Disease Activity In Giant Cell Arteritis Research Articles

The value of ultrasound for monitoring disease activity in giant cell arteritis

Giant cell arteritis (GCA) is the most common primary systemic vasculitis in the elderly. Although the diagnosis of GCA has improved, monitoring its disease activity remains challenging due to the lack of validated tools and biomarkers. The current reliance on assessing symptoms, physical signs, and inflammatory markers during disease follow-up presents limitations, notably the nonspecific nature of GCA-related symptoms and the suppressive impact of IL-6 inhibitors on inflammatory markers. Therefore, recent attention has shifted toward acknowledging imaging as a monitoring tool, particularly ultrasound, given its widespread accessibility, cost-effectiveness, and well-established role in GCA diagnosis. Research on this topic has found that ultrasound characteristics, including the number of affected arterial segments and halo size, are associated with laboratory markers and treatment response, underscoring the ultrasound’s potential as a monitoring tool for GCA. It has also been demonstrated that ultrasound abnormalities progress differently throughout the disease course, depending on the type of arterial involvement, with vessel wall changes in the axillary arteries resolving more slowly than those in the temporal arteries. Nevertheless, there are still no studies comparing the added value of regular ultrasounds for monitoring disease activity to clinical and laboratory monitoring alone; hence, this imaging modality is not yet recommended for patients with GCA in clinical and biochemical remission. This narrative review aims to synthesize the main research findings of key studies addressing the role of ultrasound for monitoring disease activity in GCA, with a focus on the pattern of arterial involvement. It highlights the potential of ultrasound, particularly halo sign assessment, for evaluating disease progression but notes that further validation and standardization of protocols are needed to improve accuracy and enable routine use.

Optic nerve sheath measurement to monitor disease activity in giant cell arteritis: a pilot study

Introduction/ObjectivesOptic nerve sheath (ONS) enhancement using magnetic resonance imaging of the orbits was observed in patients with giant cell arteritis (GCA). We previously showed that ONS diameter (ONSD) by bedside ultrasound is increased in patient with active GCA. This study aims to assess whether ONSD decreases with clinical remission in patients with GCA.MethodsA prospective cohort study was conducted from June 2022 to January 2023. Patients who had an optic nerve ultrasound at GCA diagnosis as part of a previous crosssectional study were eligible. Optic nerve ultrasound was performed by the same investigator at diagnosis and month 3. ONSD (includes the optic nerve and its sheath) and optic nerve diameter (OND) were measured. Descriptive statistics for baseline characteristics and paired sample t-test were performed to assess the mean difference in OND and ONSD between diagnosis and month 3.ResultsNine patients with GCA were included. The median age at disease onset was 79 years (interquartile range (IQR) of 79–82 years), and 7 patients were males. All patients were in clinical remission at month 3 on prednisone (median dose of 15 mg/day, IQR of 10–25 mg). The mean ONSD was lower at month 3 (3.76 mm) compared to baseline (5.98 mm), with a paired mean difference of 2.22 mm (95% CI 1.41–3.03 mm, p < 0.001). As anticipated, OND measurements did not vary between diagnosis and month 3.ConclusionONSD on ultrasound improves after 3 months of therapy in patients with GCA. A longer prospective study is required to determine if ONSD is useful to assess disease activity in GCA.Key Points• ONS ultrasound can identify patients with active GCA.• The ONSD on ultrasound is dynamic and improved after 3 months of GCA therapy.• ONS ultrasound may be useful to monitor disease activity in GCA.

Mitochondrial-mediated inflammation and platelet activation in giant cell arteritis

Markers of extracellular mitochondria are present in giant cell arteritis (GCA) patients. However, their role in promoting inflammation and platelet activation is no known. To investigate this, isolated mitochondria were opsonized with plasma from GCA patients or healthy individuals and incubated with peripheral blood mononuclear cells (PBMCs) or platelets and assessed for inflammatory cytokine production and platelet activation.Plasma from GCA patients promoted increased mitochondrial-mediated cytokine production by PBMCs as compared to healthy controls (p < 0.05). Mitochondria opsonized with plasma factors from patients with GCA induced higher platelet activation as compared to mitochondria opsonized with plasma factors from healthy individuals (p = 0.0015). Platelet levels of P-selectin were associated with disease activity in GCA (r = 0.34, p = 0.01).GCA patients have impaired ability to regulate the clearance of extracellular mitochondria, possibly contributing to excessive inflammation and platelet activation. Targeting key drivers of mitochondrial extrusion and/or their clearance could lead to new therapeutic interventions in GCA.

Longitudinal Characterization of Vascular Inflammation and Disease Activity in Takayasu Arteritis and Giant Cell Arteritis: A Single-Center Prospective Study.

To examine and compare disease activity over time in giant cell arteritis (GCA) and Takayasu arteritis (TAK) using multimodal assessment combining clinical, laboratory, and imaging-based testing. Patients with GCA or TAK were enrolled into a single-center prospective, observational cohort at any point in the disease course. Patients underwent standardized assessment, including 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) at enrollment and follow-up visits. Each FDG-PET finding was subjectively interpreted as active or inactive vasculitis. Global arterial FDG uptake was quantified by the PET Vascular Activity Score (PETVAS). Patients were stratified by disease duration at enrollment (0-2 years; 2-5 years; >5 years). Fisher exact and Mann-Whitney U tests, Spearman's correlation, and linear regression were used for statistical analyses. A total of 126 patients with large vessel vasculitis (GCA=50; TAK=76) were evaluated across 319 visits. Clinical disease activity was present in 33% of patients in the second to fifth year of disease and in 24% of patients evaluated >5 years after diagnosis. Active vasculitis by PET was observed in 66% of patients in years 2 to 5 after diagnosis and in 50% of patients enrolled >5 years into disease. PETVASs were consistently higher in GCA than TAK in the early and later phases of disease and significantly decreased over time in GCA but not TAK. Correlations between clinical, laboratory, and imaging findings were complex and varied with disease duration. Disease activity in GCA and TAK is common throughout the disease course. Patterns of vascular PET activity at diagnosis and later in disease differ between GCA and TAK.

AB0373 PSYCHOMETRIC PROPERTIES OF OUTCOME MEASUREMENT INSTRUMENTS FOR LARGE VESSEL VASCULITIS: A SYSTEMATIC LITERATURE REVIEW

Background:Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are two forms of chronic progressive large-vessel vasculitis (LVV) of unknown etiology. In 2016, the OMERACT Vasculitis Working Group proposed the development of a Core Domain Set of outcome measures for LVV including organ and arterial function, fatigue, pain, biomarkers, and death (1). Understanding the psychometric properties of outcome measurement instruments is essential when selecting among instruments to use in research; a summary of such properties for measures of LVV has not been developed.Objectives:To systematically review and summarize the psychometric properties of outcome measurement instruments used to measure the domains of the OMERACT core domain set for LVV.Methods:A comprehensive search of several databases (Medline, EMBASE, Cochrane, among others) from inception to July 14, 2020 was conducted. Articles were included if they covered psychometric properties of instruments used in LVV. Following the COSMIN and OMERACT frameworks, different psychometric properties (validity, inter- and intra-observer reliability, sensitivity to change, and feasibility) of outcome measurement instruments used in LVV (GCA and TAK) were assessed. Risk of bias was assessed according to the COSMIN checklist.Results:Among the 3534 articles identified, 15 studies focusing on the development or validation of psychometric properties on LVV met the predefined criteria. Two were development studies and 13 were validation studies. These studies provided information on 13 instruments: 5 instruments specific to TAK, 2 specific to systemic vasculitides, and 6 general, non-disease-specific instruments. No instruments specific to GCA were identified.Of the main psychometric properties assessed in the included studies, 40% had a low, 47% had moderate, and 13% had high risk of bias. Construct validity was the property most frequently assessed (in 93% of the tools) (Figure 1).In TAK, the Indian Takayasu Clinical Activity Score 2010 (ITAS2010) showed good consistency (r=0.97), reliability (intra-observer, ICC=0.60; inter-observer, ICC=0.92) and validity (correlation with Physician Global Assessment (PGA) (r=0.73)) for disease activity. Regarding disease damage, the Disease Extent Index-Takayasu (DEI-Tak) showed good validity (correlation with NIH score 94%, k=0.85). Non-specific vasculitis instruments such as the Vasculitis Damage Index (VDI) and the Birmingham Vasculitis Activity Score (BVAS) showed moderate validity in the assessment of disease damage in GCA (cumulative glucocorticoid dose and disease duration, r=0.30 and r=0.29) and TAK (cumulative glucocorticoid dose and disease duration, r=0.29 and r=0.25) in the former and disease activity in GCA in the later (PGA, r=0.50).Six non-vasculitis-specific patient-reported outcomes (PROs) instruments were identified, all showing low to moderate validity in GCA/TAK.Conclusion:The psychometric properties of 13 outcome measures to study LVV covering the OMERACT domains of disease activity, damage, and patient-reported outcomes were assessed. ITAS2010, DEI-Tak, VDI, and BVAS were the instruments with better psychometric properties for disease activity and/or damage. Disease activity and/or damage instruments specific for GCA, and validated PROs for both GCA and TAK are needed.

Evaluation of Potential Serum Biomarkers of Disease Activity in Diverse Forms of Vasculitis.

We evaluated potential circulating biomarkers of disease activity in giant cell arteritis (GCA), Takayasu arteritis (TA), polyarteritis nodosa (PAN), and eosinophilic granulomatosis with polyangiitis (EGPA). A panel of 22 serum proteins was tested in patients enrolled in the Vasculitis Clinical Research Consortium Longitudinal Studies of GCA, TA, PAN, or EGPA. Mixed models were used for most analyses. A J48 classification tree method was used to find the most relevant markers to differentiate between active and inactive GCA. Tests were done on 418 samples from 152 patients (60 GCA, 29 TA, 26 PAN, 37 EGPA), during both active vasculitis and remission. In GCA, these showed significant (p < 0.05) differences between disease states: B cell-attracting chemokine 1 (BCA)-1/CXC motif ligand 13 (CXCL13), erythrocyte sedimentation rate (ESR), interferon-γ-induced protein 10/CXC motif chemokine 10, soluble interleukin 2 receptor α (sIL-2Rα), and tissue inhibitor of metalloproteinase-1 (TIMP-1). In EGPA, these showed significant increases during active disease: granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF, interleukin (IL)-6, IL-15, and sIL-2Rα. BCA-1/CXCL13 also showed such increases, but only after adjustment for treatment. In PAN, ESR and matrix metalloprotease (MMP)-3 showed significant differences between disease states. Differences in biomarker levels between diseases were significant for 11 markers and were more striking (all p < 0.01) than differences related to disease activity. A combination of lower values of TIMP-1, IL-6, interferon-γ, and MMP-3 correctly classified 87% of samples with inactive GCA. We identified novel biomarkers of disease activity in GCA and EGPA. Differences of biomarker levels between diseases, independent of disease activity, were more apparent than differences related to disease activity. Further studies are needed to determine whether these serum proteins have potential for clinical use in distinguishing active disease from remission or in predicting longer-term outcomes.

Recent Advances in Giant Cell Arteritis.

Giant cell arteritis (GCA) is the most common systemic vasculitis. GCA is categorized as a granulomatous vasculitis of large and medium size vessels. Majority of the symptoms and signs of GCA result from involvement of the aorta and its branches intra- and extracranial. Temporal artery biopsy continues to be the cardinal diagnostic procedure despite new imaging modalities for diagnosing GCA with cranial involvement. Great advances in awareness have led to improvement in preventing irreversible vision loss due to early diagnosis. The cause of GCA has not been elucidated but major progress has been made in the knowledge of its pathogenesis leading to new therapeutic targets, particularly inhibition of interleukin 6. IL 6 plays a key role in the regulation of TH17/Tregs imbalance in GCA and appears to correlate with clinical disease activity in GCA. All of this has led to the first FDA (food and drug administration) approved treatment for GCA, Tocilizumab. Abatacept and Ustekinumab are promising targets for therapy in LVV but still need further research. This paper is a review of the recent progress in the understanding of GCA pathogenesis, diagnosis, treatment, and prognosis.

Development of a Core Set of Outcome Measures for Large-vessel Vasculitis: Report from OMERACT 2016.

Among the challenges in conducting clinical trials in large-vessel vasculitis (LVV), including both giant cell arteritis (GCA) and Takayasu arteritis (TA), is the lack of standardized and meaningful outcome measures. The Outcome Measures in Rheumatology (OMERACT) Vasculitis Working Group initiated an international effort to develop and validate data-driven outcome tools for clinical investigation in LVV. An international Delphi exercise was completed to gather opinions from clinical experts on LVV-related domains considered important to measure in trials. Patient interviews and focus groups were completed to identify outcomes of importance to patients. The results of these activities were presented and discussed in a "Virtual Special Interest Group" using telephone- and Internet-based conferences, discussions through electronic mail, and an in-person session at the 2016 OMERACT meeting. A preliminary core set of domains common for all forms of LVV with disease-specific elements was proposed. The majority of experts agree with using common outcome measures for GCA and TA, with the option of supplementation with disease-specific items. Following interviews and focus groups, pain, fatigue, and emotional effect emerged as health-related quality of life domains important to patients. Current disease assessment tools, including the Birmingham Vasculitis Activity Score, were found to be inadequate to assess disease activity in GCA and standardized assessment of imaging tests were felt crucial to study LVV, especially TA. Initial data from a clinician Delphi exercise and structured patient interviews have provided themes toward an OMERACT-endorsed core set of domains and outcome measures.

Disease Relapses among Patients with Giant Cell Arteritis: A Prospective, Longitudinal Cohort Study.

To evaluate the frequency, timing, and clinical features of relapses in giant cell arteritis (GCA). Patients with GCA enrolled in a prospective, multicenter, longitudinal study were included in the analysis. Relapse was defined as either new disease activity after a period of remission or worsening disease activity. The study included 128 subjects: 102 women (80%) and 26 men (20%). Mean ± SD age at diagnosis of GCA was 69.9 ± 8.6 years. Mean followup for the cohort was 21.4 ± 13.9 months. Median (interquartile range) duration of disease at study enrollment was 4.6 months (1.2, 16.8). During followup, 59 relapses were observed in 44 patients (34%). Ten patients (8%) experienced 2 or more relapses. The most common symptoms at relapse were headache (42%) and polymyalgia rheumatica (51%), but ischemic (some transient) manifestations (visual symptoms, tongue or jaw claudication, and/or limb claudication) occurred in 29% of relapses (12% cohort). Forty-three relapses (73%) occurred while patients were taking glucocorticoid therapy at a median (range) prednisone dose of 7.5 (0-35) mg. In 21% of relapses, both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were normal. Among 69 patients enrolled in the cohort with newly diagnosed disease, 24% experienced a first relapse within 12 months after diagnosis. Among patients with GCA, relapses are common, often occurring during treatment. ESR and CRP are frequently normal at times of clinical relapse, highlighting the need for better biomarkers to assess disease activity in GCA. There remains a need for effective therapeutic alternatives to glucocorticoids in GCA.

Th17 and Th1 T-Cell Responses in Giant Cell Arteritis

In giant cell arteritis (GCA), vasculitic damage of the aorta and its branches is combined with a syndrome of intense systemic inflammation. Therapeutically, glucocorticoids remain the gold standard because they promptly and effectively suppress acute manifestations; however, they fail to eradicate vessel wall infiltrates. The effects of glucocorticoids on the systemic and vascular components of GCA are not understood. The immunoprofile of untreated and glucocorticoid-treated GCA was examined in peripheral blood and temporal artery biopsies with protein quantification assays, flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Plasma interferon-gamma and interleukin (IL)-17 and frequencies of interferon-gamma-producing and IL-17-producing T cells were markedly elevated before therapy. Glucocorticoid treatment suppressed the Th17 but not the Th1 arm in the blood and the vascular lesions. Analysis of monocytes/macrophages in the circulation and in temporal arteries revealed glucocorticoid-mediated suppression of Th17-promoting cytokines (IL-1beta, IL-6, and IL-23) but sparing of Th1-promoting cytokines (IL-12). In human artery-severe combined immunodeficiency mouse chimeras, in which patient-derived T cells cause inflammation of engrafted human temporal arteries, glucocorticoids were similarly selective in inhibiting Th17 cells and leaving Th1 cells unaffected. Two pathogenic pathways mediated by Th17 and Th1 cells contribute to the systemic and vascular manifestations of GCA. IL-17-producing Th17 cells are sensitive to glucocorticoid-mediated suppression, but interferon-gamma-producing Th1 responses persist in treated patients. Targeting steroid-resistant Th1 responses will be necessary to resolve chronic smoldering vasculitis. Monitoring Th17 and Th1 frequencies can aid in assessing disease activity in GCA.

Association between increased CCL2 (MCP-1) expression in lesions and persistence of disease activity in giant-cell arteritis*

Patients with giant-cell arteritis (GCA) usually respond dramatically to corticosteroid treatment. However, recurrences are frequent and corticosteroid requirements are highly variable among patients. The aim of our study was to identify genes potentially involved in disease persistence. Gene expression was explored with cDNA arrays in temporal artery biopsies from six GCA patients with relapsing disease and six patients who easily achieved sustained remission. Differentially expressed genes of interest were subsequently analysed by quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry in temporal artery biopsies from 35 patients with biopsy-proven GCA and nine controls. CCL2 (MCP-1) was up-regulated in temporal artery samples from relapsing individuals. In the extended series of patients, CCL2 mRNA concentration in lesions was significantly higher than in controls (31 +/- 15.6 vs 0.44 +/- 0.10, P = 0.0001). In addition, CCL2 was more abundant in patients who experienced two or more relapses during the first year compared with those who endured sustained remission (127 +/- 82 vs 11 +/- 5.5, P = 0.0233) and correlated with the cumulated prednisolone dose (R = 0.533, P = 0.0024). CCL2 mRNA concentration correlated with IL-1beta (R = 0.45, P = 0.02), tumour necrosis factor-alpha (TNF-alpha) (R = 0.47, P = 0.013) and IL-6 (R = 0.52, P = 0.0053) mRNA. However, circulating CCL2 determined by ELISA was decreased in patients with strong systemic inflammatory response, suggesting that reduction in circulating CCL2 may reinforce the local gradient in lesions. Increased CCL2 (MCP-1) expression in lesions is associated with persistence of disease activity in GCA.