Like a complex game of chess, RA is driven by numerous players, each with their own unique roles. Pawns, the most numerous pieces in the game, can be precisely positioned to influence the defense and attack from other pieces in the game. Like pawns, cytokines and other immune signalling factors work in concert and define the landscape for the actions of the larger pieces.1,2

In RA, numerous cytokines—TNF, IL-6, IFNs, and many others—have been implicated in disease pathogenesis.2 Again, like pawns, these small proteins could seem individually insignificant, but when deployed in a coordinated manner, they can ultimately define the overall disease landscape through the migration and proliferation of immune cells and pro-inflammatory signalling that drive chronic inflammation and systemic illness.2,3

In chess, pawns work with other pieces to mount a coordinated attack on the opponent’s territory and pieces. In RA, cytokines can be viewed as using cellular signalling pathways in a similar manner, signalling through specific pathways to recruit other pieces to the cytokine response.1,2,4 These pathways, which can include the MAPK, NF-kB, JAK-STAT, and others,4 are analogous to a major chess piece such as the rook4: powerful, flexible, and capable, but operating on a board largely defined by the pawns.

The JAK-STAT pathway (pictured) is a key cellular signalling pathway that can be recruited into action by specific cytokines in different contexts.4-7 On one side, JAK-STAT pathways regulate the innate and adaptive immune response, antiviral defense, and the production of red blood cells and platelets.4-7 However, on the other side of the board, when cytokine signalling via JAK-STAT is excessive, it has been shown to drive RA pathophysiology, including chronic inflammation, synovitis, and bone erosion.1,4-7

Due to the JAK-STAT pathway’s critical role in RA pathogenesis, many oral presentations and posters at the upcoming virtual ACR Convergence 2020 will feature it.
Be sure to check back after the meeting to get updates on the latest information from this year’s discussions.

Figure adapted from Malemud 2018 and Winthrop 2017.

IFN, interferon; IL, interleukin; JAK, Janus kinase; MAPK, mitogen activated protein kinase; NF-kB, nuclear factor-kB; RA, rheumatoid arthritis; STAT, signal transducer and activator of transcription; TNF, tumour necrosis factor.

References: 1. McInnes IB, Schett G. N Engl J Med. 2011;365(23):2205-2219. 2. Smolen JS, Aletaha D, McInnes IB. Lancet. 2016;388(100055):2023-2038. 3. Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Bone Research. 2018;6:15. 4. Schwartz DM, Bonelli M, Gadina M, O’Shea JJ. Nat Rev Rheumatol. 2016;12(1):25-36. 5. Clark JD, Flanagan ME, Telliez JB. J Med Chem. 2014;57(12):5023-5038. 6. Malemud CJ. Ther Adv Musculoskelet Dis. 2018;10(5-6):117-127. 7. Winthrop KL. Nat Rev Rheumatol. 2017;13(4):234-243.

UNBP6067 10/20