Obeticholic Acid Improves Aminotransferases Early during Treatment in Patients with Primary Biliary Cholangitis Not Responding to Ursodeoxycholic Acid: A Study in Clinical Practice

Obeticholic acid (OCA) improves cholestasis and is generally well tolerated in patients with primary biliary cholangitis (PBC) not responding, or intolerant, to ursodeoxycholic acid (UDCA). As PBC is mainly a cholestatic disorder, less attention is paid to aminotransferase behavior in the course of treatment. In this study we evaluated, in clinical practice, the efficacy of OCA treatment on both alkaline phosphatase (ALP) and alanine aminotransferase (ALT) using updated healthy ranges for aminotransferases. Fifteen PBC patients, non-responders to UDCA, were evaluated at baseline and during OCA treatment with serial measurement of cholestasis indexes and ALT, that were also assessed using updated normal ranges (<30 IU/L in males, <19 IU/L in females). Median ALP and ALT decreased from 2.16 to 1.27 × upper limit of normal (p = 0.003) and from 0.93 to 0.78 × upper limit of normal (p = 0.008), respectively, in the course of OCA treatment. At treatment day-15, median ALT decreased by 29.7% and ALP by 8.8%. Bilirubin and albumin were unmodified throughout treatment. Using updated normal ranges, ALT levels were normal in 6.7% of patients at baseline and in 33.3% of patients at 18 months of treatment. OCA treatment improves cholestasis and, also, indexes of hepatocyte necrosis, with a decline in necro-inflammatory activity even predating the improvement in cholestasis. Use of recalibrated healthy ranges for aminotransferases might be a useful tool to assess hepatic histological activity and its improvement with OCA treatment.

P223 Degree of Histological Activity is not Associated with Vedolizumab Therapy Outcome in Ulcerative Colitis

Background Histological inflammation is known to be associated with increased risk of disease relapse in patients with ulcerative colitis (UC). Vedolizumab (VDZ) is a gut selective anti-integrin which inhibits intestinal immune cell-trafficking. Whether the degree of histological activity at the time of VDZ therapy initiation is associated with therapy outcome is not known. We aimed to determine if there is an association between histological activity at the time of VDZ initiation and outcome of therapy. Methods A retrospective review was performed to identify UC patients treated with VDZ who had undergone an endoscopic assessment prior to therapy commencement. Baseline demographic data, information on therapy outcome and Mayo endoscopic sub score (MES) was collected for all patients. Endoscopic biopsies were retrieved and were scored for histological activity using the Geboes Score (GS). For Kaplan Meir analyses of primary endpoint, the cohort was dichotomised around a GS grade of 5. Primary endpoint was VDZ therapy outcome defined as persistence on VDZ therapy over time. Secondary endpoints included association between GS and MES and the association between a combined endoscopic and histological endpoint (MES = 3 & GS grade 5) and VDZ therapy outcome. Results 33 patients were included [median age 44.3 years (range 17.2 -84.3); 36% male gender]. 24%, 43% and 33% of the cohort had proctitis, left-sided colitis and extensive colitis respectively. 67% of subjects had prior anti-TNF exposure. Median time from endoscopy to commencement of VDZ was 9 weeks. Median study follow-up was 68 weeks (range 6.1 – 228.7). 3%, 21%, 42% and 33% had MES of 0, 1, 2 and 3 respectively. GS grade was significantly associated with MES (p = 0.04) (Figure 1). GS grade was not associated with time to discontinuation of VDZ (p=0.64) (Figure 2). Combined endoscopic and histological endpoint was not associated with time to discontinuation of VDZ (p=0.43) (Figure 3). The presence of lamina propria eosinophils was not associated with time to discontinuation of VDZ (p=0.92). Conclusion GS grade is associated significantly with MES which has been demonstrated previously. Neither histological activity alone nor in combination endoscopic activity were associated with outcome of VDZ therapy. Assessment of histological activity does not appear to provide additional information when selecting patients for VDZ therapy.

P211 Pseudopolyps are associated with increased fecal calprotectin levels in patients with Inflammatory Bowel Disease in clinical and endoscopic remission

Background Fecal calprotectin (FC) has become a fundamental tool in the non-invasive monitorization of activity in patients with inflammatory bowel diseases (IBD). However, there is still debate over the choice of the optimal cut-off point for the different clinical settings. The aim of this study is to analyze whether the presence of pseudopolyps and their characteristics have an impact on the value of FC and should therefore be taken into account when deciding the optimal cutoff values. Methods A single-centered, retrospective analysis including data from patients with colonic Crohn′s disease or Ulcerative colitis who underwent colonoscopy for dysplasia screening at our center between 2018 and 2019. Patients that did not have a FC registered within 8 months from to the colonoscopy, or that did not maintain clinical remission between the colonoscopy and the measurement of the FC, were excluded. Patients that had activity in the colonoscopy (Mayo endoscopic score &gt;0, SESCD &gt;0) were also excluded. Results 73 patients were included. 26 (35.6%) of them had pseudopolyps in the colonoscopy. The median value of the FC was significantly different in patients with pseudopolyps (110.1 µg/g, CI 95% [48.6–171.5]) compared to those without them (52.5 µg/g, CI 95% [29.9–75.1]). In 11 (42.3%) of the patients with pseudopolyps, biopsies were taken, observing histological activity in 3 of them (27.3%) and no inflammatory activity in the other 8 (72.7%). We found that FC was higher in patients with inflammatory polyps (119.0 µg/g) in comparison to those without histological activity in their pseudopolyps (96.9 µg/g); however, these results were not statistically significant. The location of the pseudopolyps had no influence over the FC in our study. In addition, no correlation was found between the presence of polyps or diverticula and FC. Conclusion In our study, the presence of pseudopolyps is associated with significantly higher levels of FC. Moreover, our results suggest a tendency towards higher FC in patients who had active colitis in the histological samples of their pseudopolyps.

P545 Calprotectin at week 12 is a predictor for histological remission in ulcerative colitis patients treated with Vedolizumab

Background Vedolizumab (VDZ) is a gut-specific α4β7 integrin antagonist that has demonstrated efficacy for induction and maintenance of remission in moderate to severe ulcerative colitis (UC). The aim of this study was to assess the rates of histological remission (HR) in a real-world setting and to identify predictors for histological remission. Methods Retrospective cohort study of all UC patients (≥18 years) initiated on VDZ from 2016 to 2020 was completed. Clinical, biochemical, endoscopic and histologic data were collected. All patients received standard induction therapy with VDZ 300 mg IV at Weeks 0, 2, and 6 and maintained on an 8-weekly regimen. Dose was escalated to a every 4-weekly regimen as per physician’s discretion. A 52-week follow-up was completed on all patients. Endoscopic assessment was carried out between 24 and 52 weeks after commencing VDZ. Histological activity was graded as per Nancy index and histological remission was defined as Nancy grade 0. Endoscopic remission was defined as Mayo endoscopic score = 0. Clinical remission was defined as SCCAI ≤ 5. Results A total of 51 patients [55% female, median age 48 years (IQR 35–60)] were included. 16/51 (34%) were anti-TNF exposed. In 30/51 (59%) patients VDZ was combined with steroids at induction and by week 12 steroids were completely tapered in 14/30 (46.7%) patients. At weeks 12, 24 and 52, 89.6%, 87% and 97.5% of patients, respectively, were in clinical remission. 19/37 (51.3%) patients were in endoscopic remission at end of follow up. Median Nancy score prior to commencing VDZ was 3 (IQR: 2–4) and the median Nancy score at end of follow up was 1 (IQR: 0–2). 19/37 (51.3%) patients achieved HR; 3 patients who were in HR at the time of commencement of VDZ remained in HR at the end of follow up. Median baseline faeces calprotectin (FC) was 320 mcg/g (IQR 45–1000) and was similar in patients who achieved HR and those who did not. Median FC at 12 weeks was 155 mcg/g (45–720) and was significantly lower in patients who achieved HR when compared to patients who did not achieve histological remission (45 vs 420, p 0.028). FC at week 12 predicted histological remission (AUC =0.8667). FC ≥ 200mcg/g at week 12 predicted failure to achieve HR with sensitivity 70%, specificity 100%, PPV 100%, NPV 75%, accuracy 84%. Conclusion Vedolizumab is effective in achieving histological remission and FC ≥ 200 mcg/g at week 12 accurately predicts failure to achieve HR in patients treated with VDZ.

Increased mucosal IL-12 expression is associated with relapse of ulcerative colitis

Background The role of IL-12/23 in the pathogenesis of ulcerative colitis (UC) is unclear. We analyzed mucosal IL-12/23 expression and its relationship with endoscopic severity, histological activity, and UC relapse. Methods Rectal biopsies were collected from 70 UC patients with clinical remission. IL-12, IL-23, IFN-γ, IL-17A, and IL-17F mRNA expression was measured by real-time PCR. Endoscopic severity and histological activity were evaluated using the Mayo endoscopic subscore (MES) and the Geboes score, respectively. Results The longest follow-up period was 51 months. Thirty-four patients relapsed during the study period. Samples from these subsequently relapsed patients formed the “relapse” group, while those from patients that did not relapse formed the “remission” group. IL-12 (P = 0.0003) and IL-23 (P = 0.014) mRNA expression was significantly higher in the relapse than the remission group. Expression of IL-23 (P = 0.015) but not IL-12 (P = 0.374) was correlated with MES. However, in patients with an MES of 0 and 1, IL-12 expression was statistically higher in the relapse than the remission group (P = 0.0015, P = 0.0342). IL-12 and IL-23 expression did not vary significantly between histologically active and inactive mucosa; both were higher in histologically inactive patients in the remission group (IL-12: P = 0.0002, IL-23: P = 0.046). Conclusions Rectal IL-12 and IL-23 expression was elevated in the relapse group, but IL-12 was more strongly associated with UC relapse, irrespective of endoscopic severity and histological activity. Mucosal IL-12 was elevated in patients with deep mucosal healing. Our results suggest an important role of IL-12 in UC pathogenesis and the molecular mechanism of UC relapse.

Histological Remission in Ulcerative Colitis in Deep Remission under Treatment with Adalimumab

Background and Aims: Histological remission (HR) has been recently demonstrated as the last therapeutic goal in ulcerative colitis (UC), but it is unknown whether and how it may occur. Our aim was to assess the histology during the follow-up of an UC population in deep remission under treatment with adalimumab (ADA). Methods: We performed a retrospective study on 22 UC patients who were in deep remission and followed-up while receiving therapy with ADA. Colonoscopy in those patients was performed every year. Four-quadrant biopsies every 10 cm were obtained during each colonoscopy and assessed by hematoxylin and eosin stain. Histological activity was classified using the Geboes scale. Results: A total of 22 patients were enrolled in the study. The mean follow-up of those patients was 28±7 months, and 2,592 biopsy specimens in total were taken during 108 colonoscopies performed during the follow-up. At the beginning of the follow-up, histological inflammation was found in 15/22 (68.2%) of patients in deep remissio while receiving maintenance ADA therapy, 8/22 (36.4%) of them with Geboes score ≥3.1. At the end of the follow-up, when patients were still in deep remission while receiving maintenance ADA therapy, only 4 patients (18.2%) had at least one biopsy specimen with evidence of any histological inflammation during the follow-up; only two patients (9.1%) had Geboes score ≥3.1. Conclusions: Our study shows for the first time that UC patients in deep remission under ADA may reach HR, but it seems slower than other clinical or endoscopic goals.