Region-specific activation in the accumbens nucleus by itch with modified scratch efficacy in mice - a model-free multivariate analysis.

Itch is a protective/defensive function with divalent motivational drives. Itch itself elicits an unpleasant experience, which triggers the urge to scratch, relieving the itchiness. Still, it can also result in dissatisfaction when the scratch is too intense and painful or unsatisfactory due to insufficient scratch effect. Therefore, it is likely that the balance between the unpleasantness/pleasure and satisfaction/unsatisfaction associated with itch sensation and scratching behavior is determined by complex brain mechanisms. The physiological/pathological mechanisms underlying this balance remain largely elusive. To address this issue, we targeted the "reward center" of the brain, the nucleus accumbens (NAc), in which itch-responsive neurons have been found in rodents. We examined how neurons in the NAc are activated or suppressed during histamine-induced scratching behaviors in mice. The mice received an intradermal injection of histamine or saline at the neck, and the scratching number was analyzed by recording the movement of the bilateral hind limbs for about 45 min after injection. To experimentally manipulate the scratch efficacy in these histamine models, we compared histamine's behavioral and neuronal effects between mice with intact and clipped nails on the hind paws. As expected, the clipping of the hind limb nail increased the number of scratches after the histamine injection. In the brains of mice exhibiting scratching behaviors, we analyzed the expression of the c-fos gene (Fos) as a readout of an immediate activation of neurons during itch/scratch and dopamine receptors (Drd1 and Drd2) using multiplex single-molecule fluorescence in situ hybridization (RNAscope) in the NAc and surrounding structures. We performed a model-free analysis of gene expression in geometrically divided NAc subregions without assuming the conventional core-shell divisions. The results indicated that even within the NAc, multiple subregions responded differentially to various itch/scratch conditions. We also found different clusters with neurons showing similar or opposite changes in Fos expression and the correlation between scratch number and Fos expression in different itch/scratch conditions. These regional differences and clusters would provide a basis for the complex role of the NAc and surrounding structures in encoding the outcomes of scratching behavior and itchy sensations.

High prevalence of dermatophytosis of the feet in acral melanoma of the foot.

The clinical characteristics and pathogenesis of acral melanoma of the foot (AMF) have not been sufficiently elucidated. Clinical or subclinical persistent inflammation of the feet is caused by dermatophytosis of the feet (DPF). Persistent inflammation is potentially associated with oncogenesis. Moreover, diabetes has been reported to be associated with the development of dermatophytosis and cancer. The present study aimed to elucidate the clinical association between DPF and AMF, with consideration of diabetes. The medical records of 114 Japanese patients were retrospectively examined and divided into an AMF group (n = 30) and a control group consisting of patients with foot diseases other than melanoma (n = 84). Microscopic DPF screening was performed on all patients who reported symptoms in the foot, with or without AMF. Patients underwent a microscopic test to detect the presence of dermatophytes, and the diagnosis of DPF was made based on a positive result. In the AMF group, 18 (60.0%) and eight (26.7%) patients had DPF and diabetes, respectively. Four patients (13.3%) had both DPF and diabetes. In the control group, 25 (29.8%) and 11 (13.1%) patients had DPF and diabetes, respectively. Five patients (6.0%) had both DPF and diabetes. Univariate analyses showed a significantly higher prevalence of DPF in the AMF group than in the control group (odds ratio, 3.540; p = 0.003, Pearson χ2 test). Furthermore, multivariate analyses of sex, body mass index, DPF, and diabetes revealed DPF as a significant factor associated with AMF (odds ratio, 4.285; p = 0.002, logistic regression analysis). The hyperkeratotic type of DPF was more frequently observed in patients with AMF than in control patients (odds ratio, 11.083; p < 0.001, Pearson χ2 test). In conclusion, the present study found a significantly higher prevalence of DPF, especially its hyperkeratotic type, in patients with AMF. DPF may be associated with AMF pathogenesis.

Real-world Settings for the Surgical Treatment of Neurofibroma in Patients with Neurofibromatosis Type 1.

Introduction: Even though an MEK inhibitor has been recently launched, neurofibroma still negatively affects the well-being of patients with neurofibromatosis type 1 (NF1). The coronavirus disease 2019 (COVID-19) pandemic resulted in restricted access to medical care. The present study was conducted to investigate the real-world settings of patients with NF1 who underwent surgery with or without restricted medical access during the COVID-19 pandemic. Methods: Based on data obtained from medical records, the present study examined 123 and 260 patients who underwent surgery for neurofibromas with and without restricted medical access, respectively. Results: The mean numbers of surgeries performed during the periods with and without restricted medical access were 5.8 and 9.8 per month, respectively, and there were 1.18- and 1.46-fold more female patients than male patients for each group, respectively. Regardless of whether medical access was restricted, the majority of patients who underwent surgery were middle-aged females with multiple or severe neurofibromas and mild extracutaneous symptoms. Tumor burden was the most common reason for surgery. However, cutaneous neurofibromas were more likely to be treated than plexiform neurofibromas under restricted medical access. Conclusions: Patients with NF1, particularly middle-aged females with severe cutaneous manifestations and mild extracutaneous manifestations, still underwent surgery for neurofibromas regardless of whether medical access was restricted.

Bimekizumab treatment in patients with active psoriatic arthritis and prior inadequate response to tumour necrosis factor inhibitors: 52-week safety and efficacy from the phase III BE COMPLETE study and its open-label extension BE VITAL.

OBJECTIVES: To assess 52-week safety and efficacy of bimekizumab in patients with active psoriatic arthritis (PsA) and prior inadequate response/intolerance to tumour necrosis factor inhibitors. METHODS: Patients completing the 16-week phase III double-blind, placebo-controlled BE COMPLETE (NCT03896581) study entered the open-label extension, BE VITAL (NCT04009499). All patients in BE VITAL received 160 mg bimekizumab every 4 weeks. Safety and efficacy are reported to week 52. RESULTS: A total of 347/400 (86.8%) patients completed week 52. To week 52, the exposure-adjusted incidence rate/100 patient-years for ≥1 treatment-emergent adverse event (TEAE) was 126.0, and was 7.0 for serious TEAEs. The most frequent TEAEs were SARS-CoV-2 (COVID-19), oral candidiasis, nasopharyngitis and urinary tract infection. All fungal infections were mild or moderate in severity and localised; two patients discontinued the study due to oral candidiasis. No cases of active tuberculosis, uveitis or inflammatory bowel disease were reported. One sudden death occurred. Sustained efficacy was observed with bimekizumab from week 16 to |52 across clinical and patient-reported outcomes. At week 52, 51.7% bimekizumab-randomised and 40.6% placebo/bimekizumab patients (receiving bimekizumab from week 16 to 52) had ≥50% improvement in the American College of Rheumatology criteria. Complete skin clearance (Psoriasis Area and Severity Index 100) was achieved by 65.9% bimekizumab and 60.2% placebo/bimekizumab patients at week 52. Minimal disease activity was achieved by 47.2% bimekizumab and 33.1% placebo/bimekizumab patients at week 52. CONCLUSIONS: Bimekizumab demonstrated a safety profile consistent with previous reports; no new safety signals were identified. Sustained efficacy was observed from week 16 to 52.

A case of leukemia cutis showing annular erythema during the course of Philadelphia chromosome-positive acute B-lymphoblastic leukemia.

We report a case of leukemia cutis showing annular erythema during the course of Philadelphia chromosome-positive acute B-lymphoblastic leukemia. The annular appearance may be developed by immunomodulatory effects of blinatumomab.

A case of varicella due to primary varicella zoster virus infection followed by respiratory disease on the background of an immunocompromised condition.

We encountered an immunocompromised patient with severe respiratory disease immediately after the onset of varicella. Varicella zoster virus infection may be associated with more severe immunosuppressive condition.

A cross-sectional questionnaire survey involving physicians for the clarification of the diagnosis and current status of therapeutic intervention of psoriatic arthritis in Japan.

Patients with psoriatic arthritis (PsA) often experience comorbid, irreversible joint destruction, therefore early diagnosis and treatment of PsA are important. The diagnosis requires a comprehensive assessment, which includes an interview, a physical examination, a visual examination of the skin and nails, a blood test, and an imaging test. To clarify how patients with PsA are actually diagnosed and how physicians collaborate among clinical departments, we conducted a web-based questionnaire survey of 500 physicians (dermatologists, rheumatologists, and orthopedists) frequently involved in PsA treatment in Japan. The survey showed that those patients are rarely confirmed to have axial arthritis, peripheral arthritis, enthesitis, or dactylitis by general dermatology practitioners (GP dermatologists). Overall, <60% of patients suspected of having PsA underwent PsA examination by GP dermatologists more than once every 6 months; this percentage is lower than that of patients who underwent PsA examination by rheumatologists and orthopedists. The Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire is the most commonly used for PsA screening. However, users of PASE were only 11.0%, 25.3%, 14.8%, and 24.1% of GP dermatologists, attending dermatologists in hospitals (HP dermatologists), rheumatologists, and orthopedists, respectively. While >80% of HP dermatologists, rheumatologists, and orthopedists used imaging tests (ultrasound, X-ray, and magnetic resonance imaging) for PsA screening, only 40% of GP dermatologists performed imaging tests. Regarding the demands on the healthcare environment of PsA treatment, early diagnosis and treatment for PsA are crucial in every clinical department. The present study showed that GP dermatologists rarely perform imaging tests or confirm a PsA diagnosis, thus patients may miss out on appropriate treatment through collaboration among clinical departments and step-up therapy. Because patients with PsA present diverse comorbid clinical symptoms, early diagnosis, including routine imaging tests, and appropriate treatment in collaboration with other experts are necessary.

Characteristics of mild and severe apalutamide-related cutaneous adverse events in patients with prostate cancer: A review of the literature.

Apalutamide is an antiandrogen used to treat prostate cancer. Although it sometimes induces mild cutaneous adverse events and occasionally severe ones, clinical differences between severe and mild cases remain unclear. To assess the risks in patients experiencing apalutamide-related cutaneous adverse events (ARCAEs), we aimed to characterize severe and mild ARCAEs in terms of onset time and lymphocyte transformation test (LTT) for apalutamide. We reviewed 41 ARCAE cases: 24 from our institute and 17 from the literature, comprising (i) eight severe cases including six with toxic epidermal necrolysis, one with acute generalized exanthematous pustulosis, and one with drug reaction with eosinophilia and systemic symptoms, and (ii) 33 mild cases. Patients with evere cases developed ARCAEs significantly earlier than patients with mild cases (5.2 vs 9.6 weeks). No severe cases appeared ≥8 weeks after initiation of apalutamide. LTTs showed positive results in two of seven mild cases (28.6%) and four of four severe cases (100.0%). In conclusion, we found that severe ARCAEs are characterized by earlier onset and LTT positivity. Dermatologists and urologists should pay special attention to patients who develop ARCAEs <8 weeks after initiating apalutamide and/or show positive LTT results.

Real-world Evidence for the Treatment of Rosacea with Sulfur or Metronidazole Preparation in Japanese Patients.

Introduction: There remains to be lacking real-world evidence for the treatment of rosacea with a topical sulfur preparation (TSP) or topical metronidazole preparation (TMP) among Japanese patients. Therefore, in this study, we examined the effects of TSP and TMP on rosacea in Japanese patients in real-world clinical settings. Methods: This retrospective observational analysis reviewed the medical records of 47 Japanese patients who were treated with TSP or TMP for more than 8 weeks in our clinic. Disease severity was evaluated using the Investigator Global Assessment (IGA) and the visual analog scale (VAS) for itching, burning sensation, flushing, and hypersensitivity before and 8 weeks after the initiation of the intervention. Results: In total, 10 erythematotelangiectatic rosacea (ETR) and 12 papulopustular rosacea (PPR) patients treated with TSP and 12 ETR and 13 PPR patients treated with TMP were analyzed. IGA and VAS scores for itching, burning sensation, flushing, and hypersensitivity were noted to significantly improve in the ETR and PPR patient groups treated with TSP and both groups treated with TMP, except for the VAS score for itching in the TSP-treated ETR group. No significant differences were observed in terms of the improvement rates of IGA, VAS scores, or the prevalence of adverse events between the TSP- and TMP-treated groups. Conclusions: As per our findings, TSP and TMP have similarly favorable effects on both ETR and PPR in Japanese patients in real-world settings.

Monitoring Sleep and Scratch Improves Quality of Life in Patients with Atopic Dermatitis.

Atopic dermatitis itch may cause sleep disturbance and impair quality of life. For patients finding topical therapy difficult to continue, it is important to control itch and reduce scratching. This study developed algorithms to measure nocturnal sleep and scratch, using an actigraph device worn on the back of the hand, and assessed smartphone application feedback to improve adherence with therapy. In the first trial, actigraph measurements in 5 participants who wore the device were highly correlated with measurements by a sleep-monitoring device beneath the mattress. Total actigraph-measured scratching duration for each hour of sleep was highly correlated with measurements by a person rating infrared video-recording of the sleepers. In the second trial, 40 patients with atopic dermatitis were randomly allocated into an intervention group that used the actigraph and smartphone application, and a control group that did not. Both groups were instructed to use the same moisturizer. Dermatology Life Quality Index scores decreased significantly from baseline and were lower than those in the control group at week 8. It is suggested that the device and associated smartphone application reinforced therapy adherence, moisturizer use, and contributed to improved quality of life in patients with atopic dermatitis.

Bimekizumab treatment in biologic DMARD-naïve patients with active psoriatic arthritis: 52-week efficacy and safety results from the phase III, randomised, placebo-controlled, active reference BE OPTIMAL study.

OBJECTIVES: Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. BKZ treatment has demonstrated superior efficacy versus placebo (PBO) at Week 16 in biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with active psoriatic arthritis (PsA). Here, we report long-term efficacy and safety to Week 52. METHODS: BE OPTIMAL comprised a 16-week, double-blind, PBO-controlled period, then 36 weeks treatment-blind. Patients were randomised 3:2:1 to subcutaneous BKZ 160 mg every 4 weeks, PBO with switch to BKZ at Week 16, or reference arm (adalimumab (ADA) 40 mg every 2 weeks). Efficacy outcomes included the American College of Rheumatology (ACR) response criteria 20/50/70, Psoriasis Area and Severity Index (PASI) 75/90/100 in patients with baseline psoriasis affecting ≥3% body surface area and minimal disease activity (MDA); non-responder imputation. RESULTS: ACR20/50/70, PASI75/90/100 and MDA responses were sustained with BKZ to Week 52, consistent with results observed at Week 16. Patients who switched to BKZ at Week 16 demonstrated improvements in efficacy with similar results to BKZ-randomised patients by Week 52.To Week 52, 555/702 (79.1%) patients had ≥1 treatment-emergent adverse event (TEAE) during BKZ treatment; 113/140 (80.7%) on ADA. On BKZ, 46 (6.6%) patients had serious TEAEs. 54 (7.7%) Candida infections occurred during BKZ treatment and 1 (0.7%) during ADA; all cases were localised and non-serious. One death occurred in a BKZ-treated patient, unrelated to treatment. CONCLUSIONS: The efficacy of BKZ in bDMARD-naïve patients with PsA was sustained from Week 16 to Week 52. BKZ was well tolerated with no new safety signals observed. TRIAL REGISTRATION NUMBER: NCT03895203.

English version of Japanese guidance for the use of oral Janus kinase inhibitors (JAK1 and TYK2 inhibitors) in the treatments of psoriasis.

This is the English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors (JAK1 and tyrosine kinase 2 [TYK2] inhibitors) in the treatments of psoriasis. Several cytokines, such as interleukin (IL)-6, IL-7, IL-12, IL-21, IL-22, IL-23, interferon (IFN)-α, and IFN-γ, are involved in the pathogenesis of psoriasis (including psoriatic arthritis). As oral JAK inhibitors hinder the JAK-signal transducers and activators of transcription signal transduction routes involved in the signal transduction of these cytokines, they may be effective for the treatment of psoriasis. JAK has four types: JAK1, JAK2, JAK3, and TYK2. Regarding the use of oral JAK inhibitors for the treatment of psoriasis in Japan, indications of the JAK1 inhibitor upadacitinib were extended also to psoriatic arthritis in 2021, and the use of the TYK2 inhibitor deucravacitinib for plaque-type psoriasis, pustular psoriasis, and erythrodermic psoriasis became covered by health insurance in 2022. This guidance was developed for board-certified dermatologists who specialize in the treatment of psoriasis and to promote the proper use of oral JAK inhibitors. In the package inserts and guides for appropriate use, upadacitinib and deucravacitinib are classified as a "JAK inhibitor" and a "TYK2 inhibitor", respectively, and it is possible that there may be differences in safety between the two drugs. The safety of these drugs will be evaluated for the future by the postmarketing surveillance for molecularly targeted drugs for psoriasis of the Japanese Dermatological Association.

A case of systemic amyloidosis showing papular/nodular lesions due to Waldenström's macroglobulinemia.

This case report provides evidence that Waldenström's macroglobulinemia may cause cutaneous manifestations represented as papules/nodules through the development of light chain amyloidosis. Here, we report a case of a 67-year-old man.

Bimekizumab Efficacy and Safety in Japanese Patients with Plaque Psoriasis in BE VIVID: A Phase 3, Ustekinumab and Placebo-Controlled Study.

INTRODUCTION: Bimekizumab treatment resulted in improved clinical outcomes in patients with moderate-to-severe plaque psoriasis in BE VIVID, a 52-week, phase 3, randomized, ustekinumab and placebo-controlled study. We present data from the BE VIVID Japan patient subpopulation. METHODS: Globally, patients were randomized to receive bimekizumab 320 mg every 4 weeks (Q4W), ustekinumab (45/90 mg weight-based at baseline and week 4, then every 12 weeks), or placebo (Q4W through week 16, then bimekizumab 320 mg Q4W). Efficacy endpoints included week 16 Psoriasis Area and Severity Index (PASI) 90 and Investigator's Global Assessment (IGA) 0/1, and other outcomes [PASI 100, PASI 75, IGA 0, Dermatology Life Quality Index (DLQI) 0/1, absolute PASI, scalp IGA, Psoriasis Symptoms and Impacts Measure (P-SIM) responses]. Safety analyses were conducted. RESULTS: There were 108 Japanese randomized patients (bimekizumab: 62; ustekinumab: 29; placebo: 17). At week 16, bimekizumab-treated patients had a higher clinical response versus ustekinumab and placebo (PASI 90: 85.5% versus 51.7% and 5.9%; IGA 0/1: 82.3% versus 48.3% and 0.0%). Over 52 weeks, improved clinical response was maintained with bimekizumab, including patients switching from placebo at week 16. Overall, the safety profile in Japanese patients was consistent with that observed in the global population. CONCLUSION: Bimekizumab resulted in improved clinical response versus ustekinumab and placebo, and was well-tolerated in Japanese patients. TRIAL REGISTRATION: NCT03370133.

Effect of bimekizumab on symptoms and impact of disease in patients with psoriatic arthritis over 3 years: results from BE ACTIVE.

OBJECTIVES: Evaluate effects of long-term bimekizumab treatment on patient-reported outcome (PRO) measures, symptoms and the impact of PsA on patients. METHODS: Patients with active PsA were enrolled into BE ACTIVE, a 48-week randomised controlled trial (NCT02969525). After Week 48, patients could enter a 104-week open-label extension (NCT03347110), receiving bimekizumab 160 mg every four weeks. PRO measures assessed included arthritis pain visual analogue scale (VAS), PsA Impact of Disease (PsAID)-9, 36-Item Short Form Survey (SF-36) and HAQ-Disability Index (HAQ-DI). Results were analysed as mean (S.E.M.) changes from baseline (CfB) from Week 0 to the end of the open-label extension (3 years) and as percentage of patients reaching patient-acceptable symptom state (PASS) for global impact (PsAID-9 total score ≤4) and normal function (HAQ-DI total score <0.5). Non-responder imputation was applied to missing binary outcomes. RESULTS: In 206 patients (mean age 49.3 years, 51.0% male), completion rate was high; 161 (78.2%) patients completed Week 152. Bimekizumab treatment was associated with long-term sustained improvements in pain [arthritis pain VAS CfB; Week 48: -29.9 (1.9); Week 152: -32.0 (1.9)] and fatigue [PsAID-9 fatigue CfB; -2.4 (0.2); -2.7 (0.2)]. High percentages of patients achieved acceptable symptom state (PsAID-9 PASS: 75.2%; 65.0%) and normalised function (HAQ-DI <0.5: 49.0%; 46.1%). Improvements in patient global assessment and SF-36 Physical Component Summary were also sustained. CONCLUSIONS: Bimekizumab treatment was associated with long-term sustained improvements in pain and fatigue, reducing overall impact of PsA on patients. Physical function and quality of life improved up to 3 years. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02969525, NCT03347110.

Bimekizumab in patients with psoriatic arthritis, naive to biologic treatment: a randomised, double-blind, placebo-controlled, phase 3 trial (BE OPTIMAL).

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17A and IL-17F. We assessed the efficacy and safety of bimekizumab in patients with active psoriatic arthritis who were naive to biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: BE OPTIMAL was a 52-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, active reference (adalimumab) trial done at 135 sites (hospitals, clinics, doctors' offices, and research centres) in 14 countries. Eligible patients were 18 years or older with a documented diagnosis of adult-onset psoriatic arthritis that met the Classification Criteria for Psoriatic Arthritis for at least 6 months before screening. Participants were randomly assigned with an interactive-voice and web-response system on the basis of a predetermined randomisation schedule (3:2:1, stratified by region and bone erosion number at baseline) to bimekizumab 160 mg every 4 weeks, placebo every 2 weeks, or the reference group (adalimumab 40 mg every 2 weeks), all administered subcutaneously. At week 16, patients randomly assigned to placebo switched to bimekizumab 160 mg every 4 weeks. The primary endpoint was the proportion of patients reaching 50% or greater improvement in American College of Rheumatology criteria (ACR50) at week 16 (non-responder imputation). Efficacy analyses included all patients who were randomly assigned (intention-to-treat population); the safety analysis set comprised patients who received one or more doses of treatment. Data are presented to week 24 (preplanned analysis). This trial is registered at ClinicalTrials.gov, NCT03895203. FINDINGS: Between April 3, 2019, and Oct 25, 2021, 1163 patients were screened and 852 were randomly assigned to bimekizumab (n=431), placebo (n=281), and reference (adalimumab; n=140) groups. At week 16, significantly more patients receiving bimekizumab (189 [44%] of 431) reached ACR50 response versus placebo (28 [10%] of 281; odds ratio 7·1 [95% CI 4·6-10·9], p<0·0001; adalimumab 64 [46%] of 140). All secondary hierarchical endpoints were met. Treatment-emergent adverse events up to week 16 were reported in 258 [60%] of 431 patients receiving bimekizumab, 139 [49%] of 281 patients receiving placebo, and 83 [59%] of 140 patients receiving adalimumab. No deaths occurred. INTERPRETATION: Bimekizumab treatment had superior improvements in joint, skin, and radiographic efficacy outcomes at week 16 compared with placebo in patients with psoriatic arthritis who were naive to biologic DMARDs. The safety profile of bimekizumab, including the occurrence of fungal infections, was consistent with previous phase 3 studies in patients with plaque psoriasis, and with IL-17A inhibitors. FUNDING: UCB Pharma.