Ingenious Synergy of a Pathology-Specific Biomimetic Multifunctional Nanoplatform for Targeted Therapy in Rheumatoid Arthritis.

Based on the pathological characteristics of rheumatoid arthritis, including the overproduction of reactive oxygen species (ROS), inflammatory responses, and osteoclast differentiation, a biomimetic multifunctional nanomedicine (M-M@I) is designed. Iguratimod (IGU) is loaded, which inhibits inflammatory responses and osteoclast differentiation, into mesoporous polydopamine (MPDA), which scavenges ROS. Subsequently, the nanoparticles are coated with a cell membrane of macrophages to achieve actively targeted delivery of the nanoparticles to inflamed joints. It is shown that the M-M@I nanoparticles are taken up well by lipopolysaccharide-induced RAW 264.7 macrophages or bone marrow-derived macrophages (BMDMs). In vitro, the M-M@I nanoparticles effectively scavenge ROS, downregulate genes related to inflammation promotion and osteoclast differentiation, and reduce the proinflammatory cytokines and osteoclast-related enzymes. They also reduce the polarization of macrophages to a pro-inflammatory M1 phenotype and inhibit differentiation into osteoclasts. In mice with collagen-induced arthritis, the M-M@I nanoparticles accumulate at arthritic sites and circulate longer, significantly mitigating arthritis symptoms and bone destruction. These results suggest that the pathology-specific biomimetic multifunctional nanoparticles are effective against rheumatoid arthritis, and they validate the approach of developing multifunctional therapies that target various pathological processes simultaneously.

Therapeutic Effect of Colony Stimulating Factor 1 Receptor Kinase Inhibitor, JTE-952, on Methotrexate-Refractory Pathology in a Rat Model of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and the destruction of bone and cartilage in affected joints. One of the unmet medical needs in the treatment of RA is to effectively prevent the structural destruction of joints, especially bone, which progresses because of resistance to conventional drugs that mainly have anti-inflammatory effects, and directly leads to a decline in the QOL of patients. We previously developed a novel and orally available type II kinase inhibitor of colony-stimulating factor-1 receptor (CSF1R), JTE-952. CSF1R is specifically expressed by monocytic-lineage cells, including bone-resorbing osteoclasts, and is important for promoting the differentiation and proliferation of osteoclasts. In the present study, we investigated the therapeutic effect of JTE-952 on methotrexate (MTX)-refractory joint destruction in a clinically established adjuvant-induced arthritis rat model. JTE-952 did not suppress paw swelling under inflammatory conditions, but it inhibited the destruction of joint structural components including bone and cartilage in the inflamed joints. In addition, decreased range of joint motion and mechanical hyperalgesia after disease onset were suppressed by JTE-952. These results suggest that JTE-952 is expected to prevent the progression of the structural destruction of joints and its associated effects on joint motion and pain by inhibiting CSF1/CSF1R signaling in RA pathology, which is resistant to conventional disease-modifying anti-rheumatic drugs such as MTX.

Higher rates of ultrasound synovial hypertrophy, bone erosion and power doppler signal in asymptomatic Brazilian elderly versus young adults: a cross-sectional study.

To evaluate the prevalence of musculoskeletal ultrasonography (MSUS) abnormalities in asymptomatic elderly individuals. A cross-sectional controlled study was conducted and MSUS of 23 joints (wrist, metacarpophalangeal-MCP, proximal interphalangeal-PIP, elbow, glenohumeral, hip, knee, ankle, and metatarsophalangeal-MTP joints) was performed in healthy individuals aged 18-29 (young, n = 32) and 60-80 years-old (elderly, n = 32). Quantitative synovial hypertrophy (SH) was measured in mm and a semiquantitative scoring system (0-3) was used to grade SH, power doppler (PD) and bone erosion (BE). Young and elderly participants were 26.2 ± 3.2 and 65.9 ± 4.4 years-old, respectively. As compared to the young participants, elderly individuals had higher SH values in 35% of the joint surfaces (P < 0.05), higher rates of scores 1-3 for SH at the dorsal surface of the 3rd MCP, palmar surface of the 2nd MCP, 2nd PIP, 3rd MCP and 3rd PIP and subtalar joints (17.2 vs. 1.6%, P = 0.002; 29.7 vs. 6.3%, P = 0.001; 12.5 vs. 1.6%, P = 0.016; 21.9 vs. 6.3%, P = 0.011; 21.9 vs. 7.8%, P = 0.025; and 24.2 vs. 6.3%, P = 0.005, respectively), BE at the radiocarpal, ulnocarpal, dorsal surface of the 2nd MCP and posterior area of the glenohumeral joints (10.9 vs. 1.6%, P = 0.028; 12.5 vs. 0%, P = 0.003; 9.4 vs. 0%, P = 0.012; and 29.7 vs. 10.9%, P = 0.008, respectively) and PD at the dorsal surface of the 2nd and 3rd MCP joints (9.4 vs. 0%; P = 0.012 and 7.8 vs. 0%; P = 0.023, respectively). BE scores ≥ 1 were more frequent in the elderly (P < 0.05) in 22 (88%) of the joint surfaces evaluated. MSUS abnormalities are more frequent in asymptomatic elderly individuals as compared to young subjects.

A rare giant geode of humeral head in an uncontrolled rheumatoid arthritis: a case report.

INTRODUCTION: Rheumatoid Arthritis (RA) is a chronic inflammatory disease depicted by peripheral bone erosive damage leading to joint destruction, deformity and functional impairment. Shoulder involvement is less frequent than hands, wrists and feet, and relevant joint damage may be underdiagnosed if a lower threshold for careful analysis of this joint is not settled, especially in uncontrolled disease. CASE REPORT: A 70-year-old male with a difficult-to-manage RA since 2010, presenting severe shoulder arthritis with MRI showing a striking giant geode in the left humeral head. CONCLUSION: An impressive MRI image showing a giant geode in poorly controlled RA should alert rheumatologists to raise suspicion of shoulder involvement for early investigation and treatment.

The effect of disease-modifying antirheumatic drugs (DMARDs) on bone homeostasis in rheumatoid arthritis (RA) patients.

The autoimmune disease known as rheumatoid arthritis (RA) has been linked to the deterioration of bone. Bone erosion is a hallmark of RA and is linked to the severity of the disease as well as a poor functional result. Erosion of periarticular cortical bone is a common feature seen on plain radiographs of patients with RA. This characteristic feature is the result of excessive bone resorption and inadequate formation of bone. It has been determined that there is a complex interaction between the inflammatory condition seen in RA and bone destruction. Increased knowledge of the pathways and other mechanisms involved in osteoclastogenesis has resulted from advances in both animal and clinical investigations. Also, Biological and targeted medicines have modified RA's bone metabolism. Here, we provide a narrative overview of the literature on the pathomechanisms of bone structure involved in biological and targeted treatments for RA and also, the clinical implications of disease-modifying antirheumatic drugs (DMARDs) are discussed. In light of the fact that these newer treatments present patients with RA with new possibilities for disease improvement and symptom control, it is imperative that additional rigorous evidence be gathered to provide a clinical reference for both patients and their treating physicians.

Methotrexate Increases Serum Calcium Levels in Patients with Rheumatoid Arthritis: A Retrospective Study at a Referral Hospital in Indonesia.

Background: Rheumatoid arthritis (RA) is a significant issue, particularly in bone health problems, because it can prolong diseases like secondary osteoporosis. Subsequently, the anchor of drug therapy for RA is methotrexate (MTX), which also has the potential to reduce the risk of secondary osteoporosis. Objective: This study aims to examine the effect of MTX on calcium levels, an important parameter for monitoring bone health and the risk of secondary osteoporosis in patients with RA. Methods: A retrospective study was carried out by collecting data from the medical records of patients, which included demographic and patient characteristics, treatment data (drug and dosage), duration of treatment, and calcium levels. All patients were diagnosed with RA and fell within the age range of 18 to 59 years. Additionally, the effectiveness of MTX therapy was compared with other treatments, categorizing patient data accordingly. Statistical analyses, such as χ2 and ordinal regression, using IBM-SPSS Statistics version 25 (IBM-SPSS Inc, Armonk, New York) were used to establish associations between MTX treatment and calcium levels, reporting odds ratio and 95% CI values. Results: The data consisted of 123 patients with RA, comprising 99 who had a history of MTX use for more than 6 months and 24 who either did not use MTX or used it for <6 months. The majority of patients were women and their ages ranged between 40 and 59 years. MTX monotherapy was the most used with a dose range of 7.5 to 15 mg. Furthermore, this study observed that patients treated with MTX between 7.5 and 15 mg have lower serum calcium levels than those who received 17.5 to 25 mg (P = 0.022; odds ratio = 5.663; 95% CI, 0.251-3.218). Most patients with RA using MTX maintained normal calcium levels. No significant differences were observed between single MTX therapy and combination therapy. Conclusions: Although further investigation is needed, this study showed the potential properties of MTX in maintaining patients' serum calcium levels, which may help to reduce the risk of secondary osteoporosis in patients with RA.

Safety and effectiveness of denosumab in Japanese patients with rheumatoid arthritis: a 2-year post-marketing surveillance study.

OBJECTIVES: To investigate the 2-year safety and effectiveness of denosumab 60 mg in patients with rheumatoid arthritis (RA) in clinical practice in Japan. METHODS: This 2-year, prospective, observational cohort study included patients who initiated treatment with denosumab 60 mg for the progression of bone erosion associated with RA. Key endpoints were adverse drug reactions (ADRs), progression of bone erosion, and 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) or erythrocyte sedimentation rate (DAS28-ESR). Univariate and multivariate analyses were conducted to determine the risk factors for ADRs and the progression of bone erosion. RESULTS: In the safety analysis set (N=1,239), the incidence of ADRs was 3.0%; the most common ADRs were hypocalcaemia (1.2%) and osteonecrosis of jaw-related events (0.6%). A history of any drug allergy was a statistically significant risk factor associated with the occurrence of ADRs. In the effectiveness analysis set (N=815), the incidence of progression of bone erosion was 8.7%. Steinbrocker stage and initial steroid dose were statistically significant risk factors associated with the progression of bone erosion. CONCLUSION: Denosumab demonstrated safety and effectiveness over a 2-year period in RA patients without any new safety concerns.

Dual-energy CT assessment of rapid monosodium urate depletion and bone erosion remodelling during pegloticase plus methotrexate co-therapy.

OBJECTIVES: Pegloticase rapidly lowers serum urate in uncontrolled/refractory gout patients, with ≥1 tophus resolution in 70% of pegloticase responders and 28% of non-responders. Dual-energy computed tomography (DECT) non-invasively detects MSU deposition, including subclinical deposition, quantifies MSU volumes and depicts bone erosions. This report presents DECT findings in MIRROR open-label trial participants receiving pegloticase+MTX co-therapy. METHODS: Serial DECT scans were obtained during pegloticase (8 mg biweekly infusions)+oral MTX (15 mg/week) co-therapy. Bilateral hand/wrist, elbow, foot/ankle and knee images were analysed with default post-processing settings. MSU volumes were quantified and bone erosions were identified and evaluated for remodelling (decreased size, sclerosis, new bone formation). DECT and physical examination findings were compared. RESULTS: 2 patients underwent serial DECT. Patient 1 (44-year-old male) completed 52 weeks of pegloticase+MTX co-therapy (26 infusions). Baseline examination detected 4 tophus-affected joints while DECT identified 73 MSU-affected joints (total MSU volume: 128.76 cm3). At end-of-treatment, there were no clinically-affected joints and 4 joints with DECT-detected MSU deposition. MSU volume decreased by 99% and bone erosion remodelling was evident. Patient 2 (51-year-old male) had 10 weeks of therapy (5 infusions), discontinuing because of urate-lowering response loss. Baseline examination detected 7 tophus-affected joints while DECT identified 55 MSU-affected joints (total MSU volume: 59.20 cm3). At end-of-treatment, there were 5 clinically affected joints and 42 joints with DECT-detected MSU deposition. MSU volume decreased by 58% and bone erosion remodelling was evident. CONCLUSION: DECT detected subclinical MSU deposition and quantified changes over time. Rapid tophus resolution and bone erosion remodelling occurred during pegloticase+MTX co-therapy. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03635957.

CHI3L1 promotes Staphylococcus aureus-induced osteomyelitis by activating p38/MAPK and Smad signaling pathways.

AIMS: Staphylococcus aureus (S. aureus) is the most common causative bacterial pathogen involved in promoting infection-induced osteomyelitis, a disease resulting in severe bone degradation. In this study, we aimed to identify the mechanism behind inhibition of osteoclast survival and differentiation by CHI3L1, a lectin previously reported to regulate S. aureus-induced osteomyelitis. MAIN METHODS: The role of CHI3L1 in osteoclast survival, proliferation, and differentiation was studied ex vivo using primary human bone marrow derived stem cells (HBMSCs) and transducing them with lentiviral expression vectors or shRNA knockdown constructs. Cell apoptosis was analyzed by flow cytometry using annexin V-fluorescein isothiocyanate/propidium iodide staining. Cell proliferation was assessed using alkaline phosphatase, Alcian Blue, and TRAP staining. The qRT-PCR was used to measure mRNA levels of osteoclast maturation markers, and western blotting was used to analyze protein expression. An in vivo murine model for osteomyelitis and microcomputed tomography analyses of infected femurs were used to study the effects of CHI3L1 on bone erosion. KEY FINDINGS: Overexpression of CHI3L1 significantly reduced HBMSC cell viability, proliferation, and differentiation, and knockdown improved these effects in the presence of S. aureus infection. More specifically, CHI3L1 constitutively activated the p38/MAPK pathway to promote apoptosis. Furthermore, CHI3L1 induced activation of the Smad pathway by promoting phosphorylation of Smad-1/5 proteins. Finally, overexpression of CHI3L1 significantly induced bone erosion upon S. aureus infection in a murine osteomyelitis model, and knockdown of CHI3L1 significantly alleviated this effect. SIGNIFICANCE: CHI3L1 played a vital role in osteoblast differentiation and proliferation by regulating the p38/MAPK and Smad signaling pathways to promote S. aureus-induced osteomyelitis.

Factors associated with bone erosion in patients with gout: A dual-energy gemstone spectral imaging computed tomography study.

OBJECTIVES: This study aimed to assess the factors influencing bone erosion (BE) in patients with gout using dual-energy gemstone spectral imaging computer tomography. METHODS: We compared the clinical data, laboratory indices, and tissue urate levels at the monosodium urate (MSU) bone interface measured by dual-energy gemstone spectral imaging computed tomography of 87 gout patients with (n = 41) and without (n = 46) BE. Logistic regression analysis was used to investigate the risk factors associated with BE. RESULTS: In total, 47.1% of patients with gout had BE. The disease duration, serum uric acid, tissue urate levels, and the presence of tophi were significantly higher (p < .05) in gout patients with BE than in those without BE. Longer disease duration (odds ratio = 1.11, 95% confidence interval: 1.00-1.24, p < .05) and increased tissue urate levels (odds ratio = 1.01, 95% confidence interval: 1.00-1.02, p < .05) were independently associated with BE. Tissue urate levels at the MSU-bone interface were correlated with the presence of tophi (r = 0.62, p < .001), BE (r = 0.51, p < .001), renal calculus (r = 0.24, p = .03), and serum uric acid levels (r = 0.23, p = .03). CONCLUSIONS: This study found that longer disease duration and elevated tissue urate concentrations at the MSU-bone interface were associated with BE in patients with gout.

Impact of denosumab discontinuation on changes in bone mineral density and bone erosion in rheumatoid arthritis patients.

OBJECTIVES: This study investigated changes in bone mineral density (BMD) and erosion after denosumab discontinuation in rheumatoid arthritis (RA) patients without osteoporosis who participated in the DESIRABLE study. METHODS: This multicentre observational study consisted of a prediscontinuation visit (date of final assessment in DESIRABLE) and a postdiscontinuation visit (2.5 years after the last administered dose of denosumab). Percentage change in lumbar spine (LS) BMD from baseline was assessed as the primary endpoint. RESULTS: Fifty-nine patients were enrolled. The percentage change in LS BMD decreased to baseline levels at the postdiscontinuation visit. Compared with baseline, C-telopeptide of type I collagen levels increased after denosumab discontinuation but most patients had levels within the reference range. Bone erosion scores were not significantly different between the on-treatment period and after denosumab discontinuation (p = .0666) but there was a numerical increase postdiscontinuation. The progression in bone erosion score was significantly reduced in patients whose disease activity was in remission versus those not in remission (p = .0195). CONCLUSIONS: In RA patients without osteoporosis, denosumab discontinuation can be explored while considering patient background factors (disease activity and risk of fracture) and accounting for progression of bone erosion and LS BMD decrease after withdrawal.

Chronic inflammation and extracellular matrix-specific autoimmunity following inadvertent periarticular influenza vaccination.

BACKGROUND: Viral infections may trigger autoimmunity in genetically predisposed individuals. Immunizations mimic viral infections immunologically, but only in rare instances vaccinations coincide with the onset of autoimmunity. Inadvertent vaccine injection into periarticular shoulder tissue can cause inflammatory tissue damage ('shoulder injury related to vaccine administration, SIRVA). Thus, this accident provides a model to study if vaccine-induced pathogen-specific immunity accompanied by a robust inflammatory insult may trigger autoimmunity in specific genetic backgrounds. METHODS: We studied 16 otherwise healthy adults with suspected SIRVA occurring following a single work-related influenza immunization campaign in 2017. We performed ultrasound, immunophenotypic analyses, HLA typing, and influenza- and self-reactivity functional immunoassays. Vaccine-related bone toxicity and T cell/osteoclast interactions were assessed in vitro. FINDINGS: Twelve of the 16 subjects had evidence of inflammatory tissue damage on imaging, including bone erosions in six. Tissue damage was associated with a robust peripheral blood T and B cell activation signature and extracellular matrix-reactive autoantibodies. All subjects with erosions were HLA-DRB1*04 positive and showed extracellular matrix-reactive HLA-DRB1*04 restricted T cell responses targeting heparan sulfate proteoglycan (HSPG). Antigen-specific T cells potently activated osteoclasts via RANK/RANK-L, and the osteoclast activation marker Trap5b was high in sera of patients with an erosive shoulder injury. In vitro, the vaccine component alpha-tocopheryl succinate recapitulated bone toxicity and stimulated osteoclasts. Auto-reactivity was transient, with no evidence of progression to rheumatoid arthritis or overt autoimmune disease. CONCLUSION: Vaccine misapplication, potentially a genetic predisposition, and vaccine components contribute to SIRVA. The association with autoimmunity risk allele HLA-DRB1*04 needs to be further investigated. Despite transient autoimmunity, SIRVA was not associated with progression to autoimmune disease during two years of follow-up.

Monocytic MDSCs skew Th17 cells toward a pro-osteoclastogenic phenotype and potentiate bone erosion in rheumatoid arthritis.

OBJECTIVES: While myeloid-derived suppressor cells (MDSCs) were previously shown to promote a proinflammatory T helper (Th) 17 response in autoimmune conditions, a potential impact of the MDSC-Th17 immune axis on abnormal bone destruction in RA remains largely unknown. METHODS: We investigated the correlation between the frequency of MDSCs or its subsets and joint destruction in RA patients. The reciprocal actions of patient-derived MDSCs and Th17 cells were studied using osteoclast (OC) differentiation and bone resorption assays in vitro, which were further validated using mouse models of RA. Contribution of MDSCs to osteoclastogenesis and bone erosion in vivo was determined by depletion or transfer of MDSCs. RESULTS: Human MDSCs, particularly monocytic MDSCs (M-MDSCs), exhibit inherent OC-differentiating capacity and positively correlate with clinical bone erosion in RA patients. Strikingly, patient-derived M-MDSCs can program Th17 cells towards a pro-osteoclastogenic phenotype, which in return potentiates OC differentiation via the receptor activator of nuclear factor κΒ ligand (RANK-L)-RANK signalling. This enhanced osteolysis driven by the reciprocal actions of M-MDSCs and Th17 cells is further confirmed using mouse models of RA. Selective depletion of M-MDSCs significantly ameliorates osteoclastogenesis and disease severity in arthritic mice, whereas transfer of M-MDSCs aggravates bone erosion associated with increased OCs in recipient mice. CONCLUSION: Our findings highlight the functional plasticity of MDSCs and identify a novel pro-osteoclastogenic pathway governed by interplay between myeloid cells and T lymphocytes in autoimmune RA.

Efficacy of methotrexate in reducing the risk of bone erosion in patients with rheumatoid arthritis: a systematic review of randomized controlled trials.

Even though new drugs for the treatment of rheumatoid arthritis (RA) have been developed, methotrexate (MTX) remains a commonly used drug for RA management. In addition to monitoring disease activity during RA treatment, bone erosion should be closely assessed throughout long-term RA management. In this review article, we present a systematic review of MTX effectiveness in reducing the risk of bone erosion. We reviewed randomized controlled trial studies that involved MTX monotherapy or MTX in combination with placebo. Evaluation of the progression of bone erosion was examined by radiographic assessment such as total Sharp score (TSS) or van der Heijde score (SvdH or vdH TSS), joint space narrowing (JSN), erosion score (ERO), and proportion of radiographic nonprogressors. Several key factors were found to influence the response to MTX treatment, such as gene polymorphism. The exact mechanism of the prevention of bone erosion by MTX remains unclear, which warrants future investigations. The variability of RA disease activity in study subjects resulted in variations in the results reported by individual studies. Collective analysis suggests that MTX could slow down the progression of bone erosion based on a radiographic score of less than 0.5-1/year.

The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and is associated with cancer metastasis to the bone and poor patient prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression. We will discuss emerging evidence linking CTHRC1 to the pathogenic behavior of fibroblast-like synoviocytes and to cartilage and bone erosion through modulation of the balance between bone resorption and repair.

Papillary Endothelial Hyperplasia of Scalp with Bone Erosion: A Case Report with Review of Literature.

BACKGROUND: Papillary endothelial hyperplasia (PEH) is a reactive pseudoneoplastic proliferation of endothelial cells. They are typically well-circumscribed, indolent lesions and curable by complete excision. Description: We present a four-year-old girl with post traumatic scalp swelling, clinically considered to be a capillary hemangioma. Computed tomography revealed a 3.3 × 1.5 cm scalp mass with erosion of outer table and diploic space of the occipital calvarial bone, suggesting a vascular or soft tissue tumor. Histologically it was a PEH within a hemangioma. Literature Review: PEH presenting as a scalp swelling with bone erosion has only been reported thrice in the literature. Conclusion: Scalp PEH with skull bone defect can affect the pediatric age group. Bone erosion is not stage dependent; it can occur in the early stages.

[Effect of chemokines CXCL9 and CXCL10 on bone erosion in patients with rheumatoid arthritis].

OBJECTIVE: To detect the serum level of soluble chemokines CXCL9 and CXCL10 in patients with rheumatoid arthritis (RA), and to analyze their correlation with bone erosion, as well as the clinical significance in RA. METHODS: In the study, 105 cases of RA patients, 90 osteoarthritis (OA) patients and 25 healthy controls in Peking University People's Hospital were included. All the clinical information of the patients was collected, and the serum CXCL9 and CXCL10 levels of both patients and healthy controls were measured by enzyme-linked immune sorbent assay (ELISA). CXCL9 and CXCL10 levels among different groups were compared. The correlation between serum levels with clinical/laboratory parameters and the occurrence of bone erosion in RA were analyzed. Independent sample t test, Chi square test, Mann-Whitney U test, Spearman's rank correlation and Logistic regression were used for statistical analysis. RESULTS: The levels of CXCL9 and CXCL10 were significantly higher in the RA patients [250.02 (126.98, 484.29) ng/L, 108.43 (55.16, 197.17) ng/L] than in the OA patients [165.05 (75.89, 266.37) ng/L, 69.00 (33.25, 104.74) ng/L] and the health controls [79.47 (38.22, 140.63) ng/L, 55.44 (18.76, 95.86) ng/L] (all P < 0.01). Spearman's correlation analysis showed that the level of serum CXCL9 was positively correlated with swollen joints (SJC), rheumatoid factor (RF) and disease activity score 28 (DAS28) (r=0.302, 0.285, 0.289; P=0.009, 0.015, 0.013). The level of serum CXCL10 was positively correlated with tender joints (TJC), SJC, C-reactive protein (CRP), immunoglobulin (Ig) A, IgM, RF, anti-cyclic citrullinated peptide antibody (ACPA), and DAS28 (r=0.339, 0.402, 0.269, 0.266, 0.345, 0.570, 0.540, 0.364; P=0.010, 0.002, 0.043, 0.045, 0.009, < 0.001, < 0.001, 0.006). Serum CXCL9 and CXCL10 levels in the RA patients with bone erosion were extremely higher than those without bone erosion [306.84 (234.02, 460.55) ng/L vs. 149.90 (75.88, 257.72) ng/L, 153.74 (89.50, 209.59) ng/L vs. 54.53 (26.30, 83.69) ng/L, respectively] (all P < 0.01). Logistic regression analysis showed that disease duration, DAS28 and serum level of CXCL9 were correlated with bone erosion in the RA patients (P < 0.05). CONCLUSION: Serum levels of CXCL9 and CXCL10 were remarkably elevated in patients with RA, and correlated with disease activities and occurrence of bone erosion. Chemokines CXCL9 and CXCL10 might be involved in the pathogenesis and bone destruction in RA.

Alantolactone alleviates collagen-induced arthritis and inhibits Th17 cell differentiation through modulation of STAT3 signalling.

CONTEXT: Alantolactone, the bioactive component in Inula helenium L. (Asteraceae), exhibits multiple biological effects. OBJECTIVE: We aimed to determine the anti-inflammatory effect of alantolactone in a collagen-induced arthritis (CIA) mouse model and its immunomodulatory effects on Th17 differentiation. MATERIALS AND METHODS: A CIA mouse model was established with DBA/1 mice randomly divided into four groups (n = 6): healthy, vehicle and two alantolactone-treated groups (25 or 50 mg/kg), followed by oral administration of alantolactone to mice for 21 consecutive days after arthritis onset. The severity of CIA was evaluated by an arthritic scoring system and histopathological examination. Levels of cytokines and anti-CII antibodies as well as percentages of splenic Th17 and Th17 differentiation with or without alantolactone treatments (0.62, 1.2 or 2.5 µM) were detected with ELISA and flow cytometry, respectively. Western blot analysis was used to evaluate intracellular signalling in alantolactone-treated spleen cells. RESULTS: In CIA mice, alantolactone at 50 mg/kg attenuated RA symptoms, including high arthritis scores, infiltrating inflammatory cells, synovial hyperplasia, bone erosion and levels of the proinflammatory cytokines TNF-α, IL-6 and IL-17A, but not IL-10 in paw tissues. Alantolactone also reduced the number of splenic Th17 cells and the capability of naïve CD4+ T cells to differentiate into the Th17 subset by downregulating STAT3/RORγt signalling by as early as 24 h of treatment. DISCUSSION AND CONCLUSIONS: Alantolactone possesses an anti-inflammatory effect that suppresses murine CIA by inhibiting Th17 cell differentiation, suggesting alantolactone is an adjunctive therapeutic candidate to treat rheumatoid arthritis.

HR-pQCT in vivo imaging of periarticular bone changes in chronic inflammatory diseases: Data from acquisition to impact on treatment indications.

Imaging is essential for the assessment of bone and inflammatory joint diseases. There are several imaging techniques available that differ regarding resolution, radiation exposure, time expending, precision, cost, availability or ability to predict disease progression. High-resolution peripheral quantitative computed tomography (HR-pQCT) that was introduced in 2004 allows the in vivo evaluation of peripheral bone microarchitecture and demonstrated high precision in assessing bone changes in inflammatory musculoskeletal diseases. This review summarizes the use of HR-pQCT for the evaluation of the hand skeleton in inflammatory joint diseases. We conducted a review of the literature regarding the protocols that involve hand joints assessment and evaluation of bone changes as erosions and osteophytes in chronic inflammatory diseases. Apart from measuring bone density and structure of the radius and the tibia, HR-pQCT has contributed to assessment of bone erosions and osteophytes, considered the hallmark of diseases as rheumatoid arthritis and psoriatic arthritis, respectively. In this way, there are some conventions recently established by rheumatic study groups that we just summarized here in order to standardize HR-pQCT measurements.

Predictors of new bone erosion in rheumatoid arthritis patients receiving conventional synthetic disease-modifying antirheumatic drugs: Analysis of data from the DRIVE and DESIRABLE studies.

OBJECTIVE: To investigate new bone erosion and cartilage destruction predictors in rheumatoid arthritis (RA) patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). METHODS: Placebo-treated patient data from two 12-month, randomized, double-blind, phase 2 (DRIVE) and 3 (DESIRABLE) trials that evaluated denosumab efficacy in csDMARD-treated RA patients were used. Change from baseline in erosion score (ES) of ≥1.0 at 12 months was considered new bone erosion; predictors were identified using a multivariate model. RESULTS: Among 306 patients, mean ± standard deviation disease activity score 28-C-reactive protein (CRP) at baseline was 3.58 ± 1.03. New bone erosion was observed in 90 patients (29.4%). Univariate analysis identified female sex, anti-cyclic citrullinated peptide (CCP) antibody positivity, rheumatoid factor (RF) positivity, tender joint count ≥6, CRP ≥0.3 mg/dL, erythrocyte sedimentation rate (ESR) ≥28 mm/h, and baseline ES ≥3 as significant predictors for new bone erosion. In multivariate analysis, predictors were anti-CCP antibody positivity, CRP ≥0.3 mg/dL, and baseline ES ≥3; RF and ESR were excluded as they strongly correlated with anti-CCP antibody and CRP, respectively. CONCLUSION: In RA patients treated with csDMARDs, new bone erosion predictors were seropositivity, elevated inflammatory markers, and baseline ES ≥3. TRIAL REGISTRATION NUMBER: DRIVE, JapicCTI-101263; DESIRABLE, NCT01973569.