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The role of ultrasound in the diagnosis, classification and monitoring of giant cell arteritis
Publication . Ponte, Cristina; Luqmani, Raashid Ahmed; Fonseca, João Eurico Cabral da; Canhão, Helena Cristina Matos
Giant cell arteritis (GCA) is the most common form of primary systemic vasculitis in patients aged ≥50 years, causing chronic inflammation of the large- and medium-sized arteries. If left untreated, GCA can result in permanent visual loss or other ischaemic complications. However, its established treatment with glucocorticoids (GCs) can lead to significant toxicity. Therefore, it is crucial to establish a correct diagnosis in patients with suspected GCA. For many years, temporal artery biopsy (TAB) has been considered the diagnostic ‘gold standard’ for GCA, but it has many limitations, including its low sensitivity. Ultrasound has proven to be effective for diagnosing GCA and can reliably replace temporal artery biopsy in particular clinical settings. Moreover, in cases of suspected large-vessel GCA (LV GCA), other imaging modalities can also be used (e.g., positron emission tomography). However, good diagnostic algorithms that take into account the different manifestations of the disease and the uneven accessibility to all diagnostic tests between centres are yet lacking. In addition, potential diagnostic composite scores, with a strong emphasis on different imaging findings, are still an unmet need. The widespread use of vascular imaging in clinical practice has expanded the clinical spectrum of large-vessel vasculitis (LVV) and exposed the limitations of the 1990 American College of Rheumatology (ACR) classification criteria for GCA, which are biased to identify patients with disease confined to the cranial arteries. Patients with GCA may have vasculitic involvement of the aorta and primary branches in a pattern that resembles angiographic findings in Takayasu arteritis (TAK). Hence, updated classification criteria that include vascular imaging findings are needed in LVV. Not all patients with GCA follow the same course, but there are no valid biomarkers to assess therapy response. Changes in the traditional acute phase reactants - erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) - do not consistently reflect disease activity, are not GCA-specific, and have limited value in assessing patients treated with IL 6 inhibitors such as tocilizumab. The role of ultrasound as an alternative monitoring tool for these patients is still poorly understood and needs further investigation. This doctoral thesis sought to provide new evidence on the use of ultrasound to diagnose, classify and monitor patients with GCA. Its specific aims were: 1) to investigate the diferente diagnostic assessment strategies for GCA worldwide; 2) to evaluate the impact of disease extent and severity detected by ultrasound in the diagnosis of GCA; 3) to develop new classification criteria for large vessel vasculitis incorporating imaging; 4) to explore the use of ultrasound in monitoring disease activity and response to treatment in patients with GCA Encompassed by the first aim of this dissertation, we developed a Portuguese registry for patients with vasculitis – Reuma.pt/vasculitis. By July 2018, 125 patients with the diagnosis of GCA had already been registered. The ultrasound of the temporal ± axillary arteries was the diagnostic modality of choice for these patients (n=94), with 82/94 (87%) showing a non-compressible halo sign, followed by TAB (n=72), with 47/72 (65%) showing histologic features compatible with vasculitis. We further evaluated the diagnostic assessment strategies for GCA using data from a large, international cohort (the Diagnostic and Classification Criteria for Vasculitis [DCVAS] cohort). A total of 941 patients recruited into DCVAS had a confirmed diagnosis of GCA: 705 (75%) patients underwent TAB, 446 (66%) considered diagnostic for GCA, and 328 (35%) patients underwent temporal artery ultrasound, 258 (79%) with a presence of halo sign. Overall, these results reflect the current confidence of clinicians in requesting ultrasound for diagnostic proposes, and demonstrate the higher sensitivity of ultrasound to diagnose GCA, when compared to TAB. To address the second aim of this thesis, we developed a composite scoring system, including ultrasound quantitative findings, combined with clinical features, to stratify patients based on the risk of having a positive TAB. We included 135 patients with GCA recruited into a large prospective multicentre study (the Temporal Artery Biopsy vs. ULtrasound [TABUL] study) who had a positive halo sign on the temporal and/or axillary arteries. Four clinical models using “positive TAB” as the outcome of interest were tested. The best-fitting model included a combination of six positive items (maximum temporal artery intima-media thickness [IMT] >0.70 mm, bilateral temporal artery halos, maximum axillary artery IMT >1.30 mm, bilateral axillary artery halos, ischaemic GCA-features, and elevated acute phase reactants) and one negative item (symptoms of polymyalgia rheumatica). Our GCA-ultrasound score was successfully tested in an independent cohort of 72 patients, although no formal validation could be made due to the lack of TAB data in the testing cohort. We then proposed a diagnostic algorithm for patients with suspected cranial-GCA and rapid access to high-quality ultrasound. After a comprehensive literature review, we advocated that ultrasound should be the initial modality of choice and that the need for further testing should be tailored according to the clinical probability of GCA and quality of ultrasound results (e.g., presence of high IMT in various arterial segments). For the third aim, we used the DCVAS cohort to identify different patterns of arterial disease on vascular imaging able to differentiate LV-GCA from TAK. Patients with LV-GCA showed more vasculitic changes of the axillary/subclavian arteries bilaterally, more diffuse disease with vasculitic findings throughout the aorta and the aortic arch branch vessels, and less involvement of the abdominal vasculature than patients with TAK. Using the same DCVAS cohort, we then developed and validated new classification criteria for GCA and TAK, which included these different patterns of arterial involvement. In comparison to the original 1990 ACR Classification Criteria, the new ACR-European League Against Rheumatism (EULAR) Classification Criteria for GCA considers age at diagnosis of ≥50 years as a mandatory requirement to classify patients with GCA, and the new ACR/EULAR Classification Criteria for TAK defines age at diagnosis of ≤60 years as an absolute requirement to classify patients with TAK. Moreover, both criteria were developed based on weighed items with different threshold scores. The final criteria for GCA included: positive TAB or temporal artery halo sign on ultrasound (+5); ESR ≥50 mm/hour or CRP ≥10mg/L (+3); sudden visual loss (+3); and morning stiffness in shoulders or neck, jaw or tongue claudication, new temporal headache, scalp tenderness, temporal artery abnormality on vascular examination, bilateral axillary involvement on imaging, and FDG PET activity throughout the aorta (+2 each). A patient could be classified as GCA with a cumulative score of ≥6 points. The final criteria for TAK included: female sex (+1); angina (+2); limb claudication (+2); arterial bruit (+2); reduced upper extremity pulse (+2); reduced pulse or tenderness of the carotid artery (+2); blood pressure difference ≥20mmHg in the arms (+1); number of affected arterial territories (+1 to +3); paired artery involvement (+1) and abdominal aorta plus renal or mesenteric involvement (+3). A patient could be classified as TAK with a cumulative score of ≥5 points. The new 2022 ACR/EULAR classification criteria for GCA showed a sensitivity of 87.0% (95%CI: 82.0-91.0%) and a specificity of 94.8% (95%CI: 91.0-97.4%) and the new 2022 ACR/EULAR classification criteria for TAK showed a sensitivity of 93.8% (95%CI: 88.6-97.1%) and a specificity of 99.2% (95%CI: 96.7-100.0%). When compared to the original 1990 criteria, the new criteria for GCA and TAK demonstrated superior sensitivity while maintaining similar specificity. For the final aim, we performed a cross-sectional analysis of all patients from the TABUL cohort with GCA who had a temporal and/or axillary artery halo sign on ultrasound in the first 7-days of commencing GCs. A consistent reduction of the halo size with number of days on GCs was observed for the temporal arteries, but not for the axillary arteries. We then conducted a prospective analysis of 49 patients with newly diagnosed GCA looking at the following time-points: baseline and weeks 1,3,6,12 and 24. The halo size of the temporal arteries, as well as the number of temporal artery segments with halo, showed a significant reduction between all time-points and baseline. Moreover, a significant correlation between temporal artery halo features and disease activity markers (CRP, ESR and the Birmingham vasculitis activity score) and GC cumulative dose was found. Only after week 6, a significant reduction in halo size of the axillary arteries was observed, but no association between axillary halo features and disease activity markers or GC treatment was found. These findingssupport the use of ultrasound halo sign as a potential monitoring tool for patients with GCA. In conclusion, this thesis provides new evidence on the use of ultrasound to diagnose, classify and monitor patients with GCA, which will have future implications for clinical trials and research studies.
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SFRH/SINTD/96266/2013