Synovial Inflammation In Rheumatoid Arthritis Patients Research Articles

Baricitinib improves bone properties and biomechanics in patients with rheumatoid arthritis - results of the prospective interventional BARE BONE trial.

Rheumatoid arthritis (RA) is characterized by erosive joint damage, deterioration of bone mass and biomechanics. Preclinical evidence suggests a beneficial effect of Janus Kinase inhibition (JAKi) on bone properties, but clinical data are scarce to date. In this study we evaluated the effect of JAKi through baricitinib (BARI) on (i) volumetric bone mineral density (vBMD), bone microstructure, biomechanics, erosion repair and (ii) synovial inflammation in RA patients. Prospective, single-arm, interventional, open-label, single-center phase 4 study in RA patients with pathological bone status and clinical indication of JAKi (BARE BONE trial). Participants received BARI (4mg/day) over 52 weeks. To assess bone properties and synovial inflammation, high-resolution CT scans and Magnetic resonance imaging (MRI) were performed at baseline (BL), at week 24 and 52. Clinical response and safety was monitored. Thirty RA patients were included. BARI significantly improved disease activity (DAS28-ESR: 4.82±0.90 to 2.71±0.83) and synovial inflammation (RAMRIS synovitis score: 5.3 (4.2) to 2.7 (3.5)). We observed a significant improvement in trabecular vBMD with a mean change of 6.11 mgHA/mm3 (95%CI 0.01 to 12.26). Biomechanical properties also improved with mean change from baseline in estimated stiffness of 2.28 kN/mm (95% CI 0.30 to 4.25) and estimated failure load of 98.8 Newtons (95%CI 15.9 to 181.7). The number and size of erosions in the metacarpal joints remained stable. No new safety signals with baricitinib treatment were observed. Bone of RA patients improves with BARI therapy as shown by an increase in trabecular bone mass and an improvement of biomechanical properties.

GTS-21 alleviates murine collagen-induced arthritis through inhibition of peripheral monocyte trafficking into the synovium

Emerging preclinical and clinical evidence reveals a critical role for the cholinergic anti-inflammatory pathway (CAP) in mediating rheumatoid arthritis (RA). Activation of CAP via vagus nerve stimulation or alpha 7 nicotinic acetylcholine receptor (α7nAChR) agonists has previously been shown to significantly reduce inflammation and improve outcomes in animal models of experimental arthritis. In this study, we sought to determine the protective mechanism of CAP on inflammatory arthritis, specifically RA, by using a selective α7nAChR agonist, GTS-21, to examine the role of CAP in the recruitment of monocytes/macrophages into the synovium in a collagen-induced arthritis (CIA) mouse model.We found that GTS-21 ameliorated systemic and local synovial inflammation, thereby reducing synovial macrophage infiltration in CIA mice. Using in vivo imaging, we further demonstrated that GTS-21 suppressed the trafficking of monocytes into inflamed joints, while our in vitro Transwell assay data confirmed that GTS-21 reduced the migratory ability of monocytes. In addition, we found that GTS-21 reduced the number of peripheral inflammatory monocytes and down-regulated expression of the chemokines CCR2 and CCR5 on monocytes and CCL2 in the paw tissue. GTS-21 also mediated the expression levels of the adhesion molecules LFA-1 and VLA-4 on monocytes and VCAM-1 in the paw tissue, thereby blocking monocyte adhesion to the extracellular matrix.Together, our data demonstrate that GTS-21 alleviates arthritis by inhibiting peripheral monocyte trafficking into the synovium. Our findings describe a novel mechanism through which the cholinergic signaling pathway can reduce synovial inflammation in RA patients.

Plasma calprotectin as a biomarker of ultrasound synovitis in rheumatoid arthritis patients receiving IL-6 antagonists or JAK inhibitors

Objectives:To analyse the accuracy of plasma calprotectin in patients with rheumatoid arthritis (RA) receiving monoclonal antibodies against IL-6 receptors (anti-rIL-6) or JAK inhibitors (JAKis) in detecting ultrasound (US) synovitis and compare it with acute phase reactants [high-sensitivity C-reactive protein (hs-CRP) and ESR].Methods:An observational cross-sectional study of RA patients receiving anti-rIL-6 (tocilizumab or sarilumab) or JAKi, (baricitinib or tofacitinib) was made. Plasma calprotectin for the diagnosis of US synovitis [synovial hypertrophy grade (SH) ⩾ 2 plus power Doppler signal (PD) ⩾ 1] was analysed using receiver operating characteristic curves (ROCs). The performance of ESR and hs-CRP was also studied. The three ROC curves were compared to determine which had the highest discriminatory power. Associations between plasma calprotectin and US scores were made using correlation analysis.Results:Sixty-three RA patients were included. Mean plasma calprotectin levels were significantly higher in patients with US synovitis than in those without (0.89 ± 0.85 vs 0.30 ± 0.12 μg/ml; p = 0.0003). A moderate correlation between calprotectin and all US scores (HS score Rho = 0.479; PD score Rho = 0.492; and global score Rho = 0.495) was found. The discriminatory capacity of plasma calprotectin showed an AUC of 0.795 (95% CI: 0.687–0.904). The AUC of hs-CRP and ESR was 0.721 and 0.564, respectively. hs-CRP serum levels showed a low positive correlation with the three US scores (Rho < 0.40). After analysis according to the drugs administered, the correlation disappeared in patients receiving anti-rIL-6.Conclusion:Plasma calprotectin may be a sensitive biomarker of synovial inflammation in RA patients treated with anti-rIL-6 or JAKi.

Serum calprotectin (S100A8/9): an independent predictor of ultrasound synovitis in patients with rheumatoid arthritis.

IntroductionCalprotectin, a heterodimeric complex of S100A8/9 (MRP8/14), has been proposed as an important serum biomarker that reflects disease activity and structural joint damage in rheumatoid arthritis (RA). The objective of this cross-sectional study was to test the hypothesis that calprotectin is associated with clinical and ultrasound-determined disease activity in patients with RA.MethodsA total of 37 patients with RA (including 24 females, a mean disease duration of 20 months) underwent a clinical examination and 7-joint ultrasound score (German US-7) of the clinically dominant hand and foot to assess synovitis by grey-scale (GS) and synovial vascularity by power Doppler (PD) ultrasound using semiquantitative 0–3 grading. The levels of serum calprotectin and C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were determined at the time of the ultrasound assessment. We analysed the relationship between serum calprotectin level, traditional inflammatory markers, and ultrasound-determined synovitis.ResultsThe levels of serum calprotectin were significantly correlated with swollen joint count (r = 0.465, p < 0.005), DAS28-ESR (r = 0.430, p < 0.01), ESR (r = 0.370, p < 0.05) and, in particular, CRP (r = 0.629, p < 0.001). Calprotectin was significantly associated with GS (r = 0.359, p < 0.05) and PD synovitis scores (r = 0.497, p < 0.005). Using multivariate regression analysis, calprotectin, adjusted for age and sex, was a better predictor of PD synovitis score (R2 = 0.765, p < 0.001) than CRP (R2 = 0.496, p < 0.001).ConclusionsThe serum levels of calprotectin are significantly associated with clinical, laboratory and ultrasound assessments of RA disease activity. These results suggest that calprotectin might be superior to CRP for monitoring ultrasound-determined synovial inflammation in RA patients.

SAT0021 Both Gray-Scale Synovial Hypertrophy and Synovial Power Doppler Signals on a Comprehensive Ultrasound Scan are the Predictive Factors of Relapse After Discontinuation of Biological Agents in Patients with Rheumatoid Arthritis

BackgroundClinical information does not accurately predict relapse after discontinuation of biological agents in patients with rheumatoid arthritis (RA). Although ultrasound is a sensitive tool to detect sub-clinical synovial inflammation in...

The Features of the Synovium in Early Rheumatoid Arthritis According to the 2010 ACR/EULAR Classification Criteria

ObjectivesIt has been shown in early arthritis cohorts that the 2010 ACR/EULAR criteria for rheumatoid arthritis (RA) enable an earlier diagnosis, perhaps at the cost of a somewhat more heterogeneous patient population. We describe the features of synovial inflammation in RA patients classified according to these new criteria.MethodsAt baseline, synovial tissue biopsy samples were obtained from disease-modifying antirheumatic drug (DMARD)-naïve early RA patients (clinical signs and symptoms <1 year). Synovial tissue was analyzed for cell infiltration, vascularity, and expression of adhesion molecules. Stained sections were evaluated by digital image analysis. Patients were classified according to the two different sets of classification criteria, autoantibody status, and outcome.FindingsSynovial tissue of 69 RA patients according to 2010 ACR/EULAR criteria was analyzed: 56 patients who fulfilled the criteria for RA at baseline and 13 who were initially diagnosed as undifferentiated arthritis but fulfilled criteria for RA upon follow up. The synovium at baseline was infiltrated by plasma cells, macrophages, and T cells as well as other cells, and findings were comparable to those when patients were selected based on the 1987 ACR criteria for RA. There was no clear cut difference in the characteristics of the synovium between RA patients initially diagnosed as undifferentiated arthritis and those who already fulfilled classification criteria at baseline.ConclusionThe features of synovial inflammation are similar when the 2010 ACR/EULAR classification criteria are used compared to the 1987 ACR criteria.

Dynamic gadolinium-enhanced magnetic resonance imaging allows accurate assessment of the synovial inflammatory activity in rheumatoid arthritis knee joints: a comparison with synovial histology

Objective: To determine whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) evaluated using semi-automatic image processing software can accurately assess synovial inflammation in rheumatoid arthritis (RA) knee joints.Methods: In 17 RA patients undergoing knee surgery, the average grade of histological synovial inflammation was determined from four biopsies obtained during surgery. A preoperative series of T1-weighted dynamic fast low-angle shot (FLASH) MR images was obtained. Parameters characterizing contrast uptake dynamics, including the initial rate of enhancement (IRE), were generated by the software in three different areas: (I) the entire slice (Whole slice); (II) a manually outlined region of interest (ROI) drawn quickly around the joint, omitting large artefacts such as blood vessels (Quick ROI); and (III) a manually outlined ROI following the synovial capsule of the knee joint (Precise ROI). Intra- and inter-reader agreement was assessed using the intra-class correlation coefficient (ICC).Results: The IRE from the Quick ROI and the Precise ROI revealed high correlations to the grade of histological inflammation (Spearman’s correlation coefficient (rho) = 0.70, p = 0.001 and rho = 0.74, p = 0.001, respectively). Intra- and inter-reader ICCs were very high (0.93–1.00). No Whole slice parameters were correlated to histology.Conclusion: DCE-MRI provides fast and accurate assessment of synovial inflammation in RA patients. Manual outlining of the joint to omit large artefacts is necessary.

An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis

Achieving remission is the aim of treatment in rheumatoid arthritis (RA). This should represent minimal arthritis activity and ensure optimal disease outcome. However, we have previously demonstrated a high prevalence of imaging-detected synovial inflammation in RA patients who were in clinical remission. The purpose of this study was to evaluate the long-term significance of subclinical synovitis and its relationship to structural outcome. We studied 102 RA patients receiving conventional treatment who had been judged by their consultant rheumatologist to be in remission, as well as 17 normal control subjects. Subjects underwent clinical, laboratory, functional, and quality of life assessments over 12 months. In addition to standard radiography of the hands and feet, imaging of the hands and wrists was performed with musculoskeletal ultrasonography (US) and conventional 1.5 T magnetic resonance imaging (MRI) at baseline and 12 months, using validated acquisition and scoring techniques. Despite their being in clinical remission, 19% of the patients displayed deterioration in radiographic joint damage over the study period. Scores on musculoskeletal US synovial hypertrophy, power Doppler (PD), and MRI synovitis assessments in individual joints at baseline were significantly associated with progressive radiographic damage (P=0.032, P<0.001, and P=0.002, respectively). Furthermore, there was a significant association between the musculoskeletal US PD score at baseline and structural progression over 12 months in totally asymptomatic metacarpophalangeal joints (P=0.004) and 12 times higher odds of deterioration in joints with increased PD signal (odds ratio 12.21, P<0.001). Subclinical joint inflammation detected by imaging techniques explains the structural deterioration in RA patients in clinical remission who are receiving conventional therapy. Our findings reinforce the utility of imaging for the accurate evaluation of disease status and the prediction of structural outcome.

Blocking the receptor for C5a in patients with rheumatoid arthritis does not reduce synovial inflammation

All complement pathways lead to the formation of C5a, which is believed to contribute to the influx and activation of C5a-receptor (C5aR) bearing cells into the joints of patients with rheumatoid arthritis (RA). Studies in animal models of RA have suggested therapeutic potential of C5aR blockade. In this study, we examined the effects of the C5aR blockade on synovial inflammation in RA patients. We performed a double-blind, placebo-controlled study using an orally administered C5aR-antagonist. Twenty-one patients with active RA were randomized 2:1 to treatment with a C5aR-antagonist AcF- (OpdChaWR) (PMX53) vs placebo for 28 days. Serum concentrations of PMX53 were determined. Synovial tissue was obtained at baseline and after 28 days of treatment for pharmacodynamic analysis using immunohistochemistry and digital image analysis. All patients completed the study. Areas under the curve (AUCs) of PMX53 in patients' blood samples showed a mean of 40.8 nmol h/l. There was neither decrease in cell infiltration, nor changes in key biomarkers associated with clinical efficacy after active treatment. In addition, there was no trend towards clinical improvement in the C5aR-antagonist-treated group compared with placebo nor was there a correlation between the AUC and clinical response. Treatment with PMX53 did not result in a reduction of synovial inflammation despite reaching serum levels of PMX53 that block C5aR-mediated cell activation in vitro. The data suggest that C5aR blockade does not result in reduced synovial inflammation in RA patients.

Comparison in values of color flow signals and vascular resistance of synovial vascularity demonstrated by Doppler sonography between knee and metacarpophalangeal joints of patients with rheumatoid arthritis

Synovial vascularity of 12 patients with rheumatoid arthritis (RA) was examined by Doppler sonography for color flow signals and vascular resistance on knee joints and metacarpophalangeal (MCP) joints, and the results were compared with each other and with C-reactive protein (CRP) levels of the patients. A significant correlation was observed between knee resistance index (RI) and MCP-RI (P = 0.0140), but not between knee color flow signals and MCP color flow signals (P = 0.1029). A significant correlation was also observed between knee color flow signals and knee RI (P = 0.0107), and knee pulsatility index (PI) (P = 0.0146). On the other hand, no correlation was observed between MCP color flow signals and MCP-RI (P = 0.828), and MCP-PI (P = 0.434). There was no significant correlation between CRP levels and grades of color flow signals, RI, and PI for both knee and MCP joints. Doppler sonographic evaluation of RI, especially knee RI, could be a useful marker for estimating synovial inflammation in RA patients.

Comparison in values of color flow signals and vascular resistance of synovial vascularity demonstrated by Doppler sonography between knee and metacarpophalangeal joints of patients with rheumatoid arthritis

Synovial vascularity of 12 patients with rheumatoid arthritis (RA) was examined by Doppler sonography for color flow signals and vascular resistance on knee joints and metacarpophalangeal (MCP) joints, and the results were compared with each other and with C-reactive protein (CRP) levels of the patients. A significant correlation was observed between knee resistance index (RI) and MCP-RI (P = 0.0140), but not between knee color flow signals and MCP color flow signals (P = 0.1029). A significant correlation was also observed between knee color flow signals and knee RI (P = 0.0107), and knee pulsatility index (PI) (P = 0.0146). On the other hand, no correlation was observed between MCP color flow signals and MCP-RI (P = 0.828), and MCP-PI (P = 0.434). There was no significant correlation between CRP levels and grades of color flow signals, RI, and PI for both knee and MCP joints. Doppler sonographic evaluation of RI, especially knee RI, could be a useful marker for estimating synovial inflammation in RA patients.