Predictors of disease activity and structural progression after treatment with adalimumab plus methotrexate or continued methotrexate monotherapy in patients with early rheumatoid arthritis and suboptimal response to methotrexate

Abstract

Objectives: Methotrexate is considered to be first-line therapy for rheumatoid arthritis (RA). However, a substantial proportion of treated patients do not achieve the desired goals of therapy. This analysis aimed to identify predictors of insufficient response to methotrexate in patients with early RA.

Methods: The Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab (OPTIMA) and PREMIER studies in patients with RA for <1 and <3 years, respectively, examined the efficacy of methotrexate and adalimumab in methotrexate-naive patients. This post hoc analysis included patients for whom initial methotrexate monotherapy was not successful after 6 months. Candidate predictors of insufficient response and clinically relevant radiographic progression (CRRP) included demographics, baseline disease characteristics and time-averaged disease variables over a 12-week interval. In OPTIMA, adalimumab was added to therapy after insufficient treatment response; in PREMIER, initial methotrexate therapy was continued; clinical, functional and radiologic outcomes were assessed after 1 year.

Results: Baseline 28-joint Disease Activity Score based on C-reactive protein (DAS28(CRP)) and time-averaged DAS28(CRP) over 4, 8 and 12 weeks were the strongest predictors of insufficient response to methotrexate and CRRP. Addition of adalimumab to methotrexate therapy was associated with better clinical, functional and radiographic outcomes after 1 year compared with continuing on methotrexate monotherapy.

Conclusions: In patients with early RA, baseline disease characteristics and early disease activity can predict response to methotrexate treatment and radiographic progression at 6 months. The addition of adalimumab at 6 months after methotrexate failure is associated with improved outcomes. These results support treatment-to-target strategies and timely adaptation of therapy in patients with early RA.

Trial registration number: NCT00420927, NCT00195663; Post-results.

Keywords: anti-TNF; methotrexate; rheumatoid arthritis.

Conflict of interest statement

Competing interests: JSS and AK provided remunerated expert advice to and received grant/research support for his institution from AbbVie. RFvV has received grants and research support from AbbVie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche and UCB; and consulting fees and honoraria from AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB and Vertex. SF, SC and JLS are employees of AbbVie and may hold stock or stock options.

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Backward logistic regression analysis of baseline predictors, including DAS28(CRP), of insufficient response to methotrexate at 6 months (A) and CRRP at 6 months (B) in patients with early RA receiving methotrexate monotherapy. Insufficient response to methotrexate was defined as not achieving DAS28(CRP) 1.5 from baseline to week 26 (OPTIMA study) or week 24 (PREMIER study). Predictors analysis considered 500 methotrexate insufficient responders and 156 methotrexate responders; CRRP analysis considered 481 patients without CRRP and 163 patients with CRRP. The OR for each continuous variable (age, BMI, CRP at BL, DAS28 at BL, mTSS, PGA at BL, Pt Pain at BL, RF and weight) reflects the effect of a 1-unit change in that variable; thus, the ORs differ partly because of the different relative meaning of a 1-unit change, such as for DAS28 (scale, about 1–10) compared with SDAI (scale, 0 to about 86). The full regression models, before elimination of factors with p≥0.1, included age, race (white vs non-white), sex (male vs female), weight, RA duration, RF, BMI and mTSS; BL values for CRP, tender joint count based on 68 joints, swollen joint count based on 66 joints, Health Assessment Questionnaire Disability Index, Pt Pain, Pt Global Assessment of Disease Activity on a 100 mm visual analogue scale, PGA and DAS28; and prior use of DMARDs (yes vs no), number of prior DMARDs and prior use of GCs (yes vs no). *P

Figure 2

Backward logistic regression analysis of baseline and postbaseline predictors, including DAS28(CRP), of insufficient response to methotrexate at 6 months (A) and CRRP at 6 months (B) based on data from weeks 0–4, weeks 0–8 and weeks 0–12 in patients with early RA receiving methotrexate monotherapy. Week 4 analysis considered 485 methotrexate insufficient responders and 151 methotrexate responders, week 8 analysis considered 507 methotrexate insufficient responders and 160 methotrexate responders and week 12 analysis considered 500 methotrexate insufficient responders and 156 methotrexate responders. Week 4 analysis considered 471 patients without CRRP and 153 patients with CRRP, week 8 analysis considered 491 patients without CRRP and 163 patients with CRRP and week 12 analysis considered 481 patients without CRRP and 163 patients with CRRP. Insufficient response to methotrexate was defined as not achieving DAS28(CRP) 1.5 from baseline to week 26 (OPTIMA study) or week 24 (PREMIER study). The OR for each continuous variable (age, BMI, mTSS, RF, TA-CRP, TA-DAS28, TA-PGA, TA-Pt Pain, TA-PtGA, TA-TJC68, weight) reflects the effect of a 1-unit change in that variable; thus, the ORs differ partly because of the different relative meaning of a 1-unit change, such as for DAS28 (scale, about 1–10) compared with SDAI (scale, 0 to about 86). The full regression models, before elimination of factors with p≥0.1, included age, race (white vs non-white), sex (male vs female), weight, RA duration, RF, BMI and mTSS; TA values for CRP, TJC68, swollen joint count based on 66 joints, HAQ-DI, Pt Pain, PtGA, PGA and DAS28; and prior use of DMARDs (yes vs no), number of prior DMARDs and prior use of GCs (yes vs no). *P