Introduction

Crohn’s disease (CD) clinical trials have evolved from evaluating symptoms to including endoscopic outcomes as coprimary endpoints, as was done in clinical trials of upadacitinib (UPA), an oral, reversible Janus kinase inhibitor, and ustekinumab (UST), an anti-interleukin 12/23. Endoscopic healing has been recommended as a long-term treatment target by the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative.

Aims & Methods

The objective of this study is to conduct a placebo (PBO)-anchored matching-adjusted indirect comparison (MAIC) of endoscopic outcomes between UPA and UST among patients with moderately to severely active CD. Data from phase 3 UPA trials (NCT: 03105128, 03104413, 03105102) and an UST endoscopy substudy (NCT: 01369329, 01369342, 01369355) from the phase 3 UNITI/IM-UNITI program were used. For induction, patients (pts) received UPA 45mg once daily (QD) for 12 weeks (wks), UST 6mg/kg intravenously, or PBO. For maintenance, pts received UPA 15mg or 30mg QD, subcutaneous UST 90mg every 8 (Q8W) or 12 wks (Q12W), or PBO. Individual pt level data from the UPA trials included pts with baseline (BL) CD Activity Index between 220-450 and excluded pts with prior UST or vedolizumab exposure or missing data due to COVID. Induction BL characteristics identified as treatment-effect modifiers, including disease duration, location, and phenotype, median c-reactive protein, prior biologic failure, and mean Simple Endoscopic Score for CD (SES-CD), were weighted to match those reported in the UST endoscopy substudy for both induction and maintenance. Endoscopic outcomes were evaluated after induction (Wk 12 UPA, Wk 8 UST) and maintenance (Wk 52 UPA, Wk 44 UST). Endoscopic outcomes included endoscopic response (reduction of ≥50% from induction BL in SES-CD) and remission (total SES-CD ≤2), mucosal healing (present with ulceration in at least 1 ileocolonic segment at induction BL) and change in SES-CD score from induction BL.

Results

The effective sample sizes for induction MAICs were 207 UPA and 155 UST pts and ranged from 16–53 (UPA) and 17–46 (UST) for maintenance MAICs. A significantly (P<0.05) greater proportion of UPA vs UST pts achieved endoscopic response and remission, mucosal healing, and had a larger reduction from BL in mean SES-CD score at the end of induction; PBO-adjusted treatment differences were 26.3%, 9.9%, 13.0%, and –3.7 points, respectively. Endoscopic remission rates at the end of maintenance were numerically higher for UPA 30mg vs UST 90mg (Q8W+Q12W). PBO-adjusted rate differences in endoscopic response and mucosal healing between UPA 30mg and UST Q12W were significant (35.5% and 39.0%, respectively; p<0.05); other outcomes (UPA 15mg vs UST) were comparable.

Conclusion

Greater proportions of pts on UPA vs UST achieved endoscopic outcomes at the end of induction for pts with moderately to severely active CD. Although sample sizes during maintenance were limited, these MAICs show endoscopic outcomes are achieved in a numerically higher proportion of pts treated with UPA 30mg vs. UST, while outcomes are comparable with UPA 15mg vs UST.

Disclosure

C Ma has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Takeda, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Tillotts; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Takeda, Pendopharm, and Pfizer; royalties from Springer Publishing; research support from Ferring, Pfizer.
MC Dubinsky has received consulting fees from AbbVie, Abivax, Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Merck, Pfizer, Prometheus Biosciences, Prometheus Labs, Takeda
JE Axelrad reports receiving research grants from BioFire Diagnostics; consultancy fees or honorarium from BioFire Diagnostics, Janssen, Pfizer, Abbvie, and BMS; and holds US Patent 2012/0052124A1 and no other conflicts of interest.
J Griffith, S Anyanwu, and N Joshi are employees of AbbVie and may own stock.
J Tran is a funded PhD student at the University of Washington and a contractor for AbbVie.

Introduction

Filgotinib is an oral Janus kinase 1 selective inhibitor licensed for the treatment of moderate to severe ulcerative colitis (UC) following the successful UC-SELECTION registration trials.¹ However, no real-world data have been published since filgotinib first received marketing authorisation in November 2021.

Aims & Methods

The aim of this study was to assess the short-term safety and effectiveness of filgotinib for the treatment of UC. The primary outcome was post-induction clinical remission, defined as a Simple Clinical Colitis Activity Index (SCCAI) of ≤2. A retrospective, observational cohort study was conducted at a tertiary IBD referral centre using prospectively maintained records between August 2022 and February 2023. Clinical disease activity was assessed at baseline and following induction at week 10 using paired SCCAI scores, faecal calprotectin (FCAL), and C-reactive protein (CRP). Quality of life was assessed using the IBD-Control questionnaire. Non-responder imputation was used for analyses.

Results

Thirty-four patients were initiated on filgotinib during the study period, with post-induction outcome data available for 32 patients; 56% male, median age 38 (IQR range 26–53), 41% with prior biologic and/or tofacitinib exposure. Patients were treated for a median duration of 20 weeks (IQR 13–25) with treatment persistence of 69% at the time of analysis; eight patients were switched to alternative treatments due to non-response and two patients underwent colectomy.
At the end of induction, nine patients (28%) were in clinical remission; all patients were corticosteroid-free. Median SCCAI decreased significantly from a baseline of 7 (IQR 4-10) to 1 (IQR 0-6) at week 10, p<0.01, n=25. Median FCAL fell numerically from a baseline of 464 mcg/g (IQR 183-1245) to 125mcg/g (IQR 30-502) following induction, p=0.06, n=20. There was no significant change in CRP, haemoglobin, serum albumin, or lipid profile components following induction. There was a significant improvement in pre- and post-treatment quality of life scores from a median of 5 (IQR 2-9) to 16 (IQR 4-16), p<0.01.
Thirteen patients described a mild self-resolving coryzal illness, sore throat, or headaches during treatment. There was one reported case of oral herpes simplex infection requiring treatment interruption. There were no serious adverse events.

Conclusion

Filgotinib was well tolerated and clinically effective in the short term with improvements in quality of life but larger prospective cohorts with longer follow up are needed.

References

1. Feagan BG, Danese S, Loftus EV, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. The Lancet. 2021 Jun 19;397(10292):2372–84.

Disclosure

FD has received honoraria for educational meetings and speaker fees for Dr Falk. Received advisory board/nurse consultation fees for for Dr Falk, Galapagos, Pfizer and Takeda. Travel grants received from Pharmacosmos, Celtrion, and Tillotts.
KP has received honoraria for educational meetings and speaker fees from AbbVie, Janssen, Takeda, Pfizer, DrFalk, PredictImmune and Ferring and has received advisory board fees from AbbVie, Galapagos, Pfizer and Janssen.
SH served as a speaker, a consultant, and/or an advisory board member for Pfizer, Janssen, AbbVie, and Takeda. Travel grants received from Ferring, Falk Pharma, and Pharmacosmos.
RH, AA and SK have no disclosures.

Clinical Case Summary

A 22-year-old female without comorbidities presented with epigastric and lower retroesternal chest pain, nausea and vomiting since 3 days that didn't response to oral medication. Patient denied dysphagia or odinophagia. Assessed in the emergency, treated with intravenous (IV) medications and discharged with prescription. Next day, the pain increased and vomited 15 times. Patient was admitted as a case of acute gastritis on intravenous proton pump inhibitors (PPIs) and metoclopramide. Routine laboratory and upper abdominal ultrasound done without significant findings only remarkable mild hyponatremia 134 (135-145).
Physical examination looked unwell. Vitally stable 105/75 mmHg. Afebrile (36.2). Malnourished. Weight 28.7 Height 145cms BMI 14.2. Mild epigastric tenderness.
Due to refractory symptoms despite IV medication. Endoscopy was done and showed round and serpiginous ulcers in the lower third of the esophagus with yellowish exudate suggestive of infectious esophagitis Cytomegalovirus vs Herpes. Normal aspect of stomach and duodenum. Histopathology confirmed herpes simplex esophagitis.
Under the suspicion of infectious esophagitis HIV serology came negative, CMV antibodies IgM negative IgG positive. Normal immunoelectrophoresis. No previous herpes viral infection. The only risk factor identified for the patient was the malnutrition, nevertheless vitamins and proteins were normal.
With histological confirmation after 48 hours of the endoscopy she was started on Acyclovir IV 5mg/kg every 8 hours with significant improvement in the next 48 hours. Patient discharged in stable condition after re-starting oral intake and completing the oral acyclovir 400 mg every 8 hours for 10 days. Patient responded well was assessed 7 days after discharge, free of symptoms and a weight gain of 1.3 kg.
Infectious esophagitis needs to be considered in immunocompetent host. Odynophagia/dysphagia can be absent. Endoscopy findings alone isn't sufficient to make a definitive diagnosis.

References

Endoscopy and histopathology.

Introduction

Ozanimod (OZA), a sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P₁ and S1P₅, is approved in the European Union, United States, and other countries for the treatment of moderately to severely active ulcerative colitis (UC). Mucosal healing (MH), a key treatment goal for patients (pts) with UC, is associated with improved long-term pt outcomes.

Aims & Methods

The goal of this analysis was to determine the rate of early MH after treatment with OZA at Week (W) 10 using stringent MH criteria (mucosal endoscopy subscore [MES] = 0 plus histologic remission [Geboes score <2.0]) and to assess the relationship between achievement of stringent MH at W10 and clinical outcomes at W52. Outcomes were compared to pts achieving MH using a standard definition (MES ≤1 plus histologic remission). This analysis included pts from True North (NCT02435992) who achieved clinical response on once-daily oral OZA 0.92 mg at W10 and continued OZA during the 42-wk maintenance period. In this post hoc analysis, we examined MH, clinical remission, and corticosteroid (CS)–free remission at W52 in pts with stringent MH vs without stringent MH at W10 and with stringent MH vs with standard MH.

Results

Of the 230 pts who achieved clinical response on OZA at W10 and continued OZA during the maintenance period, 44 (19.1%) achieved MH using a standard definition and 13 (5.7%) achieved stringent MH at W10. Demographic and clinical characteristics were generally balanced between OZA-treated pts with stringent MH (n=13) and without stringent MH (n=217) at W10. Notably, there were fewer male pts with stringent MH vs without stringent MH, all pts with stringent MH had moderate disease (based on endoscopy), and more pts with stringent MH vs without stringent MH had left-sided UC disease. CS use at screening and prior tumor necrosis factor inhibitor (TNFi) use were lower in those with stringent MH vs without stringent MH. Similar differences in disease severity, extent of disease, and CS and TNFi use were seen in pts with stringent MH vs standard MH. At W52, more pts treated with OZA with stringent MH at W10 vs without stringent MH at W10 had clinical remission (53.8% vs 35.9%), CS-free remission (53.8% vs 30.4%), MH (61.5% vs 27.6%), endoscopic improvement (61.5% vs 44.7), and histologic remission (61.5% vs 31.8%). Except for endoscopic improvement, a slightly higher percentage of pts with stringent MH vs standard MH at W10 achieved clinical outcomes at W52 (Table).

Conclusion

While difficult to achieve, a small proportion of pts treated with OZA experienced stringent MH by W10. Compared with pts who achieved standard MH at W10, those with stringent MH at W10 demonstrated numerically better clinical outcomes at W52 on OZA treatment. Achieving stringent MH at W10 correlated with better clinical, endoscopic, and mucosal outcomes at W52.

Disclosure

The study was funded by Bristol Myers Squibb, Princeton, NJ, USA.
WR: speaker for 4SC, Abbott Laboratories, AbbVie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Medice, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, and Yakult; consulted for Abbott Laboratories, AbbVie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena, Astellas, AstraZeneca, Avaxia, Roland Berger GmbH, Bioclinica, Biogen IDEC, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celgene, Cellerix, Celltrion, Centocor, ChemoCentryx, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernst & Young, Falk Pharma GmbH, Ferring, Galapagos, Gatehouse Bio, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Intrinsic Imaging, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Landos, Lipid Therapeutics, LivaNova, Mallinckrodt, MedAhead, MedImmune, Millennium, Mitsubishi Tanabe Pharma, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Peri Consulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Quell Therapeutics, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres, Setpoint Medical, Sigmoid, Sublimity, Takeda, Teva, Therakos, Theravance, TiGenix, UCB, Vifor, Zealand, and Zyngenia; served as an advisory board member for 4SC, Abbott Laboratories, AbbVie, Aesca, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Biogen IDEC, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cellerix, Celltrion, Centocor, ChemoCentryx, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Mitsubishi Tanabe Pharma, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpoint Medical, Takeda, Therakos, TiGenix, UCB, Zealand, and Zyngenia; received research funding from Abbott Laboratories, AbbVie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnostik, Janssen, MSD, Sandoz, and Takeda.
AH: Consultant, advisory board member, or speaker for AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Falk, Ferring, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire, and Takeda. Global Steering Committee for Genentech.
CS: served as a speaker for AbbVie, Bristol Myers Squibb, Janssen, Pfizer, Takeda, and UCB.
RKC: consulted for AbbVie, Bristol Myers Squibb, Janssen, LabCorp, Pfizer, Samsung Bioepis, and Takeda.
HAA, AJ, HW, and MTO: employees and/or shareholders of Bristol Myers Squibb.
RL: consulted for Bristol Myers Squibb and Pfizer.
JA: received consulting fees from AbbVie, BioFire Diagnostics, Janssen, and Pfizer; received research grants from BioFire Diagnostics.

Introduction

Patients with gastric intestinal metaplasia (GIM) can be stratified into non-extensive and extensive GIM. In patients with extensive GIM surveillance is recommended based on a higher risk of neoplastic progression. The updated Sydney protocol is the most widely accepted biopsy system to identify extended GIM, and includes, besides biopsies of the corpus and antrum also biopsies of the incisura angularis (IA). However, data on the added value of additional biopsies of the IA in patients with premalignant gastric lesions is scarce. Our aim is to evaluate the yield and added value of the updated Sydney protocol in a low incidence gastric cancer region.

Aims & Methods

This prospective cohort study included patients with GIM who underwent follow-up endoscopies. Biopsies were taken according to the updated Sydney protocol.

Results

In total 177 patients with GIM were included. Median age was 62 (IQR 20) and 55.9% was male. During follow-up seven (4.0%) patients developed gastric neoplasia after a median follow-up of 37 months (IQR 38). At baseline 50 patients were classified as extensive GIM (28.2%), of which only one patient showed neoplastic progression. The other six patients that showed progression were classified as non-extensive GIM. At baseline, angular GIM was found in 97 (54.8%) patients of which six showed neoplastic progression; two patients had GIM in antrum and IA, two patients had GIM in IA and corpus, one patient had GIM in antrum, IA and corpus and in one patient there was GIM in the IA only.

Conclusion

In patients with gastric intestinal metaplasia angular GIM might be a better risk factor for neoplastic progression than the extension of GIM.

Introduction

Thiopurines (TP) (azathioprine AZA, and 6 mercaptopurine 6MP) are immunosuppressive drugs (IS) used in the treatment of chronic inflammatory bowel diseases (IBD), particularly Crohn's disease (CD). The aim of our work is to see if they still have an indication in monotherapy, in the era of biotherapies and small molecules.

Aims & Methods

This is a retrospective analytical study conducted at the Hepato-Gastroenterology and Proctology Department "Medicine B" from January 2012 to July 2022. 740 patients were followed for CD during this period. 407 patients were put on TP. Age, sex, different characteristics of CD, indication for and type of TP treatment, and course of treatment were collected from all patients. SPSS 20.0 software was used for statistical analysis. The khi-2 test was used to compare categorical variables. The binary logistic regression model was used for multivariate analysis.

Results

There were 375 patients followed up for CD on TP monotherapy (92.13%) and 32 on combination therapy (7.86%). The sex ratio was F/H=1.5. The average age was 39.8 years (15-72). The location was ileal in 69 patients (16.95%), colonic in 78 patients (19.16%), ileocolic in 257 patients (63.14%), 6 patients (1.47%) had upper gastrointestinal tract involvement of CD and 3 patients (0.73%) had anal CD. 99 patients (24.32%) had ano-perineal lesions (APL). The phenotype was stenosing in 47 cases (11.54%), fistulizing in 159 cases (39%), stenosing and fistulizing in 60 cases (14.74%) and inflammatory in 141 cases (34.64%). The type of TP used was AZA in 299 patients (73.46%) and 6MP in 108 patients (26.53%). TP was indicated as maintenance treatment in 270 cases (66.33%), as monotherapy in the absence of biotherapy (which was not available before 2016) in fistulizing forms in 105 cases (25.8%), and in case of cortico-dependency in 32 cases (7.86%).
Clinical remission was obtained with monotherapy in 326 cases (86.93%) and with combotherapy in 24 cases (75%), this difference is statistically non-significant p=0.08. Mucosal healing was noted with monotherapy in 124 cases (33%) in patients who performed a control endoscopy, and with combotherapy in 15 cases (46.87%), this difference is statistically not significant p=0.07.
CRP was negatived in monotherapy in 149 patients (39.73%) and in combination therapy in 27 patients (84.37%), this difference is statistically significant p<0.001. Fecal calprotectin was not always available. Among the patients who had it performed (65: 15.97%), it was negative in 18 cases (41.86%) in monotherapy and 3 cases (13.63%) in combination therapy. This difference is statistically significant p=0.015. Metabolite dosing was also rarely available. In cases where this was done (43 cases: 10.56%), 6-TGN was in the therapeutic range only in 14 cases (32.55%) and in 36 cases (83.72%) for 6-MMP, requiring therapeutic adjustment.
In multivariate analysis and adjusting for the different confounding parameters, it was found that only the combination therapy was a predictive factor for mucosal healing [OR=1.8; [0.8 - 3.9]; p=0.01].

Conclusion

The results of this study show that TPs still have a place in the therapeutic arsenal of CD, but that their combination with biotherapy allows more clinical and biological remission and especially mucosal healing.

Introduction

Intestinal ultrasound (IUS), in particular bowel wall thickness (BWT), is accurate in determining endoscopic disease activity in ulcerative colitis (UC). Reduction of BWT six weeks into advanced anti-inflammatory treatment predicted endoscopic response and clinical remission. Filgotinib is a preferential JAK1-inhibitor effective in UC. Currently, there is no data on IUS-kinetics or early prediction of treatment response with filgotinib.

Aims & Methods

In this study, we aimed to identify early IUS predictors of treatment response to filgotinib in patients with moderate to severe UC. This prospective observational study included UC patients with active endoscopic disease (i.e. endoscopic MAYO score (EMS) ≥2) starting with filgotinib. Clinical scores (UCEIS, Lichtiger), biochemical parameters and IUS parameters of the sigmoid were assessed at baseline, after 4 weeks (W4) and at the time of the second endoscopy (between W8 and W23). Endoscopic remission (i.e. EMS=0), endoscopic response (i.e. decrease in EMS ≥1 compared to baseline) and clinical remission (SCCAI ≤2 or Lichtiger score ≤3) were assessed. IUS response (i.e. defined as a reduction in BWT of >25% or >2.0 mm, or >1.0 mm and one colour Doppler signal) was assessed at week 4. All normally distributed data were reported in mean ± standard deviation [SD] and non-normally distributed in median and interquartile range [IQR]. Mann–Whitney U tests were used to compare continuous non-parametric variables, chi square tests for dichotomous variables.

Results

A total of 20 patients were included. 13 patients underwent second endoscopy, 2 refused a follow-up endoscopy and 5 patients were still in follow-up. At baseline, 9 patients (9/20, 45%) had received ≥2 biologicals, 16 patients (16/20, 80%) had previous anti-TNF exposure, and no patients were exposed to other JAK-inhibitors. 8 patients (8/20, 40%) had severe endoscopic disease at baseline (i.e. EMS=3). 5 patients (5/13, 38%) were endoscopic responders at W8-23, and no patient reached endoscopic remission. BWT was significantly lower in the sigmoid colon from W4 onwards for patients reaching endoscopic response (Table 1). Decrease in BWT compared to baseline was statistically greater in endoscopic responders from W4 onwards (Table 1). IUS response was seen at W4 in 6 patients, of which 5 were endoscopic responders (83%, p=0.002). Decrease in BWT from W4 onwards was statistically greater in patients reaching clinical remission at W8-23 (-45% (-55% to -36.6%) vs -9% (-25% to +8%), p=0.014).

Conclusion

On IUS, UC patients treated with filgotinib have significantly lower BWT from week 4 onwards compared to baseline, which could predict endoscopic response.

Disclosure

MP received speakers fees from Janssen and Tillotts
CT received speakers fees from Tillotts
FV received speaker or honoraria fees from AbbVie, Janssen and Tillotts
ML received consultancy/lecturefees from Abbvie, Bristol Myers Squibb , Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda and Tillotts.
RG Received speakers fee from Janssen and Tillotts
GD has served as a consultant and/or received speaker’s fees from AbbVie, Alimentiv, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion Healthcare, Cytoki Pharma, Eli Lilly, Ferring, Galapagos, Glaxo SmithKline, Gossamer Bio, Immunic, InDex Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Takeda, Tillotts, Ventyx Biosciences.
KG has received grants from Pfizer Inc, Celltrion and Galapagos; consultancy fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Immunic Therapeutics, Janssen Pharmaceuticals, Novartis, Pfizer Inc., Samsung Bioepis and Takeda and speaker’s honoraria from Abbvie, Celltrion, Ferring, Janssen Pharmaceuticals, Novartis, Pfizer Inc, Samsung Bioepis, Takeda and Tillotts.