Rheumatoid arthritis (RA) affects ∼1% of the population and is associated with disability and joint damage leading to reduced health-related quality of life (HRQOL), productivity loss, increased health care resource utilization, and premature mortality. Previous studies have shown that treatment for RA should be initiated as rapidly as possible and maintained to reduce the occurrence of irreversible joint damage (1). In the Tight Control of Rheumatoid Arthritis study (2), the impact of intensive management of patients with RA with frequent monitoring and drug changes in those who still had active disease was found to be much more effective than routine care. The Behandelstrategieën voor Reumatoide Artritis (BeSt) study advanced the evidence base with the inclusion of new treatment options and has become a pivotal study for changing treatment practice. However, implementing new treatment paradigms, particularly ones associated with increased initial costs, requires funding. In an economic climate of scarce resources, justifying rising costs is increasingly important.

In this issue of Arthritis Care & Research, van den Hout et al (3) report on the economic evaluation that was conducted in conjunction with the BeSt study, a randomized clinical trial of 508 patients over 12 months (4). The study collected a plethora of economic outcomes. Resource utilization diaries including medications, physician visits, and hospitalizations were prospectively collected. Health state utility values (HSUVs), which are used to incorporate the impact of HRQOL in cost-effectiveness calculations, were measured using preference-based instruments, and changes in paid and unpaid productivity predominantly through absenteeism were collected using questionnaires. Appropriate and sophisticated methodology (5) was then used to investigate which of the 4 treatment arms was the most cost-effective. By collecting such a wealth of information and implementing the analysis, it sets a new benchmark for designing clinical trials in RA in an era of economic constraints.

But how should policymakers, physicians, and patients interpret the results of this study? A primary result of this 24-month study is that the initial combination arm with infliximab generated the most quality-adjusted life years (QALYs; given no deaths within this time period, this essentially meant all improvements in QALYs were due to improved HRQOL), followed closely by the initial combination arm with prednisone (3). When comparing the costs between the 2 treatment strategies through reduced health care resources and improved productivity, in one analysis the infliximab arm was found to be cost saving. When a strategy gives more benefit at reduced cost, it is known as a dominating strategy. However, this is not the end of the story. Another analysis shows that, for the same comparison, the infliximab strategy has an incremental cost-utility ratio (ICUR) of £130,000 per QALY when compared with the prednisone strategy. How can the result vary so much?

First, in economic evaluation, different methods exist in how to value economic units. For valuing productivity loss, 2 methods are commonly used: the human capital approach and the friction cost method. For example, using the friction cost method, the ICUR for the initial combination therapy containing infliximab strategy to the initial combination therapy containing prednisone strategy was £130,000 (95% confidence interval [95% CI] £27,000, £3,000,000) per QALY compared with £22,000 (95% CI £−330,000, £1,500,000) per QALY. In contrast to many RA clinical studies, a number of HSUVs were measured directly in the study. These HSUVs permitted extensive secondary analyses using these different methods in calculating QALYs. The fact that the different methods of assessing HSUVs came up with similar patterns of results was reassuring, although the ICURs differed, which is consistent with other findings (6). It does not answer which HSUV should be believed.

Second, there are varying perspectives on which costs and outcomes to include. The societal perspective is commonly cited as the most appropriate method for conducting economic evaluation. However, many reimbursement authorities state in their guidelines that the payer perspective should be adopted. In recent changes to the National Institute for Health and Clinical Excellence guidelines, it is stated that “Some technologies may have a substantial impact on the costs (or cost savings) to other government bodies. In these exceptional circumstances, costs to other government bodies may be included if this has been specifically agreed with the Department of Health, usually before referral of the topic” (online at Whether the productivity costs will even be considered at all is questionable in many jurisdictions.

Finally, making decisions to fund new treatment paradigms has long-term impacts far beyond the 2-year time horizon of this clinical trial. For this reason, the focus of many recent cost-effectiveness studies (7) has been on models that extrapolate how short-term decisions might impact long-term outcomes rather than trial-based evaluations such as van den Hout et al describe (3). Within this analysis, it is unclear if the results would remain the same over a longer time horizon with increased time for radiographic changes and the development of adverse reactions to the various therapies. A more rapid cycle through treatments will inevitably lead to a higher requirement for new biologic therapies to switch to in case of toxicity or loss of efficacy. With different mechanisms of action, it is not clear from this study where those would stand compared with the ones that were investigated. Events such as joint replacements and changes in employment often only occur over years of treatment.

Although this study answers several questions related to the strategies included in the BeSt trial, there are still many questions remaining. As treatment paradigms continue to shift, most recently to treating people even earlier (within 12 weeks of onset) (8), and new therapies become available, this economic evaluation does not address all the issues that need to be considered in funding decisions. Although there is still much work to be done, this study sets the methodologic bar for future economic evaluations based on clinical trials in patients with RA. This study should be used as a methodologic template in giving guidance for parameters to collect and for methods to analyze results.


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