Background/Purpose: Low dose weekly MTX remains the anchor drug for treatment of Rheumatoid Arthritis. The principal mechanism by which MTX suppresses inflammation in Rheumatoid Arthritis is thought to be enhanced adenosine release from cells which suppresses inflammation by stimulating adenosine receptors on T cells, macrophages and other inflammatory cells (Nature Rev Rheumatol 13:41, 2017). Many patients do not respond to low dose MTX and studies in mice suggest that MTX resistance may be due to inadequately increased adenosine release (Clin Exp Rheumatol 31:433, 2013). Because adenosine is primarily taken up by cells from the extracellular space via the nucleoside transporter ent1 we asked whether an agent that blocks adenosine uptake could enhance the effect of MTX in the treatment of RA. We therefore carried out an open label 1 month study, adding an inhibitor of adenosine uptake via ent1, ticagrelor (a P2Y12 inhibitor that is approved for inhibition of platelet aggregation to prevent severe cardiovascular events) (Nat Rev Cardiology12:156,2014), to patients who were poorly controlled with low dose methotrexate therapy for RA. (NCT02874092)

Methods: Patients (5 female/1 male, mean age 49.6 years) who all met ACR criteria for RA and had active disease, as defined by DAS28 (ESR) > 3.6 and who were on stable doses of MTX monotherapy (for a minimum of 12 weeks), were recruited from the Bellevue Hospital Center Arthritis Clinic. Patients had no known contraindication to ticagrelor and had no history of coronary artery disease. After giving informed consent patients entered an open label protocol in which they were administered Ticagrelor (90mg) twice daily for one month in addition to their stable dose of MTX. Disease activity was reassessed and change in activity from the start of the trial was noted. This study was approved by the NYULMC-Bellevue IRB.

Results: Five of six patient achieved an improvement in their DAS28(ESR) >0.6. Half of the patients (3 patients) achieved a reduction in DAS28(ESR) >1.2, 2 patients achieved a reduction in DAS28(ESR) >0.6 but less than 1.2 and 1 patient showed no improvement. Four of six patients had a reduction in their tender joints and all had a reduction in swollen joints. No patients reported any adverse reactions, including excessive bleeding.

Conclusion: The results of this small open label trial suggest that treatment with ticagrelor enhances the effect of MTX on RA and may be a useful addition to the therapeutic armamentarium. Moreover, these results offer further support for the hypothesis that enhanced adenosine release at inflamed sites mediates the anti-inflammatory effects of MTX therapy. The limitations of this trial include the fact that it was an open label trial in a small group of patients but the results support further study of ticagrelor in combination with MTX.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/supplementation-of-methotrexate-mtx-with-ticagrelor-therapy-suppresses-disease-activity-in-patients-with-moderate-to-very-active-ra-further-evidence-that-adenosine-and-its-receptors-mediate-the-ant/