One-year Outcomes With Ustekinumab Therapy in Infliximab-refractory Paediatric Ulcerative Colitis

A Multicentre Prospective Study

Jasbir Dhaliwal; Hayley E. McKay; Colette Deslandres; Jennifer Debruyn; Eytan Wine; Ashley Wu; Hien Huynh; Nicholas Carman; Eileen Crowley; Peter C. Church; Thomas D. Walters; Amanda Ricciuto; Anne M. Griffiths

Disclosures

Aliment Pharmacol Ther. 2021;53(12):1300-1308. 

In This Article

Methods

Setting and Participants

CIDsCANN involves 12 academic paediatric IBD centres across Canada. As part of an ongoing inception cohort study, children and adolescents aged 2–17 years with new-onset IBD, are prospectively enrolled and followed until the transition to adult services. As previously described[1] patients are systematically evaluated; comprehensive baseline phenotypic and longitudinal disease activity assessments, laboratory parameters and treatments are collected prospectively at ad hoc and routine 6 monthly periodic review visits using standardised Case Report Forms (CRFs). The anonymised CRF's are entered into a central database registry (Research Electronic Data Capture [REDCap] database), hosted at SickKids Hospital, Toronto, Canada. Clinical site directors, all paediatric gastroenterologists with a clinical focus in inflammatory bowel disease (IBD), are responsible for approving diagnostic labels of IBD type using conventional clinical, endoscopic and histologic criteria. Disease phenotype is categorised according to the Paris phenotypic classification, with the extent of UC based on macroscopic findings observed via colonoscopy.[8] Baseline disease activity is assessed using paediatric ulcerative colitis activity index (PUCAI).[9] Endoscopic findings are documented locally using Mayo endoscopic score for UC.[10] Training in the application of endoscopic measures was repeatedly provided at Network investigator meetings.

Study Design

This was an open-label prospective study within CIDsCANN. Eligible children were those with UC, who were treated prior to November 30, 2019 with intravenous ustekinumab following the failure of prior infliximab. Patients were followed longitudinally while continuing ustekinumab subcutaneous maintenance therapy or until colectomy or switch to another biologic or JANUS kinase (JAK) inhibitor regimen. Data were extracted until December 31, 2020; initiation of ustekinumab 1 year earlier was required in order to ensure a minimum of 12-month follow-up for those continuing to receive the drug. For patients stopping ustekinumab, the date of the last dose was considered as the date of discontinuation. Disease activity and medication utilisation, including details concerning corticosteroid dosage reduction and discontinuation, were prospectively recorded at both ad hoc and routine 6 monthly periodic review visits, using standardised forms. Ustekinumab levels were measured by enzyme-linked immunosorbent assay (ELISA) prior to subcutaneous injections, as made available by Janssen Canada through Gamma Dynacare labs as part of clinical care from week 20 onwards. The lower limit of detection of serum ustekinumab level by this assay was 0.07 μg/mL.

Outcome Assessment

The primary outcome analysed on intent-to-treat basis was steroid-free clinical remission, defined as PUCAI <10 and no corticosteroids for ≥4 weeks, on continued ustekinumab therapy with an intact colon at 52 weeks. Secondary outcomes included steroid-free clinical remission at 26 weeks, and sustained steroid-free clinical remission, defined additionally by no corticosteroid usage during the 6 months between weeks 26 and 52. Other outcomes included endoscopic improvement defined as rectosigmoid Mayo score of ≤1 in those with pre-ustekinumab score of ≤2, biomarker remission defined as faecal calprotectin (FCP) <250 μg/g, and colectomy rate at 1 year. FCP <250 μg/g was accepted as evidence of endoscopic improvement among patients in steroid-free clinical remission, but lacking a reassessment colonoscopy. Patients were stratified by prior biologic exposure comparing those with only prior anti-TNF therapy failure (one class) vs those with prior failure also of vedolizumab (anti-integrin therapy) (two classes). Adverse events were recorded.

Statistical Analysis

Normally distributed continuous variables were described as means and standard deviations (±SD), and non-normally distributed continuous variables as medians and interquartile ranges (IQR). Categorical variables were expressed as frequency and proportions. Categorical variables were compared with the Pearson chi-squared test or Fisher Exact test, where expected cell counts were less than five. Continuous variables were compared using Mann–Whitney test. We undertook survival analysis to assess the likelihood of continuing ustekinumab by end of the follow-up period. We performed multivariable logistic regression analysis to determine the adjusted odds ratio (95% confidence interval) of week 52 remission with prior failure of one vs two biologic classes, adjusted a priori for age and sex. Statistical significance was defined as two-tailed P < 0.05. Analyses were performed using IBM SPSS Statistics Version 24; IBM Corp.

Ethical Considerations

The study protocol was approved by the Research Ethics Boards of each participating institution. Children and their parents or legal guardian provided informed assent and consent for enrolment.

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