Predicting pathology on small bowel capsule endoscopy: a good FIT.

Background and study aims Small bowel capsule endoscopy [SBCE) has an established role in investigating suspected small bowel bleeding [SSBB). Identification of a biomarker to predict pathology would maximize utility of this valuable diagnostic modality. This study aimed to investigate if fecal immunochemical test [FIT) could predict likelihood of small bowel pathology on SBCE. Patients and methods Patients referred for SBCE to investigate anaemia or suspected small bowel bleeding were prospectively recruited. All patients had negative upper and lower endoscopy prior to referral. A FIT ≥ 45 ug Hb/g was considered positive. SBCE was positive if a potential source of SSBB was identified. The primary endpoint was correlation between FIT and positive SBCE. Secondary endpoints were correlation between anemia and SBCE and a combination of anemia plus FIT and SBCE. Results Fifty-one patients were included in the final study cohort. 29.4 % had a positive FIT, 33.3 % were anemic, and 25.5 % patients had significant SBCE findings. There was a statistically significant association between positive FIT and pathology on SBCE (OR 12, 95 % CI [2.8 - 51.9), P  = 0.001). Sensitivity and specificity of positive FIT in predicting SBCE findings were 69 % and 84 %, respectively. A normal Hb had an NPV of 83 % (OR 0.30, P  = 0.09). Combining Hb and FIT was statistically significant in predicting pathology on SBCE (OR 9.14, 67 % PPV, 82 % NPV, P  = 0.025). Conclusion FIT ≥ 45 ug Hb/g is a useful tool in predicting small bowel pathology on SBCE. Use of this biomarker alone, or in combination with serum haemoglobin, has value as a screening tool and may help to better triage patients referred for SBCE.

Iron deficiency anaemia in a coeliac: a cause for concern?

A 70-year-old woman with a 15-year history of coeliac disease was admitted for treatment and investigation of symptomatic anaemia. Of note, she was recently commenced on aspirin therapy for retinal artery occlusion. This followed a normal gastro-duodenoscopy, colonoscopy and CT abdomen as workup for iron deficiency anaemia. On this occasion, the patient was further investigated with small bowel capsule endoscopy. This revealed an ulcerated lesion in her proximal jejunum suspicious for malignancy, namely lymphoma. A biopsy of the lesion confirmed adenomatous changes and high-grade dysplasia without malignant changes. Given the endoscopic appearances of the lesion, she was further evaluated with a small bowel MRI. This revealed a 3 cm lesion with associated lymphadenopathy but no distant metastases. She proceeded to resection of her small bowel which confirmed an invasive adenocarcinoma of her proximal jejunum. She is currently undergoing adjuvant chemotherapy on an outpatient basis.

One-Year Clinical Outcomes in an IBD Cohort Who Have Previously Had Anti-TNFa Trough and Antibody Levels Assessed.

BACKGROUND: Loss of response (LOR) is a big concern for anti-TNFa therapies in inflammatory bowel disease. Immunomonitoring may be useful to optimize response rates and overcome secondary LOR. METHODS: This was an observational retrospective cohort study of a group of patients with inflammatory bowel disease on infliximab (IFX) and adalimumab (ADA) who had anti-TNFa trough and antibody levels measured, during maintenance phase of treatment. Anti-TNFa trough and antibody levels were measured using standard enzyme-linked immunosorbent assay techniques. Baseline patient characteristics were determined and patients were reviewed 1 year later. Clinical assessment took place with partial Mayo scores for ulcerative colitis and Harvey-Bradshaw index for Crohn's disease. C-reactive protein (CRP) and albumin were also measured. Poor outcomes were defined as the following: need for rescue steroids, dose intensification, surgery, or treatment discontinuation. RESULTS: Seventy-four patients were included in the study, 37 (50%) were female, mean age 41 years, 61 (82%) had Crohn's disease, and 42 (57%) ulcerative colitis. Forty-two (57%) patients received IFX and 32 (43%) ADA. Mean IFX trough was 3.6 µg/mL and mean ADA troughs were 3.78 µg/mL. Twenty-seven percent of patients (n = 20) overall had a poor outcome, with a similar proportion in each group 24% (n = 10) IFX and 31% (n = 10) ADA (P value 0.24). Of the cohort, 14.2% (6/42) treated with IFX had subtherapeutic trough levels, 6.2% (2/32) of ADA patients had a trough level <1 µg/mL (P value = 0.273) There was no difference in mean trough according to outcome (4.9 µg/mL poor versus 5.4 µg/mL good, P value 0.14). Low IFX trough levels did correlate with high CRP, low albumin and response rates, mean CRP 6.66 µg/mL (n = 3), mean albumin 37 g/L for patients with low trough levels and poor response versus CRP 2.0 µg/mL (n = 24), mean albumin 43 g/L for patients with high trough levels and good response (P = 0.009, 95% confidence interval, -0.78 to -0.12). CONCLUSIONS: LOR is still a big concern with anti-TNFa therapies. Stand-alone anti-TNFa trough and antibody levels are not useful at predicting LOR/disease progression at 1 year, but low trough levels do correlate well with elevated CRP, hypoalbuminaemia, and poor response rates.

Clinical impact of immunomonitoring in the treatment of inflammatory bowel disease.

Despite improvement in outcomes, loss of response (LOR) to tumor necrosis factor-alpha (TNFα) therapies is a big concern in the management of inflammatory bowel disease. LOR is associated with flares of disease, increased hospitalisation rates, need for surgical interventions, and decline in quality of life. LOR may be multifactorial, but immunogenicity makes a significant contribution. Traditionally doses of anti-TNFα have been adjusted based on clinical response, using a standard approach. Immunomonitoring involves the measurement of anti-TNFα trough and antibody levels. It takes into account the underlying pharmacokinetics of anti-TNFα therapies. Expanding on this a treat to target approach may be used, where doses are intensified, or tailored to the individual based on the measurement of anti-TNFα trough and antibody levels. This review looks at the history, evolution, and clinical impact that immunomonitoring is having in the treatment of inflammatory bowel disease. It will focus on the role of immunomonitoring in helping to achieve long lasting deep remission and mucosal healing. It will explore the different options in terms of best measuring trough and antibody levels, explore possible advantages of immunomonitoring, and discuss its role in best optimising response, at induction, during the maintenance phase of treatment, as well as a role in withdrawing or switching therapy.

Positive relationship between infliximab and adalimumab trough levels at completion of induction therapy with clinical response rates, at a tertiary referral center.

BACKGROUND AND AIM: Anti-tumor necrosis factor alpha (TNFα) therapies have improved outcomes for patients with inflammatory bowel disease. The aim of this study was to explore the relationship between infliximab (IFX) and adalimumab (ADL) trough and antibody levels with clinical response rates at the end of induction. METHODS: This was a prospective, single-center study. Patients were recruited from July 2015 to August 2016. Inclusion criteria were all inflammatory bowel disease patients older than 17 years who started treatment with IFX or ADL. Baseline clinical disease activity indexes were performed. Clinical response was defined as HBI ≤3 or partial Mayo score ≤4% or <30% reduction from baseline. Anti-TNFα trough and antibody levels were measured using standard ELISA techniques. RESULTS: Thirty-five patients were recruited, of whom 23 had Crohn's disease and 12 had ulcerative colitis. Eighteen were treated with ADL and 17 with IFX. The mean age of the cohort was 40.3 years, 62.9% were females, 34.3% were on concomitant thiopurines, and 25.7% had prior anti-TNFα exposure. Overall response rate was 51.4%, 33.3% for ADL and 70.6% for IFX.Mean trough levels were 12.5 µg/mL for IFX and 4.4 µg/mL for ADL. There was a clear link between higher anti-TNFα trough levels at the end of induction with clinical response rates. For IFX, mean trough level was 16.4 µg/mL for responders versus 5.3 µg/mL for non-responders (P = 0.026). Area under the curve for association of IFX level at induction with clinical response was 0.864 (P = 0.0001). Similar link was present between higher ADL levels with clinical response, although not statistically significant. CONCLUSION: Higher trough levels at the end of induction are associated with improved response. Ongoing work will define optimal targets at this key timeframe.

Molecular detection of Helicobacter pylori antibiotic resistance in stool vs biopsy samples.

AIM: To compare (1) demographics in urea breath test (UBT) vs endoscopy patients; and (2) the molecular detection of antibiotic resistance in stool vs biopsy samples. METHODS: Six hundred and sixteen adult patients undergoing endoscopy or a UBT were prospectively recruited to the study. The GenoType HelicoDR assay was used to detect Helicobacter pylori (H. pylori) and antibiotic resistance using biopsy and/or stool samples from CLO-positive endoscopy patients and stool samples from UBT-positive patients. RESULTS: Infection rates were significantly higher in patients referred for a UBT than endoscopy (overall rates: 33% vs 19%; treatment-naïve patients: 33% vs 14.7%, respectively). H. pylori-infected UBT patients were younger than H. pylori-infected endoscopy patients (41.4 vs 48.4 years, respectively, P < 0.005), with a higher percentage of H. pylori-infected males in the endoscopy-compared to the UBT-cohort (52.6% vs 33.3%, P = 0.03). The GenoType HelicoDR assay was more accurate at detecting H. pylori infection using biopsy samples than stool samples [98.2% (n = 54/55) vs 80.3% (n =53/66), P < 0.005]. Subset analysis using stool and biopsy samples from CLO-positive endoscopy patients revealed a higher detection rate of resistance-associated mutations using stool samples compared to biopsies. The concordance rates between stool and biopsy samples for the detection of H. pylori DNA, clarithromycin and fluoroquinolone resistance were just 85%, 53% and 35%, respectively. CONCLUSION: Differences between endoscopy and UBT patients provide a rationale for non-invasive detection of H. pylori antibiotic resistance. However, the GenoType HelicoDR assay is an unsuitable approach.

Clinical and pathologic characteristics of hereditary apolipoprotein A-I amyloidosis in Ireland.

AIM: Apolipoprotein A-I amyloidosis is a rare, autosomal dominant disorder characterized by progressive accumulation of amyloid fibrils in tissues, leading to renal and hepatic disease. We describe the clinical manifestations and pathologic features of kidney disease in three Irish families. METHODS: This observational study examines all known cases of chronic kidney disease due to hereditary apolipoprotein A-I amyloidosis in Ireland. Patients were identified by physician interview. In all of the affected individuals the disease was caused by the Gly26Arg heterozygous mutation. Immunohistochemistry confirmed that amyloid deposits were composed of apolipoprotein A-I fibrils. Family trees and clinical data were obtained via analysis of patient medical records. RESULTS: The vast majority of affected cases had demonstrable kidney disease, with variable liver disease. Renal disease most commonly manifested as slowly progressive renal impairment with mild proteinuria. In one kindred, a severe, debilitating peripheral neuropathy was common among affected family members. Histology demonstrated tubulointerstitial fibrosis with amyloid deposition in the medulla. There was very high penetrance within affected families. Of five patients who were transplanted, one transplant was lost after 5 years due to recurrent disease. One patient died from sepsis shortly after transplant. CONCLUSION: Hereditary apolipoprotein A-I amyloidosis is characterized by slowly progressive renal disease. Amyloid is deposited in the renal medulla highlighting the need to examine the medulla on renal biopsy. Overall, kidney transplantation conferred a survival advantage.

ETV4 and Myeov knockdown impairs colon cancer cell line proliferation and invasion.

We have identified novel colorectal cancer-associated genes using NCBI's UNIGENE cDNA libraries. Colon cancer libraries were examined using Digital Differential Display and disease-associated genes were selected. Among these were ETV4 and MYEOV, novel colorectal cancer-associated genes. Samples of matched normal and neoplastic colon were obtained from human subjects and gene expression was quantified using real-time PCR. ETV4 gene expression was significantly increased in colonic neoplasia in comparison to matched normal colonic tissue (p<0.05). Myeov expression was also increased in colon neoplasia in comparison to matched normal tissue. The effect of siRNA-mediated knockdown of ETV4 and Myeov on cell proliferation and invasion was assessed. ETV4 knockdown resulted in a 90% decrease in cell proliferation (p<0.05) and a 67% decrease in cell invasion. Myeov knockdown resulted in a 48% decrease in cell proliferation (p<0.05) and a 36% decrease in cell invasion. These data suggest that ETV4 and Myeov may provide novel targets for therapeutic intervention.