TNF Inhibitors vs Standard Therapy in Rheumatoid Arthritis
TNF Inhibitors vs Standard Therapy in Rheumatoid Arthritis
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.
Design. Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months.
Setting. 24 rheumatology clinics in England.
Participants. 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.
Interventions. Biologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for nonresponders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders.
Main Outcome Measure. Primary outcome: 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. Secondary outcomes: 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.
Tumour necrosis factor inhibitors, the first biologics for rheumatoid arthritis, have changed specialist management. Placebo controlled trials in patients with active rheumatoid arthritis defined their efficacy. Long term observational studies confirmed their relative safety. Economic modelling used placebo controlled trials to justify their use in patients with active rheumatoid arthritis who were resistant to methotrexate. European and North American expert groups provided international guidance on their use in rheumatoid arthritis. English guidance from the National Institute for Health and Care Excellence (NICE) recommends starting them in patients with persistent active rheumatoid arthritis that is resistant to methotrexate and one other synthetic disease modifying drug and continuing them as long as the patients maintain good responses.
Tumour necrosis factor inhibitors are expensive. By 2012 international spending exceeded £15bn (€20.5bn, $23bn) a year. Guidance for their use is driven by results of placebo controlled trials in rheumatoid arthritis sponsored by manufacturers. Few trials have compared them with active non-biological treatments, even though lower cost strategies, such as combinations of synthetic disease modifying drugs, are effective. England spends over £600 m (€820 m, $926 m) a year on tumour necrosis factor inhibitors, which has a substantial impact on the National Health Service's budget. Healthcare commissioners would prefer lower cost alternatives provided patients were not disadvantaged.
We evaluated this possibility by testing the hypothesis that a lower cost strategy of combinations of synthetic disease modifying drugs achieves outcomes that are not inferior and costs substantially less.
Abstract and Introduction
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.
Design. Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months.
Setting. 24 rheumatology clinics in England.
Participants. 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.
Interventions. Biologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for nonresponders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders.
Main Outcome Measure. Primary outcome: 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. Secondary outcomes: 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.
Introduction
Tumour necrosis factor inhibitors, the first biologics for rheumatoid arthritis, have changed specialist management. Placebo controlled trials in patients with active rheumatoid arthritis defined their efficacy. Long term observational studies confirmed their relative safety. Economic modelling used placebo controlled trials to justify their use in patients with active rheumatoid arthritis who were resistant to methotrexate. European and North American expert groups provided international guidance on their use in rheumatoid arthritis. English guidance from the National Institute for Health and Care Excellence (NICE) recommends starting them in patients with persistent active rheumatoid arthritis that is resistant to methotrexate and one other synthetic disease modifying drug and continuing them as long as the patients maintain good responses.
Tumour necrosis factor inhibitors are expensive. By 2012 international spending exceeded £15bn (€20.5bn, $23bn) a year. Guidance for their use is driven by results of placebo controlled trials in rheumatoid arthritis sponsored by manufacturers. Few trials have compared them with active non-biological treatments, even though lower cost strategies, such as combinations of synthetic disease modifying drugs, are effective. England spends over £600 m (€820 m, $926 m) a year on tumour necrosis factor inhibitors, which has a substantial impact on the National Health Service's budget. Healthcare commissioners would prefer lower cost alternatives provided patients were not disadvantaged.
We evaluated this possibility by testing the hypothesis that a lower cost strategy of combinations of synthetic disease modifying drugs achieves outcomes that are not inferior and costs substantially less.