FRI0452 THE IMPACT OF SINGLE NUCLEOTIDE POLYMORPHISMS IN ADORA2A AND ADORA3 ON THE EARLY RESPONSE TO METHOTREXATE AND PRESENCE OF THERAPY SIDE EFFECTS IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS
Authors: J. Roszkiewicz, D. Michałek, A. Ryk, B. Szmyd, E. Smolewska
Journal: Annals of the Rheumatic Diseases (2020)

Background: Juvenile idiopathic arthritis (JIA) is the most frequent rheumatic disease in children, with an estimated prevalence between 16 and 150 per 100 000 [1]. Methotrexate (MTX) administered at the dose 10-15mg/m 2 is currently recommended as the first-line treatment in most of JIA subtypes [2]. Despite its widespread use in rheumatology, the mechanism of MTX immunomodulatory action remains incompletely understood [3]. Free adenosine is one of the particles possibly associated with the action of MTX, acting via three types of adenosine receptor: ADORA2A, ADORA2B, and ADORA3 [4]. Objectives: The aim of our study was to determine the association between single nucleotide polymorphisms in ADORA2A (rs2236624, rs2298383) and ADORA3 (rs3393) receptors genes on the disease activity and presence of MTX therapy side effects in patients with JIA. Methods: One hundred children with JIA of all subtypes treated with MTX were recruited to the study. Demographic and clinical parameters were collected at the baseline of MTX therapy and on a control visit 4-6 months (median 5.09 months) after starting MTX. The clinical parameters included inflammatory markers values, number of joints with active arthritis, number of joints with restricted range of movement, physician’s global assessment of disease activity, parent/patient global assessment of overall well-being, functional ability (measured by the Childhood Health Assessment Questionnaire – CHAQ) and the value of Juvenile Idiopathic Arthritis Disease Activity Score 71 (JADAS 71). Presence of MTX side effects was evaluated on the control visit. SNP genotyping was performed using genomic DNA isolated from peripheral blood samples. Results: Both polymorphic variants of ADORA2A (rs2236624, rs2298383 - CC/CT) were significantly associated with 3.5 times higher odds of gastrointestinal side effects occurrence (OR: 3.52, 95%CI: 1.12-11.03, p=0.03 and OR: 3.49, 95%CI: 0.89-13.66 p=0.07) after adjustment to age, sex, dose and route of MTX administration. In addition, children with the ADORA3 rs3393 polymorphic variant (CT/CC) after six months of MTX treatment had significantly lower number of joints with active arthritis (0.0 vs 1.0, p=0.04), lower JADAS 71 score (3.0 vs 5.1, p=0.16) and lower value of CRP (0.6 vs 2.4, p=0.02). Conclusion: Although future studies are needed to verify our findings, polymorphisms in ADORA2A and ADORA3 genes may become the determinants of MTX treatment efficacy and gastrointestinal toxicity in children with JIA. References: [1]Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol . 2004;31(2):390-392. [2]Ferrara G, Mastrangelo G, Barone P, et al. Methotrexate in juvenile idiopathic arthritis: advice and recommendations from the MARAJIA expert consensus meeting. PediatrRheumatol Online J . 2018;16(1):46. Published 2018 Jul 11. doi:10.1186/s12969-018-0255-8. [3]Brown, P. M., Pratt, A. G., &amp; Isaacs, J. D. (2016). Mechanism of action of methotrexate in rheumatoid arthritis and the search for biomarkers. Nature Reviews Rheumatology, 12(12), 731–742. doi:10.1038/nrrheum.2016.175. [4]Varani, K. et al. A2A and A3 adenosine receptor expression in rheumatoid arthritis: upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release. Arthritis Res. Ther. 13, R197 (2011). Disclosure of Interests: None declared