Study design and patients
The cross-sectional study, approved by the ethical committee of our hospital (B70720108722), included 63 patients fulfilling the ACR/EULAR 2010 criteria for RA (25), from July 2010 to April 2012. Written informed consent was obtained for each patient. All assessments were done on the same day by the same independent experienced investigator unaware of the other results: the clinical evaluation first in the morning with a blood sample followed by the US and terminated by the PET/CT evaluation. X-rays were available as routine controls made at maximum 6 weeks around the study day. The Patient (PtGA) and the Physician Global Assessment (PGA) were determined using a Visual Analogue Scale (VAS) (0-100 mm) as well as the Health Assessment Questionnaire (HAQ) (26). Disease activity was evaluated using the DAS28-CRP (lacking PGA) (27) and the CDAI (with PGA and without CRP) (28). Each patient was categorized as in remission (DAS28-CRP<2.6, CDAI<2.8), in low to moderate disease activity (2.6-DAS28-CRP≤5.1, 2.8-CDAI≤22), or in severe disease activity (DAS28-CRP>5.1, CDAI>22) (29). The number of joints solely tender (T), solely swollen (S), “tender or swollen” (T/S) and “tender and swollen” (T&S) was recorded.
[18F]FDG PET/CT imaging
The PET/CT studies were performed using a Gemini BigBore scanner (Philips Medical Systems, Cleveland, OH, USA). Patients fasted for 4 hours and were injected with [18F]FDG through an indwelling catheter placed in the median cubital vein and flushed with 5cc of saline solution afterwards (4 MBq/kg body weight with a maximum of 370 MBq). Blood glucose level was lower than 140 mg/dl. The uptake time was 60 minutes and the image acquisition sequence as follows: first a scoutview CT, followed by the PET emission study that included the knees, hands, wrists, elbows and shoulders, with 2 minutes per bed position for a total scanning time ranging from 14 to 18 minutes. Finally, a low-dose CT (5-mm slice thickness, tube voltage 120 Kv, tube current–time product 80 mAs) was performed over these joints. The hands and wrists were positioned and fixated on a dedicated Plexiglas device in order to avoid movements between the PET and the CT acquisitions. PET Images were reconstructed using an iterative list mode time-of-flight algorithm and corrections for attenuation, dead-time, random and scatter events were applied. The images were first analyzed visually and joints were considered as positive for synovitis when the [18F]FDG uptake was increased compared to the background in areas corresponded to joint synovium on CT, i.e. either when thickened synovium was recognized on CT or in locations corresponding anatomically to synovium, excluding uptake in other structures such as muscle and tendons. The [18F]FDG uptake was then quantified using the maximum standardized uptake value (SUVmax). In PET-positive joints according to the visual analysis, the SUVmax was obtained by drawing a region of interest (ROI) over the most active synovial area identified. When no synovitis was identified, ROIs were placed in the corresponding areas on the CT: at the dorsal surface of the radius (on top of the lunate) for the wrists, over the lateral recess at the level of the midpatella for the knees and for the small joints as metacarpophalangeal (MCP) or proximal interphalangeal (PIP) joints, ROIs were drawn around the appropriate joint. A global metabolic assessment was obtained through the number of PET-positive joints (visual evaluation) and the sum of all SUVs (cumulative SUV, CSUV).
Ultrasound and X-ray examination
US assessment was performed using a B-mode multi frequency 10-14.0 MHz transducer (Logiq 9) (GE Healthcare, Milwaukee, WI, USA). US positioning for the wrists, the MCP and the PIP joints and for the knees have been described elsewhere . Proximal and distal radiocapitellar recesses were studied for the elbows and the glenohumeral joint, posterior side for shoulders. Synovial measurements were carried out systematically perpendicular to the great axis and at the point of greatest thickness. A cut-off for US positivity was defined as a synovitis of at least 1 mm thick (3 mm for the shoulders) according to US determinations in healthy controls, described elsewhere (22). In joints where 2 (wrists) or 3 (elbows, knees) scannings were performed, the joint was considered positive if at least one measurement was positive. The cumulative synovial thickness (CST), i.e the sum of thicknesses of all US-positive joints, is the addition of all (single or multiple) synovial measurements performed. X-ray were obtained for peripheral joints (PIPs, MCPs and wrists)
Results were generally expressed as mean ± standard deviation (SD). Correlation coefficients were calculated to measure the association between PET/CT and clinical or US parameters. The Spearman correlation was used for skewed distributions. Concordance between methods was quantified by the intraclass coefficient (ICC). Ordinal logistic regression was used to assess the relationship between disease activity categories based on DAS28-CRP or CDAI (remission, low/moderate and severe disease activity), and PET/CT number of positive joints and CSUV. A test was performed whether all three diseases severity categories were distinguishable. If this was not the case, a classical logistic regression analysis was applied and optimal Youden cut-off values were determined from the Receiver Operating Characteristic (ROC) curve method. Results were considered significant at the 5% level (p<0.05). All statistical analyses were performed with SAS (version 9.4).