THU0028 Interleukin-6 receptor inhibition, as first-line b-dmard, affects b cell subpopulations distribution through epigenetic modifications in rheumatoid arthritispatients
Authors: S. Alivernini, B. Tolusso, A.L. Fedele, C. Di Mario, L. Petricca, G. Di Sante, M.R. Gigante, G. Ferraccioli, E. Gremese
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Despite IL-6R inhibition was found to influence B cell subpopulations distribution in Rheumatoid Arthritis (RA), no data are available on the effect on epigenetic signature of RA B cells by this treatment. It is well known that B cell maturation is under control of the microRNA-155 (miR-155)/PU.1 axis significantly influenced by IL-6 stimulation<sup>1</sup>. <h3>Objectives</h3> To investigate the effect of IL-6R inhibition on the epigenetic signature of B cells (miR-155/PU.1 axis) in RA patients. <h3>Methods</h3> Twenty-nine RA patients [18 (62.1%) female; 57.2±14.9 years old; disease duration 1.3±0.7 years] starting IL-6R inhibitor treatment as first b-DMARD, have been enrolled. At study entry and after 3–6–12–18 months follow-up, CD19<sup>+</sup> cells were isolated from peripheral blood (PB) by magnetic microbeads (Miltenyi) and B cells subpopulations were assessed through FACS according to the IgD/CD27 classification. MiR-155 and PU.1 endogenous expression was determined in PB-derived CD19<sup>+</sup> cells by RT-PCR at baseline and after 3–6–12–18 months follow-up. IL-6 plasma level was assessed by ELISA at study entry for each patient. ACR/EULAR criteria were used to assess the response rate to IL-6R inhibitor treatment for each RA patient. PB-derived CD19<sup>+</sup> cells of healthy individuals (HC) were used as comparison group. <h3>Results</h3> At study entry, RA patients showed higher percentage of IgD<sup>-</sup>/CD27<sup>-</sup> CD19<sup>+</sup> cells (p&lt;0.05) and IgD<sup>+</sup>/CD27<sup>+</sup> CD19<sup>+</sup> cells (p&lt;0.05) than HC. Moreover, IgD<sup>-</sup>/CD27<sup>-</sup> CD19<sup>+</sup> cells percentage directly correlated with Disease Activity Score (p=0.04) and IL-6 plasma levels (p=0.06) in RA patients. IL-6R inhibition lead to DAS and SDAI remission achievement in 73.9% and 52.2% of RA patients after 18 months follow-up, respectively, and significantly reduced IgD<sup>-</sup>/CD27<sup>-</sup> CD19<sup>+</sup> cells percentage after 18 months follow-up (p&lt;0.02). Stratifying RA patients based on the remission achievement during the follow-up, RA patients who achieved DAS remission under IL-6R inhibition showed a significant decreased of IgD<sup>-</sup>/CD27<sup>-</sup> CD19<sup>+</sup> cells percentage compared to patients not achieving this outcome (p&lt;0.05), reaching IgD<sup>-</sup>/CD27<sup>-</sup> CD19<sup>+</sup> cells percentage comparable to HC (p&gt;0.05). Analysing the epigenetic profile in B cells of RA patients, at baseline, PB-derived CD19<sup>+</sup> cells of RA patients showed significantly higher endogenous expression of miR-155 (p=0.04) than HC. Moreover, RT-PCR showed that IL-6R inhibition significantly represses endogenous miR-155 expression in PB-derived RA B cells already after 3 months of treatment (p&lt;0.05) and restores PU.1 expression in PB-derived B cells after 6 months (p&lt;0.05) only in RA patients achieving disease remission. <h3>Conclusions</h3> IL-6R inhibitor, used as first b-DMARD treatment, acts restoring B cells homeostasis through epigenetic modulation in RA. In particular, IL6-R inhibition significantly represses endogenous expression of miR-155 in PB-derived CD19<sup>+</sup> cells conversely restoring PU.1 expression mirrored by the decrease of IgD<sup>-</sup>/CD27<sup>-</sup> B cell rate in RA patients achieving disease remission. <h3>Reference</h3> [1] Alivernini S, Kurowska-Stolarska M, Tolusso B, et al. Nat Commun2016. <h3>Disclosure of Interest</h3> None declared