Predicting lymphoma in Sjögren's syndrome and the pathogenetic role of parotid microenvironment through precise parotid swelling recording

Objective: Parotid swelling (PSW) is a major predictor of non-Hodgkin lymphoma (NHL) in primary Sjögren's syndrome (pSS). However, since detailed information on the time of onset and duration of PSW is scarce, this was investigated to verify whether it may lead to further improved prediction. NHL localisation was concomitantly studied to evaluate the role of the parotid gland microenvironment in pSS-related lymphomagenesis. Methods: A multicentre study was conducted among patients with pSS who developed B cell NHL during follow-up and matched controls that did not develop NHL. The study focused on the history of salivary gland and lachrymal gland swelling, evaluated in detail at different times and for different durations, and on the localisation of NHL at onset. Results: PSW was significantly more frequent among the cases: at the time of first referred pSS symptoms before diagnosis, at diagnosis, and from pSS diagnosis to NHL. The duration of PSW was evaluated starting from pSS diagnosis, and the NHL risk increased from PSW of 2-12 months to > 12 months. NHL was prevalently localised in the parotid glands of the cases. Conclusion: A more precise clinical recording of PSW can improve lymphoma prediction in pSS. PSW as a very early symptom is a predictor, and a longer duration of PSW is associated with a higher risk of NHL. Since lymphoma usually localises in the parotid glands, and not in the other salivary or lachrymal glands, the parotid microenvironment appears to be involved in the whole history of pSS and related lymphomagenesis

Addressing the clinical unmet needs in primary Sjögren's Syndrome through the sharing, harmonization and federated analysis of 21 European cohorts

For many decades, the clinical unmet needs of primary Sjögren's Syndrome (pSS) have been left unresolved due to the rareness of the disease and the complexity of the underlying pathogenic mechanisms, including the pSS-associated lymphomagenesis process. Here, we present the HarmonicSS cloud-computing exemplar which offers beyond the state-of-the-art data analytics services to address the pSS clinical unmet needs, including the development of lymphoma classification models and the identification of biomarkers for lymphomagenesis. The users of the platform have been able to successfully interlink, curate, and harmonize 21 regional, national, and international European cohorts of 7,551 pSS patients with respect to the ethical and legal issues for data sharing. Federated AI algorithms were trained across the harmonized databases, with reduced execution time complexity, yielding robust lymphoma classification models with 85% accuracy, 81.25% sensitivity, 85.4% specificity along with 5 biomarkers for lymphoma development. To our knowledge, this is the first GDPR compliant platform that provides federated AI services to address the pSS clinical unmet needs. © 2022 The Author(s

Immunopathology of nephritis in systemic diseases

Kidneys are affected in many systemic autoimmune diseases Renalinvolvement is frequent in primary Sjogren s syndrome (pSS) and SystemicLupus Erythematosus (SLE) More specifically primary Sjogren s syndrome ischaracterized by penepithehal infiltration of the renal tubules resulting ininterstitial nephritis (IN) and Β cell hyperactivity resulting in the production ofautoantibodies immune complexes and glomerulonephritis (GMN) Althoughrenal abnormalities have been described to occur in 25% of patients with pSSthe majority of patients with interstitial IN and pSS present an indolentsubclinical form Besides GMN is a rare syndrome and only a few cases havebeen described in the literature Thus the prevalence of clinically significantrenal involvement in pSS is unknown The first aim of this study was toexamine a large cohort of patients with pSS and severe renal involvement toinvestigate the clinical and serological differences between patients with INand those with GMN and finally to evaluate the evolution and outcome ofthese entitiesIn a large cohort of 471 patients with pSS who were followed up for amean of 10 years 20 patients (4 2%) developed severe renal disease and 18 ofthem underwent a percutaneous renal biopsy Ten patients had IN 8 patientshad GMN and 2 had both entities Two distinct types of GMN were observedin renal biopsy 5 patients had membranoprohferative GMN and 4 patients hadmesangial GMN Mesangial GMN is described for first time in pSS Patientswith IN had a younger disease onset compared with patients with GMN (mean36 8 compared with 46 0 yr p=0 063) while patients with GMN had a longerdisease duration (mean 8 compared with 2 2 yr p=0 001) compared withpatients with IN Eight of 10 patients (80%) with GMN had mixed monoclonalcryoglobulinemia and lower C4 levels Furthermore 4 patients with GMN andmixed monoclonal cryoglobulinemia developed Β cell lymphoma Finally 2patients with GMN developed chronic renal failure requiring hemodialysisOverall severe renal disease is rare in pSS GMN is a late sequela is associated with mixed monoclonal cryoglobulinemia and may have a lessfavorable prognosis On the contrary IN occurs early in the disease processand has a good prognosisThe CD40 CD40L costimulatory pathway is involved in thepathogenesis of many autoimmune diseases such as SLE Sjogren s syndrome(SS) and rheumatoid arthritis (RA) Previous studies have demonstrated apossible role of this pathway m the evolution of lupus nephritis CD40Lcirculates in a soluble form of 18 20KD in the serum of patients with SLE andincreased levels of soluble CD40L (sCD40L) have been associated withdisease activity The second aim of the study was to investigate the possiblerole of sCD40L in the development of lupus nephritis and examine its possibleassociation with nephritis and cryoglobulinemia in Sjogren s syndromeWe measured the levels of sCD40L by a 2 site sandwich ELISA insera from 23 patients with SLE 23 patients with SS 16 with RA and 17healthy controls We found that patients with SLE and SS had statisticallysignificant higher levels of sCD40L compared with normals We also recordedthe clinical and laboratory parameters of SLE and SS patients We found nocorrelation of sCD40L levels with any clinical and laboratory parameter in SSincluding glomerulonephritis and cryoglobulinemia Furthermore we examinedpaired serum and first morning urine samples from 3 SLE patients with activenephritis (1 patient had focal segmental glomerulonephritis 1 patient haddiffuse proliferative glomerulonephritis and 1 had membranousglomerulonephritis) and 3 SLE patients with inactive lupus nephritis (2 patientshad mesangial lupus nephritis and 1 had focal segmental glomerulonephritis)No binding was detected in any urine sample even after concentration 10 foldFinally we examined paired serum and salivary samples from 5patients with SS and cryoglobulinemia and 5 patients with SS and anti Ro oranti La autoantibodies No binding was detected m any salivary sampleOverall soluble CD40L is elevated in sera of SS and SLE patients Wefound no correlation of sCD40L with lupus nephritis and cryoglobulinemia orglomerulonephritis in Sjogren s syndrome Further investigation is needed todetermine the possible role of sCD40L in SLE nephritis and Sjogren ssyndrome.Οι νεφροί προσβάλλονται συχνά στα συστεμικα αυτοανοσα νοσήματαΗ νεφρική προσβολή στο πρωτοπαθές σύνδρομο Sjogren (naS) και στοΣυστηματικό Ερυθηματωδη Λύκο (ΣΕΛ) είναι συχνή Ειδικότερα τοπρωτοπαθές σύνδρομο Sjogren χαρακτηρίζεται απο περιεπιθηλιακηλεμφοκυτταρική διήθηση των νεφρικών σωληνάριων που προκαλεί διάμεσηνεφρίτιδα (ΔΝ) και απο υπερδραστηριότητα των Β κυττάρων τα οποίαπαράγουν αυτοαντισωματα και ανοσοσυμπλεγματα με αποτέλεσμα ναπροκαλείται σπειραματονεφριτιδα (ΣΝ) Παρόλο που οι διαταραχές τηςνεφρικής λειτουργίας στο πσ8 ανέρχονται στο 25% η πλειοψηφία τωνασθενών με ΔΝ παρουσιάζουν ήπια υποκλινικη εικόνα Επιπλέον, η ΣΝ είναισπάνιο σύνδρομο και υπάρχουν λίγα περιστατικά στη βιβλιογραφία Ετσι οεπιπολασμος της βαριάς νεφρικής προσβολής παραμένει άγνωστος Ο πρώτοςσκοπός της μελέτης ήταν να εξετάσουμε ενα μεγάλο αριθμό ασθενών μεκλινικά σημαντική νεφρική προσβολή να διερευνήσουμε τις κλινικές καιορολογικές διάφορες μεταξύ των ασθενών με ΔΝ και αυτών με ΣΝ και νααξιολογήσουμε την εξέλιξη και την έκβαση αυτών των νοσολογικώνοντοτήτωνΣε ενα μεγάλο πληθυσμό 471 ασθενών με nöS οι οποίοιπαρακολουθούνταν για μέσο χρονικό διάστημα 10 ετών 20 ασθενείςανέπτυξαν βάρια νεφρική προσβολή και οι 18 υποβλήθηκαν σε διαδερμικηβιοψία νεφρού Δέκα ασθενείς είχαν ΔΝ 8 ασθενείς είχαν ΣΝ και 2 είχαν καιτα δυο είδη προσβολής Παρατηρήθηκαν δυο είδη ΣΝ στη βιοψία νεφρού 5ασθενείς είχαν μεμβρανουπερπλαστικη ΣΝ και 4 ασθενείς είχαν μεσαγγειακηΣΝ η οποία περιγράφεται για πρώτη φορά στο noS Οι ασθενείς με ΔΝ είχανμικρότερη ηλικία έναρξης νόσου σε σχέση με τους ασθενείς με ΣΝ (μέση τιμή36 8 σε σύγκριση με 46 0 ετη ρ=0 063) ενω οι ασθενείς με ΣΝ είχανμεγαλύτερη διάρκεια νόσου σε σχέση με τους ασθενείς με ΔΝ (μέση τιμή 8 σεσύγκριση με 2 2 ετη ρ=0 001 ) Οχτώ απο τους 10 ασθενείς με ΣΝ είχαν μεικτήμονοκλωνικη κρυοσφαιριναιμια και χαμηλά επίπεδα C4 Επιπρόσθετα 4ασθενείς με ΣΝ ανέπτυξαν λέμφωμα Β κυτταρικής αρχής Τέλος 2 ασθενείς με ΣΝ ανέπτυξαν χρονιά νεφρική ανεπάρκεια η οποία απαιτούσεαιμοκάθαρση Συνοπτικά η βάρια προσβολή στο πσ8 είναι σπάνια Η ΣΝεμφανίζεται αργά στην πορεία της νόσου σχετίζεται με την κρυοσφαιριναιμιακαι δεν έχει τόσο καλή πρόγνωση Αντίθετα η ΔΝ εμφανίζεται νωρίς και έχεικαλύτερη πρόγνωσηΗ συνενεργοποιητικη οδός CD40 CD40L εμπλέκεται στην παθογένειαπολλών αυτοανοσων νοσημάτων όπως ο ΣΕΛ το σύνδρομο Sjogren (öS) και ηρευματοειδής αρθρίτιδα (ΡΑ) Προηγούμενες μελέτες υποστηρίζουνσυμμέτοχη της οδού στην εξέλιξη της νεφρίτιδας του λύκου To CD40Lκυκλοφορεί σε διαλυτή μορφή στον ορο ασθενών με ΣΕΛ και τα αυξημέναεπίπεδα του διαλυτού CD40L (ÔCD40L) έχουν σχετιστεί με την ενεργοτητατης νόσου Ο δεύτερος σκοπός της μελέτης ήταν να διερευνήσουμε τον πιθανόρολό του ÔCD40L στην ανάπτυξη της νεφρίτιδας του λύκου και να εξετάσουμετην πιθανή του σχέση με τη νεφρίτιδα και την κρυοσφαιριναιμια στοσύνδρομο SjogrenΜετρήσαμε με τη βοήθεια μιας sandwich ELISA δυο θέσεων ταεπίπεδα του ÔCD40L στον ορο 23 ασθενών με ΣΕΛ 23 ασθενών με öS 17ασθενών με ΡΑ και 17 υγιών μαρτύρων Βρήκαμε οτι τα επίπεδα του ÔCD40Lείναι στατιστικώς σημαντικά αυξημένα στους ασθενείς με ΣΕΛ και ÖS σεσύγκριση με τους μάρτυρες Καταγράψαμε επίσης τις κλινικές καιεργαστηριακές παραμέτρους των ασθενών με ΣΕΛ και ÖS Δεν βρήκαμεκάποια συσχέτιση των επίπεδων του ÔCD40L με κάποια κλινική ηεργαστηριακή παράμετρο συμπεριλαμβανομένων της νεφρίτιδας και τηςκρυοσφαιριναιμιας στους ασθενείς με öS Στη συνέχεια εξετάσαμε ζεύγηορού πρώτων πρωινών ουρών απο 3 ασθενείς με ΣΕΛ και ενεργό νεφρίτιδα (1ασθενής είχε εστιακή τμηματική σπειραματονεφριτιδα 1 ασθενής είχε διάχυτηυπερπλαστικη σπειραματονεφριτιδα και 1 είχε μεμβρανωδησπειραματονεφριτιδα) και απο 3 ασθενείς με ΣΕΛ και ανενεργό νεφρίτιδα (2ασθενείς είχαν μεσαγγειακη σπειραματονεφριτιδα και 1 είχε εστιακήτμηματική σπειραματονεφριτιδα) Δεν ανιχνεύσαμε ÔCD40L σε κανένα δείγμαουρών ακόμα και μετά απο συμπύκνωση των ουρών 10 φορέςΤέλος εξετάσαμε ζεύγη ορού σίελου απο 5 ασθενείς με ÖS καικρυοσφαιριναιμια και 5 ασθενείς με ÖS και αντί Ro η αντί Laαυτοαντισωματα Δεν ανιχνεύσαμε ÔCD40L σε κανένα δείγμα σάλιουΣυνοπτικά τα επίπεδα του ÔCD40L είναι αυξημένα στον ορο τωνασθενών με ÖS και ΣΕΛ Δεν βρήκαμε κάποιο συσχετισμό του ÔCD40L με τηνεφρίτιδα του λύκου και την κρυοσφαιριναιμια η τη σπειραματονεφριτιδα στοÖS Απαιτείται πιο εκτεταμένη έρευνα προκείμενου να καθοριστεί ο πιθανόςρόλος του ÔCD40L στη νεφρίτιδα του λύκου και στο σύνδρομο Sjogre

Predisposing Factors, Clinical Picture, and Outcome of B-Cell Non-Hodgkin’s Lymphoma in Sjögren’s Syndrome

Among other systemic autoimmune diseases, primary Sjögren syndrome (pSS) bears the highest risk for lymphoma development. In pSS, chronic antigenic stimulation gradually drives the evolution from polyclonal B-cell expansion to oligoclonal/monoclonal B-cell predominance to malignant B-cell transformation. Thus, most pSS-related lymphomas are B-cell non-Hodgkin lymphomas (NHLs), with mucosa-associated lymphoid tissue (MALT) lymphomas predominating, followed by diffuse large B-cell lymphomas (DLBCLs) and nodal marginal zone lymphomas (NMZLs). Since lymphomagenesis is one of the most serious complications of pSS, affecting patients’ survival, a plethora of possible predisposing factors has been studied over the years, ranging from classical clinical, serological, hematological, and histological, to the more recently proposed genetic and molecular, allowing clinicians to timely detect and to closely follow-up the subgroup of pSS patients with increased risk for lymphoma development. Overall predisposing factors for pSS-related lymphomagenesis reflect the status of B-cell hyperactivity. Different clinical features have been described for each of the distinct pSS-related B-cell NHL subtypes. While generally pSS patients developing B-cell NHLs display a fairly good prognosis, outcomes in terms of treatment response and survival rates seem to differ depending on the lymphoma subtype, with MALT lymphomas being characterized by a rather indolent course and DLBCLs gravely affecting patients’ survival

Predisposing Factors, Clinical Picture, and Outcome of B-Cell Non-Hodgkin’s Lymphoma in Sjögren’s Syndrome

Among other systemic autoimmune diseases, primary Sjögren syndrome (pSS) bears the highest risk for lymphoma development. In pSS, chronic antigenic stimulation gradually drives the evolution from polyclonal B-cell expansion to oligoclonal/monoclonal B-cell predominance to malignant B-cell transformation. Thus, most pSS-related lymphomas are B-cell non-Hodgkin lymphomas (NHLs), with mucosa-associated lymphoid tissue (MALT) lymphomas predominating, followed by diffuse large B-cell lymphomas (DLBCLs) and nodal marginal zone lymphomas (NMZLs). Since lymphomagenesis is one of the most serious complications of pSS, affecting patients’ survival, a plethora of possible predisposing factors has been studied over the years, ranging from classical clinical, serological, hematological, and histological, to the more recently proposed genetic and molecular, allowing clinicians to timely detect and to closely follow-up the subgroup of pSS patients with increased risk for lymphoma development. Overall predisposing factors for pSS-related lymphomagenesis reflect the status of B-cell hyperactivity. Different clinical features have been described for each of the distinct pSS-related B-cell NHL subtypes. While generally pSS patients developing B-cell NHLs display a fairly good prognosis, outcomes in terms of treatment response and survival rates seem to differ depending on the lymphoma subtype, with MALT lymphomas being characterized by a rather indolent course and DLBCLs gravely affecting patients’ survival

Natural history and screening of interstitia lung disease in systemic autoimmune rheumatic disorders

Interstitial lung disease (ILD) is a relatively frequent manifestation of systemic autoimmune rheumatic disorders (SARDs), including systemic sclerosis (SSc), rheumatoid arthritis (RA), idiopathic inflammatory myopathies (IIM), systemic lupus erythematosus (SLE), primary Sjogren's syndrome (pSS), and anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis. Interstitial pneumonia with autoimmune features (IPAF) has been proposed to describe patients with ILD who have clinical or serological findings compatible with SARDs but they are not sufficient for a definite diagnosis. ILD may present with different patterns among patients with SARDs, but most commonly as nonspecific interstitial pneumonia (NSIP), with the exception of RA and ANCA vasculitis that more often present with usual interstitial pneumonia (UIP). The natural history of ILD is quite variable, even among patients with the same SARD. It may present with subclinical features following a slow progressively course or with acute manifestations and clinically significant rapid progression leading to severe deterioration of pulmonary function and respiratory failure. The radiographic pattern of ILD, the extent of the disease, the baseline pulmonary function, the pulmonary function deterioration rate over time and clinical variables related to the primary SARD, such as age, sex and the clinical phenotype, are considered prognostic factors for SARDs-ILD associated with adverse outcomes and increased mortality. Different modalities can be employed for ILD detection including clinical evaluation, pulmonary function tests, high resolution computed tomography and novel techniques such as lung ultrasound and serum biomarkers. ILD may determine the clinical outcome of SARDs, since it is associated with significant morbidity and mortality and therefore screening of patients with SARDs for ILD is of great clinical importance