Matti Waterman

Addition of an Immunomodulator to Infliximab Therapy Eliminates Antidrug Antibodies in Serum and Restores Clinical Response of Patients With Inflammatory Bowel Disease

There are few therapeutic options for patients with inflammatory bowel disease who lose response to infliximab because they produced antibodies against the drug. We performed a retrospective analysis to investigate whether administration of immune modulators to 5 patients who developed antibodies to infliximab (ATI) restored response to this drug; 3 patients were given azathioprine/6-mercaptopurine and 2 patients were given methotrexate. Concentrations of infliximab and ATIs, and antitumor necrosis factor (TNF) activity, were analyzed using enzyme-linked immunosorbent assay-based competition assays of serum samples collected before and after patients were given the immunomodulator. In all patients, levels of ATIs gradually decreased and trough levels of infliximab increased; clinical responses were restored to all patients. In competition assays, immunomodulator-induced elimination of ATIs was associated with increased anti-TNF activity in serum. The addition of immunomodulators to therapy might be helpful to patients who have lost response to anti-TNF agents owing to formation of antidrug antibodies.

Adalimumab drug and antibody levels as predictors of clinical and laboratory response in patients with Crohn's disease

Adalimumab is an effective treatment for Crohns disease (CD). Anti‐adalimumab antibodies (AAA) and low trough serum drug concentrations have been implicated as pre‐disposing factors for treatment failure.

A genome-wide scan of ashkenazi jewish crohn's disease suggests novel susceptibility loci

Crohns disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD–susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2–4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10−6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10−8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10−9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10−8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10−8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10−9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.

Distinct and overlapping genetic loci in Crohn's disease and ulcerative colitis: correlations with pathogenesis.

Background: A common genotypic basis for ulcerative colitis (UC) and Crohns disease (CD) is implied by overlapping clinical characteristics, epidemiological studies, and association of genes with both UC and CD. We evaluated the overlap between CD and UC genetic loci stratified by pathogenetic pathways and by disease location. Methods: The allele frequencies of six UC‐associated and 34 CD‐associated single nucleotide polymorphisms (SNPs) were determined in a Canadian IBD cohort (n = 2374). Differences between CD, UC, colon‐only CD, ileal CD, and controls were analyzed controlling for ethnicity, age of diagnosis, and gender. Results: In all, 21 of 34 CD‐associated SNPs had similar allele frequencies in UC (n = 1230) and CD (n = 1144). Three of six UC‐associated SNPs had significantly different frequencies in CD (n = 1144). Most of the divergence in allele frequency among CD and UC was noted in NOD2/autophagy pathway SNPs, while most SNPs with similar frequencies were in IL‐22/23 Th17, adaptive immunity, and barrier pathways. Colon‐only CD (n = 228) was compared with healthy controls: three of six UC SNPs (in MST1, HLA‐DRA, and IL‐23R) and 11 of 34 CD SNPs: in IRGM, NOD2 (rs2066845), CCNY, MST1, IL23R, PTPN22, C11orf30, ZNF365, PTPN2, PSMG1, and rs1456893 were significantly associated. In all, 29 of 34 CD SNPs had similar allele frequencies in colonic CD compared with ileal CD (n = 366). All UC SNPs had similar frequencies in UC and colonic CD. Conclusions: Our results suggest that CD and UC share common genetic associations related to impaired adaptive immunity and diverge in pathways of foreign antigen processing. Colon‐only CD overlaps extensively with UC and considerably with ileal CD. (Inflamm Bowel Dis 2010)

Preoperative biological therapy and short-term outcomes of abdominal surgery in patients with inflammatory bowel disease

Objective Previous investigations of short-term outcomes after preoperative exposure to biological therapy in inflammatory bowel disease (IBD) were conflicting. The authors aimed to assess postoperative outcomes in patients who underwent abdominal surgery with recent exposure to anti-tumour necrosis factor therapy. Design A retrospective case-control study with detailed matching was performed for subjects with IBD with and without exposure to biologics within 180 days of abdominal surgery. Postoperative outcomes were compared between the groups. Results 473 procedures were reviewed consisting of 195 patients with exposure to biologics and 278 matched controls. There were no significant differences in most postoperative outcomes such as: length of stay, fever (≥38.5°C), urinary tract infection, pneumonia, bacteraemia, readmission, reoperations and mortality. On univariate analysis, procedures on biologics had more wound infections compared with controls (19% vs 11%; p=0.008), but this was not significant in multivariate analysis. Concomitant therapy with biologics and thiopurines was associated with increased frequencies of urinary tract infections (p=0.0007) and wound infections (p=0.0045). Operations performed ≤14 days from last biologic dose had similar rates of infections and other outcomes when compared with those performed within 15–30 days or 31–180 days. Patients with detectable preoperative infliximab levels had similar rates of wound infection compared with those with undetectable levels (3/10 vs 0/9; p=0.21). Conclusion Preoperative treatment with TNF-α antagonists in patients with IBD is not associated with most early postoperative complications. A shorter time interval from last biological dose is not associated with increased postoperative complications. In most cases, surgery should not be delayed, and appropriate biological therapy may be continued perioperatively.

Heparanase upregulation by colonic epithelium in inflammatory bowel disease

Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, yielding HS fragments of still appreciable size (∼5–7 kDa). Heparanase activity has long been detected in a number of cell types and tissues. Importantly, heparanase activity correlated with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the extracellular matrix barrier. Similarly, heparanase activity was implicated in neovascularization, inflammation and autoimmunity, involving migration of vascular endothelial cells and activated cells of the immune system. The involvement of heparanase in inflammatory processes of the gastrointestinal tract has not been examined. Here, we utilized immunohistochemical analysis to investigate heparanase expression in acute and chronic inflammatory conditions. Heparanase expression was not detected in specimens derived from normal colon tissue. In contrast, strong heparanase staining was observed in Crohns disease and ulcerative colitis, but not in infectious colitis. Interestingly, heparanase staining was primarily observed in epithelial rather than immune cells. Importantly, un-fractionated as well as low molecular weight heparin (enoxaparin), which exhibit a strong inhibitory activity towards heparanase, have proven efficacious in ulcerative colitis and Crohns disease patients, suggesting that heparanase is actively involved in these pathologies and thus may be considered as a target for the development of anti-inflammatory therapies.

Capsule enteroscopy of the small intestine

The advent of video capsule endoscopy (VCE) in 2000 has dramatically changed the diagnosis and management of many diseases of the small intestine. In this review we discuss the procedure, the various indications and contraindications, adverse effects, and future prospects of VCE. VCE has a significant role in the diagnosis of obscure gastrointestinal hemorrhage and Crohn’s disease and has the highest diagnostic yield in comparison to other diagnostic modalities. Furthermore, VCE has gained an important role in the management and surveillance of suspected small bowel tumors and in patients with polyposis syndromes. Capsule enteroscopy may have a role in the work-up of symptomatic celiac disease and in the assessment of drug therapeutic efficacy and adverse small bowel effects. Although VCE is relatively non-invasive, it is contraindicated in patients with swallowing disorders, known or suspected gastrointestinal obstruction, strictures, or fistulas, and in patients with implanted electromedical devices. Other contraindications include pregnancy and children under 10. Capsule retention is the most feared complication of VCE with a frequency of 1%–2%. Risk factors and management of capsule retention are also discussed. It is probable that new indications for VCE will evolve and technological improvements will refine VCE’s diagnostic accuracy and simplify video reviewing.

NOD2/CARD15 genotype and phenotype differences between Ashkenazi and Sephardic Jews with Crohn's disease

OBJECTIVE:NOD2/CARD15 has been identified as a major susceptibility gene for Crohns disease (CD). Three mutations, Arg702Trp, Gly908Arg, and Leu1007fsinsC, are associated with CD. The incidence and prevalence rate of inflammatory bowel diseases is two- to four-fold higher in Ashkenazi Jews as compared to non-Jewish Caucasians. The aim of this study was to determine the significance of the NOD2/CARD15 mutations in Jewish CD patients in Israel, and more specifically, to compare the significance of the mutations to the expression of CD in the Ashkenazi and Sephardic Jewish populations.METHODS:Allele frequencies of the mutations were determined in 180 Jewish CD patients, 73 ulcerative colitis patients, and 159 ethnically matched controls. Variants were detected using allele-specific PCR and restriction enzyme digestion assay. Demographic and phenotypic characterizations of the CD patients were determined.RESULTS:The carrier rate of the three mutations in the entire Jewish Israeli CD cohort is 41.1%versus 10.7% in controls (p < 0.0001). The Ashkenazi Jewish CD patients have an increased carrier rate compared to Sephardic Jews (47.4%vs 27.45%, p= 0.034). Association analyses in Ashkenazi Jews reveal odds ratios of 10.5, 9, and 4.8 for carriage of Gly908Arg, Arg702Trp, and Leu1007fsinsC mutations, respectively. Significantly higher rates of smoking, family history of inflammatory bowel diseases, and extraintestinal manifestations were found among the Sephardic CD patients.CONCLUSIONS:NOD2/CARD15 CD-associated mutations confer increased risk mainly to the Ashkenazi Jewish CD patients in Israel. This suggests that NOD2/CARD15 mutations could contribute to the higher incidence and prevalence rates of CD among Ashkenazi Jews.

Capsule endoscopy of the esophagus.

Video capsule endoscopy has acquired wide clinical acceptance since its the US Food and Drug Administration approval in 2001. Recently, the technology of video capsule endoscopy has been adapted to other organs in the gastrointestinal tract, including the esophagus and colon. In this review, we discuss esophageal capsule endoscopy (ECE)-the procedure, its indications, contraindications, safety, and future applications. ECE is a minimally invasive procedure that uses special video capsules with ability to acquire images from 2 cameras with high image storing speed of 14 to 18 frames per second. A special ingestion procedure allows for prolonged esophageal transit time and an optimized view of the gastroesophageal junction. ECE has been shown to have moderately high sensitivity and accuracy in the diagnosis and surveillance of Barrett esophagus in patients with gastroesophageal reflux disease but has not demonstrated superiority to esogastroduodenoscopy in cost-effectiveness models. In patients with portal hypertension, ECE has a sensitivity of 63% to 100% for screening of esophageal varices, but does not seem to be superior to esogastroduodenoscopy in its cost-effectiveness. No serious complications have been reported after ECE although a low rate of esophageal capsule retention (0.7% to 2.2%) has been reported, usually because of unsuspected esophageal strictures. Contraindications to capsule endoscopy include known or suspected gastrointestinal and esophageal obstruction, strictures, or fistulas, intestinal pseudoobstruction, and children under 10 years of age. It is expected that improvements in imaging technology will improve the accuracy of ECE with the development of immunological-based and chemical-based diagnostic capabilities.

Risk Factors for Perianal Crohn's Disease: The Role of Genotype, Phenotype, and Ethnicity

OBJECTIVES:Perianal disease (PD) is a frequent complication of Crohns disease (CD). The lack of association between PD and development of intestinal penetrating disease may suggest that PD is a distinct phenotype with specific genetic or clinical risk factors. This study was undertaken to evaluate the role of genotype, clinical, and demographic characteristics with PD.METHODS:Phenotypic data on 121 CD patients with PD and 179 patients without PD were carefully characterized. The patients were genotyped for disease-associated OCTN1/2 and NOD2/CARD15 variants and the TNF-α promoter polymorphisms. Analysis was performed to evaluate the differences in phenotype and genotype frequencies between the PD group and the non-PD group.RESULTS:PD was associated with rectal involvement (odds ratio [OR] 2.27, 95% CI 1.32–3.91) and with Sephardic (non-Ashkenazi) Jewish ethnicity (OR 1.71, 95% CI 1.02–2.9). No association was found among the studied OCTN, NOD2, TNF-α variants and the risk for PD.CONCLUSIONS:The strongest factor associated with PD is rectal inflammation. OCTN1/2, NOD2/CARD15, and TNF-α promoter variants do not play a role in the risk to PD in the Jewish Israeli population. The association of ethnicity with PD may suggest that there are as yet unknown genetic variants that are associated with PD.