Risk of uveitis in autoimmune diseases patients treated with hydroxychloroquine: A population-based retrospective cohort study.

OBJECTIVE: Uveitis is a common manifestation of various autoimmune diseases and can lead to severe visual impairment. Hydroxychloroquine (HCQ) is an antimalarial drug that is also used to treat autoimmune diseases. The aim of this study was to investigate the association between HCQ use and the incidence of uveitis in patients with autoimmune diseases, as well as to identify potential risk factors for the development of uveitis in this study. METHODS: We conducted a population-based cohort study using a nationwide database to investigate the incidence of uveitis in patients with autoimmune diseases who received HCQ treatment. We selected non-HCQ comparison cohort at a 1:1 ratio by propensity score matching on age, sex, index date, urbanization, income, comorbidities, and medications. The data were analyzed using Cox proportional hazards models, and propensity score matching (PSM) was used to reduce selection bias. RESULTS: Our study included 15 822 patients with autoimmune diseases. After 1:1 PSM, there were 4555 individuals in both the HCQ group (n = 4555) and the non-HCQ group (n = 4555). The multiple Cox proportional hazard regression analysis was used for the estimation of adjusted hazard ratios on uveitis. After PSM, the adjusted hazard ratio for the HCQ group was 0.74 (95% CI = 0.58-0.95). These findings suggest that HCQ may play a protective role in reducing the risk of uveitis in patients with autoimmune diseases, including rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus groups. The Kaplan-Meier survival curves also showed a significantly lower incidence of uveitis in the HCQ group (log-rank = 0.0229) after PSM. CONCLUSION: HCQ use is associated with a lower incidence of uveitis in patients with autoimmune diseases. Further studies are needed to confirm this association and to investigate the underlying mechanisms.

Risk of new-onset glaucoma in patients with systemic lupus erythematosus: A nationwide, population-based cohort study.

To explore the relationship of systemic lupus erythematosus (SLE) and subsequent glaucoma incidence. Patients with SLE were defined as those newly diagnosed by International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code 710.0 in at least 3 outpatient visits or 1 hospitalization during 2000-2012 by using the National Health Insurance Research Database. We selected a non-SLE comparison cohort at a 1:1 ratio by propensity score matching on age, gender, index date, comorbidities and medications. We identified outcome as the incident glaucoma in patients with SLE. Multivariate Cox regression analysis was used to calculate the adjusted hazard ratio (aHR) in 2 groups. Kaplan- Meier analysis was performed to estimate the cumulative incidence rate between both groups. There were 1743 patients who were included in the SLE group and non-SLE group. The aHR of glaucoma was 1.56 (95% CI = 1.03-2.36) in the SLE group, compared to non-SLE controls. Subgroup analysis showed that SLE patients present greater risk of glaucoma, especially in males (aHR = 3.76; 95% CI, 1.5-9.42), and the P for interaction between gender and risk of glaucoma was 0.026. This cohort study showed that patients with SLE have 1.56-fold risk of glaucoma development. Gender acted as an effect modifier between SLE and the risk of new-onset glaucoma.

Dental caries and risk of newly-onset systemic lupus erythematosus: a nationwide population-based cohort study.

OBJECTIVE: This study investigated whether patients with history of dental caries are associated with an increased risk of newly-onset systemic lupus erythematosus (SLE). METHODS: A total of 501,461 carious patients and 258,918 controls without carious teeth were enrolled between 1997 and 2013 from the National Health Insurance Research Database. Subgroup analyses were conducted based on restorative materials including amalgam, composite resins, or both. The cumulative incidence and hazard ratios (HRs) of SLE development were derived after adjusting for age, sex, socioeconomic status, income, insured classification, comorbidities, and frequency of dental visit in a multivariable model. RESULTS: The risk of SLE was significantly higher in carious patients (HR = 1.98, 95% confidence interval [CI] = 1.65-2.38) compared to controls. Dose-dependent relationship between caries and risk of SLE was identified. The risk of SLE was higher among those who had dental visits ≧11 (HR = 2.53, 95% CI = 1.86-3.43), followed by those with 3-10 dental visits (HR = 1.86, 95% CI = 1.36-2.54), when compared to those with 1-2 visits, and was higher among those who had carious teeth extractions ≧5 (HR = 1.88, 95% CI = 1.19-2.97), followed by those with 1-4 carious teeth extractions (HR = 1.36, 95% CI = 1.17-1.59) than those without extraction. The risk of SLE for dental caries management among different restorative materials, including amalgam, composite resins, or both, was not statistically different. CONCLUSIONS: Patients with dental caries were associated with higher SLE risks. The relationship between dental caries and risk of SLE was dose-dependent, regardless of the material used for the restoration.

Celecoxib and Etoricoxib may reduce risk of ischemic stroke in patients with rheumatoid arthritis: A nationwide retrospective cohort study.

Background and purpose: Previous studies reported conflicting results about the risk of ischemic stroke associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA). We aimed to investigate two specific COX-2 inhibitors, Celecoxib and Etoricoxib, and their corresponding effects on the risk of ischemic stroke in patients with RA. Patients and methods: 10,857 patients newly diagnosed with RA were identified and sampled from the Taiwanese National Health Insurance Research Database during the period from 2001 to 2009. The identification of RA was based on the criteria of ICD-9-CM diagnosis code 714.0. Patients diagnosed with cerebrovascular disease and those receiving RA treatment prior to the first diagnosis of RA were excluded. Study endpoint was ischemic stroke, defined by ICD-9-CM code. Cox proportional hazard models and Kaplan Meier curves were used to reveal covariates and differences by drugs in the risk of ischemic stroke. Dosages for Celecoxib were defined as ≤ 200 and >200 mg/day; those for Etoricoxib were 0 and >0 mg/day. Results: Among 7,904 RA patients, 6,669 did not take Celecoxib and 564 (8.46%) of them experienced an ischemic stroke event. Of the 597 individuals who took ≤ 200 mg/day of Celecoxib, 58 (9.72%) had strokes. Of the 638 patients who took >200 mg/day of Celecoxib, 38 (5.96%) eventually experienced a stroke. Among the 7,681 patients who did not take Etoricoxib, 654 (8.51%) experienced an ischemic stroke, while 6 (2.69%) in 223 patients who consumed Etoricoxib had a stroke event. Consuming more than 200 mg of Celecoxib per day for <3.5 years lowered the incidence rate for strokes [hazard ratio (HR) 0.67, 95% Confidence Interval (CI) 0.48-0.93 for dosage and HR 0.22, 95% CI 0.10-0.46 for duration, both p < 0.001], while consuming any dosage of Etoricoxib significantly decreases the possibility (HR 0.35, 95% CI 0.16-0.80, p < 0.001). On the other hand, consuming Etoricoxib for 8 years might have a neutral or even a potentially protective effect compared to at 3.8 years. Conclusion: This population-based retrospective cohort study has shown that Celecoxib and Etoricoxib reduce the risk of ischemic stroke in patients with RA in a dose- and time-dependent manner.

Risk of primary Sjogren's Syndrome following human papillomavirus infections: a nationwide population-based cohort study.

Introduction: Viral infection is an exogeneous factor for primary Sjogren's syndrome (pSS). This study investigated the association between human papillomavirus (HPV) infections and pSS through a nationwide population based cohort study. Methods: Patients with HPV infections between January, 1999 and December, 2013 were included. The incidence of new-onset pSS in patients with HPV infections and non-HPV controls were derived. The multiple Cox regression model derived the risk of pSS in patients with HPV infections. Subgroup analysis and sensitivity analysis were performed to validate the association. Results: During a follow-up period of 12 years, the adjusted hazard ratio (aHR) of pSS in patients with HPV infections was significantly higher than that in non-HPV controls (aHR=1.64, 95% CI=1.47-1.83, P<0.001). The risk of pSS increased with age and the risk increased by 2.64-fold (95% CI= 2.37-2.93) for those older than 45 years. The significant association between HPV infections and the risk of pSS persisted in the sensitivity analysis restricted in HPV infections that lasted over 12 months (aHR=1.63, 95%CI=1.45-1.83, P<0.0001). Subgroup analyses revealed that both male (aHR=1.83, 95%CI=1.47-2.28, P<0.0001) and female (aHR=1.58, 95%CI=1.40-1.79, P<0.0001) patients with HPV infections and HPV-infected patients aged between 16 and 45 years (aHR=1.60, 95%CI=1.34-1.91, P<0.0001) and over 45 years (aHR=1.67, 95%CI=1.46-1.91, P<0.0001) were associated with a significantly greater risk of pSS. Conclusion: Patients with HPV infections presented with a significantly higher risk of pSS, regardless of age and sex.

Chinese herbal medicine might be associated with a lower rate of joint replacement in patients with osteoarthritis: A 12-year population-based matched cohort analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: To determine whether adjuvant Chinese herbal medicine (CHM) treatment is associated with the risk of joint replacement in osteoarthritis (OA) patients. MATERIALS AND METHODS: This retrospective study used a population-based national health insurance (NHI) database from 2000 to 2012 in Taiwan. A total of 125,023 newly diagnosed OA patients were selected from one million beneficiaries of longitudinal health insurance database. Based on applying ten selected frequently used CHM formulas for OA, patients were divided into CHM user and non-CHM user. One-CHM to four-non-CHM user were propensity score matched with age, gender, monthly income, urbanization, comorbidities, Nonsteroidal anti-inflammatory drugs (NSAIDs) and index year were adjusted to reduce selection bias and confounding. Cox regression model was used for comparing the hazard ratios (HR) for the risk of joint replacement and Kaplan-Meier curve for the proportion of joint replacement. RESULTS: OA patients who were female, younger (20-60 years), higher income and lived in urbanization location were found to preferred using CHM. Younger CHM users had a lower adjusted HR (0.63) of the risk of joint replacement (95% confidence interval (CI) = 0.42-0.94). Compared to non-CHM user, HR among CHM users (≥225 days annually) is 0.48 (95% CI = 0.31-0.76). The proportion of joint replacement in younger non-CHM user began to rise notably with time (log-rank test, p = 0.026). However, this benefit by CHM did not apply to older (over 60 years) OA patients. CONCLUSION: This study suggested that adjuvant CHM might be associated with a lower rate of joint replacement in OA patients. CHM therapy might be considered in OA patients to reduce the need of joint replacement.

Increased risk of glaucoma amongst new-onset gout patients aged 20-39 years: A nationwide population-based cohort study in Taiwan.

OBJECTIVES: To provide epidemiologic evidence of whether gout increases the risk of new-onset glaucoma. METHODS: We conducted a 13-year nationwide, population-based, retrospective cohort study to examine the association between the history of gout and risk of glaucoma by using the Longitudinal Health Insurance Database (LHID) of Taiwan. The gout cohort included 52 943 patients with newly diagnosed gout who were recruited between 2000 and 2012. Each patient was propensity score matching with 1:1 person without gout from the LHID. To determine glaucoma occurrence, the study population was followed up until the end of 2013. Cumulative incidence, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated after adjusting for age, sex, comorbidities, and ever ophthalmic visit. A Cox proportional hazard model was used to analyse the association between gout and incidence of glaucoma amongst patients with different potential risks. RESULTS: The adjusted HR for newly diagnosed glaucoma in the gout cohort was 1.00 (95% CI = 0.93-1.07, P = .931), compared with the non-gout cohort. Stratified subgroup analysis revealed that the HRs of glaucoma were 1.36 (95% CI = 1.09-1.70, P = .007), 0.99 (95% CI = 0.87-1.12, P = .871), and 0.95 (95% CI = 0.87-1.03, P = .235) in patients with gout aged 20-39, 40-54, and ≥55 years, respectively (P for interaction = .011). CONCLUSION: This nationwide population-based cohort study revealed that gout patients in the age group 20-39 years had a higher risk of glaucoma than non-gout controls.

Flat foot and spinal degeneration: Evidence from nationwide population-based cohort study.

BACKGROUND/PURPOSE: Flat foot can alter the lower limb alignment and cause knee and back pain. To explore the association between flat foot and spinal degeneration. METHODS: By using a claims dataset containing 1 million random samples, individuals with flat foot were identified between January 1, 2000, and December 31, 2013. The study assembled a flat foot group and a matched non-flat foot group. Definition of flat foot was according to International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The diagnosis date was defined as the index date for follow-up initiation. The follow-up period was defined as the duration from the index date (or nested index date for controls) to the occurrence of spinal degenerative joint disease (DJD), or December 31, 2013. The primary outcome was record of spinal DJD retrieved from the same database. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with the control group as a reference. RESULTS: We identified 13,965 patients (most aged <30 years, 88%); 2793 patients were assigned to the flat foot group and 11,172 individuals to the non-flat foot group matched by age, sex, and index year. The mean follow-up duration was approximately 74 months. In total, 329 (11.78%) patients in the study group and 931 (8.33%) patients in the comparison group developed spinal DJD. The adjusted HR (95% CI) of spinal DJD for study group was 1.423(1.250-1.619) compared with the control. Sensitivity analyses with propensity score match and different scenario about spinal DJD enrollment showed similar results. Subgroup analysis showed that in patients aged >45 years with history of flat foot, the adjusted hazard ratios were 1.434, 3.065, 3.110, and 2.061 in association with spondylosis, intervertebral disc disorder, cervical stenosis, thoracic-lumbar-sacral stenosis, respectively. CONCLUSION: Flat foot was found to be an independent risk factor for subsequent spinal DJD.

Neoplasm Risk in Rheumatic Diseases Has No Correlation With Conventional Synthetic Disease-Modifying Anti-rheumatic Drugs Usage-A Population-Based Nested Case-Control Study.

Objectives: To investigate whether there is an elevated neoplasm risk in patients with rheumatic diseases treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Methods: A population-based nested case-control study was performed by retrieving all patients newly diagnosed with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriatic arthritis (PsA) or psoriasis vulgaris (PsO) from the 2000 Longitudinal Health Insurance Database (LHID 2000) in Taiwan. Two hundred and sixty-one patients with neoplasm from 1997 to 2013 were enrolled in this study, and controls were matched in a 1:1 ratio with age, sex, and year of enrollment. Composition of demographic indices, comorbidities, medication usage, and differences in days of prescription of different medications between neoplasm and neoplasm-free (control) groups were compared. Results: Between the control and neoplasm groups, no differences in ratio were observed in the usage of hydroxychloroquine (50.96 vs. 49.04%, p = 0.6616), methotrexate (26.82 vs. 27.59%, p = 0.8441), azathioprine (3.45 vs. 3.07%, p = 0.8052), and cyclophosphamide (1.15 vs. 2.30%, p = 0.3131) from enrollment to index date. Medications within 3 years before the index date in patients that had ≥3 months of comparable duration also showed no difference (hydroxychloroquine: 33.06 vs. 30.25%, p = 0.6404; methotrexate: 20.66 vs. 25.21%, p = 0.4018; azathioprine: 2.48 vs. 2.52%, p = 0.9835; cyclophosphamide: 0.83 vs. 0.84%, p = 0.9906). We also made a subgroup analysis focusing on RA and SLE patients; no difference between control and neoplasm group in both the ratio of usage and days of prescription of hydroxychloroquine, methotrexate, azathioprine, and cyclophosphamide was observed. Conclusion: Neoplasm risk in patients with rheumatic diseases has no correlation with csDMARD usage.

Methotrexate at middle and high accumulative doses might be associated with lower risk of new-onset cancers in patients with rheumatoid arthritis: a nationwide population-based cohort study.

BACKGROUND: We investigated whether taking methotrexate (MTX) is associated with a lower risk of new-onset cancers in patients with rheumatoid arthritis (RA). METHODS: We conducted a 12-year retrospective cohort study from a population-based National Health Insurance Research Database in Taiwan. A total of 21,699 patients with newly diagnosed RA were enrolled during 2000-2009. The overall cancer rate was compared between 10,352 new users of MTX and 11,347 non-users. We used the WHO Defined Daily Dose (DDD) as a tool to assess drug exposure. Cox proportional hazard regression models were used to estimate the hazard ratio (HR) of disease after controlling for demographics and other comorbidities. RESULTS: After adjusting for age, sex, cancer-related comorbidities, and RA-combined medication, the HR of cancer risk was 0.87 (95% CI = 0.74-1.02) for the MTX user group compared with the MTX non-user group. The cumulative incidence of cancer in the MTX non-user group was significantly higher than that of the MTX user group (log-rank test p < 0.001). In the low accumulative dose group [cumulative dose <1125 mg, cumulative defined daily dose (cDDD) <450], the HR of cancer risk for MTX users was 1.20 (95% CI = 1.01-1.42) compared with the MTX-non-user group. However, the adjusted HR of cancer risk was reduced to 0.66 (95% CI = 0.49-0.87) in MTX middle-dose users (cumulative dose 1125-2250 mg, cDDD: 450-899) and 0.33 (95% CI = 0.23-0.48) for the MTX high-dose group (cumulative dose ⩾2250 mg, cDDD ⩾900), respectively (p for trend < 0.0001). CONCLUSION: MTX at middle and high accumulative doses might be associated with lower risk of new-onset cancers in patients with RA.

The risk of herpes zoster among patients with ankylosing spondylitis: A population-based cohort study in Taiwan.

OBJECTIVES: The incident rate of herpes zoster (HZ) is higher in some autoimmune diseases; however the relationship of HZ and ankylosing spondylitis (AS) is still unclear. This research aims to determine the incidence of HZ in Taiwan AS patients. METHODS: This study included 2819 AS patients and 11 276 non-AS controls between 2003 and 2013. All participants were selected from the Longitudinal Health Insurance Database 2000 Taiwan. The endpoint was diagnosis of HZ by International Classification of Diseases, Ninth Revision, Clinical Modification coding for at least 3 outpatient visits or one admission until the end of 2013. We used Chi-square test, Cox proportional hazard models and a Kaplan-Meier analysis to calculate the hazards ratio (HR), disease-free survival and incidental density of HZ. Subgroup analysis and sensitivity tests were also done. RESULTS: Comorbidities such as chronic urticaria, inflammatory bowel disease, thyroid disorders, hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, cerebrovascular accident, were higher in patients with AS than that in controls. Patients age ≥60 or comorbid disease such as thyroid disorders or cancer had a higher HR of HZ; the adjusted HRs were 2.273 (95% CI 1.314-3.931), 1.577 (95% CI 1.008-2.466) and 1.855 (95% CI 1.248-2.758) respectively, on multivariable modeling. The crude HR for HZ among AS patient was 1.178 (95% CI 0.953-1.455, P > 0.05), and the adjust HZ was 1.070 (95% CI 0.835-1.371, P > 0.05), compared to non-AS controls. CONCLUSIONS: There is no difference in incidence rate of HZ between Taiwan AS patients and non-AS controls. Among AS patients, age and cancer were major risk factors for incidental HZ.

Risk of dementia among patients with Sjogren's syndrome: A nationwide population-based cohort study in Taiwan.

OBJECTIVE: Autoimmunity may play a role in early-stage dementia. The association between Sjogren's syndrome (SS) and dementia remains unknown. This study was conducted to provide epidemiologic evidence for this relationship. METHODS: This 12-year, nationwide, population-based, retrospective cohort study analyzed the risk of dementia in the SS cohort. We also investigated the incidence of dementia among patients with SS by using data from the Longitudinal Health Insurance Database 2000, maintained by the Taiwan National Health Research Institutes. To balance the prevalence of characteristics in the cohorts, we used the propensity score to match selected comorbidities in the two cohorts. We also analyzed the association between SS and dementia among patients with different potential risks by using a Cox proportional hazard model. RESULTS: According to the analysis of data obtained from follow-up conducted during 2000-2012, the incidence of dementia in the SS cohort was 1.21-fold that in the control cohort (95% confidence interval [CI] = 1.02-1.45, p < 0.05). In the group older than 65years, the incidence of dementia was significantly high (adjusted hazard ratio [aHR] = 5.30, 95% CI = 4.26-6.60, p < 0.01). After adjustment for comorbidities, including Parkinson's disease (aHR = 2.98, 95% CI = 1.80-4.94), insomnia (aHR = 1.45, 95% CI = 1.14-1.85), and hypertension (aHR = 1.43, 95% CI = 1.19-1.71), the association between SS and dementia was still significant. CONCLUSION: This 13-year, nationwide, population-based retrospective cohort study revealed patients with SS to have a higher risk of dementia.

Increase risk of allergic diseases in patients with ankylosing spondylitis: A 10-year follow-up population-based study in Taiwan.

Th2 and Th17 cells are both associated with developing ankylosing spondylitis (AS) and asthma. Th2 cells are also associated with allergic rhinitis and atopic dermatitis (AD). The prevalence of such allergic diseases in AS patients is unknown. In this study, we intended to study the risk of allergic diseases in a 10-year follow-up population of newly diagnosed patients with AS. We used a nationwide 10-year population-based database retrieved from the Longitudinal Health Insurance Database 2005 (LHID2005) in Taiwan. The study cohort comprised 857 patients with AS who had at least 1 claim of inpatient admission or at least 2 claims of ambulatory visit. The comparison cohort consisted of 4285 randomly selected subjects matched with AS group at a ratio of 5:1. We used Cox proportional-hazards regression to determine the 10-year disease-free survival rates after adjusting for potentially confounding factors. The AS patients had a 1.31 times greater risk of developing asthma within 10 years of diagnosis when compared with non-AS age- and sex-matched subjects, after adjusting for other risk factors (95% confidence interval = 1.00-1.75). But the difference was not significantly different. The AS patients also had a 1.46 times and a 1.22 times greater risk of developing allergic rhinitis and AD significantly. AS patients also had a lower allergic disease-free survival rate compared to non-AS group. Our results showed that patients with AS had a higher risk of developing allergic diseases later in life.