Journal Article

03.24Effect of tocilizumab therapy on il-6 signalling pathway in early rheumatoid arthritis patients

Hunt, Laura, Buch, Maya H, McDermott, Michael F, Ouboussad, Lylia, Aslam, Aamir, Wong, Chi, Emery, Paul

2017

Overview

BackgroundWe previously reported increased constitutive but unchanged induced CD4+ p-STAT3 in established RA versus healthy control (HC).1 This study aims to evaluate in early RA (ERA) (i) cell-subset constitutive and Cis (IL-6) and Trans (IL-6/sIL6R)-induced IL-6 signalling (ii) effect of tocilizumab (TCZ; +/-MTX) (iii) for an association between baseline phosphorylation intensities and TCZ (+/- MTX) response.Materials and methodsMultiparameter phosphoflow cytometry was performed on 20 treatment-naive, ERA patients randomised to TCZ monotherapy or TCZ-MTX to determine STAT3, Akt and Erk phosphorylation intensities. PBMCs were isolated and cryopreserved at baseline, and weeks 24 and 48 post-TCZ. HC samples (n=10) were also obtained. PBMCs were unmodulated, stimulated with IL-6 or soluble IL-6 receptor (sIL-6R) and median fluorescence intensities (MFI) were measured.Results Baseline data, HC and ERA Constitutive CD4+ p-STAT3 was numerically higher in ERA compared to HC, with non-significant increase following stimulation in both groups.There was no significant difference in constitutive monocyte p-STAT3 in HC vs ERA. Stimulation did not induce further increase in monocyte p-STAT3 in ERA.Constitutive CD4+ p-Akt was significantly higher in ERA versus HC (p=0.01), with no change post-stimulation. Pre/Post TCZ in ERA Constitutive CD4+ pSTAT3 expression did not alter following TCZ exposure.Statistically significant decreases in IL-6 stimulated CD4+ pSTAT3 expression from baseline to weeks 24 and 48 were observed (p=0.005 and 0.01 respectively); and similarly using IL-6/sIL-6R at week 48 (p=0.01).Constitutive monocyte p-STAT3 expression appeared to increase at week 24 compared to baseline (p=0.03); similar observation following stimulation with IL-6/sIL-6R at both weeks 24 and 48 was observed (p=0.01)TCZ led to non-significant decrease in constitutive and IL6-stimulated CD4+ p-Akt expression weeks 24 and 48. TCZ otherwise had no significant effect on p-Akt and p-Erk in other studied cell subsets.ConclusionsTCZ reduced induced IL-6 signalling via CD4+ STAT3. This preliminary analysis also suggests importance of monocyte subset and relevance of Akt in IL-6 signalling. Complete analysis of these data will clarify the relative roles and impact of IL-6R targeting further.ReferencesOuboussad L, Wong C, Hunt L, Emery P, McDermott MF, Buch MF. Investigating IL-6 pathway signalling kinetics in peripheral blood single cell subsets with tocilizumab therapy in patients with early rheumatoid arthritis. Ann Rheum Dis2016; 75(Suppl 1):A31.2-A31.