The kinase inhibitor tofacitinib in patients with rheumatoid arthritis: latest findings and clinical potential.

Macrophages, T and B cells, and neutrophils concentrate mainly into the synovial tissue of rheumatoid arthritis (RA) patients and produce several inflammatory mediators including cytokines. More recently, small molecule inhibitors of signalling mediators which have intracellular targets (mainly in T and B cells) such as the Janus kinase (JAK) family of tyrosine kinases have been introduced in RA treatment. The JAK family consist of four types: JAK1, JAK2, JAK3 and TyK2. In particular, JAK3 is the only JAK family member that associates with just one cytokine receptor, the common gamma chain, which is exclusively used by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 critically involved in T and natural killer (NK)-cell development, and B-cell function and proliferation. Tofacitinib is one of the first JAK inhibitors tested and mainly interacts with JAK1 and JAK3. Four phase II (one A and three B dose-ranging) trials in RA patients, lasting from 6 to 24 weeks, achieved significant improvements of American College of Rheumatology 20% improvement criteria (ACR20) and Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) or erythrocyte sedimentation rate (DAS-ESR; in one study that analysed this), as early as week 2 and sustained at week 24 in two studies. Doses ranged from 1, 3, 5, 10, 15, 20 up to 30 mg and were administered orally twice a day. ACR20 response rates for dosages ≥3 mg were found to be significantly (p ≤ 0.05) greater than those for placebo in all phase II studies. In general, the major adverse effects included liver test elevation, neutropenia, lipid and creatinine elevation and increased incidence of infections. More recently, RA patients randomly assigned to 5 or 10 mg of tofacitinib twice daily, in both 6- and 12-month phase III trials, achieved a significantly higher ACR20 than those receiving placebo. Adverse events occurred more frequently with tofacitinib than with placebo, and included pulmonary tuberculosis and other serious infections. The balance of efficacy and safety of tofacitinib compared with standard of care therapy is bringing this first orally available biological disease-modifying antirheumatic drug (DMARD) a step closer for RA patients.

RCT Entities:   Population Interventions Outcomes