Mark Samaan

Vedolizumab in Inflammatory Bowel Disease Associated with Autoimmune Liver Disease Pre- and Postliver Transplantation: A Case Series.

To the Editor: Inflammatory bowel disease (IBD) associated with primary and autoimmune sclerosing cholangitis seems to represent a distinct clinical entity in comparison with “classical” ulcerative colitis and Crohn’s disease. Antitumor necrosis factor (TNF) therapy can be efficacious, but systemic complications remain a real concern, especially after liver transplantation (LT), whereas evidence for other therapeutic interventions is limited to preclinical models and small case series. Vedolizumab (VDZ), a humanized monoclonal antibody directed against the a4b7 integrin, is indicated for induction and maintenance of remission of moderate to severe IBD, either naive or refractory to anti-TNF agents. In this letter, we report our experience of VDZ for 10 patients with primary sclerosing cholangitis/autoimmune sclerosing cholangitis–IBD preand post-LT (n 1⁄4 5, respectively). Table 1 summarizes the disease characteristics and outcomes. Overall, a clinical response was seen in 4/10 patients (40%), 1 of whom achieved clinical remission (sustained to last follow-up). Surgery was required for 1 patient during induction because of acute severe colitis. The median duration of VDZ therapy in the 9 patients who received maintenance was 7.4 (1.4–12.5) months. In responders, a drop in fecal calprotectin (mg/g; median 708 [60–2696] versus 90 [32–960], P 1⁄4 0.03 by Wilcoxon test) and an improvement in quality of life scores were observed (5 [0, 13] versus 13 [8, 16], P 1⁄4 0.03). Abnormalities in liver biochemistry were seen in 2 postLT patients, but both had recurrence of their liver disease before VDZ initiation. No infective complications were attributed to VDZ use. There were no malignancies identified during the follow-up period. This is the first case series of VDZ use in primary sclerosing cholangitis/autoimmune sclerosing cholangitis–IBD patients preand post-LT. Therapy has been well tolerated by all patients, and no safety signals have been identified during the follow-up period despite concomitant immunosuppressants. Even in the context of anti-TNF failure, a good response rate has been documented with improvement in symptoms, objective markers of intestinal inflammation, and quality of life. Followup in this cohort is too short so far to comment on whether VDZ therapy influences the expected rate of pre-LT flares or postLT recurrence of liver disease, but to date, no such events have been recorded. As experience increases, taking into account its potential beneficial effects for autoimmune liver disease and the infectious complications associated with antiTNF use, it seems likely that VDZ will become the treatment of choice for IBD in this group of patients.

Golimumab: early experience and medium-term outcomes from two UK tertiary IBD centres

Objective To gain an understanding of the effectiveness of golimumab in a ‘real-world’ setting. Design Retrospective cohort study using prospectively maintained clinical records. Setting Two UK tertiary IBD centres. Patients Patients with ulcerative colitis (UC) were given golimumab at Guy’s & St Thomas and King’s College Hospitals between September 2014 and December 2016. Intervention Golimumab, a subcutaneously administered antitumour necrosis factor agent. Main outcome measures Clinical disease activity was assessed at baseline and at the first clinical review following induction therapy using the Simple Clinical Colitis Activity Index (SCCAI). Response was defined as an SCCAI reduction of 3 points or more. Remission was defined as an SCCAI of less than 3. Results Fifty-seven patients with UC completed golimumab induction therapy. Paired preinduction and postinduction SCCAI values were available for 31 patients and fell significantly from 7 (2–19) to 3 (0–11) (p<0.001). To these 31, an additional 13 patients who did not have paired SCCAI data but stopped treatment due to documented ‘non-response’ in the opinion of their supervising clinician, were added. Among this combined cohort, 23/44 (52%) had a clinical response, 15/44 (34%) achieved remission and 13/44 (30%) achieved corticosteroid-free remission. Faecal calprotectin and CRP fell (FC: pre-induction: 1096 (15-4800) μg/g, post-induction: 114 (11-4800) μg/g, p = 0.011; n = 20; CRP: pre-induction: 4 (1-59) mg/L, post-induction: 2 (1-34) mg/L, p = 0.01 for n = 43). Post-induction endoscopy was carried out in 23 patients and a mucosal healing (Mayo 0 or 1) rate of 35% was observed. Conclusions Our experience mirrors previously reported real-world cohorts and demonstrates similar outcomes to those observed in randomised controlled trials. These data demonstrate a meaningful reduction in clinical, biochemical and endoscopic disease activity as well as a steroid-sparing effect in patients with previously refractory disease.

Gastrointestinal toxicity of immune checkpoint inhibitors: from mechanisms to management

Immune checkpoint inhibitor therapies are a novel group of monoclonal antibodies with proven effectiveness in a wide range of malignancies, including melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma and Hodgkin lymphoma. Their use in a range of other indications, such as gastrointestinal and head and neck cancer, is currently under investigation. The number of agents included in this drug group is increasing, as is their use. Although they have the potential to improve the treatment of advanced malignancies, they are also associated with a substantial risk of immune-related adverse events. The incidence of gastrointestinal toxicity associated with their use is second only in frequency to dermatological toxicity. Thus, gastroenterologists can expect to be increasingly frequently consulted by oncologists as part of a multidisciplinary approach to managing toxicity. Here, we describe this novel group of agents and their mechanisms of action. We review the manifestations of gastrointestinal toxicity associated with their use so that it can be recognized early and diagnosed accurately. We also discuss the proposed mechanisms underlying this toxicity and describe an algorithmic and, wherever possible, evidence-based approach to its management.

The impact of updated NICE guidelines on biologic treatment of ulcerative colitis: reflections on past practices, the changing present and implications for the future

The advent of biologic therapies has led to significant changes in treatment strategies for ulcerative colitis (UC). Over the past decade, large-scale randomized controlled trials (RCTs) have demonstrated the efficacy of the antitumor necrosis factor (anti-TNF) alpha therapies comprising infliximab,[1] adalimumab, [2,3] and golimumab.[4,5] More recently, a selective leukocyte adhesion molecule inhibitor, vedolizumab,[6] has been shown to be effective in the treatment of UC. The approval of these agents by the European Medicines Agency (EMA) and the National Institute for Health and Care Excellence (NICE) has resulted in a paradigm shift in many aspects of UC care. Here, we consider the impact of recent NICE guidance on the use of these agents and changes in the management of UC over time.

PTH-074 The Presence of Total Anti-Drug Antibodies to Biologic Drugs Does not Adversely Affect Long-Term Outcomes in Crohn’s Disease Patients with Adequate Drugs Levels and Absent Free Anti-Drug Antibodies

Introduction The use of therapeutic drug monitoring (TDM) for anti-TNF drugs has become increasingly widespread over recent years. It is now used in many centres to guide clinical decisions regarding dose optimisation, the use of concomitant immunomodulators as well as switching or withdrawal of treatment.1 TDM usually includes the measurement of serum trough levels of infliximab (IFX) or adalimumab (ADA) as well as anti-drug antibodies (ADAb). There are two different approaches to measuring ADAb; some techniques measure total ADAb (drug-ADAb complexes as well as free ADAb), whilst other measure only free ADAb. However, the clinical relevance of the differing data generated by these techniques is not yet fully understood. Methods A prospective evaluation of trough drug levels and ADAb was performed using our standard ELISA assay (LISA TRACKER, Theradiag) in 145 IBD patients on anti-TNF agents between January and May 2014. This technique measures only free ADAb. The samples were also anaylsed using an ELISA assay that measures total ADAb (IDKmonitor, Immundiagnostik). Long term outcomes were evaluated for 21 (17 IFX, 4 ADA) patients with Crohn’s disease (CD) who were found to have negative free ADAb but positive total ADAb. Outcome assessments were made by review of a prospectively maintained database, with a mean follow-up period of 22 months. Clinical outcome measures included; the need to escalate/switch/withdraw biologic treatment, infusion/injection-site reactions, documented clinical flare (HBI > 5) and need for steroid treatment. Biochemical outcome measures included; CRP > 5 mg/L and faecal calprotectin >150 ug/g. The subsequent development of positive free ADAb and subtherapeutic/undetectable drug levels were also collected as outcome measures. Results Anti-drug antibody (ADAb) detection: Of the 21 CD patients with positive total ADAb and negative free ADAb at the time of initial sampling, 3 (14%) went on to subsequently develop positive free ADAb during the follow-up period. Sixteen patients (75%) were taking concomitant immunomodulators, including all 3 patients who subsequently developed free ADAb. The mean IFX trough level in patients who went on to develop free ADAb was 1.05 ug/ml, compared to 4.04 ug/ml in those who did not. Outcomes: All 3 (100%) of the patients who developed positive free ADAb subsequently went on to have subtherapeutic or undetectable drug levels and required a switch in anti-TNF therapy. Two of the 3 (67%) had a flare in disease activity with an elevated faecal calprotectin. Two (67%) also developed significant infusion reactions. Of the remaining 18 patients who did not subsequently developed free ADAb, only one patient (6%) required a switch in anti-TNF, 4 (22%) developed clinical flares and 3 (17%) required steroid treatment. None of the 18 patients who remained free ADAb negative had undetectable drug levels during the follow-up period. Conclusion Long-term outcomes were not shown to be adversely affected by the presence of total ADAb, in the absence of free ADAb and adequate drug levels. However, patients who subsequently developed free ADAb and subtherapeutic or undetectable drug levels had unfavourable long-term outcomes. The presence of total ADAb does not appear to accurately predict the development of free ADAb. This data supports the use of ELISA techniques which measure free ADAb as well as drug levels. Our study and other similar work,2 suggests that quantification of drug-ADAb complexes (total ADAb) appears to be less relevant to long-term clinical outcomes and therefore, less informative to clinical decision making. References 1 Ben-Horin S, Chowers Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nature Reviews Gastroenterology & Hepatology 2014;11:243–255. 2 van schouwenburg, et al. Long-term measurement of anti-adalimumab using pH-shift-anti-idiotype antigen binding tests shows predictive value and transient antibody formation.Ann Rheum Dis. 2013;72:1680–6. Disclosure of Interest None Declared

Long term outcomes of initial infliximab therapy for inflammatory pouch pathology: a multi-Centre retrospective study

Abstract Background: Restorative proctocolectomy with ileal pouch-anal anastomosis is considered the procedure of choice in patients with ulcerative colitis refractory to medical therapy. Subsequent inflammation of the pouch is a common complication and in some cases, pouchitis fails to respond to antibiotics, the mainstay of treatment. In such cases, corticosteroids, immunomodulatory or biologic treatments are options. However, our understanding of the efficacy of anti-tumour necrosis factor medications in both chronic pouchitis and Crohn’s-like inflammation is based on studies that include relatively small numbers of patients. Methods: This was an observational, retrospective, multi-centre study to assess the long-term effectiveness and safety of infliximab (IFX) for inflammatory disorders related to the ileoanal pouch. The primary outcome was the development of IFX failure defined by early failure to IFX or secondary loss of response to IFX. Results: Thirty-four patients met the inclusion criteria; 18/34 (53%) who were initiated on IFX for inflammatory disorders of the pouch had IFX failure, 3/34 (8%) had early failure and 15/34 (44%) had secondary loss of response with a median follow-up of 280 days (range 3–47 months). In total, 24/34 (71%) avoided an ileostomy by switching to other medical therapies at a median follow-up of 366 days (1–130 months). Conclusions: Initial IFX therapy for pouch inflammatory conditions is associated with IFX failure in just over half of all patients. Despite a high failure rate, an ileostomy can be avoided in almost three-quarters of patients at four years by using other medical therapies.

The Clinical and Cost-Effectiveness of 4 Enzyme-Linked Immunosorbent Assay Kits for Monitoring Infliximab in Crohn Disease Patients: Protocol for a Validation Study

Background Currently, treatment decisions for people with Crohn disease are based on clinical judgment and trial and error. Consequently, people may continue to receive high drug dosages and experience unnecessary toxicity when it is possible to reduce or discontinue without a detrimental effect on clinical outcomes. Therapeutic drug monitoring (TDM) involves regularly testing blood samples for drug and antibody levels that could help clinicians identify the optimal treatment strategy and pre-empt treatment failure. However, heterogeneity in the assays can lead to a discrepancy in results and difficulties in decision-making. Standardization of the kits, and therefore results, would allow clinicians to optimize the use of biologics. Currently, there is also a lack of evidence for the cost-effectiveness of TDM using commercial test kits. Objective This study aims to analyze the clinical and cost-effectiveness of 4 commercial enzyme-linked immunosorbent assay (ELISA) kits (LISA TRACKER, IDKmonitor, Promonitor, and RIDASCREEN) to generate evidence which could support a recommendation for wider adoption in the National Health Service. Methods We propose to carry out a prospective-retrospective predictive biomarker validation study using the blood samples and clinical/utilization data collected during the ongoing SPARE trial (NCT02177071). A total of 200 stored samples from people with Crohns disease who respond to treatment with infliximab will be used along with clinical and cost data from the trial. We will investigate the relationship between the drug and antidrug antibody levels with the main clinical outcomes (relapse rate at 2 years and time spent in remission), as well as resource utilization and quality of life. Results Funding is being sought to conduct this research. Conclusions This is the first study to compare the 4 ELISA kits for monitoring infliximab in patients with Crohn disease. It aims to address the uncertainties in the potential benefits of using the technologies for TDM. International Registered Report Identifier (IRRID) PRR1-10.2196/11218

Wide variation in the use and understanding of therapeutic drug monitoring for anti-TNF agents in inflammatory bowel disease: an inexact science?

ABSTRACT Background: We aimed to understand the way in which therapeutic drug monitoring (TDM) is used, understood and interpreted for anti-TNF agents in IBD. Research design and methods: We designed an 18-question survey that included 5 TDM-based clinical scenarios, for which the ‘most appropriate’ responses were based on the BRIDGe groups ‘Anti-TNF Optimizer’. This resource combines TDM evidence with expert consensus. Results: We received 110 complete responses: 50 (45%) consultants, 30 (27%) trainees, 25 (23%) IBD nurse specialists and 5 (5%) gastroenterology pharmacists. Over half (61, 55%) only carry out TDM in non-response. The remainder use TDM routinely, including during stable maintenance therapy for patients in remission. Lower therapeutic thresholds used were variable. Most (82, 75%) were unsure whether their laboratory uses a drug-tolerant or drug-sensitive antidrug antibody assay and few (15, 14%) understand the difference. Consultants, high-frequency users (> 3requests/month) and clinicians with larger anti-TNF cohorts (> 100) were significantly more likely to select the ‘most appropriate’ answer to at least 1 of the 5 TDM-based clinical scenarios. Conclusions: There exists marked heterogeneity in the practical use, understanding and interpretation of biologic TDM. Biologic decision-making, informed by TDM, should involve consultation with experienced clinicians who are frequent TDM users, ideally, as part of a multidisciplinary, biologics-focused IBD meeting. Abbreviations: TDM: therapeutic drug monitoring; CNS: clinical nurse specialist; ELISA: enzyme-linked immunosorbent assay; RIA: radioimmunoassays; HMSA: homogenous mobility shift assays; BSG: British Society of Gastroenterology.

PTU-062 Vedolizumab: Early Experience and Medium-Term Follow up Data from Two UK Tertiary IBD Centres

Introduction Vedolizumab was recently granted NICE approval for moderate-to-severe Crohn’s disease (CD) and ulcerative colitis (UC). Novel pathways agreed by our CCG meant that patients at Guy’s & St. Thomas’ and King’s College Hospitals had early access to vedolizumab. Methods Records of patients commencing vedolizumab between Nov 2014–15 were screened. Those completing at least 14 weeks of treatment were included. Clinical activity was assessed using Harvey-Bradshaw Index (HBI) or Simple Clinical Colitis Activity Index (SCCAI) at baseline, 14 and 30 weeks. Response: HBI/SCCAI reduction ≥3. Remission: HBI < 5 or SCCAI <3. Continuous data are summarised as medians (range). Pre- and post-induction values were compared using Wilcoxon signed-rank test. Results 60 patients (CD: 32, 53%, UC 25, 42%, IBD-U 3, 5%) commenced vedolizumab (m:f 29:31, age: 39 (18–74), follow-up: 5 months (1–13)). 19 were excluded from our analysis (3 IBD-U, 5 stomas, 11 treated for <14 weeks). Clinical data from the remaining 41 was analysed. Of 32 patients with active disease at baseline, 17 (53%) responded and 11 (34%) achieved remission by week 14. The response and remission rates for CD were 8/15 (53%) and 6/15 (40%). In UC they were 9/17 (53%) and 5/17 (29%). Response and remission rates in anti-TNF experienced patients were 12/26 (46%) and 6/36 (35%) compared to 5/6 (83%) and 5/6 (83%) in anti-TNF naïve patients, respectively. 7/11 (64%) with active disease at baseline who completed 30 weeks of treatment responded and achieved remission. Faecal calprotectin fell significantly (pre-induction: 1076 (90–4800), post-induction: 478 (10–3184), p = 0.029 for n = 14) and CRP remained stable (pre-induction: 4 (1–70), post-induction: 4 (1–72), p = 0.28 for n = 40). Rates of steroid use at each time point: 19/41 (46%) at baseline, 11/41 (21%) at week 14 and 3/15 (20%) at week 30. Surgery was required in 4/41 (10%, CD:3 and UC:1). Conclusion Our experience mirrors a previously reported real-world cohort1 and demonstrates similar efficacy to the GEMINI trials. This data demonstrates a meaningful reduction in clinical and biochemical disease activity as well as a steroid-sparing effect in patients with complex and previously refractory disease. We did not see a significant difference in efficacy between patients with UC and CD. Reference 1 Christensen B. et al. Post-marketing experience of vedolizumab for IBD: The University of Chicago experience. ECCO; Barcelona, 2015. Disclosure of Interest None Declared

PTU-065 Four-Way Comparison of Elisa Methods Available for the Measurement of Infliximab and Anti-Infliximab Antibody in IBD Patients

Introduction Commercial assays are now widely available and in routine use for the therapeutic drug monitoring of Infliximab (IFX) and anti-Infliximab antibody (ADAb). Although results generated using these assays are used to guide clinical decision making, there is no standardisation and data assessing the comparability between these assays is lacking. Methods A prospective evaluation of IFX drug levels and ADAb was performed using our standard ELISA assay; LISA TRACKER (Theradiag) and also Promonitor (Proteomika), IDKmonitor (Immundiagnostik) and RIDASCREEN IFX (R-Biopharm AG / KU Leuven) ELISA assays. 105 samples from 102 IBD patients were analysed for IFX, free ADAb (LT/PRO) and total ADAb (ID) automated on eRobot and Grifols Triturus analysers. LT, PRO and RS kits were provided at no cost.Method comparisons were performed using difference plots and Passing Bablok analysis. Results A summary of IFX drug level comparison data is shown in the image below. The distribution of bias between methods was variable (-6.7% to +87.8%) with PRO and ID showing scattered, bimodal distributions of %bias. A consistent, proportional relationship was observed between LT and RS results. Free ADAb were detected in 4/105 (3.8%) samples using LT and 3/105 using PRO. All patients with detectable free ADAb had undetectable IFX drug levels. Conversely, total ADAb were detected in 23/105 (21.9%) samples but IFX drug levels were sub-therapeutic (<1.0 ug/mL) in only 6/23 (26.1%) of these and therapeutic (>2.0 ug/mL) in the majority of cases (13/23).Abstract PTU-065 Figure 1 Conclusion These results show that there is significant variation in IFX drug levels obtained when using different CE marked ELISA assays and as such, results are not directly comparable. Although the clinical utility of measuring total ADAb is yet to be established, a significant proportion of patients tested will be positive for total ADAb irrespective of therapeutic IFX drug levels. In the absence of assay standardisation and external quality assurance, laboratory providers and clinicians should ensure that assays currently in routine use are fit for purpose. Disclosure of Interest None Declared