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Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc., Systemic sclerosis (SSc) disease involves multisystem fibrosis and autoimmunity with limited treatment options. Here the authors demonstrate that IL-31 and IL-31RA are overexpressed in dermal fibroblasts from SSc patients and show that fibrosis and cytokine release can be reduced upon blocking of IL-31/IL-31RA.

Raloxifene is a drug used in postmenopausal women with osteoporosis. Although hot flashes are known side effects of raloxifene, to the best of our knowledge, erythema multiforme (EM) minor has not been previously reported. Herein, we report about a 74-year-old woman who developed EM minor after the drug alfacalcidol was changed to raloxifene to treat osteoporosis. Skin biopsy revealed a suspicious eczematous drug reaction. The drug-induced lymphocyte stimulation test showed a positive result. The stimulation index was 2.2, and there were no other suspected drugs. Based on these results, we diagnosed the condition as EM minor caused by raloxifene. The patient’s symptoms disappeared after the use of antihistamine drugs and topical steroids. In conclusion, raloxifene can cause EM minor in rare cases.

Background Infections caused by Prevotella bivia, a gram-negative anaerobic bacillus, are rare, with no reported cases in Japan. We present a novel case of scrotal abscess in a Japanese patient co-infected with Prevotella bivia and Streptococcus agalactiae. Case Presentation A 41-year-old uncontrolled diabetic man complained of swelling and pain in the scrotum. On examination, computed tomography revealed an abscess of 5-cm diameter in the scrotum. Then, the abscess was incised and drained. He was treated with cefazolin empirically. Prevotella bivia and Streptococcus agalactiae were identified in the pus cultures obtained from the abscess. However, the susceptibility tests for Prevotella bivia could not be submitted. Seven days following admission, the pain reduced, and the drainage slowed. The patient was discharged on day 14 when cefazolin was discontinued and oral amoxicillin (750 mg/day) was started. Amoxicillin was continued until day 42; improvement was confirmed. Conclusion To the best of our knowledge, this case is the first report of Prevotella bivia in Japan. We suggest that cephem antibiotics such as cefazolin may be effective against Prevotella bivia in Japan.

Objectives PsA is one of the most serious comorbidities associated with psoriasis. While the early intervention in PsA is demanded, risk factors of PsA development are not well-known. This is the first prospective study to evaluate the clinical significance of nailfold capillary (NFC) changes in patients with psoriasis. Methods We conducted a prospective cohort study in a population of 449 psoriasis patients who had not been treated with systemic therapy or topical finger therapy. NFCs were observed by dermoscopy and capillaroscopy, and the correlation of NFC abnormalities, including nailfold bleeding (NFB) and enlarged capillaries, with the prevalence of PsA, incidence of new PsA, and serum levels of TNF-a, IL-17A and IL-23 were analysed. Results Detailed examination at the time of inclusion revealed that of 449 patients, 236 had Psoriasis vulgaris (PsV) and 213 had PsA. Both NFB and enlarged capillaries were significantly more frequent in patients with PsA (34.7% vs 84.5%, P Conclusions NFC abnormalities were suggested to be a predictor of PsA in psoriasis patients, and at the same time, its degree could be an indicator of disease severity.

Objective Galectin-10 (Gal-10) is a key molecule involved in eosinophil-mediated suppression of T-cell immune response. Systemic sclerosis (SSc) is characterized by T helper (Th) 2/Th17 immune response and impaired function of regulatory T cells, but the pathological role of Gal-10 has not been studied so far. Therefore, we investigated the clinical correlation of serum Gal-10 levels in SSc patients. Methods Serum Gal-10 levels were determined by enzyme-linked immunosorbent assay in 38 patients with diffuse cutaneous SSc (dcSSc), 30 with limited cutaneous SSc and 20 healthy controls. Clinical correlations of serum Gal-10 levels were examined. Results Serum Gal-10 levels were significantly lower in SSc patients than in healthy controls, especially in dcSSc patients, and inversely correlated with skin score, the percentage of predicted diffusion lung capacity for carbon monoxide and estimated right ventricular systolic pressure (RVSP). Furthermore, serum Gal-10 levels had negative correlations with leucocyte counts and inflammatory parameters. Multivariate regression analysis identified C-reactive protein and RVSP as explanatory parameters for serum Gal-10 levels. Conclusion Decreased serum Gal-10 levels may reflect the impairment of eosinophil-mediated regulatory system for T-cell immune response in SSc, possibly contributing to pulmonary vascular involvement leading to pulmonary arterial hypertension.

Cellulitis is an infection of the soft tissues of the skin. Some patients are hospitalized multiple times; lymphedema, chronic venous insufficiency, peripheral circulatory disturbance, and deep vein thrombosis are said to be risk factors for multiple admissions. Conversely, in Japan, elderly women and undernourished elderly have been reported to be at risk of multiple hospitalizations, suggesting a different patient background from that reported overseas. We investigated the characteristics of readmission cases for patients hospitalized for cellulitis in Japan. We retrospectively examined cases of cellulitis and erysipelas admitted between April 1, 2005 and March 31, 2018. Patients with cellulitis or erysipelas at multiple sites and those with osteomyelitis, pressure ulcer infection, and necrotizing fasciitis were excluded. In terms of recurrence, only hospitalizations for recurrence at the same site were considered. Patients with multiple hospitalizations had significantly lower blood albumin levels than those hospitalized only once. Furthermore, the rates of lymphedema, hypertension, and hyperlipidemia were significantly higher in patients hospitalized multiple times. Other laboratory and clinical factors were not statistically significant. Therefore, hypoalbuminemia with or without liver dysfunction, lymphedema, hypertension, and hyperlipidemia were suggested as risk factors for cellulitis recurrence. However, chronic venous insufficiency, peripheral circulatory disturbance, and deep vein thrombosis did not seem to be risk factors in Japanese cases. Japanese cases had a low body mass index (approximately 25 kg/m2), suggesting that the patient background may be different from that in existing reports. This suggests that the risk factors in Japanese cases may be different from those reported in other countries.

AIM Systemic sclerosis (SSc) is an autoimmune connective tissue disease, in which extensive fibrotic change and vasculopathy affect the skin and various internal organs. It also involves the joints, causing stiffness, arthralgia, and arthritis. Although arthropathy is commonly observed in SSc, its underlying mechanism remains unknown. CXCL12, also known as stromal cell derived factor 1, is associated with inflammation, mesenchymal cell recruitment, angiogenesis, and collagen production, and is implicated in the development of various joint diseases. To assess the potential contribution of CXCL12 to SSc development, we investigated the clinical association of serum CXCL12 levels in patients with SSc. METHOD We conducted a cross-sectional analysis of 68 patients with SSc and 20 healthy controls recruited in a single center over 9 years. Serum CXCL12 levels were measured by enzyme-linked immunosorbent assay. RESULTS Serum CXCL12 levels were significantly higher in patients with SSc than in healthy controls (median 1554.0 pg/mL, 25th-75th centiles 1313.0-1914.0 pg/mL vs 967.4 pg/mL, 608.8-1271.0 pg/mL, P < 0.001). Patients with SSc with elevated CXCL12 levels had significantly more cases of arthropathy than those with normal CXCL12 levels (85.7% vs 25.0%, P = 0.01). Furthermore, patients with SSc with elevated CXCL12 levels showed an increased trend in the prevalence of limited range of motion of the finger joints compared with those with normal CXCL12 levels (60.0% vs 18.6%, P =0 .07). Moreover, serum CXCL12 levels were significantly correlated with the titers of rheumatoid factor in patients with SSc (r = .41, P = 0.001). CONCLUSION Elevated serum CXCL12 levels may be related to the development of SSc arthropathy.

Damage-associated molecular patterns (DAMPs) have drawn much attention as a member of disease-associated molecules in systemic sclerosis (SSc). In this study, we investigated the potential contribution of S100A12, a member of DAMPs, to the development of SSc by evaluating S100A12 expression in the lesional skin and the clinical correlation of serum S100A12 levels. S100A12 expression was markedly elevated in the epidermis of SSc-involved skin at protein levels and in the bulk skin at mRNA levels. The deficiency of transcription factor Fli1, a predisposing factor of SSc, enhanced S100A12 expression and Fli1 occupied the S100A12 promoter in normal human keratinocytes. Serum S100A12 levels were higher in SSc patients, especially in those with diffuse cutaneous involvement, than in healthy controls and positively correlated with skin score. Furthermore, the presence of interstitial lung disease significantly augmented serum levels of S100A12. Importantly, serum S100A12 levels correlated inversely with both per cent forced vital capacity and per cent diffusing capacity for carbon monoxide and positively with serum levels of KL-6 and surfactant protein-D. Collectively, these results indicate a possible contribution of S100A12 to skin sclerosis and interstitial lung disease associated with SSc, further supporting the critical roles of DAMPs in the pathogenesis of this disease.

Background We have recently demonstrated that serum CCL20 levels positively correlate with mean pulmonary arterial pressure in patients with systemic sclerosis (SSc). Considering a proangiogenic effect of CCL20 on endothelial cells via CCR6, the CCL20/CCR6 axis may contribute to the development of SSc vasculopathy. Therefore, we explored this hypothesis using clinical samples, cultured cells, and murine SSc models. Methods The expression levels of CCL20 and CCR6 in the skin, mRNA levels of target genes, and the binding of transcription factor FLI1 to the target gene promoter were evaluated by immunostaining, quantitative reverse transcription PCR, and chromatin immunoprecipitation, respectively. Vascular permeability was evaluated by Evans blue dye injection in bleomycin-treated mice. Angiogenic activity of endothelial cells was assessed by in vitro angiogenesis assay. Results CCL20 expression was significantly elevated in dermal fibroblasts of patients with early diffuse cutaneous SSc, while CCR6 was significantly up-regulated in dermal small vessels of SSc patients irrespective of disease subtypes and disease duration. In human dermal microvascular endothelial cells, FLI1 siRNA induced the expression of CCR6, but not CCL20, and FLI1 bound to the CCR6 promoter. Importantly, vascular permeability, a representative SSc-like vascular feature of bleomycin-treated mice, was attenuated by Ccr6 siRNA treatment, and CCR6 siRNA suppressed the angiogenic activity of human dermal microvascular endothelial cells assayed by in vitro tube formation. Conclusions The increased expression of endothelial CCR6 due to FLI1 deficiency may contribute to the development of SSc vasculopathy.

Thrombosis is a rare complication of COVID-19 vaccines that typically affects cerebral and visceral vessels. However, skin involvement is largely unknown.5,6 Here, we describe a case of genital necrosis associated with cutaneous thrombosis following COVID-19 vaccination.

Background Two types of skin biopsies are routinely performed in dermatology: excisional and punch biopsies. A punch biopsy is a relatively low-risk procedure for surgical site infections (SSIs) because of the shallow wound depth and short operative time. In Japan, prophylactic antimicrobial agents are often used after skin biopsies due to lack of consensus, and there is no mention of antimicrobial use after skin biopsies in Japanese guidelines. In this study, we investigated whether prophylactic antibiotic use after punch biopsies reduces the risk of SSI development. Methods Cases of punch biopsy performed in our dermatology department during a one-year period from April 2018 to March 2019 were included retrospectively. The cases were divided into a group with and another without prophylactic antimicrobial use after biopsy. Results A total of 75 cases of punch skin biopsy were reviewed. There were no cases of wound infection after punch biopsy in any of the groups. The number of years of experience of the physicians in the group that used antimicrobials was significantly higher than that in the group that did not use antimicrobials (P < 0.0001). Conclusions Our result suggests that the incidence of SSI in punch biopsies without prophylaxis seems to be low. However, further research is needed due to the small number of cases in this study.

Systemic sclerosis (SSc) is an autoimmune and vascular disease resulting in multiple organ fibrosis, in which IL-6 and Th2/Th17 cytokines serve as critical disease drivers. LIGHT is a proinflammatory cytokine, promoting IL-6 production in lung fibroblasts and Th1 chemokine expression in dermal fibroblasts stimulated with interferon-γ (IFN-γ). In this study we investigated the potential contribution of LIGHT to SSc development using clinical samples and animal models. In SSc-involved skin, LIGHT was up-regulated in inflammatory cells, while HVEM, a receptor of LIGHT, was down-regulated in dermal fibroblasts. Similar expression profiles of LIGHT and HVEM were reproduced in bleomycin-treated mice. Transcription factor FLI1 bound to the HVEM promoter and FLI1 siRNA suppressed HVEM expression in normal dermal fibroblasts. In SSc dermal fibroblasts, LIGHT significantly increased IL-6 production, while IFN-γ/LIGHT-dependent Th1 chemokine induction was decreased compared with normal dermal fibroblasts. Importantly, Light siRNA significantly attenuated bleomycin-induced skin fibrosis, and serum LIGHT levels were elevated in patients with diffuse cutaneous SSc and positively correlated with clinical parameters reflecting skin and pulmonary fibrosis. Taken together, these results suggest that altered response of dermal fibroblasts to LIGHT, namely increased IL-6 production and decreased Th1 chemokine expression, contributes to the development of skin fibrosis in SSc.

BackgroundThe risk of herpes zoster is increased among older and immunocompromised patients. However, it had been reported that Japanese tend to have a low BMI and that the patient characteristics of cellulitis is different from that of other countries. Due to the different characteristics of the Japanese population, we investigated for other characteristics unique to the Japanese population.MethodWe retrospectively examined cases of disseminated herpes zoster hospitalization between April 1, 2005, and March 31, 2018.ResultsThe mean patient age was 68.35 ± 15.76 years(mean ± SD). Recurrence was observed in only one patient. Hypertension was observed in 35%, hyperlipidemia in 25%, cancer in 30%, and autoimmune disease was found in 20% of patients. Based on the results of this study and previous reports, herpes zoster was more likely to occur among older immunosuppressed patients. In contrast to previous reports of hypertension occurrence in approximately 6% of Japanese patients, our findings indicated 35%. In addition, in contrast to the previously reported rate of hyperlipidemia of approximately 2% in the Japanese population, our results showed 25%. This suggested that hypertension and hyperlipidemia were also the risk factors for disseminated herpes zoster in Japanese patients.ConclusionHypertension and hyperlipidemia were the proposed risk factors for disseminated herpes zoster in Japanese patients, in addition to age and immunodeficiency.

Vasculopathy is a critical step of systemic sclerosis (SSc) development, bridging between autoimmune inflammation and tissue fibrosis. Impaired coagulation system is a part of SSc vasculopathy, but the role of tissue factor pathway inhibitor (TFPI), a critical regulator of the extrinsic coagulation pathway, remained unknown. Therefore, we evaluated the clinical correlation of serum TFPI levels in SSc patients. Serum TFPI levels were comparable between SSc and control participants, but SSc patients with Raynaud's phenomenon and telangiectasia had significantly lower serum TFPI levels than those without. Importantly, there was a significant positive correlation between serum TFPI levels and protein S activity. These results support the critical role of impaired coagulation system in SSc.

Vasohibin-1 (VASH-1) is a potent anti-angiogenic factor mainly produced by endothelial cells. In addition, VASH-1 prevents TGF-β-dependent activation of renal fibroblasts. Since systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and fibrosis of multiple organs, VASH-1 may be involved in the development of this disease. In this study, we investigated the potential role of VASH-1 in SSc by evaluating the clinical correlation between serum VASH-1 levels and the expression of VASH-1 in SSc-involved skin. Serum VASH-1 levels were higher in SSc patients, especially those with diffuse cutaneous involvement, than in healthy controls and positively correlated with skin score. Furthermore, SSc patients with interstitial lung disease had significantly elevated levels of serum VASH-1 as compared to those without. Importantly, serum VASH-1 levels correlated inversely with both the percentage of predicted vital capacity and the percentage of predicted diffusion lung capacity for carbon monoxide and positively with serum KL-6 levels, but not serum surfactant protein D levels. In SSc-involved skin, VASH1 mRNA was remarkably upregulated compared with healthy control skin, but the major source of VASH-1 was not clear. Fli1 deficiency, a predisposing factor inducing SSc-like endothelial properties, did not affect VASH-1 expression in human dermal microvascular endothelial cells. Collectively, these results suggest that VASH-1 upregulation in the skin and sera is linked to dermal and pulmonary fibrotic changes in SSc, while the contribution of VASH-1 to SSc vasculopathy seems to be limited.

Aim Systemic sclerosis (SSc) is a chronic autoimmune disease resulting in vasculopathy and fibrosis of the skin and major internal organs. Especially, interstitial lung disease and pulmonary arterial hypertension are the leading causes of mortality. C-C motif ligand 20 (CCL20) is known as a homeostatic and inflammatory chemokine, which is associated with fibrosis and angiogenesis and constantly expressed in organs involved in SSc. Therefore, we investigated the potential contribution of CCL20 to the development of SSc. Method We conducted cross-sectional analyses of 67 SSc patients and 20 healthy controls recruited in a single center for 9 years. Serum CCL20 levels were measured by enzyme-linked immunosorbent assay. Statistical analyses were performed with the Mann-Whitney U test, the Kruskal-Wallis test followed by Dunn's multiple comparison test, Fisher's exact probability test and the Spearman's rank correlation coefficient. Results SSc patients had significantly higher serum CCL20 levels than healthy controls. In SSc patients, serum CCL20 levels correlated inversely with the percentage of predicated diffusion lung capacity for carbon monoxide and positively with mean pulmonary artery pressure (mPAP). In addition, SSc patients with increased serum CCL20 levels had anti-mitochondrial antibody M2 titer significantly elevated relative to those with normal levels, and SSc patients with asymptomatic primary biliary cholangitis (PBC) possessed higher serum CCL20 levels than those without. Importantly, serum CCL20 levels were associated positively with mPAP values and PBC presence by multivariate regression analysis. Conclusion Serum CCL20 levels may be involved in the development of pulmonary vascular involvement leading to pulmonary arterial hypertension and asymptomatic PBC in SSc patients.

Background: Sarcoidosis is a relatively rare, systemic granulomatous disease that occurs in approximately 1–40 per 100,000 individuals but affects Japanese people disproportionately. While sarcoidosis may affect any organ, morbidity and mortality is worst for cases of cardiac sarcoidosis, which is also difficult to diagnose. In this study, we investigated whether cutaneous sarcoidosis, particularly cutaneous sarcoidosis of the face, which is visible and more easily diagnosable, can be a predictor for the development of cardiac sarcoidosis. Method: We retrospectively examined patients with cutaneous sarcoidosis seen at the Department of Dermatology at the JR Tokyo General Hospital and the Department of Dermatology at the University of Tokyo Hospital between April 1, 2005 and March 31, 2019. Results: Our study found that sarcoid lesions on the face increased the risk for cardiac sarcoidosis (p = 0.0090, odds ratio 20), whereas, sarcoid lesions on the extremities decreased the risk for cardiac sarcoidosis (p = 0.0387, odds ratio 0.0961). Conclusion: Cutaneous sarcoidosis of the face is a strong predictor of cardiac sarcoidosis.

Sézary syndrome (SS) is defined by erythroderma and circulating atypical T cells, with or without lymphadenopathy. Recently, Thompson et al. identified a distinct population of SS patients with an atypical presentation: a high blood tumor burden of Sézary cells fulfilling criteria for SS but without fulfilling the criteria for erythroderma at the diagnosis. Here, we report a case of a 49-year-old Japanese man with SS who did not present with erythroderma initially, but exhibited erythematous itchy papules symmetrically located on the legs and arms. We also reviewed reported cases of SS without initial erythroderma. The skin manifestations at diagnosis varied from patches to tumors often seen in mycosis fungoides, and other rarer findings such as excoriation, palmoplantar keratoderma and alopecia. Pruritus was reported in most patients (86%), unlike early mycosis fungoides, and could be the main clue to the diagnosis of SS. Notably, three patients were reported to have presented with papular lesions, similar to our case. Little is known about why skin lesions in SS without erythroderma vary and why these cases did not exhibit erythroderma initially. Attenuated stimulation by colonized Staphylococcus aureus, impairment in recruitment of malignant T cells and suppression of inflammatory response induced by malignant T cells with regulatory phenotype may be associated with skin manifestations. Further studies are necessary to elucidate the etiology of this entity.

We describe a case of breakthrough Candida parapsilosis fungemia in an 80-year-old woman with pyoderma gangrenosum and rheumatoid arthritis. C. parapsilosis was detected in blood culture while the patient was treated with micafungin for a Candida glabrata bloodstream infection. The breakthrough infection was successfully treated with liposomal amphotericin B.

Herpes zoster is one of the most commonly encountered dermatological diseases. Disseminated herpes zoster is one of the severe forms of a herpes zoster infection. Patients with herpes zoster occasionally experience urinary retention and incontinence, which can greatly affect their quality of life. Urinary retention and incontinence appear to improve with or after the treatment of herpes zoster. There are some reports of urinary retention caused by herpes zoster, but case reports of incontinence are rare. Here a case of disseminated herpes zoster is reported that caused both urinary retention and incontinence. An 87-year-old woman visited the JR Tokyo General Hospital with complaints of erythema and headache in the right forehead, pain in the left buttock, and urinary retention that had started two days prior. Two days after the onset, the patient was hospitalized (Day 0) and treatment with acyclovir (750 mg/day) was initiated. For urinary retention, in addition to indwelling a urinary catheter, distigmine bromide at 5 mg/day was initiated. After admission, the patient experienced bowel incontinence on Day 1. Continued acyclovir treatment eliminated the blisters and alleviated pain, and incontinence did not reoccur after Day 2. At the end of the acyclovir administration, an attempt was made to remove the urinary tract catheter, but the catheter was reinserted the same day because urinary retention continued. The urinary tract catheter was ultimately removed on Day 36, after which urinary retention did not reoccur, even after distigmine bromide treatment was completed on Day 71. Similar to previous reports., it is thought that a skin rash on the head or buttocks or the onset of the disease in the elderly may be an indication for disease course with higher risk of incontinence. As the case described here was of an elderly woman with disseminated herpes zoster with skin eruptions on the face and left buttock, the combination of symptoms and the patient’s older age placed her at higher risk for incontinence. Patients with herpes zoster on the face who were previously reported with urinary retention also had a skin rash on the trunk. Urinary retention without a skin rash on the trunk is considered rare. Moreover, blood tests for this case did not indicate renal dysfunction. Urinary disorders due to herpes zoster and renal dysfunction identified by blood tests may not be related.