杉浦 一充

Pustular mycosis fungoides (pMF) is a rare variant of MF characterized by the clinical and histopathological formation of pustules. We report a 71-year-old Japanese woman with established MF who developed a generalized pustular eruption temporally triggered by systemic interferon (IFN)-γ administration. Clinically, the patient presented with generalized erythema with coalescing pustules mimicking generalized pustular psoriasis or acute generalized exanthematous pustulosis. Histological examination revealed the simultaneous presence of spongiform pustules of Kogoj and large transformed CD30+ atypical lymphoid cells. The pustules resolved rapidly upon the discontinuation of IFN-γ and the administration of systemic antibiotics. Cytokine analysis at the onset of pustulosis revealed marked elevations in serum IL-8, IL-18, IL-23, and IL-6 compared with healthy controls; these levels normalized during remission. This case suggests that systemic IFN-γ can act as a trigger for pMF. Furthermore, the distinct cytokine profile highlights that the IL-23/IL-17/IL-8 axis may be a crucial mediator in the pathogenesis of pMF.

BACKGROUND: The Prevention of Allergy via Cutaneous Intervention (PACI) randomized controlled trial (RCT) demonstrated that early enhanced topical corticosteroid (TCS) therapy modestly reduced food allergy (FA) at 28 weeks of age. The present prospective follow-up study (PACI-ON) evaluated whether these effects persisted to age 3 years. METHODS: Participants were randomized in infancy to early enhanced (proactive) or early conventional (reactive) TCS treatment (1:1) for atopic dermatitis (AD) until 28 weeks. A total of 590 (91%) children who completed the PACI RCT were followed to age 3 years. During follow-up, no protocolized interventions were given; all participants received usual care. Main outcomes included physician-diagnosed FA, AD severity (EASI, POEM), sensitization profiles, allergic comorbidities, and growth parameters as safety outcomes. RESULTS: At age 3 years, the prevalence of any FA remained lower in the early enhanced group than in the conventional group (47.4% vs. 58.8%, p = 0.006), mainly driven by a reduced prevalence of raw egg allergy (30.4% vs. 40.5%, p = 0.013). No between-group differences were observed for wheeze, asthma, or rhinitis. Japanese cedar sensitization at age 2 was lower in the enhanced group (6.1% vs. 12.2%, p = 0.02 6) but not at age 3. AD control and quality of life were well maintained and similar across groups, with > 90% achieving mild or less disease. Early growth suppression at 1 year resolved by age 3. CONCLUSION: Early enhanced AD intervention was associated with a sustained modest reduction in its planned primary follow-up outcome of FA and safety (growth) up to age 3. Although most differences were small and may reflect early diagnosis and good overall management in both groups, the findings support early AD treatment as a potential strategy to modify allergic disease trajectories.

Nemolizumab, an anti-interleukin-31 receptor A monoclonal antibody, has been approved in Japan for treating atopic dermatitis (AD)-associated pruritus. While it is effective for itch control, nemolizumab-associated cutaneous adverse events have been increasingly recognized, yet their clinical features remain poorly characterized. In this study, we aimed to investigate the incidence, clinical characteristics, and timing of cutaneous manifestations associated with nemolizumab treatment in patients with AD, and to explore potential associations with baseline disease severity and immunological parameters. We conducted a multicenter retrospective study involving 219 patients aged ≥ 13 years with AD who received nemolizumab at 13 institutions in Japan between August 2022 and February 2024. Cutaneous eruptions were classified into six categories based on clinical consensus. Patients who received fewer than three doses without developing skin reactions were excluded. Clinical and laboratory parameters were compared between patients with and without cutaneous manifestations. Cutaneous manifestations occurred in 88 patients (40.2%), most commonly within the first three doses. Erythema was the most frequent presentation (69.3%), and 62.5% of eruptions were non-pruritic. No significant associations were observed between the occurrence of skin reactions and baseline eczema area and severity index scores, eosinophil counts, serum immunoglobulin E, or thymus and activation-regulated chemokine levels. Two cases of bullous pemphigoid were identified. Despite topical corticosteroid treatment, nemolizumab therapy was discontinued in 42% of the patients affected. In conclusion, nemolizumab frequently induces early-onset, morphologically distinct cutaneous eruptions that appear to be independent of baseline disease severity or biomarkers.

Tacrolimus, a topical calcineurin inhibitor, is used to treat atopic dermatitis (AD). AD is classically T helper type (Th) 2-driven, but Th17 cells are implicated in chronic AD, yet its efficacy against Th17-dependent pathology remains unclear. We investigated the effects of tacrolimus using a murine model of Th17-mediated allergic skin inflammation. In CD4+ T cells from DO11.10/Rag2-/- mice, which express ovalbumin (OVA)-specific T cell receptor, tacrolimus differentially suppressed stimulation-induced cytokine expression by Th2 cells. At similar concentrations, tacrolimus suppressed Il21, but not Il17a or Il22, expression in Th17 cells. Subcutaneous OVA challenge elicited ear thickening in BALB/c mice after adoptive transfer of Th2 or Th17 cells, with a stronger response in Th17-transferred mice, but less than OVA-immunized controls. Topical tacrolimus reduced Th17-mediated ear swelling, corroborated by histopathology. In Th2-transferred mice, tacrolimus tended to reduce early skin thickening (day 3) but did not affect late responses (day 7). In Th17-transferred mice, tacrolimus significantly reduced allergen-specific T-cell accumulation in OVA-injected skin and tended to reduce Il21 expression, whereas Th2-cell accumulation and cytokine expression were unaffected. Tacrolimus exerts stronger inhibitory effects on Th17- than Th2-driven responses in this model, suggesting that suppression of Th17 pathways may contribute to its therapeutic benefit in AD.

Generalized pustular psoriasis (GPP) is a rare, chronic, inflammatory skin disease characterised by widespread eruption of sterile, macroscopic pustules. Patients with GPP can present with multiple comorbidities that may influence treatment. This study aimed to assess the frequency of psoriasis-related complications and non-psoriasis-related comorbidities, and clinical laboratory findings, at the time of GPP diagnosis among patients with GPP. This was a retrospective, longitudinal medical chart review of data from patients with a documented GPP diagnosis attending 29 GPP referral hospitals in Japan. Demographics and clinical characteristics were assessed at baseline (within 6 months prior to and 3 months after GPP diagnosis), including psoriasis-related complications, non-psoriasis-related comorbidities, and clinical laboratory findings. Overall, 205 patients with GPP were included; 48.3% were female, and median age at initial diagnosis was 53 years. Similar proportions of patients had mild (36.1%), moderate (30.7%) and severe (33.2%) GPP at baseline, using Japanese Dermatological Association-GPP severity criteria. Most patients (69.8%) had psoriasis-related complications at baseline, with the most common being psoriasis vulgaris (42.9%) and psoriatic arthritis (26.8%). Non-psoriasis-related comorbidities were present in 69.3% of patients with GPP at baseline, with the most common being hypertension (28.3%), dyslipidaemia (16.6%) and diabetes mellitus (16.1%). There was large variability in laboratory test values between patients. These results demonstrated that, at the time of GPP diagnosis, patients with GPP have multiple burdens of both psoriasis-related complications and non-psoriasis-related comorbidities.

The skin is a tissue highly susceptible to damage from various stressors, including reactive oxygen species, UV radiation and chemical exposure. While damaged cells are often repaired, some sustain irreversible damage and become senescent. Although the body possesses mechanisms to remove these senescent cells, they accumulate with age for reasons that remain unclear. The close relationship between chronic inflammation and cellular senescence has recently become a major focus of research. Here, we sought to analyse the mechanisms driving age-related chronic inflammation and its impact on the accumulation of senescent cells. Our analysis of the cytokine IL-17A, a key factor in chronic inflammation, revealed that its levels increase in the skin with age. We also discovered that regulatory T cells (Treg cells), which typically act to suppress IL-17A, begin to secrete it as they age. Moreover, we found that IL-17A enhances the resistance of senescent cells to apoptosis. These results propose a model in which the age-related rise in the inflammatory factor IL-17A fosters an environment where senescent cells resist clearance, thereby promoting their accumulation.

INTRODUCTION: Pseudoxanthoma elasticum (PXE) is a progressive hereditary disease caused by the calcification and degeneration of elastic fibers, affecting the skin, retina, blood vessels, and gastrointestinal tracts. The gene responsible is the ATP-binding cassette subfamily C member 6 (ABCC6). CASE PRESENTATION: A 47-year-old man presented to an ophthalmologist with a right eyelid contusion. Fundus examination revealed right macular hemorrhage and bilateral angioid streaks. PXE was suspected due to skin lesions around the neck and abdomen; he was referred to our dermatology department. Histopathological examination revealed degenerated anucleate elastic fibers with calcification in the mid-dermis. Genetic testing revealed a previously unreported heterozygous ABCC6 mutation. We established a diagnosis of PXE based on characteristic skin lesions and histopathological findings triggered by ocular manifestations. Based on in silico analysis, the ABCC6 gene mutation was predicted to be pathogenic. CONCLUSION: In some PXE cases, the ABCC6 gene mutation can be undetectable or only one mutation is detected; PXE could be diagnosed based on clinical and histopathological symptoms. When characteristic skin and eye lesions are observed, appropriate evaluation is required. Genetic testing facilitates early diagnosis and the discovery of novel mutations, contributing to a deeper understanding of the disease spectrum.

Lichen sclerosus et atrophicus (LSA) is a chronic, progressive inflammatory disorder with a risk of malignant transformation to squamous cell carcinoma (SCC). This study investigated the role of activation-induced cytidine deaminase (AID) in UV-independent SCC arising from LSA. We retrospectively analyzed 19 female patients, including 5 SCC cases. AID expression was significantly associated with SCC development, pruritus, and shorter disease duration. AID was detected in SCC lesions and adjacent LSA tissues, mainly in basal cells. Reduced AID expression was observed in higher-stage tumors, suggesting its potential as a prognostic indicator. The use of topical corticosteroids was less common in AID-positive patients, suggesting a possible association. These findings suggest a possible inverse association between topical corticosteroid use and AID expression.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare, severe, and chronic inflammatory skin disease characterized by widespread pustules that leads to unpredictable and potentially serious disease flares. Information regarding treatment status for GPP and treatment patterns for flares is important but limited as a result of the rarity of the condition. We conducted a 10-year, retrospective, longitudinal chart review of treatment patterns at GPP referral hospitals in Japan. METHODS: Eligible patients with GPP had at least 6 months of continuous observation data within 10 years after the date of protocol approval. Data were collected from patient records and annual patient reports. Patient characteristics and treatment details, including in relation to flare occurrence, were analyzed. RESULTS: The median age of patients (N = 205) was 53 years; 48.3% were female and most had mild or moderate GPP (66.8%). Patients commonly received nonbiologic systemic therapy (86.3%) and a similar proportion received biologics (79.5%); 95.1% received topical treatment and 22.4% received systemic adrenal corticosteroids. Use of nonbiologic systemic therapy decreased, and use of biologics increased, over the study period. During the observation period, the proportion of patients receiving biologic therapy increased after a flare (from 41.4% receiving biologics when flares occurred to 62.9% initiating a new biologic post flare). CONCLUSION: In Japanese clinical practice, the evolution of treatment practices for GPP has seen an increased use of biologic therapies over time. Biologic use was common after flares; however, some flares occurred during biologic therapy, indicating a need for improved treatment options to maintain stable disease and prevent flares.

Antinuclear matrix protein 2 (NXP-2) antibodies are dermatomyositis-specific antibodies that target NXP-2 involved in transcriptional regulation. However, their clinical significance and relationship with disease activity remain unclear. We performed a longitudinal examination on serum samples from three patients with dermatomyositis who tested positive for anti-NXP-2 antibodies. These serum samples were analyzed alongside clinical parameters, including disease activity, muscle enzyme levels, and treatment response. The levels of anti-NXP-2 antibodies and serum creatine kinase decreased with symptom improvement in all the cases. Anti-NXP-2 antibody levels showed a correlation with disease activity, suggesting their potential role as a marker of disease activity.

The skin, the body's largest organ, covers the entire body and consists of three layers: the epidermis, dermis, and subcutaneous tissue. Its structure and properties vary by body region. Although homeobox (HOX) genes are implicated in mechanisms contributing to regional skin property differences, their influence is not completely understood. In this study, we focused on the relationships between HOX gene expression to regional differences in dermal structure and skin elasticity. Our results revealed significantly higher HOXA cluster expression in skin tissues and cells derived from the body in comparison to those derived from the face. Among HOXA genes highly expressed in the body, HOXA9 was found to regulate dermal fibroblast proliferation and extracellular matrix (ECM)-related gene expression, both associated with skin elasticity. Furthermore, HOXA9 was shown to affect cell proliferation and ECM-related gene expression through IGF-1 signaling. Collectively, our findings suggest that HOXA genes are expressed differently in different body regions, variably affecting dermal structure and cellular functions, thus contributing to regional variation in skin.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a chronic, inflammatory disease characterized by the sudden and recurrent development of widespread sterile pustules on the skin. The treatment of GPP includes non-biologic and biologic therapies. In Japan, biologic agents are being increasingly used as first-line treatment, with more biologics approved in Japan than in other countries. A previous secondary data-based study utilizing data in the Medical Data Vision database and the Japan Medical Data Center in Japan demonstrated heterogeneity in real-world biologic treatment patterns, with at least one switch during the follow-up period (mean n switches 3.8; mean length of follow-up 3.3 years) for approximately one third of patients with GPP treated with a biologic drug. The aim of this study was to evaluate where consensus lies among experts regarding switching biologic treatments for patients with GPP in Japan. METHODS: A Delphi exercise that consists of three survey rounds was performed with ten Japanese dermatologists. Participants were asked to respond to questions related to experts' experience with specific biologics, experience with switching, timing of switches and importance of specific criteria (drivers) when making the decision to switch. The consensus threshold was 70%. RESULTS: Based on the results of the Delphi exercise, most experts rarely (60%) or never (20%) switch a biologic agent and only 20% switch often during acute symptoms/GPP flare driven by the short time of the flare; this result may be different during the maintenance phase. Lack of efficacy, loss of efficacy due to long-term use, side effects, contraindications, new products with better efficacy and safety evidence, risk of infection, and lack of adherence play an important role in making the decision to switch. CONCLUSION: Switches may occur for patients on biologics when flares occur (loss of effectiveness) or when there is insufficient response (lack of effectiveness). The decision to switch a biologic is impacted by several other criteria, including safety and the availability of more efficacious and better tolerated therapies. Overall, there is still an unmet need for robust evidence to inform GPP treatment choice.

The interleukin (IL)-1 superfamily upregulates immune responses and maintains homeostasis between the innate and adaptive immune systems. Within the IL-1 superfamily, IL-36 plays a pivotal role in both innate and adaptive immune responses. Of the four IL-36 isoforms, three have agonist activity (IL-36α, IL-36β, IL-36γ) and the fourth has antagonist activity (IL-36 receptor antagonist [IL-36Ra]). All IL-36 isoforms bind to the IL-36 receptor (IL-36R). Binding of IL-36α/β/γ to the IL-36R recruits the IL-1 receptor accessory protein (IL-1RAcP) and activates downstream signalling pathways mediated by nuclear transcription factor kappa B and mitogen-activated protein kinase signalling pathways. Antagonist binding of IL-36Ra to IL-36R inhibits recruitment of IL-1RAcP, blocking downstream signalling pathways. Changes in the balance within the IL-36 cytokine family can lead to uncontrolled inflammatory responses throughout the body. As such, IL-36 has been implicated in numerous inflammatory diseases, notably a type of pustular psoriasis called generalized pustular psoriasis (GPP), a chronic, rare, potentially life-threatening, multisystemic skin disease characterised by recurrent fever and extensive sterile pustules. In GPP, IL-36 is central to disease pathogenesis, and the prevention of IL-36-mediated signalling can improve clinical outcomes. In this review, we summarize the literature describing the biological functions of the IL-36 pathway. We also consider the evidence for uncontrolled activation of the IL-36 pathway in a wide range of skin (e.g., plaque psoriasis, pustular psoriasis, hidradenitis suppurativa, acne, Netherton syndrome, atopic dermatitis and pyoderma gangrenosum), lung (e.g., idiopathic pulmonary fibrosis), gut (e.g., intestinal fibrosis, inflammatory bowel disease and Hirschsprung's disease), kidney (e.g., renal tubulointerstitial lesions) and infectious diseases caused by a variety of pathogens (e.g., COVID-19; Mycobacterium tuberculosis, Pseudomonas aeruginosa, Streptococcus pneumoniae infections), as well as in cancer. We also consider how targeting the IL-36 signalling pathway could be used in treating inflammatory disease states.

Autosomal recessive congenital ichthyoses (ARCI) is a genetically heterogeneous condition that can be caused by pathogenic variants in at least 12 genes, including ABCA12. ARCI mainly consists of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and harlequin ichthyosis (HI). The objective was to determine previously unreported pathogenic variants in ABCA12 and to update genotype-phenotype correlations for patients with pathogenic ABCA12 variants. Pathogenic variants in ABCA12 were detected using Sanger sequencing or a combination of Sanger sequencing and whole-exome sequencing. To verify the pathogenicity of a previously unreported large deletion and intron variant, cDNA analysis was performed using total RNA extracted from hair roots. Genetic analyses were performed on the patients with CIE, LI, HI and non-congenital ichthyosis with unusual phenotypes (NIUP), and 11 previously unreported ABCA12 variants were identified. Sequencing of cDNA confirmed the aberrant splicing of the variant ABCA12 in the patients with the previously unreported large deletion and intron variant. Our findings expand the phenotype spectrum of ichthyosis patients with ABCA12 pathogenic variants. The present missense variants in ABCA12 are considered to be heterogenous in pathogenicity, and they lead to varying disease severities in patients with ARCI and non-congenital ichthyosis with unusual phenotypes (NIUP).

Erythema nodosum (EN) may be idiopathic or secondary, and usually resolves naturally within 1-2 months. In atypical EN cases, the rash extends beyond the lower limbs to the upper limbs and trunk, and histopathological findings may be accompanied by vasculitis in addition to septal panniculitis. Few studies have examined the differences in the clinical characteristics of patients with EN based on rash distribution. We retrospectively examined whether there was a correlation with clinical information, such as the presence or absence of underlying diseases, by classifying the patients into two groups: the lower limbs group (the EN rash was confined to the lower limbs) and the beyond lower limbs group (the EN rash appeared beyond the lower limbs). Among the 86 adult patients diagnosed with EN at the Dermatology Department of Fujita Medical University between 2015 and 2020, there were 65 cases of the lower limbs group and 21 cases of the beyond lower limbs group. The frequency of underlying diseases was significantly higher in the beyond lower limbs group (76.2%, 16 cases) than in the lower limbs group (40.0%, 26 cases; P < 0.005). Vasculitis was more notable in the beyond lower limbs group (P < 0.05). Significantly higher vasculitis was noted in the EN group with underlying diseases (30.2%, 13 cases) than in the idiopathic EN group without underlying diseases (11.6%, 5 cases; P < 0.05). Neutrophil extracellular traps were positive in approximately 40% of cases in both groups. In the beyond lower limbs group, the possibility of severe cases with underlying diseases, vasculitis, and inflammation must be considered for effective treatment.

OBJECTIVES: Extramammary Paget's disease (EMPD) is a neoplastic skin disease of unknown etiology. EMPD is frequently associated with forkhead box A1 (FOXA1) expression, which correlates with the expression of estrogen receptor alpha (ER). FOXA1 regulates the transcriptional activity of ER and may function cooperatively in the tumorigenesis of breast cancer. METHODS: We performed immunohistochemical staining for FOXA1 and ER using tissue samples from 16 patients with EMPD. RESULTS: The nuclei of Paget cells isolated from each of the 16 patients with EMPD (100%) were strongly FOXA1-positive, and the FOXA1 staining intensity was similar across all samples. ER staining was detected in the nuclei of Paget cells originating from seven patients with EMPD (44%), and the ER staining intensity varied between these patients. CONCLUSIONS: In the present study, we confirmed that EMPD was frequently associated with FOXA1 expression. However, ER expression varied between patients and did not always coincide with FOXA1 expression. No clear relationship was observed between ER expression, the intensity of ER staining, or EMPD metastasis and prognosis. However, the results indicate that hormone-dependent cancer therapy may be effective in patients with ER-positive EMPD.

It has recently been revealed that mutation of the IL36RN gene contributes to the development of generalized pustular psoriasis (GPP). The IL36RN gene encodes interleukin (IL)-36 receptor antagonist (IL-36Ra), which has antagonistic roles against IL-36α, -36β, and -36γ. Previously, sanger sequencing performed in 62 Chinese GPP patients to identify IL36RN mutations revealed a new variant, c.245C>T (p.Pro82Leu), in a single heterozygous state in a patient with adult-onset GPP with psoriasis vulgaris. Since this p.Pro82Leu variant was not found in the psoriasis vulgaris or control groups in their study, they speculated that this variant might lead to exacerbated inflammatory responses. Meanwhile, Sorting Intolerant From Tolerant and PolyPhen-2, pathogenicity prediction tools, predict this variant as tolerated and benign. To date, its pathogenicity is unknown. We experienced a patient with GPP harboring the p.Pro82Leu variant, and investigated mRNA and protein expressions of IL-36Ra. Polymerase chain reaction conducted on hair follicle samples obtained from the scalp of the patient with GPP harboring the p.Pro82Leu using primers to detect mRNA of exons 2 and 5 in IL36RN demonstrated mRNA expression of IL36RN. Immunohistochemical staining revealed IL-36Ra expression in the keratinocytes of the patient with GPP harboring the p.Pro82Leu as in those of a GPP patient without the mutation (positive control). Furthermore, quantitative analysis of the immunofluorescent staining by ImageJ revealed that the expression level of IL-36Ra in the keratinocytes of the patient with GPP harboring p.Pro82Leu was higher than that in the healthy control and not lower than that in the GPP patients without the mutation. Our results indicate no aberrant splicing in this variant. In addition, according to the 1000 Genomes Project, this variant could be a founder mutation. Considering these factors together, this variant is unlikely to be associated with the development of GPP.

BACKGROUND: Early-onset atopic dermatitis is a strong risk factor for food allergy, suggesting that early effective treatment may prevent transcutaneous sensitization. OBJECTIVES: This study tested whether enhanced treatment of atopic dermatitis to clinically affected and unaffected skin is more effective in preventing hen's egg allergy than reactive treatment to clinically affected skin only. METHODS: This was a multicenter, parallel-group, open-label, assessor-blind, randomized controlled trial (PACI [Prevention of Allergy via Cutaneous Intervention] study). This study enrolled infants 7-13 weeks old with atopic dermatitis and randomly assigned infants in a 1:1 ratio to enhanced early skin treatment or conventional reactive treatment using topical corticosteroids (TCSs). The primary outcome was the proportion of immediate hen's egg allergy confirmed by oral food challenge at 28 weeks of age. RESULTS: This study enrolled 650 infants and analyzed 640 infants (enhanced [n = 318] or conventional [n = 322] treatment). Enhanced treatment significantly reduced hen's egg allergy compared with the conventional treatment (31.4% vs 41.9%, P = .0028; risk difference: -10.5%, upper bound of a 1-sided CI: -3.0%), while it lowered body weight (mean difference: -422 g, 95% CI: -553 to -292 g) and height (mean difference: -0.8 cm, 95% CI: -1.22 to -0.33 cm) at 28 weeks of age. CONCLUSIONS: This study highlighted the potential of well-controlled atopic dermatitis management as a component of a hen's egg allergy prevention strategy. The enhanced treatment protocol of this trial should be modified before it can be considered as an approach to prevent hen's egg allergy in daily practice to avoid the adverse effects of TCSs. After remission induction by TCSs, maintenance therapy with lower potency TCSs or other topical therapies might be considered as alternative proactive treatments to overcome the safety concerns of TCSs.

Patients with psoriasis vulgaris have a higher incidence of pemphigoid than the general population. However, there are only a few concise reports on the coexistence of generalized pustular psoriasis (GPP) and pemphigoid. The authors describe a rare case of the simultaneous development of GPP and pemphigoid with multiple autoantibodies (i.e., BP180-C-terminal, 200-kDa protein, and laminin 332 proteins) in a complete responder of immune checkpoint inhibitor (ICI) treatment for lung cancer. Anti-interleukin 17 inhibitors for the GPP and oral corticosteroids at 10 mg/day for the pemphigoid effectively achieved remission in both diseases. It may not be uncommon to detect multiple autoantibodies in patients with pemphigoid; however, the detection of autoantibodies to more than three antigens in a single patient is relatively rare. In the current patient, the severe inflammation of GPP might have generated multiple autoantibodies. In addition, although pembrolizumab achieved a complete response and was discontinued 9 months before the onset of GPP and pemphigoid, the ICI might have affected the development of the two diseases. This case report adds useful information to the limited knowledge regarding the coexistence of GPP and pemphigoid, and aids in a better understanding of the pathological mechanisms and treatment options for such patients. Furthermore, the possibility that more patients may develop multiple autoimmune and autoinflammatory diseases in the era of ICIs should be recognized.

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Vascular Ehlers-Danlos syndrome (vEDS) is a hereditary connective tissue disorder (HCTD) characterized by arterial dissection/aneurysm/rupture, sigmoid colon rupture, or uterine rupture. Diagnosis is confirmed by detecting heterozygous variants in COL3A1. This is the largest Asian case series and the first to apply an amplification-based next-generation sequencing through custom panels of causative genes for HCTDs, including a specific method of evaluating copy number variations. Among 429 patients with suspected HCTDs analyzed, 101 were suspected to have vEDS, and 33 of them (32.4%) were found to have COL3A1 variants. Two patients with a clinical diagnosis of Loeys-Dietz syndrome and/or familial thoracic aortic aneurysm and dissection were also found to have COL3A1 variants. Twenty cases (57.1%) had missense variants leading to glycine (Gly) substitutions in the triple helical domain, one (2.9%) had a missense variant leading to non-Gly substitution in this domain, eight (22.9%) had splice site alterations, three (8.6%) had nonsense variants, two (5.7%) had in-frame deletions, and one (2.9%) had a multi-exon deletion, including two deceased patients analyzed with formalin-fixed and paraffin-embedded samples. This is a clinically useful system to detect a wide spectrum of variants from various types of samples.

Syphilis can cause a wide range of systemic manifestations, such as papular rash, malaise, weight loss, muscle aches, generalized lymphadenopathy, and meningitis. However, pulmonary involvement in patients with secondary syphilis is thought to be relatively rare. Moreover, bone involvement in patients with secondary syphilis is also considered rare, and only a few cases of involvement of lung and bone in such patients have been reported. In this paper, we report a case of secondary syphilis with pulmonary involvement in the form of multiple nodules with low attenuation areas, lymphadenopathy and multiple bone lesions detected on computed tomography and 18F fluorodeoxyglucose-positron emission tomography/computed tomography.

Solar lentigo (SL) is a hyperpigmented macule that occurs in sun-exposed areas and is characterized by the accumulation of melanin pigment in the epidermis. On the contrary, melanin-incorporated macrophages have also been identified in the dermis, which is thought to be caused by melanin transfer due to disruption of the basement membrane, but the detailed mechanism remains unclear. In this study, we analysed SL lesions by pathological methods and examined the mechanism of melanin accumulation in the dermis using cultured skin models in vitro. First, we observed a significant decrease in type IV collagen (COL4), a major component of the basement membrane, in SL lesions. The basement membrane is known to be formed by the interaction of keratinocytes and dermal cells. Therefore, we constructed skin models containing fibroblasts or dermal stem cells and examined their effects on basement membrane formation. The results showed a markedly enhanced production of COL4 mediated by dermal stem cell-derived exosomes. The analysis of melanin localization in the SL dermis revealed that CD163-positive macrophages and CD271-positive dermal stem cells both took up melanin pigment. Exosomes of dermal stem cells incorporating melanosomes were less effective in promoting COL4 expression. These findings suggest that while the promotion of COL4 production in keratinocytes by dermal stem cell-derived exosomes is important for maintaining basement membrane homeostasis, this mechanism is disrupted in SL lesions, leading to chronic melanin accumulation in the dermis.

Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), have been implicated in the pathogenesis of skin disorders. We previously reported that Il36rn-/- mice exhibit an enhanced contact hypersensitivity (CHS) response through increased neutrophil recruitment. In addition, Il36rn-/- mice show severe imiquimod-induced psoriatic skin lesions and enhanced neutrophil extracellular trap (NET) formation. We hypothesized that NETs may play an important role in the CHS response. To confirm this, we examined the CHS response and NET formation in Il36rn-/- mice. Il36rn-/- mice showed enhanced CHS responses, increased infiltration of inflammatory cells, including neutrophils, CD4+ T cells, and CD8+ T cells, NET formation, and enhanced mRNA expression of cytokines and chemokines, including IL-1β, C-X-C motif chemokine ligand (CXCL)1, CXCL2, and IL-36γ. Furthermore, NET formation blockade improved the CHS response, which consequently decreased inflammatory cell infiltration and NET formation. Consistently, we observed decreased expression of these cytokines and chemokines. These findings indicate that IL-36Ra deficiency aggravates the CHS response caused by excessive inflammatory cell recruitment, NET formation, and cytokine and chemokine production, and that NET formation blockade alleviates the CHS response. Thus, NET formation may play a prominent role in the CHS response.

Previous studies have demonstrated that the numbers of interfollicular epidermal stem cells (IFE-SCs) and dermal stem cells (DSCs) decrease with age and that this decrease is attributed to the age-related deterioration of skin homeostatic functions and the delay in wound healing. Meanwhile, functional decline in the stem cells is also considered to be responsible for the deteriorated skin homeostatic functions and the delayed wound healing associated with aging. In the present study, we focused on epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) signaling and fibroblast growth factor-2/fibroblast growth factor receptor (FGF2/FGFR) signaling to analyze the age-related changes. Immunohistological analysis revealed that the expressions of EGFR and FGFR1 declined in IFE-SCs and DSCs with age, respectively. Additionally, IFE-SCs and DSCs isolated from the skin samples of elderly subjects exhibited lowered responsiveness to EGF and FGF2, respectively. These results suggest that the lowered responsiveness of the skin stem cells to growth factors may be a factor involved in the age-related deterioration of skin regenerative functions during wound healing and skin homeostatic functions. We hope that homeostatic and wound healing functions in the skin could be maintained if the decreased expressions of EGFR and FGFR1 in IFE-SCs and DSCs, respectively, can be suppressed.

BACKGROUND: Age-related thinning and reduced cell proliferation in the human epidermis are associated with the accumulation of senescent cells and decreases in the number and function of epidermal stem cells. OBJECTIVE: This study examined the expression of INHBA/Activin-A in human epidermis and expression differences with age, and the effect of Activin-A on epidermal stem/progenitor cells. METHODS: Immunohistochemical staining was used to analyze age-related changes in the expression of INHBA/Activin-A in the epidermal tissue of young and old subjects. Epidermal INHBA/Activin-A expression levels, epidermal morphology, and the number of epidermal stem/progenitor cells or proliferating cells were investigated using older abdominal skin samples. The effects of Activin-A on the development of a three-dimensional (3D) reconstructed epidermis and cell proliferation were also assessed. RESULTS: INHBA/Activin-A expression levels in the human epidermis increased with age, although they varied among individuals. In the epidermis of older abdominal skin samples, INHBA/Activin-A expression levels negatively correlated with epidermal thickness, the rete ridge depth and the interdigitation index. The proportion of epidermal stem/progenitor cells and proliferating cells decreased with increases in INHBA/Activin-A expression levels. Activin-A had no effect on the differentiation of keratinocytes in the 3D-reconstructed epidermis; however, thinning of the 3D epidermis was noted. Moreover, the addition of Activin-A inhibited the proliferation of epidermal stem/progenitor cells in a concentration-dependent manner. CONCLUSIONS: Age-related increased in INHBA/Activin-A expression levels were observed in the human epidermis, and may contribute to epidermal thinning and decreases in the number of epidermal stem/progenitor cells and proliferative activity.