Predictive models assessing the response to ustekinumab highlight the value of therapeutic drug monitoring in Crohn's disease.

BACKGROUND: Despite the therapeutic efficacy of Ustekinumab (UST) in Crohn's disease (CD), loss of response (LOR) is observed over time. This study aims to evaluate the impact of the UST pharmacokinetics (PK) at induction on clinical and endoscopic outcomes, as well as to find predictive markers of UST response. METHODS: This retrospective study included 80 CD patients. Pharmacokinetics data (trough levels (TLs)) combined with clinical and biological parameters were fed into tailored logistic regression and tree-based ensemble techniques to predict clinical and endoscopic outcomes at one year of follow-up. RESULTS: TLs at week 16 were significantly lower among patients with moderate to severe endoscopic activity during the follow-up (p = 0.04). The best model to predict endoscopic outcome was obtained at week 16 by Random Forest with an area under the receiver operating characteristic curve of 0.92 ± 0.08, sensitivity 91% and specificity 75%, with key inputs such as lymphocyte and monocyte counts at week 8, and UST TLs and CRP at week 16. CONCLUSIONS: This real-world study confirms the relationship between early UST TLs and both clinical and endoscopic outcomes. Models were developed for the task of predicting clinical and endoscopic remission in CD patients treated with UST, highlighting the clinical relevance of UST TLs at week 16.

Collecting New Peak and Intermediate Infliximab Levels to Predict Remission in Inflammatory Bowel Diseases.

BACKGROUND: The loss of response to infliximab is a challenge for clinicians in the management of inflammatory bowel disease (IBD). Mounting evidence suggests that therapeutic drug monitoring at induction may predict remission during maintenance. The aim of the study was to improve predictive models of remission by exploring new peak and intermediate infliximab measurements during induction. METHODS: This was a prospective multicenter study evaluating the pharmacokinetics of infliximab during induction in a pioneer cohort of 63 patients with IBD. Pharmacokinetics data including peak, intermediate, and trough levels were combined with clinical and biological parameters and were subsequently fed into tailored logistic regression and tree-based techniques to predict remission at week 30. RESULTS: Infliximab peak levels at week 2, intermediate levels at week 3, and trough levels at week 6 were correlated with remission at week 30. Predictive models exhibited an increased accuracy over the successive timepoints of the induction with key inputs such as albumin, C-reactive protein, eosinophils, neutrophils, lymphocytes, intermediate level at week 3, trough level at week 6, and age at diagnosis. Our predictive model of remission at week 30 was obtained with an area under the receiver operating characteristic curve of 0.9 ±â€…0.12, a sensitivity of 89%, and a specificity of 75%. CONCLUSIONS: This study showed the clinical relevance of measuring new infliximab levels to predict remission in patients with IBD. These findings lay the foundation for a personalized medicine in which biotherapies could be monitored at an early stage, thereby improving patients' clinical management.

New approach to determine the healthy immune variations by combining clustering methods.

Immune-mediated inflammatory diseases are characterized by variability in disease presentation and severity but studying it is a challenging task. Defining the limits of a healthy immune system is therefore a prior step to capture variability in disease conditions. The goal of this study is to characterize the global immune cell composition along with their influencing factors. Blood samples were collected from 2 independent cohorts of respectively 389 (exploratory) and 208 (replication) healthy subjects. Twelve immune cells were measured in blood together with biological parameters. Three complementary clustering approaches were used to evaluate if variability related to the immune cells could be characterized as clusters or as a continuum. Large coefficients of variation confirmed the inter-individual variability of immune cells. Considering all subset variations in an overall analysis, it appeared that the immune makeup was organized as a continuum through the two cohorts. Some intrinsic and environmental factors affected the inter-individual variability of cells but without unveiling separable groups with similar features. This study provides a framework based on complementary clustering approach for analyzing inter-individual variability of immune cells. Our analyses support the absence of clusters in our two healthy cohorts. Also, our study reports some influence of age, gender, BMI, cortisol, season and CMV infection on immune variability.

Infliximab Trough Levels at Induction to Predict Treatment Failure During Maintenance.

BACKGROUND: Infliximab (IFX) is indicated for the treatment of inflammatory bowel diseases (IBD). Nevertheless, loss of response (LOR) to IFX is reported in up to 10% to 30% of patients within the first year of treatment. Our objective was to evaluate the impact of the pharmacokinetics of IFX at induction on treatment failure. METHODS: This is a longitudinal cohort study on 269 patients with IBD treated with IFX in a single center. A total of 2331 blood samples were prospectively collected from 2007 until March 2015 with a retrospective analysis of clinical data. IFX trough levels (TLs) were measured by enzyme-linked immunosorbent assay. Antibodies to IFX were measured by drug-sensitive bridging assay. RESULTS: During follow-up, patients were defined according to treatment outcome. At week 6, median IFX TL in patients requiring a switch to another treatment due to LOR (LOR switched group) (2.32 µg/mL [0.12-19.93 µg/mL]) was lower than in patients with long-term response (long-term responders) (8.66 µg/mL [0.12-12.09 µg/mL], P = 0.007) and in patients responding to optimization (LOR optimized group) (7.28 µg/mL [0.17-14.91 µg/mL], P = 0.021). At week 2, median IFX TL was lower in the LOR switched group (5.7 µg/mL [0.15-12.09 µg/mL]) compared with the long-term responders (11.92 µg/mL [0.14-19.93 µg/mL], P = 0.041) but no significant difference was reached with the LOR optimized group (11.91 µg/mL [0.23-12.09 µg/mL], P = 0.065). In the LOR switched group, median IFX TL at induction (weeks 2 and 6) was significantly lower when patients had been previously exposed to anti-tumor necrosis factor compared with naive patients (0.91 µg/mL [0.12-4.4 µg/mL] versus 6.6 µg/mL [0.15-19.93 µg/mL], P = 0.044). CONCLUSIONS: This study suggests that patients who do not respond to any optimization strategy have lower IFX TLs during induction at week 6. IFX TLs measured early on at induction might predict treatment failure to IFX during maintenance.