Targeted therapies in rheumatoid arthritis: the need for action

P. Emery, G. Panayi1, R. Sturrock2 and B. Williams3

Rheumatology and Rehabilitation Research Unit, University of Leeds, 36 Clarendon Road, Leeds LS2 9NZ,
1 Department of Rheumatology, UMDS, Guy's Hospital, London SE1 9RT,
2 Centre for Rheumatic Diseases, University Department of Medicine, Glasgow Royal Infirmary and
3 Department of Rheumatology, University of Wales, Cardiff, UK

Rheumatoid arthritis (RA) is a common, chronic, disabling disease with a significant morbidity and mortality; the reduction of life expectancy is estimated at up to 10 yr. The total cost of the disease has been calculated at over 1 billion pounds per annum in the UK.

Over the last 20 yr, insights into the understanding of the pathogenesis of RA have been one of the brightest jewels in the biomedical crown. It is generally agreed that antigenic peptides, presented in the groove of the HLA-DR4 antigen, stimulate CD4+ T cells. These, in turn, activate macrophages, B cells and synovial fibroblasts by a variety of mechanisms involving cytokines and direct cell-to-cell contact. Macrophages secrete monokines, such as interleukin (IL)-1ß and tumour necrosis factor alpha (TNF-{alpha}), B cells secrete rheumatoid factors which form immune complexes that cause inflammation by activating complement, whilst macrophages and synovial fibroblasts secrete matrix metalloproteinases which mediate joint destruction. Thus, theoretically, suppression of inflammation should prevent damage and hence reduce costs.

The existing so-called disease-modifying anti-rheumatic drugs (DMARDs) have been used for the treatment of RA based on empirical observations; they are not targeted at any particular point of the pathogenic pathway. Targeted therapies, by contrast, are specifically designed to interfere with a specific point in the pathogenesis of RA. Naturally, such therapies take time and money to develop.

At present, targeted treatment consists of biologics, i.e. proteins, such as monoclonal antibodies, soluble cytokine receptors or cytokines themselves. Since TNF-{alpha} is a potent pro-inflammatory cytokine, much effort has been invested in producing biologics which inhibit its actions. Amongst these biologics, monoclonal antibodies, such as infliximab (cA2 Remicade) and CDP-571, and soluble TNF-{alpha} receptors, such as etanercept (Enbrel), have shown marked and significant anti-inflammatory effects in randomized, placebo-controlled, clinical trials. In such studies, not only are there very high rates of response, but the improvements of quality of life are such that to maintain blinding third party observers are mandatory.

One of these biologics, Enbrel, has recently received a licence for clinical use for RA patients in the USA, whereas Remicade has a licence for Crohn's disease in the USA and has been submitted for approval in RA. It is probable that these molecules will be approved for use in the European Union (EU) within the next 12 months. Enbrel is injected twice weekly by s.c. injection, whereas Remicade is given i.v. at intervals of 2 months. The latter is used with methotrexate, whereas the former can be used as monotherapy. The current annual cost of Enbrel in the US is $12000 with the cost of Remicade predicted to be less, but not substantially so. Although the European costs are currently not known, they will be of the same order of magnitude. These costs will seem even higher to health service providers when considered against the low cost of established, off-patent, DMARDs.

The expectation is that in total managed care systems, such as the British National Health Service, there will be restrictions on such new biologics. The situation will be similar to that which arose with the use of interferon-ß for the treatment of multiple sclerosis, where availability of the drug depended on the accident of where one lived, so-called `postcode prescribing'. If this situation is to be avoided in RA, some thought needs to be given to their use before they are licensed for RA in the EU.

These are not insignificant issues as these drugs represent the most effective therapies currently studied in RA, with significant improvement 20% improvement in American College of Rheumatology (ACR) Criteria (ACR 20) seen in around 70% of patients, whilst 50% of treated individuals have a highly significant change in their disease state (ACR 50). In a disease where many patients have no reasonable alternative therapy, it is clear that these drugs will have an immediate use. The debate will be how extensive this use will be. For example, specific indications could be patients who are too sick to take conventional immunosuppression and others who do not want to preclude conception for 3–6 months. There is, therefore, an urgent need for action from rheumatologists. The following are suggested.

  1. To define algorithms to ensure that patients are being treated in the most effective way with existing DMARDs. Documentary proof may be required to ensure that patients have failed to respond to adequate doses of DMARDs before biologics are prescribed. There is, therefore, an urgent need to provide an agreed definition of DMARD failure.
  2. Equally important, a definition of loss of efficacy for the biologics is required, so that they are not continued when they are not effective; such analyses are currently being undertaken in specific studies.
  3. Patient groups need to lobby members of parliament and the Department of Health to make available money for prescriptions of the new targeted therapies.
  4. A more contentious proposal, which demands in-depth discussion, would be the setting up of regional immunotherapy centres where these drugs would be administered in a carefully controlled environment.

These proposals have the following merits.

  1. The availability of biological therapy would be based on need, rather than the vagaries of the postal code.
  2. Treatment costs would be contained because unnecessary treatment would be minimized.
  3. Regional rheumatology immunotherapy centres would increase the likelihood of new central funding for therapy.
  4. Regional immunotherapy centres would allow the creation of a register of patients treated with biologics and permit an accurate audit of the long-term toxicity of these therapies.

The National Institute for Clinical Excellence (NICE), which is likely to dictate the use of these agents, should consult as widely as possible, particularly with consultant rheumatologists, before making any decision. It is not unreasonable to expect NICE to be a gateway to better care, as their name suggests, rather than being used as a device for saving money for the Treasury.

Action is urgently required to discuss and implement these proposals.