Improvement in health utility among patients with rheumatoid arthritis treated with adalimumab (a human anti-TNF monoclonal antibody) plus methotrexate

G. W. Torrance1,2,3, P. Tugwell4, S. Amorosi5, E. Chartash6 and N. Sengupta7

1 McMaster University, Hamilton, Ontario, 2 Innovus Research Inc, Burlington, Ontario, 3 Health Utilities Inc, Dundas, Ontario, 4 University of Ottawa, Ottawa, Ontario, Canada, 5 Innovus Research Inc, Medford, MA, 6 Abbott Laboratories, Parsippany, NJ, 7 Abbott Laboratories, Abbott Park, IL, USA.

Correspondence to: G. Torrance, Innovus Research Inc., 1016-A Sutton Drive, Burlington, ON, L7L 6B8, Canada. E-mail: torrance{at}mcmaster.ca


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. To compare health-related quality of life (HRQoL), as measured by health utility, in patients with rheumatoid arthritis (RA) treated with adalimumab (a human anti-tumour necrosis factor (anti-TNF) monoclonal antibody) plus methotrexate or placebo plus methotrexate.

Methods. HRQoL data were obtained in two randomized, double-blind, placebo-controlled, multidose clinical trials conducted in the United States and Canada. The Health Utilities Index Mark 3 (HUI3) was administered in both studies at baseline, at the end of the study and at two time points in between. Patients’ HUI3 scores were compared with population norm scores. Change in HUI3 was defined as the end-of-study score minus the baseline score. Utility gained throughout the study was measured by area under the utility curve and expressed as quality-adjusted life years (QALYs). Statistical testing adjusted for confounders and used the Dunnett test to account for multiple comparisons.

Results. Patients’ utility scores at baseline were low (range of treatment group means 0.38–0.44) compared with population norms (0.88). HUI3 mean changes from baseline scores for adalimumab-treated patients were 0.22 and 0.21 in the two trials, whereas placebo patients’ changes were 0.04 and 0.07. The rate of QALYs gained per year in the treatment group compared with the placebo group were 0.145 in the ARMADA trial and 0.104 in the DE019 trial. All gains were clinically important and statistically significant.

Conclusions. Treatment with adalimumab plus methotrexate provides clinically important and statistically significant improvements in HRQoL as measured by health utility in patients with RA. This translates into measurable and important gains in QALYs.

KEY WORDS: Rheumatoid arthritis, Adalimumab, TNF-antagonists, Health-related quality of life, Health utility, Health utilities index, Outcomes, Quality-adjusted life years.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is an autoimmune disorder affecting roughly 1% of the adult population [1]. The disease course is primarily characterized by joint inflammation and erosive damage of articular cartilage and underlying bone. As a consequence, RA has a detrimental impact on a patient's health-related quality of life (HRQoL).

HRQoL can be assessed using various measurement techniques [2]. The most commonly used approaches include: health utility [3]; disease-specific instruments (e.g. the Health Assessment Questionnaire (HAQ) [4] for RA); and generic health profiles (e.g. the Short Form-36 Health Survey [5]). Health utility is a particularly useful measure in chronic diseases such as RA that have little or no impact on mortality in the short term. Health utility enables the improvements in HRQoL to not only be measured and quantified, but also to be directly transformed into quality-adjusted life years (QALYs) gained. QALYs allow policy-makers to make broad comparisons across diseases and across programmes, and are the recommended metric for use in cost-effectiveness analyses [6].

Adalimumab (Humira®, Abbott Laboratories, Abbott Park, IL, USA) is the first human anti–tumour necrosis factor (TNF) monoclonal antibody to be studied in the treatment of RA [7]. Adalimumab exerts its therapeutic effects by blocking the interaction of TNF with TNF cell-surface receptors [7]. In clinical trials, adalimumab with concomitant methotrexate (MTX) has been demonstrated to be safe and well-tolerated, and to provide substantial improvement in disease activity [8, 9]. In ARMADA, 67% of patients receiving adalimumab 40 mg every other week (eow) plus MTX achieved an ACR20 response, 55% achieved an ACR50 response and 27% achieved an ACR70 response at week 24 [8]. In DE019, 63, 39 and 21% of patients achieved ACR20, 50 and 70 responses respectively at week 24 on the same treatment [9]. All response rates were statistically significantly better than those in patients receiving placebo plus MTX (P<0.001). It has been reported that increases in clinical response are associated with increases in health-related quality of life and health utility [10]. The present analysis was undertaken to study the effect that treatment of RA patients with adalimumab has on HRQoL, as measured by health utility.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
This analysis evaluated utility data collected during two clinical trials of adalimumab in RA [8, 9]. Patients participating in these trials met classification criteria for RA established by the American College of Rheumatology (ACR) in 1987 [11]. Inclusion criteria required that they had responded inadequately to a minimum of 3–6 months’ treatment with MTX.

Study protocols
Both studies were randomized, double-blind, placebo-controlled, multidose, multicentre studies. ARMADA was a four-arm, 24-week study of 271 RA patients who had active disease while on MTX [8]. DE019 was a three-arm, 52-week trial of 619 RA patients [9]. In both studies, patients continued to receive concomitant MTX. Only data from those patients randomized to the placebo or adalimumab 40 mg eow groups were included in this analysis. Subjects provided written informed consent and the local institutional review boards approved the study protocols. The trials were conducted in the United States and Canada.

Health Utilities Index (HUI)
The HUI is a well-established, widely used, validated health utility instrument, available in many languages [12, 13]. The most recent version of the system (HUI3) was used in the trials reported here. The HUI3 consists of a health status classification system, questionnaires to collect the health status information and a scoring formula to produce the utility scores. The system produces both an overall utility score and eight individual attribute scores. The overall utility score is on the conventional interval scale, where death has a score of 0.0 and perfect health has a score of 1.0 [3]. The construct of the scale is one of preference or desirability. The more preferable or desirable a health state, the higher its utility. Negative scores are possible and represent health states considered worse than death.

The HUI3 classification system consists of eight attributes (vision, hearing, speech, ambulation, dexterity, emotion, cognition and pain) and five or six levels on each attribute, ranging from full function to severe impairment [12, 13]. The levels on each attribute are designed to be distinct in content and readily classifiable. They are not designed to be equally spaced, or even to be ordered in a particular way. The numbers on the levels, 1 to 5 or 1 to 6, are merely descriptive and cannot be used numerically for analysis. The scores for the levels come from the scoring system, which in turn has been based on preferences elicited from the general public using utility measurement techniques.

The HUI questionnaire used in the trials was self-completed by the patients and consisted of questions asking patients to reflect on their health status over the preceding 4 weeks. In the ARMADA trial, questionnaires were administered at baseline and weeks 4, 12 and 24; patients who did not show clinical improvement were administered the HUI at week 16 rather than week 24 and unblinded. In DE019, questionnaires were administered at baseline and weeks 12, 24 and 52.

Statistical analysis
Abbott Laboratories provided the patient-level raw data from the trials. Innovus Research Inc., an independent contract research firm, performed the statistical analyses for the paper with funding provided by Abbott. Methodological decisions regarding data cleaning, data exploration, dealing with missing data and analytical issues were handled by the principal authors while blinded to treatment group. All statistical analyses were performed using SAS Version 8.2.

For inclusion in the analysis, patients had to have had a HUI3 assessment at baseline and at least one other time point during the study. Patients meeting these criteria were analysed on an intent-to-treat basis. Consistent with the clinical analyses of these studies, missing data were imputed using last observation carried forward (LOCF). For application to HUI3 data, LOCF was implemented in a hierarchical fashion, thus minimizing the number of data to be imputed. First, if only certain HUI3 questions were missing, these questions were imputed using the corresponding responses to the prior assessment. Second, if selected attributes were missing, these attributes were imputed using the corresponding attribute scores from the prior assessment. Finally, if all data for a given assessment were missing, the entire HUI3 was imputed using the prior assessment.

HUI3 data were scored in three steps. First, questionnaire answers were converted into levels on the eight attributes. Second, the level on each attribute was scored on the single-attribute utility scale. Third, the complete health state (levels on all eight attributes) was scored on the overall utility scale.

Using the HUI3 scoring formula [13], HUI3 population data from the 1996/1997 Canadian National Population Health Survey [14], were used to calculate population norms. The survey data are available by sex and 5-year age cohorts. The data were age- and sex-adjusted to match the patient characteristics in each trial to provide trial-specific population norms.

The HUI3 change score was defined for each patient as the end of study score minus the baseline score. The difference in mean change scores between the treatment group and the placebo group was compared using a statistical model controlling for baseline age, sex and disease severity using the Dunnett test, which adjusts for multiple comparisons. The proportions of patients with normal HUI3 scores at baseline and end of study were compared between treatment and placebo groups.

To determine how patient HRQoL changed throughout the course of the trial, area-under-the-curve (AUC) analysis was conducted. The utility curve was plotted over time for each individual patient using the exact dates of his or her visits. Because the recall period of the HUI3 questionnaire used in the trials was 4 weeks, the curve is flat (horizontal) for the 4 weeks prior to the questionnaire date for each patient at each visit. Straight-line interpolation was used to join the flat parts of the curve. In this way, a piecewise linear ‘curve’ was developed for each patient. The AUC for each patient was then computed by summing the area under the utility curve using the utility score as the vertical measure and years as the horizontal measure. Thus, the units of the AUC were quality-adjusted life years (QALYs). Raw AUC scores (QALYs) are affected by the actual number of days a patient is enrolled in the clinical trial. For instance, the raw AUC scores for patients enrolled for more days than the specified trial length are inappropriately inflated simply because they were in the study longer than other patients. To correct for this, each patient's AUC was standardized to the study duration by multiplying his or her AUC by the standard length of study in days divided by the actual number of days the patient was in the study.

The statistical testing of the QALYs used the same approach as that for the HUI3 change scores. Specifically, in this case, the model controlled for baseline utility, country, sex, age and disease severity, with multiple testing handled by the Dunnett test.

QALYs achieved by each arm of the trial and QALYs gained (the difference between QALYs achieved by active treatment versus placebo) are a function of trial duration. To enable comparisons across trials of different durations, QALYs gained were also shown on a rate basis (QALYs gained per year), derived by dividing the result by the trial duration in years.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Demographic and baseline clinical characteristics
The baseline demographic and clinical characteristics of the patients with sufficient HUI3 data to be included in our analysis are shown in Table 1. The proportion of patients from the original trials for which utility data were available ranged from 92 to 96%, indicating that the majority of patients included in the clinical analyses of these trials were included in this analysis of health utility. In total, eight patients were excluded from ARMADA and 29 from DE019, because of either incomplete baseline HUI data, no baseline HUI data or no follow-up HUI data. The patients were predominately white females with an average age in the mid 50s and average disease duration of 10 to 12 years. Patients had moderately to severely active RA, as indicated by the joint counts, the pain measure, the global assessments of disease activity, the HAQ disability index, the serum C-reactive protein concentration and the DAS28 score. In the ARMADA trial, 98.5% of adalimumab patients and 93.5% of placebo patients completed the HUI questionnaire at the end-of-study visit. In DE019, 76.3% of adalimumab patients and 69.5% of placebo patients completed the HUI questionnaire at the end-of-study visit.


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TABLE 1. Demographic and baseline clinical characteristics of patients in the HUI3 analysisa

 
HUI3 scores at baseline
The mean HUI3 overall scores at baseline for each treatment group are shown in Fig. 1. The dashed lines depict trial age- and sex-adjusted population norm data. These data demonstrate that the HRQoL of the patients at baseline in both studies was well below normal for these populations.



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FIG. 1. HUI3 overall scores at baseline by treatment group. Error bars represent standard deviations of the data. Dashed lines represent household population norms for HUI3 overall score age- and sex-adjusted to match trial patients.

 
The HUI3 single-attribute scores that form the foundation for the overall score are shown in Fig. 2, along with their trial age- and sex-adjusted population norms. The compromise in HRQoL of these patients at baseline is primarily attributable to their problems with pain, dexterity and ambulation, and, to a lesser degree, emotion and cognition.



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FIG. 2. Baseline health utility parameters by attribute for each study.

 
Change in HUI3 scores
Fig. 3 shows the mean HUI3 overall utility scores for each trial by treatment group and over time. The pattern was similar in both studies. The treatment groups improved rapidly and the improvement was sustained over time, whereas the placebo groups improved less. The differences between treatment and placebo groups were statistically significant by week 12 (P <= 0.002), and remained so through the end of the studies. The HUI3 mean changes from baseline in the adalimumab-treated groups were 0.22 and 0.21 for ARMADA and DE019 respectively. These were statistically significantly better (P = 0.002 for ARMADA and P<0.0001 for DE019) than the changes from baseline in the placebo-treated groups, which were 0.04 and 0.07 respectively. A minimum clinically important difference for HUI3 scores is 0.03 [15, 16].



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FIG. 3. HUI3 scores over the duration of the studies.

 
The individual HUI3 attributes that had a statistically significantly greater change than that of the relevant placebo group in at least one trial are shown in Fig. 4. The largest gains in health-related quality of life in both trials occurred through the alleviation of pain and improvement in dexterity.



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FIG. 4. HUI3 attributes most affected by adalimumab treatment.

 
Fig. 5 shows the proportion of patients at baseline and end of study in each treatment group for each trial that achieved a HUI3 score greater than or equal to the population norm (0.88 for both trials). At baseline, very few patients were at or above the population norm score. By the end of the study, substantially more patients had achieved or exceeded the population norm in the adalimumab-treated groups than in the placebo groups. Overall, the increase in the proportion of adalimumab patients relative to placebo patients who achieved or exceeded the population by end of study was 16.5% in ARMADA and 15.2% in DE019.



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FIG. 5. Proportion of patients at or above the trial-adjusted population norm HUI3 score in ARMADA and DE019 clinical trials, by treatment group.

 
QALYs achieved over time
The QALY results achieved over the duration of the trials are presented in Fig. 6. Adalimumab treatment resulted in statistically significantly more QALYs achieved compared with placebo (P<0.001) in both trials. The net gain in QALYs in adalimumab-treated patients was 0.067 in the 24-week ARMADA trial and 0.104 in the 52-week DE019 trial. It is important to note that the duration of the trials must be taken into account when interpreting these net gains. To enable comparisons between trials of varying duration, the QALYs gained can be converted to a rate by dividing by the trial duration. On this basis, in ARMADA, the adalimumab 40 mg eow group gained QALYs compared to the placebo group at the rate of 0.145 QALYs gained per year, while in DE019, the patients gained at the rate of 0.104 QALYs gained per year. This was statistically significant at P<0.001 in both trials.



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FIG. 6. QALYs achieved over trial duration, adjusted for baseline covariates.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
RA seriously compromises the HRQoL of patients. The mean HUI3 overall scores at baseline in these trials were 0.38 for ARMADA and 0.44 for DE019. Both of these compare unfavourably with the trial-adjusted population norm HUI3 scores of 0.88. That is, the patients in these trials had HRQoL scores 50% or more lower than those expected for a group of the same age and sex.

Given that these HUI3 scores represent standard gamble utilities, they can also be interpreted in terms of the probability of death that a member of the general public would take to avoid the health state. As an example, the mean baseline utility in ARMADA was 0.39. This means that members of the general public surveyed to develop the scoring formula for HUI3 indicated that they would be willing to accept a risk of death as high as 0.61 to live a lifetime in perfect health rather than live a lifetime with a condition equivalent to the average condition of patients in ARMADA at baseline.

The single-attribute HUI3 scores at baseline showed that pain was the attribute most affected in these patients, followed by dexterity, ambulation and emotion. These are the four attributes one would expect, given the disease—RA. Interestingly, however, these patients are also compromised (although to a lesser degree) on the other four attributes (cognition, vision, hearing and speech), a finding consistent with the fact that they are suffering from a serious disease.

The mean change from baseline in overall utility score is impressive. In adalimumab-treated patients, the utility scores improved by 0.22 and 0.21 units in the two trials, while placebo recipients only improved by 0.04 and 0.07 units. Net gains in utility for adalimumab relative to placebo were 0.18 and 0.14 for ARMADA and DE019 respectively. These are large gains compared with those achieved in other studies. For example, in a recent study of osteoarthritis of the knee, injections of hylan G-F 20 produced a HUI3 gain of 0.10 [17].

Adalimumab treatment resulted in 23.4 and 21.4% of patients achieving HUI3 scores comparable to the normal population. This is remarkable in light of how debilitated these patients were at study entry.

Adalimumab treatment produced gains in QALYs of 0.145 QALYs gained per year and 0.104 QALYs gained per year for the ARMADA and the DE019 trials respectively. These data are valuable because they capture the overall pattern of utility change throughout the trial, rather than simply the utility at the beginning and end of the trial. The QALY scale goes from 0 to 1, with 0 representing dead and 1 representing perfect health for a year. Thus, an increase of 0.145 QALYs over a year represents a gain in quality of life that is 14.5% of perfect health. The gain is even more dramatic when taken as a per cent of baseline quality of life for these patients. In the ARMADA trial, the adalimumab patients had an average baseline quality of life of 0.38. Relative to this baseline, their improvement of 0.145 QALYs represents a 38% increase in quality of life. Similarly, in the DE019 trial, the QALY gain of 0.104 represents a 24% increase in quality of life.

Because the gain in QALYs is shown on a rate basis (QALYs gained per year), one can compare across trials of different duration. For example, the QALY gains in the ARMADA and DE019 trials compare favourably to QALY gains from other trials that also used the HUI instrument. In a 12-month study of osteoarthritis of the knee, injection of hylan G-F 20 produced a QALY gain of 0.071 per year [18]. In a 12-month study of antibiotic treatment for acute exacerbations of chronic bronchitis, the QALY gain was 0.031 per year [19].

A possible shortcoming of this study is that the analysis was performed on a defined study population. The patients participating in these trials had more severe disease than the average RA patient, as evidenced by their high baseline DAS28 scores. However, biological DMARDs are typically indicated only in patients that have moderate to severe disease, and have failed one or more traditional DMARDs. Extrapolation of these results to all RA patients should be done with caution. Additionally, the trials were of limited duration (24 and 52 weeks), and the ability of adalimumab to provide sustained improvement in utility with long-term therapy will have to be studied further.

Herein, we report improvement in HRQoL, as measured by health utility, in patients with RA treated with adalimumab plus methotrexate. These results provide strong evidence that adalimumab, at the approved dose of 40 mg eow, plus methotrexate achieves clinically important and statistically significant improvements in health utility, both when measured by comparing end-of-study scores with baseline scores (HUI3 change score) and when measured by comparing the area under the utility curve for the duration of the study (QALYs gained). The improvements in QALYs gained while on adalimumab therapy provide policy-makers with important information to use when making comparisons across diseases and programmes and when making decisions about cost-effectiveness.


    Acknowledgments
 
Funding for this research was provided by Abbott Laboratories, Abbott Park, Illinois. We would like to express our gratitude to Stacy Simpson for her editorial assistance and to Nancy Ryan and Sherry Li for their assistance with the data analysis.

The study authors retained final authority over the content of the manuscript.

G. Torrance is a professor emeritus at McMaster University, Hamilton, Canada; vice president of Innovus Research, Inc., an independent contract research firm hired by Abbott Laboratories to conduct the HUI analysis of adalimumab in the treatment of rheumatoid arthritis; and a principal of Health Utilities Inc., a firm that provides instrumentation, algorithms and assistance to users of the HUI.

P. Tugwell is a professor at the University of Ottawa, Canada; and a paid consultant for Abbott Laboratories.

S. Amorosi is a full-time employee of Innovus Research, Inc., an independent contract research firm hired by Abbott Laboratories to conduct the HUI analysis of adalimumab in the treatment of rheumatoid arthritis.

E. Chartash is a full-time employee of Abbott Laboratories.

N. Sengupta is a full-time employee of Abbott Laboratories.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 18 December 2003; revised version accepted 14 January 2004.



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