The impact of two different rituximab-based strategies in cryoglobulinaemic vasculitis secondary to Sjögren's disease: a monocentric cohort study.

OBJECTIVES: To compare two different rituximab (RTX)-based therapeutic approaches on vasculitic and lymphoproliferative-related disease activity and on non-Hodgkin lymphoma (NHL) development in a cohort of patients affected by cryoglobulinaemic vasculitis secondary to Sjögren's disease (Sjögren-CryoVasc). METHODS: Three Sjögren-CryoVasc treatment groups were identified: 1) early RTX induction followed by maintenance; 2) late RTX induction with possible on-demand retreatment; 3) no RTX treatment. The following outcomes were evaluated: a) changes in cumulative ESSDAI, considering vasculitic-related and lymphoproliferative-related domains and changes in ESSDAI specific to each single vasculitic-related and lymphoproliferative-related domain; b) development of NHL; c) occurrence of persistent hypogammaglobulinemia associated with serious infections. RESULTS: 13 Sjögren-CryoVasc patients were identified: 1) 5/13 treated earlier with RTX with subsequent maintenance; 2) 5/13 treated late with RTX with possible on-demand retreatment; 3) 3/13 not treated with RTX. The two RTX groups showed a decrease in the ESSDAI score with group 1 showing the most substantial reduction (p=0.028). Patients receiving RTX exhibited significant improvement in cutaneous, PNS, and articular vasculitic-related ESSDAI domains (p=0.007; p=0.006; p=0.03, respectively). By contrast RTX did not greatly affect the lymphoproliferative-related ESSDAI domains, even if an improvement was noted in the glandular and nodal domains for group 1 (p=0.03; p=0.03, respectively). No differences in NHL occurrence or safety concerns were observed among the groups. CONCLUSIONS: RTX is an effective and safe treatment to control Sjögren-CryoVasc disease activity with a greater impact when administered earlier with a maintenance regimen. RTX alone cannot, however, affect the possible evolution of Sjögren-CryoVasc into an overt NHL.

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's lymphoma (NHL) in primary SS (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 localization 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 localization 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 localized 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 localizes 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.

Nuts and bolts of salivary gland pathology in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic, systemic, inflammatory autoimmune disease characterised by lymphocyte proliferation and progressive damage to exocrine glands. Salivary gland histopathology based on salivary gland biopsy is relevant for the diagnosis of pSS and therefore broadly applied in clinical practice. Tissue can be obtained from labial salivary glands (LSG) biopsy or from major salivary glands (MSG) biopsy, namely the parotid; in this latter scenario, the procedure can be either an open surgical biopsy or a US guided core needle biopsy.In this review we will: i) present the histopathological findings that may be encountered by pathologists on biopsies from pSS patients; ii) discuss the advantages and disadvantages of the surgical and/or imaging guided procedures to obtain tissues from LSG or MSG; iii) describe the histopathological features of lymphoma of MSG in pSS patients.

Secretagogue effect of PDE4 inhibitor apremilast on human salivary gland organoids obtained from primary Sjögren's syndrome patients.

OBJECTIVES: The aim of the study was to culture vital salivary gland organoids obtained through labial or parotid biopsy of primary Sjögren's syndrome (pSS) patients in order to evaluate their morphological and functional features in basal condition and after stimulation with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) activator forskolin and phosphodiesterase 4 (PDE4) inhibitor apremilast, their in vitro regenerative capacity and the immune-histological resemblance with original tissue. METHODS: Salivary gland tissues from five pSS patients were processed to obtain vital organoids; swelling assay and cell proliferation tests were performed after forskolin and apremilast application. Immunochemistry evaluation on original salivary gland tissue and corresponding organoids was performed, and secretomics analysis was conducted to assess their functional status. REULTS: After application of forskolin and apremilast, we observed organoid swelling after 30 minutes, compatible with a positive functional status and enhancement of saliva production. In 3 cases, apremilast induced organoid proliferation. All cases were positive for cytokeratin 14 (CK14) and most for cytokeratin 5 (CK5). All the cases were positive for amylase; its secretion, and thus functional status of organoids, was confirmed by its high concentration in the culture medium. A focal ductal differentiation was found in some cases, highlighted by epithelial membrane antigen (EMA) positivity. The more differentiated EMA positive areas were negative for the staminal marker CK14, showing a sort of "complementary staining". CONCLUSIONS: Our data highlighted that differentiated cells and vital functional organoids that recapitulate the development of original salivary glands can be obtained from pSS epithelium. For the first time, the direct stimulating effect of PDE4 inhibitor apremilast on pSS human salivary gland organoids is reported, opening new perspectives on targeting oral dryness with drugs that combine secretagogue and immunomodulatory effects.

Usefulness of ultrasound guided core needle biopsy of the parotid gland for the diagnosis of primary Sjögren's syndrome.

OBJECTIVES: The diagnosis and classification of primary Sjögren's syndrome (pSS) relies on labial biopsy, whereas the role of open parotid biopsy is mainly reserved to evaluate the lymphoproliferative complications. Recently ultrasound-guided core needle biopsy (US-guided CNB) appeared as a novel and safe technique useful in lymphoma assessment, however, its potential role in the diagnosis of pSS has never been assessed.The main aim of this study was to evaluate the diagnostic value of US-guided CNB of the parotid glands in patients affected by pSS. METHODS: Patients affected by pSS who underwent US-guided CNB for a suspected glandular lymphoma were included. Adequacy of the samples and histopathological features related to pSS were analysed. RESULTS: US-guided CNB was performed on 29 parotid glands. The biopsied samples were adequate for diagnosis in 28/29 (96.5%) cases. Fifteen patients showed pathologic features of parotid lymphoma. Among the remaining patients, 9/13 presented focus score≥1; LELs were present in 8/13 patients, and GCs in 11/13. In 8 cases the histological features were coherent with MESA/LESA. Acinar atrophy, fibrosis and duct dilatation were also evaluated. CONCLUSIONS: This preliminary study suggests the possible usefulness of US-guided CNB for the diagnosis of pSS by enabling the collection of adequate salivary gland tissue to assess the FS, GCs, LELs, and other histopathologic features also useful in the management of pSS patients.

Sjögren's syndrome: one year in review 2022.

Primary Sjögren's syndrome (pSS) is a complex disabling systemic autoimmune disorder. The hallmark of pSS is the T-cell-mediated hyperactivation of B-cells, evolving from asymptomatic conditions to systemic complications and lymphoma development. On tissue level, the typical feature is the lymphocytic infiltration of the salivary gland by B-, T- and antigen presenting cells, as mirrored by the diagnostic cornerstone role of minor salivary gland (MSG) biopsy. B-cells show multiple possible roles in disease pathogenesis, from autoantibody production, to antigen presentation, and cytokine production. B-cells hyperactivation is supported by genetic risk factors, T-cell dependent and independent mechanisms, and the presence of different pathogenic B-cell subsets must be reminded.Many aspects have been investigated in the last year regarding genetic and epigenetics, B- and T-cell role in pSS pathogenesis, their interaction with salivary gland epithelial cells (SGECs) and in their direct or indirect use as biomarkers and predictors of disease development, activity, and lymphomagenesis.In this review, following the others of this series, we will summarise the most recent literature on pSS pathogenesis and clinical features focusing in particular on new insights into pSS molecular stratification and therapeutic advances in the era of precision medicine.

Sonographic features of lymphoma of the major salivary glands diagnosed with ultrasound-guided core needle biopsy in Sjögren's syndrome.

OBJECTIVES: To identify ultrasound (US) features of lymphomas (L) of major salivary glands (SGs) in primary Sjögren's syndrome (pSS) patients and to differentiate US pattern of L and non-L. METHODS: Prospectively, from September 2019 to March 2021, 27 pSS-patients with clinical findings suspicious for L of the SGs underwent US evaluation followed by US-guided core-needle biopsy (CNB). For each patient, we assessed the OMERACT score, dichotomised (0/1 "lower", 2/3 "higher"), and we compared it between L-pSS and nonL-pSS groups. For focal lesions, echogenicity, inner appearance, shape, margins, presence of septa, vascularisation and posterior acoustic features were also assessed and compared between the two groups; we planned to consider as "suspicious" features more frequently associated with L. We expected to compare frequencies at which two or more "suspicious" features were simultaneously present between L-pSS and nonL-pSS. P<0.05 were considered statistically significant. RESULTS: L-pSS showed more inhomogeneous glandular pattern (100% vs. 69.2% higher OMERACT; p=0.0407). For focal lesions, the "suspicious" features identified were: OMERACT grade 3, very hypoechoic, homogenous, oval shape, well-defined margins, presence of septa, colour-Doppler vascularization, posterior acoustic enhancement. 6/8 and 7/8 simultaneous suspicious features were significantly higher among L-pSS patients, compared to nonL-pSS (88.9% vs. 28.6%, p=0.034 for 6/8 features; 77.8% vs. 14.3%, p=0.040 for 7/8 features). CONCLUSIONS: L of the major SGs in pSS was always associated with OMERACT scores 2 or 3 and presented with diffuse or focal patterns. For focal lesions, the association of more "suspicious" features made the diagnosis of L increasingly more likely. This information can help to improve planning of US-guided CNB.

One year in review 2020: comorbidities, diagnosis and treatment of primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a complex and heterogeneous disorder characterised by a wide spectrum of glandular and extra-glandular features. The discovery of novel biomarkers allowed to characterise the disease not only phenotypically on the basis of clinical presentation, but also on the basis of the endotype. Moreover, a better stratification of patients has important value in the evaluation of mechanisms underlying the risk of lymphoproliferative disorders in these patients. Finally, novel targeted therapies may open new possibilities for the application of personalised medicine in pSS.

Risk of Cancer in Connective Tissue Diseases in Northeastern Italy over 15 Years.

OBJECTIVE: To evaluate cancer risk among individuals with connective tissue disease (CTD) in Friuli Venezia Giulia, northern Italy. METHODS: A population-based cohort study was conducted based on data from health records available in the regional healthcare database. Demographic characteristics, hospital discharges, exemption from medical charges, drug prescriptions, were individually matched with data from the population-based cancer registry. Cancer risk was assessed in people diagnosed with the following diseases: systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), systemic sclerosis (SSc), polymyositis (PM), and dermatomyositis (DM). RESULTS: In all, 2504 patients were followed for a total of 18,006 person-years (median follow-up: 6.8 years). After 5 and 10 years of follow-up, the cumulative cancer incidence was 2.6% and 8.5%, respectively. The most common cancers were breast (n = 34), lung (n = 24), colon-rectum-anus (n = 20), and non-Hodgkin lymphomas (NHL) (n = 20). Overall, no excess cancer risk was noted (SIR = 0.87), whereas the number of observed NHL cases was more than two-fold significantly higher than expected (SIR = 2.52). The subgroup analysis showed a higher risk of NHL among SS patients (SIR = 3.84) and SLE patients (SIR = 2.69). Conversely, the study population showed a decreased risk for breast cancers (SIR = 0.61) and corpus uteri (SIR = 0.21). CONCLUSIONS: The incidence of NHL was higher among patients with SS and SLE. Careful surveillance for hematological malignancies in these patients is recommended.

Sjögren syndrome: looking forward to the future.

Primary Sjögren's syndrome (pSS) is a heterogeneous disease characterised by a wide spectrum of manifestations that vary according to the different stages of the disease and among different subsets of patients. The aim of this qualitative literature review is to summarise the recent advances that have been reported in pSS, ranging from the early phases to the established disease and its complications. We analysed the diagnostic, prognostic, and management aspects of pSS, with a look into future clinical and research developments. The early phases of pSS, usually antedating diagnosis, allow us to investigate the pathophysiology and risk factors of the overt disease, thus allowing better and timely patient stratification. Salivary gland ultrasound (SGUS) is emerging as a valid complementary, or even alternative, tool for histopathology in the diagnosis of pSS, due to a standardised scoring system with good agreement and performance. Other promising innovations include the application of artificial intelligence to SGUS, ultrasound-guided core needle biopsy, and a wide array of novel diagnostic and prognostic biomarkers. Stratifying pSS patients through the integration of clinical, laboratory, imaging, and histopathological data; differentiating between activity-related and damage-related manifestations; and identifying patients at higher risk of lymphoma development are essential steps for an optimal management and individualised treatment approach. As new treatment options are emerging for both glandular and systemic manifestations, there is a need for a more reliable treatment response evaluation. pSS is a complex and heterogeneous disease, and many distinct aspects should be considered in the different stages of the disease and subsets of patients. In recent years, efforts have been made to improve our understanding of the disease, and certainly in the coming years, some of these novelties will become part of our routine clinical practice, thus improving the management of pSS patients.

Safety, patient acceptance and diagnostic accuracy of ultrasound core needle biopsy of parotid or submandibular glands in primary Sjögren's syndrome with suspected salivary gland lymphoma.

BACKGROUND: Enlargement of the major salivary glands (SGs) is a major risk factor for B-cell lymphoma among patients with primary Sjögren's syndrome (pSS). Ultrasound-guided core needle biopsy (US-guided CNB) could be a novel technique to manage SG enlargement among patients with pSS. OBJECTIVE: Accordingly, this study's main aim was to evaluate the safety, patient tolerance and diagnostic accuracy of US-guided CNB procedure for patients with pSS with major SG enlargement. METHODS: Patients with clinical diagnosis of pSS and a clinical indication for SG biopsy consecutively underwent US-guided CNB between September 2019 and June 2021. These patients were evaluated clinically 1, 2 and 12 weeks after US-guided CNB. Patients were asked to complete a questionnaire about postprocedural complications as well as periprocedural pain, using the Visual Analogue Scale. Complications were categorised as transient (<12 weeks) or persistent (≥12 weeks). RESULTS: US-guided CNB was performed on 30 major salivary glands (22 parotid glands and 8 submandibular glands). The procedure was well tolerated. Transient complications-such as haematoma, swelling-were observed among 43% of patients, and mean periprocedural pain was low. However, no persistent complications were reported during the study's follow-up period. CONCLUSION: US-guided CNB represents a novel approach for the management of patients with pSS with SG enlargement. The procedure showed remarkable patient safety and tolerance, allowing adequate glandular sampling and a definite diagnosis for almost all participating patients without long-term complications.

Ultrasound and Bioptic Investigation of Patients with Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is a chronic and heterogeneous disorder characterized by a wide spectrum of glandular and extra-glandular features. The hallmark of pSS is considered to be the immune-mediated involvement of the exocrine glands and B-cell hyperactivation. This leads pSS patients to an increased risk of developing lymphoproliferative diseases, and persistent (>2 months) major salivary gland enlargement is a well-known clinical sign of possible involvement by B cell lymphoma. Better stratification of the patients may improve understanding of the mechanism underlying the risk of lymphoproliferative disorder. Here, we summarize the role of different imaging techniques and a bioptic approach in pSS patients, focusing mainly on the role of salivary gland ultrasonography (SGUS) and a US-guided core needle biopsy (Us-guided CNB) as diagnostic and prognostic tools in pSS patients with persistent parotid swelling.

Shared Pathogenetic Features Between Common Variable Immunodeficiency and Sjögren's Syndrome: Clues for a Personalized Medicine.

Common variable immunodeficiency disorders (CVID) are a group of rare diseases of the immune system and the most common symptomatic primary antibody deficiency in adults. The "variable" aspect of CVID refers to the approximately half of the patients who develop non-infective complications, mainly autoimmune features, in particular organ specific autoimmune diseases including thyroiditis, and cytopenias. Among these associated conditions, the incidence of lymphoma, including mucosal associated lymphoid tissue (MALT) type, is increased. Although these associated autoimmune disorders in CVID are generally attributed to Systemic Lupus Erythematosus (SLE), we propose that Sjogren's syndrome (SS) is perhaps a better candidate for the associated disease. SS is an autoimmune disorder characterized by the lymphocytic infiltrates of lacrimal and salivary glands, leading to dryness of the eyes and mouth. Thus, it is a lymphocyte aggressive disorder, in contrast to SLE where pathology is generally attributed to auto-antibody and complement activation. Although systemic lupus erythematosus (SLE) shares these features with SS, a much higher frequency of MALT lymphoma distinguishes SS from SLE. Also, the higher frequency of germ line encoded paraproteins such as the monoclonal rheumatoid factor found in SS patients would be more consistent with the failure of B-cell VDJ switching found in CVID; and in contrast to the hypermutation that characterizes SLE autoantibodies. Thus, we suggest that SS may fit as a better "autoimmune" association with CVID. Examining the common underlying biologic mechanisms that promote lymphoid infiltration by dysregulated lymphocytes and lymphoma in CVID may provide new avenues for treatment in both the diseases. Since the diagnosis of SLE or rheumatoid arthritis is usually based on specific autoantibodies, the associated autoimmune features of CVID patients may not be recognized in the absence of autoantibodies.

Diagnosis and management of lung involvement in systemic lupus erythematosus and Sjögren's syndrome: a literature review.

Lung involvement in systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) has extensively been outlined with a multiplicity of different manifestations. In SLE, the most frequent finding is pleural effusion, while in pSS, airway disease and parenchymal disorders prevail. In both cases, there is an increased risk of pre-capillary and post-capillary pulmonary arterial hypertension (PAH) and pulmonary venous thromboembolism (VTE). The risk of VTE is in part due to an increased thrombophilic status secondary to systemic inflammation or to the well-established association with antiphospholipid antibody syndrome (APS). The lung can also be the site of an organ-specific complication due to the aberrant pathologic immune-hyperactivation as occurs in the development of lymphoma or amyloidosis in pSS. Respiratory infections are a major issue to be addressed when approaching the differential diagnosis, and their exclusion is required to safely start an immunosuppressive therapy. Treatment strategy is mainly based on glucocorticoids (GCs) and immunosuppressants, with a variable response according to the primary pathologic process. Anticoagulation is recommended in case of VTE and multi-targeted treatment regimens including different drugs are the mainstay for PAH management. Antibiotics and respiratory physiotherapy can be considered relevant complement therapeutic measures. In this article, we reviewed lung manifestations in SLE and pSS with the aim to provide a comprehensive overview of their diagnosis and management to physicians taking care of patients with connective tissue diseases.