Guy Chung-Faye

Fecal M2-Pyruvate Kinase (M2-PK): A Novel Marker of Intestinal Inflammation

Background: Surrogate markers of bowel inflammation are increasingly being recognized as important, not only as markers of disease activity in inflammatory bowel disease (IBD) but also to differentiate irritable bowel syndrome (IBS) from IBD. The dimeric M2‐isoform of pyruvate kinase (M2‐PK) has been reported to be elevated in fecal specimens from colorectal cancer (CA) patients, but its role in IBD is unknown. This study investigated the usefulness of fecal M2‐PK in cohorts of patients with IBD, IBS, and CA. Methods: Stool samples were obtained for calprotectin and M2‐PK measurements in patients with previously diagnosed IBD or new patients being investigated for lower gastrointestinal (GI) symptoms in a UK university hospital. Other investigations were performed as directed by the investigating physician and patients with known IBD were assessed for disease activity by a physician global assessment, Harvey–Bradshaw index (HBI), or endoscopic grading. Results: Fecal M2‐PK and calprotectin measurements were obtained for 148 patients: 50 with ulcerative colitis (UC); 31 with Crohns disease (CD), 43 with irritable bowel syndrome/functional bowel disorders (IBS); 7 with colorectal CA, and 17 with miscellaneous conditions (excluded from the analysis). Median M2‐PK values (U/mL) were significantly elevated in UC: 20.0 (95% confidence interval [CI] 5.4–69.0, P < 0.0001), CD: 24.3 (95% CI 6.4–44.0, P < 0.0001), and CA: 7.0 (95% CI 4.3–88.0, P < 0.0006) compared to IBS: 0.1 (95% CI 0.0–3.2). There was a strong linear correlation of M2‐PK with calprotectin levels. A predetermined cutoff level of 3.7 U/mL for a normal M2‐PK test produced a sensitivity, specificity, and positive predictive value (PPV) of 73%, 74%, and 89%, respectively, for organic disease. Furthermore, M2‐PK levels were significantly elevated in active, compared to inactive, disease for CD (30 versus 0.55 U/mL, P < 0.005) and UC (40 versus 1.2 U/mL, P = 0.006), respectively. Conclusions: Fecal M2‐PK is elevated in IBD as well as in CA patients and is a sensitive and relatively specific marker for organic GI pathology, with a PPV of 89%. Furthermore, it appears to be a potentially valuable, noninvasive marker of disease activity in IBD.

Selective white cell apheresis reduces relapse rates in patients with IBD at significant risk of clinical relapse

Background: We assessed whether selective granulocyte and monocyte/macrophage adsorption apheresis maintained clinical remission in asymptomatic inflammatory bowel disease (IBD) patients at significant risk of clinical relapse. Methods: Sixty asymptomatic patients (age 18–70 years) with IBD (in clinical remission) with fecal calprotectin over 250 &mgr;g/g (which defines those at risk of clinical relapse with >80% specificity and sensitivity) were recruited for this open‐label, prospective, randomized, controlled study. Twenty‐nine underwent selective leukocytapheresis, undergoing 5, once weekly, out‐patient sessions. Thirty‐one had unchanged maintenance treatment and acted as controls. Follow‐up for a clinical relapse was 6 months. The secondary outcome variable was the time to relapse. Results: The number of patients who remained in clinical remission at 6 months was significantly lower in controls (32.3%) than in the apheresis (72.4%) group (P = 0.0023, Fishers exact test). The time to first relapse was significantly earlier in the control group (99 ± 73 days) as compared with the apheresis group (161 ± 44 days) (log‐rank test; P = 0.0004). Mild and transient headache was reported by 16 of the 29 (55%) for up to 3 hours, but no serious side effects were observed. Conclusions: This study represents a new approach to the treatment of IBD by targeting a group of asymptomatic patients for treatment who are at significant risk of relapse based on high fecal calprotectin concentrations. Selective leukocytapheresis significantly reduced the number of, and increased the time to, clinical relapse in these patients without serious side effects.

Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn’s disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10−10, OR = 2.3[95% CI = 1.75–3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1–5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.

Remission and relapse of Crohn’s disease following autologous haematopoietic stem cell transplantation for non-Hodgkin’s lymphoma

Autologous haematopoietic stem cell transplantation (HSCT) for Crohn’s disease has been described by Oyama and co-workers as producing remission in 11 of 12 patients with refractory Crohn’s disease after a median follow up of 18.5 months.1 They postulated that autologous HSCT was useful for refractory Crohn’s disease. We report the case of a 32 year old woman with biopsy proven Crohn’s disease diagnosed when she was 16 years old. Her mother also suffered from Crohn’s disease. She developed a KI1 positive anaplastic non-Hodgkin’s lymphoma (NHL) three years later, treated successfully with ablative CHOP chemotherapy and autologous HSCT, inducing remission for …

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.

Factors influencing participation in colorectal cancer screening—a qualitative study in an ethnic and socio-economically diverse inner city population

Ethnic and socio‐economic inequalities have been reported in the uptake of colorectal cancer (CRC) screening. This study aimed to explore the factors affecting CRC screening participation in an ethnically and socio‐economically diverse inner city population.

Fecal Calproctectin is Strongly Predictive of Clinical Disease Activity and Histological Severity in Inflammatory Bowel Disease

little to the assessment based on the partial Mayo domains which can be used to predict the total Mayo score. However, endoscopy score could not be accurately predicted from clinical domains. During follow-up in trials, sigmoidoscopy may be avoided without significant loss of information. However, at the first and final visit sigmoidoscopy should be retained as the mucosal appearance cannot be predicted from the partial Mayo score. References 1 Riley SA et al. Gut 1991; 32:174-8

Early change in faecal calprotectin predicts primary non-response to anti-TNFα therapy in Crohn's disease.

Abstract Objective: The early identification of primary non-response to anti-TNFα therapy facilitates the timely management of patients with Crohn’s disease (CD). A recent, pilot study to detect prognostic markers of early response to anti-TNFα therapy identified the two genes coding for the calprotectin subunits (S100A8, S100A9) to be among the most highly expressed gene transcripts in non-responders. This study tests the hypothesis that measurements of faecal calprotectin (FCAL) pre- and post-anti-TNFα induction can predict primary non-response. Methods: Retrospective study of 32 CD patients treated over a two-year period. Outcomes were assessed at 6 months based on clinical activity scores and the use of corticosteroids: (a) remission: Harvey–Bradshaw index (HBI) < 5, off corticosteroids >2 months; (b) response: drop in HBI >3, off corticosteroids; (c) non-response: ΔFCAL (and ΔCRP, respectively) was calculated as (FCAL post-induction – FCAL pre-induction) × 100/FCAL pre induction. Results: At 6 months, 23 (72%) patients had responded (median (interquartile range) HBI: 4 (3–5), FCAL: 55 (27–146)), 17 (73%) of whom were in remission [HBI: 3 (2.5–4) and FCAL: 42 (16–115)]. There was a significant difference in the ΔFCAL from baseline to post-induction in the three groups (p < 0.0001). Comparing non-responders to combined response and remission groups, the AUC of ΔFCAL to predict outcome at 6 months was 0.97. Using ROC analysis, a Δ70% returned a sensitivity and specificity of 99% and 96%, respectively (likelihood ratio, LR= 23). ΔCRP did not predict 6 months outcomes. Conclusions: A drop in FCAL <70% after induction predicts primary non-response to anti-TNFα in CD.

P599 Home testing for faecal calprotectin: follow-up results from the first UK trial

Introduction Faecal calprotectin (FCAL) is a useful test for monitoring inflammatory bowel disease (IBD) activity. Providing a stool sample in person to the hospital laboratory is anecdotally unpopular. A new FCAL kit (IBDocTM, Bühlmann) enables selftesting using a proprietary collection tube, camera smartphone and app. The aims of this study were to: • assess patients’ adherence to and experience of using IBDocTM • compare the assay to the standard laboratory test • determine if IBDocTM can be used to predict a flare of IBD within four months.