Abstract
Objective
To evaluate the diagnostic accuracy, reproducibility, and acquisition time of focused bilateral frontal‐branch ultrasonography based on intima‐media thickness (IMT) in suspected giant cell arteritis (GCA).
Methods
In this prospective single‐center study, 171 patients underwent color Doppler ultrasonography of the temporal and large arteries and ultrasonography‐guided temporal artery biopsy. Bilateral mean frontal‐branch IMT was evaluated against the expert diagnosis established at six months. Diagnostic performance was assessed using ROC analysis and multivariable logistic regression. Reproducibility was assessed in 100 randomly selected images.
Results
GCA was diagnosed in 107 patients, including 96 biopsy‐positive cases. Mean frontal‐branch IMT had the highest observed area under the curve among the temporal artery segments (0.87). At the 0.28‐mm cutoff, sensitivity was 71%, specificity 94%, LR+ 11.4, and LR− 0.31. Frontal IMT ≥ 0.28 mm was the strongest independent predictor of GCA (odds ratio 43.0). At a cutoff of ≥3, the exploratory PAMELA (Performance Analysis of a Monosegmental Ultrasonographic Evaluation of the Frontal‐Branch of the Superficial Temporal Artery in Giant Cell Arteritis) score had a sensitivity of 74.8% and specificity of 93.7%. Focused bilateral frontal‐branch assessment required 1.07 ± 0.24 minutes versus 7.62 ± 1.11 minutes for the complete temporal artery protocol. Intraobserver and interobserver intraclass correlation coefficients were 0.96 and 0.93.
Conclusion
Focused bilateral frontal‐branch ultrasonography provides a highly specific, reproducible, and time‐efficient initial cranial assessment in suspected GCA. However, the 0.28‐mm cutoff and PAMELA score require external validation, and the remaining temporal and large‐vessel territories should be examined when frontal findings are negative or equivocal.
INTRODUCTION
Giant cell arteritis (GCA) is the most common large‐vessel vasculitis (LVV) and carries a substantial risk of irreversible ischemic complications, particularly permanent visual loss and cerebrovascular events. 1 , 2 Clinical features such as new‐onset headache, jaw claudication, scalp tenderness, and visual symptoms are common but insufficiently specific to establish the diagnosis on clinical grounds alone. 2 , 3 Temporal artery biopsy (TAB) has long been regarded as a reference test, yet its sensitivity is limited by skip lesions and sampling error, resulting in false‐negative findings. 4 , 5 High‐resolution color Doppler ultrasonography (CDUS) is recommended as a first‐line imaging modality in suspected GCA and allows direct detection of the halo sign, a homogeneous, hypoechoic, noncompressible circumferential wall thickening that reflects mural edema. 6 , 7 , 8 , 9
SIGNIFICANCE & INNOVATIONS.
In suspected giant cell arteritis, focused frontal‐branch ultrasonography provides a rapid and highly specific initial cranial assessment.
Focused bilateral frontal‐branch assessment required approximately one‐seventh of the acquisition time of the complete bilateral temporal artery protocol.
A negative or equivocal frontal‐branch examination should be followed by assessment of the remaining temporal and large‐vessel territories when clinical suspicion persists.
Quantitative ultrasonography indices such as the Halo Score and the OMERACT GCA Ultrasonography Score (OGUS) capture cranial and large‐vessel involvement and have been associated with intimal hyperplasia, visual prognosis, and treatment response. 10 , 11 , 12 , 13 , 14 Pretest probability tools such as the Southend GCA probability score (GCAPS) support triage, but lack sufficient specificity to replace imaging in intermediate or high‐risk categories. 15 , 16 , 17 In routine care, current ultrasonography protocols often require multisegment assessment of the superficial temporal artery (STA) and axillary arteries. 18 Although diagnostically informative, this approach can be time‐consuming and operator‐dependent, and its implementation remains variable across centers. 7 , 9 , 19 , 20 A focused assessment of the frontal branch of the STA could reduce complexity by targeting a cranial segment that is frequently involved, readily visualized, and commonly selected for biopsy.
The PAMELA study (Performance Analysis of a Monosegmental Ultrasonographic Evaluation of the Frontal‐Branch of the Superficial Temporal Artery in Giant Cell Arteritis) was designed to evaluate whether a focused frontal‐branch ultrasonography approach could retain the diagnostic information provided by multisegment temporal artery ultrasonography while simplifying its implementation in fast‐track pathways.
PATIENTS AND METHODS
Study design and patients
This prospective, single‐center cohort study included all consecutive patients referred for suspected GCA between September 2019 and December 2024 to the Rheumatology Unit of Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. All patients underwent both CDUS and TAB. All participants provided written informed consent before study procedures. Baseline assessment included medical history, physical examination, GCA‐related symptoms, comorbidities, current medications, erythrocyte sedimentation rate (ESR), and C‐reactive protein (CRP). GCAPS was calculated for all patients. The 1990 American College of Rheumatology (ACR) classification criteria were assessed in patients diagnosed with GCA despite negative TAB. The final diagnosis at six months was established by expert rheumatologists after review of the available clinical, laboratory, routine imaging, and histopathologic findings. The study‐derived 0.28‐mm cutoff and the PAMELA score were not used as prespecified diagnostic criteria during clinical adjudication. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of AUSL‐IRCCS Reggio Emilia, Italy (No. 943/2019/OSS/AUSLRE). No formal sample‐size calculation was performed because this was a prospective cohort of all consecutive eligible patients evaluated during the predefined study period.
Ultrasonography protocol and frontal‐branch intima‐media thickness assessment
Before TAB, all patients underwent bilateral CDUS of the STA using a high‐frequency (22 MHz) linear probe MyLab Class C system (Esaote), performed by two experienced sonographers blinded to clinical data (PM and GG). The common trunk and the frontal and parietal branches were scanned in longitudinal and transverse planes. Intima‐media thickness (IMT) was measured at the far wall, recording the maximal value for each segment after exclusion of atherosclerotic plaques. 21 , 22 When direct IMT measurement was technically challenging, the compression test was used as a complementary maneuver to facilitate vessel wall assessment; it was not analyzed as an independent diagnostic variable. 9 Bilateral axillary arteries, including their proximal, middle, and distal portions, together with the bilateral subclavian and common carotid arteries, were examined in longitudinal and transverse planes along all technically accessible segments. This extended large‐vessel ultrasonography protocol was performed in accordance with published vascular ultrasonography methodology in suspected GCA. 6 , 7 , 8 , 9 , 18 , 19 Large‐vessel ultrasonography was considered positive when IMT was ≥1.0 mm in at least one of the six bilateral arterial territories: the right or left common carotid, subclavian, or axillary artery. Patients with pathologic large‐vessel IMT or clinical signs or symptoms suggestive of extracranial LVV, such as vascular bruits or limb ischemic symptoms, underwent positron emission tomography (PET) or computed tomography (CT). Large‐vessel involvement was classified when pathologic ultrasonography findings were confirmed by PET or CT or when suggestive clinical findings were accompanied by compatible PET or CT abnormalities. The Halo Score, number of halo‐positive segments, and OGUS were calculated according to published definitions. 9 , 13 , 19 For each STA segment, bilateral mean IMT was calculated at the patient level by averaging the corresponding right and left measurements. Diagnostic analyses primarily evaluated mean frontal‐branch IMT as a continuous variable and as a dichotomous variable using the receiver operating characteristic (ROC)–derived cutoff of ≥0.28 mm.
TAB and reference standard
TAB was performed under ultrasonography guidance in all patients, targeting the segment with maximal wall thickening. When no halo was detected, a temporal artery branch was selected according to the study procedure. Specimens ≥0.5 cm were obtained and evaluated by a vasculitis pathologist who was blinded to clinical and imaging data. Histopathologic findings were classified as transmural GCA or adventitial‐only inflammation according to predefined criteria. 5 The primary reference standard was the expert diagnosis established at six months, categorized as GCA or non‐GCA. The study‐derived frontal IMT cutoff and the exploratory PAMELA score were not used as prespecified components of the reference standard. Analyses using TAB status as the alternative outcome were also performed.
Statistical analysis
Continuous variables were summarized using mean ± SD and median with interquartile range, whereas categorical variables were reported as counts and percentages. Between‐group comparisons were performed using the Student's t‐test or Mann–Whitney U test for continuous variables and the chi‐square test or Fisher's exact test for categorical variables, as appropriate. Spearman's rho was used to assess correlations between IMT and clinical, laboratory, and ultrasonography variables. ROC curves were constructed to assess diagnostic performance. The area under the curve (AUC) with 95% confidence intervals (CIs) was calculated, and optimal cut‐offs were identified using the Youden index. Diagnostic performance estimates for focused frontal‐branch assessment were descriptively compared with those of multisegment ultrasonography strategies, including the number of halo‐positive vessels, the ultrasonography Halo Score, and binary halo assessment. Internal consistency between frontal‐only OGUS and full temporal artery OGUS was assessed using Cronbach's alpha. In 20 examinations with paired acquisition‐time data, the duration of the complete bilateral temporal artery protocol and that of the focused bilateral frontal‐branch assessment were recorded and compared within patients. Multivariable logistic regression was used to identify independent baseline predictors of GCA. Candidate variables included factors associated with GCA at P < 0.20 in univariable analysis, together with mean frontal IMT ≥ 0.28 mm. The exploratory PAMELA score was derived from the predictors retained in the multivariable model. Points were assigned according to the magnitude of the adjusted odds ratios (ORs): 1 point for an OR from 1 to <10, 2 points for an OR from 10 to <20, and 3 points for an OR ≥ 20. Associations were reported as ORs with 95% CIs. Diagnostic performance of the PAMELA score was summarized using sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value. Intraobserver and interobserver reproducibility of IMT measurements was assessed in 100 randomly selected images using two‐way random‐effects intraclass correlation coefficients (ICCs) with absolute agreement. Images were remeasured after a 1‐month interval. Two‐sided P < 0.05 was considered significant. Analyses were performed with SPSS version 28. No missing‐data imputation was performed. Analyses based on data available only in predefined subsets used the corresponding available case samples. GCAPS data were available for all 171 patients, acquisition‐time data for 20 paired examinations. Large‐vessel involvement was classified in 35 patients. Segment‐level ultrasonography data were available for 34 patients.
RESULTS
Patient characteristics
Among 171 enrolled patients, 96 (56.1%) had biopsy‐confirmed GCA, including 66 with transmural inflammation and 30 with adventitial‐only inflammation. An additional 11 patients were diagnosed with GCA despite negative TAB, yielding 107 of 171 patients (62.6%) with a final diagnosis of GCA. Ten of the 11 TAB‐negative patients fulfilled the 1990 ACR classification criteria. The remaining patient had no cranial involvement: temporal artery CDUS and TAB were negative, whereas extracranial large‐vessel involvement was demonstrated by CDUS and confirmed by PET or CT. Diagnoses in the non‐GCA group were headache with transient high CRP values (24 patients), polymyalgia rheumatica (24 patients), nonarteritic anterior ischemic optic neuropathy (8 patients), cancer (4 patients), and undefined diagnosis (4 patients). At baseline, 113 patients (66.1%) were receiving glucocorticoids. The proportion of treated patients did not differ significantly between the GCA and non‐GCA groups (71.0% vs 57.8%; P = 0.077), whereas the mean prednisone dose at baseline was higher in the GCA group (26.6 ± 22.9 vs 17.8 ± 22.0 mg/day; P = 0.013) (Table 1). New‐onset headache, jaw claudication, systemic symptoms, large‐vessel involvement, and higher ESR and CRP values were more frequent in the GCA group, whereas age and sex did not differ significantly between groups.
Table 1.
Baseline characteristics of the study population*
| Variable | Non‐GCA (n = 64) | GCA (n = 107) | P value | OR (95% CI) for GCA |
|---|---|---|---|---|
| Age, mean ± SD, y | 72.1 ± 9.6 | 73.4 ± 8.6 | 0.54 | 1.01 (0.99–1.04) |
| Age, median (IQR), y | 72 (64–80) | 75 (66–80) | ||
| Sex, female, n (%) | 39 (60.9) | 60 (56.1) | 0.53 | 0.82 (0.43–1.55) |
| New‐onset headache, n (%) | 49 (76.6) | 95 (88.8) | 0.03 | 2.43 (1.10–5.60) |
| Jaw claudication, n (%) | 12 (18.8) | 56 (52.3) | <0.001 | 4.76 (2.30–9.90) |
| Large‐vessel involvement, n (%) a | 2 (3.1) | 33 (30.8) | <0.001 | 13.6 (3.2–68.9) |
| Systemic symptoms, n (%) | 18 (28.1) | 59 (55.1) | 0.001 | 3.10 (1.60–6.10) |
| ESR, mean ± SD, mm/hr | 46.1 ± 27.9 | 67.8 ± 32.7 | <0.001 | 1.02 (1.01–1.03) |
| ESR, median (IQR), mm/hr | 39 (24–60) | 69 (44–97) | ||
| CRP, mean ± SD, mg/dL | 3.3 ± 6.1 | 7.4 ± 6.1 | <0.001 | 1.17 (1.09–1.25) |
| CRP, median (IQR), mg/dL | 1.16 (0.48–2.79) | 6.16 (2.8–10.7) | ||
| Prednisone dose at baseline, mean ± SD, mg/day | 17.8 ± 22.0 | 26.6 ± 22.9 | 0.013 | 1.02 (1.00–1.03) |
| Prednisone dose at baseline, median (IQR), mg/day | 6.25 (0–50) | 25 (0–50) | ||
| Prednisone use at baseline, n (%) | 37 (57.8) | 76 (71.0) | 0.077 | 1.79 (0.93–3.42) |
CI, confidence interval; CRP, C‐reactive protein; CT, computed tomography; ESR, erythrocyte sedimentation rate; GCA, giant cell arteritis; LVV, large‐vessel vasculitis; OR, odds ratio; IMT, intima‐media thickness; IQR, interquartile range; PET, positron emission tomography.
Large‐vessel involvement was defined as IMT ≥1.0 mm in at least one right or left common carotid, subclavian, or axillary artery with PET or CT confirmation, or as compatible clinical findings accompanied by PET or CT evidence of extracranial LVV.
Diagnostic performance of frontal IMT
ROC analysis showed that mean frontal‐branch IMT had the highest observed diagnostic performance among the temporal artery segments examined (Table 2; Figure 1). Mean frontal‐branch IMT showed the highest AUC (0.87, 95% CI 0.82–0.92) and Youden index (0.65), compared with mean common STA IMT (AUC 0.78, 95% CI 0.71–0.85; Youden index 0.50) and mean parietal‐branch IMT (AUC 0.77, 95% CI 0.70–0.84; Youden index 0.47). At the 0.28‐mm cutoff, mean frontal‐branch IMT achieved a sensitivity of 71%, a specificity of 94%, a positive predictive value of 95%, and a negative predictive value of 66% for clinically diagnosed GCA, with a positive likelihood ratio of 11.4 and a negative likelihood ratio of 0.31. By contrast, neither mean parietal‐branch IMT nor mean common STA IMT provided a similarly favorable balance between sensitivity and specificity. For the parietal branch, a cutoff yielding a sensitivity of 67.3% resulted in a specificity of only 25%, whereas a cutoff yielding a specificity of 95.3% reduced sensitivity to 39%. A similarly unfavorable trade‐off was observed for the common STA: at a sensitivity of 67.3%, specificity was only 20%, whereas at a specificity of 95.3%, sensitivity was 41%. Thus, increasing sensitivity for these segments generated an excessive number of false‐positive results, whereas prioritizing specificity led to a substantial loss of sensitivity. Together with its higher AUC and Youden index, these findings indicate that mean frontal‐branch IMT provided the most favorable observed diagnostic balance among the temporal artery measurements evaluated in this cohort. Its high specificity, positive predictive value, and positive likelihood ratio support its role as a rule‐in marker; however, its negative predictive value of 66% confirms that a normal frontal‐branch IMT cannot exclude GCA when clinical suspicion persists.
Table 2.
IMT measurements of the superficial temporal artery segments according to clinical diagnosis and TAB status*
| Segment, IMT, mm | TAB‐negative (n = 75) | TAB‐positive (n = 96) | P value | Non‐GCA (n = 64) | GCA (n = 107) | P value |
|---|---|---|---|---|---|---|
| Right common, mean ± SD | 0.26 ± 0.11 | 0.45 ± 0.23 | <0.001 | 0.24 ± 0.09 | 0.44 ± 0.22 | <0.001 |
| Median (IQR) | 0.22 (0.18–0.32) | 0.40 (0.26–0.6) | 0.21 (0.18–0.30) | 0.40 (0.25–0.58) | ||
| Left common, mean ± SD | 0.27 ± 0.13 | 0.44 ± 0.22 | <0.001 | 0.25 ± 0.11 | 0.44 ± 0.22 | <0.001 |
| Median (IQR) | 0.22 (0.18–0.33) | 0.42 (0.23–0.59) | 0.20 (0.17–0.29) | 0.42 (0.23–0.56) | ||
| Right frontal, mean ± SD | 0.22 ± 0.10 | 0.42 ± 0.22 | <0.001 | 0.19 ± 0.06 | 0.41 ± 0.22 | <0.001 |
| Median (IQR) | 0.19 (0.17–0.22) | 0.37 (0.22–0.59) | 0.19 (0.17–0.22) | 0.36 (0.22–0.58) | ||
| Left frontal, mean ± SD | 0.22 ± 0.10 | 0.40 ± 0.20 | <0.001 | 0.20 ± 0.05 | 0.39 ± 0.20 | <0.001 |
| Median (IQR) | 0.20 (0.17–0.22) | 0.36 (0.23–0.52) | 0.20 (0.17–0.22) | 0.34 (0.22–0.51) | ||
| Right parietal, mean ± SD | 0.24 ± 0.10 | 0.39 ± 0.21 | <0.001 | 0.23 ± 0.09 | 0.38 ± 0.20 | <0.001 |
| Median (IQR) | 0.20 (0.18–0.29) | 0.36 (0.22–0.5) | 0.20 (0.18–0.27) | 0.35 (0.22–0.48) | ||
| Left parietal, mean ± SD | 0.24 ± 0.10 | 0.39 ± 0.21 | <0.001 | 0.24 ± 0.10 | 0.38 ± 0.20 | <0.001 |
| Median (IQR) | 0.20 (0.17–0.28) | 0.36 (0.21–0.48) | 0.20 (0.17–0.26) | 0.36 (0.21–0.46) | ||
| Mean common, a mean ± SD | 0.27 ± 0.12 | 0.45 ± 0.22 | <0.001 | 0.26 ± 0.10 | 0.43 ± 0.21 | <0.001 |
| Median (IQR) | 0.23 (0.18–0.32) | 0.43 (0.26–0.59) | 0.22 (0.18–0.38) | 0.42 (0.26–0.57) | ||
| Mean parietal, a mean ± SD | 0.24 ± 0.09 | 0.39 ± 0.20 | <0.001 | 0.23 ± 0.09 | 0.37 ± 0.19 | <0.001 |
| Median (IQR) | 0.20 (0.18–0.29) | 0.36 (0.22–0.49) | 0.20 (0.18–0.27) | 0.36 (0.32–0.48) | ||
| Mean frontal, b mean ± SD | 0.21 ± 0.10 | 0.42 ± 0.20 | <0.001 | 0.19 ± 0.05 | 0.41 ± 0.20 | <0.001 |
| Median (IQR) | 0.19 (0.17–0.21) | 0.37 (0.24–0.53) | 0.19 (0.17–0.21) | 0.38 (0.22–0.53) |
AUC, area under the curve; GCA, giant cell arteritis; IMT, intima‐media thickness; IQR, interquartile range; ROC, receiver operating characteristic; TAB, temporal artery biopsy.
Bilateral mean IMT was calculated at the patient level by averaging the corresponding right and left measurements.
Mean frontal‐branch IMT showed the highest observed AUC in ROC analysis.
Figure 1.
ROC curves for mean common, parietal‐branch, and frontal‐branch temporal artery IMT in predicting the final clinical diagnosis of giant cell arteritis. Mean frontal‐branch IMT showed the highest observed area under the curve (0.87, 95% confidence interval 0.82–0.92). At the 0.28‐mm cutoff, sensitivity was 71%, specificity was 94%, the positive likelihood ratio was 11.4, and the negative likelihood ratio was 0.31. IMT, intima‐media thickness; ROC, receiver operating characteristic.
Correlations with clinical and ultrasonography scores
Frontal‐branch IMT showed modest correlations with ESR and CRP and strong correlations with the Halo Score, OGUS, number of halo‐positive temporal artery segments, and GCAPS, while no significant correlation with age was observed (Table 3). Similar associations were found for common and parietal IMT, reflecting the shared ultrasonography information included in the segmental measurements and composite scores.
Table 3.
Spearman correlations between temporal artery IMT and clinical, laboratory, and ultrasonography variables*
| Temporal artery measurement | Age | ESR | CRP | Halo Score | Number of halo‐positive vessels | OGUS | GCAPS |
|---|---|---|---|---|---|---|---|
| Frontal IMT | 0.11 (P = 0.16) | 0.37 (P < 0.001) | 0.40 (P < 0.001) | 0.87 (P < 0.001) | 0.86 (P < 0.001) | 0.93 (P < 0.001) | 0.43 (P < 0.001) |
| Common IMT | 0.19 (P = 0.01) | 0.32 (P < 0.001) | 0.30 (P < 0.001) | 0.81 (P < 0.001) | 0.81 (P < 0.001) | 0.92 (P < 0.001) | 0.37 (P < 0.001) |
| Parietal IMT | 0.12 (P = 0.13) | 0.27 (P < 0.001) | 0.31 (P < 0.001) | 0.84 (P < 0.001) | 0.82 (P < 0.001) | 0.91 (P < 0.001) | 0.37 (P < 0.001) |
Values are Spearman correlation coefficients (rho), with corresponding two‐sided P values in parentheses. CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; IMT, intima‐media thickness; OGUS, OMERACT GCA Ultrasonography Score; GCAPS, Southend GCA Probability Score.
Univariate and multivariable predictors of GCA
Frontal IMT ≥ 0.28 mm and OGUS > 1 were more frequent, while the Halo Score and number of halo‐positive segments were higher, in patients with GCA and in TAB‐positive patients than in the respective comparison groups (Table 4). The full univariable logistic regression analysis is reported in Supplementary Table S1. In multivariable analysis, new‐onset headache, jaw claudication, large‐vessel involvement, and mean frontal‐branch IMT ≥ 0.28 mm were independently associated with the final clinical diagnosis of GCA. Mean frontal‐branch IMT ≥ 0.28 mm showed the strongest association (OR 43.0, 95% CI 10.5–175.8; P < 0.001) (Table 5). These variables were weighted according to the magnitude of their adjusted ORs to derive the exploratory PAMELA score, ranging from 0 to 7 points. Variables with an adjusted OR from 1 to <10 were assigned 1 point, those with an OR from 10 to <20 were assigned 2 points, and frontal IMT ≥0.28 mm, with an OR ≥ 20, was assigned 3 points. ROC analysis of the exploratory PAMELA score identified an optimal cutoff of ≥3, yielding a sensitivity of 74.8%, a specificity of 93.7%, an overall accuracy of 81.9%, a positive predictive value of 95.2%, and a negative predictive value of 69.0%. The combined frontal‐branch or LVV criterion yielded a sensitivity of 96.4% (95% CI 89.8–99.2), a positive likelihood ratio of 3.14 (95% CI 2.29–4.31), an negative predictive value of 95.3% (95% CI 86.9‐98.4), and an accuracy of 82.4% (95% CI 75.9–87.8) for clinical GCA. Large‐vessel involvement was classified in 35 patients. Segment‐level ultrasonography distribution data were available for 34 of these patients and involved the common carotid, subclavian, and axillary arteries (Supplementary Table S2). IMT values were higher in each of the six examined arterial territories among patients with LVV than among those without LVV (Supplementary Table S3). All patients with pathologic large‐vessel IMT or clinical signs suggestive of LVV underwent PET or CT, and all ultrasonography‐positive large‐vessel cases were PET‐ or CT‐positive.
Table 4.
Ultrasonography scores and frontal IMT according to TAB status and clinical diagnosis*
| TAB‐negative | TAB‐positive | P (TAB) | OR (95% CI) TAB | GCA‐negative | GCA‐positive | P (GCA) | OR (95% CI) GCA | |
|---|---|---|---|---|---|---|---|---|
| Mean frontal IMT, mm | 0.22 ± 0.09 | 0.41 ± 0.21 | <0.001 | >1,000 | 0.20 ± 0.05 | 0.40 ± 0.20 | <0.001 | >1,000 |
| Median (IQR) | 0.19 (0.17–0.21) | 0.37 (0.24–0.53) | 0.18 (0.17–0.21) | 0.38 (0.22–0.53) | ||||
| Frontal IMT ≥ 0.28 mm, n (%) | 8 (11) | 64 (67) | <0.001 | 16.7 (7.20–39.1) | 4 (6) | 76 (71) | <0.001 | 36.9 (10.8–125.7) |
| GCAPS, mean ± SD | 12.7 ± 3.0 | 16.3 ± 4.7 | <0.001 | 1.25 (1.15–1.38) | 12.3 ± 2.9 | 16.1 ± 4.5 | <0.001 | 1.31 (1.18–1.5) |
| Median (IQR) | 12.0 (11–15) | 17 (14–19) | 12 (10–14) | 16 (14–19) | ||||
| OGUS, mean ± SD | 0.72 ± 0.24 | 1.22 ± 0.55 | <0.001 | 48.8 (13–182) | 0.68 ± 0.18 | 1.19 ± 0.54 | <0.001 | 129 (24.4–691) |
| Median (IQR) | 0.64 (0.56–0.79) | 1.13 (0.82–1.45) | 0.62 (0.56–0.74) | 1.11 (0.8–1.43) | ||||
| OGUS > 1, n (%) | 10 (13) | 57 (60) | <0.001 | 9.9 (4.5–21.6) | 4 (6) | 63 (59) | <0.001 | 21.5 (7.3–63.4) |
| Halo Score, mean ± SD | 7.84 ± 7.9 | 16.1 ± 9.4 | <0.001 | 1.12 (1.1–1.2) | 6.8 ± 7.1 | 15.8 ± 9.4 | <0.001 | 1.14 (1.1–1.19) |
| Median (IQR) | 4 (2–11) | 16.5 (8–23) | 4 (2–9.5) | 16 (8–23) | ||||
| Number temporal segments halo | 0.97 ± 1.83 | 3.4 ± 2.5 | <0.001 | 1.58 (1.35–1.85) | 0.63 ± 1.5 | 3.3 ± 2.5 | <0.001 | 1.77 (1.5–2.1) |
| Median (IQR) | 0 (0–1) | 4 (1–6) | 0 (0–0) | 4 (0–6) |
Percentages were calculated within the corresponding analyzed group and rounded to the nearest whole number. CI, confidence interval; GCA, giant cell arteritis; GCAPS, Giant Cell Arteritis Probability Score; IMT, intima‐media thickness; IQR, interquartile range; OGUS, OMERACT GCA Ultrasonography Score; OR, odds ratio; TAB, temporal artery biopsy.
Table 5.
Multivariable logistic regression analysis of predictors of the final clinical diagnosis of GCA at six months*
| β | SE | P value | OR | 95% CI | |
|---|---|---|---|---|---|
| Cumulative GC dose before CDUS | <0.001 | 0.001 | 0.663 | 1 | 0.99–1.01 |
| Blindness | 1.43 | 1.12 | 0.203 | 4.17 | 0.46–37.7 |
| Objective temporal artery abnormality | 0.076 | 0.498 | 0.879 | 1.08 | 0.41–2.86 |
| Systemic symptoms | 0.746 | 0.532 | 0.161 | 2.11 | 0.74–5.97 |
| New‐onset headache | 1.51 | 0.66 | 0.022 | 4.51 | 1.24–16.4 |
| Large‐vessel involvement a | 2.53 | 0.86 | 0.003 | 12.6 | 2.31–68.3 |
| Jaw claudication | 1.47 | 0.50 | 0.003 | 4.37 | 1.63–11.7 |
| CRP, mg/dL | 0.07 | 0.04 | 0.062 | 1.08 | 0.99–1.16 |
| Mean frontal‐branch IMT ≥ 0.28 mm b | 3.76 | 0.73 | <0.001 | 43.0 | 10.5–175.8 |
β, regression coefficient; CDUS, color Doppler ultrasonography; CI, confidence interval; CRP, C‐reactive protein; CT, computed tomography; GC, glucocorticoid; GCA, giant cell arteritis; IMT, intima‐media thickness; OR, odds ratio. PET, PET, positron emission tomography.
Axillary or common carotid or subclavian IMT ≥ 1.0 mm.
Strongest independent predictor in the model. Large‐vessel involvement was classified when IMT ≥1.0 mm in at least one right or left common carotid, subclavian, or axillary artery was confirmed by PET or CT, or when compatible clinical findings were accompanied by PET or CT evidence of extracranial LVV.
Comparison with multisegment ultrasonography strategies and examination time
Focused frontal‐branch assessment showed diagnostic performance estimates that were numerically similar to those of multisegment temporal artery ultrasonography strategies (Supplementary Table S4). Mean frontal‐branch IMT ≥0.28 mm showed an AUC of 0.799 (SE 0.034; 95% CI 0.732–0.866), compared with 0.804 (SE 0.033; 95% CI 0.738–0.869) for the number of halo‐positive temporal artery segments, 0.785 (SE 0.037; 95% CI 0.713–0.857) for the ultrasonography Halo Score, and 0.764 (SE 0.039; 95% CI 0.689–0.840) for binary halo assessment. Internal consistency between frontal‐only OGUS and complete temporal artery OGUS was high, with a Cronbach's alpha of 0.955. In the 20 examinations with paired acquisition‐time data, focused bilateral frontal‐branch assessment required 1.07 ± 0.24 minutes, compared with 7.62 ± 1.11 minutes for the complete bilateral temporal artery protocol. This corresponded to a mean time saving of 6.55 minutes per examination (P < 0.001; Supplementary Table S5).
Reproducibility
Bilateral mean frontal‐branch IMT showed excellent intraobserver and interobserver reliability, with ICCs of 0.96 (95% CI 0.90–0.99) and 0.93 (95% CI 0.82–0.97), respectively (Supplementary Table S6).
DISCUSSION
This prospective study suggests that focused ultrasonography assessment of the frontal branch of the STA, based on bilateral mean IMT, provides a highly specific, reproducible, and time‐efficient cranial marker in patients with suspected GCA evaluated in a fast‐track setting. Among the temporal artery segments examined, frontal‐branch IMT showed the highest observed diagnostic performance, with an AUC of 0.87 and a Youden index of 0.65. At the internally derived cutoff of 0.28 mm, it remained independently associated with the diagnosis of GCA in the multivariable model. The observed advantage of the frontal branch is unlikely to be explained by statistical performance alone. Its examination is less frequently limited by scalp hair than that of the parietal branch, which may facilitate image acquisition and IMT measurement. These practical characteristics may also contribute to the excellent intraobserver and interobserver reliability observed in our study. Conversely, common STA wall thickness may be more influenced by age‐related or atherosclerotic changes, consistent with its significant correlation with age in our cohort (Table 3). 19 , 20 , 21 , 22 , 23 , 24 These explanations remain plausible, as technical image quality and cardiovascular risk factors were not specifically analyzed. At the 0.28‐mm cutoff, frontal‐branch IMT showed a specificity of 94% and a positive likelihood ratio of 11.4, with a sensitivity of 71% and a negative likelihood ratio of 0.31. This profile supports its use primarily as a rule‐in marker rather than as a stand‐alone exclusion test. A pathologic frontal‐branch IMT substantially increases the probability of GCA, whereas a normal measurement cannot exclude the disease and must be interpreted according to clinical probability and the findings from the remaining temporal and large‐vessel territories. Mean frontal‐branch IMT showed diagnostic performance estimates that were numerically similar to those of multisegment strategies, including the number of halo‐positive segments, the Halo Score, and binary halo assessment. Internal consistency between frontal‐only OGUS and complete temporal artery OGUS was high, with a Cronbach's alpha of 0.955. These findings suggest that focused frontal‐branch assessment captures a substantial proportion of the ultrasonography information provided by a complete temporal artery examination. However, frontal IMT contributes directly to the composite ultrasonography indices, and its correlations with these scores should therefore be interpreted as evidence of internal consistency rather than as independent confirmation of superiority. Similar correlations were also observed for common and parietal IMT. The marked reduction in acquisition time represents a major practical advantage of the focused approach. In 20 paired examinations, bilateral frontal‐branch assessment required 1.07 ± 0.24 minutes, compared with 7.62 ± 1.11 minutes for the complete bilateral temporal artery protocol, corresponding to a mean saving of 6.55 minutes per examination (P < 0.001). Although this analysis was based on a limited number of examinations performed by experienced operators, the observed time saving may be clinically relevant in fast‐track pathways, where diagnostic decisions must be made rapidly. Focused frontal‐branch assessment may therefore serve as an initial cranial examination, followed by evaluation of the remaining temporal and large arteries when frontal findings are negative or equivocal and clinical suspicion persists. 6 , 7 , 8 , 9 , 18 , 19 A normal frontal‐branch examination alone does not exclude GCA. A further strength of the study was the anatomic correspondence between ultrasonography and TAB. Whenever feasible, tissue sampling was directed toward the segment showing the greatest wall thickening. This approach was intended to match the imaged and biopsied arterial segments rather than to increase TAB sensitivity. In a previous randomized controlled study conducted by our group, CDUS guidance did not significantly improve TAB sensitivity compared with conventional biopsy. 25 The high proportion of biopsy‐positive cases in the present cohort is therefore more likely to reflect the high pretest probability and case mix of a tertiary fast‐track population than an increased diagnostic yield attributable to ultrasonography guidance. Among the 96 biopsy‐positive cases, 30 showed inflammation confined to the adventitia or vasa vasorum. The significance of isolated adventitial inflammation remains debated because similar findings may occasionally occur in other inflammatory or age‐related conditions. Nevertheless, when identified in an adequate specimen and accompanied by a compatible clinical, biochemical, and imaging presentation, adventitial or periadventitial inflammation may represent a limited histopathologic pattern of GCA. 5 It should therefore be interpreted within the overall diagnostic context. Several limitations should be acknowledged. Incorporation bias cannot be completely excluded because the diagnosis at six months was established by expert adjudication integrating clinical, laboratory, histopathologic, and routine imaging findings. However, 96 of 107 patients classified as having GCA had histopathologic confirmation. Ten of 11 TAB‐negative patients fulfilled the 1990 ACR classification criteria, whereas the remaining patient had negative temporal artery ultrasonography and evidence of LVV on PET or CT. 26 The study‐derived 0.28‐mm cutoff and the exploratory PAMELA score were not prespecified components of the reference standard. These features reduce, but do not eliminate, the potential for incorporation bias. Glucocorticoid treatment before ultrasonography may also have influenced the findings. Overall, 113 of 171 participants had started treatment before the baseline examination, although treatment had been initiated within five days in almost all cases. Because temporal artery halo thickness may decrease rapidly after glucocorticoid initiation, pretreatment may have attenuated ultrasonography abnormalities and reduced sensitivity. 27 The magnitude of this effect cannot be quantified from the present data. The single‐center design, the high prevalence of GCA, the involvement of experienced operators, and the use of a 22‐MHz probe may limit the generalizability of these findings. Positive and negative predictive values may differ in populations with a lower pretest probability, and the 0.28‐mm cutoff requires confirmation across different equipment, acquisition settings, and levels of operator experience. The exploratory PAMELA score provides a preliminary framework integrating frontal‐branch IMT, clinical features, and large‐vessel involvement. Because frontal‐branch IMT ≥ 0.28 mm is assigned 3 points, this variable alone reaches the proposed cutoff of ≥3. The score therefore largely reflects the strong weight of frontal IMT in the multivariable model, and its incremental value beyond frontal‐branch IMT alone remains to be established. Moreover, the score was derived and evaluated in the same cohort without internal or external validation. It should therefore be regarded as a hypothesis‐generating construct rather than as a validated clinical decision rule. Its potential role requires prospective assessment in independent multicenter cohorts, together with external validation of the 0.28‐mm cutoff and the focused frontal‐branch strategy.
Focused bilateral frontal‐branch ultrasonography based on IMT showed high specificity, excellent reproducibility, and substantially shorter acquisition time than the complete temporal artery protocol in this prospective fast‐track cohort. These findings support its use as a rapid initial cranial assessment in patients with suspected GCA. However, a normal frontal‐branch examination does not exclude GCA, and the remaining temporal and large‐vessel territories should be examined when frontal findings are negative or equivocal and clinical suspicion persists.
AUTHOR CONTRIBUTIONS
All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Germanò confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.
Supporting information
Table S1. Univariable logistic regression analysis for predictors of clinical GCA
Table S2. Distribution of involved large arteries among patients with available segment‐level ultrasound data
Table S3. Large‐vessel IMT values according to large‐vessel involvement status
Table S4. Roc characteristic performance of focused frontal‐branch and multisegment ultrasound measures for the final clinical diagnosis of giant cell arteritis
Table S5. Paired acquisition times for the complete temporal artery protocol and focused bilateral frontal‐branch assessment
Table S6. Intraobserver and interobserver reliability of temporal artery intima‐media thickness measurements.
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1Rheumatology Unit, Department of Internal Medicine, Azienda Unità Sanitaria Locale Istituto di Ricovero e Cura a Carattere Scientifico, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; 2Pathology Unit, Azienda Unità Sanitaria Locale Istituto di Ricovero e Cura a Carattere Scientifico, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
Additional supplementary information cited in this article can be found online in the Supporting Information section (https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/acr2.90144).
Author disclosures are available at https://onlinelibrary.wiley.com/doi/10.1002/acr2.90144.
References
- 1. Salvarani C, Cantini F, Boiardi L, et al. Polymyalgia rheumatica and giant‐cell arteritis. N Engl J Med 2002;347:261–271. [DOI] [PubMed] [Google Scholar]
- 2. Bosch P, Espigol‐Frigolé G, Cid MC, et al. Cranial involvement in giant cell arteritis. Lancet Rheumatol 2024;6:e384–e396. [DOI] [PubMed] [Google Scholar]
- 3. van der Geest KSM, Sandovici M, Brouwer E, et al. Diagnostic accuracy of symptoms, physical signs, and laboratory tests for giant cell arteritis: a systematic review and meta‐analysis. JAMA Intern Med 2020;180:1295–1304. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Luqmani R, Lee E, Singh S, et al. The role of ultrasound compared to biopsy of temporal arteries in the diagnosis and treatment of giant cell arteritis (TABUL): a diagnostic accuracy and cost‐effectiveness study. Health Technol Assess 2016;20:1–238. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Muratore F, Cavazza A, Boiardi L, et al. Histopathologic findings of patients with biopsy‐negative giant cell arteritis compared to those without arteritis: a population‐based study. Arthritis Care Res (Hoboken) 2016;68:865–870. [DOI] [PubMed] [Google Scholar]
- 6. Dejaco C, Ramiro S, Duftner C, et al. EULAR recommendations for the use of imaging in large‐vessel vasculitis in clinical practice. Ann Rheum Dis 2018;77:636–643. [DOI] [PubMed] [Google Scholar]
- 7. Schäfer VS, Chrysidis S, Schmidt WA, et al. OMERACT definition and reliability assessment of chronic ultrasound lesions of the axillary artery in giant cell arteritis. Semin Arthritis Rheum 2021;51:951–956. [DOI] [PubMed] [Google Scholar]
- 8. Schmidt WA. Ultrasound in the diagnosis and management of giant cell arteritis. Rheumatology (Oxford) 2018;57(Suppl 2):ii22–ii31. [DOI] [PubMed] [Google Scholar]
- 9. Chrysidis S, Duftner C, Dejaco C, et al. Definitions and reliability assessment of elementary ultrasound lesions in giant cell arteritis: a study from the OMERACT Large‐Vessel Vasculitis Ultrasound Working Group. RMD Open 2018;4:e000598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. van der Geest KSM, Borg F, Kayani A, et al. Novel ultrasonographic Halo Score for giant cell arteritis: assessment of diagnostic accuracy and association with ocular ischaemia. Ann Rheum Dis 2020;79:393–399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. van der Geest KSM, Wolfe K, Borg F, et al. Ultrasonographic Halo Score in giant cell arteritis: association with intimal hyperplasia and ischaemic sight loss. Rheumatology (Oxford) 2021;60:4361–4366. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Molina Collada J, Martínez‐Barrio J, Serrano‐Benavente B, et al. Diagnostic value of ultrasound halo count and Halo Score in giant cell arteritis: a retrospective study from routine care. Ann Rheum Dis 2022;81:e175. [DOI] [PubMed] [Google Scholar]
- 13. Dejaco C, Ponte C, Monti S, et al. The provisional OMERACT ultrasonography score for giant cell arteritis. Ann Rheum Dis 2023;82:556–564. [DOI] [PubMed] [Google Scholar]
- 14. Monti S, Ponte C, Schäfer VS, et al. The giant cell arteritis ultrasound score (OGUS) at diagnosis and after initial treatment predicts future relapses in GCA patients: results of a multicentre prospective study. Ann Rheum Dis 2025;84:823–832. [DOI] [PubMed] [Google Scholar]
- 15. Laskou F, Coath F, Mackie SL, et al. A probability score to aid the diagnosis of suspected giant cell arteritis. Clin Exp Rheumatol 2019;37(Suppl 117):104–108. [PubMed] [Google Scholar]
- 16. Sebastian A, van der Geest KSM, Tomelleri A, et al. Development of a diagnostic prediction model for giant cell arteritis by sequential application of Southend Giant Cell Arteritis Probability Score and ultrasonography: a prospective multicentre study. Lancet Rheumatol 2024;6:e291–e299. [DOI] [PubMed] [Google Scholar]
- 17. Melville AR, Donaldson K, Dale J, et al. Validation of the Southend Giant Cell Arteritis Probability Score in a Scottish single‐centre fast‐track pathway. Rheumatol Adv Pract 2022;6:rkab102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Schmidt WA, Seifert A, Gromnica‐Ihle E, et al. Ultrasound of proximal upper extremity arteries to increase the diagnostic yield in large‐vessel giant cell arteritis. Rheumatology (Oxford) 2008;47:96–101. [DOI] [PubMed] [Google Scholar]
- 19. Schäfer VS, Juche A, Ramiro S, et al. Ultrasound cut‐off values for intima‐media thickness of temporal, facial and axillary arteries in giant cell arteritis. Rheumatology (Oxford) 2017;56:1479–1483. [DOI] [PubMed] [Google Scholar]
- 20. Duftner C, Redlinger N, Bruyn GA, et al. Reliability of the OMERACT Giant Cell Arteritis Ultrasonography Score (OGUS): results of a patient‐based exercise involving experts and non‐experts in vascular ultrasonography. RMD Open 2025;11:e004667. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Stein JH, Korcarz CE, Hurst RT, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima‐Media Thickness Task Force. J Am Soc Echocardiogr 2008;21:93–111; quiz 189–190. [DOI] [PubMed] [Google Scholar]
- 22. Seitz P, Lötscher F, Bucher S, et al. Ultrasound intima‐media thickness cut‐off values for the diagnosis of giant cell arteritis using a dual clinical and MRI reference standard and cardiovascular risk stratification. Front Med (Lausanne) 2024;11:1389655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Seitz L, Lötscher F. The intima‐media thickness in suspected giant cell arteritis: sometimes it is worth taking a closer look. Rheumatology (Oxford) 2021;60:3039–3041. [DOI] [PubMed] [Google Scholar]
- 24. De Miguel E, Beltran LM, Monjo I, et al. Atherosclerosis as a potential pitfall in the diagnosis of giant cell arteritis. Rheumatology (Oxford) 2018;57:318–321. [DOI] [PubMed] [Google Scholar]
- 25. Germanò G, Muratore F, Cimino L, et al. Is colour duplex sonography‐guided temporal artery biopsy useful in the diagnosis of giant cell arteritis? A randomised study. Rheumatology (Oxford) 2015;54:400–404. [DOI] [PubMed] [Google Scholar]
- 26. Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33:1122–1128. [DOI] [PubMed] [Google Scholar]
- 27. Ponte C, Serafim AS, Monti S, et al. Early variation of ultrasound halo sign with treatment and relation with clinical features in patients with giant cell arteritis. Rheumatology (Oxford) 2020;59:3717–3726. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Univariable logistic regression analysis for predictors of clinical GCA
Table S2. Distribution of involved large arteries among patients with available segment‐level ultrasound data
Table S3. Large‐vessel IMT values according to large‐vessel involvement status
Table S4. Roc characteristic performance of focused frontal‐branch and multisegment ultrasound measures for the final clinical diagnosis of giant cell arteritis
Table S5. Paired acquisition times for the complete temporal artery protocol and focused bilateral frontal‐branch assessment
Table S6. Intraobserver and interobserver reliability of temporal artery intima‐media thickness measurements.
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