ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1518

Disentangling the Effects of Tocilizumab on Neutrophil Survival and Function

Timo Gaber1,2,3, Martin Hahne4, Cindy Strehl2, Paula Hoff1, Yvonne Doerffel5, Eugen Feist1, Gerd Burmester1 and Frank Buttgereit6, 1Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany, 2German Rheumatism Research Center (DRFZ), Berlin, Germany, 3Berlin-Brandenburg Center of Regenerative Therapies (BCRT), Berlin, Germany, 4Berlin-Brandenburg School of Regenerative Therapies (BSRT), Berlin, Germany, 5Department of Gastroenterology and Hepatology, Charité University Medicine, Berlin, Germany, 6Charité University Hospital, Berlin, Germany

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy: Novel therapies, Biosimilars, Strategies and Mechanisms in Rheumatoid Arthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose

The synovial tissue in rheumatoid arthritis (RA) represents a hypoxic environment with up-regulated pro-inflammatory cytokines and cellular infiltrates including neutrophils. Tocilizumab, a humanized IgG1 monoclonal antibody directed against the interleukin (IL) 6 receptor, is a potent biologic treatment for RA but the inhibition of the IL6 pathway may also cause unwanted effects such as a decrease in blood neutrophil counts and occasionally high grade neutropenia.

In order to understand both therapeutic and adverse effects of IL6 receptor inhibition, we analysed the effects of tocilizumab on survival, phagocytotic capacity and energy metabolism of neutrophils under normoxic versus hypoxic conditions. 

Methods

Human neutrophils were purified, pre-treated with varying doses of tocilizumab and, for comparison, dexamethasone or vehicle and finally stimulated with lipopolysaccharide (LPS) or left unstimulated. Cells were then incubated under normoxic (18% O2) or hypoxic (1% O2) conditions and subsequently analysed.

Results

Both neutrophil survival and energy availability were significantly decreased by tocilizumab in a dose-dependent manner in LPS stimulated cells, but to a greater extent under normoxia as compared to hypoxia. We also found LPS stimulated phagocytotic activity of neutrophils to be significantly higher under hypoxic versus normoxic conditions, but this difference was significantly reduced by tocilizumab.

Conclusion

Tocilizumab is known for both beneficial effects and a higher incidence of neutropenia (>1/100 bis 1/10) when treating RA patients. Our results suggest that both effects can at least in part be explained by a reduction in neutrophil survival and a dose-dependent inhibition of a hypoxia-induced phagocytic activity of infiltrating hypoxic neutrophils, mimicking conditions of the inflamed joint environment.

Disclosure:

T. Gaber,
None;

M. Hahne,
None;

C. Strehl,
None;

P. Hoff,
None;

Y. Doerffel,
None;

E. Feist,

Roche/Chugaipharma,

6,

Roche/Chugaipharma,

2;

G. Burmester,

AbbVie, Pfizer, UCB, Roche,

2,

AbbVie, BMS, Pfizer, Merck, MedImmune, UCB, Roche,

5,

AbbVie, BMS, Pfizer, Merck, UCB, Roche,

8;

F. Buttgereit,
None.

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