The measure of our measures.

Attempts to quantify various aspects of rheumatoid arthritis (RA) go back at least as far as the first half of the last century [1]. The importance of separating ‘disease activity’ from function and structural damage became increasingly clear especially with the advent of new disease-modifying anti-rheumatic drugs (DMARDs) and biological agents and the need to assess their efficacy in clinical trials. The question as to which measures of disease activity one should select is a vexing one. Should it be joint tenderness or pain, morning stiffness, joint swelling, range of movement, function? Should extra-articular manifestations such as fatigue be included? Should one add laboratory values such as the erythrocyte sedimentation rate (ESR) or the C-reactive protein (CRP)? Should such measures be reported separately, or should summation be attempted? The last question was particularly important since therapeutic trials frequently reported multiple outcomes of uncertain relative importance, often differing from outcomes reported in other trials. There have been several attempts to devise an instrument which would measure the overall activity of RA. Lansbury was one of the first to introduce a summary ‘activity index’ which incorporated morning stiffness, fatigue, the amount of aspirin used, grip strength, a count of painful/tender (but not swollen) joints, and the ESR [2]. The Lansbury index was criticized for some statistical shortcomings in therapeutic trials, and different instruments were suggested, such as the ‘pooled index’ conceived by Smythe et al. [3]. Whatever its statistical merits, that index also included measures which are either subjective or depend on patient cooperation, such as grip strength, morning stiffness, functional assessment and number of tender or painful joints [3]. The two best known and most commonly used summation measures for activity of RA are the Disease Activity Score (DAS) and the American College of Rheumatology preliminary core set of disease activity measures, often referred to as the ACR20 (meaning that a 20% improvement was sought or achieved) [4, 5]. The DAS has been further modified to the DAS28 to indicate that only 28 specified joints are assessed for pain/tenderness and swelling [6]. The DAS28 is a measurement of ‘disease activity’, whereas the ACR20 measures change over time in such activity. Both include some indices which are subjective, e.g. number of tender joints (DAS28, ACR20), patient assessment of pain, and physician and patient global assessments of disease activity (ACR20) [5, 6]. The DAS and DAS28 include a subjective general health assessment (GHA) which can reflect factors other than joint inflammation, while the ACR20 includes a measurement of function, such as the health assessment questionnaire (HAQ) [4–6]. Thus, neither the DAS28 nor the ACR20 measures exclusively joint inflammation. The DAS28 and the ACR20 have been repeatedly used in various trials, particularly in assessments of the efficacy of DMARDs and biological agents. Rheumatologists have become so familiar with them that they may forget what it is that they actually measure. In this issue of Rheumatology, Leeb and colleagues present the results they obtained using the DAS28 in a group of patients with RA compared with a group of patients with fibromyalgia (FM) [7]. Surprisingly, the two groups showed little difference in their DAS28 values. At first glance, the comparison appears to be bizarre. The DAS28, or other versions of the DAS, were not meant for assessing FM. Nevertheless, this apparently odd comparison makes one aware of both the strengths and the limitations of the DAS or any similar summation instrument. The DAS28 is based on two objective measures and two subjective ones: the former are the ESR and the number of swollen joints; the latter are the number of tender joints and the GHA. Leeb et al. found in their patients with RA that there was a high correlation between all the DAS components, both objective and subjective. This was not true in FM patients, where the GHA and the number of tender joints correlated well with each other but not with the number of swollen joints and the ESR, as one would expect in a noninflammatory disease. The presence of a large number of tender joints in FM is not surprising, and had already been reported by Reilly and Littlejohn [8]. This is consistent with the mounting evidence that FM is characterized by abnormalities in central pain processing [9]. Central pain processing may also be disturbed in RA [10]. Furthermore, patients with FM and RA both have a worse quality of life than healthy controls [11], thus influencing the GHA score. Factors other than inflammation may influence the number of tender joints in RA. For instance, FM occurs frequently in combination with RA [12]. Wolfe and Michaud found, in a study of more than 11 000 patients with RA, that 17.5% satisfied their survey criteria for FM [13]; these patients with both FM and RA had more pain, worse anxiety, more fatigue and greater work disability than patients with RA and no FM. Comorbidity with serious, potentially life-threatening diseases, such as diabetes, hypertension, ischaemic heart disease and cancer, was also significantly higher in patients with FM and RA [13]. Mortality was not reported but one must keep in mind recent studies that suggest that chronic widespread body pain, whatever its cause, appears to have a statistically significant association with decreased survival [14, 15]. Instruments used to measure the disease activity of rheumatic conditions other than RA are also affected by high pain levels and fatigue. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores in one study were higher in patients with FM than in patients with spondylarthritis [16]. In systemic lupus erythematosus the rating of disease activity was substantially affected by the presence of coexisting FM [17]. Changes in measures of disease activity have to be considered in relation to the background against which they occur. For instance, in a 12-week trial comparing etoricoxib, a COX-2 inhibitor, with naproxen and placebo in RA, 57.9% of those taking etoricoxib achieved ACR20 criteria [18]. This improvement was largely due to changes in several subjective measures, such as the number of tender joints, assessments of pain and disease activity (by patients and investigators) and the HAQ. The number of swollen joints decreased but the CRP showed no change. Similarly, celecoxib trials show that 51% of RA patients could achieve ACR20 criteria [19]. This is equivalent to the outcomes achieved in RA patients in the first 3 months of treatment with biological agents [20, 21]. Measures such as the number of tender joints, the pain severity, the GHA and the HAQ depend not only on current disease activity, but also on the extent and degree of the articular damage that has already occurred. Physicians and patients often disagree