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.

Early vedolizumab trough levels at induction in inflammatory bowel disease patients with treatment failure during maintenance.

BACKGROUND: Vedolizumab (VDZ) is effective as an induction and maintenance treatment for Crohn's disease and ulcerative colitis, but, as observed with antitumour necrosis factor-α (anti-TNFα) agents, some patients are nonetheless experiencing loss of response. OBJECTIVE: The aim of this study was to investigate the impact of the pharmacokinetics of VDZ during induction on long-term treatment response. PATIENTS AND METHODS: This study focused on a single cohort of 103 inflammatory bowel disease patients treated with VDZ. VDZ trough levels (TLs) were measured by enzyme-linked immunosorbent assay (n=536 samples), and thereafter correlated to clinical, biological, endoscopic and serological data. For patients exposed previously to infliximab, antibodies to infliximab were measured at baseline. On the basis of the outcome at the end of follow-up, patients were then categorized into long-term response, optimized and treatment failure groups. RESULTS: During VDZ induction, at week 6, inflammatory bowel disease patients with long-term response had higher TLs compared with patients in the treatment failure group (33 vs. 24 µg/ml, P=0.02). A cut-off TL of 28 µg/ml predicted a sustained response in the follow-up with an area under curve of 0.723 (95% confidence interval=0.567-0.878, P=0.02). Patients with mucosal healing in maintenance had higher TLs at week 6 (41.65 µg/ml) compared with patients with mild (26 µg/ml) or severe endoscopic activity (20.8 µg/ml), P=0.009. Positive perinuclear antineutrophil cytoplasmic antibody serology was associated with lower TLs. Patients previously exposed to anti-TNFα had lower TLs than naive patients (22.5 vs. 36 µg/ml, P=0.03) without any impact of detectable antibodies to infliximab. Finally, the presence of an immunomodulator at induction did not impact on VDZ TLs at induction. CONCLUSION: We confirmed that a drug exposure-efficacy association was found early on at induction. This study emphasizes that previous exposure to anti-TNFα and positive perinuclear antineutrophil cytoplasmic antibody serology are important factors influencing VDZ TLs at induction.