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).

1) over view of aetiology of IBD
2) discussion of diet as a precipitant: epidemiology, animal models and human studies
3) review evidence that dietary modification may impact IBD onset and natural history

Most endoscopic scoring systems (including the Mayo endoscopic subscore, MES) do not consider the extent of inflammation and can therefore not pick up segmental endoscopic improvement. The modified Mayo endoscopic score (MMES) was developed to overcome this limitation. We examined the predictive value of the MMES in addition to the MES on long-term clinical outcome in ulcerative colitis (UC).

Between 2014 and 2017, patients initiating biologic therapy for active UC (baseline MES ≥2) were recruited. Patients without assessment of the upper margin of inflammation or with a clinical follow-up <12 months were excluded. We conducted a clinical and endoscopic assessment at baseline and week 8 (adalimumab, ADM) or 14 (golimumab, GOL; infliximab, IFX; vedolizumab, VDZ). Clinical response was defined as a decrease in the adapted Mayo score (excluding physician global assessment) with ≥2 points and ≥30%, plus a decrease in rectal bleeding score ≥1 or an absolute rectal bleeding score ≤1. We classified patients by evolution of endoscopic activity at week 8/14 in group A (endoscopic healing, MES ≤1), group B (segmental healing, MES >1 but decrease in MMES ≥30%) and group C (MES >1 and no drop in MMES ≥30%). Clinical relapse-free, discontinuation-free and colectomy-free survival was estimated by Kaplan-Meier analysis with log-rank test. 

A total of 150 UC patients were included (52% male, median age 42 years, median disease duration 7 years) with a median (IQR) follow-up of 61 (48-68) months. An anti-TNF was initiated in 74 (35 IFX, 23 ADM, 16 GOL), and VDZ in 76 patients. A significant reduction in MES and MMES was observed at week 8/14 (cf. table). In group A 67/69 (97%) patients achieved clinical response compared to 15/27 (55%) in group B and 11/54 (20%) in group C. During follow-up 60/93 (65%) patients maintained clinical response, 83/150 (55%) patients discontinued treatment due to primary non-response or loss of response and 33/150 (22%) patients underwent colectomy. The ΔMMES demonstrated to be of additional predictive value: there was a significant difference between groups B and C regarding clinical relapse, drug persistence and need for colectomy (cf. figure).

Although MES ≤1 remains the best predictor of long-term outcome, the MMES - identifying a subgroup with a segmental endoscopic response - demonstrated a clear additional value predicting long-term outcome in UC. These promising results merit inclusion of the MMES in future clinical trials.


Table

The MMES is calculated by multiplying the Mayo endoscopic subscore for the different colon segments with the maximal extent of inflammation (in decimeters) divided by the number of segments with active inflammation (Lobatón T, et al. JCC 2015; 9:846-52.)

Figure

This presentation will provide an overview of current surgical management of IBD with a focus on abdominal and perianal manifestations and treatment of colitis ulcerosa and Crohn's disease, capitalizing on the most recent ECCO guidelines.

Learning Objectives:
1. Indications for exit strategy
2. Management of exit strategies with biologics
3. Similar option with other drugs

Genome-wide association studies (GWASs) have identified 243 loci associated with inflammatory bowel disease (IBD). However, the mapping of additional disease loci and causal variants is still limited by sample size. Larger GWAS can provide further insights into causal biology.

We performed a GWAS meta-analysis of 33 cohorts, totalling 54,439 IBD patients (N=30,574 with Crohn’s disease (CD), 21,193 with Ulcerative Colitis (UC)) and 37,054 European controls. Genotype imputation was undertaken using the TOPMed diverse population panel and association tests were performed using REGENIE. These results were meta-analysed with summary statistics from 4 additional studies, a Danish cohort, the UK Biobank, deCODE, and FinnGen, totalling 73,030 IBD patients and 1 million controls, Fig1.

We identified 174 novel genome-wide significant signals (32 associated with CD, 36 with UC, 106 with IBD, Fig2).

Of these, 79 are located >1Mb from any known GWAS loci. We also identified two new population specific genetic associations, Fig3.

Six new loci contain genes implicated in monogenic syndromes that include colitis: CARMIL2, DOCK8, G6PC3, HPS4, NCF1, PIK3CD. Several new loci alter the expression of nearby genes, suggesting that aberrant expression of these genes underpins the association. For instance, a new variant associated with decreased risk of IBD increases the expression of VSIR in colon Fig4.

VSIR knockout mice have increased expression of IL23 and develop chronic inflammation in multiple tissues. Fine-mapping analyses identified likely causal missense variants at three new loci. DOK2 (OR_CD=1.3, 27p=2x10^-12) encodes a protein expressed in macrophages and T cells. Loss of Dok2 in mice causes severe DSS-induced colitis with reduced IL17A and IL22 expression. The same variant has been recently associated with CD in a sequencing study. SHARPIN (OR_CD=1.2, p=1x10^-16) is part of the linear ubiquitin chain assembly complex that modulates activation of the NF-κB pathway. Loss-of-function (LOF) mutations in other proteins in the complex are associated with immunodeficiency and systemic autoinflammation. CARMIL2 (OR_UC=1.2, p=1x10^-10) is required for NF-κB signalling in both B and T cells. LOF mutations are associated with primary immunodeficiencies and paediatric forms of IBD.

The greatly expanded sample size in our latest GWAS meta-analysis has enabled the identification of low frequency variants with larger effects on IBD susceptibility than the more common variants typically identified by previous GWAS. The biological overlap between Mendelian and complex forms of IBD is demonstrated by the discovery of common non-coding variants associated with complex forms of IBD that dysregulate the function of a Mendelian IBD gene.

For patients with ulcerative colitis (UC), both subjectively and objectively reported measures are equally important treatment goals. We explored clinical, biological, HRQoL remission and endoscopic improvements as a combined endpoint (CE) from SELECTION (NCT02914522), a phase 2b/3 double-blind trial which assessed the efficacy and safety of filgotinib, a once-daily, oral, Janus 1 kinase preferential inhibitor, for the treatment of UC.

In SELECTION, patients with moderately to severely active UC were randomized 2:2:1 to 200mg filgotinib (FIL200), 100mg filgotinib, or placebo (PBO) for an 11-week induction phase followed by a 47-week maintenance period in patients who achieved clinical remission or response.¹ We defined a CE as achieving all of the following: 1) clinical remission  defined as partial Mayo Score (excluding endoscopy domain) ≤2 and no sub-score >1), 2) biological remission defined as faecal calprotectin <150 µg/g, 3) Inflammatory Bowel Disease Questionnaire (IBDQ) remission defined as IBDQ >170 and 4) endoscopic improvement defined as Mayo endoscopic sub-score ≤1. We evaluated the CE among patients treated with FIL200 vs placebo in induction (week 10) and maintenance (week 58) phases. Among those achieving the CE, we analysed MCID improvement during induction and decline during maintenance on generic QoL instruments (36-item short-form questionnaire and EuroQol 5-dimension [EQ5D]).^2,3,4

The overall population included 381 biologic-naïve and 401 biologic-experienced patients undergoing induction, of which 297 subsequently entered maintenance. A higher proportion of patients receiving FIL200 achieved CE than PBO by week 10 in the biologic-naïve induction cohort (17.6% vs 4.41%, p<0.001) and by week 58 in the maintenance cohort (22.1% vs 7.14%, p=0.002) (Table 1). Biologic-naïve CE achievers had higher MCID improvement across all generic QoL scales and domains (Table 2).Patients achieving CE in maintenance experienced a lower proportion of MCID decline in EQ5D utility, and visual analogue scale.

Treatment with filgotinib resulted in a higher proportion of patients with combined clinical, biological, HRQoL remission and endoscopic improvements. Among patients achieving this combined composite endpoint, clinically meaningful improvements were observed in their overall quality of life. Holistic assessment of several subjective and objective measures may help achieve better outcomes in UC.

1. Feagan BF, et al. Lancet 2021;397:2372–84.
2. User’s manual for the sf-36v2 health survey. Quality Metric, Inc; 2009.
3. Stark RG, et al. Inflamm Bowel Dis. 2010 Jan;16(1):42–51.
4. Irvine EJ. J Pediatr Gastroenterol Nutr. 1999 Apr;28(4):S23–27. 

Learning Objectives:
1. Prevalence and management of EIM
2. Identification of muco-cutaneous EIM and therapy
3. Classification and therapy of rheumatological EIM

4. Classification, prevalence and management of EIMs
5. Identification and therapy of muco-cutaneous EIMs
6. Identification, classification and therapy of musculoskeletal EIMs

Educational objectives:
Know the role of faecal calprotectin measurements in the management of IBD patients.
Know the pitfalls in the interpretation of the results of such tests.

Summary
1) Fecal calprotectin can be used to predict histological remission/activity in UC patients, even in quiescent disease
2) There are however different tests, a large variation in reported cut-off values, and different endoscopic sampling methods and histological scores have been applied.
3) Data are very limited in patients with Crohn’s disease.

To review the state-of-the-art in the field of intestinal fibrosis, with a focus on the inflammation-independent causes
To provide an overview of the main differences and similarities between CD and UC-associated fibrotic complications

Crohn's disease (CD) and ulcerative colitis (UC), belonging to the class of Inflammatory Bowel Diseases (IBD), are chronic inflammatory disorders of the gastrointestinal tract, that may affect any location of the gastrointestinal tract, or the large intestine only, respectively. While CD is characterized by transmural inflammation, UC is mainly featured by colonic epithelial ulcerations, both sharing an overwhelming immune response of the gut mucosa, which leads to severe clinical symptoms. CD patients, and to a lesser extent the UC, may develop a penetrating or stricturing disease due to fibrostenosis, which most of the time requires surgical intervention since no therapies have been found as effective yet. Among the histological features, the thickening of the muscularis mucosae and muscularis propria is the main hallmark, primarily due to the excessive proliferation of mesenchymal cells and the increased accumulation of a collagen-rich extracellular matrix in the submucosa, caused by multiple mechanisms, including i) the proliferation of existing local fibroblasts, the induction of both ii) epithelial-to-, and iii) endothelial-to-mesenchymal transition. Even if the alteration of these mucosal functions is mainly caused by the continuous tissue injury occurring during intestinal chronic inflammation, recent reports suggested that fibrosis may be driven by inflammation-independent triggers, such as microbiota dysbiosis. Shedding the light on this aspect of CD fibrosis may lead to the development of innovative therapeutic strategies eventually blocking the gut thickening and facilitating the management of stricturing IBD.

 
Educational objectives:

1. Typical symptoms presented by a patient

2. Epidemiological IBD data from Austria

3. Ulcerative colitis: typical symptoms, endoscopy examples, complications, extraintestinal involvement, differential diagnoses

4. Crohn´s disease: typical symptoms, clinical investigation, typical endoscpy, differential diagnoses, environmental risk factors, extraintestinal complications

Educational objectives: 

1. To understand the different treatment algorithms for treatment of patients with IBD
2. To understand the role of patient stratification
3. To understand the basics of a treat-to-target strategy
4. Tounderstand the different exit strategies

First-line infliximab (FL-IFX) induction treatment combined with azathioprine (AZA) is more effective to achieve clinical remission without treatment escalation at week 52 compared to conventional induction treatment (CONV) (Exclusive Enteral Nutrition or prednisone) combined with AZA in children with moderate-to-severe Crohn’s disease (CD). FL-IFX may lead to higher treatment costs compared to conventional treatment. However, data on cost-effectiveness of FL-IFX in children with CD is still limited. Therefore, our aim is to investigate the cost-effectiveness of FL-IFX in comparison with CONV. We hypothesized that cost effectiveness of FL-IFX is comparable to CONV in children with newly diagnosed moderate-to-severe CD in the first two years after treatment.

We included patients from the TISKids international randomized controlled trial in which children with moderate-to-severe CD were treated with either FL-IFX (Inflectra, biosimilar of IFX) or CONV.(1) Patients included outside of the Netherlands (n=6) or patients with serious comorbidity besides CD were excluded from this analysis (n=2). Data on healthcare consumption and costs were obtained per hospital for all included patients until week 104. Direct health-related costs were collected, including hospital visits, drug costs, laboratory tests, endoscopies and surgeries. The effectiveness of treatment was assessed by mean weighted paediatric CD activity index (wPCDAI) and faecal calprotectin (fcal) levels (µg/g) measured over time until week 104. This analysis was performed by a mixed model. Moreover, time to additional anti-tumor necrosis factor-α (anti-TNF) treatment up to 104 weeks after inclusion was assessed.

In this analysis, 89 patients were included, 44 in the FL-IFX group and 45 in the conventional treatment group. There were no significant differences between the two groups at baseline. Interestingly, the mean costs were similar for FL-IFX (€34,783) and CONV (€34,923) after two years, p=0.97 (Figure 1). Mean fcal levels were lower for FL-IFX compared to CONV over two years (416 vs. 625, p=0.03). The mean wPCDAI scores over two years were numerically lower for FL-IFX compared to CONV (5.95 vs. 10.34, p=0.01), but this difference became smaller over time. Furthermore, the time to (re)start anti-TNF treatment was significantly longer in the FL-IFX group (median 68 weeks) compared to the conventional treatment group (median 32 weeks) (p=0.02) (Figure 2).

Treatment with FL-IFX is cost-effective compared to conventional treatment in the first two years after diagnosis in children with moderate-to-severe CD.

References:
1. Jongsma MME et al. Gut. 2020 Dec 31; DOI: 10.1136/gutjnl-2020-322339. / PMID: 33384335

Vedolizumab is a monoclonal antibody which blocks integrin α4β7 inhibiting trafficking of T-lymphocytes into the gut. Unfortunately, up to 60% of vedolizumab patients experience non-response. The mechanism of action of vedolizumab is not elucidated, predictors of response are unknown and data for local drug distribution in the gut are lacking. In this clinical trial, we investigated the feasibility of assessing local distribution of fluorescently labelled vedolizumab in the gut mucosa of inflammatory bowel diseases (IBD) patients to finally enable prediction of therapy response in individual patients.

Vedolizumab (Entyvio, Takeda Pharma) was labelled to IRDye 800CW under cGMP conditions to yield clinical grade vedolizumab-800CW. In this dose-escalation trial, vedolizumab naïve IBD patients and IBD patients treated with vedolizumab for at least 14 weeks were included. Patients received an intravenous dose of fluorescently labelled vedolizumab of either 0 mg, 4.5 mg, 15 mg or 15 mg + 75 mg unlabelled vedolizumab 3 days prior colonoscopy. In vivo fluorescence imaging was assessed by fibre-based wide-field fluorescence molecular endoscopy (FME) and quantified by spectroscopy in healthy, mildly inflamed and severely inflamed tissue. All assessed tissue was biopsied for ex vivo examination of the fluorescent signal, fluorescence microscopy and spectroscopy.

Up to submission 34 patients completed tracer injection and FME. An interim analysis was performed after 20 patients (5 in each dose group), which showed in severely inflamed tissue an 8 fold higher fluorescent signal in the 15 mg dose group (0.049 Q*μfa,x [mm-1]) compared to the control group (0.006 μfa,x [mm-1]) (p<0.05). Furthermore, the fluorescent signal within the 15 mg dose group was also 2.5 fold higher compared to healthy tissue (0.019 Q*μfa,x [mm-1]) (p<0.05).The addition of unlabelled vedolizumab gave similar results to the 15 mg group (p>0.99), suggesting that the drug target was still not saturated. The optimal dosage group of 15 mg was expanded up to 18 IBD patients, amongst them 6 IBD patients after 14 weeks of treatment regimen. Fluorescence microscopy showed clustering of fluorescent signals especially in inflamed mucosa. Additional experiments to detect vedolizumab target cells are ongoing.

In vivo visualization of fluorescent vedolizumab revealed a clear dose-dependent correlation between mucosal drug concentrations and the severity of mucosal inflammation. Fluorescence molecular endoscopy is a promising novel tool to get insight in drug distribution in IBD, detect target cells, assess target engagement and possibly predict therapy response in individual patients.

Educational objectives:
1. To understand recent epidemiology of IBD, particularly early and very early onset IBD (VEO-IBD)
2. To review the diagnostic work-up of VEO-IBD with a focus on early identification of immunodeficiency syndromes
3. To emphasise early discussion/referral with clinical immunology to identify patients most likely to benefit from transplant and reduce pre-transplant morbidity/mortality
4. To review potential future applications of genome-informed therapeutics in IBD

This study aimed at comparing functional outcomes and quality of life (QoL) after transanal and transabdominal approach for ileal-pouch surgery in ulcerative colitis (UC)Ileal-pouch surgery ensures satisfactory intestinal function and QoL. The transanal ileal pouch-anal anastomisis (Ta-IPAA) has recently been developed in the effort to address the technical shortfalls of the traditional transabdominal approach (Tabd-IPAA). According to previous studies, Ta-IPAA is safe. However, functional outcomes after ta-IPAA are scarcely described. 

This is a retrospective study of consecutive UC patients who underwent IPAA from 2011 to 2017.  Only patients operated according to a modified-2 or 3 stage approach were included in the analysis. Close rectal dissection was systematically performed in Ta-IPAA as opposed to total mesorectal excision in Tabd-IPAA. Groups were compared after propensity score weighting. Functional outcomes were assessed using two functional scoring systems: the Pouch Functional Score (PFS) and the Öresland score (OS). The global quality of life scale (GQOL) was used for patients’ overall perspective on QoL. Follow-up was scheduled at 1, 3, 6, and 12 months postoperatively.

One hundred and nine patients were included. Of them, 38 patients underwent Ta-IPAA. At 12 months follow-up, mean OS and PFS were 4.6 (CI 3.2-6.0) vs 6.2 (CI 5.0-7.3), p=0.02 and 6.1 (CI 3.5-8.8) vs 7.4 (CI 5.4-9.5), p=0.32, for Ta and Tabd-IPAA, respectively. Mean GQOL score for Ta-IPAA was 82.7 (CI 75.1-90.2) vs 75.5 (69.4-81.6) for Tabd-IPAA (p=0.038).

Transanal IPAA provides better functional results and QoL scores than Tabd-IPAA in UC patients.