Radiography of Rheumatoid Arthritis in the Time of Increasing Drug Effectiveness Frederick Wolfe, MD*, and Vibeke Strand, MD Address *Arthritis Research Center Foundation, 1035 N. Emporia, Suite 230, Wichita, KS 67214, USA. E-mail: fwolfe@arthritis-research.org Current Rheumatology Reports 2001, 3:46–52 Current Science Inc. ISSN 1523–3774 Copyright © 2001 by Current Science Inc. Introduction In the last several years, new and old treatments for rheumatoid arthritis (RA) have been shown to be effective in preventing radiographic progression [1,2••,3,4••,5••, 6,7]. Several factors have contributed to this new effective- ness, including better study design, better radiographic techniques, more sensitive reading methods, and more potent therapies. In a signal article, written almost two decades ago, Iannuzzi et al. [8] found little evidence to support the effectiveness of disease modifying anti rheumatic therapy (DMARDs). However, in the last 10 years, almost all DMARDs have been shown to retard progression to varying degrees [1,4••,5••,6,7]. In this report, we review new agents that have been shown to be effective in the treatment of RA [2••,9–18] and compare these treatments with placebo, methotrexate (MTX), and sulfasalazine (SSZ) in regard to radiographic outcome. Why Should We Be Concerned with Radiographic Progression? Erosions and joint space narrowing evidenced on radio- graphs are easily assessable markers of cumulative damage [19], and may not be susceptible to the variability inherent in subjective assessments of pain, functional difficulty, and work disability. In addition, radiographic abnormalities are detectable early in the course of disease [20,21] at a time when other manifestations of damage, such as deformity and work disability, have not yet occurred. Radiographic assessment also fits well into our understanding of disease in RA: that disease activity, acting over time, produces damage; and that the degree of disease activity is consistent with the degree of damage [22,23,24••]. Nonsteroidal anti inflammatory drugs (NSAIDs) can produce measurable improvement in manifestations of disease in RA patients without substantially reducing disease activity or damage. This can occur when NSAIDs reduce pain and thereby improve function. Nonetheless, under such circumstances patients improve symptom- atically despite progressive worsening in terms of damage. Radiographs may produce a clearer record of the effect of disease activity because they are not subject to the patient’s assessment of pain or function, and can provide a cumulative assessment of damage over time. As important as radiographic data may be to physicians, in most instances these data will be of little importance to patients because they are often unaware of the damage that may have occurred. What Is Radiographic Progression? That retardation of radiographic progression implies disease control rather than symptom control has become important for pharmaceutical and biotechnology sponsors and regulatory authorities. There are several issues. In randomized, controlled trials, radiographic effectiveness is shown by comparing the active (test) drug to placebo or to a comparator (Table 1). This requires knowledge of the minimal clinically significant difference required to show superiority, or to show equivalence in equivalence studies. One must pick a difference that is clinically significant and then base sample size calculations on that difference. But Recent clinical development programs for new therapeutic agents in rheumatoid arthritis have included assessment of radiographic progression comparing changes with treatment to placebo and active controls. Studies now use reliable methods of assessment and sufficient study length to detect radiographic changes. Although patient populations and characteristics differ, and radiographic scoring methods vary, the direction of a series of studies appears to indicate that leflunomide (LEF), methotrexate (MTX), sulfasalazine (SSZ), etanercept, infliximab, and IL-1ra are all effective in retarding radiographic progression, as measured by erosions and joint space narrowing. Interpretation of radiograph data in future trials will be aided by utilization of common reading methods and by continuing comparison across differing rheumatoid arthritis protocol populations.