AB0122 TNF INHIBITION IN RHEUMATOID ARTHRITIS RESPONDERS TO CERTOLIZUMAB-PEGOL REDUCES LYMPHOCYTE RECRUITMENT FROM BLOOD WHILE MONOCYTE TURNOVER REMAINS INCREASED
Authors: Biljana Smiljanovic, Till Sörensen, Marc Bonin, Pascal Schendel, Sascha Johannes, Karl Skriner, Marina Backhaus, Silvia Pade, Gabriela Schmittat, Sandra Hermann, Sarah Ohrndorf, Bruno Stuhlmüller, Andreas Grützkau, Gerd Rüdiger Burmester, Thomas Häupl
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Increased turnover of monocytes is a hallmark of active RA <sup>1</sup>. Targeting the mediators of monocyte activation like TNF or IL6 is a successful strategy in reducing inflammation in RA. <h3>Objectives:</h3> To investigate differential effects of anti-TNF treatment in responders and non-responder on turnover of peripheral leukocytes in patients with rheumatoid arthritis. <h3>Methods:</h3> Immune cell profiling in a subgroup of 36 patients of the BIORAC open-label 52-weeks treatment study with certolizumab-pegol (CZP) by multicolor flow cytometry at baseline, week 12 and 52. Cell populations were analyzed with <i>immuno</i>Clust <sup>2</sup> <h3>Results:</h3> Of the 36 RA patients with initial DAS28 of 4.75, response to CZP occurred in 18 patients after 12 weeks and 15 patients after 52 weeks (both Δ-DAS28 -1.4). When comparing populations during the course of treatment, there was no relevant change in the number of monocytes or granulocytes. However, as previously reported <sup>1</sup>, the most characteristic observation was the reduced absolute number of non-classical CD16<sup>+</sup>CD14<sup>low</sup> monocytes at baseline when compared to healthy controls. This corresponds to increased monocyte turnover and recruitment to inflamed tissue. In both, responders and non-responders this monocyte population did not increase or change over time despite reduction of DAS28 disease activity in responders. In responders to CZP, the absolute number of T-cells, B-cells and NK-cells as well as their subsets including naïve-, central- and effector-memory T-cells and naïve-, unswitched- and switched memory B-cells and plasmablasts increased compared to baseline. In non-responders to CZP, the absolute number of T-cells, B-cells and NK-cell remained unchanged. In CZP responders, the cell frequencies in T-cell subsets shifted from a naïve towards a central and effector phenotype, while in non-responder no changes were identified. <h3>Conclusion:</h3> In responders, successful reduction of subsequent events of immune activation by anti-TNF drugs will decrease inflammation and thus decrease recruitment of lymphocytes to tissue. Initial triggering seems to involve especially monocytes, which are typical producers of TNF and which are still recruited to tissue much more than in healthy controls as indicated by persisting reduction of non-classical monocytes even in responders. Thus, increase of lymphocytes in the blood upon response seems to reflect ongoing mobilization from bone marrow and lymphatic organs into the blood but reduced recruitment to tissues when local inflammation is successfully suppressed. Altogether, these changes indicate that triggers for monocyte recruitment exist and persist despite immunosuppression with anti-TNF whereas lymphocyte recruitment is successfully suppressed in responders to anti-TNF. <h3>References</h3> [1] Smiljanovic B, et al. Monocyte alterations in rheumatoid arthritis are dominated by preterm release from bone marrow and prominent triggering in the joint. Ann Rheum Dis. 2018;77(2):300-308. [2] Sörensen T, et al. immunoClust-An automated analysis pipeline for the identification of immunophenotypic signatures in high-dimensional cytometric datasets. Cytometry A. 2015;87(7):603-615. <h3>Disclosure of Interests:</h3> Biljana Smiljanovic: None declared, Till Sörensen: None declared, Marc Bonin: None declared, Pascal Schendel: None declared, Sascha Johannes: None declared, Karl Skriner: None declared, Marina Backhaus: None declared, Silvia Pade: None declared, Gabriela Schmittat: None declared, Sandra Hermann: None declared, Sarah Ohrndorf: None declared, Bruno Stuhlmüller: None declared, Andreas Grützkau: None declared, Gerd Rüdiger Burmester Consultant for: Roche, Sanofi-Genzyme, Speakers bureau: Roche, Sanofi-Genzyme, Thomas Häupl: None declared