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THU0028 Interleukin-6 receptor inhibition, as first-line b-dmard, affects b cell subpopulations distribution through epigenetic modifications in rheumatoid arthritispatients
  1. S. Alivernini,
  2. B. Tolusso,
  3. A.L. Fedele,
  4. C. Di Mario,
  5. L. Petricca,
  6. G. Di Sante,
  7. M.R. Gigante,
  8. G. Ferraccioli,
  9. E. Gremese
  1. Uoc of Rheumatology, Fondazione Policlinico Universitario A. Gemelli – Catholic University of the Sacred Heart, Rome, Italy


Background 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 stimulation1.

Objectives To investigate the effect of IL-6R inhibition on the epigenetic signature of B cells (miR-155/PU.1 axis) in RA patients.

Methods 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+ 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+ 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+ cells of healthy individuals (HC) were used as comparison group.

Results At study entry, RA patients showed higher percentage of IgD-/CD27- CD19+ cells (p<0.05) and IgD+/CD27+ CD19+ cells (p<0.05) than HC. Moreover, IgD-/CD27- CD19+ 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-/CD27- CD19+ cells percentage after 18 months follow-up (p<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-/CD27- CD19+ cells percentage compared to patients not achieving this outcome (p<0.05), reaching IgD-/CD27- CD19+ cells percentage comparable to HC (p>0.05). Analysing the epigenetic profile in B cells of RA patients, at baseline, PB-derived CD19+ 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<0.05) and restores PU.1 expression in PB-derived B cells after 6 months (p<0.05) only in RA patients achieving disease remission.

Conclusions 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+ cells conversely restoring PU.1 expression mirrored by the decrease of IgD-/CD27- B cell rate in RA patients achieving disease remission.

Reference [1] Alivernini S, Kurowska-Stolarska M, Tolusso B, et al. Nat Commun2016.

Disclosure of Interest None declared

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