Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study

Abstract

Background Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn’s disease (CD) patients in real-world clinical practice. Methods A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. Results A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). Conclusions Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice.

Real-World Evidence of the Effectiveness and Safety of Ustekinumab for the Treatment of Crohn’s Disease: Systematic Review and Meta-Analysis of Observational Studies

“…Predictors of response were reported in 37 studies (59%). The most frequent predictors of poor clinical response were previous biologic exposure (anti-TNF and/or vedolizumab) [ 26 , 39 , 40 , 44 , 47 , 51 , 65 , 72 , 74 ], stricturing disease [ 19 , 20 , 39 , 44 , 65 ], penetrating disease [ 27 , 39 , 44 , 51 , 65 ], and high Harvey-Bradshaw index (HBI) at first dose [ 19 , 20 , 51 , 72 , 73 , 75 ]. Concomitant corticosteroids, extraintestinal manifestations, male sex, old age, smoking, and low body mass index were also reported in some studies.…”

Using Interpretable Machine Learning to Identify Baseline Predictive Factors of Remission and Drug Durability in Crohn’s Disease Patients on Ustekinumab

“…In retrospective non-randomized data such as this cohort [ 4 , 9 , 10 , 11 , 12 ], prior treatment history correlates with disease severity and/or frailty which can therefore act as an unobserved confounder that would explain this finding. Nevertheless, disease severity at onset was controlled for using multivariable analysis involving disease characteristics, baseline HBI values, and laboratory tests, so the fact that this effect persists is conducive to the generation of a hypothesis that earlier positioning of UST in the treatment pathway might be beneficial for patients.…”

“…The conventional analysis of this same cohort [ 4 ] found three factors associated with ustekinumab drug durability; previous abdominal surgery and concomitant steroid use correlated with drug discontinuation, whereas a maintenance schedule with ustekinumab every 8 or 12 week correlated with drug durability. The differences between the two analyses, conventional multivariate analysis vs. interpretable machine learning, highlight how this novel tool can aid in data-driven discovery of non-linear effects between each predictor and the analyzed outcome.…”

“…The SUSTAIN study [ 4 ] is a retrospective multicenter study comprising 463 patients on ustekinumab (UST) with active CD (Harvey-Bradshaw Index (HBI) > 4). The HBI index was recorded by gastroenterologists in the follow-up of patients.…”

“…Real-world data from electronic medical records and claims data often come with very large sample sizes but are also constrained by data quality issues. In contrast, observational studies such as SUSTAIN [ 4 ] benefit from high-quality data capture and a pragmatic view of clinical practice. The objective of the current study was to determine whether baseline patient characteristics, including prior treatment history, are predictive of remission and drug durability after controlling for disease severity at baseline.…”