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

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>Patients with rheumatoid arthritis (<jats:styled-content style="fixed-case">RA</jats:styled-content>) may develop lymphoproliferative disorders (<jats:styled-content style="fixed-case">RA</jats:styled-content>‐<jats:styled-content style="fixed-case">LPD</jats:styled-content>). Immunosuppressive states due to methotrexate (<jats:styled-content style="fixed-case">MTX</jats:styled-content>) and Epstein–Barr virus (<jats:styled-content style="fixed-case">EBV</jats:styled-content>) reactivation have been regarded as causes. Sometimes spontaneous regression occurs after withdrawal of <jats:styled-content style="fixed-case">MTX</jats:styled-content>. The objective of this study was to identify factors predictive of relapse and survival in patients with <jats:styled-content style="fixed-case">RA</jats:styled-content>‐<jats:styled-content style="fixed-case">LPD</jats:styled-content>, and spontaneous regression in patients with <jats:styled-content style="fixed-case">RA</jats:styled-content>‐<jats:styled-content style="fixed-case">LPD</jats:styled-content> treated with <jats:styled-content style="fixed-case">MTX</jats:styled-content> (<jats:styled-content style="fixed-case">MTX</jats:styled-content>‐<jats:styled-content style="fixed-case">LPD</jats:styled-content>).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We evaluated the clinicopathological features, clinical characteristics, and treatment outcomes in 102 cases of <jats:styled-content style="fixed-case">RA</jats:styled-content>‐<jats:styled-content style="fixed-case">LPD</jats:styled-content>. In addition, <jats:styled-content style="fixed-case">EBV</jats:styled-content> infection and clonality of immunoglobulin heavy chain gene (<jats:styled-content style="fixed-case">IGH</jats:styled-content>) were analyzed by <jats:italic>in situ</jats:italic> hybridization and polymerase chain reaction, respectively.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The 102 cases included patients with diffuse large <jats:styled-content style="fixed-case">B</jats:styled-content>‐cell lymphoma (<jats:styled-content style="fixed-case">DLBCL</jats:styled-content>;<jats:italic> n</jats:italic> = 53), <jats:styled-content style="fixed-case">H</jats:styled-content>odgkin lymphoma (<jats:italic>n</jats:italic> = 9), polymorphic <jats:styled-content style="fixed-case">B</jats:styled-content>‐cell <jats:styled-content style="fixed-case">LPD</jats:styled-content> (<jats:italic>n</jats:italic> = 20), reactive lymphadenitis (<jats:italic>n</jats:italic> = 11), peripheral <jats:styled-content style="fixed-case">T</jats:styled-content>‐cell lymphoma (<jats:styled-content style="fixed-case">PTCL</jats:styled-content>;<jats:italic> n</jats:italic> = 4), composite lymphoma (<jats:italic>n</jats:italic> = 2), and follicular lymphoma (<jats:italic>n</jats:italic> = 3). <jats:styled-content style="fixed-case">EBV</jats:styled-content> was detected in 60% (56/93) of patients. Spontaneous regression occurred in 59% (28/47) of patients in whom <jats:styled-content style="fixed-case">MTX</jats:styled-content> was withdrawn. Regression was associated with <jats:styled-content style="fixed-case">EBV</jats:styled-content> positivity (<jats:italic>P</jats:italic> = 0.007) and non‐<jats:styled-content style="fixed-case">DLBCL</jats:styled-content> (<jats:italic>P</jats:italic> = 0.006), but not with <jats:styled-content style="fixed-case">MTX</jats:styled-content> amount and other clinical features. Monoclonal bands of <jats:styled-content style="fixed-case">IGH</jats:styled-content> were observed in 31 of 74 cases. In patients with <jats:styled-content style="fixed-case">DLBCL</jats:styled-content>, poor disease‐free survival (<jats:italic>P</jats:italic> = 0.05) was associated with clonality of <jats:styled-content style="fixed-case">IGH</jats:styled-content>. In all patients, factors predictive of shorter survival were age (>70 yr) and histological type of <jats:styled-content style="fixed-case">DLBCL</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Histology, <jats:styled-content style="fixed-case">EBV</jats:styled-content> positivity, and monoclonality of <jats:styled-content style="fixed-case">IGH</jats:styled-content> are useful for predicting clinical outcomes in patients with <jats:styled-content style="fixed-case">RA</jats:styled-content>‐<jats:styled-content style="fixed-case">LPD</jats:styled-content>.</jats:p></jats:sec>