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Treatment of Rheumatoid Arthritis Patients with Abatacept and Methotrexate Significantly Improved Health-Related Quality of Life

PAUL EMERY, MARK KOSINSKI, TRACY LI, MARIE MARTIN, G. RHYS WILLIAMS, JEAN-CLAUDE BECKER, BONNIE BLAISDELL, JOHN E. WARE Jr, CHARLES BIRBARA, and ANTHONY S. RUSSELL

ABSTRACT.

Objective.
This study examined the effect of abatacept, a costimulation modulator, on the health-related quality of life (HRQOL) of patients with rheumatoid arthritis (RA).

Methods. Three hundred thirty-nine patients with RA on a background of methotrexate (MTX), who participated in a multicenter, double-blind, placebo-controlled trial, were randomized to abatacept 2 mg/kg, abatacept 10 mg/kg, or placebo. HRQOL was assessed at pretreatment, and at 3, 6, and 12 months posttreatment using the SF-36 Health Survey (SF-36). Changes in SF-36 scores from baseline to 12 months were compared across treatment and placebo groups to examine HRQOL benefits of abatacept. A link between American College of Rheumatology improvement and changes in SF-36 scores was established to demonstrate the association between HRQOL outcomes and clinical response.

Results. After 12 months of treatment, patients randomized to abatacept 10 mg/kg showed significantly better HRQOL outcomes overall versus patients randomized to placebo (MANOVA F = 4.71, p < 0.001) or to abatacept 2 mg/kg (MANOVA F = 1.97, p = 0.05). Differences in SF-36 change scores between abatacept 10 mg/kg and placebo groups reached statistical significance on all 8 domain scales, the 2 summary measures, and the SF-36 utility index (SF-6D). Differences in SF-36 change scores between abatacept 10 mg/kg and abatacept 2 mg/kg reached statistical significance on 5 of the 8 domain scales, the physical summary measure, and the SF-6D. Improvement in HRQOL was highly related to clinical response.

Conclusion. Abatacept 10 mg/kg plus MTX demonstrated a stronger HRQOL response than placebo plus MTX. The abatacept 2 mg/kg arm showed a very weak and transient response. (First Release Mar 1, 2006; J Rheumatol 2006; 33:681-9)

Key Indexing Terms:

HEALTH-RELATED QUALITY OF LIFE
RHEUMATOID ARTHRITIS
SF-36

HEALTH OUTCOMES
HEALTH ASSESSMENT
ABATACEPT


From the Rheumatology and Rehabilitation Research Unit, University of Leeds, Leeds, UK; QualityMetric Incorporated, Lincoln, Rhode Island, USA; Bristol-Myers Squibb, Princeton, New Jersey, USA; Health Assessment Lab, Boston, Massachusetts, USA; Tufts University School of Medicine, Boston, MA, USA; University of Massachusetts, Worcester, MA, USA; and Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Supported by a grant from Bristol-Myers Squibb.

P. Emery, MA, MD, FRCP, Professor, Rheumatology and Rehabilitation Research Unit, University of Leeds; M. Kosinski, MA, Senior Scientist, QualityMetric Inc.; T. Li, PhD, Associate Director, Immunology, Bristol-Myers Squibb; M. Martin, PhD, Director, Consulting Services, QualityMetric Inc.; G.R. Williams, ScD, Director, Outcomes Research; J-C. Becker, MD, Clinical Director, Bristol-Myers Squibb; B. Blaisdell, MA, Outcomes Research, QualityMetric Inc.; J.E. Ware Jr, PhD, CEO, Chief Science Officer, Chairman of the Board, QualityMetric Inc., Health Assessment Lab, Tufts University School of Medicine; C. Birbara, MD, Rheumatologist, University of Massachusetts; A.S. Russell, MD, Professor of Rheumatology, Department of Medicine, University of Alberta.

Address reprint requests to Prof. P. Emery, Department of Rheumatology and Rehabilitation, University of Leeds, 36 Clarendon Road, Leeds LS2 9N2, UK. E-mail: p.emery@leeds.ac.uk

Accepted for publication November 25, 2005.


A chronic and progressive disease such as rheumatoid arthritis (RA), characterized by joint pain, stiffness, and joint deformity as well as by varying degrees of physical impairment, fatigue, fever, and reactive depression1, places a tremendous burden on the patient, their families, the healthcare system, and society at large. For patients, early RA (average disease duration < 18 mo) places a substantial burden on their physical functioning and emotional well-being that is comparable to diabetes or congestive heart failure2. As the disease progresses, patients experience increasing functional impairment, which may lead to work disability and lost wages. For the families of patients with RA, the progression of RA is likely to place a significant burden, particularly to the extent that the patient is physically impaired, in pain, emotionally distressed, and unable to work.

For the healthcare system that attends to patients with RA, the costs of office visits, medications, surgeries, hospitalizations, occupational therapy, and other social services amount to billions of dollars per year, with direct medical care costs in 2001 for an RA patient estimated at US $9519 per year3. For society at large, the functional impairment that characterizes later stages of RA often results in work disability and lost opportunity to gain from the RA patient's contribution to the workforce. Estimates place the amount of lost wages due to RA at US $2.5 billion per year4.

Pharmacologic interventions that improve physical function so that patients are able to work longer and perform daily activities have the potential to improve patients' quality of life as well as reduce the burden that RA places on society as a whole.

Abatacept, a novel selective T cell costimulation modulator, has been shown to be safe, well tolerated, and able to produce a significant dose-dependent reduction in disease activity for RA patients who experienced inadequate responses to disease modifying antirheumatic drugs (DMARD)5,6. Recent results from a randomized, controlled study showed that abatacept significantly improved the signs and symptoms of disease in patients who had active RA despite ongoing methotrexate (MTX) treatment5. In this study, we examined the effect of abatacept therapy (10 mg/kg) in combination with MTX on a broad range of health-related quality of life (HRQOL) domains in patients who had inadequate response to MTX treatment.

MATERIALS AND METHODS

Study population. Three hundred thirty-nine patients with RA participated in a multicenter, multinational, double-blind, randomized, placebo-controlled trial comparing the efficacy of MTX plus placebo (n = 119), abatacept 2 mg/kg (n = 105), or abatacept 10 mg/kg (n = 115). Abatacept was administered by intravenous infusions at baseline, every 2 weeks for the first month, and monthly thereafter. To participate, patients were required to meet several criteria: (1) the American Rheumatism Association criteria for RA while meeting functional class I, II, or III according to the revised criteria of the American College of Rheumatology (ACR)7,8; (2) have ≥ 10 swollen, ≥ 12 tender joints, and C-reactive protein level ≥ 1 mg/dl signifying active disease; (3) have been treated with MTX for at least 6 months and on a stable dose for 28 days prior to enrollment; and (4) be washed-out of all DMARD other than MTX for at least 28 days before treatment. Provided that the prescribed dose remained stable for the first 6 months of the study, participants were permitted to continue on low-dose corticosteroids (≤ 10 mg/day) and nonsteroidal antiinflammatory drugs. This study was carried out in accordance with the ethical principles of the Declaration of Helsinki.

General health status measures. The Medical Outcomes Study Short Form-36 Health Survey (SF-36), a well-validated measure of general health status9-11, was self-administered at baseline (pretreatment) and 3, 6, and 12 months posttreatment to measure HRQOL. The SF-36 measures 8 health dimensions [physical functioning (PF), role limitations due to physical health (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF), role limitations due to emotional health (RE), mental health (MH)], which are aggregated to produce physical (PCS) and mental (MCS) summary measures. All SF-36 scales and both summary measures were scored using norm-based methods that standardize the scores to a mean of 50 and a standard deviation of 10 in the general US population, with higher scores indicative of better health12,13. A health utility index (SF-6D) was also derived from 11 items of the SF-3614. The SF-6D is a preference-based measure of health that places the observable states of health and functioning on a preference continuum with a value of 0 for death through to 1 for completely well or optimal health. These values are known as health state utilities, which are primarily used to adjust life-years saved by quality for use in economic evaluations and decision models.

Effect of treatment on HRQOL. HRQOL outcomes were evaluated in 2 ways. First, changes in SF-36 scale and summary measure scores and the SF-6D from baseline to 12 months were evaluated and compared between placebo and treatment groups. To account for multiple comparisons, multivariate analysis of variance (MANOVA) was conducted to test for overall differences in change scores across all 8 SF-36 scales between placebo and abatacept groups. MANOVA analyses were followed with independent pairwise t tests of statistically significant differences in mean change scores on each SF-36 scale, summary measure, and the SF-6D between placebo and abatacept groups. For these analyses, the last observation was carried forward for those patients who dropped out early from the study.

Since presenting mean changes in scores can mask the underlying variability in HRQOL outcomes, the second way that HRQOL outcomes were evaluated was to determine the percentage of patients in each group whose 12 month score on each SF-36 scale was "better," "the same," or "worse" than the baseline score. Given that standards for the minimal clinically important difference for the SF-36 have not been well established, the standard error of measurement (SEM) was calculated for each SF-36 scale and summary measure, which provided a boundary of measurement error that could be used to categorize changes in individual patient scores as better, the same, or worse. The SEM is a theoretically fixed characteristic of a measurement instrument incorporating a sample's variability (σx) and reliability (rxx), simply defined as σx(1 – rxx) 15, and has been used to define the minimal clinically important difference (MCID) of several HRQOL measures16,17. We used variance and reliability estimates from a representative sample of the general US population for the SF-3612, since the lack of variance in scores observed at baseline in the trial population could effectively reduce the size of the estimated SEM18. Two SEM, which corresponds to the 95% confidence interval around an individual patient score, was used to categorize patients as better, the same, or worse. In other words, there was only a one in 20 chance that we could incorrectly classify a patient as better, the same, or worse given measurement error. For the SF-6D, the classification of patients into better, same, or worse groups was based on the MCID of 0.041 points established in a previous study19. Chi-square tests were conducted to determine if significant differences existed in the proportion of RA patients whose 12-month HRQOL was "better," "the same," or "worse" than baseline between placebo and treatment groups.

Content-based interpretation of results. In an effort to provide meaningful interpretation of the differences in HRQOL outcomes observed between placebo and treatment groups we examined the responses to the following questionnaire items from each of the 9 SF-36 scales: (1) walking one block (PF); (2) cut down time spent at work because of physical health (RP); (3) pain interference (BP); (4) general health rating (GH); (5) feeling tired or worn out (VT); (6) health interferes with social activities; (7) doing work less carefully because of emotional problems (RE); and (8) feeling downhearted and blue. These items were selected because they provide the most salient interpretation of score changes on each of their respective scales. For this analysis we derived a dichotomous variable for each of the 8 SF-36 items. For example, the PF item on walking one block asks the patient to indicate the extent of limitations in walking one block. The response options for this item include "yes, limited a lot," "yes, limited a little," and "no, not limited at all." We examined the percentage of patients who indicated "any" limitations (yes, limited a lot or yes, limited a little) in walking a block at baseline and at 12 months as a way of understanding the meaning of the difference in change scores on the SF-36 physical functioning scale between the placebo and treatment groups. A similar strategy was used for evaluating the other 7 items selected for this analysis.

Linking HRQOL outcomes to clinical response. Another measure taken to improve the interpretation of HRQOL outcomes observed in this study was to link changes in SF-36 scale and summary measure scores and the SF-6D from baseline to 12 months to ACR improvement. All trial participants were placed into 4 mutually exclusive groups of ACR improvement: (1) ACR improvement < 20%; (2) ACR improvement from 20% to 49%; (3) ACR improvement from 50% to 69%; and (4) ACR improvement of 70% or greater. Mean changes in SF-36 scale and summary measure scores and SF-6D were compared across these 4 groups using ANOVA methods.

RESULTS

Patient characteristics. Baseline demographics, disease characteristics, and HRQOL summary scores of patients by treatment group and sample disposition are presented in Table 1. Demographically, the 2 groups were very similar. The disease characteristics of both groups of patients were mixed, where in some cases the patients who discontinued showed more active disease and in other cases the patients who continued showed more active disease. Lastly, baseline HRQOL was similar in terms of physical health status. However, differences were observed in 2 of the 3 groups (placebo and abatacept 10 mg), where patients who discontinued showed worse mental health status.

Table 1. Patient characteristics by sample disposition.

Baseline demographics, disease characteristics, and HRQOL scores of all 339 patients enrolled in the study are presented in Table 2. Patients had a mean age of 55 years (range 17 to 83), 68% were female, 87% were Caucasian, 82% were rheumatoid factor-positive, and the mean duration of RA was 9–10 years. Baseline mean number of tender and swollen joints was similar across the treatment groups. Despite longterm treatment with MTX, patients had a high degree of disease activity at baseline (mean tender joint count ranged from 28.2 to 30.8 and mean swollen joint count ranged from 20.2 to 21.8). As expected, given the high degree of disease activity observed at baseline, HRQOL scores at baseline were well below general population norms12, particularly those HRQOL scales measuring physical health status (SF-36 physical functioning, role physical, and bodily pain scales). No significant differences in baseline patient characteristics or HRQOL scores were detected across treatment groups.

Table 2. Patient characteristics of analytic sample†.

Effect of treatment on HRQOL ( Table 3). Overall, the changes in SF-36 scales and summary measure scores differed between abatacept 10 mg/kg and placebo group (MANOVA F = 4.7, p < 0.0001). Mean improvements from baseline ranged from 5.3 to 9.3 points across the 8 SF-36 scales, and were 8.0 and 5.7 points for the physical and mental summary measures, respectively. Results of independent t tests showed that the differences in mean change scores were statistically significant between abatacept 10 mg/kg and placebo groups on all 8 scales and both summary measures, with outcomes favoring the abatacept 10 mg/kg group. Differences in mean score changes on the SF-36 scale and summary measures between abatacept 10 mg/kg and placebo groups ranged from 2.5 to 5.8 points, with the largest differences observed on the SF-36 bodily pain (5.8 points), vitality (5.8 points), physical summary (5.4 points), and physical functioning (5.1 points) scales. A statistically significant difference in mean score change on the SF-6D (0.05 points) was also observed between abatacept 10 mg/kg and placebo groups, favoring the abatacept 10 mg/kg group.

Table 3. Mean changes in HRQOL scores from baseline to 12 months.

Significant differences in HRQOL outcomes were also observed between the abatacept 10 mg/kg and 2 mg/kg groups (MANOVA F = 1.97, p < 0.05). Results of independent t tests conducted with each scale showed that mean changes were higher (better outcome) among patients in the abatacept 10 mg/kg group on 5 of the 8 SF-36 domains scales (PF, RP, BP, VT, and SF), the physical (PCS) summary measure, and the SF-6D compared to patients in the abatacept 2 mg/kg group. Differences in mean score changes between the 2 abatacept groups on these SF-36 scales ranged from 2.5 to 4.4 points, with the largest difference observed on the vitality scale (4.4 points). The difference in mean SF-6D score change between the 2 groups was 0.05 points.

Overall, differences between the abatacept 2 mg/kg and placebo groups in HRQOL outcomes did not differ significantly (MANOVA F = 1.42, p = 0.19), although results of independent t tests conducted for each SF-36 scale and summary measure showed a significant difference in mean score change between the placebo and abatacept 2 mg/kg group on the physical functioning (2.6 points) and bodily pain (3.0 points) scales and the physical summary measure (2.6 points), all favoring the abatacept 2 mg/kg group.

Analysis of change scores categorized as better, the same, or worse confirmed the results of the average patient in each treatment group, specifically that a greater proportion of patients in each group had better HRQOL outcomes than worse HRQOL outcomes (Table 4 ). Across all SF-36 scales and summary measures and the SF-6D a greater proportion of patients in the abatacept 10 mg/kg group improved more than would be expected due to measurement error versus patients in either the placebo group or abatacept 2 mg/kg group. Differences in the proportion of patients who got better, stayed the same, or got worse reached statistical significance on 10 of 11 comparisons between the abatacept 10 mg/kg and placebo groups, 2 of 11 comparisons between the abatacept 2 mg/kg and placebo groups, and 7 of 11 comparisons between the abatacept 10 mg/kg and abatacept 2 mg/kg groups. The categorical analyses call attention to the substantial variation of outcomes observed in all 3 groups of patients. For example, a sizeable proportion of patients in each group showed changes in scores that were either within measurement error (same) or indicative of worse HRQOL outcomes.

Table 4. Categories of change in HRQOL scores from baseline to 12 months by treatment group.

Content-based interpretation of results. The content of selected SF-36 questionnaire items was examined as a basis for interpreting the differences in the HRQOL outcomes observed between treatment groups. In Table 5, results obtained at baseline for each item are contrasted to results obtained at 12 months and can be used to help interpret the changes in scores on each domain scale in Table 3. For example, patients in the abatacept 10 mg/kg group improved 7.2 points on the SF-36 physical functioning scale. Underlying that improvement was a substantial decrease in the percentage of patients reporting any limitations in walking one block from 72% at baseline to 42% at 12 months posttreatment, more than a 40% reduction in limitations in walking a block. Comparatively, there was virtually no change in the percentage of placebo patients reporting limitations in walking a block from baseline (61%) to 12 months (62%). Similarly, as Table 5 shows, underlying the significant improvement in SF-36 scale scores for the abatacept 10 mg/kg group was a substantial decrease in the percentage of patients who reported: (1) having to cut down on time at work because of health (70% to 32%); (2) pain interfered with work quite a bit or extremely (51% to 11%); (3) fair or poor health in general (64% to 26%); (4) felt tired or worn out all or most of the time (38% to 14%); (5) health interfered with social activities quite a lot or extremely (32% to 9%); (6) working less carefully than usual (42% to 23%); and (7) feeling downhearted and blue all or most of the time (18% to 4%).

Table 5. Percentage of patients reporting limitations in functional status and well-being: content-based interpretations of changes in SF-36 scale scores.

Linking HRQOL outcomes to clinical response. Table 6 presents mean changes in SF-36 scale and summary measure scores and the SF-6D across 4 categories of ACR improvement. As shown, the magnitude of the mean score improvement on each SF-36 scale, summary measure, and the SF-6D increased incrementally with increasing levels of ACR improvement, and overall the differences in mean score improvement across ACR improvement were statistically significant. The largest changes in SF-36 scale and summary measure scores and the SF-6D were observed among the group of patients who reached or exceeded 70% ACR improvement. With few exceptions these patients improved by more than 10 points on average (range 8.6 to 15.4 points) on each SF-36 scale and summary measure and by 0.17 points on the SF-6D. The next largest change on each SF-36 scale and summary measure and the SF-6D was observed among patients whose ACR improvement ranged from 50% to 69%. For these patients, score improvement ranged from 5.4 to 10.9 points across SF-36 scales and summary measures and was 0.13 points on the SF-6D. Changes in SF-36 scale and summary measure scores ranged from 2.8 to 7.6 points and the SF-6D improved by 0.09 points among patients whose ACR improvement ranged from 20% to 49%. The smallest changes in scores were observed among patients who did not reach 20% ACR improvement. Changes in scores ranged from 1.4 to 3.1 points across SF-36 scales and summary measures, and was 0.03 on the SF-6D among these patients.

Table 6. Mean changes in SF-36 scale and summary measure scores across categories of ACR improvement.

DISCUSSION

We sought to evaluate the effect of abatacept, a costimulator, on health-related quality of life in patients with rheumatoid arthritis. Patients enrolled into this study were in a highly active disease state at baseline (pretreatment), which was cause for significant HRQOL burden at the outset of this study. HRQOL scores, as measured by the SF-36, at baseline were well below general US population norms and rivaled norms of other serious medical conditions such as congestive heart failure and advanced type I diabetes12. As expected with RA, the most pronounced HRQOL burden was detected with SF-36 scales measuring physical health status (physical functioning, role physical, and bodily pain scales). On average, scores on these physical health scales were 1.5 to 2.0 standard deviation units below general population norms, which are large effect size differences, and well below the average scores of persons older than 85 years of age12. Interestingly, baseline SF-36 scores of patients in this study also showed substantial emotional burden associated with a highly active disease state. The average baseline scores on the SF-36 mental health scale and mental summary measure were at the cutpoint score (< 42) for a first-stage screen for depression12. Lastly, at baseline, average SF-6D scores ranged from 0.55 to 0.57 across the 3 treatment groups, indicating that patients enjoyed roughly one-half of "optimal" health.

Patients treated with abatacept 10 mg/kg showed statistically significant improvement from baseline to 12 months across all 8 SF-36 domain scales, both physical and mental summary measures, and the SF-36 utility index in the moderate to large effect size range20. In results not reported in this article, significant improvement in SF-36 scores observed for the abatacept 10 mg/kg group was also evident at 3 months, with the magnitude of change in SF-36 scores close to the amount of change observed at 6 and 12 months. The implication of the 3 and 6 month findings is that such rapid response perceived by the patient can have a positive impact on treatment compliance, since patients perceive the benefits of treatment early on.

The score changes from baseline to 12 months observed on the SF-36 for abatacept 10 mg/kg patients were equivalent to or larger than those observed in previous studies involving disease modifying treatments6,21-31. Using variance estimates from the general population, mean changes in all SF-36 scale and summary measure scales for the abatacept 10 mg/kg group exceeded one-half a standard deviation, which could be considered clinically important32. Further, the HRQOL benefits of abatacept 10 mg/kg as measured by the SF-36 have been linked to a variety of clinical, social, and economic benefits12,13. Relative to placebo, moderate effect size differences in outcomes were observed on the SF-36 physical functioning, bodily pain, and vitality scales and the physical summary measure for the abatacept 10 mg/kg group. Differences in outcomes between placebo and abatacept 10 mg/kg on these scales exceeded 5 points, which was more than one-half a standard deviation difference in outcomes. The differences in outcomes between abatacept 10 mg/kg and placebo on the remaining SF-36 scales and summary measures were in the small effect size range.

A feature of this study not found in most HRQOL treatment studies was the analysis of the underlying variability of HRQOL outcomes. Most HRQOL treatment studies present results in terms of mean changes in HRQOL scores, which can mask the differences in HRQOL outcomes observed across individual patients. Recognizing that not all patients would experience the average HRQOL outcome, each patient was categorized as better, the same, or worse depending upon the magnitude and direction of the change in score on each HRQOL scale from baseline to 12 months. The magnitude of change necessary to be categorized as better or worse was based on 2 standard errors of measurement (SEM), or the 95% confidence interval around an individual patient score. For all HRQOL scales, 2 SEM exceeded one-half a standard deviation, which is considered clinically important25. As the results of this analysis showed, a greater proportion of patients in each group showed meaningful improvement across all SF-36 scales and summaries and the SF-6D compared to meaningful decline. The ratio of patients who improved versus declined was largest in the abatacept 10 mg/kg group. With the exception of the SF-36 role emotional scale, the ratio of patients who improved versus declined was at least 6 to 1 in the abatacept 10 mg/kg group and as high as 25 to 1 on the SF-36 bodily pain and general health scales.

Our study featured the SF-36 utility index, the SF-6D. The primary use of utility measures like the SF-6D is to adjust life-years saved by quality for use in economic evaluations and decision models. Preference-based health state scores do not have natural units. Since health is a function of both length and quality of life, the quality-adjusted life-year (QALY) has been developed to combine the values of these 2 attributes of health into a single number. In this study we observed clinically meaningful improvement on the SF-6D in all 3 treatment groups as defined by the developer of the SF-6D and colleagues33. The improvement in SF-6D scores among patients in the abatacept 10 mg/kg group was about twice that of the other 2 groups, or 0.05 points, which can be interpreted as a difference of 5 more patients in perfect health for one year compared to placebo or abatacept 2 mg/kg groups.

It is noteworthy that a dose-related response on HRQOL was observed in this study. The abatacept 10 mg/kg group induced substantially greater improvements from baseline across all HRQOL measures, compared to the abatacept 2 mg/kg group or placebo. This finding, combined with prior reports on improvements on signs and symptoms at 6 and 12 months of the study5,6, emphasized that abatacept 10 mg/kg is a viable treatment option for patients with inadequate response to MTX. The improvement on HRQOL from abatacept 10 mg/kg was both statistically significant and clinically meaningful. Results from content-based analysis on specific SF-36 questionnaire items further demonstrated the real-life meaning of the improvements to the patients on their ability to walk, participate in work or social activities, and maintain a healthy mental status.

This study provided examples of how HRQOL measures can be used to understand the burden of disease and the potential benefits of treatment. One interpretation strategy used to translate the HRQOL scores into more salient terms was the analysis of responses to individual questions of the SF-36. This strategy has been used to interpret disease burden and treatment outcomes for the SF-36 in previous studies34,35. In our study, patients scored well below general population norms on each SF-36 scale, as expected. However, the interpretation of that burden became more salient by analyzing the content of specific items from each scale. For example, the analysis of selected SF-36 items demonstrated that more than 60% of the patients in each group reported limitations in walking one block or having to cut down time spent at work because of physical health problems. Similarly, the analysis of the content of specific items improved our interpretation of the differences in outcomes between treatment groups. As was observed, there was a 40% reduction in the percentage of patients who reported limitations in walking a block (72% to 42%) and a 50% reduction in the percentage of patients who reported having to cut down the time spent at work because of physical health (70% to 32%) in the abatacept 10 mg/kg group. By comparison, there was no reduction in the percentage of placebo patients who reported limitations in walking a block, and a 33% reduction in placebo patients who reported having to cut down time spent at work because of physical health.

Results of the analysis of changes in HRQOL scores by clinical response as measured by the ACR improvement criteria showed that patients who experienced the greatest clinical response also showed the greatest score improvement on all SF-36 scales, summary measures, and the SF-6D. The magnitude of mean score improvement on each scale increased incrementally with increasing levels of ACR improvement. However, the results showed that not all HRQOL concepts were equally responsive to ACR improvement. As expected, changes in scores on SF-36 scales measuring physical health status (physical summary, bodily pain, physical functioning, general health, and role physical scales) were more strongly related to differences in ACR improvement than score changes in SF-36 scales measuring mental health status (mental summary, mental health, and role emotional scales), as indicated by the magnitude of the F statistics. A strong relationship was also evident between ACR improvement and the SF-6D. The results of these analyses can be useful in determining the clinical meaningfulness of HRQOL outcomes. In particular, differences in mean score changes between the group of patients showing little or no improvement in disease activity (ACR < 20%) and the group of patients showing a minimum to moderate change in disease activity (ACR 20%–49%) could be considered minimal clinically important changes in outcomes on each SF-36 scale. In this regard the HRQOL outcomes observed for the abatacept 10 mg/kg group would be considered clinically meaningful.

In conclusion, the disease burden that active RA places on patients' physical and emotional HRQOL is substantial. Treatment of RA by abatacept plus MTX improves HRQOL across a wide range of measured domains. Patient-reported HRQOL improvements were greatest for those who received abatacept 10 mg/kg. Future investigation should examine the extent to which the HRQOL improvement at 12 months among RA patients receiving abatacept therapy is sustained through time.

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