Posts Tagged ‘ANCA’

anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV)

Larry H. Bernstein, MD, FCAP, Curator



Positron Emission Tomography scanning in Anti-Neutrophil Cytoplasmic Antibodies-Associated Vasculitis

Kemna, Michael J. BSc; Vandergheynst, Frédéric MD; Vöö, Stefan MD, PhD; Blocklet, et al.

Tools for evaluation of disease activity in patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) include scoring clinical manifestations, determination of biochemical parameters of inflammation, and obtaining tissue biopsies. These tools, however, are sometimes inconclusive. 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography (PET) scans are commonly used to detect inflammatory or malignant lesions. Our objective is to explore the ability of PET scanning to assess the extent of disease activity in patients with AAV.

Consecutive PET scans made between December 2006 and March 2014 in Maastricht (MUMC) and between July 2008 and June 2013 in Brussels (EUH) to assess disease activity in patients with AAV were retrospectively included. Scans were re-examined and quantitatively scored using maximum standard uptake values (SUVmax). PET findings were compared with C-reactive protein (CRP) and ANCA positivity at the time of scanning.

Forty-four scans were performed in 33 patients during a period of suspected active disease. All but 2 scans showed PET-positive sites, most commonly the nasopharynx (n = 22) and the lung (n = 22). Forty-one clinically occult lesions were found, including the thyroid gland (n = 4 patients), aorta (n = 8), and bone marrow (n = 7). The amount of hotspots, but not the highest observed SUVmax value, was higher if CRP levels were elevated. Seventeen follow-up scans were made in 13 patients and showed decreased SUVmax values.

FDG PET scans in AAV patients with active disease show positive findings in multiple sites of the body even when biochemical parameters are inconclusive, including sites clinically unsuspected and difficult to assess otherwise.


Granulomatosis with polyangiitis (GPA; Wegener’s) is an inflammatory disease entity affecting small to medium vessels. It is, together with microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA; Churg Strauss Syndrome), characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) and they are frequently grouped together under the term ANCA-associated vasculitis (AAV).1

Early diagnosis and assessment of the extent of disease activity are important for adequate therapeutic decisions.1 Multiple tools may be helpful, such as biochemical parameters of inflammation, imaging techniques, and tissue biopsies. Even though these tools suffice to diagnose active disease in most episodes, the results can sometimes be inconclusive. In particular, it is sometimes problematic to determine whether symptoms are due to active disease, vasculitic damage, and/or treatment-related side-effects.

2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography (PET) scanning is used for detecting high glucose metabolism in malignancies, infectious, and auto-immune diseases.2–4 Co-registration with computed tomography (CT) allows the increased FDG uptake to be localized to the underlying anatomy. PET scanning has been proven to be a useful diagnostic tool in large vessel vasculitis.5–8 PET scanning can visualize glucose-consuming inflamed vessels, provided that their diameter is >4 mm. The limited spatial resolution was previously thought to be insufficient to detect the involvement of small- and medium-size vessels.6,7 Recent studies, however, have shown that PET scans show abnormalities in patients with ANCA-associated vasculitis.9–11 This novel imaging technique may therefore be a useful tool for diagnosing active disease and, in addition, to assess the severity and the extent of the disease. The latter may be relevant to detect occult diagnostic biopsy sites as previously demonstrated in sarcoidosis.12

The objective of our study is to explore the ability of PET scanning to assess the extent of disease activity in patients with AAV.


Study Population

Consecutive PET scans were performed in patients with AAV at Maastricht University Medical Center (MUMC) between December 2006 and March 2014 and at Erasme University Hospital (EUH) in Brussels between July 2008 and June 2013 and were retrospectively included. All patients fulfilled a diagnosis of GPA according to the 2012 revised International Chapel Hill Consensus Conference Nomenclature.13 Patients were previously treated according to the recommendations of the European League Against Rheumatism (EULAR).14 Disease states were defined according to the EULAR recommendations.15 A PET scan was performed in patients with clinically suspected disease activity (diagnosis or relapse), whereas other tools for evaluation of activity were inconclusive. The possibility of an active bacterial or viral infection was excluded by culture, serology, and persistence of symptoms despite empirical antibiotic treatment. This study was carried out in compliance with the Helsinki Declaration.

Diagnostic Parameters

An extensive diagnostic work-up was done in all cases, including analysis of clinical features, laboratory assessment, imaging techniques, and, if appropriate, a biopsy. Laboratory assessment included high-sensitivity C-reactive protein (CRP, cutoff value ≥10 ng/mL) levels, ANCA levels, and urine analysis at the time of scanning. Hematuria was defined as ≥10 erythrocytes in a urinary sediment, combined with dysmorphic erythrocytes and/or red blood cell casts. In Maastricht, ANCA levels were determined using the Fluorescent-Enzyme Immuno-Assay (FEIA) method.16 FEIA detection for both proteinase-3 (PR3) and myeloperoxidase (MPO) antibodies were fully automated as performed in a UniCAP 100 (Pharmacia Diagnostics). Values ≥10 AU were considered positive.


A whole-body [18F]-FDG-PET/CT scan was performed in both centers. In Maastricht, a Gemini_ PET-CT (Philips Medical Systems) scanner with time-of-flight (TOF) capability was used, together with a 64-slice Brilliance CT scanner. This scanner has a transverse and axial Field of View (FOV) of 57.6 and 18 cm, respectively. The spatial resolution is around 5 mm. In Brussels, a Gemini_ PET-CT (Philips Medical Systems) scanner was used without TOF capability, but with the same PET FOV and spatial resolution, together with a 16-slice Brilliance CT scanner.



Patient Characteristics

Thirty-three patients were included; an overview of the patient characteristics is shown in Table 1. Twenty patients were positive for PR3-ANCA at diagnosis, 9 patients for MPO-ANCA, and 4 patients were ANCA-negative.

Table 1

Table 1
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Forty-four PET scans were made during an episode of suspected disease activity (Table 2). Eleven scans were performed at diagnosis and 33 scans at a suspected relapse. The suspected relapses occurred after a median of 68 (30–113) months since diagnosis. In 5 patients, ≥2 consecutive episodes occurred during which a PET scan was performed. These patients were in remission between episodes.

Table 2

Table 2
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Results of PET Scans During Suspected Disease Activity

All PET scans during an episode of suspected disease activity except 2 revealed enhanced non-physiological FDG uptake. Table 3 shows the anatomic location of the positive sites and the corresponding median SUVmax values. The majority of these sites disclosed a SUVmax value between >2.5 and <6. Examples of PET/CT images of patients with AAV are shown in Figures 1 and Figures 2.

Table 3

Table 3
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In our study, PET scans in AAV patients revealed positive findings in multiple sites of the body, including sites not clinically suspected and difficult to assess otherwise. PET scans may show FDG-positive findings during episodes in which other tools for evaluation of disease activity are inconclusive.

Similar to our findings using Gallium-67 [67Ga] scintigraphy17 in patients with GPA, PET scans seem to be a sensitive tool to assess disease activity. In our current study, all but 2 scans showed non-physiological FDG uptake during an episode of clinically suspected disease activity. Compared with gallium scanning, however, PET scanning offers additional information. First, Gallium scintigraphy suffers from practical limitations, such as the required interval between time of injection of the radiopharmaceuticals and time of scanning (48–72 hours) and the high radiation exposure. Second, the spatial resolution is higher in PET scans. Third, a low-dose CT scan may be used concomitantly to correlate the FDG uptake with the precise anatomical location. In sarcoidosis, PET scans are of value in detecting occult diagnostic biopsy sites.12 In our cohort, 41 clinically occult sites were found on the PET scan, and in 1 patient this resulted in a diagnostic biopsy.9

Whether hotspots on the PET scan can be attributed to activity of vasculitis is sometimes difficult to assess. A biopsy of PET-positive lesions would result in a definitive diagnosis. However, such a strategy is not realistic, as it does not correspond to routine clinical practice and was not performed in the current study. As we observed a favorable outcome after intensifying immunosuppressive treatment, we hypothesize that these patients indeed had active disease at the time of scanning. It is important to note that PET scans do not differentiate active vasculitis from infections, as observed in 2 of our patients with PET-positive findings due to an underlying fungal infection. In one of these patients, a biopsy of a clinically occult lesion led to the discovery of cryptococcal myositis and masquerading vasculitis.18 The differentiation between infections and ANCA-mediated disease activity remains an area of uncertainty, especially because there is strong evidence that infections may be an important trigger in the multifactorial etiology of ANCA-associated vasculitis.19In the future, more sensitive diagnostic modalities, such as the combination of PET scanning with magnetic resonance imaging (PET/MRI), may identify the infectious foci, which started the cascade leading to the (re)activation of vasculitis.

Most importantly, PET scans revealed abnormalities during episodes of active disease in which ANCA were sometimes not detected and CRP levels not increased. However, more hotspots were observed if the CRP levels were elevated. In contrast, the highest observed SUVmax values were not related to CRP levels. These findings suggest that the disease may be more extensive, but not more severe, if biochemical parameters of inflammation are increased.

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