A combination regimen consisting of prednisolone, methotrexate, and sulfasalazine may produce more robust clinical responses at equal or lower cost than sulfasalazine alone for the treatment of early rheumatoid arthritis (RA), according to Dutch researchers whose findings were published in the September issue of the Journal of Rheumatology.

According to investigators from Vrije University Medical Center in Amsterdam, The Netherlands, the Combinatietherapie Bij Reumatoide Artritis (COBRA) regimen not only produced demonstrable improvement in functional abilities among patients with early RA over a 28-week period compared with sulfasalazine alone, but the combination therapy was more than $1000 lower in indirect costs to the patient.

In the first 28 weeks of a 56-week trial, the indirect costs averaged US $2578 per patient in the COBRA group and $3,638 in the sulfasalazine group (P = 0.09). (Indirect costs were defined as a loss of work or absenteeism and productivity attributed to the RA.) "This study confirms that COBRA therapy is more effective compared to sulfasalazine in patients with early RA, and [that it produces] better disease control at equal or lower total costs," noted senior author, Maarten Boers, MD, PhD, professor of clinical epidemiology in the Department of Clinical Epidemiology and Biostatistics at the Vrije University Medical Center.

Total expenditure for that period of the trial (which, in addition to indirect costs, included costs of interventions, additional medications, periods of hospitalization, and visits to health-care providers) averaged $5931 for patients in the COBRA group and $7853 for individuals in the sulfasalazine group (P <0.05).

To assess the cost-effectiveness of the two regimens relative to efficacy, the investigators randomly assigned 76 patients with early RA to a combination of sulfasalazine (2 g/d), methotrexate (7.5 mg/wk) and prednisolone (60 mg/day), and 79 to sulfasalazine alone. The prednisolone and methotrexate were tapered and stopped from the COBRA regimen after 28 and 40 weeks, respectively.

The clinical and radiographic results, which had been published previously, "indicated that the yearly radiographic progression remained lower in the COBRA group, despite similar treatment and disease activity levels," the investigators wrote. They used a pooled index and radiographic damage score in the hands and feet to assess the utility of these treatments.

Direct and indirect costs were measured using diaries and interviews that the patients completed during the intervention and follow-up phases, each lasting 28 weeks.

"The key message is that COBRA is the dominant therapy compared to sulfasalazine alone," Dr. Boers said. "Measurement of indirect costs is difficult, and the contrast between the study arms may easily be lost due to chance imbalances between the relatively small study groups. The fact that we did find differences strengthens our earlier findings [assessing the direct costs of the two therapies]."

"The implications are that COBRA-like strategies provide strong competition for the more expensive, newer classes of drugs, especially the biologics," Dr. Boers said.

However, the differences in cost effectiveness between the COBRA regimen and sulfasalazine alone disappeared in the second 28-week arm of the study, when prednisolone and methotrexate were tapered and withdrawn. "These advantages were no longer significant when prednisolone and [methotrexate] were stopped," the authors wrote. "We suggest both validity and discrimination can increase when indirect costs are included in economic studies in RA."

"It is well known that trials are usually underpowered to demonstrate cost differences with sufficient (statistical) confidence," they continued. "Despite the considerable difficulties of assessing indirect costs adequately, the first [28 week] semester results of this study show that where such costs play an important role, power may actually be gained by including these costs in the analysis."

For the total study period, the mean total costs were $10,262 per COBRA patient and $12,788 per sulfasalazine patient (P = 0.11). When the investigators determined a point estimate of the cost per quality-adjusted life-year, the difference was $385 less for COBRA. These findings suggested that COBRA was more effective at a lower cost than was sulfasalazine alone. Therefore, they concluded that the COBRA regimen in early RA adds additional disease control at a lower or equal cost compared to sulfasalazine alone.

"We are now looking at further intensifying COBRA to achieve more remissions, and wide implementation of the COBRA strategy in routine clinical practice," Dr. Boer told CiaoMed.

Reference

Korthals-de Bos I, van Tulder M, Boers M, et al. Indirect and total costs of early rheumatoid arthritis: a randomized comparison of combined step-down prednisolone, methotrexate, and sulfasalazine with sulfasalazine alone. J Rheumatol. 2004;31:1709–1716.