Response rates for rheumatoid arthritis patients taking either 5 mg or 10 mg twice-daily of the oral Janus kinase inhibitor tofacitinib were at least 20% greater after 6 months than for those who started on placebo and switched to the therapy, according to a new study.
Lead investigator Dr. Joel Kremer and his colleagues concluded that tofacitinib (Xeljanz) – when taken in combination with a nonbiologic disease-modifying antirheumatic drug (DMARD) – rapidly reduced the signs and symptoms of RA and improved physical functioning. But, they added, since the majority of patients in their study were taking methotrexate, extrapolating the results to other nonbiologic DMARDs should be done with caution.
Dr. Joel Kremer
They also noted that this trial supported findings in previous studies that tofacitinib works well with methotrexate. One such study was published in the Lancet and was also funded by Pfizer (Lancet 2013 [doi:10.1016/S0140-6736(12)61424-X]).
In the trial, paid for by Pfizer and conducted at 114 centers in 19 countries, 792 patients were randomly assigned 4:4:1:1 to twice-daily treatment with 5 mg of tofacitinib; 10 mg of tofacitinib; or placebo. The study was published Aug. 19 in the Annals of Internal Medicine.
At 3 months, placebo patients who did not respond were blindly switched to the 5-mg or 10-mg dose. Patients taking tofacitinib who did not respond at 3 months continued on the same dose. After 6 months, all patients still on placebo were switched blindly to either the 5-mg or 10-mg dose.
At 6 months, the response rates – defined as 20% improvement in the tender or painful and swollen joint count at three months (ACR20) – were 21% greater for patients taking 5 mg, and 26% greater for patients taking 10 mg, when compared with patients who had been on placebo for 3 months and then switched to one of the two doses.
There was a significantly greater improvement (P less than .001) at 3 months in the Health Assessment Questionnaire Disability Index (HAQ-DI) for patients in the treatment arms, and more of those patients had a Disease Activity Score for 28 joints (DAS28-4) of less than 2.6 at 6 months than did the placebo groups.
Patients were enrolled if they were aged 18 years or older and had a rheumatoid arthritis diagnosis consistent with the 1987 American College of Rheumatology criteria, and an inadequate response to treatment with one or more nonbiologic or biologic DMARDs. They were also required to continue treatment with one or more nonbiologic DMARDs throughout the study. Those taking methotrexate had to have been receiving it for at least 4 months and at stable dosing over at least 6 weeks before the study start. Low-dose, oral corticosteroid therapy was also allowed.
Exclusion criteria included previous treatment with lymphocyte-depleting therapies within a year of the study start; a depressed hemoglobin, hematocrit, leukocyte, or platelet count; or a history of autoimmune rheumatic disease or most cancers. Patients were also excluded if they had experienced an infection requiring hospitalization or intravenous antibiotics within 6 months of baseline, oral antibiotics within 2 weeks of baseline, or infection with herpes zoster, hepatitis B or C, or HIV.
Only 651 (82%) of the 792 patients enrolled completed the study. The mean age across the four treatment groups was 51-53 years old, and at least three-quarters of the participants were female. Two-thirds to 73% of patients continued to take background DMARDs during the study, and at least a quarter received two or more DMARDs. Methotrexate was the most frequently prescribed DMARD.
At 3 months, half of the placebo patients did not have a response and were then switched to either 5 mg (38 patients) or 10 mg (40 patients) of tofacitinib. In the treatment group at 3 months, 80 (26%) patients taking 5 mg and 58 (18%) patients taking 10 mg had no response. A total of 27% of those taking placebo had a response according to the ACR20 criteria.
The authors reported statistically significant response rates for ACR20 and ACR50 by the second week for both treatment arms. DAS28-4, DAS28-4 less than 2.6, and Functional Assessment of Chronic Illness Therapy-Fatigue response rates also were statistically significant over time for the tofacitinib treatment groups when compared with placebo.
The authors reported a higher adverse event and serious adverse event rate for patients on placebo, but a higher discontinuation rate for those taking tofacitinib.
Over a year, the adverse event rate was 172/100 patient-years for tofacitinib 5 mg, 176 for the 10 mg group, and 342 for the placebo-to-tofacitinib groups. The most common adverse events in the tofacitinib groups were upper respiratory tract infections and nasopharyngitis. The discontinuation rate from adverse events was 5.4/100 patient-years for placebo, 6.2 for the 5-mg group, and 9.7 for the 10-mg group.