MyoD Over-Expression Rescues GST-bFGF Repressed Myogenesis.

During embryogenesis, basic fibroblast growth factor (bFGF) is released from neural tube and myotome to promote myogenic fate in the somite, and is routinely used for the culture of adult skeletal muscle (SKM) stem cells (MuSC, called satellite cells). However, the mechanism employed by bFGF to promote SKM lineage and MuSC proliferation has not been analyzed in detail. Furthermore, the question of if the post-translational modification (PTM) of bFGF is important to its stemness-promoting effect has not been answered. In this study, GST-bFGF was expressed and purified from E.coli, which lacks the PTM system in eukaryotes. We found that both GST-bFGF and commercially available bFGF activated the Akt-Erk pathway and had strong cell proliferation effect on C2C12 myoblasts and MuSC. GST-bFGF reversibly compromised the myogenesis of C2C12 myoblasts and MuSC, and it increased the expression of Myf5, Pax3/7, and Cyclin D1 but strongly repressed that of MyoD, suggesting the maintenance of myogenic stemness amid repressed MyoD expression. The proliferation effect of GST-bFGF was conserved in C2C12 over-expressed with MyoD (C2C12-tTA-MyoD), implying its independence of the down-regulation of MyoD. In addition, the repressive effect of GST-bFGF on myogenic differentiation was almost totally rescued by the over-expression of MyoD. Together, these evidences suggest that (1) GST-bFGF and bFGF have similar effects on myogenic cell proliferation and differentiation, and (2) GST-bFGF can promote MuSC stemness and proliferation by differentially regulating MRFs and Pax3/7, (3) MyoD repression by GST-bFGF is reversible and independent of the proliferation effect, and (4) GST-bFGF can be a good substitute for bFGF in sustaining MuSC stemness and proliferation.

Correlation of Disease Severity, Proinflammatory Cytokines, and Reduced Brain Gray Matter Volumes in Patients with Atopic Dermatitis.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease. However, few studies have investigated brain changes associated with chronic inflammation. We hypothesized that chronic inflammation might be related to brain structural alterations in patients with AD. Objectives: To investigate the association between disease severity (Eczema Area and Severity Index [EASI]), proinflammatory cytokines, and differences in brain gray matter (GM) volume in patients with AD. Methods: Nineteen patients with AD and 19 age- and sex-matched healthy subjects were enrolled. All participants underwent clinical assessment and brain magnetic resonance imaging. Voxel-based morphometry was performed to analyze GM volume differences. Results: Patients with AD exhibited significantly decreased GM volume in many brain regions, such as bilateral precentral gyrus, right frontal pole, and right middle temporal gyrus (P < 0.001), compared with healthy subjects. Notably, in patients with AD, the GM volume in right middle temporal gyrus was negatively associated with both EASI score and proinflammatory cytokines (sIL-2R [soluble interleukin 2 receptor] and TNF-α receptor-1), whereas the GM volume in left precentral gyrus was negatively associated with both EASI score and proinflammatory cytokines (sIL-2R and CRP). Conclusion: Patients with AD demonstrated significant brain GM volume reduction in many brain regions, which is related to disease severity and proinflammatory cytokines.

Association between vitiligo and risk of retinal detachment: a population-based cohort study in Taiwan.

BACKGROUND: Vitiligo is reportedly associated with several ocular abnormalities. However, the relationship between vitiligo and retinal detachment (RD) remains unclear. OBJECTIVES: To examine the risk of RD in patients with vitiligo. METHODS: A nationwide population-based cohort study was conducted using data from the Taiwan National Health Insurance Database from 2007 to 2018. A total of 21 132 patients with vitiligo were matched in a 1 : 4 ratio with people without vitiligo by age, sex and comorbidity propensity score. Cumulative incidence and Cox proportional hazard models were used to investigate the risk of RD in patients with vitiligo. Subgroup analysis was performed. RESULTS: The cohort with vitiligo had a significantly higher rate of RD than the cohort without vitiligo [adjusted hazard ratio (aHR) 1.44, 95% confidence interval (CI) 1.20-1.72; P < 0.001]. Patients with vitiligo who required treatments such as phototherapy, systemic corticosteroids or immunosuppressants exhibited an even greater risk of RD (aHR 1.57, 95% CI 1.16-2.14; P = 0.004). CONCLUSIONS: Our study revealed a 1.44-fold increased risk of RD in patients with vitiligo, with an even higher risk in patients receiving phototherapy, systemic corticosteroids or immunosuppressants. The risk remained consistently higher over a 10-year follow-up period.

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.

Association between chronic kidney disease and risk of bullous pemphigoid: a nationwide population-based cohort study.

BACKGROUND: Studies have shown that bullous pemphigoid (BP) occurs in patients with chronic kidney disease (CKD). However, the risk of developing BP in patients with CKD remains inconclusive. OBJECTIVE: To investigate whether CKD increases the risk of BP. METHODS: Participants were recruited from the National Health Insurance Database of Taiwan between 2007 and 2018. Overall, 637,664 newly diagnosed patients with CKD and 637,664 age-, sex-, and comorbidity-matched non-CKD participants were selected. A competing risk model was used to evaluate the risk of development of BP. RESULTS: After adjusting for age, sex, and comorbid diseases in the multivariate model, CKD was a significant risk factor for BP (adjusted hazard ratio [aHR]: 1.29; 95% confidence interval [CI]: 1.17-1.42; p < 0.001). CKD patients were classified into the dialytic or non-dialytic groups and compared to non-CKD participants, and this revealed that patients with dialysis-dependent CKD had the highest risk of BP (aHR 1.75; 95% CI 1.51-2.03), followed by patients with non-dialysis-dependent CKD (aHR 1.20; 95% CI 1.08-1.32). LIMITATIONS: We lacked detailed laboratory data on the severity of CKD. CONCLUSIONS: Compared with individuals without CKD, those with CKD had a 1.3-fold increased risk of BP. Patients with dialysis-dependent CKD had an even higher BP risk (1.8-fold).

Proton-pump inhibitors are associated with an increased risk of asthma: A nationwide nested case-control study.

Background: Proton-pump inhibitors (PPI) are among the most widely used drugs worldwide. However, the association between PPI use and the risk of asthma remains unclear. Objective: To investigate the association between PPI use and subsequent asthma risk. Methods: We included participants from the Taiwan National Health Insurance Research Database between 1999 and 2013. Patients who used PPIs and experienced new-onset asthma (n = 20,344) were assigned to the case cohort and matched in a 1:1 ratio with controls who did not subsequently develop asthma. PPI use was defined as > 30 cumulative defined daily doses (cDDD); non-PPI use was defined as ≤ 30 cDDDs. The Charlson Comorbidity Index (CCI) score was used for clinical prognosis and comorbidity adjustment. Multivariate Cox regression models were used for the calculation of adjusted odds ratios (OR). Results: There was a significant and dose-dependent association between PPI use and the risk of developing asthma. The adjusted ORs were 1.24 (95% confidence interval [CI], 1.15-1.33), 1.39 (95% CI, 1.28-1.50), and 1.61 (95% CI, 1.43-1.81) for the male subject with 31-120 cDDDs, 120-365 cDDDs, and >365 cDDDs, respectively, compared with PPI nonusers. Men were at higher risk of developing asthma with longer PPI use compared with women. Stratified analyses based on the PPI type showed that exposure to lansoprazole, pantoprazole, omeprazole, and esomeprazole was associated with subsequent asthma risk. Conclusion: Extended use of PPIs was found to be linked to an increased risk of asthma development. This association remained consistent across different age groups, sexes, demographic factors, indications for PPI use, CCI scores, and other atopic diseases. However, further prospective studies are required to elucidate the causal mechanisms involved.

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.

Increased Risk of Suicide Attempt in Patients with Alopecia Areata: A Nationwide Population-Based Cohort Study.

BACKGROUND: There is growing evidence that patients with alopecia areata (AA) have an increased risk of developing psychiatric comorbidities. However, the relationship between AA and suicidal behaviors remains unclear. OBJECTIVE: The objective of this study was to investigate the association between AA and suicidal behaviors. METHODS: Participants were recruited from the National Health Insurance Research Database in Taiwan, including 10,515 patients with AA and 10,5150 matched controls, to assess the risk of suicide attempts. A Cox regression model was used for all analyses. RESULTS: Compared with the controls, an increased risk of suicide attempts was observed in patients with AA, with an adjusted hazard ratio of 6.28 (95% confidence interval, 4.47-8.81). Suicide risk remained significantly elevated in AA patients when stratified by underlying psychiatric disorders. The mean age of initial suicidal behaviors was also lower in patients with AA. CONCLUSIONS: Patients with AA had a significantly higher incidence of suicidal attempts than controls, regardless of concurrent psychiatric illness. Further studies are needed to elucidate the pathophysiology of the association between AA and suicidality. In addition, dermatologists should be aware of the increased suicidality of patients with AA.

Management of Atopic Dermatitis During the COVID-19 Pandemic: Key Questions and Review of the Current Evidence.

Since the outbreak of COVID-19, management of atopic dermatitis (AD) has been widely discussed. Key issues include the risk of COVID-19 infection and related outcomes in AD patients, the efficacy and safety of COVID-19 vaccination in AD populations, and management of AD in the COVID-19 pandemic. Recent studies have shown that patients with AD have a slightly increased risk of COVID-19 infection but are not associated with a worse outcome than the non-AD population. COVID-19 vaccination is generally effective and safe in patients with AD. However, temporary discontinuation of certain systemic immunomodulatory agents after vaccination is suggested. During the pandemic, continuation of all immunomodulating agents is suggested, but these agents should be paused when patients with AD are infected with COVID-19 until recovery. Further studies are warranted to investigate the long-term interaction between AD and COVID-19 to aid clinical decisions during the pandemic.

Dupilumab in the treatment of genodermatosis: A systematic review.

Dupilumab interferes with the signaling pathways of IL-4 and IL-13 and is effective in treating atopic dermatitis. Specific genodermatoses, including Netherton syndrome, epidermolysis bullosa pruriginosa, and hyper-IgE syndrome, are Th2 skewed diseases with activation of type 2 inflammation. We performed this systematic review to investigate the therapeutic role of dupilumab in the treatment of genodermatosis. A systematic search was conducted of the PubMed, Embase, Web of Science, and Cochrane databases from inception to December 13, 2021. The review included studies with relevant terms including "dupilumab," "genodermatosis", "Netherton syndrome", "ichthyosis", "epidermolysis bullosa" and "hyper-IgE syndrome". The initial search yielded 2,888 results, of which 28 studies and 37 patients with genodermatosis were enrolled. The assessed genodermatoses included Netherton syndrome, epidermolysis bullosa pruriginosa, hyper-IgE syndrome, Hailey-Hailey disease, and severe eczema associated with genetic disorders. Most of the reported cases showed significant clinical improvement after the initiation of dupilumab treatment without major adverse events. Decreased immunoglobulin E levels and cytokine normalization have also been documented. In conclusion, Dupilumab may have a potential therapeutic role in certain genodermatoses skewed towards T helper 2 (Th2) immunity, including Netherton syndrome, epidermolysis bullosa pruriginosa, hyper-IgE syndrome, Hailey-Hailey disease, and severe eczema associated with some genetic disorders.

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.

Risk of malignancy in patients with psoriasis receiving systemic medications: A nested case-control study.

Large-scale, real-world studies on the side effects of systemic therapies (including biologics) in patients with psoriasis are limited. We aimed to calculate the risk of malignancy in patients with psoriasis who were treated with systemic medications. Nested case-control analyses were performed among psoriasis patients without a history of malignancy. We recruited 4188 patients with newly diagnosed psoriasis and successive malignancies, and 8376 matched controls from the National Health Insurance Research Database in Taiwan. The therapy duration was within 5 years before malignancy onset and further stratified into two groups according to the duration of medication usage. Multivariate conditional logistic regression adjusted for potential confounders was used to estimate malignancy risk associated with systemic treatments. Among psoriasis patients, long-term (> 12 months) treatment with cyclosporine increased the risk of malignancy compared with no exposure (odds ratio, 1.57; p = 0.01). Short-term (≤ 12 months) or long-term (> 12 months) use of other systemic treatments, including methotrexate, azathioprine, systemic retinoids, mycophenolate mofetil, sulfasalazine, etanercept, adalimumab, and ustekinumab, was not associated with an increased risk of malignancy in patients with psoriasis. Long-term treatment with cyclosporine increased the risk of malignancy in patients with psoriasis by 1.57-fold.

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.

Implementation of NUDT15 Genotyping to Prevent Azathioprine-Induced Leukopenia for Patients With Autoimmune Disorders in Chinese Population.

Azathioprine (AZA) is commonly used for many autoimmune disorders; however, the limitation of its clinical use is due to potential toxicities, including severe leukopenia. Recent studies have identified genetic NUDT15 variants strongly associated with AZA-induced leukopenia in Asian patients. This study aimed to investigate the strength of above genetic association and evaluate the usefulness of prospective screening of the NUDT15 variants to prevent AZA-induced leukopenia in Chinese patients. AZA-induced leukopenia in patients with autoimmune disorders were enrolled from multiple medical centers in Taiwan/China between 2012 and 2017 to determine the strength of genetic association of NUDT15 or TPMT variants by whole exome sequencing (WES). Furthermore, a prospective study was conducted between 2018 and 2021 to investigate the incidence of AZA-induced leukopenia with and without genetic screening. The WES result showed the genetic variants of NUDT15 R139C (rs116855232) (P = 3.7 × 10-25 , odds ratio (OR) = 21.7, 95% confidence interval (95% CI) = 12.1-38.8) and NUDT15 rs746071566 (P = 4.2 × 10-9 , OR = 7.1, 95% CI = 3.7-13.7), but not TPMT, were associated with AZA-induced leukopenia and NUDT15 R139C variant shows the highest sensitivity with 92.5%. Furthermore, the targeted screening of 1,013 participants for NUDT15 R139C enabled those identified as carriers to use alternative immunosuppressants. This strategy resulted in a significant decrease in the incidence of AZA-induced leukopenia compared with historical incidence (incidence rate = from 7.6% decreased to 0.4%; P = 9.3 × 10-20 ). In conclusion, the NUDT15 R139C variant was strongly associated with AZA-induced leukopenia in Chinese patients. The genetic screening of NUDT15 R139C followed by use of alternative immunosuppressants in identified carriers effectively decreased the incidence of AZA leukopenia for patients with autoimmune disorders.