Rheumatoid Arthritis
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The data reported by O'Dell (June 17 issue)1 and by Olsen and Stein (May 20 issue)2 on biologic drugs for the treatment of rheumatoid arthritis reveal many points of uncertainty. First, the number of randomized trials that have compared new biologic agents plus methotrexate with methotrexate alone is small — a single, unreplicated trial of infliximab and adalimumab and two trials of etanercept. (The latest trial is very recent3 and is not mentioned by Olsen and Stein.) In addition, the number of patients who were enrolled in these trials is small (83 in the infliximab group, 67 in the adalimumab group, and 59 and 231 in the two etanercept groups). Furthermore, no head-to-head trial has been conducted that compares biologic agents.
Regulatory agencies that approve these drugs when the evidence of their effectiveness is preliminary do a disservice to the scientific community by discouraging drug manufacturers from undertaking confirmatory studies and trials that directly compare the new drugs. In this way, practitioners are led to prescribe these agents widely, despite limited evidence of their effectiveness.
Giulia Burchini, Pharm.D.
Cecilia Orsi, Pharm.D.
Azienda Ospedaliera Careggi
50134 Florence, Italy
References
O'Dell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med 2004;350:2591-2602.
Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl J Med 2004;350:2167-2179.
Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004;363:675-681.
To the Editor: O'Dell's update on rheumatoid arthritis provides insight into new therapeutic advances. However, these therapies appear to be suited for well-to-do patients with medical insurance, especially those who live in Western, developed countries. The author has not mentioned the treatment options for specific coexisting problems or complications of rheumatoid arthritis, such as associated vasculitis, activation of subclinical tuberculosis, restrictive lung disease, renal parenchymous disease, hypothyroidism, altered glucose tolerance, frank diabetes, and cardiomyopathy. The problem of rheumatoid arthritis is compounded in countries with inadequate resources1 as a result of economic constraints, malnutrition, and a limited number of specialists. Most affected patients initially go to a primary care physician, and if the patient's condition worsens, with complications such as bone destruction, severe pain, and the development of fibrous or bony ankylosis, the primary care physician may refer the patient to an orthopedic surgeon or a consultant physician. Physicians and patients alike will benefit if inexpensive yet effective therapies are discussed, so that the progress of science may also reach the poor.
Niranjan Bhattacharya, D.Sc., M.D.
Bijoygarh State Hospital
Calcutta 700029, India
niranjanb@vsnl.net
References
Bhattacharya N, Chhetri MK, Mukherjee KL, et al. Human fetal adrenal transplant: a possible role in relieving intractable pain in advanced rheumatoid arthritis. Clin Exp Obstet Gynecol 2002;29:197-206.
Dr. O'Dell replies: I certainly agree with Drs. Burchini and Orsi that more studies comparing tumor necrosis factor (TNF) inhibitors with active therapies and with each other would be very helpful to clinicians trying to make critical decisions about these expensive therapies. However, the evidence that TNF inhibition is an extremely effective strategy for a subgroup of patients with rheumatoid arthritis is overwhelming. Although I eagerly await comparative trials, as outlined in my review, I do not believe that this is the responsibility of the regulatory agencies.
The meta-analysis of data on the efficacy of anti-TNF drugs, presented in the recent letter by Messori et al. (August 26 issue),1 is severely flawed by the fact that it combined three studies in which patients had previously had a failure of methotrexate therapy2,3,4 with one in which they had not5 and by the use of fixed-effect rather than random-effect statistical analysis. It is no surprise that patients who were selected as having had a failure of methotrexate2,3,4 did not do well on methotrexate alone. Methotrexate remains the most widely used treatment for rheumatoid arthritis, and patients receiving this drug will continue to be an important control group for many trials.
James R. O'Dell, M.D.
University of Nebraska Medical Center
Omaha, NE 68198-3025
jrodell@unmc.edu
References
Messori A, Santarlasci B, Vaiani M. New drugs for rheumatoid arthritis. N Engl J Med 2004;351:937-938.
Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340:253-259.
Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumor necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial. Lancet 1999;354:1932-1939.
Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48:35-45.
Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004;363:675-681.
Related Letters:
New Drugs for Rheumatoid Arthritis
Messori A., Santarlasci B., Vaiani M.
Regulatory agencies that approve these drugs when the evidence of their effectiveness is preliminary do a disservice to the scientific community by discouraging drug manufacturers from undertaking confirmatory studies and trials that directly compare the new drugs. In this way, practitioners are led to prescribe these agents widely, despite limited evidence of their effectiveness.
Giulia Burchini, Pharm.D.
Cecilia Orsi, Pharm.D.
Azienda Ospedaliera Careggi
50134 Florence, Italy
References
O'Dell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med 2004;350:2591-2602.
Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl J Med 2004;350:2167-2179.
Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004;363:675-681.
To the Editor: O'Dell's update on rheumatoid arthritis provides insight into new therapeutic advances. However, these therapies appear to be suited for well-to-do patients with medical insurance, especially those who live in Western, developed countries. The author has not mentioned the treatment options for specific coexisting problems or complications of rheumatoid arthritis, such as associated vasculitis, activation of subclinical tuberculosis, restrictive lung disease, renal parenchymous disease, hypothyroidism, altered glucose tolerance, frank diabetes, and cardiomyopathy. The problem of rheumatoid arthritis is compounded in countries with inadequate resources1 as a result of economic constraints, malnutrition, and a limited number of specialists. Most affected patients initially go to a primary care physician, and if the patient's condition worsens, with complications such as bone destruction, severe pain, and the development of fibrous or bony ankylosis, the primary care physician may refer the patient to an orthopedic surgeon or a consultant physician. Physicians and patients alike will benefit if inexpensive yet effective therapies are discussed, so that the progress of science may also reach the poor.
Niranjan Bhattacharya, D.Sc., M.D.
Bijoygarh State Hospital
Calcutta 700029, India
niranjanb@vsnl.net
References
Bhattacharya N, Chhetri MK, Mukherjee KL, et al. Human fetal adrenal transplant: a possible role in relieving intractable pain in advanced rheumatoid arthritis. Clin Exp Obstet Gynecol 2002;29:197-206.
Dr. O'Dell replies: I certainly agree with Drs. Burchini and Orsi that more studies comparing tumor necrosis factor (TNF) inhibitors with active therapies and with each other would be very helpful to clinicians trying to make critical decisions about these expensive therapies. However, the evidence that TNF inhibition is an extremely effective strategy for a subgroup of patients with rheumatoid arthritis is overwhelming. Although I eagerly await comparative trials, as outlined in my review, I do not believe that this is the responsibility of the regulatory agencies.
The meta-analysis of data on the efficacy of anti-TNF drugs, presented in the recent letter by Messori et al. (August 26 issue),1 is severely flawed by the fact that it combined three studies in which patients had previously had a failure of methotrexate therapy2,3,4 with one in which they had not5 and by the use of fixed-effect rather than random-effect statistical analysis. It is no surprise that patients who were selected as having had a failure of methotrexate2,3,4 did not do well on methotrexate alone. Methotrexate remains the most widely used treatment for rheumatoid arthritis, and patients receiving this drug will continue to be an important control group for many trials.
James R. O'Dell, M.D.
University of Nebraska Medical Center
Omaha, NE 68198-3025
jrodell@unmc.edu
References
Messori A, Santarlasci B, Vaiani M. New drugs for rheumatoid arthritis. N Engl J Med 2004;351:937-938.
Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340:253-259.
Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumor necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial. Lancet 1999;354:1932-1939.
Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48:35-45.
Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004;363:675-681.
Related Letters:
New Drugs for Rheumatoid Arthritis
Messori A., Santarlasci B., Vaiani M.