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

Abstract

Objective: CONCERTO 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).

Methods: Early, 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.

Results: Statistically 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.

Conclusions: Increasing 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.

Figure 1

Patient disposition. Primary reasons for discontinuation are listed.

Figure 2

Clinical and functional efficacy following 26 weeks of open-label adalimumab in combination with different doses of MTX. Proportion of patients achieving DAS28(CRP) <3.2 (A), <2.6 (B), ACR70 (C) and change from baseline HAQ-DI≤−0.22 (D). DAS28, 28-joint disease activity score; CRP, C reactive protein; ACR, American College of Rheumatology; HAQ-DI, Health Assessment Questionnaire Disability Index; ADA, adalimumab; MTX, methotrexate. Missing values were imputed using non-responder imputation. *, ** and *** denote statistical significance at the 0.05, 0.01 and 0.001 levels, respectively.

Figure 3

Clinical LDA, remission and adalimumab pharmacokinetics following 26-week treatment with adalimumab in combination with ascending MTX doses. Proportion of patients achieving LDA or remission measured by CDAI (A and B, respectively) or SDAI (C and D, respectively). Mean adalimumab trough concentrations (±SD) over time (E). CDAI, clinical disease activity index; LDA, low disease activity; SDAI, simplified disease activity index; ADA, adalimumab; MTX, methotrexate. Missing values were imputed using non-responder imputation. *, ** and *** denote statistical significance at the 0.05, 0.01 and 0.001 levels, respectively.

Figure 4

Radiographic and composite measures of disease following 26 weeks of adalimumab + MTX treatment. Proportion of patients with no radiographic progression (ΔmTSS ≤0.5) (A), probability of mTSS change from baseline (B), comprehensive disease control using DAS28(CRP) <3.2 (C) and comprehensive disease control using DAS28(CRP) <2.6 (D). ADA, adalimumab; MTX, methotrexate; mTSS, modified total Sharp score; DAS28, 28-joint disease activity score; CRP, C reactive protein; HAQ-DI, Health Assessment Questionnaire Disability Index. Missing values were imputed using non-responder imputation.