van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: Twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum 2013;65:559–570.
This study is a 12 month report of a 24 month study for radiographic data in patients on methotrexate and tofacitinib (Xeljanz) or placebo.
The patients had to have significantly active disease. Inclusion criteria included patients on doses of MTX from 15-25 with < 10 mg daily of prednisone equivalent and with > 5 tender joints and > 5 swollen joints with an elevated inflammatory marker and erosive disease had tofacitinib (Xeljanz) 5 BID, 10 BID or placebo added to their regimen. At 3 months, non-responders were blindly increased to tofacitinib (Xeljanz). After 6 months all patients were increased to tofacitinib (Xeljanz).
One this I'm not sure I understand is why all patients were advanced to tofacitinib (Xeljanz) at 6 months. It's probably not complicated, but I'm missing it. Maybe they just wanted more side effect data?
Regarding the interesting primary end point, the Sharp score:
The least squares mean (LSM) changes in total SHS at month 6 were 0.12 and 0.06 for patients receiving tofacitinib 5 mg and 10 mg twice daily, respectively, versus 0.47 for patients receiving placebo (P = 0.0792 [not significant] and P ≤ 0.05, respectively)
In English: Tofacitinib (Xeljanz) 10mg BID decreased erosive damage, but 5mg BID did not. This raises an interesting question: Why is the 5 mg dose the only one that is on the FDA label? I don't mean to imply that the 5mg dose doesn't have any disease modifying properties, improvement in physical function and other symptoms, etc. but in multiple studies it appears that the 10mg BID dose is more efficacious. Is it side effects? Not in this study. Perhaps in others? That does seem to be the potential concern with need for more data. (Also, why did they report the P value of the 5 mg dose to the 10 thousandth place but the 10 mg to the hundredth place?)
At month 12, ACR20, ACR50, and ACR70 response rates were 48.5%, 32.7%, and 18.8%, respectively, for tofacitinib at 5 mg twice daily and 57.0%, 41.1%, and 27.5%, respectively, for tofacitinib at 10 mg twice daily
Rates of remission as defined by DAS28-ESR < 2.6 at month 6 were 7.2% and 16.0% for tofacitinib at 5 mg and 10 mg twice daily, respectively, versus 1.6% for placebo.
I am concerned by the number of deaths, cardiovascular events, and malignancies. 6 deaths occurred in all. 1 on treatment group and one in the placebo group were clearly not related to the study drug. This leaves 4 to 0. Then there was 6 to 0 non-fatal CV events and 9 to 0 malignancies. I don't know if this is significant or if this is different than other DMARDs/biologicals. They didn't really discuss it in the study, but it's something to pay attention to and mention when giving informed consent.