Paraproteinemias in Sjögren disease: cryoglobulinemia and serum monoclonal gammopathy identify distinct clinical phenotypes and differential lymphoma susceptibility

• Isolated detectable serum monoclonal gammopathy, cryoglobulinemia, and their coexistence delineate distinct phenotypic subsets in Sjögren disease (SjD). • Cryoglobulinemia is linked with a predominant vasculitic phenotype. • The combination of cryoglobulinemia and monoclonal gammopathy is linked with high lymphoproliferative activity and lymphoma susceptibility. • SjD patients with both serum detectable monoclonal gammopathy and cryoglobulinemia require careful monitoring due to increased lymphoma risk. Sjögren disease (SjD) is a systemic autoimmune disease characterized by increased risk of B-cell non-Hodgkin lymphoma. Although cryoglobulinemia and serum monoclonal component (MC) are well-recognized paraproteinemias in SjD, no large-scale study has directly compared their isolated and combined impact on phenotype and lymphoproliferative risk. A retrospective, multicenter, cross-sectional study was conducted within the Italian GRISS registry. Patients with SjD were stratified into four groups: isolated monoclonal gammopathy (MC-alone), isolated cryoglobulinemia (CRYO-alone), both (MC+CRYO), or neither (controls). Demographics, lymphoma history, ever-documented ClinESSDAI domains, and laboratory lymphoproliferative risk-related markers were analyzed. Primary and secondary outcomes assessed lymphoma diagnosis and the distribution of laboratory lymphoproliferative risk-related markers and ClinESSDAI domains across groups, with associations tested using logistic regression adjusted for confounders. 1202 SjD patients were enrolled: 58 (4.83%) in the MC-alone, 32 (2.66%) in the CRYO-alone, 35 (2.91%) in the MC+CRYO, and 1077 (89.60%) controls. Compared with controls, only the MC+CRYO group showed significant association with lymphoma (OR 6.30, 95%CI 2.66–14.92; p<0.001), while MC-alone and CRYO-alone were not associated. Cryoglobulinemia, alone or combined with MC, correlated with laboratory lymphoproliferative risk-related markers such as rheumatoid factor (p<0.001) and low C4 (p<0.001), and with ClinESSDAI vasculitic features (cutaneous p<0.001, renal p<0.05, PNS p<0.001). The MC+CRYO group additionally displayed a lymphoproliferative phenotype correlating with constitutional (p<0.05), glandular (p<0.05), hematological (p<0.001), and lymphadenopathy (p<0.001) domains. Cryoglobulinemia in SjD associates with vasculitic disease activity, whereas the coexistence of serum MC and cryoglobulins identifies a distinct, high-risk subset characterized by advanced B-cell expansion and increased lymphoma susceptibility.