Drug survival and change of disease activity using a second janus kinase inhibitor in patients with difficult-to-treat rheumatoid arthritis who failed to a janus kinase inhibitor and subsequent biologics.

BACKGROUND: To assess the drug survival and change of disease activity using a second Janus kinase inhibitor (JAKi) after failure to a JAKi and subsequent biologic disease-modifying anti-rheumatic drugs (bDMARDs) in patients with difficult-to-treat rheumatoid arthritis (RA). METHODS: This retrospective cohort study included 32 patients with difficult-to-treat RA who failed to a JAKi and subsequently to one or more bDMARDs and then switched to a second JAKi. To assess drug survival, electronic medical records of each patient were reviewed. Data on whether the second JAKi was discontinued, and the reasons for discontinuation were collected. The change of disease activity was assessed by analyzing changes in tender joint count (TJC), swollen joint count (SJC), patient's global assessment of disease activity on a visual-analogue scale (VAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Disease Activity Score for 28 joints with ESR (DAS28-ESR), and DAS28-CRP from baseline to that at six months from initiation of the second JAKi. RESULTS: Overall, discontinuation of the second JAKi occurred in 20 (62.5%) patients. Primary failure, secondary failure, adverse events, and insurance coverage issues were the reasons for discontinuation in 9 (45.0%), 5 (25.0%), 2 (10.0%), and 4 (20.0%) patients, respectively. The estimated 2-year drug survival rate was 39.3%. In terms of change of disease activity, the second JAKi significantly improved TJC (p < 0.001), SJC (p < 0.001), VAS (p < 0.001), CRP (p = 0.026), DAS28-ESR (p < 0.001), and DAS28-CRP (p < 0.001) at 6-month compared with that at the baseline. CONCLUSIONS: Second JAKi could be a therapeutic option in patients with difficult-to-treat RA who have failed to a JAKi and subsequent bDMARDs.

Comparative risk of incident and recurrent acute anterior uveitis across different biological agents in patients with ankylosing spondylitis.

OBJECTIVE: To evaluate the comparative risk of incident and recurrent acute anterior uveitis (AAU) across different biological disease-modifying anti-rheumatic drugs (bDMARDs) in patients with ankylosing spondylitis (AS). METHODS: A retrospective nationwide cohort study was conducted on 34 621 patients with AS without a previous history of AAU using a national claims database. Patients were followed-up from 2010 to 2021. The comparative risk of incident and recurrent AAU across different bDMARDs was examined using multivariable time-dependent Cox models and counting process (AG) models, respectively. RESULTS: The adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for incident AAU (bDMARDs non-exposure as reference) were: adalimumab 0.674 (0.581-0.891), etanercept 1.760 (1.540-2.012), golimumab 0.771 (0.620-0.959), infliximab 0.891 (0.741-1.071), and secukinumab 1.324 (0.794-2.209). Compared with adalimumab exposure, etanercept (aHR = 2.553 [2.114-3.083]), infliximab (aHR = 1.303 [1.039-1.634]), and secukinumab exposures (aHR = 2.173 [1.273-3.710]) showed a higher risk of incident AAU. The aHRs and 95% CIs for recurrent AAU (bDMARDs non-exposure as reference) were: adalimumab 0.798 (0.659-0.968), etanercept 1.416 (1.185-1.693), golimumab 0.874 (0.645-1.185), infliximab 0.926 (0.729-1.177), and secukinumab 1.257 (0.670-2.359). Compared with adalimumab exposure, etanercept exposure (aHR = 1.793 [1.403-2.292]) was associated with a higher risk of recurrent AAU. CONCLUSION: Our data suggest preference for bDMARDs in the following order: adalimumab/golimumab > infliximab > secukinumab > etanercept (for incident AAU prevention) and adalimumab > golimumab/infliximab/secukinumab > etanercept (for recurrent AAU prevention).

Patients with systemic lupus erythematosus who are underweight have distinct disease characteristics.

OBJECTIVE: This study aimed to detail the disease characteristics of systemic lupus erythematosus (SLE) in individuals who are underweight and assess whether underweight status is associated with SLE disease activity. METHODS: This was a retrospective cohort study involving 218 patients newly diagnosed with SLE. Patients were categorized as underweight (body mass index [BMI] <18.5 kg/m2) or not underweight (BMI ≥18.5 kg/m2). We reviewed disease characteristics including the SLE Disease Activity Index 2000 (SLEDAI-2K) at diagnosis. High disease activity was defined as SLEDAI-2K ≥10. Disease characteristics were compared between those who were underweight and not underweight. We used multivariable logistic regression analysis to determine whether underweight status is associated with high disease activity. RESULTS: Out of the 218 patients, 35 (16.1%) were underweight and 183 (83.9%) were not. Underweight patients had less renal involvement (5.7% vs 20.2%, p = .040), lower C-reactive protein levels (1.0 [0.3-2.3] mg/L vs 1.2 [0.8-5.0] mg/L, p = .028), and lower SLEDAI-2K scores (6.7 ± 4.6 vs 9.1 ± 5.7, p = .009), and were less likely to be at high disease activity status (22.9% vs 42.6%, p = .028), compared with those who were not underweight. Following adjustment for multiple covariates, being underweight was inversely associated with high disease activity status (adjusted odds ratio = 0.38, 95% confidence interval = 0.16 to 0.92, p = .031). CONCLUSION: Patients with SLE who were underweight showed less renal involvement and lower SLEDAI-2K scores compared with those who were not underweight. Moreover, those with SLE who were underweight had a 60% lower risk of exhibiting high disease activity.

Drug survival and change of disease activity using a second janus kinase inhibitor in patients with difficult-to-treat rheumatoid arthritis who failed to a janus kinase inhibitor and subsequent biologics

Abstract Background To assess the drug survival and change of disease activity using a second Janus kinase inhibitor (JAKi) after failure to a JAKi and subsequent biologic disease-modifying anti-rheumatic drugs (bDMARDs) in patients with difficult-to-treat rheumatoid arthritis (RA). Methods This retrospective cohort study included 32 patients with difficult-to-treat RA who failed to a JAKi and subsequently to one or more bDMARDs and then switched to a second JAKi. To assess drug survival, electronic medical records of each patient were reviewed. Data on whether the second JAKi was discontinued, and the reasons for discontinuation were collected. The change of disease activity was assessed by analyzing changes in tender joint count (TJC), swollen joint count (SJC), patient's global assessment of disease activity on a visual-analogue scale (VAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Disease Activity Score for 28 joints with ESR (DAS28-ESR), and DAS28-CRP from baseline to that at six months from initiation of the second JAKi. Results Overall, discontinuation of the second JAKi occurred in 20 (62.5%) patients. Primary failure, secondary failure, adverse events, and insurance coverage issues were the reasons for discontinuation in 9 (45.0%), 5 (25.0%), 2 (10.0%), and 4 (20.0%) patients, respectively. The estimated 2-year drug survival rate was 39.3%. In terms of change of disease activity, the second JAKi significantly improved TJC (p < 0.001), SJC (p < 0.001), VAS (p < 0.001), CRP (p = 0.026), DAS28-ESR (p < 0.001), and DAS28-CRP (p < 0.001) at 6-month compared with that at the baseline. Conclusions Second JAKi could be a therapeutic option in patients with difficult-to-treat RA who have failed to a JAKi and subsequent bDMARDs.

Higher gamma-glutamyl transferase levels are associated with an increased risk of incident systemic sclerosis: a nationwide population-based study.

Gamma-glutamyl transferase (GGT) is known to promote oxidative stress. As oxidative stress is a key component in the pathogenesis of systemic sclerosis (SSc), we investigated whether GGT levels are associated with the risk of incident SSc. A cohort of individuals without SSc who underwent national health examination in 2009 were extracted from the Korean National Health Insurance Service database. The incidence rate of SSc during the observation period, between 2009 and 2019, was estimated. GGT levels measured in 2009 were categorized into quartiles (Q1 [lowest], Q2, Q3, and Q4 [highest]). Multivariable Cox proportional hazard models were used to estimate the risk of incident SSc according to the quartiles of GGT, using Q1 as the reference. A total of 6,091,788 individuals were included. Incidence rate of SSc was 1.16 per 100,000 person-years over a mean observation period of 9.2 years. After adjusting for age, sex, body mass index, economic income, smoking status, alcohol consumption, physical activity, hypertension, type 2 diabetes, dyslipidemia, and chronic kidney disease, higher quartiles of GGT levels were significantly associated with a higher risk of incident SSc (Q4: adjusted hazard ratio [aHR] 1.807, 95% confidence interval CI 1.446-2.259; Q3: aHR 1.221, 95% CI 0.971-1.536; and Q2: aHR 1.034, 95% CI 0.807-1.324; p for trend < 0.001). Higher GGT levels were associated with a higher risk of incident SSc. These findings could lead to a closer monitoring for high risk individuals and an earlier diagnosis and treatment.

Association Between Lipid Profile and Risk of Incident Systemic Sclerosis: A Nationwide Population-Based Study.

Background and Aims: Lipid metabolism is altered in systemic sclerosis (SSc), mediating activation of immune cells and fibroblasts. However, it is unclear whether altered lipid profile is associated with a risk of developing SSc. We aimed to assess the association between lipid profile and risk of incident SSc. Methods: From a Korean nationwide database, individuals without SSc who underwent national health check-ups in 2009 were selected and followed-up through 2019. Serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride were measured on the health check-up date in 2009. Individuals who developed SSc during follow-up were identified. Multivariable Cox models were performed to estimate the risk of incident SSc according to TC, HDL-C, LDL-C, and triglyceride levels, respectively. Results: Of the 9,894,996 individuals selected, 1355 individuals developed SSc during a mean follow-up of 9.2 years (incidence rate=1.49 per 100,000 person-years). Levels of TC (adjusted hazard ratio [aHR] 0.959, 95% confidence interval [CI] 0.945-0.974), HDL-C (aHR 0.968, 95% CI 0.950-0.987), LDL-C (aHR 0.968, 95% CI 0.952-0.983) were inversely associated with the risk of incident SSc, whereas no significant association was observed between levels of triglyceride (aHR 1.004, 95% CI 0.998-1.011) and risk of incident SSc. Conclusion: Serum levels of TC, HDL-C, and LDL-C were inversely associated with the risk of incident SSc. Our findings provide new insights that altered lipid profile could be considered a non-causal biomarker associated with incident SSc, which could help early diagnosis. The underlying mechanism for this association needs further studies.

Risk of atrial fibrillation in patients with systemic sclerosis: a nationwide population-based study.

OBJECTIVE: Atrial fibrillation (AF) is the most common arrhythmia in the general population causing substantial economic burden, morbidity, and mortality. The incidence rate and risk of AF in patients with systemic sclerosis (SSc) are unclear. We aimed to assess the incidence rate of AF in patients with SSc, and the risk of incident AF in patients with SSc compared with the general population. METHODS: The Korean National Health Insurance Service database was used as the data source. Patients with claims data for SSc between 2010 and 2017 were extracted from the database along with 1:5 age- and sex-matched controls. The index date was the earliest date with claims data for SSc between 2010 and 2017. The follow-up duration was from the index date to 2019. Multivariable Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for AF in patients with SSc. RESULTS: Overall, 2,519 patients with SSc and 12,595 age- and sex-matched controls were included. Over a mean follow-up duration of 5.2±2.6 years, the incidence rates of AF were 3.52 and 1.68 per 1,000 person-years for patients with SSc and controls, respectively. Compared with controls, patients with SSc had a significantly higher risk of incident AF (adjusted HR = 2.095, 95% CI = 1.466-2.994). CONCLUSION: Patients with SSc had a two-fold higher risk of incident AF than controls. Given the significant economic burden, morbidity, and mortality that AF poses, close monitoring for incident AF in patients with SSc is warranted.

Systemic sclerosis is a risk factor of incident psoriasis: results from a nationwide cohort study.

Objective: Although the co-existence of systemic sclerosis (SSc) and psoriasis (PsO) has been reported, the risk relationship between the two diseases remains unclear. We aimed to assess whether SSc is associated with the risk of incident PsO. Methods: From the Korean National Health Insurance Service database, 4,933 patients with SSc and 24,665 age- and sex-matched controls were selected. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident PsO were estimated using multivariable Cox proportional hazard models adjusted for known risk factors of PsO. Further, we selected individuals whose health check-up data were available (2,355 patients with SSc and 11,775 age- and sex-matched controls). In this population, we further adjusted for additional risk factors of PsO using the health check-up data. Results: In the analysis of 4,933 patients with SSc and 24,665 age- and sex-matched controls, incidence rates of PsO in patients with SSc and controls were 10.26 and 3.20 per 1,000 person-years, respectively. After adjusting for risk factors of PsO, patients with SSc had a significantly higher risk of incident PsO (adjusted HR: 3.055 [95% CI: 2.597, 3.594]). Moreover, in the analysis of individuals who had health check-up data, additional risk factors of PsO were further adjusted; the result also showed that patients with SSc have a significantly higher risk of incident PsO (adjusted HR: 2.820 [95% CI: 2.207, 3.603]). Conclusion: Patients with SSc had a 3-fold higher risk of developing incident PsO than controls, independent of known risk factors of PsO.

Risk of kidney failure in patients with systemic sclerosis: a nationwide population-based study.

OBJECTIVE: Data from a decade ago have shown that patients with systemic sclerosis (SSc) have a higher risk of kidney failure than the general population. However, as the incidence of kidney failure due to SSc has been declining, the comparative risk of kidney failure between patients with SSc and the general population could have changed over time. We investigated the risk of kidney failure in patients with SSc compared with the general population, up to more recent years. METHODS: This was a nationwide population-based study using the Korean National Health Insurance Service database. Patients with claims data for SSc between 2010 and 2017 (n=2591) and 1:5 age-matched and sex-matched controls (n=12 955) were selected. The index date was the earliest date of claim for SSc between 2010 and 2017. The follow-up duration was from the index date to 2019. The adjusted HRs (aHRs) and 95% CI for kidney failure were estimated using multivariable Cox proportional hazard models. RESULTS: Over 5.2±2.6 years, the incidence rates of kidney failure in patients with SSc and controls were 2.88 and 0.35 per 1000 person-years, respectively. Patients with SSc had a significantly higher risk of kidney failure than controls (aHR=7.244, 95% CI=4.256 to 12.329). The effect size was larger in patients diagnosed with SSc between 2014 and 2017 (aHR=9.754, 95% CI=3.254 to 29.235) than in those diagnosed before 2010 (aHR=6.568, 95% CI=2.711 to 15.571) or between 2010 and 2013 (aHR=6.553, 95% CI=2.721 to 15.781). CONCLUSION: The risk of kidney failure remains higher in patients with SSc than in the general population.

Drug Retention Rate and Factors Associated with Discontinuation of Interleukin-17 Inhibitors in Patients with Axial Spondyloarthritis.

PURPOSE: To assess the drug retention rate of interleukin-17 inhibitors (IL-17is) over long-term observation in patients with axial spondyloarthritis (axSpA) in whom treatment with tumor necrosis factor inhibitors (TNFis) failed and to determine baseline factors associated with discontinuation of IL-17is. MATERIALS AND METHODS: This retrospective cohort study included 68 patients with axSpA started on IL-17is after an inadequate response or intolerance to ≥1 TNFis. Drug retention rates at 1, 2, and 3 years were assessed. Baseline (i.e., at initiation of IL-17is) factors associated with discontinuation of IL-17is were evaluated using multivariable Cox proportional hazard regression analysis. RESULTS: Over 1933.9 person-months of observation in 68 patients, discontinuation of IL-17is occurred in 27 (39.7%) patients. Twenty (29.4%) patients discontinued IL-17is because of ineffectiveness, and 7 (10.3%) patients discontinued IL-17is because of adverse events. The 1-year, 2-year, and 3-year drug retention rates for IL-17is were 71.9%, 66.5%, and 62.0%, respectively. Current smoking was associated with a higher risk of IL-17is discontinuation [adjusted hazard ratio (HR)=2.256, 95% confidence interval (CI)=1.053-4.831, p=0.036], while previous use of ≥3 TNFis (vs. 1) was significantly associated with a lower risk of IL-17is discontinuation (adjusted HR=0.223, 95% CI=0.051-0.969, p=0.045). CONCLUSION: In patients with axSpA in whom TNFis failed, the long-term drug retention rate of IL-17is appears to be acceptable, with a 3-year drug retention rate of approximately 60%. Current smoking was associated with a higher risk of discontinuing IL-17is, whereas previous use of ≥3 TNFis was associated with a lower risk of discontinuing IL-17is.

Risk of all-cause and cause-specific mortality associated with immune-mediated inflammatory diseases in Korea.

Objective: Immune-mediated inflammatory disease (IMID) is associated with an increased risk of mortality. It is unclear whether the higher mortality is attributable to the IMIDs themselves or to the higher prevalence of comorbidities in IMIDs. We aimed to investigate whether IMIDs per se confer a higher risk of mortality. Methods: From the Korean National Health Insurance Service-National Sample Cohort database, this population-based cohort study included 25,736 patients newly diagnosed with IMIDs between January 2007 and December 2017, and 128,680 individuals without IMIDs who were matched for age, sex, income, hypertension, type 2 diabetes, dyslipidemia, and the Charlson comorbidity index. All individuals were retrospectively observed through December 31, 2019. The outcomes included all-cause and cause-specific mortalities. Adjustments for age, sex, and comorbidities were performed using multivariable Cox proportional hazard regression analyses, and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the outcomes were estimated. Results: The adjusted risk of all-cause mortality was significantly lower in patients with IMIDs than that in those without (aHR, 0.890; 95% CI, 0.841-0.942). Regarding cause-specific mortality, cancer-specific (aHR, 0.788; 95% CI, 0.712-0.872) and cardiovascular disease-specific (aHR, 0.798; 95% CI, 0.701-0.908) mortalities were the two causes of death that showed significantly lower risks in patients with IMIDs. A similar trend was observed when organ based IMIDs were analyzed separately (i.e., gut, joint, and skin IMIDs). Conclusion: After adjusting for comorbidities, IMIDs were associated with a lower risk of all-cause mortality compared to those without IMIDs. This was attributable to the lower risks of cancer-and cardiovascular disease-specific mortalities.

Disease course of non-radiographic axial spondyloarthritis: Data from a long-term retrospective observational cohort.

BACKGROUND: Disease course of non-radiographic axial spondyloarthritis (axSpA) has been extensively studied in non-Asian population; however, there are limited data in Asian population. This study aimed to evaluate the long-term disease course of non-radiographic axSpA in Asian patients and identify factors associated with progression to radiographic axSpA. METHODS: In this retrospective observational cohort study, 56 Korean patients newly diagnosed with non-radiographic axSpA between 2006 and 2015 were included. All patients fulfilled the Assessment of SpondyloArthritis international Society classification criteria for axSpA, and did not fulfil the radiological criterion of the 1984 modified New York criteria. Disease course was assessed by the rate of progression to radiographic axSpA. Factors associated with the risk of progression to radiographic axSpA were assessed using multivariable Cox proportional hazard regression analysis. RESULTS: The mean age at baseline was 31.4±13.3 years, and 37 (66.1%) patients were men. Over a mean observation period of 8.4±3.7 years, 28 (50.0%) patients progressed to radiographic axSpA. In multivariable Cox proportional hazard regression analysis, the presence of syndesmophytes at diagnosis (adjusted hazard ratio [HR]: 4.50, 95% confidence interval [CI]: 1.54-13.15, p = 0.006) and active sacroiliitis on magnetic resonance imaging (MRI) at diagnosis (adjusted HR: 5.88, 95% CI: 2.05-16.82, p = 0.001) were significantly associated with a higher risk of progression to radiographic axSpA, whereas longer exposure to tumor necrosis factor inhibitors (TNFis) was significantly associated with a lower risk of progression to radiographic axSpA (adjusted HR: 0.89, 95% CI: 0.80-0.98, p = 0.022). CONCLUSION: During long-term follow-up, a substantial proportion of Asian patients with non-radiographic axSpA progressed to radiographic axSpA. The presence of syndesmophytes and active sacroiliitis on MRI at the time of non-radiographic axSpA diagnosis were associated with a higher risk of progression to radiographic axSpA, while longer exposure to TNFis was associated with a lower risk of progression to radiographic axSpA.

Association of immune-mediated inflammatory diseases with depression and anxiety in patients with type 2 diabetes: A nationwide population-based study.

Objective: Patients with type 2 diabetes (T2DM) are at a high risk of developing depression and anxiety. To better stratify the risk, we aimed to assess whether the presence of immune-mediated inflammatory diseases (IMIDs) confers a higher risk of depression and anxiety in these patients. Methods: Patients with T2DM without prior depression or anxiety who underwent national health examination between 2009 and 2012 (n = 1,612,705) were enrolled from the nationwide health check-up data from Korean National Health Insurance Service. The outcome events were incident depression and anxiety, defined as International Classification of Diseases, 10th Revision codes F32-F33 and F40-F41, respectively. Multivariable Cox proportional hazard regression analyses were conducted to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) according to the existence of IMIDs. Results: Over an average follow-up time of 6.4 years, existence of gut IMIDs was associated with a higher risk of depression (aHR: 1.28 [95% CI: 1.08-1.53]) and anxiety (1.22 [1.06-1.42]). Existence of joint IMIDs was associated with a higher risk of depression (1.34 [1.31-1.37]) and anxiety (1.31 [1.29-1.34]). Existence of skin IMID was associated with a higher risk of depression (1.18 [1.14-1.23]) and anxiety (1.13 [1.09-1.16]). The effect sizes of IMIDs on depression and anxiety were larger in those with ≥ 2 IMIDs (1.42 [1.19-1.69] and 1.49 [1.29-1.72], respectively) than in those with one IMID (1.30 [1.27-1.32] and 1.26 [1.24-1.28], respectively). Conclusion: In patients with T2DM, presence of IMIDs was associated with a higher risk of depression and anxiety. More stringent attention and screening for anxiety and depression should be encouraged in patients with T2DM and comorbid IMIDs due to clinical implications of psychological distress on patient-reported outcomes and prognosis.

Interleukin-32 as a biomarker in rheumatic diseases: A narrative review.

Interleukin-32 (IL-32) is an important cytokine involved in the innate and adaptive immune responses. The role of IL-32 has been studied in the context of various diseases. A growing body of research has investigated the role of IL-32 in rheumatic diseases including inflammatory arthritides (rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis) and connective tissue diseases (systemic lupus erythematosus, systemic sclerosis, granulomatosis and polyangiitis, and giant cell arteritis). IL-32 has been shown to play different roles according to the type of rheumatic diseases. Hence, the putative role of IL-32 as a biomarker is also different in each rheumatic disease: IL-32 could serve as a biomarker for disease activity in some diseases, whereas in other diseases it could be a biomarker for certain disease manifestations. In this narrative review, we summarize the associations between IL-32 and various rheumatic diseases and discuss the putative role of IL-32 as a biomarker in each disease.

Risk of systemic lupus erythematosus flares according to autoantibody positivity at the time of diagnosis.

To estimate the risk of systemic lupus erythematosus (SLE) flares based on the autoantibody positivity at the time of SLE diagnosis. This retrospective cohort study included 228 patients with newly diagnosed SLE. Clinical characteristics including autoantibody positivity at the time of diagnosis of SLE were reviewed. Flares were defined as a new British Isles Lupus Assessment Group (BILAG) A score or BILAG B score for at least one organ system. Multivariable Cox regression analyses were performed to estimate the risk of flares according to autoantibody positivity. Anti-dsDNA, anti-Sm, anti-U1RNP, anti-Ro, and anti-La antibodies (Abs) were positive in 50.0%, 30.7%, 42.5%, 54.8%, and 22.4% of the patients, respectively. The incidence rate of flares was 28.2/100 person-years. Multivariable Cox regression analysis, adjusted for potential confounders, revealed that anti-dsDNA Ab positivity (adjusted hazard ratio [HR]: 1.46, p = 0.037) and anti-Sm Ab positivity (adjusted HR: 1.81, p = 0.004) at the time of diagnosis of SLE were associated with higher risk of flares. To better delineate the flare risk, patients were categorized as double-negative, single-positive, double-positive for anti-dsDNA and anti-Sm Abs. Compared with double-negativity, double-positivity (adjusted HR: 3.34, p < 0.001) was associated with higher risk of flares, while anti-dsDNA Ab single-positivity (adjusted HR: 1.11, p = 0.620) or anti-Sm Ab single-positivity (adjusted HR: 1.32, p = 0.270) was not associated with higher risk of flares. Patients who are double-positive for anti-dsDNA and anti-Sm Abs at the time of the diagnosis of SLE are at higher risk of flares and may benefit from stringent monitoring and early preventive treatment.

Correlation between serologic parameters and disease activity of IgG4-related disease: Differences between patients with normal and elevated serum IgG4 concentrations.

Objective: We aimed to identify serologic parameters that correlate with the disease activity of IgG4-related disease (IgG4-RD) in patients with normal and elevated serum IgG4 concentrations, respectively. Methods: This retrospective cohort study included 148 patients with IgG4-RD. Patients were categorized into normal (≤201 mg/dL) and elevated (>201 mg/dL) serum IgG4 concentration groups. Disease activity was assessed using the IgG4-RD responder index (RI). The correlations between IgG4-RD RI and serologic parameters (erythrocyte sedimentation rate [ESR], C-reactive protein, C3, C4, IgG4 concentration, IgG concentration, and IgG4/IgG ratio) were evaluated in each group, using Spearman's correlation coefficient. Results: Of the 148 patients with IgG4-RD, 38 (25.7%) and 110 (74.3%) patients were categorized into the normal and elevated serum IgG4 concentration groups, respectively. In the normal serum IgG4 concentration group, IgG concentration was the only serologic parameter that showed a significant correlation with IgG4-RD RI (rho=0.411, p=0.013). However, in the elevated serum IgG4 concentration group, ESR (rho=0.196, p=0.041), C3 (rho=-0.432, p<0.001), C4 (rho=-0.363, p=0.001), IgG4 concentration (rho=0.423, p<0.001), IgG concentration (rho=0.224, p=0.020), and IgG4/IgG ratio (rho=0.328, p=0.001) correlated with IgG4-RD RI. The combination of C3 and IgG4 concentration (rho=0.509, p<0.001) had the strongest correlation with IgG4-RD RI in this group. Conclusion: Among the serologic parameters tested, IgG concentration was the only parameter that correlated with IgG4-RD RI in patients with normal serum IgG4 concentrations, whereas multiple parameters correlated with IgG4-RD RI in those with elevated serum IgG4 concentrations. The combination of C3 and IgG4 concentration had the strongest correlation coefficient in the latter group.

Derivation and Validation of a New Disease Activity Assessment Tool With Higher Accuracy for Takayasu Arteritis.

Objective: To develop a new disease activity assessment tool with high accuracy for Takayasu arteritis. Methods: Individual items from National Institute of Health (NIH) criteria and the Indian Takayasu Clinical Activity Score (ITAS2010) were tested as candidate variables to develop a new disease activity assessment tool in a derivation cohort (N = 100). Physician global assessment on disease activity was used as the gold standard. Multivariable logistic regression models were constructed and the model with the highest accuracy was identified. A formula assessing disease activity was generated using simplified ß coefficients (rounded to decimal place). Diagnostic performance was evaluated through estimating the area under the curve (AUC). The new assessment tool was subsequently validated in a validation cohort (N = 46). Results: The multivariable model yielding the highest accuracy consisted of a high erythrocyte sedimentation rate (ESR), NIH criteria 1 and 4, and carotidynia. Using simplified ß coefficients, the following disease activity assessment tool was developed: high ESR (3 points), NIH criterion 1 (2 points), NIH criterion 4 (4 points), and carotidynia (3 points) (total score ≥5, active; total score <5, inactive). The new disease activity assessment tool had a higher AUC (89.37) for discriminating active and inactive diseases than NIH criteria (AUC 77.96), ITAS2010 (AUC 66.12), ITAS-ESR (AUC 75.58), and ITAS-C-reactive protein (AUC 71.34). The AUC (85.23) of the new assessment tool was similar in the validation cohort. Conclusion: A new disease activity assessment tool that consists of high ESR, NIH criteria 1 and 4, and carotidynia had higher accuracy in discriminating active and inactive disease than currently used clinical assessment tools.

Effects of immune-mediated inflammatory diseases on cardiovascular diseases in patients with type 2 diabetes: a nationwide population-based study.

Both type 2 diabetes and immune-mediated inflammatory diseases (IMIDs), such as Crohn's disease (CD), ulcerative colitis, rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis (PsO) are risk factors of cardiovascular disease. Whether presence of IMIDs in patients with type 2 diabetes increases their cardiovascular risk remains unclear. We aimed to investigate the risk of cardiovascular morbidity and mortality in patients with type 2 diabetes and IMIDs. Patients with type 2 diabetes without cardiovascular disease were retrospectively enrolled from nationwide data provided by the Korean National Health Insurance Service. The primary outcome was cardiovascular mortality, and the secondary outcomes were myocardial infarction (MI), stroke, and all-cause mortality. Inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazard regression analysis was performed to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for each IMID. Overall 2,263,853 patients with type 2 diabetes were analyzed. CD was associated with a significantly higher risk of stroke (IPTW-adjusted HR: 1.877 [95%CI 1.046, 3.367]). UC was associated with a significantly higher risk of MI (1.462 [1.051, 2.032]). RA was associated with a significantly higher risk of cardiovascular mortality (2.156 [1.769, 2.627]), MI (1.958 [1.683, 2.278]), stroke (1.605 [1.396, 1.845]), and all-cause mortality (2.013 [1.849, 2.192]). AS was associated with a significantly higher risk of MI (1.624 [1.164, 2.266]), stroke (2.266 [1.782, 2.882]), and all-cause mortality (1.344 [1.089, 1.658]). PsO was associated with a significantly higher risk of MI (1.146 [1.055, 1.246]), stroke (1.123 [1.046, 1.205]) and all-cause mortality (1.115 [1.062, 1.171]). In patients with type 2 diabetes, concomitant IMIDs increase the risk of cardiovascular morbidity and mortality. Vigilant surveillance for cardiovascular disease is needed in patients with type 2 diabetes and IMIDs.

Therapeutic functions of astrocytes to treat α-synuclein pathology in Parkinson's disease.

Intraneuronal inclusions of misfolded α-synuclein (α-syn) and prion-like spread of the pathologic α-syn contribute to progressive neuronal death in Parkinson's disease (PD). Despite the pathologic significance, no efficient therapeutic intervention targeting α-synucleinopathy has been developed. In this study, we provide evidence that astrocytes, especially those cultured from the ventral midbrain (VM), show therapeutic potential to alleviate α-syn pathology in multiple in vitro and in vivo α-synucleinopathic models. Regulation of neuronal α-syn proteostasis underlies the therapeutic function of astrocytes. Specifically, VM-derived astrocytes inhibited neuronal α-syn aggregation and transmission in a paracrine manner by correcting not only intraneuronal oxidative and mitochondrial stresses but also extracellular inflammatory environments, in which α-syn proteins are prone to pathologic misfolding. The astrocyte-derived paracrine factors also promoted disassembly of extracellular α-syn aggregates. In addition to the aggregated form of α-syn, VM astrocytes reduced total α-syn protein loads both by actively scavenging extracellular α-syn fibrils and by a paracrine stimulation of neuronal autophagic clearance of α-syn. Transplantation of VM astrocytes into the midbrain of PD model mice alleviated α-syn pathology and protected the midbrain dopamine neurons from neurodegeneration. We further showed that cografting of VM astrocytes could be exploited in stem cell-based therapy for PD, in which host-to-graft transmission of α-syn pathology remains a critical concern for long-term cell therapeutic effects.

Effect of tumor necrosis factor inhibitors on risk of cardiovascular disease in patients with axial spondyloarthritis.

BACKGROUND: Axial spondyloarthritis (axSpA) is associated with an increased risk of cardiovascular disease. We aimed to evaluate the effect of tumor necrosis factor inhibitors (TNFis) on the risk of cardiovascular disease in patients with axSpA. METHODS: This retrospective study included 450 patients with axSpA without pre-existing cardiovascular disease. The outcome was incident cardiovascular disease (myocardial infarction or stroke) after the diagnosis of axSpA. The effect of TNFis on cardiovascular risk was analyzed in the total study population and in an inverse probability of treatment weighting (IPTW)-adjusted population. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for cardiovascular disease, according to exposure to TNFis. RESULTS: Of the 450 patients, 233 (51.8%) and 217 (48.2%) patients were and were not exposed to TNFis, respectively. Twenty cardiovascular diseases occurred during 2868 person-years of follow-up (incidence rate: 6.97/1000 person-years). In the total study population, exposure to TNFis was associated with a reduced cardiovascular risk when adjusted for traditional cardiovascular risk factors (HR 0.30, 95% CI 0.10-0.85, p = 0.024). However, when time-averaged erythrocyte sedimentation rate and C-reactive protein were additionally adjusted, this association was attenuated and lost statistical significance (HR 0.37, 95% CI 0.12-1.12, p = 0.077). Furthermore, in the IPTW-adjusted population, exposure to TNFis showed no significant reduction in cardiovascular risk (HR 0.60, 95% CI 0.23-1.54, p = 0.287). CONCLUSIONS: Although controlling inflammation through TNFis could be beneficial in cardiovascular risk reduction, our data indicate no TNFi-specific reduction in cardiovascular risk in patients with axSpA.