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Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis In Vivo and Baseline Signaling Profile

Maaria Palmroth1, Krista Kuuliala2, Ritva Peltomaa3

  • 1Molecular Immunology Group, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Frontiers in Immunology
|October 11, 2021
PubMed
Abstract

Insights

Tofacitinib effectively suppresses Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways in rheumatoid arthritis (RA) patients in vivo. This treatment also downregulates key pathway components, with baseline markers predicting treatment response.

Area of Science:

  • Rheumatology
  • Immunology
  • Pharmacology

Background:

  • Current understanding of tofacitinib's effects on cytokine signaling in rheumatoid arthritis (RA) relies heavily on in vitro data.
  • There is a need to investigate tofacitinib's in vivo mechanisms in RA patients.

Purpose of the Study:

  • To investigate the in vivo effects of tofacitinib on Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways in patients with active RA.
  • To explore the association between baseline signaling profiles and treatment response to tofacitinib.

Main Methods:

  • A 3-month study involving 16 RA patients treated with tofacitinib (5 mg twice daily) alongside conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).
  • Measurement of phosphorylated STATs in peripheral blood cells (monocytes, T cells, B cells) via flow cytometry.
  • Quantification of JAK, STAT, and suppressor of cytokine signaling (SOCS) mRNA expression in peripheral blood mononuclear cells (PBMCs) using quantitative PCR.

Main Results:

  • Tofacitinib significantly reduced disease activity score (DAS28) and inhibited cytokine-induced STAT phosphorylation in a cell- and cytokine-specific manner (10-73% inhibition).
  • Downregulation of constitutive STAT phosphorylation (STAT1, STAT3, STAT4, STAT5) in monocytes and T cells was observed.
  • Tofacitinib treatment reduced the expression of JAK-STAT pathway components, notably SOCS, and baseline STAT/SOCS3 levels correlated with treatment response.

Conclusions:

  • Tofacitinib suppresses multiple JAK-STAT pathways in RA patients in vivo in a manner dependent on cytokine and cell type.
  • The drug downregulates the expression of JAK-STAT pathway components, potentially explaining in vivo versus in vitro differences.
  • Baseline immunological markers are associated with treatment response to tofacitinib in RA patients.
Keywords:
B cellsJAK inhibitorT cellscytokinesmonocytesrheumatoid arthritis

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