title: EBV-induced lymphoproliferative disorders in rheumatic patients: A systematic review of the literature.
abstract: Epstein-Barr virus (EBV) is involved in the pathogenesis of approximately 40% of lymphoproliferative disorders (LPDs) arising in patients receiving immunosuppressive treatment (IST) for rheumatic diseases, but data from large cohorts are still not available. We aimed to identify clinicopathological features, management and outcome of this condition.
  
  
  
  We reviewed all published cases of EBV-encoded RNA (EBER)-positive LPDs and included in our analysis one unpublished patient diagnosed in our Hospital. We excluded those cases without an underling rheumatic condition, a specific IST or not reporting univocal data.
  
  
  
  In the cumulative cohort of 159 patients, most were affected by rheumatoid arthritis (83.0%) and treated with methotrexate (75.4%). 68.5% of LPDs developed between the age of 40 and 70 years, after 13.3±9.6 years from rheumatic disease onset and 58.7±47.0 months of IST. LPDs were mostly B-cell lineage derived (39.0%), Ann Arbor disease's stage I (38.3%) and presented with extra-nodal involvement in 63.1%, which was most frequently represented by central nervous system (17.6%). The most common approach was IST withdrawal (93.3%), variably associated with radiotherapy(RT)/chemotherapy(CT) in 38.3% of cases. Overall, 61.7% of patients achieved a complete remission (CR; 30.2±24.0 months). Among published cases of patients that only suspended IS as first line treatment approach, 67.2% achieved CR. No significant demographic, clinical and histological differences between patients who achieved CR and who did not, and between who achieved CR by IST withdrawal alone and who did not were observed (P>0.05 in all comparison).
  
  
  
  The current study reviews all the published evidences of EBV-induced LPDs in patients receiving IST treatment for rheumatic conditions.
authors.affiliation: Unit of medicine and clinical immunology, IRCCS San Raffaele scientific institute, Vita-Salute San Raffaele university, 20132 Milan, Italy; Rheumatology unit, Santa Chiara hospital, Trento, Italy. Electronic address: berti.alvise@hsr.it.
authors.forename: Alvise
authors.initials: A
authors.lastname: Berti
authors.affiliation: Rheumatology unit, Santa Chiara hospital, Trento, Italy; Department of rheumatology, university of Padua, Padua, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Felicetti
authors.affiliation: Rheumatology unit, Santa Chiara hospital, Trento, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Peccatori
authors.affiliation: Rheumatology unit, Santa Chiara hospital, Trento, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bortolotti
authors.affiliation: Hematology unit, Santa Chiara hospital, Trento, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Guella
authors.affiliation: Hematology unit, Santa Chiara hospital, Trento, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vivaldi
authors.affiliation: Pathology, Santa Chiara hospital, Trento, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Morelli
authors.affiliation: Pathology, Santa Chiara hospital, Trento, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Barabareschi
authors.affiliation: Rheumatology unit, Santa Chiara hospital, Trento, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paolazzi
mesh_terms: D020031:Epstein-Barr Virus Infections / Q000139:chemically induced* / Q000821:virology; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D008232:Lymphoproliferative Disorders / Q000139:chemically induced* / Q000821:virology; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D012367:RNA, Viral / Q000032:analysis*; D012216:Rheumatic Diseases / Q000188:drug therapy*
chemical_list: D007166:Immunosuppressive Agents; D012367:RNA, Viral; D008727:Methotrexate
keywords: Autoimmune diseases; EBV-induced LPD; Epstein-Barr virus; Iatrogenic immunosuppression; Lymphoproliferative disorder; Rheumatoid arthritis