Phf7 has impacts on the body growth and bone remodeling by regulating testicular hormones in male mice.

PHD finger protein 7 (Phf7) is a member of the PHF family proteins, which plays important roles in spermiogenesis. Phf7 is expressed in the adult testes and its deficiency causes male infertility. In this study, we tried to find the causal relationship between Phf7 deficiency and reduced growth retardation which were found in null knock-out (Phf7-/-) mice. Phf7-/- mice were born normally in the Mendelian ratio. However, the Phf7-/- males showed decreased body weight gain, bone mineral density, and bone mineral content compared to those in wild-type (WT) mice. Histological analysis for tibia revealed increased number of osteoclast cells in Phf7-/- mice compared with that in WT mice. When we analyzed the expressions for marker genes for the initial stage of osteoclastogenesis, such as receptor activator of nuclear factor kappa B (Rank) in tibia, there was no difference in the mRNA levels between Phf7-/- and WT mice. However, the expression of tartrate-resistant acid phosphatase (Trap), a mature stage marker gene, was significantly higher in Phf7-/- mice than in WT mice. In addition, the levels of testosterone and dihydrotestosterone (DHT), more potent and active form of testosterone, were significantly reduced in the testes of Phf7-/- mice compared to those in WT mice. Furthermore, testicular mRNA levels for steroidogenesis marker genes, namely Star, Cyp11a1, Cyp17a1 and 17ß-hsd, were significantly lower in Phf7-/- mice than in WT mice. In conclusion, these results suggest that Phf7 deficiency reduces the production of male sex hormones and thereby impairs associated bone remodeling.

Effects of Hormone Replacement Therapy on Bone Mineral Density in Korean Adults With Turner Syndrome.

BACKGROUND: Turner syndrome (TS) is a common chromosomal abnormality, which is caused by loss of all or part of one X chromosome. Hormone replacement therapy in TS is important in terms of puberty, growth and prevention of osteoporosis however, such a study has never been conducted in Korea. Therefore, the purpose of our study was to determine relationship between the starting age, duration of estrogen replacement therapy (ERT) in TS and develop a hormone replacement protocol suitable for the situation in Korea. METHODS: This is retrospective study analyzed the medical records in TS patients treated at the Severance hospital, Yonsei University College of Medicine, Seoul, Korea from 1997 to 2019. Total of 188 subjects who had received a bone density test at least once were included in the study. Korean National Health and Nutrition Examination Survey (KNHANES) was used for achieving bone mineral density (BMD) of normal control group. Student's t-test, Mann-Whitney U test, ANOVA and correlation analysis were performed using SPSS 18.0. RESULTS: Each BMD measurement was significantly lower in women with TS than in healthy Korean women. Early start and longer duration of ERT is associated with higher lumbar spine BMD but not femur neck BMD. Femur neck BMD, but not lumbar spine BMD was significantly higher in women with mosaicism than 45XO group. CONCLUSION: Early onset and appropriate duration of hormone replacement therapy is important for increasing bone mineral density in patients with Turner syndrome. Also, ERT affects differently to TS patients according to mosaicism.

Effect of catheter-directed ethanol sclerotherapy on ovarian reserve in patients with recurrent endometrioma: comparative analysis with primary endometriosis.

OBJECTIVE: Catheter-directed ethanol sclerotherapy (CDS) is known to less affect the ovarian function, with comparable efficacy. This study aims to investigate the change in ovarian reserve after catheter-directed ethanol sclerotherapy in patients with recurrent endometrioma, as compared to primary endometrioma. MATERIALS AND METHODS: Retrospective, observational study. Electronic medical records and images of patients with endometrioma who underwent CDS from August 2014 to April 2022 at a single institution were obtained. Patients aged > 18 years old and with anti-Müllerian hormone (AMH) level between 0.8 and 10.0 with regular menstruation were enrolled. Cyst diameter, laterality, AMH level, and CA-125 level before and after 1 month, 6 months, 1 year, 2 years, and 3 years of sclerotherapy were obtained. RESULTS: A total of 180 patients were fit for analysis. There was no statistical difference in age and cyst size between the two groups. Mean values of AMH in each group were 3.35 in the primary group and 3.00 in the recurrent group prior to the procedure (p = 0.347). There was no significant difference in delta value of AMH after sclerotherapy in both groups at each follow-up period. Also, this result was consistent when stratified by laterality, preprocedural AMH level, and initial size of endometrioma. No case of recurrence was reported in both groups. CONCLUSIONS: The effect of CDS on ovarian reserve is not inferior in recurrent endometrioma compared to primary endometrioma. Since sclerotherapy is known to less deteriorate the ovarian function than surgical removal of endometrioma, clinician could consider this as the first-line therapy in patients with recurrent endometrioma. CLINICAL RELEVANCE STATEMENT: Catheter-directed ethanol sclerotherapy for patients with recurrent endometrioma has similar effect on ovarian reserve compared to patients with primary endometrioma. KEY POINTS: • Secondary surgery for endometrioma has significant deleterious effect on ovarian function. • Catheter-directed sclerotherapy (CDS) for endometrioma had equally minimal adverse effect on ovarian reserve, represented as anti-Müllerian hormone (AMH), in both primary and recurrent groups. • Physicians should consider CDS for patients with recurrent endometrioma who desire to preserve ovarian function.

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.

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.

Comparison of survival rates between total knee arthroplasty after a previous anterior cruciate ligament reconstruction and primary total knee arthroplasty via propensity score matching.

INTRODUCTION: Although the survival rate of total knee arthroplasty (TKA) in patients treated with anterior cruciate ligament reconstruction (ACLR) is not as favorable as that in patients treated with primary TKA without ligament reconstruction, the exact survival rates and complications associated with these procedures are still controversial. Therefore, the purpose of the current study was to compare the revision rates of TKA in patients with knee osteoarthritis (OA) with a previous ACLR and those of patients with primary TKA with no history of knee surgery by using propensity score matching analysis. MATERIALS AND METHODS: A list of patients who underwent TKA from January 1, 2008 to May 31, 2019 was obtained from the Korean National Health Insurance database. Among these, 460 patients underwent TKA in a knee with a previous ACLR and 569,766 patients who underwent primary TKA due to degenerative OA. We performed propensity scoring matching to compare the revision rates including septic revision due to prosthetic joint infection after TKA and perioperative complication rates within 90 days after revision TKA between the two groups. RESULTS: Matched patients were assigned to one of the two groups (group A: 2,201 patients who underwent TKA due to primary OA, group B: 448 patients who underwent TKA in a knee with a previous ACLR) based on the propensity score. The total number of revisions per 1000 person-years was significantly higher in group B than in group A (10.16 vs 4.66, respectively). Group B showed a higher risk of revision than group A at 10 years post-TKA (hazard ratio: 2.49, 95% confidence interval: 1.30-4.77). However, group B showed a similar risk of septic revision as group A (p = 0.44). Perioperative complications within 90 days after TKA showed no significant differences between the groups. CONCLUSIONS: Surgeons should be aware of the relatively higher revision rate of TKA in patients who had previously undergone an ACLR compared to that in patients who underwent primary TKA.

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.

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.

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.

A comparative study of 21,194 UKAs and 49,270 HTOs for the risk of unanticipated events in mid-age patients from the national claims data in South Korea.

BACKGROUND: Both high tibial osteotomy (HTO) and unicompartmental knee arthroplasty (UKA) are well-established treatments for medial knee osteoarthritis (OA). However, over the past 20 years, results of comparisons of long-term survival rates and outcomes have remained controversial. Furthermore, in patients at the boundary age, from 50 to 70 years, considering age as a treatment indication, selecting a surgical method is difficult. Therefore, we aimed to investigate conversion rates to total knee arthroplasty (TKA) and perioperative adverse outcomes between the two surgical methods in mid-age patients. METHODS: We extracted data from the Korean National Health Insurance claims database. A total of 70,464 patients aged between 50 and 70 years, considered as mid-age patients were included in the final study population. We used a multivariable Cox proportional hazard regression model, adjusting for potential confounders such as age, sex, insurance type, region of residence, hospital type, comorbidities, and the Charlson comorbidity Index (CCI). RESULTS: Of the 70,464 patients, 21,194 were treated with UKA and 49,270 were treated with HTO. HTO showed a higher risk of revision than UKA at five, and 10 years and during the whole observation period. The incidence of deep vein thromboembolism, and surgical site infection was significantly higher in UKA than in HTO. CONCLUSIONS: It is important to choose an appropriate surgical method considering that UKA has better results in terms of long-term survival rates but may have a higher incidence of various complications.

Aortic valve replacement in patients aged 50 to 69 years: Analysis using Korean National Big Data.

BACKGROUND: The aim of this study was to compare the clinical outcomes and long-term survival in patients who underwent isolated aortic valve replacement (AVR) with mechanical versus bioprosthetic valves. METHODS: Patients aged 50-69 years who had undergone AVR from 2002 to 2018 were identified and their characteristics were collected from Korean National Health Information Database formed by the National Health Insurance Service, Republic of Korea. Of the 5792 patients, 1060 patients were excluded due to missing values on characteristics. Of the 4732 study patients, 1945 patients (41.1%) had received bioprosthetic valves (Group B) and 2787 patients (58.9%) had received mechanical valves (Group M). A propensity score-matched analysis was performed to match 1429 patients in each group. Data on mortality, cardiac mortality, reoperations, cerebrovascular accidents, and bleeding complications were obtained. RESULTS: The overall survival rates at 5 and 10 years postoperatively were 87.8% and 75.2% in the matched Group B and 91.2% and 76.7% in the matched Group M, respectively (p = .140). Freedom from cardiac death rates at postoperative 5 and 10 years were 95.6% and 92.4% in the matched Group B and 96.0% and 92.1% in the matched Group M, respectively (p = .540). The cumulative incidence of reoperation was higher in the matched Group B than in the matched Group M (p = .007), and the cumulative incidence of major bleeding was higher in the matched Group M than in the matched Group B (p = .039). CONCLUSION: In patients aged 50-69 years who underwent isolated AVR, the patients who received bioprosthetic valves showed similar cardiac mortality-free survival and long-term survival rates to the patients who received mechanical valves.

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.

Topoisomerase IIIß Deficiency Induces Neuro-Behavioral Changes and Brain Connectivity Alterations in Mice.

Topoisomerase IIIß (Top3ß), the only dual-activity topoisomerase in mammals that can change topology of both DNA and RNA, is known to be associated with neurodevelopment and mental dysfunction in humans. However, there is no report showing clear associations of Top3ß with neuropsychiatric phenotypes in mice. Here, we investigated the effect of Top3ß on neuro-behavior using newly generated Top3ß deficient (Top3ß-/-) mice. We found that Top3ß-/- mice showed decreased anxiety and depression-like behaviors. The lack of Top3ß was also associated with changes in circadian rhythm. In addition, a clear expression of Top3ß was demonstrated in the central nervous system of mice. Positron emission tomography/computed tomography (PET/CT) analysis revealed significantly altered connectivity between many brain regions in Top3ß-/- mice, including the connectivity between the olfactory bulb and the cerebellum, the connectivity between the amygdala and the olfactory bulb, and the connectivity between the globus pallidus and the optic nerve. These connectivity alterations in brain regions are known to be linked to neurodevelopmental as well as psychiatric and behavioral disorders in humans. Therefore, we conclude that Top3ß is essential for normal brain function and behavior in mice and that Top3ß could be an interesting target to study neuropsychiatric disorders in humans.

Importin-11 is Essential for Normal Embryonic Development in Mice.

Importin-11 (Ipo11) is a novel member of the human importin family of transport receptors (karyopherins), which are known to mediate the nucleocytoplasmic transport of protein and RNA cargos. Despite its role in the transport of protein, we found that knockout of Ipo11 nuclear import factor affects normal embryonic development and govern embryo-lethal phenotypes in mice. In this study, we for the first time produced a mouse line containing null mutation in Ipo11 gene utilized by gene trapping. The Ipo11-/- embryos showed an embryonic lethal phenotype. The Ipo11-/- embryos showed a reduced size at embryonic day 10.5 (E10.5) when compared with Ipo11+/+ or Ipo11+/- embryos and died by E11.5. Whereas Ipo11+/- mice were healthy and fertile, and there was no detectable changes in embryonic lethality and phenotype when reviewed. In the X-gal staining with the Ipo11-/- or Ipo11+/- embryos, strong X-gal staining positivity was detected systematically in the whole mount embryos at E10.5, although almost no X-gal positivity was detected at E9.5, indicating that the embryos die soon after the process of Ipo11 expression started. These results indicate that Ipo11 is essential for the normal embryonic development in mice.

Reciprocal interaction between macrophage migration inhibitory factor and interleukin-8 in gout.

OBJECTIVES: Macrophage migration inhibitory factor (MIF) is a proinflammatory, chemotactic, and tissue destructive cytokine. This study determined monosodium urate crystal-induced MIF production and its interaction with interleukin (IL)-8 in gout. METHODS: Peripheral blood (PB), synovial fluid (SF), and clinical data were obtained from 98 patients with gout. SF and serum concentrations of MIF and IL-8 were measured using ELISA. SF monocytes and neutrophils were cultured with monosodium urate (MSU) crystals and the cytokine production was determined. The signalling pathways involved were determined using signal inhibitors. The interaction between MIF and IL-8 was investigated. RESULTS: SF MIF was higher in acute gout and that in serum was higher in patients with intercritical gout compared with controls. SF MIF was positively correlated with SF leukocyte and neutrophil counts and IL-8. The expression of MIF was similar in SF neutrophils and monocytes, while IL-8 was higher in monocytes. MSU crystals induced MIF production in monocytes and IL-8 production in neutrophils. This effect was decreased by inhibiting Fc-gamma receptor 1 and toll-like receptor 4. IL-8 increased MIF production in monocytes while MIF increased interleukin-8 production in neutrophils. CONCLUSIONS: MIF and IL-8 are highly produced in acute gout. MSU crystals induced MIF production in monocytes and IL-8 production in neutrophils with a reciprocal interaction between the two cytokines.