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Pharmacoeconomics of rheumatoid arthritis drugs

Sonja Merkesdal
Working Group Epidemiology and Health Economics
Department Rheumatology
Hannover Medical School

Jörg Ruof
Centre for Health Economics
University of Hannover

Thomas Mittendorf
Centre for Health Economics
University of Hannover

Henning Zeidler
Professor of Internal Medicine and Rheumatology
Working Group Epidemiology and Health Economics
Dept Rheumatology
Hannover Medical School
Hannover, Germany

Medication costs make up a substantial proportion of total disease-related costs in patients with rheumatoid arthritis (RA) and are of increasing importance due to the introduction of new and expensive biological drugs. Therefore economic aspects of antirheumatic drug treatment are playing an increasingly relevant role in treatment choice.

Calculating the cost of RA
Pharmacoeconomic assessments evaluate the costs related to an illness and the effectiveness or benefits of drug therapy in order to quantify the ratio of costs to clinical outcomes. Disease-related costs include direct costs (resource utilisation) and indirect costs (productivity losses). In patients with RA indirect costs play a major role, and cost-of-illness studies reveal that RA has an important economic impact similar to other chronic conditions like obstructive pulmonary diseases.(1)

Cost-of-illness studies in RA
Current cost-of-illness studies of RA vary widely in their estimation of overall costs. A recent review examined 10 studies, showing annual average direct costs of about e. 5,000 per patient (range from e. 1,610 to e. 9,970) and indirect costs ranging from e. 1,330 to e. 17,860.(1) The main cost components of annual direct costs per patient also vary extremely: inpatient costs e. 1,130–6,940, medication costs e. 220–1,300, physician costs e. 350–1,210, and costs for diagnostic and therapeutic procedures and tests e. 170–700. On average, costs related to RA medication account for about 15% of overall direct costs in these studies.

Two major reasons for this wide variation in costs have been identified. First, a defined core set of cost domains that should be covered by economic analyses is missing, and second, differences in the cost assessment methodologies used can be observed.(2)

A microcosting approach based on valid statutory health insurance plan data from the payer’s perspective revealed RA-related direct costs of e. 2,312, with medication costs accounting for 44% (e. 1,020 per patient-year), possibly reflecting earlier and increasing DMARD (disease-modifying antirheumatic drug) use and the availability of more expensive antirheumatic drugs (DMARDs accounting for 71% of medication costs).(3) These results indicate the growing impact of DMARD costs on the overall costs of RA. The present review focuses therefore on economic evaluations of these drugs.

Costs of DMARD treatment
In Germany, regular DMARDs incur annual medication costs ranging from e. 170 (oral methotrexate) up to e. 1,380 (IV methotrexate, hydroxychloroquine, sulfasalazine) per patient (see Table 1).(1) There is certainly a range of pricing data in different European countries, but a direct comparison has not been performed as yet. Leflunomide treatment is as costly as combination therapy with IV methotrexate, sulfasalazine and hydroxychloroquine, while ciclosporin A treatment costs are at least three times higher (e. 4,640). In comparison with these regular DMARDs, the costs of the new biological drugs are significantly higher (e. 16,650– 20,450/ year) – about 15 times higher than the combination of IV methotrexate, sulfasalazine and hydroxychloroquine.


The question arises as to whether these new and expensive drugs can reach similar cost-effectiveness ratios as regular DMARDs in the treatment of RA.

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Cost-effectiveness/cost-utility of DMARDs and biological treatments
Currently, there are only a few investigations of cost-effectiveness or cost-utility of DMARD and biological therapies in RA. Choi reports on the similar cost- effectiveness of the treatment of methotrexate-naive RA with methotrexate (versus no DMARD) and the treatment of methotrexate-resistant RA with the combination of methotrexate, hydroxychloroquine and sulfasalazine (versus continuation of methotrexate monotherapy).(5) Additional costs of US$1,100 and US$1,500 per ACR20 improvement occur (where US$1= e. 1), thus these therapies can be considered cost-effective. The ACR20 criteria are applied as a measure of disease activity in most economic evaluations and reflect the number of patients achieving at least 20% improvement in several clinical and serological outcomes.

Ciclosporin A treatment is less cost-effective than combination therapy (methotrexate, hydroxychloroquine and sulfasalazine) in methotrexate-resistant RA, with almost three times higher costs(5); similar results are shown in comparison with azathioprine therapy.(6) However, the cost-effectiveness of ciclosporin A in patients with RA refractory to combination therapy or azathioprine remains to be investigated.

Another cost-effectiveness analysis, by Choi, shows that both methotrexate and sulfasalazine are cost-effective in DMARD-naive RA (versus no DMARD).(7) Sulfasalazine was found to be both less expensive and more effective than leflunomide. The comparison of utilities and costs in methotrexate and leflunomide therapy reveals no significant differences except for the higher acquisition costs of leflunomide and hence higher overall treatment costs related to leflunomide.(8)

Combination therapy with methotrexate and etanercept in methotrexate-resistant RA incurred additional costs of US$1,1000 per ACR20 response, in comparison with methotrexate alone. The costs of methotrexate and etanercept per ACR20 amount to US$42,600 when compared with combination therapy with methotrexate, hydroxychloroquine and sulfasalazine.(5) The cost-effectiveness ratio of the methotrexate and etanercept combination in patients resistant to methotrexate, hydroxychloroquine and sulfasalazine combination therapy might be superior to the present results. Since the effectiveness of methotrexate and etanercept is not achieved by other DMARDs, this combination has to be regarded cost-effective, although the question arises whether these costs are socially acceptable.

Wong reports costs of US$30,500 (considering direct costs only) and of US$9,100 (considering overall costs from a societal perspective) per quality-adjusted life-year (QALY) for infliximab and methotrexate use in active, refractory RA over a period of 54 weeks.(9) These results confirm that the cost-effectiveness of the combination of infliximab and methotrexate is comparable to other accepted drug therapies and lies below US$50,000 per QALY gained (the threshold for a treatment being considered cost-effective in the US healthcare system).

Other cost-effectiveness studies find additional costs of US$12,150 per QALY gained administering etanercept (versus no DMARD) in refractory RA,(10) and even cost savings per QALY gained with combined infliximab and methotrexate when compared with methotrexate alone.(11)

Economic aspects of antirheumatic drug treatment
Significant direct and indirect disease-related costs are incurred by patients with RA. The proportion of medication costs is rising and thus of increasing importance since future choice of treatments will depend on economic aspects as well.

Current economic evaluations prove the cost-effectiveness of the DMARDs methotrexate and sulfasalazine in DMARD-naive RA, as well as the cost-effectiveness of combination therapy with methotrexate, sulfasalazine and hydroxychloroquine, as well as the biologicals (etanercept and infliximab) in methotrexate-resistant RA. Therapies that prove to be economically less efficient in the present studies still may be cost-effective in other patient groups, especially in those with previous multiple DMARD failures.

Biologicals like etanercept and infliximab show acceptable cost-effectiveness and utility-ratios (QALYs), comparable to those of other well-accepted and cost-effective treatments. The use of these expensive biologicals proves to be not only clinically effective but also economically efficient, and should form an important element of antirheumatic treatment in patients with methotrexate-refractory RA.

Shortcomings of economic evaluations
Some of the economic evaluations do not consider indirect costs. Since cost savings due to the reduction of productivity losses reflect a major component of the expected favourable economic effects of biologic regimens, inclusion of indirect costs is of great importance. The predominantly applied timeframe of six months is too short to capture the improvements of the biologicals’ greater effectiveness (especially considering indirect cost components). Future studies should aim at employing longer investigation periods (>12 months).

There is still a great need for further cost-effectiveness and cost-utility analyses in RA drug treatment. These analyses should focus on stratification of patients according to disease severity, and also on providing original data in patients with multiple previous DMARD failures.


  1. Merkesdal S, Ruof J, Mittendorf T, Mau W, Zeidler H. Health economic research in rheumatoid arthritis. Z Rheumatol 2002;61:21-9.
  2. Ruof J, Huelsemann JL, Stucki L. Evaluation of costs in rheumatic diseases: a literature review. Curr Opin Rheumatol 1999;11:104-9.
  3. Ruof J, Huelsemann JL, Mittendorf T, et al. Costs of rheumatoid arthritis in Germany: a micro-costing approach based on healthcare payer’s data sources. Ann Rheum Dis 2003. In press.
  4. Rote Liste 2000. German drug pricing list. Rote Liste Service GmbH, Frankfurt/Main, ECV, Editio Cantor Verlag, Aulendorf; 2000.
  5. Choi HK, Seeger JD, Kuntz KM. A cost-effectiveness analysis of treatment options for patients with methotrexate-resistant rheumatoid arthritis. Arthritis Rheum 2000;43:2316-27.
  6. Anis AH, Tugwell PX, Wells GA, Stewart DG. A cost effectiveness analysis of cyclosporine in rheumatoid arthritis. J Rheumatol 1996;23:609-16.
  7. Choi HK, Seeger JD, Kuntz KM. A cost-effectiveness analysis of treatment options for methotrexate-naive rheumatoid arthritis. J Rheumatol 2002;29:1156-65.
  8. Maetzel A, Strand V, Tugwell P, Wells G, Bombardier C. Economic comparison of leflunomide and methotrexate in patients with rheumatoid arthritis: an evaluation based on a 1-year randomised controlled trial. Pharmacoeconomics 2002;20:61-70.
  9. Wong JB, Singh G, Kavanaugh A. Estimating the cost-effectiveness of 54 weeks of infliximab for rheumatoid arthritis. Am J Med 2002;113:400-8.
  10. Brennan A, Bansback N, Conway P, Reynolds AV. Modelling the cost-effectiveness of etanercept in adults with rheumatoid arthritis (RA) in the UK. Arthritis Rheum 2001;44 Suppl 9:157.
  11. Kobelt G, Johnsson L, Lindquist E, Eberhardt K. Cost effectiveness of infliximab (Remicade) in Sweden. Arthritis Rheum 2001;44 Suppl 9:158.

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