One-year outcomes with ustekinumab therapy in infliximab-refractory paediatric ulcerative colitis: a multicentre
Jasbir Dhaliwal1,2,3, Hayley E McKay1, Colette Deslandres4
1Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics and IBD Centre, SickKids Hospital, University of Toronto, Toronto, ON, Canada.
Insights
Ustekinumab effectively treated paediatric ulcerative colitis (UC) in children who failed other biologics. Treatment success was not linked to drug levels, indicating efficacy even with prior treatment failures.
Area of Science:
- Pediatric Gastroenterology
- Immunology
- Pharmacology
Background:
- Adult ulcerative colitis (UC) shows efficacy with ustekinumab (anti-interleukin 12/23) post-biologic failure.
- Limited data exists on ustekinumab's use in pediatric UC patients.
Purpose of the Study:
- To prospectively evaluate the efficacy and serum concentrations of ustekinumab in children with UC.
- To assess ustekinumab's effectiveness in pediatric UC refractory to other biologic therapies.
Main Methods:
- Children with anti-TNF refractory UC received intravenous ustekinumab.
- Primary endpoint: steroid-free clinical remission at 52 weeks (Paediatric Ulcerative Colitis Activity Index <10).
- Ustekinumab serum levels and endoscopic improvement were monitored.
Main Results:
- 44% of pediatric UC patients achieved steroid-free remission at 52 weeks.
- Higher remission rates were observed in patients who failed only anti-TNF therapy compared to those who failed vedolizumab as well.
- No adverse events were reported, and treatment failure was not due to inadequate drug exposure.
Conclusions:
- Ustekinumab is effective in pediatric patients with treatment-refractory ulcerative colitis.
- Efficacy is demonstrated even after failure of multiple prior biologic therapies.
- Adequate drug exposure is likely achieved, as treatment failure was not associated with lower drug levels.
Background:
The phase 3 (UNIFI) trial of ustekinumab (anti-interleukin 12/23) demonstrated efficacy even after prior biologic failure in adult ulcerative colitis (UC), but paediatric data are lacking.
Aim:
To prospectively monitor efficacy and serum concentrations of ustekinumab given to children with UC refractory to other biologics.
Methods:
Children with anti-TNF refractory UC initiating ustekinumab intravenously at sites of the Canadian Children IBD Network prior to 12/2019 are included. The primary endpoint was steroid-free clinical remission with subcutaneous ustekinumab at 52 weeks (Paediatric Ulcerative Colitis Activity Index <10, no steroids ≥4 weeks). Ustekinumab levels were measured after week 20. Endoscopic improvement was defined as Mayo endoscopic subscore ≤1, or faecal calprotectin (FCP) <250 μg/g if not re-colonoscoped.
Results:
At six sites between 01/2018 and 11/2019, 25 children (median [IQR] age 14.8 years [12.3-16.2], 72% female) with UC duration 2.3 years (1.1-4.2) received intravenous ustekinumab (median dose/kg of 6.4 [5.5-7.5] mg). All patients had failed prior infliximab therapy, and 12 (48%) also vedolizumab. Five patients discontinued ustekinumab after IV induction (four undergoing colectomy). On intent to treat basis, 44% achieved the primary endpoint of steroid-free remission at week 52, including nine (69%) of 13 who previously treated with anti-TNF only vs two (17%) of 12 who previously failed also by vedolizumab (P = 0.008). Seven of 11 remitters met the criteria for endoscopic improvement. The median (IQR) trough levels (μg/mL) were greater with q4 vs q8 weekly dosing (8.7 [4.6-9.9] vs 3.8 [12.7-4.8]) P = 0.02, but greater exposure was not associated with a superior rate of clinical remission. No adverse events were associated with therapy.
Conclusion:
Ustekinumab demonstrated efficacy in this paediatric cohort with otherwise treatment-refractory UC. Treatment failure was not due to inadequate drug exposure.
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