Update on the pathophysiology and treatment of primary Sjögren syndrome.

Sjögren syndrome or Sjögren disease is a chronic form of autoimmune epithelitis characterized by lymphocytic infiltration of the exocrine glands, particularly the salivary and lacrimal glands, leading to progressive glandular dysfunction and subsequent xerostomia and xerophthalmia. Other common manifestations include pain and fatigue, various systemic manifestations and non-Hodgkin's lymphoma. Sjögren syndrome is therefore a complex and disabling disease associated with a reduced quality of life and with considerable long-term damage. Most of the available treatments are merely symptomatic with limited efficacy in both preventing glandular damage and suppressing systemic disease activity. In the past 10 years, great progress has been made in understanding the pathophysiology of Sjögren syndrome, opening new avenues towards a more targeted and individualized therapeutic approach to the disease. Indeed, several randomized controlled trials have just been completed or are poised to commence evaluating the effectiveness of novel drugs targeting both innate and adaptive immune pathways, including pro-inflammatory cytokines, the type I interferon system, B cell activation, B cell and T cell co-stimulation pathway, and ectopic germinal centre formation. Novel clinical trials are also ongoing exploring various targeted approaches (that is, IgG recycling inhibition, nuclease therapy and CAR-T cell therapy) for Sjögren syndrome.

Baricitinib and Pulse Steroids Combination Treatment in Hyperinflammatory COVID-19: A Rheumatological Approach in the Intensive Care Unit.

Hyperinflammatory Coronavirus disease 2019 (COVID-19) and rapidly-progressive interstitial lung diseases (RP-ILD) secondary to inflammatory myopathies (IIM) present important similarities. These data support the use of anti-rheumatic drugs for the treatment of COVID-19. The aim of this study was to compare the efficacy of combining baricitinib and pulse steroids with the Standard of Care (SoC) for the treatment of critically ill COVID-19 patients. We retrospectively enrolled consecutive patients admitted to the Intensive Care Unit (ICU) with COVID-19-pneumonia. Patients treated with SoC (dexamethasone plus remdesivir) were compared to patients treated with baricitinib plus 6-methylprednisolone pulses (Rheuma-group). We enrolled 246 patients: 104/246 in the SoC and 142/246 in the Rheuma-group. All patients presented laboratory findings suggestive of hyperinflammatory response. Sixty-four patients (26.1%) died during ICU hospitalization. The mortality rate in the Rheuma-group was significantly lower than in the SoC-group (15.5 vs. 40.4%, p < 0.001). Compared to the SoC-group, patients in the Rheuma-group presented significantly lower inflammatory biomarker levels after one week of treatment. Higher ferritin levels after one week of treatment were strongly associated with mortality (p < 0.001). In this large real-life COVID-19 cohort, baricitinib and pulse steroids led to a significant reduction in mortality, paralleled by a prompt reduction in inflammatory biomarkers. Our experience supports the similarities between hyperinflammatory COVID-19 and the IIM-associated RP-ILD.

The role of tobacco smoking in anti-neutrophil cytoplasmic antibody-associated vasculitis: a systematic review.

OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of systemic pauci-immune necrotising vasculitides involving small vessels, characterised by the presence of specific ANCA autoantibodies directed to leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) and subdivided into three clinical entities: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). The aetiology of AAV is unknown and many genetic, epigenetic and environmental factors have been reported to be involved in pathogenesis. Smoking is widely recognised as a risk factor for the development of many autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. This systematic review will analyse known data about the role of smoking in the development, clinical presentation and outcome of AAV. METHODS: Articles that examined interactions between tobacco smoking and AAV (GPA, MPA, EGPA) were included. All articles selected were in English. No limitation on publication date was established. Case reports were excluded. The systematic search was performed using PubMed/Medline and Cochrane Library databases. RESULTS: The search provided a total of 131 articles. Three studies were added, obtained from the review of the reference lists of articles. 70 were removed because they were duplicated or written in languages other than English. The title and abstract of 64 articles were screened. Of these, 30 were excluded as the title and/or abstract did not meet the inclusion criteria. Thus, 34 remained for full-text review, of which 8 were excluded. 26 articles were therefore included in this review. The role of smoking in AAV development is unclear. AAV patients current smoking appear appear to be younger and more frequently males, with a lower prevalence of EGPA and MPA than GPA. Ever smokers show higher relapse rate. Smoking seems to be associated with a higher risk of cardiovascular events during follow-up. Smokers incur an increased risk of infections. Finally, many data support smoking as a risk factor for end stage renal disease and mortality in AAV patients. CONCLUSIONS: Current data support the hypothesis that smoking influences prevalence, clinical phenotype and prognosis of ANCA-associated vasculitis. However, further studies are required to fully determine its role.

When is the right time to change therapy? An observational study of the time to response to immunosuppressive drugs in systemic lupus erythematosus.

OBJECTIVES: To analyse the response to immunosuppressants (IS) in extrarenal flares of SLE to determine the most appropriate timing during follow-up for a change in therapeutic strategy. METHODS: Observational cohort study including a total of 81 patients with SLE with extrarenal flares requiring a change in IS over the period 2015-2022. Baseline clinical variables were described, and follow-up data at 1, 3, 6 and 12 months time-points were collected. RESULTS: Among patients flaring that achieved lupus low disease activity state (LLDAS5) at 12 months of follow-up, we identified two subgroups ('late responders' and 'early responders'), which showed no significant differences in demographic characteristics, baseline clinical data, cumulative dosage of glucocorticoids or type of IS. Cox model analysis revealed a significant association of a change in IS (p=0.019) and achieving LLDAS5. Contingency table analysis indicated a significant relationship (p=0.004) between IS change at 6 months and individuals achieving LLDAS5 and remission at 12 months. CONCLUSIONS: Our findings suggest that clinical improvement of extrarenal flares typically occurs within 6 months of initiating IS. This timeframe could represent an appropriate timing to evaluate the response in a treat-to-target approach in SLE.

The impact of environmental factors on aetiopathogenesis and clinical manifestations of Behçet's syndrome.

Behçet's syndrome (BS) is a rare multisystem vasculitis involving blood vessels of any size. BS aetiology is still unclear to date, and the heterogeneity of clinical expression among ethnics and genders make early diagnosis challenging. However, so far, considerable efforts have been made toward the understanding of BS, leading researchers to agree that the coexistence of some environmental triggers and a genetical susceptibility both underlie BS aetiopathogenesis. In particular, viral agents, oral microbial flora, and mucosal microbiota have been widely explored in this regard, but still no specific microorganism has been definitely linked to the disease aetiology. Likewise, the concept that some environmental factors may play a role in BS clinical presentation has emerged based on the growing evidence that disease severity is usually higher in male patients, and that diet and fatigue may be involved in disease recurrence, especially in mucocutaneous manifestations. Moreover, smoke cessation is acknowledged as a risk factor for oral ulcerations, although the underlying mechanism is still not clear. All those environmental factors play their effects through epigenetic mechanisms. The aim of this review is to discuss the evidence on the role of environmental factors in BS aetiopathogenesis and clinical course.

Systemic vasculitis: one year in review 2024.

Systemic vasculitides comprise a collection of rare and heterogeneous disorders capable of impacting any organ and system, posing a considerable burden of mortality and comorbidity. As with previous annual reviews of this series, this review will offer a critical overview of the latest literature on pathogenesis, biomarkers, and treatment options in both small- and large-vessel vasculitis.

Validation of the Italian version of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire.

Objectives: The primary objective of this study was the translation and validation of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire into Italian, denoted as AAV-PRO_ita. The secondary objective was to evaluate the impact of ANCA-associated vasculitis (AAV) on quality of life (QoL) and work impairment in a large cohort of Italian patients. Methods: The study design took a prospective cohort study approach. First, the AAV-PRO was translated into Italian following the step guidelines for translations. The new AAV-PRO_ita questionnaire covered three disease domains: organ-specific and systemic symptoms and signs; physical function; and social and emotional impact. Second, Italian-speaking AAV patients were recruited from 17 Italian centres belonging to the Italian Vasculitis Study Group. Participants completed the AAV-PRO_ita questionnaire at three time points. Participants were also requested to complete the work productivity and activity impairment: general health questionnaire. Results: A total of 276 AAV patients (56.5% women) completed the questionnaires. The AAV-PRO_ita questionnaire demonstrated a good internal consistency and test-retest reliability. Female AAV patients scored higher (i.e. worse) in all thee domains, especially in the social and emotional impact domain (P < 0.001). Patients on glucocorticoid therapy (n = 199) had higher scores in all domains, especially in the physical function domain (P < 0.001), compared with patients not on glucocorticoid therapy (n = 77). Furthermore, patients who had at least one relapse of disease (n = 114) had higher scores compared with those who had never had one (n = 161) in any domain (P < 0.05). Finally, nearly 30% of the patients reported work impairment. Conclusion: The AAV-PRO_ita questionnaire is a new 29-item, disease-specific patient-reported outcome measuring tool that can be used in AAV research in the Italian language. Sex, glucocorticoids and relapsing disease showed the greatest impact on QoL.

Reliability Exercise of Ultrasound Salivary Glands in Sjögren's Disease: An International Web Training Initiative.

INTRODUCTION: Major salivary gland ultrasonography (SGUS) demonstrated its good metric properties as an outcome measure for diagnosing primary Sjögren's disease (SD). The objective was to assess SGUS reliability among sonographers with different levels of experience, using web training. METHODS: Sonographers from expert centers participated in the reliability exercise. Before exercises, training was done by videoconferencing. Reliability of the two most experienced sonographers (MES) was assessed and then compared to other sonographers. Intra-reader and inter-reader reliability of SGUS items were assessed by computing Cohen's κ coefficients. RESULTS: All sets were read twice by all 14 sonographers within a 4-month interval. Intra-reader reliability of MES was almost perfect for homogeneity, substantial for Outcome Measures in Rheumatology (OMERACT) scoring system (OMERACTss). Among LES (less experienced sonographers), reliability was moderate to almost perfect for homogeneity, fair to moderate for OMERACTss, and fair to almost perfect for binary OMERACTss. Inter-reader reliability between MES was almost perfect for homogeneity, substantial for diagnosis, moderate for OMERACTss, and substantial for binary OMERACTss. Compared to MES, reliabilities of LES were moderate to almost perfect for both homogeneity and diagnosis, only fair to moderate for OMERACTss, but increased in binary OMERACTss. CONCLUSIONS: Videoconferencing training sessions in an international reliability exercise could be an excellent tool to train experienced and less-experienced sonographers. SGUS homogeneity items is useful to distinguish normal from abnormal salivary glands parenchyma independently of diagnosis. Structural damage evaluations by OMERACT scoring system is a new comprehensive score to diagnose patients with SD and could be easily used by sonographers in a binary method.

The goal of this project was to evaluate the reliability of salivary gland ultrasonography in patients with Sjögren's disease using online training in an international study. Currently, salivary gland ultrasonography is routinely used only by European expert sonographers but few studies have studied intra-reader and inter-reader reliability, among less experienced international sonographers. Many salivary gland ultrasonography scoring systems are used today, but it is difficult to know how to put them into practice. Online training on an international level allows a significant number of practitioners to use the different scoring systems including the latest OMERACT (Outcome Measures in Rheumatology) score, which is simple and comprehensive. There were two phases to this project: A first step consisted in a training session by videoconferencing to all sonographers, the second step was an inter and intra-reader reliability exercises. The results of our study showed satisfactory results, especially for parenchyma homogeneity. Regarding the comprehensive OMERACT score, the results are quite disparate, notably for less experienced sonographers and could be explained by this new comprehensive scoring system. However, when binary OMERACT score (minor damage versus major damage of salivary gland parenchyma (OMERACT score 0­1 vs. 2­3) was employed, reliability increased and can be very useful for novice sonographers in routine practice because it does not require scoring of all the pathological features in Sjögren's disease. This study highlights the need to train non-experts interested in this field and demonstrates the potential for beginners to quickly become experts.

Which extra-renal flare is 'difficult to treat' in systemic lupus erythematosus? A one-year longitudinal study comparing traditional and machine learning approaches.

OBJECTIVES: To describe phenotypes and outcomes of extra-renal flares in SLE, to identify clusters of extra-renal flares based on baseline features, and to develop a machine learning (ML) tool capable of predicting 'difficult to treat' (D2T) flares. METHODS: Extra-renal flares that occurred in our cohort over the last five years with at least one year of follow-up were included. Baseline clinical variables were described and flares assigned to clusters. Attainment of remission and low disease activity state (LLDAS) at 12 months were compared. Flares were then considered 'D2T' in case of non-attainment of LLDAS at 6 and 12 months. Baseline features were used to train a ML model able to predict future D2T-flares, at admission. Traditional approaches were then compared with informatic techniques. RESULTS: Among 420 SLE patients of the cohort, 114 flares occurred between 2015 and 2021; 79 extra-renal flares, predominantly mucocutaneous (24.1%) and musculoskeletal (45.6%), were considered. After 12 months, 79.4% and 49.4% were in LLDAS and in remission, respectively, while 17 flares were classified as D2T (21.5%); D2T flares received a higher cumulative and daily dose of glucocorticoids. Among the clusters, cluster 'D' (mild-moderate flares with mucocutaneous manifestations in patients with history of skin involvement) was associated with the lowest rate of remission. Among clinical data, not being on LLDAS at 3 months was the unique independent predictor of D2T flares. CONCLUSIONS: Our clusterization well separates extra-renal flares according to their baseline features and may propose a new identification standard. D2T flares, especially refractory skin manifestations, are frequent in SLE and represent an unmet need in the management of the disease as they are associated with higher glucocorticoid (GC) dosage and risk of damage accrual. Our ML model could help in the early identification of D2T flares, flagging them to elevate the attention threshold at admission.

Cryoglobulinemic vasculitis: a 2023 update.

PURPOSE OF REVIEW: Cryoglobulinemic vasculitis (CV) is an immune complex mediated small vessel vasculitis characterized by the presence of cryoglobulins in serum, often associated with hepatitis C infection, systemic autoimmune diseases or hematological conditions. The focus of this review is to provide an update on new insights into pathogenesis, epidemiology and therapies of infectious and noninfectious type II and type III CV. RECENT FINDINGS: The introduction of new antiviral drugs for treatment of hepatitis C infection implied major changes in HCV-related CV, allowing to shed new lights on CV pathogenesis and mechanisms of relapse and, therefore, to increase the relevance of autoimmune diseases in CV epidemiology. Specific B-cell clones are involved in the production of pathogenic immune complexes that leads to small-vessel vasculitis. Therefore, both antiviral treatments [direct-acting antivirals (DAAs) and oral nucleot(s)ide analogues] and targeted anti-CD20 therapies (rituximab) prove to be safe and effective options, leading to a better prognosis. Association of Sjögren syndrome and CV defines a specific phenotype of patients, characterized by severe manifestations and poor outcome. SUMMARY: Removing viral stimulation on B-cells through direct-acting antivirals and blocking B-cells proliferation and differentiation with rituximab are the goals of treatment of CV. However, further research is needed to identify prognostic factors of refractory and relapsing disease.

Clinical and histological features of patients with primary Sjögren's syndrome and autoimmune thyroiditis: a national multicentre cross-sectional study.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is frequently associated with autoimmune thyroiditis (AT). The aim of this study was to evaluate the prevalence of AT in a national cohort of pSS and to describe the clinical and histological phenotype of patients with pSS and associated AT. METHODS: In this multicentre cross-sectional study, data from 2546 pSS were collected and the presence of AT was reported. In a subgroup, the histology of minor salivary glands was evaluated. Differences between pSS with and without AT were evaluated. RESULTS: A concomitant pSS and AT was detected in 19.6% of cases. Patients with pSS and AT displayed a lower prevalence of lymphoma, male sex and disease-modifying anti-rheumatic drugs (DMARDs) use and a higher prevalence of fibromyalgia, coeliac disease and hypergammaglobulinaemia. Multivariable analysis confirmed a higher prevalence of fibromyalgia and coeliac disease and lower use of DMARDs. In a subgroup of patients (n=232), a significantly higher focus score and number of foci was detected in pSS without AT (n=169) as compared to pSS with AT (n=54). CONCLUSIONS: This is the largest study evaluating the coexistence of pSS and AT. We confirm a high association between pSS and AT and describe the presence of a different phenotype characterized by a higher rate of celiac disease and fibromyalgia. Although not significant, the lower prevalence of both lymphoma and intake of DMARDs, along with a significantly lower focus score and number of foci, possibly suggest a more favourable outcome in concomitant pSS and AT which further deserve future investigations.

Impact of gender and age at onset on Sjögren's syndrome presentation and outcome: state of the art.

Sjögren's syndrome (SS) is a complex and heterogeneous disease that typically affects middle-aged women. However, while it is rare, the disease may occur in male patients and in females during their childhood/adolescence or in the elderly. Contrasting data have been reported on these three subgroups clinical features and long-term outcomes. Notably, recent studies have pinpointed the severity of the disease in male patients and in both the early and the late-onset subgroups.The aim of this review is, therefore, to summarise the available evidence from the recent literature on these phenotypes. The focus will be on the clinical and laboratory features, and on the lymphoma risk observed in the three subgroups distinct phenotypes: of male patients as well as young-onset SS and elderly-onset SS. Ultimately, an accurate phenotypic stratification may represent the first step towards individualised medical approaches.

UHFUS: A Valuable Tool in Evaluating Exocrine Gland Abnormalities in Sjögren's Disease.

Sjögren's Disease (SjD) is a chronic autoimmune disorder that affects the salivary and lacrimal glands, leading to xerostomia and xerophthalmia. Ultrasonography of Major Salivary Glands (SGUS) is a well-established tool for the identification of the salivary glands' abnormalities in SjD. Recently, a growing interest has arisen in the assessment of the other exocrine glands with ultrasonography: lacrimal glands (LGUS) and labial salivary glands (LSGUS). The objective of this study is to explore the practical applications of ultra-high frequency ultrasound (UHFUS) in the assessment of lacrimal glands and labial salivary glands. Indeed, UHFUS, with its improved spatial resolution compared to conventional ultrasonography, allows for the evaluation of microscopic structures and has been successfully applied in various medical fields. In lacrimal glands, conventional high-frequency ultrasound (HFUS) can detect characteristic inflammatory changes, atrophic alterations, blood flow patterns, and neoplastic lesions associated with SjD. However, sometimes it is challenging to identify lacrimal glands characteristics, thus making UHFUS a promising tool. Regarding labial salivary glands, limited research is available with conventional HFUS, but UHFUS proves to be a good tool to evaluate glandular inhomogeneity and to guide labial salivary glands biopsy. The comprehensive understanding of organ involvement facilitated by UHFUS may significantly improve the management of SjD patients.

Primary-Sjögren's-Syndrome-Related Interstitial Lung Disease: A Clinical Review Discussing Current Controversies.

Lung involvement, especially interstitial lung disease, is a potentially severe extra-glandular manifestation of Primary Sjogren's Syndrome (pSS-ILD). ILD can manifest either as a late complication of pSS or anticipate sicca symptoms, likely reflecting two different patho-physiological entities. Presence of lung involvement in pSS subjects can remain subclinical for a long time; therefore, patients should be actively screened, and lung ultrasound is currently being investigated as a potential low cost, radiation-free, easily repeatable screening tool for detection of ILD. In contrast, rheumatologic evaluation, serology testing, and minor salivary gland biopsy are crucial for the recognition of pSS in apparently idiopathic ILD patients. Whether the HRCT pattern influences prognosis and treatment response in pSS-ILD is not clear; a UIP pattern associated with a worse prognosis in some studies, but not in others. Many aspects of pSS-ILD, including its actual prevalence, association with specific clinical-serological characteristics, and prognosis, are still debated by the current literature, likely due to poor phenotypic stratification of patients in clinical studies. In the present review, we critically discuss these and other clinically relevant "hot topics" in pSS-ILD. More specifically, after a focused discussion, we compiled a list of questions regarding pSS-ILD that, in our opinion, are not easily answered by the available literature. We subsequently tried to formulate adequate answers on the basis of an extensive literature search and our clinical experience. At the same, we highlighted different issues that require further investigation.

Gender differences in SLE: report from a cohort of 417 Caucasian patients.

BACKGROUND: SLE is an autoimmune disease that predominantly affects women. As most epidemiological and interventional studies are on populations with a clear female prevalence, the influence of gender in disease course, drug response and damage accrual is yet to be fully explored and comprehended. OBJECTIVES: To describe gender differences in disease course, comorbidities, use of medications and long-term outcomes of a large cohort of patients with SLE. METHODS: Retrospective gender-based analysis of prospectively collected data from a monocentric cohort of Caucasian patients with SLE with at least 1 year of follow-up. RESULTS: 417 patients were included, 51 men and 366 women. Men displayed a significantly higher median age at disease onset and diagnosis and a higher prevalence of late-onset SLE, serositis at disease onset, antiphospholipid syndrome (APS) and use of mycophenolate within the first year of disease. Women had a higher prevalence of haematological abnormalities, a higher cumulative exposure to azathioprine and higher cumulative dose of glucocorticoids at 5 years. Male patients had a shorter time to first damage item and a higher prevalence of damage at 1 and 5 years, but this association was no longer significant when late-onset patients were excluded. No differences were found in prevalence of childhood onset, delay between onset and diagnosis, time to renal involvement and histology, cumulative autoantibody positivity, number of flares and hospitalisations, median SLE Damage Index score, type of damage, age and time to first cardiovascular event, chronic kidney disease and death. CONCLUSIONS: In our cohort, clinical manifestations and disease course were similar in male and female patients; however, male patients displayed higher prevalence of APS and early damage accrual probably due to the later disease onset. These data highlight the importance of an intensive follow-up, prevention and treatment of complications in this category of patients, especially in the first years of disease.

Systemic vasculitis: one year in review 2023.

Systemic vasculitides are heterogeneous disabling diseases characterised by chronic inflammation of the blood vessels potentially leading to tissue destruction and organ failure. The recent COVID-19 pandemic has had a significant impact on the epidemiology and management of patients with systemic vasculitis. In parallel, new insights have been provided on systemic vasculitis pathogenetic mechanisms, possible new therapeutic targets, and newer glucocorticoid-sparing treatments with better safety profiles. As in the previous annual reviews of this series, in this review we will provide a critical digest of the most recent literature regarding pathophysiology, clinical manifestations, diagnostic tools and treatment options in small- and large-vessel vasculitis focusing on precision medicine in vasculitis.

Targeting intracellular pathways in idiopathic inflammatory myopathies: A narrative review.

In recent decades, several pieces of evidence have drawn greater attention to the topic of innate immunity, in particular, interferon (IFN) and Interleukin 6 in the pathogenesis of idiopathic inflammatory myopathies (IIM). Both of these molecules transduce their signal through a receptor coupled with Janus kinases (JAK)/signal transducer and activator of transcription proteins (STAT). In this review, we discuss the role of the JAK/STAT pathway in IIM, evaluate a possible therapeutic role for JAK inhibitors in this group of diseases, focusing on those with the strongest IFN signature (dermatomyositis and antisynthetase syndrome).

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.