Cost-Effectiveness of Interventions for RA
The result of a decade of vigorous debate about the appropriate treatment strategies for RA appears to be a consensus that patients with moderate or severe RA should be treated early and aggressively, if possible, by combining several disease-modifying antirheumatic drugs (DMARDs) (Maetzel and others 2002).
The complex medical management of RA can involve the use of a large number of agents, including NSAIDs, low-dose corticosteroids, and a long list of DMARDs. The economic literature for interventions in RA has, for good reason, tended to focus on the cost-effectiveness of the alternatives that arise when a particular management strategy fails. In that sense, the intervention-based taxonomy used in earlier sections of this chapter is a less helpful way to characterize some of the contributions to this field. Thus, the subsections used in this part of the chapter reflect at times a problem-based taxonomy and at other times an intervention-based classification.
Treatment Modalities
One of the challenges common to the developing world is that specialized medical expertise is often scarce. Thus, the consideration of a variety of treatment modalities is worthwhile, especially those that involve labor substitution between specialist and nonspecialist categories. Unfortunately, relatively few studies of this kind, let alone large randomized studies, are available for RA.
In a nonrandomized study of 26 patients in Finland, Nordstrom and others (1996) compare the costs of treating RA patients either as inpatients or as outpatients. Even though the authors find that the cost of treating patients as outpatients was approximately one-sixth the cost of inpatient treatment, the small sample size and possible bias associated with the non-randomized design mean that the study's results cannot be generalized.
An interesting and possibly cost-effective strategy for managing RA involves the use of a telephone help line staffed by specialist nurses. Hughes and others (2002) examine the costs and benefits of such an intervention in the United Kingdom and conclude that it was cost saving. Their work was based on a sample of 87 RA patients who used the telephone help line in a given month. A large proportion of respondents indicated that they used the help line in place of a visit to a general practitioner, and on this basis, the authors computed that the service produced a net saving.
The existing evidence on the effectiveness and cost-effectiveness of a telephone help line for RA patients is based on a relatively small sample. Nevertheless, this type of intervention may be useful in developing regions with good communications but low levels of access to medical care. This type of intervention may be particularly worthy of consideration when direct access to a medical practitioner is associated with large travel costs.
Disease-modifying Antirheumatic Drugs
DMARDs include cyclosporine, azathioprine, D-penicillamine, sulfasalazine, etanercept, hydroxychloroquine, methotrexate, leflunomide, and gold compounds. Gabriel, Coyle, and Moreland (2001) provide a comprehensive review of the effectiveness and cost-effectiveness of DMARDs, including a comprehensive literature search in which they retrieved 30 articles from 500 identified for possible relevance. Only six of those papers included economic evaluations, and of those six, only three included measures of both benefits and costs. Only one of the articles used a nonclinical outcome measure (QALYs). Thus, the cost-effectiveness evidence for the use of DMARDs to treat patients with RA is generally scant.
The three full economic evaluations of DMARDs that Gabriel, Coyle, and Moreland identified were studies of auranofin (oral gold) (Thompson and others 1988), cyclosporine (Anis and others 1996), and combined therapy (Verhoeven and others 1998).
Auranofin
Thompson and others (1988) compare the cost-effectiveness of auranofin with that of a placebo using data from a six-month RCT of 311 patients with RA. The authors report that the cost of auranofin was approximately US$692 greater than for the placebo treatment, but the lack of efficacy of auranofin means that it is now rarely used in RA treatment.
Cyclosporine, Azathioprine, and D-penicillamine
In a Canadian study, Anis and others (1996) conduct a cost-effectiveness analysis of cyclosporine use in patients with RA based on the results of a meta-analysis of five RCTs. Their comparators included a placebo control, azathioprine, and D-penicillamine and analyses based on societal costs or third-party payer costs, but the ICERs were expressed as the cost per patient per year improved, so the results are difficult to interpret in the context of a general priority-setting exercise for health expenditures. For the purposes of this chapter, perhaps the study's most useful result was that it found no statistically significant differences between cyclosporine, azathioprine, and D-penicillamine.
Given that the existing evidence on cyclosporine, azathioprine, and D-penicillamine indicates similar levels of efficacy, cyclosporine should be used only after less expensive and more effective therapies for the management of RA, including azathioprine and D-penicillamine.
Combination Therapy
Verhoeven and others (1998) analyze the use of combination therapy using data from the Combinatietherapie Bij Reumatoide Artritis, or COBRA study, conducted in Europe between 1993 and 1995. The study was a 56-week trial that involved treating an intervention group with sulfasalazine, methotrexate, and prednisolone versus sulfasalazine alone as a control. Even though the authors conclude that combined therapy is cost-effective, they qualify the results by stating that the study was probably underpowered. Despite the lack of good cost-effective data, the standard approach to RA treatment is to use combination therapy with DMARDs and to maintain corticosteroids at 7.5 milligrams per day or less if possible.
Biologics
A number of trials have shown that the biologic agents (tumor necrosis factor inhibitors and others) are the most effective agents available for reducing inflammation in RA. Their cost (US$10,000 to US$15,000 per patient per year); mode of administration (intramuscular, subcutaneous, or by intravenous infusion); and potential side effects (particularly the reactivation of tuberculosis) preclude their use in developing countries. Until trials are carried out in developing environments and are combined with robust cost-effectiveness data, we cannot recommend their use.
Corticosteroids
Bae and others (2003) analyze the cost-effectiveness of low-dose corticosteroids for the long-term treatment of RA. They compare the results of corticosteroid treatment with treatment using any DMARDs plus a corticosteroid and with treatment using DMARDs and NSAIDs. Their modeling includes a consideration of the rates of relevant side effects of the treatments. They also look at NSAID-use scenarios that included Proton Pump Inhibitor prophylaxis and the use of COX-2-specific inhibitors rather than nonspecific NSAIDs.
The results generally showed that corticosteroids dominate nonselective NSAIDs in terms of their cost-effectiveness. The exceptions were when the adverse events rate for corticosteroids was assumed to be 1.5 times that of the base case and when the comparators' adverse events rates were assumed to be 0.5 to 1.0 times the base case rate. In the latter case, the cost per QALY was US$114,168, and in the former, NSAIDs were dominant. The comparison of COX-2-specific inhibitors with corticosteroids produced a higher-cost and higher-utility outcome: the resulting incremental cost per QALY was US$132,880.
The authors also produced useful age-specific estimates of the cost-effectiveness of the two alternative treatment approaches. Their ICERs show that corticosteroids dominate for the management of 50- and 60-year-olds with RA. For 40-, 30-, and 20-year-olds, the ICERs were US$11,258, US$30,938, and US$46,981, respectively.
The evidence suggests that a management strategy of DMARDs plus low-dose corticosteroids is a less costly and more effective strategy than DMARDs plus NSAIDs in older age groups, largely because of the higher risks of adverse gastrointestinal events in those groups. For developing countries, a relevant question to consider is the extent to which life expectancy and risk factors for adverse gastrointestinal events will differ from the age groups Bae and others (2003) studied. Corticosteroid-induced OP is also a long-term risk, but for women with RA starting corticosteroid therapy, watchful waiting is recommended as preferable to screening, as long as the steroid dose remains below 7 milligrams per day.
