Clinical Picture, Outcome and Predictive Factors of Lymphoma in Primary Sjögren's Syndrome

Results From a Harmonized Dataset (1981-2021)

Loukas G. Chatzis; Ioanna E. Stergiou; Andreas V. Goules; Vasilis Pezoulas; Gerasimos Tsourouflis; Dimitrios Fotiadis; Athanasios G. Tzioufas; Michael Voulgarelis


Rheumatology. 2022;61(9):3576-3585. 

In This Article

Abstract and Introduction


Objectives: Primary Sjögren's Syndrome (pSS) carries the highest risk for non-Hodgkin's lymphoma (NHL) development among systemic autoimmune diseases. However, the paucity of data on the long-term survival of those patients and the lack of established predictors for each lymphoma histologic subtype prompted our present study.

Methods: We retrospectively analysed 121 patients diagnosed with NHL according to the WHO classification criteria. All patients fulfilled the 2016 ACR-EULAR classification criteria for pSS. Cumulative clinical, laboratory, radiologic, treatment regimens and histologic data were recorded, harmonized and analysed. Overall survival (OS) and event-free survival (EFS) curves were calculated. A mucosa-associated lymphoid tissue lymphoma (MALTL) prediction model was developed by applying innovative data-driven analysis of clinical features present at the time of pSS diagnosis.

Results: MALTLs constituted the majority of lymphomas (92/121, 76.0%) followed by diffuse large B-cell lymphomas (DLBCL) (11/121, 9.0%) and nodal marginal zone lymphomas (NMZL) (8/121, 7%). MALTLs show salivary glands localization, limited disease and often bone marrow and nodal involvement. The 10-year OS and EFS rates were 79% and 45.5% for MALTLs, 40.9% and 24.2% for DLBCL and 46% and 31% for NMZL. Cryoglobulinemia, focus score and the total EULAR SS Disease Activity Index (ESSDAI) composite index at pSS diagnosis were proven independent MALTL predictors. Even though MALTLs have a comparatively good survival outlook, they are accompanied by frequent events throughout their clinical course.

Conclusions: Common features of pSS, present at diagnosis, can predict future lymphomagenesis meriting a more intensive follow-up plan.


Primary Sjögren syndrome (pSS) is a systemic autoimmune disease,[1] characterized by lymphocytic infiltration of various epithelial structures, mainly affecting the exocrine salivary and lacrimal glands. The clinical spectrum of the disease is broad involving tissues far exceeding the glandular and peri-epithelial level.[2–4]

The association of pSS with different lymphoma subtypes is a well-recognized complication.[5,6] Even though numerous studies have attempted to define lymphoma predictors and outcomes, they are limited by the low number of lymphoma patients, the inclusion of patients with concurrent pSS and lymphoma diagnoses overshadowing the predicting power of pSS related manifestations, the relative short pSS-lymphoma patients' follow-up time and the fact that predictors refer to all histologic types of pSS-associated lymphomas and not mucosa-associated lymphoid tissue lymphomas (MALTLs) in particular.[7–10]

In the present study, we sought to define all the pSS-associated lymphoproliferative disorders in the largest single-center cohort of well-characterized pSS patients. The dataset of patients was extensively harmonized to define in detail the treatment strategies selected and the lymphoma outcomes as well as the survival and prognosis of the pSS-lymphoma patients. Finally, we present a data-driven prediction model defining simple clinical features at the time of pSS diagnosis that are associated with an increased risk for lymphomagenesis.