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1. Winthrop KL. Nat Rev Rheumatol. 2017;13(4):234-243.

2. Hodge JA, Kawabata TT, Krishnaswami S, et al. Clin Exp Rheumatol. 2016;34(2):318-328.

3. McInnes IB, Schett G. Nat Rev Immunol. 2007;7(6):429-442.

4. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. Nat Rev Drug Discov. 2017;16(12):843-862.

5. Schett G. Rheumatology (Oxford). 2018;57(suppl 2):ii43-ii50.

6. Dinesh P, Rasool M. J Cell Physiol. 2018;233(5):3918-3928.

7. Chen Z, Han Y, Gu Y, et al. J Immunol. 2013;190(12):5256-5266.

8. Schwartz DM, Bonelli M, Gadina M, O'Shea JJ. Nat Rev Rheumatol. 2016;12(1):25-36.

9. Srirangan S, Choy EH. Ther Adv Musculoskelet Dis. 2010;2(5):247-256.

10. Boettger MK, Leuchtweis J, Kümmel D, Gajda M, Bräuer R, Schaible HG. Arthritis Res Ther. 2010;12(4):R140.

11. Schurgers E, Billiau A, Matthys P. J Interferon Cytokine Res. 2011;31(12):917-926.

12. Aletaha D, Smolen JS. JAMA. 2018; 320(13):1360-1372.

13. Lotfi N, Thome R, Rezaei N, et al. Front Immunol. 2019;10:1265.

14. Clark JD, Flanagan ME, Telliez JB. J Med Chem 2014;57(12):5023-5038.

15. Choy EH. Rheumatology (Oxford). 2019;58(6):953-962.

16. Virtanen AT, Haikarainen T, Raivola J, Silvennoinen O. BioDrugs. 2019;33(1):15-32.

JAK pairings

Normal cytokine signalling through JAK pairs is essential for bodily functions, such as providing immunity against pathogens and haematopoiesis.1

In RA, excessive signalling through the JAK-STAT pathway may lead to overproduction of proinflammatory cytokines and activation of immune cells that may result in tissue destruction, systemic inflammation, and escalating cycles of autoimmunity.2-6

Selective JAK pairings that mediate cytokine signalling RA pathogenesis Normal physiology

Inflammation

Blood vessel formation

Bone destruction

Autoimmunity6-8

Lymphocyte proliferation1

Differentiation of NK cells1,14

Pain and inflammation

Blood vessel and pannus formation

Bone and cartilage destruction

Autoimmunity

Systemic symptoms8-10

T cell differentiation and homeostasis

Granulocyte production1,14

Inflammation

Synovial tissue remodelling

Autoimmunity8,11,12

Innate antiviral defence1

Autoimmunity13

Red blood cell production

Bone marrow production

Platelet production1

Inflammation

Synovial tissue remodelling

Autoimmunity8

Innate antiviral defence

Antitumour1

JAK1 pairs are involved in signalling for pro-inflammatory cytokines implicated in RA pathology.8,14-16
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References: 1. Winthrop KL. Nat Rev Rheumatol. 2017;13:234-243. 2. Hodge JA, et al. Clin Exp Rheumatol. 2016;34:318-328. 3. McInnes IB, et al. Nat Rev Immunol. 2007;7:429-442. 4. Schwartz DM, et al. Nat Rev Drug Discov. 2017;16:843-862. 5. Schett G. Rheumatology (Oxford). 2018;57:ii43-ii50. 6. Dinesh P, et al. J Cell Physiol. 2018;233:3918-3928. 7. Chen Z, et al. J Immunol. 2013;190:5256-5266. 8. Schwartz DM, et al. Nat Rev Rheumatol. 2016;12(1):25-36. 9. Srirangan S, et al. Ther Adv Musculoskelet Dis. 2010;2:247-256. 10. Boettger MK, et al. Arthritis Res Ther. 2010;12:R140. 11. Schurgers E, et al. J Interferon Cytokine Res. 2011;31:917-926. 12. Aletaha D, et al. JAMA. 2018; 320:1360-1372. 13. Lotfi N, et al. Front Immunol. 2019;10:1265. 14. Clark JD, et al. J Med Chem. 2014;57:5023-5038. 15. Choy EH. Rheumatology (Oxford). 2019;58:953-962. 16. Virtanen AT, et al. BioDrugs. 2019;33:15-32.