Nationwide Study of the Epidemiology, Diagnosis, and Treatment of Hypersensitivity Pneumonitis in Korea.

BACKGROUND: Hypersensitivity pneumonitis (HP) is a condition with an uncertain global incidence, and information on its diagnosis and management is limited. This study aimed to address these knowledge gaps. METHODS: This study utilized customized claims data from the Health Insurance Review and Assessment Service (HIRA) in South Korea from January 2010, to December 2021. Patients with HP were identified based on the diagnosis code (International Classification of Diseases, 10th Revision, J67) between 2011 and 2020. Incident HP cases were defined as new HP claims, excluding those with claims in the previous year. The study examined various factors such as age, sex, comorbidities, diagnostic methods, and treatment patterns. Additionally, multivariate logistic regression analysis was performed to identify risk factors associated with treatment initiation. RESULTS: A total of 8,678 HP incident cases were confirmed, with age- and sex-adjusted annual incidence rates ranging from 1.14/100,000 in 2020 to 2.16/100,000 in 2012. The mean age of patients with incident HP was 52 years, with a higher incidence observed among males. Additionally, the most common comorbidity was asthma. Bronchoscopy was performed on 16.9% of patients, and 25.4% of patients did not receive treatment within 1 year of diagnosis. Among those who received treatment, prednisone was the most used systemic steroid, and azathioprine was the most commonly used second-line immunosuppressant. Factors associated with treatment initiation included the female sex, having asthma or gastroesophageal reflux disease (GERD), and undergoing bronchoscopy. CONCLUSION: This study provides valuable insights into the incidence, diagnosis, and treatment patterns of HP in South Korea using nationwide medical claims data.

Impact of Propofol-based Total Intravenous Anesthesia Versus Inhalation Anesthesia on Long-term Survival After Cancer Surgery in a Nationwide Cohort.

OBJECTIVE: To compare the impact of propofol-based total intravenous anesthesia (TIVA) versus inhalational anesthesia (IA) on the overall survival following cancer surgery. BACKGROUND: The association between intraoperative anesthetics and patients' long-term outcomes following cancer surgery remains controversial. METHODS: This retrospective cohort study used nationwide data from the Korean National Health Insurance Service. Adult patients who underwent cancer resection surgery (breast, gastric, lung, liver, kidney, colorectal, pancreatic, esophageal, and bladder cancer) under general anesthesia between January 2007 and December 2016 were included. Patients were divided into propofol-based TIVA or IA groups according to the type of anesthesia received. A total of 312,985 patients (37,063 in the propofol-based TIVA group and 275,922 patients in the IA group) were eligible for analysis. The primary outcome was the comparison of overall survival following surgery between the groups in each cancer type. We compared the all-cause mortality between the 2 groups, stratified by cancer type using time-dependent Cox regression after propensity score-based inverse probability of treatment weighting. We further examined the comparison of overall survival in a meta-analysis using data from our study and previously published data comparing propofol-based TIVA with IA after cancer surgery. RESULTS: The number of deaths in the propofol-based TIVA and IA groups was 5037 (13.6%) and 45,904 (16.6%), respectively; the median (interquartile range) follow-up duration was 1192 (637-2011) days. Multivariable Cox proportional hazards regression analysis revealed no significant association between the type of general anesthesia and overall survival after cancer surgery in the weighted cohort for each cancer type (all P >0.05) and for total population [adjusted hazard ratio (HR): 0.98, 95% confidence interval (CI): 0.93-1.04]. In a meta-analysis, single-center studies showed higher overall survival in the TIVA group than in the IA group (pooled adjusted HR: 0.65, 95% CI: 0.47-0.91, P =0.01), while multicenter studies showed insignificant pooled adjusted HRs (pooled adjusted HR: 1.05, 95% CI: 0.82-1.33, P =0.71). CONCLUSIONS: There is no association between the type of general anesthesia used during cancer surgery and postoperative overall, 1-, and 5-year survival.

Cardiovascular outcomes between COVID-19 and non-COVID-19 pneumonia: a nationwide cohort study.

BACKGROUND: Previous studies that assessed the risk of cardiovascular outcomes in survivors of coronavirus disease 2019 (COVID-19) were likely limited by lack of generalizability and selection of controls nonrepresentative of a counterfactual situation regarding COVID-19-related hospitalization. This study determined whether COVID-19 hospitalization was associated with incident cardiovascular outcomes compared to non-COVID-19 pneumonia hospitalization. METHODS: Nationwide population-based study conducted using the Korean National Health Insurance Service database. A cohort of 132,784 inpatients with COVID-19 (October 8, 2020-September 30, 2021) and a cohort of 31,173 inpatients with non-COVID-19 pneumonia (January 1-December 31, 2019) were included. The primary outcome was the major adverse cardiovascular event (MACE; a composite of myocardial infarction and stroke). Hazard ratios (HRs) with 95% confidence intervals (CIs) of all outcomes of interest were estimated between inverse probability of treatment-weighted patients with COVID-19 and non-COVID-19 pneumonia. RESULTS: After weighting, the COVID-19 and non-COVID-19 pneumonia groups included 125,810 (mean [SD] age, 47.2 [17.6] years; men, 49.3%) and 28,492 patients (mean [SD] age, 48.6 [18.4] years; men, 47.2%), respectively. COVID-19 hospitalization was not associated with an increased risk of the MACE (HR, 0.84; 95% CI 0.69-1.03). However, the MACE (HR, 7.30; 95% CI 3.29-16.21), dysrhythmia (HR, 1.88; 95% CI 1.04-3.42), acute myocarditis (HR, 11.33; 95% CI 2.97-43.20), myocardial infarction (HR, 6.78; 95% CI 3.03-15.15), congestive heart failure (HR, 1.95; 95% CI 1.37-2.77), and thrombotic disease (HR, 8.26; 95% CI 4.06-16.83) risks were significantly higher in patients with COVID-19 aged 18-39 years. The findings were consistent after adjustment for preexisting cardiovascular disease. COVID-19 hospitalization conferred a higher risk of acute myocarditis (HR, 6.47; 95% CI 2.53-16.52) or deep vein thrombosis (HR, 1.97; 95% CI 1.38-2.80), regardless of vaccination status. CONCLUSIONS: Hospitalized patients with COVID-19 were not at an increased risk of cardiovascular outcomes compared to patients with non-COVID-19 pneumonia. Further studies are needed to evaluate whether the increased risk of cardiovascular outcomes is confined to younger patients.

Amorphous-Crystalline Interfaces on Hollow Nanocubes Derived from Ir-Doped Ni-Fe-Zn Prussian Blue Analog Enables High Capability of Alkaline/Acidic/Saline Water Oxidations.

Development of highly efficient and robust electrocatalysts for oxygen evolution reaction (OER) under specific electrolyte is a key to actualize commercial low-temperature water electrolyzers. Herein, a rational catalyst design strategy is first reported based on amorphous-crystalline (a-c) interfacial engineering to achieve high catalytic activity and durability under diverse electrolytes that can be used for all types of low-temperature water electrolysis. Abundant a-c interface (ACI) is implemented into a hollow nanocubic (pre)-electrocatalyst which is derived from Ir-doped Ni-Fe-Zn Prussian blue analogues (PBA). The implemented c-a interface is well maintained during prolonged OER in alkaline, alkalized saline, and acidic electrolytes demonstrating its diverse functionality for water electrolysis. Notably, the final catalyst exhibits superior catalytic activity with excellent durability for OER compared to that of benchmark IrO2 catalyst, regardless of chemical environment of electrolytes. Hence, this work can be an instructive guidance for developing the ACI engineered electroctalyst which can be diversely used for different types of low-temperature electrolyzers.

Cost-of-illness changes before and after the diagnosis of systemic lupus erythematosus: a nationwide, population-based observational study in Korea.

OBJECTIVES: To estimate the direct healthcare cost progression from before to after systemic lupus erythematosus (SLE) diagnosis and to compare healthcare costs by disease severity. METHODS: Patients with incident SLE diagnosed between 2008 and 2018 were identified from the Korean National Health Insurance database. Annual direct healthcare costs for 5 years before and after SLE were estimated and compared with those of age-, sex-, and calendar month-matched (1:4) controls, without SLE. Direct healthcare costs were compared by disease severity of SLE using regression analysis. RESULTS: Among 11 173 patients with SLE and 45 500 subjects without SLE, annual direct healthcare costs per person increased in the year before SLE diagnosis and peaked in the first year after diagnosis. They were 7.7-fold greater in the SLE patients than in the subjects without SLE ($5,871 vs $759). Severe SLE was associated with 3.284-fold (95% CI 3.075-3.507) higher annual costs than mild SLE during the year after diagnosis. Older age (age 60-79 years), lupus nephritis, interstitial lung diseases, and comorbidities such as avascular necrosis and chronic kidney disease were associated with higher annual direct healthcare costs (times [95% CI]) in the first year after diagnosis; aged 60-69, 1.119 [1.034-1.211], aged 70-79, 1.470 [1.342-1.611], 1.794 [1.711-1.881], 1.435 [1.258-1.638], 6.208 [4.541-8.487], and 1.858 [1.673-2.064], respectively. CONCLUSION: Patients with SLE incurred significantly high direct healthcare costs than subjects without SLE during the first year after diagnosis. Disease severity, older age, major organ involvements and comorbidities were associated with increased healthcare costs.

Antidepressants and the Risk of Ischemic Stroke in Older Adults According to the Degree of Serotonin Reuptake Inhibition: A Retrospective Cohort Study.

OBJECTIVE: The effects of serotonin reuptake inhibition induced by antidepressants on ischemic stroke and its pathophysiology remain unclear despite the frequent use of antidepressants and high fatality of ischemic stroke. We estimated the risk of ischemic stroke associated with antidepressant use in older adults according to the degree of serotonin reuptake inhibition. DESIGN: Retrospective cohort study. PARTICIPANTS: The cohort consisted of older adult patients who were treated with antidepressants. MEASUREMENTS: We estimated the risk of ischemic stroke associated with antidepressant use in older adults according to the degree of serotonin reuptake inhibition using Korea's National Health Insurance System-Senior Cohort. Exposure to antidepressants was categorized by type (strong, intermediate, or weak serotonin reuptake inhibitors [SRIs]) and by the mean prescribed dose per day and treatment duration. The risk for the strong and intermediate SRIs group was compared with that of the weak SRIs group using a Cox proportional hazards regression model. RESULTS: Of 97,411 were weak SRIs users, and 107,152 and 18,783 were users of strong and intermediate SRIs. The risk of ischemic stroke was 1.192- and 1.057-fold higher in strong and intermediate SRI users, respectively than in weak SRI users. Hazard ratios were increased in higher dose and shorter duration user groups. The risk increased 1.753-fold in strong SRI users with anticonvulsants and 1.387-fold in intermediate SRI users with PPIs. CONCLUSION: The use of strong and intermediate SRIs should be considered carefully in older adult patients, especially when high-dose antidepressants are prescribed even for a short duration.

Risk of cardiovascular events according to the tricyclic antidepressant dosage in patients with chronic pain: a retrospective cohort study.

PURPOSE: We aimed to examine the risk of cardiovascular adverse events by tricyclic antidepressant (TCA) dosage among patients with chronic pain. METHODS: A retrospective cohort study was conducted using a nationwide sample cohort. Among patients aged ≥ 18 years with a chronic pain diagnosis and no history of cardiovascular events, we extracted users and non-users of TCAs through 1:1 propensity score matching. TCA users were categorized into three groups according to the mean defined daily dose (DDD): very low doses (< 0.15 DDD), low doses (0.15-0.34 DDD), and traditional doses (≥ 0.34 DDD). A 6-month follow-up was conducted with an intention-to-treat approach. We examined the hazard ratio of cardiovascular adverse events using Cox proportional hazards analysis. RESULTS: In total, 16,660 matched patients were followed up (8330 TCA users and 8330 non-users). TCA use did not significantly increase cardiovascular adverse events (hazard ratio [HR] 1.12, 95% confidence interval [CI] 0.94-1.33). Low-dose (0.15-0.34 DDD) TCAs (HR 1.37, 95% CI 1.08-1.74), particularly low-dose (0.15-0.34 DDD) nortriptyline (HR 2.11, 95% CI 1.44-3.08), was associated with an increased risk of cardiovascular adverse events. Administration of TCAs at the traditional dose (≥ 0.34 DDD) increased the risk of ischemic stroke (HR 2.08, 95% CI 1.11-3.88). CONCLUSION: Close monitoring of patients on long-term, low-dose use of TCAs should be conducted to avoid an increase in the cumulative dose, which increases the risk of cardiovascular adverse events.

Medications influencing the risk of fall-related injuries in older adults: case-control and case-crossover design studies.

BACKGROUND: Medications influencing the risk of fall-related injuries (FRIs) in older adults have been inconsistent in previous guidelines. This study employed case-control design to assess the association between FRIs and medications, and an additional case-crossover design was conducted to examine the consistency of the associations and the transient effects of the medications on FRIs. METHODS: This study was conducted using a national claims database (2002-2015) in Korea. Older adults (≥ 65 years) who had their first FRI between 2007 and 2015 were matched with non-cases in 1:2 ratio. Drug exposure was examined for 60 days prior to the date of the first FRI (index date) in the case-control design. The hazard period (1-60 days) and two control periods (121-180 and 181-240 days prior to the index date) were investigated in the case-crossover design. The risk of FRIs with 32 medications was examined using conditional logistic regression after adjusting for other medications that were significant in the univariate analysis. In the case-crossover study, the same conditional model was applied. RESULTS: In the case-control design, the five medications associated with the highest risk of FRIs were muscle relaxants (adjusted odd ratio(AOR) = 1.35, 95% confidence interval (CI) = 1.31-1.39), anti-Parkinson agents (AOR = 1.30, 95%CI = 1.19-1.40), opioids (AOR = 1.23, 95%CI = 1.19-1.27), antiepileptics (AOR = 1.19, 95%CI = 1.12-1.26), and antipsychotics (AOR = 1.16, 95%CI = 1.06-1.27). In the case-crossover design, the five medications associated with the highest risk of FRIs were angiotensin II antagonists (AOR = 1.87, 95%CI = 1.77-1.97), antipsychotics (AOR = 1.63, 95%CI = 1.42-1.83), anti-Parkinson agents (AOR = 1.58, 95%CI = 1.32-1.85), muscle relaxants (AOR = 1.42, 95%CI = 1.35-1.48), and opioids (AOR = 1.35, 95%CI = 1.30-1.39). CONCLUSIONS: Anti-Parkinson agents, opioids, antiepileptics, antipsychotics, antidepressants, hypnotics and sedatives, anxiolytics, muscle relaxants, and NSAIDs/antirheumatic agents increased the risk of FRIs in both designs among older adults. Medications with a significant risk only in the case-crossover analysis, such as antithrombotic agents, calcium channel blockers, angiotensin II antagonists, lipid modifying agents, and benign prostatic hypertrophy agents, may have transient effects on FRIs at the time of initiation. Corticosteroids, which were only associated with risk of FRIs in the case-control analysis, had more of cumulative than transient effects on FRIs.

Developing Operational Definitions Related to Helicobacter pylori Eradication Therapy.

BACKGROUND: The lack of well-established operational definitions is a major limitation of Helicobacter pylori eradication studies that use secondary databases. We aimed to develop and validate operational definitions related to H. pylori eradication therapy. METHODS: Operational definitions were developed by analyzing a nationwide H. pylori eradication registry and validated using real-world data from hospital medical records. The primary endpoint was the sensitivity of the operational definitions in identifying individuals who received H. pylori eradication therapy. The secondary endpoint was the sensitivity and specificity of the operational definition in identifying successful H. pylori eradication therapy. RESULTS: H. pylori eradication therapy was defined as a prescription for one of the following combinations: 1) proton pump inhibitor (PPI) + amoxicillin + clarithromycin, 2) PPI + amoxicillin + metronidazole, 3) PPI + metronidazole + tetracycline, 4) PPI + amoxicillin + levofloxacin, 5) PPI + amoxicillin + moxifloxacin, or 6) PPI + amoxicillin + rifabutin. In the validation set, the sensitivity of the operational definition for identifying individuals who received H. pylori eradication therapy was 99.7% and 99.8% for the first- and second-line therapies, respectively. Operational definition to determine success or failure of the H. pylori eradication therapy was developed based on a confirmatory test and the prescription of rescue therapy. The sensitivity and specificity of the operational definition for predicting successful eradication were 97.6% and 91.4%, respectively, in first-line therapy and 98.6% and 54.8%, respectively, in second-line therapy. CONCLUSION: We developed and validated operational definitions related to H. pylori eradication therapy. These definitions will help researchers perform various H. pylori eradication-related studies using secondary databases.

Vitamin C for ≥ 5 days is associated with decreased hospital mortality in sepsis subgroups: a nationwide cohort study.

BACKGROUND: Previous randomized trials of vitamin C, hydrocortisone, and thiamine on sepsis were limited by short-term vitamin C administration, heterogeneous populations, and the failure to evaluate each component's effect. The purpose of this study was to determine whether vitamin C alone for ≥ 5 days or in combination with corticosteroids and/or thiamine was associated with decreased mortality across the sepsis population and subpopulation. METHODS: Nationwide population-based study conducted using the Korean National Health Insurance Service database. A total of 384,282 adult patients with sepsis who were admitted to the intensive care unit were enrolled from January 2017 to December 2019. The primary outcome was hospital mortality, while the key secondary outcome was 90-day mortality. RESULTS: The mean [standard deviation] age was 69.0 [15.4] years; 57% were male; and 36,327 (9%) and 347,955 did and did not receive vitamin C, respectively. After propensity score matching, each group involved 36,327 patients. The hospital mortality was lower by - 0.9% in the treatment group (17.1% vs 18.0%; 95% confidence interval, - 1.3 to - 0.5%; p < 0.001), a significant but extremely small difference. However, mortality decreased greater in patients who received vitamin C for ≥ 5 days (vs 1-2 or 3-4 days) (15.8% vs 18.8% vs 18.3%; p < 0.001). Further, vitamin C was associated with a lower hospital mortality in patients with older age, multiple comorbidities, pneumonia, genitourinary infection, septic shock, and mechanical ventilation. Consistent findings were found for 90-day mortality. Moreover, vitamin C alone or in combination with thiamine was significantly associated with decreased hospital mortality. CONCLUSIONS: Intravenous vitamin C of ≥ 5 days was significantly associated with decreased hospital and 90-day mortality in sepsis patients. Vitamin C combined with corticosteroids and/or thiamine in specific sepsis subgroups warrants further study.

Prevalence and patterns of the concurrent use of anticholinergics for the motor symptoms of Parkinson's disease and acetylcholinesterase inhibitors in Parkinson's disease patients with dementia: a cross-sectional study using Korea National Health Insurance claims data.

BACKGROUND: The concurrent use of anticholinergics and acetylcholinesterase inhibitors (ACHEIs) in Parkinson's disease (PD) patients with dementia should be avoided because the opposing pharmacological actions of both drugs reduce the treatment efficacy. We aimed to investigate the prevalence of the concurrent use of these two types of drugs in Korean patients. METHODS: In the 2017 Health Insurance Review and Assessment Service-National Aged Patient Sample data, comprising insurance claims records for a 10% random sample of patients aged ≥ 65 years in Korea, "concurrent use" was defined as the overlapping of anticholinergic and ACHEI doses for at least 2 months. RESULTS: Among 8,845 PD patients with dementia, 847 (9.58%) were co-administered anticholinergics, used to treat the motor symptoms of PD, and ACHEIs for a mean duration of 7.7 months. A total of 286 (33.77% of all co-administered) patients used both drug types concurrently all year. About 80% of concurrent users were prescribed each drug by the same prescriber, indicating that coadministration may not be due to a lack of information sharing between providers. Logistic regression analysis showed that patients mainly treated at clinics (odds ratio (OR), 1.541; 95% confidence interval (CI), 1.158-2.059), hospitals (OR, 2.135; 95% CI, 1.586-2.883), and general hospitals (OR, 1.568; 95% CI, 1.221-2.028) were more likely to be co-prescribed anticholinergics and ACHEIs than those mainly treated at tertiary-care hospitals. PD patients with dementia treated at healthcare organizations located in areas other than the capital city had an approximately 22% higher risk of concurrent use (OR: 1.227, 95% CI: 1.046-1.441). CONCLUSIONS: The concurrent use of anticholinergics for the motor symptoms of PD and ACHEIs in elderly Korean PD patients with dementia cannot be ignored, and strategies that mitigate potentially inappropriate concurrent drug use are required.

COX-2 Inhibitor Use as an Early Treatment Option for Knee Osteoarthritis Patients in Korea: A Population-Based Cross-Sectional Study.

BACKGROUND: To investigate the use of cyclooxygenase-2 (COX-2) inhibitors as an initial drug treatment for knee osteoarthritis (OA) patients. METHODS: From 2013 to 2015, patients with knee OA were identified from the Korean nationwide claims database. Among them, we extracted incident cases of knee OA to identify the initial drug treatment. Trends in the use of non-steroid anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors were analyzed during the first year after their diagnosis. Associated factors for COX-2 inhibitor use were examined using a multivariate logistic regression model. RESULTS: We identified 2,857,999 incident knee OA patients (955,259 in 2013, 981,314 in 2014, and 921,426 in 2015). The mean ± standard deviation age of patients was 64.2 ± 9.8 years. The frequency of COX-2 inhibitor use as initial treatment increased from 3.5% in 2013 to 7.2% in 2015 (P < 0.01). In patients taking the medication regularly for one year after diagnosis (medication possession ratio ≥ 50%), COX-2 inhibitor use also rapidly increased from 5.5% in 2013 to 11.1% in 2015 (P < 0.01). However, the frequencies of non-selective NSAID and analgesic use did not decrease remarkably. Factors associated with patients using COX-2 inhibitors on initial drug treatment were older age (odds ratio [OR], 1.08), female (OR, 1.24), and comorbidity (OR, 1.03). Type of institution, physician speciality, and insurance type of patients were also associated. CONCLUSION: In Korea, COX-2 inhibitors have rapidly increased as an initial treatment for knee OA patients, but it has not appeared to reduce the use of non-selective NSAIDs and analgesics.

Longitudinal study of the impact of three major regulations on the Korean pharmaceutical industry in the last 30 years.

BACKGROUND: The pharmaceutical industry is heavily regulated. Partly for this reason, new drugs generally take over 10 years from the product development stage to market entry. Although regulations affect the pharmaceutical industry over a long period, previous studies investigating the impact of new regulatory policies have usually focused on the short period before and after implementing that policy. Therefore, the purpose of this study is to examine whether and how significantly regulatory policies affect long-term innovation in the pharmaceutical industry in Korea. METHODS: This study focused on three significant regulatory policies: the introduction of the product patent system, changes in the Good Manufacturing Practice (GMP) system, and the Drug Expenditure Rationalization Plan (DERP). The study used interrupted time series (ITS) analysis to investigate the long-term impacts of the policies before and after implementation. RESULTS: Our results show that introducing the product patent system in 1987 significantly increased the number of Korean patent applications. The effect of the revised GMP policies was also statistically significant, both before and after implementation and between pre-emptive companies and non-pre-emptive ones. However, due to the companies' negotiations with the regulatory authorities or the regulatory system that links drug approval and price evaluation, the DERP did not significantly delay new drug registration in Korea. CONCLUSION: This study showed that the policies of the product patent system, GMP policies, and DERP regulations have significantly encouraged pharmaceutical companies to strive to meet regulatory requirements and promote innovation in Korea. The study suggests that it is necessary for companies to pre-emptively respond to systemic changes in development and production strategies to deal with regulatory changes and achieve sustainable growth. Also, our study results indicate that since government policies motivate the innovative system of the pharmaceutical industry, governmental authorities, when formulating pharmaceutical policies, need to consider the impact on the long-term innovation of the industry.

Uptake of Biosimilars and Its Economic Implication for the Treatment of Patients with Rheumatoid Arthritis in Korea.

BACKGROUND: We aimed to examine the uptake of infliximab and etanercept biosimilars in patients with rheumatoid arthritis (RA) and its economic implication for healthcare expenditure. METHODS: Using Korean Health Insurance Review and Assessment Service National Patient Samples, we extracted RA patients who used biologic disease modifying anti-rheumatic drugs (bDMARDs) between 2009 and 2018. Descriptive statistics were used to explain the basic features of the data. We calculated the proportion of users of each bDMARD among total patients with bDMARDs half-yearly. We assessed changes in the utilization proportions of bDMARDs including 4 tumor necrosis factor inhibitors (TNFis) and 2 non-TNFis, which have been approved for RA in Korea: etanercept, infliximab, adalimumab, golimumab, tocilizumab, and abatacept, and analyzed the changes in market share of biosimilars among the bDMARDs after their introduction. Overall trends of medical costs for each bDMARD were presented over the 10-year period. RESULTS: Since the introduction of the biosimilar TNFis in 2012, the proportion of their use among bDMARDs steadily increased to 15.8% in 2018. While there has been a gradual increase in the use of biosimilar TNFis, the use of the corresponding originators has been decreasing. The introduction of biosimilar TNFis has resulted in a decrease in the medical costs of patients using either originator or biosimilar TNFis. CONCLUSION: In Korea, the proportional use of biosimilar TNFis has gradually increased since their introduction. The availability of less expensive biosimilar TNFis seems to have brought about a decrease in the medical costs of users of the originators.

Association of Renin-angiotensin-aldosterone System Inhibitors With Coronavirus Disease 2019 (COVID-19)- Related Outcomes in Korea: A Nationwide Population-based Cohort Study.

BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) inhibitors may facilitate host cell entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or attenuate organ injury via RAAS blockade. We aimed to assess the associations between prior use of RAAS inhibitors and clinical outcomes among Korean patients with coronavirus disease 2019 (COVID-19). METHODS: We performed a nationwide population-based cohort study using the Korean Health Insurance Review and Assessment database. Claim records were screened for 69 793 individuals who were tested for COVID-19 until 8 April 2020. Adjusted odds ratios (ORs) were used to compare the clinical outcomes between RAAS inhibitor users and nonusers. RESULTS: Among 5179 confirmed COVID-19 cases, 762 patients were RAAS inhibitor users and 4417 patients were nonusers. Relative to nonusers, RAAS inhibitor users were more likely to be older, male, and have comorbidities. Among 1954 hospitalized patients with COVID-19, 377 patients were RAAS inhibitor users, and 1577 patients were nonusers. In-hospital mortality was observed for 33 RAAS inhibitor users (9%) and 51 nonusers (3%) (P < .001). However, after adjustment for age, sex, Charlson comorbidity index, immunosuppression, and hospital type, the use of RAAS inhibitors was not associated with a higher risk of mortality (adjusted OR, 0.88; 95% confidence interval, 0.53-1.44; P = .60). No significant differences were observed between RAAS inhibitor users and nonusers in terms of vasopressor use, modes of ventilation, extracorporeal membrane oxygenation, renal replacement therapy, and acute cardiac events. CONCLUSIONS: Our findings suggest that prior use of RAAS inhibitors was not independently associated with mortality among COVID-19 patients in Korea.

Piper Nigrum extract improves OVA-induced nasal epithelial barrier dysfunction via activating Nrf2/HO-1 signaling.

BACKGROUND: Piper nigrum L. (Piperaceae) is commonly used as a spice and traditional medicine in many countries. It has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the protective role of P. nigrum on epithelial function of upper respiratory tract injury in an allergic rhinitis (AR) mouse model has been unclear. This study aims to investigate the effects of P. nigrum fruit extract (PNE) on the nasal epithelial barrier function of the upper respiratory tract in an ovalbumin (OVA)-induced AR model. METHODS: AR mouse model was established by intraperitoneal injection with 200 µL saline containing 50 µg OVA adsorbed to 1 mg aluminum hydroxide, and intranasal challenge with 20 µL per nostril of 1 mg/ml OVA. Besides, mice were orally administrated once daily with PNE and dexamethasone (Dex) in 13 days. The nasal symptoms, inflammatory cells, OVA-specific immunoglobulins, cytokines, nasal histopathology, and immunohistochemistry were evaluated. RESULTS: The PNE oral administrations inhibited allergic responses via reduction of OVA-specific antibodies levels and mast cells histamine release, accordingly, the nasal symptoms in the early-phase reaction were also clearly ameliorated. In both nasal lavage fluid and nasal tissue, PNE suppressed the inflammatory cells accumulation, specifically with eosinophils. The intravenous Evans blue injection illustrated the epithelial permeability reduction of nasal mucosa layer in PNE-treated mice. Also; PNE treatments protected the epithelium integrity by preventing the epithelial shedding from nasal mucosa; as a result of enhancing the strong expression of the E-cadherin tight junction protein in cell-to-cell junctions, as well as inhibiting the degraded levels of zonula occludens-1 (ZO-1) and occludin into the nasal cavity. Additionally, PNE protected against nasal epithelial barrier dysfunction via enhancing the expression of Nrf2 activated form which led to increasing synthesis of the anti-inflammation enzyme HO-1. CONCLUSIONS: These obtained results suggest that PNE has a promising strategy for epithelial barrier stabilization in allergic rhinitis treatment.

Piperine Ameliorates Trimellitic Anhydride-Induced Atopic Dermatitis-Like Symptoms by Suppressing Th2-Mediated Immune Responses via Inhibition of STAT6 Phosphorylation.

Atopic dermatitis (AD) is a common inflammatory skin disease predominately related to Type 2 helper T (Th2) immune responses. In this study, we investigated whether piperine is able to improve AD symptoms using a trimellitic anhydride (TMA)-induced AD-like mouse model. Topical treatment with piperine reduced ear swelling (ear thickness and epidermal thickness) induced by TMA exposure. Furthermore, piperine inhibited pro-inflammatory cytokines such as TNF-α and IL-1ß in mouse ears, compared with the TMA-induced AD group. In measuring allergic immune responses in draining lymph nodes (dLNs), we found that IL-4 secretion, GATA3 mRNA level, and STAT6 phosphorylation were suppressed by piperine treatment. In an ex vivo study, piperine also inhibited the phosphorylation of STAT6 on the CD4+ T cells isolated from splenocytes of BALB/c mice, and piperine suppressed IL-4-induced CCL26 mRNA expression and STAT6 phosphorylation in human keratinocytes resulting in the inhibition of infiltration of CCR3+ cells into inflammatory lesions. These results demonstrate that piperine could ameliorate AD symptoms through suppression of Th2-mediated immune responses, including the STAT6/GATA3/IL-4 signaling pathway. Therefore, we suggest that piperine is an excellent candidate as an inhibitor of STAT6 and may help to improve AD symptoms.

Increased risk of malignancy in patients aged over 50 with idiopathic inflammatory myositis compared to patients with osteoarthritis of the knee.

Objectives: To estimate risk of malignancy in patients with idiopathic inflammatory myositis (IIM) compared to patients with knee osteoarthritis (OA).Methods: Patients with IIM and knee OA aged over 50, who had no history of malignancy, were identified using Korean National claims database from January 2012 to December 2014. They had been observed until a malignancy was diagnosed or up to the end of the study, December 2015. The incidence rate (IR) of malignancy in IIM patients was calculated and compared with knee OA patients using standardized incidence ratio (SIR).Results: A total of 634 polymyositis (PM) and 556 dermatomyositis (DM) patients were included. Overall, 100 solid (IR 270.4/10,000 person-years (PY), 95% confidence interval (CI) 217.4-323.4) and 12 hematologic malignancies (IR 32.4/10,000 PY, 95% CI 14.1-50.8) occurred. Compared with knee OA, risk of overall (SIR 1.5, 95% CI 1.2-1.8), solid (SIR 1.4, 95% CI 1.1-1.6), and hematologic malignancy (SIR 5.7, 95% CI 2.5-9.0) were increased in IIM patients. This was due to increased incidence of malignancy in DM (hematologic malignancy, SIR 8.7, 95% CI 2.7-14.7, solid malignancy, SIR 1.5, 95% CI 1.1-1.9).Conclusion: Patients with IIM, especially DM, have an increased risk of malignancy compared to patients with knee OA.

Drug holiday patterns and bisphosphonate-related osteonecrosis of the jaw.

OBJECTIVES: There is limited evidence regarding the appropriate length of a bisphosphonate (BP) holiday to reduce the risk of osteonecrosis of the jaw (ONJ). In this cross-sectional study, we investigated the population-based patterns of the gaps between BP discontinuation and ONJ diagnosis. SUBJECTS AND METHODS: We used the claims database of the National Health Insurance Service in Korea. Among BP users between 2006 and 2015, incident ONJ cases during 2010-2015 with no history of ONJ in the last 4 years were identified. We assessed the time gap from the last BP administration to ONJ diagnosis. RESULTS: Among 1,569 incident ONJ cases, 836 (53.3%) occurred after BP discontinuation. The cumulative proportions of ONJ occurrence within 1 month, 3 months, 1 year, 2 years, and 3 years after discontinuation were 58.9%, 70.8%, 87.0%, 93.2%, and 96.1%, respectively. The length of drug holidays showed no significant difference between patients with or without comorbid cancer and diabetes mellitus (p-value, 0.12 and 0.52, respectively). However, the use of injectable BP formulations significantly affected ONJ incidence (p < 0.01). CONCLUSIONS: Most ONJ cases occurred within 3 years from BP suspension, with a higher prevalence among BP injection users with 1 year or lesser BP holiday.