Large Vessel Vasculitis

2-[18F] fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) has become part of the worldwide standard of care in oncology. For a decade, this functional imaging tool has also demonstrated important diagnostic results in inflammatory diseases, especially in large vessel vasculitis (LVV). Since clinical PET imaging is increasingly used in these two conditions, this chapter aims to assist imaging specialists and clinicians by getting acquainted with the PET imaging procedures and the current status in clinical practice for LVV. General background information, PET technical considerations (including patient preparation, imaging protocols, scoring methodology), diagnostic and prognostic performance, and response monitoring will be addressed, in line with recent international expert-based recommendations.Also, in the era of personalized medicine, new hybrid technologies such as PET/MR and PET radiotracers will be discussed.</sub

Visual and semiquantitative assessment of cranial artery inflammation with FDG-PET/CT in giant cell arteritis

BACKGROUND AND AIM: Assessing cranial artery inflammation plays an important role in the diagnosis of cranial giant cell arteritis (C-GCA). However, current diagnostic tests are limited. The use of fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT imaging is an established tool for assessing large vessel inflammation but is currently not used for assessment of the cranial arteries. This study aimed to evaluate the accuracy of FDG-PET/CT in the diagnosis of biopsy proven C-GCA and its relation to clinical presentation. METHODS: This retrospective case control study included temporal artery biopsy (TAB) positive C-GCA patients and age- and sex-matched controls. FDG-PET/CT scans were performed according to EANM/EARL guidelines, visually assessed by an experienced nuclear medicine physician, and semiquantitatively assessed using the maximum standardised uptake value (SUVmax). The visual and semiquantitative assessments were performed on the temporal arteries, maxillary arteries, vertebral arteries, and occipital arteries. Clinical signs and symptoms were scored for comparison. RESULTS: A total of 24 C-GCA patients and 24 controls were included in the study. Visual analysis revealed an 83% sensitivity and a 75% specificity. Receiver operating characteristic (ROC) analysis of the semiquantitative assessment revealed a 79% sensitivity and a 92% specificity when measuring SUVmax in the cranial arteries. Visual and semiquantitative assessments showed moderate agreement (Fleiss kappa 0.55). There was a positive correlation between the number of cranial symptoms and the SUVmax in the vertebral artery. CONCLUSION: FDG-PET/CT can reliably diagnose C-GCA by assessing cranial artery inflammation using SUVmax. Extending the use of FDG-PET/CT to include assessment of the cranial arteries may improve its diagnostic value in GCA and provide a suitable alternative to TAB. Moderate agreement between visual and semiquantitative assessment methods suggest diagnostic accuracy may be improved by further standardisation

A Review on the Value of Imaging in Differentiating between Large Vessel Vasculitis and Atherosclerosis

Imaging is becoming increasingly important for the diagnosis of large vessel vasculitis (LVV). Atherosclerosis may be difficult to distinguish from LVV on imaging as both are inflammatory conditions of the arterial wall. Differentiating atherosclerosis from LVV is important to enable optimal diagnosis, risk assessment, and tailored treatment at a patient level. This paper reviews the current evidence of ultrasound (US), 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET), computed tomography (CT), and magnetic resonance imaging (MRI) to distinguish LVV from atherosclerosis. In this review, we identified a total of eight studies comparing LVV patients to atherosclerosis patients using imaging-four US studies, two FDG-PET studies, and two CT studies. The included studies mostly applied different methodologies and outcome parameters to investigate vessel wall inflammation. This review reports the currently available evidence and provides recommendations on further methodological standardization methods and future directions for research

Limitations and Pitfalls of FDG-PET/CT in Infection and Inflammation

White blood cells activated by either a pathogen or as part of a systemic inflammatory disease are characterized by high energy consumption and are therefore taking up the glucose analogue PET tracer FDG avidly. It is therefore not surprising that a steadily growing body of research and clinical reports now supports the use of FDG PET/CT to diagnose a wide range of patients with non-oncological diseases. However, using FDG PET/CT in patients with infectious or inflammatory diseases has some limitations and potential pitfalls that are not necessarily as pronounced in oncology FDG PET/CT. Some of these limitations are of a general nature and related to the laborious acquisition of PET images in patients that are often acutely ill, whereas others are more disease-specific and related to the particular metabolism in some of the organs most commonly affected by infections or inflammatory disease. Both inflammatory and infectious diseases are characterized by a more diffuse and less pathognomonic pattern of FDG uptake than oncology FDG PET/CT and the affected organs also typically have some physiological FDG uptake. In addition, patients referred to PET/CT with suspected infection or inflammation are rarely treatment naïve and may have received varying doses of antibiotics, corticosteroids or other immune-modulating drugs at the time of their examination. Combined, this results in a higher rate of false positive FDG findings and also in some cases a lower sensitivity to detect active disease. In this review, we therefore discuss the limitations and pitfalls of FDG PET/CT to diagnose infections and inflammation taking these issues into consideration. Our review encompasses the most commonly encountered inflammatory and infectious diseases in head and neck, in the cardiovascular system, in the abdominal organs and in the musculoskeletal system. Finally, new developments in the field of PET/CT that may help overcome some of these limitations are briefly highlighted

Novel PET Imaging of Inflammatory Targets and Cells for the Diagnosis and Monitoring of Giant Cell Arteritis and Polymyalgia Rheumatica

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are two interrelated inflammatory diseases affecting patients above 50 years of age. Patients with GCA suffer from granulomatous inflammation of medium- to large-sized arteries. This inflammation can lead to severe ischemic complications (e.g., irreversible vision loss and stroke) and aneurysm-related complications (such as aortic dissection). On the other hand, patients suffering from PMR present with proximal stiffness and pain due to inflammation of the shoulder and pelvic girdles. PMR is observed in 40-60% of patients with GCA, while up to 21% of patients suffering from PMR are also affected by GCA. Due to the risk of ischemic complications, GCA has to be promptly treated upon clinical suspicion. The treatment of both GCA and PMR still heavily relies on glucocorticoids (GCs), although novel targeted therapies are emerging. Imaging has a central position in the diagnosis of GCA and PMR. While [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) has proven to be a valuable tool for diagnosis of GCA and PMR, it possesses major drawbacks such as unspecific uptake in cells with high glucose metabolism, high background activity in several non-target organs and a decrease of diagnostic accuracy already after a short course of GC treatment. In recent years, our understanding of the immunopathogenesis of GCA and, to some extent, PMR has advanced. In this review, we summarize the current knowledge on the cellular heterogeneity in the immunopathology of GCA/PMR and discuss how recent advances in specific tissue infiltrating leukocyte and stromal cell profiles may be exploited as a source of novel targets for imaging. Finally, we discuss prospective novel PET radiotracers that may be useful for the diagnosis and treatment monitoring in GCA and PMR.</p

Comparison and validation of FDG-PET/CT scores for polymyalgia rheumatica

OBJECTIVES: To compare and validate the diagnostic accuracy of fluorodeoxyglucose (FDG)-PET/CT scores for PMR; and to explore their association with clinical factors. METHODS: This retrospective study included 39 consecutive patients diagnosed with PMR and 19 PMR comparators. The final clinical diagnosis was established after 6 months follow-up. Patients underwent FDG-PET/CT prior to glucocorticoid treatment. Visual grading of FDG uptake was performed at 30 anatomic sites. Three FDG-PET/CT scores (the Leuven Score, two Besançon Scores) and two algorithms (the Saint-Etienne and Heidelberg Algorithms) were investigated. Receiver operating characteristic (ROC) analysis with area under the curve (AUC) was performed. Diagnostic accuracy was assessed at predefined cut-off points. RESULTS: All three FDG-PET/CT scores showed high diagnostic accuracy for a clinical diagnosis of PMR in the ROC analysis (AUC 0.889–0.914). The Leuven Score provided a sensitivity of 89.7% and specificity of 84.2% at its predefined cut-off point. A simplified Leuven Score showed similar diagnostic accuracy to that of the original score. The Besançon Scores showed limited specificity at their predefined cut-off points (i.e. 47.4% and 63.2%), while ROC analysis suggested that substantially higher cut-off points are needed for these scores. The Heidelberg and Saint-Etienne Algorithms demonstrated high sensitivity, but lower specificity (i.e. 78.9% and 42.1%, respectively) for PMR. Female sex and presence of large-vessel vasculitis were associated with lower FDG-PET/CT scores in patients with PMR. CONCLUSION: The Leuven Score showed the highest diagnostic utility for PMR. A modified, concise version of the Leuven Score provided similar diagnostic accuracy to that of the original score

Plasma Pyruvate Kinase M2 as a marker of vascular inflammation in Giant Cell Arteritis

OBJECTIVES: Giant Cell Arteritis (GCA) is a large vessel vasculitis in which metabolically active immune cells play an important role. GCA diagnosis is based on CRP/ESR and temporal artery biopsies (TABs), in combination with [18F]FDG-PET/CT relying on enhanced glucose uptake by glycolytic macrophages. Here, we studied circulating Pyruvate Kinase M2 (PKM2), a glycolytic enzyme, as a possible systemic marker of vessel wall inflammation in GCA. METHODS: Immunohistochemical detection of PKM2 was performed on inflamed (n = 12) and non-inflamed (n = 4) TABs from GCA patients and non-GCA (n = 9) patients. Dimeric PKM2 levels were assessed in plasma of GCA patients (n = 44), age-matched healthy controls (HC, n = 41), metastatic melanoma patients (n = 7) and infection controls (n = 11). CRP, ESR and macrophage markers calprotectin and YKL-40 were correlated with plasma PKM2 levels. To detect the cellular source of plasma PKM2 in tissue, double immunofluorescence staining was performed on inflamed GCA TABs. [18F]FDG-PET scans of 23 GCA patients were analyzed and maximum standard uptake values (SUVmax) and target to background ratios (TBR) were calculated. RESULTS: PKM2 is abundantly expressed in TABs of GCA patients. Dimeric PKM2 plasma levels were elevated in GCA and correlated with CRP, ESR, calprotectin, and YKL-40 levels. Elevated plasma PKM2 levels were downmodulated by GC-treatment. PKM2 was detected in both macrophages and T cells at the site of vascular inflammation. Circulating PKM2 levels correlated with average TBR PET scores. CONCLUSION: Elevated plasma PKM2 levels reflect active vessel inflammation in GCA and may assist in disease diagnosis and in disease monitoring

18F-BMS986192 PET imaging of PD-L1 in metastatic melanoma patients with brain metastases treated with immune checkpoint inhibitors:A pilot study

Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 frequently induces tumor response in metastatic melanoma patients. However, tumor response often takes months and may be heterogeneous. Consequently, additional local treatment for non-responsive metastases may be needed, especially in the case of brain metastases. Non-invasive imaging may allow the characterization of (brain) metastases to predict response. This pilot study uses 18F-BMS986192 PET for PD-L1 expression to explore the variability in metastatic tracer uptake and its relation to tumor response, with a special focus on brain metastases. Methods: Metastatic melanoma patients underwent whole-body 18F-BMS986192 PET/CT scanning before and 6 weeks after starting ICI therapy. 18F-BMS986192 uptake was measured in healthy tissues, organs, and tumor lesions. Tumor response was evaluated at 12 weeks using CT thorax/abdomen and MRI brain. RECIST v 1.1 was used to define therapy response per patient. Response per lesion was measured by the percentage change in lesion diameter. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.0. Results: Baseline 18F-BMS986192 PET/CT was performed in 8 patients, with follow-up scans in 4 patients. The highest tracer uptake was observed in the spleen, bone marrow, kidneys, and liver. Tracer uptake in tumor lesions was heterogeneous. In total, 42 tumor lesions were identified at baseline with most lesions in the lungs (n = 21) and brain (n = 14). Tracer uptake was similar between tumor locations. 18F-BMS986192 uptake in lesions at baseline, corrected for blood pool activity, was negatively correlated with the change lesion diameter at response evaluation (r=-0.49, P = 0.005), both in intra- and extracerebral lesions. Receiver operating characteristic (ROC) analysis demonstrated that 18F-BMS986192 uptake can discriminate between responding and nonresponding lesions with an area under the curve of 0.82. At the follow-up scan an increased 18F-BMS986192 uptake compared to baseline scan was correlated with an increased lesion diameter at response evaluation. In the follow-up 18F-BMS986192-PET scan of two patients, ICI-related toxicity (thyroiditis and colitis) was detected. Conclusion: In this pilot study, 18F-BMS986192 PET showed heterogeneous uptake in intra and extracerebral metastatic lesions in melanoma patients. Baseline 18F-BMS986192 uptake was able to predict an ICI treatment-induced reduction in lesion volume, whereas the follow-up PET scan allowed the detection of treatment-induced toxicity