Risk of urolithiasis associated with allopurinol versus benzbromarone among patients with gout: a population-based cohort study.

OBJECTIVES: To compare the risk of urolithiasis in gout patients initiating allopurinol, a xanthine oxidase inhibitor, vs benzbromarone, a uricosuric. METHODS: Using the 2011-2020 Korea National Health Insurance Service database, we conducted a cohort study on gout patients initiating allopurinol vs benzbromarone as the 1st-line urate-lowering treatment (ULT). The primary outcome was a new onset urinary stone. The secondary outcome was a stone requiring intervention. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazard models with a 5:1 ratio propensity-score matching on > 80 variables. Subgroup analyses were done by age, sex, thiazide use, and cardiovascular (CV) risk. RESULTS: 61 300 allopurinol initiators PS-matched on 12 260 benzbromarone initiators were included (mean age 59 years, 79% male). During a mean follow-up of 322 days, 619 urolithiasis cases occurred with an incidence rate of 0.87 per 100 person-years in allopurinol and 1.39 in benzbromarone initiators, showing a HR of 0.64 (95% CI, 0.51-0.80). ∼44% of urinary stones required intervention with a HR of 0.61 (95% CI 0.43-0.88). The lower risk associated with allopurinol compared with benzbromarone persisted across subgroups but was greater in the high than non-high CV risk subgroup (p for interaction = 0.02). CONCLUSION: This population-based cohort study found that allopurinol compared with benzbromarone was associated with a substantially lower risk of urolithiasis particularly in the presence of the high CV risk. This finding provides important safety information for clinicians' decision-making on ULTs of different mechanisms of action.

All-cause and cause-specific mortality among patients with Behçet's disease versus the general population.

BACKGROUND: Comparative risk regarding cause-specific mortality between patients with Behcet's disease (BD) and the general population is not known. OBJECTIVES: To compare the risk of all-cause and cause-specific mortality among patients with BD versus the general population. METHODS: Using the 2002-2020 Korea National Health Insurance Service database, we conducted a cohort study comparing BD patients and the general population matched on age and sex at a 1:4 ratio. We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality. Subgroup analyses by age and sex were done. RESULTS: We included 24,669 BD patients and 98,676 age- and sex-matched controls (mean age 40.5 years, 34% male). During a mean follow-up of 11.9 years, the incidence rate of death per 100 person-years was 0.36 in BD and 0.29 in controls with the HR (95% CI) of 1.28 (1.20-1.38). The risk of mortality was highest for one year after BD diagnosis showing a HR (95% CI) of 2.66 (2.09-3.40). BD patients died more in this period due to malignancy, cardiovascular (CV), gastrointestinal, and respiratory disease, and infection: the corresponding cause-specific HR (95% CI) was 1.96 (1.30-2.98), 2.68 (1.45-4.97), 3.50 (1.35-9.07), 5.00 (1.34-18.62), and 3.33 (1.02-10.92), respectively. Mortality by neurological (HR 1.58, 95% CI 1.06-2.35) and genitourinary disease (HR 2.20, 95% CI 1.43-3.37) was also more common in BD during the overall follow-up. Subgroup analyses showed consistent results. The risk of CV mortality compared to the general population was higher in the young than elderly (p for interaction = 0.006), and the risk of gastrointestinal mortality in women than men (p for interaction = 0.04). CONCLUSIONS: This population-based cohort study shows the first year of the disease as the highest risk window for excess mortality among BD patients. The mortality burden in BD derived from a wide spectrum of organ involvements, warning clinicians about the systemic nature of the disease.

Impact of socioeconomic status on biologics utilization in rheumatoid arthritis: revealing inequalities and healthcare efficiency.

Background/Aims: This cross-sectional study aimed to investigate biologics treatment disparities in rheumatoid arthritis (RA) patients based on socioeconomic status (SES). Methods: Data from the KOrean Observational Study Network for Arthritis (KORONA) database were analyzed to assess various factors associated with SES, health behaviors, and biologics use. Logistic regression and structured equation modeling (SEM) were utilized for data analysis. Results: Among 5,077 RA patients included, 393 (7.7%) patients were identified as biologics users. Within the entire cohort, 31.8% of the participants were in the low-income and low-education groups, and 39.3% of the participants were in the high-income and high-education groups. Despite the patients with low income or low education experienced higher disease activity at diagnosis, had more comorbidities, exhibited higher medication compliance, underwent more check-ups, and had more hospital admissions than their counterparts, the odds of patients with low-income receiving biologics were 34% lower (adjusted odds ratio = 0.76, 95% confidence interval: 0.60-0.96, p = 0.021) after adjustment for demographics and comorbidities. SEM and pathway analyses confirmed the negative impact of low SES on biologics use. Conclusions: The findings suggest that SES plays a significant role in biologics use among RA patients, indicating potential healthcare inefficiencies for low SES patients. Moreover, adverse healthcare habits negatively affect biologics use in RA patients. The study highlights the importance of considering socioeconomic factors while discussing biologics use and promoting equitable access to biologics for optimal RA management.

Recurrent focal myofasciitis of Behçet syndrome mimics infectious myofasciitis: a case report.

Behçet syndrome (BS) is a chronic inflammatory disease with multiorgan manifestations. However, muscular involvement in BS has rarely been reported. Herein, we report the case of a 30-year-old male with BS who had recurring pain and swelling of the lower legs. The patient was administered antibiotics on several occasions as the condition was misinterpreted to be infectious myositis. Magnetic resonance imaging revealed myofascial involvement with focal necrotic lesions, and muscle biopsy revealed acute suppurative myositis with perivascular infiltration of polymorphonuclear leukocytes. His symptoms improved after treatment with corticosteroids. Azathioprine and colchicine therapy was beneficial for preventing further relapse after short-term corticosteroid treatment. Therefore, BS should be considered in the differential diagnosis of focal suppurative myofasciitis.

Comparative risk of infections between JAK inhibitors versus TNF inhibitors among patients with rheumatoid arthritis: a cohort study.

BACKGROUND: To compare infectious risk between JAK inhibitors (JAKis) versus TNF inhibitors (TNFis) among rheumatoid arthritis (RA) patients in Korea. METHODS: Using 2009-2019 Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating a JAKi or TNFi. The primary outcomes were herpes zoster (HZ), serious bacterial (SBI), and opportunistic infections (OI). Propensity-score fine-stratification (PSS) and weighting were applied to adjust for > 70 baseline covariates. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing JAKi versus TNFi users. RESULTS: We included 2963 JAKi initiators PSS-weighted on 5169 TNFi initiators. During a follow-up of 1.16 years, the most frequent type of infections was HZ with incidence rate (IR) per 100 person-years of 11.54 and 4.88 in JAKi and TNFi users, respectively. The IR of SBI was 1.39 and 1.32, respectively. The OI was rare with a majority being tuberculosis and showed an IR of 0.11 and 0.49 in JAKi and TNFi users, respectively. The PSS-weighted HR (95% CI) for individual types of infections was 2.37 (2.00-2.80) for HZ, 1.04 (0.71-1.52) for SBI, and 0.25 (0.09-0.73) for OI. CONCLUSIONS: This population-based cohort study on RA patients treated with JAKi or TNFi in Korea showed an exceptionally high IR of HZ in both treatment groups compared to that from Western countries, with an approximately doubled risk associated with JAKi versus TNFi use. The risk of SBI was comparable, but the risk of OI, particularly tuberculosis, was less among JAKi than TNFi initiators.

Risk-Benefit Analysis of Primary Prophylaxis Against Pneumocystis Jirovecii Pneumonia in Patients With Rheumatic Diseases Receiving Rituximab.

OBJECTIVE: To identify a specific population of patients with rheumatic diseases receiving rituximab treatment for whom the benefit from primary prophylaxis against Pneumocystis jirovecii pneumonia (PJP) outweighs the risk of adverse events (AEs). METHODS: This study included 818 patients treated with rituximab for rheumatic diseases, among whom 419 received prophylactic trimethoprim/sulfamethoxazole (TMP/SMX) with rituximab, while the remainder did not. Differences in 1-year PJP incidence between the groups were estimated using Cox proportional hazards regression. Risk-benefit assessment was performed in subgroups stratified according to risk factors based on the number needed to treat (NNT) to prevent 1 case of PJP and the number needed to harm (NNH) due to severe AEs. Inverse probability of treatment weighting was applied to minimize the confounding by indication. RESULTS: During the 663.1 person-years, there were 11 PJP cases, with a mortality rate of 63.6%. Concomitant use of high-dose glucocorticoids (≥30 mg/day of prednisone or equivalent during 4 weeks after rituximab administration) was the most important risk factor. The PJP incidence (per 100 person-years) was 7.93 (95% confidence interval [95% CI] 2.91-17.25) in the subgroup receiving high-dose glucocorticoids compared with 0.40 (95% CI 0.01-2.25) in the subgroup without high-dose glucocorticoid use. Although prophylactic TMP/SMX significantly reduced the overall PJP incidence (HR 0.11 [95% CI 0.03-0.43]), the NNT to prevent 1 case of PJP (146) was higher than the NNH (86). In contrast, the NNT fell to 20 (95% CI 10.7-65.7) in patients receiving concomitant high-dose glucocorticoids. CONCLUSION: The benefit associated with primary PJP prophylaxis outweighs the risk of severe AEs in patients with rheumatic diseases receiving rituximab and concomitant high-dose glucocorticoid treatment.

Anterior and Lateral Femoroacetabular Excursion Angles Are Helpful for Assessing Femoroacetabular Impingement Syndrome: A Cross-Sectional Cohort Study.

PURPOSE: To develop a radiographic measurement to evaluate the femoroacetabular space using 3-dimensional (3D) hip models in asymptomatic hips, and to evaluate the reliability and validity of the femoroacetabular excursion angle (FAEA) in symptomatic patients. METHODS: From January 2020 to December 2020, we recruited patients with healthy hips to establish 3D models. Through the simulation of 14 activities of daily living (ADLs), anterior and lateral impingement-free FAEAs were measured. Another cross-sectional cohort was formed from consecutive symptomatic subjects with impingement signs during the same period. In the validation cohort, anterior and lateral FAEAs were assessed on modified Dunn's and anteroposterior views of the hip, respectively. We evaluated the reliability and clinical implications of the FAEAs. RESULTS: In the discovery cohort (n = 33), hips with collisions tended to have smaller computed tomography-based FAEAs than collision-free hips, although alpha and lateral center-edge (CE) angles were comparable. Additionally, hips with a lower quartile of FAEAs had a significantly higher number of ADLs with collisions. In the validation cohort (n = 411), the FAEA measurement was highly reliable (kappa statistics >0.95 for both interobserver and intraobserver reliabilities). The femoroacetabular impingement syndrome (FAIS) group (n = 165) showed significantly smaller anterior and lateral FAEAs than the non-FAIS group (all P < .001, Cramer V = .420). The optimal cut-off values for anterior and lateral FAEAs were 32.6° and 48.9°, respectively. In univariate regression, anterior (odds ratio [OR] = 0.91; 95% confidence interval [CI] = 0.89-0.94) and lateral (OR = 0.91; 95% CI = 0.89-0.93) FAEAs were significantly associated with FAIS. Moreover, in multivariate regression adjusted for alpha and lateral CE angles, anterior FAEA remained a significant predictor (OR = 0.96; 95% CI = 0.93-0.99), and small FAEA was an independent risk factor for FAIS (OR = 1.99; 95% CI = 1.06-3.71) for any small FAEA (OR = 2.88; 95% CI = 1.32-6.31) for both small FAEAs. CONCLUSION: The FAEA is a valid measurement for FAIS with high reliability. Small FAEA was an independent risk factor for FAIS in the multivariate regression model, even after adjusting for alpha and lateral CE angles. LEVEL OF EVIDENCE: Level III, diagnostic study.

Impact of early age at menopause on disease outcomes in postmenopausal women with rheumatoid arthritis: a large observational cohort study of Korean patients with rheumatoid arthritis.

OBJECTIVES: To assess the differences in clinical outcomes between patients with rheumatoid arthritis (RA) with early menopause (EM) (<45 years) and usual menopause (UM) (≥45 years) and to identify the impact of EM on longitudinal changes in RA activity and patient-reported outcomes (PROs). METHODS: We recruited 2878 postmenopausal women with RA from the Korean Observational Study Network for Arthritis. Patients were examined at baseline and for 5 consecutive years using the Simplified Disease Activity Index (SDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) and other PROs. Generalised estimating equation (GEE) analyses were performed among patients with a baseline SDAI of >11 to evaluate the impact of EM on longitudinal changes in RA activity and PROs. RESULTS: The EM group (n=437) was younger than the UM group (n=2441), but the RA duration was similar between the two groups. The EM group was more educated and more likely to be seronegative at enrolment. Moreover, the EM group demonstrated higher disease activity and worse PROs for global assessment, fatigue, sleep disturbance and health-related quality of life (HRQoL) (all p<0.05) at baseline. The GEE model revealed that EM significantly influenced the rate of SDAI change (ß=1.265, p=0.004) after adjusting for age, RA duration, biologics use and SDAI at baseline. The EM group was also significantly associated with increased HAQ-DI scores and decreased EQ-5D-utility values during the 5-year follow-up period. CONCLUSION: Patients with RA and EM demonstrate higher disease activity and poorer HRQoL. Furthermore, EM significantly affects the longitudinal changes in disease activity and PROs in patients with RA.

Performance of cut-offs adjusted with positive control band intensity in line-blot assays for myositis-specific antibodies.

The diagnostic performance of band intensity (BI) cut-offs, adjusted by a positive control band (PCB) in a line-blot assay (LBA) for myositis-related autoantibodies (MRAs) is investigated. Sera from 153 idiopathic inflammatory myositis (IIM) patients with available immunoprecipitation assay (IPA) data and 79 healthy controls were tested using the EUROLINE panel. Strips were evaluated for BI using the EUROLineScan software, and the coefficient of variation (CV) was calculated. Sensitivity and specificity, area under the curve (AUC), and the Youden's index (YI) were estimated at non-adjusted or PCB-adjusted cut-off values. Kappa statistics were calculated for IPA and LBA. Although inter-assay CV for PCB BI was 3.9%, CV was 12.9% in all samples, and a significant correlation was found between BIs of PCB and seven MRAs (all P < 0.05). At adjusted BI (aBI) > 10, the negative conversion rate of myositis-specific autoantibody (MSA)-positivity at BI > 10 was 11.5% in controls and 1.3% in patients. The specificity, AUC, and YI for MSAs at aBI > 10 or > 20 were higher than those at non-adjusted cut-off values. Additionally, AUC (0.720), YI (0.440), and the prevalence of MRAs with kappa > 0.60 (58.3%) were the highest at aBI > 20. The overall sensitivity and specificity for MSAs were 50.3% and 93.7% at aBI > 20, respectively, and 59.5% and 65.8% with BI > 10, respectively. The diagnostic performance of LBA can be improved using PCB-adjusted BIs. aBI > 20 is the optimal cut-off for IIM diagnosis using the EUROLINE LBA panel.

A Multicenter, Prospective, Randomized, Parallel-Group Trial on the Effects of Temporary Methotrexate Discontinuation for One Week Versus Two Weeks on Seasonal Influenza Vaccination in Patients With Rheumatoid Arthritis.

OBJECTIVE: This clinical trial was conducted to investigate whether discontinuing methotrexate (MTX) for 1 week after seasonal influenza vaccination is noninferior to discontinuing for 2 weeks after vaccination in patients with rheumatoid arthritis (RA). METHODS: In this multicenter, prospective, randomized, parallel-group noninferiority trial, RA patients receiving a stable dose of MTX were randomly assigned at a ratio of 1:1 to discontinue MTX for 1 week or for 2 weeks after they received the quadrivalent 2021-2022 seasonal influenza vaccine containing H1N1, H3N2, B/Yamagata, and B/Victoria strains. The primary outcome measure was the proportion of patients with a satisfactory vaccine response, which was defined as ≥4-fold increase in antibody titers, as determined with the hemagglutination inhibition assay, against ≥2 of the 4 vaccine strains at 4 weeks after vaccination. RESULTS: The modified intent-to-treat population included 90 patients in the 1-week MTX hold group and 88 patients in the 2-week MTX hold group. The mean ± SD MTX doses were 12.6 ± 3.4 mg/week in the 1-week MTX hold group and 12.9 ± 3.3 mg/week in the 2-week MTX hold group. The proportion of satisfactory vaccine responses did not differ between the groups (68.9% versus 75.0%; P = 0.364). The rate of seroprotection and the fold increase in antibody titers for each of the 4 influenza antigens were similar between the groups. CONCLUSION: A temporary discontinuation of MTX for 1 week after vaccination was noninferior to a discontinuation of MTX for 2 weeks after vaccination, regarding induction of a satisfactory vaccine response to a seasonal influenza vaccine in patients with RA receiving a stable dose of MTX.

Comparative risk of blindness and vision-threatening ocular comorbidities in patients with Behçet's disease versus the general population.

OBJECTIVE: To compare the risk of blindness and vision-threatening ocular comorbidities in patients with Behçet's disease (BD) vs the general population. METHODS: Using 2002-2017 Korea National Health Insurance Service database, we did a population-based cohort study comparing newly diagnosed BD patients and age- and sex-matched non-BD controls at a 1:5 ratio. The primary outcome was blindness, defined as a best-corrected visual acuity of ≤20/500 in the better-seeing eye. Secondary outcomes were vision-threatening ocular comorbidities (cataract, glaucoma and retinal disorders) that require surgical interventions and incident uveitis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. We performed subgroup analyses by sex and BD diagnosis age. RESULTS: We included 31 228 BD patients and 156 140 controls. During a follow-up of 9.39 years, the incidence rate of blindness per 1000 person-years was 0.24 in BD and 0.02 in controls with an HR of 10.73 (95% CI 7.10, 16.22). The HR for secondary outcomes was 2.06 (95% CI 1.98, 2.15) for cataract surgery, 5.43 (4.57, 6.45) for glaucoma surgery and 2.71 (2.39, 3.07) for retinal surgery. The HR of incident uveitis was 6.19 (95% CI 5.83, 6.58). Males suffered a disproportionately higher risk of blindness than females due to greater severity rather than a lower incidence of uveitis. The risk of uveitis and blindness decreased as BD diagnosis age increased. CONCLUSIONS: In this large population-based cohort study, BD patients compared with the general population have a 10.73-fold risk of blindness in 10 years and also a substantially higher risk of diverse ocular comorbidities that pose potential threats to vision.

The effect of rebamipide on non-steroidal anti-inflammatory drug-induced gastro-enteropathy: a multi-center, randomized pilot study.

BACKGROUND/AIMS: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly-used medications, and ailments such as arthritis or heart disease, require long-term use of these drugs, which can induce gastroenteropathy with bleeding and ulcers. This study investigated the associations between efficacy, safety, and gastrointestinal symptoms linked to rebamipide and proton pump inhibitor administration in patients requiring long-term NSAID use. METHODS: This study was a multi-center, randomized, open-labeled, pilot design. RESULTS: Thirty-three patients were included. Of these, 15 were included in the study group and 18 were in the control group. NSAID-induced gastric ulcers, which were the primary outcome of this study, did not occur in either the study or control group. Changes in the number of small bowel erosions and ulcers were -0.6 ± 3.06 in the study group and 1.33 ± 4.71 in the control group. The number of subjects with mucosal breaks (defined as multiple erosions and/or ulcers) was three (20%) in the study group and six (40%) in the control group (p = 0.427). No serious adverse events occurred in either group. However, dyspepsia and skin rashes occurred in six patients (31.58%) in the study group and 13 (65%) in the control group (p = 0.036). CONCLUSION: Although statistically significant differences were not generated, possibly as a result of the small sample size, mucosal breaks observed via capsule endoscopy revealed that rebamipide was likely to be more effective than lansoprazole in preventing small intestine damage caused by NSAIDs. Furthermore, fewer side-effects emerged with rebamipide.

Mitochondrial double-stranded RNAs as a pivotal mediator in the pathogenesis of SjÓ§gren's syndrome.

SjÓ§gren's syndrome (SS) is a systemic autoimmune disease that targets the exocrine glands, resulting in impaired saliva and tear secretion. To date, type I interferons (I-IFNs) are increasingly recognized as pivotal mediators in SS, but their endogenous drivers have not been elucidated. Here, we investigate the role of mitochondrial double-stranded RNAs (mt-dsRNAs) in regulating I-IFNs and other glandular phenotypes of SS. We find that mt-dsRNAs are elevated in the saliva and tears of SS patients (n = 73 for saliva and n = 16 for tears) and in salivary glands of non-obese diabetic mice with salivary dysfunction. Using the in-house-developed 3D culture of immortalized human salivary gland cells, we show that stimulation by exogenous dsRNAs increase mt-dsRNAs, activate the innate immune system, trigger I-IFNs, and promote glandular phenotypes. These responses are mediated via the Janus kinase 1 (JAK1)/signal transducer and activator of transcription (STAT) pathway. Indeed, a small chemical inhibitor of JAK1 attenuates mtRNA elevation and immune activation. We further show that muscarinic receptor ligand acetylcholine ameliorates autoimmune characteristics by preventing mt-dsRNA-mediated immune activation. Last, direct suppression of mt-dsRNAs reverses the glandular phenotypes of SS. Altogether, our study underscores the significance of mt-dsRNA upregulation in the pathogenesis of SS and suggests mt-dsRNAs as propagators of a pseudo-viral signal in the SS target tissue.

Association between sarcopenia defined as low lean mass by dual-energy X-ray absorptiometry and comorbidities of rheumatoid arthritis: Results of a nationwide cross-sectional health examination.

BACKGROUND: To examine the association between sarcopenia and comorbidities among patients with rheumatoid arthritis (RA). METHODS: We selected RA patients and age- and sex-matched non-RA controls at a 1:5 ratio from 2008-2011 Korea National Health and Nutrition Examination Survey database. Sarcopenia was defined by appendicular skeletal muscle mass. After investigating associations between sarcopenia and individual comorbidities among RA patients, we performed a stratified analysis comparing three subgroups (RA/sarcopenia, RA/non-sarcopenia, non-RA/sarcopenia) versus a non-RA/non-sarcopenia subgroup to evaluate interactive as well as independent effects of sarcopenia and RA on comorbidities. Health-related behaviors (exercise, smoking, drinking, and diet) were also examined. The weighted logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for age, sex, and income. RESULTS: We included 400 RA patients and 2,000 non-RA controls (mean age 57.4 years, 79.6% female). Sarcopenia was observed in 20.5% of RA and 19.3% of non-RA group. Among RA patients, sarcopenia was associated with obesity (OR 2.61, 95% CI 1.42-4.83), dyslipidemia (3.09, 1.37-6.99), diabetes (2.07, 0.99-4.33), chronic obstructive pulmonary disease (18.77, 2.40-146.55), and hepatitis B ever-infection (8.69, 1.15-65.58). Among three stratified subgroups, only a RA/sarcopenia subgroup was associated with such comorbidities, cardiovascular diseases, and depression compared to a non-RA/non-sarcopenia subgroup. Health-related behaviors were comparable between patients with and without sarcopenia. CONCLUSIONS: In this nation-wide cross-sectional study, a wide spectrum of comorbidities were preferentially found among RA patients with sarcopenia than without, suggesting that sarcopenia is significantly associated with RA-related comorbidities. Particular attention should be paid to comorbidities of sarcopenic RA patients.

Mitochondrial double-stranded RNAs govern the stress response in chondrocytes to promote osteoarthritis development.

Protein kinase R (PKR) is an immune response protein that becomes activated by double-stranded RNAs (dsRNAs). PKR overactivation is associated with degenerative diseases with inflammation, including osteoarthritis (OA), but the dsRNA activator remains largely unknown. Here, we find that mitochondrial dsRNA (mt-dsRNA) expression and its cytosolic efflux are facilitated in chondrocytes under OA-eliciting conditions, leading to innate immune activation. Moreover, mt-dsRNAs are released to the extracellular space and activate Toll-like receptor 3 at the plasma membrane. Elevated levels of mt-dsRNAs in the synovial fluids and damaged cartilage of OA patients and in the cartilage of surgery-induced OA mice further support our data. Importantly, autophagy prevents PKR activation and protects chondrocytes from mitochondrial stress partly by removing cytosolic mtRNAs. Our study provides a comprehensive understanding of innate immune activation by mt-dsRNAs during stress responses that underlie the development of OA and suggests mt-dsRNAs as a potential target for chondroprotective intervention.

Cardiovascular safety associated with febuxostat versus allopurinol among patients with gout: Update with accumulated use of febuxostat.

BACKGROUND: To re-evaluate comparative cardiovascular (CV) safety of febuxostat versus allopurinol among patients with gout following recent accumulated use of febuxostat. METHODS: Using 2011-2019 Korea National Health Insurance database, we conducted a cohort study comparing gout patients initiating febuxostat versus allopurinol, 1:1 matched on a propensity-score (PS) for >60 covariates. The primary outcome was a composite endpoint of myocardial infarction, coronary revascularization, and stroke. Secondary outcomes were individual components of the primary outcome, hospitalized heart failure, and all-cause mortality. Subgroup analyses were done for those at high CV risk, long-term users (follow-up >3 years), and those without chronic kidney disease. We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We included 160,930 PS-matched pairs of febuxostat and allopurinol users (mean age 59.3 years, 79.6% male). Incidence rates of the primary outcome were 2.06 and 2.27 per 100 person-years for febuxostat and allopurinol users, respectively, with a HR [95% CI] of 1.03 [0.95-1.12] comparing febuxostat versus allopurinol initiators. We also observed similar risks for secondary outcomes, except for reduced all-cause mortality among febuxostat users (HR [95% CI] of 0.84 [0.78-0.91]). Subgroup analyses also showed non-inferior CV safety of febuxostat. CONCLUSION: In this population-based cohort study including the largest number of febuxostat users to date, we found non-inferior CV safety of febuxostat versus allopurinol. There was a 16% reduction in all-cause mortality among febuxostat users.

Electrochemical detection of uric acid in undiluted human saliva using uricase paper integrated electrodes.

In this study, we introduce a uricase-immobilized paper (UOx--paper) integrated electrochemical sensor for detection of uric acid (UA) in saliva. The UOx was immobilized on the detection zone in the wax-patterned paper substrate. This UOx-paper was integrated with a Prussian blue--modified, screen-printed carbon electrode after electropolymerization of o-phenylenediamine to construct an electrochemical cell for small-volume (20 µL) of samples. First, we optimized the fabrication conditions of UOx-paper. Next, the amperometric response of the UOx-paper-based electrochemical UA sensor was analyzed using a known concentration of UA standard solution in artificial saliva at an applied potential of - 0.1 V (versus Ag pseudo-reference electrode). The UOx--paper based electrochemical UA sensor showed a sensitivity of 4.9 µA·mM-1 in a linear range of 50 to 1000 µM (R2 = 0.998), high selectivity and good reproducibility, as well as a limit of detection of 18.7 µM (0.31 mg/dL) UA. Finally, we quantified the UA levels in undiluted saliva samples of healthy controls (n = 20) and gout patients (n = 8). The levels were correlated with those measured with conventional salivary UA enzymatic assays as well as serum UA levels. The UOx-paper-based electrochemical UA sensor is a user-friendly and convenient tool to assess salivary UA levels.

Infectious risk of add-on leflunomide or tacrolimus versus TNF inhibitors among patients with rheumatoid arthritis receiving background methotrexate: A population-based cohort study.

BACKGROUND: To compare infectious risk between leflunomide versus TNF inhibitors (TNFi), and between tacrolimus versus TNFi among rheumatoid arthritis (RA) patients receiving methotrexate (MTX). METHODS: Using Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating TNFi, leflunomide, or tacrolimus. The primary outcome was any serious infections defined as a composite endpoint of serious bacterial, opportunistic, and herpes zoster infections. Secondary outcomes were individual components of the primary outcome. Propensity-score fine-stratification (PSS) and weighting were applied to adjust for confounding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing leflunomide versus TNFi, and tacrolimus versus TNFi. RESULTS: Among 72,516 RA patients receiving MTX, we identified 3,336 TNFi initiators, 11,122 leflunomide initiators, and 5,136 tacrolimus initiators. Two study cohorts were 10,992 leflunomide initiators PSS-weighted on 1,623 TNFi initiators and 5,126 tacrolimus initiators PSS-weighted on 2,521 TNFi initiators. The incidence rate per 100 person-years of herpes zoster infection (3.70-4.27) was beyond 3-times that of serious bacterial infection (1.12-1.36), but opportunistic infection was relatively rare (0.11-0.23). The PSS-weighted HR [95% CI] for any serious infection was 1.03 [0.89-1.22] comparing leflunomide versus TNFi, and 0.91 [0.77-1.08] comparing tacrolimus versus TNFi. Analyses on the secondary outcomes showed consistent results. CONCLUSION: In this nation-wide cohort study, we did not find a significant difference in the risk of serious infections (i.e., serious bacterial, opportunistic, and herpes zoster infections) between leflunomide versus TNFi, and between tacrolimus versus TNFi among RA patients receiving background MTX.