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Background and Aims Radiological imaging is crucial for diagnosing and monitoring patients with inflammatory bowel diseases (IBD). With increasing awareness of radiation risks, imaging doses should be "as low as reasonably achievable," with a risk level that one should try to stay underneath 75 mSv. However, real-world data on cumulative exposure are limited. We retrospectively analyzed the radiation exposure of patients with IBD in a Belgian tertiary referral center. Methods Radiation exposure examinations were reviewed using the electronic health records. Annual (AED) and cumulative effective dose (CED) were calculated. A sub-analysis of patients diagnosed after January 1, 2007 was performed, as detailed radiation doses were maintained prospectively from that date onwards. Results In total, 4333 IBD patients (2753 Crohn's disease [CD], 1512 ulcerative colitis [UC]) were included. The median (Interquartile range [IQR]) AED was 0.47 (0.02-1.67) mSv/year, and higher in CD than in UC (0.59 [0.05-1.79] vs 0.28 [0.01-1.44] mSv/year, P  = .855). CED ≥ 75 mSv was reached in 5.5% of patients after a median [IQR] of 24 [13-34] years of follow-up. Sub-analysis of 1754 patients diagnosed from 2007 showed a median (IQR) AED of 0.74 (0.02-2.76) mSv/year, again higher for CD than UC (1.16 [0.02-3.42] vs 0.29 [0.01-2.28] mSv/year, P  = .189). Here, 3.3% reached a CED ≥ 75 mSv after a median (IQR) of 9 [6-12] years of follow-up. The most common reasons for radiation exposure were comorbidities like malignancy. Conclusions Up to 5.5% of IBD patients reached a CED ≥ 75 mSv. While most imaging decisions were deemed appropriate, caution against excessive radiation remains crucial. [ABSTRACT FROM AUTHOR]

Introduction It remains unclear why up to 30% of ulcerative colitis (UC) patients do not respond to tumor necrosis factor inhibitors (TNFi). Validated biomarkers for nonresponse (N)R) are lacking. Most studies investigating underlying mechanisms do not differentiate between pharmacokinetic and inflammatory mechanisms. We therefore aimed to develop a framework to correct for mucosal drug exposure (MDE) and applied this to mucosal cytokine profiles previously linked to (N)R. Methods In a prospective international cohort, we studied patients with active moderate–severe UC starting TNFi treatment. Patients underwent endoscopy before (baseline) and after induction treatment (follow-up). NR was defined as the absence of Mayo endoscopic subscore improvement by central read or need for colectomy. The ratio of mucosal concentrations of TNFi/TNF was used to define high or low MDE. Mucosal concentrations of interleukin-6 (IL-6), Oncostatin M (OSM), interleukin-10 (IL-10), and interleukin-12/23p40 (IL-12/IL-23p40) were measured. Results Fifty-four UC patients were included (43 infliximab, 11 adalimumab) of whom 39 (72%) were endoscopic responders (after a median treatment of 62 days [48–96]). NR with high MDE had high IL-6 at both time points. R with low MDE exhibited low mucosal IL-10 at baseline. At follow-up, high OSM was associated with NR (irrespective of MDE) and high IL-12/IL-23p40 with R. Conclusions We incorporated MDE in mucosal cytokine research to avoid bias due to the insufficient presence of anti-TNF. When applied to mucosal cytokines previously linked to (N)R, IL-6 appears to drive inflammation in TNFi-resistant UC patients, while OSM seems to parallel inflammation and does not cause refractoriness. [ABSTRACT FROM AUTHOR]

Seventeen percent of patients with ulcerative colitis that undergo proctocolectomy with pouch surgery will develop chronic pouchitis. W e evaluated the efficacy of ustekinumab for these patients. We performed a prospective study of patients with chronic pouchitis receiving ustekinumab intravenously at baseline (∼6 mg/kg) and 90 mg ustekinumab subcutaneously every 8 weeks thereafter. The Modified Pouchitis Disease Activity Index (mPDAI) was assessed at baseline and weeks 16 and 48. The primary endpoint was the proportion of patients achieving steroid-free remission (mPDAI <5 and reduction by ≥2 points) at week 16. Secondary endpoints included the proportion of patients achieving remission at week 48, the proportion of patients achieving response (reduction of mPDAI by ≥2 points) at weeks 16 and 48, and change in mPDAI. We enrolled 22 patients (59% male; median age, 42.2 years). Remission was achieved in 27.3% at week 16 and 36.4% at week 48. Response was achieved in 54.5% both at weeks 16 and 48. The median mPDAI decreased from 8 (interquartile range [IQR], 7–10) to 7 (IQR, 4–9) at week 16 (P =.007) and 4 (IQR, 1.75–7.25) at week 48 (P <.001). The clinical mPDAI subscore decreased from 3.5 (IQR, 2–4) to 2 (IQR, 1–3) at week 16 (P =.009) and 1 (IQR, 0–2.25) at week 48 (P =.001). The endoscopic mPDAI subscore decreased from 5.5 (IQR, 4–6) to 4 (IQR, 3–6) at week 16 (P =.032) and 3 (IQR, 1.75–4.25) at week 48 (P =.001). Ustekinumab was efficacious in one-half of the patients suffering from chronic pouchitis. Ustekinumab should therefore be positioned in the treatment algorithm of chronic pouchitis. (ClinicalTrials.gov Number NCT04089345) [ABSTRACT FROM AUTHOR]

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). 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. 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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Aims Etrasimod is an oral, once daily, selective, sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis [UC]. This subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo by prior biologic/Janus kinase inhibitor [bio/JAKi] exposure in ELEVATE UC 52 and ELEVATE UC 12. Methods Pre-defined efficacy endpoints were assessed at Weeks 12 and 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12 in bio/JAKi-naïve and -experienced patients, and at Week 12 [pooled] based on prior advanced therapy exposure mechanism. Results In the ELEVATE UC 52 and ELEVATE UC 12 analysis populations, 80/274 [29.2%] and 74/222 [33.3%] patients receiving etrasimod and 42/135 [31.1%] and 38/112 [33.9%] patients receiving placebo, respectively, were bio/JAKi-experienced. In both bio/JAKi-naïve and -experienced patients, a significantly greater proportion receiving etrasimod vs placebo achieved clinical remission [ p  < 0.05] in ELEVATE UC 52 at Weeks 12 [naïve: 30.9% vs 9.7%; experienced: 17.5% vs 2.4%] and 52 [naïve: 36.6% vs 7.5%; experienced: 21.3% vs 4.8%]; in ELEVATE UC 12, this was observed only for bio/JAKi-naïve patients [naïve: 27.7% vs 16.2%, p  = 0.033; experienced: 18.9% vs 13.2%, p  = 0.349]. Similar patterns were observed for most efficacy endpoints. Among patients with prior anti-integrin exposure [ N  = 90], a significantly greater proportion achieved clinical response [54.1% vs 27.6%, p  = 0.030], but not clinical remission [9.8% vs 3.4%, p  = 0.248], with etrasimod vs placebo. Conclusions Bio/JAKi-naïve and -experienced patients had clinically meaningful induction and maintenance treatment benefits with etrasimod vs placebo. ClinicalTrials.gov NCT03945188; NCT03996369 [ABSTRACT FROM AUTHOR]

Background and Aims Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis [UC]. This post-hoc analysis of the phase 2 OASIS trial [NCT02447302] evaluated its efficacy for endoscopic improvement–histologic remission [EIHR] and assessed correlation between faecal calprotectin [FCP] and C-reactive protein [CRP] levels with efficacy outcomes. Methods In total, 156 adults with moderately to severely active UC received once-daily etrasimod (1 mg [ n  = 52]; 2 mg [ n  = 50]) or placebo [ n  = 54] for 12 weeks. Clinical, endoscopic, and histologic variables were evaluated at baseline and Week 12. EIHR was defined as achievement of endoscopic improvement [endoscopic subscore ≤ 1, without friability] and histologic remission [Geboes score < 2.0]. Outcomes included the relationships between FCP and CRP concentration and clinical, endoscopic, and histologic variables. Results Achievement of EIHR was significantly higher in patients who received etrasimod 2 mg versus placebo [19.5% vs 4.1%; Mantel–Haenszel estimated difference, 15.4%; p  = 0.010]. In the etrasimod 2 mg group, median FCP and CRP levels at Week 12 were significantly lower in patients who achieved clinical remission, endoscopic improvement, histologic remission, and EIHR versus patients who did not [all p  < 0.05]. An FCP concentration cutoff of 250 µg/g achieved optimum sensitivity and specificity for efficacy, including EIHR [0.857 and 0.786, respectively; κ coefficient, 0.3584]. Higher proportions of patients with FCP ≤ 250 µg/g achieved efficacy outcomes at Week 12 versus patients with FCP > 250 µg/g. Conclusions Etrasimod was effective for inducing EIHR in patients with UC. FCP and CRP may be useful, noninvasive biomarkers to monitor treatment response. ClinicalTrials.gov number NCT02447302. [ABSTRACT FROM AUTHOR]

Background & aimsGenome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.MethodsWe sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.ResultsWe identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.ConclusionsWe have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.

Backgrounds and Aims This interim analysis from the True North open-label extension [OLE] study examines efficacy and safety of approximately 3 years of continuous ozanimod treatment in patients with moderately to severely active ulcerative colitis. Methods Clinical responders after 52 weeks of ozanimod during the phase 3 True North study, who continued treatment in the OLE, were evaluated. Efficacy, including endoscopic and histological endpoints, was assessed during the OLE for approximately 2 additional years through OLE Week 94, using observed case [OC] and nonresponder imputation [NRI] analyses. Adverse events were monitored from True North baseline through OLE data cutoff and expressed as exposure-adjusted incidence rates. Results This analysis included 131 patients; 54% had achieved corticosteroid-free remission at True North Week 52. In OC analyses, clinical response, clinical remission, and corticosteroid-free remission were achieved by 91.4%, 69.1%, and 67.9% of patients, respectively, at OLE Week 94 [146 weeks of total treatment]. Similarly, endoscopic improvement, histological remission, and mucosal healing were achieved by 73.3%, 67.3%, and 56.3% of patients, respectively, at OLE Week 94. Efficacy rates were lower using NRI analyses, but maintenance of efficacy was demonstrated through OLE Week 94. No new safety signals emerged from this analysis. Serious infections, malignancy, cardiovascular events, and hepatic events occurred infrequently. Conclusions Among patients who achieved clinical response after 1 year of ozanimod treatment during True North, a high percentage sustained clinical and mucosal efficacy over 2 additional years in the OLE. No new safety signals were observed with long-term ozanimod use. [ABSTRACT FROM AUTHOR]

Background and Aims Maintenance treatment for ulcerative colitis may be discontinued for multiple reasons. This post hoc analysis assessed the efficacy and safety of re-treatment with filgotinib, an oral, once-daily, Janus kinase 1 preferential inhibitor, in the phase 2b/3 SELECTION trial and its long-term extension [LTE] study in ulcerative colitis. Methods Partial Mayo Clinic Score [pMCS] response and remission were evaluated in patients who received induction with filgotinib 200 mg [FIL200] or 100 mg [FIL100], were randomized to treatment withdrawal [placebo] during maintenance, and following disease worsening, were re-treated with open-label FIL200 in the LTE study. Factors were evaluated for association with pMCS remission at LTE week 12, and safety outcomes were reported. Results Analyses included 86 patients [FIL200: n  = 51; FIL100: n  = 35]. Median time to disease worsening following treatment withdrawal was 15.1 weeks (95% confidence interval [CI]: 9.1–18.7) for FIL200-induced patients and 9.6 weeks [95% CI: 6.3–12.0] for FIL100-induced patients. Three-quarters [75%] of patients achieved a pMCS response within 4–5 weeks of re-treatment in both groups. At LTE week 48, pMCS remission was achieved by 45.1% and 51.4% of FIL200- and FIL100-induced patients, respectively. Factors independently associated with restoring efficacy included no concomitant use of corticosteroids at induction baseline, and high albumin levels, pMCS remission, and endoscopic score at maintenance baseline. No new safety signals were reported among re-treated patients. Conclusions In induction responders, re-treatment with FIL200 following temporary withdrawal from therapy restores response and/or remission in the majority of patients within 12 weeks. Re-treatment is well-tolerated. ClinicalTrials.gov identifiers: NCT02914522, NCT02914535 [ABSTRACT FROM AUTHOR]

Biologic agents and oral small molecules are the mainstays of inflammatory bowel disease [IBD] management. However, an unmet clinical need remains for additional agents with novel mechanism of action which are effective, safe, and disease-modifying; this is due to the substantial proportion of patients who do not respond, lose response, or develop intolerance to currently marketed products. microRNAs [miRNAs] that play a role in the modulation of signal transduction pathways implicated in the development of IBD hold the potential to be used as therapeutic targets. Recently, a novel first-in-class compound, obefazimod, originally conceived as a human immunodeficiency virus [HIV] infection drug, has shown great promise in phase II induction trials for ulcerative colitis [UC] patients. Findings from the maintenance phases of trials showed that long-term obefazimod treatment provides continued improvement in clinical symptoms of disease, with a substantial proportion of patients in clinical remission, and an overall good safety profile. With a novel mechanism of action, obefazimod is an orally available small molecule with anti-inflammatory properties through the specific and selective upregulation of miR-124 expression. The aim of this paper is to critically review the available evidence related to pharmacokinetics and pharmacodynamics, and to discuss the potential clinical implications of this first-in-class oral small molecule. [ABSTRACT FROM AUTHOR]

Background and Aims Corticosteroid-free remission is an important treatment goal for patients with ulcerative colitis [UC]. The corticosteroid-sparing effects of filgotinib, an oral, Janus kinase 1 preferential inhibitor, were assessed in SELECTION, a placebo-controlled, phase 2b/3 trial in moderately to severely active UC. Methods These post hoc analyses assessed 1-, 3-, 6-, and 8-month rates of corticosteroid-free clinical remission at Week 58 and change in median daily prednisone-equivalent dose over time. A matching-adjusted indirect comparison [MAIC] of maintenance studies assessed corticosteroid-free remission with filgotinib 200 mg, intravenous vedolizumab, subcutaneous vedolizumab, and oral tofacitinib. Results The Maintenance Study full analysis set included 199 patients receiving filgotinib 200 mg and 98 receiving placebo. Among patients receiving corticosteroids at Maintenance Study baseline, at Week 58, 30.4%, 29.3%, 27.2%, and 21.7% receiving filgotinib had been in corticosteroid-free remission for ≥1, ≥3, ≥6, or ≥8 months, respectively, versus 6.4% receiving placebo across thresholds [ p  <0.05]. Median daily prednisone-equivalent dose decreased from 17.5 mg/day to 10.0 mg/day with filgotinib treatment during the Maintenance Study. Based upon the MAIC, filgotinib was associated with greater likelihood of corticosteroid-free clinical remission versus intravenous vedolizumab (odds ratio [OR], 15.2; 95% confidence interval [CI], 1.6–139.9; p  <0.05]) and similar odds to subcutaneous vedolizumab [OR, 3.8; CI, 0.2–63.8; p  = 0.36] in biologic-naïve patients, and similar odds to tofacitinib overall [OR, 2.0; 0.4–9.1; p  = 0.39]. Conclusions Filgotinib 200 mg demonstrated corticosteroid-sparing effects and maintained corticosteroid-free clinical remission in patients with UC. MAIC results should be interpreted cautiously given the large CIs and differences in study design and patient populations. [ClinicalTrials.gov: NCT02914522]. [ABSTRACT FROM AUTHOR]

Background Histo-endoscopic outcomes are being proposed as new treatment targets in ulcerative colitis [UC]. Little is known about the pharmacokinetic-pharmacodynnamic [PK-PD] relationship of ustekinumab [UST] in UC patients or whether serum UST concentrations reflect tissue drug exposure. We aimed to study UST serum concentrations and their relation to tissue exposure and drug effectiveness in a real-world setting. Methods A total of 42 UC patients starting UST were prospectively followed by clinical, endoscopic and histological assessments at Week 16. Histological remission was defined as Nancy Histology Index of 0. Analogous to the UNIFI programme, histo-endoscopic mucosal improvement was defined as a combination of histological improvement [Geboes ≤3.1] and endoscopic improvement [MES ≤1]. Paired trough serum samples and colonic mucosal biopsies were collected for UST levels measurement. Results After 16 weeks [IQR 15.8–16.4] of therapy, histological remission and histo-endoscopic mucosal improvement were observed in 19 [45%] and 18 [43%] patients, respectively. Patients who achieved these outcomes had higher serum UST levels than those who did not. Patients with shorter disease duration and clinical response at Week 8 had higher odds to achieve histological remission. UST concentrations from paired serum and biopsy samples revealed a strong positive correlation [r = 0.88, p < 0.001], in both inflamed and uninflamed tissue. Conclusions In this real-world cohort of refractory UC patients initiating UST, more than a third of the patients achieved histological remission. A drug exposure-response relationship was observed for histo-endoscopic outcomes, with no added value of measuring tissue exposure given the strong correlation with serum exposure. [ABSTRACT FROM AUTHOR]

Background and Aims Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. Here, we evaluate the efficacy and safety of tofacitinib re-treatment following treatment interruption in patients with ulcerative colitis. Methods Here, patients with clinical response to tofacitinib 10 mg b.d. induction therapy were randomised to receive placebo in OCTAVE Sustain. Those experiencing treatment failure after Week 8 of OCTAVE Sustain entered OCTAVE Open and re-initiated tofacitinib 10 mg b.d. [re-treatment subpopulation]; efficacy and safety data are presented up to Month 36 of OCTAVE Open. Results Median time to treatment failure following interruption was 169 (95% confidence interval [CI], 94.0–179.0) and 123 [95% CI, 91.0–168.0] days for induction remitters, and induction responders but non-remitters, respectively. Following re-treatment with tofacitinib, rates (non-responder imputation after a patient discontinued; latest observation carried forward imputation after a patient advanced to a subsequent study [NRI-LOCF]) of clinical response, remission, and endoscopic improvement were 74.0%, 39.0%, and 55.0% at Month 2, and 48.5%, 37.4%, and 42.4% at Month 36, respectively. Among induction remitters and induction responders but non-remitters, clinical response rates at Month 36 were 60.6% and 42.4% [NRI-LOCF], respectively. Efficacy was recaptured regardless of prior tumour necrosis factor inhibitor failure status. The safety profile of tofacitinib 10 mg b.d. re-treatment was consistent with the overall cohort and demonstrated no new safety risks associated with exposure of ≤36 months. Conclusions Median time to treatment failure was numerically higher in induction remitters versus induction responders but non-remitters. Following treatment interruption, efficacy was safely and successfully recaptured with tofacitinib 10 mg b.d. re-treatment in a substantial proportion of patients [ClinicalTrials.gov:NCT01458574;NCT01470612]. [ABSTRACT FROM AUTHOR]

Background and Aims This analysis examined the long-term safety and efficacy of ozanimod in patients with moderately to severely active ulcerative colitis [UC] with ≥ 4 years of follow-up in the phase 2 TOUCHSTONE open-label extension [OLE]. Methods Patients receiving placebo or ozanimod HCl 0.5 mg or 1 mg during the double-blind period could enter the OLE [ozanimod HCl 1 mg daily]. Partial Mayo score [pMS] clinical response and remission were assessed through OLE week 200 and summarized descriptively using observed cases [OC] and non-responder imputation [NRI]. Endoscopy was required at OLE week 56 and the end of treatment. Parameters associated with endoscopy were summarized at weeks 56 and 104 [OC], and week 56 [NRI]. C-reactive protein and faecal calprotectin were assessed. Adverse events were monitored throughout the study. Results Of 197 patients receiving double-blind treatment, 170 entered the OLE. Discontinuation rates were 28% at year 1 and 15–18% annually through year 4. Partial Mayo measures indicated clinical response and remission rates at OLE week 200 of 93.3% and 82.7%, respectively, using OC and 41% and 37% with the more conservative NRI analysis. At weeks 56 and 104, respectively, histological remission rates were 46.3% and 38.5%, and endoscopic improvement rates were 46.4% and 46.5% [OC]. No new safety signals were identified during ≥ 4 years of follow-up. Conclusions There was a high rate of continued study participation and long-term benefit with ozanimod HCl 1 mg daily based on clinical, histological and biomarker measures in patients with moderately to severely active UC in the TOUCHSTONE OLE. [NCT02531126] [ABSTRACT FROM AUTHOR]

Background and Aims Etrasimod is an oral, selective, sphingosine 1-phosphate receptor modulator. In a phase 2, randomised, double-blind, placebo-controlled trial in adults with moderately-to-severely active ulcerative colitis [OASIS], etrasimod 2 mg provided significant benefit versus placebo and was generally well tolerated. This open-label extension [OLE] evaluated safety and efficacy of etrasimod for up to 52 weeks. Methods In OASIS, 156 patients received etrasimod 1 mg, etrasimod 2 mg, or placebo, once daily for 12 weeks. After completing OASIS, patients could enrol in the OLE and receive etrasimod 2 mg for an additional 34–40 weeks. Results In all, 118 patients enrolled in the OLE; 112 patients received etrasimod 2 mg at any point and were evaluated for safety and efficacy. A total of 92 [82%] patients who received etrasimod 2 mg in the OLE completed the study. Treatment-emergent adverse events occurred in 60% [67/112] of patients receiving etrasimod 2 mg at any time, most commonly worsening ulcerative colitis and anaemia; 94% of adverse events were mild/moderate. At end of treatment, 64% of patients met the criteria for clinical response, 33% for clinical remission, and 43% for endoscopic improvement. Week 12 clinical response, clinical remission, or endoscopic improvement was maintained to end of treatment in 85%, 60%, or 69% of patients, respectively. Steroid-free clinical remission occurred in 22% of overall patients. Conclusions In this long-term extension study, etrasimod 2 mg demonstrated a favourable safety profile. Most patients with clinical response, clinical remission, or endoscopic improvement at Week 12 maintained that status to end of treatment. [ABSTRACT FROM AUTHOR]

Background and Aims Vedolizumab was shown to be safe and effective for the treatment of Crohn's disease [CD] and ulcerative colitis [UC] in the GEMINI Long-Term Safety [LTS] study. The vedolizumab Extended Access Program [XAP] provides patients with continued treatment. This XAP pharmacokinetics [PK] sub-study investigated vedolizumab efficacy, safety, and PK. Methods Vedolizumab dosing frequency was reduced from every 4 weeks [Q4W] to every 8 weeks [Q8W] at XAP enrolment, and patients were followed for 56 weeks. Outcomes included: efficacy, loss of clinical benefit, and re-escalation to Q4W dosing; and vedolizumab PK, immunogenicity, and adverse events. Results Among 167 enrolled patients [CD = 88, UC = 79], 80 [91%] with CD and 73 [92%] with UC completed 56 weeks; 76 [86%] and 71 [90%] with CD and UC, respectively, remained on Q8W dosing for 56 weeks. Clinical remission, corticosteroid-free clinical remission, and C-reactive protein levels were stable among patients remaining on Q8W through Week 56. Four patients with CD and two with UC resumed Q4W dosing [three with CD regained clinical response]. Patients with CD who completed Week 56 on Q8W dosing had median trough vedolizumab concentrations of 43.6 µg/mL at enrolment and 10.4 µg/mL at Week 56; concentrations were 42.4 µg/mL and 13.3 µg/mL, respectively, in patients with UC. Treatment-related adverse events were infrequent; no new or serious adverse events related to vedolizumab were reported. Conclusions In the XAP-PK sub-study, adherence to Q8W dosing was high, with no loss of efficacy; very few patients required re-escalation to Q4W. There were no new safety signals. [ABSTRACT FROM AUTHOR]

Background and Objectives Vedolizumab has demonstrated efficacy and safety in patients with Crohn's disease [CD] and ulcerative colitis [UC]. Endoscopic outcome data are limited, especially in anti-tumour necrosis factor [TNF] naïve patients. The present study compared endoscopic outcome in anti-TNF naïve and exposed patients, and explored if this was affected by drug exposure. Methods We retrospectively analysed all patients initiating vedolizumab at our tertiary referral centre since 2015. For UC, endoscopic improvement was defined as a Mayo endoscopic subscore ≤1 at week 14. For CD, endoscopic remission was defined as absence of ulcerations at week 22. Vedolizumab trough concentrations were measured at week 6, week 14 and during maintenance. Results A total of 336 patients were identified [53.3% CD], 20% of them being anti-TNF naïve. Endoscopic improvement was achieved by 56.1% of UC patients and endoscopic remission by 39.1% of CD patients. Endoscopic outcomes were significantly better in anti-TNF naïve vs exposed patients [all: 67.2% vs 42.0%, p = 0.0002; UC: 74.4% vs 50.0%, p = 0.02; CD: 57.1% vs 35.8%, p = 0.03]. Achievement of endoscopic end points significantly impacted long-term treatment continuation [ p = 9.7 × 10−13]. A better endoscopic outcome was associated with significantly higher drug exposure in both CD and UC. Conclusions The results of this observational, single-centre real-life study suggest that vedolizumab may induce endoscopic remission in both CD and UC. Although anti-TNF naïve patients had a significantly better outcome, 42% of anti-TNF exposed patients still benefited endoscopically. A clear exposure–endoscopic response relationship exists, but not all patients will benefit from treatment intensification. Hence, predictive biomarkers remain necessary. Podcast This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast [ABSTRACT FROM AUTHOR]

Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC). In a phase 2, proof-of-concept, double-blind, parallel-group study, adult outpatients with modified Mayo Clinic scores (MCSs) (stool frequency, rectal bleeding, and endoscopy findings) of 4–9, endoscopic subscores of 2 or more, and rectal bleeding subscores of 1 or more were randomly assigned to groups given once-daily etrasimod 1 mg (n = 52), etrasimod 2 mg (n = 50), or placebo (n = 54) for 12 weeks. The study was performed from October 15, 2015, through February 14, 2018, at 87 centers in 17 countries. The primary endpoint was an increase in the mean improvement in modified MCS from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement (subscores of 1 or less) from baseline to week 12. Exploratory endpoints, including clinical remission, are reported in the article, although the study was statistically powered to draw conclusions only on the primary endpoint. At week 12, the etrasimod 2 mg group met the primary and all secondary endpoints. Etrasimod 2 mg led to a significantly greater increase in mean improvement in modified MCS from baseline than placebo (difference from placebo, 0.99 points; 90% confidence interval, 0.30–1.68; P =.009), and etrasimod 1 mg led to an increase in mean improvement from baseline in modified MCS of 0.43 points more than placebo (90% confidence interval, reduction of 0.24 to increase of 1.11; nominal P =.15). Endoscopic improvement occurred in 41.8% of patients receiving etrasimod 2 mg vs 17.8% receiving placebo (P =.003). Most adverse events were mild to moderate. Three patients had a transient, asymptomatic, low-grade atrioventricular block that resolved spontaneously all patients had evidence of atrioventricular block before etrasimod exposure. In patients with moderately to severely active ulcerative colitis, etrasimod 2 mg was more effective than placebo in producing clinical and endoscopic improvements. Further clinical development is warranted. Clinicaltrials.gov , Number: NCT02447302 [ABSTRACT FROM AUTHOR]

In the era where new biologicals are entering the market, the place of immunomodulators in the treatment of pediatric inflammatory bowel disease (IBD) needs to be reassessed. All children with Crohn's disease (CD) or ulcerative colitis (UC) followed at our center over the last 10 years were reviewed. Children who received conventional therapy (including 5-aminosalicylates, steroids, thiopurines and methotrexate) since diagnosis were included. Primary outcome was steroid-free clinical remission without need for rescue therapy (biologics or surgery) at 6 and 12 months after diagnosis and at last follow-up. Cox proportional hazard modelling was performed to determine variables at diagnosis associated with outcomes. In total, 176 IBD patients (121 CD, 55 UC) were identified with a median follow-up of 4.6 [2.0–8.1] years. Remission rates were 79.6% at month 6, but decreased to 60.2% at month 12, and 31.8% at last follow-up. Higher CRP [1.006 (1.001–1.011)], lower albumin [1.050 (1.012–1.086)] and growth impairment [1.214 (1.014–1.373)] in CD patients and higher PUCAI score [1.038 (1.006–1.072)] and low iron [1.023 (1.003–1.043)] in UC patients were associated with treatment failure (all p < 0.05). Only 32% pediatric IBD patients will remain free of biologics or surgery 5-years after diagnosis. Especially children with a high disease burden at diagnosis were more likely to fail conventional therapy. [ABSTRACT FROM AUTHOR]

Background and Aims In vitro studies using immortalised cancer cell lines showed that butyrate has an overall positive effect on epithelial barrier integrity, but the physiological relevance of cancer cell lines is limited. We developed epithelial monolayers from human tissue samples of patients with ulcerative colitis [UC] to assess the effect of butyrate on epithelial barrier function. Methods A protocol to establish monolayers from primary epithelial cells of UC patients [ n = 10] and non-UC controls [ n = 10] was optimised. The monolayers were treated with 8 mM sodium butyrate ± tumour necrosis factor alpha [TNFα] and type II interferon [IFNγ] for 48 h. Changes in transepithelial electrical resistance were monitored. Barrier gene expression levels were measured. Inflammatory proteins in the supernatant of the cells were quantified with OLINK. Results We demonstrated that primary monolayer cultures can be grown within 1 week of culture with robust resistance values and polarised tight junction expression. Butyrate treatment of the cultures increased resistance but was detrimental in combination with TNFα and IFNγ. The combined treatment further induced even higher IL8 mRNA and inflammatory protein secretion than for the inflammatory mediators alone. The observed effects were similar in cultures from patients and non-UC controls, suggesting that there were no patient-specific responses responsible for these findings. Conclusions We found that butyrate does not protect against inflammation-induced barrier dysfunction and even worsens its effects in primary epithelial monolayers of UC patients and controls. The basic mechanisms of butyrate should therefore be reconsidered in future studies, in particular in patients with active inflammation and pre-existing barrier defects as is known for UC. [ABSTRACT FROM AUTHOR]

Background and Aims: This review is the first to evaluate the burden of ulcerative colitis [UC] on patients' quality of life by synthesizing data from studies comparing scores from the SF-36® Health Survey, a generic measure assessing eight quality-of-life domains, between UC patients and matched reference samples. Methods: A systematic review of the published literature identified articles reporting SF-36 domains or physical and mental component summary scores [PCS, MCS] from UC and reference samples. Burden of disease for each SF-36 domain was then summarized across studies by comparing weighted mean differences in scores between patient and reference samples with minimally important difference thresholds. Results: Thirty articles met pre-specified inclusion criteria. SF-36 scores were extracted from five samples of patients with active disease, 11 samples with a mixture of disease activity, five samples of patients in clinical remission, and 13 samples of patients following proctocolectomy with ileostomy or ileal pouch-anal anastomosis, along with respective reference samples. Clinically meaningful burden was observed in samples with active or mixed disease activity [deficits: PCS = 5.6, MCS = 5.5] on all SF-36 domains except Physical Functioning. No burden was observed in samples in remission or post-surgical patients [deficits: PCS = 0.8, MCS = 0.4] except for the General Health perception domain. Conclusions: Patients with active UC experience a clinically meaningful burden of disease across most aspects of quality of life. Patients with inactive UC exhibit negligible disease burden and are comparable to the general population on most quality-of-life outcomes. Thus, treatments which effectively induce and maintain remission may restore physical and mental health status. [ABSTRACT FROM AUTHOR]

Background and Aims Tofacitinib is an oral, small molecule Janus kinase [JAK] inhibitor that is being investigated for ulcerative colitis [UC]. We evaluated health-related quality of life [HRQoL] in tofacitinib UC Phase 3 studies. Methods Patients ≥ 18 years old in OCTAVE Induction 1 [N = 598] and 2 [N = 541] with moderately to severely active UC were randomised [1:4] to placebo or tofacitinib 10 mg twice daily [BID] for 8 weeks. Subsequently, OCTAVE Sustain re-randomised [1:1:1] clinical responders [N = 593] from induction studies to placebo, tofacitinib 5 mg BID, or 10 mg BID, for 52 weeks. Inflammatory Bowel Disease Questionnaire [IBDQ] and SF-36v2® Health Survey [SF-36v2] assessed HRQoL. Results In OCTAVE Induction 1 and 2, mean changes from baseline IBDQ were greater with tofacitinib 10 mg BID at Week 8 [40.7 and 44.6] versus placebo [21.0 and 25.0; p < 0.0001]; mean changes from baseline SF-36v2 Physical and Mental Component Summaries [PCS/MCS] were also greater with 10 mg BID [PCS: 6.8 and 6.8; MCS: 6.8 and 7.6] versus placebo [PCS: 2.5 and 4.6; MCS: 3.5 and 4.4; p < 0.01]. In OCTAVE Sustain atWeek 52, changes in IBDQ were maintained with tofacitinib 5 mg [3.7] and 10 mg BID [4.8], and larger with placebo [-26.5; p < 0.0001]. Changes in SF-36v2 PCS/MCS were also maintained with 5 mg [PCS: 0.0; MCS: -1.0] and 10 mg BID [PCS: 0.3; MCS: 0.1] versus placebo [PCS: -5.2; MCS: -6.7; p < 0.0001] at Week 52 in OCTAVE Sustain. Conclusions Tofacitinib 10 mg BID induction therapy significantly improved HRQoL versus placebo at Week 8. Improvements were maintained through 52 weeks' maintenance therapy with tofacitinib 5 mg and 10 mg BID. ClinicalTrials.gov registration numbers NCT01465763, NCT01458951 and NCT01458574 [ABSTRACT FROM AUTHOR]

Background and Aims: Preoperative use of vedolizumab has been associated with increased short-term postoperative infectious complications. We assessed this risk in a single-centre cohort of patients with ulcerative colitis undergoing colectomy. Methods: Chart review was performed for all colectomies between 2006 and 2016. Short-term postoperative [non]infectious complications were evaluated within 30 days after colectomy. The comprehensive complication index was calculated based on all reported events. Results: We identified 170 eligible patients [46% female, median age 40 years]. Thirty-four patients [20%] received vedolizumab within 16 weeks, 60 [35%] received anti-tumour necrosis factor [TNF] within 8 weeks, 32 [19%] received a moderate-to-high dose of prednisone and 71 [42%] received other therapies at colectomy. Pouch construction was performed at first stage in 47 patients [28%], and less frequently in patients under vedolizumab, anti-TNF or steroids [all p < 0.01]. Sixtytwo short-term infectious and 75 noninfectious complications were reported in, respectively, 49 [29%] and 64 [38%] patients. Only pouch construction at first stage of surgery was independently associated with short-term postoperative infectious (odds ratio 2.40 [95% confidence interval 1.18-4.90], p = 0.016), overall complications (3.11 [1.52-6.40], p = 0.002) and more severe complications (comprehensive complication index 20.9 [0.0-30.8] vs 0.0 [0.0-20.9], p = 0.001). Perioperative medical therapy [including vedolizumab] did not influence short-term outcome, either in the overall population or in the subpopulation of patients with pouch construction at a second stage. Conclusions: Perioperative use of vedolizumab was not associated with short-term postoperative [infectious] complications. However, postponing pouch construction to a second stage of surgery is advisable in patients under biological therapy or moderate-to-high doses of steroids. [ABSTRACT FROM AUTHOR]

Background and Aims: The GEMINI long-term safety [LTS] study is a continuing phase 3 trial investigating the safety and efficacy of vedolizumab, an α4β7 integrin antagonist for ulcerative colitis [UC] and Crohn's disease. We provide an interim analysis of efficacy in patients with UC. Methods: Patients from the C13004 and GEMINI 1 studies and a cohort of vedolizumab-naïve patients received open-label vedolizumab every 4 weeks. Interim data were collected from May 22, 2009 to June 27, 2013. Clinical response and remission, evaluated using partial Mayo scores, and health-related quality of life [HRQL] were assessed for up to 152 weeks of cumulative treatment in the efficacy population. Results: As of June 27, 2013, 63% of the efficacy population [n = 532/845] were continuing treatment. Among patients who responded to vedolizumab induction and had data available, 88% [n = 120/136] were in remission after 104 weeks of exposure (96% [n = 70/73] after 152 weeks). Among patients who withdrew from every-8-week vedolizumab maintenance in GEMINI 1 [n = 32] before week 52, increased dosing to every 4 weeks in GEMINI LTS resulted in response and remission rates of 41% and 28%, respectively, after 52 weeks, an increase from 19% and 6%, respectively, from before the dose increase. Similar benefits were demonstrated regardless of prior tumour necrosis factorantagonist exposure. Durable benefits on HRQL were also observed. Conclusions: Patients with UC experienced clinical and HRQL improvements with continued vedolizumab treatment. Increased dosing frequency to every 4 weeks was beneficial in patients who had loss of response to 8-weekly dosing. [ABSTRACT FROM AUTHOR]

Background and Aims: The original Geboes Score [OGS] is the most commonly used histological score in ulcerative colitis [UC], but rather complicated to use in daily clinical practice. The aim of this study was to develop a Simplified Geboes Score [SGS] and to compare it with the OGS in patients newly diagnosed with UC. Methods: All patients diagnosed with UC at a tertiary referral centre between 2005 and 2010, who had serial colonoscopies with biopsies, were retrospectively included. The 5-year endoscopic/ histological evolution after diagnosis was recorded. Histological activity was scored by an experienced inflammatory bowel disease pathologist and three trained readers using the OGS and also the new SGS that only includes variables linked to active inflammatory disease. The correlation between endoscopic and histological activity and the histological inter-observer agreement were measured. Results: A total of 528 slides from 339 colonoscopies of 103 UC patients were reviewed. Forty [12%] colonoscopies presented Mayo 0, 74 [22%] Mayo 1, 107 [31%] Mayo 2 and 118 [35%] Mayo 3. Active microscopic disease [≥ 3.1 in both scores] was described in 10/40 [25%] patients who were in complete endoscopic remission [Mayo 0], and 62/74 [84%] with mild endoscopic lesions [Mayo 1]. The correlation analysis between endoscopy and OGS/SGS did not show significant differences between the histological scores. The inter-observer agreement was moderate for all the grades of the SGS. Conclusions: The assessments of histological activity based on the OGS and the SGS were comparable in newly diagnosed active UC patients. Further prospective validation should now be done to replace the OGS with the SGS. [ABSTRACT FROM AUTHOR]

We evaluated the efficacy of once-daily (QD) upadacitinib 45 mg, an oral, reversible Janus kinase inhibitor, on early symptomatic improvement for ulcerative colitis (UC). Post hoc analyses were performed on pooled data from 2 replicate, phase 3, multicenter induction trials, U-ACHIEVE Induction and U-ACCOMPLISH, to determine the earliest time point of efficacy onset. Diary entry data through 14 days from the first dose of placebo or upadacitinib 45 mg QD were analyzed for daily improvement in UC symptoms (stool frequency, rectal bleeding, abdominal pain, and bowel urgency). Changes in inflammatory markers, high-sensitivity C-reactive protein (hs-CRP), and fecal calprotectin (FCP) were assessed at week 2 and quality of life (QoL) at weeks 2 and 8. Regression analysis determined the association between changes in UC symptoms and the likelihood of achieving clinical remission/response per Adapted Mayo score at week 8. Overall, 988 patients (n = 328 placebo, n = 660 upadacitinib) were analyzed. Patients treated with upadacitinib demonstrated significant improvements vs placebo in all UC symptoms between days 1 and 3 and maintained through day 14. A >50% reduction from baseline in hs-CRP and FCP levels was achieved by 75.7% and 48.2% of patients, respectively (P <.001 vs placebo). Increased rates of clinical remission/response per Partial Mayo score from week 2 (26.9%/59.4% upadacitinib 45 mg QD vs 4.3%/22.3% placebo, P <.001) and significant improvements in QoL at weeks 2 and 8 were observed. Early improvement in stool frequency and bowel urgency by day 3 and reductions in hs-CRP and FCP by week 2 were significantly associated with clinical remission/response at week 8. Upadacitinib 45 mg QD provided rapid relief of UC symptoms from day 1. Clinicaltrials.gov: U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026). [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Aims: Mucosal healing is associated with favourable therapeutic outcomes in patients with ulcerative colitis [UC]. We investigated whether adalimumab concentrations during induction therapy are associated with short-term mucosal healing [STMH] in UC patients. Methods: This was a retrospective, single-centre study including consecutive UC patients treated with adalimumab from June 2005 to May 2014, who underwent an endoscopy both at baseline and after induction therapy [weeks 8-14] and at least one serum sample available at week 2 and/ or week 4. STMH was defined as Mayo endoscopic sub-score of ≤1 with a baseline sub-score of ≥2. Adalimumab concentrations were evaluated using an in-house developed enzyme-linked immunosorbent assay. Results: The study population consisted of 43 patients, the majority of whom [n = 38] were prior infliximab failures; the rest showed primary non-response [PNR, n = 5]. Twelve patients [27 .9%] achieved STMH. Patients with STMH had higher adalimumab concentrations at week 4 compared to those without [10.6 vs 7 .4 µg/ml, p = 0.014]. A receiver operating characteristic [ROC] analysis identified an adalimumab concentration threshold at week 4 of 9.4 µg/ml (area under the ROC curve [AUROC]: 0.778) and 7 .5 µg/ml [AUROC: 0.798], after excluding patients with PNR to infliximab, to be associated with STMH. Multiple logistic regression analysis, after excluding patients with PNR to infliximab, identified adalimumab concentration ≥7 .5 µg/ml at week 4 (odds ratio [OR]: 15.7; 95% confidence interval [CI]: 1.3-185; p = 0.029) and baseline endoscopic Mayo score 3 [OR: 0.13; 95% CI: 0.02-0.98; p = 0.047] as factors independently associated with STMH. Conclusions: This study, reflecting real-life clinical practice, demonstrated that post-induction adalimumab concentrations are associated with STMH, while higher baseline mucosal inflammation is related to lack of STMH in UC. [ABSTRACT FROM AUTHOR]

Background and Aims: We studied the long-term outcome of patients with ulcerative colitis [UC] and primary non response [PNR] to infliximab and searched for predictors of colectomy in these patients. Methods: This retrospective, multi-centre study included UC patients from three European referral centres, with PNR to infliximab defined as a lack of clinical improvement after the induction therapy, leading to drug discontinuation. Relapse, for patients who continued on biologicals after PNR to infliximab, was defined as drug discontinuation for PNR, loss of response, or serious adverse event. Serum infliximab concentrations at Weeks 2 and 6 were evaluated using an enzyme-linked immunosorbent assay [ELISA] developed in house. Results: The study population consisted of 99 anti-tumour necrosis factor [TNF]-naïve patients with UC and PNR to infliximab. At the end of follow-up (median: 3.2 [interquartile range 1-6.3] years), 55 [55.6%] of these patients underwent colectomy. Multiple Cox regression analysis identified acute severe UC (hazard ratio [HR]: 24; 95% confidence interval [CI]: 2.5-231; p = 0.006], baseline C-reactive protein [CRP] > 5 mg/l [HR: 11; 95% CI: 2.1-58.8; p = 0.005], baseline albumin < 40 g/l [HR: 9.5; 95% CI: 1.3-71.4; p = 0.026], and infliximab concentration at Week 2 < 16.5 μg/ml [HR: 5.6; 95% CI: 1.1-27.8; p = 0.034] as independent predictors of colectomy. Regarding patients who continued on biologicals after PNR to infliximab, there was a marginally higher cumulative probability for relapse in patients switching to another anti-TNF agent compared with those swapping to vedolizumab [p logrank = 0.08]. Conclusions: About half of UC patients with PNR to infliximab will undergo colectomy. Patients with severe inflammation and low serum infliximab concetrations during the induction phase are at greatest risk. [ABSTRACT FROM AUTHOR]

Background and Aims: AVX-470 is an oral, polyclonal bovine-derived anti-tumour necrosis factor (TNF) antibody in development for treatment of inflammatory bowel disease (IBD). AVX-470 neutralizes TNF locally in the gastrointestinal tract, minimizing systemic exposure. This was a double-blind, placebo-controlled, first-in-human trial designed to assess the safety, pharmacokinetics, immunogenicity and preliminary efficacy of 4 weeks of AVX-470 in patients with active ulcerative colitis (UC). Methods: Thirty-seven patients with active UC were randomized and 36 received AVX-470 (0.2,1.6 or 3.5g/day) or placebo over 4 weeks. Endoscopic activity was assessed by colonoscopy pre- and post-treatment.The primary endpoint was safety. Secondary endpoints included pharmacokinetics and immunogenicity. Clinical and endoscopic response and remission were assessed as exploratory endpoints. Results: Thirty-three (92%) patients completed treatment and follow-up.The incidence of adverse events was similar across treatment groups and no allergic reactions or opportunistic infections were reported. AVX-470 therapy did not induce human anti-bovine antibodies (HABA). Bovine immunoglobulin (Ig) with TNF binding capacity was detected in stool, while bovine Ig levels in serum were low. Across all AVX-470 doses, 25.9% of patients achieved clinical response compared with 11.1% on placebo, with greatest improvements in the 3.5 g/day group associated with proximal colon endoscopic improvement and reductions in serum CRP and IL-6. Conclusions: AVX-470 was safe and well tolerated in this first-in-human trial in UC, with efficacy trends for clinical, endoscopic and biomarker endpoints in the highest dose group (3.5g/day). Results suggest benefit of an orally delivered locally active agent in moderate to severe UC. [ABSTRACT FROM AUTHOR]

Background and Aims: Golimumab has been approved recently to treat refractory moderate-to-severe ulcerative colitis [UC]. To date it is not clear why a considerable fraction of patients do not respond, or lose initial response, to golimumab therapy. Our aim was to investigate whether a low golimumab serum concentration and/or a positive anti-golimumab antibody status reduces the efficacy of this drug in patients with UC. Methods: Serum samples of 21 patients with moderate-to-severe UC were collected during the first 14 weeks of golimumab therapy. For measurement of golimumab serum concentrations, both a tumour necrosis factor [TNF]-coated enzyme-linked immunosorbent assay [ELISA] and a sandwich-type ELISA were developed. Anti-golimumab antibodies were measured using a bridging ELISA and a newly-developed drug-tolerant immunoassay. Clinical response and mucosal healing were assessed 14 weeks after start of treatment. Results Out of 21 patients, 10 [48%] reached partial clinical response at Week 14. Median [interquartile range] serum golimumab concentration was significantly higher in partial clinical responders than in non-responders: 10.0 [7.8-10.5] µg/ml versus 7.4 [4.8-8.3] µg/ml at Week 2 [p = 0.035] and 5.1 [4.0-7.9] µg/ml versus 2.1 [1.8-4.2] µg/ml at week 6 [p = 0.037]. Four out of 21 UC patients developed anti-golimumab antibodies, detectable only using a drug-tolerant immunoassay, and three had a partial clinical response at that time. Clinical non-responders had a significantly more severe colitis, indicated by a higher endoscopic Mayo score at baseline compared with partial clinical responders [p = 0.048]. Conclusion: Adequate exposure to golimumab drives clinical response. A worse disease at baseline influences clinical response rate negatively. [ABSTRACT FROM AUTHOR]

Background & Aims Mucosal healing is an independent predictor of sustained clinical remission in patients with ulcerative colitis (UC) treated with infliximab. We investigated whether infliximab concentrations during induction therapy are associated with short-term mucosal healing (STMH) in patients with UC. Methods We performed a retrospective, single-center analysis of data collected from a tertiary referral center from 101 patients with UC who received scheduled induction therapy with infliximab at weeks 0, 2, and 6 and had an endoscopic evaluation at baseline and after induction therapy. STMH was defined as Mayo endoscopic sub-score ≤1, assessed at weeks 10–14, with baseline sub-score ≥2. Infliximab concentrations were evaluated in serum samples collected at weeks 0, 2, 6, and 14 of infliximab therapy by using an enzyme-linked immunosorbent assay we developed. Results Fifty-four patients (53.4%) achieved STMH. Patients with STMH had a higher median infliximab concentration at weeks 2, 6, and 14 than patients without STMH. A receiver operating characteristic (ROC) analysis identified infliximab concentration thresholds of 28.3 (area under the ROC curve [AUROC], 0.638), 15 (AUROC, 0.688), and 2.1 μg/mL (AUROC, 0.781) that associated with STMH at weeks 2, 6, and 14, respectively. Multiple logistic regression analysis identified infliximab concentration ≥15 at week 6 ( P = .025; odds ratio, 4.6; 95% confidence interval, 1.2–17.1) and ≥2.1 μg/mL at week 14 ( P = .004; odds ratio, 5.6; 95% confidence interval, 1.7–18) as independent factors associated with STMH. Conclusions In an analysis of data from real-life clinical practice, we associated infliximab concentrations during the induction therapy with STMH in patients with UC. [ABSTRACT FROM AUTHOR]

Background and aims: Current endoscopic activity scores for ulcerative colitis (UC) do not take into account the extent of mucosal inflammation. We have developed a simple endoscopic index for UC that takes into account the severity and distribution of mucosal inflammation. Methods: In this multicentre trial, UC patients undergoing colonoscopy were prospectively enrolled. For the Modified Score (MS), the sum of Mayo Endoscopic Subscores (MESs) for five colon segments (ascending, transverse, descending, sigmoid and rectum) was calculated. The Extended Modified Score (EMS) was obtained by multiplying the MS by the maximal extent of inflammation. The Modified Mayo Endoscopic Score (MMES) was obtained by dividing the EMS by the number of segments with active inflammation. Colon biopsies were obtained from the rectum and sigmoid, as well as from all inflamed segments, by standard methods. Clinical activity was scored according to the Partial Mayo Score (PMS). Biological activity was scored according to C-reactive protein (CRP) and faecal calprotectin (FC) levels. Histological activity was scored according to the Geboes Score (GS). Results: One hundred and seventy-one UC patients (38% female, median age 47 years, median disease duration 13 years) were included. The MMES correlated significantly with the PMS (r = 0.535), CRP (r = 0.238), FC (r = 0.730) and GS (r = 0.615) (all p < 0.001). Median MMES scores were significantly higher in patients with clinical, biological or histological activity (all p ≤ 0.001) Conclusions: The MMES is an easy to use endoscopic index for UC that combines the severity analysis of the MES with disease extent, and correlates very well with clinical, biological and histological disease activity. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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.) [Display omitted] This multicentered study shows that oral intake of 5-hydroxytryptophan is not better than placebo in the treatment of fatigue in patients with inflammatory bowel diseases. [ABSTRACT FROM AUTHOR]

Background and aims Although inflammatory bowel diseases (IBD) significantly impact the patient's quality of life, no European-level data exists on patients' perspectives. The primary objective of this survey was to obtain an international perspective of the impact of IBD on patients' lives. Secondary objectives included obtaining a better understanding of the quality of care, access to care, and differences between countries, age groups, and sub-groups of IBD. Methods The survey questionnaire consisted of 52 questions in six categories. The survey was translated into ten languages, tested on volunteers, and promoted across 25 national IBD associations. Data was collected anonymously online, and participation was optional. Results 4670 patients completed the survey. Most respondents received a final diagnosis within a year from noticing first symptoms, but 67% had to visit emergency clinic at least once before diagnosis. 85% had been hospitalized in the last five years. 64% felt that gastroenterologists should ask more probing questions and 54% that they did not get to tell something potentially important to their physician. Most respondents experienced symptoms weekly also in remission. Most had been absent from work due to IBD and 24% had received unfair comments about their work performance. 45% felt that IBD had negatively affected their performance in educational settings. Conclusions The results of this survey can be used in defining strategic priorities and planning projects and awareness raising activities. The unmet needs of IBD patients can be better demonstrated and communicated to the public, health service managers and politicians. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To investigate the association between known inflammatory bowel disease (IBD)-associated genetic variants and development of paediatric IBD, and specific clinical sub-phenotypes. Material and methods: In this case–control study we included IBD patients <18years of age at diagnosis from the Danish National Patient Registry and healthy children <18years of age were randomly selected from the Danish Central Office of Civil Registration. The latter had filled out a questionnaire regarding health status, and DNA was obtained from blood samples and the buccal mucosa. Patient files were retrieved and clinical information was extracted. DNA was obtained from Guthrie cards from the Danish National Neonatal Screening Biobank (PKU-biobanken) at Statens Serum Institut and from blood samples. Results: A total of 588 IBD patients (244 Crohn's disease (CD), 318 ulcerative colitis (UC) and 26 IBD-unclassified (IBDU)) and 543 healthy controls were included. We found an association between CD and rs22411880 (ATG16L1, odds ratio (OR)=1.7 [1.1–1.7], p=0.003), rs5743289 (NOD2, OR=1.4 [1.1–1.9], p=0.009) and the paediatric specific rs1250550 (ZMIZ1, OR=0.7 [0.5–0.9], p=0.01). None of the investigated 41 SNPs were associated with disease localisation, medical treatment or surgery after correcting for multiple analyses. Conclusion: We found an association between CD and three previously published genetic variants and replicated the association with the paediatric specific ZMIZ1 gene. No Bonferroni corrected significant genotype–phenotype associations were found. For future studies aimed at finding predictors for disease course in (paediatric) IBD, it will be worthwhile to include a combination of genetic, clinical and serological markers. [Copyright &y& Elsevier]

Abstract: Background and Aims: Inflammatory bowel disease (IBD) is a chronic disease affecting mainly young people in their reproductive years. IBD therefore has a major impact on patients’ family planning decisions. Management of IBD in pregnancy requires a challenging balance between optimal disease control and drug safety considerations. This article aims to provide a framework for clinical decision making in IBD based on review of the literature on pregnancy-related topics. Methods: Medline searches with search terms ‘IBD’, ‘Crohn''s disease’ or ‘ulcerative colitis’ in combination with keywords for the topics fertility, pregnancy, congenital abnormalities and drugs names of drugs used for treatment of IBD. Results: IBD patients have normal fertility, except for women after ileal pouch-anal anastomosis (IPAA) and men under sulfasalazine treatment. Achieving and maintaining disease remission is a key factor for successful pregnancy outcomes in this population, as active disease at conception carries an increased risk of preterm delivery and low birth weight. Clinicians should discuss the need for drug therapy to maintain remission with their patients in order to ensure therapy compliance. Most IBD drugs are compatible with pregnancy, except for methotrexate and thalidomide. If possible, anti-TNF therapy should be stopped by the end of the second trimester and the choice of delivery route should be discussed with the patient. Conclusions: Disease control prior to conception and throughout pregnancy is the cornerstone of successful pregnancy management in IBD patients. [Copyright &y& Elsevier]

Abstract: Aim: To evaluate the effect of infliximab induction therapy on calprotectin levels in patients with ulcerative colitis (UC). Patients and Methods: In this prospective study 53 patients with active UC from 17 centers were treated with infliximab therapy (5mg/kg) at baseline, week 2, and week 6. Faecal calprotectin was measured every week. Sigmoidoscopies were performed at baseline, week 6 and week 10. Results: Median calprotectin levels decreased from 1260 (IQR 278.5- 3418 ) at baseline to 72.5 (IQR 18.5 - 463) at week 10 (p<0.001). After 10weeks, infliximab therapy induced endoscopic remission and a decrease in calprotectin to<50mg/kg or at least a 80% decrease from baseline level in 58% of patients. A significant and steep decrease of calprotectin levels was seen at week 2 for patients with an endoscopic remission at week 10 as compared to patients who did not show a remission. (p<0.001). At week 10 an excellent correlation was found between endoscopic remission and clinical Mayo score reflected by an AUC of ROC analyses of 0.94 (0.87-1) and with calprotectin measurements (AUC 0.91 (0.81-1)) : all patients with calprotectin levels <50mg/kg, and a normal clinical Mayo score (=0) were in endoscopic remission. Conclusions: Infliximab induces a fast and significant decrease of faecal calprotectin levels in anti-TNF naïve patients with ulcerative colitis predictive for remission of disease [Copyright &y& Elsevier]

Abstract: Background and aims: Infliximab is currently the only biologic approved for treatment of adults with moderate to severe, active ulcerative colitis (UC) unresponsive to conventional therapies. It rapidly controls symptoms, induces and sustains steroid-free remission, stimulates mucosal healing, and reduces serious complications. Although infliximab tends to be reserved for patients with severe disease, it may be even more beneficial for moderate disease earlier in the disease course. Therefore, it is important to identify which patients are candidates for infliximab therapy. Methods: A collaborative Delphi survey was used to obtain consensus on use of biologic therapy in patients with UC from an expert panel of 12 gastroenterologists with substantial experience using infliximab in clinical practice and clinical trials. The panel also addressed issues that influence the use of infliximab in UC, including its potential as an alternative to surgery. Results: The panel agreed that: (1) it is necessary to adopt additional treatment goals beyond symptom control, i.e., complete mucosal healing, steroid-free remission, improved QoL, and reduced long-term complications; (2) it may be possible to achieve these treatment goals with infliximab, especially if it is used earlier in the course of UC; and (3) infliximab should be offered as an alternative to surgery in patients being considered for colectomy. The panel also agreed on factors for identifying candidates for infliximab therapy (e.g., persistently active UC, steroid-dependent/refractory disease, and high C-reactive protein). Conclusions: This consensus statement provides useful and practical information on how to achieve evolving treatment goals with infliximab in moderate to severe UC. [Copyright &y& Elsevier]

Abstract: Aim of the study: To determine the occurrence of intestinal and extraintestinal cancers in the 1993–2009 prospective European Collaborative Inflammatory Bowel Disease (EC-IBD) Study Group cohort. Patients–methods: A physician per patient form was completed for 681 inflammatory bowel disease patients (445UC/236CD) from 9 centers (7 countries) derived from the original EC-IBD cohort. For the 15-year follow up period, rates of detection of intestinal and extraintestinal cancers were computed. Results: Patient follow-up time was fifteen years. In total 62/681 patients (9.1%) [41 with ulcerative colitis/21 with Crohn''s disease, 36 males/26 females] were diagnosed with sixty-six cancers (four patients with double cancers). Colorectal cancer was diagnosed in 9/681 patients [1.3%] (1 Crohn''s disease and 8 ulcerative colitis). The remaining 53 cancers were extraintestinal. There was a higher prevalence of intestinal cancer in the Northern centers compared to Southern centers [p=NS]. Southern centers had more cases of extraintestinal cancer compared to Northern centers [p=NS]. The frequency of all observed types of cancers in Northern and in Southern centers did not differ compared to the expected one in the background population. Conclusions: In the fifteen-year follow up of the EC-IBD Study Group cohort the prevalence of cancer was 9.1% with most patients having a single neoplasm and an extraintestinal neoplasm. In Northern centers there were more intestinal cancers while in Southern centers there were more extraintestinal cancers compared to Northern centers. In this IBD cohort the frequency of observed cancers was not different from that expected in the background population. [Copyright &y& Elsevier]

Abstract: Background and aims: Inflammatory Bowel Disease (which includes Crohn''s Disease and Ulcerative Colitis), is a chronic condition characterised by substantial morbidity. Inflammatory Bowel Disease patients are considered expensive to manage, hence accurate estimates of care costs are crucial to help healthcare providers plan clinical management. The aim of this study is to estimate the cost of care for Crohn''s Disease and Ulcerative Colitis patients in the United Kingdom and Western mainland Europe. Methods: Decision models were built to simulate the natural disease history of Crohn''s Disease and Ulcerative Colitis, informed by United Kingdom and European clinical pathways. A healthcare provider perspective was adopted, model inputs were informed by published sources and expert opinion, and UK healthcare costs were used (2008 prices). Cohorts of 25year old patients presenting with symptoms of varying severity were modelled over ten years, and annual treatment costs calculated per patient. Results: The average annual cost of care per Crohn''s Disease/Ulcerative Colitis patient was £631/£762 (United Kingdom) and £838/£796 (Europe). Most costs were incurred immediately following diagnosis, particularly in European Crohn''s patients, reflecting the earlier use of more aggressive treatments. Surgery, hospitalisation, and the use of biological therapies and mesalazine (in Ulcerative Colitis) were key cost drivers. The total annual cost to the United Kingdom National Health Service of caring for Inflammatory Bowel Disease patients was estimated to be £131million. Conclusions: This study confirms that Inflammatory Bowel Disease patients are expensive to manage and illustrates the importance of differentiating between alternative clinical management scenarios. [Copyright &y& Elsevier]