title: Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial.
abstract: OBJECTIVE
  To determine whether intensive combinations of synthetic disease modifying drugs can achieve similar clinical benefits at lower costs to high cost biologics such as tumour necrosis factor inhibitors in patients with active rheumatoid arthritis resistant to initial methotrexate and other synthetic disease modifying drugs.
  
  
  METHODS
  Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months.
  
  
  METHODS
  24 rheumatology clinics in England.
  
  
  METHODS
  Patients with rheumatoid arthritis who were eligible for treatment with tumour necrosis factor inhibitors according to current English guidance were randomised to either the tumour necrosis factor inhibitor strategy or the combined disease modifying drug strategy.
  
  
  METHODS
  Biologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for non-responders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders.
  
  
  METHODS
  
  
  
  METHODS
  reduction in disability at 12 months measured with patient recorded heath assessment questionnaire (range 0.00-3.00) with a 0.22 non-inferiority margin for combination treatment versus the biologic strategy.
  
  
  RESULTS
  quality of life, joint damage, disease activity, adverse events, and costs. Intention to treat analysis used multiple imputation methods for missing data.
  
  
  RESULTS
  432 patients were screened: 107 were randomised to tumour necrosis factor inhibitors and 101 started taking; 107 were randomised to the combined drug strategy and 104 started taking the drugs. Initial assessments were similar; 16 patients were lost to follow-up (seven with the tumour necrosis factor inhibitor strategy, nine with the combined drug strategy); 42 discontinued the intervention but were followed-up (19 and 23, respectively). The primary outcome showed mean falls in scores on the health assessment questionnaire of -0.30 with the tumour necrosis factor inhibitor strategy and -0.45 with the alternative combined drug strategy. The difference between groups in unadjusted linear regression analysis favoured the alternative strategy of combined drugs. The mean difference was -0.14, and the 95% confidence interval (-0.29 to 0.01) was below the prespecified non-inferiority boundary of 0.22. Improvements at 12 months in secondary outcomes, including quality of life and erosive progression, were similar with both strategies. Initial reductions in disease activity were greater with the biologic strategy, but these differences did not persist beyond six months. Remission was seen in 72 patients (44 with biologic strategy; 36 with alternative strategy); 28 patients had serious adverse events (18 and 10, respectively); six and 10 patients, respectively, stopped treatment because of toxicity. The alternative strategy reduced health and social care costs per patient by £3615 (€4930, $5585) for months 0-6 and £1930 for months 6-12.
  
  
  CONCLUSIONS
  In patients with active rheumatoid arthritis who meet English criteria for biologics an alternative strategy with combinations of intensive synthetic disease modifying drugs gives non-inferior outcomes to treatment with tumour necrosis factor inhibitors. Costs are reduced substantially.Trial Registration ISRCTN 37438295.
authors.affiliation: Department of Rheumatology, King's College London School of Medicine, London SE5 9RJ, UK d.scott1@nhs.net.
authors.forename: David L
authors.initials: DL
authors.lastname: Scott
authors.affiliation: Department of Rheumatology, King's College London School of Medicine, London SE5 9RJ, UK.
authors.forename: Fowzia
authors.initials: F
authors.lastname: Ibrahim
authors.affiliation: MRC Biostatistics Unit, Institute of Public Health, University Forvie Site, Cambridge CB2 0SR, UK.
authors.forename: Vern
authors.initials: V
authors.lastname: Farewell
authors.affiliation: Department of Statistical Science, University College London, London WC1E 7HB, UK.
authors.forename: Aidan G
authors.initials: AG
authors.lastname: O'Keeffe
authors.affiliation: Musculoskeletal Unit, Freeman Hospital, High Heaton, Newcastle upon Tyne NE7 7DN, UK.
authors.forename: David
authors.initials: D
authors.lastname: Walker
authors.affiliation: Department Of Rheumatology, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Kelly
authors.affiliation: Department Of Rheumatology, Northumbria Healthcare, Northumberland NE63 9JJ, UK.
authors.forename: Fraser
authors.initials: F
authors.lastname: Birrell
authors.affiliation: Department Of Rheumatology, Queen's Hospital, Romford RM7 0AG, UK.
authors.forename: Kuntal
authors.initials: K
authors.lastname: Chakravarty
authors.affiliation: School of Medical Sciences, Bangor University, Bangor LL57 2DG, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Maddison
authors.affiliation: Centre for the Economics of Mental and Physical Health, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Heslin
authors.affiliation: Centre for the Economics of Mental and Physical Health, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
authors.forename: Anita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Rheumatology, King's College London School of Medicine, London SE5 9RJ, UK.
authors.forename: Gabrielle H
authors.initials: GH
authors.lastname: Kingsley
mesh_terms: D000068879:Adalimumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D000069285:Infliximab; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept; D008727:Methotrexate