Active Behçet's Disease Patients Research Articles

Assessment of α9β1 ıntegrın as a new dıagnostıc and therapeutıc target ın Behcet's dısease.

This study aimed to investigate the roles of α9β1 integrin and its ligands in Behçet's disease (BD) by examining serum levels and gene expressions. 15 healthy controls and 30 BD patients (14 active and 16 inactive) were included in the study. Serum levels of ITGA9, ITGB1, TNC, OPN, VCAM-1, VEGF, TSP1, TGM2, Emilin-1, and vWF, were measured by ELISA. Gene expressions of α9β1 (ITGA9 and ITGB1) and its ligands (TNC and SPP1) were evaluated by RT-PCR. Laboratory findings (CRP, ESR, HGB, WBC, RBC, neutrophil, lymphocyte, PLT, RDW, MPV, PCT, and HLA-B51) were obtained from the electronic database. Active BD patients had higher serum levels of α9β1 integrin and its ligands than inactive patients and healthy controls. No significant difference was observed between healthy controls and inactive patients. Gene expressions of ITGB1 and SPP1 were increased in both patient groups compared to healthy controls. ITGA9 and TNC gene expression levels were lower in the active group than in the inactive group. No noticeable differences were found in ITGB1 and SPP1 gene expressions between the patient groups. BD patients exhibited elevated CRP, ESR, WBC, neutrophil, PLT, and PCT levels, while HGB, RBC, and RDW values were lower than healthy controls. Active patients had higher CRP, ESR, WBC, neutrophil, and PLT levels. Significant positive correlations were found between CRP, ESR, WBC, neutrophil, PLT, PCT and serum levels of α9β1 integrin and its ligands. Increased release of α9β1 integrin and its ligands is associated with BD, suggesting their potential as markers for disease severity.

Deregulated DNA damage response network in Behcet's disease

Behcet's disease (BD) is a chronic, relapsing systemic vasculitis of unknown etiology. Since the DNA repair enzyme NEIL1 has been identified as one of the two genetic risk factors for BD by whole exome study, we examined the potential involvement of the DNA damage response (DDR) network in BD. Peripheral blood mononuclear cells from 26 patients and 26 age−/sex-matched healthy controls were studied. Endogenous DNA damage levels were increased in active BD patients compared to controls or patients in remission. In parallel, BD patients had defective nucleotide excision repair capacity. RNA-sequencing revealed reduced expression of NEIL1 that negatively correlated with DNA damage accumulation. On the other hand, expression of genes involved in senescence and senescence-associated secretory phenotype positively correlated with individual endogenous DNA damage levels. We conclude that deregulated DDR contributes to the proinflammatory environment in BD.

Transcriptional analysis of neutrophils from patients with Behçet's disease reveals activation and chemotaxis of neutrophils

Behçet's disease (BD) is a systemic vasculitis characterized by neutrophil activation with unclear pathogenesis. This study aimed to explore the transcriptional profiles of BD neutrophils and identify specific gene signatures. We performed RNA sequencing on neutrophils from treatment-naive active BD patients and healthy controls, then analyzed differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) and transcription regulatory network. Quantitative real-time PCR and Western Blot were used to validate chemotaxis-related DEGs expression. We detected 567 DEGs, including 520 upregulated genes and 47 downregulated genes. 9 KEGG pathways were enriched, dominated by the NF-κB pathway and chemotaxis. The transcription regulatory network suggests ETS1 regulated the enhanced chemotaxis of BD neutrophils. Validation experiments demonstrated the overexpression of ETS1, CCR6 and CCL5 in BD neutrophils compared with HC, and ETS1 was significantly increased in vascular BD compared with other BD subgroups. Our study revealed increased activation and chemotaxis of BD neutrophils characterized by the overexpression of CCL5, CCR6 and ETS1.

Effect of different cytokines in combination with IL-15 on the expression of activating receptors in NK cells of patients with Behçet's disease.

Behçet's disease (BD) is a systemic, autoinflammatory, chronic disorder which affects various parts of the body in genetically susceptible individuals. BD has a multi-factorial etiopathogenesis which encompasses both innate and adaptive arms of immunity. NK cells, which kill virus-infected or malign cells and provide interaction between adaptive and innate immune system, are also known to involve in the pathogenesis of autoimmune/autoinflammatory diseases including BD. NK cells function in immune responses via the signals obtained from surface-expressed activating and inhibitory receptors. In this study, we aimed to explore NK cell activation status by measuring the levels of activation marker CD69 and activating receptors NKG2D, NKp30, and NKp46 as well as proliferative and cytotoxic capacities in response to stimulation with interleukin (IL)-15-combined cytokines in BD patients. CD4+ and CD8+ T cell responses were also evaluated to compare with those of NK cells. As a result, the expression of activating receptors on NK cells was demonstrated to be varied among patients with active and inactive BD and healthy controls. The proliferation levels of NK cells were elevated in BD patients, especially in inactive phase of disease compared to healthy controls. Additionally, CD107a levels of inactive BD patients were detected to be lower in comparison with healthy controls and active BD patients. These findings suggest that BD patients in active and inactive phases display different activation status of NK cells which indicate NK cells might be associated with immune attacks and remissions during the course of BD.

The pro-inflammatory effect of triglyceride on human CD4+ T cells and experimental autoimmune uveitis

Aberrant lipid metabolism plays a role in inflammation and progression of autoimmune diseases but the definite mechanism remains unclear. In this study we investigate lipidomic profiles in Behçet's disease (BD) and the role of triglyceride (TAG) in the pathogenesis of autoimmune uveitis. Lipidomics revealed a distinct lipid metabolite profile including increased TAG metabolites in plasma of active BD patients. TAG could stimulate the proliferation, IL-17 and IFN-γ expression by CD4+ T cells and Th1, Th17 cell differentiation in vitro, but did not influence neutrophils. A922500 inhibited the TAG generation, ameliorated the EAU severity, decreased Th17 frequency and IL-17 expression by CD4+ T cells in vivo. The proteomocis analysis showed an up-regulation of apoptosis-related protein, Pik3r2, in CD4+ T cells from A922500-treated mice. In conclusion, TAG can stimulate human CD4+ T cells and the inhibition of its generation could significantly ameliorate EAU activity in association with down-regulated Th17 cell response.

IL-17A and IFN-γ are Up-regulated in CD4 and γδ T Cells in Active Behcet's Disease Patients

Involvement of γδ T cells is implicated in the pathogenesis of Behçet's disease (BD) as a bridge between innate and adaptive responses. IL-17 and IL-22 have also been shown to participate in the BD pathogenesis in addition to IFN-γ. Mainly CD4+ T cells are investigated previously for the production of these inflammatory cytokines. In this study, the role of γδ T cells in cytokine-related mechanisms was evaluated in BD in comparison to CD4+ T cells. Surface expression of markers for functional states of both CD4+ and γδ T cells were compared in ex vivo samples collected from patients with BD and healthy controls (HC).Sixteen active BD (a-BD), 9 inactive BD (i-BD) patients and 25 HC were investigated. The expression of CD161, CCR6 as markers for IL-17 producing cells were analyzed on γδ and CD4+ T cells. IFN-γ, IL-17A, IL-22, as well as CD107a (LAMP1) and CD16 (FcγRIII) were evaluated in both cell subtypes after in vitro stimulation.Only IFN-γ production was increased in γδ T cells of a-BD patients. There was no difference in increase of CD107a or decrease of CD16 surface expression on γδ T cells upon stimulation between the groups. Ex vivo IL-17A and both IL-17A/IFN-γ production and expression of CD161, CCR6 by CD4+ T cells were increased in a-BD.Along with CD4+ T cells, γδ T cells have complementary roles in cytokine production in BD. Higher IFN-γ production of γδ T cells suggests the role of an environmental triggers in BD pathogenesis, whereas IL-17 related activity is mainly provided by CD4+ T cells.

Inflammatory status might direct ILC and NK cells to IL-17 expressing ILC3 and NK subsets in Behcet's disease

Innate lymphoid cells (ILCs) are lymphoid cells that have important effector and regulatory functions in innate immunity and tissue remodeling. Uncontrolled activation and proliferation of ILCs can contribute to inflammatory autoimmune diseases. Behcet's disease (BD) is a complex systemic inflammatory disorder of unknown etiology. It has been shown that natural killer (NK) cells may play an immunoregulatory role in BD, however the role of ILCs is unknown. In this study, the levels and functions of ILCs and NK cell subsets in BD patients were investigated. Cell surface and cytotoxic granules (perforin and granzyme) expression of NK cells and ILCs were evaluated and labeled according to whole blood lysing protocol in peripheral blood samples obtained from the patients and healthy subjects. Cytokine levels of NK cells were investigated in stimulated peripheral blood mononuclear cells. All data were analyzed by flow cytometry. Total ILC and ILC3+ cells were increased in active BD patients compared to inactive BD patients and healthy subjects. There was no significant difference between the patients and healthy subjects regarding NK cell surface and intracellular molecule expression. Although, an increase in IFN-γ and IL-17, and a decrease in IL-4 levels were observed in CD56dim NK cell subset of BD patients. Recent studies showed increased neutrophilic infiltration and IL-17 secreting Th17 cells in BD patients. It is known that ILC3+cells are similar to Th17 subset regarding their cytokine profile and transcription factor expression patterns. Results of current study may suggest that inflammatory microenvironment in BD patients might direct ILC cells to differentiate into ILC3+ subset, and IL-17 released by NK cells might have a role in neutrophilic infiltration.

Functional Genetic Polymorphisms in the IL1RL1–IL18R1 Region Confer Risk for Ocular Behçet’s Disease in a Chinese Han Population

Single nucleotide polymorphisms (SNPs) in the IL1RL1–IL18R1 region are associated with various immune-mediated diseases. This study was carried out to investigate the causal variant for ocular Behçet’s disease (BD) and elucidate its target genes in the IL1RL1–IL18R1 region. Nine candidate functional SNPs were prioritized with bioinformatics analysis, followed by a two-stage association study in 694 ocular BD patients and 1,458 unaffected controls. Functional studies were performed in the peripheral blood mononuclear cells (PBMCs) of 45 healthy men and 16 active male BD patients. Genotyping was performed using the MassARRAY System. The mRNA expressions of IL1RL1, IL18R1, IL18RAP, and SLC9A4 were assayed by real-time PCR and secretion of cytokines was examined by ELISA. Significantly lower frequencies of the rs12987977 GG genotype/G allele (Pc = 8.93 × 10–7, OR = 0.39; Pc = 2.60 × 10–3, OR = 0.77, respectively), rs12999364 TT genotype/T allele (Pc = 3.15 × 10–4, OR = 0.51; Pc = 1.13 × 10–2, OR = 0.80, respectively), and rs4851569 AA genotype/A allele (Pc = 3.29 × 10–4, OR = 0.52; Pc = 9.72 × 10–3, OR = 0.80, respectively) were observed in BD patients compared with the controls. Functional experiments revealed a downregulation of IL1RL1, IL18R1, and SLC9A4 and a decreased secretion of IFN-γ in the anti-CD3/CD28 antibody-treated PBMCs as well as a decreased production of TNF-α in the lipopolysaccharide (LPS)-stimulated PBMCs in carriers of the protective homozygous rs12987977/GG genotype compared with the TT genotype. Our findings show that functional SNPs—rs12987977, rs12999364, and rs4851569—in the IL1RL1–IL18R1 region confer susceptibility to ocular BD in a Chinese Han population. And IL1RL1, IL18R1, and SLC9A4 may be the target genes of rs12987977.

Effect of combined colchicine-corticosteroid treatment on neutrophil/lymphocyte ratio: a predictive marker in Behçet disease activity.

Behçet's disease (BD) is an auto-immune vasculitis, characterized by episodic inflammation of multiple organs. The neutrophil to lymphocyte ratio (NLR) is used as a marker of inflammation in several diseases nowadays. While nitric oxide (NO) seem to be involved in BD pathogenicity. Our study aims to investigate the NLR as an inflammatory marker of BD activity as well as to evaluate the relationship between the NO production and NLR in Algerian BD patients with different clinical manifestations before and under colchicine + corticosteroid treatment. For this purpose, we evaluated the NLR as the ratio of neutrophil count to lymphocyte count in naïve and treated active BD patients with different clinical manifestations and in inactive ones. Furthermore, we assessed NO production by the Griess' method in the same patients. Additionally, we evaluated in vivo interferon-γ (IFN-γ) and interleukin-4 (IL-4) levels using ELISA. Our results indicate that the NLR and nitrite levels were higher in naïve active BD patients. Interestingly, this high ratio and NO production differed according to the clinical manifestations and was associated with an increased risk of mucocutaneous and vascular involvement. Importantly, in treated BD patients NLR was higher in active patients especially in those with mucocutaneous involvement while increased nitrites levels were regardless of the clinical manifestations studied. Both NLR and NO production decreased in these treated active patients. In addition, IL-4 production differed according to the clinical manifestations studied contrary to the IFN-γ production. Collectively our results suggest that the NLR is a potential marker of BD activity in Algerian patients, predicting the disease severity. Moreover, the positive relationship between the NLR and NO production is related to an increased risk of mucocutaneous lesions and vascular involvement. Thus, the application of these two accessible tools could be benefit for the clinical prognosis and treatment of BD.

MRNA Expression Profile of SFKs and Involvement of SFKs in the Regulation of LPS-Induced Erk1/2 Signaling in PBMCs of Active BD Patients.

Behcet's Disease (BD) is a multisystemic inflammatory disorder affecting large vessels, lungs joints, gastrointestinal and neurological systems. The pathogenesis of BD remains poorly understood. Identifying the key signaling pathway is crucial for a complete understanding of the pathogenesis of BD. The aim of this study was to determine mRNA expression level of Src family kinases (SFKs) members and their involvement in lipopolysaccharide (LPS)-induced mitogen-activated protein kinases (MAPKs) regulation in peripheral blood mononuclear cells (PBMCs) of active BD patients. Twenty- five active BD patients and twenty-five healthy controls were included in the study. PBMCs were isolated from total blood by density gradient centrifugation. The mRNA expression levels of SFKs members were measured by real-time quantitative PCR (RT-qPCR). The effect of SFKs activity on LPS-induced activation MAPKs (Erk1/2, p38 and JNK) was examined by Western blot. The mRNA expression levels of Hck, Src, Lyn, Yes and Fyn were found to be slightly decreased in active BD patients compared to the control subjects, but a slight change in mRNA level of SFKs members did not impact on protein levels and protein activity. LPS-induced Erk1/2 phosphorylation was significantly increased in the absence of SFKs activity in active BD patients. However, inhibition of SFKs activity had no effect on LPS-induced phosphorylation of p38 and JNK in both controls and active BD patients. SFKs downregulate LPS-induced Erk1/2 phosphorylation in PBMCs of active BD patients.

Serum Cortistatin Levels in Patients with Ocular Active and Ocular Inactive Behçet Disease

ABSTRACT Purpose To evaluate serum cortistatin (CST) levels in patients with ocular active and ocular inactive Behçet disease (BD) and its relationship with disease activity. Methods 24 BD patients with ocular active, 24 BD patients with ocular inactive patients and 24 healthy control subjects were included in the study. Results In ocular active and ocular inactive BD patients and healthy control subjects, the mean serum CST levels were 4.38 ± 1.63ng/ml, 5.46 ± 1.81ng/ml and 7.56 ± 1.73ng/ml, respectively. ESR, serum CRP, CST levels and NLR were significantly different between the groups (p < 0.001 for all). The CST levels were similar between ocular active and inactive BD patient groups (p = 0.197). ESR, CRP and NLR were significantly higher in ocular active BD patients compared to ocular inactive BD patients and healthy control subjects (p < 0.05 for all). Conclusion Serum CST level was significantly lower in BD patients. CST may be a neuropeptide that plays a role in the pathogenesis of BD.

Role of Serum miR-181b, Proinflammatory Cytokine, and Adhesion Molecules in Behçet's Disease.

Behçet's disease (BD) is a chronic multi-systemic inflammatory disease of uncertain pathogenesis and with no definitive diagnostic test. The aims of this study were to investigate serum levels of miR-181b in BD patients and to correlate this candidate biomarker with disease activity, cytokines, and adhesion molecules to identify new markers that can be used as a diagnostic tool for BD. Blood samples were collected from 96 participants who were classified according to their BD current activity form into 3 groups: healthy control, active BD, and inactive BD patients. MiR-181b was estimated by real-time polymerase chain reaction. However, high sensitive C-reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), E-selectin, and vascular cell adhesion molecule 1 (VCAM-1) levels were determined by enzyme-linked immunosorbent assay. Serum levels of miR-181b, hs-CRP, TNF-α, IL-6, E-selectin, and VCAM-1 were significantly higher in patients than in controls, but no significant difference was observed between the active and inactive BD groups. IL-6 was positively correlated with adhesion molecules, E-selectin, and VCAM-1. MiR-181b was positively correlated with hs-CRP, TNF-α, IL-6, and VCAM-1 in all subjects. In conclusion, miR-181b could play an important role in BD pathophysiology. MiR-181b could be utilized as potential biomarker for diagnosis and therapeutic targeting of BD. However, further studies with larger patient number are required to support these findings.

Auto-immunity profile evaluation during different clinical manifestations of Behçet disease in Algerian patients: effect of corticosteroid treatment.

Behçet disease (BD) is a chronic multisystem disease. It stands at the crossroads between the auto-immunity and auto-inflammatory disorders. Our study aims to evaluate corticosteroids therapy effects on serum immunoglobulin isotypes and anti-phospholipid auto-anti-body production in Algerian BD patients with different clinical manifestations. We evaluated serum immunoglobulin isotypes and anti-phospholipid (anti-cardiolipin, anti-β2glycoprotein I, anti-prothrombin) auto-anti-body production using Turbidimetric or Luminex platform assays. Our study was conducted in naïve active BD patients and in corticosteroid-treated patients with different clinical manifestations. Our results indicate that IgM, IgG, and IgA levels were higher in naïve active patients. The increase in sera isotypes did not differ according to the clinical manifestation, except for IgA production, which was associated with an increased risk of mucocutaneous and ocular involvement. Interestingly, in corticosteroid-treated active patients, no difference was reported between each clinical subgroup. Furthermore,anti-cardiolipin, anti-β2glycoprotein I and anti-prothrombin auto-anti-body levels were elevated in naïve active patients. Contrary to anti-prothrombin, high anti-cardiolipin and anti-β2glycoprotein I, production differed according to the clinical manifestations and was associated with an increased risk of mucocutaneous and ocular involvement. Importantly, corticosteroid therapy significantly reduced these immune markers regardless of the clinical manifestations. Our results suggest that high IgA production could be a risk marker of uveitis in naïve active patients. Moreover, concomitant high anti-cardiolipin, anti-β2glycoprotein I and anti-prothrombin production is related to an increased risk of mucocutaneous lesions, ocular and vascular involvement. Collectively, our data indicate the importance of evaluating the corticosteroid effect on immune responses associated with BD to ensure an adequate investigation of each related clinical manifestation.

An evaluation of depression, anxiety and fatigue in patients with Behçet's disease.

Behçet's disease (BD) is a type of systemic vasculitis and inflammatory disease of unknown etiology, which is associated with fatigue and lower quality of life (QoL). The aim of this study was to assess the relationship between Behçet's Disease Current Activity Form (BDCAF) and Behçet's Disease Quality of Life (BDQoL), depression, anxiety and fatigue in Behçet's disease. We conducted a cross-sectional study of 155 BD patients and 107 healthy subjects in a single center over a 1year period. All participants completed the Multidimensional Assessment of Fatigue (MAF) questionnaire, and the Hospital Anxiety and Depression (HADS) scale. Disease activity in the BD patients was assessed using the BDCAF, and the physician's global assessment (PGA). BD patients also completed the BDQoL questionnaire. There was no significant difference in age and gender between the groups. BD patients had significantly higher HADS-anxiety (HADS-A), HADS-depression (HADS-D) and MAF scores than the healthy control group (P<0.05). BD patients with active disease had significantly higher MAF and HADS-A scores compared to inactive BD patients (P<0.05). MAF scores showed positive correlations with HADS-A, HADS-D, BDCAF and BDQoL. Fatigue and anxiety are common in clinically active BD patients compared with healthy control subjects and inactive BD patients.

Neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in Behçet's disease: which and when to use?

Behçet's disease (BD) is an uncommon autoimmune/autoinflammatory disease. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were investigated in many diseases as a marker of inflammation. In this study, we investigated NLR and PLR in patients with BD as a marker of disease activity and its association with different clinical manifestations. The study included 23 BD patients; their mean age was (32.5 ± 6.76) and M:F ratio was 16:7. Complete blood picture was done for all patients. NLR and PLR were compared in both active and inactive BD patients and its relation with different clinical manifestations was assessed. NLR was higher in active BD patients than in inactive BD patients (P < 0.01). Although both NLR and PLR were correlated with Behçet's Disease Current Activity Form (BDCAF), the correlation of NLR with BDCAF was much stronger than that of PLR. NLR was associated with some mucocutaneous lesions. Both NLR and PLR were associated with articular and GIT manifestations, but also NLR showed more significant results. In our studied patients, both NLR and PLR were not informative about any ongoing ocular activity (P > 0.05). Both ratios were not affected by the presence of neurologic deficits nor previous vascular events (P > 0.05). NLR was superior to PLR as an indicator of disease activity. NLR was closely related to skin manifestations while PLR was not. In our study, both were not considered reliable in representing ocular activity.

LPS-induced Src family kinases activity mediates IL-10 production through activation of STAT3 in peripheral blood mononuclear cells of patients with Behçet's Disease

Behçet's disease (BD) is achronic inflammatory disorder characterized by recurrent oral and genital ulcers, uveitis and skin lesions. Although,the pathogenesis of BD remains poorly understood, excessive or dysregulatedcytokine production including IL-10 is associated with BD. Revealing the key molecular mechanism by which IL-10 expression is regulated is crucial to understanding the pathogenesis of BD. The aim of this study was to investigate whether Src family kinases (SFKs) are upstream mediators of STAT3/IL-10 pathway in peripheral blood mono nuclear cells(PBMCs) of active BD patients.Twenty active BD patients and twenty healthy subjects used as control were included in the study. PBMCs were isolated from total blood by density gradient centrifugation.Western blot and ELISA methods were applied to analyzelipopolysaccharide (LPS)-induced SFKs/STAT3/IL10 signaling pathway in BD.Inhibition of SFKs activity suppressed LPS-induced IL-10 production in PBMCs fromboth controls and active BD patients. Similarly, blockage of STAT3 activation abrogated LPS-induced IL-10 production. However, LPS-induced STAT3 activation required for IL-10 production was found to be dependent on SFKs activity as LPS-induced STAT3 phosphorylation was reduced by the inhibition of SFKs activity in PBMCs of active BD patients.SFKs activity is essential for LPS-induced STAT3/IL-10 pathway in PBMCs of active BD patients. Manipulation of the SFKs activity may offer a novel therapeutic approach for BD.

Aberrant DNA methylation of GATA binding protein 3 (GATA3), interleukin-4 (IL-4), and transforming growth factor-β (TGF-β) promoters in Behcet's disease.

The pathogenesis of Behcet's disease (BD) remains poorly understood. The purpose of this study was to investigate whether an aberrant DNA methylation of transcriptional and inflammatory factors, including TBX21, GATA3, RORγt, FOXP3, IFN-γ, IL-4, IL-17A and TGF-β, in CD4+T confers risk to BD. We found that the promoter methylation level of GATA3, IL-4 and TGF-β was significantly up-regulated in active BD patients and negatively correlated with the corresponding mRNA expression. The mRNA expression of GATA3 and TGF-β was markedly down-regulated in active BD patients compared to healthy individuals. Treatment with corticosteroids and cyclosporine (CsA) resulted in a decrease of the methylation level of GATA3 and TGF-β in inactive BD patients. Our results suggest that an aberrant DNA methylation of GATA3 and TGF-β is associated with their mRNA expression and participates in the pathogenesis of BD.

Carotid artery stiffness in Behçet's disease.

Increased carotid arterial stiffness (CAS) is a predictor of subclinical early atherosclerosis as well as carotid intima-media thickness (cIMT). We aimed to determine CAS and cIMT in Behçet's disease (BD). BD (n=49) and rheumatoid arthritis (RA) (n=64) patients and healthy controls (HC) (n=40) were included in the study. cIMT was measured. CAS indices, including arterial compliance (AC), arterial distensibility (AD), Young's elastic modulus (YEM), Peterson's elastic modulus (Ep), and β stiffness index (βSI) were measured based on the diameter-pressure relationship. When compared to the HC group, the mean cIMT was significantly higher in the RA group (p=0.033), but it was not higher in the BD group. The CAS indices, including AD, AC, Ep, and βSI were not significantly different among the study groups. Moreover, the cIMT and CAS indices were not significantly different between active (n=20) and inactive BD patients, and these indices were not correlated with the scores of disease activity. AD, AC and Ep were significantly lower in the BD patients with a positive pathergy reaction than in those with a negative reaction. These results suggest that BD does not directly lead to arterial stiffness or to an increase in cIMT.

Ocular Behcet's disease is associated with aberrant methylation of interferon regulatory factor 8 (IRF8) in monocyte-derived dendritic cells.

Aberrant methylation of interferon regulatory factor 8 (IRF8) has been noted in various tumors. IRF8 has also been reported to be involved in many autoimmune diseases, including Behcet's disease (BD). However, the methylation status of IRF8 in BD has not been reported. To address this issue, we investigated whether the degree of methylation of IRF8 in dendritic cells (DCs) plays a role in the development of BD. We found a lower mRNA expression and a higher methylation level of IRF8 in active ocular BD patients as compared to normal subjects and inactive patients. Treatment with a demethylation agent, 5-Aza-2’-deoxycytidine (DAC) resulted in an increase of mRNA expression and a reduction of the IRF8 methylation level. It also down-regulated the expression of the co-stimulatory molecules CD86, CD80, CD40, and reduced the production of IL-6, IL-1β, IL-23 and IL-12. An inhibition of Th1/Th17 responses was observed as evidenced by a decreased production of IFN-γ, IL-17, and a reduction of IFN-γ/IL-17- producing CD4+ T cells following treatment with DAC. This study shows that active ocular BD patients have an aberrant IRF8 methylation status. These findings suggest that epigenetic control of IRF8 expression may offer a future target in the treatment of ocular BD.

Long-Term Outcomes and Predictors of Sustained Response in Patients with Intestinal Behcet's Disease Treated with Infliximab.

Intestinal Behcet's disease (BD) is a specific subtype of BD. Effective drug therapy for intestinal BD remains elusive. To investigate long-term outcomes and identify predictors of sustained response in intestinal BD patients receiving infliximab (IFX) treatment. The medical records were reviewed of patients received IFX from September 2012 to March 2016. The cumulative probabilities of sustained response were calculated using the Kaplan-Meier. Predictor factors for sustained response were accessed by receiver operating characteristic curve. Totally, 27 active intestinal BD patients were enrolled. Sustained responses were observed in 17 patients, after a median follow-up duration 24months (interquartile range 9-37). The proportion of clinical remission at week 14, 30, and 52 had occurred in 84.6, 70, and 70%, respectively, with the proportion of clinical remission of 69.2, 40, and 55%. The mucosal healing (MH) rate at week 14 was 72%. Kaplan-Meier estimated patients with achievement of clinical and biological responses at week 14 or MH was likely to remain sustained clinical response. ROC curve analysis revealed CRP level (of 6.85mg/L) at week 14 is a potential predictor for discriminating patients with sustained response from relapse, with an area under the curve values of 0.837. IFX is effective and safe for induction and maintenance therapy in Chinese patients with moderate-to-severe active intestinal BD. Early achievement of clinical response and mucosal healing might associate long-term response. A lower CRP level seems to be associated with a more benign clinical course.