Costotransverse joint ankylosis and their association with syndesmophyte progression in patients with radiographic axial spondyloarthritis.

Background: Abnormal new bone formation can occur not only in the vertebral body but also can occur in facet, costovertebral, and costotransverse joints in radiographic axial spondyloarthritis (r-axSpA) patients. Little is known about the association between syndesmophyte progression and paravertebral joint ankylosis in r-axSpA. Objectives: Costotransverse joint ankylosis in r-axSpA patients was measured. Furthermore, the association between syndesmophyte progression for 2 years assessed by computed tomography syndesmophyte score (CTSS) and facet, costovertebral, and costotransverse joints ankylosis were evaluated. Design: Single-center, prospective, cohort study. Methods: Whole spine CT images taken at baseline and 2-year follow-up were used to calculate the CTSS of the vertebral body. In addition, ankylosis of the facet/costovertebral/costotransverse joints was scored. CTSS (range, 0-552) and facet joint ankylosis (range, 0-46) were assessed at 23 vertebral units. Costovertebral joints at T1-T12 (range, 0-48) and costotransverse joints at T1-T10 (range, 0-20) were also assessed by independent two readers. Intraclass correlation coefficients (ICC) were calculated to determine inter-reader reliability. Odds ratios (OR) were calculated to identify the associations between syndesmophyte progression and the baseline status of facet, costovertebral, and costotransverse joints. Results: In all, 50 patients with r-axSpA were included. Readers 1 and 2 identified C7-T3 (facet joints), T5-T7 and T12 (costovertebral joints), and T8-T9 (costotransverse joints), as common sites of ankylosis at baseline and at 2-year follow-up. The ICCs for the facet, costovertebral, and costotransverse joints at baseline were 0.876, 0.952, and 0.753, respectively. OR of baseline costovertebral and costotransverse joint ankylosis for predicting syndesmophyte progression of the vertebral body was 4.644 [95% confidence interval (CI), 2.295-9.398] and 1.524 (95% CI, 1.036-2.244), respectively. Conclusion: Costotransverse joint ankylosis in r-axSpA patients can be measured semi-quantitatively on whole spine CT, and ankylosis of the costotransverse and costovertebral joints predicts the progression of syndesmophytes.Trial registration: Not applicable.

Nailfold capillaroscopy findings of interstitial pneumonia with autoimmune features.

BACKGROUND/AIMS: We evaluated nailfold capillaroscopy (NFC) of interstitial pneumonia with autoimmune features (IPAF) and compared it with that of patients with connective tissue disease-interstitial lung disease (CTD-ILD) and idiopathic interstitial pneumonia (IIP). METHODS: Patients with newly diagnosed as ILD were evaluated using NFC. Baseline demographic, clinical, serological, and high-resolution CT findings were collected. NFC was semi-quantitatively scored with six domains ranging from 0 to 18. In addition, the overall patterns (scleroderma/non-scleroderma patterns) were determined. RESULTS: A total of 81 patients (31 with CTD-ILD, 18 with IPAF, and 32 with IIP) were included. The non-specific interstitial pneumonia pattern was the most common ILD pattern in the CTD-ILD and IPAF groups, whereas the usual interstitial pneumonia pattern was the most common in the IIP group. The semi-quantitative score of the CTD-ILD group was higher than that of the IPAF or IIP groups (5.8 vs 4.2 vs 3.0, p < 0.001, respectively). Giant capillaries and haemorrhages were more frequently present in the CTD-ILD and IPAF groups than in the IIP group. A scleroderma pattern was present in 27.8% of the IPAF group, whereas none of the IIP patients showed a scleroderma pattern. CONCLUSION: NFC findings may be useful in classifying patients with ILD into CTD-ILD/IPAF/IIP.

Identification of gut dysbiosis in axial spondyloarthritis patients and improvement of experimental ankylosing spondyloarthritis by microbiome-derived butyrate with immune-modulating function.

Introduction: Dysbiosis is an environmental factor that affects the induction of axial spondyloarthritis (axSpA) pathogenesis. In the present study, we investigated differences in the gut microbiota of patients with axSpA and revealed an association between specific gut microbiota and their metabolites, and SpA pathogenesis. Method: Using 16S rRNA sequencing data derived from feces samples of 33 axSpA patients and 20 healthy controls (HCs), we examined the compositions of their gut microbiomes. Results: As a result, axSpA patients were found to have decreased α-diversity compared to HCs, indicating that axSpA patients have less diverse microbiomes. In particular, at the species level, Bacteroides and Streptococcus were more abundant in axSpA patients than in HCs, whereas Faecalibacterium (F). prausnitzii, a butyrate-producing bacteria, was more abundant in HCs. Thus, we decided to investigate whether F. prausnitzii was associated with health conditions by inoculating F. prausnitzii (0.1, 1, and 10 µg/mL) or by administrating butyrate (0.5 mM) into CD4+ T cells derived from axSpA patients. The levels of IL-17A and IL-10 in the CD4+ T cell culture media were then measured. We also assessed osteoclast formation by administrating butyrate to the axSpA-derived peripheral blood mononuclear cells. The CD4+ IL-17A+ T cell differentiation, IL-17A levels were decreased, whereas IL-10 was increased by F. prausnitzii inoculation. Butyrate reduced CD4+ IL-17A+ T cell differentiation and osteoclastogenesis. Discussion: We found that CD4+ IL-17A+ T cell polarization was reduced, when F. prausnitzii or butyrate were introduced into curdlan-induced SpA mice or CD4+ T cells of axSpA patient. Consistently, butyrate treatment was associated with the reduction of arthritis scores and inflammation levels in SpA mice. Taken together, we concluded that the reduced abundance of butyrate-producing microbes, particularly F. prausnitzii, may be associated with axSpA pathogenesis.

Interleukin-18 binding protein regulates the apoptosis and necroptosis of fibroblast-like synoviocytes and chondrocytes in rheumatoid arthritis.

OBJECTIVES: Interleukin (IL)-18 plays a pro-inflammatory role in rheumatoid arthritis (RA), and its soluble inhibitor IL-18 binding protein (IL-18BP) has a potential therapeutic role. We investigated the role of IL-18BP on the joint destruction process of RA by accessing the effects of IL-18BP on fibroblast-like synoviocytes (FLSs) and chondrocytes. METHODS: Peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy controls were cultured under T cell proliferative conditions with 10, 50, or 100 ng/mL of IL-18BP. After three days of culture, flow cytometry for CD4+ T cells was performed using various IL-18BP concentrations. The apoptosis and necroptosis of FLSs and chondrocytes were measured by flow cytometry using annexin V and propidium iodide (PI) and western blot under TNF-α stimulation with IL-18BP (10, 50, and 100 ng/mL). RESULTS: Differentiation of CD4+ IL-17A+ and CD4+ IL-4+ cells decreased and that of CD4+ CD25high Foxp3+ and CD4+ interferon (IFN)-γ+ cells increased on addition of IL-18BP to cultured RA patient-driven PBMCs. RA-FLS migration ability was not suppressed by IL-18BP after 12 or 24 h. IL-18BP increased annexin V+ FLS level and reduced annexin V+ chondrocyte level in a dose-dependent manner, whereas PI+ annexin V- FLS and chondrocyte levels were suppressed by 50, 100 ng/mL IL-18BP in culture. CONCLUSIONS: The administration of IL-18BP regulated the type 17 helper T cell/ regulatory T cell imbalance and attenuated the production of pro-inflammatory cytokines. IL-18BP further increased FLS apoptosis and decreased the necroptosis of FLS/chondrocytes and apoptosis of chondrocytes suggesting the joint preservative potential of IL-18BP.

Risk of cancer, cardiovascular disease, thromboembolism, and mortality in patients with rheumatoid arthritis receiving Janus kinase inhibitors: a real-world retrospective observational study using Korean health insurance data.

OBJECTIVES: This study investigated whether Janus kinase inhibitors (JAKis) raise the risk of cardiovascular disease (CVD), venous thromboembolism (VTE), and cancer in patients with rheumatoid arthritis (RA). METHODS: We conducted a real-world retrospective observational study using data obtained from the Korean National Health Insurance Service database. Two data sets were analyzed: tumor necrosis factor inhibitor (TNFi)/JAKi-naive RA patients (set 1) and all RA patients who used TNFis or JAKis (set 2). The incidence rate ratios (IRRs) and hazard ratios (HRs) for acute myocardial infarction (AMI), stroke, cardiovascular (CV)-related mortality, major adverse cardiovascular events (MACE), VTE, arterial thromboembolism (ATE), cancer, and all-cause mortality were compared between the JAKi and TNFi groups. RESULTS: Set 1 included 1,596 RA patients (JAKi group: 645; TNFi group: 951), and set 2 included 11,765 RA patients (JAKi group: 2,498; TNFi group: 9,267). No adverse events (AEs) showed significantly higher IRRs in the JAKi groups than in the TNFi groups of sets 1 and 2. The HRs for MACE in the JAKi groups of sets 1 and 2 were 0.59 (95% confidence [CI], 0.35 to 0.99) and 0.80 (95% CI, 0.67 to 0.97), respectively. The JAKi group of set 2 showed a significantly higher risk of all-cause mortality (HR, 1.71; 95% CI, 1.32 to 2.20), but the other AEs did not demonstrate increased risks in the JAKi groups. CONCLUSIONS: In this study, JAKis did not increase the risk of AMI, stroke, CV-related mortality, MACE, VTE, ATE, or cancer in Korean RA patients relative to TNFis.

Dasatinib, a selective tyrosine kinase inhibitor, prevents joint destruction in rheumatoid arthritis animal model.

AIM: We aimed to evaluate the preventive role of the tyrosine kinase inhibitor dasatinib in an animal model of rheumatoid arthritis (RA). METHODS: DBA/1J mice were injected with bovine type II collagen to induce arthritis (collagen-induced arthritis [CIA]). There were four experimental groups of mice, namely negative control (non-CIA), vehicle-treated CIA, dasatinib-pretreated CIA, and dasatinib-treated CIA. After collagen immunization, arthritis progression in the mice was clinically scored twice weekly for 5 weeks. Flow cytometry was used to evaluate in vitro CD4+ T-cell differentiation and ex vivo mast cell/CD4+ T-cell differentiation. Osteoclast formation was evaluated using tartrate-resistant acid phosphatase (TRAP) staining and by estimating the resorption pit area. RESULTS: We found that the clinical arthritis histological scores were lower in the dasatinib pretreatment group than in the vehicle and dasatinib post-treatment groups. Flow cytometry showed that FcεR1+ cells were downregulated and regulatory T cells were upregulated in splenocytes of the dasatinib pretreatment group compared with those in the vehicle group. Additionally, there was a decline in IL-17+ CD4+ T-cell differentiation and an increase in CD4+ CD24high Foxp3+ T-cell differentiation with in vitro dasatinib treatment of human CD4+ T cells. The number of TRAP+ osteoclasts and the area of the resorption were decreased in the bone marrow cells derived from dasatinib-pretreated mice compared with those derived from vehicle group. CONCLUSION: Dasatinib protected against arthritis in an animal model of RA by regulating the differentiation of regulatory T cells and IL-17+ CD4+ T cells and inhibiting osteoclastogenesis, indicating the therapeutic potential of dasatinib in the treatment of early RA.

A green-lipped mussel prevents rheumatoid arthritis via regulation of inflammatory response and osteoclastogenesis.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive joint destruction. Green-lipped mussel (GLM) has chondro-modulatory and anti-inflammatory properties, but the mechanism underlying the effect of GLM on RA is unclear. To investigate the roles of GLM on the pathogenesis of RA, we examined the effects of GLM in collagen-induced arthritis (CIA) mice and osteoclast differentiation. GLM was orally administrated CIA mice at 3 weeks after chicken type II collagen (CII) immunizations. GLM reduced arthritis severity and the histologic score of CIA mice compared to vehicle. The expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-17) was decreased in the ankle joints of GLM-treated CIA mice. The expression of CD4+ IL-17+ cells decreased in ex vivo splenocytes and the spleens of GLM-treated CIA mice. Moreover, GLM inhibited TRAP+ multinucleated cells among mouse bone marrow-derived monocytes/macrophages (BMM), and the expression of osteoclast-related genes in mouse BMMs and human monocytes in vitro. These results suggest that GLM has potential as a therapeutic agent that can improve disease by controlling pathologic immune cells and osteoclastogenesis.

Proposal of simplified CT syndesmophyte score (sCTSS) and comparison with CTSS in patients with ankylosing spondylitis.

The CT syndesmophyte score (CTSS) can evaluate spinal progression more precisely than mSASSS in ankylosing spondylitis (AS); however, it is complex and time consuming. Here, we propose a simplified CTSS (sCTSS) for measuring spinal structural changes in AS. Patients with AS were recruited from a single tertiary hospital. Baseline and 2-year follow-up whole spine CT images were used to calculate CTSS and sCTSS. The sCTSS used the anterior and posterior vertebral corners, and ranged 0-184. Intraclass correlation coefficients (ICC) were calculated, as well as the smallest detectable changes. Fifty AS patients were included. For reader 1, the mean sCTSS at baseline and 2-year follow-up were 11.7 ± 14.6 and 15.8 ± 16.1, whereas those for reader 2 were 12.0 ± 12.5 and 15.8 ± 15.7, respectively. The ICCs for CTSS at baseline and at 2-year follow-up were 0.97 (95% confidence interval [CI] 0.96-0.99) and 0.98 (0.97-0.99), respectively, and that for changes over the 2 years was 0.48 (95% CI 0.23-0.67). For sCTSS, the ICCs were 0.96 (95% CI 0.92-0.97), 0.97 (95% CI 0.94-0.98), and 0.58 (95% CI 0.36-0.74), respectively. Detection rates for syndesmophyte progression were comparable between CTSS and sCTSS. The detection rate for syndesmophytes on only lateral side was 13.2 and 11.4%, and 11.4 and 15.2% at baseline and 2-year follow-up (reader 1 and 2). sCTSS and CTSS showed similar detection rates for syndesmophyte progression. sCTSS may be a reliable method for evaluating spinal structural damage in AS.

Clinical efficacy of alternative TNF inhibitor and secukinumab between primary non-responder and secondary non-responder of prior TNF inhibitor in ankylosing spondylitis.

OBJECTIVES: To compare the drug retention times and clinical efficacy of alternative tumour necrosis factor inhibitors (TNFi) and secukinumab in primary and secondary non-responders with ankylosing spondylitis (AS). METHODS: AS patients treated with biologics and enrolled in the Korean College of Rheumatology Biologics registry were examined. Patients who did not respond to previous TNFi treatment were defined as primary and secondary non-responders. Data regarding drug discontinuation and clinical efficacy were collected after 1 year. Kaplan-Meier and Cox regression analyses were performed to compare drug survival and associated factors. Logistic regression analyses were conducted to compare the clinical efficacy secukinumab with that of alternative TNFi. RESULTS: In total, 124 patients (83 receiving alternative TNFi and 41 receiving secukinumab) had biologic changes due to clinical inefficacy. Drug retention rates in the alternative TNFi and secukinumab groups were similar (P = 0.096). However, subgroup analyses including only secondary non-responders revealed that secukinumab users showed a higher hazard ratio (HR) for drug discontinuation (HR = 3.77, P = 0.045). In addition, secukinumab was negatively associated with achieving BASDAI50 or a major improvement in the ASDAS. CONCLUSION: Alternative TNFi showed better drug retention and clinical efficacy in AS patients experiencing previous TNFi failure, in secondary non-responders. Therefore, alternative TNFi may be a more suitable treatment for secondary non-responders.

Effect of Janus kinase inhibitors on T cell responses to herpes zoster in rheumatoid arthritis patients.

OBJECTIVES: The incidence of herpes zoster (HZ) in rheumatoid arthritis (RA) patients is greater than that in healthy controls (HC), particularly in RA patients treated with Janus kinase inhibitors (JAKi). Here, we examined the effect of JAKi on CD4+/CD8+ T cells, cytokine production, and regulation of transcriptional factors in RA patients and HC. METHODS: Peripheral blood mononuclear cells (PBMCs) obtained from RA patients (n=14) and HCs (n=7) were stimulated with varicella zoster virus lysates and exposed to three JAKi inhibitors (ruxolitinib [JAK1/2 inhibitor]; AG490 [JAK2 inhibitor]; and WHI-P154 [JAK3 inhibitor]) in the presence/absence of methotrexate. The CD4+ and CD8+ T cell populations were measured by flow cytometry. Cytokine levels in culture medium were measured by ELISA. Transcription factor expression was examined by RT-qPCR. RESULTS: There was a reduction in the CD4+IFN-γ+, CD4+CD69+IFN-γ+, CD8+IFN-γ+, and CD8+CD69+IFN-γ+ populations, and an increase in the CD4+CD25highFoxp3+ cell population, in PBMCs from RA patients and HCs after exposure to the three JAKi. ELISA revealed a reduction in IFN-γ and granzyme B levels in the presence of JAKi. JAKi reduced expression of mRNA encoding STAT1 and T-bet, but increased that of mRNA encoding STAT5 and Foxp3. Methotrexate plus the highest dose of each JAKi did not affect the Th1, cytotoxic T cell, or Treg populations, the levels of IFN-γ and granzyme B, or expression of transcription factors, significantly. CONCLUSIONS: JAKi reduce the Th1/cytotoxic T cell population and increase the Treg population in both RA patients and HC patients.

Therapeutic Utility and Adverse Effects of Biologic Disease-Modifying Anti-Rheumatic Drugs in Inflammatory Arthritis.

Targeting specific pathologic pro-inflammatory cytokines or related molecules leads to excellent therapeutic effects in inflammatory arthritis, including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. Most of these agents, known as biologic disease-modifying anti-rheumatic drugs (bDMARDs), are produced in live cell lines and are usually monoclonal antibodies. Several types of monoclonal antibodies target different pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-17A, IL-6, and IL-23/12. Some bDMARDs, such as rituximab and abatacept, target specific cell-surface molecules to control the inflammatory response. The therapeutic effects of these bDMARDs differ in different forms of inflammatory arthritis and are associated with different adverse events. In this article, we summarize the therapeutic utility and adverse effects of bDMARDs and suggest future research directions for developing bDMARDs.

Baseline bony erosions and time-averaged DAS28 predict discontinuation of TNF inhibitors in rheumatoid arthritis.

The present study evaluated the predictive role of baseline radiographic change and disease activity on drug retention and clinical response in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor inhibitor (TNFi). Korean Observational Study Network for Arthritis (KORONA) registry was evaluated to identify RA patients treated with a TNFi. Disease activity score-28 (DAS28) was evaluated at baseline and 1 year after TNFi initiation or at termination of TNFi due to inefficacy (within 1 year). The retention rate of TNFi was compared in patients with and without bony erosions. The hazard ratio (HR) for drug retention was evaluated by Cox regression analysis, as was the odds ratio (OR) for achieving remission (DAS28 < 2.6). This study included 109 RA patients, including 97 (89%) women and 30 (27.5%) with erosions, who were treated with a TNFi. Higher baseline DAS28 was negatively associated with achievement of remission (OR = 0.56, 95% CI 0.35-0.88). The TNFi retention rate was significantly lower in RA patients with than in those without erosions (p = 0.04). Factors significantly associated with drug discontinuation included the presence of erosions (HR = 2.45, 95% CI 1.08-5.51) and higher time-averaged DAS28 (HR = 2.17, 95% CI 1.47-3.20), whereas concomitant methotrexate was associated with lack of drug discontinuation (HR = 0.40, 95% CI 0.17-0.95). The presence of erosions and high time-averaged disease activity could predict poor retention of TNFi by RA patients. Higher baseline DAS28 was associated with a reduced clinical response in patients with RA.Trial registration Clinical Research Information Service of South Korea https://cris.nih.go.kr : KCT0000086, registered May 26, 2009.

Ultrasonographic evaluation of lacrimal glands in patients with primary Sjögren's syndrome.

OBJECTIVES: This study focused on distinguishing the characteristic ultrasonographic findings of lacrimal glands in primary Sjögren's syndrome (pSS) from those in idiopathic sicca syndrome. We aimed to set up a semi-quantitative scoring system of lacrimal gland ultrasonography (LGUS) for patients with pSS. METHODS: Fifty-six patients with pSS and 40 patients with idiopathic sicca syndrome were evaluated. Lacrimal glands were examined with ultrasonography using area, major/minor axis length, and five components (presence of intraglandular branch of lacrimal artery, inhomogeneity, hyperechoic bands, hypoechoic areas, and delineation). Except for the area and maximal/minimal length of lacrimal glands, other components were classified as dichotomous variables (present or absent). Using the receiver operating characteristics curve, we inferred the most appropriate combination of LGUS scoring for pSS diagnosis. RESULTS: Patients with pSS had a higher proportion of intraglandular branch of lacrimal artery (70.5% vs. 42.5%, p<0.001), inhomogeneity (72.3% vs. 46.3%, p<0.001), and hyperechoic bands (56.2% vs. 37.5%, p=0.016) than patients with idiopathic sicca syndrome. LGUS A, which represents the summation of one point assigned for the presence of intraglandular branch of lacrimal artery and one for inhomogeneity, was the most suitable diagnostic criterion (area under curve = 0.724, 95% confidence interval 0.620-0.828). If both sides have a score of 2, it results in a total of 4 points. With a cut-off value of 3 out of 4 points, LGUS A had 60.7% sensitivity, 71.1% specificity, 60.7% positive predictive value, and 72.5% negative predictive value. CONCLUSIONS: Semi-quantitative scoring of LGUS was useful when distinguishing patients with pSS from those with idiopathic sicca syndrome. The combination of intraglandular branch of lacrimal artery and inhomogeneity on both sides was most suitable for classifying pSS using LGUS.

DJ-1 controls T cell differentiation and osteoclastogenesis in rheumatoid arthritis.

Herein, we investigated the effect of DJ-1 on helper T cell differentiation, fibroblast-like synoviocyte (FLS) activation, and osteoclastogenesis in rheumatoid arthritis (RA). Serum and synovial fluid (SF) of RA and osteoarthritis (OA) patients were collected, and DJ-1 and H2O2 levels were investigated. CD4+ cells from peripheral blood mononuclear cells (PBMCs) were cultured under type 17 helper T cell (Th17) polarization conditions, and CD4+ T cell differentiation, pro-inflammatory cytokine levels, and soluble receptor activator of nuclear factor kappa-Β ligand (RANKL) were assessed. RA-FLSs were stimulated with 50 µM H2O2, and DJ-1 (10, 50, 100 ng/mL) to evaluate MMP-9, VEGF, TNF-α, and sRANKL production, while RANKL+ FLSs were assessed using flow cytometry. Monocytes were cultured with RANKL or IL-17A with or without DJ-1 and H2O2-pretreated RA-FLS, and tartrate-resistant acid phosphatase (TRAP) staining and RT-qPCR of osteoclast-related genes were performed. The levels of DJ-1 and H2O2 in serum and SF of RA patients were higher than those of OA patients. Under Th17-polarizing conditions, CD4+RANKL+ and CD4+CCR4+CCR6+CXCR3- T cells decreased, whereas CD4+CD25highFoxp3+ T cell increased after DJ-1 administration. Additionally, IL-17A, TNF-α, and sRANKL levels decreased in DJ-1-treated groups. DJ-1 lowered MMP-9, VEGF, TNF-α, and sRANKL levels, and RANKL+ FLS in ROS-stimulated RA-FLS. Both RANKL and IL-17A stimulated osteoclast differentiation, DJ-1 decreased TRAP+ cell count, and the expression levels of TRAP, ATP6v0d2, NFATc1, and CTSK. These findings were also observed in in vitro osteoclastogenesis with DJ-1 pretreated RA-FLS. As DJ-1 regulates Th17/Treg imbalance, pro-inflammatory cytokine production, RA-FLS activation, and osteoclastogenesis, it holds potential for RA therapy.

A pilot study of nailfold capillaroscopy in hereditary transthyretin amyloidosis.

Nailfold capillaroscopy (NFC) is a safe and non-invasive imaging tool for evaluating microvascular abnormalities. This retrospective cross-sectional study aimed to analyze the NFC outcomes and clinical characteristics in patients and an asymptomatic carrier with transthyretin (TTR) gene mutation. The participants consist of eight patients with genetically and clinically confirmed hereditary amyloidogenic transthyretin (ATTRv) amyloidosis and one asymptomatic carrier. The TTR gene mutant forms of six male and three female participants from six families were Asp38Ala (five patients), Lys35Asn (three patients), and Ala36Pro (one patient). All participants showed decreased capillary density, dilatated capillaries, and destructed architecture in NFC. Early progression identification of a carrier to patients with symptoms is a major concern from a therapeutic viewpoint in ATTRv amyloidosis. Therefore, further studies with a larger number of subjects will be needed to determine the use of NFC as an early detection tool.

A vitronectin-derived peptide prevents and restores alveolar bone loss by modulating bone re-modelling and expression of RANKL and IL-17A.

AIM: This study investigated whether a vitronectin-derived peptide (VnP-16) prevents and/or reverses alveolar bone resorption induced by ligature-induced periodontitis in rodents and identified the underlying mechanism. MATERIALS AND METHODS: We evaluated the effects of VnP-16 on osteogenic differentiation in human periodontal ligament cells (hPDLCs), lipopolysaccharide-induced inflammatory responses in gingival fibroblasts, and immune response in T lymphocytes. Ligature-induced periodontitis was induced by ligating the bilateral mandibular first molars for 14 days in rats and for 7 days in mice (n = 10/group). VnP-16 (100 µg/10 µl) was applied topically into the gingival sulcus of rats via intra-sulcular injection, whereas the peptide (50 µg/5 µl) was administered directly into the gingiva of mice via intra-gingival injection. To evaluate the preventive and therapeutic effects of VnP-16, micro-computed tomography analysis and histological staining were then performed. RESULTS: VnP-16 promoted osteogenic differentiation of periodontal ligament cells and inhibited the production of lipopolysaccharide-induced inflammatory mediators in gingival fibroblasts. Concomitantly, VnP-16 modulated the host immune response by reducing the number of receptor activator of NF-κB ligand (RANKL)-expressing lipopolysaccharide-stimulated CD4+ and CD8+ T cells, and by suppressing RANKL and interleukin (IL)-17A production. Furthermore, local administration of VnP-16 in rats and mice significantly prevented and reversed alveolar bone loss induced by ligature-induced periodontitis. VnP-16 enhanced osteoblastogenesis and simultaneously inhibited osteoclastogenesis and suppressed RANKL and IL-17A expression in vivo. CONCLUSIONS: Our findings suggest that VnP-16 acts as a potent therapeutic agent for preventing and treating periodontitis by regulating bone re-modelling and immune and inflammatory responses.

Time-averaged DAS28 and HAQ predict cardiovascular disease in patients with rheumatoid arthritis: Data from KORONA registry.

OBJECTIVE: To evaluate the predictive role of time-averaged disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ) on cardiovascular disease (CVD) events in patients with rheumatoid arthritis (RA). METHODS: Patients with RA were recruited from 23 tertiary hospitals. Baseline and annual follow-up data of demographic, laboratory, questionnaire, RA-associated parameters, and occurrence of CVD were collected. Patients were divided into three groups according to time-averaged DAS28: 1) remission (<2.6), 2) low (2.6-3.2), 3) moderate (3.2-5.1), and 4) high (>5.1). Kaplan-Meier curves was performed to compare the cumulative probability of CVD. Hazard ratios of each factor on the occurrence of CVD were obtained using Cox regression analyses. RESULTS: A total of 4,034 RA patients with 826 for remission, 938 for low, 2,002 for moderate, and 268 for high time-averaged DAS28 groups were included. Baseline age, disease duration, ESR, CRP, DAS28, and HAQ scores were higher in the high time-averaged DAS28 group. The incidence rate of CVD was 2.86, 2.71, 3.53, and 8.13 events per 1,000 person-years for the remission, low, moderate, and high time-averaged DAS28 groups, respectively. The incidence rate ratio of CVD in the high time-averaged DAS28 group were 3.01 (95% CI 1.20-8.50) when compared to low time-averaged DAS28 group. The cumulative hazard for CVD in the high time-averaged DAS28 group was significantly high (log-rank P<0.01). In multivariate Cox regression analysis, age, high time-averaged DAS28, and time-averaged HAQ>0.5, were positively associated with CVD events in RA patients. CONCLUSIONS: In patients with RA, time-averaged DAS28 and HAQ could predict the occurrence of CVD. TRIAL REGISTRATION: Clinical Research Information Service of South Korea https://cris.nih.go.kr: KCT0000086, registered May 26, 2009.

Increased risks of aortic regurgitation and atrial fibrillation in radiographic axial spondyloarthritis patients: a 10-year nationwide cohort study.

Background: To compare the incidences of aortic regurgitation, atrial fibrillation (AF), and atrioventricular (AV) block II-III between radiographic axial spondyloarthritis (r-axSpA) patients and the general population (GP). Methods: National Health Insurance Services data were used. R-axSpA patients (N = 8877) and the age- and sex-matched GP (N = 26,631) were followed from August 2006 to December 2019. Incidence rates and standardized incidence ratios (SIRs) of aortic regurgitation, AF, and AV block II-III were compared between these groups. Ten-year incidence rates and hazard ratios (HRs) were calculated by the Kaplan-Meier method and Cox regression analysis. Results: Incidence rates of aortic regurgitation, AV block II-III, and AF in the r-axSpA group were 0.42, 0.21, and 4.0 per 1000 person-years (PYs), respectively. In the r-axSpA group, the SIR for aortic regurgitation was highest among 40- to 49-year-old men (4.11). Incidence rates of aortic regurgitation and AF were higher in the r-axSpA group than in the GP group (0.42 versus 0.18 per 1000 PYs 4.00 versus 3.13 per 1000 PYs, both p < 0.001, respectively), whereas the difference was insignificant for AV block II-III (0.21 versus 0.14 per 1000 PYs, p = 0.222). In multivariate analysis, r-axSpA was associated with a higher hazard (risk) for the development of aortic regurgitation and AF [HR (95% confidence interval) = 2.55 (1.49-4.37) and 1.20 (1.04-1.39), respectively], but the difference was insignificant for AV block II-III [HR (95% confidence interval) = 1.17 (0.59-2.31)]. Conclusions: Compared with the GP, r-axSpA patients are at increased risk of aortic regurgitation and AF, but not AV block II-III. These patients should be carefully monitored for occurrence of aortic regurgitation and AF.

Impact of lifestyle and comorbidities on seropositive rheumatoid arthritis risk from Korean health insurance data.

Rheumatoid arthritis (RA) is a systemic inflammatory arthritis in which primary prevention is key. However, the impact of lifestyle and comorbidities on RA development is unknown. Data from the Korean National Health Insurance Service (NHIS)-national sample cohort from 2002 to 2016 were used. At baseline, demographic characteristics, socioeconomic status, type of residential area, lifestyle behaviours (including exercise), and comorbidities (including the Charlson Comorbidity Index, CCI) were included. Cox regression analysis and Kaplan-Meier curves were used to evaluate the impact of lifestyle and comorbidities on seropositive RA occurrence. A total of 517,053 participants were included in the analysis for seropositive RA occurrence. Mean follow up duration was 71.5 and 142.3 person-month for seropositive RA occurrence group and non-occurrence group, respectively. Seropositive RA was diagnosed in 1,948 participants (0.37%) during follow-up. Cox regression analysis revealed that being aged between 40 and 79, a higher CCI, and hyperlipidemia resulted in elevated hazard ratios (HRs) for seropositive RA, whereas male gender, city residence, moderate alcohol consumption, high regular exercise and a BMI between 23 and 34.9 kg/m2 resulted in lower HRs. Using Korean NHIS data, the present study demonstrates that high-intensity regular physical exercise and moderate alcohol consumption are negatively associated with seropositive RA occurrence, which are modifiable lifestyle habits that might aid the primary prevention of seropositive RA.