Moderate Colitis Research Articles

Predictors of Unplanned Health Care Utilization Among Children with Inflammatory Bowel Disease in a Rural Region of the Southeastern US.

Pediatric Inflammatory Bowel Disease (IBD) imposes significant healthcare costs and strains emergency services. This study aimed to identify factors associated with unplanned healthcare usage among children with IBD in a rural, medically underserved region in the southeastern United States. In this retrospective cohort study, we analyzed children (<18years) with moderate or severe IBD followed at an academic pediatric gastroenterology clinic between 2016 and 2021. Each planned visit was treated as a separate observation, and patients were followed after each planned visit until the occurrence of the earliest unplanned healthcare event, until the next planned visit, or until censoring. In our analysis of 471 planned visits from 70 children with IBD, we observed 84 (18%) unplanned visits within 12months, with 39 of these visits related to IBD. Unplanned visits occurred at a median interval of 39 days, predominantly to the emergency department (ED). Multivariate Cox proportional hazards analysis revealed a higher hazard of unplanned visits among female patients, individuals with elevated C-reactive protein levels and anemia, those covered by Medicaid insurance, and those residing closer to the clinic. This study elucidates the challenges faced by children with IBD in rural settings. By identifying factors associated with unplanned healthcare utilization, we can better pinpoint patients who may benefit from targeted interventions to reduce such visits.

A real-world disproportionality analysis of mesalazine data mining of the public version of FDA adverse event reporting system.

Background: Mesalazine, a preparation of 5-aminosalicylic acid, is a medication widely used in clinical practice as a first-line therapy in the treatment of mild and moderate inflammatory bowel disease. However, the long-term safety of mesalazine in large sample population was unknown. The current study was to assess mesalazine -related adverse events of real-world through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio the Bayesian confidence propagation neural network and the multi-item gamma Poisson shrinker (MGPS) algorithms were employed to quantify the signals of mesalazine -associated AEs. Results: Out of 14,149,980 reports collected from the FDA Adverse Event Reporting System database, 24,284 reports of mesalazine -associated AEs were identified. A total of 170 significant disproportionality preferred terms conforming to the four algorithms simultaneously were retained. The most common AEs included colitis ulcerative, diarrhoea, condition aggravated, crohn's disease, fatigue, abdominal pain, nausea, haematochezia, which were corresponding to those reported in the specification and clinical trials. Unexpected significant AEs as dizziness, drug ineffective, drug hypersensitivity, infection, off label use, weight decreased, decreased appetite, arthralgia, rash might also occur. The median onset time of mesalazine -related AEs was 1,127days (interquartile range [IQR] 1,127-1,674days), and most of the cases occurred 2years later (n = 610, 70.93%) and within the first 1month (n = 89, 10.35%) after mesalazine initiation. Conclusion: Results of our study were consistent with clinical observations. We also found potential new and unexpected AEs signals for mesalazine, suggesting prospective clinical studies were needed to confirm these results and illustrate their relationship. Our results could provide valuable evidence for further safety studies of mesalazine.

Screening of silent inflammatory bowel disease in seronegative spondyloarthritis patients: Fecal calprotectin, ileo-colonoscopy and histopathology assessment

IntroductionSeronegative spondyloarthritis (SpA) patients are at an increased risk of developing silent inflammatory bowel disease (IBD). Early diagnosis may help avoid future complications and choose the most effective treatment. Aimof the workto screen for silent IBD in SpA patients. Patients and methodsThis study included 41 SpA patients subjected to clinical assessment regarding gastrointestinal symptoms, laboratory data and ileo-colonoscopy with tissue histopathology.Fecal calprotectin levels were measured by enzyme linked-immunosorbant assay (ELISA). The Bath ankylosing spondylitis disease activity index (BASDAI) and psoriatic arthritis disease activity score (PASDAS) were assessed. ResultsThe median age of patients was 40 years (23–58 years) with 27 males and 14 females (M: F 1.9:1); 28 had axial SpA and 13 psoriatic arthritis (PsA); 25 (61%) patients were active. Only 19.5% received non-steroidal anti-inflammatory drugs (NSAIDs) while 61% received biologics. Median fecal calprotectin was 88 mcg/g and was elevated in 71% of patients. Patients receiving biologics had significantly lower median levels of fecal calprotectin than those who did not (72.7 vs 436.7mcg/g; p = 0.012). Abnormal colonoscopy was seen in 14.6% of patients (three Crohn’s disease and three ulcerative colitis). 17 (41.5%) showed abnormal histopathology; 9 had moderate colitis and activity while five patients had moderate colitis with minimal activity. There was a significant relation between platelet count and abnormal colonoscopy findings (p = 0.01). ConclusionSpA patients can have macroscopic or microscopic silent IBD changes. Fecal calprotectin may be used for screening of silent IBD among those patients, however, it should be supported by ileo-colonoscopic examination and histopathological assessment.

Short-term efficacy and safety of vedolizumab in patients with inflammatory bowel disease

Objective: To evaluate the short-term efficacy and safety of vedolizumab in patients with inflammatory bowel disease (IBD). Methods: Patients with moderate and severe active IBD at the first use of vedolizumab from May 1 to October 31, 2021 were retrospectively enrolled. Then the clinical characteristics, and the efficacy and safety of vedolizumab were evaluated. Meanwhile, the clinical response rate, biological response rate and endoscopic response rate were calculated. Multivariate analysis was used to evaluate the independent influencing factors of short-term clinical efficacy and safety. Results: A total of 78 patients (44 males and 34 females) with IBD were enrolled, with a mean age of (40.5±11.9) years. The clinical remission rate, clinical response rate, biological remission rate, biological response rate and endoscopic remission rate was 60.3% (47/78), 85.9% (67/78), 70.5% (55/78), 43.6% (34/78) and 47.0% (31/66) respectively after 14 weeks of treatment. Body mass index (BMI) ≥ 18.5 kg/m2 (HR=5.04, 95%CI: 1.50-16.91, P=0.009) and biological remission at 6 weeks of treatment (HR=15.22, 95%CI: 3.16-73.38, P=0.001) were predictors of endoscopic remission at 14 weeks of treatment. Adverse reactions occurred in 57 patients, with an incidence of 73.1%. The main manifestations were liver and kidney damage (37.2%) and infection (26.9%). Conclusions: More than half of patients with moderate and severe active IBD can achieve clinical remission after 14 weeks of vedolizumab treatment. Baseline BMI level and biological remission at 6 weeks of treatment are predictors of mucosal healing at 14 weeks. The incidence of adverse reactions is not low, although serious adverse reactions are rare in short-term treatment.

S2227 A Rare Case of Primary Diffuse Large B Cell Lymphoma of the Colon

Introduction: Primary colorectal lymphomas are rare and account for 0.3% of all large intestinal malignancies, with Diffuse Large B-Cell Lymphoma (DLBCL) representing the most common subtype. We present a case of primary colonic DLBCL that was diagnosed after surgical resection of the sigmoid colon. Case Description/Methods: An 86-year-old White female with a past medical history of diverticulosis and atrial fibrillation presented to the emergency department complaining of abdominal cramping and rectal bleeding. Physical examination was significant for mild abdominal tenderness and vital signs revealed blood pressure of 151/83 mmHg. Laboratory investigations were significant for white blood cell count of 10.56 x 10^3 cells/uL and potassium 2.8 mmol/L. Abdominal and pelvic computed tomography with contrast revealed sigmoid colonic diverticulosis with interposition of colon between liver and right hemidiaphragm. The patient underwent colonoscopy that showed a stricture of benign intrinsic appearance in the sigmoid colon measuring 10 cm in diameter and 3 cm in length. Histological analysis of tissue biopsies taken at that time were only significant for mild to moderate colitis. After colonoscopy, she was taken for laparoscopic low anterior resection of the sigmoid colonic mass that was later converted to an open approach due to the size of the mass. After the incision was extended, the sigmoid colon was further mobilized and the uninvolved portions of the proximal rectum and descending colon were transected. After the sigmoid colon was removed and sent to pathology, the proximal rectum and descending colon were anastomosed with no air leaks identified. Pathology report of the surgical specimen later showed malignant lymphoma with transmural invasion and involvement of numerous adjacent pericolonic nodes with negative tumor margins. Immunostains revealed the tumor to be positive for BCL-2, BCL-6, CD10, and CD20 but negative for CD3 and BCL-1. High proliferative activity was discerned for KI-67 staining in 90% of tumor cells; all evidence supporting the diagnosis of DLBCL. After an uneventful postoperative period and clinical improvement, the patient was discharged to home for close follow-up. Discussion: Primary colonic lymphomas are rare and usually present with nonspecific symptoms. Although in the case discussed, the patient did not present with any obvious predisposing conditions for DLBCL, further data is necessary to determine other possible associations and develop a standardized treatment regimen.

Moderate Colitis Not Requiring Intravenous Steroids Is Associated with Improved Survival in Stage IV Melanoma after Anti-CTLA4 Monotherapy, But Not Combination Therapy.

BackgroundFor patients with melanoma, gastrointestinal immune-related adverse events are common after receipt of anti-CTLA4 therapy. These present difficult decision points regarding whether to discontinue therapy. Detailing the situations in which colitis might predict for improved survival and how this is affected by discontinuation or resumption of therapy can help guide clinical decision-making.Materials and MethodsPatients with stage IV melanoma receiving anti-CTLA4 therapy from 2008 to 2019 were analyzed. Immune-related colitis treated with ≥50 mg prednisone or equivalent daily or secondary immunosuppression was included. Moderate colitis was defined as receipt of oral glucocorticoids only; severe colitis was defined as requiring intravenous glucocorticoids or secondary immunosuppression. The primary outcome was overall survival (OS).ResultsIn total, 171 patients received monotherapy, and 91 received dual checkpoint therapy. In the monotherapy group, 25 patients developed colitis and a nonsignificant trend toward improved OS was observed in this group. Notably, when colitis was categorized as none, moderate or severe, OS was significantly improved for moderate colitis only. This survival difference was not present after dual checkpoint therapy. There were no differences in known prognostic variables between groups, and on multivariable analysis neither completion of all ipilimumab cycles nor resumption of immunotherapy correlated with OS, while the development of moderate colitis did significantly affect OS.ConclusionThis single-institution retrospective series suggests moderate colitis correlates with improved OS for patients with stage IV melanoma treated with single-agent anti-CTLA4, but not dual agent, and that this is true regardless of whether the immune-checkpoint blockade is permanently discontinued.

Differences in MUC2 Gene Expression Based on the Clinical Severity of Colitis and the Degree of Histopathological Damage to the Colonic Mucosa in Colitis-induced Rat

BACKGROUND: Inflammatory bowel disease (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by intestinal inflammation and epithelial damage. Impaired mucosal cell barrier function mainly associated with thinning of the mucin layer may be the initial events underlying injury and inflammation in UC. Impaired expression of specific mucins is closely associated with IBD. MUC2 is a gene that produces mucin, which is predominant in the colon in humans and rats. METHODS: This study is an experimental study with a posttest-only design. The sample comprised 16 colitis-induced rats. Induction of colitis was done by giving a solution of dextran sodium sulfate (DSS) 2.5% 1 mL/day orally for 7 days. MUC2 gene expression was measured by rtPCR. The clinical severity of colitis was classified based on the disease activity index (DAI) score. The degree of histopathological damage was classified based on the score of colonic histology observations. The statistical analysis was done by the Shapiro–Wilk normality test and continued with an independent samples t-test. RESULTS: There were differences in MUC2 gene expression in mild and moderate colitis (1.81 vs. 2.99) but the difference was not significant (p &gt; 0.05). MUC2 gene expression also differed in mild and severe histopathological damage degrees (2.32 vs. 2.1) but the difference was not significant (p &gt; 0.05). CONCLUSION: It was concluded in this study that MUC2 gene expression did not have significant differences based on the clinical severity of colitis and the degree of histopathological damage to the colonic mucosa in colitis-induced rats.

Divergent Adaptations in Autonomic Nerve Activity and Neuroimmune Signaling Associated With the Severity of Inflammation in Chronic Colitis.

The autonomic nervous system (ANS) is thought to play a critical role in the anti-inflammatory reflex pathway in acute colitis via its interaction with the spleen and colon. Inflammation in the intestine is associated with a blunting of vagal signaling and increased sympathetic activity. As a corollary, methods to restore sympatho-vagal balance are being investigated as therapeutic strategies for the treatment of intestinal inflammation. Nevertheless, it is indefinite whether these autonomic signaling adaptations in colitis are detrimental or beneficial to controlling intestinal inflammation. In this study, models of moderate and severe chronic colitis are utilized to resolve the correlations between sympatho-vagal signaling and the severity of intestinal inflammation. Spleens and colons were collected from Winnie (moderate colitis), Winnie-Prolapse (severe colitis), and control C57BL/6 mice. Changes to the size and histomorphology of spleens were evaluated. Flow cytometry was used to determine the expression of adrenergic and cholinergic signaling proteins in splenic B and T lymphocytes. The inflammatory profile of the spleen and colon was determined using a RT-PCR gene array. Blood pressure, heart rate, splanchnic sympathetic nerve and vagus nerve activity were recorded. Spleens and colons from Winnie and Winnie-Prolapse mice exhibited gross abnormalities by histopathology. Genes associated with a pro-inflammatory response were upregulated in the colons from Winnie and further augmented in colons from Winnie-Prolapse mice. Conversely, many pro-inflammatory markers were downregulated in the spleens from Winnie-Prolapse mice. Heightened activity of the splanchnic nerve was observed in Winnie but not Winnie-Prolapse mice. Conversely, vagal nerve activity was greater in Winnie-Prolapse mice compared with Winnie mice. Splenic lymphocytes expressing α1 and β2 adrenoreceptors were reduced, but those expressing α7 nAChR and producing acetylcholine were increased in Winnie and Winnie-Prolapse mice. Sympathetic activity may correlate with an adaptive mechanism to reduce the severity of chronic colitis. The Winnie and Winnie-Prolapse mouse models of moderate and severe chronic colitis are well suited to examine the pathophysiology of progressive chronic intestinal inflammation.

The Deletion of IL-17A Enhances Helicobacter hepaticus Colonization and Triggers Colitis.

ObjectiveIL-17 is a key regulator of the inflammatory response, and as such, it is involved in the constraint and clearance of pathogens. The mechanism of IL-17 in the pathogenesis of inflammatory bowel disease (IBD) caused by microbial infection is still unclear. Helicobacter hepaticus infection can induce colitis in many mouse strains, and thus, it has been widely used in the study of IBD pathogenesis.MethodsIn this study, male C57BL/6, BALB/c, Il-10−/−, and Il-17a−/− mice were infected with H. hepaticus for several weeks. Histopathology, H. hepaticus colonization and distribution, expression of inflammatory cytokines and lysozyme, and distribution of mucus in proximal colon were examined.ResultsThe colonic colonization of H. hepaticus was abnormally high in Il-17a−/− mice. H. hepaticus infection caused only mild to moderate colitis symptoms in Il-17a−/− mice, including low levels of lymphocyte infiltration, epithelial cell defects, goblet cell reduction, and crypt atrophy without obvious hyperplasia in the later stage of infection. Furthermore, many inflammatory genes were significantly increased in the proximal colon of H. hepaticus-infected Il-17a−/− mice compared with C57BL/6 mice. In addition, the reduction of colonic mucus and the down-regulation of ZO-1, Claudin-1, and IL-22 were observed in Il-17a−/− mice compared with C57BL/6 mice post H. hepaticus infection.ConclusionThese results demonstrated that the deletion of IL-17A impaired the integrity of the intestinal epithelium, weakened the secretion of mucus, attenuated colonic mucosal regeneration, reduced the ability to resist microbial infection, and finally led to colitis caused by H. hepaticus.

Fourier-Transform Infra-Red Microspectroscopy Can Accurately Diagnose Colitis and Assess Severity of Inflammation.

The diagnosis and management of inflammatory bowel disease relies on histological assessment, which is costly, subjective, and lacks utility for point-of-care diagnosis. Fourier-transform infra-red spectroscopy provides rapid, non-destructive, reproducible, and automatable label-free biochemical imaging of tissue for diagnostic purposes. This study characterises colitis using spectroscopy, discriminates colitis from healthy tissue, and classifies inflammation severity. Hyperspectral images were obtained from fixed intestinal sections of a murine colitis model treated with cell therapy to improve inflammation. Multivariate analyses and classification modelling were performed using supervised and unsupervised machine-learning algorithms. Quantitative analysis of severe colitis showed increased protein, collagen, and nucleic acids, but reduced glycogen when compared with normal tissue. A partial least squares discriminant analysis model, including spectra from all intestinal layers, classified normal colon and severe colitis with a sensitivity of 91.4% and a specificity of 93.3%. Colitis severity was classified by a stacked ensemble model yielding an average area under the receiver operating characteristic curve of 0.95, 0.88, 0.79, and 0.85 for controls, mild, moderate, and severe colitis, respectively. Infra-red spectroscopy can detect unique biochemical features of intestinal inflammation and accurately classify normal and inflamed tissue and quantify the severity of inflammation. This is a promising alternative to histological assessment.

Long non-coding RNA ANRIL serves as a potential marker of disease risk, inflammation, and disease activity of pediatric inflammatory bowel disease

BackgroundLong non-coding antisense RNAs in the INK4 locus (lnc-ANRIL) have been reported to be involved in inflammation and immunity. However, few studies have reported its clinical application in pediatric inflammatory bowel disease (IBD). Therefore, we conducted this study to investigate the correlation between lnc-ANRIL expression and disease risk, inflammation, and activity in pediatric IBD patients. MethodsPediatric patients with Crohn's disease (CD; n = 40), ulcerative colitis (UC; n = 40), and controls (n = 20) were recruited. For all pediatric IBD patients, lnc-ANRIL expression in peripheral blood mononuclear cells and serum inflammatory cytokine levels were measured by RT-qPCR and ELISA, respectively. For the controls, lnc-ANRIL expression was also measured. ResultsLnc-ANRIL levels were lower in CD (P = 0.002) and UC (P = 0.001) patients compared with the controls; negatively correlated with C-reactive protein levels (P<0.01), erythrocyte sedimentation rate (P<0.01), disease activity (P<0.05), and severity (P<0.05) in CD and UC patients; and inversely associated with tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-17, and IL-23 levels in both CD and UC patients (all P<0.01). Further subgroup analyses revealed that the association between lnc-ANRIL and inflammatory cytokines and disease activity was more remarkable in pediatric patients with moderate or severe IBD. ConclusionLnc-ANRIL may serve as a potential marker for evaluating disease risk and monitoring disease activity in pediatric IBD patients.

Room to Improve Prior Authorization in Children With Complex Medical Needs

Since the 1980s, US health insurers have used prior authorization (PA) to determine whether a health care service or treatment is medically necessary before covering its cost. To initiate this process, a patient’s clinician submits an application that justifies the need for the service or treatment. The insurer then adjudicates necessity. PA was designed to mitigate overuse of expensive health services and treatments that patients may not need, thereby containing health care costs and promoting evidence-based care. PA originated largely from overuse of health services and treatments among elderly Medicare beneficiaries.1 Despite widespread use of PA among public and private insurers for adult patients, there is a paucity of information on PA in children, including the risks and benefits to children who experience it.To advance knowledge on PA in children, Constant and colleagues2 assessed the initiation of expensive biologic medications (eg, antitumor-necrosis factor α) in 190 children with inflammatory bowel disease (IBD). IBD is a complex chronic gastrointestinal condition with a relapsing and remitting disease course that can become debilitating if insufficiently treated. Biologic medications are effective in moderate and severe IBD. The per-member-per-year (PMPY) cost of biologic mediations for pediatric patients with IBD is high (∼$41 100).3 Constant and colleagues found that nearly three-fourths of children experienced PA for use of a biologic medication. Thirteen percent experienced complicated PA, which included peer-to-peer review, letter of appeal, and/or step-therapy before approval was granted. Uncomplicated and complicated PA delayed biologic initiation for IBD by over 1 and 3 weeks, respectively. Children experiencing PA had significantly higher rates of IBD exacerbation that necessitated emergency department use, hospitalization, and exposure to systemic corticosteroids.The findings from this study question the value of PA for biologic medications in children with IBD. On completion of the PA process, biologic medications were approved for all children with IBD in the study, suggesting that no unnecessary use occurred. Despite this, health might have been compromised because of the need to wait for PA approval. Although the retrospective case-control study design cannot be used to infer causal relationship between the need for PA and health outcomes, the imbalance of risk without benefit with PA for biologic medications in children with IBD in the study is evident.Reading the study by Constant and colleagues invoked recollection of myriad PA and insurer-led denial-of-care experiences for children with complex medical needs cared for in our clinical practice. We have had patients with epilepsy experience recurrent seizures while waiting on PA approval for antiepileptic medications. Patients with severe neurologic impairment have vomited and aspirated while waiting on PA for gastroesophageal reflux and gastric promotility medications. One patient hospitalized with hypoxia because of a critical airway who was scheduled for tracheotomy and a laryngotracheal separation was denied hospital coverage because the insurer perceived that the patient’s health problems did not necessitate hospital level of care. Most if not all of these patients received coverage approval by the insurer after significant time and effort justifying need was performed by the patients’ clinicians.With these experiences in mind, the findings from the study by Constant and colleagues complement the disdain expressed by many pediatric clinicians that PA is an administrative nuisance without any clear benefit to children. Multiple initiatives to reform and standardize the PA process have emerged to optimize efficiency and transparency as well as to address variation across insurers. Despite state-level legislation and national efforts from the American Medical Association,4 the burden of PA on clinicians remains heavy. US physicians reportedly spend up to 16 hours weekly on PA tasks. Forty percent of physicians hire office staff dedicated to PA.5 Labor costs for PA processing exceed $500 million annually.6Constant and colleagues remind us that pediatric clinicians have no choice currently but to remain steadfast to complete the PA process for the patients who need it to get them the medications and treatments that require PA approval. This is especially true for general pediatric, complex care, and specialty clinicians caring for large numbers of children with complex and chronic medical needs. These children are at risk for a disproportionate share of PAs to attain needed medications and medical equipment. Strong partnerships among insurers, clinicians, patients, and families are essential when designing and implementing solutions to optimize the value of PA for pediatric patients. Future quality improvement and research endeavors should distinguish and disseminate successful PA collaborations. We should all work together to ensure safe and timely access to pediatric health services and treatments, regardless of their cost.

A189 INFLAMMATORY BOWEL DISEASE IN PEDIATRIC PATIENTS POST RENAL TRANSPLANT:A CASE SERIES

BackgroundDiarrhea in renal transplant recipients may be due to infection, medication induced colitis and post-transplant lymphoproliferative disease. Uncommonly a subset of these children develop denovo inflammatory bowel disease (IBD), despite being already immunosuppressed. Paucity of literature in the pediatric population has been noted.AimsTo describe the clinical presentation, investigations and response to treatment in a cohort of children diagnosed with IBD post renal transplantMethodsPatients diagnosed with IBD post renal transplant between January 1 - October 1, 2021 at BC Children’s Hospital were identified. Medical history, symptoms at presentation, histological characteristics, results of investigations and response to treatment were reviewedResultsData of 3 children were collected. Ages of the children were 11, 16 and 17 years (2 female). All patients had bloody diarrhea, abdominal pain and weight loss for 1 to 2 months. IBD diagnosis was made 8, 7 and 4 years respectively post renal transplant. All children were on maintenance immunosuppression with prednisone, MMF and tacrolimus. Bacterial, viral and parasitic causes were ruled out by relevant studies. All patients had negative anti-tissue transglutaminase.Patient 1 (transplanted for renal dysplasia) was diagnosed with Crohn disease involving the antrum, ileum, and colon with rectal sparing. Fecal calprotectin (FC) was 1742 ug/g, CRP elevated at 56mg/L. Histology showed focally active chronic gastritis and changes in ileum with cryptitis and crypt dropout. The colon had features of moderate chronic active colitis with focal severe ulceration in the rectum. The patient achieved clinical remission on treatment with methylprednisolone, then started on vedolizumab in context of rising BK virus titre.Patient 2 (transplanted for focal segmental glomerulosclerosis) was diagnosed with indeterminate colitis involving the IC valve and scattered colonic ulcers. FC was 674 ug/g and CRP and ESR were normal. Histology showed normal ileum, moderate active chronic changes in colon and rectal sparing. Clinical remission was achieved with oral mesalamine.Patient 3 (transplanted for Bardet-Biedl syndrome) was diagnosed with indeterminate colitis with a colonoscopy that showed patchy colonic erythema and normal ileum. FC was 966 ug/g, and CRP and ESR were normal. Histology showed patchy chronic active colitis and mild active ileitis. Clinical remission was achieved with oral and rectal mesalamine.ConclusionsDenovo IBD occurs in children post renal transplant and must be considered in the differential for ongoing diarrhea in these patients. It can be a challenge to distinguish between IBD and other causes of diarrhea. The patients in this series entered clinical remission in a short period of time. Further exploration of the pathogenesis of IBD in these immunosuppressed patients would be valuableFunding AgenciesNone

A144 CHRONIC DSS LEADS TO ALTERED EXPRESSION OF IRAK4/TPL2 PATHWAYS IN UC-COLONIZED MICE

BackgroundUlcerative colitis (UC) is one of two forms of inflammatory bowel disease (IBD). The exact cause of IBD is unknown but altered host-microbe interactions and genetic susceptibility are involved in its pathogenesis. Many patients with IBD do not respond to biological therapies targeting single cytokines, therefore new therapies that target common immune pathways are being developed and need to be tested in relevant preclinical models. Previously we have shown that mice colonized with UC microbiota upregulated genes related to inflammation without induction of colitis compared to healthy volunteer-colonized mice. We thus investigated whether IRAK4 and TPL2-induced pathways, new therapeutic targets in development upstream of inflammatory cytokine gene activation, are upregulated in mice colonized with UC microbiota and chronic colitis.AimsOur aim was to characterize TPL2 and IRAK4 signalling pathways and T cell phenotypes in UC-colonized mice following chronic low-dose dextran sodium sulfate (DSS) colitis.Methods10-16-week-old germ-free C57BL/6 mice were colonized with fecal microbiota from a patient with UC experiencing a flare (n=16). Mice were housed in a gnotobiotic facility during the experiment. Three weeks following colonization, colitis was induced in half of the mice by three cycles (5 d each; 2.0%, 1.5% and 1.5%, respectively) of DSS in drinking water with a 5-d wash-out period between cycles. All mice were fed a control diet (7004, Teklad). Fecal samples were collected weekly. At sacrifice, disease activity (colon length, occult blood in feces, stool consistency, and spleen weight) was measured and colon tissue was collected for histological analysis and RNA sequencing. Mesenteric lymph nodes (MLNs) were acquired for flow cytometry to analyze T cell phenotypes.ResultsIn UC-colonized mice, chronic low-dose DSS induced softer feces (p<0.0001), shorter colon length (p<0.0001), and increased spleen weight (p<0.0001), compared with water treated mice. This was paralleled by detectable blood in stool, development of moderate colitis (DSS: 1.9+/-1.4 vs H2O: 0.5+/-0.2; p<0.02) and higher proportion of IL-17 (p=0.003) and IFN-γ-producing T cells (p=0.06) in MLNs compared with water treated mice. RNA sequencing revealed that inflammatory genes, mainly related to the IRAK4/TPL2 pathway (e.g., Gadd45b, Socs3, Il1b), were significantly increased (p≤0.05) in the colon of mice treated with DSS compared with water.ConclusionsWhen challenged with a chronic low-dose chemical injury agent, mice colonized with UC microbiota develop clinical and histological signs of colitis and upregulation of genes involved in inflammation like Gadd45b, Socs3, and Il1b. Thus, this model represents a new valuable tool for preclinical testing of new drug candidates, such as those related to the modulation of IRAK4/TPL2 pathways.Funding AgenciesCCC

DOP04 Inflammatory Bowel Disease (IBD) and Solid Organ Transplantation. Natural history of pre-existing and de novo IBD patients. (EITOS study of GETECCU)

Abstract Background Limited data is available of the outcome of inflammatory bowel disease (IBD) in patients with solid organ transplantation (SOT). The aim of our study was to describe the natural history of pre-existing IBD and de novo IBD after SOT. Methods A retrospective, observational, multi-centre, nationwide study was designed. IBD patients with SOT were included. We identified two separate cohorts: (1) patients with pre-existing IBD at the time of SOT and (2) patients without IBD at the time of SOT (de novo IBD). The primary outcome was IBD progression, defined by the escalation of medical treatment, surgical therapy for medically refractory IBD or IBD-related hospitalization during follow-up. Risk factors were identified using multivariate Cox proportional hazard analysis. Results A total of 177 patients (106 pre-existing IBD and 71 de novo IBD) from 31 centres were included. Baseline characteristics are shown in Table 1. Eighty-six patients with IBD and SOT underwent liver transplantation, while 82 required renal, 4 lung, 3 heart, 1 liver/kidney and 1 pancreas/kidney transplantation. Pre-existing IBD patients were followed-up over a median of 4.8 years (range 2.6–9.4). At the time of SOT, 61 patients (59.8%) were not under maintenance treatment or were treated with 5-aminosalicylates, 10 (9.8%) were on immunosuppressive therapy and 31 (30.4%) were receiving biological agents, of which 8 were on combo therapy. At the moment of SOT, only 8 patients (7.5%) had moderate IBD activity whereas the remaining patients were in remission. During follow-up 33.7% of patients with pre-existing IBD had disease progression, with a median time between SOT and IBD progression of 2.2 years (range 1.3–4.6). No differences between Crohn′s disease and ulcerative colitis were found (Figure 1). The median time of follow-up in de novo IBD group was 5.1 years (range 2.1–8.2). In this cohort, 55.9% of patients had disease progression during follow-up (Figure 2), with a median time to flare of 1.9 years (range 0.8–3.9) from diagnosis. In pre-existing IBD cohort, multivariate Cox-regression analysis identified active IBD at the time of SOT (HR=1.80; 95%CI: 1.14–2.84; p=0.012) and the presence of extraintestinal manifestations (HR=3.10; 95%CI: 1.47–6.54; p=0.003) as predictive factors of IBD progression after SOT. Conclusion One third of patients with pre-existing IBD have disease progression, needing medical therapy escalation, surgery or hospitalization after SOT. Active IBD at the time of SOT and the presence of extraintestinal manifestations were identified as risk factors for disease progression. In de novo IBD cohort, about half of patients showed disease progression during follow-up.

Severe pseudomembranous colitis in patients with previous coronavirus infection

To analyze treatment outcomes in patients with severe pseudomembranous colitis and previous coronavirus infection. We retrospectively analyzed treatment outcomes, clinical, laboratory and histological data in convalescents of COVID-19 who admitted to the department of coloproctology for moderate-to-severe pseudomembranous colitis confirmed by endoscopic examination between 2020 and 2021. There were 13 patients with moderate pseudomembranous colitis and 6 ones with severe pseudomembranous colitis. Mean period after recovery from coronavirus infection was 19 days. Endoscopy revealed whitish-yellow or gray raised plaques on colonic mucosa in all cases. Four patients with signs of peritonitis underwent emergency surgery. Three patients had perforation of caecum; one patient had perforation of sigmoid colon and widespread peritonitis. Two patients underwent urgent surgery for progressive toxic megacolon and ineffective therapy. Subtotal colectomy and ileostomy were performed in all cases. Histological examination revealed necrosis of not only superficial layer of colon mucosa typical for clostridial colitis, but also the entire thickness of mucosa, as well as submucosal and partially muscular layers in some cases. Mucosal crypt atrophy, fibrinoid effusion in muscular layer, diffuse polymorphonuclear cell infiltration and necrosis of muscular and submucosal nerve plexuses, as well as necrosis of vascular walls with deposition of hyaline-like structures characterize microcirculatory ischemic processes in the colon wall. Severe pseudomembranous colitis associated with COVID-19 may not be associated with clostridial infection. Further analysis of possible ischemic etiology and pathogenesis of gastrointestinal lesions in COVID-19 is needed for preventive and therapeutic measures.

Risk Factors for Extraintestinal Manifestations in Inflammatory Bowel Diseases - Data from the Romanian National Registry.

Identifying the risk factors for extraintestinal manifestations (EIMs) in inflammatory bowel diseases (IBD) may optimize the therapeutic decision. We aimed to assess the prevalence of EIMs in IBD patients in Romania and to determine the risk factors. We analyzed 2,626 patients registered in the Romanian IBD Prospect National Registry. We performed a descriptive cross-sectional study to assess the point prevalence of EIMs, calculating global prevalence and analyzing the different types of EIMs and their respective frequencies were carried out. Demographic and clinical risk factors were researched as possible predictors for EIMs development, based on the results of the univariate and multivariate logistic regression analysis. The overall point prevalence of EIMs was 16.3%. A significantly higher frequency of EIMs in Crohn's disease (CD) was noted in comparison to ulcerative colitis (UC) and IBD unclassified (IBDU) (23.2% vs 11.3% and 16.3%, respectively, p<0.001). The most frequent type of EIM was peripheral arthropathy (8.3%), significantly associated with CD (p<0.001). Univariate analysis highlighted the significant independent common predictive risk factors for EIMs, in both CD and UC patients: female gender, patient's urban area of origin, anemia, hypoalbuminemia, and high level of C-reactive protein (CRP), while significant independent IBD phenotype-related risk factors were ileocolonic location and concomitant involvement of upper gastrointestinal tract for CD, non-smoker status and both moderate and severe disease activity for UC (p<0.05). Multivariate analysis determined that female CD patients with moderate or severe disease activity, with other than isolated ileal disease, and female UC patients with moderate or severe extensive colitis are the most likely to develop EIMs. IBD patients are experiencing EIMs in a large proportion, with higher rates for CD. As EIMs negatively affect patient outcomes, foreseeing the risk by identifying independent and associated predictive factors could be a first step to optimal work-up and treatment.

Comparing the clinical application values of the Degree of Ulcerative ColitisBurden of Luminal Inflammation (DUBLIN) score and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) in patients with ulcerative colitis.

BackgroundThe significance of endoscopic evaluation in the diagnosis and management of ulcerative colitis (UC) has been widely recognized. Over the years, scholars have established several endoscopic scores. Herein, we assessed the clinical application value of the Mayo Endoscopic Subscore (Mayo ES), the Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) score, and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score in UC patients, by comparing their correlation with disease activity and their predictive potential for treatment response and clinical outcomes.MethodsUC patients hospitalized from September 2015 to September 2019 were retrospectively analysed. We employed Spearman's rank correlation coefficient to assess the linear association of the assessed endoscopic scores with the clinical parameters. The receiver-operating characteristic curve was applied to evaluate the predictive capabilities of the endoscopic scores for treatment escalation and 1-year readmission.ResultsA total of 178 patients were enrolled; most of them (82%) suffered moderate or severe colitis. Among them, 48 (27%) patients received treatment escalation and 59 (33%) were readmitted within 1 year. The DUBLIN and UCEIS scores demonstrated higher correlations with clinical parameters than the Mayo ES. The DUBLIN scores significantly differed between patients with mild, moderate, and severe colitis (all P < 0.001). The UCEIS scores demonstrated the best predictabilities for treatment escalation and 1-year readmission with an area under the curve of 0.88 and 0.75, respectively. Compared to the UCEIS and DUBLIN scores, the predictive capabilities of the Mayo ES for treatment escalation (both P < 0.001) and 1-year readmission (P < 0.001 and P = 0.002, respectively) were lower. The UCEIS scores exhibited a significant difference between the steroid-responsive group and the steroid-dependent or steroid-refractory group (both P < 0.001), while no significant differences in the Mayo ES and DUBLIN scores were found among the three groups (both P > 0.05).ConclusionThis study demonstrates that both the DUBLIN and UCEIS scores outperform the Mayo ES in assessing disease severity and predicting treatment response and clinical outcomes in UC patients.

Hyaluronic Acid Increases Anti-Inflammatory Efficacy of Rectal 5-Amino Salicylic Acid Administration in a Murine Colitis Model.

5-amino salicylic acid (5-ASA) is a standard therapy for the treatment of mild to moderate forms of inflammatory bowel diseases (IBD) whereas more severe forms involve the use of steroids and immunosuppressive drugs. Hyaluronic acid (HA) is a naturally occurring non-sulfated glycosaminoglycan that has shown epithelium protective effects in experimental colitis recently. In this study, both 5-ASA (30 mg/kg) and HA (15 mg/kg or 30 mg/kg) were administered rectally and investigated for their potential complementary therapeutic effects in moderate or severe murine colitis models. Intrarectal treatment of moderate and severe colitis with 5-ASA alone or HA alone at a dose of 30 mg/kg led to a significant decrease in clinical activity and histology scores, myeloperoxidase activity (MPO), TNF-α, IL-6 and IL-1β in colitis mice compared to untreated animals. The combination of HA (30 mg/kg) and 5-ASA in severe colitis led to a significant improvement of colitis compared to 5-ASA alone. Combined rectal therapy with HA and 5-ASA could be a treatment alternative for severe cases of IBD as it was the only treatment tested that was not significantly different from the healthy control group. This study further underlines the benefit of searching for yet unexplored drug combinations that show therapeutic potential in IBD without the need of designing completely new drug entities.

P679 The keystone bacterium Christensenella minuta improves colitis in in vivo preclinical Inflammatory Bowel Disease models

Abstract Background There is increasing evidence that microbiome-based therapies can correct dysbiosis and reduce inflammation associated with Inflammatory Bowel Diseases (IBD). In particular, the human commensal family of Christensenellaceae bacteria has been reported as missing in several cohorts of Crohn’s disease patients, indicating that it may have a role in maintaining microbial symbiosis in this population. To assess its potential for IBD management, we used the reference type species Christensenella minuta DSM 22607 to examine its anti-inflammatory properties. Methods We first performed two distinct independent preclinical colitis models: i) a moderate DNBS-induced colitis model in mice and ii) a severe TNBS-induced colitis model in rats. To decipher the mechanisms of action of C. minuta underlying the observed effects, we determined its ability to produce short chain fatty acids (SCFA) at different growth phases and we assessed its capacity to modulate the inflammatory response of human colonic cells. Results Our results showed that in both rodent models, C. minuta prevented intestinal damages by decreasing macroscopic scores, reduced colonic inflammation by limiting neutrophils infiltration in the colon and stimulated mucosal healing. We also confirmed that C. minuta is a high acetate and moderate butyrate producer. Finally, we showed that C. minuta displayed potent anti-inflammatory properties by decreasing the secretion of the pro-inflammatory cytokine IL-8 through NF-kB inhibition in HT-29 cells. Conclusion Together, these results revealed for the first time the strong anti-inflammatory properties of C. minuta and confirm its high potential as an innovative microbiome-based biotherapy for IBD.