Rigorous Donor Selection for Fecal Microbiota Transplantation in Active Ulcerative Colitis: Key Lessons From a Randomized Controlled Trial Halted for Futility.

BACKGROUND & AIMS: Rigorous donor preselection on microbiota level, strict anaerobic processing, and repeated fecal microbiota transplantation (FMT) administration were hypothesized to improve FMT induction of remission in ulcerative colitis (UC). METHODS: The RESTORE-UC trial was a multi-centric, double-blind, sham-controlled, randomized trial. Patients with moderate to severe UC (defined by total Mayo 4-10) were randomly allocated to receive 4 anaerobic-prepared allogenic or autologous donor FMTs. Allogenic donor material was selected after a rigorous screening based on microbial cell count, enterotype, and the abundance of specific genera. The primary endpoint was steroid-free clinical remission (total Mayo ≤2, no sub-score >1) at week 8. A pre-planned futility analysis was performed after 66% (n = 72) of intended inclusions (n = 108). Quantitative microbiome profiling (n = 44) was performed at weeks 0 and 8. RESULTS: In total, 72 patients were included, of which 66 received at least 1 FMT (allogenic FMT, n = 30 and autologous FMT, n = 36). At week 8, respectively, 3 and 5 patients reached the primary endpoint of steroid-free clinical remission (P = .72), indicating no treatment difference of at least 5% in favor of allogenic FMT. Hence, the study was stopped due to futility. Microbiome analysis showed numerically more enterotype transitions upon allogenic FMT compared with autologous FMT, and more transitions were observed when patients were treated with a different enterotype than their own at baseline (P = .01). Primary response was associated with lower total Mayo scores, lower bacterial cell counts, and higher Bacteroides 2 prevalence at baseline. CONCLUSION: The RESTORE-UC trial did not meet its primary endpoint of increased steroid-free clinical remission at week 8. Further research should additionally consider patient selection, sterilized sham-control, increased frequency, density, and viability of FMT prior to administration. CLINICALTRIALS: gov, Number: NCT03110289.

Perianal Fistulizing Crohn's Disease: Utilizing the TOpClass Classification in Clinical Practice to Provide Targeted Individualized Care.

BACKGROUND & AIMS: Perianal fistulation is a challenging phenotype of Crohn's disease, with significant impact on quality of life. Historically, fistulae have been classified anatomically in relation to the sphincter complex, and management guidelines have been generalized, with lack of attention to the clinical heterogenicity seen. The recent 'TOpClass classification system' for perianal fistulizing Crohn's disease (PFCD) addresses this issue, and classifies patients into defined groups, which provide a focus for fistula management that aligns with disease characteristics and patient goals. In this article, we discuss the clinical applicability of the TOpClass model and provide direction on its use in clinical practice. METHODS: An international group of perianal clinicians participated in an expert consensus to define how the TOpClass system can be incorporated into real-life practice. This included gastroenterologists, inflammatory bowel disease surgeons, and radiologists specialized in PFCD. The process was informed by the multi-disciplinary team management of 8 high-volume fistula centres in North America, Europe, and Australia. RESULTS: The process produced position statements to accompany the classification system and guide PFCD management. The statements range from the management of patients with quiescent perianal disease to those with severe PFCD requiring diverting-ostomy and/or proctectomy. The optimization of medical therapies, as well as the use of surgery, in fistula closure and symptom management is explored across each classification group. CONCLUSION: This article provides an overview of the system's use in clinical practice. It aims to enable clinicians to have a pragmatic and patient goal-centered approach to medical and surgical management options for individual patients with PFCD.

Effect of 5-Hydroxytryptophan on Fatigue in Quiescent Inflammatory Bowel Disease: A Randomized Controlled Trial.

BACKGROUND & AIMS: Fatigue is highly prevalent among patients with inflammatory bowel disease (IBD), and only limited treatment options are available. Based on the hypothetical link between low serum tryptophan concentrations and fatigue, we determined the effect of 5-hydroxytryptophan supplementation on fatigue in patients with inactive IBD. METHODS: A multicenter randomized controlled trial was performed at 13 Belgian hospitals, including 166 patients with IBD in remission but experiencing fatigue, defined by a fatigue visual analog scale (fVAS) score of ≥5. Patients were treated in a crossover manner with 100 mg oral 5-hydroxytryptophan or placebo twice daily for 2 consecutive periods of 8 weeks. The primary end point was the proportion of patients reaching a ≥20% reduction in fVAS after 8 weeks of intervention. Secondary outcomes included changes in serum tryptophan metabolites, Functional Assessment of Chronic Illness Therapy Fatigue scale, and scores for depression, anxiety, and stress. The effect of the intervention on the outcomes was evaluated by linear mixed modeling. RESULTS: During 5-hydroxytryptophan treatment, a significant increase in serum 5-hydroxytryptophan (estimated mean difference, 52.66 ng/mL; 95% confidence interval [CI], 39.34-65.98 ng/mL; P < .001) and serotonin (3.0 ng/mL; 95 CI, 1.97-4.03 ng/mL; P < .001) levels was observed compared with placebo. The proportion of patients reaching ≥20% reduction in fVAS was similar in placebo- (37.6%) and 5-hydroxytryptophan (35.6%)-treated patients (P = .830). The fVAS reduction (-0.18; 95% CI, -0.81 to 0.46; P = .581) and Functional Assessment of Chronic Illness Therapy Fatigue scale increase (0.68; 95% CI, -2.37 to 3.73; P = .660) were both comparable between 5-hydroxytryptophan and placebo treatment as well as changes in depression, anxiety, and stress scores. CONCLUSIONS: Despite a significant increase in serum 5-hydroxytryptophan and serotonin levels, oral 5-hydroxytryptophan did not modulate IBD-related fatigue better than placebo. (Trial Registration: Belgian Federal Agency for Medication and Health Products, EudraCT number: 2017-005059-10 and ClinicalTrials.gov: NCT03574948, https://clinicaltrials.gov/ct2/show/NCT03574948.).

Distinct immune modulatory roles of regulatory T cells in gut versus joint inflammation in TNF-driven spondyloarthritis.

OBJECTIVES: Gut and joint inflammation commonly co-occur in spondyloarthritis (SpA) which strongly restricts therapeutic modalities. The immunobiology underlying differences between gut and joint immune regulation, however, is poorly understood. We therefore assessed the immunoregulatory role of CD4+FOXP3+ regulatory T (Treg) cells in a model of Crohn's-like ileitis and concomitant arthritis. METHODS: RNA-sequencing and flow cytometry was performed on inflamed gut and joint samples and tissue-derived Tregs from tumour necrosis factor (TNF)∆ARE mice. In situ hybridisation of TNF and its receptors (TNFR) was applied to human SpA gut biopsies. Soluble TNFR (sTNFR) levels were measured in serum of mice and patients with SpA and controls. Treg function was explored by in vitro cocultures and in vivo by conditional Treg depletion. RESULTS: Chronic TNF exposure induced several TNF superfamily (TNFSF) members (4-1BBL, TWEAK and TRAIL) in synovium and ileum in a site-specific manner. Elevated TNFR2 messenger RNA levels were noted in TNF∆ARE/+ mice leading to increased sTNFR2 release. Likewise, sTNFR2 levels were higher in patients with SpA with gut inflammation and distinct from inflammatory and healthy controls. Tregs accumulated at both gut and joints of TNF∆ARE mice, yet their TNFR2 expression and suppressive function was significantly lower in synovium versus ileum. In line herewith, synovial and intestinal Tregs displayed a distinct transcriptional profile with tissue-restricted TNFSF receptor and p38MAPK gene expression. CONCLUSIONS: These data point to profound differences in immune-regulation between Crohn's ileitis and peripheral arthritis. Whereas Tregs control ileitis they fail to dampen joint inflammation. Synovial resident Tregs are particularly maladapted to chronic TNF exposure.

The effect of aging on infliximab exposure and response in patients with inflammatory bowel diseases.

AIMS: Controversies regarding infliximab treatment in elderly patients with inflammatory bowel diseases remain. We evaluated the effect of patient's age on infliximab exposure, efficacy and safety. METHODS: Retrospective case-control data of patients receiving infliximab induction treatment were analysed. A population pharmacokinetic model was developed to estimate individual pharmacokinetic parameters. A logistic regression model was used to investigate the effect of exposure on endoscopic remission. Repeated time-to-event models were developed to describe the hazard of safety events over time. RESULTS: A total of 104 patients (46 elderly, ≥65 years) were included. A two-compartment population pharmacokinetic model with linear elimination adequately described the data. Infliximab clearance decreased with older age, higher serum albumin, lower fat-free mass, lower C-reactive protein and absence of immunogenicity. Yet, infliximab exposure was not significantly different between elderly and nonelderly. Regardless of age, an infliximab trough concentration at week (w)14 of 15.6 mg/L was associated with a 50% probability of attaining endoscopic remission between w6 and w22. Infliximab exposure during induction treatment was not a risk factor of (severe) adverse events. The hazard of severe adverse events and malignancy increased by 2% and 7%, respectively, with increasing year of age. Concomitant immunomodulator use increased the hazard of infection by 958%, regardless of age. CONCLUSIONS: Elderly patients attained infliximab exposure and endoscopic remission similarly to nonelderly patients. Therefore, the same infliximab trough concentration target can be used in therapeutic drug monitoring. The hazards of severe adverse events and malignancy increased with age, but not with infliximab exposure.

Nivolumab-induced immune-mediated colitis: an ulcerative colitis look-alike-report of new cases and review of the literature.

PURPOSE: Nivolumab, a monoclonal antibody-targeting programmed cell death protein-1, is being increasingly used for the treatment of some advanced neoplasms. Several of its adverse effects are a result of the upregulation of T cells, with colitis as one of the most severe, and a challenging differential diagnosis with ulcerative colitis. However, few real-life clinical practice cases have been reported beyond trials. Our aim was to report a series of new cases, reviewing previously communicated endoscopic-proven nivolumab-induced colitis. METHOD: All patients treated with nivolumab in three university centers were identified and those who developed immune-mediated colitis (defined as the presence of diarrhea and evidence of colitis demonstrated by colonoscopy) were described. Additionally, a review of case reports of nivolumab-induced colitis reported in the literature up to March 2018 was performed. RESULTS: Six new cases of nivolumab-induced colitis and 13 previously reported cases out of randomized clinical trials are described. Colonoscopy showed a mucosal pattern mimicking ulcerative colitis in a large proportion of patients. Clostridium difficile superinfection was observed in two out of 19 cases. All but three patients definitively discontinued nivolumab therapy. Most patients were initially managed with oral or intravenous corticosteroids, but five of them required rescue therapy with infliximab. CONCLUSIONS: Nivolumab-induced colitis may mimic ulcerative colitis. Steroid therapy (oral or intravenously) is often efficient, but one-fourth of patients need rescue therapy with anti-TNF. Intestinal superinfection with Clostridium difficile or cytomegalovirus should be ruled out before starting immunosuppressive therapy.

Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on the utility of the determination of faecal calprotectin in inflammatory bowel disease. / Recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) sobre la utilidad de la determinación de calprotectina fecal en la enfermedad inflamatoria intestinal.

The management of inflammatory bowel disease (IBD) is currently based on the objective evaluation of intestinal lesions. It would therefore be interesting to have access to simple and non-invasive tools to monitor IBD activity and to identify the presence of lesions. Faecal calprotectin (FC) is the main cytosolic protein of neutrophils, it is resistant to bacterial degradation and it is stable at room temperature for several days, characteristics that make it suitable for use in clinical practice. It can be used to differentiate between inflammatory and functional processes, it correlates with endoscopic activity, it is associated with clinical and endoscopic response to treatment and it has short-term prognostic value. This paper offers an up-to-date perspective on the information that FC can provide clinicians to aid diagnosis, monitoring and management of IBD.

Therapeutic requirements in active ulcerative proctitis: A single-centre study.

BACKGROUND: Ulcerative proctitis (UP) presents distinctive clinical characteristics, outcomes and therapeutic approaches as compared to left-sided and extensive ulcerative colitis (UC). AIM: To describe the current therapeutic requirements and clinical outcomes in patients with active UP. METHODS: Retrospective observational study conducted in a referral IBD centre. Patients with UP in follow-up between 1989 and 2014 were included. The clinical characteristics, as well as the different treatments and drug formulations administered to treat flares, were recorded. RESULTS: Out of 687 UC patients, 101 patients (15%) with UP were included. Median follow-up was 8 years (IQR 3-14) and 49% of patients presented disease activity during the study period. Topical mesalazine monotherapy (90%) was the most commonly administered treatment for disease activity (mostly as suppositories), followed by topical steroids (47%) and oral mesalazine (56%) in monotherapy or combination therapy. Only 14% and 16% of patients required oral prednisone and beclomethasone, respectively. CONCLUSIONS: In clinical practice, active UP presents mostly favourable outcomes. Mesalazine suppositories are by far the most used treatment for these patients.

Fecal level of calprotectin identifies histologic inflammation in patients with ulcerative colitis in clinical and endoscopic remission.

BACKGROUND & AIMS: Histologic recovery of patients with ulcerative colitis (UC) often is incomplete, even among those in clinical and endoscopic remission. Persistent active microscopic inflammation is associated with an increased risk of relapse and colorectal neoplasia. A high level of fecal calprotectin (FC) is a reliable marker of endoscopic lesions in patients with UC. We evaluated the accuracy of FC in identifying patients with UC in clinical and endoscopic remission who still have histologic features of inflammation. METHODS: We performed a prospective observational study of 59 patients with UC in clinical and endoscopic remission undergoing colonoscopy. Several biopsy specimens were collected from each colonic segment. Endoscopic remission was defined as a Mayo endoscopic subscore with a grade of 0 or 1. Active histologic inflammation was defined by the presence of neutrophils infiltrating crypt epithelial cells. FC was determined by enzyme-linked immunosorbent assay analysis. RESULTS: Eighteen patients (30.5%) showed evidence of active histologic inflammation. Patients with active histologic inflammation had a significantly higher median level of FC (278 µg/g; interquartile range, 136-696 µg/g) than those without active histologic inflammation (68 µg/g; interquartile range, 30-172 µg/g) (P = .002). In multivariate analysis, the FC and Mayo endoscopic subscore (0 or 1) were each independent predictors of histologic inflammation. The level of FC identified active histologic inflammation in patients in clinical and endoscopic remission, with an area under the receiver operator characteristic curve value of 0.754. CONCLUSIONS: Histologic inflammation is common among patients with UC in clinical and endoscopic remission. Patients with histologic features of inflammation can be identified reliably based on their fecal level of calprotectin.

Case report and review of literature: IgG4-gastroduodenitis in upper GI Crohn's disease: two separate entities or just a marker of disease severity?

A 20-year-old man was presented with ulcerative gastritis and duodenitis complicated by pyloric stenosis. Helicobacter pylori infection was excluded, and the lesions did not respond to treatment with proton pump inhibitors. No other parts of the intestinal tract showed signs of inflammation. Histopathological review showed signs of chronic inflammation with granuloma formation. A tentative diagnosis of isolated upper gastrointestinal (UGI) Crohn's disease was performed. However, additional work-up revealed significantly positive IgG4 staining as well as elevated IgG4 serum levels. Since granulomatous disease is unlikely in IgG4-related disease, an eventual diagnosis of overlapping IgG4-related disease and Crohn's disease (CD) was performed. Treatment with systemic steroids and anti-TNF in combination with azathioprine led to rapid symptomatic improvement. In this article, we review the available literature on IgG4-related gastroduodenitis, granulomatous gastritis, and upper GI CD. We suggest the possibility that IgG4-infiltration may be a marker of severely active inflammatory bowel disease rather than a separate disease entity.

Unraveling the fatigue puzzle: insights into the pathogenesis and management of IBD-related fatigue including the role of the gut-brain axis.

A significant percentage of patients with an inflammatory bowel disease (IBD) encounter fatigue which can profoundly diminish patients' quality of life, particularly during periods of disease remission when gastrointestinal symptoms have receded. Various contributing risk factors have been identified including active inflammation, anemia, psychological, lifestyle and drug-related factors. While addressing these risk factors has been suggested as the initial approach to managing fatigue, a considerable number of patients still experience persisting symptoms, the primary causes of which remain incompletely understood. Recent insights suggest that dysfunction of the gut-brain axis may play a pathogenic role. This review provides an overview of established risk factors for fatigue, alongside emerging perspectives on the role of the gut-brain axis, and potential treatment strategies.

Did We Overreact? Insights on COVID-19 Disease and Vaccination in a Large Cohort of Immune-Mediated Inflammatory Disease Patients during Sequential Phases of the Pandemic (The BELCOMID Study).

INTRODUCTION: As the COVID-19 pandemic becomes an endemic state, still many questions remain regarding the risks and impact of SARS-CoV-2 infection and vaccination in patients with immune-mediated inflammatory diseases (IMIDs) who were excluded from the phase 3 COVID-19 vaccination trials. METHODS: The BELCOMID study collected patient data and serological samples from a large, multicentric IMID patient cohort that was prospectively followed during sequential stages of the pandemic. Patients were stratified according to vaccination status into five groups across three sampling periods. Interactions between SARS-CoV-2 infection, COVID-19 vaccination status, IMID-treatment modalities and IMID course were explored. RESULTS: In total, 2165 patients with IBD, a dermatological or rheumatological IMID participated. SARS-CoV-2 infection rates increased over the course of the pandemic and were highest in IMID patients that had refused every vaccine. After baseline COVID-19 vaccination, serologic spike (S)-antibody responses were attenuated by particular types of immune-modulating treatment: anti-TNF, rituximab, JAKi, systemic steroids, combined biologic/immunomodulator treatment. Nonetheless, S-antibody concentration increased progressively in patients who received a booster vaccination, reaching 100% seroconversion rate in patients who had received two booster vaccines. Previous SARS-CoV-2 infection was found as a predictor of higher S-antibody response. Patients who had refused every vaccine showed the lowest rates of S-seroconversion (53.8%). Multiple logistic regression did not identify previous SARS-CoV-2 infection as a risk factor for IMID flare-up. Furthermore, no increased risk of IMID flare-up was found with booster vaccination. CONCLUSIONS: Altogether, the BELCOMID study provides evidence for the efficacy and safety of COVID-19 vaccination and confirms the importance of repeated booster vaccination in IMID patients.

Safety and Effectiveness of Vedolizumab and Ustekinumab in Elderly Patients with Inflammatory Bowel Disease: A Real-Life Multicentric Cohort Study.

BACKGROUND: Data on ustekinumab and vedolizumab in the elderly inflammatory bowel disease (IBD) population are limited. The aim of the current study was to assess the safety and effectiveness of both in an elderly real-life population. METHODS: A multicentric retrospective study was performed on IBD patients who started vedolizumab or ustekinumab between 2010 and 2020. Clinical and endoscopic remission rates and (serious) adverse events (AE) were assessed. RESULTS: A total of 911 IBD patients were included, with 171 (19%) aged above 60 (111 VDZ, 60 UST). Elderly patients treated with vedolizumab or ustekinumab had an increased risk for non-IBD hospitalization (10.5% vs. 5.7%, p = 0.021) and malignancy (2.3% vs. 0.5%, p = 0.045) compared to the younger population. Corticosteroid-free clinical (50% vs. 44%; p = 0.201) and endoscopic remission rates (47.9% vs. 31%, p = 0.07) at 1 year were similar. Comparing vedolizumab to ustekinumab in the elderly population, corticosteroid-free (47.9% vs. 31%, p = 0.061) and endoscopic remission rates (66.7% vs. 64.4%, p = 0.981) were similar. Vedolizumab- and ustekinumab-treated patients had comparable infection rates (13.5% vs. 10.0%, p = 0.504), IBD flare-ups (4.5% vs. 5%, p = 1.000), the occurrence of new EIMs (13.5% vs. 10%, p = 0.504), a risk of intestinal surgery (5.4% vs. 6.7%, p = 0.742), malignancy (1.8% vs. 3.3%, p = 0.613), hospitalization (9.9% vs. 11.7%, p = 0.721), and mortality (0.9% vs. 1.7%, p = 1.000). AE risk was associated only with corticosteroid use. CONCLUSIONS: Ustekinumab and vedolizumab show comparable effectiveness and safety in the elderly IBD population. Elderly IBD patients have an increased risk for non-IBD hospitalizations and malignancy compared to the younger IBD population, with corticosteroid use as the main risk factor.

Prophylactic Versus Endoscopy-driven Treatment of Crohn's Postoperative Recurrence: A Retrospective, Multicentric, European Study [PORCSE Study].

BACKGROUND AND AIMS: No consensus exists on optimal strategy to prevent postoperative recurrence [POR] after ileocaecal resection [ICR] for Crohn's disease [CD]. We compared early medical prophylaxis versus expectant management with treatment driven by findings at elective endoscopy 6-12 months after ICR. METHODS: A retrospective, multicentric, observational study was performed. CD patients undergoing first ICR were assigned to Cohort 1 if a biologic or immunomodulator was [re]started prophylactically after ICR, or to Cohort 2 if no postoperative prophylaxis was given and treatment was started as reaction to elective endoscopic findings. Primary endpoint was rate of endoscopic POR [Rutgeerts >i1]. Secondary endpoints were severe endoscopic POR [Rutgeerts i3/i4], clinical POR, surgical POR, and treatment burden during follow-up. RESULTS: Of 346 included patients, 47.4% received prophylactic postoperative treatment [proactive/Cohort 1] and 52.6% did not [reactive/Cohort 2]. Endoscopic POR [Rutgeerts >i1] rate was significantly higher in Cohort 2 [41.5% vs 53.8%, OR 1.81, p = 0.039] at endoscopy 6-12 months after surgery. No significant difference in severe endoscopic POR was found [OR 1.29, p = 0.517]. Cohort 2 had significantly higher clinical POR rates [17.7% vs 35.7%, OR 3.05, p = 0.002] and numerically higher surgical recurrence rates [6.7% vs 13.2%, OR 2.59, p = 0.051]. Cox proportional hazards regression analysis showed no significant difference in time to surgical POR of proactive versus expectant/reactive approach [HR 2.50, p = 0.057]. Quasi-Poisson regression revealed a significantly lower treatment burden for immunomodulator use in Cohort 2 [mean ratio 0.53, p = 0.002], but no difference in burden of biologics or combination treatment. CONCLUSIONS: The PORCSE study showed lower rates of endoscopic POR with early postoperative medical treatment compared with expectant management after first ileocaecal resection for Crohn's disease.

Post-Discharge Outcomes of Elderly Patients Hospitalized for Inflammatory Bowel Disease Flare Complicated by Clostridioides difficile Infection.

OBJECTIVES: Elderly hospitalized patients with inflammatory bowel disease (IBD) flare and concurrent Clostridioides difficile infection (CDI) are considered at high risk of IBD-related complications. We aimed to evaluate the short, intermediate, and long-term post-discharge complications among these patients. METHODS: A retrospective multicenter cohort study assessing outcomes of elderly individuals (≥60 years) hospitalized for an IBD flare who were tested for CDI (either positive or negative) and discharged. The primary outcome was the 3-months post-discharge IBD-related complication rates defined as: steroid dependency, re-admissions (emergency department or hospitalization), IBD-related surgery, or mortality. We assessed post-discharge IBD-related complications within 6-months and mortality at 12-months among secondary outcomes. Risk factors for complication were assessed by multivariable logistic regression. RESULTS: In a cohort of 654 patients hospitalized for IBD (age 68.9 [interquartile range {IQR}]:63.9-75.2) years, 60.9% ulcerative colitis), 23.4% were CDI-positive. Post-discharge complication rates at 3 and 6-months, and 12-months mortality, did not differ significantly between CDI-positive and CDI-negative patients (32% vs. 33.1%, p=0.8; 40.5% vs. 42.5%, p=0.66; and 4.6% vs. 8%, p=0.153, respectively). The Charlson comorbidity index was the only significant risk factor for complications within 3-months (aOR 1.1), whereas mesalamine (5-aminosalicylic acid [5-ASA]) use was protective (aOR 0.6). An ulcerative colitis diagnosis was the sole risk factor for complication at 6-months (aOR 1.5). CDI did not significantly impact outcomes or interact with IBD type. CONCLUSIONS: In elderly IBD patients hospitalized for IBD flare and subsequently discharged, a concurrent CDI infection was not associated with post-discharge IBD-related complications or mortality up to 1-year.

[Fecal calprotectin in the diagnosis of inflammatory bowel diseases]. / Calprotectina fecal en el diagnóstico de enfermedades inflamatorias.

The diagnosis of inflammatory bowel diseases has classically been based on assessment of digestive symptoms. The development of these symptoms usually results in colonoscopy, which has a low diagnostic yield. Likewise, there is an increasing tendency to base treatment of inflammatory bowel disease on objective data, since the disappearance of signs of activity on colonoscopy (called « mucosal cure ¼) has been associated with sustained clinical remission and reduced rates of hospitalization and surgery. Consequently, there is a need for biomarkers that would aid the selection of those patients who would derive most benefit from an endoscopic examination. One substance that has been proposed as a biomarker of bowel inflammation is fecal calprotectin. This substance allows inflammatory bowel disease to be distinguished from irritable bowel syndrome and shows a better correlation with the degree of inflammation than clinical indicators and serological markers. In addition, it could also be useful to predict mucosal cure and the risk of recurrence.

A comprehensive metabolite fingerprint of fibrostenosis in patients with Crohn's disease.

Intestinal fibrostenosis in patients with Crohn's disease (CD) is a common and untreatable comorbidity that is notoriously difficult to monitor. We aimed to find metabolites associated with the presence of fibrostenosis in patients with CD using targeted and untargeted metabolomics analyses of serum and primary cell cultures using hyphenated ultra-high performance liquid chromatography high-resolution mass spectrometry. Targeted metabolomics revealed 11 discriminating metabolites in serum, which were enriched within the arginine and proline metabolism pathway. Based on untargeted metabolomics and discriminant analysis, 166 components showed a high predictive value. In addition, human intestinal fibroblasts isolated from stenotic tissue were characterized by differential levels of medium-chain dicarboxylic acids, which are proposed as an energy source through beta-oxidation, when oxidative phosphorylation is insufficient. Another energy providing pathway in such situations is anaerobic glycolysis, a theory supported by increased expression of hexokinase 2 and solute carrier family 16 member 1 in stenotic fibroblasts. Of interest, four (unannotated) metabolic components showed a negative correlation with hexokinase 2 gene expression. Together, this study provides a discriminative metabolic fingerprint in the serum and in intestinal fibroblasts of stenotic and non-stenotic patients with CD suggestive for increased production of building blocks for collagen synthesis and increased glycolysis.

Treatment of antibiotic refractory chronic pouchitis with JAK inhibitors and S1P receptor modulators: an ECCO CONFER Multicentre Case Series.

BACKGROUND AND AIMS: Data regarding effectiveness and safety of JAK inhibitors and S1P receptor modulators in antibiotic refractory chronic pouchitis (CARP) are lacking. METHODS: This ECCO-CONFER project retrospectively collected JAK inhibitors or S1P receptor modulators treatments for CARP with at least 3-months follow up. The outcomes included corticosteroid and antibiotics-free clinical response and remission at three and twelve months, trend in mPDAI, endoscopic PDAI, CRP and calprotectin. RESULTS: Seventeen treatments in 15 patients were collected. Previous pouchitis treatments included infliximab (5/15), adalimumab (4/15), vedolizumab (9/15), and ustekinumab (5/15). Pooling data on JAK inhibitors (8 tofacitinib, 1 filgotinib and 6 upadacitinib), after 3 months (T3), steroid and antibiotics-free clinical response was achieved in 53.3% (8/15), steroid and antibiotics-free clinical remission was achieved in 40% (6/15). Of the patients with at least 12 months of follow-up, steroid and antibiotics-free clinical response was achieved in 50% (3/6) and remission in one patient (16.7%), endoscopic response in 50% (3/6), endoscopic remission in 50% (3/6). Of the two ozanimod treatments at T3, steroid and antibiotics-free clinical response was achieved in one patient, without remission; both discontinued ozanimod before T12. No side effects reported. CONCLUSIONS: Small molecules may represent a suitable option for CARP refractory to multiple biologics, deserving further investigation.

ECCO Topical Review on Biological Treatment Cycles in Crohn's Disease.

There are now a growing number of licensed biological therapies for patients with Crohn's disease. However, there can be significant costs associated with long-term maintenance treatment, as well as some concerns about potential side-effects. As a result, there has been increasing interest in elective biological treatment discontinuation in selected patients, after a sustained period of remission. Following discontinuation, in cases of relapse, evidence to date has suggested that remission may often be regained by re-treatment with the same biological agent. Therefore, a concept has emerged in which cycles of biological therapy might be used. If this treatment strategy were to be applied in a subgroup of patients at low risk of relapse, cycling might allow a substantial number of patients to have a lower, overall therapeutic burden-ensuring decreased exposure to biological therapy but still enabling appropriate disease control. Currently, there remains uncertainty about the benefit-risk balance for using cycles of biological treatment for patients with Crohn's disease. Accordingly, an expert panel was convened by the European Crohn's and Colitis Organisation [ECCO] to review the published literature and agree a series of consensus practice points. The panel aimed to provide evidence-based guidance on multiple aspects of biological treatment discontinuation and cycling, including the risk of relapse after elective treatment discontinuation, predictors of probable relapse or remission, safety, patient preferences, and pharmacoeconomic aspects. Crucially, discussions about biological treatment discontinuation and cycling should be individualized, to enable shared decision-making by patients with their clinicians.