Factors Associated with Myelosuppression Related to Low-Dose Methotrexate Therapy for Inflammatory Rheumatic Diseases

PLoS One. 2016 Apr 29;11(4):e0154744. doi: 10.1371/journal.pone.0154744. eCollection 2016.


Objective: Severe myelosuppression is a serious concern in the management of rheumatic disease patients receiving methotrexate (MTX) therapy. This study was intended to explore factors associated with the development of MTX-related myelosuppression and its disease severity.

Methods: We retrospectively examined a total of 40 cases of MTX-related myelosuppression that had been filed in the registries of participating rheumatology and hematology divisions. Data before onset were compared with those of 120 controls matched for age and sex. Cytopenia was graded according to the National Cancer Institute criteria for adverse events. Data before and at onset were compared between the severe and non-severe groups.

Results: Non-use of folic acid supplements, concurrent medications, and low renal function were significantly associated with the development of myelosuppression (p < 0.001, p < 0.001, and p = 0.002, respectively). In addition, significantly lower MTX dosages, higher blood cell counts, and lower hemoglobin levels were seen in the myelosuppression group (p < 0.001). No patients exhibited leukocytopenia, neutropenia, or thrombocytopenia in routine blood monitoring taken within the past month. One-fourth developed myelosuppression within the first two months (an early-onset period). Myelosuppression was severe in approximately 40% of patients. Hypoalbuminemia and non-use of folic acid supplements were significantly associated with the severity of pancytopenia (p = 0.001 and 0.008, respectively). Besides these two factors, early onset and the use of lower doses of MTX were significantly associated with the severity of neutropenia (p = 0.003, 0.007, 0.003, and 0.002, respectively).

Conclusions: Myelosuppression can occur abruptly at any time during low-dose MTX therapy, but severe neutropenia is more likely to occur in the early-onset period of this therapy. Contrary to our expectations, disease severity was not dependent on MTX doses. Serum albumin levels and folic acid supplementation are the important factors affecting the severity of MTX-related pancytopenia and neutropenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antirheumatic Agents / administration & dosage
  • Antirheumatic Agents / adverse effects*
  • Arthritis, Rheumatoid / drug therapy
  • Case-Control Studies
  • Female
  • Folic Acid / administration & dosage
  • Hematologic Diseases / blood
  • Hematologic Diseases / etiology*
  • Humans
  • Hypoalbuminemia / blood
  • Hypoalbuminemia / complications
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects*
  • Middle Aged
  • Neutropenia / blood
  • Neutropenia / etiology
  • Pancytopenia / blood
  • Pancytopenia / etiology
  • Retrospective Studies
  • Rheumatic Diseases / drug therapy*
  • Risk Factors
  • Serum Albumin / metabolism


  • Antirheumatic Agents
  • Serum Albumin
  • Folic Acid
  • Methotrexate

Grant support

This study was supported by research funds from the National Hospital Organization (NHO), Japan. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.