Identification of early risk factors for anti-citrullinated-protein-antibody positive rheumatoid arthritis-a prospective cohort study.

OBJECTIVE: Individuals positive for anti-cyclic-peptide-antibodies (anti-CCP) and musculoskeletal complaints (MSK-C) are at risk for developing rheumatoid arthritis (RA). In this study we aimed to investigate factors involved in arthritis progression. METHODS: Anti-CCP2-positive individuals with MSK-C referred to a rheumatologist were recruited. Individuals lacked arthritis at clinical and ultrasound examination and were followed for ≥three years or until clinical arthritis diagnosis. Blood samples from inclusion were analyzed for; nine anti-citrullinated-protein-antibody (ACPA) reactivities (citrullinated α-1-enolase, fibrinogen, filaggrin, histone, vimentin and tenascin peptides); 92 inflammation-associated proteins; and HLA-shared epitope alleles. Cox regression was applied to the data to identify independent predictors in a model. RESULTS: 267 individuals were included with median follow up of 49 months (IQR: 22-60). 101 (38%) developed arthritis after median 14 months (IQR: 6-27). The analysis identified that presence of at least one ACPA reactivity (HR 8.0, 95% CI 2.9-22), ultrasound detected tenosynovitis (HR 3.4, 95% CI 2.0-6.0), IL6 levels (HR 1.5, 95% CI 1.2-1.8) and IL15-Rα levels (HR 0.6, 95% CI 0.4-0.9) are significant independent predictors for arthritis progression in a prediction model (Harrell's C 0.76 [SE 0.02], AUC 0.82 [95% CI 0.76-0.89], cross-validated AUC 0.70 [95% CI 0.56-0.85]). CONCLUSION: We propose a high-Risk-RA phase characterized by presence of ACPA reactivity, tenosynovitis, IL6, and IL15-Rα and suggest that these factors need to be further investigated for their biological effects and clinical values, to identify individuals at particular low risk and high risk for arthritis progression.

Distinct Fluorescence Optical Imaging Patient Clusters Emerge for Seropositive and Seronegative Rheumatoid Arthritis.

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.

Combination of Two Monoclonal Anti-Citrullinated Protein Antibodies Induced Tenosynovitis, Pain, and Bone Loss in Mice in a Peptidyl Arginine Deiminase-4-Dependent Manner.

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.

Joint Mobilization of the Hands of Patients With Rheumatoid Arthritis: Results From an Assessor-Blinded, Randomized Crossover Trial.

OBJECTIVE: The purpose of this study was to assess the clinical feasibility and effectiveness of manual mobilization of the hands of patients with rheumatoid arthritis (RA). METHODS: A total of 320 individual hand joints were evaluated after recruiting an experimental research group of 12 participants with RA and, for clinical comparability, 8 participants with hand osteoarthritis (OA). One hand per participant was randomized to receive weekly low-grade (I-II) Kaltenborn manual mobilization, using passive sustained stretch of the metacarpophalangeal (MCP) joints II to V by licensed manual therapists. After 2 weeks, the randomized treated hand was crossed over to control (untreated) during weeks 3 to 4 and vice versa. Final assessment was at 2 months, which was 1 month after the last treatment at week 4. Primary hand outcomes included pain by visual analog scale, tender or swollen joint count, and presence of Doppler signal or synovial fluid and radiographic joint space by musculoskeletal ultrasound. RESULTS: In the RA group, both the initially randomized treated hand and the contralateral hand improved significantly from baseline to crossover to follow-up at 2 months (pain outcomes and Doppler signal, P < .050; synovial fluid and MCP joint space, P ≤ .001). Hand pain and MCP joint space also improved significantly in OA. There were no dropouts or reported adverse events in either the RA or OA group. CONCLUSION: In this study, manual mobilization of the hands of patients with RA was shown to be feasible, safe, and effective to integrate into specialized healthcare.

Fully automated joint space width measurement and digital X-ray radiogrammetry in early RA.

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/cm2 to 0.566 (±0.074) g/cm2 (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.

Analysis of correlation and causes for discrepancy between quantitative and semi-quantitative Doppler scores in synovitis in rheumatoid arthritis.

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.

Detection of clinically manifest and silent synovitis in the hands and wrists by fluorescence optical imaging.

OBJECTIVES: The correct identification of synovitis is critical for achieving optimal therapy results. Fluorescence optical imaging (FOI) is a novel modality based on the use of an intravenous fluorophore, which enables fluorescent imaging of the hands and wrists with increased focal optical signal intensities in areas of high perfusion and/or capillary leakage. The study objective was to determine the diagnostic utility of FOI in detecting apparent and clinically non-apparent active synovitis. METHODS: Bilateral hand and wrist joints (n=872) of 26 patients with inflammatory arthritis assessed by standard clinical examination, musculoskeletal ultrasound (MSUS) and FOI were studied. Synovitis was defined as tender and swollen joints on clinical examination, presence of synovial thickening and intra-articular Doppler signals on MSUS, and abnormal focal optical signal intensities on FOI, respectively. Subclinical synovitis was defined as being clinically non-apparent, but positively inflamed on MSUS. RESULTS: Depending on the standard used to define inflammation, FOI ranged from 73-83% sensitive and 83-95% specific for detecting manifest synovitis. For detecting clinically silent synovitis, the sensitivity, specificity and positive and negative predictive values of FOI were 80%, 96%, 77% and 97%, respectively. CONCLUSIONS: The high degree of agreement between MSUS and FOI suggest its use in clinical practice, especially when MSUS is not available, in order to identify synovitis earlier and with greater confidence. FOI may be particularly useful in identifying patients with clinically non-apparent joint inflammation of the hands and/or wrists.

Diagnostic utility of musculoskeletal ultrasound in patients with suspected arthritis--a probabilistic approach.

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.