Background

Rheumatoid arthritis (RA) is a chronic illness characterised by inflammation of the synovial tissue in joints, which can lead to joint destruction. Treatment aims to control pain and inflammation, reduce joint damage and disability, and maintain or improve physical function and quality of life.

Description of technology

Drugs that inhibit joint destruction are known as disease-modifying antirheumatic drugs (DMARDs). There are around eight DMARDs, which are not biologics, in common use in the UK. These drugs are not always effective, may lose effectiveness with time or may cause adverse effects. Alternative DMARDs are therefore needed and tumour necrosis factor (TNF) inhibitors are one class of new agents that has been developed.

Tumour necrosis factor-α (TNF--α) is a cytokine that plays an important role in joint inflammation. TNF inhibitors have been designed to inhibit its actions. Three are currently licensed for use in the UK:

• adalimumab: given by subcutaneous injections (40 mg) every other week, but the dose may be increased to weekly if the disease is poorly controlled
• etanercept: given by a once-weekly subcutaneous injection (50 mg) or twice weekly (25 mg each)
• infliximab: given by intravenous infusion (3 mg kg^-1) at 0, 2 and 6 weeks and at 8-weekly intervals thereafter. It is only licensed for use concomitantly with methotrexate.

Objective to the report

This report reviews the clinical and cost-effectiveness of adalimumab, etanercept and infliximab when used in the treatment of RA in adults.

Methods

Systematic reviews of the literature on effectiveness and cost-effectiveness were undertaken. A wide range of databases was searched and information sought from researchers and industry. Industry submissions to NICE were reviewed. Meta-analyses of effectiveness data were undertaken for each agent.

The Birmingham Rheumatoid Arthritis Model (BRAM), a simulation model, was further developed and used to produce an incremental cost-effectiveness analysis.

Results

Conclusions

Adalimumab, etanercept and infliximab are effective treatments compared with placebo for RA patients who are not well controlled by conventional DMARDs, improving control of symptoms, improving physical function and slowing radiographic changes in joints. When used alone, adalimumab is marginally less effective and etanercept is marginally more effective than methotrexate, in methotrexate-naïve patients. The combination of a TNF inhibitor with methotrexate was more effective than methotrexate alone in early RA, although the clinical relevance of this additional benefit is yet to be established, particularly in view of the well-established effectiveness of MTX alone. In addition, an increased risk of serious infection cannot be ruled out for the combination of methotrexate with adalimumab or infliximab.

Results of published economic evaluations vary: some analyses suggest that the use of TNF inhibitors may fall within the usual acceptable cost-effectiveness ranges, whereas others report very high ICERs. Although most are of high quality, none of them uses all the appropriate parameters, effectiveness data, perspective and comparators required to make their results generalisable to the NHS context. The societal perspective generates more favourable ICERs. All economic evaluations submitted by the manufacturers report ICERs that fall within the currently accepted thresholds of cost-effectiveness. However, in the authors' opinion, these models make assumptions and use data that favour the TNF inhibitor being evaluated, the appropriateness of which can be questioned.

The results of the economic evaluation based on BRAM are consistent with the observations from the review of clinical effectiveness, including the ranking of treatments. TNF inhibitors are most cost-effective when used as last active therapy, with the ICER for etanercept (£24,000 per QALY) being significantly lower than the ICER for adalimumab (£30,000 per QALY) or infliximab (£38,000 per QALY). Other things being equal, etanercept would be, therefore, the TNF inhibitor of choice based on this evidence. However, the most appropriate choice of TNF inhibitor may also depend on patient preference as to route of administration.

The next most cost-effective use of TNF inhibitors is third line, as recommended in the 2002 NICE guidance, which gives ICERs around £30,000 per QALY using early RA effectiveness data. Using data for late RA, however, gives an ICER of around £50,000 per QALY for etanercept, with higher figures for adalimumab and infliximab. First-line use gives ICERs around £50,000 per QALY for adalimumab and etanercept as monotherapies with much higher figures for combinations with methotrexate.

Sequential use of TNF inhibitors was modelled, with the TNF inhibitors starting as third line therapy and using the 'late RA' values for the TNF inhibitors. The results are similar to those using the given TNF inhibitor as the sole TNF inhibitor in third place, except that the two other TNF inhibitors are somewhat less cost-effective if used after etanercept.

Recommendations for further research

Direct comparative RCTs of TNF inhibitors against each other and against other DMARDs, and sequential use in patients who have failed a previous TNF inhibitor, are needed. Longer term studies of the quality of life in patients with RA and the impact of DMARDs on this are needed, as are longer studies that directly assess effects on joint replacement, other morbidity and mortality.

Publication

• Chen Y-F, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, et al. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. Health Technol Assess 2006;10(42). [PubMed: 17049139]

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The research reported in this monograph was commissioned and funded by the HTA Programme on behalf of NICE as project number 04/26/01. The protocol was agreed in January 2005. The assessment report began editorial review in March 2006 and was accepted for publication in May 2006. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors' report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

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