Non-Hodgkin lymphomas have a substantial impact on individuals with Sjögren's disease. This study focuses on mucosal-associated lymphoid tissue (MALT) lymphomas, which constitute the majority of Sjögren's disease-associated non-Hodgkin lymphomas. We aimed to identify reliable lymphoma predictors in patients with Sjögren's disease and study their progression over time. In this case-control study, patients diagnosed with Sjögren's disease-associated MALT lymphoma, with a minimum of 3 years between Sjögren's disease diagnosis and MALT lymphoma diagnosis, were included from three centres specialising in Sjögren's disease (University of Athens, Athens, Greece; University of Pisa, Pisa, Italy; and University of Udine, Udine, Italy) and matched 1:1 with control participants with Sjögren's disease who did not have lymphoma according to age, sex, disease duration at last follow up, and treatment modality. Three harmonised datasets were constructed, curated, and analysed to identify MALT lymphoma predictors, representing three distinct timepoints in lymphomagenesis progression: V1 at Sjögren's disease diagnosis, V2 3-4 years before lymphoma diagnosis, and V3 0·5-1·5 years before lymphoma diagnosis. All recruited patients fulfilled the 2016 American College of Rheumatology-European League Against Rheumatism criteria for Sjögren's disease. The primary outcome was to identify MALT lymphoma predictors in Sjögren's disease, present at the timepoint of Sjögren's disease diagnosis and 3-4 years before the diagnosis of MALT lymphoma. A fast correlation-based feature selection and logistic regression model was used at V1 and V2 to identify MALT lymphoma predictors. The progression of potential predictors was studied across V1, V2, and V3. Histological parameters were not included in the analysis. An individual with lived experience of Sjögren's disease was involved in the study design. 80 patients with Sjögren's disease-associated MALT lymphoma were included in the V1 dataset, 68 in the V2 dataset, and 80 in the V3 dataset, and matched to control participants with Sjögren's disease who did not have lymphoma. In both groups, 72 (90%) of 80 participants were women and eight (10%) were men. The mean age at Sjögren's disease diagnosis was 48·6 years (SD 11·6) in the lymphoma group and 48·7 years (11·5) in the control group. All patients were White, with 88 (55%) of 160 individuals of Greek nationality and 72 (45%) of Italian nationality. At the V1 timepoint, rheumatoid factor was the only independent lymphoma predictor (odds ratio 3·33 [95% CI 1·96-5·64]). At the V2 timepoint, rheumatoid factor (3·66 [95% CI 2·08-6·42]) and European League Against Rheumatism Sjögren's Syndrome Disease Activity Index ≥5 (3·88 [1·69-8·90]) were identified as independent lymphoma risk factors. The high disease activity during the transition from the V1 to V2 timepoint was attributed to specific B-cell-derived manifestations, including cryoglobulinaemia and glandular, cutaneous, and hematological manifestations. Following up patients with high-risk of Sjögren's disease-associated MALT lymphoma based on the temporal progression of predictors presents an opportunity for early diagnosis and potential therapeutic interventions. Rheumatoid factor was the earliest and most persistent independent predictor of lymphoma. Specific B-cell manifestations in combination with rheumatoid factor indicate a more advanced stage of the lymphomagenesis process. European Commission-Horizon 2020.
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