Clinical Joint Swelling Research Articles

Chondroitin sulfate-based microneedles for transdermal delivery of stem cell-derived extracellular vesicles to treat rheumatoid arthritis

For the non-invasive treatment of rheumatoid arthritis (RA), a chondroitin sulfate C (CSC)-based dissolving microneedles (cMN) was prepared to deliver human adipose stem cell-derived extracellular vesicles (hASC-EV) into inflamed joints. Owing to their anti-inflammatory function, the hASC-EV-bearing cMN (EV@cMN) significantly suppressed activated fibroblast-like synoviocytes (aFLS) and M1 macrophages (M1), which are responsible for the progression of RA. In addition, EV@cMN facilitated the chondrogenic differentiation of bone marrow-derived stem cells. In mice with collagen-induced arthritis, EV@cMN efficiently delivered both hASC-EV and CSC to inflamed joints. Interestingly, pro-inflammatory cytokines in the inflamed joints were remarkably downregulated by the synergistic effect of CSC and hASC-EV. Consequently, as judged from the overall clinical score and joint swelling, EV@cMN showed an outstanding therapeutic effect, even comparable to the wild-type mice, without significant adverse effects. Overall, EV@cMN might have therapeutic potential for RA by efficiently delivering CSC and hASC-EV into the inflamed joints in a non-invasive manner.

Loss of AKAP12 aggravates rheumatoid arthritis-like symptoms and cardiac damage in collagen-induced arthritis mice.

A-kinase anchoring protein 12 (AKAP12) has been identified as an anti-inflammatory and anti-fibrotic regulator in chronic inflammation and cardiovascular disease. However, the potential of AKAP12 in autoimmune disorders, rheumatoid arthritis (RA) and associated cardiac complications remains elusive. Here, a murine model of collagen-induced arthritis (CIA) was successfully induced, followed by adenovirus-mediated AKAP12 short hairpin RNA (shRNA) treatment. AKAP12 silenced mice displayed elevated clinical arthritis scores and significant ankle joint swelling. AKAP12 loss in CIA mice increased inflammatory cell infiltration and cartilage erosion, increased the levels of anti-IIC IgG and inflammatory cytokines IL-1β, IL-6, tumor necrosis factor (TNF)-α in serum, and upregulated the expression of cartilage-degrading enzymes MMP-1, MMP-3, MMP-13 in synovium, but reduced IL-10. The number of M1 macrophages and the expression of the markers (CCR7, IL-6, TNF-α and iNOS) was enhanced in synovial tissues, while M2 polarized macrophages and the makers (IL-10 and arginase-1) were reduced in response to AKAP12 loss. Moreover, low expression of AKAP12 was detected in the hearts of CIA mice. Loss of AKAP12 results in increased cardiac inflammation and fibrosis. This work suggests that AKAP12 loss aggravates joint inflammation likely through the promotion of M1 macrophage polarization and exacerbates inflammation-caused cardiac fibrosis.

Therapeutic effects of dracocephalum heterophyllum in collagen-induced arthritis

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease characterized by synovial inflammation, joint swelling, and cartilage and bone destruction. Dracocephalum heterophyllum (DH) is a compound in traditional Chinese herbal medicine well known for its anti-inflammatory, antiviral and antioxidant activities. In the present work, the therapeutic effects of DH were investigated in collagen-induced arthritis. Arthritis severity was assessed by clinical score, X-ray, and histopathological features. Expression of inflammatory cytokines was detected by qPCR and ELISA whereas anti-type II collagen antibodies were determined by ELISA. DH treatment significantly alleviated clinical scores, synovial inflammation, joint swelling, and cartilage and bone destruction. DH also reduced the production of inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin-1β (IL-1β), and decreased the serum levels of anti-type II collagen specific IgG antibodies in collagen-induced arthritis. The therapeutic effects of DH in collagen-induced arthritis provide evidence that DH might be a potential therapeutic drug for rheumatoid arthritis.

During development of rheumatoid arthritis, intermetatarsal bursitis may occur before clinical joint swelling: a large imaging study in patients with clinically suspect arthralgia.

ObjectivesIntermetatarsal bursitis (IMB) represents juxta-articular synovial inflammation of the intermetatarsal bursae. Recent MRI studies identified IMB as feature of early RA, but whether IMB already occurs in the pre-arthritic phase is unknown. We performed a large MRI study in clinically suspect arthralgia (CSA) to assess the occurrence and prognostic value of IMB.MethodsA total of 577 consecutive CSA patients underwent contrast-enhanced MRI of the forefoot, metacarpophalangeal joints and wrist. MRIs were evaluated for subclinical synovitis/tenosynovitis/osteitis in line with the RA MRI scoring system (summed as RAMRIS inflammation) and for IMB. IMB was considered present if uncommon in the general population at the same location (i.e. size scored above the 95th percentile in age-matched symptom-free controls). The relation of IMB with other MRI-detected subclinical inflammation (synovitis/tenosynovitis/osteitis) was studied. Cox-regression assessed the association with clinical arthritis development during median 25 months follow-up. ACPA stratification was performed.ResultsAt presentation with CSA, 23% had IMB. IMB was more frequent in ACPA-positive than ACPA-negative CSA (47% vs 19%, P < 0.001). Patients with IMB were more likely to also have subclinical synovitis [OR 3.4 (95% CI 1.8, 6.5)] and tenosynovitis [5.9(2.8, 12.6)]. IMB conferred higher risk of developing arthritis [HR 1.6(1.0–2.7) adjusted for other subclinical inflammation]. IMB-presence predicted arthritis development in ACPA-positive CSA [adjusted HR 2.2(1.0–4.7)], but not in ACPA-negative CSA-patients [0.8(0.4–1.7)].ConclusionApproximately a quarter of CSA patients have IMB, which is frequently accompanied by subclinical synovitis and tenosynovitis. IMB precedes development of clinical arthritis, particularly in ACPA-positive CSA. These results reinforce the notion that juxta-articular synovial inflammation is involved in the earliest phases of RA development.

Wilforlide A ameliorates the progression of rheumatoid arthritis by inhibiting M1 macrophage polarization

Rheumatoid arthritis (RA) is an autoimmune disease with increased M1 macrophages. The classical activated M1 macrophages produce various cytokines to control inflammation. Wilforlide A is a natural product that displays anti-inflammatory activities. However, the effect of Wilforlide A on RA progression and the potential mechanisms are unclear. Herein, the collagen-induced arthritis (CIA) mouse was used as an experimental model of RA. The administration of Wilforlide A reduced clinical scores, joint swelling and histological damage in ankle joints of RA mice. The secreted pro-inflammatory factors (MCP1, GM-CSF and M-CSF) and M1 biomarker iNOS in synovium were inhibited by Wilforlide A. In vitro, macrophages deriving from THP-1 cells were stimulated with LPS/IFN-γ to mimic M1 polarization. Similarly, Wilforlide A blocked macrophages polarizing towards M1 subsets. The in vitro results demonstrated that Wilforlide A suppressed LPS/IFN-γ-induced TLR4 upregulation, IκBα degradation and NF-κB p65 activation. In addition, TAK242 (a TLR4 inhibitor) treatment caused a similar inhibitory effect on M1 polarization with Wilforlide A, whereas it was less than the combination of TAK242 and Wilforlide A. Therefore, this work supports that Wilforlide A ameliorates M1 macrophage polarization in RA, which is partially mediated by TLR4/NF-κB signaling pathway inactivation.

Effect of Orally-administration Niclosamide on serum level of VCAM-1 and E-selectin in Collagen induced arthritis: Experimental study

Soluble adhesion molecules (mainly VCAM-1 and E-selectin) have a vital role in the pathogenesis of the rheumatoid arthritis (RA) and consider as angiogenic mediators for this disease. The main goal for this research is to evaluate the efficacy of orally administer niclosamide (NCS) in prevention the angiogenic mediators (VCAM-1 and E-selectin) using collagen induced arthritis model in rats (CIA). Fifty male Spraque-Dawley rats underwent collagen induced arthritis (CIA) model. When arthritis was fully developed, the rats were either treated orally with low-dose (50mg/kg) NCS or high-dose (100mg/kg) NCS or treated intrapertonially (IP) with 30mg/kg NCS or leave without treatment for 4 weeks. Body weight measurement and arthritis index were monitor before and after treatment in all groups. At the end of the treatment period serum level of vascular cell adhesion molecule-1 (VCAM-1), E-selectin and TNFα were measured together with collection of articular synovial tissue to evaluate the pathological changes. The experiment showed that NCS significantly reduce the arthritis index, foot pad thickness and ankle swelling (p value &lt; 0.05) when given orally in a high dose and IP to the experimental animal. Comparing to the CIA model group, significant reduction in the serum level of VCAM1 and E-selectin has been observed in those rats treated with high dose of oral NCS or IP injection of NCS (p value &lt; 0.05). Niclosamide can effectively decrease, in dose dependent manner, the clinical scores, joint swelling, VCAM1, E-selectin and pathological changes in arthritic rats induced by collagen type II.

Implication of baseline levels and early changes of C-reactive protein for subsequent clinical outcomes of patients with rheumatoid arthritis treated with tocilizumab

BackgroundRheumatoid arthritis (RA) is characterised by clinical joint swelling and elevation of acute phase reactant levels, typically measured by the C-reactive protein (CRP). Clinical and inflammatory responses are usually concordant,...

The Anti-Rheumatoid Activity of Niclosamide in Collagen-Induced Arthritis in Rats.

This study aims to evaluate the anti-arthritic effect of orally administered niclosamide (NCL) on collagen-induced arthritis (CIA) in rats. The study included 35 Sprague Dawley rats (age range, 3 to 4 months; average weight, 100±10 g) of which seven were used as a negative control group (group A) whereas 28, in which arthritis was induced by injection of collagen type II emulsified by incomplete Freund's adjuvant and which were considered as CIA rats, were randomly divided equally into four groups and treated for 28 days with: normal saline (group B), low-dose NCL (group C), high-dose NCL (group D), and diclofenac sodium (group E). Body weight, arthritis index, ankle swelling, and footpad thickness were monitored before and after treatment in all groups. At the end of the treatment period, serum levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and IL-6 were measured together with a collection of articular synovial tissue to evaluate the pathological changes. After four weeks of treatment period, a high dose of orally administered NCL significantly reduced the arthritis index, footpad thickness, and ankle swelling. Significantly decreased serum levels of inflammatory biomarkers including TNF-α, IL-1β, and IL-6 were observed in rats treated with high-dose oral NCL or intramuscular injection of diclofenac sodium, compared with groups B and C. Histopathological examination revealed that a high dose of NCL significantly reduced the infiltration of inflammatory cells, synovial hyperplasia, and bone and cartilage destruction. Niclosamide can effectively decrease the clinical scores, joint swelling, inflammatory markers, and pathological changes in arthritic rats.

Endogenous glucocorticoid signaling in chondrocytes attenuates joint inflammation and damage.

Previous studies demonstrated that endogenous glucocorticoid signaling in osteoblasts promotes inflammation in murine immune arthritis. The current study determined whether disruption of endogenous glucocorticoid signaling in chondrocytes also modulates the course and severity of arthritis. Tamoxifen-inducible chondrocyte-targeted glucocorticoid receptor-knockout (chGRKO) mice were generated by breeding GRflox/flox mice with tamoxifen-inducible collagen 2a1 Cre (Col2a1-CreERT2) mice. Antigen-induced arthritis (AIA) and K/BxN serum transfer-induced arthritis (STIA) were induced in both chGRKO mice and their Cre-negative GRflox/flox littermates [wild type (WT)]. Arthritis was assessed by measurement of joint swelling and histology of joints collected at d 14. Neutrophil activity and gene expression patterns associated with cartilage damage were also evaluated. In both arthritis models clinical (joint swelling) and histologic indices of inflammatory activity were significantly greater in chGRKO than in WT mice. The STIA model was characterized by early up-regulation of CXCR2/CXCR2 ligand gene expression in ankle tissues, and significant and selective expansion of splenic CXCR2+ neutrophils in chGRKO arthritic compared to WT arthritic mice. At later stages, gene expression of enzymes involved in cartilage degradation was up-regulated in chGRKO but not WT arthritic mice. Therefore, we summarize that chondrocytes actively mitigate local joint inflammation, cartilage degradation and systemic neutrophil activity via a glucocorticoid-dependent pathway.-Tu, J., Stoner, S., Fromm, P. D., Wang, T., Chen, D., Tuckermann, J., Cooper, M. S., Seibel, M. J., Zhou, H. Endogenous glucocorticoid signaling in chondrocytes attenuates joint inflammation and damage.

A83: Power Doppler Visualization of Epiphyseal and Growth Plate Vascularity in Affected and Contralateral Unaffected Joints in Patients with Juvenile Idiopathic Arthritis

Background/Purpose:Children with juvenile idiopathic arthritis (JIA) may develop limb asymmetry, thought to be mediated by growth plate hyperemia adjacent to areas of synovial inflammation. Synovial hyperemia signifies active inflammatory arthritis in adults and vessels visible within in the joint capsule are considered abnormal. In growing children, however, blood vessels supplying the growth plate and surrounding areas are frequently visible sonographically even in unaffected joints, but have not been described systematically. We used power Doppler (PD) to compare epiphyseal and growth plate vascularity in affected and contralateral unaffected joints in children with clinically asymmetric inflammatory arthritis.Methods:Children between 2 and 16 years of age who had clinical joint swelling in one ankle or knee but not the contralateral joint were examined with gray scale (GS) and PD ultrasound using a Philips CX50 machine (5–12 mHz linear transducer). Images (GS) and video clips (PD) were taken at the knees (medial, lateral, posteromedial and posterolateral femoral condyles, medial and lateral proximal tibia, and lateral proximal fibula), or ankles (anterior and medial distal tibia and lateral distal fibula), in addition to standard images to document disease activity. Vessels were noted as present or absent in each view, and localized as epiphyseal cartilage, growth plate, or periosteal.Results:Knees of 8 subjects and ankles of 3 subjects were imaged. The most common vessels seen were extraarticular, parallel to the periosteum but not visibly entering cartilage or joint spaces. Vessels were visible in the epiphyseal cartilage in the majority of the lateral femur, medial femur, and anterior distal tibial views, and less frequently in the posterolateral femoral condyle, posteromedial femoral condyle, proximal lateral tibia, proximal medial tibia, and proximal fibula. Four subjects had vessels seen within the growth plate; 3 of these were in the lateral aspect of the knee, and one in the anterior ankle. Visible vessels by location* total ≥ of paired views Knee distal lateral femur distal medial femur posterolateral femur posteromedial femur proximal medial tibia proximal lateral tibia proximal fibula Ankle distal anteriortibia distal medialtibia distal fibula n = 8 n = 6 n = 7 n = 7 n = 6 n = 8 n = 7 n = 3 n = 3 n = 3 a u a u a u a u a u a u a u a u a u a u epiphyseal 5 (63) 6 (75) 4 (67) 4 (67) 1 (14) 0 (0) 2 (29) 0 (0) 2 (33) 2 (33) 3 (38) 3 (38) 1 (14) 2 (29) 1 (33) 2 (67) 0 (0) 0 (0) 0 (0) 0 (0) growth plate 2 (25) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (13) 2 (25) 0 (0) 0 (0) 1 (33) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) periosteal 5 (63) 7 (88) 6 (100) 5 (83) 4 (57) 3 (43) 2 (29) 0 (0) 4 (67) 4 (67) 7 (88) 7 (88) 2 (29) 2 (29) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) a=affected, u=unaffected. number(percentage)Conclusion:This is the first study to our knowledge that specifically addresses the sonographic appearance of vessels within the growth plate and epiphyseal cartilage in JIA. These vessels were readily seen, especially within the epiphyseal cartilage, suggesting that this methodology is appropriate for further study. There was no clear difference between vascularity of clinically swollen and unaffected joints. Though this was a small population, this finding raises questions about hyperemia as the mechanism leading to the growth asymmetry seen in children with JIA. Future work should include a larger population, greater age representation to explore differing vascularity related to age and pubertal status, and healthy controls.

Sonographic Joint Assessment in Rheumatoid Arthritis: Associations With Clinical Joint Assessment During a State of Remission

Sonography, as compared with clinical assessment, is a sensitive tool for evaluating synovitis in rheumatoid arthritis (RA). However, differences between these assessment tools may depend on how joint activity (i.e., an active joint) is defined. The present study was undertaken to compare clinically active joints with sonographically active joints in patients with RA, applying different sonographic definitions of an active joint. Sonographic assessment of the finger and wrist joints (total of 11 joints) of each hand was performed in RA patients whose disease was in remission (Clinical Disease Activity Index ≤2.8; n = 60). Gray-scale (GS) and power Doppler (PD) ultrasound signals for synovitis were evaluated on a 4-point scale (grade 0 = none, grade 3 = severe). The sensitivity and specificity of swollen joint counts were investigated using, as reference, increasingly stringent sonographic definitions of an active joint. Sonographic findings were also assessed for correlations with other clinical variables, including the Health Assessment Questionnaire (HAQ) disability index (DI). Followup analyses were performed after 6-12 months. GS ultrasound signals yielded positive findings for synovitis in 67.2% of the 1,320 joints assessed, and PD ultrasound signals indicated signs of synovitis in 20.4% of the joints assessed. Clinical identification of joint swelling was 100% specific for sonographic joint activity, independent of the stringency of the sonographic definition used; maximum sensitivity of the swollen joint counts was 25% for the most stringent definition (i.e., GS grade 3 and PD grade 3). Furthermore, patients with a higher-grade PD signal (grade 3) showed a higher HAQ DI score compared to patients with lower-grade PD signals (mean ± SD HAQ DI 0.45 ± 0.62 versus 0.20 ± 0.35). A higher grade of PD signal at baseline was found in joints that were assessed as clinically swollen at the consecutive followup visit. Low-grade PD and GS ultrasound signals may not necessarily reflect the presence of active synovitis in RA joints. High-grade PD signals correlate well with the presence of clinical joint swelling and clinical disease activity, and a higher grade of PD signal is associated with higher degrees of functional impairment.

OP0174 Ultrasonographic Findings in an Inception Cohort of 175 Dmard NaïVe Rheumatoid Arthritis Patients

BackgroundThe use of ultrasonography (US) for investigation and management of RA is rapidly increasing. However, to our knowledge there have not been any studies with systematical reporting of US findings...

OP0173 Concordance Between Joint Swelling or Tenderness at Physical Examination and Inflammation on MRI in Early Arthritis Patients

BackgroundMagnetic Resonance Imaging (MRI) is increasingly used to measure disease activity in Rheumatoid Arthritis (RA) patients for research purposes. A main advantage of MRI is that it measures inflammation of...

OP0197 CGEN-15001, A Novel Negative Co-Stimulator Fusion Protein is Effective in the Collagen-Induced Arthritis Mouse Model of Rheumatoid Arthritis

BackgroundCGEN-15001 is a fusion protein composed of the extracellular domain of CGEN-15001T fused to IgG Fc. CGEN-15001T was recently identified as a novel member of the B7/CD28 costimulatory family based...

Inhibition of cartilage degradation in rat collagen-induced arthritis but not adjuvant arthritis by the neutrophil elastase inhibitor MDL 101,146.

The neutrophil elastase inhibitor MDL 101,146 was examined for its anti arthritic effect and to determine the role of neutrophil elastase in collagen-induced arthritis and adjuvant arthritis. The collagen-induced arthritis model was performed in female DA rats immunized on day 0 an 1.7 with chick type II collagen in Freund's incomplete adjuvant. Adjuvant arthritis was induced in female Lewis rats by an intradermal injection of heat-killed Mycobacterium tuberculosis H37RA. The clinical signs of arthritis were assessed, joint swelling was measured using calipers and bone degradation, new bone proliferation, pannus formation and cartilage degradation were evaluated histologically. MDL 101,146 administered orally inhibited the severity of collagen-induced arthritis as measured by a reduction in clinical score and joint swelling. Histological evaluation demonstrated a bone and cartilage sparing effect of MDL 101,146 in the tibio-tarsal joint of animals with collagen-induced arthritis. These results suggest that destruction of the joint in collagen-induced arthritis is at least partially due to neutrophil elastase.

Pathogenicity of field isolates of Erysipelothrix rhusiopathiae in mice, rats and pigs

Eight field isolates of Erysipelothrix rhusiopathiae serotypes 1 and 2, from different sources, were examined for their pathogenicities for mice and pigs. Arthritogenicity for pigs correlated with virulence for mice at the highest and lowest levels, but not with strains of intermediate virulence. The most virulent strain was also arthritogenic in rats. In pigs, after repeated intravenous challenge the number of affected joints ranged from 0 to 11 of 12 examined. For the 8 strains, the mean number of affected joints ranged from 1 to 7.7 per pig. Clinical course and pathological findings were correlated, but the onset, severity and duration of lameness was variable both within and between groups. Clinical lameness, joint swelling and urticariae were of limited use as indicators of joint changes. The more virulent strains caused lameness as early as 2 days, whereas strains of low virulence took up to 8 weeks.