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Leflunomide and methotrexate combination therapy in daily clinical practice
  1. A Dendooven,
  2. L De Rycke,
  3. X Verhelst,
  4. H Mielants,
  5. E M Veys,
  6. F De Keyser
  1. Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
  1. Correspondence to:
    Dr F De Keyser
    Department of Rheumatology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium; Filip.DeKeyser{at}

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A few years ago, the immunomodulatory molecule leflunomide was licensed as a new disease modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). Several randomised clinical trials have established its safety and efficacy, which is comparable to that of sulfasalazine and methotrexate.1,2 Some questions remain about the performance of this agent in current therapeutic strategies.3 One particular important query about the applicability of leflunomide is its use in combination therapy with methotrexate. Although there have been some conflicting opinions, it was shown by van Riel and Weinblatt et al that such combination therapy is safe and more effective than treatment with leflunomide or methotrexate alone.4,5 A major tool to confirm the usefulness of a drug in daily practice is a survival study. It informs clinicians about potential discrepancies with the results from randomised clinical trials, because patients included in a trial might differ from a real population in age, comorbidity, and atypical or refractory disease.

In this context, we examined the survival of leflunomide with or without concomitant methotrexate treatment in a Belgian clinical setting for a follow up period of 30 months. Our cohort consisted of 60 patients with RA with established disease and fulfilling the American College of Rheumatology classification criteria for RA.6 According to their rheumatologist, treatment with classical DMARDs was insufficient in all patients. They were treated with leflunomide as part of a compassionate sampling programme, for which enrolment took place between August 2000 and April 2002 in the rheumatology departments of three Belgian Centres (St Augustinus Hospital Antwerp, University Hospital Ghent, Elisabeth Hospital Sijsele-Damme).

All patients received a loading dose of 100 mg leflunomide for three consecutive days. Afterwards, leflunomide was given at a dose of 20 mg/day, with or without methotrexate, and this according to the rheumatologist’s decision. Forty of 60 patients received concomitant methotrexate from the start, at different doses. Twenty patients received leflunomide monotherapy. After 30 months, 37 (62%) of the 60 patients with RA were still receiving leflunomide treatment. In the groups with concomitant methotrexate and with leflunomide monotherapy 26/40 (65%), and 11/20 (55%), respectively, continued treatment (fig 1). Two major reasons for discontinuation were inefficacy and adverse events (respectively 18.3% and 15.0% at 30 months). The number and nature of adverse events were comparable in both groups and were mainly gastrointestinal (nausea, diarrhoea, raised liver enzymes), alopecia, anaemia, skin rashes, and hypertension. These side effects are consistent with those reported in previous studies.1,2,5

Figure 1

 Treatment duration and the percentage of patients still receiving leflunomide after 30 months in the total leflunomide cohort and in the leflunomide cohorts with and without concomitant methotrexate.

Another interesting observation is that whereas the leflunomide dosage remained stable during 30 months in the majority of the patients, the methotrexate dose was decreased in a substantial number of patients: it was reduced in 14 (35%) and even stopped in an additional 11 (27.5%) patients with RA. In contrast, it was increased in only four (10%) and remained stable in 11 (27.5%) patients with RA. This further supports the beneficial effect of combining both drugs.

Our observations indicate that combination therapy of leflunomide and methotrexate is useful in the treatment of RA in daily practice.


Leen De Rycke was supported by a grant from the “Vlaams instituut voor de bevordering van het wetenschappelijk-technologisch onderzoek in de industrie” (IWT/SB/11127).


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