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1.
Clin Exp Rheumatol ; 37 Suppl 117(2): 72-78, 2019 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30620296

RESUMO

OBJECTIVES: The diagnosis of giant cell arteritis (GCA) is primarily a clinical one. Temporal artery (TA) ultrasound (US) has been proposed as a new diagnostic tool. We aimed to assess the performance characteristics of TA US in routine clinical practice. METHODS: All patients presenting with suspected GCA to our institution are recruited to a prospective registry. Patients who had both a TA US and biopsy (TAB) performed at the time of presentation were included in the current study. The performance characteristics of TA US was compared to physician diagnosis at six months following presentation. Predictive factors for a positive TA US were explored in univariate and multivariable logistic regression analyses. RESULTS: 162 patients were included, 123 (76%) with GCA. Mean (SD) duration of glucocorticoid therapy was 6.6 days (19.4) at the time of TA US. TA US had a sensitivity of 52.8% (95%CI 43.7, 61.9) and specificity of 71.8% (95%CI 54.9, 84.5) for the diagnosis of GCA. Glucocorticoid duration did not significantly impact the results. A sequential strategy of TA US followed by TAB in the case of a negative US had a sensitivity of 78.9% (95%CI 70.1, 85.5) and specificity of 71.8% (95%CI 54.9, 84.5), equivalent to a simultaneous testing strategy. The only factor independently predictive of a positive TA US was male sex (OR 5.53, 95% CI 2.72 to 11.22, p<0.001). CONCLUSIONS: TA US is potentially useful in the diagnosis of GCA; however, interpretation of its results requires knowledge of the performance characteristics in the target population.


Assuntos
Arterite de Células Gigantes , Artérias Temporais , Ultrassonografia/métodos , Biópsia , Estudos de Coortes , Feminino , Arterite de Células Gigantes/diagnóstico , Humanos , Masculino , Estudos Prospectivos , Artérias Temporais/diagnóstico por imagem
2.
Ann Rheum Dis ; 77(12): 1815-1824, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30097452

RESUMO

OBJECTIVES: The pathogenesis of giant cell arteritis (GCA) remains unclear. TH1 and TH17 pathways are implicated, but the proximal initiators and effector cytokines are unknown. Our aim was to assess the role of interleukin 12 (IL-12) and interleukin 23 (IL-23) in GCA pathogenesis. METHODS: IL-12 and IL-23 expression were quantified by immunohistochemistry in temporal artery biopsies (TABs). Temporal artery (TA) explant, peripheral blood mononuclear cell (PBMC) and myofibroblast outgrowth culture models were established. PBMCs and TA explants were cultured for 24 hours in the presence or absence of IL-12 (50 ng/mL) or IL-23 (10 ng/mL). Gene expression in TA was quantified by real-time PCR and cytokine secretion by ELISA. Myofibroblast outgrowths were quantified following 28-day culture. RESULTS: Immunohistochemistry demonstrated increased expression of interleukin 12p35 (IL-12p35) and interleukin 23p19 (IL-23p19) in biopsy-positive TAs, localised to inflammatory cells. IL-12p35 TA expression was significantly increased in those with cranial ischaemic complications (p=0.026) and large vessel vasculitis (p=0.006). IL-23p19 TA expression was increased in those with two or more relapses (p=0.007). In PBMC cultures, exogenous IL-12 significantly increased interleukin 6 (IL-6) (p=0.009), interleukin 22 (IL-22) (p=0.003) and interferon γ (IFN-γ) (p=0.0001) and decreased interleukin 8 (IL-8) (p=0.0006) secretion, while exogenous IL-23 significantly increased IL-6 (p=0.029), IL-22 (p=0.001), interleukin 17A (IL-17A) (p=0.0003) and interleukin 17F (IL-17F) (p=0.012) secretion. In ex vivo TA explants, IL-23 significantly increased gene expression of IL-8 (p=0.0001) and CCL-20 (p=0.027) and protein expression of IL-6 (p=0.002) and IL-8 (p=0.004). IL-12 (p=0.0005) and IL-23 (p<0.0001) stimulation increased the quantity of myofibroblast outgrowths from TABs. CONCLUSION: IL-12 and IL-23 play central and distinct roles in stimulating inflammatory and proliferative pathways relevant to GCA pathogenesis.

3.
Artigo em Inglês | MEDLINE | ID: mdl-29776658

RESUMO

OBJECTIVES: Giant cell arteritis (GCA) is the most common form of systemic vasculitis. Glucocorticoids are an effective treatment but have significant adverse events and relapses are common. Interleukins 12 (IL-12) and 23 (IL-23) stimulate TH1 and TH17 responses and are implicated in the pathogenesis of GCA. The aim of this study was to evaluate the efficacy and safety of IL-12/23 blockade with ustekinumab in GCA. METHODS: We performed a prospective open label study of ustekinumab in patients with refractory GCA. Ustekinumab 90mg was administered subcutaneously every 12 weeks. The primary outcome was the comparison of the median glucocorticoid dose prior to commencement of ustekinumab and at 52 weeks. Secondary outcomes included physician assessed relapse, acute phase reactants, and imaging assessment of large vessel vasculitis (LVV). RESULTS: Twenty-five GCA patients received ustekinumab. All patients had failed to taper glucocorticoids despite addition of a median of 1 other immunosuppressive agent. At week 52, median (IQR) daily prednisolone dose decreased from 20 (15, 25)mg to 5 (2.5, 5)mg (p < 0.001). Six patients (24%) stopped prednisolone completely. No patient experienced a relapse of GCA while receiving ustekinumab. Median (IQR) CRP decreased significantly from 12.9 (5.3, 42) to 6 (2.6, 12.5)mg/L (p = 0.006). CT angiography demonstrated improvement of LVV in all patients studied. No unexpected adverse events were observed with ustekinumab. CONCLUSIONS: Ustekinumab may be effective for the treatment of GCA and warrants further assessment in a randomized controlled trial.

4.
Am J Hum Genet ; 100(1): 64-74, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28041642

RESUMO

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10-54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10-10, OR = 1.28; and rs128738, p = 4.60 × 10-9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.


Assuntos
Alelos , Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla , Arterite de Células Gigantes/genética , Plasminogênio/genética , Prolil Hidroxilases/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Europa (Continente)/etnologia , Feminino , Humanos , Masculino , Neovascularização Fisiológica , Polimorfismo de Nucleotídeo Único/genética , Risco
6.
Rheumatology (Oxford) ; 55(11): 1921-1931, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26893518

RESUMO

GCA is a common primary systemic vasculitis that results in granulomatous inflammation of medium to large arteries. Both innate and adaptive immune mechanisms combine to drive intimal hyperplasia, luminal stenosis and ultimately occlusion. While the pathogenesis of GCA is incompletely understood, the activation of resident adventitial dendritic cells via toll like receptors (TLRs) appears to be a crucial inciting event. Here we explore the role of TLRs in the pathogenesis of GCA, including their effects on dendritic cell and T cell activation and recruitment, putative infectious triggers for GCA and the potential of TLR inhibition as a novel therapeutic strategy in GCA.


Assuntos
Arterite de Células Gigantes/etiologia , Receptores Toll-Like/fisiologia , Células Dendríticas/fisiologia , Arterite de Células Gigantes/terapia , Humanos , Infecção/fisiopatologia , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária , Neovascularização Patológica/fisiopatologia , Polimorfismo Genético/genética , Transdução de Sinais/fisiologia , Linfócitos T/fisiologia , Receptor 4 Toll-Like/genética , Receptores Toll-Like/antagonistas & inibidores , Remodelação Vascular/fisiologia , Vasculite/etiologia
7.
Case Rep Oncol Med ; 2015: 934039, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26558124

RESUMO

Malignant disease may be associated with a wide variety of musculoskeletal syndromes. Rarely the musculoskeletal system can be indirectly affected by paraneoplastic phenomena, such as carcinomatous polyarthritis (CP). The differential diagnosis for CP is broad and is often a diagnosis of exclusion. CP often presents similarly to other forms of inflammatory arthritis, and a detailed history and physical examination can often distinguish CP from other more common causes of polyarticular arthritis. However serological tests such as rheumatoid factor (RF) and anti-citrullinated peptide (anti-CCP) antibody positivity, while rare, can be misleading. Clinical awareness and suspicion are paramount in achieving an accurate diagnosis and early detection of an occult neoplasm is critical for prompt management and therapy. We report two cases presenting with this unique clinical phenotype associated with paraneoplastic polyarthropathy and review the literature.

8.
World J Clin Cases ; 3(6): 484-94, 2015 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-26090367

RESUMO

Glucocorticoids remain the cornerstone of medical therapy in giant cell arteritis (GCA) and should be started immediately to prevent severe consequences of the disease, such as blindness. However, glucocorticoid therapy leads to significant toxicity in over 80% of the patients. Various steroid-sparing agents have been tried, but robust scientific evidence of their efficacy and safety is still lacking. Tocilizumab, a monoclonal IL-6 receptor blocker, has shown promising results in a number of case series and is now being tested in a multi-centre randomized controlled trial. Other targeted treatments, such as the use of abatacept, are also now under investigation in GCA. The need for surgical treatment is rare and should ideally be performed in a quiescent phase of the disease. Not all patients follow the same course, but there are no valid biomarkers to assess therapy response. Monitoring of disease progress still relies on assessing clinical features and measuring inflammatory markers (C-reactive protein and erythrocyte sedimentation rate). Imaging techniques (e.g., ultrasound) are clearly important screening tools for aortic aneurysms and assessing patients with large-vessel involvement, but may also have an important role as biomarkers of disease activity over time or in response to therapy. Although GCA is the most common form of primary vasculitis, the optimal strategies for treatment and monitoring remain uncertain.

9.
Arthritis Rheumatol ; 67(9): 2447-56, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26016600

RESUMO

OBJECTIVE: Giant cell arteritis (GCA) is pathologically characterized by dysfunctional angiogenesis and inflammatory cell infiltration. Acute-phase serum amyloid A (A-SAA) is an acute-phase reactant, but is also produced at sites of inflammation and may contribute to vascular inflammation in atherosclerosis. This study was undertaken to examine the effect of A-SAA on proinflammatory pathways and angiogenesis in GCA, using a novel ex vivo temporal artery tissue explant model. METHODS: Serum A-SAA levels were measured by enzyme-linked immunosorbent assay (ELISA). Temporal artery explants and peripheral blood mononuclear cell (PBMC) cultures were established from patients with GCA. Temporal artery explant morphology, viability, and spontaneous release of proinflammatory mediators following 24-hour culture were assessed by hematoxylin and eosin, calcein viability staining, and ELISA. Temporal artery explants and PBMC cultures were stimulated with A-SAA (10 µg/ml), and interleukin-6 (IL-6), IL-8, vascular endothelial growth factor, Ang2, and matrix metalloproteinase 2 (MMP-2)/MMP-9 were quantified by ELISA and gelatin zymography. The effect of conditioned medium from temporal artery explants on angiogenesis was assessed using endothelial cell Matrigel tube-formation assays. Temporal artery explants were also embedded in Matrigel, and myofibroblast outgrowth was assessed. RESULTS: Serum A-SAA levels were significantly higher in GCA patients versus healthy controls (P < 0.0001). Intact tissue morphology, cell viability, and spontaneous cytokine secretion were demonstrated in temporal artery explants. A-SAA treatment induced a significant increase in the levels of IL-6 and IL-8 from temporal artery explants (P < 0.05) and IL-8 from PBMCs (P < 0.05) compared to basal conditions. Conditioned medium from A-SAA-treated explants significantly induced angiogenic tube formation (P < 0.05 versus basal controls). Finally, A-SAA induced myofibroblast outgrowth and MMP-9 activation. CONCLUSION: Our findings demonstrate a functional role for A-SAA in regulating temporal artery inflammation, angiogenesis, and invasion, all key processes in the pathogenesis of GCA.


Assuntos
Arterite de Células Gigantes/imunologia , Miofibroblastos/efeitos dos fármacos , Neovascularização Patológica/imunologia , Proteína Amiloide A Sérica/farmacologia , Artérias Temporais/efeitos dos fármacos , Proteínas da Fase Aguda/imunologia , Proteínas da Fase Aguda/farmacologia , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Feminino , Arterite de Células Gigantes/metabolismo , Humanos , Técnicas In Vitro , Inflamação/imunologia , Interleucina-6/imunologia , Interleucina-8/efeitos dos fármacos , Interleucina-8/imunologia , Leucócitos Mononucleares , Masculino , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/imunologia , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/imunologia , Pessoa de Meia-Idade , Proteína Amiloide A Sérica/imunologia , Artérias Temporais/imunologia , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/imunologia , Proteínas de Transporte Vesicular/efeitos dos fármacos , Proteínas de Transporte Vesicular/imunologia
10.
Arthritis Rheum ; 64(5): 1601-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22127978

RESUMO

OBJECTIVE: To examine the role of interferon regulatory factor 3 (IRF-3) in the regulation of interleukin-23 (IL-23) production in patients with systemic lupus erythematosus (SLE). METHODS: Bone marrow-derived macrophages were isolated from both wild-type and IRF3(-/-) C57BL/6 mice. These cells were stimulated with the Toll-like receptor 3 (TLR-3) agonist poly(I-C), and IL-23p19 cytokine levels were analyzed by enzyme-linked immunosorbent assay. IRF-3 binding to the IL-23p19 gene promoter region in monocytes from patients with SLE and healthy control subjects was analyzed by chromatin immunoprecipitation (ChIP) assay. Luciferase reporter gene assays were performed to identify key drivers of IL-23p19 promoter activity. TANK-binding kinase 1 (TBK-1) protein levels were determined by Western blotting. RESULTS: ChIP assays demonstrated that IRF-3 was stably bound to the human IL-23p19 promoter in monocytes; this association increased following TLR-3 stimulation. Patients with SLE demonstrated increased levels of IRF-3 bound to the IL-23p19 promoter compared with control subjects, which correlated with enhanced IL-23p19 production in monocytes from patients with SLE. Investigations of the TLR-3-driven responses in monocytes from patients with SLE revealed that TBK-1, which is critical for regulating IRF-3 activity, was hyperactivated in both resting and TLR-3-stimulated cells. CONCLUSION: Our results demonstrate for the first time that patients with SLE display enhanced IL-23p19 expression as a result of hyperactivation of TBK-1, resulting in increased binding of IRF-3 to the promoter. These findings provide novel insights into the molecular pathogenesis of SLE and the potential role for TLR-3 in driving this response.


Assuntos
Fator Regulador 3 de Interferon/metabolismo , Subunidade p19 da Interleucina-23/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Imunoprecipitação da Cromatina , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Fator Regulador 3 de Interferon/genética , Subunidade p19 da Interleucina-23/genética , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Poli I-C/farmacologia , Análise Serial de Proteínas/métodos , Ligação Proteica , Proteínas Serina-Treonina Quinases/farmacologia , Receptor 3 Toll-Like/imunologia
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