G Jones

Systematic review: the use of thiopurines or anti‐TNF in post‐operative Crohn's disease maintenance – progress and prospects

Post‐operative recurrence of Crohns disease is an important management challenge, with 2‐year recurrence rates defined by clinical, endoscopic and radiological parameters of up to 77%, 64% and 49%. Clinical and severe endoscopic recurrence vary widely in controlled trials from 13% to 36% and 22% to 56% with thiopurine treatment or 0% and 9% with infliximab treatment respectively at 1 year.

Endothelium-derived hyperpolarizing factor and potassium use different mechanisms to induce relaxation of human subcutaneous resistance arteries

This investigation examined the hypothesis that release of K+ accounts for EDHF activity by comparing relaxant responses produced by ACh and KCl in human subcutaneous resistance arteries. Resistance arteries (internal diameter 244±12u2003μm, n=48) from human subcutaneous fat biopsies were suspended in a wire myograph. Cumulative concentration‐response curves were obtained for ACh (10−9u2003–u20033×10−5u2003M) and KCl (2.5u2003–u200325u2003mM) following contraction with noradrenaline (NA; 0.1u2003–u20033u2003μM). ACh (Emax 99.07±9.61%; −LogIC50 7.03±0.22; n=9) and KCl (Emax 74.14±5.61%; −LogIC50 2.12±0.07; n=10)‐induced relaxations were attenuated (P<0.0001) by removal of the endothelium (Emax 8.21±5.39% and 11.56±8.49%, respectively; n=6u2003–u20037). Indomethacin (10u2003μM) did not alter ACh‐induced relaxation whereas L‐NOARG (100u2003μM) reduced this response (Emax 61.7±3.4%, P<0.0001; n=6). The combination of ChTx (50u2003nM) and apamin (30u2003nM) attenuated the L‐NOARG‐insensitive component of ACh‐induced relaxation (Emax: 15.2±10.5%, P<0.002, n=6) although these arteries retained the ability to relax in response to 100u2003μM SIN‐1 (Emax 127.6±13.0%, n=3). Exposure to BaCl2 (30u2003μM) and Ouabain (1u2003mM) did not attenuate the L‐NOARG resistant component of ACh‐mediated relaxation (Emax, 76.09±8.92, P=0.16; n=5). KCl‐mediated relaxation was unaffected by L‐NOARG+indomethacin (Emax; 68.1±5.6%, P=0.33; n=5) or the combination of L‐NOARG/indomethacin/ChTx/apamin (Emax; 86.61±14.02%, P=0.35; n=6). In contrast, the combination of L‐NOARG, indomethacin, ouabain and BaCl2 abolished this response (Emax, 5.67±2.59%, P<0.0001, n=6). The characteristics of KCl‐mediated relaxation differed from those of the nitric oxide/prostaglandin‐independent component of the response to ACh, and were endothelium‐dependent, indicating that K+ does not act as an EDHF in human subcutaneous resistance arteries.

A Novel Approach to the Implementation of Biosimilar Infliximab CT-P13 for the Treatment of IBD Utilising Therapeutic Drug Monitoring: The Edinburgh Experience

Introduction The introduction of biosimilar infliximab with CT-P13 offers substantial potential cost savings. Data on switching from Remicade to CT-P13 is only just emerging and was not available in early 2016. Therapeutic drug monitoring (TDM) is increasingly recognised as an effective means to optimise patient outcomes on anti-TNF therapy, but is not widely adopted in the UK. Following discussions with hospital management, we took the opportunity to implement TDM whilst switching patients established on Remicade to biosimilar CT-P13. Method A switch pathway was agreed and implemented, with all data collected prospectively. Routine blood tests, disease activity scores (Partial Mayo/HBI), faecal calprotectin (FC) and serum for infliximab trough levels (ITL) and antibodies to infliximab (ATI) were obtained. Results were reviewed in a virtual biologics clinic and decision made on further management as per NICE DG-22 TDM algorithm. Clinical remission was defined as HBI Results 169/170 patients currently receiving Remicade agreed to our switch process. 95/169 (56%) patients were switched to CT-P13 with no dose change whilst 15/169 (9%) switched with dose escalation and 8/169 (5%) with dose de-escalation. 27/169 (16%) patients stopped biologic therapy altogether due to a combination of immunogenicity (ITL 8u2009µg/ml), clinical and biochemical remission. 24/169 (14%) patients had immunogenicity with infliximab but were not in remission and therefore switched to an alternative biologic (ADA n=18; VDZ n=6). Remission rates of patients switched with no dose change were 97% pre-switch, compared to 91%, 95%, and 96% at week 6–8, week 12–16 and week 18–24 respectively. In the patients with CD (n=91) median HBI remained unchanged pre-switch and at week 6–8 (HBI 0, p=0.5), week 12–16 (HBI 0, p=0.5) and week 18–24 post-switch (HBI 0, p=0.4). There was no significant difference between ITL and incidence of ATI pre-switch and at week 18–24 (4.2u2009µg/ml vs 3.7u2009µg/ml, p=0.4; 30% vs 26%, p=0.5). 100% of patients who switched with dose de-escalation (n=8) remained in remission at week 18–24. Data on patients who switched with dose escalation or who stopped treatment are presently being analysed. No infusion reactions were reported. Health-economic evaluation of the switch process/TDM implementation has projected a cost-saving of approximately £7u200900u2009000 in year 1. Conclusion Our local experience further supports interchangeability between originator and biosimilar infliximab whilst also demonstrating the significant cost saving that can be achieved through the adoption of biosimilars and TDM. Disclosure of Interest None Declared

Letter: faecal calprotectin and lactoferrin - accurate biomarkers in post-operative Crohn's disease - authors' reply. Letter: biologic therapies are effective for prevention of post-operative Crohn's disease recurrence - authors' reply

SIRS, We welcome the comments from Bodini et al. in response to our review. This letter highlights the confusion clinicians face when considering the heterogeneous evidence for post-operative prophylaxis in patients with Crohn’s disease (CD). It also highlights the difficulties clinicians face in predicting which patients are at highest risk of recurrence. While our review had focused on randomised controlled studies, other data are now available, as Savarino et al. discuss. In these, reported endoscopic recurrence (ER) rates with adalimumab (ADA) vary widely. Aguas et al. reported a 21% ER (Rutgeerts score i ≥2) at 12 months in 29 patients treated with 160/80/40 mg ADA every other week (eow). It is of interest that only two of the pre-requisite ‘high risk’ inclusion criteria predicted recurrence, neither of which was smoking. Papamichael et al. reported a 25% recurrence rate at 24 months (Rutgeerts score i ≥2) in eight patients treated with ADA 180/60/40 mg eow after curative resection, with Savarino et al. reporting 6.3% ER over the same period. On further literature review, we note the modest total of 59 ADA treated patients in 4 uncontrolled studies assessing efficacy in post-operative recurrence. We feel it is difficult therefore to position anti-TNF as first line therapy for post-operative recurrence, notwithstanding the health economic considerations of a treatment 80 times more expensive than, for example, azathioprine (£9295 per year ADA 40 mg eow, £114 per year Azathioprine 150 mg/day). Safety issues are also worthy of consideration in the asymptomatic post-operative setting, especially as drug withdrawal is problematic, and there is an increasing body of opinion favouring indefinite duration of therapy. We think it is very likely that anti-TNF medications will be an important part of future treatment algorithms, but the use and combination of existing immunomodulators in such an algorithm is yet to be established. It remains vital for the treatment stratification of patients that indices, such as biomarkers be utilised to detect the evolution of post-operative recurrence as Yamamoto et al. have suggested. We agree that faceal calprotectin represents an attractive monitoring modality in this area, and look forward to the publication of the trial of prevention of post-operative Crohn’s disease (TOPPIC) that employs this as a defined end-point. Accepting the limitations of current published data we agree with the assertion that there is emerging evidence for anti-TNF efficacy in this setting, but that further confirmation in larger cohorts is required, particularly in identifying those most likely to benefit. We look forward to the imminent publication of the post-operative Crohn’s endoscopic recurrence study (POCER) and of the future PREVENT trial (NCT01190839).

Higher Adalimumab Drug Levels During Maintenance Therapy for Crohn’s Disease Are Associated With Biologic Remission

BACKGROUNDnAdalimumab is an established treatment for Crohns disease. Limited data are available regarding the relationship between adalimumab drug levels and serum/fecal markers of gut inflammation. We therefore aimed to characterize the relationship between adalimumab levels and biologic remission during maintenance therapy.nnnMETHODSnA single-center prospective cross-sectional study was undertaken on Crohns disease patients who had received adalimumab therapy for a minimum of 12 weeks after induction. Data on clinical activity (Harvey-Bradshaw Index), C-reactive protein (CRP), adalimumab drug and antibody levels, and fecal calprotectin were collected. Biologic remission was defined as a CRP <5 mg/L and fecal calprotectin <250 µg/g. Adalimumab drug and antibody levels were processed using the Immundiagnostik monitor enzyme-linked immunosorbent assay.nnnRESULTSnOne hundred fifty-two patients had drug and antibody samples matched with CRP and fecal calprotectin. Patients in biologic remission had significantly higher adalimumab levels compared with others (12.0 µg/mL vs 8.0 µg/mL, P < 0.0001). Receiver operating characteristic curve analysis demonstrated an optimal adalimumab level of >8.5 µg/mL (sensitivity, 82.2%; specificity, 55.7%; likelihood ratio, 1.9) for predicting biologic remission. Multivariable logistic regression revealed that adalimumab levels >8.5 µg/mL were independently associated with biologic remission (odds ratio, 5.27; 95% confidence interval, 2.43-11.44; P < 0.0001).nnnCONCLUSIONSnHigher adalimumab levels are associated with biologic remission. An optimal level of >8.5 µg/mL was identified.

AODWE-007 Real world data on the effectiveness and safety of vedolizumab in the treatment of crohn’s disease and ulcerative colitis: the edinburgh experience

Introduction The GEMINI clinical trials programme has demonstrated the efficacy and safety of vedolizumab in the induction and maintenance of Crohn’s disease and ulcerative colitis. 2 years after licensing and subsequent approvals (eg. NICE/SMC), there is great interest in real world effectiveness and safety data from early adopters. Here, we present the short and medium term outcomes from a single centre cohort of IBD patients treated with vedolizumab. Method The following were prospectively collected for all patients at each infusion: observations, routine haematology, biochemistry and inflammatory markers, clinical disease activity score, faecal calprotectin (FC) and adverse events. Clinical effectiveness was evaluated by assessing changes in HBI and SCCAI at 12–14 weeks and 26 weeks. Clinical remission was defined as a HBI <5u2009and SCCAI <3. Response was defined as a change in disease activity ≥3. Changes in CRP/FC were also analysed. Results By the end of November 2016, 94 patients had received vedolizumab treatment. 63/94 (27 CD, 33 UC, 3 IBDU) had completed 12–14u2009week follow-up and are included in the primary analysis of clinical efficacy. Median disease duration was 7.9 years (IQR 4–15) with 36/63 (57%) patients previously exposed to anti-TNF therapy. Median HBI and SCCAI at baseline were 4 (IQR 2–7) and 5 (IQR 2–6) respectively. At 12–14 weeks median HBI was 3 (IQR 1–7) (p=0.37) with SCCAI dropping to 1 (IQR 1–3) (p=0.004). At 26 weeks median HBI fell to 2 (IQR 0.5–3, n=15) (p=0.02) and SCCAI remained at 1 (IQR 0–1, n=26) (p=0.0001). 23/63 (37%) patients were in clinical remission at baseline (59% on steroids) with 42/63 (67%) at 12–14 weeks (24% on steroids) and 35/41 (85%) at 26 weeks (12% on steroids). Clinical response and remission rates of those patients with clinically active disease at baseline were 61% and 53% at week 12–14 (n=36), and 78% for both at week 26 (n=24). Median FC was 730u2009µg/g (IQR 215–858, n=50) at baseline, 170u2009µg/g (IQR 60–465, n=36) at week 12–14 (p=0.00018) and 70u2009µg/g (IQR 30–180, n=29) at week 26 (p=0.00001). No significant drug related complications were observed. Arthralgia was the most commonly reported side effect (12/94). 7/94 (7%) patients underwent surgery within 30 weeks of starting vedolizumab. 2 pregnancies and 1 colorectal cancer were reported in our cohort. Conclusion Our experience further supports the clinical effectiveness and safety data for the use of vedolizumab. We demonstrate a clear benefit in clinical/biochemical disease activity in a cohort of IBD patients many of which had complex and previously refractory disease. Disclosure of Interest None Declared

OC-166 Predictive factors of disease relapse following thiopurine withdrawal for sustained clinical remission of IBD: Abstract OC-166 Figure 1

Introduction Thiopurine therapy is effective in maintaining clinical remission in IBD. However, long-term therapy is associated with an increased risk of lymphoma; therefore in clinical practice we aim to withdraw therapy after 4–5u2005years. Nevertheless, many patients will experience disease relapse within 12u2005months of drug withdrawal.1 Methods The aim of the present study was to retrospectively determine the relapse rate in ulcerative colitis (UC) and Crohns disease (CD) following azathioprine (AZA) or mercaptopurine (MP) withdrawal and to determine factors predictive of relapse. Patients were identified by electronic case note review of an IBD research database in Edinburgh. Major inclusion criteria were AZA and/or MP therapy for a minimum of 3u2005years, AZA/MP withdrawn due to sustained clinical remission no steroid therapy for 6u2005months prior to drug withdrawal, and minimum 12u2005months follow-up. The primary outcome was disease relapse requiring AZA reinitiation, steroids or colectomy within 12u2005months of AZA/MP withdrawal, with secondary outcome assessed at 24u2005months. Clinical/laboratory predictors of relapse were sought. 1826 electronic records were reviewed (865 CD and 961 UC). 634 were treated with a thiopurine (348 CD and 286 UC). 74 met the strict study inclusion criteria (45 CD and 29 UC). Results CD was associated with a significantly higher risk of relapse than UC on Kaplan–Meier analysis (Abstract OC-166 figure 1, p=0.026). The moderate-severe relapse rate for 12u2005months was 44% for CD and 14% for UC. For 24u2005months, relapse rates were 60% for CD and 48% for UC. Elevated platelet count (p=0.03) and elevated white cell count (p=0.03) were predictive of relapse for UC, while no predictive factors were identified for CD. Median (range) duration of thiopurine use was 6.2 (3.4–18.7)u2005years for CD and 6.0 (3.1–18.0)u2005years for UC. Median duration of follow-up was 32u2005months for CD and 45u2005months for UC. Retreatment with a thiopurine after relapse was successful in 7/7 cases for UC and 18/24 for CD.Abstract OC-166 Figure 1 Survival curves for moderate to severe relapse following thiopurine withdrawal in Crohns disease and ulcerative colitis Conclusion Relapse rates after withdrawal of a thiopurine are high, particularly for CD, and predicting this remains difficult. To help increase the power of this study, we are now expanding it across the UK. Competing interests None declared. Reference 1. Treton. Clin Gastroenterol Hepatol 2009;7:80.

T1706 BMI is Superior to Symptom Characteristics or Esophageal pH Metry in Predicting Response to PPI Therapy in Patients With Normal Endoscopy

Background: Most patients with upper gastrointestinal symptoms are now H. pylori negative and no abnormalities are seen at endoscopy. Proton pump inhibitors (PPIs) are usually prescribed to these patients, though only a proportion benefit. Aim: To identify factors predicting response to PPI therapy in patients with upper GI symptoms and normal endoscopy. Methods: 105 patients with upper gastrointestinal symptoms of >3 months, normal endoscopy and HP-ve tests were prospectively recruited. Patients with hiatus hernia or taking NSAIDs were excluded. Character of symptoms and lifestyle factors were assessed by validated questionnaires and baseline severity over 7 days. The predominant symptom was retrosternal discomfort in 43, epigastric discomfort in 42, nausea/vomiting in 10, fullness/satiety in 1 and other symptoms in 6. Their median BMI was 26 (range 17.6-40.4) with 39% overweight and 20% obese. 24h esophageal pH monitoring and manometry of the lower esophageal sphincter (LES) by perfusion pull through technique (1cm every minute) was performed. Patients were then randomised in double-blind fashion to two weeks daily treatment with 2/3 receiving lansoprazole 30mg/day and 1/3 placebo. Symptomswere re-assessed throughout the second week of treatment, with the primary outcome being absolute change in symptom severity score (Glasgow Dyspepsia Score). Results: 102 individuals were treated (69 randomised to Lansoprazole, 33 to placebo). The mean pre-treatment symptom score in the active treatment group was 10.4 (SD 2.2) and in placebo 10.9 (SD2.7). The mean reduction in score following active treatment was 3.8 (SD 3.8) vs 0.6 (SD 2.1) following placebo (p<0.001). Within the PPI treated group, univariate analysis showed that BMI, LES pressure, LES abdominal length and % time esophageal pH<4 were statistically significant predictors of response. Multivariate regression modelling revealed that in the best model only BMI (p= 0.003) and LES abdominal length (p=0.013) were independent predictors of response (Rsquared = 19.4%). Neither predominant symptom nor any other symptom characteristic predicted response. Conclusion: This study indicates the lack of value of detailed symptom assessment in predicting response to PPI therapy. The strong predictive value of BMI is likely to be due to its association with gastroesophageal reflux which will respond to PPI therapy and highlights the important role of BMI in reflux disease.