title: Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication.
abstract: OBJECTIVE
  Individuals with rheumatoid arthritis (RA) with or without methotrexate (MTX) medication occasionally develop lymphoproliferative disorders (MTX-LPD and non-MTX-LPD, respectively). The hyperimmune state of RA itself or the immunosuppressive state induced by MTX administration might contribute to development of LPD. Our objective was to characterize MTX-LPD in comparison to non-MTX-LPD and sporadic LPD in patients with RA.
  
  
  METHODS
  We compared MTX-LPD to non-MTX-LPD and sporadic LPD by evaluating 48 cases of MTX-LPD, 28 non-MTX-LPD, and 150 sporadic LPD.
  
  
  RESULTS
  Later onset age of LPD and female predominance were evident in patients with RA-LPD compared to sporadic LPD. The interval between the diagnosis of RA and LPD in MTX-LPD (median 132 mo) was significantly shorter than that in non-MTX-LPD (240 mo). The frequency of diffuse large B cell lymphoma (DLBCL) and positive rate of Epstein-Barr virus (EBV) in RA-LPD was significantly higher than in sporadic LPD (57.9% vs 42.7%, 27.6% vs 9.9%, respectively). After withdrawal of MTX, 11 of the MTX-LPD cases showed a spontaneous regression of tumors. The 5-year survival rate in RA-LPD (59.2%) was significantly worse than that in sporadic LPD (74.6%).
  
  
  CONCLUSIONS
  The majority of cases of RA-LPD show similar clinicopathological characteristics irrespective of MTX medication, except for spontaneous regression of LPD after withdrawal of MTX in MTX-LPD, and a shorter interval between the diagnosis of RA and LPD in MTX-LPD than in non-MTX-LPD. RA-LPD cases showed younger age of onset, female predominance, unfavorable prognosis, and higher frequencies of DLBCL and EBV positivity compared to sporadic LPD.
authors.affiliation: Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. hoshida@molpath.med.osaka-u.ac.jp
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hoshida
authors.forename: Jing-Xian
authors.initials: JX
authors.lastname: Xu
authors.forename: Shigeki
authors.initials: S
authors.lastname: Fujita
authors.forename: Itsuko
authors.initials: I
authors.lastname: Nakamichi
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Ikeda
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tomita
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Nakatsuka
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Tamaru
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iizuka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Aozasa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000188:drug therapy / Q000401:mortality; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000821:virology; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D016867:Immunocompromised Host; D007124:Immunoenzyme Techniques; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D017403:In Situ Hybridization; D016403:Lymphoma, Large B-Cell, Diffuse / Q000209:etiology / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000209:etiology* / Q000276:immunology / Q000401:mortality; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D008875:Middle Aged; D009367:Neoplasm Staging; D016377:Organ Transplantation / Q000009:adverse effects; D012367:RNA, Viral / Q000235:genetics; D015996:Survival Rate
chemical_list: D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D012367:RNA, Viral; D008727:Methotrexate