1. Patients with rheumatoid arthritis (RA) taking tofacitinib in combination with non-biologic disease-modifying antirheumatic drugs (DMARDs) demonstrated an improvement in disease activity when compared to placebo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Many patients with RA do not have adequate improvement in their disease activity despite treatment with currently available non-biologic DMARDs. Tofacitinib is a novel Janus Kinase (JAK) inhibitor introduced for the treatment of RA. In this randomized, placebo-controlled trial, the safety and efficacy of tofacitinib was evaluated as an additional therapy in patients with inadequate response to stable therapy with non-biologic DMARDs. The study randomized the patients to three treatment arms: (1) placebo, (2) 5mg tofacitinib or (3) 10mg tofacitinib. At 6 months, results showed a significant improvement in disease activity as well as reduced disability in both treatment arms associated with both tofacitinib groups compared to placebo: 21.4% and 25.8% treatment difference in the 5mg and 10mg tofacitinib groups compared to placebo, respectively. No significant difference in adverse events was noted between the study arms, although tofacitinib was associated with a decrease in neutrophil count, an increase in low-density lipoprotein (LDL) levels and an increase in liver transaminases. As most of the patients were taking methotrexate, a major limitation of this study is that it lacks the power to fully examine the efficacy of combination treatment of tofacitinib and other non-biologic DMARDs.
Relevant Reading: Tofacitinib or Adalimumab versus Placebo in Rheumatoid Arthritis
In-Depth [randomized, placebo-advanced study]: This study randomly assigned 795 patient with RA to two placebo arms (n=159) advanced to 5/10mg tofacitinib twice daily or two experimental arms (n=633) directly to 5 or 10mg twice daily. Non-responder placebo patients were advanced to treatment group at 3 months, and all other placebo patients were advanced at 6 months. Primary end points, measured at 6 months, were rates of improvement, measured by ACR20, rates of remission (defined by Disease Activity Score for 28-joint counts based on the ESR (DAS28-4[ESR]) <2.6, and disability, defined by HAQ-DI. Among patients receiving 5 and 10mg tofacitinib, 52.1% (p<0.001) and 56.6% (p<0.001), respectively, responded to treatment by ACR20, compared to 30.8% in the placebo group. Similarly, tofacitinib-treated patients had a 0.44 (5mg, p<0.001) and 0.53 (10mg, p<0.001) reduction from baseline HAQ-DI, compared to 0.16 in the placebo group. Finally, the proportion of patients with DAS28-4(ESR)<2.6 treated with tofacitinib increased to 8.5% (5mg, p=0.0038) and 12.5% (10mg, p<0.001), compared to 2.6% in the placebo group. No statistically significant difference in adverse or serious adverse events was detected between tofacitinib and placebo treatments, although tofacitinib treatment was associated with a decreased neutrophil count, -0.75×109 (5mg) and -0.99 x109 (10mg), an increase in LDL levels, 15.65% (5mg) and 18.26% (10mg), and an increase in AST (23.5% [5mg] and 29.4% [10mg] >ULN, compared to 13.8% with placebo) and ALT (27.9% [5mg] and 34.2% [10mg] >ULN, compared to 17.6% with placebo).
By Sai Folmsbee and Aimee Li, MD
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