Search

Atopic dermatitis (AD), a chronic relapsing inflammatory skin disease with a high disease burden, is one of the most common dermatological conditions in Japan. Herein, we report the disease profiles and current AD treatment during 2-year management of Japanese adults with moderate-to-severe AD. ADDRESS-J was a prospective, longitudinal, observational study that evaluated real-world effectiveness and safety of current AD treatments of adult patients with moderate-to-severe AD (Investigator's Global Assessment score 3 or 4) in Japan. The maximum follow-up period was 2 years. Among 300 patients enrolled, 288 had ≥1 post-baseline evaluation and were analyzed (mean age, 35.5 years; 60.1% male). Almost all patients (99.7%) received topical therapy; the most commonly used therapy was topical corticosteroids of the second-highest potency (86.5%) (e.g., 0.1% mometasone furoate) followed by medium-potency topical corticosteroids (50.3%) (e.g., 0.05% clobetasol butyrate). At month 12 of the study, 10.4% of patients had Investigator's Global Assessment 0/1, similarly at month 24 (10.8%). A total of 132 patients (45.8%) had ≥1 AD flare-up during the observation period, with the majority of first flares occurring within the first year of the study. Various physician- and patient-reported outcomes improved considerably during the first 3 months of the study, with only minor changes after this time. In this cohort, 16.7% of patients had skin infections requiring treatment; 7.3% had adverse events (AE) potentially related to treatment; 1.7% had serious AE; and 1.0% had treatment discontinuations due to AE. Limitations include missing data at later timepoints and the inclusion criteria limiting generalizability. In summary, this analysis of the ADDRESS-J study showed that some patients with moderate or severe AD respond to conventional therapies, while others do not. For those with inadequately controlled moderate-to-severe AD, the newly emerged systemic agents, such as biologics, may provide a potential strategy for long-term disease management.

ImportanceQuality of life (QOL) of patients with atopic dermatitis (AD) is reported to be the lowest among skin diseases. To our knowledge, mindfulness and self-compassion training has not been evaluated for adults with AD.ObjectiveTo evaluate the efficacy of mindfulness and self-compassion training in improving the QOL for adults with AD.Design, Setting, and ParticipantsThis randomized clinical trial conducted from March 2019 through October 2022 included adults with AD whose Dermatology Life Quality Index (DLQI) score, a skin disease–specific QOL measure, was greater than 6 (corresponding to moderate or greater impairment). Participants were recruited from multiple outpatient institutes in Japan and through the study’s social media outlets and website.InterventionsParticipants were randomized 1:1 to receive eight 90-minute weekly group sessions of online mindfulness and self-compassion training or to a waiting list. Both groups were allowed to receive any dermatologic treatment except dupilumab.Main Outcomes and MeasuresThe primary outcome was the change in the DLQI score from baseline to week 13. Secondary outcomes included eczema severity, itch- and scratching-related visual analog scales, self-compassion and all of its subscales, mindfulness, psychological symptoms, and participants’ adherence to dermatologist-advised treatments.ResultsThe study randomized 107 adults to the intervention group (n = 56) or the waiting list (n = 51). The overall participant mean (SD) age was 36.3 (10.5) years, 85 (79.4%) were women, and the mean (SD) AD duration was 26.6 (11.7) years. Among participants from the intervention group, 55 (98.2%) attended 6 or more of the 8 sessions, and 105 of all participants (98.1%) completed the assessment at 13 weeks. The intervention group demonstrated greater improvement in the DLQI score at 13 weeks (between-group difference estimate, −6.34; 95% CI, −8.27 to −4.41; P d) at 13 weeks was −1.06 (95% CI, −1.39 to −0.74). All secondary outcomes showed greater improvements in the intervention group than in the waiting list group.Conclusions and RelevanceIn this randomized clinical trial of adults with AD, integrated online mindfulness and self-compassion training in addition to usual care resulted in greater improvement in skin disease–specific QOL and other patient-reported outcomes, including eczema severity. These findings suggest that mindfulness and self-compassion training is an effective treatment option for adults with AD.Trial Registrationhttps://umin.ac.jp/ctr Identifier: UMIN000036277

As the first biologics for psoriasis in Japan, infliximab and adalimumab, anti-tumor necrosis factor-α antibodies, became available in the field of dermatology in 2010, followed by ustekinumab, an anti-interleukin (IL)-12/IL-23p40 antibody, which was launched in Japan in 2011. Since 2015, three IL-17 inhibitors of secukinumab and ixekizumab, anti-IL-17A antibodies, and brodalumab, an anti-IL-17 receptor antibody, and two anti-IL-23p19 antibodies of guselkumab and risankizumab, have also been launched. It is important for physicians to select appropriate biologic therapy for each psoriatic patient after due consideration of disease factors, treatment factors and patient background factors, sharing such information with patients. The following can be listed as points to be considered for the selection of biologics: drug effects (e.g. strength of effectiveness, time to onset of effectiveness, effectiveness against arthritis, primary failure, secondary failure), safety (e.g. infections, administration-related reactions and relationships with other comorbidities), convenience for patients (e.g. hospital visit intervals, self-injection, maintenance therapy at clinics, feasibility of drug discontinuation/re-administration) and payment (medical costs) borne by patients. This guidance has been prepared with the aim of allowing dermatologists experienced in the treatment of psoriasis to use biologics appropriately according to the circumstances of individual patients after consideration of the above-mentioned factors.

We report the successful treatment of two cases of difficult-to-treat pressure ulcers with botulinum toxin type A (BoNT-A). A 71-year-old male patient with Parkinson's disease presented with severe hand grip deformities of the fingers and a pressure ulcer (PU) on the right hand. He received 240U of BoNT-A into the upper limb muscles, which improved finger mobility during passive extension and resulted in resolution of the palm PU. No recurrence was noted. A 69-year-old female patient with Lewy body dementia presented with a PU on the palm side of the middle finger apex of the right hand, with exposure of the phalanx bone and dark red oedematous granulation of the tip of the finger. Severe muscle tone was noted. She received 240U of BoNT-A injected into the muscles of the upper extremities. This resulted in the disappearance of the contracture between the middle finger cusp and palm, and prompt healing of the PU. A protective finger orthosis was also used to improve hand finger grip and prevent further PUs. Although BoNT-A injection resulted in only slight improvement in the range of motion, it produced relief of pressure with consequent healing of the PU. Injection of BoNT-A into the affected muscles of the patients in this case report was effective in reducing flexor muscle tone, relief of pressure on the palm skin and healing of hand PUs.

Moderate to severe atopic dermatitis (AD) has a high disease burden and a significant effect on quality of life. Observational studies are necessary to determine the patient disease burden and long‐term disease control in the Japanese population. ADDRESS‐J is a non‐interventional, observational registry of adult Japanese patients with moderate to severe AD. Herein, we report baseline data from the ADDRESS‐J study describing disease characteristics and current treatment practices. At baseline, 300 adult AD patients with Investigator's Global Assessment (IGA) scores (range, 0–4) of 3 (moderate) or 4 (severe) whose treatments for AD were intensified, were assessed for clinical and patient‐reported outcomes and current AD treatments. The registry patients’ median age was 34.0 years; 60.7% were male and 71.7% had had AD for more than 20 years. At baseline, 220 study patients had an IGA score of 3 and 80 had an IGA score of 4. The median Eczema Area and Severity Index score was 21.7 (range, 0–72), the median body surface area involvement was 46.25%, and the median pruritus numerical rating scale score was 7.0 (range, 0–10); for each of these measures, higher scores represent greater severity. Most registry patients (86.7%) had recently used topical corticosteroids or topical calcineurin inhibitors as treatment for AD. This registry cohort represents a population of Japanese patients with moderate to severe AD and provides an important resource for characterizing the disease burden and evaluating the safety and effectiveness of various AD treatments.

Double-filtration plasmapheresis is an effective and safe treatment for pemphigus. We retrospectively evaluated the decrease in autoantibody titer and pemphigus disease area index following double-filtration plasmapheresis in five patients with moderate to severe pemphigus, who were physically and/or serologically unresponsive to 1.0 mg/kg per day of prednisolone and other supportive drugs and ointments. The percentage reduction in autoantibodies 85.6 ± 14.4% (P = 0.00014), and that in pemphigus disease area index was 75.4 ± 24.3% (P = 0.0023). No side-effects were observed. All patients exhibited clinical improvement after undergoing double-filtration plasmapheresis, and the prednisolone dose was reduced by 41 ± 8.9 mg (P = 0.0005) approximately 3 months after double-filtration plasmapheresis. To our knowledge, this is the first report evaluating the efficacy of double-filtration plasmapheresis with pemphigus disease area index, and it demonstrated that double-filtration plasmapheresis is a safe “subtracting” treatment for patients with drug-resistant pemphigus.

BACKGROUND: Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis.METHODS: In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigator's Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov, NCT02260986.FINDINGS: Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients] who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who received placebo plus topical corticosteroids; pINTERPRETATION: Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety.FUNDING: Sanofi and Regeneron Pharmaceuticals Inc.

Interleukin-31 may play a role in the pathobiologic mechanism of atopic dermatitis and pruritus. We wanted to assess the efficacy and safety of nemolizumab (CIM331), a humanized antibody against interleukin-31 receptor A, in the treatment of atopic dermatitis.In this phase 2, randomized, double-blind, placebo-controlled, 12-week trial, we assigned adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments to receive subcutaneous nemolizumab (at a dose of 0.1 mg, 0.5 mg, or 2.0 mg per kilogram of body weight) or placebo every 4 weeks or an exploratory dose of 2.0 mg of nemolizumab per kilogram every 8 weeks. The primary end point was the percentage improvement from baseline in the score on the pruritus visual-analogue scale (on which a negative change indicates improvement) at week 12. Secondary end points included changes in the score on the Eczema Area and Severity Index (EASI, on which a negative change indicates improvement), and body-surface area of atopic dermatitis.Of 264 patients who underwent randomization, 216 (82%) completed the study. At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual-analogue scale were -43.7% in the 0.1-mg group, -59.8% in the 0.5-mg group, and -63.1% in the 2.0-mg group, versus -20.9% in the placebo group (P0.01 for all comparisons). Changes on the EASI were -23.0%, -42.3%, and -40.9%, respectively, in the nemolizumab groups, versus -26.6% in the placebo group. Respective changes in body-surface area affected by atopic dermatitis were -7.5%, -20.0%, and -19.4% with nemolizumab, versus -15.7% with placebo. Among the patients receiving nemolizumab every 4 weeks, treatment discontinuations occurred in 9 of 53 patients (17%) in the 0.1-mg group, in 9 of 54 (17%) in the 0.5-mg group, and in 7 of 52 (13%) in the 2.0-mg group, versus in 9 of 53 (17%) in the placebo group.In this phase 2 trial, nemolizumab at all monthly doses significantly improved pruritus in patients with moderate-to-severe atopic dermatitis, which showed the efficacy of targeting interleukin-31 receptor A. The limited size and length of the trial preclude conclusions regarding adverse events. (Funded by Chugai Pharmaceutical; XCIMA ClinicalTrials.gov number, NCT01986933 .).

Introduction Le dupilumab (DPL) est approuve dans plusieurs pays pour le traitement des patients (pts) adultes souffrant de dermatite atopique (DA) moderee a severe insuffisamment controlee. Materiel et methodes Il s’agit d’une analyse post-hoc des donnees groupees de deux essais de phase 3 (SOLO1 : NCT02277743 ; SOLO2 : NCT02277769 ) visant a determiner si des pts adultes atteints de DA moderee a severe traites par le DPL et non parvenus a un score d’evaluation globale par l’investigateur (IGA) de 0/1 a la 16e semaine (s) presentaient une amelioration cliniquement significative pour un ou plusieurs des trois domaines majeurs de la DA (signes, symptomes et qualite de vie [QdV]). Les pts ont ete randomises selon un rapport 1/1/1 pour recevoir pendant 16 s 300 mg de DPL par voie SC une fois par S (1×/s), toutes les 2 s (1×/2 s) ou un placebo (PBO). Les reponses cliniquement significatives etaient definies sur un ou plusieurs des criteres suivants : reduction ≥ 50 % du score EASI (indice de surface et de severite de l’eczema) (EASI-50), amelioration ≥ 3 points de la moyenne hebdomadaire du score NRS de prurit, amelioration ≥ 4 points du score DLQI (indice de qualite de vie dermatologique) ou amelioration ≥ 4 points du POEM (mesure de l’eczema par le patient) par rapport a l’initiation. Les criteres d’evaluation ont ete evalues apres 1, 2, 4, 8, 12 et 16 s. Resultats Au total, 1379 pts ont ete randomises : 460 pour PBO, 457 pour DPL 300 mg 1×/2 s et 462 pour DPL 300 mg 1×/s. Dans les groupes PBO/1×/2 s/1×/s, 417/288/292 pts respectivement ne sont pas parvenus a un IGA de 0/1 a la s16. Parmi ceux-ci, une proportion significativement plus importante de pts des deux groupes de traitement DPL vs PBO etait parvenue a un resultat cliniquement significatif pour une ou plusieurs des quatre mesures de severite de la DA/QdV apres seulement S1 (1×/s/1×/2 s vs PBO : 60,6 %/60,4 % vs 38,4 % ; p Fig. A ). Lorsque l’on analyse les scores de severite de la DA/QdV entre les s2 et s16, une proportion significativement plus importante de pts des groupes 1×/s/1×/2 s vs PBO sont parvenus a une reponse cliniquement significative pour chacune des mesures de severite de la DA/QdV. Les evenements indesirables plus frequents avec le DPL qu’avec le PBO etaient des reactions au site d’injection (1×/s/1×/2 s vs PBO : 15,82 %/10,97 % vs 6,14 %) et une conjonctivite (1×/s/1×/2 s vs PBO : 7,3 %/9,7 % vs 2,2 %). Conclusion Des pts adultes atteints de DA moderee a severe traites par le DPL et non parvenus a un IGA 0/1 a s16 ont presente une amelioration cliniquement significative rapide et persistante dans un ou plusieurs des principaux domaines de la DA (signes, symptomes et QdV) compare au PBO apres seulement s1 et jusqu’a s16.

Summary Background Dupilumab, a human monoclonal antibody, blocks the shared receptor unit for interleukin‐4 and interleukin‐13. International phase II and III studies have evaluated the efficacy and safety of dupilumab in adults with moderate‐to‐severe atopic dermatitis (AD), but the effects of dupilumab in Japanese patients have not been reported. Objectives To evaluate the efficacy and safety of dupilumab in Japanese patients with moderate‐to‐severe AD. Methods We analysed the efficacy and safety of dupilumab in the Japanese cohorts of a 16‐week, phase IIb dose‐finding trial (AD‐1021; NCT01859988); a 16‐week, phase III, placebo‐controlled monotherapy trial (LIBERTY AD SOLO 1; NCT02277743) and a 52‐week, phase III, placebo‐controlled study of dupilumab with topical corticosteroids (LIBERTY AD CHRONOS; NCT02260986). Results Twenty‐seven, 106 and 117 Japanese patients were enrolled in AD‐1021, SOLO 1 and CHRONOS, respectively. Baseline disease severity was numerically higher in the Japanese cohort than in the overall study population. Generally, dupilumab significantly improved signs and symptoms of AD, including pruritus and patient quality of life, compared with placebo in the Japanese cohort, consistent with the overall study population. The combined safety profile of dupilumab in the Japanese cohort was similar to that in the total study populations; dupilumab was associated with an increased incidence of injection‐site reactions and conjunctivitis compared with placebo. Dupilumab was associated with rapid reduction in thymus and activation‐regulated chemokine and gradual IgE reductions. Conclusions Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD, had an acceptable safety profile, and suppressed biomarkers of type 2 inflammation compared with placebo in Japanese adult patients with moderate‐to‐severe AD. What's already known about this topic? Differences in atopic dermatitis (AD) pathology have been reported between Asian and Western populations, in which distinct helper T‐cell activation profiles have been observed.International clinical studies in adults with moderate‐to‐severe AD have evaluated the efficacy and safety of dupilumab, which blocks interleukin‐4 and interleukin‐13, key molecules in type 2 inflammation.The effects of dupilumab in Japanese patients specifically have not yet been reported. What does this study add? Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD and had an acceptable safety profile compared with placebo in Japanese patients with moderate‐to‐severe AD.The effects were comparable with those observed in the overall study population.Reported immunological differences in AD pathology in Asian patients may be secondary to type 2 immune activation., Plain language summary available online Respond to this article

Introduction La dermatite atopique erythrodermique (DA-E : ≥ 90 % de la surface corporelle atteinte [SCA] par la DA et un score initial d’erytheme ≥ 1 a l’evaluation globale des signes individuels par le score GISS [Global Individual Sign Score]) est difficile a traiter et peut menacer le pronostic vital. Le dupilumab beneficie d’une autorisation de mise sur le marche (AMM) aux Etats-Unis pour les adultes et adolescents atteints de DA moderee a severe insuffisamment controlee. Nous rapportons les donnees d’efficacite poolees des etudes sur le dupilumab en monotherapie et en association avec des dermocorticoides (DC) chez des patients atteints de DA-E. Materiel et methodes Lors des etudes sur 16 semaines portant sur le dupilumab en monotherapie (3 chez des adultes, 1 chez des adolescents [12–17 ans]), 136 patients atteints de DA-E ont recu 300 mg de dupilumab une fois par semaine (1/s) (n = 38), 200 mg ou 300 mg toutes les 2 semaines (1/2s) selon que le poids initial etait Resultats L’utilisation du dupilumab en monotherapie a conduit a une amelioration significative (1/s/1/2s/placebo) des valeurs suivantes : SCA moyenne (Inclusion : 94,78 %/94,56 %/95,54 % ; S16 : 51,69 %/55,64 %/81,94 % ; 1/s/1/2s, p = 0,0279/p = 0,0259) ; score EASI (Eczema Area and Severity Index, indice de surface et de severite de l’eczema) (Inclusion : 58,65/54,98/59,25 ; S16 : 24,41/24,28/46,35 ; p = 0,0026/p = 0,0031) ; moyenne hebdomadaire du score NRS (Numeral Rating Scale) de prurit maximal journalier (inclusion : 7,38/7,82/8,03 ; S16 : 4,20/4,78/7,37 ; p Discussion Le dupilumab en monotherapie ou en association avec des DC ameliore significativement les signes et symptomes chez les patients atteints de DA-E.

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. Most patients have an atopic predisposition. The definitive diagnosis of AD requires the presence of all three features: (i) pruritus; (ii) typical morphology and distribution of the eczema; and (iii) chronic and chronically relapsing course. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.

Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis and psoriatic arthritis. Japanese patients aged 20 years or more with moderate to severe plaque psoriasis and/or psoriatic arthritis were double‐blindly randomized 1:1 to tofacitinib 5 or 10 mg b.i.d. for 16 weeks, open‐label 10 mg b.i.d. for 4 weeks, then variable 5 or 10 mg b.i.d. to Week 52. Primary end‐points at Week 16 were the proportion of patients achieving at least a 75% reduction in Psoriasis Area and Severity Index (PASI75) and Physician's Global Assessment of “clear” or “almost clear” (PGA response) for psoriasis, and 20% or more improvement in American College of Rheumatology criteria (ACR20) for patients with psoriatic arthritis. Safety was assessed throughout. Eighty‐seven patients met eligibility criteria for moderate to severe plaque psoriasis (5 mg b.i.d., n = 43; 10 mg b.i.d., n = 44), 12 met eligibility criteria for psoriatic arthritis (5 mg b.i.d., n = 4; 10 mg b.i.d., n = 8) including five who met both criteria (10 mg b.i.d.). At Week 16, 62.8% and 72.7% of patients achieved PASI75 with tofacitinib 5 and 10 mg b.i.d., respectively; 67.4% and 68.2% achieved PGA responses; all patients with psoriatic arthritis achieved ACR20. Responses were maintained through Week 52. Adverse events occurred in 83% of patients through Week 52, including four (4.3%) serious adverse events and three (3.2%) serious infections (all herpes zoster). No malignancies, cardiovascular events or deaths occurred. Tofacitinib (both doses) demonstrated efficacy in patients with moderate to severe plaque psoriasis and/or psoriatic arthritis through 52 weeks; safety findings were generally consistent with prior studies.

This exploratory study was designed to evaluate the safety and efficacy profile of the topical phosphodiesterase 4 inhibitor E6005 in Japanese children with mild-to-moderate atopic dermatitis. The present randomized, multicenter study included 62 patients who were treated with 0.05% E6005, 0.2% E6005 or vehicle ointment twice daily for 2 weeks. Safety and pharmacokinetics were assessed with a focus on the occurrence of adverse events and the whole blood concentrations of E6005 and its metabolite. Exploratory efficacy evaluations included assessments of lesion severity and pruritus score. The 2-week application of topical E6005 was safe and well tolerated with no cutaneous adverse events. The whole blood concentration of E6005 was quantified in only one subject receiving 0.2% E6005 treatment, while its major metabolite was undetectable. The 0.2% E6005 group showed a greater decrease in the severity score than the vehicle group (-45.94% vs -32.26%), although this difference was not statistically significant. Similarly, the treatment success rate according to the investigator's global assessment of the total application sites was higher in the 0.2% E6005 group than in the vehicle group (34.4% vs 20.0%). Moreover, the 0.2% E6005 group showed a greater decrease in the pruritus score than the vehicle group (-37.5% vs -6.7%) in a predefined subpopulation. The efficacy of 0.05% E6005 treatment was comparable to that of vehicle treatment. These results suggest that topical 0.2% E6005 treatment is safe and effective in children with atopic dermatitis, although further large confirmatory clinical trials are warranted.

Background Nemolizumab, an anti–IL-31 receptor A mAb, improved pruritus, dermatitis, and sleep in adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments in a phase II, 12-week, randomized, double-blind, placebo-controlled study (part A; NCT01986933 ). Objective We sought to assess the long-term efficacy and safety of nemolizumab injected subcutaneously every 4 weeks (Q4W) or every 8 weeks (Q8W) in a 52-week, double-blind extension (part B). Methods During part B, patients continued the previous nemolizumab dose (0.1, 0.5, or 2.0 mg/kg Q4W or 2.0 mg/kg Q8W). Part B end points included percentage improvement from baseline in pruritus visual analog scale and dermatitis scores (including the Eczema Area and Severity Index). Results Overall, 216 of 264 patients completed part A, and 191 entered part B; 131 completed part B. In 153 patients randomized to nemolizumab in part A, improvement from baseline in pruritus visual analog scale score was maintained/increased from weeks 12 to 64, with greatest improvement in the 0.5-mg/kg Q4W group (percentage change from baseline at week 64: −73.0, −89.6, −74.7, and −79.1 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Improvement from baseline in dermatitis scores was also maintained/increased to week 64 (percentage change in Eczema Area and Severity Index score: −68.5, −75.8, −78.9, and −69.3 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Over 64 weeks, 83% to 89% had 1 or more adverse events, with no new safety concerns identified. Conclusion Nemolizumab for up to 64 weeks was efficacious and overall well tolerated in patients with moderate-to-severe atopic dermatitis inadequately controlled by topical therapy.

Double-filtration plasmapheresis is an effective and safe treatment for pemphigus. We retrospectively evaluated the decrease in autoantibody titer and pemphigus disease area index following double-filtration plasmapheresis in five patients with moderate to severe pemphigus, who were physically and/or serologically unresponsive to 1.0 mg/kg per day of prednisolone and other supportive drugs and ointments. The percentage reduction in autoantibodies 85.6 ± 14.4% (P = 0.00014), and that in pemphigus disease area index was 75.4 ± 24.3% (P = 0.0023). No side-effects were observed. All patients exhibited clinical improvement after undergoing double-filtration plasmapheresis, and the prednisolone dose was reduced by 41 ± 8.9 mg (P = 0.0005) approximately 3 months after double-filtration plasmapheresis. To our knowledge, this is the first report evaluating the efficacy of double-filtration plasmapheresis with pemphigus disease area index, and it demonstrated that double-filtration plasmapheresis is a safe "subtracting" treatment for patients with drug-resistant pemphigus.

The clinical use of adalimumab and infliximab, human anti-tumor necrosis factor (TNF)-α monoclonal antibodies, for psoriasis began in January 2010. In January 2011, ustekinumab, a human anti-interleukin-12/23p40 (IL-12/23p40) monoclonal antibody, was newly approved as the third biologic with an indication for psoriasis. While all of these biologics are expected to exhibit excellent therapeutic effect for psoriasis and to contribute to the improvement of quality of life in patients, these drugs require careful safety measures to prevent adverse drug reactions, such as serious infections. The new guidance, an English version prepared by revising the Japanese Guidance/Safety Manual for Use of Biologics for Psoriasis 2011 (in Japanese), is intended to provide up-to-date, evidence-based recommendations and safety measures on the use of biologics, and describes the optimal use of the three biologics, medical requirements for facilities for using biologics, details of safety measures against reactivation of tuberculosis and hepatitis B virus infection, and recommendable combination therapies with biologics.

Background Generalized pustular psoriasis (GPP) is a chronic autoimmune disease characterized by fever, erythema, and neutrophilic pustules over large areas of the skin. GPP does not respond well to pharmacologic intervention. Objective We sought to assess efficacy of selectively depleting the myeloid lineage leukocytes in patients with GPP. Methods Fifteen patients with persistent moderate to severe GPP despite conventional therapy were included. Eligible patients had more than 10% of their skin area covered by pustules. Treatment with oral etretinate, cyclosporine, methotrexate, prednisolone, and topical prednisolone/vitamin D3 was continued if had been initiated well in advance of study entry. Five sessions of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn (JIMRO Co Ltd, Takasaki, Japan) were administered (1 session/wk over 5 weeks) to selectively deplete Fcγ receptor and complement receptor bearing leukocytes. Efficacy was assessed by measuring the skin areas covered by pustules at baseline and 2 weeks after the last GMA session. Results One patient did not complete the first GMA session. Based on the GPP severity scores relative to entry, the overall scores improved (n = 14, P = .0027), and the area of erythroderma ( P = .0042), pustules ( P = .0031), and edema ( P = .0014) decreased. Likewise, Dermatology Life Quality Index improved ( P = .0016), reflecting better daily function and quality of life. Twelve patients were judged as responders (85.7%), and 10 patients maintained the clinical response for 10 weeks after the last GMA session without any change in medication. Limitations This study was unblinded and without a placebo arm. Conclusion GMA in this clinical setting was safe and effective, suggested a major role for granulocytes/monocytes in the immunopathogenesis of GPP.

Incidence of psoriasis vulgaris in Asians is estimated at 0.05-0.3%. Studies in North America and Europe demonstrated that adalimumab, a fully human, recombinant, immunoglobulin G(1) monoclonal antibody, was efficacious and well-tolerated in patients with chronic plaque psoriasis. This 24-week, placebo-controlled study evaluated the efficacy and safety of three different dosing regimens of adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis (n = 169). Patients were randomized to receive adalimumab 40 mg every other week (eow), adalimumab 80-mg loading dose at week 0 followed by adalimumab 40 mg eow starting at week 2, adalimumab 80 mg eow, or placebo eow given as s.c. injections. The primary efficacy endpoint was the percentage of patients achieving a 75% or greater improvement in Psoriasis Area and Severity Index (PASI 75) score at week 16. At week 16, PASI 75 response rates were significantly greater for all three adalimumab groups (40 mg eow: 57.9%, P < 0.001; 40 mg eow plus loading dose: 62.8%, P < 0.001; 80 mg eow: 81.0%, P < 0.001) versus placebo (4.3%). As early as week 4, the 40-mg eow plus loading dose and 80-mg eow groups achieved significantly greater PASI 75 response rates compared with placebo. Injection-site reactions and hepatic events occurred in greater percentages of adalimumab-treated patients compared with placebo. Adalimumab therapy demonstrated efficacy and safety at all three dosage regimens. Rapid response rate in patients receiving 40 mg eow plus loading dose supports using an 80-mg loading dose in the treatment of psoriasis.

The tumor necrosis factor-α inhibitor, adalimumab, is approved to treat moderate-to-severe plaque psoriasis (40 mg every-other-week or 80 mg every-other-week following inadequate response at 40 mg in Japan). This open-label extension (OLE) trial evaluated the optimal adalimumab dose for long-term efficacy and safety in Japanese patients with moderate-to-severe plaque psoriasis following a prior 24-week, phase 2/3, randomized, double-blind study. Of the 169 patients from the phase 2/3 trial, 147 entered the OLE on 40 mg (n = 89) or 80 mg (n = 58) adalimumab every-other-week. Patients on 40 mg with Psoriasis Area and Severity Index (PASI) of less than 50 could escalate to 80 mg. At week 52 (28 of OLE), patients entering the OLE on 80 mg were reduced to 40 mg, with the option to re-escalate. For patients entering the OLE on 40 mg, final PASI 50/75/90 response rates were 85.1%/73.3%/60.4%, respectively, including effects of dose escalation. Among patients whose dose was escalated, final PASI 50/75/90 response rates were 70.0%/53.3%/36.7%, respectively. For patients entering the OLE on 80 mg, final PASI 50/75/90 response rates were 92.5%/84.9%/73.6%, respectively, including effects of dose re-escalation. Overall incidence rates of adverse events (AE) and injection-site reaction AE declined over time; rates for serious AE and infections were generally stable. Clinically meaningful efficacy of adalimumab was sustained to 4 years. Dose escalation to 80 mg every-other-week for patients with suboptimal response to 40 mg every-other-week, and dose reduction to 40 mg every-other-week for patients satisfactorily controlled on 80 mg every-other-week, are viable strategies for adalimumab optimization.

Twenty percent of dermatologists have experienced a separation of water or deterioration of topical corticosteroids mixed with commercially available ointments and/or creams. However, few investigations of this deterioration of admixtures have been reported. To assess the effects of preservatives in preventing microbial contamination of these admixtures, we attempted to investigate the concentration of preservative agents in admixtures and the microbial contamination of these admixtures with a topical corticosteroid ointment (Antebate). The concentration of parabens was reduced by half using an admixture of corticosteroid ointment with four types of moisturizing creams, Urepearl, Pastaronsoft, Hirudoid, and Hirudoidsoft. After a further 3 months, no decrease in parabens was seen. No microbial contamination was found in any admixture stored at room temperature for 1 week and touched two times daily with a finger. The concentration and ratio of the parabens in the aqueous phase and oil phase were entirely different in the admixtures before being centrifuged. The aqueous phase of the admixtures of the oil/water (O/W)-type emulsions of Urepearl and Hirudoid was not found to have microbial contamination immediately after being centrifuged. All aqueous phases stored at room temperature or in a refrigerator for 1 week and touched with a finger twice daily exhibited microbial contamination. These experiments demonstrated that O/W-type emulsions, in which the water easily separates from the bases, should be thoroughly mixed to prevent microbial contamination.

We investigated the role of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in the growth regulation. Primary (PM-WK and KHm-4), recurrent primary (RPM-EP and RPM-MC), lymph node metastatic (MM-AN, MM-BP and MM-RU), and a visceral metastatic (MM-LH) melanoma cell lines were used. Reverse transcriptase-coupled polymerase chain reaction and Western blotting revealed that all expressed and produced TIMP-1 and TIMP-2 except for PM-WK, which neither expressed nor produced TIMP-1. TIMP-1 and TIMP-2 secretion levels were measured by enzyme-linked immunosorbent assay in supernatants of cells. We found that the TIMP-1 production level was correlated with the cell migration rate. Moreover, TIMP-1 enhanced the cell migration of PM-WK. The growth of the primary melanoma cell lines was stimulated by TIMP-1 and inhibited by TIMP-2. In contrast, the growth of the visceral metastatic melanoma cell line was stimulated by TIMP-2.

A constitutive complex of beta-catenin and LEF-1 has been detected in melanoma cell lines expressing either mutant beta-catenin or mutant APC (Rubinfeld et al., Science, 275, 1790-1792, 1997). However, it has been recently reported that beta-catenin mutations are rare in primary malignant melanoma, but its nuclear and/or cytoplasmic localization, a potential indicator of Wnt/beta-catenin pathway activation, is frequently observed in melanoma (Rimm et al., Am. J. Pathol., 154, 325-329, 1999). In human malignant melanoma, the appearance of the tumorigenic phase represents a capacity for metastasis and is the significant phenotypic step in disease progression. Cell motility in invasive melanoma is thought to play a crucial role in metastatic behavior. In this work, we sought to determine which transcription factor of the LEF/TCF family was preferentially involved in human melanoma from different stages of tumor progression. We show that LEF-1 mRNA expression is predominant in highly migrating cells from metastatic melanomas. These actively migrating melanoma cells showed nuclear and cytoplasmic accumulation of beta-catenin and active transcription from a reporter plasmid of the LEF/TCF binding site. These results may provide a new insight into the role of the Wnt/beta-catenin signaling pathway in the tumor progression of malignant melanoma.

48歳, 女性. 食欲不振, 全身倦怠感, 悪心で近医を受診し, 黄疸と肝障害を指摘されて入院した. AST605IU/l, ALT620IU/l, 総ビリルビン3.4mg/dl. A, B, C, G型肝炎ウイルスマーカーは陰性で, EBウイルス, サイトメガロウイルスは既往感染だった. IgG2009mg/dl, 抗平滑筋抗体160×, HLADR4陽性, 慢性肝炎の組織所見から, 国際診断基準スコアが治療前17点となり, 自己免疫性肝炎 (AIH) (definite) と診断した. プレドニン40mg/日で治療を開始し, 4週間後には肝機能検査が正常化して退院. 18カ月後の現在, プレドニン10mg/日でトランスアミナーゼ, IgG濃度とも正常範囲である. 治療後スコアは19点で, AIH (definite) と診断した. 本例の抗核抗体 (ANA) はHEp-2細胞を用いた間接蛍光抗体法で, 抗セントロメア抗体 (ACA) を示す散在斑紋型 (discretespeckled) のみ陽性だった. 文献上わが国のAIHの約10%がACA/散在斑紋型 ANA 陽性であり, 他の自己免疫疾患の合併が多い以外は臨床像に差異を認めなかった. AIH診断スコアの算定に散在斑紋型も ANA 陽性と見なすことを提案した.

Tacrolimus (FK506), a new immunosuppressant used clinically in the prevention of allograft rejection, has been shown to be effective when used topically in atopic dermatitis, especially for face and neck lesions. Because Malassezia furfur, normally found in the seborrhoeic area, has been suggested to be one of the major allergens in atopic dermatitis and a provocative factor for face and neck lesions, the antifungal activity of tacrolimus against M. furfur was investigated. 26 strains of M. furfur were isolated from healthy adults and adult patients with atopic dermatitis. The growth of all the strains was inhibited by 0.5 to 32 mg/L of tacrolimus, whereas cyclosporin showed no such antifungal activity. This inhibition was found to be mediated by the fungicidal effects of tacrolimus. Microscopic examinations of M. furfur on the faces of patients with atopic dermatitis showed markedly diminished numbers of spores after 1 week’s treatment with topical tacrolimus ointment. The antifungal effects of tacrolimus against the causative allergenic yeast, M. furfur, may also be beneficial when treating face and neck atopic dermatitis with tacrolimus ointment.

In this study, we examined the endothelin (ET) receptor subtype involved in mitogenic signaling in human primary and metastatic melanoma cell lines. In a reverse transcriptase-polymerase chain reaction (RT-PCR) study, ET(B) mRNA expression in metastatic melanoma cells was decreased from that of primary melanoma. Only RPM-EP, a primary recurrent melanoma cell line, showed strong ET(A) mRNA expression. ET-1 and ET-3 stimulated DNA synthesis of primary and recurrent cutaneous melanoma cells in serum-deprived cultures. The growth response to ET-1 in metastatic melanoma cells was decreased from that in primary melanoma cells. [125I]-IRL-1620 binding to PM-WK, a primary melanoma cell line, was significantly blocked by excessive amounts of unlabeled BQ-788. [125I]-IRL-1620 binding to metastatic melanoma cells was significantly decreased from that of primary melanoma cells. From these results, we conclude that the mitogenic effects of ET in human primary melanoma are mainly mediated through ET(B) receptors and that down-regulation of ET(B) receptors causes the decreased growth response of ET-1 in metastatic melanoma cells.

We examined polymorphisms of transporter associated with antigen processing (TAP) genes in 37 Japanese patients with atopic dermatitis and 52 control subjects. We have evaluated, again, the specificity polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method since our previous report and have also developed a mismatch PCR-RFLP method for discriminating two dimorphic sites of TAP1 gene and four dimorphic sites of TAP2 gene. Amplified products from genomic DNA were digested with restriction endonucleases: Sau3A1 for TAP1 codon 333 (Ile-Val), AccI for TAP1 codon 637 (Asp-Gly), and BfaI for TAP2 codon 687 (Stop-Gln). The other sites of TAP2 gene were analyzed by mismatch PCR-RFLP: AccII for TAP2 codon 379 (Val-Ile), RsaI for codon 565 (Ala-Thr), and MspI for codon 665 (Thr-Ala). We observed three TAP1 alleles and six TAP2 alleles. Infrequent allele TAP1 C was observed in one patient and one control subject. We did not identify any differences in TAP allele frequencies between those patients with atopic dermatitis and Japanese control subjects. Analysis of TAP gene polymorphisms will provide better understanding of susceptibility loci in HLA class II-associated disease because TAP genes are located between HLA-DQB1 and HLA-DPB1 loci. (J ALLERGY CLIN IMMUNOL 1995;96:1051-60.)

We report a case of angiosarcoma of the left lower extremity arising from lymphedema of the left foot.A 42-year old Japanese woman visited our clinic for the evaluation of a toroser lesion on the dorsal of her foot and restiform subcutaneous nodules on her lower leg. Intralesional injection and intravenous drip of recombinant interleukin 2 (rIL-2) were partically effective.

Interleukin (IL)-5 was produced in vitro by peripheral blood mononuclear cells (PBMCs) of mite-sensitive atopic patients upon challenge with specific allergen, while PBMCs of healthy controls produced essentially no IL-5. Stimuli delivered by the combination of phorbol ester (PMA) and CA2+ ionophore (ionomycin) induced marked IL-5 production by PBMCs obtained from atopic as well as nonatopic asthmatics. CD2- or CD4-bearing-cell depletion almost completely removed IL-5 production and gene transcription while CD8 depletion did not. These findings indicated that CD4+ T cells are the principal source of IL-5 in asthmatic PBMCs. The capacity of PBMCs of atopic asthmatics, nonatopic asthmatics and healthy controls to produce IL-2, IL-3, IL-4, interferon-gamma and granulocyte/macrophage-colony-stimulating factor was comparable among the three groups. FK506 suppressed IL-5 production and gene expression in vitro in a dose-dependent manner.

Infliximab, a tumor necrosis factor-alpha antagonist, is used to treat many inflammatory diseases. Various forms of demyelinating neuropathies have been reported as neurological complications associated with infliximab use. There have been few reports of pure sensory neuropathy associated with infliximab. We report the clinical, electrophysiological, and pathological findings of a patient with subacute sensory polyradiculopathy 1 month after infliximab therapy for psoriasis vulgaris. Immune-mediated pathogenesis was suggested by positive anti-ganglioside antibodies and rapid response to intravenous immunoglobulin. This is the first reported case of sensory polyradiculopathy with positive anti-ganglioside antibodies following infliximab therapy. Our findings suggest the clinical importance of immunological investigations and treatment in demyelinating neuropathies following infliximab therapy.

Upon stimulation with phorbol ester and ionomycin, peripheral blood mononuclear cells (PBMC) of atopic patients with moderate eosinophilia produced significantly higher amounts of IL-5 compared to that of normal subjects. This finding renders further support to the notion that T cell-eosinophilic inflammation plays a central role in allergic disorders. IL-5 induction in vitro was completely inhibited by immunosuppressant FK506, cyclosporin A and dexamethasone. FK506 applied in vivo effectively suppressed clinical symptoms of atopic dermatitis and IL-5 production of PBMC. FK506 and cyclosporin A may become a better therapeutic modality against allergic diseases.

The random cell migration of four human melanoma cell lines on laminin and type IV collagen-coated substrates was studied by video time-lapse image analysis and compared to the expression of a number of beta 1 integrins including alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, and alpha 6 beta 1 using flow cytometry. These integrins were heterogeneously expressed in the four cell lines tested with three of four lines expressing alpha 2 beta 1. The melanoma cell line that did not express alpha 2 beta 1 exhibited weak attachment and low cell migration rate on both laminin and type IV collagen, whereas the other melanoma cell lines showed an increase in attachment and mean cell migration rate in a dose-dependent manner on the matrix molecules (p0.001). The enhanced migration seen in the three cell lines could be specifically inhibited by function blocking anti-beta 1 and anti-alpha 2 monoclonal antibodies (p0.001) but not by function blocking anti-alpha 3 and anti-alpha 6 monoclonal antibodies. Image analysis of the cells before and after treatment with anti-beta 1 and anti-alpha 2 MoAb indicated that the inhibition of migration did not result in detectable cell detachment, retraction of cell processes, or other significant cell-shape change. Taken together, the findings suggest that the observable enhanced migration on laminin and type IV collagen of a number of human melanoma cell lines is largely mediated by integrin alpha 2 beta 1.