The Clinical Impact of Using 18F-FDG-PET/CT in the Diagnosis of Suspected Vasculitis: The Effect of Dose and Timing of Glucocorticoid Treatment

18F-Fluorodeoxyglucose positron-emission tomography (18F-FDG-PET) with computed tomography (CT) is effective for diagnosing large vessel vasculitis, but its usefulness in accurately diagnosing suspected, unselected vasculitis remains unknown. We evaluated the feasibility of 18F-FDG-PET/CT in real-life cohort of patients with suspicion of vasculitis. The effect of the dose and the timing of glucocorticoid (GC) medication on imaging findings were in special interest. 82 patients with suspected vasculitis were evaluated by whole-body 18F-FDG-PET/CT. GC treatment as prednisolone equivalent doses at the scanning moment and before imaging was evaluated. 38/82 patients were diagnosed with vasculitis. Twenty-one out of 38 patients had increased 18F-FDG accumulation in blood vessel walls indicating vasculitis in various sized vessels. Vasculitis patients with a positive vasculitis finding in 18F-FDG-PET/CT had a significantly shorter duration of GC use (median = 4.0 vs 7.0 days, P=0.034), and they used lower GC dose during the PET scan (median dose = 15.0 mg/day vs 40.0 mg/day, p=0.004) compared to 18F-FDG-PET/CT-negative patients. Vasculitis patients with a positive 18F-FDG-PET/CT result had significantly higher C-reactive protein (CRP) than patients with a negative 18F-FDG-PET/CT finding (mean value = 154.5 vs 90.4 mg/L, p=0.018). We found that 18F-FDG-PET/CT positivity was significantly associated with a lower dose and shorter duration of GC medication and higher CRP level in vasculitis patients. 18F-FDG-PET/CT revealed clinically significant information in over half of the patients and was effective in confirming the final diagnosis.


Introduction
e diagnosis of vasculitis is a challenge, especially when vasculitis affects vital organs, and the patient presents nonspecific symptoms [1]. Vasculitis requires prompt recognition and initiation of treatment even if the diagnosis is uncertain. e diagnostic process is often laborious. A biopsy is considered as a gold standard for diagnosing vasculitis, but in many cases, the optimal biopsy location is unavailable. e combination of 18 F-fluorodeoxyglucose-positron emission tomography ( 18 F-FDG-PET) with computed tomography (CT) is a promising diagnostic tool in the workup for vasculitis [2][3][4]. e accuracy and usefulness of 18 F-FDG-PET/CT in the diagnostic procedure of vasculitis are still under debate. 18 F-FDG-PET/CT has showed good performance in detecting large-vessel vasculitis (LVV) [4][5][6][7]. European League Against Rheumatism (EULAR) recommendation for the use of imaging in LVV in clinical practice recommends an early imaging test with ultrasound or MRI as first choices. PET may be used alternatively especially considering its ability to identify other serious differential diagnostic conditions [8].
In 2018, nuclear medicine interest committees gave a joint procedural recommendation on 18 F-FDG-PET/CTA (angiography) imaging advising in data acquisition and interpretation in LVV and polymyalgia rheumatica [9]. Less is known about how 18 F-FDG-PET/CTperforms in other types of vasculitis than LVV. ere is some evidence that PET may be useful in detecting small-vessel vasculitis [10,11]. e ongoing multinational Diagnostic and Classification Criteria for Vasculitis (DCVAS) study aims to validate diagnostic criteria and to improve classification criteria for primary systemic vasculitis [12].
With a strong suspicion of vasculitis, rapid initiation of treatment is necessary. Glucocorticoids (GCs) are the most important first-line immunosuppressive treatment of noninfectious vasculitidies [13,14]. Unfortunately, the use of immunosuppressive medication probably deteriorates the diagnostic accuracy of 18 F-FDG-PET [7]. GC may attenuate 18 F-FDG-uptake as early as after three days, but more confirmation is needed, since this is clinically a crucial question [15][16][17][18].
Here, we evaluated the impact of using 18 F-FDG-PET/ CT for accurately diagnosing vasculitis in real-life cohort of patients. We had a special interest in observing the effect of GC treatment prior to the 18 F-FDG-PET/CT scan. We evaluated also differential diagnostic findings in patients with vasculitis suspicion.

Patients and Study Design.
Eighty-two patients with suspected vasculitis were evaluated by whole-body 18 F-FDG-PET/CT. e enrolment was done prospectively among inpatients. All diagnostic procedures were done at Turku University Hospital, Turku, Finland, between May 2011 and June 2015. e hospital is a tertiary-care centre for a population of 470 000. e institutional ethical committee approved the study protocol. All patients gave a written informed consent, according to the Declaration of Helsinki.
is study is part of the Positron Emission Tomography of Infection and Vasculitis (PETU) study, which is registered as a clinical trial (NCT01878721). e PETU study researched different branches of infectious and inflammatory diseases which are reported separately [19][20][21][22]. Our series of vasculitis patients are previously unpublished.
e inclusion criterion of this study was vasculitis suspicion. Vasculitis suspicion was raised by an experienced specialist based on the clinical symptoms and signs of the patient. Vasculitis was confirmed or excluded by a consensus-based decision made by the specialists, while taking notice of the medical history, results of clinical examination, extensive laboratory work, 18 F-FDG-PET/CT result, other imaging modalities, response to GC therapy, and follow-up. A minimum of 6 months clinical follow-up was considered sufficient to establish the diagnosis.
Special attention was paid to examine features and GC use in patients with diagnosed vasculitis in relation to 18 F-FDG-PET/CT results. e cumulative GC dose was calculated from patients with a history of continuous GC use. GC use was evaluated as prednisolone equivalent doses.

Evaluation of the Diagnoses.
e final diagnosis was based on the clinical picture as well as on the imaging findings of different sizes of affected vessels and histology. Based on the diagnosis, we divided the vasculitis patients into the following groups: LVV, medium-and small-vessel vasculitis, and unspecified vasculitis or antineutrophilic cytoplasmic antibodies-(ANCA-) associated vasculitis (AAV). Due to a low number of patients, vasculitis patients with granulomatous polyangiitis (GPA), eosinophilic granulomatous polyangiitis (EGPA), and microscopic polyangiitis (MPA) were combined into a group called AAV. In this group, five out of six patients were ANCA-positive, and an ANCA-negative patient had a histological finding of vasculitis.
All patients were evaluated by using the clinical criteria for vasculitis by American College of Rheumatology (ACR) 1990 [23,24]. We evaluated the ACR criteria for GCA, GPA, EGPA, MPA, and polyarteritis nodosa (PAN). Due to a limited number of patients, cases from GPA, EGPA, and MPA formed a single group.

18 F-FDG-PET/CT Imaging Protocol.
A whole-body 18 F-FDG-PET/CT scan (64-slice Discovery VCT, General Electric Medical Systems, Milwaukee, WI, USA) was performed in all patients. Patients fasted at least 10 hours before the study. e mean injected radioactive dose of 18 F-FDG was 273 MBq (range � 197-390 MBq). After an average of 57 minutes (range � 44-79 minutes), a whole-body PET acquisition (3 min/bed position) was performed following lowdose CT (kV 120, Smart mA range 10-80). In some patients, this was followed by a diagnostic contrast-enhanced CT scan (kV 120, Smart mA range 100-440) during the arterial phase after an automated i.v. injection of contrast agent.
Blood glucose levels were <10 mmol·L − 1 prior to injection of the tracer in all patients. PET images were reconstructed in 128 × 128 matrix size in full 3D mode using maximum-likelihood reconstruction with an ordered-subset expectation maximization algorithm (VUE Point, GE Healthcare).
Visual analysis of the images was performed by an experienced nuclear medicine specialist, and the results were reevaluated by the research team for a consensus-based diagnosis. All image analyses were done blinded with respect to patient's clinical details. 18 F-FDG-PET/CT scans were considered positive, when a linear uptake pattern was found in the large arterial walls and/or its branches with an intensity similar or higher than the liver [25]. A positive finding for small-to medium-sized vasculitis was considered, when activity was higher than the vascular background activity and showed a tree-root-like uptake pattern [21] (Figure 1).

Statistical Analysis.
Normally distributed continuous data were expressed as mean (standard deviation, SD), and for skewed distributions, data were expressed as median (interquartile range, IQR), unless stated otherwise. Categorical variables were described with absolute and relative (percentage) frequencies. An independent sample t test or Mann-Whitney U test was applied to determine the significance of differences for continuous variables as appropriate and a chi-squared or Fischer's exact test for categorical variables. All statistical analyses were calculated using SPSS Software Package (IBM SPSS Statistics Version 24). P values ≤0.05 were considered significant.

Patients' Characteristics, Diagnosis, and 18 F-FDG-PET/ CT Findings.
A total of 82 patients with a clinical suspicion of vasculitis were referred for 18 F-FDG-PET/CT and prospectively screened for this study (38 males and 44 females) ( Figure 2). e mean age for patients was 62.7 years (age range � 19-89 years, SD � 16.0 years). An abnormal or clinically significant 18 F-FDG-PET/CT finding was encountered in 46/82 patients (56%) ( Table 1). A clinically significant 18 F-FDG-PET/CT finding in different diagnostic subgroups is depicted in Table 1.
e vasculitis diagnosis was confirmed in 38 (46%) of the patients ( Table 2). Most common cases of vasculitis were LVV (n � 14, 37%) and unspecified vasculitis (n � 10, 26%). Increased 18 F-FDG accumulation in blood vessels suitable for vasculitis was detected in 21 of these 38 (55%) patients (Tables 2 and 3). 18 F-FDG-PET/CT-positive patients fulfilled the ACR criteria for GCA significantly more often than 18 F-FDG-PET/CT-negative patients (38% vs 8%, p � 0.015). No accumulation of 18 F-FDG in blood vessels was detected in 44 patients who did not fulfil the vasculitis diagnosis. Among patients without vasculitis diagnosis, the most common diagnostic groups were autoimmune diseases other than vasculitis (not including polymyalgia rheumatica, PM) (n � 18, 41%), infection (n � 12, 27%), PM (n � 5, 11%), and malignancy (n � 4, 9%) ( Figure 2). In the PM group, one patient had 18 F-FDG accumulation in the shoulder area relating to PM. One patient had a biopsy proven panniculitis which was clinically significant but not related to PM. Rest of the three patients did not have significant 18 F-FDG-PET/CT findings.

Effect of Glucocorticoid Treatment on 18 F-FDG-PET/CT Findings among the Vasculitis Patients.
e duration and dose of GC treatment had a significant effect on the outcomes of the 18 F-FDG-PET/CT scans. Out of 38 vasculitis patients, 9 patients (24%) had no GC treatment previously and 8 (21%) had used GC over 31 days.
Vasculitis patients with positive 18 F-FDG-PET/CT had significantly fewer days of GC use before imaging than patients with negative 18 F-FDG-PET/CT (median � 4.0 (IQR 9) vs 7.0 (IQR 154) days, p � 0.034) ( Table 3). In patients scanned within 3 days of GC treatment, 77% had vascular 18 F-FDG uptake suitable for vasculitis in comparison to 42% after one week of treatment ( Figure 3). Among these 38 vasculitis patients, there was a significant association of 18 F-FDG-PET/ CTpositivity with a lower GC dose on the scanning day with a median dose 15.0 (IQR 40.0) mg/day vs 40.0 (IQR 30.0) mg/ day (p � 0.004) ( Table 3).
Patients with vasculitis used a higher GC dose during 18 F-FDG-PET/CT scan than patients without vasculitis having a median prednisolone use of 30.0 (IQR 33.0) mg/day vs 0 (IQR 20.0) mg/day (p � 0.001). Among vasculitis patients, 9 patients (24%) used no GC on the scanning day in comparison to the nonvasculitis group, where 24 patients (55%) used no GC on the scanning day.   18 F-FDG uptake pattern in large-and medium-sized arteries in the lower limbs. Physiological tracer uptake is noted in the brain, the neck muscles, the myocardium, the kidneys, and the bladder. SD 100.2 mg/L vs 90.4 mg/L; SD 55.6 mg/L, respectively; p � 0.018) ( Table 3). No difference was found in procalcitonin (PCT) values (data available from 62 patients) between vasculitis patients with positive or negative 18 F-FDG-PET/ CT findings (Table 3). ere was no difference in CRP or PCT values between vasculitis and nonvasculitis patients ( Table 2).

Discussion
e spectrum of conditions causing vasculitis-like symptoms is wide. We found that in real-life cohort of patients, 18 F-FDG-PET/CT was effective in confirming the final diagnosis among inpatients with vasculitis suspicion. 18 F-FDG-PET/CT showed vasculitis in 26% of all patients and revealed clinically significant information in over half of the patients.
We found that among vasculitis patients, a shorter duration of prednisolone use is significantly associated with positive 18 F-FDG-PET/CT vasculitis findings (Table 3). Vasculitis patients with positive 18 F-FDG-PET/CT imaging had a median of 4 days of prednisolone treatment versus 7 days in the negative 18 F-FDG-PET/CT group.
is implicates that withholding diagnostic imaging for over one week during GC treatment increases the risk of a falsenegative diagnosis. In the vasculitis group, a lower GC dose at the scanning moment was significantly associated with an 18 F-FDG-PET/CT-based vasculitis diagnosis (Table 3).
In a previous study, good sensitivity, at 80%, and specificity, at 79%, have been reported for 18 F-FDG-PET/CT in patients with GCA receiving GC less than 3 days [6]. In another study, Fuchs et al. reported that the sensitivity of 18 F-FDG-PET/CT lowers from 99% to 53% in patients with GCA receiving an immunosuppressant [7]. A reduction of  F-FDG accumulation under treatment has been reported in follow-up studies [16,26]. A study by Imfeld et al. shows that prednisone treatment ≥10 days significantly reduced 18 F-FDG-PET/CT sensitivity. e first effect of lowered sensitivity was seen as early as 3 days after treatment initiation in the abdominal aorta [17] and in supra-aortic vessels [15]. Surprisingly, a study by Clifford et al. [18] did not find a correlation. Clifford et al. explained that their study subject number was low (n � 28), patients had received treatment over long time (on an average of 11.9 days), and doses were similarly high among all patients.
In a real clinical setting, withholding the treatment initiation until imaging is often impossible, so the knowledge of the GC effect on 18 F-FDG-PET diagnostic performance is important. Our study supports the data that GC treatment reduces the diagnostic power of 18 F-FDG-PET/CT after one week. us, there is a need for fast 18 F-FDG-PET/CT availability for suspected vasculitis patients. ese patients represent often a diffuse clinical picture. Ultrasound, which nowadays is the recommended standard protocol in LVV, performs poorly in thoracic aorta area or in small, deep vessels without focal symptoms. In our material, 18 F-FDG-PET/CT was useful also in other vasculitis than LVV and performs well in thoracic vessels. A lower GC dose during PET/CT scanning was associated with vasculitis findings in 18 F-FDG-PET/CT, but our study cannot answer the question that, if lowering temporarily the GC dose helps avoid falsenegative results. In few patients, 18 F-FDG-PET/CT showed vascular uptake suitable for vasculitis even after long GC treatment. In our cohort, the duration of use and dosage of GC treatment varied in patients at the 18 F-FDG-PET/CT imaging due to the study design.
We found a significant correlation between higher CRP value and 18 F-FDG-PET/CT positivity in patients diagnosed with vasculitis. A high CRP value might reflect more active inflammation and less use of GC at the scanning moment.
ere are several studies testing the correlation of laboratory parameters and diagnostic performance of 18 F-FDG-PET/ CT in GCA, in fever of unknown origin (FUO), or in inflammation of unknown origin (IUO) [17,[27][28][29]. FUO and IUO are essential differential diagnostic challenges for vasculitis. Schönau et al. reported that an age over 50 years, a CRP level over 30 mg/L, and the absence of fever predicted the helpfulness of 18 F-FDG-PET/CT [27] in FUO and IUO. Papathanasiou et al. noticed a significant positive association between maximal aortic 18 F-FDG uptake and inflammatory markers [29].
Our study had limitations that should be considered. e study was done in a real clinical setting, and the inclusion criterion was vasculitis suspicion; therefore, the vasculitis patient group was heterogeneous. e vasculitis diagnosis was confirmed later, and the spectrum of different vasculitis was detected. Our study did not exclude patients who did not fulfil the ACR inclusion criteria. is might be a limitation when comparing the results to previous studies with more restricted inclusion criteria.

Conclusions
We found that in patients with confirmed vasculitis diagnosis, 18 F-FDG-PET/CT positivity was significantly related to a lower dose and shorter duration of GC medication and a higher CRP level. In real-life circumstances, 18 F-FDG-PET/CT revealed different types of vasculitidies as well as other clinically significant information in over half of the patients and had an impact in confirming the final diagnosis.
Data Availability e data included in this study are available upon request from the corresponding author.

Conflicts of Interest
e authors declare that they have no conflicts of interest.