Background/Purpose: Methotrexate (MTX) is first line of therapy to treat Rheumatoid Arthritis (RA) patients and one third of patients do not respond to this drug. MTX reduces inflammation by increasing extracellular adenosine levels. Adenosine acts via four G-protein coupled adenosine receptors; ADORA1, ADORA2a, ADORA2b and ADORA3. Activation of ADORA2b and ADORA1 leads to pro-inflammatory response, whereas activation of ADORA2a and ADORA3 mediates anti-inflammatory response. MTX also modulates the expression levels of adenosine receptors. Thus, to see if baseline levels of adenosine receptors (ADORA1, ADORA2a, ADORA2b and ADORA3) can predict response to MTX we analysed their levels in whole blood RNA.

Methods: Patients with RA (ACR 2010 criteria), DMARD naïve with active disease (DAS 28 >3.2) were enrolled. Blood samples were collected at baseline before start of MTX. All patients were treated with MTX monotherapy by gradually increasing dose to a maximum of 25mg/week or the maximal tolerated dose. After 4 months of therapy EULAR response was assessed. Adenosine receptors gene expression (ADORA1, ADORA2a, ADORA2b and ADORA3) in the whole blood RNA sample was measured using real time qPCR. HPRT1 was used as a housekeeping gene. The adenosine receptor expression was correlated with response to MTX.

Results: Ninety-nine patients (86.86% females; median age 40 [17-67] years); median duration of disease 24 (2-120) months; median DAS28-CRP 4.48 (3.16-7.63) were enrolled. Among 99 patients 51 were classified as good responders, 28 moderate responders and 20 as non-responders at 4 months. In whole blood RNA, there was predominant expression of ADORA2a and ADORA3 and almost no expression of ADORA1 and ADORA2b. Baseline adenosine receptor expression did not correlate with DAS28 score.

Both adenosine receptors ADORA2a and ADORA3 expression was lower in non-responders (n=20) as compared to good and moderate responders (n=79). However, significant difference was observed only for ADORA3 between good vs non-responder (p=0.03) and moderate vs non-responder (p=0.002). ROC curve analysis showed that ADORA3 with cut-off value of less than -0.21 (∆Ct) predicted non-response to MTX treatment with a sensitivity of 63.6% and a specificity of 65% (AUC:0.695, p=0.007).

Conclusion: Adenosine receptor A3 (ADORA3) mRNA levels in whole blood may serve as a biomarker for response to MTX.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/adenosine-receptors-expression-as-predictor-of-response-to-methotrexate-therapy-in-patients-with-rheumatoid-arthritis/