NPC Archive Item: Does adding in tocilizumab to DMARDs help in rheumatoid arthritis (TOWARD study)?

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Tocilizumab plus DMARDs was more effective than DMARDs alone at increasing ACR20 response rates in patients with moderate to severe rheumatoid arthritis who had experienced an inadequate response to treatment with stable doses of DMARDs.

Tocilizumab received a positive opinion from the European licensing agency (EMEA) in November 2008 and may receive market authorisation in a few months. NICE guidance on a number of established treatments for rheumatoid arthritis (RA) is already available and is anticipated for tocilizumab in October 2009. During the interim, local decision making bodies, in conjunction with stakeholders, will need to decide where tocilizumab fits in the management of RA based on published evidence, such as the TOWARD study.

What is the background to this?
As reported in “On the Horizon, Future Medicines” (NHSnet connection required), tocilizumab is a humanised anti-interleukin 6 monoclonal antibody, in development for the management of active RA. The approved licence indication will be for use in combination with methotrexate (MTX)  for adults suffering from moderate to severe RA and who have either responded inadequately to, or who were intolerant of, previous therapy with DMARDS or tumour necrosis factor (TNF) antagonists. Where use of MTX is inappropriate, tocilizumab can be given as monotherapy.

A NICE clinical guideline on RA is due to be published in February 2009. Further information on the management of RA is available from the pain management/RA floor of NPC.

What does this study claim?
The primary outcome was a 20% improvement in disease criteria as measured by the ACR20 at week 24.  This was seen in 61.0% of the tocilizumab group (n=803) versus 25.0% of the control group (n=413) (P<0.0001). No confidence intervals were quoted in the paper. Remission, a secondary endpoint measured by DAS28 scores of <2.6, was achieved in significantly more patients in the tocilizumab group than in the control group (30.0% vs.3.0%, P<0.0001).

How does this relate to other studies?
The OPTION and RADIATE trials of tocilizumab have already been published. OPTION included patients who were already receiving methotrexate. The ACR20 response rate at 24 weeks was 59.0% in the tocilizumab 8mg/kg group (n=205), 48.0% in the 4mg/kg group  (n=214) and 26.0% in the placebo patients (n=204), odds ratio (OR) 4·0 (95% confidence interval [CI] 2·6 to 6·1), P<0·0001 for 8mg/kg vs. placebo, and OR 2·6 (95% CI 1·7 to 3·9), P<0·0001 for 4mg/kg vs. placebo).

Patients enrolled in the RADIATE study all received MTX and had either responded inadequately to, or had been intolerant of, an anti-TNF agent. We have blogged this previously. The primary outcome was the ACR20 at week 24. This was seen in 50.0% of tocilizumab 8mg/kg group (n=170), 30.4% of the 4mg/kg group (n=159) and 10.1% of the placebo patients (n=158) (P<0.0001 for both tocilizumab doses vs. placebo).

So what?
ACR20 is considered to be the minimum response to distinguish active treatment from placebo in clinical trials [1]. ACR50, 70 and 90 indicate greater improvement. However, the aim in treating RA is achievement of the lowest disease activity possible and, ideally, remission should be achieved in a considerable proportion of patients in trials and in practice.

As in other published studies, increases in lipid levels were seen in patients given tocilizumab. Longer term studies are required to establish if this may lead to adverse cardiovascular (CV) outcomes. Patients should be assessed to determine if lipid lowering drugs and other measures to reduce CV risk are necessary.

Study details
Genovese MC, McKay JD, Nasonov EL et al.  Interleukin-6 Receptor Inhibition With Tocilizumab Reduces Disease Activity in Rheumatoid Arthritis with Inadequate Response to Disease-Modifying Antirheumatic Drugs. Arthritis and Rheumatism 2008; 58:2968-80

Design: phase III, randomised, double-blind, placebo controlled, multicentre trial.

Patients: adults with moderate to severe active RA of greater than 6 months duration, who had received stable doses of permitted DMARDs. All patients were treated with folate.

Intervention: tocilizumab 8mg/kg intravenously over 1 hour every 4 weeks plus DMARDs for 24 weeks (n =805).

Comparison: placebo infusion every 4 weeks plus DMARDs for 24 weeks (n= 415).

Outcomes and Results: efficacy was assessed in all patients who had received at least one dose of study drug i.e. the intention to treat (ITT) population. Patients who did not achieve 20% improvement from baseline at week 16 were offered rescue therapy and considered nonresponders in the primary efficacy analysis at 24 weeks.  The primary end point was ACR20 response. This is an American College of Rheumatology criterion for assessing response to treatment, based on improvements in key measures of disease activity (e.g. tender joint count) [2].

Secondary outcomes were ACR50, ACR70, DAS28 and EULAR responses. ACR50 and ACR70 are more stringent response rates than ACR20; a DAS28 score of less than 2.6 equates to remission and EULAR criteria were developed from the DAS measure by the European League Against Rheumatism [2].

Adverse Events: Overall 73.0% of patients in the tocilizumab group (n=802) compared to 61.0% in the control group (n=414) had ≥ 1 adverse event, of which serious adverse events occurred in 6.7% and 4.3% of patients respectively. Serious infections occurred in 2.7% and 1.9% of the tocilizumab and control groups respectively. More patients in the tocilizumab group had an increase in alanine aminotransferase levels than in the placebo group, but the majority of such increases were<3 times the upper limit of normal. Elevated total cholesterol levels also occurred more frequently (23.0% versus 5.5% respectively). Transient neutropenia, gastro-intestinal and skin adverse events were more common in patients who received tocilizumab.

Sponsorship: F.Hoffmann-La Roche Ltd.


1. Smolen JS, Aletaha D, Koeller M, et al. New therapies for treatment of rheumatoid arthritis. Lancet 2007; 370:1861-74

2. NICE. Rituximab for the treatment of rheumatoid arthritis. TA126. August 2007. Available from URL: Accessed on 24.11.08

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