Three cases of subcorneal pustular dermatosis with immunohistochemical examinations.

Subcorneal pustular dermatosis, a rare, benign skin disease, is a type of neutrophilic dermatosis. The authors reported three cases of subcorneal pustular dermatosis. In case 1, a 9-year-old girl developed a skin rash with blisters following a mycoplasma infection and had a flare-up due to a common cold. She was successfully treated with a topical corticosteroid. In case 2, a 70-year-old woman who had been treated for rheumatoid arthritis with adalimumab, salazosulfapyridine, and leflunomide developed 3- to 5-mm pustules on her trunk and thighs 4 days after flu vaccination. The rash disappeared with drug withdrawal and treatment with diaminodiphenyl sulfone. In case 3, an 81-year-old man, who was diagnosed with pyoderma gangrenosum at 61 years old, developed multiple small flaccid pustules on his trunk and extremities due to an infection in the arteriovenous shunt area on the forearm. The pustule disappeared with intravenous antibiotic therapy; however, the pustules subsequently flared up along with ulcers typical of pyoderma gangrenosum. He was given oral prednisolone therapy, which was effective for the small pustules and some ulcers. Immunohistochemical examination of the three cases revealed neutrophilic infiltration in the subcorneal layer of the epidermis. The pustules contained neutrophils as well as some CD68+ and a few CD1a+ cells. The epidermis and dermis were more predominantly infiltrated by CD4+ cells than by CD8+ cells. Positive stainings for interleukin 8, interleukin 36γ, and phospho-extracellular signal-regulated kinases 1 and 2 were observed in the upper layers of the epidermis below the pustules. Although the pathogenesis of subcorneal pustular dermatosis has not been clarified, the current results suggest that a variety of inflammatory cells, including those responsible for both innate and acquired immunity, are involved in the accumulation of neutrophils in subcorneal pustular dermatosis.

Single-center survey of incidental imaging findings on computed tomography in patients with psoriasis on biologic therapy.

Psoriasis is an immune-mediated chronic inflammatory disease that predominantly affects the skin and joints. Systemic therapies are required for patients with moderate-to-severe psoriasis, and biologics can provide significant symptomatic improvement. Computed tomography (CT) analysis is recommended before and after biologic therapy to exclude the possibility of comorbid infections and malignancies; incidental findings are often detected in asymptomatic patients. In this study, we analyzed the common incidental findings on CT in 227 patients with psoriasis on biologic therapy and 219 living-kidney transplant donors at our hospital. Incidental findings on CT were observed in 176 (77.5%) patients with psoriasis. The most common were fatty liver (82 patients, 36.1%), urolithiasis (54 patients, 23.8%), pulmonary lesions (47 patients, 20.7%), gallstones or postoperative gallstones (38 patients, 16.7%), liver cysts (36 patients, 15.9%), renal cysts (33 patients, 14.5%), and colonic diverticulum (22 patients, 9.7%), which were observed in 38 (17.4%), eight (3.7%), 68 (31.1%), 12 (5.5%), 58 (26.5%), 88 (40.2%), and 10 (4.6%) donors, respectively. The prevalence of fatty liver, urolithiasis, gallstones, and postoperative gallstones was significantly higher in patients with psoriasis. Multivariate logistic regression showed that psoriasis was a risk factor for fatty liver disease, urolithiasis, and gallstones. Currently, incidental findings on CT in patients with psoriasis have not been well studied. The results of this survey will lead to increased awareness of the incidental findings on CT as a complication of psoriasis.

Drug Survival of Tumor Necrosis Factor-Alpha Inhibitors and Switched Subsequent Biologic Agents in Patients with Psoriasis: A Retrospective Study.

INTRODUCTION: This study aimed to retrospectively examine the drug survival of tumor necrosis factor (TNF)-alpha inhibitors and switched subsequent biologic agents after discontinuation of TNF inhibitors. METHODS: This real-world setting study was conducted at a single academic center. We included patients who were treated with adalimumab (n = 111), certolizumab pegol (n = 12), and infliximab (n = 74) at Jichi Medical University Hospital from 1 January 2010 to 31 July 2021. RESULTS: No significant differences were noted in drug survival between the three TNF inhibitors. The 10-year drug survival rate for adalimumab and infliximab was 14% and 18%, respectively. Of the patients who discontinued TNF inhibitors for any reason (n = 137), 105 chose biologics as their subsequent treatment. The subsequent biologics included 31 cases of TNF inhibitors (adalimumab in 20, certolizumab pegol in 1, and infliximab in 10), 19 of interleukin-12/23 inhibitor (ustekinumab), 42 of interleukin-17 inhibitors (secukinumab in 19, brodalumab in 9, and ixekizumab in 14) and 13 of interleukin-23 inhibitors (guselkumab in 11, risankizumab in 1, and tildrakizumab in 1). Cox proportional hazards analysis for the subsequent drugs in cases of discontinuation due to inadequate efficacy revealed that female sex was a predictor of drug discontinuation (hazard ratio 2.58, 95% confidence interval 1.17-5.70) and that taking interleukin-17 inhibitors rather than TNF inhibitors was a predictor of drug persistence (hazard ratio 0.37, 95% confidence interval 0.15-0.93). CONCLUSIONS: Interleukin-17 inhibitors may be a favorable option for patients who need to switch from TNF inhibitors due to inadequate efficacy. However, this study is limited by the small number of cases and its retrospective design.

With many biologic options available for the treatment of psoriasis, choosing the optimal drug can be challenging, especially when switching drugs. Tumor necrosis factor (TNF) inhibitors are the oldest category of biologics used for psoriasis, with adalimumab and infliximab being available since 2010 and certolizumab pegol since 2019 in Japan. In this study, we examined the drug survival of TNF inhibitors in patients treated with adalimumab (n = 111), certolizumab pegol (n = 12), and infliximab (n = 74) at Jichi Medical University Hospital from 1 January 2010 to 31 July 2021. No significant differences were noted in drug survival between the three TNF inhibitors, and the 10-year drug survival rate for adalimumab and infliximab was 14% and 18%, respectively. We examined the drug survival of subsequent biologics used by patients who discontinued TNF inhibitors for any reason (n = 137) and found that among patients who discontinued TNF inhibitors due to inadequate efficacy, female sex was a predictor of drug discontinuation and that taking interleukin-17 inhibitors rather than TNF inhibitors was a predictor of drug continuation. The study results suggest that interleukin-17 inhibitors is a favorable option for patients who discontinue TNF inhibitors due to inadequate efficacy and need to switch to other agents. However, this study has limitations, including the small number of cases and the single-center and retrospective study design.

Four-year drug survival of apremilast in patients with psoriasis.

This real-world study at a single academic center retrospectively examined the drug survival of apremilast for patients with psoriasis. Retrospective information was extracted from the medical records of patients with psoriasis treated with apremilast at the Department of Dermatology, Jichi Medical University Hospital, between March 1, 2017, and June 31, 2021. In total, 281 patients were included in this study. Of these patients, 22% had psoriatic arthritis and 57% had a history of prior systemic treatment, including biologics, before the initiation of apremilast. The 1-, 2-, 3-, and 4-year drug survival rates were 54%, 41%, 32%, and 30%, respectively. Cox regression analysis revealed that sex, duration of plaque psoriasis (<10 years vs ≥10 years), presence of psoriatic arthritis, involvement of scalp lesions, involvement of palmoplantar lesion, involvement of nail lesions, having cardiometabolic comorbidities, and a history of prior systemic treatment did not have any significant impact on drug survival. The most common reason for apremilast discontinuation was inadequate efficacy (27%), followed by adverse events (12%). Approximately 49% of the patients experienced one or more adverse events. Diarrhea was the most common adverse event (24%), followed by nausea (19%) and headache (11%).

STAT3 Activation in Psoriasis and Cancers.

Activation of signal transducer and activator of transcription (STAT)3 has been reported in many cancers. It is also well known that STAT3 is activated in skin lesions of psoriasis, a chronic skin disease. In this study, to ascertain whether patients with psoriasis have a predisposition to STAT3 activation, we examined phosphorylated STAT3 in cancer cells of psoriasis patients via immunohistochemistry. We selected patients with psoriasis who visited the Department of Dermatology, Jichi Medical University Hospital, from January 2000 to May 2015, and had a history of cancer. We performed immunostaining for phosphorylated STAT3 in tumor cells of five, four, and six cases of gastric, lung, and head and neck cancer, respectively. The results showed that there was no significant difference in STAT3 activation in any of the three cancer types between the psoriasis and control groups. Although this study presents limitations in its sample size and inconsistency in the histology and differentiation of the cancers, results suggest that psoriasis patients do not have a predisposition to STAT3 activation. Instead, STAT3 activation is intricately regulated by each disorder or cellular microenvironment in both cancer and psoriasis.

Single-center survey of biologic use for inflammatory skin diseases during the coronavirus disease 2019 pandemic.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ongoing COVID-19 pandemic has affected both daily life and medical care; therefore, the aim of this study was to analyze the use of biologics for inflammatory skin diseases during the COVID-19 pandemic in our hospital. The observation period was between 1 January 2020 and 23 February 2021. In this study, we enrolled 227 patients with psoriasis, six patients with palmoplantar pustulosis (PPP), 69 patients with atopic dermatitis (AD), and five patients with hidradenitis suppurativa (HS). Bioswitch was performed in 25 patients with psoriasis (11.0%). Biologics were discontinued in 14 patients with psoriasis (6.2%), 10 patients with AD (14.5%), and four patients with HS (80.0%); they were not discontinued in patients with PPP. The introduction of biologics was observed in 27 patients with psoriasis (11.9%), four patients with PPP (66.7%), 33 patients with AD (47.8%), and two patients with HS (40.0%). The use of telephone consultations was observed in four patients with psoriasis and two patients with AD. One patient, who received adalimumab for the treatment of psoriatic arthritis, suffered from COVID-19 and recovered after a mild course. In conclusion, we report our experience regarding the use of biologic drugs for inflammatory skin diseases. The use of biologics seemed safe for use amidst COVID-19 infection during the observation period; however, further observation on a larger number of patients is required to confirm the risks and benefits of biologic use in the COVID-19 era.

Which symptoms negatively affect the oral health-related quality of life in patients with osteonecrosis of the jaw?

OBJECTIVES: One of the treatment goals for osteonecrotic lesions of the jaw, such as medication-related osteonecrosis of the jaw (MRONJ) or osteoradionecrosis (ORN), is restoration of quality of life (QOL). This study aimed to identify symptoms that negatively affect QOL in patients with unhealed MRONJ or ORN. STUDY DESIGN: This cross-sectional study included patients who were previously diagnosed with MRONJ or ORN and who underwent treatment at the Kobe University Hospital between June 2015 and February 2016. Patient QOL was measured by using the Oral Health Impact Profile (OHIP-14). The predictor variable was disease status (stage and healing). The outcome variable was OHIP-14. One-way analysis of variance and Tukey's test were performed. RESULTS: The study included 74 patients (37 men and 37 women; mean age 70 years). Although there was no significant difference between the OHIP-14 scores of unhealed MRONJ and ORN (stages 1-3) and those of healed ones, the "worsened sense of taste" resulted in significant differences among stages in patients with unhealed MRONJ (P = .027) and the "painful mouth aching" in patients with unhealed ORN (P = .041). CONCLUSIONS: Worsened sense of taste and pain negatively affected QOL in patients with unhealed MRONJ and ORN.

Remote neuropsychological assessment of elderly Japanese population using the Alzheimer's Disease Assessment Scale: A validation study.

INTRODUCTION: Studies have demonstrated the high agreement of several remote neuropsychological tests using video teleconferencing (VTC) with face-to-face (FTF) tests. However, the reliability of the remotely administered Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog), one of the most commonly used neuropsychological tests to detect cognitive decline, has not been substantially elucidated, particularly in Japanese populations. Therefore, this study aimed to evaluate the reliability of the remotely administered ADAS-cog compared with FTF-administered ADAS-cog among elderly Japanese participants. METHODS: Participants aged ≥60 years with and without cognitive impairment, i.e. those with mild cognitive impairment (MCI), those with dementia and healthy controls (HCs), were assessed with the ADAS-cog using VTC and FTF testing at an interval of >2 weeks and <3 months. The assessment order (VTC or FTF) was randomized by participants. Participants' scores were compared among the entire sample, as well as subgroups, using intra-class correlation coefficients (ICCs) in a mixed-effects model. RESULTS: A total of 73 participants were included in the study (36 men; age, 76.3 ± 7.6 years). The ICC for the ADAS-cog total score was high in the entire sample (0.86), whereas ICCs were moderate to high for the subgroups (MCI: 0.63, dementia: 0.80 and HC: 0.74). DISCUSSION: The results indicate that a VTC-administered ADAS-cog could be an alternative for an FTF-administered ADAS-cog, although further replication studies with larger sample sizes and a wider range of cognitive functionalities are warranted.

A Validation Study of the Remotely Administered Montreal Cognitive Assessment Tool in the Elderly Japanese Population.

Background: In an aging society, neuropsychological testing using video teleconferencing (VTC) is increasingly important. Despite the potential benefit of a VTC-administered Montreal Cognitive Assessment Tool (MoCA) to detect cognitive decline, only a limited number of studies have investigated this tool's reliability. Therefore, we aimed to evaluate the reliability of VTC-administered MoCA compared with face-to-face (FTF)-administered MoCA among elderly Japanese participants. Moreover, we examined participants' satisfaction with VTC-administered MoCA. Methods: Participants ≥60 years of age with and without cognitive impairment (i.e., those with mild cognitive impairment [MCI], those with dementia, and healthy controls [HC]) were assessed with VTC- and FTF-administered MoCA at an interval of >2 weeks and <3 months. The order effect (VTC first vs. FTF first) and time effect (first vs. second testing session), as well as several covariates such as age and years of education were controlled. Intraclass correlation coefficients (ICCs) were calculated using a mixed-effects model to assess the agreement between the two (VTC- vs. FTF-administered) groups. Participants' satisfaction with VTC-administered MoCA was examined using a Likert scale asking seven questions. Results: We included 73 participants in the study (36 men; age, 76.3 ± 7.5 years). The ICC for the MoCA total score was high in the entire sample (0.85), whereas ICCs were moderate to high for the subgroups (MCI: 0.82, dementia: 0.82, and HC: 0.53). Furthermore, we found good overall participant satisfaction with VTC-administered MoCA. Discussion: VTC-administered MoCA appears viable as an alternative to FTF-administered MoCA, although further replication studies with larger sample sizes are needed.

Drug survival of biologic agents for psoriatic patients in a real-world setting in Japan.

This is a Japanese retrospective single-center study carried out between 1 January 2010 and 21 November 2018 at the Department of Dermatology in Jichi Medical University Hospital. The drug survival rate for six biologic agents used for the treatment of psoriasis was investigated. We reviewed the clinical records of 315 treatment series of 205 patients with moderate to severe psoriasis treated with adalimumab (103 cases), infliximab (70 cases), ustekinumab (66 cases), secukinumab (38 cases), brodalumab (12 cases) and ixekizumab (26 cases). In our study, ustekinumab revealed a trend towards higher drug survival among the six biologic agents. Ustekinumab had a higher drug survival rate than infliximab and secukinumab with significant differences by log-rank test among all patients and among biologic-naive (bio-naive) patients. There was no significant difference in drug survival between bio-naive and biologic-experienced (non-naive) patients in the treatment courses with adalimumab, infliximab, ustekinumab, secukinumab and ixekizumab. The dose augmentation therapy in infliximab-treated patients was associated with longer drug survival. Of all patients, 25 cases with generalized pustular psoriasis (GPP) were included, who functioned as the negative predictor for drug persistence with a hazard ratio of 1.87 (95% confidence interval, 1.12-3.11; P = 0.016). Our results reveal that ustekinumab had a superior drug survival, which is supported by the previous studies. Further studies are needed to clarify the efficacy of biologic agents on patients with GPP.

Risk Factors for the Development of Psoriasis.

Psoriasis is an immune-mediated genetic skin disease. The underlying pathomechanisms involve complex interaction between the innate and adaptive immune system. T cells interact with dendritic cells, macrophages, and keratinocytes, which can be mediated by their secreted cytokines. In the past decade, biologics targeting tumor necrosis factor-α, interleukin (IL)-23, and IL-17 have been developed and approved for the treatment of psoriasis. These biologics have dramatically changed the treatment and management of psoriasis. In contrast, various triggering factors can elicit the disease in genetically predisposed individuals. Recent studies suggest that the exacerbation of psoriasis can lead to systemic inflammation and cardiovascular comorbidity. In addition, psoriasis may be associated with other auto-inflammatory and auto-immune diseases. In this review, we summarize the risk factors, which can be divided into two groups (namely, extrinsic and intrinsic risk factors), responsible for the onset and exacerbation of psoriasis in order to facilitate its prevention.

Drug survival of apremilast in a real-world setting.

Apremilast is a novel oral phosphodiesterase-4 inhibitor approved for treatment of plaque psoriasis and psoriatic arthritis in Japan in December 2016. We have treated a substantial number of patients with psoriasis with apremilast and investigated the length of the treatment period with apremilast (drug survival of apremilast) in 138 patients with psoriasis who were treated at the Department of Dermatology in Jichi Medical University Hospital from 1 March 2017 to 31 August 2018 using the Kaplan-Meier survival curve. The drug survival rate of apremilast at 1 year was 53.4%. The median length of the drug survival period was 453 days. There were no statistical differences in the drug survival rate in terms of the type of psoriasis, previous systemic treatment or presence of one or more adverse events. Drug efficacy was investigated in 115 patients who were followed for more than 16 weeks. There was no correlation between drug efficacy and sex, previous systemic treatment or presence of one or more adverse events; however, there was a correlation between drug efficacy and plaque size (P < 0.01, rs = -0.29). The result of our study indicates that apremilast is effective regardless of the history of prior systemic treatment, and it supports our previous finding that small plaque-type psoriasis is more sensitive to treatment with apremilast.

Results of a retrospective study on the efficacy and safety of adalimumab 80 mg administrated every other week in patients with psoriasis at a single Japanese institution.

Adalimumab (ADA) is one of the tumor necrosis factor (TNF)-α monoclonal antibodies used for the treatment of psoriasis. In Japan, standard dosing of ADA for adults is an initial s.c. injection of 80 mg, followed by 40 mg every other week. Some patients who initially do not respond to treatment are allowed an increased dose of 80 mg every other week. However, studies on the efficacy and safety of ADA dose escalation to 80 mg every other week are few. In this study, we retrospectively studied 92 patients with psoriasis who received ADA therapy in our hospital. In 45 out of 92 patients, the dose of ADA 80 mg was administrated every other week, and the efficacy was observed within 12 weeks. The most common adverse drug reaction was upper respiratory infection, followed by diarrhea. In three patients, malignancies occurred during the observation period. No deaths or other severe complications were observed. In conclusion, this study showed the efficacy and safety of ADA dose escalation to 80 mg every other week in patients with psoriasis.

Real-world use of apremilast for patients with psoriasis in Japan.

Apremilast is a novel oral phosphodiesterase 4 inhibitor effective for psoriasis. It regulates the production of pro-inflammatory mediators. Apremilast was approved in December 2016 in Japan; however, its efficacy and safety in a real-world setting among Japanese patients have not been reported. We report on 44 patients treated with apremilast between March and October 2017. The median treatment duration was 25 weeks (range, 2-33). Thirty-five patients (79.5%) continued the drug for at least 23 weeks, and five (11.4%) achieved a Psoriasis Area and Severity Index 100 response within 12 weeks. Nine patients discontinued the drug within 24 weeks mainly due to insufficient efficacy (n = 3) and adverse events (n = 4). Seven patients continued their previous systemic therapies such as cyclosporin (n = 1), methotrexate (n = 1), etretinate + methotrexate (n = 1) and biologics (n = 4) combined with apremilast. Of these patients, 55.9% had at least one adverse event although no severe adverse events. The most common adverse event was diarrhea (31.8%), followed by nausea (25.0%), headache (13.6%), abdominal discomfort (6.8%) and vomiting (6.8%). The proportion of diarrhea in our patients was higher than those of previous clinical trials. Among 10 patients with psoriatic arthritis, apremilast did not improve joint pain in nine (90%). To investigate the relationship between treatment efficacy and plaque size, we defined a small plaque as an individual rash diameter of 1 inch or less. The efficacy of apremilast was greater in patients with small plaques than in patients with large plaques.

Maxillary Swing Approach for Removal of Palatal Carcinoma: A Modified Procedure.

INTRODUCTION: We report a modification of the maxillary swing approach to remove a palatal tumor while preserving the anterior alveolar area. METHODS: Case report using clinical records. RESULTS: The patient was a 54-year-old male. TNM grade was T4bN0M0, and invasion to the base of the pterygoid process was seen. Two courses of induction chemotherapy were administered prior to the operation. Because there was no evidence of anterior maxillary invasion, the maxillary swing approach was chosen. The left anterior maxilla was cut and swung laterally, preserving the blood supply. After removal of the palatal tumor, the maxilla was repositioned and the defect was restored with an anterior lateral thigh flap. Postoperative course was typical, and facial appearance, speech, and masticatory function were satisfactory. CONCLUSIONS: This technique is particularly useful for preserving appearance as well as speech and mastication.

Delayed Socket Healing After Dental Extraction in Patients Undergoing Myelosuppressive Chemotherapy for Hematological Malignancy: Incidence and Risk Factors.

PURPOSE: The purpose of this study was to measure the frequency and identify factors associated with delayed socket healing after dental extraction in patients undergoing myelosuppressive chemotherapy for hematologic malignancy. MATERIALS AND METHODS: This prospective cohort study focused on delayed healing after extraction in patients with hematologic malignancy. Sockets with delayed healing were defined as those with intense pain and bone exposure 1 week postoperatively. Patients with and without delayed socket healing were compared using the Fisher exact test and Mann-Whitney U test with some variables. Receiver operating characteristics curve analysis was conducted to define cutoff values for delayed healing. RESULTS: One hundred ninety-four dental extractions in 93 patients (median age, 64 yr; range, 20 to 85 yr) were analyzed. The incidence of delayed socket healing was 7.5% (7 of 93 patients). There was no postoperative bleeding. Older age, type of hematologic malignancy (acute leukemia), shorter time from dental extraction to initiation of chemotherapy, low platelet count or hemoglobin level, requirement for red blood cell concentrate or platelet transfusion, and use of an absorbable hemostatic agent were statistically associated with the occurrence of delayed socket healing. Platelet and hemoglobin cutoffs were 4.6 × 104/µL and 7.7 g/dL, respectively. CONCLUSIONS: Although dental extraction can be safely performed in patients undergoing myelosuppressive chemotherapy for hematologic malignancy, oral surgeons should understand the potential risk for delayed socket healing. When considering dental extraction, patients with hematologic malignancy and low hemoglobin or platelet levels should be informed about the possibility of delayed socket healing.

Ionizing Radiation Enhances Paracellular Permeability Through Alteration of Intercellular Junctions in Cultured Human Lymphatic Endothelial Cells.

BACKGROUND: A problematic complication after radiation therapy is lymphedema. Development of lymphedema is associated with an increase in lymphatic paracellular permeability. The current study investigated the effects of radiation on intercellular junctions and paracellular permeability in cultured human dermal lymphatic endothelial cells (HDLECs). METHODS AND RESULTS: Double immunofluorescence staining with vascular endothelial (VE)-cadherin and actin immediately after X-ray irradiation (5 or 20 Gy) was performed. Morphological changes induced by irradiation were assessed. Cell viability and paracellular permeability after irradiation were also evaluated. Broad junctions in which VE-cadherin was accumulated at cell-cell contacts and almost colocalized with actin were significantly decreased in a dose-dependent manner in confluent and sparse irradiated HDLECs. Irradiation shortened the width of VE-cadherin-positive areas at the cell-cell contacts. Actin filaments did not colocalize with VE-cadherin after 20 Gy irradiation. Although cell viability was not affected by irradiation, paracellular permeability significantly increased in a dose-dependent manner. CONCLUSIONS: A dose of 5 or 20 Gy irradiation in HDLECs does not affect cell viability, but changes VE-cadherin mediated intercellular junctions and actin structure, resulting in an increase of paracellular permeability. Further investigations on the regulatory proteins involved in radiation-induced changes, which were observed in the current study, may contribute to development of lymphedema therapy.