Post-traumatic stress disorder and post-traumatic stress symptoms in patients with systemic autoimmune diseases during the COVID-19 pandemic.

OBJECTIVES: The COVID-19 outbreak led to an increase in mental disorders, particularly post-traumatic stress disorder (PTSD), in the general population and especially in high-risk populations such as patients with rheumatologic conditions. Although these latters are considered vulnerable to developing PTSD, few specific data have been particularly reported in the framework of the pandemic. The aim of the present study was to investigate PTSD and post-traumatic stress symptoms (PTSS) in a sample of patients with systemic autoimmune disease (SAD), followed in the framework of a prospective observational study during the pandemic. METHODS: The PERMAS project is a prospective observational study including patients with SAD and involving the Rheumatology and the Psychiatric Clinics of the Azienda Ospedaliero Universitaria Pisana (AOUP, Pisa, Italy) and the Institute of Management of the Scuola Superiore Sant'Anna (Pisa, Italy). The assessments included: a data-sheet for sociodemographic and clinical characteristics; the Trauma and Loss Spectrum-Self Report (TALS-SR) and the Impact of Event Scale-Revised (IES-R), for PTSD and PTSS; the 36-item Short Form Survey (SF-36) to assess quality of life. RESULTS: The total sample consisted of 252 patients with SAD, including 131 with connective tissue disease, 101 with arthritis and 20 with systemic vasculitis. The diagnostic groups differed significantly in age (p<0.001), gender (p<0.001), prevalence of full-blown and partial PTSD (p=0.001), and other psychopathologic variables. Connective tissue disease and SF-36 were significantly associated with the TALS-SR scores in both univariate (p<0.001) and multivariate (p<0.025; p<0.001) analyses. CONCLUSIONS: Patients with SAD, and, in particular, patients with connective tissue diseases reported an increased risk of developing stress-related psychopathological symptoms, indicating the need for special psychological monitoring of this high-risk group.

Sjögren's syndrome: one year in review 2023.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disorder characterised by the T-cell-mediated hyperactivation of B-cells and cytokine production. The condition may evolve from an asymptomatic, indolent course, with glandular involvement, to extra-glandular systemic manifestations up to 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. Recently, increasing research focused on the investigation of mechanisms underlying the complex pathogenesis of the disease and highlighted the multi-factorial nature of SS consisting of concomitant involvement of environmental, genetic, neuroendocrine and immune factors. In particular, many aspects have been investigated regarding genetic and epigenetics, the role of specific B- and T-cell phenotypes and the investigation of disease-specific biomarkers as predictors of disease development, activity, and lymphomagenesis. Surely, a deeper understanding of these multiple mechanisms may facilitate earlier diagnosis, enable subphenotyping of patients and open novel therapeutic possibilities to address the unmet needs of the disease in the upcoming years.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.

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.

Philadelphia chromosome-negative myeloproliferative chronic neoplasms: is clonal hematopoiesis the main determinant of autoimmune and cardio-vascular manifestations?

In this article, we reviewed the possible mechanisms linking the clonal hematopoiesis of indeterminate potential (CHIP) to chronic myeloproliferative neoplasms (MPNs), autoimmune diseases (ADs), and cardiovascular diseases (CADs). CHIP is characterized by the presence of clonal mutations with an allelic frequency >2% in the peripheral blood without dysplasia, overt hematological neoplasms, or abnormalities in blood cell count. The prevalence may reach 20% of elderly healthy individuals and is considered a risk factor for myelodysplastic neoplasms and acute leukemia. In MPNs, CHIP is often associated with mutations such as JAK2V617F or DNMT3A, TET2, or ASXL1, which exhibit a 12.1- and 1.7-2-fold increase in CADs. Specifically, JAK2-mutated cells produce excessive cytokines and reactive oxygen species, leading to proinflammatory modifications in the bone marrow microenvironment. Consequently, the likelihood of experiencing thrombosis is influenced by the variant allele frequency (VAF) of the JAK2V617F mutation, which also appears to be correlated with anti-endothelial cell antibodies that sustain thrombosis. However, DNMT3A mutations induce pro-inflammatory T-cell polarization and activate the inflammasome complex, while TET2 downregulation leads to endothelial cell autophagy and inflammatory factor upregulation. As a result, in patients with TET2 and DNMT3A-related CHIP, the inflammasome hyperactivation represents a potential cause of CADs. CHIP also occurs in patients with large and small vessel vasculitis, while ADs are more frequently associated with MPNs. In these diseases, monocytes and neutrophils play a key role in the formation of neutrophil extracellular trap (NET) as well as anti-endothelial cell antibodies, resulting in a final procoagulant effect. ADs, such as systemic lupus erythematosus, psoriasis, and arthritis, are also characterized by an overexpression of the Rho-associated coiled-coil containing protein kinase 2 (ROCK2), a serine/threonine kinase that can hyperactivate the JAK-STAT pathway. Interestingly, hyperactivation of ROCK2 has also been observed in myeloid malignancies, where it promotes the growth and survival of leukemic cells. In summary, the presence of CHIP, with or without neoplasia, can be associated with autoimmune manifestations and thrombosis. In the presence of these manifestations, it is necessary to consider a "disease-modifying therapy" that may either reduce the clonal burden or inhibit the clonally activated JAK pathway.

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.

Ultra-High-Frequency Ultrasonography of Labial Glands in Pediatric Sjögren's Disease: A Preliminary Study.

Sjögren's disease (SD) is a chronic autoimmune disease primarily affecting lacrimal and salivary glands. The diagnosis of pediatric SD mostly relies on clinical suspect, resulting in a significant diagnostic delay. Recently, ultrahigh-frequency ultrasound (UHFUS) of labial glands has been proposed as a diagnostic method in adults with suspected SD. Until now, there have been no studies about UHFUS in pediatric diagnostic work-up. The aim of the study was to evaluate the potential role of UHFUS of minor salivary glands in pediatric SD. Consecutive pediatric patients with a diagnosis of pediatric SD seen at AOU Meyer IRCSS were evaluated. Intraoral UHFUS scan of the lip mucosa was performed with Vevo MD equipment, using a 70 MHz probe with a standardized protocol and the images were independently reviewed by two operators. Lip salivary glands were assessed by using a four-grade semiquantitative scoring system for parenchymal alteration and vascularization. Twelve patients were included. When applying UHFUS to this cohort of patients, all patients showed a UHFUS grade of ≥1 with 8/12 showing a mild glandular alteration (i.e., grade 1), 2/12 a moderate glandular alteration (i.e., grade 2) and finally 2/12 a severe glandular alteration (i.e., grade 3). Moderate intraglandular vascularization was seen in 9/12, with only 3/12 showing mild intraglandular vascularization. Due to limited size of the sample, the relationship between histological findings, autoantibodies status and UHFUS grade could not be performed. This preliminary study seems to report UHFUS as feasibility technique to identify salivary gland alterations in children with a clinical suspect of SD.

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.

Glandular involvement in primary Sjögren's syndrome patients with interstitial lung disease-onset and sicca-onset, a single centre cross-sectional study.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is an autoimmune exocrinopathy classically presenting with sicca symptoms. Nonetheless, disease onset with extraglandular manifestations, including interstitial lung disease (ILD), is increasingly reported. However, studies investigating pSS patients presenting with ILD (pSS-ILD) are limited.Aim of this study was to better characterise the phenotype of pSS patients presenting with ILD in comparison to pSS patients with classicsicca-onset. We especially investigated whether the two groups differed in glandular involvement comparing functional, imaging andhistologic findings, as well as patient reported outcome (PRO). METHODS: Consecutive newly diagnosed pSS patients, all fulfilling the ACR/EULAR 2016 criteria, were included in this cross-sectional study from September 2016 to October 2021. Presence of ILD at pSS diagnosis was defined based on clinical findings, imaging assessment and pulmonary function tests (PFT). In addition to functional tests, a minor salivary gland biopsy was performed in all cases, recording number of foci, focus score (FS) and GC-like structures. Salivary glands ultrasonography (SGUS) was graded using the OMERACT semiquantitative scoring system (0-3) based on parenchyma inhomogeneity. PRO including ESSPRI, OHIP and OSSDI were collected.Extraglandular clinical features and biological abnormalities included in the ESSDAI were recorded. Data were expressed as mean±SD for continuous variables and as absolute frequencies and percentages for categorical variables. Chi-Square test and Mann-Whitney U-test and ANOVA were performed for comparisons of categorical variables and continuous variables, respectively. RESULTS: We included 178 newly diagnosed pSS patients (F:M=158:20). ILD was the first pSS manifestation in 11 (6%) cases, 8 F and 3 M, with a median time from ILD onset to pSS diagnosis of 2 years (25-75 IQ 1-4.5). Of the 11 pSS-ILD patients, HRCT pattern was defined as NSIP in 4, UIP in 4, NSIP+OP in 2 and LIP in 1 patient. Dyspnoea on exertion or chronic cough were reported by 7/11 (63.6%) patients.In comparison to sicca-onset patients, pSS-ILD patients presented an older age at diagnosis (55±13 vs. 70±7, p= 0.001) and a higher ESSDAI (3.9±4.7 vs. 12.3±4.3, p=0.001), driven by the pulmonary domain. Regarding glandular involvement, pSS-ILD patients reported milder xeropthalmia (VAS 5.8±3.1 vs. 2.8±3.5, p=0.002) and significative lower scores in OSDI (35.6±24.9 vs. 15.3±22.9, p=0.04) and OHIP (4.8±4.4 vs. 1.4±3.8, p=0.04), despite no significant differences observed between the two groups in ocular tests and unstimulated salivary flow rate. With respect to histology, no significant differences were found in number of foci, FS and GC-like structures. We observed a significantly different distribution of the SGUS OMERACT score in the two groups: none of pSS-ILD patients presented a SGUS OMERACT score ≥2 in the submandibular glands (SG), in contrast to 41/132 (31.1%) of the patients in the classical sicca-onset group (p=0.03). Finally, no significant differences were observed between the two groups with respect to non-pulmonary extraglandular manifestations, serologic features and other biological parameters. CONCLUSIONS: ILD-onset pSS patients represent an atypical phenotypic subset, with less pronounced sialadenitis structural changes in salivary glands, and with sicca symptoms probably overshadowed by the respiratory disease.

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.

Connexin Expression in Human Minor Salivary Glands: An Immunohistochemical Microscopy Study.

Connexins (Cxs) are transmembrane proteins involved in the formation of hemichannels and gap junctions (GJs). GJs are involved in various physiological functions, including secretion in glandular tissue. It has been demonstrated that Cx26, Cx32, and Cx43 are mainly expressed in glands, but no data are available in human salivary glands to date. The aim of our study was to investigate the presence and the localization of Cxs in human minor labial salivary glands. Immunofluorescence and immunoelectron microscopy were employed to evaluate the Cx26, Cx32, and Cx43 protein in human labial salivary gland biopsies (hLSGBs). RT-PCR was also used to detect their mRNA expression. Cx expression was found at both the mRNA and protein levels in all hLSGBs analysed. Cxs were observed at the level of the duct and acinar cells, as well as in myoepithelial cells. The localization of the three Cx types was very similar, suggesting colocalization of these Cxs in the same connexons. These results demonstrated the presence of Cxs in human salivary glands for the first time. Moreover, the few samples with primary Sjögren's Syndrome analysed only by immunofluorescence showed an alteration of the Cx expression, indicating that these proteins could be involved in salivary gland dysfunctions.

Reliability of OMERACT Scoring System in Ultra-High Frequency Ultrasonography of Minor Salivary Glands: Inter-Rater Agreement Study.

Minor salivary gland ultra-high frequency ultrasonography (UHFUS) has recently been introduced for the evaluation of patients with suspected primary Sjögren's Syndrome (pSS). At present, ultrasonographic assessment of major salivary glands is performed using the Outcome Measures in Rheumatology (OMERACT) scoring system. Previous reports have explored the possibility of applying the OMERACT scoring system to minor salivary glands UHFUS, with promising results. The aim of this study was to test the inter-reader concordance in the assignment of the OMERACT score to minor salivary gland UHFUS. The study was conducted on 170 minor salivary glands UHFUS scans of patients with suspected pSS. Three independent readers performed UHFUS image evaluation. Intraclass correlation coefficient (ICC) was employed to assess inter-reader reliability. Bland and Altman analysis was employed to test the agreement with a gold standard examiner. ICC values > 0.9 were found for scores 0 and 1, while score 2 and score 3 presented ICCs of 0.873 and 0.785, respectively. The measurements performed by the three examiners were in agreement with the gold standard examiner. According to these results, UHFUS interpretation showed good inter-observer reliability, suggesting that OMERACT score can be effectively used for the evaluation of glandular alterations, even for minor salivary glands.

Sjögren's syndrome and other rare and complex connective tissue diseases: an intriguing liaison.

Sjögren's syndrome (SS) is a systemic autoimmune disease that frequently occurs concomitantly with other systemic connective tissue disorders, including rare and complex diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The presence of SS influences the clinical expression of the other autoimmune diseases, thus offering the unique opportunity to explore the similarities in genetic signatures, as well as common environmental and biologic factors modulating the expression of disease phenotypes. In this review, we will specifically discuss the possibility of defining "SS/SLE" and "SS/SSc" as distinct subsets within the context of connective tissue diseases with different clinical expression and outcomes, thus deserving an individualised assessment and personalised medical interventions.

One year in review 2021: Sjögren's syndrome.

Sjögren's syndrome (SS) is a multifactorial systemic autoimmune disease of unknown aetiology characterised by a wide spectrum of different clinical manifestations and scattered complications. Recently, great efforts have been made to elucidate mechanisms involved in the pathogenesis of the disease in order to identify exploitable therapeutic targets in SS. Similarly, novel insights have enabled to better define disease phenotypes and different outcomes. Ultimately, the discovery of new potential therapeutic targets and a better stratification of patients are paving new avenues for novel treatment options and treat-to-target therapeutic approach. In this review, we will provide a critical digest of the recent literature published in 2020 on SS pathogenesis, clinical manifestations and novel treatment options.

Impact of first wave of SARS-CoV-2 infection in patients with Systemic Lupus Erythematosus: Weighting the risk of infection and flare.

INTRODUCTION: The aim of this study was to investigate the incidence and clinical presentation of SARS-CoV-2 infections in a Systemic Lupus Erythematosus (SLE) cohort; to assess correlations with disease characteristics and rheumatic therapy; and to evaluate the occurrence of treatment discontinuation and its impact on disease activity. MATERIALS AND METHODS: SLE patients monitored by a single Italian centre were interviewed between February and July 2020. Patients were considered to be positive for SARS-CoV-2 infections in case of 1) positive nasopharyngeal swab; 2) positive serology associated with COVID19 suggesting symptoms. The following data were also recorded: clinical symptoms, adoption of social distancing measures, disease activity and treatment discontinuation. RESULTS: 332 patients were enrolled in the study. Six patients (1.8%) tested positive for SARS-CoV-2 infection, with the incidence being significantly higher in the subgroup of patients treated with biological Disease-Modifying Anti-Rheumatic Drugs (p = 0.005), while no difference was observed for other therapies, age at enrollment, disease duration, type of cumulative organ involvement or adoption of social isolation. The course of the disease was mild. Thirty-six patients (11.1%) discontinued at least part of their therapy during this time period, and 27 (8.1%) cases of disease flare were recorded. Correlation between flare and discontinuation of therapy was statistically significant (p<0.001). No significant increase of rate of flare in a subgroup of the same patients during 2020 was observed. CONCLUSION: Treatment discontinuation seems to be an important cause of disease flare. Our findings suggest that abrupt drug withdrawal should be avoided or evaluated with caution on the basis of individual infection risk and comorbidities.

One year in review 2020: pathogenesis of primary Sjögren's syndrome.

The pathogenesis of primary Sjögren's syndrome (pSS) remains poorly understood. However, important efforts have been made during the last few months. In this review, following the others of this series we will summarise the most recent literature on pSS pathogenesis focusing in particular on new insights into pSS animal models, genetics and epigenetics, innate and adaptive immune system abnormalities and tertiary lymphoid structures. Hopefully, novel insights into pSS pathogenesis will pave the way to new therapeutic approaches to the disease improving patients' management and prognosis.

Total area of inflammatory infiltrate and percentage of inflammatory infiltrate identify different clinical-serological subsets of primary Sjögren's syndrome better than traditional histopathological parameters.

OBJECTIVES: Recently, the total area of the inflammatory infiltrate and the percentage of inflammatory infiltrate have been proposed as novel histopathological parameters to improve the stratification of patients with Sjögren's syndrome (SS) in clinical trials. Both these parameters provide a more accurate assessment of the extent of the infiltrate in minor salivary gland biopsies (MSGBs) and may overcome the bias related to the Focus score (FS). To date, however, only few studies have investigated their clinical value and feasibility. In this study we revised consecutive MSGBs obtained routinely in a real-life clinical setting and correlated the total area of the inflammatory infiltrate and the percentage of inflammatory infiltrate both with the other MSGB histopathological parameters and with patients' clinical features in order to explore their usefulness in SS diagnostic work-up. METHODS: We assessed the area of the inflammatory infiltrate and the percentage of the inflammatory infiltrate in consecutive MSGBs and correlated these parameters with the number of foci, the FS and the presence of ectopic lymphoid structures (ELS). We also correlated these additional parameters with patients' clinical and biological data. RESULTS: We revised 69 MSGB samples: 46 from patients with a diagnosis of SS and 23 from subjects with no SS. The total area of inflammatory infiltrate and the percentage of inflammatory infiltrate appeared significantly higher in patients fulfilling the ACR/EULAR classification criteria for SS and correlated significantly with both the number of foci (p<0.001) and the FS (p<0.001). Particularly, they correlated better with the ELS in MSGBs than the number of foci and the FS. When we limited the analysis to the 32/69 patients with a FS<1, both the total area of the inflammatory infiltrate (p=0.02) and the percentage of the inflammatory infiltrate (p=0.03), but not the number of foci (p=0.12) remained significantly higher in the 10/32 anti-Ro/SSA positive patients fulfilling the ACR/EULAR classification criteria. Finally, the total area of inflammatory infiltrate and the percentage of inflammatory infiltrate correlated significantly with several biological and haematological SS-related abnormalities including hypergammaglobulinaemia, C4 levels, total number of white blood cells and the number of circulating lymphocytes. CONCLUSIONS: The total area of the inflammatory infiltrate and the percentage of the inflammatory infiltrate in SS referral centres, and particularly for selected cases, may maximise the information on disease activity at tissue level, ultimately improving SS patients' assessment.