Background Tocilizumab (TCZ) is an effective treatment in Rheumatoid Arthritis (RA) inducing modifications of B cell subsets in vivo.1–3
Objectives To define whether the study of circulating B cell subsets could represent a possible tool to understand the pharmacological action of TCZ, helping the clinician to identify the best responders to IL6R blockade.
Methods 70 RA patients (age 52.3±15.2 years, disease duration 8.5±10.1 years, 74.3% female) not responder to previous cDMARDs (n=39) and/or bDMARDS (n=31) were enrolled in the study, of which 19 (27.1%) with early RA (ERA) and 51 (72.9%) with a long-standing disease (LSRA). All patients were treated with TCZ at a dose of 8 mg/kg every 4 weeks. At each visit remission was evaluated according to ACR/EULAR criteria4 and peripheral blood (PB) derived B cells were collected for the analysis of B-cell subsets distribution by FACS using IgD-CD27 classification5. Among them, PB-derived B cells from 13 bDMARDs naïve RA patients were analyzed for specific genes expression through RT-PCR.
Results In RA cohort, 16.7% and 19.3% of TCZ-treated RA patients reached ACR/EULAR remission (SDAI≤3.3) at 6th and 12th months FU. At TCZ baseline, a higher percentage of post-switched memory B-cells (p=0.005) together with plasmablasts (p<0.001) and a lower percentage of pre-switched memory B cells (p=0.01) were observed in RA patients compared to Healthy Controls (HC, n=45) mainly in bDMARDs naïve patients. After TCZ treatment, we showed an increase of pre-switched memory and a reduction of post-switched memory and double negative (DN) B cells in responders, more evident in patients reaching remission. In particular, patients reaching SDAI remission at 6 and 12 months of TCZ-treatment had a higher reduction of DN B cell subsets already after 3 months reaching a comparable value as in HC (p<0.05). At the multivariate analysis, a disease duration less than 12 months [OR (95%CI): 18.0 (1.6–203.9)], a moderate disease activity (SDAI≤26) at baseline [OR (95%CI): 20 (1.7–250)] and a higher reduction of DN B cells at 3 months of FU [OR (95%CI): 1.05 (1.01–1.08)] arose as significant independent predictors of ACR/EULAR remission (SDAI≤3.3) at 6th months of TCZ treatment. Finally, TCZ-treatment seems to influence B-cell genes expression inducing an up-regulation of proinflammatory molecules (TNF-alpha, IL6) genes, together with the related STAT3, SYK and ZAP-70 genes, in the earlier treatment phases (3 and 6 months respectively) and the subsequent down-regulation of their receptors (TNF-RII and IL6R). Interestingly, the expression of JAK1 decreased significantly at the 12th month, whereas that of JAK3 did not change at the different time points.
Conclusions In our cohort of TCZ-treated RA patients, a significant reduction of DN memory B cells at the 3th month of FU has emerged as an early biomarker of remission afterwards. At the same time, profound effects at the JAK1 gene level occurred in B cells after TCZ treatment, even if an increase of Syk and ZAP-70 genes expression was observed, suggesting that B cells are not fully deactivated even after 6–12 months of treatment.
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Muhammad K et al. Ann Rheum Dis 2011;
Mahmood Z et al. Arth Res Ther 2015;
Felson DT et al. Arthritis Rheum 2011;
Sanz I et al. Semin Immunol 2008.
Disclosure of Interest None declared