Some patients who have received long-term methotrexate therapy may develop a lymphoproliferative disorder. Some of these disorder disappear if methotrexate is discontinued but others progress to malignant lymphoma or Hodgkin's disease.


Most patients have rheumatoid arthritis and have been treated with methotrexate for months or years prior to onset of the lymphoproliferative disorder.


Factors to investigate in each patient:

(1) other medications that may be associated with lymphoproliferative disorders such as 6-mercaptopurine or immunomodulating antibodies

(2) the underlying disease being treated (which may be associated with an increased risk for lymphoma)

(3) evidence of Epstein Barr virus (EBV)

(4) course (reversibility on drug discontinuation or progression)


Moseley et al reported a patient with a lymphoproliferative disorder that reversed after discontinuation of methotrexate therapy, only to develop Hodgkin's disease later.



(1) a patient receiving long-term methotrexate should be monitored for signs of a lymphoproliferative disorder

(2) a patient receiving methotrexate who develops lymphoma should not be treated until the methotrexate has been discontinued and sufficient time has passed to identify reversibility

(3) a patient with a reversible lymphoproliferative disorder should be monitored for later development of a lymphoproliferative disorder

(4) if the methotrexate is stopped then do not restart it later


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