We included participants from the Nor-Hand study, an observational hand OA cohort from the rheumatology outpatient clinic at Diakonhjemmet Hospital, Oslo, Norway (10). The participants were between 40 and 70 years old with proven hand OA by clinical and/or ultrasound examination and had no suspected diagnosis of systemic inflammatory joint diseases, psoriasis or major somatic and/or psychiatric comorbidities. Further exclusion criteria are described elsewhere (10). All participants signed informed consent and the study was approved by the regional ethics committee.
Fluorescence optical imaging (FOI)
The Xiralite®-system is the only FOI device available for clinical use in rheumatology. To perform the FOI scan, the patient receives an intravenous injection with a fluorescent dye (ICG pulsion, 0.1 mg/kg body weight) and have near-infrared light from light-emitting diodes (LED) projected down on the hands for six minutes. With a highly sensitive camera, 360 images (one/second) are produced, showing the flooding in, distribution and washing out of the dye. All images can be scrolled through after the examination, and a composite picture (Prima Vista Mode, PVM) from the 240 first images is automatically generated by the XiraView software. In short, four images are assessed with the FOI activity score (FOIAS); PVM and three images representing phase 1, 2, and 3 based on the distribution and washing out of the fluorescent dye in relation to the fingertips (Figure 1). The distal interphalangeal (DIP), proximal interphalangeal (PIP) including the 1st interphalangeal and metacarpophalangeal (MCP) joints and the thumb base were graded on 0-3 scales based on color intensity and width of enhancement according to the FOIAS (8,10,21). All FOI images were scored by one reader (SH) blinded for MRI and ultrasound results and all clinical data except age and sex. The reader was trained in assessing FOI images with good inter-reader reliability with an experienced reader (SO) and excellent intra-reader reliability for all phases except Phase 1 (intraclass correlation coefficient for sum scores; PVM=0.89, Phase 1=0.10, Phase 2=0.87, Phase 3=0.89) in 21 patients(11). Persons with known allergy to iodine or indocyanine, untreated hyperthyroidism with fT4 above 21 pmol/L and thyroid-stimulating hormone (TSH) below 0.5 mIE/L, poor liver function (transaminases above twice the upper reference limit), reduced kidney function (glomerular filtration rate below 40 mL/min), pregnancy or breast-feeding did not perform the FOI scan.
Magnetic resonance imaging (MRI)
Participants without contraindications underwent 1.5T MRI (Siemens Aera, Germany) of the dominant hand. MRI was obtained mean (standard deviation; SD) 9 (13.9) days after the FOI scan. The fingers and thumb base joints were covered by a 16-channel hand/wrist-coil and an intravenous contrast (Dotarem 279.3 mg/mL, 0.2 mL/kg body weight) was given. A T1-weighted volumetric interpolated breath-hold examination (VIBE) was reconstructed into three planes with 2.0 mm thickness, and the axial and sagittal planes were used for evaluation of synovitis (10). The images were scored by a PhD-student (ØM) trained in assessing synovitis in hand joints. Repeated training sessions with an experienced reader (IKH) were arranged prior to the calibration exercise with demonstration of atlases and evaluation of example images (n=20). For calibration, 30 patients were scored separately in intervals of 13, 7 and 10 patients. Both readers scored the images until good inter-reader reliability (weighted kappa > 0.60) was obtained. For the last 10 patients the scorers obtained a weighted kappa of 0.69. Joints with a difference of two or more grades and scores of 0 and 1 between the readers were reassessed and scored by consensus. For the remaining patients, the experienced reader was consulted (IKH) in case of uncertainties. The MRI reader was blinded for FOI and ultrasound results and all clinical data except age and sex. Synovitis in the DIP and PIP (incl. IP1) joints was assessed on a 0-3 scale according to the Hand OA MRI scoring system (HOAMRIS) (12), and the MCP joints were scored with same criteria as the PIP joints. All finger joints were assessed in the sagittal and axial planes and had to demonstrate consistent findings in 3 consecutive slices in both planes to qualify as MRI enhancement. The 1st carpometacarpal joint (CMC-1) and scaphotrapeziotrapezoidal
(STT) joints were evaluated in the frontal and axial plane and evaluated using the TOMS atlas (13). Flexor tenosynovitis was assessed according to the Oslo hand OA MRI scoring system (OHOA-MRI) and peritendinous inflammation along the extensor tendon was evaluated as absent/present (14).
A GE Logic S8 ultrasound machine with a linear 6-15MHz probe preset for optimal grey-scale synovitis and power Doppler was used. The ultrasound examination was performed by a medical student trained by two experienced ultrasonographers (HBH, AM). A training session was arranged prior to study start with demonstration of the probe, normal B-mode musculoskeletal anatomy of the hand and presentation of an atlas of synovitis grade 1-3 in the bilateral DIP, PIP including first interphalangeal, MCP and CMC-1 joints(15). The hand joints were longitudinally scanned from the radial to the ulnar dorsal side, with additional transverse scanning in case of uncertainties. All joints were scored for grey scale (GS) synovitis and power Doppler (PD) activity on semiquantitative 0-3 scales using the atlas from the training session as reference. The reader was blinded to MRI, FOI and radiographic findings. The medical student and one of the experienced readers evaluated the 14 first patients together, and the medical student performed the remaining examinations independently. By the end of the data collection, a reliability exercise with the medical student and one ultrasonographer (AM) was performed, with consecutive enrollment of n=10 patients with good inter-reader reliability (Prevalence and bias adjusted kappa (PABAK) for GS in DIP/PIP (0.80) and CMC-1 joints (0.92) and power Doppler activity in DIP/PIP (0.85) and CMC-1 joints (0.92)(16).
Frontal images of bilateral hands were obtained with posterior-anterior view. One experienced reader (IKH) evaluated the DIP, PIP including first interphalangeal, MCP and CMC-1 according to Kellgren Lawrence (KL) scale (grade 0-4) (17, 18) and Verbruggen Veys (VV) anatomical phase scoring system(19). Erosive hand OA was defined as having at least one DIP or PIP joint(s) in the erosive or remodeling phase according to the VV anatomical phase scoring system. The reader demonstrated excellent intrareader reliability for both scoring systems with weighted kappa on 0.92 (KL) and kappa on 0.93 (erosive vs. non-erosive for the VV score).
Frequencies for different grades of FOI enhancement and synovitis detected by MRI and ultrasound were calculated and presented in histograms. Frequencies and trend of FOI enhancement in PVM across erosive vs. non-erosive and KL grades were assessed in cross tables and presented in histograms. We calculated Spearman’s correlations for sum scores of the dominant hand for MRI-detected synovitis and FOI and the bilateral hands for ultrasound-detected synovitis and FOI. For diagnostic performance we calculated sensitivity, specificity, negative (NPV) and positive predictive values (PPV) and area under the curve (AUC) using either MRI or GS synovitis as reference. Percent agreement (PA) was calculated on FOI enhancement yes/no vs. GS/MRI synovitis yes/no. For all imaging modalities, joints missing due to amputation, trapeziectomy or arthrodesis were imputed with an average value from the remaining joints in the same hand for sum scores, while they remained missing in calculations on frequencies and diagnostic performance. All results are presented for all joints together and for joint groups. Stratified analyses for persons with erosive hand OA vs. non-erosive hand OA were performed. Stata 14.0 was used for all the statistical analyses.