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Objectives: To determine the risk factors for mortality in Korean patients with rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) in comparison to patients with RA but without ILD (RA-nonILD). Methods: Data were extracted from a single-centre prospective cohort of RA patients with a chest computed tomography scan at an academic referral hospital in Korea. Patients with RA-ILD enroled between May 2017 and August 2022 were selected, and those without ILD were selected as comparators. The mortality rate was calculated, and the causes of each death were investigated. We used Cox proportional hazard regression with Firth’s penalised likelihood method to identify the risk factors for mortality in patients with RA-ILD. Results: A total of 615 RA patients were included: 200 with ILD and 415 without ILD. In the RA-ILD group, there were 15 deaths over 540.1 person-years (PYs), resulting in mortality rate of 2.78/100 PYs. No deaths were reported in the RA-nonILD group during the 1669.9 PYs. The primary causes of death were infection (nine cases) and lung cancer (five cases), with only one death attributed to ILD aggravation. High RA activity (adjusted HR 1.87, CI 1.16–3.10), baseline diffusing capacity for carbon monoxide (DLCO) < 60% (adjusted HR 4.88, 95% CI 1.11–45.94), and usual interstitial pneumonia (UIP) pattern (adjusted HR 5.13, 95% CI 1.00–57.36) were identified as risk factors for mortality in RA-ILD patients. Conclusion: Patients with RA-ILD have an elevated risk of mortality compared with those without ILD. Infection-related deaths are the main causes of mortality in this population. High RA activity, low DLCO, and the UIP pattern are significantly associated with the mortality in patients with RA-ILD.

Objective: To compare the effectiveness of azathioprine (AZA) and cyclosporine (CsA) as initial treatments for patients with idiopathic inflammatory myopathies (IIM). Methods: A retrospective cohort study was conducted using information from the National Health Insurance Service database of Republic of Korea. Patients with IIM who had started AZA or CsA as initial treatment between January 2007 and December 2011 were selected for the study. They were followed from the day of treatment initiation to the occurrence of study outcomes or the end of the study until December 2016. Effectiveness outcomes, defined as switching the drug or adding immunosuppressants, and discontinuation of corticosteroids, were compared between the two groups. The Cox proportional-hazards model was used to calculate the adjusted relative risk (aRR) with 95% confidence interval (CI) between the AZA and CsA groups. Results: A total of 376 patients with incident IIM who used AZA (n= 288) or CsA (n= 88) were identified. The aRR of switching the drug or adding immunosuppressants (1.45 [95% CI 0.99–2.11]) was not significantly different between the CsA and AZA groups. Among patients who were treated with corticosteroids at baseline, the rate of discontinuation of corticosteroids was not different between the two groups (1.69 [95% CI 0.82–3.47]). Conclusions: The effectiveness of AZA and CsA as initial treatments for the management of IIM was comparable.

Since January 2013, a nationwide drug utilization review (DUR) system for therapeutic duplication (TD) of nonsteroidal antiinflammatory drugs (NSAIDs) has been implemented in Korea. Our objective was to perform an interrupted time series study to assess changes in the pattern of NSAIDs use in knee osteoarthritis patients after implementation of the regulations. We compared the prescribing patterns in 2012 and 2013 by means of an interrupted time series study, using the Health Insurance Review and Assessment Service database. TD was defined as use of concurrent NSAIDs either on the same or on different prescriptions for >3 days in a patient. Level change and trend change (with 95% confidence intervals [95% CIs]), and absolute and relative changes in the proportion of TDs, were estimated using segmented regression models. Multivariable logistic regression models were used to explore patient and provider characteristics associated with the TDs. Approximately 2.5 million patients were prescribed NSAIDs in both 2012 and 2013. The proportion of TDs before and after introduction of the DUR system was 7.4% and 5.6%, respectively. Overall, an absolute reduction of 89% and a relative reduction of 30% in TDs were observed. In the postregulation period, older patients, medical aid subscribers (odds ratio [OR] 1.87 [95% CI 1.84, 1.90]), and veterans (OR 3.28 [95% CI 3.10, 3.46]) were most likely to receive NSAID TDs. The prescription of NSAID TDs decreased with the introduction of the nationwide DUR system. Continuous adherence to the DUR regulations and safety monitoring are needed, especially with the elderly, medical aid subscribers, and veterans.

Structural variations such as copy number variations (CNVs) have a functional impact on various human traits. This study profiled genome-wide CNVs in Korean patients with rheumatoid arthritis (RA) to investigate the efficacy of treatment with TNF-α blockers. A total of 357 Korean patients with RA were examined for the efficacy of TNF-α blocker treatment. Disease activity indexes were measured at baseline and 6 months after the treatment. The patients were classified as responders and non-responders based on the change in disease activity indexes according to the EULAR response criteria. CNVs in the same patients were profiled using fluorescence signal intensity data generated by a genome-wide SNP array. The association of CNVs with response to TNF-α blockers was analyzed by multivariate logistic regression accounting for genetic background and clinical factors including body mass index, gender, baseline disease activity, TNF-α blocker used, and methotrexate treatment. The study subjects varied in their responses to TNF-α blockers and had 286 common CNVs in autosomes. We identified that the 3.8-kb deletion at 2q14.3 in 5% of the subjects was associated with response to TNF-α blockers (1.37 × 10− 5≤ P≤ 4.07 × 10− 4) at a false discovery rate threshold of 5%. The deletion in the identified CNV was significantly more frequent in the non-responders than in the responders, indicating worse response to TNF-α blockers in the deletion carriers. The 3.8-kb deletion at 2q14.3 is located in an intergenic region with the binding sites of two transcription factors, MAFF and MAFK. This study obtained the CNV landscape of Korean patients with RA and identified the common regional deletion associated with poor response to treatment with TNF-α blockers.

Background: To introduce a prospective cohort for rheumatoid arthritis (RA) patients with interstitial lung disease (ILD) and to identify their clinical features in comparison with RA patients without ILD. Methods: Using a multidisciplinary collaborative approach, a single-center cohort for RA patients with ILD (RA-ILD) was established in May 2017, and enrolment data from May 2017 to March 2021 were used to compare the clinical features of RA patients without ILD (RA-non ILD). Multivariable logistic regression analysis was used to identify factors associated with ILD in RA patients. Results: Among 148 RA-ILD and 410 RA-non ILD patients, participants in the RA-ILD group were older (65.8 ± 9.9 vs. 58.0 ± 10.4 years, P< 0.001) and included more males (35.8% vs. 14.6%, P< 0.001) than in the RA-non ILD group. The RA-ILD group had a higher proportion of late-onset RA patients (age ≥ 60 years) than in the comparator group (43.9% vs. 14.2%, P< 0.001). Multivariable logistic regression analysis showed that higher age at RA onset (OR 1.056, 95% CI 1.021–1.091), higher body mass index (BMI; OR 1.65, 95% CI 1.036–2.629), smoking history (OR 2.484, 95% CI 1.071–5.764), and oral glucocorticoid use (OR 3.562, 95% CI 2.160–5.874) were associated with ILD in RA patients, whereas methotrexate use was less likely to be associated with ILD (OR 0.253, 95% CI 0.155–0.412). Conclusions: Higher age at RA onset, smoking history, and higher BMI were associated with the presence of ILD among RA patients. Oral glucocorticoids were more frequently used whereas methotrexate was less likely to be used in RA-ILD patients.

Panax ginsengis a well-known immune modulator, and there is concern that its immune-enhancing effects may negatively affect patients with rheumatoid arthritis (RA) by worsening symptoms or increasing the risk of adverse effects from other drugs. In this randomized, crossover clinical trial, we evaluated the impact of Korean Red Ginseng (KRG) on disease activity and safety in RA patients.

Objective.To identify the effects of glucocorticoids (GC) on various types of fractures in patients with rheumatoid arthritis (RA).Methods.We used the Korean National Healthcare Claims database from 2010 to establish a retrospective cohort of patients with RA ≥ 19 years old. We then followed those patients through December 2013. The incidence rates of total and major fractures were calculated. We evaluated the effects of GC dose and duration on fractures using multivariable logistic regression analyses. We also examined the influence of GC on fractures in RA patients without a history of osteoporosis.Results.A total of 11,599 fractures was observed in 9964 out of 138,240 patients with RA. During followup, 68.2% of patients used oral GC for > 3 months. Adjusted analysis showed the risk of vertebral fractures was increased by the following characteristics: duration of GC ≥ 6 months (OR 1.76, p < 0.01); mean dose of GC ≥ 2.5 mg (OR range = 1.37–1.71, p < 0.01); and highest daily dose of GC ≥ 10 mg (OR range = 1.23–1.75, p < 0.03). However, neither the duration nor the dose of oral GC increased the risk of hip and nonvertebral/nonhip fractures in patients with RA. Consistent results were observed in RA patients without osteoporosis.Conclusion.Longer duration and higher dose of oral GC in patients with RA increased the risk of vertebral fractures. However, the dose and duration of GC did not influence the risk of hip and nonvertebral/nonhip fractures.

Treatment with disease-modifying anti-rheumatic drugs (DMARDs) has raised concerns about the risk of malignancies in rheumatoid arthritis (RA) patients. However, the association between biologic DMARDs (bDMARDs) and malignancy in previous reports remains controversial. Therefore we aimed to estimate the incidence of malignancy in early RA patients and to evaluate the relative risk of malignancy with use of bDMARDs. A retrospective cohort of incident RA patients was established using the Korean National Claims Database. Among a total of 14,081 RA patients identified, 1684 patients with a history of malignancy were excluded. We calculated the incidence rate of overall and individual malignancies. The standardized incidence ratio (SIR) of malignancies in bDMARD users was compared to that in nonusers. Multivariable logistic regression analysis was used to evaluate the impact of bDMARDs on the development of malignancies in early RA patients. A total of 12,397 early RA patients without a history of malignancy were enrolled. During 41,599 person-years (PY) of follow-up, 725 malignancies developed in 561 patients (174.3/10,000 PY) and 21 hematologic malignancies developed (5.0/10,000 PY). Patients treated with bDMARDs had a significantly lower incidence of overall malignancy compared to those not treated with bDMARDs (SIR 0.45 (95% CI 0.28–0.70)). However, this relationship was not significant with regard to hematologic malignancies (SIR 2.65 (95% CI 0.55–7.76)). On multivariable analysis, bDMARD use was a protective factor against the development of overall malignancy (odds ratio 0.42 (95% CI 0.25–0.73)). However, bDMARD use had no significant protective effect against the development of hematologic malignancies (odds ratio 1.69 (95% CI 0.38–7.59)). In early RA patients, bDMARD use decreases the overall risk of developing malignancies; however, it does not affect the risk of developing hematologic malignancies.

Single modal cancer therapy that targets one pathological pathway often turns out to be inefficient. For example, relapse of chronic myelogenous leukemia (CML) after inhibiting BCR-ABL fusion protein using tyrosine kinase inhibitors (TKI) (e.g., Imatinib) is of significant clinical concern. This study developed a dual modal gene therapy that simultaneously tackles two key BCR-ABL-linked pathways using viral/nonviral chimeric nanoparticles (ChNPs). Consisting of an adeno-associated virus (AAV) core and an acid-degradable polymeric shell, the ChNPs were designed to simultaneously induce pro-apoptotic BIM expression by the AAV core and silence pro-survival MCL-1 by the small interfering RNA (siRNA) encapsulated in the shell. The resulting BIM/MCL-1 ChNPs were able to efficiently suppress the proliferation of BCR-ABL+ K562 and FL5.12/p190 cells in vitroand in vivoviasimultaneously expressing BIM and silencing MCL-1. Interestingly, the synergistic antileukemic effects generated by BIM/MCL-1 ChNPs were specific to BCR-ABL+ cells and independent of a proliferative cytokine, IL-3. The AAV core of ChNPs was efficiently shielded from inactivation by anti-AAV serum and avoided the generation of anti-AAV serum, without acute toxicity. This study demonstrates the development of a synergistically efficient, specific, and safe therapy for leukemia using gene carriers that simultaneously manipulate multiple and interlinked pathological pathways.

Objective.Rheumatoid arthritis (RA) is a chronic autoimmune disease that is often painful and debilitating. Patients with RA are increasingly receiving complementary and alternative medicine (CAM). We aimed to identify the patient characteristics and disease-specific factors associated with Korean patients with RA who decide to start treatment with CAM.Methods.Among the total 5371 patients with RA in the KORean Observational study Network for Arthritis (KORONA), 2175 patients who had no experience with CAM were included in our study. In our study, we assessed the frequency of new incident CAM use, its patterns, and the predictive factors of new CAM use.Results.Of the 2175 patients, 229 patients (10.5%) newly started receiving CAM within a year of enrolling in the cohort. Of those who started treatment with CAM, 17.0% received only herbal medicine, 54.6% only acupuncture treatments (7.0% used a combination of both), and 21.4% “Other” (e.g., physical therapy and placental extract injections). Women (OR 1.89, 95% CI 1.13–3.14) and patients with depression (OR 3.52, 95% CI 1.65–7.50) were significantly more likely to be treated with CAM. Regarding household types, patients who lived in an extended family (OR 1.78, 95% CI 1.08–2.95) or as part of a couple (OR 1.55, 95% CI 1.07–2.24) were more likely to be treated with CAM than patients living in a nuclear family.Conclusion.Our study found, within a year, an incidence rate of 10.5% for new CAM use among patients with no previous experience with CAM. Sex, depression, and household type were significantly associated with new CAM use.

Background: This study aimed to evaluate the crude incidence rates and relative risk of malignancy in Korean patients with SLE. Methods: We conducted a retrospective nationwide cohort study using databases from the National Health Insurance Service in Korea. All prevalent SLE patients aged over 19 were identified from January 2012 to December 2014 and observed until the diagnosis of malignancy, death, or end of the study, December 2015. The crude incidence rates (IRs) and standardised incidence ratios (SIRs) of overall and site-specific malignancies in SLE patients were estimated. Results: We identified 17,854 SLE patients and during the observation period (60,511 person-years [PYs]), 768 solid malignancies (126.9/10,000 PYs) and 68 haematologic malignancies (11.2/10,000 PYs) occurred in SLE patients. In SLE patients, breast and reproductive system and thyroid cancers occurred predominantly, followed by liver and colon cancers. The SIRs of overall, solid, and haematologic malignancies of SLE patients compared to the general population were 1.8 (95% confidence interval [CI] 1.6–1.9), 1.7 (95% CI 1.5–1.8), and 5.9 (95% CI 4.8–7.3), respectively. In solid malignancies, head and neck (2.7, 95% CI 1.1–4.2), bladder (2.4, 95% CI 1.1–3.8), liver (1.9, 95% CI 1.4–2.3), pancreas (1.9, 95% CI 1.3–2.6), lung (1.8, 95% CI 1.2–2.4), colon (1.7, 95% CI 1.3–2.2), thyroid (1.6, 95% CI 1.3–1.8) and breast and reproductive system (1.5, 95% CI 1.2–1.7) cancers are at increased risk in SLE patients. Conclusion: An increased risk of haematologic and solid malignancies was observed in Korean patients with SLE compared to the general population.

Objective: To evaluate the effectiveness of bazedoxifene in preventing bone loss in patients with rheumatoid arthritis (RA) receiving low-dose glucocorticoids (GCs). Methods: In this randomized, controlled, open-label study, we assigned postmenopausal women with osteopenia who had been receiving low-dose GCs for RA to two groups: a group receiving bazedoxifene (20 mg/day) with elemental calcium 1200 mg and vitamin D 800 IU daily (bazedoxifene group) and a group receiving the same doses of calcium and vitamin D only (control group). As primary outcome, bone mineral density (BMD) change in the lumbar spine (L-spine) from baseline to 48 weeks was assessed. Changes in BMD in the femur, trabecular bone score, bone turnover markers, and development of fracture were assessed as secondary outcomes. For intention-to-treat analysis, 20 completed data sets were created by applying multiple imputations by chained equations. Results: A total of 114 patients (57 patients in each group) were recruited. A significant increase in L-spine BMD (0.015 g/cm2, P= 0.007) was observed in the bazedoxifene group, and the increase was significantly higher than in the control group (0.013, 95% CI 0.0003–0.026, P= 0.047). Reductions in bone turnover markers in the bazedoxifene group were significantly greater than in the control group. Only one fracture was observed in the bazedoxifene group, while four fractures developed in the control group. Conclusion: In postmenopausal patients with RA receiving low-dose GCs, bazedoxifene improved BMD and reduced bone turnover markers. However, the change in BMD did not exceed the least significant change. Trial registration: ClinicalTrials.gov, NCT02602704.

Objectives: To compare healthcare utilization and medical costs between patients with seronegative (SN) and seropositive (SP) rheumatoid arthritis (RA).Methods: We conducted a nationwide population study using the Korean health insurance claims database in 2016. We divided patients with RA into SN and SP groups and compared healthcare utilization including medications, medical utilization, and direct medical costs for 1 year between the groups in a cross-sectional analysis. Differences in costs between patients with SPRA and SNRA were assessed using the quantile regression model. We performed longitudinal analysis using data from 2012 and 2016 to examine changes over time.Results: A total of 103,815 SPRA and 75,809 SNRA patients were included in the analyses. The SPRA group used significantly more methotrexate (73.2% versus30.3%) and biologic agents (7.9% versus2.9%) than the SNRA group. The number of RA-related outpatient visits [6.0 ± 3.7 versus4.4 ± 4.0 times/year, standardized difference (SD) = 0.41] and annual medical costs per patient ($1027 versus$450/year, SD = 0.25) were higher in the SPRA group than the SNRA group. Quantile regression results indicated that the incremental cost of seropositivity on total medical costs of RA patients gradually increased as medical costs approached the upper quantile. The annual direct medical costs for each patient between 2012 and 2016 increased in both groups: by 25.1% in the SPRA group and 37.6% in the SNRA group.Conclusion: Annual RA-related direct medical costs and RA-related healthcare utilization per patient are higher in patients with SPRA than those with SNRA.

Objective: To examine factors related to the use of opioids as an early treatment option for knee OA patients Methods: Using the Korean nationwide claim database, we selected knee OA patients between 2013 and 2015. Among them, patients without any claim of knee OA for 2?years before the index date were included as our study population. We analyzed their first claim for prescriptions, including tramadol and stronger opioids, at the index date of each patient. Using a multinomial model, we identified factors associated with the early use of tramadol and stronger opioids in knee OA patients. Results: Among a total of 2,857,999 knee OA patients, 12.2% (n?=?348,516) were treated with opioids as their first treatment. However, the prevalence of stronger opioid use was only 0.07% (n?=?1972). Male sex (OR 1.28 in tramadol, OR 1.13 in stronger opioids) and comorbidities with depression (OR 1.05, 1.46), low back pain (OR 1.13, 1.30), intervertebral disc disorder (OR 1.11, 1.40), and spinal stenosis (OR 1.27, 1.55) were the factors for the early use of tramadol or stronger opioids in knee OA patients. Patients in a tertiary referral hospital tended to use tramadol or stronger opioids than those in clinics (OR 1.04, 56.63, respectively). Conclusion: In Korea, 12.2% of knee OA patients were treated with opioids as an early treatment, and tramadol was used more commonly than stronger opioids. Male sex and having comorbidities such as depression or musculoskeletal disease are patient factors associated with the early use of opioids in knee OA patients.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio=1.93, P=2.5×10−4), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.