Prognostic Value of Colonic Tissue and Blood Eosinophils in Ulcerative Colitis.

BACKGROUND It has been suggested that eosinophils may be a prognostic marker of disease outcome in ulcerative colitis (UC), but conflicting data exist. The objective was to investigate the extent of mucosal eosinophils and peripheral blood eosinophil count in newly diagnosed UC patients and to investigate its predictive value in short- and long-term disease outcomes. METHODS The degree of eosinophilia in baseline colonic biopsies and blood of newly diagnosed UC patients was retrospectively analyzed. It was investigated if tissue and blood eosinophilia could be a marker of a severe phenotype of UC, defined as the need for corticosteroids or immunomodulators in the first year or treatment with therapeutic monoclonal antibodies or colectomy during follow-up. Time to therapeutic monoclonal antibodies and time to colectomy were also evaluated as outcomes. RESULTS There were 103 UC patients (median age 26 years) included. Median tissue peak eosinophil count (PEC) was 70.0 and median peripheral blood eosinophil count was 0.3 × 109/L at diagnosis. Tissue PEC (r = -0.161, P = .104) and blood eosinophil count (r = 0.022, P = .877) were not correlated with the severity of histologic inflammation. Logistic regression analyses did not identify PEC and blood eosinophil count as predictors of more severe disease outcomes. Tissue PEC and peripheral blood eosinophil count did not predict the time the initiation of therapeutic monoclonal antibodies or colectomy. CONCLUSION Baseline tissue or peripheral blood eosinophils are not markers of disease activity and cannot be used as a predictor of severe disease outcomes in both adults and children with UC

The risk of colectomy and colorectal cancer after appendectomy in patients with ulcerative colitis:a systematic review and meta-analysis

Background: Appendectomy decreases the risk of developing ulcerative colitis [UC], and is suggested to have a beneficial effect on the clinical course of established UC. However, recent studies showed no significantly decreased colectomy rate, and moreover an apparently increased risk of colorectal cancer [CRC]. We aimed to investigate the suggested correlation in a meta-analysis and to analyse possible confounding factors. Methods: A systematic review and meta-analysis were performed using MEDLINE, EMBASE, and the Cochrane Library. Data from studies describing the influence of appendectomy on colectomy and CRC were extracted from published reports. Exclusion criteria were patients aged <18 years, non-UC, and animal studies. Results: From 891 studies, 13 studies evaluating 73 323 UC patients [appendectomy n = 2859] were included. All studies, except one, were rated as poor quality. Overall, colectomy rate in appendectomised and non-appendectomised patients was not significantly different (odds ratio [OR] 1.25, 95% confidence interval [CI] 0.88-1.77, I2 = 53%). The proportion of colectomies undertaken for CRC or high-grade dysplasia [HGD] was significantly higher after appendectomy [OR 2.85, 95% CI 1.40-5.78, I2 = 32%], with 50% of the colectomies indicated for CRC/HGD compared with 9.4% in non-appendectomised patients. Possible additional confounding factors were a longer UC disease duration, less medication use, and a higher prevalence of primary sclerosing cholangitis [PSC] in appendectomised patients. Conclusions: Appendectomy in established UC is associated with apparently higher rates of subsequent CRC/HGD, but this appears to be due to inequalities in at-risk exposure between groups, presumably secondary to positive clinical effects of appendectomy on disease symptoms. This finding emphasises the importance of regular endoscopic surveillance in this patient group

The clinical relevance of an inflamed appendix in Crohn's disease.

BACKGROUND AND AIMS An appendectomy for appendiceal inflammation has been suggested to ameliorate the clinical course of patients with ulcerative colitis (UC). In contrast, for Crohn's disease (CD) an inverse association has been suggested with a higher incidence of CD and worse prognosis after appendectomy. The aim of this study was to analyse the clinical relevance of an inflamed appendix in CD patients undergoing ileocoecal resection (ICR). METHODS All consecutive patients undergoing primary ICR between 2007 and 2018 were considered for inclusion. Microscopic data of available appendiceal resection specimens (n=99) were revised by a dedicated IBD-pathologist and scored as inflamed or not inflamed. Eighteen patients had a previous appendectomy. Pathological findings were correlated with disease characteristics and recurrence rates (clinical, endoscopic and intervention-related). RESULTS In total, 117 patients were included: 77 (65.8%) females with a median age of 30 years [IQR 24 - 43] with a median follow up of 102 months [IQR 76-114]. Of patients without previous appendectomy (n=99), 39% had an inflamed appendix. No significant differences in disease characteristics (e.g. disease location, behaviour, time to surgery) or prognosis could be demonstrated between the two groups. In contrast, previous appendectomy (n=18) was associated with penetrating disease and numerically shorter disease duration at the time of resection. Furthermore, a trend was seen towards a stronger association with postoperative recurrence. CONCLUSION The current study could not confirm a different prognosis for CD patients with and without an inflamed appendix. In contrast, in patients with a previous appendectomy a trend was seen towards increased postoperative recurrence, which might be related to the higher incidence of penetrating disease

Fecal microbiota transplantation as novel therapy in gastroenterology : A systematic review

AIM: To study the clinical efficacy and safety of Fecal microbiota transplantation (FMT). We systematically reviewed FMT used as clinical therapy. METHODS: We searched MEDLINE, EMBASE, the Cochrane Library and Conference proceedings from inception to July, 2013. Treatment effect of FMT was calculated as the percentage of patients who achieved clinical improvement per patient category, on an intention-to-treat basis. RESULTS: We included 45 studies; 34 on Clostridium difficile-infection (CDI), 7 on inflammatory bowel disease, 1 on metabolic syndrome, 1 on constipation, 1 on pouchitis and 1 on irritable bowel syndrome (IBS). In CDI 90% resolution of diarrhea in 33 case series (n = 867) was reported, and 94% resolution of diarrhea after repeated FMT in a randomized controlled trial (RCT) (n = 16). In ulcerative colitis (UC) remission rates of 0% to 68% were found (n = 106). In Crohn's disease (CD) (n = 6), no benefit was observed. In IBS, 70% improvement of symptoms was found (n = 13). 100% Reversal of symptoms was observed in constipation (n = 3). In pouchitis, none of the patients (n = 8) achieved remission. One RCT showed significant improvement of insulin sensitivity in metabolic syndrome (n = 10). Serious adverse events were rare. CONCLUSION: FMT is highly effective in CDI, and holds promise in UC. As for CD, chronic constipation, pouchitis and IBS data are too limited to draw conclusions. FMT increases insulin sensitivity in metabolic syndrome.Peer reviewe

Patients' perspectives on a drug safety monitoring system for immune-mediated inflammatory diseases based on patient-reported outcomes

Patient-reported outcomes (PROs) on adverse drug reactions (ADRs) are increasingly used in cohort event monitoring (CEM) to obtain a better understanding of patients’ real-world experience with drugs. Despite the leading role for patients, little is known about their perspectives on CEM systems. In a cross-sectional open survey following the rationale of the Technology Acceptance Model, we aimed to obtain insight in patients’ perspectives on the perceived usefulness, ease of use and attitude toward using a PRO-based drug safety monitoring system for ADRs attributed to biologics. Patients considered structural reporting of ADRs in web-based questionnaires as useful and not burdensome. It was preferred to link the questionnaire frequency to regular hospital consultations or the biologic administration schedule. Various respondents were interested in sharing questionnaires with their medical specialist (49.0%) or pharmacist (34.2%), and suggested to minimize the questionnaire frequency in case of an unaltered situation or absence of ADRs. Patients’ perspectives should be considered in the setup of PRO-based CEM studies, as this contributes to data quality and patient centeredness. Since incorporation of patients’ perspectives in CEM studies is indispensable, a delicate balance should be found between user-friendliness and study aims.</p

Tofacitinib as induction and maintenance therapy for ulcerative colitis

Background: Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. METHODS: We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks. RESULTS: In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels. CONCLUSIONS: In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.

Open-label extension of a phase 2 trial of risankizumab in patients with moderate-to-severe Crohn's disease

Background: Risankizumab, an anti-interleukin-23 antibody, was superior to placebo in achieving clinical and endoscopic remission at week 12 in a randomised, phase 2 induction study in patients with moderately to severely active Crohn’s disease. The efficacy and safety of extended intravenous induction and/or subcutaneous maintenance therapy with risankizumab was assessed. Methods: Following 12-week, double-blind, randomised, induction treatment comparing 200 mg or 600 mg intravenous risankizumab to placebo every 4 weeks, patients without deep remission, defined as clinical (Crohn’s Disease Activity Index <150) and endoscopic remission (Crohn’s Disease Endoscopic Index of Severity [CDEIS] ≤4 [≤2 for patients with isolated ileitis]), received open-label 600 mg intravenous risankizumab (every 4 weeks) and patients in deep remission underwent washout until week 26 (Period 2). At week 26, patients in clinical remission received maintenance treatment (Period 3) with 180 mg subcutaneous risankizumab (every 8 weeks). Efficacy endpoints included clinical and endoscopic response and remission at weeks 26 (Period 2) and 52 (Period 3) respectively; safety was assessed through both periods. Study registration: ClinicalTrials.gov, NCT02031276. Findings: In Period 2, 101 patients were treated with 600 mg risankizumab resulting in an increase in clinical remission rates at week 26 versus week 12 for all original designated treatment groups: 55% versus 18%, 59% versus 21%, and 47% versus 26% for placebo, 200, and 600 mg risankizumab, respectively. Of the 62 patients receiving maintenance treatment, 54 completed treatment. At week 52, clinical remission was maintained by 71% of patients; endoscopic remission and response (>50% CDEIS reduction from baseline) was achieved by 35% and 55% of patients, respectively, and 29% of patients achieved deep remission. Risankizumab was well tolerated with no new safety signals. Interpretation: Extended induction treatment with open-label intravenous risankizumab was effective in increasing clinical response and remission rates at week 26. Open-label subcutaneous risankizumab maintained remission till week 52 in most patients who were in clinical remission at week 26. Selective blockade of interleukin-23 warrants further evaluation as treatment for Crohn’s disease.Boehringer Ingelhei

A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE):a multicentre, open-label randomised controlled trial

Background: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. Methods: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP &gt;upper limit of normal or faecal calprotectin ≥200 μg/g, or both), while remission was the converse—ie, quiescent symptoms (HBI &lt;5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin &lt;200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). Findings: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0–191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker–treatment interaction effect (absolute difference 1 percentage points, 95% CI –15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p&lt;0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). Interpretation: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. Funding: Wellcome and PredictImmune Ltd.</p

Clinical and humoral response after SARS-CoV-2 breakthrough infection in patients receiving immunosuppressant therapy

Background: Despite impaired humoral response in patients treated with immunosuppressants (ISPs), recent studies found similar severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection compared to controls. One potential explanation is the rapid generation of humoral response on infection, but evidence is lacking. Objectives: We investigated the longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infection in patients with immune-mediated inflammatory diseases (IMIDs) receiving ISP therapy and controls. Methods: As a prospective substudy of the national Target-to-B! (T2B!) consortium, we included IMID patients receiving ISPs therapy and controls who reported SARS-CoV-2 breakthrough infection between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, 3 antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at 4 time points after SARS-CoV-2 breakthrough infection. Results: We included 302 IMID patients receiving ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infection in both groups. However, in IMID patients receiving therapy with anti-CD20 and sphingosine-1 phosphate receptor modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild, and hospitalization was required in less than 1% of cases. Conclusions: Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones toward new virus variants. However, in patients treated with anti-CD20 therapy or sphingosine-1 phosphate receptor modulators, the dynamics were greatly impaired, and to a lesser extent in those who received anti-TNF. Nevertheless, only a few severe breakthrough cases were reported.</p