title: The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterised by infiltration of immune cells into the affected synovium, release of inflammatory cytokines and degradative mediators, and subsequent joint damage. Both innate and adaptive arms of the immune response play a role, with activation of immune cells leading to dysregulated expression of inflammatory cytokines. Cytokines work within a complex regulatory network in RA, signalling through different intracellular kinase pathways to modulate recruitment, activation and function of immune cells and other leukocytes. As our understanding of RA has advanced, intracellular signalling pathways such as Janus kinase (JAK) pathways have emerged as key hubs in the cytokine network and, therefore, important as therapeutic targets. Tofacitinib is an oral JAK inhibitor for the treatment of RA. Tofacitinib is a targeted small molecule, and an innovative advance in RA therapy, which modulates cytokines critical to the progression of immune and inflammatory responses. Herein we describe the mechanism of action of tofacitinib and the impact of JAK inhibition on the immune and inflammatory responses in RA.
authors.affiliation: Pfizer Inc, New York, NY, USA. jennifer.a.hodge@pfizer.com.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Hodge
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Kawabata
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswami
authors.affiliation: Pfizer Inc, Cambridge, MA, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Clark
authors.affiliation: Pfizer Inc, Cambridge, MA, USA.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Telliez
authors.affiliation: Pfizer Inc, Cambridge, MA, USA.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Dowty
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Menon
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Lamba
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Zwillich
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000502:physiology; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D016131:Lymphocyte Subsets / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016207:Cytokines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053612:Janus Kinases