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AB0529 Rituximab therapy monitoring by mtor, autophagy-related ULK1, caspase 3, CDK-inhibitor P21, TNF alpha, and osteoclast-specific cathepsin K and gelatinase MMP-9 gene expression in the peripheral blood of rheumatoid arthritis patients
  1. E.V. Tchetina1,
  2. K.H. Kuzikyants2,
  3. A.Y. Devyataikina2,
  4. G.V. Lukina2,
  5. E.L. Nasonov3
  1. 1Genetics
  2. 2Clinical Pharmacology
  3. 3Systemic Rheumatological Disorders, Research Institute of Rheumatology, Moscow, Russian Federation

Abstract

Background Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial hyperplasia, mononuclear cell infiltration, bone erosion and joint destruction. Altered rates of cell proliferation and apoptosis were also observed in RA. We hypothesized that expression of the genes responsible for cell growth and proliferation (mTOR, p21), autophagy (ULK1), apoptosis (caspase 3), inflammation (TNFalpha), and bone resorption (cathepsin K and gelatinase MMP-9) measured in the peripheral blood could serve important biomarkers for anti-rheumatic therapy monitoring.

Objectives To find peripheral blood gene expression indicators pointing to treatment efficacy of rituximab in RA patients.

Methods 12 seropositive RA females aged 52±12.0 years old, disease duration 7.6±5.8 years (with previous failure to DMARD and anti-TNFalpha blockers) treated with rituximab (0.5-1g) for a single treatment course, and 47 healthy age-matched control femaleswere examined in this study. Clinical response was assessed by disease activity score (DAS) 28, erythrocyte sedimentation rate (ESR), serum levels of anti-CCP antibodies, C-reactive protein (CRP), and rheumatoid factor (RF). Bone erosion and joint space narrowing scores were monitored by X-ray analysis. Total RNA isolated from the peripheral blood was used in gene expression studies performed with quantitative Real-time RT-PCR. p70-S6K, p21, and caspase 3 protein levels were quantified by ELISA.

Results Expression of all the examined genes measured in the peripheral blood was significantly upregulated (p<0.05) in RA patients compared to control at baseline. Rituximab treatment resulted in a significant decrease (p<0.05) in DAS 28, ESR, and CRP values. This was associated with significant downregulation of mTOR, p21, caspase 3, ULK1, MMP-9, and cathepsin K gene expression, which attained the levels observed in healthy subjects. TNFalpha gene expression has also decreased (p<0.05) versus the baseline values. However it remained significantly higher than that in control subjects. No effect on erosion numbers or joint space narrowing was observed in response to rituximab therapy.

Conclusions Our results show that the examined gene expression measured in the peripheral blood could provide essential information for disease monitoring in RA patients treated with rituximab. Residual upregulated TNFalpha gene expression after rituximab treatment course might indicate the risk of further disease relapse.

Acknowledgments: This study was funded by Russian Foundation for Basic Research (project no. 09-04-01158-r and no. 12-04-00038-r).

Disclosure of Interest None Declared

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