Interleukin-6 receptor inhibition with tocilizumab induces a selective and substantial increase in plasma IP-10 and MIP-1β in non-ST-elevation myocardial infarction

Ola Kleveland; Thor Ueland; Gabor Kunszt; Marte Bratlie; Arne Yndestad; Kaspar Broch; Espen Holte; Liv Ryan; Brage H Amundsen; Bjørn Bendz; Svend Aakhus; Terje Espevik; Bente Halvorsen; Tom E Mollnes; Rune Wiseth; Lars Gullestad; Pål Aukrust; Jan Kristian Damås

doi:10.1016/j.ijcard.2018.04.136

Interleukin-6 receptor inhibition with tocilizumab induces a selective and substantial increase in plasma IP-10 and MIP-1β in non-ST-elevation myocardial infarction

Int J Cardiol. 2018 Nov 15:271:1-7. doi: 10.1016/j.ijcard.2018.04.136. Epub 2018 Jun 29.

Authors

Ola Kleveland¹, Thor Ueland², Gabor Kunszt³, Marte Bratlie⁴, Arne Yndestad⁵, Kaspar Broch⁶, Espen Holte⁷, Liv Ryan⁸, Brage H Amundsen⁷, Bjørn Bendz⁹, Svend Aakhus⁷, Terje Espevik⁸, Bente Halvorsen¹⁰, Tom E Mollnes¹¹, Rune Wiseth⁷, Lars Gullestad¹², Pål Aukrust¹³, Jan Kristian Damås⁸

Affiliations

¹ Clinic of Cardiology, St. Olavs Hospital, Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology NTNU, Trondheim, Norway. Electronic address: ola.kleveland@stolav.no.
² Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway; K.G. Jebsen Centre of Inflammatory Research, University of Oslo, Norway; K.G. Jebsen Cardiac Research Centre, University of Oslo, Norway.
³ Institute of Clinical Medicine, University of Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁴ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁵ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway; K.G. Jebsen Centre of Inflammatory Research, University of Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Norway.
⁶ K.G. Jebsen Cardiac Research Centre, University of Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁷ Clinic of Cardiology, St. Olavs Hospital, Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
⁸ Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
⁹ Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
¹⁰ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway.
¹¹ Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway; K.G. Jebsen Centre of Inflammatory Research, University of Oslo, Norway; Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Research laboratory, Nordland Hospital, Bodø, Norway; Faculty of Health Sciences, K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway.
¹² Institute of Clinical Medicine, University of Oslo, Norway; K.G. Jebsen Cardiac Research Centre, University of Oslo, Norway; Centre for Heart Failure Research, University of Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
¹³ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Norway; K.G. Jebsen Centre of Inflammatory Research, University of Oslo, Norway.

PMID: 29961572
DOI: 10.1016/j.ijcard.2018.04.136

Abstract

Aim: To evaluate the effect of interleukin-6 inhibition with tocilizumab on the cytokine network in patients with acute non-ST-elevation myocardial infarction (NSTEMI).

Methods: 117 patients with acute NSTEMI were randomised to an intravenous infusion of 280 mg tocilizumab or placebo prior to coronary angiography. Blood samples were obtained at baseline, at 6 consecutive points in time during hospitalisation, and at follow-up after 3 and 6 months. Cytokines (n = 27) were analysed with a multiplex cytokine assay.

Results: Using a mixed between-within subjects analysis of variance, we observed a significant (p < 0.001) between-group difference in changes for interferon gamma-inducible protein (IP-10) and macrophage inflammatory protein-1β (MIP-1β), due to significant increases in the tocilizumab group during hospitalisation (i.e., IP-10 median change from baseline during hospitalisation (m_Δ), placebo: 3 (-60, 68) pg/ml vs tocilizumab: 209 (69, 335) pg/ml; MIP-1β m_Δ, placebo: 5 (-2, 12) pg/ml vs tocilizumab: 39 (24, 63) pg/ml). MIP-1β was inversely correlated to troponin T (r = -0.28, p < 0.05) and neutrophils (r = -0.32, p < 0.05) in the tocilizumab group. In contrast, tocilizumab had only modest or no effects on the other examined cytokines.

Conclusions: Tocilizumab led to a selective and substantial increase in IP-10 and MIP-1β during the acute phase of NSTEMI, with no or only minor effects on the other measured cytokines. ClinicalTrials.gov, NCT01491074.

Keywords: IP-10; Inflammation; Interleukin-6; MIP-1β; Myocardial infarction; Tocilizumab.

Publication types

Multicenter Study
Randomized Controlled Trial

MeSH terms

Aged
Antibodies, Monoclonal, Humanized / pharmacology*
Antibodies, Monoclonal, Humanized / therapeutic use
Biomarkers / blood
Chemokine CCL4 / blood*
Chemokine CXCL10 / blood*
Female
Humans
Male
Middle Aged
Non-ST Elevated Myocardial Infarction / blood*
Non-ST Elevated Myocardial Infarction / drug therapy
Receptors, Interleukin-6 / antagonists & inhibitors*
Receptors, Interleukin-6 / blood*

Substances

Antibodies, Monoclonal, Humanized
Biomarkers
CXCL10 protein, human
Chemokine CCL4
Chemokine CXCL10
Receptors, Interleukin-6
tocilizumab

Associated data

ClinicalTrials.gov/NCT01491074