Reversal of recalcitrant cardiac allograft rejection with methotrexate

Refractory cardiac transplant rejection is a major therapeutic dilemma. The effectiveness of methotrexate (MTX) in autoimmune diseases prompted us to explore its efficacy in 10 cardiac transplant recipients, aged 20-53 years (39 +/- 13 years; mean +/- SD), with biopsy evidence of drug-refractory cardiac allograft rejection. Nine cardiac transplant recipients were maintained on triple antirejection therapy (cyclosporine, azathioprine, and prednisone), and the remaining recipient was maintained on cyclosporine and prednisone. Rejection episodes treated with MTX occurred 20-422 days (165 +/- 137 days) after transplantation and were the sixth episode of rejection for one recipient, the third for four recipients, the second for four recipients, and the first for one recipient. Before MTX administration, cardiac allograft rejection persisted despite intensified immunosuppression including OKT3 antibody. MTX, given intravenously, orally, or by both routes at a dose of 10-175 mg (85 +/- 62 mg), reversed rejection in nine of 10 recipients (90%) within 7-63 days (26 +/- 18 days). Elevated pulmonary artery wedge pressures were reduced to normal levels after MTX therapy (15.2 +/- 3.5 before vs. 10.6 +/- 3.0 mm Hg after; p less than 0.05). Leukopenia occurred in five cardiac transplant recipients after treatment with MTX. Adverse reactions to MTX resolved after MTX therapy was discontinued in all but one recipient. This recipient received one of the larger MTX doses (150 mg) and developed fatal Pseudomonas pneumonia. Twelve moderate rejection episodes recurred in nine recipients, seven episodes of which were successfully re-treated with MTX. Two of these seven recipients have now been rejection-free for 15 months. Of five recurrent episodes of cardiac transplant rejection not treated with MTX, two could not be reversed and were fatal. MTX may be a valuable drug for reversing refractory cardiac allograft rejection. Before MTX therapy gains wider use, however, a clearer understanding of its enhanced ability to suppress the bone marrow is needed.