Ann Rheum Dis. 2021 Mar 19:annrheumdis-2020-219012. Epub ahead of print. DOI: 10.1136/annrheumdis-2020-219012The first study to combine in vitro inhibition of cytokine responses in whole blood with clinical pharmacokinetics of individual JAKinibs to model daily cytokine-mediated pharmacodynamic profiles in healthy individuals and patients with RA, has demonstrated that JAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type.Traves and colleagues have observed that JAKinibs have unique, differential effects on specific cytokine signalling pathways, dependent on cytokine stimulus, STAT substrate and cell type. These data indicate differential cytokine profiles, which may provide a mechanistic rationale for reported efficacy and safety, for example, preferential JAK1 activity is sufficient to drive RA efficacy, while JAK2 and JAK3 inhibition may increase the incidence of adverse events of special interest.