Patients
This retrospective study was approved by the Kagawa University institutional review board with the requirement for obtaining informed consent waived. From September 2010 to July 2020, 17 patients (13 males, 4 females; mean age, 67.8 years; age range, 41–87 years) with IgG4-RD who underwent [18F]FDG PET/CT studies both before and during therapy were included in the study. All patients fulfilled the 2019 American College of Rheumatology/European League Against Rheumatism (2019 ACR/EULAR) Classification Criteria for IgG4-Related Disease [3]. Twelve patients had biopsy proven disease (biopsy site; 5 salivary glands, 2 cervical lymph nodes, 3 pancreas, 1 liver, 1 skin) and the mean total points of 2019 ACR/EULAR classification criteria per patient was 33 (median 30, range 20–53). Three of them had recurrent disease for which corticosteroid treatment had been administered within 6 months prior to the initial [18F]FDG PET/CT study. After the initial [18F]FDG PET/CT study, all patients received corticosteroid-based therapy. Serum levels of inflammatory biomarkers including IgG4 and soluble IL-2 receptor (sIL-2R) were performed within one month before or after the [18F]FDG PET/CT study.
PET/CT imaging
[18F]FDG was produced using an automated synthesis system with HM-18 cyclotron (QUPID; Sumitomo Heavy Industries Ltd, Tokyo, Japan).
All acquisitions were performed using a hybrid PET/CT scanner (Biograph mCT, Siemens Medical Solutions USA Inc., Knoxville, TN, USA), which has an axial field of view of 21.6 cm and a 64-slice multi-detector CT scanner. Patients were instructed to fast for more than 5 h before [18F]FDG administration. A normal glucose level in the peripheral blood was confirmed before injecting the [18F]FDG. PET emission scanning (2 min per bed position) was performed 90 min after intravenous injection of [18F]FDG (5 MBq/kg) from the skull to upper-thigh, and co-registered with a non-contrast-enhanced CT of the same region. The PET data were reconstructed with a baseline ordered-subset expectation maximization algorithm, incorporating correction with point-spread function and time-of-flight model (2 iterations, 21 subsets).
PET/CT data analysis
[18F]FDG PET/CT images were first visually assessed by two board-certified nuclear medicine physicians independently. Any difference of opinion was resolved by consensus. Visually, abnormal [18F]FDG uptake seen in locations unaccounted for by the normal biodistribution of [18F]FDG were interpreted as lesions. The hilar/mediastinal inflammatory lymph nodes are commonly seen and nonspecific on [18F]FDG PET/CT scan. Therefore, interpreting hilar/mediastinal lymph nodes were excluded, unless there was other supporting data. Next, a board-certified nuclear medicine physician performed the semiquantitative analyses. The SUV was calculated using the following formula: SUV = cdc/(di/w), where cdc is the decay-corrected tracer tissue concentration (Bq/g); di is the injected dose (Bq); and w is the patient’s body weight (g). The lesion boundary was determined using a fixed threshold of SUV ≥ 2.5 based on a previous report [10]. In semiquantitative analysis, the urinary system was excluded because we could not completely exclude the influence of physiological excretion in the urine. The lesion volume was calculated as the MTV. The TLG was calculated as MTV × mean SUV within the same region. The highest SUVmax among all affected lesions was also evaluated for each patient. If there was no abnormal uptake during therapy, SUVmax of the previously involved organs on the basis of before therapy [18F]FDG PET/CT scan were measured. The percent change in SUVmax was calculated from before therapy (before) to during therapy (during) as follows: (during SUVmax – before SUVmax) × 100/ before SUVmax. The percent change in total MTV, total TLG, IgG4, and sIL-2R were calculated by the same manner. For the PET index calculation, we used Metavol, an open-source software tool developed for the efficient measurement of tumor volume on PET/CT [15]. For patient-based assessment, we summed the MTV and TLG of each affected lesion to generate a total MTV and total TLG.
Clinical assessments of therapy response
The course of disease activity was evaluated according to the clinical criteria, which included improvement in patients’ symptoms, resolution or amelioration of physical findings, serial testing of serum inflammatory biomarkers, improvement on imaging studies, and ability to taper corticosteroid successfully [16]. Patients under therapy were then classified as improved, unchanged, or worsened.
Statistical analysis
All statistical analyses were performed using a software package (SPSS Statistics, version 26; IBM). Data were analyzed for statistical significance using Wilcoxon signed-rank test and Spearman’s correlation coefficient. Differences were considered statistically significant at P values less than 0.05.