Patients In Endoscopic Remission Research Articles

P551 Platelet-to-lymphocyte ratio index for non-invasive assessment of endoscopic activity in small bowel Crohn’s disease: application and prospective validation.

Abstract Background The platelet-to-lymphocyte ratio (PLR) index has recently been a focus of investigation as a reliable marker of inflammation, being shown to have a good accuracy upon predicting endoscopic remission in patients with colonic Crohn’s Disease (CD). We aimed to evaluate and validate the discriminative power of PLR index in patients with small bowel CD. Methods Single center study including patients with isolated small bowel CD (L1 ± L4 disease according to Montreal classification) undergoing small bowel capsule endoscopy (SBCE) for assessment of endoscopic activity. CD endoscopic activity was classified according to the Lewis score (LS) value. Complete blood count, C-reactive protein and fecal calprotectin values were collected within 1 month of SBCE. A retrospective sample was used for initial assessment of PLR index performance, followed by a prospective 2-years application on a distinct sample. Results The initial sample included 49 and the validation sample 48 patients, both groups being age- and gender-matched. On the initial cohort, PLR index presented a positive moderate correlation with LS (k=0.597; p<0.001), which was stronger than the one found with fecal calprotectin (k=0.525; p=0.001) or C-reactive protein (k=0.321; p=0.029). PLR index presented an excellent accuracy for predicting patients with a moderate-to-severe endoscopic activity (AUC=0.91; 95%CI=0.82-0.99; p<0.001), and a good accuracy for prediction of mucosal healing (AUC=0.74; 95%CI=0.60-0.89; p=0.007). These results were confirmed on the prospective validation cohort, as the correlation of LS with PLR index (k=0.631; p<0.001) was further stronger than with fecal calprotectin (k=0.355; p=0.040) and C-reactive protein (k=0.183; p=0.219). The accuracy of PLR index was confirmed to be excellent for moderate-to-severe endoscopic activity (AUC=0.87; 95%CI=0.76-0.98; p<0.001) and good for mucosal healing (AUC=0.74; 95%CI=0.59-0.87; p<0.001). Conclusion PLR index demonstrated an excellent acuity in predicting moderate-to-severe disease and good acuity in predicting mucosal healing in patients with small bowel CD, with both associations confirmed on a prospective validation cohort. Our findings establish this index as a promising and easy-to-apply tool for non-invasive and regular follow-up of patients with small bowel CD.

P182 Modified Multiplier SES-CD (MM-SES-CD) and laboratorial Crohn’s disease activity parameters: is there any association?

Abstract Background Contrary to the Simple Endoscopic Score for Crohn’s Disease (SES-CD), Modified Multiplier SES-CD (MM-SES-CD) is a new endoscopic severity assessment tool that was able to predict one-year endoscopic remission in patients with Crohn’s Disease (CD) on active therapy. Unlike SES-CD, MM-SES-CD accounts for the number of segments affected and the different prognostic weight of individual SES-CD parameters according to disease location. Nevertheless, there is scarce information regarding its relationship with laboratorial parameters, namely C-reactive protein (CRP) and fecal calprotectin (FC). We aimed to analyze the association between MM-SES-CD and these laboratorial parameters. Methods Retrospective cohort-study including all ileocolonoscopies performed in adult CD patients between January 2020 and October 2022 with CRP (mg/dL) and FC (ug/g) collected within one month. Patients with previous intestinal surgery or inadequate bowel preparation were excluded. MM-SES-CD, ranging from 0 to 130.5, was calculated and different severity categories were defined as follows: remission (<14), mild (≥14 to <31), moderate (≥31 to <45), and severe (≥45). MM-SES-CD values were correlated and compared, according to severity categories, with laboratorial biomarkers. Results A total of 272 ileocolonoscopies from 218 CD patients were included, most females (54.1%) with a mean age of 41 years old. Most patients were A2 (72.8%), L1 (51.1%) and B1 (73.9%), according to Montreal classification. Median MM-SES-CD, CRP and FC was 12.0, 2.9 and 222.0, respectively. Despite MM-SES-CD values correlated weakly with CRP (r=0.376, P<0.001) and moderately with FC (r=0.531, P<0.001), patients with endoscopic remission had significantly lower median CRP (2.9 vs 7.7, P<0.001) and FC (128 vs 587, P<0.001) than patients with active disease. Additionally, median CRP (2.9 vs 6.0 vs 16.0 vs 30.7, P<0.001), and median FC (128 vs 531 vs 637 vs 877, P<0.001) were significantly different between MM-SES-CD severity categories (remission vs mild vs moderate vs severe), respectively. CRP and FC optimal cut-offs for endoscopic remission were 8.5 mg/dL (Sensitivity 74.7%, Specificity 43.6%, negative predictive value (NPV) 77.4%, positive predictive value (PPV) 40.0%) and 471.5 ug/g (Sensitivity 62.6%, Specificity 87.3%, NPV 82.3%, PPV 71.3%), respectively. Conclusion To the best of our knowledge, this is the first study reporting an association between CRP and FC and increasing degrees of disease activity assessed by MM-SES-CD. A CRP <8.5 mg/dL and a FC <471.5 ug/g are suggested as cut-offs associated with endoscopic remission.

P197 A biomarker of early mucosal destruction: Neutrophil-mediated type IV collagen degradation is elevated in patients with Crohn’s Disease and Ulcerative Colitis

Abstract Background Inflammatory bowel disease (IBD) is characterized by chronic inflammation due to an uncontrolled immune response orchestrated through, i.e. neutrophils. The basement membrane acts as a front-line defense promoting tissue integrity, where the α-3 chain of type IV collagen is solely expressed on the outermost layer of the mucosa. Detection of subclinical ulceration is crucial since early-stage IBD presents a unique window of opportunity for intervention, as the disease might become a self-sustaining process once deep inflammation becomes established. We therefore, wanted to develop a biomarker reflecting early tissue injury, aiding in the implementation of prompt treatment. Methods A competitive enzyme-linked immunosorbent assay quantifying a human neutrophil elastase (HNE) degraded fragment of type IV collagen α-3 chain was developed (C4A3-HNE). Dilution- and spiking recovery, inter- and intra-variability, and interference were evaluated. Acceptance criteria for technical validation were a recovery of 100% ±25 and an inter-intra variability of <15%. Commercial serum samples were purchased from ProteoGenex. Biological relevance was validated in an observational study from Odense University Hospital (OUH) and healthy controls. Groups were compared using Kruskal Wallis (Dunn‘s corrected). Results The technical validation of the C4A3-HNE assay demonstrated acceptable results for recovery, variation, and interference (table 1). Biological relevance was assessed in commercial IBD samples and healthy donors. C4A3-HNE was elevated in both CD and UC compared to healthy (p=0.001 and <0.0001)(AUC [95% CI]: 0.820 [0.669-0.971]; 0.875 [0.775-1.000]). The results were validated in a cohort of IBD patients (both p<0.0001)(fig.1). For UC, analysis showed that compared to patients in endoscopic remission, C4A3-HNE is elevated in patients with mild endoscopic activity, decreasing dose-dependently for moderate and severe disease. Fecal calprotectin and CRP levels were also lower in IBD patients with high levels of C4A3-HNE (fig.2). With a cut-off value of 54.1 ng/ml, C4A3-HNE could significantly discriminate between mild and severe endoscopic disease (table 2). Conclusion Our study demonstrates the biological and possible clinical relevance of the novel C4A3-HNE biomarker. The biomarker is elevated in patients with IBD compared with healthy, and high levels may reflect early mucosal damage in patients with UC. Furthermore, inflammatory markers were lower in IBD patients with high levels of C4A3-HNE, pointing towards high levels being indicative of early disease. C4A3-HNE may provide early detection of mucosal damage; however, further studies are required to assess the clinical validity of this biomarker.

Combination therapy is not associated with improved rates of clinical or endoscopic remission in patients with inflammatory bowel disease treated with ustekinumab or vedolizumab: a retrospective study.

Management of inflammatory bowel disease (IBD) involves biological agents, often in combination with thiopurines or methotrexate. The aim of our study was to compare clinical and endoscopic outcomes in IBD patients treated with vedolizumab or ustekinumab, as monotherapy or in combination with thiopurines or methotrexate. We conducted a retrospective cohort study of all patients aged ≥18 years with a diagnosis of ulcerative colitis or Crohn's disease, commenced on vedolizumab or ustekinumab between October 2015 and March 2022. Primary outcome was clinical remission or response calculated by partial Mayo score (remission: <3; response: improvement >1) for ulcerative colitis or Harvey-Bradshaw index (<5, >2 respectively) for Crohn's disease over 1 year. Secondary endpoints were treatment failure, relapse, endoscopic remission at 1 year. Statistical analysis was done using 2-sample Student's t and chi-square tests. A total of 159 IBD patients were included in the study, 85 (53%) on vedolizumab and 74 (47%) on ustekinumab. For those on vedolizumab, 61 (72%) patients had ulcerative colitis, and 24 (28%) has Crohn's disease. All patients on ustekinumab had Crohn's disease. Mean disease duration in was 9.4 and 13.5 years respectively. There was no difference in clinical response or remission for vedolizumab or ustekinumab monotherapy compared to combination therapy at 1 year. There was also no difference in treatment failure, relapse or endoscopic remission. Combining vedolizumab or ustekinumab with an immunomodulator is not superior to monotherapy in terms of clinical response or endoscopic remission up to 1 year in IBD.

Evaluation of serum cytokines and acute phase proteins as possible pharmacodynamic biomarkers to monitor endoscopic remission during ustekinumab therapy in patients with Crohn's disease.

Since not all Crohn's disease (CD) patients respond adequately to ustekinumab therapy, biomarkers could aid to monitor treatment response and optimize therapeutic outcomes. To explore the dynamics of serum biomarker concentrations to monitor the response to ustekinumab treatment in CD patients. Retrospective, exploratory study to evaluate concentrations of serum cytokines and acute phase proteins and their relation to endoscopic remission in CD patients during ustekinumab treatment. Serum concentrations of 16 proteins including cytokines and acute phase proteins were measured using the Mesoscale Discovery Platform in serum of healthy controls (n = 13), and CD patients (n = 61) at baseline (week 0), week 8 and week 24 during ustekinumab treatment. Endoscopic remission was defined as simple endoscopic score for CD (SES-CD) <3 after 6 months of therapy. Absolute concentrations of serum amyloid A protein (SAA; week 8), IL-6 (week 24), AGP (weeks 8 and 24), interferon (IFN)-γ (weeks 8 and 24), lipopolysaccharide binding protein (LBP; weeks 8 and 24) and IL-22 (weeks 8 and 24) were significantly lower in endoscopic remitters compared to non-responders (p-values ranging between <0.001 and <0.05). SAA (week 8) and AGP (week 24) were the biomarkers with the highest area under the ROC curve (AUROC; 0.761 and 0.760, respectively) for identifying patients in endoscopic remission, though their performance was not superior to C-reactive protein (CRP) or faecal calprotectin. AUROCs of the predictive probability of biomarker combinations showed superiority in discriminating endoscopic remitters from non-responders in comparison to single biomarker measurements, but not as compared to faecal calprotectin. Although not superior to faecal calprotectin, measurement of AGP, SAA, LBF, IFN-γ, IL-6 and IL-22 concentrations, and combinations thereof with or without CRP and faecal calprotectin, during ustekinumab therapy might contribute to adequate monitoring of treatment response in CD patients.

Endo-histologic Normalization Is Achievable with Tofacitinib and Is Associated with Improved Clinical Outcomes.

Recent real-world effectiveness studies investigating tofacitinib have been encouraging. Questions remain regarding the long-term effectiveness and safety of tofacitinib, effect on endoscopic remission rates, histologic changes, and alterations in fecal calprotectin levels. This retrospective study includes consecutive patients with inflammatory bowel disease (IBD) who initiated tofacitinib therapy. We reviewed electronic medical records for demographic and clinical data, as well as all adverse events and hospitalizations. All patients receiving tofacitinib were included in the safety analysis and only patients with ulcerative colitis (UC) were included in the effectiveness analysis. 119 patients with IBD (97 UC, 12 CD, and 10 pouchitis) seen at our center between 2014 and 2020 were included in this study. Median follow-up was 32weeks (interquartile range (IQR) 3-252). Clinical response and remission were observed in 70% and 21%, 59% and 33%, and 49%, and 37% at weeks 8, 24, and 52, respectively. Endo-histologic healing was achieved by 11%, 25%, and 37.5% of patients at weeks 8, 24, and 52, respectively. Histologic normalization occurred as early as 24weeks in this cohort and was achieved by 26% of patients in endoscopic remission. Overall, there were 27 (25%) adverse events with 6 (5%) resulting in treatment discontinuation. There were 11 (10%) infections, none required treatment discontinuation. Ten (10.3%) patients underwent colectomy during the follow-up period. There were no cardiovascular adverse events in the cohort during follow-up. This study demonstrates the effectiveness and long-term safety of tofacitinib in patients with UC. Importantly, we show that the endpoint of endo-histologic healing is achievable with tofacitinib and can occur as early as week 8 of therapy.

The impact of inflammation on the expression of drug transporters and metabolic enzymes in colonic tissue from ulcerative colitis patients

The intestinal tract forms an important barrier against xenobiotics while allowing nutrients to pass. In ulcerative colitis (UC), a chronic inflammatory bowel disease, this barrier function is impaired leading to an abnormal immune response and inflammation of the colonic mucosa. Transporter proteins and metabolic enzymes are an integral part of the protective barrier in the gut and play an important role in the disposition of nutrients, toxins and oral drugs. In this study, the protein expression of 13 transporters and 13 enzymes was determined in the sigmoid and rectum of UC patients in endoscopic remission and during active inflammation. In inflamed conditions (endoscopic Mayo sub-score 1, 2 or 3), a significant decrease (q < 0.05) was observed in the median expression of the transporters P-gp (0.046 vs 0.529 fmol/µg protein), MRP4 (0.003 vs 0.023 fmol/µg protein) and MCT1 (0.287 vs 1.090 fmol/µg protein), and the enzymes CYP3A5 (0.031 vs 0.046 fmol/µg protein) and UGT2B7 (0.083 vs 0.176 fmol/µg protein). Moreover, during severe inflammation, the decrease was even more pronounced. Expression levels of other proteins were not altered during inflammation (e.g., OATP2B1, CYP3A4, CYP2B6 and UGT2B15). The results suggest a decreased transport and metabolism of xenobiotics in the colon of UC patients during active inflammation potentially altering local drug concentrations and thus treatment outcome.

Mesalazine in the induction of clinical and endoscopic remission of mild and moderate ulcerative colitis

Introduction. Treatment of ulcerative colitis (UC) is necessary to induce remission and subsequently to maintain it. Given the good tolerability, safety and efficacy of mesalazine, it is considered as a first-line therapy for patients with mild to moderate forms.Aim of the study. To evaluate the effectiveness of induction of clinical and endoscopic remission in patients with mild and moderate UC during 8 weeks therapy with mesalazine in routine clinical practice.Materials and methods. The study included 40 patients aged 18 to 75 years with mild to moderate attacks of UC who received therapy for 8 weeks. Efficacy was evaluated after 2 and 8 weeks. The dynamics of the quality of life of patients was assessed on the basis of the IBS-QOL questionnaire, satisfaction with therapy was assessed using the Likert scale.Results. During therapy, the Mayo index significantly decreased, amounting to 4.95 ± 1.74 vs 4.08 ± 1.58 vs 2.53 ± 1.45 for visits 1, 2 and 3, respectively (p &lt; 0.05). The mean value of the level of calprotectin decreased by 2.5 times during 8 weeks of therapy (p &lt; 0.05). After 8 weeks of observation, there were no endoscopic signs of inflammation in 10 patients (25%), in 3 patients (7.5%) endoscopic activity was moderate, and in the remaining 27 subjects (67.5%) it was minimal. The mean IBS-QOL score decreased from 84.25 ± 19.67 to 69.80 ± 17.96 after 8 weeks of therapy (p &lt; 0.05). Satisfaction with treatment according to the Likert scale was 4.13 ± 0.79 points, which corresponds to a high degree of satisfaction. No adverse events were recorded during the entire observation period.Conclusion. Data analysis demonstrated the effectiveness of induction of clinical and endoscopic remission of mild to moderate forms of left-sided UC and pancolitis with a significant positive effect on the quality of life and good tolerability of the drug.

Crohn’s disease in endoscopic remission, obesity, and cases of high genetic risk demonstrate overlapping shifts in the colonic mucosal-luminal interface microbiome

BackgroundCrohn’s disease (CD) patients demonstrate distinct intestinal microbial compositions and metabolic characteristics compared to unaffected controls. However, the impact of inflammation and underlying genetic risk on these microbial profiles and their relationship to disease phenotype are unclear. We used lavage sampling to characterize the colonic mucosal-luminal interface (MLI) microbiome of CD patients in endoscopic remission and unaffected controls relative to obesity, disease genetics, and phenotype.MethodsCecum and sigmoid colon were sampled from 110 non-CD controls undergoing screening colonoscopy who were stratified by body mass index and 88 CD patients in endoscopic remission (396 total samples). CD polygenic risk score (GRS) was calculated using 186 known CD variants. MLI pellets were analyzed by 16S ribosomal RNA gene sequencing, and supernatants by untargeted liquid chromatography-mass spectrometry.ResultsCD and obesity were each associated with decreased cecal and sigmoid MLI bacterial diversity and distinct bacterial composition compared to controls, including expansion of Escherichia/Shigella. Cecal and sigmoid dysbiosis indices for CD were significantly greater in obese controls than non-overweight controls. CD, but not obesity, was characterized by altered biogeographic relationship between the sigmoid and cecum. GRS was associated with select taxonomic shifts that overlapped with changes seen in CD compared to controls including Fusobacterium enrichment. Stricturing or penetrating Crohn’s disease behavior was characterized by lower MLI bacterial diversity and altered composition, including reduced Faecalibacterium, compared to uncomplicated CD. Taxonomic profiles including reduced Parasutterella were associated with clinical disease progression over a mean follow-up of 3.7 years. Random forest classifiers using MLI bacterial abundances could distinguish disease state (area under the curve (AUC) 0.93), stricturing or penetrating Crohn’s disease behavior (AUC 0.82), and future clinical disease progression (AUC 0.74). CD patients showed alterations in the MLI metabolome including increased cholate:deoxycholate ratio compared to controls.ConclusionsObesity, CD in endoscopic remission, and high CD genetic risk have overlapping colonic mucosal-luminal interface (MLI) microbiome features, suggesting a shared microbiome contribution to CD and obesity which may be influenced by genetic factors. Microbial profiling during endoscopic remission predicted Crohn’s disease behavior and progression, supporting that MLI sampling could offer unique insight into CD pathogenesis and provide novel prognostic biomarkers.

Upadacitinib Is Safe and Effective for Crohn's Disease: Real-World Data from a Tertiary Center.

Upadacitinib is a selective JAK-1 inhibitor approved for the treatment of rheumatoid arthritis and more recently, ulcerative colitis. Phase II trials demonstrated that upadacitinib induces endoscopic remission in patients with moderate-to-severe Crohn's disease. However, real-world data are lacking. We present a short report on our experience with off-label upadacitinib in patients with CD at a tertiary center. In this cohort of medically refractory patients with CD, treatment with upadacitinib resulted in subjective and objective responses in 25 and 42% of patients, respectively. Even at doses that are considered lower than currently being studied for CD, upadacitinib was associated with a favorable benefit-to-risk profile.

Appendiceal Orifice Inflammation Is Associated with Lower Rate of Complete Endoscopic Remission in Patients with Ulcerative Colitis.

Appendiceal orifice inflammation (AOI) is commonly considered a skip lesion in ulcerative colitis (UC). However, the clinical significance of AOI in UC patients remains controversial. This study aimed to evaluate the clinical feature and long-term outcomes of AOI by comparing UC patients with and without AOI. This study was conducted as a retrospective design of patients who were newly diagnosed or referred within 3 months after diagnosis at Seoul St. Mary’s Hospital from 1 January 2001 to 31 December 2020. All patients underwent index and follow-up colonoscopies. The long-term outcomes involved achieving complete endoscopic remission (ER), use of biologics, hospitalization, and proximal disease extension. Complete ER was defined as Mayo endoscopic subscore 0. In total, 318 UC patients were included, of which 140 had AOI. The baseline characteristics were not significantly different between AOI and non-AOI groups. The cumulative risk of complete ER was a significant difference between AOI and non-AOI groups (p = 0.041). The other cumulative risks of disease outcomes were not significantly different between AOI and non-AOI groups (use of biologics, p = 0.542; hospitalization, p = 0.795; proximal disease extension, p = 0.403). The multivariate Cox regression analysis also revealed that AOI was the significant factor of complete ER (hazard ratio, 0.656; 95% confidence interval, 0.462–0.932; p = 0.019) in UC patients. AOI shows a significant association with lower rate of complete ER in UC patients. Therefore, a meticulous treatment strategy may be recommended to achieve complete ER in UC patients with AOI.

Ustekinumab trough levels predicting laboratory and endoscopic remission in patients with Crohn\u2019s disease

BackgroundsOptimal concentration of ustekinumab (UST) predicting endoscopic remission has not been fully investigated in Crohn’s disease (CD). We aimed to identify the optimal UST trough levels predicting clinical, laboratory and endoscopic remission in CD patients.MethodsTwenty-eight patients with CD were enrolled and investigated (27 patients by enteroscopy and 1 by colonoscopy). The endoscopic activity was assessed using the scoring system that applied the Rutgeerts score to observed intestine. Serum UST trough levels and anti-UST antibodies (AUAs) levels were determined by in-house immunoassays.ResultsEndoscopic activity was negatively correlated with serum UST trough levels (Spearman’s rank correlation coefficient (ρ) = − 0.66, P = 0.0001) and serum albumin levels (ρ = − 0.60, P = 0.0007). The endoscopic activity was positively and significantly correlated with CRP (ρ = 0.59, P = 0.0009) and ESR (ρ = 0.44, P = 0.033). There was no significant association between the endoscopic score and AUA levels and/or Crohn’s disease activity index (CDAI). Serum UST trough levels and albumin levels were significantly higher in the endoscopic remission group (scores of 0 and 1) than in the non-endoscopic remission group (UST trough, mean 3.3 vs. 1.8 μg/mL). No significant difference was observed in AUAs between the endoscopic remission and non-remission groups. Receiver operation curve (ROC) analysis revealed that the optimal cutoff value of UST trough levels predicting normal CRP and serum albumin levels was 1.7 μg/mL for each, and the optimal cutoff value predicting endoscopic remission was 2.0 μg/mL (AUC: 0.80, 95% CI 0.64–0.96).ConclusionAchievement of endoscopic remission requires higher UST trough levels than required for normalization of CRP and serum albumin levels.

Histological Indices and Risk of Recurrence in Crohn's Disease: A Retrospective Study of a Cohort of Patients in Endoscopic Remission.

Although histological healing is raising interest in ulcerative colitis to predict recurrence, its meaning in Crohn's disease (CD) remains unknown. We aimed to study the performances of different histological indices to predict recurrence of CD patients with mucosal healing. Crohn's disease patients with mucosal healing diagnosed between 2010 and 2018 were included if there was available clinical and endoscopical data. Nancy Histological index (NHI), Geboes score (GS), Robarts Histopathology index (RHI), Global Histological Disease Activity Score (GHAS), and Inflammatory Bowel Disease-Distribution Chronicity Activity score (IBD-DCA) were independently assessed by 3 pathologists. Eighty-eight patients were included, of which 28 relapsed (32%) within 30.5 months. All 4 histological indices were associated with recurrence, with significant relapse risk (NHI, odds ratio [OR], 1.67; GHAS, OR, 2.33; RHI, OR, 1.19; GS, OR, 2.09; and IBD-DCA, OR, 2.14). Microscopic activity was significantly associated with relapse only with the IBD-DCA score. Predicting performances of all these scores were poor. Calibration curves indicate that the GHAS and IBD-DCA are the closest to the ideal predicted probability curve and thus could better predict recurrence than the other scores. Interobserver agreement varied from poor for GHAS (k = .39) to good for RHI (k = .68). Histological scores are valuable indicators to predict recurrence. Histological assessment of activity seems insufficient to predict CD course with most of the score evaluated, highlighting the need for new indices or adaptation of actual scores to CD specificities.

Additive effect of probiotics (Mutaflor) on 5-aminosalicylic acid therapy in patients with ulcerative colitis.

Background/AimsIn ulcerative colitis (UC) patients, Escherichia coli Nissle 1917 (EcN) is equivalent to mesalazine for preventing disease relapse; however, evidence of the ability of EcN to increase health-related quality of life or induce remission remains scarce. We investigated the efficacy of EcN as an add-on therapy for UC.MethodsIn this multicentre, double-blind, randomised, placebo-controlled study, a total of 133 UC patients were randomly assigned to receive either EcN or placebo once daily for 8 weeks. Inflammatory bowel disease questionnaire (IBDQ) scores (primary endpoint) and clinical remission and response rates (secondary endpoints) were compared (Clinical trial registration number: NCT04969679).ResultsIn total, 118 patients (EcN, 58; placebo, 60) completed the study. The number of patients reaching the primary endpoint did not differ between the EcN and placebo groups (30 [51.7%] vs. 31 [51.7%]; per-protocol analysis, p = 1.0; intention-to-treat analysis, p = 0.86). However, significantly fewer patients in the EcN group exhibited a decreased IBDQ score (1 [1.7%] vs. 8 [13.3%]; per-protocol analysis, p = 0.03; intention-to-treat analysis, p = 0.02). Moreover, a significantly higher number of patients in the EcN group displayed clinical response at 4 weeks (23 [39.7%] vs. 13 [21.7%], p = 0.04) and endoscopic remission at 8 weeks (26 [46.4%] vs. 16 [27.1%], p = 0.03).ConclusionsAlthough the number of patients reaching the primary endpoint did not differ between the EcN and placebo groups, EcN was found to be safe and effective in preventing the exacerbation of IBDQ scores and achieving clinical responses and endoscopic remission in patients with mild-to-moderate UC.

A Specific Calprotectin Neo-epitope [CPa9-HNE] in Serum from Inflammatory Bowel Disease Patients Is Associated with Neutrophil Activity and Endoscopic Severity.

Background and AimsEndoscopy and the use of faecal calprotectin [faecal CP] are among the least-favoured methods for assessing disease activity by inflammatory bowel disease [IBD] patients; the handling/processing of faecal samples is also impractical. Therefore, we sought to develop a novel neo-epitope serum calprotectin enzyme-linked immunosorbent assay [ELISA], CPa9-HNE, with the aim of quantifying neutrophil activity and neutrophil extracellular trap [NET]-osis and proposing a non-invasive method for monitoring disease activity in IBD patients.Methods In vitro cleavage was performed by mixing calprotectin [S100A9/S100A8] with human neutrophil elastase [HNE], and a novel HNE-derived calprotectin neo-epitope [CPa9-HNE] was identified by mass spectrometry for ELISA development. The CPa9-HNE ELISA was quantified in supernatants from ex vivo activated neutrophils and serum samples from patients with ulcerative colitis [UC, n = 43], Crohn’s disease [CD, n = 93], and healthy subjects [HS, n = 23]. For comparison, faecal CP and MRP8/14 biomarkers were also measured.ResultsCPa9-HNE was specific for activated neutrophils ex vivo. Serum CPa9-HNE levels were 4-fold higher in CD [p <0.0001] and UC [p <0.0001] patients than in HS. CPa9-HNE correlated well with the Simple Endoscopic Score [SES]-CD score [r = 0.61, p <0.0001], MES [r = 0.46, p = 0.0141], and the full Mayo score [r = 0.52, p = 0.0013]. CPa9-HNE was able to differentiate between CD and UC patients in endoscopic remission and moderate/severe disease activity (CD: area under the curve [AUC] = 0.82 [p = 0.0003], UC: AUC = 0.87 [p = 0.0004]). The performance of CPa9-HNE was equipotent or slightly better than that of faecal CP.ConclusionsSerum CPa9-HNE levels were highly associated with CD and UC patients. CPa9-HNE correlated with the SES-CD score and the full Mayo score, indicating a strong association with disease activity.

THE MICROBIAL LANDSCAPE OF ULCERATIVE COLITIS IN ENDOSCOPIC REMISSION

Abstract BACKGROUND Achieving endoscopic remission (Mayo endoscopic score of 1 or 0) appears to be the optimal clinical target in ulcerative colitis, reducing risk of relapse, hospitalizations, complications, and need for surgery. While attaining complete endoscopic remission (MES 0) appears to reduce these risks further over mild endoscopic activity (MES 1), the etiologic factors for why MES 0 might be the superior target is poorly understood. Given the putative role of the gut microbiome in driving underlying endoscopic activity and subsequent relapse risk, we sought to define the microbial landscape of UC among patients who achieve either MES 0 vs MES 1 endoscopic remission, especially since the colonic microbial constituents of UC in remission remain uncharacterized. METHODS We performed a retrospective cohort study, utilizing data from The Study of a Prospective Adult Research Cohort with IBD (SPARC IBD), part of the IBD Plexus network established by the Crohn’s and Colitis Foundation. SPARC IBD is a national, multi-center, longitudinal cohort study enrolling eligible (&amp;gt;= 18 years) patients with IBD that includes demographic and disease specific clinical data, endoscopic scores, and stool metagenomics. To examine the microbiome, we evaluated beta-diversity (Bray-curtis dissimilarity), and phylum and genera-level differential taxal abundance, utilizing linear models (limma), between patients with UC in either MES 1 vs MES 0 endoscopic remission. Statistical analysis was performed using phyloseq and limma packages in R (ver 4.1). RESULTS Within the SPARC cohort, we identified 77 patients in endoscopic remission (48 with MES 0, 29 with MES 1), of which 52% were female and 91% white, with median age of 48. Patients in MES 0 or MES 1 had no significant differences in exposure to anti-TNF therapy (50% vs 50%), vedolizumab (25% vs 19%) or mesalamine (69% vs 72%). Beta-diversity was similar between MES 0 and MES 1 remission [Figure 1]. Both MES 1 and MES 0 remission were dominated by Bacteroidetes and Firmicutes, and were specifically abundant for Bacteroides uniformis, unclassified Subdoligranulum, and Akkermansia mucuniphila. Compared to MES 1 remission, patients with MES 0 remission had increased abundance of Bacteroidetes, Firmicutes, and Actinobacteria, but reduced levels of Proteobacteria and Verrucomicrobia, although after adjusting for multiple comparisons, differential abundance at the phylum and taxa-level between both groups were comparable [Figure 2]. CONCLUSIONS The microbial landscape of ulcerative colitis in MES 1 vs MES 0 endoscopic remission is comparable with respect to beta-diversity, phylum and genera-level differential taxal abundance. Further investigation will include comparison of UC in remission to healthy controls, and whether the presence of specific microbial groups in remission can predict subsequent relapse.

P228 Appendiceal Orifice Inflammation Is Associated with Lower Rate of Complete Endoscopic Remission in Patients with Ulcerative Colitis

Abstract Background Appendiceal orifice inflammation (AOI) is commonly considered a skip lesion in ulcerative colitis (UC). However, the clinical significance of AOI in UC patients remains controversial. This study aimed to evaluate the clinical feature and long-term outcomes of AOI by comparing UC patients with and without AOI. Methods This study was conducted as a retrospective design of patients who were newly diagnosed or referred within 3 months after diagnosis at Seoul St. Mary’s Hospital from January 1, 2001 to December 31, 2020. All patients underwent index and follow-up colonoscopies. The long-term outcomes involved achieving complete endoscopic remission (ER), use of biologics, hospitalization, and proximal disease extension. Complete ER was defined as Mayo endoscopic subscore 0. Results In total, 318 UC patients were included, of which 140 had AOI. The baseline characteristics were not significantly different between AOI and non-AOI groups. The cumulative risk of complete ER was a significant difference between AOI and non-AOI groups (p=0.041). The other cumulative risks of disease outcomes were not significantly different between AOI and non-AOI groups (use of biologics, p=0.542; hospitalization, p=0.795; proximal disease extension, p=0.403). The multivariate Cox regression analysis also revealed that AOI was the only significant factor of complete ER (hazard ratio, 0.636; 95% confidence interval, 0.446–0.906; p=0.012) in UC patients. Conclusion AOI shows a significant association with lower rate of complete ER in UC patients. Therefore, a meticulous treatment strategy may be recommended to achieve complete ER in UC patients with AOI.

DOP70 Anti-TNF withdrawal according to a risk-stratified protocol does not reduce the risk of relapse in patients with Inflammatory Bowel Disease in endoscopic remission: A prospective study

Abstract Background Discontinuation of anti-tumour necrosis factor alpha agents (anti-TNF) in patients with inflammatory bowel disease (IBD) in remission may reduce side effects and costs, but this has to be weighed against the risk of relapse. We developed a risk-stratified protocol for anti-TNF withdrawal, and aimed to assess the risk of relapse after risk-stratified anti-TNF withdrawal. Methods This was a single arm prospective observational cohort study. Patients were recruited between September 2018–2020 in 13 hospitals in the Netherlands. Inclusion criteria were a diagnosis of IBD, age &amp;gt;18 years, elective anti-TNF withdrawal in a patient with quiescent disease (according to the treating physician), no current or planned use of vedolizumab, ustekinumab or tofacitinib, no hospitalization, and no active or planned pregnancy. According to the protocol, patients were recommended to withdraw anti-TNF only when in endoscopic remission either without high-risk criteria (age at diagnosis &amp;lt;18 years, and for Crohn’s disease [CD]: smoking, stricturing/penetrating disease behaviour, small bowel resection &amp;gt;50cm), or when trough levels were undetectable. We constructed Kaplan-Meier curves with log-rank test to compare the risk of relapse in patients who discontinued anti-TNF in accordance with, versus against, the protocol. Cox regression analysis was performed to identify predictors of relapse. Results We enrolled 115 patients (CD: n=61, 53%), with a median follow-up time of 1.9 (IQR 1.8 – 2.1) years. Baseline endoscopic remission was confirmed in 103 (89.6%) patients, and 35 (30.4%) patients continued an immunomodulator. During follow-up, 57 (49.6%) patients relapsed (Figure 1). The relapse rate was similar in patients in endoscopic remission who withdrew anti-TNF in according with, versus against, the protocol (50.7% versus 44.4%, p=0.65), and in patients with versus without an immunomodulator (hazard rate [HR] 0.89, 95%CI 0.50 – 1.59), but was lower in patients with subtherapeutic anti-TNF trough levels (adjusted HR: 0.55, 95%CI: 0.31 – 0.99), and in patients with UC/IBD-unclassified (IBDU) who were treated with mesalamine maintenance therapy (HR: 0.35, 95%CI 0.13 – 0.94). Anti-TNF was reintroduced in 41 (71.9%) patients, with remission rates of 64.5% and 81.8% at 3 and 12 months, respectively. In 6 (15.0%) patients anti-TNF therapy was discontinued again due to primary non-response or loss of response. Conclusion The risk of relapse after anti-TNF withdrawal remains high in a strictly selected group of patients with uncomplicated IBD in endoscopic remission. Therapeutic drug monitoring prior to anti-TNF withdrawal, and mesalamine therapy for patients with UC or IBDU, may reduce the risk of relapse.

P249 Serum calprotectin is useful to confirm Inflammatory Bowel Disease activity but is not effective to predict relapse

Abstract Background Serum calprotectin (SC), a novel biomarker of inflammatory bowel diseases (IBD), has been recently investigated with conflicting results. The purpose of this study was to assess the ability of SC for predicting disease relapse in patients with IBD treated by biologic therapies, and to evaluate the correlation between SC and clinical and endoscopic relapse and with other biomarkers including fecal calprotectin (FC) and C-reactive protein (CRP). Methods All consecutive IBD patients in deep remission (clinical and endoscopic or imaging remission) were recruited in this prospective study and followed 12 months. Blood and stool samples were collected for SC, serum CRP and FC measurement. SC was measured the day of inclusion (baseline, D0), 3 months (M3) and 6 months (M6) later and in case of relapse during the study period. Relapse was defined as clinical, biomarkers, or endoscopic/imaging activity. So, firstly, we looked at evolution of SC before relapse to analyze a predicting value of loss of response (LOR). We also compared SC for patients with active IBD and those with symptoms without inflammation. Results Among the 119 patients included, 54 (46.4%) patients experienced a disease relapse during follow-up. When we looked at the kinetic of SC during follow-up, median SC levels did not increase in patients who relapsed: 3.15 µg/l at baseline, 3.38 µg/l at M3, 3.33 µg/l at M6 and 3.99 µg/l in case of relapse (p=0.63). We compared SC during relapse with patients in endoscopic remission but clinical symptoms which defined secondary Irritable Bowel Syndrome, we found that SC levels were higher in active IBD and similar between the groups of patients with IBS or deep remission (3.05µg/l IBS vs 2.99µg/l remission vs 5.1µg/l for relapsers, p=0.04). In patients with clinical symptoms, SC presents a good predictive value for relapse. (AUROC 0.764, IC95: 0.68–0.88), giving a sensitivity of 72% with a specificity of 77%, using a cut-off value of 4.45mg/ml. A weak, but significant correlation was found between SC and FC levels (r=0.35, P= 0.001). A combined score with CRP, FC and SC didn’t improve its diagnostic accuracy. Conclusion SC was significantly higher in patients with relapse compared to those in endoscopic remission with or without clinical symptoms. It seemed that it permit to oppose patients with active IBD and those with symptoms of IBS. However, it failed to predict relapse.

P168 Matrix Gla protein, a potential marker of tissue remodelling and physiological ageing of the gut in Crohn’s Disease

Abstract Background Matrix Gla protein (MGP) is an extracellular matrix protein. The inactive dephosphorylated and uncarboxylated form of this protein, called dp-ucMGP, has been shown to be increased in plasma of Crohn’s disease (CD) patients compared to non IBD patients (Brnic et al., 2020). Our aim was to assess if the plasmatic level of dp-ucMGP could reflect disease endoscopic activity and could be a potential marker of mucosal healing in CD. Methods The plasmatic level of dp-ucMGP was measured in a blood sample collected the same day as the ileocolonoscopy by CLIA method using IDS-iSYS InaKtif MGP. In addition to classical clinical data (gender, age, body mass index or BMI, disease duration, IBD treatment), endoscopic (disease localisation, Crohn’s Disease endoscopic index or CDEIS, as well as the presence of erythema, ulcer, oedema, pseudopolyp, stricture) and biological (C-reactive protein or CRP) parameters were collected as well as faecal calprotectin to assess CD activity. Results A total of 82 colonoscopies and dp-ucMGP assays were performed in 75 CD patients (44 females and 31 males; 43 colonic diseases, 22 ileal diseases and 19 ileocolic diseases) between October 2012 and November 2019. Out of the 82 performed colonoscopies, 22 showed a mucosal healing. Although MGP level was significantly correlated with CDEIS (r=0.21, p=0.040), it was neither associated with endoscopic remission (737 ± 205 pmol/L for patients in endoscopic remission vs 809 ± 332 pmol/L for those who were not, p=0.37), nor correlated with faecal calprotectin (r=0.074, p=0.51) or with CRP (r=0.12, p=0.27) levels. Plasma MGP levels increased significantly with age (r=0.38, p=0.0004) and disease duration (r=0.37, p=0.0006) but not with the BMI (r=0.045, p=0.69). Patients on corticosteroids at the time of colonoscopy had a higher level of MGP (1065 ± 531 pmol/L vs 729 ± 179 pmol/L, p=0.0003). There was no association with other treatments (5-ASA, immunomodulators, anti-TNF, anti-α4β7 integrin or anti-IL-12/IL-23 p40 monoclonal antibody). Regarding endoscopic CD lesions, MGP values were significantly higher in cases of oedema (1153 ± 628 pmol/L vs 766 ± 261 pmol/L, p=0.019) and pseudopolyps (1099 ± 569 pmol/L vs 766 ± 264 pmol/L, p=0.018) but there was no association with the presence of other lesions. Conclusion The significant increase of plasmatic MGP levels with age, disease duration but also in patients with pseudopolyps suggests that this extracellular matrix protein could rather be a marker of tissue remodelling (not necessarily stricturing) and physiological ageing of the gut in CD than a marker of disease activity. The relevance of the plasmatic dosage of this protein to assess CD bowel damages deserves to be further investigated.