The New England Journal of Medicine -- November 30, 2000 -- Vol. 343, No. 22
This year marks the 50th anniversary of the awarding of the Nobel Prize in Physiology and Medicine to Kendall, Hench, and Reichstein for the isolation and characterization of adrenocorticotrophic hormones. (1) Until now, nothing has even begun to approach the dramatic effect glucocorticoids have had in improving the care of patients with rheumatoid arthritis and other systemic inflammatory diseases and creating optimism in the arthritis community. Products devised by the biotechnology industry for the treatment of rheumatoid arthritis have now been introduced into the clinic and appear to have ushered in a new era of scientifically based therapy for arthritis. Products that inhibit tumor necrosis factor (alpha) (TNF-(alpha)) are the first to have been introduced, and other biologic therapies are expected to follow.
The cytokine TNF-(alpha) has a major role in both inflammation and bone resorption in rheumatoid arthritis. (2) This knowledge has led to the development of approaches to block the interaction between TNF-(alpha) and its receptor. The Food and Drug Administration (FDA) has now approved two such biologic agents -- etanercept and infliximab -- for the treatment of rheumatoid arthritis. Etanercept is a fusion protein of the ligand-binding region of the 75-kd (p75) TNF receptor that is linked to the Fc portion of human IgG1, and infliximab is a chimeric (mouse and human) monoclonal antibody against TNF-(alpha).
In addition to being approved for use in patients with rheumatoid arthritis, etanercept has been approved for the treatment of children with polyarticular juvenile rheumatoid arthritis, (3) and infliximab for use in patients with active Crohn's disease and fistulas due to Crohn's disease. (4) However, TNF-(alpha) inhibitors are now being given to patients with other types of chronic inflammatory and immune disorders on the assumption that TNF-(alpha) has a similar key role in their pathogenesis. The real challenge is how, or perhaps whether, we will ever determine the role of TNF-(alpha) inhibition in the treatment of these disorders.
The studies by Bathon et al. (5) and Lipsky et al. (6) in this issue of the Journal expand our understanding of the effects of the inhibition of TNF-(alpha) in the early phases of rheumatoid arthritis. As compared with methotrexate, which is generally considered to be the standard treatment for rheumatoid arthritis in this country, TNF-(alpha) inhibitors are associated with greater improvements in the symptoms and signs of arthritis and, more important, a lower risk of joint damage. In fact, it is reassuring to document that some drugs indeed are able to retard the progression of joint damage in patients with rheumatoid arthritis. Although this outcome has been widely accepted as the objective of so-called disease-modifying antirheumatic drugs such as methotrexate, there is little evidence that these drugs are capable of achieving this outcome. On the basis of the studies by Bathon et al. and Lipsky et al., as well as other evidence, the FDA earlier this year expanded the indications for the use of both etanercept and infliximab in patients who have moderate-to-severe, active rheumatoid arthritis who have not been treated with disease-modifying antirheumatic drugs to delay joint damage.
It is far too early to know how this new information will change clinical practice. To date, the majority of the experience with TNF-(alpha) inhibitors has been in patients with progressive, erosive rheumatoid arthritis who had an inadequate response to treatment with disease-modifying antirheumatic drugs. However, it seems reasonable to argue, on the basis of this evidence, that TNF-(alpha) inhibitors should be used as early as possible in all patients who have documented rheumatoid arthritis. The unavailability of data on the long-term efficacy and safety of TNF-(alpha) inhibitors, the lack of studies comparing these drugs with newer drugs that also slow the rate of structural damage to joints, (7) and the high cost of these drugs are barriers to the adoption of this approach. The chief barrier at the moment is clearly cost, which is in the range of $10,000 to $12,000 per patient per year. Analyses of the cost effectiveness of various drug therapies for short-term outcomes, including TNF-(alpha) inhibitors, are helpful, (8) but the true cost savings of early therapy will be realized in the form of reductions in the need for long-term care for chronic disease and in the extent of disability caused by joint damage.
TNF-(alpha) inhibitors have surprisingly few side effects. The most common are reactions at the injection site (in the case of etanercept) and hypersensitivity reactions (in the case of infliximab) and minor upper respiratory tract infections. Serious, life-threatening infections have occurred, although the exclusion of patients with chronic, recurrent, or active infections from randomized trials has markedly diminished the risk. A full understanding of the risk of other serious adverse events as well as long-term effects must await reports from surveillance systems that monitor the agents. As evidence that the surveillance systems are working, just this past month, physicians in the United States and Europe received a letter calling attention to the development of pancytopenia, including several cases of fatal aplastic anemia, as well as demyelinating syndromes in a small number of patients who were treated with etanercept. The finding of demyelinating syndromes is of interest, and perhaps not totally unexpected, since inhibition of TNF-(beta) has been associated with worsening in patients with multiple sclerosis. (9) Although it seems unlikely that these newly reported effects will have any major influence on the use of these agents, they serve as a reminder that our understanding of the risks of inhibiting TNF-(alpha) remains incomplete.
From the data available, there is no clinical or scientific rationale for choosing one TNF-(alpha) inhibitor over another. The improvements in the symptoms and signs, the effects on radiographic evidence of progression, the costs, and the risks of side effects of the two agents appear to be similar. Practical considerations such as the frequency or route of administration (twice-weekly subcutaneous injections in the case of etanercept and intermittent intravenous infusions in the case of infliximab) or the need for concomitant methotrexate therapy in patients who receive etanercept may factor into the decision. For patients who are eligible for Medicare, however, there is an important difference in the level of reimbursement for the two agents. Currently, the cost of agents requiring intravenous infusions such as infliximab is fully covered by Medicare, whereas the cost of self-injected medications such as etanercept is not. Legislation introduced in the most recent session of Congress, the Access to Innovation for Medicare Patients Act, proposes to eliminate this consideration by expanding coverage for certain self-injected biologic therapies, including etanercept.
Finally, on the basis of the available data, there is no reason to believe that agents that inhibit TNF-(alpha) or any other currently available treatments used in rheumatoid arthritis cure the disease. Disease activity is suppressed only during treatment, and thus relapses are inevitable once treatment is discontinued, regardless of the duration of treatment. This point must be kept in mind so that advances in therapy -- no matter how major -- do not diminish the commitment to research that will eventually achieve a cure.
John H. Klippel, M.D.
Atlanta, GA 30309
Copyright © 2000 Massachusetts Medical Society