title: Methotrexate or total lymphoid radiation for treatment of persistent or recurrent allograft cellular rejection: a comparative study.
abstract: BACKGROUND
  Methotrexate and total lymphoid irradiation (TLI) have been used successfully for treatment of recurrent and persistent rejection in orthotopic heart transplant recipients; however, there has been no comparison of these two modalities.
  
  
  METHODS
  We retrospectively compared the efficacy of methotrexate (n = 29) versus TLI (n = 28) in heart transplant recipients with recurrent or persistent rejection. All patients received induction therapy (rabbit anti-thymocyte globulin or OKT3) and standard triple immunosuppressive therapy. Methotrexate (7.5 mg to 22.5 mg per wk) or TLI (80 cGy x 10 fractions) was used for the treatment of recurrent or persistent rejection on the basis of clinical indications. Average biopsy scores (International Society of Heart and Lung Transplantation biopsy score/total number of biopsies performed) calculated over 3-month periods, daily maintenance prednisone dose before and after methotrexate or TLI treatment, and actuarial survival and freedom from angiographic coronary artery disease and infection were compared. To control for the general decrease in prednisone with increased time from transplantation, a control group matched for time from transplantation was selected.
  
  
  RESULTS
  Recipient sex and age at transplant, donor age, and donor ischemic time were similar in both groups. Days after transplantation to start of therapy was longer in patients receiving methotrexate; however, this did not reach statistical significance. Patients receiving TLI had received more cumulative corticosteroids and OKT3 before the start of TLI therapy (p < 0.001). There were no differences in actuarial freedom from infection or coronary artery disease between the two groups and between the treatment groups and the control group. Actuarial survival was reduced in patients receiving TLI 3 years after transplantation (p < 0.05). Maintenance prednisone doses from 3 months before until 9 months after therapy (mg/kg) were not different between patients receiving TLI and methotrexate and were significantly greater than the prednisone doses in the control group. Four months after treatment initiation, the prednisone dose was significantly reduced in both treatment groups compared with the pretherapy dose (methotrexate 0.28 +/- 0.16 to 0.22 +/- 0.13, p = 0.05; TLI 0.36 +/- 0.16 to 0.22 +/- .07, p < 0.001). The average biopsy score was significantly reduced by both methotrexate and TLI therapy (methotrexate 1.8 +/- 0.7 to 0.83 +/- 0.9, p = 0.0001; TLI 2.1 +/- 0.8 to 1.0 +/- 0.9, p = 0.0001).
  
  
  CONCLUSIONS
  Methotrexate and TLI are both effective for the treatment of recurrent or persistent rejection after heart transplantation, reducing average biopsy scores and daily maintenance prednisone doses. There was a reduction in actuarial survival rates in patients treated with TLI, possibly reflecting the greater rejection therapy received before TLI initiation. Because both agents are effective, the choice of methotrexate or TLI may be based on clinical indications, as well as other issues, such as cost, compliance, and availability.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, California, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Ross
authors.forename: L
authors.initials: L
authors.lastname: Gullestad
authors.forename: J
authors.initials: J
authors.lastname: Pak
authors.forename: S
authors.initials: S
authors.lastname: Slauson
authors.forename: H A
authors.initials: HA
authors.lastname: Valantine
authors.forename: S A
authors.initials: SA
authors.lastname: Hunt
mesh_terms: D000206:Actuarial Analysis; D000328:Adult; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000532:radiotherapy*; D016027:Heart Transplantation / Q000276:immunology* / Q000401:mortality; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015182:Lymphatic Irradiation; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D011241:Prednisone / Q000009:adverse effects / Q000627:therapeutic use; D012008:Recurrence; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D011241:Prednisone; D008727:Methotrexate