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1.
Clin Exp Rheumatol ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34665703

RESUMO

OBJECTIVES: To describe the clinical spectrum of Sjögren's syndrome (SS) patients with combined seronegativity. METHODS: From a multicentre study population of consecutive SS patients fulfilling the 2016 ACR-EULAR classification criteria, patients with triple seronegativity [anti-Ro/SSA(-), anti-La/SSB(-), RF(-) and ANA(+)] and quadruple seronegativity [anti-Ro/SSA(-), anti-La/SSB(-), RF(-) and ANA(-)] were identified retrospectively. Both groups were matched in an 1:1 ratio with 2 distinct control SS groups: i) classic anti-Ro/SSA seropositive patients [SS(+)] and ii) classic anti-Ro/SSA seropositive patients with negative rheumatoid factor [SS(+)/RF(-)] to explore their effect on disease expression. Clinical, laboratory and, histologic features were compared. A comparison between triple and quadruple seronegative SS patients was also performed. REESULTS: One hundred thirty-five SS patients (8.6%) were identified as triple seronegative patients and 72 (4.5%) as quadruple. Triple seronegative patients had lower frequency of peripheral nervous involvement (0% vs. 7.2% p=0.002) compared to SS(+) controls and lower frequency of interstitial renal disease and higher prevalence of dry mouth than SS(+)/RF(-) controls. Quadruple seronegative patients presented less frequently with persistent lymphadenopathy (1.5% vs. 16.9 p=0.004) and lymphoma (0% vs. 9.8% p=0.006) compared to SS(+) controls and with lower prevalence of persistent lymphadenopathy (1.5% vs. 15.3% p=0.008) and higher frequency of dry eyes (98.6% vs. 87.5% p=0.01) and autoimmune thyroiditis (44.1% vs. 17.1% p=0.02) compared to SS(+)/RF(-) SS controls. Study groups comparative analysis revealed that triple seronegative patients had higher frequency of persistent lymphadenopathy and lymphoma, higher focus score and later age of SS diagnosis compared to quadruple seronegative patients. CONCLUSIONS: Combined seronegativity accounts for almost 9% of total SS population and is associated with a milder clinical phenotype, partly attributed to the absence of rheumatoid factor.

2.
J Clin Med ; 10(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34501407

RESUMO

BACKGROUND: Alterations of the insulin-like growth factor (IGF) pathway along with genetic variations of the IGF1 receptor (IGF1R) gene have been linked to the development of systemic autoimmunity, possibly through apoptosis induction. This study aims to investigate whether genetic variations of the IGF1R contribute to Sjögren's syndrome (SS) pathogenesis and explores potential functional implications. METHODS: DNA extracted from whole peripheral blood derived from 277 primary SS patients, complicated or not by lymphoma, and 337 Healthy controls (HC) was genotyped for the rs2229765 IGF1R polymorphism using the RFLP-PCR assay. Gene expression of IGF1R and IGF1 isoforms, caspases 1, 4, and 5, and inflammasome components NLRP3, ASC, IL1ß, IL18, IL33, IGFBP3, and IGFBP6 were quantitated by RT-PCR in total RNA extracted from minor salivary gland biopsies (MSGs) of 50 SS patients and 13 sicca controls (SCs). In addition, IGF1R immunohistochemical (IHC) expression was assessed in formalin-fixed, paraffin-embedded MSG tissue sections derived from 10 SS patients and 5 SCs. RESULTS: The prevalence of the A/A genotype of the rs2229765 IGF1R polymorphism was significantly higher in the anti-Ro/SSA positive SS population compared to healthy controls (24.8% vs. 10.7%, p = 0.001). Moreover, IGF1Rs at both mRNA and protein levels were reduced in SS-derived MSGs compared to SCs and were negatively associated with caspase 1 transcripts. The latter were positively correlated with NLRP3, ASC, and IL1ß at the salivary gland tissue level. IGF1R expression in peripheral blood was negatively correlated with ESR and IgG serum levels and positively correlated with urine-specific gravity values. CONCLUSIONS: The rs2229765 IGF1R variant confers increased susceptibility for seropositive primary SS. Dampened IGF1R mRNA and protein expression in salivary gland tissues could be related to increased apoptosis and subsequently to the activation of inflammasome pathways.

3.
Mediterr J Rheumatol ; 32(2): 179-181, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34447918

RESUMO

Rheumatoid Arthritis (RA) is a common chronic inflammatory disorder affecting 0,5-1% of the population, characterised by intense cellular activation and inflammation in the affected joints ultimately leading to bone and cartilage destruction. Cardiovascular disease is the leading cause of death among patients suffering from RA, with chronic inflammation and genetic background emerging as major predisposing factors. Although the pathogenetic events leading to an increased rate of atherosclerosis in the affected group are not precisely described, several genetic variations have been suggested as possible mediators of this process. The aim of the current research proposal is to investigate the role of B-cell activating factor (BAFF) variants in the pathogenesis of RA-related atherosclerosis. Stored DNA samples from the Biobank in the Department of Physiology of the Medical School of the University of Athens from RA individuals and healthy controls will be analysed for polymorphisms of B-cell activating factor (BAFF) by polymeric chain reaction (PCR) based assays. Detection of plaque formation and calculation of the mean intima media thickness (mIMT) of the vessel wall will be performed in RA patients by using carotid and femoral artery ultrasonography. Complete personal and family history, biochemical and serological markers will be obtained from the RA group and associated with the genetic and IMT data. The results will be compared across the different subgroups in order to determine whether any particular genetic variants can act as prognostic markers for RA-related cardiovascular disease giving eventually new insights to atherosclerotic processes in the context of chronic inflammatory diseases. Such a result would invariably lead to a possible new treatment approach and/or prevention method to benefit this group of patients.

4.
Front Immunol ; 12: 683623, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220834

RESUMO

Background: B-cell non-Hodgkin's lymphoma (B-NHL) is one of the major complications of primary Sjögren's syndrome (SS). Chronic inflammation and macrophages in SS minor salivary glands have been previously suggested as significant predictors for lymphoma development among SS patients. Lipoprotein-associated phospholipase A2 (Lp-PLA2)-a product mainly of tissue macrophages-is found in the circulation associated with lipoproteins and has been previously involved in cardiovascular, autoimmune, and malignant diseases, including lymphoma. Objective: The purpose of the current study was to investigate the contributory role of Lp-PLA2 in B-NHL development in the setting of primary SS. Methods: Lp-PLA2 activity in serum samples collected from 50 primary SS patients with no lymphoma (SS-nL), 9 primary SS patients with lymphoma (SS-L), and 42 healthy controls (HC) was determined by detection of [3H]PAF degradation products by liquid scintillation counter. Moreover, additional sera from 50 SS-nL, 28 SS-L, and 32 HC were tested for Lp-PLA2 activity using a commercially available ELISA kit. Lp-PLA2 mRNA, and protein expression in minor salivary gland (MSG) tissue samples derived from SS-nL, SS-L patients, and sicca controls (SC) were analyzed by real-time PCR, Western blot, and immunohistochemistry. Results: Serum Lp-PLA2 activity was significantly increased in SS-L compared to both SS-nL and HC by two independent methods implemented [mean ± SD (nmol/min/ml): 62.0 ± 13.4 vs 47.6 ± 14.4 vs 50.7 ± 16.6, p-values: 0.003 and 0.04, respectively, and 19.4 ± 4.5 vs 15.2 ± 3.3 vs 14.5 ± 3.0, p-values: <0.0001, in both comparisons]. ROC analysis revealed that the serum Lp-PLA2 activity measured either by radioimmunoassay or ELISA has the potential to distinguish between SS-L and SS-nL patients (area under the curve [AUC]: 0.8022, CI [95%]: 0.64-0.96, p-value: 0.004 for radioimmunoassay, and AUC: 0.7696, CI [95%]: 0.66-0.88, p-value: <0.0001, for ELISA). Lp-PLA2 expression in MSG tissues was also increased in SS-L compared to SS-nL and SC at both mRNA and protein level. ROC analysis revealed that both MSG mRNA and protein Lp-PLA2 have the potential to distinguish between SS-nL and SS-L patients (area under the curve [AUC] values of 0.8490, CI [95%]: 0.71-0.99, p-value: 0.0019 and 0.9444, CI [95%]: 0.79-1.00, p- value: 0.0389 respectively). No significant difference in either serum Lp-PLA2 activity or MSG tissue expression was observed between SS-nL and HC. Conclusions: Lp-PLA2 serum activity and MSG tissue mRNA/protein expression could be a new biomarker and possibly a novel therapeutic target for B-cell lymphoproliferation in the setting of SS.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Linfoma/etiologia , Linfoma/patologia , Síndrome de Sjogren/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Adolescente , Adulto , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Linfoma/sangue , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , Radioimunoensaio , Reação em Cadeia da Polimerase em Tempo Real , Síndrome de Sjogren/etiologia , Adulto Jovem
5.
J Autoimmun ; 123: 102687, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34311142

RESUMO

The impact of SARS-CoV-2 infection in patients with autoimmune/auto-inflammatory rheumatic diseases (AARD) under immunomodulatory treatment has been a focus of interest during the COVID-19 pandemic. In this observational study, demographic data, disease related features and comorbidities, COVID-19 manifestations and outcome as well as antibody responses to SARS-CoV-2 were recorded among 77 consecutive patients with underlying AARD infected by SARS-CoV-2. Analysis of data was performed using univariate and multivariate models. Most patients (68.8%) had a mild COVID-19 course. The predominant clinical manifestations were fatigue (58.4%), low grade fever (45.4%) and upper respiratory tract symptoms (68.8%). About a quarter of patients required hospitalization (23.3%) and the mortality rate was 1.3%. Regarding COVID-19 severity, prior treatment with corticosteroids, mycophenolate mofetil or rituximab was more common in patients who developed a more serious disease course (60.0 vs 29.9%, p = 0.003, 40.0 vs 7.5%, p = 0.003, 10.0 vs 0.0%, p = 0.009, respectively). When disease related features and comorbidities were considered in multivariate models, older age and lung disease in the context of the AARD were found to be independent predictive factors for hospitalization (OR [95%]: 1.09 [1.03-1.15] and 6.43 [1.11-37.19]). Among COVID-19 related features, patients with shortness of breath and high-grade fever were more likely to get hospitalized (OR [95%]: 7.06 [1.36-36.57], 12.04 [2.96-48.86]), while anosmia was independently associated with lower hospitalization risk (OR [95%]: 0.09 [0.01-0.99]). Though the majority of AARD patients displayed a mild COVID-19 course, certain underlying disease features and COVID-19 related manifestations should prompt alertness for the physician to identify patients with AARD at high risk for severe COVID-19 and need for hospitalization.


Assuntos
Doenças Autoimunes/epidemiologia , COVID-19/epidemiologia , Doenças do Tecido Conjuntivo/epidemiologia , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/biossíntese , Infecções Assintomáticas/epidemiologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Comorbidade , Doenças do Tecido Conjuntivo/tratamento farmacológico , Doenças do Tecido Conjuntivo/imunologia , Estado Terminal , Feminino , Grécia/epidemiologia , Hospitalização/estatística & dados numéricos , Humanos , Hipotireoidismo/epidemiologia , Hospedeiro Imunocomprometido , Imunoglobulina G/biossíntese , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Inflamação , Pneumopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Literatura de Revisão como Assunto , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/epidemiologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Avaliação de Sintomas
6.
J Autoimmun ; 123: 102704, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298409

RESUMO

OBJECTIVE: We investigated whether interferon (IFN) induced genes could serve as biomarkers for the detection of lymphoma development among patients with Sjögren's syndrome (SS). METHODS: Total RNA was extracted from 98 labial minor salivary glands (LMSG) biopsies of SS patients [61 not complicated by lymphoma (SS-nL) and 37 complicated by Non-Hodgkin Lymphoma (NHL) (SS-L)] and 67 matched peripheral blood (PB) samples, as well as from 30 LMSG biopsies and 17 matched PB derived from sicca controls (SC). RNA sequencing was performed in LMSG biopsies of high and low risk SS patients for lymphoma development and SC. Expression analysis of type I (MX-1, IFIT-1, IFI44 and ISG-15) and type II IFN induced (CXCL9/MIG-1, GBP-1) genes was performed by real time PCR. RESULTS: ISG-15 transcript levels were significantly higher in SS-L patients compared to SS-nL patients in both LMSG tissues and PB specimens. Additionally, MIG-1 was found to display higher expression values in LMSG tissues, but not in PB derived from SS-L patients compared to the SS-nL group. A coordinate expression in PB/LMSG of type I IFN (ISG-15, MX-1 and IFI44), but not type II IFN induced genes was also observed. CONCLUSION: ISG-15 gene expression was able to distinguish SS-nL and SS-L at both periphery and tissue level and therefore could represent a novel biomarker for lymphoma development among SS patients. PB and LSMG seem to share a common transcriptional profile of type I IFN pathway.

8.
Clin Immunol ; 229: 108765, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34089859

RESUMO

Whether and how an acute immune challenge may affect DNA Damage Response (DDR) is unknown. By studying vaccinations against Influenza and SARS-CoV-2 (mRNA-based) we found acute increases of type-I interferon-inducible gene expression, oxidative stress and DNA damage accumulation in blood mononuclear cells of 9 healthy controls, coupled with effective anti-SARS-CoV-2 neutralizing antibody production in all. Increased DNA damage after SARS-CoV-2 vaccine, partly due to increased oxidative stress, was transient, whereas the inherent DNA repair capacity was found intact. In contrast, in 26 patients with Systemic Lupus Erythematosus, who served as controls in the context of chronic immune activation, we validated increased DNA damage accumulation, increased type-I interferon-inducible gene expression and induction of oxidative stress, however aberrant DDR was associated with deficiencies in nucleotide excision repair pathways. These results indicate that acute immune challenge can indeed activate DDR pathways, whereas, contrary to chronic immune challenge, successful repair of DNA lesions occurs.


Assuntos
Anticorpos Neutralizantes/fisiologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Dano ao DNA , Lúpus Eritematoso Sistêmico/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , COVID-19/patologia , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Interferon Tipo I/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Vacinas Sintéticas/imunologia , Adulto Jovem
9.
Expert Rev Clin Immunol ; 17(8): 883-903, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34096436

RESUMO

INTRODUCTION: Accumulating data highlights that the dysregulation of type I interferon (IFN) pathways plays a central role in the pathogenesis of several systemic and organ-specific autoimmune diseases. Advances in understanding the role of type I IFNs in these disorders can lead to targeted drug development as well as establishing potential disease biomarkers. AREAS COVERED: Here, we summarize current knowledge regarding the role of type I IFNs in the major systemic, as well as organ-specific, autoimmune disorders, including prominent inflammatory CNS disorders like multiple sclerosis. EXPERT OPINION: Type I IFN involvement and its clinical associations in a wide spectrum of autoimmune diseases represents a promising area for research aiming to unveil common pathogenetic pathways in systemic and organ-specific autoimmunity.

10.
J Autoimmun ; 121: 102648, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34029875

RESUMO

The aim of this study is to explore the role of labial minor salivary gland (LMSG) focus score (FS) in stratifying Sjögren's Syndrome (SS) patients, lymphoma development prediction and to facilitate early lymphoma diagnosis. Ιn an integrated cohort of 1997 patients, 618 patients with FS ≥ 1 and at least one-year elapsing time interval from SS diagnosis to lymphoma diagnosis or last follow up were identified. Clinical, laboratory and serological features were recorded. A data driven logistic regression model was applied to identify independent lymphoma associated risk factors. Furthermore, a FS threshold maximizing the difference of time interval from SS until lymphoma diagnosis between high and low FS lymphoma subgroups was investigated, to develop a follow up strategy for early lymphoma diagnosis. Of the 618 patients, 560 were non-lymphoma SS patients while the other 58 had SS and lymphoma. FS, cryoglobulinemia and salivary gland enlargement (SGE) were proven to be independent lymphoma associated risk factors. Lymphoma patients with FS ≥ 4 had a statistically significant shorter time interval from SS to lymphoma diagnosis, compared to those with FS < 4 (4 vs 9 years, respectively, p = 0,008). SS patients with FS ≥ 4 had more frequently B cell originated manifestations and lymphoma, while in patients with FS < 4, autoimmune thyroiditis was more prevalent. In the latter group SGE was the only lymphoma independent risk factor. A second LMSG biopsy is patients with a FS ≥ 4, 4 years after SS diagnosis and in those with FS < 4 and a history of SGE, at 9-years, may contribute to an early lymphoma diagnosis. Based on our results we conclude that LMSG FS, evaluated at the time of SS diagnosis, is an independent lymphoma associated risk factor and may serve as a predictive biomarker for the early diagnosis of SS-associated lymphomas.

11.
J Clin Med ; 10(4)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567548

RESUMO

BACKGROUND: Primary Sjogren's syndrome (SS) is an autoimmune disease with a strong predilection for lymphoma development, with earlier disease onset being postulated as an independent risk factor for this complication. Variations of the Leukocyte immunoglobulin-like receptor A3(LILRA3) gene have been previously shown to increase susceptibility for both SS and non-Hodgkin B-cell lymphoma (B-NHL) in the general population. We aimed to investigate whether variations of the LILRA3 gene could predispose for lymphoma development in the context of SS. METHODS: Study population, all of Greek origin, included 101 SS cases with a current or previous diagnosis of lymphoma (SS-lymphoma, SS-L) and 301 primary SS patients not complicated by lymphoma (SS-non-lymphoma, SS-nL). All SS patients fulfilled the 2016 SS American College of Rheumatology/European league against Rheumatism (ACR/EULAR) classification criteria. A total of 381 healthy controls (HC) of similar age/sex/race distribution were also included. On the basis of the age of SS onset and the presence or absence of adverse predictors for lymphoma development, SS patients were further stratified into younger (≤40 years) and older (>40 years) age of disease onset, as well as into high/medium and low risk groups. Polymerase chain reaction (PCR) was implemented for the detection of the following LILRA3 gene variants: homozygous non-deleted or functional wild type (+/+) heterozygous (+/-) and homozygous deleted (-/-). LILRA3 serum protein levels were quantitated by enzyme-linked immunosorbent assay (ELISA) in 85 individuals (29 SS-L, 35 SS-nL patients and 21 HC). RESULTS: While no statistically significant differences were detected in the overall frequency of LILRA3 gene variants between SS-L, SS-nL and HC groups, LILRA3 serum protein levels were increased in the SS-L group compared to HC (1.27 ± 1.34 vs. 0.38 ± 0.34 ng/mL, p-value: 0.004). After stratification according to the age of SS onset and history of lymphoma, as well as the presence or absence of adverse predictors for lymphoma development, the prevalence of the functional LILRA3 gene variant was found to be significantly increased in the young onset SS-L group compared to the HC of similar age and sex distribution (100% vs. 82.9%, p = 0.03), as well as in the high/medium risk SS compared to the low risk SS (91.3 vs. 78.3%, p = 0.0012). Of note, young onset SS-L and SS-nL groups displayed higher LILRA3 serum levels compared to their older counterparts (p-values: 0.007 and 0.0005, respectively). CONCLUSION: The functional LILRA3 gene variant increases susceptibility to SS-related lymphoma development in patients with a disease onset of <40 years old, implying that genetically determined deranged immune responses in younger SS individuals could underly their pronounced risk for lymphoma development.

12.
Clin Immunol ; 223: 108649, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33326823

RESUMO

OBJECTIVE: To explore whether APOBEC family members are involved in the response to inappropriate expression of L1 retroelements in primary Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE), as well as in SS related lymphomagenesis. METHODS: Minor salivary glands (MSG) and kidney biopsy (KB) specimens were obtained from 41 SS patients (10 with lymphoma) and 23 patients with SLE, respectively. PBMC and sera were also collected from 73 SLE patients. Full-length L1 transcripts, members of the APOBEC and IFN family were quantitated by real time PCR. Type I IFN activity was assessed in lupus plasma by a cell assay. RESULTS: APOBEC3A was increased in SS MSG, SLE KB and PBMC and correlated with L1. AID and APOBEC3G were particularly overexpressed in MSG tissues derived from SS lymphoma patients. CONCLUSION: These data reveal a previously unappreciated role of APOBEC family proteins in the pathogenesis of systemic autoimmunity and SS related lymphomagenesis.


Assuntos
Citidina Desaminase/metabolismo , Retrovirus Endógenos/genética , Rim/fisiologia , Leucócitos Mononucleares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Linfoma/imunologia , Proteínas/metabolismo , Glândulas Salivares/fisiologia , Síndrome de Sjogren/imunologia , Autoimunidade , Transformação Celular Neoplásica , Células Cultivadas , Citidina Desaminase/genética , Regulação da Expressão Gênica , Humanos , Interferons/metabolismo , Proteínas/genética
13.
Front Immunol ; 11: 594096, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193443

RESUMO

Objectives: To study the clinical, serological and histologic features of primary Sjögren's syndrome (pSS) patients with early (young ≤35 years) or late (old ≥65 years) onset and to explore the differential effect on lymphoma development. Methods: From a multicentre study population of 1997 consecutive pSS patients, those with early or late disease onset, were matched and compared with pSS control patients of middle age onset. Data driven analysis was applied to identify the independent variables associated with lymphoma in both age groups. Results: Young pSS patients (19%, n = 379) had higher frequency of salivary gland enlargement (SGE, lymphadenopathy, Raynaud's phenomenon, autoantibodies, C4 hypocomplementemia, hypergammaglobulinemia, leukopenia, and lymphoma (10.3% vs. 5.7%, p = 0.030, OR = 1.91, 95% CI: 1.11-3.27), while old pSS patients (15%, n = 293) had more frequently dry mouth, interstitial lung disease, and lymphoma (6.8% vs. 2.1%, p = 0.011, OR = 3.40, 95% CI: 1.34-8.17) compared to their middle-aged pSS controls, respectively. In young pSS patients, cryoglobulinemia, C4 hypocomplementemia, lymphadenopathy, and SGE were identified as independent lymphoma associated factors, as opposed to old pSS patients in whom SGE, C4 hypocomplementemia and male gender were the independent lymphoma associated factors. Early onset pSS patients displayed two incidence peaks of lymphoma within 3 years of onset and after 10 years, while in late onset pSS patients, lymphoma occurred within the first 6 years. Conclusion: Patients with early and late disease onset constitute a significant proportion of pSS population with distinct clinical phenotypes. They possess a higher prevalence of lymphoma, with different predisposing factors and lymphoma distribution across time.


Assuntos
Síndrome de Sjogren/epidemiologia , Síndrome de Sjogren/etiologia , Adulto , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Suscetibilidade a Doenças , Feminino , Humanos , Linfoma/epidemiologia , Linfoma/etiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Prevalência , Estudos Retrospectivos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Adulto Jovem
14.
Front Immunol ; 11: 582401, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123169

RESUMO

Increased endogenous DNA damage and type I interferon pathway activation have been implicated in systemic sclerosis (SSc) pathogenesis. Because experimental evidence suggests an interplay between DNA damage response/repair (DDR/R) and immune response, we hypothesized that deregulated DDR/R is associated with a type I interferon signature and/or fibrosis extent in SSc. DNA damage levels, oxidative stress, induction of abasic sites and the efficiency of DNA double-strand break repair (DSB/R) and nucleotide excision repair (NER) were assessed in peripheral blood mononuclear cells (PBMCs) derived from 37 SSc patients and 55 healthy controls; expression of DDR/R-associated genes and type I interferon-induced genes was also quantified. Endogenous DNA damage was significantly higher in untreated diffuse or limited SSc (Olive tail moment; 14.7 ± 7.0 and 9.5 ± 4.1, respectively) as well as in patients under cytotoxic treatment (15.0 ± 5.4) but not in very early onset SSc (5.6 ± 1.2) compared with controls (4.9 ± 2.6). Moreover, patients with pulmonary fibrosis had significantly higher DNA damage levels than those without (12.6 ± 5.8 vs. 8.8 ± 4.8, respectively). SSc patients displayed increased oxidative stress and abasic sites, defective DSB/R but not NER capacity, downregulation of genes involved in DSB/R (MRE11A, PRKDC) and base excision repair (PARP1, XRCC1), and upregulation of apoptosis-related genes (BAX, BBC3). Individual levels of DNA damage in SSc PBMCs correlated significantly with the corresponding mRNA expression of type I interferon-induced genes (IFIT1, IFI44 and MX1, r=0.419-0.490) as well as with corresponding skin involvement extent by modified Rodnan skin score (r=0.481). In conclusion, defective DDR/R may exert a fuel-on-fire effect on type I interferon pathway activation and contribute to tissue fibrosis in SSc.


Assuntos
Interferon Tipo I/genética , Pulmão/patologia , Escleroderma Sistêmico/genética , Adulto , Idoso , Apoptose/genética , Autoanticorpos/metabolismo , Dano ao DNA , Reparo do DNA/genética , Feminino , Fibrose , Humanos , Interferon Tipo I/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/genética , Escleroderma Sistêmico/imunologia
15.
Clin Exp Rheumatol ; 38 Suppl 126(4): 174-179, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33095144

RESUMO

OBJECTIVES: The objective of this work is to present a Training Tool designed to support healthcare professionals involved in the diagnosis and management of Sjögren's syndrome. METHODS: The Training Tool aims to fulfil the gap of targeted education by providing a structured protocol of training including state of the art guidelines and practices. For the development of the Training Tool, latest relevant technologies have been used to assure efficiency and usability. Core functionalities include training by a series of multimedia courses, testing during the learning process, and profiling for monitoring the progress. An iterative requirement analysis process was established involving a large number of clinical experts, with the objective to identify user's training needs. RESULTS: Comprehensive usability evaluation was performed by applying, an Unmoderated Remote Usability Test resulting to 97.2% Success Rate; and the well-established System Usability Scale, reaching a score of 90.4 which classifies the Training Tool as "A" graded-excellent. CONCLUSIONS: The Training Tool offers open-online training of healthcare professionals involved in the diagnosis and management of Sjögren's syndrome, using a well-designed training protocol in highly usable manner. To our knowledge, this is the first such tool for Sjögren's syndrome.


Assuntos
Síndrome de Sjogren , Pessoal de Saúde , Humanos , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/terapia
16.
Lupus Sci Med ; 7(1)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32913010

RESUMO

OBJECTIVE: A link between bone metabolism and cardiovascular (CV) disease has been suggested mainly in the general population. In the current study we explored whether altered bone metabolism influence CV risk in patients with SLE. METHODS: In 138 consecutive patients with SLE, atherosclerosis was assessed by the presence of plaque and/or arterial wall thickening in carotid/femoral arteries by ultrasound. Bone mineral density (BMD) levels and hip/spinal cord fractures together with classical CV disease and osteoporosis risk factors including serum 25(OH) vitamin D3 and parathormone (PTH) levels were recorded in all patients. Serum osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-Β ligand were quantitated by commercial ELISA. Statistical analysis included both univariate and multivariate models. RESULTS: Abnormal PTH serum concentrations (>65 pg/mL)-but not 25(OH) vitamin D3 serum levels-were identified as a risk factor for both plaque formation and arterial wall thickening in patients with SLE (ORs (95% CIs): 8.2 (1.8 to 37.4) and 3.9 (1.3 to 11.8), respectively). This association remained significant following adjustment for vitamin D3 levels and classical CV risk factors. Moreover, an independent association between osteoporosis with plaque formation and arterial wall thickening was detected following adjustment for total steroid dose, premature menopause and disease duration (ORs (95% CIs): 5.3 (1.1 to 26.2) and 3.5 (1.1 to 11.4), respectively). An inverse correlation between femoral neck BMD values and intima-medial thickness scores was also observed (r: -0.42, p=0.008). CONCLUSIONS: These findings further strengthen the concept of shared pathophysiological mechanisms between atherogenesis and altered bone metabolism in autoimmune populations, revealing heightened PTH levels as a potential marker for atherosclerosis among patients with SLE.


Assuntos
Aterosclerose , Lúpus Eritematoso Sistêmico , Adulto , Aterosclerose/complicações , Densidade Óssea , Espessura Intima-Media Carotídea , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo
17.
Clin Case Rep ; 8(8): 1586-1587, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32884802

RESUMO

Respiratory complaints alone or in association with musculoskeletal complaints can be the predominant presenting feature of antisynthetase syndrome. Therefore, antibodies to cellular antigens should be evaluated in such clinical settings.

18.
Inflamm Bowel Dis ; 26(10): 1543-1553, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32812029

RESUMO

BACKGROUND: Anti-TNF agents have been a cornerstone of IBD therapy; however, response to treatment has been variable, and clinically applicable biomarkers are urgently needed. We hypothesized that the type I and type II interferon (IFN) signatures may be a confounding factor for response to antitumor necrosis factor (TNF) treatment via interactions with the host and its gut microbiota. METHODS: Peripheral blood from 30 IBD patients and 10 healthy controls was subjected to real-time quantitative real-time polymerase chain reaction for type I and type II IFN genes (IFNGs), both at baseline and after treatment with anti-TNF. Correlation between IFN signatures and microbiota composition was also determined for a subgroup of patients and controls. RESULTS: At baseline, type I IFN score was significantly higher in IBD patients (P = 0.04 vs controls). Responders to subsequent anti-TNF treatment had significantly lower baseline scores for both type I and II IFN signatures (P < 0.005 vs nonresponders for both comparisons). During treatment with anti-TNF, the expression of type I and II IFNGs was significantly elevated in responders and decreased in nonresponders. In addition, changes in IFN signatures correlated to specific alterations in the abundance of several microbial taxa of the gut microbiome. CONCLUSIONS: Baseline expression of type I and II IFN signatures and their kinetics during anti-TNF administration significantly correlate to treatment responses in IBD patients. Peripheral blood IFN signatures may serve as clinically meaningful biomarkers for the identification of subgroups of patients with favorable response to anti-TNF treatment. Additionally, the distinct synergies between different IFN types and microbiota might help drive therapeutic intervention.

19.
Clin Immunol ; 217: 108497, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32531346

RESUMO

The recent approval of Immunologic checkpoint inhibitors as an effective therapeutic strategy against cancer came at the cost of toxicities mediated by an excessive activation of immune system against health tissues, including among others musculoskeletal and sicca complaints.The latter occur in the context of an entity reminiscent of Sjogren's syndrome, with distinct characteristics such as abrupt onset, male predominance, lower prevalence of autoantibodies and response to steroids.


Assuntos
Inibidores de Checkpoint Imunológico/efeitos adversos , Ipilimumab/efeitos adversos , Nivolumabe/efeitos adversos , Síndrome de Sjogren/induzido quimicamente , Idoso , Autoanticorpos/sangue , Autoanticorpos/efeitos dos fármacos , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Ipilimumab/uso terapêutico , Masculino , Neoplasias/tratamento farmacológico , Nivolumabe/uso terapêutico , Síndrome de Sjogren/imunologia
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