Anti-TNF drug certolizumab pegol in combination with methotrexate achieves significantly better outcomes in early active rheumatoid arthritis than does methotrexate alone, according to researchers.
They conducted a randomized, double-blind, placebo-controlled phase III trial of certolizumab pegol (CZP) in combination with dose-optimized methotrexate (MTX) versus dose-optimized methotrexate and placebo (PBO) in 879 treatment-naive patients with moderate to severe, active, progressive RA, and with poor prognostic factors.
Dr. Paul Emery
After 1 year of treatment, 28.9% of the 660 patients who received the CZP and MTX combination had achieved sustained remission, compared with 15% of the 219 patients in the PBO+MTX group (P less than .001) (Ann Rheum Dis. 2016 May 10. doi: 10.1136/annrheumdis-2015-209057).
The study also found that 43.8% of patients in the treatment arm achieved sustained low disease activity, compared with 28.6% of the control arm (P less than .001). Adjustment for withdrawals in each arm did not significantly bias the results.
CZP with MTX has shown efficacy both in patients with established RA who have shown an insufficient response to MTX alone, and in MTX-naive individuals with early RA, which the authors said justified further study in recently-diagnosed individuals.
“These data demonstrate that CZP+MTX combination therapy results in a significantly higher proportion of patients achieving sREM [sustained remission] than those treated with PBO+MTX, even when using a ‘treat-to-tolerance’ dosing strategy for MTX,” wrote Dr. Paul Emery of Leeds Institute of Rheumatic and Musculoskeletal Medicine at the University of Leeds, England, and coauthors.
“Consequently, for patients with poor prognostic factors for severe disease progression, treating early and aggressively may represent a unique opportunity to achieve maximal clinical benefit.”
Significantly more patients treated with CZP and MTX than with PBO achieved an ACR50 response (61.8% vs. 52.6%, P = .023), signifying at least a 50% improvement in the number of tender and swollen joints, and in the patient assessments of disease status, pain, and function.
Patients in the active group also showed greater improvements in physical function, as measured by the Health Assessment Questionnaire–Disability Index, and significantly less radiographic progression. Researchers noted that patients in the active arm of the study showed less joint erosion and less joint space narrowing compared with those in the placebo arm.
“The analysis of radiographic data in C-EARLY demonstrates that CZP+MTX therapy can inhibit structural damage significantly more than MTX alone – the percentage of patients with radiographic nonprogression was significantly higher in the CZP+MTX group compared with the PBO+MTX group,” the authors reported.
The incidence of adverse events was similar in both groups, with nausea, upper respiratory tract infection, urinary tract infection, nasopharyngitis, headache, and increased levels of alanine aminotransferase the most commonly reported events in the active arm.
One death in a patient taking CZP and MTX was caused by disseminated, noncharacterized, mycobacterium infection, which the investigators considered to be related to the study medication. However, the overall rates of serious adverse events and withdrawals due to adverse events were similar between both arms of the study.
Patients given CZP began on a dose of 400 mg at baseline, week 2 and week 4, then 200 mg every 2 weeks until week 52, while the dose of oral MTX used in the study was titrated up from an initial dose of 10 mg/week by 5 mg every 2 weeks, to a maximum of 25 mg/week by week 8.
The authors suggested that the methotrexate titration was an important part of the treatment because it ensured each patient received the maximum-tolerated dose within 8 weeks.
“To our knowledge, there are no previous studies in MTX-naive or DMARD-naive patients with RA where MTX doses have been optimized per-protocol to the levels achieved in C-EARLY,” they wrote. “This optimization may have been responsible, in part, for the response observed for the PBO+MTX and CZP+MTX arms.”
The study and manuscript development was sponsored by UCB Pharma, which also signed off on the manuscript after a review. The authors declared consultancy, speaker’s fees, grants and other funding from a range of pharmaceutical companies including UCB Pharma, and five authors were employees of UCB Pharma.