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Immunosuppressive treatment in patients with rheumatic diseases can maintain disease remission but also increase risk of infection. Their response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is frequently blunted. In this study we evaluated the effect of immunosuppression exposure on humoral and T cell immune responses to SARS-CoV-2 infection and vaccination in two distinct cohorts of patients; one during acute SARS-CoV-2 infection and 3 months later during convalescence, and another prior to SARS-CoV-2 vaccination, with follow up sampling 6 weeks after vaccination. Results were compared between rituximab-exposed (in previous 6 months), immunosuppression-exposed (in previous 3 months), and non-immunosuppressed groups. The immune cell phenotype was defined by flow cytometry and ELISA. Antigen specific T cell responses were estimated using a whole blood stimulation interferon-γ release assay. A focused post-vaccine assessment of rituximab-treated patients using high dimensional spectral cytometry was conducted. Acute SARS-CoV-2 infection was characterised by T cell lymphopenia, and a reduction in NK cells and naïve CD4 and CD8 cells, without any significant differences between immunosuppressed and non-immunosuppressed patient groups. Conversely, activated CD4 and CD8 cell counts increased in non-immunosuppressed patients with acute SARS-CoV-2 infection but this response was blunted in the presence of immunosuppression. In rituximab-treated patients, antigen-specific T cell responses were preserved in SARS-CoV-2 vaccination, but patients were unable to mount an appropriate humoral response.
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Vacinas contra COVID-19 , COVID-19 , Rituximab , SARS-CoV-2 , Vacinação , Humanos , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , SARS-CoV-2/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Vacinas contra COVID-19/imunologia , Rituximab/uso terapêutico , Rituximab/farmacologia , Idoso , Adulto , Terapia de Imunossupressão , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Anticorpos Antivirais/imunologia , Imunidade Humoral/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologiaRESUMO
OBJECTIVES: This study investigates pathogenic and protective polyfunctional T-cell responses in patient with rheumatoid arthritis (RA), individuals at risk (IAR) and healthy control (HC) synovial-tissue biopsies and identifies the presence of a novel population of pathogenic polyfunctional T-cells that are enriched in the RA joint prior to the development of clinical inflammation. METHODS: Pathway enrichment analysis of previously obtained RNAseq data of synovial biopsies from RA (n=118), IAR (n=20) and HC (n=44) was performed. Single-cell synovial tissue suspensions from RA (n=10), IAR (n=7) and HC (n=7) and paired peripheral blood mononuclear cells (PBMC) were stimulated in vitro and polyfunctional synovial T-cell subsets examined by flow cytometric analysis, simplified presentation of incredibly complex evaluations (SPICE) and FlowSom clustering. Flow-imaging was utilised to confirm specific T-cell cluster identification. Fluorescent lifetime imaging microscopy (FLIM) was used to visualise metabolic status of sorted T-cell populations. RESULTS: Increased plasticity of Tfh cells and CD4 T-cell polyfunctionality with enriched memory Treg cell responses was demonstrated in RA patient synovial tissue. Synovial-tissue RNAseq analysis reveals that enrichment in T-cell activation and differentiation pathways pre-dates the onset of RA. Switch from potentially protective IL-4 and granulocyte macrophage colony stimulating factor (GMCSF) dominated polyfunctional CD4 T-cell responses towards pathogenic polyfunctionality is evident in patient with IAR and RA synovial tissue. Cluster analysis reveals the accumulation of highly polyfunctional CD4+ CD8dim T-cells in IAR and RA but not HC synovial tissue. CD4+ CD8dim T-cells show increased utilisation of oxidative phosphorylation, a characteristic of metabolically primed memory T-cells. Frequency of synovial CD4+ CD8dim T-cells correlates with RA disease activity. CONCLUSION: Switch from potentially protective to pathogenic T-cell polyfunctionality pre-dates the onset of clinical inflammation and constitutes an opportunity for therapeutic intervention in RA.
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Artrite Reumatoide/imunologia , Membrana Sinovial/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sintomas ProdrômicosRESUMO
OBJECTIVES: Immune and stromal cell communication is central in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), however, the nature of these interactions in the synovial pathology of the two pathotypes can differ. Identifying immune-stromal cell crosstalk at the site of inflammation in RA and PsA is challenging. This study creates the first global transcriptomic analysis of the RA and PsA inflamed joint and investigates immune-stromal cell interactions in the pathogenesis of synovial inflammation. METHODS: Single cell transcriptomic profiling of 178 000 synovial tissue cells from five patients with PsA and four patients with RA, importantly, without prior sorting of immune and stromal cells. This approach enabled the transcriptomic analysis of the intact synovial tissue and identification of immune and stromal cell interactions. State of the art data integration and annotation techniques identified and characterised 18 stromal and 14 immune cell clusters. RESULTS: Global transcriptomic analysis of synovial cell subsets identifies actively proliferating synovial T cells and indicates that due to differential λ and κ immunoglobulin light chain usage, synovial plasma cells are potentially not derived from the local memory B cell pool. Importantly, we report distinct fibroblast and endothelial cell transcriptomes indicating abundant subpopulations in RA and PsA characterised by differential transcription factor usage. Using receptor-ligand interactions and downstream target characterisation, we identify RA-specific synovial T cell-derived transforming growth factor (TGF)-ß and macrophage interleukin (IL)-1ß synergy in driving the transcriptional profile of FAPα+THY1+ invasive synovial fibroblasts, expanded in RA compared with PsA. In vitro characterisation of patient with RA synovial fibroblasts showed metabolic switch to glycolysis, increased adhesion intercellular adhesion molecules 1 expression and IL-6 secretion in response to combined TGF-ß and IL-1ß treatment. Disrupting specific immune and stromal cell interactions offers novel opportunities for targeted therapeutic intervention in RA and PsA.
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OBJECTIVES: Although evidence is accumulating globally, data on outcomes in rheumatic disease and COVID-19 in Ireland are limited. We used data from the COVID-19 Global Rheumatology Alliance (C19-GRA) to describe time-varying COVID-19 outcomes for people with rheumatic disease in Ireland. METHODS: Data entered into the C19-GRA provider registry from Ireland between 24 March 2020 and 9 July 2021 were analysed. Differences in the likelihood of hospitalization and mortality according to demographic and clinical variables were investigated using Chi-squared test or Fisher's exact test, as appropriate. Trends in odds of hospitalization and mortality over time were investigated using logistic regression with the time period as a categorical variable. RESULTS: Of 212 cases included, 59.4% were female and median age was 58.0 years (range 13-96). Of the 212 cases, 92 (43%) were hospitalized and 22 (10.4%) died. Increasing age, a diagnosis of gout, ever smoking, glucocorticoid use, having comorbidities and specific comorbidities of cancer, cardiovascular and pulmonary disease were more common in those hospitalized. A diagnosis of inflammatory arthritis, csDMARD and/or b/tsDMARD use were less frequent in those hospitalized. Increasing age, a diagnosis of gout, ever smoking, having comorbidities and specific comorbidities of obesity, cardiovascular and pulmonary disease were more common in those who died. Odds of hospitalization or mortality did not change over time. CONCLUSION: No temporal trend was observed in either COVID-19-related hospitalization or mortality outcomes for people with rheumatic disease in Ireland.
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COVID-19 , Gota , Doenças Reumáticas , Reumatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/epidemiologia , Feminino , Humanos , Irlanda/epidemiologia , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Doenças Reumáticas/epidemiologia , SARS-CoV-2 , Adulto JovemRESUMO
OBJECTIVE: This study examines polyfunctional T-cells in psoriatic arthritis (PsA) synovial tissue and their associations with clinical disease and implications for therapy. METHODS: PsA synovial tissue was enzymatically/mechanically digested to generate synovial tissue single cell suspensions. Frequencies of polyfunctional CD4, CD8, T-helper 1 (Th1), Th17 and exTh17 cells, using CD161 as a marker of Th17 plasticity, were determined by flow cytometry in matched PsA synovial tissue and peripheral blood. Synovial T-cell polyfunctionality was assessed in relation to Disease Activity in PSoriatic Arthritis (DAPSA) and in synovial cell suspensions cultured with a current mode of treatment, phosphodiesterase 4 (PDE4) inhibitor. RESULTS: PsA synovial tissue infiltrating CD4+ T-cells expressed higher levels of interleukin (IL)-17A, interferon gamma (IFN-γ), GM-CSF and CD161, with parallel enrichment of Th1, Th17 and exTh17 T-helper subsets (all p<0.05). Interestingly, a significant proportion of synovial T-cell subsets were triple-positive for GM-CSF, tumour necrosis factor (-TNF), -IL-17 or IFN-γ compared with matched blood (all p<0.05). Importantly, frequencies of polyfunctional T-cells correlated with DAPSA: Th1-GM-CSF+/TNF+/IFN-γ+ (r=0.7, p<0.01), Th17-GM-CSF+/TNF+/IL-17+ (r=0.6, p<0.057) and exTh17-GM-CSF+/TNF+/IFN-γ+ (r=0.7, p=0.0096), with no associations observed for single cytokine-producing T-cells. Following ex vivo culture of PsA synovial tissue cell suspensions, polyfunctional GM-CSF+TNFα+IL-17A+ or/IFN-γ+-producing T-cells (p<0.05), but not single cytokine-producing T-cells, were inhibited with a PDE4 inhibitor. CONCLUSION: These data demonstrate enrichment of polyfunctional T-cells in PsA synovial tissue which were strongly associated with DAPSA and ex vivo therapeutic response.
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Artrite Psoriásica/imunologia , Artrite Psoriásica/fisiopatologia , Linfócitos T CD4-Positivos/imunologia , Membrana Sinovial/citologia , Subpopulações de Linfócitos T/imunologia , Antígenos CD4/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígenos CD8/efeitos dos fármacos , Técnicas de Cultura de Células , Citometria de Fluxo , Humanos , Interferon gama/efeitos dos fármacos , Interleucina-17/imunologia , Inibidores da Fosfodiesterase 4/farmacologia , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologiaAssuntos
Osteíte , Psoríase/diagnóstico , Sarcoidose , Dermatopatias , Falanges dos Dedos do Pé , Ferimentos e Lesões/complicações , Adolescente , Diagnóstico Diferencial , Progressão da Doença , Hallux/diagnóstico por imagem , Hallux/patologia , Humanos , Masculino , Osteíte/complicações , Osteíte/fisiopatologia , Osteíte/terapia , Medicina Preventiva , Prognóstico , Sarcoidose/diagnóstico , Sarcoidose/imunologia , Sarcoidose/fisiopatologia , Sarcoidose/terapia , Dermatopatias/diagnóstico , Dermatopatias/etiologia , Falanges dos Dedos do Pé/diagnóstico por imagem , Falanges dos Dedos do Pé/patologiaRESUMO
OBJECTIVE: To investigate the relationship between acute-phase serum amyloid A (A-SAA) and joint destruction in inflammatory arthritis. METHODS: Serum A-SAA and C-reactive protein (CRP) levels, the erythrocyte sedimentation rate (ESR), and levels of matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, MMP-9, MMP-13, tissue inhibitor of metalloproteinases 1 (TIMP-1), vascular endothelial growth factor (VEGF), and type I and type II collagen-generated biomarkers C2C and C1,2C were measured at 0-3 months in patients with inflammatory arthritis commencing anti-tumor necrosis factor α (anti-TNFα) therapy and were correlated with 1-year radiographic progression. The effects of A-SAA on MMP/TIMP expression on RA fibroblast-like synoviocytes (FLS), primary human chondrocytes, and RA/psoriatic arthritis synovial explant cultures were assessed using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, antibody protein arrays, and gelatin zymography. RESULTS: Serum A-SAA levels were significantly (P < 0.05) correlated with MMP-3, the MMP-3:TIMP-1 ratio, C1,2C, C2C, and VEGF. The baseline A-SAA level but not the ESR or the CRP level correlated with the 28-joint swollen joint count and was independently associated with 1-year radiographic progression (P = 0.038). A-SAA increased MMP-1, MMP-3, MMP-13, and MMP/TIMP expression in RA FLS and synovial explants (P < 0.05). In chondrocytes, A-SAA induced MMP-1, MMP-3, and MMP-13 messenger RNA and protein expression (all P < 0.01), resulting in a significant shift in MMP:TIMP ratios (P < 0.05). Gelatin zymography revealed that A-SAA induced MMP-2 and MMP-9 activity. Blockade of the A-SAA receptor SR-B1 (A-SAA receptor scavenger receptor-class B type 1) inhibited MMP-3, MMP-2, and MMP-9 expression in synovial explant cultures ex vivo. Importantly, we demonstrated that A-SAA has the ability to induce TNFα expression in RA synovial explant cultures (P < 0.05). CONCLUSION: A-SAA may be involved in joint destruction though MMP induction and collagen cleavage in vivo. The ability of A-SAA to regulate TNFα suggests that A-SAA signaling pathways may provide new therapeutic strategies for the treatment of inflammatory arthritis.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/metabolismo , Progressão da Doença , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Proteína Amiloide A Sérica/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Idoso , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Colágeno Tipo II/metabolismo , Feminino , Seguimentos , Articulações do Pé/diagnóstico por imagem , Articulação da Mão/diagnóstico por imagem , Humanos , Masculino , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Radiografia , Líquido Sinovial/metabolismo , Membrana Sinovial/diagnóstico por imagem , Membrana Sinovial/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoAssuntos
Histiocitose de Células não Langerhans , Neoplasias Cutâneas , Diagnóstico Diferencial , Orelha/patologia , Feminino , Dedos/patologia , Histiocitose de Células não Langerhans/diagnóstico , Histiocitose de Células não Langerhans/patologia , Humanos , Joelho/patologia , Pessoa de Meia-Idade , Pele/citologia , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: The impact of inflammatory arthritis (IA) on occupational performance and on participation in meaningful life roles is recognised. However, limited research has explored how clinical services support broader life impact and participation restrictions associated with early disease as part of routine healthcare. This exploratory study was undertaken to describe how a novel multidisciplinary-led early arthritis service approach addresses client-identified participation restrictions in early IA. METHODS: Qualitative Description (QD) approaches were used to explore perspectives of staff and clients of these multidisciplinary-led early arthritis services in Ireland. Data were gathered using focus groups with staff, and individual semi-structured interviews with clients. Transcripts were analysed using thematic analysis. RESULTS: Fifteen staff working in these services participated in the focus groups and 43 clients with IA participated in interviews (female n = 31); diagnosis duration ranged from 5 to 24 months. Participants described how the multidisciplinary-led service had a clear remit to address participation alongside traditional symptom management and provided automatic, immediate access to interventions focussed on identification and management of participation restrictions experienced in early disease. The service model utilised a delivery approach that allowed for ease of early access to a full multidisciplinary team and prolonged support. The most significant feature of the service approach was 'the centrality of the client' which influenced a person-centred approach to identification of needs and priorities for interventions. CONCLUSION: Findings indicate the role and value of this innovative multidisciplinary approach in addressing client-identified participation restrictions in routine clinical practice that is positively regarded by clients and staff.
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Artrite , Atenção à Saúde , Humanos , Feminino , Masculino , Pesquisa Qualitativa , IrlandaRESUMO
PURPOSE: To describe the impact of early inflammatory arthritis on work participation. MATERIALS AND METHODS: Thirty individuals (24 women) of working age (age 18-69 years) with inflammatory arthritis (<2 years duration) who were in paid employment or fulltime education were interviewed using qualitative description methodology. Data was analysed using thematic analysis. RESULTS: Half of participants (n = 15) reported work disability within the first two-years of diagnosis. Five descriptive themes were identified that explained the early impact of IA on participation in paid employment. These themes were: (i) altered capacity for work; (ii) work comes first; (iii) the invisible burden; (iv) the disclosure effect; and (v) a reconstructed work future. CONCLUSION: The scale of early work disability appears to be higher than previously understood. Although early medical intervention has improved disease management, significant work-based restrictions requiring intervention remain. Internalised and invisible work-related anxieties present early in the disease and need to be acknowledged and addressed by healthcare providers.IMPLICATIONS FOR REHABILITATIONEarly inflammatory arthritis causes significant challenges in work ability, and early work-based participation restrictions are present despite early use of drug therapy.Assessment of the client's subjective experience, including understanding the invisible burden, is an important aspect in determining the types of work interventions required.Disclosure of diagnosis in the work environment is associated with anxiety and fear, however, disclosure is influential in supporting capacity to retain work participation and should be included in work interventions.Routine healthcare should include early interventions to address work-based restrictions and supporting work retention to avoid work disability.
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Artrite , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Emprego , Pesquisa Qualitativa , Atenção à Saúde , MedoRESUMO
PURPOSE: To explore the impact of early inflammatory arthritis on participation in parenting roles. MATERIALS AND METHODS: Twenty-four individuals (20 female) aged between 32 and 62 years with early inflammatory arthritis (<2 years duration) and who were parents of dependent children (≤21 years) were interviewed. A qualitative description study design was used, and thematic analysis methodologies were employed in the data analysis. RESULTS: Parenting roles were significantly impacted in early disease and extensive parenting restrictions were identified regardless of age and gender. Physical symptoms hampered "everyday mammy activities." Parent-child interactions were altered by the emotional impact of early arthritis including low mood and irritability. Participants emphasised remorse at the negative impact of their arthritis on their children's childhood. Parent-role identity and parents' perception of how they were viewed by their children were negatively impacted by early disease with considerable self-imposed pressure to shield children from the consequences of arthritis. A forced "role switch" requiring relinquishing of some parenting tasks was identified as an unwanted burden associated with inflammatory arthritis. CONCLUSION: Inflammatory arthritis has a negative impact on parenting which is present from disease onset. Understanding factors which influence parenting with arthritis is important to identify appropriate healthcare interventions.Implications for rehabilitationAn early diagnosis of inflammatory arthritis is synonymous with considerable challenges in performing parenting tasks and activities which are present despite early medical management and drug therapy.Physical and psychosocial sequelae of early inflammatory arthritis result in restrictions in the execution of parenting activities and are accompanied by a forced "role switch".The disease impact on parenting differs in early and established inflammatory arthritis and requires distinct healthcare approaches and interventions to adequately address the needs.Parent role identity and perceived lack of control are intrinsically linked to the degree of perceived negative impact on parenting and these factors should be considered in the design and evaluation of appropriate healthcare interventions for this population.
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Artrite , Poder Familiar , Humanos , Feminino , Criança , Adulto , Pessoa de Meia-Idade , Poder Familiar/psicologia , Pais/psicologia , Relações Pais-Filho , Pesquisa QualitativaRESUMO
BACKGROUND: Poor COVID-19 outcomes occur with higher frequency in people with rheumatic and musculoskeletal diseases (RMD). Better understanding of the factors involved is crucial to informing patients and clinicians regarding risk mitigation. AIM: To describe COVID-19 outcomes for people with RMD in Ireland over the first 2 years of the pandemic. METHODS: Data entered into the C19-GRA provider registry from Ireland between 24th March 2020 and 31st March 2022 were analysed. Differences in the likelihood of hospitalisation and mortality according to demographic and clinical variables were investigated. RESULTS: Of 237 cases included, 59.9% were female, 95 (41.3%) were hospitalised, and 22 (9.3%) died. Hospitalisation was more common with increasing age, gout, smoking, long-term glucocorticoid use, comorbidities, and specific comorbidities of cardiovascular and pulmonary disease, and cancer. Hospitalisation was less frequent in people with inflammatory arthritis and conventional synthetic or biologic disease-modifying antirheumatic drug use. Hospitalisation had a U-shaped relationship with disease activity, being more common in both high disease activity and remission. Mortality was more common with increasing age, gout, smoking, long-term glucocorticoid use, comorbidities, and specific comorbidities of cardiovascular disease, pulmonary disease, and obesity. Inflammatory arthritis was less frequent in those who died. CONCLUSION: Hospitalisation or death were more frequently experienced by RMD patients with increasing age, certain comorbidities including potentially modifiable ones, and certain medications and diagnoses amongst other factors. These are important 'indicators' that can help risk-stratify and inform the management of RMD patients.
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COVID-19 , Gota , Doenças Musculoesqueléticas , Humanos , Feminino , Masculino , Irlanda/epidemiologia , Pandemias , Glucocorticoides , COVID-19/epidemiologia , Doenças Musculoesqueléticas/epidemiologiaRESUMO
Serum amyloid A (A-SAA), an acute-phase protein with cytokine-like properties, is expressed at sites of inflammation. This study investigated the effects of A-SAA on chemokine-regulated migration and angiogenesis using rheumatoid arthritis (RA) cells and whole-tissue explants in vitro, ex vivo, and in vivo. A-SAA levels were measured by real-time PCR and ELISA. IL-8 and MCP-1 expression was examined in RA synovial fibroblasts, human microvascular endothelial cells, and RA synovial explants by ELISA. Neutrophil transendothelial cell migration, cell adhesion, invasion, and migration were examined using transwell leukocyte/monocyte migration assays, invasion assays, and adhesion assays with or without anti-MCP-1/anti-IL-8. NF-kappaB was examined using a specific inhibitor and Western blotting. An RA synovial/SCID mouse chimera model was used to examine the effects of A-SAA on cell migration, proliferation, and angiogenesis in vivo. High expression of A-SAA was demonstrated in RA patients (p < 0.05). A-SAA induced chemokine expression in a time- and dose-dependent manner (p < 0.05). Blockade with anti-scavenger receptor class B member 1 and lipoxin A4 (A-SAA receptors) significantly reduced chemokine expression in RA synovial tissue explants (p < 0.05). A-SAA induced cell invasion, neutrophil-transendothelial cell migration, monocyte migration, and adhesion (all p < 0.05), effects that were blocked by anti-IL-8 or anti-MCP-1. A-SAA-induced chemokine expression was mediated through NF-kappaB in RA explants (p < 0.05). Finally, in the RA synovial/SCID mouse chimera model, we demonstrated for the first time in vivo that A-SAA directly induces monocyte migration from the murine circulation into RA synovial grafts, synovial cell proliferation, and angiogenesis (p < 0.05). A-SAA promotes cell migrational mechanisms and angiogenesis critical to RA pathogenesis.
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Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Movimento Celular/imunologia , Inflamação/metabolismo , Neovascularização Patológica/imunologia , Proteína Amiloide A Sérica/metabolismo , Membrana Sinovial/citologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Western Blotting , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Inflamação/imunologia , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Amiloide A Sérica/imunologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Quimeras de Transplante , Adulto JovemRESUMO
Ultrasound (US) is being increasingly used to diagnose Giant Cell Arteritis (GCA). The traditional diagnostic Gold Standard has been temporal artery biopsy (TAB), but this is expensive, invasive, has a false-negative rate as high as 60% and has little impact on clinical decision-making. A non-compressible halo with a thickened intima-media complex (IMC) is the sonographic hallmark of GCA. The superficial temporal arteries (STA) and axillary arteries (AA) are the most consistently inflamed arteries sonographically and imaging protocols for evaluating suspected GCA should include at least these two arterial territories. Studies evaluating temporal artery ultrasound (TAUS) have varied considerably in size and methodology with results showing wide discrepancies in sensitivity (9-100%), specificity (66-100%), positive predictive value (36-100%) and negative predictive value (33-100%). Bilateral halos increase sensitivity as does the incorporation of pre-test probability, while prior corticosteroid use decreases sensitivity. Quantifying sonographic vasculitis using Halo Counts and Halo Scores can predict disease extent/severity, risk of specific complications and likelihood of treatment response. Regression of the Halo sign has been observed from as little as 2 days to as late as 7 months after initiation of immunosuppressive treatment and occurs at different rates in STAs than AAs. US is more sensitive than TAB and has comparable sensitivity to MRI and PET/CT. It is time-efficient, cost-effective and allows for the implementation of fast-track GCA clinics which substantially mitigate the risk of irreversible blindness. Algorithms incorporating combinations of imaging modalities can achieve a 100% sensitivity and specificity for a diagnosis of GCA. US should be a standard first line investigation in routine clinical care of patients with suspected GCA with TAB reserved only for those having had a normal US in the context of a high pre-test probability.
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Acute phase apoprotein Serum Amyloid A (A-SAA), which is strongly expressed in rheumatoid arthritis synovial membrane (RA SM), induces angiogenesis, adhesion molecule expression, and matrix metalloproteinase production through the G-coupled receptor FPRL-1. Here we report alternative signaling through the high-density lipoprotein receptor scavenger receptor-class B type 1 (SR-B1). Quantitative expression/localization of SR-B1 in RA SM, RA fibroblast-like cells (FLCs), and microvascular endothelial cells (ECs) was assessed by Western blotting and immunohistology/fluorescence. A-SAA-mediated effects were examined using a specific antibody against SR-B1 or amphipathic alpha-Helical Peptides (the SR-B1 antagonists L-37pA and D-37pA), in RA FLCs and ECs. Adhesion molecule expression and cytokine production were quantified using flow cytometry and ELISA. SR-B1 was strongly expressed in the RA SM lining layer and endothelial/perivascular regions compared with osteoarthritis SM or normal control synovium. Differential SR-B1 expression in RA FLC lines (n = 5) and ECs correlated closely with A-SAA, but not tumor necrosis factor alpha-induced intercellular adhesion molecule-1 upregulation. A-SAA-induced interleukin-6 and -8 production was inhibited in the presence of anti-SR-B1 in human microvascular endothelial cells and RA FLCs. Moreover, D-37pA and L-37pA inhibited A-SAA-induced vascular cell adhesion molecule-1 and intercellular adhesion molecule expression from ECs in a dose-dependent manner. As SR-B1 is expressed in RA synovial tissue and mediates A-SAA-induced pro-inflammatory pathways, a better understanding of A-SAA-mediated inflammatory pathways may lead to novel treatment strategies for RA.
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Artrite Reumatoide/metabolismo , Antígenos CD36/fisiologia , Regulação da Expressão Gênica , Inflamação/patologia , Proteína Amiloide A Sérica/biossíntese , Membrana Sinovial/metabolismo , Artroscopia/métodos , Biópsia , Antígenos CD36/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/citologia , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Peptídeos/química , FenótipoRESUMO
Sarcoidosis is a multisystem inflammatory disorder of uncertain aetiology. There are numerous case reports of sarcoidosis occurring during treatment with biological immunotherapies. Here, we describe the case of a 52-year-old woman with psoriatic arthritis who developed multisystem sarcoidosis while being treated with secukinumab (anti-interleukin-17A) therapy which, to our knowledge, is the first such case. We discuss existing literature and hypothesise that IL-17 blockade may precipitate the development of granulomatous disease.
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Artrite Psoriásica , Sarcoidose , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Artrite Psoriásica/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Sarcoidose/induzido quimicamente , Sarcoidose/diagnóstico , Sarcoidose/tratamento farmacológicoRESUMO
Dendritic cells (DC) have a key role in the initiation and progression of inflammatory arthritis (IA). In this study, we identified a DC population that derive from monocytes, characterized as CD209/CD14+ DC, expressing classical DC markers (HLADR, CD11c) and the Mo-DC marker (CD209), while also retaining the monocytic marker CD14. This CD209/CD14+ DC population is present in the circulation of Healthy Control (HC), with increased frequency in Rheumatoid Arthritis (RA) and Psoriatic arthritic (PsA) patients. We demonstrate, for the first time, that circulatory IA CD209/CD14+ DC express more cytokines (IL1ß/IL6/IL12/TNFα) and display a unique chemokine receptor expression and co-expression profiles compared to HC. We demonstrated that CD209/CD14+ DC are enriched in the inflamed joint where they display a unique inflammatory and maturation phenotype, with increased CD40 and CD80 and co-expression of specific chemokine receptors, displaying unique patterns between PsA and RA. We developed a new protocol of magnetic isolation and expansion for CD209+ DC from blood and identified transcriptional differences involved in endocytosis/antigen presentation between RA and PsA CD209+ DC. In addition, we observed that culture of healthy CD209+ DC with IA synovial fluid (SF), but not Osteoarthritis (OA) SF, was sufficient to induce the development of CD209/CD14+ DC, leading to a poly-mature DC phenotype. In addition, differential effects were observed in terms of chemokine receptor and chemokine expression, with healthy CD209+ DC displaying increased expression/co-expression of CCR6, CCR7, CXCR3, CXCR4 and CXCR5 when cultured with RA SF, while an increase in the chemokines CCR3, CXCL10 and CXCL11 was observed when cultured with PsA SF. This effect may be mediated in part by the observed differential increase in chemokines expressed in RA vs PsA SF. Finally, we observed that the JAK/STAT pathway, but not the NF-κB pathway (driven by TNFα), regulated CD209/CD14+ DC function in terms of activation, inflammatory state, and migratory capacity. In conclusion, we identified a novel CD209/CD14+ DC population, which is active in the circulation of RA and PsA, an effect potentiated once they enter the joint. Furthermore, we demonstrated that JAK/STAT inhibition can be used as a therapeutic strategy to decrease the inflammatory state of the pathogenic CD209/CD14+ DC.
Assuntos
Artrite Psoriásica/imunologia , Artrite Reumatoide/imunologia , Moléculas de Adesão Celular/imunologia , Células Dendríticas/imunologia , Lectinas Tipo C/imunologia , Receptores de Lipopolissacarídeos/imunologia , Receptores de Superfície Celular/imunologia , Líquido Sinovial/imunologia , Membrana Sinovial/imunologia , Adulto , Idoso , Quimiocinas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologiaRESUMO
Rheumatoid arthritis (RA) is a progressive erosive autoimmune disease that affects 1% of the world population. Anti-citrullinated protein autoantibodies (ACPA) are routinely used for the diagnosis of RA, however 20-30% of patients are ACPA negative. ACPA status is a delineator of RA disease endotypes with similar clinical manifestation but potentially different pathophysiology. Profiling of key peripheral blood and synovial tissue immune populations including B cells, T follicular helper (Tfh) cells and CD4 T cell proinflammatory cytokine responses could elucidate the underlying immunological mechanisms involved and inform a treat to target approach for both ACPA-positive and ACPA-negative RA. Detailed high dimensionality flow cytometric analysis with supervised and unsupervised algorithm analysis revealed unique RA patient peripheral blood B cell and Tfh cell profiles. Synovial tissue single cell analysis of B cell subpopulation distribution was similar between ACPA- and ACPA+ RA patients, highlighting a key role for specific B cell subsets in both disease endotypes. Interestingly, synovial tissue single cell analysis of CD4 T cell proinflammatory cytokine production was markedly different between ACPA- and APCA+ RA patients. RNAseq analysis of RA patient synovial tissue highlighted disease endotype specific gene signatures. ACPA status associates with unique immune profile signatures that reinforce the need for a treat to target approach for both endotypes of RA.