The clinical phenotype of primary Sjögren's syndrome patients with lymphadenopathy.

OBJECTIVES: Previous cohort studies have shown that around 10% of patients with primary Sjögren's syndrome (pSS) develop lymphadenopathy during their disease course. However, no studies have described their clinical phenotype. The present study aims to describe the clinical manifestations and laboratory findings of pSS patients presenting long-standing lymphadenopathy. METHODS: From a total of 1234 consecutive pSS patients fulfilling the 2016 ACR-EULAR criteria, those with stable lymphadenopathy unrelated to lymphoma were identified (lymphadenopathy group). Their clinical data were collected and compared with 2 control groups: a) the remaining unmatched pSS patients without lymphadenopathy (unmatched non-lymphadenopathy group) and b) pSS patients without lymphadenopathy matched for age, sex, and disease duration, in an approximately 1:1 ratio (matched non-lymphadenopathy group). RESULTS: One hundred and sixty-five (13.37%) patients presented persistent, stable lymphadenopathy. They were characterised by younger age at both pSS onset and diagnosis, and by shorter disease duration. Compared to the unmatched nonlymphadenopathy group, patients with lymphadenopathy had more frequently salivary gland enlargement (p<0.001), higher focus score at first salivary gland biopsy (p=0.017), palpable purpura (p<0.001), peripheral nervous system involvement (p=0.012), glomerulonephritis (p<0.001), and leukopenia (p<0.001), while the results of the matched comparison were similar. Regarding the serological profile, the comparison with the unmatched group demonstrated higher frequency of ANA (p=0.013), anti-Ro/SSA (p=0.001), and anti-La/SSB (p<0.001) positivity for the lymphadenopathy group, while in the matched comparison only higher rates of anti-Ro/SSA positivity (p=0.002) remained statistically significant. CONCLUSIONS: pSS patients presenting non-lymphoma related stable lymphadenopathy constitute a subgroup of younger individuals with B-cell hyperactivation.

Clinical and laboratory findings of primary Sjögren's syndrome patients without sicca symptoms.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterised by oral and eye dryness. A minority of patients can present without dryness but studies on their clinico-laboratory manifestations are scarce. Our purpose was to describe the clinical phenotype of pSS patients lacking sicca symptoms. METHODS: From a total of 1738 consecutive pSS patients fulfilling the 2016 ACR-EULAR criteria, those who presented without sicca symptoms were identified (non-dryness group). Their medical data was collected and compared with 2 control groups: a) the remaining unmatched sicca pSS patients with both oral and eye dryness (unmatched dryness group) and b) matched sicca pSS patients according to age, sex, and disease duration, in 1:2 ratio (matched dryness group). RESULTS: Thirty-eight (2.19%) patients lacked sicca manifestations presenting mainly with arthralgias (47%), parotid enlargement (24%), Raynaud's phenomenon (11%) and persistent lymphadenopathy (11%) that led them to be evaluated for pSS. Non-dryness pSS patients were younger than the unmatched sicca controls, displaying a higher frequency of anti-Ro/SSA antibodies (100% vs. 79.7%, p<0.001), ANA positivity (100% vs. 90.4%, p<0.001), neutropenia (20.8% vs. 7.5%, p=0.04) and thrombocytopenia (13.8% vs. 4.2%, p=0.04). They also had lower frequency of positive ocular tests compared to both unmatched and matched dryness patients. No differences were found between non-dryness pSS patients and both control groups regarding focus score or any other extraglandular manifestation. CONCLUSIONS: pSS patients without sicca complaints constitute a distinct phenotype involving younger patients, sharing common immunopathologic mechanisms with typical sicca patients.

Sjögren's syndrome towards precision medicine: the challenge of harmonisation and integration of cohorts.

Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease with diverse clinical picture and outcome. The disease affects primarily middle-aged females and involves the exocrine glands leading to dry mouth and eyes. When the disease extends beyond the exocrine glands (systemic form), certain extraglandular manifestations involving liver, kidney, lungs, peripheral nervous system and the skin may occur. Primary SS is considered the crossroad between autoimmunity and lymphoproliferation, since approximately 5% of patients develop NHL associated lymphomas. As with every chronic disease with complex aetiopathogenesis and clinical heterogeneity, pSS has certain unmet needs that have to be addressed: a) classification and stratification of patients; b) understanding the distinct pathogenetic mechanisms and clinical phenotypes; c) defining and interpreting the real needs of patients regarding the contemporary diagnostic and therapeutic approaches; d) physician and patients' training regarding the wide spectrum of the disease; e) creating common policies across European countries to evaluate and manage SS patients. To achieve these goals, an intense effort is being currently undertaken by the HarmonicSS consortium in order to harmonise and integrate the largest European cohorts of pSS patients. In this review, we present an overview of our perception and vision, as well as new issues arising from this project such as harmonisation protocols and procedures, data sharing principles and various ethical and legal issues originating from these approaches.

Identification and evolution of predictors of Sjögren's disease-associated mucosa-associated lymphoid tissue lymphoma development over time: a case-control study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: European Commission-Horizon 2020.

Comparison of three U-Net family architectures for left ventricular myocardial wall automatic segmentation.

Left ventricular (LV) segmentation is an important process which can provide quantitative clinical measurements such as volume, wall thickness and ejection fraction. The development of an automatic LV segmentation procedure is a challenging and complicated task mainly due to the variation of the heart shape from patient to patient, especially for those with pathological and physiological changes. In this study, we focus on the implementation, evaluation and comparison of three different Deep Learning architectures of the U-Net family: the custom 2-D U-Net, the ResU-Net++ and the DenseU-Net, in order to segment the LV myocardial wall. Our approach was applied to cardiac CT datasets specifically derived from patients with hypertrophic cardiomyopathy. The results of the models demonstrated high performance in the segmentation process with minor losses. The model revealed a dice score for U-Net, Res-U-net++ and Dense U-Net, 0.81, 0.82 and 0.84, respectively.