Primary Large-vessel Vasculitides Research Articles

P190 Protocolised ultrasonography led pathway has a high sensitivity for diagnosis of primary large vessel vasculitis

Abstract Background/Aims Ultrasonography (US) for diagnosis of large vessel vasculitis (LVV) is a recommended first line diagnostic procedure. Our county has an annual incidence of 57.5/million for primary LVV (giant cell arteritis (GCA) 48.3/million; Takayasu 2.5/million; unclassified LVV 6.4/million). Our protocolised fast-track US pathway has reduced visual loss from 18.7% to 11.5%. We present the results of our first 1000 unique referrals. Methods Unique requests for US from January 2017 were analysed. Protocolised US examination of the arteries includes superficial temporal artery (STA) and its rami, followed by the entire axillary artery, followed by other arteries as necessary. Halo sign in at least two different arteries was needed for diagnosis of LVV. A temporal artery biopsy (TAB) or positron emission tomography (PET) were requested if the US was negative AND CRP was ≥20mg/L (or missing) AND an alternate explanation for the raised CRP was not immediately apparent. For those where a second test was not requested OR if it was negative, prednisolone was tapered rapidly, and a patient-initiated follow-up allowed rapid re-assessment. If referring physician or patient did not want a second test, GCA was diagnosed on clinical grounds alone and the pathway was considered to have failed. Results Median age was 73 (IQR 13); 11/1000 referrals were for people <50 years of age. The median delay for the procedure was 4 (IQR 4) days. Prednisolone had been started a median of 4 (IQR 5) days previously. 279/1000 (28%) US scans demonstrated vasculitis. Pre-steroid CRP was ≥20mg/L in 283 cases and unavailable in 7. An alternate explanation for the raised CRP was found in 102 cases, 181 were referred for a second test, and 7 received a clinical diagnosis of GCA without a second test. The second test was diagnostic in 31/181 (17%) - 24/139 (17%) TAB, 7/42 (17%) PET. 3/150 cases with a negative second test and 4/431 cases with CRP <20mg/L were diagnosed with GCA on patient-initiated follow-up. The delayed diagnosis did not result in visual loss. 202/279 (72%) US positive cases had bilateral STA involvement. The addition of axillary artery imaging picked up a further 53 (19%) cases; 24/279 (9%) cases needed imaging of other arteries. The sensitivity and negative predictive value of the pathway are 96% (310/324) and 98% (683/690) respectively. Conclusion Our protocolised US led pathway for diagnosis of LVV is highly sensitive and allows disease exclusion with high certainty. Routine US of the superficial temporal artery and its rami, and the entire axillary artery provide diagnosis in 91% of cases but ability to scan more arteries improves yield in a further 9% of cases. Composite testing with US plus second test, stratified by CRP levels, can be recommended as a gold standard diagnostic tool for LVV. Disclosure C.B. Mukhtyar: None. G. Ducker: None. C. Beadsmoore: None. K. Sisson: None. C. Jones: None.

Primary Large Vessel Vasculitis: Takayasu Arteritis and Giant Cell Arteritis.

Takayasu arteritis (TA) and Giant cell arteritis (GCA) are large vessel vasculitides, with TA targeting the aorta and its branches, and GCA targeting both large and medium-sized arteries. Early diagnosis of TA and GCA are of great importance, since delayed, inappropriate or no treatment can result in severe and permanent complications. Imaging plays a central role in establishing diagnosis, targeting lesions for confirmational diagnostic biopsy, specifically for GCA, and longitudinal disease evolution. In this article, we discuss imaging diagnosis of large artery vasculitis and the value of different imaging modalities.

Incidence of primary large vessel vasculitis in Norfolk, UK from 2011 to 2020

ObjectivesTo report the annual incidence of primary large vessel vasculitis (LVV) in the adult population of Norfolk County, UK, including giant cell arteritis (GCA) (in those ≥50 years) and Takayasu...

Changes in the molecular profiles of large-vessel vasculitis treated with biological disease-modifying anti-rheumatic drugs and Janus kinase inhibitors.

Giant cell arteritis and Takayasu arteritis are two types of primary large-vessel vasculitis (LVV). Although glucocorticoids (GC) are the standard treatment for LVV, the disease relapse rates are high. Recent clinical trials on biological disease-modifying anti-rheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors have demonstrated their efficacy in reducing LVV relapse rates and GC dosages. However, the control of residual inflammation and degenerative alterations in the vessel wall remains an outstanding requirement in the clinical management of LVV. The analysis of immune cell phenotypes in patients with LVV may predict their response to treatment with bDMARDs and JAK inhibitors and guide their optimal use. In this mini-review, we focused on molecular markers, including the immune cell proportions and gene expression, in patients with LVV and in mouse models of LVV treated with bDMARDs and JAK inhibitors.

Distinct gene signatures of monocytes and B cells in patients with giant cell arteritis: a longitudinal transcriptome analysis

BackgroundGiant cell arteritis (GCA) is a primary large-vessel vasculitis (LVV) of unknown origin. Its management is a challenge due to the late onset of disease symptoms and frequent relapse; therefore, clarifying the pathophysiology of GCA is essential to improving treatment. This study aimed to identify the transition of molecular signatures in immune cells relevant to GCA pathogenesis by analyzing longitudinal transcriptome data in patients.MethodsWe analyzed the whole blood transcriptome of treatment-naive patients with GCA, patients with Takayasu arteritis (TAK), age-matched, old healthy controls (HCs), and young HCs. Characteristic genes for GCA were identified, and the longitudinal transition of those genes was analyzed using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT).ResultsRepeated measures analysis of variance revealed 739 differentially expressed genes among all patients and HCs. Of the 739 genes, 15 were characteristically upregulated and 36 were downregulated in patients with GCA compared to those with TAK and HCs. Pathway enrichment analysis showed that downregulated genes in GCA were associated with B cell activation. CIBERSORT analysis revealed that upregulation of “M0-macrophages” and downregulation of B cells were characteristic of GCA. Upregulation of “M0-macrophages” reflects the activation of monocytes in GCA toward M0-like phenotypes, which persisted under 6 weeks of treatment. Combined treatment with prednisolone and an interleukin-6 receptor antagonist normalized molecular profiles more efficiently than prednisolone monotherapy.ConclusionsGene signatures of monocyte activation and B cell inactivation were characteristic of GCA and associated with treatment response.

Treatment of Giant Cell Arteritis (GCA).

Giant cell arteritis (GCA) is the most frequent primary large-vessel vasculitis in individuals older than 50. Glucocorticoids (GCs) are considered the cornerstone of treatment. GC therapy is usually tapered over months according to clinical symptoms and inflammatory marker levels. Considering the high rate of GC-related adverse events in these older individuals, immunosuppressive treatments and biologic agents have been proposed as add-on therapies. Methotrexate was considered an alternative option, but its clinical impact was limited. Other immunosuppressants failed to demonstrate a significant favourable benefit/risk ratio. The approval of tocilizumab, an anti-interleukin 6 (IL-6) receptor inhibitor brought significant improvement. Indeed, tocilizumab had a noticeable effect on cumulative GCs’ dose and relapse prevention. After the improvement in pathophysiological knowledge, other targeted therapies have been proposed, with anti-IL-12/23, anti-IL-17, anti-IL-1, anti-cytotoxic T-lymphocyte antigen 4, Janus kinase inhibitors or anti-granulocyte/macrophage colony stimulating factor therapies. These therapies are currently under evaluation. Interestingly, mavrilimumab, ustekinumab and, to a lesser extent, abatacept have shown promising results in phase 2 randomised controlled trials. Despite this recent progress, the value, specific condition and optimal application of each treatment remain undecided. In this review, we discuss the scientific rationale for each treatment and the therapeutic strategy.

The Italian Society of Rheumatology clinical practice guidelines for the management of large vessel vasculitis.

Since of the last publication of last recommendations on primary large-vessel vasculitis (LVV) endorsed by the Italian Society of Rheumatology (SIR) in 2012, new evidence emerged regarding the diagnosis and the treatment with conventional and biologic immunosuppressive drugs. The associated potential change of clinical care supported the need to update the original recommendations. Using the grading of recommendations assessment, development and evaluation (GRADE)-ADOLOPMENT framework, a systematic literature review was performed to update the evidence supporting the European Alliance of Associations for Rheumatology (EULAR) guidelines on LVV as reference. A multidisciplinary panel of 12 expert clinicians, a trained nurse, and a patients' representative discussed the recommendation in cooperation with an Evidence Review Team. Sixty-one stakeholders were consulted to externally review and rate the recommendations. Twelve recommendations were formulated. A suspected diagnosis of LVV should be confirmed by imaging or histology. In active GCA or TAK, the prompt commencement of high dose of oral glucocorticoids (40-60 mg prednisone-equivalent per day) is strongly recommended to induce clinical remission. In selected patients with GCA (e.g., refractory or relapsing disease or patients at risk of glucocorticoid related adverse effects) the use of an adjunctive therapy (tocilizumab or methotrexate) is recommended. In all patients diagnosed with TAK, adjunctive therapies, such as conventional synthetic or biological immunosuppressants, should be given in combination with glucocorticoids. The new set of SIR recommendations was formulated in order to provide a guidance on both diagnosis and treatment of patients suspected of or with a definite diagnosis of LVV.

Decreased Absolute Number of Circulating Regulatory T Cells in Patients With Takayasu's Arteritis.

BackgroundTakayasu’s arteritis (TA) is a type of primary large vessel vasculitis. Th1, Th17, and Tfh cells have been reported to be associated with TA relapse. However, the relationship between regulatory T cells (Tregs) and TA remains unclear.ObjectiveTo analyze the levels of circulating lymphocytes, especially Treg cells (CD4+CD25+FOXP3+ T cells) and serum cytokines in TA patients and explore their relationship with their changes and TA disease activity.MethodsA total of 57 TA patients and 43 sex- and age-matched healthy controls (HCs) were enrolled. According to NIH standards, 36 patients had active disease status. Flow cytometry combined with counting was used to detect the absolute numbers and ratios of Th1, Th2, Th17, and Treg cells in the peripheral blood of all the subjects. Magnetic bead-based multiplex immunoassay was used to detect cytokines.ResultsCompared to HCs, the absolute number and proportion of peripheral Treg cells in TA patients was significantly decreased, while Th17 cells were significantly increased. Furthermore, compared to the inactive group, the TA active group had significantly increased levels of interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α, but lower IL-10 levels. The absolute number of Th2 cells was negatively associated with platelet (PLT) and NIS scores in TA patients. The proportion of Th2 cells was negatively associated with the erythrocyte sedimentation rate in TA patients. After treatment, Treg cells were markedly increased.ConclusionThere was a Th17-Treg cell imbalance with a significant reduction in peripheral Treg cells and an increase in Th17 cells in TA patients compared to the HCs. The levels of IL-6, IL-10, IL-17, and TNF-α appeared to be related to disease activity.

Large-vessel vasculitis.

Large-vessel vasculitis (LVV) manifests as inflammation of the aorta and its major branches and is the most common primary vasculitis in adults. LVV comprises two distinct conditions, giant cell arteritis and Takayasu arteritis, although the phenotypic spectrum of primary LVV is complex. Non-specific symptoms often predominate and so patients with LVV present to a range of health-care providers and settings. Rapid diagnosis, specialist referral and early treatment are key to good patient outcomes. Unfortunately, disease relapse remains common and chronic vascular complications are a source of considerable morbidity. Although accurate monitoring of disease activity is challenging, progress in vascular imaging techniques and the measurement of laboratory biomarkers may facilitate better matching of treatment intensity with disease activity. Further, advances in our understanding of disease pathophysiology have paved the way for novel biologic treatments that target important mediators of disease in both giant cell arteritis and Takayasu arteritis. This work has highlighted the substantial heterogeneity present within LVV and the importance of an individualized therapeutic approach. Future work will focus on understanding the mechanisms of persisting vascular inflammation, which will inform the development of increasingly sophisticated imaging technologies. Together, these will enable better disease prognostication, limit treatment-associated adverse effects, and facilitate targeted development and use of novel therapies.

A French cohort of patients with giant cell arteritis: glucocorticoid treatment and its associated side effects.

Giant cell arteritis (GCA) is the most common primary large-vessel vasculitis. Glucocorticoids (GC) therapy remains the standard of care for GCA despite frequent side effects (SEs). However, treatment modality changes, prophylactic treatment of osteoporosis, or vaccinations might have decreased the frequency of GC-related SEs. This study aims to describe GCA treatment and GC-related SEs in a recent cohort. Patients with a diagnosis of GCA between May 2009 and March 2018 were included in this multicentric retrospective study. Characteristics of patients, treatment modalities and GC-related SEs were collected and analysed. Risk factors associated with the occurrence of SE were studied. We analysed the files from 206 patients (153 women, 53 men; median age 74 years). Median follow-up was 34 months. Patients received GC for a median of 25 months, starting at 0.7 mg/kg/day, with tapering to 5 mg/day after 11 months follow-up. Flares occurred in 83/201 (41%) patients. Among the 132 patients who stopped GC, 29 (22%) experienced a relapse. SEs occurred in 129 (64%) patients: bone fractures and infections in 13% each and hypertension onset in 9%. Age >75 years, treatment duration >2 years, past medical history of diabetes were risk factors associated with GC-related SEs. Flares occur in 41% of patients during GC withdrawal. As much as 64% of patients had treatment related SEs. An age> 75 year and a past medical history of diabetes were predictive of SEs during follow-up.

[Current trends in diagnosis and treatment of giant cell arteritis].

Giant cell arteritis (GCA) is the most common form of the primary large vessel vasculitides and typically occurs in individuals aged ≥ 50 years. This concise review article discusses current trends in the management of GCA, including important developments in sonographic assessment (B-mode sonography, contrast enhanced ultrasound) and medical treatment (biological treatment with the interleukin-6 receptor alpha inhibitor tocilizumab).

Imaging in diagnosis, outcome prediction and monitoring of large vessel vasculitis: a systematic literature review and meta-analysis informing the EULAR recommendations

ObjectivesTo perform a systematic literature review on imaging techniques for diagnosis, outcome prediction and disease monitoring in large vessel vasculitis (LVV) informing the European League Against Rheumatism recommendations for imaging...

EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice

To develop evidence-based recommendations for the use of imaging modalities in primary large vessel vasculitis (LVV) including giant cell arteritis (GCA) and Takayasu arteritis (TAK). European League Against Rheumatism (EULAR)...

MRI parametric monitoring of biological therapies in primary large vessel vasculitides: a pilot study

To evaluate the development of characteristic MRI changes in patients with primary large-vessel vasculitis (LVV) when treated with biological therapies. 12 patients with primary LVV (8 patients with Takayasu arteritis and 4 patients with giant-cell arteritis) received biological therapy with tumour necrosis factor-α blockers (n = 9) or an interleukin-6 inhibitor (n = 3). MRI investigations were performed at baseline (pre-treatment) and follow-up. All patients underwent the same MRI/MR angiography (MRA) protocol. Laboratory parameters (C-reactive protein and erythrocyte sedimentation rate) and clinical response (Birmingham Vasculitis Activity Score) were assessed. Wall thickness was 4.2 ± 0.3 mm pre-treatment and significantly decreased to 3.2 ± 0.3 mm post treatment in 9/12 patients. Mural enhancement was increased in all 12/12 patients with LVV, and subsided with therapy in 5/12 patients. Mural oedema or ill-defined contour were less prevalent but also improved with biological treatment. C-reactive protein and erythrocyte sedimentation rate levels decreased, and clinical assessment revealed a significant improvement from pre-treatment to post-treatment. However, the course of imaging characteristics often did not parallel that of laboratory or clinical parameters. In all three patients receiving interleukin-6 blockade, laboratory markers and clinical scores normalized despite persistent vascular inflammation in one patient which was disclosed by MRI. Contrast-enhanced MRI/MRA may be useful when evaluating the development of disease activity in primary LVV under biological therapies. A high degree of suspicion and regular imaging follow-up is needed to detect persistent inflammation. This is the first study investigating the applicability of different MRI/MRA parameters for monitoring biological therapy in patients with primary LVV.

Cell Immunity in Inflammatory Vasculitis

The vasculitides are a highly heterogeneous group of disorders characterized by the presence of inflammatory leukocytes in the vessel walls and reactive inflammation. Giant cell arteritis (GCA) and Takayasu’s arteritis (TA) are the two primary large-vessel vasculitides. Two distinct cellular pathways have been identified in GCA: Th17 polarization and IL-17 secretion and generation of Th1 cells which secrete IFN-γ. These two pathways may play different roles in the pathogenesis of vasculitides. The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are small vessel vasculitis associated with antibodies directly to myeloperoxidase (MPO-ANCA) such as eosinophilic granulomatosis with polyangiitis (EGPA) and microscopic polyangiitis (MPA) or with antibodies directly to proteinase 3 (PR3-ANCA) such as granulomatosis with polyangiitis (GPA). Both in vitro and in vivo experimental data have shown that MPO-ANCA can induce necrotizing smallvessel vasculitis; however the presence of granulomatous lesions suggests the involvement of cell-mediated immune responses. Behçet syndrome (BS) is a chronic relapsing vasculitis of arteries and veins with unclear etiology. Exogenous and endogenous antigens, innate immune cells such as dendritic, NK, neutrophils and adaptive-immune cells are involved.

Interleukin-1 blockade in refractory giant cell arteritis

Giant cell arteritis is a primary large-vessel vasculitis characterized by an arterial wall inflammation associated with intimal hyperplasia leading to arterial occlusion. Glucocorticoids remain the mainstay of giant cell arteritis treatment. However, relapses and glucocorticoid-related complications are frequent and therapeutic options for refractory giant cell arteritis are quite limited. Like tumor necrosis factor-α and interleukin-6, interleukin-1β is also highly expressed in inflamed arterial walls of patients with giant cell arteritis and may contribute in the pathogenesis of this disease. We report treatment of three cases of refractory giant cell arteritis successfully treated with anakinra, an interleukin-1 blockade therapy. Anakinra was effective for all patients, yielding improvement in their inflammation biomarkers and/or in their symptoms, as well as a disappearance of arterial inflammation in PET/CT for two of them.

Entzündliche Erkrankungen der Aorta

Inflammatory diseases of the aorta fall under the umbrella term "aortitis" and encompass a broad spectrum of autoimmune and infectious disorders. Giant cell arteritis and Takayasu arteritis represent the most common causative primary large vessel vasculitides. Isolated aortitis is a further important entity, whilst IgG4-associated systemic disease today represents yet another disease entity belonging to this group. Clinical presentation is highly variable, ranging from asymptomatic incidental findings to acute aortic syndrome due to rupture. Diagnostic imaging techniques form the cornerstone of the diagnostic workup. These techniques should also be used in screening for diseases with frequent aortic involvement. The treatment approach depends on the underlying disease and on the extent of aortic damage secondary to vascular inflammation. Against this background, differentiation between autoimmune and infectious aortitis is therefore necessary due to the contrasting treatment strategies. The present article is intended to provide the internist with an overview of this heterogeneous disease entity.

Großgefäßvaskulitiden

Giant cell arteritis and Takayasu's arteritis are classified as primary large-vessel vasculitides. Inflammatory cell infiltrates and cytokines induce destruction and hyperplasia of the vessel wall, leading to stenoses or aneurysms. When extracranial large arteries are involved, there is often a similar clinical and radiologic disease pattern of an inflammatory aortic arch syndrome. Rare causes of large-vessel vasculitis include Behçet's disease, association with other autoimmune diseases, and infection. Depending on the localization, imaging is usually performed by means of duplex ultrasound, magnetic resonance imaging, computed tomography, or positron emission tomography. These imaging modalities are used not only to establish the diagnosis but also to determine the disease extent and activity and to perform follow-up in the course of medical therapy. Angiography offers the option to perform interventional therapy for vascular stenoses and occlusions.

The spectrum of granulomatous vasculitides

Granulomatous vasculitides include some primary systemic vasculitides, but can also be secondary to other systemic diseases (e.g., systemic lupus erythematosus and rheumatoid arthritis), other granulomatous diseases (Crohn’s disease, sarcoidosis or lymphomatoid granulomatosis), and infections (tuberculosis or fungal infections) or lymphoma or lymphoproliferative hemopathic diseases. Wegener’s granulomatosis and Churg–Strauss syndrome are the two main primary granulomatous vasculitides that affect small vessels. Granulomatous vasculitis can also be observed on histology in giant cell (temporal) arteritis and, more occasionally, in Takayasu’s arteritis (the two primary large-vessel vasculitides), but only very rarely in polyarteritis nodosa, a medium-sized vessel vasculitis. Treatment for primary necrotizing vasculitides is now fairly well established, although there remain some issues to be clarified, such as the optimal maintenance therapy in Wegener’s granulomatosis or the exact indications of biotherapy...

What is the best approach to diagnosing large-vessel vasculitis?

Temporal arteritis, including large-vessel giant cell arteritis, and Takayasu's arteritis are the two primary large-vessel vasculitides. Patients with temporal arteritis often present with headache, swollen temporal arteries, impairment of vision or symptoms of polymyalgia rheumatica. Clinical examination includes palpation of the temporal arteries and radial pulses, auscultation of the subclavian and axillary region, and fundoscopy. The presence of jaw claudication, diplopia and temporal artery abnormalities correlates with a high probability of positive histology. Duplex ultrasonography of the temporal arteries delineates a characteristic hypoechoic, oedematous wall swelling, stenoses and occlusions. It detects the same pathologies in the axillary arteries and other arteries in large-vessel giant cell arteritis. Angiography, magnetic resonance imaging, magnetic resonance angiography, electron beam computed tomography, computed tomography angiography and positron emission tomography show characteristic changes in the aorta and its primary branches in large-vessel giant cell arteritis and Takayasu's arteritis. Takayasu's arteritis often begins with diffuse symptoms such as low-grade fever, arthralgia, fatigue and weight loss. Clinical examination is important to detect bruits, pulse reduction and blood pressure differences. Profound experience exists with angiography. Other imaging methods are interesting alternatives as they are less invasive and may depict the inflammatory wall swelling.