A novel predictor of clinical response to methotrexate in patients with rheumatoid arthritis: a pilot study of in vitro T cell cytokine suppression

Abstract

Objective: Methotrexate (MTX) is an important drug for treatment of rheumatoid arthritis; however, there is variation in the clinical response. MTX inhibits T cell cytokine production, with significant interindividual variability in the dose required. We investigated if the variability in clinical response was related to variability in the in vitro assay. Methods: Patients with disease modifying antirheumatic drug-naive, active RA [1982 American College of Rheumatology (ACR) criteria] seen from September 2005 through January 2006 were enrolled. MTX was started at 10 mg/week and increased monthly by 2.5 mg/week. Baseline whole-blood cultures were set up with anti-CD3, anti-CD28, and increasing doses of MTX. Supernatants were harvested at 96 hours and tumor necrosis factor-α (TNF-α ), interferon-γ (IFN-γ ), and inter-leukin 10 (IL-10) concentrations were estimated by ELISA. The dose of MTX (ID₅₀) required for 50% suppression of production of cytokines and the change in Disease Activity Score-28 (Δ DAS) at 4 months were noted. Results: T cell stimulation resulted in significant increase in cytokine release, and addition of MTX led to a dose-dependent suppression of all 3 cytokines. There was significant negative correlation of Δ DAS with ID₅₀ values for TNF-α (R = -0.62, p < 0.01) and IFN-γ (R = -0.43, p = 0.04). At 4 months, EULAR moderate and ACR 20% responses were achieved by 13 and 16 patients, respectively. EULAR moderate response could be predicted using ROC curves for TNF-α (sensitivity 93%, specificity 86%) and IFN-γ (60% specificity, 71% sensitivity). ACR response was correctly predicted in 14 of 16 ACR 20% responders and in all ACR 50% and ACR 70% responders. Conclusion: An in vitro TNF-α suppression assay may help predict clinical response to MTX in RA.