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Objective: To investigate whether digital activity fluorescence optical imaging (FOI) patterns of inflammation can identify distinct rheumatoid arthritis (RA) phenotypes., Methods: The hands of newly diagnosed patients with RA were evaluated by clinical examination, musculoskeletal ultrasound, and FOI. Inflammation on FOI was defined when capillary leakage and/or fluorophore perfusion was present. The FOI composite image was quantified into a digital disease activity (DACT) score, using novel computerized algorithms. Unsupervised clustering on FOI inflammatory patterns was used to identify subgroups of patients relative to anticyclic citrullinated peptides (ACPA) and/or rheumatoid factor (RF)., Results: Of 1326 examined hand joints in 39 patients with RA (72% female; 56% ever-smokers; 54% RF positive and 69% ACPA positive), 400 (30%) showed inflammation by FOI, and 95% (37 of 39) of patients had DACT-FOI scores greater than 1. Unsupervised analysis on FOI patterns revealed two patient clusters, cluster 1 (n = 29) and cluster 2 (n = 10). The proportion of seropositive patients was significantly higher in cluster 1 versus cluster 2 (90%, 26 of 29 vs. 30%, 3 of 10; P < 0.01), whereas C-reactive-protein levels (minimum-maximum) were significantly higher in cluster 2 (20 mg/l [1-102]) versus cluster 1 (2 mg/l [0-119]; P = 0.01). A wider variety and proportion of inflamed joints emerged for patients with RA in cluster 2 versus cluster 1, in which inflammation was more concentrated around the wrists and the right metacarpophalangeal 2 (MCP2), bilateral MCP3, and, to a lesser degree, left MCP2 and proximal interphalangeal joint and tendon regions. Cluster 1 displayed lower mean (±SD) DACT scores compared with cluster 2 (3.6 ± 2.1 vs. 5.4 ± 2.1; P = 0.03)., Conclusion: FOI-based digital quantification of hand joint inflammation revealed two distinct RA subpopulations with and without ACPA and RF related autoantibodies., (© 2023 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: The appearance of anti-citrullinated protein antibodies (ACPAs) in the circulation represents a major risk factor for developing rheumatoid arthritis (RA). Patient-derived ACPAs have been shown to induce pain and bone erosion in mice, suggesting an active role in the pathogenicity of RA. We undertook this study to investigate whether ACPAs can induce tenosynovitis, an early sign of RA, in addition to pain and bone loss and whether these symptoms are dependent on peptidyl arginine deiminase 4 (PAD4)., Methods: Monoclonal ACPAs generated from plasma cells of RA patients were transferred to wild-type and PAD4-deficient mice. Pain-like behavior and macroscopic inflammation were monitored for a period of 4 weeks, followed by the analyses of tenosynovitis in the ankle joints using magnetic resonance imaging (MRI) and bone microarchitecture in the tibia using an X-ray microscope. Microscopic changes in the tendon sheath were analyzed in decalcified ankle joint sections., Results: The combination of 2 monoclonal ACPAs (1325:04C03 and 1325:01B09) induced long-lasting pain-like behavior and trabecular bone loss in mice. Although no synovitis was observed macroscopically, we detected tenosynovitis in the ACPA-injected mice by MRI. Microscopic analyses of the joints revealed a cellular hyperplasia and a consequent enlargement of the tendon sheath in the ACPA-treated group. In PAD4 -/- mice, the effects of ACPAs on pain-like behavior, tenosynovitis, and bone loss were significantly reduced., Conclusion: Monoclonal ACPAs can induce tenosynovitis in addition to pain and bone loss via mechanisms dependent on PAD4-mediated citrullination., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Fluorescence Optical Imaging (FOI) demonstrates indocyanine green (ICG)-enhanced microcirculation in wrist and finger joints, as a sign of inflammation. We wanted to assess the reliability of three FOI scoring methods from Berlin, Stockholm, and Copenhagen, to assess the validity of FOI with MRI as reference and to compare enhancement in hand joints in erosive hand osteoarthritis (OA) vs. rheumatoid arthritis (RA)., Design: Five readers scored all finger and wrist joints of 26 patients with erosive hand OA and RA on semi-quantitative 0-3 scales using three different FOI scoring methods. To evaluate inter-reader reliability, we calculated the intraclass correlation coefficients (ICC) for sum scores and prevalence and bias adjusted kappa values for ordinal scales (Pabak-OS) on joint level. Enhancement in joint groups in erosive hand OA vs. RA was compared using Mann-Whitney test. Sensitivities and specificities of FOI was calculated with MRI as reference for hand OA patients only., Results: We found moderate to good inter-reader reliability for all FOI scoring methods (Pabak-OS: 0.50-0.78, ICC: 0.43-0.85) and different patterns of enhancement in erosive hand OA vs. RA with significantly more FOI enhancement in DIP joints in erosive hand OA across all methods. With MRI as reference the different FOI scoring methods reached similar sensitivities (63-65%) and specificities (76-91%)., Conclusion: FOI enhancement can be measured reliably in erosive hand OA and RA using three different scoring methods. More DIP enhancement in erosive hand OA patients and good agreement with MRI support the diagnostic performance of FOI., (© 2019 The Authors.)

Objectives: To study fully automated digital joint space width (JSW) and bone mineral density (BMD) in relation to a conventional radiographic scoring method in early rheumatoid arthritis (eRA)., Methods: Radiographs scored by the modified Sharp van der Heijde score (SHS) in patients with eRA were acquired from the SWEdish FarmacOTherapy study. Fully automated JSW measurements of bilateral metacarpals 2, 3 and 4 were compared with the joint space narrowing (JSN) score in SHS. Multilevel mixed model statistics were applied to calculate the significance of the association between ΔJSW and ΔBMD over 1 year, and the JSW differences between damaged and undamaged joints as evaluated by the JSN., Results: Based on 576 joints of 96 patients with eRA, a significant reduction from baseline to 1 year was observed in the JSW from 1.69 (±0.19) mm to 1.66 (±0.19) mm (p<0.01), and BMD from 0.583 (±0.068) g/cm 2 to 0.566 (±0.074) g/cm 2 (p<0.01). A significant positive association was observed between ΔJSW and ΔBMD over 1 year (p<0.0001). On an individual joint level, JSWs of undamaged (JSN=0) joints were wider than damaged (JSN>0) joints: 1.68 mm (95% CI 1.70 to 1.67) vs 1.54 mm (95% CI 1.63 to 1.46). Similarly the unadjusted multilevel model showed significant differences in JSW between undamaged (1.68 mm (95% CI 1.72 to 1.64)) and damaged joints (1.63 mm (95% CI 1.68 to 1.58)) (p=0.0048). This difference remained significant in the adjusted model: 1.66 mm (95% CI 1.70 to 1.61) vs 1.62 mm (95% CI 1.68 to 1.56) (p=0.042)., Conclusions: To measure the JSW with this fully automated digital tool may be useful as a quick and observer-independent application for evaluating cartilage damage in eRA., Trial Registration Number: NCT00764725., Competing Interests: Competing interests: JK is employed by Sectra AB. No other conflicts of interests to declare.

Objectives: The aim of this study was to evaluate the association between two semi-quantitative Doppler US scoring systems (SQS), and the quantitative scoring (QS) of Doppler pixel count., Methods: Adult patients with RA and inadequate clinical response to anti-rheumatic therapy were examined with musculoskeletal US (MSUS). Dorsal MSUS of the wrists, MCP and MTP 2-5 were performed. MSUS images with sign of synovitis were collected and the QS was measured. Five assessors blinded to the QS evaluated the images independently, according to either SQS method. Association between QS and SQS was studied using correlations and multilevel models taking into account the clustering of ratings at the rater, patient and joint levels., Results: Analysis of the 1190 ratings revealed a strong correlation (ρ = 0.89, P < 0.0001) and significant associations (P < 0.0001) between QS and SQS. Correlations between QS and SQS according to Szkudlarek et al. (ρ = 0.87, P < 0.0001) or Hammer et al. (ρ = 0.91, P < 0.0001) were similar. A total of 239 (20.1%) images were given a SQS grade that did not match that expected based on initial QS, using pre-defined cut-offs. Main explanations for discrepancies were different perceived region of interest (40.7%) and Doppler pixel count near cut-offs between SQS grades (32.3%)., Conclusion: We showed that both SQS methods correlated well with QS to assess synovitis, but SQS methods are intrinsically limited when the Doppler pixel count is close to the cut-offs between the SQS grades. Analysis discrepancies between these methods may help further revision of criteria used to assess disease activity with MSUS in RA., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: This study aimed to assess the utility of musculoskeletal ultrasound (MSUS) in patients with joint symptoms using a probabilistic approach., Methods: One hundred and three patients without prior rheumatologic diagnosis and referred to our clinic for evaluation of inflammatory arthritis were included. Patients were assessed clinically including joint examination, laboratory testing including acute-phase reactants, rheumatoid factor (RF) and anti citrulinated protein antibody (ACPA), and radiographs of hands and feet if clinically indicated. A diagnostic assessment was then performed by the responsible rheumatologist where the probability of a) any inflammatory arthritis and b) rheumatoid arthritis was given on a 5-point scale ranging from 0 to 20% up to 80 to 100% probability. Subsequently, an ultrasound examination of the wrist, metacarpophalangeal (MCP), proximal interphalangeal (PIP) joints 2 to 5 in both hands, metatarsophalangeal (MTP) joints 2 to 5 in both feet and any symptomatic joints was performed and the results presented to the same rheumatologist. The latter then assessed the diagnostic probabilities again, using the same scale., Results: The rheumatologists' certainty for presence/absence of inflammatory arthritis and rheumatoid arthritis was increased significantly following ultrasound performance. The proportion of patient for whom diagnostic certainty for inflammatory arthritis was maximal was 33.0% before and 71.8% after musculoskeletal ultrasound (P <0.001). With regard to a diagnosis of RA, the proportions were 31.1% pre-test and 61.2% post-test (P <0.001). MSUS findings agreed with the final diagnosis in 95% of patients., Conclusion: Musculoskeletal ultrasound, when added to routine rheumatologic investigation, greatly increases the diagnostic certainty in patients referred for the evaluation of inflammatory arthritis. The changes from pre-test to post-test probability quantify the diagnostic utility of musculoskeletal ultrasound in probabilistic terms.