Activation of Toll-like and interleukin-1 receptors results in expression of proinflammatory cytokines, such as TNFα and IL-6, that propagate and amplify the intensity of the the innate immune response. When receptors are activated, they initiate a signaling cascade that recruits neutrophils, monocytes, and lymphocytes and results in a robust inflammatory response.3-5

The kinase activity of IRAK4 is a central node in this signaling cascade and may be key in helping to regulate the intensity of the immune response.6

PF-06650833 is a once-daily oral IRAK4 inhibitor under investigation in adult patients with moderate to severe rheumatoid arthritis.1,2

IRAK4 PATHWAY

IRAK4 plays an important role in innate immunity. Inhibiting IRAK4 kinase activity may
have implications for chronic inflammatory diseases such as rheumatoid arthritis.6-10

Figure adapted from Patra MC, Choi S. Molecules. 2016;21(11):1-16; Chaudhary D et al. J Med Chem. 2015;58(1):96-110; O'Neill LAJ. Immunol Rev. 2008;226:10-18.

  • The Toll-like interleukin-1 receptors are primary mediators of innate immunity9,10
  • Activation of these receptors by endogenous ligands can result in expression of proinflammatory cytokines such as tumor necrosis factor α and IL-8, thus triggering the inflammatory and immune responses5, 14-16
  • In mice with genetically deleted IRAK4, the TLR/IL-1 signaling is severely impaired, suggesting that IRAK4 plays a key role in innate immunity. Humans with mutations in the IRAK4 gene have impaired innate and acquired immunity and may be susceptible to clinically important recurrent infections7,8,17,18
  • Toll-receptor activity is increased in rheumatoid arthritis; increased TLR signaling and IRAK4 activation may explain the pathogenesis and progression of this disease5,9,10