Interleukin-18 binding protein regulates mast cell activation and mast cell induced osteoclastogenesis of rheumatoid arthritis.

OBJECTIVES: Mast cell activation induces pathological responses, including increased osteoclastogenesis in rheumatoid arthritis (RA). Interleukin (IL)-18 binding protein (IL-18BP) has anti-inflammatory effects. In this study, we evaluated the effect of IL-18BP on mast cell activation and mast cell induced osteoclastogenesis. METHODS: Mast cells were activated by IL-33 (100 ng/mL) and cultured with IL-18BP (10, 50, and 100 ng/mL). The proliferation, apoptosis, and necroptosis of mast cells were measured using flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of mast cell enzymes, matrix metalloproteinase (MMP), soluble RANKL (sRANKL), and pro-inflammatory cytokines in the culture media. Monocytes from patients with RA patients (n=5) were cultured with activated mast cells with various concentrations of IL-18BP. TRAP+ multinucleated osteoclasts, bone resorption area, and osteoclast differentiation-related genes were measured. RESULTS: Proliferation of tryptase+chymase+c-kit+FcεR1+ mast cells was suppressed following incubation with IL-18BP (10, 50, and 100 ng/mL). RNA expression levels of tryptase and chymase were reduced by 100 ng/mL IL-18BP. Additionally, the levels of MMP-3/9, IL-17A, IL-6, TNF-α, and sRANKL were significantly inhibited by 100 ng/mL IL-18BP. Annexin V+ and annexin V-PI+ mast cells were reduced following incubation with 100 ng/mL IL-18BP. The addition of IL-33 significantly stimulated mast cell and increased TRAP+ multinucleated cells and bone resorption area, and these effects were suppressed by IL-18BP. The osteoclast-related genes (TRAP, ATP6v0d2, RANK, and cathepsin K) expression were suppressed by IL-18BP. CONCLUSIONS: IL-18BP suppressed mast cell activation and mast cell induced osteoclastogenesis. This suggests a potential anti-arthritic role for IL-18BP in patients with RA.

Suppressing anti-citrullinated protein antibody-induced osteoclastogenesis in rheumatoid arthritis using anti-CD64 and PAD-2 inhibitors.

OBJECTIVES: To evaluate the role of Fcγ receptors (FcγR) and peptidyl arginine deiminase (PAD) in anti-citrullinated protein antibody (ACPA)-induced fibroblast-like synoviocytes (FLSs)-mediated osteoclastogenesis in patients with rheumatoid arthritis (RA). METHODS: FLSs and peripheral blood mononuclear cells were collected from patients with RA. We stimulated RA-FLS with ACPA (100 ng/ml) with and without anti-cluster of differentiation (CD)32a/CD64 (FcγRIIA/FcγRI) antibody and PAD-2/4 inhibitors. Flow cytometry and enzyme-linked immunosorbent assay were also performed. CD14+ monocytes were cultured with receptor activator of nuclear factor kappa beta (RANKL) and macrophage colony-stimulating factor, and ACPA-stimulated RA-FLSs were added. These cells were cultured for 14 days, and osteoclastogenesis was quantified using tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: ACPA increased RANKL+ and tumour necrotic factor-alpha (TNF-α+) FLS, which decreased dose-dependently by adding 5 and 10 ug/mL anti-CD64 antibody rather than anti-CD32a antibody. In PAD inhibitor experiments, the proportion of RANKL+ and TNF-α+ FLS decreased in 50 µM condition containing PAD-2 inhibitor rather than PAD-4 inhibitor. The co-culture of ACPA-stimulated RA-FLSs and osteoclast precursors increased the TRAP+ multinucleated osteoclast count, which was decreased by anti-CD64 antibody and PAD2 inhibitor. CONCLUSIONS: The present study showed that ACPA increased RANKL and pro-inflammatory cytokine expression in RA-FLSs, and ACPA-activated RA-FLSs could augment osteoclastogenesis. These processes were inhibited by treatment with anti-CD64 antibody and PAD-2 inhibitors. These results show that CD64 and PAD-2-induced pathways may be involved in ACPA-induced FLS activation and osteoclastogenesis in patients with RA. Therefore, regulating the CD64 and PAD-2 pathways may improve RA treatment.

Self-Compliant Threshold Switching Devices with High On/Off ratio by Control of Quantized Conductance in Ag Filaments.

Threshold switches based on conductive metal bridge devices are useful as selectors to block sneak leakage paths in memristor arrays used in neuromorphic computing and emerging nonvolatile memory. We demonstrate that control of Ag-cation concentration in Al2O3 electrolyte and Ag filament size and density play an important role in the high on/off ratio and self-compliance of metal-ion-based volatile threshold switching devices. To control Ag-cation diffusion, we inserted an engineered defective graphene monolayer between the Ag electrode and the Al2O3 electrolyte. The Ag-cation migration and the Ag filament size and density are limited by the pores in the defective graphene monolayer. This leads to quantized conductance in the Ag filaments and self-compliance resulting from the formation and dissolution of the Ag conductive filament.

Palsy of Both the Tibial Nerve and Common Peroneal Nerve Caused by a Ganglion Cyst in the Popliteal Area.

A ganglion cyst is a benign mass consisting of high-viscosity mucinous fluid. It can originate from the sheath of a tendon, peripheral nerve, or joint capsule. Compressive neuropathy caused by a ganglion cyst is rarely reported, with the majority of documented cases involving peroneal nerve palsy. To date, cases demonstrating both peroneal and tibial nerve palsies resulting from a ganglion cyst forming on a branch of the sciatic nerve have not been reported. In this paper, we present the case of a 74-year-old man visiting an outpatient clinic complaining of left-sided foot drop and sensory loss in the lower extremity, a lack of strength in his left leg, and a decrease in sensation in the leg for the past month without any history of trauma. Ankle dorsiflexion and great toe extension strength on the left side were Grade I. Ankle plantar flexion and great toe flexion were Grade II. We suspected peroneal and tibial nerve palsy and performed a screening ultrasound, which is inexpensive and rapid. In the operative field, several cysts were discovered, originating at the site where the sciatic nerve splits into peroneal and tibial nerves. After successful surgical decompression and a series of rehabilitation procedures, the patient's neurological symptoms improved. There was no recurrence.

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.

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.

Design of High-Speed, Low-Power Sensing Circuits for Nano-Scale Embedded Memory.

This paper comparatively reviews sensing circuit designs for the most widely used embedded memory, static random-access memory (SRAM). Many sensing circuits for SRAM have been proposed to improve power efficiency and speed, because sensing operations in SRAM dominantly determine the overall speed and power consumption of the system-on-chip. This phenomenon is more pronounced in the nanoscale era, where SRAM bit-cells implemented near minimum-sized transistors are highly influenced by variation effects. Under this condition, for stable sensing, the control signal for accessing the selected bit-cell (word-line, WL) should be asserted for a long time, leading to increases in the power dissipation and delay at the same time. By innovating sensing circuits that can reduce the WL pulse width, the sensing power and speed can be efficiently improved, simultaneously. Throughout this paper, the strength and weakness of many SRAM sensing circuits are introduced in terms of various aspects-speed, area, power, etc.

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.

Correlation between salivary gland ultrasonography and scintigraphy in primary Sjögren's syndrome.

OBJECTIVE: To compare findings on salivary gland ultrasonography (SGUS) and salivary gland scintigraphy (SGS) in patients with primary SS (pSS). METHODS: The study cohort included patients newly diagnosed with pSS who underwent SGUS and SGS at the same time at our tertiary care hospital. Baseline demographics, laboratory data, clinical data and SGUS and SGS findings were collected. An SGUS cut-off score ≥14 defined positive SGUS findings and was used to classify patients in SGUS+ and SGUS- groups. SGS findings were quantified by the parotid:submandibular uptake ratio (PU:SU) and percentage parotid/submandibular excretion (%PE/%SE). The correlation between SGUS and SGS findings was evaluated. RESULTS: For analysis, 18 patients with SGUS+ findings and 18 with SGUS- findings were recruited, for a total study cohort of 36 patients. There were no between-group differences in baseline demographics and clinical and laboratory data. The PU, %PE, SU and %SE were significantly lower in the SGUS+vs SGUS- group. The SGUS score for the parotid gland was negatively correlated to the PU (r = -0.36, P = 0.03) and %PE (r = -0.35, P = 0.04). The SGUS score of the submandibular gland was negatively correlated to the SU (r = -0.42, P = 0.01) and %SE (r = -0.39, P = 0.02). CONCLUSIONS: Patients with a higher SGUS score had lower salivary gland function. The SGUS score showed a significant correlation with PU, %PE, SU and %SE. These findings are indicative of a possible predictive role of SGUS to diagnose salivary gland dysfunction.

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.

Biologic retention rate and efficacy in patients with cluster-based phenotypes of ankylosing spondylitis: data from a Korean national biologics registry.

OBJECTIVES: Patients with ankylosing spondylitis (AS) have a heterogenic disease course and treatment response. Cluster-based phenotypes are useful for predicting AS disease course. Here, we compared drug retention and clinical efficacy of biologic disease-modifying anti-rheumatic drugs (bDMARDs) in AS patients with cluster A and cluster B phenotypes. METHODS: AS patients enrolled in the Korean College of Rheumatology BIOlogics registry were divided into cluster A (axial symptoms predominant) and cluster B (both axial and peripheral symptoms). Retention of bDMARDs was measured using Kaplan-Meier curve and Cox regression analyses. Clinical efficacy (BASDAI50, ASAS20, ASAS40, ASDAS inactive state, and clinically important improvement/major improvement of ASDAS) at 1-year follow-up was measured by logistic regression analysis. Also, propensity score (PS)-matched analyses were conducted. RESULTS: 1600 AS patients (1468 for cluster A, 132 for cluster B) were included. Kaplan-Meier curve analysis revealed that the drug retention rate was lower in cluster B patients (p=0.03). PS-matched analyses showed that the hazard ratio (HR) for drug discontinuation was signi cantly higher in cluster B patients (HR=1.568; 95% con dence interval =1.055-2.329). The odds ratio for BASDAI50 at 1-year was comparable between cluster A and cluster B patients in PS-matched and multivariate logistic regression analyses. A similar result was obtained in other clinical efficacy assessments. CONCLUSIONS: The drug retention rate was lower in cluster B patients than in cluster A patients; clinical efficacy was comparable between the two groups at 1-year follow-up. These results may help predict drug retention and clinical efficacy in AS patients.

Prognostic signature of interferon-γ and interleurkin-17A in early rheumatoid arthritis.

OBJECTIVES: CD4+ T cells are crucial for the pathogenesis of rheumatoid arthritis (RA). Here, we evaluated gene expression in CD4+ T cells in early RA, and main purpose of present study was to seek the changes in CD4+ T-cell-related cytokines according to RA progression. METHODS: Early RA was defined as methotrexate (MTX)-naïve patients. Established RA was defined as patients with more than 6 months of DMARDs. Patients with osteoarthritis were evaluated as controls. Microarray analysis was used to identify overexpressed genes in CD4+ T cells, and RT-qPCR was used to validate. Plasma cytokine were measured in patients with early and established RA, and correlations with disease activity were assessed in patients with early RA, whereas clinical prognosis was assessed in established patients with RA. RESULTS: Thirty-four genes showed overexpression in CD4+ T cells from patients with early RA compared with OA controls. Nineteen were related to interferon (IFN)-γ, and eight were related to interleukin (IL)-17A. Plasma levels of IL-17A, IL-6, IL-12, and TNF-α correlated with IFN-γ, and correlation coefficient was highest between DAS28-ESR and plasma IFN-γ levels in patients with early RA (Rho=0.553, p=0.0025). In established RA with low disease activity, drug reduction group showed lower plasma IFN-γ and IL-17A than drug maintenance/relapse group (13.61±5.75 vs. 29.89±18.72, p<0.001; and 10.91±3.92 vs. 21.04±12.81 pg/mL, p<0.001, respectively). CONCLUSIONS: The IFN-γ and IL-17 gene signature in CD4+ T cells was significantly increased in early RA. Patients with established RA with low levels of IFN-γ and IL-17A could be eligible for dose reduction.

NEAR: Named entity and attribute recognition of clinical concepts.

Named Entity Recognition (NER) or the extraction of concepts from clinical text is the task of identifying entities in text and slotting them into categories such as problems, treatments, tests, clinical departments, occurrences (such as admission and discharge) and others. NER forms a critical component of processing and leveraging unstructured data from Electronic Health Records (EHR). While identifying the spans and categories of concepts is itself a challenging task, these entities could also have attributes such as negation that pivot their meanings implied to the consumers of the named entities. There has been little research dedicated to identifying the entities and their qualifying attributes together. This research hopes to contribute to the area of detecting entities and their corresponding attributes by modelling the NER task as a supervised, multi-label tagging problem with each of the attributes assigned tagging sequence labels. In this paper, we propose 3 architectures to achieve this multi-label entity tagging: BiLSTM n-CRF, BiLSTM-CRF-Smax-TF and BiLSTM n-CRF-TF. We evaluate these methods on the 2010 i2b2/VA and the i2b2 2012 shared task datasets. Our different models obtain best NER scores of 0.903 and 0.808 on the i2b2 2010/VA and i2b2 2012 respectively. The highest span based micro-averaged F1 polarity scores obtained were 0.832 and 0.836 on the i2b2 2010/VA and i2b2 2012 datasets respectively, and the highest macro-averaged F1 polarity scores obtained were 0.924 and 0.888 respectively. The modality studies conducted on i2b2 2012 dataset revealed high scores of 0.818 and 0.501 for span based micro-averaged F1 and macro-averaged F1 respectively.

Accurate Ship Detection Using Electro-Optical Image-Based Satellite on Enhanced Feature and Land Awareness.

This paper proposes an algorithm that improves ship detection accuracy using preprocessing and post-processing. To achieve this, high-resolution electro-optical satellite images with a wide range of shape and texture information were considered. The developed algorithms display the problem of unreliable detection of ships owing to clouds, large waves, weather influences, and shadows from large terrains. False detections in land areas with image information similar to that of ships are observed frequently. Therefore, this study involves three algorithms: global feature enhancement pre-processing (GFEP), multiclass ship detector (MSD), and false detected ship exclusion by sea land segmentation image (FDSESI). First, GFEP enhances the image contrast of high-resolution electro-optical satellite images. Second, the MSD extracts many primary ship candidates. Third, falsely detected ships in the land region are excluded using the mask image that divides the sea and land. A series of experiments was performed using the proposed method on a database of 1984 images. The database includes five ship classes. Therefore, a method focused on improving the accuracy of various ships is proposed. The results show a mean average precision (mAP) improvement from 50.55% to 63.39% compared with other deep learning-based detection algorithms.

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.

IL-18 binding protein suppresses IL-17-induced osteoclastogenesis and rectifies type 17 helper T cell / regulatory T cell imbalance in rheumatoid arthritis.

BACKGROUND: Patients with rheumatoid arthritis (RA) have increased levels of interleukin-18 (IL-18) and decreased levels of IL-18 binding protein (IL-18BP) in the serum and synovial fluid (SF) compared to those in patients with osteoarthritis (OA) or in healthy controls. In this study, we evaluated the effects of IL-18BP on osteoclastogenesis and T cell differentiation in RA in vitro. METHODS: Serum and SF of patients with RA and OA were collected to compare IL-18 and IL-18BP levels by the enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells (PBMCs) and SF mononuclear cells (SFMCs) of RA patients were cultured under type 17 helper T cell (Th17) polarisation conditions with or without IL-18BP. In addition, PBMCs were cultured in the presence of receptor activator of nuclear factor kappa-Β ligand (RANKL) or IL-17A with or without IL-18BP, and tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative polymerase chain reaction for expression levels of osteoclast-related genes were performed. RESULTS: IL-18 levels were higher in the serum and SF of patients with RA, whereas IL-18BP was lower in the SF of patients with RA than in the control group. Treatment of patients' PBMCs with IL-18BP decreased the differentiation of CD4+ IL-17A+ and CD4+ RANKL+ T cells, whereas the differentiation of CD4+CD25highFOXP3+ T cell population increased in a dose-dependent manner. These changes in CD4+ T cell differentiation were also observed in the SFMCs of patients with RA. The levels IL-17A and soluble RANKL in the culture medium were significantly decreased by IL-18BP. IL-18BP administration decreased TRAP+ cell counts in a dose-dependent manner on the background of stimulation with RANKL-and IL-17A. In addition, expression levels of TRAP, NFATC1, CTSK, and TNFRSF11A (RANK) genes were lower in the IL-18BP treated cells. CONCLUSION: We showed that IL-18BP can rectify the Th17/Treg imbalance and decrease IL-17-induced osteoclastogenesis in PBMCs from patients with RA. Therefore, IL-18BP may have therapeutic potential for RA treatment.

Retention rate and effectiveness of secukinumab vs TNF inhibitor in ankylosing spondylitis patients with prior TNF inhibitor exposure.

OBJECTIVES: The choice of second-line biologics for AS patients previously treated with a TNF inhibitor (TNFi) remains unclear. Here, we compared drug retention and clinical efficacy between AS patients who switched biologics to secukinumab and those who switched to a different TNFi. METHODS: AS patients enrolled in the Korean College of Rheumatology BIOlogics registry were included, and patients with non-radiographic axial spondyloarthritis were excluded. Patients with previous TNFi exposure were divided into the secukinumab group and the TNFi switching group. Drug retention and clinical efficacy [BASDAI50, Assessment of Spondylo-Arthritis International Society (ASAS)20, ASAS40, AS disease activity score (ASDAS) <2.1, ASDAS clinically important improvement and ASDAS major improvement] were assessed at the 1 year follow-up. Propensity score (PS)-matched and covariate-adjusted logistic regression analyses were performed. RESULTS: Two hundred and forty-six had available 1 year follow-up data. Secukinumab as third- or later-line biologic was more frequent than alternative TNFi (54% vs 14%). PS-matched and multiple covariate-adjusted analyses showed that the odds ratio (OR) for drug discontinuation was comparable between the secukinumab and TNFi switching groups [OR 1.136 (95% CI 0.843, 1.531) and 1.000 (95% CI 0.433-2.308), respectively]. The proportion of patients who achieved BASDAI50 was also comparable between the two groups [OR 0.833 (95% CI 0.481, 1.441) in PS-matched analysis]. Other clinical efficacy parameters were also comparable. In the subgroup analysis of AS patients with previous TNFi discontinuation due to ineffectiveness, all clinical efficacy parameters were comparable between the two groups. CONCLUSION: In AS patients with previous exposure to a TNFi, switching biologics to secukinumab and switching to an alternative TNFi resulted in comparable drug retention and clinical efficacy.

Semiquantitative analysis of sacroiliac joint to sacrum ratio of bone scintigraphy to predict spinal progression in early axial spondyloarthritis: a pilot study.

OBJECTIVES: To investigate whether bone scintigraphy with semiquantitative analysis in patients with early axial spondyloarthritis (axSpA) has prognostic value for predicting spinal structural progression of these patients after 2 years. METHODS: The records of 53 patients with early axSpA who underwent baseline bone scintigraphy were reviewed retrospectively. The sacroiliac joint to sacrum (SIS) ratio of bone scintigraphy was measured for semiquantitative analysis, and modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and syndesmophyte growth were calculated at baseline and after 2 years. Receiver operating characteristic (ROC) curve analysis was used to determine the cut-off for the SIS ratio of bone scintigraphy. To identify factors associated with significant spinal structural progression, univariate and multivariate logistic regression analyses were performed. Significant progression of spinal structural damage over 2 years was defined as an increase of mSASSS of at least 2 units for 2 years or new syndesmophyte growth/bridging of pre-existing syndesmophytes. RESULTS: Multivariate regression analysis revealed current smoking status (p=0.010), and high SIS ratio of bone scintigraphy (p=0.016) as independent predictors for worsening mSASSS by at least 2 units over 2 years. For new syndesmophyte growth/bridging of pre-existing syndesmophytes over 2 years, current smoking (p=0.013), high SIS ratio of bone scintigraphy (p=0.025), and pre-existing syndesmophyte (p=0.036) were independent predictors. CONCLUSIONS: Semiquantitative analysis of bone scintigraphy (high SIS ratio) in patients with early axSpA may be useful for identifying patients at high risk for spinal structural progression after 2 years.

Comparison of sampling methods in assessing the microbiome from patients with ulcerative colitis.

BACKGROUND: Dysbiosis of ulcerative colitis (UC) has been frequently investigated using readily accessible stool samples. However, stool samples might insufficiently represent the mucosa-associated microbiome status. We hypothesized that luminal contents including loosely adherent luminal bacteria after bowel preparation may be suitable for diagnosing the dysbiosis of UC. METHODS: This study included 16 patients with UC (9 men and 7 women, mean age: 52.13 ± 14.09 years) and 15 sex- and age-matched healthy individuals (8 men and 7 women, mean age: 50.93 ± 14.11 years). They donated stool samples before colonoscopy and underwent luminal content aspiration and endoscopic biopsy during the colonoscopy. Then, the composition of each microbiome sample was analyzed by 16S rRNA-based next-generation sequencing. RESULTS: The microbiome between stool, luminal contents, and biopsy was significantly different in alpha and beta diversities. However, a correlation existed between stool and luminal contents in the Procrustes test (p = 0.001) and Mantel test (p = 0.0001). The stool microbiome was different between patients with UC and the healthy controls. Conversely, no difference was found in the microbiome of luminal content and biopsy samples between the two subject groups. The microbiome of stool and lavage predicted UC, with AUC values of 0.85 and 0.81, respectively. CONCLUSION: The microbiome of stool, luminal contents, and biopsy was significantly different. However, the microbiome of luminal contents during colonoscopy can predict UC, with AUC values of 0.81. Colonoscopic luminal content aspiration analysis could determine microbiome differences between patients with UC and the healthy control, thereby beneficial in screening dysbiosis via endoscopy. TRIAL REGISTRATION: This trial was registered at http://cris.nih.go.kr . Registration No.: KCT0003352), Date: 2018-11-13.

Caffeic Acid Phenethyl Ester-Incorporated Radio-Sensitive Nanoparticles of Phenylboronic Acid Pinacol Ester-Conjugated Hyaluronic Acid for Application in Radioprotection.

We synthesized phenylboronic acid pinacol ester (PBPE)-conjugated hyaluronic acid (HA) via thiobis(ethylamine) (TbEA) linkage (abbreviated as HAsPBPE conjugates) to fabricate the radiosensitive delivery of caffeic acid phenetyl ester (CAPE) and for application in radioprotection. PBPE was primarily conjugated with TbEA and then PBPE-TbEA conjugates were conjugated again with hyaluronic acid using carbodiimide chemistry. CAPE-incorporated nanoparticles of HAsPBPE were fabricated by the nanoprecipitation method and then the organic solvent was removed by dialysis. CAPE-incorporated HAsPBPE nanoparticles have a small particle size of about 80 or 100 nm and they have a spherical shape. When CAPE-incorporated HAsPBPE nanoparticles were irradiated, nanoparticles became swelled or disintegrated and their morphologies were changed. Furthermore, the CAPE release rate from HAsPBPE nanoparticles were increased according to the radiation dose, indicating that CAPE-incorporated HAsPBPE nanoparticles have radio-sensitivity. CAPE and CAPE-incorporated HAsPBPE nanoparticles appropriately prevented radiation-induced cell death and suppressed intracellular accumulation of reactive oxygen species (ROS). CAPE and CAPE-incorporated HAsPBPE nanoparticles efficiently improved survivability of mice from radiation-induced death and reduced apoptotic cell death. We suggest that HAsPBPE nanoparticles are promising candidates for the radio-sensitive delivery of CAPE.