Rapid improvement of systemic sclerosis-associated intestinal pseudo-obstruction with intravenous immunoglobulin administration.

OBJECTIVES: SSc is an autoimmune disease characterized by excessive fibrosis in multiple organs, including the gastrointestinal (GI) tract. GI symptoms of SSc such as intestinal pseudo-obstruction (IPO) are often refractory to conventional intervention and can result in longer in-hospital stay or even increased mortality. We aimed to summarize the insights to date regarding the efficacy of IVIG against GI symptoms of SSc to unveil what we should focus on in future studies. METHODS: Herein we report the response of GI symptoms in three cases with SSc-myositis overlap who received IVIG administration. We also conducted a systematic literature review to summarize previous reports regarding the efficacy of IVIG upon the GI manifestations of SSc, according to the PRISMA 2020 guideline. RESULTS: The case series demonstrated remarkable and rapid improvement of GI symptoms, including IPO, after IVIG administration. The literature review revealed that previous reports also support the efficacy and safety of IVIG against GI manifestations of SSc. However, they were all retrospective studies and lacking description of the short-term outcome after IVIG administration with objective and quantitative metrics. CONCLUSION: IVIG seems to be a promising therapeutic option for the management of GI symptoms in SSc, including IPO. Investigators should focus more on short-term outcomes to properly assess the therapeutic benefit of IVIG, ideally using reliable quantitative measures in a multicentre randomized placebo-controlled setting.

Serum Cytokeratin 18 as a Metastatic and Therapeutic Marker for Extramammary Paget's Disease.

Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma with unfavourable prognosis once it becomes invasive. A tumour marker that reflects disease progression is required for adequate management of EMPD. Cytokeratin 18 is highly expressed in many types of cancer and its soluble forms are detected by M30 (for caspase-cleaved form) and M65 (for both caspase-cleaved and intact forms) assays. We report here that tumour cells of EMPD in both lesional skin and lymph node metastasis are immunohistochemically positive for CK18, and the baseline serum M30 and M65 levels in patients with metastatic EMPD are significantly higher than those in non-metastatic patients. In addition, serial serum M30 and M65 levels might reflect recurrence of EMPD and response to chemotherapy. These results suggest that serum CK18 levels may be a useful tumour marker for advanced EMPD.

A potential contribution of decreased serum galectin-10 levels to systemic inflammation and pulmonary vascular involvement in systemic sclerosis.

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.

Serum S100A12 levels: Possible association with skin sclerosis and interstitial lung disease in systemic sclerosis.

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.

Serum vasohibin-1 levels: A potential marker of dermal and pulmonary fibrosis in systemic sclerosis.

Vasohibin-1 (VASH-1) is a potent anti-angiogenic factor mainly produced by endothelial cells. In addition, VASH-1 prevents TGF-ß-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.

Prognostic Relevance of Pretreatment Peripheral Neutrophil Count and Neutrophil-to-lymphocyte Ratio in Primary Cutaneous Angiosarcoma.

Systemic inflammatory response markers, including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and monocyte-to-lymphocyte ratio, are useful prognostic factors for various malignant tumours. The aim of this study was to investigate the clinical relevance of these markers in primary cutaneous angiosarcoma. Twenty-six patients were retrospectively divided into 2 groups according to pretreatment peri-pheral blood cell counts or systemic inflammatory response marker levels; overall survival and progression-free survival were compared. Univariate analysis found that high neutrophil count (> 3.1×109/l), high neutrophil-to-lymphocyte ratio (> 2.4), high platelet-to-lymphocyte ratio (> 175) and low lymphocyte count (≤ 1.3×109/l) were related to shorter overall survival, while high neutrophil and low lymphocyte groups had shorter progression-free survival. In multivariate analysis, high neutrophil count and high neutrophil-to- lymphocyte ratio (hazard ratio 7.44 and 5.04, 95% confidence interval 1.48-37.2 and 1.26-20.1, respectiv-ely) were identified as independent prognostic factors for poor overall survival. These results indicate that systemic inflammatory response markers serve as prognostic predictors in primary cutaneous angiosarcoma, as well as in other types of soft-tissue sarcoma.

Elevated serum vasohibin-1 levels in atopic dermatitis: Implications for disease chronicity.

Atopic dermatitis (AD) is often characterized by chronic skin changes of dermal fibrosis, typically regulated by inflammatory and angiogenic factors. However, the significance of angiogenesis inhibitory factors in the development of AD is poorly understood. The present study investigated the potential role of an angiogenesis inhibitory factor, vasohibin-1 (VASH1), in AD by evaluating serum and skin VASH1 levels and their correlation with clinical features. The results showed that VASH1 expression levels in both the serum and skin of patients with AD were significantly elevated compared to healthy controls. Immunohistochemical staining of AD skin showed increased VASH1 expression in dermal vascular endothelial cells. Notably, there was a significant correlation between serum VASH1 levels and disease duration as well as VASH1 and vascular endothelial growth factor A expression levels in the skin tissue of patients with AD. These results may suggest a pathogenesis of increased angiogenesis and associated elevated inhibitory processes accompanying inflammation in the chronic phase of AD.

Prevalence of antiphospholipid autoantibodies associated with biologics treatment for psoriasis.

Psoriasis is a chronic inflammatory disease that sometimes necessitates therapeutic intervention with biologics. Autoantibody production during treatment with tumor necrosis factor (TNF) inhibitors is a recognized phenomenon, however, the production of autoantibodies associated with antiphospholipid syndrome (APS) has not been comprehensively evaluated in patients with psoriasis. This study was conducted to assess the prevalence of APS-associated autoantibodies in patients with psoriasis treated with different biologics and to investigate the potential associations between autoantibody production and clinical or serological parameters. Patients with psoriasis undergoing biologics treatments were enrolled in this study, and were categorized based on the type of biologics administered, TNF, interleukin (IL)-17, or IL-23 inhibitors. Clinical and serological data were collected and analyzed in conjunction with data on APS autoantibodies. TNF inhibitors were associated with a higher frequency of APS autoantibodies compared to IL-17 and IL-23 inhibitors. Notably, the presence of APS autoantibodies correlated with concurrent arthritis and higher disease severity at treatment initiation in patients treated with TNF inhibitors. Elevated Psoriasis Area and Severity Index scores and anti-nuclear antibody titers higher than × 320 were predictors of APS autoantibody production. Despite the higher autoantibody rates, clinical symptoms of APS were absent in these patients. This study provides the first comprehensive evidence of an increased frequency of APS autoantibodies associated with TNF inhibitor treatment in patients with psoriasis. The observed association between APS autoantibody positivity and TNF inhibitor treatment or clinical parameters suggests a potential immunomodulatory interplay between autoimmunity and inflammation in the pathogenesis of psoriasis.

Impact of Pretreatment Systemic Inflammatory Markers on Treatment Persistence with Biologics and Conventional Systemic Therapy: A Retrospective Study of Patients with Psoriasis Vulgaris and Psoriatic Arthritis.

Systemic inflammation plays a central role in the pathophysiology of psoriasis. This study examined accessible systemic inflammatory markers in patients with psoriasis vulgaris and psoriatic arthritis. We aimed to evaluate their association with psoriasis severity, the presence of arthritis, and drug continuation rates. The findings revealed that neutrophil, monocyte, and platelet count, neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, systemic inflammation response index, systemic immune/inflammation index (SII), and CRP were positively correlated with Psoriasis Area and Severity Index scores. Patients presenting with higher platelet/lymphocyte ratio (PLR) or CRP values were more likely to be diagnosed with psoriatic arthritis than with psoriasis vulgaris in the multivariate regression analysis. Importantly, patients with higher pretreatment neutrophil or platelet count, PLR, and SII were associated with lower treatment continuation rates of conventional systemic agents. Higher pretreatment scores of systemic inflammatory markers did not affect treatment retention rates of biologics. These findings suggest that several accessible systemic inflammatory markers may effectively assess underlying systemic inflammation and may provide an indication for a therapeutic approach in patients with psoriasis vulgaris and psoriatic arthritis.

Interleukin-26-DNA complexes promote inflammation and dermal-epidermal separation in a modified human cryosection model of bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune disease characterized by autoantibody-mediated activation of immune cells and subepidermal blister formation. Excess amounts of extracellular DNA are produced in BP, however, it remains unclear how extracellular DNA contributes to BP pathogenesis. Here we show a possible mechanism by which interleukin (IL)-26 binds to extracellular DNA released from neutrophils and eosinophils to support DNA sensing. Patients with BP exhibited high circulating levels of IL-26, forming IL-26-DNA complexes in the upper dermis and inside the blisters. IL-26-DNA complexes played a dual role in regulating local immunity and blister formation. First, they enhanced the production of inflammatory cytokines in monocytes and neutrophils. Second, and importantly, the complexes augmented the production and activity of proteases from co-cultured monocytes and neutrophils, which induced BP180 cleavage in keratinocytes and dermal-epidermal separation in a modified human cryosection model. Collectively, we propose a model in which IL-26 and extracellular DNA synergistically act on immune cells to enhance autoantibody-driven local immune responses and protease-mediated fragility of dermal-epidermal junction in BP.

The Contribution of LIGHT (TNFSF14) to the Development of Systemic Sclerosis by Modulating IL-6 and T Helper Type 1 Chemokine Expression in Dermal Fibroblasts.

Systemic sclerosis (SSc) is an autoimmune and vascular disease resulting in multiple organ fibrosis, in which IL-6 and T helper (Th)2/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 (DFs) stimulated with 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 upregulated in inflammatory cells, whereas herpesvirus entry mediator (HVEM), a receptor of LIGHT, was downregulated in DFs. Similar expression profiles of LIGHT and HVEM were reproduced in bleomycin-treated mice. Transcription factor FLI1 bound to the HVEM promoter, and FLI1 small interfering RNA suppressed HVEM expression in normal DFs. In SSc DFs, LIGHT significantly increased IL-6 production, whereas IFN-γ/LIGHT-dependent Th1 chemokine induction was decreased compared with that in normal DFs. Importantly, LIGHT small interfering RNA 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 DFs to LIGHT, namely increased IL-6 production and decreased Th1 chemokine expression, contributes to the development of skin fibrosis in SSc.

Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs.

In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding the ubiquitin-editing enzyme A20 are also associated with fibrosis in systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to SSc pathogenesis, and which cell types drive the disease due to SSc-specific genetic alterations. We therefore characterize the expression, function, and role of A20, and its negative transcriptional regulator DREAM, in patients with SSc and disease models. Levels of A20 are significantly reduced in SSc skin and lungs, while DREAM is elevated. In isolated fibroblasts, A20 mitigates ex vivo profibrotic responses. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulate major pathological features of SSc, whereas DREAM-null mice with elevated A20 expression are protected. In DREAM-null fibroblasts, TGF-ß induces the expression of A20, compared to wild-type fibroblasts. An anti-fibrotic small molecule targeting cellular adiponectin receptors stimulates A20 expression in vitro in wild-type but not A20-deficient fibroblasts and in bleomycin-treated mice. Thus, A20 has a novel cell-intrinsic function in restraining fibroblast activation, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc. A20 and DREAM represent novel druggable targets for fibrosis therapy.

Unusual type of scleromyxedema with multiple subcutaneous nodules, IgM-λ paraproteinemia, and scleroderma-like microangiopathy.

Scleromyxedema is a mysterious cutaneous mucinosis of unknown etiology. Various types of scleromyxedema variant have been reported, which often give us a clue to understand the key aspects of this disease. Here, we describe a woman with highly unusual type of scleromyxedema. In addition to the rare manifestations of multiple subcutaneous nodules and IgM-λ paraproteinemia, our patient showed several characteristic symptoms of scleroderma such as shortened nails and fingertips, sclerodactyly, and bone resorption of fingertips and mandibles as a result of peripheral circulatory insufficiency, although this disease is known to be pathophysiologically different from scleroderma. A skin biopsy revealed cutaneous microvascular stenosis and occlusion due to intravascular mucin deposition and fibrotic changes, suggesting that scleromyxedema potentially develops peripheral circulatory disorders and other vascular involvement. The subcutaneous nodules were responsive to high-dose intravenous immunoglobulin. Scleromyxedema can represent a wide variety of systemic involvement, and therefore, we should pay attention to those symptoms as well as skin lesions.

Endothelial CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemic sclerosis.

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.

Association of serum CXCL12 levels with arthropathy in patients with systemic sclerosis.

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.

Serum levels of tissue factor pathway inhibitor: Potential association with Raynaud's phenomenon and telangiectasia in patients with systemic sclerosis.

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.

Association of serum CCL20 levels with pulmonary vascular involvement and primary biliary cholangitis in patients with systemic sclerosis.

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.

Primary cutaneous γδ T-cell lymphoma with unusual immunophenotype: A case report and review of published work.

Primary cutaneous γδ T-cell lymphoma (CGD-TCL) is a rare form of primary cutaneous lymphoma. The histopathological features of CGD-TCL are still unclear because of its rarity. Here, we report a case of a 77-year-old Japanese man who presented with a 9-month history of erythematous plaques on his left forearm. Skin biopsy specimens revealed the infiltration of atypical medium/large-sized lymphocytes from the epidermis to the deep dermis. Atypical lymphocytes were positive for CD3, CD5, CD8 and Vδ1, and negative for CD4, CD7, CD56, EBER-ISH, intracellular antigen-1, granzyme B and perforin. CD30 was partially expressed. We also reviewed 246 cases of CGD-TCL from the published work. CD4- CD8- double-negative cases were 113 of 196 cases (57.6%), followed by CD4- CD8+ cases (52/196, 26.5%). CD5 was expressed in 25.8% of the cases (34/132). At least one cytotoxic molecule marker was expressed in 150 of 160 cases (93.8%). Some cases showed an indolent clinical course, especially in mycosis fungoides-like CGD-TCL cases. CD5 positivity and lack of cytotoxic molecule expression could be associated with a better prognosis. In addition, CD30 expression was found in approximately half of CGD-TCL cases (51/112 cases), suggesting that brentuximab vedotin could be a good treatment option for such patients. Further studies with more cases with detailed clinical and pathological information are necessary to elucidate the etiology and prognostic markers of this entity.