Lymphoma represents the most severe complication of Sjögren’s syndrome (SS) and is the primary determinant of mortality in affected patients. The majority of lymphomas in SS are extranodal non-Hodgkin B-cell lymphomas of mucosa-associated lymphoid tissue, most frequently originating in the salivary glands, the principal site of chronic autoimmune inflammation. Extensive research on lymphomagenesis in SS has demonstrated that progression to B-cell lymphoma follows a multistep process driven by persistent local antigenic stimulation of B cells. The neoplastic B cells typically arise from autoreactive clones, most commonly rheumatoid factor–producing B cells, which undergo unchecked proliferation and ultimately malignant transformation.
A landmark prospective multicenter cohort study, published in Rheumatology International, has provided newer insights into the magnitude of this risk. The Spanish study followed 314 patients with SS over a median of 9.5 years, reporting that 11 patients (3.5%) developed non-Hodgkin lymphoma. During the study period, eleven patients (3.5%) developed non-Hodgkin lymphoma, yielding a standardized incidence ratio of 15.36 compared to the general population. Cryoglobulinemia emerged as the most significant independent predictor of lymphoma development, with a hazard ratio of 11.07. This biomarker’s presence substantially increased the likelihood of lymphoma occurrence in affected patients.
According to previous studies, the overall risk non-Hodgkin’s lymphoma in patients with SS is estimated to be 5–15 times higher than in the general population. Clinical and laboratory features associated with higher lymphoma risk include persistent or asymmetric parotid gland enlargement, lymphadenopathy, splenomegaly, palpable purpura due to cutaneous vasculitis, hypocomplementemia (low C3 and C4), cryoglobulinemia, monoclonal gammopathy, and high disease activity. Suspicion should be raised when patients present with chronic or progressive salivary gland swelling, constitutional symptoms, or unexplained cytopenias.
The current findings highlight the critical importance of enhanced surveillance protocols for SS disease patients, particularly those with cryoglobulinemia. The substantial elevation in lymphoma risk necessitated refined clinical approaches to risk stratification and early detection strategies. These results emphasized the need for tailored interventions and monitoring strategies to reduce lymphoma-related mortality in SS patients. The identification of cryoglobulinemia as a key predictor offered clinicians a valuable tool for identifying high-risk patients who may benefit from intensified surveillance protocols. Future research should focus on validating these findings across diverse patient populations and exploring targeted therapeutic approaches to reduce lymphoma risk in this vulnerable group.
References
- Rusinovich-Lovgach O, Plaza Z, Fernández-Castro M, Rosas-Gómez de Salazar J, Martínez-Taboada VM, Olive A, et al. High incidence of lymphoma in Sjögren’s disease: predictors and mortality implications in a prospective cohort study. Rheumatol Int. 2025 Aug 6;45(8):184.
- Nocturne G, Pontarini E, Bombardieri M, Mariette X. Lymphomas complicating primary Sjögren’s syndrome: from autoimmunity to lymphoma. Rheumatology (Oxford). 2021 Aug 2;60(8):3513-3521.