Elsevier

The Lancet

Volume 388, Issue 10042, 23–29 July 2016, Pages 343-355
The Lancet

Articles
Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial

https://doi.org/10.1016/S0140-6736(16)30363-4Get rights and content

Summary

Background

For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines.

Methods

We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov, number NCT01034137.

Findings

Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72–78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59–2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48–2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00–1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01–1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study.

Interpretation

For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards.

Funding

Roche Nederland BV.

Introduction

Rheumatoid arthritis is a potentially debilitating autoimmune inflammatory joint disease, which requires rapid disease control as soon as possible after diagnosis to prevent disability and improve long-term outcomes.1, 2, 3 Therapeutic strategies aim to achieve early remission through frequent monitoring and medication adjustments tailored to the individual patient. These treat-to-target strategies are described in recommendations from the European League against Rheumatism (EULAR) and the American College of Rheumatology (ACR) guideline.1, 4 According to these recommendations, therapy in early rheumatoid arthritis is initiated with one conventional synthetic disease-modifying antirheumatic drug (DMARD), preferably methotrexate, or a combination of conventional synthetic DMARDs. If the treatment target is not achieved within 6 months, one option is to add a biological DMARD. However, in clinical practice, approximately a third of patients with rheumatoid arthritis receiving a biological DMARD are on monotherapy, mainly because of methotrexate intolerance or non-compliance.5 In several trials, monotherapy with a tumour necrosis factor (TNF) inhibitor (a biological DMARD commonly used for rheumatoid arthritis) was inferior in efficacy compared with a TNF inhibitor combined with methotrexate.5, 6, 7 By contrast, monotherapy with tocilizumab, an interleukin-6 receptor-blocking monoclonal antibody inhibiting interleukin-6-mediated pro-inflammatory signalling, seems to be similarly effective whether used in combination with methotrexate or as monotherapy.5, 8, 9 These findings could be a rationale to use tocilizumab as a DMARD for a treat-to-target strategy in daily practice, in view of the potential safety, tolerance, and compliance issues with methotrexate. Tocilizumab has been shown to be effective in rheumatoid arthritis,9, 10, 11 but it has not yet been used in a treat-to-target strategy study in early rheumatoid arthritis.

Research in context

Evidence before this study

The European League Against Rheumatism (EULAR) recommends early treatment in rheumatoid arthritis to achieve clinical remission (evidence level 1a). An individualised treat-to-target approach is recommended by the EULAR guideline, including biological disease-modifying antirheumatic drugs (DMARDs), if conventional synthetic DMARDs, with methotrexate as a first choice, do not achieve the treatment target (evidence level 1b). We did a PubMed search of publications dated up to March 21, 2016, for articles on the treatment of early rheumatoid arthritis with strategies including randomisation for double-blind addition of a registered biological DMARD or placebo from start of the trial to methotrexate as the only conventional synthetic DMARD. Using the search terms “rheumatoid arthritis”, “biologic” and “clinical trial”, we identified 17 original trials. In these studies, the arm with methotrexate and a biological showed greater efficacy compared with the methotrexate-monotherapy arms, except for two trials in which in the methotrexate comparator arm, methotrexate was combined with glucocorticoids. Although in several trials the biological was discontinued, generally the conventional synthetic DMARDs were continued. Only two trials reported on drug-free remission and only one trial had an individualised treat-to-target design.

Added value of this study

Our study applied a double-blind, double-dummy design with an individualised treat-to-target approach, similar to that used in clinical practice, in DMARD-naive patients with rheumatoid arthritis. The results from our study are therefore directly applicable to clinical practice. It compared the efficacy of adding a biological DMARD only when conventional synthetic DMARDs fail to induce remission, in line with international recommendations, versus initiating from the start of therapy a biological DMARD—ie, tocilizumab. The findings from our study showed that a greater proportion of patients achieved sustained remission on strategies using tocilizumab from treatment start (with or without methotrexate), than on the reference methotrexate-based strategy. The high proportions of patients in sustained remission and sustained drug-free remission after controlled withdrawal of both methotrexate and the biological are distinctive findings compared with previous studies. The results from our study indicate that drug-free remission is an achievable treatment goal. No additional safety issues were identified.

Implications of all the available evidence

Current management of early rheumatoid arthritis can be improved by initiating therapy with biological DMARDs from the start of therapy. Currently, an individualised tocilizumab-based strategy appears the most effective choice for a strategy aimed at drug-free remission. The challenge is to identify patients with early rheumatoid arthritis who will respond sufficiently to conventional synthetic DMARDs and do not need a biological DMARD. Drug-free remission will probably become a future treatment target.

The aim of our study, therefore, was to assess in patients with newly diagnosed rheumatoid arthritis who were DMARD-naive, the efficacy and safety of treat-to-target strategies initiating tocilizumab with or without methotrexate, compared with initiating methotrexate (in line with international recommendations and guidelines).1, 4

Section snippets

Study design and participants

We did a 2-year, multicentre, three-parallel-arm, randomised, double-blind, double-dummy, treat-to-target strategy study of patients with newly diagnosed rheumatoid arthritis in outpatient clinics of 21 participating rheumatology departments in the Netherlands. The medical ethics research committee of the University Medical Center Utrecht approved the study with subsequent sanctioning of all participating hospitals (protocol amendments are in the appendix). We verbally invited patients at the

Results

Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm; figure 2). The last patient completed the study on Sept 10, 2014. All patients received at least one dose of the assigned study medication and were included in the intention-to-treat and safety analyses. Baseline characteristics (table 1) show only slight imbalances between treatment

Discussion

Our study, which applied a treat-to-target design in DMARD-naive patients with early rheumatoid arthritis, showed that strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate monotherapy in line with current standards. This contemporary treatment strategy approach, including tapering of drug dose when sustained remission is achieved, is more

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