Significance of anti-transcobalamin receptor antibodies in cutaneous arteritis revealed by proteome-wide autoantibody screening.

Cutaneous arteritis (CA) is a single-organ vasculitis that exclusively affects the small to medium-sized arteries of the skin. Diagnosis depends on a histological investigation with skin biopsy, which could be burdensome for both patients and clinicians. Moreover, the pathogenesis of CA remains unstudied, and treatment has not yet been established. Herein, we applied our proteome-wide autoantibody screening method to explore autoantibodies in the serum of CA patients. As a result, anti-transcobalamin receptor (TCblR) antibodies (Abs) were specifically detected in 24% of CA patients. Patients with positive anti-TCblR Abs were spared from peripheral neuropathy compared to those with negative anti-TCblR Abs, showing characteristics as CA confined to the skin. In addition, we revealed that anti-TCblR Abs trigger the autocrine loop of interleukin-6 mediated by tripartite motif-containing protein 21 in human endothelial cells and induce periarterial inflammation in murine skin. Furthermore, we demonstrated that methylcobalamin, a ligand of TCblR, ameliorates inflammation caused by anti-TCblR Abs both in vitro and in vivo. Collectively, our investigation unveils the pathologic significance of anti-TCblR Abs in CA and their potential as a diagnostic marker and a pathophysiology-oriented therapeutic target.

Interleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis.

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.

Development of a prediction model of treatment response in patients with cutaneous arteritis: Insights from a cohort of 33 patients.

Cutaneous arteritis (CA) is necrotizing vasculitis invading the small- to medium-sized arteries of the skin. The majority of patients can be favorably managed by low- to medium-dose systemic corticosteroids (prednisolone, <0.5 mg/kg/day) or other oral medications such as non-steroidal anti-inflammatory drugs, dapsone, and azathioprine. Meanwhile, some patients require more intensive therapy including high-dose systemic corticosteroids (prednisolone, ≥0.5 mg/kg/day), i.v. immunoglobulin, and i.v. cyclophosphamide therapy. Although predicting such treatment response among CA patients is critical in clinical decision-making, prediction rules have not yet been established. Herein, we retrospectively reviewed 33 patients regularly visiting our clinic to reveal predictive factors of their treatment response. Clinical data were collected from electronic medical records. Association between each factor and treatment response was examined by logistic regression analysis. Progression-free time was calculated by Kaplan-Meier's method and analyzed by log-rank test and Cox progression hazard model. Potential predictive factors were selected, given 1 point for each, and integrated into a classification model. Discrimination of the model was examined by the receiver operating characteristic (ROC) curve analysis. In total, 33 CA patients were enrolled in our study. Of these, 11 patients required intensive therapy, classified as treatment non-responders. Logistic analyses revealed that treatment response was significantly associated with male sex, presence of skin ulcers, and elevated serum levels of C-reactive protein at the initial work-up. Kaplan-Meier analyses also demonstrated that those factors are predictive of progression-free time. The area under the ROC curve of our classification model was 0.92 (95% confidence interval, 0.83-1.00), which classified non-responders from the others with a sensitivity of 90.9% and specificity of 81.8% at the cut-off point of 2 or more. Collectively, treatment response of CA could be predictable by a combination of sex, presence of skin ulcers, and serum levels of C-reactive protein.

Serum Calponin 3 Levels in Patients with Systemic Sclerosis: Possible Association with Skin Sclerosis and Arthralgia.

Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis and vasculopathy in various organs with a background of inflammation initiated by autoimmune abnormalities. Calponin 3 plays a role in the cell motility and contractibility of fibroblasts during wound healing in the skin. We aimed to evaluate serum calponin 3 levels in SSc patients and their association with clinical manifestations of SSc. Serum samples were collected from 68 patients with SSc and 20 healthy controls. Serum calponin 3 levels were examined using enzyme-linked immunosorbent assay kits, and their association with clinical features of SSc was statistically analyzed. The upper limit of the 95% confidence interval of serum calponin 3 levels in healthy controls was utilized as the cut-off value when dividing SSc patients into the elevated and normal groups. Serum calponin 3 levels were significantly higher in SSc patients than in healthy controls (mean (95% confidence interval), 15.38 (14.66-16.11) vs. 13.56 (12.75-14.38) ng/mL, p < 0.05). The modified Rodnan total skin thickness score was significantly higher in the elevated serum calponin 3 level group than in the normal level group (median (25-75th percentiles), 10.0 (2.0-16.0) vs. 6.5 (3.25-8.75), p < 0.05). Moreover, SSc patients with increased serum calponin 3 levels also had a higher frequency of arthralgia (40% vs. 9%, p < 0.05). Elevated serum calponin 3 levels were associated with skin sclerosis and arthralgia in SSc patients. Serum calponin 3 levels might be a biomarker that reflects the severity of skin sclerosis and joint involvement in SSc.

Case of aquagenic urticaria: Case report and the results of histopathological examination.

Aquagenic urticaria (AU) is a rare skin condition in which dermal contact with water serves as a trigger of urticaria and pruritus. To make a diagnosis, a water challenge test is useful. We herein report a 16-year-old Japanese boy diagnosed with AU by water provocation test. The induced skin lesion histologically showed prominent degranulation of mast cells and lymphocytic infiltration throughout the dermis. This is the second report documenting the histopathological features of AU.

Interleukin (IL)-17F and IL-17E are related to fibrosis and vasculopathy in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease that causes fibrosis and vasculopathy of the skin and internal organs against a background of autoimmune abnormalities. In recent years, the importance of the interleukin (IL)-17 family for inflammatory diseases has received much attention, but autoimmune diseases have not yet been fully explored. As for SSc, there is also no unified perspective on the involvement of the IL-17 family in its development, and few studies have been conducted linking IL-17F and IL-17E particularly to the disease severity. In the present study, we examined the correlation between serum IL-17F and IL-17E levels and disease severity in SSc patients. Moreover, the expression of the receptors for these cytokines, IL-17RB and IL-17RC, in skin tissues obtained by skin biopsy was examined by immunohistochemistry. Both cytokines were significantly elevated in the sera of patients with diffuse cutaneous SSc patients compared with healthy controls. Serum IL-17F levels correlated with modified Rodnan total skin thickness score, a semiquantitative measure of skin sclerosis, percent predicted forced vital capacity, percent predicted carbon monoxide lung diffusion capacity and serum levels of Krebs von den Lungen-6 and surfactant protein-D, serological markers of interstitial lung disease. Serum IL-17E levels were significantly correlated with percent predicted forced vital capacity and serum Krebs von den Lungen-6 levels. Serum levels of IL-17F and IL-17E also correlated with the prevalence of digital ulcers, and serum IL-17F levels were associated with elevated right ventricle systolic pressure values. In addition, IL-17RC and IL-17RB expression was increased in the skin tissues of diffuse cutaneous SSc patients. These results suggested that IL-17F and IL-17E could be involved in fibrosis and vasculopathy in SSc through their respective receptors in the affected organ tissues.

Fli1 deficiency induces endothelial adipsin expression, contributing to the onset of pulmonary arterial hypertension in systemic sclerosis.

OBJECTIVES: Adipsin, or complement factor D, is a serine proteinase catalysing complement factor C3 breakdown, leading to the production of opsonin (C3b), membrane attack complex (C5b-C9) and anaphylatoxins (C3a and C5a). Since adipsin is potentially associated with pulmonary arterial hypertension in SSc, we investigated adipsin expression in dermal small vessels of SSc-involved skin, the mechanism regulating adipsin expression in endothelial cells, and the correlation of serum adipsin levels with SSc clinical symptoms. METHODS: Adipsin expression was assessed by immunohistochemistry with skin sections of SSc and healthy subjects. mRNA levels of target genes and transcription factor binding to the ADIPSIN promoter were evaluated by quantitative reverse transcription PCR and chromatin immunoprecipitation, respectively. Serum adipsin levels were determined by enzyme-linked immunosorbent assay. RESULTS: Adipsin expression was remarkably increased in dermal small vessels of SSc-involved skin as compared with those of healthy control skin. Consistent with the notion that Fli1 deficiency induces SSc-like phenotypes in various types of cells, FLI1 siRNA enhanced adipsin expression at protein and mRNA levels and Fli1 bound to the ADIPSIN promoter in human dermal microvascular endothelial cells. Serum adipsin levels were significantly lower in diffuse cutaneous SSc patients than in limited cutaneous SSc patients and healthy controls, and were associated positively with elevated right ventricular systolic pressure and inversely with interstitial lung disease by multivariate regression analysis. CONCLUSION: Adipsin is up-regulated at least partially by Fli1 deficiency in endothelial cells, potentially contributing to the development of pulmonary vascular involvement in SSc.

Estrogen dermatitis: Case report and examination of estrogen receptor-ß in the skin.

Many women experience some skin reaction or trouble in their monthly menstrual cycle, including the exacerbation of pre-existing diseases and skin eruptions directly associated with sex hormones. We herein report a Japanese woman who experienced repeated systemic urticaria in her premenstrual period, and was diagnosed as having estrogen dermatitis based on a positive result of intradermal estrogen skin test. Of note, the expression of estrogen receptor-ß was increased in small dermal vessels of this case as well as in those of patients with other inflammatory skin diseases. These results suggest that inflammation may induce estrogen receptor-ß expression in small dermal vessels, which potentially modifies the pathological skin inflammation during the menstrual period, leading to the development of estrogen dermatitis.

Japanese familial anetoderma: A report of two cases and review of the published work.

Anetoderma is a rare cutaneous disorder characterized by focal loss of dermal elastic tissue, resulting in macular atrophy or herniated saclike skin. Some families with hereditary anetoderma have been described, but there have been no reports on Japanese familial anetoderma so far. We herein report two Japanese sibling cases of primary anetoderma. A healthy 13-year-old Japanese girl and a healthy 15-year-old Japanese girl presented to our hospital with a 6-month history of small atrophic pittings on their arms and trunks. All lesions were less than 0.5 cm in diameter, which are relatively small for non-familial anetoderma. Preceding infections or skin lesions were not observed. A skin biopsy revealed a focal, complete loss of elastic tissue in the superficial to mid-dermis which was surrounded by fine, irregular or twisted elastic fibers. Based on these findings, the diagnosis of anetoderma was made. Review of published works demonstrated that the mode of inheritance of familial anetoderma is not simple, suggesting that it is important to survey any family member of the patients with anetoderma.