Takayasu Arteritis

BackgroundAssessing inflammatory disease activity in large vessel vasculitis (LVV) can be challenging by conventional measures.ObjectivesWe aimed to investigate somatostatin receptor 2 (SST2) as a novel inflammation-specific molecular imaging target in LVV.MethodsIn a prospective, observational cohort study, in vivo arterial SST2 expression was assessed by positron emission tomography/magnetic resonance imaging (PET/MRI) using 68Ga-DOTATATE and 18F-FET-βAG-TOCA. Ex vivo mapping of the imaging target was performed using immunofluorescence microscopy; imaging mass cytometry; and bulk, single-cell, and single-nucleus RNA sequencing.ResultsSixty-one participants (LVV: n = 27; recent atherosclerotic myocardial infarction of ≤2 weeks: n = 25; control subjects with an oncologic indication for imaging: n = 9) were included. Index vessel SST2 maximum tissue-to-blood ratio was 61.8% (P 2 signal was not elevated in any of the control subjects. SST2 PET/MRI was generally consistent with 18F-fluorodeoxyglucose PET/computed tomography imaging in LVV patients with contemporaneous clinical scans but with very low background signal in the brain and heart, allowing for unimpeded assessment of nearby coronary, myocardial, and intracranial artery involvement. Clinically effective treatment for LVV was associated with a 0.49 ± 0.24 (standard error of the mean [SEM]) (P = 0.04; 22.3%) reduction in the SST2 maximum tissue-to-blood ratio after 9.3 ± 3.2 months. SST2 expression was localized to macrophages, pericytes, and perivascular adipocytes in vasculitis specimens, with specific receptor binding confirmed by autoradiography. SSTR2-expressing macrophages coexpressed proinflammatory markers.ConclusionsSST2 PET/MRI holds major promise for diagnosis and therapeutic monitoring in LVV. (PET Imaging of Giant Cell and Takayasu Arteritis [PITA], NCT04071691; Residual Inflammation and Plaque Progression Long-Term Evaluation [RIPPLE], NCT04073810).

Autoimmune and autoinflammatory diseases of the medium and large arteries, including the aorta, cause life-threatening complications due to vessel wall destruction but also by wall remodeling, such as the formation of wall-penetrating microvessels and lumen-stenosing neointima. The two most frequent large vessel vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are HLA-associated diseases, strongly suggestive for a critical role of T cells and antigen recognition in disease pathogenesis. Recent studies have revealed a growing spectrum of effector functions through which T cells participate in the immunopathology of GCA and TAK; causing the disease-specific patterning of pathology and clinical outcome. Core pathogenic features of disease-relevant T cells rely on the interaction with endothelial cells, dendritic cells and macrophages and lead to vessel wall invasion, formation of tissue-damaging granulomatous infiltrates and induction of the name-giving multinucleated giant cells. Besides antigen, pathogenic T cells encounter danger signals in their immediate microenvironment that they translate into disease-relevant effector functions. Decisive signaling pathways, such as the AKT pathway, the NOTCH pathway, and the JAK/STAT pathway modify antigen-induced T cell activation and emerge as promising therapeutic targets to halt disease progression and, eventually, reset the immune system to reestablish the immune privilege of the arterial wall.

Giant cell arteritis (GCA) is a granulomatous systemic vasculitis of large- and medium-sized arteries that affects the elderly. In recent years, advances in diagnostic imaging have revealed a greater degree of large vessel involvement than previously recognized, distinguishing classical cranial- from large vessel (LV)- GCA. GCA often co-occurs with the poorly understood inflammatory arthritis/bursitis condition polymyalgia rheumatica (PMR) and has overlapping features with other non-infectious granulomatous vasculitides that affect the aorta, namely Takayasu Arteritis (TAK) and the more recently described clinically isolated aortitis (CIA). Here, we review the literature focused on the immunopathology of GCA on the background of the three settings in which comparisons are informative: LV and cranial variants of GCA; PMR and GCA; the three granulomatous vasculitides (GCA, TAK, and CIA). We discuss overlapping and unique features between these conditions across clinical presentation, epidemiology, imaging, and conventional histology. We propose a model of GCA where abnormally activated circulating cells, especially monocytes and CD4+ T cells, enter arteries after an unknown stimulus and cooperate to destroy it and review the evidence for how this mechanistically occurs in active disease and improves with treatment.

Takayasu arteritis (TAK) is a rare, immune-mediated large-vessel vasculitis that affects predominantly young women and carries a substantial risk of both vascular complications and long-term cardiovascular disease. Although glucocorticoids and conventional immunosuppressive therapies remain the cornerstone of treatment, relapse rates are high, and current strategies fail to adequately mitigate future cardiovascular risk. This review synthesizes evidence on current treatment strategies, unmet clinical needs, and novel approaches, including immunological and vascular-targeted therapies, and argues for a shift in management paradigm toward integrated cardiovascular risk reduction. We discuss advances in understanding the pathogenesis of TAK, highlighting the roles of innate and adaptive immunity in disease progression, and the challenges of early diagnosis and disease monitoring. We critically appraise current treatment paradigms, including glucocorticoids, conventional disease-modifying antirheumatic drugs, and biologics such as tocilizumab and tumor necrosis factor-α inhibitors, and outline emerging therapies targeting novel pathways, including interleukin-17, interleukin-12/23, Janus kinase/signal transducer and activator of transcription, and Notch-1/mammalian target of rapamycin complex signaling. We highlight the increasing recognition of cardiovascular morbidity as a major contributor to mortality in TAK and the need for integrated approaches to risk factor modification. We explore a road map for advancing management of cardiovascular disease in TAK, including comprehensive screening tools that integrate serological and imaging biomarkers to interrogate cardiovascular risk and potential therapeutic cardioprotective strategies such as sodium-glucose cotransporter 2 inhibitors and endothelin receptor antagonists. Despite recent progress, clinical management remains limited by diagnostic uncertainty, heterogeneous treatment approaches, and a paucity of high-quality randomized controlled trials. Future work should focus on interventions that target both immune-mediated vascular injury and cardiovascular disease progression. Achieving long-term disease remission while reducing cardiovascular mortality must become the primary therapeutic goal in TAK.