Biologics have changed the landscape of therapy for\u00a0rheumatoid arthritis (RA). While they have substantially\u00a0improved outcomes in patients with RA who are\u00a0disease-modifying antirheumatic drug (DMARD) incomplete responders (IRs), they require administration\u00a0via the subcutaneous or intravenous routes. Recently, a\u00a0new class of oral DMARDs has been developed which\u00a0inhibit Janus kinase enzymes.<\/p>\n
JAK<\/a> enzymes are constitutively bound to the intracellular domains of cytokine receptors. When extracellular\u00a0cytokines and growth factors bind to these receptors,\u00a0JAKs are phosphorylated, leading to activation of signal\u00a0transducers and activators of transcription<\/a> (STATs). The\u00a0result is modulation of a variety of signaling cascades\u00a0involved in innate and acquired immunity and hematopoiesis, including many thought to be involved in the\u00a0pathogenesis of rheumatoid arthritis.<\/p>\n There at least four JAK enzymes, JAK1, JAK2, JAK3, and\u00a0Tyk2, and they are associated with receptors in pairs. JAK3 is expressed mostly in lymphoid cells and binds\u00a0primarily with the gamma chain of the IL-2 family of\u00a0receptors, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.\u00a0JAK1 is also expressed in lymphoid cells, but also more\u00a0widely, including the central nervous system, and is associated with the beta chain of the IL-2 family of receptors and\u00a0also with other cytokine receptors including interferongamma and IL-6, IL-10, IL-12, and IL-23. JAK2 is expressed\u00a0on a wide variety of cells, inhibits signaling by erythropoetin\u00a0and growth hormone, and is important in controlling the\u00a0production of blood cells from hematopoetic stem cells,\u00a0and JAK2 mutations are associated with myeloproliferative\u00a0syndromes. Tyk2 also has somewhat ubiquitous expression\u00a0and is a component of alpha and beta-interferon signaling\u00a0as well as IL-6, IL-10, IL-12, and IL-23 transduction.<\/p>\n Tofacitinib is a selective JAK inhibitor with higher affinity for JAK3 and JAK1\u00a0than JAK2 with limited affinity for Tyk2. Tofacitinib significantly inhibited\u00a0JAK1\/JAK2, JAK1\/JAK3, and JAK2\/JAK3 combinations in in vitro assays.\u00a0Tofacitinib represents the first drug in a new class of nonbiological DMARDs.\u00a0Multiple in vitro studies demonstrate the immunosuppressive effects of\u00a0tofacitinib. In studies of mouse and human T cells,\u00a0tofacitinib inhibited several signaling pathways, including IL-2-induced phosphorylation of a variety of STATs, IL-6-induced phosphorylation of STATs, and\u00a0other downstream effects of JAK3 as well as JAK1 and JAK2. In in vitro\u00a0studies of rheumatoid synoviocytes, tofacitinib inhibited IL-6-induced expression of the acute-phase serum amyloid A, which is known to induce the\u00a0synthesis of other pro-inflammatory cytokines, and inhibited TNF-induced\u00a0expression of multiple lymphocyte attracting cytokines and chemokines. In\u00a0CD4 T cells from RA patients, tofacitinib inhibited the proliferation of these\u00a0cells and the synthesis and transcription of IL-17 and TNF-gamma (but not IL-6\u00a0or IL-8).<\/p>\n