Physician preference: Filling the evidence gap

The availability of methotrexate (MTX) and the more recent development of biologic response modifiers represent major advances in the treatment of rheumatoid arthritis (RA). Once considered a “lofty” and even unrealistic therapeutic goal, disease remission has finally achieved a much deserved promotion, increasingly targeted as a study outcome in major randomized clinical trials (RCTs) in RA. Where rheumatologists once used words such as “reducing” and “slowing” to characterize RA treatment goals referent to radiographic disease progression, they now use words such as “stopping,” “reversing,” or even “healing. ” In addition to MTX and many other nonbiologic diseasemodifying antirheumatic drugs (DMARDs), there are now 8 approved biologic treatments for RA in the US with other promising agents sure to follow. Of these, agents targeting tumor necrosis factor (anti-TNF agents) are the most commonly prescribed and have been subject to the most comprehensive investigation. A recent PubMed search of the terms “anti-TNF” and “rheumatoid arthritis” yielded more than 1,000 reports. Many of these reports are large multicenter RCTs, studies that arguably reside atop the pecking order of evidence. With a wide breadth of investigations focused on antiTNF treatment strategies and the high level of corresponding evidence, it would seem improbable that something as subjective (and fickle) as physician preference would have a major impact on the decision to use anti-TNF therapy in RA. To the contrary, physician preference appears to play a preeminent role in such decisions. In their article, which appears in this issue of Arthritis Care & Research, Curtis et al provide evidence that supports the important and robust role that physician preference plays in prescribing DMARDs (1). Their results are reminiscent of those from prior studies showing the importance of physician preference in the receipt of cyclooxygenase 2 selective nonsteroidal antiinflammatory drugs (2). In their study of RA patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA), Curtis et al found that physician preference (based on prescribing behaviors over the previous year) were strongly and positively associated with the receipt of anti-TNF therapy in patients never taking biologic agents. These associations were independent of other physician, third-party payer, and patient-level factors including several core measures of RA disease activity. It is noteworthy that the role of physician preference in the receipt of anti-TNF therapy appears to be greatest in patients for whom there is a paucity of supporting evidence or the evidence is contradictory. Despite the fact that most RCTs have excluded patients with low to moderate levels of disease activity, the role of physician preference in predicting the receipt of anti-TNF treatment appears to be strongest in this patient group. Likewise, physician preference appears to have a greater impact in DMARD selection among patients never taking MTX compared with patients previously receiving MTX, which, as Curtis and colleagues suggest, may reflect an increased use of biologic therapies in patients with “relative contraindication” to MTX. If we assume that the differences between patients never taking MTX and MTX exposed patients are not completely accounted for by relative contraindication to MTX, then physician preference would appear to trump existing evidence. Recognizing the availability of limited trial data comparing active therapies, studies in early RA suggest that MTX monotherapy is either equivalent or superior to anti-TNF monotherapy in reducing the signs and symptoms of RA. In the seminal Early RA study (a study of patients never taking MTX), there were no significant efficacy differences between etanercept and MTX monotherapy (3). In the PREMIER study, also a study of patients who had never received MTX, American College of Rheumatology 20% improvement criteria treatment responses (4) were significantly more frequent after 1 year of treatment among patients with early RA receiving MTX than in patients receiving adalimumab at its approved dose (63% versus 54%; P 0.043) (5). Although numerically showing a greater influence in patients who never received MTX, physician preference also appears to be a significant predictor of anti-TNF receipt among MTX exposed patients. In the accompanying report by Curtis et al, MTX exposed RA patients seen by rheumatologists with the highest propensity to prescribe Ted R. Mikuls, MD, MSPH, James R. O’Dell, MD: University of Nebraska Medical Center and Omaha Veterans Affairs Medical Center, Omaha, Nebraska. Dr. O’Dell has received consultant fees, speaking fees, and/or honoraria (less than $10,000) from Amgen. Address correspondence to Ted Mikuls, MD, MSPH, Nebraska Arthritis Outcomes Research Center, University of Nebraska Medical Center, 986270 Nebraska Medical Center, Omaha, NE 68198-6270. E-mail: tmikuls@unmc.edu. Submitted for publication August 17, 2009; accepted in revised form August 25, 2009. Arthritis Care & Research Vol. 62, No. 1, January 15, 2010, pp 1–3 DOI 10.1002/acr.20006 © 2010, American College of Rheumatology