Study design and population
Patients with rheumatoid arthritis, according to the ACR/EULAR (2010) classification criteria [11], were recruited from the outpatient clinic at the Department of Rheumatology, Aarhus University Hospital. Inclusion criteria were the ability to give consent, age ≥ 18 years and disease duration ≥ 5 years. Exclusion criteria were fracture or luxation of the MCP joints in both hands, evidence of active malignant disease, hypocalcemia, impaired renal function (Estimated glomerular filtration rate <35ml/min), untreated hypo- or hyperthyroidism or pregnancy.
A full medical history was obtained, and a clinical examination was performed for all individuals. Specifically, demographic and clinical data were obtained, including age, gender, disease duration, number of tender and swollen joints, C-reactive protein, as well as anti-citrullinated protein antibodies and immunoglobulin M rheumatoid factor.
Conventional radiography
All patients had their hands, wrist and feet examined with radiographs using the standard dorsopalmar projection, the image was generated at a focus distance of 100-115 cm, 50-55 kV and 2-12 mAs. If radiographs had been performed within the last three months or were scheduled in the three months following inclusion, this was recorded as the baseline. The radiographs were evaluated with the Sharp/van-der-Heijde method [12].
HR-pQCT acquisition procedure
An image acquisition protocol endorsed by the Study grouP for xtrEme-Computed Tomography in Rheumatoid Arthritis (SPECTRA) was used [13]. The 2nd and 3rd MCP joint were imaged using first-generation XtremeCT (Scanco Medical, Brüttiselen, Switzerland). A 2.7-cm-long volume of interest was scanned with a spatial resolution of 82 μm3, an X-ray tube voltage of 59.4 kVp, a current of 900 μA, and an integration time of 100 ms. The scan was performed within a region of 80 slices (6.56 mm) distal and 250 slices (20.5 mm) proximal to the distal end of the third metacarpal head. The dominant hand was scanned except in cases with prior fracture or luxation in the MCP joints.
The patients were scanned with two methods of standardized positioning of the hand using custom-made positioning devices. Splint without the inflatable immobilization device: The hand and forearm were positioned parallel to the long axis of a rigid splint and strapped down to the rigid splint at the MCP joints and the distal and proximal part of the forearm. The splint-supported hand and forearm were then positioned within a cylindrical holder manufactured by Scanco Medical AG, Switzerland. The cylindrical holder was placed inside the HR-pQCT unit for scan acquisition (Figure 1A-B). Splint with the inflatable immobilization device: The hand was immobilized using a rigid splint as described above. However, an inflatable immobilization device (Multipad Bendy, Pearltec AG, Zurich, Switzerland) was then positioned over the fingers and inflated to immobilize the fingers (Figure 1C-D).
Twenty-five patients were scanned first without the inflatable immobilization device and subsequently with the inflatable immobilization device. The other 25 patients were scanned first with the inflatable immobilization device and subsequently without the inflatable immobilization device in order to minimize bias. Each image was anonymized before analysis in random order using the Osirix software (Version 9.0.1; Pixmeo, Bernex, Switzerland) and a 27-inch cinema screen iMac.
Patient-Reported Experience Measure
A questionnaire was developed, in conjunction with RA patients at our department, to investigate the patient-reported experience measure [10]. The questionnaire investigated the acceptance of HR-pQCT imaging, with and without the inflatable immobilization device (Table 2). The patients were asked to fill out the questionnaire after the conventional radiographs and both HR-pQCT acquisitions.
Visual grading of motion artefacts for HR-pQCT Images
For each anonymized acquisition, the motion-induced image degradation was graded for the distal, middle, and proximal 110-slices stack of the 330-slices stack. The grading of motion-induced image degradation was based on a grading scale proposed by the scanner manufacturer for the 110-slices stack of radius and tibia acquisitions, where the presence and extent of horizontal streaking, disruption of cortical contiguity and trabecular smearing is used for grading [14]. Five different grades were defined from grade 1 (no visible motion artefacts) to grade 5 (severe motion artefacts). A visual grade ≤ 3 has been shown to be adequate for the reproducibility of standard morphological parameters such as bone mineral density and microstructure in the radius [15].
HR-pQCT erosion measures
The metacarpal head and proximal phalanx of the 2nd and 3rd metacarpophalangeal joints were assessed for erosions by a single trained reader (RKJ). Erosions were defined according to the SPECTRA collaboration: 1) a definite break in the cortical bone; 2) the cortical break must extend over at least two consecutive slices; 3) the cortical break must be detectable in two perpendicular planes; 4) the cortical interruption must have a loss of underlying trabecular bone, and 5) the cortical interruption must be nonlinear in shape to differentiate from vascular channels penetrating the cortices [16]. For all erosions, the maximum width, depth and length were measured. Width and depth were measured in the axial plane. The length was measured in the coronal plane for erosions located in either the radial or ulnar quadrant. Conversely, the length was measured in the sagittal plane for erosions located in the palmar or dorsal quadrant.
Intrareader repeatability
Ten images from the acquisitions without the inflatable immobilization device and ten images from the acquisition with the inflatable immobilization device were chosen at random and reevaluated by a single trained reader (RKJ) one week later, to determine intrareader repeatability of the visual grading for motion artefacts and the erosion measures.
Ethical considerations
The Ethics Committee of Medical Research in Central Denmark Region (J. no. 1-10-72-437-17) and The Danish Data Protection Agency (J.nr: 2012-58-006) approved the study. Written informed consent was obtained from the patients.
Statistics
Data were analyzed using STATA 12 (StataCorp LP, College Station, TX, USA). Normal distribution of the data was investigated with Q-Q plots and histograms. Normally distributed data were presented as arithmetic mean (95% CI) and statistical significance tested using students t-test. Non-normally distributed data were presented as median (25th to 75th percentile), and statistical significance was tested using the Mann-Whitney U test.
The number of erosions and the average maximum width, depth, and length of the erosions were measured, and the statistical significance was investigated between acquisitions with and without the inflatable immobilization device. The measures of erosion were compared between the acquisitions with and without the inflatable immobilization device using Bland-Altman Plots[17]. The intrareader repeatability of maximum width, depth, length, and the number of erosions was investigated by the intraclass correlation coefficient (ICC) for both custom-made positioning devices. For visual grading of motion artefacts, the intrareader repeatability was investigated with Cohen's kappa coefficient (κ) for every 110-slices of the 330-slices image stacks.
Correlation between the patient-reported experience and either disease duration, age, BMI, sex, Sharp/van der Heijde score, erosion number and size were investigated using Spearman's rank correlation coefficient in order to identify whether disease severity influenced the patients' experience of having their hand imaged by HR-pQCT. The results were considered significant at p < 0.05.