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Increase in methotrexate dose in patients with rheumatoid arthritis who have an inadequate response to infliximab
  1. P Ornetti1,
  2. E Solau2,
  3. P Gaudin3,
  4. J Sibilia4,
  5. J-M Berthelot5,
  6. X Puechal6,
  7. C Tavernier1,
  8. J F Maillefert1,
  9. on behalf of the “Club Rhumatismes et Inflammation”, from the French Society of Rheumatology
  1. 1Department of Rheumatology, Dijon University Hospital, Dijon, France
  2. 2Department of Rheumatology, Lille University Hospital, Lille, France
  3. 3Department of Rheumatology, Grenoble University Hospital, Grenoble, France
  4. 4Department of Rheumatology, Strasbourg University Hospital, Strasbourg, France
  5. 5Department of Rheumatology, Nantes University Hospital, Nantes, France
  6. 6Department of Rheumatology, le Mans Hospital, le Mans, France
  1. Correspondence to:
    Dr J F Maillefert
    Department of Rheumatology, Hôpital Général, 3 rue du Faubourg Raines, 21000 Dijon, France;

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The strategy needed for patients with inadequate response to treatment with infliximab and methotrexate (MTX) is not well defined. It has been suggested that an increase in the infliximab dosage, a shortening of the intervals between infusions, or a switch to another anti-tumour necrosis factor α agent might provide clinical benefit.1–4 Another, less expensive, strategy might be to increase the MTX weekly dose in patients not co-treated with MTX at the maximal dose. This study aimed at evaluating the efficacy of increasing the MTX dose in patients with rheumatoid arthritis (RA) with active disease despite treatment with infliximab and MTX.


Data were obtained from six rheumatology departments that measure the 28 joint count Disease Activity Score (DAS28) before each infliximab infusion. All patients with RA with active disease (DAS28 ⩾3.2), despite treatment with a stable regimen of infliximab (3 mg/kg at 0, 2, 6 weeks, thereafter every 8 weeks) and MTX, in whom the MTX weekly dose was increased in order to obtain a better disease control, were included. The exclusion criteria were a change in corticosteroid daily dose or in infliximab regimen at the time of the change of MTX dose, or during the 16 weeks following. The DAS28 scores obtained at the first and second infusion after the change in MTX dose were compared with those obtained before the change (Wilcoxon paired test), and the percentages of responders (EULAR criteria) at the first and second infliximab infusion after the adjustment in MTX dosage were obtained.

A total of 22 patients with RA were included (15 female and 7 male, mean (SD) age 47 (9.1) years, mean (SD) disease duration 7.3 (3.9) years). At the time of adjustment of MTX dosage, patients had been treated with MTX and infliximab for a mean (SD) of 7.6 (6.4) months. The mean (SD) MTX weekly dose was increased from 9.9 (3.9) mg to a mean of 15 (4.3) mg because of primary (n = 8), or secondary infliximab treatment failure (n = 7) or because the response was judged to be insufficient (n = 7). The change was tolerated well in all patients. The DAS28 scores decreased significantly after the MTX dose adjustment (table 1). Five (23%) patients were considered as responders at 8 weeks (four moderate and one good response) and eight (36%) at 16 weeks (seven moderate and one good response) (fig 1). However, according to the EULAR criteria, 21 (95%) of the patients presented with active disease (DAS28 ⩾3.2) 16 weeks after the adjustment, and a disease remission (DAS28 ⩽2.6) was never observed.

Table 1

 Disease activity before, and at the first (8 weeks) and second (16 weeks) infliximab infusion after MTX dose adjustment

Figure 1

 percentage of patients with good and moderate response (EULAR criteria) 8 and 16 weeks after an increase in the MTX weekly dose.


These results might be regarded as disappointing: the mean disease activity showed only modest improvements, and the disease remained active in most patients. However, a response was observed in more than a third of the patients, a percentage which cannot be considered as anecdotal. This study was an observational cohort study, so it cannot be claimed that an increase in MTX dose is useful in patients with active disease despite infliximab treatment, because two main hypotheses can be put forward for explanation: (a) the increase in the MTX dose induces a clinical response in a relevant number of patients; (b) the observed results are due to a regression to the mean effect; adjustment in the MTX dose is likely to be proposed when disease activity increases, so the observed improvement in disease activity might have occurred without a change in the MTX dose. Such a hypothesis was recently proposed to explain the improvement observed after infliximab dose escalation.5

Further prospective studies are needed to determine the precise strategy to be used in patients with active RA despite infliximab treatment. While waiting for these, an increase in the MTX dose might be an inexpensive but well tolerated strategy which might be used as a first therapeutic option, or in combination with other changes in treatment for patients not treated with MTX at a maximal dose.


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