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Published on: December 7, 2014

In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis

Y Tanaka1, K Maeshima, Y Maeshima

  • 1The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Kitakyushu, 807-8555, Japan. tanaka@med.uoeh-u.ac.jp

Annals of the Rheumatic Diseases
|March 31, 2012
PubMed

Insights

Tofacitinib, a Janus kinase (JAK) inhibitor, effectively treats rheumatoid arthritis (RA) by suppressing inflammatory cytokines. Clinical trials show significant improvement in patients, supporting its use alongside methotrexate for RA management.

Area of Science:

  • Immunology
  • Pharmacology
  • Rheumatology

Background:

  • Rheumatoid arthritis (RA) pathogenesis involves multiple cytokines and Janus kinase (JAK) signaling pathways.
  • JAK family members are crucial for cytokine signaling implicated in RA development.

Purpose of the Study:

  • To evaluate the efficacy and safety of the JAK inhibitor CP-690,550 (tofacitinib) for rheumatoid arthritis (RA) treatment.
  • To assess tofacitinib's effects on cytokine production, T cell proliferation, and disease activity in preclinical and clinical settings.

Main Methods:

  • In vitro studies assessed tofacitinib's impact on interleukin-17 (IL-17) and interferon-gamma (IFN-γ) production and CD4 T cell proliferation.
  • Ex vivo and in vivo studies utilized a humanized SCID mouse model of RA (SCID-HuRAg) to evaluate tofacitinib's effects on serum cytokines and synovial inflammation.
  • A Phase 2 double-blind study in Japanese patients with active RA compared tofacitinib (1-10 mg twice daily) plus methotrexate (MTX) against placebo.

Main Results:

  • In vitro, tofacitinib suppressed IL-17 and IFN-γ production and CD4 T cell proliferation.
  • In the SCID-HuRAg mouse model, tofacitinib reduced human IL-6 and IL-8 levels, synovial inflammation, and cartilage invasion.
  • In the Phase 2 trial, all tofacitinib doses demonstrated significant American College of Rheumatology 20% improvement criteria (ACR20) response rates at week 12 compared to placebo.

Conclusions:

  • Tofacitinib is an effective orally available JAK inhibitor for RA treatment, demonstrating efficacy in preclinical models and human clinical trials.
  • Combination therapy with tofacitinib and MTX showed a manageable safety profile and significant efficacy in Japanese patients with active RA.
  • Tofacitinib dosages of 5 and 10 mg twice daily warrant further investigation for optimizing RA treatment.

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