POS0099 CLINICAL REMISSION IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH TOFACITINIB IS ASSOCIATED WITH LOW BASELINE EXPRESSION OF GENES RELATED TO ENERGY METABOLISM AND WITH CELLULAR CAPACITY OF THEIR UPREGULATION DURING FOLLOW-UP
Authors: E. Tchetina, A. Satybaldyev, G. Markova
Journal: Annals of the Rheumatic Diseases (2021)

Background: Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, which is characterized by erosive arthritis (synovitis) and systemic inflammation. Tofacitinib (TFCN) is a small molecule Janus kinase (JAK) inhibitor that targets JAK1/JAK3. Identification of patients sensitive to TFCN before treatment could significantly improve therapy outcome. Presently it is not possible to predict TFCN efficacy in every patient while some patients are non-responsive to the drug that may produce adverse effects. TFCN function in RA patients has been recently associated with alterations in bioenergetics, mitochondrial function, and ATP production [1]. Therefore, we hypothesized that baseline metabolic status of RA patients prior to drug administration can predict the therapeutic outcome. Objectives: To investigate the importance of baseline expression of genes involved in energy generation in RA patients, which could serve prognostic biomarkers for treatment response to tofacitinib. Methods: Peripheral blood of 28 RA patients aged 52.2±15.6 years old, average disease duration 3.5 years (range 0.6-19) treated with TFCN (5-10 mg twice a day) during three months and 26 healthy age-matched control subjects were examined. Clinical response was assessed by disease activity score (DAS28-ESR), serum levels of ACPA antibodies, rheumatoid factor (RF), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Clinical remission was assessed according to ACR criteria and DAS28 (DAS28 &lt;2.6). Protein concentrations were measured using ELISA. Total RNA was isolated and used in gene expression studies performed with quantitative real-time RT-PCR. Results: All of the patients were Steinbrocker’s radiographic stage II-III at baseline. The majority of patients demonstrated erosive arthritis (23 out of 28), they were ACPA- (25 out of 28) and RF- (24 out of 28) positive. TFCN treatment significantly decreased the disease activity according to DAS28. At the end of the study the majority of patients demonstrated moderate disease activity (3.2&lt; DAS28 &lt;5.1), four patients retained high disease activity while 8, attained remission (DAS28 &lt;2.6). This was accompanied by significant decrease in CRP and the number of swollen and tender joints. ESR values were not changed significantly. Gene and protein expression analysis revealed that RA patients, which attained clinical remission after TFCN treatment demonstrated significantly lower baseline expression of genes associated with glycolysis (pyruvate kinase), oxidative phosphorylation (succinate dehydrogenase and uncoupling protein (UCP) 2) compared to other examined RA patients and control subjects. Moreover, these gene expressions increased in RA patients who attained clinical remission in the course of follow-up while in refractory for TFCN treatment patients these gene expressions were tending to downregulate. Conclusion: Clinical remission attainment in RA patients treated with tofacitinib is associated with lower baseline expression of genes associated with energy generation pathways (pyruvate kinase, succinate dehydrogenase, and UCP2) compared to other examined subjects. Non-responsiveness to tofacitinib is accompanied by high baseline expression of genes related to glycolysis and oxidative phosphorylation compared to controls. References: [1]McGarry et al. JAK/STAT Blockade Alters Synovial Bioenergetics, Mitochondrial Function, and Proinflammatory Mediators in Rheumatoid Arthritis. Arthritis Rheumatol, 2018; 70:1959. Acknowledgements: Russian Ministry of Education and Science (Project No. AAAA-A19-11-9021190145-2 to EVT). Disclosure of Interests: None declared