McInnes IB, Byers NL, Higgs RE, et al. - Researchers compared the in vitro cellular pharmacology of baricitinib, upadacitinib, and tofacitinib across relevant leukocyte subpopulations, coupled with their in vivo pharmacokinetics and discovered their impacts on distinct cytokine pathways, many implicated in RA pathogenesis. Various in vitro pharmacologic profiles were exhibited by distinct Janus kinase inhibitors (JAKis, bind to type I and type II cytokine receptors and transmit extracellular cytokine signals to activate signal transducers and activators of transcription, which translocate to the nucleus and modulate transcription of effector genes). For example, tofacitinib and upadacitinib were the most potent inhibitors of the JAK1/3-dependent cytokines tested (interleukin [IL]-2, IL-4, IL-15, and IL-21) with lower inhibitory concentration (IC₅₀) values and rose time above IC₅₀ translating to higher overall inhibition of signal transducers and activators of transcription signaling during the dosing interval. Every JAKis tested hindered JAK1/2-dependent cytokines (eg, IL-6 and interferon [IFN]-γ), the JAK1/tyrosine kinase 2 (TYK2)-dependent cytokines IL-10 and IFN-α, the JAK2/2-dependent cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the JAK2/TYK2-dependent cytokine granulocyte colony-stimulating factor (G-CSF), however, usually to significantly varying degrees. In conclusion, various JAKis modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously restrained an individual cytokine signaling pathway throughout the dosing interval. Prominently, baricitinib inhibited JAK1/3 signaling to a minor extent in comparison with upadacitinib and tofacitinib, while upadacitinib, baricitinib, and tofacitinib inhibited the signaling of JAK2/2-dependent cytokines, including GM-CSF and IL-3, as well as the signaling of the JAK2/TYK2-dependent cytokine G-CSF.