Elsevier

The Lancet

Volume 387, Issue 10031, 7–13 May 2016, Pages 1921-1927
The Lancet

Articles
Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(16)00560-2Get rights and content

Summary

Background

Giant cell arteritis is an immune-mediated disease of medium and large-sized arteries that affects mostly people older than 50 years of age. Treatment with glucocorticoids is the gold-standard and prevents severe vascular complications but is associated with substantial morbidity and mortality. Tocilizumab, a humanised monoclonal antibody against the interleukin-6 receptor, has been associated with rapid induction and maintenance of remission in patients with giant cell arteritis. We therefore aimed to study the efficacy and safety of tocilizumab in the first randomised clinical trial in patients with newly diagnosed or recurrent giant cell arteritis.

Methods

In this single centre, phase 2, randomised, double-blind, placebo-controlled trial, we recruited patients aged 50 years and older from University Hospital Bern, Switzerland, who met the 1990 American College of Rheumatology criteria for giant cell arteritis. Patients with new-onset or relapsing disease were randomly assigned (2:1) to receive either tocilizumab (8 mg/kg) or placebo intravenously. 13 infusions were given in 4 week intervals until week 52. Both groups received oral prednisolone, starting at 1 mg/kg per day and tapered down to 0 mg according to a standard reduction scheme defined in the study protocol. Allocation to treatment groups was done using a central computerised randomisation procedure with a permuted block design and a block size of three, and concealed using central randomisation generated by the clinical trials unit. Patients, investigators, and study personnel were masked to treatment assignment. The primary outcome was the proportion of patients who achieved complete remission of disease at a prednisolone dose of 0·1 mg/kg per day at week 12. All analyses were intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01450137.

Results

Between March 3, 2012, and Sept 9, 2014, 20 patients were randomly assigned to receive tocilizumab and prednisolone, and ten patients to receive placebo and glucocorticoid; 16 (80%) and seven (70%) patients, respectively, had new-onset giant cell arteritis. 17 (85%) of 20 patients given tocilizumab and four (40%) of ten patients given placebo reached complete remission by week 12 (risk difference 45%, 95% CI 11–79; p=0·0301). Relapse-free survival was achieved in 17 (85%) patients in the tocilizumab group and two (20%) in the placebo group by week 52 (risk difference 65%, 95% CI 36–94; p=0·0010). The mean survival-time difference to stop glucocorticoids was 12 weeks in favour of tocilizumab (95% CI 7–17; p<0·0001), leading to a cumulative prednisolone dose of 43 mg/kg in the tocilizumab group versus 110 mg/kg in the placebo group (p=0·0005) after 52 weeks. Seven (35%) patients in the tocilizumab group and five (50%) in the placebo group had serious adverse events.

Interpretation

Our findings show, for the first time in a trial setting, the efficacy of tocilizumab in the induction and maintenance of remission in patients with giant cell arteritis.

Funding

Roche and the University of Bern.

Introduction

Giant cell arteritis is characterised by a destructive, granulomatous inflammation of the walls of medium and large-sized arteries. Annual incidence varies between six and 32 cases per 100 000 people worldwide.1, 2, 3, 4 Glucocorticoids are the gold-standard for controlling symptoms and reducing the risk of vascular complications, such as blindness. However, necessary doses and long duration of treatment invariably lead to high morbidity and substantial mortality.5 Neither conventional immunosuppressive drugs nor biological agents effectively induce remission,6, 7and the extent of their steroid-sparing effect during maintenance, for instance with methotrexate, remains a matter of debate.8, 9

Interleukin-6 induces acute phase responses and has a central role in the pathogenesis of giant cell arteritis.10, 11 Serum and tissue samples of patients with this disorder show increased concentrations of interleukin-6.12, 13 Tocilizumab, used to treat rheumatoid arthritis and juvenile rheumatoid arthritis,14, 15 is a humanised immunoglobulin G1 kappa monoclonal antibody that blocks signalling by binding to the alpha chain of the human interleukin-6 receptor.16

Results of several case studies have shown rapid induction and maintenance of remission of giant cell arteritis using tocilizumab.17, 18, 19, 20 We therefore decided to do the first randomised, placebo-controlled trial to study the efficacy and safety of induction and maintenance of disease remission in patients with newly diagnosed or recurrent giant cell arteritis.

Research in context

Evidence before this study

We searched PubMed for studies published in any language between Jan 1, 1980, and Feb 18, 2016, with the terms “giant cell arteritis” and “IL-6”. We included clinical trials, clinical observations, and preclinical studies, both in vitro and in vivo in animals and human beings. We also searched conference abstracts from the American College of Rheumatology and The European League Against Rheumatism from the past 5 years. Besides laboratory studies, we found 15 case series and one open-label study. ClinicalTrials.gov lists an ongoing double-blind, placebo-controlled trial of subcutaneous tocilizumab treatment for giant cell arteritis with proportion of patients in sustained remission at week 52 as the primary outcome (NCT01791153).

Added value of this study

This study is the first randomised, placebo-controlled trial to show the efficacy of tocilizumab in the induction and maintenance of remission in patients with giant cell arteritis.

Implications of all the available evidence

These findings are consistent with the hypothesis that interleukin-6 plays an important part in the pathogenesis of giant cell arteritis, and that inhibition of interleukin-6 might induce and maintain remission of the disease. A phase 3 study of tocilizumab in giant cell arteritis is needed to confirm these findings.

Section snippets

Study design and patients

In this phase 2, randomised, double-blind, placebo-controlled study, we recruited patients from the University Hospital Bern, Switzerland. The protocol was approved by the local ethics committee and the study was done in accordance with the Declaration of Helsinki. Tocilizumab was provided by Roche.

Patients older than 50 years of age with new-onset or relapsing giant cell arteritis who fulfilled the 1990 American College of Rheumatology criteria21 were eligible for study participation. Giant

Results

Between March 3, 2012, and Sept, 9 2014, 20 patients were randomly assigned to receive either tocilizumab and prednisolone and ten to receive placebo and prednisolone (figure 1); 16 (80%) and seven (70%) patients, respectively, had new-onset giant cell arteritis (table 1). In two patients, diagnosis was confirmed by biopsy without additional MR angiography. All patients with negative temporal artery biopsy had a positive MR angiography.

Two patients in the tocilizumab group and three patients in

Discussion

This is the first randomised controlled trial of tocilizumab in patients with giant cell arteritis, and our findings show the drug's effectiveness in inducing remission and preventing relapse. Glucocorticoids could be rapidly tapered and discontinued by 36 weeks after the initiation of tocilizumab treatment. As a consequence, the cumulative prednisolone doses were reduced. Our data corroborate the findings of several recent publications regarding the clinically important therapeutic value of

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