Relationship Between Serum Ustekinumab Trough Concentration and Clinical and Biochemical Disease Activity: A Real-World Study in Adult Patients with Crohn's Disease.

BACKGROUND AND OBJECTIVES: The role of therapeutic drug monitoring for ustekinumab in the treatment of Crohn's disease has not been defined. This study aimed to explore the relationship of serum ustekinumab trough concentration (UTC) with clinical and biochemical disease outcomes in a real-world setting. METHODS: We performed a retrospective analysis of Crohn's disease patients treated at a single tertiary centre. Ustekinumab was given as a single intravenous induction dose, followed by maintenance subcutaneous injections every 4 to 8 weeks. Rates of clinical remission (Harvey-Bradshaw Index ≤ 4), biochemical remission (C-reactive protein < 5 mg/l and faecal calprotectin < 150 µg/g) and complete remission were assessed at baseline and at the time of UTC testing during maintenance therapy. The association between baseline variables and UTC was tested using linear regression. We also performed an external validation analysis of UTC cut-offs established in four previously published studies. RESULTS: This study included 43 patients. Compared to 8-weekly dosing, a 2.49- and 2.65-fold increase in UTC was associated with 6-weekly and 4-weekly dosing respectively. However, there was no significant difference in clinical, biochemical or complete remission among the dosing groups. An external validation of previously published optimal UTC cut-offs found low predictive value for our patient population. CONCLUSIONS: In this study, dosing interval was the only determinant significantly associated with a higher UTC for patients on maintenance ustekinumab therapy. While a higher UTC may be achieved with dose escalation, it was not associated with improved rates of clinical or biochemical response in our cohort.

Systematic review: efficacy of escalated maintenance anti-tumour necrosis factor therapy in Crohn's disease.

BACKGROUND: Loss of response to anti-TNF agents is a common clinical problem. Dose escalation may be effective for reestablishing clinical response in Crohn's disease (CD). AIMS: To perform a systematic review assessing the efficacy of escalated maintenance anti-TNF therapy in CD. METHODS: EMBASE, MEDLINE, Web of Science, and CENTRAL databases were searched for English language publications through to April 25, 2021. Full-text articles evaluating escalated maintenance treatment (infliximab or adalimumab) in adult CD patients were included. RESULTS: A total of 4733 records were identified, and 68 articles met eligibility criteria. Rates of clinical response (33%-100%) and remission (15%-83%) after empiric dose escalation for loss of response to standard anti-TNF therapy were high but varied across studies. Dose intensification strategies (doubling the dose versus shortening the therapeutic interval) were similarly efficacious. Dose-escalated patients tended to have higher serum drug levels compared to those on standard dosing. An exposure-response relationship following dose escalation was found in a number of observational studies. Randomised controlled trials comparing therapeutic drug monitoring (TDM) to empiric treatment intensification have failed to reach their primary end-points. Strategies including Bayesian dashboard-dosing and early treatment escalation targeting biomarker normalisation were found to be associated with improved long-term outcomes. CONCLUSIONS: Empiric escalation of maintenance anti-TNF therapy can recapture clinical response in a majority of patients with secondary loss of response to standard maintenance doses. Proactive optimisation of maintenance dosing might prolong time to loss of response in some patients.