Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression

Eur J Haematol. 2013 Jul;91(1):20-8. doi: 10.1111/ejh.12116. Epub 2013 May 13.


Objectives: Patients with rheumatoid arthritis (RA) may develop lymphoproliferative disorders (RA-LPD). Immunosuppressive states due to methotrexate (MTX) and Epstein-Barr virus (EBV) reactivation have been regarded as causes. Sometimes spontaneous regression occurs after withdrawal of MTX. The objective of this study was to identify factors predictive of relapse and survival in patients with RA-LPD, and spontaneous regression in patients with RA-LPD treated with MTX (MTX-LPD).

Methods: We evaluated the clinicopathological features, clinical characteristics, and treatment outcomes in 102 cases of RA-LPD. In addition, EBV infection and clonality of immunoglobulin heavy chain gene (IGH) were analyzed by in situ hybridization and polymerase chain reaction, respectively.

Results: The 102 cases included patients with diffuse large B-cell lymphoma (DLBCL; n = 53), Hodgkin lymphoma (n = 9), polymorphic B-cell LPD (n = 20), reactive lymphadenitis (n = 11), peripheral T-cell lymphoma (PTCL; n = 4), composite lymphoma (n = 2), and follicular lymphoma (n = 3). EBV was detected in 60% (56/93) of patients. Spontaneous regression occurred in 59% (28/47) of patients in whom MTX was withdrawn. Regression was associated with EBV positivity (P = 0.007) and non-DLBCL (P = 0.006), but not with MTX amount and other clinical features. Monoclonal bands of IGH were observed in 31 of 74 cases. In patients with DLBCL, poor disease-free survival (P = 0.05) was associated with clonality of IGH. In all patients, factors predictive of shorter survival were age (>70 yr) and histological type of DLBCL.

Conclusions: Histology, EBV positivity, and monoclonality of IGH are useful for predicting clinical outcomes in patients with RA-LPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / therapeutic use
  • Arthritis, Rheumatoid / complications
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / virology
  • Disease Progression
  • Disease-Free Survival
  • Female
  • Herpesvirus 4, Human / isolation & purification*
  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Immunohistochemistry
  • Lymphoproliferative Disorders / chemically induced*
  • Lymphoproliferative Disorders / complications
  • Male
  • Methotrexate / therapeutic use*
  • Middle Aged
  • Regression Analysis
  • Treatment Outcome
  • Virus Activation


  • Antimetabolites, Antineoplastic
  • Immunoglobulin Heavy Chains
  • Methotrexate