Genes deregulated in giant cell arteritis by Nanostring nCounter gene expression profiling in temporal artery biopsies.

OBJECTIVE: To identify differentially expressed genes in temporal artery biopsies (TABs) from patients with giant cell arteritis (GCA) with different histological patterns of inflammation: transmural inflammation (TMI) and inflammation limited to adventitia (ILA), compared with normal TABs from patients without GCA. METHODS: Expression of 770 immune-related genes was profiled with the NanoString nCounter PanCancer Immune Profiling Panel on formalin-fixed paraffin-embedded TABs from 42 GCA patients with TMI, 7 GCA patients with ILA and 7 non-GCA controls. RESULTS: Unsupervised clustering of the samples revealed two distinct groups: normal TABs and TABs with ILA in one group, 41/42 TABs with TMI in the other one. TABs with TMI showed 31 downregulated and 256 upregulated genes compared with normal TABs; they displayed 26 downregulated and 187 upregulated genes compared with TABs with ILA (>2.0 fold changes and adjusted p values <0.05). Gene expression in TABs with ILA resembled normal TABs although 38 genes exhibited >2.0 fold changes, but these changes lost statistical significance after Benjamini-Yekutieli correction. Genes encoding TNF superfamily members, immune checkpoints, chemokine and chemokine receptors, toll-like receptors, complement molecules, Fc receptors for IgG antibodies, signalling lymphocytic activation molecules, JAK3, STAT1 and STAT4 resulted upregulated in TMI. CONCLUSIONS: TABs with TMI had a distinct transcriptome compared with normal TABs and TABs with ILA. The few genes potentially deregulated in ILA were also deregulated in TMI. Gene profiling allowed to deepen the knowledge of GCA pathogenesis.

Clinical features, imaging use, and management in giant cell arteritis: a retrospective single-center study.

This study examines the characteristics of patients with giant cell arteritis (GCA), the utilization of imaging in GCA diagnosis, and variations in GCA management among specialties. Subjects were identified from the Dallas VAMC database spanning 2010 to 2021 using ICD-9/10 codes for GCA and polymyalgia rheumatica, and a list of temporal artery biopsies (TAB). Patients lacking sufficient data to meet the ACR 1990 classification criteria for GCA were excluded. Categorical variables were compared using Fisher's exact test. Continuous variables were analyzed with the Kruskal-Wallis test. Among 209 identified patients, 41 were excluded due to insufficient data for ACR classification. The cohort comprised 91.9% males with a median age of 69. Of the remaining 168 patients, 42 received a final diagnosis of GCA, and 15 of these were confirmed with a positive TAB. The most reported initial symptoms were visual disturbances (75.5%) and headaches (67.7%). Ophthalmology was the initial physician for 46% of patients. GCA correlated with co-existing autoimmune diseases, glucocorticoid-sparing treatments, and consultation with a rheumatologist (p < 0.05). There were no significant differences in clinical features or management of the positive and negative TAB GCA groups. GCA presents with heterogeneous symptoms making diagnosis challenging. Scalp tenderness and headaches were significantly higher in GCA patients, but sub-group analysis revealed no significant differences among GCA patients. Vascular assessments and adjunct imaging modalities are underutilized. The establishment of multidisciplinary or fast-track clinics may enhance the optimization of GCA management. Key Points • The most common presenting symptoms were blurry vision/visual loss (75.5%), headache (67.7%), and scalp tenderness (35.9%) in descending order. • In sub-group analysis, no significant differences were found between GCA sub-groups, but when compared to the non-GCA group, were found to have significantly higher rates of headache and scalp tenderness. • Compared to other specialties, rheumatologists were more likely to use advanced imaging, and to prescribe glucocorticoid-sparing treatments. • Systematic and comprehensive assessment and multidisciplinary approach could improve diagnosis and management.

The impact of histopathological criteria for definite vasculitis in giant cell arteritis: retrospective analysis of temporal artery biopsies.

Histopathological findings associated with definite vasculitis in temporal artery biopsy (TAB) defined in 2022 ACR/EULAR classification criteria for Giant Cell Arteritis (GCA) was published in 2022. We aimed to evaluate the TAB of our GCA patients for histopathological findings associated with definite vasculitis. Patients who were diagnosed with GCA by clinicians and underwent TAB between January 2012 and May 2022 were included. Hospital electronic records and patients' files were reviewed retrospectively. A total of 90 patients' pathology reports were evaluated by a pathologist and a rheumatologist. In cases where microscopic findings were not specified in the pathology reports, histopathologic specimens were re-evaluated (n = 36). A standard checklist was used for histopathological findings of definite vasculitis. Patients were divided into two groups; (i) definite vasculitis-GCA and (ii) non-definite-GCA group, and the clinical and demographic characteristics for all patients were compared. The mean age of patients was 69.8 (± 8.5) years and 52.2% were female. In the first evaluation, 66 (73.3%) patients had a diagnosis of vasculitis according to pathology reports. In the re-evaluation of biopsy specimens, at least one definite finding of vasculitis was observed in TAB of 10/24 (41.6%) patients whose microscopic findings were not specified in the pathology reports. The ROC analysis showed that biopsy length had diagnostic value in predicting the diagnosis of definite vasculitis (AUC: 0.778, 95% CI: 0.65-0.89, p < 0.001). In those with a biopsy length of ≥ 1 cm, sensitivity was 76.5%, specificity was 64.3%, and PPV value was 92. In multivariate analysis, the most significant factor associated with definite vasculitis was biopsy length (OR: 1.18 (1.06-1.31), p = 0.002). Microscopic findings were reported in over 70% of patients. Reinterpretation of results according to a standard check-list improved the impact of TAB in the diagnosis of GCA. A biopsy length ≥ 1 cm was found to contribute towards a definitive histopathological vasculitis diagnosis.

Bilateral juvenile temporal arteritis: a case-based review.

Juvenile Temporal Arteritis (JTA) is a rare non-granulomatous vasculitis affecting the superficial temporal arteries, mostly in individuals under 45 years old. It is often misdiagnosed due to its benign nature and the absence of systemic symptoms. Herein, we present a case report of a 40-year-old woman who initially presented with painless nodules in the left temporal area. Following a biopsy, the patient developed additional nodules not only in the same temple but also on the contralateral side. Remarkably, these nodules underwent spontaneous regression without further treatment, highlighting the variability in JTA's course and distinctive response to intervention. In addition, through a systematic literature review of 43 case reports - 17 with bilateral involvement - we aimed to thoroughly understand the clinical and histopathological findings, diagnostic processes, and treatment responses in JTA, with an emphasis on cases with bilateral involvement. Findings indicate that JTA typically presents as painless or painful temporal nodules, rarely accompanied by other non-specific symptoms, making histopathological examination crucial for accurate diagnosis. Collectively, our work provides the most extensive account of bilateral JTA cases to date. It emphasizes the need for clinical awareness of this condition, contributes valuable data to the limited information available on this rare condition and serves as a stepping-stone for further inquiry. The main takeaway from this review is the variable nature of JTA and the importance of histopathology in diagnosis, which helps clinicians avoid excessive testing and overtreatment and anticipate possible spontaneous resolution.

The Spectrum of Isolated Retinal Artery Occlusion Secondary to Giant Cell Arteritis.

We systematically reviewed the literature to investigate the clinical features of isolated arteritic retinal artery occlusion (A-RAO) associated with giant cell arteritis (GCA). The four primary types of A-RAO were central retinal artery occlusion (CRAO), hemi-central retinal artery occlusion (hCRAO), branch retinal artery occlusion (BRAO), and cilioretinal artery occlusion (CLRAO). The most reported presentation was unilateral CRAO, followed by bilateral CRAO, unilateral CLRAO, and bilateral BRAO. Most RAOs were accompanied by typical GCA signs and symptoms, which can help distinguish them from non-arteritic RAOs. When reported, temporal artery biopsy confirmed GCA in most cases. Patients with GCA may present with a broad spectrum of isolated unilateral and bilateral A-RAOs. [Ophthalmic Surg Lasers Imaging Retina 2024;55:536-540.].

Clinical Manifestations and Prognosis of Giant Cell Arteritis: A Retrospective Cohort Study.

The aim of the study was to evaluate the clinical manifestations and survival of patients with giant cell arteritis (GCA). MATERIALS AND METHODS: . A retrospective study included 166 patients with newly diagnosed GCA. Clinical, laboratory, and instrumental data and three sets of classification criteria were used to confirm the diagnosis: the American College of Rheumatology (ACR) 1990, the revised ACR criteria of 2016 and/or the new ACR and European Alliance of Rheumatologic Associations (EULAR) 2022 criteria. Some of the patients underwent instrumental investigations: temporal artery ultrasound Doppler (n = 61), contrast-enhanced computed tomography (n = 5), CT angiography (n = 6), magnetic resonance imaging (n = 4), MR angiography (n = 3), and 18F-FDG PET/CT (n = 47). Overall and recurrence-free survival rates were analyzed using survival tables and Kaplan-Meier method. RESULTS: . The most frequent first manifestations of GCA were headache (81.8%), weakness (64%), fever (63.8%), and symptoms of rheumatic polymyalgia (56.6%). Changes in temporal arteries in color duplex scanning were detected in 44 out of 61 patients. GCs therapy was performed in all patients who agreed to be treated (n = 158), methotrexate was used in 49 out of 158 patients, leflunomide in 9 patients. In 45 (28.5%) out of 158 patients, a stable remission was achieved as a result of GC monotherapy; in 120 (75.9%) patients, long-term maintenance therapy with GCs was required to prevent exacerbations, including 71 (44.9%) patients in combination with methotrexate or other immunosuppressive drugs. The follow-up period of patients with a history of relapses was 21.0 (8.0-54.0) months. Relapses developed in 73 (46.2%) patients. The overall one-year survival rate was 97.1% [95% CI 94.3; 99.9], and the five-year survival rate of patients was 94.6% [95% CI 90.2; 99.0]. The one-year relapse-free survival rate was 86.4% [95% CI 80.5; 92.3], and the five-year relapse-free survival rate was 52.4% [95% CI 42.0; 62.8]. Twelve (7.2%) of 166 patients died. The cause of death was myocardial infarction in two patients, stroke in two patients, and breast cancer in one patient; in the remaining seven cases, the cause of death was not determined. CONCLUSIONS: : Given the high frequency of disease exacerbation, patients with GCA require long-term follow-up, especially during the first year after diagnosis.

Transorbital ultrasound in the diagnosis of giant cell arteritis.

OBJECTIVES: The objective of this study was to prospectively evaluate the diagnostic efficacy of transorbital ultrasound (TOS) in patients newly diagnosed with giant cell arteritis (GCA), presenting with visual symptoms. METHODS: Patients with newly diagnosed, untreated GCA were examined using TOS, assessing central retinal artery flow velocity [peak systolic velocity (PSV), end-diastolic velocity (EDV), resistance index (RI)], and optic nerve diameter (OND). Vascular ultrasound was conducted to evaluate the superficial temporal arteries, their branches, facial, axillary, carotid, and vertebral arteries. RESULTS: We enrolled 54 GCA patients, 27 with visual symptoms, and 27 healthy controls. Eyes of GCA patients with visual symptoms demonstrated significantly lower PSV and EDV (PSV: ß = -1.91; P = 0.029; EDV: ß = -0.57; P = 0.032) and significantly elevated OND (ß = 0.79; P = 0.003) compared with controls. RI did not significantly differ from controls (ß = -0.06, P = 0.129). Vascular ultrasound identified an average of 8.7 (SD ± 2.8) pathological vessels per GCA patient. A significant negative association was observed between the number of affected vessels and both PSV (P = 0.048) and EDV (P = 0.040). No association was found with RI (P = 0.249), while a positive significant association was noted with OND (P < 0.001). CONCLUSIONS: This study pioneers the application of TOS to assess structural eye changes in newly diagnosed, untreated GCA patients with visual symptoms. Our findings suggest reduced central retinal artery flow and increased optic nerve diameter as potential biomarkers for serious ocular involvement in GCA. The detected association between internal and external carotid artery involvement indicates a common pathophysiological mechanism underlying systemic and ocular manifestations of GCA.

Broadening the clinical spectrum of giant cell arteritis: from the classic cranial to the predominantly extracranial pattern of the disease.

INTRODUCTION: Giant cell arteritis (GCA) is a large vessel (LV) vasculitis that affects people aged 50 years and older. Classically, GCA was considered a disease that involved branches of the carotid artery. However, the advent of new imaging techniques has allowed us to reconsider the clinical spectrum of this vasculitis. AREASCOVERED: This review describes clinical differences between patients with the cranial GCA and those with a predominantly extracranial LV-GCA disease pattern. It highlights differences in the frequency of positive temporal artery biopsy depending on the predominant disease pattern and emphasizes the relevance of imaging techniques to identify patients with LV-GCA without cranial ischemic manifestations. The review shows that so far there are no well-established differences in genetic predisposition to GCA regardless of the predominant phenotype. EXPERT COMMENTARY: The large branches of the extracranial arteries are frequently affected in GCA. Imaging techniques are useful to identify the presence of 'silent' GCA in people presenting with polymyalgia rheumatica or with nonspecific manifestations. Whether these two different clinical presentations of GCA constitute a continuum in the clinical spectrum of the disease or whether they may be related but are definitely different conditions needs to be further investigated.

Diagnostic Strategy Using Color Doppler Ultrasound of Temporal Arteries in Patients With High Clinical Suspicion of Giant Cell Arteritis : A Prospective Cohort Study.

BACKGROUND: Giant cell arteritis (GCA) is the most prevalent systemic vasculitis in people older than 50 years. Any delay in diagnosis impairs patients' quality of life and can lead to permanent damage, particularly vision loss. OBJECTIVE: To evaluate a diagnostic strategy for GCA using color Doppler ultrasound of the temporal artery as a first-line diagnostic test, temporal artery biopsy (TAB) as a secondary test, and physician expertise as the reference method. DESIGN: Prospective multicenter study with a 2-year follow-up. (ClinicalTrials.gov: NCT02703922). SETTING: Patients were referred by their general practitioner or ophthalmologist to a physician with extensive experience in GCA diagnosis and management in one of the participating centers: 4 general and 2 university hospitals. PATIENTS: 165 patients with high clinical suspicion of GCA, aged 79 years (IQR, 73 to 85 years). INTERVENTION: The diagnostic procedure was ultrasound, performed less than 7 days after initiation of corticosteroid therapy. Only ultrasound-negative patients underwent TAB. MEASUREMENTS: Bilateral temporal halo signs seen on ultrasound were considered positive. Ultrasound and TAB results were compared with physician-diagnosed GCA based on clinical findings and other imaging. RESULTS: Diagnosis of GCA was confirmed in 44%, 17%, and 21% of patients by ultrasound, TAB, and clinical expertise and/or other imaging tests, respectively. Their diagnosis remained unchanged at 1 month, and 2 years for those with available follow-up data. An alternative diagnosis was made in 18% of patients. The proportion of ultrasound-positive patients among patients with a clinical GCA diagnosis was 54% (95% CI, 45% to 62%). LIMITATION: Small sample size, no blinding of ultrasound and TAB results, lack of an objective gold-standard comparator, and single diagnostic strategy. CONCLUSION: By using ultrasound of the temporal arteries as a first-line diagnostic tool in patients with high clinical suspicion of GCA, further diagnostic tests for patients with positive ultrasound were avoided. PRIMARY FUNDING SOURCE: Tender "Recherche CH-CHU Poitou-Charentes 2014."

Altered Plasma Levels and Tissue Expression of Fibroblast Activation Protein Alpha in Giant Cell Arteritis.

OBJECTIVE: Giant cell arteritis (GCA) is characterized by granulomatous inflammation of the medium- and large-sized arteries accompanied by remodeling of the vessel wall. Fibroblast activation protein alpha (FAP) is a serine protease that promotes both inflammation and fibrosis. Here, we investigated the plasma levels and vascular expression of FAP in GCA. METHODS: Plasma FAP levels were measured with enzyme-linked immunosorbent assay in treatment-naive patients with GCA (n = 60) and polymyalgia rheumatica (PMR) (n = 63) compared with age- and sex-matched healthy controls (HCs) (n = 42) and during follow-up, including treatment-free remission (TFR). Inflamed temporal artery biopsies (TABs) of patients with GCA (n = 9), noninflamed TABs (n = 14), and aorta samples from GCA-related (n = 9) and atherosclerosis-related aneurysm (n = 11) were stained for FAP using immunohistochemistry. Immunofluorescence staining was performed for fibroblasts (CD90), macrophages (CD68/CD206/folate receptor beta), vascular smooth muscle cells (desmin), myofibroblasts (α-smooth muscle actin), interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9). RESULTS: Baseline plasma FAP levels were significantly lower in patients with GCA compared with patients with PMR and HCs and inversely correlated with systemic markers of inflammation and angiogenesis. FAP levels decreased even further at 3 months on remission in patients with GCA and gradually increased to the level of HCs in TFR. FAP expression was increased in inflamed TABs and aorta of patients with GCA compared with control tissues. FAP was abundantly expressed in fibroblasts and macrophages. Some of the FAP+ fibroblasts expressed IL-6 and MMP-9. CONCLUSION: FAP expression in GCA is clearly modulated both in plasma and in vessels. FAP may be involved in the inflammatory and remodeling processes in GCA and have utility as a target for imaging and therapeutic intervention.

Giant Cell Arteritis. / Riesenzellarteriitis.

Giant cell arteritis (GCA) is the most common primary vasculitis and is associated with potential bilateral blindness. Neither clinical nor laboratory evidence is simple and unequivocal for this disease, which usually requires rapid and reliable diagnosis and therapy. The ophthalmologist should consider GCA with the following ocular symptoms: visual loss or visual field defects, transient visual disturbances (amaurosis fugax), diplopia, eye pain, or new onset head or jaw claudication. An immediate ophthalmological examination with slit lamp, ophthalmoscopy, and visual field, as well as color duplex ultrasound of the temporal artery should be performed. If there is sufficient clinical suspicion of GCA, corticosteroid therapy should be initiated immediately, with prompt referral to a rheumatologist/internist and, if necessary, temporal artery biopsy should be arranged. Numerous developments in modern imaging with colour duplex ultrasonography, MRI, and PET-CT have the potential to compete with the classical, well-established biopsy of a temporal artery. Early determination of ESR and CRP may support RZA diagnosis. Therapeutically, steroid-sparing immunosuppression with IL-6 blockade or methotrexate can be considered. These developments have led to a revision of both the classification criteria and the diagnostic and therapeutic recommendations of the American College of Rheumatologists and the European League against Rheumatism, which are summarised here for ophthalmology.

Should all patients with polymyalgia rheumatica have a vascular ultrasound assessment?

There is a growing appreciation that both giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are closely interrelated conditions that have significant overlap in aetiology, clinical characteristics and treatment regimens. Subclinical GCA in PMR is becoming increasingly recognised, and there is evolving evidence that this may be a more aggressive disease phenotype than PMR. Ultrasound (US) lends itself well as a screening tool for GCA in PMR; it is inexpensive, non-invasive, widely available, lacks ionising radiation, may be performed at the bedside and is recommended by EULAR as a first-line investigation for suspected GCA. There is insufficient evidence to currently recommend that all patients with PMR should have a US assessment for vascular involvement. However, as clinical and laboratory parameters alone do not accurately diagnose patients with subclinical GCA, we suggest that vascular US will be increasingly performed by rheumatologists in practice to identify these patients with PMR, preferably as part of larger prospective outcome studies.

Analysis of Temporal Artery Biopsy by Provider Across a Large Multi-State Health Care Network.

Temporal artery biopsy (TAB) is the standard test for diagnosing giant cell arteritis. Our objective was to determine which specialists perform TABs and if there is variation across the United States. We performed a cross-sectional analysis in a multi-state health care system, evaluating differences between observed counts of surgical specialty by region, positive diagnoses by region, and positive diagnoses by specialty. Temporal arterial biopsy was performed on 3825 patients with the proportion of specialties performing TAB differing between regions. Temporal artery biopsy was performed by a significantly higher percentage of general surgeons in the Midwest (53.6%) and less vascular surgeons in the West (30.4%). The percentage of positive diagnoses was higher for vascular surgeons (32.7%). We concluded that TAB is performed by physicians of many specialties with the specialty performing most of these procedures varying by region. There is also a difference in the rate of positive diagnoses that varies with surgical specialty.

Giant cell arteritis: insights from a monocentric retrospective cohort study.

Giant cell arteritis (GCA), more common in Northern European populations, has limited data in Arabcountries. Our study reports GCA's clinical manifestations in Jordan and reviews published research on GCA across Arab nations. In this retrospective analysis, GCA patients diagnosed from January 2007 to March 2019 at a Jordanian academic medical center were included through referrals for temporal artery biopsy (TAB). A comprehensive search in PubMed, Scopus, and the DOAJ (Directory of Open Access Journals) databases was conducted to identify all relevant English-language manuscripts from Arab countries on GCA without time limitations. Among 59 diagnosed GCA patients, 41 (69.5%) were clinically diagnosed with a negative TAB, and 19 (30.5%) had a positive result. Females comprised 74.6% (n = 44) with 1:3 male-female ratio. The mean age at diagnosis was 67.3 (± 9.5) years, with most presenting within two weeks (n = 40, 67.8%). Headache was reported by 54 patients (91.5%). Elevated ESR occurred in 51 patients (78%), with a mean of 81 ± 32.2 mm/hr. All received glucocorticoids for 13.1 ± 10 months. Azathioprine, Methotrexate, and Tocilizumab usage was 15.3% (n = 9), 8.5% (n = 5), and 3.4% (n = 2), respectively. Remission was observed in 57.6% (n=34), and 40.7% (n = 24) had a chronic clinical course on treatment. Males had higher biopsy-based diagnoses (p = .008), and biopsy-diagnosed patients were older (p = .043). The literature search yielded only 20 manuscripts originating in the Arab world. The predominant study types included case reports and retrospective analyses, with only one case series and onecase-control study.