Cytopenia induced by low-dose methotrexate: An analysis of 433 cases from the French pharmacovigilance database


      • 40% of low-dose MTX-induced cytopenia occur in patients only exposed to MTX.
      • A toxic mechanism is much more frequently involved than an idiosyncratic reaction.
      • A triggering factor is found in almost two thirds of cases.
      • Low-dose MTX-induced cytopenia are also frequently due to MTX medication errors.
      • Older patients receiving MTX orally are at higher risk of MTX medication errors.



      Up to 5% of individuals exposed to low-dose methotrexate (MTX) (i.e., ≤30 mg/week) may develop cytopenia. However, MTX-induced cytopenia have been poorly described.

      Material and methods

      All cases of cytopenia (i.e., anaemia, leukopenia, thrombocytopenia, bi- or pancytopenia) in patients receiving low-dose MTX reported to the French pharmacovigilance database during 2006–2016 were analysed. Three groups were defined: cytopenia due to MTX medication errors (e.g., daily rather than weekly administration), cytopenia in people receiving several medications including MTX, cytopenia in people receiving only MTX.


      433 cases were analysed. Eighty-four cases (19.4%) were due to medication errors, 180 (41.6%) occurred in individuals exposed both to MTX and other drugs, and 169 (39.0%) occurred in individuals only exposed to MTX. By comparison to other patients, those with cytopenia due to medication errors were older (74 ± 13 vs 69 ± 15 years, p = 0.002), received more frequently MTX orally (92.9% vs 65.3%, p<0.001) and had more frequently pancytopenia (71.4% vs 54.4%, p = 0.005). By comparison to individuals exposed to multiple drugs (n = 180), those exposed only to MTX (n = 169) were older (71 ± 15 vs 67 ± 14, p = 0.02), and had more often pancytopenia (62.7% vs 46.7%, p = 0.001). Among those only exposed to MTX, most cases (n = 140, 82.8%) were considered as toxic rather than idiosyncratic reactions and a trigger (e.g. diarrhoea) was found in 59.3% of those cases. Overall 30 (6.9%) deaths occurred, including 8 in the “medication error” group and 8 in the “MTX only” group.


      These data may be useful for defining optimal biological monitoring of patients prescribed low-dose MTX.
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