Without much doubt, the most significant development in rheumatoid arthritis (RA) therapeutics during the past year has been the advancement of the first small-molecular agent in many years, the Janus kinase (JAK) inhibitor tofacitinib (Xeljanz™), to clinical use in the United States. Use in Europe is probably around the corner. The identification and detailed description of a large family of membrane-bound and intracellular kinase enzymes, and the subsequent recognition of the importance of many of the subfamilies included therein, has been a major focus in medicine and physiology over the past 20 years or so.
Along with the biochemical characterization and understanding of these molecules came the development of specific antagonist agents, and currently around 15 tyrosine kinase inhibitors are approved for a range of indications in the United States — mostly in oncology — with dozens of additional ones in clinical or preclinical development. These developments are beautiful examples of bench-to-bedside translational medicine in the best sense of the word, where understanding at the basic science level leads to important advances in the treatment of patients.
As a corollary, the development of specific JAK inhibitors was based on the groundbreaking discovery of the critical role of this small group of 4 closely related intracellular enzymes in the transduction that occurs after binding of the cell-surface receptors for a range of cytokines, chemokines, growth factors, and hormones. After such binding, autophosphorylation of JAK and subsequent phosphorylation of additional intracellular signaling molecules, including STATs (signal transducers and activators of transcription), eventually lead to nuclear rearrangement and activation, ensuring the appropriate response in the cell and the subsequent effects on its surroundings.
Although the 4 JAKs are closely related, each one is responsible for the transduction associated with the binding of specific ligands, thereby yielding some specificity to each of these molecules and to their specific blocking agents. According to current thinking, JAK1 and JAK3 may be more closely involved in the inflammatory process, whereas JAK2 is also responsible for signaling after binding of hematopoietic growth factors, such as erythropoietin and thrombopoietin. The main role of the fourth member of this family, TYK2, is less clearly defined.