Editorials

Treating rheumatoid arthritis with tumour necrosis factor  blockade

May be a giant therapeutic leap or a small expensive step

Rheumatoid arthritis is one of the commonest autoimmune diseases, with a prevalence of about 1%, and it is perhaps the most common reversible disability in the Western world. After 10 years, 50% of people with rheumatoid arthritis in employment no longer work, most losing their jobs in the first 12 months after diagnosis.¹ Excessive amounts of the pro-inflammatory cytokines, tumour necrosis factor, TNF interleukin-1 (IL-1), and interleukin-6 (IL-6), mediate most of the pathogenic features of rheumatoid arthritis. Infliximab, the chimeric antibody to tumour necrosis factor , and etanercept, a fusion protein p75 tumour necrosis factor  receptor immunoglobulin, have been shown to be very effective in reducing the chronic symptoms and signs of rheumatoid arthritis in patients who fail to respond to conventional treatment with disease modifying drugs.² Both these molecules produce response rates which are at least as high as those seen with other treatments given for milder disease. Importantly, these drugs have been shown to be effective in patients who were thought to be resistant to all treatment. Before these new drugs such patients were left to deteriorate, resulting in cachexic individuals with destroyed joints, a picture all too familiar to physicians.

Most physicians believed that because of the redundancy of the overlapping actions of the pro-inflammatory cytokines, blockade of a single cytokine would be insufficient to control the disease.³ Experimental evidence, however, suggests a hierarchy of cytokines, and a phase II study of infliximab, which is a chimeric mouse-human antitumour necrosis factor  molecular antibody, showed that blockade could be effective.⁴ The downside was tachyphylaxis on repeated infusions, which meant long term treatment would not be possible. Giving methotrexate concurrently, however, suppressed tachyphylaxis, probably by preventing the production of human antichimeric antibodies.⁵

Though tumour necrosis factor  blockade was expected to have a major impact on inflammatory symptoms, we did not know whether it would influence bony disease, where evidence suggested that IL-1 was a major mediator.⁶ Surprisingly, radiological damage showed more improvement than did clinical symptoms, particularly with infliximab. Radiological progression over a one and two year period was effectively abolished.⁷

The drugs were licensed in the European Union over 18 months ago: infliximab to be given intravenously with methotrexate at intervals of eight weeks after an induction period, and etanercept given subcutaneously twice a week either as monotherapy or with methotrexate. At registration their known toxicities were the rare induction of autoantibodiesparticularly antinuclear antibodies and double stranded deoxyribonucleic acid antibodies, reversible systemic lupus erythematosus, a slight increase in upper respiratory tract infections, and minor problems in giving the drugs such as infusion and injection site reactions. In addition, there were concerns about an increase in rates of malignancy.

Since registration around 300 000 patients have been treated worldwide with these agents. Most are in the United States, where health maintenance organisations have reimbursed treatment, and the licensing authorities have accepted the data on radiological and clinical improvement. An increased risk of malignancy has not been confirmed, but there have been other problems like reactivation of mycobacterial infection on infliximab, worsening of demyelinating disease, suppression of bone marrow on etanercept, and a variety of unusual idiosyncratic side effects. Patients at increased risk of sepsis, for example those on high doses of steroids or with poorly controlled diabetes, are excluded from treatment. In clinical practice these drugs have been as effective as in controlled clinical trials, but these are complex drugs with major effects on the immune system and they need close monitoring. At present they remain drugs to be used in secondary care by experienced physicians.

(Credit: MOREDON LTD/PANOS PICTURES) View larger version (141K): [in this window] [in a new window]   False colour scanning electron micrograph of the head of a femur showing damage to the surface caused by rheumatoid arthritis

The most difficult question is: at what stage of the disease do we use these drugs? In the United States they are becoming first line therapy, whereas in Europe they are used only after one or two disease modifying drugs have failed. Guidelines have been issued for their use.^8-10 Etanercept has been compared with methotrexate in early disease and shown benefits but probably insufficient to recommend unlimited use.¹¹ The availability of these agents has encouraged better use of existing disease modifying drugs and at a higher dose. This in turn has reduced the cost effectiveness of the non-selective use of tumour necrosis factor  therapy.

Guidelines for their use in the United Kingdom are expected by March 2002 from the National Institute for Clinical Excellence. Meanwhile, health authorities have had to make money available on an ad hoc basis. Optimal treatment for an important disease is being determined by arbitrary factors, such as a person's address ("postcode prescribing"). A recent review suggests that up to 50% of people with rheumatoid arthritis in the United Kingdom do not have access to these drugs. Yet there is wide agreement, aided by the realisation of the severe side effects of untreated active disease, that these drugs are cost effective in patients who have failed to respond to an adequate trial of conventional drugs.¹²

Tumour necrosis factor  blockade costs about £6000-£8000 ($9000-$12 000) a year per patient. In countries with limited budgets this has necessitated targeting treatment to appropriate patients and prompted a realisation that it should not be continued in the 25% of patients who do not respond. The non-response may be due to the heterogeneity of disease with genetic factors, dominant cytokines, and currently used doses. The imminent availability of blockade of IL-1 via the use of an IL-1 receptor antagonist (anakrina) and the evidence that combined blockade of both tumour necrosis factor  and IL-1 is very effective in animal models will stimulate further research. Present evidence suggests that blockade of tumour necrosis factor , though effective, does not cure and that permanent treatment is needed. The positive side is that these drugs have confirmed that the underlying disease of rheumatoid arthritis is treatable. The absence of a cure has also stimulated more research for agents capable of long term immunomodulation.

Paul Emery, professor. 
Maya Buch, research fellow. 

Academic Unit, Musculoskeletal Disease, Leeds Teaching Hospitals Trust, Leeds LS2 9NZ

Footnotes

   PE has been reimbursed by both Centocor-Schering-Plough, manufacturers of infliximab, and Immunex-Wyeth, manufacturers of etanercept, for running educational programmes, undertaking clinical trials, and consultancy.

1.	Markenson JA. Worldwide trends in the socio-economic impact and long-term prognosis of rheumatoid arthritis. Sem Arthritis Rheumatism 1991; 21(suppl1): 4-12[CrossRef][ISI][Medline].
2.	Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, et al. Etanercept therapy in rheumatoid arthritis: a randomised, controlled study. Ann Intern Med 1999; 130: 478-486[Abstract/Free Full Text].
3.	Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996; 14: 397-440[CrossRef][ISI][Medline].
4.	Elliot MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor  (cA2) versus placebo in rheumatoid arthritis. Lancet 1994; 344: 1105-1110[CrossRef][ISI][Medline].
5.	Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, MacFarlane JD, et al. Therapeutic efficacy of multiple infusions of anti-tumour necrosis factor  monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheumatism 1998; 41: 1552-1563[CrossRef][ISI][Medline].
6.	Joosten LA, Helsen MM, Saxne T, van De Loo FA, Heinegard D, van Den Berg WB. IL-1/ blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF- blockade only ameliorates joint inflammation. J Immunol 1999; 163: 5049-5055[Abstract/Free Full Text].
7.	Lipsky PE, Van Der Heijde DMFM, St Claire EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000; 343: 1594-1602[Abstract/Free Full Text].
8.	British Society for Rheumatology. Guidelines for prescribing TNF  blockers in adults with RA. London: British Society for Rheumatology, 2001.
9.	Smolen JS, Breedveld FC, Burmester GR, Combe B, Emery P, Kalden JR, et al. Consensus statement on the initiation and continuation of tumour necrosis factor blocking therapies in rheumatoid arthritis. Ann Rheum Dis 2000; 59: 504-505[Free Full Text].
10.	Emery P, Peginster J-Y, Appelboom T, Breedveld FC, Edelmann E, Kekow J, et al. WHO collaborating centre consensus meeting on anti-cytokine therapy in rheumatoid arthritis. Rheumatology 2001; 40: 699-702[Abstract/Free Full Text].
11.	Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone JR, et al. A comparison of etanercept and methotrexate in patients with early rehumatiod arthritis. N Engl J Med 2000; 343: 1586-1593[Abstract/Free Full Text].
12.	Emery P, Pannayi GS, Sturrock R, Williams BD. Targeted therapies in rheumatoid arthritis: the need for action. Rheumatology 1999; 38: 911-916[Free Full Text].