title: 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: 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.
authors.affiliation: Clinical Immunology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Tchetina
authors.affiliation: Clinical Pharmacology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russia.
authors.forename: Anastasya N
authors.initials: AN
authors.lastname: Pivanova
authors.affiliation: Clinical Immunology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russia.
authors.forename: Galina A
authors.initials: GA
authors.lastname: Markova
authors.affiliation: Clinical Pharmacology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russia.
authors.forename: Galina V
authors.initials: GV
authors.lastname: Lukina
authors.affiliation: Clinical Immunology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russia.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Aleksandrova
authors.affiliation: Clinical Immunology Department, Nasonova Research Institute of Rheumatology, Moscow 115522, Russia.
authors.forename: Andrey P
authors.initials: AP
authors.lastname: Aleksankin
authors.affiliation: Department of Surgery, Nasonova Research Institute of Rheumatology, Moscow 115522, Russia.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Makarov
authors.affiliation: Forensic Medicine Service, Moscow City Health Department, Moscow 115516, Russia.
authors.forename: Aleksandr N
authors.initials: AN
authors.lastname: Kuzin