Synovitis Score Research Articles

Diagnostic and prognostic role of synovial tissue analysis in juvenile idiopathic arthritis: a monocentric study

ObjectivesThis study investigates the diagnostic role of synovial tissue analysis in children presenting with arthritis and assesses its prognostic significance to predict clinical outcome in juvenile idiopathic arthritis (JIA).MethodsSynovial samples...

The Histopathological Landscape of Synovitis in Hemophilic Arthropathy

Recurrent joint bleeding leads to chronic arthropathy in severe hemophilia A and B. With the recent introduction of novel therapies and the increased availability of treatments for patients with hemophilia, a very tight control of bleeding is achievable, but some patients still experience synovitis oat target joints. A deeper knowledge of the synovial membranes in hemophilic synovitis may help the personalised treatment. However, very few data are available regarding the histopathological characteristics of the synovial membrane of patients with hemophilic arthropathy. We studied the histopathological aspects of the synovial membranes of nine patients undergoing orthopedic surgery in order to describe the overall characteristics and the immune infiltrate. Hematoxylin-eosin coloration was applied. Immunohistochemical analysis was performed and two synovitis scores currently used for rheumatoid arthritis were applied: the Krenn and the Humby scores. Moreover, we evaluated synovial collagen fibrosis by means of Masson trichromic staining, grading subintimal fibrosis semiquantitatively. Iron deposits were parallelly assessed with Perls histochemical stain and graded semiquantitatively. For each case we also evaluated whether iron deposits were mostly found in the intracellular (mainly siderophages) or extracellular compartment. Nine patients (six affected by severe hemophilia A, one by moderate hemophilia A and two by severe hemophilia B) with a mean age of 41 ± 14 years, were included. All patients were in prophylaxis with replacement drugs. Synovial membrane was collected during surgery (four total knee replacement, one arthroscopic knee synovectomy, two total ankle replacement, two arthroscopic ankle debridement), following good clinical practice. Informed consent was obtained before the procedure. All the synovial membrane samples were characterised by synovial hyperplasia and hemosiderin deposits. In seven out of nine samples a pauci-immune infiltrate was observed, whereas in two samples a lymphoid-myeloid infiltrate with lymphoid aggregates was present. All cases showed ≥1 grade fibrosis, with eight out of nine cases showing moderate to severe subintimal fibrosis and only one case with lympho-myeloid infiltrate exhibiting mild fibrosis. Iron deposition across the cohort was heterogeneous, with equal distribution of cases with mild (33%), moderate (33%) and severe (33%) iron deposition. Iron deposits were observed mostly in the intracellular compartment (i.e siderophages) with scattered extracellular presence, with the exception of one case with mild and almost exclusive extracellular deposition. In hemophilic arthropathy, we fount typical characteristics of the blood-induced synovial hyperplasia in the majority of the studied synovial membranes, with a pauci-immune infiltrate resembling degenerative arthropathies such as osteoarthritis. By contrast, lymphoid aggregates similar to inflammatory arthritis were less frequent. Fibrosis and iron deposition were more frequent than in osteoarthritis. It should be noted that all the samples were collected from patients undergoing orthopedic surgery due to long-lasting synovitis. A larger study including patients at different stages of arthropathy may help clarify if a different histopathological landscape may correlate with a different clinical history and predict the response to different therapeutic approaches.

Whole-body MRI for the investigation of joint involvement in inflammatory arthritis

ObjectivesThis study aimed to develop a novel whole-body MRI protocol capable of assessing inflammatory arthritis at an early stage in multiple joints in one examination.Materials and methodsForty-six patients with inflammatory joint symptoms and 9 healthy volunteers underwent whole-body MR imaging on a 3.0 T MRI scanner in this prospective study. Image quality and pathology in each joint, bursae, entheses and tendons were scored by two of three radiologists and compared to clinical joint scores. Participants were divided into three groups based on diagnosis at 1-year follow-up (healthy volunteers, rheumatoid arthritis and all other types of arthritis). Radiology scores were compared between the three groups using a Kruskal-Wallis test. The clinical utility of radiology scoring was compared to clinical scoring using ROC analysis.ResultsA protocol capable of whole-body MR imaging of the joints with an image acquisition time under 20 min was developed with excellent image quality. Synovitis scores were significantly higher in patients who were diagnosed with rheumatoid arthritis at 12 months (p < 0.05). Radiology scoring of bursitis showed statistically significant differences between each of the three groups—healthy control, rheumatoid arthritis and non-rheumatoid arthritis (p < 0.05). There was no statistically significant difference in ROC analysis between MRI and clinical scores.ConclusionThis study has developed a whole-body MRI joint imaging protocol that is clinically feasible and shows good differentiation of joint pathology between healthy controls, patients with rheumatoid arthritis and patients with other forms of arthritis.

Silencing of STUB1 relieves osteoarthritis via inducing NRF2-mediated M2 macrophage polarization

ObjectivesShifting macrophages towards an anti-inflammatory state is key in treating osteoarthritis (OA) by reducing inflammation and tissue damage. However, the underlying mechanisms guiding this shift remain largely undefined. STUB1, an E3 ubiquitin ligase, known for its regulatory role in macrophage polarization. This study aims to explore the function and underlying action mechanisms of STUB1 in OA. MethodsAn in vivo OA model was established in rats. Hematoxylin-Eosin and safranin O-fast green staining were performed to reveal the hispathological injuries in knee-joint tissues. Immunohistochemistry and flow cytometry were performed to detect the distribution of M1 and M2 macrophages. The inflammatory response (TNF-α and IL-6 levels) was evaluated by ELISA. In vitro, the interaction between STUB1 and NFR2 was determined by CO-IP and pull-down assays. After treated with LPS (an in vitro model of OA), the viability and apoptosis of chondrocytes were measured by CCK-8 and flow cytometry, respectively. ResultsSilencing STUB1 alleviated OA in rats, as indicated by reduced subchondral bone thickness, knee synovitis score, histopathological damages, and inflammatory response. STUB1 silencing also decreased M1 macrophages and increased M2 macrophages in both in vivo and in vitro settings. NRF2 was identified as a target of STUB1, with STUB1 mediating its ubiquitination. Silencing NRF2 reversed the effects of STUB1 silencing on inducing M2 macrophage polarization. Furthermore, silencing STUB1 upregulated NRF2 expression in LPS-treated chondrocytes, promoting cell viability and inhibiting apoptosis. ConclusionSilencing STUB1 induces M2 macrophage polarization by inhibiting NRF2 ubiquitination, thereby contributing to the mitigation of OA.

Relationship between pain and intra-articular pathology in patients with chronic lateral ankle instability.

Repeated ankle sprains can lead to chronic lateral ankle instability (CLAI). It is unclear whether CLAI causes pain unless complicated by intra-articular lesions. This study aimed to analyze the characteristics of pain and the relationship between pain and intra-articular pathology in patients with CLAI. Fifty-three ankles in 46 patients with CLAI who had undergone surgery were retrospectively reviewed. The self-administered foot evaluation questionnaire (SAFE-Q) was given to patients the day before surgery. Intra-articular lesions were assessed using arthroscopy and magnetic resonance imaging (MRI). In addition, the Hounsfield Unit (HU) on computed tomography (CT) of the medial gutter was measured. The relationship between pain and intra-articular findings was also analyzed. The pain and pain-related scores in the SAFE-Q were significantly correlated with synovitis in 96.3% (rs = - 0.532). HU ratios in the tibia and talus were also significantly correlated with pain (rs = - 0.603, - 0.534, respectively). The arthroscopic synovitis score and HU ratios in patients with high pain scores were significantly higher than those in patients with low pain scores. Forty ankles (75.5%) had synovitis and articular cartilage injuries were observed in 22 ankles (41.5%). Patients with fluid collection or bone marrow lesions (BML) scored significantly lower in pain than those without, but there was no significant difference between patients with and without cartilage injury. Multiple regression analysis revealed that a high synovitis score and HU ratio of the talus were significantly associated with high pain. Intra-articular lesions such as synovitis and BML were associated with pain in patients with CLAI. Osteosclerotic changes in the medial gutter also induced ankle pain, indicating that osteoarthritic changes had already begun. Therefore, lateral ankle ligament injuries after ankle sprain should be appropriately treated to avoid secondary degenerative changes.

OA susceptibility in mice is partially mediated by the gut microbiome, is transferrable via microbiome transplantation and is associated with immunophenotype changes

ObjectivesThe Murphy Roths Large (MRL)/MpJ ‘superhealer’ mouse strain is protected from post-traumatic osteoarthritis (OA), although no studies have evaluated the microbiome in the context of this protection. This study characterised...

The Effect of Arthroscopic Triangular Fibrocartilage Repair on Accompanying Extensor Carpi Ulnaris Tendinitis and Synovitis in Triangular Fibrocartilage Tears.

Purpose Management of ulnar-sided wrist pain is difficult due to the complexity of the anatomy and the similarity of the signs and symptoms of possible diagnoses. The study's main purpose is to examine the effect of arthroscopic triangular fibrocartilage (TFC) repair on untreated extensor carpi ulnaris (ECU) tendinitis and synovitis. Methods Thirteen patients who underwent arthroscopic TFC repair in our clinic and preoperatively demonstrated ECU tendon pathology with magnetic resonance imaging (MRI) were included in the retrospective study. Pre- and postoperative visual analog scale (VAS), pre- and postoperative tendinitis and synovitis, postoperative Mayo and patient-rated wrist evaluation score, postoperative grip strength of the operated and control sides, short and long diameters of the ECU tendon in ultrasonography were recorded. Results The mean age of 13 patients (9 females and 4 males) was 39.54 ± 13.54, and the mean follow-up period was 26 ± 7.25 months. While there was no significant difference between pre- and postoperative tendinitis or synovitis levels, VAS decreased significantly (8.46 ± 1.33 vs. 3.00 ± 2.31, p = 0.0016). While the grip strength was 21.78 ± 7.83 on the control side, it was 18.28 ± 7.51 on the surgery side, being significantly lower ( p = 0.0252). Ulnar variance did not affect tendinitis or synovitis. Short and long diameters of ECU were similar for the operated and control sides. While the short diameter did not affect the synovitis-tendinitis score, the bigger the long diameter, the higher the synovitis score (rho = 0.5162). Conclusion In the presence of ECU, tendon pathologies accompanying TFC lesions, additional surgical interventions are mandatory as arthroscopic TFC repair has no significant effect on the healing of ECU. Level of evidence : 4.

Can Whole-Body Magnetic Resonance Imaging Predict Relapse in Juvenile Idiopathic Arthritis? A Longitudinal Pilot Study.

To determine the utility of whole-body magnetic resonance imaging (WB MRI) to predict relapse in children with juvenile idiopathic arthritis (JIA) in clinical remission. Consecutive patients with JIA who fulfilled the Wallace criteria for remission were recruited into this longitudinal pilot study and underwent WB MRI. A radiological score was devised, incorporating synovitis, bone marrow edema, sacroiliitis, enthesitis, and bone erosions. Two readers independently scored the MR data sets. The same score was calculated for both knee joints individually and correlated with outcome for that joint. Score-based models incorporating clinical and laboratory variables were generated. Logistic regression analysis was done to determine predictors for relapse. Receiver operating characteristic curve was drawn for significant variables. Twenty-two children (median age, 12 years; interquartile range, 9.5-14.25 years) were included in the final analysis. At 24 months' follow-up, 15 joints in 5 children relapsed; knee was the most common site. Seven knee joints had disease relapse. On univariate analysis, synovitis and total score on WB MRI were significant predictors of relapse at follow-up, with odds ratios of 9.46 (bias-corrected 95% confidence interval, 3.07-29.13) and 2.8 (bias-corrected 95% confidence interval, 1.23-6.39) respectively. Two models, which included a higher number of joints involved at presentation and abrupt drug withdrawal strategy as predictor variables, were also statistically significant (odds ratio, approximately 1.9). On multivariate analysis of the predictors variables in models where p < 0.6, it was found that only synovitis score and total score were near statistical significance ( p = 0.06); no clinical or laboratory variables were significant. The areas under the receiver operating characteristic curve for relapse prediction were approximately 0.82, 0.87, 0.79, and 0.81 for synovitis score, total MRI score, and both models, respectively. Synovitis on WB MRI is the strongest independent predictor for disease relapse in children with JIA in remission.

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

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

Sexual dimorphism of the synovial transcriptome underpins greater PTOA disease severity in male mice following joint injury

Osteoarthritis is a disease with sex-dependent prevalence and severity in both humans and animal models. We sought to elucidate sex differences in synovitis, mechanical sensitization, structural damage, bone remodeling, and the synovial transcriptome in the anterior cruciate ligament rupture (ACLR) mouse model of post-traumatic osteoarthritis (PTOA). Male and female 12-week-old C57/BL6J mice were randomized to Sham or noninvasive ACLR with harvests at 7d or 28d post-ACLR (n=9 per sex in each group - Sham, 7d ACLR, 28d ACLR). Knee hyperalgesia, mechanical allodynia, and intra-articular MMP activity (via intravital imaging) were measured longitudinally. Trabecular and subchondral bone remodeling and osteophyte formation were assessed by µCT. Histological scoring of PTOA and synovitis and anti-MMP13 immunostaining were performed. NaV1.8-Cre;tdTomato mice were used to document localization and sprouting of nociceptors. Bulk RNA-seq of synovium in Sham, 7d, and 28d post-ACLR, and contralateral joints (n=6 per group per sex) assessed injury-induced and sex-dependent gene expression. Male mice exhibited more severe joint damage at 7d and 28d and more severe synovitis at 28d, accompanied by 19% greater MMP activity, 8% lower knee hyperalgesia threshold, and 43% lower hindpaw withdrawal threshold in injured limbs compared to female injured limbs. Females had injury-induced catabolic responses in trabecular and subchondral bone, whereas males exhibited 133% greater normalized osteophyte volume relative to females and sclerotic remodeling of trabecular and subchondral bone. NaV1.8+ nociceptor sprouting in subchondral bone and medial synovium was induced by injury and comparable between sexes. RNA-seq of synovium demonstrated similar injury-induced transcriptomic programs between the sexes at 7d, but only female mice exhibited a transcriptomic signature indicative of synovial inflammatory resolution by 28d, whereas males had persistent pro-inflammatory, pro-fibrotic, pro-neurogenic, and pro-angiogenic gene expression. Male mice exhibited more severe overall joint damage and pain behavior after ACLR, which was associated with persistent activation of synovial inflammatory, fibrotic, and neuroangiogenic processes, implicating persistent synovitis in driving sex differences in murine PTOA.

Mesenchymal stem cells in synovial fluid increase in number in response to synovitis and display more tissue-reparative phenotypes in osteoarthritis

BackgroundSynovial fluid mesenchymal stem cells (SF-MSCs) originate in the synovium and contribute to the endogenous repair of damaged intra-articular tissues. Here, we clarified the relationship between their numbers and joint structural changes during osteoarthritis (OA) progression and investigated whether SF-MSCs had phenotypes favorable for tissue repair, even in an OA environment.MethodsPartial medial meniscectomy (pMx) and sham surgery were performed on both knees of rats. SF and knee joints were collected from intact rats and from rats at 2, 4, and 6 weeks after surgery. SF was cultured for 1 week to calculate the numbers of colony-forming cells and colony areas. Joint structural changes were evaluated histologically to investigate their correlation with the numbers and areas of colonies. RNA sequencing was performed for SF-MSCs from intact knees and knees 4 weeks after the pMx and sham surgery.ResultsColony-forming cell numbers and colony areas were greater in the pMx group than in the intact and sham groups and peaked at 2 and 4 weeks, respectively. Synovitis scores showed the strongest correlation with colony numbers (R = 0.583) and areas (R = 0.456). RNA sequencing revealed higher expression of genes related to extracellular matrix binding, TGF-β signaling, and superoxide dismutase activity in SF-MSCs in the pMx group than in the sham group.ConclusionThe number of SF-MSCs was most closely correlated with the severity of synovitis in this rat OA model. Tissue-reparative gene expression patterns were observed in SF-MSCs from OA knees, but not from knees without intra-articular tissue damage.

Relationship between Clinical, Serological and Ultrasound Assessment of Rheumatoid Arthritis Activity

Abstract Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovial tissue that leads to damage of cartilage and bone, resulting in irreversible joint destruction. Aim of the Work Our study’s aim was to assess the relationship between systematic ultrasound (US) evaluation using 7-joint and 12-joint scores and both clinical and serological evaluations in the determination of disease activity in rheumatoid arthritis patients. Also, we assessed the difference between both scores to know which is more accurate in assessing disease activity. Patients and Methods It was a cross sectional study that was carried out on fifty-five Egyptian RA patients diagnosed according to the 2010 American College of Rheumatology (ACR)/EULAR criteria. Patients were recruited from the rheumatology outpatient clinic at Ain Shams university hospital. Results Regarding 7-joint score parameters, mean and standard deviation for GS synovitis was 5.72 ± 4.44, PD synovitis was 3.74 ± 5.24, GS tenosynovitis was 1.15 ± 1.68, PD tenosynovitis was 1.76 ± 3.44 and erosions 1.07 ± 1.37. Regarding the examined areas for 7-joint score, wrist dorsal synovitis was the most common synovitis (98%), 2nd metacarpo-phalangeal joint (56%) then 2nd metatarso-phalangeal joint (49%). Wrist dorsal tenosynovitis (36%) was the most frequent tenosynovitis. Radial (33%), dorsal erosions (18%) of 2nd metacarpo-phalangeal joint and radial erosions (13%) of 5th metatarso-phalangeal joint were the most common erosions found. Our study detected significant positive correlation (P value &amp;lt;0.05 and positive correlation coefficient) between majority of 7-joint and 12-joint score parameters (both GS and PD) and clinical disease activity variables, ESR, CRP and platelet count. Our study showed highly significant positive correlation (P value &amp;lt;0.01 and positive correlation coefficient) between all parameters of 7-joint and 12-joint scores. We found that 12 joint score is slightly better than 7 joint score in accuracy and sensitivity in assessing rheumatoid arthritis disease activity despite being more time-consuming. Conclusion The 7-joint and 12-joint ultrasound scores were simple and practical sum scoring systems for use in the detection of synovitis in patients with RA and in assessment of disease activity in synovium. The correlations between the clinical disease activity indices, ESR, CRP, platelet count and components of the 7-joint and 12-joint scores may indicate their value in assessment of disease activity and severity up to date. The composite score (Combined synovitis score) for 12-joint score was significantly differentiating between moderate-severe patient groups (classified according to DAS28) with P value 0.029, so 12-joint score was better in identifying minimal difference in disease activity despite being time-consuming.

Effects of secukinumab on synovitis and enthesitis in patients with psoriatic arthritis: 52-week clinical and ultrasound results from the randomised, double-blind ULTIMATE trial with open label extension

ObjectivesIn the ULTIMATE study with an open label extension, we assessed the long-term effect of secukinumab at tissue level on synovitis and enthesitis, and across all psoriatic arthritis (PsA) manifestations, using both clinical evaluations and power Doppler ultrasonography (PDUS). MethodsThis randomised, placebo-controlled, Phase 3 study (ULTIMATE) included biologic-naïve patients with PsA with active PDUS synovitis and clinical enthesitis, and inadequate response to conventional synthetic disease-modifying antirheumatic drugs. The study consisted of 3 treatment periods; in the first period (baseline to week 12) patients were randomised to receive subcutaneous secukinumab (150 mg or 300 mg according to severity of skin psoriasis) or placebo every week until week 4 and once every 4 weeks up to week 12. In the second period (weeks 12–24) all patients received open-label secukinumab with placebo patients switching to secukinumab (150 mg or 300 mg). The third period (weeks 24–52) was an extended open-label treatment period. The long-term responsiveness of the Global EULAR-OMERACT Synovitis Score (GLOESS), clinical enthesitis and global PDUS-detected enthesitis score (using two candidate definitions of activity) at patient level, together with clinical efficacy across key manifestations of PsA and safety were assessed. ResultsOf the 166 patients enrolled, 144 completed week 52. A significant reduction in GLOESS was demonstrated in the secukinumab group vs placebo at week 12, followed by a stable reduction of synovitis until week 52 in the secukinumab group while placebo switchers from week 12 reached a similar level of reduction at week 24 with stability thereafter. Likewise, a significant reduction in the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index was shown in the secukinumab group vs placebo at week 12 with sustained improvement to week 52. Global OMERACT PDUS enthesitis scores were numerically lower in secukinumab vs placebo switchers in the first two treatment periods, with some stability in the third period in both groups. Improvements in clinical responses were also observed across all key domains of PsA up to week 52 in both treatment groups with no new or unexpected safety signals. ConclusionsULTIMATE showed consistent improvements in clinically and ultrasound-assessed synovitis and enthesitis and sustained clinical efficacy through week 52 in patients with PsA treated with secukinumab and placebo switched to secukinumab.

Clinical and radiological efficacy of single-dose intra-articular high-molecular-weight hyaluronic acid in knee osteoarthritis.

While visco-supplementation is being used for the treatment of knee osteoarthritis (OA), the published reports vary widely in benefits afforded by this treatment. It was therefore proposed to assess the objective parameters along with subjective outcomes. Our study assessed the radiological and clinical efficacy of single-dose high-molecular-weight intra-articular hyaluronic acid (HMW-IAHA) injection in knee OA. This interventional cohort study was conducted in a calculated sample size of 44 patients with knee OA. Visual analog scale (VAS) and knee OA and outcome score (KOOS) were used for clinical assessment, and whole organ magnetic resonance imaging score (WORMS) for radiological assessment. The subjects were given a single dose of HMW-IAHA injection, 90 mg/3 ml, and were assessed on day 0 and day 90. Statistical Package for Social Sciences (SPSS) software was used. At the day 90 follow-up, there was an improvement in mean ± standard deviation values of VAS score (day 0: 8.53 ± 0.81, day 90: 5.97 ± 0.87), KOOS score (day 0: 27.33 ± 15.18, day 90: 57.26 ± 14.26), and the cartilage signal and morphology in the medial femorotibial joint (day 0: 11.02 ± 6.26 and day 90: 10.91 ± 6.22) and patellofemoral joint (day 0: 10.35 ± 4.36 and day 90: 10.28 ± 4.39) compartments. There was a decrease in synovitis score from 2.3 ± 1.61 to 1.3 ± 1.3 in the medial femorotibial joint compartment and total WORMS score (day 0: 66.57 ± 36.06, day 90: 65.14 ± 35.62). A single dose of intra-articular injection with high-molecular-weight hyaluronic acid produces improvement in the clinical symptoms and quality of life as well as is effective in maintaining the articular cartilage integrity and reducing synovial inflammation.

Mild Synovitis Impairs Chondrogenic Joint Environment

The impact of mild synovitis on the chondrogenic environment in the joint pertaining to cartilage repair is often neglected. In this study, 21 synovial samples were collected from foot surgeries for histology and isolation of fibroblast-like synoviocytes (FLSs). Of the 21 samples, 13 were normal and eight were mild synovitis, according to their synovitis scores. In mild synovitis, CD3+ lymphocytes were increased in the sublining layer. When chondrocytes were cultured and treated with the conditioned medium produced by FLSs, their glycosaminoglycan production was negatively correlated with the synovitis scores of the synovium, from which FLSs were isolated. In conclusion, mild synovitis in common joint conditions compromises the process of chondrogenesis, via inhibiting chondrocyte matrix production by FLSs. The results suggest that the concomitant synovitis, even being mild, could significantly alter the joint environment for chondrogenesis and impair the outcome of cartilage repair.

Synovial and serum B cell signature of autoantibody-negative rheumatoid arthritis vs autoantibody-positive rheumatoid arthritis and psoriatic arthritis.

Autoantibody-negative RA differs from autoantibody-positive RA in several clinical aspects, possibly underpinned by pathogenetic differences. At present, the role of adaptive immune responses in autoantibody-negative RA remains unclear. Here, we investigated the synovial and serum immunophenotype indicative of B lymphocyte involvement across the spectrum of autoantibody-positive and -negative chronic arthritides. Ultrasound-guided synovial biopsies were retrieved from 131 patients: 43 autoantibody-positive RA, 35 autoantibody-negative RA, 25 polyarticular PsA and 28 oligoarticular PsA. Samples were analysed for the degree of histological inflammation, B lymphocyte infiltration and the distribution of different pathotypes (lympho-myeloid, myeloid, pauci-immune). Serum levels of the B cell chemoattractant CXCL13 were compared among groups. Synovitis scores and CD68+ sublining macrophage infiltration were comparable irrespective of clinical diagnosis and disease subtype. In contrast, the degree of B lymphocyte infiltration and the frequency of lympho-myeloid synovitis in autoantibody-negative RA were lower than those of autoantibody-positive RA (mean [s.d.] 1.8 [1] vs 2.4 [0.6], P = 0.03, and 38.2% vs 62.9%, P = 0.07, respectively), and similar to polyarticular PsA. Oligoarticular PsA had the lowest B cell scores. Serum CXCL13 was associated with lympho-myeloid synovitis and followed a similar gradient, with the highest levels in autoantibody-positive RA, intermediate and comparable levels in autoantibody-negative RA and polyarticular PsA, and low levels in oligoarticular PsA. The synovial and serum immunophenotype indicative of B lymphocyte involvement in autoantibody-negative RA differs from that of autoantibody-positive RA and more closely resembles that observed in polyarticular PsA. The pathobiological stratification of chronic inflammatory arthritides beyond clinical diagnosis may fuel personalized treatment strategies.

Deep learning-based automatic scoring models for the disease activity of rheumatoid arthritis based on multimodal ultrasound images.

We aimed to investigate the value of deep learning (DL) models based on multimodal ultrasonographic (US) images to quantify RA activity. Static greyscale (SGS), dynamic greyscale (DGS), static power Doppler (SPD) and dynamic power Doppler (DPD) US images were collected and evaluated by two expert radiologists according to the EULAR-OMERACT Synovitis Scoring system. Four DL models were developed based on the ResNet-type structure, evaluated on two separate test cohorts, and finally compared with the performance of 12 radiologists with different levels of experience. In total, 1244 images were used for the model training, and 152 and 354 for testing (cohort 1 and 2, respectively). The best-performing models for the scores of 0/1/2/3 were the DPD, SGS, DGS and SPD models, respectively (Area Under the receiver operating characteristic Curve [AUC] = 0.87/0.95/0.74/0.95; no significant differences). All the DL models provided results comparable to the experienced radiologists on a per-image basis (intraclass correlation coefficient: 0.239-0.756, P < 0.05). The SPD model performed better than the SGS one on test cohort 1 (score of 0/2/3: AUC = 0.82/0.67/0.95 vs 0.66/0.66/0.75, respectively) and test cohort 2 (score of 0: AUC = 0.89 vs 0.81). The dynamic DL models performed better than the static ones in most of the scoring processes and were more accurate than the most of senior radiologists, especially the DPD model. DL models based on multimodal US images allow a quantitative and objective assessment of RA activity. Dynamic DL models in particular have potential value in assisting radiologists to improve the accuracy of RA US-based grading.

Knee Osteotomy Decreases Joint Inflammation Based on Synovial Histology and Synovial Fluid Analysis

To examine the biological changes in the joints of patients with knee osteoarthritis (OA) before and after around-knee osteotomy (AKO), focusing on synovial fluid (SF) and synovial pathological changes. Patients who underwent AKO for medial compartment knee OA between 2019 and 2021 were examined. SF and synovium were obtained at the time of AKO and plate removal after bone union (mean, 16.8 months [range: 11-38 months] postoperatively). SF volume and interleukin (IL)-6 concentrations in SF were assayed using enzyme-linked immunosorbent assay. Synovitis was assessed histologically using a semiquantitative scoring system. Macrophage infiltration was assessed by immunohistochemistry using a semiquantitative score for F4/80 expression. The M1/M2 ratio was calculated using percentage of cells positive for CD80 and CD163. The expression of proinflammatory cytokines was assessed by the percentage of IL-1β- and IL-6-positive cells. The number of vascular endothelial growth factor-positive luminal structures was counted to assess angiogenesis. The change in each parameter was compared before and after AKO using the Wilcoxon matched-pairs signed-rank test. Twenty-four knees of 21 patients were included. SF volume and IL-6 concentration significantly decreased postoperatively (12.6 ± 2.1 mL vs 4.2 ± 0.6 mL; P < .0001 and 50.5 ± 8.6 pg/mL vs 20.7 ± 3.8 pg/mL; P= .0001, respectively). A significant reduction in synovitis score (P= .0001), macrophage infiltration (P < .0003), M1/M2 ratio (P < .0007), angiogenesis (P < .0001), and the percentage of IL-1β- and IL-6-positive cells in the intima (P < .008 and P < .002, respectively) was found after AKO. SF volume and IL-6 concentrations in the SF decreased and inflammatory synovium pathology improved after AKO. In addition to biomechanical changes, the biological environment of the joint can be improved after AKO. Level IV, retrospective therapeutic case series.

Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/Cl− efflux signaling pathway

BackgroundOsteoarthritis (OA), in which macrophage-driven synovitis is considered closely related to cartilage destruction and could occur at any stage, is an inflammatory arthritis. However, there are no effective targets to cure the progression of OA. The NOD-, LRR-,and pyrin domain-containing protein 3 (NLRP3) inflammasome in synovial macrophages participates in the pathological inflammatory process and treatment strategies targeting it are considered to be an effective approach for OA. PIM-1 kinase, as a downstream effector of many cytokine signaling pathways, plays a pro-inflammatory role in inflammatory disease.MethodsIn this study, we evaluated the expression of the PIM-1 and the infiltration of synovial macrophages in the human OA synovium. The effects and mechanism of PIM-1 were investigated in mice and human macrophages stimulated by lipopolysaccharide (LPS) and different agonists such as nigericin, ATP, Monosodium urate (MSU), and Aluminum salt (Alum). The protective effects on chondrocytes were assessed by a modified co-culture system induced by macrophage condition medium (CM). The therapeutic effect in vivo was confirmed by the medial meniscus (DMM)-induced OA in mice.ResultsThe expression of PIM-1 was increased in the human OA synovium which was accompanied by the infiltration of synovial macrophages. In vitro experiments, suppression of PIM-1 by SMI-4a, a specific inhibitor, rapidly inhibited the NLRP3 inflammasome activation in mice and human macrophages and gasdermin-D (GSDME)-mediated pyroptosis. Furthermore, PIM-1 inhibition specifically blocked the apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization in the assembly stage. Mechanistically, PIM-1 inhibition alleviated the mitochondrial reactive oxygen species (ROS)/chloride intracellular channel proteins (CLICs)-dependent Cl− efflux signaling pathway, which eventually resulted in the blockade of the ASC oligomerization and NLRP3 inflammasome activation. Furthermore, PIM-1 suppression showed chondroprotective effects in the modified co-culture system. Finally, SMI-4a significantly suppressed the expression of PIM-1 in the synovium and reduced the synovitis scores and the Osteoarthritis Research Society International (OARSI) score in the DMM-induced OA model.ConclusionsTherefore, PIM-1 represented a new class of promising targets as a treatment of OA to target these mechanisms in macrophages and widened the road to therapeutic strategies for OA.

Diagnostic performance of double inversion recovery MRI sequence for synovitis of the wrist joints in rheumatoid arthritis.

To assess the diagnostic accuracy of double inversion recovery (DIR) magnetic resonance imaging (MRI) sequences for synovitis of the wrist joints in patients with rheumatoid arthritis (RA). Participants with newly diagnosed RA were enrolled between November 2019 and November 2020. MRI examinations of the wrist joints were performed using a contrast-enhanced T1-weighted imaging sequence (CE-T1WI) and DIR sequence. We measured synovitis score, number of synovial areas, synovial volume, mean synovium-to-bone signal ratio (SBR), and synovial contrast-to-noise ratio (SNR). The inter-reviewer agreement rated on a four-point scale was evaluated by calculating the weighted k statistics. Two MRI sequences were assessed using Bland-Altman analyses, and the diagnostic performance of DIR images was calculated using the chi-square test. A total of 47 participants were evaluated, and 282 joint regions in 5076 images were reviewed by two readers. There was no significant difference in synovitis scores (P = 0.67), number of synovial areas (P = 0.89), and synovial volume (P = 0.086) between the two MRI sequences. DIR images showed better SBR and SNR (all P < 0.01). There was good agreement between the two reviewers in terms of synovitis distribution (κ = 0.79). The synovitis was well agreed upon by the two readers according to Bland-Altman analyses. Using CE-T1WI as the reference standard, DIR imaging demonstrated a sensitivity of 94.1% and a specificity of 84.6% at the patient level. The non-contrast DIR sequence showed good consistency with CE-T1WI and potential for evaluating synovitis in patients with RA.