Safety and efficacy of leflunomide and infliximab versus methotrexate and infliximab combination therapy in rheumatoid arthritis

T. Cobo Ibáñez, M. Yehia Tayel, A. Balsa Criado, A. Hernández Sanz and E. Martín Mola

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 [1–4]. 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 {chi}2 test and Student's t-test. Drug survival analysis was done using Kaplan–Meier 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) 185–480 vs 556 days, 95% CI 391–720; P = 0.19]. More patients withdrew INF in the LEF group (65.2 vs 14.8%, P<0.05, survival 476 days, 95% CI 324–628 vs 1288 days, 95% CI 1173–1403; 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 222–535 vs 157 days, 95% CI 92–222; P = 0.013).


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TABLE 1. Baseline characteristics and causes of INF withdrawal

 
This study showed that patients in the LEF group had more severe infusion reactions leading to INF withdrawal. Other studies with the LEF-INF combination also reported an increase in the number of such reactions when compared with patients on INF alone [1]. This high number of adverse events has been partially explained by the concomitant initiation of the LEF and INF or the short interval between them [5]. In this study, all patients started LEF at least 6 months before INF. In agreement with Bingham et al. [4], we found high rates of positive ANA in the LEF-INF group, although the highest rates (100%) were reached by patients on MTX. Furthermore, none of our patients showed relevant clinical manifestations that could be attributed to this ANA production.

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

  1. Kiely PD, Jonson DM. Infliximab and leflunomide combination therapy in rheumatoid arthritis: an open-label study: Rheumatology 2002;41:631–7.[Abstract/Free Full Text]
  2. Hansen K, Cush J, Singhal A et al. The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis. Arthritis Rheum 2004;51:228–32.[CrossRef][Medline]
  3. Godinho F, Godfrin B, Elmahous S, Navaux F, Zabraniecki L, Cantagrel A. Safety of leflunomide plus infliximab combination therapy in rheumatoid arthritis. Clin Exp Rheumatol 2004;22:328–30.[ISI][Medline]
  4. Bingham SJ, Buch MH, Ker MA, Barcelos A, Emery P. Induction of antinuclear antibodies in patients with rheumatoid arthritis treated with infliximab an leflunomide. Arthritis Rheum 2004;50:4072–3.[CrossRef][ISI][Medline]
  5. Flendrie M, Creemers MCW, Welsing PMJ, Van Riel PLCM. The influence of previous and concomitant leflunomide on the efficacy and safety of infliximab therapy in patients with rheumatoid arthritis: a longitudinal observational study. Rheumatology 2005;44:472–8.[Abstract/Free Full Text]
  6. Arnett FC, Edworthy SM, Blotch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24.[ISI][Medline]
  7. Prevoo ML, van't Hof MA, Kuper HH et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8.[ISI][Medline]
Accepted 16 August 2005





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