title: Prognostic factors of methotrexate-associated lymphoproliferative disorders associated with rheumatoid arthritis and plausible application of biological agents.
abstract: OBJECTIVE
  To determine prognostic factors of methotrexate-associated lymphoproliferative disorder (MTX-LPD) and evaluate the efficacy and safety of biological therapy in rheumatoid arthritis (RA) complicated with MTX-LPD.
  
  
  METHODS
  Thirty RA patients who developed MTX-LPD were investigated in this study. We compared the clinical and laboratory parameters of patients who achieved regression of LPD by MTX withdrawal with those who required chemotherapy and evaluated the clinical course of RA after LPD development.
  
  
  RESULTS
  Twenty-three patients (76.7%) achieved regression of LPD by MTX withdrawal. Chemotherapy-free patients had a tendency of shorter RA duration (13.1 vs. 22.0 years, p = 0.108) and higher doses of MTX at LPD diagnosis (8.0 vs. 5.3 mg/w, p = 0.067) than patients who required chemotherapy. A significantly higher positive rate of peripheral blood Epstein-Barr virus (EBV)-DNA was observed in the chemotherapy-free group (9/9 vs. 0/3, p = 0.0002). Of 15 patients that received biological agents after LPD development, 14 patients (93.3%) demonstrated an improved disease activity of RA and persistent remission of LPD, whereas only one patient experienced relapse of LPD during tocilizumab therapy.
  
  
  CONCLUSIONS
  Peripheral blood EBV-DNA positivity is a potential prognostic marker of better outcome in MTX-LPD. Biological agents could be an option for the treatment of RA patients with MTX-LPD.
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.|b Department of Internal Medicine , Chugoku Central Hospital , Fukuyama , Japan , and.
authors.forename: Takayuki
authors.identifier: http://orcid.org/0000-0002-7159-5537
authors.initials: T
authors.lastname: Katsuyama
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Ken-Ei
authors.initials: KE
authors.lastname: Sada
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Minglu
authors.initials: M
authors.lastname: Yan
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Sonia
authors.initials: S
authors.lastname: Zeggar
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Sumie
authors.initials: S
authors.lastname: Hiramatsu
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Yoshia
authors.initials: Y
authors.lastname: Miyawaki
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Morishita
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Katsuyama
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Takano-Narazaki
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.|b Department of Internal Medicine , Chugoku Central Hospital , Fukuyama , Japan , and.
authors.forename: Noriko
authors.initials: N
authors.lastname: Toyota-Tatebe
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.|b Department of Internal Medicine , Chugoku Central Hospital , Fukuyama , Japan , and.
authors.forename: Katsue
authors.initials: K
authors.lastname: Sunahori-Watanabe
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kawabata
authors.affiliation: c Department of Internal Medicine , Himeji Medical Center , Himeji , Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyake
authors.affiliation: b Department of Internal Medicine , Chugoku Central Hospital , Fukuyama , Japan , and.
authors.forename: Toru
authors.initials: T
authors.lastname: Kiguchi
authors.affiliation: a Department of Nephrology, Rheumatology, Endocrinology and Metabolism , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001685:Biological Factors / Q000627:therapeutic use; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D007564:Japan; D008232:Lymphoproliferative Disorders / Q000139:chemically induced / Q000175:diagnosis; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects*; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011379:Prognosis; D028761:Withholding Treatment
chemical_list: D018501:Antirheumatic Agents; D001685:Biological Factors; D004279:DNA, Viral; D008727:Methotrexate
keywords: Biological therapy; Epstein–Barr virus; Methotrexate-associated lymphoproliferative disorders; Prognostic factors; Rheumatoid arthritis