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

• ClinicalTrials.gov Identifier: NCT03765424
• Recruitment Status: Completed
• First Posted: December 5, 2018
• Last Update Posted: October 4, 2021
• Sponsor: University of Aarhus
• Collaborators: The Danish Rheumatism Association; Hartmann Fonden; AP Moeller Foundation; Aase and Ejnar Danielsens Foundation
• Information provided by (Responsible Party): University of Aarhus

Study Description

Brief Summary:

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)

Condition or disease	Intervention/treatment
Giant Cell Arteritis; Vasculitis	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 Design

• Study Type: Observational
• Actual Enrollment: 101 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Evaluation of Ultrasound and PET/CT in the Diagnosis and Monitoring of Giant Cell Arteritis
• Actual Study Start Date: October 1, 2014
• Actual Primary Completion Date: July 1, 2018
• Actual Study Completion Date: December 31, 2018

Groups and Cohorts

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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Other Outcome Measures:

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

Biospecimen Retention:   Samples With DNA

Full blood EDTA plasma Lithium-heparin plasma serum

Eligibility Criteria

• Ages Eligible for Study: 50 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• 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.

Criteria

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.

Contacts and Locations

Sponsors and Collaborators

University of Aarhus

The Danish Rheumatism Association

Hartmann Fonden

AP Moeller Foundation

Aase and Ejnar Danielsens Foundation

Investigators

• Principal Investigator: Berit Nielsen, MD; Department of Rheumatology

More Information

• Responsible Party: University of Aarhus
• ClinicalTrials.gov Identifier: NCT03765424
• Other Study ID Numbers: ULvsPET GCA cohort
• First Posted: December 5, 2018
• Last Update Posted: October 4, 2021
• Last Verified: November 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Polymyalgia Rheumatica; Giant Cell Arteritis; Vasculitis; Arteritis; Vascular Diseases; Cardiovascular Diseases; Vasculitis, Central Nervous System; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Skin Diseases, Vascular; Skin Diseases; Autoimmune Diseases; Immune System Diseases; Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases