JAK Inhibitors: What Is New?
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RHEUMATOID ARTHRITIS (L MORELAND, SECTION EDITOR)
JAK Inhibitors: What Is New? Virginia Reddy 1 & Stanley Cohen 2,3,4
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of the Review Three Janus kinase (JAK) inhibitors are approved for rheumatoid arthritis (RA) with a fourth awaiting approval. Multiple clinical trial results with these molecules have recently been reported. These were the first small molecule oral targeted synthetic DMARDs (tsDMARDs) to be approved for RA. Recent Findings Preclinical studies have suggested differential affinity for JAK isoform inhibition but it is not presently clear that there is any difference in efficacy in the clinic with these therapies. Preliminary data has suggested that filgotinib may have a modestly different safety profile but lacking direct comparisons, this will be difficult to confirm. Long-term safety studies have suggested similar safety signals to biologics although a possible signal for VTE/PE risk has been noted with tofacitinib and baricitinib. Summary Having an oral small molecule such as the JAK inhibitors with similar or better efficacy than biologics has been a major advance in RA treatment. Keywords Janus kinases . Rheumatoid arthritis . Tofacitinib . Baricitinib . Upadacitinib . Filgotinib
Introduction The introduction of parenteral biologics targeting initially TNF alpha and IL1 in 1998 and subsequent therapies targeting activated T cells, B cells, and IL6 dramatically improved clinical outcomes for rheumatoid arthritis (RA) patients. However, biologics require injection or intravenous infusions and are expensive. Based on basic research beginning in the 1990s, signal transduction pathways resulting in inflammatory cytokine production for type I and II cytokines were identified [1–3]. Receptors for type 1/2 cytokines require activation by intracellular protein tyrosine kinases. Unraveling this pathway led to develop of inhibitors of the Janus kinase (JAK) pathway resulting in the approval of JAK inhibitors for RA treatment. Topical Collection on Rheumatoid Arthritis * Stanley Cohen [email protected] 1
Division of Rheumatology, Texas Health Dallas Presbyterian Hospital, Dallas, TX, USA
2
UT Southwestern Medical School, Dallas, TX, USA
3
Metroplex Clinical Research Center, 8144 Walnut Hill Lane, Suite 800, Dallas, TX 75231, USA
4
Texas Health Dallas Presbyterian Hospital, Dallas, TX, USA
Tofacitinib was approved in 2012, and baricitinib, pefecitinib (Asia only), and upadacitinib were subsequently approved for RA in DMARD failure patients. Filgotinib has submitted application for approval from the regulatory agencies, and approval is expected later this year.
Janus Kinase Inhibitors JAK are intracytoplasmic protein tyrosine kinases that bind the cytoplasmic region of transmembrane cytokine receptors and mediate signaling through type 1 and type 2 cytokine receptors [4]. After receptor-ligand interaction, various JAK are activated, resulting in tyrosine phosphorylation of the receptor and subsequent activation of S
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