Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, E pstein– B arr virus, and clonality are important predictors of disease progression and regression

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), H odgkin 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 Spontaneous regression occurred in 59% (28/47) of patients in whom MTX was withdrawn.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 .