Auto-antibodies to post-translationally modified proteins in osteoarthritis.

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.

Increased serum levels of microfibrillar-associated protein 4 (MFAP4) are not associated with clinical synovitis in rheumatoid arthritis but may reflect underlying cardiovascular comorbidity.

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.

Comparison of Role of Hand and Wrist Ultrasound in Diagnosis of Subclinical Synovitis in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis: A Retrospective, Single-Center Study.

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.

Serum cartilage oligomeric matrix protein (COMP) expression in individuals who sustained a youth sport-related intra-articular knee injury 3-10 years previously and uninjured matched controls.

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 MOAKSSYNOVITIS 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.

Serum YKL-40 and IL-6 levels correlate with ultrasound findings of articular and periarticular involvement in patients with systemic sclerosis.

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 (rs = 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 (rs = 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.

Monocyte activation is elevated in women with knee-osteoarthritis and associated with inflammation, BMI and pain.

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-1ß) 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-1ß 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.

Association of CXCL13 serum level and ultrasonographic findings of joints in patients with systemic lupus erythematosus and Jaccoud's arthropathy.

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.

Is synovitis detected on non-contrast-enhanced magnetic resonance imaging associated with serum biomarkers and clinical signs of effusion? Data from the Osteoarthritis Initiative.

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.

RS3PE syndrome developing during the course of probable toxic shock syndrome: a case report.

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.

Obesity and rates of clinical remission and low MRI inflammation in rheumatoid arthritis.

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.

Magnetic resonance imaging assessed inflammation in the wrist is associated with patient-reported physical impairment, global assessment of disease activity and pain in early rheumatoid arthritis: longitudinal results from two randomised controlled trials.

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.

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) case presentation and comparison with other polyarthritides affecting older people.

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.

Ultrasound-defined remission for good functional status in rheumatoid arthritis.

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.

Clinical outcomes in the first year of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome.

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.

T cell subsets: an immunological biomarker to predict progression to clinical arthritis in ACPA-positive individuals.

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.

High LDL levels lead to increased synovial inflammation and accelerated ectopic bone formation during experimental osteoarthritis.

OBJECTIVE: A relation between osteoarthritis (OA) and increased cholesterol levels is apparent. In the present study we investigate OA pathology in apolipoprotein E (ApoE)(-)(/-) mice with and without a cholesterol-rich diet, a model for high systemic low density lipoprotein (LDL) cholesterol levels independent of weight. METHOD: Wild type (WT), Apoe(-)(/-), S100a9(-/-) and Apoe(-)(/-)S100a9(-/-) mice (C57BL/6 background) received a standard or cholesterol-rich diet. Experimental OA was induced by intra-articular injection of collagenase and animals were sacrificed at day 10 and day 36. RESULTS: Although minimal differences in cartilage damage were found between the WT and ApoE(-)(/-) mice, increased synovial thickening was found in the latter. Thirty-six days after OA-induction, ApoE(-)(/-) mice on a standard diet showed increased ectopic bone formation, particularly at the medial collateral ligament, compared with OA in WT mice. Furthermore, a significant increase in synovial gene expression of both S100a8 and S100a9 and S100A8/S100A9 protein levels was found in ApoE(-)(/-) mice, suggesting an activated inflammatory status of synovial cells. In both ApoE(-)(/-) and WT mice, addition of a cholesterol-rich diet resulted in excessive bone formation in the medial collateral ligament at late-time-point OA. Interestingly, at the early time point, proteoglycan deposition was already significantly increased in ApoE(-)(/-) mice compared with WT mice. Mice deficient for both ApoE and S100a9 also showed increased ectopic bone formation, but not synovial activation, suggesting a role for S100-proteins in cholesterol-mediated synovial activation. CONCLUSIONS: Increased cholesterol levels strongly elevate synovial activation and ectopic bone formation in early-stage collagenase-induced OA.

Ultrasound power Doppler synovitis is associated with plasma IL-6 in established rheumatoid arthritis.

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.

Deep clinical remission: an optimised target in the management of rheumatoid arthritis? Experience from an ultrasonography study.

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

Ultrasound-detected joint inflammation and B cell count: related variables for rituximab-treated RA patients?

This cross-sectional observational study aimed to explore the relationship between B cell count and ultrasound (US)-detected synovitis, in patients with rheumatoid arthritis treated with rituximab. Thirty-seven consecutive RA patients treated with RTX were recruited for the study. The patients underwent clinical [i.e., Disease Activity Score 28 joints (DAS28)], laboratory, and US assessment of 12 joints. Each joint was semiquantitatively (0-3) scored on B-mode and power Doppler mode. The scores were summed, and a global index was created for BM (BMS) and PD scores (PDI) synovitis. BM subclinical synovitis was evident in all patients, with PD synovial signal detected in 16 patients (43.2 %). No correlation was found between DAS28 and US scores. B cells were detected in 27 (72.9 %) patients, but there was no association in the mean B cell count and disease activity as measured by DAS28 (DAS28 < 2.6 = 34.53, DAS28 > 2.6 = 49.45, p = 0.52) and PDI score (PDI < 1 = 49.48, PDI > 1 = 35.44, p = 0.54). There was no correlation between the B cell count and DAS28, BMS, and PDI (r = 0.020, p = 0.907; r = -0.151, p = 0.371; r = -0.099, p = 0.558, respectively). In RTX-treated RA patients, no relationship could be established between US-detected synovitis and peripheral blood B cell count.

The synovial grade corresponding to clinically involved joints and a feasible ultrasound-adjusted simple disease activity index for monitoring rheumatoid arthritis.

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.