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.

Plasminogen activating inhibitor‐1 (PAI‐1) is associated with poor clinical outcomes, and elevated levels of PAI‐1 in both tissue and serum are correlated with poor response to therapy in various cancers, including skin cancer. Cutaneous angiosarcoma (CAS) is a vascular tumor histologically characterized by detachment of endothelial cell‐derived tumor cells. Since CAS expresses multiple angiogenic growth factors and has increased expressions of angiogenic receptor tyrosine kinase transcripts including VEGFR1/2/3, angiogenesis‐promoting factors are potential drug targets in CAS. In this study, the expression of PAI‐1 was examined in 31 cases of CAS, and the immunomodulatory effects of PAI‐1 on a human CAS cell line, ISO‐HAS‐B, were evaluated. We found that, of the angiogenesis‐promoting factors, PAI‐1 was expressed in almost all cases of CAS, and PAI‐1 increased the mRNA expressions of IL‐23p19, VEGF‐C, CXCL5 and CCL20 on ISO‐HAS‐B. Moreover, PAI‐1 stimulated ISO‐HAS‐B culture supernatant promoted favourable tube networks, suggesting that these tumor‐derived factors promote the pro‐angiogenic effect on tumor development. In addition, IL‐23p19 was expressed in 61.3% of cases, whereas VEGF‐C was expressed in 41% of cases. The results of the present study suggest that PAI‐1 promotes angiogenesis that results in tumor progression in CAS.

No abstract

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.

Systemic sclerosis (SSc) is a multisystem autoimmune and vascular disease resulting in multiple organ fibrosis with unknown aetiology. 1 It is generally accepted that an orchestrated complex network of signalling pathways drives a common SSc-specific pathological cascade across multiple organs, 2 which can be affected by organ-specific disease modifiers. 3-5 Recently, damage-associated molecular patterns (DAMPs) have drawn attention as molecules underlying SSc development. 6-9 DAMPs are evolutionally conserved endogenous molecules normally localized inside cells. Upon cellular stress or injury, DAMPs are released into the extracellular space from damaged cells, subsequently activating innate immune cells. The S100A protein family, a

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.

No abstract

Background The therapeutic goal of rheumatoid arthritis (RA) is clinical remission. However, patient characteristics associated with clinical remission by abatacept (ABT) are little known. Objectives The aim of this study is to determine the predicting factors of clinical remission induced by ABT in biologic-naïve RA patients. Methods The ABROAD (ABatacept Research Outcome as a first-line biological Agent in the real worlD) study is an ongoing prospective multicenter cohort study for investigating the efficacy and safety of ABT for treating biologic-naïve RA in the west side of Japan. Baseline profiles of the enrolled 155 RA patients (female = 83.2%, mean age at the ABT initiation = 61.3 years old, and disease duration = 8.1 years) and simplified disease activity index (SDAI) remission rate at 24 weeks were examined and then clinical factors associated with remission were determined. Anti-citrullinated protein antibodies (ACPA) titers at baseline were classified into 4 groups; negative (less than the upper limit of normal [ULN], <4.5IU/mL), low-positive (less than 3 times of the ULN, 4.5-13.5 IU/mL), high-positive (less than 22 times of the ULN, 13.6-99 IU/mL), and very high-positive (equal or more than 22 times of the ULN, >=99 IU/mL). Results SDAI remission (<3.3) was achieved in 16% of our patients. Short disease duration (<1 year) (Odds ratio [OR] = 2.79, 95% confidence interval [CI] = 1.02-7.61, p = 0.045), and very high-positive ACPA (OR = 4.44, 95% CI = 1.28-15.38, p = 0.019) were significantly associated with clinical remission at 24weeks. Also, low disease activity defined by DAS28-CRP (<2.7) at baseline (OR = 4.97, 95% CI = 0.97-25.4, p = 0.054) and male gender (OR = 2.76, 95% CI = 0.91-8.40, p = 0.072) appeared to be linked with SDAI remission. However, age at ABT initiation, concomitant use of methotrexate, CRP level at baseline, and the 1987 ACR criteria fulfillment were not statistically associated with SDAI remission. Although ACPA positivity was associated with a better response to ABT in the ORA registry (ref.), our data demonstrated that low- or high-positive ACPA was not determined as the predicting factor for remission. Conclusions Biologic-naïve RA patients with disease duration less than 1 year and very high-positive ACPA can achieve SDAI remission by ABT more frequently than without, suggesting that T cells play a critical role in synovial inflammation in such patients. References Gottenberg JE, et al. Ann Rheum Dis 2012;71:1815. Disclosure of Interest T. Fujii Grant/research support from: Bristol-Myers Squibb Japan, M. Sekiguchi Grant/research support from: Bristol-Myers Squibb Japan, K. Matsui Grant/research support from: Bristol-Myers Squibb Japan, M. Kitano Grant/research support from: Bristol-Myers Squibb Japan, M. Hashimoto Grant/research support from: Bristol-Myers Squibb Japan, K. Ohmura Grant/research support from: Bristol-Myers Squibb Japan, A. Yamamoto Grant/research support from: Bristol-Myers Squibb Japan, H. Nakahara: None Declared, K. Maeda: None Declared, A. Yokota: No...