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BackgroundTo develop an accurate mortality risk predictive model among patients with lung cancer.MethodsThe development cohort included 96,255 patients with lung cancer aged ≥19 years, who underwent a Korean National Health Insurance Service health check-up from 2005 to 2015. The validation cohort consisted of 18,432 patients (≥19 years) with lung cancer from another region. The outcome was all-cause mortality between January 1, 2005, and December 31, 2020.ResultsApproximately 60.5% of the development cohort died within a median follow-up period of 2.32 (0.72–5.00) years. Risk score was highest in participants aged ≥65 years, followed by those who underwent treatment, had a history of emergency room visits, and were current smokers. Participants treated by surgery had the lowest risk score, followed by combined surgery and chemotherapy, combined surgery and radiation therapy, women, and regular exercisers. The C statistic in the development and validation cohorts was 0.78 (95% confidence interval, 0.77–0.78) and 0.81 (95% confidence interval, 0.78–0.84), respectively.ConclusionAdvanced age, lung cancer stage, and treatment type were strong risk factors of mortality in lung cancer patients, while being a woman and exercise were preventive factors. These will aid in the prediction of mortality and management of lung cancer patients.

Abstract Urinary tract infection (UTI) is the most prevalent urological condition worldwide. Choosing appropriate antibiotics for patients who have fever before receiving a culture result is challenging. This retrospective study enrolled patients 394 patients hospitalized at Gangneung Asan Hospital for UTI from May 2017 to April 2021. Fever at 48 h of hospitalization was the analysis point, as this is when the response to antibiotic therapy manifest, although the results of antibiogram are not available. Multivariate analysis was performed to assess the correlation between ESBL producing bacteria (EPB) and fever at 48 h. Overall, 36.3% of patients had EPB and 27.9% had fever at 48 h. In multivariate analysis, a significant positive association was found between EPB and fever (odds ratio 1.17, 95% CI 1.05–1.30, P = 0.004) Female had negative association with multivariate model (OR 0.83, 95% CI 0.73–0.94, P = 0.004). Diabetes did not demonstrate a significant association with EPB. (OR 1.10, 95% CI 0.99–1.22, P = 0.072). Fever at 48 h is associated with EPB and could be considered a predictive factor for EPB infection in patients with UTI. Antibiotic escalation may be considered in patients with fever at 48 h.

Abstract Idiopathic sudden sensorineural hearing loss (ISSNHL) is challenging for both nephrologists and otolaryngologists treating patients undergoing dialysis. This single-center, retrospective, observational study investigated the treatment outcomes of patients with ISSNHL undergoing dialysis, enrolling 700 patients (47 undergoing and 653 not undergoing dialysis) diagnosed with ISSNHL between January 2005 and December 2021 at Asan Medical Center, Republic of Korea. To balance pre-existing clinical characteristics, 1:5 propensity score matching (PSM) was performed with the patients who were not undergoing dialysis. Treatment included high-dose systemic steroid therapy or intra-tympanic steroid injections. The pure tone average of the groups was compared before and 2 weeks and 2 months after treatment. The hearing-improvement degree was evaluated using Siegel's criteria. Before PSM, age, prevalence of diabetes or hypertension, initial hearing threshold at each frequency level (0.5, 1, 2, and 4 kHz), and treatment strategies exhibited significant between-group differences. However, in the PS-matched cohort, none of the confounders showed significant between-group differences. Two months after steroid treatment, the non-dialysis patient group demonstrated significantly higher average improvement in pure tone audiometry (P = 0.029) and greater percentage of complete response according to Siegel's criteria. This study suggests that treatment outcomes for ISSNHL are significantly poorer for patients undergoing than for those not undergoing dialysis.

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.

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. Conclusions NFC findings may be useful in classifying patients with ILD into CTD-ILD/IPAF/IIP.

Background/Aims We aimed to compare the effectiveness and safety of Janus kinase inhibitors (JAKi) vs. biologic disease-modifying antirheumatic drugs (bDMARD) in Korean patients with rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic DMARDs. Methods A quasi-experimental, multi-center, prospective, non-randomized study was conducted to compare response rates between JAKi and bDMARDs in patients with RA naïve to targeted therapy. An interim analysis was performed to estimate the proportion of patients achieving low disease activity (LDA) based on disease activity score (DAS)–28– erythroid sedimentation rate (ESR) (DAS28-ESR) at 24 weeks after treatment initiation and to evaluate the development of adverse events (AEs). Results Among 506 patients enrolled from 17 institutions between April 2020 and August 2022, 346 (196 JAKi group and 150 bDMARD group) were included in the analysis. After 24 weeks of treatment, 49.0% of JAKi users and 48.7% of bDMARD users achieved LDA (p = 0.954). DAS28-ESR remission rates were also comparable between JAKi and bDMARD users (30.1% and 31.3%, respectively; p = 0.806). The frequency of AEs reported in the JAKi group was numerically higher than that in the bDMARDs group, but the frequencies of serious and severe AEs were comparable between the groups. Conclusions Our interim findings reveal JAKi have comparable effectiveness and safety to bDMARDs at 24 weeks after treatment initiation.

Background: Interstitial lung disease (ILD) is a critical extra-articular manifestation of rheumatoid arthritis (RA). However, little is known about the risk factors of RA-ILD. Objectives: Here, we examined the effect of demographic, clinical, therapeutic, and environmental factors on the incidence of ILD in RA patients using the Korean College of Rheumatology Biologics and Targeted Therapy (KOBIO) registry. Design: We used data from the KOBIO registry, a multi-center, prospective, observational cohort that included RA patients in South Korea. Methods: RA patients who used biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) or conventional synthetic (cs)DMARDs, and were enrolled in the KOBIO registry, were examined. Demographic, clinical, and radiographic characteristics, as well as medications, were recorded at baseline and annually thereafter. Kaplan–Meier curves and the log-rank test were used to compare the incidence of ILD between RA patients taking different b/tsDMARDs. Hazard ratios (HRs) were calculated by Cox regression analyses. Results: In total, 2492 patients (1967 in the b/tsDMARDs group and 525 in the csDMARDs group) were analyzed. The b/tsDMARDs group showed longer disease duration, higher erythrocyte sedimentation rate/C-reactive protein, and higher disease activity score-28 (DAS28) than the csDMARDs group. The incidence of ILD was significantly higher in those taking tumor necrosis factor inhibitors and abatacept than in those taking csDMARDs (log ranked p

We aimed to evaluate the association between daily dietary calcium intake and the risk of cardiovascular disease (CVD) in postmenopausal women using data from the Korean National Health and Nutrition Examination Survey (KNHANES). This cross-sectional study included 12,348 women aged 45–70 years who had reached natural menopause. They were classified into three groups according to daily dietary calcium intake: 800 mg. The risks of CVD, stroke, angina, and myocardial infarction were assessed in each group. Further, we performed subgroup analysis according to the post-menopause duration (≤10 vs. >10 postmenopausal years). We performed logistic regression analysis with adjustment for age, menopausal age, income, urban area, education, insulin use, body mass index, hypertension, diabetes mellitus, dyslipidemia, high alcohol intake, smoking, exercise, oral contraceptive use, and hormonal therapy use. Calcium intake level was not significantly associated with the risk of CVD in the total population and the ≤10 postmenopausal years subgroup. However, in the >10 postmenopausal years subgroup, daily calcium intake >800 mg was associated with significantly decreased risks of all CVD (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.11–0.64), stroke (OR, 0.06; 95% CI, 0.01–0.42), and myocardial infarction (OR, 0.27; 95% CI, 0.11–0.64). Our findings suggest that a dietary calcium intake of >800 mg/day decreases the risk of CVD events in women who have been menopausal for >10 years.

Abstract 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.

Musculoskeletal conditions are common in patients with diabetes. Several musculoskeletal disorders are viewed as chronic complications of diabetes because epidemiological studies have revealed high correlations between such complications and diabetes, but the pathophysiological links with diabetes remains unclear. Genetic predispositions, shared risk factors, microvascular impairments, progressive accumulation of advanced glycation end-products, and diabetic neuropathy may underlie the development of musculoskeletal disorders. Musculoskeletal complications of diabetics have received less attention than life-threatening microvascular or macrovascular complications. Here, we review several diabetic musculoskeletal complications with a focus on the clinical importance of early recognition and management, which would improve quality of life and physical function.

Abstract 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

Abstract 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.

Abstract 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.

Our understanding and management of rheumatoid arthritis (RA) have greatly improved, but perioperative and anesthetic management remain challenging. RA is not limited to joints; systemic evaluation is thus required when planning perioperative management. Especially, careful airway evaluation is needed; management of airway-related arthritis is challenging. A multidisciplinary approach is essential to prevent complications without exacerbating RA disease activity. Guidelines published in 2017 are available for perioperative management of anti-rheumatic medication in patients with rheumatic diseases undergoing elective total hip or total knee arthroplasty. However, the guidelines focus only on anti-rheumatic medications, and do not consider all aspects of perioperative management (including anesthesia). Here, we discuss the perioperative and anesthetic management of patients with RA.

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.

Abstract 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.

Abstract 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.

Abstract Among various patient risk factors affecting survival after high tibial osteotomy (HTO), the ideal age limit for HTO is unclear. This study was performed to evaluate the effect of age on survival rate and complications after HTO for medial unicompartmental osteoarthritis. Among of 61,145 HTO patients from Korean National Health Insurance database, 41,112 patients underwent the procedure before the age of 60 years (Group A), 13,895 patients between the age of 60 and 65 years (Group B), and 6138 patients after the age of 65 years (Group C). We compared the survival rate in person-years among the three groups from the date of primary surgery until subsequent total knee arthroplasty. Perioperative complications were also recorded. The adjusted hazard ratio (HR) were calculated using the multivariable Cox proportional hazard regression model, adjusting for the potential confounders: age, sex, type of medical insurance, region of residence, hospital type, comorbidities, and Charlson comorbidity index score. The total number of HTO increased 6.5-fold, especially in patients aged > 65 years (by 8.2-fold) from 2008 to 2018. The overall revision rate was 4.2% in Group A, 6.4% in Group B, and 7.3% in Group C. The 5- and 10-year revision rate was significantly lower in Group A (p

BackgroundMechanical stress are one of the pathogenesis of axial spondyloarthritis (axSpA). During pregnancy, the mechanical overload on the spine and pelvis increases due to gravid uterus. We aimed to investigate whether pregnancy affects radiographic progression in patients with radiographic axSpA (r-axSpA) based on computed tomography (CT) evaluations.Materials and methodsThis retrospective study included women with r-axSpA aged 19–49 years who underwent at least two CT evaluations of the whole spine and/or sacroiliac joints (SIJs) at intervals of 2–4 years. To compare radiographic progression after delivery, we classified the patients into two groups: delivery group and controls. The delivery group was restricted to women who had the first CT ∼2 years before delivery and the second CT ∼2 years after delivery. The CT Syndesmophyte Score (CTSS) (0–522) and SIJ scores (0–40) were used to evaluate spinal syndesmophytes and erosion, joint space narrowing, and sclerosis of the SIJs.ResultsA total of 21 women in the delivery group and 38 women in the control group were included. The median (Q1–Q3) CTSS at baseline in the delivery group and controls was 19 (16–23) and 20 (13.25–27.75), and the median progression was 1 (0–3) and 0 (0–1) during the median 2.9-year follow-up, respectively. The median (Q1–Q3) SIJ score at baseline in the delivery group and controls was 13 (8–22) and 11 (6–22), and the median progression was 1.5 (0–3) and 1 (0–2), respectively. Using cut-off 0.5, 52.9, and 61.9% of r-axSpA patients and 39.3 and 44.4% of controls showed progression of whole spine and SIJs, respectively. However, no difference in proportion of spinal and SIJ progression and absolute score changes per time point was observed between two groups. Moreover, the SIJ score changes were comparable according to the delivery method.ConclusionPregnancy and delivery do not affect the radiographic progression of the spine and SIJs in women with r-axSpA assessed by CT.

Abstract The clinical data on the biologic disease-modifying antirheumatic drug (bDMARD) use in late-onset ankylosing spondylitis (LOAS) is limited. Thus, this study aimed to evaluate the drug efficacy and retention rate of bDMARDs in LOAS and compare it to young-onset ankylosing spondylitis (YOAS). Data of patients with AS receiving bDMARDs were extracted from the Korean College of Rheumatology Biologics and Targeted Therapy registry. Patients whose age of onset was > 50 years and ≤ 50 years were classified as having LOAS and YOAS, respectively. Their baseline characteristics and disease-associated parameters were evaluated. Drug efficacy [Ankylosing Spondylitis Disease Activity Score (ASDAS)-clinically important improvement (CII), ASDAS-major improvement (MI), Assessment of SpondyloArthritis International Society (ASAS) 20, and ASAS 40] at 1-year follow-up and drug retention rates were assessed. A total of 1708 patients (comprising 1472 patients with YOAS and 236 patients with LOAS) were included in this analysis. The LOAS group had a lower prevalence among males, lower HLA-B27 positivity and a higher prevalence of peripheral arthritis. Patients with LOAS were more likely to have higher disease-associated parameters (inflammatory reactants, patient global assessment, ASDAS-erythrocyte sedimentation rate, and ASDAS-C-reactive protein). LOAS was negatively associated with achieving ASDAS-CII, ASAS 20, and ASAS 40. The drug retention rate was lower in LOAS; however, the propensity score-matched and covariate-adjusted hazard ratios for bDMARD discontinuation were comparable to YOAS. There were no differences in the drug retention rates based on the type of bDMARD used in LOAS. Inferior clinical efficacy and shorter drug retention time were found in patients with LOAS receiving bDMARDs using real-world nationwide data. There were no differences among each bDMARD type.

Abstract 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.

BackgroundAge-related changes and different patterns of salivary gland abnormalities according to age may affect the diagnostic performance of unstimulated salivary flow rate (USFR) and salivary gland ultrasound (SGUS) for primary Sjögren's syndrome (pSS). We aimed to evaluate the threshold and diagnostic performance of USFR and whether incorporating SGUS or replacing USFR with SGUS affects the performance of the ACR/EULAR criteria for pSS according to age.Materials and methodsThis medical chart review study included patients with suspected pSS who completed evaluations for pSS. Patients were classified based on age at pSS evaluation: elderly (≥65 years), middle-aged (40–64), and young (< 40). The USFR's optimal thresholds were evaluated using the ROC curve. The diagnostic performances of the USFR and modified ACR/EULAR criteria were compared.ResultsIn total, 239 pSS patients and 92 patients with idiopathic sicca syndrome were included. The cut-off of USFR ≤ 0.1 mL/min was irrelevant to age, demonstrating the best sensitivity (44.3–53.0%) and specificity (74.1–90.9%). SGUS had a significantly better AUC than USFR in the young (p < 0.01) and middle-aged groups (p < 0.01). The middle-aged group demonstrated better diagnostic performance of the ACR/EULAR criteria incorporating SGUS (AUC 0.957) (p < 0.01) and criteria replacing USFR with SGUS (AUC 0.957) (p < 0.001) compared to the original criteria (AUC 0.916). In the young and elderly groups, adding SGUS to the ACR/EULAR criteria or replacing USFR with SGUS did not significantly increase the AUC.ConclusionsThe thresholds of USFR ≤ 0.1 mL/min was optimal, irrespective of age. Using SGUS can improve diagnostic accuracy of ACR/EULAR criteria by supplementing the USFR, especially in middle-aged patients.

Abstract Background Cardiovascular diseases (CVDs) are the leading cause of death in patients with rheumatoid arthritis (RA). Coronary artery calcium (CAC) score quantifies the severity of atherosclerosis. We estimated CVD risk using several methods and compared these with the CAC score to identify the most suitable CVD risk calculator in RA patients. Methods We recruited RA patients, and the 10-year CVD risk was assessed using various tools, viz. Framingham risk score, Systemic Coronary Risk Evaluation (SCORE), Atherosclerotic Cardiovascular Disease (ASCVD) risk estimator plus, QRISK3, Expanded Risk Score in Rheumatoid Arthritis (ERS-RA), and Reynolds risk score. Computed tomography was used to determine the CAC score of each patient. Correlation analysis and linear regression analysis between the CAC score and CVD risk score was performed. Results In total, 54 RA patients were enrolled. ERS-RA showed the highest correlation coefficient (r = 0.430, P = 0.001). In multivariate linear regression analysis, ERS-RA (β = 10.01, 95% confidence interval 3.78–16.23) showed a positive association with the CAC score in RA patients. Conclusions The ERS-RA method was highly correlated with the CAC score in RA patients. Therefore, the application of the ERS-RA method may be suitable for predicting subclinical atherosclerosis and CVD risk in RA patients.

Interstitial pneumonia with autoimmune feature (IPAF) is a recently established disease entity that is comprised of interstitial lung diseases with evidence of autoimmune features but that does not fulfill the criteria for definite autoimmune rheumatic diseases. The classification criteria for IPAF were defined by the European Respiratory Society and American Thoracic Society in 2015. However, further studies to establish IPAF subgroups and treatment modalities for each subgroup are still needed. In this review, we discuss recent advances regarding IPAF and raise critical points for the diagnosis and management of patients with IPAF from the perspective of rheumatologists.

Abstract Background In the pathogenesis of rheumatoid arthritis (RA), the role of mast cells has not been revealed clearly. We aimed to define the inflammatory and tissue-destructive roles of mast cells in rheumatoid arthritis (RA). Methods Serum and synovial fluid (SF) concentration levels of tryptase, chymase, and histamine were quantified using ELISA. After activating mast cells using IL-33, the production of TNF-α, IL-1β, IL-6, IL-17, RANKL, and MMPs was determined using real-time PCR and ELISA. Osteoclastogenesis was assessed in CD14+ monocytes from peripheral blood and SF, which were cultured with IL-33-activated mast cells, by counting TRAP-positive multinucleated cells. Results The concentration levels of serum tryptase, chymase, and histamine and SF histamine were higher in patients with RA than in controls. FcεR1 and c-kit-positive mast cells were higher in RA synovium than in osteoarthritic (OA) synovium. Stimulation of mast cells by IL-33 increased the number of trypatse+chymase− and tryptase+chymase+ mast cells. IL-33 stimulation also increased the gene expression levels of TNF-α, IL-1β, IL-6, IL-17, RANKL, and MMP-9 in mast cells. Furthermore, IL-33 stimulated human CD14+ monocytes to differentiate into TRAP+ multinucleated osteoclasts. When CD14+ monocytes were co-cultured with mast cells, osteoclast differentiation was increased. Additionally, IL-33-activated mast cells stimulated osteoclast differentiation. The inhibition of intercellular contact between mast cells and monocytes using inserts reduced osteoclast differentiation. Conclusions IL-33 increased inflammatory and tissue-destructive cytokines by activation of mast cells. Mast cells stimulated osteoclast differentiation in monocytes. Mast cells could stimulate osteoclastogenesis indirectly through production of tissue-destructive cytokines and directly through stimulation of osteoclast precursors.

PurposeThis study aimed to investigate the characteristics, severity, and treatment of adult patients with acute appendicitis in Korea over a 2-year period during the coronavirus disease (COVID-19) pandemic compared to those before the pandemic. We also investigated whether there were any changes in clinical characteristics of acute appendicitis before and after vaccination against the coronavirus.MethodsWe retrospectively reviewed the medical records of patients who were diagnosed with acute appendicitis at our institution between March 1, 2019, and August 31, 2021. We divided the patients into three groups (pre-pandemic, before vaccination, and after vaccination) and analyzed the clinical outcomes.ResultsThe time from symptom onset to hospital arrival and the time from symptom onset to operation increased during the COVID-19 pandemic period compared to the pre-pandemic period. The rate of complicated appendicitis during the pandemic was higher than that before the pandemic. In addition, the number of new daily cases showed a positive correlation with the time from symptom onset to hospital arrival (OR, 0.03; 95% CI, 0.02 to 0.04; P

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

Abstract Background The present study aimed to evaluate the suppressive role of interleukin (IL)-25 in IL-22-induced osteoclastogenesis and receptor activator of nuclear factor κB ligand (RANKL) expression in rheumatoid arthritis (RA). Methods Serum from patients with RA and osteoarthritis (OA), and healthy controls, and synovial fluid from patients with RA and OA were collected, and the levels of IL-22 and IL-25 were measured. RA and OA synovial tissues were stained against IL-25. Fibroblast-like synoviocytes (FLSs) of patients with RA were cultured with IL-22, in the presence or absence of IL-25, and RANKL expression was measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA). Human peripheral blood monocytes were cultured under IL-22/RANKL + M-CSF, with or without IL-25, and tartrate-resistant acid phosphatase (TRAP)-positive cells and osteoclast-related markers were investigated to determine osteoclastogenesis. Results Serum and synovial IL-25 levels in RA were upregulated compared to those in OA and healthy control, and elevated expression of IL-25 in RA synovial tissue was re-confirmed. IL-25 and IL-22 levels showed significant correlation in serum and synovial fluid. Pre-treatment of FLS with IL-25 reduced IL-22-induced RANKL expression at the RNA level. The suppressive effects of IL-25 were confirmed to occur through the STAT3 and p38 MAPK/IκBα pathways. IL-25 reduced osteoclast differentiation and suppressed the expression of osteoclast-related markers. Conclusion In the current study, we demonstrated the regulatory effect of IL-25 on IL-22-induced osteoclastogenesis. Therapeutic approach involving augmentation of IL-25 regulatory response may serve as a novel treatment option for RA, especially by suppressing osteoclastogenesis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory arthritis, and the complex interaction and activation of innate and adaptive immune cells are involved in RA pathogenesis. Mast cells (MCs) are one of the tissue-resident innate immune cells, and they contribute to RA pathogenesis. In the present review, the evidence of the pathologic role of MC in RA is discussed based on human and animal data. In addition, the potential role of MC in RA pathogenesis and the research area that should be focused on in the future are suggested.

Abstract Background The inflammatory cascade in the rheumatoid arthritis (RA) synovium is modulated by a variety of cytokine and chemokine networks; however, the roles of IL-26, in RA pathogenesis, are poorly defined. Here, we investigated the functional role of interleukin-26 (IL)-26 in osteoclastogenesis in RA. Methods We analyzed levels of IL-20 receptor subunit A (IL-20RA), CD55, and receptor activator of nuclear factor kappaB (NF-κB) ligand (RANKL) in RA fibroblast-like synoviocytes (FLSs) using confocal microscopy. Recombinant human IL-26-induced RANKL expression in RA-FLSs was examined using real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Human peripheral blood monocytes were cultured with macrophage colony-stimulating factor (M-CSF) and IL-26, after which osteoclastogenesis was evaluated by counting the number of tartrate-resistant acid phosphatase-positive multinucleated cells. Additionally, osteoclastogenesis was evaluated by monocytes co-cultured with IL-26-prestimulated FLSs. Results The expression of IL-20RA in RA-FLSs was higher than that in osteoarthritis-FLSs. Additionally, in IL-26-pretreated RA-FLSs, the expression of IL-20RA (but not IL-10 receptor subunit B) and RANKL increased in a dose-dependent manner, with IL-26-induced RANKL expression reduced by IL-20RA knockdown. Moreover, IL-26-induced RANKL expression was significantly downregulated by inhibition of signal transducer and activator of transcription 1, mitogen-activated protein kinase, and NF-κB signaling. Furthermore, IL-26 promoted osteoclast differentiation from peripheral blood monocytes in the presence of low dose of RANKL, with IL-26 exerting an additive effect. Furthermore, co-culture of IL-26-pretreated RA-FLSs with peripheral blood monocytes also increased osteoclast differentiation in the absence of addition of RANKL. Conclusions IL-26 regulated osteoclastogenesis in RA through increased RANKL expression in FLSs and direct stimulation of osteoclast differentiation. These results suggest the IL-26/IL-20RA/RANKL axis as a potential therapeutic target for addressing RA-related joint damage.

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.

Abstract Although extra‐glomerular involvement of microscopic polyangiitis is not regarded as a characteristic finding of the disease, tubulointerstitial nephritis should be considered as a new subclass of renal involvement.

Background/Aims To define standard reference values for musculoskeletal ultrasonography (MSUS) in Korea. Methods A total of 251 healthy adults were recruited for this study. Ultrasonography was performed by experienced rheumatologists who had undergone four appropriate training programs in Korea. A General Electric LOGIQ electronic ultrasound device fitted with a 12 MHz linear transducer was employed. Mean values ± standard deviations (SDs) were defined as standard reference values. Intraclass correlation coefficients was employed to evaluate the extent of inter- and intraobserver agreement when MSUS measurements were made. Results The 251 study participants included 122 males. Mean subject age was 28.6 years. The average bone-to-capsule distance of the right-side second and third metacarpophalangeal (MCP) joints were 0.68 and 0.72 mm respectively, and those of the left-side joints 0.62 and 0.68 mm. The cartilage thicknesses of the right-side second and third MCP joints were 0.55 and 0.55 mm, and those of the left-side joints were 0.55 and 0.56 mm, respectively. The bone-to-capsule distances of the right and left wrists were 0.80 and 0.82 mm. In 12.4% of participants (31/251), the erosion score of the humeral head was 1.71. In the right-side knee joint, mean cartilage thicknesses of the medial and lateral condyles were 1.86 and 2.03 mm in longitudinal scans. High overall interobserver agreement was evident after appropriate training that included instruction on standard MSUS methodology. Conclusions We defined standard reference values for MSUS in healthy Korean adults. The reliabilities of interobserver agreements were high after appropriate training program.

Immune checkpoint inhibitors (ICIs) have revolutionized anticancer therapy due to their long-term clinical benefits and immune boosting mechanisms. However, despite their consistent therapeutic effects, the use of ICIs is associated with a spectrum of adverse events due to their autoimmune and auto-inflammatory actions. These adverse events can affect any organ system, including the endocrine, neurologic, gastrointestinal, cardiac, skin, pulmonary, and musculoskeletal systems. Of the immune-related adverse events (irAEs), rheumatic complications are common and appear to be distinct from irAEs in other organs in terms of variability of onset time, capacity for persistence, and relationship with pre-existing autoimmune rheumatologic diseases. In this article, we review the mechanisms of the anti-cancer effects of ICIs, the irAEs of immuno-oncology drugs, and the general recommendations for managing irAEs. In particular, we focus on rheumatologic irAEs and discuss their prevalence, clinical characteristics, and management.

Background/Aims Magnetic resonance imaging (MRI) is a sensitive and useful method for the detection of synovitis and joint destruction in rheumatoid arthritis (RA) patients. However, the patterns of MRI-detected bone erosion, bone marrow edema (BME), synovitis, and tenosynovitis have received insufficient attention. Therefore, this study evaluated the patterns of bone erosion, BME, synovitis, and tenosynovitis, and calculated the RA-MRI score (RAMRIS) of patients with RA at the carpal and metacarpophalangeal (MCP) joints using MRI. Methods MRI datasets from 43 RA patients were analyzed. All patients had undergone MRI of one wrist. In addition, 36 patients had MCP joint images taken, and three had also received MRI of the contralateral wrist and MCP joints. The MR images were evaluated for bone erosion, BME, and synovitis in consensus by two blinded readers according to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) RAMRIS. The MRI-detected tenosynovitis was evaluated based on Haavardsholm’s tenosynovitis score. Results The capitate, lunate, triquetrum, and hamate bones were the most common sites of erosion and BME and showed the highest RAMRIS erosion and BME scores. Moreover, MRI-detected tenosynovitis was present in 78.3% of all patients with RA, and the extensor compartment 4 and flexor digitorum profundus and superficialis were frequently affected. Conclusions This study identified the distribution and prevalence of MRI-detected bone erosion, BME, synovitis, and tenosynovitis of the wrist and MCP joints in RA patients. The patterns of the MRI-detected abnormalities may help to select sites for the application of MRI protocols in clinical trials and practice.

Background/Aims This study aimed to determine the regulatory role of N-acetyl-l-cysteine (NAC), an antioxidant, in interleukin 17 (IL-17)-induced osteoclast differentiation in rheumatoid arthritis (RA). Methods After RA synovial fibroblasts were stimulated by IL-17, the expression and production of receptor activator of nuclear factor κ-B ligand (RANKL) was determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). Osteoclastogenesis was also determined after co-cultures of IL-17-stimulated RA synovial fibroblasts, Th17 cells and various concentrations of NAC with monocytes. After human peripheral CD4+ T cells were cultured with NAC under Th17 condition, IL-17, interferon γ, IL-4, Foxp3, RANKL, and IL-2 expression and production was determined by flow cytometry or ELISA. Results When RA synovial fibroblasts were stimulated by IL-17, IL-17 stimulated the production of RANKL, and NAC reduced the IL-17-induced RANKL production in a dose-dependent manner. NAC decreased IL-17-activated phosphorylation of mammalian target of rapamycin, c-Jun N-terminal kinase, and inhibitor of κB. When human peripheral blood CD14+ monocytes were cultured with macrophage colony-stimulating factor and IL-17 or RANKL, osteoclasts were differentiated, and NAC reduced the osteoclastogenesis. After human peripheral CD4+ T cells were co-cultured with IL-17-pretreated RA synovial fibroblasts or Th17 cells, NAC reduced their osteoclastogenesis. Under Th17 polarizing condition, NAC decreased Th17 cell differentiation and IL-17 and RANKL production. Conclusions NAC inhibits the IL-17-induced RANKL production in RA synovial fibroblasts and IL-17-induced osteoclast differentiation. NAC also reduced Th17 polarization. NAC could be a supplementary therapeutic option for inflammatory and bony destructive processes in RA.

Background/Aims The present study aimed to investigate whether tocotrienol regulates interleukin 17 (IL-17)-induced osteoclastogenesis in rheumatoid arthritis (RA). Methods We evaluated the effect of tocotrienol on IL-17-induced receptor activator of nuclear factor kappa B ligand (RANKL) production using RA fibroblast-like synoviocyte (FLS), together with real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Osteoclast differentiation was confirmed after culturing IL-17-treated RA FLS and Th17 cells with tocotrienol and monocytes. We analyzed the suppressive effect of tocotrienol on Th17 cells percentage or Th17-cytokine levels among peripheral blood mononuclear cells using flow cytometry. Results We found that IL-17 stimulated FLS to produce RANKL and tocotrienol decreased this IL-17-induced RANKL production. Tocotrienol decreased the IL-17-induced activation of mammalian target of rapamycin, extracellular signal-regulated kinase, and inhibitor of kappa B-alpha. When monocytes were incubated with IL-17, RANKL, IL-17-treated FLS or Th17 cells, osteoclasts were differentiated and tocotrienol decreased this osteoclast differentiation. Tocotrienol reduced Th17 cell differentiation and the production of IL-17 and sRANKL; however, tocotrienol did not affect Treg cell differentiation. Conclusions Tocotrienol inhibited IL-17- activated RANKL production in RA FLS and IL-17-activated osteoclast formation. In addition, tocotrienol reduced Th17 differentiation. Therefore, tocotrienol could be a new therapeutic choice to treat bone destructive processes in RA.

Purpose To investigate salivary gland ultrasonography (SGUS) findings in primary Sjögren’s syndrome (pSS) patients positive for the anti-centromere antibody (ACA) and compare these with those in ACA-negative pSS patients. Methods We analyzed demographic, clinical, laboratory, and SGUS data of pSS patients who fulfilled the 2002 American-European Consensus Group classification criteria for pSS. SGUS findings of four major salivary glands (bilateral parotid and submandibular glands) were scored in five categories and compared between ACA-positive and ACA-negative pSS patients. Linear regression analysis was performed to elucidate the factors associated with SGUS score. Results In total, 121 pSS patients were enrolled (19, ACA-positive). The ACA-positive patients were older (67.0 vs 58.0 years, P = 0.028), whereas anti-Ro/SSA and anti-La/SSB positivity was more prevalent in the ACA-negative group (89.2% vs 21.1%, P < 0.001, and 47.1% vs 10.5%, P = 0.007, respectively). The total SGUS and hypoechoic area scores were lower in ACA-positive patients (16.0 vs 23.0, P = 0.027, and 4.0 vs 7.0, P = 0.004, respectively). In univariate regression analysis, being positive for unstimulated salivary flow rate (USFR < 1.5 ml/15 min), anti-Ro/SSA, and rheumatoid factor were positively associated whereas ACA positivity was negatively associated with the SGUS score. In multivariate regression analysis, being positive for USFR, anti-Ro/SSA, and rheumatoid factor showed significant association with the SGUS score. Conclusions ACA-positive pSS patients showed a lower SGUS score than ACA-negative patients, which was especially prominent in the hypoechoic area component.

Abstract Background The aim of this study was to investigate if epigenetically modified human mesenchymal stromal cells (hMSCs) can regulate the Th17-related immune responses. Methods We tested epigenetic drug combinations at various doses and selected the four combinations that resulted in maximal interleukin (IL)-10 and indoleamine 2,3-dioxygenase gene expression in hMSCs. We examined the effects of epigenetically modified hMSCs (epi-hMSCs) on CD4+ T-cell proliferation and inflammatory cytokine secretion under Th0- and Th17-polarizing conditions using mixed lymphocyte reactions and enzyme-linked immunosorbent assays (ELISAs). We determined Th17 cytokine levels and the percentage of Th17 cells among synovial fluid mononuclear cells (SFMCs) from rheumatoid arthritis (RA) patients by ELISA and flow cytometry. Results Epi-hMSCs inhibited the development of IL-17-producing cells in culture. The percentages of IL-17+ and interferon (IFN)-γ+ cells among peripheral blood mononuclear cells from healthy donors were lower under both the Th0 and Th17 conditions in the presence of epi-hMSCs than in the presence of no or untreated hMSCs. Epi-hMSC-treated RA patient SFMCs secreted lower levels of IL-17 and IFN-γ than RA patient SFMCs cultured without hMSCs or with untreated hMSCs. Conclusions An optimal combination of hypomethylating agents and histone deacetylase inhibitors can enhance the immunomodulatory potential of hMSCs, which may be useful for RA treatment.

Topoisomerase IIIβ (Top3β), 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 Top3β with neuropsychiatric phenotypes in mice. Here, we investigated the effect of Top3β on neuro-behavior using newly generated Top3β deficient (Top3β−/−) mice. We found that Top3β−/− mice showed decreased anxiety and depression-like behaviors. The lack of Top3β was also associated with changes in circadian rhythm. In addition, a clear expression of Top3β 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 Top3β−/− 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 Top3β is essential for normal brain function and behavior in mice and that Top3β could be an interesting target to study neuropsychiatric disorders in humans.

Osteoclasts are involved in arthritis, and their differentiation depends on RANKL signaling. The author show that the ROS-scavenging protein DJ-1 negatively regulates RANKL signaling and that its ablation increases osteoclast numbers and exacerbates bone damage in mouse models of arthritis.

Abstract Histamine H4 receptor (H4R) has immune-modulatory and chemotaxic effects in various immune cells. This study aimed to determine the osteoclastogenic role of H4R in rheumatoid arthritis (RA). The concentration of histamine in synovial fluid (SF) and sera in patients with RA was measured using ELISA. After RA SF and peripheral blood (PB) CD14+ monocytes were treated with histamine, IL-17, IL-21 and IL-22, and a H4R antagonist (JNJ7777120), the gene expression H4R and RANKL was determined by real-time PCR. Osteoclastogenesis was assessed by counting TRAP–positive multinucleated cells in PB CD14+ monocytes cultured with histamine, Th17 cytokines and JNJ7777120. SF and serum concentration of histamine was higher in RA, compared with osteoarthritis and healthy controls. The expression of H4R was increased in PB monocytes in RA patients. Histamine, IL-6, IL-17, IL-21 and IL-22 induced the expression of H4R in monocytes. Histamine, IL-17, and IL-22 stimulated RANKL expression in RA monocytes and JNJ7777120 reduced the RANKL expression. Histamine and Th17 cytokines induced the osteoclast differentiation from monocytes and JNJ7777120 decreased the osteoclastogenesis. H4R mediates RANKL expression and osteoclast differentiation induced by histamine and Th17 cytokines. The blockage of H4R could be a new therapeutic modality for prevention of bone destruction in RA.

Objective: To evaluate the relationships between sociodemographic factors, reproductive history, and subsequent risk of osteoarthritis (OA) or pain of the hip, knee, and back in Korean women. Materials and Methods: This study included data of 5101 women aged over 50 years, taken from the Korean National Health and Nutritional Examination Survey V from 2010 to 2012. Women were stratified according to parity, as well as delivery mode. Multivariate logistic regression analysis was conducted to evaluate relationships between radiographic OA or symptomatically possible OA (back, knee, or hip), and historical factors. Results: Vaginal delivery was associated with an increased risk of symptomatic back OA [odds ratio (OR) 1.75, 95% confidence interval (CI) 1.062, 2.881] but was not associated with symptomatic knee and hip OA in adjusted analysis. Radiographically, vaginal delivery was not associated with risks of back and knee OA, but was negatively associated with hip OA (OR 0.184, 95% CI 0.039, 0.863), compared to cesarean delivery. High parity (over 5) was associated with radiographic knee OA (OR 1.328, 95% CI 1.006, 1.754) in adjusted analysis. High parity (over 3) was associated with symptomatic back OA. Conclusion: Parity was associated with higher risk of radiographic knee OA. Vaginal delivery was positively associated with symptomatic back OA, but negatively associated with radiographic knee OA. Further study is required to evaluate the mechanism between delivery mode and subsequent OA.

Vascular endothelial growth factor (VEGF) has angiogenic, inflammatory, and bone-destructive roles in rheumatoid arthritis (RA). We aimed to determine the unique role of VEGF in osteoclastogenesis in RA. VEGF-induced receptor activator of nuclear factor ҡB ligand (RANKL) expression was determined in RA synovial fibroblasts by real-time PCR, luciferase assays, and ELISA. Osteoclastogenesis in peripheral blood monocytes cultured with VEGF was assessed by determining the numbers of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. Synovial fluid RANKL was correlated with VEGF concentration in the RA patients. VEGF stimulated the expression of RANKL in RA synovial fibroblasts. The RANKL promoter activity was upregulated by VEGF in the synovial fibroblasts transfected with RANKL-reporter plasmids. The VEGF-induced RANKL expression was decreased by the inhibition of both VEGF receptors (VEGFR) 1 and 2, Src, protein kinase C (PKC) and p38 MAPK. VEGF induced osteoclast differentiation from monocytes in the absence of RANKL and this was decreased by the inhibition of VEGFR1 and 2, Src, PKC and p38 MAPK. On coculturing with VEGF-prestimulated RA synovial fibroblasts, the monocytes differentiated into osteoclasts, and the osteoclastogenesis decreased by inhibition of Src and PKC pathways. VEGF plays dual roles on osteoclastogenesis in RA: direct induction of osteoclastogenesis from the precursors and stimulation of RANKL production in synovial fibroblasts, which is mediated by Src and PKC pathways. The axis of VEGF and RANKL could be a potential therapeutic target for RA-associated bone destruction.