Current Insights into Tissue Injury of Giant Cell Arteritis: From Acute Inflammatory Responses towards Inappropriate Tissue Remodeling.

Giant cell arteritis (GCA) is an autoimmune disease affecting large vessels in patients over 50 years old. It is an exemplary model of a classic inflammatory disorder with IL-6 playing the leading role. The main comorbidities that may appear acutely or chronically are vascular occlusion leading to blindness and thoracic aorta aneurysm formation, respectively. The tissue inflammatory bulk is expressed as acute or chronic delayed-type hypersensitivity reactions, the latter being apparent by giant cell formation. The activated monocytes/macrophages are associated with pronounced Th1 and Th17 responses. B-cells and neutrophils also participate in the inflammatory lesion. However, the exact order of appearance and mechanistic interactions between cells are hindered by the lack of cellular and molecular information from early disease stages and accurate experimental models. Recently, senescent cells and neutrophil extracellular traps have been described in tissue lesions. These structures can remain in tissues for a prolonged period, potentially favoring inflammatory responses and tissue remodeling. In this review, current advances in GCA pathogenesis are discussed in different inflammatory phases. Through the description of these-often overlapping-phases, cells, molecules, and small lipid mediators with pathogenetic potential are described.

Giant Cell Arteritis: Advances in Understanding Pathogenesis and Implications for Clinical Practice.

Giant cell arteritis (GCA) is a noninfectious granulomatous vasculitis of unknown etiology affecting individuals older than 50 years. Two forms of GCA have been identified: a cranial form involving the medium-caliber temporal artery causing temporal arteritis (TA) and an extracranial form involving the large vessels, mainly the thoracic aorta and its branches. GCA generally affects individuals with a genetic predisposition, but several epigenetic (micro)environmental factors are often critical for the onset of this vasculitis. A key role in the pathogenesis of GCA is played by cells of both the innate and adaptive immune systems, which contribute to the formation of granulomas that may include giant cells, a hallmark of the disease, and arterial tertiary follicular organs. Cells of the vessel wall cells, including vascular smooth muscle cells (VSMCs) and endothelial cells, actively contribute to vascular remodeling responsible for vascular stenosis and ischemic complications. This review will discuss new insights into the molecular and cellular pathogenetic mechanisms of GCA, as well as the implications of these findings for the development of new diagnostic biomarkers and targeted drugs that could hopefully replace glucocorticoids (GCs), still the backbone of therapy for this vasculitis.

The Contribution of Innate Immunity in Large-Vessel Vasculitis: Detangling New Pathomechanisms beyond the Onset of Vascular Inflammation.

Large-vessel vasculitis (LVV) are autoimmune and autoinflammatory diseases focused on vascular inflammation. The central core of the intricate immunological and molecular network resides in the disruption of the "privileged immune state" of the arterial wall. The outbreak, initially primed by dendritic cells (DC), is then continuously powered in a feed-forward loop by the intimate cooperation between innate and adaptive immunity. If the role of adaptive immunity has been largely elucidated, knowledge of the critical function of innate immunity in LVV is still fragile. A growing body of evidence has strengthened the active role of innate immunity players and their key signaling pathways in orchestrating the complex pathomechanisms underlying LVV. Besides DC, macrophages are crucial culprits in LVV development and participate across all phases of vascular inflammation, culminating in vessel wall remodeling. In recent years, the variety of potential pathogenic actors has expanded to include neutrophils, mast cells, and soluble mediators, including the complement system. Interestingly, new insights have recently linked the inflammasome to vascular inflammation, paving the way for its potential pathogenic role in LVV. Overall, these observations encourage a new conceptual approach that includes a more in-depth study of innate immunity pathways in LVV to guide future targeted therapies.

The contributions of deleterious rare alleles in NLRP12 and inflammasome-related genes to polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is a chronic inflammatory disease characterized by arthralgia and myalgia of the shoulder and hip girdles, and fever. PMR is linked to autoimmune diseases and autoinflammatory disorders. Exome sequencing has revealed the roles of rare variants in some diseases. Causative genes for monogenic autoinflammatory disorders might be candidate genes for the selective exome analysis of PMR. We investigated rare variants in the coding and boundary regions of candidate genes for PMR. Exome sequencing was performed to analyze deleterious rare variants in candidate genes, and the frequencies of the deleterious rare alleles in PMR were compared with those of Japanese population controls. Deleterious rare alleles in the NLRL12 gene were associated with PMR (P = 0.0069, Pc = 0.0415, odds ratio [OR] 4.49, 95% confidence interval [CI] 1.79-11.27). A multigene analysis demonstrated the deleterious rare allele frequency of the candidate genes for autoinflammatory disorders was also increased in PMR (P = 0.0016, OR 3.69, 95%CI 1.81-7.54). The deleterious rare allele frequencies of the candidate genes including NLRP12 were increased in PMR patients, showing links to autoinflammatory disorders in the pathogenesis of PMR.

Assessment and comparison of probability scores to predict giant cell arteritis.

INTRODUCTION/OBJECTIVES: To assess and compare the performance of the giant cell arteritis probability score (GCAPS), Ing score, Bhavsar-Khalidi score (BK score), color Doppler ultrasound (CDUS) halo count, and halo score, to predict a final diagnosis of giant cell arteritis (GCA). METHOD: A prospective cohort study was conducted from April to December 2021. Patients with suspected new-onset GCA referred to our quaternary CDUS clinic were included. Data required to calculate each clinical and CDUS probability score was systematically collected at the initial visit. Final diagnosis of GCA was confirmed clinically 6 months after the initial visit, by two blinded vasculitis specialists. Diagnostic accuracy and receiver operator characteristic (ROC) curves for each clinical and CDUS prediction scores were assessed. RESULTS: Two hundred patients with suspected new-onset GCA were included: 58 with confirmed GCA and 142 without GCA. All patients with GCA satisfied the 2022 ACR/EULAR classification criteria. A total of 5/15 patients with GCA had a positive temporal artery biopsy. For clinical probability scores, the GCAPS showed the best sensitivity (Se, 0.983), whereas the BK score showed the best specificity (Sp, 0.711). As for CDUS, a halo count of 1 or more was found to have a Se of 0.966 and a Sp of 0.979. Combining concordant results of clinical and CDUS prediction scores showed excellent performance in predicting a final diagnosis of GCA. CONCLUSION: Using a combination of clinical score and CDUS halo count provided an accurate GCA prediction method which should be used in the setting of GCA Fast-Track clinics. Key Points • In this prospective cohort of participants with suspected GCA, 3 clinical prediction tools and 2 ultrasound scores were compared head-to-head to predict a final diagnosis of GCA. • For clinical prediction tools, the giant cell arteritis probability score (GCAPS) had the highest sensitivity, whereas the Bhavsar-Khalidi score (BK score) had the highest specificity. • Ultrasound halo count was both sensitive and specific in predicting GCA. • Combination of a clinical prediction tool such as the GCAPS, with ultrasound halo count, provides an accurate method to predict GCA.

Use of high-plex data provides novel insights into the temporal artery processes of giant cell arteritis.

Objective: To identify the key coding genes underlying the biomarkers and pathways associated with giant cell arteritis (GCA), we performed an in situ spatial profiling of molecules involved in the temporal arteries of GCA patients and controls. Furthermore, we performed pharmacogenomic network analysis to identify potential treatment targets. Methods: Using human formalin-fixed paraffin-embedded temporal artery biopsy samples (GCA, n = 9; controls, n = 7), we performed a whole transcriptome analysis using the NanoString GeoMx Digital Spatial Profiler. In total, 59 regions of interest were selected in the intima, media, adventitia, and perivascular adipose tissue (PVAT). Differentially expressed genes (DEGs) (fold-change > 2 or < -2, p-adjusted < 0.01) were compared across each layer to build a spatial and pharmacogenomic network and to explore the pathophysiological mechanisms of GCA. Results: Most of the transcriptome (12,076 genes) was upregulated in GCA arteries, compared to control arteries. Among the screened genes, 282, 227, 40, and 5 DEGs were identified in the intima, media, adventitia, and PVAT, respectively. Genes involved in the immune process and vascular remodeling were upregulated within GCA temporal arteries but differed across the arterial layers. The immune-related functions and vascular remodeling were limited to the intima and media. Conclusion: This study is the first to perform an in situ spatial profiling characterization of the molecules involved in GCA. The pharmacogenomic network analysis identified potential target genes for approved and novel immunotherapies.

Performance of the new 2022 ACR/EULAR classification criteria for giant cell arteritis in clinical practice in relation to its clinical phenotypes.

BACKGROUND: To examine the performance of the new 2022 American College of Rheumatology (ACR)/EULAR classification criteria for giant cell arteritis (GCA) in routine clinical care, compared with the 1990 ACR GCA classification criteria. METHODS: The fulfilment of 2022 ACR/EULAR and 1990 ACR criteria was tested in our real-life cohort of GCA patients with proven vasculitis by temporal artery biopsy or imaging (a necessary pre-requisite to apply the new criteria is the presence of a confirmed diagnosis of medium- or large-vessel vasculitis). The performance of classification criteria was evaluated in all patients with GCA across different subsets of the disease. Patients with GCA were compared with unselected controls with suspected GCA. RESULTS: A total of 136 patients with proven GCA were identified. The new criteria had a sensitivity of 92.6% and a specificity of 85.2%. According to the clinical phenotypes, the sensitivity was 98.8% in cranial GCA, 92% in extracranial large vessel (LV) GCA and 75% in occult systemic GCA. These data are much better than those observed with the 1990 ACR classification criteria, which showed a sensitivity of 66.1% and a specificity of 85.1% for the total sample, with a sensitivity of 89.1% in cranial GCA, 24% in extracranial LV-GCA and 35.7% in occult systemic GCA. Ten (7.4%) patients in our cohort did not fulfil either of the criteria sets (8 with occult systemic GCA and 2 with extracranial LV-GCA). The sensitivity of the new criteria in patients with occult systemic and extracranial LV-GCA could be greatly improved assigning more weight (3 points) to some imaging findings (axillary involvement and FDG-PET activity throughout the aorta). CONCLUSION: Our study confirms that the new classification criteria are more sensitive in real-life settings than the old ACR criteria across all clinical phenotypes.

Age-related histopathological findings in temporal arteries.

AIMS: Giant cell arteritis (GCA) is a systemic vasculitis affecting medium and large arteries in patients aged over 50 years. Involvement of temporal arteries (TA) can lead to complications such as blindness and stroke. While the diagnostic gold standard is temporal artery biopsy (TAB), comorbidities and age-related changes can make interpretation of such specimens difficult. This study aims to establish a baseline of TA changes in subjects without GCA to facilitate the interpretation of TAB. METHODS AND RESULTS: Bilateral TA specimens were collected from 100 consecutive eligible postmortem examinations. Subjects were divided into four age groups and specimens semiquantitatively evaluated for eccentric intimal fibroplasia, disruption and calcification of the internal elastic lamina (IEL), medial attenuation and degree of lymphocytic inflammation of the peri-adventitia, adventitia, media and intima. The individual scores of intimal fibroplasia, IEL disruption and medial attenuation were added to yield a 'combined score (CS)'. Seventy-eight 78 decedents were included in the final analysis following exclusion of 22 individuals for either lack of clinical information or inability to collect TA tissue. A total of 128 temporal artery specimens (50 bilateral from individual decedents, 28 unilateral) were available for examination. Intimal proliferation, IEL loss, IEL calcification and CS increased with age in a statistically significant fashion. Comparison of the oldest age group with the others showed statistically significant differences, although this was not uniformly preserved in comparison between the three youngest groups. CONCLUSION: Senescent arterial changes and healed GCA exhibit histological similarity and such changes increase proportionally with age. The CS demonstrates significant association with age overall and represents a potential avenue for development to 'normalise' TA biopsies from older individuals.

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.

Incidence of giant cell arteritis mimicking non-arteritic anterior optic neuropathy.

PURPOSE: Giant cell arteritis (GCA) involving ophthalmic circulation often manifests as anterior ischemic optic neuropathy (AAION), presenting with severe vision loss and pallid optic disc edema. Non-arteritic anterior ischemic optic neuropathy (NAION) classically presents with segmental optic disc edema and corresponding altitudinal visual field defect (VFD) with small cup-to-disc ratio in the fellow eye. Differentiating these two entities is critical as GCA requires immediate treatment to prevent vision loss in the fellow eye. This study investigated how often GCA mimics NAION at presentation. METHODS: Retrospective chart review of patients with temporal artery biopsy (TAB) positive GCA with ocular manifestations seen at a tertiary neuro-ophthalmology practice between 2015 and 2020. Patients presenting with segmental non-pallid optic disc swelling and corresponding altitudinal VFD mimicking NAION were identified. RESULTS: The clinical presentation of 7.1% (3/42) of patients with TAB-positive GCA mimicked NAION. Two of three patients had cup-to-disc ratio of <0.3 in the fellow eye. Two patients were women, mean age was 67.3 ± 6.5 years, and mean presenting visual acuity was 0.45 ± 0.48 LogMAR. Two patients had a normal temporal artery ultrasound. Two of three patients had at least one systemic symptom of GCA at presentation and all had elevation of one or both inflammatory markers. CONCLUSIONS: There should be high index of suspicion for GCA, even in patients highly suspected to have NAION. Inflammatory markers must be checked in every patient with presumed NAION and TAB performed if one or both are elevated to avoid missing GCA.

Arterial wall fibrosis in Takayasu arteritis and its potential for therapeutic modulation.

Arterial wall damage in Takayasu arteritis (TAK) can progress despite immunosuppressive therapy. Vascular fibrosis is more prominent in TAK than in giant cell arteritis (GCA). The inflamed arterial wall in TAK is infiltrated by M1 macrophages [which secrete interleukin-6 (IL-6)], which transition to M2 macrophages once the inflammation settles. M2 macrophages secrete transforming growth factor beta (TGF-ß) and glycoprotein non-metastatic melanoma protein B (GPNMB), both of which can activate fibroblasts in the arterial wall adventitia. Mast cells in the arterial wall of TAK also activate resting adventitial fibroblasts. Th17 lymphocytes play a role in both TAK and GCA. Sub-populations of Th17 lymphocytes, Th17.1 lymphocytes [which secrete interferon gamma (IFN-γ) in addition to interleukin-17 (IL-17)] and programmed cell death 1 (PD1)-expressing Th17 (which secrete TGF-ß), have been described in TAK but not in GCA. IL-6 and IL-17 also drive fibroblast activation in the arterial wall. The Th17 and Th1 lymphocytes in TAK demonstrate an activation of mammalian target organ of rapamycin 1 (mTORC1) driven by Notch-1 upregulation. A recent study reported that the enhanced liver fibrosis score (derived from serum hyaluronic acid, tissue inhibitor of metalloproteinase 1, and pro-collagen III amino-terminal pro-peptide) had a moderate-to-strong correlation with clinically assessed and angiographically assessed vascular damage. In vitro experiments suggest the potential to target arterial wall fibrosis in TAK with leflunomide, tofacitinib, baricitinib, or mTORC1 inhibitors. Since arterial wall inflammation is followed by fibrosis, a strategy of combining immunosuppressive agents with drugs that have an antifibrotic effect merits exploration in future clinical trials of TAK.

Deficiency of the CD155-CD96 immune checkpoint controls IL-9 production in giant cell arteritis.

Loss of function of inhibitory immune checkpoints, unleashing pathogenic immune responses, is a potential risk factor for autoimmune disease. Here, we report that patients with the autoimmune vasculitis giant cell arteritis (GCA) have a defective CD155-CD96 immune checkpoint. Macrophages from patients with GCA retain the checkpoint ligand CD155 in the endoplasmic reticulum (ER) and fail to bring it to the cell surface. CD155low antigen-presenting cells induce expansion of CD4+CD96+ T cells, which become tissue invasive, accumulate in the blood vessel wall, and release the effector cytokine interleukin-9 (IL-9). In a humanized mouse model of GCA, recombinant human IL-9 causes vessel wall destruction, whereas anti-IL-9 antibodies efficiently suppress innate and adaptive immunity in the vasculitic lesions. Thus, defective surface translocation of CD155 creates antigen-presenting cells that deviate T cell differentiation toward Th9 lineage commitment and results in the expansion of vasculitogenic effector T cells.

Indication of Activated Senescence Pathways in the Temporal Arteries of Patients With Giant Cell Arteritis.

OBJECTIVE: Giant cell arteritis (GCA) affects almost exclusively individuals above 50 years old, suggesting a role of aging-related changes such as cellular senescence in its pathobiology. The kinases p21(WAF1/CIP1) and p16/INK4A play key roles in 2 distinct pathways leading to senescence. The proinflammatory molecules interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are key components of the senescence-associated secretory phenotype (SASP), are effective targets of treatment in GCA. Here, we aimed to investigate the presence of p21+ and p16+ cells producing these SASP cytokines in temporal artery biopsies (TABs) of patients with GCA. METHODS: Eight patients with GCA and 14 age-matched, non-GCA individuals who underwent a TAB were included. Immunohistochemical staining of p21, p16, IL-6, and GM-CSF was performed. Multiplex immunofluorescent staining was performed to investigate the colocalization of p21 and p16 with IL-6, GM-CSF, and immune cell markers (CD68, CD3, CD20). RESULTS: We found that expression levels of p16, p21, IL-6, and GM-CSF were elevated in the TABs of patients with GCA. Both p16- and p21-expressing cells were mainly found near the internal lamina elastica, especially among giant cells and macrophages, although p21 and p16 expression could be found in all 3 layers of the vessels. Expression of p16 and p21 was occasionally found in T cells but not B cells. The p16+ and p21+ cells expressing GM-CSF/IL-6 were detected throughout the TABs. CONCLUSION: Our data suggest the presence of activated senescence pathways at the site of vascular inflammation in GCA and support further research into the role of senescence in the pathophysiology of GCA.

Cranial and extracranial giant cell arteritis do not exhibit differences in the IL6 -174 G/C gene polymorphism.

OBJECTIVES: Since interleukin-6 (IL-6) is a pivotal proinflammatory cytokine implicated in the pathogenesis of giant cell arteritis (GCA), we aimed to determine the potential association of the functional IL6 -174 G/C polymorphism with GCA as well as if the single base change variation at the promoter region in the human IL-6 gene may account for differences in the clinical spectrum of GCA between cranial and extracranial large vessel vasculitis (LVV)-GCA. METHODS: The IL6 -174 G/C polymorphism (rs1800795) was genotyped in 191 patients with biopsy-proven GCA who had typical cranial manifestations of the disease, 109 patients with extracranial LVV-GCA, without cranial ischaemic manifestations of GCA, and 877 ethnically matched unaffected controls. A comparative study was carried out between patients with cranial and extracranial LVV-GCA and controls. RESULTS: No significant differences in genotype and allele frequencies of IL6 -174 G/C polymorphism were found between the whole cohort of GCA patients and healthy controls. It was also the case when cranial and extracranial LVV-GCA were compared or when each of these subgroups was compared to controls. Moreover, no significant results in genotype and allele frequencies of IL6 -174 G/C polymorphism were disclosed when the whole cohort of GCA patients were stratified according to the presence of polymyalgia rheumatica, severe ischaemic manifestations, including permanent visual loss and peripheral arteriopathy, and HLA-DRB1*04:01 status. CONCLUSIONS: Our results show that the IL6 -174 G/C polymorphism does not influence the phenotypic expression of GCA.

Temporal Artery Biopsy: When Is It Worth the Headache?

BACKGROUND: Temporal artery biopsy is ordered when clinical symptoms and an elevated C-reactive protein values and/or erythrocyte sedimentation rates suggest giant cell arteritis. The percentage of temporal artery biopsies positive for giant cell arteritis is low. The objectives of our study were to analyze the diagnostic yield of temporal artery biopsies at an independent academic medical center and to develop a risk stratification model for triaging patients for possible temporal artery biopsy. METHODS: We retrospectively reviewed the electronic health records of all patients who underwent temporal artery biopsy in our institution from January 2010 through February 2020. We compared clinical symptoms and inflammatory marker (C-reactive protein and erythrocyte sedimentation rate) values of patients whose specimens were positive for giant cell arteritis with those of patients with negative specimens. Statistical analysis included descriptive statistics, chi-square test, and multivariable logistic regression. A risk stratification tool, which included point assignments and measures of performance, was developed. RESULTS: Of 497 temporal artery biopsies for giant cell arteritis performed, 66 were positive and 431 were negative. Jaw/tongue claudication, elevated inflammatory marker values, and age were associated with a positive result. Using our risk stratification tool, 3.4% of low-risk patients, 14.5% of medium-risk patients, and 43.9% of high-risk patients were positive for giant cell arteritis. CONCLUSIONS: Jaw/tongue claudication, age, and elevated inflammatory markers were associated with positive biopsy results. Our diagnostic yield was much lower when compared with a benchmark yield determined in a published systematic review. A risk stratification tool was developed based on age and the presence of independent risk factors.

Listeria rhombencephalitis mimicking stroke in a patient with giant cell arteritis.

Listeria monocytogenes sometimes causes central nervous system infections. However, rhombencephalitis is a rare form of L. monocytogenes infection. Its clinical symptoms and magnetic resonance imaging (MRI) findings are often similar to those of vertebrobasilar stroke. We present the case of a 79-year-old woman with Listeria rhombencephalitis presenting with rhinorrhea and productive cough. She had giant cell arteritis (GCA) treated with prednisolone and methotrexate. She was admitted for loss of appetite, rhinorrhea, and productive cough. These symptoms were alleviated without specific treatment; however, she suddenly developed multiple cranial nerve palsies, and MRI showed hyperintense signals on diffusion-weighted imaging and hypointense signals on apparent diffusion coefficient in the brainstem. Ischemic stroke due to exacerbation of GCA was suspected, and treatment with intravenous methylprednisolone was initiated; however, seizures occurred, and a lumbar puncture was performed. Cerebrospinal fluid and blood cultures revealed L. monocytogenes, and she was diagnosed with Listeria rhombencephalitis. Although antibiotic treatment was continued, the patient died. Thus, when patients with rhinorrhea or productive cough develop sudden cranial nerve palsy, Listeria rhombencephalitis should be considered as a differential diagnosis, and lumbar puncture should be performed.

Myelomonocytic cells in giant cell arteritis activate trained immunity programs sustaining inflammation and cytokine production.

OBJECTIVE: Trained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production. METHODS: Monocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes. RESULTS: GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production. CONCLUSIONS: Myelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production.

The Effect of Corticosteroids on Temporal Artery Biopsy Positivity in Giant Cell Arteritis: Timing is Everything.

OBJECTIVE: Temporal artery biopsy (TAB) remains the standard criterion for the diagnosis of giant cell arteritis (GCA). Temporal artery biopsy is suggested to be performed within 2 weeks from the initiation of corticosteroids. However, the effects of TAB timing on the sensitivity of its findings still warrant further investigation. METHODS: We reviewed the medical records of patients with GCA from a tertiary medical center in Germany over an 8-year period. RESULTS: We analyzed data from 109 patients with a median age of 76 years and a median time from glucocorticoid treatment to TAB of 4 days. Approximately 60% of biopsies were positive. Our analysis yielded a nonsignificant trend toward shorter duration of corticosteroid treatment in the TAB(+) group ( p = 0.06). A more than 7 days' duration of steroid treatment was independently linked with lower rates of positive TAB (adjusted odds ratio, 0.33; 95% confidence interval, 0.11-1.00). CONCLUSION: We conclude that the duration of corticosteroid treatment seems to affect the positivity of TAB in patients with suspected GCA. Further larger studies are required to confirm the generalizability of our findings.

Fast-track pathway for early diagnosis and management of giant cell arteritis: the combined role of vascular ultrasonography and [18F]-fluorodeoxyglucose PET-computed tomography imaging.

Giant cell arteritis (GCA) is a medical emergency, which can lead to irreversible blindness and other ischaemic vascular events if left untreated. Prompt access to specialist assessment, diagnostics in the form of a fast-track pathway (FTP) and access to appropriate treatment are key factors in preventing morbidity associated with this disease. Recent developments in vascular imaging prompted review of our management of GCA patients. Here, we present the newly implemented FTP in GCA at the University College London Hospital, with added vascular imaging in the form of temporal artery ultrasound (TAUS) and [18F]-fluorodeoxyglucose PET-computed tomography ( 18 F-FDG PET-CT) with temporal artery biopsy. The initial pilot data on the FTP showed a significant negative predictive value of the combined TAUS and 18 F-FDG PET-CT, and the vast majority of cases positive on imaging were confirmed by biopsy. Through the new FTP in GCA, the diagnosis was completed within 48-72 h, compared with the conventional pathway time of up to 2-3 weeks awaiting biopsy results. Prompt and accurate diagnosis of GCA enables commencement of corticosteroid (prednisolone) treatment in the appropriate patient population while avoiding unnecessary steroid exposure and toxicity in GCA-negative patients.