Attenuation of inflammatory response with IL-6 receptor antagonist in NSTEMI patients
Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial
Kleveland O, Kunszt G, Bratlie M, et al.
Eur Heart J 2016; published online ahead of print
BackgroundThe prognosis of ACS has been associated with inflammation . IL-6 is a multifunctional cytokine with an apparent causal role in CAD, since IL-6 contributes to:
- atherosclerotic plaque development and destabilisation [2,3]
- myocardial ischemia and reperfusion injury 
- increased mortality in ACS patients 
- activation of the C-reactive protein, a predictor of adverse outcomes in ACS [1,5]
Tocilizumab is a humanized IL-6R antibody that is effective and generally well-tolerated in patients with autoimmune disorders [7,8], and may also attenuate the acute inflammatory response in ACS and reduce TnT release.
In this randomised, controlled trial, the effect of short-time inhibition of IL-6 signaling with tocilizumab in 117 patients with NSTEMI was evaluated.
- The median area under the curve (AUC) for high-sensitivity C-reactive protein during hospitalisation was 2.1 times higher in the placebo compared with the tocilizumab group (4.2 vs. 2.0 mg/L/h; P < 0.001).
- The median AUC for hsTnT during hospitalisation was 1.5 times higher in the placebo group compared with the tocilizumab group (234 vs. 159 ng/L/h; P = 0.007).
- The differences between the two treatment groups were observed mainly in patients included ≤2 days from symptom onset and patients treated with PCI
- in the tocilizumab group there was a pronounced increase in IL-6 that persisted during hospitalisation
- in the placebo group, there was a modest but significant increase in IL-6 levels
- the between-group differences in changes from baseline were significant throughout hospitalisation
- changes of C-reactive protein were inversely correlated with changes in IL-6, only in the tocilizumab group
- The total leukocyte count increased in the placebo group but decreased in the tocilizumab group (from 7.7 [109/L] at baseline to 4.4 at day 3; P < 0.001), resulting in significant between-group differences in changes from baseline (P < 0.001). This difference was mainly driven by a decrease in neutrophils in patients receiving tocilizumab, but levels returned to normal during the long-term follow-up
- There were modest between-group differences in changes from baseline in alanine aminotransferase and total cholesterol during hospitalisation, but there were no between-group differences at follow-up
ConclusionIn 117 patients with NSTEMI, short-time inhibition of IL-6 with tocilizumab attenuated the inflammatory response and primarily PCI-related TnT release, suggesting a link between inflammation and myocardial injury in these patients. There were no major safety concerns.
An increase in IL-6 levels has also been observed in autoimmune patients treated with tocilizumab and may reflect attenuated elimination of IL-6 from the circulation, as IL-6 receptor interaction is blocked and thereby IL6-R-mediated clearance .
Find this article online at Eur Heart J
1. Zamani P, Schwartz GG, Olsson AG, et al. Inflammatory biomarkers, death, and recurrent nonfatal coronary events after an acute coronary syndrome in the MIRACL study. J Am Heart Assoc 2013;2:e003103.
2. Yudkin JS, Kumari M, Humphries SE, et al. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 2000;148:209–214.
3. Swerdlow DI, Holmes MV, Kuchenbaecker KB, et al. The interleukin-6 receptor as a target for prevention of coronary heart disease: a Mendelian randomisation analysis. Lancet 2012;379:1214–1224.
4. Sawa Y, Ichikawa H, Kagisaki K, et al. Interleukin-6 derived from hypoxic myocytes promotes neutrophil-mediated reperfusion injury in myocardium. J Thorac Cardiovasc Surg 1998;116:511–517.
5. Castell JV, Gomez-Lechon MJ, David M, et al. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett 1989;242:237–239.
6. Verma S, Li SH, Badiwala MV, et al. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation 2002;105:1890–1896.
7. Nishimoto N, Terao K, Mima T, et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 2008;112:3959–3964.
8. Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo controlled, randomised trial. Lancet 2008;371:987–997.
9. Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 2008;112:3959–3964.