title: Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases.
abstract: OBJECTIVE
  To determine the clinicopathologic features of lymphoproliferative disorders (LPD) that occur in the setting of methotrexate (MTX) therapy for rheumatic diseases (RD) and to define the relationship between the presence of Epstein-Barr virus (EBV) in tumor cells and the response of LPD to MTX withdrawal.
  
  
  METHODS
  In addition to nine new cases, we analyzed 28 cases previously reported in the literature of LPD in patients receiving MTX for RD. In addition to MTX, immunosuppressive therapy included corticosteroids in 19 patients, azathioprine in three, and cyclosporine in one. Extranodal disease was identified in 16 patients, but none had CNS involvement. Pathologic findings included five cases of Hodgkin's disease and seven low-grade lymphomas. The remaining patients had intermediate or aggressive lymphomas. In situ hybridization studies (ISHS) for EBV-RNA transcripts were positive in 12 of 27 patients (44%).
  
  
  RESULTS
  Among 37 patients, 16 were initially observed after MTX withdrawal without additional antitumor therapy. Six achieved a spontaneous complete remission (CR), three had a partial response (PR), one had a minimal response, and six had no response to MTX withdrawal. Of 10 responding patients, EBV was detected by ISHS (n = 6) or polymerase chain reaction (PCR) (n = 2); one patient had a CR despite the absence of EBV by PCR and one had a CR but did not have viral assays performed. Only one of six patients with negative EBV by ISHS or PCR responded to MTX withdrawal.
  
  
  CONCLUSIONS
  MTX withdrawal and observation for a short period should be considered in the initial management of patients who develop LPD while on MTX therapy. Responses were consistently observed, but not limited to patients in whom EBV was detected by ISHS or PCR. Further studies are required to confirm these findings and to evaluate the role for EBV in LPD that occur in patients receiving MTX.
authors.affiliation: Department of Medicine, Yale University School of Medicine, Yale Cancer Center, New Haven, CT 06520-8032. emile-salloum@qm.yale.edu
authors.forename: E
authors.initials: E
authors.lastname: Salloum
authors.forename: D L
authors.initials: DL
authors.lastname: Cooper
authors.forename: G
authors.initials: G
authors.lastname: Howe
authors.forename: J
authors.initials: J
authors.lastname: Lacy
authors.forename: G
authors.initials: G
authors.lastname: Tallini
authors.forename: J
authors.initials: J
authors.lastname: Crouch
authors.forename: M
authors.initials: M
authors.lastname: Schultz
authors.forename: J
authors.initials: J
authors.lastname: Murren
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D005260:Female; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008232:Lymphoproliferative Disorders / Q000139:chemically induced* / Q000821:virology; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged
chemical_list: D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D008727:Methotrexate