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

Very early onset inflammatory bowel disease (VEO-IBD) is often associated with a severe disease course and unique characteristics including an underlying monogenic defect. In this study, we identified new pathogenic mutations in CGNL1 associated with VEO-IBD and other inflammatory GI disease. CGNL1 (Cingulin Like 1) encodes an epithelial junctional protein whose function was previously unknown in the gastrointestinal tract.

Aims & Methods

Whole exome sequencing (WES) was performed on the affected patient with VEO-IBD and all first-degree relatives with IBD and other inflammatory disease. Intestinal epithelial organoids (IEOs) were generated from the affected patient and were characterized by transepithelial electrical resistance (TEER), FITC-dextran permeability assay on epithelial cell monolayer, immunostaining, RNA sequencing, and transmission electron microscopy (TEM). In addition, we generated a new Cgnl1^-/- mouse model, which was characterized using FITC-dextran permeability assay, TEM, dextran-sodium sulfate (DSS)-induced colitis, and infections by Citrobacter rodentium and Clostridioides difficile. Single-cell datasets were analyzed to determine CGNL1 expression in IBD, primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH).

Results

In the affected patient with VEO-IBD who required early total colectomy and pouch formation with coexistent PSC and celiac disease, WES identified two rare, new, pathogenic variants in the CGNL1 gene. Both pathogenic variants were also present in the patient’s younger sister, who has a similar history including early-onset, fulminant ulcerative colitis requiring total colectomy with ileostomy and PSC-AIH overlap syndrome. Furthermore, multiple relatives of the patient suffer from IBD and other inflammatory conditions including celiac disease, eosinophilic esophagitis, and type-1 diabetes. The RNA and protein levels of CGNL1 were significantly diminished in the patient’s intestinal epithelial cells compared to that of healthy individuals and other IBD patients by RNA-seq, immunoblotting, and immunostaining. The patient’s IEOs from pouch body and pre-pouch ileum formed smaller 3D spheroids with altered cell composition and significantly impaired barrier function compared to those from healthy controls and other IBD patients. Immunofluorescence and TEM demonstrated that CGNL1 is required for the assembly of junctional complexes in human IEOs and an epithelial cell line. Similarly to findings from the patient, impaired junctional complexes in intestinal epithelial cells and elevated intestinal permeability were present in Cgnl1^-/- mice at steady state. Cgnl1^-/- mice showed substantial vulnerability to DSS-induced colitis and bacterial infections that directly compromise the epithelial barrier. In addition, 6-month-old Cgnl1^-/- mice exhibited spontaneous inflammation in the colon and terminal ileum due to disrupted intestinal barrier, which was microbiome-dependent. Furthermore, single-cell analysis revealed diminished expression of CGNL1 in the intestinal and hepatic epithelial cells from patients with IBD or PSC/AIH, respectively.

Conclusion

The pathogenic CGNL1 variants contribute to VEO-IBD by disrupting gut barrier integrity, as demonstrated by patient’s cells and novel murine models. This study expands our understanding of epithelial barrier impairment in the pathogenesis of VEO-IBD, and highlights intestinal epithelium as a therapeutic target in some IBD patients.