Long-term efficacy and safety of ixekizumab in Japanese patients with erythrodermic or generalized pustular psoriasis: subgroup analyses of an open-label, phase 3 study (UNCOVER-J).

BACKGROUND: Erythrodermic and generalized pustular psoriasis are rare, difficult to treat forms of psoriasis. In previous reports, we documented 24- and 52-week findings of an open-label, phase 3 trial (UNCOVER-J) of ixekizumab in Japanese patients with erythrodermic or generalized pustular psoriasis; most patients responded to treatment and maintained response through 52 weeks. OBJECTIVE: To assess the long-term (>3 years) efficacy and safety of ixekizumab in Japanese patients with erythrodermic or generalized pustular psoriasis. METHODS: These subgroup analyses were of a partial population of patients from UNCOVER-J (NCT01624233; Sponsored by Eli Lilly and Company), specifically those with erythrodermic psoriasis (N = 8) or generalized pustular psoriasis (N = 5). These patients received 160 mg ixekizumab at Week 0, ixekizumab 80 mg every 2 weeks through Week 12, and ixekizumab 80 mg every 4 weeks thereafter up to Week 244. This regimen is consistent with the regimen approved in Japan for plaque, erythrodermic, and generalized pustular psoriasis and psoriatic arthritis. Efficacy assessments included Global Improvement Score (GIS), Psoriasis Area and Severity Index (PASI), dermal symptoms (for patients with generalized pustular psoriasis), Dermatology Life Quality Index (DLQI) and Itch Numeric Rating Scale (NRS). Safety assessments included treatment-emergent adverse events and adverse events of special interest. RESULTS: Most patients had a GIS of resolved or improved from Week 12 onwards, and all patients had early and sustained improvement in PASI and dermal symptom (generalized pustular psoriasis only) scores. Mean improvements in DLQI and Itch NRS at Week 12 were sustained through Week 244. Ixekizumab was well tolerated over 3 years of treatment in patients with erythrodermic psoriasis or generalized pustular psoriasis, and no new safety concerns were identified. CONCLUSION: These findings suggest that ixekizumab can be an effective long-term treatment option for erythrodermic or generalized pustular psoriasis.

Long-term efficacy and safety results from an open-label phase III study (UNCOVER-J) in Japanese plaque psoriasis patients: impact of treatment withdrawal and retreatment of ixekizumab.

BACKGROUND: Long-term management of moderate-to-severe psoriasis is usually discussed in terms of continuous administration; however, there are many situations in clinical practice where treatment may be withdrawn with subsequent retreatment. OBJECTIVE: To assess the clinical course after ixekizumab treatment withdrawal and retreatment, as well as the effectiveness of ixekizumab retreatment, in Japanese patients with plaque psoriasis. METHODS: This single-arm, open-label study (UNCOVER-J; NCT01624233) comprised 78 patients with plaque psoriasis. After ixekizumab treatment (160-mg loading dose, 80 mg every 2 weeks for the first 12 weeks, and then 80 mg every 4 weeks (IXE Q4W) until Week 52), 70 patients achieved a Psoriasis Area Severity Index (PASI)75 response at Week 52. These 70 patients withdrew from ixekizumab treatment from Weeks 52 to 100. Patients who relapsed (PASI ≤50) during the Treatment Withdrawal Period were retreated with IXE Q4W for 192 weeks. RESULTS: At Weeks 52, 76 and 100, PASI75 response rates were 100%, 26% and 7%; PASI90 response rates were 87%, 11% and 3%; and PASI100 response rates were 53%, 0% and 0%. After treatment withdrawal, 87% of patients relapsed; median time to relapse was 143 days. After 12 weeks of retreatment with IXE Q4W, 83% of relapsed patients achieved PASI75, 68% achieved PASI90 and 25% achieved PASI100; improvements were maintained up to 120 weeks of retreatment. Treatment-emergent adverse events and serious adverse events were reported in 56% and 4% of patients during the Treatment Withdrawal Period, and in 88% and 14% of patients during the Retreatment Period. CONCLUSION: In patients withdrawn from ixekizumab after achieving PASI75, approximately half relapsed within 5 months of withdrawal; however, most patients recaptured response within 12 weeks, and response was maintained for up to 120 weeks of retreatment.

Analysis of treatment goal alignment between Japanese psoriasis patients and their paired treating physicians.

BACKGROUND: Appropriate goal-oriented treatment strategies are important for optimal treatment outcomes and may prevent under-treatment. As treatment goals vary by patient, a study to examine treatment goals is more meaningful when patients and their physicians are paired. There has not been any study that examines alignment between paired psoriasis patients and physicians in real-world clinical practice using skin clearance as a treatment goal indicator. OBJECTIVES: To evaluate treatment goal alignment between psoriasis patients and their paired physicians, and to quantitatively identify factors associated with goal misalignment. METHODS: The study was a nationwide multicenter cross-sectional observational study. Subjects were physician-reported moderate-to-severe psoriasis patients with a history of systemic treatments, directly paired with their treating physicians. Subjects completed surveys independently. Treatment goals included seven categories, and patient-physician pairs were grouped as 'aligned' or 'misaligned' when the answers were the same or different, respectively. RESULTS: A total of 425 pairs (mean response rate, 94.7%) of responses were collected from 54 sites (64.8% general practitioners or clinics; 35.2% university or large hospitals). Treatment goal misalignment was found in 67.9% of the patient-physician pairs. The misalignment was mainly 'patient predominant' (60.9%) indicating that patients had higher goals ('complete clearance') than physicians. In the multivariate logistic regression analyses, patients' treatment expectation for 'complete clearance' [odds ratio (OR): 1.927; 95% confidential interval (CI): 1.232-3.016] and physician rating of 'level of understanding on treatment options' being low (OR: 1.552, 95% CI; 1.082-2.227) were significant factors for treatment goal misalignment. CONCLUSIONS: The majority of treatment goal misalignment was found between paired psoriasis patients and their treating physicians in Japan. The most important contributing factors to misalignment were patients' treatment expectation for 'complete clearance' and physicians' rating of their patients' 'level of understanding on treatment options' being low.

Orbital Fat Volumetry and Water Fraction Measurements Using T2-Weighted FSE-IDEAL Imaging in Patients with Thyroid-Associated Orbitopathy.

BACKGROUND AND PURPOSE: The quantitative evaluation of orbital fat proliferation and edema and the assessment of extraocular muscles are useful for diagnosing and monitoring thyroid-associated orbitopathy. To evaluate therapy-induced quantitative changes in the orbital fat of patients with thyroid-associated orbitopathy, we performed volumetric and water fraction measurements by using T2-weighted FSE iterative decomposition of water and fat with echo asymmetry and least-squares estimation (FSE-IDEAL) imaging. MATERIALS AND METHODS: Orbital FSE-IDEAL images of 30 volunteers were acquired twice within 1 week. Nine patients with thyroid-associated orbitopathy underwent FSE-IDEAL imaging before and after methylprednisolone pulse therapy, and the treatment results were assessed by using their pre- and post-methylprednisolone pulse therapy clinical activity scores. We performed volumetric and water fraction measurements of orbital fat by using FSE-IDEAL imaging and evaluated interscan differences in the volunteers. In patients with thyroid-associated orbitopathy, we compared pre- and posttherapy orbital fat measurements and assessed the correlation between the pretherapy values and clinical activity score improvement. RESULTS: The reproducibility of results obtained by the quantitative evaluation of orbital fat in volunteers was acceptable. After methylprednisolone pulse therapy, the water fraction in the orbital fat of patients with thyroid-associated orbitopathy was significantly decreased (P < .001). There was a significant positive correlation between the pretherapy water fraction and clinical activity score improvement (right, r = 0.82; left, r = 0.79) and a significant negative correlation between the pretherapy volume and clinical activity score improvement (bilateral, r = -0.84). CONCLUSIONS: Volumetric and water fraction measurements of orbital fat by using FSE-IDEAL imaging are feasible and useful for monitoring the effects of therapy and for predicting the response of patients with thyroid-associated orbitopathy to methylprednisolone pulse therapy.

Pathological response after chemoradiation for T3 rectal cancer.

OBJECTIVE: The aim of this study was to investigate the effect of preoperative chemoradiotherapy (CRT) on nodal disease in locally advanced rectal adenocarcinoma. METHOD: Thirty-two patients staged uT3N0 and 27 patients staged uT3N1 rectal adenocarcinoma who underwent pre-CRT staging using endoscopic ultrasound or rectal protocol CT were included. The median radiation dose was 50.4 Gy (range: 45-50.4 Gy) at 1.8 Gy per fraction and all patients received concurrent 5-FU or capecitabine-based chemotherapy. Low anterior resection or abdomino-perineal resection occurred at a median of 46 days (range: 27-112 days) after CRT. RESULTS: Eleven of 32 uT3N0 patients (34.4%) and 13 of 26 uT3N1 patients (50.0%) had ypN+ (P = 0.29). For patients with uT3N0, 10 of 20 (50.0%) with ypT2-3 and 1 of 12 (8.3%) with ypT0-1 were ypN+ (P = 0.02). For patients with uT3N1, 12 of 20 (60.0%) with ypT2-3 and 1 of 6 (16.7%) with ypT0-1 were ypN+ (P = 0.16). Overall, the ypN+ rate was 11.1% in the ypT0-yT1 group compared with 55.0% in the ypT2-yT3 group (P = 003). Among patients with uT3N0 disease, the ypN+ rate in patients who had surgery > 46 days vs 46 days vs 46 days vs

Lipoprotein analysis using agarose gel electrophoresis and differential staining of lipids.

We established a strategy to directly measure cholesterol and triglyceride levels of each lipoprotein fraction using a combination of agarose gel electrophoresis and differential staining. The cholesterol and triglyceride levels determined by electrophoresis correlated significantly with those of ultracentrifugation. The correlation coefficients between these methods were, for cholesterol levels 0.975(very low density lipoproteins, VLDL), 0.986(low density lipoproteins, LDL) and 0.965(high density lipoproteins, HDL) and for triglyceride levels 0.994(VLDL), 0.963(LDL) and 0.959(HDL) respectively. Both intra-and inter-assays showed low values of coefficients of variation (CV) (less than 3.57%). We observed a strong linearity between staining and triglyceride concentration. An increased VLDL-cholesterol was observed in type III subjects, a result which enabled distinction between type III and type IIb or type V lipoproteinemia. The method revealed lipoprotein patterns in some samples otherwise unexpected from their corresponding serum lipid parameters. Analyses of these electrophoretic patterns thus provide an effective technique to classify types of hyperlipidemia defined by the WHO. Furthermore, quantitative measurement of chylomicrons, usually difficult, proved to be achievable, providing an additional analysis of postprandial hyperlipidemia and the exact measurement of LDL-cholesterol after diet. Consequently, we recommend this simple and easy method for clinical evaluation of abnormalities in lipoprotein profiles.

Liver cancer in atomic-bomb survivors: histological characteristics and relationships to radiation and hepatitis B and C viruses.

Histological features of primary liver cancer among atomic-bomb survivors and their relationship to hepatitis B (HBV) and C viral (HCV) infections are of special interest because of the increased risk of liver cancer in persons exposed to ionizing radiation and the high and increasing liver cancer rates in Japan and elsewhere. We conducted a pathology review of liver cancers occurring from 1958 to 1987 among subjects in the 120,321 member cohort of 1945 Hiroshima and Nagasaki residents. A panel of pathologists classified tumor histological types and defined accompanying cirrhotic changes of the liver. Archival tissue samples were assessed for HBV using pathology stains and PCR. Reverse transcriptase (RT) PCR was used to determine HCV status. We used unconditional logistic regression to compare 302 hepatocellular carcinoma (HCC) cases to 53 cholangiocarcinoma (CC) cases, adjusting for age, year of diagnosis, sex and viral status. Cirrhotic changes occurred significantly more often among HCC than CC cases (76% in HCC and 6% in CC). Compared to CC cases, HCC cases were 10.9 times more likely to be HBV-positive (95% confidence interval: 2.1-83.2) and 4.3 times more likely to be HCV-positive (95% confidence interval: 1.1-20.5). No significant differences were found between HCC and CC cases in radiation exposures. The predominance of HCC in the atomic-bomb survivors follows the background liver cancer pattern in Japan. Our findings suggest that HBV and HCV are involved in the pathogenesis of HCC with or without cirrhosis and are significantly less important in that of CC.

Suppressive mechanisms of EPA on human T cell proliferation.

In vivo and in vitro experiments show that polyunsaturated fatty acids (PUFAs) including eicosapentaenoic acid (EPA) inhibit mitogen- or antigen-stimulated proliferation of T cells in rodents and humans. However, the exact manner and mechanisms by which PUFA inhibits T cell proliferation is not clear. In the present study, we investigated the suppressive effects of EPA, an n-3 PUFA, on PHA stimulated human peripheral blood T cells. Our results showed that EPA suppresses mitogen- or antigen-stimulated human T cell proliferation by at least 2 steps; step 1) EPA suppresses T cell proliferation by inhibiting IL-2R alpha expression and IL-2 production; step 2) EPA induces cell death of blast T cells without reducing the expression of IL-2R alpha. We also showed that EPA selectively stimulates the cell death of blast T cells but not resting T cells. The suppressive effect of EPA was mediated via the production of reactive oxygen products, because EPA-stimulated H2O2 production and the suppressive effect of EPA was restored by addition of catalase or NAC. These results taken together suggest that such immunosuppressive effects of EPA may explain the apparent benefits of EPA-enriched diets for patients with inflammatory disorders.

Generation and characterization of a fairly stable triplet carbene.

Most molecules are held together by covalent bonds-electron pairs jointly shared by the two atoms that are linked by the bond. Free radicals, in contrast, have at least one unpaired electron. In the case of carbon-based radicals, the carbon atom at the radical centre no longer makes four bonds with other atoms as it would do in its normal, tetravalent state. The presence of unpaired electrons renders such radicals highly reactive, so they normally occur only as transient intermediates during chemical reactions. But the discovery by Gomberg in 1900 of triphenylmethyl, the first relatively stable free radical containing a central trivalent carbon atom, illustrated that radicals with suitable geometrical and electronic structures can be stable. Compounds containing a divalent carbon atom that uses only two of its four valence electrons for bonding are usually less stable than Gomberg-type radicals with trivalent carbon. Although the role of these so-called carbenes in chemical reactions has long been postulated, they were unambiguously identified only in the 1950s. More recently, stable carbenes have been prepared, but the singlet state of these molecules, with the two nonbonding valence electrons paired, means that they are not radicals. Carbenes in the second possible electronic state, the triplet state, are radicals: the two nonbonding electrons have parallel spins and occupy different orbitals. Here we report the preparation and characterization of a triplet carbene, whose half-life of 19 minutes at room temperature shows it to be significantly more stable than previously observed triplet carbenes.

Temporal changes in liver cancer incidence rates in Japan: accounting for death certificate inaccuracies and improving diagnostic techniques.

Primary liver cancer (PLC) rates have risen dramatically during the past few decades in some regions, particularly in Japan, where PLC is now the third major cause of cancer death. PLC is one of the most difficult tumors to diagnose correctly, because (i) the liver is a frequent site of cancer metastasis and (ii) death from PLC is often attributed to cirrhosis or chronic hepatitis. Also, because the disease is often rapidly fatal, a large proportion of liver cancer cases are identified based on death certificates alone without confirmation by clinical records. Thus, worldwide differences in published incidence rates for this disease reflect regional or national differences in both the accuracy of death certificates and the sensitivity of diagnostic methods. By comparing death certificate causes of death with those based on pathology review, we were able to adjust 1958--1994 incidence rates for a large Japanese cohort for these errors. Although the death certificate false-positive error rate declined, the false-negative error rate remained high throughout the study. The introduction of improved liver cancer diagnostic methods in Japan in the early 1980s was associated with a sharp increase in PLC incidence. We conclude that errors in death certificate causes of death and changes in liver cancer diagnostic techniques have had an important impact on the reported incidence of this disease. Taking these factors into account, rates of hepatocellular carcinoma rose between 2.4- and 4.3-fold in our Japanese cohort from 1960 to 1985, peaked about 1993 and declined thereafter. Incidence rates of cholangiocarcinoma remained stable through 1987.

[Effects of aging on oxidisability of low density lipoprotein].

Oxidised LDL is taken up by macrophages via scavenger receptors, leading to foam cell formation and is thus considered to contribute to atherogenesis. Aging results in the increase of lipids and the decrease of antioxidant enzyme activity in serum. In this study, we investigated the effects of aging on LDL oxidisability. We measured LDL oxidation lag time, plasma lipids, albumin and uric acid were examined in 306 Japanese (169 men, 137 women). The mean +/- SE of LDL oxidation-lag time in subjects was 58.9 +/- 1.0 min. The lag time (80.3 +/- 4.8 min) was longest in subjects in their 20 s and shortest in those in their 40 s (58.9 +/- 1.0 min). The longest lag time was in second-decade men (88.9 +/- 6.2 min) and shortest in fourth-decade women (50.7 +/- 2.2 min), and these results were similar even excluding subjects with abnormal biochemical data (total cholesterol, triglyceride, GOT, GPT, gamma GTP, creatinine and glucose). We analyzed the effects of various factors on lag time using multiple linear regression. Aging, uric acid and LDL-cholesterol significantly influenced lag time. Our results suggest that LDL oxidisability might been regulated by aging, changes in LDL-cholesterol with aging and variations in physical antioxidant function.

Solubilization of phytosterols in diacylglycerol versus triacylglycerol improves the serum cholesterol-lowering effect.

OBJECTIVE: This study was performed to investigate the difference in the serum-cholesterol- and triglyceride-lowering activities between phytosterols dissolved in diacylglycerol (PS/DG) and dispersed in triacylglycerol (PS/TG). The effects of the solvent on the concentrations of serum beta-sitosterol and campesterol were examined. DESIGN: The study had a randomised crossover design. SUBJECTS: Twelve healthy normocholesterolemic or moderately hypercholesterolemic men aged 29-50 y participated in this study. INTERVENTIONS: For 2 weeks before the test period (designated as the control period), all subjects consumed control mayonnaise (PS free) daily with supper and were randomly assigned to two groups for the 2 week test period; one group was given mayonnaise containing PS (500 mg/day) dissolved in DG (10 g/day), and the other mayonnaise containing PS (500 mg/day) dispersed in TG (10 g/day). After a wash out period consuming control PS-free mayonnaise for 4 weeks, the groups were reversed for 2 weeks. RESULTS: PS/TG feeding had no effect on the serum cholesterol level. In contrast, PS/DG feeding significantly reduced the total and LDL cholesterol levels from the initial value of 5.57 to 5.31 mmol/l (4.7%; P<0.05) and from 3.69 to 3.39 mmol/l (7.6%; P<0.05), respectively. Moreover, the degree of total cholesterol reduction induced by PS/DG feeding in the test period was significantly greater than that induced by PS/TG feeding (P<0.05). In addition, the serum beta-sitosterol and campesterol concentrations did not change during the PS/TG or PS/DG feeding periods. CONCLUSIONS: Dissolution of PS in DG had a better serum cholesterol lowering effect than dissolution in TG. SPONSORSHIP: Kao Corporation.

Energy value and digestibility of dietary oil containing mainly 1,3-diacylglycerol are similar to those of triacylglycerol.

Diacylglycerol (DAG) is a component of various vegetable oils. Approximately 70% of the DAG in edible oils are in the configuration of 1,3-DAG. We recently showed that long-term ingestion of dietary oil containing mainly 1,3-DAG reduces body fat accumulation in humans as compared to triacylglycerol (TAG) oil with a similar fatty acid composition. As the first step to elucidate the mechanism for this result, we examined the difference in the bioavailabilities of both oils by measuring food energy values and digestibilities in rats. Energy values of the DAG oil and the TAG oil, measured by bomb calorimeter, were 38.9 and 39.6 kJ/g, respectively. Apparent digestibility expressed according to the formula: (absorbed) x (ingested)(-1) x 100 = (ingested - excreted in feces) x (ingested)(-1) x 100 for the DAG oil and the TAG oil were 96.3+/-0.4 and 96.3+/-0.3% (mean +/- SEM), respectively. The similarity in the bioavailabilities of both oils supports the hypothesis that the reduced fat accumulation by dietary DAG is caused by the different metabolic fates after the absorption into the gastrointestinal epithelial cells.

Regulation by long-chain fatty acids of the expression of cholesteryl ester transfer protein in HepG2 cells.

Cholesteryl ester transfer protein (CETP) is an important determinant of lipoprotein function, especially high density lipoprotein (HDL) metabolism, and contributes to the regulation of plasma HDL levels. Since saturated and polyunsaturated fatty acids (FA) appear to influence the CETP activity differently, we decided to investigate the effects of FA on the expression of CETP mRNA in HepG2 cells using an RNA blot hybridization analysis. Long-chain FA (>18 carbons) at a 0.5 mM concentration were added to the medium and incubated with cells for 48 h at 37 degrees C under 5% CO2. After treatment with 0.5 mM arachidonic (AA), eicosapentaenoic (EPA), and docosahexaenoic acid (DHA), the levels of CETP mRNA were less than 50% of the control levels (AA, P = 0.0005; EPA, P < 0.01; DHA, P < 0.0001), with a corresponding significant decrease in the CETP mass. These results suggest that FA regulate the gene expression of CETP in HepG2 and this effect is dependent upon the degree of unsaturation of the acyl carbon chain in FA.

Protective effects of Saiko-ka-ryukotsu-borei-to (Chai-Hu-Jia-Long-Gu-Mu-Li-Tang) against atherosclerosis in Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits.

We investigated the protective effects of the traditional Japanese herbal medicine Saiko-ka-ryukotsu-borei-to (Chai-Hu-Jia-Long-Gu-Mu-Li-Tang in Chinese) (SRBT) against hypercholesterolemia and atherosclerotic lesions. We focused on atherosclerosis using female heterozygous Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. The total plasma cholesterol levels increased for up to 12 weeks after beginning a diet containing 0.1% cholesterol and then reached a plateau of about 600 mg dl(-1). When SRBT was administered at a dose of 1.0 g kg(-1)per day for 24 weeks, total plasma cholesterol levels were significantly decreased after 20-24 weeks. On the other hand, pravastatin at a dose of 10 mg kg(-1)per day produced a significant decrease in total plasma cholesterol levels from 4 to 24 weeks (about 105-130 mg dl(-1)). Moreover, 1.0 g kg(-1)per day of SRBT significantly decreased plasma low density lipoprotein (LDL) cholesterol levels but did not change either very low density lipoprotein (VLDL), or high density lipoprotein (HDL) cholesterol levels. Animals that received pravastatin had significantly decreased LDL cholesterol levels and VLDL cholesterol levels after 8 weeks and at 24 weeks. We also examined the expression of apoB, E and LDL receptor mRNA levels in the liver at 24 weeks after beginning the administration of 1.0 g kg(-1)per day of SRBT. Both apoE and LDL receptor mRNA levels were significantly increased compared with those in rabbits receiving the 0.1% cholesterol diet. SRBT at a dose of 1.0 g kg(-1)per day significantly depressed the intimal surface area of the thoracic aortae involved with atheromatous plaques. The present results suggest that SRBT may protect against hypercholesterolemia and atheromatous lesions by affecting apoE and LDL receptor mRNA gene expression in the liver.