Ticagrelor added to methotrexate improves rheumatoid arthritis disease severity

Rheumatology key message

• Ticagrelor added to methotrexate may improve rheumatoid arthritis disease severity.

Dear Editor, Low-dose weekly MTX remains the anchor drug for treatment of RA. One mechanism by which MTX suppresses inflammation in RA is enhancing systemic adenosine release, which suppresses inflammation by stimulating adenosine receptors on T cells, macrophages and other inflammatory cells. Many RA patients exhibit a poor response to low-dose MTX, and murine findings suggest that MTX resistance may be due to inadequately increased adenosine release [1]. Because adenosine is primarily taken up from the extracellular space via the nucleoside transporter equilibrative nucleoside transporter 1 (ENT1), we asked whether an agent that blocks adenosine uptake enhances the effect of MTX in the treatment of RA [2]. We therefore conducted a 1-month proof-of-concept clinical trial to investigate whether ticagrelor (an inhibitor of the adenosine transporter ENT1) and platelet P2Y₁₂ inhibitor [used to prevent cardiovascular (CV) events] improves RA severity in those on low-dose MTX [2].

Ticagrelor in Methotrexate-Resistant Rheumatoid Arthritis—NCT02874092 enrolled RA patients without clinical CV disease if they met ACR criteria for RA, and had active disease defined by a DAS28-ESR > 3.6 on stable doses of MTX monotherapy for a minimum of 12 weeks. RA participants entered a 1-month open-label protocol in which they were administered ticagrelor (90 mg) twice daily. Disease activity, including DAS28-ESR, and the number of tender and swollen joints, were assessed by a board-certified rheumatologist. This study was approved by the NYU Langone Health–Bellevue institutional review board, and all subjects provided written informed consent before participation, consistent with the Declaration of Helsinki.

Platelet activation, indicated by P-selectin and PAC-1 and aggregation to adenosine diphosphate (ADP), was performed as previously described (Supplementary Data S1, available at Rheumatology online) [3]. ESR values were obtained from the clinical laboratory. To measure plasma adenosine, HPLC with concentration (nM) determined by comparison to standards was performed (Supplementary Data S1, available at Rheumatology online) [4].

Ticagrelor in Methotrexate‐Resistant Rheumatoid Arthritis was initially powered to detect at least a 50% reduction in ADP‐induced platelet aggregation and a >1.2 unit improvement in DAS28 score after 1‐month of ticagrelor added to MTX therapy. A recruitment goal of n = 23 subjects was intended to provide 80% power to detect these differences at a 0.05 significance level. The study was stopped after 1 year due to slow enrolment (full details in Supplementary Data S1, available at Rheumatology online).

The baseline characteristics of the study participants are listed in Fig. 1A. A total of 7 RA patients were enrolled who were young [mean age 48 (16) years], predominantly female (86%) and who had a low prevalence of traditional CV risk factors and high RA disease activity. After 1 month of ticagrelor, 6 (of 7) RA patients displayed improvement in the DAS28-ESR score, including 4 achieving a reduction of >1.2 and 2 patients achieving a reduction of >0.6 but <1.2 response (Fig. 1B). Individually, a reduction in swollen (11 → 5, P = 0.02, Fig. 1C) and borderline reduction in tender (8 → 3, P = 0.08, Fig. 1D) joints was also observed.

Fig. 1.

Ticagrelor added to low-dose MTX improves RA severity and reduces platelet activation

(A) Baseline characteristics of RA patients at study enrolment. Change in RA severity as assessed by (B) DAS28-ESR, (C) number of swollen and (D) tender joints at baseline (before) and after 1 month of 90 mg twice daily ticagrelor. (E) Platelet expression by flow cytometry of P-selectin. (F) Serum adenosine measured through HPLC. MFI; mean fluorescent intensity. P-value indicates Wilcoxon paired signed-rank test (P-selectin—Mann-Whitney U test). N = between 4 and 7 measures/group. *P < 0.05.

As expected, light transmission aggregometry to both low (2 µM) and high (5 µM) concentrations of ADP revealed significant platelet inhibition after ticagrelor therapy, demonstrating study drug compliance (Supplementary Fig. S1, available at Rheumatology online). Furthermore, other markers of platelet activation, including P-selectin (Fig. 1E) and PAC-1 after ADP stimulation (Supplementary Fig. S1C/D, available at Rheumatology online), were reduced. Finally, in a subset of 3 participants who underwent adenosine measurement, adenosine trended upwards (Fig. 1F) following 1 month of ticagrelor.

MTX remains the first-line therapy for the treatment of RA, yet despite this, many RA patients will require further therapies to achieve appropriate disease control [5]. MTX indirectly inhibits AMP deaminase and adenosine deaminase, thereby leading to increased accumulation of intracellular adenosine, with subsequent extracellular adenosine release [6]. In fibroblast-like synoviocytes and inflammatory cells, MTX-driven adenosine release activates inflammatory cell adenosine receptors, leading to inhibition of NFkB-driven processes [6]. In murine models, diminished MTX-induced adenosine accumulation was shown to be one mechanism leading to resistance to the anti-inflammatory properties of MTX [4]. Ticagrelor is a potent P2Y₁₂ receptor blocker that inhibits platelet aggregation and is commonly used in CV disease prevention, and it also increases extracellular adenosine, thus providing mechanistic rationale for our study [2].

Limitations of our study include its observational nature (with lack of a control group), small sample size (thus potentially allowing a type I error), lack of blinding (which could lead to observation bias) and that other medications exist and are approved for RA treatment that do not enhance bleeding risk. However, RA is a known CV risk factor. Reducing RA disease activity is linked to a reduction in CV events [7], and many RA patients may require anti-platelet therapy for other clinical indications to prevent CV events, thus potentially supporting a unique indication for ticagrelor. In conclusion, in this pilot open-label clinical trial, 1 month of ticagrelor therapy added to weekly MTX significantly reduced RA disease severity, platelet aggregation and platelet activation, while showing a trend towards increase in circulating adenosine. Larger studies are needed to assess the benefit vs the risk of such an approach.

Supplementary data

Supplementary data are available at Rheumatology online.