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Anterior Segment Ocular Surface Immunomodulatory Effects of Topical Ophthalmic Tofacitinib (Cp-690,550) in Dry Eye Disease Jing-Feng Huang, PhD President, La Jolla BioConsulting LLC, San Diego, California, US Abstract Ocular surface inflammation is thought to play a key role in dry eye pathogenesis and clinical manifestation. Multiple inflammatory cytokines signal through intracellular janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways. Tofacitinib (CP-690,550), a potent and selective inhibitor of JAKs, has been approved for the treatment of rheumatoid arthritis in the US and is in clinical development for the treatment of other autoimmune diseases. Topical ophthalmic tofacitinib was evaluated and has shown immunomodulatory activity in reducing ocular surface inflammation in dry eye, thus, has the potential to improve ocular surface health in dry eye. Keywords Immunomodulatory, inflammation, dry eye, ocular surface, JAK, tofacitinib, CP-690,550, cytokine Disclosure: The author is a former employee of Pfizer. Received: December 20, 2013 Accepted: February 28, 2014 Citation: US Ophthalmic Review, 2014;7(1):12–5 Correspondence: Jing-Feng Huang, PhD, 4653 Carmel Mountain Road, Suite 308-245, San Diego, CA 92130 E: Cytokines are not only critical for host defense and immunoregulation, but are also major players in the immunopathogenesis of inflammatory and autoimmune diseases. Janus kinases (JAKs) are critical for the intracellular signaling of a large family of cytokines. Tofacitinib (CP-690,550) is a potent and selective inhibitor of JAKs. Oral tofacitinib has been approved for the treatment of rheumatoid arthritis (RA) in the US and is in clinical development for the treatment of other autoimmune diseases. This review highlights the recent observation that topical ophthalmic tofacitinib has immunomodulatory activity in dry eye, indicating that ophthalmic tofacitinib has the potential to reduce ocular surface inflammation and improve ocular surface health in dry eye disease (DED). Tofacitinib—A Janus Kinase Inhibitor JAK is a family of intracellular non-receptor tyrosine kinases that are associated with the cytoplasmic domain of Type I and II cytokine receptors. There are four members in the JAK family: JAK1, JAK2, JAK3, and TYK2. 1 Upon cytokine binding and activation of the cognate receptors on the cell surface, JAKs phosphorylate the cytoplasmic tail of the receptor and allow the recruitment of various signaling molecules, including members of the signal transducer and activator of transcription (STAT) family. STATs, phosphorylated by JAKs, dimerize, translocate to the nucleus, and regulate the expression of numerous genes. Cytokine receptors are paired with different JAKs, for example, interferon gamma (IFN-g) signals through JAK1/ JAK2, interleukin (IL)-2 signals through JAK1/JAK3, IL-12 and IL-23 signal through JAK2/TYK2, while IL-6 signals through JAK1/JAK2/TYK2. 12 Many of the major cytokines that are critical to immune cell activation and proinflammatory cytokine production use the intracellular JAK/STAT pathway to exert their effects (and multiple inflammatory cytokines signal through pathways involving JAK1 and JAK3) rendering them amenable to therapeutic blockade with JAK inhibitor. 2 Tofacitinib (former CP-690,550, tasocitinib), a small molecule selective inhibitor of the JAK family, binds to the active site of JAK and prevents JAK activation. Inactive JAK is unable to phosphorylate STAT, thus tofacitinib inhibits the JAK pathways preventing translocation of STAT and reducing cytokine signaling from inside the cell. Tofacitinib inhibits JAK3 and JAK1 and, to a lesser extent JAK2, exhibits functional selectivity for JAK1/3 and JAK1/2 signaling over JAK2/2 signaling in a cellular setting. It has little effect on TYK2, and has high selectivity and specificity, sparing other protein kinases. 2,3 Development of Tofacitinib for the Treatment of Immune Mediated Diseases US Food and Drug Administration Approval for the Treatment of Rheumatoid Arthritis Oral tofacitinib (Xeljanz ® ) has demonstrated efficacy and a manageable safety profile in the treatment of RA and in the US is indicated for the treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other non-biologic disease-modifying antirheumatic drugs (DMARDs). 4,5 © TOU C H M E D ICA L ME D IA 2014