John P. Hamlin

Efficacy, tolerability, and predictors of response to infliximab therapy for Crohn's disease: A large single centre experience

BACKGROUND Infliximab is licenced for use in Crohns disease (CD). Trial data demonstrate that infliximab is effective for inducing remission of active CD, healing fistulising CD, and preventing relapse once in remission. However, long-term data regarding efficacy, safety, and predictors of response are still emerging. AIM To examine these issues in a large cohort of patients who received infliximab for CD. METHODS A retrospective analysis of prospectively collected data was performed for 210 patients receiving infliximab for luminal or fistulising CD. Response to infliximab induction therapy, and sustained clinical benefit, were assessed by a decrease in Harvey-Bradshaw Index (HBI) of ≥ 2 points. Remission was defined as an HBI ≤ 4. Physicians global assessment was used where HBI could not be obtained. Demographic and disease factors that may predict response to therapy were analysed by Kaplan-Meier plots and univariate and multivariate analyses. RESULTS Overall, 173 (82.4%) patients responded to infliximab induction, with 114 (65.9%) achieving sustained clinical benefit. Almost 40% of the study cohort had an HBI ≤ 4, indicating remission, at last point of follow-up (median 24 months). Concomitant immunosuppression predicted sustained clinical benefit in the first 6 months of therapy (P=0.03). An inflammatory disease phenotype (P=0.04 univariate analysis, P=0.03 Kaplan Meier analysis) and male gender (P=0.03) also predicted sustained clinical benefit. Episodic therapy was associated with an increased likelihood of secondary non-response. Adverse events, including malignancies, were few. CONCLUSION In this single centre study, infliximab was efficacious and well-tolerated in CD.

Ipilimumab-induced colitis: experience from a tertiary referral center

Background: Ipilimumab is an anticytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody used for the treatment of malignant melanoma. It can cause immune-mediated inflammatory adverse events, including diarrhoea and even intestinal perforation or death in clinical trials but there is a dearth of data on postmarketing outcomes. Methods: A total of 546 patients attending for treatment of metastatic melanoma between 1 January 2009 and 31 August 2015 were identified by interrogation of the oncology database. A total of 83 of these patients received ipilimumab. Clinical information was extracted from chart reviews, endoscopy and radiology reports, and prescription data. Results: A total of 83 patients received ipilimumab. Only 19.3% (n = 16) of patients developed a diarrhoeal illness not attributable to other causes. The median grade of diarrhoea among included patients was 2 (range 1–4). In two cases, diarrhoea settled spontaneously without any specific treatment. A total of 87.5% of patients received antidiarrhoeal agents such as loperamide or codeine. These resolved symptoms in all patients with grade 1 diarrhoea. For other treatment, 50% patients received systemic glucocorticosteroids and 31.3% required infliximab. Infliximab resolved symptoms in 100% of cases compared with 50% for systemic glucocorticosteroids. Conclusions: The rate of diarrhoea related to ipilimumab in real-world practice is substantial, but below the range observed in data from RCTs. Grade 1 colitis can usually be managed symptomatically, without recourse to stopping ipilimumab. When diarrhoea was grade 2 or above, results from glucocorticosteroids use proved disappointing; but infliximab has been shown to work well. Further research is required into the earlier use of infliximab as an effective treatment for ipilimumab-induced diarrhoea.

Relationship of Body Mass Index to Clinical Outcomes after Infliximab Therapy in Patients with Crohn’s Disease

BACKGROUND & AIMS There are conflicting data for the role of obesity in Crohns disease (CD) and the effect on long-term clinical outcomes is poorly studied. Some evidence suggests obesity is associated with diminished responsiveness to biological agents, especially anti-tumour necrosis factor antibodies. METHODS We aimed to examine the influence of body mass index (BMI) on the response to infliximab in CD in a retrospective analysis. The outcomes of interest within 12 months were: (1) Composite loss of response (CD-related flare or surgery; LOR); (2) any CD-related surgery (CDRS); and (3) CD-related intestinal resectional surgery (CDRIS). RESULTS A total of 388 patients were included. The mean BMI was 24.2kg/m(2) [± standard deviation (SD) 5.1]. Of the 388 patients, 137 (35.4%) were overweight (BMI: 25-29.9kg/m(2)) or obese (BMI: ≥30kg/m(2))-160 (41.6%) patients had LOR during the 12 months follow-up; 121 (31.4%) required CDRS, and 109 (28.2%) required CDRIS. Multivariate analysis showed that increasing BMI (per unit, kg/m(2) increase) reduced the risk of LOR [odds ratio (OR): 0.98], CDRS (OR: 0.95), and CDRIS (OR: 0.95). Rates for all outcomes were higher, but not significantly so, in the extreme categories (underweight and obese) and lower in the underweight categories compared with normal BMI. Exclusion of the obese category of patients strengthened this relationship. CONCLUSIONS Body mass index at first infusion of infliximab has a non-linear relationship with outcomes at 12 months. The worst outcomes are at the extremes of weight (underweight and obese categories). Increasing BMI is associated with a modest reduction in risk of LOR, CDRS, and CDRIS within 12 months, increasing with the exclusion of the obese category.

OC-028 High definition white light endoscopy (HDWLE) versus high definition with chromoendoscopy (HDCE) in the detection of dysplasia in long standing ulcerative colitis: a randomised controlled trial

Introduction Patients with ulcerative colitis (UC) have an increased risk for colorectal cancer. The yield of surveillance can be improved by addition of newer endoscopic methods like chromoendoscopy (CE)1and HDWLE when compared to standard definition endoscopy.2There are no studies comparing HDCE and HDWLE. The aim of this trial is to compare the rate of detection of dysplasia in patients with long standing UC with HDWLE compared to HDCE. Method Parallel group randomised controlled trial (clinicaltrials.gov number NCT02138318) in which patients with long standing UC (>10 years) requiring surveillance colonoscopy were randomised to either HDWLE or HDCE (with 0.2% indigo carmine spray). HD scopes (Olympus CF260L or 290L) and processors (Olympus Spectrum CV260 or Elite CV290) and HD monitors were used for all procedures. Time to reach caecum and withdrawal time was recorded. Presence of dysplasia was confirmed by two expert GI histopathologists. Data was analysed according to the number of patients who had dysplastic endoscopic lesions detected (per patient analysis) and also to the number of dysplastic lesions (per lesion analysis). Results In total 53 patients were randomised to HDWLE and 50 to the HDCE arm. Baseline characteristics including duration of disease, bowel preparation, endoscopists, concomitant PSC and previous dysplasia were similar in both arms. A total of 14 dysplastic lesions (1 with high grade and 13 with low grade dysplasia) were detected in 11 patients (22%) in the HDCE arm and 6 dysplastic lesions (all low grade dysplasia) in 5 patients (9.4%) in the HDWLE arm. HDCE was significantly better (p = 0.04) than HDWLE on a per patient basis for the detection of endoscopically visible dysplastic lesions. HDCE (0.26 ± 0.6) detected more dysplastic lesions per-patient than HDWLE (0.12 ± 0.4). Withdrawal time was significantly (p < 0.001) higher in HDCE (21.2 ± 5.8 min) compared to HDWLE (13.6 ± 3.3 min). Conclusion HDCE significantly improves the detection of dysplastic lesions in patients undergoing surveillance endoscopy for UC and should be the procedure of choice in these patients. On average it increases procedure time by 8 min over HDWLE. Disclosure of interest None Declared. References Subramanian V, Mannath J, Ragunath K, Hawkey CJ. Meta-analysis: the diagnostic yield of chromoendoscopy for detecting dysplasia in patients with colonic inflammatory bowel disease. Aliment Pharmacol Ther.2011;33:304–312 Subramanian V, Ramappa V, Telakis E, et.al. High definition versus standard definition endoscopy for detection of dysplasia in colonic inflammatory bowel disease. Inflamm Bowel Dis. 2013;19:350–5

Role of 5-aminosalicylate in preventing colorectal cancer.

was noticed. During the work-up for the breast lump, a right submandibular mass was noted as well. Biopsies from the breast revealed mucinous carcinoma, and from the submandibular mass revealed follicular lymphoma. Extensive workup did not show any metastasis or HCC reappearance. Defi nitive surgeries were performed for both sites then fi nally she got the diagnosis of stage Ia non-Hodgkin ’ s lymphoma (NHL, Figure 2 ) and stage IIa breast cancer. She received adjuvant chemoradiotherapy for breast cancer and chemotherapy for lymphoma. She is disease free aft er 5 years from liver surgery and 2 years from the diagnosis of lymphoma and breast cancer. A study from United States with more than 200,000 control subjects included, revealed nearly three times more NHL cases in hepatitis B virus (HBV)-infected group ( 2 ). Th ere are cohorts and case – control studies pointing the increased risk of lymphoma in hepatitis C virus (HCV) patients ( 3 ). A meta-analysis revealed 2.5 relative risk for NHL in HCV patients ( 4 ). Th is metaanalysis also indicated that the number of patients included in the studies and HCV prevalence in the study region aff ected the relative risks reported in individual studies. In our opinion, this diligent study should not be interpreted by the readers that HCV or HBV is not related to extrahepatic malignancies, particularly lymphoma.

PWE-047 The impact of infliximab (ifx) therapeutic drug monitoring on decisions made in a virtual biologics clinic for ibd

Introduction Virtual biologics clinics (VBC) are used to review annually patients receiving biological therapy. Decisions on continuing, switching or stopping therapy are based on review of clinical symptoms, disease history and investigations. Therapeutic drug monitoring (TDM) of Infliximab trough levels (ITL) and anti-drug antibodies (ADA) has previously not been universally available in the UK. The aim of this study was to assess whether access to TDM influences decision making within VBC. Method All IBD patients receiving Infliximab maintenance therapy were reviewed and two treatment decisions were recorded. The first decision was based on assessment of all clinical details but clinicians remained blinded to ITL and ADA data (Biohit assay). An administrator revealed ITL and ADA data and clinicians formed a second decision incorporating TDM. Decisions were standardised to: A - continue without change B -shorten infusion interval/increase IFX dose C - lengthen infusion interval D - stop IFX E - other. N= blindN= unblinded A 169122 B 916 C 515 D 528 E 3122 Results Of 201 patients reviewed TDM data were available for 191 (mean 40y old, 57% male). Diagnoses were Crohn’s disease in 160, ulcerative colitis in 18 and IBD-U in 13 cases. Mean duration of IFX treatment was 4 years (minimum 6 months), 57% received co-therapy with immunomodulator and 38% had shortened infusion intervals. Disease activity was remission in 70%, mild in 19%, moderate in 10% and severe in 1%. ITL were sub-therapeutic in 25% (<1.8 mg/L), therapeutic in 61% and supra-therapeutic in 14% (>7 mg/L); mean ITL was 3.85 mg/L. ADA were detected in 30% and were >50 AU/ml in 14%. Blinded treatment decisions were changed on unblinded review in 56 cases (29%, table 1, chi-square test: p<0.0001). Knowledge of ITL and ADA led to 7 patients receiving higher dose IFX or more frequent infusions whereas 33 patients were able to dose de-escalate or stop IFX therapy. Decision Conclusion Basing decisions on TDM rather than clinical acumen alone led to change in 29%. An additional 23 patients discontinued therapy (undetectable ITL + high ADA). This represents a considerable cost saving and reduces the exposure to potentially toxic therapies. Routine TDM should be considered as an integral part of VBC. Disclosure of Interest None Declared

PTU-009 The utility of routine chromoendoscopy for detection of dysplastic lesions during surveillance colonoscopy in patients with colonic inflammatory bowel disease. does research translate to clinical practice?

Introduction Dysplasia in colonic inflammatory bowel disease (IBD) is often multifocal and flat. Chromoendoscopy (CE) has been shown in prospective studies to improve dysplasia detection rates by improving the ability to detect subtle mucosal changes.1The utility of CE in dysplasia detection in patients with IBD during routine clinical practice has not been reported so far. We aimed to compare the yield of dysplastic lesions detected by CE with standard white light endoscopy (WLE). Method Retrospective cohort study of patients with long standing (>7 years) colonic IBD undergoing surveillance colonoscopy at Leeds Teaching Hospital NHS Trust between January 2012 to December 2013. Details of diagnosis, duration of disease and outcomes of the colonoscopy were collected from the endoscopy database, electronic patient records and patient notes. Results There were 120 colonoscopies in the CE group and 220 colonoscopies in the WLE group. The groups were well matched for all demographic variables. 27 dysplastic lesions were detected in 20 patients in the CE group and 9 dysplastic lesions were detected in 6 patients in the WLE group. All the lesions were detected on targeted biopsy and harboured low grade dysplasia. The adjusted prevalence ratio (on a per patient basis) for detecting any dysplastic lesion was 4.6 (95% CI 1.6–13.7) in favour of CE. Conclusion CE colonoscopy improves detection of dysplastic lesions during surveillance colonoscopy of patients with colonic IBD even in routine clinical practice, confirming data from prospective trials. CE should be the standard of care for all IBD surveillance procedures as advocated by both BSG and ECCO guidelines. Disclosure of interest None Declared. Reference Subramanian V, Mannath J, Ragunath K, et al. Meta-analysis: the diagnostic yield of chromoendoscopy for detecting dysplasia in patients with colonic inflammatory bowel disease. Aliment Pharmacol Ther. 2011;33(3):304–12