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

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 (4, 5); 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 (11, 12). 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, 13, 14). 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. Figure. 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 left and bottom right ) (data from Vanderbilt University, 1987) in relation to baseline disease markers. One source of confusion about long-term outcomes in rheumatoid arthritis is that some people who meet classification criteria have a self-limited process with spontaneous remission, a phenomenon commonly seen in epidemiologic studies (15, 16). Patients who have no evidence of progressive arthritis are likely to receive diagnoses other than rheumatoid arthritis, including benign polyarthritis of the aged (17), polymyalgia rheumatica (18), reactive arthritis (19, 20), and inflammatory polyarthritis differing from rheumatoid arthritis (21). Spontaneous remission is generally seen within 6 to 12 months of symptom onset. Patients with sustained signs of rheumatoid arthritis for longer than 3 to 6 months, including most patients monitored in clinical settings (even in the community [22]), generally have a progressive disease known as type III rheumatoid arthritis (23) or progressive inflammatory symmetrical arthritis (PISA) (24). A second source of confusion is that rheumatoid arthritis is assessed in clinical trials according to measures of inflammatory activity, such as joint swelling and erythrocyte sedimentation rate (25-28), whereas long-term treatment goals include prevention of severe long-term outcomes, such as work disability, joint replacement, and premature death (Table 1). Unlike measures of inflammatory activity, which are reversible with drug therapy, measures of damage, such as joint deformity or radiographic changes, are irreversible. Inflammatory markers may be stable or somewhat improved over 5 to 10 years, during which time patients experience radiographic progression (29-31) and functional declines (32). These markers of inflammation may not, therefore, be ideal surrogates (33, 34) for long-term outcomes. Table 1. Measures for Assessing Clinical Status in Patients with Rheumatoid Arthritis Recognition of poor long-term outcomes and results of therapies has led to calls for more aggressive treatment approaches (4, 5, 35), including use of a disease-modifying antirheumatic drug early in the disease course and use of combinations of these drugs when residual inflammation remains after maximum doses of single agents, as is usually the case (36-39). At this time, combinations of disease modifying antirheumatic drugs are used in at least some patients by almost all rheumatologists (40-42). Many aspects of an aggressive approach to rheumatoid arthritis remain controversial. However, definitive documentation of long-term effectiveness, in contrast to short-term efficacy in clinical trials (43), will require many years of observation, during which millions of people will develop rheumatoid arthritis. Physicians and their patients should be made aware that therapy with individual disease-modifying antirheumatic drugs is rarely remission-inducing (44) and that evidence now exists that certain aggressive approaches might prevent or retard long-term consequences. Combinations of disease-modifying antirheumatic drugs, including the newest agents approved for rheumatoid arthritisleflunomide (45, 46), etanercept (47), and infliximab (48)will probably be used increasingly over the next decade. We briefly discuss the rationale for a treatment strategy in rheumatoid arthritis designed to control inflammation as completely as possible in order to prevent or retard joint damage, evidence from randomized, controlled clinical trials of the efficacy of combination disease-modifying antirheumatic drug therapies to control inflammation at higher levels than achievable by therapy with single agents, and a contemporary approach to rheumatoid arthritis. This perspective is not designed to propose specific optimal combination regimens for individual patients, which will probably vary among different patients, but rather to introduce the general concept of combination therapy as a strategy in treatment of rheumatoid arthritis. Rationale for a Preventive Strategy In clinical trials and many clinical studies, rheumatoid arthritis is assessed primarily according to measures of inflammatory activity, such as joint swelling and erythrocyte sedimentation rate (25-28). These measures are reversible through drug therapy. In contrast, measures of joint damage, such as joint deformity and radiographic changes, are irreversible. Thus, measures of inflammatory activity may be stable or improve somewhat over 5 to 10 years while patients experience radiographic progression (31) and functional decline (32). Radiographic damage is seen in more than 70% of patients with rheumatoid arthritis within the first 2 years of disease (49-51). Furthermore, radiographic progression is seen in almost all patients; often, the rates are often highest in early disease. However, clinicians may not recognize a severe problem until physical joint deformity and radiographic malalignment are seen after more than 5 years of disease (52), by which time much irreversible damage has occurred. Functional disability also is often seen in patients with early rheumatoid arthritis and historically has progressed in most patients (32). Although traditional disease-modifying antirheumatic drugs, such as injectable gold salts and penicillamine, were designated as remission-inducing, sustained remission was seen in fewer than 2% of patients treated during the 1980s (44). More than 80% of courses of traditional disease-modifying antirheumatic drugs were discontinued within 2 years (53, 54). Contemporary disease-modifying antirheumatic drugs, such as methotrexate, hydroxychloroquine, and sulfasalazine, have a considerably greater efficacy/toxicity ratio than traditional agents (53-55). In particular, methotrexate has substantially greater long-term effectiveness than traditional disease-modifying antirheumatic drugs (56-59) and was taken by more than 50% of patients with rheumatoid arthritis in 15 private practices in the United States by 1992 (54). Given individually, disease-modifying antirheumatic drugs may provide substantial benefit to many patients (60-63), including retardation of radiographic progression (64-67). However, even therapy with methotrexate, the most effective disease-modifying antirheumatic drug, rarely leads to true remission, even when it is used with low-dose prednisone (36, 38, 40, 58, 59). When blood pressure is not controlled with a single antihypertensive agent, multiple agents are used to control the dysregulation. Likewise, many if not most patients with rheumatoid arthritis may be candidates for combination therapy (24, 38, 39) to achieve optimal control of inflammation to prevent or retard joint damage (42, 68). Although the Hippocratic dictum primum non nocere (first do no harm) always remains applicable in medical care, it seems inappropriate to defer therapy for rheumatoid arthritis beyond a few months. In most patients, the consequences of rheumatoid arthritis seem to be considerably more severe than the side effects of contemporary disease-modifying antirheumatic drugs (69). Clinical Trials of Combination Therapy with Disease-Modifying Antirheumatic Drugs Early uncontrolled clinical studies suggested that combination therapy with disease-modifying antirheumatic drugs was efficacious in clinical care (70-72). However, early randomized, controlled clinical trials yielded varying results; some suggested no advantages to combination therapy (73-77). The apparently conflicting conclusions of these early studies may partly reflect design issues in clinical trials, such as patient selection, short time frame, and use of surrogate markers, all of which may limit recognition of differences between various regimens despite inclusion of a control group (33, 78-86). Three types of designs have been used: parallel, in which patients begin therapy with a single drug and with combinations at the same time; step-up, in which therapy with a second drug or placebo is introduced after maximal but suboptimal benefit is seen from a first drug; and step-down, in which therapy with several drugs is begun, followed by protocol-directed sequential tapering, withdrawal of one or more agents, or both (42). In general, advantages to combination therapies may be more easily documented over 1 year or less in a step-up or step-down design than in a parallel design (42). Over the past 4 years, six published