Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study

Abstract

Objective: To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission.

Methods: ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued.

Results: Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%).

Conclusions: Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement.

Trial registration number: NCT00810199.

Keywords: DMARDs (biologic); Methotrexate; Rheumatoid Arthritis.

Figure 1

(A) Schematic of study design and (B) patient disposition through 3 years. AE, adverse event; csDMARD, conventional synthetic disease-modifying antirheumatic drug; DAS28-ESR, Disease Activity Score in 28 joints using erythrocyte sedimentation rate; ITT, intent-to-treat population; MTX, methotrexate; OL, open-label; PBO, placebo; TCZ, tocilizumab.

Figure 2

Kaplan–Meier plots of (A) time to TCZ-free remission and (B) time to flare after TCZ-free remission. (C) Evolution of mean DAS28-ESR and TJC (68) after reinitiation of TCZ in patients who restarted TCZ after flare. Error bars represent SD. DAS28-ESR, Disease Activity Score in 28 joints using erythrocyte sedimentation rate; TCZ, tocilizumab; TJC (68), tender joint count using 68 joints.

Figure 3

Radiographic results. (A) Mean change from baseline to weeks 24, 52 and 104 in total GSS and (B) cumulative distribution plot of change from baseline to week 104 in total GSS. Area between grey lines is within the SDC for GSS (2.1). ^aBaseline biannualised progression rate was 2×baseline GSS divided by RA duration. Error bars represent the SE of the mean. p Values are from an ANCOVA adjusting for baseline DAS28-ESR, baseline GSS and region. Missing week 52 data were imputed by linear extrapolation if baseline and week 24 values were present. For the week 104 analysis, no imputation of missing data was performed. ANCOVA, analyses of covariance; DAS28-ESR, Disease Activity Score in 28 joints using erythrocyte sedimentation rate; GSS, Genant-modified Sharp score; RA, rheumatoid arthritis; SDC, smallest detectable change.