title: Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study.
abstract: OBJECTIVE
  To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission.
  
  
  METHODS
  ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued.
  
  
  RESULTS
  Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%).
  
  
  CONCLUSIONS
  Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement.
  
  
  BACKGROUND
  NCT00810199.
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: T W J
authors.initials: TW
authors.lastname: Huizinga
authors.affiliation: NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Conaghan
authors.affiliation: Department of Rheumatology, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Martin-Mola
authors.affiliation: Department of Rheumatology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Medicine 'B', Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Howard
authors.initials: H
authors.lastname: Amital
authors.affiliation: Division of Rheumatology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Xavier
authors.affiliation: Division of Rheumatology, University of Southern California Keck School of Medicine, Santa Monica, California, USA.
authors.forename: Orrin
authors.initials: O
authors.lastname: Troum
authors.affiliation: F.Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Maher
authors.initials: M
authors.lastname: Aassi
authors.affiliation: F.Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Corrado
authors.initials: C
authors.lastname: Bernasconi
authors.affiliation: Rheumatology B Department, Paris-Descartes University, Cochin Hospital, Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Dougados
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D001799:Blood Sedimentation; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D033023:Foot Joints / Q000000981:diagnostic imaging*; D050823:Hand Joints / Q000000981:diagnostic imaging*; D006801:Humans; D060828:Induction Chemotherapy; D008137:Longitudinal Studies; D060046:Maintenance Chemotherapy; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D011859:Radiography; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C502936:tocilizumab; D008727:Methotrexate
keywords: DMARDs (biologic); Methotrexate; Rheumatoid Arthritis