Sweat Protects against Contact Hypersensitivity: Transient Sweat Suppression Compromises Skin Barrier Function in Mice.

Although subtle barrier defects may facilitate allergen penetration, thereby enabling allergic sensitization, the relationship between sweating disturbance and skin barrier function is unknown. However, many studies on contact hypersensitivity in mice examined ear skin, which does not sweat, instead of the footpad, where sweating is uniquely present. In this study, we assessed whether sweat suppression in the footpad before hapten application provoked a skin barrier abnormality and reduced inflammatory thresholds to topical haptens. Mice without any genetic skin barrier dysfunction displayed markedly reduced inflammatory thresholds to haptens under transient sweat suppression before hapten application. Epicutaneously applied haptens penetrated the skin more robustly in the presence of sweat suppression compared with that in its absence, although this increase was abolished by exposure to high-humidity conditions. These mice displayed a subtle atopic dermatitis-like inflammation mediated by type 2 response-dominant inflammation and increased IgE responses, mimicking some events occurring in nonlesional atopic dermatitis skin in humans and in murine models. These lesions were dramatically attenuated by exposure to high-humidity conditions. In our model, hapten sensitization does not require mechanical injury, explaining why sensitization occurs through nonlesional atopic dermatitis skin. Awareness of the importance of preserving sweating responses is essential to prevent occupational contact dermatitis and atopic dermatitis.

BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state.

ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.

[Hematological malignancies driven by aberrant splicing].

The process of RNA splicing plays a pivotal role in gene expression and genetic information modification by converting pre-mRNA into mature mRNA. Dysregulation of this process has been associated with aberrant gene expression and function, leading to hematopoietic malignancies. Through recent clinical and mouse model analyses, insights have been gained into the mechanisms underlying splicing factor mutations that aid in myelodysplastic syndrome and acute myeloid leukemia. These mutations affect genes that modulate diverse cellular processes, including chromatin regulation, transcription factors, proliferation signaling, and inflammation pathway. The relationship between aberrant splicing and cancer remains unclear despite progress in understanding the functional consequences of splicing factor mutations. This review focuses on the mechanisms of disease development because of splicing factor mutations and their potential mechanism-based therapeutic applications.

A single-blind, randomized, crossover study on the efficacy of icatibant for sweating-induced dermal pain (icatibant for sweating-induced dermal pain).

INTRODUCTION: Severe dermal pain triggered by sweating stimuli, such as bathing, exercise, and mental stress, significantly affects patients' daily lives. The pathomechanism underlying the sweating-induced dermal pain remains poorly understood and there exists no standard treatment for such pain. This study aims to evaluate the effectiveness of icatibant as an analgesic, a bradykinin B2 receptor antagonist, in treating sweating-induced dermal pain, and to establish the role of bradykinin in pain induction. METHODS/DESIGN: A multicenter, exploratory, crossover, single-blinded, placebo-controlled randomized, comparative study will be conducted to evaluate the efficacy of subcutaneous icatibant injection (30 mg) in treating sweating-induced dermal pain. Ten patients will be enrolled and assigned randomly in a 1:1 ratio to either the icatibant-placebo or placebo-icatibant groups. The primary endpoint is the change in the visual analog scale scores for dermal pain induced by thermal load before and after treatment with icatibant or placebo. Secondary endpoints include changes in the duration of dermal pain, blood and plasma histamine levels, serum angiotensin-converting enzyme levels, and histological evaluation of skin tissue samples at the site of dermal pain. DISCUSSION: The effectiveness of icatibant against sweating-induced dermal pain would provide clear evidence for the involvement of the bradykinin-bradykinin B2 receptor pathway in the pathogenesis of this condition. This finding may contribute to a better understanding of the underlying mechanisms of dermal pain associated with sweating stimuli and has the potential to improve patients' quality of life by suggesting potential treatment options, specifically, using drugs that inhibit bradykinin or suppress its production.

A Case of Mucopolysaccharidosis II Caused by a Novel Variant with Skin Linear Hyperpigmented Streaks along Blaschko's Lines.

We report a case of an eight-year-old boy with mucopolysaccharidosis (MPS) II with atypical skin lesions of hyperpigmented streaks along Blaschko's lines. This case presented with mild symptoms of MPS such as hepatosplenomegaly, joint stiffness, and quite mild bone deformity, which was the reason for the delay in diagnosis until the age of seven years. However, he showed an intellectual disability that did not meet the diagnostic criteria for an attenuated form of MPS II. Iduronate 2-sulfatase activity was reduced. Clinical exome sequencing of DNA from peripheral blood revealed a novel pathogenic missense variant (NM_000202.8(IDS_v001):c.703C>A, p.(Pro235Thr)) in the IDS gene, which was confirmed in the mother with a heterozygous state. His brownish skin lesions differed from the Mongolian blue spots or "pebbling" of the skin that are observed in MPS II.

Intravenous immunoglobulin in patients with bullous pemphigoid insufficient response to corticosteroids: Nationwide post-marketing surveillance in Japan.

BACKGROUND: In Japan, intravenous immunoglobulin (IVIG) has been approved for corticosteroid-unresponsive bullous pemphigoid (BP); however, its usage, efficacy, and safety in clinical settings remain unclear. OBJECTIVE: To elucidate IVIG efficacy, we examined the improvement in disease severity based on the Bullous Pemphigoid Disease Area Index (BPDAI). METHODS: In this 3-year (April 2016-March 2019), prospective, post-marketing, observational surveillance study, we enrolled 379 patients (51.3 % men; mean age, 74.5 years) with corticosteroid-unresponsive BP treated with IVIG from 143 institutions in Japan (720 treatment cycles). The percentage of patients who improved by at least one severity stage or whose symptoms completely resolved based on the BPDAI score was evaluated at 15, 30, and 60-90 days. RESULTS: The improvement rates at 15, 30, and 60-90 days after initial treatment in the 328 IVIG-naïve patients were 70.7 %, 83.5 %, and 84.3 %, respectively. The BPDAI score decreased rapidly and significantly by 15 days compared with that observed during pre-treatment. Further improvement was observed at 30 and 60-90 days. The corticosteroid dose and anti-BP180 antibody titers decreased significantly post-treatment (both, p < .001). Approximately 25 % of IVIG-naïve patients underwent multiple treatment cycles. The improvement rate at 30 days after the final dose was 88 %, and the symptoms completely resolved in 44 % of patients. The incidence of adverse drug reactions per cycle was 8.34 %; the most common reaction was transient thrombocytopenia. CONCLUSION: Most patients showed improvement in severity and decrease in corticosteroid dose and anti-BP180 antibody levels post-treatment, indicating that IVIG is useful for corticosteroid-unresponsive BP treatment.

SARS-CoV-2 vaccine-triggered conversion from systemic lupus erythematosus (SLE) to bullous SLE and dipeptidyl peptidase 4 inhibitors-associated bullous pemphigoid.

Bullous systemic lupus erythematosus (BSLE) is a rare blistering disease in patients with SLE. BSLE is a heterogenous disease caused by autoantibodies to the basement membrane, mainly type VII collagen. The pathogenesis of the development of autoantibodies in BSLE remains unknown. We report a case of SLE taking dipeptidyl peptidase 4 inhibitors (DPP4i) who developed tense blister lesions after administration of SARS-CoV-2 vaccine. Initial erythematous lesion before administration of SARS-CoV-2 vaccine had not shown IgG deposition at basement membrane both direct and indirect immunofluorescence (IIF). However, the result of those examinations became positive after the administration of SARS-CoV-2 vaccine. Furthermore, IIF test results using NaCl split skin had shown positive against epidermal side. These observations suggest that SARS-CoV-2 vaccination triggered production of autoantibodies that cause bullous SLE. The present case fulfills the diagnostic criteria for both BSLE and DPP4i-associated bullous pemphigoid. Skin lesions were cleared after withdrawal of DPP4i. Therefore, physicians should ask patients who develop blisters after the vaccination whether they are taking DPP4i.

Role of basal sweating in maintaining skin hydration in the finger: A long-standing paradox in dry skin resolved.

A long-standing paradox in dermatology is why skin dehydration in the fingers can be triggered by repeated water exposure despite the action of water to hydrate skin tissue. Potential clues might be provided by identifying a mechanism through which water is held in the skin of the fingers. We speculated that this mechanism would be impaired after repeated water exposure. Here, we investigated whether there might be glabrous skin-specific water-holding machinery and whether this machinery might be impaired in dry skin/hand eczema. We examined this by using an impression-mould technique, allowing for an accurate quantification of sweat gland/duct activity and optical coherence tomography. Unlike in hairy skin, sweat pores were rarely detected at the folds of the finger at baseline. Surprisingly, after water exposure, sweat pores at the folds opened and those at the ridges closed in healthy controls (HCs). Sweating in the dermal folds of the hands correlated with skin hydration, and decreased in dry skin/hand eczema, suggesting that its impairment may be one of the causes of dry skin. After repeated water exposure, basal sweating response at the folds was exhausted in patients with dry skin/hand eczema as well as HCs. This exhaustion was rescued by exposing individuals to high humidity. Basal sweating defects would be a target for dry skin/hand eczema. Maintaining basal sweating responses in the finger is the best preventive measures in achieving prevention of dry skin/hand eczema.

Herpes simplex virus-induced murine dry skin model through sweating disturbance.

BACKGROUND: Given that ocular glands become infected secondarily to herpes simplex virus 1 (HSV-1) keratitis, resulting in the loss of tear production, sweat glands may also be susceptible to HSV-1 infection, resulting in sweating disturbance, which is observed frequently in atopic dermatitis. However, due to the lack of sweat glands on the hairy skin of mice, the role of sweating in the maintenance of skin hydration has not been elucidated. OBJECTIVE: To determine the relationship between HSV-1 infection of sweat glands and sweating disturbance-induced dry skin. METHODS: By using the impression mold technique, we examined the sweating response together with the detection of HSV-1 DNA in the sweat glands of footpads, the only area with sweat glands in mice, after local cutaneous HSV-1 inoculation of immunocompetent mice. RESULTS: The sweating response and skin surface hydration were significantly decreased at 7-14 days post-infection. Sweating disturbance and dry skin was markedly enhanced when HSV-1 inoculation was followed by hyperthermic stress. Both resolved spontaneously and became resistant to a second HSV-1 inoculation, associated with increased anti-HSV-IgG antibodies. HSV-1 DNA was detected in sweat glands and dorsal root ganglia. The sweating response remained decreased after subcutaneous injection with pilocarpine, correlating histologically with marked dilatation of sweat gland lumens. These findings indicate that sweating disturbance is unlikely to be the outcome of nerve damage by HSV-1 infection. CONCLUSION: Sweating disturbance could be due to HSV-induced dysfunction of sweat glands. We developed a sweating disturbance-induced dry skin mouse model by infection with HSV-1.

Anti-Cytomegalovirus Therapy: Whether and When to Initiate, Those Are the Questions.

Cytomegalovirus (CMV) reactivation in patients with autoimmune bullous disease (AIBD) or severe drug eruption treated with immunosuppressive therapy was traditionally thought to be merely an epiphenomenon of the underlying immunosuppression. However, a detailed review of the clinical course of these patients revealed that CMV reactivation occurs upon rapid immune recovery, which is termed immune reconstitution inflammatory syndrome (IRIS), and that the timely initiation of anti-CMV therapy, when combined with maintenance doses of immunosuppressive agents, contributes to a rapid resolution of severe infectious complications thought to be refractory to conventional immunosuppressive therapies and unrelated to CMV reactivation. Thus, CMV reactivation resulting in fatal outcomes (CMV-IRIS) can be prevented by the timely detection of CMV DNA or antigens in the blood and by rapidly starting anti-CMV therapy while maintaining immunosuppressive therapy. Anti-CMV therapy is highly recommended for patients with CMV-IRIS or severe drug eruption who have risk factors for CMV reactivation resulting in fatal outcomes.

Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia.

Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3' end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3' splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).

Adrenal Insufficiency Secondary to Abrupt Dose Reduction of Topical Corticosteroid Therapy after Starting Brodalumab for Psoriasis: A Case Report.

The risk of treating psoriasis with biologic drugs in patients treated with topical corticosteroids over prolonged periods requires careful attention to their underlying adrenal insufficiency because the development of adrenal insufficiency symptoms frequently occurs after cessation of the topical corticosteroids: the dose and duration of topical corticosteroid therapy and etretinate use correlate with risk. In this case report, we present a 65-year-old man with psoriatic erythroderma who developed arthralgia, joint pain, muscle pain, fatigue, and headache after starting brodalumab and a reduction of topical potent corticosteroid doses in the treatment of psoriasis. Because his plasma cortisol levels were decreased and the levels and various signs recovered by administration of physiological doses of hydrocortisone replacement, we concluded that these clinical signs observed after starting brodalumab could be clinical manifestations of adrenal insufficiency secondary to an abrupt reduction in the amount of a topical corticosteroid, but not adverse effects of brodalumab. We found another 2 cases with psoriatic erythroderma who developed secondary to adrenal insufficiency after starting biologic drugs and a reduction of topical corticosteroid doses in the literature. Notably, the side effects of brodalumab include arthralgia, headache, and fatigue, and suspicion of side effects may include the clinical manifestations of adrenal insufficiency. Clinicians have to predict adrenal insufficiency secondary to an abrupt reduction of topical corticosteroids after remarkable improvement of psoriasis by biologics. The routine monitoring of plasma cortisol levels is necessary for all erythrodermic psoriasis patients treated with topical corticosteroids over prolonged periods before starting biologics.

Herpes zoster in lung cancer patients treated with PD-1/PD-L1 inhibitors.

Background: Herpes zoster (HZ) occurs mostly in elderly and immunocompromised individuals. Immune reconstitution may be associated with the pathogenesis of HZ. As immune checkpoint inhibitor (ICI) treatment amplifies the immune response, use of ICI may increase the incidence of HZ. There have been few studies of HZ in lung cancer patients treated with ICI. This study was performed to investigate the frequency of HZ in lung cancer patients who received ICI or cytotoxic chemotherapeutic agents. Methods: We searched the electronic medical records for lung cancer patients receiving anticancer drug therapy at our hospital, who developed HZ between April 2011 and June 2020. Results: The review identified 80 patients with a history of ICI treatment (ICI group) and 356 who had been treated with cytotoxic chemotherapeutic agents alone (non-ICI group). Among the 20 patients who developed HZ, 4 (5.0%) belonged to the ICI group and 16 (4.5%) to the non-ICI group (P=0.782). After exclusion of patients aged 65 years and older, to avoid effects of advanced age on the results, the ICI and non-ICI groups consisted of 24 and 81 patients, respectively. In total, 3 of the 24 patients (12.5%) in the ICI group and 1 of the 81 (1.2%) patients in the non-ICI group developed HZ (P=0.0365). Conclusions: There was no significant difference in the rate of HZ between lung cancer patients treated with ICI and those treated with cytotoxic chemotherapy alone. However, patients younger than 65 years treated with ICI might be at increased risk of HZ. Because this is a retrospective small study, further prospective observational studies are needed.

Clinical features of dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid in Japan: A nationwide retrospective observational study.

Many cases of bullous pemphigoid (BP) have been reported in patients taking dipeptidyl peptidase-4 inhibitors (DPP-4i), which are the most widely used antidiabetic drug for type 2 diabetes mellitus. However, no large-scale survey has been conducted in Japan. This retrospective study investigated the incidence, clinical presentation, and clinical course of DPP-4i-associated BP (DPP-4i-BP) using epidemiological data from a nationwide registry for BP. In 2016, 713 new BP patients at 94 dermatological institutes were registered, 243 (34.1%) with DPP-4i-BP and 461 (64.7%) with non-DPP-4i-BP. The male-to-female ratio was 1.9 and 0.84, respectively. Patients with DPP-4i-BP were predominantly male. Non-inflammatory BP was more common in DPP-4i-BP (33.3%) than in non-DPP-4i-BP (14.6%), while inflammatory BP was common in both. No specific subtype or difference in disease severity was evident in DPP-4i-BP. The most common gliptins administered to DPP-4i-BP patients were vildagliptin (37.2%) and linagliptin (23.8%). DPP-4i intake was discontinued in 79.9% of cases after diagnosis. Some DPP-4i-BP patients (17.6%) achieved spontaneous remission after discontinuing DPP-4i without requiring the use of systemic corticosteroids and/or adjuvant therapy. Mean duration to achieve disease control was 2.87 months. The odds ratio for non-inflammatory BP requiring systemic corticosteroids and/or adjuvant therapy was low (0.52), suggesting that remission was achieved easily with supportive care in that phenotype. Non-inflammatory and mild cases of DPP-4i-BP may resolve spontaneously with supportive care, including the discontinuation of DPP-4i and no oral corticosteroid therapy.

Anhidrosis accompanied by cholinergic urticaria-like rash and dermal pain in a patient with Sjögren's syndrome.

Cholinergic urticaria (CholU)-like rash and dermal pain on sweating occur in patients with acquired idiopathic generalized anhidrosis (AIGA). However, it is unclear whether these are symptoms specific to AIGA among the various types of acquired generalized anhidrosis/hypohidrosis (AGAH). Moreover, the pathogenesis underlying CholU-like rash and dermal pain observed with anhidrosis remains to be clarified. A 20-year-old Japanese man with Sjögren's syndrome (SS) presented with anhidrosis. Transient stinging pain on the skin and pinpoint wheals were observed when his body temperature increased. Thermoregulatory sweat testing revealed anhidrotic areas covering 69% of the body surface area with a symmetrical distribution. A high concentration of histamine was detected (506 ng/mL) in the sweat. A skin biopsy specimen from the anhidrotic area showed the inflamed secretory portion of eccrine glands. This suggested inflammation-mediated damage to sweat glands, consistent with AGAH related to SS. Furthermore, immunohistochemical analysis revealed an ectopic distribution of dermcidin, a sweat-specific peptide, in the dermal tissue surrounding the secretory portion of eccrine glands. The expression of claudin-3, a tight junction (TJ) component of sweat glands, decreased or distributed in a mottled manner in the secretory portion. No decreased expression of muscarinic cholinergic receptor M3 was detected. These results suggested that sweat had leaked into the dermis in association with impaired TJ in the secretory portion, along with the damage to inflamed sweat glands related to SS. Collectively, CholU-like rash and dermal pain on sweating were observed in an AGAH patient with SS. The sweat leakage into the dermis may contribute to the development of the rash and pain.

Case Report: Appearance of Various Disease-Specific Antibodies After the Onset of Dipeptidyl Peptidase-4 Inhibitor-Associated Bullous Pemphigoid.

Bullous pemphigoid (BP) is a rare autoimmune blistering disease, and the prevalence of type 2 diabetes mellitus (T2DM) is relatively high in subjects with BP. It is known that dipeptidyl peptidase-4 inhibitor (DPP-4i), one kind of antidiabetic drugs, can cause BP, although precise mechanism of DPP-4i-related BP remains unclear. In this report, we showed a case with appearance of various disease-specific antibodies after the onset of DPP-4i-related BP. Furthermore, various disease-specific antibodies became positive and showed high titers two years after the onset of DPP-4i-related BP and discontinuation of DPP-4i. These data showed that it is possible for immune tolerance to be broken after the onset of DPP-4i-related BP, and it may be important to check autoimmune antibodies in DPP-4i-related BP subjects even when BP symptoms are improved.

Characteristics of hemodialysis patient with critical COVID-19.

INTRODUCTION: The clinical course of hemodialysis patients with COVID-19 still remains unclear. METHODS: Thirty-four hemodialysis patients were retrospectively enrolled. Patients were divided according to disease severity, and clinical symptoms and laboratory data at admission were compared. RESULTS: The serum C-reactive protein (CRP) level, d-dimer level, and white blood cell (WBC) count were significantly higher in the group with critical disease than in the group with mild to severe disease (p = 0.005, p = 0.039, and p = 0.045). The serum CRP level exceeded 10 mg/dl within 7 days of clinical onset in all the cases with critical disease. CONCLUSION: Hemodialysis patients with COVID-19 who have elevated serum CRP and d-dimer levels, and an elevated WBC count at admission and patients with serum CRP levels exceeding 10 mg/dl before day 7 after clinical onset should be carefully monitored for possible progression to critical disease.

Risk of Progression to Autoimmune Disease in Severe Drug Eruption: Risk Factors and the Factor-Guided Stratification.

The identification of risk factors is key not only to uncover the pathogenesis of autoimmune disease but also to predict progression to autoimmune disease. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms is likely the best prototypic example for analyzing the sequential events. We conducted a retrospective study of 55 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms followed up for the possibility of later development of autoimmune disease ∼18 years after resolution. Nine patients progressed to autoimmune sequelae regardless of treatment. The generation of autoantibodies was preceded by 8 years in eight of the nine patients. The combination of increases in lymphocyte counts, severe liver damage, a rebound increase in globulin, persistent reactivations of Epstein‒Barr virus and human herpesvirus-6, and low IL-2 and IL-4 at the acute/subacute phases were significant risk factors for the future development of autoimmune disease. On the basis of these factors, we established a scoring system that can identify high-risk patients. When stratified these patients into three risk categories (low/intermediate/high), occurrence of autoimmune disease was exclusively detected in the high group. Our data represent a scoring system to identify patients at high risk of developing autoimmune disease, although a larger study is required to validate the scoring system.