Background The goal of treatment in early RA is to reach and, importantly, maintain remission of disease activity. Tocilizumab (TCZ), an IL-6 receptor antagonist, might, alone or in combination with methotrexate (MTX), be specifically suited to this aim.
Objectives To compare the sustained remission (SR) rate in early RA patients (diagnosis <1 year and no previous disease-modifying therapy), applying a treat-to-target strategy with TCZ+MTX, TCZ monotherapy, or MTX monotherapy.
Methods A multicenter, randomized, double-blind, double-dummy, placebo-controlled, 3-parallel-arm, 2-year study was performed. TCZ was dosed at 8 mg/kg IV every 4 weeks. MTX was started at 10 mg/week and was increased every 4 weeks by 5 mg/week (maximum 30 mg/week) until remission or dose-limiting toxicity. Patients were evaluated every 4 weeks. SR was defined as disease activity score (DAS28) <2.6 and swollen joint count ≤4, sustained for ≥23 weeks, with the exception of ≤2 visits at which DAS28 was allowed to be ≥2.6 but <3.2. If remission was not reached with the randomized regimen or the addition of hydroxychloroquine (initial regimen), treatment was intensified (Figure A). If remission was sustained for 24 weeks, doses of MTX and TCZ were reduced stepwise until flare (DAS28 >2.6) or drug-free remission. The primary end point was SR rate, with patients not reaching SR with the initial treatment classified as nonresponders. Time to first SR was assessed by the Kaplan-Meier method, with censoring at the time of withdrawal for patients not reaching SR with the initial treatment. A predetermined hierarchy for testing (Cochran-Mantel-Haenszel test) was applied to account for multiple testing for the primary end point (primary comparison TCZ+MTX vs MTX).
Results All 317 randomized patients (TCZ+MTX, 106; TCZ, 103; MTX, 108) were included in intent-to-treat and safety analyses. Approximately 75% of patients completed the 2-year study; completion rates were similar across arms. Average ± SD age of patients was 53±13 years; 67% were female, and 73% were rheumatoid factor positive. Initial mean DAS28 was 5.2±1.1, and median (interquartile range) disease duration was 3.5 (2-6) weeks. Clinical characteristics were generally well balanced among arms. SR rates were 86% for TCZ+MTX, 84% for TCZ, and 44% for MTX (p<0.001 for TCZ+MTX vs MTX and TCZ vs MTX; p=0.62 for TCZ+MTX vs TCZ), with a median duration of remission of 61 (43-93), 65 (44-88), and 49 (28-74) weeks, respectively (p=0.008) over the 2-year study duration. Median time to SR in weeks was 9.9 (7.1-23.3), 12.7 (4.7-29.1), and not estimable (<50% reached SR; 1st quartile: 24.1), respectively (overall p<0.001; Figure B). Safety outcomes were compatible with previous experiences with the study drugs, with no clear differences among arms in terms of serious adverse events and serious infections. No deaths occurred.
Conclusions In patients with very early RA, both TCZ+MTX and TCZ monotherapy increased SR rate up to 2-fold compared with MTX monotherapy and increased duration of remission, offering an opportunity to decrease or even stop medication very early in the disease.
Disclosure of Interest J. Bijlsma Grant/research support from: Roche, Pfizer, MSD, AbbVie, BMS, Consultant for: Roche, Pfizer, MSD, UCB, AbbVie, BMS, Multipharma, Janssen, SUN Pharma, P. Welsing: None declared, T. Woodworth Employee of: Roche (clinical science leader involved at the time of study design and data collection methodology), L. Middelink Consultant for: Roche Nederland BV, Employee of: Roche Nederland BV (until September 2013), C. Bernasconi Consultant for: Roche, M. Borm Employee of: Roche, F. Lafeber Grant/research support from: Roche, J. Jacobs: None declared