title: Clinicopathological characteristics and rituximab addition to cytotoxic therapies in patients with rheumatoid arthritis and methotrexate-associated large B lymphoproliferative disorders.
abstract: OBJECTIVE
  To analyse the clinicopathological characteristics and prognosis of 40 rheumatoid arthritis (RA) patients with methotrexate (MTX)-associated large B cell lymphoproliferative disorders (MTX-BLPD).
  
  
  RESULTS
  Soluble interleukin 2 receptor titres (median 1500 U/ml) in 40 patients with MTX-BLPD were lower than those of 24 RA patients with non-MTX- associated (non-MTX) BLPD (5731 U/ml) and 15 with control diffuse large B cell lymphoma (DLBCL, 5918 U/ml) (P < 0.01). Using in-situ hybridization, Epstein-Barr virus (EBV) was detected in tumour cells of 25 of 40 RA patients with MTX-BLPD (63%). Immunohistologically, BCL2 expression was detected in 35% of patients with MTX-BLPD, which was lower than 93% of control DLBCL patients (P < 0.01). Eleven patients with EBV(+) MTX-BLPD (44%) showed remission after MTX withdrawal. In RA patients with clinical stage III/IV BLPD, 15 with rituximab (R)+ cytotoxic therapies pursued better prognosis than 10 with R- cytotoxic therapies (P < 0.05). Among the 15 patients, seven with MTX-BLPD showed better overall survival than nine control DLBCL patients (P < 0.01).
  
  
  CONCLUSIONS
  In RA patients with MTX-BLPD, immunosuppression by MTX, EBV infection and low BCL2 expression in tumour cells may play roles in tumorigenesis and tumour regression. R+ cytotoxic therapies as well as MTX withdrawal were highly effective in these patients.
authors.affiliation: Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Kozue
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Pathology, Matsuyama Red Cross Hospital, Matsuyama, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Oshiro
authors.affiliation: Department of Internal Medicine, Clinical Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Okamura
authors.affiliation: Department of Hematology, Matsuyama Red Cross Hospital, Matsuyama, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Fujisaki
authors.affiliation: Department of Internal Medicine, Clinical Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kondo
authors.affiliation: Department of Pathology, Clinical Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.
authors.forename: Yoshifuku
authors.initials: Y
authors.lastname: Nakayama
authors.affiliation: Department of Internal Medicine, Clinical Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Suematsu
authors.affiliation: Division of Medical Oncology, Hematology and Infectious Disease, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Morishige
authors.initials: M
authors.lastname: Takeshita
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* / Q000473:pathology / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000175:diagnosis; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D017403:In Situ Hybridization; D016403:Lymphoma, Large B-Cell, Diffuse / Q000097:blood / Q000139:chemically induced* / Q000473:pathology* / Q000821:virology; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000097:blood; D012367:RNA, Viral / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000097:blood; D000069283:Rituximab / Q000627:therapeutic use*
chemical_list: D018501:Antirheumatic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D012367:RNA, Viral; D015375:Receptors, Interleukin-2; D000069283:Rituximab; D008727:Methotrexate
keywords: B lymphoproliferative disorders; BCL2; Epstein-Barr virus; methotrexate; rheumatoid arthritis; rituximab; sIL2R