Synovitis Score Research Articles

OA02 Longitudinal high throughput proteomics identifies novel proteins associated with inflammation and future response in new-onset, treatment-naïve rheumatoid arthritis

Abstract Background/Aims Despite the availability of effective targeted therapies, only 20-30% achieve low disease activity and even fewer attain remission. There remains a pressing need to identify meaningful biomarkers and disease endotypes to enable precision medicine. We aimed to identify serum protein biomarkers that associate with RA inflammation and future remission in a treatment-naïve, new-onset RA trial cohort. Methods Serum from 105 patients from the ‘VEDERA’ trial (first-line tumour necrosis factor inhibitor + methotrexate [TNFi + MTX] versus methotrexate treat-to-target [MTX-TT]) at baseline, week 24 and 48 were analysed for 92 proteins using the Olink Target 96 Inflammation panel. Clinical and MSUS assessments completed at baseline, weeks 24 and 48 were used for the analyses. Clinical remission was defined as DAS28-ESR ≤ 2.6 and joint-level remission as absence of power Doppler ultrasound synovitis (PDUS). After adjusting for age, gender and seropositive status, Bayesian mixed effects regression (posterior estimates and 95% credible intervals reported) was used to identify association of (i) proteins with clinical disease activity (DAS28-ESR) and joint-level inflammation (total power Doppler ultrasound synovitis (PDUS) scores] and (ii) baseline proteins with future (week 24 or 48) clinical and joint-level remission. Results Longitudinally, out of 92 proteins, 10 and 14 were significantly associated with DAS28-ESR and total PDUS scores respectively, with 3 proteins in common: leukaemia inhibitory factor receptor (LIF-R); fractalkine (CX3CL1); interleukin-10 receptor alpha (IL-10RA). Baseline levels of 9 proteins were associated with future clinical remission (week 24 = 6 proteins; week 48 = 3 proteins) while 6 were associated with future PDUS status (week 24 = 4 proteins; week 48 = 3 proteins). Proteins that were associated with inflammation longitudinally and whose baseline levels associated with future remission included IL-17C, fibroblast growth factor 5 (FGF-5), lymphotoxin alpha and TNF. Posterior estimates and 95% credible intervals for above proteins are reported in Table 1. Conclusion Using longitudinal high-throughput proteomics in a treatment-naïve early onset RA cohort, this study sheds new light on known and novel protein associates of inflammation and future remission. With future validation, these biomarkers could provide mechanistic understanding and allow for individualised treatment strategies to improve outcomes. Disclosure R. Shukla: None. R. Wakefield: None. A. Tan: None. P. Emery: Consultancies; BristolMyersSquibb, AbbVie, Gilead, Galapagos, Eli Lilly, MSD, Pfizer, Novartis, Roche and Samsung. Grants/research support; AbbVie, Eli Lilly, Novartis, BristolMyersSquibb, Pfizer and Roche, outside the submitted work. D. Plant: None. M.H. Buch: Consultancies; AbbVie, Arxx Therapeutics, Boehringer Ingelheim, Galapagos, Gilead, and Pfizer; and speaker fees from AbbVie, CESAS Medical, Galapagos, Gilead, Medistream, and Pfizer. Grants/research support; grant support from Gilead.

E058 Disease activity measurement in rheumatoid arthritis - simpler in not always better!

Abstract Background/Aims Rheumatoid arthritis is one of the commonest inflammatory arthritis (1). The traditional method of disease activity assessment would incorporate activity measures like DAS 28, CDAI and SDAI which have been validated in clinical research (2). All these indices use 28 joint assessment method. These measures use different aspects of disease activity including swollen joint count, tender joint count, patient global scores and physician global assessment scores and inflammatory markers are included in some of the measures. We conducted a small study to compare these outcome measures in patients with moderate RA (per DAS criteria) who were recruited for disease activity assessment through MSK ultrasound. Methods Of the 30 biologic naive patients recruited, 27 were included in this study. Patients with moderate disease activity (per DAS criteria) were recruited for MSK ultrasound evaluation by a single rheumatologist. Patients with a diagnosis of fibromyalgia were excluded. These patients had been reviewed by two assessors prior to USS assessment and disease activity measures updated. Patient data was collected through electronic patient records. Data was analysed through MS Excel. Results The median age was 63. There were 66% females and 34% male patients. Majority were sero positive for either RhF, Anti CCP or both (77%). Mean DAS-28 score was 4.4 and corresponding mean CDAI and SDAI scores were 22.8 and 23.5 respectively. Mean HAQ score 1.08 and median CRP was 8.6. The median composite EULAR OMERACT synovitis score was 9.18. The average physician global assessment score for disease activity before USS was 4.9/10 and it correlated well with decision to escalate treatment in 41% patients as a result of USS assessment. Conclusion With a small sample size, this project shows that simplified disease activity measures do not necessarily provide clear evidence of disease activity and are heavily influenced by patient reported outcome measures (tender joint count and global pain scores). CDAI scores can be slightly higher compared to DAS and SDAI scores for the similar patients. Physician assessment and ultrasound can provide robust evaluation of disease activity and help in decision-making. A multicentric study with a large simple size to evaluate these findings would be helpful. Judicious use of clinical evaluation and imaging can help in tailoring treatment according to patient’s clinical condition and can also save money. Disclosure H. Crawshaw: None. E. Gates: None. C. Acebes: None. M. Jamal: None.

Syndecans, Exostosins and Sulfotransferases as Potential Synovial Inflammation Moderators in Patients with Hip Osteoarthritis.

The gradual deterioration of articular cartilage was thought to be the central event in osteoarthritis (OA), but recent studies demonstrated the importance of low-grade synovitis in the progression of OA. The Syndecan (SDC) family of membrane proteoglycans is known to be involved in the regulation of inflammation, but there is limited evidence considering the role of syndecans in OA synovitis. Our study aimed to investigate the hip OA synovial membrane expression patterns of SDC1, SDC2 and SDC4, as well as exostosins and sulfotransferases (enzymes involved in the polymerisation and modification of syndecans' heparan sulphate chains). Synovial membrane samples of patients with OA (24) were divided into two groups according to their Krenn synovitis score severity. The immunohistochemical expressions of SDC1, SDC2, SDC4, EXT1, EXT2, NDST1 and NDST2 in synovial intima and subintima were then analysed and compared with the control group (patients with femoral neck fracture). According to our study, the immunoexpression of SDC1, NDST1 and EXT2 is significantly increased in the intimal cells of OA synovial membrane in patients with lower histological synovitis scores and SDC4 in patients with higher synovitis scores, in comparison with non-OA controls. The difference in the expression of SDC2 among the OA and non-OA groups was insignificant. SDC1, SDC4, NDST1 and EXT2 seem to be involved as inflammation moderators in low-grade OA synovitis and, therefore, should be further investigated as potential markers of disease progression and therapeutic goals.

How Does Ultrasound Global OMERACT-EULAR Synovitis Score (GLOESS) for Rheumatoid Arthritis (RA) Activity Assessment Perform in Real-Life?

This study aimed to assess the effectiveness of the Global OMERACT-EULAR Synovitis Score (GLOESS) of bilateral second to fifth metacarpophalangeal joints (MCP 2-5) in evaluating rheumatoid arthritis (RA) activity in a real-life setting. This cross-sectional study included consecutive RA patients without hyperalgesia. Clinical data were extracted from electronic medical records. Evaluations were conducted on bilateral MCP 2-5 by two independent experts in musculoskeletal ultrasound (MSUS). Correlation between clinical and ultrasonographic parameters was analyzed, aiming to define a cutoff value for detecting disease activity. Sixty-nine patients were included. The mean DAS28-ESR was 4.3 (±1.4), and the median GLOESS was 7 (13). The correlation between GLOESS and DAS28 was moderate (r = .62; P < .05). A total GLOESS score of ≤3 and all joints with both GS and PD ≤1 showed good sensitivity and specificity for detecting disease activity (remission/low vs moderate/high, P = 0). In a real-life scenario, GLOESS for MCP 2-5 emerges as a valuable measure of RA activity. The optimal cutoff distinguishing remission/low from moderate/high disease activity was determined to be GLOESS ≤3, with all MCP joints exhibiting both GS and PD scores of ≤1.

Nanomedicines Promote Cartilage Regeneration in Osteoarthritis by Synergistically Enhancing Chondrogenesis of Mesenchymal Stem Cells and Regulating Inflammatory Environment.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive erosion of the articular cartilage and inflammation. Mesenchymal stem cells' (MSCs) transplantation in OA treatment is emerging, but its clinical application is still limited by the low efficiency in oriented differentiation. In our study, to improve the therapeutic efficiencies of MSCs in OA treatment by carbonic anhydrase IX (CA9) siRNA (siCA9)-based inflammation regulation and Kartogenin (KGN)-based chondrogenic differentiation, the combination strategy of MSCs and the nanomedicine codelivering KGN and siCA9 (AHK-CaP/siCA9 NPs) was used. In vitro results demonstrated that these NPs could improve the inflammatory microenvironment through repolarization of M1 macrophages to the M2 phenotype by downregulating the expression levels of CA9 mRNA. Meanwhile, these NPs could also enhance the chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) by upregulating the pro-chondrogenic TGF-β1, ACAN, and Col2α1 mRNA levels. Moreover, in an advanced OA mouse model, compared with BMSCs alone group, the lower synovitis score and OARSI score were found in the group of BMSCs plus AHK-CaP/siCA9 NPs, suggesting that this combination approach could effectively inhibit synovitis and promote cartilage regeneration in OA progression. Therefore, the synchronization of regulating the inflammatory microenvironment through macrophage reprogramming (CA9 gene silencing) and promoting MSCs oriented differentiation through a chondrogenic agent (KGN) may be a potential strategy to maximize the therapeutic efficiency of MSCs for OA treatment.

Correlation of US-7 and US-9 Scores with Disease Activity Score using 28 Joint Counts (DAS28) in Patients with Rheumatoid Arthritis.

The attentive management of rheumatoid arthritis (RA) has attracted particular attention. The German 7-joint Ultrasound (US-7) is the first scoring system that combines bone erosions and soft tissue lesions in a single composite scoring system. This study aimed to assess the correlation between US-7 and Disease Activity Score Using 28 Joint Counts (DAS28) in clinically active RA patients. The efficacy of a novel ultrasound score-based system, the US-9 score (joints assessed with US-7 plus knees), was also compared with the standard US-7 score. All the RA patients referred to the outpatient rheumatology clinic of Ghaem Hospital, Mashhad, Iran, during 2019-2020 were included. 28 joints were clinically examined to calculate DAS28. Nine joints were assessed comprising the German US-7 plus knees using grayscale ultrasonography (GSUS) and power Doppler ultrasonography (PDUS). Retrieved data were analyzed by SPSS software, version 22. The Spearman Correlation test was used to find the correlation between DAS28 and ultrasonographic findings. The statistical significance level was set at P<0.05. This study was composed of thirty-five RA patients with a mean age of 49.1±12.0 years. US-7 synovitis scores in GSUS and PDUS were significantly correlated with DAS28 (P=0.02, r=0.38 and P=0.003, r=0.48, respectively). US-9 synovitis scores in GSUS and PDUS were also significantly correlated with DAS28 (P=0.003, r=0.49 and P=0.006, r=0.45, respectively). The synovitis score measured by GSUS was significantly correlated with the GSUS knee synovial score (P=0.01, r=0.42). Ultrasound assessment of large joints such as knees can be an effective approach to determining RA severity. However, it can be proposed that adding more involved joints into the sonographic assessment does not necessarily provide a better clinical correlation.

Transcript-dependent effects of the CALCA gene on the progression of post-traumatic osteoarthritis in mice

Osteoarthritis represents a chronic degenerative joint disease with exceptional clinical relevance. Polymorphisms of the CALCA gene, giving rise to either a procalcitonin/calcitonin (PCT/CT) or a calcitonin gene-related peptide alpha (αCGRP) transcript by alternative splicing, were reported to be associated with the development of osteoarthritis. The objective of this study was to investigate the role of both PCT/CT and αCGRP transcripts in a mouse model of post-traumatic osteoarthritis (ptOA). WT, αCGRP−/− and CALCA−/− mice were subjected to anterior cruciate ligament transection (ACLT) to induce ptOA of the knee. Mice were sacrificed 4 and 8 weeks post-surgery, followed by micro-CT and histological evaluation. Here we show that the expression of both PCT/CT and αCGRP transcripts is induced in ptOA knees. CALCA−/− mice show increased cartilage degeneration and subchondral bone loss with elevated osteoclast numbers compared to αCGRP−/− and WT mice. Osteophyte formation is reduced to the same extent in CALCA−/− and αCGRP−/− mice compared to WT controls, while a reduced synovitis score is noticed exclusively in mice lacking CALCA. Our data show that expression of the PCT/CT transcript protects from the progression of ptOA, while αCGRP promotes osteophyte formation, suggesting that CALCA-encoded peptides may represent novel targets for the treatment of ptOA.

Comprehensive in vitro and in vivo investigations of the therapeutic potential of Jeju lava seawater salt in osteoarthritis

Salts play a crucial role in maintaining human health by regulating fluid levels and supporting various physiological processes. However, conventional seawater-derived salts are associated with microplastic pollution and pose potential health risks. Jeju lava seawater (JLS), sourced exclusively from Jeju Island, has emerged as a unique alternative, free of microplastics and enriched with essential minerals such as magnesium, calcium, zinc, and iron. In this study, we investigated the effects of JLS on osteoarthritis (OA) pathogenesis, focusing on chondrocyte metabolism and OA development. We performed surgical destabilization of the medial meniscus to establish a murine model of OA. We examined the expression of catabolic and anabolic factors in JLS-treated chondrocytes. Our cell viability assay revealed that JLS treatment was not cytotoxic to chondrocytes at concentrations ≤ 0.5%. Additionally, JLS treatment resulted in a concentration-dependent increase in the expression of anabolic factors like aggrecan, SOX9, and COL2A1 while decreasing the expression of catabolic factors such as MMP3, MMP13, ADAMTS4, and ADAMTS5 in the chondrocytes stimulated with pro-inflammatory cytokines. Although not statistically significant compared to the control group, JLS intake slightly attenuated the OARSI score, osteophyte score, synovitis score, subchondral bone thickness, and osteophyte size in the mouse model of OA. Conclusively, these results suggest that JLS ameliorates OA by positively influencing chondrocyte metabolism, making it a promising therapeutic candidate for OA management.

Development of patellofemoral osteoarthritis with knee joint malalignment and lateral patellar dislocation after hindlimb suspension in growing rats.

Knee malalignment is a risk factor for patellar instability and patellofemoral osteoarthritis (PFOA), but etiologies remain unknown. We investigated the potential effects of decreased weight loading during growth on knee alignments and patellofemoral (PF) joint pathology. Hindlimb suspension (HS) was performed in 4-week-old female rats for 2, 4, and 8 weeks (HS groups). Age-matched rats were used as controls. Three-dimensional reconstructed images of the knee were obtained using X-ray computed tomography. Tibial tubercle-trochlear groove (TT-TG) distance, patellar tilt angle, and bisect offset were measured as indices of knee alignment. Histological analysis was also performed to evaluate the changes in cartilage and synovium in the PF joints. At Week 8, TT-TG distance, patella tilt angle, and bisect offset were significantly larger in the HS group than in the control group, respectively, indicating tibial external rotation, outward patellar tilt, and external displacement of the patella. Lateral patellar dislocation was frequently found in the HS group at Week 8 (five of eight knee joints, p < 0.05). Degenerative changes in the cartilage of the trochlear groove were observed at Week 8, and synovial changes such as hypertrophy and synovitis were observed at Weeks 4 and 8. Correlation analyses revealed significant relationships between the Mankin score and bisect offset, and between the OARSI synovitis score and all knee alignments indices. These results suggest that decreased weight loading on the lower extremities in growing rats resulted in knee malalignments characterized by external rotation of tibia and high incidence of lateral patellar dislocation with concomitant PFOA.

Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial

Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. Bristol Myers Squibb.

Inflammatory Knee Synovitis: Evaluation of an Accelerated FLAIR Sequence Compared With Standard Contrast-Enhanced Imaging.

The aim of this study was to assess the diagnostic value and accuracy of a deep learning (DL)-accelerated fluid attenuated inversion recovery (FLAIR) sequence with fat saturation (FS) in patients with inflammatory synovitis of the knee. Patients with suspected knee synovitis were retrospectively included between January and September 2023. All patients underwent a 3 T knee magnetic resonance imaging including a DL-accelerated noncontrast FLAIR FS sequence (acquisition time: 1 minute 38 seconds) and a contrast-enhanced (CE) T1-weighted FS sequence (acquisition time: 4 minutes 50 seconds), which served as reference standard. All knees were scored by 2 radiologists using the semiquantitative modified knee synovitis score, effusion synovitis score, and Hoffa inflammation score. Diagnostic confidence, image quality, and image artifacts were rated on separate Likert scales. Wilcoxon signed rank test was used to compare the semiquantitative scores. Interreader and intrareader reproducibility were calculated using Cohen κ. Fifty-five patients (mean age, 52 ± 17 years; 28 females) were included in the study. Twenty-seven patients (49%) had mild to moderate synovitis (synovitis score 6-13), and 17 patients (31%) had severe synovitis (synovitis score >14). No signs of synovitis were detected in 11 patients (20%) (synovitis score <5). Semiquantitative assessment of the whole knee synovitis score showed no significant difference between the DL-accelerated FLAIR sequence and the CE T1-weighted sequence (mean FLAIR score: 10.69 ± 8.83, T1 turbo spin-echo FS: 10.74 ± 10.32; P = 0.521). Both interreader and intrareader reproducibility were excellent (range Cohen κ [0.82-0.96]). Assessment of inflammatory knee synovitis using a DL-accelerated noncontrast FLAIR FS sequence was feasible and equivalent to CE T1-weighted FS imaging.

Tranexamic Acid Attenuates the Progression of Posttraumatic Osteoarthritis in Mice

Background: Posttraumatic osteoarthritis (OA) is a common disorder associated with a high socioeconomic burden, particularly in young, physically active, and working patients. Tranexamic acid (TXA) is commonly used in orthopaedic trauma surgery as an antifibrinolytic agent to control excessive bleeding. Previous studies have reported that TXA modulates inflammation and bone cell function, both of which are dysregulated during posttraumatic OA disease progression. Purpose: To evaluate the therapeutic effects of systemic and topical TXA treatment on the progression of posttraumatic OA in the knee of mice. Study Design: Controlled laboratory study. Methods: OA was induced via anterior cruciate ligament (ACL) transection on the right knee of female mice. Mice were treated with TXA or vehicle intraperitoneally daily or intra-articularly weekly for 4 weeks, starting on the day of surgery. Articular cartilage degeneration, synovitis, bone erosion, and osteophyte formation were scored histologically. Micro−computed tomography evaluation was conducted to measure the subchondral bone microstructure and osteophyte volume. Cartilage thickness and bone remodeling were assessed histomorphometrically. Results: Both systemic and topical TXA treatment significantly reduced cartilage degeneration, synovitis, and bone erosion scores and increased the ratio of hyaline to calcified cartilage thickness in posttraumatic OA. Systemic TXA reversed ACL transection-induced subchondral bone loss and osteophyte formation, whereas topical treatment had no effect. Systemic TXA decreased the number and surface area of osteoclasts, whereas those of osteoblasts were not affected. No effect of topical TXA on osteoblast or osteoclast parameters was observed. Conclusion: Both systemic and topical TXA exerted protective effects on the progression of posttraumatic OA. Drug repurposing of TXA may, therefore, be useful for the prevention or treatment of posttraumatic OA, particularly after ACL surgery. Clinical Relevance: TXA might be beneficial in patients with posttraumatic OA of the knee.

Blood flow velocity in the anterior humeral circumflex artery and tear size can predict synovitis severity in patients with rotator cuff tears.

Rotator cuff tears are often associated with synovitis, but the ability of noninvasive ultrasonography to predict the severity of synovitis remains unclear. We investigated whether ultrasound parameters, namely peak systolic velocity in the anterior humeral circumflex artery and Doppler activity in the glenohumeral joint and subacromial space, reflect synovitis severity. A total of 54 patients undergoing arthroscopic rotator cuff repair were selected. Doppler ultrasound was used to measure peak systolic velocity in the anterior humeral circumflex artery and Doppler activity in the glenohumeral joint and subacromial space, and these values were compared with the intraoperative synovitis score in univariate and multivariate analyses. Univariate analyses revealed that tear size, peak systolic velocity in the anterior humeral circumflex artery, and Doppler activity in the glenohumeral joint were associated with synovitis in the glenohumeral joint (P=0.02, P<0.001, P=0.02, respectively). In the subacromial space, tear size, peak systolic velocity in the anterior humeral circumflex artery, and Doppler activity in the subacromial space were associated with synovitis severity (P=0.02, P<0.001, P=0.02, respectively). Multivariate analyses indicated that tear size and peak systolic velocity in the anterior humeral circumflex artery were independently associated with synovitis scores in both the glenohumeral joint and the subacromial space (all P<0.05). These findings demonstrate that tear size and peak systolic velocity in the anterior humeral circumflex artery, which can both be measured noninvasively, are useful indicators of synovitis severity. Level of evidence: IV.

Macrophage Activation in Synovitis and Osteoarthritis of Temporomandibular Joint and Its Relationship with the Progression of Synovitis and Bone Remodeling

This study investigates the regulatory mechanisms of synovial macrophages and their polarization in the progression of temporomandibular joint osteoarthritis (TMJOA). Macrophage depletion models were established by intra-articular injection of clodronate liposomes and unloaded liposomes. TMJOA was induced by intra-articular injection of 50 μL Complete Freund's Adjuvant and the surgery of disc perforation. The contralateral joint was used as the control group. The expression of F4/80, CD86, and CD206 in the synovium was detected by immunofluorescence staining analysis. Hematoxylin and eosin staining and TMJOA synovial score were detected to show the synovial changes in rat joints after TMJOA induction and macrophage depletion. Changes in rat cartilage after TMJOA induction and macrophage depletion were shown by safranin fast green staining. The bone-related parameters of rats' joints were evaluated by micro-computed tomography analysis. The TMJOA model induced by Complete Freund's Adjuvant injection and disc perforation aggravated synovial hyperplasia and showed a significant up-regulation of expression of F4/80-, CD86-, and CD206-positive cells. F4/80, CD86, and CD206 staining levels were significantly decreased in macrophage depletion rats, whereas the synovitis score further increased and cartilage and subchondral bone destruction was slightly aggravated. Macrophages were crucially involved in the progression of TMJOA, and macrophage depletion in TMJOA synoviocytes promoted synovitis and cartilage destruction.

High-grade synovitis associates with clinical markers and response to therapy in chronic inflammatory arthritis: post hoc analysis of a synovial biomarkers prospective cohort study.

Inflammatory arthritis (IAs), such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), are characterized by the presence of chronic synovitis. The Krenn's synovitis score (KSS), a simple tool detectable by haematoxylin/eosin staining of synovial biopsy samples, allows the discrimination between high-grade and low-grade synovitis. The aim of this study was to identify the clinical associations of KSS and to evaluate the relationship between high-grade synovitis and treatment response in IA patients. Clinical, laboratory and ultrasound data were retrieved from RA and PsA patients recruited in the prospective MATRIX cohort study. Inclusion criteria were age≥18 years, RA or PsA diagnosis, and presence of active disease with eligibility to start/modify therapy. Patients underwent ultrasound-guided synovial biopsy of one of the most involved joints before starting/modifying treatment according to treat-to-target strategy. The samples were analysed by an expert pathologist for KSS calculation. Univariable and multivariable logistic regression analyses were performed to evaluate the relationship between KSS and baseline variables. The association between KSS and treatment response at 24 weeks of follow-up was investigated in univariable logistic regression analysis. 53 patients, 34 RA and 19 PsA, completed 24 weeks of follow-up after synovial biopsy. Patients were either treatment naïve (N=6, 11%), csDMARDs-experienced (N=46, 87%) or b/tsDMARDs-experienced (N=20, 38%). Median KSS was 6.00 (Q1-Q3 4.00-7.00) in RA and 4.00 (3.00-6.00) in PsA (p=0.040), and inflammatory infiltrates score was significantly higher in RA than in PsA patients (median 3.00 vs 2.00, p=0.021). In multivariable analysis, synovial effusion in the biopsied joint (OR 9.26, 95%CI 2.12-53.91) and erythrocyte sedimentation rate (ESR) (OR 1.04, 95%CI 1.01-1.08) associated with high KSS. High-grade synovitis significantly associated with a higher probability of achieving DAS28 remission, ACR20/50 response, and Boolean2.0 remission, independently from diagnosis. Several markers of pro-inflammatory pathways associated with the presence of high-grade synovitis, and patients with higher KSS shared a higher probability of treatment targets achievement in the follow up. The integration of a simple and feasible tool like KSS in the clinical and prognostic stratification of patients with IA might help in intercepting patients with a disease more prone to respond to available treatment paradigms.

The Effects of Extracellular Matrix Allograft Administration on Knee Inflammation Following an Anterior Cruciate Ligament Injury in Mice

Background and Hypothesis:A human placental-derived extracellular matrix (ECM) allograft has previously been developed and is indicated by the manufacturer for reducing tissue inflammation and accelerated repair. To evaluate the efficacy of this product for reducing post-anterior cruciate ligament (ACL) injury inflammation, we used a novel murine in vivo ACL injury model. This model has previously been shown to induce significant synovitis, infrapatellar fat pad (IFP) fibrosis, and articular cartilage (AC) degradation within 2 weeks following an ACL injury. We hypothesized that intra-articular injections of the allograft would correspond with a decrease in synovitis, fibrosis, and articular cartilage degradation.&#x0D; Experimental Design or Project Methods:Ten-week-old C57BL/6J mice were randomly placed into 4 groups (n=10/group). For all mice, the right ACL was ruptured. One group served as sham controls, with a single intra-articular saline injection 24-hours following injury. The remaining three groups received 1, 2, and 6 allograft injections respectively beginning 24-hours after injury. Mice were euthanized 14 days after injury. Following euthanasia, the degree of IFP fibrosis, knee synovitis, and AC degradation were histopathologically evaluated.&#x0D; Results:Thus far, 5 mice per group have been analyzed. Within this subset of mice, those that received 6 injections demonstrated a significantly higher synovitis score (p &lt; 0.01) than the sham group. The 1-injection (p &lt; 0.01), 2-injection (p = 0.16), and 6-injection (p = 0.03) groups each displayed greater IFP fibrosis, relative to sham. No significant differences were found in AC degeneration across groups.&#x0D; Conclusion and Potential Impact:If the current results hold, following the analyses of the remaining mice, then this particular orthobiologic may not be suitable for reducing the post-ACL injury inflammatory response in mice. However, there are several limitations to this pilot study that will first need to be accounted for to confirm the lack of efficacy found.

Real-World Clinical Equivalence of Generic and Branded Tofacitinib: A Prospective Longitudinal Cohort Study in Patients With Rheumatoid Arthritis

ObjectivesTo explore the clinical efficacy and safety of generic tofacitinib vs brand name tofacitinib in patients with rheumatoid arthritis (RA) in a single-center comparative study based on a prospective real-world cohort. MethodsPatients with RA receiving tofacitinib, either generic (Kelejia) or branded (Xeljanz), from March 2017, to December 31, 2022, were enrolled. The primary outcome was the simplified disease activity index (SDAI)–defined remission rate at month 6. Secondary outcomes included the rates of remission and low disease activity defined by other composite scores; European Alliance of Associations for Rheumatology response rate, and ultrasonic synovitis scores at months 1, 3, 6, and 12. Cost-effectiveness was investigated. Propensity score–based inverse probability of treatment weighting was adopted to reduce selection bias. ResultsA total of 204 patients were enrolled: 59 in the generic group and 145 in the branded group. An SDAI-defined remission was achieved in 41.1% and 39.2% of patients in the generic and branded groups, respectively, at month 6 (P=.85). Rates of remission and low disease activity achievement, changes in clinical disease activity scores, and power Doppler and gray scale synovitis scores at months 1, 3, 6, and 12 were comparable between the 2 groups. Similar proportions of patients in the groups achieved moderate/good response at months 1, 3, 6, and 12. Rates of drug retention and adverse effects were also similar in the 2 groups. Both Kelejia and Xeljanz were cost-effective, but Kelejia had a lower average cost-effectiveness ratio. ConclusionGeneric tofacitinib (Keljia) had equivalent clinical efficacy and safety and better cost-effectiveness compared with its originator (Xeljanz).

Sex-Linked Discrepancies in C57BL6/J Mouse Osteoarthritis are Associated With the Gut Microbiome and are Transferrable by Microbiome Transplantation.

Females have reduced osteoarthritis (OA) in surgical models. The objective of the current study was to evaluate a sex-linked gut microbiome in the pathogenesis of OA. We induced OA via destabilization of the medial meniscus surgery in adult male and female C57BL6/J mice with and without opposite-sex microbiome transplantation. Eight weeks later, animals were euthanized, and OA severity, synovitis, and osteophyte scores were determined. Serum lipopolysaccharide was measured chromogenically, and serum cytokines were quantified via multiplex immunoassay. Cecal microbiome profiles were generated using 16S deep sequencing. Males had worse OA histology (3.5x, P = 6 × 10-7 ), synovitis (2.4x, P = 5 × 10-4 ), and osteophyte scores (3.7x, P = 3 × 10-4 ) than females. Male-into-female transplantation worsened all outcomes (histology 1.8x, P = 0.02; synovitis 2.0x, P = 3 × 10-5 ; osteophyte 2.1x, P = 0.01) compared to females, whereas female-into-male transplantation improved all outcomes except for synovitis (histology 0.53x, P = 2 × 10-4 ; osteophyte 0.28x, P = 5 × 10-4 ) compared to males. In the gut microbiome analysis, 44 clades were different in at least one group comparison; 5 clades were correlated with the Osteoarthritis Research Society International score (Lactobacillus R = -0.40, Aldercreutzia R = -0.40, rc4_4 R = -0.55, Sutterella R = -0.37, and Clostridiales R=0.36). In the cytokine analysis, 10 analytes were different in at least one group comparison; 3 were different in two groups (female and female-into-male transplants vs male comparisons, all reduced in female and female-into-male transplants), including interleukin-12 (0.66x, P = 0.02; 0.66x, P = 0.02, respectively), eotaxin (0.74x, P = 5 × 10-6 ; 0.57x, P = 0.03), and tumor necrosis factor ⍺ (0.49x, P = 0.03; 0.52x, P = 0.009). Sex-linked differences in the mouse gut microbiome are associated with OA outcomes, are reversible by opposite-sex microbiome transplantation, and are associated with serum cytokine changes.

Reactive oxygen species (ROS)-mediated M1 macrophage-dependent nanomedicine remodels inflammatory microenvironment for osteoarthritis recession

Osteoarthritis (OA) is a common chronic inflammatory disorder. Effective remodeling of inflammatory microenvironment in the joint is a promising strategy to prevent OA. However, current drugs remain unsatisfactory due to a lack of targeted and effective ways for relieving inflammatory conditions in OA joints. Bortezomib (BTZ), a proteasome inhibitor, could effectively inhibit proinflammatory cytokines but with poor accumulation in the inflammatory tissues. To overcome the shortcomings of BTZ delivery and to improve the efficacy of OA therapy, herein, we designed a novel nanomedicine (denoted as BTZ@PTK) by the co-assembly of BTZ and an amphiphilic copolymer (denoted as PTK) with ROS-cleaved thioketal (TK) linkages. The TK units in BTZ@PTK are first cleaved by the excessive ROS at OA sites, and then triggered the controlled release of BTZ, resulting in the accurate delivery and the inflammatory microenvironment remodeling. Accordingly, BTZ@PTK suppressed ROS generation and proinflammatory cytokines while promoting M1 macrophage apoptosis in lipopolysaccharide (LPS)-activated RAW264.7 macrophages or LPS/IFN-γ-treated primary macrophages, which leads to a better effect than BTZ. In OA mice, BTZ@PTK passively accumulates into inflamed joints to attenuate pain sensitivity and gait abnormality. Importantly, BTZ@PTK treatment successfully ameliorates synovitis with the reduction of synovial hyperplasia and synovitis scores by suppressing M1 macrophage polarization and promoting M1 macrophage apoptosis in the synovium, thereby delaying cartilage damage. Collectively, BTZ@PTK can effectively modulate inflammatory microenvironment for OA recession by activating M1 macrophage apoptosis and inhibiting M1macrophage-mediated inflammatory response.

Ultrasonographic study of hand joints erosions in rheumatoid arthritis: Relation to clinical characteristics, disease activity and functional status

BackgroundRheumatoid arthritis (RA) is a commonly diagnosed chronic inflammatory arthritis. Bone erosion can occur early during RA and is considered as an important predictor of a severe clinical course. Aim of the workTo assess ultrasound-detected bone erosions in RA patients and establish their associations with clinical and laboratory variables. Patients and methodsThis study included sixty RA patients. The dorsal and volar joint aspects of the wrist (midcarpal and radiocarpal joints), the first to the fifth metacarpophalangeal (MCP) and proximal interphalangeal joints were scanned in the long and short axes for synovial hypertrophy, tenosynovitis, and erosions. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and anti-cyclic citrullinated peptide (anti-CCP) were performed. The disease activity score (DAS28) and health assessment questionnaire (HAQ) was evaluated ResultsThe mean age of the patients was 43 ± 11.04 years with median disease duration of 5 (0.1–20) years and there were 57 females. Forty-one patients had bone erosions and 19 did not. Erosions were most frequently found in the MCP joints (48.3 % of examined patients). There was no significant difference between the two groups regarding age (p = 0.36), gender (p = 1), RF (p = 0.4), and anti-CCP (p = 0.6). The bone erosion scores significantly correlated with swollen joint count (p = 0.001), tender joint count (p = 0.018), patient global health (p = 0.024), DAS28 (p = 0.003), HAQ (p = 0.032), ESR (p = 0.005), presence of synovitis (p = 0.005), and synovitis score (p < 0.001). ConclusionsThe US-detected bone erosions are predominant in RA, most frequently at the MCP joints, and are associated with disease activity, inflammatory markers, and synovitis.