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Dose escalation of leflunomide (LEF) to 40 mg once daily in patients with rheumatoid arthritis and insufficient response to standard dose LEF
  1. C Fiehn,
  2. E Rochel,
  3. A D Ho,
  4. R Max
  1. Department of Internal Medicine V, University of Heidelberg, Germany
  1. Correspondence to:
    Dr C Fiehn
    Centre for Rheumatic Diseases, Baden-Baden, Rotenbachtalstr 5, 76530 Baden-Baden, Germany;

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Leflunomide (LEF) is a new disease modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA) and it is recommended that it is given in a loading dose of 100 mg over 3 days followed by a stable dose of 20 mg/day.1,2 The dose of 20 mg/day LEF was recommended because in an initial study which compared 5, 10, and 25 mg/day LEF the highest dose tended to result in an increased rate of adverse events.3 However, in this study a clear dose-response relationship with best results in the 25 mg/day group was observed as well. Therefore, the aim of this investigation was to evaluate whether patients who tolerate LEF in the standard dose of 20 mg/day will tolerate a dose escalation of LEF to 40 mg/day and whether this improves the efficacy of the treatment.


Eleven patients with RA were included in this prospective clinical investigation (table 1). All had received LEF in a dose of 20 mg/day for at least 3 months without adverse effects, but still had active disease with a mean (SD) disease activity score (DAS284) of 4.9 (0.6) (range 3.9–5.8). All of them had responded to the prior treatment with 20 mg/day LEF, but either the response was not sufficient or the disease activity increased again despite continuous treatment.

Table 1

Characteristics of the patients with RA included in the study and effects of dose escalation of LEF from 20 to 40 mg once daily on disease activity and the occurrence of adverse events. The response was calculated according to van Gestel 1996 et al4 after 2 months of treatment with 20 mg LEF once daily. All adverse events were mild and reversible

To obtain better control of the disease the dose of LEF was increased from 20 to 40 mg p.o. once daily. The patients were monitored by analysing the disease activity and the occurrence of adverse events after 2 months of treatment and after every subsequent 2 months for as long as the patient was receiving 40 mg LEF.


Table 1 summarises the data obtained. After a mean (SD) follow up of 4.4 (3.7) months (range 0.5–11) 5 of 11 patients were still receiving treatment with 40 mg/day LEF. Four patients had stopped treatment with LEF or reduced the dose to 20 mg/day again because of adverse events: one patient with concomitant MTX treatment developed increased liver enzymes more than twice the normal values and stopped LEF 1.5 months after dose escalation. One patient who took concomitant rofecoxib reversed the dose escalation of LEF after 4 months because of glossitis, another patient after 2 weeks because of nausea and diarrhoea, and a third patient after 7 months because of abdominal pain of unknown origin. All adverse events were reversible after dose reduction of LEF. Six of 9 patients who were still receiving 40 mg/day LEF after 2 months responded to the dose escalation of LEF: two had a good response (reduction of DAS28 >1.2 and inactive disease) and four had a moderate response (reduction of DAS28 from 0.6 to 1.2 or active disease despite reduction of DAS28 >1.2) as defined by van Gestel et al 1996.4 Two patients showed no change in disease activity. In all five patients who continued to receive LEF in a dose of 40 mg/day, the response remained stable up to the last follow up.


In these preliminary findings the dose escalation of LEF to 40 mg/day seems to increase the effectiveness of the treatment in a number of patients with RA. The adverse events of the dose escalation which appeared in four of 11 patients were mild and reversible. If confirmed in larger studies, the dose escalation of LEF might be especially valuable for patients with RA who tolerate LEF at the standard dose of 20 mg/day but show insufficient response. For them the dose escalation might be a way to further improve disease activity and an alternative to an early switch to DMARD combination treatment or treatment with biological substances.