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Combination Therapy with Multiple Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis: A Preventive Strategy

Theodore Pincus, MD; James R. O'Dell, MD; and Joel M. Kremer, MD
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From Vanderbilt University Medical Center, Nashville, Tennessee; University of Nebraska Medical Center, Omaha, Nebraska; and Albany Medical College, Albany, New York.

Grant Support: By the Jack C. Massey Foundation, Maury County Lupus Fund, and the Arthritis Foundation.

Requests for Reprints: Theodore Pincus, MD, Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, 203 Oxford House, Box 5, Nashville, TN 37232-4500.

Current Author Addresses: Dr. Pincus: Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, 203 Oxford House, Box 5, Nashville, TN 37232-4500.

Dr. O'Dell: Department of Internal Medicine, University of Nebraska Medical Center, 983025 Nebraska Medical Center, Omaha, NE 68198-3025.

Dr. Kremer: Division of Rheumatology, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208.

Ann Intern Med. 1999;131(10):768-774. doi:10.7326/0003-4819-131-10-199911160-00009
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Rheumatoid arthritis is a progressive inflammatory disease that affects 0.5% to 1% of the population and involves costs of approximately 1% of the U.S. gross national product (1). Historically, most patients with rheumatoid arthritis were treated according to a “pyramid” (2) or sequential (3) strategy, beginning with a nonsteroidal anti-inflammatory drug. Clinicians sought to avoid using disease-modifying antirheumatic drugs until evidence of joint damage was seen. However, this strategy was ineffective over more than a few years (45); most patients experienced poor long-term outcomes, including severe functional declines (6), radiographic progression (7), considerable economic losses (8), work disability (9), and premature mortality (6, 10). Unfavorable outcomes were predicted primarily by more severe disease and rarely were secondary to drug toxicity (1112). Patients with the poorest functional status and more involved joints had a 5-year survival rate of 50% or less, similar to survival seen in stage IV Hodgkin disease or three-vessel coronary artery disease in the 1970s (Figure) (10, 1314). Therefore, current approaches to rheumatoid arthritis emphasize aggressive control of inflammation to prevent long-term damage; this strategy may be analogous to tight control of dysregulation in diabetes or hypertension to prevent organ damage.

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Survival over 9 to 10 years of patients with coronary artery disease (top left) (data from Cleveland Clinic, 1978), Hodgkin disease (top right) (data from Stanford University, 1972), and rheumatoid arthritis (bottom leftandbottom right) (data from Vanderbilt University, 1987) in relation to baseline disease markers.

Patients with the most severe clinical status had survival rates of 40% to 60% over the subsequent 5 years, including patients with three involved vessels or left main disease, stage IV Hodgkin disease, or more than 30 involved joints or poor functional status in rheumatoid arthritis. By contrast, 5-year survival rates of 90% were seen in patients with most favorable baseline clinical status—right coronary artery one-vessel disease, stage I or II Hodgkin disease, and few involved joints and good functional status in rheumatoid arthritis. ADL = activities of daily living. Reproduced with permission from Pincus T, Callahan LF. Taking mortality in rheumatoid arthritis seriously—predictive markers, socioeconomic status and comorbidity. J Rheumatol. 1986;13:841-5.

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