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Background: Although normal acute phase reactants (APRs) play an important role in assessing disease activity of rheumatoid arthritis (RA), some studies pointed out the discordance between disease activity and APR level. Neutrophil-to-lymphocyte ratios (NLRs), platelet-to-lymphocyte ratios (PLRs) and lymphocyte-to-monocyte ratios (LMRs) have been reported to be sensitive measures of inflammatory reaction. This study aims to explore the value of these haematological makers in assessment of APR-negative RA patients., Methods: Out of a cohort of 418 consecutive patients with RA, we enrolled 135 patients with normal APR for this study. We performed ultrasound assessments to evaluate synovitis and bone erosion in the affected joints. Synovitis was evaluated by ultrasound grey scale (GS) and power Doppler (PD) with semi-quantitative scoring (0-3). Demographic, clinical and laboratory data were collected from the patients. Disease Activity Score-28 joints (DAS28), NLR, MLR and PLR were calculated., Results: In RA patients with normal APR, PLR exhibited a positive correlation with ultrasound-detected synovitis and bone erosion, whereas NLR, MLR showed no significant correlation with ultrasonography parameters. The area under the ROC curve (AUC) for identifying synovitis with a GS grade ≥2 based on a PLR cutoff value of ≥159.6 was 0.7868 (sensitivity: 80.95%, specificity: 74.24%). For synovitis with a PD grade ≥2, the AUC was 0.7690, using a PLR cutoff value of ≥166.1 (sensitivity: 68.0%, specificity: 83.87%)., Conclusions: Our findings suggested that PLR might be a reliable and cost-effective marker for identifying moderate-to-severe synovitis in RA patients with normal APR.

Objectives: Autoantibody-negative RA differs from autoantibody-positive RA in several clinical aspects, possibly underpinned by pathogenetic differences. At present, the role of adaptive immune responses in autoantibody-negative RA remains unclear. Here, we investigated the synovial and serum immunophenotype indicative of B lymphocyte involvement across the spectrum of autoantibody-positive and -negative chronic arthritides., Methods: Ultrasound-guided synovial biopsies were retrieved from 131 patients: 43 autoantibody-positive RA, 35 autoantibody-negative RA, 25 polyarticular PsA and 28 oligoarticular PsA. Samples were analysed for the degree of histological inflammation, B lymphocyte infiltration and the distribution of different pathotypes (lympho-myeloid, myeloid, pauci-immune). Serum levels of the B cell chemoattractant CXCL13 were compared among groups., Results: Synovitis scores and CD68+ sublining macrophage infiltration were comparable irrespective of clinical diagnosis and disease subtype. In contrast, the degree of B lymphocyte infiltration and the frequency of lympho-myeloid synovitis in autoantibody-negative RA were lower than those of autoantibody-positive RA (mean [s.d.] 1.8 [1] vs 2.4 [0.6], P = 0.03, and 38.2% vs 62.9%, P = 0.07, respectively), and similar to polyarticular PsA. Oligoarticular PsA had the lowest B cell scores. Serum CXCL13 was associated with lympho-myeloid synovitis and followed a similar gradient, with the highest levels in autoantibody-positive RA, intermediate and comparable levels in autoantibody-negative RA and polyarticular PsA, and low levels in oligoarticular PsA., Conclusions: The synovial and serum immunophenotype indicative of B lymphocyte involvement in autoantibody-negative RA differs from that of autoantibody-positive RA and more closely resembles that observed in polyarticular PsA. The pathobiological stratification of chronic inflammatory arthritides beyond clinical diagnosis may fuel personalized treatment strategies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Blau syndrome (BS), a rare, autosomal-dominant autoinflammatory syndrome, is characterized by a clinical triad of granulomatous recurrent uveitis, dermatitis, and symmetric arthritis and associated with mutations of the nucleotide-binding oligomerization domain containing 2 (NOD2) gene. Aim of this study was to assess the efficacy of tofacitinib in Chinese paediatric patients with BS., Methods: Tofacitinib was regularly administered to three BS patients (Patient 1, Patient 2, and Patient 3) at different dosages: 1.7 mg/day (0.11 mg/kg), 2.5 mg/day (0.12 mg/kg), and 2.5 mg/day (0.33 mg/kg). The clinical manifestations of the patients, magnetic resonance imaging results, serological diagnoses, therapeutic measures and outcomes of treatments are described in this report., Results: The clinical characteristics and serological diagnoses of all BS patients were greatly improved after the administration of tofacitinib treatment. All patients reached clinical remission of polyarthritis and improvements in the erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP) and inflammatory cytokines., Conclusion: Tofacitinib, a Janus kinase (JAK) inhibitor, is a promising agent for BS patients who have unsatisfactory responses to corticosteroids, traditional disease-modifying antirheumatic drugs, and biological agents., (© 2021. The Author(s).)

To investigate the association between markers of synovial inflammation and matrix turnover (MRI-based and serum biomarkers) and knee symptoms in established knee osteoarthritis (KOA). This cross-sectional study utilised data from a randomised, multicentre placebo-controlled trial (UK-VIDEO) of vitamin D therapy in symptomatic KOA. Data on serum biomarkers, type III collagen degradation (C3M), metabolite of C-reactive protein (CRPM) and cartilage oligomeric matrix protein (COMP), were available at baseline whilst contrast-enhanced (CE) MRI data were acquired in a subsample at baseline and annually. Knee symptoms were assessed using WOMAC at all visits. We examined the cross-sectional association between knee symptoms and three MRI-based and three serum markers of synovitis and matrix turnover, respectively. A total of 447 participants were included in the serum and 136 participants in the MRI analyses. MRI-defined medial perimeniscal synovitis was positively associated with knee pain and, suprapatellar and medial perimeniscal synovitis with knee function in multivariate analysis. We observed a statistically significant, negative association between a higher concentration of serum C3M and CRPM and knee pain, respectively. Furthermore, the highest CRPM quartile was negatively associated with knee function. Our findings suggest that, in established painful radiographic KOA, MRI-defined medial perimeniscal and suprapatellar synovitis were positively associated with knee symptoms. Serum-based C3M and CRPM markers were negatively associated with knee symptoms. Pain fluctuations are common in KOA and a better understanding of the relationship between markers of synovitis and matrix turnover and knee symptoms would facilitate a more accurate assessment of temporal changes in disease progression.

Objective: Autoantibodies (AutoAbs) have been observed in osteoarthritis (OA) with broad antigenicity, although their prevalence and role remain unclear. Post-translational modification (PTMs) of proteins (oxidation, carbamylation, citrullination) is associated with synovitis and can lead to AutoAb development. Given the prevalence of synovitis, we explored whether AutoAbs to PTM-antigens are common in OA compared with rheumatoid arthritis (RA)., Methods: Serum (n = 895) was obtained from healthy controls, OA and RA patients; and arthritic synovial fluid (SF, n = 290). ELISAs were used to quantify anti-citrullinated peptide (ACPA), anti-carbamylated protein (anti-CarP), anti-oxidized collagen (anti-ROS-CI/CII) antibodies., Results: In sera, positivity for PTM-antigens AutoAbs was observed at a lower frequency in OA with 64.1% (95%CI: 57.2-70.1%) more ACPA+ and 29.8% (21.0-37.3%) more anti-CarP + patients in RA (both P < 0.0001). Levels of ACPA, anti-CarP were also lower in OA (P < 0.0001). Anti-ROS-CII positivity was lower in OA compared to RA (16.6%, 4.8-28.6%) less frequent, P = 0.033) but not anti-native-CII. There was no impact of age/gender on AutoAbs associations with diseases either looking at positivity or levels. In SF, OA patients were often ACPA+ (45.9%) although less frequently than in RA (P = 0.004). Anti-CarP were rarely observed (<5% all samples). All collagen AutoAbs were more frequent in RA compared to OA (all P < 0.010) but only levels of anti-CII and anti-ROS-CII were significantly higher in they RA (P < 0.050)., Conclusion: Although the frequency of AutoAbs for PTM proteins were lower in OA sera compared to RA, a higher proportion of OA SF were positive. The relative retention of AutoAbs in the OA joint requires further investigation., (Copyright © 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

1,25-dihydroxyvitamin-D3 and its derivatives have shown anti-arthritic and chondroprotective effects in experimental animal models with prophylactic dosing. The purpose of this preliminary study was to test the efficacy and safety of calcipotriol, vitamin D analog, as a treatment for a fully-developed knee arthritis in Zymosan-induced arthritis (ZIA) model. Forty 5-month-old male Sprague-Dawley rats were randomized into three arthritis groups and a non-arthritic control group with no injections (10 rats/group). A day after Zymosan (0.1 mg) had been administrated into the right knee joints, the same knees were injected with calcipotriol (0.1 mg/kg), dexamethasone (0.1 mg/kg) or vehicle in a 100 μl volume. The left control knees were injected with saline (PBS) on two consecutive days. All injections, blood sampling and measurements were performed under general anesthesia on days 0, 1, 3 and 8. Internal organs and knees were harvested on day 8 and the histology of the whole knees was assessed blinded. Joints treated with calcipotriol showed a milder histological synovitis than those treated with vehicle (p = 0.041), but there was no statistically significant difference between the dexamethasone and vehicle groups. The clinical severity of arthritis did not differ between the arthritis groups measured by body temperature, swelling of the knee, thermal imaging, clinical scoring or cytokine levels on days 1, 3 and 8. Weight loss was bigger in rats treated with dexamethasone, propably due to loss of appetite,compared to other arthritis groups on days 2-3 (p<0.05). Study drugs did not influence serum calcium ion and glucose levels. Taken together, this preliminary study shows that a single intra-articular injection of calcipotriol reduces histological grade of synovitis a week after the local injection, but dexamethasone did not differ from the vehicle. Calcipotriol may have an early disease-modifying effect in the rat ZIA model without obvious side effects., Competing Interests: The authors have declared that no competing interests exist.

Osteoarthritis is characterized by structural alteration of joints. Fibrosis of the synovial tissue is often detected and considered one of the main causes of joint stiffness and pain. In our earlier proteomic study, increased levels of vitronectin (VTN) fragment (amino acids 381-397) were observed in the serum of osteoarthritis patients. In this work, the affinity of this fragment for integrins and its putative role in TGF-β1 activation were investigated. A competition study determined the interaction of VTN (381-397 a.a.) with α V β 6 integrin. Subsequently, the presence of α V β 6 integrin was substantiated on primary human fibroblast-like synoviocytes (FLSs) by western blot and flow cytometry. By immunohistochemistry, β 6 was detected in synovial membranes, and its expression showed a correlation with tissue fibrosis. Moreover, β 6 expression was increased under TGF-β1 stimulation; hence, a TGF-β bioassay was applied. We observed that α V β 6 could mediate TGF-β1 bioavailability and that VTN (381-397 a.a.) could prevent TGF-β1 activation by interacting with α V β 6 in human FLSs and increased α-SMA. Finally, we analyzed serum samples from healthy controls and patients with osteoarthritis and other rheumatic diseases by nano-LC/Chip MS-MS, confirming the increased expression of VTN (381-397 a.a.) in osteoarthritis as well as in lupus erythematosus and systemic sclerosis. These findings corroborate our previous observations concerning the overexpression of VTN (381-397 a.a.) in osteoarthritis but also in other rheumatic diseases. This fragment interacts with α V β 6 integrin, a receptor whose expression is increased in FLSs from the osteoarthritic synovial membrane and that can mediate the activation of the TGF-β1 precursor in human FLSs.

BACKGROUND This retrospective study aimed to compare the roles of hand and wrist ultrasound in diagnosing subclinical synovitis in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) at a single center in Sichuan, China. MATERIAL AND METHODS Forty-one patients with SLE and 20 patients with RA were included. SLE was diagnosed using the American rheumatology Society (ACR) classification standard. Severity of SLE was evaluated using the SLE disease activity index (SLEDAI). General and clinical manifestations and laboratory indicators were measured. Spearman correlation analysis was used for analyzing correlations between musculoskeletal ultrasound results and indexes. RESULTS Among 41 patients with SLE, 26 (63.4%) had joint pain, and 39 (95.1%) had at least 1 joint abnormality. Thirteen patients with SLE (31.7%) had wrist joint involvement, 7 (17.1%) had metacarpal phalangeal-1 (MCP1) involvement, 8 (19.5%) had MCP2 involvement, 17 (41.5%) had MCP3 involvement, 14 (34.1%) had MCP4 involvement, and 5 (12.2%) had MCP5 involvement. Meanwhile, 2 (4.8%) had proximal interphalangeal-1 (PIP1) involvement, 10 (24.4%) had PIP2 involvement, 17 (41.5%) had PIP3 involvement, 12 (29.3%) had PIP4 involvement, and 3 (7.3%) had PIP4 involvement. Twelve patients demonstrated knee joint involvement. MCP joints had the highest involvement frequency (P=0.003). The most frequently detected disease was synovitis, followed by tenosynovitis, joint effusion, and bone erosion. ESR (P=0.002), CRP (P=0.020), and SLEDAI (P=0.011) of patients with SLE with arthralgia were significantly higher compared to patients without arthralgia. In patients with RA, musculoskeletal ultrasound scores were correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), disease activity score-28 (DAS28), and interleukin-6 (IL-6). In patients with SLE, musculoskeletal ultrasound scores were correlated with double-stranded DNA (dsDNA), ribonucleoprotein (RNP), DAS28, and IL-6. CONCLUSIONS Musculoskeletal ultrasound is highly sensitive in evaluating subclinical synovitis in patients with SLE, and its score is positively correlated with dsDNA, RNP IL-6, and DAS28 in patients with SLE.

To investigate synovitis' influence on early knee osteoarthritis (EKOA) by serum biomarkers and magnetic resonance imaging (MRI) findings in Japanese women. We enrolled 255 women aged 30-70 without radiographic abnormalities (Kellgren-Lawrence grade ≥ 2). Knee injury, OA outcome scores (KOOS), clinical examinations, and standing radiograph were used for classification criteria of EKOA. Participants were classified into normal knee group and EKOA group. All participants underwent MRIs of their right knee. The amount of effusion-synovitis volume was quantified. We compared serum matrix metalloproteinases-3 levels (MMP-3), high-sensitivity C-reactive protein, interleukin-6, and adiponectin between the groups. The relationship between synovitis and EOKA was investigated using multiple linear regression. Fifty-four participants (21%) were classified as EKOA. Serum MMP-3 concentration and effusion-synovitis volume were higher in patients with EKOA (p = 0.025 and p = 0.001, respectively). Effusion-synovitis volume negatively correlated with all KOOS subscales and positively correlated with serum MMP-3 concentration. Serum MMP-3 concentration was associated with effusion-synovitis volume β = 0.60, p < 0.001). There was mildly active but definitive synovitis in EKOA. This was an observational study so that no conclusions can be drawn regarding cause-effect for synovitis and symptoms. Future studies should conduct follow-up of participants with synovitis to assess the progression of knee OA.

While the use of lipopolysaccharide (LPS) to induce inflammation has been well described in the horse, the object of this study was to evaluate the effect of repeated intra-articular LPS injections and determine whether this method may be of use to assess changes in gene expression related to inflammation. Six mixed breed horses were utilized for this study, with three horses aged 10-17 years (older group) and three horses aged 3 years (younger group). One milliliter of phosphate-buffered saline containing 3 μg of LPS from Escherichia coli O111:B4 was aseptically injected into either the radiocarpal or front fetlock joint a total of four times, with at least two weeks between each injection and a different joint injected each time. Serum for protein concentration quantification and whole blood for expression analysis of 20 different genes were collected before each injection, as well as at multiple times post-injection. Statistical analysis was performed using analysis of variance (one-way and two-way) (P < 0.05). All horses experienced minimal or non-weight bearing lameness at 4-6 hours post-LPS injection, which generally improved by 24 h and resolved by 48 h. Multiple genes exhibited significantly differential expression when compared to both the pre-injection and sham injection time points, including CD14, TLR4, MMP1, MMP9, IL-1β, IL1RN, IL-10, ALOX5AP, IL-8, TNFα, CCL8, IGF1, and PTGS2. Additionally, multiple genes exhibited increased expression in horses where the radiocarpal joint was injected when compared to the fetlock joint, as well as in younger horses compared to older horses. Serum concentrations of serum amyloid A (SAA) were negative prior to injection while all horses demonstrated an increase by 9 h post-injection, which often remained until at least 144 h. Attempts to measure in vivo serum cytokine levels using a multiplex assay were not successful and believed to be due to the lower limits of detection for the assays. The measurement of mRNA expression of pro- and anti-inflammatory genes provide sensitive and rapid information regarding the inflammatory response to an acute, localized stimulus, although care must be taken when selecting target joints or age groups of horses as the transcriptional response may vary based on these choices., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose with respect to the information contained within this report., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To assess the burden of subclinical intra-articular inflammation using ultrasound in people with gout., Methods: A pilot, prospective longitudinal cohort of 28 participants with gout were examined twice, once during a gout flare (n = 25) and then during an inter-critical phase (n = 27). At each visit, a 52 joint count was done followed by ultrasound examination for detection of intra-articular power Doppler (PD) signal. Clinically active joints were defined as tender and swollen. Data was collected on patient reported gout pain - visual analog scale (VAS) (painVAS), physician global VAS (physicianVAS), Health Assessment Questionnaire (HAQ), serum uric acid, erythrocyte sedimentation rate (ESR), and high-sensitivity C-reactive protein (HsCRP)., Results: At the flare visit, participants had a median of 1 clinically active joint (interquartile range [IQR] 1-2), and a median of 5 joints with a PD score ≥ 2 (IQR 4-10, P < .001). At the inter-critical visit, participants reported an median of 0 clinically active joints (IQR 0-0), and a median of 4 joints with a PD score ≥ 2 (IQR 3-7, P < .001). Physician VAS (5.69 vs 3.40, P < .001), painVAS (6 vs 0, P < .001), HAQ (0.75 vs 0.12, P = .032), and ESR (29 vs 13.5 mm/h, P = .02) were higher at the acute visit, but HsCRP levels were similar (8.88 vs 5.15 mg/L, P = .062)., Conclusion: This pilot study established the presence of subclinical intra-articular inflammation in gout at both acute and inter-critical phases. Despite the apparent resolution of symptoms after an acute flare, a relatively high proportion of joints had subclinical inflammation in the inter-critical visit. The long-term implications of untreated subclinical joint inflammation are not clear., (© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objectives: To evaluate the performance of the European League Against Rheumatism (EULAR) definition of arthralgias suspicious for progression to RA in patients with hand arthralgias and to estimate the added value of both auto-antibodies and ultrasound (US) with power Doppler (PD)., Methods: Consecutive patients admitted for hand arthralgias to "Reuma-check" ® program were included. This program includes the following at baseline: clinical assessment, laboratory tests, US with PD of both hands, and radiography of both hands and feet. All patients were followed-up after baseline evaluation by their treating rheumatologists, and a definitive diagnosis of RA (ACR/EULAR 2010 criteria) was established or not., Results: A total of 465 consecutive patients were included. During follow-up, 44 (9.4%) were diagnosed with RA. Mean of baseline EULAR features describing arthralgia suspicious for progression to RA was 4.1 in patients with final diagnosis of RA vs 2.3 in non-RA patients (p < 0.0001). The AUC for the EULAR defined features describing arthralgia suspicious for progression to RA for the final diagnosis of RA was 0.7827, while adding US with PD, rheumatoid factor (RF), and anti-cyclic citrullinated peptide antibodies (ACPA) data, the AUC was 0.9172 (p < 0.0001). In the multivariate regression logistic analysis, baseline features associated with a final diagnosis of RA were difficulty with making a fist, RF, ACPA, and US with PD., Conclusions: EULAR definition of arthralgia suspicious for progression to RA had an acceptable performance to predict the future development of RA and improves adding information of both RF, ACPA and US with PD data.Key Points• Clinically suspect arthralgia may trigger rheumatologists to monitor patients closely for an early diagnosis.• EULAR definition of arthralgia suspicious for progression to RA predicts future development of arthritis.• Auto-antibodies and ultrasound improve EULAR definition of arthralgia suspicious for progression to RA.

Objective: Sclerostin is an osteocyte-derived glycoprotein which inhibits the canonical Wnt pathway essential for osteoblastic activity decreasing bone formation. Its potential role in rheumatoid arthritis (RA) pathogenesis was highlighted by experimental studies. Here we measured the serum sclerostin in RA patients and evaluated its relationship with disease activity and damage., Methods: One hundred RA patients and 80 age and sex-matched healthy controls were enrolled in the study. Bone biomarkers were evaluated for all participants including total calcium, phosphorus, alkaline phosphatase, 25-hydroxy vitamin D, and intact parathyroid hormone, in addition to fibroblast growth factor-23 (FGF23) and serum sclerostin. For RA patients, carotid intima-media thickness, brachial artery flow dilatation, and musculoskeletal ultrasonography using ultrasonography-7 joint score were done, and DAS28-ESR was calculated., Results: Median serum sclerostin in our patients was 186.5 ± 22.7 pg/ml which was significantly higher than in controls 60.6 ± 7.1 pg/ml (p < 0.002). Serum sclerostin showed no correlation with disease activity, bone erosions, carotid intima-media thickness, brachial flow dilatation, and the examined bone biomarkers. However, it had a strong correlation with FGF23 (r coefficient 0.988, p < 0.000)., Conclusion: Although serum sclerostin was elevated in RA patients, it could not be used as a prognostic marker for disease activity, bone erosions or atherosclerosis.Key Points• Serum sclerostin may not reflect changes in the joint microenvironment being not correlated with ultrasonography-detected synovitis or erosions.• Serum sclerostin was elevated in RA patients irrespective to their age or gender.• The positive correlation with FGF23 may provide evidence for sclerostin contribution in bone demineralization in RA patients.

Objectives: To study circulating MFAP4 in rheumatoid arthritis (RA) and its associations with clinical phenotype., Methods: Early RA (ERA): 47 patients with newly diagnosed, treatment naïve RA were included. Serum MFAP4, clinical and laboratory disease variables were recorded serially during 12 months of intensive synovitis suppressive treatment. Long-standing RA (LRA): 317 patients participated, all receiving DMARD treatment. Disease activity, autoantibody status, extra-articular manifestations and cardiovascular morbidity were recorded. Paired serum and synovial fluid samples were obtained from 13 untreated ERA patients. Healthy blood donors served as reference points. MFAP4 was quantified by AlphaLISA immunoassay. Univariate, multivariate and mixed effects regression models were applied in the statistical analysis., Results: ERA: MFAP4 increased from baseline and was significantly elevated at the 12-month follow-up, 17.8 U/l [12.6;24.1] vs. healthy controls, 12.7 U/l [9.5;15.6], p<0.001. MFAP4 did not correlate with joint counts or C-reactive protein. LRA: MFAP4 was increased, 25.9 U/l [20.4;33.7] vs. healthy controls, 17.6 U/l [13.7;21.2], p<0.0001, but did not correlate with disease activity measures or presence of extra-articular manifestations. Notably, MFAP4 correlated inversely with smoking (p<0.0001) and presence of antibodies against cyclic citrullinated peptides (anti-CCP), p=0.005. There was a positive association with systolic blood pressure, p=0.001 and co-occurrence of three cardiovascular events and/or risk factors, p<0.0001. The serum:synovial fluid MFAP4 ratio was 2:1., Conclusions: MFAP4 increases from diagnostic baseline despite intensive treatment but does not associate with synovitis at early or late stages of RA. Correlation patterns indicate that increased MFAP4 may reflect enhanced RA-related vascular remodelling.

Systemic sclerosis (SSc) is a rare connective tissue disease characterized by vascular, immune and fibrotic abnormalities in the skin and in many internal organs. New biomarkers with predictive value associated with target organ involvement are needed. The up-regulation of IL-6 production is associated with the disease activity and in the development of cardiopulmonary manifestations in SSc patients. The protein YKL-40 is a promising and intensively investigated biomarker related to inflammatory and tumor diseases. The objective of the study was to investigate how serum levels of YKL-40 and IL-6 correlate with articular and periarticular involvement in patients with SSc assessed by high-frequency ultrasonography. 59 SSc patients (56 women, 3 men) and 23 age-matched healthy subjects (21 women and 2 men) were investigated for serum YKL-40 and IL-6 (by ELISA). All the patients and healthy controls underwent clinically and high-frequency ultrasound assessment of articular and periarticular structures. Joint involvement was scored according to the new US10SSc score. Clinical data about the SSc patients showed significantly higher mRSS in the dcSSc patients (p = 0.015). Clinical synovitis was diagnosed in 16.9% of all patients: 22.5% of the dcSSc group and 10.7% of the lcSSc group (p = 0.306). On the other hand, US synovitis was detected in a higher percentage: 44% of all SSc patients; 54.8% of the dcSSc group and 32% of the lcSSc patients (p = 0.116). Clinical tenosynovitis was established in 6.7% of all patients: 9.7% of the dcSSc group and 3.5% of the lcSSc group (p = 0.614). US tenosynovitis was detected at a higher rate: 27% of all patients; 32.25% of the dcSSc group and 21.4% of the lcSSc group (p = 0.393). Serum level of YKL-40 was significantly higher in SSc patients (115.62 ng/ml ± 89.51, median 86.76) compared to the healthy controls (46.28 ng/ml ± 18.91, median 44.02), p < 0.001. IL-6 level was also significantly higher in the patient group (27.60 ± 48.80 pg/ml; median 8.32) vs. the healthy controls (5.79 ± 2.46 pg/ml, median 5.52). In the patient subgroups, YKL-40 and IL-6 levels were significantly elevated in dcSSc compared to lcSSc patients: YKL-40 dcSSc (159.52 ng/ml ± 102.81; median 136.20 ng/ml) vs. lcSSc patients (89.31 ng/ml ± 50.36; median 68.03 ng/ml;), p < 0.001; IL-6 dcSSc patients (49.64 pg/ml ± 46.37; median 16.36 pg/ml) vs. lcSSc patients (13.22 pg/ml ± 8.95; median 8.65 pg/ml), p = 0.048. A statistically significant correlation of high magnitude (r s  = 0.884, p < 0.001) was observed between YKL-40 and the ultrasound 10 Systemic sclerosis score (US10SSc) and between IL-6 and the US10SSc score (r s  = 0.808, p < 0.001). Serum YKL-40 and IL-6 in combination with US may have a potential role in defining disease activity and stratification, predicting organ involvement, and in the prognosis of SSc.

Aim: We conducted this retrospective study to identify objective and comprehensive diagnostic criteria for early-stage rheumatoid arthritis (RA) that are based on ultrasound (US) and serologic findings., Method: From August 2014 to May 2016, we recruited 216 consecutive patients at Hospital 1 and 223 consecutive patients at Hospital 2 who were suspected to have RA and underwent US of bilateral hands. In the US of bilateral hands from 22 sites, the findings obtained by grayscale and power Doppler (PD) assessments were each graded on a semi-quantitative scale from 0 to 3. We also examined the assessment of the novel outcome measures in rheumatology (OMERACT)-European League Against Rheumatism (EULAR) combined power Doppler ultrasound score (ie the cPD score) and the Global OMERACT-EULAR Synovitis Score. We used the US findings and the combination of US and serologic findings to evaluate the diagnostic performance of these modalities., Results: Seventy patients (32.4%) at Hospital 1 and 59 patients (26.5%) at Hospital 2 were diagnosed as having RA. The best-balanced diagnostic performance at each hospital was achieved using a combination, such as (1) the presence of PD grade ≥2 articular synovitis or (2) the presence of PD grade ≥1 articular synovitis and serologic positivity, as well as by using (1) the presence of cPD grade = 3 or (2) a cPD grade ≥2 and serologic positivity., Conclusion: The combination of a PD assessment or the cPD score with the measurement of autoantibodies of rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies can accurately identify patients with early-stage RA., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

A 55-year-old man with post-traumatic central cord injury, diagnosed with remitting seronegative symmetrical synovitis with pitting edema (RS3PE syndrome). The clinical picture begins with an acute pain in hands, swelling and stiffness. The physical examination revealed edema with fovea on the back of both hands, with pain and swelling in the metacarpophalangeal joints. Given this, different analytical tests and radiography of hands were requested. We started treatment with 30mg of prednisone, showing significant clinical improvement, disappearing arthritis and edema, and normalization of the analytical values. The peculiarity of presentation of RS3PE syndrome in a patient with a central cord injury is due to the difficulty of identifying it due to the superposition of clinical manifestations together with the lack of knowledge of it, being in the absence of this lesion, an easily diagnosable pathology, do not require excessive complementary tests, and with an excellent prognosis after the appropriate early treatment., (Copyright © 2018 Sociedad Española de Rehabilitación y Medicina Física. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objectives: Systemic juvenile idiopathic arthritis (sJIA) has recently become regarded as one of the autoinflammatory syndromes (AIS). However, other AIS, such as familial Mediterranean fever (FMF) and Blau syndrome, have been initially misdiagnosed as sJIA because of the clinical similarities. Making the correct diagnosis in the early stage of these AIS is desirable. Therefore, we evaluated serum S100A12 and vascular endothelial growth factor (VEGF) levels to determine if they could be biomarkers for differentiating these AIS., Method: Serum S100A12 and VEGF levels were examined in patients with Blau syndrome (n = 4), FMF (n = 4), and sJIA (n = 11) in the active and inactive phases., Results: In the active phase, S100A12 levels were significantly higher in patients with sJIA and FMF compared with those with Blau syndrome (p < 0.001). VEGF levels of patients with sJIA were significantly higher than those of patients with others (p = 0.001). In the inactive phase, there was no significant difference in VEGF levels. However, colchicine-resistant patients or patients without treatment with FMF showed high levels of S100A12 compared with others., Conclusions: Measuring both serum S100A12 and VEGF levels may be useful for differentiating patients with Blau syndrome and FMF from those with sJIA at the early stage.

Objective: This study investigates the relationship between a youth sport-related intra-articular knee injury and cartilage oligomeric matrix protein (COMP), a biomarker of cartilage turnover., Design: Participants included a sub-sample (n = 170) of the Alberta Youth Prevention of Early Osteoarthritis (PrE-OA) study group. Specifically, 85 individuals with a 3-10 year history of sport-related intra-articular knee injury and 85 age, sex and sport-matched controls. COMP levels were investigated in serum. Between group differences in COMP levels, COMP fragmentation patterns and, the relationship between serum COMP and clinical outcomes (i.e., Magnetic Resonance Imaging (MRI) Osteoarthritis Knee Score; MOAKS, Knee Osteoarthritis Outcome Score; KOOS, Fat mass index; FMI) were examined., Results: Participant median age was 22.3 years (range 16-26) and 63% were female. Although there was no difference in COMP levels between previously injured and uninjured females, previously injured males demonstrated an ∼15% greater (171.5 ng/ml, 95% CI 11.0-428.0, P = 0.04) serum COMP level than uninjured males. However after controlling for FMI, this difference was absent. Within the injured participants, COMP levels were associated with MOAKS SYNOVITIS and FMI. Furthermore, COMP fragmentation patterns were distinct between injured and uninjured individuals., Conclusions: In this study group, serum COMP levels were greater in injured males, but not females, compared to matched controls. However, after controlling for FMI, no differences in COMP were observed. A unique COMP fragmentation pattern was observed in injured vs uninjured participants. These results further the hypothesis that COMP levels and/or degradation of the protein may be a marker of cartilage injury which could predispose to later OA., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Polymyalgia rheumatica (PMR) and remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome are common inflammatory rheumatic diseases in the elderly. In this study, we investigate predictive factors which correspond to subsequent disease control of PMR and RS3PE syndrome. Twenty four patients, which contained 18 PMR and 6 RS3PE syndrome, were treated with initial dosages of 10-20 mg per day oral prednisolone, and the dosage of prednisolone was then tapered. Significantly higher initial CRP was observed in patients with poor disease control than in those with good disease control afterwards. The number of patients with negative CRP after 4 weeks was significantly more in patients with good disease control after 1 year than in those with poor disease control. Patients were shown to be in good disease control status after 1 year when CRP after 4 weeks became negative even if they had initial high CRP. Our study clarify that to make CRP negative after 4 weeks is associated with subsequent suppression of the disease activity and with decreased dosages of corticosteroids. J. Med. Invest. 66 : 112-118, February, 2019.

Objective: To assess potential associations among serum cytokines and microRNA (miR) levels with ultrasound (US) findings suggestive of urate deposits in chronic asymptomatic hyperuricemia and gout., Methods: All participants underwent musculoskeletal US and measurements of serum interleukin-1β (IL-1β), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, interferon-γ, tumor necrosis factor, monocyte chemoattractant protein 1, and epithelial neutrophil-activating peptide 78, as well as miR-146a, miR-155, and miR-223 levels., Results: Thirty individuals with asymptomatic hyperuricemia, 31 normouricemic controls, and 30 patients with gout were included. The frequency of synovitis and double contour sign using US was similar between asymptomatic hyperuricemia (67% and 27%, respectively) and patients with gout (77% and 27%, respectively), and each had a higher frequency than controls (45% and 0%, respectively). Serum IL-6 and IL-8 levels were similar between patients with asymptomatic hyperuricemia (mean ± SD 69.7 ± 73.4 and 18.5 ± 25.6 pg/ml, respectively) and gout (mean ± SD 75.8 ± 47.6 and 24.4 ± 31.7 pg/ml, respectively), and higher than controls (mean ± SD 28.2 ± 17.6 and 7.4 ± 6.0 pg/ml, respectively). A similar distribution was observed for miR-155 levels in asymptomatic hyperuricemia, patients with gout, and controls (mean ± SD 0.22 ± 0.18, 0.20 ± 0.14, and 0.08 ± 0.04, respectively). Associations between morphostructural abnormalities suggestive of urate deposits (regardless of clinical diagnosis) and serum markers were assessed. Subjects with urate deposits had higher IL-6 (257.2 versus 47.0 pg/ml; P = 0.005), IL-8 (73.2 versus 12.0 pg/ml; P = 0.026), and miR-155 (0.21 versus 0.16; P = 0.015) levels than those without deposition findings., Conclusion: In individuals with chronic asymptomatic hyperuricemia, the presence of synovitis and double contour sign by US may represent a subclinical manifestation of monosodium urate crystal nucleation, capable of triggering inflammatory pathways (IL-6 and IL-8) and mechanisms of intercellular communication (miR-155), similar to what is observed in patients with gout., (© 2018, American College of Rheumatology.)

Aim: To explore the performance of routine assessment of patient index data 3 (RAPID3) in reflecting disease activity in Chinese rheumatoid arthritis (RA) patients., Method: The clinical data of 189 consecutive RA patients, including RAPID3 questionnaire, Disease Activity Score based on 28-joint count (DAS28), clinical disease activity index (CDAI) and simplified disease activity index (SDAI), and ultrasonography of hand and wrist joints were collected. The consistency between RAPID3 and DAS28, CDAI, SDAI in RA patients with different disease activities was performed by Spearman's correlations, kappa and/or weighted kappa coefficients., Result: RAPID3 score was significantly associated with DAS28 and erythrocyte sedimentation rate (ESR), DAS28 with C-reactive protein (CRP), CDAI, SDAI (r = 0.797, 0.786, 0.784, and 0.760 respectively, P < 0.001 for all). RAPID3 was also significantly correlated with tender joint count, swollen joint count, ESR and CRP. The agreement of RAPID3 with DAS28 scoring systems was better in patients with moderate/high disease activity than those in remission/low disease activity. Ultrasonographic subclinical synovitis was presented in 42.3%-48.6% of patients in remission/low disease activity defined by various scoring criteria including RAPID3 with no significant difference observed (P = 0.22, >0.05)., Conclusion: RAPID3 showed good correlation with DAS28 scoring systems, especially in patients with moderate/high disease activity. RAPID3 is a reliable and convenient tool to monitor disease activity., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

This study aims to develop a sandwich ELISA system for the measurement of soluble folate receptor β (sFRβ) and evaluate whether base line levels of serum sFRβ are a biomarker for the activity of RA synovitis and the response to anti-TNF agents. Serum sFRβ from normal controls (41 samples), patients with OA (29 samples), and patients with RA (27 samples) and synovial fluid sFRβ from patients with RA (17 samples) were measured by sandwich ELISA, using anti-FRαβ and anti-FRβ antibodies as capture and detection antibodies, respectively. Baseline levels of serum sFRβ before therapy were evaluated in relation with DAS28-CRP or CRP and response to anti-TNF agents at 3-month follow-up. sFRβ levels in RA synovial fluids were higher than those in RA sera, and sFRβ levels in RA sera were higher than those in osteoarthritis and normal control sera. A significant relationship was observed between serum sFRβ levels and the DAS28-CRP scores or CRP values. The area under curve (AUC) values for receiver-operating characteristic curves defined using the serum sFRβ levels of RA patients before therapy had a higher predictive capacity than DAS28-CRP and CRP for the effective response of anti-TNF agents. The high serum sFRβ levels with a cutoff value of 8 ng/mL were 100% specificity for the effective response of anti-TNF agents. The findings support that the serum sFRβ levels in patients with RA act as a disease activation biomarker and that high serum sFRβ levels act as a predictive biomarker for the response to anti-TNF agents.

Background: To explore to what extent synovial hypertrophy in joints without Doppler activity is a sign of active disease, we investigated the sensitivity to change of synovial hypertrophy without Doppler activity during biological disease-modifying antirheumatic drug (bDMARD) treatment in rheumatoid arthritis (RA) patients., Method: RA patients initiating or switching bDMARD treatment had ultrasound (US) performed on 36 joints at baseline, and at 3 and 6 months. Synovial hypertrophy by grayscale US and Doppler activity were graded separately from 0 to 3 at the joint level for all time points. Changes in synovial hypertrophy in joints without Doppler activity during treatment were assessed and compared with changes in synovial hypertrophy in joints with Doppler activity., Results: We included 151 patients (82.8% women, 80.1% seropositive for anticyclic citrullinated peptide) with a mean ± standard deviation age of 51.4 ± 13.2 years, a disease duration of 9.9 ± 7.9 years, and baseline Disease Activity Score 28-joint count C-reactive peptide (DAS28-CRP) of 4.14 ± 1.32. At baseline, 44.8% of all joints examined (n = 5225) had synovial hypertrophy ≥ 1 and 50.7% of these had synovial hypertrophy without Doppler activity. The improvement in synovial hypertrophy was similar in joints with and without Doppler activity but, when adjusting for the baseline score of synovial hypertrophy, joints with synovial hypertrophy without Doppler had a higher tendency towards a decrease than joints with synovial hypertrophy with Doppler activity independent of grade (3 months: p < 0.0001; 6 months: p = 0.0003)., Conclusion: Joints with synovial hypertrophy without Doppler activity improve during treatment, independent of the grade. Thus, SH without Doppler activity is not a sign of inactive disease. These findings indicate that joints with synovial hypertrophy without Doppler activity should also be taken in to account when assessing disease activity by US.

Objectives: To determine the relationship between synovitis detected on non-contrast-enhanced (non-CE) magnetic resonance imaging (MRI), biochemical markers of inflammation, and clinical assessment of effusion in people with knee osteoarthritis (OA)., Method: We examined data from the OA Biomarkers Consortium within the Osteoarthritis Initiative (n = 600). Non-CE MRIs were semi-quantitatively scored (grades 0-3) for severity of Hoffa synovitis and effusion synovitis. Serum (s) matrix metalloproteinase-3 (sMMP-3), hyaluronic acid (sHA), and nitrated epitope of the α-helical region of type II collagen (sColl2-1NO2) were quantified. The bulge and patellar tap clinical tests were performed at baseline and performance characteristics were assessed for the detection of effusion synovitis on MRI. Multinomial logistic regression adjusted for covariates was used to assess the association between biochemical and imaging markers at baseline and over 12 and 24 months., Results: At baseline, sHA and sMMP-3 were associated with moderate to large (score ≥ 2, n = 117) effusion synovitis, with odds ratio = 1.35 and 1.30 per 1 standard deviation in biochemical markers (95% confidence intervals 1.07, 1.71 and 1.00, 1.69), c-statistics 0.640 and 0.626, respectively. The c-statistics for the presence of Hoffa synovitis (score ≥ 2) were 0.693, 0.694, and 0.694 for sHA, sMMP-3, and sColl2-1NO2, respectively. There was no significant association between biochemical markers (baseline and 12 and 24 month time-integrated concentrations) and changes in MRI markers. The bulge and patellar tap signs were 22.0% and 4.3% sensitive and 88.8% and 94.8% specific, respectively, for detecting effusion synovitis (score ≥ 1) on MRI., Conclusions: sHA and sMMP-3 were modestly associated with effusion synovitis at baseline. Clinical signs of effusion are insensitive but highly specific for the presence of any effusion synovitis on non-CE MRI.

Objectives The objective of this paper is to perform an ultrasonography (US) analysis of hands and wrists in two groups of patients with systemic lupus erythematosus (SLE), with and without Jaccoud's arthropathy, matched by age and disease duration and to correlate them with levels of CXCL13 clinical features, laboratory tests and disease activity score. Methods Sixty-four patients with SLE were enrolled, 32 with and 32 without Jaccoud's arthropathy. Each patient underwent physical examination, laboratory tests (including CXCL13 by ELISA) and bilateral US. Synovial hypertrophy, tenosynovitis and erosions were evaluated according to a semiquantitative grading system with a 0-3 rating. US findings were correlated with serum levels of CXCL13, other serological parameters and disease activity index. Results Synovitis was found in 25/64 patients (39%) and tenosynovitis in 14/64 (22%). These findings were more frequent in SLE patients with Jaccoud's arthropathy, particularly tenosynovitis ( p = 0.002) and synovitis ( p = 0.01). Median serum level of CXCL13 was 20.16 pg/ml in the whole population (23.21 pg/ml in the Jaccoud's arthropathy group and 11.48 pg/ml in the group without). There was an association between the presence of disease activity and high level of CXCL13 ( p = 0.004). However, no association was found between high levels of CXCL13 and "arthritis" in SLEDAI, swollen joints on physical examination or synovitis on US. Conclusions US findings in joints of SLE patients with Jaccoud's arthropathy confirm that synovitis and tenosynovitis are common in these patients. In addition, serum level of CXCL13 is associated with disease activity in SLE but does not seem to be a biomarker for arthritis in these patients.

Background: Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare syndrome characterized by "remitting," "seronegative" (namely rheumatoid factor-negative), and "symmetrical" synovitis with pitting edema on the dorsum of the hands and feet. Recently, there have been reports that serum vascular endothelial growth factor (VEGF) is elevated in this condition., Case Presentation: An 85-year-old man visited our department with a rash that had appeared 2 days earlier and a fever that had developed on the day of his visit. Based on clinical findings of fever, erythema exudativum multiforme, transitory hypotension, conjunctiva hyperemia, elevated creatine kinase, and desquamation, we suspected toxic shock syndrome (TSS). Therefore, we started treatment with vancomycin (1 g/day) and clindamycin (600 mg/day), after which his fever rapidly remitted. However, pitting edema on the dorsum of his hands and feet appeared on day 7, and the patient also had painful wrist and ankle joints. Additional tests were negative for rheumatoid factor, and anti-cyclic citrullinated protein antibodies were < 0.2 U/mL. Further, serum matrix metalloproteinase-3 (199.6 ng/mL; reference value ≤123.8 ng/mL) and serum VEGF (191 pg/mL; reference value ≤38.3 pg/mL) levels were elevated, and human leukocyte antigen-A2 was detected. The patient was thus diagnosed with RS3PE syndrome, for which he satisfied all four diagnostic criteria: 1) pitting edema in the limbs, 2) acute onset, 3) age ≥ 50 years, and 4) rheumatoid factor negativity. He was treated with oral prednisolone, resulting in the normalization of his serum VEGF level to 34.5 pg/mL 1 month after starting treatment. It is currently 1 year since disease onset, and although the patient has stopped taking prednisolone, there has been no recurrence of RS3PE syndrome., Conclusions: To the best of our knowledge, this is the first reported case of a patient developing RS3PE syndrome during the clinical course of TSS. We propose that the onset mechanism involved an increase in blood VEGF due to TSS, which induced RS3PE syndrome. As serum VEGF becomes elevated with both severe infections associated with shock and RS3PE syndrome, awareness that these conditions can occur concurrently is essential.

Objective: Monocytes contribute to synovitis and disease pathogenesis in osteoarthritis (OA). Low-grade inflammation occurs in OA and correlates with disease severity and progression. Since monocyte development and function is altered by systemic inflammation, we analyzed monocyte numbers and function between individuals with knee OA and healthy age- and sex-matched controls., Design: We analyzed markers of soluble and cellular inflammation in peripheral blood of women with knee OA and compared them to healthy age- and sex-matched controls. Soluble inflammatory mediators (TNF, IL-6, IL-10 and CRP) in the serum were measured by high-sensitivity ELISA. Leukocyte numbers, surface expression of monocyte activation markers, and monocyte production of pro-inflammatory mediators (TNF and IL-1β) following stimulation were measured by flow cytometry., Results: Women with knee OA (n = 15) had elevated levels of serum c-reactive protein (CRP) and a lower proportion of circulating monocytes. Monocytes from OA participants had elevated expression of the activation markers CD16, CCR2, and HLA-DR and induced greater production of tumor necrosis factor (TNF) and IL-1β compared to healthy controls. Higher serum TNF and BMI were correlated with increased monocyte expression of CCR2. Additionally monocyte CCR2 expression and serum TNF were correlated with worse pain on a validated questionnaire., Conclusions: Our findings suggest monocytes are activated prior to their entry into the synovium. Modulating systemic inflammation and monocyte recruitment to the synovium could be of therapeutic benefit., (Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine clinical and sonographic biomarkers predicting structural damage progression at 12 months of follow-up as measured by magnetic resonance imaging (MRI) in rheumatoid arthritis (RA) patients in clinical remission., Patients and Methods: We included patients with RA in clinical remission, defined as 28-joint disease activity score (DAS28)-erythrocyte sedimentation rate (ESR) <2.6 for >6 months. Ultrasound scans of both hands and knees and MRI of the dominant hand were performed at baseline and at 12 months., Results: Out of 55 patients, 42 completed the follow-up. Among them, 78% were female, aged (median) 54 years; disease duration was 93 months. In total, 12 (28%) patients were taking oral prednisone, 34 (81%) conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and 20 (47%) biological therapies. At baseline, 45% fulfilled criteria previously defined for ultrasound-defined active synovitis (UdAS) [PD (power Doppler) signal + synovial hyperplasia ≥2]. Multivariate analysis showed significant associations between baseline MRI erosion score, body mass index (BMI), disease duration, prednisone treatment, absence of biologic and csDMARDs, UdAS, and MRI erosion score progression after 12 months. In an exploratory analysis, serum levels of calprotectin correlated significantly with bone edema progression., Conclusions: We identified clinical and sonographic markers of structural damage progression after 12 months follow-up in patients with RA in clinical remission. Meeting the criteria of ultrasound active synovitis, defined as simultaneous relevant synovial hyperplasia and PD, was associated with erosion progression after 12 months. Calprotectin was associated with bone edema, in an exploratory analysis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Obesity has been proposed as a risk factor for refractory rheumatoid arthritis (RA). We evaluated the impact of obesity on achieving clinical and imaging definitions of low disease activity., Methods: This study evaluated 470 patients with RA from GO-BEFORE and GO-FORWARD randomised clinical trials. Included patients had blinded clinical disease activity measures and MRI at baseline, 24 and 52 weeks. Synovitis, osteitis and total inflammation scores were determined using the RA MRI scoring system. Multivariable logistic regression analyses compared odds of achieving Disease Activity Score using 28 joints and C-reactive protein (DAS28-CRP) remission, low component measures, or low MRI inflammation measures at 24 weeks in patients with obesity versus no obesity., Results: At 24 weeks, patients with obesity were significantly less likely to achieve DAS28(CRP) remission (OR 0.47; 95% CI 0.24 to 0.92, p=0.03). In contrast, patients with obesity had similar odds of achieving low synovitis (OR 0.94; 95% CI 0.51 to 1.72, p=0.84) and inflammation scores (OR 1.16; 95% CI 0.61 to 2.22, p=0.64) and greater odds of achieving low osteitis scores (OR 2.06; 95% CI 1.10 to 3.84, p=0.02) versus normal weight patients., Conclusions: Patients with RA and obesity have lower rates of DAS28 remission but similar rates of low MRI activity compared with patients without obesity, suggesting that obesity and its associated comorbidities can bias clinical disease activity measures., Trial Registration Number: NCT00361335 and NCT00264550; Post-results., Competing Interests: Competing interests: PGC has done speakers bureaus or consultancies for AbbVie, BMS, Janssen, Lilly, Novartis, Pfizer and Roche. PE has received consulting fees, speaking fees and/or honoraria from Pfizer, Merck, AbbVie, UCB, Roche, BMS, Lilly and Novartis (less than US$10,000 each). DGB is an employee of Janssen Biotech. M Østergaard has received fees for consultancy or speaker fees and/or research support from Abbott, AbbVie, BMS, Boehringer-Ingelheim, Celgene, Centocor, Eli-Lilly, GlaxoSmithKline, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Sanofi, Schering-Plough, Roche, UCB, Takeda and Wyeth., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: To examine whether MRI assessed inflammation and damage in the wrist of patients with early rheumatoid arthritis (RA) are associated with patient-reported outcomes (PROs)., Methods: Wrist and hand MRIs of 210 patients with early RA from two investigator-initiated, randomised controlled studies (CIMESTRA/OPERA) were assessed according to the Outcome Measures in Rheumatology RA MRI score (RAMRIS) for synovitis, tenosynovitis, osteitis, bone erosions and joint space narrowing (JSN) at baseline, 1 and 5 years follow-up. These features, and changes therein, were assessed for associations with health assessment questionnaires (HAQ), patient global visual analogue scales (VAS-PtGlobal) and VAS-pain using Spearman's correlations, generalised estimating equations and univariate/multivariable linear regression analyses. MRI features were further tested for trends against specific hand-related HAQ items using Jonckheere trend tests., Results: MRI inflammation, but not damage, showed statistically significant associations with HAQ, VAS-PtGlobal and VAS-pain for status and change scores, independently of C reactive protein and swollen joint count. MRI-assessed synovitis was most consistently associated with PROs, particularly VAS-PtGlobal and VAS-pain. MRI-assessed synovitis and tenosynovitis mean scores were positively associated with patient-reported difficulty to cut meat and open a milk carton (p<0.01), and similar patterns were seen for other hand-related HAQ items. Incorporating metacarpophalangeal joints in the analyses did not strengthen the associations between MRI pathology and PROs., Conclusions: MRI-assessed inflammation, but not damage, in early RA wrists is associated with patient-reported physical impairment, global assessment of disease activity and pain and influences the physical function in the hand., Trial Registration Number: NCT00660647., Competing Interests: Competing interests: MLH: research support and grants from: BMS, AbbVie, Pfizer, UCB-Nordic, MSD and Biogen; consultation fees from: Orion, KH-P: consultation fees from: AbbVie and UCB, MBA: research support and grants from: AbbVie, MØ: consultation fees from: AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB, Wyeth; research support and grants from: AbbVie, BMS, Janssen and Merck., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background & Objectives: It has been shown that joint damage due to subclinical synovitis progresses despite apparent clinical remission in rheumatoid arthritis (RA). Hence, finding more objective methods to investigate subclinical synovitis has become a current issue. Ultrasonography (US) has been among the most investigated methods. This study was conducted to detect whether there was subclinical inflammation in RA patients in clinical remission by power Doppler ultrasonography (PDUS) and to evaluate the effects of this inflammation on upper extremity function., Methods: Forty five RA patients fulfilled the remission criteria of disease activity score 28 using erythrocyte sedimentation rate (DAS28-ESR), were enrolled in the study. Bilateral wrist, 2nd and 3th metacarpophalangeal and proximal interphalangeal joints and 2nd and 5th metatarsophalangeal joints were examined by PDUS. Upper extremity function was assessed with Michigan Hand Outcomes Questionnaire (MHQ) and handgrip strength. The pain was evaluated by visual analogue scale (VAS)., Results: In 29 of 45 RA patients in clinical remission, synovitis was detected by PDUS at least in one joint. VAS and DAS28-ESR scores were significantly lower and total MHQ, some subgroup scores of MHQ (overall hand function, activity of daily living and work performance) and grip strength of the dominant hand were higher in patients with PD signal negativity., Interpretation & Conclusions: PDUS showed a crucial role in determining the subclinical synovitis. Subclinical synovitis negatively affects the upper extremity function. Ultrasound-defined remission may be considered for good functional status and real remission in patients with RA.

Objective: To evaluate by ultrasonography the effect of chondroitin sulfate (CS) on synovitis in patients with knee osteoarthritis (KOA). To collaborate in the understanding of the biochemical mechanisms involved in the synovial inflammation process., Methods: Randomized, single-blind, controlled trial involving 70 patients with primary KOA treated for 6 months with CS or acetaminophen (ACT). Evaluation of KOA status at baseline, 6 weeks, 3 and 6 months included: ultrasonography to assess synovitis (following the OMERACT expertise group definition), visual analogue scale and Lequesne index to measure pain and function, and ELISA to quantify inflammatory mediators in serum and synovial fluid., Results: Synovitis presence was reduced by 50% in the CS group while a 123% increase was observed in ACT group. Conversely, patients without initial synovitis and treated with ACT reached 85.71% synovitis onset, but only 25% in CS group. Both therapies improved articular function, but only CS resulted in significant pain improvement at the end of the treatment. Changes in RANTES and UCN synovial fluid concentration were associated with CS treatment., Conclusions: Treatment with CS had a sustained beneficial effect, preventing synovitis onset or reducing its presence as well as reducing KOA symptoms. ACT ameliorated clinical symptoms but had no effect on inflammation. The CS anti-inflammatory effect could be related to the observed changes in RANTES and UCN concentration., (Copyright © 2017 Elsevier España, S.L.U. All rights reserved.)

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare condition in the elderly and can appear as a first presentation of various types of rheumatic and malignant diseases. We presented a 62-year-old man with the diagnosis of RS3PE based on the clinical sign and laboratory data. Because of the possibility of associated malignancies in RS3PE, FDG PET/CT was performed to exclude occult tumors. The images showed multiple, symmetrically, diffusely increased F-FDG uptake in the soft tissue around joints and bones in the shoulders, hips, knees, and ankles.

Background: Undifferentiated arthritis (UA) is a label applied to patients with joint complaints which cannot be classified according to current criteria, which implies a need for precision diagnostic technologies. We studied serum galectin-3, a proinflammatory mediator, and seromarkers of structural joint elements in patients with early, UA and their associations with disease profile and biochemical and imaging findings., Methods: One hundred and eleven UA patients were followed-up for at least 12 months and reclassified according to appropriate criteria (TUDAR). At baseline, demographics and laboratory and clinical disease measures, as well as wrist magnetic resonance imaging (MRI) synovitis, erosion, and bone marrow edema scorings, were recorded. Galectin-3, the type IIA collagen N-terminal propeptide (PIIANP), which is a marker of regenerative cartilage formation, and hyaluronan (HYA), which is prevalent in synovial tissue swellings, were measured by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curve analysis was carried out to assess the discriminant capacity of galectin-3 against arthritis subsets., Results: Galectin-3 was increased in pre-rheumatoid arthritis (RA) (4.6 μg/l, interquartile range (IQR) 3.8-5.5) versus non-RA (4.0 μg/l, IQR 3.1-4.9; p = 0.03) and controls (3.8 μg/l, IQR 3.0-4.8; p = 0.009). PIIANP was equally depressed in either subset (p < 0.01). Galectin-3 in non-RA and HYA in UA did not differ from healthy controls. In the entire UA cohort, galectin-3 correlated with the MRI bone marrow edema score, while PIIANP correlated with the MRI erosion score, and HYA with the synovitis and erosion scores. ROC curve analysis showed that baseline galectin-3 discriminated well between pre-RA and non-RA with univariate area under the curve (AUC) of 0.64 (95% confidence interval (CI) 0.53-0.76) while AUC for galectin-3 + anti-CCP increased to 0.71 (95% CI 0.59-0.83)., Conclusions: Galectin-3 in serum was increased in patients with early UA of pre-RA origin. Cartilage remodeling assessed by PIIANP was diminished in UA irrespective of subsequent clinical differentiation, while HYA did not differ from controls. ROC analysis showed a potential for galectin-3 to discriminate between pre-RA and non-RA., Trial Registration: KF 11 315829. Registered 25 July 2006.

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome mainly affects elderly men and responds well to steroids. Since this syndrome can resemble other diseases, its diagnosis is a significant challenge. Through the following paper, we hope to improve the diagnosis of RS3PE by presenting a table comparing RS3PE to two other common polyarthritic conditions affecting the elderly., (© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

No studies have yet reported the influence of swelling in individual joints on serum C-reactive protein and erythrocyte sedimentation rate. To examine this association, we used data from the NinJa registry, the largest registry of rheumatoid arthritis patients in Japan. Sixty-six palpable joints were categorized by size into three groups (small, medium-sized, and knees) with surface area cutoffs of 10 and 100 cm 2 . Of 10,720 cases registered in NinJa in 2012, 8444 cases with either no swollen joints or swelling limited to one joint-size category were analyzed. Groups with larger numbers of swollen joints showed higher levels of both markers in each joint-size category. Groups with larger swollen joints had higher levels of both markers compared with groups with the same number of (smaller) swollen joints. Linear regression revealed that the increments of C-reactive protein (mg/dL/joint) and erythrocyte sedimentation rate (mm/1 h/joint) were 0.056 and 0.89, 0.24 and 5.0, and 0.46 and 8.9 for small and medium-sized joints and knee joints, respectively. The levels of systemic inflammation markers increased with the involvement of larger and/or more joints. These results were successfully illustrated by the use of large-scale data, which eliminated wide intragroup scattering of the marker values.

Background: Calprotectin (S100A8/A9 or MRP8/14) and S100A12 (leukocyte-derived proteins), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) are markers of inflammation and angiogenesis. Ultrasound (US) is sensitive for detection of greyscale synovitis and power Doppler (PD) vascularization. The objective of the present study was to explore the associations between calprotectin, S100A12, IL-6, VEGF, erythrocyte sedimentation rate, C-reactive protein and a comprehensive US assessment in patients with rheumatoid arthritis (RA) starting biologic disease-modifying anti-rheumatic drug (bDMARD) treatment., Methods: A total of 141 patients with RA were assessed by US, clinical examination and biomarker levels at baseline and at 1, 2, 3, 6 and 12 months after initiation of bDMARDs. US assessment of 36 joints and 4 tendon sheaths were scored semi-quantitatively (0-3 scale). European League Against Rheumatism (EULAR) response was calculated. Statistical assessments performed to explore the associations between biomarkers and US sum scores included Spearman's rank correlation analysis as well as linear and linear mixed model regression analyses., Results: Calprotectin showed the overall strongest correlations with both US sum scores (r s  = 0.25-0.62) and swollen joint counts (of 32) (r s  = 0.24-0.47) (p < 0.05 at all examinations). An association with US sum scores remained after we adjusted for age, sex, disease duration and all the other markers in a regression analysis at baseline. Decreased calprotectin at the first month was predictive of both EULAR response (p ≤ 0.001) and decreased sum PD scores at 3, 6 and 12 months (p ≤ 0.05)., Conclusions: Calprotectin had the highest association with US synovitis and predicted treatment response. It may thus be considered as a marker for evaluating inflammation and responsiveness in patients with RA on bDMARD treatment., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) identifier: ACTRN12610000284066 . Registered on 8 April 2010 (retrospectively registered).

Objective: We investigated clinical outcomes in patients with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome., Methods: This is a retrospective multicenter study conducted in Nagasaki, Japan. We consecutively diagnosed a total of 41 patients with RS3PE syndrome between October 2003 and September 2012 and evaluated their outcomes from medical records from the first year of follow-up., Results: Although an excellent initial response to corticosteroids was noted in all 41 patients, 34 (82.9%) were still receiving corticosteroids and 13 (31.7%) showed elevated C-reactive protein (CRP) at one year. Multivariate analysis demonstrated that male gender and high CRP level at entry were independent variables associated with patients' one-year CRP level being ≥0.5 mg/dL. Odds ratios were 17.05 ([95% CI 2.41-370.12], p < 0.026) and 12.99 ([95% CI 1.78-269.62], p < 0.0096), respectively. Twenty-four patients (58.5%) were still receiving prednisolone (PSL) ≥ 5 mg/day at one year. Disease-modifying anti-rheumatic drugs including methotrexate were required in three patients (10.3%). Neoplasms were found in 14 patients (34.1%) and 1 of these had died due to lung cancer at one year., Conclusions: RS3PE syndrome initially responds well to corticosteroids with remission of symptoms. However, outcomes of RS3PE syndrome appear to be worse than expected, and may be influenced by gender and initial CRP level.

Objectives: To determine which grade of ultrasound (US) synovitis corresponds to clinically involved joints in rheumatoid arthritis (RA) and develops a new US-adjusted composite measure., Methods: Clinical and US examinations were performed on 137 patients with RA (28 joints). Synovial effusion, hypertrophy, and blood flow were semiquantitatively graded from 0 to 3 using gray scale (GS) and power Doppler (PD) modes. We calculated US-adjusted simple disease activity index (SDAI) and assessed feasibility, and external validity by comparing with erythrocyte sedimentation rate (ESR), and modified health assessment questionnaires (MHAQ)., Results: GS ≥2 and PD ≥0 corresponds to clinically swollen joints, and GS ≥2 and PD ≥1 corresponds to tender joints. The US-adjusted SDAI showed the highest correlation when US-determined swollen joints were defined as PD ≥2 with ESR, and GS ≥3 and PD ≥2 with MHAQ. A feasible US-adjusted SDAI examining only clinically involved joints still showed a higher correlation with ESR and MHAQ than SDAI., Conclusion: Our composite measure complemented by US only for clinically involved joints is feasible and reliable for monitoring disease activity.

Objectives: Anticitrullinated protein antibody (ACPA)+ individuals with non-specific musculoskeletal symptoms are at risk of inflammatory arthritis (IA). This study aims to demonstrate the predictive value of T cell subset quantification for progression towards IA and compare it with previously identified clinical predictors of progression., Methods: 103 ACPA+ individuals without clinical synovitis were observed 3-monthly for 12 months and then as clinically indicated. The end point was the development of IA. Naïve, regulatory T cells (Treg) and inflammation related cells (IRCs) were quantified by flow cytometry. Areas under the ROC curve (AUC) were calculated. Adjusted logistic regressions and Cox proportional hazards models for time to progression to IA were constructed., Results: Compared with healthy controls (age adjusted where appropriate), ACPA+ individuals demonstrated reduced naïve (22.1% of subjects) and Treg (35.8%) frequencies and elevated IRC (29.5%). Of the 103 subjects, 48(46.6%) progressed. Individually, T cell subsets were weakly predictive (AUC between 0.63 and 0.66), although the presence of 2 T cell abnormalities had high specificity. Three models were compared: model-1 used T cell subsets only, model-2 used previously published clinical parameters, model-3 combined clinical data and T cell data. Model-3 performed the best (AUC 0.79 (95% CI 0.70 to 0.89)) compared with model-1 (0.75 (0.65 to 0.86)) and particularly with model-2 (0.62 (0.54 to 0.76)) demonstrating the added value of T cell subsets. Time to progression differed significantly between high-risk, moderate-risk and low-risk groups from model-3 (p=0.001, median 15.4 months, 25.8 months and 63.4 months, respectively)., Conclusions: T cell subset dysregulation in ACPA+ individuals predates the onset of IA, predicts the risk and faster progression to IA, with added value over previously published clinical predictors of progression., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Synovitis is a frequent condition in knee osteoarthritis (KOA) and has been associated with pain. This study investigated the links between the pressure hyperalgesia, the clinical pain, the degree of the synovitis, inflammatory biomarkers, and tissue-specific biomarkers in KOA patients., Materials and Methods: Fifty-eight KOA patients and 33 pain-free controls participated in this study. The patients were magnetic resonance imaging scanned, and the Boston-Leeds OA Knee Score (BLOKS, 0 to 3) was used to assess the degree of synovitis. The maximal knee pain intensity over the last 24 hours was scored on a visual analog scale (VAS). The pressure pain thresholds (PPTs) were assessed over the KOA-affected knee. Serological biomarkers were measured in fasting serum: high-sensitive C-reactive protein, matrix metalloproteinase-mediated degradation of CRP, and matrix metalloproteinase-mediated collagen type I, II, and III degradation (C1M [connective tissue], C2M [cartilage], C3M [synovial membrane])., Results: Compared with controls, the KOA patients showed increased levels of C1M (P<0.02), C2M (P<0.001), and high-sensitive C-reactive protein (P<0.02), decreased level of C3M (P<0.03), and reduced PPTs (P<0.03). Patients with no (BLOKS 0) and moderate to severe (BLOKS 2&3) synovitis had significantly lower PPTs compared with mild synovitis (BLOKS 1). Significantly negative correlations were found between VAS and PPTs. No correlations were found between BLOKS and the VAS, PPT, or biomarkers., Discussion: Patients without and with moderate to severe synovitis demonstrated local pressure hyperalgesia and increased degrees of: (1) systemic inflammation, (2) connective tissue degradation, (3) cartilage degradation, and (4) decreased synovial membrane degradation as compared with controls.

Aim: We studied the usefulness of magnetic resonance imaging (MRI) in detecting subclinical inflammation in patients with asymptomatic RA and tested the hypothesis of interleukin (IL)-18 as a marker of disease activity., Methods: Thirteen RA patients with Disease Activity Score of 28 joints (DAS28) < 2.6 were evaluated. The patients underwent clinical evaluation, laboratory tests and MRI assessment. Imaging of bilateral hands and wrists was performed using validated acquisition and scoring techniques. Serum IL-18 levels were concurrently measured., Results: MRI assessments showed that 92.3% and 76.9% of patients had synovitis and bone marrow edema, respectively, despite being in clinical remission. Eight out of 12 patients (66.7%) had erosions on MRI which were not visualised on plain radiographs. Of all the 182 joints studied for synovitis on MRI, only one had clinical evidence of joint swelling. Comparison of the total sum scores of synovitis between the right and left hand and wrist joints of individual patients showed a significant difference between the two sides. Measurements of IL-18 indicated that a large proportion (54%) of the patients had undetectable or very low levels of the cytokine., Conclusion: MRI is more sensitive in detecting erosions compared with X-rays, and is superior in its ability to detect subclinical inflammation in RA patients. Despite being in clinical remission, a large majority of patients had imaging-detected synovitis and bone marrow edema. Our study highlights the usefulness of MRI for the accurate evaluation of disease activity. In the utility of MRI, it may be important to assess bilateral hands and wrists, instead of limiting to the dominant side., (© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Background: Serum levels of calprotectin, a major S100 leucocyte protein, are associated with disease activity in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients. Higher drug trough serum levels are associated with good response in patients treated with tumour necrosis factor inhibitors (TNFi). Power Doppler ultrasound (PDUS) synovitis is predictive of flare and progression of structural damage in patients in clinical remission. The purpose of this study was to analyse the accuracy of calprotectin and TNFi trough serum levels in detecting PDUS synovitis in RA and PsA patients in clinical remission or with low disease activity who were receiving TNFi., Methods: We conducted a cross-sectional study of 92 patients (42 with RA, 50 with PsA) receiving adalimumab (ADA), etanercept (ETN) or infliximab who were in remission or had low disease activity (28-joint Disease Activity Score based on erythrocyte sedimentation rate <3.2). Associations of calprotectin, TNFi trough serum levels and acute phase reactants with PDUS synovitis were assessed using correlation and linear regression analyses. The accuracy and discriminatory capacity in detecting PDUS synovitis was assessed using ROC curves., Results: PDUS synovitis was found in 62.4 % of RA patients and 32 % of PsA patients. Both RA and PsA patients with PDUS synovitis had higher calprotectin levels and lower TNFi trough serum levels. Calprotectin positively correlated with ultrasound scores (all r coefficients >0.50 in RA). Calprotectin correlated with the PDUS synovitis score in patients treated with ADA and ETN. Using PDUS synovitis (yes or no) as the reference variable, calprotectin had an AUC of 0.826. The best cut-off was ≥1.66 μg/ml, with a likelihood ratio of 2.77. C-reactive protein (AUC 0.673) and erythrocyte sedimentation rate (AUC 0.731) had a lower discriminatory capacity. TNFi trough serum levels were significantly associated with PDUS synovitis (OR 0.67, 95 % CI 0.52-0.85, p < 0.001) but their accuracy (AUC <0.5) was less than that of calprotectin. TNFi trough serum levels were inversely correlated with calprotectin and PDUS synovitis in RA and PsA patients receiving ADA and ETN., Conclusions: Calprotectin and TNFi trough serum levels may help identify PDUS synovitis in RA and PsA patients in clinical remission or with low disease activity.

Objectives: Treat-to-target strategy, aiming at clinical remission, has greatly improved the prognosis of RA. However, ultrasonographic subclinical synovitis is correlated with bone erosion and disease flare. The aim of this study was to evaluate whether deeper clinical remission (DAS28(ESR)≤1.98) reflects the better control of subclinical synovitis., Methods: One hundred and twenty-six RA patients in clinical remission were enrolled in the study. Disease activity and ultrasongraphy were evaluated at baseline, and every 3 months during a 12-month follow-up. The power Doppler (PD) synovitis and synovial hypertrophy (SH) of 22 joints were recorded semi-quantitatively. The relationship between the extent of clinical remission, flare and ultrasonographic features was analysed., Results: In 126 RA patients, 76 achieved deep clinical remission (defined as DAS28(ESR)≤1.98) and 50 achieved mild clinical remission (defined as 1.98

Objectives: The objective of this study is to investigate whether ultrasonography (US) images of joints that underwent surgery reflected the synovial histological findings or clinical indicators and to compare the results of the findings related to large joints (LJs) with those of small joints (SJs)., Methods: The operations were performed on 215 joints in 177 patients with rheumatoid arthritis (RA). The 215 joints included 64 LJs and 151 SJs. The joints with the power Doppler (PD) signal grades 0 and 1 were assigned to group L, while those with grades 2 and 3 were assigned to group H. The Rooney score, Disease Activity Score-erythrocyte sedimentation rate (DAS28), serum matrix metallopeptidase 3 (MMP-3), and C-reactive protein (CRP) levels were determined., Results: The Rooney score, DAS28, MMP-3, and CRP levels of the LJs were significantly lower in group L than in group H. In group H, similar results were found in the LJs and SJs, with a significant increase in the disease activity, CRP and MMP-3 levels and the histological findings in comparison to group L., Conclusions: The PD signal grade was one of the indicators that reflected the degree of synovitis in the histological findings of the active joints of RA patients.

Background and Objective: Cytokines have an important role in the pathogenesis of rheumatoid arthritis (RA). Although plasma levels of IL-6 have been related to musculoskeletal ultrasound (MSUS) synovitis in early DMARD-naïve RA, there are no similar studies in established disease., Methods: 64 RA patients treated with non-biological DMARDs and 30 healthy controls were included in this prospective cross-sectional study. A blood sample was taken before evaluation of disease activity (DAS28) and ultrasonography (all tests performed in a blinded fashion). MSUS was performed by one of two ultrasound-trained rheumatologists on 10 joints of both hands. Gray scale (GS) and pD (power Doppler) synovitis were evaluated using a semi-quantitative scale (0-3) in individual joints, and their sum (score 10) was calculated. Plasma cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF, IFN-γ, and VEGF) were quantified by flow cytometry., Results: Levels of all cytokines, excepting VEGF, were significantly higher in RA patients than in controls (P⩽0.05). In RA patients, IL-6, but not other cytokines, correlated positively with DAS28 and swollen joint count (P⩽0.01), as well as with 10-joint pD score, and GS and pD of both wrists (P<0.01 for all tests). In multiple linear regression, the association of IL-6 with 10-joint pD score was maintained even after adjustment for DAS28. However, there was no correlation of IL-6 with tender joint count, 10-joint GS score, or presence of erosions., Conclusion: We demonstrated an association of inflammatory findings on MSUS and plasma IL-6 independently of DAS28 in established RA., (Copyright © 2016 Elsevier Ltd. All rights reserved.)