Inflammation of the temporalis muscle and adjacent nerve tissue in giant cell arteritis: expanding the spectrum of inflammatory lesions.

OBJECTIVES: To investigate the histopathological features of the temporalis muscle (TM) and adjacent nerve tissue in active cranial giant cell arteritis (C-GCA). METHODS: Temporal artery biopsy (TAB) specimens containing fragments of the TM from patients with active C-GCA fulfilling the 2022 ACR/EULAR classification criteria (n = 11) were assessed by conventional histology and immunohistochemistry in comparison with non-GCA controls (n = 3). Clinical, laboratory and imaging features based on patient charts at time of biopsy were retrospectively recorded. RESULTS: The majority of the studied TAB specimens showed inflammation of the TM (10/11) and adjacent nerve fascicles (7/11) that was characterized by prominent endomysial lymphomonocytic infiltrates, whereas controls showed no inflammatory lesions and no disruption of the local architecture. Association of active C-GCA with sarcolemmal MHC class I (8/8) and MHC class II (6/11) upregulation suggests primary inflammation of the TM in a subset of patients. αB-Crystallin positivity (10/11) highlights areas of pre-necrotic myofibres within the TM. The presence of endomysial fibrosis, signs of atrophy and variations of muscle fibre size suggest a rather longstanding and potentially subclinical process of myoinflammation. CONCLUSION: Our results expand the spectrum of inflammatory lesions known to be associated with active C-GCA. Specifically, inflammatory infiltration of the TM and adjacent nerve structures could contribute to localized symptoms of the temporomandibular region and may be included in future concepts of pathophysiology.

Ultrasonography led multimodal diagnostic pathway for giant cell arteritis.

OBJECTIVES: To establish the sensitivity and negative predictive value of a multimodal pathway incorporating ultrasonography, 18-fluorodeoxyglucose labelled positron emission tomography computed tomography and temporal artery biopsy for the diagnosis of giant cell arteritis. METHODS: 1000 consecutive referrals for a new diagnosis of giant cell arteritis were analysed. All patients had a protocolized examination. Patients with a negative ultrasonography and a C-reactive protein of ≥ 20 mg/l received an extended ultrasound examination. If that was negative, and there was no other explanation for their presentation, a second test in the form of either a temporal artery biopsy or an 18-fluorodeoxyglucose labelled positron emission tomography computed tomography was offered. We calculated the sensitivity and negative predictive value of the interventions for diagnosing giant cell arteritis. RESULTS: 279/1000 patients had positive ultrasonography for giant cell arteritis. 202 had bilateral superficial temporal arterial involvement. Ultrasonography of the axillary artery and other head/neck arteries increased the yield by 53 and 24 patients respectively. 181 patients were referred for a second test. 24/139 temporal artery biopsies and 7/42 18-fluorodeoxyglucose labelled positron emission tomography computed tomography scans were positive. The sensitivity and negative predictive value rise from 62.3% and 84.7% respectively for imaging superficial temporal arteries alone, to 95.7% and 98.0% respectively for extended ultrasonography plus a second test. CONCLUSIONS: This is the first real world evidence of the utility of ultrasonography for the diagnosis of giant cell arteritis as part of a multimodal diagnostic pathway.

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.

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.

Predictive Factors for Biopsy-Negative Giant Cell Arteritis and Alternative Diagnoses in a Neuro-Ophthalmology Context.

Giant cell arteritis is a challenging diagnosis for patients given the high prevalence of negative temporal artery biopsies (TAB). Despite the lack of histopathological evidence of giant cell arteritis in the TAB, patients can still have TAB-negative giant cell arteritis. The purpose of this paper is to analyse the predictors for TAB-negative giant cell arteritis and the alternative diagnosis of biopsy-negative patients without a giant cell arteritis diagnosis. A retrospective electronic database review of all TABs performed at the Royal Victorian Eye and Ear Hospital from February 2015 to May 2020. Logistic regression analysis was performed to determine predictive factors for a diagnosis of TAB-negative giant cell arteritis. In all cases, a clinical diagnosis of TAB-negative giant cell arteritis was determined by a neuro-ophthalmologist. Alternative diagnoses for negative TABs were identified and explored. A total of 368 TABs were analysed with 287 (78%) negative for histopathological evidence of GCA. Twenty-seven (9.4%) patients were diagnosed and treated as TAB-negative giant cell arteritis. The clinical predictors of a TAB-negative giant cell arteritis diagnosis were the presence of jaw claudication (OR 2.77, 95% CI 1.10-6.98) and CRP (OR 1.02, 95% CI 1.00-1.03). Alternative diagnoses included non-specific headache, non-arteritic anterior ischaemic optic neuropathy, retinal vessel occlusions, and ocular nerve palsies. Predictive factors for a diagnosis of TAB-negative giant cell arteritis were jaw claudication and an elevated CRP. Several alternative diagnoses can be considered for patients with a negative TAB in a neuro-ophthalmology context.

Estimating overdiagnosis in giant cell arteritis diagnostic pathways using genetic data: genetic association study.

OBJECTIVES: Giant cell arteritis (GCA) may be confirmed by temporal artery biopsy (TAB) but false negatives can occur. GCA may be overdiagnosed in TAB-negative cases, or if neither TAB nor imaging is done. We used Human Leucocyte Antigen (HLA) genetic association of TAB-positive GCA as an "unbiased umpire" test to estimate historic overdiagnosis of GCA. METHODS: Patients diagnosed with GCA between 1990-2014 were genotyped. During this era, vascular imaging alone was rarely used to diagnose GCA. HLA region variants were jointly imputed from genome-wide genotypic data of cases and controls. Per-allele frequencies across all HLA variants with p< 1.0x1 0 -5 were compared with population control data to estimate overdiagnosis rates in cases without a positive TAB. RESULTS: Genetic data from 663 GCA patients were compared with data from 2619 population controls. TAB-negative GCA (n = 147) and GCA without TAB result (n = 160) had variant frequencies intermediate between TAB-positive GCA (n = 356) and population controls. For example, the allele frequency of HLA-DRB1*04 was 32% for TAB-positive GCA, 29% for GCA without TAB result, 27% for TAB-negative GCA and 20% in population controls. Making several strong assumptions, we estimated that around two-thirds of TAB-negative cases and one-third of cases without TAB result may have been overdiagnosed. From these data, TAB sensitivity is estimated as 88%. CONCLUSIONS: Conservatively assuming 95% specificity, TAB has a negative likelihood ratio of around 0.12. Our method for utilising standard genotyping data as an "unbiased umpire" might be used as a way of comparing the accuracy of different diagnostic pathways.

Evaluation of Arterial Histopathology and microRNA Expression That Underlie Ultrasonography Findings in Temporal Arteries of Patients with Giant Cell Arteritis.

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.

Presenting Features of Giant Cell Arteritis with Active Versus Healed Arteritis on Biopsy.

Giant cell arteritis (GCA) is often categorised as "active" or "healed" on temporal artery biopsy (TAB). The purpose of this study was to compare the initial clinical presentation of patients with GCA according to active versus healed arteritis on TAB. A retrospective chart review was performed for patients with biopsy-proven GCA (BP-GCA) at a single academic medical institution from a previously reported cohort. The arteritis on TAB was categorised as "active" or "healed" based on the pathological reports. Demographic information, clinical presentation, past medical history, and test results were collected from the date of TAB. These baseline characteristics were entered into the GCA Risk Calculator. Of 85 patients with BP-GCA, 80% had active and 20% had healed disease according to histopathology. A higher percentage of those with active arteritis had ischaemic optic neuropathy (ION) (36% versus 6%, p = .03), elevated erythrocyte sedimentation rates (92% versus 63%, p = .01), elevated C-reactive protein levels (79% versus 46%, p = .049), GCA risk score > 7.5% (99% sensitivity, 100% versus 71%, p < .001), higher mean GCA risk calculator scores (neural network p = .001; logistic regression p = .002). Patients with healed arteritis were less likely to have visual manifestations than the active arteritis group (38% versus 71%, p = .04). Patients with active vasculitis on biopsy had higher rates of ION and elevated inflammatory markers, as well as higher predictive scores from the GCA risk calculator. Further research is needed regarding correlation of biopsy findings and risk of complications or relapses.

All-cause and cause-specific mortality in patients with giant cell arteritis: a nationwide, population-based cohort study.

OBJECTIVES: To investigate whether GCA is associated with increased all-cause and cause-specific mortality. METHODS: A nationwide, population-based cohort study in Denmark using medical and administrative registries. GCA cases were defined as patients aged ≥50 years from 1996-2018 with a first-time discharge diagnosis of GCA and ≥3 prescriptions for prednisolone within 6 months following diagnosis. Each GCA patient was matched based on age, sex and calendar time to 10 persons without a history of GCA. Index date was the date for the third prednisolone prescription. We used a pseudo-observation approach to calculate all-cause and cause-specific mortality, adjusted risk differences (RDs) and relative risks (RRs). RESULTS: We included 9908 GCA patients and 98 204 persons from the general population. The median time for GCA patients to redeem the third prednisolone prescription was 74 days [interquartile range (IQR: 49-106)]. Among GCA patients, the overall mortality was 6.4% (95% CI: 5.9, 6.9) 1 year after index date and 45% (95% CI: 44, 47) after 10 years. Compared with the reference cohort, adjusted RDs and RRs of deaths in the GCA cohort were 2.2% (95% CI: 1.7, 2.7) and 1.49 (95% CI: 1.36, 1.64) after 1 year, and 2.1% (95% CI: 1.0, 3.3) and 1.03 (95% CI: 1.00, 1.05) 10 years after index date. GCA patients had a higher risk of death due to infectious, endocrine, cardiovascular and gastrointestinal diseases. CONCLUSIONS: GCA is associated with increased all-cause mortality, particularly within the first year following the diagnosis. Cause-specific mortality indicates that mortality in GCA may in part be due to glucocorticoid-related complications.

The utility of the bilateral temporal artery biopsy for diagnosis of giant cell arteritis.

OBJECTIVE: A surgical temporal artery biopsy (TAB) is the gold standard for diagnosis of giant cell arteritis (GCA). The necessity of performing a bilateral biopsy remains under debate. The primary objective of this study was to assess the rate of discordance between pathology results in patients who underwent bilateral TAB for suspected GCA. METHODS: We performed a retrospective review of patients who underwent bilateral TAB for the diagnosis of GCA between 2011 and 2020. The primary end point was the rate of discordance between specimens for patients with pathology positive GCA. Secondary end points included assessments of the sensitivity of preoperative temporal artery duplex and the effects of specimen length and specialty of referring provider on the diagnostic yield of the biopsy. RESULTS: During the study period, 310 patients underwent bilateral TAB for the diagnosis of GCA. These patients were primarily female (73.9%), elderly (mean age, 70.8 years), and Caucasian (95.8%). Preoperative symptoms for patients were typically bilateral (59%) and included headache (81%), vision changes (45.2%), and temporal tenderness (32.6%). Most patients (85.2%) were on preoperative steroid therapy at the time of surgical biopsy with a mean preoperative duration of steroid therapy of 15.1 days. Overall, 91 patients (29.4%) had a positive pathologic diagnosis after bilateral TAB. Of these patients, 11 had a positive pathology result in only a single specimen, resulting in a discordance rate of 12.1%. Preoperative temporal artery duplex demonstrated a low sensitivity (27.3%) for identifying patients with pathologic positive disease. There were no significant differences between the pathology-positive and -negative patients in terms of mean surgical specimen length (1.67 cm vs 1.64 cm; P = .67) or the specialty of the referring provider (P = .73). CONCLUSIONS: At our institution, we observed a 12.1% discordance rate between pathology results in patients who underwent bilateral TAB for diagnosis of GCA. A preoperative temporal artery duplex provided little value in identifying patients with biopsy-proven GCA.

Presentation characteristics and clinical outcome of patients with giant cell arteritis followed by a single center.

BACKGROUND: Giant cell arteritis (GCA) is a large vessel vasculitis that may cause significant morbidity in the elderly population. We aimed to evaluate presentation characteristics, treatment, and outcome in a cohort of patients with GCA diagnosed and followed in a single center. METHODS: A retrospective chart review revealed 84 (41 M/43 F) registered patients diagnosed with GCA between 1990 and 2020. Clinical features at presentation and follow-up, radiographical imaging, temporal artery biopsy (TAB), and laboratory findings were retrieved from digital medical records or hard-copy patient files. Of these, 33 patients' follow-up period was less than 12 months; hence, relapses and treatment outcomes were examined in the remaining 51 (60.5%) patients. RESULTS: A total of 84 patients were included in the cohort. The mean age at diagnosis was 68.4 ± 7.9 years (range: 49-85). At presentation, 60 (71.4%) patients had headache, 22 (26.2%) had symptoms compatible with polymyalgia rheumatica (PMR), and 23 (27.4%) had visual loss. Three (3.6%) patients had solid organ malignancies while two had hematologic malignancies (2.4%) before GCA diagnosis. TAB was obtained in 63 (75%) patients, in 47 of whom (74.6%) the pathological findings were consistent with GCA. A PET/ CT scan has been performed before glucocorticoids (GCs) initiation in 43 (51.2%) patients and of these, 37 (86.0%) revealed uptake consistent with large vessel involvement. The median follow-up time of the 51 patients was 3.7 (IQR: 1.8-6.8) years. GCs were started promptly after the diagnosis. During the follow-up period, 28 (54.9%) patients experienced a relapse. Thirty-nine (78%) patients were under GC treatment, with a mean dosage of 4.8 ± 2.8 g/day at the final visit. At the final visit, 20.3% (17:84) had died whereas 9.8% (5:51) had permanent vision loss. DISCUSSION: Treatment of GCA is challenging. GCA causes serious morbidities and increased mortality. PET/CT is highly effective in detecting large vessel vasculitis in GCA and could perhaps replace TAB in the future.

[Giant cell arteritis diagnosed by a temporal artery biopsy without abnormal imaging and physical findings in an elderly patient presenting with fever].

Giant cell arteritis (GCA) is considered in the differential diagnosis of fever of unknown origin in the elderly. We describe the case of an 83-year-old man with GCA diagnosed by temporal artery biopsy (TBA), who did not exhibit abnormal physical and imaging findings. The patient had fever and elevated C-reactive protein (CRP), which had persisted for two months. He was examined and treated with antibiotics and antipyretic analgesics in a local clinic, but they had little effect. He was referred to us. He showed no abnormal physical findings. Image examinations, including ultrasonography, CT, MRI, and PET-CT, showed no abnormal findings. We performed TBA. The histological examination of the artery showed inflammatory cell invasion and rupture of the internal elastic membrane, indicating GCA. We initiated oral corticosteroid treatment. The patient's fever quickly disappeared and his CRP level returned to normal. TBA has been the gold standard for the diagnosis of GCA. However, TBA is an invasive procedure and the sensitivity depends on the operator's skill level. Recently, imaging examinations have frequently been used for the diagnosis of GCA. The sensitivity of imaging examinations is similar to that of TBA. However, our case did not show any abnormal imaging findings and was only diagnosed by TBA. This case suggested that TBA remains a useful examination for elderly patients with fever that persists for a long time.

An immunohistochemical analysis of fibroblasts in giant cell arteritis.

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.

Giant cell arteritis: controversial issues.

Giant cell arteritis is the most common vasculitis in adults. The author presents the latest findings in diagnostics and treatment emphasising the growing importance of non-invasive examination methods where a biopsy of the temporal artery is no longer considered the only possible examination that confirms the diagnosis. He emphasises the importance of early diagnosis and initiation of treatment and also points out difficulties in treatment, especially frequent relapses. In addition to glucocorticoids, modern drugs influencing the decisive factors in the pathogenesis of inflammation are beginning to gain ground in treatment. Despite of new findings, there is a number of controversial issues remaining that the author addresses in more details: from terminology and epidemiology to diagnosis and treatment.

Sensitivity of temporal artery biopsy in the diagnosis of giant cell arteritis: a systematic literature review and meta-analysis.

OBJECTIVES: Temporal artery biopsy (TAB) is a reference test for the diagnosis of GCA but reveals inflammatory changes only in a subset of patients. The lack of knowledge of TAB sensitivity hampers comparisons with non-invasive techniques such as temporal artery ultrasonography. We performed a systematic literature review and meta-analysis to estimate the sensitivity of TAB in GCA and to identify factors that may influence the estimate. METHODS: A systematic literature review involved searching electronic databases and cross-references. Eligibility criteria included publications reporting at least 30 GCA cases fulfilling the original or modified 1990 ACR classification criteria. The pooled proportion of TAB-positive GCA cases was calculated by using aggregated-data meta-analysis with a random-effects model and assessment of heterogeneity with the I2 statistic. Subgroup analyses and meta-regression were used to examine the effect of patient and study characteristics on TAB positivity. RESULTS: Among 3820 publications screened, 32 studies (3092 patients) published during 1993-2017 were analysed. The pooled proportion of TAB-positive GCA cases was 77.3% (95% CI: 71.8, 81.9%), with high between-study heterogeneity (I2 = 90%). The proportion of TAB-positive cases was slightly higher in publications before than in 2012 and after (P = 0.001). CONCLUSION: The estimated sensitivity of 77% provides indirect evidence that TAB is not less sensitive than temporal artery imaging. The unexplained high between-study heterogeneity could result from differences in TAB sampling, processing or interpretation. The decrease in TAB-positive GCA cases over time could reflect an increasing propensity for clinicians to accept a GCA diagnosis without proof by TAB.

Identification of microRNAs and their target gene networks implicated in arterial wall remodelling in giant cell arteritis.

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.

Diagnosis of giant cell arteritis.

GCA is the most common form of primary systemic vasculitis affecting older people. It is considered a clinical emergency because it can lead to irreversible blindness in around 20% of untreated cases. High doses of glucocorticoids should be initiated promptly to prevent disease-related complications; however, glucocorticoids therapy usually results in significant toxicity. Therefore, correct diagnosis is crucial. For many years, temporal artery biopsy has been considered the diagnostic 'gold standard' for GCA, but it has many limitations (including low sensitivity). US has proven to be effective for diagnosing GCA and can reliably replace temporal artery biopsy in particular clinical settings. In cases of suspected GCA with large-vessel involvement, other imaging modalities can be used for diagnosis (e.g. CT and PET). Here we review the current evidence for each diagnostic modality and propose an algorithm to diagnose cranial-GCA in a setting with rapid access to high quality US.

Evaluation of deeper levels in initially negative temporal artery biopsies and likelihood of a positive result.

Giant cell arteritis is a vasculitis that affects large- and medium-sized vessels in patients over the age of 50 years. The demonstration of granulomatous arteritis is the criterion standard to establish a definitive diagnosis. However, temporal arteritis is known to discontinuously involve the artery, and there is no standardization of the number of sections which should be examined in a length of sampled artery. The goal of the study is to determine, if by examining additional sections from temporal artery (TA) biopsy cases initially interpreted as negative, do we uncover cases of vasculitis. We conducted a retrospective review of the clinical and histologic features of 75 consecutive temporal artery biopsy cases. Our findings showed that the vast majority (94%) of cases that were biopsy "proven" to be negative for temporal arteritis on initial examination remained negative after examination of all subsequent deeper levels (median of 337 total levels examined). These cases were less likely to show classical GCA signs and symptoms and typically presented at a younger age than the biopsy-positive cases. However, 4 (6%) of the initially "biopsy-negative" cases did turn out to be positive on deeper levels, with 56, 109, 346, and 590 total levels examined, respectively. At least 2 of these 4 patients did not receive prednisone or were weaned off prednisone treatment and experienced persistent/recurrent GCA symptoms. We conclude that routine sampling may miss the diagnosis in a subset of cases and in some cases, sectioning deeper into the paraffin block may be warranted.

Practice Preferences: Temporal Artery Biopsy versus Doppler Ultrasound in the Work-Up of Giant Cell Arteritis.

To determine whether temporal artery biopsy (TABx) or Doppler ultrasound (US) of the temporal artery is the preferred confirmatory test for giant cell arteritis, an online survey of ophthalmologists and neurologists in North America, Europe and Israel was conducted in 2019; Canadian rheumatologists were also included. There were 406 survey participants with an estimated survey response rate of 18%. Ninety-four per cent of North American practitioners preferred TABx compared with 74% of their European counterparts. Two per cent of North American practitioners preferred Doppler US versus 24% of European physicians. Regional differences were statistically significant (p < .001).

Survival predictors in biopsy-proven giant cell arteritis: a northern Italian population-based study.

OBJECTIVE: To evaluate the influence of disease-related findings and treatment outcomes on survival in a population-based cohort of Northern Italian patients with GCA. METHODS: A total of 281 patients with incident temporal artery biopsy (TAB)-proven GCA, diagnosed over a 26-year period (1986-2012) and living in the Reggio Emilia area, were retrospectively evaluated. We analysed clinical, imaging and laboratory findings at diagnosis, pathological patterns of TAB, CS treatment and therapeutic outcomes, and traditional cardiovascular risk factors as factors predictive of survival. RESULTS: Univariate analysis showed that increased mortality was associated with large vessel involvement at diagnosis [hazard ratio (HR) 5.84], while reduced mortality was associated with female sex (HR 0.66), PMR (HR 0.54), higher haemoglobin levels (HR 0.84) at diagnosis, long-term remission (HR 0.47) and inflammation limited to adventitia or to the adventitial vasa vasorum (HR 0.48) at TAB examination. Multivariate analysis confirmed the association between increased mortality and large vessel involvement (HR 5.14) at diagnosis, between reduced mortality and PMR (HR 0.57) at diagnosis and adventitial inflammation (HR 0.31) at TAB. CONCLUSION: PMR at diagnosis and inflammation limited to the adventitia at TAB appear to identify subsets of patients with more benign disease, while large vessel involvement at diagnosis is associated with reduced survival.