The prognostic power of the NOD2 genotype for complicated Crohn's disease: a meta-analysis.

OBJECTIVES: Crohn's disease is often purely inflammatory at presentation, but most patients develop strictures and fistulae over time (complicated disease). Many studies have suggested that nucleotide-binding oligomerization domain 2 (NOD2) mutations are associated with a varying but increased risk of complicated disease. An accurate and sufficiently powerful predictor of complicated disease could justify the early use of biological therapy in high-risk individuals. We performed a systematic review and meta-analysis to obtain accurate estimates of the predictive power of the identified mutations (such as p.R702W, P.G908R, and p.Leu1007fsX1008) in NOD2 for the risk of complicated disease. METHODS: An electronic search of MEDLINE, Embase, and Web of Science identified 917 relevant papers. Inclusion required specification of genetic mutations at the individual level and disease phenotypes by Vienna classification (inflammatory (B1), stricturing (B2), and fistulizing (B3)). A total of 49 studies met these criteria, which included 8,893 subjects, 2,897 of whom had NOD2 mutations. Studies were weighted by median disease duration. Studies not providing duration data were weighted at the level of the study with the shortest disease duration (3.9 years). RESULTS: The relative risk (RR) of the presence of any NOD2 mutant allele for complicated disease (B2 or B3) was 1.17 (95% confidence interval (95% CI) 1.10-1.24; P<0.001). P.G908R was associated with an RR of complicated disease of 1.33 (95% CI 1.11-1.60; P=0.002). NOD2 did not predict perianal disease (P=0.4). The RR of surgery was 1.58 (95% CI 1.38-1.80; P<0.001). There was substantial heterogeneity across all studies (I(2)=66.7%). On the basis of logistic regression of these data, the sensitivity of any mutation in predicting complicated disease was 36% and specificity was 73%, with the area under the receiver operating characteristic curve 0.56. CONCLUSIONS: The presence of a single NOD2 mutation predicted an 8% increase in the risk for complicated disease (B2 or B3), and a 41% increase with 2 mutations. Surgery risk is increased by 58% with any NOD2 mutation, whereas perianal disease was unchanged. The predictive power associated with a single NOD2 mutation is weak. The RR of any NOD2 mutations for complicated disease was only 17% across 36 studies. However, the presence of two NOD2 mutations had 98% specificity for complicated disease. These data provide insufficient evidence to support top-down therapy based solely on single NOD2 mutations, but suggest that targeted early-intensive therapy for high-risk patients with two NOD2 mutations might be beneficial, if prospective trials can demonstrate changes in the natural history in this subset of patients.

Voting With their Feet (VWF) endpoint: a meta-analysis of an alternative endpoint in clinical trials, using 5-ASA induction studies in ulcerative colitis.

BACKGROUND: Strict clinical remission endpoints in ulcerative colitis (UC) trials produce low remission rates and do not reflect the good outcomes of UC therapy. We proposed the use of the VWF (Voting With their Feet) endpoint, the percentage of subjects leaving a randomized controlled trial (RCT) arm for lack of efficacy). The aims were 1) to determine if the VWF endpoint can be extracted from 5-aminosalicylate (5-ASA) RCTs in UC; 2) to perform meta-analyses of VWF and clinical remission (CR) endpoints; and 3) to determine the statistical power of the VWF endpoint. METHODS: Fixed effects meta-analysis and power calculations were used. RESULTS: In 5 studies, including 1048 subjects, 9.5% of patients left 5-ASA study arms for lack of efficacy, versus 28.3% leaving placebo. The rate of failure to achieve CR was 68.2% with 5-ASA, versus 86.9% with placebo. The relative risk (RR) of treatment failure for 5-ASA using the VWF endpoint was 0.33 (95% confidence interval [CI] 0.24-0.44), which was significantly smaller than with the CR endpoint (RR 0.81, 95% CI 0.76-0.88). The statistical power of VWF was slightly greater than CR. CONCLUSIONS: VWF is inexpensive, intuitive, and has similar statistical power to CR. The VWF endpoint can confirm the validity of outcome measures in clinical trials, and estimate real-world clinical efficacy.

Noninvasive ultrasound elasticity imaging (UEI) of Crohn's disease: animal model.

Inflammation occurs in episodic flares in Crohn's disease, which are part of the waxing and waning course of the disease. Healing between flares allows the intestine to reconstitute its epithelium, but this healing results in the deposition of fibrotic scar tissue as part of the healing process. Repeated cycles of flares and healing often lead to clinically significant fibrosis and stenosis of the intestine. Patients are treated empirically with steroids, with their many side effects, in the hope that they will respond. Many patients would be better treated with surgery if we could identify which patients truly have intestinal fibrosis. Ultrasound elasticity imaging (UEI) offers the potential to radically improve the diagnosis and management of local tissue elastic property, particularly intestinal fibrosis. This method allows complete characterization of local intestine tissue with high spatial resolution. The feasibility of UEI on Crohn's disease is demonstrated by directly applying this technique to an animal model of inflammatory bowel disease (IBD). Five female Lewis rats (150-180g) were prepared with phosphate buffered solution (PBS) as a control group and six were prepared with repeated intrarectal administration of trinitrobenzenesulfonic acid (TNBS) as a disease group. Preliminary strain measurements differentiate the diseased colons from the normal colons (p < 0.0002) and compared well with direct mechanical measurements and histology (p < 0.0005). UEI provides a simple and accurate assessment of local severity of fibrosis. The preliminary results on an animal model also suggest the feasibility of translating this imaging technique directly to human subjects for both diagnosis and monitoring.