Department of Rheumatology, Hospital Universitario La Paz, Madrid, Spain
Correspondence to: T. Cobo Ibáñez, Department of Rheumatology, Hospital Universitario La Paz, P. Castellana 261, 28046 Madrid, Spain. E-mail: tcoboiba{at}yahoo.es
SIR, There is little experience about the safety and efficacy of the combination of leflunomide with infliximab (LEF-INF) in rheumatoid arthritis (RA), and published data have shown some controversy [14]. We have read with interest the paper of Flendrie et al. [5], where they compare previous and concomitant LEF therapy plus INF with treatment with INF plus other DMARDs [5]. In order to provide further information in this field we present our results on the safety and efficacy of LEF plus INF in comparison with administration of methotrexate plus infliximab (MTX-INF).
Fifty patients with active RA defined by the ACR criteria [6], seen between December 1999 and September 2004, were divided into two groups according to the treatment received, i.e. LEF or MTX. They were matched for sex, age and duration of disease at the start of INF therapy and their records were analysed. At baseline and before each INF infusion, 28-joint disease activity score (DAS28), ANA and anti-double-stranded DNA (anti-dsDNA; tested by indirect immunofluorescence and with the Crithidia luciliae assay) were performed and any adverse event or drug modification was recorded. A titre 1/40 and 15 IU/ml was considered positive for ANA and anti-dsDNAs, respectively. Categorical data were analysed using the
2 test and Student's t-test. Drug survival analysis was done using KaplanMeier life curves. P<0.05 was considered statistically significant. Informed patient consent was signed for all patients treated with infliximab.
Twenty three RA patients were included in the LEF-INF group and 27 in the MTX-INF group. Rheumatoid factor, DAS28 and mean number of DMARDs previously used were similar at baseline (Table 1). All patients on LEF started INF at least 6 months after beginning LEF therapy and 66.8% of these, had been treated with LEF for at least 1 yr. All patients except one had been treated previously with MTX and were switched to LEF mainly due to adverse events (73; 68%). In the MTX group all patients started treatment at least 1 yr before INF administration, and only six patients had received LEF before. Follow-up was 16.7 and 29 months in the LEF and MTX groups, respectively. There was no difference in efficacy measured by DAS28 between groups; DAS28 showed a moderate response (DAS28 was reduced >1.2) according to European League Against Rheumatism criteria [7]. We did not find differences between the LEF and MTX groups in the frequency of adverse events (69.6 vs 59.3%, P = 0.44), the number of adverse events (1.6±0.8 vs 2 ± 1.1, P = 0.29) or the duration of INF treatment before an adverse event [332 days, 95% confidence interval (CI) 185480 vs 556 days, 95% CI 391720; P = 0.19]. More patients withdrew INF in the LEF group (65.2 vs 14.8%, P<0.05, survival 476 days, 95% CI 324628 vs 1288 days, 95% CI 11731403; P<0.001), mainly due to adverse events. The causes of INF withdrawal, in both groups, are shown in Table 1. In brief, INF was interrupted in six patients in the LEF group and one patient in the MTX group, due to severe infusion reactions. Four patients in the LEF group and two receiving MTX discontinued INF, due to inefficacy (i.e. persistent high DAS28 score). One patient in the MTX group had a sudden death, apparently unrelated to the antirheumatic therapy. ANA were positive in 34.78 and 25.92% of the patients (not significant), before INF administration, in the LEF and MTX groups, and in 78.16% (LEF) and 100% (MTX) (P<0.05) at the end of follow up. Only one patient in the MTX group developed positive anti-ds-DNA without clinical manifestations. Positive ANA appeared earlier in the MTX-treated patients, although this difference was not statistically significant (378 days, 95% CI 222535 vs 157 days, 95% CI 92222; P = 0.013).
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Flendrie et al. [5] did not find more discontinuations in patients on LEF. Differences in the study design or even genetic differences might account for this discrepancy.
Our study confirms that LEF might be a valid alternative in non-tolerant MTX patients, but we suggest monitoring these patients closely due to the potential increase in severe infusion reactions.
The authors have declared no conflicts of interest.
References
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