A Bond

Review article: cytomegalovirus and inflammatory bowel disease

The association between ulcerative colitis and cytomegalovirus (CMV) has been recognised for over 50 years; and the role of CMV in ulcerative colitis in general, and steroid resistance in particular, remains a topic of ongoing controversy. The outcome for patients with CMV reactivation appears worse than that for patients without reactivation, but it is not entirely clear whether CMV is a contributor or a bystander and if treatment with anti‐virals alters the course of inflammatory bowel disease (IBD).

Comparative analysis of the influence of clinical factors including BMI on adalimumab and infliximab trough levels.

Introduction Optimal trough levels of the anti-tumour necrosis factor agents, infliximab and adalimumab, are correlated with clinical remission. Obesity adversely affects response to infliximab and adalimumab, but the influence of BMI on trough levels has not been adequately investigated. We investigated the relationship between clinical variables, including BMI, and trough levels of infliximab and adalimumab. Methods This prospective cross-sectional study included patients treated with infliximab and adalimumab on maintenance therapy, with concurrent measurements of trough levels and BMI. The associations between categorical trough levels and clinical variables, including BMI, were estimated. Results Of the 122 patients included in the study, 80 (66%) were on infliximab and 42 (34%) were on adalimumab. Eighty-three per cent had Crohn’s disease and the remainder had ulcerative colitis. None of the clinical variables, including smoking, BMI, concurrent immunosuppression, duration of disease and treatment, were associated with categorical trough levels of infliximab or adalimumab. The effect of BMI did not differ between the two anti-tumour necrosis factor agents, although there was a trend towards a lower trough level in adalimumab-treated patients with a BMI greater than 30 (P=0.09). In infliximab-treated patients, antibodies to infliximab (P<0.001) and a C-reactive protein level of at least 5 mg/dl were associated with trough levels less than 3 µg/ml (P=0.008). Conclusion BMI does not differentially influence trough levels of adalimumab and infliximab, although a trend towards a lower trough level was observed in adalimumab-treated patients with a BMI greater than 30. Raised C-reactive protein levels and antibodies to infliximab were associated with subtherapeutic levels of infliximab.

New technologies and techniques to improve adenoma detection in colonoscopy.

Adenoma detection rate (ADR) is a key component of colonoscopy quality assessment, with a direct link between itself and future mortality from colorectal cancer. There are a number of potential factors, both modifiable and non-modifiable that can impact upon ADR. As methods, understanding and technologies advance, so should our ability to improve ADRs, and thus, reduce colorectal cancer mortality. This article will review new technologies and techniques that improve ADR, both in terms of the endoscopes themselves and adjuncts to current systems. In particular it focuses on effective techniques and behaviours, developments in image enhancement, advancement in endoscope design and developments in accessories that may improve ADR. It also highlights the key role that continued medical education plays in improving the quality of colonoscopy and thus ADR. The review aims to present a balanced summary of the evidence currently available and does not propose to serve as a guideline.

Investigation of Volatile Organic Compounds Emitted from Faeces for the Diagnosis of Giardiasis.

BACKGROUND Giardiasis is a common intestinal infection caused by the flagellated intestinal protozoan Giardia duodenalis. Several methods are available for the laboratory diagnosis of Giardia, ranging from the microscopic identification of the parasite trophozoite and cyst stages, to immunodiagnosis and PCR. Giardia has unique metabolic pathways resulting from its lack of mitochondria, making it an ideal target for volatile organic compound (VOC) profiling. AIM To characterise the VOC profile of stool infected with Giardia to detect differences from those found in samples of diarrhoea without Giardia or other infections. METHOD Stool was obtained from patients with confirmed Giardia infection and controls with diarrhoea but no identifiable infection. Faecal headspace gas extraction and gas chromatography-mass spectrometry were used to extract and identify VOCs. RESULTS More than 100 VOCs were identified when control and Giardia groups were combined, of which 24 showed significant differences between the two groups (p<0.05). Three VOCs had a significantly greater prevalence amongst Giardia cases (p<0.0001) and 9 VOCs showed a significant difference in terms of abundance (p<0.05). AUROC analysis demonstrated a value of 0.902. CONCLUSION There is a significant difference in the VOC profile of stool from subjects infected with Giardia spp, when compared with non-infected controls. These findings can be explained by the unique metabolism of Giardia.

Concurrent immunomodulator therapy is associated with higher adalimumab trough levels during scheduled maintenance therapy

Abstract Introduction: Combination therapy with infliximab and immunomodulators is superior to monotherapy, resulting in better outcomes and higher trough levels of infliximab. The role of concurrent immunomodulatory therapy on adalimumab trough levels has not been adequately investigated. We evaluated the impact of concomitant immunomodulation on adalimumab trough levels in patients on scheduled maintenance therapy. Method: We conducted a prospective observational, cross-sectional study of all inflammatory bowel disease patients on maintenance therapy who had adalimumab trough levels measured between January 2013 and January 2016. Drug level and anti-drug antibody measurements were performed on sera using a solid phase assay. Pairwise comparison of means was used to compare trough levels in patients with and without concomitant immune modulator therapy. Results: In total, 79 patients were included. Twenty-three patients (29.1%) were on weekly dosing whereas 56 (70.9%) were on alternate weeks. Median adalimumab trough levels were comparable in patients with and without clinical remission (6.8 μg/ml (IQR 5.6–8.1) versus 6.7 μg/ml (IQR 3.9–8.1), respectively. Patients with an elevated faecal calprotectin >250 μg/g had lower adalimumab trough levels (median 6.7, IQR 3.9–8) compared to patients with faecal calprotectin <250 μg/g (median 7.7, IQR 6.1–8.1) though this did not achieve statistical significance (p = .062). Median adalimumab trough levels among patients on concurrent immunomodulators was 7.2 μg/ml (IQR 5.7–8.1) compared to those not on concurrent immunomodulator, 6.1 μg/ml (IQR 2.7–7.7, p = .0297). Conclusion: Adalimumab trough levels were significantly higher in patients on concurrent immunomodulators during maintenance therapy. There was a trend towards a lower adalimumab trough level in patients with elevated calprotectin.

New-Generation High-Definition Colonoscopes Increase Adenoma Detection when Screening a Moderate-Risk Population for Colorectal Cancer

Background and Aim Adenoma detection rate (ADR) is the most important quality indicator for screening colonoscopy, due to its association with colorectal cancer outcomes. As a result, a number of techniques and technologies have been proposed that have the potential to improve ADR. The aim of this study was to assess the potential impact of new‐generation high‐definition (HD) colonoscopy on ADR within the Bowel Cancer Screening Programme (BCSP). Method This was a retrospective single‐center observational study in patients undergoing an index screening colonoscopy. The examination was performed with either standard‐definition colonoscopes (Olympus Q240/Q260 series) or HD colonoscopes (Olympus HQ290 EVIS LUCERA ELITE system) with the primary outcome measures of ADR and mean adenoma per procedure (MAP) between the 2 groups. Results A total of 395 patients (60.5% male, mean age 66.8 years) underwent screening colonoscopy with 45% performed with HD colonoscopes. The cecal intubation rate was 97.5% on an intention‐to‐treat basis and ADR was 68.6%. ADR with standard‐definition was 63.13%, compared with 75.71% with HD (P = .007). The MAP in the HD group was 2.1 (± 2.0), whereas in the standard‐definition group it was 1.6 (± 1.8) (P = .01). There was no significant difference in withdrawal time between the 2 groups. In the multivariate regression model, only HD scopes (P = .03) and male sex (P = .04) independently influenced ADR. Conclusion Olympus H290 LUCERA ELITE HD colonoscopes improved adenoma detection within the moderate‐risk population. A 12% improvement in ADR might be expected to increase significantly the protection afforded by colonoscopy against subsequent colorectal cancer mortality. Micro‐Abstract This retrospect observational study of 395 patients undergoing colonoscopy as part of the UK Bowel Cancer Screening Programme, demonstrated that the Olympus H290 LUCERA ELITE high‐definition colonoscopes improved adenoma detection within the moderate‐risk population. Moreover, it did so when used by operators with a higher‐than‐average baseline adenoma detection rate.

Correlation between Faecal Tumour M2 Pyruvate Kinase and Colonoscopy for the Detection of Adenomatous Neoplasia in a Secondary Care Cohort

BACKGROUND AND AIMS Colorectal cancer screening programmes that target detection and excision of adenomatous colonic polyps have been shown to reduce colorectal cancer related mortality. Many screening programmes include an initial faecal occult blood test (FOBt) prior to colonoscopy. To refine the selection of patients for colonoscopy other faecal-based diagnostic tools have been proposed, including tumour M2-pyruvate kinase (tM2-PK). To determine whether tM2-PK quantification may have a role in diverse settings we have assessed the assay in a cohort of patients derived from both the England bowel cancer screening programme (BCSP) and symptomatic individuals presenting to secondary care. METHOD Patients undergoing colonoscopy provided faecal samples prior to bowel preparation. Faecal tM2-PK concentrations were measured by ELISA. Sensitivity, specificity, positive predictive value, negative predictive value and ROC analyses were calculated. RESULTS Ninety-six patients returned faecal samples: 50 of these with adenomas and 7 with cancer. Median age was 68. Median faecal tM2-PK concentration was 3.8 U/mL for individuals without neoplastic findings at colonoscopy, 7.7 U/mL in those with adenomas and 24.4 U/mL in subjects with colorectal cancer (both, p=0.01). ROC analysis demonstrated an AUROC of 0.66 (sensitivity 72.4%, specificity 48.7%, positive predictive value 67.7%, negative predictive value 36.7%). Amongst BCSP patients with a prior positive FOBt faecal tM2-PK was more abundant (median 6.4 U/mL, p=0.03) and its diagnostic accuracy was greater (AUROC 0.82). CONCLUSION Our findings confirm that faecal tM2-PK ELISA may have utility as an adjunct to FOBt in a screening context, but do not support its use in symptomatic patients.

How Can We Improve Adenoma Detection Rate

Adenoma detection rate (ADR) is a considerable component of colonoscopy quality assurance; it has a clear link to future morbidity and mortality from colorectal cancer. There are a number of potential factors, both modifiable and non-modifiable that can impact upon ADR. Modes of improving ADR include techniques and behaviours during colonoscopy, image enhancement techniques, technological advancements, advancements in endoscope designs, developments in accessories and continued medical education. However, whilst a number of technologies are emerging to improve ADR, at present, it seems that education, team work and optimising current practice will provide the biggest gains in ADR whilst maintaining financial acceptability. The review aims to present a balanced summary of the evidence currently available and does not propose to serve as a guideline.

PTU-138 Feasibility Study of Volatile Organic Compounds in Constipation in Parkinson’s Disease

Introduction Patients with Parkinson’s disease (PD) have constipation. Constipation often precedes the classical motor signs. Enteric neuropathy may play a role of the aetiology of PD. Exposure to fungi is a risk factor for PD: in vitro models have shown specific fungi-produced volatile organic compounds (VOC), 1 octen-3-ol and 2 octanone, may cause loss of dopaminergic neurones in fruit flies. We propose the hypothesis that intestinal fungal metabolites may a risk factor for PD. This study assessed the feasibility of performing faecal VOCs analysis in people with PD and controls. Methods 8 patients with diagnosed PD were invited from an exercise class (Dancing for Parkinson’s). Their partners/carers were also invited as aged-matched controls. Samples from lab volunteers (14) were also analysed. Patients or controls that had taken any antibiotics or antifungals in the 4 weeks prior to sampling were excluded. VOCs from 2 aliquots per donor were extracted using Solid Phase Micro Extraction (SPME), separated by gas chromatography–mass and analysed by gas spectrometry (GC-MS). VOCs were identified using AMDIS and comparison with the current NIST library of mass spectra. Reported were prepared using Metab, and statistical analysis undertaken using Metaboanalyst software. Results All 8 PD patients provided samples, despite their constipation. 5 of 6 aged-matched controls provided samples. The average result from the paired technical replicates was used for statistical analysis. There were significantly fewer VOC in samples from PD patients (63), than from controls (74, p < 0.007). Young and older controls had a similar number of VOCs (80 and 71 respectively, p = ns). The abundance of VOCs in PD and all controls was compared: 33 differed, 7 of which persisted after correction for multiple comparison, including 2 octanone. Conclusion The study of VOCs in people with constipation is feasible. Those with constipation have fewer VOCs that controls as a whole. There were clear differences in the VOCs from patients with Parkinson’s disease in the control group. One of the VOCs that was increased, 2 octanone, in Parkinson’s disease is a fungal metabolite that causes damage to dopaminergic neurones in an insect model. More work is necessary to explore the association between PD: a full study will need to include more patients and controls with constipation. Disclosure of Interest None Declared

PTH-049 Successful Reversal of High Titre Antibodies to Infliximab and Adalimumab with The Addition of Immunomodulator Therapy

Introduction Immunogenicity is a common problem associated with anti-tumour necrosis factor (TNF) therapy and is often associated with loss of clinical response. Concomitant immunomodulatory therapy reduces the rate of anti-drug antibody (ADA) formation with infliximab and is associated with better outcomes.1 However, the impact of immunomodulator initiation specifically to reverse established ADA has not been adequately investigated. Current guidelines recommend switching of anti-TNF agent or class switch in the presence of ADA titre >9 u/ml. However, outcomes with further biologics are poor and reversal of ADA may be preferable. We report the successful reversal of very high titre ADA with immunomodulator initiation. Methods This was a retrospective study of patients with established ADA on infliximab or adalimumab monotherapy, in whom an immunomodulator was commenced. Levels of ADA and trough levels of drug were monitored by ELISA (Theradiag). Results Four patients were included (3 Crohn’s disease and 1 ulcerative colitis), of which two patients were receiving infliximab and 2 adalimumab. There were 3 males and 1 female with a mean age of 50 years (SD ±17.6). All patients had initial titres of ADA > 200 ng/ml for infliximab and >160 ng/ml for adalimumab, with undetectable trough levels (<0.1 µg/ml). Three patients were treated with thiopurines and one with methotrexate. Three patients (2 thiopurines, 1 methotrexate) had successful reversal of antibodies accompanied by an increase in trough levels and clinical improvement. One infliximab and one adalimumab patient also had dose escalation after reversal of ADA to achieve therapeutic drug concentration. One patient who achieved reversal stopped their thiopurine due to side effects and had recurrence of ADA and a subsequent loss of response. Conclusion In patients undergoing monotherapy with anti-TNF treatment who develop ADA, the addition of an immunomodulator agent has the potential to reverse even high antibody titres and regain clinical response. This strategy is particularly useful as the risk of ADA with a subsequent anti-TNF is higher in patients with ADA to one anti-TNF agent[2]. References 1 Ruffolo C, Scarpa M, Bassi N. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;363:1086–8. doi:10.1056/NEJMoa0904492 2 Frederiksen MT, Ainsworth MA, Brynskov J, Thomsen OO, Bendtzen K SC. Antibodies against infliximab are associated with de novo development of antibodies to adalimumab and therapeutic failure in infliximab-to-adalimumab switchers with IBD. Inflamm Bowel Dis 2014;20:1714–21. Disclosure of Interest None Declared