Background/Purpose: Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, which is characterized by erosive arthritis and systemic inflammation. Tofacitinib (TFCN) is a Janus kinase (JAK) inhibitor that targets JAK1/JAK3. 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. However, identification of patients sensitive to TFCN before treatment could significantly improve therapy outcome. TFCN function in RA patients has been recently associated with alterations in bioenergetics, mitochondrial function, and ATP production [McGarry et al. Arthritis Rheumatol, 2018; 70:1959.]. Therefore, we hypothesized that baseline metabolic status of RA patients prior to drug administration can predict the therapeutic outcome. We aimed 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 serum levels of ACPA antibodies, rheumatoid factor (RF), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and disease activity score (DAS28-ESR). Clinical remission was assessed according to ACR criteria and DAS28 (DAS28 < 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< DAS28 < 5.1), four patients retained high disease activity while 8, attained remission (DAS28 < 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) and oxidative phosphorylation (succinate dehydrogenase) compared to other examined RA patients. Moreover, in RA patients who attained clinical remission these gene expressions were tending to increase while in other examined patients, to downregulate in the course of follow-up.

Conclusion: Our preliminary study demonstrated that clinical remission attainment in RA patients treated with tofacitinib was associated with lower baseline expression of genes related to energy generation pathways (pyruvate kinase and succinate dehydrogenase) compared to other examined subjects.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/low-baseline-expression-of-pyruvate-kinase-and-succinate-dehydrogenase-genes-in-the-peripheral-blood-of-rheumatoid-arthritis-patients-treated-with-tofacitinib-is-associated-with-clinical-remission-at/