Current Insights into Tissue Injury of Giant Cell Arteritis: From Acute Inflammatory Responses towards Inappropriate Tissue Remodeling.

Giant cell arteritis (GCA) is an autoimmune disease affecting large vessels in patients over 50 years old. It is an exemplary model of a classic inflammatory disorder with IL-6 playing the leading role. The main comorbidities that may appear acutely or chronically are vascular occlusion leading to blindness and thoracic aorta aneurysm formation, respectively. The tissue inflammatory bulk is expressed as acute or chronic delayed-type hypersensitivity reactions, the latter being apparent by giant cell formation. The activated monocytes/macrophages are associated with pronounced Th1 and Th17 responses. B-cells and neutrophils also participate in the inflammatory lesion. However, the exact order of appearance and mechanistic interactions between cells are hindered by the lack of cellular and molecular information from early disease stages and accurate experimental models. Recently, senescent cells and neutrophil extracellular traps have been described in tissue lesions. These structures can remain in tissues for a prolonged period, potentially favoring inflammatory responses and tissue remodeling. In this review, current advances in GCA pathogenesis are discussed in different inflammatory phases. Through the description of these-often overlapping-phases, cells, molecules, and small lipid mediators with pathogenetic potential are described.

Senescent cells in giant cell arteritis display an inflammatory phenotype participating in tissue injury via IL-6-dependent pathways.

OBJECTIVES: Age is the strongest risk factor of giant cell arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multimarker algorithm in temporal artery biopsies (TABs) of GCA patients. METHODS: 75(+) TABs from GCA patients, 22(-) TABs from polymyalgia rheumatica (PMR) patients and 10(-) TABs from non-GCA/non-PMR patients were retrospectively retrieved and analysed. Synovial tissue specimens from patients with inflammatory arthritis and aorta tissue were used as disease control samples. Senescent cells and their histological origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype by triple costaining. GCA or PMR artery culture supernatants were applied to fibroblasts, HUVECs and monocytes with or without IL-6R blocking agent to explore the induction of IL-6-associated cellular senescence. RESULTS: Senescent cells were present in GCA arteries at higher proportion compared with PMR (9.50% vs 2.66%, respectively, p<0.0001) and were mainly originated from fibroblasts, macrophages and endothelial cells. IL-6 was expressed by senescent fibroblasts, and macrophages while MMP-9 by senescent fibroblasts only. IL-6(+) senescent cells were associated with the extension of vascular inflammation (transmural inflammation vs adventitia limited disease: 10.02% vs 4.37%, respectively, p<0.0001). GCA but not PMR artery culture supernatant could induce IL-6-associated senescence that was partially inhibited by IL-6R blockade. CONCLUSIONS: Senescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk, suggesting a potential implication in disease pathogenesis.

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.

Utilisation of primary healthcare services by Sjögren's syndrome patients in the Community of Madrid and associated factors: a population-based cross-sectional study.

OBJECTIVES: To describe the utilisation of primary health care (PHC) services and factors associated with its use by patients diagnosed with Sjögren's syndrome (SS). METHODS: Population-based cross-sectional cohort of SS patients in Madrid, Spain (SIERMA). Sociodemographic, diagnostic, clinical and PHC service utilisation variables were studied by bivariate analyses and regression models. RESULTS: A total of 4,778 SS patients were included, 65.2% classified as primary SS (pSS), while 34.8% associated with another autoimmune disease (associated SS). Mean age was 64.3 years, and 92.8% of the patients were women. A total of 87.5% used PHC services, with a mean of 19.8 consultations/year. The general practitioner was the most visited health professional, with a mean of 10.9 consultations/year, followed by the nurse, with a mean of 5.7. Characteristics associated with a greater use of PHC services in SS patients were associated SS, higher adjusted morbidity groups (AMG) risk level and older age. Additional factors included symptoms such as dry mouth, fatigue, dry vagina and joint and muscle pain; comorbidities such as atrial fibrillation, diabetes, hypertension, solid malignant neoplasms, coronary heart disease and chronic obstructive pulmonary disease; and treatments such as sterile saline solution, corticosteroids, opioids and biologic disease-modifying anti-rheumatic drugs. CONCLUSIONS: Most SS patients used PHC services during the study period, and the mean number of consultations was remarkably high. Utilisation was mainly associated with AMG risk level, ageing, glandular and extra-glandular symptoms, substantial comorbidities and various treatments. An optimised design of PHC policies will facilitate early diagnosis, improved management and better quality of life for SS patients.

Tocilizumab improves clinical outcome in patients with active corticosteroid-resistant moderate-to-severe Graves' orbitopathy: an observational study.

Background: Graves' orbitopathy (GO) is an autoimmune disorder affecting the orbital fat and muscles. A significant role of IL-6 in the pathogenesis of GO has been described and tocilizumab (TCZ), an IL-6 inhibitor targeting IL-6R has been given in some patients. The aim of our case study was to evaluate the therapeutic outcome of TCZ in non-responders to first line treatments with corticosteroids. Methods: We conducted an observational study of patients with moderate to severe GO. Twelve patients received TCZ in intravenous infusions at a dose of 8mg/kg every 28 days for 4 months and followed up for additionally 6 weeks. The primary outcome was improvement in CAS by at least 2 points, 6 weeks after the last dose of TCZ. Secondary outcomes included CAS <3 (inactive disease) 6 weeks after TCZ last dose, reduced TSI levels, proptosis reduction by > 2mm and diplopia response. Results: The primary outcome, was achieved in all patients 6 weeks after treatment course. Furthermore all patients had inactive disease 6 weeks after treatment cessation. Treatment with TCZ reduced significantly median CAS by 3 units (p=0.002), TSI levels by 11.02 IU/L (p=0.006), Hertel score on the right eye by 2.3 mm (p=0.003), Hertel score on the left eye by 1.6 mm (p=0.002), while diplopia persisted in fewer patients (25%) after treatment with TCZ (not statistically significant, p=0.250). After treatment with TCZ, there was a radiological improvement in 75% of patients, while 16.7% showed no response, and in 8.3% of patients deterioration was established. Conclusion: Tocilizumab appears to be a safe and cost effective therapeutic option for patients with active, corticosteroid-resistant, moderate to severe Graves' orbitopathy.

Comparison of pulmonary and small airways function between idiopathic inflammatory myopathies patients with and without interstitial lung disease.

OBJECTIVES: To evaluate pulmonary and small airways function in patients with idiopathic inflammatory myopathies (IIM) and make comparisons between patients with and without interstitial lung disease (ILD). METHODS: Newly diagnosed IIM patients with and without ILD determined by high resolution computed tomography were included in the study. Pulmonary and small airways function was assessed by spirometry, diffusing capacity for carbon monoxide (DLCO), body plethysmography, single and multiple breath nitrogen washout, impulse oscillometry and measurement of respiratory resistance by the interrupter technique (Rint) using the Q-box system. We used discrepancies between lung volumes measured by multiple breath nitrogen washout and body plethysmography to evaluate for small airways dysfunction. RESULTS: Study cohort comprised of 26 IIM patients, 13 with and 13 without ILD. IIM-ILD patients presented more frequently with dyspnoea, fever, arthralgias and positive anti-synthetase antibodies, compared to IIM patients without ILD. Classic spirometric parameters and most lung physiology parameters assessing small airway function did not differ between the two groups. Predicted total lung capacity and residual volume (TLCN2WO, RVN2WO) measured by multiple breath nitrogen washout and the TLCN2WO/TLCpleth ratio were significantly lower in IIM-ILD patients compared to those without ILD (mean: 111.1% vs. 153.4%, p=0.034, median: 171% vs. 210%, p=0.039 and median: 1.28 vs. 1.45, p=0.039, respectively). Rint tended to be higher among IIM-ILD patients (mean:100.5% vs. 76.6%, p=0.053). CONCLUSIONS: Discrepancies between lung volumes measured by multiple breath nitrogen washout and body plethysmography in IIM-ILD patients indicate an early small airways dysfunction in these patients.

Prevalence and comorbidities of Sjogren's syndrome patients in the Community of Madrid: A population-based cross-sectional study.

OBJECTIVES: To estimate the prevalence, sociodemographic characteristics and comorbidities of Sjogren's syndrome (SS) patients in the Community of Madrid. METHODS: A population-based cross-sectional cohort of SS patients was derived from the information system for rare diseases in the Community of Madrid (SIERMA) and confirmed by a physician. The prevalence per 10,000 inhabitants among people aged ≥18years in June 2015 was calculated. Sociodemographic data and accompanying disorders were recorded. Univariate and bivariate analyses were performed. RESULTS: A total of 4,778 SS patients were confirmed in SIERMA; 92.8% were female, with a mean age of 64.3 (standard deviation=15.4) years. A total of 3,116 (65.2%) patients were classified as primary SS (pSS), and 1,662 (34.8%) as secondary SS (sSS). The prevalence of SS among people aged ≥18 years was 8.4/10,000 (95%Confidence interval [CI]=8.2-8.7). The prevalence of pSS was 5.5/10,000 (95%CI=5.3-5.7), and that of sSS was 2.8/10,000 (95%CI=2.7-2.9), with rheumatoid arthritis (20.3%) and systemic lupus erythematosus (8.5%) being the most prevalent associated autoimmune diseases. The most common comorbidities were hypertension (40.8%), lipid disorders (32.7%), osteoarthritis (27.7%) and depression (21.1%). The most prescribed medications were nonsteroidal anti-inflammatory drugs (31.9%), topical ophthalmic therapies (31.2%) and corticosteroids (28.0%). CONCLUSION: The prevalence of SS in the Community of Madrid was similar to the overall prevalence worldwide observed in previous studies. SS was more frequent in women in their sixth decade. Two out of every three SS cases were pSS, while one-third were associated predominantly with rheumatoid arthritis and systemic lupus erythematosus.

Incidence of autoantibodies related to systemic autoimmunity in patients with severe COVID-19 admitted to the intensive care unit.

OBJECTIVES: To assess the prevalence of autoantibodies (AAbs) in mechanically ventilated COVID-19 patients and to investigate whether AAbs influence the clinical outcome. METHODS: Serum samples were drawn within the first 48 hours upon admission to the intensive care unit (ICU) from 217 consecutive patients, from January 1st, 2021, to May 10th, 2021, and investigated for the presence of AAbs using conventional techniques. Serum samples (n=117) of age- and sex-matched healthy individuals collected before COVID-19 pandemic were used as controls. RESULTS: COVID-19 patients in the ICU had more commonly AAbs compared to age- and sex-matched controls (174/217, 80.2% vs. 73/117, 62.4%, p<0.001). Patients expressed more frequently ANAs (48.4% vs. 21.4%, p<0.001), anti-dsDNA (5.1% vs. 0%, p=0.01), anti-CCP (8.3% vs. 1.7%, p=0.014) and anti-CL IgM AAbs (21.7% vs. 9.4%, p=0.005) than controls, respectively. Simultaneous reactivity against at least three autoantigens, occurred in 144 out of 174 (82.8%) patients. The two groups did not differ in terms of clinicoepidemiologic characteristics or the mortality ratio within the ICU. Patients who died compared to convalescents were older, had higher ferritin, D-dimers levels, APACHE II score, lower oxygen saturation, higher prevalence of comorbidities and cognitive dysfunction. However, AAbs were not found to correlate with the clinical outcome. CONCLUSIONS: Patients with severe COVID-19 express AAbs more commonly compared to controls. No correlation was found between AAbs and disease outcome.

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.

The Role of Nailfold Capillaroscopy in Evaluating Patients with Interstitial Lung Disease Related to Connective Tissue Disease.

Capillaroscopy is a non-invasive and safe imaging method that allows the evaluation of the microcirculation of the small vessels of the skin. The method's main advantage is the early detection of microvascular changes that may occur in certain connective tissue diseases (CTDs). Today, the presence of specific autoantibodies and capillaroscopic findings are generally accepted and emerge as a powerful diagnostic tool for detecting underlying CTDs in patients with Raynaud's phenomenon. The role of capillaroscopy has also been investigated in patients with CTD and interstitial lung disease (ILD). In these patients, lung involvement is considered one of the most severe complications, potentially leading to significant morbidity and mortality. So far, studies have shown an association of the scleroderma pattern in capillaroscopy with lung involvement in Scleroderma patients. Although there are studies on the association of capillary findings in patients with other CTDs, further efforts are needed to evaluate this technique and produce high-performance algorithms in the early detection of involvement and the progression of (CTD) related ILD (CTD-ILD). The present study aims to perform capillaroscopy in CTDILD patients with different imaging patterns and to correlate the method's findings with those found in high-resolution computed tomography, pulmonary tests, and the immunological profile of patients. Furthermore, the impact of ILD treatment on the capillaroscopic findings will be evaluated.

Small airways dysfunction in patients with systemic sclerosis and interstitial lung disease.

Background: A number of studies report small airways involvement in patients with systemic sclerosis (SSc). Furthermore, small airways dysfunction is increasingly recognized in patients with interstitial lung disease (ILD) of idiopathic or autoimmune etiology. The objectives of this study were to evaluate small airways function in SSc patients with ILD and explore the effect of treatment on small airways function by using conventional and contemporary pulmonary function tests (PFTs). Methods: This single-center, prospective, observational study included a total of 35 SSc patients, with and without ILD based on HRCT scan, evaluated by a special radiologist blindly. Clinical data were collected from all patients who were also assessed for HRCT findings of small airways disease. Small airways function was assessed by classic spirometry, measurement of diffusing capacity for carbon monoxide, body plethysmography, single breath nitrogen washout (N2SBW) and impulse oscillometry (IOS). The prevalence of small airways dysfunction according to R5-R20, phase III slopeN2SBW and CV/VC methodologies was calculated in the total SSc population. Pulmonary function tests were compared between: (a) SSc-ILD and non-ILD patients and (b) two time points (baseline and follow up visit) in a subset of SSc-ILD patients who received treatment for ILD and were re-evaluated at a follow up visit after 12 months. Results: Phase III slopeN2SBW and R5-R20 showed the highest diagnostic performance for detecting small airways dysfunction among SSc patients (61 and 37.5%, respectively). Twenty three SSc patients were found with ILD and 14 of them had a 12-month follow up visit. SSc-ILD patients compared to those without ILD exhibited increased phase III slopeN2SBW ≥120% (p = 0.04), R5-R20 ≥0.07 kPa/L/s (p = 0.025), airway resistance (Raw) (p = 0.011), and special airway resistance (sRaw) (p = 0.02), and decreased specific airway conductance (sGaw) (p = 0.022), suggesting impaired small airways function in the SSc-ILD group. Radiographic features of SAD on HRCT were observed in 22% of SSc-ILD patients and in none of SSc-non-ILD patients. Comparison of PFTs between baseline and follow-up visit after 12 months in the 14 SSc-ILD treated patients, showed improvement of phase III slopeN2SBW (p = 0.034), R5-R20 (p = 0.035) and Raw (p = 0.044) but not sRaw and sGaw parameters. Conclusion: Phase III slopeN2SBW and R5-R20 may reveal small airways dysfunction in SSc associated ILD before structural damage and may be partially improved in a subset of patients receiving treatment for ILD.

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

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

Experimental models of Sjögren's syndrome: differences and similarities with human disease.

Mouse models have been employed extensively to provide pathogenetic insights into many complex human disorders including systemic autoimmune diseases. The explosion of biotechnology and molecular biology have simplified the procedures to design and generate mouse models with the phenotype of interest. In this line, more than 30 mouse models have been proposed or developed to resemble Sjögren's syndrome (SS) in humans, in an attempt to better understand the pathophysiology of the disease and design more effective treatments. So far, none of these models has been proven an ideal recapitulation of the human disease, although each model mimics particular aspects of the human SS counterpart. This review summarises the main characteristics of the mouse models of SS that have been developed hitherto, comparing them with the human SS in terms of clinical features, sex predilection, histopathology, autoantibodies production, and propensity for lymphoma. The interpretation of these experimental models with cautiousness and the realisation of the differences between human and mouse physiology and disease pathophysiology, may render mice a useful tool to study in depth SS and reveal new therapeutic perspectives.

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

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

Towards the identification of novel autoantibodies in Sjögren's syndrome.

Primary Sjögren's syndrome may be difficult to diagnose when antibodies against Ro/SSA are lacking, and can be grouped in at least four clusters indicating different pathophysiological pathways. Novel biomarkers, in particular autoantibodies, would be helpful in diagnosing Sjögren's syndrome and in further identification and characterisation of the clusters.In this review, we describe new technologies that may be utilised in the rapid identification of novel autoantibodies, and an example of how well characterised patients, here from the HarmonicSS cohort, are a prerequisite in the discovery of clinically meaningful biomarkers. This translational approach hold promise to optimise the diagnosis and treatment of individual pSS patient subsets.

Liver Fibrosis in Primary Sjögren's Syndrome.

Background: Primary Sjögren syndrome (pSS) is a systemic autoimmune epithelitis, potentially affecting salivary epithelium, biliary epithelium, and hepatocytes. Common immunological mechanisms might cause clinically silent liver inflammation, and combined with non-alcoholic fatty liver disease (NAFLD), liver fibrosis (LF) may occur. No studies have explored the occurrence of LF in the context of NAFLD among pSS patients. Methods: Consecutive pSS patients from the rheumatology outpatient clinic of the Department of Pathophysiology and individuals evaluated in the hepatology outpatient clinic for possible NAFLD serving as comparators underwent transient elastography (TE) to assess LF and liver steatosis (LS). All participants had no overt chronic liver disease. Clinical, demographic, and laboratory data were collected from all participants at the time of TE. Results: Fifty-two pSS patients and 198 comparators were included in the study. The median age (range) of pSS and comparators was 62.5 (30-81) and 55 (19-86) years, respectively. Both groups had similar prevalence regarding type 2 diabetes mellitus, hyperlipidemia, and similar body mass index (BMI). Patients with pSS had less frequently high LS (S2, S3) (27% vs. 62%, p < 0.001) and significant LF (F2-4) [2 (3.8%) vs. 34 (17.2%), p = 0.014] than comparators. Univariable analysis showed that advanced LF was significantly associated with older age, higher LS, greater BMI, and disease status (comparators than pSS); of these, only age was identified as an independent LF risk factor in the multivariable logistic regression analysis. Conclusion: Liver fibrosis among pSS patients is most likely not attributed to the disease per se.

Hashimoto Thyroiditis, Anti-Parietal Cell Antibodies: Associations With Autoimmune Diseases and Malignancies.

Background: Hashimoto thyroiditis (HT) is an autoimmune disease which may result in extensive damage of the thyroid gland. Chronic atrophic gastritis (CAG), is the most frequent HT-associated disorder, with anti-parietal cell autoantibodies (APCA) being a screening test for autoimmune CAG. The aim of this study was to investigate, in a cohort of HT patients: a) the prevalence of APCA in an attempt to define their clinical phenotype and b) any possible associations of APCA with other autoimmune diseases and malignancies. Methods: This is a single-center, case-control study, conducted at a University Hospital. The study included patients with HT diagnosed between November 2017 and November 2020. Excluded were patients <18 years old, with sonographic features of HT but negative thyroid peroxidase (TPOAbs) or thyroglobulin autoantibodies (TgAbs), Graves' disease, Down or Turner's syndrome. Results: A total of 840 patients with HT were included in the study, from whom 180 (21.4%) had positive APCA. A total of 79 patients (9.4%) had one or more organ-specific autoimmune diseases and 61 (7.3%) had a systemic autoimmune disease. Autoimmune diseases were more frequent in female than in male patients (17.9% versus 10.9%, p = 0.05). APCA-positive patients were older than APCA-negative (54.1 ± 13.5 versus 49.0 ± 14.6, p <0.001) and had more often positive TPOAbs (93.3% versus 83.9%, p=0.001). Gastric neoplasms were documented only in APCA-positive patients (p <0.001). A higher frequency of organ-specific autoimmune diseases was observed in the APCA-positive group (14.4% versus 8%, p = 0.024). In the subgroup of patients with additional autoimmune diseases (n = 140), younger age and positive APCA were independently associated with the presence of organ-specific autoimmunity (OR 0.954, 95% CI 0.927-0.982 and OR 3.100, 95% CI 1.256-7.652, respectively). Papillary thyroid cancer (PTC) occurred in 3.5% of patients (26/29 women). Positive family history for thyroid autoimmunity and negative TPOAbs were the only independent risk factors for PTC among women (OR 3.228, 95% CI 1.173-8.887 and 0.315, 95% 0.113-0.881, respectively). Conclusion: This study reveals for the first time an association of APCA with organ-specific autoimmunity in HT patients. APCA together with patient age were independently associated with the presence of organ-specific autoimmunity. Finally, this study showed an association between APCA and gastric neoplasms in these patients.

Clinical Phenotype and Mechanisms of Leukopenia/Neutropenia in Patients with Primary Sjögren's Syndrome.

Sjögren's syndrome (SS) is a chronic, systemic autoimmune disease which afflicts mainly the exocrine salivary and lachrymal glands, leading to mouth and eye dryness. However, any organ can be affected during the disease course, resulting in a variety of clinical manifestations. Sjögren's syndrome clinical manifestations can be classified into glandular (sicca manifestations or parotid swelling), extra-glandular, either nonspecific (arthralgias, arthritis, Raynaud's phenomenon, fatigue) or peri-epithelial (primary biliary cirrhosis, interstitial nephritis, bronchiolitis), and extra-epithelial (palpable glomerulonephritis, peripheral neuropathy, purpura). In addition, SS patients display high risk for B cell lymphomas due to chronic antigenic stimulation. Although disease pathogenesis remains unclear, genetic, environmental, and immunologic factors are implicated. In the context of systemic autoimmune manifestations, SS patients may also present with hematologic abnormalities including anaemia, leukopenia (mainly neutropenia or lymphopenia), and thrombocytopenia. Although leukopenia has been reported as a laboratory finding in many case series or cohorts of SS patients and in very few studies it has been proposed as an independent risk factor for lymphoma, the clinical phenotype of SS patients with leukopenia/neutropenia and the implicated pathogenetic mechanisms have not been elucidated. In the current study, we intend to analyse the clinical phenotype of leukopenic/neutropenic SS patients and explore the possible pathogenetic mechanisms by detecting anti-neutrophil antibodies and investigate the role of apoptotic pathways, especially the contribution of TRAIL pathway and the cFLIP molecule.