A direct comparison in diagnostic performance of CDUS, FDG-PET/CT and MRI in patients suspected of giant cell arteritis.

OBJECTIVES: This study directly compares diagnostic performance of Colour Duplex Ultrasound (CDUS), Fluor-18-deoxyglucose Positron Emission Tomography Computed Tomography (FDG-PET/CT) and Magnetic Resonance Imaging (MRI) in patients suspected of giant cell arteritis (GCA). METHODS: Patients with suspected GCA were included in a nested-case control pilot study. CDUS, whole body FDG-PET/CT and cranial MRI were performed within 5 working days after initial clinical evaluation. Clinical diagnosis after six months follow-up by experienced rheumatologists in the field of GCA, blinded for imaging, was used as reference standard. Diagnostic performance of the imaging modalities was determined. Stratification for GCA subtype was performed and imaging results were evaluated in different risk stratification groups. RESULTS: In total, 23 patients with GCA and 19 patients suspected of but not diagnosed with GCA were included. Sensitivity was 69.6% (95%CI 50.4%-88.8%) for CDUS, 52.2% (95%CI 31.4%-73.0%) for FDG-PET/CT and 56.5% (95%CI 35.8%-77.2%) for MRI. Specificity was 100% for CDUS, FDG-PET/CT and MRI. FDG-PET/CT was negative for GCA in all isolated cranial GCA patients (n = 8), while MRI was negative in all isolated extracranial GCA patients (n = 4). In 4 GCA patients with false-negative (n = 2; intermediate and high risk) or inconclusive (n = 2; low and intermediate risk) CDUS results, further imaging confirmed diagnosis. CONCLUSIONS: Sensitivity of CDUS was highest, while specificity was excellent in all imaging modalities. Nevertheless, confidence intervals of all imaging modalities were overlapping. Following EULAR recommendations, CDUS can be used as a first test to diagnose GCA. With insufficient evidence for GCA, further testing considering GCA subtype is warranted.

Diagnostic delay in patients with giant cell arteritis: results of a fast-track clinic.

Giant cell arteritis (GCA) can lead to severe complications if left untreated. The aim of this study was to describe time from onset of symptoms to diagnosis and treatment in GCA suspected patients in a fast-track clinic (FTC), and secondarily to assess the influence of GCA symptoms on this time. A retrospective cohort consisting of suspected GCA patients who visited the FTC between January 2017 and October 2019 was used. Time between symptom onset, first general practitioner visit, FTC referral, first FTC visit, and treatment initiation was analysed. Furthermore, this was stratified for subtypes of GCA and GCA symptoms. Of 205 patients referred with suspected GCA, 61 patients received a final diagnosis of GCA (GCA+) and 144 patients had no GCA (GCA-). Median time after onset of symptoms to first FTC visit was 31.0 days (IQR 13.0-108.8) in all referred patients. Time between onset of symptoms and first GP visit was 10.5 (4.0-36.3) days, and time between first GP visit and FTC referral was 10.0 (1.0-47.5) days. Patients were generally seen at the FTC within 1 day after referral. For patients with isolated cranial GCA (n = 41), median delay from onset of symptoms to treatment initiation was 21.0 days (11.0-73.5), while this was 57.0 days (33.0-105.0) in patients with extracranial large-vessel involvement (n = 20) (p = 0.02). Our results indicate considerable delay between symptom onset and FTC referral in patients suspected of GCA. Suspected patients were examined and GCA+ patients were treated instantly after referral. Key Points • GCA can cause severe complications with delayed treatment, but non-specific symptoms make diagnosis challenging. • Diagnostic delay still occurs despite introducing a successful fast-track clinic resulting from delay between start of symptoms and FTC referral. • Patients who presented with constitutional symptoms had longer delay than patients who presented with isolated cranial symptoms.

Evidence for increased interferon type I activity in CD8+ T cells in giant cell arteritis patients.

Introduction: Giant cell arteritis (GCA) is a vasculitis of the medium- and large-sized arteries. Interferon type I (IFN-I) is increasingly recognized as a key player in autoimmune diseases and might be involved in GCA pathogenesis, however evidence is limited. IFN-I activates Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways, leading to increased expression of interferon stimulated genes. In this study, IFN-I activity in GCA is explored, focusing on CD8+ T cells. Methods: Expression of phospho-STAT (pSTAT) 1, 3 and 5 was investigated in IFN-α-stimulated peripheral mononuclear cells (PBMCs) gated separately for CD8+ T cells of patients with GCA (n=18), healthy controls (HC, n=15) and infection controls (n=11) by Phosphoflow method combined with fluorescent cell barcoding technique. Furthermore, IFN-I induced myxovirus-resistance protein A (MxA) and CD8+ T cell expression was investigated by immunohistochemistry in temporal artery biopsies (TAB) of GCA patients (n=20) and mimics (n=20), and in aorta tissue of GCA (n=8) and atherosclerosis patients (n=14). Results: pSTAT1 expression was increased in IFN-α stimulated CD8+ T cells from GCA patients, whereas no difference was observed in pSTAT3 and pSTAT5 expression. MxA was present in TABs of 13/20 GCA patients compared to 2/20 mimics and in 8/8 GCA+ compared to 13/14 GCA- aorta tissues. MxA location partially co-localized with CD8+T cells. Conclusions: Our results provide evidence for increased IFN-I activity in CD8+ T cells of GCA patients, both systemically and locally. These findings warrant further investigation regarding IFN-I induced biomarkers and IFN-I related novel therapeutic options in GCA.

External validation of the 2022 ACR/EULAR classification criteria in patients with suspected giant cell arteritis in a Dutch fast-track clinic.

OBJECTIVE: Recently the Diagnostic and Classification Criteria in Vasculitis Study group developed and published new American College of Rheumatology/EULAR classification criteria for giant cell arteritis (GCA). To test robustness in a different clinical setting and inform clinicians on performance in clinical practice, we aim to externally validate them in patients with a suspicion of GCA referred to our GCA fast-track clinic. METHODS: Patients with suspected GCA from the Hospital Group Twente Early GCA in Twente prospective cohort were included. The clinical diagnosis of GCA verified after 6 months of follow-up made by the treating rheumatologist was used as a reference standard. A cut-off score of ≥6 was tested as described in the original article. Area under the receiver operating characteristics curve, sensitivity and specificity were calculated. RESULTS: In total, 133 patients with suspected GCA were included, of whom 53 were diagnosed with GCA and 80 patients were not diagnosed with GCA. The area under the curve (AUC) was 0.96 (95% CI 0.92 to 0.98). Using the proposed cut-off score of≥6, we found that sensitivity was 98.0% (95% CI 89.9% to 100%) and specificity was 57.5% (95% CI 45.9% to 68.5%). The majority of misclassified patients without GCA had classification scores of 6 and 7 as clinical and/or laboratory criteria were often present in our non-GCA population. CONCLUSION: Our results showed an excellent AUC and sensitivity with a moderate specificity for classification of GCA patients. Considering our relevant study population, we found that the new classification criteria might also be useful for diagnostic purposes, albeit with careful interpretation.

Comparing Diagnostic Performance of Short and Long [18F]FDG-PET Acquisition Times in Giant Cell Arteritis.

(1) Background: In giant cell arteritis (GCA), the assessment of cranial arteries using [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) combined with low-dose computed tomography (CT) may be challenging due to low image quality. This study aimed to investigate the effect of prolonged acquisition time on the diagnostic performance of [18F]FDG PET/CT in GCA. (2) Methods: Patients with suspected GCA underwent [18F]FDG-PET imaging with a short acquisition time (SAT) and long acquisition time (LAT). Two nuclear medicine physicians (NMPs) reported the presence or absence of GCA according to the overall image impression (gestalt) and total vascular score (TVS) of the cranial arteries. Inter-observer agreement and intra-observer agreement were assessed. (3) Results: In total, 38 patients were included, of whom 20 were diagnosed with GCA and 18 were without it. Sensitivity and specificity for GCA on SAT scans were 80% and 72%, respectively, for the first NMP, and 55% and 89% for the second NMP. On the LAT scans, these values were 65% and 83%, and 75% and 83%, respectively. When using the TVS, LAT scans showed especially increased specificity (94% for both NMPs). Observer agreement was higher on the LAT scans compared with that on the SAT scan. (4) Conclusions: LAT combined with the use of the TVS may decrease the number of false-positive assessments of [18F]FDG PET/CT. Additionally, LAT and TVS may increase both inter and intra-observer agreement.

External validation of the giant cell arteritis probability score in the Netherlands.

OBJECTIVES: To prevent complications of giant cell arteritis (GCA), early and accurate diagnosis is essential. Recently, Laskou et al. (2019) developed the giant cell arteritis probability score (GCAPS) which allows physicians to assess the likelihood of GCA at an early stage. The aim of this study was to validate the GCAPS in a Dutch hospital. METHODS: A retrospective cohort of patients with suspected GCA between January 1st, 2017 and October 1st, 2019 was used. As the variable extracranial artery abnormality was not measured, a modified GCAPS was used (m-GCAPS). Clinical diagnosis of the rheumatologist after six months follow-up was used as reference. The m-GCAPS was assessed for discrimination and calibration. We applied risk stratification according to Sebastian et al. (2020) (low, intermediate and high-risk groups based on the median and 75th percentile). RESULTS: Our study included 209 suspected GCA patients. 135 patients had complete records. Of these patients, 40 had GCA. The m-GCAPS had an area under the curve of 0.83, a sensitivity of 80.0% and specificity of 75.8% at the optimal cut-off value >10.5. The Hosmer-Lemeshow test was non-significant. Using risk stratification, GCA prevalence was 12.5% in the low (score<9), 23.3% in the intermediate (9-12) and 78.6% in the high-risk group (>12). CONCLUSIONS: The m-GCAPS showed good discrimination and calibration in a Dutch retrospective cohort and can aid early recognition of GCA. Stratification into low, intermediate and high-risk is promising, but might need optimisation.

A Tale of Diagnostic Delay with Detrimental Consequences: Illustrating the Challenging Nature of Diagnosing Giant Cell Arteritis.

Giant cell arteritis is a medical emergency as severe, irreversible complications may occur if it is not treated in a timely manner. However, in daily practice early diagnosis can be challenging. We report the case of a 70-year-old woman who presented with multiple ischaemic cerebral vascular accidents related to newly diagnosed giant cell arteritis. Review of her charts revealed a substantial delay from the onset of symptoms to diagnosis. This case demonstrates the need for additional efforts to reduce delay in referring patients with giant cell arteritis and the need to implement fast-track clinics to prevent serious complications. LEARNING POINTS: Giant cell arteritis is a medical emergency and unnecessary diagnostic delay can result in severe complications.Despite implementation of fast-track clinics, diagnostic delay still occurs due to the generic nature of signs and symptoms and inadequate case finding.As diagnostic delay can lead to preventable complications, increased knowledge and awareness of the characteristics and urgency of giant cell arteritis is needed among referring physicians.

Culture Conditions Affect Chemical-Induced Developmental Toxicity In Vitro: The Case of Folic Acid, Methionine and Methotrexate in the Neural Embryonic Stem Cell Test.

In vitro tests are increasingly applied in chemical hazard assessment. Basic culture conditions may affect the outcome of in vitro tests and should be optimised to reduce false predictions. The neural embryonic stem cell test (ESTn) can predict early neurodevelopmental effects of chemicals, as it mimics the differentiation of stem cells towards the neuroectodermal lineage. Normal early neural differentiation depends crucially on folic acid (FA) and methionine (MET), both elements of the one-carbon (1C) cycle. The aim of this study was to assess the concentration-dependent influence of FA and MET on neural differentiation in the ESTn, and its consequences for assay sensitivity to methotrexate (MTX), a compound that interferes with the 1C cycle. Neural differentiation was inhibited below 0.007 mM and above 0.22 mM FA, while both stem cell viability (< 0.097 mM, > 1.52 mM) and neural differentiation (< 0.181 mM, > 1.35 mM) were affected when changing MET concentrations. A 10-day exposure to 13 nM MTX inhibited neural differentiation, especially in FA- and MET-deficient conditions. However, a 24-hour exposure to 39 nM MTX decreased neural cell and neural crest cell differentiation markers only when the concentration of FA in the medium was three times the standard concentration, which was expected to have a protective effect against MTX. These results show the importance of nutrient concentrations, exposure scenarios and timing of read-outs for cell differentiation and compound sensitivity in the ESTn. Caution should be taken when interpreting results from a single in vitro test, especially when extrapolating to effects on complex morphogenetic processes, like neural tube development.