Guselkumab versus secukinumab for the treatment of moderate-to-severe psoriasis (ECLIPSE): results from a phase 3, randomised controlled trial.

BACKGROUND: Antibodies targeting interleukin (IL)-23 and IL-17A effectively treat moderate-to-severe psoriasis. ECLIPSE is the first comparator study of an IL-23p19 inhibitor, guselkumab, versus an IL-17A inhibitor, secukinumab. The primary objective of this study was to show superiority of clinical response at week 48 for guselkumab versus secukinumab. METHODS: In this phase 3, multicentre, double-blind, randomised, comparator-controlled trial at 142 outpatient clinical sites in nine countries (Australia, Canada, Czech Republic, France, Germany, Hungary, Poland, Spain, and the USA), eligible patients were aged 18 years or older, had moderate-to-severe plaque-type psoriasis, and were candidates for phototherapy or systemic therapy. Eligible patients were randomly assigned with permuted block randomisation using an interactive web response system to receive either guselkumab (100 mg at weeks 0 and 4 then every 8 weeks) or secukinumab (300 mg at weeks 0, 1, 2, 3, and 4, and then every 4 weeks). The primary endpoint, the proportion of patients in the intention-to-treat population who achieved 90% reduction or more from baseline of Psoriasis Area and Severity Index (PASI 90 response) at week 48, and major secondary endpoints (the proportions of patients in the guselkumab group and in the secukinumab group who achieved a PASI 75 response at both weeks 12 and 48, a PASI 90 response at week 12, a PASI 75 response at week 12, a PASI 100 response at week 48, an Investigator's Global Assessment [IGA] score of 0 [cleared] at week 48, and an IGA score of 0 or 1 [minimal] at week 48) were to be tested in a fixed sequence to control type I error rate. Safety was evaluated in patients who received one or more doses of study drug from week 0 to 56. The study is registered with ClinicalTrials.gov, NCT03090100. FINDINGS: This study was done between April 27, 2017, and Sept 20, 2018. 1048 eligible patients were enrolled and, of these, 534 were assigned to receive guselkumab and 514 to receive secukinumab. The proportion of patients with a PASI 90 response at week 48 was greater in the guselkumab group (451 [84%]) than in the secukinumab group (360 [70%]; p<0·0001). Although non-inferiority (margin of 10 percentage points) was established for the first major secondary endpoint (452 [85%] of patients in the guselkumab group vs 412 [80%] of patients in the secukinumab group achieving a PASI 75 response at both weeks 12 and 48), superiority was not established (p=0·0616). Consequently, formal statistical testing was not done for subsequent major secondary endpoints. Proportions of patients with adverse events, infections, and serious adverse events were similar between the two treatments and, in general, safety findings were consistent with registrational trial observations. INTERPRETATION: Guselkumab showed superior long-term efficacy based on PASI 90 at week 48 when compared with secukinumab for treating moderate-to-severe psoriasis. This finding could assist health-care providers in their decision making process when selecting a biologic for treating moderate-to-severe psoriasis. FUNDING: This study was funded by Janssen Research & Development.

Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: results of the randomized phase 3 CADMUS study.

BACKGROUND: Safe and effective therapies are needed for pediatric patients with psoriasis. OBJECTIVE: The purpose of this study was to evaluate ustekinumab in patients age 12 to 17 years who had moderate-to-severe psoriasis. METHODS: Patients (n = 110) were randomly assigned to ustekinumab standard dosing (SD; 0.75 mg/kg [≤60 kg], 45 mg [>60-≤100 kg], and 90 mg [>100 kg]) or half-standard dosing (HSD; 0.375 mg/kg [≤60 kg], 22.5 mg [>60-≤100 kg], and 45 mg [>100 kg]) at weeks 0 and 4 and every 12 weeks or placebo at weeks 0 and 4 with crossover to ustekinumab SD or HSD at week 12. Clinical assessments included the proportion of patients achieving a Physician's Global Assessment of cleared/minimal (PGA 0/1), at least 75% improvement in Psoriasis Area and Severity Index (PASI 75), and at least 90% in PASI (PASI 90). Adverse events (AEs) were monitored through week 60. RESULTS: At week 12, 67.6% and 69.4% of patients receiving ustekinumab HSD and SD, respectively, achieved PGA 0/1 versus 5.4% for placebo (P < .001). Significantly greater proportions receiving ustekinumab achieved PASI 75 (HSD, 78.4%; SD, 80.6%; placebo, 10.8%) or PASI 90 (HSD, 54.1%; SD, 61.1%; placebo, 5.4%) at week 12 (P < .001). Through week 12, 56.8% of placebo patients, 51.4% of HSD patients, and 44.4% of SD patients reported at least one AE; through week 60, 81.8% reported AEs. LIMITATIONS: The study was small relative to adult trials. CONCLUSIONS: In this patient population (12-17 years), the standard ustekinumab dose provided response comparable to that in adults with no unexpected AEs through 1 year.

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.

Immune response to pneumococcus and tetanus toxoid in patients with moderate-to-severe psoriasis following long-term ustekinumab use.

BACKGROUND: Little is known about the impact of long-term use of immunosuppressive agents on immune response. OBJECTIVES: Assess the impact of continuous maintenance ustekinumab treatment on patients' ability to mount immune responses to pneumococcal (T-cell-independent) and tetanus toxoid (T-cell-dependent) vaccines. PATIENTS AND METHODS: Ustekinumab-treated patients with moderate-to-severe psoriasis treated in the long-term extension of the Phase 3 PHOENIX 2 trial (n=60) were compared with control psoriasis patients not receiving systemic therapy (n=56). Patients were vaccinated with both 23-valent pneumococcal and tetanus toxoid vaccines. Serum samples collected pre-vaccination and 4 weeks post-vaccination were assessed for antibody responses. RESULTS: No differences in the ability of ustekinumab-treated patients to respond to pneumococcal or tetanus toxoid vaccinations were observed compared with controls. A ≥2-fold increase in antibody levels in ≥7 of 14 serotypes of the pneumococcal vaccine was observed in ustekinumab-treated (96.6%) and untreated control (92.6%) patients following vaccination. Ustekinumab-treated patients achieved a ≥4-fold increase (84.7%) in anti-tetanus antibody vs. 77.8% in the control group. No differences were detected in ex-vivo responses to anti-CD3/CD28 or tetanus toxoid between ustekinumab-treated and control groups. CONCLUSION: Long-term treatment (≥3 years) with ustekinumab does not compromise the immune response to T-cell-dependent/-independent vaccines in patients with moderate-to-severe psoriasis.

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.

Underdiagnosis and undertreatment of cardiovascular risk factors in patients with moderate to severe psoriasis.

BACKGROUND: Patients with psoriasis are known to have an increased number of cardiovascular (CV) risk factors and be at increased risk for CV events. OBJECTIVES: We sought to describe and characterize the underdiagnosis and undertreatment of CV risk factors in patients with moderate to severe psoriasis. METHODS: Medical histories including diabetes, hypertension, and hyperlipidemia were obtained from 2899 patients in 3 phase III ustekinumab trials, a therapeutic anti-interleukin (IL)-12/IL-23p40 monoclonal antibody. Reported history was compared with measured fasting glucose, fasting lipids, and blood pressure. Ten-year Framingham risk scores and the proportion of patients achieving glycemic, lipid, and blood pressure targets were evaluated. RESULTS: Significant risk factors existed in patients with moderate to severe psoriasis (58.6% and 28.8% of patients had ≥ 2 and ≥ 3 established CV risk factors, respectively). Based on Framingham risk score, 18.6% of patients were at high risk and 12.3% were at intermediate risk for CV events. At baseline, a small proportion of patients with diabetes (2.3%), hypertension (9.1%), or hyperlipidemia (4.9%) were previously without a diagnosis. However, 19.1%, 21.8%, and 38.6% of patients with diabetes, hypertension, or hyperlipidemia, respectively, were untreated at baseline, and the proportion at treatment goal was not ideal (hypertension 59.6% and hyperlipidemia 69.7%), especially for diabetes (36.7%). LIMITATIONS: Results are based on a clinical trial population and findings may not be generalizable to the general psoriasis population. CONCLUSIONS: In this moderate to severe psoriasis population, a high prevalence of undiagnosed and undertreated CV risk factors existed, emphasizing the importance of screening patients with psoriasis for CV risk factors.

Evidence for inhibitory effects of flupirtine, a centrally acting analgesic, on delayed rectifier k(+) currents in motor neuron-like cells.

Flupirtine (Flu), a triaminopyridine derivative, is a centrally acting, non-opiate analgesic agent. In this study, effects of Flu on K(+) currents were explored in two types of motor neuron-like cells. Cell exposure to Flu decreased the amplitude of delayed rectifier K(+) current (I(K(DR))) with a concomitant raise in current inactivation in NSC-34 neuronal cells. The dissociation constant for Flu-mediated increase of I(K(DR)) inactivation rate was about 9.8 µM. Neither linopirdine (10 µM), NMDA (30 µM), nor gabazine (10 µM) reversed Flu-induced changes in I(K(DR)) inactivation. Addition of Flu shifted the inactivation curve of I(K(DR)) to a hyperpolarized potential. Cumulative inactivation for I(K(DR)) was elevated in the presence of this compound. Flu increased the amplitude of M-type K(+) current (I(K(M))) and produced a leftward shift in the activation curve of I(K(M)). In another neuronal cells (NG108-15), Flu reduced I(K(DR)) amplitude and enhanced the inactivation rate of I(K(DR)). The results suggest that Flu acts as an open-channel blocker of delayed-rectifier K(+) channels in motor neurons. Flu-induced block of I(K(DR)) is unlinked to binding to NMDA or GABA receptors and the effects of this agent on K(+) channels are not limited to its action on M-type K(+) channels.

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.

Efficacy of guselkumab versus secukinumab in subpopulations of patients with moderate-to-severe plaque psoriasis: results from the ECLIPSE study.

PURPOSE: Guselkumab, an interleukin (IL)-23 inhibitor, effectively treats moderate-to-severe plaque psoriasis. MATERIALS AND METHODS: ECLIPSE, was a Phase 3, multicenter, 56-week, double-blinded, active-comparator study of guselkumab vs. secukinumab (IL-17A inhibitor) in patients with moderate-to-severe psoriasis. Patients were treated with guselkumab 100 mg (n = 534) or secukinumab 300 mg (n = 514) through week 44. Efficacy (at least a 90% and 100% improvement from baseline in Psoriasis Area and Severity Index [PASI 90 and PASI 100], Investigator's Global Assessment [IGA] 0/1, and IGA 0) was analyzed across subpopulations defined by baseline: age (<45, 45 to <65, and ≥65 years old), body weight, body mass index (BMI), psoriasis disease severity (body surface area, disease duration, PASI, and IGA), psoriasis by body regions (head, trunk, upper and lower extremities), and prior psoriasis medication history at week 48. RESULTS: Overall, 1048 patients were randomized. At week 48, numerically greater proportions of patients achieved PASI 90, PASI 100, IGA 0/1, and IGA 0 with guselkumab vs. secukinumab regardless of baseline age, body weight, BMI, disease severity, body region, and prior medication. The largest differences were in patients ≥65 years old and patients weighing >100 kg. CONCLUSIONS: Guselkumab treatment provided greater efficacy vs. secukinumab at week 48 in most subpopulations of patients with psoriasis.

Ustekinumab significantly improves symptoms of anxiety, depression, and skin-related quality of life in patients with moderate-to-severe psoriasis: Results from a randomized, double-blind, placebo-controlled phase III trial.

BACKGROUND: Anxiety, depression, and impaired health-related quality of life (HRQoL) are common in patients with psoriasis. OBJECTIVE: We sought to analyze the effect of ustekinumab on these conditions in patients with moderate-to-severe psoriasis. METHODS: Patients with moderate-to-severe psoriasis (n = 1230) were randomized 1:1:1 to receive 45 mg of ustekinumab, 90 mg of ustekinumab, or placebo. The Hospital Anxiety and Depression Scale was used to measure anxiety and depression, and the Dermatology Life Quality Index to measure HRQoL. RESULTS: At baseline, 40.3% and 26.7% of patients reported symptoms of anxiety and depression, respectively, and 54.6% reported Dermatology Life Quality Index scores greater than 10, indicating a very high impact of disease on HRQoL. Greater improvements at week 12 in mean Hospital Anxiety and Depression Scale-Anxiety (13.9%), Hospital Anxiety and Depression Scale-Depression (29.3%), and Dermatology Life Quality Index (76.2%) scores were reported in ustekinumab groups compared with placebo (P < .001 each). LIMITATIONS: Results for these measures are reported only through 24 weeks. CONCLUSION: Patients receiving ustekinumab reported significant improvements in symptoms of anxiety, depression, and HRQoL.

Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).

BACKGROUND: Ustekinumab, a human monoclonal antibody against interleukins 12 and 23, has shown therapeutic potential for psoriasis. This study assessed the efficacy and safety of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders. METHODS: In this multicentre, phase III, double-blind, placebo-controlled study, 1230 patients with moderate-to-severe psoriasis (defined by a psoriasis area and severity index [PASI] score > or =12, and at least 10% total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n=409) or 90 mg (n=411) at weeks 0 and 4, then every 12 weeks, or placebo (n=410). Partial responders (ie, patients achieving > or =50% but <75% improvement from baseline in PASI) were re-randomised at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks. Both randomisations were done with a minimisation method via a centralised interactive voice response. The primary endpoint was the proportion of patients achieving at least 75% improvement in PASI (PASI 75) at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00307437. FINDINGS: All randomised patients were included in the efficacy analysis. 273 (66.7%) patients receiving ustekinumab 45 mg, 311 (75.7%) receiving ustekinumab 90 mg, and 15 (3.7%) receiving placebo achieved the primary endpoint (difference in response rate 63.1%, 95% CI 58.2-68.0, p<0.0001 for the 45 mg group vs placebo and 72.0%, 67.5-76.5, p<0.0001 for the 90 mg group vs placebo). More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks (22 [68.8%] vs 11 [33.3%]; difference in response rate 35.4%, 95% CI 12.7-58.1, p=0.004). There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45 mg. During the placebo-controlled phase, 217 (53.1%) patients in the 45 mg group, 197 (47.9%) in the 90 mg group, and 204 (49.8%) in the placebo group experienced adverse events; serious adverse events were seen in eight (2.0%) patients in the 45 mg group, five (1.2%) in the 90 mg group, and eight (2.0%) in the placebo group. INTERPRETATION: Although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen.

Baseline nail disease in patients with moderate to severe psoriasis and response to treatment with infliximab during 1 year.

BACKGROUND: Although nail psoriasis occurs frequently in patients with psoriatic skin lesions, effective treatments are limited. OBJECTIVE: Occurrence of nail psoriasis by type and incidence of nail clearance using the Nail Psoriasis Severity Index were evaluated. METHODS: This was a 50-week, phase III study in which 378 patients with moderate to severe psoriasis were randomized 4:1 to infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and every 8 weeks through week 46, with placebo crossover to infliximab at week 24. RESULTS: Of the 373 evaluated patients, 305 (81.8%) had baseline nail psoriasis. The right thumbnail was most often the worst involved nail, and pitting and onycholysis were the most common lesions. Among patients with baseline nail psoriasis, 6.9%, 26.2%, and 44.7% in the infliximab group had nail disease clearance at weeks 10, 24, and 50, respectively, versus 5.1% in the placebo group at week 24 (P < .001). Mean percent improvements in Nail Psoriasis Severity Index score at weeks 10 and 24 were 26.8% and 57.2%, respectively, in the infliximab group versus -7.7% and -4.1%, respectively, in the placebo group (both P < .001). At week 24, mean percent improvements in nail matrix and nail bed features were 52.9% and 69.2%, respectively (vs -1.9% and 18.4% for placebo; P < .001). LIMITATIONS: The study did not evaluate nail response beyond 1 year. CONCLUSIONS: Patients with psoriasis receiving infliximab experienced marked and sustained nail improvement.

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.

Bidirectionality of the dentato-rubro-thalamo-cortical tract allows concurrent hypoperfusion in ipsilateral cerebellum and contralateral cerebral hemisphere: A case report.

RATIONALE: The brain circulation of the dentato-rubro-thalamo-cortical tract (DRTT) has been reported for decade, but is rarely observed using nuclear medicine imaging tools, to analyze a patient with midbrain hemiatrophy syndrome. We present a case that revealed notable interruption in the middle of the DRTT. Finding out whether the superior cerebellar peduncle of the midbrain was injured was a decisive element for developing bidirectional effect of DRTT. PATIENT CONCERNS: A 34-year-old right-handed female presented with progressive weakness and bradykinesia in the left-sided limbs for about 6 months. She had difficulty with hand dexterity for activities of daily life and general tasks. She reported poor balance during walking and sitting. Muscle strength was 3 in the left hand and 4 in the foot due to atrophy of left limbs. The circumference of 10 cm proximally/distally from the lateral epicondyle of the humerus was 25.7/23.8 cm at right and 24.2/20.8 cm at left in the upper limbs, and 15 cm proximally/distally from the lateral joint space was 42.1/35.0 cm at right and 43/30.8 cm at left in the lower limbs. The brain magnetic resonance imaging study revealed a small-sized right midbrain. DIAGNOSIS: Based on the distinct features of limbs atrophy and the locations of the lesions on the magnetic resonance (MR) imaging, the patient was diagnosed with midbrain hemiatrophy syndrome. INTERVENTIONS: The patient was only willing to accept physical and occupational training programs at our outpatient clinic. OUTCOMES: We utilized serial anatomic and functional neuroimaging of the brain to survey the neurologic deficit. Brain perfusion single-photon emission computed tomography (SPECT) showed hypoperfusion over the left fronto-parietal regions, left anterior temporal region, and left occipital region, and also the left striatum and right cerebellum. Symptoms were gradually recovered with rehabilitation, and he was transferred to a rehabilitation facility on hospital day 40. LESSONS: This is the first report to demonstrate concurrent hypoperfusion of ipsilateral cerebellum and contralateral cerebral hemisphere observed on SPECT images in a case of midbrain hemiatrophy syndrome. In our case, with midbrain hemiatrophy syndrome could be explained as mutual direction effect of DRTT.

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.

Newton Output Blocking Force under Low-Voltage Stimulation for Carbon Nanotube-Electroactive Polymer Composite Artificial Muscles.

This is a study on the development of carbon nanotube-based composite actuators using a new ionic liquid-doped electroactive ionic polymer. For scalable production purposes, a simple hot-pressing method was used. Carbon nanotube/ionic liquid-Nafion/carbon nanotube composite films were fabricated that exhibited a large output blocking force and a stable cycling life with low alternating voltage stimuli in air. Of particular interest and importance, a blocking force of 1.5 N was achieved at an applied voltage of 6 V. Operational durability was confirmed by testing in air for over 30 000 cycles (or 43 h). The superior actuation performance of the carbon nanotube/ionic liquid-Nafion/carbon nanotube composite, coupled with easy manufacturability, low driving voltage, and reliable operation, promises great potential for artificial muscle and biomimetic applications.

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.

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.