Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

Cranial involvement in giant cell arteritis.

Since its first clinical description in 1890, extensive research has advanced our understanding of giant cell arteritis, leading to improvements in both diagnosis and management for affected patients. Imaging studies have shown that the disease frequently extends beyond the typical cranial arteries, also affecting large vessels such as the aorta and its proximal branches. Meanwhile, advances in comprehending the underlying pathophysiology of giant cell arteritis have given rise to numerous potential therapeutic agents, which aim to minimise the need for glucocorticoid treatment and prevent flares. Classification criteria for giant cell arteritis, as well as recommendations for management, imaging, and treat-to-target have been developed or updated in the last 5 years, and current research encompasses a broad spectrum covering basic, translational, and clinical research. In this Series paper, we aim to discuss the current understanding of giant cell arteritis with cranial manifestations, describe the clinical approach to this condition, and explore future directions in research and patient care.

Large vessel giant cell arteritis.

Giant cell arteritis is the principal form of systemic vasculitis affecting people over 50. Large-vessel involvement, termed large vessel giant cell arteritis, mainly affects the aorta and its branches, often occurring alongside cranial giant cell arteritis, but large vessel giant cell arteritis without cranial giant cell arteritis can also occur. Patients mostly present with constitutional symptoms, with localising large vessel giant cell arteritis symptoms present in a minority of patients only. Large vessel giant cell arteritis is usually overlooked until clinicians seek to exclude it with imaging by ultrasonography, magnetic resonance angiography (MRA), computed tomography angiography (CTA), or [18F]fluorodeoxyglucose-PET-CT. Although the role of imaging in treatment monitoring remains uncertain, imaging by MRA or CTA is crucial for identifying aortic aneurysm formation during patient follow up. In this Series paper, we define the large vessel subset of giant cell arteritis and summarise its clinical challenges. Furthermore, we identify areas for future research regarding the management of large vessel giant cell arteritis.

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.

Neointimal myofibroblasts contribute to maintaining Th1/Tc1 and Th17/Tc17 inflammation in giant cell arteritis.

Vascular smooth muscle cells (VSMCs) have been shown to play a role in the pathogenesis of giant cell arteritis (GCA) through their capacity to produce chemokines recruiting T cells and monocytes in the arterial wall and their ability to migrate and proliferate in the neointima where they acquire a myofibroblast (MF) phenotype, leading to vascular stenosis. This study aimed to investigate if MFs could also impact T-cell polarization. Confocal microscopy was used to analyze fresh fragments of temporal artery biopsies (TABs). Healthy TAB sections were cultured to obtain MFs, which were then treated or not with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) and analyzed by immunofluorescence and RT-PCR. After peripheral blood mononuclear cells and MFs were co-cultured for seven days, T-cell polarization was analyzed by flow cytometry. In the neointima of GCA arteries, we observed a phenotypic heterogeneity among VSMCs that was consistent with a MF phenotype (α-SMA+CD90+desmin+MYH11+) with a high level of STAT1 phosphorylation. Co-culture experiments showed that MFs sustain Th1/Tc1 and Th17/Tc17 polarizations. The increased Th1 and Tc1 polarization was further enhanced following the stimulation of MFs with IFN-γ and TNF-α, which induced STAT1 phosphorylation in MFs. These findings correlated with increases in the production of IL-1ß, IL-6, IL-12 and IL-23 by MFs. Our study showed that MFs play an additional role in the pathogenesis of GCA through their ability to maintain Th17/Tc17 and Th1/Tc1 polarizations, the latter being further enhanced in case of stimulation of MF with IFN-γ and TNF-α.

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.