Introduction

​Intestinal fibrosis and strictures is one of the most challenging complications in patients with Crohn’s disease (CD). There is an urgent medical need for non-invasive serological biomarkers for intestinal fibrosis, as magnetic resonance enterography (MRE) is not a feasible tool for repeated monitoring. Here we wanted to investigate the role of the minor collagens; fibrillar type XI collagen and the Fibril-Associated Collagens with Interrupted Triple Helices (FACIT) type XVI collagen in relation to intestinal fibrosis. Therefore, we quantified the biomarkers PRO-C11 (formation of type XI collagen) and PRO-C16 (formation of type XVI collagen) in serum from pediatric CD (pCD).

Aims & Methods

We enrolled children with CD who underwent MRE in the ImageKids study. (ImageKids study: NCT01881490). Serum samples were collected at enrolment (n=203), and from healthy age- and gender-matched healthy subjects (HS) (n=82). The Nordic PFA biomarkers of tissue fibrosis PRO-C11 and PRO-C16 were measured. Intestinal fibrosis and stenosis were determined by MRE, and VAS score was applied to assess severity of intestinal fibrosis. Pearson-r correlation, students t-test and one-way-ANOVA with false discovery rate correction were applied for statistical analysis.

Results

The sample size of the different groups were as follows, no fibrosis [n=138]: VAS=0, mild fibrosis [n=55]: VAS=1-44, moderate/severe [n=17]: VAS>44). PRO-C11 (r=0.20, p=0.01) and PRO-C16 (r=0.20, p=0.01) correlated with the MRE VAS score. Both PRO-C11 (with fibrosis: median 26.4 ng/mL [IQR: 13.25-39.53 ng/mL]) and without fibrosis: median 20.6 ng/mL IQR 11.3-28.8 ng/mL) and PRO-C16 (with fibrosis: median 2990 ng/mL IQR: 2093-3884 ng/mL, and without fibrosis: median 2548 ng/mL [IQR: 1579-3286 ng/mL]) were significantly elevated in those with fibrosis compared to without fibrosis MRE-confirmed stenosis[AG1] [JHM2] (p<0.01). Serum PRO-C11 levels were significantly elevated in patients with moderate/severe intestinal fibrosis (median 32.2 ng/mL [IQR: 19.5-46.7 ng/mL]) as judged by VAS compared to patients with mild intestinal fibrosis (p<0.05, median 28.8 ng/mL [IQR: 12.6-37.3 ng/mL]), with no intestinal fibrosis (p<0.01) and HS (p<0.0001, median 8.3 ng/mL [IQR: 7.0-12.5 ng/mL]). PRO-C16 was significantly elevated in patients with moderate/severe intestinal fibrosis (median 3567 ng/mL [IQR: 2287-4608 ng/mL]) compared to patients with mild intestinal fibrosis (p<0.05, (median 2791 ng/mL [IQR: 1970-3670 ng/mL]), with no intestinal fibrosis (p<0.001, (median 2548 ng/mL [IQR: 1579-3286 ng/mL]) and HS (p<0.0001, (median 1456 ng/mL [IQR: 1072-1804 ng/mL]).

Conclusion

Based on these biomarker data from the ImageKids study, PRO-C11 and PRO-C16 demonstrate potential as important non-invasive biomarkers reflecting intestinal fibrosis and stenosis.

Disclosure

Full time employee at Nordic Bioscience A/S

Introduction

Ustekinumab (UST), a monoclonal antibody targeting the p40 subunit of interleukins IL-12 and IL-23, has been approved by the European Medicines Agency for the treatment of ulcerative colitis (UC) in 2019. Although clinical effectiveness and safety of UST in UC have been shown in clinical trials, long-term real-world data are limited, especially beyond one year of follow-up.

Aims & Methods

We collected data from the IBDREAM registry¹, a telemedicine platform for IBD patients, and the Initiative on Crohn and Colitis (ICC) registry². Both Dutch multicentre registries collect prospective observational data from IBD patients. Adult patients with UC who received at least one intravenous and two subcutaneous doses of UST with no prior history of colectomy were included. The two primary outcomes were corticosteroid-free clinical remission, defined as Simple Clinical Colitis Activity Index (SCCAI) ≤ 2, and corticosteroid-free biochemical remission, as defined by fecal calprotectin ≤ 250µg/g, at week 52 and week 104. Furthermore, data on effectiveness up to week 156, drug persistence rate, dose escalations, concomitant medication use and adverse events were collected.

Results

A total of 127 patients were included, 53 (41.7%) of which were female. Median age at baseline was 49 (IQR: 26). Seven patients (5.5%) had not previously been treated with at least one biological and/or small molecule agent, while 35.4%, 30.7%, and 28.3% of patients had previously been treated with one, two or at least three different advanced therapies, respectively. Effectiveness results are summarised in Table 1. At week 52 and week 104, 39.4% and 39.2% of patients were in corticosteroid-free clinical remission and 36.8% and 33.9% of patients were in corticosteroid-free biochemical remission, respectively. At these timepoints, 39.2% and 37.1% of patients who had clinically active disease at baseline (n=75) achieved corticosteroid-free clinical remission. In the subgroup of patients with biochemically active disease at baseline (n=56), 47.2% and 40.6% achieved corticosteroid-free biochemical remission. Similar rates were observed at week 156, although less patients reached this follow-up time. Drug persistence rate was 77.2% after one year, and 65.6% after two years. A total of 39 patients discontinued UST before completing two years of follow-up; 27 of these patients stopped during the first year. Seventeen patients discontinued UST because of primary non-response, sixteen due to secondary loss of response and nine because of other reasons (including colorectal carcinoma (n=1), sustained remission and side effects). Sixty-two adverse drug reactions were recorded in 36 patients and eight patients required hospitalisation during follow-up.

Conclusion

In this real-world study, over one third of patients with UC were in corticosteroid-free clinical and/or biochemical remission two years after starting UST. The medication was relatively effective, despite the partly treatment-refractory study population. UST was well-tolerated and no new safety signals were identified. The study results indicate that UST is an effective and safe long-term therapy for patients with UC.

References

1. de Jong ME, Smits LJT, van Ruijven B, den Broeder N, Russel M, Romkens TEH, et al. Increased Discontinuation Rates of Anti-TNF Therapy in Elderly Inflammatory Bowel Disease Patients. J Crohns Colitis. 2020;14(7):888-95.
2. Biemans VBC, van der Meulen-de Jong AE, van der Woude CJ, Lowenberg M, Dijkstra G, Oldenburg B, et al. Ustekinumab for Crohn's Disease: Results of the ICC Registry, a Nationwide Prospective Observational Cohort Study. J Crohns Colitis. 2020;14(1):33-45.

Disclosure

RW served as a speaker and/or an advisory board member for Ferring, Galapagos, Janssen and Pfizer; ACdV served as an advisory board member for AbbVie, Bristol Meyers Squibb, Janssen and Takeda; AEvdM served as a speaker and/or an advisory board member for AbbVie, Dear Health, Ferring, Galapagos, Janssen, Takeda, Tramedico, and Vedanta, and has received research grants from Cablon, Galapagos, Nestle, Norgine, and ZonMW; ML served as a speaker and/or principal investigator for Abbvie, Celgene, Covidien, Dr. Falk, Ferring, Gilead, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, Protagonist therapeutics, Receptos, Takeda, Tillotts, Tramedico; and has received research grants from AbbVie, Merck Sharp & Dohme, Achmea healthcare and ZonMw; FvS served as an advisory board member for Galapagos and Takeda; SvdM served as an advisory board member for AbbVie, Janssen and Pfizer; MP served as a speaker for Bristol Meyers Squibb, Janssen-Cilag and Takeda, has received non-restricted research grants from AbbVie, Galapagos, Horizon 2020, Johnson and Johnson, Maag Lever Darm Stichting, Takeda and ZonMw, and non-financial support from Immunodiagnostics; ZM served as a speaker and/or adviser for Abbvie, Galapagos, Johnson and Johnson, Lilly and Pfizer, and has received grants from Galapagos, Maag Lever Darm Stichting, Niels Stensen Fellowship and ZonMw; TER served as a speaker and/or an advisory board member for Abbvie, Bristol Meyers Squibb and Janssen
MD served as a speaker and/or an advisory board member for AbbVie, Bristol Meyers Squibb, Celltrion, Galapagos, Janssen and Takeda, and has received grants/research support from Bristol Meyers Squibb, Galapagos Janssen and Pfizer.

Introduction

Anti-tumor necrosis factor (TNF)-α are the first target therapies approved for the treatment of steroid-dependent or -refractory ulcerative colitis (UC). Drugs with different mechanisms of action have recently entered the market, but data on the optimal management of UC after failure of first-line anti-TNF-α are lacking.

Aims & Methods

The PODIUM study is a multicentre, retrospective, observational study that aims to compare the real-life effectiveness and safety of second-line vedolizumab (VDZ), ustekinumab (UST) and tofacitinib (TOF) in patients with UC. Consecutive patients with UC who had failed at least one anti-TNF-α and were never exposed to other target therapies were enrolled from 12 centres across Europe. Sociodemographic data, data on clinical activity and adverse events of interest (AEIs, defined as AE requiring temporary/permanent drug discontinuation or medical intervention) were retrospectively extracted from medical records, from the initiation of second-line therapy until one year of observation/drug discontinuation/last available follow-up. The primary outcome was the cumulative probability of achieving steroid-free clinical remission (SFCR), defined as stool frequency=0-1 and rectal bleeding=0 and no concomitant steroids, over the first year of treatment; inverse probability of treatment weighting (IPTW), calculated as the inverse of the probability of receiving each drug (IPTW=1/Propensity Score), was applied to the primary outcome to account for imbalances in cohorts’ characteristics. We performed an interim analysis including all data collected up to March 15^th 2024; data collection is still ongoing at the submission of this Abstract.

Results

Data on 303 patients (172 VDZ, 63 UST, 68 TOF) were included in the analysis. The main baseline characteristics are presented in Table 1. After IPTW, the cumulative probability of achieving SFCR during the first year was 51.0%, 59.1% and 64.1% for VDZ, UST and TOF, respectively; both UST and TOF were superior to VDZ at Log-rank test (p<0.001), with no differences between the two. At weighted logistic regression, female sex (adjusted Odds Ratio, aOR, 0.06, Confidence Interval, CI, 95% 0.41-0.73, p<0.001) and higher Charlosn Comorbidity Index calculated without considering age (aOR 0.73, 95% CI 95% 0.60-0.88, p=0.001) were independently associated with a lower probability of achieving SFCR during the first year. Recorded AEIs were 16 (4 infections) in the VDZ group (9.3% of VDZ-treated patients), 6 (1 infection) in the UST group (9.5% of UST-treated patients), and 15 (5 infections, including 1 Zoster reactivation) in the TOF group (22.1% of TOF-treated patients).
Table 1

Conclusion

This preliminary analysis suggests that both UST and TOF might have superior effectiveness, compared to VDZ, as second-line agents in patients with UC after anti-TNF-α. Confirmatory analysis with a larger sample size will be performed. A slightly higher rate of AEIs was observed in the TOF group.

Disclosure

Giuseppe Privitera received consultancy fees from Alphasigma and Janssen. Cristina Bezzio received lecture fees and served as a consultant for Takeda, MSD, Ferring, Abbvie, Galapagos and Janssen. Edoardo Vincenzo Savarino has served as speaker for Abbvie, Agave, AGPharma, Alfasigma, Aurora Pharma, CaDiGroup, Celltrion, Dr. Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, MayolyBiohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, and Unifarco; has served as a consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, DiademaFarmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas GmbH, Takeda, and Unifarco; he has received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, Zeta Farmaceutici. Daniela Pugliese received speaker fees and/or advisory board from AbbVie, Galapagos, MSD, Takeda and Janssen, Pfizer. Iago Rodriguez-Lago has received financial support for traveling and educational activities from or has served as an advisory board member for Abbvie, Adacyte, Celltrion, Chiesi, Danone, Ferring, Faes Farma, Janssen, Galapagos, MSD, Pfizer, Roche, Takeda, and Tillotts Pharma. Financial support for research: Tillotts Pharma. Manuel Barreiro-de Acosta has served as a speaker, consultant and advisory member for and has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Gilead, Celgene, Pfizer, Sandoz, Biogen, Fresenius, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte and Vifor Pharma. Sara Onali has received speaker fees from AbbVie, Takeda, Janssen, Amgen, Galapagos and Norgine. Massimo Claudio Fantini has received speaker and consultancy fees from AbbVie, Takeda, Janssen-Cilag, Pfizer, Sandoz, Biogen, Galapagos, Bristol-Myers Squibb, and MSD; and research grants from Pfizer and Janssen-Cilag. Karmiris K has served as speaker, consultant, and advisory member for Abbvie, Amgen, Enorasis, Ferring, Galenica, Genesis, Janssen, MSD, Pfizer, Takeda and Vianex. Henit Yanai has received consulting fees Abbvie, Ferring, Janssen, Neopharm Ltd., Pfizer, Takeda; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Abbvie, Janssen, Pfizer, Takeda, Neopharm Ltd.; Participation on a Data Safety Monitoring Board or Advisory Board Abbvie, Neopharm Ltd., Pfizer, Takeda. Ana Gutierrez has served as speaker, consultant and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Tillotts Pharma, Chiesi and Otsuka Pharmaceutical. Luca Pastorelli has received consultant and/or speaker fees from Giuliani, Ferring, Janssen, Takeda. María Chaparro has served as a speaker and consultant for and has received research or education funding from MSD, AbbVie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Biogen, Gilead and Lilly. Yamile Zabana has received speaker and/or consultant fees from AbbVie, Adacyte, Almirall, Amgen, Dr Falk Pharma, FAES Pharma, Ferring, Janssen, MSD, Otsuka, Pfizer, Shire, Takeda, Galapagos, Boehringer Ingelheim and Tillots. Alessandro Armuzzi: consulting and/or advisory board fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda; lecture and/or speaker bureau fees from AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mitsubishi-Tanabe, Novartis, Pfizer, Roche, Sandoz, Samsung Bioepis, Takeda; and research grants from MSD, Pfizer, Takeda and Biogen. The remaining authors declare no competing interests. The remaining Authors declare no competing interests.