Efficacy, safety and patient-reported outcomes of combination etanercept and sulfasalazine versus etanercept alone in patients with rheumatoid arthritis: a double-blind randomised 2-year study

Abstract

Objective: To determine the efficacy and safety of etanercept and etanercept plus sulfasalazine versus sulfasalazine in patients with rheumatoid arthritis (RA) despite sulfasalazine therapy.

Methods: Patients were randomly assigned to etanercept (25 mg twice weekly; sulfasalazine was discontinued at baseline), etanercept plus sulfasalazine (unchanged regimen of 2-3 g/day) or sulfasalazine in a double-blind, randomised, 2-year study in adult patients with active RA despite sulfasalazine therapy. Efficacy was assessed using the American College of Rheumatology criteria, disease activity scores (DAS) and patient-reported outcomes (PRO).

Results: Demographic variables and baseline disease characteristics were comparable among treatment groups; mean DAS 5.1, 5.2 and 5.1 for etanercept (n = 103), etanercept plus sulfasalazine (n = 101) and sulfasalazine (n = 50), respectively. Withdrawal due to lack of efficacy was highest with sulfasalazine (26 (52%) vs 6 (6%) for either etanercept group, p<0.001). Patients receiving etanercept or etanercept plus sulfasalazine had a more rapid initial response, which was sustained at 2 years, than those receiving sulfasalazine: mean DAS 2.8, 2.5 versus 4.5, respectively (p<0.05); ACR 20 response was achieved by 67%, 77% versus 34% of patients, respectively (p<0.01) Overall, PRO followed a similar pattern; a clinically significant improvement in health assessment questionnaire was achieved by 76%, 78% versus 40% of patients, respectively (p<0.01). Commonly reported adverse events occurring in the etanercept groups were injection site reactions and pharyngitis/laryngitis (p<0.01).

Conclusion: Etanercept and etanercept plus sulfasalazine are efficacious for the long-term management of patients with RA. The addition of etanercept or substitution with etanercept should be considered as treatment options for patients not adequately responding to sulfasalazine.

Figure 1

Percentage of patients remaining in the study versus time (in weeks). Based on the log-rank test, the p values for the comparisons of the time to discontinuation are <0.001 (sulfasalazine versus etanercept), <0.001 (sulfasalazine versus combination), and 0.06 (etanercept versus combination).

Figure 2

Mean disease activity score (DAS) over time (in weeks; last-observation-carried-forward, modified intent-to-treat analysis). ▿ Etanercept plus sulfasalazine; • etanercept; ▪ sulfasalazine. ^*p<0.05 etanercept versus combination; ^†p<0.05 sulfasalazine versus combination; ^‡p<0.05 sulfasalazine versus etanercept.

Figure 3

Percentage of patients in each treatment group achieving an American College of Rheumatology (ACR) response (last-observation-carried-forward). (A) ACR 20; (B) ACR 50 and (C) ACR 70. ▿ Etanercept plus sulfasalazine; • etanercept; ▪ sulfasalazine. ^*p<0.01 etanercept versus combination; ^†p<0.01 sulfasalazine versus combination; ^‡p<0.05 sulfasalazine versus etanercept.

Figure 4

Mean health assessment questionnaire (HAQ) scores from baseline to week 104 for patients with rheumatoid arthritis receiving sulfasalazine (SSZ), etanercept (ETN), or combination therapy with sulfasalazine and etanercept (last-observation-carried-forward analysis). ▿ Etanercept plus sulfasalazine; • etanercept; ▪ sulfasalazine. ^*p<0.01 sulfasalazine versus etanercept; ^†p<0.01 sulfasalazine versus combination.

Figure 5

Health status at baseline and week 104 for patients with rheumatoid arthritis receiving etanercept, sulfasalazine, or combination therapy as measured by least squares means for EQ-5D, patient general health assessment (GHVAS) and global assessment of overall rheumatoid arthritis activity (PGAD) (last-observation-carried-forward analysis). (A) EQ-5D; (B) GHVAS; (C) PGAD.