Longitudinal evolution of rheumatoid factor-expressing lymphoma precursors in a patient with Sjögren's disease

Objective: Patients with Sjögren's disease (SjD) have an increased risk of developing B cell lymphomas, which may express rheumatoid factors (RhF). However, it remains unclear whether RhF-secreting cells undergo malignant transformation. To address this question, we longitudinally tracked the evolution of a RhF clone in a rare SjD case before and after lymphoma diagnosis. Methods: Peripheral blood B cells, serum and malignant lymph node biopsy were collected from a 68-year-old male with SjD who developed diffuse large B cell lymphoma (DLBCL). Clonal RhF sequences were identified in serum by mass spectrometry and in B cells by mRNA sequencing. Recombinant IgM were generated from clonal sequences and assessed for RhF activity and cryoaggregation. Results: A monoclonal RhF was detected in serum and circulating B cells six months before DLBCL diagnosis. The same clone was expressed by the lymphoma. Clonal analysis demonstrated divergence into two branches: one with seven antibody mutations expressed by blood B cells, and a second with twelve antibody mutations in the serum RhF and lymphoma. Recombinant IgM representing the blood and serum RhF demonstrated RhF activity, whereas the lymphoma clone acquired three additional mutations that impaired RhF binding. Conclusions: Our prospective and longitudinal analyses provide direct evidence for a RhF secreting clone evolving into a lymphoma in a SjD patient. This work expands on previous cross-sectional studies of RhF expressing lymphomas in SjD and provides a proof-of-concept case, which potentially supports early therapeutic targeting of expanded RhF clones.