Risk of Type 1 Diabetes Mellitus in Patients with Atopic Dermatitis: A Nationwide Population-Based Cohort Study.

INTRODUCTION: Atopic dermatitis (AD) is a disease frequently occurring in children. The immune response is characterized by T-helper (Th)-2-dependent inflammation. Type 1 diabetes mellitus (T1DM) is an autoimmune disease that destroys pancreatic islet beta cells. In contrast, it is mainly mediated by a Th-1-dependent response. An inverted association has been hypothesized between T1DM and AD since Th1 and Th2 responses are mutually inhibitory. METHODS: Data was retrieved from a nationwide healthcare database in Taiwan. A logistic regression model was used to evaluate the association of T1DM in patients with AD within a year. A Cox proportional hazards analysis was used to evaluate the subsequent risk of developing T1DM 1 year after AD diagnosis. RESULTS: We identified 396,461 patients with AD and 1,585,844 age- and sex-matched controls. During the first year of follow-up, after adjusting variates, the association between T1DM and AD showed no statistical differences (odds ratio: 1.40; 95% confidence interval [CI]: 0.83-2.38, p = 0.207). After excluding those T1DM cases within 1 year of AD diagnosis and those with a follow-up duration of less than 1 year, AD did not significantly increase the risk of T1DM (hazard ratio [HR]: 1.02; 95% CI, 0.83-1.25, p = 0.843). CONCLUSIONS: Our study revealed that there was no significant association between AD and T1DM in the first year after AD diagnosis, and there was no increased risk of T1DM in AD patients in the average 5-year follow-up in our study.

Risk of Serious Infections in Patients with Bullous Pemphigoid: A Population-based Cohort Study.

Patients with bullous pemphigoid are susceptible to serious infections, which are the leading cause of death in these patients. The aims of this population-based cohort study were to investigate the incidence and spectrum of serious infections in patients with bullous pemphigoid and to identify associated risk factors. The outcome measure was any infection requiring hospitalization. Hazard ratios with 95% confidence intervals were estimated using subdistribution hazard models. In total, 12,300 patients with bullous pemphigoid and 49,200 matched controls were identified through the National Health Insurance Research Database in Taiwan. Within 2 years of bullous pemphigoid diagnosis, 5,006 (40.7%) patients developed serious infections, with an incidence of 385.5/1,000 person-years. Patients with bullous pemphigoid were twice as likely to develop serious infections as controls (adjusted hazard ratio, 2.01; 95% confidence interval 1.92-2.10). Systemic corticosteroid use was the strongest risk factor, resulting in a 2-fold increase in the risk for serious infections. Other independent risk factors were advanced age, female sex, low income, and certain comorbidities. In conclusion, this study demonstrated an increased risk of serious infections following a diagnosis of bullous pemphigoid. Prophylaxis of serious infections through active intervention with the risk factors may be essential in reducing the morbidity and mortality associated with bullous pemphigoid.

Association between bullous pemphigoid and atopic dermatitis: a population-based case-control study in Taiwan.

Although bullous pemphigoid (BP) and atopic dermatitis (AD) share pathogenic mechanisms, their relationship remains controversial. Therefore, we conducted a population-based case-control study to investigate the association between BP and AD in Taiwan. Based on the Taiwan National Health Insurance Research Database, 9344 patients with BP and 18,688 age- and sex-matched controls were enrolled between 2000 and 2013. Furthermore, the study included 7,196 BP patients and 14,392 controls, matched for age, sex, and propensity score of comorbidities, with a case to controls ratio of 1:2. Logistic regression analysis was performed to examine the association between AD and BP. In the age- and sex-matched cohorts, AD (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.50-1.95) was independently associated with BP. In the age, sex, and comorbidities-matched cohorts, AD (OR 1.76, 95% CI 1.55-2.00) remained a significant risk factor for BP. Other significant risk factors included psoriasis, hypertension, diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease, neuropsychiatric diseases, and autoimmune connective tissue disease. Limitations of this study include the lack of information on disease severity and phenotypes of BP and misclassification of diseases as potential sources of bias. In conclusion, AD increased the risk of developing BP by 76%, and this association was independent of many BP comorbidities. Further studies are warranted to investigate the clinical and pathophysiological relevance of factors contributing to BP and AD.

Association between sodium-glucose co-transporter 2 inhibitors and risk of psoriasis in patients with diabetes mellitus: a nationwide population-based cohort study.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitor (SGLT2i) treatment may exert anti-inflammatory effects by modulating the NOD-like receptor family pyrin domain-containing 3 inflammasome and interleukin-17/23 inflammatory axis, which are both involved in the pathogenesis of psoriasis. However, the relationship between SGLT2i treatment and psoriasis remains unclear. AIM: To investigate the association between SGLT2i treatment and incident psoriasis. METHODS: Using the Taiwan National Health Insurance Database for the period 2007-2018, we matched 103 745 patients with Type 2 diabetes mellitus (T2DM) receiving SGLT2i with a control group of patients with T2DM who did not use SGLT2i, matching them in a 1 : 2 ratio by age, sex, diabetes duration, insulin use and comorbidities, and evaluating the psoriasis risk in both groups. RESULTS: The incident psoriasis risk did not significantly differ between the SGLT2i and control groups [hazard ratio (HR) = 1.24, 95% CI 0.95-1.64] after adjustment for potential confounders. Insulin use (HR = 1.65, 95% CI 1.24-2.19) and chronic liver disease and cirrhosis (HR = 1.34, 95% CI 1.01-1.77) were significantly associated with increased psoriasis risk. A slightly increased psoriasis risk was also detected in certain SGLT2i user subgroups, especially those with renal disease (HR = 2.73, 95% CI 1.45-5.13). CONCLUSION: SGLT2i-mediated protective effects in psoriasis could not be established. SGLT2i treatment increased psoriasis risk by 2.7-fold in patients with T2DM exhibiting renal diseases.

Association between bullous pemphigoid and risk of venous thromboembolism: A nationwide population-based cohort study.

Bullous pemphigoid (BP) has been reported to be associated with an increased risk of venous thromboembolism (VTE). However, the exact time course is unclear, and no previous studies have been reported in the Asian population. This nationwide population-based cohort study examined the risk of VTE among BP patients in Taiwan between 2007 and 2018. A total of 12 692 BP patients were 1:2 matched with non-BP patients by age, sex, and propensity score of comorbidities. Cumulative incidence and Cox proportional hazards models were used to investigate the risk of VTE. The BP cohort had a significantly higher VTE rate than the non-BP cohort (0.17% vs. 0.08%, p = 0.015) in 1 year; the finding was more prominent within the first 6 months after diagnosis. BP was a significant risk factor for VTE (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.01-4.06); the association mildly diminished but remained significant after extending the follow-up period to 2 years (HR, 1.73; 95% CI, 1.06-2.81). Other significant risk factors for VTE included cancer, chronic liver disease and cirrhosis, and female sex. In conclusion, this study revealed a 2.02-fold increased risk of VTE in patients with BP in Taiwan.

Testicular dmrt1 is involved in the sexual fate of the ovotestis in the protandrous black porgy.

In hermaphroditic fish, the ovotestis can respond to external stimuli so that only one type of gonadal tissue (either ovarian or testicular tissue) will remain reproductively active and the other will recede to a rudimentary stage. However, the molecular mechanism for sexual fate determination is still poorly understood in hermaphroditic fish. In the present study, we examined whether sexual fate determination with respect to testis development is due to differential expression of dmrt1. Expression of dmrt1 was limited to the spermatogonia-surrounding cells (Sertoli cells) throughout testis development. Testicular dmrt1 was differentially expressed in fish (black porgy [Acanthopagrus schlegeli Bleeker]) depending on if fish were destined to be female or male. Expression of dmrt1 in Sertoli cells did not require germ cell factors with busulfan treatment. To examine the role of dmrt1, we used virus-based RNA interference. Deficiency of dmrt1 resulted in a reduced number of germ cells in the testis and stimulated a male-to-female sex change. Higher serum luteinizing hormone levels were detected in 2(+)- to 3-yr-old male fish as compared to sex-changing female fish. Furthermore, we showed that fish treated in vivo with gonadotropin-releasing hormone (Gnrh) and fish treated in vitro with gonadotropin (Gth) had higher dmrt1 expression in the testis, suggesting that these endocrine factors may affect the male-to-female sex change. Therefore, our data suggest that dmrt1 plays a key role in initial testis differentiation and in later maintenance of male development. We show, to our knowledge for the first time, the functions of dmrt1 in hermaphroditic fish, which indicate that male-phase maintenance may be regulated by the brain-pituitary-gonadal axis via the Gnrh-Gth-Dmrt1 axis.

The expression of amh and amhr2 is associated with the development of gonadal tissue and sex change in the protandrous black porgy, Acanthopagrus schlegeli.

The protandrous black porgy, Acanthopagrus schlegeli, has a striking life cycle, with sex differentiation at the juvenile stage, mono-male development, a bisexual gonad during the first 2 yr of life, and a male-to-female sex change (with vitellogenic oocytes) at 3 yr of age. In the present study, we investigated the possible roles of amh and amhr2 in gonadal development in a nonmammalian model organism (protandrous black porgy), especially in relation to sex differentiation, testicular and ovarian growth, and sex change. Fish of various ages were treated with estradiol or an aromatase inhibitor to induce the fish to become female. Furthermore, a natural sex change (2(+)-yr-old [>2 yr and <3 yr] fish) and a nonchemical method to surgically remove one of the pair of gonads to examine the possible roles of amh in the natural sex change were conducted. We present integrative in situ hybridization, immunohistochemical, cellular, and molecular data describing these phenomena. During gonadal sex differentiation, an increase in amh and amhr2 expression was detected. Higher levels of amh and amhr2 transcripts were observed in the testicular tissue when compared to the ovarian tissue in the bisexual gonad of 1(+)-yr-old (>1 yr and <2 yr) fish. Transcripts of amh reached peak levels in November (prespermatogenesis period) and then declined to the lowest levels in January (spawning period). Chemical-induced ovarian tissue had very low amh transcript levels but high levels of amhr2. Active testes had significantly higher amh and amhr2 expression levels as compared to inactive testes. In contrast, no difference in the expression of amh and amhr2 between active and inactive ovarian tissues was found. Transcripts of amh were expressed in the somatic cells of the spermatogonia and vitellogenic oocytes, and amhr2 was expressed in the somatic cells of the spermatogonia. Transcripts of amh decreased in the testicular tissue 5 mo before occurrence of the sex change into a female. In contrast, testicular amh expression remained high if the fish remained male. Human chorionic gonadotropin regulated amh and amhr2 expression in the testicular tissue but not in the ovarian tissue. The present results suggest that amh plays important roles in early testicular and ovarian development, late ovarian growth (e.g., vitellogenic oocytes), and natural sex change in the protandrous black porgy.