An Immunohistopathologic Study to Profile the Folate Receptor Beta Macrophage and Vascular Immune Microenvironment in Giant Cell Arteritis
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Giant cell arteritis (GCA) is a chronic immune-mediated disease of medium-to-large sized arteries that affects older adults. GCA manifests with arthritis and occlusive symptoms of headaches, stroke or vision loss. Macrophages and T-helper lymphocytes infiltrate the vascular wall and produce a pro-inflammatory response that lead to vessel damage and ischemia. To date, there is no GCA biomarker that can monitor disease activity and guide therapeutic response. Folate receptor beta (FRB) is a glycosylphosphatidylinositol protein that is anchored on cell membranes and normally expressed in the myelomonocytic lineage and in the majority of myeloid leukemia cells as well as in tumor and rheumatoid synovial macrophages, where its expression correlates with disease severity. The ability of FRB to bind folate compounds, folic acid-conjugates and antifolate drugs has made it a druggable target in cancer and inflammatory disease research. This report describes the histopathologic and immunohistochemical methods used to assess expression and distribution of FRB in relation to GCAimmunopathology. Formalin-fixed and paraffin-embedded temporal artery biopsies from GCA and normal controls were stained with Hematoxylin and Eosin to review tissue histology and identify pathognomonic features.Immunohistochemistry was used to detect FRB, CD68 and CD3 expression. A microscopic analysis was performed to quantify the number of positively stained cells on 10 selected high-power-field sections and their respective locations in the arterial wall. Lymphohistiocytic (LH) inflammation accompanied by intimal hyperplasia and disrupted elastic lamina was seen in GCA with none found in controls. The LH infiltrate was composed of approximately 60% lymphocytes and 40% macrophages. FRB expression was restricted to macrophages, comprising 31% of the total CD68+ macrophage population and localized to the media and adventitia. No FRB was seen in controls. This protocol demonstrated a distinct numerical and spatial pattern of the FRB macrophage relative to the vascular immune microenvironment in GCA.Keywords:
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Polymyalgia rheumatica
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Systemic vasculitis
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Both giant-cell arteritis and polymyalgia rheumatica are immune-mediated diseases that are treated with glucocorticoids, with higher doses used for giant-cell arteritis. Prompt initiation of high doses and a biopsy are recommended when ischemic optic neuropathy is suspected.
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In the presence of temporal arteritis, clinicians often refer to the diagnosis of giant cell arteritis (GCA). However, differential diagnoses should also be evoked because other types of vascular diseases, vasculitis or not, may affect the temporal artery. Among vasculitis, Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is probably the most common, and typically affects the peri-adventitial small vessel of the temporal artery and sometimes mimics giant cell arteritis, however, other symptoms are frequently associated and more specific of ANCA-associated vasculitis prompt a search for ANCA. The Immunoglobulin G4-related disease (IgG4-RD) can cause temporal arteritis as well. Some infections can also affect the temporal artery, primarily an infection caused by the varicella-zoster virus (VZV), which has an arterial tropism that may play a role in triggering giant cell arteritis. Drugs, mainly checkpoint inhibitors that are used to treat cancer, can also trigger giant cell arteritis. Furthermore, the temporal artery can be affected by diseases other than vasculitis such as atherosclerosis, calcyphilaxis, aneurysm, or arteriovenous fistula. In this review, these different diseases affecting the temporal artery are described.
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Giant cell arteritis (GCA) is the most common large-vessel vasculitis that primarily affects older individuals.1 Prompt diagnosis and treatment with empiric glucocorticoids (GCs) is important because GCA can lead to ischemic complications, including visual loss.1,2
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Giant cell arteritis (GCA) is the commonest form of large-vessel vasculitis and affects branches of the external carotid artery but also the ciliary and retinal arteries. The symptoms are caused by local ischaemia due to endovascular damage and cytokine-mediated systemic illness. There is considerable overlap with polymyalgia rheumatica (PMR): 16–21% of patients with PMR have GCA on temporal artery biopsy, and symptoms of PMR are present in 40–60% of patients with GCA.1 GCA occurs in 2.2 per 10 000 patient-years in the UK.2 A full-time GP may expect to see one new case every 1–2 years. It is virtually unknown in people aged under 50 years. Early recognition is critical to prevent visual loss, that otherwise occurs in up to 20% of cases.3 Once high-dose corticosteroids are started, visual loss is extremely rare.
Guidelines for the diagnosis and management of GCA, have recently been published by the British Society of Rheumatologists and British Health Professionals in Rheumatology.4
A 2002 systematic review analysed the presenting clinical features in a mixture of studies, with a total of 1435 cases of giant cell arteritis.5 The mean duration of symptoms at diagnosis was 3.5 months.5 The …
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Background: Evidence of a dark halo on ultrasonography has been considered a specific sign of giant-cell arteritis and may replace temporal artery biopsy for the diagnosis of giant-cell arteritis in patients with typical clinical manifestations. Objective: To assess the usefulness of temporal artery duplex ultrasonography and to compare this mode of ultrasonography with physical examination of temporal arteries for the diagnosis of giant-cell arteritis in patients with suspected giant-cell arteritis or polymyalgia rheumatica. Design: Diagnostic test study. Setting: Several divisions of Reggio Emilia Hospital, Reggio Emilia, Italy. Patients: 86 consecutive patients with a suspected diagnosis of giant-cell arteritis or polymyalgia rheumatica identified over a 22-month period. Measurements: The temporal arteries were examined in all 86 patients. Duplex ultrasonography of the temporal arteries was then performed by two ultrasonographers who were unaware of the clinical diagnosis. Before corticosteroid therapy was started, temporal artery biopsies were performed in all patients at the site targeted by the ultrasonographer. Results: A hypoechoic halo around the lumen of the temporal arteries had a sensitivity of only 40% (95% CI, 16% to 68%) and a specificity of 79% (CI, 68% to 88%) for the diagnosis of biopsy-proven giant-cell arteritis. The negative likelihood ratio was 0.8 (CI, 0.5 to 1.2), and the positive likelihood ratio was 1.9 (CI, 0.9 to 4.1). When the thickness of the halo was at least 1 mm, specificity increased to 93% (CI, 84% to 98%) and the positive likelihood ratio increased to 5.7 (CI, 2.0 to 16.2); however, sensitivity remained low at 40% (CI, 16% to 68%). On physical examination, temporal artery abnormalities had a higher sensitivity of 67% (CI, 38% to 88%), a higher specificity of 99% (CI, 92% to 100%), and a higher positive likelihood ratio of 47.3 (CI, 6.5 to 342.4) than did ultrasonographic findings. None of the patients with giant-cell arteritis had a normal temporal artery inspection and a hypoechoic halo on ultrasonography. Conclusion: Evidence on ultrasonography of a halo around temporal arteries, either any halo or a halo 1 mm or greater in thickness, only modestly increased the probability of biopsy-proven giant-cell arteritis but did not improve the diagnostic accuracy of a careful physical examination.
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Polymyalgia rheumatica and giant cell (cranial/temporal) arteritis are common debilitating conditions affecting people nearly always over the age of 55. Although the two syndromes are closely linked their precise relationship is not fully understood. Polymyalgia rheumatica or giant cell arteritis can occur in a ‘pure’ form or clinical features of each may be present in the same patient. Treatment with a systemic corticosteroid has long been considered mandatory in patients with giant cell arteritis in order to prevent serious vascular complications, particularly blindness 1 . Treatment with corticosteroid is also usual for patients with polymyalgia rheumatica. Many patients remain on steroids for years. What is the basis for current approaches to management? How should steroids be given and eventually stopped?
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Polymyalgia rheumatica, next to rheumatoid arthritis the most common inflammatory rheumatic disorder of the elderly, is a nonspecific clinical syndrome involving pain in the shoulder and pelvic girdles. Giant cell arteritis appears to localize in elastin-containing arteries and can cause similar myalgias. A relationship exists between the two diseases, as evidenced by their frequent coexistence in the same patient. The symptoms of polymyalgia rheumatica respond to low-dose corticosteroid therapy, while giant cell arteritis requires higher doses to prevent blindness due to involvement of the temporal artery. The key decision in therapy, therefore, concerns the dose and duration of use of steroid for polymyalgic symptoms. In this decision, prevention of the catastrophic complications of giant cell arteritis and avoidance of needless side effects of high-dose steroid therapy in the elderly are competing considerations.
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The American College of Rheumatology (ACR) has proposed a list of criteria for diagnosis of giant cell arteritis in order to guide clinical research by differentiating it from other vasculitis. The aim of this retrospective investigation, based on the findings of 415 temporal artery biopsies was to assess the diagnostic value of these criteria in the daily clinical setting.The demographic, clinical and biological characteristics of patients with positive (confirmed cases of giant cell arteritis) or negative (controls) histopathological temporal artery biopsy findings were analyzed using downward step-by-step logistic regression analysis. This analysis enabled investigators to list signs with inherent diagnostic value. Based their odds-ratio, these factors were used to determine a clinical score for giant cell arteritis.A score of over 7 - out of a maximum score of 32 - enables the diagnosis for giant cell arteritis with the best possible compromise between a sensitivity of 75.7% and a specificity of 72.2%. ACR criteria had a sensitivity of 97.5% and a specificity of 78.9% when used in our patient group.Our study results are original in that the control group was composed of patients in whom the diagnosis of giant cell arteritis had been suggested but refuted by the absence of histopathological findings on the temporal artery biopsy. This pragmatic attitude in selecting the control group may explain the difference observed with the ACR criteria in terms of sensitivity and specificity. Further research is needed to develop a diagnostic method for giant cell arteritis without resorting to temporal artery biopsy.
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Macrophages are important cells for the innate immunity. Circulating monocytes are attracted to tissues by chemotactic factors and become macrophages under the influence of their microenvironment. Several studies have shown that macrophages are important to the prognosis of patients with different types of cancer. The aim of this study was to evaluate the expression of CD68 in OSCC patients and to investigate the possible relationship of macrophages using CD68 in various histopathological grades, stages and other clinical parameters of OSCC. preoperative diagnosed specimens (n=30)were processed for immunohistochemistry to detect CD68 positive cells. Expression of macrophages was semiquantitatively analyzed. Immunohistochemical study show expression of CD68 in all specimens. A significant correlation between CD68 infiltration and gender of patients was found,where it high in females than males. Other clinicopathological findings of OSCC show non-significant correlation. Immunohistochemical expression of CD68 were observed in all studying samples of oral squamous cell carcinoma. however, statistically non-significant correlation was found between the mean expression level of these infiltrates macrophages with clinicopathological findings of OSCC expect with Gender.
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