title: Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial.
abstract: BACKGROUND
  Biological agents offer good control of rheumatoid arthritis, but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate alone are unclear. The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining (or not) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy.
  
  
  METHODS
  This trial was done at 161 sites worldwide. Patients with early (<1 year duration) rheumatoid arthritis naive to methotrexate were randomly allocated (by interactive voice response system, in a 1:1 ratio, block size four) to adalimumab (40 mg every other week) plus methotrexate (initiated at 7·5 mg/week, increased by 2·5 mg every 1-2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks (period 1). Patients in the adalimumab plus methotrexate group who completed period 1 and achieved the stable low disease activity target (28-joint disease activity score with C-reactive protein [DAS28]<3·2 at weeks 22 and 26) were randomised to adalimumab-continuation or adalimumab-withdrawal for an additional 52 weeks (period 2). Patients achieving the target with initial methotrexate continued methotrexate-monotherapy. Inadequate responders were offered adalimumab plus methotrexate. All patients and investigators were masked to treatment allocation in period 1. During period 2, treatment reallocation of patients who achieved the target was masked to patients and investigators; patients who did not achieve the target remained masked to original randomisation, but were aware of the subsequent assignment. The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78, compared between adalimumab-continuation and methotrexate-monotherapy. Adverse events were monitored throughout period 2. This trial is registered with ClinicalTrials.gov, number NCT00420927.
  
  
  RESULTS
  The study was done between Dec 28, 2006, and Aug 3, 2010. 1636 patients were assessed and 1032 were randomised in period 1 (515 to adalimumab plus methotrexate; 517 to placebo plus methotrexate). 466 patients in the adalimumab plus methotrexate group completed period 1; 207 achieved the stable low disease activity target, of whom 105 were rerandomised to adalimumab-continuation. 460 patients in the placebo plus methotrexate group completed period 1; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy. 73 of 105 (70%) patients in the adalimumab-continuation group and 61 of 112 (54%) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 (mean difference 15% [95% CI 2-28%], p=0·0225). Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses. Overall, 706 of 926 patients in period 2 had an adverse event, of which 82 were deemed serious; however, distribution of adverse events did not differ between groups.
  
  
  CONCLUSIONS
  Treatment to a stable low disease activity target resulted in improved clinical, functional, and structural outcomes, with both adalimumab-continuation and methotrexate-monotherapy. However, a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone. Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate.
  
  
  BACKGROUND
  AbbVie.
authors.affiliation: Division of Rheumatology, Department of Medicine Three, Medical University of Vienna, Vienna, Austria; Second Department of Medicine, Hietzing Hospital, Vienna, Austria. Electronic address: josef.smolen@meduniwien.ac.at.
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.affiliation: Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK; NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.affiliation: Division of Rheumatology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Fleischmann
authors.affiliation: Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ronald F
authors.initials: RF
authors.lastname: van Vollenhoven
authors.affiliation: Institute and Clinic of Rheumatology, First Medical Faculty, Charles University, Prague, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Pavelka
authors.affiliation: Service et Pôle de Rhumatologie, Cliniques Universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Durez
authors.affiliation: AbbVie, North Chicago, IL, USA.
authors.forename: Benoît
authors.initials: B
authors.lastname: Guérette
authors.affiliation: AbbVie Deutschland GmbH and Company KG, Ludwigshafen, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kupper
authors.affiliation: AbbVie, North Chicago, IL, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Redden
authors.affiliation: AbbVie, North Chicago, IL, USA.
authors.forename: Vipin
authors.initials: V
authors.lastname: Arora
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Kavanaugh
mesh_terms: D000068879:Adalimumab; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000188:drug therapy*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D011859:Radiography; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D005938:Glucocorticoids; D000068879:Adalimumab; D008727:Methotrexate