Is Fibromyalgia Risk Higher Among Male and Young Inflammatory Bowel Disease Patients? Evidence from a Taiwan Cohort of One Million.

BACKGROUND: Prior literatures have shown inflammatory bowel disease (IBD) could increase fibromyalgia (FM) risk. However, studies about gender and age distributions of FM risk among patients with IBD are rare. With large study samples, this study aimed to evaluate the FM risk among IBD patients with different gender and different age. OBJECTIVE: We aim to estimate the FM risk among male and younger IBD patients with a large patient sample. STUDY DESIGN: A retrospective cohort study was arranged in this research. SETTING: The data used in this research were selected from the Taiwan National Health Insurance Research Database (NHIRD). METHODS: From the Taiwan NHIRD, we selected 4,510 patients with IBD and 18,040 randomly gender- and age-matched patients without a history of IBD from the beginning of 2000 to the end of 2005 to analyze the development of FM over a 12-year follow-up period (2000-2011). The Cox regression model was used to assess the effects of IBD on the risk of FM by adjusting for gender, age, and comorbidities, including hypertension, diabetes, hyperlipidemia, depression, anxiety, and sleep disorder. RESULTS: After adjusting suitable covariates, the IBD patients had a greater FM risk (adjusted hazard ratio [aHR] 1.70, 95% confidence interval [CI] 1.59-1.83) than the controls. Male IBD patients had a higher FM risk than female IBD patients did (aHR 2.00, 95% CI 1.79-2.23 and aHR 1.52, 95% CI 1.38-1.67, respectively). The greatest age-specific FM risk occurred in the youngest IBD subgroup (= 39 years old) (aHR 1.92, 95% CI 1.68-2.19). LIMITATIONS: The information about personal behaviors was unobtainable in the Taiwan NHIRD. Other risk factors for cardiovascular disease that might augment FM cannot be excluded entirely in this study. CONCLUSION: IBD is disclosed to be correlated with an enhanced risk to develop FM, particularly in male and younger IBD patients. For preventing FM, it is necessary to pay more attention to the management of the IBD patients. Future researches are needed to further confirm the findings in this study. KEY WORDS: Inflammation, inflammatory bowel disease, fibromyalgia, Taiwan National Health Insurance Research Database.

Association of Higher Migraine Risk Among Female and Younger Chronic Osteomyelitis Patients: Evidence from a Taiwan Cohort of One Million.

BACKGROUND: Inflammation may trigger migraine development through neurovascular reactions in the brain. Most of the migraine patients, particularly the younger ones, do not have any risk factors for this disease. Hence, we assessed whether chronic osteomyelitis (COM), a chronic inflammatory disease, increases the risk of migraine. OBJECTIVE: We aim to evaluate the risk of migraine among female and middle-age COM patients with a large patient sample. STUDY DESIGN: A retrospective cohort study was conducted in this study. SETTING: The data used in this study were extracted from the Taiwan National Health Insurance (NHI) Research Database. METHODS: A study group with 2,012 COM patients and 8,048 randomly chosen gender- and age-matched controls were chosen from the Taiwan NHI Research Database (NHIRD) from the start of 2000 to the end of 2009. The risk of migraine was estimated with Cox proportional regression model. Both COM and control groups were followed-up until the occurrence of migraine during the study period (2000-2011). Prevalent covariates, such as age, gender, hypertension, diabetes, hyperlipidemia, stroke, coronary artery disease, depression, anxiety, sleep disorder, bipolar disorder, and epilepsy, were included for further evaluation. The hazard ratio (HR) of migraine was measured with Cox proportional hazard regression model. The primary outcome was the overall migraine risk among COM patients, and the secondary outcome was the migraine risk among COM patients lacking the comorbidities. Additional outcomes included migraine risk among COM patients in different age and gender subgroups. RESULTS: The overall migraine risk was increased in COM patients (adjusted hazard ratio [aHR] 1.74, 95% confidence interval [CI] 1.14-2.65). Even without any prevalent comorbidities, COM patients still exhibited an increased risk of migraine (aHR 2.05, 95% CI 1.06-3.97) than the controls did. Moreover, this risk was relatively higher in COM patients aged < 40 and 45-54 years (aHR 2.07, 95% CI 0.97-4.46 and aHR 2.11, 95% CI 0.97-4.57, respectively) than in their counterparts. Female COM patients had a relatively higher migraine risk (aHR 1.85, 95% CI 1.05-3.24) than male patients did (aHR 1.68, 95% CI 0.89-3.16). LIMITATIONS: The messages about personal behaviors were unavailable in the Taiwan NHIRD. Other neurovascular risk factors that might increase migraine cannot be excluded completely in this research. CONCLUSION: An association between COM and increased risk of migraine was shown in this study. The results suggest that COM is a significant migraine predictor, and thus imply the necessity for rigorous migraine prevention in COM patients, especially female and younger ones. KEY WORDS: Inflammation, migraine, chronic osteomyelitis, Taiwan National Health Insurance Research Database.

Management of gout and hyperuricemia: Multidisciplinary consensus in Taiwan.

Gout is an inflammatory disease manifested by the deposition of monosodium urate (MSU) crystals in joints, cartilage, synovial bursa, tendons or soft tissues. Gout is not a new disease, which was first documented nearly 5,000 years ago. The prevalence of gout has increased globally in recent years, imposing great disease burden worldwide. Moreover, gout or hyperuricemia is clearly associated with a variety of comorbidities, including cardiovascular diseases, chronic kidney disease, urolithiasis, metabolic syndrome, diabetes mellitus, thyroid dysfunction, and psoriasis. To prevent acute arthritis attacks and complications, earlier use of pharmacotherapeutic treatment should be considered, and patients with hyperuricemia and previous episodes of acute gouty arthritis should receive long-term urate-lowering treatment. Urate-lowering drugs should be used during the inter-critical and chronic stages to prevent recurrent gout attacks, which may elicit gradual resolution of tophi. The goal of urate-lowering therapy should aim to maintain serum uric acid (sUA) level <6.0 mg/dL. For patients with tophi, the initial goal can be set at lowering sUA to <5.0 mg/dL to promote tophi dissolution. The goal of this consensus paper was to improve gout and hyperuricemia management at a more comprehensive level. The content of this consensus paper was developed based on local epidemiology and current clinical practice, as well as consensuses from two multidisciplinary meetings and recommendations from Taiwan Guideline for the Management of Gout and Hyperuricemia.

Reduced risk of all-cancer and solid cancer in Taiwanese patients with rheumatoid arthritis treated with etanercept, a TNF-α inhibitor.

Biologics has been widely used in the treatment of rheumatoid arthritis. We aimed to determine whether etanercept, a TNF-α inhibitor (TNFi) that is used to treat patients with rheumatoid arthritis (RA), affects cancer risk.This retrospective matched cohort study used data in the Registry of Catastrophic Illness Database in Taiwan from January 1, 1996 to December 31, 2010. RA, all-cancer, and solid cancer were defined using International Classification of Disease codes (ICD-9-CM 714.X, 140-208, and 140-199, respectively). Cox proportional hazard modeling was used to estimate the hazard ratio (HR) of cancer in all TNFi-treated RA patients, with a focus on the risk in the etanercept-treated patients, after adjusting for comorbidities and concomitant medication.In this Taiwanese dataset, there were 1111 TNFi-treated RA patients and 16,812 RA patients who were naive to all biologics identified. Among the 1002 pairs of etanercept-treated and biologic-naive patients who were matched 1-to-1 for age, gender, RA duration, methotrexate-use, and index date of TNFi prescription, the mean age was 48.9 ±â€Š15.0 years. The highest proportion of patients was in the age subgroup of 30 to 60 years (63.8%). Most patients (77.2%) were women. The mean RA duration before etanercept treatment was 2.0 ±â€Š1.5 years. During a mean 2.1 years of observation, etanercept was associated with significant risk reduction for all-cancer (HR 0.59, 0.36-0.98) and solid cancer (HR 0.46, 0.27-0.79) relative to the matched biologic-naive patients.The current study explored the safety profile of TNFi and identified a potential benefit of etanercept on the incidence of all-cancer and solid cancer in RA patients.

Performance of Ultrasound in the Diagnosis of Gout in a Multicenter Study: Comparison With Monosodium Urate Monohydrate Crystal Analysis as the Gold Standard.

OBJECTIVE: To examine the performance of ultrasound (US) for the diagnosis of gout using the presence of monosodium urate monohydrate (MSU) crystals as the gold standard. METHODS: We analyzed data from the Study for Updated Gout Classification Criteria (SUGAR), a large, multicenter observational cross-sectional study of consecutive subjects with at least 1 swollen joint who conceivably may have gout. All subjects underwent arthrocentesis; cases were subjects with confirmed MSU crystals. Rheumatologists or radiologists who were blinded with regard to the results of the MSU crystal analysis performed US on 1 or more clinically affected joints. US findings of interest were double contour sign, tophus, and snowstorm appearance. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Multivariable logistic regression models were used to examine factors associated with positive US results among subjects with gout. RESULTS: US was performed in 824 subjects (416 cases and 408 controls). The sensitivity, specificity, PPV, and NPV for the presence of any 1 of the features were 76.9%, 84.3%, 83.3%, and 78.2%, respectively. Sensitivity was higher among subjects with a disease duration of ≥2 years and among subjects with subcutaneous nodules on examination (suspected tophus). Associations with a positive US finding included suspected clinical tophus (odds ratio [OR] 4.77 [95% confidence interval (95% CI) 2.23-10.21]), any abnormality on plain radiography (OR 4.68 [95% CI 2.68-8.17]), and serum urate level (OR 1.31 [95% CI 1.06-1.62]). CONCLUSION: US features of MSU crystal deposition had high specificity and high PPV but more limited sensitivity for early gout. The specificity remained high in subjects with early disease and without clinical signs of tophi.

Increased Risk of New-Onset Fibromyalgia Among Chronic Osteomyelitis Patients: Evidence From a Taiwan Cohort Study.

Chronic inflammation, which changes the neurotransmitter metabolism and kindles neuroendocrine system dysfunction in the central nervous system, might cause fibromyalgia (FM) formation. In FM patients without traditional FM risk factors, such as hypertension, hyperlipidemia, diabetes, sleep disorder, depression, and anxiety, the chronic inflammatory process is a possible risk factor for FM. Thus, we investigated whether chronic osteomyelitis (COM), a disease characterized by chronic inflammation, increases FM risk. Including data for 1 million enrollees, the Longitudinal Health Insurance Database was used, and 1,244 COM patients without FM history and 4,976 randomly selected sex- and age-matched control subjects without COM or FM history were extracted. The development of FM over a 13-year follow-up period from 1999 to 2011 was evaluated, and FM risk was estimated using the Cox proportional regression model. The aforementioned FM risk factors were more common in COM patients, who had a significantly greater FM risk than did the control subjects. Compared with those who had no associated risk factors, patients with COM had a greater FM risk than did the control subjects (adjusted hazard ratio [aHR] = 1.32, 95% confidence interval [CI], .99-1.75). Younger people had an even greater risk (age younger than 35 years: aHR = 1.58, 95% CI, 1.03-2.44; age 60 years or older: aHR = 1.03, 95% CI, .78-1.36). To our knowledge, this is the first study to link COM to an enhanced risk of FM development. The results imply that COM is a predictor of FM, suggesting that close follow-up for patients with COM is required to prevent FM, especially in younger populations. PERSPECTIVE: COM is associated with the augmented risk of developing FM, and rigorous treatments for COM patients might decrease the future risk of FM formation, especially in those with relatively younger ages.

Increased risk of a suicide event in patients with primary fibromyalgia and in fibromyalgia patients with concomitant comorbidities: A nationwide population-based cohort study.

An increased risk of suicide ideation and death has been reported in patients with fibromyalgia. This study aimed to evaluate the risk of a suicide event in patients with primary fibromyalgia and in fibromyalgia patients with comorbidities. We used the Longitudinal Health Insurance Database, a subset of the national insurance claim dataset, which enrolled 1 million Taiwanese people from 2000 to 2005, to identify 95,150 patients with incident fibromyalgia (ICD-9-CM 729.0-729.1) and 190,299 reference subjects matched by sex, age, and index date of diagnosis, with a mean of 8.46 ±â€Š2.37 years of follow-up until 2011. The risk of a suicide event (ICD-9-CM, External-Cause Codes 950-959) was analyzed with a Cox proportional hazards model. Stratification analysis was performed by separating fibromyalgia patients and reference subjects with respect to each comorbidity to determine the risk of suicide in fibromyalgia patients with or without comorbidity relative to subjects who had neither fibromyalgia nor comorbidity. In this Taiwanese dataset, there were 347 suicide events in patients with fibromyalgia (4.16 per 10 person-years) and 424 in matched reference subjects (2.63 per 10 person-years) with a significant crude hazard ratio (HR) of 1.58 (95% confidence interval [CI] 1.38-1.83) and an adjusted HR of 1.38 (95% CI 1.17-1.71) for fibromyalgia patients relative to the matched reference subjects. According to the 2 × 2 stratification analysis, we found that fibromyalgia patients without comorbidity had an independent but mild risk of a suicide event with adjusted HRs ranging from 1.33 to 1.69 relative to subjects with neither fibromyalgia nor comorbidity. Meanwhile, fibromyalgia patients with comorbidity led to a markedly enhanced risk of a suicide event relative to the matched reference subjects, with adjusted HRs ranging from 1.51 to 8.23. Our analysis confirmed a mild-to-moderate risk of a suicide event in patients with primary fibromyalgia. Attention should be paid to the prevention of suicide in fibromyalgia patients with concomitant comorbidities.

Effect of Systemic Lupus Erythematosus on the Risk of Incident Respiratory Failure: A National Cohort Study.

PURPOSE: We conducted a nationwide cohort study to investigate the relationship between systemic lupus erythematosus (SLE) and the risk of incident respiratory failure. METHODS: From the National Health Insurance Research Database, we identified 11 533 patients newly diagnosed with SLE and 46 132 controls without SLE who were randomly selected through frequency-matching according to age, sex, and index year. Both cohorts were followed until the end of 2011 to measure the incidence of incident respiratory failure, which was compared between the 2 cohorts through a Cox proportional hazards regression analysis. RESULTS: The adjusted hazard ratio (aHR) of incident respiratory failure was 5.80 (95% confidence interval [CI] = 5.15-6.52) for the SLE cohort after we adjusted for sex, age, and comorbidities. Both men (aHR = 3.44, 95% CI = 2.67-4.43) and women (aHR = 6.79, 95% CI = 5.93-7.77) had a significantly higher rate of incident respiratory failure in the SLE cohort than in the non-SLE cohort. Both men and women aged <35 years (aHR = 31.2, 95% CI = 21.6-45.2), 35-65 years; (aHR = 6.19, 95% CI = 5.09-7.54) and ≥65 years (aHR = 2.35, 95% CI = 1.92-2.87) had a higher risk of incident respiratory failure in the SLE cohort. Moreover, the risk of incident respiratory failure was higher in the SLE cohort than the non-SLE cohort, for subjects with (aHR = 2.65, 95% CI = 2.22-3.15) or without (aHR = 9.08, 95% CI = 7.72-10.7) pre-existing comorbidities. In the SLE cohort, subjects with >24 outpatient visits and hospitalizations per year had a higher incident respiratory failure risk (aHR = 21.7, 95% CI = 18.0-26.1) compared with the non-SLE cohort. CONCLUSION: Patients with SLE are associated with an increased risk of incident respiratory failure, regardless of their age, sex, and pre-existing comorbidities; especially medical services with higher frequency.

Survey Definitions of Gout for Epidemiologic Studies: Comparison With Crystal Identification as the Gold Standard.

OBJECTIVE: To identify the best-performing survey definition of gout from items commonly available in epidemiologic studies. METHODS: Survey definitions of gout were identified from 34 epidemiologic studies contributing to the Global Urate Genetics Consortium (GUGC) genome-wide association study. Data from the Study for Updated Gout Classification Criteria (SUGAR) were randomly divided into development and test data sets. A data-driven case definition was formed using logistic regression in the development data set. This definition, along with definitions used in GUGC studies and the 2015 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) gout classification criteria were applied to the test data set, using monosodium urate crystal identification as the gold standard. RESULTS: For all tested GUGC definitions, the simple definition of "self-report of gout or urate-lowering therapy use" had the best test performance characteristics (sensitivity 82%, specificity 72%). The simple definition had similar performance to a SUGAR data-driven case definition with 5 weighted items: self-report, self-report of doctor diagnosis, colchicine use, urate-lowering therapy use, and hyperuricemia (sensitivity 87%, specificity 70%). Both of these definitions performed better than the 1977 American Rheumatism Association survey criteria (sensitivity 82%, specificity 67%). Of all tested definitions, the 2015 ACR/EULAR criteria had the best performance (sensitivity 92%, specificity 89%). CONCLUSION: A simple definition of "self-report of gout or urate-lowering therapy use" has the best test performance characteristics of existing definitions that use routinely available data. A more complex combination of features is more sensitive, but still lacks good specificity. If a more accurate case definition is required for a particular study, the 2015 ACR/EULAR gout classification criteria should be considered.

Increased Risk of Stroke in Patients With Fibromyalgia: A Population-BASED Cohort Study.

Neuropsychiatric diseases might enhance stroke development, possibly through inflammation and atherosclerosis. Approximately 25% to 40% of patients with stroke, largely younger patients, are not associated with any conventional stroke risk factors. In this research, we explored whether fibromyalgia (FM), a neuropsychosomatic disorder, increases stroke risk.From a claims dataset with one million enrollees sourced of the Taiwan National Health Insurance database, we selected 47,279 patients with FM and randomly selected 189,112 age- and sex-matched controls within a 3-year period from January 1, 2000 to December 31, 2002. Stroke risk was assessed using Cox proportional hazards regression.Comorbidities associated with increased stroke risk, such as hypertension, diabetes, hyperlipidemia, coronary heart disease, irritable bowel syndrome, and interstitial cystitis, were more prevalent in patients with FM and high stroke risk than in the controls. The overall stroke risk was 1.25-fold (95% confidence interval [CI]: 1.21-1.30) higher in the FM group than in the non-FM group. Even without comorbidities, stroke risk was higher in patients with FM than in the controls (adjusted hazard ratio [aHR] = 1.44, 95% CI: 1.35-1.53, P < 0.001). The relative risk of stroke was 2.26-fold between FM and non-FM groups in younger patients (age <35 years, 95% CI: 1.86-2.75).This is the first investigation associating FM with an increased risk of stroke development. The outcomes imply that FM is a significant risk factor for stroke and that patients with FM, particularly younger patients, require close attention and rigorous measures for preventing stroke.

Subsequent risk of gout for women with hypertensive disorders in pregnancy: a retrospective cohort study.

BACKGROUND: The association between the risk of subsequent gout and hypertensive disorders in pregnancy (HDP), including gestational hypertension and preeclampsia has not been well investigated. We investigated the risk of gout in later life for women with a history of HDP. METHODS: We identified 1133 newly diagnosed HDP women aged 14-40 years from Taiwan insurance claims data from the period of 2000-2010. From the same database, 9064 women without HDP were randomly selected as the control cohort, with frequency matched by age and diagnosis year. Those with a baseline history of hypertension or gout were excluded from this study. All study participants were followed until the development of gout, withdrawal from the insurance program, or the end of 2011. Cox proportional hazards regression was used to assess the risk for gout in the HDP cohort compared with the controls. RESULTS: The incidence of gout was 2.83 folds higher in the HDP cohort than in the control cohort (2.66 vs. 0.94 per 1000 person-years) with an adjusted hazard ratio of 2.34 (95% confidence interval = 1.36-4.02) and 1.84 (95% confidence interval = 1.03-3.32) after controlling for comorbidities prior to and after pregnancy, respectively. In addition, the risk for gout increased as the severity of HDP increased. CONCLUSION: Women with HDP are at higher risk of developing gout in their later life. Close surveillance for hyperuricemia and lifestyle intervention should be considered for these high risk women. Further prospective study is needed for investigating the relationship between HDP and subsequent gout.

Diagnostic Arthrocentesis for Suspicion of Gout Is Safe and Well Tolerated.

OBJECTIVE: To determine the frequency of adverse events of diagnostic arthrocentesis in patients with possible gout. METHODS: Consecutive patients underwent arthrocentesis and were evaluated at 6 weeks to determine adverse events. The 95% CI were obtained by bootstrapping. RESULTS: Arthrocentesis was performed in 910 patients, and 887 (97.5%) were evaluated for adverse events. Any adverse event was observed in 12 participants (1.4%, 95% CI 0.6-2.1). There was 1 case (0.1%, 95% CI 0-0.34) of septic arthritis. CONCLUSIONS: Diagnostic arthrocentesis is associated with a low frequency of adverse events. Septic arthritis rarely occurs.

Performance of classification criteria for gout in early and established disease.

OBJECTIVES: To compare the sensitivity and specificity of different classification criteria for gout in early and established disease. METHODS: This was a cross-sectional study of consecutive rheumatology clinic patients with joint swelling in which gout was defined by presence or absence of monosodium urate crystals as observed by a certified examiner at presentation. Early disease was defined as patient-reported onset of symptoms of 2 years or less. RESULTS: Data from 983 patients were collected and gout was present in 509 (52%). Early disease was present in 144 gout cases and 228 non-cases. Sensitivity across criteria was better in established disease (95.3% vs 84.1%, p<0.001) and specificity was better in early disease (79.9% vs 52.5%, p<0.001). The overall best performing clinical criteria were the Rome criteria with sensitivity/specificity in early and established disease of 60.3%/84.4% and 86.4%/63.6%. Criteria not requiring synovial fluid analysis had sensitivity and specificity of less than 80% in early and established disease. CONCLUSIONS: Existing classification criteria for gout have sensitivity of over 80% in early and established disease but currently available criteria that do not require synovial fluid analysis have inadequate specificity especially later in the disease. Classification criteria for gout with better specificity are required, although the findings should be cautiously applied to non-rheumatology clinic populations.

An Independent Risk of Gout on the Development of Deep Vein Thrombosis and Pulmonary Embolism: A Nationwide, Population-Based Cohort Study.

Previous studies indicated that gout is a risk factor of cardiovascular diseases. This study aimed to determine if patients with gout have an increased risk of deep vein thrombosis (DVT) or pulmonary embolism (PE).We used the Longitudinal Health Insurance Database, a subset of the national insurance claim dataset, which enrolled 1 million Taiwanese to identify 57,981 patients with gout and 115,961 reference subjects matched by sex, age, and entry date of diagnosis. The risk of DVT and PE was analyzed using the Cox proportional hazards model.In this Taiwanese dataset observed from 2000 to 2010, we found the incidence of DVT was 5.26 per 10 person-years in the gout cohort, which was twofold higher than the incidence of 2.63 per 10 person-years in the reference cohort. After adjusting for age, sex, and 9 comorbidities, the hazard ratio (HR) of developing DVT was 1.66 (95% confidence interval [CI] = 1.37-2.01). Among patients with gout, the youngest age group had the highest increase in the risk of developing DVT (HR [95% CI] = 2.04 [1.24-3.37] for ages 20 to 49 years, 1.80 [1.28-2.51] for ages 50 to 64 years, and 1.45 [1.11-1.91] for ages ≥65 years). The incidence of PE was about one-fifth that of DVT in gout patients, but the effect of gout on the risk was similar (HR [95% CI] = 1.53 [1.01-2.29]).Our analysis confirmed that gout increased the risk of DVT and PE. Further exploration is needed in the future.

Effect of Urate-Lowering Therapy on All-Cause and Cardiovascular Mortality in Hyperuricemic Patients without Gout: A Case-Matched Cohort Study.

OBJECTIVES: An increased risk of mortality in patients with hyperuricemia has been reported. We examined (1) the risk of all-cause and cardiovascular disease (CVD) mortality in untreated hyperuricemic patients who did not receive urate-lowering therapy (ULT), and (2) the impact of ULT on mortality risk in patients with hyperuricemia. METHODS: In this retrospective case-matched cohort study during a mean follow-up of 6.4 years, 40,118 Taiwanese individuals aged ≥17 years who had never used ULT and who had never had gout were examined. The mortality rate was compared between 3,088 hyperuricemic patients who did not receive ULT and reference subjects (no hyperuricemia, no gout, no ULT) matched for age and sex (1:3 hyperuricemic patients/reference subjects), and between 1,024 hyperuricemic patients who received ULT and 1,024 hyperuricemic patients who did not receive ULT (matched 1:1 based on their propensity score and the index date of ULT prescription). Cox proportional hazard modeling was used to estimate the respective risk of all-cause and CVD (ICD-9 code 390-459) mortality. RESULTS: After adjustment, hyperuricemic patients who did not receive ULT had increased risks of all-cause (hazard ratio, 1.24; 95% confidence interval, 0.97-1.59) and CVD (2.13; 1.34-3.39) mortality relative to the matched reference subjects. Hyperuricemic patients treated with ULT had a lower risk of all-cause death (0.60; 0.41-0.88) relative to hyperuricemic patients who did not receive ULT. CONCLUSION: Under-treatment of hyperuricemia has serious negative consequences. Hyperuricemic patients who received ULT had potentially better survival than patients who did not.

Risk relation between rhinitis and acute ischemic stroke.

BACKGROUND AND PURPOSE: Chronic inflammation that triggers endothelial dysfunction and atherosclerosis may promote the evolution of cardiovascular diseases, including acute ischemic stroke (AIS). In this study, we assessed the association between rhinitis (RN), an immunoglobulin E-related atopic disease, and the risk of AIS. METHODS: We used a Taiwan national insurance claims data set of 1 million enrollees to distinguish 61,899 patients with RN and 123,798 randomly selected age- and sex-matched controls from January 1, 2000, to December 31, 2010. Both cohorts were followed up until the occurrence of stroke or the end of follow-up. The risk of AIS was evaluated by using the Cox proportional hazards regression model. RESULTS: After adjustment of the relevant covariates, the RN group showed a lower risk of AIS (adjusted hazard ratio [aHR] 0.74 [95% confidence interval {CI}, 0.70-0.79]) compared with the control cohort at the end of follow-up. Among the participants without comorbidities, the RN cohort still had a lower risk of AIS compared with the control cohort (aHR 0.69 [95% CI, 0.59-0.81]). Moreover, in the three stratified age groups, RN was associated with a significantly decreased risk of AIS (ages ≤49 years: aHR 0.77 [95% CI, 0.63-0.95]; ages 50-64 years: aHR 0.72 [95% CI, 0.64-0.81]; ages ≥65 years: aHR 0.78 [95% CI, 0.71-0.85]). CONCLUSIONS: RN was associated with a decreased risk of developing AIS. Although a reduction in risk of AIS was observed, it warrants further consideration to prevent AIS in patients with RN.

Increased Risk of Coronary Heart Disease in Patients with Primary Fibromyalgia and Those with Concomitant Comorbidity-A Taiwanese Population-Based Cohort Study.

OBJECTIVES: Fibromyalgia has seldom been associated with coronary heart disease (CHD). The aim of this study was to evaluate the risk of CHD in patients with fibromyalgia. METHODS: We used a dataset of one million participants, systemically scrambled from the Taiwanese national insurance beneficiaries, to identify 61,612 patients with incident fibromyalgia (ICD-9-CM 729.0-729.1) and 184,834 reference subjects matched by sex, age and index date of diagnosis in a 1:3 ratio from 2000 to 2005, with a mean 8.86 ± 2.68 years of follow-up until 2011. Risk of CHD was analyzed by Cox proportional hazard modeling. RESULTS: Patients with fibromyalgia had a mean age of 44.1 ± 16.5 years. CHD events developed in fibromyalgia patients (n = 8,280; 15.2 per 103 person-years) and reference subjects (n = 15,162; 9.26 per 103 person-years) with a significant incidence rate ratio of 1.64 (95% confidence interval: 1.61-1.68). The adjusted hazard ratio for CHD in fibromyalgia patients relative to reference subjects was 1.47 (1.43-1.51), after adjusting for age, gender, occupation, monthly income, traditional cardiovascular comorbidities, depression and anxiety. We noted that fibromyalgia and cardiovascular comorbidities had a significant interaction effect on CHD risk (p for interaction <0.01), which was markedly enhanced in fibromyalgia patients with concomitant comorbidities relative to patients with primary fibromyalgia and reference subjects (no fibromyalgia, no comorbidity). CONCLUSIONS: Our report shows that fibromyalgia patients have an independent risk for CHD development. Fibromyalgia patients with concomitant comorbidities have markedly increased CHD risk relative to those with primary fibromyalgia.

Chronic osteomyelitis as a risk factor for development of rheumatoid arthritis: a nationwide, population-based, cohort study.

An association between occult infection and the development of rheumatoid arthritis (RA) has been suggested. This study aimed to determine if patients with chronic osteomyelitis (COM) are at increased risk of developing RA. A national insurance claim dataset of 22 million enrollees in Taiwan was used to identify 21,105 hospital inpatients with COM and 84,420 reference subjects matched by sex, age, and index date of diagnosis with a mean of 5.12 years of follow-up from 2000 to 2011. The risk of RA development was analyzed using Cox proportional hazards modeling. The mean age of hospital inpatients with COM was 55.8 ± 19.4 years. The incidence of RA was 5.43 per 10(4) person-years in the case cohort, which was more than twofold higher than that of 2.20 per 10(4) person-years in the reference cohort. After adjustment, the hazard ratio (HR) was 2.21 (95 % confidence interval, 1.51-3.24). The HR was greatest in the youngest age group (<45 years, HR [95 % confidence interval] = 9.08 [3.22-25.6]; 45-64 years, 1.76 [1.01-3.06]; ≥65 years, 1.68 [0.88-3.24]). In addition, HR was greatest in inpatients with more severe COM (HR [95 % confidence interval] = 0.72 [0.40-1.30] and 11.2 [6.63-18.9] for patients with ≤1 or >2 hospitalization due to recurrent osteomyelitis every two follow-up years, respectively). This is the first report linking COM to risk of incident RA. Patients of a younger age and with frequently recurrent COM had a greater increase in RA risk.

Effect of Urate-lowering Therapy on the Risk of Cardiovascular Disease and All-cause Mortality in Patients with Gout: A Case-matched Cohort Study.

OBJECTIVE: To examine (1) the risk of death from cardiovascular disease (CVD) and from all causes in patients with gout who do not undergo urate-lowering therapy (ULT), and (2) the effect of ULT on mortality risk in patients with gout. METHODS: In this prospective case-matched cohort study, 40,623 Taiwanese individuals aged ≥ 17 years were followed for 6.5 years. Mortality rate was compared between 1189 patients with gout who did not receive ULT and reference subjects (no gout, no ULT) matched for age, sex, and the index date of gout diagnosis (1:3 patients with gout/reference subjects), and between 764 patients with gout who received ULT and 764 patients with gout who did not receive ULT matched 1-to-1 based on their propensity score and the index date of ULT prescription. Cox proportional hazard modeling was used to estimate the respective risk of CVD (International Classification of Diseases, 9th ed. code 390-459) and all-cause mortality. RESULTS: After adjustment, patients with gout not treated with ULT had an increased risk of CVD mortality (HR 2.43, 95% CI 1.33-4.45) and all-cause mortality (1.45, 1.05-2.00) relative to the matched reference subjects (no gout, no ULT). Patients with gout treated with ULT had a lower risk of CVD (0.29, 0.11-0.80) and all-cause mortality (0.47, 0.29-0.79) relative to patients with gout not treated with ULT. This survival benefit persisted for users of either allopurinol or benzbromarone. CONCLUSION: Patients with gout who received ULT had significantly better survival rates than those who did not. Thus, undertreatment of gout has serious negative consequences.

The metastatic tumor antigen 1-transglutaminase-2 pathway is involved in self-limitation of monosodium urate crystal-induced inflammation by upregulating TGF-ß1.

INTRODUCTION: Transglutaminase 2 (TG2), a protein crosslinking enzyme with multiple biochemical functions, has been connected to various inflammatory processes. In this study, the involvement of TG2 in monosodium urate (MSU) crystal-induced inflammation was studied. METHODS: Immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) were performed to detect TG2 expression in synovial fluid mononuclear cells (SFMCs) and synovial tissue from patients with gouty arthritis. MSU crystal-exposed RAW264.7 mouse macrophages were analyzed for interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), transforming growth factor ß1 (TGF-ß1) and TG2 expression by RT-PCR and enzyme-linked immunosorbent assay (ELISA). TG2 small interfering (si)-RNA-mediated silencing and overexpression in RAW264.7 cells were used to evaluate the involvement of TG2 in resolving MSU crystal-induced inflammation. The role of metastatic tumor antigen 1 (MTA1), a master chromatin modifier, was investigated by MTA1 si-RNA-mediated knockdown. In addition, the inflammatory responses were followed in wild type and TG2 null mice after being challenged with MSU crystals in an in vivo peritonitis model. RESULTS: TG2 expression was up-regulated in the synovium tissue and SFMCs from patients with gouty arthritis. The levels of MTA1, TG2, TGF-ß1, IL-1ß and TNF-α mRNAs were consistently increased in MSU crystal-stimulated RAW264.7 cells. si-MTA1 impaired the basal, as well as the MSU crystal-induced expression of TG2 and TGF-ß1, but increased that of IL-1ß and TNF-α. TG2 overexpression dramatically suppressed MSU crystal-induced IL-1ß and TNF-α, but significantly enhanced the TGF-ß1 production. Neutralizing TGF-ß antibodies or inhibition of the crosslinking activity of TG2 attenuated these effects. On the contrary, loss of TG2 resulted in a reduced TGF-ß, but in an increased IL-1ß and TNF-α production in MSU crystal-stimulated RAW264.7 cells and mouse embryonic fibroblasts (MEFs). MSU crystal-stimulated IL-1ß production was Janus kinase 2 (JAK2)-signaling dependent and TG2-induced TGF-ß suppressed the activity of it. Finally, TG2-deficient mice exhibited hyper inflammatory responses after being challenged with MSU crystals in an in vivo peritonitis model. CONCLUSIONS: These findings reveal an inherent regulatory role of the MTA1-TG2 pathway in the self-limitation of MSU crystal-induced inflammation via positively regulating the levels of active TGF-ß1 in macrophages that opposes the MSU crystal-induced JAK2-dependent pro-inflammatory cytokine formation.