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. 2001 Oct;60(10):913–923. doi: 10.1136/ard.60.10.913

Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine

D Scott 1, J Smolen 1, J Kalden 1, L B A van de Putte 1, A Larsen 1, T Kvien 1, M Schattenkirchner 1, P Nash 1, C Oed 1, I Loew-Friedrich 1
PMCID: PMC1753377  PMID: 11557646

Abstract

OBJECTIVE—Recent studies have demonstrated the short term efficacy of leflunomide. This study evaluates the efficacy and safety of leflunomide and sulfasalazine in rheumatoid arthritis over a two year follow up period.
METHODS—358 patients with rheumatoid arthritis in a double blind trial were randomly allocated to receive either leflunomide 20 mg/day, placebo, or sulfasalazine 2 g/day. Those completing six months of treatment (n=230) were given the option to continue in 12 (n=168) and 24 (n=146) month double blinded extensions; the placebo group switched to sulfasalazine. This report compares efficacy and safety of leflunomide with sulfasalazine in the 6, 12, and 24 month patient cohorts.
RESULTS—The efficacy seen at six months was maintained at 12 and 24 months. Twenty four month cohorts on leflunomide showed significant improvement compared with sulfasalazine in doctor (−1.46 v −1.11, p=0.03) and patient (−1.61 v −1.04, p<0.001) global assessments, ACR20% response (82% v 60%, p<0.01), and functional ability (Δmean HAQ −0.65 v −0.36, p=0.0149; ΔHAQ disability index −0.89 v −0.60, p=0.059). Improvement in other variables was comparable for the two drugs, including slowing of disease progression. Improved HAQ scores in 6, 12, and 24 month leflunomide cohorts were seen in both non-responders (24%, 29%, 35%, respectively v sulfasalazine 8%, 10%, 27%) and ACR20% responders (leflunomide 63%, 62%, 66% v sulfasalazine 50%, 64%, 44%). Leflunomide is well tolerated at doses of 20 mg. No unexpected adverse events or late toxicity were noted during the two year period. Diarrhoea, nausea, and alopecia were less frequent with continued treatment.
CONCLUSION—These long term data confirm that leflunomide is an efficacious and safe disease modifying antirheumatic drug.



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Figure 1  .

Figure 1  

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Study design. LEF= leflunomide; SSZ = sulfasalazine; PL = placebo; PL-SSZ = PL group switched to sulfasalazine; R = ACR20% responders; NR = ACR non-responders.

Figure 2  .

Figure 2  

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Mean changes (SD) in (A) tender and (B) swollen joint counts in 0-6 (LEF = 130, SSZ = 132, PL = 91), 0-12 (LEF = 78, SSZ = 74, PL-SSZ = 37), and 0-24 (LEF = 60, SSZ = 57, PL-SSZ = 25) patient cohorts at 6, 12, and 24 months. LEF = leflunomide; SSZ = sulfasalazine; PL = placebo; PL-SSZ = PL group switched to sulfasalazine. Baseline tender joint counts were: 0-6 month cohort (LEF = 18.8, SSZ = 16.7, PL = 16.3), 0-12 month cohort (LEF = 18.7, SSZ = 15.8, PL = 14.9), and 0-24 month (LEF = 18.4, SSZ = 15.7, PL = 14.1). Baseline swollen joint counts were: 0-6 month cohort (LEF = 16.2, SSZ = 15.3, PL = 15.8), 0-12 month cohort (LEF = 16.3, SSZ = 15.0, PL-SSZ = 14.4), and 0-24 month (LEF = 16.7, SSZ = 15.2, PL-SSZ = 13.9). Numbers in parentheses represent the percentage change from baseline. *p<0.0001 v PL.

Figure 3  .

Figure 3  

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Mean changes (SD) in (A) patient and (B) doctor global scores in 0-6 (LEF = 130, SSZ = 132, PL = 91), 0-12 (LEF = 78, SSZ = 74, PL-SSZ= 37), and 0-24 (LEF = 60, SSZ = 57, PL-SSZ = 25) patient cohorts at 6, 12, and 24 months. LEF= leflunomide; SSZ = sulfasalazine; PL = placebo; PL-SSZ = PL group switched to sulfasalazine. Baseline doctor global scores were: 0-6 month cohort (LEF = 3.6, SSZ = 3.5, PL = 3.5), 0-12 month cohort (LEF = 3.7, SSZ = 3.5, PL-SSZ = 3.3), and 0-24 month (LEF = 3.6, SSZ = 3.4, PL-SSZ = 3.3). Baseline patient global scores were: 0-6 month cohort (LEF = 3.7, SSZ = 3.6, PL = 3.6), 0-12 month cohort (LEF = 3.7, SSZ = 3.6, PL-SSZ = 3.4), and 0-24 month (LEF = 3.7, SSZ = 3.5, PL-SSZ = 3.3). Numbers in parentheses represent the percentage improvement from baseline. * p<0.001 v PL; †p<0.001 v SSZ.

Figure 4  .

Figure 4  

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Changes in Health Assessment Questionnaire (HAQ) scores in 0-6 (LEF = 106, SSZ = 113), 0-12 (LEF = 66, SSZ = 62), and 0-24 (LEF = 51, SSZ = 45) patient cohorts at 6, 12, and 24 months. LEF= leflunomide; SSZ = sulfasalazine. Overall (O) HAQ scores as well as scores in ACR20% responders (R) and non-responders (N) are shown. *p<0.01, v SSZ.

Figure 5  .

Figure 5  

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ACR20%, 50%, and 70% response rates in 0-6 (LEF = 130, SSZ = 132), 0-12 (LEF = 78, SSZ = 74), and 0-24 (LEF = 60, SSZ = 57) patient cohorts at 6, 12, and 24 months. LEF= leflunomide; SSZ = sulfasalazine. *p<0.05, v SSZ; †p<0.01, v SSZ.

Figure 6  .

Figure 6  

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Response rates (ACR20% and Paulus 20%) in completers (LEF = 60, SSZ = 57) from 0 to 24 months. LEF= leflunomide; SSZ = sulfasalazine. *p<0.05, v SSZ.    

Selected References

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