Non-invasive imaging of arthritis activity in rheumatoid arthritis (RA) patients using macrophage PET holds promise for early diagnosis and therapeutic response monitoring. Previously obtained results with macrophage tracer (R)-[ 11 C]PK11195 were encouraging, but the imaging signal could be further improved by reduction of background uptake. Recently, the novel macrophage tracer [ 18 F]fluoro-PEGfolate was developed. This tracer showed excellent targeting of the folate receptor β on activated macrophages in synovial tissue in a preclinical arthritic rat model. We performed three substudies to investigate the biodistribution, potential for imaging arthritis and kinetic properties of [18F]fluoro-PEGfolate in RA patients. Firstly, biodistribution demonstrated fast clearance of [ 18 F]fluoro-PEG-folate from heart and blood vessels and no dose limiting uptake in organs. Secondly, [ 18 F]fluoro-PEG-folate showed uptake in arthritic joints with significantly lower background and hence significantly higher target-tobackground ratios as compared to reference macrophage tracer (R)-[ 11 C]PK11195. Lastly, dynamic scanning demonstrated fast tracer uptake in affected joints, reaching a plateau after 1 minute, coexisting with a rapid blood clearance. In conclusion, this first in man study demonstrates the potential of [ 18 F]fluoro-PEG-folate to image arthritis activity in RA with favourable imaging characteristics of rapid clearance and low background uptake, that allow for detection of inflammatory activity in the whole body.

ObjectivesExcessive bone formation is an important hallmark of AS. Recently it has been demonstrated that axial bony lesions in AS patients can be visualized using 18F-fluoride PET-CT. The aim of this study was to assess whether 18F-fluoride uptake in clinically active AS patients is related to focal bone formation in spine biopsies and is sensitive to change during anti-TNF treatment.MethodsTwelve anti-TNF-naïve AS patients [female 7/12; age 39 years (SD 11); BASDAI 5.5 ± 1.1] were included. 18 F-fluoride PET-CT scans were performed at baseline and in two patients, biopsies were obtained from PET-positive and PET-negative spine lesions. The remaining 10 patients underwent a second 18F-fluoride PET-CT scan after 12 weeks of anti-TNF treatment. PET scans were scored visually by two blinded expert readers. In addition, 18F-fluoride uptake was quantified using the standardized uptake value corrected for individual integrated whole blood activity concentration (SUVAUC). Clinical response to anti-TNF was defined according to a ⩾ 20% improvement in Assessment of SpondyloArthritis international Society criteria at 24 weeks.ResultsAt baseline, all patients showed at least one axial PET-positive lesion. Histological analysis of PET-positive lesions in the spine confirmed local osteoid formation. PET-positive lesions were found in the costovertebral joints (43%), facet joints (23%), bridging syndesmophytes (20%) and non-bridging vertebral lesions (14%) and in SI joints (75%). After 12 weeks of anti-TNF treatment, 18F-fluoride uptake in clinical responders decreased significantly in the costovertebral (mean SUVAUC −1.0; P < 0.001) and SI joints (mean SUVAUC −1.2; P = 0.03) in contrast to non-responders.Conclusions 18F-fluoride PET-CT identified bone formation, confirmed by histology, in the spine and SI joints of AS patients and demonstrated alterations in bone formation during anti-TNF treatment.

BackgroundPositron emission tomography (PET) imaging of macrophages using the translocator protein (TSPO) tracer (R)-[11C]PK11195 has shown the promise to image rheumatoid arthritis (RA). To further improve TSPO PET for RA imaging, second generation TSPO tracers [11C]DPA-713 and [18F]DPA-714 have recently been evaluated pre-clinically showing better imaging characteristics.ObjectiveA clinical proof of concept study to evaluate [11C]DPA-713 and [18F]DPA-714 to visualize arthritis in RA patients.MethodsRA patients (n = 13) with at least two active hand joints were included. PET/CT scans of the hands were obtained after injection of [18F]DPA-714, [11C]DPA-713 and/or (R)-[11C]PK11195 (max. 2 tracers pp). Standardized uptake values (SUVs) and target-to-background (T/B) ratios were determined. Imaging data of the 3 different tracers were compared by pooled post-hoc testing, and by a head to head comparison.ResultsClinically active arthritis was present in 110 hand joints (2–17 pp). Arthritic joints were visualized with both [11C]DPA-713 and [18F]DPA-714. Visual tracer uptake corresponded with clinical signs of arthritis in 80% of the joints. Mean absolute uptake in PET-positive joints was significantly higher for [11C]DPA-713 than for [18F]DPA-714, the latter being not significantly different from (R)-[11C]PK11195 uptake. Background uptake was lower for both DPA tracers compared with that of (R)-[11C]PK11195. Higher absolute uptake and lower background resulted in two-fold higher T/B ratios for [11C]DPA-713.Conclusions[11C]DPA-713 and [18F]DPA-714 visualize arthritic joints in active RA patients and most optimal arthritis imaging results were obtained for [11C]DPA-713. Second generation TSPO macrophage PET provides new opportunities for both early diagnosis and therapy monitoring of RA.

Background:Clinical assessment of arthritis is the cornerstone in the diagnosis and treatment of rheumatoid arthritis (RA). Nevertheless, reliable determination of (sub)clinical arthritis can be difficult, especially in the feet. Advanced imaging techniques may contribute to early diagnosis and therapy monitoring through sensitive detection and (quantitative) monitoring of synovitis. Previously, it has been demonstrated that macrophage imaging using (R)-[11C]PK11195 positron emission tomography (PET) allows for highly sensitive and specific imaging of RA disease activity in the hands.(1,2)Whole body macrophage PET imaging that includes the feet has not yet been evaluated in RA.Objectives:To compare whole body macrophage PET imaging to clinical assessment of arthritis activity in clinically active, early RA patients.Methods:Thirty-five previously untreated RA patients (age 54 ± 12, 51% male) with at least two clinically inflamed joints were included. They underwent a whole body (R)-[11C]PK11195 PET/computed tomography (CT) scan in addition to standard clinical assessment of number of tender and swollen joints (TJC and SJC, respectively). Two readers blinded to clinical assessment (GZ and CvdL) visually scored intensity of uptake in joints on a 0 to 3 scale. A PET positive joint score was defined at ≥ 1. Additionally, (R)-[11C]PK11195 uptake in joints was assessed quantitatively as standardized uptake values (SUV). Visual parameters were compared to clinical parameters using Cohen’s kappa, and quantitative parameters were analyzed using an independent T-test.Results:All patients showed enhanced tracer uptake in one or more joints (Figure 1). A total of 168 joints were visually PET positive, with the following distribution: 16% in the wrists, 14% in the metacarpophalangeal joints, 25% in the proximal interphalangeal joints, 4% in the ankles, 37% in the metatarsophalangeal joints. Positivity in other large joints was rare (4%). The number of discrepant findings between PET and clinical outcome (TJC and/or SJC) varied based on anatomic localization; more joints were clinically active in the hands, and more joints were active on the PET scan in the feet. Consequently, agreement between visual PET positivity and clinical activity was low, with only moderate agreement found in the ankles (κ = 0.46 and 0.41 for SJC and TJC respectively). Quantitative PET data showed a trend towards higher SUV values in joints that were clinically tender and/or swollen, reaching a significant difference in the feet (ankles + MTPs) versus SJC (Figure 2; 0.7 vs 1.0,p< 0.001). However, parts of the clinically non-affected joints also depicted moderately increased SUV values, and vice versa.Figure 1.Visual PET uptake in the left MTP5-joint.Figure 2.(R)-[11C]PK11195 (SUV) in both clinically affected and non-affected feet joints (defined as swollen yes or no).Conclusion:Whole body macrophage PET imaging showed clear uptake of (R)-[11C]PK11195 in several joints of clinically active, early RA patients, especially in MTP-joints. The best correlation between quantitative PET data and clinical assessment of swelling was observed in the feet. In general, however, PET also provided distinct information from clinical assessment, which may provide a means for detecting subclinical synovitis. We are performing longitudinal studies to further assess the value of macrophage PET in RA.References:[1]Elzinga EH, et al. J Nucl Med. 2011; 52(1): 77-80.[2]Gent YY, et al. J Rheumatology. 2014; 41: 2145-52Acknowledgments:We thank ReumaNederland and Pfizer for financial support of this investigator initiated study.Disclosure of Interests:Nicki J.F. Verweij: None declared, Marieke ter Wee: None declared, Jerney de Jongh: None declared, Gerben C.J. Zwezerijnen: None declared, Maqsood Yaqub: None declared, Maarten Boers: None declared, Alexandre Voskuyl: None declared, Adriaan A. Lammertsma: None declared, WIllem Lems Grant/research support from: Pfizer, Consultant of: Lilly, Pfizer, Conny J. van der Laken: None declared

BackgroundImaging arthritis activity in rheumatoid arthritis (RA) patients using PET macrophage tracers holds promise for both early diagnostics and monitoring response to therapy (1,2). Previously, (R)-[11C]PK11195 has been used, but this macrophage tracer is limited due to high background uptake, especially in bone and bone marrow. Recently, a novel macrophage tracer, [18F]fluoro-PEG-folate, was developed, which showed excellent targeting of the folate receptor beta on activated macrophages in synovial tissue in a preclinical arthritic rat model (3).ObjectivesTo assess the value of [18F]fluoro-PEG-folate PET-CT for imaging inflamed joints in patients with clinically active RA.MethodsNine RA patients with at least two clinically inflamed hand joints were included. PET-CT scans of the hands were acquired after intravenous administration of either 185 MBq of [18F]fluoro-PEG-folate (n=6) or 425 MBq of (R)-[11C]PK11195 (n=3). Volumes of Interest (VOI) were drawn over joints with visually marked uptake and Standardized Uptake Values (SUVs) were calculated. Background VOIs were drawn on metacarpal bone in order to calculate Target-to-Background (T/B) ratios.ResultsNo side effects were observed, establishing the safety of [18F]fluoro-PEG-folate for use in humans. [18F]fluoro-PEG-folate clearly showed uptake in arthritic joints, as shown in Figure 1. In patients scanned with [18F]fluoro-PEG-folate, 25 positive joints were seen, with a minimum of two joints per patient. Clinical arthritis was confirmed in 10 of these 25 joints, and was absent in 15 positive joints, suggesting the presence of subclinical inflammation. Whilst both [18F]fluoro-PEG-folate and (R)-[11C]PK11195 accumulated in arthritic joints, [18F]fluoro-PEG-folate showed a significantly lower background uptake than (R)-[11C]PK11195 (SUV of 0.18 vs 0.75; p<0.001) respectively. T/B-ratios were significantly higher for [18F]fluoro-PEG-folate (3.60vs 1.72, p=0.009).ConclusionsThis first in patient study clearly demonstrates the potential of [18F]fluoro-PEG-folate PET-CT as macrophage tracer to image both clinically and sub-clinically affected joints in RA patients. [18F]fluoro-PEG-folate showed better characteristics for arthritis imaging than the established tracer (R)-[11C]PK11195 because of its lower background signal.References Gent YY, et al. J Rheumatology. 2014; 41: 2145–52.Gent YY, et al. Arthritis Rheum. 2012; 64: 62–6.Gent YY, et al. Arthritis Res Ther. 2013; 15: R37. Disclosure of InterestNone declared