Transiently increased circulating CD39+FoxP3+ Treg cells predicts the clinical response to methotrexate in early rheumatoid arthritis

Abstract

Abstract Objectives A subset of human circulating FoxP3+ regulatory T cells expresses CD39 (cTreg39+) and hydrolyses pro-inflammatory adenine nucleotides released at inflammatory foci, releasing the anti-inflammatory agent adenosine. Methotrexate (MTX), inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide transformylase, enhances the extrusion of adenine nucleotides and may help Treg39+ cells control inflammation. Therefore, we examined the relation of cTreg39+ cells with the effect of MTX in early rheumatoid arthritis (eRA). Methods Freshly isolated peripheral blood lymphocytes from 98 untreated eRA patients and 98 healthy controls (HC) were examined by cytometry. Twelve months (12 m) after initiating MTX, 82 patients were clinically re-evaluated and cytometry was repeated in 40 of them. The effect of MTX on Treg cell potency was assessed in Treg/Tresp cocultures. Results The baseline (0 m) cTreg39+ cell frequency was elevated in eRA above HC levels. Patients who reached low disease activity at 12 months (12 m-LDA, DAS28-ESR ≤ 3.2, n = 51) had presented with a significantly higher 0 m cTreg39+ frequency vs those who did not (n = 31). The 0 m cTreg39+ cutoff for attaining 12 m-LDA was 42.0% (sensitivity = 90.4%, specificity = 96.8%). At 12 m, the cTreg39+ frequency was no longer elevated but its association with disease activity remained: it was still significantly higher in patients who had reached LDA vs those who had not. In vitro, MTX augmented the Treg39+ cell potency but had no effect on Treg39− cells. Conclusion MTX cooperates with Treg39+ cells and the baseline cTreg39+ frequency predicts the response to MTX in eRA. In addition, the transiently elevated baseline cTreg39+ frequency in eRA may provide a slot for prompt MTX initiation.