CD83 as a novel prognostic biomarker for diffuse large B-cell lymphoma arising in immune deficiency/dysregulation among rheumatoid arthritis patients treated with methotrexate.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of methotrexate-associated lymphoma arising in immune deficiency/dysregulation (MTX-associated IDD-DLBCL) among rheumatoid arthritis patients treated with MTX and is characterized by frequent spontaneous regression (SR) after MTX withdrawal. However, some patients do not achieve SR and have poor outcomes. Epstein-Barr virus (EBV) infection correlates with frequent SR but does not fully explain clinical heterogeneity. We investigated prognostic factors irrespective of EBV infection status. We analyzed 21 MTX-associated IDD-DLBCL cases applying the nCounter PanCancer Immune Profiling Panel and immunohistochemistry (IHC) to identify predictors of non-SR cases. Ten patients were classified as SR and 11 as non-SR. Gene expression profiling revealed higher expression of CD83, ICOSLG, IL21R, BCL6, CD40, PAX5, CXCR5, CD79A, DMBT1, and TNFRSF13C in non-SR cases. We therefore focused on CD83, which showed the highest fold change and the most significant P value among these markers. Although CD83 is reported to be a surface marker of mature dendritic cells, IHC analysis revealed that CD83 was more frequently expressed on tumor cells than on dendritic cells. High CD83 IHC positivity (≥15%) in tumor cells correlated with mRNA levels and predicted non-SR after MTX withdrawal. Multivariate analysis identified CD83 IHC high expression as an independent predictor of non-SR cases. High CD83 expression is an independent prognostic factor in MTX-associated IDD-DLBCL, and combined evaluation may refine risk stratification and guide clinical decisions.