STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor of Treatment Response in Rheumatoid Arthritis

PLoS One. 2016 Dec 12;11(12):e0167975. doi: 10.1371/journal.pone.0167975. eCollection 2016.

Abstract

Objective: To find novel predictors of treatment response to disease-modifying antirheumatic drugs (DMARDs), we studied activation of STAT (signal transducers and activators of transcription) 6 and 1 in circulating leukocytes of patients with rheumatoid arthritis (RA).

Methods: 19 patients with untreated recent-onset RA, 16 patients with chronic RA irresponsive to synthetic DMARDs and 37 healthy volunteers provided blood samples for whole blood flow cytometric determination of intracellular STAT6 and STAT1 phosphorylation, expressed as relative fluorescence units, in response to IL-4 and IFN-γ, respectively. Phosphorylation was restudied and treatment response (according to European League Against Rheumatism) determined after 1-year treatment with synthetic DMARDs in recent-onset RA and with biological DMARD in synthetic DMARD-irresponsive RA. Estimation-based exact logistic regression was used to investigate relation of baseline variables to treatment response. 95% confidence intervals of means were estimated by bias-corrected bootstrapping and the significance between baseline and follow-up values was calculated by permutation test.

Results: At baseline, levels of phosphorylated STAT6 (pSTAT6) induced by IL-4 in monocytes were higher in those who achieved good treatment response to synthetic DMARDs than in those who did not among patients with untreated RA (OR 2.74, 95% CI 1.05 to 9.47), and IFN-γ -stimulated lymphocyte pSTAT1 levels were higher in those who achieved good treatment response to a biological drug than in those who did not among patients with chronic RA (OR 3.91, 95% CI 1.12 to 20.68). During follow-up, in recent-onset RA patients with good treatment response to synthetic DMARDS, the lymphocyte pSTAT6 levels decreased (p = 0.011), and, consequently, the ratio of pSTAT1/pSTAT6 in lymphocytes increased (p = 0.042).

Conclusion: Cytokine-stimulated STAT6 and STAT1 phosphorylation in circulating leukocytes was associated with treatment response to DMARDs in this pilot study. The result, if confirmed in larger studies, may aid in developing personalized medicine in RA.

MeSH terms

  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / blood*
  • Arthritis, Rheumatoid / drug therapy*
  • Chronic Disease
  • Humans
  • Lymphocytes / metabolism*
  • Male
  • Middle Aged
  • Monocytes / metabolism*
  • Phosphorylation
  • Pilot Projects
  • STAT1 Transcription Factor / blood*
  • STAT6 Transcription Factor / blood*
  • Treatment Outcome

Substances

  • Antirheumatic Agents
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT6 Transcription Factor
  • STAT6 protein, human

Grant support

This work was supported by Paulo Foundation and Finnish Cultural Foundation (to KK); Helsinki University Central Hospital Research Funds (to MLR and HR); and Finska Läkaresällskapet (to MLR and HR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.