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THU0463 Biological Treatments Given in Patients with Rheumatoid Arthritis or Ankylosing Spondylitis Modify the Histone Acetyltransferase (HAT)/Histone Deacetylase (HDAC) Balance
  1. E. Toussirot1,
  2. D. Wendling2,
  3. G. Herbein3
  4. on behalf of CIC BT 506
  1. 1Clinical Investigation Center Biotherapy
  2. 2Rheumatology
  3. 3Virology, University Hospital, Besançon, France

Abstract

Background Acetylation or deacetylation of the histone proteins are controlled by histone acetyltransferase (HAT) and histone deacetylase (HDAC), respectively. The equilibrium between HAT and HDAC gives insights into the level of gene transcription, including genes coding for inflammatory cytokines such as TNFa. We previously reported an imbalance between HAT and HDAC in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) (ref). The influence of biological treatments, given for these inflammatory rheumatic diseases, on HAT/HDAC ratio is currently unknown.

Objectives to determine whether biological agents used in routine clinical practice in RA or AS may influence the HAT/HDAC ratio.

Methods seven patients with RA and five with AS were evaluated. All were biologic-naïve. Two patients with RA and five with AS received a TNFa inhibitor (etanercept, n=4; infliximab, n=2; adalimumab, n=1) and five patients with RA received rituximab (RTX). Patients were evaluated at baseline and after three months of anti-TNFa or four months of RTX. HAT/HDAC activity was evaluated in PBMC nuclear extracts using colorimetric assay (HAT: Enzo Life Sciences, Koropi, Greece; HDAC: EpiQuik™, Epigentek, Farmingdale, NY, USA). Activity was measured prior to, and after ex vivo exposure of PBMCs to the HDAC inhibitors (HDACi) trichostatin A (TSA) and sirtinol (Sirt)

Results all patients responded to treatment. With TNFa inhibitors, HAT activity increased considerably in patients with RA (+236%) or AS (+198%). Similar changes were observed for HAT with TSA (+114.5%) or Sirt (+38%) added to PBMC nuclear extracts in RA. In AS, there were no changes for HAT in PBMCs measured with TSA or Sirt. For HDAC, there was a decrease in RA (-41%) while in AS, no variation was observed. With HDACi, we found a decrease in the levels of HDAC in RA (TSA: -22.7%; Sirt: -41.5%) while in AS, only TSA induced a decline in HDAC (-43.6%). Under RTX, both HAT and HDAC increased (+445.2% and +73.9%). The addition of TSA or Sirt to PBMC nuclear extracts increased the levels of HAT (+15.6% and +109.8%) while HDAC tended to decrease (- 32.6% and -17.9%).

Conclusions Our results indicate a clear increase of the HAT/HDAC ratio in RA and AS during anti-TNFa therapy, while RTX increased both HAT and HDAC. HDACi have been reported to limit production of proinflammatory cytokines including TNFa, and expression of the sirtuin 1 (SIRT1) gene is under the control of NF-kB, which is activated by TNFa. TNFa inhibitors via deactivation of NF-kB could decrease SIRT1 gene expression and activity, and ultimately enhance HAT/HDAC ratio in PBMCs of patients. Our results suggest that an anti-inflammatory biological profile was expressed under the influence of anti-TNFa therapy that increases HAT/HDAC ratio and therefore may contribute to the disease improvement.

References

  1. Toussirot E et al. PlosOne 2013, 8:e70939

Disclosure of Interest : None declared

DOI 10.1136/annrheumdis-2014-eular.2164

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