Several
cytokines and
growth factors, as well as their downstream signalling pathways, are implicated in the pathogenesis of haematological and immune-mediated diseases. These mediators act through binding to their cognate receptor and activation of one or more of the four Janus family
tyrosine kinases (JAKs). Gene knock-out studies together with evidence from patients carrying activating mutant forms of JAKs (eg, JAK2 V617F in
myeloproliferative disorders) provided strong rationale for the development of
JAK inhibitors. Based on encouraging preclinical data showing the capacity of
JAK inhibitors to suppress the signalling from multiple
cytokines, an extensive
drug development program was set out, with the initial successful introduction of
tofacitinib,
baricitinib and
ruxolitinib in various chronic rheumatic and myeloproliferative diseases, respectively. Importantly, advancements with the design of next-generation, hyper-selective
JAK inhibitors hold promise for the better control of
inflammation, while reducing the risk for harms, in an expanding spectrum of medical disorders.