Yoav Mazor

Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis.

Infliximab is effective as salvage therapy for patients with steroid refractory acute severe ulcerative colitis (UC). Although current data suggest that the pharmacokinetics of infliximab are influenced by inflammatory burden in patients with acute severe UC, data comparing infliximab trough levels in patients with acute severe UC vs. moderately severe UC are scarce.

Risk Factors for Serious Adverse Effects of Thiopurines in Patients with Crohn’s Disease

PURPOSE Thiopurines are effective in attaining and maintaining remission in patients with inflammatory bowel diseases (IBD). The major drawback of these drugs are their serious adverse effects (SAE), highlighting the importance of preemptive identification of patients at risk. We aimed to examine whether gene polymorphisms in GSTM1, GSTT1 and TPMT, combined with various clinical parameters, can predict thiopurine induced SAE. METHODS A retrospective cohort of 176 Crohns Disease (CD) patients treated with thiopurines (131 with 6MP and 45 with azathioprine) was genotyped for common polymorphisms in GSTM1, GSTT1 and TPMT. Clinical data including SAE, age, ethnicity, gender and smoking status were extracted from patient charts. SAEs evaluated were myelosuppression, hepatotoxicity and pancreatitis. Associations between demographic, clinical, and genetic variables and thiopurine induced SAE were assessed. RESULTS Twenty-four patients (14%) developed SAE, revealing a significant association between thiopurine induced SAE and GSTM1-null genotype (P=0.05), older age (P=0.016) and active smoking status (P=0.043) and SAE. On multi-variant analysis, past or current smokers were at increased risk for developing thiopurine related SAE (OR 2.915, CI 95%: 1.199- 7.084), specifically pancreatitis (p<0.001). No association was found between TPMT or GSTT1 polymorphisms and the development of SAE. CONCLUSIONS Active smoking and GSTM1-null genotype appear to be risk factors for thiopurine induced SAEs (i.e. myelosuppression, hepatotoxicity and pancreatitis) in patients with CD. Corroboration of these associations in larger cohorts is warranted.

Prediction of disease complication occurrence in Crohn's disease using phenotype and genotype parameters at diagnosis.

BACKGROUND AND AIMS Complications associated with Crohns disease (CD) are common and influence treatment decisions and outcomes. Appropriate early treatment may offer a therapeutic advantage to patients. The aim of our study was to indentify predictive factors for occurrence of complications at the time of CD diagnosis. METHODS The study population consisted of 269 CD patients treated during a ten year period. Risk factors compared between complicated and non-complicated disease included phenotypical characteristics, disease classification and the presence of NOD2/CARD15 mutations and single nucleotide polymorphisms in selected autophagy and phagosome genes. RESULTS Complete data was obtained for 146 patients with an average follow up of 12years. Sixty five patients (44%) developed a complication during follow up. The only independent risk factors associated with developing a complication were smoking and male gender. There was no association between developing complications and the presence of selected SNPs (P=0.07 for Tyrosine residue on both alleles in NCF4 SNP rs4821544 and P=0.06 for a Guanine residue on both alleles in ATG16L SNP rs2241880). Multivariate analysis using a backwards logistic regression model left only male gender as an independent statistically significant association with complicated disease (OR 2.6017, 95% CI: 1.17 to 5.75). The median time to developing a complication was 4years, and the most common complication was the need for surgical intervention (54%). CONCLUSIONS In the present study, a risk factor for developing CD complication was male gender. Further studies are warranted to assess additional risk factors and how such findings should affect therapy.

Granulomas in Crohn's disease: Are newly discovered genetic variants involved?

BACKGROUND Non-caseating granulomas exist in a substantial portion of patients with Crohns disease (CD). Several single nucleotide polymorphisms (SNPs) have been identified as a having strong association with CD, including SNPs within the autophagy related 4 homolog A (ATG4A) gene and the neutrophil cytosolic factor 4 (NCF4) gene. We hypothesized a possible association between the presence of granulomas in CD patients and variants in the ATG4A and NCF4 genes. AIMS To investigate whether variants in the NCF4 and ATG4A genes are associated with granuloma formation in a cohort of Israeli patients with CD, exploring demographic and clinical characteristics that differ between granuloma positive and granuloma negative patients. METHODS 307 Israeli patients with CD were studied. Patients with CD who underwent biopsy or resection of the intestine were classified according to presence or absence of granulomas. Using PCR-RFLP we determined the allele frequency in SNP rs4821544 (NCF4 gene) and SNP rs807185 (ATG4A gene) for all patients. RESULTS Granulomas were found in 85 out of 307 CD patients (27%). There were no significant differences between patients with or without granulomas in allele frequency in SNPs rs4821544 and rs807185. CD Patients with granuloma were younger at diagnosis than patients without granuloma (mean age 19 vs. 27, respectively, P<0.0001) and were more likely to undergo surgery (55.3% vs. 34.8%, respectively, P=0.002). CONCLUSIONS No association was found between SNPs rs4821544 and rs807185 and the presence of granulomas in CD patients. Granuloma positive patients were more likely to be younger and to undergo surgery.

Su1121 Anti-TNF and Anti-Drug Antibodies Levels Predict the Outcomes of Interventions After Loss of Response to Adalimumab and Infliximab

Background: Anti-TNFalpha agents are commonly used for ulcerative colitis (UC) therapy in the event of non-response to conventional strategies or as colon-salvaging therapy. The objectives were to assess the appropriateness of biological therapies for UC patients and to study treatment discontinuation over time, according to appropriateness of treatment, as a measure of outcome. Methods: We selected adult ulcerative colitis patients from the Swiss IBD cohort who had been treated with anti-TNFalpha agents. Appropriateness of the firstline anti-TNFalpha treatment was assessed using detailed criteria developed during the European Panel on the Appropriateness of Therapy for UC. Treatment discontinuation as an outcome was assessed for categories of appropriateness. Results: Appropriateness of the first-line biological treatment was determined in 186 UC patients. For 64% of them, this treatment was considered appropriate. During follow-up, 37% of all patients discontinued biological treatment, 17% specifically because of failure. Time-to-failure of treatment was significantly different among patients on an appropriate biological treatment compared to those for whom the treatment was considered not appropriate (p=0.0007). Discontinuation rate after 2 years was 26% compared to 54% between those two groups. Patients on inappropriate biological treatment were more likely to have severe disease, concomitant steroids and/or immunomodulators. They were also consistently more likely to suffer a failure of efficacy and to stop therapy during follow-up. Conclusion: Appropriateness of first-line anti-TNFalpha therapy results in a greater likelihood of continuing with the therapy. In situations where biological treatment is uncertain or inappropriate, physicians should consider other options instead of prescribing anti-TNFalpha agents.

Early histological findings may predict the clinical phenotype in Crohn’s colitis

Background and aims Predicting the clinical course of Crohn’s disease (CD) is relevant for treatment selection. Currently, such diagnostic tools are lacking. In a previous pilot study, morphometric tissue image analysis showed promise in predicting the clinical phenotype and need for surgery. In this study, we aimed to validate our previous results on a larger cohort. Methods Colonic biopsies from CD patients with colonic or ileocolonic disease and at least five years of post-biopsy clinical follow-up were analyzed. The results were used to predict post-biopsy clinical phenotypes and outcomes. Data analysis was performed using multivariate regression models, discriminant score (DS) computations and Neural Network (NNET). Results Multivariate analysis of morphometric variables differentiated between B1 and B2 phenotypes (sensitivity 81%, specificity 74%, accuracy on cross-validation 75%; area under the curve (AUC) of 0.74 (CI 0.6–0.84; NNET model sensitivity 87%, specificity 67% on the testing population)). Differentiation between B1 and B3 phenotypes was also possible (sensitivity 69%, specificity 76%, accuracy 70.5% on cross-validation; AUC 0.78 (CI 0.68–0.89); NNET model sensitivity 78%, specificity 77% on the testing population)). Differentiating between B2 and B3 phenotypes was not possible using morphometric variables. Multivariate analysis predicted surgery (sensitivity 67%, specificity 72.5%, accuracy 69%; AUC 0.72 (CI 0.61–0.82); NNET model sensitivity 80%, specificity 91% on the testing population)). Conclusions This study validates previous results and suggests that morphometric image analysis of early biopsies from Crohn’s colitis patients may contribute to the prediction of future outcomes such as clinical phenotype and surgery. Prospective validation on larger cohorts is still needed.

Su1303 Early Histological Findings May Predict the Clinical Phenotype in Crohn's Colitis

Background: The clinical course of Crohns disease (CD) is variable and relevant for treatment selection. Early aggressive treatment may change disease course, but should be balanced with safety considerations. Currently, diagnostic tools for prediction of disease phenotype and complications are lacking. Histomorphometric analysis allows for quantitative measurements of size, shapes and orientation of cells and structures in tissues. In a previous pilot study, we were able to show that morphometric analysis may contribute to the prediction of the clinical phenotype and surgery in patients with Crohns colitis. Aim: To further evaluated and validate the histomorphometric features of early colonic biopsies from patients with Crohns colitis and their relationship to evolving clinical phenotypes. Methods: Colonic biopsies from 100 CD patients classified according to the Montreal classification with at least 5 years post biopsy follow up were analyzed. The results were used to predict post biopsy clinical phenotypes and outcomes. Data analysis was performed using multivariate regression models, discriminant score (DS) computations and Neural Network (NNET). Results: Multivariate analysis differentiated between B1 and B2 phenotypes (sensitivity-81%, specificity-74%, accuracy on cross validation-75%). ROC analysis of the discriminant score (DS) yielded an area under the curve (AUC) of 0.74 (CI 0.6-0.84). A NNET model also differentiated between B1and B2 phenotypes (sensitivity87%, specificity-67% on the testing population). Differentiation between B1 and B3 phenotypes, had a sensitivity of 69% and a specificity of 76% with an accuracy of 70.5% on cross validation. ROC analysis of the DS