RESUMEN
The aim of this study was to assess the interrelation between vascular ultrasonography (US) findings, histopathological data, and the expression of selected dysregulated microRNAs (miRNAs) in giant cell arteritis (GCA). The study included data on the clinical parameters, US measurements, and temporal artery biopsies (TABs) of 46 treatment-naïve patients diagnosed with GCA and 22 age-matched non-GCA patient controls. We performed a comprehensive comparative and correlation analysis along with generation of receiver operating characteristic (ROC) curves to ascertain the diagnostic performance of US examination parameters and selected miRNAs for GCA diagnosis. We showed significant differences in the US-measured intima-media thickness of the temporal arteries, the presence of a halo sign, and the presence of luminal stenosis between GCA-positive/TAB-positive, GCA-positive/TAB-negative, and non-GCA patients. Correlation analysis revealed significant associations between several histopathological parameters, US-measured intima-media thickness, and the halo sign. We found that the significant overexpression of miR-146b-5p, miR-155-5p, miR-511-5p, and miR-21-5p, and the under-expression of the miR-143/145 cluster, miR-30a-5p, and miR-125a-5p, coincides and is associated with the presence of a halo sign in patients with GCA. Notably, we determined a high diagnostic performance of miR-146b-5p, miR-21-3p, and miR-21-5p expression profiles in discriminating GCA patients from non-GCA controls, suggesting their potential utilization as putative biomarkers of GCA. Taken together, our study provides an insight into the US-based diagnostic evaluation of GCA by revealing the complex interrelation of clearly defined image findings with underlying vascular immunopathology and altered arterial tissue-specific miRNA profiles.
Asunto(s)
Arteritis de Células Gigantes , MicroARNs , Arterias Temporales , Humanos , Biopsia , Grosor Intima-Media Carotídeo , Arteritis de Células Gigantes/diagnóstico por imagen , Arteritis de Células Gigantes/genética , Arteritis de Células Gigantes/patología , MicroARNs/genética , MicroARNs/metabolismo , Sensibilidad y Especificidad , Arterias Temporales/diagnóstico por imagen , Arterias Temporales/metabolismo , Arterias Temporales/patología , UltrasonografíaRESUMEN
AIM: To explore demographic characteristics, biopsy length, and blood biomarker performance in an Australian cohort of patients who have undergone temporal artery biopsy (TAB) for giant cell arteritis (GCA). METHODS: We extracted data on biopsies performed for GCA between January 2016 and December 2020 at public hospitals in Perth. Sensitivity, specificity, and area under the curve (AUC) were calculated for blood results. We evaluated the proportion of biopsies with post-fixation length less than 15 mm and explored several length associations. RESULTS: We retrospectively reviewed biopsies of 360 patients (65.8% female, mean age 72.1 years). Biopsy-positive patients were older (6.0 years, P < 0.01), and had higher C-reactive protein (CRP) (44.5 mg/L, P < 0.01), erythrocyte sedimentation rate (ESR) (18.9 mm/h, P < 0.01), and platelets (86.8 × 103 /µL, P < 0.01) compared with biopsy-negative patients. CRP and platelets had the highest AUCs at 0.76 and 0.71, respectively. Sensitivities for CRP and ESR were 96.2% and 91.5%, respectively. Specificities were comparatively low at 41.3% for CRP and 37.4% for ESR. The proportion of biopsies with sub-optimal length was 55.9% and this varied significantly by site (P < 0.01). Smaller sites performed worse, with a sub-optimal biopsy rate of 87% amongst the three smallest sites. CONCLUSION: ESR and CRP are helpful preliminary investigations, especially in identifying low-risk patients, but their specificity is limited. Smaller centers had a higher proportion of biopsies with sub-optimal length. Considering the importance of biopsy length for TAB diagnostic value, reviewing biopsy data may assist services in developing improvement strategies.
Asunto(s)
Arteritis de Células Gigantes , Humanos , Femenino , Anciano , Masculino , Arterias Temporales/química , Arterias Temporales/metabolismo , Arterias Temporales/patología , Estudios Retrospectivos , Australia Occidental , Australia , Biomarcadores , Biopsia/métodos , Proteína C-Reactiva/análisisRESUMEN
In this study, we explored expression of microRNA (miR), miR-target genes and matrix remodelling molecules in temporal artery biopsies (TABs) from treatment-naïve patients with giant cell arteritis (GCA, n = 41) and integrated these analyses with clinical, laboratory, ultrasound and histological manifestations of GCA. NonGCA patients (n = 4) served as controls. GCA TABs exhibited deregulated expression of several miRs (miR-21-5p, -145-5p, -146a-5p, -146b-5p, -155-5p, 424-3p, -424-5p, -503-5p), putative miR-target genes (YAP1, PELI1, FGF2, VEGFA, KLF4) and matrix remodelling factors (MMP2, MMP9, TIMP1, TIPM2) with key roles in Toll-like receptor signaling, mechanotransduction and extracellular matrix biology. MiR-424-3p, -503-5p, KLF4, PELI1 and YAP1 were identified as new deregulated molecular factors in GCA TABs. Quantities of miR-146a-5p, YAP1, PELI1, FGF2, TIMP2 and MMP9 were particularly high in histologically positive GCA TABs with occluded temporal artery lumen. MiR-424-5p expression in TABs and the presence of facial or carotid arteritis on ultrasound were associated with vision disturbances in GCA patients. Correlative analysis of miR-mRNA quantities demonstrated a highly interrelated expression network of deregulated miRs and mRNAs in temporal arteries and identified KLF4 as a candidate target gene of deregulated miR-21-5p, -146a-5p and -155-5p network in GCA TABs. Meanwhile, arterial miR and mRNA expression did not correlate with constitutive symptoms and signs of GCA, elevated markers of systemic inflammation nor sonographic characteristics of GCA. Our study provides new insights into GCA pathophysiology and uncovers new candidate biomarkers of vision impairment in GCA.
Asunto(s)
Regulación de la Expresión Génica , Redes Reguladoras de Genes , Arteritis de Células Gigantes/etiología , Arteritis de Células Gigantes/metabolismo , MicroARNs/genética , Interferencia de ARN , ARN Mensajero/genética , Arterias Temporales/metabolismo , Biomarcadores , Biopsia , Susceptibilidad a Enfermedades , Perfilación de la Expresión Génica , Arteritis de Células Gigantes/diagnóstico , Humanos , Inmunohistoquímica , Factor 4 Similar a Kruppel , Evaluación de Síntomas , Arterias Temporales/patología , UltrasonografíaRESUMEN
OBJECTIVE: Macrophages mediate inflammation, angiogenesis, and tissue destruction in giant cell arteritis (GCA). Serum levels of the macrophage-associated protein YKL-40 (chitinase 3-like protein 1), previously linked to angiogenesis and tissue remodeling, remain elevated in GCA despite glucocorticoid treatment. This study was undertaken to investigate the contribution of YKL-40 to vasculopathy in GCA. METHODS: Immunohistochemistry was performed on GCA temporal artery biopsy specimens (n = 12) and aortas (n = 10) for detection of YKL-40, its receptor interleukin-13 receptor α2 (IL-13Rα2), macrophage markers PU.1 and CD206, and the tissue-destructive protein matrix metalloproteinase 9 (MMP-9). Ten noninflamed temporal artery biopsy specimens served as controls. In vitro experiments with granulocyte-macrophage colony-stimulating factor (GM-CSF)- or macrophage colony-stimulating factor (M-CSF)-skewed monocyte-derived macrophages were conducted to study the dynamics of YKL-40 production. Next, small interfering RNA-mediated knockdown of YKL-40 in GM-CSF-skewed macrophages was performed to study its effect on MMP-9 production. Finally, the angiogenic potential of YKL-40 was investigated by tube formation experiments using human microvascular endothelial cells (HMVECs). RESULTS: YKL-40 was abundantly expressed by a CD206+MMP-9+ macrophage subset in inflamed temporal arteries and aortas. GM-CSF-skewed macrophages from GCA patients, but not healthy controls, released significantly higher levels of YKL-40 compared to M-CSF-skewed macrophages (P = 0.039). In inflamed temporal arteries, IL-13Rα2 was expressed by macrophages and endothelial cells. Functionally, knockdown of YKL-40 led to a 10-50% reduction in MMP-9 production by macrophages, whereas exposure of HMVECS to YKL-40 led to significantly increased tube formation. CONCLUSION: In GCA, a GM-CSF-skewed, CD206+MMP-9+ macrophage subset expresses high levels of YKL-40 which may stimulate tissue destruction and angiogenesis through IL-13Rα2 signaling. Targeting YKL-40 or GM-CSF may inhibit macrophages that are currently insufficiently suppressed by glucocorticoids.
Asunto(s)
Proteína 1 Similar a Quitinasa-3/metabolismo , Arteritis de Células Gigantes/patología , Subunidad alfa2 del Receptor de Interleucina-13/metabolismo , Macrófagos/patología , Neovascularización Patológica/patología , Arterias Temporales/patología , Aorta/metabolismo , Aorta/patología , Arteritis de Células Gigantes/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Factor Estimulante de Colonias de Macrófagos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Neovascularización Patológica/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Arterias Temporales/metabolismoRESUMEN
BACKGROUND: Giant cell arteritis (GCA) is a systemic vasculitis of large and medium vessels characterized by an inflammatory arterial infiltrate. GCA begins in the adventitia and leads to vascular remodeling by promoting proliferation of myofibroblasts in the intima. The morphology of the fibroblasts in the adventitia in GCA is unclear. Access to temporal artery biopsies allows morphological studies and evaluation of the microenvironment of the arterial wall. We evaluated the distribution of vascular fibroblasts and of markers of their activation in GCA. METHODS: Formalin-fixed paraffin-embedded tissue sections from 29 patients with GCA and 36 controls were examined. Immunohistochemistry was performed for CD90, vimentin, desmin, alpha-smooth muscle actin (ASMA), prolyl-4-hydroxylase (P4H), and myosin to evaluate the distribution of fibroblasts within the intima, media, and adventitia. RESULTS: Temporal arteries from patients with GCA showed increased levels of CD90, vimentin, and ASMA in the adventitia and intima compared to the controls. Desmin was expressed only in the media in both groups. P4H was expressed similarly in the adventitia and intima in the two groups. Adventitial and intimal CD90+ cells co-expressed P4H, ASMA, and myosin at a high level in GCA. CONCLUSION: The results suggest a role for adventitial fibroblasts in GCA. Inhibiting the differentiation of adventitial fibroblasts to myofibroblasts has therapeutic potential for GCA.
Asunto(s)
Fibroblastos/metabolismo , Arteritis de Células Gigantes/patología , Inmunohistoquímica/métodos , Arterias Temporales/patología , Actinas/metabolismo , Adventicia/metabolismo , Anciano , Biomarcadores/metabolismo , Biopsia , Estudios de Casos y Controles , Proliferación Celular , Desmina/metabolismo , Femenino , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/fisiopatología , Humanos , Masculino , Arterias Temporales/metabolismo , Antígenos Thy-1/metabolismo , Microambiente Tumoral , Túnica Íntima/metabolismo , Remodelación Vascular , Vimentina/metabolismoRESUMEN
Identifying comorbidities in polymyalgia rheumatica/giant cell arteritis (PMR/GCA) is crucial for patients' outcomes. The present study aimed to evaluate the impact of the inflammatory process and glucocorticoid treatment on aortic arterial stiffness and body composition in PMR/GCA. 77 patients with newly diagnosed PMR/GCA were treated with oral glucocorticoids and followed for 40 weeks. Aortic pulse wave velocity (PWV) was measured at baseline and during the follow-up period and compared to the results of temporal artery biopsy (TAB) and 18F-FDG PET/CT. Body composition was assessed by total body DXA at baseline and the end of the study. Of 77 patients (49 (63.6%) female, mean of age: (71.8 ± 8.0)), 64 (83.1%) had pure PMR, 10 (13.0%) concomitant PMR and GCA, and 3 (3.9%) pure GCA. Compared to baseline values, aortic PWV was initially decreased at week 16 (p = 0.010) and remained lower than baseline at week 28 (p = 0.002) and week 40 (p < 0.001), with no association with results of TAB and 18F-FDG PET/CT. Aortic PWV was significantly associated with age, male gender, left systolic and diastolic blood pressure, right diastolic blood pressure, and CRP. Total bone mineral content (BMC) was decreased in both genders (p < 0.001), while fat mass (FM) was significantly increased (p < 0.001). However, lean body mass did not significantly change during the study. Changes in FM were correlated with cumulative prednisolone dose (rho: 0.26, p = 0.031). Glucocorticoid treatment of patients with PMR/GCA had several prognostic impacts. Arterial stiffness was decreased due either to the treatment or a reduction in the inflammatory load. Additionally, treatment led to changes in body composition, including a decrease in BMC and FM excess.
Asunto(s)
Aorta/efectos de los fármacos , Arteritis de Células Gigantes/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Polimialgia Reumática/tratamiento farmacológico , Prednisolona/uso terapéutico , Tejido Adiposo Blanco/diagnóstico por imagen , Tejido Adiposo Blanco/efectos de los fármacos , Factores de Edad , Anciano , Anciano de 80 o más Años , Aorta/metabolismo , Biopsia , Presión Sanguínea/efectos de los fármacos , Composición Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Proteína C-Reactiva/metabolismo , Femenino , Fluorodesoxiglucosa F18/metabolismo , Arteritis de Células Gigantes/sangre , Arteritis de Células Gigantes/diagnóstico por imagen , Arteritis de Células Gigantes/patología , Humanos , Estudios Longitudinales , Masculino , Polimialgia Reumática/sangre , Polimialgia Reumática/diagnóstico por imagen , Polimialgia Reumática/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Análisis de la Onda del Pulso , Factores Sexuales , Arterias Temporales/efectos de los fármacos , Arterias Temporales/metabolismo , Rigidez Vascular/efectos de los fármacosRESUMEN
Giant cell arteritis (GCA) is a granulomatous systemic vasculitis of large- and medium-sized arteries that affects the elderly. In recent years, advances in diagnostic imaging have revealed a greater degree of large vessel involvement than previously recognized, distinguishing classical cranial- from large vessel (LV)- GCA. GCA often co-occurs with the poorly understood inflammatory arthritis/bursitis condition polymyalgia rheumatica (PMR) and has overlapping features with other non-infectious granulomatous vasculitides that affect the aorta, namely Takayasu Arteritis (TAK) and the more recently described clinically isolated aortitis (CIA). Here, we review the literature focused on the immunopathology of GCA on the background of the three settings in which comparisons are informative: LV and cranial variants of GCA; PMR and GCA; the three granulomatous vasculitides (GCA, TAK, and CIA). We discuss overlapping and unique features between these conditions across clinical presentation, epidemiology, imaging, and conventional histology. We propose a model of GCA where abnormally activated circulating cells, especially monocytes and CD4+ T cells, enter arteries after an unknown stimulus and cooperate to destroy it and review the evidence for how this mechanistically occurs in active disease and improves with treatment.
Asunto(s)
Aorta/patología , Arteritis de Células Gigantes/patología , Arteritis de Takayasu/patología , Arterias Temporales/patología , Animales , Aorta/inmunología , Aorta/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Arteritis de Células Gigantes/epidemiología , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Arteritis de Takayasu/epidemiología , Arteritis de Takayasu/inmunología , Arteritis de Takayasu/metabolismo , Arterias Temporales/inmunología , Arterias Temporales/metabolismoRESUMEN
Objectives: The aim of this study was to quantitatively assess distinct immune cell subsets comprising inflammatory infiltrate in temporal artery biopsies (TABs) from patients with giant cell arteritis (GCA), and to link the obtained histopathological data with expression profiles of immune-related microRNAs (miRNAs). Methods: The study included 68 formalin-fixed, paraffin-embedded TABs from treatment-naïve patients, including 30 histologically positive GCA and 16 negative GCA TABs, and 22 control non-GCA TABs. Quantitative assessment of histological parameters was performed using histopathological and immunohistochemical techniques. miRNA expression analysis was performed by quantitative real-time PCR. Results: Intense transmural mononuclear inflammatory infiltrates in TAB-positive GCA arteries were predominantly composed of CD3+, CD4+ and CD8+ T lymphocytes, and CD68+ macrophages, accompanied by a strong nuclear overexpression of the nuclear factor of activated T cells, cytoplasmic 1 (NFATC) in the lymphocyte infiltrate fraction. Furthermore, TAB-positive GCA arteries were characterized by significant overexpression of nine pro-inflammatory miRNAs (miR-132-3p/-142-3p/-142-5p/-155-5p/-210-3p/-212-3p/-326/-342-5p/-511-5p) and a significant under-expression of six regulatory immune-related miRNAs (miR-30a-5p/-30b-5p/-30c-5p/-30d-5p/-30e-5p/-124-3p), whose expression levels significantly associated with most evaluated histopathological parameters. Notably, we revealed miR-132-3p/-142-3p/-142-5p/-155-5p/-212-3p/-511-5p as major promoters of arterial inflammation and miR-30a-5p/-30c-5p/-30d-5p as putative regulators of NFATC signaling in TAB-positive GCA arteries. Conclusion: Overall, we demonstrated that an altered arterial tissue-specific pro-inflammatory miRNA signature favors enhanced T cell-driven inflammation and macrophage activity in TAB-positive GCA arteries. Moreover, dysregulation of several immune-related miRNAs seems to contribute crucially to GCA pathogenesis, through impairing their regulatory activity towards T cell-mediated immune responses driven by the calcineurin (CaN)/NFAT signaling pathway, indicating their therapeutic, diagnostic and prognostic potential.
Asunto(s)
Arteritis de Células Gigantes/genética , Macrófagos/metabolismo , MicroARNs/genética , Linfocitos T/metabolismo , Arterias Temporales/metabolismo , Transcriptoma , Anciano , Anciano de 80 o más Años , Biopsia , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/patología , Humanos , Macrófagos/inmunología , Masculino , MicroARNs/inmunología , MicroARNs/metabolismo , Persona de Mediana Edad , Fenotipo , Linfocitos T/inmunología , Arterias Temporales/inmunología , Arterias Temporales/patologíaRESUMEN
Giant cell arteritis (GCA) is a common form of primary systemic vasculitis in adults, with no reliable indicators of prognosis or treatment responses. We used single cell technologies to comprehensively map immune cell populations in the blood of patients with GCA and identified the CD66b+CD15+CD10lo/-CD64- band neutrophils and CD66bhiCD15+CD10lo/-CD64+/bright myelocytes/metamyelocytes to be unequivocally associated with both the clinical phenotype and response to treatment. Immature neutrophils were resistant to apoptosis, remained in the vasculature for a prolonged period of time, interacted with platelets, and extravasated into the tissue surrounding the temporal arteries of patients with GCA. We discovered that immature neutrophils generated high levels of extracellular reactive oxygen species, leading to enhanced protein oxidation and permeability of endothelial barrier in an in vitro coculture system. The same populations were also detected in other systemic vasculitides. These findings link functions of immature neutrophils to disease pathogenesis, establishing a clinical cellular signature of GCA and suggesting different therapeutic approaches in systemic vascular inflammation.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Arteritis de Células Gigantes/metabolismo , Neutrófilos/inmunología , Vasculitis Sistémica/inmunología , Enfermedades Vasculares/metabolismo , Anciano , Antígenos CD/metabolismo , Antígenos de Superficie/inmunología , Antígenos de Superficie/metabolismo , Apoptosis/genética , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Moléculas de Adhesión Celular/metabolismo , Línea Celular , Linaje de la Célula/genética , Técnicas de Cocultivo , Femenino , Proteínas Ligadas a GPI/metabolismo , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/patología , Células Precursoras de Granulocitos/metabolismo , Células Precursoras de Granulocitos/patología , Humanos , Recuento de Leucocitos , Antígeno Lewis X/metabolismo , Masculino , Persona de Mediana Edad , Neprilisina/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patología , Oxidación-Reducción , Pronóstico , Especies Reactivas de Oxígeno/efectos adversos , Especies Reactivas de Oxígeno/metabolismo , Análisis de la Célula Individual , Vasculitis Sistémica/sangre , Vasculitis Sistémica/metabolismo , Vasculitis Sistémica/patología , Arterias Temporales/inmunología , Arterias Temporales/metabolismo , Arterias Temporales/patología , Enfermedades Vasculares/sangre , Enfermedades Vasculares/inmunología , Enfermedades Vasculares/patologíaRESUMEN
OBJECTIVES: To identify dysregulated microRNAs (miRNAs) and their gene targets in temporal arteries from GCA patients, and determine their association with GCA pathogenesis and related arterial wall remodelling. METHODS: We included 93 formalin-fixed, paraffin-embedded temporal artery biopsies (TABs) from treatment-naïve patients: 54 positive and 17 negative TABs from clinically proven GCA patients, and 22 negative TABs from non-GCA patients. miRNA expression analysis was performed with miRCURY LNA miRNome Human PCR Panels and quantitative real-time PCR. miRNA target gene prediction and pathway enrichment analysis was performed using the miRDB and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) databases, respectively. RESULTS: Dysregulation of 356 miRNAs was determined in TAB-positive GCA arteries, among which 78 were significantly under-expressed and 22 significantly overexpressed above 2-fold, when compared with non-GCA controls. Specifically, TAB-positive GCA arteries were characterized by a significant overexpression of 'pro-synthetic' (miR-21-3p/-21-5p/-146a-5p/-146b-5p/-424-5p) and under-expression of 'pro-contractile' (miR-23b-3p/-125a-5p/-143-3p/-143-5p/-145-3p/-145-5p/-195-5p/-365a-3p) vascular smooth muscle cell phenotype-associated regulatory miRNAs. These miRNAs targeted gene pathways involved in the arterial remodelling and regulation of the immune system, and their expression correlated with the extent of intimal hyperplasia in TABs from GCA patients. Notably, the expression of miR-21-3p/-21-5p/-146a-5p/-146b-5p/-365a-3p differentiated between TAB-negative GCA arteries and non-GCA temporal arteries, revealing these miRNAs as potential biomarkers of GCA. CONCLUSION: Identification of dysregulated miRNAs involved in the regulation of the vascular smooth muscle cell phenotype and intimal hyperplasia in GCA arterial lesions, and detection of their expression profiles, enables a novel insight into the complexity of GCA pathogenesis and implies their potential utilization as diagnostic and prognostic biomarkers of GCA.
Asunto(s)
Arteritis de Células Gigantes/genética , MicroARNs/genética , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Arterias Temporales/metabolismo , Túnica Íntima/patología , Remodelación Vascular/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Redes Reguladoras de Genes , Humanos , Hiperplasia , Masculino , Persona de Mediana Edad , Músculo Liso Vascular/citología , FenotipoRESUMEN
OBJECTIVES: To investigate whether expression of pro-inflammatory cytokines in the temporal artery may aid in differentiating biopsy-negative giant cell arteritis (GCA) patients from those with a negative biopsy without arteritis. METHODS: We investigated cytokine expression in temporal artery biopsy (TAB) of 54 consecutive patients: 17 with biopsy-positive GCA, 17 with biopsy-negative GCA, and 20 biopsy-negative without arteritis. We compared the expression rate of the following cytokines among these 3 groups of patients: interleukin-6 (IL-6), osteopontin (OPN), COX-2, and TNF-α. RESULTS: IL-6 was expressed in 13 (76%) patients with biopsy-positive GCA, 0 patients in biopsy-negative GCA, and 1(5%) patient with biopsy-negative without arteritis (p<0.05). OPN was expressed in 17 (100%) patients with biopsy-positive GCA, 2 (12%) patients with biopsy-negative GCA, and 0 patients with biopsy-negative without arteritis (p<0.05). Cox-2 was expressed in 16 (94%) patients with biopsy-positive GCA, 0 patients with biopsy-negative GCA, and 3 (15%) patients with biopsy-negative without arteritis (p<0.05). TNF- α was expressed in 17 (100%) patients with biopsy-positive GCA, 14 (82%) patients with biopsy-negative GCA, and 8 (40%) patients with biopsy-negative without arteritis (p<0.05). CONCLUSIONS: IL-6, COX-2 and OPN are significantly more expressed in the presence of a positive TAB compared to a negative TAB. TNF-α is significantly more expressed in GCA patients compared to non-GCA patients. Thus, TNF-α expression may suggest a diagnosis of GCA despite a negative TAB. Further larger studies are needed to confirm these findings.
Asunto(s)
Citocinas/metabolismo , Arteritis de Células Gigantes , Arterias Temporales , Anciano , Biopsia , Citocinas/biosíntesis , Femenino , Arteritis de Células Gigantes/metabolismo , Arteritis de Células Gigantes/patología , Humanos , Masculino , Arterias Temporales/metabolismo , Arterias Temporales/patología , Factor de Necrosis Tumoral alfaRESUMEN
OBJECTIVES: To evaluate whether interleukin-6 expression in the temporal arteries could be a more sensitive marker of active inflammation compared to the presence of an inflammatory infiltrate. METHODS: Sixty-three formalin-fixed, paraffin-embedded temporal artery biopsies performed between 2009 and 2012 from 32 patients with biopsy-proven giant cell arteritis, 8 patients with a negative biopsy but with a final diagnosis of giant cell arteritis, and 23 controls (patients with an initial clinical suspicion of giant cell arteritis in whom an alternative diagnosis subsequently was made) were examined. Biopsy specimens showing a transmural inflammatory infiltrate were considered positive for giant cell arteritis. Immunochemistry was performed to detect interleukin-6 in the temporal artery specimens. Slides of temporal artery biopsies were independently assessed by five readers. Interleukin-6 expression was graded as 0 (absent), 1 (mild), 2 (moderate) and 3 (marked). We considered anti-IL-6 staining positive if staining was of grade 2 or 3. RESULTS: Temporal artery biopsies specimens from patients with biopsy-proven giant cell arteritis, biopsy-negative giant cell arteritis and controls were positive for anti-interleukin-6 staining in 59%, 13% and 48% of cases, respectively. CONCLUSIONS: Interleukin-6 expression does not increase the sensitivity of temporal artery biopsy in patients with giant cell arteritis who have morphologically uninflamed arteries.
Asunto(s)
Biomarcadores/análisis , Arteritis de Células Gigantes , Interleucina-6/análisis , Arterias Temporales , Anciano , Arterias , Biopsia , Femenino , Humanos , Masculino , Arterias Temporales/metabolismo , Arterias Temporales/patologíaRESUMEN
PURPOSE: To provide quantitative evidence linking the CD68 (cluster of differentiation 68)+ macrophage marker found on temporal artery biopsies (TABs) with disease prognosis. DESIGN: Retrospective, cross-sectional study. METHODS: We examined 42 consecutive patients who had undergone unilateral TABs at a single hospital in 2015. Clinical data, laboratory data, and histopathologic features of TABs were recorded. Inclusion criteria were clinical diagnosis of giant cell arteritis (GCA) with TAB performed at the same center. CD68 immunohistochemistry was used to label macrophages in the TABs. Primary outcome was multiple logistic regression and bivariate comparisons to measure the association between CD68+ cells per histologic section with placement on immunomodulatory therapy (IMT). RESULTS: Twenty seven patients were female (64%), with a mean age of 72 (standard deviation [SD.] ±7.7). Eleven patients (26%) were placed on IMT, 17 (40%) had disease recurrence during steroid taper, and 25 (60%) were referred to rheumatology. Of 42 biopsies, 35 underwent staining with CD68 to confirm active inflammation in suspicious, but not diagnostic, specimens. Patients eventually placed on IMT had increased CD68+ cells per slice compared to those not on IMT (median 5.00 [25th-75th quartile 2.00-7.15] vs 1.21 [0.38-2.57], P = .031, respectively). A receiver operating characteristic (ROC) curve demonstrates that 2.17 CD68+ cells/slice predicts placement on IMT with an odds ratio of 1.54 (95% confidence interval 1.02-2.33, P = .038). CONCLUSIONS: Patients refractory to initial steroid tapers and those eventually placed on IMT had increased CD68 cells per section. CD68+ macrophages and their location on the internal elastic lamina may predict disease severity in patients with presumed GCA. Our results suggest that this marker may expedite patient triaging to alternate treatment to the usual steroid therapy.
Asunto(s)
Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Biomarcadores/metabolismo , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/metabolismo , Arterias Temporales/metabolismo , Anciano , Biopsia , Estudios Transversales , Femenino , Arteritis de Células Gigantes/tratamiento farmacológico , Humanos , Inmunomodulación , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Pronóstico , Curva ROC , Estudios Retrospectivos , Arterias Temporales/patologíaRESUMEN
OBJECTIVE: To evaluate whether CD3 staining performed routinely on temporal artery biopsy specimens might improve the sensitivity of temporal artery biopsy in patients with biopsy-negative GCA. METHODS: Two hundred and seventy biopsies were considered for this study, stained with haematoxylin and eosin and with an anti-CD3 antibody. RESULTS: The addition of CD3 staining modified the sensibility and the specificity of the histologic examination in 89.47 and 95.00%, respectively, with a positive and negative predictive values of 97.00 and 79.78% . CONCLUSION: The addition of CD3 immunostaining to the classic histologic evaluation is accompanied by a significant increase in the sensibility with a comparable specificity.
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Complejo CD3/metabolismo , Arteritis de Células Gigantes/diagnóstico , Inmunohistoquímica/métodos , Arterias Temporales/patología , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Biopsia , Complejo CD3/inmunología , Femenino , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Fotomicrografía , Curva ROC , Estudios Retrospectivos , Arterias Temporales/metabolismoRESUMEN
Objectives: Takayasu arteritis (TA) and GCA are large-vessel vasculitides characterized by vascular remodelling involving endothelial cells (ECs) and vascular smooth muscle cells. Mammalian target of rapamycin (mTOR) pathway has been involved in vascular remodelling. We hypothesized that the mTOR pathway was involved in the pathogenesis of large-vessel vasculitis. Methods: We used IF analysis on aortic and temporal artery biopsies from patients with TA and GCA to assess the involvement of the mTOR pathway and searched for antibodies targeting ECs in serum by IIF and cellular ELISA. We evaluated in vitro the effect of purified IgG from patients on mTOR pathway activation and cell proliferation. Results: IF analyses on tissues revealed that both mTORC1 and mTORC2 are activated specifically in ECs from TA patients but not in ECs from GCA patients and healthy controls (HCs). Using IIF and ELISA, we observed higher levels of antibodies binding to ECs in TA patients compared with GCA patients and HCs. Using western blot, we demonstrated that purified IgG from TA patients caused mTORC1 activation in ECs, whereas this effect was not observed with purified IgG from GCA patients or HCs. Purified IgG from TA patients induced a significant EC proliferation compared with to GCA and HC IgG, and this effect was decreased after EC exposure with sirolimus, a specific mTOR inhibitor and PI3K inhibitor. Conclusion: Our results suggest that antibodies targeting ECs drive endothelial remodelling in TA through activation of the mTOR pathway, but not in GCA. Inhibition of the mTOR pathway could represent a therapeutic option in TA.
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Anticuerpos/inmunología , Células Endoteliales/metabolismo , Inmunoglobulina G/sangre , Serina-Treonina Quinasas TOR/metabolismo , Arteritis de Takayasu/metabolismo , Arterias Temporales/fisiopatología , Remodelación Vascular , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos/sangre , Western Blotting , Supervivencia Celular , Células Cultivadas , Células Endoteliales/inmunología , Células Endoteliales/patología , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/inmunología , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Serina-Treonina Quinasas TOR/inmunología , Arteritis de Takayasu/patología , Arteritis de Takayasu/fisiopatología , Arterias Temporales/metabolismo , Arterias Temporales/patología , Adulto JovenRESUMEN
Objectives: GCA is characterized by arterial remodelling driven by inflammation. IL-22 is an attractive cytokine which acts at the crosstalk between immune and stromal cells. We hypothesized that IL-22 might be induced in GCA and might be involved in disease pathogenesis. Methods: Patients subjected to temporal artery biopsies (TABs) naïve from therapy were enrolled: 27 biopsy-proven GCA, 8 biopsy-negative GCA, 21 biopsy-negative non-GCA patients. Expression of IL-22 was determined in TABs by immunohystochemistry, in plasma by ELISA, in peripheral blood mononuclear cells by real-time PCR and flow cytometry. Effects of IL-22 on viability and gene expression of primary cultures obtained from TABs were also evaluated. Results: Inflamed TABs from GCA patients showed a higher expression of IL-22 and IL-22 specific receptor subunit (IL-22R1) than non-inflamed TABs. IL-22 was expressed in infiltrating immune cells and spindle shaped cells, IL-22R1 was expressed in endothelial cells. Patients with biopsy-proven GCA showed increased levels of IL-22 in plasma than patients with biopsy-negative GCA, without GCA and healthy subjects. Peripheral blood mononuclear cells from GCA patients expressed higher IL-22 transcript than healthy subjects. After stimulation in vitro with phorbol 12-myristate 13-acetate and ionomycin, the frequencies of Th22 and IL-22+ CD4+ lymphocytes were similar between patients with and without GCA. Treatment with IL-22 of primary cultures obtained from TABs increased cell viability under stress conditions and expression of B-cell activating factor. Conclusion: IL-22 is increased in patients with GCA and affects viability and gene expression of arterial cells, supporting a potential role in disease pathogenesis.
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Arteritis de Células Gigantes/metabolismo , Interleucinas/metabolismo , Arterias Temporales/metabolismo , Anciano , Anciano de 80 o más Años , Linfocitos T CD4-Positivos , Ionóforos de Calcio/farmacología , Carcinógenos/farmacología , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Arteritis de Células Gigantes/genética , Humanos , Inmunohistoquímica , Técnicas In Vitro , Interleucinas/sangre , Interleucinas/genética , Ionomicina/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Acetato de Tetradecanoilforbol/farmacología , Interleucina-22RESUMEN
In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), granular osmiophilic material (GOM) may play some roles in inducing cerebrovascular events. To elucidate the pathogenesis of CADASIL, we used laser microdissection and liquid chromatography-tandem mass spectrometry to analyze cerebrovascular lesions of patients with CADASIL for GOM. The analyses detected serum amyloid P component (SAP), annexin A2, and periostin as the proteins with the largest increase in the samples, which also demonstrated NOTCH3. For the three proteins, anti-human SAP antibody had the strongest reaction in the lesions where the anti-human NOTCH3 antibody showed positive staining. Moreover, immunofluorescence staining with the two antibodies clearly showed co-localization of SAP and NOTCH3. mRNA analyses indicated no positive SAP expression in the brain materials, which suggested that the source of SAP found in the GOM was only the liver. A solid phase enzyme-linked immunosorbent assay confirmed the binding of SAP with NOTCH3. Serum SAP concentrations were neither up-regulated nor down-regulated in CADASIL patients, when compared with those in control subjects. SAP may play an important role in GOM formation although precise mechanisms remain to be elucidated.
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CADASIL/metabolismo , CADASIL/patología , Componente Amiloide P Sérico/biosíntesis , Arterias Temporales/metabolismo , Arterias Temporales/patología , Anciano , Anciano de 80 o más Años , CADASIL/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptor Notch3/análisis , Receptor Notch3/biosíntesis , Receptor Notch3/genética , Componente Amiloide P Sérico/análisis , Componente Amiloide P Sérico/genéticaRESUMEN
Giant cell arteritis is the most common primary vasculitis of the elderly. The acute complications of untreated giant cell arteritis, such as vision loss or occasionally stroke, can be devastating. The diagnosis is, however, not altogether straightforward due to variable sensitivities of the temporal artery biopsy as a reference diagnostic test. In this review, we discuss the increasing role of imaging in the diagnosis of giant cell arteritis. Glucocorticoid treatment is the backbone of therapy, but it is associated with significant adverse effects. A less toxic alternative is required. Conventional and novel immunosuppressive agents have only demonstrated modest effects in a subgroup of steroid refractory Giant cell arteritis due to the different arms of the immune system at play. However, recently a study of interleukin-6 blockade demonstrated benefits of giant cell arteritis. The current status of these immunosuppressive agents and novel therapies are also discussed in this review.
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Arteritis de Células Gigantes/diagnóstico por imagen , Arteritis de Células Gigantes/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Esteroides/uso terapéutico , Arterias Temporales/diagnóstico por imagen , Animales , Biopsia , Ensayos Clínicos como Asunto/métodos , Arteritis de Células Gigantes/metabolismo , Glucocorticoides/uso terapéutico , Humanos , Arterias Temporales/metabolismoRESUMEN
AIMS: Intracranial aneurysms (IAs) express a variety of differentially expressed genes when compared to the normal artery. The aim of this study was to evaluate the expression level of a few genes in the aneurysm wall and to correlate them with various clinicoradiological factors. MATERIALS AND METHODS: The mRNA level of collagen 1A2 (COL1A2), tissue inhibitor of metalloproteinase 4 (TIMP4), and cathepsin B (CTSB) genes were studied in 23 aneurysmal walls and 19 superficial temporal arteries harvested from 23 patients undergoing clipping of IAs, by real-time polymerase chain reaction method. RESULTS: The mean fold change of COL1A2 gene between the aneurysm sample and the superficial temporal artery (STA) sample was 2.46 ± 0.12, that of TIMP4 gene was 0.31 ± 0, and that of CTSB gene was 31.47 ± 39.01. There was a positive correlation of TIMP4 expression level with maximum diameter of aneurysm (P = 0.008) and fundus of aneurysm (P = 0.012). The mean fold change of CTSB of patients who had preoperative hydrocephalus in the computed tomogram (CT) scan of the head at admission was 56.16 and that of the patients who did not have hydrocephalus was 13.51 (P = 0.008). The mean fold change of CTSB of patients who developed fresh postoperative deficits or worsening of the preexisting deficits was 23.64 and that of the patients who did not develop was 42.22 (P = 0.039). CONCLUSIONS: COL1A2 gene and CTSB genes were overexpressed, and TIMP4 gene was underexpressed in the aneurysmal sac compared to STA and their expression levels were associated with a few clinicoradiological factors.
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Catepsina B/metabolismo , Colágeno Tipo I/metabolismo , Aneurisma Intracraneal/metabolismo , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Catepsina B/genética , Colágeno Tipo I/genética , Expresión Génica , Humanos , Aneurisma Intracraneal/genética , Arterias Temporales/metabolismo , Inhibidores Tisulares de Metaloproteinasas/genética , Inhibidor Tisular de Metaloproteinasa-4RESUMEN
18F-FDG PET/CT imaging is useful in patients with fever of unknown origin and can detect giant cell arteritis in extracranial large arteries. However, it is usually assumed that temporal arteries cannot be visualized with a PET/CT scanner due to their small diameter. Three patients with clinical symptoms of temporal arteritis were examined using a standard whole body PET/CT protocol (skull base - mid thighs) followed by a head PET/CT scan using the brain protocol. High 18F-FDG uptake in the aorta and some arterial branches were detected in all 3 patients with the whole body protocol. Using the brain protocol, head imaging led to detection of high 18F-FDG uptake in temporal arteries as well as in their branches (3 patients), in occipital arteries (2 patients) and also in vertebral arteries (3 patients).