Background Behcet’s Disease Research Articles

Novel Serum Markers that Distinguish Behcet’s Disease from Idiopathic Recurrent Aphthous Stomatitis

ABSTRACT Background Behcet’s disease (BD) is a rare and recurrent autoinflammatory disorder characterized by systemic vasculitis, frequently manifested as recurrent aphthous stomatitis (RAS). We aim to identify specific serum proteins to discriminate between BD and idiopathicRAS. Method Peripheral blood was collected from 12 BD patients, 12 idiopathic RAS patients, and 21 healthy volunteers. The serum samples underwent Tandem Mass Tag-based mass spectrometry analysis. Differentially expressed proteins (DEPs) were identified for KEGG pathway enrichment, Gene Ontology (GO), and protein-protein interaction (PPI) analyses. ELISA was utilized to verify two BD-specific DEPs in another cohort consisting of 18 BD patients, 18 idiopathic RAS patients, and 18 controls. Results Compared with RAS serum, BD serum showed 242 DEPs. 49 proteins were differentially expressed in BD but not RAS serum compared to healthy controls. KEGG pathway and GO analyses revealed that DEPs in BD and RAS have similar biological functions and cellular distributions, featuring a significant association with pathways regulating blood coagulation and immune response. When comparing DEPs between BD and RAS, several keratins emerged as markers that distinguish RAS from BD. We also identified multiple DEPs in BD but not RAS patients. PPI analysis uncovered that lipoprotein metabolism regulators serve as hub proteins, indicating their potentially essential roles in BD pathology. In addition, ELISA results confirmed the elevated LRG1 and SOD3 levels in BD, but not RAS patients, compared to healthy donors. Conclusion Our data uncovered novel serum proteins that distinguish BD from RAS, which may potentially be useful in BD diagnosis and treatment.

A patient with Behcet’s disease and IgA nephropathy in China

BackgroundBehcet’s disease (BD) is an inflammatory disorder of unknown cause that is characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. Local vasculitis can cause damage to the visceral system, but it is rare in kidney patients, especially those with IgA nephropathy (IgAN). In China, a small number of related cases have been reported. Here we present a case of co-occurrence of BD and IgAN.Case presentation: An 18-year-old female who presented with a history of recurrent oral ulcers was found ten years ago. Four years later, the patient presented with reddish nodules on the skin of both lower limbs and then presented with vulvar ulcers. This patient was clinically diagnosed with Behcet’s disease after left calf skin biopsy and presented severe proteinuria and hematuria during this period. IgAN was diagnosed after percutaneous renal biopsy. The patient was treated with hormonal, anti-inflammatory, immunomodulatory, kidney protective, and protein-lowering urine agents. After 3 years of follow-up, the patient reappears oral ulcers, reddish nodules on the skin of both lower limbs and renal dysfunction.ConclusionsBD is less common in China and is clinically prone to missed diagnosis and misdiagnosis. BD with IgAN is rarer. We should regularly pay attention to the routine urine and renal function of BD patients for early detection and treatment and to prevent further progression of the disease.

Toll-like receptor 9 (TLR9) genetic variants rs187084 and rs352140 confer protection from Behcet’s disease among Iranians

BackgroundBehcet’s disease (BD) is a multisystem and multifactorial autoimmune disease characterized by relapsing episodes of oral aphthae, genital ulcers, and ocular and skin lesions. Toll-like receptor 9 (TLR9) has pro-inflammatory roles and its genetic variants might be involved in the pathogenesis of inflammatory diseases. MethodsTwo hundred five BD patients and 207 age and sex-matched healthy controls were evaluated for TLR9 single nucleotide polymorphisms − 1486 T/C (rs187084) and + 2848:G/A (rs352140) using polymerase chain reaction-restriction fragment length polymorphism (RFLP-PCR).ResultsHealthy individuals had a significantly higher frequency of rs187084 AG and AG + GG genotypes than BD patients (p = 0.02 and p = 0.018; respectively). Of interest, healthy males had a significantly higher frequency of rs187084 AG + GG genotype and G allele than male BD patients (p = 0.035 and p = 0.045; respectively). However, rs187084 AG genotype and G allele frequencies were significantly higher in male patients with genital aphthous (p = 0.01 and p = 0.046; respectively). Furthermore, a significantly higher frequency of rs352140 CT and TT + CT genotypes was detected in healthy individuals than in BD patients (p = 0.01, and p = 0.032; respectively). Such results were also seen in healthy females than female patients (p = 0.001, and p = 0.004; respectively). Haplotype analysis revealed a significantly higher frequency of A-C and G-C haplotypes among patients and healthy subjects, respectively (p = 0.002 and p = 0.000; respectively).ConclusionOur data suggested that rs187084 AG and AG + GG genotypes and rs352140 CT and TT + CT genotypes protect Iranian individuals from BD but rs187084 AG genotype and G allele predispose male BD individuals to genital aphthous. However, additional studies are required to verify these results.

Potential gastrointestinal Behcet’s disease flare after treatment with anti-interleukin 17a therapy

BackgroundBehcet’s disease (BD) is a systemic disease characterized by recurrent oral and genital ulcers. The underlying disease pathway likely involves interleukin (IL)-17 A, a proinflammatory cytokine that is implicated in Behcet’s uveitis. Secukinumab is an anti-IL-17 A drug that may have an emerging role in the treatment of refractory BD. This is the first known case report of gastrointestinal BD flare up after anti-IL-17 A therapy.Case presentationWe presented a case of BD with cutaneous and articular features being treated with secukinumab. After the third dose of loading secukinumab, the patient developed acute lower abdominal pain required hospital admission. Urgent computer tomography (CT) abdomen showed fatty stranding of caecum. Colonoscopy with caecal showed increased number of inflammatory cells in lamina propria. Secukinumab was stopped and patient was started on medium dose steroid. His abdominal symptoms resolved after treatment.ConclusionsThis case report illustrates a case of gastrointestinal (GI) BD presenting as acute inflammatory colitis after the use of secukinumab. Therefore, anti-IL-17 A agents should be used cautiously in patients with GI BD, and preferably guided by a phenotype-tailored approach.

Platelet lymphocyte ratio, lymphocyte monocyte ratio, mean platelet volume, and neutrophil lymphocyte ratio in Behcet’s disease and their relation to disease activity

BackgroundBehcet’s disease (BD) does not have specific laboratory finding or pathological physical examination sign, and only few studies have investigated Neutrophil to lymphocyte ratio (NLR), platelets to lymphocytes ratio (PLR), lymphocytes to monocytes ratio (LMR), or mean platelet volume (MPV) values in patients with BD. We conducted this study to investigate the relationship between these indices and Behcet’s disease (BD) and to determine their relation to BD disease activity.ResultsThis study is a case-control study that included 36 Behcet’s disease patients and 36 healthy controls. BD patients showed significant increase in the mean of NLR and PLR in comparison to control (P = 0.008 and 0.011) respectively, and highly significant decrease in LMR and MPV levels in BD patients in comparison to control (P < 0.001 and < 0.001) respectively. Also, we found that NLR, PLR, and LMR were significantly related to BD activity, and there were significant associations between the studied hematological parameters with some of muco-cutaneous, articular, gastrointestinal, eye, and nervous system manifestations in BD patients.ConclusionThe blood indices NLR, PLR, LMR, and MPV are potential inflammatory markers that can be used to evaluate inflammatory status and disease activity in patients with BD. NLR and PLR showed positive relation being higher in active disease and also higher in highly active disease than in low disease activity. Also, LMR was significantly decreased in Behcet’s disease patients in relation to disease activity. Furthermore, NLR and PLR levels were significantly more associated with muco-cutaneous and nervous system involvement while, LMR levels were significantly associated with muco-cutaneous, articular, gastrointestinal and eye manifestations and MPV levels were associated with articular manifestations being significantly related to disease activity. These easily evaluated markers could help in the management of this disease with multisystem affection that are sometimes serious and potentially life threatening.

Candidate Drugs Screening for Behcet's Disease Based on Bioinformatics Analysis and Mouse Experiments.

BackgroundBehcet’s disease (BD) is a chronic immune disease that involves multiple systems. As the pathogenesis of BD is not clear, and new treatments are needed, we used bioinformatics to identify potential drugs and validated them in mouse models.MethodsBehcet’s disease-related target genes and proteins were screened in the PubMed and UVEOGENE databases. The biological functions and pathways of the target genes were analyzed in detail by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein-protein interaction (PPI) network was constructed by the STRING database, and hub genes were identified by the Cytoscape plug-in CytoHubba. Gene-drug interactions were identified from the DGIdb database. Experimental autoimmune uveitis (EAU) mice were used as an animal model for drug validation.ResultsA total of 249 target genes and proteins with significant differences in BD were screened, and the results of functional enrichment analysis suggested that these genes and proteins were more located on the cell membrane, involved in regulating the production of cytokines and affecting the activity of cytokines. They mainly regulated “Cytokine- Cytokine receptor interaction”, “Inflammatory bowel disease (IBD)” and “IL-17 signaling Pathway”. In addition, 10 hub genes were obtained through PPI network construction and CytoHubba analysis, among which the top 3 hub genes were closely related to BD. The DGIdb analysis enriched seven drugs acting together on the top 3 hub genes, four of which were confirmed for the treatment of BD or its complications. There is no evidence in the research to support the results in omeprazole, rabeprazole, and celastrol. However, animal experiments showed that rabeprazole and celastrol reduced anterior chamber inflammation and retinal inflammation in EAU mice.ConclusionsThe functional analysis of genes and proteins related to BD, identification of hub genes, and validation of potential drugs provide new insights into the disease mechanism and potential for the treatment of BD.

POS1336 BEHCET’S DISEASE AND PREGNANCY OUTCOMES

BackgroundBehcet’s disease (BD) is multisystemic disease of unknown cause. The relationship between BD and pregnancy is reported in limited number of studies.ObjectivesTo evaluate outcomes of pregnancies in BD patients (pts).MethodsWe retrospectively collected data of 45 women with BD diagnosis (according to ISGBD 1990 and ICBD 2014) and their 118 pregnancies. Pts’ mean age was 31,3 [27;35] years., disease duration 6,0 [3;8] years. 11,1% pts had severe BD according to Ch.Zouboulis classification (due to generalized uveitis, retinal vasculitis and parenchymatous CNS lesions), 31,1% pts had a moderate disease, 57,8% pts had a mild disease with mainly dermal-mucous manifestations.Results118 pregnancies in 35 pts resulted in 75 live birth (6 cesarean section in 3 pts). Thirty-nine incomplete pregnancies were observed in 26 patients. Ten patients had 20 medical abortions on request before 12 weeks of gestation, one patient had an abortion due to medical reasons (rubella on the 7 th week of gestation), two patients had premature birth at 28 and 32 weeks with subsequent perinatal death of the baby. Fifteen out of 35 pts had 20 adverse pregnancy outcomes: 8 spontaneous abortion, 12 missed miscarriage. Nine patients had 12 Missed miscarriage at 6-11 weeks of gestation, one patient had 3 missed miscarriage, two had 2, and the others had 1 missed miscarriage. Six patients had 8 spontaneous abortions (early miscarriage). In the control group of 15 women, 7 had 15 pregnancies, 13 live birth of healthy children on time. Table 1 presents a comparison of pregnancy outcomes in patients with BD and healthy control.Table 1.Pregnancy outcomesPregnancy, nBD, n=118 (%)Control, n=15 (%)pBirth77 (65)13 (87)0,01Abortion21 (18)00,00Unfavorable pregnancy outcome20 (17)2 (13)nsMissed miscarriage12 (10)0nsSpontaneous abortion8 (7)2 (13)nsPatients with BD were more likely to terminate pregnancy of their own volition compared to control group. All women with unfavorable pregnancy outcomes are re-pregnant, have healthy children born on time, all had a second or subsequent pregnancy with an unfavorable outcome. Immunosuppressive therapy of BD was not received by any of the pregnant women, which makes it possible to exclude the connection of the outcome of pregnancy with BD therapy.The manifestation of BD with skin-mucous lesion of the patient in the first and third trimester of pregnancy was noted by 3 patients. In one patient, the appearance of a recurrent ulcer on the vulva was an indication for cesarean section.Only three women had one favorably completed pregnancy, all the others had from 2 to 7 pregnancies. Out of 45 patients, 10 patients did not have pregnancies, 9 of them are not married, 1 patient is planning a pregnancy.Table 2 shows the frequency of pregnancy pathology with varying degrees of severity of BD.ConclusionPatients with BD were more to terminate pregnancy compared to control group. Unfavorable outcomes of pregnancy were documented in pts regardless (with all grades of) BD severity.

Novel Insights Into Gene Signatures and Their Correlation With Immune Infiltration of Peripheral Blood Mononuclear Cells in Behcet’s Disease

BackgroundBehcet’s disease (BD) is a chronic inflammatory disease that involves systemic vasculitis and mainly manifests as oral and genital ulcers, uveitis, and skin damage as the first clinical symptoms, leading to gastrointestinal, aortic, or even neural deterioration. There is an urgent need for effective gene signatures for BD’s early diagnosis and elucidation of its underlying etiology.MethodsWe identified 82 differentially expressed genes (DEGs) in BD cases compared with healthy controls (HC) after combining two Gene Expression Omnibus datasets. We performed pathway analyses on these DEGs and constructed a gene co-expression network and its correlation with clinical traits. Hub genes were identified using a protein–protein interaction network. We manually selected CCL4 as a central hub gene, and gene-set enrichment and immune cell subset analyses were applied on patients in high- and low-CCL4 expression groups. Meanwhile, we validated the diagnostic value of hub genes in differentiating BD patients from HC in peripheral blood mononuclear cells using real-time PCR.ResultsTwelve hub genes were identified, and we validated the upregulation of CCL4 and the downregulation of NPY2R mRNA expression. Higher expression of CCL4 was accompanied by larger fractions of CD8 + T cells, natural killer cells, M1 macrophages, and activated mast cells. Receiver operator characteristic curves showed good discrimination between cases and controls based on the expression of these genes.Conclusion CCL4 and NPY2R could be diagnostic biomarkers for BD that reveal inflammatory status and predict vascular involvement in BD, respectively.

Angiographic patterns and temporal changes of arterial lesions in Behcet's disease.

Behcet's disease (BD) can entail vascular involvement in various forms including aneurysm. We evaluated the angiographic patterns and changes in arterial lesions over time in BD patients with arterial involvement. We reviewed the medical records of BD patients diagnosed with arterial lesions between 1995 and 2018. Angiographic patterns were categorized as stenosis, occlusion, dilatation, or aneurysm. Patients were divided according to symptom duration (<5, 5-10, >10 years). Cox proportional-hazards model was used to evaluate the risk factors for vascular progression. 47 BD patients had arterial involvement in the following patterns: aneurysm (n = 31), stenosis (n = 17), dilatation (n = 13), and occlusion (n = 8). Aneurysm (70.8%) was the most common pattern in 24 patients with short (<5 years) symptom duration. Stenosis was more common (50.0%) in 12 patients with longer symptom durations (>10 years). In 23 patients with follow-up imaging (median, 5.7 years), eight (34.8%) developed 11 new lesions: stenosis (n = 5), dilatation (n = 1), and aneurysm (n = 5). One stenotic lesion progressed to occlusion, and two dilated lesions progressed to aneurysms. Lower extremity involvement and methotrexate use were associated with arterial progression, with hazard ratios of 5.716 (p = 0.029) and 0.101 (p = 0.049), respectively. In BD patients with arterial involvement, aneurysm was the most common pattern in earlier stages of BD, while stenosis was more common in later stages of BD. Methotrexate use was associated with lower risk of arterial lesion progression.

Myocardial involvement in Behçet’s disease may be higher in patients with Neuro-Behçet’s disease: a speckle tracking echocardiographic study

Background Behcet’s disease (BD) may present with life threating complications including neurological and cardiovascular involvement. Neuro-Behcet’s disease (NBD) is one of the most important causes of morbidity and mortality in patients with BD. The aim of the present study is to investigate whether patients with NBD are different than BD patients with other manifestations in terms of subclinical myocardial dysfunction. Methods Forty patients with NBD (23 female, mean age: 42.4 ± 9.4 years), 40 patients with BD (9 female, mean age: 39.7 ± 9.0 years) and 40 controls (20 male, mean age: 41.8 ± 6.5 years) were consecutively included in the study. All subjects underwent a transthoracic echocardiography for evaluation of left ventricular (LV) and atrial (LA) functions with two-dimensional (2D) speckle tracking echocardiography (STE). Results Baseline characteristics, clinical data, LV dimensions, systolic and diastolic functions were all in normal range among the groups. LV global longitudinal strain (LV-GLS) was significantly lower in patients with NBD and BD patients without neurologic involvement compared to controls. LA conduit strain was significantly lower in patients with NBD compared to controls. Patients with both parenchymal NBD and vascular NBD manifestations had significantly lower LV-GLS and LA conduit strain compared to controls. Linear regression analysis demonstrated that among cardiovascular risk factors only presence of NBD was the independent predictor of LV-GLS. Conclusions BD is associated with impaired LV and LA functions. LV-GLS and LA conduit strains of the patients with NBD were lower. NBD was an independent predictor of LV-GLS, suggesting a link between neurological manifestations and cardiac dysfunction in BD patients.

Specific sweat metabolite profile in ocular Behcet’s disease

BackgroundBehcet’s disease (BD) is an autoimmune disorder with the serious possibility of blindness, calling for further research on its pathogenesis. Our aim was to study the metabolite composition of sweat in BD and to identify possible biomarkers. MethodsMetabolomics analysis was performed on sweat samples from 20 BD patients and 18 normal controls by liquid chromatography tandem mass spectrometry. ResultsA significantly different metabolic profile of sweat was observed when BD patients were compared with healthy controls. The result of the orthogonal partial least squared-discrimination analysis (OPLS-DA) showed that these two comparison groups could be separated with a relatively satisfactory fitting degree (R2Y = 0.995 and Q2 = 0.817 in positive ion mode; R2Y = 0.991 and Q2 = 0.721 in negative ion mode). Based on OPLS-DA, a panel of metabolites was selected as candidate biomarkers, including l-citrulline, l-pyroglutamic acid, urocanic acid, 2-oxoadipic acid, cholesterol 3-sulfate, and pentadecanoic acid. ConclusionThis is the first report on the metabolite profile of sweat in BD. Our results demonstrated a significantly different metabolite composition of sweat in BD compared to that of healthy controls.

An association study between FokI, BsmI, miR-146a, and miR-155 and Behcet\u2019s disease in the Egyptian population

BackgroundBehcet’s disease (BD) is a systemic inflammatory disease of the blood vessels and affects various body parts. This study aimed to determine the association of four single-nucleotide polymorphisms (SNPs) and BD in the Egyptian population using multiple statistical models and show the resulting associations along with previous studies of different populations. Four SNPs were examined for their association with BD: two SNPs from vitamin D receptor gene (FokI and BsmI) were selected and the other two were selected from miR-146a and miR-155. These four SNPs were selected for their association and role with BD in different populations and in the immune system. A marker check was conducted using the Hardy-Weinberg equilibrium and minor allele frequency. The associations were tested using four different statistical models: multiplicative, dominant, recessive, and codominant models. All statistical models used the odd’s ratio (OR) with confidence interval (CI) of 95% to evaluate the association of each SNP.ResultsBsmI showed association using the four models, while FokI did not show any association through any model. miR-155 showed association using the multiplicative and recessive models. miR-146a showed association using the multiplicative model only.ConclusionsAs a result, BsmI, miR-155, and miR-146a SNPs could have a role in the development of BD in the Egyptian population, while FokI could have a weak role, if any, in the development of BD in the Egyptian population.

A metagenomic study of the gut microbiome in Behcet\u2019s disease

BackgroundBehcet’s disease (BD) is a recalcitrant, multisystemic inflammatory disease that can lead to irreversible blindness. Microbial agents have been considered to contribute to the pathogenesis of this disease, but the underlying mechanisms remain unclear. In this study, we investigated the association of gut microbiome composition with BD as well as its possible roles in the development of this disease.MethodsFecal and saliva samples were collected from 32 active BD patients and 74 healthy controls. DNA extracted from fecal samples was subjected to metagenomic analysis, whereas DNA extracted from saliva samples was subjected to 16S rRNA gene sequencing analysis. The results were used to compare the composition and biological function of the microbiome between patients and healthy controls. Lastly, transplantation of pooled fecal samples from active BD patients into B10RIII mice undergoing experimental autoimmune uveitis (EAU) was performed to determine the causal relationship between the gut microbiome and BD.ResultsFecal samples from active BD patients were shown to be enriched in Bilophila spp., a sulfate-reducing bacteria (SRB) and several opportunistic pathogens (e.g., Parabacteroides spp. and Paraprevotella spp.) along with a lower level of butyrate-producing bacteria (BPB) Clostridium spp. and methanogens (Methanoculleus spp. Methanomethylophilus spp.). Analysis of microbial functions revealed that capsular polysaccharide transport system, oxidation-reduction process, type III, and type IV secretion systems were also increased in active BD patients. Network analysis showed that the BD-enriched SRB and opportunistic pathogens were positively correlated with each other, but they were negatively associated with the BPB and methanogens. Animal experiments revealed that fecal microbiota transplantation with feces from BD patients significantly exacerbated EAU activity and increased the production of inflammatory cytokines including IL-17 and IFN-γ.ConclusionsOur findings revealed that BD is associated with considerable gut microbiome changes, which is corroborated by a mouse study of fecal microbiota transplants. A model explaining the association of the gut microbiome composition with BD pathogenesis is proposed.

AB0765 Quality of life and fatigue in patients with behcet’s disease

BackgroundBehcet’s disease (BD) is a multi-systemic, chronic inflammatory disorder characterized by vasculitis. Fatigue, a common symptom of inflammatory rheumatological disorders such as systemic lupus erythematosus (SLE) and vasculitides, is insufficiently...

AB0058 Cytokine secretion and cytotoxic activity of natural killer cells in behÇet’s disease

BackgroundBehcet’s disease (BD) is a multi-system inflammatory disorder with recurrent inflammation attacks. BD pathogenesis includes genetical, environmental and immunological factors. The main genetic susceptibility is HLA-B*51, but the mechanism is...

AB1228 HLA-B27-associated HLA factor with behcet’s disease patient

BackgroundBehcet’s disease (BD) is characterized by recurrent oral aphthae and any of several systemic manifestations including genital aphthae, ocular disease, skin lesions, or arthritis. Increased risk of developing BD is...

AB0461 The burden of behçet’s disease in the south thames and, se coast regions – a regional review

BackgroundBehcet’s disease(BD) is a rare inflammatory disorder of unknown aetiology, with estimated prevalence of 1- 2 per 100,000 in the UK. In routine clinical practice patients with BD present challenges...

OP0185 Behcet’s disease in germany: Differences and similarities in patients of german and turkish origin – a single center experience

BackgroundBehcet’s disease (BD) is a multisystem disease with vasculitic features and possibly an autoinflammatory pathogenesis. It is rare in Germany with an estimated prevalence of 0,6/100.000 inhabitants, whereas it is...

AB0017 Hla-g 3′utr 14bp polymorphism and shla-g levels in tunisian patients with behçet’s disease

BackgroundBehcet’s disease (BD) is a chronic relapsing multisystemic inflammatory disease. Although the actual etiology is still unclear, BD symptoms are considered to be the resultant of genetic intrinsic factors and...

FRI0238 Can thromboloelastography be a new tool to asses the risk of thrombosis in behcet’s disease?

BackgroundBehcet’s Disease (BD) is a multisystemic disorder characterised by recurrent oral and genital ulcers (1). Vasculitis and thrombotic events are the most important causes of mortality (2). Thrombosis is the...