Is the recommended dose of leflunomide the best regimen to treat rheumatoid arthritis patients?

A. Erra, C. Tomas, P. Barcelo, M. Vilardell1 and S. Marsal

Unitat de Reumatologia and
1 Servei de Medicina Interna, Hospital General i Universitari Vall d'Hebron, Barcelona, Spain

SIR, The aim of this letter is to show our experience in the use of leflunomide (LFN) and express our opinion about the recommended dose [1, 2]. As far as we know, no data exist about a possible association between the loading dose and the presence of adverse events. Any new suggestion about the use of LFN should be appreciated, specially after the safety of this drug has been questioned.

In our clinical practice we have observed that patients starting LFN contact us very early after initiating the drug because of the presence of adverse events. Furthermore, we appreciated that the introduction of LFN (at a lower loading dose) in patients taking methotrexate is best tolerated. On the basis of these two clinical observations we decided to reduce the loading dose of leflunomide so that a large number of patients could benefit from this drug. We analysed our data retrospectively, looking for a possible association between the period in which the adverse events appeared and the loading dose. We focused primarily on the presence of adverse events and secondarily on its clinical efficacy.

Thirty-five rheumatoid arthritis patients taking LFN were included in this study. Adverse events were classified as serious if LFN was withdrawn and mild if it was not withdrawn. Early serious adverse events were defined as those that appeared in the first month of therapy. The clinical efficacy was evaluated according to the ACR20 response criteria.

The sex ratio (male:female) of the patients was 1:4 and their mean age was 58 yr. The mean disease duration was 15 yr (range 4–34 yr) and 25 patients were positive for rheumatoid factor. The number of DMARDs (disease-modifying anti-rheumatic drugs) used before LFN was 4.2. The drugs used concomitantly with LFN were NSAIDs (non-steroidal anti-inflammatory drugs) (31%), prednisone (57%) (mean dose 5.3 mg/day), methotrexate (29%) (mean dose 18 mg/week), hydroxychloroquine (6%) and cyclosporin (6%).

In our study the following dose schedule was observed: 14 (40%) of patients had a loading dose of 300 mg, 14 (40%) had a loading dose of 200 mg, and seven (20%) patients had no loading dose.

Sixty-nine per cent of the patients (n=24) achieved an ACR20 response at 3 months, 17% (n=6) were non-responders (ACR <20) and in five patients (14%) LFN was discontinued before efficacy could be evaluated.

Twenty-two patients (63%) had adverse events (Table 1Go). The most common were diarrhoea (eight patients, 23%) and proctitis (four patients, 11%). LFN had to be withdrawn in three patients with proctitis because of its severity. The symptoms occurred very early after starting the LFN and the patients affected had to use a hospital emergency service. LFN was also withdrawn in 25% of patients with diarrhoea, which also appeared very soon after starting treatment. Other previously reported [2, 3] side-effects of LFN were observed at a low frequency (<9%).


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TABLE 1. Adverse events in rheumatoid arthritis patients treated with leflunomide

 
We did not find a significant association between the presence of adverse events and the loading dose (Table 1Go). However, the data indicate that our failure to detect a significant difference in the frequency of side-effects between patients taking and those not taking a loading dose probably arose because the numbers were too low rather than because there was no difference (43 vs 68%). Furthermore, when we looked at the time when the serious adverse events appeared we found that 66% of the patients with an early serious adverse event had taken a loading dose of 300 mg.

In summary, in our series of rheumatoid arthritis patients treated with LFN, adverse events were frequent but in most cases the drug was well tolerated. There was no correlation between the loading dose and adverse events, but it is possible that a correlation exists between the loading dose and the occurrence of early serious adverse events. LFN is an effective treatment for the clinical control of rheumatoid arthritis and it is possible that the clinical efficacy in the long term is not influenced by the loading dose.

Large prospective studies exploring new dose regimens are needed in order to improve the safety of this drug. A large number of patients may benefit from LFN if the dose is adjusted.

Notes

Correspondence to: Dr Sara Marsal. E-mail saramarsal{at}eresmas.com Back

References

  1. Mladenovic V, Domljan Z, Rozman B et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis: results of a randomized, placebo-controlled, phase II study. Arthritis Rheum 1995;38:1595–603.[ISI][Medline]
  2. Smolen JS, Kalden JR, Scott DL et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. Lancet 1999;353:259–66.[CrossRef][ISI][Medline]
  3. Emey P, Breedveld FC, Lemmel EM et al. A comparison of the efficacy and safety of leflunomide and metotrexate for the treatment of rheumatoid arthritis. Rheumatology 2000;39:655–65.[Abstract/Free Full Text]
Accepted 27 January 2003