Crohn's Disease Patients In Remission Research Articles

Blood-Based Biomarkers Reflecting Protease 3 and MMP-12 Catalyzed Elastin Degradation as Potential Noninvasive Surrogate Markers of Endoscopic and Clinical Disease in Inflammatory Bowel Disease.

Chronic inflammation in inflammatory bowel disease (IBD) triggers significant extracellular matrix remodeling, including elastin remodeling, leading to severe clinical complications. Novel methods to assess intestinal tissue destruction may act as surrogate markers of endoscopic disease activity, relieving patients of invasive endoscopy. We explored the noninvasive blood-based biomarkers ELP-3 and ELM-12, measuring elastin degradation in IBD. In a study involving 104 Crohn's disease (CD), 39 ulcerative colitis (UC), and 29 healthy donors, we assessed these biomarkers' association with endoscopic and clinical disease activity using ELISA. Patients were evaluated based on the SES-CD and CDAI for CD patients and modified MES and partial Mayo for UC patients. ELP-3 and ELM-12 were elevated in patients with IBD. Discerning CD patients in endoscopic remission and mild from moderate to severe, ELP-3 provided an AUC of 0.69 and ELM-12 an AUC of 0.73. The ELP-3 biomarker was associated with UC patients and provided the highest diagnostic power of 0.87 for remission vs. active clinical disease. The data suggest an association of ELP-3 with active CD and ELM-12 with endoscopic remission in CD patients. Additionally, ELP-3 could identify UC patients with active clinical disease from patients in remission. The noninvasive biomarkers ELP-3 and ELM-12 could be potential surrogate biomarkers of elastin degradation and endoscopic and clinical disease markers.

Identification of IL-27 as a novel regulator of major histocompatibility complex class I and class II expression, antigen presentation, and processing in intestinal epithelial cells.

Antigen presentation via major histocompatibility complex (MHC) class I and class II receptors plays a fundamental role in T cell-mediated adaptive immunity. A dysregulation of this fine-tuned recognition might result in the development of autoimmune diseases such as inflammatory bowel diseases that are characterized by chronic relapsing inflammation of the intestinal tract and a damaged intestinal epithelial barrier. While MHCII receptors are usually expressed by professional antigen presenting cells (APC) only, there is increasing evidence that non-immune cells such as intestinal epithelial cells (IEC) might express MHCII upon stimulation with IFN-γ and thus act as non-professional APC. However, little is known about other factors regulating intestinal epithelial MHC expression. Here, we identify IL-27 as an inducer of different MHCI and MHCII receptor subtypes and the invariant chain (CD74/li) in IEC via the STAT1/IRF1/CIITA axis. CIITA, MHCII, and CD74 expression was significantly increased in IEC from Crohn's disease (CD) patients with active disease compared to controls or CD patients in remission. IEC phagocytosed and digested external antigens and apoptotic cells. IL-27 strongly stimulated antigen processing via the immunoproteasome in a IRF1-dependent manner. In co-culture experiments, antigen-primed IEC strongly enhanced lymphocyte proliferation and IL-2 secretion, dependent on direct cell-cell contact. IL-27 pretreatment of IEC significantly increased CD4+ T cell proliferation and reduced IL-2 levels in lymphocytes in coculture. In summary, we identified IL-27 as a novel regulator of IEC antigen processing and presentation via MHCI and MHCII receptors, underscoring the importance of IEC as non-professional APC.

Expression of Circulating let-7e and miR-126 May Predict Clinical Remission in Patients With Crohn's Disease Treated With Anti-TNF-α Biologics.

The identification of new biomarkers predictive of response to antitumor necrosis factor alpha (anti-TNF-α) monoclonal antibodies remains an unmet medical need in Crohn's disease (CD) because a high percentage of patients show no clinical improvement after treatment or can lose response over time. MicroRNAs (miRNAs) can regulate inflammatory and immunological responses and were found to play a role in CD. Baseline serum samples from 37 CD patients previously treated with infliximab or adalimumab, as per clinical practice, were obtained from the serum library at the Gastroenterology Unit of the University Hospital of Pisa, Italy. Patients were categorized as responders or nonresponders based on the following treatment outcomes: clinical remission at weeks 14 and 54 and endoscopic remission at week 54. The expression levels of a panel of selected miRNAs were analyzed by real-time polymerase chain reaction. Comparisons of miRNA expression between responders and nonresponders and statistical analyses were performed by MedCalc and GraphPad Prism software. Receiver operating characteristic curve analyses were calculated to evaluate the predictive performance of potential biomarkers. Patients in clinical remission at week 14 had a lower let-7e expression, whereas those in clinical remission at week 54 had lower levels of circulating miR-126 than nonresponders. The receiver operating characteristic curve analysis identified optimal cutoff values with assay sensitivity and specificity of 92.9% and 61.1%, for let-7e, and 62.5% and 83.3%, for miR-126, respectively. These results provide evidence that expression levels of circulating let-7e and miR-126 at baseline may predict clinical remission in CD patients treated with anti-TNF-α biologics.

Differential Brain Structural and Functional Patterns in Crohn's Disease Patients are Associated with Different Disease Stages.

Crohn's disease (CD) is an inflammatory, chronic disorder that alternates between a quiescent phase and inflammatory flare-ups. Research has begun to elucidate the impact of CD in modulating brain structure and function. The previous neuroimaging studies mainly involved CD patients in remission (CD-R); therefore, little is known about how inflammation influences brain-related features in different stages of the disease. We carried out a magnetic resonance imaging (MRI) study to explore whether the different levels of disease activity may differentially affect brain structure and function. Fourteen CD-R patients, 19 patients with mild to moderate inflammatory activity (CD-A), and 18 healthy controls (HCs) underwent an MRI scan including structural and functional sequences. Between-group comparisons showed morphological and functional brain differences distinctively associated with the stage of disease activity. The CD-A patients had reduced gray matter within the posterior cingulate cortex (PCC) relative to CD-R patients. Analysis on resting fMRI data showed the following patterns: (1) increased connectivity within the left fronto-parietal network (in the superior parietal lobe) in CD-R patients relative to CD-A patients; (2) decreased connectivity in the motor network (in parietal and motor areas) in the CD-A group relative to the HC group; (3) reduced connectivity in the motor network and (4) in the language network (in parietal areas and in the PCC) in CD-R patients relative to HC. The present findings represent a further step towards understanding brain morphological and functional changes in the active vs remission stages of CD patients.

Disruption of Periaqueductal Gray-default Mode Network Functional Connectivity in Patients with Crohn's Disease with Abdominal Pain

Abdominal pain in Crohn's disease (CD) has been known to be associated with changes in the central nervous system. The periaqueductal gray (PAG) plays a well-established role in pain processing. However, the role of PAG-related network and the effect of pain on the network in CD remain unclear.Resting-state functional magnetic imaging (fMRI) data were collected from 24 CD patients in remission with abdominal pain, 24 CD patients without abdominal pain and 28 healthy controls (HCs). Using the subregions of PAG (dorsomedial (dmPAG), dorsolateral (dlPAG), lateral (lPAG) and ventrolateral (vlPAG)) as seeds, the seed-based FC maps were calculated and one-way analysis of variance (ANOVA) was performed to investigate the differences among the three groups.Results showed that the group differences were mainly involved in the FC of the vlPAG with the precuneus, medial prefrontal cortex (mPFC) as well as orbitofrontal cortex (OFC), and the FC of the right lateral PAG (lPAG) with the precuneus, inferior parietal lobule (IPL), angular gyrus and premotor cortex. The FC values of all these regions decreased successively in the order of HCs, CD without abdominal pain and CD with abdominal pain. The pain score was negatively correlated with the FC of the l/vlPAG with the precuneus, angular gyrus and mPFC in CD patients with abdominal pain.This study implicated the disrupt communication between the PAG and the default mode network (DMN). These findings complemented neuroimaging evidence for the pathophysiology of visceral pain in CD patients.

A29 HIGH DIMENSIONAL SINGLE CELL ANALYSIS OF IL-4 TREATED MACROPHAGES REVEALS A HETEROGENIC PHENOTYPE AND THE ABSENCE OF CD206+ SUBSETS IN CROHN'S DISEASE PATIENTS

Abstract Background Individuals with IBD have a reduced quality of life and while treatment has improved, a cure remains elusive. Interleukin-4 differentiated macrophages (M(IL4)s) from healthy donors and IBD patients in remission promote epithelial wound repair and reduce the severity of colitis in a mouse model: findings that support the autologous transfer of M(IL4)s to treat IBD. However, issues remain if this novel therapy is to advance to clinical evaluation: a much greater understanding of the possible heterogeneity within the human M(IL4) population, the biology of any sub-groups therein and the biology of any M(IL4) subtypes is needed. Purpose To determine if cryopreservation, sex, and disease status in Crohn's disease (CD) impact the phenotype and function of M(IL4) Method Blood mononuclear cells were collected from healthy donors, and individuals with active CD or in remission (n=6/group), and differentiated to macrophages with GMP-grade recombinant human M-CSF (10 ng/ml, 7 days). Macrophages (2.5 x105) were activated with IL-4 (10ng/ml, 48h). Fresh and cryopreserved M(0) and M(IL4) were stained using a panel of 18 metal-conjugated antibodies. Data were acquired on a Helios CyTOFII mass cytometer. FCS files were imported into Cytobank for manual gating (viable CD45+CD3-CD19- singlet cell events) and exported for meta-clustering in R with the CATALYST package using the FlowSOM function with 10 metaclusters. Result(s) FlowSOM analysis on M(IL4) from healthy donors indicated clear differences between M(0) and M(IL4), with 8 metaclusters >1.5% of M(IL4)s: the most abundant metaclusters express high and intermediate CD206, PDL1, CD11b, CD33, CD64, HLA-DR and low CD14 levels. There were no significant differences in these M(IL4)s metaclusters between males and females, or fresh vs. cryopreserved cells using this characterization strategy. M(IL4) from patients with active CD, were markedly different with the absence of three high-intermediate CD206+PDL1+ metaclusters and a general lack of CD206+ metaclusters compared to healthy controls. Surprisingly, and despite M(IL4)s from CD patients in remission showing increased CD206 mRNA, CYTOF analysis revealed that the macrophages were more similar to those from individuals with active disease than those from healthy controls Conclusion(s) Here human macrophages activated with IL4 in vitro are revealed as a heterogeneous population, and subsets characterized by increased high CD206 expression are generally absent in active Crohn’s disease. Intriguing while prior experiments with M(IL4) from CD patients in remission reduced the severity of colitis in rag1-/- mice, the characterization of these cells via 18 protein markers indicates they are more like M(IL4)s from patients with active disease compared to healthy controls. While presenting autologous M(IL4) transfer as a novel approach for IBD, a much fuller understanding of the phenotype and function of M(IL4)s (and sub-populations therein) is required before this would become a therapeutic option Please acknowledge all funding agencies by checking the applicable boxes below CAG Disclosure of Interest None Declared

Predictive models assessing the response to ustekinumab highlight the value of therapeutic drug monitoring in Crohn's disease.

Despite the therapeutic efficacy of Ustekinumab (UST) in Crohn's disease (CD), loss of response (LOR) is observed over time. This study aims to evaluate the impact of the UST pharmacokinetics (PK) at induction on clinical and endoscopic outcomes, as well as to find predictive markers of UST response. This retrospective study included 80 CD patients. Pharmacokinetics data (trough levels (TLs)) combined with clinical and biological parameters were fed into tailored logistic regression and tree-based ensemble techniques to predict clinical and endoscopic outcomes at one year of follow-up. TLs at week 16 were significantly lower among patients with moderate to severe endoscopic activity during the follow-up (p=0.04). The best model to predict endoscopic outcome was obtained at week 16 by Random Forest with an area under the receiver operating characteristic curve of 0.92±0.08, sensitivity 91% and specificity 75%, with key inputs such as lymphocyte and monocyte counts at week 8, and UST TLs and CRP at week 16. This real-world study confirms the relationship between early UST TLs and both clinical and endoscopic outcomes. Models were developed for the task of predicting clinical and endoscopic remission in CD patients treated with UST, highlighting the clinical relevance of UST TLs at week 16.

P105 Epithelial microRNA signatures as potential biomarkers in Crohn’s disease related to clinical and endoscopic activity

Abstract Background Emerging evidence suggests that epithelial cell-derived microRNAs (miRNA) are involved in the pathogenesis of inflammatory bowel disease; however, as of now specific implications in the real clinical practice, especially in relation to biologics use are yet far-fetched. Therefore, we tried to investigate specific epithelial cell derived miRNA signatures related to clinical and endoscopic activity in Crohn’s disease (CD) patients. Methods We prospectively collected terminal ileum tissue samples via ileocolonoscopy from healthy control (n=12), CD patients in remission (n=32) and active CD patients (n=36). CD remission was defined as clinical remission of Crohn's disease activity index (CDAI) <150 and achievement of endoscopic mucosal healing. Both inflamed and non-inflamed lesions were sampled in the active CD patients. Clinical information, medication use, chemistry data were measured within a week from the tissue sample date. miRNA levels were measured by small-RNA sequencing and qRT-PCR. Diagnostic ability of specific miRNA found were evaluated by receiver operating characteristic (ROC) curve analysis. Results The study cohort was followed up until January 2022. Mean follow-up period of the prospective CD cohort was 13.06 months. In comparing to the healthy control, CD patients in remission and active state revealed specific miRNA profiles in small-RNA sequencing. Through RT-PCR validation, we found that the expression levels of miR-141-3p, miR-338-3p, miR-378a-3p, and miR-200b-3p were significantly decreased, while miR-125b-5p, miR-29b-3p and miR-155-5p were significantly increased in the inflamed tissue of active CD patients. Moreover, in case of active CD patients, expressions of miR-150-5p, miR-200b-3p and miR-155-5p were significantly down-regulated in those using biologics, compared with biologics naïve patients. This may suggest that these miRNAs were not only as biomarkers of CD patients, but also as biomarkers related to inflammation and biologics response. ROC curve analysis suggested miRNAs with different diagnostic activity related to both clinical disease activity and endoscopic inflammation status. MiR-338-3p, miR-141-3p and miR-378a-3p demonstrated area under curve of greater than 0.9 in predicting active CD patients. Conclusion We report specific miRNA biomarkers identifying CD and its disease inflammation activity with relation to biologics use, suggesting potential treatment target in CD pathogenesis. These miRNA signatures could also be of potential clinical use in positioning biologics, which we intend to explore in the near future.

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.

Intestinal mucosal and fecal microbiota profiles in Crohn's disease in Chinese children

Imbalance in the microbiota has been identified in Crohn's disease (CD). We explored the difference of the microbiota in fecal and intestinal mucosa (including ileocecal junction, terminal ileum and transverse colon) in pediatric patients with active CD, CD patients in remission, nonspecific enteritis (NE) and the healthy children. Seven children had active CD, 5 cases of patients achieve remission (CDR), 19 were NE patients, and 11 were healthy controls (Col). A total of 168 samples were collected. Microbiota compositions were analyzed using 16 ​S rRNA sequencing. The results showed that, in fecal samples, Clostridium_sensu_stricto, Enterobacter and Akkermansia had a higher relative abundance in the CD group than that in CDR, Col and NE groups. Fusobacterium and Streptococcus showed a higher abundance in both CD and CDR than that in Col group. In intestinal mucosa samples, the bacterial communities of the three sampling sites were extremely similar. Escherichia-Shigella was the most abundant mucosal bacteria in the CD group, and the abundance of Bacillus, Ruminococcus_torques_group, Streptococcus, Faecalibacterium and Blautia was lower in the CD group than in other groups. In conclusion, as a very characteristic bacteria, the abundance of Escherichia-Shigella in the intestinal mucosa can be used as a diagnostic criterion for CD patients. Also, the Bacilus and Blautia, which were not as prominent as Escherichia-Shigella could still be used as a diagnostic candidate due to their neatness in CD patients. Mucosal samples may be better than stool samples when assessing the community and diversity of patients' intestinal microbes.

The relationship between Central Nervous System morphometry changes and key symptoms in Crohn’s disease

Alterations in grey matter volume (GMV) and cortical thickness (CT) in Crohn’s disease (CD) patients has been previously documented. However, the findings are inconsistent, and not a true representation of CD burden, as only CD patients in remission have been studied thus far. We investigate alterations in brain morphometry in patients with active CD and those in remission, and study relationships between brain structure and key symptoms of fatigue, abdominal pain, and extraintestinal manifestations (EIM). Magnetic Resonance Imaging brain scans were collected in 89 participants; 34 CD participants with active disease, 13 CD participants in remission and 42 healthy controls (HCs); Voxel based morphometry (VBM) assessed GMV and white matter volume (WMV), and surface-based analysis assessed cortical thickness (CT). We show a significant reduction in global cerebrospinal fluid (CSF) volume in CD participants compared with HCs, as well as, a reduction in regional GMV, WMV and CT in the left precentral gyrus (motor cortex), and an increase in GMV in the frontal brain regions in CD compared with HCs. Atrophy of the supplementary motor area (SMA) was associated with greater fatigue in CD. We also show alterations in brain structure in multiple regions in CD associated with abdominal pain and extraintestinal inflammations (EIMs). These brain structural alterations likely reflect neuroplasticity to a chronic systemic inflammatory response, abdominal pain, EIMs and fatigue. These findings will aid our understanding of the cross-linking between chronic inflammation, brain structural changes and key unexplained CD symptomatology like fatigue.

Relationships of circulating CD4+ T cell subsets and cytokines with the risk of relapse in patients with Crohn's disease.

We aimed to analyze circulating CD4+ T cell subsets and cytokines during the course of Crohn's disease (CD). CD4+ T cell subsets, ultrasensitive C-reactive protein (usCRP), and various serum cytokines (IL-6, IL-8, IL-10, IL-13, IL-17A, IL-23, TNFα, IFNγ, and TGFβ) were prospectively monitored every 3 months for 1 year, using multicolor flow cytometry and an ultrasensitive Erenna method in CD patients in remission at inclusion. Relapse occurred in 35 out of the 113 consecutive patients (31%). For patients in remission within 4 months prior to relapse and at the time of relapse, there was no significant difference in Th1, Th17, Treg, and double-positive CD4+ T cell subsets co-expressing either IFNγ and FOXP3, IL-17A and FOXP3, or IFNγ and IL-17A. On the contrary, in patients who remained in remission, the mean frequency and number of double-positive IL-17A+FOXP3+ CD4+ T cells and the level of usCRP were significantly higher (p ≤ 0.01) 1 to 4 months prior to relapse. At the time of relapse, only the IL-6 and usCRP levels were significantly higher (p ≤ 0.001) compared with those patients in remission. On multivariate analysis, a high number of double-positive IL-17A+FOXP3+ CD4+ T cells (≥1.4 cells/mm3) and elevated serum usCRP (≥3.44 mg/L) were two independent factors associated with risk of relapse. Detection of circulating double-positive FOXP3+IL-17A+ CD4+ T cell subsets supports that T cell plasticity may reflect the inflammatory context of Crohn's disease. Whether this subset contributes to the pathogenesis of CD relapse needs further studies.

Altered structural covariance and functional connectivity of the insula in patients with Crohn's disease.

Crohn's disease (CD) is a clinically chronic inflammatory bowel disease, which has been shown to be closely related to the brain-gut axis dysfunction. Although traditionally considered to be a limbic region, the insula has also been commonly identified as an abnormal brain region in previous CD-related studies. Structural magnetic resonance imaging (MRI) and resting-state functional MRI images were acquired from 45 CD patients in remission and 40 healthy controls (HCs). Three neuroimaging analysis methods including voxel-based morphometry (VBM), structural covariance, and functional connectivity (FC) were applied to investigate structural and functional alterations of the insulae between the CD patients and HCs. Pearson correlation was then used to examine the relationships between neuroimaging findings and clinical symptoms. Compared with the HCs, CD patients exhibited decreased gray matter volume (GMV) in the left dorsal anterior insula (dAI) and bilateral posterior insula (PI). Taking these three areas including the left dAI, right PI, and left PI as regions of interest (ROIs), differences were observed in the structural covariance and FC of the ROI with several regions between the two groups. After controlling for psychological factors, the differences of several regions involved in emotional processing in GMV in the left dAI, the FC of the dAI, and the right PI were not significant. The FC of the parahippocampus/hippocampus with dAI and PI were negatively correlated with the CD activity index (CDAI). We suggest that the insula-centered structural and/or functional changes may be associated with abnormal visceral sensory processing and related emotional responses in CD patients.

P053 The intestinal complement system and its role in dysregulation of the intestinal B-cell compartment in Crohn’s Disease patients

Abstract Background For several decades, there is growing evidence that a hyperactive B-cell compartment may be involved in the disturbed mucosal immune response in Crohn’s disease (CD) patients. This is reflected by approximately one third of all CD patients displaying an excessive production of autoantibodies against the intestinal M-cell expressed FimH receptor glycoprotein 2 (GP2) which inhibits induction of adaptive immunity against adherent-invasive flagellated bacteria. However, underlying mechanisms of an imbalanced B-cell compartment in CD patients still remain elusive. Given that the complement system plays a critical role in the detection and clearance of bacteria and promotes B-cell immunity, we asked if the complement system contributes to a dysregulated B-cell response in CD. Methods Systematical expression analyses of the intestinal complement components were performed in IBD patients, including CD and ulcerative colitis (UC) patients, versus non-IBD controls. Additionally, activity of the three activation pathways of complement system was studied in serum samples of CD patients and controls. Further, immunoglobulin levels in intestinal biopsies, sera and fecal samples were analyzed. Results CD patients, but no UC patients, showed increased expression of the early classical complement pathway components C1QA, C1QB, C1S, C2, C3, C4A, CR1 and CR2 in sigmoidal biopsy samples that does not differ significantly between remission and active disease state. This could be verified by immunohistochemistry, displaying an over-representation of mucosal C1q, C3 and B-cell expressed CR2 (also CD21) in colon biopsies of CD patients in remission. In line with this, CD patients in remission present with enhanced activity of the classical as well as alternative pathway of complement activation in serum compared to non-IBD controls. Accordingly, high protein levels of C3 cleavage fragments were detected in fecal samples from CD patients in contrast to non-IBD controls. While there were no differences in systemic immunoglobulin levels in serum, intestinal IgM was increased in CD patients in remission. Notably, fecal IgA levels were strongly diminished in these patients, while expression of the polymeric immunoglobulin receptor was not affected. Conclusion In summary, our findings demonstrate an augmented activation of the intestinal complement system that may potentially be involved in the etiology of CD. Expansion of mucosal IgM+/CR2+ B cells together with a reduced fecal IgA level, points to a locally disturbed induction of intestinal IgA secreting plasma cells in CD patients.

Poor Patient-Reported Outcomes and Impaired Work Productivity in Patients With Inflammatory Bowel Disease in Remission

Background and AimsThis study aimed to evaluate associations between disease severity, patient-reported outcomes (PROs), and work productivity in patients with inflammatory bowel disease (IBD [Crohn’s disease (CD) and ulcerative colitis (UC)]).MethodsPatients diagnosed with CD or UC enrolled in CorEvitas’ IBD Registry (May 2017 to September 2019) were included (N = 1543; CD, n = 812; UC, n = 731). Disease severity was assessed using the Harvey-Bradshaw Index (CD) and partial Mayo Score (UC); psychosocial PROs (Patient-Reported Outcomes Measurement Information System [PROMIS]) and work productivity (Work Productivity and Activity Impairment [WPAI]) were assessed. Univariable and multivariable regression analyses assessed associations between PROs and disease severity.ResultsAmong CD patients, 67.4% were in remission, 19.2% had mild disease, and 13.4% had moderate/severe disease; among UC patients, 52.7% were in remission, 35.3% had mild disease, and 12.0% had moderate/severe disease. For CD patients in remission, unadjusted percentages of patients with PROMIS scores outside normal limits ranged from 18.9% (depression) to 34.9% (fatigue). For CD patients in remission, 54.3% reported work productivity loss, and 57.1% reported activity impairment. The unadjusted percentage of UC patients in remission with scores outside normal limits ranged from 15.7% (depression) to 28.7% (fatigue) for PROMIS and 10.5% (absenteeism) to 43.5% (activity impairment) for WPAI. Impairment increased with IBD severity. Congruently, adjusted estimates showed significant impairment in PROMIS and WPAI scores for CD and UC patients in remission.ConclusionIn this real-world analysis, IBD patients across the spectrum of activity, from remission to severe disease, experienced impaired psychosocial function and reduced work productivity. Impairment, even among patients in remission, indicates an unmet need in this patient population. This study aimed to evaluate associations between disease severity, patient-reported outcomes (PROs), and work productivity in patients with inflammatory bowel disease (IBD [Crohn’s disease (CD) and ulcerative colitis (UC)]). Patients diagnosed with CD or UC enrolled in CorEvitas’ IBD Registry (May 2017 to September 2019) were included (N = 1543; CD, n = 812; UC, n = 731). Disease severity was assessed using the Harvey-Bradshaw Index (CD) and partial Mayo Score (UC); psychosocial PROs (Patient-Reported Outcomes Measurement Information System [PROMIS]) and work productivity (Work Productivity and Activity Impairment [WPAI]) were assessed. Univariable and multivariable regression analyses assessed associations between PROs and disease severity. Among CD patients, 67.4% were in remission, 19.2% had mild disease, and 13.4% had moderate/severe disease; among UC patients, 52.7% were in remission, 35.3% had mild disease, and 12.0% had moderate/severe disease. For CD patients in remission, unadjusted percentages of patients with PROMIS scores outside normal limits ranged from 18.9% (depression) to 34.9% (fatigue). For CD patients in remission, 54.3% reported work productivity loss, and 57.1% reported activity impairment. The unadjusted percentage of UC patients in remission with scores outside normal limits ranged from 15.7% (depression) to 28.7% (fatigue) for PROMIS and 10.5% (absenteeism) to 43.5% (activity impairment) for WPAI. Impairment increased with IBD severity. Congruently, adjusted estimates showed significant impairment in PROMIS and WPAI scores for CD and UC patients in remission. In this real-world analysis, IBD patients across the spectrum of activity, from remission to severe disease, experienced impaired psychosocial function and reduced work productivity. Impairment, even among patients in remission, indicates an unmet need in this patient population.

Altered gut microbiota and gut permeability in Crohn’s disease patients in clinical remission

Rationale: Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD), which is associated with alterations in gut microbiota (GM) and increased gut permeability (GP). The aim of this study was to evaluate GM composition and GP in CD patients in remission comparing to healthy subjects.

P014 Postoperative Recurrence in Crohn's Disease Patients Treated with Adalimumab versus Infliximab: A Systematic Review and Meta-Analysis.

Up to 80% of patients with Crohn's disease (CD) undergo intestinal resection at one point. However, the risk of post-operative recurrence (POR) increases with time, with half of these patients developing recurrence at five years after surgery. Treatment with anti-tumor necrosis factor (anti-TNF) agents has been shown to decrease the risk of clinical and endoscopic recurrence post-operatively. This meta-analysis aims to compare the rate of the two mostly commonly used anti-TNF agents (infliximab (IFX) and adalimumab (ADA)) and their efficacy in maintaining clinical and endoscopic remission in CD patients who were treated with adalimumab versus infliximab after surgery. A comprehensive search of Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Scopus was conducted from each database's inception to May 29th 2021. Comparative studies assessing the efficacy and safety of infliximab and adalimumab for postoperative CD patients were included. Primary outcomes included postoperative clinical and endoscopic remission. Secondary outcome was the risk of adverse events due to anti-TNF agents. Pooled event rates were calculated per person-year of follow-up. Four studies with total of 361 CD patients were included in the final analysis. Our meta-analysis showed no statistically significant difference in maintaining clinical and endoscopic remission rates between patients treated with infliximab and those with adalimumab (Pooled incidence rate ratio of 0.75 (95% CI 0.43-1.3), and 0.94 (95% CI 0.71-1.2), respectively) (Figure 1A, 2A). There were low to moderate heterogeneities (I2 = 57.1% for clinical remission and I2 = 0% for endoscopic remission). The funnel plot in each analysis indicated no publication bias, which was supported by Begg's and Egger's tests (Figure 1B, 2B). There was also no significant difference in the risk of adverse events between the two groups (RR= 0.56, 95% CI 0.068-4.5) (Figure 3). Our meta-analysis demonstrated comparable efficacy of infliximab and adalimumab in maintaining post-operative clinical and endoscopic remission in Crohn's disease, with similar rates of adverse events. Our meta-analysis was limited by the small number of total studies and patients included and the lack of randomized controlled trials.

Elevated Levels of IL-27 Are Associated with Disease Activity in Patients with Crohn's Disease.

Immune disorders play an important role in the pathogenesis of Crohn's disease (CD). Notably, the increased immune response of Th1 cells and related cytokines is associated with the onset of CD. IL-27 is a newly discovered IL-12-related cytokine, but its expression and clinical significance in CD patients are still controversial. This study is aimed at evaluating the serum levels of IL-27 in CD patients and analyzing their clinical significance. The results indicated that serum levels of IL-27 in CD patients were significantly higher than those in control subjects (median (interquartile range (IQR)): 110.0 (95.0, 145.0) vs. 85.0 (80.0, 95.0) pg/ml, P < 0.001). Furthermore, the IL-27 levels significantly increased in CD patients at the active stage compared with CD patients in remission (CDR) (127.5 (100.0, 150.0) vs. 90 (80.0, 110.0) pg/ml, P < 0.001). However, there was no difference in IL-27 levels between CDR and control subjects. The levels of IL-27 were positively correlated with Crohn's disease activity index (CDAI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin (FC), and Simple Endoscopic Score for Crohn's Disease (SES-CD) and negatively correlated with hemoglobin (Hb) and serum albumin (ALB). IL-27 combined with CRP favored the prediction of CD activity (area under the curve (AUC): 0.88). Additionally, the proportions of Th17 and Th1 cells in peripheral blood were higher in CD patients than in control subjects. Active CD patients exhibited significantly higher proportions of Th17 and Th1 cells than those in remission. Moreover, correlation analysis indicated that the serum levels of IL-27 were positively associated with the frequency of Th17 cells in CD patients (r = 0.519, P = 0.013) but not associated with the frequency of Th1 cells in CD patients. IL-27 is positively associated with multiple inflammation indicators and may exert a proinflammatory profile by regulating Th17 cell differentiation in the development of Crohn's disease. In the future, IL-27 combined with CRP is expected to become an important biological marker of CD activity.

Ovarian reserve assessment in crohn patients of reproductive age.

Crohn's disease (CD) is a repeating bowel disease characterized by remission and exacerbation periods. The disease mostly affects adults of reproductive age. Women with desires to conceive are concerned about the effects of CD on their fertility. To demonstrate the relationship between ovarian reserve and CD anti-Müllerian hormone (AMH) levels, antral follicle count (AFC) and ovarian volüme were evaluated. The prospective case-controlled study was conducted at a tertiary referral center in Istanbul between March-August 2019. Ovarian functions were evaluated in 50 patients with CD and in 95 healthy women. Serum gonadotropin and AMH levels were determined. AFCs and ovarian volumes were calculated for all subjects. AMH levels were significantly lower in CD patients (2.1 ± 0.8) compared to the control group (3.3 ± 0.9) (p = 0.001). Serum AMH levels were significantly lower in patients with active CD (2.1 ± 0.6) than the CD patients in remission (2.6 ± 0.8) (p = 0.002). Ovarian volumes and AFC values were significantly lower in both ovaries in CD patients compared to the controls (p < 0.05). AMH levels, ovarian volume and AFC counts, and thus ovarian reserve was shown to be decreased in CD patients of reproductive age compared to healthy control subjects. Because possible effects of inflammatory damage may be seen in newly diagnosed female CD patients who desire to have a child, we believe that CD patients should be comprehensively assessed for ovarian reserve.

DOP25 Association of Enterobacteriaceae with Crohn’s Disease subtypes during remission

Abstract Background Members of the Enterobacteriaceae have been associated with active Crohn’s Disease (CD), possibly as a result of intestinal inflammation via production of a lipopolysaccharide that can trigger TLR4 signalling. This study aims to assess whether this association persists in remission of CD patients and whether correlation with disease phenotype is present. Methods Stool samples of 32 CD patients in remission and 97 healthy controls were analyzed by 16S rRNA sequencing. High quality Amplicon sequence variants (ASV) were derived and classified via DADA2. Results ASV 6-Escherichia/Shigella uncl. was found to be more abundant in CD (padj=0.0003) while ASV 24, another member of the Escherichia/Shigella cluster was identified as being an indicator species for CD (padj=0.09). Differential abundance analysis according to phenotype as per Montreal classification revealed that, compared to patients with the B1 phenotype, patients with the B2 and/or B3 have a higher abundance of Escherichia/Shigella uncl. (ASVs 13, 31, 282 and 422), Klebsiella uncl. (ASVs 75 and 101) and Enterobacter uncl. (ASV 219) (Figure 1). Furthermore, patients with L3 involvement had higher abundances of Klebsiella uncl. (ASVs 75 and 101) and Parasutturella uncl. (ASVs 22, 53, 120, 199, 249 and 510), the latter being a Proteobacteria, compared to patients with L1 and/or L2 involvement. No significant association with “Age of Onset” was identified. In addition, network analyses revealed a strongly correlated group of Enterobacteriaceae ASVs (Klebsiella, Escherichia/Shigella, Enterobacter, Citrobacter) which appear to collectively associate to CD. Abstract DOP25 – Figure 1: Heatmap visualizing significant differentially abundant ASVs in CD patients with respect to behaviour subgroups Conclusion Enterobacteriaceae persist in the faecal microbiota in significantly higher levels than controls despite remission and furthermore are associated with the more severe phenotypes of stricturing and penetrating disease. Further studies might indicate whether microbiota assessment on diagnosis might predict CD subtypes and therefore influence therapeutic choices.