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BACKGROUND: Prurigo nodularis (PN), a chronic inflammatory skin condition, adversely affects the quality of life of affected individuals. Current treatment options for PN in Japan are limited. OBJECTIVES: To evaluate the optimal dose, efficacy and safety of long-term treatment with nemolizumab in patients with PN in Japan. METHODS: In a 16-week double-blind phase II/III study, patients aged ≥ 13 years with PN were randomly assigned (1 : 1 : 1) to nemolizumab 30-mg, 60-mg or placebo groups, with concomitant topical corticosteroids, every 4 weeks. The primary efficacy endpoint was the percentage change in the weekly mean Peak Pruritus Numerical Rating Scale (PP-NRS) score (range 0-10, with higher scores indicating worse itching) from baseline to week 16. Secondary efficacy endpoints assessed the impact of treatment on pruritus, PN severity, sleep and quality of life. RESULTS: At week 16, the least-squares mean percentage change from baseline in the PP-NRS score was -61.1% in the nemolizumab 30-mg group (n = 77), -56.0% in the 60-mg group (n = 76), and -18.6% in the placebo group (n = 76). Differences between both nemolizumab groups and placebo were significant; the difference between the 30-mg and placebo groups was -42.5% [95% confidence interval (CI) -51.9 to -33.1; P < 0.0001], and between the 60-mg and placebo groups was -37.4% (95% CI -46.7 to -28.1; P < 0.0001). Patients treated with nemolizumab also had greater improvements in the number and severity of prurigo nodules, and in sleep and quality of life compared with the placebo group. Both nemolizumab doses were well tolerated. CONCLUSIONS: Improvements in PN were greater following nemolizumab treatment, despite continuation of topical corticosteroids in both groups.

Prurigo nodularis (PN) is a skin condition in which firm, raised bumps are seen on the arms, legs and trunk. These bumps are extremely itchy and can cause interruptions to sleep, as well as anxiety and distress. There are few available treatments for PN in Japan; and better options are needed. Nemolizumab is a new treatment which has been shown to reduce itching associated with several skin conditions, including PN. In this study, we investigated whether nemolizumab could reduce itch and nodules and improve quality of life in patients aged 13 years or older in Japan who had already tried topical steroids or antihistamines to treat their PN. We treated 229 patients with PN by injecting either nemolizumab or placebo under the skin every 4 weeks. Seventy-seven patients received a first dose of nemolizumab 60 mg, followed by 30 mg every 4 weeks, and 76 patients received nemolizumab 60 mg at every injection. Another 76 patients received placebo at each injection. All patients were allowed to continue using their topical treatments during the study. We found that both doses of nemolizumab were better than placebo at reducing itch over 16 weeks. After nemolizumab treatment, patients also had less severe PN, better sleep and better quality of life. Both doses of nemolizumab were well tolerated by patients and there were no severe side-effects associated with nemolizumab treatment. Overall, nemolizumab could be a helpful new treatment option for people with PN who do not get enough itch relief with current medication.

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BACKGROUND: Atopic dermatitis (AD) is a chronic, inflammatory skin condition affecting up to one-quarter of children. Uncontrolled pruritus associated with childhood AD, and the accompanying scratching, negatively impacts quality of life (QoL), sleep and development. The humanized monoclonal antibody nemolizumab, used concomitantly with topical agents, was shown to reduce pruritus and improve QoL in patients with AD aged ≥ 13 years. However, data relating to its efficacy and safety in younger children (aged < 13 years) have been lacking. OBJECTIVES: To evaluate the efficacy and safety of nemolizumab, administered concomitantly with topical agents, in Japanese paediatric patients (aged 6-12 years) with AD and inadequately controlled moderate-to-severe pruritus. METHODS: This was a randomized, placebo-controlled, double-blind, parallel-group, multicentre, 16-week, phase III study. Patients aged ≥ 6 and < 13 years, with confirmed AD, and an inadequate pruritic response despite treatment with topical agents and oral antihistamines were randomly assigned (1 : 1) to receive nemolizumab 30 mg or placebo every 4 weeks (Q4W). The primary efficacy endpoint was the change in the weekly mean 5-level itch score from baseline to week 16; secondary efficacy endpoints were related to pruritus, indicators for AD and QoL. Safety was assessed via adverse events (AEs) and laboratory test results. RESULTS: In total, 89 patients were enrolled, received either nemolizumab 30 mg (n = 45) or placebo (n = 44) Q4W, and completed the study. The mean patient age was 9.1 (SD 1.9) years, and mean duration of AD was 8.5 (2.7) years. The change in 5-level itch score from baseline to week 16 showed a statistically significant difference in the nemolizumab treatment group (-1.3) compared with placebo (-0.5; least-squares mean difference -0.8, 95% confidence interval -1.1 to -0.5; P < 0.0001). Improvements with nemolizumab were observed from the second day of administration. Secondary endpoints were in favour of nemolizumab. No AEs resulted in discontinuation, and the overall safety profile in patients aged 6-12 years was comparable with that in older patients (aged ≥ 13 years) with AD. CONCLUSIONS: Nemolizumab is a potential new treatment option for paediatric patients with AD whose pruritus has not been sufficiently improved with topical treatments and antihistamines.

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INTRODUCTION: Atopic dermatitis (AD), with its signs and symptoms of pruritus, dryness, and erythema, severely reduces the quality of life (QOL) of affected patients. We investigated the impact of nemolizumab 60 mg on QOL in Japanese patients aged ≥ 13 years with AD and inadequately controlled moderate-to-severe pruritus, using data derived from patient-reported outcome (PRO) measures. METHODS: PROs were the Insomnia Severity Index (ISI), Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), and Work Productivity and Activity Impairment: Atopic Dermatitis questionnaire (WPAI-AD). Correlations between PRO scores and symptom severity, assessed by the pruritus visual analog scale (VAS) and the Eczema Area and Severity Index (EASI), were explored. RESULTS: The mean percent change (standard error) from baseline in the pruritus VAS and EASI scores at week 16 was, respectively, -45.6% (2.7) and -46.0% (3.2) in the nemolizumab group, and -24.1% (3.7) and -33.2% (4.9) in the placebo group. By week 16, significantly more patients in the nemolizumab group versus the placebo group had an ISI score of 0 for difficulty falling asleep (41.6% versus 13.1%, nominal p < 0.01) or difficulty staying asleep (45.4% versus 10.9%; nominal p < 0.01). Similarly, more nemolizumab- than placebo-treated patients had a DLQI score of 0 for interference with shopping, or home/garden activities (45.2% versus 18.6%, nominal p < 0.01), and 0 days per week of nighttime sleep disturbance (50.8% versus 16.9%, nominal p < 0.01) or bleeding skin (43.4% versus 7.5%, nominal p < 0.01) measured by POEM at week 16. Based on WPAI-AD scores, long-term administration of nemolizumab also improved the ability to conduct work activities. CONCLUSIONS: Subcutaneous administration of nemolizumab ameliorated pruritus and skin signs, and thereby produced improvement in patient QOL across multiple PRO measures, including sleep, interpersonal relationships, and the ability to conduct social or work activities. CLINICAL TRIAL REGISTRATION: JapicCTI-173740 (registered 20 October 2017).

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BACKGROUND: Data from the Japanese phase 3 Nemolizumab-JP01 study (JapicCTI-173740) found that nemolizumab in combination with topical treatments reduced pruritus associated with atopic dermatitis inadequately controlled with current therapies. METHODS: This post-hoc analysis examined associations between improvements in pruritus (visual analog scale [VAS]) and eczema (Eczema Area and Severity Index [EASI]), and achievement of other clinically relevant endpoints including the Insomnia Severity Index (ISI), Dermatology Life Quality Index (DLQI), and Patient-Oriented Eczema Measure (POEM). RESULTS: Pruritus VAS responders (≥50% improvement from baseline to week 16) showed greater improvements from baseline in these additional endpoints as early as week 1, compared with non-responders. Responders also had EASI improvement, and more than 80% achieved an ISI score ≤7, or had improvement in the DLQI or POEM. The percent change from baseline in VAS and EASI scores at week 16 was in favor of nemolizumab in all subgroups based on baseline characteristics. No specific factor affecting treatment response to nemolizumab was identified. CONCLUSIONS: In this post-hoc analysis, nemolizumab-treated patients who had greater pruritus reductions also showed improvements in other eczema symptoms; pruritus alleviation appeared to be responsible for the improvements in eczema, sleep and daily life.

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BACKGROUND: Nemolizumab is a subcutaneously administered humanized monoclonal antibody against interleukin-31 receptor A, which is involved in pruritus and inflammation in atopic dermatitis. In phase 2 studies, nemolizumab lessened the severity of atopic dermatitis. METHODS: In a 16-week, double-blind, phase 3 trial, we randomly assigned Japanese patients with atopic dermatitis and moderate-to-severe pruritus and an inadequate response to topical agents in a 2:1 ratio to receive subcutaneous nemolizumab (60 mg) or placebo every 4 weeks until week 16, with concomitant topical agents. The primary end point was the mean percent change in the visual-analogue scale (VAS) score for pruritus (range, 0 to 100, with higher scores indicating worse pruritus) from baseline to week 16. Secondary end points included the time course of change in the VAS score for pruritus up to week 4, the change in the Eczema Area and Severity Index (EASI) score (range, 0 to 72, with higher scores indicating greater severity), a score of 4 or less on the Dermatology Life Quality Index (DLQI; range, 0 to 30, with higher scores indicating a greater effect on daily life), a score of 7 or less on the Insomnia Severity Index (ISI; range, 0 to 28, with higher scores indicating greater severity), and safety. RESULTS: A total of 143 patients were randomly assigned to receive nemolizumab and 72 to receive placebo. The median VAS score for pruritus at baseline was 75. At week 16, the mean percent change in the VAS score was -42.8% in the nemolizumab group and -21.4% in the placebo group (difference, -21.5 percentage points; 95% confidence interval, -30.2 to -12.7; P<0.001). The mean percent change in the EASI score was -45.9% with nemolizumab and -33.2% with placebo. The percentage of patients with a DLQI score of 4 or less was 40% in the nemolizumab group and 22% in the placebo group; the percentage of patients with an ISI score of 7 or less was 55% and 21%, respectively. The incidence of injection-related reactions was 8% with nemolizumab and 3% with placebo. CONCLUSIONS: In this 16-week trial, the use of subcutaneous nemolizumab in addition to topical agents for atopic dermatitis resulted in a greater reduction in pruritus than placebo plus topical agents. The incidence of injection-site reactions was greater with nemolizumab than with placebo. Longer and larger trials are necessary to determine whether nemolizumab has a durable effect and is safe for atopic dermatitis. (Funded by Maruho; JapicCTI number, 173740.).

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A 62-year-old woman was admitted for epigastralgia, nausea and tarry stool.Abdominal CT showed a tumor to the jejunum from the duodenum, and peritoneal dissemination.Gastroduodenoscopy showed a type 2 tumor, and the histopathological examination revealed a well-to moderately-differentiated adenocarcinoma.Accordingly, she was diagnosed with primary adenocarcinoma of the small intestines and underwent surgery.The first-line chemotherapy with S-1/CPT-11 was started after surgery, and the tumor marker returned to normal.The treatment of 14 courses was continued until PD due to the enlargement of the peritoneal dissemination.Second - and third-line chemotherapy were performed; however, she died 20 months after the initial treatment.Although the incidence of primary adenocarinoma of the small intestines is relative- ly low, and there is no established chemotherapy at present, this case suggested that S-1/CPT-11may be an effective regimen for advanced primary adenocarcinoma of the small intestines.

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PURPOSE: The objective of this study was to describe the current state of smoking and alcohol drinking among pregnant women, and assess the factors related to smoking behavior during pregnancy. METHODS: Subjects were mothers whose children had undergone 4-month checkups publicly provided by Kyoto City in February 2007. An anonymous self-administered questionnaire survey about their smoking and alcohol drinking behavior was conducted. Chi-square tests and a logistic regression analysis were carried out to assess the factors related to smoking behavior during pregnancy. RESULTS: Out of a total of 999, 722 questionnaires were returned (response rate, 72.3%). Usable questionnaires were 689 (available response rate, 69.0%). The prevalence levels of alcohol drinking during prenatal, pregnant and postnatal periods were 55.9%, 9.1%, 22.1%, respectively. In 586 breast feeding mothers, the prevalence of alcohol drinking was 19.5%. The percentages of women smoking during prenatal, pregnant and postnatal periods were 23.4%, 7.5%, 9.0%, respectively. Out of prenatal smokers, the rate of quit smoking taking advantage of pregnancy was 67.7%. The prevalence of their husbands' smoking was 43.1%. Logistic regression analysis showed that "young age (<25 years)", "drinking alcohol during pregnancy" and "passive smoking due to their husbands" were significantly related to smoking during pregnancy. CONCLUSION: Maternal smoking and alcohol drinking are important public health problems. The prevalence of smoking during pregnancy was found to be especially high in young women, and some pregnant women could not quit smoking. Approximately half of pregnant women were exposed to passive smoking. The prevalence of alcohol drinking during pregnancy was high in women aged more than 40 years. It is necessary to give knowledge about obstetric and perinatal complications of smoking and alcohol drinking for childbearing-age women, and provide support help quit smoking and alcohol drinking giving due consideration to age.

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BACKGROUND: Due to the low measles vaccination rate, localized measles epidemics occasionally occur in Japan with the majority of sufferers being children under 2 years of age. Despite an increased risk of infection at day-care centers, the measles vaccination coverage for day-care attendees is lower than children who are reared-at-home or attend kindergartens. This study aims to describe the current state of measles prevention policy at day-care centers and to examine factors associated with vaccine promotion. METHODS: A cross-sectional study using anonymous self-administered questionnaires were distributed to the director or person-in-charge at 250 all licensed day-care centers in Kyoto City, Japan, in 2004. The preventive measures against measles at day-care centers and factors related to carrying out the promotion of measles vaccination were examined. Descriptive statistics and odds ratios (OR) using a logistical model were presented. RESULTS: Out of 250 day-care centers, 187 questionnaires were returned (response rate, 74.8%). Measles vaccination history was taken at 161 day-care centers (86.1%) at the time of enrollment; only 61 day-care centers (32.6%) took a history during the school year. A total of 101 day-care centers (54.0%) promoted measles vaccination in day-care attendees who had not yet been immunized. Day-care centers which promoted it were more likely to be 'public facility' (OR, 3.09) and 'having opportunities to learn about vaccination' (OR, 5.55). After adjustment, 'having opportunities to learn about vaccination' and 'having knowledge that measles vaccination is best under the age of 15 months' were significantly related to carrying out the promotion of measles vaccination (OR, 6.47; 95% confidence interval, 2.52-18.61; OR, 3.12; 95% confidence interval, 1.45-6.95, respectively). CONCLUSION: Preventive measures for measles at day-care centers are currently insufficient. Increasing opportunities to learn about vaccination may encourage promotional behavior.

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A number of previous studies have suggested the involvement of phosphoinositide 3-kinase (PI3K) in Toll-like receptor (TLR) signaling. However, there have also been a number of conflicting reports. The PI3K inhibitor wortmannin greatly enhanced TLR-mediated inducible nitric-oxide synthase (iNOS) expression and cytokine production in the mouse macrophage cell line Raw264.7. The effect of wortmannin was common to TLR2, -3, -4, and -9 and was accompanied by activation of nuclear factor-kappaB and up-regulation of cytokine mRNA production. We were surprised to find that another PI3K inhibitor, LY294002, strongly suppressed the production of iNOS and cytokines. This effect of 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) was based on its inhibitory effect on mRNA synthesis. Expression of dominant-negative mutants of PI3K in macrophages augmented the lipopolysaccharideinduced expression of iNOS. Introduction of a pH1 vector producing short hairpin RNA that targets a catalytic subunit of PI3K (p110beta) also enhanced the TLR-mediated responses. Thus, the augmentation of TLR signals by wortmannin was mediated through the inhibition of PI3K, whereas the effect of LY294002 was not explained by its effect on PI3K. These discrepancies in the effects of pharmacological inhibitors in TLR-signaling may have caused confusion regarding the role of PI3K in innate immunity.

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BACKGROUND: Due to low vaccine coverage, Japan has not only experienced outbreaks of measles but has also been exporting it overseas. This study aims to survey measles vaccine coverage and the factors uncompleted vaccination among community-living children. METHODS: Subjects were the parents whose children had undergone either an 18-month or a 36-month checkup publicly provided by Kyoto City during November 2001 to January 2002. An anonymous self-administered questionnaire survey was conducted. RESULTS: The coverage was 73.2% among the 18-month-old children (n = 2707) and 88.9% among the 36-month-old children (n = 2340), respectively. The following characteristics of mothers were related to uncompleted measles vaccination: aged below 30, working, concerned about the adverse events of the vaccine, and had insufficient knowledge. Similarly, the following characteristics among children were related to uncompleted measles vaccination: not the first-born child, interacting with other children in group settings. The coverage was the lowest among the children whose mothers were concerned about the adverse events of the vaccine without proper knowledge of measles and its vaccination. CONCLUSION: To increase vaccine coverage among children, parents' awareness about measles and vaccination against it should be promoted, especially for working mothers. Efforts to enhance access to vaccination services and to communicate with parents about changing vaccination schedules are necessary.

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