Methotrexate-induced immune haemolytic anaemia

A woman with metastatic breast carcinoma developed acute haemolytic anaemia on two occasions following treatment with methotrexate (MTX) and 5-fluorouracil (5-FU). The direct antiglobulin test was positive. Compatible control cells were pretreated with either MTX or 5-FU and subsequently incubated with patient and control sera. Agglutination in the indirect antiglobulin test was observed only in the presence of patient serum and MTX, and did not occur following pretreatment with 5-FU, folic acid, folinic acid or triamterene. There was no evidence of complement binding to the red cell surface. A macrophage assay showed increased phagocytic uptake of MTX-treated cells in the presence of patient serum. This phagocytosis was not enhanced by the addition of complement. The antibody subclass was predominantly IgG-3. The 51Cr red cell survival of autologous MTX cells was markedly shortened, indicating rapid in vivo destruction. These studies demonstrate the occurrence of acute haemolytic anaemia due to an IgG-3 antibody that reacts with erythrocytes in the presence of methotrexate. This antibody does not fix complement, but sensitizes red blood cells to phagocytosis by macrophages.