Biologics have changed the landscape of therapy for rheumatoid arthritis (RA). While they have substantially improved outcomes in patients with RA who are disease-modifying antirheumatic drug (DMARD) incomplete responders (IRs), they require administration via the subcutaneous or intravenous routes. Recently, a new class of oral DMARDs has been developed which inhibit Janus kinase enzymes.
JAK enzymes are constitutively bound to the intracellular domains of cytokine receptors. When extracellular cytokines and growth factors bind to these receptors, JAKs are phosphorylated, leading to activation of signal transducers and activators of transcription (STATs). The result is modulation of a variety of signaling cascades involved in innate and acquired immunity and hematopoiesis, including many thought to be involved in the pathogenesis of rheumatoid arthritis.
There at least four JAK enzymes, JAK1, JAK2, JAK3, and Tyk2, and they are associated with receptors in pairs. JAK3 is expressed mostly in lymphoid cells and binds primarily with the gamma chain of the IL-2 family of receptors, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. JAK1 is also expressed in lymphoid cells, but also more widely, including the central nervous system, and is associated with the beta chain of the IL-2 family of receptors and also with other cytokine receptors including interferongamma and IL-6, IL-10, IL-12, and IL-23. JAK2 is expressed on a wide variety of cells, inhibits signaling by erythropoetin and growth hormone, and is important in controlling the production of blood cells from hematopoetic stem cells, and JAK2 mutations are associated with myeloproliferative syndromes. Tyk2 also has somewhat ubiquitous expression and is a component of alpha and beta-interferon signaling as well as IL-6, IL-10, IL-12, and IL-23 transduction.
Tofacitinib is a selective JAK inhibitor with higher affinity for JAK3 and JAK1 than JAK2 with limited affinity for Tyk2. Tofacitinib significantly inhibited JAK1/JAK2, JAK1/JAK3, and JAK2/JAK3 combinations in in vitro assays. Tofacitinib represents the first drug in a new class of nonbiological DMARDs. Multiple in vitro studies demonstrate the immunosuppressive effects of tofacitinib. In studies of mouse and human T cells, tofacitinib inhibited several signaling pathways, including IL-2-induced phosphorylation of a variety of STATs, IL-6-induced phosphorylation of STATs, and other downstream effects of JAK3 as well as JAK1 and JAK2. In in vitro studies of rheumatoid synoviocytes, tofacitinib inhibited IL-6-induced expression of the acute-phase serum amyloid A, which is known to induce the synthesis of other pro-inflammatory cytokines, and inhibited TNF-induced expression of multiple lymphocyte attracting cytokines and chemokines. In CD4 T cells from RA patients, tofacitinib inhibited the proliferation of these cells and the synthesis and transcription of IL-17 and TNF-gamma (but not IL-6 or IL-8).
Baricitinib is a potent inhibitor of JAK1 and JAK2, and, as discussed previously, has the ability to block downstream inflammatory activity. It is administered orally, once daily. Clinical trials for RA are ongoing, and the drug has not yet been submitted for approval from regulatory agencies. Baricitinib selectively and reversibly inhibits JAK1 and JAK2 through binding and intracellular mechanisms similar to those described for tofacitinib. As a result, cytokines such as IL-6, IL-12, and IL-23, as well as granulocytemacrophage colony-stimulating factor and interferon-gamma may be inhibited as downstream effects. In animal models of inflammatory arthritis, baricitinib was shown to have significant anti-inflammatory effects, but also led to preservation of cartilage and bone, with no detectable suppression of humoral immunity or adverse hematologic effects.
Reference:
Cohen, Marc D., and Edward C. Keystone. “JAK Inhibitors for Rheumatoid Arthritis.” Current Treatment Options in Rheumatology 1.4 (2015): 305-319.