The PREMIER study: A multicenter, randomized, double‐blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment

Abstract

Objective. To compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive rheumatoid arthritis (RA) who had not previously received MTX treatment.Methods. This was a 2-year, multicenter, doubleblind, active comparator-controlled study of 799 RA patients with active disease of <3 years' duration who had never been treated with MTX. Treatments included adalimumab 40 mg subcutaneously every other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. Co-primary end points at year 1 were American College of Rheumatology 50% improvement (ACR50) and mean change from baseline in the modified total Sharp score.Results. Combination therapy was superior to both MTX and adalimumab monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) than did patients who received MTX or adalimumab monotherapy (46% and 41%, respectively; both P < 0.001). Similar superiority of combination therapy was seen in ACR20, ACR70, and ACR90 response rates at 1 and 2 years. There was significantly less radiographic progression (P < 0.002) among patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units) or the adalimumab arm (3.0 and 5.5 Sharp units). After 2 years of treatment, 49% of patients receiving combination therapy exhibited disease remission (28-joint Disease Activity Score <2.6), and 49% exhibited a major clinical response (ACR70 response for at least 6 continuous months), rates approximately twice those found Supported by Abbott Laboratories.

Rheumatoid arthritis joint progression in sustained remission is determined by disease activity levels preceding the period of radiographic assessment

“…We used data from the PREMIER trial, a multicenter, randomized, double-blind, controlled, phase III clinical trial comparing adalimumab (40 mg every other week), MTX (mean dosage 16.9 mg weekly), and the combination of adalimumab and MTX in patients with early RA who had not been previously treated with MTX (24). For the present study, we were provided data on all patients enrolled in the trial.…”

“…To investigate the presence of such a "carryover" effect of disease activity on joint damage, we used a large clinical trial database of patients with early RA who were treated with methotrexate (MTX) monotherapy, adalimumab monotherapy, or the combination of adalimumab plus MTX (24), with a 2-year followup of disease activity and radiographic assessments.…”

Targeting Interleukin-6 in Rheumatoid Arthritis

“…More importantly, there is a lack head-to-head success in regards to superiority of the biologics given as monotherapy against methotrexate [3][4][5]. Even when a TNF-inhibitor is given in combination with DMARDs, the rate of inadequate response has been quoted about 20-40% in various populations studied [6], prompting the clinician to switch to different form of biologics.…”

My Treatment Approach to Rheumatoid Arthritis

“…57 This conclusion is supported by a 2010 Cochrane systematic review that emphasized lack of evidence of a statistically significant advantage for initial combination therapy using MTX and other conventional DMARDs over monotherapy with MTX. 58 A [59][60][61][62][63][64] The results of these studies suggest that the combination of MTX with a TNF inhibitor or CTLA-4:Ig (abatacept) has greater efficacy than MTX monotherapy insofar as both clinical and radiographic outcomes are concerned.…”

“…36,60,72,74 In this setting, both TNF inhibitors 59,62,[76][77][78] and abatacept 79 are approved and are recommended biologic response modifiers for step-up treatment. Although interleukin 1 receptor antagonist therapy (anakinra) is approved for treatment in this context, we regard this medication as generally less effective than the above-mentioned agents, and, thus, cannot recommend its use at this disease stage.…”