Kinase inhibition--a new approach to the treatment of rheumatoid arthritis.

Two placebo-controlled trials reported in this issue of the Journal show the efficacy of an oral Janus kinase (JAK) inhibitor, tofacitinib, in the treatment of rheumatoid arthritis.1,2 If this agent is approved by the Food and Drug Administration (FDA) for use in patients with rheumatoid arthritis, clinicians will confront several complex questions. What is the rationale for targeting this family of kinases? How effective is tofacitinib as compared with other proven agents that are used to treat rheumatoid arthritis? What safety concerns need to be kept in focus? How should JAK inhibition be combined with other medications in the management of rheumatoid arthritis? In addition, health systems will be interested in understanding the cost–benefit balance in the use of tofacitinib. The JAK family includes four tyrosine kinases: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). These enzymes, which are expressed primarily in hematopoietic cell lineages, form part of the signaling apparatus used by receptors for various cytokines and growth factors. When such receptors are engaged by their specific ligands, JAKs phosphorylate and thus activate members of the signal transducer and activator of transcription (STAT) family. STATs 1 through 6 have specific and distinct effects on gene transcription in cells of the immune system that are critical in processes such as lymphocyte differentiation, immune regulation, and inflammation.3 The importance of JAKs is emphasized by the delineation of profound immune deficiencies in the relatively few persons who have defects in the genes encoding JAK1 or JAK3.4 The compound now known as tofacitinib was first described in 2003 as a specific inhibitor of JAK3 that could prevent allograft rejection.5 However, it is now considered to inhibit both JAK1 and JAK3 — two enzymes that can associate with the same cytokine receptors and function as signaling heterodimers. Tofacitinib is less active against JAK2, which associates primarily with growth factor receptors and which is therapeutically inhibited by ruxolitinib in the treatment of myelofibrosis.6 Phase 3 clinical trials of tofacitinib for the treatment of rheumatoid arthritis in humans are based in part on beneficial effects of this JAK inhibitor in animal models of inflammatory arthritis7,8 and in phase 2 studies involving patients with rheumatoid arthritis.9,10 Each of the trials reported in this issue of the Journal examined the use of tofacitinib (5 or 10 mg twice daily) in patients with rheumatoid arthritis whose disease was resistant to other diseasemodifying drugs. Van Vollenhoven et al. added tofacitinib, adalimumab (an anti–tumor-necrosisfactor [TNF] antibody that is well established as a treatment for rheumatoid arthritis), or placebo to weekly methotrexate therapy in patients who had active disease despite methotrexate therapy. Fleischmann et al. enrolled patients who had not had a response to a variety of prior diseasemodifying drugs — conventional, biologic, or both — and compared tofacitinib with placebo without the concurrent use of methotrexate or other disease-modifying drugs except hydroxychloroquine. The study design minimized the percentage of patients who received placebo and the length of time that these patients received the placebo. Both sets of investigators were successful in recruiting patients with very active rheumatoid arthritis and assessed the response to treatment using standard composite indexes of rheumatoid arthritis disease activity. Over a 6-month period, clinically meaningful improvement was seen in the patients who received tofacitinib. In the von Vollenhoven trial,