Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomised CONCERTO trial

Abstract

ObjectiveCONCERTO was a randomised, double-blind, parallel-armed study of methotrexate (MTX) in combination with adalimumab to assess whether an increasing trend of efficacy and decreased safety exists when increasing MTX dose in patients with early rheumatoid arthritis (RA).MethodsEarly, biologic and MTX-naive RA patients (N=395) were evenly randomised to open-label adalimumab (40 mg every other week) plus weekly blinded 2.5, 5, 10 or 20 mg MTX for 26 weeks. Clinical, radiographic and functional outcomes were analysed using two-sided linear trend tests or one-way analysis of covariance.ResultsStatistically significant increasing trends were observed in the proportion of patients achieving the primary endpoint, 28-joint count disease activity score with C reactive protein (DAS28(CRP)) <3.2 (42.9%, 44.0%, 56.6% and 60.2% for 2.5, 5, 10 or 20 mg/week MTX, respectively), DAS28(CRP) <2.6 and American College of Rheumatology 50/70/90 responses with increasing doses of MTX in combination with adalimumab. No statistical differences in minimal clinically important differences in physical function were detected. Statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose by validated clinical indices; differences comparing 10 and 20 mg MTX were minimal. Adalimumab serum concentrations increased with ascending dose up to 10 mg MTX. More patients experienced infectious adverse events with increasing MTX dose.ConclusionsIncreasing doses of MTX in combination with adalimumab demonstrated a statistically significant trend in improved clinical outcomes that mimicked the adalimumab pharmacokinetic profile. In early RA patients initiating adalimumab combination therapy, efficacy of 10 and 20 mg/week MTX appeared equivalent.

Similar Improvements in Patient-Reported Outcomes Among Rheumatoid Arthritis Patients Treated with Two Different Doses of Methotrexate in Combination with Adalimumab: Results From the MUSICA Trial

“…In MUSICA, we cannot rule out that persistent levels of polyglutamated MTX may have contributed to the lack of difference observed between the two MTX dosage groups for many of the PROs assessed. The findings in MUSICA are similar to those in the CONCERTO trial [19], where the initiation of treatment with a combination of adalimumab plus 2.5/5/10 or 20 mg/week MTX in treatment-naïve patients with early RA, led to similar improvements in a range of PROs including physical function, disease activity, sleep, and quality of life after 8 weeks [20]. The interpretation of the CON-CERTO results was not affected by prior MTX usage as it was in MUSICA, which was conducted in MTX-IR patients.…”

Effects of Concomitant Methotrexate on Large Joint Replacement in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors: A Multicenter Retrospective Cohort Study in Japan

“…However, little is known about the minimally effective dose of MTX when used in combination with a TNF inhibitor in patients with RA. Recently, the CONCERTO trial demonstrated that 10 mg/week of MTX is a possible dosage for use in combination with TNF inhibitors (30). Moreover, the unique situation in Japan has provided interesting data showing that concomitant MTX of 7-8 mg/week works additively with TNF inhibitors (31)(32)(33).…”

Rheumatoid Arthritis: A Novel Approach in Diagnosis and Treatment

“…Conventional synthetic DMARD-s applied in patients with RA decrease swelling of joints, reduce pain, lower the parameter values of acute phase of inflammation and improve joint function (21,(39)(40)(41)(42)(43)(44)(45).…”