Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway.

The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient's life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn's disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFß1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.

Morphological and regional spontaneous functional aberrations in the brain associated with Crohn's disease: a systematic review and coordinate-based meta-analyses.

Crohn's disease is an acknowledged "brain-gut" disorder with unclear physiopathology. This study aims to identify potential neuroimaging biomarkers of Crohn's disease. Gray matter volume, cortical thickness, amplitude of low-frequency fluctuations, and regional homogeneity were selected as indices of interest and subjected to analyses using both activation likelihood estimation and seed-based d mapping with permutation of subject images. In comparison to healthy controls, Crohn's disease patients in remission exhibited decreased gray matter volume in the medial frontal gyrus and concurrently increased regional homogeneity. Furthermore, gray matter volume reduction in the medial superior frontal gyrus and anterior cingulate/paracingulate gyri, decreased regional homogeneity in the median cingulate/paracingulate gyri, superior frontal gyrus, paracentral lobule, and insula were observed. The gray matter changes of medial frontal gyrus were confirmed through both methods: decreased gray matter volume of medial frontal gyrus and medial superior frontal gyrus were identified by activation likelihood estimation and seed-based d mapping with permutation of subject images, respectively. The meta-regression analyses showed a positive correlation between regional homogeneity alterations and patient age in the supplementary motor area and a negative correlation between gray matter volume changes and patients' anxiety scores in the medial superior frontal gyrus. These anomalies may be associated with clinical manifestations including abdominal pain, psychiatric disorders, and possibly reflective of compensatory mechanisms.

Brain network topological changes in inflammatory bowel disease: an exploratory study.

Although the aetio-pathogenesis of inflammatory bowel diseases (IBD) is not entirely clear, the interaction between genetic and adverse environmental factors may induce an intestinal dysbiosis, resulting in chronic inflammation having effects on the large-scale brain network. Here, we hypothesized inflammation-related changes in brain topology of IBD patients, regardless of the clinical form [ulcerative colitis (UC) or Crohn's disease (CD)]. To test this hypothesis, we analysed source-reconstructed magnetoencephalography (MEG) signals in 25 IBD patients (15 males, 10 females; mean age ± SD, 42.28 ± 13.15; mean education ± SD, 14.36 ± 3.58) and 28 healthy controls (HC) (16 males, 12 females; mean age ± SD, 45.18 ± 12.26; mean education ± SD, 16.25 ± 2.59), evaluating the brain topology. The betweenness centrality (BC) of the left hippocampus was higher in patients as compared with controls, in the gamma frequency band. It indicates how much a brain region is involved in the flow of information through the brain network. Furthermore, the comparison among UC, CD and HC showed statistically significant differences between UC and HC and between CD and HC, but not between the two clinical forms. Our results demonstrated that these topological changes were not dependent on the specific clinical form, but due to the inflammatory process itself. Broader future studies involving panels of inflammatory factors and metabolomic analyses on biological samples could help to monitor the brain involvement in IBD and to clarify the clinical impact.

Qualitative and Psychometric Evaluation of 29-Item Patient-Reported Outcomes Measurement Information System® to Assess General Health-Related Quality of Life in Patients With Moderately to Severely Active Inflammatory Bowel Disease.

OBJECTIVES: To evaluate content validity and psychometric properties of the 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29) to determine its suitability in inflammatory bowel disease (IBD) clinical trials. METHODS: Content validity of PROMIS-29 was evaluated using qualitative interviews, including concept elicitation and cognitive debriefing, among patients living with Crohn's disease (Crohn's disease n = 20) or ulcerative colitis (UC, n = 19). PROMIS-29 validity, reliability, and responsiveness were assessed using data from phase II clinical trials of Crohn's disease (N = 360) and UC (N = 518). RESULTS: Common (≥74%) symptoms reported in qualitative interviews were increased stool frequency, fatigue, abdominal pain/cramping, blood/mucus in stool, bowel urgency, and diarrhea. Disease impact aligned with PROMIS-29 content (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles/activities). Cognitive debriefing indicated that PROMIS-29 instructions were easily understood, items were relevant, and the recall period was appropriate. Psychometric evaluations demonstrated that PROMIS-29 scores indicating worse symptoms/functioning were associated with lower health-related quality of life and greater disease activity and severity. PROMIS-29 domain scores correlated (rs ≥ 0.40) with IBD Questionnaire domains and EuroQol-5-Dimension-5-Level dimensions measuring similar concepts. Test-retest reliability among patients with stable disease was moderate-to-excellent (0.64-0.94) for nearly all domains in all studies. PROMIS-29 was responsive to change in disease status from baseline to week 12. Thresholds for clinically meaningful improvement ranged from ≥3 to ≥8, depending on domain. CONCLUSIONS: PROMIS-29 is valid, reliable, and responsive for assessing general health-related quality of life and treatment response in IBD clinical trials.

Unravelling the role of beta-CGRP in inflammatory bowel disease and its potential role in gastrointestinal homeostasis.

BACKGROUND: The role of beta calcitonin gene-related peptide (beta-CGRP) in gastrointestinal tract is obscure, but experimental models suggest an effect on the homeostasis of the intestinal mucosa. We measured beta-CGRP circulating levels in a large series of subjects with a recent diagnosis of inflammatory bowel disease (IBD), in order to assess the potential role of this neuropeptide in IBD pathogenesis. METHODS: Morning serum beta-CGRP levels were measured by ELISA (CUSABIO, China) in 96 patients recently diagnosed of IBD and compared with those belonging from 50 matched healthy controls (HC) and 50 chronic migraine (CM) patients. RESULTS: Beta-CGRP levels were lower in patients with IBD (3.1 ± 1.9 pg/mL; 2.9 [2.4-3.4] pg/mL) as compared to HC (4.7 ± 2.6; 4.9 [4.0-5.8] pg/mL; p < 0.001) and to CM patients (4.6 ± 2.6; 4.7 [3.3-6.2] pg/mL; p < 0.001). Beta-CGRP levels in CM were not significantly different to those of HC (p = 0.92). Regarding IBD diagnostic subtypes, beta-CGRP levels for ulcerative colitis (3.0 ± 1.9pg/mL; 2.5 [2.1-3.4] pg/mL) and Crohn's disease (3.3 ± 2.0 pg/mL; 3.2 [2.4-3.9] pg/mL) were significantly lower to those of HC (p < 0.01 and p < 0.05, respectively) and CM (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: We have found a significant reduction in serum beta-CGRP levels in patients with a recent diagnosis of all kinds of IBD as compared to two control groups without active intestinal disease, HC and CM, which may suggest a role for this neuropeptide in the pathophysiology of IBD. Our data indicate a protective role of beta-CGRP in the homeostasis of the alimentary tract.

Ocular endothelial dysfunction in pediatric inflammatory bowel disease.

OBJECTIVES: To assess ocular microvasculature changes using optical coherence tomography angiography (OCTA) in pediatric patients with inflammatory bowel disease (IBD). METHODS: Patients (aged 6-18 years) with IBD were recruited between September 2021 and May 2023. All eligible participants underwent comprehensive clinical assessment and laboratory investigation. Patients with functional gastrointestinal disorders served as the controls. This study assessed specific IBD phenotypes, disease duration, clinical and endoscopic activity indices, laboratory markers, and medication histories. OCTA was utilized to evaluate ocular microvasculature changes in both groups. RESULTS: A total of 63 children (mean age 12.9 ± 3.3 years) were enrolled, comprising 38 in the IBD group (16 ulcerative colitis, 22 Crohn's disease, and 25 in the control group). Most patients in the IBD group were in remission or had mild-to-moderate disease activity at enrollment. Analysis of the OCTA results revealed significant differences in the choroidal luminal area and total choroidal area between the IBD and control groups. CONCLUSIONS: The study identified distinct ocular microvasculature changes in pediatric IBD patients through OCTA, suggestive of potential systemic endothelial dysfunction. These findings underscore the utility of OCTA in evaluating microvascular alterations associated with pediatric IBD, offering insights into potential systemic complications linked to inflammation in IBD patients.

Factors associated with decreased ovarian reserve in Crohn's disease: A systematic review and meta-analysis.

INTRODUCTION: It is still unclear whether Crohn's disease (CD) might be associated with diminished ovarian reserve (OvR) and factors influencing anti-Mullerian hormone (AMH) levels in CD are poorly known. MATERIAL AND METHODS: We conducted a comprehensive literature search of multiple electronic databases from inception to June 2022 to identify all studies reporting AMH levels or factors associated with diminished OvR in patients with CD. RESULTS: Of the 48 studies identified in our search, eight (including 418 patients with CD) were finally included. The mean difference (95% confidence interval [CI]) in the AMH level between pooled CD patients and controls was -0.56 (-1.14 to 0.03) (p = 0.06). A history of CD-related surgery was not associated with a lower OvR (odds ratio, OR [95% CI] 1.34, [0.66-2.7]; p = 0.4). While disease activity and perianal disease seems associated with a low OvR, disease location (L2 vs. L1, OR [95% CI] = 95% CI [0.47-7.4]; p = 0.4) and L3 vs. L1 (OR [95% CI] = 1.44 [0.67-3.12]; p = 0.3), CD medication, and disease behavior were not. CONCLUSIONS: Our systematic review and meta-analysis did not identify a significantly low OvR in patients with CD. Contrary to CD-related surgery risk factor, active disease was associated lower AMH levels.

Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn's Disease.

BACKGROUND: Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn's disease (CD). METHODS: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12. RESULTS: At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4-41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7-54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6-55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3-18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort. CONCLUSION: Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226.

Efficacy of Biologic Drugs in Short-Duration Versus Long-Duration Inflammatory Bowel Disease: A Systematic Review and an Individual-Patient Data Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may be associated with higher efficacy, especially in Crohn's disease (CD). METHODS: This was a systematic review and individual-patient data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (October 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction of remission in patients with short-duration (≤18 months) vs long-duration disease (>18 months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients' characteristics on the primary outcome. RESULTS: We included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab, or vedolizumab (6168 patients with CD and 3227 patients with UC). In CD, remission induction rates were higher in pooled placebo and patients in active arms with short-duration disease of ≤18 months (41.4% [244 of 589]) compared with disease duration of >18 months (29.8% [852 of 2857], meta-analytically estimated odds ratio, 1.33; 95% confidence interval, 1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction of remission, was not different in short-duration disease of ≤18 months (n = 589, odds ratio, 1.47; 95% confidence interval, 1.01-2.15) compared with longer disease duration (n = 2857, odds ratio, 1.43; 95% confidence interval, 1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable, regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cutoffs and when modeled for individual patient's covariates, including prior anti-tumor necrosis factor exposure. CONCLUSIONS: There are higher rates of induction of remission with biologics and with placebo in early CD, resulting in a treatment to placebo effect ratio that is similar across disease durations. No such relationships between disease duration and outcomes was found in UC. PROSPERO registration: CRD42018041961.

Mesenteric Excision and Exclusion for Ileocolic Crohn's Disease: Feasibility and Safety of an Innovative, Combined Surgical Approach With Extended Mesenteric Excision and Kono-S Anastomosis.

INTRODUCTION: Ileocolic resection for Crohn's disease traditionally does not include a high ligation of the ileocolic pedicle, and most commonly is performed with a stapled side-to-side ileocolic anastomosis. The mesentery has recently been implicated in the pathophysiology of Crohn's disease. Two techniques have been developed and are associated with reduced postoperative recurrence: the Kono-S anastomosis that excludes diseased mesentery and extended mesenteric excision that resects diseased mesentery. We aimed to assess the technical feasibility and safety of a novel combination of techniques: mesenteric excision and exclusion. TECHNIQUES: This initial report is a single-center descriptive study of consecutive adults who underwent mesenteric excision and exclusion for primary or recurrent ileocolic Crohn's disease from September 2020 to June 2021. Medication exposure and endoscopic balloon dilation before surgery were recorded. Phenotype was classified using the Montreal Classification. Thirty-day outcomes were reported. A video of the mesenteric excision and exclusion including the Kono-S anastomosis is presented. RESULTS: Twenty-two patients with ileocolic Crohn's disease underwent mesenteric excision and exclusion: 100% had strictures, 59% had fistulas, 81% were on biologics, and 27% had previous ileocolic resection(s). Seventy-two percent underwent laparoscopic procedures, a mesenteric defect was closed in 86%, omental flaps were fashioned in 77%, and 3 patients were diverted. Median operative time was 175 minutes. Median postoperative stay was 4 days. At 30 days, there were 2 readmissions for reintervention: 1 seton placement and 1 percutaneous drainage of a sterile collection. There were no cases of intra-abdominal sepsis or anastomotic leak. CONCLUSIONS: Mesenteric excision and exclusion represents an innovative, progressive, and promising approach that appears to be highly feasible and safe. Further study is warranted to determine if mesenteric excision and exclusion is associated with reduced postoperative recurrence of ileocolic Crohn's disease.

Endoscopic Evaluation at 1 Month After Ileocolic Resection for Crohn's Disease Predicts Future Postoperative Recurrence and Is Safe.

BACKGROUND: Endoscopy remains the gold standard for evaluating postoperative recurrence in Crohn's disease. Timely therapy adjustment according to endoscopic findings can improve long-term outcomes. OBJECTIVE: We aimed to determine the characteristics, clinical values, and safety of the endoscopic evaluation at 1 month after surgery. DESIGN: This was a prospective observational study. SETTINGS: This study was conducted in a tertiary referral hospital. PATIENTS: Patients with Crohn's disease undergoing ileocolic resection between January 2016 and November 2018 were included. INTERVENTIONS: The first postoperative ileocolonoscopy was performed at 4-5 weeks after surgery. MAIN OUTCOME MEASURES: The primary outcome was postoperative recurrence within 12 months after surgery. Univariate and multivariate analyses were performed to identify risk factors. RESULTS: Among 84 ileocolonoscopies at 4-5 weeks, no endoscopic complication occurred. The main endoscopic findings at the first evaluation were anastomotic circumferential ulcers (10, 11.9%), anastomotic scattered ulcers (35, 41.7%), ulcers in the neoterminal ileum (16, 19.0%), edema in anastomosis (50, 59.5%), mild narrowing in anastomosis (7, 8.3%), and mild narrowing in neoterminal ileum (3, 3.6%). Anastomotic scattered ulcers were associated with future postoperative recurrence (OR, 2.532 (95% CI, 1.02-6.32), p = 0.046). Fecal calprotectin >150 ug/g on postoperative day 14 could predict anastomotic scattered ulcers (OR' 2.91 (95% CI, 1.31-7.47), p = 0.027). The modified Rutgeerts score was used to define endoscopic findings: i0, 37 (44.0%); i1, 4 (4.8%); i2a, 29 (34.5%); i2b, 11 (13.1%); i3, 0; i4, 3 (3.6%). Score ≥i2a were associated with future postoperative recurrence (OR, 3.17 (95% CI, 1.22-8.27), p = 0.018). No factor was associated with a Rutgeerts score of ≥i2a at the first endoscopic evaluation. LIMITATIONS: This was a single-center study with a small cohort of patients. CONCLUSIONS: Endoscopic evaluation at 1 month after surgery in CD was safe. Anastomotic scattered ulcers occurred in nearly half of patients and were associated with future postoperative recurrence. See Video Abstract at http://links.lww.com/DCR/B760.LA EVALUACIÓN ENDOSCÓPICA A UN MES DESPUÉS DE LA RESECCIÓN ILEOCÓLICA PARA LA ENFERMEDAD DE CROHN, PREDICE FUTURA RECURRENCIA POSOPERATORIA Y ES SEGURAANTECEDENTES:La endoscopia sigue siendo el estándar de oro para evaluar la recurrencia posoperatoria en la enfermedad de Crohn (EC). El ajuste oportuno en la terapia de acuerdo con los hallazgos endoscópicos, puede mejorar los resultados a largo plazo.OBJETIVO:Determinar las características, valores clínicos y seguridad de la evaluación endoscópica, al mes de la cirugía.DISEÑO:Estudio observacional prospectivo.ENTORNO CLINICO:El estudio se llevó a cabo en un hospital de referencia terciario.PACIENTES:Se incluyeron pacientes con EC sometidos a resección ileocólica entre enero de 2016 y noviembre de 2018.INTERVENCIONES:La primera ileocolonoscopia posoperatoria se realizó a las 4-5 semanas posteriores a la cirugía.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la recurrencia posoperatoria dentro de los 12 meses posteriores a la cirugía. Se realizaron análisis univariados y multivariados para identificar factores de riesgo.RESULTADOS:Entre 84 ileocolonoscopias a las 4-5 semanas, no ocurrió ninguna complicación endoscópica. Los principales hallazgos endoscópicos en la primera evaluación, fueron úlceras anastomóticas circunferenciales (10, 11,9%), úlceras anastomóticas dispersas (35, 41,7%), úlceras en el íleon neo-terminal (16, 19,0%), edema en la anastomosis (50, 59,5%), estrechamiento leve en la anastomosis (7, 8,3%) y estrechamiento leve en el íleon neo-terminal (3, 3,6%). Las úlceras anastomóticas dispersas se asociaron con recurrencia posoperatoria futura (OR, 2,532 (95% CI, 1,02-6,32), p = 0,046). La calprotectina fecal en el post d 14 > 150 ug / g podría predecir úlceras anastomóticas dispersas (OR' 2,91 (95% CI, 1,31-7,47), p = 0,027). Se utilizó la puntuación de Rutgeerts modificada para definir los hallazgos endoscópicos: i0, 37 (44,0%); i1, 4 (4,8%); i2a, 29 (34,5%); i2b, 11 (13,1%); i3, 0; i4, 3 (3,6%). La puntuación ≥i2a se asoció con recurrencia posoperatoria futura (OR, 3,17 (95% CI, 1,22-8,27), p = 0,018). Ningún factor se asoció con ≥i2a en la primera endoscopia.LIMITACIONES:Estudio de un solo centro con una pequeña cohorte de pacientes.CONCLUSIONES:La evaluación endoscópica al mes de la cirugía en EC, fue segura. Se produjeron úlceras anastomóticas dispersas en casi la mitad de los pacientes y se asociaron con una futura recurrencia posoperatoria. Consulte Video Resumen en http://links.lww.com/DCR/B760. (Traducción - Dr. Fidel Ruiz Healy).

Small Bowel Crohn's Disease Recurrence is Common After Total Proctocolectomy for Crohn's Colitis.

BACKGROUND: Surgical intervention for Crohn's disease involving the colon is often a total proctocolectomy with end ileostomy. There are limited data regarding postoperative small bowel recurrence rates in the recent era. OBJECTIVE: The purpose of this study was to determine the rate of small bowel Crohn's disease recurrence following total proctocolectomy and secondarily define risk factors for disease recurrence. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at four hospitals within a single healthcare system. PATIENTS: Patients were those with Crohn's disease undergoing total proctocolectomy with end ileostomy between 2009-2019. MAIN OUTCOME MEASURES: Main outcome measures were clinical, endoscopic, radiographic, and/or surgical Crohn's disease recurrence. RESULTS: In total, 193 patients were included with a median follow-up of 1.8 years (IQR 0.4-4.6). Overall, 74.6% (n = 144) of patients had been previously exposed to biologic therapy, and 51.3% (n = 99) had a history of small bowel Crohn's disease. Postoperatively, 14.5% (n = 28) of patients received biologic therapy. Crohn's disease recurrence occurred in 23.3% (n = 45) of patients with an estimated median 5-year recurrence rate of 40.8% (95% CI' 30.2-51.4). Surgical recurrence occurred in 8.8% (n = 17) of patients with an estimated median 5-year recurrence rate of 16.9% (95% CI' 8.5-25.3). On multivariable analysis, prior small bowel surgery for Crohn's disease (HR 2.61; 95% CI' 1.42-4.81) and Crohn's diagnosis at age <18 years (HR 2.56; 95% CI' 1.40-4.71) were associated with Crohn's recurrence. In patients without prior small bowel Crohn's disease, 14.9% (n = 14) had Crohn's recurrence with an estimated 5-year overall recurrence rate of 31.1% (95% CI' 13.3-45.3) and 5-year surgical recurrence rate of 5.7% (95% CI' 0.0-12.0). LIMITATIONS: The study was limited by its retrospective design and lack of consistent follow-up on all patients. CONCLUSIONS: Greater than one third of patients who underwent total proctocolectomy for Crohn's disease were estimated to have small bowel Crohn's recurrence at 5 years after surgery. Patients with a history of small bowel surgery for Crohn's and diagnosis at any early age may benefit from more intensive postoperative surveillance and consideration for early medical prophylaxis. See Video Abstract at http://links.lww.com/DCR/B762. RECURRENCIA FRECUENTE DE LA ENFERMEDAD DE CROHN DEL INTESTINO DELGADO DESPUS DE LA PROCTOCOLECTOMA TOTAL POR COLITIS DE CROHN: ANTECEDENTES:La cirugia para la enfermedad de Crohn que involucra el colon es a menudo una proctocolectomía total con ileostomía terminal. Hay datos limitados con respecto a las tasas de recurrencia posoperatoria de la enfermedad de Crohn del intestino delgado en la actualidad.OBJETIVO:Buscamos determinar la tasa de recurrencia de la enfermedad de Crohn del intestino delgado después de la proctocolectomía total y, en segundo lugar, definir los factores de riesgo de recurrencia de la enfermedad.DISEÑO:Estudio de cohorte retrospectivo.ENTORNO CLINICO:Cuatro hospitales de un mismo sistema sanitario.PACIENTES:Pacientes con enfermedad de Crohn sometidos a proctocolectomía total con ileostomía terminal entre 2009-2019.PRINCIPALES MEDIDAS DE VALORACIÓN:Recurrencia clínica, endoscópica, radiográfica y / o quirúrgica de la enfermedad de Crohn.RESULTADOS:Se incluyeron 193 pacientes con un seguimiento promedio de 1,8 años (IQR 0,4-4,6). El 74,6% (n = 144) de los pacientes habían recibido previamente terapia biológica y el 51,3% (n = 99) tenían antecedentes de enfermedad de Crohn del intestino delgado. Después de la operación, el 14,5% (n = 28) de los pacientes recibieron terapia biológica. La recurrencia de la enfermedad de Crohn ocurrió en el 23,3% (n = 45) de los pacientes con una tasa de recurrencia media estimada a los 5 años del 40,8% (IC del 95%: 30,2-51,4). La recidiva quirúrgica se produjo en el 8,8% (n = 17) de los pacientes con una tasa de recidiva media estimada a los 5 años del 16,9% (IC del 95%: 8,5-25,3). En el análisis multivariable, la cirugía previa del intestino delgado para la enfermedad de Crohn (HR 2,61, IC del 95%: 1,42-4,81) y el diagnóstico de Crohn a la edad <18 (HR 2,56, IC del 95%: 1,40-4,71) se asociaron con la recurrencia de Crohn. En pacientes sin enfermedad previa de Crohn del intestino delgado, el 14,9% (n = 14) tuvo recurrencia de Crohn con una tasa de recurrencia general estimada a 5 años del 31,1% (IC del 95%: 13,3-45,3) y una tasa de recurrencia quirúrgica a 5 años del 5,7% (IC del 95%: 0,0-12,0).LIMITACIONES:Diseño retrospectivo, falta de seguimiento constante de todos los pacientes.CONCLUSIONES:Se estimó que más de un tercio de los pacientes que se sometieron a proctocolectomía total tenían recurrencia de Crohn del intestino delgado a los 5 años después de la cirugía. Los pacientes con antecedentes de cirugía por enfermedad de Crohn del intestino delgado y diagnóstico a una edad temprana pueden beneficiarse de una vigilancia posoperatoria más intensiva y la consideración de una profilaxis médica temprana. Consulte Video Resumen en http://links.lww.com/DCR/B762. (Traducción- Dr. Ingrid Melo).

A Simple Emergency Department-Based Score Predicts Complex Hospitalization in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Thirty percent of inflammatory bowel disease (IBD) patients hospitalized with flare require salvage therapy or surgery. Additionally, 40% experience length of stay (LOS) > 7 days. No emergency department (ED)-based indices exist to predict these adverse outcomes at admission for IBD flare. We examined whether clinical, laboratory, and endoscopic markers at presentation predicted prolonged LOS, inpatient colectomy, or salvage therapy in IBD patients admitted with flare. METHODS: Patients with ulcerative colitis (UC) or colonic involvement of Crohn's disease (CD) hospitalized with flare and tested for Clostridioides difficile infection (CDI) between 2010 and 2020 at two urban academic centers were studied. The primary outcome was complex hospitalization, defined as: LOS > 7 days, inpatient colectomy, or inpatient infliximab or cyclosporine. A nested k-fold cross-validation identified predictive factors of complex hospitalization. RESULTS: Of 164 IBD admissions, 34% (56) were complex. Predictive factors included: tachycardia in ED triage (odds ratio [OR] 3.35; confidence interval [CI] 1.79-4.91), hypotension in ED triage (3.45; 1.79-5.11), hypoalbuminemia at presentation (2.54; 1.15-3.93), CDI (2.62; 1.02-4.22), and endoscopic colitis (4.75; 1.75-5.15). An ED presentation score utilizing tachycardia and hypoalbuminemia predicted complex hospitalization (area under curve 0.744; CI 0.671-0.816). Forty-four of 48 (91.7%) patients with a presentation score of 0 (heart rate < 99 and albumin ≥ 3.4 g/dL) had noncomplex hospitalization. CONCLUSIONS: Over 90% of IBD patients hospitalized with flare with an ED presentation score of 0 did not require salvage therapy, inpatient colectomy, or experience prolonged LOS. A simple ED-based score may provide prognosis at a juncture of uncertainty in patient care.

Inflammatory Bowel Disease Patients Who Respond to Treatment with Anti-tumor Necrosis Factor Agents Demonstrate Improvement in Pre-treatment Frailty.

BACKGROUND: Frailty may be a risk factor for complications in inflammatory bowel diseases (IBD) patients. We examined the impact of treatment on IBD patients who were frail prior to treatment and identified predictors of post-treatment change in frailty. METHODS: In an electronic health record-based cohort of IBD patients initiating anti-tumor necrosis factor (TNF)-α agents, we applied a validated claims-based frailty index to determine frailty in the 1 year prior to and after treatment initiation. We characterized treatment non-response using a composite outcome of IBD-related hospitalization, surgery, change in therapy, or initiation of systemic steroids. We constructed multivariable logistic regression models to identify determinants of post-treatment frailty. RESULTS: The 1210 patients initiating anti-TNF therapy had a median age of 30 years; 20% were ≥ 50 years. In the first year after anti-TNF initiation, 40% were non-responders. Many more treatment non-responders were frail in the year following treatment compared with treatment responders (27% vs 7%, p < 0.001). Pre-treatment frailty (OR 2.01, 95% CI 1.35-3.00) and prior IBD-related hospitalization (OR 1.63, 95% CI 1.15-2.30) were independently predictive of higher likelihood of post-treatment frailty. Therapy response was associated with a lower likelihood (OR 0.24, 95% CI 0.16-0.34) of post-treatment frailty. Nearly 85% of patients who were frail prior to treatment demonstrated improvement in frailty following treatment CONCLUSIONS: Response to anti-TNF therapy is an important determinant of post-treatment frailty in patients with IBD. Our findings suggest that effectively treating inflammatory states in older patients with IBD may improve frailty.

Crohn's versus Cancer: Comparison of Functional and Surgical Outcomes after Right-Sided Resections.

BACKGROUND: The objective of this study was to compare functional and surgical outcomes of patients undergoing ileocecal resection for Crohn's disease (CD) to patients undergoing oncological right colectomy. METHODS: Retrospective single-center cohort study including consecutive patients undergoing right colectomy for adenocarcinoma (oncological resection) or CD (mesentery-sparing resection) between July 2011 and November 2017. Outcome measures were pathological details (lymph node yield), postoperative recovery (pain levels, return to flatus and stool, intake of fluids, weight change, and mobilization), and early (30-day) outcomes (surgical/medical complications, hospital stay, readmissions). RESULTS: A total of 195 patients (153 [78%] with cancer and 42 [22%] with CD) were included. Overall compliance with the institutional enhanced recovery protocol was comparable between the 2 groups (compliance ≥70%: 60% in CD patients vs. 62% in cancer, p = 0.458). The adenocarcinoma group had a larger lymph node yield than the CD group (26 ± 13 vs. 2.4 ± 5, respectively, p < 0.001). While the CD group experienced significantly more pain (3.7 ± 1.9/10 vs. 2.8 ± 2.5/10, p = 0.007, patients requiring opioids: 65 vs. 28%, p = 0.001), return of flatus (2.3 ± 1.2 days vs. 2.4 ± 2.8 days, p = 0.642) and stool (4.1 ± 6.0 vs. 3.0 ± 1.8 days, p = 0.292) was no different in both groups. No difference was observed regarding postoperative complications, length of stay, and readmission rate. CONCLUSION: This study revealed no differences in both functional and surgical outcomes in CD and cancer patients undergoing mesentery-sparing or formal oncological right colectomy, respectively.

Fecal microbiota transplantation therapy in Crohn's disease: Systematic review.

BACKGROUND: The gastrointestinal microbiota is the key antigenic drive in the inflammatory bowel diseases. Randomized controlled trials (RCTs) in ulcerative colitis have established fecal microbiota transplantation (FMT) as an effective therapy. We have conducted a systematic review to evaluate the efficacy of FMT in Crohn's disease. METHODS: A systematic literature search was performed through to August 2020 (MEDLINE; Embase). Studies were included if they reported FMT administration in patients with Crohn's disease, and reported on clinical outcomes. RESULTS: Fifteen studies published between 2014 and 2020, comprising 13 cohort studies and two RCTs, were included in the analysis. The majority of trials evaluated FMT for induction of remission, with follow-up duration varying from 4 to 52 weeks. One RCT in 21 patients, of single-dose FMT versus placebo, following steroid-induced remission, showed a higher rate of steroid-free clinical remission in the FMT group compared to the control group: 87.5% vs 44.4% at week 10 (P = 0.23). Another RCT, two-dose FMT in 31 patients, showed an overall clinical remission rate of 36% at week 8, however, with no difference in clinical or endoscopic endpoints between FMT administered by gastroscopy and colonoscopy. Considering all studies, the clinical response rates in early follow up were higher following multiple FMT than with single FMT. FMT dose did not appear to influence clinical outcomes, nor did whether FMT was fresh or frozen. FMT delivered via upper gastrointestinal route demonstrated higher early efficacy rates of 75 to 100% compared with lower delivery route rates of 30% to 58%, but on follow up beyond 8 weeks, this difference was not maintained. Whether pre-FMT antibiotic administration was beneficial was not able to be determined due to the limited number of patients receiving antibiotics and varying antibiotic regimens. No serious adverse events were reported. CONCLUSIONS: Preliminary studies suggest that FMT may be an effective therapy in Crohn's disease. However large controlled trials are needed. No serious safety concerns have been identified.

Putting Crohn's on the MAP: Five Common Questions on the Contribution of Mycobacterium avium subspecies paratuberculosis to the Pathophysiology of Crohn's Disease.

For decades, Mycobacterium avium subspecies paratuberculosis (MAP) has been linked to the pathogenesis of Crohn's disease. Despite many investigations and research efforts, there remains no clear unifying explanation of its pathogenicity to humans. Proponents argue Crohn's disease shares many identical features with a granulomatous infection in ruminants termed Johne's disease and similarities with ileo-cecal tuberculosis. Both are caused by species within the Mycobacterium genus. Sceptics assert that since MAP is found in individuals diagnosed with Crohn's disease as well as in healthy population controls, any association with CD is coincidental. This view is supported by the uncertain response of patients to antimicrobial therapy. This report aims to address the controversial aspects of this proposition with information and knowledge gathered from several disciplines, including microbiology and veterinary medicine. The authors hope that this discussion will stimulate further research aimed at confirming or refuting the contribution of MAP to the pathogenesis of Crohn's disease and ultimately lead to advanced targeted clinical therapies.

Prevalence, Indirect Costs, and Risk Factors for Work Disability in Patients with Crohn's Disease at a Tertiary Care Center in Rio de Janeiro.

BACKGROUND AND AIMS: Crohn's disease (CD) can lead to work disability with social and economic impacts worldwide. In Brazil, where its prevalence is increasing, we assessed the indirect costs, prevalence, and risk factors for work disability in the state of Rio de Janeiro and in a tertiary care referral center of the state. METHODS: Data were retrieved from the database of the Single System of Social Security Benefits Information, with a cross-check for aid pension and disability retirement. A subanalysis was performed with CD patients followed up at the tertiary care referral center using a prospective CD database, including clinical variables assessed as possible risk factors for work disability. RESULTS: From 2010 to 2018, the estimated prevalence of CD was 26.05 per 100,000 inhabitants, while the associated work disability was 16.6%, with indirect costs of US$ 8,562,195.86. Permanent disability occurred more frequently in those aged 40 to 49 years. In the referral center, the prevalence of work disability was 16.7%, with a mean interval of 3 years between diagnosis and the first benefit. Risk factors for absence from work were predominantly abdominal surgery, anovaginal fistulas, disease duration, and the A2 profile of the Montreal classification. CONCLUSIONS: In Rio de Janeiro, work disability affects one-sixth of CD patients, and risk factors are associated with disease duration and complications. In the context of increasing prevalence, as this disability compromises young patients after a relatively short period of disease, the socioeconomic burden of CD is expected to increase in the future.

Impaired Quality of Working Life in Inflammatory Bowel Disease Patients.

BACKGROUND: Work-related aspects are important determinants of health for inflammatory bowel disease (IBD) patients. AIMS: We aimed to describe quality of working life (QWL) in IBD patients and to assess variables that are associated with QWL. METHODS: Employed IBD patients of two tertiary and two secondary referral hospitals were included. QWL (range 0-100) was measured using the Quality of Working Life Questionnaire (QWLQ). Work productivity (WP), fatigue, and health-related quality of life (HRQL) were assessed using the Work Productivity and Activity Impairment questionnaire, Multidimensional Fatigue Inventory, and Short Inflammatory Bowel Disease Questionnaire, respectively. Active disease was defined as a score > 4 for the patient-reported Harvey-Bradshaw index in Crohn's disease (CD) or Simple Clinical Colitis Activity Index in ulcerative colitis patients. RESULTS: In total, 510 IBD patients were included (59% female, 53% CD, mean age 43 (SD 12) years). The mean QWLQ score was 78 (SD 11). The lowest subscore (54 (SD 26)) was observed for "problems due to the health situation": 63% reported fatigue-related problems at work, 48% agreed being hampered at work, 46% had limited confidence in their body, and 48% felt insecure about the future due to their health situation. Intermediate/strong associations were found between QWL and fatigue (r = - 0.543, p < 0.001), HRQL (r = 0.527, p < 0.001), WP loss (r = - 0.453, p < 0.001) and disease activity (r = - 0.331, p < 0.001). Independent predictors of impaired QWL in hierarchical regression analyses were fatigue (B = - 0.204, p < 0.001), WP loss (B = - 0.070, p < 0.001), and impaired HRQL (B = 0.248, p = 0.001). CONCLUSIONS: IBD-related problems at work negatively influence QWL. Fatigue, reduced HRQL, and WP loss were independent predictors of impaired QWL in IBD.

The Clinical Significance of Anastomotic Ulcers After Ileocolic Resection to Predict Postoperative Recurrence of Crohn's Disease.

BACKGROUND: The Rutgeerts score is used to predict postoperative recurrence in CD patients after ileocolic resection and is primarily based on endoscopic findings at the neoterminal ileum. However, the optimal assessment of anastomotic ulcers (AUs) remains subject to debate. AIMS: We aimed to investigate the association between anastomotic ulcers (AUs) and endoscopic recurrence in postoperative Crohn's disease (CD) patients. METHODS: This single-center retrospective study, conducted between 2000 and 2016, evaluated postoperative CD patients with endoscopic remission at the first ileocolonoscopy within 1 year after ileocolic resection and those who underwent subsequent ileocolonoscopic follow-up. The study outcome was the clinical significance of AUs in predicting endoscopic recurrence. RESULTS: Among 116 patients who were in endoscopic remission defined as the RS of i0 to i1 at the index postoperative ileocolonoscopy, 84.5% (98/116) underwent subsequent ileocolonoscopies. During the median 30.0 months (interquartile range, 21.3-53.3) of follow-up after the first ileocolonoscopy, 56.1% (55/98) of patients showed endoscopic recurrence. Furthermore, 65.8% (48/73) with AUs and 75.5% (40/53) with major AUs, defined as either an ulcer occupying ≥ 1/4 of the circumference, ≥ 3 ulcers confined to anastomotic ring, or any ulcers extending to the ileocolonic mucosa, showed endoscopic recurrence. On multivariable analysis, AUs (adjusted hazard ratio [aHR], 4.33; 95% confidence interval [CI], 1.87-10.0; P < 0.001) and major AUs (aHR, 3.64; 95% CI, 1.95-79; P < 0.001) were associated with endoscopic recurrence. CONCLUSIONS: AUs are associated with a significantly high risk of endoscopic recurrence in postoperative CD patients who are in endoscopic remission.