Management of Paediatric Patients With Medically Refractory Crohn’s Disease Using Ustekinumab: A Multi-Centred Cohort Study
Mallory ChavannesChristine Martinez‐VinsonLara HartNicole KanikiChe‐Yung ChaoSally LawrenceKevan JacobsonJean‐Pierre HugotJérôme VialaColette DeslandresPrévost JantchouErnest G. Seidman
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Ustekinumab [UST] is effective in the treatment of adults with moderate to severe Crohn's disease [CD]. There is a paucity of data on its use in children.To evaluate the response to UST in children with moderate to severe CD.This multicentre retrospective cohort study identified children under 18 years old with CD, who received open-labelled subcutaneous UST. The primary outcome was changes in mean abbreviated Paediatric Crohn's Disease Activity Index [aPCDAI] between baseline and 3 and 12 months, and rate of clinical remission at 3 and 12 months. Secondary outcomes were clinical response at the same time points, changes in C-reactive protein [CRP] and albumin, improvement in growth parameters, and rate of adverse events.A total of 44 patients who failed at least one biological treatment were identified. Linear mixed model [LMM] analysis revealed a statistically significant effect of UST (χ2[1] = 42.7, p = 1.2 × 10-8) which lowered the aPCDAI scores by about 16 ± 2.7 at 3 months, and 19.6 ± 2.9 at 12 months. At 12 months, 38.6% of the patients achieved clinical remission and 47.8% achieved clinical response. There was a significant increase in mean weight z-score of 0.48 [±0.13] [p <0.001] and in mean body mass index [BMI] z score of 0.66 [±0.16] [p <0.001]. The probability of remaining on UST at 12 months was 76.9%. The rate of adverse events was 12.4 per 1000 patient-months.Subcutaneous UST should be considered a viable therapeutic option for paediatric patients who are refractory to other biological agents. Prospective randomised trials are needed.Keywords:
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Ustekinumab concentrations at week 4 and beyond have been associated with treatment outcomes in patients with Crohn’s disease. However, the exposure-response relationship during the first 2 weeks of treatment is unclear. We summarize the @GIJournal discussion held on November 10, 2021, during which we discussed the article by Hanžel et al. entitled “Peak concentrations of ustekinumab after intravenous induction therapy identify patients with Crohn's disease likely to achieve endoscopic and biochemical remission”. Key findings were critically reviewed by our experts E. V. Loftus, Jr., and A. Charabaty, and the session was moderated by S. Mahmood.
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Patients with moderate to severe Crohn’s disease refractory or intolerant to steroids, immunomodulators and anti-TNF therapy currently have few options for medical management outside of clinical trials. Ustekinumab, a monoclonal antibody, which inhibits interleukins 12 and 23 is currently being used safely and effectively to treat patients with psoriasis and recent studies suggest that it may be of value in treating moderate to severe Crohn’s disease in patients both naive and refractory to anti-TNF therapy. Currently the intravenous formulation of ustekinumab used in these studies is unavailable for use outside of clinical trials. The aim of this study was to examine the clinical efficacy of subcutaneously (sc) loaded ustekinumab in patients with moderate to severe Crohn’s disease who had failed at least one anti-TNF agent. All patients given a loading dose of ustekinumab 270 mg sc over two weeks were included in this retrospective analysis. Baseline demographic data was collected. The primary outcome was the proportion of patients who achieved a Harvey-Bradshaw Index (HBI)
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Ustekinumab
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Ustekinumab
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Ustekinumab is a fully human monoclonal IgGk antibody that blocks the p40 subunit shared by IL-12/23, inhibiting its binding to the receptor in T, NK and CPA cells 1. Multiple clinical trials have proved its efficacy in the treatment of psoriasis and for the induction and maintenance of remission in anti-TNF resistant Crohn's disease.1,2 Its effectiveness and experience in Latin American patients is nonexistent. In this study we report the experience of 3 centers that treated patients with moderate to severe anti-TNF-resistant Crohn's disease. Open, retrospective, observational study. Clinical response was evaluated by CDAI score at 3, 6, 12 months, and until last meeting, in addition to CRP levels. Seven patients were included in the study, 4 females and 3 males, mean age 49 ± 15, 4 patients had perianal involvement. The initial clinical response was reached at 3 months in 71.4% of patients (CDAI <150). At 6 months, 80% of patients with initial response maintained their response. At 12 months of follow-up, 60% of responders held initial response, in one of them treatment was suspended because of multiple episodes of sinusitis. At the time of the latest follow-up (10 ± 2.3 months) 57% of patients were in remission and 85% were able to discontinue steroids. In this cohort of Mexican patients with moderate to severe Crohn's disease resistant to anti-TNF, initial response was observed in 71.4% of patients. This response was maintained in most patients at 6 months. At 12 months 60% of the initial responders maintained their response. Ustekinumab is a therapeutic option in this group of patients highly difficult to control.
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Although anti-tumour necrosis factor (TNF) agents have caused a paradigm shift in the management of moderate-to-severe Crohn's, they are sometimes associated with diminished or absent response in a considerable proportion of patients. Hence agents targeting pathways other than TNF are needed. Ustekinumab is a monoclonal antibody directed against the p40 subunit of IL-12 and 23.This manuscript summarises the available evidence on the efficacy and safety of Ustekinumab in Crohn's disease through data available from randomised controlled trials and compassionate use programs across the world.Current literature strongly supports the fact that ustekinumab is clinically efficacious and reasonably safe for induction and maintenance of remission in moderate-to-severe Crohn's disease.
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Ustekinumab is a monoclonal antibody targeting interleukins 12 and 23. Its effectiveness in clinical practice has not yet been demonstrated. The aim of this study was to assess the real-world, short-term effectiveness of ustekinumab in medically refractory Crohn’s disease (CD) (CROHNUSK study). Multi-centre study of CD patients receiving ustekinumab after June 2017 (when it was approved in Spain) and at the recommend dose (a single iv infusion of 6 mg/kg followed by a sc injection of 90 mg at Week 8). The Harvey‐Bradshaw Index (HBI) was used to evaluate clinical remission (HBI score ≤4). Values for HBI, C-reactive protein (CRP), and faecal calprotectin (FC) were recorded at baseline and at Weeks 8 and 14. Demographic and clinical data, endoscopy at baseline when available, previous treatments, adverse events (AEs), and hospitalisations were documented. Possible predictors of clinical remission were examined. A total of 305 CD patients were analysed (Table 1). Characteristics of study population At baseline, 217 (72%) had an HBI score of >4 points. Of these, 101 (47%) and 126 (58%) achieved clinical remission at Weeks 8 and 14, respectively. Of the 109 patients who were on corticosteroids at baseline, 52 (48%) were in corticosteroid-free remission at Week 14. FC levels returned to normal (<250 µg/g) in 66 (22%) and 74 (24%) patients at Weeks 8 and 14, respectively. CRP returned to normal levels (<3 mg/l) in 122 (40%) and 106 (35%) patients at Week 8 and 14, respectively. HBI, FC, and CRP values over time are shown in Figure 1. HBI, FC, and CRP values over time. AEs were recorded in 12% of patients. A total of 40 patients (13%) were hospitalised, in 7 cases owing to AEs. Intolerance to the most recent anti-TNF agent and fewer previous anti-TNF agents were associated with clinical remission at Week 14. Endoscopic severity, but not previous vedolizumab treatment, was associated with poor response. This is the first study to show the real-world safety and effectiveness of ustekinumab in a large cohort of highly refractory CD patients.
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