Background: The identification of responders to methotrexate (MTX) would optimize the therapy of patients with early rheumatoid arthritis (eRA). Our aim was to identify protein biomarkers for the prediction of the response to MTX.

Methods: We analysed patients with eRA ( N  = 135) from the Swedish Pharmacotherapy (SWEFOT) trial population (Trial registration number: NCT00764725). Baseline serum levels of 177 proteins with an inflammatory signature were profiled via 380 antibodies in a suspension bead array format. Protein levels were analysed for their associations with the achievement of a low 28-joint disease activity score (LDA = DAS28 ≤ 3.2) after 3 months of MTX therapy (primary outcome) or a good response according to the European Alliance of Associations for Rheumatology (EULAR) criteria (secondary outcome).

Results: Multivariable analysis revealed that the serum levels of two of the 177 proteins at baseline, matrix metalloproteinase 7 (MMP-7) and the alpha-chain of fibrinogen (FGA), were significantly different between patients who did and did not achieve LDA at 3 months. Among patients with low versus high levels of either MMP-7 or FGA, 60% versus 24% and 58% versus 22%, respectively, achieved LDA ( p  < 0.001). Among patients with low levels of both proteins, 79% achieved LDA at 3 months, whereas only 18% of those with high levels of both proteins achieved LDA at 3 months ( p  < 0.001). The results were similar when a secondary outcome was used.

Conclusions: Low levels of MMP-7 and FGA at baseline were associated with improved clinical outcomes in eRA patients. Validation of these results in another eRA cohort is now warranted, and if confirmed, it may facilitate clinical decision-making regarding whether to start with MTX in monotherapy or more potent alternatives.