Background Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial hyperplasia, mononuclear cell infiltration, bone erosion and joint destruction. We have shown recently the involvement of genes responsible for proliferation, autophagy, apoptosis, tissue degradation, and inflammation measured in the peripheral blood mononuclear cells (PBMCs) in the disease activity and joint destruction in rheumatoid arthritic patients treated with methotrexate (MTX) (Tchetina et al., Int J Rheumatol, 2013; 2013:457876). Here we hypothesized that expression of the genes responsible for cell proliferation and growth (mTOR), autophagy (ULK1), bone and articular cartilage resorption (MMP-9), and inflammation (TNFα) measured in the PBMCs at baseline might be associated with treatment outcome.
Objectives We seek an association between the baseline gene expression of MMP-9, ULK1, mTOR, and TNFα in PBMCs with the disease activity and joint degeneration indices after 24 months of follow-up in RA patients treated with MTX.
Methods Peripheral blood of 40 RA patients aged 47.5±15.5 years old, disease duration 7.9±6.0 weeks treated with MTX (15 mg/week) during two years and 26 healthy age-matched control subjects were examined in this study. Clinical response was assessed by DAS28, serum levels of ACPA, CRP, and RF. Bone erosion and joint space narrowing (JSN) scores were monitored by X-ray analysis. Total RNA isolated from the PBMCs was used in gene expression studies performed with quantitative Real-time RT-PCR.
Results Treatment of RA patients with MTX during 24 months resulted in significant decrease of DAS28, CRP, RF values, joint stiffness, tender and swollen joint numbers and an increase in bone erosion numbers and JSN versus that at baseline. Expression of MMP-9 and ULK1 measured in the PBMCs was significantly upregulated both at baseline and after 24 months of follow-up in RA patients compared to controls while the upregulated baseline mTOR and TNFα gene expression decreased to the level of healthy subjects after 24 months. Positive correlation (Spearman's correlation coefficient) of baseline MMP9 (r=0.370, p=0.04) and ULK1 (r=0.360, p=0.04) gene expression with swollen joint numbers measured after 24 months of follow-up was observed. Negative correlation was noted between baseline mTOR gene expression with swollen joints (r=-0.446, p=0.01) and erosion numbers (r=-0.430, p=0.02) both measured after 24 months of follow-up. Baseline TNFα gene expression also negatively correlated with joint stiffness (r=-503, p=0.002), swollen (r=-0.434, p=0.01), and tender (r=-0.362, p=0.03) joint numbers measured after 24 months of follow-up.
Conclusions Our results show that baseline MMP9 and ULK1 gene expression is associated with joint inflammation. High baseline gene expression of mTOR and TNFα in PBMCs is associated with better response to MTX treatment in terms of joint function (TNFα), joint inflammation (TNFα and mTOR), and bone destruction (mTOR) in RA patients after 24 months of follow-up and therefore might be protective.
Acknowledgments This study was funded by Russian Foundation for Basic Research (project no. 12-04-00038-a to EVT).
Disclosure of Interest None declared