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Rituximab Downregulates Gene Expression Associated with Cell Proliferation, Survival, and Proteolysis in the Peripheral Blood from Rheumatoid Arthritis Patients:A Link between High Baseline Autophagy-Related ULK1 Expression and Improved Pain Control


Affiliations
1 Clinical Immunology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russian Federation
2 Clinical Pharmacology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russian Federation
3 Department of Surgery, Nasonova Research Institute of Rheumatology, Moscow 115522, Russian Federation
4 Forensic Medicine Service, Moscow City Health Department, Moscow 115516, Russian Federation
 

Objective: To clarify molecular mechanisms for the response to rituximab in a longitudinal study. Methods: Peripheral blood from 16 RA patients treated with rituximab for a single treatment course and 26 healthy controls, blood and knee articular cartilages from 18 patients with long-standing RA, and cartilages from 14 healthy subjects were examined. Clinical response was assessed using ESR, ACPA, CRP, RF, DAS28 levels, CD19+ B-cell counts, bone erosion, and joint space narrowing scores. Protein expression in PBMCs was quantified using ELISA. Gene expression was performed with quantitative real-time PCR. Results: A decrease (p < 0.05) in DAS28, ESR, and CRP values after rituximab treatment was associated with the downregulation of MTOR, p21, caspase 3, ULK1, TNFα, IL-1β, and cathepsin K gene expression in the peripheral blood to levels found in healthy subjects. MMP-9 expression remained significantly higher compared to controls although decreased (p < 0.05) versus baseline. A negative correlation between baseline ULK1 gene expression and the number of tender joints at the end of follow-up was observed. Conclusions: The response to rituximab was associated with decreased MTOR, p21, caspase 3, ULK1, TNFα, IL-1β, and cathepsin K gene expression compared to healthy subjects. Residual increased expression in MMP-9, IFNα, and COX2 might account for remaining inflammation and pain. High baseline ULK1 gene expression indicates a good response in respect to pain.
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  • Rituximab Downregulates Gene Expression Associated with Cell Proliferation, Survival, and Proteolysis in the Peripheral Blood from Rheumatoid Arthritis Patients:A Link between High Baseline Autophagy-Related ULK1 Expression and Improved Pain Control

Abstract Views: 75  |  PDF Views: 6

Authors

Elena V. Tchetina
Clinical Immunology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russian Federation
Anastasya N. Pivanova
Clinical Pharmacology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russian Federation
Galina A. Markova
Clinical Immunology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russian Federation
Galina V. Lukina
Clinical Pharmacology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russian Federation
Elena N. Aleksandrova
Clinical Immunology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russian Federation
Andrey P. Aleksankin
Clinical Immunology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russian Federation
Sergey A. Makarov
Department of Surgery, Nasonova Research Institute of Rheumatology, Moscow 115522, Russian Federation
Aleksandr N. Kuzin
Forensic Medicine Service, Moscow City Health Department, Moscow 115516, Russian Federation

Abstract


Objective: To clarify molecular mechanisms for the response to rituximab in a longitudinal study. Methods: Peripheral blood from 16 RA patients treated with rituximab for a single treatment course and 26 healthy controls, blood and knee articular cartilages from 18 patients with long-standing RA, and cartilages from 14 healthy subjects were examined. Clinical response was assessed using ESR, ACPA, CRP, RF, DAS28 levels, CD19+ B-cell counts, bone erosion, and joint space narrowing scores. Protein expression in PBMCs was quantified using ELISA. Gene expression was performed with quantitative real-time PCR. Results: A decrease (p < 0.05) in DAS28, ESR, and CRP values after rituximab treatment was associated with the downregulation of MTOR, p21, caspase 3, ULK1, TNFα, IL-1β, and cathepsin K gene expression in the peripheral blood to levels found in healthy subjects. MMP-9 expression remained significantly higher compared to controls although decreased (p < 0.05) versus baseline. A negative correlation between baseline ULK1 gene expression and the number of tender joints at the end of follow-up was observed. Conclusions: The response to rituximab was associated with decreased MTOR, p21, caspase 3, ULK1, TNFα, IL-1β, and cathepsin K gene expression compared to healthy subjects. Residual increased expression in MMP-9, IFNα, and COX2 might account for remaining inflammation and pain. High baseline ULK1 gene expression indicates a good response in respect to pain.