Among adults with treatment-refractory rheumatoid arthritis, the investigative oral Janus kinase inhibitor tofacitinib taken at doses of 5 and 10 mg twice a day in combination with methotrexate produced rapid and clinically meaningful improvements in signs and symptoms of the disease as well as in physical function at 6 months, results from a large multicenter phase III trial showed.
In the study, funded by Pfizer, makers of tofacitinib, and published online Jan. 5, 2013, in The Lancet, investigators at 82 centers in 13 countries evaluated 399 adult patients with moderate to severe arthritis who were unresponsive to tumor necrosis factor inhibitors. The patients were randomly assigned in a 2:2:1:1 ratio to tofacitinib 5 mg twice a day (133 patients); tofacitinib 10 mg twice a day (134 patients); placebo (132) for 3 months then advanced to 5 mg tofacitinib twice a day; or placebo for 3 months then advanced to 10 mg tofacitinib twice a day, all with stable doses of methotrexate (Lancet 2013 Jan. 5 [doi:10.1016/S0140-6736(12)61424-X]). The three primary endpoints were the American College of Rheumatology–20 (ACR20) response rate, the mean change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ-DI), and Disease Activity Score of less than 2.6 in 28 joints (DAS28 less than 2.6).
After 3 months, ACR20 response rates were 41.7% in the 5-mg tofacitinib twice-a-day group and 48.1% in the 10-mg tofacitinib twice-a-day group compared with 24.4% in the placebo group. Improvements from baseline in the HAQ-DI were -0.43 in the 5-mg tofacitinib twice-a-day group and -0.46 in the 10-mg tofacitinib twice-a-day group compared with -0.18 in the placebo group. At the same time, DA28 less than 2.6 rates were 6.7% in the 5-mg tofacitinib twice-a-day group and 8.8% in the 10-mg tofacitinib twice-a-day group compared with 1.7% in the placebo group.
The researchers, who were led by Dr. Gerd R. Burmester, a rheumatologist and professor of medicine at Charité Hospital in Berlin, also observed changes in laboratory parameters for both dosing levels compared with placebo, including decreases in mean neutrophil counts and increases in mean HDL and LDL concentration. "Whether changes in lipid levels associated with immune modulatory therapy are necessarily associated with increased cardiovascular risk is unclear," they wrote. Further studies are warranted "to achieve better understanding of the mechanism underlying the lipid changes seen with tofacitinib in patients with rheumatoid arthritis," they added.
The most common safety events observed across all tofacitinib groups during the first 3 months were diarrhea (4.9%), nasopharyngitis (4.1%), headache (4.1%), and urinary tract infection (3%). Nausea was the most common adverse event seen in the placebo group (6.8%).
Dr. Burmester and his associates acknowledged certain limitations of the study, including the fact that most of the patients were white (83%) and from North America or Europe (88%). "Because these patients had severe treatment-refractory rheumatoid arthritis, placebo treatment duration was limited to 3 months; therefore, definitive conclusions about the long-term efficacy and safety of tofacitinib can only be made after additional data are available for longer treatment durations," they wrote.
Pfizer funded the study. Dr. Gerd R. Burmester of Charité in Berlin has a financial relationship with Pfizer as do many of the coauthors.