Optimisation of anti-interleukin-6 therapy: Precision medicine through mathematical modelling

BackgroundDysregulated interleukin (IL)-6 production can be characterised by the levels present, the kinetics of its rise and its inappropriate location. Rapid, excessive IL-6 production can exacerbate tissue damage in vital organs. In this situation, therapy with an anti-IL-6 or anti-IL-6 receptor (IL-6R) monoclonal antibody, if inappropriately dosed, may be insufficient to fully block IL-6 signalling and normalise the immune response.MethodsWe analysed inhibition of C-reactive protein (CRP) – a biomarker for IL-6 activity – in patients with COVID-19 or idiopathic multicentric Castleman disease (iMCD) treated with tocilizumab (anti-IL-6R) or siltuximab (anti-IL-6), respectively. We used mathematical modelling to analyse how to optimise anti-IL-6 or anti-IL-6R blockade for the high levels of IL-6 observed in these diseases.ResultsIL-6 signalling was insufficiently inhibited in patients with COVID-19 or iMCD treated with standard doses of anti-IL-6 therapy. Patients whose disease worsened throughout therapy had only partial inhibition of CRP production. Our model demonstrated that, in a scenario representative of iMCD with persistent high IL-6 production not controlled by a single dose of anti-IL-6 therapy, repeated administration more effectively inhibited IL-6 activity. In a situation with rapid, high, dysregulated IL-6 production, such as severe COVID-19 or a cytokine storm, repeated daily administration of an anti-IL-6/anti-IL-6R agent, or alternating daily doses of anti-IL-6 and anti-IL-6R therapies, could neutralise IL-6 activity.ConclusionIn clinical practice, IL-6 inhibition should be individualised based on pathophysiology to achieve full blockade of CRP production.FundingEUSA Pharma funded medical writing assistance and provided access to the phase II clinical data of siltuximab for analysis

Efficacy and Safety of Prostatic Arterial Embolization: Systematic Review with Meta-Analysis and Meta-Regression

Purpose: This study attempted to overcome the limitations of previous systematic reviews to determine the overall treatment efficacy and safety of prostatic arterial embolization compared with standard therapy. Materials and Methods: Meta-analyses were done of randomized, controlled and single group trials. Meta-regression analysis of the moderator effect was performed with single group analysis. The outcomes measured were mean changes in I-PSS (International Prostate Symptom Score), quality of life, maximal urinary flow rate, prostate volume, post-void residual volume and prostate specific antigen. Adverse events were compared as proportional differences between the embolization group and groups receiving other therapies in comparative studies. Results: A total of 16 studies met our selection criteria and were included in the meta-analysis. Three studies were comparative and included a total of 297 subjects, including 149 in the experimental groups and 148 in the control groups. The other 13 studies were noncomparative and included a total of 750 experimental subjects. Pooled overall standardized mean differences for embolization in I-PSS, maximal urinary flow rate and prostate volume were significantly impaired in the experimental vs control groups. Overall weighted mean differences for all outcomes except prostate specific antigen were significantly improved from baseline by embolization treatment in noncomparative studies. Sensitivity analysis of study duration showed that all outcome measurements did not differ before vs after 6 months. Conclusions: Although there is growing evidence of the efficacy and safety of prostatic arterial embolization for benign prostatic hyperplasia, this systematic review using meta-analysis and meta-regression showed that prostatic arterial embolization should still be considered an experimental treatment modality.11148sciescopu