Abstract

Objective. Rheumatoid arthritis (RA) patients who have inadequate response to anti-tumour necrosis factor (TNF) therapy currently have treatment options that are limited and less than optimal in their risk-to-benefit ratio. Abatacept provides a new generation of RA medications that has previously been demonstrated to have positive clinical outcomes with this population. The current study sought to demonstrate the efficacy of abatacept on quality of life (QoL) for RA patients with inadequate response to anti-TNF therapy.

Methods. Patients were entered into a double-blind, placebo-controlled, multicentre randomized clinical trial, with 258 patients randomized to abatacept + disease-modifying anti-rheumatic drugs (DMARDs) and 133 patients randomized to placebo + DMARDS. The QoL was measured with the Short Form Health Survey (SF-36), Health Assessment Questionnaire (HAQ) and fatigue visual analogue scale, and was analysed with basic (ANOVA, chi-square) and multigroup growth curve techniques to assess differential change over time.

Results. Treatment group QoL improved significantly more than placebo on the HAQ and fatigue indices, as well as seven of the eight SF-36 scales and SF-36 physical and mental summary scores. Improvement rate was faster for abatacept than for placebo on the QoL measures, and the improvements from abatacept related to normal levels of QoL on many domains.

Conclusion. Clinically relevant benefits of abatacept over placebo are discussed regarding improving QoL. Importantly, the larger rate of change for abatacept over placebo provides clinicians with a medication that can lead to meaningful changes in a patient's life within a few weeks, even when the patient previously failed anti-TNF therapy.

Rheumatoid arthritis (RA) is a chronic, systemic and inflammatory disorder of unknown aetiology that primarily involves bodily joints. It may be remitting, but if uncontrolled, can lead to joint deformity by cartilage destruction and bone erosion, tendon involvement, but also to more generalized issues including fatigue, muscle atrophy and osteoporosis. This symmetrical disease often progresses from peripheral to more proximal joints, frequently resulting in significant functional disability [ 1 ]. To date, patient outcomes have not been explained fully by clinical joint evaluation, laboratory, or radiographic measures.

RA has been linked to significant deficits in patients’ daily functioning and quality of life (QoL), with frequent RA symptoms of joint pain and stiffness leading to marked degradation in physical functioning and mental health compared with the general population [ 2 ]. Diminished functionality and QoL experienced by RA patients leads to substantial financial burden for both the patient and the health care system: an estimated 50% of RA patients are unable to function in their jobs within 10 yrs of disease onset [ 2 ]; the national cost in the US of approximately 14 billion dollars [ 3 ]; direct medical costs of three times more than the costs of treating non-RA patients in age- and sex-matched populations [ 4 ], with direct medical care costs in 2001 estimated at $9519 per patient [ 5 ].

Current treatment for RA includes DMARDs, such as methotrexate (MTX) and newly developed biological DMARDS consisting of mainly anti-TNF therapies, including etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira). Anti-TNF therapies have demonstrated efficacy in MTX failure, however, a proportion of patients does not benefit from these treatments either due to inadequate response or adverse reactions [ 6–10 ]. There are currently limited treatment options with acceptable clinical benefits, safety and tolerability profiles for patients with inadequate response to anti-TNF-α therapy. Along with RA clinical symptoms, patients who have failed anti-TNF therapy suffer from reduced physical functioning to carry out day-to-day activities, and in general, a reduced QoL. Even when the anti-TNF treatment provides relief of RA symptoms, these treatments have insufficient mental health QoL improvement [ 11 ]. General population scores on the Short Form Health Survey (SF-36) are 50, RA patients average a score of 45, but participants in the current study began with QoL scores in the 20s and 30s; one to two standard deviations below general US population norms [ 12 ]. Previous work has found that a difference of 23 points on the physical functioning scale reflects the impact of a complicated chronic medical condition (such as hypertension, diabetes, or congestive heart failure) on everyday physical functioning. Additionally, a difference of 27 points on the mental health scale reflects the impact of serious depression symptoms [ 13 ].

Abatacept is the first in a new class of agents for the treatment of RA that selectively modulates a specific costimulatory signal required for full T-cell activation [ 14 , 15 ]. The efficacy of abatacept has been examined previously in Phase II [ 15–17 ] and Phase III [ 18 , 19 ] clinical trials. In patients with active RA and an inadequate response to MTX, abatacept in combination with MTX led to significant improvements in the signs and symptoms of RA, physical function and QoL over 12 months [ 16 ].

The effect of abatacept in anti-TNF inadequate responders was examined in a phase III trial, Abatacept Trial in Treatment of Anti-TNF I n adequate responders (ATTAIN; 18). Given the positive initial findings [ 15–18 ] of abatacept's impact on QoL, the current study was undertaken to examine in more detail the impact of abatacept on patients with inadequate response to anti-TNF therapy. As patients have an increased likelihood of maintaining their medication regimen when they perceive a positive impact [ 20 ], such as with their daily functioning, the current research examines differences in QoL in a variety of manners to determine if, and when, significant differences occur between abatacept treatment and placebo.

Methods

Study population

Inclusion criteria for the current study necessitated that eligible patients were at least 18 yrs of age, had RA for at least 1 yr and met the ACR criteria for RA [ 21 ]. Furthermore, patients must have been treated with the anti-TNF-α therapy of etanercept, infliximab, or both, at the approved dose for at least 3 months and ultimately had inadequate treatment efficacy. It should be noted that this study was initiated prior to broad usage of adalimumab. Additionally, patients were included in the current study who experienced safety problems with anti-TNF-α therapy, but discontinued primarily due to a lack of efficacy.

Although, participants currently receiving anti-TNF-α therapy at the time of enrollment ( current users) and those who had previously received anti-TNF-α therapy ( prior users) were admitted into the study, all users were required to washout etanercept or infliximab for at least 30 or 60 days, respectively, prior to randomization. At randomization, participants were admitted only if they had ≥10 swollen and ≥12 tender joints and CRP levels of at least 1 mg/dl (upper limit of normal range: 0.5 mg/dl). Oral corticosteroid use (stable dose equivalent to prednisolone ≤10 mg/day for at least 28 days) was allowed.

RA patients not treated with oral DMARDs or anakinra for at least 3 months prior to the study, not receiving a stable dose for at least 28 days, or both, were excluded. Use of mycophenolate mofetil, cyclosporine, other calcineurin inhibitors and d -penicillamine was not permitted. Women who were pregnant or nursing were excluded. Changes in the dose of background DMARDs were not permitted except for toxicity.

A total of 391 participants were randomized to the abatacept and placebo groups in a 2:1 ratio. Of those who completed the study, fewer abatacept-treated participants than placebo-treated participants discontinued therapy (13.6 and 25.6%, respectively). Lack of efficacy was the main reason for discontinuation in both groups (5.4 and 20.3%, respectively). The 2:1 sampling ratio was used to provide sufficient power for examination of specific clinical and safety issues of abatacept (reported elsewhere). Although using a sample size that is not a 1:1 ratio decreases the maximum power of a study, the 2:1 ratio was properly powered for the clinical outcomes. It should be noted that the sample size determinants were based on the clinical markers only, and were not based on the power of QoL outcomes.

The study was conducted as a 6-month, multicentre, randomized, double-blind, placebo-controlled study with the goal of assessing the efficacy of abatacept in RA participants who have had previous inadequate response to anti-TNF-α therapy while continuing to receive background DMARDs. Patients received a fixed dose of abatacept approximating 10 mg/kg or placebo; patients weighing <60, 60–100 and >100 kg received abatacept 500, 750 and 1000 mg, respectively. Study medication was administered by 30 min intravenous infusion on days 1, 15, 29 and every 28 days thereafter. During the study, 93.8 vs 94.0% of patients in the abatacept vs placebo groups received oral DMARDs; 2.7 vs 2.3% received anakinra. Corticosteroids and NSAIDs were used by approximately 70% of the patients in each group.

This study was approved by institutional review boards and independent ethics committees, and the study was carried out in accordance with the ethical principles of the Declaration of Helsinki. All participants provided written informed consent prior to randomization.

Patient characteristics

Tests of baseline demographic characteristics were analysed to determine the similarity between treatment and placebo groups prior to hypothesis testing. Demographic similarity was assessed with either a Pearson's χ 2 test (for categorical data) or an analysis of variance (ANOVA; for continuous data). If data were found to be different between the groups, appropriate controls of baseline differences would be included during the hypothesis tests.

Demographic information and baseline RA and QoL measures of the study participants are provided in Table 1 . The treatment group had a mean age of 53.4 yrs ( s . d . = 12.4 yrs), had an average disease duration of 12.2 yrs ( s . d . = 8.5 yrs), was 77.1% female and 96.1% Caucasian; placebo group was similarly comprised with a mean age of 52.7 yrs ( s . d . = 11.3 yrs), had an average disease duration of 11.4 yrs ( s . d . = 8.9 yrs), was 79.7% female and 93.2% Caucasian. No significant differences were found between the treatment and placebo groups on age, gender, race and disease duration. The treatment groups were also comparable on the QoL outcomes, swollen and tender joint counts, as well as disease activity and pain scores.

T able 1.

Baseline patient demographic, disease characteristic and outcome variables

Baseline variable  Abatacept + DMARDS ( n = 258)   Placebo + DMARDS ( n = 133)  
Demographic variables 
    Mean age ( s . d .)  53.4 (12.4) 52.7 (11.3) 
    Female (%) 199 (77.1) 106 (79.7) 
    Caucasian (%) 248 (96.1) 124 (93.2) 
    Mean RA duration ( s . d .) in years  12.2 (8.5) 11.4 (8.9) 
    Rheumatoid factor positive (%) 189 (73.3) 97 (72.9) 
    Mean tender joint count ( s . d .)  22.3 (10.2) 22.0 (10.0) 
    Mean swollen joint count ( s . d .)  31.2 (13.0) 32.8 (13.4) 
    Disease activity score ( s . d .) a 6.5 (0.9) 6.5 (0.8) 
    VAS pain ( s . d .)  70.8 (19.8) 69.9 (19.0) 
Outcomes variables 
    Physical functioning ( s . d .)  26.2 (9.0) 26.4 (8.7) 
    Role physical ( s . d .)  30.5 (6.2) 31.8 (6.8) 
    Bodily pain ( s . d .)  30.6 (6.7) 31.1 (6.7) 
    General health ( s . d .)  34.9 (9.2) 34.9 (8.5) 
    Vitality ( s . d .)  35.1 (8.5) 36.7 (9.1) 
    Social functioning ( s . d .)  33.0 (10.8) 33.5 (11.6) 
    Role emotional ( s . d .)  35.7 (13.7) 36.9 (13.9) 
    Mental health ( s . d .)  40.5 (12.7) 42.9 (11.1) 
    Physical component score ( s . d .)  27.6 (7.0) 27.7 (6.4) 
    Mental component score ( s . d .)  41.2 (12.4) 42.9 (11.9) 
    HAQ-DI ( s . d .)  1.8 (0.6) 1.8 (0.6) 
    Fatigue VAS ( s . d .)  73.6 (19.8) 72.5 (19.3) 
Baseline variable  Abatacept + DMARDS ( n = 258)   Placebo + DMARDS ( n = 133)  
Demographic variables 
    Mean age ( s . d .)  53.4 (12.4) 52.7 (11.3) 
    Female (%) 199 (77.1) 106 (79.7) 
    Caucasian (%) 248 (96.1) 124 (93.2) 
    Mean RA duration ( s . d .) in years  12.2 (8.5) 11.4 (8.9) 
    Rheumatoid factor positive (%) 189 (73.3) 97 (72.9) 
    Mean tender joint count ( s . d .)  22.3 (10.2) 22.0 (10.0) 
    Mean swollen joint count ( s . d .)  31.2 (13.0) 32.8 (13.4) 
    Disease activity score ( s . d .) a 6.5 (0.9) 6.5 (0.8) 
    VAS pain ( s . d .)  70.8 (19.8) 69.9 (19.0) 
Outcomes variables 
    Physical functioning ( s . d .)  26.2 (9.0) 26.4 (8.7) 
    Role physical ( s . d .)  30.5 (6.2) 31.8 (6.8) 
    Bodily pain ( s . d .)  30.6 (6.7) 31.1 (6.7) 
    General health ( s . d .)  34.9 (9.2) 34.9 (8.5) 
    Vitality ( s . d .)  35.1 (8.5) 36.7 (9.1) 
    Social functioning ( s . d .)  33.0 (10.8) 33.5 (11.6) 
    Role emotional ( s . d .)  35.7 (13.7) 36.9 (13.9) 
    Mental health ( s . d .)  40.5 (12.7) 42.9 (11.1) 
    Physical component score ( s . d .)  27.6 (7.0) 27.7 (6.4) 
    Mental component score ( s . d .)  41.2 (12.4) 42.9 (11.9) 
    HAQ-DI ( s . d .)  1.8 (0.6) 1.8 (0.6) 
    Fatigue VAS ( s . d .)  73.6 (19.8) 72.5 (19.3) 

a Disease activity score is a summary measure for measuring disease activity in RA, based on the number of tender and swollen joints among 28 selected joints, ESR and the patient's self-evaluation of disease activity.

General health outcomes measures

SF-36 health survey

Health-related QoL (HRQoL) was measured in the current study using the Medical Outcomes Study SF-36. The SF-36 has a well-documented psychometric history as an excellent measure of HRQoL [ 12 , 13 , 22–24 ]. Analyses in the current study used both SF-36 scales and composite summary measures. The eight scales of the SF-36 are: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE) and mental health (MH). The scales are aggregated to comprise the physical component summary (PCS) and the mental component summary (MCS) measures. Standardized scores with a mean of 50 and a s . d . of 10 in the general US population were used for all SF-36 scales and summary measures using norm-based methods; higher scores indicate better HRQoL [ 12 , 23 ]. The SF-36 was self-administered at baseline and 1, 3 and 6 months post-baseline.

Specific outcomes measures

Health assessment questionnaire (HAQ)

The HAQ is a specific outcome measure of functional status or QoL (measuring activities of daily living), intended for use in arthritis [ 25 ]. The HAQ is a 20-item, self-administered questionnaire that examines difficulties with the performance of activities of daily living on a 0–3 scale in eight subscales (dressing and grooming, arising, eating, walking, hygiene, reach, grip and other activities). A Grade 2 of difficulty is assigned for patients using assistive/adaptive devices (such as canes, walker). A disability index (HAQ-DI) is calculated by summing the highest score in each of the eight subscales and dividing the sum by eight, giving a score between 0 and 3 on an ordinal scale (no disability to severe disability). Both observational studies [ 26–28 ] and clinical trials [ 9 , 29 , 30 ] have used the HAQ-DI and found its scores to be a reliable and valid predictor of work disability [ 31 ], morbidity [ 31 , 32 ], and mortality [ 33 ]. The HAQ was self-administered at baseline and at multiple post-baseline assessments (2 weeks and 1, 2, 3, 4, 5 and 6 months).

VAS fatigue scale

Fatigue was assessed on a 100 mm visual analogue scale (VAS) [ 35 ]. Participants were asked to indicate the degree of fatigue they experienced because of their condition over the past week by placing a mark on a horizontal line anchored by no fatigue (0 mm) to extreme fatigue (100 mm).

Disease Activity Score 28 (DAS28)

The disease activity score (DAS) is a combined index of swollen and tender joint counts as well as ESR and the patient's self-evaluation of disease activity, developed in the 1990s to measure the disease activity in patients with RA [ 35 ]. Presented as a number between 0 and 10, DAS28 indicates how active the RA is at this moment (higher scores indicating higher activity). It has been extensively validated for its use in clinical trials [ 35 ].

Data analyses

Differential treatment effectiveness between the treatment and placebo groups was determined in a three-step process. The first analyses examined differential impact of treatment by comparing change scores (6 month-baseline) between the two groups using a standard ANOVA [ 18 ]. For participants who discontinued treatment prior to 6 months, their final value was determined using intent-to-treat standards [ 36 ] and their last observed value(s) was carried forward (LOCF) in case of discontinuation. Change score analyses were used to examine differential QoL treatment benefits in the ATTAIN study by examining scores from the SF-36, HAQ and fatigue score. Furthermore, change scores were examined for all baseline severity scores of the key QoL outcomes between treatment and placebo in the two subsamples for (i) patients with a baseline DAS28 [ 37 ] score below the upper quartile and (ii) patients with a baseline DAS28 score at or above the upper quartile.

The second-level of differential treatment effect was measured using a categorical approach. Whereas analyses with the continuous outcomes portray the overall group trends, categorical analyses have the advantage of measuring the proportion of participants with follow-up scores that differ from baseline and characterizes the underlying variability in outcomes between treatment groups masked by mean changes scores [ 38 ]. A 95% confidence intervals (CIs) about the population baseline mean was utilized to classify patients in the current sample into three categories of change, if follow-up scores (i) did not change from baseline beyond this range ( same group); (ii) improved by more than this range ( better group); or (iii) declined from baseline by more than this range ( worse group). Changes large enough to be labelled ‘better’ or ‘worse’ have been shown to be relevant in terms of a wide range of clinical and social criteria [ 12 , 23 ].

For the third level of analysis of differential treatment effect over time, latent growth curve analysis was employed. Growth curve modelling is a comprehensive tool for analysing repeated measures data [ 39 ]. In analysing change over time, growth modelling estimates are similar to techniques of certain repeated measures ANOVAs in that growth modelling measures change over time for the groups (i.e. fixed effects) and the variations of each person from the group averages (i.e. random effects). Growth modelling is also similar to regression in that regression co-efficients, variances of the time points and correlations among the time points are also measured for each group [ 39 ]. The particular advantages to using growth modelling over standard change score analysis (including repeated measures ANOVA) are: (i) both linear and more typical non-linear rates of change can be measured; (ii) the integration of interpreting group and individuals’ means, variances and correlations in a single analysis gives more power to each analysis; (iii) there is no need to control for baseline differences between groups as such differences are accounted for in the analysis and (iv) differences between groups are easily examined as coming from baseline values, the rate of change over time or the combination of both [ 39–41 ]. Models will demonstrate sufficient fit as measured by comparative fit index of at least 0.95, root mean square error of approximation of no more than 0.06 and a standardized root mean error of no more than 0.07.

In the current study, the primary analyses of latent growth curve modelling were to determine if the slope (rate of change) was significantly more favourable for the treatment group compared with the placebo group. Significant differences between slopes are determined by (i) assuring that the latent growth curve model is appropriate for the data and (ii) by comparing the mean slope from each group given the standard error of the mean (using a simple t -test formula). Growth models were designed to match validated construction of the SF-36 [ 12 ] and HAQ [ 1 ].

Results

Effect of treatment on HRQoL

Prior to analysis of SF-36 study data, data were inspected to assure conformity to the SF-36 measurement model [ 42 ]. This data review is used to assure that SF-36 scores met required scaling assumptions and minimum standards of reliability, as is commonly conducted in comprehensive examinations of SF-36 data [ 43 ]. Items and scales performed in accordance with the SF-36 measurement model.

Results from the change score analyses of each of the QoL outcomes are presented in Table 2 . For each of the SF-36 subscales and composite scores, the HAQ-DI, and the fatigue measure, the abatacept group had significantly increased QoL compared with similar patients on DMARDS alone (i.e. placebo group, Table 2 ). In addition to statistical significance, these results indicated effect sizes (measured as R2 effects, a measure of the variance explained by the effect) that were medium-large in size, ranging from 19% (RE) to 43% (BP).

T able 2.

Treatment vs control on change score (baseline to endpoint)—LOCF sample

Scale  Abatacept + DMARDS score ( s . d .)   Placebo + DMARDS score ( s . d .)  P R2 
SF-36 
Physical functioning 5.3 (10.5) 1.2 (8.6) 14.80 0.0001 0.28 
Role physical 6.7 (11.4) 0.8 (9.0) 26.89 <0.0001 0.37 
Bodily pain 8.7 (10.3) 2.2 (8.1) 39.72 <0.0001 0.43 
General health 3.9 (8.3) 0.7 (7.8) 13.68 0.0002 0.27 
Vitality 6.9 (10.7) 1.2 (9.8) 25.43 <0.0001 0.36 
Social functioning 7.4 (12.1) 2.2 (10.8) 16.89 <0.0001 0.30 
Role emotional 6.3 (16.1) 2.0 (15.3) 6.19 0.0133 0.19 
Mental health 4.6 (10.1) 1.1 (9.5) 10.65 0.0012 0.24 
Physical component score 6.5 (9.6) 1.0 (7.7) 31.65 <0.0001 0.40 
Mental component score 5.4 (11.7) 1.7 (10.2) 9.25 0.0025 0.23 
HAQ-DI −0.5 (0.6) −0.1 (0.4) 34.42 <0.0001 0.42 
Fatigue VAS −22.1 (28.6) −5.3 (27.4) 30.07 <0.0001 0.39 
Scale  Abatacept + DMARDS score ( s . d .)   Placebo + DMARDS score ( s . d .)  P R2 
SF-36 
Physical functioning 5.3 (10.5) 1.2 (8.6) 14.80 0.0001 0.28 
Role physical 6.7 (11.4) 0.8 (9.0) 26.89 <0.0001 0.37 
Bodily pain 8.7 (10.3) 2.2 (8.1) 39.72 <0.0001 0.43 
General health 3.9 (8.3) 0.7 (7.8) 13.68 0.0002 0.27 
Vitality 6.9 (10.7) 1.2 (9.8) 25.43 <0.0001 0.36 
Social functioning 7.4 (12.1) 2.2 (10.8) 16.89 <0.0001 0.30 
Role emotional 6.3 (16.1) 2.0 (15.3) 6.19 0.0133 0.19 
Mental health 4.6 (10.1) 1.1 (9.5) 10.65 0.0012 0.24 
Physical component score 6.5 (9.6) 1.0 (7.7) 31.65 <0.0001 0.40 
Mental component score 5.4 (11.7) 1.7 (10.2) 9.25 0.0025 0.23 
HAQ-DI −0.5 (0.6) −0.1 (0.4) 34.42 <0.0001 0.42 
Fatigue VAS −22.1 (28.6) −5.3 (27.4) 30.07 <0.0001 0.39 

LOCF, last observation carried forward; VAS, visual analogue scale.

R2 = explained variance (effect size).

QoL improvement was also examined for patients with different severity levels at baseline. The DAS28 baseline upper quartile was 7.59, allowing for subgroups to be examined for group differences (treatment vs placebo) in change scores for the subgroups: (i) patients below a DAS28 baseline values of 7.59 and (ii) patients at or above a DAS28 baseline value of 7.59. Results for these analyses indicated that most (i.e. HAQ, fatigue and seven of eight SF-36 subscales; all but RE) of the QoL measures were significantly more improved among the abatacept patients compared with placebo with lower DAS28 scores at baseline. Among those with higher DAS28 baseline scores, all of the mental SF-36 scales indicated similar improvement between the treatment groups, as did the HAQ and the fatigue outcomes. A check of key demographic variables revealed no demographic differences between the DAS28 groups on age ( t = −0.51, P = 0.61) or gender (χ 2 = 0.38, P = 54). Upon reviewing the differences in results, post hoc analyses examining the impact of the continuous DAS28 score at baseline on the rate of change in growth analyses was conducted. These results are presented after the primary growth curve analyses.

In the second assessment of differential change over time, the counts of persons in each of the categories of change (i.e. better, same or worse) for the treatment and placebo groups were compared. As is shown in Table 3 , results indicated that the treatment group had significantly more patients in the favourable change than did the control for seven of the eight SF-36 scales and PCS. Only RE failed to reach significance, and MCS approached statistical significance: P = 0.072. MCS is a weighted average of all mental subscales on the SF-36 and RE has the second largest weight in the MCS calculation [ 12 ]. Therefore, it is likely that the primary reason the MCS did not significantly change was due to the weight of the non-significant RE scale. Each of the other three SF-36 scales with strong loadings on MCS were significant, including the primary MCS scale of Mental Health ( P = 0.006). Results also show a greater rate of decline for placebo; in many instances a 2:1 ratio.

T able 3.

Percentage of patients doing better, same, or worse between treatment and control groups

 Abatacept + DMARDS Placebo + DMARDS   
 
 

 
  
Scores Better Same Worse Better Same Worse  χ 2 P 
Physical functioning 44.9 42.9 12.2 24.6 60.8 14.6 15.27 0.0005 
Role physical 43.9 48.6 7.5 21.5 58.5 20.0 24.81 <0.0001 
Bodily pain 54.9 39.9 5.1 24.6 64.6 10.8 32.39 <0.0001 
General health 38.4 51.8 9.8 23.1 60.0 16.9 10.75 0.0046 
Vitality 49.8 41.2 9.0 30.0 51.5 18.5 16.19 0.0003 
Social functioning 42.9 49.2 7.9 23.9 61.5 14.6 14.87 0.0006 
Role emotional 38.3 45.1 16.6 30.0 47.7 22.3 3.32 0.1901 
Mental health 39.6 50.6 9.8 29.2 50.0 20.8 10.24 0.0060 
Physical component score 44.6 45.8 9.6 23.1 63.1 13.9 17.03 0.0002 
Mental component score 43.0 40.3 16.7 31.5 45.4 23.1 5.26 0.0723 
 Abatacept + DMARDS Placebo + DMARDS   
 
 

 
  
Scores Better Same Worse Better Same Worse  χ 2 P 
Physical functioning 44.9 42.9 12.2 24.6 60.8 14.6 15.27 0.0005 
Role physical 43.9 48.6 7.5 21.5 58.5 20.0 24.81 <0.0001 
Bodily pain 54.9 39.9 5.1 24.6 64.6 10.8 32.39 <0.0001 
General health 38.4 51.8 9.8 23.1 60.0 16.9 10.75 0.0046 
Vitality 49.8 41.2 9.0 30.0 51.5 18.5 16.19 0.0003 
Social functioning 42.9 49.2 7.9 23.9 61.5 14.6 14.87 0.0006 
Role emotional 38.3 45.1 16.6 30.0 47.7 22.3 3.32 0.1901 
Mental health 39.6 50.6 9.8 29.2 50.0 20.8 10.24 0.0060 
Physical component score 44.6 45.8 9.6 23.1 63.1 13.9 17.03 0.0002 
Mental component score 43.0 40.3 16.7 31.5 45.4 23.1 5.26 0.0723 

In the third assessment of differential change over time, latent growth curve analyses provided similar results to those of the change scores. Figures 1 and 2 display the slope changes for each group on each of the QoL outcomes. In each of the plots in Figure 1 , the value for each point is an estimate of the value for the specific questionnaire after controlling for residuals associated with (i) non-linear changes between each participant, (ii) retest reliability of the questionnaire and (iii) the reliability of the questionnaire at that time point. For practical use, this means that scores at each time are corrected for various sources of noise that can distort the clinical interpretation of a questionnaire score.

F ig . 1.

Mean rate of change on SF-36 scales by treatment group and visit.

F ig . 1.

Mean rate of change on SF-36 scales by treatment group and visit.

F ig . 2.

Mean slope changes on SF-36 summary scores, HAQ and fatigue by treatment group and visit.

F ig . 2.

Mean slope changes on SF-36 summary scores, HAQ and fatigue by treatment group and visit.

Results of the growth curve analyses indicated that the abatacept group had significantly larger rates of change for all QoL outcomes (HAQ, fatigue and SF-36), except for RE. In order to determine significant differences at each time, 95% CIs were calculated and significant group differences are marked with asterisk. All of the QoL measures had significant group differences during their final time in the study. Moreover, most of the results indicate the significant difference between treatment and placebo occurred by the 12th week. Some of the results were significantly different between the groups by week eight, including the MH scale on the SF-36 and the fatigue scale.

As noted, the impact of continuous DAS28 baseline score on the rate of improvement for QoL outcomes was examined after reviewing the findings from the DAS28 split score analyses. Specifically, we examined the impact of the baseline DAS28 score on the slope of change for each outcome. Results indicated that QoL improvement was significantly more related to lower baseline DAS28 values among the abatacept patients compared with placebo. The strength of the relationship between DAS28 baseline value and QoL improvement among abatacept patients ranged from a small effect for SF-36 mental health improvement (standard path = 0.039) to a small-medium effect for HAQ improvement (standard path = 0.211).

To measure a return to normal QoL, a set of 95% CIs were calculated for PCS and MCS based on age- and gender-adjusted population means and s . d .s [ 12 ]. These CIs were used as ranges to obtained the percent of patients in each treatment group whose (age- and gender-adjusted) PCS and MCS scores at each time point fell within these ranges. In other words, differences in the percent of people by treatment group were examined for those whose PCS or MCS scores had improved enough to fall within the normal range of the population norm. For PCS, this percentage was significantly higher for the abatacept group at 12 weeks (abatacept at 19% vs placebo at 9%; z = 244.82, P <0.0001) and 24 weeks (abatacept at 23% vs placebo at 10%; z = 297.85, P <0.0001). For MCS, however, the treatment and placebo groups were doing better at different time points and, overall, the difference was not significant during the 24-week study period.

Finally, the improvement in PCS, MCS, HAQ and fatigue score was examined by reviewing the percent of patients who improved by at least half a s . d . by 24 weeks. Such a review provides important clinical information as a half s . d . is commonly accepted as a measure for indicating clinical change [ 44 ]. On all four measures the percentages were significantly higher for the abatacept group (again, using the z -score for difference between proportions, all P <0.0001).

Discussion

Results of the current analyses provide compelling evidence that patients on abatacept had significantly increased QoL after 6 months of treatment compared with similar patients on a placebo. These findings are especially noteworthy for two primary reasons. First, patients in the current study represent participants with severe and refractory RA—those who have failed anti-TNF therapy and who were functioning between one and two s . d .s below QoL norms. The ability to provide both clinical [ 18 ] and QoL improvement to those who have previously been without an effective treatment demonstrates a unique benefit of abatacept for patients and clinicians. Second, patients on abatacept obtained marked improvement on physical and mental scales of the QoL. Studies on existing treatments for arthritis have shown that QoL benefits from treatment have either ignored or not measured the impact of treatment on the mental health scales, limiting analyses to the physical scales [ 45 ]. Nevertheless, abatacept treatment led to significant improvements across the physical and mental scores on the SF-36.

Results from the three different analyses of differential change over time between the treatment groups provided are enlightening and of value to practicing rheumatologists. The common assessment of change score analyses resulted in significant differences between groups on all the ten measures on the SF-36, the HAQ and the fatigue measure with effect sizes ranging from small–medium to medium–large. This tells rheumatologists that abatacept led to a greater improvement than placebo in QoL functioning from the beginning to the end of the treatment. However, the change score analysis does not capture the number of people that improve from either abatacept or placebo, nor does it allow for the assessment on non-linear change, a more realistic analysis of change over time [ 39 ].

The use of categorical changes demonstrated significant differences between abatacept and placebo groups on the number of people improving (favouring abatacept) for all SF-36 scales, except RE and MCS. Even on RE and MCS, patients on abatacept were nearly three times more likely to improve than get worse compared with traditional DMARDs alone. Categorical analyses are important to measure because mean score changes mask the underlying variability in outcomes of RA. Current results show a greater likelihood of improving and less likelihood of declining when a patient takes abatacept compared with traditional DMARDs alone. The likelihoods are nearly 2:1 on most scales.

The latent growth curve analyses provided a strong review of the differential change over time, using all time points, including evidence that treatment benefits were found for nearly all measures of HRQoL at 12 weeks. To the practicing rheumatologist, the early responses noted in the growth curve analyses increases the likelihood of treatment adherence among patients; patients who believe they are receiving benefit from their medication are more likely to continue their regimen. For example, abatacept patients experienced significant fatigue improvement over placebo by the 15th day of the treatment. This highly sensitive measure of differential change over time was used to reveal various group by time differences for all of the QoL measures. Specifically, the slope of change (a measure of the overall change throughout all of the baselines) was significantly better for all QoL measures, except for RE. Additionally, the plots in Figures 1 and 2 show that the groups had significant differences at many of the time points. Importantly, the abatacept group was significantly better on all of the QoL measures at 24 weeks.

RE revealed an interesting non-linear change over time, and differential slopes for the two groups, in that the first three times were nearly identical, but varied markedly by day 169. Specifically, the abatacept group had a stronger growth rate from week 12 to 24 than it did from week 8 to 12, whereas the placebo group showed its decline in RE between week 12 and 24. Delayed improvement of specific mental QoL measures, especially in pain-related diseases, has been demonstrated elsewhere [ 46 ] and may suggest that continued QoL benefits for abatacept over placebo can be extended beyond 6 months.

Examining change scores between the most severe participants at baseline (DAS28 score ≥7.59) as well as participants with lower baseline severity (DAS28 scores <7.59) revealed an unexpected relationship between disease severity and the rate of QoL improvement. The most severe patients at baseline showed improvement on the most sensitive measures of RA QoL improvement (i.e. PF, RP, BP, VT, PCS and the SF-36 and the HAQ-DI score), but failed to reach the same improvements found for the overall sample. Conversely, participants without the marked baseline clinical severity showed marked improvement across a wide breadth of QoL measures. Examination of the continuous DAS28 scores on the rate change found similar results: there is significant negative relationship between baseline disease severity and QoL improvement such that those with lower disease severity at baseline should be expected to improve more than those with higher disease severity at baseline.

These findings may suggest a marked benefit of treating patients who fail anti-TNF therapy with abatacept before clinical symptoms become irreversible (i.e. cartilage destruction or bone erosion). If one experiences a disease state so severe as to create irreversible damage, thus exhibiting higher baseline disease severity, the impact of medicine would conceivably be far less than for those who received proper medication prior to such damage. It should be noted, however, that the relationship between baseline disease severity and rate of QoL improvement is not well-understood currently, and further investigation is encouraged. For rheumatologists, this means it appears that level of severity impacts ability to improve, and as some RA patients may be subjected to various anti-TNF treatments prior to alternative medications, it may be appropriate to examine abatacept use earlier in a patient's treatment regimen.

The current findings provided marked strengths in the assessment of QoL in this severe RA patient population through the use of carefully constructed research design and multiple methods to analyse group by time differences. The research design provides results clearly generalizable to the population of RA patients that have failed currently available treatments, including treatment with anti-TNF therapy. Using multiple group by time analyses allows a multiple-perspective review of the study data. For example, although the change score analyses suggested all of the QoL measures were significantly better with abatacept, the other analyses suggested that RE may be less sensitive to change. Without these additional analyses, the specifics of RE changing later than the other measures may have been overlooked.

Certain limitations were present in the current study, including the duration of the study and typical limitations of validity. The mixed findings of RE among the various analyses may have been further clarified if more time points were assessed. However, other studies using Version 1 of the SF-36 on RA patients have found that this particular scale on the SF-36 may not have relevance for RA populations [ 47 ]. Future analyses may provide more information on the continued improvement of RE for patients on abatacept compared with placebo. Moreover, the SF-36 Version 2 has a RE scale with more favourable psychometrics that may help future studies overcome some of the RE limitations examined in the current study. Finally, typical limitations of validity suggest that results of this trial must be taken as a part of the entire effort of research to validate the efficacy of abatacept and should not be interpreted as conclusive validation unto themselves [ 48 ].

Conclusions

Previously, patients had suboptimal treatment alternatives after failing to maintain a treatment response to anti-TNF and MTX. In addition to recent Phase III clinical findings, regarding the clinical benefit of abatacept for these patients, the current findings provide comprehensive evidence of the QoL benefits associated with abatacept for the same group of severe RA patients. QoL benefits were demonstrated on both disease-specific and general measures of QoL. Findings indicated that in each of the multiple assessments, nearly all of the measures showed significant differences in improvement over time, favouring abatacept over placebo. All of the QoL measures were significantly better for the abatacept patients than placebo patients at 6 months. Therefore, by improving a wide range of QoL markers, abatacept may provide meaningful benefits for this population of RA patients who have limited treatment alternatives. These findings support the use of abatacept with inadequate responses to anti-TNF therapies.

graphic

TL, RM and RA are employees of BMS; RW and YS were consultants for BMS.

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