the study groups. The primary outcome was relapse rate and the secondary outcome was frequency of adverse events. Other outcomes to assess efficacy were change in disease activity scores and time to first relapse. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality. Meta-analysis weighted by the Mantel-Haenszel method was performed using RevMan 4.2.8 software. Random or fixed effect models were used according to degree of heterogeneity and subgroup analyses were performed to explore heterogeneity. A sensitivity analysis was performed excluding a study of questionable quality . MAIN RESULTS: The three studies that were included used different formulation and dosing of n-3 but none used enteric coated capsules. The pooled analysis showed a similar relapse rate in the n-3 treated patients and controls (RR 1.02; 95% CI 0.51 to 2.03; P = 0.96). Combining the studies resulted in virtually no statistical heterogeneity (P = 0.93, I(2) = 0%). Various subgroup and sensitivity analyses showed similar results. However, the total number of patients enrolled in these studies was small (n = 138). No significant adverse events were recorded in any of the studies and not enough data were available to pool the other secondary outcomes for meta-analysis. AUTHORS' CONCLUSIONS: No evidence was found that supports the use of omega 3 fatty acids for maintenance of remission in UC. Further studies using enteric coated capsules may be justified.

Systematic review: the potential influence of mesalazine formulation on maintenance of remission in Crohn's disease.

AIM: To evaluate the effectiveness of pH 6-/pH 7-dependent and controlled-release mesalazines in maintaining medically and surgically induced Crohn's disease remission. METHODS: A systematic search identified 13 randomized controlled trials (RCTs). The rate of symptomatic relapse (Crohn's disease activity index >150, or an increase in baseline by at least 60-100 points) was extracted from each randomized controlled trial. Pooled odds ratios (OR), the number needed to treat (NNT), and percentage therapeutic benefit (absolute risk reduction) were calculated. RESULTS: Treatment with pH 7-dependent mesalazine significantly reduced the risk of relapse in patients with either surgically [OR 0.28; 95% confidence interval (CI) 0.12-0.65; P = 0.0032] or medically induced remission (OR 0.38; 95% CI 0.17-0.85; P = 0.0113). However, treatment with controlled-release mesalazine and pH 6-dependent mesalazine failed to show any significant advantage over placebo. The NNT to maintain surgically or medically induced remission was lowest for pH 7-dependent mesalazine (NNT = 4 and 5, respectively; NNT = 15 and 16 for controlled-release mesalazine and NNT = 11 and 23 for pH 6-dependent mesalazine). Therapeutic benefit was highest for pH 7-dependent mesalazine (surgical = 30.6%, medical = 22.8%). This compared with 6.9% (surgical) and 6.4% (medical) for controlled-release mesalazine, and 9.8% and 4.4%, respectively, for pH 6-dependent mesalazine. CONCLUSION: Further trials of pH 7-dependent mesalazine formulations are warranted in the maintenance of remission in Crohn's disease.

The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases.

The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.

Budesonide for induction of remission in Crohn's disease.

BACKGROUND: Corticosteroids continue to play a central role in induction of remission in active Crohn's disease. However, their use comes at a price of significant adverse effects when used repeatedly or for extended periods. Newer corticosteroid agents with limited systemic bioavailability offer a tantalizing option, if they can be shown to be efficacious and safer than conventional corticosteroids. Budesonide is the main alternative corticosteroid currently available in an enteric formulation. OBJECTIVES: To evaluate the effectiveness of oral budesonide for the treatment of acute flares of Crohn's disease. A secondary but important endpoint was to evaluate the adverse effect profile. SEARCH STRATEGY: The following sources were used to search the literature for potentially relevant papers and trials. 1. A computer-assisted search of the on-line bibliographic database MEDLINE from 1986 onwards. 2. Hand searching the reference lists of trials and review articles identified by means of the computer- assisted search. 3. Proceedings from major gastrointestinal meetings were manually searched from 1990 onwards. 4. Contact with the relevant pharmaceutical companies that have been involved in the development of budesonide. SELECTION CRITERIA: Potentially relevant articles were reviewed in an independent unblinded fashion by two authors to determine if they met the criteria specified below: 1) STUDY POPULATION: Patients of any age with acutely active Crohn's disease, as defined by a CDAI > 150. 2) METHODOLOGY: Randomized double blind controlled trials comparing budesonide to a control treatment. Patients in the control arm may have received placebo, conventional corticosteroids, 5-aminosalicylic acid or sulfasalazine. 3) OUTCOME MEASURES: Clinical remission was the outcome measure of interest. The definition of remission was usually a CDAI < 150 by 8 to 16 weeks of therapy. DATA COLLECTION AND ANALYSIS: Eligible articles were reviewed in duplicate and the results of the primary research trials were abstracted onto specially designed data extraction forms. The proportion of patients achieving remission in the active treatment and control groups of each study were derived from the data provided in the original research papers. Where possible, data were broken down based on site of disease or other strata used by the individual trials. STATISTICAL ANALYSIS: Data extracted from the original research articles were converted, where necessary, into individual 2 x 2 tables (remission versus no remission x budesonide versus control) for each of the individual studies. Where available, individual 2 x 2 tables for strata within studies were also used. The presence of significant heterogeneity among studies was tested for using the chi-square test. Because this is a relatively insensitive test for the presence of heterogeneity, a p-value of 0.10 was regarded as statistically significant. Where p < 0.10 the data from the individual studies were still combined but the pooled results were interpreted with caution. The 2 x 2 tables were synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel. A fixed effects model was used for the pooling of data. The analysis was performed initially by combining data from all trials to estimate the response rate to budesonide therapy. The analysis was also performed by combining only studies with comparable control groups. MAIN RESULTS: Eight studies were deemed eligible for review. EFFICACY: Budesonide was superior to placebo for induction of remission with a pooled odds ratio for the two placebo-controlled trials of 2.85 (95% CI 1.67 - 4.87). A single trial comparing budesonide with mesalamine demonstrated an odds ratio of 2.80 (95% CI 1.50 - 5.20) in favour of budesonide over mesalamine for induction of remission in active Crohn's disease. However, budesonide was inferior to conventional corticosteroids (prednisone or prednisolone) for induction of remission with a pooled odds ratio for the five trials of 0.69 (95% CI 0.51 - 0.95). SAFETY: The two trials comparing budesonide versus placebo (Greenberg 1994; Tremaine 2002) showed no difference between study groups for proportion of reported corticosteroid-related adverse effects with the pooled odds ratio for both trials of 0.98 (95% CI 0.58 - 1.67). Five trials comparing budesonide versus prednisone showed the budesonide study group had fewer reported corticosteroid-related adverse effects than the prednisone study group (pooled odds ratio was 0.38 (95% CI 0.28 - 0.53). AUTHORS' CONCLUSIONS: With disease in the ileum or ascending colon, budesonide offers an effective therapy which is somewhat less efficacious but with fewer adverse effects than conventional corticosteroids (e.g. prednisone, prednisolone, or 6-methylprednisolone).

Corticosteroids for maintenance of remission in Crohn's disease.

BACKGROUND: The efficacy of corticosteroids in the setting of maintenance therapy for Crohn's disease has never been clearly demonstrated. It would be important to determine, based upon the currently available data from controlled trials, if the use of chronic corticosteroid therapy is of benefit in patients with quiescent Crohn's disease or if there is an identifiable subgroup of Crohn's disease patients, such as those in whom therapy cannot be successfully tapered, who might benefit from such treatment. OBJECTIVES: To evaluate the effectiveness and safety of conventional systemic corticosteroid therapy in maintaining clinical remission in Crohn's disease. SEARCH STRATEGY: A computer-assisted search of the on-line bibliographic database MEDLINE of studies published in English, French, Spanish, Italian and German between 1966 and July, 2003. Manual searches of the reference lists from the potentially relevant studies were performed in order to identify additional studies that may have been missed using the computer-assisted search strategy. Proceedings from major gastrointestinal meetings were also manually searched from 1985 to 2003 in order to identify unpublished studies. The Cochrane Central Register of Controlled Trials and the Inflammatory Bowel Disease Review Group Specialized Trials Register were also searched. SELECTION CRITERIA: Randomized double-blind placebo-controlled trials involving patients of any age with Crohn's disease in clinical remission as defined by a CDAI < 150 or by the presence of no symptoms or only mild symptoms at the time of entry into the trial. The experimental treatment consisted of oral conventional corticosteroid therapy (excluding budesonide, fluticasone, etc). Clinical disease relapse was used as the outcome measure of interest. DATA COLLECTION AND ANALYSIS: Eligible studies were selected by 4 reviewers and data were extracted onto standardized data extraction forms. Disagreements in eligibility or data extraction were resolved by consensus. Data were converted into individual 2x2 tables for each study. The presence of significant heterogeneity among studies was tested using the chi-square test. The 2x2 tables were synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel (the 'odds ratio' in MetaView). A fixed effects model was used for the pooling of data. MAIN RESULTS: Four studies were initially judged as being eligible for inclusion. After obtaining additional information on one of the studies it was excluded because it was not double-blind. The total number of subjects included in the analysis at the time points of 6, 12 and 24 months were 142, 131 and 95 for the corticosteroid group and 161, 138 and 87 for the control group. The odds ratios for relapse on active treatment and the corresponding 95% confidence intervals were 0.71 (0.39, 1.31), 0.82 (0.47, 1.43) and 0.72 (0.38, 1.35) at 6, 12 and 24 months. REVIEWER'S CONCLUSIONS: The use of conventional systemic corticosteroids in patients with clinically quiescent Crohn's disease does not appear to reduce the risk of relapse over a 24 month period of follow-up. This review updates the existing review of corticosteroids for maintaining remission of Crohn's disease which was published in the Cochrane Library (Issue 2, 2003).