Evaluation of Ultrasound and PET/CT in the Diagnosis and Monitoring of Giant Cell Arteritis

The aim of this project is to prospectively evaluate the diagnostic accuracy of different imaging tools in specific giant cell arteritis disease subsets before and after treatment initiation. Diagnostic tools with high sensitivity and specificity are a prerequisite for optimal treatment of GCA patients.

Specifically, the diagnostic accuracy of ultrasound (US) as compared to 18F-FDG PET/CT in new-onset, treatment naïve large vessel(LV)-GCA patients is investigated. Furthermore, long-term follow up including US, 18F-FDG PET/CT and cross sectional imaging is performed to explore the potential of imaging as monitoring and prognostic tools.

In this observational cohort, the diagnostic accuracy of 18F-FDG PET/CT after three and ten days of glucocorticoid treatment in the subset of LV-GCA patients and the diagnostic accuracy of 18F-FDG PET/CT in cranial artery inflammation in new-onset, treatment naïve c-GCA patients as compared to a control group of patients with a previous diagnosis of malignant melanoma was also evaluated and is registered elsewhere (ClinicalTrials.gov Identifier: NCT03285945 and NCT03409913, respectively)

Study Overview

• Status: Completed
• Conditions: Vasculitis; Giant Cell Arteritis
• Intervention / Treatment: Diagnostic test: Ultrasound

Detailed Description

The diagnosis of GCA is clinical and syndrome-based. Only few years ago, temporal artery biopsy (TAB) was the standard diagnostic tool to confirm diagnosis, although sensitivity is moderate[3,4] and its outcome seldom affects treatment management[5]. Today, the European League Against Rheumatism (EULAR) recommends diagnostic imaging in all patients suspected of GCA[6]. The imaging of choice is based on the suspected vessel involvement. In patients suspected of cranial GCA (c-GCA), vascular ultrasound (US) is the recommended first line imaging test, whereas Fluorine-18-fluorodeoxyglucose (18F-FDG) positron emissions tomography/computed tomography (PET/CT) is not recommended for the assessment of cranial arteries.

In patients suspected of large vessel involvement (LV-GCA), 18F-FDG PET/CT, US, magnetic resonance imaging (MRI) or CT can be used to confirm disease, but no specific priority of the imaging tests is given. US is an attractive first line imaging in LV-GCA suspected patients since it is increasingly used in the diagnosis of c-GCA, is readily available and cheap. 18F-FDG PET/CT is an appealing diagnostic tool in LV-GCA suspected patients, since it also evaluates malignancy and infection, differential diagnoses often considered in this disease subset. However, 18F-FDG PET/CT is often not readily available, is expensive and exposes patients to radiation. Moreover, its sensitivity seems to decrease with glucocorticoid (GC) treatment and the window of opportunity in which sensitivity is unaffected is unknown.

Relapse during glucocorticoid tapering is frequent in GCA. However, the evaluation of potential GCA disease activity relies on unspecific symptoms and inflammatory biomarkers. There is a significant overlap between symptoms of GCA disease activity and GC adverse effect and the same holds for symptoms and biomarkers of disease activity and infection, making the evaluation difficult. Accurate tools to support treatment decisions, avoid over-treatment without risk of GCA related complications are lacking.

The aim of this project is to prospectively evaluate the diagnostic accuracy of different imaging tools in specific giant cell arteritis disease subsets before and after treatment initiation. Diagnostic tools with high sensitivity and specificity are a prerequisite for optimal treatment of GCA patients.

Specifically, the diagnostic accuracy of ultrasound (US) as compared to 18F-FDG PET/CT in new-onset, treatment naïve large vessel(LV)-GCA patients is investigated. Furthermore, long-term follow up including US, 18F-FDG PET/CT and cross sectional imaging is performed to explore the potential of imaging as monitoring and prognostic tools.

In this observational cohort, the diagnostic accuracy of 18F-FDG PET/CT after three and ten days of glucocorticoid treatment in the subset of LV-GCA patients and the diagnostic accuracy of 18F-FDG PET/CT in cranial artery inflammation in new-onset, treatment naïve c-GCA patients as compared to a control group of patients with a previous diagnosis of malignant melanoma was also evaluated and is registered elsewhere (ClinicalTrials.gov Identifier: NCT03285945 and NCT03409913, respectively)

• Study Type: Observational
• Enrollment (Actual): 101

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

For the GCA suspect cohort, patients referred to Department of Rheumatology, Aarhus University Hospital due to suspicion of GCA are considered for inclusion. Patients in whom a 18F-FDG PET/CT is not performed by the time of referral and who presents with unequivocal cranial symptoms of GCA requiring acute initiation of GC treatment are not considered for inclusion.

Description

Inclusion Criteria:

1. Age more than 50 years
2. C-reactive protein (CRP)>15 mg/L or erythrocyte sedimentation rate (ESR)>40 mm/h

3. Either

   1. cranial symptoms such as new-onset headache or scalp tenderness, jaw or tongue claudication, visual disturbances
   2. new-onset limb claudication
   3. protracted constitutional symptoms, defined as weight loss>5 kilograms or fever>38 degrees Celcius for >3 weeks
   4. Bilateral shoulder pain and morning stiffness.

Exclusion Criteria:

1. oral glucocorticoid treatment within the past month;
2. subcutaneous, intramuscular, intra-articular or intravenous glucocorticoid within the past 2 months;
3. DMARD treatment or other immunosuppressive therapy within the past 3 months;
4. ongoing treatment with interleukin2;
5. previous diagnosis of GCA or polymyalgia rheumatica;
6. any disease potentially causing large vessel inflammation, that is autoimmune diseases; rheumatoid arthritis, Cogans syndrome, relapsing polychondritis, ankylosing spondylitis, systemic lupus erythematosus, Buerger's disease, Bechet's disease, inflammatory bowel disease, infections; syphilis, known active current or history of recurrent tuberculosis, hepatitis or HIV, or other large vessel disease; sarcoidosis, neurofibromatosis, congenital coarctation, Marfans syndrome, Ehlers-Danlos syndrome, retroperitoneal fibrosis.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
GCA cases; GCA cases were patients with a clinical diagnosis of GCA based on a rheumatologists evaluation of history taking, physical examination, laboratory screening and initial PET report (reporting potential large vessel inflammation but not considering cranial artery inflammation). GCA was considered large vessel (LV) and/or cranial (c) GCA cases: LV-GCA cases were patients with a clinical diagnosis of GCA and verified LV inflammation by 18F-FDG PET/CT with or without concomitant c-GCA. C-GCA cases, for the exploratory analysis of the performance of US and PET in c-GCA, were patients with a clinical diagnosis of GCA fulfilling the 1990 American College of Rheumatology (ACR) criteria, with or without concomitant LV-GCA.	Diagnostic test: Ultrasound; Ultraosund of temporal, carotid and axillary arteries
controls; Controls were GCA suspected patients in whom GCA diagnosis was dismissed.	Diagnostic test: Ultrasound; Ultraosund of temporal, carotid and axillary arteries

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic accuracy of large vessel ultrasound with PET/CT as reference	Large vessel ultrasound for LV-GCA diagnosis is considered positive in the presence of a halo in carotid and/or axillary arteries.	Time of diagnosis/pre-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Large vessel intima-media thickness (IMT) cut off for LV-GCA diagnosis with PET/CT as reference	IMT measurement performed on the distal vessel wall in carotid and axillary arteries	Time of diagnosis/pre-treatment
Diagnostic accuracy vascular ultrasound (overall)	Vascular ultrasound for GCA diagnosis is considered positive in the presence of a halo in temporal, carotid and/or axillary arteries.	Time of diagnosis/pre-treatment
Diagnostic accuracy of vascular ultrasound after treatment (day 3, 10 and week 8)	Vascular ultrasound for GCA diagnosis is considered positive in the presence of a halo in temporal, carotid and/or axillary arteries.	3 days, 10 days and 8 weeks after initiated treatment
Diagnostic accuracy of PET/CT of cranial arteries for c-GCA diagnosis (reference: American College of Rheumatology 1990 criteria)	cranial artery (vertebral, maxillary and temporal) FDG uptake above surrounding tissue FDG uptake is considered consistent with vasculitis	Time of diagnosis/pre-treatment
Temporal artery biopsy	Temporal artery biopsy considered positive in the presence of an inflammatory infiltrate in any vessel wall layer	Time of diagnosis
Halo sign for monitoring disease activity (week 8, 24 and 15 months)	Presence or absence of halos on US	week 8, 24 and 15 months after initiated treatment
Composite halo score for monitoring disease activity (week 8, 24 and 15 months)	Composite halo score	week 8, 24 and 15 months after initiated treatment
Intima media thickness for monitoring disease activity (week 8, 24 and 15 months)	Maximum intima media thickness (IMT) measurement on US	week 8, 24 and 15 months after initiated treatment
PETVAS for monitoring disease activity (15 months)	Composite PET scores (e.g.PETVAS)	15 months after treatment is initiated
Semiquantitative FDG measure for monitoring disease activity (15 months)	Maximum semiquantitative FDG measures	15 months after treatment is initiated
FDG burden for monitoring disease activity (15 months)	Composite scores of FDG inflammatory burden (summarising FDG uptake in voxels of interest)	15 months after treatment is initiated
PETVAS for GCA prognosis (baseline)	PETVAS score (summarising graded (1-4) FDG uptake in arterial vessel segments)	4-5 years after diagnosis
Semiquantitative FDG measure for GCA prognosis (baseline)	Maximum semiquantitative FDG measures	4-5 years after diagnosis
FDG burden for GCA prognosis (baseline)	Composite scores of arterial FDG uptake (summarising FDG uptake in voxels of interest)	4-5 years after diagnosis
Aortic diameter 4-5 years after diagnosis	Aortic diameter on cross sectional imaging	4-5 years after diagnosis
Vessel wall thickening 4-5 years after diagnosis	Vessel wall thickening	4-5 years after diagnosis

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient global NRS	Patients global experience of disease activity on a numerical range scale (0-10)	Baseline, day 10, week 8, 24 and 15 months
Physician NRS	Physicians global judgement of disease activity on a numerical range scale (0-10)	Baseline, day 10, week 8, 24 and 15 months
CRP	c-reactive protein (mg/l)	Baseline, day 3 and 10, week 8, 24 and 15 months
Physicians judgement of disease activity	Overall judgement of disease activity (remission, possible activity not requiring treatment, activity/relapse)	Baseline, day 10, week 8, 24 and 15 months
Cumulated glucocorticoid dose	Cumulated glucocorticoid dose (mg)	Baseline, day 10, week 8, 24 and 15 months
Glucocorticoid dose	Glucocorticoid dose (mg)	Baseline, day 10, week 8, 24 and 15 months
Cardiovascular events	Cardiovascular events (number)	4-5 years

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: AP Moeller Foundation; The Danish Rheumatism Association; Hartmann Fonden; Aase and Ejnar Danielsens Foundation
• Investigators: Principal Investigator: Berit Nielsen, MD, Department of rheumatology

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2014
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): December 31, 2018

Study Registration Dates

• First Submitted: November 28, 2018
• First Submitted That Met QC Criteria: December 4, 2018
• First Posted (Actual): December 5, 2018

Study Record Updates

• Last Update Posted (Actual): October 4, 2021
• Last Update Submitted That Met QC Criteria: October 1, 2021
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Immune System Diseases; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Muscular Diseases; Skin Diseases, Vascular; Vasculitis, Central Nervous System; Polymyalgia Rheumatica; Giant Cell Arteritis; Arteritis; Vasculitis
• Other Study ID Numbers: ULvsPET GCA cohort

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No