Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract with a progressive course characterised by alternating periods of inflammatory activity (flare-ups) and clinical remission.1,2 The main therapeutic objective is therefore to induce and maintain remission of symptoms, thereby avoiding complications and the need for surgery, while promoting a better quality of life for patients.1,2

The advent of biological therapies, particularly tumour necrosis factor alpha inhibitors (anti-TNF), represented a milestone in the treatment of patients with inflammatory bowel disease (IBD). However, approximately 70% of patients experience a loss of response or toxicity to this class of drugs.3,4 This situation has led to the development of new monoclonal antibodies such as ustekinumab (UST), which targets the p40 subunit of interleukin IL-12 and IL-23.5 Ustekinumab has demonstrated effectiveness in more than two-thirds of patients after 3 months of treatment; over half of patients on maintenance therapy with UST sustain a favourable long-term response, while avoiding the need for surgery and maintaining an optimal safety profile.6–9 However, approximately 30% to 40% of patients do not achieve short-term clinical benefit, and up 40% to 50% may experience long-term treatment failure.6–9

One clinical strategy for improving the effectiveness and safety of treatment is to personalise therapy through therapeutic drug monitoring (TDM). This approach is particularly relevant in several areas of medicine, including IBD, as it enables individuals at higher risk of therapeutic failure to be identified early and therapy to be optimised for each individual.10,11 In the case of anti-TNF agents, several studies have determined the trough plasma concentrations required to achieve an optimal clinical response, increasing the likelihood of treatment success and reducing the risk of immunogenicity. These findings have enabled the development of recommendations for personalising therapy with this class of drugs, with dosing guided by plasma concentrations.10–13 However, information on the serum concentrations of other pharmacological agents, such as UST, and their relationship to clinical responses in patients with CD remains limited. Therefore, an appropriate plasma UST concentration threshold should be established before developing a TDM programme for use in clinical practice.

Furthermore, the persistence, or durability, of these therapies is a key factor that is currently being investigated to evaluate the clinical benefit of biological treatments for IBD. Since CD is a chronic disease, continued treatment is often recommended to achieve long-term remission and prevent relapse; consequently, treatment persistence has become a surrogate measure of the clinical benefit of these therapies.

In this context, we evaluated the association between trough plasma concentrations of UST at week 8 (USTconc-8w) and biochemical remission at week 24 (BCR-24w) in patients with CD and analysed the relationship between these concentrations and treatment persistence.

An observational, prospective study including all adult patients with CD who started UST treatment between 2020 and 2023.

Inclusion criteria were as follows: age over 18 years, a confirmed diagnosis of CD, and receipt of the standard UST regimen: induction via a weight-adjusted 60-min intravenous infusion (260 mg for patients weighing less than 55 kg, 390 mg for patients weighing 55–85 kg, and 520 mg for patients weighing more than 85 kg); a subcutaneous dose of 90 mg at week 8; and maintenance treatment of 90 mg every 8 weeks. Exclusion criteria were as follows: patients who required intensification or reinduction before week 24, and patients with incomplete plasma concentration or biochemical follow-up data at that time point. Therefore, the analysis only included patients who remained on the standard regimen without any treatment modifications until week 24.

USTconc-8w values were measured in all participants, and laboratory tests were scheduled to evaluate BCR-24w.

Trough plasma concentrations were determined by taking blood samples before the drug was administered at week 8. Plasma UST concentrations were quantified using an enzyme-linked immunosorbent assay (ELISA) with the Shikari Q-UST kit on the TRITURUS automated system (Grifols, Barcelona, Spain).

The participants' clinical characteristics of interest were obtained from their medical history: demographic data (gender, age at diagnosis); body surface area; extent and phenotype of Crohn's disease; disease duration; previous biological treatments; BCR-24w, defined as obtaining faecal calprotectin (FC) ≤150 mg/kg at week 24 of UST treatment; persistence of UST treatment defined as the time from its first administration to its definitive discontinuation for any reason.

The Mann–Whitney U test was used to determine differences in USTconc-8w values between patients who achieved BCR-24w and non-responders. Correlations between USTconc-8w values and BCR-24w rates were evaluated using quartile analysis, with USTconc-8w values expressed as medians with interquartile ranges (25th–75th percentile). A chi-squared test was used to determine any differences in the BCR-24w rates observed in each quartile. Binary logistic regression was used to determine whether USTconc-8w values could predict BCR-24w.

The Kaplan–Meier method was used to evaluate UST treatment persistence by determining the median time to definitive drug discontinuation for patients in each quartile. The log-rank test was used to analyse differences between the resulting cumulative survival curves.

A P-value of <0.05 was used as a cutoff for statistical significance. Statistical analyses were performed using SPSS v22 (IBM, Armonk, NY).

To ensure the confidentiality of participant data, all information was anonymised. All patients were given an information sheet and signed an informed consent form to participate in the study.

The study was approved by the Clinical Research Ethics Committee of the participating hospital (code NIVUSTEII-1).

The study included 36 patients with CD (median age: 44 years; range: 25–76; 52.7% male) who started UST treatment after other biologics had failed. Table 1 shows the baseline characteristics of the study population.

The median plasma UST concentration was 7.87 μg/mL (range: 0.85–20.16) at week 8. No patients had anti-UST antibodies. In total, 66.67% (n = 24) of the participants achieved BCR-24w and had significantly higher mean UST concentrations at week 8 than participants who did not achieve BCR-24w (10.64 μg/mL vs 5.83 μg/mL; P = 0.016) (Fig. 1).

Figure 1.

Trough plasma concentrations of UST (μg/mL) at week 8 in patients with or without biochemical remission at week 24 of treatment.

In the quartile analysis, patients in Q4 (USTconc-8w >13.29 μg/mL) had higher BCR-24w rates than the other participants (100% vs 57.1%; P = 0.023) (Fig. 2). Logistic regression analysis found an association between higher USTconc-8w values and higher BCR-24w rates (OR = 1.20; 95% CI: [1.02–1.42]; P = 0.027).

Figure 2.

Quartile analysis showing the relationship between trough plasma concentrations of UST (μg/mL) at week 8 and the biochemical remission rate at week 24 of treatment. Q, quartile; w, weeks.

After a median follow-up period of 26 months (range: 8–48), treatment was permanently discontinued in 33.3% (n = 12) of patients, which was due to loss of response in all cases.

Analysis of treatment persistence by quartile showed that the median persistence was not reached in any group (Fig. 3). No statistically significant differences were found between the survival curves (Table 2).

Figure 3.

Kaplan–Meier curves of ustekinumab treatment persistence for each plasma concentration quartile at week 8. UST, ustekinumab; Q, quartile; Q1: <3.87 μg/mL; Q2: 3.87–7.87 μg/mL; Q3: 7.88–13.29 μg/mL; Q4: >13.29 μg/mL.

The percentage of patients who continued to receive UST after 1 year of treatment was 77.8% in Q1, 90% in Q2, and 100% in Q3 and Q4 (P = 0.133). However, after 2 years, the percentage dropped to 55.6% and 50% in Q1 and Q2, respectively, while remaining at 100% in Q3 and Q4 (P = 0.014).

The use of biological therapies has revolutionised the therapeutic management of IBD. However, although a high percentage of patients (70–90%) show an optimal response at treatment initiation, rates of loss of effectiveness after the induction phase are substantial (20–50%), largely due to the wide pharmacokinetic variability and immunogenicity associated with this type of drug.3,4,13 Specifically, the kinetic behaviour of UST is influenced by patient-dependent variables, including body weight, a high inflammatory load, hypoalbuminaemia, the presence of anti-drug antibodies, and previous anti-TNF treatment, which increases the clearance of this biologic.14,15 This variability was also evident in our patient cohort. At week 8, plasma UST concentrations ranged from 0.85 to 20.16 μg/mL, with just half of the individuals falling within the range 3.87 to 13.29 μg/mL. Given the clinical impact of this phenomenon, one of the greatest challenges in contemporary medicine is to develop strategies to improve the persistence and effectiveness of these therapies. Consequently, TDM has become a critical component in managing these diseases.

This approach has proven useful in IBD, particularly when using anti-TNF agents. Concentration thresholds associated with greater clinical effectiveness have been determined for these agents.10–13 However, there is currently a lack of robust evidence to enable clinicians to determine the target UST concentrations that should be considered for patients with CD. Nevertheless, some studies have highlighted the clinical significance of the correlation between exposure and the pharmacological response to UST. A prospective study of 41 patients with CD receiving the standard UST regimen found that mean plasma concentrations at week 8 post-induction were significantly higher in participants who achieved clinical remission at week 24 than in non-responders (7.1 μg/mL vs 3.3 μg/mL; P = 0.018).15 In addition, individuals with plasma UST concentrations above 6.85 μg/mL and 11.1 μg/mL at week 8 were found to have a higher likelihood of biochemical remission and endoscopic remission at week 24, respectively.15 Similar results were observed in a subsequent study of a large cohort of CD patients. Participants who achieved biochemical remission at week 24 had higher UST concentrations at week 8 than non-responders (6.3 μg/mL vs 3.9 μg/mL; p < 0.01).16 In the same study, quartile analysis showed that patients with UST concentrations in Q4 (i.e. ≥6.3 μg/mL at week 8) had higher rates of biochemical remission at week 24.16 Similarly, we observed that patients who achieved biochemical remission at week 24 had significantly higher plasma concentrations at week 8 post-induction (10.64 μg/mL) than non-responders (5.83 μg/mL). The binary logistic regression analysis also showed that higher drug concentrations at week 8 increased the likelihood of biochemical remission at week 24. This finding was also corroborated by the quartile analysis, which showed that individuals with UST concentrations in Q4 (i.e. >13.29 μg/mL) had a significantly higher rate of biochemical remission at week 24 than the other patients. Similar findings were observed by Straatmijer et al.16

Although USTconc-8w values in our cohort were higher than those reported in other studies, this discrepancy may be explained by the inherent limitations of the ELISA analytical technique, which has an inter-assay variability of ±30%. This aspect necessitates internal validation in each laboratory, which limits direct comparisons of cohorts. In addition, other factors influencing the pharmacokinetics of the drug, such as the characteristics of the included population, may also have an impact. However, all studies agree on one key point: there is an association between higher UST concentrations and a higher likelihood of achieving biochemical remission.

Currently, persistence, or durability, is one of the most relevant parameters used to evaluate the clinical benefit of biological treatments for IBD. A recent study analysing the persistence of UST in patients with IBD estimated that, after 4 years of therapy, more than half of patients with CD were still being treated with this drug.17 Furthermore, 64.1% of patients with CD were still receiving UST at 2 years of follow-up.17 Similar results have been obtained in other studies.18,19 We observed that 66.7% of patients were still receiving treatment with UST after a median follow-up of 26 months. Bressler et al. evaluated several patient-related variables potentially influencing UST persistence, finding that it was significantly higher in biologic-naive participants than in those who had previously received biologic therapies.17 However, to the best of our knowledge, no previous study has evaluated the influence of plasma UST concentrations on the persistence of this treatment. When we stratified our patients by concentration quartile, no statistically significant differences were found between the persistence curves obtained. However, by week 8, there was a marked trend towards greater persistence in individuals with higher UST concentrations (Q3 and Q4) than in those with lower concentrations (Q1 and Q2). Furthermore, we observed that 100% of patients with Q3 to Q4 concentrations at week 8 were still receiving UST therapy at 2 years of follow-up; however, this proportion fell by almost half in patients with Q1 to Q2 concentrations (P = 0.014). These results demonstrate how TDM can improve the effectiveness of UST compared with pivotal trial outcomes: the IM-UNIT study reported that clinical response was maintained in only 73% of patients after 96 weeks of treatment (approximately 2 years).20 Although our data already suggest that plasma UST concentrations at week 8 post-induction are a predictive variable in patients with CD, future studies including more patients may clarify the clinical relevance of these concentrations for treatment persistence.

The limitations of this study include its small sample size and the exclusive use of biochemical data to evaluate the effectiveness of UST treatment. Endoscopic response was not taken into account because FC concentrations do not always accurately reflect inflammatory activity in CD when located in the small intestine. This condition affected 47% of our cohort.21 This aspect may have resulted in the inflammatory activity in this subgroup of patients being underestimated. However, the available evidence suggests that, despite this limitation, FC remains superior to other serum biomarkers. It should also be noted that C-reactive protein (CRP) levels were not included as a criterion for biochemical remission, as its sensitivity as an inflammatory marker in CD is limited. Discordance is frequently observed between normal CRP values and elevated FC concentrations in the presence of active inflammation.22,23 Nevertheless, a strength of our study is its prospective design, which was implemented under routine clinical practice conditions.

In conclusion, the findings demonstrate that monitoring plasma UST concentrations is a valid strategy to optimise this treatment and improve health outcomes in patients with CD. This study, which was conducted under routine clinical practice conditions, found an association between UST exposure and its medium- and long-term effectiveness, thereby supporting the implementation of TDM in hospitals. The results also suggest that a plasma UST concentration > 13.29 μg/mL at week 8 could indicate a higher likelihood of achieving biochemical remission at week 24. This finding could inform future therapeutic decision-making algorithms.

This study provides valuable clinical evidence of the effectiveness of therapeutic drug monitoring for ustekinumab in patients with Crohn's disease. It demonstrates a significant association between plasma concentrations at week 8 post-induction and biochemical remission at week 24, as well as with drug persistence. The findings also identify a plasma UST concentration > 13.29 μg/mL at week 8 as a therapeutic target. This study therefore makes a novel contribution to the field by emphasising the role of early therapeutic drug monitoring as a means of optimising ustekinumab treatment in clinical practice.

All of the authors of this study made substantial contributions to its preparation. The study was designed by Betel Del Rosario, Laura Ramos, Ruth Ramos Díaz, Marta Carrillo Palau, Cristina Reygosa Castro, Inmaculada Alonso Abreu, Sergio Medina Chico, and Fernando Gutiérrez Nicolás. The literature search was conducted by Betel Del Rosario, Laura Ramos, Laura Ramos, Ruth Ramos Díaz, Ana Salas Pérez, Marta Carrillo Palau, Cristina Reygosa Castro, Inmaculada Alonso Abreu, Sergio Medina Chico, and Fernando Gutiérrez Nicolás. Data collection and statistical analysis were conducted by Betel Del Rosario and Laura Ramos. The manuscript was prepared and reviewed by Betel Del Rosario, Laura Ramos, Ruth Ramos Díaz, Ana Salas Pérez, Marta Carrillo Palau, Cristina Reygosa Castro, Inmaculada Alonso Abreu, Sergio Medina Chico, and Fernando Gutiérrez Nicolás.

All authors accept their responsibilities as defined by the International Committee of Medical Journal Editors (available at http://www.icmje.org/ In the event of publication, the authors exclusively assign the rights of reproduction, distribution, translation, and public communication (by any means or audio, audiovisual, or electronic medium) of this work to Farmacia Hospitalaria and, by extension, to the SEFH. To this end, a letter of assignment of rights will be signed at the time of submission of the work through the online manuscript management system.

None declared.

Betel del Rosario García: Writing – original draft, Visualisation, Validation, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Laura Ramos: Writing – review & editing, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Ruth Ramos Díaz: Writing – review & editing, Validation, Software, Resources, Formal analysis, Data curation. Ana Salas Pérez: Validation, Software, Resources, Methodology, Investigation, Data curation, Conceptualization. Marta Carrillo Palau: Writing – review & editing, Validation, Formal analysis, Data curation, Conceptualization. Cristina Reygosa Castro: Writing – review & editing, Validation, Formal analysis, Data curation. Inmaculada Alonso Abreu: Writing – review & editing, Validation, Formal analysis, Data curation. Sergio Medina Chico: Writing – review & editing, Validation, Formal analysis, Data curation. Fernando Gutiérrez Nicolás: Writing – review & editing, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

None declared.