The Risk of Mortality among Psoriatic Patients with Varying Severity: A Nationwide Population-Based Cohort Study in Taiwan.

Background: Previous studies showed conflicting results regarding the mortality risk in psoriasis patients with respect to disease severity and presence of psoriatic arthritis. This study aimed to determine the mortality risk in patients with mild and severe psoriasis and patients with psoriatic arthritis (PsA). Methods: A nationwide population-based cohort study was conducted based on data from the Taiwan National Health Insurance Research Database between 2002 and 2012. Incident psoriasis subjects were classified into two groups: psoriasis without arthritis and psoriasis with arthritis. Patients who had received systemic therapy and/or phototherapy were classified as having severe psoriasis; otherwise, patients were classified as having mild psoriasis. Control subjects without psoriasis were selected to match each psoriasis patient from the database within the same observational period. Cox proportional hazards analysis was used to compare the hazard ratio (HR) of time to death. Results: A total of 106,701 patients with psoriasis were included in this study. After controlling for demographics and comorbidities, psoriasis patients had a higher mortality risk compared with the control group (HR 1.41; 95% confidence interval (CI) 1.36 to 1.46). Compared with psoriasis alone, the mortality risk was not increased for PsA (HR = 1.01; 95% CI 0.93 to 1.10). Besides, severe psoriasis did not increase mortality risk compared with mild psoriasis (HR = 1.0; 95% CI 0.95 to 1.06). Conclusions: Patients with psoriasis had a higher mortality risk compared with control subjects, whereas psoriasis severity and presence of PsA had no impact on mortality risk in psoriasis patients.

Secondary neoplasms arising from nevus sebaceus: A retrospective study of 450 cases in Taiwan.

Nevus sebaceus is frequently associated with the development of secondary neoplasms. Incidences of malignant transformation vary among different reports and few data is available regarding Asian populations. We aimed to determine the characteristics of secondary tumors developing from nevus sebaceus in a Taiwanese population and to review the published work. Patients with clinically and histologically confirmed nevus sebaceus were identified from 1992 to 2012 in a medical center. Among the 450 cases of nevus sebaceus, 38 secondary neoplasms were noted, accounting for 8.5% of all cases. Benign tumors represented more than 80% of all tumors. Syringocystadenoma papilliferum (2.7%) was the most common benign tumor, followed by trichoblastoma (1.6%) and trichilemmoma (1.6%) whereas basal cell carcinoma (0.9%) was the most frequent malignant tumor on nevus sebaceus and its clinical features were not typical. All the malignant tumors on nevus sebaceus were noted only in adulthood and the mean age of those with basal cell carcinoma was significantly older than that of trichoblastoma (P = 0.028). Our study concludes that malignant transformation is rare in nevus sebaceus and occurs uniquely in adulthood. On the basis of the findings, prophylactic excision of nevus sebaceus can be elective during childhood but is strongly advocated at puberty due to the increased risk of malignant transformation with time.

Identification of minuscule inward currents as precursors to membrane electroporation-induced currents: real-time prediction of pore appearance.

BACKGROUND/AIMS: The objective of this study is to examine the current signals in response to large hyperpolarizations with the aid of principal component analysis (PCA) to search for or even predict current fluctuations related to membrane electroporation-induced current (I(MEP)). METHODS: The characteristics of principal eigenvalues generated for I(MEP) and the current signals at 10 sec prior to the start of initial I(MEP) (I(Pre)) were examined. As membrane hyperpolarizations were applied at 0.1 Hz, the appearance of I(MEP) coincided with the higher principal eigenvalues extracted in PCA. RESULTS: Subsequent addition of LaCl3 (100 µM) greatly reduced I(MEP) and associated principal eigenvalues. In real-time analysis for a single frame (i.e, 300 msec), in response to large hyperpolarization, multiple runs of heralded minuscule inward currents (Imin) occurring before large rise in current amplitudes were detected. With PCA, such heralded Imin was noted to coincide with the extreme principal eigenvalues. The duration of Imin together with large principal eigenvalues was influenced by different levels of membrane hyperpolarization. In GH3 cells, palmitoyl-L-carnitine (PALCAR), a long-chain acylcarnitine, effectively increased the I(MEP) amplitude with an EC50 value of 2.4 µM. However, in PALCAR-treated cells, the Imin together with higher principal eigenvalues disappeared, while in isoflurane-treated cells, Imin occurring before large rise of current amplitude remained intact. Similarly, the PCA analysis from I(Pre) in RAW 264.6 macrophages showed the presence of herald Imin accompanied by the extreme principal eigenvalues. CONCLUSION: It is clear from this study that these large principal eigenvalues are representative of MEP-associated formation of electropores. Therefore, different compositions around the surface membrane of cells may alter the appearance of Imin followed by I(MEP) emergence.

An update on the long-term safety experience of ustekinumab: results from the psoriasis clinical development program with up to four years of follow-up.

BACKGROUND: The efficacy and safety profile of ustekinumab with up to three years of exposure suggested a favorable benefit-risk profile in patients with moderate to severe psoriasis. OBJECTIVE: To evaluate the safety of ustekinumab in patients with moderate to severe psoriasis treated for up to four years. METHODS: Safety data were pooled across four Phase II/III randomized controlled trials. Rates over time and cumulative rates of adverse events (AEs), AEs leading to treatment discontinuation, serious adverse events (SAEs), serious infections, malignancies, and major adverse cardiovascular events (MACE) (i.e., cardiovascular death, myocardial infarction [MI], or stroke as adjudicated by an independent panel of academic cardiologists) were evaluated. Observed rates of AEs of interest were compared with those expected in the general (malignancies, MI, and stroke) and psoriasis (serious infections, MI, and stroke) populations. RESULTS: Overall, 3,117 patients were followed for up to four years (6,791 patient-years). Rates of AEs, AEs leading to treatment discontinuation, and SAEs remained stable over time, whereas cumulative rates were generally comparable between patients who received 45 mg and 90 mg of ustekinumab. The rates of AEs of interest also remained stable over time, and cumulative rates per 100 patient-years were 0.80 and 1.32 (serious infections), 0.70 and 0.53 (nonmelanoma skin cancer), 0.63 and 0.61 (other malignancies), and 0.56 and 0.46 (MACE) in patients treated with 45 mg and 90 mg, respectively. Rates of AEs of interest were consistent with those in the general and psoriasis populations. CONCLUSION: The safety profile of long-term ustekinumab treatment with up to four years of continuous use remains consistent with previous reports, with no evidence of cumulative toxicity.

Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (Part II of II): results from analyses of infections and malignancy from pooled phase II and III clinical trials.

BACKGROUND: Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate to severe psoriasis. OBJECTIVE: We sought to evaluate the impact of ustekinumab on infections and malignancies, both theoretical risks of blocking IL-12 and IL-23, in patients exposed up to 3 years. METHODS: Rates of infections and malignancies were evaluated in cumulative safety data from 3117 ustekinumab-treated patients across 4 studies. RESULTS: During the placebo-controlled periods, rates of overall infections per 100 patient-years were similar among placebo (121.0), ustekinumab 45-mg (145.7), and ustekinumab 90-mg (132.2) groups, with overlapping confidence intervals, and remained stable through 3 years in ustekinumab groups. Rates of serious infections during the placebo-controlled periods were similar between placebo (1.70) and 90-mg (1.97) groups, yet lower in the 45-mg group (0.49). Rates remained stable (90 mg) or decreased (45 mg) over time, and were comparable with those for the US psoriasis population based on a managed care database. Rates of malignancies during the placebo-controlled periods were comparable among groups (placebo: 1.70; 45 mg: 0.99; 90 mg: 0.98) and remained stable over time in ustekinumab groups. Rates of malignancies, excluding nonmelanoma skin cancer, were comparable with rates expected in the general US population based on the Surveillance, Epidemiology, and End Results database. LIMITATIONS: Controlled periods do not extend beyond 12 to 20 weeks. Only 1247 patients were treated for at least 2 years, to date. Comparator database populations may not fully represent the clinical trial population. CONCLUSIONS: The emerging safety profile of ustekinumab remains favorable and does not suggest increased rates of infection or malignancy through 3 years.

Long-term safety experience of ustekinumab in patients with moderate-to-severe psoriasis (Part I of II): results from analyses of general safety parameters from pooled Phase 2 and 3 clinical trials.

BACKGROUND: Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate-to-severe psoriasis. OBJECTIVE: To evaluate overall pooled study data to assess the safety profile of ustekinumab through 3 years of treatment. METHODS: Cumulative safety data were pooled from studies in 3117 ustekinumab-treated patients. RESULTS: During the placebo-controlled periods (Phase 2, PHOENIX 1, PHOENIX 2), rates of adverse events (AEs) were comparable among patients treated with placebo (50.4%), with ustekinumab 45 mg (57.6%), or with ustekinumab 90 mg (51.6%); similar findings were observed during the controlled period of the ACCEPT trial (etanercept: 70.0%; ustekinumab 45 mg: 66.0%; and ustekinumab 90 mg: 69.2%). Rates of serious AEs (SAEs) through the controlled periods were low and comparable among all groups (1.2% to 1.9%). Through 3 years, rates of AEs per 100 patient-years of follow-up (/100 patient-yrs) (45 mg: 305.2/100 patient-yrs; 90 mg: 305.9/100 patient-yrs) and SAEs (45 mg: 6.8/100 patient-yrs; 90 mg: 8.2/100 patient-yrs) were comparable between ustekinumab doses. No cases of demyelination or tuberculosis were reported in these trials. No dose response in rates of AEs, overall infections, or SAEs was apparent through 3 years. Rates of AEs, infections, SAEs, and AEs leading to study agent discontinuation remained generally stable or decreased over time. LIMITATIONS: Controlled periods did not extend beyond 12 to 20 weeks. Only 1247 of the 3117 ustekinumab-treated patients were treated for 2 or more years. CONCLUSIONS: The safety profile of continued ustekinumab exposure through up to 3 years is favorable and consistent with previous short-term reports.

Adverse drug events in infliximab-treated patients compared with the general and psoriasis populations.

INTRODUCTION: Infliximab is indicated for severe plaque psoriasis (PsO). The investigators compared safety event rates in infliximab PsO trials with those of the general United States and PsO populations. METHODS: Integrated data (n=1373 patients) were compared with external databases. RESULTS: The analyses reported here are based on 1106 patient years and 116 patient years of follow-up in the infliximab group and the placebo group, respectively. The standardized mortality ratio in infliximab-treated patients (0.17 [95% confidence interval [CI]: 0.00-0.92], 1 patient died) was lower than that of the general PsO population. No death occurred in the placebo group. Comparing with the psoriasis population, the standardized incidence ratios (SIRs) for hospitalization were 1.16 (95% CI: 0.92-1.43) in infliximab-treated patients and 1.07 (95% CI: 0.46-2.11) in placebo-treated patients. For serious infection, the SIRs were 1.28 (95% CI: 0.78-1.97) in infliximab-treated patients and 1.47 (95% CI: 0.18-5.32) in placebo patients. The incidence of tuberculosis (TB) among infliximab-treated patients was 0.18 per 100 patient-years (95% CI: 0.02-0.65). No TB occurred in the placebo group. Standardized incidence ratio for malignancy (excluding nonmelanoma skin cancers) was 0.39 (95% CI: 0.05-1.42; 2 malignancies) in infliximab-treated patients. No malignancy occurred in the placebo group. LIMITATIONS: Exclusion criteria in clinical studies may bias selection of subjects who are healthier than the general population. Additionally, the limited number of patients followed over a maximum of 1 year can limit the ability to detect infrequent events or those events that require prolonged follow-up to detect. Nonmelanoma skin cancers were excluded from the analysis. Finally, populations and adverse event definitions may have differed in external databases and studies. CONCLUSION: Based on the data from external databases, mortality, hospitalization, and serious infection rates in infliximab-treated patients were generally comparable to or less than that of the PsO population. Internal malignancy rates were similar to that expected in the general US population. However, the limitations of these data must be considered when compared with the totality of the safety profile of infliximab generated across all indications.

Piceatannol upregulates endothelial heme oxygenase-1 expression via novel protein kinase C and tyrosine kinase pathways.

Piceatannol is an anti-inflammatory and anti-proliferative plant-derived stilbene. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme to activate by various phytochemicals. In this study, we examined the ability of piceatannol to upregulate HO-1 expression in endothelial cells. We found piceatannol at micromolar (10-50 microM) concentrations dramatically increased HO-1 protein levels in a time-dependent manner. Piceatannol was similarly potent in the induction of HO-1 as hemin, arsenate, and 15d-PGJ2, and was more potent than some other phytochemicals including curcumin, EGCG, baicalein, and quercetin. In contrast, the similar chemical structure compounds, trans-stilbene, stilbene oxide, and resveratrol had no HO-1-inducing effects, suggesting a critical role for the hydroxyl groups in HO-1 induction. No cytotoxicity and superoxide production was observed after 10-50 microM piceatannol treatments. Piceatannol-mediated HO-1 induction was abrogated in the presence of N-acetylcysteine and glutathione, but not by other antioxidants. Induction of HO-1 by piceatannol was further enhanced by using buthionine sulfoximine. In addition, we determined that tyrosine kinase was involved in the induction of HO-1 by using tyrosine kinase inhibitors, herbimycin A, erbstatin, and genistein; in contrast, no significant changes in the pretreatment of PI3 kinase or MAP kinase inhibitors was determined. HO-1 induction was blocked by the protein kinase C inhibitors calphostin C, rottlerin, and long PMA pretreatment, whereas conventional PKC inhibitors, Go6976, and Ca2+ chelator BAPTA/AM, had no effect. Elevated HO-1 protein levels were associated with the inhibition of tumor necrosis factor-alpha (TNFalpha)-induced intercellular adhesion molecule-1 (ICAM-1) expression. Treating ECs with zinc protoporphyrin, an HO-1 inhibito blocked the anti-inflammatory effect of piceatannol. In summary, this study identified piceatannol as a novel phytochemical inducer of HO-1 expression and identified the mechanisms involved in this process.