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Overall survival of systemic lupus erythematosus (SLE) patients significantly increased in recent decades, however, the relative risk of mortality is still high. Long-term survival outcome of pediatric SLE remains unclear. This study aims to explore the long-term survival rate and its predictors in patients with systemic lupus erythematosus (SLE).A retrospective, hospital-based cohort study was performed between 2004 and 2018 in a tertiary referral medical center in Taiwan. Data on comorbidities, medications, and causes of admission were collected for risk factor analysis using time-dependent multivariate Cox proportional hazards models.A total of 2392 adults and 115 pediatric SLE patients were enrolled (female, n = 2157 and 95, respectively). The 10-year survival rates were 93.2%, 90.2%, 98.9%, and 100% in adult women, adult men, girls, and boys with SLE, respectively. The overall mortality rate was 2.09 case/100 patient-years (PY) for male SLE and 1.39 case/100 PY for female SLE patients. Male SLE patients did not have a statistically significantly higher mortality rate than female SLE patients in each age stratification. Infectious disease (n = 119), heart failure (n = 21), and cerebrovascular accident (n = 14) were the leading causes of death in adult SLE patients. Advanced age (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 1.03-1.05), treatment with mean dosage of systemic glucocorticoid equivalent to10 mg/d of prednisolone (HR: 1.71, 95% CI: 1.14-2.57), comorbidities with malignancy (HR: 1.94, 95% CI: 1.22-3.09), chronic kidney disease (HR: 1.86, 95% CI: 1.25-2.77), hypertension (HR: 1.42, 95% CI: 1.01-1.98), and admission due to bacterial pneumonia (HR: 1.92, 95% CI: 1.12-3.31) and sepsis (HR: 2.78, 95% CI: 1.51-5.13) were independent risk factors for mortality in SLE patients.SLE patients with advanced age, malignancy, chronic kidney disease, hypertension, treated with a higher average dosage of glucocorticoids, and admission due to bacterial pneumonia and sepsis have an increased risk of mortality.

Objectives The data concerning the association between Tx and ADs remain unclear and are scarce. This study was undertaken to investigate whether people with Tx are more likely to develop ADs, compared to those without Tx. Methods Individuals who received Tx between 2002 and 2015 were identified and matched on age and sex with individuals without Tx. We performed multivariate and stratified analysis using the Kaplan–Meier method and Cox proportional hazards models in order to estimate the association between Tx and the risk of developing ADs. Results A total of 2550 thymectomized (Txd) patients and 24,664.941 non‐Txd comparison subjects were selected from NHIRD. Tx‐MG (myasthenia gravis) as compared with general population (nonTx‐nonMG), adjusted hazard ratio (aHR) were higher for incident Addison disease (aHR = 10.40, 95% CI 1.01–107), autoimmune hemolytic anemia (aHR = 21.54, 95% CI 2.06–14.8), Hashmoto thyroiditis (aHR = 5.52, 95% CI 1.34–34.7), ankylosing spondylitis (aHR = 2.73, 95% CI 1.09–6.84), rheumatoid arthritis (aHR = 5.25, 95% CI 1.79–15.47), primary Sjogren syndrome (pSS) (aHR = 3.77, 95% CI 1.30–11.0), and systemic lupus erythemtoasus (aHR = 10.40). Tx‐nonMG as compared with general population, aHR were higher for incident autoimmune hemolytic anemia (aHR = 25.50), Hashmoto thyroiditis (aHR = 6.75) and systemic lupus erythematosus (SLE) (aHR = 13.38). NonTx‐MG as compared with general population, aHR were higher for incident Hashmoto thyroiditis (aHR = 6.57), pSS (aHR = 4.50), SLE (aHR = 17.29), and systemic vasculitis (aHR = 25.86). Interpretation In conclusion, based on a retrospective cohort study throughout Taiwan, patients with Tx have a higher risk of new onset ADs than patients without Tx.

The real-world outcomes of golimumab (GLM) use have been rarely studied in Asian patients with rheumatoid arthritis (RA). This study assessed the real-world effectiveness and safety of GLM in a Taiwanese cohort.One hundred and eight GLM-treated RA patients were enrolled. Predictors of a good European League Against Rheumatism (EULAR) response at 24 months and drug retention were identified through multivariate analyses.After 24 months of GLM treatment, the mean Disease Activity Score using 28 joint counts with the erythrocyte sedimentation rate (DAS28-ESR) decreased from 6.7 to 3.1 (p0.001). Up to 58.9% of patients achieved a good EULAR response at 24 months. Multivariate logistic regression analysis revealed that after adjustment for other variables, a higher baseline C-reactive protein was an independent negative predictor of good EULAR responses (odds ratio, 0.82; 95% confidence interval [CI], 0.67-0.99; p = 0.043). During the mean follow-up period of 38.3 months, 15 (13.9%) patients discontinued GLM due to treatment failure. In multivariate analysis, high baseline ESR level, high DAS28-ESR, and the experience of biologic therapy were independent risk factors for GLM discontinuation (adjusted hazard ratio [HR], 1.03; 95% CI, 1.01-1.05; p = 0.003; adjusted HR, 2.93; 95% CI, 1.42-6.08; p = 0.004; and adjusted HR, 5.00; 95% CI, 1.75-14.26; p = 0.003, respectively). In receiver operator characteristic curve analysis, the optimal cutoff values of baseline ESR and DAS28-ESR for predicting drug survival were 52 mm/h (sensitivity: 60.0% and specificity: 77.4%) and 7.7 (sensitivity: 46.7% and specificity: 94.3%), respectively. During the follow-up period, 22 patients (20.4%) developed adverse events. The safety profile of GLM in this study was comparable with that in previous clinical trials.GLM was effective and safe for the real-life management of Taiwanese RA patients and showed a high retention rate in biologic-naive patients compared with biologic-experienced patients.

ObjectiveTo compare changes in bone mineral density (BMD) in rheumatoid arthritis (RA) patients receiving three-year conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD), tumor necrosis factor-α inhibitors (TNFi), and abatacept.MethodsPatients with RA were recruited from September 2014 to February 2021. Dual-energy X-ray absorptiometry was used to measure BMD at the femoral neck (FN), total hip (TH), and lumbar spine (L1-4) at enrollment and three years later. Changes in the BMD of each regimen group were analyzed. Multiple ordinary least squares regression was used with the dependent variables to develop a model to predict the change in BMD.ResultsA total of 752 participants were enrolled and 485 completed the three-year follow-up period. Of these, 375 (Group I), 84 (Group II), and 26 (Group III) participants received csDMARDs, TNFi, and abatacept therapy, respectively. Considering both type of therapy and completion of the follow-up period, participants were divided into groups A (csDMARDs, n = 104), B (TNFi, n = 52), and C (abatacept, n = 26). Compared to baseline, BMD decreased significantly at FN (p = 0.003) and L1-4 (p = 0.002) in Group A and at L1-4 (p = 0.005) in Group B, but remained stable at all sites in Group C. In terms of regression-adjusted percent change in BMD, there was a significant difference seen at all measured sites between group C compared to both groups A and B (+0.8%, -2.7%, -1.8% at FN; +0.5%, -1.1%, -1.0% at TH; +0.8%, -2.0%, -3.5% at L1-4, respectively; all p < 0.05). Anti-osteoporosis therapy had a BMD-preserving effect in RA.ConclusionCompared with csDMARDs and TNFi, abatacept may have a better BMD-preserving effect in RA. Anti-osteoporosis therapy can prevent systemic bone loss irrespective of RA therapy.

BackgroundPrevious study revealed proton pump inhibitors (PPIs) have an effect on gut microbiota. Alteration of the microbiome causes changes of the host immune system and then induces the development of autoimmune diseases (ADs). This study aimed to explore the possible association between PPIs use and ADs.MethodsThis study was conducted using data from the Taiwan National Health Insurance Research Database in the period between 2002 and 2015. We performed multivariate and stratified analysis through the Kaplan-Meier method and Cox proportional hazard models to estimate the association between proton pump inhibitor use and the risk of autoimmune diseases.ResultsOf the 297,099 patients treated with PPI identified, the overall mean (SD) age was 49.17 (15.63) years and 56.28% of the subjects was male. As compared with the non-PPI group, the adjusted hazard ratio (aHR) were higher for incident organ specific ADs such as Graves disease (aHR=3.28), Hashmoto thyroiditis (aHR=3.61), autoimmune hemolytic anemia (aHR=8.88), immune thrombocytopenic purpura (aHR=5.05) Henoch-Schonlein pupura (aHR=4.83) and Myasthenia gravis (aHR=8.73). Furthermore, the adjusted hazard ratio (aHR) were also higher for incident systemic ADs such as ankylosing spondylitis (aHR=3.67), rheumatoid arthritis (aHR=3.96), primary Sjogren syndrome (aHR=7.81), systemic lupus erythemtoasus (aHR=7.03). systemic vasculitis (aHR=5.10), psoriasis (aHR=2.57), systemic scleroderma (aHR=15.85) and inflammatory myopathy (aHR=37.40). Furthermore, we observed no dose-dependent effect between PPI use and the risk of ADs.ConclusionsOur retrospective population-based cohort study showed that the prescription of proton pump inhibitors is associated with a higher risk of ADs.

Sarcopenia is a negative predictor for postoperative recovery. This study was performed to evaluate the short-term outcomes of laparoscopic surgery in colorectal cancer patients with sarcopenia. We conducted a study of patients who underwent curative surgeries for colorectal cancer in two centers from July 2014 to July 2018. In order to reduce selection bias, we conducted a propensity score matching analysis. Preoperative characteristics including age, gender, anemia, body mass index, hypoalbuminemia, America society of anesthesiology scores, epidural anesthesia, operative procedure, stoma, tumor location, and combined resection were incorporated in the model, and produced 58 matched pairs. The third lumbar skeletal muscle mass, handgrip strength, and 6 m usual gait speed were measured to define sarcopenia. Short-term outcomes were compared between the two groups. In a total of 1136 patients, 272 had sarcopenia diagnosed, and 227 were further analyzed in this study. Among them, 108 patients underwent laparoscopic colorectal surgery and 119 underwent open colorectal surgery. In the matched cohort, the clinical characteristics of the two groups were well matched. The laparoscopic group had significantly reduced overall complications (15.5% vs. 36.2%, P = 0.016) and shorter postoperative hospital stays (10.5 vs. 14, P = 0.027). Subgroup analysis of postoperative complications showed that the incidence of surgical complications (P = 0.032) was lower in the laparoscopic group. Hospitalization costs (P = 0.071) and 30-day readmissions (P = 0.215) were similar between the two groups. Laparoscopic surgery for colorectal cancer is a safe and feasible option with better short-term outcomes in patients with sarcopenia.

Objective We studied the risk of dementia in patients with primary Sjögren's syndrome (pSS) using a nationwide, population‐based cohort in Taiwan. Methods Our study analyzed the medical data of the Taiwanese population from 2000 to 2014. We identified 17,072 patients with pSS and 68,270 controls. Dementia risk was analyzed using a Cox proportional hazards regression model stratified by sex, age, and comorbidities. Results A higher incidence of dementia development in the pSS group during the observation period (P = 0.0001). In multivariate analysis adjusted by age groups, gender, and the comorbidities, the adjusted hazard ratio (aHR) of developing dementia was 1.246 (95% CI 1.123–1.384) times greater in the pSS group than in the non‐pSS group. When stratified by sex, age, and comorbidities, the patients with pSS less than 60 years (aHR 1.67, 95% CI 1.16–2.41), and without any comorbidity (aHR 2.27, 95% CI 1.76–2.93) were particularly associated with a higher risk of dementia. Furthermore, the patients with pSS combined with any other comorbidity had an additionally higher risk of dementia (aHR: 3.978, 95% CI 3.309–4.782), also suggesting that pSS was an independent risk factor for the development of dementia. Interpretation Primary Sjogren's syndrome is associated with increased dementia risk and further study is needed to understand why and what the specific dementia phenotypes are.

Objective To compare Pneumocystis jirovecii pneumonia (PJP) risk between patients with autoimmune rheumatic diseases (ARD) and the general population Methods We identified patients with ARD recorded in the National Health Insurance Research Database of Taiwan from 2002 to 2015 and randomly selected a comparison cohort from the general population matched for age and sex. We analyzed PJP risk stratified by sex, age, comorbidities, and medications using Cox proportional hazard model. Results We enrolled 103,117 patients with ARD. PJP risk significantly increased in patients with any ARD and with each individual ARD like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren’s syndrome (SjS), polymyositis and dermatomyositis (PM/DM), systemic sclerosis (SSc), and systemic vasculitis. Patients with PM/DM showed prominent risk with incidence rate of 12.47/100,000 patient year (95% confidence interval (CI), 32.16–86.70). In a time-dependent Cox proportional hazard model with comorbidities and medications as covariates, PM/DM, SSc, SLE, and SjS significantly increased adjusted hazard ratios (aHR) of 5.40, 5.12, 4.09, and 3.64, respectively (95% CI of 2.82–10.35, 2.16–12.13, 2.41–6.95, and 2.06–6.42, respectively). AHR after adjusting for male sex, cancer, human immunodeficiency virus infection (HIV), and interstitial lung disease also significantly increased. Use of daily oral steroid dose of >10 mg conferred the highest risk followed by mycophenolate. Use of injected steroids, cyclophosphamide, biological agents, methotrexate, and cyclosporine conferred a significantly higher risk. Conclusion Underlying ARD significantly predisposes patients to PJP, with PM/DM posing the highest threat. In addition to underlying disease, comorbidities and concomitant immunosuppressants are major risks. The strongest risk is recent daily steroid dose of >10 mg. Mycophenolate seems to be a more prominent risk factor than cyclophosphamide.Key Points• Autoimmune rheumatic diseases (ARD) significantly increased the overall risk of PJP, and so did each individual ARD.• Use of steroids, mycophenolate, cyclophosphamide, biological agents, methotrexate, and cyclosporine all significantly increased risk of PJP.• Male, elderly, malignancy, HIV, and interstitial lung disease are also related to increased risk of PJP.• Underlying ARD, comorbidities, and use of immunosuppressant should all be considered in determining the overall risk of PJP.

To evaluate Pneumocystis jirovecii pneumonia (PJP) infection risk in patients with systemic lupus erythematosus (SLE) in Taiwan.We identified 24,367 patients with SLE from the National Health Insurance research database between 1997 and 2012 and compared the PJP incidence rates (IRs) with those in 243,670 age- and sex-matched non-SLE controls. PJP risk in the patients was evaluated using a Cox multivariate proportional hazards model.The SLE patients exhibited a significantly higher PJP risk than the controls, with an IR of 2.63 per 10,000 person-years and IR ratio of 27.65 (95% confidence interval 17.2-45.3; P 0.001). Male sex (hazard ratio [HR] 2.42, P 0.01), end-stage renal disease (ESRD; HR 1.74, P = 0.01), recent use of mycofenolate mofetil (MMF; HR 4.43, P 0.001), intravenous steroid pulse therapy (HR 108.73, P 0.001), and average oral dosage of7.5 mg/day prednisolone or equivalent treatment (HR 4.83, P 0.001) were associated with PJP in SLE, whereas hydroxychloroquine use reduced its risk (HR 0.51, P = 0.01). Of note, cyclophosphamide was not associated with PJP infection in the multivariate Cox proportional hazard model.Patients with SLE have a considerably high PJP risk. Cyclophosphamide does not increase PJP risk. Male sex, ESRD, MMF use, intravenous steroid pulse therapy, and oral prednisolone or equivalent treatment (7.5 mg/day) are risk factors for PJP, whereas hydroxychloroquine use reduces PJP risk.

In our previous study, we have shown that CRLF1 can promote proliferation and metastasis of papillary thyroid carcinoma (PTC); however, the mechanism is unclear. Herein, we investigated whether the interaction of CRLF1 and MYH9 regulates proliferation and metastasis of PTC cells via the ERK/ETV4 axis. Immunohistochemistry (IHC), qPCR, and Western blotting assays were performed on PTC cells and normal thyroid cells to profile specific target genes. In vitro assays and in vivo assays were also conducted to examine the molecular mechanism. Results showed that CRLF1 directly bound MYH9 to enhance the stability of CRLF1 protein. Inhibition of MYH9 in PTC cells overexpressing CRLF1 significantly reversed malignant phenotypes, and CRLF1 overexpression activated ERK pathway, in vitro, and in vivo. RNA-sequencing revealed that ETV4 is a downstream target gene of CRLF1, which was up-regulated following ERK activation. Moreover, it was revealed that ETV4 is highly expressed in PTC tissues and is associated with poor prognosis. Finally, the ChIP assays showed that ETV4 induces the expression of matrix metalloproteinase 1 (MMP1) by binding to its promoter on PTC cells. Altogether, our study demonstrates that CRLF1 interacts with MYH9, promoting cell proliferation and metastasis via the ERK/ETV4 axis in PTC.

Aim To assess the real-world effectiveness and safety of rituximab (RTX) at 24 months in patients with established rheumatoid arthritis (RA) and to identify predictors of low disease activity/remission and a good European League Against Rheumatism (EULAR) response. Methods Seventy RTX-treated RA patients were enrolled. Predictors for low disease activity/remission and a good EULAR response at 24 months were identified by multivariate analyses. Results At 24 months, the mean Disease Activity Score of 28 joints-erythrocyte sedimentation rate (DAS28-ESR) decreased from 6.88 ± 0.85 at baseline to 3.47 ± 0.85. Twenty-nine patients (41.4%) reached low disease activity/remission, while all patients had a moderate/good EULAR response. After adjustment by multivariate analyses, we found concomitant methotrexate at a dosage >10 mg/week (odds ratio [OR] 5.17; 95% CI 1.34-19.93; P = 0.017) predicted low disease activity/remission, and baseline DAS28 ≤6.5 (OR 4.97; 95% CI 1.22-20.30; P = 0.026) predicted good EULAR response at 24 months. The most common adverse events were infusion-related (5.7%), and there was no incidence of malignancy or mortality during the treatment. Conclusions RTX was effective and safe in real-life management of RA patients with high disease activity. Patients taking concomitant methotrexate and with lower baseline DAS28-ESR were more likely to benefit from RTX.

Background/purpose: To investigate the Janus kinase-1 and 3 (JAK-1 and 3) expression in peripheral blood mononuclear cells (PBMCs) in ankylosing spondylitis (AS). Methods: The levels of JAK-1 and JAK-3 mRNA in PBMCs, CD3+ T cells and CD14+ monocytes were measured by RT-PCR in 52 AS patients and 31 healthy controls (HCs). The demographic features, BASDAI, BASFI, HLA-B27, ESR, CRP and serum immunoglobulin A (IgA) level were recorded and correlated with the JAK-1 & JAK-3 transcripts in patients and HCs as appropriate. Results: JAK-1 and JAK-3 expression in PB CD3+ T cells plus CD14+ monocytes was significantly higher in AS patients than in HCs (p 4) and BASFI (>4) than ESR or CRP in AS patients. Conclusion: In AS, JAK-1 expression in PB cells rather than ESR or CRP might be regarded as a bio-marker for monitoring disease activity and functional index in AS. These findings have also suggested that JAK-1 and JAK-3 expression may play a role in the inflammatory processes in patients with AS. Keywords: Ankylosing spondylitis, Janus kinase (JAK), Acute-phase reactant

Objective The objective of this paper is to investigate the incidence rate, risk factors and outcome of osteomyelitis among patients with systemic lupus erythematosus (SLE). Materials and methods We conducted a cohort study using data for patients enrolled in the Taiwan National Health Insurance Database from 2000 to 2012. Patients with SLE and age- and sex-matched controls without SLE were enrolled. Primary endpoint was the first occurrence of osteomyelitis. Risks of osteomyelitis in SLE patients were analyzed with Cox proportional hazards regression models, including age, sex, comorbidities and medications. Results Among 24,705 SLE patients (88.4% women, mean age 35.8 years) with a median follow-up of 9.1 years, 386 patients had osteomyelitis. The incidence rate ratio (IRR) of osteomyelitis in the SLE group vs the control group was 8.52 (95% confidence interval (CI) 7.24–10.05). The SLE group had higher incidence rates of osteomyelitis than the control group, especially in pediatric subgroups (IRR 41.1 95% CI 18.57–107.35). Compared to controls, SLE patients experienced osteomyelitis at a younger age (42.3 vs 58.1 years) but did not have an increased risk of mortality (hazard ratio 0.7; 95% CI 0.21–2.38). Age >60 years, male gender, malignancy within five years, prior bone fracture and higher daily prednisolone dose (>7.5 mg) cumulatively for >180 days increased risk for osteomyelitis. Conclusions SLE patients have a higher IRR of osteomyelitis than controls. Pediatric and elder SLE patients, patients with a history of bone fracture, malignancy within five years and higher-dose glucocorticoid use have a higher risk of osteomyelitis and should be carefully monitored.

Objectives Previous studies have shown myasthenia gravis (MG) and autoimmune rheumatic diseases (ARDs) share common pathogenetic mechanisms. Therefore, the present study investigated the possible relationship between MG and ARDs. Methods We analysed Taiwanese medical data from the Registry of Catastrophic Illness and identified patients with MG. From the entire general population data of the National Health Insurance Research Database, we randomly selected a comparison cohort that was frequency-matched by age (in 5-year increments), sex, and index date. We analysed the risk of ARDs by using a Cox proportional hazards regression model stratified by sex, age and treatment. Results In the present study, we enrolled 6478 patients with MG (58.03% women; mean age, 50.55 years) and 25 912 age- and sex-matched controls. The risk of total ARDs was 6.25 times higher in the MG cohort than in the non-MG cohort after adjustment for age and sex. Furthermore, the MG cohort was associated with a significantly higher risk of primary SS (pSS), SLE and other ARD types (adjusted hazard ratios: 15.84 [95% CI: 8.39, 23.91]; 11.32 [95% CI: 5.04, 25.429]; and 4.07 [95% CI: 1.31, 12.62], respectively). The MG cohort who underwent thymectomy had an increased risk of RA, pSS and SLE (adjusted hazard ratios: 4.41; 15.06; and 23.68, respectively). Conclusion The present nationwide cohort study revealed an association between MG and incident ARDs. The MG cohort who underwent thymectomy had an increased risk of RA, pSS and SLE. Future studies are needed to elucidate the underlying pathogenesis and to translate this into clinical therapeutic options.

In autoimmune rheumatic diseases (ARDs), the levels of inflammatory mediators are increased and microglia may be activated, resulting in an inflammatory state and the degeneration of dopaminergic neurons. We investigated the association between ARDs and Parkinson disease (PD).We identified ARD patients through the Taiwan National Health Insurance Research Database from 2001 to 2012. From the general population, we randomly selected a comparison cohort that was frequency-matched by age (in 5-year increments), sex and index year. We analysed the risk of PD, stratified by sex, age and comorbidities, by using a Cox regression model.The risk of PD was 1.37 times greater in ARD patients than in controls after adjustment for age, sex, and comorbidities. ARD subgroups, such as the rheumatoid arthritis and Sjogren syndrome (SS) cohorts, were associated with a significantly higher risk of PD (adjusted hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.03-1.2 and adjusted HR, 1.56; 95% CI, 1.35-1.79, respectively). Furthermore, primary and secondary SS patients had significantly higher risks of PD (adjusted HR, 1.58; 95% CI, 1.32-1.88 and adjusted HR, 1.53, 95% CI, 1.23-1.90, respectively).The risk of PD was significantly higher in the ARD patients. Prospective studies are needed to confirm whether ARDs indeed increase the risk of PD.

Patients with obstructive sleep apnea (OSA) have a higher risk of Behcet’s disease (BD) and Sjogren syndrome (SS). However, the bidirectional relationship between these autoimmune diseases and OSA is unclear. We investigated the relationship between autoimmune diseases (SS and BD) and OSA. SS and BD patients were identified through the Taiwan National Health Insurance Research Database from 2002 to 2012. Patients with SS or BD were matched according to age and sex with a control group in a ratio of 1:4. The study included 12,926 patients with SS and 51,704 non-SS controls. Similarly, 1221 patients with BD were matched with 4884 non-BD controls. We used a Cox regression model, stratified by age, gender, and comorbidities, to assess the risk of OSA. OSA was diagnosed in 0.61% of the SS cohort and 1.23% of the BD cohort. The higher overall risk for OSA was observed significantly in patients with SS than in controls (adjusted hazard ratio [HR] = 2.48, 95% confidence interval [CI] = 1.89–3.24). The higher risk was also observed significantly in BD patients than in controls (HR = 1.99, 95% CI = 1.06–3.72). Furthermore, men with SS or BD exhibited HR of 2.62 (95% CI 1.89 to 3.62) and 6.40 (95% CI 2.96 to 13.84) for developing OSA, respectively. Risk of OSA was significantly elevated in SS or BD patients compared with controls. Further study is warranted to elucidate underlying mechanisms.

Study objectives To explore associations between obstructive sleep apnea (OSA) and autoimmune diseases and evaluate whether OSA management reduces the incidence of autoimmune diseases. Methods This was a retrospective cohort study using nationwide database research. The data was from 105,846 adult patients in whom OSA was diagnosed and recorded in the Taiwan National Health Insurance Research Database between 2002 and 2011 were the patients were analyzed retrospectively. Patients with antecedent autoimmune diseases were excluded. A comparison cohort of 423,384 participants without OSA served as age- and sex-matched controls. Multivariable Cox regression analysis was performed on both cohorts to compute risk of autoimmune diseases during follow-up. Time-dependent OSA treatment effect was analyzed among patients with OSA. There were no interventions. Results Among patients with OSA, overall risk for incident autoimmune diseases was significantly higher than that in controls (adjusted hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.66-2.27). Risk for individual autoimmune diseases, including rheumatoid arthritis (RA), Sjogren syndrome (SS), and Behcet disease, was significantly higher in patients with OSA than in controls (HRs [95% CI]: RA 1.33 [1.03-1.72, SS 3.45 [2.67-4.45] and Behcet disease 5.33 [2.45-12.66]). Increased risk for systemic lupus erythematosus (HR 1.00 [0.54-1.84]) and systemic sclerosis (HR 1.43 [0.51-3.96]) did not reach statistical significance. Patients with OSA receiving treatment had an overall reduced risk of RA and other autoimmune diseases (time-dependent HRs [95% CI]: 0.22 [0.05-0.94] and 0.51 [0.28-0.92], respectively). Conclusions Patients with OSA are associated with higher risk for developing RA, SS, and Behcet disease. OSA management is associated with reduced risk of RA.

The systemic capillary leak syndrome (SCLS, Clarkson disease) is a disorder of unknown etiology characterized by recurrent episodes of vascular leakage of proteins and fluids into peripheral tissues, resulting in whole-body edema and hypotensive shock. The pathologic mechanisms and genetic basis for SCLS remain elusive. Here we identify an inbred mouse strain, SJL, which recapitulates cardinal features of SCLS, including susceptibility to histamine- and infection-triggered vascular leak. We named this trait “Histamine hypersensitivity” (Hhs/Hhs) and mapped it to Chromosome 6. Hhs is syntenic to the genomic locus most strongly associated with SCLS in humans (3p25.3), revealing that the predisposition to develop vascular hyperpermeability has a strong genetic component conserved between humans and mice and providing a naturally occurring animal model for SCLS. Genetic analysis of Hhs may reveal orthologous candidate genes that contribute not only to SCLS, but also to normal and dysregulated mechanisms underlying vascular barrier function more generally., Raza et al. report a naturally occurring animal model that recapitulates cardinal features of Systemic Capillary Leak Syndrome and map its histamine-triggered vascular leak trait to Chromosome 6. They suggest that the predisposition to develop vascular hyperpermeability has a strong genetic component conserved between humans and mice.

ObjectivePatients with systemic lupus erythematosus (SLE) are susceptible to herpes simplex virus (HSV) infection, which occasionally leads to severe complications including meningoencephalitis and keratitis. However, few attempts to analyse the associated incidence and risk factors have been made.MethodsWe enrolled patients with SLE recorded between 1997 and 2012 and compared the incidence rate (IR) of severe HSV infection, including meningoencephalitis, septicaemia, ocular and visceral involvement, and other specific complications demanding hospitalisation, with that of a non-SLE cohort. A Cox multivariate proportional hazards model was applied to analyse the risk factors of severe HSV infection in patients with SLE.ResultsA total of 122 520 subjects (24 504 patients with SLE and 98 016 age-matched and sex-matched non-SLE controls) were included, and a higher IR of severe HSV infection was revealed in the SLE group (IR ratio=3.93, pConclusionsPatients with SLE are at higher risk of severe HSV infection, and related risk factors include being older than 18 years, having a history of HSV mucocutaneous infection, recent receipt of steroid pulse therapy and a daily oral dose of steroid over 7.5 mg prednisolone.

Background: The clinical features and outcomes of cytomegalovirus (CMV) diseases in patients with systemic lupus erythematosus (SLE) are unknown. We analyzed such data from a medical center in Taiwan. Methods: We retrospectively reviewed the medical records of patients with SLE who were diagnosed with CMV diseases between 2006 and 2016 in Taipei Veterans General Hospital Taiwan. Clinical and laboratory parameters and treatment outcomes were analyzed. Results: The study enrolled 56 eligible patients with CMV diseases and separated them into survival (n = 24) and mortality (n = 32) groups. All cases showed a significantly high incidence of pneumonitis (71.43%). The patients in the mortality group had a higher SLE disease activity index (SLEDAI)-2000 (p = 0.009), more cases of recent methylprednisolone pulse therapy (p = 0.013) and pancytopenia (p = 0.001), stronger evidence of CMV infection demonstrated by polymerase chain reaction (PCR) in blood (p

PURPOSE Although members of the galectin family of carbohydrate-binding proteins are thought to play a role in the immune response and regulation of allograft survival, little is known about the galectin expression signature in failed corneal grafts. The aim of this study was to compare the galectin expression pattern in accepted and rejected murine corneal allografts. METHODS Using BALB/c mice as recipients and C57BL/6 mice as donors, a total of 57 transplants were successfully performed. One week after transplantation, the grafts were scored for opacity by slit-lamp microscopy. Opacity scores of 3+ or greater on postoperative week 4 were considered rejected. Grafted corneas were harvested on postoperative week 4, and their galectin expressions were analyzed by Western blot and immunofluorescence staining. RESULTS As determined by the Western blot analyses, galectins-1, 3, 7, 8 and 9 were expressed in normal corneas. Although in both accepted and rejected grafts, expression levels of the 5 lectins were upregulated compared with normal corneas, there were distinct differences in the expression levels of galectins-8 and 9 between accepted and rejected grafts, as both the Western blot and immunofluorescence staining revealed that galectin-8 is upregulated, whereas galectin-9 is downregulated in the rejected grafts compared with the accepted grafts. CONCLUSIONS Our findings that corneal allograft rejection is associated with increased galectin-8 expression and reduced galectin-9 expression, support the hypothesis that galectin-8 may reduce graft survival, whereas galectin-9 may promote graft survival. As a potential therapeutic intervention, inhibition of galectin-8 and/or treatment with exogenous galectin-9 may enhance corneal allograft survival rates.

To investigate the effect of inflammation on expressions of bone morphogenetic proteins (BMPs) in peripheral blood mononuclear cells (PBMCs) and its association with individual radiographic changes in patients with ankylosing spondylitis (AS).The changes in BMP-2, -4, and -7 gene expressions in PBMCs were measured after stimulation by tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The correlation of increase in gene expression with clinical and radiographic findings in patients with AS were analyzed.Both TNF-α and IL-1β could enhance BMP-2 expression in PBMCs from AS patients. Increases in BMP-2, -4, and -7 expressions in PBMCs positively correlated with total modified Stoke Ankylosing Spondylitis Spinal Score (all p0.05). Moreover, increases in BMP-2, -4, and -7 gene expressions after TNF-α and IL-1β stimulation were greater among AS patients with versus without severe sacroiliitis (all p0.05). Increases in BMP-2 and -7 expressions were greater in PBMCs from 4 patients with total (cervical, thoracic, and lumbar) spinal ankylosis than in the 8 patients who did not have total spinal ankylosis (all p0.05).In AS, inflammation upregulates the expression of BMPs in PBMCs which may lead to the radiographic progression with new bone formation.

Background Systemic Capillary Leak Syndrome (SCLS) is an extremely rare and life-threatening vascular disorder of unknown etiology. SCLS is characterized by abrupt and transient episodes of hypotensive shock and edema due to plasma leakage into peripheral tissues. The disorder has garnered attention recently because its initial presentation resembles more common vascular disorders including systemic anaphylaxis, sepsis, and acute infections with the Ebola/Marburg family of filoviruses. Although approximately 70–85% of patients with SCLS have a concurrent monoclonal gammopathy of unknown significance (MGUS), any contribution of the paraprotein to acute flares is unknown. Procedure To identify circulating factors that might trigger acute SCLS crises, we profiled transcriptomes of paired peripheral blood mononuclear cell fractions obtained from patients during acute attacks and convalescent intervals by microarray. Results This study uncovered 61 genes that were significantly up- or downregulated more than 2.5-fold in acute samples relative to respective baselines. One of the most upregulated genes was ADM, which encodes the vasoactive peptide adrenomedullin. A stable ADM protein surrogate (pro-ADM) was markedly elevated in SCLS acute sera compared to remission samples or sera from healthy controls. Monocytes and endothelial cells (ECs) from SCLS subjects expressed significantly more ADM in response to proinflammatory stimuli compared to healthy control cells. Application of ADM to ECs elicited protective effects on vascular barrier function, suggesting a feedback protective mechanism in SCLS. Conclusions Since ADM has established hypotensive effects, differentiating between these dual actions of ADM is crucial for therapeutic applications aimed at more common diseases associated with increased ADM levels.

Treatment with biological disease-modifying anti-rheumatic drugs (bDMARDs) for rheumatoid arthritis (RA) and ankylosing spondylitis (AS) is popular. The aim of this study was to investigate changes in the quality of life (QoL) in patients after receiving, tapering, or stopping bDMARD treatment. Three hundred and thirty patients with RA and 120 patients with AS were enrolled. Data on the patients receiving bDMARDs were obtained by self-completed questionnaires including the short-form 36 (SF-36) and Global Quality of Life (GQL) scale. A relapse was defined as the QoL becoming worse than that before bDMARD treatment. Significant improvement in all domains of the SF-36 and GQL was noted in the patients after receiving bDMARDs. Improvement in SF-36 was significantly greater in RA patients with a shorter disease duration ( 6 years) and milder patient-assessed disease activity and in AS patients with a shorter disease duration and younger age. There were significant decreases in all domains of the SF-36 and GQL in both groups after reducing/discontinuing bDMARD treatment. The patients in both groups with a shorter period of bDMARD treatment (≤ 3 years) had significantly worse SF-36 scores compared to those with a longer period of bDMARD treatment ( 3 years). The relapse rate after reducing/discontinuing treatment was over 90.0% in the RA patients and over 50.0% in the AS patients within 12 months. bDMARDs significantly improved the QoL of the patients with RA and AS. However, interrupting or stopping the treatment protocol worsened the QoL and led to relapses, especially in the patients who used bDMARDs for a shorter period.

Objective Dementia is a common neurological disease that substantially affects public health. A previous study revealed that dementia occurs when the body’s immune system attacks the cells of the brain, indicating that dementia may be similar to autoimmune rheumatic diseases (ARDs). In the current retrospective cohort study, we focused on middle-aged ARD patients (45 years or older) to investigate the association between ARDs in middle-aged people and dementia by using a nationwide population-based database in Taiwan. Method Our study analyzed the medical data of the Taiwanese population from 2001 to 2012, with a follow-up period extending until the end of 2011. We identified middle-aged patients with ARDs by using the Taiwan National Health Insurance Research Database. We selected a comparison cohort from the general population that was randomly frequency-matched by age (in 5-year increments), sex, and index year and further analyzed the dementia risk by using a Cox regression model that considers sex, age, and comorbidities. Results The study enrolled 34,660 middle-aged ARD patients (77% female, mean age = 59.8 years) and 138,640 controls. The risk of developing dementia was 1.18 times higher for middle-aged patients with ARDs compared with patients without ARDs after adjustment for age, sex, and comorbidities. Among the patients with ARDs, the subgroups with rheumatoid arthritis, systemic lupus erythematosus, and Sjogren syndrome (SS) were associated with a significantly higher dementia risk (adjusted hazard ratio [HR] 1.14, 95% confidence index [CI] 1.06–1.32; adjusted HR 1.07, 95% CI 0.86–1.34; adjusted HR 1.46, 95% CI 1.32–1.63, respectively). Furthermore, primary SS and secondary SS patients had the highest risks of dementia among all the ADR subgroups (adjusted HR 1.35, 95% CI 1.18–1.54; adjusted HR 1.67, 95% CI 1.43–1.95 respectively). Conclusion This nationwide retrospective cohort study demonstrated that dementia risk is significantly higher in middle-aged patients with ARDs compared with the general population.

Objective The objective of our study was to determine the incidence rates and risk factors of aortic aneurysm and aortic dissection among patients with systemic lupus erythematosus (SLE) using a nationwide population-based data set. Methods We conducted a retrospective cohort study using data from the Taiwan National Health Insurance database. Patients with SLE and age-, sex- and comorbidity-matched control patients without SLE were identified. The primary endpoint was the first occurrence of aortic aneurysm or aortic dissection. The incidence rate ratios (IRRs) were calculated based on a 95% confidence interval (CI). A Cox proportional-hazards model was used to evaluate the risk factors for aortic aneurysm and aortic dissection in the SLE cohort. Results Among the 15,209 patients with SLE (89.9% women and mean age of 38.3 years), 20 developed aortic aneurysm and 13 developed aortic dissection (overall incidence rate, 4.26 per 10,000 person-years). Compared with the control patients, the overall IRR for developing aortic aneurysm or aortic dissection was 3.34 (95% CI, 1.71–6.91; p Conclusion Aortic aneurysm and aortic dissection occur at higher rates in SLE patients than in people without SLE and a longer disease duration is associated with a higher risk of these rare vascular complications.

ObjectivesTo identify the incidence rate (IR) and risk factors of osteoporotic fractures (OFs) among systemic sclerosis (SSc) patients.MethodsA cohort study was conducted using the Taiwan National Health Insurance database. Patients with SSc and respective age- and gender-matched controls without SSc were enrolled. The primary endpoint was the first occurrence of OF. The Cox proportional hazard model was used to investigate the risk factor of OFs in the SSc cohort.ResultsAmong 1712 SSc patients (77.8% female, mean age 50.3 years) with a median follow-up of 5.2 years, 54 patients developed vertebral fractures, 17 patients developed hip fractures, and 7 patients developed radius fractures (IR: 6.99, 2.18 and 0.90 per 1000 person-years, respectively). Compared with the controls, the incidence rate ratios (IRRs) (95% CIs) among SSc patients were 1.78 (1.30 to 2.39, p7.5 mg, and bowel dysmotility treated with intravenous metoclopramide are associated with OF.ConclusionsSSc patients had a high IR of vertebral and hip fractures, especially those who were female, older, used a high dose of corticosteroid or experienced bowel dysmotility.

A relatively common occurrence of spontaneous subarachnoid hemorrhage (SAH) in patients with systemic lupus erythematosus (SLE) has been noted; however, the subsequent studies were conflicting. This nationwide population-based study aimed to evaluate the risk of SAH in patients with SLE.We identified 16,967 SLE patients from the Taiwan National Health Insurance (NHI) database between 2000 and 2006, and compared the incidence rate of SAH with 16,967 randomly selected age- and sex-matched non-SLE subjects. A Cox multivariable proportional hazards model was used to evaluate the risk factors of SAH in the SLE cohort.The SLE cohort had a higher risk of SAH, with an incidence rate ratio of 4.84 (P0.001). Despite a younger age, the mortality rate after SAH was significantly higher in the SLE cohort compared to all of the non-SLE SAH patients identified from the 1 million NHI beneficiaries (60.0% versus 38.9%; P = 0.007). Age (hazard ratio [HR] 1.03, 95% confidence interval [95% CI] 1.01-1.05), platelet transfusion (HR 2.75, 95% CI 1.46-5.17), red blood cell transfusion (HR 7.11, 95% CI 2.81-17.97), and a mean daily steroid dose10 mg of prednisolone or equivalent (HR 4.36, 95% CI 2.19-8.68) were independent risk factors for the new onset of SAH.This study demonstrated that SAH is a rare but associated complication of SLE with a high mortality rate. Other than age, higher mean daily steroid use and a history of platelet or red blood cell transfusion were associated with the occurrence of SAH in patients with SLE.

PURPOSE. Corneal neovascularization and scarring commonly lead to significant vision loss. This study was designed to determine whether a small-molecule inhibitor of galectin-3 can inhibit both corneal angiogenesis and fibrosis in experimental mouse models. METHODS. Animal models of silver nitrate cautery and alkaline burn were used to induce mouse corneal angiogenesis and fibrosis, respectively. Corneas were treated with the galectin-3 inhibitor, 33DFTG, or vehicle alone and were processed for whole-mount immunofluorescence staining and Western blot analysis to quantify the density of blood vessels and markers of fibrosis. In addition, human umbilical vein endothelial cells (HUVECs) and primary human corneal fibroblasts were used to analyze the role of galectin-3 in the process of angiogenesis and fibrosis in vitro. RESULTS. Robust angiogenesis was observed in silver nitrate-cauterized corneas on day 5 post injury, and markedly increased corneal opacification was demonstrated in alkaline burn-injured corneas on days 7 and 14 post injury. Treatment with the inhibitor substantially reduced corneal angiogenesis and opacification with a concomitant decrease in a-smooth muscle actin (α-SMA) expression and distribution. In vitro studies revealed that 33DFTG inhibited VEGF-A-induced HUVEC migration and sprouting without cytotoxic effects. The addition of exogenous galectin-3 to corneal fibroblasts in culture induced the expression of fibrosis-related proteins, including α-SMA and connective tissue growth factor. CONCLUSIONS. Our data provide proof of concept that targeting galectin-3 by the novel, smallmolecule inhibitor, 33DFTG, ameliorates pathological corneal angiogenesis as well as fibrosis. These findings suggest a potential new therapeutic strategy for treating ocular disorders related to pathological angiogenesis and fibrosis. (Less)

Studies on the clinical efficacy of influenza vaccination on patients with systemic lupus erythematosus (SLE) are scant. The present study compared the incidence of hospitalization, morbidity, and mortality in patients with SLE between cohorts with and without influenza vaccination. We used the Taiwan’s insurance claims data between 2001 and 2012 for identifying annual adult patients with SLE with (N = 1765) and without (N = 8360) influenza vaccination. The incidence rate ratio and hazard ratio (HR) for morbidities and mortality were measured for the vaccine and nonvaccine cohorts. The vaccine cohort had a lower hospitalization rate than did the nonvaccine cohort, with an adjusted HR of 0.82 (95% CI 0.73–0.92). Furthermore, the vaccine cohort was less likely to be admitted to the intensive care unit [adjusted HR 0.55 (95% CI 0.39–0.79)], to be hospitalized for septicemia, bacteremia, or viremia [adjusted HR 0.48 (95% CI 0.32–0.73)], to undergo in-hospital dialysis [adjusted HR 0.40 (95% CI 0.20–0.81)], and were less predisposed to death [adjusted HR 0.41 (95% CI 0.27–0.61)]. In conclusion, influenza vaccination in patients with SLE is associated with a reduced risk of morbidity and mortality.

Objectives This study aimed to identify the risk factors for mortality and the impact of dialysis modalities on the survival in SLE patients with end-stage renal disease (ESRD). Methods This retrospective nationwide population-based study using the National Health Insurance Research Database in Taiwan collected data from 1073 SLE ESRD patients starting maintenance dialysis between March 1997 and December 2006. A multivariate Cox regression hazard model was applied to identify factors predicting mortality in cohorts using different dialysis modalities and the impact of dialysis modalities on the survival outcome of these patients of both genders. Results The major threat to SLE patients on maintenance dialysis was infections. For SLE patients undergoing regular haemodialysis (HD), age, male sex, and high or absence of daily steroid dosing were predictive of higher mortality. For those undergoing regular peritoneal dialysis (PD), age and high daily steroid dosing were the predictive factors. After adjusting confounding factors, male patients with HD had a significantly poorer outcome than the counterpart with PD or female patients with HD. There was no survival difference among female SLE patients with different dialysis modalities. Conclusion No underlying comorbidities were identified to increase the mortality of patients receiving particular dialysis modalities after correcting for age and steroid factors. There was no impact of different dialysis modalities on survival of female SLE patients. However, male SLE patients seemed susceptible to fatal events complicated by HD, which led to an inferior survival rate.

Background Ankylosing spondylitis (AS) is a chronic arthritis with a pathogenesis which is not fully understood. A third subset of IL-17-producing T helper cells, called Th17 cells, has been discovered and characterized. We investigated whether IL-17 and IL-23, two Th17-related cytokines, play any roles in the pathogenesis of, and have any correlations with, disease activity and clinical manifestations in AS. Methods This cross-sectional study included 49 AS patients and 25 healthy control subjects. The serum IL-17 and IL-23 levels were measured using enzyme-linked immunosorbent assay kits. At the same time, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Patient Global Score (BAS-G) levels were measured, and physical examinations were performed on study participants to determine their extent of physical mobility. Results The serum IL-17 and IL-23 levels of the AS patients were significantly higher than those of the healthy controls. In the AS patients, the BASDAI scores had a better correlation with the serum IL-17 or IL-23 levels (IL-17, r = 0.351, p = 0.014; IL-23, r = 0.398, p = 0.005) than with ESR (r = 0.078, p = 0.600) and CRP (r = 0.012, p = 0.993). IL-17 or IL-23 correlate to the BASFI, BAS-G and parameters related to physical mobility. In the receiver operating characteristic (ROC) analysis, the serum IL-17 and IL-23 levels act better in discriminating patients with BASDAI≥4 (AUC value 0.88, p = 0.001) than ESR and CRP (AUC value 0.727, p = 0.008). Conclusion Serum IL-17 and IL-23 levels were significantly higher in AS patients than in healthy controls and the levels correlate to disease activity measured by BASDAI scores, but not parameters of functional ability and spinal mobility. These results suggest the existence of a role of IL-17 and IL-23 in the pathogenesis of inflammation in AS.

Objective.The aim of our study was to compare the clinical, functional, and radiographic outcomes at different ages of onset in patients with ankylosing spondylitis (AS).Methods.A total of 546 patients were enrolled consecutively and classified into 3 groups based on their age at symptom onset: (1) juvenile-onset AS (age ≤ 16 years; JoAS); (2) adult-onset AS (> 16 but < 40 years; AoAS); and (3) late-onset AS (≥ 40 years; LoAS). We compared the differences among the 3 groups. OR for disease outcomes were calculated and adjusted for sex, HLA-B27, and disease duration.Results.There were 67 patients (12.3%) with JoAS, 460 (84.2%) with AoAS, and 19 (3.5%) with LoAS. Male sex and HLA-B27 were associated with a younger age at onset (p < 0.001). Compared to patients with AoAS, patients with JoAS were more likely to present with peripheral arthritis, while patients with JoAS and LoAS were less likely to have back pain at the onset of AS (p < 0.05). After controlling for multiple covariates, JoAS was found to be associated with a worse functional outcome and global assessment, and a high serum immunoglobulin A level (p < 0.05). Patients with JoAS had less lumbar spinal radiographic severity (p < 0.05). There were no statistical differences in clinical or functional outcome between the LoAS and AoAS groups. None of the LoAS patients had radiographic hip involvement.Conclusion.Sex and HLA-B27 are significantly associated with age at onset of AS. Both JoAS and LoAS have their distinctive symptoms/signs at onset and different disease outcomes.

Warfarin is widely prescribed for patients with atrial fibrillation. In addition to unexpected bleeding, allergic skin reaction is one of its uncommon adverse effects. We herein report an 89-year-old man who, after taking warfarin for 4 years, suffered extensive skin eruptions. The skin biopsy disclosed leukocytoclastic vasculitis. The causal relationship between skin lesions and warfarin was confirmed after re-challenge of warfarin. A literature review revealed only 13 such cases reported from 1980 to 2011. Clinicians should be aware of this potential adverse effect of warfarin.

To determine the factors associated with radiographic spinal involvement and hip involvement in ankylosing spondylitis (AS) and assess the influence of the damage seen in the radiographs on functional outcome in patients with AS.We included 531 consecutive patients and recorded the clinical, laboratory, and radiographic data. Based on the spinal radiographs, patients were classified into 3 categories: (1) no spinal involvement; (2) spinal involvement without fusion; and (3) spinal involvement with fusion. Hip involvement was assessed by the Bath Ankylosing Spondylitis Radiology Hip Index and defined by a score of at least 2. Logistic regression analyses were used to investigate the factors associated with the radiographic spine and hip involvements.Ninety-eight (18.5%) patients had radiographic evidence of spinal fusion and 48 (9.0%) had radiographic evidence of hip involvement. Patients who had longer disease duration, elevated C-reactive protein levels, advanced sacroiliitis, and radiographic hip involvement were significantly more likely to have spinal fusion (P0.05). Elevated C-reactive protein levels and advanced sacroiliitis were also significantly associated with the presence of spinal involvement without fusion (P0.05). Early disease onset and more radiographic severity in the spine and sacroiliac joints were the predictors of radiographic hip involvement (P0.05). Patients with either spine or hip involvement had significantly higher Bath Ankylosing Spondylitis Functional Index scores (P0.001).There is a relationship between radiographic sacroiliitis, spinal fusion, and hip involvement in patients with AS. Damage to the spine and hip seen radiographically can contribute to functional impairment.

Thrombotic microangiopathy (TMA) co-existing with SLE is rarely reported. This study aimed to investigate the triggering factors, clinical features and outcomes of SLE patients with TMA in Northern Taiwan.Twenty-five TMA cases out of 2461 SLE patients admitted to Taipei Veterans General Hospital, between 2000 and 2010, were enrolled.When TMA occurred, 16 (64.0%) patients had infection; 22 (88.0%) were in an active disease state with a SLEDAI score10. Among the infection group, 13 (81.3%) had an increase in the SLEDAI score of ≥ 4. We found that older age (≥ 50 years), low platelets (≤ 20,000/nm(3)), presence of infection, acute renal failure (ARF) or four or more TMA features were independent risk factors for persistent haematological abnormalities (P 0.05); older age (≥ 50 years) and a high reticulocyte index (2%) were the risk factors for persistent renal function impairment (P 0.05). The overall mortality rate was 52.0% (13 out of 25); older age (≥ 40 years), low complement value, presence of infection (P 0.001), two or more infection sources, ARF and four or more TMA features were the statistically significant factors contributing to a higher mortality rate. Patients receiving plasma exchange seven times or more had a significantly higher rate of improvement in renal function and haematological abnormalities.Our study showed that infection was one of the major triggers for the flare-up of SLE disease activity and occurrence of TMA in SLE. Infection is also a strong risk factor for outcome in SLE patients with TMA. Plasma exchange can be considered as an adjuvant treatment modality.

Objective.Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune disease in which cytokines such as B lymphocyte chemoattractant (BLC, or CXC motif ligand 13, CXCL13) may play important roles in pathogenesis. We investigated the implications of CXCL13 in SLE and lupus nephritis.Methods.Serum samples from 425 patients with SLE and 106 healthy control individuals were analyzed for the concentration of CXCL13 by ELISA. Tissue expression of CXCL13 and its corresponding receptor CXCR5 were observed in lupus kidney. The CXCR5-bearing B cells in SLE patients were analyzed by flow cytometry.Results.Serum levels of CXCL13 were higher in SLE patients compared to controls. SLE patients with lupus nephritis or positive anti-dsDNA antibodies had significantly higher serum CXCL13 levels. The peripheral venous blood B cells that bear CXCR5 were more abundant in SLE patients as detected by flow cytometry. CXCR5 and CXCL13 were highly expressed in the renal cortex from patients with lupus nephritis.Conclusions.Our results suggest that BLC/CXCL13 as well as its corresponding receptor, CXCR5, may play important roles in the pathogenesis of SLE and in lupus nephritis.

Background: To study the clinical effectiveness and adverse reactions of etanercept in patients with active rheumatoid arthritis (RA), in whom combination therapies with disease-modifying antirheumatic drugs (DMARDs) had failed. Methods: One hundred and thirty-three patients with active RA who had been treated without satisfactory effect with DMARDs were entitled, by the Taiwan Bureau of National Health Insurance, to undergo etanercept injection (25 mg subcutaneously, twice weekly) along with oral methotrexate (15 mg weekly) in Taipei Veterans General Hospital. The disease activity score in 28 swollen and 28 tender joints (DAS28), erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), rheumatoid factors (RFs), tender joint count (TJC), and swollen joint count (SJC) were recorded at the beginning, 3, 6, 9, and 12 months after treatment. Any adverse event, relevant or irrelevant to the therapy, was recorded throughout the whole course of treatment. Results: Ninety-four patients completed the 1-year therapeutic program. There were significant improvements in all parameters (DAS28, ESR, CRP, TJC and SJC), which approached satisfactory values at the end of the first 3 months and which were sustained thereafter in most patients. Patients also tolerated the treatment protocol well, with adverse events occurring sporadically. Significant clinical response occurred as early as 3 months after the start and might last beyond 1 year in some patients. Adverse effects such as injection site reaction or infections rarely occurred. Conclusion: Combination therapy with etanercept and DMARDs seemed to be effective at improving the aching symptoms associated with rheumatoid activity and was well tolerated in this cohort study. It was generally safe, though a small number of non-fatal infections were observed. [J Chin Med Assoc 2009;72(11):581–587]

Objective.To measure serum concentration and analyze the expression of interleukin 18 (IL-18) mRNA in mononuclear cells of patients with systemic lupus erythematosus (SLE).Methods.IL-18 concentrations in sera and culture supernatants of peripheral blood mononuclear cells (PBMC) from healthy controls and patients with active SLE were measured by ELISA. PBMC and polymorphonuclear leukocytes (PMN) purified from patients with active SLE were stimulated with phytohemagglutinin (PHA), pokeweed mitogen (PWM), and lipopolysaccharide (LPS). Expression of IL-18 mRNA in cells was analyzed by RT-PCR.Results.Serum IL-18 levels were significantly higher in SLE patients than in controls, and correlated with disease activity in SLE patients (r2= 0.602). Two patients receiving intravenous methylprednisolone therapy (1.0 g/day for 3 days) showed profound decreases in serum IL-18 levels after therapy. The quiescent PBMC from SLE patients (30/30) expressed IL-18 transcript more frequently than control PBMC (20/30). PBMC from SLE patients produced more IL-18 than control PBMC after 72 hours of incubation, by RT-PCR. PHA and PWM inhibited the production of IL-18 in PBMC from both SLE patients and controls. Inhibition by PWM was more pronounced than that by PHA, especially in SLE-PBMC. Control and SLE-PMN with or without LPS stimulation produced negligible IL-18.Conclusion.IL-18 is involved in the autoimmune derangement of leukocyte function in patients with active SLE.

A 71-year-old man presented with quadriplegia, seizures, dysarthria, motor aphasia and urinary incontinence lasting for several years. The development of proteinuria and increased susceptibility to infections brought the physician's attention to possible underlying autoimmune diseases. Laboratory investigations revealed evidence for systemic lupus erythematosus (SLE) and antiphospholipid syndrome. Imaging studies showed obstructive hydrocephalus. Several courses of methylprednisolone therapies followed by maintenance therapy with low-dose steroid, ventriculoperitoneal shunt, and antihypertensives improved the proteinuria and dysarthria but not the urinary incontinence or dementia. A thromboembolic event in the central nervous system secondary to phospholipid antibodies or lupus activity may represent a pathogenetic basis for hydrocephalus. When encountering a patient with hydrocephalus but without apparent predisposing factors, it is always important to include SLE as a differential diagnosis.

Hemolytic uremic syndrome (HUS) is not a commonly reported complication in post-transplantation patients treated with cyclosporine-A (CSA), and is extremely rare in systemic sclerosis (SSc) patients treated with this drug. CSA may contribute to the development of chronic ischemic glomerulonephropathy and vasculopathy, features not easily distinguished from SSc-related nephropathy. Here, we describe a 41-year-old Chinese man with diffuse-type SSc treated with CSA who developed thrombocytopenia, acute renal failure and hemolytic anemia and was diagnosed with HUS. Renal function and thrombocytopenia improved gradually after intensive treatment of plasma exchange (PE) and high-dose steroid therapy. After PE, renal biopsy showed ischemic glomerulonephropathy and obliterative vasculopathy. This case illustrates that PE can improve the hematological disorders and characteristic renal changes of HUS in SSc patients treated with CSA. However, this therapy may not be effective in normalizing serum creatinine level in SSc patients once CSA has triggered the normal kidney to develop glomerulonephropathy and vasculopathy with ischemic and sclerotic changes.

To understand the cytokine levels in different disease activities of patients with ankylosing spondylitis (AS), we measured proinflammatory and antiinflammatory cytokine production from peripheral blood mononuclear cells (PBMC) in patients with AS and their first-degree relatives (FDR).PBMC were obtained from 26 patients with AS and 24 FDR and then stimulated with PHA for 72 h. In the supernatants, the following three cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), and IL-10, were measured by ELISA. Disease activity in AS patients was divided into high disease activity (Group 1) and low disease activity (Group 2), based on the Bath AS Disease Activity Index (BASDAIor =4 or4). Healthy FDR of AS patients (Group 3) and healthy subjects (Group 4) were used as a control group.TNF-alpha production from PBMC was significantly increased in Group 1 patients compared to Group 2 patients (1371 +/- 1008 pg/mL vs. 355 +/- 89 pg/mL, p0.05) or FDR (1371 +/- 1008 pg/mL vs. 552 +/- 89 pg/mL, p0.05) or healthy subjects (1371 +/- 1008 pg/mL vs. 436 +/- 114 pg/mL, p0.01). IL-1beta also showed a similarly significant difference between the two groups (Group 1 vs. Group 2, Group 1 vs. Group 4) (p0.05). In contrast, IL-10 was significantly decreased in Group 1 when compared to Group 2 (126 +/- 64 pg/mL vs. 272 +/- 150 pg/mL, p0.05).Patients with high BASDAI had increased production of TNF-alpha and IL-1beta compared to those with low BASDAI or healthy FDR, suggesting that proinflammatory cytokines may play an important role during active inflammation.

A 79-year-old male with acute myelogenous leukemia developed acute right knee arthritis during admission, after the use of broad-spectrum antibiotics before chemotherapy. The initial synovial fluid sample appeared to be mildly inflammatory with a low white cell count. The fungal septic arthritis was not diagnosed until Candida tropicalis, a rare species of Candida, was isolated in the synovial fluid. Although fluconazole is effective in treating the microorganism, the untreated leukemia rendered the infection incurable and led to the growth of fluconazole-resistant Candida krusei. We reported the unusual case of fungal arthritis and reviewed the literature.

Background Aldosterone levels correlate with the incidence of myocardial infarction and mortality in cardiovascular patients. Aldosterone promotes atherosclerosis in animal models, but the mechanisms are poorly understood. Methods and Results Aldosterone was infused to achieve pathologically relevant levels that did not increase blood pressure in the atherosclerosis‐prone apolipoprotein E–knockout mouse (ApoE−/−). Aldosterone increased atherosclerosis in the aortic root 1.8±0.1‐fold after 4 weeks and in the aortic arch 3.7±0.2‐fold after 8 weeks, without significantly affecting plaque size in the abdominal aorta or traditional cardiac risk factors. Aldosterone treatment increased lipid content of plaques (2.1±0.2‐fold) and inflammatory cell content (2.2±0.3‐fold), induced early T‐cell (2.9±0.3‐fold) and monocyte (2.3±0.3‐fold) infiltration into atherosclerosis‐prone vascular regions, and enhanced systemic inflammation with increased spleen weight (1.52±0.06‐fold) and the circulating cytokine RANTES (regulated and normal T cell secreted; 1.6±0.1‐fold). To explore the mechanism, 7 genes were examined for aldosterone regulation in the ApoE−/− aorta. Further studies focused on the proinflammatory placental growth factor (Pl GF ), which was released from aldosterone‐treated ApoE−/− vessels. Activation of the mineralocorticoid receptor by aldosterone in human coronary artery smooth muscle cells ( SMC s) caused the release of factors that promote monocyte chemotaxis, which was inhibited by blocking monocyte Pl GF receptors. Furthermore, Pl GF ‐deficient ApoE−/− mice were resistant to early aldosterone‐induced increases in plaque burden and inflammation. Conclusions Aldosterone increases early atherosclerosis in regions of turbulent blood flow and promotes an inflammatory plaque phenotype that is associated with rupture in humans. The mechanism may involve SMC release of soluble factors that recruit activated leukocytes to the vessel wall via Pl GF signaling. These findings identify a novel mechanism and potential treatment target for aldosterone‐induced ischemia in humans.

To determine the incidence rates and risk factors of cervical and trochanteric hip fractures (HFs) among patients with systemic lupus erythematosus (SLE) based on a nationwide population-based data set.We conducted a cohort study using data from the Taiwan National Health Insurance database. Patients with SLE and their age- and sex-matched counterparts without SLE were identified. The primary end point was the first occurrence of HF. Cox proportional hazards model was used to evaluate the respective risk factors of cervical and trochanteric HFs in the lupus cohort.Among 14,544 patients with SLE (90% women, mean age 38.1 years) with a mean followup of 6 years, 75 developed HF (incidence rate 8.60 per 10,000 person-years). Compared to controls, the incidence rate ratios (IRRs) for developing HF among lupus patients were 3.17 (95% confidence interval [95% CI] 1.92-5.39, P0.001) for cervical HF and 1.11 (95% CI 0.58-2.11, P = 0.571) for trochanteric HF. The IRRs for HF were 2.38 (95% CI 1.58-3.63, P0.001) for women and 1.06 (95% CI 0.21-4.93, P = 0.922) for men. Lupus patients with cervical HF were younger than controls with cervical HF (mean age 56.7 versus 67.8 years; P = 0.007). Multivariable Cox regression analyses showed that age, use of intravenous cyclophosphamide, higher dose of steroid, and stroke were associated with cervical HF, whereas age was the only associated factor for trochanteric HF.SLE is associated with a higher risk for cervical but not trochanteric HF, and these 2 types of HFs have different risk factors.

To analyze the clinical features and outcomes of patients with posterior reversible encephalopathy syndrome(PRES), the risk factors of PRES-related intracranial hemorrhage (ICH), and all-cause mortality in patients with systemic lupus erythematosus (SLE).Twenty-six episodes of PRES were identified in 23 SLE patients, using an electronic medical records database of 3,746 SLE patients.The prevalence of PRES was 0.69% among SLE patients. The scores of the SLE Disease Activity Index without neurologic descriptors (SLEDAI-N) were significantly elevated from baseline for a mean of 3.3 during PRES (P = 0.009). Rapidly deteriorating renal function, pulmonary hemorrhage, thrombotic microangiopathy, macrophage activation syndrome, or multiple organ dysfunction syndrome appeared during 65.4% of episodes. In 16 episodes, patients completely recovered from PRES-related symptoms within a median of 7 days. Visual impairment was reversed within 2 days in 8 of 15 patients, but impairment in other patients was protracted for up to 4 months, especially when ICH was present. Hypoalbuminemia (20 gm/liter; odds ratio [OR] 30, 95% confidence interval [95% CI] 2.04–441.84) and thrombocytopenia (30,000/mm(3); OR 21, 95% CI 1.27–346.93) were risk factors for PRES-related ICH. Patients with SLEDAI-N scores18 during a PRES attack had significantly higher mortality rates than did patients with SLEDAI-N scores ≤18 (P = 0.009 by log rank test).PRES frequently occurs during active SLE with multiple complications. Hypoalbuminemia and thrombocytopenia may contribute to PRES-related ICH. The extra neurologic disease activity of lupus during PRES may influence the mortality rate of SLE patients.

Relapsing polychondritis (RP) is a rare and debilitating rheumatic disease featuring recurrent and at times disseminated inflammation of cartilaginous structures, including auricles, eyes, peripheral joints, and airway1. Symptomatic airway compromise in RP is considered a common but severe cause of morbidity and mortality, which necessitates aggressive medical and bronchoscopic intervention2. We describe a refractory airway stenosis in a young patient with RP. A 24-year-old man attended our clinic because of progressive pain and swelling in his left ear that had progressed to the right side with tenderness in his right eye for 1 year. He had been diagnosed with auricle chondritis with scleritis …

Programmed death 1 (PD-1) has been shown to be involved in the negative regulation of the immune response. However, the role of PD-1 in ankylosing spondylitis (AS) has not been studied. Therefore, we analyzed the expression of PD-1 in peripheral blood mononuclear cells (PBMC) from patients with AS. Twenty-three AS patients, 20 rheumatoid arthritis (RA) patients, and 25 normal healthy subjects were recruited. The percentage of the PBMC and PD-1 levels in these subjects were measured by flow cytometry. A higher percentage of CD4+ T cells was noted in AS patients than in healthy controls (37.53 ± 1.65% vs. 31.55 ± 0.92%, P