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Rheumatology Advance Access originally published online on January 3, 2008
Rheumatology 2008 47(2):188-193; doi:10.1093/rheumatology/kem317
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Personal and economic burden of late-stage rheumatoid arthritis among patients treated with adalimumab: an evaluation from a patient's perspective

T. Mittendorf1, B. Dietz2, R. Sterz2, M. A. Cifaldi3, H. Kupper2 and J.-M. von der Schulenburg1

1Center for Health Economics, Leibniz University Hannover, Hannover, 2Abbott GmbH Co KG, Ludwigshafen, Germany and 3Abbott Laboratories, Abbott Park, IL, USA.

Correspondence to: T. Mittendorf, Gottfried Wilhelm Leibniz University Hannover, Center for Health Economics, Koenigsworther Platz 1, D-30167 Hannover, Germany. E-mail: tm{at}ivbl.uni-hannover.de


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. This study evaluated the patients’ perspective of burden of disease among 505 patients with severe, long-standing rheumatoid arthritis receiving adalimumab.

Methods. Health-related quality-of-life and resource use data were collected during a 144-week open-label study.

Results. Adalimumab maintained pain control and reduced the duration of morning stiffness. Work impairment decreased and work productivity was maintained over the duration of the study. Costs were estimated at ~{euro}2100 over the course of the study, and personal help and transportation costs comprised a large percentage of total costs.

Conclusions. These results suggest that adalimumab could improve many aspects of a patient's burden of disease.

KEY WORDS: Rheumatoid arthritis, Patient perspective, Adalimumab, Out-of-pocket payments


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Health care systems are moving towards increasing the responsibility of patients, particularly with regard to costs and copayments. The clinical and financial burden of chronic diseases such as RA can be overwhelming for patients. Because there is no cure for RA and clinical remission is infrequent, research efforts must then focus on ways to improve the burden of illness of these patients. However, the different facets of the burden of illness are quite heterogeneous for chronic diseases overall, even within the field of rheumatology. In 2003, the World Health Organization reported that musculoskeletal conditions, such as RA, critically impair the health-related quality of life (HRQOL) of the patient. In its view, this impact was affected not only by the clinical manifestations of the illness but also by socioeconomic, personal, environmental and other factors [1]. Based on the World Health Organization assessment, the following domains would be considered of major concern for patients with RA: HRQOL (e.g. physical well-being, oppressive fatigue), psychosocial factors (e.g. social impact, impact on family life, loss in personal interaction), pain, burden on caregivers (e.g. time consumption, direct and indirect costs, mental implications), work-related issues (e.g. lost income, less productivity) and copayments or out-of-pocket expenditures (OOPEs).

Although there are many published clinical studies describing the epidemiology and clinical aspects of RA and its treatment, few publications focus on the cost and additional burden of the disease. Even fewer publications address the burden of the disease and its different facets from the perspective of the patient [2]. Understanding the view of the patient may be important for the interpretation of study results in this field of research. A patient's expectations toward an effective novel therapy may be different from a clinical expert's definition of an effective therapy. Similarly, a patient's satisfaction with a specific treatment may vary from a clinical assessor's point of view. Both expectations and satisfaction influence treatment preference decisions made by patients, who, as mentioned, are becoming increasingly responsible for their overall health care budget. Fortunately, patient-reported outcomes (PROs) are gaining importance among regulatory agencies such as the US Food and Drug Administration and the European Medicines Agency, who now consider the role of PROs in the evaluation of medicines not only for terminal diseases but also for chronic conditions such as RA [3, 4].

This article describes the burden of illness from the point of view of patients with long-standing severe RA receiving the tumour necrosis factor antagonist adalimumab during a 3-year open-label observational study. Adalimumab is the first fully human anti-tumour necrosis factor monoclonal antibody available for the treatment of RA. In clinical trials in patients with RA, adalimumab significantly reduced the signs and symptoms of the disease, improved physical function, and inhibited radiographic progression of joint damage [5–7]. Effects were sustained during long-term treatment of up to 4 yrs [8, 9]. Results from clinical trials and post-marketing surveillance studies have demonstrated the safety of adalimumab in patients with RA [10]. In economic evaluations, adalimumab achieved favourable cost-effectiveness ratios as compared with traditional DMARDs [11, 12].


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients and study design
This long-term, open-label, health outcomes extension study (DE033) included patients with long-standing RA who had received adalimumab therapy during one of six Phase I–III studies, all of which included a double-blind, randomized, placebo-controlled period of at least 12 weeks. In the open-label extension, all patients received adalimumab 40 mg every other week, regardless of whether they received placebo or adalimumab in the preceding study, and were observed for up to 144 weeks. The study was performed as a multinational study at 47 investigational sites in Europe (30 sites), Australia (9 sites) and Canada (8 sites). The study protocol was approved by an independent ethics committee or institutional review board at each study site. Informed consent was obtained from all patients before entering the study.

The largest of the preceding randomized dose-finding studies, DE026, was a pivotal 6-month, Phase III, placebo-controlled study. Because certain data in DE026 were collected in a manner similar to this study, data from patients in the placebo and adalimumab treatment arms are reported as a subset (DE026 subset) of this study.

Sociodemographic and medical history data were assessed at the baseline visit. To be able to further describe the patient cohort, clinical examination findings (e.g. joint examination, morning stiffness), disease assessments (patient's and physician's global assessments of disease activity and patient's assessment of pain) and HRQOL data were recorded every 8 weeks. The primary goal of the study was to assess patients who completed a health economic questionnaire at baseline and every 6 months, retrospectively recording outpatient resource use, impairments while working or housekeeping, use of alternative care, transportation, formal and informal help by caregivers, and copayments or OOPEs. The composition of the health economic questionnaires followed the recommendations described in the review by Rosery et al. [2]. The investigators completed similar questionnaires for inpatient resource use, medications and further resource use domains at baseline (capturing data for the 6 months prior to baseline) and at several time points during the study.

Data presentation
Data on resource use are presented in two formats: (i) resource or time consumption by natural units without monetary valuation in cost domains and (ii) copayments or OOPE in monetary terms using German item costs (pooling resource use data over all countries) on a per-patient basis. These cost calculations were based on official remuneration schemes of the German statutory health insurance scheme or other official sources (e.g. Uniform Valuation Scheme, EBM). Costs were based on the tariffs of 2003. Costs are displayed as reported during the overall study period. No discounting of costs was performed because the time frame was less than 3 yrs. Only RA-related resource use was included in this evaluation; costs related to comorbidities or other diseases were not included. All investigations that were attributable to the study (protocol driven costs) were excluded.

Baseline data collected retrospectively for the preceding 6 months were compared with data collected during the study. For comparison purposes, outcomes were standardized to 6-month periods. For dichotomous and categorical variables, absolute and relative frequencies were calculated. Means and standard deviations (S.D.) and/or standard errors of the mean (S.E.M.) were calculated for metric parameters. All data are presented on the basis of observed cases. Statistical analyses were performed using SAS® Version 8.2 (SAS Institute Inc., USA).


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Patients
A total of 505 patients were enrolled in this multinational study; the greatest number of enrollees was from Germany (n = 153). Of these, 303 patients were included in the preceding DE026 study and the remaining 202 patients were from the five other preceding studies. The mean follow-up period was 1.57 ± 0.63 yrs (median: 1.80 yrs). Patient characteristics are summarized in Table 1.


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  		TABLE 1. Demographic baseline data for open-label extension study (n = 505)

 
The majority of patients had long-standing, severe RA (disease duration of more than 12 yrs) and had previously failed approximately four DMARD therapies. Three-quarters of patients were female, reflecting the typical gender distribution of patients with RA within industrialized countries.

Clinical parameters
Pain
The mean pain score using a visual analogue scale (with scores ranging from 0 to 100; greater numbers indicate greater pain) was 33.52 ± 24.79 (median: 29.0; n = 453) at baseline and 29.87 ± 24.23 (median: 24.0; n = 358) at Week 144. Hence, patients did not experience a further rise in pain over time, maintaining treatment effects. Mean values among the DE026 subset of patients (n = 113) who received adalimumab 40 mg every other week were 70.1 ± 19.9 at baseline of that study and 27.6 ± 31.1 at Week 26 (baseline of this study) (P < 0.05 vs baseline and placebo), demonstrating a rapid onset of action.

Morning stiffness
Morning stiffness is a disease-specific factor important to patients. The mean total duration of morning stiffness decreased during the 3-yr study period (Table 2). The greatest decrease in morning stiffness duration occurred between Visit 1 and Visit 7 (Week 48). These decreases were maintained beyond Visit 7. For the DE026 subset (n = 113), the mean duration of morning stiffness at baseline was 133.4 ± 91.6 min. Morning stiffness was present for 67.3 ± 109.0 min after 26 weeks of treatment (P < 0.05 vs baseline and placebo). Other clinical outcomes, such as tender joint counts, also improved during the study (data not shown).


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  		TABLE 2. Total duration of morning stiffness by visit (min)

 
Copayments and OOPEs
Personal help
During the treatment period of up to 3 yrs, the percentage of patients receiving personal help was only slightly greater than it was at baseline (40.8 vs 48.7%, respectively). By far, patients received the greatest degree of personal help for tasks in the household, followed by help for personal care (Table 3). With the exception of child care, the majority of personal help was free of charge. The duration of personal help received per patient was not greater when the standardized 6-month treatment period was compared with the 6 months prior to baseline. In addition, the duration of personal help that was free of charge or paid for by the patient was smaller during the follow-up period (Table 4).


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  		TABLE 3. Type and duration of personal help

 

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  		TABLE 4. Duration of personal help (in hours) observed in the whole study population and type of payer

 
Transportation
At baseline and during the treatment period, the majority of patients needed transportation at least one time (Tables 5 and 6). Patients most frequently reported the need for transportation to the physician during both time periods (47.8% at baseline, 46.3% during the follow-up period), followed by transportation to a pharmacy (25.6% at baseline, 27.4% during the follow-up period). Analysed on a per-patient basis, the mean numbers of transportations needed during the treatment period (standardized to 6 months) and at baseline (6 months prior to baseline) were comparable. Regardless of the destination, journeys were generally paid for by the patient. Compared with baseline, slightly more journeys during the treatment period were free of charge (e.g. own car) and slightly fewer journeys were paid for by the patient or a third party (Tables 5 and 6).


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  		TABLE 5. Use of transportation by all patients by type of payer

 
Devices and aids
A total of 212 (42%) patients used at least one device or technical aid; 35.2% did not use any technical aids during the 6-month period preceding the study. There were no data for 22.8% of patients. Devices and aids used are presented in Table 7 by type of payer. Shoes, shoe padding and support, and aids for everyday use or household appliances were most frequently used by the patients. Overall, devices or aids were paid for with comparable frequency by the government and by the patient. Aids for everyday use or household appliances, constructional works in homes and raised beds were more frequently paid for by patients, whereas third parties more frequently paid for positioning or power splints, shoe padding or support and wheelchairs.


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  		TABLE 7. Payers for devices or aids 6 months prior to baseline

 
Productivity at work, sick leave
On average, patients worked ~30 h/week at baseline, regardless of whether they were employed, self-employed or homemakers. Self-employed patients (n = 28) and employed patients (n = 120) worked slightly more than 30 h/week (33.14 ± 16.41 and 30.89 ± 14.14, respectively), whereas homemakers (n = 209) tended to work slightly less (28.31 ± 18.85). The extent of impairment in productivity owing to RA was analysed using a 100 mm visual analogue scale, with values of 0 mm representing no impairment in productivity and values of 100 mm representing completely diminished productivity (Table 8). During the treatment period as well as at baseline, homemakers assessed their productivity as being more affected by RA than did employed or self-employed patients. Work productivity impairment decreased both at work and at home from baseline to the follow-up period (changes over time were not statistically significant). Work productivity data followed a skewed (vs normal) distribution. However, these findings may be interpreted as showing a trend towards maintaining the productivity levels in patients treated with adalimumab in this severely affected patient population.


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  		TABLE 8. Changed productivity at work owing to RA measured with a visual analogue scale

 
Table 9 presents the frequencies and durations of sick leave and disability caused by RA. Of the patients employed or self-employed, approximately one-third reported having to take sick leave as a result of RA at baseline. During the follow-up period, the percentage of patients who reported having to take sick leave was 47.1%, reflecting the longer time horizon of the study. During its 6-month treatment period, adalimumab decreased duration of sick leave vs the 6-month period prior to the study.


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  		TABLE 9. Duration of sick leave and temporary disability (in days) owing to RA

 
The percentages of patients requiring temporary disability enabling them to work in the household as a result of their RA were similar to those requiring sick leave, with approximately one-third requiring disability at baseline and approximately half requiring disability within the follow-up period. Adalimumab decreased the duration of disability during the study as compared with the 6-month period prior to the study (changes over time were not statistically significant).

Direct health care cost on a per-patient basis
Costs for the individual patient during follow-up were more than {euro}2120, with the greatest percentage coming from non-medical direct costs, such as personal help, transportation and devices and aids (Table 10). Table 10 does not include cost estimates for reduced productivity or early retirement. Natural units are displayed in Table 8. Patients have to cover all reported direct costs by themselves; there is no third-party payer. For at least half of the patients, no costs for home support/personal help and medical devices were documented (median costs for these items were considered to be zero). Patients who required home support (n = 246) paid a mean of {euro}3718.14 ± 7037.47 during the study period. Hence, those patients were significantly more affected by the disease economically than patients not receiving home support. Overall direct costs from a payers’ perspective were reported recently [13].


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  		TABLE 10. RA-related costs (in euros, 2003) during the study period using German item costa

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
This was an exploratory analysis to identify trends in patient-reported burden in RA. The results show that the burden of illness from a patient's view has additional and more detailed facets than typically assessed in daily practice or in clinical trial settings. These results should enhance the awareness of the daily challenges and additional financial burdens with which RA patients cope. In addition to the PRO data presented here, extensive HRQOL data (Short Form 36 Health Survey, Functional Assessment of Chronic Illness Therapy-Fatigue, Health Utilities Index Mark 3 scale, Health Assessment Questionnaire) were recorded during the study, and these data have been reported elsewhere [14–17].

Historically, pain is cited as the most critical factor influencing the burden of illness in patients with RA [18]. Reducing pain and oppressive fatigue are considered high priorities in RA management [19]. However, physical outcomes, such as pain, mobility and fatigue, are not the only important factors influencing burden of illness. From a patient’s view, psychosocial items (e.g., self-confidence, independence, living a normal life, coping with a new social role) should also be considered [20]. This implies the ability to manage daily activities, such as dressing, walking and housekeeping. One outcome from this follow-up study may be considered a weak surrogate or subdomain for those factors: physical independence. In this study, this aspect improved during adalimumab therapy, as evidenced by reductions in morning stiffness.

Patients with RA may experience social impairments in family life. Other family members may compensate for the tasks that the family member with RA is not able to perform. Such functional disabilities are strongly correlated with depression, which may lead to another source of increasing health care costs [21]. Psychological well-being is an important predictor for early DMARD discontinuation [22]. One of the prime directives accompanying DMARD therapy lies in influencing psychological factors, which are positively affected by a rapid onset of treatment success.

The burden of patients (and their caregivers) through formal and informal caregiving is an aspect often overseen by rheumatologists in their clinical assessment. As the results from this study indicate, patients carry a substantial financial burden from formal home help services. The fact that there also is an enormous impact on informal caregivers as well is often neglected. To the knowledge of the authors, researchers from The Netherlands are the only ones who have intensively evaluated informal caregiving and the medical, economic and HRQOL issues surrounding that field [23–25]. Results from this study showed a trend towards reduction by adalimumab in the need for both informal and formal personal care.

A complete picture of burden of illness also includes RA-related OOPEs and consequences of occasional illness-related absenteeism from work that may lead to work disability and early retirement. In their evaluation of data from the American National Data Bank for Rheumatic Diseases, Allaire and colleagues [26] demonstrated that premature work cessation is a serious problem in RA. In her editorial published in an issue of the Journal of Rheumatology dedicated to work impairment and its effects, Boonen [27] went so far as to include the ability to work in rheumatic patients as part of the human rights of everyone.

Determining the societal and personal impact of premature work cessation through patient-derived socioeconomic or PRO data is of major importance. Research groups led by Puolakka [28] and de Croon [29], respectively, demonstrate that socioeconomic and PRO data predicted future productivity losses. Biomedical variables had no predictive value in this issue. One unique feature of our study was highlighting the patients’ views in this area of research. Earlier works evaluated the perspectives of society or the payer [30]. They did not capture the burden to housekeepers, underestimating the overall work-related burden of RA in study cohorts, as more women and retired persons are suffering from RA. One focus of this observational study was to assess the productivity and work impairments of all study participants, regardless of whether patients were employed or homemakers. Results showed that patients were also able to maintain their productivity at work.

OOPEs are a significant issue for patients with chronic conditions [31]. US and European studies indicate that OOPEs for deductibles, copayments and payment of uncovered services account for up to 20% of total health care expenditures and that this portion of overall costs is increasing [32, 33]. However, these estimates did not include personal help among OOPEs, a facet explored in detail in this study.

This study had certain limitations. It was constructed as an open-label observational study and was designed to limit interference with the usual clinical therapy of patients receiving long-term treatment with adalimumab. However, because all participants were previously enrolled in one of six Phase II–III studies and most patients remained under the care of the same physician who enrolled them in those studies, they may have behaved as though they were still in a clinical trial. This may have biased the responses reported by patients. It also cannot be ruled out that patients may have reported resource uses that are not solely the result of RA, but could possibly be associated with comorbidity.

The study population included patients with long-standing severe RA who were receiving adalimumab after having failed four DMARDs on average. This population may not be representative of the general RA population. Because RA is a progressive, incurable chronic disease, patients in the general RA population may eventually face the functional limitations and cost burden displayed by the population in this study at some point in their lifetimes. The encouraging results of adalimumab treatment in this population indicate that adalimumab may have even greater and more profound effects if treatment were initiated in an early RA.

It may be argued that the use of patient and investigator questionnaires to recall data from the previous 6-month time frame could be considered a limitation of this study. An alternative methodological approach would have been to use health insurance claims data [34]. However, the latter approach was used for one region in one country only. This approach would have been insufficient for the purpose of this study focusing on the burden of illness from the patients’ view in a multinational setting. Claims databases in 11 different countries would not have been accessible or as comparable as the assessment through questionnaires. Furthermore, claims data results may not have been as transparent as the results from questionnaires applied in this study. Furthermore, the chosen approach is supported by recent work demonstrating that patients with a chronic condition such as RA are able to recall resource use with a substantial degree of detail when asked to report natural units [35]. Finally, the focus of this study was to observe trends in the burden of disease over the 3-yr period. Therefore, the estimates were not adjusted for patients dropping out of the study. These estimates are more qualitative in nature, but still provide useful information about a patient's burden of disease.

Several areas of research arise from the results of the current study. One question is whether all aspects of the patients’ views of their burden of illness were captured. The Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) group is leading the way in researching patients’ perceptions [36]. A deeper evaluation of what informal caregivers perceive as important in the overall burden of caregiving may provide additional information on how to reorganize ambulatory care and home services [37]. Another topic in the future would be determining which facets of the burden of disease substantially affect newly diagnosed RA patients treated with biologics and whether there is a difference between newly diagnosed patients with RA and those with long-standing RA, which may impact the management strategy of these patients.

Information on the burden of illness from the patient's view is of value to researchers owing to the complexity of associated items. Adalimumab treatment maintained or showed a tendency to improvement in most of these parameters during this prospective 3-yr observational study. These results are particularly encouraging given the late stage of disease of the patient population.

Formula


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  		TABLE 6. Total distance (in kilometres) of transportation used by type of payer

 


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors would like to acknowledge the editorial support of Lori Lush, JK Associates, Inc., in the preparation of this article.

Funding: The preparation of our publication was supported by an unrestricted educational grant by Abbott GmbH & Co KG, Germany. The underlying study was funded by Abbott as part of their clinical developing program.

Disclosure statement: B.D. is an Abbott employee. T.M. received an unconditional educational research grant from Abbott for analyses and preparation of the article. R.S. is an Abbott employee. H.K. is a full-time employee of Abbott. J.-M.vd.S. received an unconditional educational research grant from Abbott for analyses and preparation of the article. M.A.C. is a full-time employee at Abbott Laboratories where she holds stock and stock options in Abbott Laboratories.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 31 May 2007; revised version accepted 31 October 2007.
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