The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis

Boyle, D L; Soma, Koshika; Hodge, Jennifer; Kavanaugh, Arthur; Mandel, David R.; Mease, Philip J.; Shurmur, R; Singhal, Atul; Wei, Nathan; Rosengren, Sanna; Kaplan, Irina V.; Krishnaswami, Sriram; Luo, Zhen; Bradley, John; Firestein, Gary S.

doi:10.1136/annrheumdis-2014-206028

Cited by 240 publications

(191 citation statements)

References 28 publications

Supporting

Mentioning

170

Contrasting

Unclassified

Order By: Relevance

“…The results indicate that or the knee joint core needle biopsy is the most suitable procedure in this setting notably due to a low invasiveness, high superficial synovial layer tissue yield and good visualization. The results presented here are in line with the recommendations of the EULAR synovitis study group favoring needle-based approach for synovial biopsy over arthroscopy despite arthroscopy-guided techniques still are applied in current studies [10]. The integrated needle system demonstrated here seemed also suitable for hrMSUS-guided biopsy.…”

Section: Discussionsupporting

confidence: 77%

Needle versus Forceps Technique in Ultrasound-Guided Synovial Biopsy of the Knee Joint

Hügle¹

2017

JRAD

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 77%

Needle versus Forceps Technique in Ultrasound-Guided Synovial Biopsy of the Knee Joint

Hügle¹

2017

JRAD

View full text Add to dashboard Cite

show abstract

“…Previous suggestions included a suppression of pathogenic Th1/Th17 differentiation (7,25) or a local effect on IFN and IL-6 signaling in RA joints (26). Our results flag innate cell populations as alternative or additional contributors.…”

Section: Discussionmentioning

confidence: 52%

Network pharmacology of JAK inhibitors

Moodley

Yoshida

Mostafavi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Small-molecule inhibitors of the Janus kinase family (JAKis) are clinically efficacious in multiple autoimmune diseases, albeit with increased risk of certain infections. Their precise mechanism of action is unclear, with JAKs being signaling hubs for several cytokines. We assessed the in vivo impact of pan-and isoform-specific JAKi in mice by immunologic and genomic profiling. Effects were broad across the immunogenomic network, with overlap between inhibitors. Natural killer (NK) cell and macrophage homeostasis were most immediately perturbed, with network-level analysis revealing a rewiring of coregulated modules of NK cell transcripts. The repression of IFN signature genes after repeated JAKi treatment continued even after drug clearance, with persistent changes in chromatin accessibility and phospho-STAT responsiveness to IFN. Thus, clinical use and future development of JAKi might need to balance effects on immunological networks, rather than expect that JAKis affect a particular cytokine response and be cued to long-lasting epigenomic modifications rather than by short-term pharmacokinetics.JAK inhibitor | tofacitinib | systems pharmacology A drug's mechanism of action usually refers to the specific molecular or biologic activity that it perturbs, and drug optimization aims at maximizing potency and specificity vs. this target. However, the molecular target may be far removed from the processes that ultimately drive the therapeutic effect. For instance, even though the target is known, it remains unclear which cell or pathway is pivotally affected by anti-PD1 during cancer immunotherapy. Given the interdependencies of cellular and molecular players in biological systems, a drug is likely to have effects far broader than its molecular target. Conversely, it may be hampered by inherent resistance to perturbation of interconnected networks. This complexity is encapsulated in the concepts of network pharmacology, which proposes that drug development focus on network-level alterations, rather than on exquisite specificity for an individual target (1).JAK kinase inhibitors (JAKis) have been intensively and successfully pursued over the last two decades (2, 3) and could be considered poster children of network pharmacology. JAK kinases (JAK1/2/3 and TYK2) are the initial mediators of signaling pathways triggered by many cytokines and hematopoietic growth factors, and activate transducers of the STAT family to prompt cell activation and phenotypic differentiation in all immunocyte lineages (4). The cytokine network is an unusually interconnected one, because cytokines can induce each other, or each other's receptors, and can enhance or stifle each other's signaling pathways. Further complexity stems from the widespread sharing of JAK kinases by cytokine receptors (e.g., JAK1 is connected to receptors for interferons,

show abstract

“…Boyle at al. showed that changes in synovial phosphorylation of STAT1 and STAT3 strongly correlated with four-month clinical responses in RA patients treated with 10 mg of tofacitinib twice a day [26].…”

Section: Discussionmentioning

confidence: 99%