Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study

Abstract

Objective: To assess the efficacy and safety of adalimumab plus methotrexate (ADA+MTX) compared with methotrexate monotherapy in achieving stable low disease activity (LDA; disease activity score (DAS28(CRP)) <3.2 at weeks 22 and 26) and clinical, radiographic and functional outcomes in methotrexate-naive patients with early rheumatoid arthritis (RA).

Methods: 1032 patients with active RA were randomly assigned 1:1 to ADA+MTX or placebo plus methotrexate (PBO+MTX) for 26 weeks. Treatment modifications were to be made in a subsequent study period based on the achievement of DAS28(CRP) <3.2 at weeks 22 and 26. Post-hoc analyses compared patients achieving stable remission using DAS28 and 2010 ACR/EULAR criteria with those achieving LDA but not remission.

Results: Among patients completing 6 months, 44% (207/466) ADA+MTX versus 24% (112/460) PBO+MTX patients achieved stable LDA at weeks 22 and 26 (p<0.001). Combination therapy was statistically superior to methotrexate in obtaining higher ACR20/50/70 responses, more clinical remissions, greater mean reductions in DAS28(CRP), no radiographic progression, and normal functional status at week 26 (p<0.001 for all). The only factor predicting stable LDA was disease activity at week 12. Patients achieving ACR/EULAR remission, particularly in the PBO+MTX group, had some advantage in radiographic outcomes compared with patients who only achieved LDA (but not remission). The overall frequency of adverse events was comparable between groups. There were more serious infections and deaths in the ADA+MTX group, with a possible age effect.

Conclusions: Treatment with ADA+MTX was significantly superior to methotrexate alone with respect to clinical, radiographic and functional outcomes in patients with early active RA. Before initiating treatment with adalimumab, individual patient evaluation of the benefit/risk ratio should be carefully considered.

Figure 1

Study design and patients' disposition to 26 weeks. ^aInvestigators may have listed more than one reason. ^bStable low disease activity target defined as disease activity score in 28 joints (DAS28) C-reactive protein less than 3.2 at weeks 22 and 26. ADA, adalimumab; MTX, methotrexate; PBO, placebo.

Figure 2

Clinical and functional improvements with adalimumab plus methotrexate (ADA+MTX) or placebo plus methotrexate (PBO+MTX) to 26 weeks (A). Percentage of patients achieving the stable low disease activity target (disease activity score in 28 joints (DAS28) C-reactive protein <3.2) at weeks 22 and 26 among patients who completed week 26 (B). Percentage of patients achieving American College of Rheumatology (ACR) 20/50/70 responses at week 26 (C). Percentage of patients achieving low disease activity and remission at week 26 (D). Mean health assessment questionnaire disability index (HAQ-DI) values to week 26. *p<0.001 versus PBO+MTX by χ2 test, non-responder imputation analysis for completers (A) or intent-to-treat (B, C); by analysis of covariance, last observation carried forward analysis (D). SDAI, simplified disease activity index.

Figure 3

Radiographic changes with adalimumab plus methotrexate (ADA+MTX) or placebo plus methotrexate (PBO+MTX) from baseline to week 26 (A). Mean change in the van der Heijde modified total Sharp score (mTSS), joint erosion (JE) and joint space narrowing (JSN). *p<0.001 versus PBO+MTX by analysis of covariance, multiple imputation analysis. (B). Cumulative probability plot of change in mTSS.

Figure 4

Radiographic and functional consequences of achieving increasingly stringent targets (stable disease activity score in 28 joints (DAS28) C-reactive protein (CRP) low disease activity or remission vs simplified disease activity index (SDAI) remission) (A). Percentage of patients exclusively achieving stable DAS28(CRP) targets versus SDAI remission at weeks 22 and 26 (B). Percentage of patients with no radiographic progression (van der Heijde modified total Sharp score (ΔmTSS) ≤0.5) at week 26 among those who exclusively achieved stable DAS28(CRP) targets or SDAI remission at weeks 22 and 26 (C). Mean ΔmTSS from baseline to week 26 among patients who exclusively achieved stable DAS28(CRP) targets or SDAI remission (D). Percentage of patients with normal function among those who exclusively achieved stable DAS28(CRP) targets or SDAI remission at weeks 22 and 26 (E). Mean change in health assessment questionnaire disability index (HAQ-DI) at week 26 in patients in who exclusively achieved stable DAS28(CRP) targets or SDAI remission at weeks 22 and 26. *p<0.05 for DAS28(CRP) response versus SDAI of 3.3 or less within treatment group by χ2 test, observed analysis among week 26 completers (B, D) or by analysis of covariance, observed analysis (C, E). ADA+MTX, adalimumab plus methotrexate; PBO+MTX, placebo plus methotrexate.