title: Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial.
abstract: 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Roche and the University of Bern.
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital, University of Bern, Bern, Switzerland. Electronic address: peter.villiger@insel.ch.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Villiger
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Adler
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kuchen
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Wermelinger
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Dan
authors.affiliation: Clinical Trials Unit, University of Bern, Bern, Switzerland.
authors.forename: Veronika
authors.initials: V
authors.lastname: Fiege
authors.affiliation: Clinical Trials Unit, University of Bern, Bern, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Bütikofer
authors.affiliation: Department of Rheumatology, Immunology and Allergology, University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Seitz
authors.affiliation: Institute for Primary Care, University of Bern, Bern, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Reichenbach
mesh_terms: D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D013700:Giant Cell Arteritis / Q000188:drug therapy*; D006801:Humans; D060828:Induction Chemotherapy; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D011239:Prednisolone / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D011239:Prednisolone; C502936:tocilizumab