Serum Biomarkers for Prediction of Response to Methotrexate Monotherapy in Early Rheumatoid Arthritis: Results from the SWEFOT Trial

J Rheumatol. 2019 Jun;46(6):555-563. doi: 10.3899/jrheum.180537. Epub 2019 Feb 1.


Objective: To investigate baseline levels of 12 serum biomarkers that constitute a multibiomarker disease activity test, as predictors of response to methotrexate (MTX) in patients with early rheumatoid arthritis (eRA).

Methods: In 298 patients from the Swedish Pharmacotherapy (SWEFOT) clinical trial, baseline serum levels of 12 proteins were analyzed for association with disease activity based on the 28-joint count Disease Activity Score (DAS28) after 3 months of MTX monotherapy using uni-/multivariate logistic regression. Primary outcome was low disease activity (LDA; DAS28 ≤ 3.2).

Results: Of 298 patients, 104 achieved LDA after 3 months on MTX. Four of the 12 biomarkers [C-reactive protein (CRP), leptin, tumor necrosis factor receptor I (TNF-RI), and vascular cell adhesion molecule 1 (VCAM-1)] significantly predicted LDA based on stepwise logistic regression analysis. Dichotomization of patients using receiver-operating characteristic curve analysis-based cutoffs for these biomarkers showed significantly higher proportions with LDA among patients with lower versus higher levels of CRP or leptin (40% vs 23%, p = 0.004, and 40% vs 25%, p = 0.011, respectively), as well as among those with higher versus lower levels of TNF-RI or VCAM-1 (43% vs 27%, p = 0.004, and 41% vs 25%, p = 0.004, respectively). Combined score based on these biomarkers, adjusted for known predictors of LDA (smoking, sex, and age), associated with decreased chance of LDA (adjusted OR 0.45, 95% CI 0.32-0.62).

Conclusion: Low baseline levels of CRP and leptin, and high baseline levels of TNF-RI and VCAM-1 were associated with LDA after 3 months of MTX therapy in patients with eRA. Combination of these 4 biomarkers increased accuracy of prediction. [Trial registration number: NCT00764725].


Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / drug therapy*
  • Biomarkers / blood*
  • C-Reactive Protein / metabolism
  • Female
  • Humans
  • Leptin / blood
  • Male
  • Methotrexate / therapeutic use*
  • Middle Aged
  • Receptors, Tumor Necrosis Factor, Type I / blood
  • Remission Induction
  • Treatment Outcome
  • Vascular Cell Adhesion Molecule-1 / blood


  • Antirheumatic Agents
  • Biomarkers
  • Leptin
  • Receptors, Tumor Necrosis Factor, Type I
  • Vascular Cell Adhesion Molecule-1
  • C-Reactive Protein
  • Methotrexate

Associated data