Publications
View and download slide summaries of the latest original articles focusing on cytokine signalling therapies within rheumatoid arthritis. All materials produced by the CSF team are subsequently reviewed and approved by individual Steering Committee members.
Differential Properties of Janus Kinase Inhibitors in the Treatment of Immune-mediated Inflammatory Diseases
Rheumatology (Oxford) 2023 doi 10.1093/rheumatology/kead448 Epub ahead of print
JAKis differ in structure, which affects their inhibitory concentration for different JAKs.
This review by Taylor, et al. compares the pharmacological profiles of JAKis, including abrocitinib, baricitinib, filgotinib, peficitinib, tofacitinib, and upadacitinib.
Comparison of drug retention of TNF inhibitors, other biologics and JAK inhibitors in RA patients who discontinued JAK inhibitor therapy
Rheumatology (Oxford) 2022 doi: 10.1093/rheumatology/keac285
Real-world population-based study shows that a switch to a second JAKinib results in a higher drug retention, as compared to switching to a TNFi, in patients with RA who discontinue original JAKinib therapy.
A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis
Rheumatology (Oxford) 2019;58(10):1755–66
Absolute serious infection rates were low. However, across the JAKinibs, the incidence of HZ is higher than expected for the population. While the risk was numerically greatest with BARI, indirect comparisons between the drugs did not demonstrate any significant difference in risk. How JAKinibs increase the risk of HZ reactivation is unclear, but how different JAKs interact in the immune response suggest that there may be differences in safety profiles between JAKinib drugs, underpinned by their...
A Systematic Review and Meta-Analysis of Infection Risk with Small Molecule JAK Inhibitors in Rheumatoid Arthritis
Rheumatology (Oxford). DOI: 10.1093/rheumatology/kez087
How JAKinibs increase the risk of HZ reactivation is unclear. Roles of different JAKs in the immune response may suggest differences in safety profiles between drugs, underpinned by their differential JAK selectivity profiles. The authors undertook a systematic review and meta-analysis to evaluate SI and opportunistic indicator infections including HZ in RA Phase II/III clinic trials with JAKinibs. A literature review of RCT of TOF (5 mg BID), BARI (4 mg OD) and UPA (15 mg OD) was conducted. A p...
JAK Inhibition as a Therapeutic Strategy for Immune and Inflammatory Diseases
Nat Rev Drug Discov 2017;16:843–62 DOI: 10.1038/nrd.2017.201
Janus kinases (JAKs) are essential mediators of downstream signaling pathways in many inflammatory and autoimmune diseases. This review summarizes current clinical data on first- and second-generation JAK inhibitors (jakinibs) and discusses their use for the treatment of immune and inflammatory conditions.First generation jakinibs such as tofacitinib, baricitinib, and ruxolitinib, non-selectively inhibit JAK-dependent pro-inflammatory cytokines, which are major contributors to immunopathology. T...
The Emerging Safety Profile of JAK Inhibitors in Rheumatic Disease
Nature Reviews Rheumatology 2017;13:234–43
This review discusses the current understanding of the safety of JAK inhibitors, including providing an overview of the changes in laboratory parameters, infection and malignancy risks associated with each JAK inhibitor compound.The review discusses the adverse event profiles and cellular changes characteristically seen with each JAK inhibitor, as well as the overlap or differences between the various compounds. The relative specificities for different JAKs between each compound do not always p...
The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels
Rheumatology (Oxford). 2014 Nov 17. pii: keu430. [Epub ahead of print]
Non-response, parenteral administration and cost to produce are all aspects associated with the currently available anti-cytokine agents for RA. These related factors mean that alternative drugs are now being developed. Recent developments in therapeutic drugs to treat RA have focused on Janus kinases (JAKs) and signal transducer and activator of transcription (STATs) transcription pathways. Several cytokines that regulate immune responses in RA, such as IFN-g, IL-6 and IL-10, activate JAK-STAT ...Keywords:
Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition
Proc Natl Acad Sci U S A. 2014 May 19. pii: 201401180. [Epub ahead of print]
The JAK family of kinases (JAK1, JAK2, JAK3 and TYK2) are receptor-associated tyrosine kinases that act downstream of many cytokines and interferons. Recent studies have provided structural information about the kinase and pseudokinase domains of JAKs however the molecular mechanism by which JAK activity is regulated by the pseudokinase domain is poorly understood. This study builds on a recent finding that the N terminus of the JAK1 pseudokinase group may act as a switch for kinase activation b...Keywords:
Structural basis for the recognition of interferon-α receptor by tyrosine kinase 2
Nat Struct Mol Biol. 2014 May;21(5):443-8. doi: 10.1038/nsmb.2807. Epub 2014 Apr 6
Janus kinases, JAKs, are essential in the mediation of cytokine and interferon signalling whilst also being crucial to body processes such as immune function, hematopoeises, metabolism and cellular growth. However, it is not known is how the four members of the JAK family interact with and are activated by over 30 cytokine receptors with near perfect affinity and specificity. Currently, there are no crystal structures available for any JAK bound to a cytokine receptor. This study sought address ...Keywords:
Molecular pathways: Molecular basis for sensitivity and resistance to JAK inhibitors
Clin Cancer Research doi:10.1158/1078-0432.CCR-13-0279
Janus kinases (JAKs) mediate the regulation of a variety of cytokine signals with alterations in JAK1, JAK2, JAK3 and Tyk2 signalling contributing to many disease states including autoimmune diseases and haematological malignancies. Recently tofacitinib and ruxolitinib have been approved for treatment for rheumatoid arthritis and myelofibrosis respectively. Several JAK2 inhibitors, such as momelotinib and pacritinib, currently in development for myelofibrosis and the JAK1/2 inhibitor baricitinib...