Clinically Important Changes in Short Form 36 Health Survey Scales for Use in Rheumatoid Arthritis Clinical Trials: The Impact of Low Responsiveness

Measures of health status and health-related quality of life have been recognized as essential components of clinical evaluations because they provide patients’ perspectives on how they are affected by a disease (1,2). Consequently, patient-reported outcomes have been included as endpoints in many clinical trials, allowing treatment effects to be assessed more comprehensively. In rheumatoid arthritis (RA), measures such as pain scales and the Health Assessment Questionnaire Disability Index have been used for decades, and clinical trials have also increasingly included generic health status measures, particularly the Short-Form 36 (SF-36) (3–9). The SF-36 includes eight scales that assess pain, physical functioning, general health, fatigue/vitality, mental health, social functioning, and role limitations due to either physical or emotional problems. Two summary scores, the physical component summary (PCS) and mental component summary (MCS) can also be computed. The SF-36 therefore assesses a broader range of health concerns than RA-specific measures, and because it is a generic measure, comparisons are possible across diseases. The SF-36 is the most commonly used patient-reported measure worldwide, and has had extensive testing of reliability and validity (10–12). Interpretation of SF-36 scores has been aided by development of population-based normative values, and by rescaling methods that allow patients’ scores to be directly compared to general population means. However, interpretation of changes in SF-36 scores is not intuitive, and requires knowledge of the degree of change that corresponds to improvement (or deterioration) in health that is recognized as important or meaningful to patients (13). Scores may improve significantly with treatment, but the magnitude of the change may not be clinically important. Determination of thresholds for clinically important improvement, and reporting the proportion of patients who had changes exceeding this threshold, were highlighted by the U.S. Food and Drug Administration as important considerations in using patient-reported outcomes in clinical trials (14). Despite its wide use, estimates of minimal clinically important improvement (MCII) for SF-36 scales are not well-established (15). Thresholds of 3, 5, or 10 points on the individual scales, and 2.5, 3, or 5 points on the physical and mental component summaries, have been cited as MCIIs in studies of RA (5–8,16). A uniform threshold has commonly been applied to all scales, even though the interpretation of changes in individual scales may differ. The single study that served as the source of these estimates in RA used the original version of the SF-36, which has a one week recall period rather than the 4 week recall version more commonly used in RA clinical trials, and examined normalized scores for the PCS and MCS but not for the individual scales (17). In this study, MCIIs varied from 2.4 to 16.4 for individual scale scores, and were 4.4 and 3.1 for the PCS and MCS, respectively. The investigators noted that a single best estimate of MCII could not be established, and that estimates for the scales related to mental health had limited validity because they did not vary much with RA severity (17). They did not use these estimates in a subsequent study (18). Complicating matters further, it is difficult to generalize estimates of MCIIs across diseases and treatments, because different diseases impact different aspects of health, and different aspects of health are responsive to different treatments (19). In this study, we sought to estimate MCIIs for the SF-36 for patients with active RA who are receiving treatment with disease-modifying medications, biologics, or prednisone, so that these may be applied in clinical trials that use the SF-36. We examined population-normalized scores for the SF-36-version 2 with 4 week recall, as this is the version most commonly used in clinical trials currently.