Rheumatoid Arthritis Synovitis Research Articles

B Cell Synovitis and Clinical Phenotypes in Rheumatoid Arthritis: Relationship to Disease Stages and Drug Exposure.

ObjectiveTo define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA).MethodsSynovial biopsy specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients with untreated early RA (n = 165) and one of patients with established RA with an inadequate response to tumor necrosis factor inhibitors (TNFi‐IR; n = 164). Synovial tissue was subjected to hematoxylin and eosin and immunohistochemical staining and semiquantitative assessment for the degree of synovitis (on a scale of 0–9) and of CD20+ B cell infiltrate (on a scale of 0–4). B cell scores were validated by digital image analysis and B cell lineage–specific transcript analysis (RNA‐Seq) in the early RA (n = 91) and TNFi‐IR (n = 127) cohorts. Semiquantitative CD20 scores were used to classify patients as B cell rich (≥2) or B cell poor (<2).ResultsSemiquantitative B cell scores correlated with digital image analysis quantitative measurements and B cell lineage–specific transcripts. B cell–rich synovitis was present in 35% of patients in the early RA cohort and 47.7% of patients in the TNFi‐IR cohort (P = 0.025). B cell–rich patients showed higher levels of disease activity and seropositivity for rheumatoid factor and anti–citrullinated protein antibody in early RA but not in established RA, while significantly higher histologic synovitis scores in B cell–rich patients were demonstrated in both cohorts.ConclusionWe describe a robust semiquantitative histologic B cell score that closely replicates the quantification of B cells by digital or molecular analyses. Our findings indicate an ongoing B cell–rich synovitis, which does not seem to be captured by standard clinimetric assessment, in a larger proportion of patients with established RA than early RA.

High-resolution MRI of flexor tendon pulleys using a 16-channel hand coil: disease detection and differentiation of psoriatic and rheumatoid arthritis

BackgroundTo evaluate the value of 3 Tesla (T) magnetic resonance imaging (MRI) changes of flexor tendon pulleys for the differentiation of psoriatic (PsA) and rheumatoid arthritis (RA), using a novel 16-channel high-resolution hand coil.MethodsSeventeen patients with active PsA, 20 patients with active RA, and 16 healthy controls (HC) underwent high-resolution 3 T MRI using the dedicated 16-channel hand coil. Images were analyzed by three independent readers for the degree of inflammatory changes, thickness of flexor tendon pulleys, and comparison to the outcome measures for RA clinical trials (OMERACT) PsA MRI score (PsAMRIS) and to its sub-scores. For correlation analyses, Spearman rho correlation was calculated.ResultsFlexor tendon pulleys were thicker in PsA than in RA patients (mean difference 0.16 mm, p < 0.001) and HC (mean difference 0.2 mm, p < 0.001) and showed a higher degree of associated inflammatory changes (mean difference from RA 4.7, p = 0.048; mean difference from HC 14.65, p < 0.001). Additionally, there was a strong correlation of accessory pulley inflammation and PsAMRIS and its acute-inflammatory sub-scores, flexor tenosynovitis, synovitis, and periarticular inflammation (for the second digit synovitis ρ = 0.72, flexor tenosynovitis ρ = 0.7, overall PsAMRIS ρ = 0.72, p < 0.01). Similar robust correlations were evident in digits 3–5. Weaker correlations were evident in RA (synovitis ρ = 0.49, flexor tenosynovitis ρ = 0.49, periarticular inflammation ρ = 0.4).ConclusionThe assessment of MRI changes of flexor tendon pulleys is potentially beneficial for disease detection in PsA, as well as for its distinction from RA and HC.Trial registration2014123117, December 2014.

Cyanidin prevents the hyperproliferative potential of fibroblast-like synoviocytes and disease progression via targeting IL-17A cytokine signalling in rheumatoid arthritis

The hyperplastic phenotype of fibroblast-like synoviocytes (FLSs) plays an important role for synovitis, chronic inflammation and joint destruction in rheumatoid arthritis (RA). Interleukin 17A (IL-17A), a signature pro-inflammatory cytokine effectively influences the hyperplastic transformation of FLS cells and synovial pannus growth. IL-17A cytokine signalling participates in RA pathology by regulating an array of pro-inflammatory mediators and osteoclastogenesis. Cyanidin, a key flavonoid inhibits IL-17A/IL-17 receptor A (IL-17RA) interaction and alleviates progression and disease severity of psoriasis and asthma. However, the therapeutic efficacy of cyanidin on IL-17A cytokine signalling in RA remains unknown. In the present study, cyanidin inhibited IL-17A induced migratory and proliferative capacity of FLS cells derived from adjuvant-induced arthritis (AA) rats. Cyanidin treatment reduced IL-17A mediated reprogramming of AA-FLS cells to overexpress IL-17RA. In addition, significantly decreased expression of IL-17A dependent cyr61, IL-23, GM-CSF, and TLR3 were observed in AA-FLS cells in response to cyanidin. At the molecular level, cyanidin modulated IL-17/IL-17RA dependent JAK/STAT-3 signalling in AA-FLS cells. Importantly, cyanidin activated PIAS3 protein to suppress STAT-3 specific transcriptional activation in AA-FLS cells. Cyanidin treatment to AA rats attenuated clinical symptoms, synovial pannus growth, immune cell infiltration, and bone erosion. Cyanidin reduced serum level of IL-23 and GM-CSF and expression of Cyr 61 and TLR3 in the synovial tissue of AA rats. Notably, the level of p-STAT-3 protein was significantly decreased in the synovial tissue of AA rats treated with cyanidin. This study provides the first evidence that cyanidin can be used as IL-17/17RA signalling targeting therapeutic drug for the treatment of RA and this need to be investigated in RA patients.

Interleukin 17A and IL-17F Expression and Functional Responses in Rheumatoid Arthritis and Peripheral Spondyloarthritis.

Targeting the interleukin 17 (IL-17) axis is efficacious in psoriasis and spondyloarthritis (SpA), but not in rheumatoid arthritis (RA). We investigated potential differences in tissue expression and function of IL-17A and IL-17F in these conditions. mRNA expression of cytokines and their receptors was assessed by quantitative PCR in psoriasis skin samples, in SpA and RA synovial tissue (ST) samples and in fibroblast-like synoviocytes (FLS). Cytokines were measured in synovial fluid (SF) and FLS supernatants by ELISA. FLS were stimulated with IL-17A or IL-17F cytokines supplemented with tumor necrosis factor (TNF), or with pooled SF from patients with SpA or RA. Levels of IL-17A (P = 0.031) and IL-17F (P = 0.017) mRNA were lower in psoriatic arthritis ST compared to paired psoriasis skin samples. The level of IL-17A mRNA was 2.7-fold lower than that of IL-17F in skin (P = 0.0078), but 17.3-fold higher in ST (P < 0.0001). In SF, the level of IL-17A protein was 37.4-fold higher than that of IL-17F [median 292.4 (IQR 81.4-464.2) vs median 7.8 (IQR 7.7-8.7) pg/mL; P < 0.0001]. IL-17A and IL-17F mRNA and protein levels did not differ in SpA compared to RA synovitis samples, and neither were the IL-17 receptors IL-17RA and IL-17RC, or the TNF receptors TNFR1 and TNR2, differentially expressed between SpA and RA ST, nor between SpA and RA FLS. SpA and RA FLS produced similar amounts of IL-6 and IL-8 protein upon stimulation with IL-17A or IL-17F cytokines, supplemented with 1 ng/ml TNF. Pooled SpA or RA SF samples similarly enhanced the inflammatory response to IL-17A and IL-17F simulation in FLS. The IL-17A/IL-17F expression ratio is higher in SpA synovitis compared to psoriasis skin. Expression of IL-17A and IL-17F, and the functional response to these cytokines, appear to be similar in SpA and RA synovitis.

Doubtful swelling on clinical examination reflects synovitis in rheumatoid arthritis.

Aims:The aim of this study was to evaluate the implication of doubtful joint swelling on clinical examination with respect to objective markers of synovitis by ultrasound (US) in patients with rheumatoid arthritis (RA).Methods:Two independent observers performed a modified 28 swollen joint assessment (28SJC), in which joints could be graded as either definitely swollen, non-swollen, or doubtfully swollen. Two examiners blinded to clinical information performed US assessment of the hands. We performed descriptive statistics and models to analyse the links between clinical assessment and objective markers of inflammation.Results:A total of 1204 joints were evaluated in 43 RA patients; 93% (40/43) of patients had ⩾1 joint with doubtful swelling (range: 0–4/patient). Inter-reader reliability for the modified 28SJC was good (0.74). Generally, both grey scale (GS) and power Doppler (PD) discriminated across not swollen, doubtful, and swollen joints. GS signals discriminated better than PD between doubtful swelling and no swelling [odds ratio (OR) for GS: 5.2; 95% confidence interval (CI) 1.2–23.3 versus OR for PD 1.7; 95% CI 0.2–13.0], whereas PD discriminated better than GS between swelling and doubtful swelling (OR for PD: 28.7; 95% CI 3.6–228.2 versus GS: 1.7; 95% CI 0.3–8.4). Joint osteophytes did not increase the degree of doubtfulness.Conclusion:Clinical doubt in the assessment of joint swelling constitutes an intermediate state between unequivocal swelling and the lack thereof also regarding the objectively quantified level of inflammation. In order to increase sensitivity for joint inflammation, the historical clinical approach of considering doubtful swelling the absence of swelling should be revisited to interpret clinical doubtfulness as an indication of swelling.

Baihu Jia Guizhi Decoction Improves Rheumatoid Arthritis Inflammation by Regulating Succinate/SUCNR1 Metabolic Signaling Pathway

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis. Succinate is an inflammatory metabolic signal that exacerbates RA synovitis by activating succinate receptor 1 (SUCNR1) to amplify the release of IL-1β. Thus, inhibition of succinate activation of SUCRN1 could be an effective method to inhibit the inflammation of RA. Baihu Jia Guizhi decoction (BHGZ), which is composed of Gypsum Fibrosum, Anemarrhena asphodeloides Bge., Cinnamomum cassia Presl., Glycyrrhiza uralensis Fisch., and Oryza sativa L., is a Traditional Chinese Medicine (TCM) prescription used to treat RA in clinic. In addition, TCM believes that damp and heat environment is one of the causes of RA. In this study, we tested the role of damp and heat environments in exacerbating RA inflammation and the anti-inflammatory effect of BHGZ, based on succinate/SUCNR1/IL-1β pathway in the adjuvant arthritis (AA) model with damp and heat environment (AA + DHE). Results showed that paw swelling and synovial pathology were significantly increased in AA rats, and these results were aggravated by stimulation in damp and heat environment. BHGZ improved AA + DHE rats' paw swelling, synovial hyperplasia, and inflammatory cell infiltration and reduced IL-1β. In addition, AA rats significantly increased the expression of SUCNR1, and the stimulation of damp and heat environment not only increased the expression of SUCNR1 but also promoted the accumulation of succinate. BHGZ simultaneously reduced the concentration of succinate and the expression of SUCNR1. Finally, SDH activity was decreased in AA rats and AA + DHE rats, while BHGZ increased SDH activity and then reduced succinate concentration. Therefore, we prove that damp and heat environment deteriorated the inflammation of RA which is the activation of succinate/SUCNR1 pathway, while BHGZ regulates SDH activity to reduce the accumulation of succinate and inhibit the activation of SUCNR1 that is the underlying mechanism of its treatment of RA.

Synovitis in rheumatoid arthritis detected by grey scale ultrasound predicts the development of erosions over the next three years.

ObjectivesTo evaluate grey scale US (GSUS) and power Doppler US synovitis (PDUS), separately or in combination (CombUS), to predict joint damage progression in RA.MethodsIn this cohort study nested in the Swiss RA register, all patients with sequential hand radiographs at their first US assessment were included. We analysed the summations of semi-quantitative GSUS, PDUS and CombUS assessments of both wrists and 16 finger joints (maximum 54 points) at their upper limit of normal, their 50th, 75th or 87.5th percentiles for the progression of joint damage (ΔXray). We adjusted for clinical disease activity measures at baseline, the use of biological DMARDs and other confounders.ResultsAfter a median of 35 months, 69 of 250 patients with CombUS (28%), 73 of 259 patients with PDUS (28%) and 75 of 287 patients with available GSUS data (26%) demonstrated joint damage progression. PDUS beyond upper limit of normal (1/54), GSUS and CombUS each at their 50th (9/54 and 10/54) and their 75th percentiles (14/54 and 15/54) were significantly associated with ΔXray in crude and adjusted models. In subgroup analyses, GSUS beyond 14/54 and CombUS higher than 15/54 remained significantly associated with ΔXray in patients on biological DMARDs, while clinical disease activity measures had no significant prognostic power in this subgroup.ConclusionHigher levels of GSUS and CombUS are associated with the development of erosions. GSUS appears to be an essential component of synovitis assessment and an independent predictor of joint damage progression in patients on biological DMARDs.

Where to Stand with Stromal Cells and Chronic Synovitis in Rheumatoid Arthritis?

The synovium exercises its main function in joint homeostasis through the secretion of factors (such as lubricin and hyaluronic acid) that are critical for the joint lubrication and function. The main synovium cell components are fibroblast-like synoviocytes, mesenchymal stromal/stem cells and macrophage-like synovial cells. In the synovium, cells of mesenchymal origin modulate local inflammation and fibrosis, and interact with different fibroblast subtypes and with resident macrophages. In pathologic conditions, such as rheumatoid arthritis, fibroblast-like synoviocytes proliferate abnormally, recruit mesenchymal stem cells from subchondral bone marrow, and influence immune cell activity through epigenetic and metabolic adaptations. The resulting synovial hyperplasia leads to secondary cartilage destruction, joint swelling, and pain. In the present review, we summarize recent findings on the molecular signature and the roles of stromal cells during synovial pannus formation and rheumatoid arthritis progression.

TNF-induced inflammatory genes escape repression in fibroblast-like synoviocytes: transcriptomic and epigenomic analysis

ObjectiveWe investigated genome-wide changes in gene expression and chromatin remodelling induced by tumour necrosis factor (TNF) in fibroblast-like synoviocytes (FLS) and macrophages to better understand the contribution of FLS to...

Mesenchymal stem cell repression of Th17 cells is triggered by mitochondrial transfer

BackgroundMesenchymal stem cells (MSCs) are multipotent cells with broad immunosuppressive capacities. Recently, it has been reported that MSCs can transfer mitochondria to various cell types, including fibroblast, cancer, and endothelial cells. It has been suggested that mitochondrial transfer is associated with a physiological response to cues released by damaged cells to restore and regenerate damaged tissue. However, the role of mitochondrial transfer to immune competent cells has been poorly investigated.Methods and resultsHere, we analyzed the capacity of MSCs from the bone marrow (BM) of healthy donors (BM-MSCs) to transfer mitochondria to primary CD4+CCR6+CD45RO+ T helper 17 (Th17) cells by confocal microscopy and fluorescent-activated cell sorting (FACS). We then evaluated the Th17 cell inflammatory phenotype and bioenergetics at 4 h and 24 h of co-culture with BM-MSCs. We found that Th17 cells can take up mitochondria from BM-MSCs already after 4 h of co-culture. Moreover, IL-17 production by Th17 cells co-cultured with BM-MSCs was significantly impaired in a contact-dependent manner. This inhibition was associated with oxygen consumption increase by Th17 cells and interconversion into T regulatory cells. Finally, by co-culturing human synovial MSCs (sMSCs) from patients with rheumatoid arthritis (RA) with Th17 cells, we found that compared with healthy BM-MSCs, mitochondrial transfer to Th17 cells was impaired in RA-sMSCs. Moreover, artificial mitochondrial transfer also significantly reduced IL-17 production by Th17 cells.ConclusionsThe present study brings some insights into a novel mechanism of T cell function regulation through mitochondrial transfer from stromal stem cells. The reduced mitochondrial transfer by RA-sMSCs might contribute to the persistence of chronic inflammation in RA synovitis.

Serum level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a biomarker of synovitis in rheumatoid arthritis.

Serum level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a biomarker of synovitis in rheumatoid arthritis.

Validating an Empirical Mathematical Model for Dynamic Contrast-enhanced MR Imaging of Hand and Wrist Synovitis in Rheumatoid Arthritis: Correlation of Model Parameters with Clinical Disease Activity.

Purpose:To evaluate the feasibility of an empirical mathematical model (EMM) to fit dynamic contrast-enhanced MRI (DCE-MRI) data of hand and wrist synovitis and whether parameters of EMM are significantly correlated with clinical disease activity in patients with rheumatoid arthritis (RA).Methods:Thirty-one consecutive patients with RA prospectively underwent Institutional Review Board (IRB)- approved DCE-MRI scans with temporal resolution of 20 s using a 1.5T system. ROIs were placed where the highest signal increase was observed and the kinetic curves were analyzed using an EMM: ΔS(t) = A(1 − e−αt) e−βt, where ΔS is relative enhancement, t is time from when the signal increase was first observed, starting from baseline (ΔS = 0), A is the upper limit of signal intensity, α (s−1) is the rate of signal increase, and β (s−1) is the rate of signal decrease during washout. The initial slope of the kinetic curve (Aα), the initial area under the curve (AUC30), the time at which the kinetic curve reached its peak (Tpeak) and the signal enhancement ratio (SER) defined as the change in signal intensity between the initial and delayed time points (t = 60 and 300 s, respectively) were calculated. RA magnetic resonance imaging scores (RAMRIS) with and without contrast media were evaluated. These parameters or scores were compared with the Disease Activity Score (DAS) 28-erythrocyte sedimentation rate (ESR).Results:A showed a significant correlation with DAS28-ESR (r = 0.58; P = 0.0005). β, AUC30 and Tpeak were also significantly correlated with DAS28-ESR with a lesser degree (r = 0.49; P = 0.0051, r = 0.50; P = 0.0038 and r = −0.51; P = 0.0028, respectively), whereas α, Aα, SER and RAMRIS were not.Conclusion:EMM could fit the DCE-MRI data of hand and wrist synovitis. AUC30 obtained from the uptake phase of the kinetic curve as well as A, β and Tpeak obtained throughout the kinetic curve might be effective to predict the clinical disease activity.

Six-month prospective trial in early and long-standing rheumatoid arthritis: evaluating disease activity in the wrist through sequential synovial histopathological analysis, RAMRIS magnetic resonance score and EULAR-OMERACT ultrasound score

IntroductionStandardised scoring systems for rheumatoid arthritis (RA) joint disease activity include Larsen score for radiographs, rheumatoid arthritis magnetic resonance imaging score (RAMRIS) for MRI and using the European League Against...

Detection of Increased Vascular Signal in Arthritis-Prone Rats Without Joint Swelling Using Superb Microvascular Imaging Ultrasonography

This study aimed to determine whether ultrasonography (US) can detect increased vascular signal in the synovial tissue before overt synovitis in rheumatoid arthritis (RA). Env-pX rats that spontaneously develop RA-like synovitis were used. Ankle joints of 15 pre-morbid env-pX rats were observed with power Doppler and superb microvascular imaging (SMI) using an ultrahigh-frequency (8–24 MHz) probe. Signal values were counted as the number of pixels. The total number of vessels and vessel area in the synovial tissue were histologically evaluated. Dilated vessels were determined from the mean value of synovial vessels in three wild-type rats. In all env-pX rats, apparent synovial proliferation was not observed. However, vasodilation was evident. Only SMI values were significantly correlated with the number of dilated vessels (r = 0.585, p = 0.022) but not with the total number of vessels. US with SMI using ultrahigh-frequency probe can detect increased vascular signal in the synovial tissue of arthritis-prone rats.

The superb microvascular imaging is more sensitive than conventional power Doppler imaging in detection of active synovitis in patients with rheumatoid arthritis.

This study evaluated Superb Microvascular Imaging (SMI) technology for detection of active synovitis in patients with rheumatoid arthritis (RA). Between June 2015 and October 2016, 56 patients with RA (42 females; mean age, 53.2years) underwent gray-scale ultrasound (US) imaging, power Doppler imaging (PDI), and SMI for synovitis of both wrists and hands (total 22 joints), scored for each joint from grades 0 to 3. The sum of grades for 22 joints was determined for gray-scale (SYN-sum), PDI (PDI-sum), and SMI (SMI-sum) according to clinical parameters. Follow-up US was performed in 17 patients (mean interval, 251.6days). The SMI-sum (7.27 ± 4.56) was significantly higher than the PDI-sum (4.38 ± 3.09, p < 0.001) and the SYN-sum (4.55 ± 3.72, p < 0.001), and was significantly correlated with the erythrocyte sedimentation rate, C-reactive protein (CRP), and Disease Activity Score-28 (DAS28)-CRP (γ = 0.409, p = 0.002; γ = 0.695, p < 0.001; γ = 0.726, p < 0.001, respectively). Moreover, in 28 patients with clinical remission, the SMI-sum (4.32 ± 2.01) was greater than the PDI-sum (2.61 ± 1.60, p < 0.001). In 17 patients with follow-up US, the SMI-sum (2.35 ± 1.73) was significantly greater than the PDI-sum (1.24 ± 1.20; p < 0.001) and was also significantly correlated with DAS28 (γ = 0.880). SMI may detect active synovitis with greater sensitivity than PDI in RA patients, even with clinical remission, and is well-correlated with inflammatory parameters during follow-up. • SMI correlated well with PDI and was more sensitive for detection of active synovitis in RA. • The SMI-sum was not only of greater value but also more strongly correlated than the PDI-sum with clinical inflammatory indicators including ESR, CRP, and DAS28 on initial and follow-up US examinations. • The SMI-sum was even significantly increased in patients with clinical remission.

Mast Cells in Early Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammation of the synovial membrane, with thickening of the synovial layer, cellular hyperplasia, and infiltration of immune cells. Mast cells (MCs) are cells of the innate immunity present in healthy synovia and part of the cellular hyperplasia characterizing RA synovitis. Although their presence in synovia has been well described, the exact functions and the correlation of MCs with disease development and progression have been debated, particularly because of contradictory data obtained in animal models and from patients with longstanding disease. Here, we present a revision of the literature on MCs in RA, including the most recent observations obtained from patients with early RA, indicating MCs as relevant markers of disease severity in early RA.

Synovial Tissue: Turning the Page to Precision Medicine in Arthritis.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease targeting the joints. Current treatment strategies are based on clinical, biological and radiological features, yet still fail to reach the goal of early low disease activity in a significant number of cases. Hence, there is a need for refining current treatment algorithms, using accurate markers of response to therapy. Because RA induces histological and molecular alterations in the synovium even before apparition of clinical symptoms, synovial biopsies are a promising tool in the search of such new biomarkers. Histological and molecular characteristics of RA synovitis are heterogeneous. Variations in synovial lining layer hyperplasia, in cellular infiltration of the sublining by immune cells of myeloid and lymphoid lineages, and in molecular triggers of these features are currently categorized using well-defined pathotypes: myeloid, lymphoid, fibroid and pauci-immune. Here, we first bring the plasticity of RA synovitis under scrutiny, i.e., how variations in synovial characteristics are associated with relevant clinical features (disease duration, disease activity, effects of therapies, disease severity). Primary response to a specific drug could be, at least theoretically, related to the representation of the molecular pathway targeted by the drug in the synovium. Alternatively, absence of primary response to a specific agent could be due to disease severity, i.e., overrepresentation of all synovial molecular pathways driving disease activity overwhelming the capacity of any drug to block them. Using this theoretical frame, we will highlight how the findings of previous studies trying to link response to therapy with synovial changes provide promising perspectives on bridging the gap to personalized medicine in RA.

Validity of a two-component imaging-derived disease activity score for improved assessment of synovitis in early rheumatoid arthritis.

ObjectivesImaging of joint inflammation provides a standard against which to derive an updated DAS for RA. Our objectives were to develop and validate a DAS based on reweighting the DAS28 components to maximize association with US-assessed synovitis.MethodsEarly RA patients from two observational cohorts (n = 434 and n = 117) and a clinical trial (n = 59) were assessed at intervals up to 104 weeks from baseline; all US scans were within 1 week of clinical exam. There were 899, 163 and 183 visits in each cohort. Associations of combined US grey scale and power Doppler scores (GSPD) with 28 tender joint count and 28 swollen joint count (SJC28), CRP, ESR and general health visual analogue scale were examined in linear mixed model regressions. Cross-validation evaluated model predictive ability. Coefficients learned from training data defined a re-weighted DAS28 that was validated against radiographic progression in independent data (3037 observations; 717 patients).ResultsOf the conventional DAS28 components only SJC28 and CRP were associated with GSPD in all three development cohorts. A two-component model including SJC28 and CRP outperformed a four-component model (R2 = 0.235, 0.392, 0.380 vs 0.232, 0.380, 0.375, respectively). The re-weighted two-component DAS28CRP outperformed conventional DAS28 definitions in predicting GSPD (Δtest log-likelihood <−2.6, P < 0.01), Larsen score and presence of erosions.ConclusionA score based on SJC28 and CRP alone demonstrated stronger associations with synovitis and radiographic progression than the original DAS28 and should be considered in research on pathophysiological manifestations of early RA. Implications for clinical management of RA remain to be established.

Role of Anti-Fractalkine Antibody in Suppression of Joint Destruction by Inhibiting Migration of Osteoclast Precursors to the Synovium in Experimental Arthritis.

To elucidate the role of the fractalkine (FKN)/CX3 CR1 pathway in joint destruction in rheumatoid arthritis. We examined the effect of treatment with anti-mouse FKN (anti-mFKN) monoclonal antibody (mAb) on joint destruction and the migration of osteoclast precursors (OCPs) into the joint, using the collagen-induced arthritis (CIA) model. DBA/1 mice were immunized with bovine type II collagen to induce arthritis, and then treated with anti-mFKN mAb. Disease severity was monitored by arthritis score, and joint destruction was evaluated by soft x-ray and histologic analyses. Plasma levels of joint destruction markers were assessed by enzyme-linked immunosorbent assay. FKN expression on endothelial cells was detected by immunohistochemistry. Bone marrow-derived OCPs were labeled with fluorescein and transferred to mice with CIA, and the migration of the OCPs to the joints was then analyzed. Both prophylactic and therapeutic treatment with anti-mFKN mAb significantly decreased the arthritis and soft x-ray scores. Plasma levels of cartilage oligomeric matrix protein and matrix metalloproteinase 3 decreased after treatment with anti-mFKN mAb. Histologic analysis revealed that anti-mFKN mAb inhibited synovitis, pannus formation, and cartilage destruction, as well as suppressed bone damage, with a marked reduction in the number of tartrate-resistant acid phosphatase-positive osteoclasts. Anti-mFKN mAb strongly inhibited the migration of bone marrow-derived OCPs into the affected synovium. Anti-mFKN mAb notably ameliorates arthritis and joint destruction in the CIA model, as well as inhibits migration of OCPs into the synovium. These results suggest that inhibition of the FKN/CX3 CR1 pathway could be a novel strategy for treatment of both synovitis and joint destruction in rheumatoid arthritis.

Enhancing convolutional neural network scheme for rheumatoid arthritis grading with limited clinical data**Project supported by the National Key Research and Development Program of China (Grant No. 2017YFC0111402) and the Natural Science Funds of Jiangsu Province of China (Grant No. BK20181256).

The gray-scale ultrasound (US) imaging method is usually used to assess synovitis in rheumatoid arthritis (RA) in clinical practice. This four-grade scoring system depends highly on the sonographer’s experience and has relatively lower validity compared with quantitative indexes. However, the training of a qualified sonographer is expensive and time-consuming while few studies focused on automatic RA grading methods. The purpose of this study is to propose an automatic RA grading method using deep convolutional neural networks (DCNN) to assist clinical assessment. Gray-scale ultrasound images of finger joints are taken as inputs while the output is the corresponding RA grading results. Firstly, we performed the auto-localization of synovium in the RA image and obtained a high precision in localization. In order to make up for the lack of a large annotated training dataset, we performed data augmentation to increase the number of training samples. Motivated by the approach of transfer learning, we pre-trained the GoogLeNet on ImageNet as a feature extractor and then fine-tuned it on our own dataset. The detection results showed an average precision exceeding 90%. In the experiment of grading RA severity, the four-grade classification accuracy exceeded 90% while the binary classification accuracies exceeded 95%. The results demonstrate that our proposed method achieves performances comparable to RA experts in multi-class classification. The promising results of our proposed DCNN-based RA grading method can have the ability to provide an objective and accurate reference to assist RA diagnosis and the training of sonographers.