scholarly journals Blocking interferon γ reduces expression of chemokines CXCL9, CXCL10 and CXCL11 and decreases macrophage infiltration in ex vivo cultured arteries from patients with giant cell arteritis

2015 ◽  
Vol 75 (6) ◽  
pp. 1177-1186 ◽  
Author(s):  
Marc Corbera-Bellalta ◽  
Ester Planas-Rigol ◽  
Ester Lozano ◽  
Nekane Terrades-García ◽  
Marco A Alba ◽  
...  
Keyword(s):  
Giant Cell Arteritis ◽  
Giant Cell ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Selective Reduction ◽  
Temporal Artery ◽  
Interferon Γ ◽  
Peripheral Blood Mononuclear ◽  
Temporal Arteries ◽  
Infiltrating Cells

BackgroundInterferon γ (IFNγ) is considered a seminal cytokine in the pathogenesis of giant cell arteritis (GCA), but its functional role has not been investigated. We explored changes in infiltrating cells and biomarkers elicited by blocking IFNγ with a neutralising monoclonal antibody, A6, in temporal arteries from patients with GCA.MethodsTemporal arteries from 34 patients with GCA (positive histology) and 21 controls were cultured on 3D matrix (Matrigel) and exposed to A6 or recombinant IFNγ. Changes in gene/protein expression were measured by qRT-PCR/western blot or immunoassay. Changes in infiltrating cells were assessed by immunohistochemistry/immunofluorescence. Chemotaxis/adhesion assays were performed with temporal artery-derived vascular smooth muscle cells (VSMCs) and peripheral blood mononuclear cells (PBMCs).ResultsBlocking endogenous IFNγ with A6 abrogated STAT-1 phosphorylation in cultured GCA arteries. Furthermore, selective reduction in CXCL9, CXCL10 and CXCL11 chemokine expression was observed along with reduction in infiltrating CD68 macrophages. Adding IFNγ elicited consistent opposite effects. IFNγ induced CXCL9, CXCL10, CXCL11, CCL2 and intracellular adhesion molecule-1 expression by cultured VSMC, resulting in increased PBMC chemotaxis/adhesion. Spontaneous expression of chemokines was higher in VSMC isolated from GCA-involved arteries than in those obtained from controls. Incubation of IFNγ-treated control arteries with PBMC resulted in adhesion/infiltration by CD68 macrophages, which did not occur in untreated arteries.ConclusionsOur ex vivo system suggests that IFNγ may play an important role in the recruitment of macrophages in GCA by inducing production of specific chemokines and adhesion molecules. Vascular wall components (ie, VSMC) are mediators of these functions and may facilitate progression of inflammatory infiltrates through the vessel wall.

Interleukin 12 and interleukin 23 play key pathogenic roles in inflammatory and proliferative pathways in giant cell arteritis

2018 ◽  
Vol 77 (12) ◽  
pp. 1815-1824 ◽  
Author(s):  
Richard Conway ◽  
Lorraine O’Neill ◽  
Geraldine M McCarthy ◽  
Conor C Murphy ◽  
Aurelie Fabre ◽  
...  
Keyword(s):  
Gene Expression ◽  
Giant Cell Arteritis ◽  
Giant Cell ◽  
Ex Vivo ◽  
Inflammatory Cells ◽  
Temporal Artery ◽  
Interferon Γ ◽  
Interleukin 12 ◽  
Peripheral Blood Mononuclear ◽  
Interleukin 23

ObjectivesThe 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.MethodsIL-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.ResultsImmunohistochemistry 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.ConclusionIL-12 and IL-23 play central and distinct roles in stimulating inflammatory and proliferative pathways relevant to GCA pathogenesis.

The sensitivity of temporal artery biopsy in the detection of giant cell arteritis is independent of tissue length

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S28-S29
Author(s):  
H J Hurley ◽  
P Q Deb
Keyword(s):  
Giant Cell Arteritis ◽  
Giant Cell ◽  
Average Length ◽  
Statistical Significance ◽  
Temporal Artery ◽  
Temporal Artery Biopsy ◽  
Temporal Arteries ◽  
Biopsy Specimens ◽  
Two Samples ◽  
Left And Right

Abstract Introduction/Objective Giant cell arteritis (GCA) is the most common vasculitis of the elderly, and the most common primary systemic vasculitis overall, with an annual incidence of 200/million. The long term sequelae, namely vision loss and stroke, are permanent and devastating. While GCA is often treated empirically based on clinical presentation, panarteritis on temporal artery biopsy is required for diagnosis. However, these biopsies have the tendency to be falsely negative due to skip lesions, a common feature of GCA. Therefore, we set out to determine whether longer biopsy specimens were more sensitive in the detection of GCA. Methods/Case Report A census of temporal artery biopsies performed with the indication of clinical symptoms of GCA was taken at our institution. The patient age, sex, biopsy laterality, biopsy length, and pathological diagnosis were recorded for each cataloged sample. Statistical significance of difference in biopsy length was tested using an unpaired t-test in R 4.1.0. Results (if a Case Study enter NA) A total of 114 temporal artery specimens were biopsied from 94 different patients with the indication of GCA and assigned a definitive positive or negative diagnosis. Of the 94 patients, 54 were female and 40 were male. Of the total pathological specimens, 11 were positive and 103 were negative. The overall average length of biopsy specimens was 2.13 cm with a standard deviation of 0.65 cm. The average positive biopsy was 2.26 cm long, and the average negative was 2.12 cm, an insignificant difference (0.14 cm, t = 0.7, p = 0.43). In 25 patients, biopsies were taken from both the left and right temporal arteries. Of those patients, 2 were positive for GCA and the remaining 23 were negative. Interestingly, the biopsy result in every case was identical between the left and right samples; we found no instances of pathological evidence of GCA in only one of the two samples from the same patient. Conclusion According to data taken at our institution, there is no indication to lengthen the biopsy requirements from the existing 1.5 cm. However, we have demonstrated evidence that it may be unnecessary to biopsy both temporal arteries in a single patient. Larger studies would be required to confirm our findings.

Increased expression of the endothelin system in arterial lesions from patients with giant-cell arteritis: association between elevated plasma endothelin levels and the development of ischaemic events

2009 ◽  
Vol 69 (2) ◽  
pp. 434-442 ◽  
Author(s):  
E Lozano ◽  
M Segarra ◽  
M Corbera-Bellalta ◽  
A García-Martínez ◽  
G Espígol-Frigolé ◽  
...  
Keyword(s):  
Western Blot ◽  
Giant Cell Arteritis ◽  
Giant Cell ◽  
Protein Level ◽  
Messenger Rna ◽  
Tissue Concentration ◽  
Temporal Artery ◽  
Glucocorticoid Treatment ◽  
Temporal Arteries ◽  
Endothelin System

Objective:Approximately 15–20% of patients with giant-cell arteritis (GCA) develop ischaemic complications often preceded by transient ischaemia. The expression of the endothelin (ET) system in GCA lesions was investigated to assess its relationship with the development of ischaemic complications.Methods:Plasma ET-1 was quantified by immunoassay in 61 patients with biopsy-confirmed GCA and 16 healthy donors. ET-1, endothelin-converting enzyme (ECE-1) and endothelin receptor (ETAR and ETBR) messenger RNA were measured by real-time quantitative reverse transcriptase–PCR in temporal arteries from 35 of these patients and 19 control arteries. Proteins were measured by immunoassay and Western blot.Results:ET-1 concentration was increased at the protein level in temporal artery samples from GCA patients compared with controls (0.98 (SEM 0.32) vs 0.28 (SEM 0.098) fmol/mg, p = 0.028). ECE-1, ETAR and ETBR/actin ratios (Western blot) were also significantly higher in GCA patients. Intriguingly, mRNA expression of ET-1, ECE-1 and both receptors was significantly reduced in GCA lesions compared with control arteries. When investigating mechanisms underlying these results, platelet-derived growth factor and IL-1β, present in GCA lesions, were found to downregulate ET-1 mRNA in cultured human temporal artery-derived smooth muscle cells. Glucocorticoid treatment for 8 days did not result in significantly decreased endothelin tissue concentration (0.87 (SEM 0.2) vs 0.52 (SEM 0.08); p = 0.6). Plasma endothelin concentrations were higher in patients with ischaemic complications (1.049 (SEM 0.48) vs 1.205 (SEM 0.63) pg/ml, p = 0.032).Conclusions:The endothelin system is increased at the protein level in GCA lesions creating a microenvironment prone to the development of ischaemic complications. Recovery induced by glucocorticoids is delayed, indicating persistent exposure to endothelin during initial treatment.

scholarly journals Imaging Tests in the Early Diagnosis of Giant Cell Arteritis

2021 ◽  
Vol 10 (16) ◽  
pp. 3704
Author(s):  
Diana Prieto-Peña ◽  
Santos Castañeda ◽  
Isabel Martínez-Rodríguez ◽  
Belén Atienza-Mateo ◽  
Ricardo Blanco ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Giant Cell Arteritis ◽  
Giant Cell ◽  
Early Recognition ◽  
Imaging Modality ◽  
Imaging Techniques ◽  
Vascular Complications ◽  
Temporal Artery ◽  
Temporal Artery Biopsy ◽  
Temporal Arteries

Early recognition of giant cell arteritis (GCA) is crucial to avoid the development of ischemic vascular complications, such as blindness. The classic approach to making the diagnosis of GCA is based on a positive temporal artery biopsy, which is among the criteria proposed by the American College of Rheumatology (ACR) in 1990 to classify a patient as having GCA. However, imaging techniques, particularly ultrasound (US) of the temporal arteries, are increasingly being considered as an alternative for the diagnosis of GCA. Recent recommendations from the European League Against Rheumatism (EULAR) for the use of imaging techniques for large vessel vasculitis (LVV) included US as the first imaging option for the diagnosis of GCA. Furthermore, although the ACR classification criteria are useful in identifying patients with the classic cranial pattern of GCA, they are often inadequate in identifying GCA patients who have the extracranial phenotype of LVV. In this sense, the advent of other imaging techniques, such as magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET)/CT, has made it possible to detect the presence of extracranial involvement of the LVV in patients with GCA presenting as refractory rheumatic polymyalgia without cranial ischemic manifestations. Imaging techniques have been the key elements in redefining the diagnostic work-up of GCA. US is currently considered the main imaging modality to improve the early diagnosis of GCA.

A case of giant cell arteritis lacking typical symptoms presenting with recurrent cerebellar infarctions: A case report and case-based review

2021 ◽  
Author(s):  
Ryuichiro Hiyama ◽  
Hiroshi Oiwa ◽  
Yukari Kanou ◽  
Shiho Nishibe ◽  
Tomoyuki Kono ◽  
...  
Keyword(s):  
Physical Examination ◽  
Ischaemic Stroke ◽  
Giant Cell Arteritis ◽  
Giant Cell ◽  
Temporal Artery ◽  
Temporal Artery Biopsy ◽  
Protein Levels ◽  
Temporal Arteries ◽  
First Case ◽  
Case Based

ABSTRACT Giant cell arteritis (GCA) occasionally presents with ischaemic stroke. Generally, symptoms related to GCA or elevated levels of inflammation markers would be a clue for the diagnosis of GCA. However, we encountered a rare case of GCA that presented with recurrent cerebellar infarctions without symptoms related to GCA (headache, fever, or jaw claudication). Furthermore, C-reactive protein levels, measured at the time of two of the stroke attacks, were within the normal range. On physical examination, the temporal arteries were prominent and weakly pulsatile. Temporal artery ultrasonography showed halo signs, and temporal artery biopsy revealed GCA. To our knowledge, this is the first case of GCA presenting with recurrent ischaemic stroke lacking GCA features but diagnosed before death. Considering this case-based review, we suggest that GCA may have been missed in elderly patients with ischaemic stroke, especially in those with posterior circulation infarction. Therefore, physical examination of the temporal arteries, temporal artery ultrasonography, and vessel wall magnetic resonance imaging may be useful in those patients.

Giant cell arteritis complicated by tongue necrosis and bilateral cerebellar ischaemic stroke

2021 ◽  
Vol 14 (12) ◽  
pp. e244948
Author(s):  
Emily Charlotte Rose ◽  
Liam Stuart Carroll ◽  
Sue Evans ◽  
Alice Mason
Keyword(s):  
Ischaemic Stroke ◽  
Giant Cell Arteritis ◽  
Giant Cell ◽  
Temporal Artery ◽  
Visual Disturbance ◽  
Temporal Artery Biopsy ◽  
Stroke Risk Factors ◽  
Temporal Arteries ◽  
Oral Pain ◽  
Oral Candida

Giant cell arteritis (GCA) typically presents with headache, scalp tenderness or visual disturbance. Other symptoms include orofacial pain, constitutional symptoms and ischaemic stroke. An 81-year-old woman with a background of type-2 diabetes and hypertension presented with headache, oral pain and right visual loss. Examination showed hypertension, nodular temporal arteries, reduced visual acuity and suspected oral candida. Inflammatory markers were raised and she was diagnosed with GCA and commenced on corticosteroids. During treatment she developed tongue ulceration, then acute vertigo and incoordination with nystagmus and ataxia. Neuroimaging confirmed bilateral, cerebellar ischaemic strokes and temporal artery biopsy was consistent with GCA. With corticosteroids and secondary prevention of stroke measures she is now functionally independent. Oral pain is an uncommon symptom of GCA and delays in recognition may lead to catastrophic consequences. Clinicians should be aware of uncommon presentations and to optimise additional ischaemic stroke risk-factors.

scholarly journals Giant Cell Arteritis: Current Advances in Pathogenesis and Treatment

2020 ◽  
Author(s):  
Marília A. Dagostin ◽  
Rosa M.R. Pereira
Keyword(s):  
Giant Cell Arteritis ◽  
Giant Cell ◽  
Visual Loss ◽  
Imaging Techniques ◽  
Limb Ischemia ◽  
Temporal Artery ◽  
Medical Emergency ◽  
Common Symptom ◽  
Irreversible Damage ◽  
Temporal Arteries

Giant cell arteritis (GCA) is the most common vasculitis in adults, with the incidence increasing with the advancing age. The aorta and its branches, especially the carotid extracranial branches, are the classic targets of inflammation in GCA. Visual loss, upper limb ischemia, and stroke are complications described. Suspicion of GCA is a medical emergency, and patients need to be quickly diagnosed/treated to prevent irreversible damage. Headache is the most common symptom, and a new-onset headache in older adults should always raise the suspicion of GCA. Patients may also present with scalp tenderness or tongue/jaw pain. GCA is often found to be the cause of an obscure-origin fever in older patients. A positive temporal artery biopsy is considered the gold standard for the diagnosis, but imaging techniques enable the assessment of cranial and extracranial arteries and the aorta. Ultrasound of temporal arteries is recommended and noncompressible “halo” sign is the typical finding. PET, MRI, or CT may be useful for the detection of the disease in the aorta and other vessels. The treatment must be started promptly with prednisone 1 mg/kg/day. When visual symptoms/unilateral visual loss is present, methylprednisolone pulse is recommended. Methotrexate, leflunomide and tocilizumab may be effective and well-tolerated glucocorticoid-sparing agents in GCA. Cardiovascular diseases are the leading causes of death in patients.

scholarly journals Rapid visual recovery following intravenous tocilizumab in glucocorticoid resistant refractory giant cell arteritis

2019 ◽  
Vol 12 (10) ◽  
pp. e229236 ◽  
Author(s):  
Carl Richard Svasti-Salee ◽  
Susan P Mollan ◽  
Ann W Morgan ◽  
Vanessa Quick
Keyword(s):  
Giant Cell Arteritis ◽  
Giant Cell ◽  
Vision Loss ◽  
Rescue Therapy ◽  
Temporal Artery ◽  
High Dose ◽  
Temporal Artery Biopsy ◽  
Sustained Remission ◽  
Temporal Arteries ◽  
Multiple Pulses

A 72-year-old man presented with a short history of headache, jaw claudication, double vision, amaurosis fugax and distended temporal arteries. A diagnosis of giant cell arteritis (GCA) was confirmed on temporal artery ultrasound and temporal artery biopsy. Despite treatment with high-dose oral glucocorticoid (GC) and multiple pulses of intravenous methylprednisolone, his vision deteriorated to hand movements in one eye. 8 mg/kg intravenous tocilizumab, a humanised, recombinant anti-IL-6 receptor antibody, was administered within 48 hours of vision loss and continued monthly, resulting in marked visual improvement within days, as well as sustained remission of GCA. This case suggests a possible role for tocilizumab as a rescue therapy to prevent or recover visual loss in patients with GCA resistant to GC treatment, termed refractory GCA. Further research is required to elucidate the role of intravenous administration of tocilizumab in this setting.

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