title: Randomised controlled trial of tumour necrosis factor inhibitors against combination intensive therapy with conventional disease-modifying antirheumatic drugs in established rheumatoid arthritis: the TACIT trial and associated systematic reviews.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is initially treated with methotrexate and other disease-modifying antirheumatic drugs (DMARDs). Active RA patients who fail such treatments can receive tumour necrosis factor inhibitors (TNFis), which are effective but expensive.
  
  
  OBJECTIVE
  We assessed whether or not combination DMARDs (cDMARDs) give equivalent clinical benefits at lower costs in RA patients eligible for TNFis.
  
  
  METHODS
  An open-label, 12-month, pragmatic, randomised, multicentre, two-arm trial [Tumour necrosis factor inhibitors Against Combination Intensive Therapy (TACIT)] compared these treatment strategies. We then systematically reviewed all comparable published trials.
  
  
  METHODS
  The TACIT trial involved 24 English rheumatology clinics.
  
  
  METHODS
  Active RA patients eligible for TNFis.
  
  
  METHODS
  The TACIT trial compared cDMARDs with TNFis plus methotrexate or another DMARD; 6-month non-responders received (a) TNFis if in the cDMARD group; and (b) a second TNFi if in the TNFi group.
  
  
  METHODS
  The Heath Assessment Questionnaire (HAQ) was the primary outcome measure. The European Quality of Life-5 Dimensions (EQ-5D), joint damage, Disease Activity Score for 28 Joints (DAS28), withdrawals and adverse effects were secondary outcome measures. Economic evaluation linked costs, HAQ changes and quality-adjusted life-years (QALYs).
  
  
  RESULTS
  In total, 432 patients were screened; 104 started on cDMARDs and 101 started on TNFis. The initial demographic and disease assessments were similar between the groups. In total, 16 patients were lost to follow-up (nine in the cDMARD group, seven in the TNFi group) and 42 discontinued their intervention but were followed up (23 in the cDMARD group and 19 in the TNFi group). Intention-to-treat analysis with multiple imputation methods used for missing data showed greater 12-month HAQ score reductions with initial cDMARDs than with initial TNFis [adjusted linear regression coefficient 0.15, 95% confidence interval (CI) -0.003 to 0.31; p = 0.046]. Increases in 12-month EQ-5D scores were greater with initial cDMARDs (adjusted linear regression coefficient -0.11, 95% CI -0.18 to -0.03; p = 0.009) whereas 6-month changes in HAQ and EQ-5D scores and 6- and 12-month changes in joint damage were similar between the initial cDMARD group and the initial TNFi group. Longitudinal analyses (adjusted general estimating equations) showed that the DAS28 was lower in the initial TNFi group in the first 6 months (coefficient -0.63, 95% CI -0.93 to -0.34; p < 0.001) but there were no differences between the groups in months 6-12. In total, 36 patients in the initial cDMARD group and 44 in the initial TNFi group achieved DAS28 remission. The onset of remission did not differ between groups (p = 0.085 on log-rank test). In total, 10 patients in the initial cDMARD group and 18 in the initial TNFi group experienced serious adverse events; stopping therapy because of toxicity occurred in 10 and six patients respectively. Economic evaluation showed that the cDMARD group had similar or better QALY outcomes than TNFi with significantly lower costs at 6 and 12 months. In the systematic reviews we identified 32 trials (including 20-1049 patients) on early RA and 19 trials (including 40-982 patients) on established RA that compared (1) cDMARDs with DMARD monotherapy; (2) TNFis/methotrexate with methotrexate monotherapy; and (3) cDMARDs with TNFis/methotrexate. They showed that cDMARDs and TNFis had similar efficacies and toxicities.
  
  
  CONCLUSIONS
  Active RA patients who have failed methotrexate and another DMARD achieve equivalent clinical benefits at a lower cost from starting cDMARDs or from starting TNFis (reserving TNFis for non-responders). Only a minority of patients achieve sustained remission with cDMARDs or TNFis; new strategies are needed to maximise the frequency of remission.
  
  
  BACKGROUND
  Current Control Trials ISRCTN37438295.
  
  
  BACKGROUND
  This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 66. See the NIHR Journals Library website for further project information.
authors.affiliation: Department of Rheumatology, King's College London School of Medicine, London, UK.
authors.forename: David L
authors.initials: DL
authors.lastname: Scott
authors.affiliation: Department of Rheumatology, King's College London School of Medicine, London, UK.
authors.forename: Fowzia
authors.initials: F
authors.lastname: Ibrahim
authors.affiliation: MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK.
authors.forename: Vern
authors.initials: V
authors.lastname: Farewell
authors.affiliation: MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK.
authors.forename: Aidan G
authors.initials: AG
authors.lastname: O'Keeffe
authors.affiliation: Department of Rheumatology, King's College London School of Medicine, London, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Ma
authors.affiliation: Musculoskeletal Unit, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: David
authors.initials: D
authors.lastname: Walker
authors.affiliation: Centre for the Economics of Mental and Physical Health, Institute of Psychiatry, King's College London, London, 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, UK.
authors.forename: Anita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Rheumatology, King's College London School of Medicine, London, UK.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Kingsley
mesh_terms: D000368:Aged; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000191:economics / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D017281:Cost of Illness; D003362:Cost-Benefit Analysis; D004359:Drug Therapy, Combination; D004739:England; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000191:economics / Q000627:therapeutic use; D008875:Middle Aged; D011788:Quality of Life; D019057:Quality-Adjusted Life Years; D012720:Severity of Illness Index; D012947:Social Work / Q000191:economics; D012959:Socioeconomic Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D008727:Methotrexate