17 patients (mean age 53.7 ± 11.6; minimum/maximum 26/72 years, male/female 9/8) fulfilling the CASPAR criteria with a mean disease duration of 4 ± 3.6 years and peripheral joint involvement and dactylitis were prospectively recruited for the “Analysis of the DActylic Melange” (ADAM) research initiative. All patients had failed methotrexate (MTX) monotherapy and were escalated to Etanercept (Enbrel® 50 mg s.c. fortnightly) after a baseline MRI scan.
Additionally, 20 therapy naïve patients (mean age 46 ± 15.7, minimum/maximum 19/67 years, male/female 9/11), fulfilling the ACR/EULAR 2010 criteria for RA with a mean disease duration < 6 months (mean duration 8 weeks, minimum/maximum 2/22 weeks) from the ‘Cartilage in early RA’ (CAR-ERA) study, were included. Patients were allowed a daily dose of oral prednisone at <10 mg. After a baseline scan, patients received either MTX monotherapy or a combination of MTX and adalimumab. Patients were blinded for their therapy regime.
Furthermore, 16 patients (mean age 39 ± 16.1, minimum/maximum 17/78 years, male/female 9/7) with no history of arthritis were retrospectively recruited as healthy controls (HC). MRI studies were performed due to clinical reasons (e.g. suspected carpal ganglion) in our daily routine. At the time of retrospective recruitment, all subjects of HC were over 18 years of age. The study was approved by the local ethics committee (MO-LKP-719, 4962R). Written and informed consent was obtained from all patients before initiation of the study.
- MR imaging
For MR imaging, a 3T MRI scanner (Magnetom Skyra, Siemens Healthineers, Erlangen, Germany) and a purpose built dedicated 16-channel hand coil (figure 1; 3T Tim Coil, Siemens Healthineers, Erlangen, Germany) were used, allowing for a high-resolution imaging over a wide area.. PsA patients received a baseline (T0) and a follow-up (T1) scan with an approximately 6.2 ± 0.85 month (minimum/maximum: 5/8 months) interval in between. A baseline (T0) and two follow-up (T1 and T2) scans were performed in the RA population with approximately 2.8 ± 0.1 months (minimum/maximum 2.6/3 months) between T0 and T1 and 5.6 ± 0.1 months (minimum/maximum 5.4/5.8 months) between T0 and T2. For HC only a single scan was performed.
The imaging protocol followed the recommendations of the OMERACT working group for PsA and RA (21, (27). In PsA patients this included pre- and post-contrast (DOTA- , Dotarem, Guerbet, Villepinte, France; intravenous-injection of 0.4 ml/kg bodyweight) T1-weighted turbo spin echo (TSE) and non-contrast enhanced fat-saturated T2-weighted TSE or short tau inversion recovery (STIR) sequences in two different orthogonal planes. The field of view covered MCP, PIP and DIP of digits 2-5. In RA patients the protocol included the following sequences: pre- and post-contrast (DOTA- , Dotarem, Guerbet, Villepinte, France intravenous-injection of 0.4 ml/kg bodyweight) coronal T1-weighted TSE and transversal fat-saturated T1-weighted spin echo (SE) after contrast agent application as well as a coronal STIR. The field of view covered MCP 2-5, carpometacarpal, carpal, radiocarpal and distal radioulnar joints.
In control patients our in-house standard protocol was used, which included the same sequences as detailed for the RA patients above. In addition, a transversal fat-saturated proton-density weighted sequence was acquired. The field of view differed according to the clinical region of interest.
The sequence parameters were as follows:
PsA: coronal T1 TSE (TR/TE in ms, PsA: 862/27, RA: 862/27; flip angle in °, PsA: 150, RA: 150; slice thickness in mm, PsA: 2.5, RA: 2.5; field of view in mm, PsA: 140, RA: 130; pixel size: PsA: 0.3 x 0.3 mm, RA: 0.3 x 0.3; acquisition matrix: 512 x 512), coronal STIR (TR/TE in ms, PsA: 5560/31, RA: 5560/31; flip angle in °, PsA: 120, RA: 120; slice thickness in mm, PsA: 2.5, RA: 2.5; field of view in mm, PsA: 140, RA: 130; pixel size: PsA: 0.3 x 0.3 mm, RA: 0.3 x 0.3 mm; acquisition matrix: 448 x 314), sagittal PD TSE fat-saturated (only PsA: TR/TE in ms 3150/47, flip angle 150°, slice thickness 2.5 mm, field of view 150 mm; pixel size: 0.3 x 0.3 mm; acquisition matrix: 448 x 182), transversal T2 TSE fat-saturated (only PsA: TR/TE in ms: 5693.8/89, flip angle 180°, slice thickness 3.0 mm, field of view: 160 mm; pixel size: 0.3 x 0.3 mm; acquisition matrix: 512 x 358), transversal T1 SE fat-saturated after iv contrast (TR/TE in ms, PsA: 807/16, RA: 702/16; flip angle in °, PsA: 90, RA: 90; slice thickness in mm, PsA: 3.0, RA 2.5; field of view in mm, PsA:130, RA: 120; pixel size: PsA: 0.3 x 0.3 mm, RA: 0.3 x 0.3 mm; acquisition matrix: 384 x 288) and coronal T1 TSE after iv contrast (TR/TE in ms, PsA: 862/27, RA: 862/27; flip angle in °, PsA: 150, RA; 150; slice thickness in mm, PsA: 2.5, RA: 2.5; field of view in mm, PsA; 140, RA: 140; pixel size: PsA: 0.3 x 0.3 mm, RA: 0.3 x 0.3 mm; acquisition matrix: 512 x 512).
- Image analysis
MR images were read and analyzed in consensus by two radiologists (one attending physician [CS], one resident physician [DBA]) and one rheumatologist (attending physician [PS]), with long-term experience in musculoskeletal imaging of > 8 years (CS and PS) and all trained in RAMRIS and PsAMRIS-Scoring according to the OMERACT guidelines [15, 16]. Readers were blinded to the diagnosis of the patients. Flexor tendon pulleys A1 and A2 were analyzed in digits 2 to 5. Each pulley was evaluated regarding its thickness in mm and its intrinsic and/or surrounding signal intensity at the radial, ulnar and volar aspect of each pulley (see figure 2 and 3 for typical changes). The PsAMRIS was adapted due to the clear visualization of the pulleys with abnormalities being scored as 0-3 as per PsAMRIS scoring at other sites such as synovium and tenosynovium (21). Consequently, the score reflected the degree of enhancing and/or hyperintense signals within the pulley complex and scores 0, - 3 indicated the absence of any abnormality (score 0), the involvement of < 50 % of the pulley thickness (score 1), of ≥ 50 % (score 2), and of its entire thickness (score 3). For each pulley we took the sum of the radial, ulnar and volar grading regarding the sourrounding and/or intrinsic inflammatory changes and the mean of the radial and ulnar thickness of the pulley itself in mm. Additionally, PsA patients were evaluated according to PsAMRIS at MCP, PIP and DIP joint level of digits 2-5 for synovitis (score 0-3), flexor tenosynovitis (score 0-3), bone edema (score 0-3), erosion (score 0-10), proliferation (score 0 or 1) and periarticular inflammation (score 0 or 1) (21). In case of different findings, the analysts reached a common consensus.
- Statistical analysis
All statistical analyses were performed using SPSS software (IBM, version 22, Armonk, NY, USA). For descriptive analysis, the mean, standard deviation, minimum and maximum are presented. Mean values were compared with a one-way analysis of variance (ANOVA) and a post-hoc Scheffé test. For correlation analyses, Spearman rho correlation coefficient (ρ) was used. Correlation strength was graded as suggested by Cohen (28): small (< 0.3), moderate (0.3 - 0.5) and large (> 0.5).
Due to the large number of comparisons between PsA patients, RA patients, and healthy controls, Bonferroni correction was applied, and the level of significance was set to p≤ 0.05 / 3= 0.0167. Three patient cohorts were comparatively evaluated and therefore may be considered as separate experiments. In a stricter statistical sense, correction of all 66 sub-experiments (i.e. three cohorts, two assessed MRI characteristics, and 11 anatomical flexor tendon pulley levels) ought to be performed; however, the increased risk of producing false negatives secondary to overly conservative statistical analyses rendered this option impractical. Accordingly, we decided to use (design-adapted) Bonferroni correction and look for consistent and significant changes of the pulleys as a function of disease entity instead of relying on statistical formalism. Inter- and intra-rater reliability for pulley thickness and pulley inflammatory changes was calculated by two-way mixed intraclass correlation coefficients (single-measure ICC (sICC) for intra-rater and average-measure ICC (aICC) for inter-rater reliability).