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Abstract Background Sepsis is the leading cause of death worldwide, and a number of biomarkers have been developed for early mortality risk stratification. Red blood cell distribution width (RDW) is a routinely available hematological data and has been found to be associated with mortality in a number of diseases; therefore, we aim to address the association between RDW and mortality in critically ill patients with sepsis. Methods We analyzed data of critically ill adult patients with sepsis on the TriNetX platform, excluding those with hematologic malignancies, thalassemia, and iron deficiency anemia. Propensity score-matching (PSM) (1:1) was used to mitigate confounding effects, and hazard ratio (HR) with 95% confidence (CI) was calculated to determine the association between RDW and 30-day mortality. We further conducted sensitivity analyses through using distinct cut-points of RDW and severities of sepsis. Results A total of 256,387 critically ill septic patients were included in the analysis, and 40.0% of them had RDW equal to or higher than 16%. After PSM, we found that high RDW was associated with an increased 30-day mortality rate (HR: 1.887, 95% CI 1.847–1.928). The associations were consistent using distinct cut-points of RDW, with the strength of association using cut-points of 12%, 14%, 16%, 18% and 20% were 2.098, 2.204, 1.887, 1.809 and 1.932, respectively. Furthermore, we found consistent associations among critically ill septic patients with distinct severities, with the association among those with shock, receiving mechanical ventilation, bacteremia and requirement of hemodialysis being 1.731, 1.735, 2.380 and 1.979, respectively. Conclusion We found that RDW was associated with 30-day mortality in critically ill septic patients, underscoring the potential as a prognostic marker in sepsis. More studies are needed to explore the underlying mechanisms.

Abstract Ferritin, comprising heavy (FTH1) and light (FTL) chains, is the main iron storage protein, and pancreatic cancer patients exhibit elevated serum ferritin levels. Specifically, higher ferritin levels are correlated with poorer pancreatic ductal adenocarcinoma (PDAC) prognosis; however, the underlying mechanism and metabolic programming of ferritin involved in KRAS-mutant PDAC progression remain unclear. Here, we observed a direct correlation between FTH1 expression and cell viability and clonogenicity in KRAS-mutant PDAC cell lines as well as with in vivo tumor growth through the control of proline metabolism. Our investigation highlights the intricate relationship between FTH1 and pyrroline-5-carboxylate reductase 1 (PYCR1), a crucial mitochondrial enzyme facilitating the glutamate-to-proline conversion, underscoring its impact on proline metabolic imbalance in KRAS-mutant PDAC. This regulation is further reversed by miR-5000-3p, whose dysregulation results in the disruption of proline metabolism, thereby accentuating the progression of KRAS-mutant PDAC. Additionally, our study demonstrated that deferasirox, an oral iron chelator, significantly diminishes cell viability and tumor growth in KRAS-mutant PDAC by targeting FTH1-mediated pathways and altering the PYCR1/PRODH expression ratio. These findings underscore the novel role of FTH1 in proline metabolism and its potential as a target for PDAC therapy development.

Abstract Background To investigate the association between maternal sepsis during pregnancy and poor pregnancy outcome and to identify risk factors for poor birth outcomes and adverse perinatal events. Methods We linked the Taiwan Birth Cohort Study (TBCS) database and the Taiwanese National Health Insurance Database (NHID) to conduct this population-based study. We analysed the data of pregnant women who met the criteria for sepsis-3 during pregnancy between 2005 and 2017 as the maternal sepsis cases and selected pregnant women without infection as the non-sepsis comparison cohort. Sepsis during pregnancy and fulfilled the sepsis-3 definition proposed in 2016. The primary outcome included low birth weight (LBW,

Background: Detecting vertebral structural damage in patients with ankylosing spondylitis (AS) is crucial for understanding disease progression and in research settings. Objectives: This study aimed to use deep learning to score the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) using lateral X-ray images of the cervical and lumbar spine in patients with AS in Asian populations. Design: A deep learning model was developed to automate the scoring of mSASSS based on X-ray images. Methods: We enrolled patients with AS at a tertiary medical center in Taiwan from August 1, 2001 to December 30, 2020. A localization module was used to locate the vertebral bodies in the images of the cervical and lumbar spine. Images were then extracted from these localized points and fed into a classification module to determine whether common lesions of AS were present. The scores of each localized point were calculated based on the presence of these lesions and summed to obtain the total mSASSS score. The performance of the model was evaluated on both validation set and testing set. Results: This study reviewed X-ray image data from 554 patients diagnosed with AS, which were then annotated by 3 medical experts for structural changes. The accuracy for judging various structural changes in the validation set ranged from 0.886 to 0.985, whereas the accuracy for scoring the single vertebral corner in the test set was 0.865. Conclusion: This study demonstrated a well-trained deep learning model of mSASSS scoring for detecting the vertebral structural damage in patients with AS at an accuracy rate of 86.5%. This artificial intelligence model would provide real-time mSASSS assessment for physicians to help better assist in radiographic status evaluation with minimal human errors. Furthermore, it can assist in a research setting by offering a consistent and objective method of scoring, which could enhance the reproducibility and reliability of clinical studies.

Background: Patients with ankylosing spondylitis (AS) suffer from impaired physical activity and are prone to motor vehicle accidents (MVA), but definite instruction regarding the relationship between disease evolvement and MVA and potential risk factors is lacking. Objectives: To explore the risk factors and their impact on recorded MVA with profound injuries in AS patients with prescriptions. Design: Nationwide, population-based, matched retrospective cohort study. Methods: Using Taiwanese administrative healthcare databases, with available claims data from 2003 to 2013, we selected 30,911 newly diagnosed adult AS patients with concurrent prescriptions from 2006 to 2012 as AS patients, along with 309,110 non-AS individuals as the control group, matched in gender, age at index date and year of the index date. The risk of recorded MVA with profound injuries was compared between the two groups in terms of incidence rate ratio (IRR) and log-rank test p -value. Using Cox regression analysis, we studied associations between the risk and AS diagnosis. Results: The risk of recorded MVA with profound injuries in AS patients was significantly higher than in non-AS individuals, specifically 2 years after AS diagnosis (IRR, 2.00; 95% confidence interval (CI), 1.42–2.81). For patients with follow-up periods >2 years, the adjusted risk was positively associated with suburban residence (adjusted hazard ratio (aHR), 2.18; 95% CI, 1.55–3.06), rural residence (aHR, 1.89; 95% CI, 1.27–2.80), lower insured income (aHR, 1.35; 95% CI, 1.01–1.81) and recorded MVA with profound injuries before AS diagnosis (aHR, 6.16; 95% CI, 2.53–14.96). AS diagnosis (aHR, 1.81; 95% CI, 1.27–2.59) and frequency of ambulatory visits (aHR, 1.01; 95% CI, 1.004-–1.02) were specific associated factors for them compared with those with follow-up periods ⩽2 years. Conclusion: For adult AS patients in Taiwan, factors such as AS disease evolution and frequent ambulatory visits for disease control in the second year of the disease course may significantly increase the risk of recorded MVA with profound injuries beyond 2 years after AS diagnosis.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is prevalent among rheumatoid arthritis (RA) patients, but its pathogenesis has rarely been explored. Galectin-9 (Gal-9) interacts with T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3) expressed on hepatocytes and thus regulates T cell proliferation in a murine model of NAFLD. We aimed to examine the pathogenic role of the Gal-9/TIM-3 pathway in RA-NAFLD.MethodsSerum levels of Gal-9, soluble TIM-3 (sTIM-3), fatty acid-binding proteins (FABP)1, and FABP4 were determined by ELISA in forty-five RA patients and eleven healthy participants. Using Oil-red O staining and immunoblotting, we examined the effects of Gal-9 and free fatty acid (FFA) on lipid accumulation in human hepatocytes and FABP1 expression.ResultsSerum Gal-9, sTIM-3 and FABP1 level were significantly higher in RA patients (median 5.02 ng/mL, 3.42 ng/mL, and 5.76 ng/mL, respectively) than in healthy participants (1.86 ng/mL, 0.99 ng/mL, and 0.129 ng/mL, all p 3.30) was a significant predictor of NAFLD development, and Gal-9 and sTIM-3 were predictors of NAFLD severity (both p

Anti-interferon (IFN)-γ autoantibodies are linked to varicella zoster virus (VZV) infection. Given the elevated risks of herpes zoster (HZ) in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis), we aimed to examine the relationship between anti-IFN-γ autoantibodies with HZ development in JAKi-treated patients. Serum titers of anti-IFN-γ autoantibodies, plasma levels of IFN-γ, monocyte chemoattractant protein-1 (MCP-1), and IFN-γ-inducible protein-10 (IP-10) were measured by ELISA. Among the 66 enrolled RA patients, 24 developed new-onset HZ. Significantly lower MCP-1 levels were observed in patients with HZ compared to those without (median, 98.21 pg/mL, interquartile range (IQR) 77.63–150.30 pg/mL versus 142.3 pg/mL, IQR 106.7–175.6 pg/mL, p < 0.05). There was no significant difference in anti-IFN-γ titers, IFN-γ levels, or IP-10 levels between patients with and without HZ. Three of 24 patients with HZ had severe HZ with multi-dermatomal involvement. Anti-IFN-γ titers were significantly higher in patients with severe HZ than in those with non-severe HZ (median 24.8 ng/mL, IQR 21.0–38.2 ng/mL versus 10.5 ng/mL, IQR 9.9–15.0 ng/mL, p < 0.005). Our results suggest an association between reduced MCP-1 levels and HZ development in JAKi-treated RA patients. High-titer anti-IFN-γ autoantibodies may be related to severe HZ in these patients.

Abstract Introduction Elderly-onset rheumatoid arthritis (EORA) is associated with an increased mortality risk; however, the effect of conventional synthetic, biologics or targeted synthetic disease-modifying anti-rheumatic drugs (csDMARDs, bDMARDs or tsDMARDs) on the EORA-specific mortality risk is unknown. In this study, we investigated the risk factors for all-cause mortality of patients with EORA. Methods Data of EORA patients diagnosed with RA at age > 60 years between January 2007 and June 2021 were extracted from the electronic health record of Taichung Veterans General Hospital, Taiwan. Multivariable Cox regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI). The survival of patients with EORA was analyzed by Kaplan-Meier method. Results Among the 980 EORA patients who were enrolled (survivors 852 and non-survivor 128), the significant mortality-associated risk factors [HR (95% CI)] included higher age (1.10 [1.07–1.12], p

Abstract Background Outdoor air pollution has been found to trigger systemic inflammatory responses and aggravate the activity of certain rheumatic diseases. However, few studies have explored the influence of air pollution on the activity of ankylosing spondylitis (AS). As patients with active AS in Taiwan can be reimbursed through the National Health Insurance programme for biological therapy, we investigated the association between air pollutants and the initiation of reimbursed biologics for active AS. Methods Since 2011, hourly concentrations of ambient air pollutants, including PM2.5, PM10, NO2, CO, SO2, and O3, have been estimated in Taiwan. Using Taiwanese National Health Insurance Research Database, we identified patients with newly diagnosed AS from 2003 to 2013. We selected 584 patients initiating biologics from 2012 to 2013 and 2336 gender-, age at biologic initiation-, year of AS diagnosis- and disease duration-matched controls. We examined the associations of biologics initiation with air pollutants exposure within 1 year prior to biologic use whilst adjusting for potential confounders, including disease duration, urbanisation level, monthly income, Charlson comorbidity index (CCI), uveitis, psoriasis and the use of medications for AS. Results are shown as adjusted odds ratio (aOR) with 95% confidence intervals (CIs). Results The initiation of biologics was associated with exposure to CO (per 1 ppm) (aOR, 8.57; 95% CI, 2.02–36.32) and NO2 (per 10 ppb) (aOR, 0.23; 95% CI, 0.11–0.50). Other independent predictors included disease duration (incremental year, aOR, 8.95), CCI (aOR, 1.31), psoriasis (aOR, 25.19), use of non-steroidal anti-inflammatory drugs (aOR, 23.66), methotrexate use (aOR, 4.50; 95% CI, 2.93–7.00), sulfasalazine use (aOR, 12.16; 95% CI, 8.98–15.45) and prednisolone equivalent dosages (mg/day, aOR, 1.12). Conclusions This nationwide, population-based study revealed the initiation of reimbursed biologics was positively associated with CO levels, but negatively associated with NO2 levels. Major limitations included lack of information on individual smoking status and multicollinearity amongst air pollutants.

Background Although the non-alcoholic fatty liver disease (NAFLD) is prevalent in the general population, NAFLD risk in newly diagnosed rheumatoid arthritis (RA) has rarely been explored. In this population-based cohort, we examined NAFLD risk in patients with RA and identified the potential risk factors.Design Retrospective study.Setting Taiwan.Participants 2281 newly diagnosed patients with RA and selected 91 240 individuals without RA to match with patients with RA (1:40) by age, gender, income status and urbanisation level of the residence.Outcomes In this retrospective study using the 2000–2018 claim data from two-million representative Taiwanese population, we identified and compared the incidence rates (IRs) of NAFLD and alcoholic fatty liver disease (AFLD) between RA and non-RA groups. Using multivariable regression analyses, we estimated adjusted HR (aHR) of NAFLD development in patients with RA compared with individuals without RA, with 95% CIs.Results The incidences of NALFD and AFLD were not significantly different between individuals with RA and without RA during the 17-year follow-up period. However, patients with RA had significantly increased NAFLD risk during the first 4 years after RA diagnosis, with IR ratio of 1.66 fold (95% CI 1.18 to 2.33, p

Abstract To investigate the impact of an electronic medical record management system (EMRMS) on disease activity and the frequency of outpatient visits among patients with ankylosing spondylitis (AS). We identified 652 patients with AS who were followed up for at least 1 year before and after the first Ankylosing Spondylitis Disease Activity Score (ASDAS) assessment and compared the number of outpatient visits and average visit time within 1 year before and after the initial ASDAS assessment. Finally, we analyzed 201 patients with AS who had complete data and received ≥ 3 continuous ASDAS assessments at an interval of 3 months, and we compared the results of the second and third ASDAS assessments with those of the first. The number of annual outpatient visits increased after ASDAS assessment (4.0 (4.0, 7.0) vs. 4.0 (4.0, 8.0), p

Abstract Background Sepsis is a frequent complication in critically ill patients, is highly heterogeneous and is associated with high morbidity and mortality rates, especially in the elderly population. Utilizing RNA sequencing (RNA-Seq) to analyze biological pathways is widely used in clinical and molecular genetic studies, but studies in elderly patients with sepsis are still lacking. Hence, we investigated the mortality-relevant biological features and transcriptomic features in elderly patients who were admitted to the intensive care unit (ICU) for sepsis. Methods We enrolled 37 elderly patients with sepsis from the ICU at Taichung Veterans General Hospital. On day-1 and day-8, clinical and laboratory data, as well as blood samples, were collected for RNA-Seq analysis. We identified the dynamic transcriptome and enriched pathways of differentially expressed genes between day-8 and day-1 through DVID enrichment analysis and Gene Set Enrichment Analysis. Then, the diversity of the T cell repertoire was analyzed with MiXCR. Results Overall, 37 patients had sepsis, and responders and non-responders were grouped through principal component analysis. Significantly higher SOFA scores at day-7, longer ventilator days, ICU lengths of stay and hospital mortality were found in the non-responder group, than in the responder group. On day-8 in elderly ICU patients with sepsis, genes related to innate immunity and inflammation, such as ZDHCC19, ALOX15, FCER1A, HDC, PRSS33, and PCSK9, were upregulated. The differentially expressed genes (DEGs) were enriched in the regulation of transcription, adaptive immune response, immunoglobulin production, negative regulation of transcription, and immune response. Moreover, there was a higher diversity of T-cell receptors on day-8 in the responder group, than on day-1, indicating that they had better regulated recovery from sepsis compared with the non-response patients. Conclusion Sepsis mortality and incidence were both high in elderly individuals. We identified mortality-relevant biological features and transcriptomic features with functional pathway and MiXCR analyses based on RNA-Seq data; and found that the responder group had upregulated innate immunity and increased T cell diversity; compared with the non-responder group. RNA-Seq may be able to offer additional complementary information for the accurate and early prediction of treatment outcome.

Abstract Background Previous studies have shown systemic lupus erythematosus (SLE) patients had a significantly higher prevalence of thyroid diseases and hypothyroidism than matched controls, and some case reports showed SLE may occur after Hashimoto’s thyroiditis (HT). Objective This study aimed to investigate the subsequent risk of SLE in patients with HT. Methods In this retrospective cohort study done by the Taiwan National Health Insurance Research Database, the HT group (exposure group) and the non-HT group (comparator group) were propensity score matched at a ratio of 1:2 by demographic data, comorbidities, medications, and the index date. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Several sensitivity analyses were done for cross-validation of our findings. Results We identified 15,512 HT patients and matched 31,024 individuals. The incidence rate ratio of SLE was 3.58 (95% CI, 2.43–5.28; p < 0.01). Several sensitivity analyses show adjusted hazard ratio (aHR) (CIs) of 4.35 (3.28–5.76), 4.39 (3.31–5.82), 5.11 (3.75–6.98), and 4.70 (3.46–6.38), consistent with the results of the main model. Conclusion Our study showed an increased risk of SLE in the HT group after adjustment for baseline characteristics, comorbidities, and medical confounders compared with the reference group.

Abstract We aim to investigate the alteration in disease activity of ankylosing spondylitis (AS) individuals before, during, and after the COVID-19 wave in Taiwan by using electronic medical-record management system (EMRMS). We identified 126 AS individuals from the single center, and gathered data of the three disease activities (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Ankylosing Spondylitis Disease Activity Score with erythrocyte sedimentation rate [ASDAS-ESR], and Ankylosing Spondylitis Disease Activity Score with C-Reactive Protein [ASDAS-CRP]) by using EMRMS before (7 February to 1 May, 2021), during (2 May to 24 July, 2021), and after the COVID-19 wave (25 July to 16 October, 2021). We compared the disease activity measures of the three phases through a paired t test. Among the 126 individuals, CRP was significantly higher during the COVID-19 wave (0.2 (0.1, 0.5) mg/dl, p = 0.001) than before the wave (0.2 (0.1, 0.4) mg/dl), ESR (8.0 (4.0, 15.0) mm/h, p = 0.003) and ASDAS-ESR (1.4 (1.0, 1.9), p = 0.032) were significantly higher after the wave than during the wave (6.0 (3.0, 12.0) mm/h and 1.2 (0.9, 1.8) mm/h) e. ESR, CRP, ASDAS-ESR and ASDAS-CRP were all significant higher after COVID-19 wave than before. The disease activities of AS individuals in Taiwan worsened after 2021 COVID-19 wave in Taiwan.

Abstract Background Rheumatoid arthritis (RA) and systemic lupus erythematous (SLE) are autoimmune rheumatic diseases that share a complex genetic background and common clinical features. This study’s purpose was to construct machine learning (ML) models for the genomic prediction of RA and SLE. Methods A total of 2,094 patients with RA and 2,190 patients with SLE were enrolled from the Taichung Veterans General Hospital cohort of the Taiwan Precision Medicine Initiative. Genome-wide single nucleotide polymorphism (SNP) data were obtained using Taiwan Biobank version 2 array. The ML methods used were logistic regression (LR), random forest (RF), support vector machine (SVM), gradient tree boosting (GTB), and extreme gradient boosting (XGB). SHapley Additive exPlanation (SHAP) values were calculated to clarify the contribution of each SNPs. Human leukocyte antigen (HLA) imputation was performed using the HLA Genotype Imputation with Attribute Bagging package. Results Compared with LR (area under the curve [AUC] = 0.8247), the RF approach (AUC = 0.9844), SVM (AUC = 0.9828), GTB (AUC = 0.9932), and XGB (AUC = 0.9919) exhibited significantly better prediction performance. The top 20 genes by feature importance and SHAP values included HLA class II alleles. We found that imputed HLA-DQA1*05:01, DQB1*0201 and DRB1*0301 were associated with SLE; HLA-DQA1*03:03, DQB1*0401, DRB1*0405 were more frequently observed in patients with RA. Conclusions We established ML methods for genomic prediction of RA and SLE. Genetic variations at HLA-DQA1, HLA-DQB1, and HLA-DRB1 were crucial for differentiating RA from SLE. Future studies are required to verify our results and explore their mechanistic explanation.

Objective To examine the risk and risk factors of mortality in patients with rheumatoid arthritis (RA) with interstitial lung disease (ILD).Methods Using the 1997–2013 Taiwanese National Health Insurance Research Database, we identified 32 289 incident patients with RA by using International Classification of Diseases, Ninth Revision codes from 2001 to 2013, and 214 patients developed ILD subsequently. We matched (1:10) RA-ILD with controls for sex, age, time of ILD diagnosis and disease duration. In addition, we conducted propensity score matching (PSM) (1:1) for selected comorbidities to choose RA-ILD patients and controls. Using the Cox proportional hazard model, we estimated the association of mortality with ILD for the two matched populations and assessed factors associated with mortality among 214 RA-ILD patients, shown as adjusted HRs (aHRs) with 95% CIs.Results In the populations selected before and after PSM, we included 164 and 155 patients with RA-ILD and 1640 and 155 controls, respectively. ILD was associated with mortality in the population before PSM (aHR, 1.73; 95% CI 1.19 to 2.52) and in the PSM population (HR 4.38; 95% CI 2.03 to 9.43). Among 214 patients with RA-ILD, age (aHR 1.04; 95% CI 1.03 to 1.08), chronic obstructive pulmonary disease (COPD) (aHR 2.12; 95% CI 1.25 to 3.58), diabetes mellitus (DM) with end-organ damage and corticosteroid dose (prednisolone equivalent, mg/day) (aHR 1.09; 95% CI 1.07 to 1.11) were associated with mortality in RA-ILD.Conclusion This population-based cohort study showed that ILD was associated with risk of mortality in patients with RA, and risk factors associated with mortality in patients with RA-ILD included age, COPD, DM with end-organ damage and average daily prednisolone dose.

Abstract Background Infectious disease is an increasing threat to patients with systemic lupus erythematosus (SLE); however, the long-term outcome in critically ill septic patients with SLE remains unclear, and we aimed to address the impact of SLE on 5-year survival in critically ill septic patients. Methods We used the 2003–2017 nationwide data with 825,556 patients with sepsis in Taiwan. We identified lupus cases with sepsis that required admission to the intensive care unit and mechanical ventilation and selected controls matched (1:4) for age, sex, and index-year. Conditional logistic regression analysis was used to determine risk factors for mortality risk and shown as odds ratios (HRs) with 95% confidence intervals (CIs). Results A total of 513 SLE-sepsis patients and 2052 matched non-SLE septic individuals were enrolled. The mortality rate was higher in the SLE group (38.5 per 100,000 person-year) than that in the non-SLE group (13.7 per 100,000 person-year), with an IRR of 2.8 (95% CI, 2.5–3.2). We found that SLE was independently associated with a high mortality rate after adjusting relevant variables (HR 1.47, 95% CI 1.27–1.77). In addition to SLE, a higher age (HR 1.02, 95% CI 1.02–1.02), more comorbidities, and receiving prednisolone equivalent dose higher than 5 mg/day (HR 1.55, 95% CI 1.27–1.90), methotrexate (HR 2.19, 95% CI 1.61–2.99), and immunosuppressants (HR 1.45, 95% CI 1.22–1.74) were also independent risks for mortality. Conclusions We identified that SLE affects the long-term mortality in critically ill septic patients, and more studies are warranted for the underlying mechanism.

Objective Viral infection is an exogenous factor for Sjögren’s syndrome (SS). The relationship between herpes zoster infection and the ensuring risk of SS has remained unclear. This study investigated the association between a history of herpes zoster infection and the risk of SS through a nationwide population-based case–control study.Design Retrospective case–control study.Setting General population of Taiwan.Data source 2003–2013 National Health Insurance Research Database of Taiwan.Participants We identified all patients with newly diagnosed SS between 1 January 2007 and 31 December 2012 without a history of rheumatoid arthritis or systemic lupus erythematosus as the SS group.Controls We randomly selected patients without SS between 1 January 2003 and 31 December 2012 and matched 1:5 with controls based on index year, age and sex.Main outcome measure Conditional logistic regression analysis to examine the association between a history of herpes zoster and the risk of SS.Results The study included 5751 patients with SS and 28 755 matched controls. The risk of SS was significantly associated with a history of herpes zoster (model A (adjusted for Charlson Comorbidity Index (CCI) (excluding connective tissue disease, CTD)): OR 1.89; 95% CI 1.71 to 2.08; model B (adjusted for comorbidities used to calculate CCI (excluding CTD)): OR 1.90; 95% CI 1.72 to 2.10), in particular if the interval from the last visit for herpes zoster infection to the index date was

Oxaliplatin, a third-generation platinum derivative, has become one of the main chemotherapeutic treatments for esophagus, gastric and colorectal cancer; however, it is still unclear the potential effectiveness for pancreatic ductal adenocarcinoma (PDAC) with gemcitabine resistance. Here, we observed that PDAC tumors have low level of organic cation transporter 2 (OCT2, also known as SLC22A2) compared with non-tumor tissues and identified that OCT2 expression is positively correlated with oxaliplatin sensitivity in PDAC cells. Treatment of OCT2 inhibitors or knockdown of OCT2 expression significantly decreased the sensitivity to oxaliplatin in PANC-1 cells. In addition, bisulfite sequencing polymerase chain reaction analysis revealed that higher methylation frequency represses OCT2 expression in gemcitabine-resistant PANC-1 (PANC-1/GR) cells. Moreover, we found that treatment of DNA methyltransferase (DNMT) inhibitors, decitabine or 5-azacytidine recover OCT2 expression and oxaliplatin sensitivity in PANC-1/GR cells, and DNMT1 level has inverse correlation with OCT2 expression in PDAC cells and tumors. Our findings jointly suggest that OCT2 expression is a potential and predictive marker for evaluating oxaliplatin sensitivity and developing alternative treatments for PDAC patients with gemcitabine resistance.

ObjectivesTo investigate the differences between the vector vaccine ChAdOx1 nCoV-19/AZD1222 (Oxford-AstraZeneca) and mRNA-based vaccine mRNA-1273 (Moderna) in patients with autoimmune rheumatic diseases (AIRD), and to explore the cell-cell interactions between high and low anti-SARS-CoV-2 IgG levels in patients with rheumatic arthritis (RA) using single-cell RNA sequencing (scRNA-seq).MethodsFrom September 16 to December 10, 2021, we consecutively enrolled 445 participants (389 patients with AIRD and 56 healthy controls), of whom 236 were immunized with AZD1222 and 209 with mRNA-1273. The serum IgG antibodies to the SARS-CoV-2 receptor-binding domain was quantified by electrochemiluminescence immunoassay at 4-6 weeks after vaccination. Moreover, peripheral blood mononuclear cells (PBMCs) were isolated from RA patients at 4-6 weeks after vaccination for scRNA-seq and further analyzed by CellChat. ScRNA-seq of PBMCs samples from GSE201534 in the Gene Expression Omnibus (GEO) database were also extracted for analysis.ResultsThe anti-SARS-CoV-2 IgG seropositivity rate was 85.34% for AIRD patients and 98.20% for healthy controls. The anti-SARS-CoV-2 IgG level was higher in patients receiving mRNA-1273 than those receiving AZD1222 (β: 35.25, 95% CI: 14.81-55.68, p=0.001). Prednisolone-equivalent dose >5 mg/day and methotrexate use in AIRD patients, and non-anti-tumor necrosis factor-α biologics and Janus kinase inhibitor use in RA patients were associated with inferior immunogenicity. ScRNA-seq revealed CD16-monocytes were predominant in RA patients with high anti-SARS-CoV2-IgG antibodies, and enriched pathways related to antigen presentation via MHC class II were found. HLA-DRA and CD4 interaction was enhanced in high anti-SARS-CoV2-IgG group.ConclusionsmRNA-1273 and AZD1222 vaccines exhibited differential immunogenicity in AIRD patients. Enriched pathways related to antigen presentation via MHC class II in CD16-monocytes might be associated with higher anti-SARS-CoV2-IgG level in RA patients and further study is warranted.

BackgroundTo investigate the association between a history of acute anterior uveitis (AAU) and the risk of major adverse cardiovascular events (MACE) among patients with ankylosing spondylitis (AS).MethodsWe identified 38,691 newly diagnosed AS patients between 2003 and 2013 from the Taiwan National Health Insurance Research Database. The exposure group was defined as people with uveitis diagnosis by ophthalmologist before AS diagnosis date. The incidence of MACE in patients with AS according to the International Classification of Diseases, Ninth Revision. We randomly selected a comparison group without a history of AAU at a 1:4 ratio matched by age, sex, and index year in relation to the risk of developing MACE. We used cox proportional hazard regression model to compare the risk of MACE between groups, shown as adjusted hazard ratios (aHRs) with 95% confidence intervals (CI). Further subgroup analysis and sensitivity tests were also performed.ResultsThere were 3,544 patients in the AAU group and 14,176 patients in the non-AAU group. The aHR of MACE for the AAU group was 0.79 (95% CI = 0.57–1.10) at a 1:4 ratio for age, sex and index year. Sensitivity analyses using various adjustment variables showed consistent results. Cox proportional hazard regression model demonstrated that use of non-steroidal anti-inflammatory drugs (NSAIDs) was associated with an increased risk of MACE in this cohort (HR = 3.44; 95% CI = 2.25–5.25).ConclusionThis cohort study showed that subjects with AAU was not associated with the risk of MACE among AS patients, compared to non-AAU controls.

Background: Infection due to nontuberculous mycobacteria (NTM) is an emerging issue worldwide, and we aimed to address the epidemiology and mortality association of NTM infection requiring treatment in Taiwan. Methods: We used the 2003–2018 data of 2 million representative individuals in Taiwan’s National Health Insurance Research Database. We identified patients with newly diagnosed NTM infection and received treatment as NTM cases. Age- and sex-matched (1:40) as well as propensity score-matched (PSM) (1:2) non-NTM individuals were selected as non-NTM controls. We used a Cox proportional hazard model to determine hazard ratios (HRs) with 95% confidence intervals (CIs). Results: We identified 558 patients with NTM infection requiring treatment. The mean age was 62.5 ± 15.4 years, and 57.5% of them were male. The incidence increased from 0.54 per 100,000 person-year in 2003 to 3.35 per 100,000 person-year in 2018. The overall mortality was 35.2%, with a mean follow-up duration of 4.1 ± 3.6 years. We found that NTM infection was independently associated with a greater risk of mortality (HR: 1.71; 95% CI: 1.47–1.98) compared with age- and sex-matched controls, and the association remained consistent (HR: 1.44; 95% CI: 1.19–1.75) compared with propensity-matched controls. We also found that old age, male, high Charlson comorbidity index, and the use of steroids or anti-neoplastic agents/immunosuppressants were associated with mortality risk. Conclusion: In conclusion, we found a steady increase in patients with NTM infection requiring treatment in Taiwan and further demonstrated that NTM infection was associated with greater risk of mortality using two comparable non-NTM control subjects.

Abstract Background Hymenoptera stings can induce dysregulated inflammation and immediate hypersensitivity reactions including anaphylaxis. However, the molecular mechanisms underlying peripheral immune responses during Hymenoptera venom allergy (HVA) remain elusive. Methods Here we determined the single‐cell transcriptomic profiling from highly heterogeneous peripheral blood cells in patients with HVA through unbiased single‐cell RNA sequencing and multiple models of computational analyses. Results Through clustering analysis by uniform manifold approximation and projection, we revealed an increased number of monocytes in the acute phase and identified innate immune responses, leukocyte activation, and cellular detoxification as the main involved biological processes. We used filter analysis to identify that CLU that encodes clusterin was highly expressed in monocytes, and the co‐expressed genes of CLU further supported the key role of monocyte. We further used pseudo‐temporal ordering of cells and scRNA velocity analysis to delineate disease‐associated monocyte lineages and states in patients with HVA. Conclusions Our comprehensive molecular profiling of blood samples from patients with HVA revealed previously unknown molecular changes, providing important insights into the mechanism of venom allergy and potential therapeutic targets.

ObjectivesThe Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) has been widely utilized to evaluate disease activity in patients with ankylosing spondylitis (AS) by an arbitrary cut-off of ≥4 to indicate high disease activity and initiate biological therapy. The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a new composite index to assess AS disease activity states that have been defined and validated. ASDAS ≥2.1 was selected as a criterion to start biological therapy. The purpose of this study was to estimate the corresponding BASDAI and ASDAS cut-off in a Taiwanese AS cohort.MethodsFrom November 2016 to October 2018, we assessed the ASDAS and the BASDAI regularly and recorded demographic data for 489 AS patients in Taichung Veterans General hospital (TCVGH) using an electronic patient-reported data system linked to electronic medical records. We used receiver operating characteristic curves with Youden's J statistic to determine the BASDAI values that correspond to ASDAS disease activity cut-offs (i.e., 1.3, 2.1, and 3.5).ResultsIn our population, the best trade-off BASDAI values corresponding to ASDAS -C-reactive protein (CRP) 1.3, 2.1, and 3.5 were 2.1, 3.1, and 3.7, respectively. The optimal BASDAI values corresponding to ASDAS-erythrocyte sedimentation rates 1.3, 2.1, and 3.5 were 2.0, 2.6, and 4.8, respectively.ConclusionWe propose a revised BASDAI cut-off based on our data, as BASDAI scores are commonly used globally. A more reasonable, lower BASDAI cut-off to initiate or change biological therapy will bring us closer to better decisions to treat AS patients.

In Taiwan, the incidence and prevalence of psoriatic arthritis (PsA) have risen significantly in recent years. Moreover, data from the Taiwan National Health Insurance Research Database (NHIRD) show that more than 85% of PsA patients are treated with just non-steroidal anti-inflammatory drugs (NSAIDs) and/or conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Taiwanese clinicians have also expressed concerns regarding uncertainties in the diagnosis of PsA and the delayed, interrupted, and/or tapered use of biologics, as well as differences in therapeutic preferences between and within dermatologists and rheumatologists. To address these issues, the Taiwan Rheumatology Association and the Taiwanese Association for Psoriasis and Skin Immunology jointly convened a committee of 28 clinicians from the fields of rheumatology, dermatology, orthopedics, and rehabilitation, to develop evidence-based consensus recommendations for the practical management of PsA in Taiwan. A total of six overarching principles and 13 recommendations were developed and approved, as well as a treatment algorithm with four separate tracks for axial PsA, peripheral PsA, enthesitis, and dactylitis. Psoriasis (PsO) management was not discussed here, as the Taiwanese Dermatological Association has recently published a comprehensive consensus statement on the management of PsO. Together, these recommendations provide an up-to-date, evidence-based framework for PsA care in Taiwan.

Background/Purpose: Multiple sclerosis is classified as a rare disease in Taiwan. This study evaluated the safety and effectiveness of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) from routine clinical practice in Taiwan. Methods: In this retrospective, multicentre, observational study, we collected clinical data of patients treated with fingolimod 0.5 mg/day in routine clinical practice between September 2012 and December 2015. Primary outcome was the overall safety of fingolimod; secondary outcome was the annualized relapse rate (ARR). Results: Overall, 62/69 (86.1%) patients were on fingolimod by the end of data collection period. Mean age (±standard deviation [SD]) at inclusion was 37.7 ± 10.10 years; mean duration of MS was 5.4 ± 4.52 years and mean duration of fingolimod exposure was 135.8 patient-years. The most common adverse events (AEs) were bradycardia (21.7%; first-dose related), upper respiratory tract infection, dizziness, and hypoaesthesia (numbness) (11.6% each), followed by urinary tract infection and back pain (7.2% each). Seven patients had liver enzyme-related AEs. Eight patients had absolute lymphocyte counts

Background: Enthesopathy is a main characteristic of ankylosing spondylitis (AS). However, ultrasonographic features of supraspinous enthesis in AS have not yet been reported. Methods: Forty-seven AS patients and 22 healthy individuals were enrolled and completed the study. L4 supraspinous entheses were assessed through an ultrasound (US) unit with the participants in a lateral decubitus position. Entheseal echogenicity was interpreted upon inspection of the US image. An entheseal grayscale (GS) value determination, along with an echotexture analysis using a gray-level co-occurrence matrix algorithm, was performed. The thoracolumbar fascia just above the enthesis was also analyzed. An enthesis-to-fascia ratio (EFR) of each texture feature was used for the purpose of intergroup comparison. Results: The prevalence of abnormal entheseal echogenicity in the AS and healthy groups was 19.1% and 13.6%, respectively (P = 0.42). The AS group experienced a higher GS EFR (0.56 [0.10–1.08] vs. 0.40 [0.12–0.89], P = 0.007), higher contrast EFR (0.62 [0.15–1.23] vs. 0.49 [0.23–1.33], P = 0.049), higher variance EFR (0.44 [0.06–1.21] vs. 0.35 [0.13–1.10], P = 0.023), and lower homogeneity EFR (1.07 [0.97–1.27] vs. 1.11 [1.04–1.19], P = 0.011) in comparison to the healthy group. Conclusion: Echotexture analysis identified the subtle structural changes in L4 supraspinous enthesis in AS patients. It proved to be superior to the inspection method and may possess the potential for providing early detection of supraspinous enthesopathy in AS.

Hyperspectral imaging (HSI) is an optical remote sensing technology that has the advantages of high spatial and spectral resolution. Aside from its use in geographical research, HSI has been widely used in medical diagnosis. Systemic sclerosis (SSc) is a multiorgan autoimmune disease that leads to skin tightness, thickness, and fibrosis. Internal organ involvement and mortality in this progressive disease are strongly correlated with the extent and severity of abnormal skin thickness. Our prior study demonstrated that HSI can outperform conventional assessment tools as a diagnostic modality to evaluate the severity of skin sclerosis in SSc patients. However, the analysis algorithm has its limitations. This study aimed to investigate a novel soft abundance score for HSI. We also explored the influence of band selection on the HSI analysis of SSc patients. In total, we enrolled 30 SSc patients (male: 10; female: 20, median age±range, 49.9±17.0 years) and 24 healthy controls (male: 12; female: 12, median age±range, 37.0±11.0 years). We found that most of the spectral bands generated by different band selection methods were similar. Moreover, in the task of distinguishing SSc patients from healthy controls, the soft abundance scores calculated from these bands exhibited greater discriminative power than a spectral angle mapper (SAM), skin scores determined by clinical assessments, or skin thickness determined through ultrasonography. Our results suggest that the spectral bands selected in this study should be taken into consideration to guide future hardware improvement. The analytic algorithm can also be applied as a new clinical method.

Abstract Background Pneumocystis pneumonia (PCP) is increasingly being diagnosed in patients with systemic lupus erythematosus (SLE), and hydroxychloroquine (HCQ) has been found to possess antifungal activities. We hence aimed to investigate the association between HCQ and PCP risk among patients with SLE. Methods Using the 1997–2013 nationwide claim data, we identified 24,343 newly-diagnosed SLE patients. We then identified 58 PCP cases and selected 348 non-PCP controls matching (1:6) by age, sex, disease duration and the year of PCP diagnosis date. The risk of PCP was assessed by determing odds ratios (ORs) with 95% confidence intervals (CIs) by using multivariable conditional logistic regression. Results The risk of PCP was associated with moderate to severe renal disease (OR 6.73, 95% CI 1.98–22.92), higher doses of glucocorticoids (≤5 mg/day, reference; 5–10 mg/day, OR 25.88, 95% CI 2.97–225.33; > 10 mg/day, OR 286.58, 95% CI 28.58–> 999), higher 3-month cumulative dose of cyclophosphamide (not use, reference; ≤1.4 g, OR 0.64, 95% CI 0.14–3.01; > 1.4 g, OR 11.52, 95% CI 1.97–67.39) and use of mycophenolate mofetil/mycophenolic acid (OR 50.79, 95% CI 5.32–484.77), whereas 3-month cumulative dose of HCQ was associated with a reduced risk of PCP among patients with SLE (not use, reference; ≤14 g, OR 0.69, 95% CI 0.21–2.24; > 14 g, OR 0.20, 95% CI 0.05–0.71). Conclusions This study demonstrated incident PCP was associated with mycophenolate mofetil/mycophenolic acid use and higher doses of cyclophosphamide or glucocorticoid, whereas the use of a higher dose of HCQ was associated with a reduced risk of PCP in lupus patients.

PurposeTo conduct stratified analysis of the association between periodontitis exposure and the risk of female breast cancer based on age, comorbidities and level of urbanization.MethodsUsing claims data taken from the 1997-2013 Taiwanese National Health Insurance Research Database (NHIRD), we identified 60,756 newly-diagnosed female breast cancer patients during the period 2003-2013 from all beneficiaries. We then randomly selected 243,024 women without breast cancer matching (1:4) for age and the year of the index date during 1997-2013 from a one million representative population acting as the control group. A conditional logistic regression analysis was used to examine the association between periodontitis (ICD-9-CM codes 523.3-4) and the risk of breast cancer, shown as an odds ratio (OR) with a 95% confidence interval (CI) after adjustments for the Charlson Comorbidity Index (CCI) and level of urbanization. Subgroup analyses were conducted based on age, CCI and level of urbanization.ResultsThe mean ± standard deviation age was 53 ± 14 years. After adjusting for potential confounders, the risk of female breast cancer was found to be associated with a history of periodontitis (OR, 1.12; 95% CI, 1.10-1.14). Such an association was significantly different between patients aged < 65 years (OR, 1.09; 95% CI, 1.06-1.11) and patients aged ≥ 65 years (OR, 1.23; 95% CI, 1.18-1.28; p for interaction 0 (OR, 0.99; 95% CI, 0.96-1.03; p for interaction ConclusionsThis population-based nested case-control study demonstrated that periodontitis was significantly associated with the risk of female breast cancer and such an association was modified by both age and comorbidities.

Abstract Background Previous case reports have demonstrated the occurrence of ischemic optic neuropathy (ION) following intravitreal injections of antivascular endothelial growth factor (anti-VEGF). However, no previous studies have investigated the impact of injection numbers on the risk of ION. The aim of our study was to investigate whether repeated intravitreal injections of anti-VEGF would increase the risk of subsequent ION in patients with neovascular age-related macular degeneration (AMD). Methods A population-based, retrospective cohort study using the Taiwan National Health Insurance Research Database was conducted from 2007 to 2013. Neovascular AMD patients receiving intravitreal injections of anti-VEGF during the study period were enrolled in the study cohort. Enrollees were divided into three groups according to the categorized levels of injection number (first level: 15 times). Kaplan-Meier curves were generated to compare the cumulative hazard of subsequent ION among the three groups. Cox regression analyses were used to estimate crude and adjusted hazard ratios (HRs) for ION development with respect to the different levels of injection numbers. The confounders included for adjustment were age, sex, and comorbidities (diabetes, hypertension, hyperlipidemia, ischemic heart disease, and glaucoma). Results In total, the study cohort included 77,210 patients. Of these, 26,520, 38,010, and 12,680 were in the first-, second-, and third-level groups, respectively. The Kaplan-Meier method revealed that the cumulative hazards of ION were significantly higher in those who had a higher injection number. After adjusting for confounders, the adjusted HRs for ION in the second- and third-level groups were 1.91 (95% confidence interval [CI], 1.32–2.76) and 2.20 (95% CI, 1.42–3.43), respectively, compared with those in the first-level group. Conclusions Among patients with neovascular AMD, those who receive a higher number of anti-VEGF injections have a significantly higher risk of developing ION compared with individuals who receive a lower number of injections.

Objective: Sepsis is life threatening and leads to complex inflammation in patients with immunocompromised conditions, such as cancer, and receiving immunosuppressants for autoimmune diseases and organ transplant recipients. Increasing evidence has shown that RNA-Sequencing (RNA-Seq) can be used to define subendotype in patients with sepsis; therefore, we aim to use RNA-Seq to identify transcriptomic features among immunocompromised patients with sepsis.Methods: We enrolled patients who were admitted to medical intensive care units (ICUs) for sepsis at a tertiary referral centre in central Taiwan. Whole blood on day-1 and day-8 was obtained for RNA-Seq. We used Gene Set Enrichment Analysis (GSEA) to identify the enriched pathway of day-8/day-1 differentially expressed genes and MiXCR to determine the diversity of T cell repertoire.Results: A total of 18 immunocompromised subjects with sepsis and 18 sequential organ failure assessment (SOFA) score-matched immunocompetent control subjects were enrolled. The ventilator-day, ICU-stay, and hospital-day were similar between the two groups, whereas the hospital mortality was higher in immunocompromised patients than those in immunocompetent patients (50.0 vs. 5.6%, p < 0.01). We found that the top day-8/day-1 upregulated genes in the immunocompetent group were mainly innate immunity and inflammation relevant genes, namely, PRSS33, HDC, ALOX15, FCER1A, and OLR1, whereas a blunted day-8/day-1 dynamic transcriptome was found among immunocompromised patients with septic. Functional pathway analyses of day-8/day-1 differentially expressed genes identified the upregulated functional biogenesis and T cell-associated pathways in immunocompetent patients recovered from sepsis, whereas merely downregulated metabolism-associated pathways were found in immunocompromised patients with septic. Moreover, we used MiXCR to identify a higher diversity of T cell receptor (TCR) in immunocompetent patients both on day-1 and on day-8 than those in immunocompromised patients.Conclusions: Using RNA-Seq, we found compromised T cell function, altered metabolic signalling, and decreased T cell diversity among immunocompromised patients with septic, and more mechanistic studies are warranted to elucidate the underlying mechanism.

Purpose: To determine the association between a history of clinically diagnosed dengue infection and the risk of systemic autoimmune rheumatic diseases (SARDs).Methods: Using claims data from the 1997–2013 Taiwanese National Health Insurance Research Database, we included 74,422 patients who were diagnosed with SARDs and 297,688 patients without SARDs who were matched (in a 1:4 ratio) for age, sex, year of SARDs index date, and city of residence. The associations between the development of SARDs and a history of dengue infection (International Classification of Diseases, Ninth Revision, Clinical Modification code 061) were investigated using conditional logistic regression analysis shown as odds ratios (ORs) with 95% confidence intervals (CIs) after adjusting for potential confounders.Results: We included 17,126 patients with systemic lupus erythematosus (SLE), 15,531 patients with Sjogren's syndrome (SS), 37,685 patients with rheumatoid arthritis (RA), 1,911 patients with systemic sclerosis (SSc), 1,277 patients with dermatomyositis (DM), and 892 patients with polymyositis (PM). SLE (OR, 4.55; 95% CI, 2.77–7.46; p

ObjectiveWe investigated the correlation between nontyphoidal Salmonella (NTS) infection and systemic lupus erythematosus (SLE) risk.MethodsThis case-control study comprised 6,517 patients with newly diagnosed SLE between 2006 and 2013. Patients without SLE were randomly selected as the control group and were matched at a case-control ratio of 1:20 by age, sex, and index year. All study individuals were traced from the index date back to their NTS exposure, other relevant covariates, or to the beginning of year 2000. Conditional logistic regression analysis was used to analyze the risk of SLE with adjusted odds ratios (aORs) and 95% confidence intervals (CIs) between the NTS and control groups.ResultsThe mean age was 37.8 years in the case and control groups. Females accounted for 85.5%. The aOR of having NTS infection were significantly increased in SLE relative to controls (aOR, 9.20; 95% CI, 4.51-18.78) in 1:20 sex-age matching analysis and (aOR, 7.47; 95% CI=2.08-26.82) in propensity score matching analysis. Subgroup analysis indicated that the SLE risk was high among those who dwelled in rural areas; had rheumatoid arthritis, multiple sclerosis, or Sjogren’s syndrome; and developed intensive and severe NTS infection during admission.ConclusionsExposure to NTS infection is associated with the development of subsequent SLE in Taiwanese individuals. Severe NTS infection and other autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, or Sjogren’s syndrome also contributed to the risk of developing SLE.

Objectives: To evaluate the relationship between systemic lupus erythematosus (SLE) and the risk of retinal vasculitis (RV) using a population-based database.Methods: Using the 1997–2013 Taiwanese National Health Insurance Database, we identified newly diagnosed SLE patients between 2001 and 2012 as the SLE group. We matched the SLE group with non-SLE individuals selected from a representative one million sample of the population in a 1:20 ratio for age, sex, and the year of the index date. After adjusting for potential confounders, including urbanization of the patient's residence, the level of the payroll-related insured amount, and selected comorbidities, we examined the association between SLE and the risk of RV using the Cox proportional hazard model shown as hazard ratios (HRs) with 95% confidence intervals (CIs). Sensitivity analyses were conducted using various definitions of RV.Results: We included 11,586 patients with SLE and 231,720 matched non-SLE individuals. The mean age of the study participants was 36.7 ± 16.9 years, and the female-to-male ratio was 6.8:1. The incidence rates of RV were 56.39 cases per 100,000 person-years and 2.45 cases per 100,000 person-years, respectively. After adjusting for potential confounders, the incidence rate of RV in the SLE cohort was 22.99 times higher than that in the non-SLE cohort (56.39 vs. 2.45 per 100,000 person-years). The adjusted HR for RV in the SLE group was 23.61 (95% CI, 14.94–37.32). The results remained robust in the sensitivity analysis.Conclusion: This nationwide population-based study revealed that SLE patients had a significantly higher risk of RV than non-SLE individuals.

Objective: This study aimed to assess the associations of the risk of asthma diagnosed in children aged 6 years or younger and having maternal immune-mediated inflammatory diseases (IMIDs), including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory myositis, rheumatoid arthritis (RA), Sjögren's syndrome (SS), ankylosing spondylitis (AS), and autoimmune thyroiditis.Methods: A total of 628,878 singleton newborns documented in 2006–2009 and followed up for at least 6 years were identified. Overall, 153,085 (24.3%) children developed asthma at the age of ≤ 6 years. Two groups of maternal ages, i.e.,

Objectives: To investigate factors associated with major adverse cardiovascular events (MACEs) in patients with rheumatoid arthritis (RA). Methods: We conducted a nationwide, population-based, case-control study using Taiwan’s National Health Insurance Research Database for 2003–2013. From 2004 to 2012, we identified 108,319 newly diagnosed RA patients without previous MACEs, of whom 7,580 patients (7.0%) developed MACEs during follow-up. From these incident RA patients, we included 5,994 MACE cases and 1:4 matched 23,976 non-MACE controls for analysis. The associations of MACEs with comorbidities and use of anti-rheumatic medications within 1 year before the index date were examined using conditional logistic regression analyses. Results: Using multivariable conditional logistic regression analysis, the risk of MACE in RA patients was associated with use of golimumab [odd’s ratio (OR), 0.09; 95% confidence interval (CI), 0.01-0.67], abatacept (OR, 0.13; 95% CI, 0.02–0.93), hydroxychloroquine (OR, 0.90; 95% CI, 0.82-0.99), methotrexate (OR, 0.72; 95% CI, 0.64–0.81), cyclosporin (OR, 1.43; 95% CI, 1.07–1.91), nonsteroidal anti-inflammation drugs (NSAIDs) (OR, 1.36; 95% CI, 1.27–1.46), antiplatelet agent (OR, 2.47; 95% CI, 2.31-2.63), hypertension (without anti-hypertensive agents: OR, 1.04; 95% CI, 0.96-1.12; with anti-hypertensive agents: OR, 1.47; 95% CI, 1.36-1.59), diabetes (OR, 1.27; 95% CI, 1.18-1.37), hyperlipidemia without lipid-lowering agents (OR, 1.09; 95% CI, 1.01-1.17), ischemic heart disease (OR, 1.20; 95% CI, 1.10-1.31), and chronic obstructive pulmonary disease (COPD) (OR, 1.12; 95% CI, 1.03-1.23) in the parsimonious model. The risk of MACE in RA patients also increased markedly in participants younger than 65 years with some comorbidities. Conclusions: This population-based case-control study revealed that the use of golimumab, abatacept, hydroxychloroquine, and methotrexate were associated with a decreased risk of MACE development in newly diagnosed RA patients, while the use of cyclosporin, NSAIDs, and antiplatelet agents, and comorbidities, including hypertension, diabetes, hyperlipidemia without lipid-lowering agent therapy, ischemic heart disease, and COPD, were associated with an increased risk of MACE development in RA patients.

Objective: Primary Sjögren's syndrome (pSS) is characterized by exocrine glandular inflammation; however, the association between preceding mammary-gland-inflammation-related diseases and newly diagnosed pSS remains unexplored.Methods: We used the 2003–2013 data retrieved from Taiwan's National Health Insurance Research Database (NHIRD) to conduct the present population-based study. We identified newly diagnosed pSS female patients during the 2001–2013 period, as well as age-matched (1:20) and propensity-score-matched (1:2) non-SS individuals (as controls). We explored the associations between pSS and a history of mastitis and fibrocystic breast disease by determining adjusted odds ratios (aORs) with 95% confidence intervals (CIs) using a conditional logistical regression analysis after controlling for potential confounders.Results: We identified 9,665 patients with pSS and 193,300 age-matched non-SS controls, as well as 9,155 SS cases and 18,310 propensity-score-matched non-SS controls. We found that fibrocystic breast disease (aOR, 1.75; 95% CI, 1.63–1.88) were independently associated with incident SS, whereas mastitis and childbirth-associated breast infections were not associated with incident SS. We also found positive associations between SS and previously reported SS-associated diseases, including cardiovascular diseases, thyroid diseases, pancreatitis, bronchiectasis, infectious diseases, osteoporosis, and ankylosing spondylitis. In the propensity-score-matched populations, the associations between pSS and fibrocystic breast disease (aOR, 1.74; 95% CI, 1.58–1.91) remained consistent.Conclusion: The present population-based study revealed a previously unexplored association between pSS and history of fibrocystic breast disease, and the finding highlights the need to survey pSS in patients with mammary-gland-inflammation-associated diseases.

Objectives: Use of biologics or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) is associated with infection in patients with rheumatoid arthritis (RA). Socioeconomic status is substantial in infectious diseases; however, the impact of socioeconomic status on risk for infection in patients with RA receiving b/tsDMARD remains unclear.Methods: We used the 2003–2017 Taiwanese National Health Insurance Research Database to identify patients with RA receiving b/tsDMARDs. A Cox regression analysis was used to estimate the associations of covariates with the risk of hospitalised infection shown as hazard ratios (HRs) with 95% confidence interval (CIs).Results: We identified 7,647 RA patients who started their first bDMARD/tsDMARD treatment. Log-rank analyses demonstrated the association between age (p < 0.001), urbanisation (p = 0.001), the insured amount (p = 0.021), and the hospitalisation. Cox proportional regression analyses showed that age was independently associated with hospitalised infection in a dose–response manner, whereas a high-income category had an inverse association (HR 0.48, 95% CI 0.23–0.96). Hospitalisation for infection within 5 years was a strong risk factor (HR 5.63, 95% CI 1.91–16.62), and living in a rural area tended to be a risk factor (HR 1.76, 95% CI 0.98–3.14) for incident hospitalised infection.Conclusions: This study showed the crucial impacts of age, socioeconomic status, and history of infection on hospitalised infection in patients with RA receiving b/tsDMARDs. These findings highlight the largely ignored role of socioeconomic status in risk stratification among patients receiving b/tsDMARDs for RA.

Objective: To investigate the association between anti-phospholipid syndrome (APS) and the risk of newly diagnosed systemic lupus erythematosus (SLE).Methods: We used 2003–2013 data derived from Taiwan's National Health Insurance Research Database to conduct this nationwide, population-based. We identified AS patients newly diagnosed between 2005 to 2013 as the study group and applied age-sex matched (1:20) and propensity score-matched (PSM) (1:2) non-SLE individuals as controls. The association between APS and risk of incident SLE was determined by calculating hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox proportional hazard regression analysis.Results: We identified 1,245 patients with APS as well as 24,900 age- and sex-matched non-APS controls and 727 APS patients as well as 1,454 PSM non-APS controls. We found that the risk for incident SLE in the APS group was 80.70 times higher than the non-APS group, and the association remained robust after PSM (HR, 28.55; 95% CI, 11.49–70.91). The increased risk for SLE in patients with APS mainly existed within 5 years after the diagnosis of APS. The sensitivity analyses found that the risk for SLE in patients with APS was consistent excluding patients with ITP/AIHA and using distinct definitions of SLE.Conclusion: The present population-based study revealed a robust association between SLE risk and recent APS and highlights the need for vigilance of SLE-associated symptoms in patients who had been diagnosed with APS.

Abstract Background Increasing prevalence of childhood allergic diseases including asthma is a global health concern, and we aimed to investigate prenatal risk factors for childhood asthma and to address the potential shared prenatal impacts among childhood asthma, allergic rhinitis (AR) and atopic dermatitis (AD). Methods We used two claim databases, including Taiwan Birth Cohort Study (TBCS) and National Health Insurance Research Database (NHIRD), to identify independent paired mother–child data (mother–child dyads) between 2006 and 2009. The association between prenatal factors and asthma was determined by calculating adjusted odds ratio (aOR) with 95% confidence interval (CI) using conditional logistic regression analysis. Results A total of 628,878 mother–child dyads were included, and 43,915 (6.98%) of children developed asthma prior to age 6. We found that male gender (aOR 1.50, 95% CI 1.47–1.53), maternal asthma (aOR 1.80, 95% CI 1.71–1.89), maternal AR (aOR 1.33, 95% CI 1.30–1.37), preterm birth (aOR 1.32, 95% CI 1.27–1.37), low birth weight (aOR 1.14, 95% CI 1.10–1.19) and cesarean section (aOR 1.10, 95% CI 1.08–1.13) were independent predictors for childhood asthma. A high urbanization level and a low number of older siblings were associated with asthma in a dose–response manner. Notably, we identified that the association between maternal asthma and childhood asthma (aOR 1.80, 95% CI 1.71–1.89) was stronger compared with those between maternal asthma and childhood AR (aOR 1.67, 95% CI 1.50–1.87) as well as childhood AD (aOR 1.31, 95% CI 1.22–1.40). Similarly, the association between maternal AR and childhood AR (aOR 1.62, 95% CI 1.53–1.72) was higher than those between maternal AR and childhood asthma (aOR 1.33, 95% CI 1.30–1.37) as well as childhood AD (aOR 1.35, 95% CI 1.31–1.40). Furthermore, the number of maternal allergic diseases was associated with the three childhood allergic diseases in a dose–response manner. Conclusions In conclusion, this population-based study provided evidence of prenatal impacts on childhood asthma and demonstrated the shared maternal impacts among childhood asthma, AR, and AD. These findings highlight the shared prenatal impacts among allergic diseases, and studies are warranted to address the pivotal pathway in allergic diseases.

Abstract Objective To investigate the risk of immune-mediated inflammatory diseases (IMIDs) in patients with ankylosing spondylitis (AS). Methods Using 2003–2012 claims data from the Taiwanese National Health Insurance Research Database, we identified 30,911 newly diagnosed AS patients requiring medical therapy from 2006 to 2012. In addition, we randomly selected 309,110 non-AS individuals matching (1:10) the AS patients with regard to age, sex and the year of the index date. After excluding subjects with the corresponding prior IMIDs, we calculated the incidence rates (IRs) of various IMIDs in the AS and non-AS cohorts and estimated the hazard ratios (HRs) with 95% confidence intervals after adjusting for age, sex, the Charlson comorbidity index, the frequency of ambulatory visits during the follow-up period and medications. We conducted sensitivity analyses by excluding those who developed IMIDs within 3 months after the index date. Results In the follow-up period, we found that newly diagnosed AS patients had significantly increased risks of acute anterior uveitis, psoriasis, Sjögren’s syndrome, thromboangiitis obliterans, Behcet’s disease and sarcoidosis. However, the risk of Sjögren’s syndrome did not increase in AS patients in the sensitivity analysis. In the same period, this study found no significant differences in the risks of Crohn’s disease, ulcerative colitis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, polymyositis, pemphigus and vitiligo between newly diagnosed AS patients and non-AS individuals. AS patients had a significantly reduced risk of rheumatoid arthritis. Conclusion Newly diagnosed Taiwanese AS patients had increased risks of acute anterior uveitis, psoriasis, thromboangiitis obliterans, Behcet’s disease and sarcoidosis, but a reduced risk of rheumatoid arthritis.

In recent years, the development and application of artificial intelligence have both been topics of concern. In the medical field, an important direction of medical technology development is the extraction and use of applicable information from existing medical records to provide more accurate and helpful diagnosis suggestions. Therefore, this paper proposes using the development of diseases with easily discernible symptoms to predict the development of other medically related but distinct diseases that lack similar data. The aim of this study is to improve the ease of assessing the development of diseases in which symptoms are difficult to detect, and to improve the utilization of medical data. First, a time series model was used to capture the continuous manifestations of diseases with symptoms that could be easily found at different time intervals. Then, through transfer learning and attention mechanism, the general features captured were applied to the predictive model of the development of diseases with insufficient data and symptoms that are difficult to detect. Finally, we conducted a comprehensive experimental study based on a dataset collected from the National Health Insurance Research Database in Taiwan. The results demonstrate that the effectiveness of our transfer learning approach outperforms state-of-the-art deep learning prediction models for disease course prediction.

Psoriasis is an immune-mediated skin disease with a worldwide prevalence of 2–4% that causes scaling erythematous skin lesions. It is a chronic relapsing and complex multifactorial disease that often necessitates long-term therapy. Despite various novel therapies, psoriasis remains a treatable but non-curable disease. Because the antitussive medication dextromethorphan (DXM) can inhibit murine bone marrow and human monocytes and slow the progression of arthritis in mice with type II collagen-induced arthritis, we explored whether the oral administration of DXM to mice with imiquimod (IMQ)-induced psoriasis can effectively alleviate psoriasis symptoms and improve immune regulation. Herein, we examined the therapeutic effects of DXM on psoriasis and its potential mechanisms of action in an IMQ-induced psoriasis mice model. We found that an oral dose of DXM (10 mg/kg) could more significantly reduce psoriasis symptoms compared with intraperitoneal injection. Seven days after the oral administration of DXM, the Psoriasis Area and Severity Index (PASI) score was significantly decreased compared with that in the vehicle group. Furthermore, DXM treatment also significantly ameliorated the psoriasis symptoms and the histopathological features of psoriasis, including stratum corneum thickening, desquamation, and immune cell infiltration. Additionally, DXM reduced the mRNA levels of the cytokines TNF-α, IL-6, IL-17A, and IL-22 in skin and the percentage of IL-17A and IL-22 producing T cell receptor γδ T cells (TCRγδT). Taken together, our research demonstrated that DXM could inhibit keratinocyte proliferation and alleviate psoriasis symptoms, which suggests the potential application of DXM in the treatment of chronic inflammation and autoimmune diseases.

Abstract Background Increasing evidence indicates a pathogenic role of deregulated autophagy in rheumatoid arthritis (RA). We examined the relationship between autophagy and inflammatory parameters in patients with RA receiving biologic therapy. Methods In 72 patients with RA and 20 healthy control subjects (HC), autophagosome levels were determined by the mean fluorescence intensity (MFI) of autophagosomotropic dye incorporated into circulating immune cells, and p62 expression levels in immune cells were measured by flow cytometry. We used immunoblotting to examine protein expression of LC3-II and p62 in peripheral blood mononuclear cells. Results Patients with RA had significantly higher levels of autophagosome reflected by MFI of Cyto-ID in circulating lymphocytes, monocytes, and granulocytes (median values, 3.6, 11.6, and 64.8, respectively) compared with HC (1.9, 6.0, and 35.8; respectively) (all p

Objectives To investigate whether uveitis is a predictor of acute myocardial infarction (AMI) among patients with Behcet’s disease (BD).Design Retrospective cohort study.Setting Patients with BD were retrieved from the whole population of the Taiwan National Health Insurance Research Database from 1 January 2001 to 31 December 2013.Participants Among the 6508 patients with BD, 2517 (38.7%) were in the uveitis group and 3991 were in the non-uveitis group.Primary and secondary outcome measures Kaplan-Meier curves were generated to compare the cumulative hazard of AMI in the uveitis and non-uveitis groups. Multivariate Cox regression analysis was used to estimate the adjusted HRs and 95% CI of AMI, and was adjusted for age, gender, systemic comorbidities (eg, hypertension, diabetes, hyperlipidaemia, smoking) and clinical manifestation of BD (eg, oral ulcers, genital ulcers, skin lesions, arthritis and gastrointestinal involvement).Results The mean age of the BD cohort was 38.1±15.1 years. Compared with non-uveitis patients, uveitis patients were significantly younger and male predominant. There was no significant difference between the two groups for most proportions of systemic comorbidities and clinical manifestations. The Kaplan-Meier method with the log-rank test showed that the uveitis group had a significantly higher cumulative hazard for patients with AMI compared with the non-uveitis group (p

Objective To evaluate whether the risk of subsequent psoriasis and psoriatic arthritis development is increased in patients with uveitis. Methods In Taiwan’s national health insurance research database, we identified 195,125 patients with new-onset uveitis between 2001 and 2013. We randomly selected 390,250 individuals without uveitis who were matched 2:1 to uveitis cases based on age, sex and year of enrolment. The characteristics of the two groups were compared. Using multivariate Cox regression, hazard ratios (HRs) for psoriasis or psoriatic arthritis corresponding to uveitis were computed after adjustment for age, sex, insurance cost and comorbidities. In subgroup analyses, separate HRs for mild psoriasis, severe psoriasis and psoriatic arthritis were calculated. Results The mean age of the study cohort was 50.2 ± 17.2 years. Hypertension, diabetes, hyperlipidaemia and obesity were more prevalent in the uveitis group (all p < 0.0001). The hazard of psoriasis or psoriatic arthritis development was significantly greater in the uveitis group than in the non-uveitis group (p < 0.0001); this increased risk persisted after adjustment for confounders [adjusted HR = 1.41; 95% confidence interval (CI), 1.33–1.48]. Adjusted HRs showed an increasing trend from mild psoriasis (1.35; 95% CI, 1.28–1.44) to severe psoriasis (1.59; 95% CI, 1.30–1.94) and psoriatic arthritis (1.97; 95% CI, 1.60–2.42). Conclusions This nationwide population-based cohort study revealed that patients with uveitis have an increased risk of subsequent psoriasis or psoriatic arthritis development.

Anti-drug antibody (ADAb) development is associated with secondary therapeutic failure in biologic-treated rheumatoid arthritis (RA) patients. With a treat-to-target goal, we aimed to identify biomarkers for predicting ADAb development and therapeutic response in adalimumab-treated patients. Three independent cohorts were enrolled. In Cohort-1, 24 plasma samples (6 ADAb-positive and 6 ADAb-negative patients at baseline and week 24 of adalimumab therapy, respectively) were assayed with immune-related microarray containing 1,636 correctly folded functional proteins. Next, we executed statistically powered autoantibody profiling analysis of 50 samples in Cohort-2 (24 ADAb-positive and 26 ADAb-negative patients). Subsequently, immunofluorescence assay was performed on 48 samples in Cohort-3 to correlate with ADAb titers and drug levels. The biomarkers were identified for predicting ADAb development and therapeutic response using the immune-related microarray and machine learning approach. ADAb-positive patients had lower drug levels at week 24 (median=0.024 μg/ml) compared with ADAb-negative patients (median=6.38 μg/ml, p

In this study we aimed to identify the predictors of drug survival for biologic and targeted synthetic DMARDs (bDMARDs and tsDMARDs) among patients with rheumatoid arthritis (RA) in a real-world setting. Data from RA patients receiving bDMARDs and tsDMARDs between 2007 and 2019 were extracted from the Taiwan Rheumatology Association Clinical Electronic Registry (TRACER). Patients were categorized into tumor necrosis factor-alpha (TNF-α) inhibitors, non-TNF-α inhibitors, and tofacitinib groups. The primary outcome was 3-year drug retention and the causes of bDMARDs and tsDMARDs discontinuation were recorded. Baseline demographic data before the initiation of bDMARDs and tsDMARDs treatment were analyzed to identify the predictors of 3-year drug survival. A total of 1,270 RA patients were recruited (TNF-α inhibitors: 584; non-TNF-α inhibitors: 535; tofacitinib: 151). The independent protective factors for 3-year drug survival were positive rheumatoid factor (RF) (HR: 0.48, 95% CI: 0.27-0.85, p = 0.013) and biologics-naïve RA (HR: 0.61, 95% CI: 0.39-0.94, p = 0.024). In contrast, positive anti-citrullinated protein antibody (ACPA) (HR: 2.24, 95% CI: 1.32-3.79, p = 0.003) and pre-existing latent tuberculosis (HR: 2.90, 95% CI: 2.06-4.09, p