Ustekinumab Trough Concentrations Research Articles

Relationship between Ustekinumab trough concentrations and clinical, biochemical and endoscopic outcomes in Crohn's disease: A multi-center nationwide retrospective study (TARGET STUDY).

Ustekinumab has been shown to be effective in inducing and maintain clinical and endoscopic remission in Crohn disease (CD). We aim to assess whether ustekinumab trough levels are associated with improved outcomes in CD in real-life. We recruited patients with CD who were treated with ustekinumab for at least 6 months from January 2017 to June 2023. Patients received ustekinumab 6 mg/kg intravenous induction followed by 90 mg every 4-, 8-, or 12-weeks during maintenance were included. We assessed clinical, biochemical, and endoscopic outcomes. Trough concentrations of ustekinumab that were taken from week 42 to week 52 were measured. Primary outcome was to evaluate the relationship between ustekinumab trough concentrations and clinical remission, biochemical normalization, and endoscopic remission. Logistic regression was conducted to assess outcomes. A total of 137 patients with CD, median age of 32 years and 83 (60.6%) males. The median serum levels of ustekinumab measured was 7.2 mcg/mL (interquartile range [IQR] 3.1-9.6). Using Spearman correlation analysis, a strong negative correlation was observed between ustekinumab drug levels and simple endoscopic score (SES-CD) (r = -0.464, P < .001). Additionally, ustekinumab drug levels demonstrated substantial negative correlations with disease severity measured by Harvey-Bradshaw index (HBI) score (r = -0.582, P < .001), C-Reactive Protein (CRP) levels (r = -0.598, P < .001) and fecal calprotectin (FC) levels (r = -0.529, P < .001). A multivariable analysis adjusted for age, sex and body mass index (BMI) showed a significant association between ustekinumab serum drug levels and predefined outcomes. Ustekinumab serum drug level above 4.5 mcg/mL was associated with 24% increase in the likelihood of having an SES-CD score <3 (OR 1.24, confidence interval [CI] 1.12-1.37, P value < .001), 44% more likely to achieve HBI score <5 (OR 1.44, CI 1.26-1.65, P value < .001), 52% higher likelihood of CRP more than 10 (OR 1.52, CI 1.31-1.77, P < .001), and 42% increased likelihood of FC more than 250 (OR 1.42, CI 1.24-1.62, P < .001). Ustekinumab trough concentrations above 4.5 mcg/mL were associated with clinical, biochemical and endoscopic remission in CD. Prospective data is warranted to confirm these findings.

P794 Relationship between Ustekinumab Trough Concentrations and Clinical, Biochemical and Endoscopic Outcomes in Crohn’s Disease; A Multi-Center Nationwide Study (TARGET STUDY)

Abstract Background Ustekinumab (UST) has been shown to be effective in inducing and maintain clinical and endoscopic remission in Crohn’s disease (CD). We aim to assess whether ustekinumab trough levels are associated with improved outcomes in CD in real life settings Methods We recruited patients with CD who were treated with ustekinumab for at least 6 months from January 2017 to June 2023. Patients received ustekinumab 6mg/kg intravenous induction followed by 90 mg every 4 or 8 weeks during maintenance were included. Clinical, biochemical, and endoscopic outcomes, trough concentrations of ustekinumab that was taken from week 42 to week 52 were included. Primary outcome was to assess if ustekinumab trough concentrations were associated with clinical remission, biochemical normalization, and endoscopic remission. Logistic regression was conducted to assess outcomes Results A total of 137 patients with CD. mean age of 34.1 years and 83 (60.6%) males. The mean serum levels of ustekinumab was 7.2 (SD 4.5). Using Spearman correlation analysis, a strong negative correlation was observed between ustekinumab drug levels and SES-CD score (r = -0.464, p &amp;lt; 0.001. Additionally, ustekinumab drug levels demonstrated substantial negative correlations with disease severity measured by HBI score (r = -0.582, p &amp;lt; 0.001), C-Reactive Protein(CRP) levels (r = -0.598, p &amp;lt; 0.001) and fecal calprotectin (FCAL) levels (r = -0.529, p &amp;lt; 0.001). A multivariate analysis adjusted for age, sex and BMI showed a significant association between ustekinumab serum drug levels and predefined outcomes. Ustekinumab serum drug level above 4.5 mcg/ml was associated with 24% increase in the likelihood of having an SES-CD score less than 3 (OR 1.24, CI 1.12-1.37, P&amp;lt;0.001), 44% more likely to achieve HBI score less than 5 (OR 1.44, CI 1.26-1.65, P&amp;lt;0.001), 52% higher likelihood of CRP less than 10 (OR 1.52, CI 1.31-1.77, p &amp;lt; 0.001), and 42% increased likelihood of FCAL less than 250 (OR 1.42, CI 1.24-1.62, p &amp;lt; 0.001). Conclusion Ustekinumab trough concentrations above 4.5 mcg/ml was associated with clinical, biochemical and endoscopic remission in Crohn’s disease. Prospective data is warranted to confirm these findings

P1053 Ustekinumab trough concentration could predict the aggravation of endoscopic severity after de-escalation in the sub-analysis of CD-EXTEND study

Abstract Background De-escalation was a useful strategy for improving patient’s QOL and reduction of medical expenses. However, endoscopic data after de-escalation of ustekinumab (UST) has not been reported. The aim of this study was to elucidate UST trough concentration for the prediction of endoscopic aggravation after de-escalation of UST. Methods This CD-EXTEND study was a single-centre prospective observational study approved by the institutional review board of our hospital. Thirty CD patients who selected de-escalate UST treatment after administration of intravenous UST 6 mg/kg and subcutaneous UST 90mg every 8 weeks until 54 weeks were enrolled in this cohort. Endoscopic evaluation was performed at baseline and at one year. Endoscopic aggravation was defied as the increase of SES-CD score. Cut-off values of prediction for endoscopic aggravation was calculated by receiver operating characteristic (ROC) curve. Results Endoscopic evaluation could be evaluated in 25 patients. Endoscopic aggravation was recognized in 9 patients. There was no significant differences of patient’s characteristics and biomarkers including CRP, fecal calprotectin (FC) and Leucin-rich alpha-2-glycoprotein (LRG) between aggravated and non-aggravated groups at the baseline. However, trough concentration was significantly higher in aggravated group than non-aggravated group at the base line (1.5 ± 0.7 vs 2.8 ± 1.3 μg/mL, p=0.02). CRP, FC and LRG significantly increased in aggravated group, not in non-aggravated group. However, trough concentration significantly decreased in both aggravated and non-aggravated groups. Trough at one year was significantly lower in aggravated group than non-aggravated group (0.44 ± 0.3 vs 1.0 ± 0.71 μg/mL, p=0.02). Cut-off values of trough concentration of prediction for endoscopic aggravation at base line and at one year were 2.15 and 0.4 μg/mL, respectively. Conclusion UST trough concentration was a good prediction marker for endoscopic aggravation.

Relationship between ustekinumab trough concentrations and both clinical and biological remission in patients with Crohn's disease

Relationship between ustekinumab trough concentrations and both clinical and biological remission in patients with Crohn's disease

Extra intravenous Ustekinumab reinduction is an effective optimization strategy for patients with refractory Crohn's disease.

Ustekinumab (UST) optimization strategies, including shortening intervals and intravenous reinduction, should be administered to patients with partial or loss of respond. Evidence comparing these types of optimization treatments is limited. We evaluated the efficacy and safety of weight-based UST intravenous reinduction in patients with refractory Crohn's disease (CD). This was a single-center retrospective observational study. Optimization strategies were designed for patients showing partial or loss of response to standardized UST therapy. Clinical, biochemical, and endoscopic response and remission rate were determined by Crohn's disease activity index (CDAI), C-reactive protein (CRP) levels, and SES-CD evaluation. UST trough concentrations were detected and adverse events were recorded. A total of 128 patients receiving UST optimization therapies were included, with 105 patients administered shortening intervals of q8w or q4w, and 23 receiving intravenous reinduction followed by subcutaneous q8w or q4w. The follow-up duration for the shortening interval and reinduction cohorts were 15.0 (10.0, 31.0) and 23.0 (13.0, 70.0) weeks, respectively. A significant CDAI delta variation pre-and post-treatment could be found between groups [17.0 (-4.4, 65.9) vs. 69.0(10.7, 151.0), p = 0.013]. the trough concentration of UST increased [2.5 (1.3, 5.3) vs. 1.1 (0.5, 2.3), p = 0.001] after intravenous reinduction. Clinical and endoscopic remission were achieved in 69.6 and 31.8% of patients in the intravenous reinduction cohort, and 62.9 and 22.2% of patients in the shortening interval cohort, respectively. No significant difference was found between groups regarding safety. Intravenous reinduction brought about favorable recapture of clinical and endoscopic remission, and should have significant priority over the strategy of merely shortening drug intervals, which should be launched before switching to other biologics targeting different inflammatory pathways.Clinical Trial Registration: identifier NCT04923100. https://classic.clinicaltrials.gov/ct2/show/NCT04923100?id=04923100&draw=2&rank=1.

Systematic Review and Meta-analysis: The Association Between Serum Ustekinumab Trough Concentrations and Treatment Response in Inflammatory Bowel Disease.

Optimizing therapy and monitoring response are integral aspects of inflammatory bowel disease treatment. We conducted a systematic review and meta-analysis to determine whether serum ustekinumab trough concentrations during maintenance therapy were associated with ustekinumab treatment response in patients with inflammatory bowel disease. A systematic review was performed to March 21, 2022, to identify studies using MEDLINE, EMBASE, and the Cochrane library. We included studies that reported the association between serum ustekinumab trough concentrations with clinical or endoscopic remission. Outcome measures were combined across studies using the random-effects model with an odds ratio (OR) for binary outcomes of endoscopic and clinical remission. We identified 14 observational studies that were included in the analysis for clinical remission (919 patients, 63% with Crohn's disease) or endoscopic remission (290 patients, all with Crohn's disease). Median ustekinumab trough concentrations were higher amongst individuals achieving clinical remission compared with those not achieving remission (mean difference, 1.6 ug/mL; 95% confidence interval [CI], 0.21-3.01 ug/mL). Furthermore, individuals with median serum trough concentration in the fourth quartile were significantly more likely to achieve clinical (OR, 3.61; 95% CI, 2.11-6.20) but not endoscopic remission (OR, 4.67; 95% CI, 0.86-25.19) compared with those with first quartile median trough concentrations. Based on the results of this meta-analysis primarily relating to patients with Crohn's disease on maintenance ustekinumab treatment, it appears that there is an association between higher ustekinumab trough concentration and clinical outcomes. Prospective studies are required to determine whether proactive dose adjustments of ustekinumab therapy provides additional clinical benefit.

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

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. 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. 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. 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.

Ustekinumab Trough Concentrations Are Associated with Biochemical Outcomes in Patients with Crohn’s Disease

ObjectiveIt is unknown whether ustekinumab (UST) levels can predict clinical outcomes in Crohn’s disease (CD) patients. We assessed the exposure–response relationship of UST trough concentrations with biochemical outcomes at week 24 in a prospective, real-world setting.MethodsWe performed a prospective study in patients with CD starting UST in four academic centres in the Netherlands. All patients received a weight-adjusted intravenous (IV) UST induction dose, followed by one subcutaneous (SC) dose of 90 mg UST at 8 weeks. Maintenance therapy consisted of 90 mg subcutaneous UST every 8 or 12 weeks. Individual UST concentration time course during treatment were estimated using a population pharmacokinetic (PK) model. Quartile analysis and logistic regression were performed to analyse if UST concentrations at week 8 were associated with biochemical remission rates at week 24 (C-reactive protein (CRP) ≤ 5 mg/L and / or faecal calprotectin (FC) ≤ 250 mg/kg).ResultsIn total, 124 patients with CD were included. Patients achieving biochemical remission at week 12 and 24 had significantly higher UST levels at week 8 compared to patients without biochemical remission (6.6 µg/mL versus 3.9 µg/mL, P < 0.01 and 6.3 µg/mL versus 3.9 µg/mL, P < 0.01, respectively). In quartile analysis, patients with UST levels in the highest quartile (≥ 6.3 µg/mL at week 8) had higher biochemical remission rates at week 12 and week 24. There was no association between UST levels at and corticosteroid-free clinical remission rates.ConclusionIn this real-world cohort of patients with CD, UST levels in the highest quartile (≥ 6.3 µg/mL) at week 8 were associated with higher biochemical remission rates at week 24.

P153 Association between ustekinumab trough concentrations and clinical, biochemical, and endoscopic outcomes in patients with Inflammatory Bowel Disease

Abstract Background Ustekinumab (UST), an inhibitor of the p40 subunit of interleukins 12 and 23, is an effective treatment for patients with Crohn’s disease (CD) and ulcerative colitis (UC). There is limited data on therapeutic outcomes and UST trough levels (UTL). We aimed to evaluate the association between UTL and corticosteroid-free clinical remission. We also assessed the relationship between UTL and endoscopic remission as a secondary outcome. Methods We performed a cross-sectional study on IBD patients receiving maintenance therapy with UST (&amp;gt;6 months). We included UTL, C reactive protein (CRP), faecal calprotectin (FC), and clinical and endoscopic indexes (Harvey Bradshaw [HBI] and simple endoscopic score [SES-CD] for CD patients; and partial Mayo score [PMS] and endoscopic Mayo score [EMS] for UC patients). Corticosteroid-free clinical remission (CSF-CR) was defined as HBI&amp;lt;5 or PMS&amp;lt;2 plus normal CRP and/or FC values without corticosteroids. Endoscopic remission was defined as SES-CD&amp;lt;3 or EMS&amp;lt;2. Results We included 105 patients; the mean age was 50 years, and 59% were female (Figure 1). Eighty-seven patients had CD, and 92% had previously received an anti-TNF. The median time on UST was 121 weeks at inclusion. Sixty-four patients received 90mg subcutaneous (SC) every 4 weeks, 40 patients 90mg SC every 8 weeks, and 1 patient 90mg SC every 12 weeks. Eighty percent were in CSF-CR, and 53% were in endoscopic remission. Median UTL were 2,7µg/mL (IQR: 1,7-4,1µg/mL); UST antibodies were not detected. Patients in CSF-CR and endoscopic remission did not show significantly higher UTL (3,4µg/mL vs. 2,5µg/mL, p=0,147; and 3,6µg/mL vs. 3,7µg/mL, p=0,903, respectively). No differences in UTL were detected between patients on monotherapy and combination therapy (2,9µg/mL vs. 3,3µg/mL, p=0,456). Conclusion No association between UTL and clinical or endoscopic activity was observed in our predominantly biologic-experienced cohort. Further prospective studies are needed to determine the role of therapeutic drug monitoring while on UST.

Real-world use of ustekinumab therapeutic drug monitoring in moderate to severe psoriasis.

There is growing evidence that therapeutic drug monitoring of biologic therapy is beneficial in psoriatic patients. With respect to ustekinumab, the available evidence has not shown any relationship yet. The objective of this study is to identify correlations among ustekinumab trough concentrations, anti-ustekinumab antibodies and clinical response in moderate-to-severe plaque psoriasis patients, in a real-world setting. Observational prospective follow-up study in psoriatic patients treated with ustekinumab. Patients were classified in optimal (PASI ≤ 3) and suboptimal responders (PASI > 3). Mann-Whitney U test and Spearman's rank correlation coefficient were used. Receiver-operator characteristic curve analysis was performed to identify ustekinumab concentration cut-off to achieve optimal response. A p-value < 0.05 was considered statistically significant. A total of 59 patients were included. Forty-eight patients (81.4%) corresponded to optimal responders and 11 (18.6%) to suboptimal responders. There was significant difference to ustekinumab concentrations: 0.7 μg/mL (range <0.1-1.8) vs. 0.4 μg/mL (range <0.1-0.8) respectively (p = 0.007). Positive correlation between ustekinumab concentration and psoriasis area and severity index (PASI) value was detected (p = 0.009). A cut-off value of 0.6 μg/mL ustekinumab concentration was found to achieve clinical response. Anti-ustekinumab antibodies were detected in 2 (3.4%) samples, both suboptimal responders. A positive correlation exits between ustekinumab concentration and clinical response (optimal response PASI values ≤ 3) in blood draws performed before drug administration. The measurement of anti-ustekinumab antibodies could be considered in treatment failure.

S729 Serum Ustekinumab Concentrations Are Associated With Improved Outcomes With the Magnetic Resonance Index of Activity for Crohn's Disease

Introduction: Controversy exists for ustekinumab concentrations needed in Crohn’s disease (CD). No data exist comparing ustekinumab concentrations and validated radiologic outcomes. We characterized these relationships and clarified concentrations needed. Methods: CD patients on maintenance ( > 16 weeks) ustekinumab with both ustekinumab concentrations and simplified magnetic resonance index of activity (sMaRIA) scoring were included. Ustekinumab concentrations were compared between those with and without (1) radiologic remission (sMaRIA < 2), (2) severe radiologic inflammation (sMaRIA < 3) and (3) fecal calprotectin (FCP) biomarker remission (FCP < 50 μg/g). Area under the receiver-operating characteristic (AUROC) curve determined optimal ustekinumab concentrations. Outcomes were compared between patients above and below identified ustekinumab thresholds. Results: Thirty-eight paired ustekinumab concentrations and MRE were included. Ustekinumab concentrations were higher with radiologic remission (11.4 μg/mL vs. 6.4 μg/mL, P=.005) and had good diagnostic accuracy for radiologic remission (AUROC 0.76, 95% CI 0.60 – 0.91) and for absence of severe inflammation (AUROC 0.71, 95% CI 0.55 – 0.88, optimal concentration 8.4 μg/mL). With ustekinumab ≥ 8.4 μg/mL, higher proportions had radiologic remission (63.2% vs. 21.1%, P=.01) and absence of severe inflammation (78.9% vs. 36.8%, P=.01) compared to patients with lower concentrations. Ustekinumab concentrations had good diagnostic accuracy (AUROC 0.73, 95% CI 0.52 – 0.94) for FCP biomarker remission (optimal concentration: 6.1 μg/mL). Patients with ustekinumab concentrations ≥ 6.1 μg/mL had higher proportions with biomarker remission (72.2% vs. 12.5% P < .01) compared to those with lower concentrations. (Figure) Conclusion: Ustekinumab concentrations are associated with radiologic and biomarker outcomes in CD. These data validate the need for higher ustekinumab concentrations.Figure 1.: (A) Receiver-operating characteristic curve analysis for sMaRIA score of < 2, absence of any inflammation, based on ustekinumab trough concentrations. The optimal concentration is 8.4 μg/mL as indicated by the best receiver-operating characteristic curve (area under curve, 0.76; sensitivity, 75%; specificity 68%). (B) Receiver-operating characteristic curve analysis for sMaRIA score of < 3, absence of severe inflammation, based on ustekinumab concentrations. The optimal serum concentration is 8.4 μg/mL as indicated by the best receiver-operating characteristic curve (area under curve, 0.71).

Comparison of Ustekinumab Trough Concentrations Measured by 2 ELISA Kits and Evaluation of Clinical Response in Crohn's Disease.

Ustekinumab is a recently introduced biological agent for the treatment of Crohn's disease. The clinical use of the trough concentration of ustekinumab is not as standardized as that of infliximab. The authors aimed to introduce a measurement method and the results of trough concentrations of ustekinumab in clinical applications. Thirty-two blood samples from 10 young adult patients diagnosed with Crohn's disease were analyzed. During the maintenance treatment, injection intervals were shortened from 12 weeks to 8 weeks in 4 patients who exhibited a loss of response. Ustekinumab trough concentrations were measured using 2 commercial ELISA kits, kit A and kit B. The median trough concentrations measured with kits A and B were 0.26 and 0.38 mcg/mL, respectively. In the case of kit A, low trough concentrations were undetected on many occasions and measured as zero, whereas kit B displayed their relative values even at low concentrations. Poor clinical parameters, elevated erythrocyte sedimentation rate, C-reactive protein, and calprotectin levels were significantly correlated with lower trough concentrations ( P < 0.05). The area under the receiver operating characteristics curve of kit B (0.921) was greater than that of kit A (0.744). The optimal cutoff values for prediction clinical responses were 0.17 and 0.41 mcg/mL for kit A and kit B, respectively. The trough concentration of ustekinumab measured by the 2 ELISA kits correlated with laboratory results that indicated the activity of Crohn's disease. Furthermore, kit B detected even minute changes in trough concentrations.

P317 Ustekinumab Trough Concentrations Associated with Biochemical Outcomes in Patients with Crohn’s Disease

Abstract Background Ustekinumab (UST) is a monoclonal antibody which binds to the p40 subunit of interleukins-12/23 and is an effective and safe treatment for patients with Crohn’s disease (CD). An association between serum drug concentrations and therapeutic outcomes is required to justify Therapeutic Drug Monitoring (TDM). However, it is currently unknown if TDM is of additional value in UST treatment. We assessed the exposure-biochemical response relationship of UST trough concentrations at week, 8 in a prospective, real-world setting. Methods We performed a prospective study in CD patients with biochemical, radiologic or endoscopic disease activity in four academic centers in the Netherlands. All patients (n=90) received weight adjusted intravenously (IV) UST induction. First subcutaneous (SC), 90 mg induction dose was administered at week, 8 followed by a maintenance dose of, 90 mg SC every, 8 or, 12 weeks, at the discretion of the physician. Blood for drug levels were drawn at different time points during follow up (median follow up was, 52 weeks (IQR, 50–52)) with a median amount of, 2 measurements (IQR, 1–4) per patient. Plasma concentrations of UST were determined by means of a validated enzyme-linked immune assay. A population pharmacokinetic (PK) model was developed based on these measurements and the UST FDA review documents. Subsequently, the individual UST concentration time course during treatment were predicted using the developed model. Corticosteroid-free clinical remission (HBI ≤, 4) and biochemical remission (C-reactive protein (CRP) ≤5 mg/L or faecal calprotectin (FC) ≤, 250) were assessed at week, 12 and, 24. Quartile analysis and logistic regression was performed to analyse if UST concentration at week, 8 was associated with biochemical remission rates at week, 24. An independent cohort of, 34 patients was used to validate the primary outcomes. Results Basis characteristics of all patients are shown in table 1. Median estimated trough concentrations of UST were, 4.23 µg/mL (IQR, 2.79–5.83) and, 7.19 µg/mL (IQR, 3.30–10.67) at week, 8 in the primary and validation cohort respectively. Patients achieving biochemical remission at week, 12 and, 24 had statistically significantly higher UST levels at week, 8 (P&amp;lt;0.01) compared to patients without biochemical remission (fig, 1). Also, higher UST levels at week, 8 were associated with better biochemical remission rates at week, 12 and, 24 in quartile analysis and logistic regression (fig, 2,3). Associations of UST levels at week, 8 and biochemical remission at week, 12 and, 24 were confirmed in the validation cohort. No UST antibodies were detected. Conclusion In this real-world cohort of CD patients, ustekinumab levels of ≥5.9 µg/mL at week, 8 were associated with higher biochemical remission rates at week, 12 and, 24.

Ustekinumab trough concentration affects clinical and endoscopic outcomes in patients with refractory Crohn\u2019s disease: a Chinese real-world study

BackgroundUstekinumab (UST), a newly-used biologic targeting p40 subunit of IL12 and IL23 in China, exerts a confirmed therapeutic effect on the induction and maintenance therapies for refractory Crohn’s disease (CD). Therapeutic drug monitoring based on trough and antibody concentration is of core importance when treating patients who lose response to UST. We aimed to analyze the UST exposure–response relationship in CD treatment in the real-world setting.MethodsWe retrospectively enrolled patients with CD who received UST between March 1, 2020 and May 31, 2021, at the inflammatory bowel disease (IBD) center of the Sun Yat-Sun Affiliated Sixth Hospital. Baseline characteristic information, biomarker examination, clinical outcomes determined by the Crohn’s disease activity index (CDAI), and endoscopic outcomes evaluated using a simple endoscopic score for Crohn’s disease (SES-CD) at week 16/20 were collected. The optimal UST cut-off trough concentration was identified using receiver operating characteristic curve (ROC) analysis.ResultsNineteen eligible patients were included in the study, the mean age was 29.1 ± 9.1 years and the mean disease duration was 5.5 ± 4.7 years. At the initiation of the study, 89.5% of the patients had been exposed to prior biologics, 42.1% had previous CD-related surgeries, and 52.6% had perianal diseases. At week 16/20 after the UST initiation, clinical response, clinical remission, endoscopic response, and endoscopic remission were 89.5%, 84.2%, 42.2%, and 73.7%, respectively. The cut-off optimal trough concentration for UST was 1.12 μg/mL, as determined by the ROC with an area under the curve (AUC) of 0.78, sensitivity of 87.5%, and specificity of 72.7%. Patients with a UST trough concentration > 1.12 μg/mL had a significantly higher rate of endoscopic remission than those without (70.0% vs. 11.1%, P = 0.02).ConclusionsUST is an effective therapeutic option for refractory CD treatment. A UST trough concentration above 1.12 μg/mL was associated with endoscopic remission at week 16/20 after UST initiation.Trial registration This study was approved and retrospectively registered by the Ethics Committee of Sun Yat-Sen University (2021ZSLYEC-066, March 29, 2021) and the Clinical Trial Registry (NCT04923100, June 10, 2021).

P307 Modelling of the relationship between ustekinumab exposure, faecal calprotectin and endoscopic outcomes in patients with Crohn’s disease

Abstract Background In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn’s disease (CD) on ustekinumab achieved endoscopic response and 10.9% achieved endoscopic remission at week (w)44. We aimed to investigate if improved endoscopic outcomes can be achieved through dose optimisation based on a population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis. Methods Real-world data were obtained from 83 patients with moderate-to-severe CD (94% multi-refractory) enrolled in a prospective cohort study receiving ustekinumab 6 mg/kg induction and every eight-week (q8w) 90 mg maintenance therapy. Ustekinumab serum concentrations were measured at mid-dose (w4) and trough (w8, w16, w24). Faecal calprotectin (fCal) was measured at baseline and at w4, w8, w16, w24. Endoscopic response (≥50% decrease in simple endoscopic score for CD [SES-CD]) and endoscopic remission (SES-CD ≤2) were assessed at w24. Modelling and simulation were performed using NONMEM 7.4. Results Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fCal, and a logistic regression popPD model linking fCal at w8 to endoscopic outcomes at w24 (Figure 1). Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. The terminal half-life of ustekinumab in a median patient (bodyweight 65 kg, serum albumin 42.7 g/L) was 20.4 days. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1,800 μg/g to 694 μg/g (Figure 2a) The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1,800 μg/g to 214 μg/g (Figure 2b).The results from the simulation-based comparison of q8w and q4w maintenance dosing are shown in Table 1. Dose doubling (180 mg q8w), as opposed to interval halving (90 mg q4w), was predicted to result in a ustekinumab trough concentration of 2.4 μg/mL instead of 4.8 μg/mL. Conclusion The developed model can guide clinical trial design and support model-informed dose optimisation to improve endoscopic outcome rates. Although our analyses showed that q4w dosing resulted in higher ustekinumab and lower fCal concentrations, the proportion of patients achieving endoscopic remission was limited.

A nationwide real-world study on dynamic ustekinumab dosing and concomitant medication use among Crohn’s disease patients in Finland

Background Real-world evidence to support optimal ustekinumab dosing for refractory Crohn’s disease (CD) patients remains limited. Data from a retrospective nationwide chart review study was utilized to explore ustekinumab dosing dynamics and optimization, identify possible clinical predictors of dose intensification, and to evaluate ustekinumab trough concentrations (TCs) and concomitant medication use in Finland. Methods Information gathered from17 Finnish hospitals included clinical chart data from 155 adult CD patients who received intravenous ustekinumab induction during 2017–2018. Data on ustekinumab dosing and TCs, concomitant corticosteroid and immunosuppressant use, and antiustekinumab antibodies were analyzed in a two-year follow-up, subject to availability. Results Among 140 patients onustekinumab maintenance therapy, dose optimization was required in 55(39%) of the patients, and 41/47 dose-intensified patients (87%) persisted on ustekinumab. At baseline, dose-intensified patient group had significantly higher C-reactive protein (CRP) levels, and at week 16, significantly lower ustekinumab TCs than in patients without dose intensification. Irrespective of dose optimization, a statistically significant reduction in the use of corticosteroids was observed at both 16 weeks and one year, coupled with an increased proportion of patients on ustekinumab monotherapy. Antiustekinumab antibodies were undetectable in all 28 samples from 25 patients collected throughout the study period. Conclusions Nearly a third of all CD patients on ustekinumab maintenance therapy, with a history of treatment-refractory and long-standing disease, required dose intensification. These patients persisted on ustekinumab and had significant reduction of corticosteroid use. Increased baseline CRP was identified as the sole indicator of dose intensification. Trial registration EUPAS30920

DOP26 Real-life dosing patterns and concomitant drug use among ustekinumab-treated patients with Crohn’s disease

Abstract Background Real-life long-term evidence on ustekinumab treatment in patients with Crohn’s disease (CD) is limited. We performed a retrospective non-interventional nation-wide chart review study of dosing and long-term clinical outcomes in Finnish CD patients treated with ustekinumab (FINUSTE2, EUPAS30920). Methods FINUSTE2 was carried out in 17 Finnish centres. Eligible patients were adults with CD, receiving an intravenous (IV) first dose of ustekinumab during 2017 or 2018. Data on disease activity, dosage, and concomitant medications were collected at baseline, 16 weeks, and 1 year from treatment initiation. All measurements on ustekinumab trough concentrations (TC) were recorded. Results The study included 155 patients (48% female) with a mean age of 44 and disease duration of 14 years. The disease was stricturing or penetrating in 69% of patients, 59% had prior CD-related surgeries, and 96% had a treatment history of at least one biologic agent. After one IV dose and one to two subcutaneous (SC) doses at 8 to 16 weeks, 140 patients (93%) continued to maintenance treatment with SC ustekinumab, of which nearly three-quarters with a dosage interval of 8 weeks (Figure 1). Of 93 patients with a follow-up of at least 1 year, 77 were still on ustekinumab. During follow-up, 55 patients (39%) had their ustekinumab dose adjusted, mostly (n = 44, 31.4%) as a shortening of the dosage interval. Forty-nine patients had in total 65 ustekinumab TC measurements performed, with a mean of 2.2 µg/ml at 16 weeks (n = 23) and 2.7 µg/ml at 1 year (n = 25). In 67% of cases, the reason for measuring TC was lack of or insufficient response. No anti-drug antibodies appeared at any time point. The proportion of patients on ustekinumab monotherapy increased significantly, from 34% (n = 52) at baseline to 54% (n = 79/146; p &amp;lt; 0.001) at 16 weeks and 64% (n = 49/77; p &amp;lt; 0.01) at 1 year. Correspondingly, corticosteroid use decreased significantly, and a trend towards reduced use of immunomodulators was observed (Figure 2). Conclusion In this nationwide real-life study, treatment with ustekinumab in patients with longstanding and complicated CD was persistent and allowed for significant corticosteroid tapering. A vast majority started the maintenance treatment with an 8-week dosage interval and nearly one-third of all patients required a dose increase, suggesting a highly refractory disease phenotype. The lack of detected antidrug antibodies during follow-up indicates low immunogenicity for ustekinumab.

Association between ustekinumab trough concentrations and biochemical outcomes in patients with Crohn's disease. A real life study.

numerous studies have shown a positive correlation between serum biologic drug concentrations and favorable therapeutic outcomes during the induction and maintenance period in patients with Crohn's disease (CD). To our knowledge, only a few and contradictory studies have determined the association between ustekinumab (UST) trough concentrations and biological outcomes. This study aimed to investigate the relationship between ustekinumab trough concentrations and biological outcomes in a real-world setting. a cross-sectional cohort study was performed. All adult patients with CD who received maintenance therapy (≥ 24 weeks) with ustekinumab were included in the study. Clinical response was determined using the Harvey-Bradshaw Index. Biochemical remission was defined as a fecal calprotectin level < 150 µg/g in feces and a biochemical response as > 50 % reduction of fecal calprotectin. a total of 58 CD patients were included in the study and the median UST trough concentration was 1.78 µg/ml (IQR: 2.56). Differences in ustekinumab trough concentrations were observed for clinical (2.25 µg/ml vs 0.65 µg/ml; p = 0.006) and biochemical remission (2.33 µg/ml vs 1.03 µg/ml; p = 0.047). According to ROC analysis, a cut-off of 1.4 µg/ml (AUC: 077) and 2.0 µg/ml (AUC: 0.65) were identified for predicting clinical and biochemical remission, respectively. Likewise, ustekinumab trough levels were also higher in "composite clinical/biochemical remission" (2.38 µg/ml vs 1.08 µg/ml; p = 0.042). The trough level that was best associated with composite clinical/biochemical remission was 2.2 µg/ml (AUC: 0.69). this real-life study shows the association between ustekinumab trough concentration and clinical and biochemical remission and we suggest an optimal cut-off point higher than 2.2 µg/ml. Further studies are needed to confirm the findings and to identify the optimal cut-off in different disease outcomes and disease phenotypes.

637 Clinical Prediction Model and Decision Support Tool for Ustekinumab in Crohn's Disease

INTRODUCTION: Identifying predictors of response to treatment with ustekinumab (UST) may improve therapeutic decisions. We created a clinical decision support tool (CDST) for UST therapy in active Crohn's disease (CD). METHODS: Patients from the UNITI trials were included if they received IV UST induction and SQ UST maintenance irrespective of Week 8 response status (derivation set; n = 781). Cox proportional hazard analyses were used to identify baseline factors associated with clinical remission (CDAI 150) by Week 16. The final model was transformed into a CDST and patients were stratified into 3 response probability groups (low, intermediate, high). Secondary analyses were performed to assess the ability of the CDST to predict exposure-efficacy relationships as measured by reduction in CDAI from baseline and differences in trough UST concentrations at weeks 8 and 16. RESULTS: In the derivation analysis, baseline albumin g/L (HR 1.041, 95% CI 1.019–1.063), no prior smoking history (HR 1.233, 95% CI 0.995–1.527), absence of baseline actively draining fistula (HR 1.330, 95% CI 0.906–1.952), absence of prior bowel surgery (HR 1.425, 95% CI 1.140–1.781), and absence of prior exposure to tumor necrosis factor antagonist (HR 1.591, 95% CI 1.214–1.900), were associated with achieving clinical remission by Week 16 of UST therapy. Rates of clinical remission at weeks 3, 6, 8, and 16 were significantly higher in the high probability group versus the intermediate and low probability groups (Table 1). The high probability group had a significantly greater reduction from baseline in CDAI compared to the intermediate and low probability groups at week 8 (high vs. intermediate 94 vs. 54 P &lt; 0.0001; high vs. low 94 vs. 40, P &lt; 0.0001) and week 16 (high vs. intermediate 155 vs. 112 P &lt; 0.0001; high vs. low 155 vs. 84, P &lt; 0.0001). The high probability group had significantly higher trough UST concentrations compared to the intermediate and low probability groups at week 8 (high vs. intermediate 5.2 vs. 3.6 μg/mL P = 0.052; high vs. low 5.2 vs. 2.2 μg/mL, P &lt; 0.0001) and week 16 (high vs. intermediate 2.9 vs. 2.1 μg/mL P = 0.0053; high vs. low 2.9 vs. 1.2 μg/mL, P &lt; 0.0001). CONCLUSION: Predictors of response to UST were identified and successfully modelled into a CDST which can stratify the probability of achieving early clinical remission and rapidity in onset of action in individual CD patients. A statistically significant relationship between UST trough concentrations, probability groups, and efficacy was observed.

Clinical Consequences of Antibody Formation, Serum Concentrations, and HLA-Cw6 Status in Psoriasis Patients on Ustekinumab.

Background:Ustekinumab for the treatment of psoriasis is currently administered in a standard dosing regimen. However, some patients tend to benefit from alternative dosing regimens, a step toward personalized medicine.Methods:To investigate the role of ustekinumab serum concentrations, anti-ustekinumab antibodies [AUA] and HLA-Cw6 status as tools for optimizing ustekinumab treatment, a multicenter prospective cohort study was conducted at an academic hospital with affiliated nonacademic hospitals in Belgium (cohort 1) and 2 academic hospitals in the Netherlands (cohort 2 and 3). Patients with plaque-type psoriasis were eligible if treated with ustekinumab for ≥16 weeks. Serum samples and Psoriasis Area and Severity Index scores were obtained at baseline, week 16, 28, 40, 52, and/or ≥64 of ustekinumab treatment.Results:A total of 137 patients with 229 observations for serum concentrations and AUA and 61 observations for HLA-Cw6 status were included. Presence of AUA (prevalence of 8.7%) was significantly associated with a diminished clinical response (P = 0.032). The median ustekinumab trough concentration was 0.3 mcg/mL (<0.02–3.80). No differences in serum concentrations were observed between moderate to good responders and nonresponders (P = 0.948). Serum trough concentrations were not affected by methotrexate comedication. Prevalence of HLA-Cw6 positivity was 41% with no statistically significant difference in clinical response between HLA-Cw6–positive and HLA-Cw6–negative patients (P = 0.164).Conclusions:The presence of AUA was associated with treatment failure in this patient population; measurement of AUA may therefore be a candidate marker for personalized pharmacotherapy. The clinical utility of ustekinumab serum trough concentrations or HLA-Cw6 status determination remains less clear. Further exploration on the potential of measuring ustekinumab serum concentrations and other biomarkers in predicting therapy outcomes should be encouraged.