Immunology and Biotherapies

Abstract

Cytokine-targeted therapy has generated a paradigm shift in the treatment of several immune-mediated diseases. Interleukin-6 (IL-6), which was initially identified as B-cell stimulatory factor 2, is a prototypical cytokine with wide-ranging biological effects on immune cells such as B and T cells, on hepatocytes, hematopoietic cells, vascular endothelial cells and on many others. IL-6 is thus crucially involved in the regulation of immune responses, hematopoiesis and inflammation. When infections and tissue injuries occur, IL-6 is promptly synthesized and performs a protective role in host defense against such stresses and traumas. However, excessive production of IL-6 during this emergent process induces potentially fatal complications, including systemic inflammatory response syndrome (SIRS), and dysregulated, persistently high expression of IL-6 causes the onset or development of various chronic immune-mediated disorders. For these reasons, IL-6 blockade was expected to become a novel therapeutic strategy for various diseases characterized by IL-6 overproduction. Indeed, worldwide clinical trials of tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, have successfully proved its outstanding efficacy against rheumatoid arthritis, juvenile idiopathic arthritis and Castleman disease, leading to the approval of tocilizumab for the treatment of these diseases. Moreover, various reports regarding off-label use of tocilizumab strongly suggest that it will be widely applicable for acute, severe complications such as SIRS and cytokine-release syndrome and other refractory chronic immune-mediated diseases.

Via Krishan Maggon

An evaluation of risk factors for major adverse #cardiovascular events during #tocilizumab therapy http://t.co/EymLTiXiv1 #rheum

 

Abstract

Objective. To explore associations of baseline and on-treatment lipid levels, inflammation, and rheumatoid arthritis (RA) disease activity with risk for major adverse cardiovascular events (MACE) in tocilizumab-treated RA patients.

Methods. In retrospective post hoc analyses, data were pooled from 3986 adults with moderate to severe RA administered ≥1 dose of tocilizumab 4 or 8 mg/kg intravenously every 4 weeks in randomized controlled trials and extension studies. Cox proportional hazards modeling was used to evaluate associations among baseline characteristics and posttreatment initiation variables (week 24) and change from baseline to week 24 disease activity and laboratory values, with risk for future MACE during extended follow-up.

Results. There were 50 independently adjudicated cases of MACE during 14,683 patient-years (PY) of follow-up (0.34 MACE/100 PY). At baseline, age, history of cardiac disorders, disease activity score using 28 joints (DAS28), and total cholesterol/high-density lipoprotein ratio were independently (P<0.05 for all) associated with MACE in multivariable models. On treatment, higher DAS28 scores and swollen and tender joint counts at week 24 were associated with future MACE. In separate models, greater reductions in DAS28 score and joint counts from baseline to week 24 were inversely associated with future MACE; changes in lipid parameters were not statistically significantly associated with risk for MACE.

Conclusion. As in the general population, an association was observed between baseline total cholesterol/high-density lipoprotein ratio and increased risk for MACE. Risk for on-treatment MACE, however, was found to be associated with control of disease activity but not lipid changes. Larger studies are needed to confirm these findings. © 2014 American College of Rheumatology.

Via Krishan Maggon