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Anti-IL23p19 inhibitors are emerging as promising treatment options for ulcerative colitis (UC). Mirikizumab (miri) is a humanized, IgG4 monoclonal antibody directed against the p19 subunit of IL-23, a key mediator in the pathogenesis of inflammatory bowel diseases. We assessed the induction efficacy and safety of miri with a Phase 3, multi-center, randomized, parallel-arm, double-blind, placebo (PBO)-controlled trial (LUCENT 1; NCT03518086) in patients with moderately to severely active UC (Modified Mayo Score 4-9 points and centrally read Mayo endoscopic subscore ≥2) who had inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, biologic therapies, or tofacitinib.

Adult patients (N=1281) were randomized in a 3:1 ratio to receive blinded intravenous administration of 300 mg miri or PBO every 4 weeks for 12 weeks. Randomization was stratified by biologic failure status, baseline (BL) corticosteroid use, BL disease activity as measured by modified Mayo score, and world region. The primary objective was to test the hypothesis that miri was superior to PBO in inducing clinical remission at Week 12. Key secondary objectives were clinical response, endoscopic remission, symptomatic remission, clinical response in biologic-failed patients, histologic-endoscopic mucosal improvement, and improvement in bowel urgency at Week 12 (see Figure for endpoint definitions). Mixed Model for Repeated Measures was used to assess urgency; the Cochran-Mantel-Haenszel test, with missing data imputed as nonresponse, was used to assess all other outcomes.

BL characteristics were balanced across the two treatment groups. A significantly greater proportion of patients treated with miri achieved clinical remission at Week 12 (Miri: 24.2%; PBO: 13.3%; Δ=11.1 [99.875%CI: 3.2, 19.1]; p=0.00006). Miri-treated patients achieved all key secondary endpoints, including a significantly greater average reduction in bowel urgency severity compared to PBO (p<0.00001). The frequencies of treatment-emergent adverse events in miri-treated patients were similar to PBO. There were numerically fewer serious adverse events (Miri: 27 [2.8%], PBO: 17 [5.3%]) and discontinuations due to adverse events (Miri: 15 [1.6%], PBO: 23 [7.2%]) in miri-treated patients compared to PBO. There were 2 colon malignancies in the miri arm (0.2%) and no deaths during the treatment period.

In this phase 3 UC study, 300mg miri IV demonstrated statistically significant and clinically meaningful improvements vs PBO in all primary and key secondary endpoints across clinical, endoscopic, histologic, and symptomatic measures, with an acceptable safety profile.

Total coloproctectomy with ileoanal anastomosis (IAA) is the procedure of choice for patients with treatment-resistant ulcerative colitis (UC). It is most often curative, but can be complicated by pouchitis in 30% of cases, which becomes chronic in 10% of patients. Its treatment is not codified after failure of conventional treatments and a first line of anti-TNF. The objective of our study was to determine the efficacy and safety of vedolizumab (VDZ) in patients with anti-TNF refractory chronic pouchitis.

This was a retrospective, multicenter study conducted in 17 hospital centers. Patients were selected from July 2019 to January 2021. All patients had chronic pouchitis refractory to a first line of anti-TNF. We evaluated clinical, endoscopic and biological characteristics at initiation of VDZ therapy, at week (W) 10 as well as at W52. The primary objective of the study was to assess clinical response (improvement ≥ 50% in stool frequency and rectal bleeding) at W52. Secondary objectives were to assess clinical response and remission (absence of symptom) at W10, endoscopic response (improvement ≥ 50% of endoscopic lesions) and remission (mucosal healing) at W10 and 52. Adverse events were also collected.

Forty-nine patients were included in the study (23 women, 26 men, mean age 48 years). Thirty-one patients (63%) had received only one line of biologic.
Forty-four (90%) patients had endoscopic evaluation before initiation of VDZ, and 25 (51%) patients at W10 and 52. CRP was assessed in all patients at baseline, 43 (88%) patients at W10, and 33 (67%) patients at W52.At W10, 17 (34%) patients were clinically responders without corticosteroids, of whom 3 (6%) were in remission; among the 25 patients evaluated, endoscopic response was obtanine in 5 (20%) patients and endoscopic remission in 11 (44%) patients. At W52, 22 (44%) patients were clinically responders, 12 (24%) of whom were in remission; endoscopic response was obtained in 15 (60%) patients and endoscopic remission in 5 (20%) patients. 
Although there was a trend for CRP to decrease during follow-up (17.3 mg/L at inclusion vs. 7.9 mg/L at W52) in the responder group, there was no significant difference between this subgroup and the non-responder patients at W52. Eight patients (16%) had adverse events, leading to discontinuation of treatment in three of them.
Optimization of VDZ at W10 was the only factor predicting nonresponse at W52: 40% in the non-responder group vs 8% in the responder group (p=0.05).
At 1 year, 69% of patients were continuing treatment.

This retrospective multicenter study shows that VDZ is a therapeutic option that may be considered in the treatment of chronic pouchitis refractory to anti-TNF.

Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may associate with higher efficacy, especially in Crohn’s disease (CD).

A systematic review and individual-patient-data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (Oct 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction-of-remission in patients with short-duration (≤18months) versus long-duration disease (>18months) analyzed separately for CD and ulcerative colitis (UC).  We used meta-regression to examine the impact of patients’ characteristics on the primary outcome. Study PROSPERO registration: CRD42018041961.

We obtained data from five biologics drug manufacturers and included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab or vedolizumab (6,168 CD, 3,227 UC patients). In CD, induction-of-remission rates were higher in pooled placebo and active arms’ patients with short-disease duration≤18 months (41.4%, 244/589) compared with disease-duration>18months (29.8%, 852/2857, meta-analytically estimated OR=1.33, 95%CI:1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction-of-remission, was not different in short-duration disease ≤18 months (n= 589, OR 1.47, 95%CI:1.01-2.15) compared with longer disease-duration (n=2857, OR 1.43, 95%CI:1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cut-offs and when modelled for individual-patients’ co-variates, including prior anti-TNFs exposure. In exploratory post-hoc analysis comparing  patients with colonic-CD (L2) versus small-bowel L1 CD (and excluding ileo-colonic L3 disease) the OR for induction-of-remission in long-duration disease>18months compared with short-duration disease was 0.62 for small-bowel CD (95%CI: 0.42; 0.91) but was not significant in pooled colonic CD population (OR=0.94, 95%CI: 0.66; 1.34)

This Individual patient level meta-analysis of clinical trials of multiple biologics found there are higher rates of induction-of-remission in early CD for both biologics and placebo, resulting in a treatment-to-placebo effect ratio which is similar across different disease durations. No such relationships between disease-duration and outcomes is found in UC

In Crohn’s disease (CD), disease location affects treatment outcomes.¹ This post hoc analysis assessed the efficacy of risankizumab (RZB), an interleukin 23 p19 inhibitor, by disease location.

In ADVANCE (NCT03105128) and MOTIVATE (NCT03104413), patients with moderately to severely active CD and intolerance or inadequate response to conventional and/or biologic therapy (ADVANCE) or to biologic therapy (MOTIVATE) received intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients achieving clinical response to IV RZB induction were re-randomised in a maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or SC PBO (ie, withdrawal) for 52 weeks. This post hoc analysis included patients who received RZB 600 mg IV in either ADVANCE or MOTIVATE and patients who received RZB 360 mg SC in FORTIFY. Clinical and endoscopic outcomes were evaluated in patient subgroups stratified by CD location at baseline (ileal only, colonic only, ileal-colonic) using non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19.

At week 12, significantly greater proportions of patients receiving RZB 600 mg IV achieved the co-primary endpoints CD Activity Index (CDAI) clinical remission and endoscopic response vs PBO in the colonic only (n = 190) and ileal-colonic (n = 252) subgroups (P < .001; Figure 1A–1B). At week 12, statistically higher proportions of RZB-treated patients achieved the composite endpoint CDAI clinical remission and endoscopic response, as well as endoscopic remission in the colonic only and ileal-colonic subgroups vs PBO (P < .001; Figure 1C–1D). At week 52, significantly greater proportions of patients receiving RZB 360 mg SC achieved the co-primary endpoints CDAI clinical remission and endoscopic response, composite CDAI clinical remission and endoscopic response, and endoscopic remission vs withdrawal (PBO SC) in the colonic only (n = 59) and ileal-colonic (n = 67) subgroups (P ≤ .05; Figure 2A–2D). In patients with endoscopic remission after 12 weeks of IV RZB (week 0 of maintenance), significantly more RZB-treated patients achieved sustained endoscopic remission at week 52 vs withdrawal (PBO SC) in the colonic only and ileal-colonic subgroups (P ≤ .01; Figure 2E). At weeks 12 and 52, efficacy rates were numerically lower in ileal only CD relative to colonic only and ileal-colonic CD. Results for ileal only CD are limited by the small number of patients in the subgroup (induction, n = 85; maintenance, n = 15).

RZB induction and maintenance therapy was effective in patients with moderately to severely active CD with greater benefits observed in patients with any colonic involvement.   

The efficacy and safety of 12 weeks of induction and 52 weeks of maintenance treatment with risankizumab (RZB), an interleukin 23 p19 inhibitor, in patients with moderately to severely active Crohn’s disease (CD) was previously demonstrated in 3 phase 3 trials (ADVANCE, MOTIVATE, and FORTIFY). We investigated outcomes in patients with inadequate response to subcutaneous (SC) RZB or SC placebo (PBO) treatment and required RZB rescue therapy during maintenance.

In FORTIFY, a phase 3, double-blind, re-randomised responder withdrawal, maintenance study (NCT03105102), patients that responded to 12 weeks of RZB IV induction received RZB 180 mg SC, RZB 360 mg SC, or PBO (ie, withdrawal) every 8 weeks for 52 weeks. Starting at week 16, patients with inadequate response, defined as average daily stool frequency [SF] ≥ 3.3 and/or average daily abdominal pain score [APS] ≥ 1.5 as well as high‑sensitivity C-reactive protein ≥ 5 mg/L and/or faecal calprotectin ≥ 250 μg/g; or Simple Endoscopic Score for CD (SES-CD) ≥ 6 (≥ 4 for isolated ileal disease), excluding the narrowing component as scored by the site Investigator, were eligible to receive open-label rescue therapy (1 dose of intravenous [IV] RZB 1200 mg, followed by RZB 360 mg SC every 8 weeks). Up to 2 rescue therapy visits ≥ 16 weeks apart were permitted. Efficacy at week 52 was assessed in the intent-to-treat population using nonresponder imputation for missing data. Patients were also considered nonresponders when maximum equivalent steroid dose exceeded the dose used at baseline or if patients initiated any new steroids. Safety was assessed throughout the study.

In the maintenance study, a greater proportion of patients in the withdrawal (PBO SC) arm (40.2% [66/164]) were administered RZB rescue therapy vs RZB 180 mg SC (24.2% [38/157]) and RZB 360 mg SC (21.3% [30/141]; Figure A); most patients (71.1%–81.8%) required 1 rescue visit, and 16.7%–26.3% required 2 visits.Median time to first RZB rescue therapy was 178 days for the withdrawal (PBO SC) group, 179 days for the RZB 180 mg SC group, and 154 days for the RZB 360 mg SC group. At week 52, 52.5%–75.0% of patients who received RZB rescue therapy achieved SF/APS clinical response (Figure B), and 20.0–36.4% of patients who received rescue therapy achieved clinical remission (per CDAI or SF/APS) and/or endoscopic response (Figures C-E).The safety profile of RZB in CD has previously been reported.

RZB rescue therapy (one dose of RZB 1200 mg IV followed by RZB 360 mg SC every 8 weeks) may be beneficial to patients with moderately to severely active CD experiencing inadequate response to or interruption in RZB maintenance treatment.

STARDUST is a phase 3b randomized trial comparing two therapeutic strategies with ustekinumab (UST) in patients (pts) with Crohn’s disease (CD): treat-to-target (T2T) using early endoscopic assessment vs standard of care (SoC). Results from the Week (W)48 and long-term extension (LTE) (W48 to W104) were published previously.^1,2 Here we explore the efficacy of the T2T approach in modifying disease course with UST by analyzing time-to-disease modifying (DM) event up to W104.

Adult pts with moderate–severe active CD, received iv, weight-based UST ~6mg/kg at W0; then sc UST 90mg at W8. At W16, pts with ≥70-point reduction in CD Activity Index were randomized 1:1 to either T2T or SoC and received sc UST 90mg, every 12W/8W (up to 4W in the T2T arm), as per the protocol. From W48, eligible pts could continue to receive sc UST up to W104 with further protocol-guided dose adjustment. DM events were recorded through W48 and W104 starting at randomization, and time-to-event analysis was performed for pts in both arms. DM events are represented by combined bowel damage events (defined as the development of new strictures/fistulae or the occurrence of an intra-abdominal abscess) or CD-related hospitalizations or surgeries based on the adverse event analysis. Time-to-first bowel damage event, CD-related surgery, hospitalization, hospitalization or surgery was analyzed separately; Kaplan–Meier (K–M) curves with corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) are shown here.

Of 440 pts randomized to either T2T or SoC at W16, 74 discontinued before W48. Of the remaining 366 pts completing W48, 43 discontinued and did not enter LTE. At W48, 323 pts entered LTE; 20.1% of these pts discontinued before completing W104. HRs (95% CI) for time-to-first DM event from randomization through W48 and W104 are shown in Table 1, suggesting a numeric benefit in favour of the T2T arm. The separation of the K–M curves for time-to-first DM eventbetween the two arms was apparent at W48 and continued up to W104, without significant difference (Figure 1a and b).

In STARDUST, with UST, starting at W48, numerically less DM events were observed in the T2T arm, mainly driven by the lower number of CD-related hospitalizations and bowel damage events, potentially linked to numerically higher proportion of endoscopic responders at W48.¹ These results advocate for an optimized T2T approach using strictly defined targets like endoscopic response, on top of clinical and biomarkers, to facilitate decision making in clinical practice.

¹Danese S, et al. United European Gastroenterol J. 2020;8:1264–1265 (Abstract LB11).
²Peyrin-Biroulet L, et al. United European Gastroenterol J. 2021;9 (Suppl 1).

Endoscopic Assessment and Management of Strictures

This course was developed by Professor. Simon Travis and Dr. Rebecca Palmer in cooperation with Leading Edge Medical Education. This course is designed for gastroenterologists, paediatricians, surgeons, nurses and other interdisciplinary medical professional interested in the endoscopy of ulcerative colitis (UC) The intended result of this activity is competence and knowledge of endoscopy, in the assessment and follow-up of patients with UC.  The course is divided into three parts: the first is about the UCEIS and descriptors; the second is Self Assessment, which does not contribute to the final score and the third is the UCEIS Certification itself, to confirm  competence in using the UCEIS.  

Upon completion of this activity learners will:

• Be trained in the evaluation of endoscopic images in the assessment of activity in UC
• Understand why UCEIS was developed
• Understand how UCEIS was developed
• Understand the role of UCEIS
• Utilise UCEIS in clinical practice

Bram Verstockt reports a large, single centre experience of Vedolizumab use in both UC and CD from Leuven, Belgium with interesting findings for endoscopic outcomes as well as therapeutic drug monitoring.

This course has been developed for physicians and endoscopists interested in Inflammatory Bowel Disease(s) (IBD). One major aim of this e-learning activity is to increase competence and knowledge with regard to endoscopy in IBD in order to improve patient outcomes.

After this case you will be able to assess:

• Endoscopic scoring systems in Ulcerative Colitis (UC) 
• Endoscopic scoring systems to assess Pouchitis 
• Endoscopic scoring systems in Crohn’s Disease (CD) 
• Small bowel Crohn’s Disease and capsule endoscopy (CE) 
• Surveillance colonoscopy in IBD

Endoscopic Scoring Systems in Crohn's Diesase